The American Journal of Cardiologyா Contents Vol

THE AMERICAN JOURNAL OF CARDIOLOGYா CONTENTS VOL. 99, NO. 12 JUNE 15, 2007

Coronary Artery Disease Yield of Early Rest and Stress Myocardial Perfusion Single-Photon Emission Computed Tomography and Impact of Metabolic Syndrome on Atherosclerotic Electrocardiographic Exercise Test in Patients With Burden and Cardiovascular Prognosis...... 1623 Atypical Chest Pain, Nondiagnostic Christine Espinola-Klein, Hans J. Rupprecht, Electrocardiogram, and Negative Biochemical Christoph Bickel, Felix Post, Sabine Genth-Zotz, Markers in the Emergency Department ...... 1662 Karl Lackner, Thomas Munzel, and Stefan Blankenberg, for the AtheroGene Investigators Jaume Candell-Riera, Guillermo Oller-Martıńez, Gustavo de Leoń, Joan Castell-Conesa, and The Effects of Aging and Physical Activity on Santiago Aguade´-Bruix Doppler Measures of Diastolic Function ...... 1629 Anand Prasad, Zoran B. Popovic, Armin Arbab-Zadeh, Usefulness of Contrast Echocardiography for Qi Fu, Dean Palmer, Erika Dijk, Neil L. Greenberg, Assessment of Left Ventricular Thrombus After Acute Mario J. Garcia, James D. Thomas, and Benjamin D. Levine Myocardial Infarction ...... 1667 Nicolas Mansencal, Imad Abi Nasr, Re´my Pillie`re, Adjusted Indirect Meta-Analysis of Aspirin Plus Jean-Christian Farcot, Thierry Joseph, Pascal Lacombe, Warfarin at International Normalized Ratios 2 to 3 and Olivier Dubourg Versus Aspirin Plus Clopidogrel After Acute Coronary Syndromes...... 1637 Relation of Myocardial Blush Grade to Microvascular Luca Testa, Giuseppe Biondi Zoccai, Italo Porto, Perfusion and Myocardial Infarct Size After Primary or Graziana Trotta, Pierfrancesco Agostoni, Rescue Percutaneous Coronary Intervention ...... 1671 Felicita Andreotti, and Filippo Crea Italo Porto, Francesco Burzotta, Marta Brancati, Carlo Trani, Antonella Lombardo, Enrico Romagnoli, Prevalence and Prognosis of Asymptomatic Left Giampaolo Niccoli, Luigi Natale, Lorenzo Bonomo, and Ventricular Diastolic Dysfunction in Ambulatory Filippo Crea Patients With Coronary Heart Disease ...... 1643 Xiushui Ren, Bryan Ristow, Beeya Na, Sadia Ali, Impact of Admission Hyperglycemia and Diabetes Nelson B. Schiller, and Mary A. Whooley Mellitus on Short- and Long-Term Mortality After Acute Myocardial Infarction in the Coronary Effect of Estradiol-Drospirenone Hormone Treatment Intervention Era ...... 1674 on Myocardial Perfusion Reserve in Postmenopausal Masaharu Ishihara, Eisuke Kagawa, Ichiro Inoue, Women With Angina Pectoris ...... 1648 Takuji Kawagoe, Yuji Shimatani, Satoshi Kurisu, Juhani Knuuti, Riikka Kalliokoski, Tuula Janatuinen, Yasuharu Nakama, Tatsuya Maruhashi, Jarna Hannukainen, Kari K. Kalliokoski, Juha Koskenvuo, Keisuke Ookawa, Kazuoki Dai, and Yasuyuki Aokage and Stefan Lundt Impact of Time to Treatment on Myocardial Size of Coronary Artery in a Myocardial Bridge Reperfusion and Infarct Size With Primary Compared With Adjacent Nontunneled Left Anterior Percutaneous Coronary Intervention for Acute Descending Coronary Artery ...... 1653 Myocardial Infarction (from the EMERALD Trial) ...1680 Juying Qian, Feng Zhang, Hongyi Wu, Bing Fan, Bruce R. Brodie, John Webb, David A. Cox, Lei Ge, Yan Lu, and Junbo Ge Mansoor Qureshi, Anna Kalynych, Mark Turco, Heinz P. Schultheiss, Daniel Dulas, Barry Rutherford, Diagnostic Performance of 64-Channel Multislice David Antoniucci, Tom Stuckey, Mitch Krucoff, Computed Tomography in Assessment of Significant Raymond Gibbons, Alexandra Lansky, Yingbo Na, Coronary Artery Disease in Symptomatic Roxana Mehran, and Gregg W Stone, for the EMERALD Subjects ...... 1656 Investigators Abbas Arjmand Shabestari, Seifollah Abdi, Shahram Akhlaghpoor, Mitra Azadi, Association of Prerandomization Anticoagulant Hamidreza Baharjoo, Mohammad Danesh Pajouh, Switching With Bleeding in the Setting of Zyae Emami, Fatemeh Esfahani, Iraj Firouzi, Percutaneous Coronary Intervention Mahmoud Hashemian, Morad Kouhi, (A REPLACE-2 Analysis) ...... 1687 Mahmoud Mozafari, Iraj Nazeri, Mahmoud Roshani, C. Michael Gibson, Yuli Ten, Sabina A. Murphy, Babak Salevatipour, Hedayatollah Tavalla, Lauren N. Ciaglo, Matthew C. Southard, Mahmoud Tehrai, and Ali Zarrabi A. Michael Lincoff, and Ron Waksman

A4 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE, 2007 Six-Month Clinical and Angiographic Results of a Clinical and Echocardiographic Markers of Mortality Dedicated Drug-Eluting Stent for the Treatment of Risk in Patients With Atrial Fibrillation ...... 1733 Coronary Bifurcation Narrowings ...... 1691 Taiyeb M. Khumri, Madhuri Idupulapati, Valerie J. Rader, Eberhard Grube, Lutz Buellesfeld, Franz J. Neumann, Sunil Nayyar, Casey N. Stoner, and Michael L. Main Stefan Verheye, Alexandre Abizaid, Dougal McClean, Ralf Mueller, Alexandra Lansky, Roxana Mehran, A Novel Mutation in Human Ether-a-Go-Go-Related Ricardo Costa, Ulrich Gerckens, Brett Trauthen, and Gene, Alanine to Proline at Position 490, Found in Peter J. Fitzgerald a Large Family With Autosomal Dominant Long QT Syndrome...... 1737 Roundtable Discussion (CME) Pier Luigi Pellegrino, Valeria Bafunno, Riccardo Ieva, Natale Daniele Brunetti, Giovanni Mavilio, The Editor’s Roundtable: High-Density Lipoprotein Francesco Sessa, Massimo Grimaldi, Cholesterol ...... 1698 Maurizio Margaglione, and Matteo Di Biase Vincent E. Friedewald, Jr., H. Brian Brewer, Jr., Scott M. Grundy, Daniel J. Rader, and Heart Failure William C. Roberts Effect of Medical Therapy for Heart Failure on Preventive Cardiology Segmental Myocardial Function in Patients With Ischemic Cardiomyopathy ...... 1741 Comparison of Effects of Ezetimibe/Simvastatin David S. Blondheim, Mark Kazatsker, Zvi Friedman, Versus Simvastatin Versus Atorvastatin in Reducing Peter Lysyansky, Simcha R. Meisel, Aya Asif, C-Reactive Protein and Low-Density Lipoprotein Nahum Smirin, and Avraham Shotan Cholesterol Levels ...... 1706 Thomas Pearson, Christie Ballantyne, Christine Sisk, Arvind Shah, Enrico Veltri, and Darbie Maccubbin Relation of Etiology of Heart Failure (Ischemic Versus Nonischemic) Before Transplantation to Delayed Pulmonary Oxygen Uptake Kinetics After Effect of Simvastatin (80 mg) on Coronary and Heart Transplantation ...... 1745 Abdominal Aortic Arterial Calcium (from the Corey R. Tomczak, Nicholas G. Jendzjowsky, Coronary Artery Calciﬁcation Treatment with Zocor Kenneth J. Riess, Wayne Tymchak, Daniel Kim, [CATZ] Study) ...... 1714 Robert Haennel, and Mark J. Haykowsky James G. Terry, J. Jeffrey Carr, Ethel O. Kouba, Donna H. Davis, Lata Menon, Kathryn Bender, Cardiomyopathy E. Ted Chandler, Timothy Morgan, and John R. Crouse III Mutations in the Genes for Sarcomeric Proteins in Japanese Patients With Onset Sporadic Measuring and Treating Serum Lipids in Patients in Hypertrophic Cardiomyopathy After Age 40 a Chest Pain Observation Unit ...... 1718 Years ...... 1750 Michael J. Gillespie, Cheryl J. Davis, Nathan D. Lambert, Ryuichiro Anan, Hideshi Niimura, Toshihiro Takenaka, Frederick M. Costello, Sidney C. Smith, Shuichi Hamasaki, and Chuwa Tei Mauricio G. Cohen, and Venu Menon

Arrhythmias and Conduction Usefulness of Percutaneous Left Ventricular Assist Disturbances Device as a Bridge to Recovery from Myocarditis ...... 1755 A Comparative Study of the Efﬁcacy and Safety of Divay Chandra, Biswajit Kar, Gary Idelchik, Procainamide Versus Propafenone Versus Leo Simpson, Pranav Loyalka, Igor D. Gregoric, Amiodarone for the Conversion Reynolds M. Delgado III, and O.H. Frazier of Recent-Onset Atrial Fibrillation ...... 1721 George E. Kochiadakis, Nikos E. Igoumenidis, Congenital Heart Disease Michail E. Hamilos, Maria E. Marketou, Gregory I. Chlouverakis, and Panos E. Vardas Comparison of Late Post-Operative Cardiopulmonary Responses in the Fontan Versus Ventricular Septation for Double-Inlet Left Meta-Analysis of Magnesium Therapy for the Acute Ventricular Repair ...... 1757 Management of Rapid Atrial Fibrillation ...... 1726 Hideo Ohuchi, Kenichi Watanabe, Kanako Kishiki, Orhan Onalan, Eugene Crystal, Amin Daoulah, Masaki Nii, Yuko Wakisaka, Toshikatsu Yagihara, and Ching Lau, Alexander Crystal, and Ilan Lashevsky Shigeyuki Echigo

CONTENTS A5 Editorial Reader’s Comment Predicting Left Ventricular End-Diastolic Pressure by Cardiac Function Before and After Surgery for Echocardiography ...... 1776 Pectus Excavatum ...... 1762 Warren G. Guntheroth and Philip S. Spiers Author and Subject Indexes can be found online at www.AJConline.org Case Report Instructions to Authors can be found at the AJC Superior Vena Cava Syndrome Induced by website: www.AJConline.org Endocardial Deﬁbrillator and Pacemaker Leads ...... 1765 Classiﬁeds on pages A11–A12 Arash Aryana, Kristi D. Sobota, Dennis J. Esterbrooks, and Andrew I. Gelbman Full Text: www.ajconline.org From the Editor

Proceedings of the Editorial Board Meeting of The American Journal of Cardiology on 26 March Visit our INTERNET Home Page: 2007 ...... 1768 http://www.AJConline.org William Clifford Roberts

A6 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE, 2007 EDITOR IN CHIEF ASSOCIATE EDITORS William C. Roberts, MD Paul A. Grayburn Baylor Heart & Vascular Institute Clyde W. Yancy Baylor University Medical Center ASSISTANT EDITORS Wadley Tower No. 457 Vincent E. Friedewald 3600 Gaston Avenue Robert C. Kowal Dallas, Texas 75246 Carlos E. Velasco (214)826-8252 Fax: (214)826-2855

EDITORIAL BOARD

CARDIOVASCULAR Rodney H. Falk Carl J. Lavie Prediman K. Shah MEDICINE John A. Farmer Carl V. Leier Jamshid Shirani In Adults David P. Faxon Joseph Lindsay, Jr. Robert J. Siegel Ted Feldman Gregory Y.H. Lip Marc A. Silver J. Dawn Abbott Jack Ferlinz Joseph Loscalzo Mark E. Silverman Jonathan Abrams Jerome L. Fleg G.B. John Mancini Ross J. Simpson, Jr. Joseph S. Alpert Gerald F. Fletcher Francis E. Marchlinski Steven N. Singh Martin A. Alpert James S. Forrester Frank I. Marcus Sidney C. Smith, Jr. Ezra A. Amsterdam Joseph A. Franciosa Barry J. Maron Burton E. Sobel Jeffrey L. Anderson Gary S. Francis Randolph P. Martin John C. Somberg Richard W. Asinger W. Bruce Fye Attilo Maseri David H. Spodick Gary John Balady William H. Gaasch Dean T. Mason Lynne W. Stevenson Thomas M. Bashore William Ganz Charles Maynard John R. Stratton Eric Bates Julius M. Gardin Michael D. McGoon Jonathan M. Tobis Jeroen J. Bax Bernard J. Gersh Darren K. McGuire Eric J. Topol George A. Beller Mihai Gheorghiade Raymond G. McKay Teresa S. M. Tsang William E. Boden Raymond Gibbons Jawahar L. Mehta Byron F. Vandenberg Monty M. Bodenheimer D. Luke Glancy Richard S. Meltzer Hector O. Ventura Robert O. Bonow Stephen P. Glasser Franz H. Messerli George W. Vetrovec Jeffrey S. Borer Michael R. Gold Eric L. Michelson Robert A. Vogel Harisios Boudoulas Samuel Z. Goldhaber Richard V. Milani Ron Waksman Martial G. Bourassa Robert E. Goldstein Alan B. Miller David D. Waters Eugene Braunwald Sidney Goldstein Gary S. Mintz Nanette K. Wenger Jeffrey A. Brinker Steven A. Goldstein Fred Morady Robert Wilensky David L. Brown J. Anthony Gomes Arthur J. Moss James T. Willerson Alfred E. Buxton Antonio M. Gotto, Jr. James E. Muller Barry L. Zaret Michael E. Cain K. Lance Gould Robert J. Myerburg Douglas P. Zipes Richard O. Cannon III Donald C. Harrison Gerald B. Naccarelli In Infants and Children Bernard R. Chaitman Richard H. Helfant Navin C. Nanda Hugh D. Allen Kanu Chatterjee Philip D. Henry Christopher O’Connor Bruce S. Alpert John S. Child L. David Hillis Robert A. O’Rourke Stanley J. Goldberg Robert J. Cody David R. Holmes, Jr. Erik Magnus Ohman Warren G. Guntheroth Lawrence S. Cohen Mun K. Hong Antonio Pacifico Howard P. Gutgesell Marc Cohen Yuling Hong Richard L. Page John D. Kugler C. Richard Conti William G. Hundley Sebastian T. Palmeri James E. Lock Michael H. Crawford Ami S. Iskandrian Eugene R. Passamani John W. Moore Gregory J. Dehmer Allan S. Jaffe Alan S. Pearlman Lowell W. Perry Efthymios N. Deliargyris Joel S. Karliner Carl J. Pepine David J. Sahn James A. de Lemos John A. Kastor Joseph K. Perloff Richard M. Schieken Anthony N. DeMaria Sanjiv Kaul Bertram Pitt Pablo Denes Kenneth M. Kent Don Poldermans CARDIOVASCULAR SURGERY George A. Diamond Richard E. Kerber Philip J. Podrid Eugene H. Blackstone John P. DiMarco Dean J. Kereiakes Arshed A. Quyyumi Lawrence I. Bonchek Michael J. Domanski Morton J. Kern Charles E. Rackley Lawrence H. Cohn Gerald Dorros Spencer B. King III C. Venkata Ram John A. Elefteriades Uri Elkayam Robert E. Kleiger Nathaniel Reichek Thomas L. Spray Kenneth A. Ellenbogen George J. Klein Robert Roberts RELATED SPECIALISTS Myrvin H. Ellestad Lloyd W. Klein William J. Rogers L. Maximilian Buja Stephen G. Ellis Paul Kligfield Maurice E. Sarano Michael Emmett Toby R. Engel Robert A. Kloner Melvin M. Scheinman Barry A. Franklin Andrew E. Epstein John B. Kostis David J. Schneider Charles B. Higgins N. A. Mark Estes, III Charles Landau John S. Schroeder Jeffrey E. Saffitz Michael Ezekowitz Richard L. Lange Pravin M. Shah Renu Virmani

A2 Impact of Metabolic Syndrome on Atherosclerotic Burden and Cardiovascular Prognosis

Christine Espinola-Klein, MDa,*, Hans J. Rupprecht, MDa, Christoph Bickel, MDc, Felix Post, MDa, Sabine Genth-Zotz, MDa, Karl Lackner, MDb, Thomas Munzel, MDa, and Stefan Blankenberg, MDa, for the AtheroGene Investigators

Patients with metabolic syndrome (MS) are at increased risk of cardiovascular atherosclerosis. The aim of this study was to evaluate the impact of MS on cardiovascular prognosis in context with atherosclerotic burden. A total of 811 patients with coronary heart disease (CHD) were included and carotid and leg arteries were examined using sonographic or high atherosclerotic burden (%52.8 ,428 ؍ methods. Patients with low (CHD only, n were compared. Patients with >3of (%47.2 ,383 ؍ CHD and peripheral atherosclerosis, n) the following criteria: triglycerides >150 mg/dl, high-density lipoprotein cholesterol <40 mg/dl (men) and <50 mg/dl (women), body mass index >30 kg/m2, blood pressure >130/85 .(%43.0 ,349 ؍ mm Hg, and fasting glucose >100 mg/dl were defined as having MS (n Follow-up data (median 6.7 years) were available for 807 patients (99.5%), and 175 patients (21.7%) experienced cardiovascular events (myocardial infarction, death, and stroke). The presence of MS significantly increased cardiovascular events in patients with low and high high: MS yes 34.3%, MS ;0.02 ؍ atherosclerotic burden (low: MS yes 21.2%, MS no 12.9%, p MS could be identified as an independent predictor for cardiovascular .(0.01 ؍ no 26.5%, p events in all patients (hazard ratio 1.7, 95% confidence interval 1.3 to 2.3, p <0.0001, adjusted) and patients with high atherosclerotic burden in particular (hazard ratio 1.8, 95% adjusted). In conclusion, MS markedly worsens ,0.005 ؍ confidence interval 1.2 to 2.6, p the long-term prognosis of patients with both low and high atherosclerotic burden. More- over, patients with high atherosclerotic burden and MS should be considered a high-risk population and treated accordingly. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1623–1628)

Few data were published about whether cardiovascular risk as smoking and hyperlipidemia were defined according to is increased by the presence of metabolic syndrome (MS) in previous publications.5,6 Patients were considered to have context with atherosclerotic burden.1–4 We undertook the CHD after coronary artery bypass surgery or in the presence present study in 811 patients with coronary heart disease of Ն1 diameter stenosis Ͼ30% in a major coronary artery. (CHD) and examined peripheral arteries using duplex and Evaluation was performed during coronary angiography us- Doppler sonographic methods to address the following ing visual assessment after sublingual administration of questions. (1) Does MS correlate with atherosclerotic bur- nitroglycerin 0.8 mg. After exclusion of 97 patients without den involving various vascular beds? (2) Does the presence CHD, 811 patients were included in the final evaluation. of MS influence the long-term prognosis of patients in Unstable coronary syndrome was defined as unstable angina accordance with atherosclerotic burden, including coronary (Braunwald classification B or C), acute ST-segment eleva- and peripheral arteries? tion, and non–ST-segment elevation myocardial infarction. The diagnosis unstable coronary syndrome was made in 301 Methods patients (37.1%), and coronary syndrome was stable in 510 Study population: From November 1996 to July 1998, patients (62.9%). A total of 807 patients (99.5%) were a total of 1,168 consecutive patients were admitted to Med- followed up for a median of 6.7 years (maximum 7.6). ical Department II of the University Hospital of Mainz, Cardiovascular events were defined as death from cardio- Germany, for diagnostic heart catheterization. In a subgroup vascular causes, myocardial infarction, or stroke. Follow-up of 908 patients, additional examinations of the carotid and information was obtained from admitting hospitals or gen- leg arteries were performed. Patient selection was described eral practitioner charts. In general, study participants had in previous publications.5,6 Cardiovascular risk factors such German nationality and particularly were inhabitants of the Rhein-Main area. All study participants were Caucasian. The study was approved by the Ethics Committee of the Departments of aMedicine II and bClinical Chemistry, Johannes Guten- University of Mainz. Participation was voluntary, and each berg-University, Mainz; and cDepartment of Internal Medicine, Bundeswe- study subject provided written informed consent. hrzentralkrankenhaus, Koblenz, Germany. Manuscript received November 11, 2006; revised manuscript received and accepted January 29, 2007. Evaluation of vascular status: Patients were defined as *Corresponding author: Tel.: 49-6131-17-7293; fax: 49-6131-17-6407. having cerebrovascular disease (CVD) if they previously E-mail address: [email protected] (C. Espinola-Klein). underwent carotid surgery or significant stenosis was de-

Table 1 according to the World Health Organization definition and Baseline characteristics of the study population previous publications.13–15 Patients with Ն3 of the follow- Variable MS p Value ing criteria: (1) triglycerides Ն150 mg/dl or on drug treatment for increased triglycerides, (2) high-density lipopro- No Yes tein cholesterol Ͻ40 mg/dl in men and Ͻ50 mg/dl in (n ϭ 462) (n ϭ 349) women, (3) blood pressure increased to Ͼ130 mm Hg Age (yrs) 62.6 Ϯ 9.6 62.9 Ϯ 9.0 0.68 systolic or Ͼ85 mm Hg diastolic or on antihypertensive Men 357 (77.3%) 252 (72.2%) 0.10 drug treatment, (4) body mass index Ͼ30 kg/m2, and (5) Hypertension 271 (58.7%) 314 (90.0%) Ͻ0.0001 fasting blood glucose Ն100 mg/dl or on drug treatment Diabetes mellitus 56 (12.1%) 137 (39.3%) Ͻ0.0001 for increased glucose were defined as having MS. Hyperlipidemia 296 (64.1%) 221 (63.3%) 0.82 Ever smoker 271 (58.7%) 210 (60.2%) 0.36 Laboratory methods: Blood samples were drawn from Previous myocardial 217 (47.0%) 163 (46.7%) 0.50 each subject after an overnight fast under standardized con- infarction ditions. Serum was centrifuged at 4,000g for 10 minutes and Unstable coronary 170 (36.8%) 131 (37.5%) 0.99 immediately divided into aliquots. Serum lipids, blood glu- syndrome cose, and insulin were measured immediately. Multivessel coronary 335 (72.5%) 263 (73.4%) 0.51 artery disease Statistical analysis: Differences between patients with Blood pressure (mm Hg) and without MS were tested using chi-square test for cate- Systolic 132.9 Ϯ 22 140.2 Ϯ 20 0.04 gorical variables and analysis of variance test for continuous Ϯ Ϯ Diastolic 75.7 10 77.4 8 0.12 variables. Survival was estimated using the Kaplan-Meier Body mass index (kg/m2) 25.8 Ϯ 2.9 28.1 Ϯ 3.8 Ͻ0.0001 Blood evaluation method and compared using log-rank test. In survival anal- LDL cholesterol (mg/dl) 141.1 Ϯ 34.4 136.9 Ϯ 40.3 0.11 yses, end points were cardiovascular death and cardiovas- HDL cholesterol (mg/dl) 53.0 Ϯ 15.1 39.9 Ϯ 11.0 Ͻ0.0001 cular events. Data for patients who died from other causes Triglycerides (mg/dl) 127.8 Ϯ 77.5 223.8 Ϯ 126.4 Ͻ0.0001 were censored at the time of death. Odds ratios and corre- Blood glucose (mg/dl) 105.4 Ϯ 30.1 133.7 Ϯ 50.6 Ͻ0.0001 sponding 95% confidence intervals (CIs) were estimated Insulin (␮U/ml) 11.0 Ϯ 9.9 14.7 Ϯ 12.7 Ͻ0.0001 using multivariate logistic regression analysis adjusted for Medication at enrollment potential confounders. Hazard ratios (HRs) and correspond- Antiplatelet therapy 401 (86.8%) 303 (86.8%) 0.54 ing 95% CIs for future cardiovascular death or future car- ␤ blockers 263 (56.9%) 187 (53.6%) 0.19 diovascular events were estimated using Cox regression Ͻ ACE inhibitors 197 (42.6%) 196 (56.2%) 0.0001 analysis adjusted for potential confounders. A p value Calcium antagonists 89 (19.3%) 77 (22.1%) 0.19 Յ Statins 142 (30.7%) 100 (28.7%) 0.29 0.05 was considered locally significant. Computations were carried out using SPSS, version 12.0 (SPSS Inc, Chi- Values expressed as mean Ϯ SD or number (percent). cago, Illinois). ACE ϭ angiotensin-converting enzyme; HDL ϭ high-density lipoprotein; LDL ϭ low-density lipoprotein. Results Metabolic syndrome: Table 1 lists baseline characteris- tected using duplex sonography (7.5-MHz transducer, Ul- tics according to the presence of MS. The sum of MS tramark 9, Advanced Technology Laboratories, Bothelle, components was distributed as 51 patients (6.3%) with Washington). Percentage of diameter stenosis was esti- none, 169 patients (20.8%) with 1, 242 patients (29.8%) mated for each internal and external carotid artery using with 2, 204 patients (25.2%) with 3, 108 patients (13.3%) both color duplex imaging and Doppler peak systolic flow with 4, and 37 patients (4.6%) with all. As expected, pa- velocities. Per previous reports, peak velocities Ͼ1.4 m/s tients with MS had significantly higher blood glucose, in- were assumed to indicate a Ͼ50% diameter lumen stenosis.7 sulin, and systolic blood pressure. There was no difference Peripheral vascular status was investigated using continuous between patients with and without MS with regard to low- wave Doppler examination with a 4-MHz transducer for density lipoprotein cholesterol, ever smoking, CHD in the femoral and popliteal arteries and an 8-MHz transducer for family history, or history of myocardial infarction or unsta- foot arteries. Clinically manifest peripheral artery disease ble coronary syndrome. (PAD) was diagnosed after a previous peripheral revascu- Atherosclerotic burden: In 160 patients (19.7%), CHD larization or if ankle-arm index (systolic blood pressure and CVD could be diagnosed, and in 332 patients (40.9%), ankle/arm) Ͻ0.9 could be detected in Ն1 pedal artery with CHD and PAD were diagnosed. A total of 94 patients monophasic continuous-wave Doppler curves.8 (11.6%) had CHD, CVD, and PAD. Patients with CHD and Definition of metabolic syndrome: Patients were pro- peripheral manifestations of atherosclerosis (CVD and/or spectively included starting in 1996. For the present sub- PAD) were defined to have a high atherosclerotic burden study, we retrospectively defined MS according to the cur- (n ϭ 383, 47.2%), whereas patients with only CHD were rent consensus definition of the American Heart Association defined to have a low atherosclerotic burden (n ϭ 428, (AHA) and National Heart, Lung, and Blood Institute.9–13 52.8%). Figure 1 shows the prevalence of MS according In that definition, waist circumference Ͼ88 cm in women to atherosclerotic manifestations. Patients with additional and Ͼ102 cm in men is defined as obesity. Because waist CVD and/or additional PAD had a significantly higher circumference is lacking in our study population, body mass prevalence of MS than patients without additional periph- index Ͼ30 kg/m2 was used as a comparable parameter eral atherosclerotic manifestations. Logistic regression anal- Coronary Artery Disease/Metabolic Syndrome and Atherosclerotic Burden 1625

(%) 80 (% ) 80 P=0.005 P=0.03

60 52.5 60 47.0 40.7 40.3 40 40

20 20

0 0 no yes no yes CHD + CVD CHD + PAD

(% ) 80 (%) 80 P=0.01 P=0.04

60 54.3 60 46.5 41.6 40.0 40 40

20 20

0 0 no yes low high CHD + CVD + PAD atherosclerotic burden

Figure 1. Prevalence of MS according to extent of atherosclerosis.

Table 2 Odds ratios (ORs) for atherosclerotic burden according to metabolic syndrome (MS) No. of End Points/No of Age-and Gender-adjusted p Value Fully-Adjusted p Value Patients OR (95% CI) Model* OR (95% CI) End point: CHD ϩ CVD MS no 76/462 (16.5%) 1.00 1.00 MS yes 84/349 (24.1%) 1.65 (1.15–2.35) 0.006 1.62 (1.13–2.33) 0.009 p ϭ 0.005 End point: CHD ϩ PAD MS no 176/462 (38.1%) 1.00 1.00 MS yes 156/349 (44.7%) 1.31 (0.98–1.74) 0.07 1.20 (0.89–1.62) 0.22 p ϭ 0.03 End point: CHD ϩ CVD ϩ PAD MS no 43/462 (9.3%) 1.00 1.00 MS yes 51/349 (14.6%) 1.72 (1.11–2.67) 0.02 1.66 (1.06–2.60) 0.03 p ϭ 0.01 End point: high atherosclerotic burden MS no 205/462 (44.4%) 1.00 1.00 MS yes 178/349 (51.0%) 1.30 (0.98–1.74) 0.07 1.22 (0.91–1.64) 0.18 p ϭ 0.04

High atherosclerotic burden indicates CHD with CVD and/or PAD. Adjusted for age, gender, smoking, unstable coronary syndrome, CHD in family, ␤-blockers, angiotensin converting enzyme inhibitors, and statin medication. ysis was performed to address the impact of MS on addi- independent predictor for CHD and PAD or for high tional peripheral atherosclerotic manifestations (Table 2). atherosclerotic burden. The presence of MS could be identified as an independent predictor for the end point CHD and CVD in a fully Cardiovascular prognosis and atherosclerotic burden: adjusted model (adjusted for age, gender, statin medica- One hundred seventy-five patients (21.7%) experienced tion, ␤-blocker medication, angiotensin-converting en- cardiovascular events (myocardial infarction, stroke, or zyme-inhibitor medication, CHD in the family history, cardiovascular death), 98 patients (12.1%) died from ever smoking, and unstable coronary syndrome). Further- cardiovascular causes, and 38 patients (4.7%) died from more, MS was identified as an independent predictor for causes not related to heart disease. Patients were compared CHD with both additional CVD and PAD. MS was not an with regard to cardiovascular events according to the extent 1626 The American Journal of Cardiology (www.AJConline.org)

according to the presence of MS. The prognosis of patients with low atherosclerotic burden was worse in patients with MS compared with those without MS (event rate: MS yes 21.2% vs MS no 12.9%, p ϭ 0.02; mortality: MS yes 10.0% vs MS no 5.1%, p ϭ 0.04). In patients with high atherosclerotic burden, dramatically more patients with MS experienced events compared with patients without MS (event rate: MS yes 34.3% vs MS no 26.5%, p ϭ 0.01; mortality: MS yes 26.4% vs MS no 10.3%; p Ͻ0.0001). Table 3 lists results of Cox regression analysis for the end points cardiovascular death and cardiovascular events. In patients with high atherosclerotic burden, MS was an independent predictor for cardiovascular death and cardiovascular events. In patients with low atherosclerotic burden, MS was not iden- tiﬁed as an independent predictor for the end points cardiovascular death and cardiovascular events. Figure 3 shows the Cox regression analysis according to atherosclerotic burden and presence of MS. For the end point cardiovascular death, HR was 4.3 (95% CI 2.3 to 8.1) for patients with high atherosclerotic burden and MS compared with patients with low atherosclerotic burden without MS (p Ͻ0.0001). For the end point cardiovascular events, HR was 2.5 (95% CI 1.6 to 3.8) for patients with high atherosclerotic burden and MS compared with patients with low atherosclerotic burden without MS (p Ͻ0.0001).

Discussion In this study, we showed that patients with MS and preexisting atherosclerosis were at a markedly higher risk of cardiovascular events within a 6-year follow-up period than Figure 2. Cardiovascular survival as a life-table analysis (Kaplan-Meier) those without MS. Risk of cardiovascular events positively according to MS and atherosclerotic burden for the end points (A) cardiovascular death and (B) cardiovascular events. correlated with extent of atherosclerosis. Furthermore, patients with both advanced atherosclerosis and MS were shown to be a high-risk population. The increasing preva- of atherosclerosis and presence of MS. Cardiovascular lence of MS in different populations has been documented, events occurred in 69 patients (16.2%) with low atheroscle- and the prevalence of MS is high in patients with different rotic burden and 106 patients (27.7%) with high atheroscle- manifestations of atherosclerosis.16–18 Gorter et al2 found rotic burden (p Ͻ0.0001). Thirty patients (7.1%) with low MS prevalences of 58% in patients with PAD, 41% in atherosclerotic burden and 68 patients (17.8%) with high patients with CHD, 43% in patients with CVD, and 47% in atherosclerotic burden died from cardiovascular causes patients with abdominal aortic aneurysm. We showed an (p Ͻ0.0001). In Cox regression analysis, HRs were 2.0 increasing number of patients with MS corresponding to (95% CI 1.3 to 3.1, p ϭ 0.002) for the end point cardio- increasing numbers of vascular beds with atherosclerosis. vascular death and 1.5 (95% CI 1.1 to 2.0, p ϭ 0.01) for the We found MS prevalences of 53% in patients with CHD and end point cardiovascular events for patients with high ath- additional CVD, 47% in patients with CHD and additional erosclerotic burden compared with those with low athero- PAD, and 54% in patients with atherosclerosis in all 3 sclerotic burden in a fully adjusted model (p Ͻ0.0001). vascular territories. Several other studies examined the association between Cardiovascular prognosis and metabolic syn- 19–21 drome: In addition, we found signiﬁcantly higher event MS and incidence of cardiovascular events. In the Turkish Adult Risk Factor Study, which included patients rate and cardiovascular mortality in patients with compared Ն with without MS (event rate: MS yes 27.9% vs MS no aged 28 years, the odds ratio for fatal and nonfatal cardiovascular disease was 1.7 after a 3-year follow-up 17.0%; mortality: MS yes 18.4% vs MS no 7.4%; p 20 Ͻ0.0001). In Cox regression analysis, HRs were 2.5 (95% period. Results were similar in the National Health and Ͻ Nutrition Mortality Study, which included patients Ն30 CI 1.6 to 3.8, p 0.0001) for the end point cardiovascular 19 death and 1.7 (95% CI 1.3 to 2.3, p Ͻ0.0001) for the end years. HR was 1.3 for cardiovascular mortality after an point cardiovascular events for patients with compared with average follow-up of 13.5 years. Median follow-up in our without MS in a fully adjusted model. trial was 6.7 years with HRs of 1.7 for future cardiovascular events and 2.5 for cardiovascular death for patients with MS Cardiovascular prognosis, metabolic syndrome, and compared with those without MS. The HR was higher in our atherosclerotic burden: Figure 2 shows Kaplan-Meier study than in the National Health and Nutrition Mortality analysis for patients with low or high atherosclerotic burden Study or the Turkish Adult Risk Factor Study. This may be Coronary Artery Disease/Metabolic Syndrome and Atherosclerotic Burden 1627

Table 3 Hazard ratios (HRs) for cardiovascular death and cardiovascular events according to metabolic syndrome (MS) for patients with low or high atherosclerotic burden No. of Events/No. Age- and Sex-adjusted p Value Fully Adjusted p Value of Patients HR (95% CI) model* HR (95% CI) End point: cardiovascular death Low atherosclerotic burden MS no 13/255 (5.1%) 1.00 1.00 MS yes 17/170 (10.0%) 2.11 (1.02–4.36) 0.04 1.80 (0.86–3.77) 0.12 p ϭ 0.04 High atherosclerotic burden MS no 21/204 (10.3%) 1.00 1.00 MS yes 47/178 (26.4%) 3.06 (1.82–5.14) Ͻ0.0001 2.94 (1.73–4.98) Ͻ0.0001 p Ͻ 0.0001 End point: cardiovascular events Low atherosclerotic burden MS no 33/255 (12.9%) 1.00 1.00 MS yes 36/170 (21.2%) 1.76 (1.09–2.82) 0.02 1.59 (0.98–2.57) 0.06 p ϭ 0.02 High atherosclerotic burden MS no 45/204 (26.5%) 1.00 1.00 MS yes 61/178 (34.3%) 1.82 (1.23–2.68) 0.003 1.76 (1.18–2.61) 0.005 p ϭ 0.01

Low atherosclerotic burden indicates CHD only, high atherosclerotic burden indicates CHD with PAD and/or CVD. Adjusted for age, gender, smoking, unstable coronary syndrome, CHD in family, ␤-blockers, angiotensin-converting enzyme inhibitors, and statin medication.

explained by the population of the present investigation, which had CHD and a mean age of 63 years. In contrast, our results are similar to those of the Kuopio Ischaemic Heart Disease Risk Factor Study, which reports an older population aged 42 and 60 years. In that investigation, relative risk for men with MS was 2.3 for death from cardiovascular causes after a mean follow-up of 11.6 years.21 In the present study, patients with advanced atherosclerosis including multiple vascular regions had a higher risk of cardiovascular events compared with those with CHD alone. HRs were 1.5 for future cardiovascular events and 2.0 for cardiovascular death for patients with high atherosclerotic burden compared with those with CHD alone. It is not surprising that patients with this accumulation of risk factors and a high atherosclerotic burden had the highest cardiovascular event rate. The combination of multivessel atherosclerosis and multiple cardiovascular risk factors is more frequent than expected. Patients with MS are at increased risk of advanced atherosclerosis, and manifestations of atherosclerosis such as PAD or CHD are very often asymptomatic, especially in patients with diabetes.9–11 Therefore, it is important to screen patients with MS for asymptomatic manifestations of atherosclerosis to improve assessment of the individual risk profile. Limitations of this study should be considered. The study describes changes in a highly selected patient group, and this population may not necessarily represent other populations. We included patients from 1996 to 1998, but retrospectively defined MS according to the current AHA defi- Figure 3. HRs (95% CIs) according to MS and atherosclerotic burden using nition.9–13 In the AHA definition, as well as in the current patients without MS and low atherosclerotic burden as the reference group for the end points (A) cardiovascular death and (B) cardiovascular events. Fully definition of the International Diabetes Foundation for MS, adjusted model was adjusted for age, gender, statin medication, ␤-blocker waist circumference is a central point. In addition, a recent medication, angiotensin-converting enzyme inhibitor medication, CHD in investigation was able to show that waist–hip ratio is sig- family history, ever smoking, and unstable coronary syndrome. nificantly associated with risk of myocardial infarction.22 1628 The American Journal of Cardiology (www.AJConline.org)

Unfortunately, in the present Caucasian population, waist– tute; American Diabetes Association. Clinical management of hip ratio was not measured and body mass index was used metabolic syndrome: report of the American Heart Association/Na- to describe obesity. tional Heart, Lung, and Blood Institute/American Diabetes Associa- tion conference on scientific issues related to management. Circulation 2004;109:551–556. 1. Liese AD, Mayer-Davies EJ, Haffner SM. Development of the multi- 12. Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin ple MS: an epidemiologic perspectives. Epidemiol Rev 1998;20:157– BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, Spertus JA, Costa 172. F. Diagnosis and management of the metabolic syndrome. An Amer- 2. Gorter PM, Olijhoeck JK, Graf van der Y, Algra A, Rabelink TJ, ican Heart Association/National Heart, Lung, and Blood Institute Sci- Visseren FLJ, for the SMART Study Group. Prevalence of the meta- entific Statement. Circulation 2005;112:2735–2752. bolic syndrome in patients with coronary heart disease, cerebrovascu- 13. Wilson PWF, Grundy SM. The metabolic syndrome. A practical guide lar disease, peripheral arterial disease or abdominal aortic aneurysm. to origins and treatment: part I. Circulation 2003;108:1422–1425. Atherosclerosis 2004;173:363–369. 14. Sattar N, Gaw A, Scherbakowa O, Ford I, O’Reilly DS, Haffner SM, 3. Cupples LA, Gagnon DR, Wong ND, Ostfeld AM, Kannel WB. Preexisting cardiovascular conditions and long-term prognosis after Isles C, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd J. Meta- initial myocardial infarction: the Framingham Study. Am Heart J bolic syndrome with and without C-reactive protein is a predictor of 1993;125:863–872. coronary heart disease and diabetes in the West of Scotland Coronary 4. Weiss R, Dziura J, Bungert TS, Tamborlane WV, Taksali SE, Yeckel Prevention Study. Circulation 2003;108:414–419. CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio 15. Ridker PM, Buring JE, Cook NR, Rifai N. C-Reactive protein, the S. Obesity and the metabolic syndrome in children and adolescents. metabolic syndrome, and risk of incident cardiovascular events. Cir- N Engl J Med 2004;350:2362–2374. culation 2003;107:391–397. 5. Espinola-Klein C, Rupprecht HJ, Blankenberg SC, Kopp H, Rippin G, 16. Larsson B, Svardsudd K, Welin L. Abdominal adipose tissue distri- Victor A, Hafner G, Schlumberger W, Meyer J. Impact of infectious bution, obesity, and risk of cardiovascular disease and depth: 13-year burden on extent and long-term prognosis of atherosclerosis. Circula- follow-up of participants in the study of men born in 1913. Br Med J tion 2002;105:15–21. 1984;288:1401–1404. 6. Rupprecht HJ, Blankerberg S, Bickel C, Rippin G, Hafner G, Prellwitz 17. Grundy S. Obesity, metabolic syndrome, and coronary atherosclerosis. W, Schlumberger W, Meyer J. Impact of viral and bacterial infectious Circulation 2002;105:2696–2698. burden on long-term prognosis in patients with coronary artery dis- 18. Wilson PWF, Kannel WB, Silershatz H, D’Agostino RB. Clustering of ease. Circulation 2001;104:25–31. metabolic factors and coronary heart disease. Arch Intern Med 1999; 7. Arbeille P, Desombre C, Aesh B, Philippot M, Lapierre F. Quantifi- 159:1104–1109. cation and assessment of carotid artery lesions: degree of stenosis and 19. Ford ES. The metabolic syndrome and mortality from cardiovascular plaque volume. J Clin Ultrasound 1995;23:113–124. disease and all-causes: findings from the National Health and Nutrition 8. Newman AB, Shemanski L, Manolio TA, Cushman M, Mittelmark M, Examinations Survey II Mortality Study. Atherosclerosis 2004;173: Polak JF, Powe NR, Siscovick D. Ankle-arm index as a predictor of 309–314. cardiovascular disease and mortality in the Cardiovascular Health 20. Onat A, Ceyhan K, Basar O, Erer B, Toparak S, Sansoy V. Metabolic Study. Arterioscler Thromb Vasc Biol 1999;19:538–545. syndrome: major impact on coronary risk in a population with low 9. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the Third Report of the cholesterol levels—a prospective and cross-sectional evaluation. Ath- National Cholesterol Education Program Expert Panel on Detection, erosclerosis 2002;165:285–292. Evaluation and Treatment of High Blood Cholesterol in Adults (Adult 21. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Treatment Panel III) JAMA 2001;285:2486–2497. Tuomilehto J. The metabolic syndrome and total and cardiovascular 10. Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day INM, Palmer disease mortality in middle-aged men. JAMA 2002;288:2709–2716. LJ, Hattersley AT, Ebrahim S, Lowe GDO, Rumley A, Smith GD. 22. Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerfold C-Reactive protein and its role in metabolic syndrome: Mendelian P, Lang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsop S, Wangai randomisation study. Lancet 2005;366:1954–1959. P Jr, for the INTERHEART Study Investigators. Obesity and the risk 11. Grundy SM, Hansen B, Smith SC, Cleemann JI, Kahn RA, for the of myocardial infarction in 27 000 participants from 52 countries: a American Heart Association; National Heart, Lung, and Blood Insti- case-control study. Lancet 2005;366:1640–1649. The Effects of Aging and Physical Activity on Doppler Measures of Diastolic Function

Anand Prasad, MDa, Zoran B. Popovic, MDb, Armin Arbab-Zadeh, MDc, Qi Fu, MD, PhDa, Dean Palmer, MSa, Erika Dijk, BSd, Neil L. Greenberg, PhDb, Mario J. Garcia, MDb, James D. Thomas, MDb, and Benjamin D. Levine, MDa,*

Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70 ؎ 4 years) and 12 fit Masters athlete (68 ؎ 3 years) seniors were recruited. Twelve young healthy (32 ؎ 9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), ؊15 and ؊30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI Emean), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p <0.001), TDI Emean (p <0.001), and propagation velocity of mitral Lifelong endurance training did not .(0.001 ؍ inflow (p <0.001) and an increase in IVRT (p or propagation ,(0.546 ؍ IVRT (p ,(0.212 ؍ completely prevent the changes in E/A ratio (p Fit seniors were able to achieve E/A ratios of 1.0 during .(1.00 ؍ velocity of mitral inflow (p baseline and saline solution infusion. TDI Emean was higher in fit versus sedentary seniors but ,(0.036 ؍ and during maximal lower body negative pressure (p (0.012 ؍ at baseline (p In conclusion, age-associated abnormalities .(0.493 ؍ not during saline solution infusion (p in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1629–1636)

Normal aging, even in the absence of co-morbidities, results reflect a secondary cardiac adaptation to a more sedentary in marked changes in Doppler measures of ventricular fill- lifestyle.3 ing and relaxation, including reversal of the early and late Recently, our laboratory showed that static left ventric- mitral inflow velocities (decreased E/A ratio) and prolon- ular stiffness markedly increased during healthy sedentary gation of isovolumetric relaxation time (IVRT).1 These aging, whereas lifelong endurance training preserved static variables, although reproducible, have several limitations in left ventricular compliance.4 These data showed that Ն1 their ability to accurately reflect diastolic function, includ- component of diastole, namely static chamber compliance, ing significant preload dependence and lack of specificity was significantly influenced by fitness. We therefore hy- for dynamic relaxation processes.2 In addition, it is unclear pothesized that normal healthy, but sedentary, aging would whether alterations in these Doppler variables with senes- result in slowing of Doppler measures of diastolic filling cence are a specific manifestation of the aging process or and dynamic myocardial relaxation, whereas lifelong endurance training would prevent such changes. To test this hypothesis, traditional Doppler mitral inflow variables, as a Institute for Exercise and Environmental Medicine, Presbyterian Hos- well as modern echocardiographic techniques such as tissue pital and University of Texas Southwestern Medical Center, Dallas, Texas; b c Doppler imaging (TDI) and color M-mode–derived data, Cleveland Clinic Foundation, Cleveland, Ohio; Johns Hopkins Univer- were measured cross-sectionally in young subjects and sed- sity, Baltimore, Maryland; and dDepartment of Integrative Physiology, University Medical Center, Nijmegen, The Netherlands. Manuscript re- entary and fit seniors across a broad range of loading con- ceived December 19, 2006; revised manuscript received and accepted ditions. This approach allowed for direct comparison of January 23, 2007. effects of static ventricular chamber compliance and relax- This study was supported by Grant No. AG17479-02 from the National ation and their integrative effect on diastolic function. Institutes of Health, Bethesda, Maryland; The S. Finley Ewing. Jr., Chair for Wellness at Presbyterian Hospital, Dallas, Texas; and The Harry S. Moss Heart Foundation, Dallas, Texas. Methods *Corresponding author: Tel.: 214-345-4619; fax: 214- 345-4618. Subjects: Thirteen sedentary healthy (70 Ϯ 4 years; 7 E-mail address: [email protected] (B.D. Levine). men, 6 women) and 12 fit (68 Ϯ 3 years; 6 men, 6 women)

Table 1 Baseline hemodynamic measurements Variable Young Sedentary Seniors Fit Seniors (nϭ12) (nϭ13) (nϭ12)

Age (yrs) 32.3 Ϯ 9.0*† 69.8 Ϯ 3.0 67.8 Ϯ 3.0 Body surface area (m2) 1.90 Ϯ 0.27 1.85 Ϯ 0.17 1.74 Ϯ 0.24 Maximal oxygen uptake (mL · minϪ1 ·mϪ2) 40.6 Ϯ 10.1* 21.6 Ϯ 2.8 38.3 Ϯ 5.9* Stroke volume index at rest (ml/m2) 34.2 Ϯ 6.9 39.2 Ϯ 6.9 57.1 Ϯ 15.7*‡ Left ventricular end-diastolic volume index at rest (ml/m2) 53 Ϯ 656Ϯ 10 80 Ϯ 11*‡ Left ventricular systolic volume index at rest (ml/m2) 19 Ϯ 517Ϯ 423Ϯ 6*‡ Ejection fraction (%) 64.0 Ϯ 0.1 70 Ϯ .03 72 Ϯ 0.1‡ Left ventricular mass index (g/m2) 76.0 Ϯ 11* 69.2 Ϯ 11 78 Ϯ 18* Mass-to-volume ratio (g/ml) 1.44 Ϯ 0.24 1.27 Ϯ 0.31 1.18 Ϯ 0.42‡ Left ventricular wall thickness (mm) 1.25 Ϯ 0.19 1.17 Ϯ 0.10 1.22 Ϯ 0.18

Data presented as mean Ϯ SD. Left ventricular end-diastolic volume, end-systolic volume, and stroke volume were determined using magnetic resonance imaging as previously described.4 * Statistically significant difference from sedentary seniors. † Statistically significant difference from fit seniors. ‡ Statistically significant difference from young controls. seniors were recruited for this study. Twelve young healthy fluid-filled catheter (Edwards Lifesciences, Irvine, Califor- sedentary (32 Ϯ 9 years; 9 men, 3 women) subjects were nia) was placed using fluoroscopic guidance through an also studied and used for comparison. Senior subjects are antecubital vein into the pulmonary artery. The catheter was the same patients who had their hemodynamic parameters connected to a physiologic pressure transducer with the zero and static left ventricular compliance reported previously, reference point set at 5.0 cm below the sternal angle. The whereas young controls were drawn from published and wedge position of the catheter tip was confirmed using unpublished studies in our laboratory.4 Hemodynamic data fluoroscopy, as well as by the presence of an appropriate are listed in Table 1. All subjects were meticulously pulmonary capillary wedge pressure (PCWP) waveform. screened for systemic hypertension using 24-hour ambula- Cardiac filling was first decreased using lower body tory blood pressure monitoring and cardiac disease, includ- negative pressure (LBNP) as previously described.5 Two ing structural heart and hemodynamically significant ob- levels of LBNP used were Ϫ15 and Ϫ30 mm Hg. Measure- structive coronary disease, using a history, physical ments of mean PCWP, immediately followed by Doppler examination, and resting and after-exercise transthoracic echocardiographic measurements (discussed next), were echocardiograms. made after 5 minutes at each level of LBNP. After release Exclusion criteria for this study included valvular heart of the negative pressure and confirmed return to hemody- disease, atrial flutter/fibrillation, systemic hypertension namic baseline, cardiac filling was increased through a rapid (mean daytime blood pressure Ͼ140/90 mm Hg), electro- infusion of warm (37°C) isotonic saline solution at 100 cardiogram changes suggestive of ischemic disease, left ml/min. Measurements were repeated after the infusion of branch bundle block, greater than first-degree atrioventric- 15 and 30 ml/kg. ular block, baseline or exercise-induced wall motion abnor- Echocardiography: For all subjects, at each level of malities, untreated thyroid disorders, renal insufficiency, cardiac loading/unloading, a transthoracic echocardiogram chronic lung disease, regular cigarette smoking within the 2 was obtained using an ATL (Advanced Technology Labo- past 10 years, body mass index Ն30 kg/m , cardiovascular medication, or warfarin use. ratories, Bothell, Washington) HDI 5000CV (software ver- All participants in the fit group had performed and were sion 10.1) echocardiograph. Apical 4-chamber views were still actively competing in multiple endurance competitions, used to make each measurement. Volumes were determined using a modified Simpson’s method that was used in our including marathons, triathlons, and/or middle-distance 4 events for decades (23 Ϯ 8 years) and several competed at previous studies. Every effort was made to ensure that the a national and even international level. Mean maximal ox- images were not foreshortened and there was optimal en- ygen uptakes of men and women Masters athletes were in docardial definition. All images were stored on 3.5-inch the top 10% of their age group (40.3 Ϯ 7 and 35.3 Ϯ 4 magnetic optical disc and evaluated blindly offline by an ml/kg/min, respectively). In contrast, sedentary participants experienced sonographer. were excluded if they performed aerobic exercise for Ͼ30 DOPPLER MEASUREMENTS: To evaluate mechanical minutes 3 times a week. All subjects signed an informed processes influencing early and late diastolic filling, both consent approved by the institutional review boards of the traditional (E, A, and IVRT) and newer (TDI and propaga- University of Texas Southwestern Medical Center at Dallas tion velocity of early mitral inflow) Doppler variables were and Presbyterian Hospital of Dallas. measured. Figure 1 shows a guide of the relation between pressure gradients and Doppler measurements. Individual Experimental protocol: Subjects were studied in the measures, although not specific for catheter-derived pres- resting, supine, or left lateral position. A 6Fr balloon-tipped sures, provide a general overview of processes occurring Coronary Artery Disease/Aging, Physical Activity, and Diastolic Function 1631

Figure 2. Early (E) to late (A) transmitral Doppler velocity ratios across loading conditions. Two-way repeated-measures analysis of variance: young versus seniors (p Ͻ0.001), fit seniors versus sedentary seniors (p ϭ Figure 1. Composite evaluation of diastolic function using Doppler echo- 0.212). In contrast to sedentary seniors, fit subjects had E/A ratios Ͼ1.0 at ϭ ϭ cardiography. LAP left atrial pressure; LV compliance left ventricular baseline (mean E/A ratio 1.06 Ϯ 0.31 in the fit group vs 0.822 Ϯ 0.18 in ϭ end-diastolic pressure–volume relation; LVP left ventricular pressure; the sedentary group, p ϭ 0.002) and during saline solution infusion (mean ϭ Vp early propagation velocity of mitral inflow. E/A ratio 1.3 Ϯ 0.39 in the fit group vs 0.97 Ϯ 0.19 in the sedentary group, p ϭ 0.005). during specific phases of the Wiggers cycle.6 All of the following measurements were made during quiet held ex- filling were performed using 1-way analysis of variance. A Ͻ piration with 4 to 6 consecutive cardiac cycles averaged for p value 0.05 was considered statistically significant. each level of cardiac filling. PULSED WAVE DOPPLER: Pulse-waved Doppler, using a Results sample volume of 2.0 mm placed at the tips of the mitral E/A ratio: Healthy, but sedentary, aging resulted in a decrease in E/A ratio at baseline, as well as during cardiac valve leaflets, was used to determine peak velocities of Ͻ mitral inflow (E and A velocities). Using a 5-chamber apical unloading and loading (young vs seniors, p 0.001; Figure view, the interval between aortic outflow during systole and 2). Sedentary seniors were unable to generate an E/A ratio Ն1.0, even during maximal cardiac filling, whereas young opening of the mitral valve (IVRT) was also determined subjects had an E/A ratio Ͼ1.0 even at maximal cardiac after the sample volume was increased to 4.0 mm. unloading. As previously documented in the literature, E/A TISSUE DOPPLER IMAGING: In the apical 4-chamber ratio was preload dependent.2 In all 3 groups of subjects, view, the septal wall was first highlighted in the tissue E/A ratios increased as filling pressures increased. This Doppler mode. Using pulse-wave Doppler, a sample vol- relation was most noticeable in young subjects, who had a ume of 4.0 mm was placed at the septal side of the mitral marked increase in E/A ratio with cardiac filling (young vs annulus. The resulting early diastolic waveform velocity seniors, p Ͻ0.001). was recorded and the process was repeated for the lateral Across loading conditions, fit seniors had markedly 7 wall. Values were averaged to obtain TDI Emean. lower E/A ratios than the young (p Ͻ0.001). Overall, fit COLOR M-MODE/PROPAGATION VELOCITY OF EARLY seniors had E/A ratios similar to sedentary seniors (2-way MITRAL INFLOW: A color M-mode image of left ventricu- repeated-measures analysis of variance, p ϭ 0.212). How- lar inflow was obtained with the sampling area positioned to ever, in contrast to sedentary seniors, fit seniors had E/A extend from midatrium to the apex, directly through the ratios Ͼ1.0 at baseline (mean E/A ratio 1.06 Ϯ 0.31 in the mitral valve orifice. The scale was reduced sufficiently to fit group vs 0.822 Ϯ 0.18 in the sedentary group, p ϭ 0.002) result in clear aliasing within the early portion of the mitral and during saline solution infusion (mean E/A ratio 1.3 Ϯ inflow. The resulting mitral inflow spatiotemporal velocity 0.39 in the fit group vs 0.97 Ϯ 0.19 in the sedentary group, profile pattern was used to derive the early propagation p ϭ 0.005). velocity of mitral inflow. This technique was described previously.8 Isovolumetric relaxation time: Like E/A ratio, IVRT was also preload dependent. IVRT at baseline was signifi- Statistical analysis: Data are presented as mean Ϯ cantly longer in sedentary seniors compared with young SEM. Groups were compared using 2-way repeated-mea- subjects, and this relation was further magnified during sures analysis of variance with analysis of interactions cardiac unloading (p ϭ 0.001; Figure 3). During increased (group ϫ filling condition). Analysis of slope relationships cardiac filling, sedentary seniors were able to shorten the and comparison of data during specific levels of cardiac IVRT (from 144.91 Ϯ 5.44 ms at baseline to 114.38 Ϯ 4.45 1632 The American Journal of Cardiology (www.AJConline.org)

Figure 3. IVRT: 2-way repeated-measures analysis of variance for young Figure 4. TDI Emean velocities across filling pressures. Healthy sedentary versus seniors (p Ͻ0.001) and fit seniors versus sedentary seniors Ͻ aging resulted in slowing of TDI Emean velocities (p 0.001). Fit senior (p Ͼ0.50). subjects had faster TDI Emean velocities at baseline and during cardiac unloading (p ϭ 0.012 and p ϭ 0.036) than sedentary seniors, but not during saline solution infusion (p ϭ 0.493). at maximal saline solution infusion). However, by comparison, young subjects still had significantly shorter IVRTs at higher filling pressures (90.98 Ϯ 2.93 ms, p ϭ 0.001). IVRT was longer in fit seniors than young subjects across all filling conditions (p Ͻ0.001). There was no significant effect of training noted at any filling pressure (p ϭ 0.546). Like sedentary seniors, fit subjects were also able shorten the IVRT during cardiac loading. However, even during maximal saline solution infusion, the fit were still unable to normalize the relaxation time in comparison to the young (p Ͻ0.001).

TDI Emean of septal and lateral ventricular walls: Contrary to previously published data,9 TDI velocities in the present study were very preload dependent, increasing in all groups in response to volume loading and decreasing in response to cardiac unloading (Figure 4). Healthy sedentary aging resulted in a significant slowing of TDI Emean myocardial motion velocities across all filling conditions (p Figure 5. Early propagation velocity of mitral inflow (Vp) across loading Ͻ conditions. Aging resulted in a decrease in Vp (p Ͻ0.001). Endurance 0.001). training had no significant impact on Vp (p ϭ 1.00). At baseline, fit senior subjects had TDI Emean myocardial motion velocities that were significantly slower than those Discussion of young subjects (p Ͻ0.001) and halfway between the young and older sedentary seniors. However, at maximal There are 2 primary findings of the present study. First, cardiac unloading, fit subjects and young subjects had sim- measures of transmitral left ventricular filling (E/A ratio), ϭ ilar TDI Emean velocities (p 0.334). Fit subjects during global relaxation (IVRT), dynamic longitudinal wall relax- baseline and maximal cardiac unloading had TDI Emean ation (TDI velocities), and diastolic suction (propagation velocities that were significantly faster than those of their velocity of early mitral inflow) were profoundly altered by sedentary counterparts (p ϭ 0.012 and p ϭ 0.036, respec- aging, and these differences were present across a wide tively). This relation was not maintained during saline so- range of physiological filling pressures. Specifically, despite lution infusion (p ϭ 0.493). the preload dependence of all Doppler measurements, volume loading did not normalize Doppler measures of ven- Propagation velocity of early mitral inflow: Aging tricular filling in aged individuals and did not impair filling resulted in a decrease in propagation velocity of early parameters in young subjects to the same degree as present mitral inflow at all filling pressures measured (p Ͻ0.001, in seniors at rest. Furthermore, in distinct contrast to previ- Figure 5). Despite the described fitness effects on TDI ously published static chamber compliance data for these velocities, there was no alteration in propagation velocity subjects, lifelong endurance training had only a modest of early mitral inflow with lifelong endurance training (p effect on preserving myocardial relaxation. Although age- ϭ 1.00). related changes in certain measures of myocardial relax- Coronary Artery Disease/Aging, Physical Activity, and Diastolic Function 1633 ation and diastolic filling (IVRT and propagation velocity of TDI E-wave velocity: Tissue Doppler E wave velocities early mitral inflow) appeared to be specific to cardiac se- reflect annular myocardial motion in the longitudinal plane. nescence, TDI and E/A velocities appeared to be at least The onset of TDI E velocity under supine resting conditions somewhat sensitive to training. precedes the onset of the conventional Doppler E-wave 12 Comprehensive Doppler assessment of diastolic func- velocity. TDI E velocities therefore reflect myocardial tion: Previously, Fleg et al10 showed a lack of lifelong relaxation and recoil after aortic valve closure just before training effect on peak E/A ratios at rest in male athletes and then during early mitral inflow (Figure 1). Again, like aged 52 to 76 years compared with sedentary and young the previously discussed Doppler variables, TDI E in all 3 controls. However, such attempts to delineate the effects of groups of healthy subjects was preload dependent. There aging versus physical activity on Doppler measures of “di- was a clear age-related decrease in TDI E velocities across astolic function” were limited by issues related to subject loading conditions. In contrast to other Doppler measures, selection (wide age range and male predominance), lack of TDI velocities appeared to be more responsive to physical invasive hemodynamic correlation, and use of only trans- fitness, and these improvements may be caused by multiple mitral filling velocities.3,10 factors. It is possible that TDI variables are influenced by The findings of the present study are unique in that they factors other than intrinsic relaxation. For example, the assess multiple aspects of diastole with concomitant mea- influence of static ventricular compliance on TDI velocities surement of PCWP. Each Doppler variable gives a window is unclear. Fit senior subjects had much more compliant into the different phases of diastole (Figure 1). Each Dopp- hearts than sedentary subjects, and this may have contrib- ler variable reflects multiple interrelated mechanical pro- uted to faster lateral wall velocities in this group. However, cesses. Individually, they are neither perfect nor absolute young and fit subjects were nearly identical in terms of measures of diastole, but taken together, they allow better static compliance and yet clearly had different TDI veloci- understanding of overall global diastolic performance. To ties at higher filling pressures, suggesting that chamber reach such a comprehensive characterization of left ventric- compliance is not the exclusive regulator of wall velocities ular lusitropy, the information gained from each Doppler during cardiac loading. variable must be examined individually in the context of Alternatively, the improvement in mean TDI velocities pressure gradients and static left ventricular compliance. may partially be influenced by a slower heart rate in fit In the following discussion, each Doppler measurement senior subjects compared with sedentary senior subjects and its associated phase of diastole is examined sequentially (Table 2). In animal models, early TDI velocities at the in time beginning with IVRT, then TDI E and propagation mitral annulus correlated inversely with heart rates.13 How- velocity of early mitral inflow, and finally the global com- ever, such a phenomenon would be expected to increase posite measurement E/A ratio. The role of afterload and its TDI velocities of fit subjects during both cardiac unloading impact on diastolic suction that links systole with diastole and loading. The underlying mechanism responsible for the during the subsequent cardiac cycle is discussed last. training-induced changes in TDI velocities remains unclear. IVRT: IVRT reflects a relatively specific measure of Vp: Propagation velocity of early mitral inflow repre- prefilling ventricular relaxation determined by the relation sents the propagation velocity of the earliest influx of blood between left atrial pressure and left ventricular early dia- entering the left ventricle just after mitral valve opening stolic pressure (Figure 1). In both human and animal stud- (Figure 1). Like IVRT, propagation velocity of early mitral ies, direct catheter-derived measurements of Tau correlated inflow is also strongly influenced by intrinsic left ventricular closely with Doppler determinations of IVRT.11 In the relaxation. In addition, propagation velocity of early mitral present study, healthy sedentary aging resulted in prolonga- inflow is impacted on by passive filling and small intraven- tion of IVRT across a broad spectrum of physiologic filling tricular pressure gradients within the ventricular cavity that pressures, and lifelong training did not alter this finding. actively draw blood from the base to the apex.14 These Whereas IVRT was clearly influenced by preload, the intraventricular pressure gradients previously were shown higher IVRTs in seniors relative to young controls were not to reflect the magnitude of myocardial suction during early caused by differences in left atrial pressure. Baseline PCWP diastole.15 In the present study, propagation velocity of was not different among the 3 subject groups despite early mitral inflow increased in all 3 groups with saline marked differences in static compliance. Moreover, even at solution infusion and decreased during LBNP, showing the the highest filling pressures, IVRT of older subjects was preload dependence of propagation velocity of early mitral considerably longer than that of young subjects at baseline. inflow in normal healthy subjects. For a given PCWP, These data taken together suggest that normal aging leads to sedentary aging resulted in decreased velocity of blood a decrease in rate of left ventricular relaxation occurring moving from the mitral annulus toward the left ventricular before opening of the mitral valve. This loss of relaxation is apex. This process was specific to aging and not altered by specific to the aging process and not a function of physical physical fitness. Again, much like IVRT, the age-related fitness. Furthermore, fit and sedentary seniors had IVRTs decrease in propagation velocity of early mitral inflow can- that were nearly identical despite marked differences in not be explained by changes in static chamber compliance. static left ventricular chamber compliance. Mechanical processes occurring during IVRT take place during the earliest E/A ratio: E/A ratio is a composite measure of both portion of diastole before the influx of blood into the ven- early and late transmitral filling. It is a relatively nonspecific tricle and thus appear to be independent of static myocardial measure influenced by early diastolic mechanics, ventricu- stiffness. lar stiffness, left atrial pressure, and atrial systole (Figure 1). 1634 The American Journal of Cardiology (www.AJConline.org)

Table 2 Effect of load on hemodynamic variables Loading Condition Young Sedentary Seniors Fit Seniors (nϭ12) (nϭ13) (nϭ12) LBNP Ϫ30 Heart rate (beats/min) 86 Ϯ 14* 73 Ϯ 12 62 Ϯ 6*‡ Systolic blood pressure (mm Hg) 107 Ϯ 14* 130 Ϯ 15 112 Ϯ 17* Diastolic blood pressure (mm Hg) 68 Ϯ 11* 76 Ϯ 466Ϯ 11* PCWP (mm Hg) 3.5 Ϯ 1.5 5.0 Ϯ 2.1 2.9 Ϯ 1.4* LBNP Ϫ15 Heart rate (beats/min) 72 Ϯ 13 68 Ϯ 955Ϯ 4*‡ Systolic blood pressure (mm Hg) 109 Ϯ 13* 136 Ϯ 15 119 Ϯ 17* Diastolic blood pressure (mm Hg) 67 Ϯ 9* 76 Ϯ 769Ϯ 8* PCWP (mm Hg) 5.4 Ϯ 1.9* 7.2 Ϯ 2.0 5.2 Ϯ 1.6* LBNP baseline Heart rate (beats/min) 65 Ϯ 13 66 Ϯ 953Ϯ 6*‡ Systolic blood pressure (mm Hg) 115 Ϯ 12* 138 Ϯ 14 124 Ϯ 20* Diastolic blood pressure (mm Hg) 68 Ϯ 7* 78 Ϯ 869Ϯ 9* PCWP (mm Hg) 10.8 Ϯ 1.9 11.4 Ϯ 2.0 10.1 Ϯ 1.3 Normal saline solution baseline Heart rate (beats/min) 68 Ϯ 12 71 Ϯ 958Ϯ 5*‡ Systolic blood pressure (mm Hg) 116 Ϯ 11* 130 Ϯ 12 118 Ϯ 17† Diastolic blood pressure (mm Hg) 67 Ϯ 870Ϯ 564Ϯ 8 PCWP (mm Hg) 9.9 Ϯ 2.2 9.1 Ϯ 2.5 8.5 Ϯ 1.4 Normal saline solution infusion 1 Heart rate (beats/min) 79 Ϯ 11 77 Ϯ 762Ϯ 6*‡ Systolic blood pressure (mm Hg) 122 Ϯ 16 132 Ϯ 10 120 Ϯ 17 Diastolic blood pressure (mm Hg) 65 Ϯ 870Ϯ 463Ϯ 7 PCWP (mm Hg) 15.8 Ϯ 2.9 15.5 Ϯ 3.0 12.9 Ϯ 1.7*‡ Normal saline solution infusion 2 Heart rate (beats/min) 84 Ϯ 14 82 Ϯ 863Ϯ 6*‡ Systolic blood pressure (mm Hg) 123 Ϯ 18 135 Ϯ 13 124 Ϯ 17 Diastolic blood pressure (mm Hg) 67 Ϯ 10 73 Ϯ 565Ϯ 8 PCWP (mm Hg) 18.3 Ϯ 3.1 18.7 Ϯ 2.8 15.7 Ϯ 2.2*‡

Data presented as mean Ϯ SD from lowest to highest cardiac filling pressure. Systolic and diastolic blood pressures were obtained using 24-hour ambulatory blood pressure monitoring. PCWP was obtained using right heart catheterization. * Statistically significant difference from sedentary seniors. † Statistically significant difference from fit seniors. ‡ Statistically significant difference from young controls.

In the present study, sedentary aging resulted in a decrease significantly hinder early diastolic filling because diastasis in E/A ratio across loading conditions, suggesting greater was maintained in these subjects with clear separation of the dependence on late diastolic filling. Fit seniors in compar- E and A waves during pulse wave Doppler interrogation of ison to sedentary seniors appeared to have an improvement mitral inflow patterns. in E/A ratio (Ͼ1.0) at baseline and during saline solution infusion. Influence of afterload on Doppler measures of dia- It is possible that preservation of static ventricular com- stolic function: Left ventricular diastolic function, in addi- pliance may have allowed the relaxing ventricle to accom- tion to being preload dependent, is also afterload depen- modate a larger volume of blood at a faster rate in early dent.17 Higher afterload decreases the ability of the ventricle diastole during these conditions. In addition, baseline A- to contract below the equilibrium volume during end-sys- wave velocities were slower in the young and fit compared tole, thus preventing the development of diastolic suction with sedentary subjects (44 Ϯ 11, 63 Ϯ 19, and 72 Ϯ 18 during the next cardiac cycle. In the present study, the cm/s, respectively, p Ͻ0.05), potentially explainable by a highly screened healthy, but sedentary, seniors had normal smaller volume of atrial contraction into a chamber that is 24-hour ambulatory blood pressures, although as previously statically and operationally more compliant. Based on these detailed, arterial elastance increased in sedentary seniors data, E/A ratio appears to be influenced by both ventricular compared with fit seniors.4 However, this increased arterial compliance and relaxation. In addition, E/A ratio is affected elastance did not result in a higher end-systolic volume by changes in heart rate, specifically decreasing during index at rest in sedentary seniors (Table 1). This finding periods of tachycardia.16 The trained seniors had slower argues that at least at these levels of afterload, the healthy heart rates at rest than sedentary subjects, and this finding aged heart has sufficient contractile reserve to overcome may have partially contributed to the higher baseline E/A modest increases in arterial elastance. This maintenance of ratios in the fit group. However, the modestly increased ventricular contractile function in the face of increased heart rate in the sedentary group was likely insufficient to afterload was shown in these subjects from their preserva- Coronary Artery Disease/Aging, Physical Activity, and Diastolic Function 1635 tion or even augmented preload recruitable stroke work, as or endoplasmic reticulum calcium (SERCA2) ATPase and previously reported.4 phospholamban in human myocytes may be similarly resis- The difference between baseline end-systolic volumes tant to exercise training. Aging of these systems may be the and equilibrium volumes derived from previously published underlying cause of impaired myocardial relaxation with compliance curves were also similar between the 2 groups senescence. of seniors (Ϫ17.9 Ϯ 19 ml in sedentary subjects, Ϫ18.6 Ϯ 30 in fit subjects, p ϭ 0.95), suggesting equivalent de- Clinical implications: Findings of the present study grees of utilization of diastolic suction and consistent with have important clinical implications for the aging popula- their equivalent propagation velocity of early mitral inflow tion. For example, the elderly appear to be particularly data.18 Thus, despite dramatic differences in both arterial predisposed to the development of congestive heart failure elastance and static chamber compliance, both senior co- because this diagnosis is the leading cause of hospitaliza- Ͼ 30 horts had similar contractile function and Doppler parame- tions in those 65 years of age. In seniors, the underlying ters of ventricular relaxation. These data suggest that myo- substrate for heart failure, particularly with preserved ejec- cyte senescence rather than long-term adaptation of the tion fraction, may in part be the age-associated changes in heart to increased arterial elastance is the major pathophys- both compliance and relaxation that we described. Although iological process responsible for altered myocardial relax- these mechanical changes may not be enough to explain the ation with aging. cause of congestive heart failure with preserved systolic function by themselves, superimposed conditions such as Physiologic differences between ventricular compli- diabetes, coronary disease, or hypertension may tip the scale ance and relaxation: The impact of endurance training on toward increased filling pressures and pulmonary conges- static ventricular compliance and dynamic relaxation is tion. Moreover, the development of a rapid irregular pattern strikingly disparate. Compliance appears to be a property of electrical activity, such as atrial fibrillation, may have that can be more readily influenced by changes in physical particularly severe consequences for hearts that are rela- activity. The alteration in pressure–volume relation of the tively stiff and relax slowly. Regular lifelong physical ac- ventricle appears to be fluid in response to conditioning/ tivity may be expected to preserve cardiac compliance (in deconditioning.19 In contrast, relaxation appears more resis- the absence of co-morbid conditions) and thereby decrease tant to changes in physical activity in humans. left ventricular end-diastolic pressure when relaxation is The training response discrepancy of these 2 diastolic complete. However, given the data presented here, it should components may reflect their fundamental physiological not be expected to completely normalize myocardial and mechanistic differences. Ventricular compliance is de- relaxation. termined largely by the relation between relatively compli- Conclusions: We show that in contrast to chamber com- ant cardiac muscle and comparatively less compliant con- pliance, age-associated changes in Doppler measures of nective tissue/extracellular matrix, which is regulated by a ventricular relaxation were only minimally influenced by sizable collection of signaling pathways, including cyto- lifelong endurance training. These findings are present kines, angiotensin, and natriuretic peptides.20,21 In this re- across a broad range of physiological filling pressures. gard, aging has prominent effects on the balance between These data show that changes in ventricular compliance myocyte volume and extracellular matrix. For example, the with senescence are strongly influenced by physical activ- aged heart has substantially fewer myocytes than young hearts, accompanied by significant increases in volume frac- ity, whereas changes in ventricular relaxation are more likely specific to cardiac senescence and may result from tion of collagen.22 In rats, this decreased number of myocytes is associated with increases in the size of each indi- alterations in cardiac regulatory proteins that occur with vidual myocyte, which may be adaptive.22,23 Increased aging. myocardial fibrosis also was noted in senescent animal 1. Bryg RJ, Williams GA, Labovitz AJ. Effect of aging on left ventricular hearts and otherwise healthy, but aged, human hearts. These diastolic filling in normal subjects. Am J Cardiol 1987;59:971–974. areas of interstitial fibrosis, predominantly in the subendo- 2. Choong CY, Herrmann HC, Weyman AE, Fifer MA. Preload depen- cardium of the left ventricle, increase with age and may be dence of Doppler-derived indexes of left ventricular diastolic function related to the loss of myocyte volume as “replacement in humans. J Am Coll Cardiol 1987;10:800–808. fibrosis.”22,24 Connective tissue content and collagen cross- 3. Palka P, Lange A, Nihoyannopoulos P. The effect of long-term train- 25,26 ing on age-related left ventricular changes by Doppler myocardial linking also decreased with endurance training. Further- velocity gradient. Am J Cardiol 1999;84:1061–1067. more, exercise appears to have an antiapoptotic effect on 4. Arbab-Zadeh A, Dijk E, Prasad A, Fu Q, Torres P, Zhang R, Thomas myocytes that likely enhances chamber distensibility be- JD, Palmer D, Levine BD. Effect of aging and physical activity on left cause myocytes are less stiff than collagen.26,27 Thus, it is ventricular compliance. Circulation 2004;110:1799–1805. possible that lifelong endurance training may maintain myo- 5. Levine BD, Lane LD, Buckey JC, Friedman DB, Blomqvist CG. Left ventricular pressure-volume and Frank-Starling relations in endurance cyte volume and cell size and limit the development of athletes. Implications for orthostatic tolerance and exercise perfor- fibrosis, thus preserving cardiac compliance. mance. Circulation 1991;84:1016–1023. In contrast, myocardial relaxation is predominantly in- 6. Wiggers CJ. The Henry Jackson memorial lecture: dynamics of ven- fluenced by myocyte calcium handling, but appears to be tricular contraction under abnormal conditions. Circulation 1952;5: species specific. For example, endurance training enhances 321–348. 7. Sohn DW, Chai IH, Lee DJ, Kim HC, Kim HS, Oh BH, Lee MM, Park calcium uptake and improves myocyte excitation–contrac- YB, Choi YS, Seo JD, Lee YW. Assessment of mitral annulus velocity tion coupling in rats, but not in canines.28,29 We speculate by Doppler tissue imaging in the evaluation of left ventricular diastolic that key myocyte calcium regulators such as sarcoplasmic function. J Am Coll Cardiol 1997;30:474–480. 1636 The American Journal of Cardiology (www.AJConline.org)

8. Rivas-Gotz C, Manolios M, Thohan V, Nagueh SF. Impact of left 19. Levine BD, Zuckerman JH, Pawelczyk JA. Cardiac atrophy after ventricular ejection fraction on estimation of left ventricular filling bed-rest deconditioning: a nonneural mechanism for orthostatic intol- pressures using tissue Doppler and flow propagation velocity. Am J erance. Circulation 1997;96:517–525. Cardiol 2003;91:780–784. 20. Yamamoto K, Masuyama T, Sakata Y, Nishikawa N, Mano T, Yo- 9. Appleton CP, Firstenberg MS, Garcia MJ, Thomas JD. The echo- shida J, Miwa T, Sugawara M, Yamaguchi Y, Ookawara T, Suzuki K, Doppler evaluation of left ventricular diastolic function. A current Hori M. Myocardial stiffness is determined by ventricular fibrosis, but perspective. Cardiol Clin 2000;18:513–546, ix. not by compensatory or excessive hypertrophy in hypertensive heart. 10. Fleg JL, Shapiro EP, O’Connor F, Taube J, Goldberg AP, Lakatta EG. Cardiovasc Res 2002;55:76–82. Left ventricular diastolic filling performance in older male athletes. 21. Li YY, McTiernan CF, Feldman AM. Interplay of matrix metallopro- JAMA 1995;273:1371–1375. teinases, tissue inhibitors of metalloproteinases and their regulators in 11. Thomas JD, Flachskampf FA, Chen C, Guererro JL, Picard MH, cardiac matrix remodeling. Cardiovasc Res 2000;46:214–224. Levine RA, Weyman AE. Isovolumic relaxation time varies predict- ably with its time constant and aortic and left atrial pressures: impli- 22. Anversa P, Palackal T, Sonnenblick EH, Olivetti G, Meggs LG, cations for the noninvasive evaluation of ventricular relaxation. Am Capasso JM. Myocyte cell loss and myocyte cellular hyperplasia in the Heart J 1992;124:1305–1313. hypertrophied aging rat heart. Circ Res 1990;67:871–885. 12. Garcia MJ, Rodriguez L, Ares M, Griffin BP, Thomas JD, Klein AL. 23. Lakatta EG. Arterial and cardiac aging: major shareholders in cardio- Differentiation of constrictive pericarditis from restrictive cardiomy- vascular disease enterprises: part III: cellular and molecular clues to opathy: assessment of left ventricular diastolic velocities in longitudi- heart and arterial aging. Circulation 2003;107:490–497. nal axis by Doppler tissue imaging. J Am Coll Cardiol 1996;27:108– 24. Eghbali M, Eghbali M, Robinson TF, Seifter S, Blumenfeld OO. 114. Collagen accumulation in heart ventricles as a function of growth and 13. Nagueh SF, Rao L, Soto J, Middleton KJ, Khoury DS. Haemodynamic aging. Cardiovasc Res 1989;23:723–729. insights into the effects of ischaemia and cycle length on tissue Dop- 25. Burgess ML, McCrea JC, Hedrick HL. Age-associated changes in pler-derived mitral annulus diastolic velocities. Clin Sci (Lond) 2004; cardiac matrix and integrins. Mech Ageing Dev 2001;122:1739–1756. 106:147–154. 26. Thomas DP, Cotter TA, Li X, McCormick RJ, Gosselin LE. Exercise 14. Garcia MJ, Smedira NG, Greenberg NL, Main M, Firstenberg MS, training attenuates aging-associated increases in collagen and collagen Odabashian J, Thomas JD. Color M-mode Doppler flow propagation crosslinking of the left but not the right ventricle in the rat. Eur J Appl velocity is a preload insensitive index of left ventricular relaxation: Physiol 2001;85:164–169. animal and human validation. J Am Coll Cardiol 2000;35:201–208. 27. Jin H, Yang R, Li W, Lu H, Ryan AM, Ogasawara AK, Van Peborgh 15. Popovic ZB, Prasad A, Garcia MJ, Arbab-Zadeh A, Borowski A, Dijk J, Paoni NF. Effects of exercise training on cardiac function, gene E, Greenberg NL, Levine BD, Thomas JD. Relationship among dia- expression, and apoptosis in rats. Am J Physiol Heart Circ Physiol stolic intraventricular pressure gradients, relaxation, and preload: im- 2000;279:H2994–H3002. pact of age and fitness. Am J Physiol Heart Circ Physiol 2006;290: 28. Tate C, Hamra M, Shin G, Taffet G, McBride P, Entman M. Canine H1454–H1459. 16. Johannessen KA, Cerqueira M, Veith RC, Stratton JR. Influence of cardiac sarcoplasmic reticulum is not altered with endurance exercise sympathetic stimulation and parasympathetic withdrawal on Doppler training. Med Sci Sports Exerc 1993;25:1246–1257. echocardiographic left ventricular diastolic filling velocities in young 29. Tate CA, Taffet GE, Hudson EK, Blaylock SL, McBride RP, Michael normal subjects. Am J Cardiol 1991;67:520–526. LH. Enhanced calcium uptake of cardiac sarcoplasmic reticulum in 17. Kass DA. Ventricular arterial stiffening: integrating the pathophysiol- exercise-trained old rats. Am J Physiol 1990;258:H431–H435. ogy. Hypertension 2005;46:185–193. 30. Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, 18. Nikolic SD, Feneley MP, Pajaro OE, Rankin JS, Yellin EL. Origin of Marburger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysio- regional pressure gradients in the left ventricle during early diastole. logical characterization of isolated diastolic heart failure in comparison Am J Physiol 1995;268:H550–H557. to systolic heart failure. JAMA 2002;288:2144–2150. Adjusted Indirect Meta-Analysis of Aspirin Plus Warfarin at International Normalized Ratios 2 to 3 Versus Aspirin Plus Clopidogrel After Acute Coronary Syndromes Luca Testa, MDa,*, Giuseppe Biondi Zoccai, MDb, Italo Porto, MDc, Graziana Trotta, MDc, Pierfrancesco Agostoni, MDd, Felicita Andreotti, MDc, and Filippo Crea, MDc

After acute coronary syndromes, the beneficial effect of aspirin plus clopidogrel (A ؉ C) or -aspirin plus dose-adjusted warfarin (A ؉ W) compared with aspirin alone is well estab lished. However, these regimens were never compared. To compare the risk–benefit profile of A ؉ C versus A ؉ W after acute coronary syndromes, major medical databases for randomized controlled trials comparing 1 of these combined approaches versus aspirin alone after an acute coronary syndrome (updated June 2006) were searched. Evaluated end points were major adverse events [MAEs: all-cause death, acute myocardial infarction [AMI], thromboembolic stroke, major bleeds, and overall risk of stroke [hemorrhagic or ischemic]). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for (1) A ؉ W versus aspirin alone, (2) A ؉ C versus aspirin alone, and (3) A ؉ W versus A ؉ C using adjusted indirect meta-analysis. Thirteen studies were included, totaling 69,741 patients. Ten compared A ؉ W versus aspirin alone and 3 compared A ؉ C versus aspirin alone. Each combined approach yielded a significantly lower risk of MAEs, albeit an increased risk of major bleeds, compared with aspirin alone. No significant difference was found for A ؉ W versus A ؉ C for risk of overall MAEs, death, or AMI. However, A ؉ W versus A ؉ C was associated with a significantly lower risk of thromboembolic stroke (OR 0.53, 95% CI 0.31 to 0.88, number needed to treat 60) and all types of stroke (OR 0.58, 95% but also with increased risk of major bleeds (OR 1.9, 95% CI ,(0.038 ؍ CI 0.35 to 0.94, p 1.2 to 2.8, number needed to harm 300). In conclusion, after an acute coronary syndrome, A ؉ W and A ؉ C are comparable in the prevention of MAEs, death, and AMI compared with aspirin alone. Allocating 100 patients to A ؉ W (at international normalized ratio 2 to 3) with respect to A ؉ C could prevent 17 thromboembolic strokes while causing 3 major bleeds. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1637–1642)

Although the pivotal role of aspirin in secondary prevention Methods after an acute coronary syndrome is currently accepted BioMedCentral, CENTRAL, mRCT, and PubMed were worldwide,1 recent studies showed an additive benefit for searched without language restrictions (updated to Septem- both clopidogrel2 and warfarin at international normalized ber 2006) according to an established method.8 Pertinent ratio 2 to 33–5 on top of aspirin despite an increased risk of bleeding complications. Of note, no data are available on trials were also searched in major recent international car- the direct comparison of these different approaches. Ad- diology meetings. References of original and review arti- justed indirect meta-analyses enable the head-to-head com- cles, including a recent thorough meta-analysis (to which parison of treatments evaluated in different trials against a the reader is referred for extensive search, study abstraction, 5 common reference treatment by adjustment of results of and validity assessment), were cross-checked. their direct comparisons to such a common control. The Specifically, inclusion criteria were (1) randomized allo- 6,7 cation; (2) controlled comparison of aspirin plus warfarin at scientific validity of this approach is well established. We ϩ conducted this study aiming to provide an adjusted indirect international normalized ratio 2 to 3 (A W) or aspirin plus clopidogrel (A ϩ C) versus aspirin alone or plus placebo assessment of the risk–benefit profile of 1 combination ϩ versus the other in patients recovering from an acute coro- (A P) in the setting of acute coronary syndromes, and nary syndrome. (3) intention-to-treat analysis. Exclusion criteria were (1) an equivocal treatment allocation process, (2) significant imbalances in major baseline characteristics among study groups, and (3) incomplete (Ͻ80%) follow-up. aInstitute of Cardiology, John Radcliffe Hospital, Oxford, United King- b c End points of interest were (1) the combined rate of dom; Division of Cardiology, University of Turin, Turin; Institute of major adverse events (MAEs), defined as all-cause death, Cardiology, Catholic University, Rome, Italy; and dAntwerp Cardiovascu- lar Institute Middelheim, Antwerp, Belgium. Manuscript received Decem- nonfatal acute myocardial infarction (AMI), or nonfatal ber 24, 2006; revised manuscript received and accepted January 29, 2007. thromboembolic stroke; and (2) the combined rate of major *Corresponding author: Tel.: 39-338-842-0721; fax: 44-018-6522- bleeds, intra- and extracranial. 0585. Additional analyses were carried out for single end points E-mail address: [email protected] (L. Testa). and the overall risk of stroke (ischemic or hemorrhagic).

Review Manager 4.2.5 (available from The Cochrane Collaboration at http://www.cochrane.org/***), OpenOffice. org (Sun Microsystems), and SPSS 11.0 for Windows (SPSS Inc., Chicago, Illinois) were used for analysis. Data regarding the comparison of A ϩ W versus A ϩ P (or aspirin alone) were available from a previous publication of our group,5 and no further trials were published or presented to date. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were used as summary statistics. Binary outcomes from individual studies were combined with both random- and fixed-effect models. Z test values were 2 tailed. Hypothesis testing results were considered significant at p Ͻ0.05. Co- chrane Q heterogeneity tests were also computed and considered significant at p for heterogeneity Ͻ0.10.9 As per protocol, we calculated the number needed to treat to prevent an MAE and the number needed to harm by causing an MB. The degree of inconsistency among studies (I2) was estimated according to Higgins et al,10 with scores Ͻ25%, 25% to 75%, and Ͼ75% representing low, moderate, or high inconsistency, respectively. The internal validity of included trials was appraised according to the Cochrane Collaboration criteria, in other words, judging the risk of selection, performance, attrition, and adjudication biases. Risk of bias was expressed as low (A), moderate (B), or high (C), and incomplete reporting leading to Figure 1. Flow diagram according to the QUOROM statement for the inability to ascertain the underlying risk of bias was scored as appraisal of study comparing A ϩ C versus aspirin alone or A ϩ P. RCT ϭ D. Allocation concealment was distinguished as adequate (A), randomized controlled trial. unclear (B), inadequate (C), or not used (D).9 Sensitivity analyses were performed excluding trials 1 at time, from those with Table 1 the lowest to those with the highest quality score, to assess the Main characteristics of studies comparing aspirin plus dose-adjusted contribution of each study to the pooled estimates.9 warfarin versus aspirin alone or plus placebo The likelihood of publication or small-study bias was Trial n Type of ACS Follow-Up Aspirin Dose assessed using Egger’s test (p for significant asymmetry (mo) (mg/d) Ͻ 11 UAP, NSTEMI 3 325 69 ءATACS14 .(0.1 According to established methods, adjusted indirect ATACS15 214 UAP, NSTEMI 3 162.5 comparisons with inverse variance weighting of pooled es- Williams et al15 57 UAP, AMI 2.5 150 timates were then performed for MAEs, major bleeds, and OASIS Pilot16 197 UAP, NSTEMI 3 325 single end points. From random-effect ORs comparing A ϩ Huyhn et al17 90 UAP, NSTEMI 12 80 W versus A ϩ P and A ϩ C versus A ϩ P, we generated an OASIS-2 3,712 UAP 5 “Standard” interaction OR with 95% CI for the different combined Warfarin treatments and Z score for 2-tailed hypothesis testing (p is Substudy18 19 significant if Ͻ0.05). Specifically, interaction ORs with ASPECT 2 669 UAP, AMI 12 80 APRICOT 220 274 STEMI 3 80 respective 95% CIs and inconsistency among trials are WARIS 221 2414 AMI 48 75–160 calculated according to the following formulas: ϭ Ϫ Zibaeenezhad 140 AMI 12 100 ln (ORAϩWvsAϩC) ln (ORAϩWvsAϩP) ln et al22 ϭ (ORAϩCvsAϩP); var [ln (ORAϩWvsAϩC)] var [ln ϩ ACS ϭ acute coronary syndrome; APRICOT 2 ϭ Antithrombotics in (ORAϩWvsAϩP)] var [ln (ORAϩCvsAϩP)]; and 2 the Prevention of Reocclusion in Coronary Thrombolysis; ASPECT 2 ϭ I ϩ ϩ ϭ (chi-square ϩ ϩ chi-square ϩ ) ϫ (A WvsAC) (A W) (A C) Antithrombotics in the Secondary Prevention of Events in Coronary 10/degress of freedom ϩ degrees of freedom 7,12 (AϩW) (AϩC). Thrombosis-2; ATACS ϭ Antithrombotic Therapy in Acute Coronary Finally, to appraise the magnitude of the population Syndromes; NSTEMI ϭ non–ST-elevation myocardial infarction; OASIS needed for a reliable head-to-head comparison, we com- ϭ Organization to Assess Strategies for Ischemic Syndromes; STEMI ϭ puted a post hoc sample size aiming for 80% power and ST-elevation myocardial infarction; UAP ϭ unstable angina pectoris; 2-tailed alpha of 0.05. WARIS II ϭ Warfarin, Aspirin, Reinfarction Study II.

Results included studies are listed in Tables 1 and 2. End point definitions were homogeneous among included studies. Ten studies13–22 compared A ϩ W at international normal- In a previous meta-analysis of our group, combined treat- ized ratio 2 to 3 versus aspirin alone or A ϩ P for a total of ment with A ϩ W (at international normalized ratio 2 to 3) 7,836 patients.5 Of 234 potentially relevant citations, we fi- compared with A ϩ P was associated with a lower risk of nally included 3 studies comparing A ϩ C versus A ϩ P for a MAEs (OR 0.73, 95% CI 0.63 to 0.84). Specifically, A ϩ W total of 61,905 patients2,23,24 (Figure 1). Main characteristics of was associated with a lower risk of AMI (OR 0.70, 95% CI Coronary Artery Disease/Combined Approaches After ACS 1639

Table 2 Main characteristics of studies comparing aspirin plus clopidogrel versus aspirin alone or plus placebo Trial n Type of ACS Follow-Up (mo) Aspirin Dose (mg/d)

CURE23 12,562 NSTE-ACS 9–12 75–325 CLARITY-TIMI2824 3,491 STEMI 1 150–325 day 1 by 75–162 COMMIT2 45,852 AMI Յ1 162

ACS ϭ acute coronary syndrome; CLARITY-TIMI28 ϭ Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction; COMMIT ϭ Clopidogrel and Metoprolol in Myocardial infarction Trial; CURE ϭ Clopidogrel in Unstable angina to prevent Recurrent Events; NSTE-ACS ϭ non–ST-elevation acute coronary syndrome; STEMI ϭ ST-elevation myocardial infarction.

Figure 3. Overall analysis of risk of (A) major bleeds for study comparing Figure 2. Overall analysis of risk of (A) MAEs for study comparing A ϩ A ϩ C versus aspirin alone or A ϩ P. Single study ORs and 95% CIs C versus aspirin alone or A ϩ P. Single study ORs and 95% CIs shown by shown by squares and lines. Single study random-effect overall OR with squares and lines. Single study random-effect ORs and 95% CIs shown by 95% CI shown by diamonds. Overall analysis of risk of (B) intracranial squares and horizontal lines. Overall OR with 95% CI shown by diamonds. bleeds and (C) extracranial major bleeds. Overall analysis of risk of (B) death; (C) AMI; and (D) thromboembolic stroke. ASA ϭ aspirin. with A ϩ P was associated with an overall decrease in risk 0.52 to 0.95) and thromboembolic stroke (OR 0.43, 95% CI of MAEs (OR 0.86, 95% CI 0.78 to 0.94, p ϭ 0.0008, p for 0.27 to 0.70), whereas all-cause mortality was not signifi- heterogeneity ϭ 0.13, I2 ϭ 50.9%). Specifically, A ϩ C cantly affected. A ϩ W was also associated with increased significantly decreased the risk of all-cause death (OR 0.93, risk of major bleeds (OR 2.32, 95% CI 1.63 to 3.29).5 95% CI 0.87 to 0.99, p ϭ 0.02, p for heterogeneity ϭ 0.95, Results according to both random- and fixed-effect mod- I2 ϭ 0%), AMI (OR 0.77, 95% CI 0.70 to 0.86, p Ͻ0.01, p els did not differ significantly; thus, in the case of significant for heterogeneity ϭ 0.58, I2 ϭ 0%), and thromboembolic inconsistency, data are presented according to the random- stroke (OR 0.81, 95% CI 0.68 to 0.98, p ϭ 0.03, p for effect model. Combination therapy with A ϩ C compared heterogeneity ϭ 0.03, I2 ϭ 10.3%, Figure 2). In absolute 1640 The American Journal of Cardiology (www.AJConline.org)

Figure 4. Overall analysis of risk of MAEs for study comparing A ϩ W (left side) and A ϩ C (right side) versus aspirin alone. Abbreviation as in Figure 2. terms, A ϩ C was associated with an overall risk of MAEs of 9.8% versus about 11% with A ϩ P. Specifically, the risk of all-cause death decreased with A ϩ C from 7.4% to 6.9%; risk of AMI, from 2.7% to 2.1%; and risk of thromboembolic stroke, from 1% to 0.8%. The number needed to treat for A ϩ C by saving 1 MAE was 50. Compared with A ϩ P, A ϩ C was associated with a significantly increased risk of major bleeds (OR 1.22, 95% CI 1.01 to 1.48, p ϭ 0.04, p for heterogeneity ϭ 0.23, I2 ϭ 31.1%). In detail, A ϩ C was associated with an increased risk of extracranial bleeds (OR 1.31, 95% CI 1.11 to 1.54, p ϭ 0.002, p for heterogeneity ϭ 0.49, I2 ϭ 0%), but not of intracranial bleeds (OR 0.96, 95% CI 0.69 to 1.33, p ϭ 0.79, p for heterogeneity ϭ 0.57, I2 ϭ 0%, Figure 3). In absolute terms, the risk of major bleeds increased from 1% with aspirin alone to 1.2% with A ϩ C. The risk of intracranial bleeds was 0.2% in both treatment modes, whereas the risk ϩ of extracranial bleeds increased from 0.8% to 1% with A Figure 5. Adjusted indirect comparison of A ϩ W versus A ϩ C. ORs and C. Given the small difference between the 2 strategies, no 95% CIs shown by squares and horizontal lines. MB ϭ overall major significant risk difference was found, thus making the num- bleed; TES ϭ thromboembolic stroke. ber needed to harm calculation impossible. Combination therapy did not significantly affect overall risk of stroke sensitivity analysis, exclusion of any single trial did not (ischemic or hemorrhagic, OR 0.83, 95% CI 0.67 to 1.01, p substantially alter overall results. 2 ϭ 0.07, p for heterogeneity ϭ 0.23, I ϭ 31.6%. None of the possible relevant citations was excluded for No heterogeneity was found among trials comparing A ϩ incomplete follow-up. Thus, such predefined exclusion cri- W at international normalized ratio 2 to 3 versus aspirin alone.5 teria could not have introduced a selection bias into results. Moderate inconsistency was present among studies comparing Using adjusted indirect comparison, no significant dif- A ϩ C versus aspirin alone in the analysis for MAEs and major ferences were found between A ϩ W and A ϩ C in risk of bleeds, possibly consistent with the different sample size of the MAEs (OR 0.84, 95% CI 0.71 to 1.20, p ϭ 0.2; I2 ϭ 32.5%; Clopidogrel and Metoprolol Infarction Trial (COMMIT) Figures 4 and 5), all-cause death (OR 1.06, 95% CI 0.85 to mega-trial because excluding the latter, such inconsistency 1.31, p ϭ 0.5, I2 ϭ 5%), and nonfatal myocardial infarction became nonsignificant. (OR 0.9, 95% CI 0.66 to 1.24, p ϭ 0.6, I2 ϭ 6%, Figure 4). The likelihood of bias in studies comparing A ϩ W Notably, A ϩ W was associated with a lower risk of throm- versus aspirin alone previously was assessed.5 All studies boembolic stroke (OR 0.53, 95% CI 0.31 to 0.88, p ϭ 0.03, comparing A ϩ C versus A ϩ P were of good quality, in I2 ϭ 6.5%; Figure 4). In absolute terms, the risk of throm- other words, at low risk of bias, according to Cochrane boembolic stroke decreased from 0.8% with A ϩ C to 0.5% Collaboration criteria. Publication or small-study bias was with A ϩ W, with a number needed to treat to save 1 excluded because p values for asymmetry according to thromboembolic stroke of 60. MAEs and major bleeds were 0.4 and 0.3, respectively. On The risk of major bleeds was increased by A ϩ W com- Coronary Artery Disease/Combined Approaches After ACS 1641

Figure 6. Overall analysis of risk of major bleeds for study comparing A ϩ W (left side) and A ϩ C (right side) versus aspirin (ASA) alone. pared with A ϩ C (OR 1.9, 95% CI 1.2 to 2.8, p ϭ 0.005, I2 Aspirin deserved its cornerstone position as a treatment for ϭ 6%; Figures 5 and 6), mainly because of a significant reducing cardiovascular events in patients with established increase in rate of extracranial bleeds (OR 1.8, 95% CI 1.02 to vascular disease based on consistent results of the large num- 3.2, p ϭ 0.04, I2 ϭ 5%), whereas the risk of intracranial bleeds ber of randomized controlled trials.1 Clopidogrel, by offering a was not significantly different (OR 3.14, 95% CI 0.6 to 16.1, p different mechanism of action to decrease platelet activation ϭ 0.7, I2 ϭ 2.7%; Figure 4). In absolute terms, the risk of and aggregation, showed similar or even greater effectiveness major bleeds increased from 1.3% to 2.6%. Such increased risk in reducing the risk of vascular events in patients with estab- of major bleeds was related to the increased risk of extracranial lished vascular disease.25 However, in the Clopidogrel for bleeds because it increased from 1% to 2.2% with A ϩ W. The High Atherothrombotic Risk and Ischemic Stabilization, Man- number needed to harm by causing 1 major bleed was 300. agement, and Avoidance (CHARISMA) trial, its beneficial These estimates suggest that allocating 1,000 patients to A ϩ effect was not additive to that of aspirin in a low-risk popula- W should avoid 17 thromboembolic strokes while causing 3 tion.26 A possible benefit during a 28-month follow-up was major bleeds. observed in the subgroup of patients with symptomatic vascu- Of note, A ϩ W was associated with a decrease in risk of lar disease (MAE rates 6.9% with A ϩ C and 7.9% with A ϩ overall stroke with an OR of 0.59 (95% CI 0.35 to 0.97, p P), but a suggestion of harm was disclosed in asymptomatic 2 ϭ 0.03, I ϭ 3%). In absolute terms, overall incidences of patients (death rates from cardiovascular causes 3.9% in those ϩ stroke (hemorrhagic or ischemic) were 0.7% for A W and receiving clopidogrel and 2.2% in those receiving placebo).26 ϩ ϭ 1% for A C (chi square test p 0.03). In contrast, in the setting of acute coronary syndromes, the ϩ Assuming the event rates for A C and risk change addition of clopidogrel to aspirin showed incremental benefit.27 ϩ associated with A W obtained from our indirect meta- Also for warfarin (at international normalized ratio 2 and 3) on analysis (2,908 of 30,972 [9.4%] and 0.86, respectively)5 and top of aspirin, a number of data showed superiority versus aiming for 80% power with 2-tailed alpha of 0.05, we calcu- aspirin alone.3–5 Such findings translated in current guidelines lated that 14,462 patients (7,231 per group) should be enrolled with various levels of evidence and recommendation.28,29 in a hypothetical future trial to adequately compare the impact ϩ ϩ Aspirin should be continued indefinitely in the absence of A W versus A C for the occurrence of MAEs. of clear contraindication, and also warfarin when indicated (i.e., atrial fibrillation, prosthetic valve, and left ventricle Discussion thrombus in the absence of high bleeding risk). Notably, The risk–benefit profile of the combined approach of A ϩ there is no indication for the addition of clopidogrel on top W over aspirin alone in secondary prevention after an acute of aspirin for Ͼ1 year.28,29 coronary syndrome is well established.3–5 Our data compre- A limitation inherent to all meta-analyses is the potential hensively assessed efficacy and safety of the double anti- heterogeneity among studies in terms of protocols (e.g., platelet therapy with A ϩ C compared with aspirin alone, type of acute coronary syndrome and length of follow-up), showing a lower risk of the composite end point of MAEs, patients, and sample sizes. Such diversities may lead to but also of the single end points of overall mortality, non- inaccurate conclusions. However, both the Cochrane Q het- fatal AMI, and nonfatal thromboembolic stroke. Indirect erogeneity test (which assesses heterogeneity among ORs adjusted comparisons showed no difference between A ϩ and the validity of pooling results) and test of inconsistency W and A ϩ C with regard to MAEs, overall mortality, and (I2) indicated significant diversity only among studies com- AMIs. Intriguingly, A ϩ W was associated with a 50% paring A ϩ C versus aspirin alone in the analysis for MAEs, lower risk of stroke (in particular thromboembolic stroke), possibly consistent with a significant difference in sample but at the price of a higher risk of extracranial major bleeds. sizes of included studies. Although indirect comparisons, 1642 The American Journal of Cardiology (www.AJConline.org) adjusted meta-analyses with inverse variance weighting are aspirin users. Primary end points analysis from the ATACS Trial. useful instruments in the assessment of different treatment Circulation 1994;89:81–88. 15. Williams MJA, Morison IM, Parker JH, Stewart RAH. Progression of strategies because they are usually confirmed by later ran- the culprit lesion in unstable coronary artery disease with warfarin and 8,12,30 domized trials. Moreover, such methods are receiving aspirin versus aspirin alone: preliminary study. J Am Coll Cardiol progressive attention and diffusion.31 1997;30:364–369. 16. Anand SS, Yusuf S, Pogue J, Weitz JI, Flather M, for the OASIS Pilot Appendix Study Investigators. Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Model for the calculation of natural logarithm (ln), variance pilot study results. Circulation 1998;98:1064–1070. (var), and inconsistency (I2) of competing interventions using 17. Huynh T, Theroux P, Bogaty P, Nasmith J, Solymoss S. Aspirin, adjusted indirect meta-analysis with inverse variance weight- warfarin, or the combination for secondary prevention of coronary ing. A ϭ first intervention/drug; B ϭ common control; C ϭ events in patients with acute coronary syndromes and prior coronary ϭ artery bypass surgery. Circulation 2001;103:3069–3074. second intervention/drug, chi-square test for heterogeneity. 18. The Organization to Assess Strategies for Ischemic Syndromes ϭ Ϫ (1) ln (ORAvsC) ln (ORAvsB) ln (ORCvsB); (2) 2. var [ln (OASIS) Investigators. Effects of long term, moderate intensity oral ϭ ϩ anticoagulation in addition to aspirin in unstable angina. J Am Coll (ORAvsC)] var [ln (ORAvsB)] var [ln (ORAvsC)]; (3) 2 ϭ ϩ ϫ Cardiol 2001;37:475–484. I (A vs C) (chi-square(A) chi-square(C)) 10/degrees of ϩ 19. van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE. Aspirin freedom(A) degrees of freedom(C); (4) Once calculated the and Coumadin after acute coronary syndromes (the ASPECT-2 study): a variance, it is necessary to calculate the SE, in other words, the randomised controlled trial. Lancet 2002;360:109–113. square root of the variance; (5) CIs at 95% of ln are then 20. Brouwer MA, van den Bergh PJ, Aengevaeren WR, Veen G, Luijten calculated as ln ϩ1,96 * SE (upper CI) and ln Ϫ1.96 * SE HE, Hertzberger DP, van Boven AD, Vromans R, Uijen G, Verheugt (lower CI); (6) The OR for the comparison of A versus C F. Aspirin plus coumarin versus aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of can be calculated as the exponent of the ln; (7) CIs of ORs the APRICOT 2 trial. Circulation 2002;106:659–665. are finally calculated as the exponent of the CI of the ln; and 21. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, (8) Zeta score for calculation of p value for significance is aspirin, or both after myocardial infarction. N Engl J Med 2002;347: finally derived from ln/SE. 969–974. 22. Zibaeenezhad MJ, Mowla A, Sorbi MH. Warfarin and aspirin versus aspirin alone in patients with acute myocardial infarction: a pilot study. 1. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of Angiology 2004;55:17–20. randomised trials of antiplatelet therapy for prevention of death, myocar- 23. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial dial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. Investigators. Effects of clopidogrel in addition to aspirin in patients 2. COMMIT Collaborative Group. Addition of clopidogrel to aspirin in with acute coronary syndromes without ST-segment elevation. N Engl 45852 patients with acute myocardial infarction: randomised placebo- J Med 2001;345:494–502. controlled trial. Lancet 2005;366:1607–1621. 24. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot 3. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, artery disease: a meta analysis. JAMA 1999;282:2058–2067. Braunwald E, for the CLARITY–TIMI 28 Investigators. Addition of 4. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction artery disease. J Am Coll Cardiol 2003;41(suppl):S62–S69. 5. Andreotti F, Testa L, Biondi-Zoccai G, Crea F. Aspirin plus warfarin with ST segment elevation. N Engl J Med 2005;352:1179–1189. compared to aspirin alone after acute coronary syndromes: a comprehen- 25. CAPRIE Steering Committee. A randomised, blinded trial of Clo- sive meta-analysis of 25307 patients. Eur Heart J 2006;27:519–526. pidogrel versus Aspirin in Patients at Risk of Ischaemic Events 6. Patsopoulos NA, Analatos AA, Ioannidis JPA. Relative citation impact of (CAPRIE). Lancet 1996;348:1329–1339. various study designs in health sciences. JAMA 2005;293:2362–2366. 26. Bhatt DL, Fox KA, Hacke W, Berger PB, Black AR, Boden WE, Cacoub 7. Song F, Altman D, Glenny A-M, Deeks JJ. Validity of indirect com- P, Cohen FA, Creager MA, Easton SD, Flatner MD, Hapfner SM, et al. parison for estimating efficacy of competing interventions: empirical Clopidogrel plus aspirin versus aspirin alone for the prevention of athero- evidence from published meta-analysis. BMJ 2003;326:472. thrombotic events. N Engl J Med 2006;354:1706–1717. 8. Biondi Zoccai GG, Agostoni P, Abbate A, Testa L, Burzotta F. A 27. Mehta SR, Yusuf S, Peters RJ, Bertrand M, Lewis BS, Natarajan MK, simple hint to improve Robinson and Dickersin’s highly sensitive Malmberg K, Rupprecht H, Zhad F, et al. Effects of pretreatment with PubMed search strategy for controlled clinical trials. Int J Epidemiol clopidogrel and aspirin followed by long-term therapy in patients 2005;34:224–225. undergoing percutaneous coronary intervention: the PCI-CURE study. 9. Clarke M, Oxman AD, eds. Cochrane Reviewers’ Handbook 4.1.3. In: Lancet 2001;358:527–533. The Cochrane Library, Issue 3, 2001. Oxford, UK: Update Software. 28. ACC/AHA Guidelines for the Management of Patients With ST- Updated quarterly. Elevation Myocardial Infarction. A Report of the American College of 10. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring incon- Cardiology/American Heart Association Task Force on Practice sistency in meta-analyses. BMJ 2003;327:557–560. Guidelines (Committee to Revise the 1999 Guidelines for the Man- 11. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis agement of Patients With Acute Myocardial Infarction) Developed in detected by a simple, graphical test. BMJ 1997;315:629–634. Collaboration With the Canadian Cardiovascular Society. Available at 12. Biondi-Zoccai GGL, Agostoni P, Abbate A, Testa L, Burzotta F, www.americanheart.org. Accessed October 2006. Lotrionte M, Crea F, Biasucci M, Vetrovec GW, Colombo A. Adjusted 29. ACC/AHA. Guidelines for the Management of Patients With Unstable indirect comparison of intracoronary drug-eluting stents: evidence Angina and Non-ST-Segment Elevation Myocardial Infarction. JAm from a metaanalysis of randomized bare-metal-stent-controlled trias. Coll Cardiol 2000;36:970–1062. Int J Cardiol 2005;100:119–123. 30. Kastrati A, Mehilli J, von Beckerath N, Dibra A, Hausleiter J, Pache 13. Cohen M, Adams PC, Hawkins L, Bach M, Fuster V. Usefulness of J, Schuhlen H, Schmitt C, Dirschinger J, Schomig A, for the ISAR- antithrombotic therapy in resting angina pectoris or non Q wave DESIRE Study Investigators. Sirolimus-eluting stent or paclitaxel- myocardial infarction in preventing death and myocardial infarction (a eluting stent vs balloon angioplasty for prevention of recurrences in pilot study from the Antithrombotic Therapy in Acute Coronary Syn- patients with coronary in-stent restenosis: a randomized controlled dromes study group). Am J Cardiol 1990;66:1287–1292. trial. JAMA 2005;293:165–171. 14. Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D, Wieczorek I, 31. Zhou Z, Rahme E, Pilote L. Are statins created equal? Evidence from Fox KA, Chesebro JH, Strain J, Keller C. Combination antithrombotic randomized trials of pravastatin, simvastatin, and atorvastatin for car- therapy in unstable rest angina and non-Q-wave infarction in non prior diovascular disease prevention. Am Heart J 2006;151:273–281. Prevalence and Prognosis of Asymptomatic Left Ventricular Diastolic Dysfunction in Ambulatory Patients With Coronary Heart Disease

Xiushui Ren, MDa,*, Bryan Ristow, MDa, Beeya Na, MPHb, Sadia Ali, MD, MPHb, Nelson B. Schiller, MDb,c, and Mary A. Whooley, MDb,d,e

The association of asymptomatic left ventricular (LV) diastolic dysfunction with cardiovascular outcomes in ambulatory patients with coronary heart disease (CHD) and no history of heart failure (HF) was examined. LV diastolic HF predicts adverse cardiovascular outcomes. However, the prevalence and prognosis of asymptomatic LV diastolic dysfunction in patients with established CHD in the absence of clinical HF is unknown. Six hundred ninety-three patients with stable CHD, normal systolic function (LV ejection fraction >50%), and no history of HF were evaluated. Echocardiography was used to classify LV diastolic function, and Cox proportional hazards models were used to evaluate the association of LV diastolic dysfunction with cardiovascular outcomes during 3 years of follow-up. Of 693 subjects with normal systolic function and no history of HF, 455 (66%) had normal LV diastolic function, 166 (24%) had mild LV diastolic dysfunction, and 72 (10%) had moderate to severe LV diastolic dysfunction. After multivariable adjustment, the presence of moderate to severe LV diastolic dysfunction was strongly predictive of incident (0.0003 ؍ hospitalization for HF (hazard ratio 6.3, 95% confidence interval 2.4 to 16.1, p In .(0.05 ؍ and death from heart disease (HR 3.9, 95% confidence interval 1.0 to 14.8, p conclusion, moderate to severe LV diastolic dysfunction was present in 10% of patients with stable CHD with normal ejection fraction and no history of HF and predicts subsequent hospitalization for HF and death from heart disease. Patients with asymptomatic LV diastolic dysfunction may benefit from more aggressive therapy to prevent or delay the development of HF. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99: 1643–1647)

Left ventricular (LV) diastolic heart failure (HF) accounts (CHD) is unknown. We evaluated the prevalence and prog- for nearly half of all HF diagnoses and is associated with nosis of asymptomatic LV diastolic dysfunction in ambula- increased morbidity and mortality.1–3 The prevalence and tory patients with CHD with preserved systolic function and prognosis of asymptomatic LV diastolic dysfunction is un- no history of HF. We hypothesized that asymptomatic LV clear because most studies of the association between LV diastolic dysfunction would be an independent predictor of diastolic dysfunction and adverse outcomes examined pa- adverse cardiovascular outcomes in these patients. tients with clinical HF.1–3 One previous study examined the association of LV diastolic dysfunction with cardiovascular Methods 4 outcomes in patients without known heart disease, but the Patients: Patients were enrolled in the Heart and Soul prevalence and prognosis of asymptomatic LV diastolic Study, a prospective cohort study investigating the inﬂuence dysfunction in outpatients with stable coronary heart disease of psychosocial factors on cardiovascular events. Methods were described previously.5 Administrative databases were aDepartment of Cardiology, California Paciﬁc Medical Center; bSec- used to identify outpatients with documented coronary ar- tion of General Internal Medicine, VA Medical Center; and cDepartment of tery disease at 2 Department of Veterans Affairs medical Medicine, Division of Cardiology, and dDepartments of Medicine and center databases (San Francisco and Palo Alto, California), eEpidemiology and Biostatistics, University of California, San Francisco, 1 university-based medical center (University of California California. Manuscript received December 17, 2006; revised manuscript Medical Center–San Francisco), and 9 public health clinics received and accepted January 29, 2007. in the Community Health Network of San Francisco, Cali- This work was supported by grants from the Department of Veterans fornia. Criteria for enrollment included 1 of (1) history of Affairs, Washington, DC; Grant No. R01 HL079235 from the National myocardial infarction, (2) angiographic evidence of Ն50% Heart, Lung, and Blood Institute, Bethesda, Maryland; the American Fed- stenosis in Ն1 coronary vessel, (3) previous evidence of eration for Aging Research (Paul Beeson Scholars Program), New York, exercise-induced ischemia using treadmill electrocardio- New York; the Robert Wood Johnson Foundation (Faculty Scholars Pro- gram), Princeton, New Jersey, the Ischemia Research and Education Foun- gram or stress nuclear perfusion imaging, or (4) history of dation; and the Nancy Kirwan Heart Research Fund, San Francisco, coronary revascularization. Patients were excluded if they California. deemed themselves unable to walk 1 block, experienced an *Corresponding author: Tel.: 415-377-1404; fax: 415-563-5939. acute coronary syndrome in the previous 6 months, or were E-mail address: [email protected] (X. Ren). planning to move out of the local area within 3 years.

Table 1 Characteristics of 693 patients with stable coronary heart disease, normal ejection fraction, and no history of heart failure Variable LV Diastolic Function p Value Normal Impaired Relaxation Pseudonormal or Restrictive (n ϭ 455) (n ϭ 166) (n ϭ 72) Age (yrs) 65 Ϯ 10 72 Ϯ 970Ϯ 12 Ͻ0.0001 Men 373 (82%) 127 (77%) 61 (85%) 0.4 White 261 (57%) 98 (59%) 51 (71%) 0.2 African-American 72 (16%) 98 (59%) 51 (71%) 0.03 Asian 62 (14%) 19 (11%) 7 (10%) 0.7 Other 60 (13%) 28 (17%) 7 (10%) 0.09 Current smoker 88 (19%) 25 (15%) 10 (14%) 0.04 Habitual alcohol use 139 (31%) 50 (30%) 23 (32%) 0.5 Not physically active 159 (35%) 61 (37%) 23 (32%) 0.9 Hypertension 322 (71%) 118 (71%) 52 (72%) 0.1 Diabetes mellitus 110 (24%) 36 (22%) 22 (31%) 0.0001 History of myocardial infarction 208 (46%) 89 (54%) 33 (46%) 0.0002 Stroke 53 (12%) 21 (13%) 12 (17%) 0.001 Coronary revascularization Percutaneous 124 (27%) 52 (31%) 48 (68%) Ͻ0.0001 Bypass surgery 178 (39%) 58 (35%) 27 (39%) 0.4 ␤ blocker 276 (61%) 67 (40%) 49 (68%) Ͻ0.0001 Angiotensin-converting enzyme inhibitor 200 (44%) 79 (48%) 37 (51%) 0.005 or angiotensin receptor blocker Statin 290 (64%) 102 (62%) 50 (69%) 0.3 Aspirin 365 (80%) 138 (83%) 57 (79%) 0.8 LV hypertrophy 203 (45%) 95 (59%) 41 (57%) Ͻ0.0001 LV mass index 90.7 Ϯ 20.4 97.8 Ϯ 24.3 92.9 Ϯ 22.2 Ͻ0.0001 LV ejection fraction (%) 0.65 Ϯ 0.05 0.64 Ϯ 0.06 0.64 Ϯ 0.07 Ͻ0.0001 Inducible myocardial ischemia 63 (15%) 45 (30%) 20 (30%) Ͻ0.0001 Body mass index (kg/m2) 28.5 Ϯ 5.0 28.2 Ϯ 4.9 28.6 Ϯ 5.8 0.9 Total cholesterol (mg/dl) 179 Ϯ 41 183 Ϯ 41 173 Ϯ 37 0.2 Low-density lipoprotein (mg/dl) 105 Ϯ 34 110 Ϯ 36 98 Ϯ 27 0.04 High-density lipoprotein (mg/dl) 46 Ϯ 14 47 Ϯ 14 48 Ϯ 14 0.5 Systolic blood pressure (mm Hg) 132 Ϯ 21 138 Ϯ 22 134 Ϯ 24 0.05 Diastolic blood pressure (mm Hg) 75 Ϯ 11 76 Ϯ 11 71 Ϯ 11 0.02 Heart rate (beats/min) 66 Ϯ 11 72 Ϯ 13 63 Ϯ 11 Ͻ0.0001 Creatinine clearance 87 Ϯ 28 74 Ϯ 26 74 Ϯ 28 Ͻ0.0001

From September 2000 to December 2002, a total of dominant pulmonary venous flow using velocity time inte- 1,024 patients were enrolled in the Heart and Soul Study. gral. Based on previously published criteria,4 normal LV We excluded 168 who had an LV ejection fraction Ͻ50% diastolic pattern was defined as E/A ratio of 0.75 to 1.5 and using echocardiography. We also excluded 51 patients for systolic dominant pulmonary venous flow. Impaired relax- whom LV diastolic function could not be determined be- ation pattern (mild LV diastolic dysfunction) was defined as cause of non–sinus rhythm, LV pacing, heart rate Ͼ100 E/A ratio Յ0.75 and systolic dominant pulmonary venous beats/min, severe mitral valve disease, or technical reasons. flow. Pseudonormal pattern (moderate LV diastolic dys- This resulted in an analytic sample of 805 patients, of whom function) was defined as E/A ratio of 0.75 to 1.5 and LV 693 had no history of HF. The study protocol was approved diastolic dominant pulmonary venous flow. Restrictive pat- by the institutional review boards at each participating site, tern (advanced LV diastolic dysfunction) was defined as and all patients provided written informed consent. E/A ratio Ͼ1.5 and LV diastolic dominant pulmonary venous flow. We did not differentiate between reversible and Diastolic function: We performed echocardiography in irreversible restrictive patterns. Because Ͻ5% of the study the standard left lateral recumbent and supine positions sample had restrictive filling, pseudonormal and restrictive using a commercially available ultrasound system with har- groups were combined for analysis. monic imaging (Acuson Sequoia, Siemens Corp, Mountain View, California). From the standard apical 4-chamber Cardiovascular outcomes: We evaluated all-cause view, spectral Doppler signals of mitral inflow and pulmo- mortality, nonfatal myocardial infarction, incident hospital- nary vein flow were obtained according to guidelines of the ization for HF, or death from heart disease during 3 years American Society of Echocardiography.6 Patterns of LV (range 2 to 4) of follow-up. We conducted annual telephone diastolic dysfunction were based on mitral inflow E/A ratios follow-up interviews with patients (or their proxies) to ask of peak velocities at early rapid filling (E) and late filling about death or hospitalization for “heart trouble.” For any due to atrial contraction (A) and systolic or LV diastolic reported event, medical records, electrocardiograms, death Coronary Artery Disease/Diastolic Dysfunction in Coronary Heart Disease 1645

Table 2 Outcomes Variable Normal Impaired Relaxation Pseudonormal or Restrictive p Value (n ϭ 455) (n ϭ 166) (n ϭ 72) All-cause mortality 34 (7.5%) 20 (12.0%) 11 (15.3%) 0.05 Heart disease death 5 (1.1%) 6 (3.6%) 5 (6.9%) 0.01 Hospitalization for HF 13 (2.9%) 12 (7.2%) 8 (11.1%) 0.01 Hospitalization for myocardial infarction 21 (4.6%) 19 (11.4%) 8 (11.1%) 0.01

Values expressed as number (percent). certificates, and coroner’s reports were retrieved and re- Statistical analysis: The goal of this study was to ex- viewed by 2 independent and blinded adjudicators. If the amine the association of asymptomatic LV diastolic dys- adjudicators agreed on the outcome classification, their clas- function with cardiovascular outcomes. Differences in par- sification was binding. In the event of disagreement, the ticipant characteristics by category of LV diastolic function adjudicators conferred, reconsidered their classification, and were determined using analysis of variance for continuous requested consultation from a third blinded adjudicator. variables and chi-square tests for dichotomous variables. All-cause mortality was determined using review of We used Cox proportional hazard models to evaluate the death certificates. Nonfatal myocardial infarction was de- independent association of LV diastolic dysfunction with fined using standard diagnostic criteria.7 Death was consid- cardiovascular events after adjusting for all variables in ered caused by CHD if the patient (1) died during the same Table 1. For these analyses, we report hazard ratios (HRs) hospitalization in which an acute myocardial infarction was with 95% confidence intervals (CIs). Analyses were per- documented or (2) experienced sudden CHD death defined formed using Statistical Analysis Software (version 9, SAS as an unexpected otherwise unexplained fatality within 1 Institute Inc, Cary, North Carolina). hour of the onset of terminal symptoms. HF was defined as hospitalization for a clinical syndrome involving Ն2 of paroxysmal nocturnal dyspnea, orthopnea, Results increased jugular venous pressure, pulmonary rales, third Of 693 patients with LV ejection fraction Ն50% and no heart sound, cardiomegaly on chest x-ray, or pulmonary history of HF, 455 (66%) had normal LV diastolic function, edema on chest x-ray. These clinical signs and symptoms 166 (24%) had impaired relaxation (mild LV diastolic dys- must have represented a clear change from the normal function), and 72 (10%) had pseudonormal or restrictive clinical state of the patient and been accompanied by either filling (moderate to severe LV diastolic dysfunction). Com- failing cardiac output, determined as peripheral hypoperfu- pared with patients with normal LV diastolic function, those sion (hypotension in the absence of other causes, such as with LV diastolic dysfunction were older; more likely to sepsis or dehydration) or peripheral or pulmonary edema. have experienced a previous myocardial infarction, stroke, Supportive documentation of decreased cardiac index, in- or revascularization; and less likely to smoke (Table 1). creasing pulmonary capillary wedge pressure, decreasing Compared with patients with normal LV diastolic function, oxygen saturation, and end-organ hypoperfusion, if avail- those with LV diastolic dysfunction had greater LV mass, able, were included in adjudication. lower LV ejection fraction, more inducible myocardial isch- Other characteristics: Each patient completed a de- emia, and lower creatinine clearance (Table 1). tailed questionnaire that included age, gender, race, medical During an average 3 years of follow-up, patients with history, level of physical activity, current smoking, and moderate to severe LV diastolic dysfunction were more level of alcohol consumption. Study personnel recorded all likely than those with normal LV diastolic function to be current medications and measured height, weight, and blood hospitalized for HF (11% vs 3%, p Ͻ0.001) and die from pressure. Medication categories were categorized using Ep- heart disease (7% vs 1%, p ϭ 0.01l Table 2). After multi- ocrates Rx (San Mateo, CA). LV ejection fraction was variable adjustment, the presence of moderate to severe LV measured quantitatively using the 2-dimensional echocardi- diastolic dysfunction remained strongly predictive of inci- ography biplane method of discs.8,9 We defined LV hyper- dent hospitalization for HF (HR 6.3, 95% CI 2.3 to 17.2, trophy as LV mass index Ͼ90 g/m2 based on the 2-dimen- p ϭ 0.0003) and death from CHD (HR 3.9, 95% CI 1.0 to sional echocardiography truncated ellipse method.10 A 14.8, p ϭ 0.05; Table 3). Asymptomatic LV diastolic dys- symptom-limited graded exercise treadmill test was per- function predicted hospitalization for myocardial infarction formed, and we used stress echocardiography to seek in- in unadjusted, but not adjusted, analyses (Table 3). ducible ischemia, defined as the presence of cardiac wall Having normal LV diastolic function resulted in an ex- motion abnormality at peak exercise that was not present at cellent probability of survival free of HF, whereas moderate rest. A single cardiologist (NBS) blinded to clinical and to severe LV diastolic dysfunction resulted in a significantly laboratory information evaluated all echocardiograms. To- decreased probability of survival free of HF. Patients with tal, low-density lipoprotein, and high-density lipoprotein mild LV diastolic dysfunction were also more likely than cholesterol were measured from fasting serum samples. those with normal LV diastolic function to be hospitalized Creatinine clearance was determined using 24-hour urine for HF (7% vs 3%, p ϭ 0.01) or myocardial infarction (12% sample. vs 5%, p ϭ 0.003). However, mild LV diastolic dysfunction 1646 The American Journal of Cardiology (www.AJConline.org)

Table 3 Relative rates of cardiovascular outcomes according to the presence of isolated diastolic dysfunction or heart failure Variable Normal Impaired Relaxation HR p Value Pseudonormal or Restrictive HR p Value (95% CI) (95% CI) Unadjusted All-cause mortality 1.0 1.3 (0.8–2.1) 0.3 1.6 (0.8–2.8) 0.1 Heart disease death 1.0 1.5 (0.6–4.1) 0.4 3.3 (1.3–8.7) 0.01 Hospitalization for HF 1.0 2.0 (1.0–3.7) 0.04 3.9 (2.0–7.5) Ͻ0.0001 Hospitalization for myocardial infarction 1.0 2.4 (1.4–4.2) 0.003 2.0 (0.9–4.2) 0.09 Adjusted for all Table 1 variables All-cause mortality 1.0 0.7 (0.4–1.3) 0.3 1.2 (0.6–2.4) 0.6 Heart disease death 1.0 1.0 (0.3–3.8) 0.9 3.9 (1.0–14.8) 0.05 Hospitalization for HF 1.0 1.7 (0.7–4.5) 0.3 6.3 (2.4–16.1) 0.0001 Hospitalization for myocardial infarction 1.0 1.7 (0.8–3.7) 0.2 1.3 (0.5–3.2) 0.6 was no longer associated with cardiovascular outcomes af- LV diastolic dysfunction in our patients, we found a 24% ter adjustment for potential confounding variables. prevalence of mild LV diastolic dysfunction. Thus, the overall prevalence of LV diastolic dysfunction was 34%. 2 Discussion Bursi et al found that LV diastolic dysfunction was present in 44% of community-dwelling patients with HF. The lower We found that moderate to severe LV diastolic dysfunction prevalence of LV diastolic dysfunction in our study is likely was present in 10% of outpatients with CHD who had no explained by our study population, which consists of pa- systolic dysfunction or history of HF. The presence of tients with stable CHD, but no history of HF. Although asymptomatic moderate to severe LV diastolic dysfunction impaired relaxation predicted subsequent myocardial infarc- predicted a more than sixfold increased risk of incident HF tion and death from heart disease in unadjusted analyses, and an almost fourfold increased risk of death from heart this association was no longer significant after adjusting for disease. The increased risk of cardiovascular events associ- potential confounding variables. This indicates that other ated with asymptomatic LV diastolic dysfunction was sim- factors associated with impaired relaxation, such as LV ilar to that observed for patients with known HF.2 Our hypertrophy or inducible ischemia, may have been respon- results highlight the importance of asymptomatic LV dia- sible for the increased rate of adverse events. This is sup- stolic dysfunction and raise the possibility that patients with ported by higher incidences of LV hypertrophy and induc- LV diastolic dysfunction may benefit from more aggressive ible ischemia in the impaired-relaxation group compared therapy to prevent or delay the development of clinical HF. with normal patients. In this study, we sought to define the prevalence of American College of Cardiology/American Heart Asso- asymptomatic LV diastolic dysfunction in patients with ciation guidelines for the evaluation and management of stable CHD and examine the prognosis of LV diastolic chronic HF recommend specific therapies for each of 4 dysfunction in patients without systolic dysfunction or his- stages in the evolution of HF.12 In adults at high risk of HF, tory of HF. One previous study examined the association of but without structural heart disease or symptoms of HF LV diastolic dysfunction with cardiovascular outcomes in (stage A), the guidelines recommend aggressive risk-factor patients without known heart disease,4 but the prevalence reduction, including smoking cessation, exercise, and treat- and prognosis of asymptomatic LV diastolic dysfunction in ment of hypertension. In patients with structural heart dis- outpatients with stable CHD is unknown. Because patients ease, but without symptoms of HF (stage B), the guidelines with CHD are at high risk of developing HF,11 this group specifically recommend therapy with angiotensin-convert- represents a relevant target population for which closer ing enzyme inhibitors and ␤ blockers. In our study patients follow-up and earlier interventions to prevent HF might be with CHD, the presence of asymptomatic LV diastolic dys- considered. function appeared to differentiate between those with stage We found that asymptomatic moderate to severe LV A HF (at risk of HF, but without structural heart disease or diastolic dysfunction predicted hospitalization for HF and symptoms of HF) and those with stage B HF (structural death from heart disease at rates similar to those observed heart disease, but without symptoms of HF). Thus, the with clinically overt HF. Because LV diastolic dysfunction presence of LV diastolic dysfunction identifies a subgroup did not predict subsequent myocardial infarction, the asso- of patients who may benefit from more aggressive afterload ciation of LV diastolic dysfunction with death from heart reduction with angiotensin-converting enzyme inhibitors disease was likely caused by the interim development of and ␤ blockers. However, although treatments for asymp- HF. We considered the possibility that greater LV mass, tomatic systolic dysfunction have been well established, lower LV ejection fraction, more inducible ischemia, or therapies for asymptomatic LV diastolic dysfunction have lower creatinine clearance might explain the observed as- yet to be evaluated in clinical trials. sociation between LV diastolic dysfunction and HF. How- ever, even after adjusting for these factors, the association 1. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu of LV diastolic dysfunction with HF remained strong. PP. Outcome of heart failure with preserved ejection fraction in a In addition to the 10% prevalence of moderate to severe population-based study. N Engl J Med 2006;355:260–269. Coronary Artery Disease/Diastolic Dysfunction in Coronary Heart Disease 1647

2. Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo method for determining ejection fraction with two-dimensional VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in echocardiography. Circulation 1981;64:744–753. the community. JAMA 2006;296:2209–2216. 9. Cheitlin MD, Alpert JS, Armstrong WF, Aurigemma GP, Beller GA, 3. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield Bierman FZ, Davidson TW, Davis JL, Douglas PS, Gillam LD, et al. MM. Trends in prevalence and outcome of heart failure with preserved ACC/AHA guidelines for the clinical application of echocardiography: ejection fraction. N Engl J Med 2006;355:251–259. executive summary. A report of the American College of Cardiology/ 4. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, American Heart Association Task Force on practice guidelines (Com- Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunc- mittee on Clinical Application of Echocardiography). Developed in tion in the community: appreciating the scope of the heart failure collaboration with the American Society of Echocardiography. JAm epidemic. JAMA 2003;289:194–202. Coll Cardiol 1997;29:862–879. 5. Ruo B, Rumsfeld JS, Hlatky MA, Liu H, Browner WS, Whooley MA. 10. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigen- Depressive symptoms and health-related quality of life: the Heart and baum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, et al. Recom- mendations for quantitation of the left ventricle by two-dimensional Soul Study. JAMA 2003;290:215–221. echocardiography. American Society of Echocardiography Committee 6. Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. on Standards, Subcommittee on Quantitation of Two-Dimensional Recommendations for quantification of Doppler echocardiography: a Echocardiograms. J Am Soc Echocardiogr 1989;2:358–367. report from the Doppler Quantification Task Force of the Nomencla- 11. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: ture and Standards Committee of the American Society of Echocardi- a manifestation of coronary artery disease. Circulation 1998;97:282– ography. J Am Soc Echocardiogr 2002;15:167–184. 289. 7. Luepker RV. Case definitions for acute coronary heart disease in 12. Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, epidemiology and clinical research studies: a statement from the AHA Francis GS, Ganiats TG, Goldstein S, Gregoratos G, Jessup ML, et al. Council on Epidemiology and Prevention; AHA Statistics Committee; ACC/AHA Guidelines for the Evaluation and Management of Chronic World Heart Federation Council on Epidemiology and Prevention; the Heart Failure in the Adult: Executive Summary A Report of the European Society of Cardiology Working Group on Epidemiology and American College of Cardiology/American Heart Association Task Prevention; Centers for Disease Control and Prevention; and the Na- Force on Practice Guidelines (Committee to Revise the 1995 Guide- tional Heart, Lung, and Blood Institute. Circulation 2003;108:2543– lines for the Evaluation and Management of Heart Failure): developed 2549. in collaboration with the International Society for Heart and Lung 8. Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB, Transplantation; Endorsed by the Heart Failure Society of America. Winters WL Jr, Ribeiro LG, Miller RR. A new, simplified and accurate Circulation 2001;104:2996–3007. Effect of Estradiol-Drospirenone Hormone Treatment on Myocardial Perfusion Reserve in Postmenopausal Women With Angina Pectoris

Juhani Knuuti, MDa,*, Riikka Kalliokoski, PhDa, Tuula Janatuinen, MDa, Jarna Hannukainen, PhDa, Kari K. Kalliokoski, PhDa, Juha Koskenvuo, MDa, and Stefan Lundt, MDb

Recent randomized clinical studies failed to show cardiovascular protection with postmenopausal hormone therapy (HT), instead raising widespread concerns about possible increased cardiovascular risk. However, these studies primarily assessed the combination of conjugated equine estrogen and medroxyprogesterone acetate, which is suspected to abolish the beneficial effects of estrogen on the microcirculation. This preliminary study evaluated the effects of HT combining 17␤-estradiol (E2) with a new progestin, drospirenone, on myocardial perfusion reserve, a surrogate marker of coronary function. In this double-blind randomized study, 56 postmenopausal women with angina pectoris received oral E2 1 mg plus drospirenone 2 mg or placebo for 6 weeks. Myocardial perfusion reserve was measured using radioactive oxygen–labeled water and positron emission tomography before and after therapy. Myocardial perfusion reserve increased significantly in the E2-drospirenone group after 6 weeks versus placebo (p <0.0008). Mean myocardial perfusion reserve increased from 4.83 at base- but decreased from ,(27 ؍ line to 5.13 after 6 weeks in the E2-drospirenone group (n No significant side effects were observed with .(29 ؍ to 4.13 in the placebo group (n 4.84 E2-drospirenone. A larger trial is needed to investigate whether myocardial perfusion improvements will be sustained and translate into a clinical benefit in postmenopausal women at risk of coronary heart disease. In conclusion, E2-drospirenone HT for 6 weeks has favorable effects on myocardial function in postmenopausal women with angina pectoris. These data suggest that drospirenone has the desired progestin actions on the endometrium, but does not abolish the beneficial effects of estradiol on cardiac microcirculation. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99: 1648–1652)

Drospirenone is a novel progestin derived from 17␣-spiro- using positron emission tomography and radioactive oxy- lactone. It has been used as hormone therapy (HT) in com- gen–labeled water before and after treatment. bination with 17␤-estradiol (E2) and as an oral contraceptive in combination with ethinylestradiol. The pharma- codynamic properties of drospirenone are similar to natural Methods progesterone. It exerts antimineralocorticoid effects that This study was designed as a double-blind, randomized, pla- may also in part counteract the salt-retaining actions of cebo-controlled study in postmenopausal women with angina. estrogens. Large multicenter trials comparing ethinylestra- Women were assigned to oral treatment with E2 1 mg com- diol-drospirenone with ethinylestradiol-desogestrel showed bined with drospirenone 2 mg or placebo, administered as 1 good ovulation inhibition, cycle control, and safety and also tablet of identical appearance each day for 6 weeks. significantly greater weight reduction in the ethinylestra- During the screening phase, subjects underwent physical diol-drospirenone group.1,2 The current study aimed to and gynecologic examination and transvaginal ultrasound test- investigate the actions of E2-drospirenone on the cardio- ing. Use of HT shortly before enrollment and additional HT vascular system. A double blind, randomized, placebo- controlled study was conducted in postmenopausal women use in the E2-drospirenone group was excluded using follicle- with angina. Myocardial perfusion reserve was measured stimulating hormone, E2, and drospirenone blood levels. Before treatment with E2-drospirenone or placebo, baseline examinations of myocardial blood flow at rest and aTurku PET Centre, University of Turku, Finland; and bMed Dev STH under stress were performed using radioactive oxygen– Cardiovascular Europe, Berlin, Germany. Manuscript received September labeled water positron emission tomography, and myocar- 17, 2006; revised manuscript received and accepted January 22, 2007. dial perfusion reserve was calculated. Positron emission This study was supported by a grant from Schering AG, Berlin, tomographic studies were repeated after completion of 6 Germany *Corresponding author: Tel.: ϩ358-2-313-2842; fax: ϩ358-2-231- weeks of treatment. Compliance in the E2-drospirenone 8191. group was assessed by measuring drospirenone levels. E-mail address: juhani.knuuti@utu.fi (J. Knuuti). Safety parameters, clinical symptoms, adverse events, elec-

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.01.042 Coronary Artery Disease/HT and Myocardial Perfusion Reserve 1649 trocardiograms, and blood pressure readings were recorded Table 1 before and during stress imaging throughout the study. Subject baseline characteristics An independent ethics committee approved the study Variable E2-Drospirenone Placebo protocol and any amendment. The study was conducted in (n ϭ 27) (n ϭ 29) accordance with the ethical principles of the Declaration of Age (yrs) 60.1 Ϯ 5.9 60.1 Ϯ 4.7 Helsinki and the International Congress on Harmonization Body weight (kg) 66.3 Ϯ 8.3 68.8 Ϯ 10.0 guideline on Good Clinical Practice. Local laws for radia- Body mass index (kg/m2, severe 24.7 Ϯ 2.9 25.9 Ϯ 3.4 tion were followed. All patients signed an informed consent obesity Ͼ30 kg/m2) form at enrollment. Plasma triglycerides Women with symptoms of angina pectoris with onset Ն1 (mmol/L) 1.3 Ϯ 0.43 1.5 Ϯ 0.91 year before inclusion were enrolled into the study. Patients (mg/dl) 115 Ϯ 38 133 Ϯ 81 with heart failure symptoms worse than New York Heart Total cholesterol in plasma Association stage II classification; history of myocardial (mmol/L) 6.1 Ϯ 0.75 6.3 Ϯ 0.80 infarction, atrial fibrillation, cardiac transplantation, or cor- (mg/dl) 236 Ϯ 29 244 Ϯ 31 onary revascularization using either percutaneous tech- High-density lipoprotein cholesterol (mmol/L) 1.7 Ϯ 0.46 1.6 Ϯ 0.42 niques or coronary artery bypass grafting; coronary artery (mg/dl) 66 Ϯ 18 62 Ϯ 16 disease worse than Canadian Cardiovascular Society class II Low-density lipoprotein cholesterol classification; history of stroke or transient ischemic attack; (mmol/L) 3.7 Ϯ 0.51 3.9 Ϯ 0.72 current hypertension; or smoking Ͼ10 cigarettes per day (mg/dl) 143 Ϯ 20 151 Ϯ 28 were excluded from the study. Plasma glucose The postmenopausal state, either natural or surgically (mmol/L) 5.0 Ϯ 0.5 5.1 Ϯ 0.3 induced, was required to be present for Ն2 years and be (mg/dl) 90 Ϯ 992Ϯ 5 represented by a serum follicle-stimulating hormone level Glycosylated hemoglobin A10 5.6 Ϯ 0.41 5.7 Ϯ 0.45 Ͼ40 mU/ml and serum E2 Ͻ20 pg/ml. Women who had (mmol/L) received estrogen and antiestrogen therapy (all routes, eg, Values expressed as mean Ϯ SD. tamoxifen, raloxifene, and phytoestrogen) within 2 years before the start of the study were excluded. Women with a history of or suspected steroid hormone–dependent malig- All acquired data were corrected for dead time, decay, nancy and those with abnormal clinically significant find- and photon attenuation and reconstructed in a 128 ϫ 128 ings during gynecologic examination, abnormal cervical matrix. Average myocardial perfusion in the anterior wall of smear result, or Ͼ5 mm endometrial thickness in a trans- the heart was measured for each individual patient. Myo- vaginal ultrasound study and abnormal endometrial biopsy cardial perfusion reserve was defined as the ratio of myo- result were not enrolled. cardial blood flow during adenosine stress to myocardial Selection criteria were set to enroll patients with in- blood flow at baseline. Myocardial blood flow resistance creased risk of coronary dysfunction that could potentially was calculated by dividing mean arterial blood pressure by respond to HT. Asymptomatic patients were not included the respective myocardial blood flow value. because improvements in vascular function were unlikely Results are expressed as mean Ϯ SD if not otherwise be induced in subjects with normal coronary function re- mentioned. For comparisons between the 2 treatment gardless of intervention. However, subjects with clinically groups, analysis of covariance was performed using loga- more advanced coronary heart disease that could potentially rithmic-scale estimations with 95% confidence intervals for require coronary interventions or lead to an acute coronary magnitude of treatment effect. p Value Ͻ0.05 is interpreted event during the study were avoided. as statistically significant. Patients were examined in a supine position using a whole-body positron emission tomographic scanner (GE Results Advance General Electric, Milwaukee, Wisconsin). Alco- hol, smoking, and caffeine were prohibited for 12 hours Fifty-six postmenopausal women were enrolled. Mean age before assessment. Correct positioning of the patient’s heart of all women in our study was 60.1 years (Table 1). Of 56 within the axial field of view of the tomograph was ascer- women enrolled, 27 were randomly assigned to treatment tained on a rectilinear transmission scan, followed by a with E2-drospirenone, and 29, to placebo. There were no transmission scan. For each positron emission tomographic relevant group differences regarding mean age and systolic study, 700 to 900 MBq of radioactive oxygen–labeled water blood pressure. Body mass indexes in both groups were was injected over 20 seconds. Subsequently, acquisition of similar and within the range of 20 to 30 kg/m2, which the serial transaxial tomographic images of the heart started excluded patients with severe obesity. At baseline, the ma- (15 ϫ 5-second, 3 ϫ 10-second, 3 ϫ 20-second, and 4 ϫ jority of women in both groups had angina at exertion 30-second frames). After a 10-minute period to allow for (E2-drospirenone 66.7%, placebo 75.9%) and occasionally radioactive decay, the adenosine infusion (140 ␮g/min/ at rest (E2-drospirenone 92.6%, placebo 69.0%). kg) was started, and 2 minutes later, the radioactive Fasting triglycerides, total cholesterol, high-density li- oxygen–labeled water positron emission tomographic poprotein cholesterol, low-density lipoprotein cholesterol, scan was repeated. Total amount of radiation from radio- fasting glucose, and glycosylated hemoglobin A1c were active oxygen-labeled water was estimated to be 2.97 within normal ranges at baseline and confirmed the exclu- mSv. sion of women with diabetes and hyperlipidemia (Table 1). 1650 The American Journal of Cardiology (www.AJConline.org)

Table 2 groups. However, it did not change throughout the course of Baseline heart rate, blood pressure, and cardiovascular status in the the study. study groups Multiparous women and women with previous hysterec- Variable E2- Placebo All tomy were more common in the placebo group (Table 4). Drospirenone (n ϭ 29) Patients High baseline plasma follicle-stimulating hormone and low (n ϭ 27) (n ϭ 56) estradiol confirmed the postmenopausal state and levels Baseline were almost identical in both groups. Drospirenone plasma Heart rate (beats/min) 67 Ϯ 12 61 Ϯ 863Ϯ 10 levels confirmed good compliance of women on active Systolic blood pressure (mm 141 Ϯ 11 138 Ϯ 14 140 Ϯ 13 treatment (start, 0.5 ng/ml; end, 25.4 Ϯ 8.4). No relevant Hg, upper range 160) side effects of E2-drospirenone were observed. Diastolic blood pressure (mm 83 Ϯ 881Ϯ 782Ϯ 8 Myocardial perfusion reserve was used as a surrogate Hg, upper range 100) marker for coronary function and represented the primary Cardiovascular status baseline study end point. After 6 weeks of treatment, myocardial Angina Ն1 yr 27 (100%) 29 (100%) 56 (100%) perfusion reserve in the E2-drospirenone group significantly Angina at rest 25 (93%) 20 (69%) 45 (80%) increased compared with the placebo group (p Ͻ0.0008; Angina at exertion 18 (67%) 22 (76%) 40 (71%) Table 5). Mean myocardial perfusion reserve in the E2- Canadian Cardiovascular 26 (96%) 22 (76%) 48 (86%) ϭ Society clinical angina drospirenone group (n 27) increased from 4.83 at baseline class I to 5.13 after 6 weeks of treatment, whereas mean myocar- New York Heart 26 (96%) 22 (76%) 48 (86%) dial perfusion reserve in the placebo group (n ϭ 29) de- Association heart failure creased from 4.84 to 4.13. class I Values expressed as mean Ϯ SD or number (percent). Discussion This study is the first to show the effects of 6 weeks of HT Table 3 with E2-drospirenone, a new estrogen/progestin combina- Continuous concomitant cardiovascular medication at baseline tion, on coronary function. Postmenopausal women with Variable E2-Drospirenone Placebo All angina pectoris were investigated before and after therapy, (n ϭ 27) (n ϭ 29) Patients and favorable effects on myocardial perfusion reserve, a ϭ (n 56) surrogate marker of coronary function, were detected. The Platelet inhibitor 2 (7%) 5 (17%) 7 (13%) positive effect may indicate that drospirenone, although ␤ Blocker 1 (4%) 4 (14%) 5 (9%) developing the desired progestin actions on the endome- Calcium channel blocker 0 (0%) 3 (10%) 3 (5%) trium, does not abolish E2 effects on the cardiac microcir- Angiotensin II inhibitor 2 (7%) 1 (3%) 3 (5%) culation. Diuretic 0 (0%) 2 (7%) 2 (4%) Pharmacologic and clinical evidence support a beneficial Angiotensin-converting 0 (0%) 1 (3%) 1 (2%) effect of estrogen on the cardiovascular system.3–5 Estrogen enzyme inhibitor reverses changes in intramural coronary resistance arteries caused by female sex hormone depletion.6 Vascular endothelial and smooth muscle cells express 2 kinds of estrogen Values remained within normal ranges with no significant receptors. Estrogen has both short-term vasodilatory effects differences between groups throughout the study. In line and long-term actions that inhibit the response to vascular with previous reports of E2, slight decreases in total cho- injury and prevent atherosclerosis.4 lesterol (from 6.1 mmol/L at entry to 5.4 mmol/L at week 6, The randomized placebo-controlled Heart and Estrogen/ p ϭ NS) and low-density lipoprotein cholesterol (from 3.7 progestin Replacement Studies (HERS I7 and HERS II8–10) mmol/L at entry to 3.2 mmol/L at week 6, p ϭ NS) were and Women’s Health Initiative (WHI) studies investigated observed in the E2-drospirenone group, but not the placebo HT with conjugated equine estrogen 0.625 mg/day and 11 group. All women who were smokers at the start of the medroxyprogesterone acetate 2.5 mg/day or conjugated 12 study (Ͻ10 cigarettes/day) continued to smoke throughout equine estrogen monotherapy. These studies failed to show the prevention of cardiovascular disease with post- the study. menopausal HT. In contrast, widespread concerns about Heart rates and systolic and diastolic blood pressures at increased cardiovascular risk due to HT were raised. How- baseline did not differ between groups and indicated a ever, there is evidence that the medroxyprogesterone acetate cohort without extensive hypertension (Table 2). component used to prevent estrogen-induced endometrial Concomitant medications are listed in Table 3. The most hyperplasia also attenuates beneficial estrogen actions on frequent reason for continuous cardiovascular medication the coronary circulation12 and atherosclerosis.13 was hypertension (3 women in the E2-drospirenone group, Myocardial perfusion reserve is an independent predictor 7 women in the placebo group). Treatment was stopped in of adverse cardiovascular outcome. Endothelial dysfunction 1 woman receiving an angiotensin II inhibitor and 1 woman predicts atherosclerosis before structural changes in larger receiving a platelet inhibitor at study initiation. All other vessels become detectable.14 Many risk factors that predis- cardiovascular medications were maintained throughout the pose to atherosclerosis cause endothelial dysfunction15 and, study. Overall, despite randomization, concomitant cardio- vice versa, the presence of multiple risk factors predicts vascular treatment was not ideally balanced between endothelial dysfunction.16,17 Coronary dysfunction is linked Coronary Artery Disease/HT and Myocardial Perfusion Reserve 1651

Table 4 Baseline postmenopausal gynecologic status E2-Drospirenone Placebo All Patients (n ϭ 27) (n ϭ 29) (n ϭ 56) Age at menarche (yrs) 13.4 Ϯ 1.4 13.3 Ϯ 1.4 13.4 Ϯ 1.4 Plasma follicle-stimulating hormone (mu/ml, upper range Ն40) 71.0 Ϯ 27.4 74.7 Ϯ 25.5 n.a. Plasma estradiol (pg/ml, lower range 20) 5.3 Ϯ 1.0 5.5 Ϯ 2.5 n.a. Endometrial thickness in transvaginal ultrasound study (mm, upper range 5) 2.14 Ϯ 0.93 2.33 Ϯ 1.20 2.23 Ϯ 1.05 Multiparity 18 (67%) 25 (86%) 43 (77%) Hysterectomy 5 (19%) 11 (38%) 16 (29%) Oophorectomy 3 (11%) 4 (14%) 7 (13%) HT history (2 yrs estrogen or antiestrogen therapy before enrollment) 10 (37%) 16 (55%) 26 (46%)

Values expressed as mean Ϯ SD or number (percent).

Table 5 Myocardial perfusion at baseline and after 6 weeks of hormone therapy Mean Myocardial Mean Myocardial Mean Myocardial Blood Flow at Rest Blood Flow at Stress Perfusion Reserve (ml/min/g tissue) (ml/min/g tissue) (ml/min/g tissue) Baseline 6 Wks Baseline 6 Wks Baseline 6 Wks Difference E2-drospirenone 1.12 1.00 5.43 5.05 4.83 5.13* ϩ14% Placebo 0.95 0.97 4.55 4.07 4.84 4.13 Ϫ15%

*pϽ0.0008 compared with placebo. to adverse cardiovascular outcome in women with ischemic parallel protocol. Thus, these differences cannot be caused heart disease,18–20 as well as patients with normal or only by bias in subject selection or timing of measurements. In minimally diseased coronary arteries.21,22 addition, the clinical reproducibility and comparability of Unfortunately, some recent positron emission tomogra- myocardial perfusion reserve was repeatedly shown to be phy studies in the setting of HT and postmenopausal isch- good.28,29 One explanation could be seasonal changes in emic heart disease were limited by lack of power, as well as myocardial perfusion reserve. Whether changes are caused the heterogeneity and suboptimal selection of the study by less attenuation of estrogen effects or intrinsic effects of cohort. Duvernoy et al23 examined 15 postmenopausal the new drospirenone component30 cannot be answered by women using 13-N-ammonia positron emission tomography this study. Selection criteria for the study were set to enroll in a placebo-controlled crossover trial. Myocardial perfu- patients with increased risk of coronary dysfunction that sion reserve did not significantly change after 3 months of could potentially respond to E2-drospirenone therapy. Be- treatment with conjugated equine estrogen and medroxy- cause coronary angiography was not considered ethically 24 progesterone acetate. A second study by Duvernoy et al in justified and was not performed, we cannot document the women with risk factors for ischemic heart disease or es- exact pathophysiologic status of the coronary vessels. An- tablished ischemic heart disease and previous myocardial gina criteria were used to increase the likelihood of existing infarction did not lead to different results and conclusions. coronary dysfunction. However, for safety reasons, we ex- However, Campisi et al25 showed that long-term HT during menopause can reverse worsened myocardial perfusion re- cluded subjects with clinically more advanced coronary serve in the absence of considerable cardiovascular risk heart disease. This led to a study group with a somewhat factors. In a study by Wakatsuki et al,26 the addition of increased risk of coronary pathological states and dysfunc- medroxyprogesterone acetate attenuated the significant in- tion, but mostly nonclinical, if any, epicardial coronary crease in peripheral endothelial function observed after artery disease. This selection reflects the relatively high treatment with conjugated equine estrogen alone in 48 post- absolute perfusion and myocardial perfusion reserve values menopausal Japanese women without clinical and labora- in the studied groups. tory signs of cardiovascular disease or related major risk A larger trial is needed to investigate whether the im- factors. provement in myocardial perfusion will be sustained and There are some limitations to the present study that need translate into a clinical benefit in postmenopausal women at to be addressed. Active and passive smoking has a consid- risk of coronary heart disease. erable effect on myocardial perfusion reserve.27 There were some smokers in both study groups (Ͻ10 cigarettes/day). 1. Foidart JM, Wuttke W, Bouw GM, Gerlinger C, Heithecker R. A However, all those who smoked remained smokers through- comparative investigation of contraceptive reliability. Eur J Contra- out the study. In the present study, the significant differ- cept Reprod Health Care 2000;5:124–134. 2. Huber J, Foidart JM, Wuttke W, Merki-Feld GS, The HS, Gerlinger C, ences in cardiac perfusion between treatment groups are Schellschmidt I, Heithecker R. Efficacy and tolerability of a monopha- partly explained by changes in the placebo group. The study sic oral contraceptive containing ethinylestradiol and drospirenone. used a randomized, double-blinded, placebo-controlled, Eur J Contracept Reprod Health Care 2000;5:25–34. 1652 The American Journal of Cardiology (www.AJConline.org)

3. Redberg RF, Nishino M, McElhinney DB, Dae MW, Botvinick EH. 18. Reis SE, Holubkov R, Smith AJC, Kelsey SF, Sharaf BL, Reichek N, Long-term estrogen replacement therapy is associated with improved Rogers WJ, Bairey Merz CN, Sopko G, Pepine CJ, for the WISE exercise capacity in postmenopausal women without known coronary Investigators. Coronary microvascular dysfunction is highly prevalent artery disease. Am Heart J 2000;139:739–744. in women with chest pain in the absence of coronary artery disease: 4. Mendelsohn ME. Genomic and nongenomic effect of estrogen in the results from the NHLBI WISE study. Am Heart J 2001;141:735–741. vasculature. Am J Cardiol 2000;90(suppl):S3F–S6F. 19. von Mering GO, Arant CB, Wessel TR, McGorray SP, Bairey Merz 5. Dubey RK, Tofovic SP, Jackson EK. Cardiovascular pharmacology of CN, Sharaf BL, Smith KM, Olson MB, Johnson BD, Sopko G, et al. estradiol metabolites. J Pharmacol Exp Ther 2004;308:403–409. Abnormal coronary vasomotion as a prognostic indicator of cardio- 6. Mericli M, Nadasy GL, Szekeres M, Varbiro S, Vajo Z, Matrai M, Acs vascular events in women: results from the National Heart, Lung, and N, Monos E, Szekacs B. Estrogen replacement therapy reverses Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation changes in intramural coronary resistance arteries caused by female (WISE). Circulation 2004;109:722–725. sex hormone depletion. Cardiovasc Res 2004;61:317–324. 20. Fearon WF, Aarnoudse W, Pijls HJN, De Bruyne B, Balsam LB, 7. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Cooke DT, Robbins RC, Fitzgerald PJ, Yeung AC, Yock P. Micro- Vittinghoff E, for the Heart and Estrogen/progestin Replacement vascular resistance is not influenced by epicardial coronary artery Study (HERS) Research Group. Randomized trial of estrogen plus stenosis severity. Experimental validation. Circulation 2004;109: progestin for secondary prevention of coronary heart disease in post- 2269–2272. menopausal women. JAMA 1998;280:605–613. 8. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky 21. Britten MB, Zeiher AM, Schachinger V. Microvascular dysfunction in M, Hsia J, Hulley S, Herd A, Khan S, et al, for the Heart and angiographically normal or mildly diseased coronary arteries predicts Estrogen/Progestin Replacement Study Follow-up (HERS II) Research adverse cardiovascular long-term outcome. Coron Artery Dis 2004; Group. Cardiovascular disease outcomes during 6.8 years of hormone 15:259–64 therapy. JAMA 2002;288:49–57. 22. Schindler TH, Nitzsche EU, Schelbert HR, Olschewski M, Sayre J, 9. Hulley S, Furberg C, Barrett-Connor E, Cauley J, Grady D, Haskell W, Mix M, Brink I, Zhang XL, Kreissl M, Magosaki N, Just H, Solzbach Knopp R, Lowery M, Satterfield S, Schrott H, Vittinghoff E, Hun- U. Positron emission tomography-measured abnormal responses of ninghake D, for the Heart and Estrogen/Progestin Replacement Study myocardial blood flow to sympathetic stimulation are associated with Follow-up (HERS II) Research Group. Non-cardiovascular disease the risk of developing cardiovascular events. J Am Coll Cardiol 2005; outcomes during 6.8 years of hormone therapy, Heart and Estrogen/ 45:1505–1512. Progestin Replacement Study Follow-up (HERS II). JAMA 2002;288: 23. Duvernoy CS, Rattenhuber J, Seifert-Klauss V, Bengel F, Meyer C, 58–66. Schwaiger M. Myocardial blood flow and flow reserve in response to 10. Writing Group for the Women’s Health Initiative Investigators. Risks short-term cyclical hormone replacement therapy in postmenopausal and benefits of estrogen plus progestin in healthy postmenopausal women. J Gender Specific Med 2001;4:21–27. women, principle results from the Women’s Health Initiative random- 24. Duvernoy C, Martin J, Briesmiester A, Bargardi A, Muzik O, Mosca ized controlled trial. JAMA 2002;288:321–333. L. Myocardial blood flow and flow reserve in response to hormone 11. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, therapy in postmenopausal women with risk factors for coronary Black H, Bonds D, Brunner R, Brzyski R, Caan B, et al, Women’s disease. J Clin Endocrinol Metab 2004;89:2783–2788. Health Initiative Steering Committee. Effects of conjugated equine 25. Campisi R, Nathan L, Pampaloni MH, Schöder H, Sayre JW, estrogen in postmenopausal women with hysterectomy. The Women’s Chaudhuri G, Schelbert HR. Noninvasive assessment of coronary Health Initiative randomized controlled trial. JAMA 2004;291:1701– microcirculatory function in postmenopausal women and effects of 1712. short-term and long-term estrogen administration. Circulation 2002; 12. Adams MR, Register TC, Golden DL, Wagner JD, Williams JK. 105:425–430. Medroxyprogesterone acetate antagonizes inhibitory effect of conju- 26. Wakatsuki A, Okatani Y, Ikenoue N, Fukukaya T. Effect of medroxy- gated equine estrogens on coronary artery atherosclerosis. Arterioscler progesterone acetate on vascular inflammatory markers in postmeno- Thromb Vasc Biol 1997;17:217–221. pausal women receiving estrogen. Circulation 2002;105:1436–1439. 13. Miyagawa K, Rosch J, Stancyk F, Hermsmeyer K. Medroxyproges- 27. Otsuka R, Watanabe H, Hirata K, Tokai K, Muro T, Yoshiama M, terone interferes with ovarian steroid protection against coronary va- Takeuchi K, Yoshikawa J. Acute effects of passive smoking on the sospasm. Nat Med 1997;3:324–327. JAMA 14. Sdringola S, Patel D, Gould L. High prevalence of myocardial perfu- coronary circulation in healthy young adults. 2001;286:436– sion abnormalities on position emission tomography in asymptomatic 441. persons with a parent or sibling with coronary artery disease. Circu- 28. Kaufmann PA, Gnecchi-Ruscone T, Yap JT, Rimoldi O, Camici PG. lation 2001;103:496–501. Assessment of the reproducibility of baseline and hyperemic myocar- 15. Laine H, Raitakari OT, Niinikoski H, Pitkanen OP, Iida H, Viikari J, dial blood flow measurements with 15-O-labeled water and PET. Nuutila P, Knuuti J. Early impairment of coronary flow reserve in J Nucl Med 1999;40:1848–1856. young men with borderline hypertension.J Am Coll Cardiol 1998;32: 29. Johansson BL, Sundell J, Ekberg K, Jonsson C, Seppanen M, Raitakari 147–153. O, Luotolahti M, Nuutila P, Wahren J, Knuuti J. C-Peptide improves 16. Kjaer A, Meyer C, Nielsen FS, Parving H-H, Hesse B. Dipyramidole, adenosine-induced myocardial vasodilation in type 1 diabetes patients. cold pressor test and demonstration of endothelial dysfunction: a PET Am J Physiol Endocrinol Metab 2004;286:E14–E19. study on myocardial perfusion in diabetes. J Nucl Med 2003;44:19– 30. Macdonald JE, Kennedy N, Struthers AD. Effects of spironolactone on 23. endothelial function, vascular angiotensin converting enzyme activity, 17. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclero- and other prognostic markers in patients with mild heart failure already sis. Circulation 2004;109(suppl):SIII27–SIII32. taking optimal treatment. Heart 2004;90:765–770. Size of Coronary Artery in a Myocardial Bridge Compared With Adjacent Nontunneled Left Anterior Descending Coronary Artery

Juying Qian, MDa,b, Feng Zhang, MBsa,b, Hongyi Wu, MBsa,b, Bing Fan, MDa,b, Lei Ge, MDa,b, Yan Lu, MBa, and Junbo Ge, MDa,b,*

Patients with myocardial bridging (MB) may experience myocardial ischemia. Coronary stenting was reported to serve as an effective interventional approach to improve symptoms in selected patients with MB, but is related to high risk of coronary perforation. The aim of this study is to investigate vessel area in the myocardial bridge segment in comparison to that of adjacent segments proximal and distal to MB using intravascular ultrasound. A total of 81 myocardial bridge segments, characterized by a half-moon–shaped echolucent zone surrounding the intramural artery, were found in 78 patients using intravascular ultrasound. The cross-sectional area within the external elastic membrane and minimum and maximum diameters in the myocardial bridge segment and adjacent reference vessel segments were measured. Diastolic cross-sectional area within the external elastic membrane in the myocardial bridge segment was signiﬁcantly smaller than that in adjacent ,segments both proximal and distal to MB (5.48 ؎ 2.59 vs 9.40 ؎ 3.48 and 7.22 ؎ 2.87 mm2 respectively, both p <0.001). Maximum vessel diameter in the myocardial bridge segment during diastole was also smaller than that in the segment distal to MB (2.74 ؎ 0.61 vs 3.12 mm, p <0.001). In conclusion, our study showed that vessel area in the myocardial 0.59 ؎ bridge segment was smaller than that in adjacent segments proximal and distal to MB. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1653–1655)

Myocardial bridging (MB), a congenital coronary abnormality, and the angiographically “milking effect,”26 defined as sys- is defined as a segment of an epicardial coronary artery or its tolic compression and complete or partial release of the major branch, the tunneled artery, that goes intramurally compression in diastole, was seen in left anterior descending through the myocardium beneath the muscle bridge. Patients (LAD) coronary arteries of all patients. with MB may experience myocardial ischemia and acute cor- The IVUS catheter used in this study consisted of an onary syndromes,1–6 cardiac arrhythmias,7–9 and even sudden Ultracross 3.2-Fr or Atlantis 3.0-Fr IVUS imaging catheter death.10–13 For clinically symptomatic patients, many thera- (Boston Scientific Co, Boston, Massachusetts) with a 30- or peutic approaches have been attempted, but the optimal treat- 40-MHz ultrasound transducer inside the catheter. The ment of MB still remains controversial.14,15 Recently, coronary transducer was mechanically rotated within the catheter at stenting was reported to serve as an effective interventional 600 to 800 rpm to provide cross-sectional images through approach to improve symptoms in selected patients.16–21 How- an ultrasound diagnostic imaging console (ClearView or ever, a high risk of coronary perforation during the angioplasty Galaxy2, Boston Scientific). Resolution of the IVUS cathe- procedure was reported.20,22–24 The reason for this phenome- ter was approximately 80 to 100 ␮m axially and 200 to 250 non is not clear. The aim of this study was therefore to use ␮m laterally. The gain setting was adjusted to provide the intravascular ultrasound (IVUS) to investigate whether MB best gray-scale differentiation to obtain optimal morpholog- has some special structural characteristics that may be associ- ical and structure visualization. ated with the high risk of coronary perforation related to Each patient received oral aspirin (300 mg) and clopi- coronary stenting. dogrel (300 mg) on the day before the procedure and intravenous heparin (3,000 U) before catheterization. After the Methods and Results diagnostic coronary angiography, an additional bolus of In the IVUS databases of our institute from August 2002 to heparin (3,000 U) was given intravenously. A 6-Fr or 7-Fr February 2006, a total of 78 patients (60 men; mean age giant lumen guiding catheter was positioned in the ostium of 59 Ϯ 12 years, range 33 to 83) with MB characterized by a the left coronary artery, and a 0.014-inch flexible guidewire half-moon–like echolucent area surrounding the bridging was inserted into the LAD artery. After administration of segment during the entire cardiac cycle25 were identified, intracoronary nitroglycerin (200 ␮g), the imaging catheter was advanced 10 mm distal to the myocardial bridge and the transducer was withdrawn at 0.5 mm/s back to the guiding aDepartment of Cardiology, Zhongshan Hospital, Fudan University; b catheter. The position of the IVUS probe was documented and Shanghai Institute of Cardiovascular Diseases, Shanghai, China. on x-ray film at every stop frame to have a precise match Manuscript received October 27, 2006; revised manuscript received De- cember 21, 2006, and accepted January 10, 2007. between numbered IVUS images and angiograms. An elec- *Corresponding author: Tel.: 86-21-6404-1990 (ext 2745); fax: 86-21- trocardiogram was recorded simultaneously. All imaging 6422-3006. data were recorded continuously on s-VHS videotapes E-mail address: [email protected] (J. Ge). and/or compact disc for off-line analysis.

Figure 1. Coronary angiogram and IVUS imaging of myocardial bridge in the midsegment of the LAD artery. A signiﬁcant milking effect is seen during systole (B) that is released in diastole (A), and a half-moon echolucent zone is seen surrounding the vessel during both systole and diastole (double arrows in F and E). IVUS shows that the vessel area of the bridging segment in diastole (E) and systole (F) is smaller than the proximal reference (C, D) and the distal reference (G, H) segments. The thickness of the half-moon region is illustrated using the white double headed arrow (F). The distance between 2 calibration marks is 1 mm in the IVUS image.

Table 1 ness of the half-moon region was defined as the maximum Demographic data for patients with myocardial bridging (MB) distance between the 2 leading edges of the echolucent zone Variable Values along the line passing through the center of the lumen during systole (Figure 1). Men 60 (77%) Women 18 (23%) All measurements and calculations were analyzed using Age (yrs) 59 Ϯ 12 SPSS 11.5 statistical software (SPSS Inc, Chicago, Illinois). Indication for angiography Categorical data are presented as frequencies and compared Acute myocardial infarction 10 (13%) using chi-square statistics or Fisher’s exact test. Continuous Previous myocardial infarction 5 (6%) variables are presented as mean Ϯ SD and compared using Unstable angina pectoris 17 (22%) unpaired or paired Student’s t test or Mann-Whitney U test. Stable angina pectoris 11 (14%) p Value Ͻ0.05 was considered statistically significant. Atypical angina or others 35 (45%) Indications for diagnostic coronary angiography and Hypertension 45 (58%) Hyperlipidemia 28 (36%) other clinical characteristics of the 78 patients are listed in Diabetes mellitus 7 (9%) Table 1. Atherosclerotic lesions proximal to the myocardial Smoker 33 (42%) bridge were found in 48 (62%) of the 78 patients, and 27 Atherosclerotic lesions (35%) of the 78 patients with significant atherosclerotic Proximal to MB 48 (62%) stenosis were treated with stent implantation. Distal to MB 10 (13%) IVUS was successfully performed in all 78 patients and Stent implantation proximal to myocardial bridge 27 (35%) a total of 81 myocardial bridge segments (3 patients had 2 myocardial bridge segments in the same LAD artery) were IVUS images were reviewed offline by independent observ- detected using IVUS. A specific half-moon–like echolucent ers. Interpretation of IVUS images was based on the American area surrounding the bridging segment was seen in all pa- College of Cardiology clinical expert consensus document on tients in both systole and diastole (Figure 1). Table 2 lists IVUS.27 The bridging segment was determined as the presence IVUS measurements in the myocardial bridge segment and of a specific half-moon–like echolucent area surrounding the adjacent proximal and distal segments. The thickness of the epicardial coronary artery.25 The normal proximal or distal half-moon region was 0.35 Ϯ 0.14 mm (range 0.1 to 0.7). reference segment without half-moon phenomenon or plaque Minimum and maximum of the cross-sectional area within was identified within a distance of 10 mm from the MB site, the external elastic membrane (EEM-CSA) in the myocar- without intervening side branches. Using computerized dial bridge segment were 4.52 Ϯ 2.45 and 5.48 Ϯ 2.59 planimetry, quantitative IVUS analysis was performed at myo- mm2, respectively. The maximum lumen of the myocardial cardial bridge sections and reference segments frame by frame bridge segment was seen in mid-diastole and the minimum during the cardiac cycle in all patients. Quantitative measure- lumen was seen between end-systole and early diastole. ments were made for the vessel area and diameter within the Maximum diastolic EEM-CSA in the myocardial bridge external elastic membrane and half-moon region. The thick- segment was significantly smaller than that in the adjacent Coronary Artery Disease/Vessel Size in Myocardial Bridge 1655

Table 2 Intravascular ultrasound measurement of the segment of myocardial bridging (MD) and adjacent proximal and distal segments Segment MB Proximal Distal p Value Diastole Systole * †

EEM-CSA (mm2) 5.48 Ϯ 2.59 4.52 Ϯ 2.45 9.40 Ϯ 3.48 7.22 Ϯ 2.87 Ͻ0.001 Ͻ0.001 Minimum vessel, diameter (mm) 2.41 Ϯ 0.54 2.13 Ϯ 0.54 3.25 Ϯ 0.60 2.82 Ϯ 0.55 Ͻ0.001 Ͻ0.001 Maximum vessel, diameter (mm) 2.74 Ϯ 0.61 2.51 Ϯ 0.62 3.57 Ϯ 0.63 3.12 Ϯ 0.59 Ͻ0.001 Ͻ0.001

* MB segment in diastole versus segment proximal to MB. † MB segment in diastole versus segment distal to MB. segment proximal to the myocardial bridge and the average 10. Bestetti RB, Costa RS, Kazava DK, Oliveira JS. Can isolated myocardial reference EEM-CSA (defined as average EEM-CSA at the bridging of the left anterior descending coronary artery be associated with Acta Cardiol proximal and distal reference sites, 5.48 Ϯ 2.59 vs 8.31 Ϯ sudden death during exercise? 1991;46:27–30. 2 11. Tio RA, Van Gelder IC, Boonstra PW, Crijns HJ. Myocardial bridging 3.06 mm ,pϽ0.001). More importantly, maximum dia- in a survivor of sudden cardiac near-death: role of intracoronary stolic EEM-CSA in the myocardial bridge segment was Doppler flow measurements and angiography during dobutamine even smaller than that in the adjacent segment distal to the stress in the clinical evaluation. Heart 1997;77:280–282. myocardial bridge. Of 81 myocardial bridges, vessel area in 12. Cutler D, Wallace JM. Myocardial bridging in a young patient with sudden death. Clin Cardiol 1997;20:581–583. the myocardial bridge was smaller than that of the distal 13. Cheng TO. Myocardial bridging in a young patient with sudden death. reference vessel in 72 myocardial bridges (89%) and was Clin Cardiol 1997;20:743. equal to or larger than that of distal reference vessel seg- 14. Alegria JR, Herrmann J, Holmes DR Jr, Lerman A, Rihal CS. Myo- ments in 9 myocardial bridges (11%). Minimum and max- cardial bridging. Eur Heart J 2005;26:1159–1168. 15. Mohlenkamp S, Hort W, Ge J, Erbel R. Update on myocardial bridg- imum vessel diameters in the myocardial bridge segment ing. Circulation 2002;106:2616–2622. during diastole were also smaller than those in the adjacent 16. Stables RH, Knight CJ, McNeill JG, Sigwart U. Coronary stenting in segment distal to the myocardial bridge. the management of myocardial ischemia caused by muscle bridging. Br Heart J 1995;74:90–92. 17. Klues HG, Schwarz ER, vom Dahl J, Reffelmann T, Reul H, Potthast Discussion K, Schmitz C, Minartz J, Krebs W, Hanrath P. Disturbed intracoronary hemodynamics in myocardial bridging: early normalization by intra- In this retrospective IVUS analysis consisting of 78 patients coronary stent placement. Circulation 1997;96:2905–2913. with 81 myocardial bridges, we showed for the first time 18. Haager PK, Schwarz ER, vom Dahl J, Klues HG, Reffelmann T, that the vessel area in the myocardial bridge segment was Hanrath P. Long term angiographic and clinical follow up in patients significantly smaller than that in the adjacent reference with stent implantation for symptomatic myocardial bridging. Heart 2000;84:403–408. segments proximal and distal to the myocardial bridge 19. Kursaklioglu H, Barcin C, Iyisoy A, Kose S, Amasyali B, Isik E. throughout the cardiac cycle in 89% of myocardial bridges Angiographic restenosis after myocardial bridge stenting. Jpn Heart J (72 of 81). This finding might explain the higher rate of 2004;45:581–589. coronary perforation (ϳ10% to 33%) associated with cor- 20. Liu YW, Liu Q, Jin GL, Lou JF, Ai SZ, Wang FS. Stenting for 20,22–24 symptomatic myocardial bridge and its clinical results. Lin Chuang onary stent implantation of myocardial bridges. Xin Xue Guan Bing Za Zhi 2004;20:332–334. 21. Wang NF, Pan H, Tong GX. The evaluation on stent implantation 1. Tauth J, Sullebarger T. Myocardial infarction associated with myocar- efficacy of myocardial bridge and severe atherosclerosis lesions in the dial bridging: case history and review of the literature. Cathet Car- segments proximal to the myocardial bridge. Zhonghua Xin Xue Guan diovasc Diagn 1997;40:364–367. Bing Za Zhi 2005;33:684–486. 2. Arjomand H, AlSalman J, Azain J, Amin D. Myocardial bridging of 22. Broderick TM, Kereiakes DJ, Whang DD, Toltzis RJ, Abbottsmith left circumflex coronary artery associated with acute myocardial in- CW. Myocardial bridging may predispose to coronary perforation farction. J Invasive Cardiol 2000;12:431–434. during rotational atherectomy. J Invasive Cardiol 1996;8:161–163. 3. Akdemir R, Gunduz H, Emiroglu Y, Uyan C. Myocardial bridging as 23. Hering D, Horstkotte D, Schwimmbeck P, Piper C, Bilger J, Schul- a cause of acute myocardial infarction: a case report. BMC Cardiovasc theiss HP. Acute myocardial infarct caused by a muscle bridge of the Disord 2002;2:15. anterior interventricular ramus: complicated course with vascular per- 4. Gowda RM, Khan IA, Ansari AW, Cohen RA. Acute ST segment foration after stent implantation. Z Kardiol 1997;86:630–638. elevation myocardial infarction from myocardial bridging of left an- 24. Berry JF, von Mering GO, Schmalfuss C, Hill JA, Kerensky RA. terior descending coronary artery. Int J Cardiol 2003;90:117–118. Systolic compression of the left anterior descending coronary artery: a 5. Baldassarre S, Unger P, Renard M. Acute myocardial infarction and case series, review of the literature, and therapeutic options including myocardial bridging: a case report. Acta Cardiol 1996;51:461–465. stenting. Cath Cardiovasc Intervent 2002;56:58–63. 6. Mazzu A, Di Tano G, Cogode R, Lo Presti G. Myocardial bridging 25. Ge J, Erbel R, Rupprecht HJ, Koch L, Kearney P, Gorge G, Haude M, involving more than one site of the left anterior descending coronary Meyer J. Comparison of intravascular ultrasound and angiography in the artery: an uncommon cause of acute ischemic syndrome. Cathet Car- assessment of myocardial bridging. Circulation 1994;89:1725–1732. diovasc Diagn 1995;34:329–332. 26. Portmann WC, Iwig J. Die intramurale koronarie im angiogramm. 7. Feld H, Guadanino V, Hollander G, Greengart A, Lichstein E, Shani J. Fortschr Rontgenstr 1960;92:129–132. Exercise-induced ventricular tachycardia in association with a myo- 27. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald cardial bridge. Chest 1991;99:1295–1296. PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American 8. Kracoff OH, Ovsyshcher I, Gueron M. Malignant course of a benign College of Cardiology clinical expert consensus document on stan- anomaly: myocardial bridging. Chest 1987;92:1113–1115. dards for acquisition, measurement and reporting of intravascular 9. den Dulk K, Brugada P, Braat S, Heddle B, Wellens HJ. Myocardial ultrasound studies (IVUS). A report of the American College of bridging as a cause of paroxysmal atrioventricular block. J Am Coll Cardiology Task Force on clinical expert consensus documents. JAm Cardiol 1983;1:965–969. Coll Cardiol 2001;37:1478–1492. Diagnostic Performance of 64-Channel Multislice Computed Tomography in Assessment of Significant Coronary Artery Disease in Symptomatic Subjects Abbas Arjmand Shabestari, MDa,g,*, Seifollah Abdi, MDb,h, Shahram Akhlaghpoor, MDc, Mitra Azadi, MDf,h, Hamidreza Baharjoo, MDg, Mohammad Danesh Pajouh, MDh, Zyae Emami, MDh, Fatemeh Esfahani, MD, MPHe, Iraj Firouzi, MDb,h, Mahmoud Hashemian, MDh, Morad Kouhi, MDh, Mahmoud Mozafari, MDg, Iraj Nazeri, MDd,h, Mahmoud Roshani, MDh, Babak Salevatipour, MDa, Hedayatollah Tavalla, MDh, Mahmoud Tehrai, MDg, and Ali Zarrabi, MDh

The recent development of 64-channel multislice computed tomography (MSCT) has resulted in noninvasive coronary artery imaging improvement. This study was conducted to determine the accuracy of 64-slice MSCT in a relatively unselected group of 143 patients with presentations suggestive of coronary artery disease, including those with unstable angina pectoris, who underwent both coronary computed tomographic angiography and invasive coronary angiography. No arrhythmia was considered an exclusion criterion except for atrial fibrillation or frequent extrasystoles. In patients with fast heart rates, a ␤ blocker was administered orally. Data were obtained using electrocardiography gated 64-slice MSCT. Computed tomographic angiography and invasive coronary angiography findings of each coronary segment were compared to determine the sensitivity, specificity, positive predictive value, and negative predictive value of MSCT in the detection of their normalcy or insignificant (<50% diameter decrease) stenosis versus significant (>50% diameter decrease) stenosis or total occlusion. In per-patient assessment, the calculated sensitivity, specificity, positive predictive value, and negative predictive value of MSCT were 96%, 67%, 91%, and 83%, respectively. These values in per-artery evaluation were 94%, 94%, 87%, and 97%, and corresponding values in per-segment analysis were 92%, 97%, 77%, and 99%, respectively. In conclusion, computed tomographic angiography has high diagnostic performance in the assessment of significant coronary artery disease in most patients in a daily routine practice, including those presenting with unstable angina pectoris symptoms. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1656–1661)

Currently, coronary artery disease (CAD) is the leading tively unselected group of patients, some of whom pre- cause of adult death in many Western countries and is sented with unstable angina pectoris. increasing in incidence in urban regions of Oriental countries.1,2 Catheter-based invasive coronary angiography Methods (ICA) is the standard of reference technique to determine During approximately 7 months from September 2005 to 3,4 the severity of stenotic CAD. However, in recent years, March 2006, a total of 143 consecutive patients who under- multislice computed tomography (MSCT) has gained sub- went both coronary MSCT and ICA in a single institution stantial popularity in the noninvasive assessment of CAD, were studied in a prospective manner. Their assessment mainly because it offers safety, patient convenience, and indications were suspicion for CAD (based on either clinical faster performance.3 Our investigation aim is to determine presentation in the form of stable angina or unstable angina the diagnostic accuracy of 64-slice MSCT in a wider rela- pectoris and/or equivocal exercise tolerance test/myocardial perfusion radionuclide study results in patients presenting with atypical chest pain) or their schedule for coronary artery bypass grafting. Exclusion criteria were history of aDepartment of Radiology, Shahid Beheshti University of Medical previous adverse reaction to contrast media; renal functional Sciences; bDepartment of Cardiology; Rajaie Heart Center; Departments of impairment (serum creatinine Ͼ1.5 mg/dl); previous coro- cRadiology and dCardiology, Tehran University of Medical Sciences; eDe- nary artery bypass graft or percutaneous coronary interven- partment of Research and Development, Shariati Hospital, Tehran Univer- tion, including placement of stent(s); and atrial ﬁbrillation sity of Medical Sciences; fDepartment of Cardiology, Iran University of Ͼ g h or frequent ( 15 extrasystoles/min) extrasystoles. How- Medical Sciences; and Departments of Radiology and Cardiology, Day Ͻ General Hospital, Tehran, Iran. Manuscript received October 1, 2006; ever, no other type of arrhythmia, including 15 extrasys- revised manuscript received and accepted January 11, 2007. toles/min, was regarded as an exclusion criterion. All pa- *Corresponding author: Tel: 0098-912-171-5491; fax: 0098-21-2240- tients gave informed consent. 3694. Patients with a heart rate Ͼ70 beats/min received an oral E-mail address: [email protected] (A.A. Shabestari). dose of metoprolol 100 to 150 mg and chlordiazepoxide

Figure 1. (A to C) Curved maximum intensity projection type of computed tomographic images of the right coronary artery (RCA) in a patient with normal coronary assessment results shows ordinarily patent artery.

5 mg approximately 45 to 60 minutes before scanning. If graphic tracing of patients. First, noncontrast electrocardi- there was a contraindication for ␤ blockers or the slower ography gated scanning for calcium score determination heart rate was unsatisfactory, the scanning procedure was was carried out. Thereafter, in the coronary computed to- performed with faster heart rates to assess the effects of mographic angiography phase, a bolus of nonionic contrast limited ␤-blocker use. No intravenous ␤ blocker was used medium (Visipaque 320 mgI/ml, Amersham Health, Cork, because of its regional unavailability. Furthermore, all pa- Ireland) was injected through an 18-G intravenous line into tients received glyceryl trinitrate (nitroglycerin) 0.8 mg sub- the antecubital vein, followed by a bolus of saline solution lingually just before the start of the scan. chaser. Approximately 80 to 100 ml of contrast medium, Scanning was performed using a 64-slice MSCT scanner according to the patient’s body weight, was injected at a rate (Somatom Sensation 64, Siemens Medical Solutions, Forch- of 5 ml/s, followed by 50 ml of saline solution chaser heim, Germany) associated with synchronous electrocardio- through a dual-head injector. Before that, we used a test 1658 The American Journal of Cardiology (www.AJConline.org)

Figure 2. (A) Subtotal occlusion of the left circumflex (LCx) artery on maximum intensity projection view of computed tomographic angiography. (B, C) Volume-rendered image of this patient and corresponding invasive coronary angiographic view, respectively. Both show subtotal occlusion of the LCx artery (single long arrow), significant stenosis of the proximal left anterior descending artery (short arrow), and insignificant stenoses of the middle left anterior descending artery (arrowhead) and its large diagonal branch (double long arrows). (D, E) Maximum intensity projection view of computed tomographic angiography and corresponding invasive coronary angiographic view both show insignificant stenosis of the middle segment of the right coronary artery (arrow) just beyond the takeoff site of its right ventricular branch. Coronary Artery Disease/MSCT Diagnosis of Coronary Stenosis 1659 bolus technique, injecting 10 to 15 ml of the same contrast Table 1 agent, and afterward, 40 ml of saline solution chaser, to Patient characteristics (n ϭ 143) determine the contrast medium transit time of individual Mean age (yrs) 63 Ϯ 10 patients. Computed tomographic angiography parameters Men 103 (72%) were collimation width 64 ϫ 0.6 mm, tube potential 120 Stable angina pectoris 71 (50%) kV, tube effective current 650 to 850 mA, tube rotation time Acute coronary syndrome 26 (18%) 330 ms, table feed 3.8 mm/rotation, temporal resolution 83 to Atypical chest pain 17 (12%) 165 ms (based on whether adaptive cardiovolume mode was Hypertension 109 (76%) active, this system allows selection of a bisector or monosector Diabetes mellitus 61 (43%) Smoker 67 (47%) reconstruction algorithm according to changes in heart rate), Hypercholesterolemia (serum low-density lipoprotein 81 (57%) scanning time 8 to 13 seconds in an inspiratory breath hold, cholesterol Ͼ130 mg/dl) and scan field from tracheal carina to the diaphragm. Positive family history of myocardial infarction 49 (34%) Source image data sets were loaded to reconstruct axial, ICA findings coronal, sagittal, and oblique multiplanar reconstruction; Normal 35 (25%) thin-slab maximum intensity projection; or curved recon- 1-vessel disease 59 (41%) structions and volume-rendered images on an on-line work- 2-vessel disease 38 (27%) station (Wizard, Siemens Medical Solutions, Erlangen, 3-vessel disease 9 (6%) Germany). Selected thickness of multiplanar reconstructed 3-vessel disease ϩ left main coronary artery stenosis 2 (1%) views was 0.6 mm with 0.4-mm intervals, and maximum Calcium score (Agatston units) 0–100 90 (63%) intensity projection image thickness was either 5 or 6 mm. 101–400 29 (20%) We used different retrospective electrocardiography gated 401–1,213 24 (17%) reconstruction temporal window settings at 28% to 73% of the electrocardiography peak of consecutive R waves (RR Values shown as mean Ϯ SD or number (percent). interval). The position of the reconstruction temporal window within the cardiac cycle was individually optimized to ICA in all patients was performed by experienced cardi- diminish motion artifacts. Most reconstructions were best ologists using a transfemoral approach. Standard projec- achieved in mid- to end-diastole from 60% to 70% of RR tions of ICA were obtained, and the mean diameter decrease intervals. Coronary calcium score was calculated for terri- caused by coronary lesions was determined in Ն2 orthog- tory of major coronary arteries and expressed as Agatston onal projections in a quantitative manner. The same 17- equivalent units using a dedicated Calcium Score module of segment American Heart Association nomenclature was ap- Syngo software (Siemens Medical Solutions, Erlangen, plied.6 Coronary segments distal to total occlusions were 5 Germany). No subject was excluded from the study be- nonassessable and hence not analyzable. Patients who had cause of a high calcium score. no significant stenosis in any coronary segment but had Ն1 Interpretation of computed tomographic angiography im- nonassessable segment(s) according to either computed to- ages of each patient was made by consensus of 2 experi- mographic angiography or ICA were excluded from per- enced observers, 1 radiologist and a cardiologist, who were patient analysis. unaware of the patient’s ICA results. A 17-segment modified Quantitative variables were expressed as mean Ϯ SD, American Heart Association model of coronary artery nomen- and discrete variables were presented as counts and percent- clature was used to assign major coronary arteries, including ages. All analyses were conducted using SPSS (version the left main coronary, left anterior descending, left circumflex, 11.5, SPSS Inc., Chicago, Illinois) for Windows. ICA was 6 and right coronary arteries, as well as their branches. Mini- considered the standard of reference, and descriptive statis- mum vessel diameter of assessable arteries was 1.5 mm. tics including sensitivity, specificity; positive predictive First, it was decided whether segments were assessable value (PPV), and negative predictive value (NPV) of MSCT or nonassessable. Evaluating reconstructed images of as- in determining the presence or exclusion of significant cor- sessable segments along multiple longitudinal and trans- onary artery stenosis were calculated using chi-square tests verse axes of coronary arteries, the severity of coronary of contingency. Calculations were determined in per-seg- ϭ ϭ artery stenosis was graded as a normal (no stenosis), b ment, per-artery, and per-patient bases. insignificant stenosis (Ͻ50% diameter decrease stenosis), ϭ c significant stenosis (maximal luminal diameter decrease Results stenosis Ն50%), and d ϭ total occlusion (no luminal flow shown). Negative results were considered either normal A total of 143 patients were enrolled during the study findings (Figure 1) or the presence of insignificant stenoses, period. Patient characteristics are listed in Table 1. The and positive results were regarded as Ն50% diameter de- average interval between computed tomographic angiogra- crease in stenoses (Figure 2), including total occlusion. phy and ICA was 11 Ϯ 8 days. A total of 127 individuals Applied stenosis severity criteria for MSCT and ICA were (89%) received ␤ blockers to decrease their heart rate from similar. If there were multiple lesions in a given segment, 83 Ϯ 11 beats/min to a lower rate. While scanning, median the worst stenosis was considered to classify that segment. heart rate was 65 beats/min (range 47 to 83). Heart rate was In the case of multiple stenotic segments per artery, the Ͼ70 beats/min in 17 patients (12%) and Ͻ65 beats/min in vessel was classified according to the worst segment. When 99 patients. Twenty-four patients were required to have there was Ն1 stenosis Ն50%, the result was considered manual rejection of Ն1 extrasystolic beat when reconstruct- positive for the presence of significantly stenotic CAD. ing images for further analysis. The range of spent time for 1660 The American Journal of Cardiology (www.AJConline.org)

Table 2 Diagnostic accuracy of coronary computed tomographic angiography compared with invasive coronary angiography for detection of lesions with Ն50% diameter decrease stenosis in assessed patients Sensitivity Speciﬁcity PPV NPV Patients (n ϭ 138) 104/108 (96%) 20/30 (67%) 104/114 (91%) 20/24 (83) (95% CI 91–99) (95% CI 47–83) (95% CI 84–96) (95% CI 63–95) Arteries (n ϭ 555) 160/170 (94%) 360/385 (94%) 160/185 (86) 360/370 (97) Arteries (n ϭ 555) (95% CI 89–97) (95% CI 91–96) (95% CI 81–91) (95% CI 95–99) Segments (n ϭ 2,224) 208/226 (92%) 1936/1998 (97) 208/270 (77) 1936/1954 (99) Segments (n ϭ 2,224) (95% CI 88–95) (95% CI 96–98) (95% CI 72–82) (95% CI 98–99)

Values expressed as number (percent). CI ϭ conﬁdence interval.

Table 3 these segments, 81 were not visualized on ICA and/or com- Stratification of coronary segments (n ϭ 2,224) based on stenosis puted tomographic angiography (77 and 27 segments, re- severity findings in computed tomographic angiography and invasive spectively; 23 joint segments, likely implying their congen- coronary angiography (ICA) ital absence, as a developmental variation). Consequently, Computed ICA Findings 2,224 segments comprised the study population for evalu- Tomographic ation of the accuracy of MSCT for CAD detection in per- Angiography Normal* Nonsignificant Significant Total † ‡ segment analysis. Findings Stenosis Stenosis Occlusion On a per-segment basis, MSCT had 96% accuracy in the Normal* 1,696 19 2 2 detection of the presence or absence of significant coronary Nonsignificant 29 192 13 1 disease. Table 2 lists diagnostic sensitivities, specificities, stenosis† PPVs, and NPVs of computed tomographic angiography in Significant stenosis‡ 5 54 164 6 per-patient, per-artery, and per-segment analyses, as well as Total occlusion 2 1 4 34 their 95% confidence intervals. As listed in Table 3, exact Values expressed as number of segments. agreement between MSCT and ICA was 94% (2,036 of * Normal indicates no luminal stenosis. 2,224 segments). Overall, 43 lesions (2%) were underesti- † Non significant stenosis indicates 1% to 49% luminal diameter decrease. mated using MSCT, 20 of which were reported as a normal ‡ Significant stenosis indicates 50% to 99% luminal diameter decrease. segment. Ninety-five segments (4%) were overestimated using MSCT (36 segments incorrectly graded as stenotic reconstruction and analysis of images was 15 to 45 minutes and present lesion overestimated in 59 segments). Of 9 total per patient. occlusions missed using MSCT, 7 were detected but under- In a patient-based analysis, 5 patients (3.5%) were ex- estimated, and 2 were reported as normal. Using ICA, the cluded from analysis because they had 1 or 2 nonassessable most frequent CAD involvement (either significant or in- segments on ICA in addition to entirely normal segments. significant) was seen in the left anterior descending artery One similarly behaved on MSCT. ICA showed that 108 of proximal segment (54%), whereas the least frequently in- 138 patients had significant coronary artery stenosis, 35% volved segment was the posterior left ventricular artery (5%). (38 of 108) with complete vessel occlusions. Thus, the The accuracy of computed tomographic angiography for prevalence of significant CAD was 76%. MSCT correctly detecting significant stenosis was also examined according to detected significant stenosis in 104 of 108 patients for an coronary artery calcium score (based on equivalent Agatston overall sensitivity per patient of 96%. According to ICA, 30 units). A significant proportion of patients had calcium scores individuals lacked significant stenosis (either entirely nor- Ͻ100 Agatston units (63%). In patients with a low (0 to 100 mal or showing only insignificant stenosis), 20 with results Agatston units) calcium score, sensitivity was 94%, specificity correctly diagnosed as negative using MSCT, yielding a was 64%, PPV was 93%, and NPV was 69%. These figures specificity of 67%, and 10 with results falsely diagnosed as were 100%, 83%, 96%, and 100% in the presence of moderate positive. Accuracy of the presence or absence of significant calcification (Ͼ100 to 400 Agatston units), respectively. When coronary disease was 90% (124 of 138). Based on artery calcium score was high (Ͼ400 to 1,213 Agatston units), sen- analysis, 17 of 572 arteries (3%) were reported as nonas- sitivity was 100%, specificity was 60% (6 of 10), and PPV and sessable using ICA. Nine were also nonassessable on NPV were 76.5% and 100%, respectively. MSCT. The left circumflex artery was the most frequently nonassessable artery using both methods (including 13 re- Discussion ports in ICA and 8 in MSCT). Of 170 arteries that had significant stenosis on ICA, 160 were correctly detected The first published report considering the diagnostic accu- using MSCT. Also, MSCT was truly negative in 360 of 385 racy of 64-slice computed tomographic angiography by arteries that had no significant stenosis on ICA. These val- Leschka et al7 showed sensitivity, specificity, PPV, and ues corresponded to accuracy of 94% in assessable arteries. NPV of 94%, 97%, 87%, and 99%, respectively. These Seventeen subjects had the ramus intermedius (interme- findings were obtained using a tube rotation time of 370 ms. diate branch) artery as a developmental variant; thus, in Therefore, the temporal resolution of further investigations, total, our patients had 2,305 coronary artery segments. Of including ours, is better than in their study because of Coronary Artery Disease/MSCT Diagnosis of Coronary Stenosis 1661 decreased tube rotation time to 330 ms. These values were Thus, additional MSCT evaluation remains to be carried out reported as 86% to 100%, 92% to 97%, 56% to 97%, and using a higher sample size. Another issue of concern is the 98% to 100% in additional published studies8–11 and were radiation dose of 64-slice MSCT, estimated to be more than measured as 92%, 97%, 77%, and 99% in our investigation that of previous generations of MSCT in the study of Hausle- when considering coronary artery segment-by-segment iter et al.14 Some methods are used to decrease the patient analysis, in that order. radiation dose, including use of an electrocardiography pulsing To the best of our knowledge, our report is the first such (tube current modulation) technique. Nevertheless, because of study in the Western Asia region and in some aspects is the likelihood of the requirement to apply different phases of consistent with studies of others worldwide. Nonetheless, the cardiac cycle for image reconstructions, this method was there are some differences. First, unlike previous evalua- not used in our patients. The third limitation of our study was tions, we assessed a population with relatively limited ex- semiquantitative estimation of stenosis severity using MSCT. clusion criteria; hence, the mentioned descriptive statistics However, one should bear in mind that quantitative measure- may imply that diagnostic accuracy of 64-slice MSCT is ments may not be able to be done in many segments, for acceptable in a daily routine practice. We selected a larger example, Raff et al8 showed that 17% of lesions could not be sample size in comparison to others to increase the external quantitatively analyzed in their studied subjects. validity and precision of our results weighed against previous studies, which showed relatively similar outcomes. Further- 1. American Heart Association. Heart Disease and Stroke Statistics— more, we included some patients with unstable angina pectoris 2005 Update. Dallas, Texas: American Heart Association, 2005;4–11. symptoms and our results suggest that in patients with unstable 2. Azizi F, Etemadi A, Salehi P, Zahedi-Asl M. Prevalence of metabolic angina pectoris presentation, computed tomographic angiogra- syndrome in an urban region: Tehran Lipid and Glucose Study. Dia- phy using 64-slice MSCT might be used to differentiate cor- betes Res Clin Pract 2003;61:29–37. 3. Bax JJ, Schuijf JD. Which role for multislice computed tomography in onary sources from other causes that may result in chest pain. clinical cardiology? Am Heart J 2005;149:960–961. Twenty-seven coronary artery segments (1.2%) in our 4. Achenbach S, Daniel WG. Computed tomography of the coronary evaluated patients were nonassessable using MSCT, and arteries: more than meets the (angiographic) eye. J Am Coll Cardiol only 4 were found to be normal using ICA. However, 77 2005;46:155–157. segments were nonassessable using ICA (3%). The percent- 5. Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast age of nonassessable segments in our patients (1.2% of all computed tomography. J Am Coll Cardiol 1990;15:827–832. 12 segments) is similar to that of Schuijf et al, calculated to 6. Austen WJ, Edwards JE, Frye RL, Gensini GG, Gott VL, Griffith LS, be 1.4%, but less than some other previously published McGoon DC, Murphy ML, Roe BB. A reporting system on patients reports in the range of 4% to 12%.8,11 However, Leschka evaluated or coronary artery disease: report of the AdHoc Committee et al7 and Leber et al9 had no unassessable segments in their for Grading of Coronary Artery Disease, Council on Cardiovascular multislice computed tomographic coronary assessment. Al- Surgery, American Heart Association. Circulation 1975;51:5–40. 7. Leschka S, Alkadhi H, Plass A, Desbiolles L, Grünenfelder J, Marincek though there was a limitation of assessed artery caliber B, Wildermuth S. Accuracy of MSCT coronary angiography with 64-slice down to 1.5 mm in the study of Leschka et al,7 no artery was technology: first experience. Eur Heart J 2005;26:1482–1487. excluded because of its small diameter in the investigation 8. Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic ac- of Leber et al.9 Ropers et al11 reported that 4% of their 84 curacy of noninvasive coronary angiography using 64-slice spiral patients had nonassessable coronary artery segments. The computed tomography. J Am Coll Cardiol 2005;46:552–557. 9. Leber AW, Knez A, von Ziegler F, Becker A, Nikolaou K, Paul S, difference of this percentage from ours may be partially Wintersperger B, Reiser M, Becker CR, Steinbeck G, Boekstegers P. assigned to a 0.75-mm slice thickness and 0.5-mm interval Quantification of obstructive and nonobstructive coronary lesions by in their image reconstruction technique, whereas we con- 64-slice computed tomography. J Am Coll Cardiol 2005;46:147–154. stantly applied 0.6 and 0.4 mm, respectively. Therefore, 10. Mollet NR, Cademartiri F, van Mieghem CAG, Runza G, McFadden providing better spatial resolution may have an imperative EP, Baks T, Serruys PW, Krestin GP, de Feyter PJ. High-resolution 13 spiral computed tomography coronary angiography in patients referred role in decreasing partial volume artifacts. Ehara et al for diagnostic conventional coronary angiography. Circulation 2005; recently reported 8% nonavailability of segments using 112:2318–2323. computed tomographic angiography of their 69 unselected 11. Ropers D, Rixe J, Anders K, Küttner A, Baum U, Bautz W, Daniel patients, which is remarkably higher than ours. This may be WG, Achenbach S. Usefulness of multidetector row spiral computed partially attributable to their patients’ wider range of and tomography with 64 ϫ 0.6-mm collimation and 330-ms rotation for the noninvasive detection of significant coronary artery stenoses. Am J faster heart rates (51 to 115 vs 47 to 83 beats/min). More- Cardiol 2006;97:343–348. over, only a limited number of their patients received nitro- 12. Schuijf JD, Pundziute G, Jukema W, Lamb HJ, van der Hoeven BL, de glycerin before scanning, which may have a noteworthy role Roos A, van der Wall EE, Bax JJ. Diagnostic accuracy of 64-slice in their lower coronary artery vasodilatation than that of our multislice computed tomography in the noninvasive evaluation of subjects, who persistently received it. significant coronary artery disease. Am J Cardiol 2006;98:145–148. One of major drawbacks of our study was a patient 13. Ehara M, Surmely JF, Kawai M, Katoh O, Matsubara T, Terashima M, Tsuchikane E, Kinoshita Y, Suzuki T, Ito T, et al. Diagnostic accuracy selection bias resultant from the reality that most of our of 64-slice computed tomography for detecting angiographically sig- patients were scheduled for ICA. More prevalent CAD in nificant coronary artery stenosis in an unselected consecutive patient these patients than in the general population may result in population—comparison with conventional invasive angiography. overestimation of the diagnostic accuracy of coronary com- Circ J 2006;70:564–571. puted tomographic angiography. Moreover, despite inclu- 14. Hausleiter J, Meyer T, Hadamitzky M, Huber E, Zankl M, Martinoff S, Kastrati A, Schomig A. Radiation dose estimates from cardiac sion of patients with unstable angina pectoris symptoms in multislice computed tomography in daily practice: impact of different this investigation, they were not assessed in a distinct setting scanning protocols on effective dose estimates. Circulation 2006;113: because of their relatively confined number (26 patients). 1305–1310. Yield of Early Rest and Stress Myocardial Perfusion Single-Photon Emission Computed Tomography and Electrocardiographic Exercise Test in Patients With Atypical Chest Pain, Nondiagnostic Electrocardiogram, and Negative Biochemical Markers in the Emergency Department

Jaume Candell-Riera, MD, PhDa,*, Guillermo Oller-Martínez, MD, PhDa, Gustavo de León, MDa, Joan Castell-Conesa, MD, PhDb, and Santiago Aguadé-Bruix, MDb

There are no studies in which diagnostic yield of early rest myocardial perfusion gated single-photon emission computed tomography (SPECT), electrocardiographic exercise testing, and stress SPECT were compared in patients with atypical chest pain, nondiagnostic electrocardiograms (ECGs), and negative markers of myocardial damage in the emergency department. A prospective study of 96 patients who presented with atypical chest pain and nondiagnostic ECG, but without elevated markers of necrosis, was performed. All underwent rest gated SPECT using technetium-99m methoxyisobutyl isonitrile within 6 hours after pain subsided followed by an electrocardiographic exercise test to obtain stress–rest SPECT images. After 1 year, there were no deaths and coronary artery disease was conﬁrmed in only 5 patients. Negative predictive values of the 3 techniques were high (99%, 96%, and 100%, respectively), but positive predictive values were low (27%, 22%, and 14%, respectively). Sensitivities of early SPECT (80%) and stress SPECT (100%) were higher than for the electrocardiographic exercise test (40%). In conclusion, in patients with atypical chest pain, nondiagnostic ECG, and negative biochemical markers, negative predictive values of the 3 tests analyzed are very high. The sensitivity of radionuclide tests is higher, but their widespread use does not appear warranted because their positive predictive value and incidence of complications is low. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1662–1666)

Sensitivity and negative predictive value of early rest myo- compared in a single patient group. The present study ana- cardial perfusion single-photon emission computed tomog- lyzes the value of early rest myocardial perfusion gated raphy (SPECT) with technetium-based compounds1–4 for SPECT, exercise testing, and stress gated SPECT in patients the diagnosis of acute myocardial infarction are close to with chest pain and nondiagnostic electrocardiogram (ECG) 100%. Owing to the pharmacokinetic and physical charac- and without elevated biochemical markers of necrosis. teristics of technetium-based agents, scintigraphic images can be obtained up to 6 hours after their administration, Methods showing myocardial perfusion at the time of injection. One hundred eleven patients with no history of ischemic However, because most hospitals are not equipped to per- heart disease who presented to the emergency department form early rest myocardial perfusion gated SPECT on a with chest pain that did not meet criteria for typical angina, 24-hour basis, the use of electrocardiographic exercise test- determined using a previously established questionnaire,10 ing5–7 or stress SPECT imaging8,9 when biochemical mark- and a nondiagnostic ECG (with no ST-segment elevation or ers of myocardial injury proved negative could be contem- depression Ն0.5 mm) were included consecutively at a rate plated. Nevertheless, there are no studies in which of 1 patient per day during working hours of the Nuclear diagnostic and prognostic yield of the 3 techniques were Medicine Department (from 8 A.M.to8P.M.). Fifteen of these patients had positive markers for myocardial necrosis (creatine kinase-MB Ͼ5 ␮g/L and troponin I Ͼ0.5 ␮g/L) aServei de Cardiologia and bServei de Medicina Nuclear, Hospital during an 8-hour observation period and were finally not Universitari Vall d’Hebron, Barcelona, Spain. Manuscript received Sep- included. Thus, 96 patients (average age 61 Ϯ 13 years, tember 27, 2006; revised manuscript received and accepted January 17, 49% women) were finally included in the study. 2007. Patients underwent gated SPECT with technetium-99m This study was supported by a grant from the “Redes temáticas de investigación cooperativa, Instituto Carlos III (Red C03/01, RECAVA)”, methoxy-isobutyl-isonitrile (MIBI) in which the tracer was Madrid, Spain. injected during the pain episode or within the first 6 hours *Corresponding author: Tel.: 93-274-6100 (ext 6681); fax: 93-274- after this episode, in addition to receiving standard emer- 6063. gency department management (electrocardiographic and E-mail address: [email protected] (J. Candell-Riera). serial determinations of biochemical markers of myocardial

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.01.048 Coronary Artery Disease/Atypical Chest Pain in Emergency Department 1663 injury at 0, 4, and 8 hours after arrival at the emergency Table 1 department). The day after their admission to the emergency Clinical and electrocardiographic characteristics of patients (n ϭ 96) department and Ն12 hours after pain had subsided, they Variables underwent a symptom-limited exercise test (plus concomi- Ϯ tant dipyridamole if exercise was insufficient) with injection Age (yrs) 60.4 12.4 Women 44 (46%) of the same technetium-based agent and stress/rest SPECT Diabetes mellitus 16 (17%) imaging. This prospective study was approved by the Hos- Hypertension 47 (49%) pital Ethics Committee, and informed consent was given by Smoker 45 (47%) all patients. Cholesterol Ͼ6 mmol/L 35 (36%) All patients were given an intravenous dose of 900 MBq Risk factors (25 mCi) of technetium-99m MIBI during the pain episode 0 12 (12.5%) or within 6 hours after pain had subsided, and imaging was 1 36 (37.5%) performed 1 to 3 hours later, with the patient clinically 2 35 (36.5%) stable. Tomographic imaging was performed using a Sie- 3 13 (13.5%) Ϯ mens (Hoffman States, Illinois) E-CAM dual-head 90° Heart rate (beats/min) 78 15 Systolic blood pressure (mm Hg) 143 Ϯ 21 gamma camera with high-resolution collimators and 180° Pain semicircular orbit, initiated at 45° right anterior oblique Duration (hrs) 6.1 Ϯ 12 with 1 step per 3° (25-second time frame), synchronized Retrosternal 87 (91%) with the electrocardiographic R wave. Frames were recon- Radiating 65 (68%) structed using a Butterworth filter (order 5, cutoff 0.5), and Autonomic symptoms 30 (31%) short-axis, horizontal long-axis, and vertical long-axis slices Increased with exercise 18 (19%) were obtained in accordance with current recommenda- ECG tions.11 Normal 63 (66%) The left ventricle was divided into 17 segments,12 each Atrial fibrillation 4 (4%) assessed by 3 experts, and scored as 0 (normal), 1 (mild Negative T wave 11 (12%) Flat T waves 2 (2%) defect), 2 (moderate defect), 3 (severe defect), or 4 (no Left anterior hemiblock 10 (10%) uptake). Myocardial perfusion SPECT results were consid- Right bundle block 2 (2%) ered positive when uptake scores of grade 2, 3, or 4 were observed in Ն2 segments. Gated SPECT was used to assess ventricular volumes netium-99m MIBI followed by imaging an hour later, using and left ventricular ejection fraction using the method of the same acquisition and processing methods. Positive study 13 Germano et al, and in each left ventricular segment, wall results were those with an uptake score of grade 2, 3, or 4 motion and thickening were assessed and scored as wall during exercise in Ն2 segments that became normal at rest. motion (0 ϭ normal, 1 ϭ mildly impaired, 2 ϭ moderately ϭ ϭ Sensitivity, specificity, and positive and negative predic- impaired, 3 severely impaired, and 4 dyskinesia) and tive values and diagnostic accuracy were calculated with thickening (0 ϭ normal, 1 ϭ mildly impaired, 2 ϭ moder- ϭ ϭ their respective confidence intervals for each of the 3 meth- ately impaired, 3 severely impaired, and 4 no wall ods of early rest myocardial perfusion SPECT, exercise test, thickening). Gated SPECT results were considered positive and stress SPECT. True-positive results were considered to when wall motion or thickening scores were grade 2, 3, or Ն be in patients with coronary artery disease detected using 4in 2 segments. angiography or those who developed complications during Within the first 48 hours after early rest SPECT, a symp- 1 year of follow-up. All patients were contacted by tele- tom-limited treadmill test was performed (Bruce protocol) phone at the end of 1 year. ␬ statistics were calculated to until the appearance of angina, dyspnea, muscle fatigue, or Ն determine interobserver agreement among the 3 observers ST-segment depression 2 mm with respect to baseline at who assessed early rest gated SPECT and stress gated 0.08 seconds after the J-point. For patients in whom testing 16 Ͻ Ͻ SPECT. Chi-square test was used to compare the associ- was insufficient (maximum heart rate 80% and 5 esti- ation between categorical variables, and Student’s t test was mated METS with ST-segment depression and no symp- ␮ used for continuous variables with and without positive toms), a dipyridamole infusion of 0.16 g/kg/min was given results for each test. Statistical significance was set at 5%. for 4 minutes during exercise testing.14,15 Electrocardio- graphic exercise testing was considered positive when the Results patient had angina during the test and/or horizontal or downsloping depression of the ST segment Ն1 mm with Clinical and electrocardiographic results for the patients respect to baseline at 0.08 seconds beyond the J-point. studied are listed in Table 1. No patient was using acetyl- A longer (2-day) protocol was used for this study. On the salicylic acid at the time of inclusion in the study. Patients first day, 30 to 60 seconds before completion of exercise, an spent an average of 13 Ϯ 7 hours in the emergency depart- intravenous dose of 900 MBq (25 mCi) of technetium-99m ment, and 14 were admitted by the physician in charge MIBI was administered, and about an hour later, scinti- (Table 2). Six patients underwent catheterization, and in the graphic imaging was performed. Acquisition and processing 2 patients with coronary artery disease, SPECT at rest and procedures were identical to those used in the rest study stress SPECT results were positive, whereas electrocardio- after pain. On the second day, a rest study was done with graphic exercise testing was negative. One patient (patient another intravenous infusion of 900 MBq (25 mCi) of tech- 67) underwent percutaneous revascularization. In the 4 pa- 1664 The American Journal of Cardiology (www.AJConline.org)

Table 2 Results of noninvasive tests and coronary angiography of admitted patients Patient No. Early-Rest SPECT Exercise Test Exercise SPECT Coronary Angiography 13 ϪϪϪ 17 ϩ (anterior) Ϫϩ(anterior) Normal 18 ϪϪϪ 25 ϪϪϪ Normal 26 ϪϪϪ Normal 29 ϪϪϩ(inferolateral) 30 ϪϪϩ(inferolateral) Normal 37 ϪϪϪ 40 ϩ (inferolateral) ϩϩ(inferolateral) 47 ϩ (inferolateral) Ϫϩ(inferolateral) Right 50% 52 ϩ (inferolateral) Ϫϩ(inferolateral) 67 ϩ (inferolateral) Ϫϩ(inferolateral) LAD 70%, Right 100% 70 ϩ (inferolateral) ϩϩ(inferolateral) 106 ϩ (inferolateral) ϩϩ(inferolateral)

LAD ϭ left anterior descending; ϩϭpositive; Ϫϭnegative.

Table 3 Results of noninvasive tests and coronary angiography of readmitted patients during ﬁrst year of follow-up n Early-Rest SPECT Exercise Test Exercise SPECT Coronary Angiography 37 ϪϪϪ Normal 40 ϩ (inferolateral) ϩϩ(inferolateral) LM 70%, LAD 70%, LCx 95% 55 ϩ (inferolateral) ϩϩ(inferolateral) 60 ϪϪϩ(inferolateral) LCx 50% 61 ϪϪϪ Normal 71 ϪϪϪ Normal

LCx ϭ left circumflex; other abbreviations as in Table 2. tients with a normal coronary angiogram, exercise testing ening) detected abnormalities in only 8 of 16 patients with was negative. positive myocardial perfusion SPECT results. No patient During the first year of follow-up, there were no deaths with negative early myocardial perfusion SPECT results and only 1 patient had an acute inferior myocardial infarc- showed changes in wall motion or thickening on gated tion (patient 55). Six patients returned to the emergency SPECT. department and were admitted (Table 3; 2 patients had Peak heart rate achieved was 142 Ϯ 22 beats/min (from already been admitted during the first episode of chest pain), 85 to 195 beats/min), or 89 Ϯ 12% of theoretical heart rate and only 1 was found to have coronary artery disease. One (from 55% to 115%). Peak systolic pressure was 187 Ϯ 22 patient (patient 40) underwent surgical revascularization. mm Hg (130 to 240 mm Hg). Peak oxygen consumption Five of the 6 patients underwent coronary angiography, was 9.4 Ϯ 3 METs (4 to 15 METs). Five patients were which had negative results in 3 patients for whom other being treated with ␤ blockers and 2 patients, with calcium noninvasive test results were also negative. To summarize, antagonists when they did the tests. In 6 patients, dipyrid- only 5 patients (5.2%) were found to have coronary artery amole was administered during stress testing when the latter disease during follow-up. proved insufficient. Early rest gated SPECT was positive in 16 patients (9 In 10 patients, test results were clinically or electrocar- patients, inferolateral; 7 patients, anterior location). Inter- diographically positive. Five patients had angina and ST- observer agreement among the 3 observers for their impres- segment depression Ն1 mm during the test, 4 patients had sion of rest gated SPECT with ␬ statistics was good (0.626). only ST-segment depression, and 1 patient had only angina. Rest gated SPECT results were positive in 8 of 42 patients Eight of 10 positive test results coincided with positive in whom radiotracer was injected during the pain episode stress SPECT results. Although specificity (92%) and neg- (19%), a result not significantly different from that of pa- ative predictive value (96%) were good, sensitivity (40%) tients with radiotracer injected after pain subsided (8 of 54 and positive predictive value (22%) were poor (Table 4). patients, 15%). Sensitivity, specificity, and negative predic- Stress SPECT results were positive in 35 patients (21 tive values of the early rest gated SPECT were high (80%, patients, inferolateral; 14 patients, anterior location). ␬ Sta- 88%, and 99%, respectively), but positive predictive value tistics for interobserver agreement for impression of stress was low (27%; Table 4). SPECT was better than for early rest SPECT (0.709). Left ventricular ejection fraction (66 Ϯ 8%), end-dia- Twelve of 15 patients (80%) with positive early rest SPECT stolic volume (72 Ϯ 25 ml), and end-systolic volume (6 Ϯ results had positive stress SPECT results, whereas only 13 14 ml) calculated using gated SPECT were normal in all of 81 patients (16%) with negative early rest SPECT results patients. Early gated SPECT (for wall motion and/or thick- did (p Ͻ0.0001). Location of the reversible defect in stress Coronary Artery Disease/Atypical Chest Pain in Emergency Department 1665

Table 4 Diagnostic accuracy of early-rest and exercise single-photon emission computed tomography (SPECT) and exercise test Variable Early SPECT (95% CI) Exercise Test (95% CI) Exercise SPECT (95% CI) True positive 4 2 5 True negative 80 84 61 False positive 11 7 30 False negative 1 3 0 Sensitivity (%) 80 (28–99) 40 (5–85) 100 (48–100) Speciﬁcity (%) 88 (79–94) 92 (85–97) 67 (56–76) Positive predictive value (%) 27 (8–55) 22 (3–60) 14 (5–30) Negative predictive value (%) 99 (93–99.9) 96 (90–99) 100 (94–100) Diagnostic accuracy (%) 87 (79–93) 90 (82–95) 69 (58–78)

CI ϭ conﬁdence interval.

SPECT was coincident in every patient with the location of adopted by many centers because together with clinical the defect in SPECT at rest. Sensitivity and predictive val- criteria, it permits acceptable risk stratification.21–24 Ap- ues of the test were 100% and specificity was 67%, but proximately 90% of patients with a negative exercise test positive predictive value (14%) was poor (Table 4). result remain free of complications during the first year of follow-up.25 Discussion The greatest weakness of this study is that not all patients with positive test results underwent catheterization. They Because there are no reports in which, when acute myocar- were admitted according to criteria of the clinician in charge dial infarction has been ruled out, the performance of early who knew the results of noninvasive tests. Given that most rest gated SPECT was compared with exercise testing and of these patients represent a lower risk cohort, one could stress gated SPECT in a single group of low-risk patients, speculate that if all positive and negative studies were fol- we designed a prospective study in which patients with lowed by catheterization, negative predictive values would atypical chest pain, nondiagnostic ECG, and negative mark- have been higher or about the same, but positive predictive ers for myocardial damage underwent early rest myocardial values would have been much lower. perfusion SPECT within 6 hours after pain had subsided and There are no studies in which early rest myocardial an exercise test after 12 hours with SPECT imaging. perfusion gated SPECT and stress gated SPECT were com- The percentage of positive results obtained using stress pared with exercise testing. Conti et al26 analyzed the diag- SPECT (36%) was higher than that obtained with early rest nostic effectiveness of these 2 isotopic modes in a series of SPECT (14%) and electrocardiographic exercise testing 231 patients with no history of ischemic heart disease. (10%). During a 1-year follow-up, there were no deaths, and Patients (n ϭ 80) who experienced pain within 3 hours of coronary artery disease was confirmed in only 5 patients (1 arrival at the emergency department underwent rest SPECT, patient, acute myocardial infarction; 1, surgical revascular- ϭ ization; 1, percutaneous revascularization; and 2, nonrevas- and the remainder (n 151) underwent stress SPECT cularized with 50% stenosis of the coronary artery). This within 24 hours after arrival at the emergency department. low incidence of complications should be borne in mind No statistically significant differences were observed be- when comparing results of different publications because tween stress SPECT and early rest SPECT in the diagnosis many, unlike our own, included patients with typical angi- of coronary artery disease or prediction of ischemic com- nal chest pain or a history of ischemic heart disease. plications during follow-up. Predictive values were 98% In our series, negative predictive values for stress gated and 99%, and negative predictive values were 50% and SPECT (100%), early rest gated SPECT (99%), and elec- 45%, respectively. In our series, positive predictive values trocardiographic exercise testing (96%) were high. High of these tests were also low (27% and 22%, respectively), negative predictive values can be misleading if the under- only slightly better than that of electrocardiographic exer- lying prevalence of disease in the population being tested is cise testing (14%), a result possibly explained by the low not taken into consideration. The high negative predictive percentage of true-positive results in this population. values here reflect how infrequent coronary artery disease is Sensitivities of early SPECT (80%) and stress SPECT in these low-risk patients with atypical chest pain, nonisch- (100%) were higher than that of electrocardiographic exer- emic ECGs, and normal biochemical markers. Polanczyk et cise testing (40%) in our study. Nevertheless, there is no al,17 Gibler et al,18 and Zalenski et al19 obtained a predictive basis for performing such isotopic tests indiscriminately value of 98% for an electrocardiographic exercise test done because in addition to their low positive predictive value, on patients with a low to moderate prevalence of coronary the rate of complications in these patients during the first disease after 8 to 12 hours of monitoring. The European year of follow-up is low. However, additional nuclear stress Cardiology Society Task Force recommends performing an testing as an outpatient may be warranted because 3 patients electrocardiographic exercise test before discharging the required revascularization at some point. Individual hospi- patient when severe diseases (coronary artery disease, aortic tals and emergency departments are likely to choose a stress dissection, and pulmonary embolism) have been ruled out testing strategy or imaging strategy on the basis of local and after 6 hours with no symptoms.20 This practice was experience, available facilities, and estimated cost savings. 1666 The American Journal of Cardiology (www.AJConline.org)

1. Bilodeau L, Théroux P, Grégoire J, Gagnon D, Arsenault A. Techne- 14. Santana-Boado C, Candell-Riera J, Castell-Conesa J, Olona M, Palet- tium-99m sestamibi tomography in patients with spontaneous chest Balart J, Aguadé-Bruix S, García-Burillo A, Ortega-Alcalde D, pain: correlations with clinical, electrocardiographic and angiographic Domènech-Torné FM, Soler-Soler J. Importancia de los parámetros findings. J Am Coll Cardiol 1991;18:1684–1691. ergométricos en los resultados de la tomogammagrafía de perfusión 2. Duca MD, Giri S, Wu AHB, Morris RS, Cyr GM, Ahlberg A, White miocárdica. Med Clín (Barc) 1997;109:406–409. M, Waters DD, Heller GV. Comparison of acute rest myocardial 15. Candell-Riera J, Santana-Boado C, Castell-Conesa J, Aguadé-Bruix S, perfusion imaging and serum markers of myocardial injury in patients Olona M, Palet J, Cortadellas J, García-Burillo A, Soler-Soler J. with chest pain syndromes. J Nucl Cardiol 1999;6:570–576. Simultaneous dipyridamole/maximal subjective exercise with 99mTc- 3. Kontos MC, Jesse RL, Schmidt KL, Ornato JP, Tatum JL. Value of MIBI SPECT: improved diagnostic yield in coronary artery disease. acute rest sestamibi perfusion imaging for evaluation of patients ad- J Am Coll Cardiol 1997;29:531–536. mitted to the emergency department with chest pain. J Am Coll 16. Fleiss JL. The measurement of interrated agreement. In: Fleiss JL, ed. Cardiol 1997;30:976–982. Statistical Methods for Rates and Proportions. New York, New York: 4. Kontos MC, Jesse RL, Anderson FP, Schmidt KL, Ornato JP, Tatum Wiley, 1981:212–236. JL. Comparison of myocardial perfusion imaging and cardiac troponin 17. Polanczyk CA, Johnson PA, Hartley LH, Walls RM, Shaykevich S, I in patients admitted to the emergency department with chest pain. Lee TH. Clinical correlates and prognostic significance of early neg- Circulation 1999;99:2073–2078. ative exercise tolerance test in patients with acute chest pain seen in the 5. Lewis WR, Amsterdam EA. Utility and safety of immediate exercise hospital emergency department. Am J Cardiol 1998;81:288–292. testing of low-risk patients admitted to the hospital for suspected acute 18. Gibler WB, Runyon JP, Levy RC, Sayre MR, Kacich R, Hattemer CR, myocardial infarction. Am J Cardiol 1994;74:987–990. Hamilton C, Gerlach JW, Walsh RA. A rapid diagnostic and treatment 6. Pastor-Torres LF, Pavón-Jiménez R, Reina-Sánchez M, Caparros- center for patients with chest pain in the emergency department. Ann Valderrama J, Mora-Pardo JA. Unidad de dolor torácico: seguimiento Emerg Med 1995;25:1–8. a un año. Rev Esp Cardiol 2002;55:1021–1027. 19. Zalenski RJ, Rydman RJ, McCarren M, Roberts RR, Jovanovic B, Das 7. Sanchis J, Bodí V, Núñez J, Núñez J, Ferrero JA, Chorro FJ. Valor de K, Mensah EK, Kampe LM. Feasibility of a rapid diagnostic protocol la prueba de esfuerzo precoz en un protocolo de unidad de dolor for an emergency department chest pain unit. Ann Emerg Med 1997; torácico. Rev Esp Cardiol 2002;55:1089–1092. 29:99–108. 8. Shoyeb A, Bokhari S, Sullivan J, Hurley E, Miesner B, Pia R, Giglio 20. Erhardt L, Herlitz J, Bossaert L, Halinen M, Keltai M, Koster R, J, Sayan OR, Soto L, Chiadika S, et al. Value of definitive diagnostic Marcassa C, Quinn T, van Weert H. Task force on the management of testing in the evaluation of patients presenting to the emergency chest pain. Eur Heart J 2002;23:1153–1176. department with chest pain. Am J Cardiol 2003;91:1410–1414. 21. Antman EM, Cohen M, Bernink PJLM, McCabe CH, Horacek T, 9. Conti A, Zanobetti M, Grifoni S, Berni G, Costanzo E, Gallini C, Ferri Papuchis G, Mautner B, Corbalan R, Radley D, Braunwald E. The P, Pieroni C. Implementation of myocardial perfusion imaging in the TIMI risk score for unstable angina/non-ST elevation MI. A method early triage of patients with suspected acute coronary syndromes. Nucl for prognostication and therapeutic decision making. JAMA 2000;284: Med Commun 2003;24:1055–1060. 835–842. 10. Patterson RE, Horowitz SF, Eng C, Rudin A, Meller J, Halgash DA, 22. García-Almagro FJ, Gimeno JR, Villegas M, Muñoz L, Sánchez E, Pichard AD, Goldsmith SJ, Herman MV, Gorlin R. Can exercise Teruel F, Hurtado J, González J, Antolinos MJ, Pascula D, Valdés M. electrocardiography and thallium-201 myocardial imaging exclude the Aplicación de una puntuación de riesgo coronario (TIMI Risk Score) diagnosis of coronary artery disease? Bayesian analysis of the clinical en una población no seleccionada de pacientes que consultan por dolor limits of exclusion and indications for coronary angiography. Am J torácico en un servicio de urgencias. Rev Esp Cardiol 2005;58:775– Cardiol 1982;49:1127–1135. 781. 11. Committee on Advanced Cardiac Imaging and Technology, Council 23. Martínez-Sellés M, Ortiz J, Estévez A, Andueza J, de Miguel J, Bueno on Clinical Cardiology, American Heart Association; Cardiovascular H. Un nuevo índice de riesgo para pacientes con ECG normal o no Imaging Committee, American College of Cardiology; and Board of diagnóstico ingresados en la unidad de dolor torácico. Rev Esp Cardiol Directors, Cardiovascular Council, Society of Nuclear Medicine. Stan- 2005;58:782–788. dardization of cardiac tomographic imaging. Circulation 1992;86: 24. Sanchis J, Bodí V, Llácer Á, Núñez J, Consuegra L, Bosch MJ, 338–339. Bertomeu V, Ruiz V, Chorro FJ. Risk stratification of patients with 12. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey acute chest pain and normal troponin concentrations. Heart 2005;91: WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized 1013–1018. myocardial segmentation and nomenclature for tomographic imaging 25. Pastor-Torres LF, Pavón-Jiménez R, Reina-Sánchez M, Caparros- of the heart. A Statement for Healthcare Professionals from the Car- Valderrama J, Mora-Pardo JA. Unidad de dolor torácico: seguimiento diac Imaging Committee of the Council on Clinical Cardiology of the a un año. Rev Esp Cardiol 2002;55:1021–1027. American Heart Association. Circulation 2002;105:539–542. 26. Conti A, Gallini C, Costanzo E, Ferri P, Matteini M, Paladini B, 13. Germano G, Kiat H, Kavanagh PB, Moriel M, Mazzanti M, Su HT, Francois C, Grifoni S, Migliorini A, Antoniucci D, Pieroni C, Berni G. Van Train KF, Berman DS. Automatic quantification of ejection frac- Early detection of myocardial ischaemia in the emergency department tion from gated myocardial perfusion SPECT. J Nucl Med 1995;36: by rest or exercise 99mTc tracer myocardial SPET in patients with chest 2138–2147. pain and non-diagnostic ECG. Eur J Nucl Med 2001;28:1806–1810. Usefulness of Contrast Echocardiography for Assessment of Left Ventricular Thrombus After Acute Myocardial Infarction

Nicolas Mansencal, MDa,*, Imad Abi Nasr, MDa, Rémy Pillière, MDa, Jean-Christian Farcot, MDa, Thierry Joseph, MD, PhDa, Pascal Lacombe, MDb, and Olivier Dubourg, MDa

Fifty consecutive patients referred to a coronary care unit for acute anterior myocardial infarction with ST-segment elevation underwent coronary arteriography, left ventricular (LV) angiography, and revascularization. Transthoracic echocardiography was systematically performed using fundamental imaging, second harmonic imaging, and contrast agents to assess the LV chamber. Six patients (12%) presented with a confirmed LV mural thrombus. Thirty-five percent of patients with time to revascularization >3 hours presented with an LV mural thrombus versus 0 patients with time to revascularization <3 hours The most accurate method of detecting LV mural thrombus was contrast .(0.003 ؍ p) echocardiography regardless of physician experience. No patient with a misdiagnosis of thrombus had an optimal acoustic window using fundamental imaging or second harmonic imaging. In conclusion, patients presenting with acute anterior myocardial infarction could benefit from contrast echocardiography for assessment of LV mural thrombus when acoustic windows are suboptimal and time to revascularization is >3 hours. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1667–1670)

Mechanical complications of acute myocardial infarction Table 1 include left ventricular (LV) pseudoaneurysm, rupture of Characteristics of 50 patients with anterior myocardial infarction the free wall, and perforation of the ventricular septum.1,2 Characteristics Echocardiography is widely used to assess such complications.3 The diagnosis of LV mural thrombus is also made Men 39 (78%) Women 11 (22%) using 2-dimensional echocardiography, but may be partic- Age (yrs) 65 Ϯ 10 ularly difﬁcult in the case of suboptimal acoustic windows, Medical history although wide use of second harmonic imaging (SHI) has Myocardial infarction 7 (14%) signiﬁcantly improved the imaging quality of echocardiog- Percutaneous coronary intervention 5 (10%) raphy.4,5 Contrast echocardiography recently was intro- Coronary artery bypass graft surgery 2 (4%) duced in routine practice with new contrast agents, dramat- Systemic hypertension 22 (44%) ically improves the quality of echocardiographic imaging, Diabetes mellitus 13 (26%) and was also proposed in different clinical settings, such Dyslipidemia 20 (40%) as stress echocardiography or detection of intracardiac Revasularization masses.6–9 The aim of this prospective study is to determine Coronary thrombolysis 4 (8%) Percutaneous coronary intervention 50 (100%) the value of contrast echocardiography for the detection of Procedural success 48 (96%) apical LV mural thrombus in a population of patients with Mean time to (h) 3.3 Ϯ 1.8 acute anterior myocardial infarction. Treatment at admission Antiplatelet therapy 50 (100%) Methods and Results Anticoagulation therapy 47 (94%) ␤ Blockers 40 (80%) The population of this prospective study consisted of 50 Mean no. of narrowed coronary arteries 1.5 Ϯ 0.7 consecutive patients presenting with acute anterior myocar- No. of narrowed coronary arteries dial infarction referred to our coronary care unit. Entry 1 30 (60%) criteria included age Ͼ18 years and acute anterior myocar- 2 13 (26%) dial infarction with ST-segment elevation. All patients un- 3 7 (14%) derwent coronary arteriography, LV angiography, and a

revascularization procedure. Treatment and management aCardiology and bRadiology Departments, University Hospital Am- were left to the discretion of the physician. broise Paré, Assistance Publique-Hôpitaux de Paris, UFR de médecine At day 7, transthoracic echocardiography was performed by Paris-Ile de France-Ouest, Faculté de Versailles-Saint Quentin en Yveline, a single investigator unaware of clinical data and coronary Boulogne, France. Manuscript received November 2, 2006; revised manuscript received and accepted January 24, 2007. revascularization procedure using a Siemens/Sequoia Acuson *Corresponding author: Tel.: 33-0-1-4909-5620; fax: 33-0-1-4909- system (Acuson, Mountain View, California) equipped with 5344. multifrequency transducers and capable of low energy (0.2 to E-mail address: [email protected] (N. Mansen- 0.3 mechanical index), with CPS software (Siemens/Acuson, cal). Mountain View, California), allowing use of contrast agent.

Figure 1. Contrast echocardiography detection of LV thrombus (arrow) in a patient presenting with anterior myocardial infarction.

Figure 2. (A) Suspicion of LV thrombus (arrow) using conventional echocardiography. (B) Contrast echocardiography excludes this diagnosis.

LV ejection fraction was calculated with wall motion score recorded randomly on different separate files. The quality of indexes using the 2-dimensional echocardiographic segmental endocardial delineation in 18 LV segments was systematically division of the LV wall.10 We systematically viewed the LV assessed by an experienced physician (observer 1) and used to chamber (apical 4-, 3-, and 2-chamber views) to detect LV determine the number of well-visualized LV segments. All LV mural thrombus using (1) fundamental imaging (FI), (2) SHI, chamber assessments were performed blindly and indepen- and (3) (Figures 1 and 2) contrast agent (Sonovue, Bracco dently by observer 1 and a physician trainee (observer 2). Each Altana Inc, Milan, Italy). All tracings were anonymous and observer determined the presence or absence of LV thrombus Coronary Artery Disease/Contrast Echocardiography 1669 or the impossibility of deciding (doubt). LV thrombus was also Discussion studied using LV angiography (right and left oblique anterior With the introduction of early coronary revascularization, projections).11 In patients for whom there was doubt regarding the incidence of LV mural thrombus after acute myocardial LV thrombus (n ϭ 3), computed tomography was performed. infarction significantly decreased.12 In our study, we only Statistical analysis was performed using StatView ver- studied patients presenting with anterior wall acute myocar- sion 4.5 (Abacus Concepts Inc, Cary, North Carolina). Con- Ϯ dial infarction, the main location of infarcts in patients with tinuous variables are presented as mean SD and range LV thrombus. In this high-risk population, the incidence of unless otherwise specified. Categorical data are presented as LV mural thrombus was low (12%) and should be compared absolute value and percentage. Variables were compared with previous studies performed before use of early revas- using chi-square test, paired t test, unpaired t test, or Fisch- cularization became widespread (20% to 40%),13,14 and our Ͻ er’s exact test, as appropriate. A p value 0.05 was con- results should be confirmed by the largest study. sidered significant. Echocardiography is used for the detection of LV mural Population characteristics are listed in Table 1. Seven- thrombus in routine practice.4,14 Accuracy significantly im- teen patients had time to revascularization Ͼ3 hours. Mean proved with the introduction of SHI. However, in the case LV ejection fraction using echocardiography was 44 Ϯ 9% of suboptimal acoustic windows, some doubt may arise or a (range 28% to 60%). Nine hundred LV segments were false diagnosis may be made. Contrast magnetic resonance studied, and 736 (82%), 814 (90%), and 889 (99%) LV imaging could also be of interest for the diagnosis of throm- segments were well visualized using FI, SHI, and contrast bus, but was not used in our population.15 Contrast echo- echocardiography, respectively (p Ͻ0.0001). All 300 LV cardiography allows one to distinguish a thrombus from apical segments were seen using contrast agent versus 268 trabeculations and strings, but systematic use of contrast (89%) and 283 (94%) using FI and SHI, respectively agents after an anterior myocardial infarction should not be (p Ͻ0.0001). recommended because of its cost. However, according to Six patients (12%) presented with a confirmed LV mural results of our study, a selection of patients may be per- thrombus. Mean time to revascularization and mean LV formed, including patients with anterior myocardial infarc- ejection fraction in patients with LV mural thrombus were tion, suboptimal acoustic windows, and time to revascular- 6.3 Ϯ 1.8 hours and 31.5 Ϯ 2.8% versus 2.9 Ϯ 1.4 hours ization Ͼ3 hours. In these cases, contrast agents allow the and 46.7 Ϯ 8.5% in patients without thrombus, respectively best assessment of LV chambers, may be clinically relevant, (p ϭ 0.01 and p ϭ 0.0004, respectively). Thirty-five percent and may modify the management of such patients, finally of patients with time to revascularization Ͼ3 hours pre- requiring anticoagulation. Furthermore, the certainty of the sented with an LV mural thrombus versus 0 patients when absence of thrombus is also of importance, especially with time to revascularization was Յ3 hours (p ϭ 0.003). In use of prolonged treatment with aspirin and clopidogrel patients with thrombus, using FI, observers 1 and 2 detected after angioplasty. A false diagnosis of LV thrombus using 3 and 2 thrombi and a thrombus was suspected in 1 and 3 conventional echocardiography may lead to combined treat- patients, respectively. Using SHI, each observer detected 4 ment with aspirin, clopidogrel, and warfarin, which signif- thrombi, and a thrombus was suspected by observers 1 and icantly increases the risk of hemorrhagic events, whereas no 2 in 1 and 2 patients, respectively. Using contrast echocar- anticoagulation was required. diography, the 2 observers correctly detected all thrombi. 1. Oliva PB, Hammill SC, Edwards WD. Cardiac rupture, a clinically pre- For observer 1, using FI, a false diagnosis of thrombus dictable complication of acute myocardial infarction: report of 70 cases was made in 2 patients and 3 patients had a false suspi- with clinicopathologic correlations. J Am Coll Cardiol 1993;22:720–726. cion of thrombus, whereas using SHI, a false diagnosis of 2. Hochman JS, Boland J, Sleeper LA, Porway M, Brinker J, Col J, thrombus was made in 1 patient and 3 patients had a false Jacobs A, Slater J, Miller D, Wasserman H, et al. Current spectrum of cardiogenic shock and effect of early revascularization on mortality. suspicion of thrombus. For observer 2, using FI, a false Results of an International Registry. SHOCK Registry Investigators. diagnosis of thrombus was made in 3 patients and 3 Circulation 1995;91:873–881. patients had a false suspicion of thrombus, whereas using 3. Buda AJ. The role of echocardiography in the evaluation of mechanical SHI, a false diagnosis of thrombus was made in 2 patients complications of acute myocardial infarction. Circulation 1991;84:1109– 1121. and 4 patients had a false suspicion of thrombus using 4. Mansencal N, Bordachar P, Chatellier G, Redheuil A, Diebold B, SHI. Abergel E. Comparison of accuracy of left ventricular echocardio- For observer 1, accurate diagnoses (presence or absence graphic measurements by fundamental imaging versus second har- of thrombus) were made in 86%, 92%, and 100% of patients monic imaging. Am J Cardiol 2003;91:1037–1039. ϭ 5. Rubin DN, Yazbek N, Garcia MJ, Stewart WJ, Thomas JD. Qualitative using FI, SHI, and contrast agent, respectively (p 0.03). and quantitative effects of harmonic echocardiographic imaging on For observer 2, accurate diagnoses (presence or absence of endocardial edge definition and side-lobe artifacts. J Am Soc Echocar- thrombus) were made in 80%, 86%, and 100% of patients diogr 2000;13:1012–1018. using FI, SHI, and contrast echocardiography, respectively 6. Thanigaraj S, Schechtman KB, Perez JE. Improved echocardiographic ϭ delineation of left ventricular thrombus with the use of intravenous (p 0.005). Of 10 patients with a misdiagnosis of thrombus second-generation contrast image enhancement. J Am Soc Echocar- by observer 2, only 136 (76%) and 149 (83%) LV segments diogr 1999;12:1022–1026. were well visualized using FI and SHI versus 98% using 7. Vlassak I, Rubin DN, Odabashian JA, Garcia MJ, King LM, Lin SS, contrast agent, respectively (p Ͻ0.0001). No patient with a Drinko JK, Morehead AJ, Prior DL, Asher CR, Klein AL, Thomas JD. Contrast and harmonic imaging improves accuracy and effi- misdiagnosis of thrombus had an optimal acoustic window ciency of novice readers for dobutamine stress echocardiography. using FI or SHI. Echocardiography 2002;19:483–488. 1670 The American Journal of Cardiology (www.AJConline.org)

8. Yong Y, Wu D, Fernandes V, Kopelen HA, Shimoni S, Nagueh SF, 12. Nayak D, Aronow WS, Sukhija R, McClung JA, Monsen CE, Callahan JD, Bruns DE, Shaw LJ, Quinones MA, Zoghbi WA. Diag- Belkin RN. Comparison of frequency of left ventricular thrombi in nostic accuracy and cost-effectiveness of contrast echocardiography on patients with anterior wall versus non–anterior wall acute myocar- evaluation of cardiac function in technically very difﬁcult patients in dial infarction treated with antithrombotic and antiplatelet therapy the intensive care unit. Am J Cardiol 2002;89:711–718. with or without coronary revascularization. Am J Cardiol 2004;93: 9. Kirkpatrick JN, Wong T, Bednarz JE, Spencer KT, Sugeng L, Ward 1529–1530. RP, DeCara JM, Weinert L, Krausz T, Lang RM. Differential diagno- 13. Domenicucci S, Chiarella F, Bellotti P, Bellone P, Lupi G, Vecchio C. sis of cardiac masses using contrast echocardiographic perfusion im- Long-term prospective assessment of left ventricular thrombus in an- aging. J Am Coll Cardiol 2004;43:1412–1419. terior wall acute myocardial infarction and implications for a rational 10. Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg approach to embolic risk. Am J Cardiol 1999;83:519–524. K, Videbaek J, Cole DS, Auclert L, Pauly NC. A clinical trial of the 14. Stratton JR, Lighty GWJ, Pearlman AS, Ritchie JL. Detection of angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular thrombus by two-dimensional echocardiography: left ventricular dysfunction after myocardial infarction. Trandolapril sensitivity, speciﬁcity, and causes of uncertainty. Circulation 1982; Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333: 66:156–166. 1670–1676. 15. Mollet NR, Dymarkowski S, Volders W, Wathiong J, Herbots L, 11. Rigaud M, Rocha P, Boschat J, Farcot JC, Bardet J, Bourdarias JP. Rademakers FE, Bogaert J. Visualization of ventricular thrombi with Regional left ventricular function assessed by contrast angiography in contrast-enhanced magnetic resonance imaging in patients with isch- acute myocardial infarction. Circulation 1979;60:130–139. emic heart disease. Circulation 2002;106:2873–2876. Relation of Myocardial Blush Grade to Microvascular Perfusion and Myocardial Infarct Size After Primary or Rescue Percutaneous Coronary Intervention

Italo Porto, MDa,*, Francesco Burzotta, MDa, Marta Brancati, MDa, Carlo Trani, MDa, Antonella Lombardo, MDa, Enrico Romagnoli, MDa, Giampaolo Niccoli, MDa, Luigi Natale, MDb, Lorenzo Bonomo, MDb, and Filippo Crea, MDa

Angiographic myocardial blush grade (MBG) is a potent predictor of long-term outcome after percutaneous treatment of myocardial infarction, yet little is known regarding the underlying pathophysiologic features. The relation between MBG and cardiovascular magnetic resonance (CMR)-defined amounts of necrosis and microvascular obstruction was examined in 27 patients. Another powerful prognostic indicator, ST-segment resolu- ؍ tion >70%, was correlated with other predictors. Increasing MBG was associated (p 0.001) in a linear fashion (p <0.001) with less microvascular obstruction using CMR, was ,(0.043 ؍ whereas the inverse relation with amount of necrosis, although significant (p -ST resolution was not correlated with either MBG or CMR param .(0.36 ؍ nonlinear (p eters. In conclusion, MBG is mainly influenced by microvascular patency and is less dependent on the amount of muscle necrosis, and the common practice of including MBG 2 and 3 into a single “patent microcirculation” category might not be justified. Moreover, the mechanisms of ST resolution should be searched for at the cellular level. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1671–1673)

Myocardial “blush” grade (MBG) is a semiquantitative an- ful, obtaining Thrombolysis In Myocardial Infarction giographic index of microvascular damage after recanaliza- (TIMI) 3 flow in all patients. Average number of vessels tion of the infarct-related artery.1 Although MBG is a pow- with Ͼ50% stenosis was 1.4 Ϯ 0.7, and average corrected erful predictor of long-term outcome after an ST-elevation TIMI frame counts2 were 78.3 Ϯ 32.3 before the procedure myocardial infarction (STEMI), very few data exist for and 19.8 Ϯ 9.2 after the procedure. Thrombus score was MBG functional correlates. In this study, we analyzed the 3.2 Ϯ 1.0 after wire passage and decreased to 0.1Ϯ0.3 after pathophysiologic features underlying different blush grades the procedure. MBGs were defined according to the Zwolle using early cardiovascular magnetic resonance (CMR). classification1 as 0 ϭ no myocardial blush or contrast density, 1 ϭ minimal myocardial blush or contrast density, 2 ϭ Methods and Results moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsi- Our sample consisted of 27 consecutive patients undergoing lateral non–infarct-related coronary artery, and 3 ϭ normal primary (65%) or rescue (35%) percutaneous coronary in- myocardial blush or contrast density, comparable to that tervention (PCI) for their first STEMI. Age was 58 Ϯ 12 obtained during angiography of a contralateral or ipsilateral years, 25 patients (93%) were men, 19 (52%) were smokers, non–infarct-related coronary artery. Single-lead ST-seg- and 5 (18%) had diabetes mellitus. Primary PCI was per- ment resolution was measured by comparing the most formed according to our usual protocol using low-dose prominent ST-segment deviation before coronary angiogra- heparin (5,000 to 7,500 UI) in all patients, extensive use of phy and after the procedure. ST resolution Ͼ70% at 2 hours the transradial approach (20 patients, 74%), downstream abciximab (21 patients, 76%, with intracoronary bolus in 10 occurred in 10 patients (37%). patients, 37%), thrombus aspiration using the Diver device CMR was performed 2 to 4 days after PCI (median 3 (Invatec, Brescia, Italy) (13 patients, 48%), and direct stent- days) with a 1.5-Tesla scanner (Signa Excite II, GE Medical ing (13 patients, 48%). Average Killip class was 1.4 Ϯ 0.6. Systems, Buc, Paris). The protocol included cine-CMR for Mean time from symptom onset to intervention was 4.4 Ϯ contractile function assessment and contrast imaging both at 2.5 hours. first pass and in delayed imaging to evaluate microvascular Angiograms were analyzed offline by a single observer perfusion and infarct size, respectively. For the first-pass (ER) blinded to clinical data. Treated vessels were the right perfusion imaging, 3 short-axis scout images (basal, mid- coronary (3 patients), left circumflex (3 patients), and left ventricular, and apical) were obtained using an electrocar- anterior descending arteries (21 patients). PCI was success- diogram-gated hybrid fast-gradient echo-echo planar sequence. Images were acquired continuously for 1 minute after an intravenous bolus of gadolinium-based contrast agent (Magnevist, Schering, Berlin, Germany) at dosage of Departments of aCardiovascular Medicine and bRadiology, Catholic University of the Sacred Heart, Rome, Italy. Manuscript received Novem- 0.1 mmol/kg and flow rate of 4 ml/s followed by a second ber 11, 2006; revised manuscript received and accepted January 29, 2007. equivalent dose of contrast medium at the end of first-pass *Corresponding author: Tel.: 39-06-3015-4187; fax: 39-06-3055-535. image acquisition. Delayed images were acquired after 15 E-mail address: [email protected] (I. Porto). minutes using a breath-hold inversion recovery fast gradient

left ventricular model,3 and images were matched to obtain the identical slice location. Microvascular obstruction was identified on first-pass imaging as areas of hypoenhance- ment relative to surrounding myocardium appearing with a delay Ն2 seconds and persisting for Ն10 frames. Infarct size was defined on delayed images as an area of hyperenhancement within the myocardium compared with normal noninfarcted myocardium.4,5 The extent of both microvascular obstruction and infarct size was evaluated by an experienced reader blinded to clinical data (AL) using a score per patient consisting of the sum of individual scores obtained in each left ventricular segment on the basis of the transmural extension of contrast patterns. Each segment was scored on a 5-point scale (0 ϭ no hypo- or hyperenhancement, 1 ϭ hypo- or hyperenhancement extending from 1% to 25% of left ventricular wall thickness, 2 ϭ 26% to 50%, 3 ϭ 51% to 75%, and 4 ϭ 76% to 100%). Final MBGs were 0 in 2 patients, 1 in 10 patients, 2 in 8 patients, and 3 in 7 patients. Using analysis of variance, blush grades were compared using a microvascular obstruction score (F ϭ 8, degree of freedom [df] 3, p ϭ 0.001) and Figure 1. Correlation between myocardial obstruction score (see text) and infarct size score (F ϭ 3.2, df 3, p ϭ 0.043). A largely MBG after PCI. Error bars, SE. Overall analysis of variance statistics significant linear trend term (p Ͻ0.001) indicated a clear show significant intragroup differences (p ϭ 0.001), and a clear stepwise linear trend (p Ͻ0.001) is apparent. inverse stepwise relation between MBGs and microvascular obstruction scores, not evident for infarct size scores (p ϭ 0.36; Figures 1 and 2). When MBGs were collapsed into a dichotomous variable (0 and 1 vs 2 and 3, as commonly accepted), MBGs 0 and 1 were associated with larger microvascular obstruction scores (10.0 Ϯ 4.4 vs 5.1 Ϯ 2.7, p ϭ 0.003), but the significance of the association with larger infarct score was lost (13.1 Ϯ 5.9 vs 9.7 Ϯ 6.9, p ϭ 0.18). No relation was found between the 4 blush grades (chi-square 4.371, df 3, p ϭ 0.224) or MBGs 0 and 1 versus MBGs 2 and 3 and absence of ST resolution Ͼ70% (chi-square 0.675, df 1, p ϭ 0.41). Finally, absence of ST resolution Ͼ70% did not correlate with either of the CMR-derived parameters (11.0 Ϯ 6.7 vs 11.5 Ϯ 6.8, p ϭ 0.85 for infarct score; 6.7 Ϯ 4.0 vs 8.2 Ϯ 4.8, p ϭ 0.4 for microvascular obstruction score). Subgroup analysis was performed for the 21 patients (77%) who underwent left anterior descending intervention. Main results, namely the inverse linear trend of the relation between increasing blush grade and CMR-derived microvascular obstruction score (p Ͻ0.001), not present for infarct size score (p ϭ 0.43), were maintained.

Discussion Figure 2. Correlation between infarct size score (see text) and MBG after PCI. Error bars, SE. Although overall analysis of variance statistics show Normalized epicardial flow traditionally was used to indi- significant intragroup differences (p ϭ 0.043), no linear trend is apparent cate reperfusion after STEMI in the thrombolytic age. How- (p ϭ 0.36) because MBGs 0, 1, and 2 show a similar amount of necrosis. ever, in the primary PCI era, TIMI 3 flow is obtained in p ϭ 0.4 for linear trend. Ͼ95% of patients, and the focus has shifted to assessment of perfusion at the microvascular level. Angiographic evalua- echo sequence. Images were acquired in short axis with full tion of microvascular patency using MBG or the slightly coverage of the left ventricle, copying the same localization different TIMI myocardial perfusion grade was studied in of cine-CMR. Horizontal or vertical long axes or both were large cohorts because of its easy acquisition, almost univer- also obtained, depending on the site of the infarct. sal availability, and good (even if not optimal) reproduc- Contrast patterns on first-pass and delayed images were ibility.6 Although a wealth of information is available on the visually analyzed in each segment of a standard 17-segment powerful impact of MBG and TIMI myocardial perfusion Coronary Artery Disease/MBG Correlates With MR-Derived Perfusion 1673 grade on long-term outcome after STEMI, there is a paucity tients treated with primary angioplasty for acute myocardial infarction: of functional data. myocardial blush grade: Zwolle Myocardial Infarction Study Group. Infarct size evaluated using enzyme release or assess- Circulation 1998;97:2302–2306. 2. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, ment of technetium-99m sestamibi single-photon emission Marble SJ, McCabe CH, Raymond L, Fortin T, Poole WK, Braunwald computed tomography was smaller in patients with TIMI E. TIMI frame count: a quantitative method of assessing coronary myocardial perfusion grades 2 and 3 compared with TIMI artery flow. Circulation 1996;93:879–888. myocardial perfusion grades 0 and 1,5,7 and TIMI myocar- 3. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey dial perfusion grade 2/3 was associated with a higher sal- WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS, for the Amer- 8 ican Heart Association Writing Group on Myocardial Segmentation vage index after primary PCI. Little is known about the and Registration for Cardiac Imaging. Standardized myocardial seg- relation of MBG with other measures of microvascular mentation and nomenclature for tomographic imaging of the heart: a patency, although Lepper et al9 showed that angiographic statement for healthcare professionals from the Cardiac Imaging Com- and echocardiographic myocardial perfusion are closely re- mittee of the Council on Clinical Cardiology of the American Heart lated and impaired MBG was the best multivariate predic- Association. Circulation 2002;105:539–542. tor of nonreperfusion on myocardial contrast echocardio- 4. Gerber BL, Rochitte CE, Melin JA, McVeigh ER, Bluemke DA, Wu KC, Becker LC, Lima JA. Microvascular obstruction and left ventric- graphy. ular remodeling early after acute myocardial infarction. Circulation In this report, we took advantage of the ability of CMR 2000;101:2734–2741. to provide information for both myocardial perfusion and 5. Taylor AJ, Al-Saadi N, Abdel-Aty H, Schulz-Menger J, Messroghli infarct extent. We were able to show that after primary or DR, Friedrich MG. Detection of acutely impaired microvascular reper- rescue PCI, MBG is inversely and linearly related to the fusion after infarct angioplasty with magnetic resonance imaging. Circulation 2004;109:2080–2085. extent of perfusion defects assessed using early CMR. There 6. Gibson CM, Schomig A. Coronary and myocardial angiography: an- is a relation with infarct size, but this is nonlinear. Although giographic assessment of both epicardial and myocardial perfusion. many studies collapsed MBG variability into only 2 cate- Circulation 2004;109:3096–3105. gories by merging MBG 0 and 1 and MBG 2 and 3, Ն2 7. Angeja BG, Gunda M, Murphy SA, Sobel BE, Rundle AC, Syed M, recent reports,10,11 among them the largest report to date,11 Asfour A, Borzak S, Gourlay SG, Barron HV, Gibbons RJ, Gibson showed that patients with MBG 2 are in a separate category CM. TIMI myocardial perfusion grade and ST segment resolution: association with infarct size as assessed by single photon emission carrying an intermediate prognosis between MBGs 0 and 1 computed tomography imaging. Circulation 2002;105:282–285. and MBG 3. In our sample, patients with MBG 2 showed 8. Dibra A, Mehilli J, Dirschinger J, Pache J, Neverve J, Schwaiger M, relatively preserved perfusion, similar to patients with MBG Schomig A, Kastrati A. Thrombolysis In Myocardial Infarction myo- 3, with a larger infarct size, similar to MBGs 0 and 1. Thus, cardial perfusion grade in angiography correlates with myocardial our data support the notion that researchers should avoid salvage in patients with acute myocardial infarction treated with stent- reducing blush grade variability (e.g., adding MBG 0 and 1 ing or thrombolysis. J Am Coll Cardiol 2003;41:925–929. 9. Lepper W, Sieswerda GT, Vanoverschelde JL, Franke A, de Cock CC, vs 2 and 3) or the informative value of this very simple Kamp O, Kuhl HP, Pasquet A, Voci P, Visser CA, Hanrath P, Hoff- parameter could be lost. mann R. Predictive value of markers of myocardial reperfusion in A relative limitation of our study is that angiographic acute myocardial infarction for follow-up left ventricular function. assessment and CMR were performed at different times. Am J Cardiol 2001;88:1358–1363. Regarding infarct size, although it is possible that the delay 10. Stone GW, Peterson MA, Lansky AJ, Dangas G, Mehran R, Leon MB. Impact of normalized myocardial perfusion after successful angio- between PCI and CMR could have hampered the correlation plasty in acute myocardial infarction. J Am Coll Cardiol 2002;39:591– with angiographic blush, it should be noted that infarct 597. evolution is a complex process, and infarct size might be 11. Costantini CO, Stone GW, Mehran R, Aymong E, Grines CL, Cox underestimated when delayed enhancement imaging is per- DA, Stuckey T, Turco M, Gersh BJ, Tcheng JE, et al. Frequency, formed too early after amyocardial infarction. Moreover, correlates, and clinical implications of myocardial perfusion after microvascular obstruction using CMR was assessed at 3 to primary angioplasty and stenting, with and without glycoprotein IIb/ IIIa inhibition, in acute myocardial infarction. J Am Coll Cardiol 12 5 days in the majority of published studies. 2004;44:305–312. In our small sample, ST resolution was not associated 12. Baks T, van Geuns RJ, Biagini E, Wielopolski P, Mollet NR, Cadem- with either blush or CMR-derived parameters. This suggests artiri F, van der Giessen WJ, Krestin GP, Serruys PW, Duncker DJ, de that the most powerful index of good prognosis after pri- Feyter PJ. Effects of primary angioplasty for acute myocardial infarc- mary PCI13 cannot be related to only mechanical patency of tion on early and late infarct size and left ventricular wall characteristics. J Am Coll Cardiol 2006;47:40–44. the microcirculation or extent of myocardial necrosis, and 13. Sorajja P, Gersh BJ, Costantini C, McLaughlin MG, Zimetbaum P, further elucidation at the cellular level is warranted. Cox DA, Garcia E, Tcheng JE, Mehran R, Lansky AJ, et al. Combined prognostic utility of ST-segment recovery and myocardial blush after 1. van ’t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, primary percutaneous coronary intervention in acute myocardial in- Zijlstra F. Angiographic assessment of myocardial reperfusion in pa- farction. Eur Heart J 2005;26:667–74. Impact of Admission Hyperglycemia and Diabetes Mellitus on Short- and Long-Term Mortality After Acute Myocardial Infarction in the Coronary Intervention Era

Masaharu Ishihara, MD, PhD*, Eisuke Kagawa, MD, Ichiro Inoue, MD, PhD, Takuji Kawagoe, MD, PhD, Yuji Shimatani, MD, Satoshi Kurisu, MD, PhD, Yasuharu Nakama, MD, Tatsuya Maruhashi, MD, Keisuke Ookawa, MD, Kazuoki Dai, MD, and Yasuyuki Aokage, MD

The influence of admission hyperglycemia and diabetes on short- and long-term mortality of patients with acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era was investigated. From 1996 to 2003, a total of 802 consecutive patients with AMI underwent coronary angiography. Primary PCI was performed in 724 patients (90%). Three-year mortality curves were constructed using the Kaplan-Meier method. Cox proportional hazard regression was used to identify independent predictors of 30-day mortality and mortality from 30 days to 3 years. There were 261 patients with admission hyperglycemia (admission glucose >11.1 mmol/L) and 212 patients with diabetes. Admis- sion hyperglycemia was associated with a significantly higher 30-day mortality rate (8.4% vs 2.4%, p <0.001). However, there was no significant difference in 30-day mortality rates Conversely, diabetes .(0.29 ؍ between diabetic and nondiabetic patients (5.7% vs 3.9%, p but ,(0.03 ؍ significantly increased mortality from 30 days to 3 years (10.0% vs 5.5%, p Multivariate analysis showed .(0.19 ؍ admission hyperglycemia did not (8.4% vs 5.9%, p that hyperglycemia was an independent predictor of 30-day mortality (odds ratio [OR] ,but diabetes was not (OR 0.84 ,(0.01 ؍ confidence interval [CI] 1.13 to 2.61, p 95% ,1.71 Diabetes was independently associated with mortality from .(0.42 ؍ CI 0.55 to 1.27, p 95% but hyperglycemia had a ,(0.04 ؍ days to 3 years (OR 1.43, 95% CI 1.02 to 1.97, p 30 ,In conclusion, in the PCI era .(0.92 ؍ neutral effect (OR 0.98, 95% CI 0.70 to 1.36, p admission hyperglycemia was associated with short-term mortality, whereas diabetes increased long-term mortality after convalescence in patients with AMI. Admission hyperglycemia and diabetes should be treated as 2 distinct disease states. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1674–1679)

Glucose metabolic abnormalities, both admission hypergly- development of coronary artery disease and increases the cemia and diabetes mellitus, are associated with impaired risk of death in patients who survive AMI.16–18 Therefore, outcomes in patients with acute myocardial infarction the inﬂuence of admission hyperglycemia and diabetes on (AMI). Increased plasma glucose is a common feature dur- outcome after AMI may be different and time dependent. ing early hours after AMI, not only in patients with diabetes, This study was undertaken to investigate the impact of but also in nondiabetic patients.1 Admission hyperglycemia admission hyperglycemia and diabetes on short- and long- was associated with large infarct size, impaired left ventric- term outcome after AMI in the contemporary PCI era. ular function, and high in-hospital or 30-day mortality after AMI regardless of diabetic status.2–8 Diabetes mellitus has Methods been a well-known predictor of morbidity and mortality after AMI in the prereperfusion era and thrombolysis From January 1996 to December 2003, a total of 802 con- era.9–11 However, recent progress in treatment, especially secutive patients with AMI underwent coronary angiogra- the development of percutaneous coronary intervention phy within 24 hours after the onset of chest pain at Hiro- (PCI), has improved outcomes of diabetic patients with shima City Hospital, Hiroshima, Japan. AMI was diagnosed AMI more dramatically than for nondiabetic patients.11 Re- as chest pain consistent with ongoing myocardial ischemia cent studies reported that short-term mortality was no longer persisting Ͼ30 minutes with concomitant electrocardio- different between diabetic and nondiabetic patients in the graphic changes. Serum creatine kinase was measured every PCI era.13–15 However, diabetes remains a risk factor for the 3 hours for at least 24 hours, and peak creatine kinase had to be more than twice the normal upper limit. The study protocol was reviewed and approved by the ethical com- Department of Cardiology, Hiroshima City Hospital, Hiroshima, Japan. mittee of Hiroshima City Hospital. Manuscript received December 14, 2006; revised manuscript received and Emergency coronary angiography was performed as pre- 19 accepted January 29, 2007. viously reported. Selective coronary angiography was per- *Corresponding author: Tel.: 81-82-221-2291; fax: 81-82-223-1447. formed in multiple projections before the initiation of reper- E-mail address: [email protected] (M. Ishihara). fusion therapy. Immediately after diagnostic angiography,

Table 1 Baseline clinical and angiographic characteristics of patients with and without admission hyperglycemia Variables Admission Hyperglycemia p Value No (n ϭ 541) Yes (n ϭ 261) Age (yrs) 63.0 Ϯ 11.8 64.6 Ϯ 11.1 0.06 Men 443 (82%) 188 (72%) 0.002 Hypertension 226 (42%) 115 (44%) 0.54 Diabetes mellitus 67 (12%) 145 (56%) Ͻ0.001 Current smoking 271 (50%) 126 (48%) 0.63 Previous myocardial infarction 69 (13%) 29 (11%) 0.51 Killip class ϾI 61 (11%) 58 (22%) Ͻ0.001 Admission glucose (mmol/L) 8.1 Ϯ 1.5 15.7 Ϯ 5.0 Ͻ0.001 Anterior location 257 (48%) 128 (49%) 0.68 Time to angiography (hrs) 5.0 Ϯ 5.1 4.6 Ϯ 4.7 0.25 Primary coronary intervention 488 (90%) 236 (90%) 0.92 Initial TIMI 0/1 419 (77%) 200 (77%) 0.80 Collateral circulation 159 (29%) 64 (25%) 0.15 Multivessel coronary disease 196 (36%) 117 (45%) 0.02 Final TIMI 3* 468 (88%) 215 (87%) 0.48 Medications at discharge (n ϭ 766) Antiplatelet agents 501 (95%) 223 (94%) 0.73 Angiotensin-converting enzyme inhibitors/angiotensin receptor 221 (42%) 117 (49%) 0.05 blockers ␤ Blockers 65 (12%) 31 (13%) 0.76 Calcium channel blockers 211 (40%) 100 (42%) 0.55 Nitrates 328 (62%) 152 (64%) 0.57 Statins 81 (15%) 35 (15%) 0.85

* Twenty-five patients who underwent bypass surgery were excluded. TIMI ϭ Thrombolysis In Myocardial Infarction. reperfusion therapy was performed, if appropriate. Alloca- lina) for all statistical tests. A significance level of 0.05 was tion of reperfusion therapy was determined by the physi- used and 2-tailed tests were applied. cian. Primary PCI was performed in 724 patients (90%). Of these, coronary stents were used in 604 patients (83%). Results During the study period, only bare-metal stents were used. Plasma glucose was measured at the time of hospital There were 261 patients (32%) with admission hyperglyce- admission. Admission hyperglycemia was defined as admis- mia. Baseline clinical and angiographic characteristics of sion plasma glucose Ն11.1 mmol/L (Ն200 mg/dl) regard- patients with and without admission hyperglycemia are less of diabetic status. Patients were believed to have dia- listed in Table 1. Baseline characteristics of diabetic and betes if they had a previous or current diagnosis of diabetes nondiabetic patients are listed in Table 2. There were 212 at the time of admission regardless of glycemic status at patients (26%) with diabetes. Ninety-seven patients (46%) admission. were treated with diet only; 94 patients (44%), with oral We used standard statistical methods. We tested the hypoglycemic drugs; and 21 patients (10%), with insulin. significance of the difference using chi-square test for cat- Peak creatine kinase was obtained in 743 patients (93%) and egorical variables. Student’s t test was used for continuous was significantly higher in patients with than without ad- variables. Mortality curves up to 3 years after AMI were mission hyperglycemia (3,086 Ϯ 2,473 vs 2,571 Ϯ 2,071 constructed using the Kaplan-Meier method and compared IU/L, p ϭ 0.003). There was no significant difference in using log-rank test. Three-year mortality was divided into peak creatine kinase between diabetic and nondiabetic pa- 30-day mortality and mortality from 30 days to 3 years, tients (2,571 Ϯ 1,895 vs 2,792 Ϯ 2,320 IU/L, p ϭ 0.23). representing short- and long-term mortality, respectively. Three-year mortality curves after AMI of patients with Cox proportional hazard regression was used to identify and without admission hyperglycemia are shown in Figure independent predictors of mortality, adjusting for baseline 1, and those of diabetic and nondiabetic patients are shown clinical characteristics that included age, gender, hyperten- in Figure 2. Both admission hyperglycemia (16.1% vs 8.1%, sion, current smoking, previous myocardial infarction, Kil- p Ͻ0.001) and diabetes (15.0% vs 9.1%, p ϭ 0.02) were lip class, anterior location, time to angiography, and pri- associated with higher 3-year mortality after AMI. How- mary coronary intervention. Patients were further stratified ever, patterns of mortality curves were different between into 4 groups based on the presence or absence of admission patients with admission hyperglycemia and patients with hyperglycemia and diabetes. Three-year mortality was com- diabetes. Thirty-day mortality rates were significantly pared using nondiabetic patients without admission hyper- higher in patients with than without admission hyperglyce- glycemia as the reference. We used the JMP statistical mia (8.4% vs 2.4%, p Ͻ0.001). However, there was no package (version 5.0.1 J, SAS Institute, Cary, North Caro- significant difference in 30-day mortality rates between di- 1676 The American Journal of Cardiology (www.AJConline.org)

Table 2 Baseline clinical and angiographic characteristics of patients with and without diabetes Variables Diabetes Mellitus p Value No (n ϭ 590) Yes (n ϭ 212) Age (yrs) 63.2 Ϯ 11.9 64.1 Ϯ 10.9 0.36 Men 471 (80%) 160 (75%) 0.19 Hypertension 245 (42%) 96 (45%) 0.34 Current smoking 292 (49%) 105 (50%) 0.99 Previous myocardial infarction 69 (12%) 29 (14%) 0.45 Killip class ϾI 84 (24%) 35 (17%) 0.43 Admission glucose (mmol/L) 9.3 Ϯ 3.4 14.2 Ϯ 5.8 Ͻ0.001 Anterior location 292 (49%) 93 (44%) 0.16 Time to angiography (hrs) 4.7 Ϯ 4.9 5.4 Ϯ 5.3 0.11 Primary coronary intervention 532 (90%) 192 (91%) 0.87 Initial TIMI 0/1 467 (79%) 152 (72%) 0.03 Collateral circulation 171 (29%) 52 (25%) 0.21 Multivessel coronary disease 208 (35%) 105 (50%) Ͻ0.001 Final TIMI 3* 505 (88%) 178 (87%) 0.74 Medications at discharge (n ϭ 766) Antiplatelet agents 534 (94%) 190 (96%) 0.29 Angiotensin-converting enzyme inhibitors/angiotensin receptor 247 (43%) 91 (46%) 0.55 blockers ␤ blockers 70 (12%) 26 (13%) 0.77 Calcium channel blockers 232 (41%) 79 (40%) 0.82 Nitrates 355 (63%) 125 (63%) 0.87 Statins 83 (15%) 33 (17%) 0.50

* Twenty-ﬁve patients who underwent bypass surgery were excluded. Abbreviation as in Table 1.

Figure 1. Three-year mortality curves of patients with (solid line) and Figure 2. Three-year mortality curves of diabetic (solid line) and nondia- without admission hyperglycemia (dotted line). Admission hyperglycemia betic patients (dotted line). Diabetes was associated with significantly was associated with significantly higher 3-year mortality. higher 3-year mortality. abetic and nondiabetic patients (5.7% vs 3.9%, p ϭ 0.29). betes. There were 474 nondiabetic patients without admis- Conversely, diabetes significantly increased mortality rates sion hyperglycemia, 116 nondiabetic patients with admis- from 30 days to 3 years (10.0% vs 5.5%, p ϭ 0.03), but sion hyperglycemia, 145 diabetic patients without admission hyperglycemia did not (8.4% vs 5.9%, p ϭ 0.19). admission hyperglycemia, and 67 diabetic patients with Multivariate analysis showed that admission hyperglycemia admission hyperglycemia. Three-year mortality curves for was an independent predictor of 30-day mortality, but dia- the 4 groups are shown in Figure 3. Thirty-day mortality betes was not (Table 3). Diabetes was independently asso- rates of patients without admission hyperglycemia were ciated with mortality from 30 days to 3 years, but admission low, with no difference between nondiabetic and diabetic hyperglycemia had a neutral effect on mortality from 30 patients (2.5% vs 1.5%, p ϭ 0.60; Figure 4). Compared with days to 3 years. nondiabetic patients without admission hyperglycemia, ad- Patients were further stratified into 4 groups based on the mission hyperglycemia was associated with significantly presence or absence of admission hyperglycemia and dia- higher 30-day mortality rates in both nondiabetic (9.5%, p Coronary Artery Disease/Hyperglycemia and Diabetes in AMI 1677

Table 3 Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day mortality and mortality from 30 days to 3 years OR 95% CI p Value 30-Day mortality Unadjusted Admission hyperglycemia 1.90 1.36–2.71 Ͻ0.001 Diabetes 1.21 0.84–1.70 0.30 Adjusted Admission hyperglycemia 1.71 1.13–2.61 0.01 Diabetes 0.84 0.55–1.27 0.42 Mortality from 30 d to 3 yrs Unadjusted Admission hyperglycemia 1.21 0.90–1.61 0.20 Diabetes 1.37 1.02–1.83 0.04 Figure 4. Compared with nondiabetic patients without admission hyper- Adjusted glycemia, 30-day mortality did not increase in diabetic patients without Admission hyperglycemia 0.98 0.70–1.36 0.92 admission hyperglycemia, but was significantly higher in nondiabetic and Diabetes 1.43 1.02–1.97 0.04 diabetic patients with admission hyperglycemia (left bars). Three-year mortality was significantly higher in diabetic patients without admission hyperglycemia and nondiabetic and diabetic patients with admission hyperglycemia than in nondiabetic patients without admission hyperglycemia (right bars). *p Ͻ0.001; †p ϭ 0.002; ‡p ϭ 0.02 versus nondiabetic patients without admission hyperglycemia.

Discussion This study showed that both admission hyperglycemia and diabetes increased 3-year mortality after AMI in the contemporary PCI era. However, influences of admission hyperglycemia and diabetes on mortality were different and time dependent. Admission hyperglycemia increased mortality markedly during the first 30 days, then mortality leveled off in both diabetic and nondiabetic patients. In patients without admission hyperglycemia, 30-day mortality was low regardless of diabetic status. However, diabetes increased mortality thereafter. By 3 years after AMI, mortality of diabetic patients without admission hyperglycemia Figure 3. Three-year mortality curves of diabetic patients with admission caught up to the level of patients with admission hypergly- hyperglycemia (bold solid line), nondiabetic patients with admission hy- cemia. These findings suggested that in the PCI era, admis- perglycemia (bold dotted line), diabetic patients without admission hyper- sion hyperglycemia was associated with short-term mortal- glycemia (solid line), and nondiabetic patients without admission hyper- ity after AMI, whereas diabetes increased long-term glycemia (dotted line). Nondiabetic patients without admission mortality of patients who survived AMI. hyperglycemia had the lowest 3-year mortality. There was no significant In recent years, much attention was given to the evidence difference in 3-year mortality rates among the remaining 3 groups. that concomitant hyperglycemia in patients with AMI increases the risk of mortality.6–8,14,15 In a meta-analysis of 19 articles, Capes et al6 showed that hyperglycemia with AMI Ͻ0.001) and diabetic patients (7.6%, p ϭ 0.002). Compared was associated with increased risk of in-hospital mortality with nondiabetic patients without admission hyperglycemia in patients with and without a history of diabetes. Recent (7.0%), 3-year mortality rates were significantly higher in experimental and clinical studies suggested that rapid in- diabetic patients without admission hyperglycemia (15.7%, creases in plasma glucose increased infarct size. Hypergly- p ϭ 0.02), nondiabetic patients with admission hyperglyce- cemia activates blood coagulation, aggregates inflamma- mia (17.8%, p ϭ 0.002), and diabetic patients with admis- tion, attenuates endothelium function, and abolishes sion hyperglycemia (14.8%, p Ͻ0.001). Multivariate anal- ischemic preconditioning.20–23 These changes impair coro- ysis was performed using nondiabetic patients without nary microvascular function. Although achievement of final admission hyperglycemia as reference and showed that di- Thrombosis In Myocardial Infarction (TIMI)-3 was similar abetic patients without admission hyperglycemia (odds ratio between patients with and without admission hyperglyce- [OR] 1.55, 95% confidence interval [CI] 1.05 to 2.20, p ϭ mia, Iwakura et al24 reported that hyperglycemia was asso- 0.03), nondiabetic patients with admission hyperglycemia ciated with the no-reflow phenomenon using myocardial (OR 1.48, 95% CI 1.09 to 1.97, p ϭ 0.01), and diabetic contrast echocardiography in patients with angiographically patients with admission hyperglycemia (OR 1.42, 95% CI successful reperfusion after PCI. 1.06 to 1.88, p ϭ 0.02) were independently associated with In this study, we showed that admission hyperglycemia 3-year mortality after AMI. was an independent predictor of 30-day mortality, but dia- 1678 The American Journal of Cardiology (www.AJConline.org) betes was not associated with 30-day mortality. Thirty-day 1. Oswald GA, Corcoran S, Yudkin JS. Prevalence and risk of hypergly- mortality was low in patients without admission hyperglycemia and undiagnosed diabetes in patients with acute myocardial infarction. Lancet 1984;1:1264–1267. cemia even if they had a history of diabetes. Although 2. Lakhdar A, Stromberg P, McAlpine SG. Prognostic importance of diabetes was shown to predict morbidity and mortality after hyperglycemia induced by stress after acute myocardial infarction. Br AMI in the thrombolysis era, recent progress in the treat- Med J 1984;288:288. ment of patients with AMI improved the short-term out- 3. Bellodi G, Manicardi V, Malavasi V, Veneri L, Bernini G, Bossini P, Distefano S, Magnanini G, Muratori L, Rossi G, Zuarini A. Hyper- come of diabetic patients. Primary PCI is similarly success- glycemia and prognosis of acute myocardial infarction in patients ful in diabetic and nondiabetic patients and is more effective without diabetes mellitus. Am J Cardiol 1989;64:885–888. than thrombolytic therapy in diabetic patients with AMI.12 4. O’Sullivan JJ, Conroy RM, Robinson K, Hickey N, Mulcahy R. Brener et al,25 reviewing data from the international Global In-hospital prognosis of patients with fasting hyperglycemia after first myocardial infarction. Diabetes Care 1991;14:758–760. Utilization of Streptokinase and Tissue Plasminogen Acti- 5. Fava S, Aquilina O, Azzopardi J, Muscat HA, Fenech FF. The prog- vator for Occluded Coronary Artery (GUSTO) IIb and Reo- nostic value of blood glucose in diabetic patients with acute myocar- Pro and Primary PTCA Organization and Randomized Trial dial infarction. Diabetic Med1996;13:80–83. (PAPPORT), showed that diabetes was not associated with 6. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycemia 30-day mortality after primary PCI. and increased risk after myocardial infarction in patients without diabetes: a systematic overview. Lancet 2000;355:773–778. Although diabetes was not associated with 30-day mor- 7. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL, tality, diabetes increased mortality from 30 days to 3 years. for the ICONS Investigators. Is blood glucose an independent predic- Several studies in the thrombolysis era showed that diabetes tor of mortality in acute myocardial infarction in the thrombolytic era? increased the risk of death in patients who survived myo- J Am Coll Cardiol 2002;40:1748–1754. 8. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, cardial infarction. Recently, the Second Danish Trial in Kouno Y, Umemura T, Nakamura T, Yoshida M. Impact of acute Acute Myocardial Infarction (DANAMI-2) reported that hyperglycemia on left ventricular function after reperfusion therapy in diabetes may abolish the beneficial effect of primary PCI by patients with a first anterior wall acute myocardial infarction. Am long-term risk of clinical reinfarction.26 In this study, we Heart J 2003;146:674–678. 9. GISSI-2 Investigators. Influence of diabetes on mortality in acute also showed that diabetes was associated with increased risk myocardial infarction: data from the GISSI-2 study. J Am Coll Cardiol of death in patients who survived AMI in the PCI era. 1993;22:1788–1794. Several studies showed that diabetes was associated with a 10. Barbash GI, White HD, Modan M, Van de Werf F, for the Investiga- long-term increased low-grade inflammatory state and acti- tors of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial. Significance of diabetes mellitus in patients with acute vation of platelet aggregation, which could contribute to the myocardial infarction receiving thrombolytic therapy. J Am Coll Car- acceleration of atherosclerosis and development of reinfarc- diol 1993;22:707–713. tion.27,28 11. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Conversely, although admission hyperglycemia in- Simoons M, Aylward P, Van de Werf F, Califf RM, for the GUSTO-I investigators. Predictors of 30-day mortality in the era of reperfusion creased 30-day mortality, it had a neutral effect on mortality for acute myocardial infarction. Results from an international trial of thereafter. It was discussed that admission hyperglycemia in 41021 patients. Circulation 1995;91:1659–1668. nondiabetic patients could simply be a marker of preexist- 12. Hadjadj S, Coisne D, Mauco G, Ragot S, Duengler F, Sosner P, ing, but previously undiagnosed, abnormal glucose toler- Torremocha F, Herpin D, Marechaud R. Diabetes mellitus and out- ance, and some previous studies regarded nondiabetic pa- come after primary coronary angioplasty for acute myocardial infarction: lessons from the GUSTO-IIb angioplasty substudy. J Am Coll tients with admission hyperglycemia as having diabetes. Cardiol 2000;35:1502–1512. However, recent studies reported that admission hypergly- 13. Löndahl M, Katzman P, Nilsson A, Ljungdahl L, Prütz KG. Cardio- cemia did not represent previously undiagnosed abnormal vascular prevention before admission reduces mortality following glucose tolerance.29 Our findings suggested that admission acute myocardial infarction in patients with diabetes. J Intern Med 2002;251:325–330. hyperglycemia and diabetes be treated as 2 distinct disease 14. Stranders I, Diamant M, van Gelder RE, Spruijt H, Twisk JW, Heine states. RJ, Visser FC. Admission blood glucose level as risk indicator of death This is a retrospective study. However, all consecutive after myocardial infarction in patients with and without diabetes mel- patients with AMI who underwent coronary angiography litus. Arch Intern Med 2004;164:982–988. 15. Ishihara M, Kojima S, Sakamoto T, Asada Y, Tei C, Kimura K, were prospectively included in a single-center registry. Dur- Miyazaki S, Sonoda M, Tsuchihashi K, Yamagishi M, et al, for the ing this study period, patients received contemporary man- Japanese Acute Coronary Syndrome Study (JACSS) Investigators. agement and 90% of patients underwent primary PCI. In Acute hyperglycemia is associated with adverse outcome after acute this study, use of ␤ blockers and statins was low, although myocardial infarction in the coronary intervention era. Am Heart J 2005;150:814–820. considerable improvements in medical management were 16. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality observed over time (data not shown). Use of evidence-based from coronary heart disease in subjects with type 2 diabetes and in medical therapy offers a survival advantage in patients with nondiabetic subjects with and without prior myocardial infarction. AMI, especially diabetic patients. However, the effect of N Engl J Med 1998;339:229–234. 17. Ishihara M, Sato H, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, evidence-based medical therapy on outcome was not as- Kouno Y, Umemura T, Nakamura T. Impact of diabetes mellitus on sessed because of a small sample size, which is another long-term survival after acute myocardial infarction in patients with limitation of this study. Because diabetes was defined as single vessel disease. Heart 2001;86:133–138. previous or current diagnosis of diabetes at the time of 18. Murcia AM, Hennekens CH, Lamas GA, Jimémez-Navarro M, Rou- leau JL, Flaker GC, Goldman S, Skali H, Braunwald E, Pfeffer MA. hospital admission, some diabetic patients may not have Impact of diabetes on mortality in patients with myocardial infarction been diagnosed as such. However, the prevalence of diabe- and left ventricular dysfunction. Arch Intern Med 2004;164:2273– tes in this study was similar to that in previous studies. 3379. Coronary Artery Disease/Hyperglycemia and Diabetes in AMI 1679

19. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka K, 25. Brener SJ, Ellis SG, Sapp SK, Betriu A, Granger CB, Burchenal JEB, Kouno Y, Umemura T, Nakamura T. Fifteen year trend in treatment Moliterno DJ, Califf RM, Topol EJ, for the GUSTO IIb and RAP- and outcomes after acute myocardial infarction in Japan. Circ J 2002; PORT Investigators. Predictors of death and reinfarction at 30 days 66:178–181. after primary angioplasty: the GUSTO IIb and RAPPORT trials. Am 20. Ceriello A. Coagulation activation in diabetes mellitus: the role of Heart J 2000;139:476–481. hyperglycemia and therapeutic prospects. Diabetologia 1993; 26. Madsen MM, Busk M, Søndergaard HM, Bøttcher M, Mortensen LS, 36:1119–1125. Andersen HR, Nielsen TT, for the DANAMI-2 Investigators. Does 21. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola diabetes mellitus abolish the beneficial effect of primary coronary M, Quagliaro L, Ceriello A, Giugliano D. Inflammatory cytokine angioplasty on long-term risk of reinfarction after acute ST-segment concentrations are acutely increased by hyperglycemia in humans: role elevation myocardial infarction compared with fibrinolysis? (a DANAMI-2 substudy). Am J Cardiol 2005;96:1469–1475. of oxidative stress. Circulation 2002;106:2067–2072. 27. Biondi-Zoccai GG, Abbate A, Liuzzo G, Biasucci LM. Atherothrom- 22. Williams SB, Goldfine AB, Timimi FK, Roddy MA, Simonson DC, bosis, inflammation, and diabetes. J Am Coll Cardiol 2003;41:1071– Creager MA. Acute hyperglycemia attenuates endothelium-dependent 1077. vasodilation in human in vivo. Circulation 1998;97:1695–1701. 28. Rozenman Y, Sapoznikov D, Mosseri M, Gilon D, Lotan C, Nassar H, 23. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Nishioka Y, Weiss AT, Hasin Y, Gotsman MS. Long-term angiographic follow-up Nakamura Y, Yoshida M. Effect of acute hyperglycemia on the isch- of coronary balloon angioplasty in patients with diabetes mellitus: a emic preconditioning effect of prodromal angina pectoris in patients clue to the explanation of the results of the BARI study. Balloon with an anterior wall first acute myocardial infarction. Am J Cardiol Angioplasty Revascularization Investigation. J Am Coll Cardiol 1997; 2003;92:288–291. 30:1420–1425. 24. Iwakura K, Ito H, Ikushima M, Kawano S, Okamura A, Asano K, 29. Ishihara M, Inoue I, Kawagoe T, Shimatani Y, Kurisu S, Hata T, Nakama Kuroda T, Tanaka K, Masuyama T, Hori M, Fujii K. Association Y, Kijima Y, Kagawa E. Is admission hyperglycemia in non-diabetic between hyperglycemia and the no-reflow phenomenon in patients patients with acute myocardial infarction a surrogate for previously un- with acute myocardial infarction. J Am Coll Cardiol 2003;41:1–7. diagnosed abnormal glucose tolerance? Eur Heart J 2006;27:2413–2419. Impact of Time to Treatment on Myocardial Reperfusion and Infarct Size With Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction (from the EMERALD Trial)

Bruce R. Brodie, MDa,*, John Webb, MDd, David A. Cox, MDb, Mansoor Qureshi, MDe, Anna Kalynych, MDg, Mark Turco, MDh, Heinz P. Schultheiss, MDi, Daniel Dulas, MDf, Barry Rutherford, MDj, David Antoniucci, MDk, Tom Stuckey, MDa, Mitch Krucoff, MDc, Raymond Gibbons, MDl, Alexandra Lansky, MDm, Yingbo Na, MDm, Roxana Mehran, MDm, and Gregg W Stone, MDm, for the EMERALD Investigators

The impact of time to treatment on outcomes after primary percutaneous coronary intervention (PCI) is controversial, and there are few data about time to treatment and infarct size. The EMERALD trial randomly assigned 501 high-risk patients with ST-elevation myocardial infarction undergoing primary PCI to stenting with or without GuardWire (Medtronic, Santa Rosa, California) distal protection. Infarct size using sestamibi imaging at 5 to 14 days and clinical outcomes were examined by time to treatment. There were no differences in outcomes between distal protection and control patients. Shorter time to reperfusion (<2vs2to3vs>3to4vs>4 hours) was associated with smaller infarct size and ,(0.08 ؍ trends for better myocardial blush (p ,(0.026 ؍ vs 9% vs 12% vs 11%, p 2%) Incremental delays .(0.06 ؍ lower 6-month mortality rates (0% vs 0% vs 2.4% vs 5.3%, p in reperfusion after 2 hours had little impact on infarct size. Shorter time to reperfusion impacted on infarct size in patients with anterior infarction (0% vs 17% vs 20.5% vs 30.5%, 0.022 ؍ p ,0.23 ؍ but not nonanterior infarction (3% vs 7% vs 7.5% vs 10%, p ,(0.026 ؍ p for interaction). In conclusion, very early reperfusion with primary PCI is associated with smaller infarct size and has a much greater impact in anterior versus nonanterior infarction. Incremental delays in reperfusion after 2 hours have less effect on infarct size. These data have implications regarding the triage of patients for primary PCI. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1680–1686)

The relation between time to treatment and clinical out- (EMERALD) Trial evaluated the impact of primary PCI comes after primary percutaneous coronary intervention with and without distal coronary protection on infarct size (PCI) for patients with ST-segment elevation acute myocar- measured using technetium-99m sestamibi scintigraphy.12 dial infarction (STEMI) has been controversial,1–7 and there This study did not show an effect of distal protection on are few data regarding the relation between time to treat- infarct size, but provided an opportunity to evaluate the ment with primary PCI and infarct size.8–11 Studies that impact of time to treatment with primary PCI on infarct size evaluated the impact of time to treatment with primary PCI in a large patient population. We evaluated the impact of on infarct size had only small numbers of patients and time to treatment with primary PCI on outcomes in the yielded conﬂicting results.8–10 The Enhanced Myocardial EMERALD Trial with special emphasis on myocardial in- Efﬁcacy and Removal by Aspiration of Liberated Debris farct size.

aLeBauer Cardiovascular Research Foundation and Moses Cone Heart Methods and Vascular Center, Greensboro; bMid Carolina Cardiology, Charlotte; c d Study population: The EMERALD trial was a prospec- Duke Clinical Research Institute, Durham, North Carolina; St. Paul’s tive randomized multicenter trial of distal microcirculatory Hospital, Vancouver, Canada; eSt. Joseph Mercy Hospital, Ann Arbor; fMercy Hospital, Coon Rapids, Michigan; gCardiology of Georgia, Atlanta, protection using the GuardWire Plus (Medtronic, Santa Georgia; hWashington Adventist Hospital, Tacoma Park, Maryland; iUni- Rosa, California) balloon occlusion and aspiration system versity Hospital Benjamin Franklin, Berlin, Germany; jSaint Luke’s Hos- as an adjunct to mechanical reperfusion therapy in patients pital Kansas City–Mid America Heart Institute, Kansas City, Missouri; with STEMI. Patients with STEMI Ͻ6 hours in duration kPoliclinico Careggi, Florence, Italy; lMayo Clinic Foundation, Rochester, with high-risk electrocardiographic criteria (Ն2mmofST- m Minnesota; and Cardiovascular Research Foundation and Lenox Hill segment elevation in Ն2 contiguous leads or left branch Heart and Vascular Institute, New York, New York. Manuscript received bundle block) targeted for primary or rescue PCI after failed November 9, 2006; revised manuscript received and accepted January 17, thrombolytic therapy were considered for enrollment. Pa- 2007. Ͼ This study was supported by Medtronic Inc, Minneapolis, Minnesota. tients with shock and serum creatinine 2.5 mg/dl were *Corresponding author: Tel.: 336-547-1756; fax: 336-851-8427. excluded. Of 501 patients randomly assigned in the EMER- E-mail address: [email protected] (B.R. Brodie). ALD Trial, 450 patients had adequate sestamibi scans and

Table 1 Baseline clinical, angiographic, and procedural variables and median infarct size Variable Median Infarct Size (% of left ventricle) p Value Variable Present Variable Absent Age Ͼ70 yrs 13.0 (2.0–36.0) (98) 11.0 (1.0–23.0) (339) 0.09 Women 2.0 (0.0–14.0) (91) 13.0 (3.0–27.0) (346) Ͻ0.0001 Diabetes mellitus 19.5 (6.0–48.0) (50) 11.0 (1.0–23.0) (387) 0.005 Previous myocardial infarction 12.0 (6.0–34.0) (49) 11.0 (0.5–23.5) (388) 0.14 Previous coronary bypass surgery 12.0 (0.0–30.0) (15) 11.0 (2.0–25.0) (422) 0.97 Hypertension 11.0 (2.0–31.0) (161) 11.0 (0.0–23.0) (275) 0.31 Current smoker 11.5 (1.0–23.0) (190) 11.0 (2.0–27.0) (247) 0.91 Killip class ϾII 25.0 (0.0–48.0) (53) 11.0 (2.0–22.0) (378) 0.04 Anterior infarction 22.0 (4.0–43.0) (175) 8.0 (0.0–17.0) (262) Ͻ0.0001 Baseline TIMI ﬂow 0/1 13.0 (4.0–28.0) (279) 5.5 (0.0–18.0) (142) Ͻ0.0001 Collateral ﬂow 0/1 11.0 (2.0–27.0) (314) 12.0 (1.5–20.0) (108) 0.70 3-Vessel coronary disease 11.0 (3.0–29.0) (67) 11.0 (1.0–24.0) (370) 0.40 Rescue PCI 13.0 (3.0–25.0) (81) 11.0 (0.0–24.0) (356) 0.21 Time to reperfusion Ͻ2 hrs 2.0 (0.0–13.0) (21) 11.0 (2.0–24.0) (373) 0.008

Values expressed as median (interquartile range) (number of patients). complete time-to-reperfusion data and form our study largest infarct for any patient in the study (72% of the left group. ventricle). TIMI flows at baseline and after PCI were graded on a scale Study protocol: Patients received aspirin 324 mg of 0 to 3, and myocardial blush after PCI was graded on a scale (chewed), clopidogrel 300 mg, intravenous heparin 70-U/kg of 0 to 3 using methods previously described.15,16 Collateral bolus, and intravenous ␤ blockers in the absence of contra- flow to the infarct zone was assessed on the initial angiogram indications. Glycoprotein IIb/IIIa inhibitors were used at the before PCI and graded on a scale of 0 to 3 using the method of discretion of the operator, and additional heparin was given Rentrop et al.17 All measurements were made by an angio- before PCI to prolong the activated clotting time to Ն300 graphic core laboratory blinded to randomization and patient seconds (200 to 300 seconds with glycoprotein IIb/IIIa outcomes. inhibitors). Eligible patients were randomly assigned to Summed STR was measured from continuous 24-hour primary PCI with stent implantation if appropriate, with or digital 12-lead electrocardiographic recordings at a central without distal protection. core laboratory as previously described.18,19 Percentage of End points and definitions: Primary end points of the STR from baseline to 60 minutes after the last contrast EMERALD trial were (1) infarct size measured using tech- injection was calculated using Schroder’s classification as netium-99m sestamibi imaging with sestamibi 20 to 30 mCi complete (Ͼ70%), partial (30% to 70%), or absent injected on days 5 to 14, and (2) frequency of complete (Ͻ30%).20 electrocardiographic ST-segment resolution (STR) mea- Statistical analysis: Categorical data were compared us- sured using continuous Holter monitoring after PCI. Sec- ing Fisher’s exact test, and continuous variables are pre- ondary end points included Thrombolysis In Myocardial sented as median with interquartile range and compared Infarction (TIMI) flow rates after PCI, restoration of normal using Kruskal-Wallis nonparametric test. Six-month out- (grade 3) myocardial blush, and a composite of death, re- comes are summarized as Kaplan-Meier estimates and com- infarction, ischemic target-vessel revascularization, and pared using log-rank test. The relation between time to stroke at 1 and 6 months. Reinfarction, ischemic target- treatment expressed as a continuous variable and infarct size vessel revascularization, and disabling stroke were defined was evaluated using linear regression. Predictors of infarct as previously reported.10 Time to reperfusion was defined as size were compared using multiple linear regression. All time from symptom onset until balloon inflation. Door-to- variables listed in Table 1 were entered into the model. All balloon time was time from arrival at the hospital until comparisons are 2 sided, and p Ͻ0.05 was defined as sig- balloon inflation. All clinical end points were adjudicated nificant, except when otherwise stated. by a clinical events committee. Infarct size was measured using technetium-99m sestamibi imaging at 5 to 14 days after PCI. Single-photon Results emission computed tomographic imaging equipment and Baseline variables by treatment times: Frequencies of image acquisition procedures for each site were tested and baseline clinical and angiographic variables were similar quality controlled using a cardiac phantom. Data were pro- across the 4 categories of time to reperfusion, although there cessed by staff blinded to treatment assignment at a central was a trend for patients with longer times to reperfusion to core laboratory, as previously described.13,14 Infarct size be older (Table 2). Frequencies of baseline clinical and was expressed as percentage of the left ventricle. Infarct size angiographic variables were similar across categories of for patients who died before 5 to 14 days was imputed as the door-to-balloon time, except that patients with shorter door- 1682 The American Journal of Cardiology (www.AJConline.org)

Table 2 Baseline clinical and angiographic variables by time to reperfusion Variable Time to Reperfusion (hrs) p Value Ͻ2(nϭ 24) 2–3 (n ϭ 111) Ͼ3–4 (n ϭ 130) Ͼ4(nϭ 185) Age (yrs) 58.8 (53.9–67.3) 57.9 (52.6–64.9) 58.0 (50.2–66.7) 61.8 (52.4–71.2) 0.08 Women 25.0% 12.6% 23.1% 22.7% 0.13 Diabetes mellitus 8.3% 13.5% 14.6% 12.7% 0.59 Previous myocardial infarction 12.5% 12.6% 6.2% 13.0% 0.24 Previous coronary bypass surgery 4.2% 2.7% 2.3% 3.8% 0.87 Hypertension 16.7% 8.4% 11.8% 12.0% 0.64 Current smoker 21.7% 38.7% 36.2% 38.9% 0.43 Killip class ՆII 41.7% 40.5% 43.1% 42.7% 0.98 Infarct artery Left anterior descending 33.3% 36.0% 44.6% 39.5% 0.50 Right 62.5% 50.5% 42.3% 53.3% 0.16 Circumflex 4.2% 13.5% 13.1% 7.6% 0.19 Saphenous vein graft 0% 1.8% 0.8% 1.6% 0.82 TIMI 3 flow before PCI 13.6% 18.3% 21.1% 20.6% 0.83 Collateral flow 2–3 22.7% 29.6% 21.9% 26.7% 0.57 Index ejection fraction (%) 66.5 (60.0–74.0) 65.0 (55.0–72.0) 61.5 (53.0–71.0) 62.0 (53.0–70.0) 0.21 3-Vessel coronary disease 12.5% 19.8% 13.1% 17.8% 0.48

Table 3 Baseline clinical and angiographic variables by door-to-balloon time Variable Door-to-Balloon Time (hrs) p Value Ͻ1(nϭ 33) 1–1.5 (n ϭ 70) Ͼ1.5–2 (n ϭ 98) Ͼ2(nϭ 195) Age (yrs) 59.9 (53.9–72.5) 60.5 (54.4–65.3) 57.6 (50.5–67.0) 57.2 (50.4–67.4) 0.16 Women 27.3% 12.9% 23.5% 20.0% 0.26 Diabetes mellitus 18.2% 12.9% 10.2% 10.8% 0.61 Previous myocardial infarction 9.1% 20.0% 6.1% 8.2% 0.02 Previous coronary bypass surgery 3.0% 5.7% 3.1% 1.0% 0.19 Hypertension 43.8% 38.6% 33.7% 33.3% 0.62 Current smoker 33.3% 42.9% 48.0% 42.6% 0.52 Killip class ՆII 6.1% 9.1% 11.6% 13.4% 0.57 Infarct artery Left anterior descending 24.2% 37.1% 40.4% 43.4% 0.20 Right 60.6% 51.4% 45.5% 46.5% 0.41 Circumflex 15.2% 7.1% 12.1% 9.6% 0.56 Saphenous vein graft 0% 4.3% 2.0% 0.5% 0.13 TIMI 3 flow before PCI 12.9% 13.6% 17.3% 21.5% 0.41 Collateral flow 2–3 30.0% 30.3% 26.5% 24.1% 0.71 Index ejection fraction (%) 66.5 (58.0–73.0) 63.0 (56.0–71.0) 65.0 (57.0–72.0) 61.5 (52.5–71.0) 0.22 3-Vessel coronary disease 15.2% 22.9% 11.2% 17.9% 0.24 to-balloon times had a higher frequency of previous infarc- Relation between treatment times and infarct size: tion (Table 3). Time to reperfusion expressed as a continuous variable significantly correlated with imputed infarct size using lin- Relations among treatment times and coronary flow, ear regression, but the correlation was very weak because myocardial reperfusion, and clinical outcomes: Patients much of the variation was explained by other variables (p ϭ with shorter times to reperfusion had trends for a higher 0.031, r ϭ 0.012; Figure 1). Correlation between time to frequency of final grade 3 myocardial blush, but there were reperfusion and infarct size was significant, but also very no significant correlations between time to reperfusion and weak, in patients with anterior infarction (p ϭ 0.017, r ϭ final TIMI 3 flow or STR (Table 4). Patients with longer 0.035; Figure 2) and was not significant in patients with times to reperfusion had trends for higher mortality at 6 ϭ ϭ months and significantly higher frequencies of death or nonanterior infarction (p 0.35, r 0.004; Figure 2). Time reinfarction at 6 months (Table 4). There were no other to reperfusion was a significant predictor of infarct size significant correlations between time to reperfusion and using multiple linear regression in patients with anterior clinical outcomes. There were no significant correlations infarction (p ϭ 0.042), but not in patients with nonanterior between door-to-balloon time and myocardial reperfusion infarction (p ϭ 0.73). There was a significant interaction or clinical outcomes (Table 5). between time to reperfusion and infarct location (p ϭ Coronary Artery Disease/Time to Treatment and Infarct Size 1683

Table 4 Myocardial reperfusion, infarct size, and clinical outcomes by time to reperfusion Time to Reperfusion (hrs) p Value Ͻ2(nϭ 24) 2–3 (n ϭ 111) Ͼ3–4 (n ϭ 130) Ͼ4(nϭ 185) Myocardial reperfusion Final TIMI-3 ﬂow 95.5% 91.7% 89.8% 87.8% 0.58 Final grade 3 blush 66.7% 65.3% 57.1% 50.3% 0.08 Compete STR (60 min) 62.5% 67.3% 69.4% 67.5% 0.92 Infarct size All (% of LV) 2 (0–13) 9 (0–18) 12 (2–24) 11 (2–29) 0.026 Left anterior descending (% of LV) 0 (0–14) 17 (3.5–35.5) 20.5 (6–40) 30.5 (3–54) 0.026 Right, circumﬂex (% of LV) 3 (0–13) 7 (0–14) 7.5 (2–16.5) 10 (1–19) 0.23 Clinical outcomes (6 mos) Death 0% 0% 2.4% 5.3% 0.06 Reinfarction 0% 2.8% 2.4% 5.2% 0.42 Death or reinfarction 0% 2.8% 4.0% 9.8% 0.036 Stroke 0% 0.9% 1.6% 1.2% 0.91 Target-vessel revascularization 0% 6.5% 5.2% 7.1% 0.54 Major adverse clinical events 0% 8.3% 8.3% 13.3% 0.15

LV ϭ left ventricle.

Table 5 Myocardial reperfusion, infarct size, and clinical outcomes by door-to-balloon time Door-to-Balloon Time (hrs) p Value Ͻ1(nϭ 33) 1–1.5 (n ϭ 70) Ͼ1.5–2 (n ϭ 98) Ͼ2(nϭ 195) Myocardial reperfusion Final TIMI 3 ﬂow 93.5% 83.3% 93.9% 90.5% 0.14 Final grade 3 blush 64.5% 68.3% 61.4% 52.5% 0.12 Complete STR (60 min) 54.8% 64.6% 75.0% 70.1% 0.17 Infarct size All (% of LV) 4.5 (0–14) 11 (2–22) 12 (0–22) 11 (0.5–23) 0.37 Left anterior descending (% of LV) 0 (0–14) 22 (0–38) 21.5 (9–42) 22 (3–48) 0.15 Right, circumﬂex (% of LV) 5 (3–16) 9 (2–14) 5 (0–16) 8 (2–18) 0.63 Clinical outcomes (6 mos) Death 0% 0% 1.0% 4.6% 0.11 Reinfarction 0% 5.7% 3.2% 3.3% 0.52 Death or reinfarction Stroke 0% 1.5% 1.0% 0.5% 0.83 Target-vessel revascularization 6.7% 5.7% 5.4% 6.9% 0.99 Major adverse clinical events 6.7% 8.6% 7.3% 11.3% 0.78

Abbreviation as in Table 4.

0.022). There were no interactions between time to reperfusion and other predictor variables. Time to reperfusion expressed as a categorical variable (Ͻ2vs2to3vsϾ3to4vsϾ4 hours) significantly correlated with median infarct size (2% vs 9% vs 12% vs 11%, p ϭ 0.026; Table 4 and Figure 3). The relation did not appear linear. The smallest infarct size was seen in patients with very early reperfusion (Ͻ2 hours; Table 4 and Figure 3). After 2 hours, incremental delays in time to reperfusion had only a small impact on infarct size. Time to reperfusion significantly correlated with infarct size in patients with anterior infarction (p ϭ 0.026; Table 4 and Figure 4), but not in patients with nonanterior infarction (p ϭ 0.16; Table 4 and Figure 4). Time to reperfusion expressed as a categorical variable was a significant independent predictor of infarct size using multiple linear regression (Table 6). Door-to-balloon time expressed as a continuous variable Figure 1. Plot of imputed infarct size by time to reperfusion in all pa- significantly correlated with infarct size (p ϭ 0.008, r ϭ tients. 1684 The American Journal of Cardiology (www.AJConline.org)

Figure 2. Plot of imputed infarct size by time to reperfusion in patients with (A) anterior and (B) nonanterior infarction.

STEMI treated with primary PCI; (2) time to reperfusion impacts on infarct size in patients with anterior infarction, but has less effect in patients with nonanterior infarction; (3) infarct size is smallest when reperfusion is achieved at Ͻ2 hours, after which there is less change in infarct size with incremental delays in time to reperfusion; and (4) time to reperfusion has little effect on measures of myocardial reperfusion. Previous studies evaluating time to reperfusion and infarct size had small numbers of patients and yielded conflicting results.8–10 O’Keefe et al8 evaluated predictors of myocardial salvage in 59 patients with STEMI treated using primary PCI with acute and follow-up sestamibi imaging and found that shorter times to reperfusion (Ͻ2vs2to4vs Ͼ4 hours) were associated with better myocardial salvage index (80% vs 47% vs 44%, p ϭ 0.004). Similarly, Milavetz Figure 3. Imputed infarct size (median values) by time to reperfusion. et al9 studied 55 patients with anterior STEMI undergoing successful reperfusion and found that time to reperfusion 0.020), but the correlation was very weak. The correlation Ͻ2 hours was associated with the highest myocardial sal- between door-to-balloon time and infarct size was significant vage. Conversely, Schomig et al10 found no significant in patients with anterior infarction (p ϭ 0.007, r ϭ 0.051), but relation between time to reperfusion with primary PCI and not in patients with nonanterior infarction (p ϭ 0.52, r ϭ infarct size. However, this study did not evaluate the effect 0.002). Door-to-balloon time expressed as a categorical vari- of very early reperfusion (Ͻ2 hours) on infarct size. able did not significantly correlate with infarct size (Table 5). Our study with larger numbers of patients documents the nonlinear relation between time to reperfusion and infarct Other predictors of infarct size: Relations among base- size that was shown using both primary PCI13,14 and fibrino- line clinical, angiographic, and procedural variables and lytic therapy.21 Early reperfusion (Ͻ2 hours) was associated infarct size are listed in Table 1. Infarct size was signifi- with smaller infarct size, but incremental delays in reperfu- cantly greater in men and patients with diabetes, Killip class sion after 2 hours appeared to have less effect on infarct ՆII, anterior infarction, baseline TIMI flow 0/1, and time to Ͼ size. This is consistent with animal models of reperfusion reperfusion 2 hours. described by Reimer et al22 in which the time window for Using multiple linear regression, the variables anterior in- myocardial salvage was limited to the first 3 hours. farction, diabetes, baseline TIMI flow 0/1, rescue PCI, male Several previous studies showed that the presence of gender, longer time to reperfusion, and older age were signif- residual flow to the infarct zone (baseline TIMI flow 2 to 3 icant independent predictors of larger infarct size (Table 6). or collateral flow 2 to 3) was associated with smaller infarct Infarct location, diabetes, and baseline TIMI flow accounted size.8,9,23 We found that baseline TIMI 2 to 3 flow, but not for most of the variability in infarct size. Time to reperfusion, collateral flow, was associated with smaller infarct size. In gender, and age accounted for less of the variability in infarct contrast to previous studies,9,23 we did not find a significant size. interaction between time to reperfusion and baseline TIMI flow or collateral flow on infarct size. Although time to Discussion reperfusion impacts on infarct size, most of the variability of Major findings of this study are that (1) time to reperfusion infarct size is explained by other variables (infarct location, has a significant impact on infarct size in patients with diabetes, baseline TIMI flow, rescue PCI, and male gender). Coronary Artery Disease/Time to Treatment and Infarct Size 1685

Figure 4. Imputed infarct size (median values) by time to reperfusion in patients with (A) anterior and (B) nonanterior infarction.

Table 6 acute and convalescent images, which was not done for Predictors of infarct size by multiple linear regression logistical reasons, would have allowed assessment of area at Multivariable Predictors Estimate SE p Value risk and calculation of myocardial salvage index and added Anterior infarction 15.38 1.79 Ͻ0.0001 power to our study. Infarct size was measured at 5 to 14 Diabetes mellitus 10.00 2.74 0.0003 days. Measurements at a later time may have detected ad- Baseline TIMI flow 0/1 8.43 1.90 Ͻ0.0001 ditional myocardial salvage. Rescue PCI 7.75 2.53 0.002 Our data may have implications for the triage of patients Male sex 5.44 2.23 0.02 for primary PCI, especially patients presenting at noninter- Time to reperfusion (per category)* 2.55 1.01 0.01 ventional hospitals. In patients who present with STEMI Age (per 10 yrs) 2.05 0.76 0.007 early after the onset of symptoms (Ͻ2 hours), time is im- * Time onset to first balloon was categorized as Ͻ2 versus 2 to 3 versus portant for myocardial salvage. If substantial delays to pri- 3 to 4 versus Ͼ4 hours. mary PCI are expected, alternative reperfusion strategies may be considered. In patients who present later after the onset of symptoms (Ͼ2 hours) and patients with nonanterior 6,7,24,25 26 Most, but not all, previous studies with primary infarction, delays are less important for myocardial salvage PCI showed that longer time to reperfusion was associated and transfer for primary PCI may be the best option, even with worse STR and worse myocardial blush scores. Our with longer delays. Ongoing trials with facilitated PCI study showed trends for worse blush scores with later reper- (pharmacologic reperfusion therapy followed by emergent fusion, but no significant correlation between time to reper- PCI) may help define the best reperfusion strategy for pa- fusion and STR. Reasons for these differences from previous studies are not clear, but our study has a smaller number tients in whom substantial delays to PCI are expected. of patients than some previous studies. Finally, our data show that only a small proportion of Some,2,5–7 but not all,1,3,4 previous studies showed a patients with STEMI treated with primary PCI (5.3%) un- Ͻ significant correlation between time to reperfusion with dergo reperfusion early enough ( 2 hours) to achieve a primary PCI and mortality. We found a trend for lower substantial decrease in infarct size. This emphasizes the mortality at 6 months and a significantly lower incidence of need for improvement in processes to shorten time to reper- mortality or reinfarction at 6 months with early reperfusion. fusion. Mortality appeared to increase with increasing time to reperfusion out to 6 hours. This is in contrast to some 1. Berger PB, Ellis SG, Holmes DR, Granger CB, Criger DA, Betriu A, previous studies2,7 that showed that incremental time delays Topol EJ, Califf RM. Relationship between delay in performing direct coronary angioplasty and early clinical outcomes in patients with acute after 2 to 3 hours had little impact on mortality. Our study myocardial infarction: results from the GUSTO-IIb trial. Circulation was not powered to detect differences in clinical events, and 1999;100:14–20. these differences may be related to our small sample size. 2. Brodie BR, Stuckey TD, Wall TC, Kissling G, Hansen CJ, Muncy DB, Our study has several limitations. Although this is the Weintraub RA, Kelly TA. Importance of time to reperfusion for 30 day largest primary PCI trial with data for infarct size using and late survival and recovery of left ventricular function after primary sestamibi imaging, the small number of patients treated very angioplasty for acute myocardial infarction. J Am Coll Cardiol 1998; 32:1312–1319. early limits the power to perform subgroup analyses. This is 3. Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French an observational study, and there may be differences in WJ, Gore JM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship baseline variables across categories of time to treatment (not of symptom-onset-to-balloon time and door-to-balloon time with mor- adjusted for by multivariable analyses) that could influence tality in patients undergoing angioplasty for acute myocardial infarc- our results. Time to reperfusion was defined as time from tion. JAMA 2000;283:2941–2947. symptom onset until balloon inflation, but is uncertain in 4. Brodie BR, Stone GW, Morice MC, Cox DA, Garcia E, Mattos LA, Boura J, O’Neill WW, Stuckey TD, Milks S, Lansky AJ, Grines CL, patients with TIMI 2 to 3 flow on initial angiography. There for the Stent Primary Angioplasty in Myocardial Infarction Study are limitations in the measurement of infarct size using Group. Importance of time to reperfusion on outcomes with primary sestamibi imaging described previously.14 Measurement of coronary angioplasty for acute myocardial infarction: results from the 1686 The American Journal of Cardiology (www.AJConline.org)

Stent Primary Angioplasty in Myocardial Infarction Trial. Am J plasty in acute myocardial infarction. J Am Coll Cardiol Cardiol 2001;88:1085–1090. 2002;39:591–597. 5. Antoniucci D, Valenti R, Migliorini A, Moschi G, Trapani M, 16. Costantini CO, Stone GW, Mehran R, Aymong E, Grines CL, Cox Buonamici P, Cerisano G, Bolognese L, Santoro GM. Relation of time DA, Stuckey T, Turco M, Gersh BJ, Tcheng JE, et al. Frequency, to treatment and mortality in patients with acute myocardial infarction correlates, and clinical implications of myocardial perfusion after undergoing primary coronary angioplasty. Am J Cardiol 2002;89: primary angioplasty and stenting with and without glycoprotein IIb/ 1248–1252. IIIa inhibition in acute myocardial infarction. J Am Coll Cardiol 6. De Luca G, Suryapranata H, Zijlstra F, van’t Hof AW, Hoorntje JC, 2004;44:305–312. Gosselink AT, Dambrink JH, de Boer MJ, for the ZWOLLE Myocar- 17. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral dial Infarction Study Group. Symptom-onset-to-balloon time and mor- channel filling immediately after controlled coronary artery occlusion tality in patients with acute myocardial infarction treated by primary by an angioplasty balloon in human subjects. J Am Coll Cardiol angioplasty. J Am Coll Cardiol 2003;42:991–997. 1985;5:587–592. 7. Brodie BR, Stone GW, Cox DA, Stuckey TD, Turco M, Tcheng JE, 18. Krucoff MW, Croll MA, Pope JE, Pieper KS, Kanani PM, Granger Berger P, Mehran R, McLaughlin M, Costantini C, Lansky AJ, Grines CB, Veldkamp RF, Wagner BL, Sawchak ST, Califf RM. Continu- CL. Impact of treatment delays on outcomes of primary percutaneous ously updated 12-lead ST-segment recovery analysis for myocardial coronary intervention for acute myocardial infarction: analysis from infarct artery patency assessment and its correlation with multiple the CADILLAC Trial. Am Heart J 2006;151:1231–1238. simultaneous early angiographic observations. Am J Cardiol 1993;71: 8. O’Keefe JH, Grines CL, DeWood MA, Bateman TM, Christian TF, 145–151. Gibbons RJ. Factors influencing myocardial salvage with primary 19. Roe MT, Green CL, Giugliano RP, Gibson CM, Baran K, Greenberg angioplasty. J Nucl Cardiol 1995;2:35–41. M, Palmeri ST, Crater S, Trollinger K, Hannan K, Harrington RA, 9. Milavetz JJ, Giebel DW, Christian TF, Schwartz RS, Holmes DR, Krucoff MW, for the INTEGRITI Investigators. Improved speed and Gibbons RJ. Time to therapy and salvage in myocardial infarction. stability of ST-segment recovery with reduced-dose tenecteplase and J Am Coll Cardiol 1998;31:1246–1251. eptifibatide compared with full-dose tenecteplase for acute ST-seg- 10. Schomig A, Ndrepepa G, Mehilli J, Schwaiger M, Schuhlen H, ment elevation myocardial infarction. J Am Coll Cardiol 2004;43: Nekolla S, Pache J, Martinoff S, Bollwein H, Kastrati A. Therapy- 549–556. dependent influence of time-to-treatment interval on myocardial sal- 20. Schroder R, Wegscheider K, Schroder K, Dissmann R, Meyer-Sa- vage in patients with acute myocardial infarction treated with coronary bellek W. Extent of early ST segment elevation resolution: a strong artery stenting or thrombolysis. Circulation 2003;108:1084–1088. predictor of outcome in patients with acute myocardial infarction and 11. Schomig A, Mehilli J, Antoniucci D, Ndrepepa G, Markwardt C, Di a sensitive measure to compare thrombolytic regimens. J Am Coll Pede F, Nekolla SG, Schlotterbeck K, Schuhlen H, Pache J, et al, for Cardiol 1995;26:1657–1664. the Beyond 12 hours Reperfusion AlternatiVe Evaluation (BRAVE-2) 21. Chareonthaitawee P, Gibbons RJ, Roberts RS, Christian TF, Burns R, Trial Investigators. Mechanical reperfusion in patients with acute myo- Yusuf S. The impact of time to thrombolytic treatment on outcome in cardial infarction presenting more than 12 hours from symptom onset: patients with acute myocardial infarction. Heart 2000;84:142–148. a randomized controlled trial. JAMA 2005;293:2865–2872. 22. Reimer KA, Vander Heide RS, Richard VJ. Reperfusion in acute 12. Stone GW, Webb J, Cox DA, Brodie BR, Qureshi M, Kalynych A, myocardial infarction: effect of timing and modulating factors in Turco M, Schultheiss HP, Dulas D, Rutherford BD, et al, for the experimental models. Am J Cardiol 1993;72(suppl):13G–21G. Enhanced Myocardial Efficacy and Recovery by Aspiration of Liber- 23. Clements IP, Christian TF, Higano ST, Gibbons RJ, Gersh BJ. Resid- ated Debris (EMERALD) Investigators. Distal microcirculatory pro- ual flow to the infarct zone as a determinant of infarct size after direct tection during percutaneous coronary intervention in acute ST-segment angioplasty. Circulation 1993;88:1527–1533. elevation myocardial infarction: a randomized controlled trial. JAMA 24. van’t Hof AW, Liem A, de Boer MJ, Zijlstra F. Clinical value of 2005;293:1063–1072. 12-lead electrocardiogram after successful reperfusion therapy for 13. Christian TF, Schwartz RS, Gibbons RJ. Determinants of infarct size acute myocardial infarction. Lancet 1997;350:615–619. in reperfusion therapy for acute myocardial infarction. Circulation 25. Fu Y, Goodman S, Chang WC, Van De Werf F, Granger CB, Arm- 1992;86:81–90. strong PW. Time to treatment influences the impact of ST-segment 14. Gibbons RJ, Miller TD, Christian TF. Infarct size measured by SPECT resolution on 1-year prognosis: insights from the ASSENT-II trial.Cir- imaging with technetium-99m sestamibi—a measure of the efficacy of culation2001;104:2653–2659. therapy in acute myocardial infarction. Circulation 2000;101:101– 26. Schroder K, Wegscheider K, Zeymer U, Tebbe U, Schroder R. Extent 108. of ST-segment deviation in a single electrocardiogram lead 90 minutes 15. Stone GW, Peterson MA, Lansky AJ, Dangas G, Mehran R, Leon MB. after thrombolysis as a predictor of medium term mortality in acute Impact of normalized myocardial perfusion after successful angio- myocardial infarction. Lancet 2001;358:1479–1486. Association of Prerandomization Anticoagulant Switching With Bleeding in the Setting of Percutaneous Coronary Intervention (A REPLACE-2 Analysis)

C. Michael Gibson, MDa,*, Yuli Ten, MBBSa, Sabina A. Murphy, MPHa, Lauren N. Ciaglo, BAa, Matthew C. Southard, BSa, A. Michael Lincoff, MDb, and Ron Waksman, MDc

The REPLACE-2 trial of patients who underwent urgent or elective percutaneous coronary intervention (PCI) demonstrated a significantly lower bleeding risk with bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor compared with unfractionated heparin with planned glycoprotein IIb/IIIa inhibitor. The goal of this analysis was to evaluate whether a hazard existed when unfractionated heparin or low-molecular-weight heparin was administered before study medication in the REPLACE-2 trial. The REPLACE-2 trial randomized 6,010 patients undergoing PCI to receive bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor or unfractionated heparin plus planned glycoprotein IIb/IIIa inhibitor. The present study compared bleeding among patients treated with or without antithrombin therapy in the 48 hours before study treatment. Among patients treated with bivalirudin, there was no difference in protocol-defined major or minor bleeding, bleeding according to Thrombolysis In Myocardial Infarction criteria, or noncoronary artery bypass graft blood transfusions between the patients treated with versus without antithrombin NS). However, in patients treated with unfractionated heparin plus planned ؍ therapy (p glycoprotein IIb/IIIa inhibitor, there was a significant increase in the composite of protocol- defined major or minor bleeding and in noncoronary artery bypass graft blood transfusions (p <0.05 for 3-way comparison vs no unfractionated heparin and for 2-way comparisons of no unfractionated heparin vs unfractionated heparin or low-molecular-weight heparin). In conclusion, in patients treated with bivalirudin, pretreatment with antithrombin therapy was not associated with increased bleeding. In contrast, among patients randomized to receive unfractionated heparin and planned glycoprotein IIb/IIIa, pretreatment with antithrombin therapy was associated with increased protocol-defined composite major or minor bleeding and increased need for transfusion. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1687–1690)

The purpose of this study was twofold: (1) to evaluate if who underwent elective or urgent percutaneous coronary switching from low-molecular-weight heparin or unfrac- intervention (PCI) were randomized to receive bivalirudin tionated heparin before randomization to bivalirudin was and provisional glycoprotein IIb/IIIa inhibitor or unfraction- associated with an excess of bleeding compared with biva- ated heparin plus planned glycoprotein IIb/IIIa inhibitor. lirudin therapy with no previous antithrombin therapy, and Patients were randomized to the reference standard of un- (2) to evaluate the association of prerandomization low- fractionated heparin (65 U/kg, maximum of 7,000 U) and molecular-weight heparin or unfractionated heparin therapy routine glycoprotein IIb/IIIa blockade (abciximab or eptifi- with bleeding among patients subsequently treated with batide) or bivalirudin (0.75-mg/kg bolus, 1.75 mg/kg/hour unfractionated heparin and glycoprotein IIb/IIIa inhibition. infusion) with provisional glycoprotein IIb/IIIa blockade during PCI. Within this trial, prerandomization antithrom- Methods bin therapy was not specified; patients may have received The design, methods, and primary results of the Randomized no prerandomization antithrombin therapy or may have Evaluation in Percutaneous coronary intervention Linking been pretreated with antithrombin therapy with unfraction- Angiomax to reduced Clinical Events (REPLACE-2) have ated heparin or low-molecular-weight heparin at the discre- been described in detail elsewhere.1 A total of 6,010 patients tion of the treating physician. With respect to previous anticoagulant therapy, patients were excluded if they required ongoing warfarin therapy, bivalirudin within 24 aCardiovascular Division, Beth Israel Deaconess Medical Center, Bos- hours, abciximab within 7 days, or eptifibatide or tirofiban ton, Massachusetts; bCardiovascular Division, Cleveland Clinic Founda- c within 12 hours before randomization. Patients who had tion, Cleveland, Ohio; and Washington Hospital Center, Washington, DC. been treated with low-molecular-weight heparin could be Manuscript received October 12, 2006; revised manuscript received Jan- Ͼ uary 22, 2007 and accepted January 29, 2007. enrolled if the last dose was given 8 hours previously; *Corresponding author: Tel: 617-525-6884; fax: 888-249-5261. those treated with unfractionated heparin within 6 hours E-mail address: [email protected] (C.M. Gibson). could be enrolled if the activated partial thromboplastin

Table 1 Bleeding rates associated with different antithrombin transitions UFH¡Bivalirudin LMWH¡Bivalirudin Naive¡GP UFH¡GP LMWH¡GP ءVariable Naive¡Bivalirudin (n ϭ 2,345) (n ϭ 287) (n ϭ 258) Ilb/IIIa/UFH Ilb/IIIa/UFH IlbIIIa/UFH (n ϭ 2,325) (n ϭ 349) (n ϭ 313) Protocol major bleeding 2.3%* 1.7% 2.7% 3.6% 4.9% 5.8% Protocol minor bleeding 13.4%* 13.6% 14.0% 25.0% 28.9% 29.1% Protocol major/minor bleeding 15.6%* 15.3% 16.7% 28.6%† 33.8% 34.8% TIMI major/minor bleeding 1.9%* 1.4% 1.9% 3.5% 4.3% 5.4% Ն2 Non-CABG transfusions 0.8%* 1.1% 1.2% 1.0%† 2.3% 2.9%

*pϭ NS for all 3-way comparisons versus bivalirudin alone. † p Ͻ0.05 for 2-way comparison versus GP Ilb/IIIa, UFH-naive as well as 2-way comparisons of UFH– naive versus either preceding UFH or preceding LMWH. CABG ϭ coronary artery bypass grafting; GP ϭ glycoprotein; LMWH ϭ low-molecular-weight heparin; UFH ϭ unfractionated heparin. time was Յ50 seconds or activated clotting time was Յ175 values are reported as medians and interquartile ranges. For seconds. comparisons among categorical variables, analyses were All patients received aspirin. Pretreatment with clopi- performed with the chi-square test. Cumulative distribution dogrel 300 mg was strongly encouraged 2 to 12 hours curves were used to display the relative timing of bleeding before the interventional procedure, followed by daily ad- events, and the Wilcoxon rank-sum test was used to test for ministration of 75 mg for Ն30 days. Before each patient differences in the distribution. was randomized, physicians were required to specify in the study database whether abciximab or eptifibatide was to be Results used as the glycoprotein IIb/IIIa inhibitor in the heparin group or as provisional administration in the bivalirudin group. Pa- Among the patients who received bivalirudin, 2,345 patients tients were randomized to receive bivalirudin (with provisional had not received an antithrombin agent during that hospi- glycoprotein IIb/IIIa blockade) or heparin plus planned gly- talization before randomization, 287 had received unfrac- coprotein IIb/IIIa blockade. Bivalirudin was administered as tionated heparin, and 258 patients had received low-molec- a bolus of 0.75 mg/kg before the start of intervention, ular-weight heparin. Of the patients who received followed by infusion of 1.75 mg/kg/hour for the duration of glycoprotein IIb/IIIa inhibitors and unfractionated heparin the procedure. Patients randomized to receive heparin plus during PCI, 2,325 patients were antithrombin-naive, 349 glycoprotein IIb/IIIa received a heparin bolus of 65 U/kg had received unfractionated heparin, and 313 had received (maximum 7,000 U) before PCI with abciximab (0.25- low–molecular-weight heparin (Table 1). mg/kg bolus, 0.125 ␮g/kg/min [maximum 10 ␮g/min] in- Among patients randomized to receive bivalirudin, there fusion for 12 hours) or eptifibatide (2 180-␮g/kg boluses 10 was no significant difference in major or minor bleeding, minutes apart, 2.0 ␮g/kg/min infusion for 18 hours). An noncoronary artery bypass graft blood transfusions, or additional bolus of bivalirudin (0.3 mg/kg) or heparin (20 TIMI-defined major bleeding when patients receiving pre- U/kg) was given if the activated clotting time was Ͻ225 ceding antithrombin therapy with unfractionated heparin or seconds; a matching saline solution placebo bolus was ad- low-molecular-weight heparin were compared with those ministered if the activated clotting time was Ն225 seconds. patients who were not treated with any preceding antithrom- Provisional glycoprotein IIb/IIIa blockade with the agent bin therapy (p ϭ NS for all 3-way comparisons vs bivaliru- chosen before randomization could be administered for pro- din alone; Table 1). cedural or angiographic complications at any time during In contrast, among patients randomized to receive hepa- the PCI with a blinded bolus plus infusion of active drug (in rin plus planned glycoprotein IIb/IIIa inhibitor, there was a the bivalirudin group) or placebo (in the heparin plus gly- significant increase in the composite of major or minor coprotein IIb/IIIa group). bleeding and noncoronary artery bypass graft blood trans- Bleeding complications were compared between patients fusions among patients treated with preceding antithrombin who had or had not been treated with antithrombin before therapy with unfractionated heparin or low-molecular- randomization. Protocol-defined major bleeding was de- weight heparin (p Ͻ0.05 for 3-way comparison vs glyco- fined as intracranial, intraocular, or retroperitoneal hemor- protein IIb/IIIa inhibitor or unfractionated heparin–naive rhage; clinically overt blood loss resulting in a decrease in and for 2-way comparisons of unfractionated heparin–naive hemoglobin of Ͼ3 g/dl; any decrease in hemoglobin of Ͼ4 vs unfractionated heparin or low-molecular-weight heparin; g/dl; or transfusion of Ն2 U of packed red blood cells or Table 1). There was no difference in the individual end whole blood. Protocol-defined minor bleeding was defined points of protocol- or TIMI-defined major or minor bleeding as clinically overt bleeding that did not meet criteria for (Table 1). major bleeding. Bleeding was also classified according to To further investigate the association of the duration of the criteria of the Thrombolysis In Myocardial Infarction discontinuation of unfractionated heparin or low-molecular- (TIMI) study group.2 weight heparin before PCI relative to the presence or ab- All analyses were performed with Stata software (ver- sence of major or minor bleeding, cumulative distribution sion 9.0; Stata, College Station, Texas). Continuous variable curves were prepared. There was no effect of the duration of Coronary Artery Disease/Anticoagulant Switching and Bleeding 1689

Figure 1. Time from last dose of antithrombin until PCI in patients who received bivalirudin by presence of protocol-deﬁned major or minor bleeding (A, unfractionated heparin,; B, low-molecular-weight heparin).

Figure 2. Time from last dose of antithrombin until PCI in patients who received unfractionated heparin with planned glycoprotein IIb/IIIa inhibitorbythe presence of protocol-defined major or minor bleeding (A, unfractionated heparin;B,low-molecular-weight heparin). antithrombin discontinuation on bleeding for patients who unfractionated heparin therapy, the activated partial throm- had received unfractionated heparin or low-molecular- boplastin time is Յ50 seconds or the activated clotting time weight heparin and who were subsequently randomized to is Յ175 seconds. When switching was undertaken in this receive bivalirudin (Figure 1) or unfractionated heparin plus fashion, preceding therapy by administering low-molecular- glycoprotein IIb/IIIa inhibitor (Figure 2). However, in the weight heparin or unfractionated heparin was not associated group of patients who were previously administered unfrac- with an excess of bleeding or transfusions compared with tionated heparin and who were randomized to receive un- bivalirudin therapy alone in the cardiac catheterization lab- fractionated heparin plus glycoprotein IIb/IIIa, the median oratory. time from unfractionated heparin discontinuation to PCI In contrast, preceding therapy by administering unfrac- was slightly shorter among patients who experienced bleed- tionated heparin or low-molecular-weight heparin was as- ing, although the p value did not reach statistical signifi- sociated with an excess of the composite of major or minor ϭ cance (4.6 vs 3.3 hours, p 0.15). Among patients ran- bleeding as well as transfusions among patients treated with domized to receive unfractionated heparin plus glycoprotein glycoprotein IIb/IIIa inhibition in the cardiac catheterization IIb/IIIa, the rate of major or minor bleeding trended higher laboratory when compared with patients who were anti- among patients who discontinued unfractionated heparin thrombin-naive. within 6 hours of PCI compared with those who discontin- Although it was specified that bivalirudin could not be ued unfractionated heparin Ͼ6 hours before PCI (6.1% vs administered within 8 hours of low–molecular-weight hep- 2.6%, p ϭ 0.11). arin or within 6 hours of unfractionated heparin as described earlier, the cumulative distribution curves suggest that the Discussion time between discontinuation of an antithrombin (unfrac- This analysis extends earlier observations from the Switch- tionated heparin or low-molecular-weight heparin) did not ing from Enoxaparin to Bivalirudin in Patients with Acute affect bleeding events. The time from low-molecular- Coronary Syndromes without ST-segment Elevation who weight heparin discontinuation to PCI was much longer Undergo PCI (SWITCH) trial3 and the REPLACE-2 trial1 to than required by the protocol and was significantly longer demonstrate that it is safe to switch from low-molecular- than the time from discontinuation of unfractionated heparin weight heparin or unfractionated heparin to bivalirudin before PCI. This may reflect a preference in clinical practice among patients undergoing PCI. The method of switching to delay cardiac catheterization if a patient has been admin- or transition involved administration of bivalirudin Ͼ8 istered low-molecular-weight heparin. hours after the last low-molecular-weight heparin dose or .6 It is not clear why switching to bivalirudin after unfrac- hours after unfractionated heparin unless, in the case of tionated heparin or low-molecular-weight heparin appears 1690 The American Journal of Cardiology (www.AJConline.org) to be safe, whereas switching from 1 heparinoid to another as such could be subject to observer and selection bias. has been associated with an increase in the risk of bleeding. However, the subsequent randomization to bivalirudin or As described earlier, in the REPLACE-2 trial,1 bivalirudin heparin with glycoprotein IIb/IIIa was double-blinded. The could not be administered for a prespecified time or until present analysis was retrospective and not prespecified. The clotting parameters were below specified levels after dis- number of patients who received antithrombin therapy be- continuation of an alternate antithrombin, which may have fore randomization in the bivalirudin and glycoprotein IIb/ been a safer strategy than allowing an immediate transition IIIa inhibitor groups was modest and limit the power of the to an alternate antithrombin, as was done in the Superior study. This analysis was confined to the phenomenon of Yield of the New Strategy of Enoxaprin, Revascularization prerandomization switching rather than post-randomization and Glyocoprotein IIb/IIIa Inhibitors (SYNERGY) trial.4 crossover. In the analysis of post-randomization crossover, Potential explanations include the fact that bivalirudin has a it is not clear in studies whether bleeding or ischemia caused half-life of 25 minutes5; unfractionated heparin and low- the crossover, or alternatively whether the crossover caused molecular-weight heparin have relatively long half-lives. the patient to have a bleeding or ischemic event. Therefore, Bivalirudin becomes biologically inactive when it is cleaved the direction of causality cannot be determined. by and subsequently dissociates from thrombin, allowing thrombin to return to normal hemostatic activity. Bivaliru- 1. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, din specifically inhibits thrombin, whereas unfractionated Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, et al. Bivalirudin and heparin and low-molecular-weight heparin have some provisional glycoprotein IIb/IIIa blockade compared with heparin and activity against thrombin and factor Xa. Because the planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863. anti-IIa activity of unfractionated heparin is cleared more 2. Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, Bell WR, rapidly than the anti-Xa activity, it may be possible that Knatterud G, Robertson TL, Terrin ML. Thrombolysis in Myocardial the additive effect of 2 heparinoids may increase the Infarction (TIMI) Trial–phase I: hemorrhagic manifestations and levels of anti-Xa activity to supratherapeutic levels, changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptoki- whereas adding anti-IIa activity (i.e., bivalirudin) to residual nase. J Am Coll Cardiol 1988;11:1–11. anti-Xa activity would not result in increased anti-Xa levels. 3. Waksman R, Wolfram RM, Torguson RL, Okubagzi P, Xue Z, Suddath Results of the present study are similar to those observed WO, Satler LF, Kent KM. Switching from enoxaparin to bivalirudin in in the SWITCH trial,3 in which patients with acute coronary patients with acute coronary syndromes without ST-segment elevation syndrome were treated with enoxaparin and subsequently who undergo percutaneous coronary intervention. Results from SWITCH--a multicenter clinical trial. J Invas Cardiol 2006;18:370– switched to bivalirudin for the PCI procedure after varying 375. durations of time (0 to 4, 4 to 8, or 8 to 12 hours from last 4. Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman enoxaparin dose to PCI).1 Switching from enoxaparin to S, Kereiakes DJ, Langer A, Mahaffey KW, Nessel CC, et al. Enoxaparin bivalirudin among patients undergoing PCI was not associ- vs unfractionated heparin in high-risk patients with non-ST-segment ated with an increase in major bleeding, regardless of the elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. duration from last enoxaparin administration to PCI. JAMA 2004;292:45–54. The selection of antithrombin therapy before randomiza- 5. Caron MF, McKendall GR. Bivalirudin in percutaneous coronary in- tion was done on an open-label, nonrandomized basis, and tervention. Am J Health Syst Pharm 2003;60:1841–1849. Six-Month Clinical and Angiographic Results of a Dedicated Drug- Eluting Stent for the Treatment of Coronary Bifurcation Narrowings

Eberhard Grube, MDa,*, Lutz Buellesfeld, MDa, Franz J. Neumann, MDb, Stefan Verheye, MDc, Alexandre Abizaid, MDd, Dougal McClean, MDe, Ralf Mueller, MDa, Alexandra Lansky, MDf, Roxana Mehran, MDf, Ricardo Costa, MDf, Ulrich Gerckens, MDa, Brett Trauthen, MSg, and Peter J. Fitzgerald, MDh

Percutaneous intervention for coronary bifurcation lesions has been associated with increased clinical complication rates compared with nonbifurcation lesions, primarily as a result of restenosis. Therefore, there is a need for new techniques. The purpose of this study was to evaluate a new drug-eluting stent and implantation technique for the treatment of de novo coronary bifurcation lesions. The Axxess Plus trial was a prospective multicenter single-arm study that enrolled 139 patients. Each patient received a self-expanding, con- ically shaped nickel-titanium Axxess Plus biolimus A9-eluting stent at the level of the carina. Depending on the lesion anatomy, additional nonstudy stents were placed distally if necessary. Clinical and angiographic follow-up were scheduled at 6 months after the procedure. The overall rate of target lesion revascularization was 7.5% at 6 months. A mean of 2.4 stents were implanted per patient; 51.2% of patients received a stent to the side branch, 29.4% received balloon angioplasty only, and 20.6% of side branches were not treated. In-stent late loss in the Axxess stents was 0.09 mm. Incidences of angiographic in-stent restenosis were 7.1% in the parent vessel stents and 9.2% in the group receiving stents in the side branch (7.9% excluding bare metal stents placed distal to the Axxess stent), compared with 25% for balloon angioplasty treatment and 12% for no treatment. Late stent thrombosis was observed in 3 cases, 2 of which were associated with conﬁrmed premature cessation of antiplatelet therapy. In conclusion, the Axxess Plus conical stent effectively treats bifurcation lesions alone or in conjunction with other drug-eluting stents. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1691–1697)

In the “stent era,” percutaneous coronary interventions in the side branch ostium. Serial intravascular ultrasound (US) bifurcations are associated with increased adverse clinical analysis of side branch stents suggest underexpansion of the event rates and inferior angiographic outcomes compared stent may be a contributing factor.5 Several customized with nonbifurcation lesions.1,2 In recent publications report- metal stent designs have been developed to address this ing the performance of drug-eluting stents in bifurcation problem. However, their use is associated with procedural lesions, results appear to be improved compared with bare complexity, and ﬁrst published experiences indicate that the metal stents, but adverse clinical event rates remain high, long-term outcome is still limited.6 The incorporation of an with increased restenosis rates, especially in the side antiproliferative compound might help to overcome this branch.3,4 Lesions at coronary bifurcations thus represent a problem. Therefore, we conducted a prospective multicenter challenging lesion subset in the current practice of interven- evaluation of a new specialized bifurcation stent that elutes tional cardiology. the antiproliferative agent biolimus A9. The principal cause of increased adverse event rates in bifurcation lesions appears to be the inability of current Methods devices and techniques to adequately scaffold and preserve This prospective single-arm multicenter evaluation of the Axxess Plus stent (Devax, Irvine, California) enrolled 139 patients from 13 sites located in Germany, Belgium, The aHELIOS Heart Center, Siegburg; and bHeart Center Bad Krozingen, Netherlands, United Kingdom, Brazil, and New Zealand. Bad Krozingen, Germany; cAZ Middelheim, Antwerp, Belgium; dDante Clinical follow-up was performed at 30 Ϯ 14 days after the Pazzenese Institute of Cardiology, Sao Paulo, Brazil; eChristchurch Hos- Ϯ f procedure and again 6 1 months after the procedure. pital, Christchurch, New Zealand; Cardiovascular Research Foundation, Elective angiographic follow-up was scheduled in conjunc- New York, New York; gDevax, Inc., Irvine; and hStanford University Medical Center, Stanford, California. Manuscript received October 15, tion with the 6-month follow up visit. A 1-year evaluation is 2006; revised manuscript received January 13, 2007 and accepted January ongoing before termination of the study. A data safety and 17, 2007. monitoring committee periodically reviewed safety data, *Corresponding author: Tel: 49-2241-182322; fax: 49-2241-183040. and all clinical end points were adjudicated by an indepen- E-mail address: [email protected] (E. Grube). dent clinical events committee.

Eligible patients were 18 to 80 years of age with a history of stable or unstable angina. Angiographic eligibility required a de novo target lesion with Ͼ50% stenosis in a native coronary artery within 3 mm of the juncture of a side branch measuring Ն2.2 mm in diameter at the ostium. Maximum lesion lengths were 30 mm in the parent vessel (15 mm maximum on either side of the bifurcation) and up to 15 mm in the side branch. The side branch was not required to be diseased for inclusion in the study. A second lesion in another vessel not involved in the bifurcation could be treated in the same setting as the bifurcation as long as the secondary lesion was treated successfully before the bifurcation lesion intervention. Major exclusion criteria were myocardial infarction within 72 hours of the planned procedure date, an ejection fraction Ͻ30%, a co-morbidity that might require cessation of antiplatelet therapy within 6 months of the procedure, and any known allergy to any of the study materials or medications. All patients gave their written informed consent. The study was approved by the local medical ethics committees. The primary objective of the Axxess Plus Trial was to evaluate the feasibility, safety, and efficacy of the biolimus A9–eluting Axxess stent in de novo bifurcated coronary lesions. The secondary objectives were to establish the best treatment method for the side branch based on angiographic efficacy measures, evaluate the overall efficacy of the pro- Figure 1. The Axxess biolimus-eluting stent. Note the 3 markers at the cedure, and evaluate the procedural and long-term safety distal stent edge and the single marker at the proximal stent edge. profile of the device based on comparative clinical outcomes versus other published bifurcation series that in- anatomy of a bifurcation lesion at the level of the carina volved standard devices and techniques. (Figure 1). This device, which is better adapted to the artery The primary end point of the Axxess Plus study was anatomy, might enhance the interaction between adequate in-stent angiographic late loss at 6-month follow-up, as mechanical scaffolding and accurate delivery and dosage of measured by quantitative computerized angiographic anal- the antirestenosis drugs. ysis (QCA). The safety end point was a composite of major The straight configuration was intended to be used dis- adverse cardiac events (MACEs) at 6 months after the tally to the conical stent to cover lesions that extended procedure. A MACE was defined as any death, Q-wave or beyond the carina. The protocol allowed for the use of non–Q-wave myocardial infarction, or ischemia-driven re- commercially available stents in conjunction with the vascularization of the target lesion (i.e., emergency or elec- Axxess stent in the event that the appropriate straight stent tive coronary artery bypass grafting or repeated percutane- was not available. ous coronary intervention). Secondary safety end points The drug biolimus A9 is a derivative of sirolimus (i.e., included MACEs at 1 and 12 months and any stent throm- rapamycin), an immunosuppressive compound with proven bosis or total occlusion. antiproliferative properties when eluted from the Cypher Myocardial infarction was defined as a cardiac event stent (Cordis, Miami Lakes, Florida).7 Like sirolimus, bi- with development of pathologic Q-waves, or in the absence olimus binds to FK506-binding protein 12 and inhibits of pathologic Q-waves, an increase in creatine kinase levels mammalian target of rapamycin protein activity; therefore, to more than twice the upper limit of normal with an sirolimus and biolimus inhibit growth factor–driven cell increased creatine kinase-MB level. Target lesion revascu- proliferation, including that of T cells and vascular smooth larization was considered driven by ischemia if the stenosis muscle cells. of the target vessel was Ն50% of the luminal diameter on The drug is loaded in a bioabsorbable polylactic acid the basis of QCA with electrocardiographic changes while polymer. The coating is applied to the abluminal (i.e., mu- the patient was at rest or a functional study indicating ral-facing) surface of the stent to a thickness of approxi- ischemia in the target vessel region, or if there was stenosis mately 15 ␮m. The polymer is a commonly used suture of Ն70%. material that is metabolized in the cell to carbon dioxide and The novel self-expanding Axxess stent is laser cut from water. Hence, there is no permanent residual drug trapped a nickel-titanium alloy in the austenitic (i.e., superelastic) on the stent. The nominal drug loading is 22 ␮g/mm of stent phase with a 0.006-inch (0.015 mm) strut thickness. The length for all sizes. stent is coated with biolimus A9, a sirolimus analog, sus- Before the index procedure, all patients received oral pended within a polylactic acid bioabsorbable coating. The aspirin (Ն80 mg) and oral clopidogrel (300 mg 24 hours Axxess stents were provided in straight and conical config- before the procedure). During the procedure, intravenous urations in different diameters and lengths. The Axxess heparin boluses were administered to achieve an activated stent’s conical design allows it to expand into the irregular clotting time Ͼ250 seconds. The use of intravenous glyco- Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial 1693 protein IIb/IIIa inhibitors was at the discretion of the phy- Results sician. Baseline clinical and angiographic characteristics are listed Wires were introduced into the parent vessel and side in Table 1. The bifurcations were mostly “true” bifurcation branch, and mandatory predilatation was performed in lesions involving the parent vessel and at least the ostium of the parent vessel, followed by side branch dilatation at the side branch. The mean lesion length measured 16.28 Ϯ the discretion of the investigator (Figure 2). The Axxess 7.44 mm in the parent vessel and 7.43 Ϯ 3.90 mm in the stent was then introduced over 1 of the wires (generally side branch. the wire in the vessel with the most extensive disease). Implantation of the conical Axxess stent in the parent The Axxess stent delivery system was placed as close to vessel was successful in 130 of 139 cases (device success the carina as possible, and the cover sheath was retracted rate, 93.5%). There were 3 instances in which the device partially, exposing the distal 3 radiopaque markers. The was withdrawn before deployment; in 2 of these cases, the position of the stent was assessed with a contrast medium device would have extended into the left main coronary injection and adjusted to align the markers with the artery, and in the other case the delivery system could not carina. When the stent was observed to open into the side reach the target lesion. These 3 patients are included in the branch, the sheath was retracted further and the stent was 30-day results, but are omitted from the long-term analysis. advanced into the carina. The sheath was then fully The remaining 6 device failures occurred when the stent retracted and the delivery system was withdrawn. At this was placed distal or proximal to the intended location. point, the need for additional stents was assessed by the These cases did not impact overall treatment success, as operator. If necessary to cover the lesion in the parent there were no patient complications associated with these vessel, a second stent was added. If the side branch was failures, resulting in a lesion success rate (defined by Ͻ50% not well dilated or if there was extensive disease, a stent residual stenosis at the end of the procedure) of 100%. was added to the side branch as well. In cases in which When the conical stent was in place, the remaining treat- both side branches required stent implantation, the struc- ment varied considerably according to the extent of disease ture of the Axxess stent allows for simultaneous place- in the vessels branching distal to the bifurcation. The ment and deployment of the branch vessel stents, as Axxess concept generated 4 different stent patterns: Axxess shown in Figure 2. In this example, 2 Cypher stents are conical stent only (19.1%), the cone plus a distal parent used in the branch vessels. To avoid gaps in stent cov- vessel stent (29.4%), the cone plus a side branch stent erage (and thus in drug coverage), the ends of the addi- (9.6%), and the cone plus stents to the distal parent vessel tional stents were aligned just inside the markers of the and side branch (41.9%). In lesions that required distal stent Axxess stents and the side branch stents were deployed implantation, attempts to place the straight Axxess stent simultaneously (i.e., v-stenting technique). were undertaken in 36 cases, but only 21 were successful. After intervention, an electrocardiogram was obtained, The failures were caused by an inability to advance the and cardiac enzymes were measured within 8 and 16 hours system to the desired location as a result of device stiffness and before discharge. Patients took aspirin Ն80 mg/day and and the profile of this stent type. For this reason, the straight 75 mg of clopidogrel for 6 months. There was no mandatory stent was abandoned as a branch vessel treatment option in intravascular US guidance for implantation. favor of the more deliverable Cypher stent (Cordis, Johnson Coronary angiograms obtained at baseline, at the com- & Johnson) or Taxus stent (Boston Scientific). Bare metal pletion of the procedure, and at the 6-month follow-up were stents were placed in 2 patients. In 1 instance, no drug- eluting stent was available and the operator used 2 bare independently analyzed (Cardiovascular Research Founda- metal stents in distal branch vessels, and in a second patient tion, New York, New York). The parent vessel and side a short metal stent was used to treat a dissection distal to a branch were analyzed separately. Restenosis was defined as Cypher stent (Table 2). stenosis of Ͼ50% of the luminal diameter in the target Follow-up angiographic data were available for 126 pa- lesions. Late luminal loss was defined as the difference tients (92.6%). The results are listed in Tables 3 to 5. The between the minimal luminal diameter at the completion of angiographic late loss of the Axxess conical stent (i.e., the procedure and that measured at follow-up. Quantitative primary end point) was 0.09 Ϯ 0.56 mm. angiographic measurements of the target lesion were ob- Table 4 shows the results in the parent vessel by analysis tained in the “in-stent” zone and “in-lesion” zone, which zone, from the proximal vessel through the distal vessel included a 5-mm segment proximal and distal to the stent- segment for all patients, with the bare metal stents omitted. Ͼ implanted segments. Because there was 1 brand of stent The frequencies of binary in-stent restenosis were 4.8% used in the parent vessel, a QCA subanalysis was performed within the Axxess stent, 4.5% in the stent distal to the to separate the outcomes of the Axxess stents from those of Axxess stent, and 10.5% including 5-mm nonstented seg- any other stent placed. ments proximal and distal to the stents. Intravascular US examinations were performed after the Treatment decisions in the side branch varied according stent placement procedure in 20% of the patients and at to the degree of involvement of the side branch in the lesion; 180-day follow-up in 30% of the patients. These data were 51.5% received a stent, and balloon angioplasty alone was used to make quantitative determinations of the tissue vol- performed in 29%. The patients who received a stent in the ume within the stents. All intravascular US analyses were side branch had only a 9.2% restenosis rate at 6 months; the made by an independent core laboratory (Cardiovascular restenosis rate was 7.9% for patients who received a drug- Core Analysis Laboratory, Stanford, California). eluting stent in the side branch. Patients with balloon an- 1694 The American Journal of Cardiology (www.AJConline.org)

Figure 2. Case example. (A) Bifurcation stenosis with disease in parent vessel and both distal vessels. (B) Balloon dilation. (C) Positioning of Axxess stent at the carina and expansion. (D) Kissing dilation of both distal vessels. (E,F) Positioning and simultaneous implantation of 2 Cypher stents to treat the distal disease. (G) Final kissing balloon. (H) Final angiographic result. (I) Angiographic result at 6-month follow-up. Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial 1695

Table 1 Table 3 Patient and lesion characteristics (n ϭ 139) Quantitative angiographic results of the parent vessel at 180 days Characteristic Value Angiographic Finding In-Stent Zone In-Segment Zone Men 102 (73.4%) Minimal luminal diameter (mm) Age (yrs) 64.4 Ϯ 10.2 Before the procedure 0.78 Ϯ 0.30 0.78 Ϯ 0.30 Diabetes mellitus 23 (16.5%) After the procedure 2.60 Ϯ 0.45 2.27 Ϯ 0.39 Insulin dependent 8 (5.8%) At follow-up 2.74 Ϯ 0.60 2.03 Ϯ 0.56 Hypertension* 102 (73.4%) Stenosis (% of luminal diameter) Hypercholesterolemia† 109 (78.8%) Before the procedure 72.9 Ϯ 9.4 72.9 Ϯ 9.4 Current smoker 18 (12.9%) After the procedure 12.5 Ϯ 9.8 29.3 Ϯ 16.7 Previous percutaneous coronary intervention 42 (30.2%) At follow-up 5.29 Ϯ 18.9 29.8 Ϯ 17.2 Previous myocardial infarct 43 (30.9%) Late luminal loss (mm) 0.19 Ϯ 0.42 0.21 Ϯ 48 Canadian Cardiovascular Society Classification 51 (36.7%) Restenosis at follow-up (%) grade III or IV All patients 7.1% 11.9% Lesion location Drug-eluting stents only 5.6% 10.5% Left anterior descending artery/diagonal 102 (73.4%) Ϯ branch Values are mean SD or percentages. Left circumflex artery/marginal branch 24 (17.3%) Posterior descending artery/Posterolateral 5 (3.6%) branch 77.5% for patients with side branch balloon angioplasty Left main stem 8 (5.8%) only. Removing the index failures for the balloon angio- Bifurcation lesion type plasty group decreased the restenosis rate in this group to “True” parent vessel and side branch 108 (77.7%) 13.8%. Pre-branch 18 (12.9%) Intravascular US analysis was available at follow-up in Parent vessel only 6 (4.3%) 49 patients in the parent vessel and 25 patients in the side Post-branch/ostial 6 (4.3%) branch. Within the Axxess stent, neointimal volume ob- * Defined as current use of medication and/or systolic blood pressure struction was 2.28 Ϯ 2.17%, with a minimum lumen area of Ͼ140 mm Hg and/or diastolic blood Ͼ90 mm Hg measured on 3 different 7.86 Ϯ 2.63 mm2. Ostium stent areas were 5.52 Ϯ 1.64 days. mm2 in the parent vessel and 4.58 Ϯ 1.41 mm2 at the side † Defined as current use of medication and/or a total cholesterol level Ͼ220 mg/dL. branch ostium. MACEs are listed in Table 6. In-hospital MACEs for 139 enrolled patients consisted of 6 non–Q-wave myocardial Table 2 Stent usage infarctions (4.2%) and 1 Q-wave infarction (0.7%) caused by a distal stent dissection that temporarily occluded the left Stent Detail Proximal Parent Distal Parent Side Branch anterior descending artery. There were no additional Vessel Vessel MACEs by 30-day follow-up. Follow-up at 6 Ϯ 1 months Total stents 136 115 73 was available in 134 of 136 eligible patients (98.5%). There Axxess cone 136 — — was 1 death (0.7%), 1 additional Q-wave myocardial infarc- Axxess straight — 18 2 tion (0.7%) associated with a stent thrombosis at 61 days, Cypher — 82 63 and 10 cases of target lesion revascularization (7.5%). The Taxus — 13 7 cumulative event-free survival rate was 88.8% at 180 days. Bare metal — 2 1 Ballon dilatation —40There were no cases of acute or subacute stent thrombo- only sis. Late stent thrombosis was confirmed in 3 cases (2.2%). Wire only — 26 The first of these cases occurred in a patient at 61 days who Mean no. of 1.8 1.1 was treated surgically for prostate carcinoma 51 days after stents a successful procedure, but in whom antiplatelet therapy Mean stent 26.36 Ϯ 11.86 17.32 Ϯ 8.01 was discontinued as a result of postsurgical hematuria re- length (mm) sulting in a Q-wave myocardial infarct and target lesion revascularization 10 days later. The second case occurred in gioplasty had a restenosis rate of 25%; the incidence was a patient who stopped receiving clopidogrel after 1 month 12% in cases without side branch treatment at the index because of discomfort and then presented with unstable procedure. In 2 cases with side branch stenting, the reste- angina at 98 days. A nonocclusive thrombosis at the carina nosis was located at the side branch ostium within the was confirmed by angiography and resolved with pharma- overlap region. Three patients with 2 parent vessel stents cologic treatment. Clopidogrel therapy was restarted, and (Axxess and Cypher/Taxus stents) developed restenoses at the patient returned for follow-up at 6 months symptom- the overlap site. In total, there were 5 cases with stent free, at which time a patent bifurcation was confirmed by restenosis in the overlap region. angiography. The third case was found during the 6-month The treatment mode strongly affected the angiographic angiographic follow-up in an asymptomatic patient. This success within the side branch at baseline. In patients with patient received 3 Cypher stents in the left anterior descend- side branch stenting, the success rate was 97.1%, followed ing artery distal to the Axxess stent as a result of a spiral by 96.2% in patients without side branch treatment and dissection. The thrombosis was located near the overlap of 1696 The American Journal of Cardiology (www.AJConline.org)

Table 4 Quantitative angiographic results in different analysis zones in the parent vessel Group Proximal 5 mm Axxess Stent Distal Stent Distal 5 mm All Patients Late luminal loss (mm) 0.17 Ϯ 0.46 0.09 Ϯ 0.56 0.21 Ϯ 44 0.09 Ϯ 38 Restenosis (%) 5.1 4.8 4.5 5.1 Patients receiving drug-eluting stents only Late luminal loss (mm) 0.17 Ϯ 47 0.08 Ϯ 0.55 0.19 Ϯ 42 0.09 Ϯ 38 Restenosis (%) 5.1% 4.0% 3.5% 3.3%

Values are means Ϯ SD on percentages.

Table 5 Quantitative angiographic results of side branch at 180 days Angiographic Finding Stent Balloon Angioplasty Wire Only, No Treatment Minimal luminal diameter (mm) Before the procedure 0.88 Ϯ 0.39 0.88 Ϯ 0.39 0.88 Ϯ 0.39 After the procedure 2.32 Ϯ 0.39 1.64 Ϯ 0.51 1.83 Ϯ 0.45 At follow-up 2.05 Ϯ 0.39 1.49 Ϯ 0.50 1.59 Ϯ 0.49 Stenosis (% of luminal diameter) Before the procedure 62.2 Ϯ 16.2 62.2 Ϯ 16.2 62.2 Ϯ 16.2 After the procedure 19.0 Ϯ 9.1 28.1 Ϯ 21.8 22.4 Ϯ 16.5 At follow-up 25.4 Ϯ 16.7 33.1 Ϯ 21.9 31.0 Ϯ 23.5 Late luminal loss (mm) 0.23 Ϯ 0.52 0.18 Ϯ 0.51 0.20 Ϯ 0.39 Index restenosis 2.9% 22.5% 3.8% Restenosis at follow-up All patients 9.2% 25.0% 12.0% Drug-eluting stents only 7.9% — —

Values are means Ϯ SD or percentage.

Table 6 Major adverse cardiac events Event In-Hospital Events Out-of-Hospital Events Cumulative to 180 Days Death 0 1 (0.7%) 1 (0.7%) Myocardial infarction 7 (5.0%) 1 (0.7%) 8 (6.0%) Q-wave 1 (0.7%) 1 (0.7%) 2 (1.5%) Non–Q-wave 6 (4.3%) 0 6 (4.5%) Target lesion revascularization 0 10 (7.5%) 10 (7.5%) Coronary bypass 0 0 0 Coronary angioplasty 0 10 (7.5%) 10 (7.5%) Any major adverse cardiac event 7 (5.0%) 12 (9.0%) 15 (11.2%) Target vessel failure 7 (5.0%) 12 (9.0%) 15 (11.2%) Event-free survival 95.0% 91.0% 88.8% Stent thrombosis 0 3 (2.2%) 3 (2.2%) the second and third Cypher stents, and the bifurcation was pansion, sometimes seen with regular self-expanding stents, patent. were absent given this favorable interaction of lesion morphology and device design. The combination of Axxess and (predominantly) Cypher stents was associated with a low Discussion out-of-hospital major adverse event rate (9.0%) to 6 months In this first study of a dedicated drug-eluting bifurcation after stent implantation. The angiographic late loss of the stent, we found that the biolimus A9 drug used in conjunc- Axxess cone stent (i.e., primary end point) was 0.09Ϯ 0.56 tion with the self-expanding, nickel-titanium alloy Axxess mm, which is comparable to results of sirolimus- or everoli- stent is effective in reducing neointimal hyperplasia. The mus-eluting stents in nonbifurcated de novo lesions, indi- procedural success rate with the conical stent was Ͼ90%, cating a remarkable reduction compared with historical bare although the straight stent delivery system proved cumber- metal controls.8,9 some and had to be abandoned in favor of commercially Although the Axxess stent effectively reduces neoin- available stents to treat distal vessels. The self-expanding timal hyperplasia as measured by angiographic late loss properties of the conical stent were helpful to fit the device at 180 days, the procedure necessitates the frequent use into the carina; proximal or distal dislocations during ex- of adjunctive stents in the distal branch vessels to com- Coronary Artery Disease/Axxess Plus Drug-Eluting Stent Trial 1697 plete therapy in most patients. The angiographic out- tives, this study has several limitations. The results with the comes with these distal stents were consistent with pre- biolimus-eluting Axxess stent were not compared with a vious studies with the Cypher stent,3,4 whether the stent randomized control group. In addition, this study did not was placed in the side branch or the distal parent vessel. prospectively assign a particular treatment method to the Previous studies of bifurcation lesions typically report side branch and the choice of additional stents to be used worse angiographic outcomes in the side branch, and was at the operator’s discretion, resulting in a heterogeneous stented side branches usually fare worse than cases of study population. balloon angioplasty only. This is mainly because of ostial restenosis in lesion segments insufficiently covered by 1. Lefevre T, Louvard Y, Morice MC, Dumas P, Loubeyre C, Bensli- the drug-eluting stent. When used with the Axxess stent, mane A, Premchand RK, Guillard N, Piechaud JF. Stenting of bifurcation lesions: classification, treatments, and results. Cathet Cardio- however, the angiographic results in the side branch and vasc Intervent 2000;49:274–283. parent vessel were quite similar, with comparable late 2. Al Suwaidi J, Yeh W, Cohen HA, Detre KM, Williams DO, Holmes loss values, which might be an indicator of better lesion DR Jr. Immediate and one-year Outcome in patients with coronary coverage with this new stent design. The incidence of bifurcation lesions in the modern era (NHLBI Dynamic Registry). restenosis was slightly higher in side branches compared Am J Cardiol 2001;87:1139–1144. 3. Colombo A, Moses JW, Morice MC, Ludwig J, Holmes DR Jr, Spanos with the main vessel, but the observed rate was still an V, Louvard Y, Desmedt B, Di Mario C, Leon MB. Randomized study encouraging 7.9%. to evaluate sirolimus-eluting stents implanted at coronary bifurcation Although the Axxess stent strategy results in overlapping lesions. Circulation 2004;109:1244–1249. stents in case additional stents are implanted distal to the 4. Ge L, Airoldi F, Iakovou I, Cosgrave J, Michev I, Sangiorgi GM, Montorfano M, Chieffo A, Carlino M, Corvaja N, Colombo A. Clin- conical main vessel stent, there was no incidence of an ical and angiographic outcome after implantation of drug eluting stents exaggerated neointimal response to the site of the double in bifurcation lesions with the crush stent technique. J Am Coll Cardiol stent strut layers. However, previous reports have demon- 2005;26:613–620. strated that drug-eluting stents further delay arterial healing 5. Costa RA, Mintz GS, Carlier SG, Lansky AJ, Moussa I, Fujii K, and promote inflammation at sites of overlap compared with Takebayashi H, Yasuda T, Costa JR Jr, Tsuchiya Y, Jensen LO, et al. 10 Bifurcation coronary lesions treated with the “crush” technique: an bare metal stents. In particular, Taxus stents induced intravascular ultrasound analysis. J Am Coll Cardiol 2005;46:599– greater fibrin deposition, medial cell loss, heterophils/eosin- 605. ophils, and late neointimal hyperplasia. Further larger stud- 6. Lefevre T, Ormiston J, Guagliumi G, Schultheiss HP, Quilliet L, ies and long-term observations are therefore needed to ob- Reimers B, Brunel P, Wijns W, Buettner HJ, Hartmann F, Veldhof S, et al. The Frontier stent registry: safety and feasibility of a novel serve and evaluate effects at the overlapping sites, particular dedicated stent for the treatment of bifurcation coronary artery lesions. when different kinds of drug-eluting stents are overlapped. J Am Coll Cardiol 2005;46:592–598. For this reason, we dominantly used the Cypher stent in 7. Pan M, Suarez de Lezo J, Medina A, Romero M, Hernandez E, Segura addition to the Axxess stent, staying in the same drug family J, Castroviejo JR, Pavlovic D, Melian F, Ramirez A, Castillo JC. of “limus” analogs. Simple and complex stent strategies for bifurcated coronary arterial stenosis involving the side branch origin. Am J Cardiol 1999;83:1320– Stent thrombosis is an important issue in drug-eluting 1325. stent implantations for treatment of bifurcation lesions. The 8. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, presence of a bifurcation lesion has been clearly identified O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein as an independent risk factor for stent thrombosis.11 The PS, Jaeger JL, Kuntz RE; SIRIUS Investigators. Sirolimus eluting stent versus standard stents in patients with stenosis in a native coro- stent thrombosis rate in our study was 2.2%, with a total of nary artery. N Engl J Med 2003;349:1315–1323. 3 events at Ͼ30 days, 2 of them after premature discontin- 9. Costa RA, Lansky AJ, Mintz GS, Mehran R, Tsuchiya Y, Negoita M, uation of clopidogrel. Considering only patients who con- Gilutz Y, Nikolsky E, Fahy M, Pop R, et al. Angiographic results of tinued antiplatelet therapy, the rate was Ͻ1%, which is the first human experience with everolimus-eluting stents for the treat- comparable to that with bare metal stents in simple coronary ment of coronary lesions (the FUTURE I trial). Am J Cardiol 2005; 95:113–116. lesions. Therefore, the Axxess stent strategy seems to be 10. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera safe if the antiplatelet medication is not prematurely K, Skorija K, Weber DK, Gold HK, Virmani R. Differential response stopped. This finding is in accordance with reports on drug- of delayed healing and persistent inflammation at sites of overlapping eluting stent implantations in real-world settings in sirolimus- or paclitaxel-eluting stents. Circulation 2005;112:270–278. 11 11. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, general, and not only associated with bifurcation lesion Airoldi F, Chieffo A, Montorfano M, Carlino M, et al. Incidence, treatments. predictors, and outcome of thrombosis after successful implantation of Although it was successful in terms of its stated objec- drug-eluting stents. JAMA 2005;293:2126–2130. The Editor’s Roundtable: High-Density Lipoprotein Cholesterol

Vincent E. Friedewald, Jr., MDa,*, H. Brian Brewer, Jr., MDb, Scott M. Grundy, MD, PhDc, Daniel J. Rader, MDd, and William C. Roberts, MDe

Acknowledgment AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; KOS Pharmaceuticals; Merck; Merck/Schering Plough; This activity is supported by an educational grant from Pfizer, Inc.; and Schering-Plough. Dr. Rader has also re- Pfizer, Inc. New York, New York. ceived Grant/Research Support from AstraZeneca, Wil- mington, Delaware; Boehringer Ingelheim, Ridgefield, Disclosure Connecticut; Bristol Myers Squibb, Plainsboro, New Jersey; Dr. Friedewald has no relevant financial relationship to Bruin Pharma, Los Angeles, California; GlaxoSmithKline, disclose. Dr. Brewer has received fees for consulting from Research Triangle Park, North Carolina; KOS Pharmaceu- Merck, White House Station, New Jersey; Merck/Schering ticals, Weston, Florida; Merck and Co., White House Sta- Plough, North Wales, Pennsylvania; Lipid Sciences, Pleas- tion, New York; and Pfizer, New York, New York. Dr. anton, California; Pfizer, Inc., New York, New York; No- Rader has received no honoraria, other than those listed vartis, East Hanover, New Jersey; sanofi-aventis, Bridgewa- above. Dr. Roberts has received honoraria for speaking ter, New Jersey. Dr. Grundy has received research grants from Merck, North Wales, Pennsylvania; Schering Plough, from Merck, White House Station, New Jersey; Abbott, Kenilworth, New Jersey; Pfizer, Inc., New York, NY; Abbott Park, Illinois; KOS Pharmaceuticals, Weston, Flor- AstraZeneca, Wilmington, Delaware; and Novartis, East ida; and has worked as a Consultant for Merck; Merck/ Hanover, New Jersey. Schering Plough, Kenilworth, New Jersey; KOS Pharma- ceuticals; Pfizer, Inc., New York, NY; Eli Lilly, Objectives Indianapolis, Indiana; GlaxoSmithKline, Research Triangle Upon completion of the activity, the physician should be Park, North Carolina; Abbott; Fournier, Montreal, Quebec, able to: Canada; Bristol-Myers Squibb, Plainsboro, New Jersey; Sankyo, Parsippany, New Jersey; AstraZeneca, Wilming- 1. Describe the mechanisms whereby HDL may act to ton, Delaware; and sanofi-aventis, Bridgewater, New Jer- prevent or cause regression of atherosclerosis. sey. Dr. Rader has received fees for speakers bureau from 2. Correctly interpret patients’ HDL within the context AstraZeneca, Wilmington, Delaware; Merck, White House of the overall lipid profile. Station, New Jersey; Merck/Schering Plough, North Wales, 3. Advise patients on lifestyle changes to raise the Pennsylvania; Pfizer, Inc., New York, New York; has HDL. worked on the Advisory Committees for AstraZeneca; 4. Advise patients on pharmacologic measures to raise Boehringer Ingelheim, Ridgefield, Connecticut; Bristol My- the HDL, including the use of statins for treating ers Squibb, Plainsboro, New Jersey; KOS Pharmaceuticals, increased LDLs. Weston, Florida; Merck; Merck/Schering Plough, North Wales, Pennsylvania; Pfizer; Schering-Plough, Kenilworth, Introduction New Jersey; and has worked as a Consultant for A low plasma level of high-density lipoprotein (HDL) cholesterol—defined as Ͻ40 mg/dl —is a major risk factor for coronary arterial disease.1 Low HDL is often associated aAssistant Editor, American Journal of Cardiology; Clinical Professor, Department of Internal Medicine, The University of Texas Medical School with elevated plasma triglycerides, excess body weight, at Houston, Houston, Texas; Visiting Professor, University of Notre Dame, physical inactivity, cigarette smoking, very high carbohy- Notre Dame, Indiana; bDirector, Lipoprotein and Atherosclerosis Research, drate intake, type 2 diabetes mellitus, administration of Cardiovascular Research Institute, MedStar Research Institute, Washing- certain drugs (i.e., ␤ blockers, anabolic steroids, progestins), ton Hospital Center, Washington, DC; cDirector, Center for Human Nu- and certain genetic factors. Low HDL is also a marker for trition, Chairman, Department of Clinical Nutrition, Professor, Department the metabolic syndrome. This Editor’s Roundtable dis- of Internal Medicine UT Southwestern Medical Center at Dallas, Dallas, cusses HDL as an atherosclerotic risk factor, and evaluation Texas; dDirector, Preventive Cardiovascular and Lipid Clinic, University and treatment of patients with low HDL. of Pennsylvania Health System, Associate Professor of Medicine, Pathol- ogy and Laboratory Medicine, and Pharmacology, University of Pennsyl- vania School of Medicine, Philadelphia, Pennsylvania; eEditor-in-Chief, Discussion American Journal of Cardiology; Executive Director, Baylor Heart and Dr. Friedewald: Where does HDL cholesterol originate? Vascular Institute; Dean, A. Webb Roberts Center for Continuing Medical Dr. Brewer: Most HDL and its 2 major apoproteins, Education of Baylor Health Care System, Dallas, Texas. Manuscript received March 12, 2007, and received accepted March 13, 2007. apoA-I and apoA-II, are synthesized in the liver and intes- This manuscript is based on a meeting of the authors on January 23, tinal wall. 2006. Dr. Friedewald: What controls the blood level of HDL *Corresponding author: Tel: 512-264-1611; fax: 512-264-7034. cholesterol? E-mail address: [email protected] (V.E. Friedewald). Dr. Brewer: Serum or plasma HDL cholesterol levels

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.020 Roundtable Discussion/High-Density Lipoprotein Cholesterol 1699 are regulated by 2 genetic factors: (1) the enzyme lecithin- Dr. Grundy: A fasting serum is not needed to measure cholesterol acyl transferase, which converts the nascent HDL. In contrast, the low-density lipoprotein (LDL) cho- HDL particle to mature HDL after it picks up the cholesterol lesterol estimation does require fasting. from cholesterol-enriched cells, such as foam cells in the Dr. Friedewald: Should we use HDL subfractions? coronary arteries, and (2) the cholesterol ester transfer pro- Dr. Brewer: We do not have sufficient information tein (CETP), which transfers cholesterol from HDL to B- about the clinical utility of HDL subfractions to warrant containing protein cholesterol in exchange for triglycerides. their measurement in the clinical setting. Diet, exercise, body weight, and dyslipoproteinemias also Dr. Rader: I agree. There are many misperceptions affect the concentration of plasma HDL. Patients with Tan- about HDL subfractions. Currently, there is no compelling gier’s disease, who are missing the ABCA1 cell receptor, evidence that HDL subfractionation provides any greater and patients who have deficiencies of lecithin-cholesterol risk prediction than measuring HDL cholesterol alone. acyl transferase, also have low levels of HDL. However, apo-A1 may be a different matter, because Dr. Roberts: How accurate is the measurement of apo-A1 gives more information than HDL. plasma HDL? Dr. Grundy: An important problem is that we do not Dr. Rader: Performed correctly—which is generally ascertain the kinetics of HDL by simply measuring the true with large laboratories—its accuracy is Ϯ10%. Plasma blood level. The HDL level gives us some information, but HDL, however, is the least accurate of the standard lipid the level of synthesis and metabolism and the functionality measurements. based on the flux of cholesterol through the HDL system is Dr. Roberts: An accuracy of Ϯ10% could give errors in not measured by the plasma HDL level alone. A single the HDL level up to 4 mg/dl. plasma HDL level is a poor indicator of its functionality, Dr. Rader: Yes, that is correct. What does the clinician which is a significant challenge in HDL research. The HDL do about lab inaccuracies? As with other test results, you do level rises and falls, but that does not tell us its functionality, not make a treatment decision based on a single HDL particularly in relation to reverse cholesterol transport. measurement. A low HDL or an HDL level that falls unex- Dr. Roberts: What is a normal plasma HDL level? pectedly compared to prior measurements should be con- Dr. Grundy: The relations of HDL, LDL, and total firmed with at least one repeat measurement. cholesterol to atherosclerotic disease are all continuous vari- Dr. Friedewald: Do plasma HDL levels vary among ables, so we should no longer refer to “normal” or “abnor- different ethnic groups? mal” values of any of the lipoproteins. Rather, for example, Dr. Grundy: African-Americans generally have higher it is “better” to have an HDL level of 55 mg/dl than 45 HDL levels than Caucasians and some populations in the mg/dl. Middle East and Turkey. Within individual populations, Dr. Brewer: The concept of “normal” level is changing 50% of the variation in HDL level is genetically determined. to “ideal,” which in the individual patient depends on that Dr. Roberts: How do you know that 50% of the HDL person’s other risk factors and risk benefits. Unfortunately, level is genetically determined? we have little data about the “ideal” HDL level, because we Dr. Grundy: By looking at individual families. There is lack data on its functionality. little correlation of HDL level between spouses, but a rel- Dr. Roberts: If the HDL is high enough, isn’t its func- atively high correlation with their offspring, allowing us to tionality likely to be good? estimate through inheritance studies that about 50% of HDL Dr. Rader: That is not necessarily true. One cannot variability is due to genetics. assume that a high HDL guarantees protection from coro- Dr. Rader: This fact is also strongly supported by stud- nary artery disease, because there are many anecdotal situ- ies in identical versus fraternal twins. ations in which people with very high HDLs develop cor- Dr. Grundy: Most of the gene polymorphisms respon- onary artery disease. sible for such variations, however, have not been identified. Dr. Friedewald: What is the value of the HDL to total Dr. Friedewald: Do HDL variations among populations cholesterol ratio? correlate with differing prevalence of atherosclerosis? Dr. Rader: I am not a fan of ratios. If the HDL is high, Dr. Grundy: The answer is probably “yes,” but that has should there be worry about a high LDL? The ratio argu- not been finally resolved because different populations have ment is based on large population studies, using few patients other confounding factors. For that reason, it is difficult to with high HDLs. It is, therefore, uncertain whether ratios know the exact contribution of HDL variances to differ- even apply to individuals with high HDLs. Clinicians ences in cardiovascular risk. should look at individual LDL and HDL levels rather than Dr. Friedewald: How do you study HDL? trying to factitiously simplify their patients’ risks with ra- Dr. Brewer: Data correlating cardiovascular disease and tios. HDL are based primarily on human epidemiological stud- Dr. Grundy: Using ratios depends on the validity of the ies, including early data suggesting that HDL is an inde- theory that HDL neutralizes LDL, which is not supported by pendent risk factor. Receptors and enzymes have been stud- evidence. LDL is an atherogenic lipoprotein, and the higher ied in animal models, especially mice, by turning the genes it is, the more likely that atherosclerosis is present. To on and off with transgenic and knockout models. Much of expect HDL to block the atherosclerotic effects of LDL may the information about HDL that is based on animal models, be wishful thinking. Although HDL might play some role in however, has not been fully validated in humans. mitigating the effects of LDL, HDL may not be truly pro- Dr. Friedewald: Should the HDL be measured in the tective against high LDL. fasting state? Dr. Roberts: The National Cholesterol Education Pro- 1700 The American Journal of Cardiology (www.AJConline.org) gram guidelines recommend treating LDL without regard to The second mechanism is based on a lot of new and inter- the HDL level. esting data about the role of HDL as an anti-inflammatory Dr. Grundy: That is correct. Treatment of LDL has agent. This includes the discovery that HDL modulates goals determined by overall risk, not just the HDL level. adhesion molecules on endothelial cells, thereby changing The guidelines state that a high HDL is a negative risk the inflammatory response in arteries—such as in the cor- factor, and a controversial position, which is taken by many onary arteries in acute myocardial infarction. A third mech- experts, is that an HDL Ͼ60 mg/dl allows the subtraction of anism is the modulating effect of HDL on the oxidation of one risk factor. Nonetheless, a high HDL should not divert LDL. It has enzymes that change the modified lipids present attention away from a high LDL, which still should be on HDL, which may differ from preventing the oxidation of treated. LDL. The fourth major mechanism is that HDL modulates Dr. Brewer: We do not have data to know with certainty nitrous oxide production by the cells. whether, in individual patients, elevated HDL reduces the Dr. Rader: I agree with all those mechanisms, which are risk for cardiovascular disease; there are many patients with all well-established in vitro. There is, however, a lot about high HDLs and coronary arterial disease. HDL that we do not understand, especially the in vivo proof Dr. Grundy: Framingham risk scoring is our best tool of these mechanisms, and which ones are relevant to hu- for integrating risk factors, and I therefore urge physicians mans. to incorporate Framingham risk scoring into their primary Dr. Friedewald: I wonder about ascribing all of these prevention decisions. seemingly unrelated mechanisms for achieving the single Dr. Friedewald: Is low HDL an early predictor of risk— effect of preventing or even reducing atherosclerotic plaque. for example, in a younger person with the metabolic syn- Is it possible that some, or all, of these mechanisms are drome? simply intermediary steps contributing to a single, unifying Dr. Grundy: Low HDL often manifests as part of the underlying mechanism that we have not yet discovered? metabolic syndrome or as an isolated risk factor before Dr. Brewer: That is one of the challenges facing us other risk factors become apparent. We have seen that about HDL. Among these observations of apparently unre- pattern in family studies. Family members of patients with lated functionalities that are made in vitro, are all of cardiovascular disease often include children with low them—or only some of them—the real mechanisms by HDLs, so I believe low HDL is an early predictor of risk. which HDL protects against atherosclerosis? How are they Dr. Brewer: I agree. Detailed studies on those younger related? Which ones are really clinically significant? The individuals often detect other abnormalities in their HDL clinical versus the in vitro aspects are the real challenges for and triglyceride metabolism. the field right now. Dr. Friedewald: Should we measure HDL in persons in Dr. Roberts: When was HDL discovered, and who dis- their 20s? covered it? Dr. Grundy: Yes, although there has been controversy Dr. Brewer: John Gofman discovered HDL in the sub- as to what age we should first measure total cholesterol. fractionation of lipid proteins, and first described it in 1949. Some experts say there is no reason to measure cholesterol He is probably the first investigator to point out lipid het- in premenopausal women or men before age 35. However, erogeneity and to find that plasma lipids are carried by early measurement of the lipoprotein profile identifies peo- different subfractions in the plasma. ple whose LDLs are on the high side and HDLs are on the Dr. Grundy: At one time, HDL was called “alpha- low side, and, therefore, they may be headed for future lipoprotein,” based on electrophoresis. cardiac events. Lifestyle changes, such as weight control, Dr. Roberts: Was Framingham the first study to show can be best for the younger individuals. In the guidelines, that HDL may be protective? we recommend that initial cholesterol measurements should Dr. Brewer: That was the most comprehensive study to be made by 20 years of age. identify a continuum—particularly as a function of the level Dr. Brewer: The 20s and 30s are the ages when lifestyle of HDL—in terms of potential risk and the independent changes can be introduced that may most effectively pre- nature of the risk. The Framingham group deserves the vent the development of future cardiovascular disease. credit for establishing that concept. Dr. Friedewald: How does HDL protect against athero- Dr. Roberts: What is the effect of anabolic steroids on sclerosis? HDL? Dr. Brewer: There are several possible mechanisms. Dr. Brewer: Anabolic steroids lower the HDL to an First, the major role of HDL is to remove cholesterol from extremely low level—to even Ͻ10 mg/dl in some people the cell, based on the mechanism of reverse cholesterol who abuse these drugs. transport. That was a hotly debated mechanism for a long Dr. Roberts: John Cantwell had an article in The Amer- time, until the discovery of the ABCA1 transporter, which ican Journal of Cardiology describing measurements of provided the mechanism by which HDL is able to interact serum lipids in the players on a major league baseball team. with the transporter to facilitate the removal of cholesterol Although many of the players had total cholesterols Ͼ240 from the cell. Discovery that the ABCA1 transporter is mg/dl, there were some with very low HDL levels—in the regulated by the intracellular concentration of cholesterol high teens and low 20s. He concluded that anabolic steroids answered the question why HDL removes cholesterol from were the probable cause for the low HDLs. some cells, but not all cells. The answer is that increased Dr. Grundy: Steroid abuse lowers HDL levels greatly. cholesterol in one cell turns on the ABCA1 transporter, Dr. Brewer: We have also seen very low HDL levels in causing HDL to selectively efflux cholesterol from that cell. male high school football players. Roundtable Discussion/High-Density Lipoprotein Cholesterol 1701

Dr. Friedewald: What is the effect of ␤ blockers on the also has other beneficial effects. Lower levels of exercise— HDL? such as walking 30 minutes a day—while conveying some Dr. Grundy: Beta blockers lower HDL a few milligrams protection against cardiovascular disease, has only minimal per deciliter. effect on the HDL. Dr. Roberts: What about diuretics? Dr. Friedewald: What levels of HDL do you see in Dr. Grundy: Diuretics do not have much effect on the marathon runners? HDL, but they may raise the LDL slightly. Dr. Grundy: They may have HDLs 10 to 15 mg/dl Dr. Friedewald: How does lifestyle affect the HDL? higher than average for comparative populations. It is not Dr. Grundy: Cessation of cigarette smoking, weight unusual to see HDLs of 60 or 70 mg/dl in marathon runners. loss, and exercise are our first line treatments for low HDL, Dr. Brewer: The critical facet of exercise is that it leads so a low HDL can help motivate people to improve their to ideal body weight, which improves triglyceride metabo- lifestyles. Lifestyle changes alone, however, infrequently lism and raises the HDL. Those are clearly protective optimize the HDL. When lifestyle changes are inadequate, changes in terms of the cardiovascular risk factor profile. drug treatment may be needed—particularly for people at Dr. Rader: Exercise as a way to raise HDL is overrated, high risk. Lifestyle changes followed by drug therapy is the except as part of an overall weight loss program. We must right treatment approach for patients with low HDLs. emphasize that it is modest exercise, which, when accom- Dr. Friedewald: What should we tell our patients about panied by weight loss, raises the HDL. alcohol and HDL? Dr. Friedewald: How does cigarette smoking lower the Dr. Grundy: Alcohol is a “double-edged sword.” Al- HDL? though alcohol does raise HDL a small amount, we do not Dr. Rader: We do not know. Inflammation may have know whether that type of rise is protective. There is some some role, in that smoking creates a proinflammatory state, evidence that moderate amounts of alcohol have a protec- and there is evidence linking inflammation to lower levels tive effect against coronary artery disease, and raising HDL of HDL. could be one of the reasons for that effect. Nonetheless, Dr. Friedewald: But there is no question that smoking prescribing alcohol as a therapy is problematic because of lowers the HDL? the many dangers of excessive intake. Ten percent of adults Dr. Brewer: That is correct, but kinetic studies to estab- in America abuse alcohol, so physicians have to be careful lish the mechanism of smoking-induced suppression of the when advising patients about alcohol, even though it might HDL level have never been performed. carry an element of benefit for cardiovascular protection. Dr. Friedewald: How does the composition of the Dr. Roberts: Do all forms of alcohol have the same diet—fat versus carbohydrates—affect HDL? effect on HDL? Dr. Rader: The data suggest that converting from an Dr. Rader: All forms of alcoholic drinks are the same in American Heart Association low-fat diet to an Atkins-like their effect on HDL. There is no evidence that one form of alcohol raises HDL more than another. I agree with Scott low carbohydrate diet leads to higher HDL levels. Although that this is a difficult issue, and I also agree that physicians proponents of low carbohydrate diets use that information should not prescribe alcohol for raising HDL in order to as a reason for following those diets, many of us believe that reduce coronary risk. the rise in HDL is due to increased dietary fat in the low Dr. Brewer: I also agree. The effect of alcohol on HDL carbohydrate diet, because dietary fat is a determinant of cannot be substantiated as a therapeutic approach. Regard- HDL levels. ing the common question of whether there is any specific Dr. Grundy: There is no doubt that the dietary fat protection against atherosclerosis with red wine, the answer composition or the dietary fat–carbohydrate ratio affects is that we do not know. HDL. What is not known is whether those changes affect Dr. Grundy. This relates to the so-called “French para- cardiovascular risk. dox.” The French drink a lot of wine, and France apparently Dr. Brewer: With changing fat concentration in the diet, has a lower prevalence of heart disease than the USA. They the question is how much these changes in dietary fat affect also have less obesity in France, which may account for the amount of cholesterol fluxed to the liver, since we know their lower frequency of heart disease. They also eat more that a major determinant of the plasma HDL level is the Mediterranean-type foods, which could be a factor as well. ABCA1 transporter in the liver. Dr. Roberts: Is the effect of alcohol on the HDL dose- Dr. Grundy: Jan Breslow and his group showed, in related? animal studies, that higher fat diets turned on apo-A1 syn- Dr. Rader: The dose relation between alcohol and HDL thesis. That mechanism is not understood, but the question is broad and extends to very high levels of alcohol use, but you raised is interesting, and it might relate to cholesterol the relation between alcohol use and cardiovascular disease flux. has a more U-shaped curve, perhaps because hypertension Dr. Friedewald: Do LDL and HDL levels fall in pro- occurs with high levels of alcohol use. portion to the fall of fat in the diet? Dr. Friedewald: What is the effect of exercise on the Dr. Grundy: No, the 2 do not necessarily go together. HDL? We showed several years ago that a diet high in unsaturated Dr. Grundy: People who perform vigorous aerobic ex- fat lowered the LDL, but had no effect on HDL. ercise for long periods of time tend to have higher HDL Dr. Friedewald: Thus, the type of fat in the low fat diet levels than those who do not. They also have low body fat, is important in its effect on the lipid levels? which may be a contributing factor, and exercise probably Dr. Grundy: Yes, which is why many experts believe 1702 The American Journal of Cardiology (www.AJConline.org) that, for the patient with a low HDL, it is preferable to lower and this has also been reported by others. Ketoacidosis, the LDL with a diet that is high in unsaturated fat. however, is an extremely, unusual effect of niacin. Dr. Friedewald: Should we view a low HDL as a ther- Dr. Roberts: Does the dose response of niacin extend apeutic target? beyond 2 g? Dr. Grundy: In the Adult Treatment Panel III we stated Dr. Rader: Yes, and this presents a clinical dilemma, that HDL is a potential treatment target in people with low because the most commonly-used version of niacin—Nias- HDL. There was no goal set for low HDL because we do not pan Rx—has a maximal approved dose of 2 g. Should the know what that goal should be. We therefore stated that it is patient on2gofNiaspan whose HDL remains less than reasonable—as a secondary approach—to treat low HDL optimal nonetheless be given a higher dose of Niaspan, or with drugs that will raise HDL, but without specific target should the patient be switched to immediate-release niacin, levels. or some other form of niacin, before going to a higher dose? Dr. Brewer: Even the clinical trial data on changes in Dr. Grundy: I believe it is all right to go to a higher dose HDL using a pharmacologic approach are not restricted to than2gofniacin—which can be well-tolerated—but I am changes in HDL, but also include lowering the B-containing not certain about the form of niacin, given the 2 g approved and triglyceride-containing lipoproteins. Hopefully, future maximum for Niaspan Rx. In my practice, I titrate Niaspan trials will tell us whether specifically raising HDL reduces up to 2 g and stay at that dose. I do not switch to another the risk for cardiovascular events. form of niacin to prescribe a higher dose. Regarding nia- Dr. Friedewald: How effective is niacin in raising the cin’s side effects, which are the reason some physicians do HDL? not prescribe it, many physicians see the value of niacin and Dr. Brewer: Niacin is very effective, and is one of the work through those side effects with their patients, tailoring better drugs for raising the HDL. It raises HDL by 20 to the dose to individual patients— and those patients do quite 25%. Niacin therapy also reduces triglycerides and the flux well. of free-fatty acids, as well as lowering both the very low- Dr. Rader: I agree that many patients tolerate niacin density lipoproteins and the LDL. very well. Dr. Roberts: Is the effect of niacin on HDL dose- Dr. Roberts: Do you recommend that patients take ni- related? acin at bedtime and with aspirin? Dr. Grundy: Yes, it is dose-related. Dr. Rader: It depends on the form of niacin. I recom- Dr. Roberts: Do you ever recommend2gofniacin a mend that patients take niacin and aspirin together at bed- day? time, although I do not know if aspirin is necessary with Dr. Grundy: Several years ago, we used high doses—4 Niaspan Rx. For patients taking immediate-release niacin— to5gofniacin per day. Since the introduction of the statins, which I rarely use anymore—the dose is usually 3 times a we now combine them with lower doses of niacin. The day, and I have them take aspirin with each dose. combination of 2 g niacin per day with a statin affords an Dr. Friedewald: How do statins affect the HDL level? effective HDL-raising strategy. Dr. Grundy: The primary target of statin therapy is the Dr. Brewer: That is our experience as well. Combined LDL. We have an enormous amount of clinical trial evi- with a statin,2gofniacin is sufficient to achieve the dence supporting the strategy of LDL lowering as the first maximum HDL effect. priority, and statins are the most efficacious drugs for that Dr. Roberts: How useful is niacin in patients with dia- purpose. Because people with low HDL are at added risk for betes mellitus? cardiovascular disease, statins afford them even more abso- Dr. Grundy: Niacin is quite effective in improving the lute risk reduction than those with high LDLs and normal lipoprotein profile in patients with diabetes mellitus. It HDLs. Lowering the LDL is the first priority in people with seems to be an almost perfect drug for diabetic dyslipide- low HDL levels. Statins, however, may also give them some mia. The problem with niacin is that it causes a rise in smaller, incremental benefit by raising the HDL as well. glucose levels by inducing a mild form of insulin resistance. Dr. Friedewald: There is benefit in lowering the LDL if The hyperglycemic response to niacin, however, varies the HDL is low? among diabetic patients. Some seem to be quite sensitive to Dr. Grundy: Yes, there is more absolute risk reduction niacin, with a striking rise in glucose levels, while others because patients with lower HDLs are at higher risk. If we tolerate niacin well. It is important to monitor the blood reduce risk by lowering the LDL with a statin in 2 pa- glucose closely in diabetic patients who are taking niacin. tients—one with elevated LDL and an HDL in the normal Dr. Brewer: We have the same experience with niacin. range, and the other with a comparable LDL and an HDL It is very difficult to predict which patients with diabetes lower than the normal range—the absolute risk in the pa- mellitus are going to have significant changes in insulin and tient with low HDL is twice that of the patient with a normal glucose metabolism, so careful titration of the niacin dose HDL. with changes in glucose levels is important. I recall one Dr. Brewer: This is a critical point: patients with a low patient who developed diabetic ketoacidosis on a very small HDL are at increased risk and we therefore need to be more dose of niacin. We have had other patients, however, who aggressive in them in their overall risk factor management. tolerated2gofniacin with only minimal changes in their Dr. Rader: Is HDL a predictor of cardiovascular risk in glucose levels. patients already taking statins? If this is true, low HDL Dr. Friedewald: Did the patient who developed ketoac- remains a secondary treatment target even when the LDL idosis have type 1 diabetes mellitus? has been lowered with statins. Dr. Brewer: No, he had type 2, mature-onset diabetes, Dr. Grundy: Yes, in patients already receiving treat- Roundtable Discussion/High-Density Lipoprotein Cholesterol 1703 ment for LDL, HDL is still a predictor of increased cardio- general. The in vitro data, however, show no evidence that vascular risk. Based on clinical trials, there is no question HDL becomes dysfunctional with CETP inhibition. that patients with a low HDL are at more risk than those Dr. Roberts: Is the ability of CETP inhibitors to raise with higher HDLs, regardless of the LDL level. the HDL affected by the initial HDL level? Dr. Roberts: Does the HDL level play any role in Dr. Brewer: There is not enough published data to deciding which statin to prescribe for treating the LDL? It is answer that question. my understanding that some statins, at higher doses, have Dr. Friedewald: What is the evidence of plaque revers- little or no effect on the HDL, whereas higher doses of other ibility using CETP inhibitors and statins? statins raise the HDL. Dr. Brewer: Based on intravascular ultrasound studies, Dr. Brewer: You are correct. Higher doses of some there is a significant reduction in plaque using the high-dose statins are associated with a decrease in HDL, although we statin (80 mg of atorvastatin) , or whatever dose is required do not know what this means clinically. We cannot say to reduce the LDL to Ͻ100 mg/dl . Thus, there is reduction whether a lower or higher HDL with one statin versus in total plaque volume as a result of treatment with a statin another is a detriment or a benefit, because we have no way alone. The plaque reduction obtained with the acute infu- to measure the functionality of HDL. sion of the phospholipid complex A1 Milano in 5 infusions Dr. Grundy: All statins provide about the same outcome was greater than that obtained with statin treatment for 18 benefit for a given amount of LDL lowering in clinical months. One would anticipate, however, that you may not trials. The statins that lower HDL still give a robust result in get as much change if you used a shorter time frame with a clinical trials, just like the ones that raise it, so differences statin. That is why it is surprising that such a good response among statins in their effect on HDL may not be clinically was seen with the A1 Milano infusion, but that is a very important. different form of HDL, and may have a different mode of Dr. Brewer: I agree. There are no data showing any action from the statin-reducing LDL levels assessed by clinical significance of differing effects on HDL by the intravascular ultrasound. statins. Dr. Roberts: In the Milano study using intravascular Dr. Friedewald: Let’s discuss newer approaches to rais- ultrasound, plaque reversibility was demonstrated at 6 ing HDL, beginning with CETP inhibition. weeks. Dr. Friedewald: Dr. Brewer: A new way to raise HDL to a level we have What is the status of HDL infusion therapy for plaque reduction as a clinical tool? not had with other medications is with CETP inhibition. Dr. Brewer: Infusion therapy is still in the developmen- CETP is a transfer protein that exchanges the cholesterol tal stages in terms of obtaining sufficient clinical data for its triglyceride between HDL and the B-containing lipopro- effectiveness. There has been only one published intravas- teins. Inhibition of that transfer is associated with an in- cular ultrasound study of acute HDL therapy with infusions crease in the plasma HDL level. For example, a 60 mg dose for a short period of time. Other approaches are now being of the investigational CETP inhibitor, torcetrapib, inhibited developed to confirm that initial observation. All of these the CETP about 60% and also raised the HDL level about studies with acute HDL therapy are targeted to decrease 60%, which was a greater raise than has occurred with any vulnerable plaques that have been brought to the attention of other drugs. physicians treating patients with an acute coronary syn- Dr. Friedewald: Do we have any evidence for the effi- drome. The initial problematic vessels can be “fixed” by cacy of CETP inhibitors in preventing atherosclerosis? angioplasty or stent, but these patients have other significant Dr. Brewer: Studies with CETP inhibitors in experimen- plaques in that setting, and acute HDL therapy is suggested tal animals—particularly rabbits —have shown signifi- by the A1 Milano study to be effective in decreasing the cantly reduced atherosclerosis in those models. vulnerable plaque and decreasing the potential for future Dr. Roberts: What is the effect of CETP inhibitors on coronary events. While the A1 Milano acute infusion causes triglycerides and LDL? changes in the vessel wall, we do not know whether those Dr. Brewer: The LDL level is, in part, a function of the changes lead to a reduction of clinical events. I believe, degree of CETP inhibition. Consequently, at higher doses— however, that infusion that truly reduces the size of vulner- with almost complete inhibition of the CETP—there are able plaque, including the inflammation and the cholesterol progressive decreases in LDL levels. These LDL decreases content of those plaques, should be associated with de- are due, in part, to prevention of the triglycerides from being creased clinical events. That is the hope, anyway. exchanged into LDL. At that point, enzymes hydrolyze the Dr. Rader: My feeling, like Bryan’s, is that infusion triglycerides and alter the LDL to a denser form. In patients therapy eventually will be shown to be effective. In 10 to 15 with complete CETP deficiency, there is also increased years we will have infusions as a way of stabilizing catabolism of LDL. plaques—perhaps even modestly causing plaque regres- Dr. Roberts: How much does the LDL level fall with sion—and this will reduce clinical events. It is not going to CETP inhibition? be easy, however, to get to the point where we can perform Dr. Brewer: With the maximum doses of torcetrapib— end point trials proving that infusion therapy is successful. 120 mg twice daily—LDL can fall as much as 40%. Factors like dose selection, frequency and duration of ad- Dr. Roberts: Which component of HDL rises with ministration, and other issues are difficult to determine, and CETP inhibition? we presently have no preclinical models to guide us. This is Dr. Brewer: That question is difficult to answer because why it is going to take 10 or 15 years. Infusion therapy, of our inability to look at the functionality of HDL in however, is plausible, the animal data support the general 1704 The American Journal of Cardiology (www.AJConline.org) concept, and I believe eventually we are going to have duction in risk. There is also evidence that angiotensin something like this available. receptor blockers and angiotensin-converting enzyme inhib- Dr. Friedewald: What new studies are underway that itors—beyond their antihypertensive effects—may also re- address clinical efficacy of raising the HDL with torce- duce cardiac risk. With those drugs, we have the capability trapib, and when can we expect results? to reduce cardiovascular risk beyond the effect of statins Dr. Brewer: There are 2 types of studies being done: alone. As we add more and more measures to reduce risk, imaging studies and clinical trials data. The imaging studies however, each incremental step does not give us as much are being performed with intravascular ultrasound (IVUS) added benefit as that step would provide if it were used by Steve Nissen at The Cleveland Clinic, looking at patients alone, so such a preventive strategy eventually reaches a with an acute coronary syndrome. These patients are ran- point of diminishing returns. domized into 2 groups: those receiving a statin alone, with Dr. Roberts: If longer than 5 years is necessary to titration of their LDL to Ͻ100 mg/dl, and a second group determine outcome in secondary prevention, studies of pri- also titrated to an LDL Ͻ100 mg/dl, plus receiving 60 mg mary prevention have to be even longer. of torcetrapib. These patients are being followed for 18 Dr. Grundy: One of the unresolved questions in this months, and a repeat IVUS then looks at the change in the field is how much does risk reduction amplify over time as atherosclerosis in a targeted coronary vessel with a 20% to you intervene with greater intensity? At 5 years, what per- 50% obstructive lesion at baseline. There are also, in addi- cent of the maximum risk reduction do we actually see? One tion to the acute coronary syndrome studies, 2 imaging trials school of thought is that it just keeps widening more and looking at changes in the carotid intima-media thickening in more with time, which has not been proven, because we do patients receiving torcetrapib. not have long-term clinical trials. It is, however, an intrigu- The second parallel study being conducted is a large, ing idea. Another thought is that after several years, you 12,000ϩ patient clinical trial looking at whether clinical may reach maximum risk reduction, which Dr. Malcolm end points over a period of several years will be reduced by Law believes occurs at about 6 to 7 years—but not every- raising the HDL with CETP inhibition. one agrees with him. Dr. Roberts: When will the clinical trial data be avail- Dr. Roberts: Are you referring to primary or secondary able? prevention? Dr. Brewer: Probably in 3 or 4 years. The data from the Dr. Grundy: Both. I believe that the percentage of imaging trials will be available in 2007. reduction is very similar in primary and secondary preven- Dr. Friedewald: What do we know about the safety of tion. All the clinical trials now result in about the same torcetrapib? relative risk reduction, but not the same absolute risk re- Dr. Brewer: With torcetrapib, there is a small increase duction. Nonetheless, it is possible that longer durations of in systolic and diastolic blood pressure—2.2 mm systolic therapy will widen the gap between the risks for cardiovas- and 1.5 mm diastolic—in the initial data from the clinical cular disease between untreated and treated patients. patient studies. Dr. Brewer: That is a critical question because it makes Dr. Friedewald: Are the blood pressure increases uni- a big difference when we begin preventive measures. If versal? maximum benefit continues for many years – or even in- Dr. Brewer: Yes, and there is a select group of patients definitely – earlier treatment may give patients much more who get a further increase in blood pressure. benefit as they age. Dr. Roberts: You mentioned that the studies with sur- Dr. Friedewald: Is it possible that studies of surrogate rogate end points are 18 months. markers—such as plaque size determined by intravascular Dr. Brewer: Eighteen months for the IVUS study and 2 ultrasound—will circumvent some of the need for long-term years for the carotid studies. outcome studies? Dr. Friedewald: Jim Forrester made this statement: “It Dr. Brewer: There are initial data supporting that ap- is at least reasonable to speculate that it may be possible that proach. Most attractive at this point is, as you suggest, the we will be able to reduce atherosclerosis not by the 30% we intravascular ultrasound technique to measure atherosclerosis. saw in the initial lipid-lowering trials of statins but rather The question raised with such technology is whether studies of more in the range of an 80% to 90% reduction through a surrogate markers are sufficient for correlating their results combination of aggressive LDL lowering with statins to the with actual clinical events. That is our hope, because the range of 70 mg/dl and then adding to that CETP inhibition.” successful use of surrogate markers would shorten the identi- Do you agree that the combination of statins and drugs fication of those drugs that are effective in preventing cardio- designed to raise the HDL have the potential to reduce vascular events. Another issue is whether therapy can institute atherosclerosis by as much as 90%? changes in the composition of vulnerable plaques to decrease Dr. Rader: I agree that a 90% reduction is possible, the probability of their eventual rupture. That is a question for although difficult to achieve in a standard, 4- to 5-year trial. which we do not have an answer, and is a limitation of intra- Dr. Brewer: Statin therapy alone has lowered the risk of vascular ultrasound, which does not allow us to look precisely cardiovascular events by up to 50% in secondary preven- at plaque composition. tion, based on available data, especially when we lower the Dr. Grundy: We generally think about coronary disease in LDL into the 60 to 70 mg/dl range. 2 different forms. One form is the acute coronary syndrome Dr. Grundy: There are ways, other than with lipid and the other form is chronic obstructive disease. You must modification, to lower cardiovascular risk. For example, also think about reversibility in the same terms. If you can anti-platelet therapy with aspirin affords about a 25% re- remove lipid, thereby “cooling down” the plaque, you can Roundtable Discussion/High-Density Lipoprotein Cholesterol 1705 prevent an acute coronary event. In chronic coronary arterial ologists and other healthcare specialists in cardiovascular disease, however, even after lipid reduction, significant flow medicine is based on the following premises:1 problems can persist, because fibrous tissue appears to be 1. A low level of HDL cholesterol is a major risk factor largely irreversible. Thus, if we reduce the incidence of acute for coronary heart disease. coronary syndrome through these therapies, we are still going 2. There are multiple lifestyle and genetic causes of low to be left with a residual of chronic disease in people who have HDL. built up a lot of plaque. They will continue to have angina 3. There are many misconceptions about HDL, such as pectoris, and they may require coronary angioplasty or bypass the role of subfractionation in the clinical setting and surgery, so we should not think that we have eliminated all the use of alcohol for treatment of low HDL coronary disease just by preventing acute events. 4. There are therapies for raising the HDL level, but Dr. Roberts: As you point out, the composition of the their clinical significance has not been proven. plaques is important in patients who have coronary events. About 70% of the plaque is fibrous tissue, 10% is calcium, Target Audience: This activity is designed for cardiol- and 20% is lipids. Thus, with only one-fifth of the plaque ogists and all other health care specialists caring for patients comprised of lipids, how much reversibility can occur in with acute and chronic coronary heart disease. people who have already had coronary events? I am a bit CME Credit: The A. Webb Roberts Center for Continu- cynical about the answer. If you believe, however, in the ing Medical Education of Baylor Health Care System, Dal- thesis that there must be 75% or greater obstruction in las, designates this educational activity for a maximum of 1 cross-sectional area to decrease flow through a tube and you AMA PRA Category 1 Credit(s).™ Physicians should only eliminate 15 to 20% of the plaque, the degree of narrowing claim credit commensurate with the extent of their partici- is reduced to Ͻ75% in cross-sectional area. Thus, perhaps pation in the activity. only small reductions in plaque mass could lead to very The A. Webb Roberts Center for Continuing Medical significant increases in coronary flow. Education for Baylor Health Care System, Dallas, is accred- Dr. Friedewald: Thank you. ited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Appendix CME Instructions: After reading this article, go online at www.AJConline.org to register, complete a post-test with In December 2006, data from the placebo-controlled “In- a minimum score of 80%, complete an evaluation, and print vestigation of Lipid Level Management to Understand Its a certificate. Impact in Atherosclerotic Events” (ILLUMINATE) study Combination of Media: Print and Internet revealed an increased frequency of cardiovascular events Computer Requirements: Windows 2000, Pentium 3 or and mortality in patients receiving a combination of torce- greater, 512 ram, 80 gigabytes storage trapib and atorvastatin. In March 2007, 2 completed studies Estimated Time to Complete: 1 hour of torcetrapib using intravascular ultrasound, “Rating Ath- Release Date: June 2007 erosclerotic Disease Change by Imaging with a New Cho- Termination Date: June 2008 lesterol-ester-transfer Protein Inhibitor” (RADIANCE 1) and “Investigation of Lipid Management Using Coronary 1. NCEP Expert Panel. Third Report of the National Cholesterol Educa- Ultrasound to Assess Reduction of Atherosclerosis by tion Program (NCEP) Expert Panel on detection, evaluation, and treat- CETP Inhibition and HDL Elevation” (ILLUSTRATE), ment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–3421. failed to show a favorable effect on atherosclerosis progres- 2. Kastelein JJP, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, sion.2,3 In all 3 studies the torcetrapib/atorvastatin combi- Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, nation significantly raised the mean plasma HDL choles- Bots ML, for the RADIANCE 1 Investigators. Effect of torcetrapib terol, lowered the mean plasma LDL cholesterol, and on carotid atherosclerosis in familial hypercholesterolemia. Clinical Trials.Gov number, NCT00136981 (ClinicalTrials.gov). (10.1056/ increased the incidence of hypertension. The cause of ad- NEJMoa071359). Available at: www.nejm.org. Accessed March 26, verse events associated with torcetrapib was not determined 2007. in these studies. 3. Nissen SE, Tardif J-C, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM, for the ILLUS- TRATE Investigators. Effect of torcetrapib on the progression of cor- Needs Assessment: The need for this activity for cardi- onary atherasclerosis. N Engl J Med 2007;356:1304–1316. Comparison of Effects of Ezetimibe/Simvastatin Versus Simvastatin Versus Atorvastatin in Reducing C-Reactive Protein and Low-Density Lipoprotein Cholesterol Levels Thomas Pearson, MD, PhDa,*, Christie Ballantyne, MDb, Christine Sisk, BSc, Arvind Shah, PhDc, Enrico Veltri, MDd, and Darbie Maccubbin, PhDc

The lowering effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) were compared with those of simvastatin or atorvastatin monotherapy in a large cohort of patients with primary hypercholesterolemia. To compare ezetimibe/simvastatin with simvastatin, data were combined from 3 identical, prospective 12-week trials in which patients were randomized to receive placebo; ezetimibe 10 mg; ezetimibe 10 mg added to simvastatin 10, 20, 40, or 80 mg; or simvastatin 10, 20, 40, or 80 mg. To compare ezetimibe/simvastatin with atorvastatin, data were analyzed from a phase III double-blind, active-controlled study in which patients were randomized equally to receive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 weeks. When averaged across doses, ezetimibe/simvastatin produced significantly greater reductions compared with simvastatin alone in LDL cholesterol (52.5% vs 38.0%, respectively) and CRP levels (31.0% vs 14.3%, respectively). At each individual simvastatin dose, co-administration with ezetimibe produced significant further CRP reductions versus simvastatin alone. Ezetimibe/simvastatin was significantly more effective at lowering LDL cholesterol than atorvastatin when pooled across doses (53.4% vs 45.3%, respectively) and in each milligram-equivalent dose comparison. Reductions in CRP of similar magnitude were observed with ezetimibe/simvastatin and atorvastatin when averaged across doses and at each milligram-equivalent statin dose comparison. In conclusion, the lipid-modulating and anti-inflammatory effects of ezetimibe/simvastatin provide additional benefits not realized by statin monotherapy alone. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1706–1713)

Ezetimibe is a novel agent that potently inhibits the intes- sources by blocking the Niemann-Pick C1–Like 1 protein tinal absorption of cholesterol from dietary and biliary for cholesterol transport across the intestinal wall without affecting the absorption of bile acids, fatty acids, fat-soluble vitamins, or triglycerides (TGs).1–6 Unlike 3-hydroxy-3- aUniversity of Rochester School of Medicine and Dentistry, Rochester, methylglutaryl coenzyme A reductase inhibitors (i.e., sta- New York; bMethodist DeBakey Heart Center and Baylor College of Medi- tins), the metabolic effects of ezetimibe appear to be limited cine, Houston, Texas; cMerck & Company, Rahway, New Jersey; and dSchering- to the liver and intestine; the target of ezetimibe (the sterol Plough Research Institute, Kenilworth, New Jersey. Manuscript received Octo- transporter Niemann-Pick C1–Like 1 protein) has little or ber 13, 2006; revised manuscript received and accepted January 29, 2007. no distribution outside the intestines and/or portal system.2,4 Table 2 for this article is available online at www.AJConline.org. Previous studies have shown that, in addition to the favor- These studies were supported by Merck & Co., Inc, North Wales, Penn- sylvania. Dr. Pearson has received consulting fees/honoraria from Bristol- able effects on lipid levels, combined therapy with Myers Squibb, New York, New York; Bayer, Wayne, New York; Johnson & ezetimibe plus a statin produced significant reductions in Johnson/Merck, Merck/Schering-Plough, North Wales, Pennsylvania; Sanofi/ C-reactive protein (CRP) relative to statin monotherapy. To Aventis, Bridgewater, New Jersey; and Forbes/Meditech, Vancouver, British more fully explore this observation, we conducted the Colombia, Canada; and is on the speaker’s bureau for Abbott, Abbott Park, present analysis to compare the anti-inflammatory and lipid- Illinois; AstraZeneca, New Castle County, Delaware, Bayer; Bristol-Myers/ modifying effects of ezetimibe/simvastatin therapy with Squibb; Kos, Miami, Florida; Pfizer, New York City, New York; and Merck/ those of simvastatin and atorvastatin monotherapy across Schering-Plough and Merck & Co., Inc. Whitehouse Station, New Jersey; and the marketed doses in a large number of patients with has received research grants from Kos; Merck & Co., Inc.: Pfizer; and Sanofi/ hypercholesterolemia. Aventis. Dr. Ballantyne has received consulting fees/honoraria from Merck & Co. Inc.; and Reliant, Liberty Corner, New Jersey; research grants from AstraZeneca; diaDexus, South San Francisco, California, Gene Logic, Gaith- Methods ersburg, Maryland; GlaxoSmithKline, Brentford, London, United Kingdom; Design of pooled simvastatin factorial studies: Results Kos; Merck & Co., Inc.; Novartis, Basel, Switzerland; Pfizer; Roche, Nutley, were analyzed from 3 similar phase III randomized, multi- New Jersey; Sankyo Pharma, Chuo-ku, Tokyo, Japan; Sanofi-Synthelabo, New York City, New York, Schering-Plough, Kennilworth, New Jersey, and center, double-blind, placebo-controlled, 10-arm, parallel- Takeda, Deerfield, Illinois; Merck/Schering-Plough; AstraZeneca; Pfizer; and group studies designed to evaluate the efficacy and safety GlaxoSmithKline. profile of ezetimibe/simvastatin relative to ezetimibe and *Corresponding author: Tel: 585-275-2191; fax: 585-756-7775. simvastatin monotherapy. The design of the 3 studies has E-mail address: [email protected] (T. Pearson). been previously reported.7–9 After a 4-week single-blind

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.01.062 Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents 1707

Table 1 Patient characteristics and baseline lipid variables in the pooled simvastatin factorial and atorvastatin factorial studies Variable Pooled Simvastatin Factorial Studies Atorvastatin Factorial Study Placebo Ezetimibe 10 mg Simvastatin Ezetimibe ϩ Atorvastatin Ezetimibe ϩ (n ϭ 257*) (n ϭ 246*) Monotherapy Simvastatin Monotherapy Simvastatin (n ϭ 1,031*) (n ϭ 1,007*) (n ϭ 917*) (n ϭ 915*) Age (yrs) 57 Ϯ 11 57 Ϯ 11 55 Ϯ 11 57 Ϯ 11 58 Ϯ 10 59 Ϯ 10 Ͻ65 72.8% 74.8% 76.5% 73.7% 70.1% 68.5% Ն65 27.2% 25.2% 23.5% 26.3% 29.9% 31.5% Men (%) 43.6% 42.7% 47.9% 47.4% 52.5% 51.9% Caucasian (%) 90.3% 90.2% 88.4% 90.5% 86.2% 86.1% Body mass index (kg/m2) 28 Ϯ 529Ϯ 529Ϯ 528Ϯ 530Ϯ 630Ϯ 5 Coronary heart disease (%) 19.5% 21.1% 17.8% 19.9% 19.4% 20.5% Metabolic syndrome (%) 25.7% 27.6% 31.2% 31.9% 51.8% 52.4% Diabetes mellitus (%) 9.7% 6.9% 4.4% 5.9% 21.5% 23.0% CRP (mg/L), median Ϯ SD 2 Ϯ 42Ϯ 42Ϯ 32Ϯ 32Ϯ 32Ϯ 3 Total cholesterol (mg/dl) 262 Ϯ 28 266 Ϯ 28 262 Ϯ 28 262 Ϯ 28 265 Ϯ 42 264 Ϯ 42 LDL cholesterol (mg/dl) 177 Ϯ 23 180 Ϯ 24 177 Ϯ 24 176 Ϯ 24 179 Ϯ 38 178 Ϯ 38 TG (mg/dl), median Ϯ SD 152 Ϯ 76 157 Ϯ 92 158 Ϯ 80 160 Ϯ 89 168 Ϯ 93 170 Ϯ 95 Apolipoprotein B (mg/dl) 163 Ϯ 24 166 Ϯ 23 164 Ϯ 23 163 Ϯ 23 165 Ϯ 29 165 Ϯ 29 HDL (mg/dl) 52 Ϯ 12 52 Ϯ 12 51 Ϯ 12 51 Ϯ 13 49 Ϯ 12 49 Ϯ 13

Data are presented as mean Ϯ SD or percentage, except where otherwise noted. * Number of patients with baseline and post treatment CRP measurements. placebo lead-in period, patients with primary hypercholes- study design has been reported previously.11 After a 4-week terolemia (plasma low-density lipoprotein [LDL] choles- single-blind placebo run-in period, patients with primary terol concentration of Ն145 to Յ250 mg/dl and TG levels hypercholesterolemia who were not at their LDL cholesterol Յ350 mg/dl) were randomized in equal numbers to 1 of 10 goal as defined by the Third Report of the National Cho- daily treatments for 12 weeks: ezetimibe/simvastatin 10/10, lesterol Education Program Adult Treatment Panel guide- 10/20, 10/40, or 10/80 mg; simvastatin 10, 20, 40, or 80 mg; lines were randomized in equal numbers to 8 treatment ezetimibe 10 mg; or placebo. Individual tablets of ezetimibe arms: ezetimibe/simvastatin at doses of 10/10, 10/20, 10/40, and simvastatin were co-administered in 2 of the studies7,8 or 10/80 mg or atorvastatin monotherapy at doses of 10, 20, and a single co-granulated tablet (ezetimibe/simvastatin) 40, or 80 mg for 6 weeks. Patients were eligible for enroll- was administered in the third.9 Bioequivalence between ment if they met prespecified criteria with regard to coro- co-administered ezetimibe and simvastatin and the single nary heart disease (CHD) or CHD risk and/or LDL choles- co-granulated ezetimibe/simvastatin tablet was demon- terol levels. Other criteria included fasting serum TG level strated in a previous study.10 Patients were required to have Յ350 mg/dl; alanine aminotransferase, aspartate amino- alanine aminotransferase and aspartate aminotransferase transferase, or creatine kinase level Յ1.5 times ULN; serum Յ Յ Ͻ levels 2 times the upper limit of normal (ULN) with no creatinine level 1.5 mg/dl; and hemoglobin A1c 9.0% in active liver disease and creatine kinase levels Յ1.5 times patients with diabetes. Randomization was stratified accord- the ULN. Patients with uncontrolled or unstable cardiac, ing to LDL cholesterol levels at visit 2: Ն130 and Ͻ160 endocrine, hepatic, renal, or metabolic conditions or who mg/dl, Ն160 and Ͻ190 mg/dl, and Ն190 mg/dl. Patients were taking nonstatin lipid-lowering drugs, immunosup- discontinued fibrate therapy 9 weeks before the start of the pressants, corticosteroids, or potent cytochrome P-450 3A4 study and all other lipid-lowering therapy 7 weeks before inhibitors were ineligible to participate. All lipid-altering the start of the study. Patients were instructed to maintain a drugs were discontinued for 6 weeks (for statins) or 8 weeks cholesterol-lowering diet throughout the duration of the (for fibrates) before randomization. Patients were instructed trial. Blood specimens were collected at weeks Ϫ4, Ϫ1, and to maintain a cholesterol-lowering diet throughout the du- 1, day 1; and week 6 or at discontinuation. ration of the trial. Blood samples were collected at weeks All study protocols were reviewed and approved by the Ϫ4 and Ϫ2 for an assay of qualifying parameters and at appropriate institutional review boards or independent eth- weeks 0 (i.e., baseline), 2, 4, 8, and 12 for assay of lipid ics committees. Patients provided written informed consent efficacy variables. Plasma concentrations of CRP were mea- before initiation of any study procedure. sured at baseline and end point (or the last available lipid Laboratory methods: In each study, lipid levels were determination in patients who discontinued study treatment analyzed from fasting plasma samples at Medical Research prematurely). Laboratories International (Highland Heights, Kentucky) as Design of atorvastatin factorial study: The atorvastatin described previously.7 LDL cholesterol concentrations (in factorial study was a phase III, multicenter, double-blind, milligrams per deciliter) were calculated according to the randomized, active-controlled, 8-arm parallel-group study Friedewald equation: LDL cholesterol ϭ total cholesterol Ϫ designed to evaluate the efficacy and safety profiles of high-density lipoprotein (HDL) cholesterol Ϫ (TG/5).12 As- ezetimibe/simvastatin and atorvastatin monotherapy. The says of CRP were performed in a post hoc manner on 1708 The American Journal of Cardiology (www.AJConline.org)

Pooled SIMVA EZE/SIMVA EZE Pooled EZE/ ______(mg) ______(mg/mg) PBO 10mg SIMVA SIMVA 10 20 40 80 10/10 10/20 10/40 10/80 0 -0.5

-20 * -18.3

-31.5 -34.1 -40 -38.0 -40.0

-46.4 -44.5 Mean % Change (+SEM) *** -52.5 -50.3 -60 -55.3 -59.8

*p<0.001 vs. PBO PBO **p<0.001 vs corresponding dose of SIMVA EZE 10mg ***p<0.001 vs. pooled SIMVA SIMVA EZE/SIMVA Figure 2. Mean percentage change from baseline levels in LDL cholesterol Figure 1. Mean percentage change from baseline levels in LDL cholesterol after 6 weeks of treatment with atorvastatin (ATORVA) or ezetimibe/ after 12 weeks of treatment with placebo (PBO), ezetimibe (EZE), simva- simvastatin. Other abbreviations as in Figure 1. statin (SIMVA), or ezetimibe/simvastatin. archived plasma samples stored during the study at Ϫ70°C and then batch-processed together in a treatment-blinded fashion. CRP was measured by high-sensitivity immunon- ephelometry (Dade Behring, Deerfield, Illinois), as previously described.13 Statistical analysis: Analyses of LDL cholesterol and CRP were performed on a modified intent-to-treat population, which included all randomized patients who had valid baseline and end point measurements for LDL cholesterol and CRP. Analysis of variance (ANOVA) models were used to obtain the within-treatment estimates and between-treatment comparisons for LDL cholesterol and CRP. For the LDL cholesterol analyses, the ANOVA model included terms for study and treatment (10 treatment groups) in the pooled simvastatin factorial studies and terms for treatment (8 treatment groups) and LDL cholesterol stratum at visit 2 in the atorvastatin factorial study. Because the distribution of CRP measurements Figure 3. Geometric mean percentage change from baseline levels in CRP follows a log-normal distribution, logarithms of the ratios after 12 weeks of treatment with placebo, ezetimibe, simvastatin, or of end point to baseline values (i.e., log-ratio) were ezetimibe/simvastatin Abbreviations as in Figure 1. modeled through ANOVA. The geometric mean percentage changes from baseline in CRP levels were calculated The percentage of patients in whom defined single and based on back-transformation via exponentiation of the dual LDL cholesterol levels (Ͻ70 and Ͻ100 mg/dl) and model-based least-squared means obtained from the CRP levels (Ͻ1 and Ͻ2 mg/L) were achieved, without ANOVA model with the terms for treatment (i.e., dose regard to patients’ baseline CHD risk, were examined combinations), baseline CRP, baseline LDL cholesterol, across the individual and pooled treatment groups. The and baseline HDL. Various Spearman’s correlation coef- differences between the pooled groups were tested for ficients were calculated within each treatment group to significance with Fisher’s exact test. A model-based anal- study the relations between LDL cholesterol and CRP ysis was also performed using logistic regression for the parameters. achievement of single and dual LDL cholesterol/CRP The geometric mean percentage change from baseline in levels with terms for treatment, baseline CRP, baseline CRP (ϮSE) was examined for various patient subgroups. LDL cholesterol, and baseline HDL cholesterol levels. The ANOVA model for the subgroup analyses included For both analyses, between-group comparisons for terms for treatment, baseline CRP, baseline LDL choles- ezetimibe/simvastatin versus statin monotherapy were terol, baseline HDL, subgroup, and treatment-by-subgroup performed for only the pooled treatment groups to control interaction. experiment-wise error rate. Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents 1709

20 (95% CI) (95% Difference

10 Between Treatment

BMI Metabolic 2 Overall Age (y) Gender Race (kg/m ) Diabetes CHD -10 Syndrome Yes (n=45, 59) (n=45, Yes ian (n=120, 96) 65 (n=242,265) 30 (n=296, 280) No (n=986,No 948) No (n=847,No 806) No (n=672,No 671) <65 (n=789,742) > <30 (n=618,624) Yes (n=183,Yes 200) > Yes (n=322, 304) (n=322, Yes Male (n=494,Male 477) Female (n=537,530) Overall (n=1031, 1007) Caucasian (n=911, 911)

Non-Caucas Treatment Difference (95% CI)

Figure 4. Geometric mean percentage difference between treatment groups in CRP levels from baseline across patient subgroups. Values in parentheses represent the number of patients in the pooled simvastatin and pooled ezetimibe/simvastatin groups, respectively. The treatment-by-subgroup interaction term was p Ͼ0.15 for all subgroups, indicating consistency of the treatment effect across subgroups.

Results cholesterol than pooled atorvastatin (Ϫ53.4% vs Ϫ45.3%, Demographics: Paired baseline and post-treatment CRP respectively; p Ͻ0.001; Figure 2). At each dose tested, the measurements were available for 2,541 patients in the co- LDL cholesterol reductions achieved with ezetimibe/sim- hort from the pooled simvastatin factorial studies and 1,832 vastatin were significantly greater compared with each patients from the atorvastatin factorial study. The treatment milligram-equivalent dose of atorvastatin monotherapy groups were generally well balanced in terms of patient (p Ͻ0.001 for all comparisons; Figure 2). demographics, baseline CRP levels, and baseline lipid parameters within and between studies, with the exception that Effects on CRP in pooled simvastatin factorial studies: patients in the atorvastatin factorial study had slightly In the fitted model predicting log ratio of CRP as a measure higher median TG levels compared with patients in the of CRP change, the terms for treatment, baseline CRP, and simvastatin factorial studies (Table 1). In addition, there baseline LDL cholesterol were significant (p Ͻ0.0001, p were larger proportions of patients with diabetes and met- Ͻ0.0001, and p ϭ 0.0146, respectively), whereas baseline abolic syndrome in the atorvastatin factorial study than in HDL was not a significant predictor (p ϭ 0.4833). Median the simvastatin factorial studies (Table 1). baseline CRP values were similar across individual treatment groups. Relative to placebo, treatment with ezetimibe Effects on LDL cholesterol in pooled simvastatin fac- 10 mg for 12 weeks did not produce significant reductions torial studies: After 12 weeks of treatment, ezetimibe from baseline in CRP (Figure 3). When averaged across all monotherapy was significantly more effective at reducing doses, ezetimibe/simvastatin demonstrated significantly LDL cholesterol compared with placebo (Ϫ18.3% vs greater reductions in CRP compared with simvastatin (p Ϫ0.5%, respectively; p Ͻ0.001). Averaged across all doses, Ͻ0.001; Figure 3). The geometric mean percentage reduc- pooled ezetimibe/simvastatin produced significantly greater tions from baseline in CRP were 31.0% for pooled mean percentage reductions from baseline in LDL choles- ezetimibe/simvastatin and 14.3% for pooled simvastatin, terol compared with pooled simvastatin monotherapy leading to an incremental reduction of 16.7% (95% confi- (Ϫ52.5% vs Ϫ38.0%, respectively; p Ͻ0.001; Figure 1). At dence interval 11.7% to 21.7%) in favor of ezetimibe/sim- each dose tested, ezetimibe/simvastatin was significantly vastatin therapy (Figure 3). A nonparametric analysis more effective at lowering LDL cholesterol compared with yielded similar results; the median percentage reductions each milligram-equivalent dose of simvastatin monotherapy from baseline in CRP were 33.3% for ezetimibe/simvastatin (p Ͻ0.001 for all comparisons; Figure 1). and 15.4% for simvastatin averaged across doses. Effects on LDL cholesterol in atorvastatin factorial The CRP-lowering effects of ezetimibe/simvastatin and study: After 6 weeks of treatment, pooled ezetimibe/sim- simvastatin were compared across each of the simvastatin vastatin was significantly more effective at lowering LDL doses tested. Significantly greater geometric mean percent- 1710 The American Journal of Cardiology (www.AJConline.org)

Figure 5. Effect of baseline CRP levels at clinically meaningful cut-off points (Ͻ1,1to3,Ͼ3) on CRP efficacy with placebo, ezetimibe, simvastatin monotherapy (pooled across doses), and ezetimibe/simvastatin Figure 6. Geometric mean percentage change from baseline level in CRP (pooled across doses). Shown are median percentage changes from base- after 6 weeks of treatment with atorvastatin and ezetimibe/simvastatin. line in CRP level. Bars, SE. Abbreviations as in Figure 1. Abbreviations as in Figures 1 and 2. age reductions in CRP were achieved with ezetimibe/simvastatin compared with each corresponding dose of simvastatin monotherapy (p Ͻ0.01 for ezetimibe/simvastatin 10/10 vs simvastatin 10 mg, ezetimibe/simvastatin 10/20 vs simvastatin 20 mg, ezetimibe/simvastatin 10/40 vs simvastatin 40 mg, and ezetimibe/simvastatin 10/80 vs simvastatin 80 mg; Figure 3). The relation between simvastatin and ezetimibe/simvastatin dose and CRP response was examined in this pooled analysis through pairwise comparisons (Figure 3). The reductions in CRP associated with placebo, ezetimibe 10 mg, and simvastatin 10 mg were not significantly different from zero (p Ͼ0.10 for each between-group comparison). Addi- tionally, simvastatin 10 mg did not produce significant reductions from baseline in CRP relative to placebo (Ϫ4.0% vs 7.4%, respectively; p ϭ 0.0859) or ezetimibe alone (Ϫ4.0% vs Ϫ2.8%, respectively; p ϭ 0.8406). Relative to simvastatin 10 mg, significantly greater reductions in CRP Ϫ Ϫ Figure 7. Effect of baseline CRP levels at clinically meaningful cut-off were observed with simvastatin 20 mg ( 4.0% vs 16.2%, Ͻ Ͼ respectively; p Ͻ0.05), 40 mg (Ϫ4.0% vs Ϫ17.3%, respec- points ( 1,1to3, 3 mg/L) on CRP efficacy with atorvastatin (pooled across doses) and ezetimibe/simvastatin (pooled across doses). Median tively; p Ͻ0.05), and 80 mg (Ϫ4.0% vs Ϫ18.4%, respec- Ͻ percentage changes from baseline levels in CRP are shown. Bars, SE. tively; p 0.05). However, there were no significant dif- Abbreviations as in Figures 1 and 2. ferences in CRP-lowering response among simvastatin 20, 40, and 80 mg (p Ͼ0.05 for each between-group comparison). For ezetimibe/simvastatin at every dose (Ͻ65 vs Ն65 years), gender, race (Caucasian versus non- level, significant reductions in CRP were observed rela- Caucasian), body mass index (BMI; Ͻ30 vs Ն30 kg/m2), and tive to zero, placebo, and ezetimibe alone (p Ͻ0.006 for baseline presence of diabetes, CHD, and metabolic syn- each between-group comparison). The geometric mean per- drome status (Figure 4). Median percentage changes in CRP centage reduction in CRP associated with ezetimibe/simva- varied across baseline CRP levels, with the greatest reduc- statin 10/10 mg was significantly lower than those of tions observed in the patients with the highest baseline CRP ezetimibe/simvastatin 10/20 mg (Ϫ19.0% vs Ϫ30.3%, re- levels (Figure 5). However, the trend in CRP response was spectively; p Ͻ0.05), 10/40 mg (Ϫ19.0% vs Ϫ35.0, respec- similar to that observed in the entire cohort, with ezetimibe/ tively; p Ͻ0.001), and 10/80 mg (Ϫ19.0% vs Ϫ37.8%, respec- simvastatin being more effective in reducing CRP than tively; p Ͻ0.0001). However, there were no significant simvastatin or ezetimibe alone. differences in CRP-lowering response among ezetimibe/sim- Spearman’s correlation coefficients for placebo, ezetimibe vastatin 10/20, 10/40, and 10/80 mg (p Ͼ0.05 for each 10 mg, simvastatin, and ezetimibe/simvastatin demonstrated between-group comparison). minimal associations (most coefficients Ͻ0.2) between baseline The enhanced CRP-lowering efficacy of ezetimibe/simva- LDL cholesterol and percentage change in CRP, percentage statin was consistent across patient subgroups based on age change in LDL cholesterol and percentage change in CRP, per- Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents 1711

Table 3 Percentage* of patients achieving individual and dual low-density lipoprotein (LDL) cholesterol (Ͻ70, Ͻ100 mg/dl) and C-reactive protein (CRP) (Ͻ1, Ͻ2 mg/L) levels after 12 weeks’ treatment with placebo, ezetimibe, simvastatin, and ezetimibe/simvastatin Treatment LDL Cholesterol Ͻ100 LDL Cholesterol Ͻ70 LDL Cholesterol CRP mg/dl and CRP mg/dl and CRP Ͻ100 mg/dl Ͻ70 mg/dl Ͻ2 mg/L Ͻ1 mg/L Ͻ2 mg/L Ͻ1 mg/L Ͻ2 mg/L Ͻ1 mg/L Placebo 0 0 14.1 7.3 0000 Ezetimibe 10 mg 1.6 0 14.0 5.1 1.7 0.3 0 0 Simvastatin 10 mg 20.8 0.4 23.7 9.8 7.7 3.3 0 0 Ezetimibe/simvastatin 10/10 mg 63.3 10.4 25.6 17.4 36.0 21.0 5.8 4.8 Simvastatin 20 mg 30.3 1.2 22.0 14.0 15.0 10.0 0.3 0.3 Ezetimibe/simvastatin 10/20 mg 74.4 28.0 33.6 20.6 43.4 24.9 15.4 9.2 Simvastatin 40 mg 50.6 3.4 27.9 15.9 24.7 14.6 2.0 0.7 Ezetimibe/simvastatin 10/40 mg 87.1 49.8 35.3 24.6 53.4 36.1 28.4 18.8 Simvastatin 80 mg 69.3 17.4 36.9 18.8 42.7 21.5 10.2 4.3 Ezetimibe/simvastatin 10/80 mg 90.6 59.2 42.0 22.7 58.3 34.2 38.2 22.2 Pooled simvastatin 43.1 5.7 27.7 14.7 22.2 12.2 3.2 1.3 Pooled ezetimibe/simvastatin 78.9† 37.0† 34.2‡ 21.3† 47.7† 29.0† 21.6† 13.5†

p Values are based on the Fisher’s exact test. Between-treatment group comparisons were only performed on pooled simvastatin and pooled ezetimibe/simvastatin groups to minimize multiplicity errors. * Expressed as number of patients achieving level/number of patients above level at baseline. For inclusion in the dual LDL cholesterol/CRP analysis, patients had to be above the stated LDL cholesterol and/or CRP level at baseline and have baseline and post-treatment CRP measurements. † One-sided p value Ͻ0.001 versus corresponding dose of simvastatin monotherapy. ‡ One-sided p value Ͻ0.050 versus corresponding dose of simvastatin monotherapy. centage change in LDL cholesterol and change in CRP, and significant reductions in CRP, there were no differences in the change in LDL cholesterol and change in CRP across the indi- CRP-lowering response across the individual ezetimibe/sim- vidual treatment groups (Table 2, online only). vastatin and atorvastatin doses. The similar CRP-lowering efficacy of ezetimibe/simva- Effects on CRP in atorvastatin factorial study: In the statin and atorvastatin was consistent among subgroups fitted model, predicting log ratio of CRP, the term for based on age (Ͻ65 vs Ն65 years), gender, race (Caucasian baseline CRP was significant (p Ͻ0.0001), whereas the vs non-Caucasian), BMI (Ͻ30 vs Ն30 kg/m2), and baseline terms for treatment, baseline LDL cholesterol, and baseline HDL cholesterol were not significant (p ϭ 0.20, p ϭ 0.62, presence of diabetes, CHD, and metabolic syndrome status and p ϭ 0.22, respectively). Median baseline CRP values (data not shown). Median percentage changes in CRP varied were similar across the individual treatment groups. After 6 across baseline CRP levels, with the greatest reductions weeks of treatment, the geometric mean percentage reduc- observed in the patients with the highest baseline CRP tions from baseline in CRP were 25.1% for pooled levels (Figure 7). However, the trend in CRP response was ezetimibe/simvastatin and 24.8% for pooled atorvastatin, similar to that observed in the entire cohort, with ezetimibe/ resulting in a between-group difference of 0.3% (95% con- simvastatin and atorvastatin producing reductions in CRP of fidence interval, Ϫ5.14 to 5.82; Figure 6). Similar results similar magnitude. were observed in a nonparametric analysis; the median per- Spearman’s correlation coefficients for the individual centage reductions from baseline in CRP were 26.5% for ezetimibe/simvastatin and atorvastatin groups demon- Ͻ atorvastatin averaged across doses and 26.7% for ezetimibe/ strated minimal association (most coefficients 0.2) be- simvastatin averaged across doses. Because the treatment term tween baseline LDL cholesterol and percentage change in in the fitted model was not significant, pairwise testing among CRP; percentage change in LDL cholesterol and percent- the treatment groups was not performed. This finding indicated age change in CRP; percentage change in LDL choles- that reductions in CRP of similar magnitude were observed terol and change in CRP; and change in LDL cholesterol with ezetimibe/simvastatin and atorvastatin when averaged and change in CRP (Table 2, online only). across doses and at each milligram-equivalent statin dose comparison. Attainment of single and dual LDL and CRP levels in Because the treatment term in the fitted model was not pooled simvastatin factorial studies: Predefined LDL, significant, the relation between ezetimibe/simvastatin and CRP, and dual LDL cholesterol/CRP levels were atorvastatin dose and CRP response could not be examined achieved in a significantly greater proportion of patients through pairwise comparisons. However, the geometric mean treated with pooled ezetimibe/simvastatin than with percentage reductions from baseline CRP levels observed with pooled simvastatin monotherapy (p Ͻ0.05 for CRP Ͻ2 atorvastatin 10, 20, 40, and 80 mg and ezetimibe/simvastatin mg/L, p Ͻ0.001 for all other comparisons; Table 3). In 10/10, 10/20, 10/40, and 10/80 mg were significantly different general, a trend toward greater LDL cholesterol, CRP, than zero (p Ͻ0.0001 for each comparison; Figure 6). There- and dual LDL cholesterol/CRP goal attainment was ob- fore, although ezetimibe/simvastatin and atorvastatin produced served across the individual ezetimibe/simvastatin and 1712 The American Journal of Cardiology (www.AJConline.org)

Table 4 Percentage* of patients achieving individual and dual low-density lipoprotein (LDL) cholesterol (Ͻ70, Ͻ100 mg/dl) and C-reactive protein (CRP) (Ͻ1, Ͻ2 mg/L) levels after 6 weeks’ treatment with atorvastatin and ezetimibe/simvastatin Treatment LDL Cholesterol Ͻ100 LDL Cholesterol Ͻ70 LDL Cholesterol CRP mg/dl and CRP mg/dl and CRP Ͻ100 mg/dl Ͻ70 mg/dl Ͻ2 mg/L Ͻ1 mg/L Ͻ2 mg/L Ͻ1 mg/L Ͻ2 mg/L Ͻ1 mg/L Atorvastatin 10 mg 39.7% 3.5% 28.7% 9.9% 19.2% 9.8% 1.3% 0.8% Ezetimibe/simvastatin 10/10 mg 68.9% 15.9% 32.2% 18.1% 39.3% 19.2% 8.3% 5.2% Atorvastatin 20 mg 57.5% 11.0% 28.7% 15.1% 31.3% 16.5% 7.0% 4.3% Ezetimibe/simvastatin 10/20 mg 78.2% 29.3% 35.4% 18.5% 45.0% 22.8% 15.4% 9.0% Atorvastatin 40 mg 71.9% 19.7% 23.8% 18.7% 39.1% 21.3% 12.5% 7.8% Ezetimibe/simvastatin 10/40 mg 85.9% 43.2% 33.3% 17.5% 48.5% 25.5% 26.0% 14.0% Atorvastatin 80 mg 78.6% 33.0% 36.3% 19.1% 45.2% 25.6% 18.3% 10.0% Ezetimibe/simvastatin 10/80 mg 86.0% 56.5% 30.8% 19.5% 50.2% 29.6% 32.6% 17.7% Pooled atorvastatin 61.9% 16.8% 29.5% 15.7% 33.7% 18.3% 9.7% 5.7% Pooled ezetimibe/simvastatin 79.8%† 36.2%† 33.0% 18.4% 45.7%† 24.3%‡ 20.5%† 11.5%†

p Values are based on Fisher’s exact test. Between-treatment group comparisons were only performed on pooled atorvastatin and pooled ezetimibe/simvastatin to minimize multiplicity errors. * Expressed as number of patients achieving level/number of patients above level at baseline. For inclusion in the dual LDL cholesterol/CRP analysis, patients had to be above the stated LDL cholesterol and/or CRP level at baseline and have baseline and post-treatment CRP measurements. † Two-tailed p value Ͻ0.0001 versus the corresponding pooled atorvastatin monotherapy. ‡ Two-tailed p value ϭ 0.0017 versus the corresponding pooled atorvastatin monotherapy. simvastatin doses. Similar results were obtained from the eters in some reports,14 suggesting a direct effect on inflam- model-based analysis as well (data not shown). mation in peripheral tissues or on liver metabolism. Ezetimibe provides additional insight into this mechanism, Attainment of single and dual LDL and CRP levels in as its direct effects are believed to be limited to inhibition of atorvastatin factorial study: When averaged across doses, cholesterol absorption (with consequent LDL cholesterol predefined LDL cholesterol and dual LDL cholesterol/CRP lowering) and potential direct effects on liver metabolism. levels were achieved in a significantly greater proportion of The latter may be important because the liver is the primary patients treated with ezetimibe/simvastatin than with ator- Ͻ source of CRP synthesis. Significant CRP reductions were vastatin monotherapy (p 0.002 for all comparisons; Table not observed with ezetimibe monotherapy but rather when 4). The percentage of patients in whom CRP levels Ͻ1 and Ͻ ezetimibe and simvastatin were co-administered; thus, 2 mg/L were achieved were similar between pooled ezetimibe appears to potentiate the CRP-lowering effect of ezetimibe/simvastatin and pooled atorvastatin groups. In simvastatin despite the low likelihood of direct effects of general, a trend toward greater LDL cholesterol and dual ezetimibe at peripheral sites. There were significant reduc- LDL cholesterol/CRP goal attainment was observed across tions in CRP with simvastatin 20 mg (16.2%) and atorva- the individual ezetimibe/simvastatin and atorvastatin doses. statin 10 mg (18.1%), with respective LDL cholesterol re- However, a similar proportion of patients had CRP levels ductions of 34% and 36%. One possible interpretation is that Ͻ1 and Ͻ2 mg/L across these dose groups. Similar results there is a threshold effect, meaning one needs an LDL choles- were obtained from the model-based analyses as well (data terol reduction of Ն30% to achieve a reduction in CRP. How- not shown). ever, in the present study, there was a lack of evidence of strong correlations between baseline LDL cholesterol level and Discussion percentage change in CRP, percentage change in LDL choles- The present analysis showed that, when averaged across the terol and percentage change in CRP, percentage change in dose range and at each milligram-equivalent statin dose, LDL cholesterol and change in CRP, change in LDL cholesterol ezetimibe/simvastatin produced significantly greater reduc- and change in CRP, and baseline LDL cholesterol and baseline tions in LDL cholesterol relative to simvastatin and atorva- CRP. Therefore, one possible explanation is that ezetimibe statin monotherapy in patients with hypercholesterolemia. may potentiate the effects of statins on hepatic production of The superior LDL cholesterol–lowering efficacy of CRP after a threshold of LDL cholesterol reduction is ezetimibe/simvastatin was consistently observed within all reached. This would not necessarily imply a reduction in prespecified patient subgroups, including age, gender, race, inflammation in the arterial system; therefore, the inference and BMI, and was independent of baseline presence of that a reduction in CRP indicates a reduction in cardiovas- diabetes, CHD, and metabolic syndrome. In addition, cular disease risk would require verification in trials with ezetimibe/simvastatin produced significantly greater CRP clinical end points. reductions relative to simvastatin monotherapy and similar CRP reductions compared with atorvastatin monotherapy. The precise mechanism by which statins reduce CRP Acknowledgment: We thank Hongwei Wang, PhD, and levels is not understood, but is poorly correlated with statin Jianxin Lin, MS, from Merck & Co., Inc., for computational effects on LDL cholesterol or other individual lipid param- assistance. Preventive Cardiology/Comparison of LDL Cholesterol/CRP Lowering Agents 1713

1. van Heek M, France CF, Compton DS, McLeod RL, Yumibe NP, tered with simvastatin in patients with primary hypercholesterolemia: Alton KB, Sybertz EJ, Davis HR Jr. In vivo metabolism-based dis- a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc covery of a potent cholesterol absorption inhibitor, SCH58235, in the 2004;79:620–629. rat and rhesus monkey through the identification of the active metab- 9. Bays HE, Ose L, Fraser N, Tribble DL, Quinto K, Reyes R, Johnson- olites of SCH48461. J Pharmacol Exp Ther 1997;283:157–163. Levonas AO, Sapre A, Donahue SR, for the Ezetimibe Study Group. 2. van Heek M, Farley CF, Compton DS, Hoos L, Alton KB, Sybertz EJ, A multicenter, randomized, double-blind, placebo-controlled, factorial Davis HR Jr. Comparison of the activity and disposition of the novel design study to evaluate the lipid-altering efficacy and safety profile of cholesterol inhibitor, SCH58235, and its glucuronide, SCH60663. Br J the ezetimibe/simvastatin tablet compared with ezetimibe and simva- Pharmacol 2000;129:1748–1754. statin monotherapy in patients with primary hypercholesterolemia. 3. van Heek M, Farley C, Compton DS, Hoos L, Davis HR. Ezetimibe Clin Ther 2004;26:1758–1773. selectively inhibits intestinal cholesterol absorption in rodents in the 10. Migoya EM, Bergman A, Hreniuk D, Matthews N, Yi B, Roadcap B, presence and absence of exocrine pancreatic function. Br J Pharmacol Valesky R, Liu L, Riffel K, Groff M, et al. Bioequivalence of an 2001;134:409–417. ezetimibe/simvastatin combination tablet and coadministration of 4. van Heek M, Farley C, Compton DS, Hoos LM, Smith-Torhan A, ezetimibe and simvastatin as separate tablets in healthy subjects. Int Davis HR. Ezetimibe potently inhibits cholesterol absorption but does J Clin Pharmacol Ther 2006;44:83–92. not affect acute hepatic or intestinal cholesterol synthesis in rats. Br J 11. Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose- Pharmacol 2003;138:1459–1464. 5. Altmann SW, Davis HR, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer comparison study of the combination of ezetimibe and simvastatin SP, Maguire M, Golovko A, Zeng M, et al. Niemann-Pick C1 Like 1 (Vytorin) versus atorvastatin in patients with hypercholesterolemia: protein is critical for intestinal cholesterol absorption. Science 2004; the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J 2005; 303:1201–1204. 149:464–473. 6. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun 12. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the con- MP, Crona JH, Davis HR Jr, Dean DC, Detmers PA, et al. The target centration of low-density lipoprotein cholesterols in plasma, with- of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad out use of the preparative ultracentrifuge. Clin Chem 1972;18: SciUSA2005;102:8132–8137. 499–502. 7. Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, 13. Rifai N, Tracy RP, Ridker PM. Clinical efficacy of an automated Suresh R, Sun S, Veltri E, on behalf of the Ezetimibe Study Group. high-sensitivity C-reactive protein assay. Clin Chem 1999;45:2136– Ezetimibe coadministered with simvastatin in patients with primary 2141. hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–2134. 14. Devaraj S, Autret B, Jialal I. Effects of colesevelam hydrochloride 8. Goldberg AC, Sapre A, Liu J, Capece R, Mitchel YB, for the (WelChol) on biomarkers of inflammation in patients with mild hy- Ezetimibe Study Group. Efficacy and safety of ezetimibe coadminis- percholesterolemia. Am J Cardiol 2006;98:641–643. 1713.e1 The American Journal of Cardiology (www.AJConline.org)

Table 2 Spearman’s correlation coefﬁcients Treatment Baseline LDL and Percent Change in LDL Percent Change in Change in LDL Percent Change and Percent Change LDL and Change and Change in CRP in CRP in CRP in CRP Correlation p value Correlation p value Correlation p value Correlation p value Pooled simvastatin factorial studies Placebo 0.08 0.20 Ϫ0.07 0.25 Ϫ0.10 0.13 Ϫ0.09 0.15 Ezetimibe 10 mg 0.22 0.00 Ϫ0.07 0.27 Ϫ0.05 0.48 Ϫ0.07 0.27 Pooled simvastatin 0.02 0.51 0.11 0.00 0.07 0.02 0.05 0.08 Pooled ezetimibe/simvastatin 0.07 0.03 0.16 0.00 0.09 0.00 0.06 0.08 Simvastatin 10 mg Ϫ0.03 0.62 Ϫ0.10 0.11 Ϫ0.11 0.09 Ϫ0.09 0.14 Ezetimibe/simvastatin 10/10 mg 0.22 0.00 0.12 0.06 0.09 0.17 Ϫ0.03 0.67 Simvastatin 20 mg Ϫ0.06 0.34 0.13 0.04 0.14 0.03 0.13 0.04 Ezetimibe/simvastatin 10/20 mg Ϫ0.02 0.76 0.07 0.27 Ϫ0.05 0.47 0.01 0.92 Simvastatin 40 mg 0.09 0.14 0.03 0.60 Ϫ0.00 0.99 Ϫ0.03 0.68 Ezetimibe/simvastatin 10/40 mg Ϫ0.01 0.91 0.05 0.46 0.04 0.54 0.02 0.73 Simvastatin 80 mg 0.08 0.18 0.18 0.00 0.08 0.21 0.04 0.57 Ezetimibe/simvastatin 10/80 mg 0.07 0.25 0.18 0.00 0.12 0.06 0.05 0.43 Pooled atorvastatin 0.04 0.26 0.11 0.00 0.06 0.05 0.01 0.68 Pooled ezetimibe/simvastatin Ϫ0.00 0.92 0.12 0.00 0.08 0.02 0.06 0.07 Atorvastatin factorial study Atorvastatin 10 mg 0.00 0.99 0.02 0.73 0.04 0.55 0.04 0.51 Atorvastatin 20 mg 0.04 0.57 0.08 0.25 0.01 0.85 Ϫ0.03 0.62 Atorvastatin 40 mg 0.07 0.27 Ϫ0.03 0.64 Ϫ0.08 0.23 Ϫ0.11 0.08 Atorvastatin 80 mg 0.05 0.46 0.13 0.05 0.06 0.32 0.01 0.91 Ezetimibe/simvastatin 10/10 mg Ϫ0.04 0.55 Ϫ0.02 0.79 0.00 0.97 0.03 0.66 Ezetimibe/simvastatin 10/20 mg Ϫ0.12 0.08 0.11 0.09 0.11 0.09 0.11 0.08 Ezetimibe/simvastatin 10/40 mg Ϫ0.02 0.77 0.16 0.02 0.10 0.14 0.08 0.20 Ezetimibe/simvastatin 10/80 mg 0.16 0.02 0.14 0.04 0.06 0.40 Ϫ0.03 0.62 Effect of Simvastatin (80 mg) on Coronary and Abdominal Aortic Arterial Calcium (from the Coronary Artery Calciﬁcation Treatment with Zocor [CATZ] Study)

James G. Terry, MSa,*, J. Jeffrey Carr, MD, MSb,d, Ethel O. Kouba, PhDa, Donna H. Davis, BSa, Lata Menon, MS, RNa, Kathryn Bender, PharmDc, E. Ted Chandler, MDa, Timothy Morgan, PhDd, and John R. Crouse III, MDa,d

We tested the hypothesis that, compared with placebo, simvastatin would reduce the progression of coronary artery calcium (CAC) and abdominal aortic calcium (AAC) levels in participants asymptomatic for vascular disease. Total CAC and AAC were measured with multidetector cardiac computed tomography. Inclusion criteria were a CAC score of >50 Agatston units, high-density lipoprotein (HDL) cholesterol level <50 mg/dl, low- density lipoprotein (LDL) cholesterol level between 100 and 160 mg/dl, and >2 other risk factors. Diabetes and history of vascular disease were exclusion criteria. Participants were for 12 (40 ؍ or matching placebo (n (40 ؍ randomized to receive 80 mg simvastatin (n months. Lipids were measured at 3-month intervals, and CAC and AAC measurements were repeated at 6 and 12 months. Total cholesterol, triglycerides, and LDL decreased signiﬁcantly with simvastatin treatment (p <0.0001 for all comparisons, adjusted for baseline levels), whereas lipids remained unchanged for subjects randomized to receive placebo. Total CAC volume increased from baseline in both treatment groups. For subjects in the active treatment group, CAC volume increased by 9%, whereas in the placebo group, for treatment effect). AAC volume also increased 0.12 ؍ plaque volume increased by 5% (p for treatment effect). In conclusion, simvastatin 0.15 ؍ in both treatment groups (p treatment does not reduce progression of CAC or AAC compared with placebo. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1714–1717)

In the present study, we tested the hypothesis that aggres- men or Ն55 years in women; (2) parent or sibling history of sive treatment with 80 mg simvastatin in participants early coronary artery disease and age Ͻ55 years for men or asymptomatic for vascular disease with dyslipidemia and a Ͻ65 years for women; (3) current smoking; (4) hyperten- baseline total coronary artery calcium (CAC) level of Ն50 sion defined as current treatment; or (5) HDL level Ͻ35 U measured with cardiac computed tomography (CT) would mg/dl.1 Eligible participants also had a CAC level of Ն50 U slow the progression of CAC and abdominal aortic calcium according to the Agatston method on duplicate cardiac com- (AAC) over 1 year compared with placebo. puted tomographic scans. Subjects with documented history of vascular disease or Methods diabetes were excluded, as were individuals with liver aminotransferase levels Ͼ20% than the upper limit of normal, Potentially eligible participants were 21 to 75 years of age Ͼ with triglyceride levels Ͻ600 mg/dl. In addition, eligible creatine kinase levels 50% than the upper limit of normal, Ͼ participants met 1 of the following sets of criteria: (1) creatinine levels 1.8 mg/dl, or untreated thyroid abnor- high-density lipoprotein (HDL) level Յ50 mg/dl, low-den- malities. Also excluded were women capable of becoming sity lipoprotein (LDL) levels of 100 to 130 mg/dl, and Ն2 pregnant and not practicing birth control, individuals who other risk factors that modify the LDL goal; or (2) HDL consumed Ͼ10 alcoholic drinks/week (1 drink represents 12 level Յ50 mg/dl, LDL levels of 130 to 190 mg/dl, and Ͻ2 oz. beer, 4 oz. wine, or 1 oz. liquor), those with untreated other risk factors that modify the LDL goal. Positive risk blood pressure Ͼ140/90 mm Hg, and those with a known factors affecting the LDL goal were (1) age of Ն45 years in history of intolerance to simvastatin. Participants were also excluded if they had significant incidental findings on baseline computed tomographic scan or any other significant Departments of aInternal Medicine, bRadiology, cPharmacy, and dPub- medical abnormality, as were subjects taking concomitant lic Health Sciences, Wake Forest University Health Sciences, Winston- lipid-altering medicines that might confound the study re- Salem, North Carolina. Manuscript received November 1, 2006; revised sults. manuscript received and accepted January 11, 2007. Study participants were recruited from those who had The CATZ study was supported by an unrestricted grant from Merck Pharmaceuticals and by the Wake Forest University General Clinical participated in previous studies and through mass mailings. Research Center, Winston-Salem, North Carolina. Of 446 subjects screened in the clinic, most participants *Corresponding author: Tel: 336-713-7240; fax: 336-713-7255. (n ϭ 251) failed to qualify as a result of the lipid exclusion, E-mail address: [email protected] (J.G. Terry). liver function test abnormalities, increased glucose levels,

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.01.060 Preventive Cardiology/Simvastatin Treatment and Coronary Artery Calcification 1715 or thyroid function abnormalities. Of 195 subjects who met Table 1 the initial lipid and clinical screening criteria, 80 also met Participant baseline statistics the CAC criteria and were randomized to participate in the Variable Placebo Active p Value study. The remainder had CAC levels Ͻ50U(nϭ 95) or (n ϭ 40) (n ϭ 40) incidental findings on CT that precluded participation (n ϭ Age (yrs) 66 Ϯ 666Ϯ 5 0.51 20). Men 85% 98% 0.11 The study was approved by the institutional review Smoking history 90% 93% 0.99 board, and all subjects provided informed consent. The Body mass index (kg/m2) 28 Ϯ 429Ϯ 5 0.35 initial visit included administration of consent, medical his- Total cholesterol (mg/dL) 200 Ϯ 19 198 Ϯ 18 0.74 tory and risk factor review, and lipid profile and vital sign Triglycerides (mg/dL) 149 Ϯ 67 160 Ϯ 72 0.46 screening. Lipid-eligible subjects returned to the clinic to HDL (mg/dL) 41 Ϯ 640Ϯ 5 0.58 undergo phlebotomy for complete blood cell count, com- LDL (mg/dL) 129 Ϯ 19 127 Ϯ 14 0.67 prehensive metabolic panel, thyroid function test, and repeat CAC volume 872 Ϯ 861 751 Ϯ 833 0.39 lipid profile. Also at this visit, subjects met with a dietitian CAC Agatston 659 Ϯ 725 593 Ϯ 828 0.52 Ϯ Ϯ and received dietary counseling with Step I Diet goals of AAC volume 3767 4619 4000 4082 0.68 AAC agatston 3598 Ϯ 4758 3891 Ϯ 4246 0.65 Ͻ30% total fat, Ͻ10% saturated fat, and Ͻ300 mg dietary cholesterol intake per day.1 Subjects who remained eligible Data are presented as mean Ϯ SD or percent. returned for cardiac computed tomographic scan within 1 month. Randomization to simvastatin or placebo took place scans of a standardized phantom (QCT Torso Phantom; within 1 month for those eligible based on computed tomo- Image Analysis, Columbia, Kentucky) with known amounts graphic results. At the randomization and final study visits, of calcium were measured to insure stability of the com- subjects underwent electrocardiography, and the study phy- puted tomographic system’s calibration each month. Total sician conducted a physical examination. The physical ex- calcium volume score and the Agatston scoring method amination included measurement of vital signs and exami- (modified to account for slice thickness) were used to quan- nations of circulatory, neurologic, and integumentary tify CAC on the SmartScore software package (General systems, along with review of the patient’s medical history Electric Medical Systems).5 The AAC was measured as to rule out underlying cardiovascular disease or study con- described previously.6 We have previously reported the traindication. Subjects were randomized to receive 40 mg comparability of these methods between multidetector and simvastatin or placebo (1:1 randomization) with titration to electron-beam CT.7 80 mg at 1 month after randomization. Study investigators Based on a previous report by Callister et al8 that indi- involved in any procedures and participants were blinded to cated progression rates of CAC of 52% in untreated patients study allocation. At the 1-, 2-, and 3-month visits and every versus 5% in treated patients, we determined that 20 sub- 3 months thereafter, liver function and creatine kinase tests jects in each treatment arm would provide power to detect a were checked, and subject compliance, side effects, and difference in CAC progression over 1 year. To allow for serious adverse events were documented. At all visits, lipid dropouts and to detect possible differences in CAC progres- profiles were obtained. sion at 6 months, we increased the treatment groups to 40 The CAC levels were measured in duplicate by trained subjects, providing Ͼ90% power at 1 year to detect a technicians at baseline, 6 months, and 12 months with significant difference in progression of the magnitude re- low-dose prospective electrocardiographically triggered ported.8 Treatment effects on lipid and calcification out- multidetector CT. The protocol was similar to that of the come variables were determined with analysis of covariance Multi-Ethnic Study of Atherosclerosis, which was active 2–4 general linear models adjusted for the variable of interest at during the same time as the present study. Paired cardiac baseline as previously described.9 All analyses were per- computed tomographic scans were performed within min- formed using SAS software (version 9.1; SAS Institute, utes of each other (coefficient of variation, 12.2% in 119 Cary, North Carolina). subjects with measurable CAC ).3 Imaging was performed on the General Electric LightSpeed Plus (4-channel) or Results Ultra (8-channel) scanner (General Electric Medical Sys- tems, Waukesha, Wisconsin). For the low-dose cardiac Baseline comparisons between subjects randomized to ac- computed tomographic examination, the following techni- tive and placebo treatments are shown in Table 1. Although cal parameters were used: 0.5-second gantry speed, seg- the gender distribution between groups did not statistically mented reconstruction with the standard kernal resulting in differ (p ϭ 0.11), 6 of the 7 women in the study were 250-ms temporal resolution, 120 kVp, 120 mA, and cover- randomized to receive placebo. ing the entire heart in a single breath-hold with 2.5-mm slice Measurements of CAC and AAC were moderately cor- thickness. A quality control phantom was placed under each related at baseline according to volume and Agatston scor- participant as part of the protocol. For the abdominal aorta, ing methods (r ϭ 0.40, p ϭ 0.0003; r ϭ 0.41, p ϭ 0.0001, a single helical acquisition was performed starting at the respectively). juxtarenal aorta and extending beyond the aortic bifurca- Four of the 40 subjects randomized to receive active tion. Technical parameters of the abdomen scan were as treatment withdrew before the 6-month follow-up computed follows: helical scan mode, 0.8-second gantry speed, 120 tomographic scan, and 5 of the 40 subjects randomized to kVp, 200 mA, standard reconstruction kernal, and 2.5-mm receive placebo failed to complete Ն1 follow-up computed slice thickness. During the entire study, quality control tomographic examination. In total, 18 subjects (10 in the 1716 The American Journal of Cardiology (www.AJConline.org)

Table 2 Treatment effects on lipids Lipids (mg/dl) Placebo Active p Value*

Baseline 6† 12 %⌬‡ Baseline 6 12 %⌬ Total cholesterol 200 Ϯ 3 200 Ϯ 3 197 Ϯ 3 21 198 Ϯ 3 136 Ϯ 3 140 Ϯ 3 230 Ͻ0.0001 Triglycerides 149 Ϯ 11 156 Ϯ 10 154 Ϯ 10 13 160 Ϯ 11 120 Ϯ 10 131 Ϯ 10 218 Ͻ0.0001 HDL 41 Ϯ 143Ϯ 141Ϯ 1 1140Ϯ 139Ϯ 139Ϯ 1 22 0.014 LDL 129 Ϯ 3 127 Ϯ 3 126 Ϯ 3 22 127 Ϯ 272Ϯ 374Ϯ 3 242 Ͻ0.0001

* Signiﬁcance level for average treatment effect for 6- and 12-month follow-up adjusted for baseline and using natural log transformed data. † Least-square mean Ϯ SE for 6- plus 12-month follow-up adjusted for baseline value. ‡ Percentage change (⌬) at 12 months versus baseline.

Table 3 Treatment effects on coronary and abdominal aortic calcium Calcium measures (U) Placebo Active p Value*

Baseline 6† 12 %⌬‡ Baseline 6 12 %⌬ CAC Volume 872 Ϯ 138 809 Ϯ 26 845 Ϯ 32 23 751 Ϯ 133 799 Ϯ 26 820 Ϯ 32 19 0.61 Agatston 659 Ϯ 116 651 Ϯ 16 691 Ϯ 24 15 593 Ϯ 132 631 Ϯ 16 645 Ϯ 24 19 0.12 AAC Volume 3767 Ϯ 740 4296 Ϯ 128 4378 Ϯ 335 116 4000 Ϯ 671 4442 Ϯ 113 5059 Ϯ 339 126 0.15 Agatston 3598 Ϯ 762 4093 Ϯ 110 4179 Ϯ 101 116 3891 Ϯ 698 4225 Ϯ 112 4450 Ϯ 103 114 0.34

* Significance level for average treatment effect for 6- and 12-month follow-up adjusted for baseline and using natural log-transformed data. † Least-square mean Ϯ SE for 6-month plus 12-month follow-up adjusted for baseline value. ‡ Percentage change (⌬) at 12 months versus baseline. active treatment group, 8 in the placebo group) were ran- to the volume or Agatston methods within the coronary domized but did not complete the study (i.e., did not provide arteries or abdominal aorta. Moreover, we found no signif- follow-up scans at 6 and 12 months). Reasons for study icant association between the rate of calcified plaque pro- discontinuation were muscle pains and/or increased creatine gression (in either arterial bed) and the magnitude of LDL kinase (n ϭ 8); increased liver aminotransferase levels (n ϭ reduction. The present trial and previous blinded random- 4); participant/physician wishes (n ϭ 5); and development ized clinical trials10–13 do not support the beneficial effects ϭ Ͼ of diabetes (n 1). The compliance rate was 88% for all of statin treatment on CAC progression suggested by retro- Ն subjects who underwent 1 follow-up scan for the analysis. spective and open-label studies.8,14–18 It is possible that Treatment effects on lipids at 6 and 12 months are shown lipid-lowering therapy acts more quickly to slow progres- in Table 2. The effects of treatment on CAC volume and sion of noncalcified plaque components, making techniques Agatston scores are shown in Table 3. CAC volume and such as B-mode ultrasound and intravascular ultrasound Agatston score increased by 9% over the study period preferable outcomes in short-term clinical trials. among active simvastatin treatment participants, whereas It is possible that we failed to detect a treatment effect participants who received placebo experienced a 3% decrease in CAC volume and a 5% increase in Agatston score because CAC progression was limited in the present trial. (p ϭ 0.61 and p ϭ 0.12 for treatment effect on CAC volume CAC progression rates of 25% to 50% per year have been 19 and Agatston score, respectively). AAC volume and Agat- reported in observational studies. Progression of CAC in ston score increased among all participants regardless of randomized trials has ranged from approximately 15% to treatment allocation (p ϭ 0.15 and p ϭ 0.34 for treatment 27% per year10–13; however, unlike previous studies, the effect on AAC volume and Agatston score, respectively; present clinical trial excluded participants at high risk, such Table 3). The magnitude of change in LDL cholesterol was as those with a history of cardiovascular disease or diabe- not associated with a change in CAC or AAC according to tes.11–14 Strengths of our study include the fact that it was the volume or Agatston score models. randomized, blinded, placebo-controlled, and included CAC and AAC as outcome variables. Discussion The present clinical trial tested the effect of aggressive Acknowledgment: We thank the computed tomographic treatment with 80-mg simvastatin versus placebo on CAC technologists, image analysts, nurses, nutritionists, and and AAC progression in subjects who were free from clin- other research personnel who made this project possible. ically manifest cardiovascular disease. Although our target reduction in LDL was achieved, we detected no treatment 1. NCEP Expert Panel. Summary of the second report of the National effect on the rate of calcified plaque progression according Cholesterol Education Program (NCEP) Expert Panel on Detection, Preventive Cardiology/Simvastatin Treatment and Coronary Artery Calcification 1717

Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult vastatin, vitamin C, and vitamin E. The St. Francis Heart Study Treatment Panel II). JAMA 1993;269:3015–3023. randomized clinical trial. J Am Coll Cardiol 2005;46:166–172. 2. Carr JJ, Crouse JR III, Goff DC Jr, D’Agostino RB Jr, Peterson NP, 11. Houslay ES, Cowell SJ, Prescott RJ, Reid J, Burton J, Northridge DB, Burke GL. Evaluation of subsecond gated helical CT for quantification Boon NA, Newby DE. Progressive coronary calcification despite in- of coronary artery calcium and comparison with electron beam CT. tensive lipid lowering therapy: a randomized controlled trial. Heart AJR Am J Roentgenol 2000;174:915–921. 2006;921187–1188. 3. Terry JG, Carr JJ, Tang R, Evans GW, Kouba EO, Shi R, Cook DR, 12. Raggi P, Davidson M, Callister TQ, Welty FK, Bachmann GA, Hecht Vieira JLC, Espeland MA, Mercuri MF, Crouse JR III. Coronary H, Rumberger JA. Aggressive versus moderate lipid-lowering therapy artery calcium outperforms carotid artery intima-media thickness as a in hypercholesterolemic postmenopausal women. Beyond endorsed non-invasive index of coronary artery stenosis. Arterioscler Thromb lipid lowering with EBT scanning (BELLES). Circulation 2005;112: Vasc Biol 2005;25:1723–1728. 563–571. 4. Carr JJ, Nelson JC, Wong ND, McNitt-Gray M, Arad Y, Jacobs DR Jr, 13. Schmermund A, Achenbach S, Budde T, Buziashvili Y, Forster A, Sidney S, Bild DE, Williams OD, Detrano RC. Calcified coronary Friedrich G, Henein M, Kerkhoff G, Knollmann F, Kukharchuk V, artery plaque measurement with cardiac CT in population-based stud- et al. Effect of intensive versus standard lipid-lowering treatment with ies: standardization protocol of Multi-Ethnic Study of Atherosclerosis atorvastatin on the progression of calcified coronary atherosclerosis (MESA) and Coronary Artery Risk Development in Young Adults over 12 months: a multicenter, randomized, double-blind trial. Circu- lation (CARDIA) Study. Radiology 2005;234:35–43. 2006;113:427–437. 14. Achenbach S, Ropers D, Pohle K, Leber A, Thilo C, Knez A, Menen- 5. SmartScoreTM Coronary Artery Calcification Scoring Operator Man- dez T, Maeffert R, Kusus M, Regenfus M, et al. Influence of lipid- ual. Waukesha, WI: General Electric Medical Systems, 2001; Rev. 1. lowering therapy on the progression of coronary artery calcification. A 6. Ellison RC, Zhang Y, Wagenknecht LE, Eckfeldt JH, Hopkins PN, prospective evaluation. Circulation 2002;106:1077–1082. Pankow JS, Djousse L, Carr JJ. Relation of the metabolic syndrome to 15. Budoff MJ, Lane KL, Bakhsheshi H, Mao S, Grassmann BO, Fried- calcified atherosclerotic plaque in the coronary arteries and aorta. Am J man BC, Brundage BH. Rates of progression of coronary calcium by Cardiol 2005;95:1180–1186. electron beam tomography. Am J Cardiol 2000;86:8–11. 7. Detrano RC, Anderson M, Nelson J, Wong ND, Carr JJ, McNitt-Gray 16. Budoff MJ, Yu D, Nasir K, Mehrota R, Chen L, Takasu J, Agrawal M, Bild DE. Coronary calcium measurements: effect of CT scanner N, Liu ST, Blumenthal RS. Diabetes and progression of coronary type and calcium measure on the re-scan reproducibility—MESA calcium under the influence of statin therapy. Am Heart J 2005; Study. Radiology 2005;236:477–484. 149:695–700. 8. Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of 17. Raggi P, Cooil B, Ratti C, Callister TQ, Budoff M. Progression of HMG-CoA reductase inhibitors on coronary artery disease as assessed coronary artery calcium and occurrence of myocardial infarction in by electron-beam computed tomography. N Engl J Med 1998;339: patients with and without diabetes mellitus. Hypertension 2005;46: 1972–1978. 238–243. 9. Crouse JR III, Morgan T, Terry JG, Ellis J, Vitolins M, Burke GL. A 18. Hsia J, Klouj A, Prasad A, Burt J, Adams-Campbell LL, Howard BV. randomized trial comparing the effect of casein with that of soy protein Progression of coronary calcification in healthy postmenopausal containing varying amounts of isoflavones on plasma concentrations of women. BMC Cardiovasc Disord 2004;4:1–6. lipids and lipoproteins. Arch Intern Med 1999;159:2070–2076. 19. Budoff MJ, Raggi P. Coronary artery disease progression assessed by 10. Arad Y, Spadaro LA, Roth M, Newstein D, Guerci AD. Treatment of electron-beam computed tomography. Am J Cardiol 2001;88(suppl): asymptomatic adults with elevated coronary calcium scores with ator- 46E–50E. Measuring and Treating Serum Lipids in Patients in a Chest Pain Observation Unit

Michael J. Gillespie, MD, MPHa,*, Cheryl J. Davis, MDa, Nathan D. Lambert, MDa, Frederick M. Costello, MDa, Sidney C. Smith, MDa, Mauricio G. Cohen, MDa, and Venu Menon, MDb

We evaluated opportunities to initiate statin therapy in 574 consecutive subjects admitted to a chest pain observation unit (CPOU). Ten-year Framingham risk scores were retrospectively calculated for all patients according to the National Cholesterol Education Program and Adult Treatment Panel III 2001 recommendations. Subjects were then stratiﬁed according to (1) recommendations for initiation of a lipid-lowering medication and (2) whether they received lipid-lowering drug therapy at discharge. Of 574 subjects, we excluded 50 with previously established coronary heart disease or who were already taking a statin medication on presentation, 23 with missing data, and 80 who did not have a low-density lipoprotein (LDL) measurement at admission. Of the remaining 421 subjects, the mean age was 47 years, 40% were men, 57% were white, 31% had hypertension, 27% were current smokers, and 6% had diabetes. Ten-year risk calculation classiﬁed 47% at moderate risk (>2 risk factors and (134 ؍ at low risk (<2 risk factors), 32% (n (199 ؍ n) at (40 ؍ at moderate-high risk (10% to 20% risk), and 10% (n (48 ؍ risk), 11% (n 10%> -had hypercholester (96 ؍ high risk (>20% risk). Of the entire cohort, 23% of subjects (n .met indications for initiation of lipid-lowering medication (50 ؍ olemia, of which 52% (n -were prescribed a lipid (3 ؍ Only 6% of patients with an indication for treatment (n -untreated for their hypercholes (47 ؍ lowering medication on discharge, leaving 94% (n terolemia. In conclusion, patients admitted to a CPOU have a high prevalence of hypercholesterolemia, and therefore, an increased long-term risk for cardiovascular events. In addition to their primary role, CPOUs should focus on primary prevention and reduction of long-term risk. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99: 1718–1720)

We sought to evaluate the prevalence of hypercholesterol- Subjects admitted to the CPOU with chest pain were at emia, as deﬁned by the National Cholesterol Education low risk. Referrals to the CPOU were made by the attending Program and Adult Treatment Panel III 2001 (NCEP-ATP emergency medicine physician on duty. Preprinted instruc- III) recommendations,1 based on traditional risk factors and tions for exclusion from referral to the CPOU included fasting low-density lipoprotein (LDL) levels among sub- typical anginal chest pain in the preceding 48 hours, chest jects admitted to a chest pain observation unit (CPOU). We pain or symptoms similar to previously documented anginal then examined what percentage of patients with hypercho- equivalent, prolonged ongoing (Ͼ20 minutes) pain at rest, lesterolemia met current indications for initiation of lipid- history of documented signiﬁcant coronary heart disease lowering therapy and the proportion who were then treated (CHD; including history of percutaneous coronary interven- with lipid-lowering medication at discharge. tion or coronary artery bypass grafting surgery), pulmonary edema, new or worsening mitral regurgitation, S3 gallop, Methods systolic blood pressure Ͻ90 mm Hg, heart rate Ͻ50 or This study was a retrospective cross-sectional analysis of Ͼ110 beats/min, age Ͼ75 years, electrocardiographic consecutive admissions to the CPOU at the University of changes (ST elevation in 2 contiguous leads or transient ST North Carolina Hospital at Chapel Hill between September depressions Ͼ0.05 mV), sustained ventricular tachycardia, 2002 and September 2003. Data were collected by 2 inde- or positive cardiac biomarkers (troponin or creatine kinase- pendent and blinded abstractors and entered into a database MB) on presentation. Patients who were mentally incompe- for analysis. Institutional review board approval was ob- tent, homeless, incarcerated, actively using illicit drugs, tained before data collection. residing in a nursing home, or with end-stage renal disease requiring hemodialysis were excluded from referral to the

a CPOU because of concerns with timely disposition and Division of Cardiology, University of North Carolina, Chapel Hill, were instead admitted to an in-hospital bed if warranted. In North Carolina; and bDepartment of Cardiology, The Cleveland Clinic, Cleveland, Ohio. Manuscript received October 14, 2006; revised manu- addition, inability to perform an exercise treadmill test also script received and accepted January 22, 2007. precluded referral to the CPOU. *Corresponding author: Tel: 919-423-7892; fax: 919-966-7401. Acute coronary syndrome was ruled out in all admissions E-mail address: [email protected] (M.J. Gillespie). by serial cardiac biomarkers (troponin I and creatine-MB)

Table 1 lished CHD or who were already taking a lipid-lowering Baseline characteristics (n ϭ 421) medication on presentation and 16% (n ϭ 80) who were not Characteristic Value screened for hypercholesterolemia with a fasting lipid profile during admission. We also excluded 23 subjects who Age (yrs) 47 (17–81) were missing documentation of conventional cardiovascular Men 170 (40%) Hypertension 132 (31%) risk factors essential for calculation of the Framingham risk Diabetes mellitus 27 (6%) score (e.g., no documentation of smoking history). Smoker 114 (27%) The remaining 421 subjects were retained for analysis, Family history of premature coronary heart disease 186 (44%) and percentages are calculated based on this cohort unless White 240 (57%) specifically stated otherwise. Baseline characteristics are Insured 306 (73%) presented in Table 1. Of this group, 23% (n ϭ 96) had Total cholesterol (mg/dl) 192 Ϯ 39 hypercholesterolemia and 12% (n ϭ 50) met the NCEP- LDL (mg/dL) 114 Ϯ 34 ATP III 2001 recommendations for initiation of lipid-low- High-density lipoprotein (mg/dl) 51 Ϯ 15 ering therapy. The percentage of patients who met defini- Ϯ Triglycerides (mg/dl) 135 81 tions of hypercholesterolemia differed by risk categories, as Low risk (0–1 risk factors) 199 (47%) explained later (Table 2). Framingham 10-yr risk* Ͻ Low risk (0–1 risk factors) 199 (47%) There were 199 subjects (47%) with 2 risk factors. Moderate risk (Ͻ10%) 134 (32%) Among these subjects classified at low risk, 8% (n ϭ 16) Moderate-high risk (10%–20%) 48 (11%) had hypercholesterolemia, defined by a LDL level of High risk (Ͼ20%) 40 (10%) Ն160 mg/dl, and 2% of patients (n ϭ 4) met criteria for initiation of lipid-lowering drug therapy with a LDL level 1 * Risk estimation calculated by NCEP/ATP III recommendations. of Ն190 mg/dl. There were 134 subjects (34%) with multiple (Ն2) risk every 6 hours for 3 sets. All patients underwent a stress test factors and a 10-year risk Ͻ10%. Among these subjects before discharge. All laboratory studies and tests were or- classified at moderate risk, 21% (n ϭ 28) had hypercholes- dered at the discretion of the physicians caring for the terolemia, defined by an LDL level of Ն130 mg/dl, and 5% patients using a preprinted CPOU order form. Fasting lipid (n ϭ 7) met criteria for initiation of lipid-lowering drug profiles were performed in the morning after admission, and Ն Ն therapy with a LDL level of 160 mg/dl. the patient was fasted 6 hours. For this present analysis, There were 48 subjects (11%) with multiple (Ն2) risk we chose to exclude subjects with previously known CHD factors and a 10-year risk of 10% to 20%. Among these already taking a lipid-lowering medication on presentation subjects classified at moderate-high risk, 48% (n ϭ 23) had and subjects with missing data. hypercholesterolemia, defined by an LDL level of Ն130 A Framingham 10-year risk score was calculated for mg/dl, and all met criteria for initiation of lipid-lowering each subject according to the Executive Summary of the drug therapy. Third Report of the National Cholesterol Education Pro- There were 40 subjects (10%) with multiple (Ն2) risk gram Expert Panel on Detection, Evaluation, and Treatment factors and a 10-year risk of Ն20%. Among these subjects of High Blood Cholesterol in Adults. Patient with diabetes classified at high risk, 73% (n ϭ 29) had hypercholesterol- were classified at high risk. A complete discussion on 10- emia, defined by a LDL level of Ն100 mg/dl, and 40% year Framingham risk calculations and definitions of hyper- (n ϭ 16) had a LDL level of Ն130 mg/dl, which met criteria cholesterolemia and target LDL levels by risk group has for initiation of lipid-lowering drug therapy. 1 been published elsewhere. Overall, 50 patients met indications for initiation of lipid- Based on individual Framingham 10-year risk scores, ϭ Ͻ lowering therapy; however, only 6% (n 3) were treated subjects were categorized at low risk (defined as 2 risk with a statin medication at discharge. factors), moderate risk (defined as Ն2 risk factors and a 10-year risk Ͻ10%), moderate-high risk (defined as Ն2 risk factors and a 10-year risk of 10% to 20%), or high risk Discussion Ն (10-year risk 20%) as defined by the NCEP-ATP III 2001 The present study found a relatively high prevalence (23%) summary definitions. of hypercholesterolemia among subjects admitted to a Subjects in each risk group were then categorized by CPOU. Although subjects were deemed at low risk for acute their LDL levels. Subjects with LDL levels greater than coronary syndrome, most (53%) had at least moderate 10- their target LDL goal as defined in the NCEP-ATP III 2001 year risk for a cardiovascular event. An underestimation of summary were diagnosed with hypercholesterolemia and Ն this population’s projected risk may be a reason for poor patients with LDL levels 30 mg/dl higher than their target treatment and highlights the importance of a CPOU as a LDL level were categorized as meeting an indication for primary prevention location. Despite a high prevalence of 1 lipid-lowering drug therapy. Subjects who met an indica- cardiovascular risk, 16% of the subjects admitted were not tion for therapy were then dichotomized by whether they screened for hypercholesterolemia with a fasting lipid received a lipid-lowering medication on discharge. panel. This likely occurred as a result of the prompt dispo- Results sition of patients in this unit, as most patients were discharged within 10 to 18 hours. Fasting samples were there- We retrospectively analyzed 574 consecutive admissions to fore not available in a significant minority of patients. the CPOU. We excluded 50 subjects with previously estab- More importantly, 94% of patients with hypercholester- 1720 The American Journal of Cardiology (www.AJConline.org)

Table 2 Distribution of patient’s by 10-year Framingham risk group and LDL levels Risk Group (Framingham 10-yr risk) Low-Density Lipoprotein Total Ͻ100 mg/dl 100–129 mg/dl 130–159 mg/dl 160–189 mg/dl Ն190 mg/dl

Low risk (Ͻ2 risk factors, Ͻ10%) 70 74 39 12* 4*† 199 Moderate risk (Ն2 risk factors, Ͻ10%) 51 55 21* 6*† 1*† 134 Moderate-high risk (10–20%) 10 15 15*† 5*† 3*† 48 High risk (Ͼ20%) 11 13* 7*† 7*† 2*† 40 Total 142 157 82 30 10 421 Total with hypercholesterolemia* 0 13 43 30 10 96 Total meeting indications for drug therapy 0 0 22 18 10 50

* Patients with hypercholesterolemia as defined by NCEP-ATP III recommendations. † Subjects who met indication for initiation of lipid-lowering drug therapy as defined by NCEP-ATP III.1 olemia who met an indication for treatment were not treated Our study has several limitations. First, the referral cri- with a lipid-lowering medication on discharge. Fonarow teria for our CPOU ensured a low-risk cohort for acute and colleagues2 showed that addressing and treating hyper- coronary syndrome, but also excluded several specific pop- cholesterolemia during the inpatient stay after a myocardial ulations that could affect the generalizability of our find- infarction showed a clinically significant improvement in ings. In addition, it is retrospective, and experience is lim- statin use and compliance (10% vs 91%), as well as a ited to a single tertiary health care center, which also limits dramatic improvement in reaching LDL goals (6% vs 58%) the generalizability of our findings. Finally, there was a at 1 year after discharge compared with patients who were significant number of patients who were excluded from the not started on lipid-lowering therapy as inpatients. An op- study because of lack of documentation of conventional risk portunity to educate and influence primary prevention may factors (n ϭ 23) or a failure to obtain a fasting lipid profile therefore have been missed in our CPOU. (n ϭ 80). The potential public health impact of poor screening and treatment of hypercholesterolemia in CPOUs across the United 1. Third Report of the National Cholesterol Education Program (NCEP) States is large. This is especially true given the preferential Expert Panel on Detection, Evaluation, and Treatment of High Blood utilization of emergent and urgent care by the vulnerable in- Cholesterol in Adults (Adult Treatment Panel III) final report. Circu- lation 2002;106:3143–3421. digent and uninsured populations. According to our esti- 2. Fonarow GC, Gawlinski A, Moughrabi S, Tillisch JH. Improved treat- mates, for every 1,000 patients at low risk admitted to a ment of coronary heart disease by implementation of a cardiac hospi- CPOU, approximately 230 will have hypercholesterolemia. talization atherosclerosis management program (CHAMP). Am J Car- With the use of an absolute risk reduction estimate of 3% diol 2001;87:819–822. over 5 years, we could prevent 6 occurrences of myocardial 3. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, 3 Langendorfer A, Stein EA, Kruyer W, Gotto AM. Primary prevention of infarction, unstable angina, or sudden cardiac death. This acute coronary events with lovastatin in men and women with average amounts to a number needed to screen of 145 patients to cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Cor- prevent 1 event over 5 years. onary Atherosclerosis Prevention Study. JAMA 1998;279:1615–1622. A Comparative Study of the Efficacy and Safety of Procainamide Versus Propafenone Versus Amiodarone for the Conversion of Recent-Onset Atrial Fibrillation

George E. Kochiadakis, MD, Nikos E. Igoumenidis, MD, Michail E. Hamilos, MD, Maria E. Marketou, MD, Gregory I. Chlouverakis, MSc, PhD, and Panos E. Vardas, MD, PhD*

The appropriate treatment for the restoration of sinus rhythm in patients with atrial ﬁbrillation (AF) of recent onset is still the subject of controversy. In this prospective, randomized, single-blind, placebo-controlled clinical study, we investigated the effectiveness and safety of procainamide, propafenone, and amiodarone, administered intravenously, for the conversion of recent-onset AF. We enrolled 362 consecutive patients (183 men; age 34 to 86 years; mean 65 ؎ 10) with AF duration of no >48 hours. Of these patients, 89 were given procainamide, 91 propafenone, 92 amiodarone, and 90 placebo. Treatment was considered successful if conversion to sinus rhythm was achieved within the 24-hour study period. Baseline clinical characteristics were similar in the 4 groups. The treatment was successful in 61 of the 89 patients who received procainamide (68.53%; median time 3 hours), 73 of the 91 patients who received propafenone (80.21%; median time 1 hour), 82 of the 92 patients who received amiodarone (89.13%; median time 9 hours), and 55 of the 90 patients who received placebo (61.11%; median time 17 hours; p <0.05 for all medicated groups vs placebo; p <0.05 for amiodarone and propafenone vs procainamide). In conclusion, all 3 medications, when administered intravenously, are effective in the restoration of sinus rhythm in recent-onset AF. Amiodarone and propafenone are more effective whereas procainamide and propafenone are faster. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1721–1725)

Several antiarrhythmic drugs with disparate electrophysi- Ͻ100 mm Hg, hypertrophic obstructive cardiomyopathy, ologic effects on atrial tissue have been used for the resto- severe uncontrolled heart failure (left ventricular ejection ration of sinus rhythm in patients with recent-onset atrial fraction [LVEF] Ͻ30%), or cardiogenic shock were ex- fibrillation (AF), but the appropriate treatment is still the cluded, as were those with significant chronic obstructive subject of controversy.1–10 Although class Ic antiarrhythmic pulmonary disease, pulmonary embolism, pneumonia, liver drugs have generally been found to have a higher success or kidney failure, thyroid disease, electrolyte disturbances, rate than drugs in classes Ia and III, there are minimal data digoxin intoxication, pregnancy or lactation, or age Ͻ18 from randomized clinical trials to confirm the superiority of years. Also excluded were patients with sick sinus syn- any particular drug compared with the others.1–5,7,8 The aim drome or a history of second- or third-degree atrioventric- of the present randomized, placebo-controlled study was to ular block, as well as those who had taken any antiarrhyth- compare the efficacy and safety of intravenous procain- mic drug other than digoxin within Ͻ5 half-lives of the drug amide, propafenone, and amiodarone—drugs representative in question before the study. of classes Ia, Ic, and III, respectively—in the restoration of After informed consent had been obtained, patients were recent-onset AF to normal sinus rhythm. Preliminary results randomized to receive procainamide, propafenone, amio- from pairwise comparisons based on a subset of the patients darone, or placebo. Patients allotted to receive procainamide included in this study have already been reported.1 began with 1 gram intravenously over 30 minutes, followed by 2 mg/min intravenously in the next 24 hours. Patients Methods allotted to the propafenone group began with 2 mg/kg intravenously over 15 minutes, followed by 10 mg/kg intra- The study included 362 consecutive patients (183 men; Ϯ Ͻ venously in the next 24 hours. Patients allotted to the ami- mean age 65 10 years) with AF of 48 hours duration. odarone group began with 300 mg intravenously over 1 Patients with a recent myocardial infarction, heart surgery hour, followed by 20 mg/kg intravenously in the next 24 within the previous 6 months, unstable angina, acute myo- hours. Patients in the placebo group received an identical carditis, acute pericarditis, baseline systolic blood pressure amount of saline solution intravenously over 24 hours. Digoxin (0.5-mg initial intravenous dose, followed by Cardiology Department, Heraklion University Hospital, Crete, Greece. 0.25 mg after 2 hours and 0.25 mg/6 hours until completion Manuscript received October 18, 2006; revised manuscript received and of 24 hours) was administered to all patients who had not accepted January 12, 2007. previously received it. *Corresponding author: Tel: 30-81-392422; fax: 30-81-542055. Treatment was considered successful if conversion to E-mail address: [email protected] (P.E. Vardas). sinus rhythm was achieved within the 24-hour study period.

Table 1 Clinical characteristics of the patients studied Drug Treatment Procainamide (n ϭ 89) Propafenone (n ϭ 91) Amiodarone (n ϭ 92) Placebo (n ϭ 90) p Value Men/women 47/42 46/45 46/46 44/46 0.96 Age (yrs) 64 Ϯ 10 64 Ϯ 11 65 Ϯ 11 66 Ϯ 9 0.69 Baseline ventricular rate (beats/min) 136 Ϯ 22 137 Ϯ 22 136 Ϯ 20 135 Ϯ 17 0.84 Systolic blood pressure (mm Hg) 128 Ϯ 11 128 Ϯ 13 129 Ϯ 12 128 Ϯ 13 0.97 Underlying heart disease (%) 37 (41.6%) 36 (39.6%) 39 (42.4%) 37 (41.1%) 0.28 LA diameter (mm) 40.81 Ϯ 5.54 41.57 Ϯ 6.09 42.22 Ϯ 5.40 41.25 Ϯ 6.15 0.42 LVEF (%) 52 Ϯ 10 53 Ϯ 10 52 Ϯ 10 52 Ϯ 10 0.78 No. of episodes 5 Ϯ 56Ϯ 55Ϯ 66Ϯ 6 0.97

In cases in which conversion to sinus rhythm was not achieved with a study drug, it was attempted using other antiarrhythmic drugs or direct-current cardioversion after the completion of 21 days of anticoagulation treatment with acenocoumarol (international normalized ratio of 2 to 3). In patients who were already receiving anticoagulant therapy, cardioversion was attempted directly. In patients in whom there was a suspicion of heart failure, an echocardiographic examination was performed before the study. All patients underwent echocardiographic examination at the end of the study period. All echocardiographic recordings were reviewed by 2 experienced opera- tors blinded to the results of the treatment. During therapy all patients were kept in the coronary care unit under continuous monitoring of the electrocardiogram and blood pressure. They were then kept under observation in the cardiology department for Ն2 days before being discharged from the hospital. Summary statistics are expressed as means Ϯ SD or Figure 1. The cumulative progression of conversion to normal sinus rhythm percentages as appropriate. Analysis of variance and chi- (NSR) in the procainamide, propafenone, amiodarone, and placebo groups. square tests were used for continuous and categorical vari- It is clear that placebo had the worst performance, amiodarone had a steady ables, respectively, to compare the 4 patient groups at base- conversion rate throughout the study period, and propafenone and procain- line with respect to potentially important predictors of amide reached a plateau after a fast early conversion rate. conversion, such as gender, age, left atrial (LA) diameter, duration of AF, number of episodes, and heart rate. was censored at 10 hours because he refused to continue We then followed a 2-stage approach. First, we assessed, treatment. at the univariate level, which factors were significantly In 69 patients, echocardiographic recordings were made associated with conversion. After the univariate analysis, in sinus rhythm and AF; in these patients, there were no we employed a multivariate stepwise logistic regression significant differences in LA diameter (42 Ϯ 6vs43Ϯ 7 model to identify which of the significant univariate param- mm; p ϭ NS) or LVEF (49 Ϯ 8% vs 48 Ϯ 9%; p ϭ NS) eters contained independent prognostic information for con- measured during the 2 studies. version. The thresholds for entry into and removal from the Sixty-one of the patients who received procainamide model were 5% and 10%, respectively. (68.53%) showed conversion to sinus rhythm after an av- The progression rate to sinus rhythm was also assessed erage of 9 hours, compared with 73 of those who received using Kaplan-Meier product-limit estimate curves that were propafenone (80.21%) after an average of 8 hours, 82 of compared across the groups with the log-rank test. A p value those who received amiodarone (89.13%) after an average Ͻ0.05 was the criterion for significance throughout. of 12 hours, and 55 of those receiving placebo (61.11 %) after an average of 17 hours. The likelihood of conversion Ͻ Results differed very significantly among the 4 groups (p 0.001). Post-hoc Bonferroni-adjusted chi-square tests showed that Of the 362 patients who were enrolled, 89 were randomized all 3 drugs were superior to placebo and that amiodarone to receive procainamide, 91 were randomized to receive and propafenone were associated with better conversion propafenone, 92 were randomized to receive amiodarone, rates than procainamide. Amiodarone and propafenone did and 90 were randomized to receive placebo. There were no not have significantly different rates. significant differences among the 4 groups regarding age, Figure 1 shows the cumulative conversion progression to gender, number of episodes, baseline ventricular rate, un- sinus rhythm in all treatment groups. The rate to progression derlying heart disease, systolic blood pressure, LA diame- was also different among the 4 groups (log-rank, p Ͻ0.001). ter, or LVEF (Table 1). One patient in the placebo group Post hoc analysis showed that propafenone and procain- Arrhythmias and Conduction Disturbances/Procainamide, Propafenone, or Amiodarone AF Conversion 1723

Table 2 Predictors of conversion by drug treatment (univariate analysis) Drug treatment Procainamide Propafenone Amiodarone Placebo Conversion Yes No Yes No Yes No Yes No Men 33 (70%) 14 (30%) 36 (78%) 10 (22%) 42 (91%) 4 (9%) 27 (61%) 17 (39%) Age (ys) 65 Ϯ 963Ϯ 13 64 Ϯ 11 66 Ϯ 10 64 Ϯ 11 69 Ϯ 665Ϯ 666Ϯ 9 Baseline ventricular rate (bpm) 138 Ϯ 10 137 Ϯ 13 135 Ϯ 20 137 Ϯ 26 138 Ϯ 19 136 Ϯ 20 136 Ϯ 16 134 Ϯ 15 Systolic blood pressure (mm Hg) 128 Ϯ 10 128 Ϯ 30 128 Ϯ 13 127 Ϯ 12 130 Ϯ 12 128 Ϯ 10 129 Ϯ 12 127 Ϯ 15 Underlying heart disease (%) 25 (68%) 12 (32%) 29 (81%) 7 (19%) 35 (90%) 4 (10%) 23 (62%) 14 (38%) LA diameter (mm) 39 Ϯ 446Ϯ 6* 40 Ϯ 646Ϯ 6* 41 Ϯ 548Ϯ 7* 38 Ϯ 546Ϯ 4* LVEF (%) 52 Ϯ 11 52 Ϯ 753Ϯ 11 53 Ϯ 552Ϯ 10 51 Ϯ 10 53 Ϯ 10 51 Ϯ 8 No. of episodes 5 Ϯ 55Ϯ 46Ϯ 57Ϯ 55Ϯ 46Ϯ 56Ϯ 47Ϯ 6

* Statistically signiﬁcant difference between converters and nonconverters.

Table 3 Figure 2 shows Kaplan-Meier curves stratified by drug Conversion with respect to left atrium diameter according to LA diameter as divided into 3 tertiles: small Treatment (no. of Patients) Left Atrial Diameter, Converted/Total (%) (Յ40 mm), medium (40 to 45 mm), and large (Ͼ45 mm). Patients with a smaller left atrium had a faster conversion Յ Ͼ 40 mm 40–45 mm 45 mm irrespective of treatment (p Ͻ0.001 for all). Procainamide (n ϭ 89) 37/41 (90%) 21/30 (70%) 3/18 (17%) Treatment was discontinued in 1 patient receiving ami- Propafenone (n ϭ 91) 35/37 (95%) 24/31 (77%) 14/23 (61%) odarone because of an allergic reaction and in 4 patients Amiodarone (n ϭ 92) 29/30 (97%) 36/38 (95%) 17/24 (71%) receiving propafenone because of excessive QRS widening. Placebo (n ϭ 90) 38/41 (93%) 13/27 (48%) 4/22 (18%) A significant decrease in systolic blood pressure (Ͻ90 mm Hg) was observed in 15 patients receiving amiodarone and in 6 patients receiving procainamide during the first amide had an early, fast conversion rate (median times to hour of intravenous administration. All patients did well conversion 1 and 3 hours, respectively) that reached a pla- after administration of intravenous fluids, and no additional teau after 3 hours, whereas amiodarone had a relatively treatment was required. steady conversion rate throughout the study period (median Phlebitis over the site of amiodarone infusion was ob- time 9 hours). All 3 drugs were superior to placebo. served in 17 patients. In all these cases, the amiodarone As can be seen in Table 2, LA diameter, at the univariate administration was continued at a more central site. level, was the parameter that consistently differentiated There were no proarrhythmic effects, defined by the new those in whom conversion to sinus rhythm was achieved onset of sustained ventricular tachycardia, ventricular fibril- from those in whom conversion was not achieved in all 4 lation, or Torsades de pointes, in patients who experienced conversion to sinus rhythm or in those whose AF continued. groups. Other baseline clinical characteristics were not sig- No side effects were observed in the placebo group. nificant predictors of conversion. To further examine the role of LA diameter in conversion, the LA diameter was divided into 3 tertiles and the Discussion conversion rate was calculated for each group (Table 3). In this study, we compared the efficacy and safety of intra- Among patients with LA diameters Յ40 mm, the con- venous amiodarone, propafenone, and procainamide in the version rate was high and comparable in all 4 groups. restoration of recent-onset AF to sinus rhythm. All these Among patients with LA diameters between 40 and 45 mm, drugs are known to be effective; they are representatives of the conversion rates of propafenone, procainamide, and antiarrhythmic classes III, Ic, and Ia, respectively, which are placebo were lower, whereas the rate for amiodarone was widely used in daily clinical practice for the restoration of the same. As a result, amiodarone had a better conversion recent-onset AF.1–10 However, there are only a few reports rate than propafenone and procainamide, but the difference in the literature that have compared 1 of these drugs with failed to reach significance (p ϭ 0.06). In patients with LA another, and none of them compared all 3 drugs, as done in diameter Ͼ45 mm, the conversion rates were lower in all 4 the present study.1–4,9 groups. The amiodarone and propafenone groups had a Our results confirm the findings of previous studies that significantly higher rate than the procainamide group, the all these drugs are effective and safe for the restoration of success rate of which was lower than that of placebo. recent-onset AF.1–10 Moreover, they show that amiodarone A multivariate stepwise logistic regression model and propafenone have the highest efficacy, whereas showed that LA diameter was the most important predictor propafenone and procainamide act more quickly. for 24-hour conversion (chi-square 90, p Ͻ 0.001), followed According to our results, the only factor that influences by treatment (chi-square 41, p Ͻ0.001). the effectiveness of all 3 medications is the size of the left In a subanalysis we assessed predictors for rapid conver- atrium: the smaller the left atrium, the greater the likelihood sion. LA diameter was again the most important predictor of the restoration of sinus rhythm for all 3 drugs. However, (chi-square 37.9, pϽ0.0001), followed by treatment (chi- it should be noted in the case of a small left atrium, although square 24, p Ͻ0.001). the probability of cardioversion is high for all 3 drugs, the 1724 The American Journal of Cardiology (www.AJConline.org)

Figure 2. The cumulative progression of conversion to normal sinus rhythm (NSR) stratified by drug according to LA diameter, which was categorized as small (Յ40 mm, solid line), medium (40 to 45 mm, dashed line) and large (Ͼ45 mm, dotted line). LA diameter significantly affected the time to conversion in all 4 groups: smaller atria are more likely to convert sooner. relative benefit of the treatment is small, because the spon- significant with more hours of treatment, assuming, of taneous conversion rate is equally high (Ͼ90%) in such course, that amiodarone would continue to convert at the cases. In contrast, in a medium-sized left atrium, for all 3 similar rate. It is worth noting at this point that, if this were drugs, and a large left atrium, for amiodarone and true, the patients who would benefit most would be those propafenone, although the conversion rate is lower, the with a medium or large left atrium, whose conversion to relative benefit is greater because the probability of spon- sinus rhythm is slow. Our findings indicate a small, albeit taneous conversion is much smaller. nonsignificant, advantage for amiodarone compared with Our study showed that amiodarone and propafenone are propafenone in such atria, which tends to support this hy- equally effective in restoring sinus rhythm within 24 hours pothesis. in patients with recent-onset AF. However, if we examine The delayed action of amiodarone compared with the results more carefully, there are certain differences. propafenone could be explained in terms of the pharmaco- More precisely, propafenone starts to convert earlier and kinetics of amiodarone itself. It is well known that amioda- reaches a plateau after 3 hours, whereas amiodarone had a rone has a complex pharmacokinetic profile with a multi- relatively steady conversion rate throughout our study pe- compartmental distribution and a long half-life, requiring riod. more time for sufficient tissue impregnation.11,12 Further- It is therefore possible that the slight superiority of ami- more, it has been shown that the antiarrhythmic effects of odarone observed at 24 hours (89% vs 80%) could become amiodarone, related to a prolonged refractory period, are Arrhythmias and Conduction Disturbances/Procainamide, Propafenone, or Amiodarone AF Conversion 1725 mainly because of its metabolite, desethylamiodarone; taining sinus rhythm in atrial fibrillation: comparative efficacy and therefore, it is reasonable that such effects would take some results of trials. Am J Cardiol 2003;91(suppl):15D–26D. 6. Khan IA, Mehta NJ, Gowda RM. Amiodarone for pharmacological 11,12 time to appear. cardioversion of recent-onset atrial fibrillation. Int J Cardiol 2003;89: Our results indicated that all 3 drugs were generally safe 239–248. and well tolerated in all our patients. However, previous 7. Snow V, Weiss KB, LeFevre M, McNamara R, Bass E, Green LA, 1–10,13 Michl K, Owens DK, Susman J, Allen DI, Mottur-Pilson C; AAFP studies have reported significant side effects for all. Panel on Atrial Fibrillation; ACP Panel on Atrial Fibrillation. Man- More specifically, amiodarone has been implicated in many agement of newly detected atrial fibrillation: a clinical practice guide- cardiac and noncardiac side effects. It has been proven that line from the American Academy of Family Physicians and the Amer- most of the side effects of amiodarone are dose-related; ican College of Physicians. Ann Intern Med 2003;139:1009–1017. 8. Reiffel JA. Drug choices in the treatment of atrial fibrillation. Am J thus, the absence of side effects in our patients was probably Cardiol 2000;85(suppl):12D–19D. a result of the relatively short time of administration. With 9. Blanc JJ, Voinov C, Maarek M. Comparison of oral loading dose of propafenone and procainamide, previous studies have re- propafenone and amiodarone for converting recent-onset atrial fibril- ported a significant proarrhythmic effect, especially in pa- lation. PARSIFAL Study Group. Am J Cardiol 1999;84:1029–1032. 10. Chevalier P, Durand-Dubief A, Burri H, Cucherat M, Kirkorian G, 1–10,13 tients with organic heart disease. The fact that such Touboul P. Amiodarone versus placebo and classic drugs for cardio- patients were excluded from our study could explain our version of recent-onset atrial fibrillation: a meta-analysis. J Am Coll findings with respect to the safety of these drugs. Cardiol 2003;41:255–262. 11. Mitchell LB, Wyse DG, Gillis AM, Duff HJ. Electropharmacology of In our study, all patients received digoxin, which was amiodarone therapy initiation. Time courses of onset of electrophysi- used in the control group to reduce the high ventricular rate. ologic and antiarrhythmic effects. Circulation 1989;80:34–42. We chose this drug because it did not appear to affect the 12. Wang J, Bourne GW, Wang Z, Villemaire C, Talajic M, Nattel S. likelihood of conversion.14,15 However, to exclude any po- Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation: importance of use-dependent effects on refracto- tential benefit or harm from digoxin in the conversion to riness. Circulation 1993;88:1030–1044. sinus rhythm, we used it in all groups. 13. Fenster PE, Comess KA, Marsh R, Katzenberg C, Hager WD. Con- version of atrial fibrillation to sinus rhythm by acute intravenous 1. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; procainamide infusion. Am Heart J 1983;106:501–504. 326:1264–1271. 14. Falk RH, Knowlton AA, Bernard SA, Gotlieb NE, Battinelli NJ. Digoxin for converting recent-onset atrial fibrillation to sinus rhythm. 2. Prystowsky EN, Benson DW Jr, Fuster V, Hart RG, Kay GN, Myer- A randomized, double-blinded trial. Ann Intern Med 1987;106: burg RJ, Naccarelli GV, Wyse DG. Management of patients with atrial 503–506. fibrillation. A statement for healthcare professionals from the subcom- 15. Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, mittee on electrocardiography and electrophysiology, American Heart Halperin JL, Kay GN, Klein WW, Levy S, et al. ACC/AHA/ESC Association. Circulation 1996;93:1262–1277. guidelines for the management of patients with atrial fibrillation: 3. Jung F, DiMarco JP. Treatment strategies for atrial fibrillation. Am J executive summary. A report of the American College of Cardiology/ Med 1998;104:272–286. American Heart Association Task Force on Practice Guidelines and 4. Costeas C, Kassotis J, Blitzer M, Reiffel JA. Rhythm management in the European Society of Cardiology Committee for Practice Guide- atrial fibrillation—with a primary emphasis on pharmacological ther- lines and Policy Conferences (Committee to Develop Guidelines for apy: part 2. Pacing Clin Electrophysiol 1998;21:742–752 the Management of Patients with Atrial Fibrillation): developed in 5. Naccarelli GV, Wolbrette DL, Khan M, Bhatta L, Hynes J, Samii S, collaboration with the North American Society of Pacing and Electro- Luck J. Old and new antiarrhythmic drugs for converting and main- physiology. Circulation 2001;104:2118–2150. Meta-Analysis of Magnesium Therapy for the Acute Management of Rapid Atrial Fibrillation

Orhan Onalan, MD*, Eugene Crystal, MD, Amin Daoulah, MD, Ching Lau, MD, Alexander Crystal, BA, and Ilan Lashevsky, MD

The profile of electrophysiologic effects of magnesium on the heart suggests that magnesium might be effective in the treatment of atrial fibrillation (AF) in terms of rhythm and rate control. We aimed to investigate the efficacy of magnesium administration in the acute treatment of rapid AF. Randomized controlled trials comparing intravenous magnesium versus placebo or antiarrhythmic agents for the acute management of rapid AF were included. Nine electronic databases were searched for relevant trials from the earliest possible dates through June 2005, as were abstract books from 8 cardiovascular meetings held in the past 10 years. We analyzed all outcomes using a fixed-effect model because of the low number of trials in each comparison. The results were expressed as relative risks (RRs) or odds ratios (ORs) for dichotomous outcomes and weighted mean differences for continuous outcomes, along with their 95% confidence intervals (CIs). Data were pooled for respectively, for rate control (<100 beats/min) and ,(476 ؍ and 8 trials (n (303 ؍ trials (n 4 rhythm control. Magnesium was effective in achieving rate control (OR 1.96, 95% CI 1.24 to 3.08) or rhythm control (OR, 1.60, 95% CI 1.07 to 2.39). An overall response was achieved in 86% and 56% of patients in the magnesium and control groups, respectively (OR 4.61 95% CI 2.67 to 7.96). Time to response (in hours) was significantly shorter in the magnesium group (weighted mean difference, ؊6.98; 95% CI ؊9.27 to ؊4.68). The risk of having a major adverse effect in the magnesium group was similar to that in the placebo group (RR 0.85, 95% CI 0.44 to 1.61). In conclusion, the present meta-analysis of published data suggests that intravenous magnesium administration is an effective and safe strategy for the acute management of rapid AF. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1726–1732)

Major cardiac effects of magnesium are prolongation of chronic or paroxysmal AF with rapid ventricular rate; (2) atrial1–4 and atrioventricular nodal1,4–6 refractory periods, were RCTs of a parallel or crossover design; (3) included which may facilitate rate and rhythm control in atrial fibril- intervention that consisted of intravenous magnesium com- lation (AF). In addition, hypomagnesemia is relatively compared with routine care or placebo or antiarrhythmic drugs; mon in patients presenting with AF, which could be de- and (4) adequately reported data on ventricular rate or tected in 20% to 53% of cases.7–9 Hypomagnesemia and AF rhythm control. Double-blind and nonblinded studies were are common after cardiac surgery,10 and prophylactic mag- included. In crossover trials, only the first phase of the study nesium use has resulted in a significant reduction in the was considered for meta-analysis. incidence of postoperative AF.11 Numerous clinical trials The search strategy was carried out according to recom- were performed to evaluate efficacy of magnesium for the mendations of the Cochrane Collaboration, with the follow- treatment of AF. Most of these trials were small and under- ing electronic databases from the earliest possible dates powered. We therefore conducted a systematic review and through June 2005: (1) Medline; (2) “old” Medline; (3) meta-analysis of randomized clinical trials (RCTs) on the EMBASE; (4) CENTRAL; (6) Web of Science; (7) ISI effectiveness of magnesium therapy for the acute manage- Proceedings; (8) Biosis Previews; (9) CINAHL; and (10) ment of rapid AF. HealthSTAR. No language, date, RCT filter, or other restrictions were applied. The following strategy was used to Methods search MEDLINE and adapted appropriately for other We included studies that (1) included adult patients present- databases. The capitalized terms are controlled terms: (1) ing with non-postoperative AF; (2) included patients with “ATRIAL FIBRILLATION”; (2) “ATRIAL FLUTTER”; (3) “TACHYCARDIA, SUPRAVENTRICULAR”; (4) “(atrial or atrium or auricul$) adj6 (fibrillat$ or flutter$)”; Arrhythmia Services, Division of Cardiology, Sunnybrook Health (5) “(atrial or atrium or auricul$) adj6 (arrhythmi$ or tachy- Sciences Centre, University of Toronto, Ontario, Canada. Manuscript cardi$ or tachyarrhythmi$)”; (6) or/1–5; (7) “MAGNE- received December 30, 2006; revised manuscript received and accepted January 22, 2007. SIUM”; (8) “MAGNESIUM COMPOUNDS”; (9) “mag- *Corresponding author: Tel: 416-480-6100, ext 7370; fax: 416-480- nesi$”; (10) or/7–9; and (11) 6 and 10. 5099. Abstracts from the American Heart Association, Amer- E-mail address: [email protected] (O. Onalan). ican College of Cardiology, European Society of Cardiol-

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.01.057 Arrhythmias and Conduction Disturbances/Magnesium Therapy in Atrial Fibrillation 1727

Table 1

Sifting steps for determination of relevant randomized controlled trials 0.5 0.5 (h) Ϸ Ͻ Measure Step No. of studies Outcome First step of sifting Initial number of articles 1,113 Duplicated articles 552 Nonrelevant articles: editorials, letters, replies, 525 reviews, meta-analyses, experimental studies, articles about cardiac or noncardiac surgeries and other types arrhythmias etc. Second step of sifting 100 NA100100 0.5 144/145 142/136 6 6 100160 140/135 NA 140 4 NA 120120 151/153 24 142/143 2.5 Ͼ Ͼ Ͼ Ͼ Ͼ Ͼ Initial number of articles 36 Ͼ Ͼ Non randomized prospective studies 5 Ventricular Rate (beats/min) Time to

Noncomparative 6 Inclusion Criteria Mean Mg/C Retrospective studies 4 Case series 3 Review 1

Abstracts of full-text articles 3 NA

Third step of sifting Mg level 0.84/1.02 0.85/0.88

Initial no. of articles 14 Mean Baseline (mmol/L) Mg/C Oral magnesium 1

Chronic AF patients with normal ventricular rate 1 ¶ ‡ Glucose-insulin-potassium-magnesium solution used 1

In SVT patients, no data on AF patients 1 ʈ 7 day7 day 0.85/0.82 1 hour 1.1/0.948 hour12 hour30 min NA 100–200 NA 133/131 24

Various arrhythmias (only 1 AF case) 1 Ͻ Ͻ Ն Ͻ Ͻ Ͼ

ϭ 7/ 7/ 1/ Mg/C RCTs considered for review (n 9) 48/ 12/ 30/ Ͻ Ͻ Ն Magnesium vs placebo 4 Ͻ Ͻ Ͼ Magnesium vs verapamil 2 Mean: 39/23 hour Magnesium vs diltiazem 1 Magnesium vs amiodarone 1 Magnesium vs ajmaline 1

SVT ϭ supraventricular arrhythmia. single blind. N, Mg/C Duration of Arrhythmia ϭ ogy, Hearth Rhythm Society (formerly North American 45/46 102/97 NA/NA Society of Pacing and Electrophysiology), Europace, Car- Mg/C diostim, World Congress on Cardiac Pacing and Electro- Men (%) physiology, and Asian-Paciﬁc Symposium on Cardiac Pac- non-blind; SB § ing and Electrophysiology meetings held in the past 10 ϭ 67 52/71 21/21 NANA NA 21/20 NA 30/40 years were hand-searched or electronically searched for 61/6459/56 65/6567/5936/39 50/53 21/24 43/50 34/36 10/8 61/6472/73 7/8 41/45 52/57 Mean: 4/6 day 23/23 NA/NA 0.77/0.78* 0.84/0.84* relevant studies. Additional publications were examined (yr) Mg/C with the reference lists of identiﬁed articles and published reviews about acute management of AF.

The selection of studies was assessed independently by 3 nonavailable; NB assessors (OO, AD, AC); disagreement was resolved by ϭ discussion and, when necessary, in consultation with a third vs verapamil vs placebo vs placebo vs verapamil vs amiodarone vs placebo vs diltiazem vs placebo vs ajmaline person (EC, IL, CL). The quality of each included trial was 4 4 4 4 4 4 4 4 4 assessed by 2 reviewers (OO, AD) using the standard Jadad score based on the adequacy of randomization, blinding, 24 hours and unknown in 62%, 24%, and 14% of participants, respectively.

12 magnesium; NA and withdrawals, with a maximum score of 5 points. Ն Primary outcomes were success in achieving rate control, ϭ rhythm control, and rate or rhythm control (i.e., overall 6 months in 3 and 5 patients in the magnesium and amiodarone groups, respectively. response) when available. Secondary outcomes were time to 24 hours, Ͼ response in hours and the risk of having a major adverse Ͻ effect. We deﬁned adverse effects as major if they required 323 SB22 MgSO DB3 DB1 MgSO NB5 MgSO NB1 MgSO DB MgSO SB MgSO DB MgSO NB MgSO MgSO

an additional intervention, treatment discontinuation, or double blind; Mg Jadad Score Blinding Study Arms Mean Age 3 episodes of paroxysmal AF in the last 2 months. Ն withdrawal from study; caused death; or were considered ϭ signiﬁcant in the article or by reviewers. 21 19 13

Data were pooled and analyzed using the Cochrane Col- 14 18 17 † 20 16 laboration software RevMan (version 4.2.8). Heterogeneity 15 of treatment effect was estimated by Cochrane Q test, with control; DB ϭ This study was excludedDuration form of pooled arrhythmia analysis was dueMedian to value. presence of signiﬁcant clinical heterogeneity compared with other trials. Duration of symptoms was p Ͻ0.1 considered as signiﬁcant and presented in Forrest All patients had * Basal magnesium levels were converted from milligram per deciliter to millimole per liter with a conversion factor of 0.411. † ‡ § ¶ ʈ C Chiladakis et al Davey et al Brodsky et al Hays et al Moran et al Joshi et al Walker et al Dluzniewski et al Gullestad et al plots. We analyzed all outcomes with the Mantel-Haenszel Table 2 Baseline characteristics of studies 1728 The American Journal of Cardiology (www.AJConline.org)

Table 3 Underlying conditions Heart Disease (%) HTN (%) Pulmonary Other (%) LAD (mm) (Mg/C) Disease (Mg/C) (Mg/C) Any CHD Valvular CMP (%) (Mg/C) (Mg/C) (Mg/C) (Mg/C) (Mg/C)

Gullestad et al13 77/61 50/48 12/3 15/10 – 15/6 – 36/39‡ Brodsky et al14 10/38 0/1 10/25 50/38 10/13 30/13 42/45 Hays et al15 57/50 – 57/50 – 43/50 – – NA Joshi et al16 90/91 10/4 80/87 – – 10/9 – NA Moran et al17 24/43 – – – – 24/29 – NA Chiladakis et al19 9/22 9/22 – – 35/52 4/4 30/22 37/38 Davey et al20 45/48 NA NA NA NA NA 8/10 NA Walker et al18 NA NA NA NA NA NA NA NA Dluzniewski et al21*NANANANANANANANA Total† 50/55 8/10 18/20 2/1 7/8 7/6 8/7 –

* Patients with structural heart disease or ischemia were excluded. † Values are based on 7 studies with reported data on underlying conditions. ‡ Echocardiography was performed in half of the patients. CHD ϭ coronary heart disease; CMP ϭ cardiomyopathy; HTN ϭ hypertension; LAD ϭ left atrial diameter; NA ϭ not available; other abbreviations as in Table 2.

Figure 1. Intravenous magnesium therapy and rate control. N ϭ number of patients; n ϭ number of events.

fixed-effect model because of the low number of trials in patients in an intensive care unit.17 Reported underlying heart each comparison. The results were expressed as relative risk diseases across all studies are presented in Table 3.In1 (RR) or odds ratio (OR) for dichotomous outcomes and verapamil controlled study,16 most the included patients had weighted mean difference for continuous outcomes, along rheumatic heart disease (Table 3). The age of this study pop- with their 95% confidence intervals (CIs). Analysis was ulation was also significantly younger than those in other based on the intent-to-treat principle. studies (Table 2). Therefore, this study was excluded from further analysis. The remaining 8 trials, which included 476 Results patients, were considered for analysis. Five trials (n ϭ 348) Table 1 represents literature search and elimination process. included only patients with AF.14,15,19–21 Two studies (n ϭ 86) Overall, of 1,113 initial hits, 9 randomized trials were iden- included patients with AF in addition to those with atrial tified.13–21 flutter.13,18 The remaining study included 30 patients with The most important baseline characteristics of included AF or flutter and 12 patients with other supraventricular studies are shown in Table 2. All studies excluded hemody- tachycardias.17 Overall, the type of arrhythmia was AF or namically unstable patients, but 1 study was conducted in atrial flutter in 97.5% of cases (464 of 476). Arrhythmias and Conduction Disturbances/Magnesium Therapy in Atrial Fibrillation 1729

Figure 2. Intravenous magnesium therapy and rhythm control. Abbreviations as in Figure 1.

Figure 3. Intravenous magnesium therapy and overall response. Abbreviations as in Figure 1.

All studies evaluated intravenous magnesium sulfate ad- 7 studies.13–16,18–21 The dose of magnesium was based on ministration. Magnesium was compared with placebo,14,15,18,20 plasma creatinine level or presence of continuous venous– verapamil,13 diltiazem,19 amiodarone,17 and ajmaline.21 Total venous hemoﬁltration in 1 study.17 An initial dose of 1.2- to dose of magnesium was in the range of 1.2 to 10 grams in 5-grams magnesium was administrated in all of these stud- 1730 The American Journal of Cardiology (www.AJConline.org)

Figure 4. Time to response in treatment groups. SDs were imputed for the study of Brodsky et al14 to pool data. *Patients with atrial fibrillation; **patients with atrial flutter. WMD ϭ weighted mean difference; other abbreviations as in Figure 1. ies over 1 to 30 minutes.13–15,18–21 In 1 study, a second dose Table 4 similar to the first was administrated if a positive response Available data on baseline serum magnesium (Mg) status and response was not achieved after 10 minutes.13 Magnesium infusion to treatment was continued for an additional 2 to 6 hours in 4 stud- Outcome Mean Serum Mg p 14,15,19,20 ies. In 1 study, intravenous digoxin was given in Level (mmol/L) Value both groups simultaneously with the first dose of magne- 14 20 Response Response sium or placebo. In another placebo-controlled trial, ϩ Ϫ both treatments were given in addition to usual care, includ- ( ) ( ) ing digoxin, ␤ blockers, and verapamil in 79%, 10%, and Gullestad et al13 Rhythm control 0.88 0.82 Ͻ0.05 3% of patients, respectively. Time to outcome measure Moran et al17* Rhythm control NA NA NA was Յ24 hours for all studies. In 2 studies, patients who did Davey et al20* Rhythm control NA NA NA not respond to first therapy were switched to alternate Dluzniewski et al21† Rhythm control 0.65 0.74 NA 13,21 therapy. Only the first phase of these studies was con- * No association was found between baseline serum magnesium levels sidered for analysis. and response to treatment. Seven trials reported outcome of rate control (Figure 1). † Basal magnesium levels were converted from milligram per deciliter to Four trials (n ϭ 303) used a predefined criterion for rate millimole with a conversion factor of 0.411. Abbreviation as in Table 2. control: a ventricular rate Ͻ100 beats/min in 3 trials13,18,20 and Ͻ90 beats/min in 1 trial.14 Magnesium sulfate was higher chance to regain sinus rhythm than the control group compared with placebo14,18,20 or verapamil13 in these stud- (OR 1.60, 95% CI 1.07 to 2.39). In 6 studies including 364 ies. Comparing with placebo, sufficient rate control was patients, magnesium was more effective than placebo or achieved in a significantly larger proportion of the patients calcium channel blockers in restoration of sinus rhythm (OR in the magnesium group (61% vs 35%; OR 2.97, 95% CI 2.34, 95% CI 1.42 to 3.87).13–15,18–20 1.78 to 4.97). Magnesium was also more effective in achiev- Data on overall response (rate or rhythm control) were ing rate control compared with placebo or verapamil (OR pooled for 4 trials that included 303 patients (Figure 3). 1.96, 95% CI 1.24 to 3.08). In the remaining 3 studies, data Overall, rate or rhythm control were achieved in 86% and on rate control were presented in different formats, making 56% of magnesium-treated patients and control subjects, them unsuitable for pooling.15,17,19 In 1 placebo-controlled respectively (OR 4.61, 95% CI 2.67 to 7.96). study, ventricular rate did not change significantly in the Time to rate control was available in 1 study separately placebo group during the first 30 minutes of treatment, for cases of AF and atrial flutter (Figure 4). In another study, whereas the magnesium group showed an average of 16 Ϯ time to overall response was available. Time to response (in 7% decrease in ventricular rate within 5 minutes (p Ͻ0.02), hours) was significantly shorter in the magnesium group and it was sustained during the first 30 minutes.15 In 2 than in the control group (weighted mean difference, Ϫ6.98, studies, data on rate control are presented as trend 95% CI Ϫ9.27 to Ϫ4.68). graphs.17,19 Magnesium and diltiazem19 had a similar sig- Data on the relation between baseline serum magnesium nificant reduction in ventricular rate at the first hour of levels and response to treatment were available in 4 stud- treatment, with a tendency toward a further decrease during ies.13,17,20,21 Two studies found no association between infusion times of 6 hours (p Ͻ0.001). In another study, baseline serum magnesium levels and response to treatment magnesium was compared with amiodarone in 42 severely (Table 4). Mean baseline serum magnesium levels were ill patients in an intensive care unit.17 Intravenous magne- significantly higher in patients with a positive response in 1 sium was as effective as amiodarone in slowing ventricular study (p Ͻ0.05). In another study, baseline serum magne- rate during 24-hour follow-up. There was a mean 19 beats/ sium levels were 0.65 and 0.74 mmol/L, respectively, in min decrease in ventricular rate within 30 minutes (p ϭ responders and nonresponders (p value not available). 0.0001) and another 10 beats/min decrease between 30 The most common side effects reported during magne- minutes and 24 hours in both groups. sium administration were transient sensation of warmth and All studies reported conversion rates (Figure 2). Overall, flushing. Reported numbers of withdrawals for any reason in 8 trials (n ϭ 476), magnesium-treated patients had a across all studies were 10 (4%) and 13 (5%) in the magne- Arrhythmias and Conduction Disturbances/Magnesium Therapy in Atrial Fibrillation 1731

Figure 5. Major adverse effects in treatment groups. Abbreviations as in Figure 1.

Table 5 Summary of pooled effect of intravenous magnesium versus control treatment on the outcomes Outcomes Studies (n) Participants (n) Statistical Measure Effect Size Rate control (Ͻ100 beats/min) 4 303 OR, 95% CI 1.96 (1.24 to 3.08) Rhythm control 8 476 OR, 95% CI 1.60 (1.07 to 2.39) Overall response 4 303 OR, 95% CI 4.61 (2.67 to 7.96) Time to response 2 63 WMD, 95% CI Ϫ6.98 (Ϫ9.27 to Ϫ4.68) Major adverse effects 8 476 RR, 95% CI 0.63 (0.35 to 1.13)

WMD ϭ weighted mean difference. sium and control groups, respectively. The corresponding having a major adverse effect in the magnesium group was figures for major adverse effects were 14 (6%) and 22 (9%). similar to that in the placebo group (RR 0.85, 95% CI 0.44 The risk of having a major adverse effect (Figure 5)inthe to 1.61). magnesium group was similar to that in the placebo group Shortening of the atrial effective refractory period with (RR 0.85, 95% CI 0.44 to 1.61). Overall, there was a strong loss of its rate dependency and prolongation of atrial con- trend toward less major side effects in magnesium-treated duction times are the most characteristic features of atrial patients (RR 0.63, 95% CI 0.35 to 1.13). No deaths were electrical remodeling.22,23 Consistent with these findings, reported in magnesium-treated patients. The effects of in- drug-induced prolongation of the atrial effective refractory travenous magnesium on outcomes are listed in Table 5. period is the most widely accepted mechanism for termination of AF.24 In addition, atrioventricular nodal conduction Discussion properties are the main determinant of ventricular rate in To our knowledge, this is the first meta-analysis of previous AF. From an electrophysiologic perspective, magnesium 1–4 1,4–6 publications for available evidence of the effectiveness of increases atrial and atrioventricular nodal refractory magnesium therapy in the acute management of non-post- periods, PA,2 PR, and atrio-His intervals.1–6 Therefore, operative AF. Data from 8 RCTs were pooled, with total magnesium may modulate those electrophysiologic subpopulations of 235 patients in the magnesium group and 241 strates that lead to perpetuation of AF and acceleration of its patients in the control group. Magnesium was more effec- ventricular rate in patients with AF. Consistent with this, tive than control treatments with respect to rate control (OR data from the present meta-analysis favor the efficacy of 1.96, 95% CI, 1.24 to 3.08) and rhythm control (OR 1.60, magnesium compared with the control group in the achieve- 95% CI 1.07 to 2.39). The overall response rate was signif- ment of rate control. In addition, magnesium was found to icantly higher in the magnesium group than in the control be as effective as amiodarone and diltiazem, well-known group (86% vs 56%; OR 4.61, 95% CI 2.67 to 7.96). Time rate-controlling agents in AF, with respect to rate control. to response (in hours) was significantly shorter in the mag- Intravenous magnesium administration was also more ef- nesium group than in the control group (weighted mean fective than control treatments in restoration of sinus difference, Ϫ6.98, 95% CI Ϫ9.27 to Ϫ4.68). The risk of rhythm in the present review. 1732 The American Journal of Cardiology (www.AJConline.org)

Rhythm and rate control alleviate symptoms in patients nous magnesium in patients with normal conduction systems and no with rapid AF. Therefore, a rate or rhythm control strategy clinical evidence of significant cardiac disease. Am Heart J 1988;115:367–373. may be suitable for most patients treated acutely for rapid 7. Singh RB, Manmohan MD, Dube KP, Singh VP. Serum magnesium AF. An overall response were achieved in 133 of 154 concentrations in atrial fibrillation. Acta Cardiol 1976;31:221–226. patients (86%) and 84 of 149 patients (56%), respectively, 8. Eray O, Akca S, Pekdemir M, Eray E, Cete Y, Oktay C. Magnesium in the magnesium and control groups. efficacy in magnesium deficient and nondeficient patients with rapid In addition to the plausibility of the reported findings, as ventricular response atrial fibrillation. Eur J Emerg Med 2000;7:287– a result of the physiologic effects of magnesium, its deple- 290. 9. DeCarli C, Sprouse G, LaRosa JC. Serum magnesium levels in symp- tion in a significant proportion of cases of AF may play an tomatic atrial fibrillation and their relation to rhythm control by intra- important role. Hypomagnesemia was in as many as 50% of venous digoxin. Am J Cardiol 1986;57:956–959. patients presenting with AF,7–9 and patients with hypomag- 10. Aglio LS, Stanford GG, Maddi R, Boyd JL III, Nussbaum S, Chernow nesemia required more intravenous digoxin doses for the B. Hypomagnesemia is common following cardiac surgery. J Cardio- control of symptomatic AF.9 Available limited data from thorac Vasc Anesth 1991;5:201–208. 11. Miller S, Crystal E, Garfinkle M, Lau C, Lashevsky I, Connolly SJ. this review are conflicting with regard to baseline serum Effects of magnesium on atrial fibrillation after cardiac surgery: a magnesium status and response to magnesium treatment in meta-analysis. Heart 2005;91:618–623. patients with AF and rapid ventricular rate.13,17,20,21 12. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Ga- Numerous safety limitations interfere with AF manage- vaghan DJ, McQuay HJ. Assessing the quality of reports of random- ment in emergency room settings. Most of these limitations ized clinical trials: is blinding necessary? Control Clin Trials 1996; 17:1–12. are related to the safety profile of antiarrhythmic drugs. 13. Gullestad L, Birkeland K, Molstad P, Hoyer MM, Vanberg P, Kjek- Magnesium can be used safely in most patients in whom shus J. The effect of magnesium versus verapamil on supraventricular other antiarrhythmic drugs are contraindicated or consid- arrhythmias. Clin Cardiol 1993;16:429–434. ered harmful.25,26 14. Brodsky MA, Orlov MV, Capparelli EV, Allen BJ, Iseri LT, Ginkel M, Magnesium has a relatively wide toxic/therapeutic win- Orlov YS. Magnesium therapy in new-onset atrial fibrillation. Am J dow, and the most common reported side effects are tran- Cardiol 1994;73:1227–1229; erratum, Am J Cardiol 1994;74:639. 15. Hays JV, Gilman JK, Rubal BJ. Effect of magnesium sulfate on sient sensation of warmth and flushing. When administered ventricular rate control in atrial fibrillation. Ann Emerg Med 1994;24: intravenously, magnesium has a rapid action, which may be 61–64. useful in controlling symptoms. Mean time to response was 16. Joshi PP, Deshmukh PK, Salkar RG. Efficacy of intravenous magne- available in 2 studies.13,14 Time to conversion (3.8 vs 14.9 sium sulphate in supraventricular tachyarrhythmias. J Assoc Physi- hours) in 1 study13 and mean time to overall response (4 vs cians India 1995;43:529–531. 14 17. Moran JL, Gallagher J, Peake SL, Cunningham DN, Salagaras M, 15 hours) in another study were significantly shorter in Leppard P. Parenteral magnesium sulfate versus amiodarone in the patients who received magnesium. Finally, magnesium is therapy of atrial tachyarrhythmias: a prospective, randomized study. inexpensive, easy to use and titrate, and widely available for Crit Care Med 1995;23:1816–1824. immediate use in every clinical unit.27,28 18. Walker S, Taylor J, Harrod R. The acute effects of magnesium in atrial Several limitations potentially influence the applicability fibrillation and flutter with a rapid ventricular rate. Emergency Med 1996;8:207–213. of the findings presented in this review. Although a highly 19. Chiladakis JA, Stathopoulos C, Davlouros P, Manolis AS. Intravenous sensitive search strategy was carried out in several elec- magnesium sulfate versus diltiazem in paroxysmal atrial fibrillation. tronic databases and printed materials, only a few relevant Int J Cardiol 2001;79:287–291. studies with small sample sizes were found. In addition, 20. Davey MJ, Teubner D. A randomized controlled trial of magnesium based on the adequacy of randomization, blinding, and sulfate, in addition to usual care, for rate control in atrial fibrillation. Ann Emerg Med 2005;45:347–353. withdrawals, most of the included trials have medium qual- 21. Dluzniewski M, Krol J, Kuch M, Syska Suminska J, Cedro K. In- ity. Negative studies are usually under-reported; therefore, creased efficacy of ajmaline after magnesium administration in the meta-analysis may overestimate the clinical efficacy of treatment of paroxysmal supraventricular tachyarrhythmias. Kardiol magnesium. Pol 1994;41:201–206. 22. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing: structural, functional, and electrophysiological characteristics 1. Etienne Y, Blanc JJ, Grall JY, Boschat J, Gilard M, Houel JF, Penther of a new model of sustained atrial fibrillation. Circulation 1995;91: P. Electrophysiological effects of intravenous magnesium sulfate in man. Arch Mal Coeur Vaiss 1987;80:1327–1332. 1588–1595. 2. Rasmussen HS, Thomsen PE. The electrophysiological effects of in- 23. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation travenous magnesium on human sinus node, atrioventricular node, begets atrial fibrillation. A study in awake chronically instrumented atrium, and ventricle. Clin Cardiol 1989;12:85–90. goats. Circulation 1995;92:1954–1968. 3. Christiansen EH, Frost L, Andreasen F, Mortensen P, Thomsen PE, 24. Nattel S, Ehrlich JR. Atrial fibrillation. In: Zipes DP, Jalife J, eds. Pedersen AK. Dose-related cardiac electrophysiological effects of in- Cardiac electrophysiology: from cell to bedside. Philadelphia: WB travenous magnesium. A double-blind placebo-controlled dose- Saunders, 2004:512–521. response study in patients with paroxysmal supraventricular tachycar- 25. Delva P. Magnesium and heart failure. Mol Aspects Med 2003;24: dia. Europace 2000;2:320–326. 79–105. 4. Yamamoto H, Bando S, Nishikado A, Nishimura N, Akiyama K, 26. Kaye P, O’Sullivan I. The role of magnesium in the emergency Nouzu N, Mori H. Electrophysiological effects of magnesium sulfate department. Emerg Med J 2002;19:288–291. on human conduction system. Kokyu To Junkan 1989;37:77–81. 27. Crippa G, Sverzellati E, Giorgi-Pierfranceschi M, Carrara GC. Mag- 5. DiCarlo LA Jr, Morady F, de Buitleir M, Krol RB, Schurig L, An- nesium and cardiovascular drugs: interactions and therapeutic role. nesley TM. Effects of magnesium sulfate on cardiac conduction and Ann Ital Med Int 1999;14:40–45. refractoriness in humans. J Am Coll Cardiol 1986;7:1356–1362. 28. Yusuf S, Teo K, Woods K. Intravenous magnesium in acute myocar- 6. Kulick DL, Hong R, Ryzen E, Rude RK, Rubin JN, Elkayam U, dial infarction. An effective, safe, simple, and inexpensive interven- Rahimtoola SH, Bhandari AK. Electrophysiologic effects of intrave- tion. Circulation 1993;87:2043–2046. Clinical and Echocardiographic Markers of Mortality Risk in Patients With Atrial Fibrillation

Taiyeb M. Khumri, MD, Madhuri Idupulapati, MD, Valerie J. Rader, MD, Sunil Nayyar, MD, Casey N. Stoner, MA, and Michael L. Main, MD*

Atrial ﬁbrillation (AF) is independently associated with increases in cardiovascular and all-cause mortality. Although cardiovascular co-morbidities predict stroke risk in AF, their relation with mortality has not been well described. To identify clinical and echocardiographic markers of mortality in patients with AF, 524 patients with AF underwent transesophageal echocardiography from August 2000 to March 2005. Clinical risk factors for systemic thromboembolism were determined for each patient. A CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes, and previous stroke or transient ischemic attack) score ranging from 0 to 6 was calculated for each patient. Transesophageal echocardiographic reports were reviewed for the presence of left atrial spontaneous echocardiographic contrast, left atrial thrombus, the left ventricular ejection fraction, aortic arch atheroma, and the presence and severity of mitral regurgitation. Mortality data were obtained from the Social Security Death Master File. Univariate and multivariate models were structured to assess which variables predicted mortality. In a multivariate model, a history of heart failure, age >75 years, the absence of systemic anticoagulation with warfarin, the presence of left atrial spontaneous echocardiographic contrast, and greater than moderate mitral regurgitation were independent predictors of mortality. Increasing CHADS2 score was also an independent predictor of mortality. A CHADS2 score of 5 or 6 was associated with a >50-fold increase in mortality compared with patients with CHADS2 scores of 0. In conclusion, a history of heart failure, age >75 years, the absence of chronic oral anticoagulation, a CHADS2 score >0, and greater than moderate mitral regurgitation are independent predictors of mortality in patients with AF. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1733–1736)

Although risk factors for stroke in atrial fibrillation (AF) are informed written consent before TEE. Aerosolized topical well characterized, relatively few data exist regarding inde- anesthetic solution was administered to the posterior oro- pendent risk factors for mortality in this patient population. pharynx, and conscious sedation was then achieved after the The aim of this study was to determine which clinical and intravenous injection of midazolam and fentanyl. The echocardiographic variables independently predict long- esophagus was intubated with the transesophageal echocar- term mortality in a large cohort of patients with AF. diographic probe, and standard transgastric and transesophageal views were obtained, including 2-dimensional, color Methods and Results flow, and spectral Doppler. High-resolution multiplane From August 2000 to March 2005, 524 patients with non- views of the left atrium and left atrial (LA) appendage were rheumatic AF (either chronic or paroxysmal) underwent generally acquired in patients with AF to exclude sponta- transesophageal echocardiography (TEE) at Saint Luke’s neous echocardiographic contrast (SEC) and LA thrombus. Hospital System of Kansas City and were included in the Transesophageal echocardiographic reports were subse- study. When a patient underwent TEE more than once quently reviewed by a physician for the reported presence of during the study period, only the initial transesophageal LA SEC, the presence of LA thrombus, the presence and echocardiographic study was used for analysis. Patients severity of aortic arch and descending aortic atheroma, the were excluded if normal sinus rhythm or atrial flutter was left ventricular ejection fraction, the presence of patent present during TEE, despite a history of AF. Nine patients foramen ovale, and presence and severity of mitral regur- were excluded because of inadequate transesophageal echo- gitation. cardiographic images. A retrospective medical record review was performed by TEE was performed using an ATL HDI 5000 machine a separate observer, blinded to the transesophageal echocar- (Philips Ultrasound, Bothell, Washington) equipped with a diographic findings, using inpatient records from St. Luke’s multiplane 7.4-MHz phased array probe. All patients gave Hospital System and outpatient records from Cardiovascu- lar Consultants, P.A. Records were analyzed beginning 3 months before TEE. Records were reviewed for history of Mid America Heart Institute, Kansas City, Missouri. Manuscript received November 20, 2006; revised manuscript received and accepted diabetes mellitus (including any use of antihyperglycemic January 17, 2007. agents), clinical history of heart failure, stroke (including *Corresponding author: Tel: 816-303-3245; fax: 816-931-7714. transient ischemic attack or peripheral embolus), systemic E-mail address: [email protected] (M.L. Main). hypertension (history of hypertension or documented sys-

Table 1 calculated for each patient at the time of TEE. The CHADS2 Baseline characteristics scoring scheme is a recently devised and validated method Variable Total Patients (n ϭ 524) for estimating the risk for stroke in patients with AF.1 Patients are assigned points as follows: history of conges- Men 320 (61.1%) tive heart failure ϭ 1 point, history of hypertension ϭ 1 Age (yrs) 69.2 Ն point, age Ͼ75 years ϭ 1 point, history of diabetes Age 75 yrs 204 (38.9%) ϭ Hypertension 354 (67.6%) mellitus 1 point, and history of stroke including transient Diabetes mellitus 114 (22.0%) ischemic attack or systemic embolism ϭ 2 points. Mortality Heart failure 181 (34.9%) data were derived from the Social Security Death Master Left ventricular ejection fraction Ͻ40% 126 (24.0%) File. Previous thromboembolic events 103 (19.9%) Univariate and multivariate logistic regression models Warfarin 342 (69.1%) with mortality as the outcome were used to analyze the Aspirin 284 (57.0%) predictive ability of CHADS score, LA SEC, LA throm- Antiarrhythmics 140 (28.1%) 2 LA SEC 218 (41.7%) bus, and the use of warfarin at the time of TEE. In an LA thrombus 51 (9.7%) adjusted multivariate logistic regression model, the vari- Ascending and aortic arch plaque 233 (44.9%) ables of heart failure, hypertension, age Ն75, diabetes, Patent foramen ovale 33 (7.3%) previous thromboembolic events, the use of warfarin, the Mitral regurgitation Ͼ2ϩ 26 (5.0%) use of aspirin, the left ventricular ejection fraction, the Mean follow-up period (mo) 31.4 Ϯ 16.8 presence of LA SEC, the presence of LA thrombus, aortic arch plaque, and the presence of greater than moderate mitral regurgitation were included independently to evalu- tolic blood pressure of Ͼ160 mm Hg), the use of systemic ate their ability to predict mortality. anticoagulation, the use of aspirin, and the use of antiar- A Cochran-Armitage test for trend was used to determine rhythmic drugs. A CHADS2 (congestive heart failure, hy- increasing and decreasing proportions of mortality across Ͼ pertension, age 75 years, diabetes, and previous stroke or levels of CHADS2 score. Because only 4 patients had transient ischemic attack) score ranging from 0 to 6 was CHADS2 scores of 6, we combined patients with CHADS2

Table 2 Univariate predictors of mortality in patients with atrial ﬁbrillation Parameter Estimate SE p Value Odds Ratio 95% CI Heart failure 1.149 0.229 Ͻ0.001 3.15 2.02–4.92 Hypertension 0.1556 0.237 0.5122 1.17 0.73–1.86 Age Ն75 0.915 0.223 Ͻ0.001 2.5 1.60–3.89 Diabetes mellitus 0.595 0.249 0.017 1.81 1.11–2.95 Previous thromboembolic event 0.304 0.265 0.2521 1.35 0.81–2.28 Lack of warfarin 0.849 0.237 0.0003 2.34 1.47–3.72 Aspirin 0.216 0.235 0.3577 1.24 0.78–1.97 Left ventricular ejection fraction 0.023 0.001 0.0009 1.02 1.01–1.04 Mitral regurgitation greater than moderate 1.215 0.414 0.0033 3.37 1.50–7.58 LA SEC 0.467 0.223 0.0365 1.59 1.03–2.47 LA thrombus Ϫ0.106 0.385 0.7835 0.9 0.42–1.92 Aortic arch plaque 0.105 0.223 0.6376 1.11 0.72–1.72

CI ϭ conﬁdence interval.

Table 3 Multivariate predictors of mortality in patients with atrial ﬁbrillation Parameter Estimate SE p Value Odds Ratio 95% CI Heart failure 0.5629 0.1333 Ͻ0.0001 3.09 1.83–5.21 Hypertension 0.00735 0.1352 0.9567 0.99 0.58–1.72 Age Ն75 yrs 0.5114 0.1273 Ͻ0.0001 2.78 1.69–4.59 Diabetes mellitus 0.2041 0.1416 0.1497 1.50 0.86–1.16 Previous thromboembolic event 0.2 0.1434 0.1631 1.49 0.85–1.18 Lack of warfarin 0.3529 0.122 0.0038 2.03 1.26–3.27 Aspirin 0.0612 0.1229 0.6184 1.13 0.70–1.83 Left ventricular ejection fraction 0.00588 0.00786 0.4545 1.01 0.99–1.02 Mitral regurgitation greater than moderate 0.5246 0.2149 0.0301 2.86 1.11–7.35 LA SEC 0.2398 0.1274 0.0598 1.62 0.99–2.66 LA thrombus 0.1452 0.2082 0.4855 0.75 0.33–1.69 Aortic arch plaque 0.2267 0.1277 0.0759 0.64 0.39–1.05

Abbreviation as in Table 2. Arrhythmias and Conduction Disturbances/AF and Mortality 1735

Table 4

Multivariate predictors of mortality after assimilation of CHADS2 score Parameter Estimate SE p Value Odds Ratio 95% CI

CHADS2 score 1 vs 0 2.7013 1.0385 0.0093 14.9 1.95–114.06 CHADS2 score 2 vs 0 2.7043 1.0356 0.009 14.95 1.96–113.77

CHADS2 score 3 vs 0 3.3693 1.0395 0.0012 29.06 3.79–222.9 CHADS2 score 4 vs 0 2.511 1.0877 0.021 12.32 1.46–103.84

CHADS2 score 5 or 6 vs 0 3.9493 1.0826 0.0003 51.9 6.22–433.21 LA SEC 0.4534 0.2384 0.0572 1.57 1.00–2.51 LA thrombus 0.2606 0.3921 0.5063 0.77 0.39–1.66 Lack of warfarin 0.8550 0.2320 0.0002 2.351 1.492–3.705

Abbreviation as in Table 2.

Figure 1. Kaplan-Meier survival curve in patients with AF with CHADS2 scores of 0 versus those with CHADS2 scores of 5 or 6.

Figure 2. Percentage mortality by CHADS2 score in patients with AF over the follow-up period. scores of 5 and 6 to increase the statistical strength of the erate mitral regurgitation independently predicted mortality study. Kaplan-Meier curves for survival were generated for (see Table 4). the follow-up period for multiple variables. A p value After assimilation of the clinical cardiovascular co- Ͻ 0.05 was considered signiﬁcant. SAS version 9.2 (SAS morbidities in the form of CHADS2 scores, increasing Institute Inc., Cary, North Carolina) was used for all statis- CHADS2 score and a lack of systemic anticoagulation tical analysis. with warfarin predicted mortality (Table 4). A CHADS2 Baseline characteristics of the patient population are score of 5 or 6 was associated with a Ͼ50-fold increase listed in Table 1. Mean follow-up was 31 months (range 15 in mortality compared with patients with CHADS2 scores to 48). Univariate and multivariate predictors of mortality of0(Figure 1). Mortality increased with increasing Ͻ are listed in Tables 2 and 3. History of heart failure, age CHADS2 score (p 0.0001; Figure 2), and this risk Ն75 years, the absence of systemic anticoagulation with persisted when limiting the analysis to patients receiving warfarin, the presence of LA SEC, and greater than mod- warfarin (p ϭ 0.0007). 1736 The American Journal of Cardiology (www.AJConline.org)

Discussion not likely have any contraindications to long-term oral anticoagulation and likely continued taking warfarin long AF is independently associated with increases in all-cause, 2–6 term. Although several echocardiographers performed TEE, cardiovascular, stroke, and nonstroke mortality and con- Ն tinues to independently predict mortality, even in patients all are experienced and perform 50 studies each year. with lone AF7,8 (patients aged Ͻ65 years without identifi- Finally, the severity of LA SEC can be affected by ultra- able cardiovascular co-morbidities or any structural heart sound system controls, including gain settings, but we disease). graded SEC as either present or absent, which reduces the potential for interobserver variability. Our data indicate that the CHADS2 scoring scheme may be quite useful for assessing mortality risk. This information in turn may be relevant in selecting medical treatment, 1. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Rad- particularly antithrombotic therapy. In our study population, ford MJ. Validation of clinical classification schemes for predicting stroke. Results from the national registry of atrial fibrillation. JAMA only 2 patients (2.7%) with CHADS2 scores of 0 died 2001;285:2864–2870. during the nearly 3-year follow-up period. There were no 2. Krhan AD, Manfreda J, Tate RB, Mathewson FAL, Cuddy TE. The characteristic identifiable high-risk features in either of natural history of atrial fibrillation: incidence, risk factors and these patients, and both were receiving chronic oral antico- prognosis in the Manitoba Follow-Up Study. Am J Med 1994;98: 476–484. agulation. Conversely, 13 patients (46.4%) with CHADS2 scores of 5 or 6 died during the follow-up period. Of these 3. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983– patients, only 4 were receiving anticoagulation. It is undis- 988. puted that chronic oral anticoagulation is indicated in all 4. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, patients with AF and concomitant cardiovascular co-mor- Levy D. Impact of atrial fibrillation on the risk of death: the Framing- bidities (absent a strong contraindication).9 However, in the ham Heart Study. Circulation 1998;98:946–952. present study, anticoagulation was much more likely to be 5. Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact administered to patients at relatively low stroke risk (69% of of atrial fibrillation on mortality, stroke, and medical costs. Arch Intrn Med 1998;158:229–234. patients with CHADS2 scores of 0) than to those at high 6. Kimura K, Minematsu K, Yamaguchi T, for the Japan Multicenter stroke risk (about 50% for patients with CHADS2 scores Investigators Collaboration (J-MUSIC). Atrial fibrillation as a predic- Ն4). tive factor for severe stroke and early death in 15,831 patients with Finally, multivariate analysis identified clinical heart acute ischemic stroke. J Neurol Neurosurg Psychiatry 2005;76:679– failure (but not a reduced left ventricular ejection fraction) 683. as a risk factor for mortality in patients with AF. This 7. Brand FN, Abbott RD, Kannel WB, Wolf PA. Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framing- coincides with recently published data demonstrating poor ham Study. JAMA 1985;254:3449–3453. long-term survival in patients with heart failure and pre- 8. Jouven X, Desnos M, Guerot C, Ducimetiere P. Idiopathic atrial served left ventricular ejection fractions.10 fibrillation as a risk factor for mortality. The Paris Prospective Study This was a retrospective study; a prospective study to I. Eur Heart J 1999;20:896–899. confirm these findings would be useful. The cause of mor- 9. Atrial Fibrillation Investigators. Risk factors for stroke and the tality in our patients is not known, but the substantial in- efficacy of antithrombotic therapy in atrial fibrillation. Analysis of crease in mortality with increasing CHADS score suggests pooled data from five randomized control trials. Arch Intern Med 2 1994;154:1449–1457. that the predominant cause of death was cardiovascular. We 10. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu do not have information regarding the duration of warfarin P. Outcome of heart failure with preserved ejection fraction in a use, but patients initiated on warfarin at index admission did population based study. N Eng J Med 2006;355:260–269. A Novel Mutation in Human Ether-a-Go-Go-Related Gene, Alanine to Proline at Position 490, Found in a Large Family With Autosomal Dominant Long QT Syndrome

Pier Luigi Pellegrino, MDa,*, Valeria Bafunno, MDb, Riccardo Ieva, MDa, Natale Daniele Brunetti, MD, PhDa, Giovanni Mavilio, MDa, Francesco Sessa, MDb, Massimo Grimaldi, MD, PhDa, Maurizio Margaglione, MDb,c, and Matteo Di Biase, MDa

Long-QT syndrome is a rare disease characterized by prolonged ventricular repolarization. The clinical presentation of long-QT syndrome is the occurrence of syncope, seizures, or cardiac arrest in young patients. Previous studies have demonstrated locus heterogeneity, with causative mutations reported in >8 different genes, including the human ether-a-go- go-related gene. This study was conducted in 26 members of a 4-generation family with long-QT syndrome. The proband was a 14-year-old female patient referred to the emergency department for the evaluation of recurrent syncope associated with a prolonged QT interval on electrocardiography at rest. There was a family history of sudden death in a 27-year-old woman. Sequencing of the entire coding regions of the human ether-a-go-go- related gene and the intron and exon boundaries of the proband identiﬁed a single base-pair substitution (guanine to cytosine at nucleotide 1468). This mutation resulted in a novel missense mutation, alanine to proline at position 490 (Ala490Pro), in the inner loop of the S2 and S3 domains. The proband was heterozygous for the Ala490Pro mutation. To address whether the mutational change detected in the patient would be a polymorphism, 100 control subjects from the same ethnical background were investigated. None showed the Ala490Pro substitution. Of 26 family members, 9 were mutation carriers, and none had normal electrocardiographic results. The penetrance of this pedigree was assumed to be 100%. In conclusion, the Ala490Pro mutation of the human ether-a-go-go-related gene is a rare, novel mutation that was inherited in this family, leading to Romano-Ward syndrome with complete penetrance. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007; 99:1737–1740)

Long QT syndrome (LQTS) is a rare disease character- channels, including 2 for potassium channel ␣ subunits ized by prolonged ventricular repolarization1. The clini- (the potassium voltage-gated channel, KQT-like subfam- cal presentation of LQTS is the occurrence of syncope, ily, member 1 gene and the human ether-a-go-go-related seizures, or cardiac arrest in young patients2,3 and epi- gene [HERG], responsible for LQT1 and LQT2),8,9 2 for sodic ventricular tachyarrhythmias, such as Torsades de potassium channel ␤ subunits (the potassium voltage- Pointes and ventricular fibrillation. The 2 best character- gated channel, related family, member 1 and member 2 ized forms of congenital LQTS are Jervell and Lange- genes, responsible for LQT5 and LQT6),10–12 and 1 for a Nielsen syndrome and Romano-Ward syndrome. Jervell sodium channel ␣ subunit (the sodium channel, voltage- and Lange-Nielsen syndrome is a cardioauditory syn- gated, type V, ␣ subunit gene, responsible for LQT3).13 drome that is inherited by an autosomal recessive pattern More than 90% of such genotyped patients carry muta- 4 and is associated with congenital deafness. Romano- tions in 3 of the 5 genes: the potassium voltage-gated Ward syndrome, which is more common, is inherited in channel, KQT-like subfamily, member 1 gene; HERG; an autosomal dominant pattern and is associated with and the sodium channel, voltage-gated, type V, ␣ subunit normal hearing.5,6 These syndromes usually manifest in gene. In 1 large French family,14 an atypical form of childhood or adolescence.7 LQTS (LQT4) with modest QT prolongation and atrial At least 8 genes causing LQTS have been identified so fibrillation was discovered; recently, the gene that en- far: 5 of them encode for transmembrane cardiac ion codes ankyrin B,15 a protein responsible for anchoring ion channels to cell membranes, has been associated with this form of LQTS. The last 2 genes associated with the aCardiology Department and bHuman Genetics Department, University LQTS phenotype cause prolonged repolarization associated c of Foggia, Foggia; and Atherosclerosis and Thrombosis Unit, I.R.C.C.S. with multiorgan involvement and extracardiac abnormali- “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy. Manu- script received November 8, 2006; revised manuscript received and ac- ties: the potassium inwardly rectifying channel, subfamily J, 16 cepted January 10, 2007. member 2 gene, causing LQT7 (Andersen syndrome ), and *Corresponding author: Tel: 39-338-9112358; fax: 39-0881-745424. the calcium channel, voltage-dependent, L type, ␣ 1C sub- E-mail address: [email protected] (P.L. Pellegrino). unit gene, causing LQT8 (Timothy syndrome17).

Figure 1. Pedigree structure. Generations are indicated with Roman numerals. Squares and circles, male and female family members, respectively. Hatched shading, family members carrying the Ala490Pro mutation identiﬁed in the proband, light-gray shading, family members with prolongation of the QT interval, and dark-gray shading, family members with cardiac arrest. The proband is indicated by the arrow, and deceased family members are indicated with slashes. The QTc intervals shown beneath each family member are expressed in seconds.

Figure 2. Electrocardiograpm at rest of the 14-year-old proband on admission to the emergency department.

Methods partment, including neurologic assessment, electroencepha- lography, computed tomography, magnetic resonance This study was conducted in a 4-generation family with imaging, and echocardiography, had normal results. LQTS. The pedigree with 26 members is shown in Figure 1. Detailed medical histories and electrocardiographic (ECG) Initial electrocardiography revealed sinus rhythm at 75 examinations were obtained from all 26 family members. beats/min with a biphasic T wave and a QTc interval of The diagnosis of LQTS was made on the basis of symptoms 570 ms (Figure 2). No previous ECG studies were available and corrected QT intervals on electrocardiography accord- for comparison. Ten minutes after admission, the patient ing to the criteria of Schwartz et al.3 The QT intervals were developed an episode of pulseless Torsades de Pointes, degenerating into ventricular flutter and ventricular fibrilla- measured in ECG lead II or V4 and corrected for heart rate (QTc) using Bazett’s formula (QTc ϭ QT/͙RR). QT tion, which was treated by immediate defibrillation. Shortly dispersion was defined as the difference between the max- thereafter, frequent premature ventricular contractions were imal and minimal QT intervals in any of the leads measured. seen on the monitor, followed by some short episodes of Peripheral blood was collected from all participants. Torsades de Pointes that converted in sinus rhythm sponta- The proband was a 14-year-old female patient referred to neously. A bolus of magnesium 2 g was administered in- the emergency department for the evaluation of recurrent travenously, and a continuous infusion of magnesium was syncope associated with a prolonged QT interval on elec- started. Initial laboratory examination subsequently re- trocardiography at rest. Syncope, sometimes associated with vealed slight hypokalemia (potassium level 3.4 mEq/L). seizures, occurred on 3 occasions over a 2-year period after Electrocardiography at rest on the next day noted QT pro- exercise, swimming, and emotional stress. Multiple previ- longation (QTc ϭ 0.52 seconds) with an “obvious biphid ous investigations after the first episode in a pediatric de- T-wave pattern,” resembling that seen in LQT2, as de- Arrhythmias and Conduction Disturbances/Novel Mutation HERG Gene LQTS 1739 scribed by Moss et al.18 The ␤ blocker propranolol was compared with those of the 17 unaffected family members. initiated at 1.5 mg/kg/day. The next few days were unevent- The mean QTc was 504 Ϯ 28 ms in the affected family ful. A permanent implantable cardioverter-defibrillator was members, compared with 399 Ϯ 23 ms in the unaffected placed before discharge. The patient was asymptomatic at group (p Ͻ0.01). The mean QT interval dispersion was 83 1-year follow-up, and no episodes of ventricular arrhyth- Ϯ 37 ms in the affected patients, compared with 33 Ϯ 11 ms mias were detected by the implantable cardioverter-defibril- (p Ͻ0.01) in the unaffected group. Exercise testing during lator. the 4-month follow-up visit showed inadequate shortening The screening of all immediate family members demon- of the QT interval during the exercise and recovery phases strated similar ECG changes in several of the 4-generation in the proband, whereas in the proband’s father and brother, family members. There was a family history of sudden appropriate shortening of the QT interval duration was death in an aunt of the proband, who died when she was found. The QTc interval of the proband’s brother showed aged 27 years after breast-feeding. At the beginning, family marked shortening at 4-months follow-up after the begin- members II:8 and II:9 refused clinical evaluation. They ning of ␤-blocker therapy (530 vs 420 ms), whereas the accepted clinical evaluation only after 4 months, when proband and her father showed only slight shortening (mean member III:10 was admitted to the emergency department QTc 510 Ϯ 14 vs 490 Ϯ 16 ms). The penetrance of this after cardiac arrest occurred without stress, probably be- pedigree was assumed to be 100%. cause of the consumption of an antibiotic (fluoroquinolone, prulifloxacin), treated with defibrillation at home. Discussion Informed consent was obtained from all participants before genetic testing. Deoxyribonucleic acid was extracted We described a single base-pair substitution resulting in a from peripheral blood leukocytes according to standard pro- novel missense mutation, Ala490Pro, in nonpore region of tocols.19 The amplification of all coding regions of HERG HERG in a large family with LQTS. A mutation in HERG and intron and exon boundaries were achieved using sense accounts for the second most common form of LQTS and antisense oligonucleotides designed on the basis of (LQT2). With only 1 exception,20 all HERG mutations known sequences of the HERG locus (Ensembl [Wellcome characterized to date are loss-of-function mutations that Trust Sanger Institute, Cambridge, United Kingdom] gene reduce Ikr amplitudes (via haploinsufficiency or the domi- ID ENSG00000055118; the adenine of the adenine-thym- nant-negative suppression of wild-type channels) and con- ine-guanine initiation codon is denoted as nucleotide ϩ1). secutively prolong repolarization. Of 26 family members, 9 Oligonucleotide custom synthesis service was from MWG were clinically diagnosed with LQTS according to the cri- Biotech AG (Ebersberg, Germany). teria of Schwartz et al.3 All patients had prolonged QT Polymerase chain reactions were carried out on 50-␮l intervals. There was a family history of sudden death in a samples in a Bio-Rad thermal cycler (Bio-Rad Laboratories, 27-year-old woman, who died after breast-feeding. Inc., Hercules, California). Each sample contained 0.1-␮g The mean QTc interval at rest was 504 Ϯ 28 ms in the genomic deoxyribonucleic acid, 15 pmol of each primer, affected family members, compared with 399 Ϯ 23 ms in 200 ␮mol/L deoxyribonucleoside triphosphate, 10 mmol/L the unaffected group (p Ͻ0.01). The penetrance of this tris hydrochloride (pH ϭ 8.3), 50 mmol/L potassium chlo- pedigree was assumed to be 100%. Recently, Priori et al21 ride, 1.5 mmol/L magnesium chloride, and 1.5 U Taq poly- demonstrated that LQTS may appear in some families with merase. Amplified deoxyribonucleic acid fragments were an extremely low penetrance (up to 25%) and that several purified and subjected to direct-cycle sequence analysis members would escape clinical diagnosis despite being using the Taq dye-deoxy terminator method and an ABI gene carriers, with multiple clinical implications, such as Prism 3100 genetic analyzer (Applied Biosystems, Foster the risk for developing life-threatening arrhythmias and City, California) according to the manufacturer’s instruc- transmitting the disease to 50% of their offspring. Our study tions. To address whether the mutational change detected in demonstrates complete penetrance, showing that penetrance the patient would be a polymorphism, 100 control subjects is related to specific mutations but can be profoundly mod- from the same ethnic background were investigated. None ified by other factors not yet identified. of them showed the substitution of alanine to proline at Of our 9 affected family members, only 4 were aged Ͻ30 position 490 (Ala490Pro). years; the others were aged Ͼ40 years (mean QTc interval 484 Ϯ 11 vs 530 Ϯ 21 ms, p ϭ 0.01). Of 4 affected family Ͻ Results members aged 30 years, only the proband (aged 14 years) was symptomatic for syncope and seizures before admission In all subjects, HERG was investigated for gene variants by to the emergency department, while member III:10 (aged 25 means of direct-cycle sequence analysis. The sequencing of years) was asymptomatic until admission to the emergency the entire coding regions of HERG and the intron and exon department after defibrillation at home for cardiac arrest, boundaries of the proband identified a single base-pair sub- probably because of the consumption of an antibiotic (flu- stitution (guanine to cytosine at nucleotide 1468). This oroquinolone, prulifloxacin). mutation resulted in a novel missense mutation, Ala490Pro, A recent study22 showed that mutations in different lo- in the inner loop of the S2–S3 domains. The proband was cations of the HERG potassium-channel gene are associated heterozygous for the Ala490Pro mutation. This mutational with different levels of risk for arrhythmic cardiac events in change was not present in control tests and had not been LQT2, with the greatest risk related to mutations in the reported previously. critical pore region of the channel. According to our find- The rest ECG studies of the 9 affected patients were ings, even mutations located in the inner loop of the S2 and 1740 The American Journal of Cardiology (www.AJConline.org)

mutations cause Jervell and Lange-Nielsen syndrome. Nat Genet S3 domains might be associated with a relatively higher incidence of malignant arrhythmias. The positive predictive 1997;17:267–268. power of the Ala490Pro mutation for cardiac arrest in short- 12. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA. MiRP1 forms Ikr potassium channels term follow-up was 22.2%, probably 30% if the sudden with HERG and is associated with cardiac arrhythmia. Cell 1999;97: death of family member III:4 was due to LQTS gene mu- 175–187. tation, as can be presumed. 13. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, The mean QT interval dispersion was 83 Ϯ 37 ms in the Towbin JA, Keating MT. SCN5A mutations associated with an inher- affected family members, compared with 33 Ϯ 11 ms in the ited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805–811. unaffected group (p Ͻ0.01). QT dispersion is very high in 14. Schott JJ, Charpentier F, Peltier S, Foley P, Drouin E, Bouhour JB, Donnelly P, Vergnaud G, Bachner L, Moisan JP, et al. Mapping of a typical LQTS patients, reﬂecting heterogeneities in the re- gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet covery of excitability, a factor known to increase the pro- 1995;57:1114–1122. pensity for ventricular ﬁbrillation.20,23 15. Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogne K, Kyndt F, Ali ME, et al. Ankirin-B 1. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac GM, for the SADS Foundation Task Force on LQTS. Multiple mech- death. Nature 2003;421:634–639. anisms in the long-QT syndrome. Current knowledge, gaps, and future 16. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular directions. Circulation 1996;94:1996–2012. weakness, extrasystoles, and multiple developmental anomalies. A 2. Schwartz PJ. The long QT syndrome. Curr Prob Cardiol 1997;226: new syndrome? Acta Paediatr Scand 1971;60:559–564. 302–351. 17. Splawski I, Timothy K, Sharpe ML, Decher N, Kumar P, Bloise R, 3. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria Napolitano C, Schwartz PJ, Joseph RM, Condouris K, et al. Ca(V)1.2 for the long QT syndrome. An update. Circulation 1993;88:782–784. calcium channel dysfunction causes a multisystem disorder including 4. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart arrhythmia and autism. Cell 2004;119:19–31. disease with prolongation of QT interval and sudden death. Am Heart J 18. Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, 1957;54:59–68. Schwartz PJ, Towbin JA, Vincent GM, Lehmann MH. ECG T-wave 5. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell’età patterns in genetically distinct form of the hereditary long QT syn- pediatrica. Clin Pediatr 1963;45:656–683. drome. Circulation 1995;92:2929–2934. 6. Ward OC. A new familial cardiac syndrome in children. J Irish Med 19. Margaglione M, Coalizzo D, D’Andrea G, Brancaccio V, Ciampa A, Assoc 1964;54:103–106. Grandone E, Di Minno G. Genetic modulation of oral anticoagulation 7. Hashiba K, Mitsuoka T, Mori M, Kiya F. The QT prolongation with warfarin. Thromb Haemost 2000;84:775–778. syndrome: long-term follow-up study of 13 families with Romano- 20. Lees-Miller JP, Duan Y, Teng GQ, Thorstad K, Duff HJ. Novel Ward syndrome. Heart Vessels Suppl 1987;2:47–55. gain-of-function mechanism in K(ϩ) channel-related long-QT syn- 8. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay drome: altered gating and selectivity in the HERG1 N629D mutant. TJ, Shen J, Timothy KW, Vincent GM, de Jager T, et al. Positional cloning of a novel potassium channel gene: KCNQ1 mutations cause Circ Res 2000;86:507–513. cardiac arrhythmias. Nat Genet 1996;12:17–23. 21. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT 9. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keat- syndrome. Circulation 1999;99:529–533. ing MT. A molecular basis for cardiac arrhythmia: HERG mutations 22. Moss AJ, Zareba W, Kaufman ES. Increased risk of arrhythmic events cause long QT syndrome. Cell 1995;80:795–803. in long QT syndrome with mutations in the pore region of the human 10. Splawski I, Tristani-Firouzi M, Lehmann MH, Sanguinetti MC, Keat- ether-a-go-go-related gene potassium channel. Circulation 2002;105: ing MT. Mutations in the hKCNE1 gene cause long QT syndrome and 794–799. suppress IKs function. Nat Genet 1997;17:338–340. 23. Day CP, Mc Comb JM, Campbell RWF. QT dispersion: an indication 11. Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun of arrhythmia risk in patients with long QT intervals. Br Heart J Y, Rubie C, Hordt M, Towbin JA, Borggrefe M, et al. KCNE1 1990;63:342–344. Effect of Medical Therapy for Heart Failure on Segmental Myocardial Function in Patients With Ischemic Cardiomyopathy

David S. Blondheim, MDa,*, Mark Kazatsker, MDa, Zvi Friedman, PhDb, Peter Lysyansky, PhDb, Simcha R. Meisel, MD, MSca, Aya Asif, MDa, Nahum Smirin, PhDb, and Avraham Shotan, MDa

The adjustment of medications and dosages to the needs of individual patients with heart failure is mostly intuitive, but even when their effect on global myocardial function is measured by classic indexes, their effect on segmental function is overlooked. This study was conducted to assess the feasibility of using echocardiographic myocardial strain imaging to evaluate the effect of medication on global and segmental function in 21 -ambulatory patients with heart failure (mean age 65 ؎ 11 years) who had echocardio graphic studies performed before and 2 hours after ingesting their regular morning medications. The ejection fraction, global and regional strain, and time to regional peak strain were compared between the 2 examinations. Medication induced no signiﬁcant changes in mean ejection fraction (28.6 ؎ 7.8% to 27.5 ؎ 9.9%) and mean global strain (؊9.5 ؎ 3.6% to ؊9.8 ؎ 3.2%). Changes in segmental strain depended on baseline function: normal ؎ segments (peak strain more negative than ؊12%) deteriorated (؊15.5 ؎ 2.7% to ؊13.7 (p <0.0001), but dysfunctional segments (peak strain less negative than ؊8% ,4.6% improved (؊5.3 ؎ 2.0% to ؊7.4 ؎ 4.3%, p <0.0001). Medication also improved segmental synchronization: average time to peak strain of segments in which peak strain was attained before aortic valve closure increased (325 ؎ 69 to 375 ؎ 100 ms, p <0.0001), but that of segments with postsystolic shortening at baseline decreased (451 ؎ 93 to 435 ؎ 93 ms, p <0.006). Thus, the time interval between time to peak strain of segments with systolic and post-systolic shortening at baseline was halved after medication. In conclusion, medications for heart failure induced an increase in the echocardiographically determined peak strain of myocardial segments with impaired function at baseline but decreased the peak strain of normally contracting segments. Medications also improved the synchronization of myocardial contraction. Neither the global ejection fraction nor global strain reﬂected these changes. Thus, medication tended to improve the homogeneity of left ventricular contraction. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1741–1744)

Global and regional strain and strain-rate imaging can now percutaneous intervention, or atrial fibrillation. The study be performed almost on-line during routine echocardio- was approved by the institutional review board, and patients graphic examinations with standard equipment and may gave informed consent for participation in the study. facilitate the quantification of regional myocardial func- All patients underwent standard baseline Doppler echo- tion.1 Furthermore, regional strain can be presented in a cardiographic studies before taking their routine morning “bull’s-eye” format, enabling the assessment of the func- medications and 2 hours later. Apical 2-, 3-, and 4-chamber tional status of multiple regions at a glance. We hypothe- views were digitized and stored. The echocardiographic sized that in patients with heart failure (HF), segmental studies were performed with commercially available Vivid strain would be sufficiently sensitive to detect the effect of echocardiographic systems (GE Healthcare, Milwaukee, medical therapy on segmental myocardial function. Wisconsin) and analyzed with EchoPAC station software (GE Healthcare) (2-dimensional strain). Methods and Results Analysis of the echocardiographic studies was done by We performed 26 studies on 21 hemodynamically stable an experienced technician blinded to the patients’ identities ambulatory patients (mean age 65 Ϯ 11 years, range 50 to and to the purpose of the study. The methods used for 85; 17 men) with left ventricular (LV) systolic dysfunction calculating longitudinal strain, and time to peak systolic of ischemic origin who had clinically compensated HF shortening have been described elsewhere.2 In short, 3 treated medically. Patients were excluded if they had a poor points were manually defined (both sides of the mitral echocardiographic quality, recent myocardial infarction or annulus and the apex), and a line was semiautomatically drawn along the LV endocardium on digital loops of apical 2-, 3-, and 4-chamber views. From this endocardial line a Unit of Noninvasive Cardiology, Department of Cardiology, Hillel- outward, the software selected natural acoustic markers Yaffe Medical Center, Hadera, Rappaport Faculty of Medicine, Technion; and bGeneral Electric Inc., Haifa, Israel. Manuscript received November 1, moving with the tissue and performed automatic frame-by- 2006; revised manuscript received and accepted January 17, 2007. frame tracking of these markers during the heart cycle. *Corresponding author: Tel: 972-46304488; fax: 972-46780450. From these markers, global longitudinal strain was calcu- E-mail address: [email protected] (D.S. Blondheim). lated for the entire length of the LV myocardium, equally

Table 1 Patient baseline data and changes induced by therapy on stroke volume, ejection fraction, and changes in segmental peak strain in each patient Patient Age (yrs)/Sex EDV (ml) dSV (ml) EF (%) dEF (%) Longitudinal Peak Strain Medication Segϩ Segϭ SegϪ 1 50M 240 Ϫ15 32 0 6 2 10 BB, ARB, FUR, DIG 2 50M 139 16 8 9 1 5 12 BB, ACE-I, FUR, ALD, DIG 3 51M 92 2 22 Ϫ2 6 7 5 BB, ACE-I, FUR 4 51M 146 Ϫ26 36 Ϫ17 14 1 3 BB, ACE-I, ALD 5 53M 111 Ϫ11 37 Ϫ3 7 8 3 BB, ACE-I, FUR 6 54M 174 14 20 9 4 4 10 ACE-I, FUR, ALD 7 54M 192 Ϫ31 37 Ϫ8 11 3 4 ACE-I, FUR, ALD 8 54M 202 Ϫ27 30 Ϫ4 738BB 9 60M 172 2 31 Ϫ1 4 5 9 BB, FUR, ALD, DIG 10 61F 135 Ϫ14 32 Ϫ6 14 2 2 BB, ACE-I, FUR, ALD, NIT 11 62M 127 Ϫ14 35 Ϫ8 4 4 10 BB, ACE-I, FUR, DIG 12 62M 144 Ϫ19 30 Ϫ11 4 12 2 BB, FUR, NIT 13 66M 91 8 36 9 7 5 6 BB, ACE-I 14 66M 93 10 30 8 9 4 5 BB, ACE-I 15 67M 258 Ϫ321 Ϫ4 458NIT 16 70M 133 12 17 9 6 6 6 BB, FUR, NIT 17 70M 96 15 38 3 7 3 8 ACE-I, FUR, DIG 18 73M 88 10 26 4 7 1 10 FUR, ALD, CCB, NIT, clonidine 19 75M 120 Ϫ11 30 Ϫ5 12 — 6 BB, ARB, amiodarone 20 75F 70 4 27 4 7 5 6 BB, FUR, CCB 21 75F 86 Ϫ10 38 Ϫ7 7 — 11 BB, FUR, CCB 22 76F 65 23 31 24 8 4 6 BB, ACE-I, FUR 23 77M 142 7 21 6 8 7 3 BB, ARB, FUR 24 77M 158 Ϫ18 25 Ϫ11 7 2 9 BB, ARB, FUR 25 81F 156 Ϫ10 38 Ϫ10 3 1 14 BB, FUR 26 85M 117 Ϫ421 Ϫ6 10 4 4 ACE-I, FUR, CCB

ACE-I ϭ angiotensin-converting enzyme inhibitors; ALD ϭ spironolactone; ARB ϭ angiotensin receptor blockers; BB ϭ ␤ blocker; CCB ϭ calcium channel blocker; dEF ϭ change in EF percentage points after medication; dSV ϭ change in stroke volume after medication; DIG ϭ digoxin; EDV ϭ end-diastolic volume; EF ϭ ejection fraction; FUR ϭ furosemide; NIT ϭ nitrate; Segϩ, Segϭ, and SegϪϭnumber of segments with an increase, no change, or a decrease in peak strain, respectively. divided into basal, mid, and apical segments of each wall in channel blockers 14%). There were no clinical adverse each view (i.e., 18 segments/patient). Time intervals from events due to the deferral of drug administration until 2 the QRS complex to peak strain and to aortic valve closure hours after the first echocardiographic study. were measured. The administration of drugs for HF did not alter baseline LV ejection fraction (EF) was calculated using the mod- volumes and volume-dependent indexes of LV function ified Simpson’s bi-plane method. Heart rate and blood pres- significantly (Table 1). The average end-diastolic volume sure were measured during the echocardiographic studies, decreased by 4% (136 Ϯ 49 to 131 Ϯ 47 ml, p ϭ NS), and and medications were noted. Changes in cardiac output the average end-systolic volume decreased by 1% (98 Ϯ 38 were calculated as the product of heart rate and stroke to 97 Ϯ 41 ml, p ϭ NS). The average LV stroke volume volume. decreased marginally (39 Ϯ 17 to 34 Ϯ 12 ml, p ϭ NS), but The results are expressed as mean Ϯ SD. Statistical relatively large changes (Ն10 ml) were found in 73% of the significance between means within groups was assessed studies (increases in 7, decreases in 12). Heart rate de- using the 2-tailed paired Student’s t test and between groups creased by an average of 12% (73 Ϯ 19 to 65 Ϯ 12 using the nonpaired Student’s t test. The chi-square test was beats/min, p Ͻ0.005), but despite the decreases in stroke used when indicated. A p value Ͻ0.05 was considered volume and in heart rate, changes in average cardiac output statistically significant. were not significant (2.8 Ϯ 1.4 to 2.2 Ϯ 0.9 L/min). Rela- The clinical characteristics of the 21 patients were typi- tively large changes in cardiac output (Ͼ0.5 L/min) were cal of patients with systolic dysfunction, including a high noted in 69% of studies (increases in 5, decreases in 13). prevalence of risk factors for ischemic heart disease (dys- The average EF was not changed by medication (29 Ϯ 8% lipidemia 57%, hypertension 52%, smoking 33%, diabetes to 27 Ϯ 10%, p ϭ NS), but individual changes varied mellitus 29%), and 19% had mild renal failure. All patients markedly: the EF increased by Ն5 percentage points in 62% were in a stable hemodynamic state and receiving chronic of studies (increases in 6, decreases in 10). Also, average medical therapy (Table 1) prescribed by their family phy- global peak strain was unchanged by medication (Ϫ9.5 Ϯ sicians, in accordance with contemporary guidelines (␤ 3.6% to Ϫ9.8 Ϯ 3.2%), although changes of Ն1 percentage blockers 81%, diuretics 81%, angiotensin-converting en- point were found in 77% of studies (improved in 9, deteri- zyme inhibitors 52%, spironolactone 29%, digoxin 24%, orated in 11). nitrates 20%, angiotensin receptor blockers 14%, calcium A total of 468 segments were studied. The segments Heart Failure/HF Medications Affect Segmental Myocardial Function 1743

NORMALMODERATE POOR

-21 -21 -21

-20 -20 -20

-19 -19 -19

-18 -18 -18

-17 -17 -17

-16 -16 -16

-15 -15 -15

-14 -14 -14

-13 -13 -13

-12 -12 -12

-11 -11 -11

-10 -10 -10

-9 -9 -9

-8 -8 -8

-7 -7 -7

-6 -6 -6

LONGITUDINAL STRAIN (%) -5 -5 -5

-4 -4 -4

-3 -3 -3

-2 -2 -2 PRE POSTPRE POST PRE POST

Figure 1. Changes induced by medication in the function of the averages of segments with normal, moderately reduced (moderate), and severely reduced (poor) baseline function in each study. Peak segmental strain was reduced after medication (red lines) in almost all segments with normal baseline function but increased by medication (blue lines) in almost all segments with severely reduced baseline function. Pre ϭ at baseline; Post ϭ after ingesting medication. Long horizontal lines separate normal, moderate, and poor baseline strain. were divided into 3 groups: 187 segments with normal Segments were divided into those that reached peak baseline function (defined as a longitudinal peak strain strain before closure of the aortic valve (i.e., during systole) more negative than Ϫ12%, 40% of all segments), 141 and those that reached peak strain after aortic valve closure segments with moderately reduced baseline function (de- (i.e., postsystolic shortening). After medication, the time to fined as segmental longitudinal peak strain of Ϫ8% to peak strain in the former segments increased (326 Ϯ 69 to Ϫ12%, 30% of all segments), and 140 segments with 375 Ϯ 100 ms, p Ͻ0.0001), whereas in the latter it de- severely decreased baseline function (defined as segmen- creased (452 Ϯ 93 to 436 Ϯ 93 ms, p Ͻ0.006). At baseline, tal longitudinal peak strain less negative than Ϫ8%, 30% the difference in average time to peak strain between the 2 of all segments). groups was 136 ms, but after medication, this difference Changes in segmental function induced by medication was halved to 61 ms. With regard to the time interval differed depending on baseline function: in the group with between end-systole (aortic valve closure) and time to peak normal baseline function, there was a 1.4 percentage point strain, medication shortened this interval in the group of deterioration in mean peak-strain (from –15.1 Ϯ 2.7% to segments with systolic shortening by 61 Ϯ 100 ms (15%, –13.7 Ϯ 4.6%, p Ͻ0.0001); in patients with moderately p Ͻ0.0001), and in the group of segments with postsystolic reduced baseline function, there was no significant change shortening, this interval was shortened by 24 Ϯ 111 ms (Ϫ10.0 Ϯ 1.3% to Ϫ10.3 Ϯ 4.3%); but in the group with (4%, p Ͻ0.0001). severely decreased baseline function, there was a modest Ϫ improvement of 2.1 percentage points in peak strain ( 5.3 Discussion Ϯ 2.0% to Ϫ7.4 Ϯ 4.3%, p Ͻ0.0001), which represents a 40% relative improvement from baseline. Between-group This study underscores the differential short-term effects of differences in mean longitudinal peak strain before and after medication for HF on LV segmental function as detected by medication were highly significant, especially between echocardiographic parameters. We found an inverse relation groups 1 and 3. The deterioration in contraction occurred in between baseline segmental function and the effect of 66% of segments with normal baseline function, in contrast medication on segmental peak strain. This effect was not to an improvement in contraction after medication in 70% apparent when only parameters of global LV function were of segments with severely reduced baseline contraction studied. In addition, medical therapy improved the synchro- (Figure 1). nization of segmental contraction. 1744 The American Journal of Cardiology (www.AJConline.org)

The 2-hour effect of medication on global peak strain Thus, the average time interval between segments contracting (the average peak strain of the 18 LV segments) as well as during systole and those with postsystolic shortening decreased on classic parameters of LV function (end-diastolic and by Ͼ50% (from 136 to 61 ms). Postsystolic shortening is end-systolic volumes, stroke volume, cardiac output, and detrimental to LV function because it fails to contribute to the EF) varied, improving in some and unchanged or even stroke volume and also interferes with early diastolic LV fill- deteriorating in others. Thus, echocardiographic monitoring ing.5 In addition, segments that start contracting late in systole may enable the identification of patients with undesirable (usually ischemic and dysfunctional) contract against an aug- depression of global LV function by a well-intended, albeit mented pressure produced by the earlier contraction of normal possibly harmful, combination of drugs and/or their dos- segments, and this may also be detrimental to their contraction. ages. Interestingly, we questioned 20 of the patients about Thus, the medically induced “segmental resynchronization” changes in their perceptions of well-being 2 hours after we demonstrated may contribute to the improvement in the ingesting their medications but found no significant corre- contraction of dysfunctional segments, and by doing so, to the lation between their subjective feeling and changes in LV improvement of systolic and diastolic global LV function in function (results not presented). This discordance has been some patients. The mechanism by which the time to peak strain reported by others3 and is probably because diastolic func- was influenced by medication in normal segments and in tion and peripheral vasodilatation better correlate with pa- segments with postsystolic shortening is not clear; it may have tients’ functional classes. Also, a change in subjective feel- to do with slowing of the heart rate, effects on normally ing may be influenced to a greater extent by the relief of contracting segments, or the relief of residual ischemia of pulmonary congestion (e.g., by diuretics) than by an in- dysfunctional segments. crease in the EF or cardiac output. Longitudinal studies may Some limitations of this study should be noted. First, we determine if, and to what extent, an echocardiographically studied the effect of a given medical therapy prescribed by guided titration of medication with the purpose of optimiz- each patient’s physician without attempting to verify the ing cardiac function may affect patients’ short- and long- effects of individual medications because our prime inter- term well-being and prognosis. ests were to demonstrate that the echocardiographic evalu- A marked variation was found in the effect of medication ation of medical therapy is feasible and how an effective on segmental peak strain, which depended on baseline seg- medical therapy affects global and segmental myocardial mental function. Medication depressed the performance of function. We are now studying in further detail the effect of normally contracting segments by almost 10%, but seg- individual drugs on normal and dysfunctional segments. ments that had severely reduced baseline function improved Second, the 2-hour “pill-to-test” time was arbitrarily chosen by 40% (p Ͻ0.0001 for both), whereas intermediately func- for practical reasons: it seemed to allow enough time for the tioning segments did not change (Ͻ1%, p ϭ NS). drugs to take effect, and it was short enough to secure Looking at the effect of medication on the average peak patient compliance with the study protocol. Repeating the strain of the normal segments in each study, we found an echocardiographic studies at hourly intervals may have de- improvement in only 17% (4 of 23) of the studies, in tected the optimal time to peak effect of the medical regi- segments with moderately reduced baseline function, an men for each patient, perhaps providing even more signif- improvement was found in 56% (14 of 25) of the studies, icant results. Third, the fact that our findings have a sound but in segments with poor baseline function, there was an theoretical basis and the very high statistical significance for improvement in the average peak strain in 80% (16 of 20) of each of the parameters that were tested strengthens our the studies (Figure 1). The inverse relation between the belief that our findings are not due to “regression to the effect of medications on segmental peak strain and baseline mean.” Similar findings in future studies, perhaps using function could have been anticipated on a theoretical basis: other methods, would confirm our conclusions that the reduction of the force of contraction of normal segments by short-term effect of medical therapy for HF tends to im- ␤ blockers (which 81% of our patients were taking) would prove “strain mismatch” and to promote medical “segmen- be expected to decrease the afterload against which poorly tal resynchronization.” functioning segments have to contract, thus enabling them to contract more efficiently. Whereas angiotensin-convert- 1. Sutherland GR, Di Salvo G, Claus P, D’hooge J, Bijnens B. Strain and ing enzyme inhibitors and angiotensin receptor antagonists strain rate imaging: a new clinical approach to quantifying regional unload the left ventricle primarily by causing vasodilatation, myocardial function. J Am Soc Echocardiogr 2004;17;788–802. ␤ blockers may “unload” dysfunctional segments by de- 2. Reisner SA, Lysyansky P, Agmon Y, Mutlak D, Lessick J, Friedman Z. Global longitudinal strain: a novel index of left ventricular systolic pressing the vigorous contraction of normally contracting function. J Am Soc Echocardiogr 2004;17:630–633. myocardial segments and thereby improving the homoge- 3. Ennezat PV, Ennezat CA, Vijayaraman P, Lachmann J, Asseman P, neity of segmental contraction. This salutary effect of ␤ Cohen-Solal A, Sonnenblick EH, LeJemtel TH. Dissociation between blockers on dysfunctional segments may partially explain improvement in left ventricular performance and functional class in the well-known improvement in overall LV function that patients with chronic heart failure. J Cardiovasc Pharmacol 2005;46: ␤ 262–268. has been shown for blockers despite their depressive 4. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow effect on contractility.4 MR. Carvedilol improves left ventricular function and symptoms in In this study, we also found that 2/3 of the myocardial chronic heart failure: a double-blind randomized study. J Am Coll segments had prolonged time to peak strain (i.e., postsystolic Cardiol 1995;25:1225–1231. 5. Belohlavek M, Pisraru C, Bae RY, Greenleaf JF, Seward JB. Real-time shortening) at baseline but had shorter QRS–to–peak strain strain rate echocardiographic imaging: temporal and spatial analysis of intervals 2 hours after medication, whereas the converse was postsystolic compression in acutely ischemic myocardium. JAmSoc true for segments with no delayed contraction at baseline. Echocardiogr 2001;14:360–369. Relation of Etiology of Heart Failure (Ischemic Versus Nonischemic) Before Transplantation to Delayed Pulmonary Oxygen Uptake Kinetics After Heart Transplantation

Corey R. Tomczak, MSca Nicholas G. Jendzjowsky, BSca, Kenneth J. Riess, MSca, Wayne Tymchak, MDb, Daniel Kim, MDb, Robert Haennel, PhDa, and Mark J. Haykowsky, PhDa,b,*

The effect that pretransplantation heart failure cause has on pulmonary oxygen uptake ˙ ˙ (VO2p) kinetics and peak aerobic power (VO2peak) in heart transplant recipients (HTRs) has ˙ ˙ not been studied. We examined VO2p kinetics and VO2peak in HTRs with previous ischemic mean age 64 ؎ 6 years) or nonischemic heart failure ,16 ؍ heart failure (I-HTRs; n mean age 50 ؎ 12 years). HTRs performed an incremental exercise ,13 ؍ NI-HTRs; n) ˙ ˙ (VO2peak) test and a constant work rate submaximal exercise (VO2p kinetics) test. A ˙ ␶ monoexponential model was used to determine the phase II VO2p time constant ( ). Phase ؎ ؎ ␶ ˙ II VO2p was slower in I-HTRs (49 10 seconds) than in NI-HTRs (34 10 seconds) (p ˙ <0.001). No signiﬁcant difference was found between I-HTRs and NI-HTRs for VO2peak vs 23.0 ؎ 8.2 ml · kg؊1 · min؊1, respectively), change in heart rate from rest to 6.4 ؎ 19.0) steady-state exercise (11 ؎ 8vs9؎ 9 beats · min؊1, respectively), or peak exercise heart rate (140 ؎ 22 vs 144 ؎ 22 beats · min؊1, respectively). In conclusion, the prolonged phase ˙ ␶ II VO2p in I-HTRs compared with NI-HTRs suggests that the magnitude of alteration in ˙ VO2p kinetics after heart transplantation may be dependent on previous heart failure cause. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1745–1749)

˙ ˙ ˙ Pulmonary oxygen uptake (VO2p) kinetics are prolonged in VO2p kinetics and reducing VO2peak. We tested the hypoth- 1–3 ˙ ˙ heart transplant recipients (HTRs). The slower VO2p ki- esis that VO2p kinetics would be signiﬁcantly slower and 1,4,5 ˙ netics may be due to reduced oxygen delivery secondary VO2peak would be lower in HTRs with previous ischemic to cardiac denervation,6 diastolic dysfunction4,6 and abnor- heart failure (I-HTRs) than in those with nonischemic heart mal vascular function.7,8 However, Grassi et al2 found that failure (NI-HTRs). improving cardiac output kinetics in HTRs does not alter ˙ VO2p kinetics, suggesting that skeletal muscle oxidative ˙ Methods metabolism abnormalities may prolong VO2p kinetics. A limitation of previous investigations was the failure to ex- Participants included clinically stable I-HTRs (n ϭ 16, amine the impact of pretransplantation heart failure cause. mean age 64 Ϯ 6 years) and NI-HTRs (n ϭ 13, mean age Clark et al9 and others10–12 have shown that the magnitude 50 Ϯ 12 years). I-HTRs had angiographic evidence of ˙ of decrease in peak aerobic power (VO2peak) was dependant coronary artery disease and histories consistent with previ- on heart failure cause. Furthermore, Patel et al7 demon- ous myocardial injury. The NI-HTRs did not meet these strated that abnormal peripheral vascular endothelial func- criteria. All participants were receiving standard posttrans- tion was reversible after transplantation in those with non- plantation pharmacologic therapy (Table 1). This investiga- ischemic but not ischemic heart failure. A consequence of tion received ethical approval from the University of Al- persistent impairments in peripheral vascular function found berta Health Research Ethics Board. in HTRs with antecedent ischemic cardiomyopathy is that it The incremental exercise test was performed on an elec- may alter oxygen delivery to the muscles, thus prolonging trically braked cycle ergometer (Corival; Lode Diagnostics BV, Groningen, The Netherlands). After a 2-minute rest period, the initial power out was set at 15 W and increased aCardiovascular Therapeutic Exercise Laboratory, Faculty of Rehabil- by 15 W every 2 minutes until volitional exhaustion. During itation Medicine, and bDivision of Cardiology, Faculty of Medicine, Uni- the test, expired gases were collected and analyzed with a versity of Alberta, Edmonton, Alberta, Canada. Manuscript received De- computerized metabolic system (TrueOne 2400 Metabolic cember 22, 2006; revised manuscript received and accepted January 17, Measurement System; ParvoMedics, Salt Lake City, Utah) 2007. ˙ to determine the ventilatory threshold and VO2peak.Ona Dr. Haykowsky is funded by the Heart and Stroke Foundation of separate day, subjects performed a constant work rate pro- Canada and a Canadian Institutes of Health Research (CIHR) New Inves- tocol that began with 3 to 5 minutes of rest followed by an tigator Award. Mr. Tomczak is a CIHR Strategic Training Fellow in abrupt step increase in work rate to approximately 80% of Tomorrow’s Research Cardiovascular Health Professionals (TORCH) and ˙ is supported by a doctoral Canada Graduate Scholarship from the Natural the VO2p at the ventilatory threshold for 5 minutes. ˙ Sciences and Engineering Research Council of Canada. VO2p data from the constant work rate exercise session *Corresponding author: Tel: 780-492-5970; fax: 780-492-4429. were averaged into 5-second time bins, and aberrant breaths ˙ E-mail address: [email protected] (M.J. Haykowsky). considered to not reﬂect VO2p kinetic responses were re-

Table 1 Participant characteristics and medications Variable I-HTRs NI-HTRs (n ϭ 16) (n ϭ 13) Age (yrs) 64 Ϯ 6* 50 Ϯ 12 Time after transplantation (yrs) 4.8 Ϯ 4.2 5.4 Ϯ 5.4 Body mass index (kg/m2) 30 Ϯ 428Ϯ 5 Medications† Cyclosporine 13 7 Tacrolimus 2 5 Sirolimus 2 1 Mycophenolate mofetil 9 9 Azathioprine 1 3 Prednisone 4 6 Angiotensin-converting 98 enzyme inhibitor Angiotensin II receptor —1 blocker ␣ blocker 1 — Angiotensin-converting —1 enzyme inhibitor ϩ thiazide ˙ Figure 1. Features of the biphasic response observed in VO2p after a step diuretic ˙ change in work rate. Phase I and phase II VO2p responses are illustrated. ␤ blocker 1 2 Phase II parameters correspond to those used in the first-order mathemat- Calcium channel blocker 9 9 ˙ ical model for determining VO2p kinetics. Time 0 indicates exercise onset, Diuretic 4 8 ␶ ˙ A indicates amplitude response, indicates the VO2p time constant, and TD Aspirin 12 11 indicates the time delay for the onset of the phase II response and reflects Lipid-lowering agent 11 9 the duration of the phase I response. The inset graph illustrates the square- wave protocol used for the exercise perturbation. *pϽ0.05 versus NI-HTRs. † Values are numbers of patients per respective group. x-axis, (3) a sudden increase in ␶, and (4) demonstration of moved.13 Data were smoothed using a 5-point moving av- a local threshold in the reduced chi-square value.14 The erage to reduce measurement noise and enhance the under- onset of the exponential increase in phase II was further ˙ 1 lying characteristics of the VO2p responses. After the phase verified using similar criteria. I “cardiodynamic” response, the kinetic parameters of phase Statistical analysis was performed using SPSS version ˙ II VO2p responses were determined using a first-order 11.0 (SPSS, Inc., Chicago, Illinois). Given a significant ϭ (monoexponential) mathematical model of the form Y(t) difference between groups for age and previously reported ϩ Ϫ Ϫ(t Ϫ TD)/␶) ˙ Y(b) A·[1 e ], where Y is VO2p at a given age-related differences in V˙ O 15,16 and V˙ O kinetics,17 ˙ 2peak 2p time (t), b is the baseline value of VO2p over the last 60 analysis of covariance was performed on all outcome vari- seconds previous to exercise onset, A is the amplitude ables using age as the covariate. We calculated the 95% ˙ ␶ change in the phase II VO2p response, is the time constant confidence intervals for the estimates of ␶ values for phase or time for phase II V˙ O to reach 63% of A, and TD is the ˙ 13 ϭ ϫ 2p II VO2p using the method of Lamarra et al :K1 L time delay of the phase II V˙ O onset (Figure 1). The time ␶ 2p (SD/A), where the true value of is within K1 seconds of delay of phase II reflects the duration of the phase I re- the obtained value with 95% confidence, based on the SD of sponse, and we further calculated the amplitude change (A) ˙ breath-by-breath VO2p fluctuations over a 2-minute steady- of the phase I response as the difference between V˙ O at ˙ 2p state period, the phase II VO2p amplitude (A) response, and phase II onset and b, the baseline. We then determined the a constant (L). Correlation regression was used to determine ˙ ˙ ϩ ˙ ϩ steady-state VO2p as the VO2p at b phase I VO2p A the relation between V˙ O kinetics, the duration of time ˙ 2p phase II VO2p A. after transplantation, and V˙ O . Data are presented as ˙ 2peak VO2p kinetic parameters were determined using nonlin- mean Ϯ SD, and p values Ͻ0.05 were considered statisti- ear regression. The iterative procedure of the computer cally significant. program (Origin 7.5, OriginLab Corporation, Northampton, Massachusetts) used a Levenberg-Marquardt algorithm Results whereby the best fit was defined by minimization of the ˙ residual sum of squares. The data-fitting window was ex- VO2p at the ventilatory threshold and at peak exercise, peak tended from the phase II onset to approximately 240 sec- heart rate, peak power output, peak respiratory exchange onds into the exponential response to allow the accurate ratio, and the minute ventilation/carbon dioxide production determination of the entire phase II evolution. The data- slope was not significantly different between I-HTRs and fitting window was lengthened and shortened iteratively NI-HTRs (Table 2). No significant difference was found until the exponential fit departed from the measured re- between I-HTRs and NI-HTRs for steady-state exercise sponse profile as determined by (1) visual inspection of the heart rate minus heart rate at rest (11 Ϯ 8vs9Ϯ 9 beats · curve for appropriateness of fit, (2) visual inspection of the minϪ1, respectively), steady-state heart rate (102 Ϯ 12 vs residuals for clustering and systematic deviations from the 102 Ϯ 16 beats · minϪ1, respectively), steady-state power ˙ Heart Failure/VO2p Kinetics and Heart Transplantation 1747

Table 2 Cardiopulmonary parameters from peak exercise testing Variable I-HTRs NI-HTRs Rest Heart rate (beats · minϪ1) 91 Ϯ 10 93 Ϯ 16 Mean arterial pressure (mm Hg) 95 Ϯ 890Ϯ 10 Ventilatory threshold ˙ Ϫ1 Ϯ Ϯ VO2p (L · min ) 1.07 0.26 1.17 0.33 ˙ Ϫ1 Ϫ1 Ϯ Ϯ VO2p (ml·kg · min ) 12.5 3.2 14.5 5.5 Peak exercise Power output (W) 98 Ϯ 35 115 Ϯ 35 Heart rate (beats · minϪ1) 140 Ϯ 22 144 Ϯ 22 ˙ Ϫ1 Ϯ Ϯ VO2p (L · min ) 1.63 0.50 1.82 0.54 ˙ Ϫ1 Ϫ1 Ϯ Ϯ VO2p (ml·kg · min ) 19.0 6.4 23.0 8.2 ˙ ˙ Ϯ Ϯ VE/VCO2 slope 38 4395 Respiratory exchange ratio 1.1 Ϯ 0.1 1.1 Ϯ 0.1

Values are expressed as mean Ϯ SD. ˙ ϭ ˙ ϭ VCO2 carbon dioxide production. VE minute ventilation.

Table 3 Pulmonary oxygen uptake kinetic parameters for ischemic heart transplant recipients and nonischemic heart transplant recipients Parameter I-HTRs NI-HTRs Ϫ1 Ϯ Ϯ Y(b) (L · min ) 0.34 0.07 0.30 0.10 Phase I A (L · minϪ1) 0.23 Ϯ 0.12 0.27 Ϯ 0.17 ˙ TD (s) 61 Ϯ 25 56 Ϯ 17 Figure 2. VO2p responses to a step change from rest to a work rate ˙ Phase II A (L · minϪ1) 0.28 Ϯ 0.10 0.26 Ϯ 0.12 approximating VO2p at 80% of the ventilatory threshold for a I-HTR and Phase II ␶ (s) 49 Ϯ 10* 34 Ϯ 10 NI-HTR. Data points represent 5-second averages. Monoexponential curve Steady-state V˙ O (L · minϪ1) 0.85 Ϯ 0.16 0.83 Ϯ 0.22 fits and corresponding residuals are also shown. Note that the time to reach 2p ˙ ␶ 63% of the VO2p asymptote ( ) is markedly slower in the representative Values are expressed as mean Ϯ SD. I-HTR compared with the representative NI-HTR. *pϽ0.001 versus NI-HTRs. ϭ ˙ A amplitude change in VO2p for phase I and phase II responses; TD ϭ ϭ ˙ ␶ ϭ phase II time delay; Y(b) baseline VO2p; time constant. output (24 Ϯ 9vs30Ϯ 6 W, respectively), or steady-state ˙ ˙ VO2p during the square-wave VO2p kinetics protocol (Table 3). ˙ Figure 2 illustrates the VO2p response, phase II monoexponential curve fits, and corresponding residuals for a ˙ representative I-HTR and NI-HTR. VO2p during the pre- transition baseline was not significantly different between ˙ groups (Table 3). Phases I and II VO2p amplitude responses ˙ ␶ were similar between groups, but phase II VO2p was 31% slower in I-HTRs than in NI-HTRs (p Ͻ0.001; Table 3 and Figure 3). The 95% confidence interval of ␶ for phase II ˙ Ϯ Ϯ VO2p was 4.7 seconds for I-HTRs and 5.1 seconds for ˙ NI-HTRs. These values are based on the phase II VO2p ˙ Figure 3. Vertical point plots illustrating individual phase II VO2p time amplitude responses reported in Table 3, and SDs of steady- ␶ ϭ ϭ ˙ constants ( ) for I-HTRs (n 16) and NI-HTRs (n 13). Overlapping state breath-by-breath VO2p fluctuations of 0.025 and 0.023 data points for respective groups are shown parallel to their point of origin. Ϫ1 L · min for I-HTRs and NI-HTRs, respectively. Finally, Group means are also indicated. ˙ VO2p kinetics were not related to the duration of time after ϭ ϭ ˙ ϭ transplantation (r 0.23, p 0.23) or VO2peak (r 0.16, p ϭ 0.42). kinetics found in HTRs may be related to previous heart failure cause. ˙ 1,2,4,18 Discussion The prolonged VO2p kinetics found in HTRs are attributed in part to the impaired cardiac output kinetics.19,20 ˙ The principal new finding of this investigation is that VO2p In turn, the abnormal cardiac output kinetics are related to kinetics are significantly slower in I-HTRs than in NI- blunted heart rate kinetics associated with cardiac denerva- HTRs. This finding extends the results of previous studies tion, because the rapid increase in stroke volume during the ˙ by demonstrating that the extent of the impairment in VO2p transition to submaximal constant load exercise is greater in 1748 The American Journal of Cardiology (www.AJConline.org)

HTRs than in healthy subjects.21 On the basis of these Koike et al26 for subjects with ischemic heart disease and ˙ findings, the divergent VO2p kinetics between our I-HTRs impaired left ventricular systolic function. Taken together, and NI-HTRs are unlikely due to differences in cardiac these findings suggest that our I-HTRs will quickly fatigue output kinetics, because the change in heart rate from rest to when performing activities of daily living that require steady-state and the steady-state exercise heart rate were abrupt increases in metabolic demand, such as transitioning similar in the 2 groups. from rest to a moderate walking speed, as evidenced by the ˙ ˙ ␶ The slower VO2p kinetics found in I-HTRs may be impaired phase II VO2p time constant ( ) in the I-HTR linked to impaired vascular function or oxidative metabo- group. Our findings also highlight the clinical importance of lism and a concomitant decrease in skeletal muscle blood ˙ determining VO2p kinetics for identifying patients with per- flow or use.8 Patel et al7 showed that the peripheral vascular sistent impairments in metabolic readjustment ability. endothelial dysfunction associated with nonischemic car- ˙ A limitation of our investigation is that VO2p kinetics diomyopathy is reversed after heart transplantation, but per- were determined during a single constant load exercise bout. sistent abnormalities in vascular function remain in HTRs ˙ ␶ However, our phase II VO2p values are similar to those with antecedent ischemic cardiomyopathy. Schaufelberger previously reported for HTRs.4,5 Moreover, we observed a et al22 and Stratton et al23 also demonstrated that the altered ˙ relatively narrow 95% confidence interval for phase II VO2p skeletal morphology (i.e., lower percentage type I fibers, ␶, which is notably improved on previous reports for HTRs capillary density, and oxidative enzyme activity) and abnor- (13.6 to 20.4 seconds).1 Averaging further repetitions of the mal oxidative metabolism associated with the heart failure constant load exercise bout would only serve to narrow our syndrome is not reversed after heart transplantation. Cur- ˙ ␶ observed 95% confidence interval for phase II VO2p val- rently, the effect that previous heart failure cause has on ues and would not alter our findings. A second limitation is posttransplantation skeletal morphology and bioenergetics ˙ 24 that VO2p kinetics were measured on average 5.1 years remains unknown. Braith et al recently examined the ef- (range 0.4 to 18.2) after transplantation. However, we did fect that resistance training has on skeletal morphology and not find a significant relation between V˙ O kinetics and enzymatic activity in HTRs. Fortunately, these investigators 2p time after transplantation. Thus, the slower V˙ O kinetics provided individual baseline data for HTRs with previous 2p found in I-HTRs do not appear to improve after transplan- ischemic cardiomyopathy (i.e., I-HTRs) or idiopathetic di- tation. A final limitation is that we did not examine the lated cardiomyopathy (i.e., NI-HTRs). Reanalysis of their ˙ baseline data based on pretransplantation heart failure cause underlying mechanisms for the divergent VO2p kinetics reveals no significant difference between I-HTRs and NI- between I-HTRs and NI-HTRs. However, the primary ob- Ϯ Ϯ jective of this investigation was to determine if the abnor- HTRs for percentage type I (24.9 9.1% vs 17.7 5%, ˙ respectively, p Ͼ0.05), type IIa (31.7 Ϯ 7.4% vs 35.9 Ϯ mal VO2p kinetics found in HTRs are related to pretrans- 6%, respectively, p Ͼ0.05), and type IIx (43.4 Ϯ 12% vs plantation heart failure cause. Accordingly, future 46.5 Ϯ 6%, respectively, p Ͼ0.05) myosin heavy chain investigations are required to determine the role that im- isoforms or lactate dehydrogenase (106 Ϯ 34 vs 111 Ϯ 40 pairments in oxygen delivery or use play in the abnormal Ϫ Ϫ ˙ mmol · g 1 wet weight · min 1, respectively, p Ͼ0.05), VO2p kinetics found in I-HTRs. citrate synthase (11.1 Ϯ 2.6 vs 9.4 Ϯ 1.2, mmol · gϪ1 wet weight · minϪ1, respectively, p Ͼ0.05), or 3-hydroxyacyl 1. Paterson DH, Cunningham DA, Pickering JG, Babcock MA, Boughner coenzyme-A dehydrogenase (3.6 Ϯ 0.9 vs 3.7 Ϯ 0.9 mmol DR. Oxygen uptake kinetics in cardiac transplant recipients. J Appl Ϫ1 Ϫ1 Physiol 1994;77:1935–1940. ·g wet weight · min , respectively, p Ͼ0.05). On the 2. Grassi B, Marconi C, Meyer M, Rieu M, Cerretelli P. Gas exchange ˙ basis of this analysis, we suspect that the slower VO2p and cardiovascular kinetics with different exercise protocols in heart kinetics in I-HTRs may be secondary to persistent abnor- transplant recipients. J Appl Physiol 1997;82:1952–1962. malities in vascular function and a concomitant reduction in 3. M’Bouh S, Bellmont S, Lampert E, Epailly E, Zoll J, N’Guessan B, Ribera F, Geny B, Oyono S, Arnold P, et al. An impaired cardiody- skeletal muscle blood flow, because the impairment in skel- namic phase contributes to the abnormal VO(2) kinetics at exercise etal morphology and biochemistry appear similar between onset in both congestive heart failure and heart transplant patients but I-HTRs and NI-HTRs in the study by Braith et al.24 How- results from differing mechanisms. Transplant Proc 2001;33:3543– ever, a role for impaired skeletal muscle oxygen use cannot 3545. be entirely ruled out in the present investigation. 4. Mettauer B, Zhao QM, Epailly E, Charloux A, Lampert E, Heitz- Several previous investigators have found that the extent Naegelen B, Piquard F, di Prampero PE, Lonsdorfer J. VO(2) kinetics reveal a central limitation at the onset of subthreshold exercise in heart of the decrease in peak aerobic power is related to cause of transplant recipients. J Appl Physiol 2000;88:1228–1238. heart failure, with patients with ischemic cardiomyopathy 5. Lanfranconi F, Borrelli E, Ferri A, Porcelli S, Maccherini M, Chia- ˙ having VO2peak values 13% to 21% lower than those with varelli M, Grassi B. Noninvasive evaluation of skeletal muscle oxida- nonischemic cardiomyopathy. Consistent with these results, tive metabolism after heart transplant. Med Sci Sports Exerc 2006;38: we found that V˙ O was approximately 17% lower in 1374–1383. 2peak 6. Kao AC, Van Trigt P III, Shaeffer-McCall GS, Shaw JP, Kuzil BB, I-HTRs than in NI-HTRs. However, there was no significant Page RD, Higginbotham MB. Central and peripheral limitations to ˙ ˙ relation between VO2peak and VO2p kinetics in our study upright exercise in untrained cardiac transplant recipients. Circulation group. This finding suggests that the factors limiting 1994;89:2605–2615. ˙ ˙ 7. Patel AR, Kuvin JT, Pandian NG, Smith JJ, Udelson JE, Mendelsohn VO2peak and VO2p kinetics differ. Notably, the mean V˙ O for our I-HTRs (19 ml · kgϪ1 · minϪ1) is just higher ME, Konstam MA, Karas RH. Heart failure etiology affects peripheral 2peak vascular endothelial function after cardiac transplantation. J Am Coll than the threshold level required for independent living (i.e., Ϫ Ϫ Cardiol 2001;37:195–200. 1 1 25 ˙ ␶ 15 to 18 ml · kg · min ). Finally, the phase II VO2p 8. Haykowsky M, Eves N, Figgures L, McLean A, Koller M, Taylor D, for our I-HTRs (49 seconds) is similar to that reported by Tymchak W. Effect of exercise training on VO2peak and left ventric- ˙ Heart Failure/VO2p Kinetics and Heart Transplantation 1749

ular systolic function in recent cardiac transplant recipients. Am J 18. Borrelli E, Pogliaghi S, Molinello A, Diciolla F, Maccherini M, Grassi Cardiol 2005;95:1002–1004. B. Serial assessment of peak VO2 and VO2 kinetics early after heart 9. Clark AL, Harrington D, Chua TP, Coats AJ. Exercise capacity in transplantation. Med Sci Sports Exerc 2003;35:1798–1804. chronic heart failure is related to the aetiology of heart disease. Heart 19. Cerretelli P, Marconi C, Meyer M, Ferretti G, Grassi B. Gas exchange 1997;78:569–571. kinetics in heart transplant recipients. Chest 1992;101:199S–205S. 10. Arena R, Myers J, Abella J, Peberdy MA. Influence of heart failure 20. Warburton DE, Sheel AW, Hodges AN, Stewart IB, Yoshida EM, etiology on the prognostic value of peak oxygen consumption and Levy RD, McKenzie DC. Effects of upper extremity exercise training minute ventilation/carbon dioxide production slope. Chest 2005;128: on peak aerobic and anaerobic fitness in patients after transplantation. 2812–2817. Am J Cardiol 2004;93:939–943. 11. Arena R, Tevald M, Peberdy MA. Influence of etiology on ventilatory 21. Braith RW, Plunkett MB, Mills RM Jr. Cardiac output responses expired gas and prognosis in heart failure. Int J Cardiol 2005;99:217– during exercise in volume-expanded heart transplant recipients. Am J 223. Cardiol 1998;81:1152–1156. 12. De Feo S, Franceschini L, Brighetti G, Cicoira M, Zanolla L, Rossi A, 22. Schaufelberger M, Eriksson BO, Lonn L, Rundqvist B, Sunnerhagen Golia G, Zardini P. Ischemic etiology of heart failure identifies patients KS, Swedberg K. Skeletal muscle characteristics, muscle strength and with more severely impaired exercise capacity. Int J Cardiol 2005; thigh muscle area in patients before and after cardiac transplantation. 104:292–297. Eur J Heart Fail 2001;3:59–67. 13. Lamarra N, Whipp BJ, Ward SA, Wasserman K. Effect of interbreath 23. Stratton JR, Kemp GJ, Daly RC, Yacoub M, Rajagopalan B. Effects of fluctuations on characterizing exercise gas exchange kinetics. J Appl Physiol 1987;62:2003–2012. cardiac transplantation on bioenergetic abnormalities of skeletal mus- 14. Rossiter HB, Ward SA, Howe FA, Kowalchuk JM, Griffiths JR, cle in congestive heart failure. Circulation 1994;89:1624–1631. Whipp BJ. Dynamics of intramuscular 31P-MRS P(i) peak splitting 24. Braith RW, Magyari PM, Pierce GL, Edwards DG, Hill JA, White and the slow components of PCr and O2 uptake during exercise. J Appl LJ, Aranda JM Jr. Effect of resistance exercise on skeletal muscle Physiol 2002;93:2059–2069. myopathy in heart transplant recipients. Am J Cardiol 2005;95: 15. Fitzgerald MD, Tanaka H, Tran ZV, Seals DR. Age-related declines in 1192–1198. maximal aerobic capacity in regularly exercising vs. sedentary women: 25. Paterson DH, Govindasamy D, Vidmar M, Cunningham DA, Koval JJ. a meta-analysis. J Appl Physiol 1997;83:160–165. Longitudinal study of determinants of dependence in an elderly pop- 16. Wilson TM, Tanaka H. Meta-analysis of the age-associated decline in ulation. J Am Geriatr Soc 2004;52:1632–1638. maximal aerobic capacity in men: relation to training status. Am J 26. Koike A, Hiroe M, Adachi H, Yajima T, Yamauchi Y, Nogami A, Ito Physiol Heart Circ Physiol 2000;278:H829–H834. H, Miyahara Y, Korenaga M, Marumo F. Oxygen uptake kinetics are 17. Babcock MA, Paterson DH, Cunningham DA, Dickinson JR. Exercise determined by cardiac function at onset of exercise rather than peak on-transient gas exchange kinetics are slowed as a function of age. exercise in patients with prior myocardial infarction. Circulation 1994; Med Sci Sports Exerc 1994;26:440–446. 90:2324–2332. Mutations in the Genes for Sarcomeric Proteins in Japanese Patients With Onset Sporadic Hypertrophic Cardiomyopathy After Age 40 Years

Ryuichiro Anan, MD*, Hideshi Niimura, MD, Toshihiro Takenaka, MD, Shuichi Hamasaki, MD, and Chuwa Tei, MD

This study was conducted to assess the hypothesis that mutations in the genes for sarcomeric proteins are the molecular cause for older-onset sporadic hypertrophic cardiomyopathy (HC) in Japanese patients. Molecular genetic approaches have demonstrated that familial HC is caused by mutations in genes encoding sarcomeric proteins. Recent studies have shown that sarcomeric gene mutations can also be a molecular cause of older-onset and/or sporadic HC. However, genetic studies to date have examined only a limited number of older Caucasian patients with HC. Clinical evaluations were performed in patients with HC onset after 40 years of age, and the sequence encoding the ␤-cardiac myosin heavy chain, cardiac troponin T, cardiac troponin I, cardiac myosin binding protein-C, myosin ventricular regulatory light chain, and myosin ventricular essential light chain genes was analyzed. When a putative mutation was identified, clinical evaluations and genetic studies were subsequently performed on all first-degree relatives. Forty-one patients with sporadic HC onset after 40 years of age (31 men, 10 women; mean age 63 ؎ 10 years at the time of study) were studied. Four novel missense mutations in the cardiac myosin binding protein-C gene (arginine to tryptophan at codon 160, glutamic acid to lysine at codon 334, glycine to arginine at codon 507, and threonine to methionine at codon 1,046) and a previously reported missense mutation in the ␤-cardiac myosin heavy chain gene (arginine to histidine at codon 663) were identified in 5 of the 41 patients. No family members carried these mutations or had clinical evidence of HC. In conclusion, mutations in the cardiac myosin binding protein-C are the most common cause of older-onset sporadic HC in Japan. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1750–1754)

Recent studies have shown that mutations in the sarcomeric ical examination, 2-dimensional echocardiography, and 12- protein genes can be a molecular cause of older-onset hyper- lead electrocardiography. Subjects with unexplained cardiac trophic cardiomyopathy (HC).1,2 Niimura et al2 reported that hypertrophy (ventricular wall thickness Ͼ13 mm), without mutations in the cardiac myosin binding protein-C (MyBP-C), hypertension or another cause of ventricular hypertrophy, troponin I, and ␤-cardiac myosin heavy chain (␤MHC) genes were diagnoses as affected.1–5 The end-stage phase of HC caused older-onset HC. Because many patients with older- was defined as a left ventricular ejection fraction Ͻ50% at onset disease have no known affected family members, these rest during follow-up by 2-dimensional echocardiography.6 cases may represent sporadic disease. The molecular basis for Left ventricular outflow obstruction was defined as a sub- sporadic HC is often also due to sarcomeric protein gene aortic gradient Ͼ30 mm Hg.1 Asymmetric septal hypertro- mutations. Richard et al3 reported that mutations in these genes phy was defined as a septal/posterior wall ratio Ͼ1.3.7 accounted for 15 of 25 cases of sporadic HC. Clinical and Older-onset disease was defined as HC diagnosed after the genetic studies of patients with older-onset sporadic HC have age of 40 years. Sporadic disease was defined by the ab- been restricted to Caucasian cohorts. In this study, we assessed sence of a family history of HC and was confirmed by the hypothesis that mutations in the genes for sarcomeric pro- clinical history, physical examination, 12-lead electrocardi- teins are the molecular cause of older-onset sporadic HC in ography, and echocardiography. Japanese patients. Deoxyribonucleic acid was isolated from 10 to 20 ml of peripheral blood, as previously described.4,5 Sequence anal- Methods and Results ysis was performed for the ␤MHC, cardiac troponin T, Written informed consent was obtained from all participants cardiac troponin I, MyBP-C, myosin ventricular regulatory in accordance with the ethics committees of Kagoshima light chain, and myosin ventricular essential light chain University. Study subjects were evaluated by history, phys- genes, as previously described.2–5 Each sequence variant that was predicted to have a significant effect on the structure of the proteins was assessed in 200 Department of Cardiovascular, Respiratory and Metabolic Medicine, normal unrelated chromosomes. Variants absent in control Kagoshima University, Kagoshima, Japan. Manuscript received September samples were considered disease-causing mutations. Genetic 17, 2006; revised manuscript received and accepted January 12, 2007. This study was supported in part by funding from Kagoshima Univer- studies of all surviving first-degree relatives of patients in sity, Kagoshima, Japan. whom mutations were identified were also performed. *Corresponding author: Tel: 81-99-275-5318; fax: 81-99-265-8447. Clinical histories in 41 patients (31 men and 10 women, E-mail address: [email protected] (R. Anan). mean age 63 Ϯ 10 years) indicated that each had older-onset

Table 1 Clinical features of patients with mutations Patient Age/ Age at Mutation Clinical Symptoms Electrocardiogram 2-Dimensional No. Sex Diagnosis Echocardiogram (yrs) (yrs) Chest Syncope Dyspnea Rhythm BBB ABN LVH IVSth PWth max SAM Pain Q WT 1 75/M 69 MyBP-C Arg 160Trp ϪϪ ISRϪϪϩ16 13 16 Ϫ 2 63/M 60 MyBP-C Glu334Lys ϪϪ ISRϪϪGNT 22 14 22 Ϫ 3 77/F 60 MyBP-C Gly507Arg ϪϪ ISRϪϪϩ19 10 19 Ϫ 4 67/M 67 MyBP-C Thr1046Met ϩϪ ISRϪϪGNT 18 11 18 ϩ 5 69/F 69 ␤MHC Arg663His ϪϪ II SR ϪϪϩ18 12 18 ϩ

The degree of dyspnea present was based on the New York Heart Association functional classiﬁcation. ABN Q ϭ abnormal Q waves; BBB ϭ bundle branch block; GNT ϭ giant negative T wave; IVSth ϭ thickness of the interventricular septum (mm); LVH ϭ left ventricular hypertrophy; max WT ϭ maximal wall thickness of the left ventricle (mm); PWth ϭ thickness of the posterior wall (mm); SAM ϭ systolic anterior motion of the mitral valve; SR ϭ sinus ryhthm.

Figure 1. Nucleotide sequence of 5 mutations identiﬁed in this study. The Arg160Trp, Glu334Lys, Gly507Arg, and Thr1046Met mutations were identiﬁed in the MyBP-C gene. The Arg663His mutation was found in the ␤MHC gene.

HC. Because no patient had a family history of HC, which The MyBP-C mutations affected codons in exons 5, 13, was confirmed by clinical history, physical examination, 18, and 30. In exon 5, a cytosine-to-thymine transition at 12-lead electrocardiography, and echocardiography, disease nucleotide 510 altered the arginine at codon 160 to trypto- in each patient was considered to be sporadic. Our cohort phan (designated Arg160Trp). In exon 13, a guanine-to- patients with older-onset sporadic HC consisted of 41 pa- adenine transition at nucleotide 1,032 altered the glutamic tients, including 20 with asymmetric septal hypertrophy, 3 acid at codon 334 to lysine (designated Glu334Lys). In exon with apical HC, and 4 with end-stage phase of HC. Among 18, a guanine-to-adenine transition at nucleotide 1,551 al- the 20 patients with asymmetric septal hypertrophy, 4 had tered the glycine at codon 507 to arginine (designated left ventricular outflow obstructions. Gly507Arg). In exon 30, a cytosine-to-thymine transition at Sequence analyses revealed missense mutations (Table nucleotide 3,169 altered the threonine at codon 1,046 to 1, Figure 1) in 5 of the 41 patients with HC. Four were novel methionine (designated Thr1046Met). mutations in the MyBP-C gene, and 1 was a previously A previously reported ␤MHC gene mutation in exon 18, a reported ␤MHC gene mutation (Arg663His). No mutations guanine-to-arginine transition at nucleotide 2,074, altered the were identified in the patients with apical HC. arginine at codon 663 to histidine (designated Arg663His).8 1752 The American Journal of Cardiology (www.AJConline.org)

Table 2 Species comparison of amino acid sequences ﬂanking the mutant residues MBP-C Arg160Trp 152 161 169 Subject D P I G L F V M W* P Q D G E V T V G Human AAC04620 D P I G L F V M R† PQDG E VT V G Mouse AA064202 D P I G L F L M R† PQDG E VT V G Chicken 090688 D P I G L F V T R† PQDG E VT V G XenLaevis AF417472 D E I G L F L E R† PQDG E I T V G Glu334Lys 331 341 Subject R Q A P P S E Y K* R I A F Q Y Q V T Human AAC04620 R Q A P P S E Y E† RIAF QYQV T Mouse AA064202 R Q A P P S E Y E† RIAF QHGV T Chicken 090688 R K A P P S E Y E† KIAF QYQ I T XenLaevis AF417472 K K A P P S E Y E† KIAF QYG I T Gly507Arg 501 511 Subject F K Y R F K K D R* G R H H L I I N E Human AAC04620 F K Y R F K K D G† GRHH L I I N E Mouse AA064202 F K Y R F K K D G† RKHH L I I N E Chicken 090688 F K Y R F K K D G† KKQY L I I N E XenLaevis AF417472 F K Y R F K K D G† KKHY L I I N E Thr1046Met 1041 1051 Subject V H S G T Y Q V M* V R I E N M E D K Human AAC04620 V H S G T Y Q V T† VRI E NME D K Mouse AA064202 T H S G T Y Q V T† VRI E NME D K Chicken 090688 H H S G A Y E V T† LQI E NMT D T XenLaevis AF417472 D H S G E Y K V Q I Q I E N C E D S ␤MHC Arg663His 661 671 Subject L N K L M T N L H* S T H P H F V R C Human P12883 L N K L M T N L R† STHP H FV R C Rat P02564 L N K L M T N L R† STHP H FV R C Chicken AAF99315 L N K L M T N L R† STHP H FV R C Drosophila NP523587 L Q S L M T T L R† STQP H FV R C

* Predicted amino acid changes. † Conserved amino acids at the position of mutation.

Three of these MyBP-C mutations, Arg160Trp, HC was found in any family members of the affected Glu334Lys, and Gly507Arg, and the ␤MHC mutation probands. As such, these studies excluded disease in 4 Arg663His altered residues that are conserved throughout siblings and 4 offspring at risk for the MyBP-C Arg160Trp the evolution (Table 2). The other MyBP-C mutation mutation; 1 parent, 6 siblings, and 2 children at risk for the (Thr1046Met) alters a residue conserved in human, mouse, MyBP-C Glu334Lys mutation; 5 siblings and 3 children at and chicken cardiac MyBP-C proteins.9 risk for the MyBP-C Thr1046Met mutation; and 5 siblings Each of these mutations was identified in patients recog- and 3 children at risk for the MyBP-C Gly507Arg mutation. nized to have unexplained cardiac hypertrophy after 40 One male sibling of the patient with the MyBP-C years of age. Table 1 lists the clinical features of the patients Gly507Arg mutation had sudden death at 20 years of age with mutations. Clinical evaluations in patents were initially while playing tennis; no autopsy was obtained. The ␤MHC prompted by chest pain in 1 patient, mild dyspnea in 1 Arg663His mutation was also excluded from 7 siblings and patient, and abnormal preoperative electrocardiographic re- 1 child at risk for disease. sults in 3 patients. The 2 patients with large negative T waves did not show apical hypertrophy. Two patients had Discussion systolic anterior motion of the mitral valve, but left ventricular outflow obstruction was not significant. The left atrial We defined the molecular basis for older-onset sporadic HC dimension of the patient with an Arg663His mutation in the in 5 of 41 patients. Four novel MyBP-C mutations and one ␤MHC gene was slightly enlarged to 41 mm. previously reported ␤MHC mutation were identified. Al- Family members were also clinically evaluated and though we also analyzed the cardiac troponin T, cardiac genotyped. Remarkably, no mutation or clinical findings of troponin I, myosin ventricular regulatory light chain, and Cardiomyopathy/Mutations in Genes in Japanese With HC 1753 myosin essential light chain genes, no mutation was found We could not find any mutations in patients with apical in this cohort. We conclude that mutations in the MyBP-C HC in this study. However, we and others have found gene account for 10% of older-onset HC in Japan. mutations in sarcomeric protein genes in Japanese and Cau- Previous work by Niimura et al2 found a similar fre- casian patients with apical HC.5,19 Kitaoka et al20 compared quency and distribution of mutations in 31 Caucasians with the characteristics of apical HC in Japan and the United HC diagnosed after the age of 40 years.2 More recently, States and documented variability in the phenotypic expres- Morita et al10 studied 50 patients with unexplained left sion of apical HC between countries and races, which may ventricular hypertrophy in 1,862 Framingham Heart Study due to differences in environmental factors or genetic back- subjects.10 They identified 8 patients (16%) with sarcomeric ground. Arad et al19 reported that most apical HC caused by protein gene mutations and 1 (2%) with a mutation in the a sarcomeric gene mutation reflects the interaction of mod- ␣-galactosidase A gene. In these studies, MyBP-C muta- ifying genetic background and/or local hemodynamics and tions were most often found. Van Driest et al11 reviewed other factors. several studies and observed that sarcomeric gene variants Genetic analyses were limited to sequences encoding the were identified in 5% to 30% of patients with sporadic ␤MHC, cardiac troponin T, cardiac troponin I, MyBP-C, HC.11 MyBP-C mutations were most often found also in this myosin ventricular regulatory light chain, and myosin ven- study. tricular essential light chain genes. Other genes that are rarer Our data confirm and extend these data to Japanese causes of HC were not investigated.1 Mutations in these patients with older-onset sporadic disease. In this popu- genes and others may account for older-onset sporadic HC lation, mutations in the MyBP-C gene were the most in the 36 patients for which a molecular cause was not common but altered residues that are distinct from those found. previously identified. Although the absence of these mutations from surviving family members prevented coseg- 1. Maron BJ, McKenna WJ, Danielson GK, Kappenberger LJ, Kuhn HJ, regation analyses, we suggest that the novel missense Seidman CE, Shah PM, Spencer WH III, Spirito P, Ten Cate FJ, Wigle mutations in the MyBP-C gene caused disease for the ED; Task Force on Clinical Expert Consensus Documents; American following reasons. These mutations arose in 2 genes that College of Cardiology; Committee for Practice Guidelines; European Society of Cardiology. American College of Cardiology/European are known to cause HC; each mutation was absent from Society of Cardiology clinical expert consensus document on hyper- 200 normal chromosomes (data not shown), and each trophic cardiomyopathy. A report of the American College of Cardi- mutation altered an amino acid that is highly conserved ology Foundation Task Force on Clinical Expert Consensus Docu- throughout evolution. Notably, the MyBP-C Thr1046Met ments and the European Society of Cardiology Committee for mutation in exon 30 might perturb a known function, Practical Guidelines. J Am Coll Cardiol 2003;42:1687–1713. 2. Niimura H, Patton KK, McKenna WJ, Scoults J, Maron BJ, Seidman because this residue is in a domain implicated in titin JG, Seidman CE. Sarcomere protein mutations in hypertrophic cardio- binding.9,12 In addition, some of the patients might have myopathy of the elderly. Circulation 2002;105:446–451. de novo mutations, given the lack of affected family 3. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, members. Benaiche A, Isnard R, Dubourg O, Burban M, et al, for the EURO- ␤ GENE Heart Failure Program. Hypertrophic cardiomyopathy. Distri- The MHC Arg663His mutation was previously re- bution of disease genes, spectrum of mutations, and implications for a 8,13 ported to cause familial HC. Clinical features associated molecular diagnosis strategy. Circulation 2003;107:2227–2232. with this mutation include modest hypertrophy that predom- 4. Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, inates within the proximal septum, left atrial enlargement, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, et al. and a high prevalence (47%) of atrial fibrillation.8 Some of Mutations in the gene for cardiac myosin-binding protein C and late- onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338: these characteristics were shared by our patient, a 69-year- 1248–1257. old woman with hypertrophy, systolic motion of the anterior 5. Anan R, Shono H, Kisanuki A, Arima S, Nakao S, Tanaka H. Patients mitral valve leaflet, and left atrial enlargement. Although with familial hypertrophic cardiomyopathy caused by a Phe110Ile this patient’s rhythm is currently sinus, her mutation and missense mutation in the cardiac troponin T gene have variable cardiac cardiac morphology suggest that she is at risk for atrial morphologies and a favorable prognosis. Circulation 1998;98:391– 397. arrhythmias. 6. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser The mechanism by which MyBP-C mutations cause old- JR, Mackey-Bojack S, Manning WJ, Udelson JE, Maron BJ. Preva- er-onset HC remains incompletely understood. In 389 un- lence, clinical profile, and significance of left ventricular remodeling in related patients with HC, Van Driest et al14,15 reported that the end-stage phase of hypertrophic cardiomyopathy. Circulation the age at diagnosis was 33 Ϯ18 years for 58 patients with 2006;114:216–225. ␤ Ϯ 7. Solomon SD, Wolff S, Watkins H, Ridker PM, Come P, McKenna WJ, MHC mutations and 38 15 years for 71 patients with Seidman CE, Lee RT. Left ventricular hypertrophy and morphology in MyBP-C mutations. Maron et al16 reported that MyBP-C familial hypertrophic cardiomyopathy associated with mutations of the mutations caused delayed remodeling, with the develop- beta-myosin heavy chain gene. J Am Coll Cardiol 1993;22:498–505. ment of left ventricular hypertrophy in adulthood in 3 pa- 8. Gruver EJ, Fatkin D, Dodds A, Kisslo J, Maron BJ, Seidman JG, 17 Seidman CE. Familial hypertrophic cardiomyopathy and atrial fibril- tients. Konno et al reported that the MyBP-C Arg820Gln lation caused by Arg663His beta-cardiac myosin heavy chain muta- mutation produced a “burned-out” phase of HC, and Kubo tion. Am J Cardiol 1999;83(suppl):13H–18H. et al18 reported that patients with the frameshift mutation at 9. Nanni L, Pieroni M, Chimenti C, Simionati B, Zimbello R, Maseri A, amino acid 592 had progressive LV remodeling with ad- Frustaci A, Lanfranchi G. Hypertrophic cardiomyopathy: two homozy- vanced age. The identification of factors that promote the gous cases with “typical” hypertrophic cardiomyopathy and three new mutations in cases with progression to dilated cardiomyopathy. Bio- clinical expression of MyBP-C mutations may ultimately chem Biophys Res Commun 2003;309:391–398. allow therapies to attenuate this common molecular cause of 10. Morita H, Larson MG, Barr SC, Vasan RS, O’Donnell CJ, Hirschhorn older-onset sporadic HC. JN, Levy D, Corey D, Seidman CE, Seidman JG, Benjamin EJ. 1754 The American Journal of Cardiology (www.AJConline.org)

Single-gene mutations and increased left ventricular wall thickness in 16. Maron BJ, Niimura H, Casey SA, Soper MK, Wright GB, Seidman JG, the community. The Framingham Heart Study. Circulation Seidman CE. Development of left ventricular hypertrophy in adults 2006;113:2697–2705. with hypertrophic cardiomyopathy caused by cardiac myosin-binding 11. Van Driest SL, Ommen SR, Tajik AJ, Gersh BJ, Ackerman MJ. protein C gene mutations. J Am Coll Cardiol 2001;38:315–321. Sarcomeric genotyping in hypertrophic cardiomyopathy. Mayo Clin 17. Konno T, Shimizu M, Ino H, Matsuyama T, Yamazaki M, Terai H, Proc 2005;80:463–469. Hayashi K, Mabuchi T, Kiyama M, Sakata K, et al. A novel missense 12. Sadayappan S, Gulick J, Osinska H, Martin LA, Hahn HS, Dorn GW mutation in the myosin binding protein-C gene is responsible for II, Klevitsky R, Seidman CE, Seidman JG, Robbins J. Cardiac myosin- hypertrophic cardiomyopathy with left ventricular dysfunction and binding protein-C phosphorylation and cardiac function. Circ Res dilatation in elderly patients. J Am Coll Cardiol 2003;41:781–786. 2005;97:1156–1163. 18. Kubo T, Kitaoka H, Okawa M, Matsumura Y, Hitomi N, Yamasaki N, 13. Rayment I, Holden HM, Sellers J, Fananapazir L, Epstein ND. Struc- Furuno T, Takata J, Nishinaga M, Kimura A, Doi YL. Lifelong left tural interpretation of the mutation in the ␤-cardiac myosin that have ventricular remodeling of hypertrophic cardiomyopathy caused by a implicated in familial hypertrophic cardiomyopathy. Proc Natl Acad founder frameshift deletion mutation in the cardiac myosin-binding SciUSA1995;92:3864–3868. protein C gene among Japanese. J Am Coll Cardiol 2005;46:1737– 14. Van Driest SL, Jaeger MJ, Ommen SR, Will ML, Gersh BJ, Tajik J, 1743. Ackerman MJ. Comprehensive analysis if the beta-myosin heavy 19. Arad M, Penas-Lado M, Monserrat L, Maron BJ, Sherrid M, Ho chain gene in 389 unrelated patients with hypertrophic cardiomyopa- CY, Barr S, Karim A, Olson TM, Kamisago M, et al. Gene muta- thy. J Am Coll Cardiol 2004;44:602–610. tions in apical hypertrophic cardiomyopathy. Circulation 2005; 15. Van Driest SL, Vasile VC, Ommen SR, Will ML, Tajik AJ, Gersh BJ, 112:2805–2811. Ackerman MJ. Myosin binding protein C mutations and compound 20. Kitaoka H, Doi Y, Casey SA, Hitomi N, Furuno T, Maron BJ. Com- heterozygosity in hypertrophic cardiomyopathy. J Am Coll Cardiol parison of prevalence of apical hypertrophic cardiomyopathy in Japan 2004;44:1903–1910. and the United States. Am J Cardiol 2003;92:1183–1186. Usefulness of Percutaneous Left Ventricular Assist Device as a Bridge to Recovery from Myocarditis

Divay Chandra, MDa, Biswajit Kar, MDa,b,c,*, Gary Idelchik, MDc, Leo Simpson, MDc, Pranav Loyalka, MDc, Igor D. Gregoric, MDd, Reynolds M. Delgado III, MDc, and O.H. Frazier, MDd

The TandemHeart percutaneous left ventricular assist device is a left atrial–to–femoral artery bypass system that can be implanted percutaneously within 30 minutes and provides active circulatory support. The TandemHeart has been used mainly for temporary hemodynamic assistance during high-risk coronary interventions and postcardiotomy heart failure. This report describes initial experience with this device as a successful bridge to cardiac recovery in 3 patients with acute myocarditis. All patients presented with severe cardiogenic shock (mean cardiac index 1.1 L/min/m2), and end-organ perfusion could not be maintained despite intra-aortic balloon counterpulsation and the maximal use of vasopressive agents. The patients were successfully bridged to myocardial recovery with the TandemHeart (mean duration of support 5 days, range 2 to 8). The only complication was a short episode of ventricular ﬁbrillation during device placement in 1 patient, which did not result in any morbidity or mortality. All patients were discharged home (mean duration of stay 15 days). In conclusion, the TandemHeart proved to be a safe and effective bridge to myocardial recovery in these patients with acute myocarditis. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1755–1756)

In recent years, the TandemHeart percutaneous left ventric- for patient 3 and showed normal myocardium. The Tan- ular assist device (LVAD) (CardiacAssist Inc., Pittsburgh, demHeart LVAD was inserted because of worsening he- Pennsylvania) has been increasingly used to provide hemo- patic and renal function despite maximal support with IABP dynamic support during high-risk coronary intervention and and vasopressive agents. This resulted in the steady resolu- postcardiotomy heart failure.1–5 This is mainly due to its tion of cardiogenic shock, with subsequent removal of the ability to be rapidly inserted percutaneously without the device and rapid weaning from all pressors (Table 1). All risks associated with the surgical placement of a conven- the patients were discharged home on aggressive heart fail- tional LVAD or with extracorporeal membrane oxygen- ure medication regimens that included but were not limited ation. Also, unlike intra-aortic balloon counterpulsation to a ␤ blocker, an angiotensin-converting enzyme inhibitor, (IABP), the TandemHeart provides active hemodynamic and oral diuretics. support in patients with little residual ventricular function. Placement of the TandemHeart was complicated by an We report the first 3 cases in which the TandemHeart was episode of ventricular tachycardia in patient 2, which re- implanted as a bridge to recovery from myocarditis. solved after cardioversion and the administration of intravenous amiodarone. Methods and Results Discussion The patients were transferred to the Texas Heart Institute with severe biventricular heart failure requiring multiple The TandemHeart LVAD is a left atrial–to–femoral artery vasopressive agents (Table 1). Patients 2 and 3 were also bypass system that can be implanted percutaneously within receiving invasive mechanical ventilation before transfer. 30 minutes and provides active hemodynamic support.5 The These 2 patients did not have any preceding histories of device consists of 3 subsystems: (1) a catheter set, which cardiac illness and had recently experienced viral upper includes a 21Fr venous polyurethane inflow cannula that is respiratory tract infections. Patient 1 had a history of inserted transseptally into the left atrium to aspirate oxy- chronic nonischemic cardiomyopathy that had been well genated blood, and an arterial perfusion catheter (9Fr to compensated for many years. After admission, all patients 17Fr), which returns the blood from the external pump to underwent cardiac catheterization, which showed minimal either 1 or both femoral arteries (whereas the 17Fr femoral coronary plaque. A right ventricular biopsy was performed cannula can provide flow rates of approximately 4 L/min, the 15Fr cannula can provide flows of up to 3.5 L/min); (2)

a b an external continuous-ﬂow centrifugal pump, which con- Department of Medicine, Baylor College of Medicine; Division of tains a 6-blade rotating impeller that can provide up to 4 Cardiology, Michael E. DeBakey Veterans Affairs Medical Center; and cDepartments of Cardiology and dCardiovascular Surgery, Texas Heart L/min of cardiac output; and (3) an external controller that 1 Institute, Houston, Texas. Manuscript received November 23, 2006; reis used to program and control the pump. The device can vised manuscript received and accepted January 17, 2007. remain implanted for up to 3 weeks. Like IABP recipients, *Corresponding author: Tel: 713-662-9762; fax: 713-662-9762. patients with the TandemHeart are conﬁned to bed for the E-mail address: [email protected] (B. Kar). duration of support.

Table 1 The TandemHeart percutaneous left ventricular assist device: demographics, course of illness, hemodynamic values, and markers of end-organ perfusion at device insertion, at 24 hours, and at device removal in 3 patients with acute myocarditis Variable Patient 1 Patient 2 Patient 3 Insertion 24 Hours Removal Insertion 24 Hours Removal Insertion 24 Hours Removal Age (yrs) 42 38 63 Sex M F M Baseline LVEF (%) 50 N/A N/A Insertion time (h after 36 24 12 admission) Duration of support (d) 5 8 2 Total duration of stay (d) 14 11 20 Hemodynamics LVEF (%) Ͻ10 Ͻ20 25 Ͻ20 N/A 40 Ͻ10 30 55 CI (L/min/m2) 1.6 3.4 3.7 1.6 2.6 3.2 0.2 2.5 3.5 PCWP (mm Hg) 32 18 16 19 15 8 24 15 15

SVO2 49 60 65 51 66 73 10 44 60 Lactic acid (mg/dl) 21 15 12 29 16 15 20 15 8 Vasopressive agents 2 1 0 5 4 2 4 3 0 BUN/CR (mg/dl) 85/5 74/5 21/2.1 68/1.6 60/2.7 37/0.7 17/1 27/1.3 21/0.8 UOP (L/24 h) 400 1,500 2,000 400 1,500 2,000 500 2,500 2,500 AST (U/L) 10,000 8,632 162 843 3,920 N/A 265 94 46 ALT (U/L) 7,000 6,182 566 464 912 90 108 126 73

ALT ϭ alanine aminotransferase; AST ϭ aspartate aminotransferase; BUN ϭ blood urea nitrogen; CI ϭ cardiac index; CR ϭ serum creatinine; LVEF ϭ left ϭ ϭ ϭ ϭ ventricular ejection fraction; N/A not available; PCWP pulmonary capillary wedge pressure; SVO2 mixed venous oxygen saturation; UOP urine output.

The TandemHeart fills the gap between the IABP and likely to survive with IABP support alone. For most such LVAD as a means of providing emergent short-term me- patients, the TandemHeart is less desirable compared with chanical left ventricular support. The LVAD must be in- an LVAD because of its limitation of duration of support serted through a thoracotomy, which can be hazardous, ex- (maximum 3 weeks). However, open-heart surgery for pensive, and time consuming. In contrast, the IABP is simple LVAD placement was thought to entail a high risk for and safe to insert but provides little active hemodynamic sup- mortality because of acute end-organ dysfunction. The Tan- port and depends on residual left ventricular function to be demHeart was implanted as a rescue device that could serve effective. The TandemHeart not only can be rapidly inserted as a bridge to recovery, to LVAD placement (bridge to percutaneously, with less risk than an LVAD, but also can bridge), or even to transplantation. The rapid and unantici- provide significant active hemodynamic support. pated recovery of cardiac function in these cases suggests The theoretical advantages of the TandemHeart over the that the TandemHeart may have a more definitive role than IABP in patients who undergo high-risk percutaneous cor- rescue therapy alone in selected cases of acute cardiac onary intervention were recently validated in a randomized decompensation. Our success with these 3 patients and the clinical trial.6 Compared with the IABP, the TandemHeart results of available studies provide encouragement with provided superior hemodynamic support that reduced mor- respect to the further use and development of this device. tality within the first 24 hours after insertion. After 24 hours, however, this mortality benefit was negated be- 1. Aragon J, Lee MS, Kar S, Makkar RR. Percutaneous left ventricular cause of the increased incidence of system inflammatory assist device: “TandemHeart” for high-risk coronary intervention. response syndrome and disseminated intravascular coag- Catheter Cardiovasc Interv 2005;65:346–352. 2. Kar B, Butkevich A, Civitello AB, Nawar MA, Walton B, Messner GN, ulation (TandemHeart 62%, IABP 15%), leading to mul- Gregoric ID, Feldman J, Myers TJ, Gemmato C, Delgado RM III. tiorgan dysfunction in TandemHeart patients.6 Other re- Hemodynamic support with a percutaneous left ventricular assist device ported complications of this device included a 33% during stenting of an unprotected left main coronary artery. Tex Heart incidence of limb ischemia.6 In our experience, a signifi- Inst J 2004;31:84–86. 3. Kar B, Forrester M, Gemmato C, Civitello A, Loyalka P, Myers T, cant decrease in systemic vascular resistance has occurred Reynolds D. Use of the TandemHeart percutaneous ventricular assist in some patients after day 3 of TandemHeart support (un- device to support patients undergoing high-risk percutaneous coronary published observation). Whether system inflammatory re- intervention. J Invasive Cardiol 2006;18:93–96. sponse syndrome or disseminated intravascular coagulation 4. Pitsis AA, Dardas P, Mezilis N, Nikoloudakis N, Filippatos G, Burkhoff will significantly reduce the TandemHeart’s utility will be- D. Temporary assist device for postcardiotomy cardiac failure. Ann Thorac Surg 2004;77:1431–1433. come evident only after more experience is gained with its 5. Thiele H, Lauer B, Hambrecht R, Boudriot E, Cohen HA, Schuler G. use. None of our patients experienced limb ischemia (un- Reversal of cardiogenic shock by percutaneous left atrial-to-femoral published observation). arterial bypass assistance. Circulation 2001;104:2917–2222. To the best of our knowledge, this is the first report of the 6. Thiele H, Sick P, Boudriot E, Diederich KW, Hambrecht R, Niebauer J, Schuler G. Randomized comparison of intra-aortic balloon support with use of a TandemHeart as a bridge to recovery from myo- a percutaneous left ventricular assist device in patients with revascu- carditis. Our 3 patients presented with a clinical picture larized acute myocardial infarction complicated by cardiogenic shock. compatible with acute fulminant myocarditis and were un- Eur Heart J 2005;26:1276–1283. Comparison of Late Post-Operative Cardiopulmonary Responses in the Fontan Versus Ventricular Septation for Double-Inlet Left Ventricular Repair

Hideo Ohuchi, MD, PhDa,*, Kenichi Watanabe, MDa, Kanako Kishiki, MDa, Masaki Nii, MDa, Yuko Wakisaka, MD, PhDa, Toshikatsu Yagihara, MD, PhDb, and Shigeyuki Echigo, MDa

Ventricular septation (VS) and the Fontan procedure are alternatives for definitive repair in patients with double-inlet left ventricle; although VS is theoretically preferable, the current preference in practice is the Fontan procedure. However, the long-term outcomes of both procedures remain unclear. To address this issue, cardiopulmonary responses during exercise were measured in patients with double-inlet left ventricle, and the impact of the type of procedure performed, Fontan or VS, on long-term exercise capacity and late ؎ postoperative clinical profiles was assessed. Fourteen post-Fontan patients (mean age 17 years) and 13 VS patients (mean age 19 ؎ 4 years) underwent exercise testing. Of the 13 6 VS patients, 5 required atrioventricular valve replacement (AVVR), and 7 required pacemaker implantation. Although no difference in peak oxygen uptake was found between the ؎ VS and Fontan patients, peak oxygen uptake was higher in VS patients without AVVR (30 ؎ ml/kg/min) than in VS patients with AVVR (19 ؎ 1 ml/kg/min) and Fontan patients (22 8 6 ml/kg/min) (p <0.01). There was no significant difference in peak oxygen uptake between the The clinical profiles of the .(0.09 ؍ VS patients with and without pacemaker implantation (p VS and Fontan patients were similar in terms of medication and freedom from tachyarrhythmias or reoperations during the follow-up period. In conclusion, the data suggest that VS without AVVR provides excellent future exercise capacity in selected patients with double-inlet left ventricle. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1757–1761)

Double-inlet left ventricle (DILV) can be repaired by either Methods the Fontan procedure or ventricular septation (VS); theoret- Since 1978, 22 patients with DILV underwent VS, with 8 ically, VS should be preferred because of the physiologic deaths, 4 at the time of VS and 4 late after VS (36% hemodynamics after repair. However, the current choice in mortality). In contrast, since 1987, 18 patients with DILV practice for these patients at most institutes has been the underwent the Fontan operation, with 1 late death (6% Fontan procedure, reflecting the poor results of early trials mortality). Among the survivors, 13 VS patients (2 from 1–3 of VS and recent improving survival rates for the Fontan another institute) and 14 Fontan patients were the subjects 4 procedure. However, there are reports of excellent long- of this study. In the VS group, all patients had situs solitus. 5,6 term results in VS patients and of recent improved out- Seven had d-looped hearts, and 6 had l-looped hearts. Two 7 comes after VS in selected patients with DILV. Exercise of the patients with d-looped hearts had transposed great capacity is a valuable indicator of postoperative status and a arteries, requiring arterial switches at the time of VS; the powerful prognostic factor in adult patients with congenital other 5 had normally related great arteries, the so-called heart disease.8 Therefore, maintaining high exercise capac- Holmes heart.9 Three of the 5 patients with Holmes hearts ity may convey a better long-term prognosis. Fontan pa- required enlargement of the bulboventricular foramen for tients exhibit impaired aerobic capacity, but there have been the new right ventricular outflow tract. All the patients with few reports on exercise-related physiology in the long term l-looped hearts had l-transposed great arteries. Clinical char- after VS. On the basis of these considerations, we compared acteristics are listed in Table 1. Seven VS patients had the impact of the type of repair, Fontan or VS, on the pacemakers implanted for postoperative complete heart cardiopulmonary response to exercise in patients with DILV block, DDD mode in 4 and VVI mode in 3 because of in the long term after repair. histories of atrial flutter. In the Fontan group, patients with significantly unbalanced sizes of the right and left atrioventricular valves were excluded. Two patients required early aortopulmonary shunts, and 2 patients had undergone Glenn anastomosis before the Fontan operations. Lateral tunnel, intra-atrial, and extracardiac graft rerouting procedures Department of aPediatrics and bThoracic Surgery, National Cardiovas- cular Center, Osaka, Japan. Manuscript received November 18, 2006; were used in 2, 3, and 7 patients, respectively. revised manuscript received and accepted January 22, 2007. The VS patients were subdivided into 2 groups: 5 pa- *Corresponding author: Tel: 81-6-6833-5012; fax: 81-6-6872-7486. tients with atrioventricular valve regurgitation who had un- E-mail address: [email protected] (H. Ohuchi). dergone atrioventricular valve replacement (AVVR) (the

Table 1 Clinical characteristics of the study patients with double-inlet left ventricle and controls Group VS Fontan Control (n ϭ 13) (n ϭ 14) (n ϭ 20) Age (yrs) 19 Ϯ 417Ϯ 619Ϯ 3 Body height (cm) 161 Ϯ 14 153 Ϯ 11 161 Ϯ 9 Body weight (kg) 51 Ϯ 744Ϯ 12 52 Ϯ 7 Age at repair (yrs) 4 Ϯ 2* 8 Ϯ 6— Follow-up (yrs) 14 Ϯ 4* 8 Ϯ 5— Previous operations — Pulmonary artery banding 5 7 — Aortopulmonary shunt 2 3 — Glenn anastomosis 0 3 — Repair of coarctation 1 1 — Pacemaker implantation 7 (54%) 0 — Medications Digoxin 4 (31%) 0 — Diuretics 8 (62%) 6 (43%) — Figure 1. Comparison of peak VO2 among controls, Fontan patients, and Anticoagulants 6 (46%) 12 (86%)* — VS patients with (AVVRϩ) and without (AVVRϪ) AVVR. White, gray, Angiotensin-converting enzyme 7 (54%) 4 (29%) — hatched, and black bars indicate the control, AVVRϪ, AVVRϩ, and inhibitors Fontan groups, respectively. Values are expressed as mean Ϯ SD. **p ␤ blockers 5 (38%) 5 (36%) — Ͻ0.01; ***p Ͻ0.001. Values are expressed as mean Ϯ SD. * Significant versus Fontan group. groups or among 3 groups, respectively. A chi-square test was used to compare the prevalences of medications. Free- AVVRϩ group) and 8 patients without such a complication dom from reoperation and from sustained tachyarrhythmias (the AVVRϪ group). Of the AVVRϩ patients, all had was estimated using the Kaplan-Meier method, and differ- undergone right-sided (pulmonary) AVVR, and 1 had also ences in the freedom status between groups were assessed undergone left-sided (systemic) AVVR. In 2 patients, right- using log-rank tests. Data are expressed as mean Ϯ SD. A sided atrioventricular valve repair was attempted but was p value Ͻ0.05 was considered statistically significant. followed by AVVR. The clinical characteristics of the study patients after definitive repair, their previous palliations, and Results medications are listed in Table 1. The control group consisted of 20 patients with histories Exercise time was shorter in the Fontan and VS groups than of Kawasaki disease without stenotic coronary arterial le- in controls (9.7 Ϯ 0.9 minutes), with no difference between sions, as previously described.10 None of the controls had the Fontan (6.1 Ϯ 1.7 minutes) and VS (7.1 Ϯ 1.9 minutes) abnormal findings suggesting cardiac lesions. The Ethics groups (p Ͻ0.0001). Although the AVVRϪ group had a Committee of the National Cardiovascular Center approved longer exercise time than the AVVRϩ group (p Ͻ0.0001), the study protocol. it was still shorter than that of controls (p Ͻ0.01). There was All subjects underwent symptom-limited treadmill exer- no difference in the peak gas exchange ratio between the VS 10 Ϯ Ϯ ϭ cise, and peak oxygen uptake (VO2) was measured. We and Fontan groups (1.15 0.07 vs 1.13 0.08, p NS), determined heart rate (HR) from 12-lead electrocardiography. although the values were less than those of controls (1.22 Ϯ Ventilation and gas exchange were measured by a breath-by- 0.09; p Ͻ0.01). breath method using a hot-wire anemometer (Rio AS500; A similar trend was seen for peak VO2, which was Minato Medical Science, Osaka, Japan) with a mass spectrom- smaller in the Fontan and VS groups than in controls (38 Ϯ eter (MG-300; PerkinElmer, St. Louis, Missouri). 4 ml/kg/min; p Ͻ0.0001), with no difference between the Ϯ Ϯ Oxygen pulse (O2 pulse) was calculated by dividing VO2 Fontan (22 6 ml/kg/min) and VS (26 9 ml/kg/min) Ϫ by HR and is equal to the product of the stroke volume and groups. However, the AVVR group had greater peak VO2 the arterial-venous oxygen difference. Therefore, this value than the AVVRϩ group (p Ͻ0.01), although the duration relates to stroke volume and oxygen extraction. Because the was shorter than that of controls (p Ͻ0.01; Figure 1). There magnitude of oxygen extraction at peak exercise varies little was no difference in peak VO2 between VS patients with in patients and normal subjects, the peak value reflects and without pacemakers (22 Ϯ 7vs30Ϯ 9 ml/kg/min, p ϭ stroke volume at peak exercise.11 0.09). We reviewed all medical charts to detect histories of Peak HR was lower in the Fontan and VS groups than in serious sustained cardiac tachyarrhythmias, such as su- controls, although there was no difference in HR at rest. In praventricular tachycardia, atrial tachycardia, flutter, or fi- particular, the AVVRϩ group had the lowest peak HR brillation and ventricular tachycardia. (p Ͻ0.01; Figure 2), probably because 4 of the 5 AVVRϩ An unpaired Student’s t test or analysis of variance was patients had programmed target HRs by pacemakers, in- used to compare differences in exercise cardiopulmonary cluding 3 in VVI mode. In all subjects, although HR in- ϭ Ͻ variables, including pulmonary function at rest, between 2 creases correlated with peak VO2 (r 0.67, p 0.0001), Congenital Heart Disease/Exercise Capacity After Ventricular Septation 1759

Figure 2. Comparison of peak HR, systolic blood pressure (SBP), O2 pulse, and ventilatory equivalent for carbon dioxide output (VE/VCO2) among the 4 study groups. White, gray, hatched, and black bars indicate the same groups as in Figure 1. *p Ͻ0.05, **p Ͻ0.01, ***p Ͻ0.001. this positive relation was seen only in the VS group (r ϭ of cardiac surgeries, including palliative operations (r ϭ 0.58, p Ͻ0.05), indicating that the HR response is important Ϫ0.56, p Ͻ0.005). in enabling high exercise capacity in VS patients. Supraventricular tachyarrhythmia occurred in 3 Fontan Peak systolic blood pressure was lower in the Fontan patients and ventricular tachyarrhythmia in 2 Fontan pa- group than in the controls (p Ͻ0.01). In comparing the 4 tients, and atrial flutter occurred in 5 VS patients and ven- groups, the Fontan and AVVRϩ groups showed lower peak tricular tachycardia in 4 VS patients. In the VS group, 4 of systolic blood pressures (p Ͻ0.01; Figure 2). Exercise sys- 5 patients with atrial flutter and 1 of 4 patients with ven- tolic blood pressure increases were correlated with peak tricular tachycardia were in the AVVRϩ group. There was ϭ Ͻ VO2 in all subjects (r 0.57, p 0.0001). no difference in tachyarrhythmia-free rates during the fol- No difference in peak O2 pulse was observed between low-up period (Figure 3). the VS (9 Ϯ 4 ml/min) and control (11 Ϯ 2 ml/min) groups, One Fontan patient underwent aortic valve replacement, whereas the Fontan group showed a lower peak O2 pulse and 1 underwent relief of a subaortic stenosis of the left (6 Ϯ 4 ml/min) (p Ͻ0.001). In comparing the 4 groups, no ventricular outflow tract. AVVR was performed in 5 VS difference was seen between the Fontan and AVVRϩ patients. Right-sided (pulmonary) AVVR was done in the 5 groups (Figure 2). Peak O2 pulse correlated with peak VO2 patients, 1 of whom underwent bilateral AVVR. No other in all subjects (r ϭ 0.66, p Ͻ0.0001). type of reoperation was done in the VS group. When AVVR The peak ventilatory equivalent for carbon dioxide out- was considered a reoperation, there was no difference in the put in the Fontan and VS groups was higher than in controls reoperation-free rate during the follow-up period (Figure 3). (p Ͻ0.001) and was lower in the VS group than in the Ϯ Ϯ Ͻ Fontan group (38 9vs44 6, p 0.05), indicating better Discussion ventilatory efficiency in the VS patients. However, there was no difference between the AVVRϩ and AVVRϪ The present study confirms that VS patients have excellent groups (Figure 2). exercise capacity long after the repair if AVVR is avoided. Percentage predicted vital capacity was smaller in the No significant disadvantages were found compared with Fontan (75 Ϯ 17%) and VS groups than in controls (98 Ϯ Fontan patients in terms of postoperative medications, free- 12%) (p ϭ 0.001), while there was no difference in forced dom from tachyarrhythmias, and freedom from reopera- expired volume in 1 second, indicating restrictive ventila- tions. Thus, subject to appropriate patient selection, VS tory impairment in the patient groups. In a comparison of should be the recommended option for DILV repair. the 4 groups, no difference was found between the control In the Fontan circulation, a systemic ventricle of left and AVVRϪ groups (94 Ϯ 14%). In all patients, percentage ventricular morphology has significant advantages over a predicted VC was inversely correlated with the total number systemic ventricle of right ventricular morphology in terms 1760 The American Journal of Cardiology (www.AJConline.org)

Figure 3. Comparison of tachyarrhythmia-free rate (A) and reoperation-free rate (B) between VS (solid line) and Fontan (dotted line) groups. of postoperative survival and exercise capacity.12,13 How- the atrioventricular valve is a crucial criterion for VS.7 Of ever, despite the improved postoperative outcomes, the in- the 5 VS patients in the AVVRϩ group in our series, there trinsic characteristics of the Fontan circulation limit the were preoperative concerns about the atrioventricular valve advantages and also raise significant postoperative con- in 2, moderate regurgitation in 1, and significant straddling cerns, such as an increasing prevalence of arrhythmias, of a left-sided atrioventricular valve in 1. In addition to a heart failure, and protein-losing enteropathy.14 Furthermore, pressure-dependent shift of the new septum toward the new abnormal cardiac autonomic nervous activity and activated right-sided ventricle, the spiral septum may have also neurohumoral factors are also common in Fontan patients,15 caused some geometrical distortion of the valve in some reflecting increased morbidity and mortality. In a large Holmes hearts. Two patients had residual shunts through the retrospective study of patients with DILV after Fontan re- newly created septum, and 1 patient required pacemaker pair, the 20-year survival rate was 69%.16 In addition, in that implantation because of complete atrioventricular block af- study, the prevalence of postoperative reoperation, atrial ter VS. Possibly, we could have avoided AVVR in some flutter, protein-losing enteropathy, and thrombotic events patients by using stricter selection criteria and/or different was 49%, 57%, 9%, and 6%, respectively. So far, there have surgical techniques. A single ventricle should be divided been few successful strategies for preventing these serious with a ratio of right- and left-sided new ventricles of 4:6 to complications, and cardiac transplantation is sometimes allow postoperative paradoxical motion of the new sep- necessary in patients who undergo failed Fontan proce- tum.18 However, this beneficial motion may diminish with dures.17 time because of material changes such as calcification, Given this background, biventricular repair (VS) which may adversely affect hemodynamics. In this respect, should be considered in patients with DILV when ana- early VS with a small patch for patients with small DILV tomic and hemodynamic criteria are met. In addition to may be advantageous because of compensatory develop- case reports of favorable long-term outcomes after VS, a 19 recent series of VS procedures for patients with DILV ment of the divided ventricles. Furthermore, 2-staged VS demonstrated relatively satisfactory outcomes in appro- may avoid not only this paradoxical motion but also atrio- 20 priately selected patients on the basis of the anatomic ventricular block. conditions and the timing of the procedures.5–7 In fact, Pacemaker implantation after VS had no significant ad- mortality at our institute decreased from 43% (6 of 14) in verse impact on exercise capacity, although our patient the first decade to 25% (2 of 8) in the second decade, number was small. The VVI mode was used in 3 patients in ϩ although VS was not done after 1993. Initially, a volume- the AVVR group to avoid hemodynamic deterioration in loaded left ventricle, 2 equally developed atrioventricular the event of supraventricular tachyarrhythmias. Such ar- valves, and/or elevated pulmonary artery resistance were rhythmias may be frequent in patients with severe atrioven- our criteria for VS in patients with DILV. The significant tricular regurgitation after VS. Once again, strict selection recent advances in perioperative management, improved criteria may help reduce the incidence of AVVR, decrease diagnostic detail provided by high-resolution echocardi- the number of VVI-mode pacemaker implantations, and ography and other modalities, and the association of poor improve exercise capacity. exercise capacity with late mortality in adult patients with congenital heart disease8 support renewed consideration of VS. The high exercise capacity in selected VS Acknowledgment: We are grateful to Drs. Peter M. Olley, patients is an attractive outcome, and VS should always adjunct professor of pediatrics, Sapporo Medical Univer- be considered when managing patients with DILV. sity, and Setsuko Olley for assistance in preparing this How can AVVR be avoided? Well-preserved function of report. Congenital Heart Disease/Exercise Capacity After Ventricular Septation 1761

1. McGoon DC, Danielson GK, Ritter DG, Wallace RB, Maloney JD, 12. Julsrud PR, Weigel TJ, Van Son JA, Edwards WD, Mair DD, Driscoll Marcelletti C. Correction of the univentricular heart having two atrio- DJ, Danielson GK, Puga FJ, Offord K. Influence of ventricular mor- ventricular valves. J Thorac Cardiovasc Surg 1977;74:218–226. phology on outcome after the Fontan operation. Am J Cardiol 2000; 2. Feldt RH, Mair DD, Danielson GK, Wallance RB, McGoon DC. 86:319–323. Current status of the septation procedure for univentricular heart. 13. Ohuchi H, Yasuda K, Hasegawa S, Miyazaki A, Takamuro M, J Thorac Cardiovasc Surg 1981;82:93–97. Yamada O, Ono Y, Uemura H, Yagihara T, Echigo S. Influence of 3. Franklin RCG, Spiegelhalter DJ, Filho RR, Macartney FJ, Anderson ventricular morphology on aerobic exercise capacity in patients after RH, Rigby ML, Deanfield JE. Double-inlet ventricle presenting in the Fontan operation. J Am Coll Cardiol 2001;37:1967–1974. infancy. III. Outcome and potential for definitive repair. J Thorac 14. Driscoll DJ, Offord KP, Feldt RH, Schaff HV, Puga FJ, Danielson GK. Cardiovasc Surg 1991;101:924–934. Five- to fifteen-year follow-up after Fontan operation. Circulation 4. Bando K, Turrentine MV, Park HJ, Sharp TG, Scavo V, Brown JW. 1992;85:469–496. Evolution of the Fontan procedure in a single center. Ann Thorac Surg 15. Ohuchi H, Takasugi H, Ohashi H, Yamada O, Watanabe K, Yagihara 2000;69:1873–1879. T, Echigo S. Abnormalities of neurohormonal and cardiac autonomic 5. Naito Y, Fujiwara K, Komai H, Uemura S. Midterm results after nervous activities relate poorly with functional status in Fontan pa- ventricular septation for double-inlet left ventricle in early infancy. tients. Circulation 2004;110:2601–2608. Ann Thorac Surg 2001;71:1344–1346. 16. Earing MG, Cetta F, Driscoll DJ, Mair DD, Hodge DO, Dearani JA, 6. Nomura K, Kurosawa H, Arai T. A 30-year follow-up after ventricular Puga FJ, Danielson GK, O’Leary PW. Long-term results of the Fontan septation: The first and the present. Ann Thorac Surg 2002;74:1237–1238. Am J Cardiol 7. Margossian RE, Solowiejczyk D, Bourlon F, Apfel H, Gersony WM, operation for double-inlet left ventricle. 2005;96:291– Hordof AJ, Quaegebeur J. Septation of the single ventricle: revisited. 298. J Thorac Cardiovasc Surg 2002;124:442–447. 17. Bernstein D, Naftel D, Chin C, Addonizio LJ, Gamberg P, Blume ED, 8. Diller GP, Dimopoulos K, Okonko D, Li W, Babu-Narayan SV, Broberg Hsu D, Canter CE, Kirklin JK, Morrow WR. Pediatric heart transplant CS, Johansson B, Bouzas B, Mullen MJ, Poole-Wilson PA, et al. Exercise study. Outcome of listing for cardiac transplantation for failed Fontan: intolerance in adult congenital heart disease. Comparative severity, cor- a multi-institutional study. Circulation 2006;114:273–280. relates, and prognostic implication. Circulation 2005;112:828–835. 18. Nakazawa M, Aotsuka H, Imai Y, Kurosawa H, Fukuchi S, Satomi 9. Van Praagh R, Ongley PA, Swan HJC. Anatomic types of single or G, Takao A. Ventricular volume characteristics in double-inlet left common ventricle in man: morphologic and geometric aspects of sixty ventricle before and after septation. Circulation 1990;81:1537– necropsied cases. Am J Cardiol 1964;13:367–386. 1543. 10. Ohuchi H, Nakajima T, Kawade M, Matsuda M, Kamiya T. Measure- 19. Shirakura R, Kawashima Y, Hirose H, Matsuda H, Shimazaki Y, Sano ment and validity of the ventilatory threshold in patients with congen- T. Autopsy findings 14 years after septation for single ventricle. Ann ital heart disease. Pediatr Cardiol 1996;17:7–14. Thorac Surg 1989;48:124–125. 11. Jones NL. Clinical Exercise Testing. 3rd ed. Philadelphia, Pennsylva- 20. Ebert PA. Staged partitioning of single ventricle. J Thorac Cardiovasc nia: Saunders, 1988:165–174. Surg 1984;88:908–913. Cardiac Function Before and After Surgery for Pectus Excavatum

Warren G. Guntheroth, MD*, and Philip S. Spiers, PhD

A 2006 meta-analysis concluded that thoracic surgery for pectus excavatum (PE) significantly improves cardiovascular function. However, that analysis was flawed by a high level of heterogeneity in the outcomes and inappropriate methods in 5 of the 8 publications analyzed. Therefore, a search of the published research from 1965 to the present was conducted, and only 5 publications were found that reported studies of cardiac function before and after operation, including 118 patients and 82 unoperated controls. Cardiac function was studied most frequently by echocardiography, despite the limitations imposed by the abnormal anatomy of pectus excavatum, but only studies that did not report cardiac or left ventricular dimensions or output were excluded. Studies using indirect estimates on the basis of oxygen pulse, which depends on several other variables, were not included. No improvements were found in left ventricular size, stroke volume, and cardiac output after surgery in 4 of 5 studies, using radionuclides, 2-dimensional echocardiography, radiographic planimetry, and cardiac output by the Fick method. Only a single study, with volumes calculated by squaring the diameter of the left ventricle from M-mode echocardiography, reported an increase (22%) in left ventricular stroke volume after operation, but that increased (17%) in the investigators’ unoperated controls. This and 2 other studies used in this meta-analysis were also included in a meta-analysis conducted by Malek et al. In a fourth study, Malek et al included only the first study that found an improvement, but the final study reported no improvement. In conclusion, there is no reliable documentation of improved cardiac function from thoracic surgery for pectus excavatum. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1762–1764)

In 1963, Polgar and Koop1 expressed concern over the diac status, even at rest, it is not a stand-alone indicator of number of operations for pectus excavatum (PE) that were cardiac performance. Morshuis et al6 found a dissociation being performed and whether they were justified by objec- between oxygen consumption and maximal work accom- tive measures of improvement. Forty-three years later, we plished. Maximal heart rate and maximum oxygen uptake find 2 published meta-analyses by Malek et al2,3 of func- can be changed independently by motivation and pulmonary tional outcomes for PE after thoracic surgery that found no function, as well as fitness, and do not provide a specific improvement in pulmonary data2 but significant improve- statement on cardiac status. ment in cardiovascular function.3 The pulmonary analysis Three studies8–10 of of cardiovascular testing included by was based on 12 studies with a total of 313 patients, and the Malek et al2,3 were based on echocardiographic studies. tests used were relatively homogenous, satisfying the crite- Feigenbaum et al’s11 2004 textbook on echocardiography 4 3 ria for a meta-analysis. In contrast, Malek et al’s meta- warns that the accuracy of left ventricular dimensions and analysis of cardiovascular function included only 8 publi- function is subject to anatomic limitations, specifically PE, cations, and the tests were heterogenous and sometimes imposed on conventional echocardiographic windows, a inappropriate. We performed our own review of the pub- problem that is obvious to any sonographer when attempt- lished research and critiqued the citations of Malek et al,2,3 ing a study on a patient with a funnel-shaped precordium. concentrating on direct cardiac performance rather than Although we included 2 studies based on echocardiogra- derivatives of exercise performance. phy,8,9 we excluded 1 of the echocardiographic reports10 in our synthesis that inferred cardiovascular function from Methods only the right ventricular shape and function and lacked any Methods were inadequate in 3 studies5–7 included by Malek data on left ventricular stroke volume or cardiac indexes. In et al,2,3 because they were derived from only exercise per- short, we challenge the statistical conclusion in Malek et al’s3 formance. Specifically, oxygen pulse is derived from 2 report on the improvement of cardiac function because 5 of variables, maximal oxygen consumption and maximal heart their 8 studies5–7,10,11 used inappropriate methods. rate. Although heart rate may certainly be affected by car- Another citation by Malek et al2,3 that we found inappropriate was a study by Sigalet et al,9 insofar as a subsequent publication from that group12 containing more sub- Department of Pediatrics, Division of Cardiology, University of Wash- jects reached the opposite conclusion. All in all, only 3 of ington School of Medicine, Seattle, Washington. Manuscript received 2,3 November 2, 2006; revised manuscript received and accepted January 22, the studies cited by Malek et al seem to have been ap- 8,13,14 8 2007. propriate, and 1 of those was based on only M-mode *Corresponding author: Tel: 206-543-3186; fax: 206-543-3184. echocardiography, based on squaring the diameter for vol- E-mail address: [email protected] (W.G. Guntheroth). ume. However, we have included that study.

Table 1 Cardiac function in ﬁve series of operated pectus excavatum Authors Year No. cases Interval Followed Method Results

Gyllensward et al15 1975 37 Op 10 yrs TeleXray No change 38 Unop 10 yrs TeleXray No change Bawazir et al12 2005 20 Op 3–21 mo Echo CI Ϫ4% Hu et al8 2000 40 Op 4.2 yrs M-mode Echo SVI ϩ22% Controls* 4.2 yrs M-mode Echo SVI ϩ17% Peterson et al13 1985 13 Op 6 mo Radionuclides CI No change Wynn14 1990 6 Op 6–21 mo Gas CI No change 4 Non-op 6–21 mo Gas CI ϩ8%

* No numbers were provided by Hu et al8 for their controls. References 8, 15, and 16 were also included by Malek et al.3 CI ϭ cardiac output index; Echo ϭ echocardiogram; gas ϭ acetylene–helium; Op ϭ operated; SVI ϭ stroke volume index; TeleXray ϭ radiograms from 6 to 7 feet; Unop ϭ unoperated.

We then conducted our own search for all published We begin by reviewing a 1975 Swedish study by Gyl- series including Ն5 subjects that reported pre- and postop- lensward et al,15 who performed 10-year follow-up of un- erative cardiac function of patients operated on for PE in operated patients with PE (n ϭ 38) as well as operated PubMed (National Library of Medicine, Bethesda, Mary- patients (n ϭ 37), the only such study ever reported. Other land) from 1965 (as far back as the database now extends) published series we included varied from only 6 months to to the present (January 1, 2007). When a center published 4.2 years of follow-up. The Swedish study introduced a more than once on a series of cases,9,12 we included only the quantification of the severity of PE, the sternovertebral later publication with the larger number of subjects. We separation in centimeters, on the basis of lateral radiologic excluded reports of cardiac function based on only exercise measurements. The unoperated patients with PE showed as too indirect (see later), but we included echocardio- improvement in this measurement with increasing age, as graphic studies if they provided data on left ventricular or well as improvement in pulmonary measurements consis- cardiac output. For each published series included (Table 1), tent with growth.15 The operated group had slightly lower we recorded the method and functional data used and cal- pulmonary measurements than the unoperated group, attrib- culated percentage changes. The intervals between pre- and uted to restriction secondary to the surgery. Total cardiac postoperative studies were also included because of possible volume was determined by planimetry from frontal and acute effects of the operation, as well as the effects of lateral tomography by electrocardiographically triggered 15 growth, because the study by Gyllensward et al revealed teleradiography (to achieve consistent phase of respiration that functional improvement occurred over time in subjects and diastole and to avoid the magnification effects of a with PE who were unoperated. Cardiac function in the closer tube).17 In the combined 75 subjects, only a single published research was predicted most frequently using case of heart enlargement was observed, in an operated echocardiography,8–10,12,16 but we excluded the study by patient, and it was mild.15 Exercise capacity was measured Sigalet et al,9 included by Malek et al,2,3 because those by bicycle ergometry18 (which is less frightening to children patients were included in a subsequent larger series by than a machine-driven treadmill). Wahlund18 avoided max- Bawazir et al12 that we included. Two publications10,16 re- imal performance as too dependent on motivation and in- ported only right ventricular function, with no data on left ventricular function or size, and were therefore not instead measured the work performed by subjects at a heart cluded, although Kowalewski et al’s10 study was included rate of 170 beats/min. By comparing work performed with 15 by Malek et al.2,3 a nomogram, Gyllensward et al found normal perfor- Only 1 study using radionuclide, the “gold standard,” mance in all 75 patients with PE, in the unoperated and was reported13 that provided a cardiac index (output/body postoperative patients. They compared their various func- surface area). One study used inhaled gases using the Fick tional results among different surgical techniques used over principle,14 and in 1 study, heart volume was derived from the 10 years and found no significant difference in out- 2-dimensional radiographic planimetry.15 comes. Bawazir et al12 reported in 2005 on 47 patients, but only 20 with quantitative data. Using the pre- versus postopera- Results tive cardiac index as determined by 2-dimensional echocar- The PubMed response to a search for studies of PE was a diography, the index decreased by 4%. This population list of nearly 1,600 publications. We found a total of only 5 included the patients reported earlier by Sigalet et al9 as publications8,9,13–15 that presented primary data on cardiac having an improved cardiac index of 16% postoperatively. function before and after surgery, containing 118 patients Malek et al’s3 2006 meta-analysis did not include Bawazir and 82 unoperated subjects or controls (Table 1). We in- et al’s12 report. cluded data from 3 studies8,13,14 that Malek et al3 included Hu et al8 in China in 2000 used only M-mode echocar- on the basis presented in “Methods,” and we also added 2 diography preoperatively and 4.2 years postoperatively in publications.12,15 40 patients. They reported that indexed left ventricular 1764 The American Journal of Cardiology (www.AJConline.org) stroke volume had increased by 22%, but their control group the omission of 2 important reports.12,15 Finally, they used had an improvement of 17%. The 2 calculations involved data from an earlier publication9 from a center that showed squaring the diameter of the left ventricle, because they had improved cardiac function rather than from that center’s no access to 2-dimensional echocardiography or planimetry. later publication,12 which had an augmented population and We do not regard the difference as significant, because of a modest decrease after surgery for PE. Thus, the published the limitations of their method. data fail to show convincing improvement in either pulmo- Peterson et al13 performed the only cardiac study that nary or cardiac function after thoracic surgery for PE, and used first-pass radionuclides in patients with PE, before and therefore, no advantage over plastic surgery.19 6 months after surgical repair in 13 patients. (This study was 2,3 included in Malek et al’s analysis.) The operation did not 1. Polgar G, Koop CE. Pulmonary function in pectus excavatum. Pedi- change their cardiac index at rest or during exercise. Right atrics 1963;32:209–215. ventricular end-diastolic volume increased postoperatively, 2. Malek MH, Berger DE, Marelich WD, Coburn JW, Beck TW, Housh but this had no effect on cardiac output and exercise per- TJ. Pulmonary function following surgical repair of pectus excavatum: formance. a meta-analysis. Eur J Cardiothorac Surg 2006;30:637–643. 3. Malek MH, Berger DE, Housh TJ, Marelich WD, Coburn JW, Beck 14 Our last series, by Wynn et al, was also included in TW. Cardiovascular function following surgical repair of pectus ex- Malek et al’s2,3 study. They studied 6 patients before and 6 cavatum. A metaanalysis. Chest 2006;130:506–516. to 21 months after repair of PE by applying the Fick prin- 4. Higgins JPT, Thompson SG, Deeks JD, Altman DG. Measuring in- ciple using acetylene-helium inhalation. They found no consistency in meta-analysis. BMJ 2003;327:557–560. change in the cardiac index. Interestingly, they also studied 5. Cahill JL, Lees GM, Robertson HG. A summary of preoperative and postoperative cardiorespiratory performance in patients undergoing 4 unoperated patients with PE over the same interval and pectus excavatum and carinatum repair. J Pediatr Surg 1984;19: found an increase in the cardiac index of 8%. 430–433. 6. Morshuis WJ, Folgering HT, Barentsz JO, Cox AL, van Lier HJ, Discussion Lacquet LK. Exercise cardiorespiratory function before and one year after operation for pectus excavatum. J Thorac Cardiovasc Surg 1994; Malek et al2 found “no significant improvement” in pulmo- 107:1403–1409. nary function on the basis of 12 reports with a total of 313 7. Quigley PM, Haller JA Jr, Jelus KL, Loughlin GM, Marcus L. Car- patients. Their report does not provide raw data, but using diorespiratory function before and after corrective surgery in pectus excavatum. J Pediatr 1996;128:638–643. the weighted mean from their references, we found that 67% 8. Hu T, Liu W, Jiang X, Wei F, Tang Y, Wu X, Luo Q, Liu M. Modified of all their patients had diminished pulmonary function, sternal elevation for children with pectus excavatum. Chin Med J 17% had improved pulmonary function, and 16% had no (Engl) 2000;113:451–454. change. In the absence of pulmonary improvement, the 9. Sigalet DL, Montgomery M, Harder J. Cardiopulmonary effects of defense of thoracic surgery for PE would then depend on closed repair of pectus excavatum. J Pediatr Surg 2003;38:380–385. objective data of cardiac improvement after the operation. 10. Kowalewski J, Brocki M, Dryjanski T, Zolynski K, Kotyysz R. Pectus 13 excavatum: increase of right ventricular systolic, diastolic, and stroke Radionuclide studies are more reliable than echocardio- volumes after surgical repair. J Thorac Cardiovasc Surg 1999;118: graphic estimates for right-sided cardiac volumes.10,16 The 92–93. latter are less reliable than left ventricular volume deter- 11. Feigenbaum H, Armstrong WF, Ryan T. Feigenbaum’s Echocardiog- mined by echocardiography that uses the formula based on raphy. 6th ed. Philadelphia, Pennsylvania: Lippincott Williams & a regular geometric form (an ellipse of revolution), and the Wilkins, 2004:689. 12. Bawazir OA, Montgomery M, Harder J, Sigalet Dl. Midterm evalua- right ventricle is substantially more complicated. An addition of cardiopulmonary effects of closed repair for pectus. J Pediatr tional limitation of the echocardiographic determination of Surg 2005;40:863–867. left ventricular volume is that the chest deformity of PE 13. Peterson RJ, Young WG Jr, Godwin D, Sabiston DC, Jones RH. literally interferes with transducer access to the standard Noninvasive assessment of exercise cardiac function before and after positions and therefore compromises the comparison to nor- pectus excavatum repair. J Thorac Cardiovasc Surg 1985;90:251–260. mal standards. Nevertheless, we have included echocar- 14. Wynn SR, Driscoll DJ, Ostrom NK, Staats BA, O’Connell EJ, Mot- tram CD, Telander RL. Exercise cardiorespiratory function in adoles- diographic studies, although the M-mode method used by cents with pectus excavatum. Observations before and after operation. Hu et al8 is of dubious validity because the operated J Thorac Cardiovasc Surg 1990;99:41–47. patients and controls had large “improvements” in stroke 15. Gyllensward A, Irnell L, Michaelsson M, Qvist O, Sahlstedt B. Pectus volume index, namely, 22% and 17%, respectively. Among excavatum. A clinical study with long term postoperative follow-up. the 3 studies we have in common with Malek et al3 as the Acta Paediatr Scand 1975;255(suppl):1–14. 8 16. Coln E, Carrasco J, Coln D. Demonstrating relief of cardiac compres- basis for our conclusions, Hu et al’s is the only study that sion with the Nuss minimally invasive repair for pectus excavatum. 3 supports the conclusions made by Malek et al, and the J Pediatr Surg 2006;41:683–686. relatively large number of subjects in Hu et al’s8 study 17. Jonsell SA. A method for the determination of the heart size by presumably influenced their calculations. All 4 of our other teleroentgenography. (A heart volume index.) Acta Radiol 1939;20: sources found no change or decreased function. 325–340. The difference in our results from those in Malek et al’s3 18. Wahlund H. Determination of the physical working capacity. Acta Med Scand 1948;215(suppl):1–78. meta-analysis, we suggest, is cause by the misuse of a 19. Marks MW, Iacobucci J. Reconstruction of congenital chest wall legitimate statistical test in the presence of inadequate deformities using solid silicone only prostheses. Chest Surg Clin N Am power, their inclusion of nonspecific derived estimates, and 2000;10:341–355. Superior Vena Cava Syndrome Induced by Endocardial Defibrillator and Pacemaker Leads

Arash Aryana, MS, MDa,*, Kristi D. Sobota, MDb, Dennis J. Esterbrooks, MDc, and Andrew I. Gelbman, DO, PhDd

Two cases of superior vena cava syndrome induced by endocardial deﬁbrillator and pacemaker leads are described. The 2 patients had histories of multiple endocardial leads and device upgrades and venous thrombosis. The ﬁrst patient was treated with laser lead extraction followed by percutaneous venoplasty and stenting. The second patient was treated conservatively with long-term anticoagulation. The 2 patients had symptomatic reduction. In conclusion, superior vena cava syndrome induced by transvenous leads is an uncommon but serious complication. Anticoagulation can be effective in select patients, but in severe cases, thrombolytic therapy or surgical or percutaneous intervention may be required. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99:1765–1767)

Serious thromboembolic complications history of venous thromboembolism re- heart failure, and symptomatic brady- related to endocardial implantable car- quiring chronic oral anticoagulation cardia, with the placement of a single- dioverter-defibrillator (ICD) and pace- with warfarin. His last ICD generator chamber pacemaker 33 years earlier. maker leads have been reported in 0.6% exchange was 3 months previous. At Since then, she had received an upgrade to 3.5% of cases.1 Superior vena cava the time, new atrial and ventricular to a dual-chamber device, with several (SVC) syndrome is generally an un- leads were implanted without extraction endocardial lead replacements and im- common but serious complication oc- of the 3 preexisting leads. Since then, plants, with the most recent upgrade 5 curring in Ͻ0.1% of patients.2,3 The un- the patient had noted a gradual decrease years earlier. She also had a history of derlying mechanism is believed to be in exercise tolerance, worsening dizzi- deep venous thrombosis previously lead-induced mechanical stress trigger- ness, and facial swelling. His physical treated with oral anticoagulation ther- ing vascular wall inflammation, fibrosis, examination results were remarkable apy. Examination demonstrated mild thrombosis, and ultimately obstruction.4 for facial, periorbital, and bilateral up- fullness over the left supraclavicular Here, we describe 2 cases of SVC syn- per extremity edema; jugular venous fossa, without jugular venous distention drome induced by endocardial leads, distention; and fullness of the supracla- or edema. Because of the finding of a managed successfully using 2 different vicular fossae. A computed tomo- lung nodule on a routine chest x-ray, a approaches. graphic scan of the chest (Figure 1) computed tomographic scan of the chest demonstrated the absence of blood flow was performed. It showed the absence Case Descriptions in the right internal jugular and right of flow of contrast in the SVC around the pacemaker leads, with patent but A 59-year-old man presented with dys- and left innominate veins, as well as the SVC. There was total occlusion of the engorged left hemiazygos system and pnea and facial swelling. His past car- marked venous collateralization (Figure diovascular history was remarkable for SVC with extensive venous collateralization and major venous return via the 2). A diagnosis of chronic SVC syn- ischemic cardiomyopathy, sudden car- drome due to multiple endocardial leads posterior intercostal veins to the azygos diac death, and symptomatic bradycar- was made. The patient was managed vein. The patient was diagnosed with dia status after the implantation of a medically with long-term oral anticoagu- subacute SVC syndrome caused by dual-chamber pacemaker with an up- lation, which resulted in marked improve- multiple transvenous leads. The man- grade to an ICD, with multiple genera- ment in her effort-related dyspnea. tor exchanges and endocardial lead im- agement of his SVC syndrome included plants and explants. There was also a the laser extraction of 3 of the 5 ICD leads, the insertion of new endocardial Comments atrial and ventricular leads, and multi- Infection and thrombosis account for aCardiac Arrhythmia Service, Massachusetts ple balloon venoplasties of the right and most cases of nonmalignant SVC syn- General Hospital, Boston, Massachusetts; bDe- left innominate veins and SVC, fol- drome.3 SVC syndrome related to endo- partment of Radiology, University of North Caro- lowed by the deployment of 3 stents cardial ICD and pacemaker leads is a lina, Chapel Hill, North Carolina; and cDivision extending bilaterally into the SVC in a rare but potentially serious complica- d of Cardiology, Department of Medicine, and De- double-barrel configuration. These in- tion.2–5 The diagnostic test of choice is partment of Radiology, Creighton University terventions resulted in rapid symptom- helical computed tomography with bi- Medical Center, Omaha, Nebraska. Manuscript atic relief. received November 7, 2006; revised manuscript lateral upper extremity contrast injec- 1,3 received and accepted January 17, 2007. A 64-year-old woman presented tion. The mechanism is believed to be *Corresponding author: Tel: 617-726-5036; with long-standing mild dyspnea on ex- mechanical stress induced by trans- fax: 617-726-7519. ertion, with a history of rheumatic heart venous leads, eliciting vascular wall in- E-mail address: [email protected] disease, nonischemic cardiomyopathy, flammation and fibrosis and ultimately

Figure 1. Anterior-posterior (A) and oblique (B) 3-dimensional volume-rendered images from a contrast-enhanced computed tomographic scan demonstrating numerous dilated superﬁcial veins over the right chest and neck.

Figure 2. Three-dimensional volume-rendered images from anterior (A) and lateral (B) projections demonstrating markedly dilated and tortuous superficial, paraspinal, and intercostal veins of the left hemithorax. leading to venous thrombosis and oc- temporary endocardial pacemaker wires tory of venous thrombosis.6,7 In conclusion.4 Although no clear risk factors before the implantation of a permanent trast, long-term anticoagulation therapy have been identified, several predictors device, the presence of multiple endo- seems to offer a protective effect.7 of venous occlusion in this setting have cardial leads, the retention of severed When managing patients with trans- been reported. These include a history leads, lead infection, the use of dual- venous lead-related SVC syndrome, an- of device upgrades, the presence of coil leads, hormone therapy, and a his- ticoagulation alone can also be an effec- Case Report/SVC Syndrome Caused by Endocardial Leads 1767 tive therapy in select patients.2,3,5,8 stents and the vascular wall remain defibrillators. J Interv Card Electrophysiol However, in those with more severe largely unknown.3,4,6 2005;13:9–19. cases, local and systemic thrombolytic 8. Dayal R, Bernheim J, Clair DG, Mousa AY, Hollenbeck S, DeRubertis B, McKinsey J, 5,8 therapy have been advocated. Patients 1. Barakat K, Robinson NM, Spurrell RA. Morrissey NJ, Kent KC, Faries PL. Multimo- with lead infection should also be Transvenous pacing lead-induced thrombo- dal percutaneous intervention for critical ve- treated with antibiotics; the most com- sis: a series of cases with a review of the nous occlusive disease. Ann Vasc Surg 2005; literature. Cardiology 2000;93:142–148. 19:235–240. monly isolated organism is coagulase- 2. Lin CT, Kuo CT, Lin KH, Hsu TS. Superior 9 9. Vogt PR, Sagdic K, Lachat M, Candinas R, negative Staphylococcus. However, vena cava syndrome as a complication of von Segesser LK, Turina MI. Surgical man- this treatment is rarely sufficient as the transvenous permanent pacemaker implanta- agement of infected permanent transvenous tion. Jpn Heart J 1999;40:477–480. sole therapy, and lead extraction is of- pacemaker systems: ten year experience. 3. Bakir I, La Meir M, Degrieck I, Marien C, ten required.9,10 When medical therapy J Card Surg 1996;11:180–186. Van den Hauwe K, Wellens F. Contralateral 10. Baddour LM, Bettmann MA, Bolger AF, Ep- is ineffective, surgical or percutaneous replacement of pacemaker and leads follow- 3–9 intervention becomes necessary. Sur- ing laser sheath extraction and concomitant stein AE, Ferrieri P, Gerber MA, Gewitz MH, gical treatment with SVC reconstruc- stenting for superior vena cava syndrome. Jacobs AK, Levison ME, Newburger JW, et tion using a spiral vein bypass graft was Pacing Clin Electrophysiol 2005;28: al. Nonvalvular cardiovascular device-related 1131–1134. infections. Clin Infect Dis 2004;38: first proposed in 1974, and since then, it 1128–1130. has demonstrated effective long-term 4. Park HW, Kim W, Cho JG, Kang JC. Multi- ple pacing lead-induced superior vena cava 11. Doty JR, Flores JH, Doty DB. Superior vena 5,11,12 results. Endovascular recanaliza- syndrome: successful treatment by balloon cava obstruction: bypass using spiral vein tion using percutaneous intervention angioplasty. J Cardiovasc Electrophysiol graft. Ann Thorac Surg 1999;67:1111–1116. has also been shown to be safe and 2005;16:221–223. 12. Kalra M, Gloviczki P, Andrews JC, Cherry promising, with minimal procedural or 5. Ruge H, Wildhirt SM, Poerner M, Mayr N, KJ, Bower TC, Panneton JM, Bjarnason H, Noel AA, Schleck C, Harmsen WS, et al. clinical complications.3,12,13 Prelimi- Bauernschmitt R, Martinoff S, Lange R. Se- vere superior vena cava syndrome after trans- Open surgical and endovascular treatment of nary studies so far demonstrate excel- venous pacemaker implantation. Ann Thorac superior vena cava syndrome caused by non- lent short-term patency rates with the Surg 2006;82:e41–e42. malignant disease. J Vasc Surg 2003;38:215– percutaneous approach, although its 6. Slonim SM, Semba CP, Sze DY, Dake MD. 223. long-term efficacy may be limited by Placement of SVC stents over pacemaker 13. Qanadli SD, El-Hajjam M, Mignon F, de recurrent stenosis and the need for re- wires for the treatment of SVC syndrome. J Kerviler E, Rocha P, Barre O, Chagnon S, Lacombe P. Subacute and chronic benign su- 12,13 Vasc Interv Radiol 2000;11:215–219. peat intervention. Also, the long- 7. Rozmus G, Daubert JP, Huang DT, Rosero S, perior vena cava obstructions: endovascular term effects on the ICD or pacemaker Hall B, Francis C. Venous thrombosis and treatment with self-expanding metallic stents. leads due to compression between stenosis after implantation of pacemakers and AJR Am J Roentgenol 1999;173:159–164. Proceedings of the Editorial Board Meeting of The American Journal of Cardiology on 26 March 2007

he 2007 meeting of the editorial board of The American The numbers of manuscripts TJournal of Cardiology (AJC)was held on 26 March submitted and published in the 2007 in New Orleans, Louisiana, at the time of the Annual AJC 1983 to 2006, the period of Scientiﬁc Sessions of The American College of Cardiology. the present editorship, is shown in The meeting’s purpose was to review the AJC publication Table 4. results for 2006, to recognize particularly those AJC board There has been a considerable members who reviewed the most manuscripts in 2006, and increase in the number of manu- to receive criticisms and suggestions from board members scripts submitted in the past 2 on how to improve the journal. The meeting went as fol- years. From 1992 to 2004 (12 lows: years) the number of manuscripts submitted to the regular issues of 1. Introduction of new editorial board members:These the AJC (excluding those submit- are listed in Table 1. ted to the Supplement issues) ranged from about 1,800 to 2. AJC board members reviewing the most manuscripts 2,200 (Table 4). In 2005, the number rose to 2,661 manu- in 2006:Their names are listed in Table 2. It is not the scripts, a 21% increase compared with the 2109 submitted editor’s intention to send any board member 16 manu- in 2004. The 3,061 manuscripts submitted in 2006 repre- scripts to review a year. We owe Dr. Jeroen J. Bax sents a 13% increase compared with the 2,661 submitted in hearty thanks, and we promise to go easy on him in 2007. 3. Number of manuscripts submitted and accepted in Table 3 2006: Of the 3,082 manuscripts received in 2006 Manuscripts submitted to The AJC in 2006 (these do not include Readers’ Comments submitted), Total 3,082 (100%) 653 (21%) were accepted, 2,408 (Ͼ78%) were de- Withdrawn 21 clined, and 21 (Ͻ1%) were withdrawn (Table 3). Accepted 653 (21%) Declined 2,408 (79%) Probably, the 21 withdrawn would not have been accepted. Table 4 Numbers of manuscripts submitted and published in The American Journal of Cardiology 1983–2006 Year Number of Manuscripts Number of Manuscripts Percent Table 1 Submitted Published or Accepted Accepted New board members 2006 1983 1,234 643 52% Antonio Abbatte 1984 1,605 747 46% J. Dawn Abbott 1985 1,707 645 38% Yuling Hong 1986 1,574 616 39% Vincent E. Friedewald 1987 1,525 695 46% Charles Maynard 1988 1,496 636 42% Darren K. McGuire 1989 1,740 699 40% Sebastian T. Palmeri 1990 1,717 662 38% Maurice E. Sarano 1991 1,615 680 42% Ron Waksman 1992 1,873 664 35% 1993 1,997 619 31% 1994 1,783 604 34% Table 2 1995 1,844 668 36% Top AJC board reviewers in 2006 1996 1,930 701 36% Name Number 1997 1,898 768 40% Reviewed 1998 1,992 631 31% 1999 2,170 703 32% Jeroen J. Bax 16 2000 2,226 630 28% Martin A. Alpert 11 2001 2,068 682 33% Don Poldermans 11 2002 2,171 683 31% George A. Diamond 10 2003 2,190 783 36% Charles Landau 10 2004 2,109 842 39% Gregory Y. H. Lip 10 2005 2,661 984 37% Hector O. Ventura 10 2006 3,061 653 21%

Table 5 Table 6 Number of manuscripts received and accepted from non-USA countries Number of editorial pages and articles published in The American January 1 to December 31, 2006 Journal of Cardiology in 2006 (volumes 97 & 98) (non-Symposium issues) Country Number Number Submitted Accepted Jan 1–Dec 15 (%) Volumes 97 & 98 Italy 236 37 (16%) Editorial pages—Total 3,602 Japan 232 26 (11%) Articles 3,406 Turkey 142 8 (6%) Readers’ Comments (numbers) [replies] 65 (70) [1] The Netherlands 117 27 (23%) Staff and editorial board 48 Germany 116 14 (12%) Contents 69 United Kingdom 90 10 (11%) Instructions to Authors 14 China 85 5 (6%) Volume indexes 0 Spain 85 12 (14%) Articles—Total 695 Korea 84 10 (12%) Multipatient studies 640 Canada 82 16 (20%) Case reports 10 Greece 80 13 (16%) Reviews 16 Taiwan 76 7 (9%) Editorials 11 France 73 8 (11%) Editor’s Roundtable 1 Israel 62 13 (21%) Interviews 4 Brazil 46 5 (11%) From-the-Editor columns 4 Poland 37 4 (11%) Non-patient studies 9 Australia 31 5 (16%) Topics of articles 695 Switzerland 28 4 (14%) Coronary artery disease 313 (45%) Austria 26 1 (4%) Preventive cardiology 69 (10%) Finland 23 4 (17%) Arrhythmias and conduction disturbances 55 (8%) Norway 21 4 (19%) Heart failure 60 (9%) Belgium 20 5 (25%) Valvular heart disease 32 (5%) Sweden 20 2 (10%) Cardiomyopathy 27 (4%) Denmark 17 6 (35%) Congenital heart disease 30 (4%) Iran 17 1 (6%) Methods 16 (2%) Argentina 16 5 (31%) Miscellaneous 78 (11%) Hungary 16 0 (0%) Historical studies 3 (Ͻ1%) India 12 0 (0%) Cardiovascular pharmacology 1 (Ͻ1%) 29 other countries with under 86 4 (5%) Systemic hypertension 7 (1%) 10 submissions Interviews 4 (Ͻ1%)

2005. Thus, in the past 2 years (2005 and 2006), there has manuscript’s authors: Of the 3,061 manuscripts sub- been a 25% increase in the numbers of manuscripts submit- mitted in 2006, 1,194 (39%) provided names of po- ted compared with 2003 and 2004, when 2,190 and 2,109, tential reviewers, a much higher percentage than in respectively, were submitted. As a consequence, the num- previous years. Other journals, e.g., Circulation,also bers of manuscripts accepted in 2006, namely 21%, is a encourage this option. considerable drop from the percent in previous years. The Instructions to Authorsin the AJC urge submitting The reason for the sharp increase in numbers of manu- authors to suggest several potentially nonbiased reviewers scripts submitted during the past 2 years is probably due to located in cities other than those of the authors, or, in the several factors, including: (1) a change in the journal’s case of non-USA countries, potential reviewers residing in format, such that every manuscript starts on a separate page; countries other than their own. (2) the move to online submission and processing of manuscripts, and; (3) the decrease in the numbers of clinically 6. Number of editorial pages published, types of articles, relevant manuscripts accepted in competing US cardiologic and topics of articles published in the regular issues journals. of the AJC in 2006:A total of 3,602 editorial pages (non-advertising pages) were published in the regular 4. Sources of manuscripts submitted to the AJC in issues of the AJC in 2006 (Table 6), including 3,406 2006:Of the 3,061 manuscripts submitted in 2006, pages for articles, 65 pages for Reader’s Comments, 1,085 (35%) came from the USA, and 397 (37%) of and 131 pages (4%) for listings of staff and editorial them were accepted; 1,976 (65%) came from non- board, issue contents, and Instructions to Authors. USA countries, and 256 (13%) were accepted. The The volume indexes no longer are listed in the journal non-USA sources of the manuscripts submitted in but are available online. 2006 are listed in Table 5. 5. Numbers of manuscripts submitted to the AJC in 2006 Of the 695 articles published in 2006, 640 (92%) were with names of potential reviewers suggested by the multipatient studies, 10 (1%) case reports, 16 reviews, 15 1770 The American Journal of Cardiology (www.AJConline.org)

Table 7 Interviews published in The American Journal of Cardiology Eric Jeffrey Topol July 1, 1996 Harvey Stanley Hecht November 1, 2000 Wallace Bruce Fye III August 1, 1996 Myrvin Harold Ellestad December 1, 2000 James Thornton Willerson February 15, 1997 Melvin Mayer Scheinman March 1, 2001 Michael Ellis DeBakey April 1, 1997 James Stuart Forrester III December 1, 2001 Denton Arthur Cooley April 15, 1997 Carl John Pepine December 15, 2001 Joseph Stephan Alpert May 1, 1997 Kenneth Hardy Cooper February 1, 2001 John Willis Hurst February 15, 1998 Watkins Proctor Harvey February 15, 2001 Jesse Efrem Edwards April 1, 1998 Joseph Kayle Perloff March 1, 2002 John Webster Kirklin April 15, 1998 Charles Richard Conti March 15, 2002 Howard Bertram Burchell May 15, 1998 William Watts Parmley May 1, 2002 William Howard Frishman June 1, 1998 Dean Michael Ornish August 1, 2002 Robert Ogdon Bonow June 15, 1998 Dean Towle Mason December 15, 2002 Eugene Braunwald July 1, 1998 George Allan Beller January 15, 2003 Joseph Cholmondeley Greenﬁeld July 15, 1998 Leslie David Hillis February 1, 2003 David Coston Sabiston, Jr. August 1, 1998 Douglas P. Zipes April 1, 2003 Norman Mayer Kaplan August 15, 1998 Nanette Kass Wenger May 15, 2003 Robert McKinnon Califf September 1, 1998 Andrew Peter Selwyn June 15, 2003 Bernard John Gersh November 1, 1998 Arthur Garson, Jr. August 15, 2003 Dean James Kerlakes November 15, 1998 Edward David Frolich September 1, 2003 Jeffrey Michael Isner January 1, 1999 Magdi Habib Yacoub January 15, 2003 Scott Montgomery Grundy January 15, 1999 Robert A. Vogel April 1, 2004 Burton Elias Sobel February 1, 1999 Ferid Murad July 1, 2004 Robert Anothomy O’Rourke April 1, 1999 Steven Evan Nissen August 1, 2004 David Kempton Cartwright Cooper April 15, 1999 William Peter Castelli September 1, 2004 Spencer Bidwell King III May 1, 1999 Wallace Bruce Fye III January 1, 2005 Robert Roberts May 15, 1999 Anthony Nicolas DeMaria January 15, 2005 Eugene Austin Stead, Jr. September 15, 1999 Barry L. Zaret May 15, 2005 Bertram Pitt October 1, 1999 Lawrence Harvey Cohn March 15, 2006 Christopher John Dillon Packard November 15, 1999 Joseph Loscalzo April 1, 2006 Terje Rolf Pedersen November 15, 1999 Donald Carey Harrison May 1, 2006 Francis Robicsek June 1, 2000 Hollis Bryan Brewer June 15, 2006 Richard John Bing July 1, 2000 Barry Joel Maron May 1, 2007 Valentin Fuster July 15, 2000 Lawrence Sorrell Cohen 2007 Henry Arthur Solomon July 15, 2000

Table 8 Number of articles and editorial pages for articles and Readers’ Comments published in the Regular Issues of The AJC 1983 to 2006 Year Pages for Pages for Readers’ Total Number of Articles Number of Readers’ Articles Comments Comments 1983 3,130 27 3,157 643 53 1984 3,007 36 3,113 747 80 1985 2,623 21 2,602 645 40 1986 2,627 17 2,644 616 40 1987 2,810 23 2,833 695 45 1988 2,646 26 2,672 636 60 1989 2,903 19 2,922 699 36 1990 3,001 20 3,021 662 40 1991 3,165 38 3,203 680 59 1992 3,211 46 3,257 711 53 1993 2,890 37 2,927 650 64 1994 2,493 31 2,524 604 46 1995 2,570 34 2,604 668 52 1996 2,775 29 2,804 658 52 1997 3,328 32 3,360 826 45 1998 3,048 35 3,083 664 37 1999 3,015 38 3,053 680 42 2000 2,962 38 2,964 648 37 2001 3,862 37 2,899 701 39 2002 2,835 45 2,880 680 45 2003 2,982 35 3,017 763 32 2004 3,131 39 3,170 808 42 2005 3,242 43 3,285 736 49 2006 3,406 65 3,471 (5%1) 695 (6%2) 70 (30%1) Totals (24 years) 70,696 811 71,465 16,515 1,158 Table 9 Symposia in The American Journal of Cardiology in 2006 No. Date of Topic Sponsor Symposium Guest Number of Number of Interval (months) Publication Editors Articles Pages Symposium to Publication

A January 16 Dyslipidemia and inflammation AstraZeneca Paul M. Ridker 41 14 C April 17 Statin safety Abbott, AstraZeneca, Kos, James M. McKenney 14 97 9 Merck/Schering-Plough, Sanyko D April 26–28 Angioplasty summit 2006 TCT Asia Cardiovascular Research Seung-Jung Park 0 (abstracts) 106 0 Pacific Foundation, Korea Gary S. Mintz E May 8 Nonopioid analgesia McNeil J. Michael Gaziano 54025 C. Michael Gibson F May 22 Heart failure after myocardial infarction Pfizer, Vascular Biology Carl J. Pepine 540—

and Aldosterone blockage Working Group Arthur M. Feldman Editor the From G June 19 Bypass-vs-angioplasty in type 2 diabetes NHLBIϩNIDDK ϩ 7 Katherine M. Detre 865— mellitus pharmaceutical Robert L. Frye companies Saul Genuth H July 17 Vulnerable plaque ϩ patient (SHAPE) Pfizer Morteza Naghavi 316— Valentin Fuster Prediman K. Shah Erling Falk I August 21 Omega-3 fatty acids Reliant Michael H. Davidson 9 76 — J September 4 Trimetazidine Servier William C. Stanley 6 33 12 K September 18 Contrast-induced nephropathy GE Healthcare William Laskey 9 77 12 L October 2 Carvedilol-controlled release version GlaxoSmithKline Domenic A. Sica 10 69 — M October 22–27 Transcatheter Cardiovascular Therapeutics Abbott Vascular Martin B. Leon 0 (abstracts) 275 0 Gregg W. Stone N November 20 Platelet monitoring Accumetrics Christopher P. Cannon 7 38 — P December 4 Pleotrophic effects of statins Pfizer Peter Libby 6 41 Q December 18 Preventing myocardial infarction Bristol-Myers Squibb Christopher P. Cannon 64813 Sarofi-Aventis Deepak L. Bhatt 15 94 1062 9–25 (15) Excludes abstract Excludes abstract issues issues 1771 1772 The American Journal of Cardiology (www.AJConline.org)

Table 10 Number of symposia and the number of articles and pages in symposia editorials, 4 interviews, and 9 non-patient studies. The Ed- in The AJC 1983 to 2006 itor’s Roundtable—discussions by experts—were initiated in 2006, and 1 was published that year. Probably 15 or so Year Number of Number of Number of Symposia Articles Pages will be published in 2007. The names of the interviewees since this feature was initiated in 1996 are shown in Ta- 1983 5 60 341 ble 7. 1984 9 126 567 1985 15 192 1,161 The topics of the articles published in 2006 are listed 1986 13 143 823 in Table 6. Articles on coronary artery disease, of course, 1987 19 279 1,576 continue to dominate, numbering 313 (45%). There has 1988 19 252 1,393 been a considerable increase in articles concerning pre- 1989 20 232 1,240 ventive cardiology, numbering 69 (10%) in 2006. Only 7 1990 20 226 1,169 1991 9 99 631 articles (1%) on systemic hypertension were published in 1992 15 165 979 the AJC in 2006, and yet about 65 million Americans 1993 13 167 1,076 have it. 1994 5 47 278 1995 11 156 872 7. Number of pages for articles and Readers’ Comments 1996 11 105 620 published and number of articles and Readers’ Com- 1997 17 166 1,119 ments published in the AJC from 1983 through 2006 1998 22 254 1,502 (during the present editor-in chief’s tenure):These are 1999 18 172 1,133 2000 13 132 888 listed in Table 8. Although there was a 5% increase in 2001 14 108 703 2006 compared to 2005 in the numbers of pages 2002 12 90 858 available for articles and Readers’ Comments (from 2003 14 95 620 3,285 ¡ 3,471), there was a 6% decrease in numbers 2004 6 48 520 of articles published (736 to 695) and a 30% increase 2005 13 105 1,016 2006 15 94* 1,062 in the numbers of Readers’ Comments published (49 24 years 328 3,513 22,147 ¡ 70).

* Excludes abstracts

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97/8 Full length Statin Safety: A Systematic Review (S52- Law, M.; Rudnicka, A.R. 7,270 1 article S60) 97/2 Full length The Metabolic Syndrome: Inflammation, Haffner, S.M. 6,832 article Diabetes Mellitus, and Cardiovascular Disease (3-11) 2 98/2 Supplement, From Vulnerable Plaque to Vulnerable Naghavi, M.; Falk, E; Hecht, 6,814 S1 Review Article Patient – Part III: Executive summary of H;Jamieson, M; Kaul, S; the Screening for Heart Attack Prevention Berman, D.; et al and Education (SHAPE) Task Force Report 3 (2-15) 97/8 Full length Statin Safety and Drug Interactions: Bottorff, M.B. 5,766 4 article Clinical Implications (S27-S31) 97/8 Full length Final Conclusions and Recommendations of McKenney, J.M.; Davidson, 5,326 article the National Lipid Association Statin Safety M.H.; Jacobson, T.A.; 5 Assessment Task Force (S89-S94) Guyton, J.R. 97/8 Full length Statin Safety: An Overview and Bays, H. 5,227 6 article Assessment of the Data-2005 (S6-S26)

92/2 Full length Comparison of the efficacy and safety of Jones, P.H.; Davidson, M.H.; 5,162 article rosuvastatin versus atorvastatin, Stein, E.A.; Bays, H.E.; simvastatin, and pravastatin across doses McKenney, J.M.; Miller, E.; (STELLAR Trial) (152-160) Cain, V.A.; Blasetto, J.W.; 7 STELLAR Study Group@?

Figure 1. Top 25 downloads on ScienceDirect. From the Editor 1773

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8 97/2 Full length Justification for the Use of Statins in Primary Mora, S.; Ridker, P.M. 3,160 article Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)-Can C-Reactive Protein Be Used to Target Statin Therapy in Primary Prevention? (33-41) 9 97/9 Review Intra-Aortic Balloon Counterpulsation (1391-1398) Trost, J.C.; Hillis, L.D. 2,990 article 10 97/5 Review Effects of Statins on Renal Function (748-755) Agarwal, R. 2,904 article 11 97/1 Full length Comparative Safety of Atorvastatin 80 mg Versus 10 Newman, C.; Tsai, J.; Szarek, 2,667 article mg Derived from Analysis of 49 Completed Trials in M.; Luo, D.; Gibson, E. 14,236 Patients (61-67) 12 98/1 Review Role of the Renin-Angiotensin-Aldosterone System Ferrario, C.M.; Strawn, W.B. 2,654 article and Proinflammatory Mediators in Cardiovascular Disease (121-128) 13 96/4 Full length Recent National Cholesterol Education Program Adult Stone, N.J.; Bilek, S.; 2,579 article Treatment Panel III Update: Adjustments and Rosenbaum, S. Options (53-59) 14 97/8 Full length Benefit versus Risk in Statin Treatment (S95-S97) Guyton, J.R. 2,471 article 15 98/4 Full length Dietary Omega-3 Fatty Acid Intake and Psota, T.L.; Gebauer, S.K.; 2,364 article Cardiovascular Risk (3-18) Kris-Etherton, P. 16 96/12 Full length Atrial Fibrillation Ablation: State of the Art (59-64) Pappone, C.; Santinelli, V. 2,358 article

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The American Journal of Cardiology

2006 Cumulative Article Requests: 1,115,223 2006 Monthly Average: 92,935

2006 Cumulative Article Requests: 1,095,290 2006 Monthly Average: 91,274 Full-text Article Usage 2% on ScienceDirect

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8. Symposia published in the AJC in 2006: A total of 13 symposia, including 3,513 articles occupying 22,147 symposia and 2 abstract issues were published in pages have been published. 2006 (Table 9). 9. Number of symposia and numbers of articles and Following my comments, the publisher, David Dionne, pages in symposia in the AJC from 1983 through of the AJC reviewed some other developments in the AJC in 2006 (during the present editor’s tenure): These are 2006. He showed a few power point slides detailing the Top shown in Table 10. During this 24-year tenure, 328 25 Article Downloads (January to December 2006) (Figures 1774 The American Journal of Cardiology (www.AJConline.org)

The American Journal of Cardiology

2006Cumulative Requests: 543,627 Monthly Average: 45,302 9 + Full-Text Article Usage on 2005 Cumulative Requests: 498,4719 Monthly Average: 41,539 % the Phoenix Platform +9%% Time to Benefit in Lipid-Lowering Trials 70,000 Braunwald & Gotto (2005) 63,001 62,404 60,000 Roundtable Discussion 50,000 COX-2 Inhibitors & 39,515 Cardiovascular Disease (2005) 40,000

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498,471 article requests in 2005 to 543,627 requests in American Journal of Cardiology The American Journal of Cardiology 2006. David also detailed for the editorial board members some Congratulations Bill ! of the new features of the print journal as well as some 25 Years as Editor-in-Chief enhancements to the full-text website. A new, irregular The section with free CME was added to the journal by Dr. American Journal Vince Friedewald, now an Assistant Editor of the AJC, and of Cardiology me toward the end of 2006, entitled, The Editor’s Round- table Discussion. In this section, the AJC gathers together a group of experts, who discuss and debate a specific relevant clinical topic in cardiovascular disease, transcribes the meeting, and finally prints the Roundtable Discussion with references in the AJC. David pointed out at the meeting that 5 a “navigational button” had been created at the journal’s full-text website to collect all the Roundtable Discussions in Figure 5. Congratulations for 25 years as Editor in Chief. one place and conveniently offer them to subscribers with 1 and 2) by individuals at institutions that have license free CME online. Six Roundtable Discussions have already agreements with ScienceDirect. Sixty-eight percent of the appeared in the AJC with an additional 12 to 14 scheduled 25 articles focused on statins (risks and benefits), safety during the next 10 months. recommendations and large population statin studies, com- I have interviewed close to 70 well-known cardiologists parisons of various statin drugs, and cholesterol-lowering and cardiovascular surgeons since 1996 and have had them and lipid-lowering guidelines. printed in the AJC as a permanent archival record. The In addition, David showed the group 2 slides pertaining Publisher has created an “Interviews Collection” button at to full-text article usage during that same period on Science the website with all 70 interviews collected there; it is a very Direct and on the journal’s Phoenix Platform, a platform convenient location to keep these valuable interviews. where individual print subscribers access the full-text of the The Articles in Press navigational button on the full-text journal at www.AJConline.org. The slides showed that “us- web site has been posting articles for Ͼ2 years now—the age” activity on both Platforms was considerable with a 2% articles are posted more than 4 to 6 weeks before the print increase in cumulative article requests (1,095,290 in 2005 to version appears. The AJC has been receiving more and more 1,115, 223 in 2006) on ScienceDirect (Figure 3)anda9% video clips from authors on submission of their manuscripts increase in activity on the Phoenix Platform (Figure 4) from to the editorial office. Because of the growing number of From the Editor 1775

The American Journal of Cardiology

Figure 6. The plaque received from David Dionne and Elsevier. video clips, 3-dimensional images, and animations, the AJC Journal Manager, who has been with the AJC for the past 11 has been receiving with manuscripts during the past 10 years, presented me with an engraved, Tiffany’s sterling months, the Publisher has created a “Multimedia Library silver pen. I am most grateful for the wonderful surprise and Collection.” All accepted manuscripts with multimedia our subsequent reception following the editorial board components will not only appear embedded online with the meeting. article, but will also be extracted and posted with other multimedia in the site’s Multimedia Library Collection. William Clifford Roberts, MD Much to my surprise, David and his colleagues at Editor in Chief Elsevier presented me with a plaque acknowledging their Baylor Heart and Vascular Institute appreciation of my directing the AJC as Editor in Chief for Baylor University Medical Center the past 25 years (Figures 5 and 6). Dori Birch, the Sr. Dallas, Texas 75246 READER’S COMMENT

Predicting Left Ventricular End-Diastolic Pressure by Echocardiography We read with great interest the recent report by Su et al,1 who sought to predict left ventricular end-diastolic pressure in patients with heart failure on the basis of the Doppler echocardiographic measurement of certain electromechanical parameters. We do have concerns about the definition and analysis of some of these parameters, particularly the measurement of isovolumic contraction time (IVCT) before the Q-wave inscription. Simultaneous electrocardiographic, carotid arterial pulse tracing, and pho- nocardiographic recordings by Weissler et al2 showed that the preejection period (PEP) was derived by subtracting the left ventricular ejection time from the 2 Q-S2 duration (the onset of the Q wave Figure 1. Depiction by Weissler et al of the electromechanical changes during cardiac systole using on the electrocardiogram to the onset of phonocardiography (top), carotid arterial pulse recording (middle), and electrocardiography (bottom). S on the phonocardiogram). IVCT was ICT ϭ isovolumic contraction time; LVET ϭ left ventricular ejection time; PEP ϭ preejection period; 2 ϭ ϭ then calculated by subtracting left ven- Q-I period from the onset of QRS to the onset of S1 (the electromechanical delay); S1S2 time interval between the onset of S1 and the onset of S2. tricular ejection time from the S1-S2 duration (the onset of S1 to the onset of S2 on the phonocardiogram). The interval the end of the diastolic mitral annular are rediscovered. A better communica- between the onset of ventricular depo- velocity pattern to the onset of the QRS tion of ideas between successive scien- larization, the Q wave, and the onset of (the AQ interval) should not include tific generations will be a key step in S1 on the phonocardiogram (Q-I) was either the PEP or the IVCT, because ensuring that we all speak the same therefore representative of the electro- these intervals are determined after the “jargon.” mechanical interval (Figure 1). In sim- onset of the QRS. We wonder, how pler terms, the PEP encompassed the much impact did the inclusion of the Himanshu Tandon, MD electromechanical interval and the PEP or IVCT as part of the AQ interval Anthony F. LaSala, MD IVCT (PEP ϭ Q-I ϩ IVCT). have on their finding that the AQ inter- Hartford, Connecticut 5 February 2007 However, Su et al1 described and val is a novel predictor of left ventric- pictorially depicted the PEP as part of ular end-diastolic pressure? 1. Su HM, Lin TH, Voon WC, Lee KT, Chu CS, the IVCT. Furthermore, the time inter- The more important issue here is the Cheng KH, Yen HW, Lai WT, Sheu SH. Use- val measured by the investigators from lack of the consistent application of fulness of time interval between end of dia- medical terminology in publications. stolic mitral annular velocity pattern and onset The interpretation of original scientific of QRS for predicting left ventricular end- *Letters (from the United States) concerning a diastolic pressure. Am J Cardiol 2007;99:119– particular article in The American Journal of Car- concepts in newer technologic terms is 123. diology௡ must be received within 2 months of the not always unambiguous. Precise ad- 2. Weissler AM, Harris WS, Schoenfeld CD. article’s publication, and should be limited (with herence to earlier descriptions is crucial Systolic time intervals in heart failure in man. Circulation 1968;37:149–159. rare exceptions) to 2 double-spaced typewritten and can limit the errors that may arise as pages. Two copies must be submitted. more of the older scientific principles doi:10.1016/j.amjcard.2007.02.005

Abaci, Adnan, 322 Ammar, Ronny, 925 Bagheri, Roshanak, 951 Bertomeu-Gonza´lez, Vicente, Bradford, Shannon, 1529 Abad, Laura, 903 Amoroso, Giovanni, 5 Baharjoo, Hamidreza, 1656 797 Bradshaw, Barbara H., 431 Aban, Inmaculada B., 393 Anan, Ryuichiro, 1750 Bair, Tami L., 169 Beshansky, Joni R., 1384 Brady, Thomas J., 247, 1122 Abarghouei, Alireza Afzali, Anand, Inder S., 1109 Bak, Søren, 108 Bess, Renee L., 1196 Brancati, Marta, 364, 1671 779 Andersen, Morten, 1181 Baki, Talal T., 333 Bethel, M. Angelyn, 726 Brennan, J. Matthew, 1614 Abbara, Suhny, 1122 Anderson, H. Vernon, 189 Bakris, George L., 393 Bettmann, Michael, 1481 Bresnahan, John, 465 Abbas, Mohammad A., 876 Anderson, Jeffrey L., 149, Balbarini, Alberto, 84 Beukema, Willem P., 1252 Brewer, Jr., H. Brian, 1698 Abbate, Antonio, 307 169 Balcıog˘lu, Akif Serhat, 1568 Beyar, Rafael, 509 Breña, Silvia, 19 Abbott, J. Dawn, 626 Andraws, Richard, 1006 Baldi, Alfonso, 307 Bhatt, Deepak L., 1212 Bricknell, Kristen, 300 Abdelnoor, Michael, 1544 Andreotti, Felicita, 1637 Ballantyne, Christie M., 673 Biagini, Elena, 1193 Briguori, Carlo, 779, 916 Abdi, Seifollah, 1656 Angiolillo, Dominick J., 429 Ballantyne, Christie, 1706 Bianchi, Cristina, 84 Brindis, Ralph G., 189, 329 Abedin, Moeen, 513 Anselmi, Maurizio, 584 Ballarino, Miguel, 357 Bianconi, Leopoldo, 1421 Brisson, Diane, 369 Abizaid, Alexandre, 1403, Anstrom, Kevin J., 339 Banai, Shmuel, 1504 Biase, Matteo Di, 1737 Brodie, Bruce R., 431, 1680 1691 Antero, V., 970 Banerjee, Anindita, 315 Biasucci, Luigi M., 307 Brooks, Erica, 1614 Abizaid, Andrea, 1403 Antman, Elliott M., 344 Banerjee, Sudeshna, 930 Biasucci, Luigi, 315 Brosh, David, 442 Abraham, Dennis, 860 Anton-Culver, Hoda, 830 Bang, Ji Yon, 482 Bickel, Christoph, 808, 1623 Brown, David L., 1006 Abraham, William T., 1263 Antoniucci, David, 182, 651, Bangalore, Sripal, 876 Biessaux, Yves, 31 Brown, David W., 1115 Acar, Philippe, 406 1680 Bank, Ilan, 1294 Bigi, Riccardo, 1491 Brown, Patricia, 864 Adam, Guleid, 1159 Anwar, Ashraf M., 275 Banning, Adrian P., 607 Bijnens, Bart, 974 Bruck, Rafael, 146 Adam, Terrence J., 113 Anwar, Azam, 1458 Banning, Adrian, 603 Bilchick, Kenneth C., 1425 Brucks, Steffen, 62 Adamopoulos, Stamatios, Aokage, Yasuyuki, 1674 Bansal, Nisha, 1137 Billinger, Michael, 353 Bruining, Nico, 5, 607 146 Apiyasawat, Sirin, 49, 58, Bansal, Sandeep, 1500 Biondi-Zoccai, Giuseppe Brunelleschi, Sandra, 1082 Adamopoulos, Stamatis, 558 390, 1187 Barbagelata, Alejandro, 934 G.L., 5, 307, 593 Brunetti, Natale Daniele, Adams, Jr., Kirkwood F., Applegate, Robert J., 333 Barbarini, Giorgio, 1470 Biondi-Zoccai, Giuseppe, 1737 460 Appleton, Christopher P., Barbaro, Giuseppe, 1470 364 Brunner, Martin, 1549 Agarwal, Sanjay, 1374 113 Barchetta, Sabrina, 1378 Birnbaum, Yochai, 934 Buch, Ashesh N., 424, 599, Agewall, Stefan, 1357 Aranda, Jr., Juan M., 250 Baroletti, Steve, 1002 Bishop, Andrew H., 896 1518 Aggelopoulou, Nikolitsa, 558 Arbab-Zadeh, Armin, 1629 Barresi, Elena, 307 Bisognano, John D., 1143 Buchanan, Donna M., 930 Agostoni, Pierfrancesco, 5, Arbel, Yaron, 1504 Barrett, Richard J., 1507 Bistola, Vassiliki, 146 Buchanan, Thomas A., 956 593, 1637 Ariyarajah, Vignendra, 49, Barrett-Connor, Elizabeth, Bitigen, Atila, 1429 Buecker, Arno, 1090 Aguade´-Bruix, Santiago, 58, 390, 1187 99, 227, 486 Blackman, Daniel James, Buellesfeld, Lutz, 1691 1662 Armstrong, Jr., Arthur T., Barrozo, Carlos Alberto 603 Buettner, Catherine, 661 Ahmed, Ali, 393, 460, 549 616 Mussel, 504 Blair, John E., 1614 Buhr, Christiane, 1090 Ahn, Chul, 1468 Armstrong, Paul W., 186 Bartel, Thomas, 270 Blankenberg, Stefan, 808, Bui, Sanh, 603 Ahn, Eui Soo, 707 Arnesen, Harald, 1544 Bartorelli, Antonio Luca, 1623 Bunch, T. Jared, 835 Ahn, Youngkeun, 1051 Arnett, Donna K., 1413 1062 Blankenship, James C., 616 Burden, Leah, 1369 Aihara, Naohiko, 53 Arnold, Larrie W., 519 Basaran, Yelda, 1429 Blasio, Andrea, 1434 Buring, Julie E., 1246 Airoldi, Flavio, 470, 593, Aronow, Wilbert S., 460, Bates, Eric R., 1399 Bleeker, Gabe B., 68, 657 Burke, Thomas, 530 779, 916 1468 Batista, Leonardo Alves, 504 Blom, Nico, 984 Buros, Jacqueline, 344 Aizawa, Yoshifusa, 494 Aronson, Doron, 509 Battler, Alexander, 442 Blondheim, David S., 1741 Bursac, Zoran, 879 Akhlaghpoor, Shahram, 1656 Arora, Nipun, 766 Baughman, Robert P., 1177 Blumenthal, Roger S., 42 Burstein, Jason M., 457 Akinola, Oluwaseun, 860 Arslan, Ug˘ur, 1568 Bax, Jeroen J., 68, 554, Bochenek, Andrzej, 36 Burzotta, Francesco, 364, Akins, Cary W., 1269 Artang, Ramin, 1039 657, 1193, 1485 1555 Bochenek, Tomasz, 36 1671 Akkan, Dilek, 1146 Aryana, Arash, 1765 Bayrak, Fatih, 1429 Boden, William E., 208 Bussani, Rossana, 307 Ako, Junya, 491, 1394 Asch, Federico, 1106 Bays, Harold, 1483 Bodı´, Vicent, 797 Buszman, Paweł, 36 Aksoy, Yuksel, 159 Asif, Aya, 1741 Becker, Alexander, 374 Boersma, Eric, 68, 1072 Butler, Javed, 247, 1122 Akula, Devender N., 1374 Askew, J. Wells, 1451 Becker, Christoph, 374 Bogale, Nigussie, 647 Bybee, Kevin A., 785 Albert, Michelle A., 1246 Assali, Abid, 911 Bedi, Maninder, 1151 Bogaty, Peter, 921 Byers, Patricia, 1242 Albertal, Mariano, 357 Assali, Abid R., 442 Beek, Aernout M., 563 Boltan, David Demitry, 1171 Byers, Peter H., 686 Aleksova, Aneta, 307 Assmann, Gerd, 541 Beemath, Afzal, 415, 421, Boman, Kurt, 970 Alemparte, Ma´ximo Rodri- Asztalos, Bela F., 681 1303 Bonaca, Marc P., 344 Cacciabaudo, Jean M., 1096 guez, 349 Atar, Dan, 108, 288, 867 Beeumen, Katarina Van, 79 Bonatti, Johannes, 270 Cai, Qiangjun, 616 Alexopoulos, Nikolaos A., Atar, Shaul, 934 Behar, Solomon, 667 Bonneau, Heidi N., 1394 Calevo, Maria Grazia, 1284 1473 Atsuchi, Nobuhiko, 1523 Belardi, Jorge, 357 Bonomo, Lorenzo, 1671 Califf, Robert M., 315, 726, Alfieri, Ottavio, 1434 Atwood, Charles W., 573 Bell, Malcolm, 465 Bonow, Robert O., 1269 793 Alfonso, Fernando, 429, 621 Aude, Wady, 879 Belohlavek, Marek, 1298 Bonvicini, Marco, 1462 Calkins, Hugh, 1425 Ali, Sadia, 1128, 1643 Aukrust, Pål, 513 Belonje, Anne, 849 Book, Wendy M., 704 Calo, Leonardo, 1421 Aligeti, Venkata R., 741 Auricchio, Angelo, 232 Benassi, Alberto, 1062 Borer, Jeffrey S., 91, 1269 Calvo, Luis, 429, 621 Allen, Christopher, 970 Auriti, Antonio, 1421 Bender, Kathryn, 1714 Bornemann, Michel A. Cra- Candell-Riera, Jaume, 1662 Allen, Rebecca, 1529 Aversano, Thomas, 1384 Benderly, Michal, 911 mer, 573 Cannaday, John, 1535 Allison, Matthew A., 99 Awara, Adel M.M., 1485 Ben-Horin, Shomron, 1294 Borzi, Mauro, 325 Cannavale, Mario, 779 Almagor, Yaron, 911 Azadi, Mitra, 1656 Benjamin, Emelia J., 1413, Bosch, Marıá Jose´, 797 Cannon, Chistopher P., 1389 Almasry, Ibrahim, 1425 Aznaouridis, Konstantinos A., 1598 Bosch, Xavier, 797 Cannon, Christopher P., Alnas, Majd, 421 1473 Bennett, Kyla M., 1351 Bouffard, John-Paul, 1171 1212, 1496 Alsheikh-Ali, Alawi A., 379 Aznar, Justo, 19 Berbarie, Rafic F., 1458 Boura, Judith A., 906 Cantor, Warren J., 457 Altamura, Luca, 364 Berger, Peter B., 349 Bouzas, Alberto, 1454 Caponi, Domenico, 1575 Altemose, Gregory T., 113, Baan, Jr., Jan, 1201 Berger, Ronald, 1425 Bouzas, Beatriz, 1454 Carabello, Blase´ A., 1269 1451 Babu, Sateesh, 1468 Berliner, Shlomo, 1504 Bovenzi, Francesco, 1491 Cardaioli, Paolo, 1621 Amano, Tetsuya, 1203 Bach, Richard G., 1227, Berman, Daniel S., 208 Boyden, Thomas F., 1399 Carlino, Mauro, 470, 593, Amin, Raouf S., 1298 1507 Bernardi, Vıćtor, 349 Boyle, Noel G., 242 916 Amitai, Miriam E., 864 Baeza, Ricardo, 357 Bernheim, Alain M., 292 Bracke, Franck, 966 Carlquist, John F., 169 Amlie, Jan P., 997 Bafunno, Valeria, 1737 Berrocal, Daniel, 357 Bracke, Frank, 75 Carney, Robert M., 519

©2007 Elsevier Inc. All rights reserved. 0002-9149/07/$–see front matter 1 The American Journal of Cardiology Vol. 99 June 15, 2007 Carr, J. Jeffrey, 62, 1714 Claussen, Lori, 696 Davis, Cheryl J., 1718 Downey, William E., 431 Feinberg, Micha S., 667 Carrabba, Nazario, 182 Clementi, Fabrizio, 325 Davis, Donna H., 1714 Doyle, Brendan, 465 Feit, Frederick, 1513 Carvalho, Jose A.M., 42 Clouse, Melvin E., 310 Davis, Roger B., 661 Drzewiecki, Janusz, 607 Feldman, Dmitriy N., 446 Casas, Teresa, 1279 Coady, Sean, 1448 Davutoglu, Vedat, 1024 Dubourg, Olivier, 1667 Ferencik, Maros, 247, 1122 Casazza, Laurie, 1374 Cogert, Gregory, 739 Dawkins, Keith, 1072 Dudek, Dariusz, 607 Feres, Fausto, 1403 Caso, Giuseppe, 1409 Cohen, David J., 1222, 1227 de Bruyne, Bernard, 1072 Due, Reidar, 997 Ferguson, James J., 315 Casperson, Paul, 208 Cohen, Gerald I., 1196 De Caro, Enrico, 1284 Dueñas, Antonio, 903 Feringa, Harm H.H., 1485, Cassano, June, 1087 Cohen, Mauricio G., 315, de Coo, Rene´ F.M., 264 Duffield, Emma, 673 1555 Castell-Conesa, Joan, 1662 1718 de Jaegere, Peter P.T., 1027 Dulac, Yves, 406 Ferlinz, Jack, 1330 Castro, Antonio, 1421 Cokkinos, Dennis V., 1555 de la Morena, Gonzalo, 1279 Dulas, Daniel, 1680 Fermanian, Christophe, 406 Castro-Beiras, Alfonso, 1454 Colombo, Antonio, 470, 593, de las Fuentes, Lisa, 239 Dumont, Carlos Alberto, Fernandes, Jaxon, 58, 390 Cate, Folkert J. ten, 714 607, 779, 916, 1072, 1434 de Lemos, James A., 513, 1454 Fernańdez, Cristina, 621 Cavusoglu, Erdal, 1364 Concannon, Thomas W., 825 Durakog˘lugil, Emre, 1568 Fernańdez, Xusto, 1454 Cecchi, Franco, 1575 1384 de Leoń, Gustavo, 1662 Dutcher, Jacob R., 436 Fernhall, Bo, 707 Çengel, Atiye, 1568 Condorelli, Gerolama, 779 de Luna, Antonio Baye`s, 647 Duytschaever, Mattias, 79 Ferrero, Ivana, 1575 Centemero, Marinella, 1403 Connolly, Heidi M., 292 de Marchena, Eduardo, 1242 Dyer, Alan R., 535 Ferrero, Valeria, 1082 Cerisano, Giampaolo, 651 Connor, Christy, 227 de Roos, Albert, 657 Dzavik, Vladimir, 603 Feyter, Pim de, 5 Cesario, David A., 242 Consuegra, Luciano, 797 de Sande, Meike van, 1027 Fink, Louis, 879 Cetinkaya, Yakup, 322 Conte, Maria Rosa, 1575 de Servi, Stefano, 1072 Eagle, Kim A., 939 Finsterer, Josef, 145 Chaitman, Bernard, 11 Cook, Joseph W., 585 De Vivo, Fabrizio, 779 Eber, Bernd, 673 Firouzi, Iraj, 1656 Chaitman, Bernard R., 208 Cook, Stephane, 353 de Winter, Robbert J., 1201 Eberly, Shirley W., 1100 Fisman, Enrique Z., 667 Chambers, John, 970 Cooper, Leslie, 1159 Decker, Carole, 930 Ebina, Toshiaki, 817 Fitchett, David, 186 Chan, Jonathan, 300 Cooper-DeHoff, Rhonda M., Deedwania, Prakash C., Echigo, Shigeyuki, 1757 Fitzgerald, Peter J., 491, Chan, Paul S., 1399 1549 1538 Echols, Melvin R., 315 1394, 1403, 1603, 1691 Chandler, E. Ted, 1714 Corbett, Simon, 470, 593 DeFaria Yeh, Doreen, 1 Edouard, Thomas, 406 FitzGerald, Shannon, 1535 Chandra, Divay, 1755 Corea, Francesco, 876 Degertekin, Muzaffer, 1429 Edvardsen, Thor, 1109 Fiumara, Karen, 1002 Chandrasekaran, Krish- Corey, Diane, 1598 Degiannis, Dimitrios, 558 Efthimiadis, Georgios K., Fleg, Jerome L., 460 naswamy, 835 Corretti, Mary C., 743 Dehmer, Gregory J., 329 1024, 877 Fleg, Jerome, 1448 Chang, Chi-Jen, 1479 Cortigiani, Lauro, 1491 Del Pace, Stefano, 182 Eggebrecht, Holger, 270 Flugelman, Moshe Y., 925 Chang, Shu-Mei, 579 Cosgrave, John, 593, 916 DeLao, Timothy, 124 Egstrup, Kenneth, 970 Focaccio, Amelia, 779 Channon, Keith, 603 Costa, Ricardo, 1691 Delemarre, Ben J.M., 966 Ehrsam, Jo-Ellen, 835 Fonarow, Gregg C., 242, Chapelle, Jean Paul, 31 Costantini, Costantino O., Dele-Michael, Abiola, 1413 Eisenberg, Steven, 1529 1212 Chaplin, William, 860 1067 Delgado III, Reynolds M., Eldar, Michael, 667 Formigari, Roberto, 1462 Chaturvedi, Rajiv, 699 Costello, Frederick M., 1718 1755 Elhendy, Abdou, 1193, 1485 Forrester, James S., 732 Chaudhry, Eram, 175 Coutsoumbas, Gloria, 1462 Dell’Italia, Louis J., 460 Ellis, Stephen G., 1087 Fouron, Jean-Claude, 699 Chaves, Aurea, 1403 Cowen, Mark E., 197 Delnoy, Peter Paul H.M., Elvan, Arif, 1252 Fowler, Jeffrey, 573 Chaves, Jose´, 903 Cox, David A., 202, 1055, 1252 Emami, Zyae, 1656 Fowler, Michael B., 1263 Cheema, Aamir, 1425 1067, 1680 Denke, Margot A., 382 Emery, Michael S., 939 Fox, Ervin R., 1413 Chen, Anita Y., 1351, 1389 Crea, Filippo, 307, 364, Desai, Dipan, 616 Endo, Mitsuaki, 817 Fox, Garrett, 541 Chen, Michael S., 1087 1378, 1637, 1671 DeSouza, Christopher A., 46 Eng, Calvin, 1364 Fozo, Paul K., 1196 Cheng, Alan, 1425 Crouse III, John R., 1714 Despre´s, Jean-Pierre, 369 Engel, Peter J., 1177 Francescone, Steven, 1306 Cheng, Kai-Hung, 119 Crowe, Timothy, 813 Devereux, Richard B., 1306 E.R. Silva, Expedito, 504 Franciosa, Joseph A., 1263 Cheng, Victor Y., 1183 Crystal, Alexander, 1726 Devlin, William, 906 Erbel, Raimund, 270 Franklin, Barry A., 222 Chengelis, David L., 222 Crystal, Eugene, 1726 Dey, Syamal K., 329 Erdem, Gu¨liz, 1568 Franklin, Barry, 436 Csejtei, Andras, 1025 Frazier, O.H., 1755 Cheriex, Emile C., 966 D’hooge, Jan, 974 Eros, Yoav, 1504 Cullen, Paul, 541 Freedman, Roger, 573 Chetcuti, Stanley J., 1399 Di Bello, Vitantonio, 84 Eryol, Namik Kemal, 322 Cumaranatunge, Reshmaal Freeman, Mason W., 1 Chieffo, Alaide, 593, 916 Di Cori, Andrea, 84 Escudero, Alejandro Garcia, Gomes, 951 Friedewald, Jr., Vincent E., Chierchia, Sergio, 1062 Di Mario, Carlo, 1062 357 Cundiff, David Keith, 1230 1698 Chiou, Kuan-Rau, 579 Diamond, George A., 284, Esfahani, Fatemeh, 1656 Cura, Fernando A., 357 Friedewald, Vincent E., 134, Chiricolo, Gaetano, 325 1013 Eshaghian, Shervin, 1183 Curnis, Antonio, 232 213, 382, 519, 943, 1269, Chirinos, Julio A., 1242 Diaz, Vanessa A., 1236 Espinola-Klein, Christine, Curtis, Jeptha P., 1227 1560 Chlouverakis, Gregory I., Dib, Nabil, 1507 808, 1623 Curtis, Lesley H., 339 Friedman, Gary D., 1621 1721 Dickstein, Kenneth, 647, Esterbrooks, Dennis J., 1765 Cury, Ricardo C., 247, 1122 Friedman, Zvi, 1741 Chlouverakis, Gregory, 1258 1109 Estes III, N.A. Mark, 857 Froehlich, James B., 939 Cho, Jeong Gwan, 1051 Diego, Carlos De, 242 Everett, Charles J., 1236 Frohwein, Stephen, 1529 Cho, Seung-Yun, 1571 Dieter, Robert S., 1039 Eyskens, Benedicte, 974 Dada, Marcin, 208 Fu, Qi, 1629 Choi, Donghoon, 1571 Daemen, Joost, 1027 Dietz, Harry C., 978 Fu, Yuling, 934 Chopra, Vineet, 1364 Dagenais, Gilles R., 921 Dijk, Erika, 1629 Fadden, Eugene Mc, 5 Fuchs, Shmuel, 442 Chorro, Francisco Javier, D’Agostino, Sr., Ralph B., Dima, Ioanna A., 1473 Faddis, Mitchell N., 239 Fuisz, Anthon, 1106 797 1598 Dockery, William D., 1458 Fahdi, Ibrahim, 879 Fukuta, Hidekatsu, 62 Choudhury, Robin Patrick, D’Agostino, Ralph B., 310 Doerer, Joseph J., 857 Fahmy, Samer, 1196 Fuller, Cindy J., 1312 603 Dagre, Anna, 1473 Dogan, Ali, 322 Fan, Bing, 1653 Fuse, Koichi, 494 Chow, Judy, 864 Dai, Kazuoki, 1674 Dokainish, Hisham, 961 Fang, Jianming, 939 Fuset, M. Paz, 19 Christou, Maria A.C., 450 Dalal, Darshan, 978, 1425 Domanski, Michael, 1448 Fang, Zhi Y., 844 Chronos, Nicolas, 1529 Dallal, Gerald E., 681 Domburg, Ron van, 1555 Fanikos, John, 1002 Chu, Chih-Sheng, 119 D’Andrea, Davide, 779 Donaldson, David, 1096 Fantoni, Cecilia, 232 Gabay, Jose´, 349 Chu, Po-Hsien, 1479 Danzi, Gian Battista, 1193 Dong, Jun, 1425 Faramawi, Mohammed F., Gach, Olivier, 31 Chuang, Michael L., 1321 Dao, Catherine, 1316 Donna, Paolo Di, 1575 1610 Gade, Christopher L., 446 Chung, Namsik, 1571 Daoulah, Amin, 1726 Donne, Maria Grazia Delle, Farcot, Jean-Christian, 1667 Gaita, Fiorenzo, 1575 Ciaglo, Lauren N., 1687 Dauerman, Harold L., 175, 84 Farmakis, Dimitrios, 146 Galal, Wael, 1485 Cianflone, Domenico, 916 1222 Donti, Andrea, 1462 Farouk, Samira, 951 Galantucci, Sebastiano, 876 Cianfrocca, Cinzia, 1421 Dauterman, Kent W., 1360 Doran, Aimee, 696 Fazel, Reza, 1513 Galassi, Alfredo, 1062 Claeys, Marc J., 476 Daviglus, Martha L., 535 Doughan, Abdul Rahman K., Fearon, William F., 1603 Galderisi, Maurizio, 1154 Clark, Luther T., 1364 Da´vila-Romań, Victor G., 704 Feher, Gergely, 1025 Galema, Tjebbe W., 714 Claus, Piet, 974 239 Douglas, Pamela S., 1321 Feigenbaum, Harvey, 1016 Galeote, Guillermo, 429, 621

2 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 Galiuto, Leonarda, 1378 Go´mez, Cristina, 797 Haas, Tammy S., 857 Hochadel, Matthias, 1288 Iqbal, Nayyar, 951 Gami, Apoor S., 1298 Gomez, Joseph F., 642 Haeberli, Andre, 353 Hochman, Judith S., 802, Irmiger, Heather M., 46 Ganame, Javier, 974 Gong, Yan, 250, 1549 Haennel, Robert, 1745 1351 Ischinger, Thomas, 1288 Gandhi, Sanjay K., 333 Good, Chester B., 1119 Hafez, Tariq, 584 Hod, Hanoch, 667 Ishihara, Masaharu, 1674 Garcia, Eulogio, 202, 1055, Goodman, Lawrence R., Haffner, Stephen, 382 Hodge, David O., 835 Ishii, Hideki, 1203 1067 1303 Hagiwara, Nobuhisa, 1523 Hodgson, John McB., 1507 Ishikawa, Toshiyuki, 817 Garcia, Mario J., 175, 1629 Goodman, Shaun G., 186 Hahn, Rebecca T., 1306 Hodis, Howard N., 956 Iskandrian, Ami E., 1619 Garcia-Garcia, Hećtor M., 5 Goonewardena, Sascha N., Hales, Charles A., 1303 Hoekstra, James W., 1351, Ito, Hiroshi, 885 Garcıá-Garcıá, Hećtor M., 499 Hall, W. Jackson, 642 1389 Ito, Masahiro, 494 790, 1027 Goonewardena, Sascha, Halon, David A., 472, 925 Hoetzer, Greta L., 46 Ito, Matthew K., 145 Gardin, Julius M., 830, 1196 1614 Halperin, Henry, 1425 Hoffman, Barry, 951 Iversen, Kasper Karmark, Gardiner, Paula, 661 Goovaerts, Inge, 476 Haluska, Brian A., 844 Hoffmann, Rainer, 1090 1146 Gargiulo, Gaetano, 1462 Gorelick, Philip B., 91 Hamasaki, Shuichi, 261, Hoffmann, Udo, 247, 1122 Ivy, D. Dunbar, 696 Garza, Luis, 879 Goto, Yukie, 1608 1750 Hollander, Priscilla, 382 Iwata, Kentaro, 802 Gaspar, Tamar, 472, 925 Gotto, Jr., Antonio M., 382 Hamilos, Michail E., 1721 Holm, Johan, 1593 Izgi, Akin, 1429 Gasparini, Maurizio, 232 Gotto, Jr, Antonio M., 718 Hamilos, Michalis, 1258 Holman, Eduard R., 68 Gatzoulis, Michael A., 1582 Gottschalk, Alexander, 1303 Hamman, Baron L., 1458 Holme, Ingar, 970 Jabara, Refat, 1529 Gau, Gerald, 208 Gould, Stuart D., 256 Hammill, Stephen C., 835 Holmes, Jr., David R., 1044 Jacobs, Alice K., 626 Gaudet, Daniel, 369 Granada, Juan F., 124 Han, Hui, 1413 Holmes, David, 465, 1159 Jae, Sae Young, 707 Gavri, Sagui, 993 Granatelli, Antonino, 1216 Han, Tae H., 691 Holmes, Kate, 457 Jaegere, Peter de, 5 Ge, Junbo, 1653 Granger, Christopher B., 793 Hanawa, Haruo, 494 Holmes, Kathryn W., 978 Jaeggi, Edgar T., 699 Ge, Lei, 593, 1653 Grant, April, 879 Hanekom, Lizelle, 300 Holper, Elizabeth, 626 Jaffe, Allan S., 519 Geibel, Annette, 103 Grant, Richard W., 1 Hannukainen, Jarna, 1648 Holt, D. Byron, 568 Jaffer, Farouc A., 310 Gelbman, Andrew I., 1765 Gray, William A., 1312 Hansen, Charles, 431 Homma, Shunichi, 860 Jain, Tulika, 513 Geleijnse, Marcel L., 264, Grayburn, Paul A., 1458 Hansen, Claudius, 573 Honda, Takashi, 1523 James, Margaret, 647 275, 714 Greaves, Kim, 1369 Hansen, Dorte Gilsa˙, 1181 Honda, Yasuhiro, 491, 1394, Jamieson, Michael J., 632 Gensini, Gian Franco, 182 Green, Curtis E., 175 Hansen, Mark S., 852 1603 Janatuinen, Tuula, 1648 Genth-Zotz, Sabine, 808, Green, Philip, 399 Hare, Joshua M., 1242 Hong, Myeong-Ki, 760, 774 Jang, Ik-Kyung, 1033 1623 Green, Stephen J., 1096 Harjai, Kishore J., 202 Hong, Seo Na, 1051 Jang, Yangsoo, 1571 George, Christopher E., 1518 Greenbaum, Adam B., 1389 Harms, Verna, 1312 Hong, Young Joon, 1051 Janjua, Muhammad, 415 Gerckens, Ulrich, 1691 Greenberg, Barry, 1263 Harrington, Robert A., 793, Hori, Masatsugu, 885 Jansen, Annemieke H.M., Gerdts, Eva, 970 Greenberg, Henry, 1476 1222, 1389 Horn, Howard R., 741 75, 966 Gerin, William, 860 Greenberg, Jeffrey O., 1476 Harris, Adam, 860 Horne, Benjamin D., 149, Jarlbæk, Lene, 1181 Gersh, Bernard J., 1067 Greenberg, Neil L., 175, Harris, Crystal L., 208 169 Ja¨rvenpaä¨, Jere, 295 Gerson, David S., 1481 1629 Harris, William S., 154 Horowitz, Barbara Natterson, Jassal, Davindar, 247 Gersony, Welton M., 1588 Greenland, Philip, 535 Hartigan, Pamela M., 208 242 Javaid, Aamir, 599, 1518 Geskes, Gijs, 771 Gregoric, Igor D., 1755 Hartley, Craig J., 1440 Horvath, Katalin V., 681 Jeetley, Paramjit, 1369 Gewillig, Marc, 974 Griffin, John J., 202 Hartley, Jesse, 573 Hosokawa, Shinobu, 754 Jendzjowsky, Nicholas G., Gheorghiade, Mihai, 460, Griffith, John L., 1384 Hasdai, David, 442 Hsiao, Ju-Feng, 1479 1745 1560 Griffith, John, 1137 Hashemian, Mahmoud, 1656 Hsiao, Shih-Hung, 579 Jenkins, Carly, 300 Gherardi, Sonia, 1154 Grimaldi, Antonio, 1434 Hassager, Christian, 1146 Hsu, Amy, 813 Jensen, Jesper K., 108, 867 Giannakoulas, Georgios, Grimaldi, Massimo, 1737 Hassan, Ali H.M., 491, 1394 Hsu, Daphne T., 1588 Jensen, Kurt R., 169 1024 Grines, Cindy L., 202, 906, Hassan, Timoor, 1216 Hsu, Lung-An, 1479 Jensen, Lisette Okkels, 279 Giardini, Alessandro, 1462 1055, 1067, 1384 Hauptmann, Karl Eugen, Hsue, Priscilla Y., 822 Jeong, Myung Ho, 1051 Grines, Cindy, 436 Hubbard, Bradley L., 197 Gibbons, Raymond, 1680 1288 Jeong, Young-Hoon, 760 Grinfeld, Liliana, 357 Huddleston, Jason, 930 Gibler, W. Brian, 1222, Haykowsky, Mark J., 1745 Jesurum, Jill T., 1312 Grisorio, Benvenuto, 1470 Hughes, Mark T., 1234 1351, 1389, 1496 Haythe, Jennifer, 404 Jia, Gang, 1087 Gronda, Edoardo, 232 Hull, Russell D., 1303 Gibson, C. Michael, 1389, Haze, Kazuo, 1523 Jobin, Jean, 921 Gross, Brian W., 1360 Hunt, Sharon A., 1603 1687 Hazen, Stanley L., 813 Johnson, Eric, 1610 Grossman, P. Michael, 1399 Hur, Seung-Ho, 1394 Gidrewicz, Dominica, 457 Hecht, Harvey S., 871 Johnson, Julie A., 250, 1549 Grube, Eberhard, 1691 Hurst, J. Willis, 428 Giglio, Vincenzo, 147 Heer, Tobias, 1208 Johnson, Mark C., 568 Gruberg, Luis, 357, 509, Hurst, R. Todd, 113, 1451 Gilbert, Edward M., 1263 Heffernan, Kevin S., 707 Jolly, Sanjit, 186, 457 911 Hutchison, Stuart J., 457, Gillespie, Michael J., 1718 Heinrich, Fritz, 103 Jondeau, Guillaume, 406 Grundvold, Irene, 1544 852 Gilman, Gregory, 1298 Heller, Gary V., 1096 Jones, Angela, 930 Grundy, Scott M., 541, 1698 Hwang, Eui-Seock, 760 Gimple, Lawrence W., 896 Henderson, Yvette, 1535 Jones, Peter H., 134, 681 Grundy, Scott, 382 Hwang, Seon Ho, 1051 Giordano, Salvatore, 779 Henein, Michael Y., 1582 Jones, Philip G., 1227 Gruntmanis, Ugis, 513 Høilund-Carlsen, Poul Flem- Gitt, Anselm Kai, 1208 Henrikson, Charles A., 1425 Joseph, Thierry, 1667 Gruszka, Agata, 36 ming, 108 Juenger, Claus, 1208 Glaser, Ruchira, 626 Guagliumi, Giulio, 202, 1072 Henriques, Jose´ P.S., 1201 Glazko, Galina, 1100 Herbert, William G., 585 Jukema, J. Wouter, 1072 Guerra, Rudy, 541 Jung, Jens, 1288 Gleva, Marye J., 239 Guetta, Victor, 911, 1294 Hernandez, Adrian F., 1351 Iacobellis, Gianluca, 1470 Glickstein, Julie S., 1588 Gul, Ibrahim, 322 Hernandez, Gonzalo, 903 Ichimiya, Satoshi, 1203 Glynn, Robert J., 1246 Gunderson, Erica, 1621 Hernandez, Rosana, 429 Idelchik, Gary, 1755 Kaandorp, Theodorus A.M., Godino, Cosmo, 470, 916 Guntheroth, Warren G., 1762 Hertbruggen, Els Van, 476 Idupulapati, Madhuri, 1733 657 Goedhart, Dick, 790 Guo, Chao-Yu, 1598 Hess, Otto M., 353 Ieva, Riccardo, 1737 Kachel, Erez, 1294 Goehler, Alexander, 1122 Gupta, Milan, 1538 Hesse, Barbara, 175 Igo, Stephen R., 1440 Kadota, Junichi, 1608 Goel, Radha, 743 Gurfinkel, Enrique P., 315 Hiasa, Yoshikazu, 754 Igoumenidis, Nikos E., 1721 Kagawa, Eisuke, 1674 Gogo, Jr., Prospero B., 1222 Gurm, Hitinder S., 749, Hibberd, Mark G., 1321 Ikizceli, Ibrahim, 322 Kahn, Joel, 436 Gohlke-Ba¨rwolf, Christa, 970 1399 Hibi, Kiyoshi, 817 Inami, Shigenobu, 1033 Kahveci, Gokhan, 1429 Gold, Alex, 1538 Gustat, Jeanette, 1610 Hill, James A., 250 Inanc, Tugrul, 322 Kakar, Puneet, 1617 Goldberg, Alexander, 509 Gutersohn, Achim, 270 Hirayama, Atsushi, 885 Infusino, Fabio, 1378 Kalay, Nihat, 322 Goldenberg, Ilan, 1100 Guthikonda, Sasidhar, 124 Hirohata, Atsushi, 1603 Inoue, Ichiro, 1674 Kalliokoski, Kari K., 1648 Goldhaber, Samuel Z., 1002 Hirono, Satoru, 494 Ioakeimidis, Nikolaos C., Kalliokoski, Riikka, 1648 Goldschlager, Nora, 822 Ho, John, 1535 1473 Kalynych, Anna, 1680 Goldstein, Jacob, 472 Ha, Jong-Won, 1571 Ho, Kalon K.L., 189 Ioannidis, John P.A., 450 Kamakura, Shiro, 53 Golia, Giorgio, 584 Haario, Heikki, 890 Ho, Wan-Jing, 1479 Ionescu-Ittu, Raluca, 839 Kamal-Bahl, Sachin J., 530

AUTHOR INDEX 3 Kamalesh, Masoor, 1016 Kirkpatrick, James N., 1614 Kwok, Jonathan, 573 Lester, Steven J., 113, 1451 Mager, Aviv, 442 Kanashiro, Masaaki, 1203 Kishi, Koichi, 754 Køber, Lars, 1146 Lev, Eli I., 124 Magnier, Suzel, 406 Kanaya, Alka M., 486 Kishiki, Kanako, 1757 Levin, Adeera, 1137 Mahaffey, Kenneth W., 315 Kaneda, Hideaki, 491 Kiss, Istvan, 1025 Levine, Benjamin D., 1629 Mahajan, Aman, 242 Kang, Jung Chaee, 1051 Kitzman, Dalane W., 460 La Canna, Giovanni, 1434 Levy, Ari, 1614 Main, Michael L., 1733 Kang, Seok-Min, 1571 Kizer, Jorge R., 1306 La Rosa, Claudio, 1378 Levy, Daniel, 310 Mainous III, Arch G., 1236 Kanmura, Yuichi, 261 Kjaergaard, Jesper, 1146 Laborde, Nolan Joseph, 990 Lewin, Mark B., 686 Maisano, Francesco, 1434 Kansagra, Susan M., 339 Kjoller, Erik, 1146 LaBounty, Troy M., 939 Lewis, Basil S., 472, 925 Majeed, Farhan, 743 Kanwar, Manpreet, 1196 Klatsky, Arthur L., 1621 Labrador, Eugenio, 1242 Li, Wei, 1582 Makaryus, Amgad N., 1096 Kapadia, Samir R., 813 Kleiman, Amanda, 124 Lachar, Whitney, 1171 Li, Yanjie, 956 Malbecq, William, 970 Kaplan, Norman M., 134 Kleiman, Neal S., 124 Lackner, Karl, 808, 1623 Liang, David H., 864 Mancini, Donna M., 404 Kappetein, Arie-Pieter, 1072 Klein, Jan, 1485 Lacombe, Pascal, 1667 Liao, James C., 691 Mancini, Donna, 399 Kar, Biswajit, 1755 Klein, Larry, 1529 Ladouceur, Magalie, 406 Liao, James K., 410 Mancini, G.B. John, 208 Karaahmet, Tansu, 1429 Klein, Lloyd W., 189 Lai, Wen-Ter, 119 Liao, Lawrence, 256 Mangano, Charles, 743 Karagiannis, Stefanos E., Kleine, Peter P., 1269 Lakkis, Nasser, 961 Libby, Peter, 732 Manhenke, Cord, 1109 1555 Klersy, Catherine, 232 Lam, Yat-Yin, 1582 Liebeskind, David S., 1316 Manios, Emmanuel G., 1258 Karamitsos, Theodoros D., Kligﬁeld, Paul, 711 Lambert, Nathan D., 1718 Lin, Shih-Kai, 579 Manning, Michael, 175 Lamberti, Filippo, 1421 1024 Kline-Rogers, Eva, 939 Lin, Tsung-Hsien, 119 Manning, Warren J., 310, Lamerichs, Leon, 771 Karanasios, Evangelos, 984 Knez, Andreas, 374 Lincoff, A. Michael, 1513, 1321 Lammertin, Georgeanne, 499 Karas, Maria G., 1306 Knudtson, Merril, 208 1687 Manoukian, Steven V., 1513 Lamp, Barbara, 232 Karas, Richard H., 379 Knuuti, Juhani, 1648 Lindsay, Jr, Joseph, 1106 Mansencal, Nicolas, 1667 Landi, Patrizia, 1491 Karatasakis, George, 1555 Ko, Young-Guk, 1571 Link, Mark S., 857 Marelli, Ariane J., 839 Lang, Chim C., 404 Karlin, Paula, 404 Ko, Yu-Shien, 1479 Lip, Gregory Y.H., 1617 Margaglione, Maurizio, 1737 Lang, Roberto M., 499 Karnes, Jason H., 1549 Koch, Karel T., 1201 Lipinska, Izabella, 1598 Mariani, Mario, 84 Langaee, Taimour Y., 250, Karvounis, Haralambos I., Kochiadakis, George E., Lipson, Lewis C., 896 Marine, Joseph E., 1425 1549 1024 1721 Little, Stephen H., 1440 Marino, Paolo, 1082 Langer, Anatoly, 186 Kasanuki, Hiroshi, 26, 1523 Kodama, Makoto, 494 Little, William C., 62, 333 Mark, Bernd, 1288 Lanou, Amy Joy, 1230 Kashimura, Takeshi, 494 Koglin, Joerg, 607 Liu, Jennifer E., 1306 Marketou, Maria E., 1721 Lansky, Alexandra J., 202, Livanis, Efthimios G., 558 Kasper, Wolfgang, 103 Kohsaka, Shun, 802 1055, 1067, 1403 Markiewicz, Walter, 509 Kataoka, Toru, 491 Komura, Naohiro, 817 Livneh, Avi, 1294 Marmur, Jonathan D., 1364 Lansky, Alexandra, 315, Lloyd-Jones, Donald M., Kathiresan, Sekar, 310 Konermann, Martin, 573 1680, 1691 Maron, Barry J., 857 Katoh, Marcus, 1090 Konstantinides, Stavros, 103 535 Maron, David J., 208 Lanza, Gaetano, 1378 Llàcer, Àngel, 797 Katritsis, Demosthenes G., Kontos, Michael C., 307 Lappe, Donald L., 149 Marrs, Joel, 145 450 Koopman, Richelle J., 1236 Lobmeyer, Maximilian T., Marso, Steven P., 943 Larson, Martin G., 310, 250 Katz, Stanley, 1096 Kopecky, Stephen L., 785 1598 Martuscelli, Eugenio, 325 Kaul, Sanjay, 284, 1013 Koplik, Sheri, 1621 Lokki, Marja-Liisa, 890 Maruhashi, Tatsuya, 1674 Larson, Sarah, 568 Lombardo, Antonella, 1671 Kawagoe, Takuji, 1674 Koretsune, Yukihiro, 885 LaSala Anthony F., 1776 Marwick, Thomas H., 300, Kawano, Makoto, 261 Korhonen, Petri, 295 Lopez de Sa, Esteban, 429 844 Lashevsky, Ilan, 1726 Lopez-Jimenez, Francisco, Kawano, Yoshiyuki, 1608 Kormos, Robert, 1151 Latchamsetty, Rakesh, 939 Maseri, Attilio, 916, 1434 Kaya, Mehmet G., 1582 Kornowski, Ran, 442, 911, 1298 Massie, Barry M., 1263 Lau, Ching, 1726 Lo´pez-Sendo´n, Jose´ L., 429, Kazatsker, Mark, 1741 1072 Laughlin, Gail A., 227 Matetzky, Shlomi, 911 Keaney, Jr., John F., 1598 Korsin, Rosalind, 1588 621 Matheny, Michael, 766 Lavange, Lisa, 91 Loricchio, Maria Luisa, 1421 Keith, Rebecca, 46 Korsten, Hendrikus H.M., 75, Lavie, Lena, 509 Mathew, Jehu, 1100 Kekilli, Ersoy, 159 966 Lotam, Chaim, 911 Mathew, Verghese, 465 Lavie, Peretz, 509 Lottes, Sandra R., 1263 Kelly, Patricia, 1409 Kosiborod, Mikhail, 930 Mathier, Michael A., 1151 Lawson, William E., 1409 Loughlin, Kevin R., 1325 Kelm, Malte, 1090 Koskenvuo, Juha, 1648 Matsubara, Tatsuaki, 1203 Le Maulf, Florence, 681 Lous, Jørgen, 1181 Kent, David M., 1384 Kostopoulou, Anna, 558 Mattos, Luiz, 1403 Leber, Alexander, 374 Love, Thomas E., 393, 460 Kent, Kenneth M., 599, 1518 Kostuk, William, 208 Mavilio, Giovanni, 1737 Lee, Cheol Whan, 760, 774 Lo¨wbeer, Christian, 1357 Kereiakes, Dean J., 1177 Kosuge, Masami, 817 May, Heidi T., 169 Lee, Chiu-Yen, 579 Lowe, April, 802 Keren, Gad, 1504 Kotler, Todd S., 1360 Maycock, Chloe Allen, 149 Lee, David P., 1603 Loyalka, Pranav, 1755 Kern, Morton J., 1507 Kouba, Ethel O., 1714 Mazzari, Mario Attilio, 364 Lee, Kent, 573 Lu, Yan, 1653 Kerner, Arthur, 509 Kouhi, Morad, 1656 McCann, Gerald P., 563 Lee, Ki Hong, 1051 Lukas, Mary Ann, 1263 Kesa¨niemi, Y., 970 Koyanagi, Ryo, 1523 McCarroll, Kathleen, 647 Lee, Kun-Tai, 119 Luke, May, 1087 Keyes, Michelle J., 310 Krabill, Kimberly A., 1312 McClean, Dougal, 1691 Lee, Kwan S., 113 Lund, Lars, 399 Khan, Aslam, 1621 Kranis, Mark, 390, 1187 McConnell, Michael E., 704 Lee, Moon-Kyu, 707 Lundt, Stefan, 1648 Khandheria, Bijoy K., 1298 Krause, Kevin R., 222 Lee, Sang Rok, 1051 Luo, Don, 632 McCulloch, Marti, 1440 Khera, Amit, 513, 825 Kremastinos, Dimitrios Th., Lee, Seung-Whan, 774 Lupoglazoff, Jean-Marc, 406 McCullough, Peter A., 222, Khetan, Anita, 1171 146, 558 Lee, Se-Whan, 760 Luppi, Carol, 1002 906 Khumri, Taiyeb M., 1733 Krenning, Boudewijn J., 275, Lee, Won-Young, 99 Lusk, Joan, 1451 McGuire, Darren K., 513, Kiebzak, Gary M., 585 714 Leeper, Jr., Kenneth V., Luttikhuis, Henk Oude, 1252 825 Kildemoes, Helle Wallach, Kristensen, Søren R., 108 1303 Lysyansky, Peter, 1741 McKay, Charles R., 189 1181 Krivokapich, Janine, 1316 Legrand, Victor, 31 Lytle, Bruce, 1087 McManus, David, 822 Kim, Daniel, 1745 Krombach, Gabriele A., 1090 Lehmann, Christoph U., 978 McNamara, Dennis M., 1151 Kim, Dong-Jun, 99 Krone, Ronald J., 189 Lellouche, Nicolas, 242 McNitt, Scott, 163, 642, Kim, Jae-Joong, 760, 774 Krucoff, Mitch, 1680 Lelorier, Jacques J., 428 Ma, Jing, 1482 1100 Kim, Jin-Bae, 1571 Krucoff, Mitchell, 357 Lemieux, Isabelle, 369 Macaya, Carlos, 429, 621 McNurlan, Margaret A., 1409 Kim, Ju Han, 1051 Krumholz, Harlan M., 1227 Lennon, Ryan J., 1134 Maccubbin, Darbie, 1706 McPherson, Ruth, 213 Kim, Jung-Sun, 1571 Ku¨hl, Harald P., 1090 Leo, Roberto, 325 MacEneaney, Owen J., 46 McTaggart, Fergus, 681 Kim, Kye Hun, 1051 Kukreja, Neville, 1027 Leon, Martin B., 1044 Macioce, Alanna, 1119 Mehran, Roxana, 202, 1055, Kim, Sung-Soon, 1571 Kuntz, Richard E., 1044 Leone, Antonio Maria, 364 Mack, Wendy J., 956 1067, 1680, 1691 Kim, Yong Sook, 1051 Kuo, Chi-Tai, 1479 Lepor, Norman E., 1183 Mackie, Andrew S., 839 Mehta, Amar, 1002 Kim, Young-Hak, 760, 774 Kurisu, Satoshi, 1674 Lerman, Amir, 465, 1134 Mackie, Benjamin D., 291 Mehta, Jawahar L., 325, 879 Kimmel, Stephen E., 951 Kurita, Takashi, 53 Lerman, Lilach O., 1134 Maddahi, Jamshid, 1096 Mehta, Laxmi, 906 Kimura, Kazuo, 817 Kusama, Ikuyoshi, 817 Lerman, Shir, 1134 Madyoon, Hooman, 1183 Mehta, Rajendra H., 793, 1288 Kipp, Harold, 1621 Kutcher, Michael A., 329, 333 Les´ko, Blanka, 36 Maessen, Jos, 771 Meier, Bernhard, 353

4 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 Meigs, James B., 1 Mozafari, Mahmoud, 1656 Noe¨l, Martin, 921 Park, Jong Chun, 1051 Polak, Joseph F., 310 Meijer, Albert, 75, 966 Mueller, Ralf, 1691 Nogareda, Gustavo J., 852 Park, Seong-Wook, 760, 774 Poldermans, Don, 1193, Meisel, Simcha R., 1741 Muhlestein, Joseph B., 149, Nose´, Yukihiko, 1440 Park, Seung-Jung, 760, 774 1485, 1555 Melzi, Gloria, 593 169 Nu´ñez, Julio, 797 Park, Won Hah, 707 Pollack, Jr., Charles V., Memisha, Gentian, 182 Mukherjee, Debabrata, 939 Parma, Radosław, 36 1389, 1496 Mendelsohn, Aurora, 186 Mulgund, Jyotsna, 1222, Obata, Hiroaki, 494 Parnetti, Lucilla, 876 Pongiglione, Giacomo, 1284 Mendiz, Oscar, 349, 357 1351 O’Connor, Christopher M., Parodi, Guido, 182 Pool, James L., 134 Meneghelo, Romeu S., 42 Mullany, Charles J., 785 256 Parrinello, Giovanni, 1072 Popma, Jeffrey J., 1044 Menon, Lata, 1714 Mu¨ller, Silvana, 270 Odening, Katja, 103 Pasceri, Vincenzo, 1216, Popovic, Zoran B., 1629 Menon, Santosh G., 1177 Munzel, Thomas, 808, 1623 O’Donnell, Christopher J., 1421 Popp, Richard L., 864 Menon, Venu, 802, 1718 Murakami, Daisuke, 1033 310, 1598 Pascual-Figal, Domingo A., Porter, Avital, 442 Mensah, George A., 1115 Murakami, Ryuichiro, 1203 Ogawa, Hiroshi, 1523 1279 Porto, Italo, 603, 1637, 1671 Mercado, Kristin, 49 Murali, Srinivas, 1151 Ogawa, Yasuhiro, 1203 Patel, Amar D., 1513 Post, Felix, 1623 Meredith, Kent G., 149 Murohara, Toyoaki, 1203 Ogbu, Uzor C., 1179 Patel, Mahesh J., 825 Pothineni, Koteswara R., Meri, Seppo, 890 Murphy, Sabina A., 344, Ogura, Riyo, 754 Patel, Manesh R., 1222 1180 Mertens, Luc, 974 513, 1687 Oguzhan, Abdurrahman, 322 Patel, Nikunj R., 415, 421 Powell, Brian D., 785 Messerli, Adrian W., 1325 Mussardo, Marco, 916 Ohara, Yoshikazu, 754 Patel, Rajnikant, 124, 961 Powers, Eric R., 896 Messerli, Franz H., 876, Mutlu, Bulent, 1429 Ohba, Takayoshi, 1033 Pauly, Daniel F., 250 Prasad, Abhiram, 1067 1325, 1621 Ohman, E. Magnus, 793, Pearl, Gregory John, 990 Prasad, An, 1629 Metra, Marco, 232 Pearson, Robert R., 149 Prato, Stefano Del, 84 Na, Bee Ya, 1128 1222, 1351, 1389, 1496 Miccoli, Roberto, 84 Pearson, Thomas, 1706 Prins, Johannes B., 844 Na, Beeya, 1643 Ohtani, Ryuji, 754 Michev, Iassen, 593, 916 Pedersen, Terje R., 970 Pristipino, Christian, 1216 Na, Yingbo, 202, 1055, Ohte, Nobuyuki, 62 Mickley, Hans, 108, 867 Peels, Kathinka H., 75, 966 Provost, Yves, 1593 1680 Ohuchi, Hideo, 1757 Mieres, Jennifer H., 1096 Peled, Nathan, 472, 925 Pu, Yachuan, 573 Nagai, Takayuki, 53 Oikarinen, Lasse, 295 Mignatti, Andrea, 1434 Pellegrino, Pier Luigi, 1737 Pucci, Paolo Domenico, 651 Nagashima, Michitaka, 1523 Okabe, Teruo, 599 Milei, Jose, 357 Pelliccia, Francesco, 1216 Pulsipher, Mark W., 431 Nagel, Eike, 1109 Okada, Shinsuke, 494 Milford-Beland, Sarah, 1496 Pellicelli, Adriano M., 1470 Puri, Puneet, 49 Nager, Paul, 1451 Okamura, Hideo, 53 Miller III, Joseph, 291 Pellikka, Patricia A., 292, Najjar, Husam, 49 Okin, Peter M., 711 Miller, Larry E., 585 Nakachi, Tatuya, 817 Olivotto, Iacopo, 1575 835 Qian, Juying, 1653 Miller, Michael, 743 Nakama, Yasuharu, 1674 Oller-Martıńez, Guillermo, Pena, Antonio J., 1122 Quinn, Deborah A., 1303 Minagoe, Shinichi, 261 Nakamura, Mamoo, 1394, 1662 Penman, Alan D., 1413 Qureshi, Mansoor, 1680 Minutello, Robert M., 446 1603 Olschewski, Manfred, 103 Penno, Giuseppe, 84 Mishkel, Gregory, 1044 Nakatani, Daisaku, 885 Olsen, John V., 1312 Pepine, Carl J., 1549 Rademaker, Tessa A.M., 607 Mishra, Sundeep, 599 Nallamothu, Brahmajee K., Olson, Ronald E., 1303 Perez, Francisca, 19 Rader, Daniel J., 1698 Misier, AnR. Ramdat, 1252 749, 1399 Olsson, Anders G., 632 Pe´rez, Ruth, 1454 Rader, Valerie J., 1733 Mitchell, Kristi, 329 Nangrahary, Mary, 849 Olsson, Tobias, 1357 Pe´rez-Castrilloń, Jose´ L., Radford, Nina, 1535 Mitsuhashi, Hirotsugu, 1203 Naraghi, Ashkan L., 1183 Omland, Torbjørn, 513 903 Ragosta, Michael, 896 Mitsuma, Wataru, 494 Nardi, Carmela, 84 Ommen, Steve R., 835 Perez-Vizcayno, Maria J., Rahme, Elham, 839 Mittleman, Murray A., 661 Naruse, Keiko, 1203 Onalan, Orhan, 1726 429 Raizner, Albert E., 1044 Miyajima, Hitoshi, 754 Nasir, Khuram, 978 O’Neill, William, 357 Perles, Zeev, 993 Ram, C. Venkata S., 1168 Miyamoto, Koji, 53 Nasir, Khurram, 42 O’Neill, William W., 906 Perloff, Joseph K., 691 Ramabadran, Ramanujam S., Miyata, Masaaki, 261 Nasr, Imad Abi, 1667 Ong, Lawrence, 1096 Perron, Patrice, 369 124 Miyazaki, Shinichiro, 754 Natale, Luigi, 1671 Ookawa, Keisuke, 1674 Perry, Gilbert J., 393 Ramadan, Mahmoud M., 494 Miyazawa, Akiyoshi, 491 Nayyar, Sunil, 1733 Orakzai, Raza, 42 Peteiro, Jesu´s, 1454 Ramp, Warren K., 585 Mizuno, Hiroya, 885 Nazarian, Saman, 1425 Ørn, Stein, 647, 1109 Peterson, Eric D., 1222, Rampersaud, Tilkawatee, Mizuno, Kyoichi, 1033 Nazeri, Iraj, 1656 O’Rourke, Robert A., 208 1351, 1389, 1496 1096 Moccetti, Tiziano, 673 Negassa, Abdissa, 482 Otsuji, Yutaka, 261 Peñafiel, Pablo, 1279 Ramsamujh, Rachael, 603 Moens, An L., 476 Neilan, Tomas, 247 Otten, Richard F., 939 Philips, Binu, 825 Rangarajan, Krishnan, 1316 Mohr, Frederick W., 1072 Neizel, Mirja, 1090 Ottenkamp, Jaap, 984 Phillips, Russell S., 661 Raspanti, Silvia, 651 Moller, James H., 568 Nell, Christine, 291 Ottervanger, Jan Paul, 1252 Picano, Eugenio, 1154, 1491 Rassaf, Tienush, 1090 Mongiardo, Rocco, 364 Nelson, Jeanenne J., 1263 Otto, Catherine M., 686 Picchio, Fernando Maria, Ravekes, William J., 978 Monrad, E. Scott, 482 Nemes, Attila, 275, 714 Otto, Maria E., 1298 1462 Ray, Simon, 970 ¨ Monserrat, Lorenzo, 1454 Neumann, Franz J., 1691 Ozdemir, Murat, 1568 Pichard, Augusto D., 599, Razzini, Cinzia, 325 Montefusco, Antonio, 1575 Neuzner, Joerg, 573 Ozdogru, Ibrahim, 322 1518 Rebuzzi, Antonio Giuseppe, Montorfano, Matteo, 470, Newby, L. Kristin, 315, Pickens, Gary, 749 364 593, 916 1351, 1389 Pacheco, Rebecca, 879 Piek, Jan J., 1201 Rechavia, Eldad, 442 Mookadam, Farouk, 1159 Newman, Tiffany, 1535 Pachinger, Otmar, 270 Pieper, Karen S., 315, 793 Redondo, Beleń, 1279 Moran, Mark G., 1360 Niccoli, Giampaolo, 364, Pagonidis, Kostas, 1258 Pierard, Luc A., 31 Reed, Shelby D., 256 Morel, Marie-Ange`le, 1072 1671 Pajouh, Mohammad Danesh, Pierson, Lee M., 585 Reid, Cheryl L., 830 Moreno, Carlos A., 113 Nicholls, Stephen J., 813 1656 Pierson, Mary E., 585 Reid, Kimberly J., 154, 636 Moreno, Raul, 429 Nichols, John H., 1122 Palacios, Alejandro, 357 Pijls, Nico H.J., 504 Reilly, Muredach P., 951 Moreno, Rau´l, 621 Nichols, John, 247 Palagi, Caterina, 84 Pillie`re, Re´my, 1667 Reimers, Bernhard, 1062 Moreyra, Abel E., 1374 Nicola´s, Francisco, 1279 Palamara, Antonio, 1421 Pillutla, Priya, 822 Rein, Azaria J.J.T., 993 Morgan, Timothy, 1714 Nidorf, Mark, 805 Palikhe, Anil, 890 Pilote, Louise, 839 Reisman, Mark, 1312 Morice, Marie Claude, 1072 Nieminen, Markku S., 890 Palmer, Dean, 1629 Pinamonti, Bruno, 307 Rekhi, Rachna, 1394 Morray, Brian, 1100 Nienaber, Christoph, 970 Palmeri, Sebastian T., 1374 Pinsky, David J., 1364 Ren, Xiushui, 822, 1643 Morrow, David A., 344 Nigg, Claudio Renato, 1230 Pan, Sharon X., 91 Piotrowicz, Katarzyna, 163 Renard, Marleen, 974 Moscardo, Antonio, 19 Nii, Masaki, 699, 1757 Pandozi, Claudio, 1421 Piovaccari, Giancarlo, 1062 Resnic, Frederic S., 766 Moscucci, Mauro, 1399 Niimura, Hideshi, 1750 Panwar, Sadik R., 1180 Piraino, Ruben, 357 Reuss, Christina S., 1451 Moses, Jeffrey W., 1044 Nijveldt, Robin, 563 Papadopoulos, Christodoulos Pirat, Bahar, 1440 Reynolds, Matthew R., 766 Mosley, Jr, Thomas H., 1413 Nikolsky, Eugenia, 1055 E., 1024 Piro, Maddalena, 307 Ribichini, Flavio, 1082 Moss, Arthur J., 163, 642, Nir, Amiram, 993 Parharidis, Georgios E., 1024 Piñon, Marta, 19 Ricciardelli, Bruno, 779 1100 Nissen, Steven E., 813 Parissis, John T., 146 Pizzuto, Francesco, 325 Riccitelli, Miguel Angel, 357 Mosseri, Morris, 911 Nistri, Stefano, 1575 Park, Duk-Woo, 760, 774 Plotnick, Gary D., 743 Rice, Janet, 1610 Moustafa, Sherif, 1159 Noda, Takashi, 53 Park, Hyung Wook, 1051 Poirier, Paul, 921 Rice, Tasha N., 1234

AUTHOR INDEX 5 Rich, Michael W., 393, 460 Salvadori, Claudia, 182 Seljeflot, Ingebjørg, 1544 Sisk, Christine, 1706 Steinberg, Daniel H., 599 Richichi, Giuseppe, 1216 Samman, Ahmed M., 1593 Selker, Harry P., 1384 Sisson, Stephen D., 1234 Steinbuch, Robert, 1166 Ridker, Paul M., 1246, 1500 Sanada, Fumihiro, 494 Selzer, Faith, 626 Siu, Samuel C., 1593 Stolfus, Lisa, 1535 Rieber, Johannes, 1122 Sanchez-Aquino, Rosa, 621 Senges, Jochen, 1208, 1288 Siviglia, Massimo, 364 Stoll, Hans-Peter, 1072 Riess, Kenneth J., 1745 Sanchez-Recalde, Angel, 429 Sengupta, Ranjita, 961 Sjauw, Krischan D., 1201 Sto¨llberger, Claudia, 145 Rifai, Nader, 344 Sańchez-Recalde, Angel, 621 Senior, Roxy, 1369 Skaf, Elias, 415 Stone, Gregg W., 202, 906, Rigatelli, Gianluca, 1621 Sanchis, Juan, 797 Seppa¨nen, Mikko, 890 Skalidis, Emmanuel I., 1258 1055, 1067 Rigby, Michael L., 984 Sanders, Paul W., 393 Serdoz, Roberto, 1062 Skeif, Basel, 482 Stone, Gregg W, 1680 Rigo, Fausto, 1154 Sandhu, Gurpreet, 465 Serebruany, Victor L., 288 Skelding, Kimberly A., 616, Stoner, Casey N., 1733 Rihal, Charanjit, 465 Sands, Scott A., 154 Serruys, Patrick W., 5, 607, 906 Stoner, Casey, 930 Ristow, Bryan, 1128, 1643 Sangiorgi, Giuseppe M., 593 790, 1027 Skelton, Thomas N., 1413 Stout, Karen K., 686 Rizzello, Vittoria, 1193 Sangiorgio, Pietro, 1062 Serruys, Patrick Washington, Skjærpe, Terje, 970 St-Pierre, Julie, 369 Roberts, Robert, 213 Saniuk, Catherine, 1002 1072 Slavin, Leo, 1316 Strawderman, Robert L., 197 Roberts, William C., 134, Sant’Anna, Fernando M., 504 Sessa, Francesco, 1737 Sleeper, Lynn A., 802 Stuckey, Thomas D., 431, 213, 382, 519, 943, 1269, Santas, Enrique, 797 Sestito, Alfonso, 1378 Slottow, Tina L. Pinto, 599 1067 1334, 1560, 1698 Santini, Massimo, 1421 Sgueglia, Gregory A., 1378 Smallhorn, Jeffrey F., 699 Stuckey, Thomas, 202 Roberts, William Clifford, Santoro, Giovanni Maria, Shabestari, Abbas Arjm, Smeets, Hubert J.M., 264 Stuckey, Tom, 1680 588, 990, 1171, 1768 651 1656 Smeraldi, Attilio, 1284 Stulak, John, 1159 Rodriguez, Esther, 1454 Santos, M. Teresa, 19 Shah, Arvind, 1706 Smirin, Nahum, 1741 Støvring, Henrik, 1181 Rodriguez-Granillo, Gastoń Santos, Raul D., 42 Shah, Dipak, 1614 Smith, Jr., Sidney C., 189, Su, Ho-Ming, 119 A., 5 Santos, Renato M., 333 Shah, Prediman K., 1183 1222 Suddath, William O., 599, Roe, Matthew T., 1222, Santos, Renato, 315 Shah, Sangeeta, 1106 Smith, Kimberly A., 599, 1518 1351, 1389, 1496 Santure´, Marta, 369 Shah, Sanjiv J., 1128 1518 Sudhir, Krishnankutty, 1394 Roes, Stijntje D., 657 Sanz, Alberto, 903 Shalaby, Alaa A., 573 Smith, Pal, 1544 Suh, Il-Woo, 760 Rognoni, Andrea, 1082 Sarembock, Ian J., 896 Shapira, Itzhak, 1504 Smith, Sidney C., 1718 Sukhija, Rishi, 879 Rogowski, Ori, 1504 Sari, Ibrahim, 1024 Shapiro, Haim, 146 Sobota, Kristi D., 1765 Sulla, Antonio, 651 Roguin, Ariel, 509 Sarmiento, Ricardo, 349 Shapiro, Michael D., 247, Soler, Rafaela, 1454 Sumiyoshi, Tetsuya, 1523 Romagnoli, Enrico, 364, Sarnak, Mark J., 1137 1122 Soliman, Osama I.I., 264, Summay, Gabriel, 349 1671 Satija, Sameer, 291 Shaqra, Hussein, 482 275, 714 Suna, Shinichiro, 885 Roman, Kevin S., 699 Satler, Lowell F., 599, 1044, Sharaf, Barry L., 626 Solowiejczyk, David E., 1588 Sutherland, George R., 974 Roman, Mary J., 1306 1518 Sharma, Arya M., 1470 Somberg, John, 1020 Sutter, Johan De, 79 Romeo, Francesco, 325 Sato, Hiroshi, 885 Sharman, James E., 844 Somers, Virend K., 1298 Suyama, Kazuhiro, 53 Romero-Corral, Abel, 1298 Satomi, Kazuhiro, 53 Shaw, Leslee J., 1096 Sonel, Ali F., 1119 Suzuki, Kaori, 26 Ronan, Adam, 1614 Saucedo, Jorge F., 1222 Shaw, Leslee, 208 Song, Chan-Hee, 99 Suzuki, Naoki, 754 Roncella, Adriana, 1216 Saul, J. Philip, 997 Shaw, Richard E., 189, 329 Song, Ze-Zhou, 1482 Svatikova, Anna, 1298 Ronnow, Brianna S., 169 Sawada, Stephen, 1016 Shechter, Michael, 911 Sonke, Gabe S., 1481 Swart, Hans de, 849 Rosanio, Salvatore, 934 Scaglione, Marco, 1575 Sheiban, Imad, 1062 Sonmez, Kenan, 1429 Szarek, Michael, 632 Rosen, Stacey E., 1096 Schaefer, Benjamin M., 686 Shenkman, Heather J., 1143 Sosef, Froukje, 673 Szarfer, Jorge, 349 Roshani, Mahmoud, 1656 Schaefer, Ernst J., 681 Sheps, David S., 519 Sostman, H. Dirk, 1303 Szkro´bka, Iwona, 36 Rosman, Howard S., 1196 Schalij, Martin J., 68, 554, Sherwin, Roger, 1610 Sousa, Amanda G.M.R., Ross, Amy M., 1360 657 Sheth, Tej N., 1122 1403 Taçoy, Gu¨lten, 1568 Rossebø, Anne B., 970 Scherr, Daniel, 1425 Sheu, Sheng-Hsiung, 119 Sousa, J. Eduardo, 1403 Rostykus, Paul S., 1360 Tacy, Theresa Ann, 1462 Schiavoni, Giovanni, 364 Shim, Won-Heum, 1571 Southard, Matthew C., 1687 Tajik, A. Jamil, 1451 Roubin, Gary, 871 Schiele, Francois, 607 Shimada, Yoshihisa, 1394 Sozzi, Fabiola B., 1193 Rovner, Aleksandr, 239 Takagi, Atsushi, 26 Schiele, Rudolf, 1208 Shimatani, Yuji, 1674 Specchia, Salvatore, 1462 Roy, Probal, 599, 1518 Takahashi, Takefumi, 491, Schiller, Nelson B., 1128, Shimbo, Daichi, 860 Speciale, Giulio, 1216 Ruano, Miguel, 19 754 1643 Shimizu, Masahiko, 885 Spencer, Kirk T., 1614 Rubinshtein, Ronen, 472, Takano, Masamichi, 1033 Schinkel, Arend F.L., 1193 Shimizu, Wataru, 53 Spencer, Merrill P., 1312 925 Takenaka, Toshihiro, 261, Schliamser, Jorge E., 925 Shin, Jaekyu, 250 Sperling, Laurence S., 291 Rumsfeld, John S., 189, 1750 Schnabel, Renate, 808 Shinfeld, Ami, 1294 Spertus, John A., 154, 208, 1351 Talini, Enrica, 84 Schnittger, Ingela, 864 Shinozaki, Kazuhiro, 1608 636, 930, 1227 Rupprecht, Hans J., 808, Tamburino, Corrado, 1062 Schnugg, Stephen J., 1360 Shivkumar, Kalyanam, 242 Spevak, Philip J., 978 1623 Tamura, Akira, 1608 Schoenhagen, Paul, 813 Shlipak, Michael G., 393 Spiers, Philip S., 1762 Russell, Mary E., 607 Tan, Mary, 186 Schofield, Richard S., 250 Shotan, Avraham, 1741 Spodick, David H., 49, 58, Ruthazer, Robin, 1384 Tanabe, Naohito, 494 Schoonderwoerd, Kees, 264 Sianos, Georgios, 1027 390, 1187 Rutherford, Barry D., 202 Tanajura, Luis Fernando, Rutherford, Barry, 1680 Schouten, Olaf, 1485, 1555 Sicari, Rosa, 1154, 1491 Spragg, David, 1425 1403 Ruwende, Cyril, 1364 Schramm, Alexander, 1288 Siddiqui, Tehmina, 415 Squire, Iain, 1109 Tanaka, Koji, 53 Ryan, Daniel, 1100 Schulman, Kevin A., 256, Siegel, Robert J., 739 Srinivas, Vankeepuram S., Tandogan, Izzet, 1179 Rybicki, Frank J., 1481 339 Silverman, Jon, 1002 482 Tandon, Himanshu, 1776 Schulte, Helmut, 541 Silversides, Candice K., Staico, Rodolfo, 1403 Tanimoto, Shuzou, 1027 Schultheiss, Heinz P., 1680 1593 Stankovic, Goran, 916 Tanne, David, 667 Sabatine, Marc S., 344 Schussler, Jeffrey M., 1458 Silvestri, Furio, 307 Stauffer, Brian L., 46 Tavalla, Hedayatollah, 1656 Sabbadini, Gastone, 307 Schutta, Mark, 951 Simari, Robert D., 1134 Stebbins, Amanda, 315 Tavano, Davide, 470 Sachdev, Vandana, 1448 Schwammethal, Ehud, 667 Simonetti, Ignazio, 182 Steendijk, Paul, 68 Tavernier, Rene, 79 Sacrinty, Matthew T., 333 Schwartz, Gregory G., 632 Simpson, Leo, 1755 Stefanadi, Elli C., 1473 Taylor, Herman A., 1413 Sadeghi, Mehrdad, 1055 Schwartz, Lewis B., 1403 Simpson, Robert, 573 Stefanadis, Christodoulos I., Taylor, Lisa, 1177 Safavi, Kaveh, 749 Schwartz, Roseline, 667 Sinagra, Gianfranco, 307 1473 Tcheng, James E., 202, Sakai, Shinichi, 1203 Schwartz, Stan, 951 Singh, Anurag, 1180 Stefanadis, Christodoulos, 1055, 1067 Sakata, Yasuhiko, 885 Schwerzmann, Markus, 1593 Singh, Ripudamanjit, 465 984 Tehrai, Mahmoud, 1656 Saleeb, Susan F., 1588 Scirica, Benjamin M., 344 Singh, Suman, 1518 Steg, P. Gabriel, 1212 Tei, Chuwa, 261, 1750 Salehian, Omid, 1593 Scott, Margaret, 879 Singla, Ish, 1119 Stein, Evan, 681 Teirstein, Paul S., 1044 Salem, Deeb, 1137 Scott, Mark, 1177 Sinha, Sunil, 1425 Stein, Michael, 1538 Tekin, Gulacan Ozgun, 159 Salevatipour, Babak, 1656 Segal, Alan Z., 1306 Sinisalo, Juha, 890 Stein, Paul D., 415, 421, Ten Berg, Jurrien M., 563 Salisbury, Adam C., 636 Seimiya, Koji, 1033 Siontis, George C.M., 450 1303 ten Cate, Folkert J., 264, Salton, Carol J., 1321 Selby, Van, 822 Sipahi, Ilke, 813 Steinberg, Benjamin A., 1212 275

6 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 Ten Cate, Folkert J., 563 Tymchak, Wayne, 1745 Vedala, Giridhar, 197 Weilbacher, Dana, 1535 Yagmur, Julide, 159 Ten, Yuli, 1687 Vega, Gemma, 903 Weinberger, Judah, 1020 Yamaguchi, Jun-ichi, 1523 Tendera, Michał, 36 Uckan, Ahmet, 159 Veire, Nico Van de, 79 Weiner, Daniel, 1137 Yamamoto, Masanori, 1033 Tendera, Zoﬁa, 36 Ueland, Thor, 513 Velazquez, Eric, 315 Weiner, Ethan, 91 Yamasaki, Masao, 1394 Tenenbaum, Alexander, 667 Uetani, Tadayuki, 1203 Veltri, Enrico, 1706 Weintraub, William S., 189, Yanagawa, Takao, 494 Teo, Koon K., 208 Umans, Victor, 849 Ventura, Fa´bio Machado, 208, 329 Yanamadala, Sunitha, 1364 Teplitsky, Igal, 442 Umemura, Satoshi, 817 504 Weir, Matthew, 743 Yancy, Clyde W., 1560 Teraguchi, Hiroyuki, 261 Urashima, Mitsuyoshi, 1523 Ventura, Hector O., 878 Weiss, Melvin B., 1468 Yang, Eric H., 1134 Terashima, Mitsuyasu, 491 Urban, Lynn H., 835 Verburg, Kenneth M., 91 Weiss, Robert, 673 Yang, Qinghong, 793 Terembula, Karen, 951 Uretsky, Seth, 876 Vered, Yafa, 1504 Weisse, Allen B., 129 Yang, Shu-Hsin, 579 Terry, James G., 1714 Uyttebroeck, Anne, 974 Verheye, Stefan, 1691 Weissman, Neil J., 943 Yaniv, Nisan, 925 Testa, Luca, 1637 Vetrovec, George W., 11, Weisz, Giora, 1044 Yarandi, Hossein, 250 Tettinger, Antal, 1025 Va¨a¨na¨nen, Heikki, 295 307 Welch, William R., 1325 Yarmenitis, Spyridon, 1258 Thakore, Avni H., 1598 Vagelos, Randall H., 1603 Vidakovic, Radosav, 1555 Wenaweser, Peter, 353 Yc˘as, Joseph, 1538 Thanopoulos, Basil (Vasilios) Vaina, Sophia, 1072 Viganò, Giorgio, 1434 Wendelen, Luc C., 476 Yen, Hsueh-Wei, 119 D., 984 Vainer, Jindra, 771 Viitasalo, Matti, 295 Wenger, Nanette K., 11 Yetkin, Ertan, 159, 1179 Thaulow, Erik, 997 Valantine, Hannah A., 1603 Vikraman, Narayanan, 1196 Wentworth, Chuck, 530 Thayssen, Per, 279 Valde´s, Mariano, 1279 Vis, M. Marije, 1201 West, Christine R., 91 Yeung, Alan C., 1603 Theodorakis, George N., 558 Valeti, Uma, 785 Vlachopoulos, Charalambos Whellan, David J., 256 Yock, Paul G., 491, 1394, Therrien, Judith, 1593 Valgimigli, Marco, 1072 V., 1473 Whiddon, Lonnie Lee, 588 1603 Thierer, Jorge, 357 Vallabhan, Ravi C., 1458 Vlachos, Helen A., 626 White, Charles, 743 Yokokawa, Miki, 53 Thomas, James D., 1629 Valles, Juana, 19 Vlagopoulos, Panagiotis, White, Harvey D., 793 Yoon, Nam Sik, 1051 Thomas, Randal J., 785 Valtonen, Ville, 890 1137 White, William B., 91 Yoshifuku, Shiro, 261 Thompson, Peter L., 805 van Dantzig, Jan Melle, 75 Vletter, Wim B., 264, 275 Whitehead, Robin, 1535 Younes, Naji, 822 Thompson, W. Reid, 978 van Dantzig, Jan melle, 966 Voeltz, Michele D., 1513 Whooley, Mary A., 1128, Young, James B., 460, 1560 Tian, Xin, 1448 van den Bosch, Bianca J.C., Vogel, Jody A., 222 1643 Young, Janet, 749 Tibold, Antal, 1025 264 Vogel, Robert, 743 Wienbergen, Harm, 1208 Ypenburg, Claudia, 554, 657 Tibrewala, Amit V., 1106 van den Brand, Marcel J., Vogt, Anja, 673 Wiener, Isaac, 242 Yu, Bo, 261 Tickoo, Sumit, 1496 1072 Vogt, Juergen, 232 Wilczyn´ski, Mirosław, 36 Yuasa, Toshinori, 261 Tighiouart, Hocine, 1137 van den Brink, Renee B.A., Vohl, Marie-Claude, 369 Wildman, Rachel P., 1610 Yuba, Kenichiro, 754 Tijssen, Jan G.P., 1201 966 von Ziegler, Franz, 374 Wilensky, Robert L., 1044 Yucel, E. Kent, 1481 Tilley, Barbara C., 1236 van der Schaaf, Rene´ J., Voon, Wen-Chol, 119 Willems, Roger, 573 Yumino, Dai, 26 Tobis, Jonathan M., 1165, 1201 Vourvouri, Eleni, 1193 Willenheimer, Ronnie, 970 Yunis, Carla, 830 1316 van der Voort, Pepijn H., 75 Vrints, Christiaan J., 476 Willens, Howard J., 1242 Togni, Mario, 353 van der Wall, Ernst E., 68, Vydt, Tom C.G., 264 Willett, DuWayne, 541 Toivonen, Lauri, 295 554, 657 Williams, Craig, 145 Zacharis, Evangelos A., 1258 Tomczak, Corey R., 1745 van der Wouw, Pol A., 966 Wachtell, Kristian, 970 Williams, David O., 626 Zahger, Doron, 667 Tommasi, Mariasilvia, 651 Van Dockum, Willem G., Waggoner, Alan D., 239 Wilsch, Mareile, 103 Zahid, Maliha, 1119 Torguson, Rebecca, 599 563 Wagner, Galen S., 934 Wilson, Alan C., 1374 Zahn, Ralf, 1288 Torp-Pedersen, Christian, van Domburg, Ron T., 1027, Wakisaka, Yuko, 1757 Wilson, Peter W.F., 1236 Zaizen, Hirofumi, 1608 1146 1193, 1485 Waksman, Ron, 424, 599, Windecker, Stephan, 353 Zalenski, Robert J., 1384 Torzewski, Micheal, 808 van Erven, Lieselot, 554 1518, 1687 Winowich, Steve, 1151 Zalesin, Kerstyn C., 222 Towae, Frank, 1208 van Es, Gerrit-Anne, 607 Waltenberger, Johannes, 771 Wittebols, Kristel, 1072 Zarayelyan, Armine, 984 Trabattoni, Daniela, 1062 van Gaal, William Joseph, Wang, Chun-Li, 1479 Wiviott, Stephen D., 344 Zareba, Wojciech, 163, 642, Trani, Carlo, 364, 1671 603 Wang, Patrick, 1044 Wojakowski, Wojciech, 36 1100, 1143 Trauthen, Brett, 1691 van Gelder, Berry, 75 Wang, Renwei, 535 Wolf, Philip A., 310 Zarrabi, Ali, 1656 Tricoci, Pierluigi, 1389 van Geuns, Robert-Jan M., Wang, Thomas J., 1598 Wolfe, Megan L., 951 Zaugg, Margo J., 1403 Trivax, Justin E., 222 264 Ward, R. Parker, 499 Wolski, Kathy, 813 Trivi, Marcelo S., 357 Van Guilder, Gary P., 46 Waseda, Katsuhisa, 491, Wong, S. Chiu, 446 Zehender, Manfred, 103 Trocchio, Gianluca, 1284 van Hemel, Norbert M., 75, 1603 Wood, G. Craig, 616 Zehr, Kenton, 1159 Trotta, Graziana, 1637 966, 1252 Wassel Fyr, Christina L., Woodard, Pamela K., 1303 Zeymer, Uwe, 1208, 1212, Tsai, Thomas T., 1399 Van Hoof, Viviane O., 476 486 Woods, Jeffrey A., 707 1288 Tsao, Lana, 404 van Ommen, Vincent, 771 Watanabe, Kenichi, 1757 Wright, R. Scott, 785 Zhang, Feng, 1653 Tsetis, Dimitrios K., 1258 Van Rossum, Albert C., 563 Waters, David D., 213, 822 Wu, Hongyi, 1653 Zheng, Ling, 956 Tsuchida, Keiichi, 607, 1072 Vanbelle, Sophie, 31 Watkins, Matthew W., 175 Wuyts, Floris L., 476 Zhou, Zheng, 607 Tsurumi, Yukio, 26 Vardas, Panos E., 1258, Watson, Denny D., 896 Wyller, Vegard Bruun, 997 Zile, Michael R., 393, 460 Turco, Mark, 202, 1680 1721 Watson, Douglas, 530 Zimarino, Marco, 1062 Turhan, Hasan, 159, 1179 Vasaiwala, Samip, 1614 Watson, Timothy, 1617 Xie, Jipan, 1115 Zineh, Issam, 250 Turnage II, Thomas Alpert, Vasan, Ramachandran S., 1598 Weaver, W. Douglas, 1360 Xue, Zhenyi, 599 Zmudka, Krzysztof, 607 588 Vaseghi, Marmar, 242 Webb, Gary D., 1593 Zoccai, Giuseppe Biondi, Tuzcu, E. Murat, 813, 943 Vasiliadou, Carmen, 1473 Webb, John, 1680 Yagihara, Toshikatsu, 1757 1637 Tveit, Arnljot, 1544 Vassanelli, Corrado, 584, 1082 Weg, John G., 1303 Yagmur, Cengiz, 159 Zoghbi, William A., 1440

AUTHOR INDEX 7 SUBJECT INDEX JANUARY 1, 2007 THROUGH JUNE 15, 2007

ACE inhibitors. See Angiotensin-converting enzyme inhibitors predicting prognosis in unselected patients admitted to the coronary care unit Acronyms, CAMELOT tales about, 878 (Readers’ Comments) and usefulness of troponin levels below the diagnostic cut-off level for, ACS. See Acute coronary syndrome 1357 Acute aortic dissection, frequency of and inappropriate treatment of misdiagnosis of, primary percutaneous coronary intervention for, time to treatment impact on 852 myocardial reperfusion and infarct size with, in the EMERALD Trial, 1680 Acute coronary syndrome recent trends in hospitalization in United States for, 749 aspirin plus warfarin vs aspirin plus clopidogrel after, 1637 relative effectiveness of ACE inhibitors after, 428 (Readers’ Comments) changes in patterns of coronary revascularization strategies for patients with, in reperfused the CRUSADE Quality Improvement Initiative, 1222 predictors of left ventricular remodeling after, 1024 (Readers’ Comments) differentiation between acute pulmonary embolism on the basis of negative T relation of plasma brain natriuretic peptide to serum indexes of collagen type waves and, 817 I turnover and left ventricular remodeling after, 651 intravascular ultrasound of, relation of plaque size to necrotic core in patients short- and long-term mortality in the percutaneous coronary intervention era and with, 790 admission hyperglycemia and diabetes mellitus after, 1674 metabolic syndrome impact on clinical outcomes of non-clinically diagnosed unfractionated heparin after primary angioplasty in patients not receiving glyco- diabetic patients with, 667 protein IIb/IIIa inhibitors for, usefulness of, 202 Ն MIRACL Study of high-dose atorvastatin benefits in patients 65 years of age Ad hoc percutaneous coronary intervention, outcomes following staged vs, 446 with, 632 Adipose tissue, subepicardial, in patients with HIV, relation of carotid intima-media non–ST-elevation thickness to, 1470 aspirin dosing patterns, in the CRUSADE Quality Improvement Initiative, Adolescents, with or without chronic fatigue, usefulness of an abnormal 1496 cardiovascular response during low-grade head-up tilt-test for enoxaparin vs unfractionated heparin effectiveness in silent and clinically discriminating between, 997 apparent, 186 ␤ 2-Adrenoceptor haplotype, relation to risk of death and heart transplantation with heart failure with preserved left ventricular systolic function among patients heart failure, 250 with, 1351 Adults racial differences among high-risk patients with, 315 aged 21 to 35 years, prevalence and clinical correlates of isolated mitral regur- usefulness of ST depression with T-wave inversion in leads V to V for 4 6 gitation, isolated aortic regurgitation, and both, from the CARDIA Study, predicting one-year mortality in, Electrocardiographic Analysis of the 830 Global Use of Strategies to Open Occluded Coronary Arteries IIB Trial, cardiac involvement with m.3243AG MELAS gene mutation in, 264 934 with congenital heart disease, health care resource utilization by, 839 previous, self-reported use of alternative and complementary medicine in pa- with cyanotic congenital heart disease, nitric oxide metabolism in, 691 tients with, 930 U.S., dietary supplement use with coronary artery disease and atherosclerotic prognostic value of transient and sustained increase in in-hospital creatinine on risks by, 661 outcomes of patients admitted with, 939 Adult Treatment Panel III, metabolic syndrome definition comparisons of serum complement C3/C4 ratio, as biomarker for recurrent cardiovascular events International Diabetes Federation and, 541 in, 890 African-Americans statin therapy in, 213 (Editor’s Roundtable) free of coronary heart disease, left ventricular architecture and survival in, from suspected, blood transfusions in patients with anemia and, 1119 the Atherosclerosis Risk in Communities (ARIC) Study, 1413 usefulness of baseline plasma myeloperoxidase levels as independent predictor SYNERGY trial of high-risk patients with non–ST-elevation acute coronary syn- of myocardial infarction at two years in patients presenting with, 1364 drome and, 315 Acute decompensated heart failure, 1560 (Editor’s Roundtable) Age Acute myocardial infarction after percutaneous coronary intervention, usefulness of ultrasonic strain mea- among fibrinolytic-treated patients with acute STEMI presenting with cardiogenic surements to predict regional wall motion recovery in patients with, 754 shock, impact of initial heart rate and systolic pressure on mortality and, bare metal vs drug-eluting stents and risk of, 621 793 baseline platelet count impact in patients undergoing primary percutaneous cor- blood pressure response to trandolapril add-on therapy in patients taking vera- onary intervention in, CADILLAC Trial, 1055 pamil SR and, INVEST Study, 1549 body mass index impact on outcomes after PCI for, 903 Doppler measures of diastolic function and, 1629 bundle branch block patterns in prediction of death after, usefulness of, 647 multidetector spiral computed tomography for diagnosis of acute pulmonary comparison of left ventricle ejection fraction and exercise capacity as predictors embolism according to gender and, 1303 of two- and five-year mortality after, 436 Alcohol septal ablation, for obstructive hypertrophic cardiomyopathy, contrast- comparison of mortality benefit of immediate thrombolytic therapy vs delayed enhanced MRI with and without right bundle branch block after, 563 primary angioplasty for, 1384 Alternative medicine, self-reported use of, in patients with previous ACS and, 930 contrast echocardiography for left ventricular thrombus assessment after, 1667 American College of Cardiology/American Heart Association Guidelines for PCI, drug-eluting vs bare metal stents impact on later frequency of, 333 risk-adjusted mortality analysis of, 189 early statin treatment effect at standard doses on long-term clinical outcomes in American College of Cardiology–National Cardiovascular Data Registry, PCI trends patients with, 1523 report by, 329 folic acid effect on endothelial function after, 476 American Journal of Cardiology, proceedings of the Editorial Board meeting on 26 metabolic syndrome impact, and its additive effect with smoking on subsequent March 2007, 1768 (From the Editor) cardiac events after, 885 AMI. See Acute myocardial infarction microbiological profile of septic complication in patients with cardiogenic shock Amino-terminal Pro-BNP. See N-Terminal Pro-BNP following, from the SHOCK Study, 802 Amiodarone, safety and efficacy comparison of propafenone vs procainamide for no re-flow during primary percutaenous coronary intervention for, effect on six- conversion of recent onset atrial fibrillation vs, 1721 month mortality of, 442 Amplatzer perimembranous ventricular septal defect occluder, transcatheter closure in patients with vs without aortic valve sclerosis, statin therapy and, in Heart of perimembranous ventricular septal defects in infants and children and Soul Study, 1128 using, 984

8 ©2007 by Excerpta Medica Inc. All rights reserved. 0002-9149/07/$–see front matter The American Journal of Cardiology Vol. 99 June 15, 2007 Anemia Aortic dissection, type B, intraluminal phased-array imaging vs transesophageal blood transfusions in patients with suspected ACS and, 1119 echocardiography or intravascular ultrasound in, 270 hemorrhagic complications and mortality following PCI and, 1513 Aortic regurgitation risk of kidney function decline with heart failure and, 1137 isolated, and isolated mitral regurgitation, and both, prevalence and clinical cor- Aneurysms, sinus of Valsalva, surgical repair of, retrospective study of 47 years of relates of, in adults aged 21 to 35 years, from the CARDIA Study, 830 a single center experience and systematic overview of published reports subaortic ventricular septal defect at Ͻ1 year of age, development of aortic cus- on, 1159 pal prolapse and, 1588 Anger provocation, effect on endothelium-dependent and -independent vasodilation Aortic stiffness, relation of habitual cocoa consumption to wave reflections and of, 860 central hemodynamics in healthy individuals and, 1473 Angina pectoris Aortic thrombus, giant floating, in transesophageal echocardiography, 739 chronic, gender comparison of efficacy and safety of ranolazine for, 11 Aortic valve estradiol-drospirenone hormone treatment and myocardial perfusion reserve in bicuspid postmenopausal women with, 1648 isolated, progressive dilation of the ascending aorta in children with, 978 preexisting, short- and long-term outcomes of intravenous nicorandil in first usefulness in predicting elastic properties of the ascending aorta, 686 acute STEMI patients with, 1203 calcium, relation to myocardial ischemic perfusion in patients with low coronary serial intravascular ultrasonic study of outcomes of coronary culprit lesions with artery calcium score and, 1535 plaque rupture following bare metal stent implantation in patients with, sclerosis, AMI in patients with vs without, statin therapy and, in Heart and Soul 1394 Study, 1128 stable Apadenoson, in stress myocardial perfusion imaging, 1619 (Editorial) CRP relation to coronary collaterals with coronary artery disease and, 509 Apoptosis, left ventricular diastolic filling pattern in fatal AMI and, 307 high-sensitivity CRP before and after coronary angioplasty in, 31 AQ interval, measurements of, usefulness for prediction of left ventricular end- unstable diastolic pressure, 119 hospitalization in diastolic and systolic heart failure, 460 Argatroban, impact of smart infusion technology on administration of, 1002 safety of sirolimus-eluting stenting and its effect on restenosis in patients Arrhythmias with, a SIRIUS substudy, 1044 exercise-induced, prognostic significance in hypertrophic cardiomyopathy of, 835 Angiography. See also Coronary angiography good books appearing in 2006 on, 745 vascular, good books appearing in 2006 on, 745 intraatrial block and, 49 Angioplasty coronary artery involvement in, 58 coronary (See Coronary angioplasty) Asians, safety and efficacy of statins for, 410 delayed primary, for AMI, comparison of mortality benefit of immediate thrombo- Aspirin lytic therapy vs, 1384 Angiotensin-converter enzyme inhibitor therapy in STEMI patients and, prognos- primary, relation between leukocyte count, myonecrosis, myocardial perfusion, tic impact of acute beta blocker therapy with, 1208 and outcomes following, 1067 alone vs aspirin plus ticlopidine or clopidogrel after intracoronary implantation with stable angina pectoris, high-sensitivity CRP before and after, 31 of a Carbofilm-coated stent, 1062 Angio-Seal vascular closure device, cost-minimization analysis following PCI of, antiplatelet effects of, ranitidine and, 124 766 colchicine effect on high-sensitivity CRP in patients with stable CAD indepen- Angiotensin-converting enzyme inhibitors dent of atorvastatin and, 805 after AMI, relative effectiveness of, 428 (Readers’ Comments) coronary artery disease, platelet TXA , and myonecrosis in STEMI patients and, aspirin therapy in STEMI patients and, prognostic impact of acute beta blocker 2 19 therapy with, 1208 measuring clopidogrel responsiveness, postprocedural myonecrosis markers in development of type 2 diabetes mellitus and, 1006 patients undergoing PCI and resistance to, 1518 Angiotensin receptor blockers, development of type 2 diabetes mellitus and, 1006 Ankle–brachial index plus warfarin vs plus clopidogrel after ACS, 1637 abnormalities, prediction of coronary atherosclerosis in asymptomatic subjects statins and platelet inhibition in patients with coronary stent thrombosis by, 353 with diabetes mellitus type 2 and, 951 Asynchrony, intra- and interatrial, in patients with heart failure, 79 association with carotid intimal media thickness in the Rancho Bernardo study, Atherosclerosis 876 (Readers’ Comments) assessment confounders in the Rancho Bernardo study, 876 (Readers’ Com- Annuloplasty, reductive, need in patients undergoing mitral repair for chronic mitral ments) Ն regurgitation due to mitral valve prolapse, annular-to-leaflet mismatch depressive symptoms in Americans 65 years of age and, 1610 Յ Ͼ 2 and, 1434 glomerular filtration rates of 60 vs 60 ml/min/1.73 m and, 813 Anthracycline, infusions in children, acute cardiac functional and morphological GPX-1 activity, cardiovascular prognosis and, 808 changes after, 974 prediction in asymptomatic patients with diabetes mellitus type 2, value of elec- Anticoagulants trocardiographic and ankle–brachial index abnormalities for, 951 impact of smart infusion technology on administration of, 1002 right coronary artery narrowing in endarterectomy specimens compared to au- prerandomization switching association with bleeding in PCI setting of, 1687 topsy studies and, 588 Antidiabetic agents, role in prevention of type 2 diabetes mellitus and risks cardiovascular disease, 726 dietary supplement use among U.S. adults with coronary artery disease and, Anxiety disorders, link among mitral valve prolapse, inheritance and, 1350 (Readers’ 661 Comments) metabolic syndrome impact on cardiovascular prognosis and, 1623 Aorta, ascending. See also Transposition of the great arteries subclinical, Framingham risk score and, 310 progressive dilation of, with isolated bicuspid aortic valve in children, 978 Atherosclerosis Risk in Communities (ARIC) Study, left ventricular architecture and usefulness of bicuspid aortic valve to predict elastic properties of, 686 survival in African-Americans free of coronary heart disease, 1413 Aortic atheroma, complex, relation between mitral annular calcium and in patients Atorvastatin with cerebral ischemia referred for transesophageal echocardiography colchicine effect on high-sensitivity CRP in patients with stable CAD indepen- with, 1306 dent of aspirin and, 805 Aortic coarctation, aortic arch geometry and exercise-induced hypertension in, 1284 effects of high doses of rosuvastatin on subpopulations of high-density lipopro- Aortic cuspal prolapse, subaortic ventricular septal defect at Ͻ1 year of age, teins vs, 681 development of aortic regurgitation and, 1588 effects on vitamin D levels in patients with acute ischemic heart disease, 903

SUBJECT INDEX 9 high-dose effects in patients Ն65 years of age with ACS, in the MIRACL Study, effect in patients with transposition of great arteries and systemic right ventricu- 632 lar dysfunction, 704 monotherapy vs simvastatin monotherapy vs ezetimibe/simvastatin combination Beta Blocker Evaluation of Survival Trial (BEST), effect of statin therapy on survival for reduction of CRP and LDL cholesterol levels, 1706 in patients with nonischemic dilated cardiomyopathy, 1448 platelet inhibition by aspirin and clopidogrel in patients with coronary stent Beta blockers. See Beta-adrenergic blocking agents thrombosis and, 353 Bicuspid aortic valve, usefulness in prediction of elastic properties of the ascending safety of lovastatin/extended release niacin vs, 379 aorta, 686 in South-Asian patients at risk of CAD, rosuvastatin vs, from the IRIS Trial, Bifurcation lesions, Axxess Plus drug-eluting stent trial for treatment of, 1691 1538 Binodenoson Atrial enlargement, left, ECG methods and criteria for, 113 coronary circulation responses to, 1507 Atrial fibrillation in stress myocardial perfusion imaging, 1619 (Editorial) cardioversion for, role of inflammation in, 1617 (Editorial) Biomarkers the challenge of new enigmas in research, 1330 (Editorial) of inflammation clinical and echocardiographic markers of mortality risk with, 1733 angiographic severity of CAD, patient outcome and, 879 comparison of usefulness of CRT in patients with heart failure and, vs patients association with carotid intima-media thickness and stenosis, from the Fra- with sinus rhythm and heart failure, 1252 mingham Heart Study, 1598 endothelial cell function after restoration of sinus rhythm and during, 1258 of mortality risk in patients with atrial fibrillation, 1733 with interatrial block, comparable echocardiographic parameters in, 390 serum complement C3/C4 ratio as, for recurrent cardiovascular events in ACS, intraatrial block and, 49 890 permanent, circumferential ablation with pulmonary vein isolation in, 1425 Biopsy, endomyocardial, comparison of three-dimensional echocardiography to two- procainamide vs propafenone vs amiodarone for conversion of recent onset, dimensional echocardiography and fluoroscopy for monitoring of, 864 safety and efficacy comparison of, 1721 Bivalirudin, smart infusion technology impact on administration of, 1002 rapid, meta-analysis of magnesium therapy for acute management of, 1726 Bleeding. See Hemorrhage relation of CRP to long-term risk of recurrence after electrical cardioversion of, Blood pressure 1421 response to trandolapril add-on therapy in patients taking verapamil SR, factors sinus rhythm maintenance after electrical cardioversion for, effect of candesartan influencing, INVEST Study, 1549 and various inflammatory markers on, 1544 systolic, and initial heart rate among fibrinolytic-treated patients with acute transcatheter ablation in patients with hypertrophic cardiomyopathy, usefulness STEMI presenting with cardiogenic shock, impact on age and mortality of, and safety of, 1575 793 Atrial overdrive pacing, acute, sleep-related breathing disorder and, 573 Blood transfusions, impact in patients presenting with anemia and suspected ACS, Atrial pacing, transesophageal, stress echocardiography safety and, 584 (Readers’ 1119 Comments) Blood urea nitrogen, for predicting events in hospitalized patients with heart failure, Atrial pressure, right, estimation of by internal medicine residents using hand- prognostic significance of N-terminal pro-BNP vs, 1143 carried ultrasound vs physical examination, 1614 BMD. See Bone mineral density Atrial septal defect BNP. See Natriuretic peptides, B-type multislice computed tomography measurement of right ventricular volumes be- Body composition, changes in men after CABG, 585 fore and after closure of, 1458 Body mass index Sideris septal occluder device for closure of, and late migration into the left impact on outcomes after PCI in patients with AMI, 903 atrium with mitral valve obstruction, 1479 relation to outcome in patients with known or suspected CAD, 1485 Axxess Plus drug-eluting stent trial, for treatment of bifurcation lesions, 1691 Bone mineral density cardiovascular risk factors and mitral annular calcium association with, 159 changes in men after CABG, 585 Bare metal stents Bone resorption, valve calcification, cytokines and, 1024 (Readers’ Comments) implantation in patients with angina pectoris, serial intravascular ultrasonic study BP. See Blood pressure of outcomes of coronary culprit lesions with plaque rupture following, Breathing, sleep-related disorder of, acute atrial overdrive pacing and, 573

1394 Brugada syndrome, ECG at higher V1 to V2 recording in men with, 53 vs drug-eluting stents B-type natriuretic peptides. See Natriuretic peptides, B-type angiographic outcomes of late lumen loss and neointimal growth in TAXUS BUN. See Blood urea nitrogen II Trial, 607 Bundle branch block in diabetes mellitus patients, meta-analysis of randomized trials of, 1399 left effectiveness compared in large (Ն3.5 mm) coronary arteries, 599 as diagnostic challenge in cardiology, 1179 (Readers’ Comments) frequency of coronary arterial late angiographic stent thrombosis in the ﬁrst terminology and diagnostic criteria review of, 428 (Readers’ Comments) six months, outcomes with, 774 patterns after AMI, prediction of death and, 647 later frequency of AMI and, 333 right, contrast-enhanced MRI after alcohol septal ablation for obstructive hyper- risk of AMI and, 621 trophic cardiomyopathy with and without, 563 vs paclitaxel- and sirolimus-eluting stents in patients with STEMI, three-year comparison, RESEARCH and T-SEARCH Registries, 1027 Bare metal stents and drug-eluting stents, overlapping heterogenous, outcome of, CABG. See Coronary artery bypass grafting 364 CAD. See Coronary artery disease Bariatric surgery CADILLAC trial, baseline platelet count impact in AMI patients undergoing primary effects of weight loss on epicardial fat measured using echocardiography after, PCI, 1055 1242 Calcium reduction in predicted coronary heart disease risk after substantial weight reduc- coronary and abdominal aortic arterial, effect of simvastatin on, CATZ Study, tion from, 222 1714 Beta-adrenergic blocking agents coronary artery acute therapy with, prognostic impact of aspirin and ACE inhibitor therapy in association with carotid intimal media thickness in the Rancho Bernardo STEMI patients and, 1208 study, 227 in children with Marfan syndrome, 406 and estrogen/progestin therapy in postmenopausal women, 374

10 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 family history of MI in various age and risk factor groups and presence of, Cardiopulmonary exercise testing. See Exercise testing 825 Cardiovascular disease osteoprotegerin relation to aortic plaque in the Dallas Heart Study and, 513 good books appearing in 2006 on, 745 and uric acid in men asymptomatic for myocardial ischemia and with vs GPX-1 activity, atherosclerotic burden, and prognosis in, 808 without metabolic syndrome, 41 left ventricular contractile asynchrony in patients with type 2 diabetes mellitus zero and low, 64-slice computed tomographic angiography of noncalcified with and without clinically evident, 1482 (Readers’ Comments), Reply, coronary plaque in, 1183 1483 mitral annular lifestyle and oral antidiabetic agents roles in prevention of type 2 diabetes melli- BMD, cardiovascular risk factors and, 159 tus and, 726 complex aortic atheroma in patients with cerebral ischemia referred for trans- lifetime burden for death by, in Chicago Heart Association Detection Project in esophageal echocardiography and, 1306 Industry, 535 zero or low score, and coronary artery disease in 64-slice multidetector com- long-term predictors of, after drug-eluting stent implantation for aorto-ostial puted tomography for chest pain syndrome, 472 coronary artery disease, angiographic restenosis and, 760 Candesartan, and maintenance of sinus rhythm after electrical cardioversion for metabolic syndrome and, 382 (Editor’s Roundtable) atrial fibrillation and, inflammatory markers and, 1544 prevention, cost and effectiveness of Screening for Heart Attack Prevention and Carbon monoxide poisoning, cardiovascular effects of, 322 Education (SHAPE), 1013 (Editorial) Carcinoid heart disease, without hepatic metastases, 292 risk Cardiac arrest alcohol-induced hypertension and, 1621 (Readers’ Comments), Reply, 1621 crack cocaine smoking and, 822 CRP role in reduction of, 718 QT interval changing capacity and ventricular fibrillation after myocardial infarc- mortality prediction using CBC-derived score for, 169 tion with and without, 296 screening programs for individuals at risk of, 1481 (Readers’ Comments) Cardiac catheterization, good books appearing in 2006 on, 745 Cardioversion, electrical Cardiac events, major adverse for atrial fibrillation, effect of candesartan and various inflammatory markers on after AMI, clinical impact of metabolic syndrome and smoking on, 885 sinus rhythm maintenance after, 1544 during endurance sports, 849 for atrial fibrillation, inflammation and, 1617 (Editorial) Cardiac function, before and after surgery for pectus excavatum, 1762 CRP and long-term risk of atrial fibrillation recurrence after, 1421 Cardiac imaging, good books appearing in 2006 on, 745 Carotid artery Cardiac output, noninvasive measurement of, and peak VO determination at rest 2 endarterectomy, frequency and extent of arterial media in specimens from, 990 and during exercise with heart failure, 404 IL-6 and CRP as predictors of subclinical atherosclerosis in, 98 Cardiac resynchronization therapy stenting, inhospital outcomes of patients with vs without previous carotid endar- in heart failure, and prediction of response to M-mode echocardiography vs terectomy undergoing, German ALKK CAS Registry, 1288 tissue Doppler imaging, 68 Carotid intima-media thickness isovolumic times after, heart failure or exercise capacity and, 75 ankle–brachial index in the Rancho Bernardo study and, 876 (Readers’ Com- left ventricular lead placement in, left ventricular remodeling and dyssynchrony ments) and, 239 coronary artery calcium in the Rancho Bernardo study and, 227 long-term survival with heart failure and ventricular conduction delay treated multiple inflammatory markers with stenosis and, from the Framingham Heart with, 232 Study, 1598 preimplantation B-type natriuretic peptide levels and response to, 242 in patients with HIV, relation of subepicardial adipose tissue to, 1470 qualitative observation of left ventricular multiphasic septal motion and septal-to- progression of, antihypertensive therapy effect in patients with type 2 diabetes lateral apical shuffle predicts left ventricular reverse remodeling after, 966 mellitus on, 956 total scar burden effect on contrast-enhanced MRI on response to, 657 Carvedilol usefulness in patients with heart failure and atrial fibrillation, vs patients with sinus rhythm and heart failure of, 1252 across a spectrum left ventricular ejection fractions in patients with heart failure, Cardiac syndrome X, noninvasive evaluation of flow reserve in the left anterior comparison of outcomes and usefulness of, 1263 descending coronary artery in patients with, 1378 in patients with transposition of great arteries and systemic right ventricular Cardiac valve surgery, (Editor’s Roundtable), 1269 dysfunction, 704 CARDIA Study, prevalence and clinical correlates of isolated mitral regurgitation, Catheter-tip embolectomy, in acute massive pulmonary embolism management, 415 isolated aortic regurgitation, and both in adults aged 21 to 35 years, 830 Celecoxib, cardiovascular event risk and, 91 Cardiogenic shock CHD. See Coronary heart disease microbiological profile of septic complication in patients with cardiogenic shock Chest barriers, for protection against sudden death due to commotio cordis, 857 following AMI (from the SHOCK Study), 802 Chest pain prognostic value of hemoglobin admission levels in STEMI patients presenting acute, prognostic value of myocardial contrast echocardiography in patients pre- with, 1201 senting to hospital with negative troponin and, 1369 Cardiomegaly, in diastolic heart failure, right-sided heart enlargement and, 62 atypical, in emergency department, early rest SPECT vs stress SPECT vs electro- Cardiomyopathy cardiographic exercise test for diagnosis of, 1662 good books appearing in 2006 on, 745 diagnostic triage of patients with negative or nondiagnostic exercise treadmill hypertrophic (See Hypertrophic cardiomyopathy) test result and, usefulness of 64-slice multidetector computed tomography idiopathic dilated in, 925 B-type natriuretic peptide levels before and after exercise and functional ca- ECG recording and timeliness of clinician evaluation in the emergency depart- pacity in patients with, 1279 ment in patients with, 1115 independent prognostic value of contractile and coronary flow reserve deter- with non–ST-segment elevation and normal troponin, risk categories for prog- mined by dipyridamole stress echocardiography in, 1154 nostic assessment of, 797 neurocardiogenic mechanisms of unexplained syncope in, 558 observation unit, serum lipids treatment in, 1718 nonischemic dilated, effect of statin therapy on survival in patients with, in Beta in patients treated with statins, coenzyme Q10 and, 1409 Blocker Evaluation of Survival Trial, 1448 zero or low score calcium, and coronary artery disease in 64-slice multidetector transient, isolated left ventricular basal ballooning phenotype in young women computed tomography for, 472 of, 1451 Chicago Heart Association Detection Project in Industry, lifetime burden for type 1 diabetes mellitus and, 84 cardiovascular disease death, 535

SUBJECT INDEX 11 Children 64-slice multidetector acute cardiac functional and morphological changes after anthracycline infusions coronary angiography to assess patency of CABG vs, 1529 in, 974 diagnostic performance of, in assessment of significant CAD in symptomatic with Marfan syndrome, beta blockers in, 406 subjects, 1656 primary pulmonary vein stenosis in, 568 for diagnostic triage of patients with chest pain and negative or nondiagnos- progressive dilation of the ascending aorta with isolated bicuspid aortic valve in, tic exercise treadmill test result, 925 978 zero or low calcium score and obstructive CAD, 472 stable patients with pulmonary arterial hypertension, and transition from IV coronary angiography, diagnostic accuracy of, for clinical decision making, 1122 epoprostenol to IV treprostinil, 696 coronary angiography, for guiding PCI, usefulness of, 871 (Editorial) transcatheter closure of perimembranous ventricular septal defects using the coronary angiography, non-biased assessment of the usefulness of, 1165 (Edito- Amplatzer perimembranous ventricular septal defect occluder, 984 rial) Cholesterol electron beam, of subclinical atherosclerosis, Framingham risk score and, 310 high-density lipoprotein, 1698 (Editor’s Roundtable) multidetector, left ventricular assessment with two-dimensional transthoracic elevated, coronary artery disease risk factors with, 1 echocardiography of heart failure vs, 247 high doses of rosuvastatin vs atorvastatin on subpopulations of, 681 multidetector spiral, usefulness according to age and gender for diagnosis of low-density lipoprotein, ezetimibe/simvastatin vs atorvastatin vs simvastatin for acute pulmonary embolism, 1303 reduction in level of, 1706 multislice physician knowledge of national guidelines on, before and after an interactive in asymptomatic high-risk population, 326, 1621 (Readers’ Comments) curriculum, 1234 measurement of right ventricular volumes before and after atrial septal defect Chronic fatigue, usefulness of an abnormal cardiovascular response during low- closure using, 1458 grade head-up tilt-test for discriminating adolescents with or without, 997 for suspected CAD, incidental detection of cancers and other non-cardiac Chronic illnesses among elderly patients, physician workforce and growth of, 1476 abnormalities on, 1608 (Editorial) single-photon emission myocardial perfusion Chronic kidney disease. See Kidney disease, chronic for determining lesion significance in multivessel coronary disease, compari- Chronic obstructive pulmonary disease, impact on post-myocardial infarction son between angiography and fractional flow reserve vs, 896 outcomes, 636 early rest-type vs stress-type of atypical chest pain in emergency department, Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation electrocardiographic exercise test vs, 1662 (COURAGE) trial, baseline characteristics of, 208 Conduction disturbances Clinical trials good books appearing in 2006 on, 745 assessment of bleeding events in, proposed new classification for, 288 (Edito- repolarization duration after myocardial infarction and, 163 rial) Congenital heart disease CAMELOT tales, 878 (Readers’ Comments) cyanotic, nitric oxide metabolism in adults with, 691 celecoxib and cardiovascular event risk, 91 health care resource utilization by adults with, 839 comparison of sirolimus vs paclitaxel-eluting stents, lessons for the future of, left-sided, chronic afterload increase effect on left ventricular function in patients 424 (Editorial) with, 1582 COURAGE baseline characteristics, evolving pattern of symptomatic coronary Congress, U.S., regulatory changes for the treatment of patients with heart attacks, artery disease in the US and Canada, 208 considerations for, 1166 (Editorial) noninferiority, meaning and clinical measurement of, 284 (Editorial) Contractile reserve, left ventricular, in idiopathic dilated cardiomyopathy as Clopidogrel determined by dipyridamole stress echocardiography, independent aspirin plus, after ACS, aspirin plus warfarin vs, 1637 prognostic value of coronary flow reserve and, 1154 aspirin plus ticlopidine or, vs aspirin alone after Carbofilm-coated stent implan- Contrast agents, image quality in real-time three-dimensional stress tation, 1062 long-term vs short-term, coronary stenting and, 349 echocardiography and, 275 responsiveness in patients undergoing PCI to, measuring aspirin resistance, Contrast echocardiography postprocedural myonecrosis markers and, 1518 in left ventricular hypertrabeculation/noncompaction diagnosis, conventional SSRIs may interfere with the antiplatelet effect of, 1025 (Readers’ Comments) echocardiography vs, 145 (Reader’s Comments) statins and platelet inhibition in patients with coronary stent thrombosis by, 353 for left ventricular thrombus assessment after AMI, 1667 Cocaine smoking, cardiac arrest and, 822 myocardial, prognostic value in patients presenting to hospital with acute chest Cocoa consumption, habitual, relation to aortic stiffness and wave reflections, and pain and negative troponin, 1369 to central hemodynamics in healthy individuals, 1473 Controlled Abciximab and Device Investigation to Lower Late Angioplasty Coenzyme Q10, myopathic symptoms in patients treated with statins and, 1409 Complications (CADILLAC) trial, baseline platelet count impact in AMI Colchicine, high-sensitivity CRP independent of aspirin and atorvastatin in patients patients undergoing primary PCI, 1055 with stable coronary artery disease and, 805 COPD. See Chronic obstructive pulmonary disease Collagen type I turnover, serum indexes of, relation of plasma brain natriuretic Coronary angiography peptide and left ventricular remodeling after reperfused AMI to, 651 comparison between SPECT myocardial perfusion imaging for determining lesion Commotio cordis. See also Ventricular fibrillation significance in patients with multivessel coronary disease, vs fractional chest barriers for protection against sudden death due to, 857 flow reserve and, 896 Complementary medicine, self-reported use of, in patients with previous ACS and, computed tomographic 930 analytic approaches to establish diagnostic accuracy of, for clinical decision Complement C3/C4 ratio, serum levels of, as biomarker for recurrent cardiovascular making, 1122 events, 890 for guiding PCI, usefulness of, 871 (Editorial) Complete blood count (CBC), CVD risk score derived from, usefulness in mortality non-biased assessment of the usefulness of, 1165 (Editorial) prediction in suspected CVD of, 169 coronary artery involvement in intraatrial block after positive exercise tolerance Computed tomography. See also Optical coherence tomography test, 58 40-channel, for detection of coronary artery stenosis with multisegment recon- disease severity, inflammatory biomarkers, patient outcome and, 879 struction, 175 late follow-up in adults with initial angiographic normal or minimally narrowed 64-slice, noncalcified coronary plaque in patients with zero and low coronary coronary arteries, 1374 artery calcium, 1183 luminal loss in sirolimus- and paclitaxel-eluting stents, 593

12 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 multidetector 64-slice computed tomography to assess patency of CABG vs, exercise-induced hypertension and endothelial cell dysfunction in a marathon 1529 runner and, 743 quantitative, and/or noninvasive imaging for myocardial ischemia evaluation, guideline-recommended PCI vs CABG vs medical therapy only in patients with, fractional flow reserve vs, 450 in the REACH International Registry, 1212 radial artery function after cannulation for, 457 left bundle branch block and diagnostic challenge of, 1179 (Readers’ Comments) ultrasound outcomes of late lumen loss and neointimal growth in Taxus and mitral annular calcium association with BMD and risk factors for, 159 bare metal stents vs, in TAXUS II Trial, 607 multislice computed tomography for, incidental detection of cancers and other wide-range CRP vs high-sensitivity CRP in patients undergoing, 1504 non-cardiac abnormalities and, 1608 Coronary angioplasty obstructive, 40-channel computed tomography with multisegment reconstruction percutaneous transluminal, trends in operator and hospital procedure volume for detection of, 175 and outcomes, 339 PCI outcomes with obstructive sleep apnea, 26 primary, glycoprotein IIb/IIIa inhibitor effectiveness during, 482 prediction, usefulness of carotid ultrasound with stress testing in, 1196 radial artery function after cannulation for, 457 prognostic implications of dipyridamole or dobutamine stress echocardiography Coronary arteries for evaluation of patients Ն65 years of age with known or suspected, epicardial stenosis of, invasive fractional flow reserve vs perfusion MRI for as- 1491 sessment of hemodynamic significance of, 1090 risk heart transplantation and anatomical and physiological changes in, 1603 CRP role in reduction of, 718 intravascular ultrasonic imaging of, 943 (Editor’s Roundtable) elevated HDL cholesterol and, 1 large (Ն3.5 mm), effectiveness of bare metal stents vs drug-eluting stents in, multislice computed tomography in asymptomatic high-risk population, 326, 599 1621 (Readers’ Comments) late angiographic follow-up in adults with initial angiographic normal or mini- significant, diagnostic performance in assessment of 64-channel multislice com- mally narrowed, 1374 puted tomography in symptomatic subjects, 1656 late angiographic stent thrombosis of, frequency in the first six months with simvastatin effects on CRP in, 149 bare metal stents vs drug-eluting stents, 774 stable, colchicine effect on high-sensitivity CRP independent of aspirin and ator- late thrombosis of, with drug-eluting stents, 1039 vastatin in patients with, 805 left anterior descending with three-vessel lumen obstruction undergoing PCI, using Syntax score to pre- in patients with cardiac syndrome X, noninvasive evaluation of flow reserve dict clinical outcome in, 1072 of, 1378 trends in PTCA operator and hospital procedure volume and outcomes, 339 size of adjacent nontunneled vs, myocardial bridge of, 1653 Turner’s syndrome and, 741 low calcium score, relation of aortic valve calcium to myocardial ischemic perfu- zero or low calcium score, 64-slice multidetector computed tomography and, sion in patients with, 1535 472 luminal size Coronary Artery Risk Development in Young Adults (CARDIA) Study, prevalence angiographic analysis of loss in bare metal and paclitaxel-eluting stents, and clinical correlates of isolated mitral regurgitation, isolated aortic ultrasound neointimal volume from TAXUS II Trial and, 607 regurgitation, and both in adults aged 21 to 35 years, 830 angiographic analysis of loss in sirolimus- and paclitaxel-eluting stents, 593 Coronary artery stenting, gender differences and neointimal hyperplasia after, 491 narrowing in, electrocardiographic-gated vs nongated volumetric intravascular Coronary blood flow velocity, binodenoson effects on, 1507 ultrasound measurements of, 279 Coronary flow reserve plaque size vs necrotic core in patients with ACS as determined by intravascular in idiopathic dilated cardiomyopathy as determined by dipyridamole stress echo- ultrasonic imaging radiofrequency, 790 cardiography, independent prognostic value of left ventricular contractile right, narrowing in endarterectomy specimens compared to autopsy studies, 588 reserve and, 1154 wave properties in type 2 diabetes, diastolic dysfunction and, 844 in left anterior descending coronary artery in patients with cardiac syndrome X, Coronary artery bypass grafting noninvasive evaluation of, 1378 in diabetes mellitus patients, comparison of coronary drug-eluting stents vs, 779 Coronary heart disease guideline-recommended PCI vs medical therapy only vs, in the REACH Interna- asymptomatic left ventricular diastolic dysfunction in ambulatory patients with, tional Registry, 1212 1643 in men, bone mineral and body composition changes after, 585 coronary collateral formation and serum endostatin in coronary circulation with, patency assessment, multidetector 64-slice computed tomography vs coronary 494 angiography for, 1529 endothelin-1 in the Rancho Bernardo study and, 486 PCI for ischemic cardiomyopathy vs, 37 major depression and, 519 (Editor’s Roundtable) preoperative lipid-lowering therapy influence on postoperative outcome in pa- metabolic syndrome impact on atherosclerotic burden and, 1623 tients undergoing, 785 risk right coronary artery narrowing of endarterectomy specimens at death compared dietary factors known to reduce, omega-3 fatty acid intake and, 1230 with narrowing in same artery at time of, 588 reduced predictions for, substantial weight loss after bariatric surgery and, Coronary Artery Calcification Treatment with Zocor (CATZ) Study, simvastatin effect 222 on coronary and abdominal aortic arterial calcium, 1714 score based on patient-reported information, 1236 Coronary artery disease unknown, association of myocardial ischemia and coronary angiographic lesions acute, blood omega-3 and trans fatty acids in middle-aged, 154 with increased left atrial dimension during exercise tolerance tests among angiographic severity of, inflammatory markers and patient outcome in, 879 patients with, 1187 aorto-ostial, drug-eluting stent implantation for, results and predictors of angio- Coronary lesions graphic restenosis and long-term adverse cardiac events after, 760 with plaque rupture, serial intravascular ultrasonic study of outcomes following body mass index relation to outcome in patients with known or suspected, 1485 bare metal stent implantation in patients with angina pectoris and, 1394 carbon monoxide poisoning and, 322 Coronary revascularization. See also Percutaneous coronary intervention CRP relation to coronary collaterals with stable angina pectoris and, 509 changes in strategies for patients with acute coronary syndrome, the CRUSADE in diabetics, hypertriglyceridemic waist relation to, 369 Quality Improvement Initiative, 1222 dietary supplement use among U.S. adults with atherosclerotic risks and, 661 recent trends in hospitalization in United States for, 749 dobutamine stress echocardiography in women for detection of, 714 Coronary stenting, long-term vs short-term clopidogrel with, 349 evolving patterns in US and Canada, baseline characteristics of COURAGE trial, Corrections, 430, 878, 1182, 1350, 1622 208 Costs. See Health care costs

SUBJECT INDEX 13 Crack cocaine smoking, cardiac arrest and, 822 arterial wave properties and diastolic dysfunction in patients with, 844 C-reactive protein electrocardiographic and ankle–brachial index abnormalities and prediction of coronary collaterals with stable angina pectoris and CAD and, 509 coronary atherosclerosis in asymptomatic subjects with, 951 coronary risk reduction and, 718 hypertriglyceridemic waist relation to CAD manifestations in, 369 ezetimibe/simvastatin vs atorvastatin vs simvastatin for reduction in level of, left ventricular contractile asynchrony concerns in patients with and without 1706 clinically evident heart disease, 1482 (Readers’ Comments), Reply, 1483 heart rate recovery after exercise and, 707 lifestyle and oral antidiabetic agents role in prevention of cardiovascular dis- high-sensitivity, baseline high vs baseline low levels in women, and future MI ease and, 726 characteristics, 1500 renin-angiotensin system inhibition and development of, 1006 high sensitivity, before and after coronary angioplasty, 31 Diagnosis high-sensitivity, colchicine effect in patients with stable CAD independent of for acute aortic dissection vs acute coronary syndrome, misdiagnosis frequency atorvastatin and aspirin, 805 and inappropriate treatment with, 852 long-term risk of recurrence of atrial fibrillation after electrical cardioversion and, historical review of mitral valve prolapse, 129 1421 of significant CAD in symptomatic subjects, 64-channel multislice computed simvastatin effects on coronary artery disease and, 149 tomography for, 1656 subclinical carotid atherosclerosis and, 98 Diastolic dysfunction, arterial wave properties in patients with diabetes mellitus type wide-range vs high-sensitivity, in coronary angiography patients, 1504 2 and, 844 Creatine kinase-MB, increased, after PCI and myocardial infarction prediction, 616 Diastolic function, aging and physical activity effects on Doppler measures of, 1629 Creatinine, in-hospital, prognostic value of transient and sustained increase in, for Diastolic heart failure, systolic heart failure and unstable angina pectoris vs, 460 ACS, 939 Diastolic-mitral-annular-velocity-pattern-to-onset-of -QRS-interval, measurements of, CRP. See C-reactive protein usefulness for prediction of LVEDP, 119 CRT. See Cardiac resynchronization therapy Diet CRUSADE Quality Improvement Initiative and CAD risk reduction, relation of omega-3 fatty acids to, 1230 aspirin dosing patterns in non–ST-elevation acute coronary syndromes in, 1496 modification in renal disease, estimated glomerular filtration rate and, 584 changes in coronary revascularization strategies for patients with ACS in, 1222 (Readers’ Comments) glycoprotein IIb/IIIa inhibitor use timing and outcomes among non–ST-segment Dietary supplements, use among U.S. adults with CAD and atherosclerotic risks, elevation MI patients undergoing PCI, 1389 661 CVD. See Cardiovascular disease Dipyridamole stress echocardiography Cypher stents, clinical trials comparing Taxus stents to, lessons for the future, 424 evaluation of patients Ն65 years of age with known or suspected CAD, prog- (Editorial) nostic implications of, 1491 Cytokines, bone resorption, valve calcification and, 1024 (Readers’ Comments) independent prognostic value of contractile and coronary flow reserve in idiopathic dilated cardiomyopathy as determined by, 1154 Dallas Heart Study, osteoprotegerin relation to coronary calcium and aortic plaque Disease management, and financial implications of heart failure, 256 in, 513 Dobutamine stress echocardiography Death. See also Mortality for coronary artery disease diagnosis in women, 714 after AMI, usefulness of bundle branch block patterns after, 647 evaluation of patients Ն65 years of age with known or suspected CAD, prog- after simvastatin therapy, widespread skeletal myopathy and, 1171 nostic implications of, 1491 by cardiovascular disease, lifetime burden for, in Chicago Heart Association myocardial ischemia during, in asymptomatic patients with diabetes mellitus and Detection Project in Industry, 535 no prior history of coronary events, 1193 or AMI, risk of, impact of drug-eluting vs bare metal stents on, 333 risk assessment before noncardiac vascular surgery in patients with left ventricu- right coronary artery narrowing of endarterectomy specimens with CABG com- lar ejection fraction Ͻ35%, value of myocardial viability estimation using, pared with narrowing in same artery after, 588 1555 ␤ risk of, 2-adrenoceptor haplotype relation to heart failure and, 250 Doppler imaging statin use and age at, 1181 (Readers’ Comments), Reply, 1182 aging and physical function effects on diastolic function measures using, 1629 Decision making, clinical, analytic approaches to establish diagnostic accuracy of real-time three-dimensional color, in vitro validation of, for direct measurement coronary computed tomographic angiography for, 1122 of proximal isovelocity surface area in mitral regurgitation, 1440 Depression right ventricular, usefulness to predict left ventricular heart failure outcome inde- coronary endothelial function and, 1134 pendent of left ventricular diastolic function, 961 major, coronary heart disease and, 519 (Editor’s Roundtable) tissue, M-mode echocardiography vs, cardiac resynchronization therapy with Depressive symptoms, atherosclerosis in Americans Ն65 years of age and, 1610 heart failure predictions and, 68 Diabetes mellitus Drospirenone-estradiol hormone treatment, myocardial perfusion reserve in admission hyperglycemia and, impact on short- and long-term mortality after postmenopausal women with angina pectoris and, 1648 AMI in the PCI era, 1674 Drug-eluting stents. See Stents, drug-eluting assessing prognosis in patients with, cardiac stress imaging tests and, 1016 Drug infusion systems, smart infusion technology impact on administration of (Editorial) anticoagulants, 1002 CABG vs drug-eluting stents in patients with, 779 Drug interactions, ranitidine and antiplatelet effects of aspirin, 124 meta-analysis of randomized trials of drug-eluting stents vs bare metal stents in Duchenne muscular dystrophy, during second decade of life, left ventricular patients with, 1399 function response to enalapril, 147 (Reader’s Comments) myocardial ischemia during dobutamine stress echocardiography in asymptom- Dyslipidemia, hypertension and, 134 (Editor’s Roundtable) atic patients with no prior history of coronary events and, 1193 non-clinically diagnosed, impact of metabolic syndrome on clinical outcomes of patients with ACS and, 667 ECG. See Electrocardiogram

relation of increased hemoglobin A1c levels to severity of peripheral arterial dis- Echocardiography. See also Doppler imaging; Stress echocardiography ease in patients with, 1468 abnormal cardiac ﬁndings with and without peripheral arterial disease in, fre- type 1, cardiomyopathy and myocardial alterations with, 84 quency of, 499 type 2 of asymmetric left ventricular basal posterior wall thinning in cardiac Fabry’s antihypertensive therapy effect on progression of carotid intima-media thick- disease, 261 ness in patients with, 956 atrial ﬁbrillation and interatrial block comparable parameters with, 390

14 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 cardiac MRI for assessing right ventricular function in adults with repaired tetral- protection in high-risk patients with acute ST-segment elevation myocardial in- ogy of Fallot vs, 1593 farction, in PREMIAR Trial, 357 contrast EMERALD Trial, time to treatment impact on myocardial reperfusion and infarct size conventional vs, in diagnosing left ventricular hypertrabeculation/noncompac- with primary PCI for AMI, 1680 tion, 145 (Reader’s Comments) Emergency department for left ventricular thrombus assessment after AMI, 1667 ECG recording and timeliness of clinician evaluation in patients with chest pain, myocardial, prognostic value in patients presenting to hospital with acute 1115 chest pain and negative troponin, 1369 predictors and outcomes of visits within 30 days after PCI to, 197 good books appearing in 2006 on, 745 shortening time to infarct artery patency in STEMI patients in, 1360 M-mode, tissue Doppler imaging vs, cardiac resynchronization therapy with Enalapril, left ventricular function response to, with Duchenne muscular dystrophy heart failure predictions and, 68 during second decade of life, 147 (Reader’s Comments) mortality risk biomarkers in patients with atrial fibrillation, 1733 Endarterectomy, carotid pulmonary embolism diagnosis and usefulness of, 579 frequency and extent of arterial media in specimens from, 990 real-time three-dimensional inhospital outcomes of patients undergoing carotid stenting with vs without pre- comparison of magnetic resonance imaging for follow-up of left ventricular vious, German ALKK CAS Registry, 1288 volumes after myocardial infarction vs, 300 Endocarditis, active infective, prognostic value of N-terminal pro-BNP in patients left ventricular mass assessment by, 1180 (Readers’ Comments) with, 1425 real-time three-dimensional color Doppler, in vitro validation of, for direct mea- Endostatin, serum levels in coronary circulation with coronary heart disease, surement of proximal isovelocity surface area in mitral regurgitation, 1440 coronary collateral formation and, 494 three-dimensional, relation between number of component views and accuracy of Endothelial cell dysfunction left ventricular mass determined by, 1321 depression and, 1134 transesophageal exercise-induced hypertension and CAD in a marathon runner and, 743 giant floating aortic thrombus in, 739 Endothelial cell function intraluminal phased-array imaging in type B aortic dissection vs, 270 during atrial fibrillation and after restoration of sinus rhythm, 1258 mitral annular calcium and complex aortic atheroma in patients with cerebral folic acid effect after AMI on, 476 Endothelial progenitor cells, gender differences in colony-forming and migratory ischemia referred for, 1306 activity of, 46 two-dimensional Endothelin-1, association with coronary heart disease in the Rancho Bernardo comparison of MRI for follow-up of left ventricular volumes after myocardial study, 486 infarction vs, 300 Endothelium, vasodilation dependent and independent of, anger provocation effect for endomyocardial biopsy monitoring, comparison of three-dimensional on, 860 echocardiography and fluoroscopy to, 864 Enoxaparin, unfractionated heparin effectiveness in reducing silent and clinically transthoracic, left ventricular assessment with multidetector computed tomog- apparent AMI with non–ST-segment elevation vs, 186 raphy of heart failure vs, 247 Epoprostenol, intravenous, transition of stable pediatric patients with pulmonary variables, prognostic significance in hypertrophic cardiomyopathy of, 835 arterial hypertension from intravenous treprostinil to, 696 weight loss effects after bariatric surgery on epicardial fat measured using, 1242 Estradiol-drospirenone hormone treatment, myocardial perfusion reserve in ED. See Emergency department postmenopausal women with angina pectoris and, 1648 Eisenhower, Dwight D., pheochromocytoma and, 1325 Estrogen/progestin therapy in postmenopausal women, coronary calcium and, 374 Ejection fractions, left ventricle EXamination of Potential Lipid-modifying effects Of Rosuvastatin in combination Ͻ35%, value of myocardial viability estimation using dobutamine stress echo- with Ezetimibe vs Rosuvastatin alone (EXPLORER) study, 673 cardiography in risk assessment before noncardiac vascular surgery in Exercise. See also Hypertension, exercise-induced patients with, 1555 cardiopulmonary, usefulness to predict long-term prognosis in adults with re- carvedilol usefulness and outcomes in patients with heart failure, 1263 paired tetralogy of Fallot, 1462 exercise capacity as predictor of two- and five-year mortality after AMI vs, 436 functional capacity in patients with idiopathic dilated cardiomyopathy and rela- Electrocardiogram tion of B-type natriuretic peptides levels before and after, 1279 at higher V1 to V2 recording in men with Brugada syndrome, 53 relation of CRP and white blood cell count to heart rate recovery after, 707 left atrial enlargement, methods and criteria for, 113 Exercise capacity Electrocardiographic Analysis of the Global Use of Strategies to Open Occluded comparison of Fontan procedure ventricular septation for double-inlet left ven- Coronary Arteries IIB Trial, predicting usefulness of ST depression with tricular repair and, 1757 T-wave inversion in leads V4 to V6 in non–ST-elevation ACS, one-year isovolumic times after cardiac resynchronization therapy and, 75 mortality predictions and, 934 left ventricular ejection fraction as predictor of two- and five-year mortality after Electrocardiography AMI vs, 436 abnormalities, prediction of coronary atherosclerosis in asymptomatic subjects relation of left ventricular chamber stiffness at rest in hypertrophic cardiomyopa- with diabetes mellitus type 2 and, 951 thy to, 1454 differentiation between acute pulmonary embolism and acute coronary syn- Exercise testing dromes on the basis of negative T waves, 817 64-slice multidetector computed tomography usefulness in diagnostic triage of good books appearing in 2006 on, 745 patients with chest pain and negative or nondiagnostic treadmill test re- recording, and timeliness of clinician evaluation in emergency department in sult, 925 patients with chest pain, 1115 electrocardiographic, of atypical chest pain in the emergency department, early routine, improper filter settings in, prevalence and clinical implications of, 711 rest SPECT vs stress SPECT vs, 1662 Embolectomy good books appearing in 2006 on, 745 catheter-tip, in acute massive pulmonary embolism management, 415 ramp and standard Bruce protocol, different thresholds of myocardial ischemia pulmonary, outcome of, 421 in patients with positive exercise stress tests and angiographically dem- Embolism, paradoxical, patent foramen ovale in patients with, outcomes after onstrated coronary arterial narrowing, 921 transcatheter closure of, 1312 Exercise tolerance Embolus, distal among patients with unknown coronary heart disease, association of myocardial FilterWire EZ in PCI for acute STEMI and, 911 ischemia and coronary angiographic lesions with increased left atrial di- prediction during PCI in saphenous vein grafts, 603 mension during, 1187

SUBJECT INDEX 15 arrhythmias and conduction disturbances with coronary artery involvement in estimated formula in modiﬁcation of diet in renal disease and, 584 (Readers’ intraatrial block and, 58 Comments)

with heart failure, noninvasive measurement of cardiac output and peak VO2 Glucose intolerance, hypertriglyceridemic waist relation to coronary artery disease determination at rest and during, 404 manifestations in, 369

peak VO2 vs heart value survival score prognosis predictions in men vs women, Glutathione peroxidase-1, atherosclerotic burden, cardiovascular prognosis and 399 activity of, 808 EXPLORER (EXamination of Potential Lipid-modifying effects Of Rosuvastatin in Glycoprotein IIb/IIIa inhibitors combination with Ezetimibe vs Rosuvastatin alone) study, 673 effectiveness during primary coronary angioplasty, 482 Ezetimibe timing of use and outcomes among non–ST-segment elevation MI patients un- alone or with rosuvastatin, efficacy and safety of, in EXPLORER Study, 673 dergoing PCI, CRUSADE Initiative, 1389 and simvastatin GPX-1. See Glutathione peroxidase-1 in aortic stenosis, SEAS study, 970 for reduction of CRP and LDL cholesterol levels, simvastatin monotherapy vs HDL cholesterol. See High-density lipoprotein cholesterol atorvastatin monotherapy vs, 1706 Health care costs, cost-minimization analysis of Angio-Seal vascular closure device following PCI, 766 Fabry’s disease, cardiac, asymmetric basal posterior wall thinning in, 261 Health care resource utilization, by adults with congenital heart disease, 839 Fatty acids. See Omega-3 fatty acids; Trans fatty acids Heart and Soul Study, AMI in patients with vs without aortic valve sclerosis, and Femoral artery, comparison of access-related bleeding complications with PCI in statin therapy in, 1128 women vs men using the radial artery vs, 1216 Heart attacks, regulatory changes for the treatment of patients with, 1166 (Editorial) Fetal myocardial performance, myocardial deformation analysis for assessment of, Heart enlargement, right-sided, cardiomegaly in diastolic heart failure and, 62 993 Heart failure Fetal pulmonary valve stenosis or atresia with intact ventricular septum, acute, levosimendan for, clinical criteria assessing response to, 146 (Reader’s determinants of outcome in, 699 Comments) Fibrinogen, relation between soluble ICAM-1, homocysteine levels and acute decompensated, 1560 (Editor’s Roundtable) race/ethnicity in women without cardiovascular disease and, 1246 ␤ 2-adrenoceptor haplotype relation to risk of death and heart transplantation Fibrinolytics, impact of initial heart rate and systolic pressure on relation of age with, 250 and mortality among patients with acute STEMI presenting with anemia and risk of kidney function decline with, 1137 cardiogenic shock treated with, 793 carvedilol across a spectrum of left ventricular ejection fractions in patients with, FilterWire EZ, safety and efficacy of, in acute STEMI, 911 comparison of outcomes and usefulness of, 1263 Financial factors, of heart failure disease management, 256 comparison of usefulness of CRT in patients with atrial fibrillation and, vs pa- Fish oil composition of Omacor and the GISSI Trial, 1483 (Readers’ Comments) tients with sinus rhythm and, 1252 Fluoroscopy, for endomyocardial biopsy monitoring, comparison of two-dimensional decompensated, intrathoracic impedance monitoring for prediction of, 554 echocardiography and three-dimensional echocardiography to, 864 diastolic, right-sided heart enlargement and cardiomegaly in, 62 Folic acid, endothelial function after AMI and, 476 diastolic and systolic, unstable angina pectoris and, 460 Fontan procedure, for double-inlet left ventricular repair, late post-operative diastolic vs systolic, chronic kidney disease associated mortality in, 393 cardiopulmonary responses in ventricular septation vs, 1757 etiology of, before transplantation relation to delayed pulmonary oxygen uptake Food and Drug Administration, Public Health Notification on the adoption of drug- kinetics after transplantation, 1745 eluting stents, impact of, 1227 financial implications of disease management program model of, 256 Fractional flow reserve good books appearing in 2006 on, 745 comparison between single-photon emission computed tomographic myocardial intra- and interatrial asynchrony in, 79 perfusion imaging for determining lesion significance in patients with isovolumic times after cardiac resynchronization therapy and, 75 multivessel coronary disease, vs angiography and, 896 left ventricular, usefulness of right ventricular tissue Doppler imaging to predict invasive, perfusion MRI for assessment of hemodynamic significance of epicar- outcome independent of left ventricular diastolic function in, 961 dial coronary artery stenosis vs, 1090 medical therapy effect on segmental myocardial function with ischemic cardio- quantitative coronary angiography and noninvasive imaging for myocardial isch- myopathy and, 1741 emia evaluation vs, 450 multidetector computed tomography vs 2-D transthoracic echocardiography for routine assessment of, influence on decision making during PCI, 504 left ventricular assessment in, 247 Framingham Heart Study, association of multiple inflammatory markers with carotid New York Heart Association functional class and natural history end points and, 549 intima-media thickness and stenosis from, 1598 noninvasive measurement of cardiac output and peak VO2 determination at rest Framingham risk score, subclinical atherosclerosis and, 310 and during exercise with, 404 preimplantation B-type natriuretic peptide levels and CRT response with, 242 Gender differences. See also Men; Women with preserved left ventricular systolic function among patients with non–ST- colony-forming and migratory activity of endothelial progenitor cells and, 46 segment elevation acute coronary syndromes, 1351 multidetector spiral computed tomography for diagnosis of acute pulmonary prognostic importance of pulmonary hypertension in patients with, 1146 embolism according to age and, 1303 prognostic significance of amino-terminal pro-BNP vs blood urea nitrogen for neointimal hyperplasia after coronary artery stenting and, 491 predicting events in patients hospitalized for, 1143 PCI with drug-eluting stents and, 626 with ventricular conduction delay treated with CRT, long-term survival in, 232 ranolazine for chronic angina pectoris, efficacy and safety comparisons and, 11 Heart rate risk-to-benefit ratio of thrombolysis for acute submassive pulmonary embolism initial, and systolic pressure among fibrinolytic-treated patients with acute STEMI and, 103 presenting with cardiogenic shock, impact on age and mortality of, 793 Gene polymorphisms variability in symptomatic patients with mitral valve prolapse, metoprolol and, long-term patency of aortocoronary saphenous vein grafts and, 1087 1568 paraoxonase and endothelial nitric oxide synthase genes, early-onset MI risk Heart rate recovery after exercise, relation to CRP and white blood cell count, 707 and, 1100 Heart transplantation GISSI Trial, fish oil composition of Omacor and, 1483 (Readers’ Comments) changes in coronary anatomy and physiology after, 1603 Glomerular filtration rate(s) etiology of heart failure before and relation to delayed pulmonary oxygen uptake of Յ60 vs Ͼ60 ml/min/1.73 m2, meta-analysis of coronary atherosclerotic vol- kinetics after, 1745 ␤ ume in patients with, 813 risk of, 2-adrenoceptor haplotype relation to heart failure and, 250

16 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 Heart value survival score, peak VO2 prognosis predictions in men vs women Inﬂammation compared to, 399 biomarkers Hemodynamics, central, relation of habitual cocoa consumption to aortic stiffness angiographic severity of coronary artery disease, patient outcome and, 879 and wave reﬂections in healthy individuals and, 1473 association with carotid intima-media thickness and stenosis, from the Fra- Hemoglobin, admission levels of, prognostic value in STEMI patients presenting mingham Heart Study, 1598 with cardiogenic shock of, 1201 hypothesis, potential relevance to statin therapy and, 732

Hemoglobin A1c, increased levels of, relation to severity of peripheral arterial Interatrial block, atrial fibrillation and, comparable echocardiographic parameters in, disease in patients with diabetes mellitus and, 1468 390 Hemorrhage Intercellular adhesion molecule-1, soluble, relation between soluble homocysteine, in clinical trials, assessment of, proposed new classification for, 288 (Editorial) fibrinogen levels and race/ethnicity in women without cardiovascular following PCI, anemia effect on mortality and, 1513 disease and, 1246 PCI, and prerandomization anticoagulant switching with, 1687 Interleukin-6, subclinical carotid atherosclerosis and, 98 Hemostasis, good books appearing in 2006 on, 745 International Diabetes Federation, metabolic syndrome definition comparisons of Heparin, unfractionated Adult Treatment Panel III and, 541 enoxaparin effectiveness in reducing silent and clinically apparent AMI with Intraatrial block non–ST-segment elevation vs, 186 arrhythmias and conduction disturbances or embolic stroke and, 49 smart infusion technology impact on administration of, 1002 coronary artery involvement in, arrhythmias and conduction disturbances in, 58 usefulness after primary angioplasty for AMI in patients not receiving glycopro- Intrathoracic impedance monitoring, decompensated heart failure prediction and, tein IIb/IIIa inhibitors, 202 554 HERG gene. See Human ether-a-go-go gene Intravascular ultrasound High-density lipoprotein cholesterol, 1698 (Editor’s Roundtable) assessment of temporal changes in coronary plaque volume with, 5 elevated, coronary artery disease risk factors with, 1 of coronary arteries, 943 (Editor’s Roundtable) high doses of rosuvastatin vs atorvastatin on subpopulations of, 681 electrocardiographic-gated vs nongated volumetric measurements of coronary Hispanics, SYNERGY trial of high-risk patients with non–ST-elevation acute arterial narrowing, 279 coronary syndrome and, 315 intraluminal phased-array imaging in type B aortic dissection vs, 270 HIV. See Human immunodeficiency virus meta-analysis of coronary atherosclerotic volume in patients with glomerular Homocysteine, relation between soluble ICAM-1, fibrinogen levels and race/ethnicity filtration rates Յ60 vs Ͼ60 ml/min/1.73 m2, 813 in women without cardiovascular disease and, 1246 relation of plaque size to necrotic core in patients with ACS as determined by, Hospitalization trends in the United States, recent, for AMI and coronary 790 revascularization, 749 IRIS Trial, atorvastatin vs rosuvastatin in South-Asian patients at risk of CAD, 1538 Human ether-a-go-go gene, Ala490Pro mutation in autosomal dominant long QT Ischemia, cerebral, relation between mitral annular calcium and complex aortic syndrome and, 1737 atheroma in patients referred for transesophageal echocardiography with, Human immunodeficiency virus, relation of subepicardial adipose tissue to carotid 1306 intima-media thickness in patients with, 1470 Ischemic cardiomyopathy HVSS. See Heart value survival score medical therapy for heart failure effect on segmental myocardial function with, Hyperglycemia, on admission, diabetes mellitus and, impact on short- and long- 1741 term mortality after AMI in the PCI era, 1674 PCI vs CABG for, 37 Hyperplasia, neointimal, after coronary artery stenting, gender differences and, 491 Ischemic heart disease, acute, atorvastatin effects on vitamin D levels in patients Hypertension with, 903 alcohol-induced, as cardiovascular risk factor, 1621 (Readers’ Comments), Re- ply, 1621 JUMBO-TIMI 26 trial, N-terminal pro-BNP assessment of periprocedural myocardial dyslipidemia and, 134 (Editor’s Roundtable) injury after PCI in, 344 exercise-induced aortic arch geometry in aortic coarctation and, 1284 Kidney disease endothelial dysfunction, coronary artery disease in a marathon runner and, chronic, diastolic vs systolic heart failure associated mortality in, 393 743 modification of diet in, estimated glomerular filtration rate and, 584 (Readers’ pulmonary (See Pulmonary hypertension) Comments) systemic, evolving definition of, 1168 (Editorial) risk, anemia with heart failure and, 1137 Hypertriglyceridemic waist, coronary artery disease manifestations in diabetics and, 369 Left atrium Hypertrophic cardiomyopathy in hypertrophic cardiomyopathy, clinical importance of, 877 (Readers’ Com- left atrium in, clinical importance of, 877 (Readers’ Comments) ments) prognostic significance of echocardiographic variables and exercise-induced increased dimension during exercise tolerance tests in patients with unknown arrhythmias in, 835 coronary heart disease, myocardial ischemia and coronary angiographic relation of left ventricular chamber stiffness at rest to exercise capacity in, 1454 lesions and, 1187 Ͻ sporadic, in Japanese patients 40 years, mutations in sarcomeric protein late migration of Sideris septal occluder device for closure of atrial septal defect genes and, 1745 into, mitral valve obstruction and, 1479 transcatheter ablation of atrial fibrillation in patients with, 1575 Left bundle branch block. See Bundle branch block Left ventricle IAB. See Intraatrial block architecture and survival in African-Americans free of coronary heart disease, ICAM-1. See Intercellular adhesion molecule-1 from the Atherosclerosis Risk in Communities (ARIC) Study, 1413 IL-6. See Interleukin-6 asymmetric basal posterior wall thinning in cardiac Fabry’s disease, 261 Implantable cardioverter-defibrillators, superior vena cava syndrome induced by, chamber stiffness at rest, and exercise capacity in hypertrophic cardiomyopathy, 1765 1454 IMPRESS-LD study, prednisone after PCI, comparison of efficacy and safety of contrast echocardiography assessment after AMI for thrombus in, 1667 lower-dose to higher-dose, 1082 diastolic filling pattern and apoptosis in fatal AMI, 307 Infants, transcatheter closure of perimembranous ventricular septal defects using the ejection fraction and exercise capacity as predictors of two- and five-year mor- Amplatzer perimembranous ventricular septal defect occluder in, 984 tality after AMI, comparison of, 436

SUBJECT INDEX 17 ejection fractions, spectrum of, carvedilol usefulness and outcomes in patients Lipids, serum with heart failure across, 1263 Omacor effects on levels of, clinical outcome and, 145 (Reader’s Comments) enalapril effects on, with Duchenne muscular dystrophy during second decade of of patients in a chest pain observation unit, measurement of and treatment for, life, 147 (Reader’s Comments) 1718 heart failure independent of left ventricular diastolic function, usefulness of right Liver, carcinoid heart disease without metastases to, 292 ventricular tissue Doppler imaging to predict outcome in, 961 Long QT syndrome, autosomal dominant, Ala490Pro mutation in human ether-a-go- lead placement in CRT, left ventricular remodeling, diastolic dyssynchrony and, go gene and, 1737 239 Lovastatin/extended release niacin, safety of lovastatin alone, atorvastatin alone, pump failure, survival in shock due to right ventricle infarction after PCI for pravastatin alone, and simvastatin alone compared with, 379 STEMI vs, 431 Low-density lipoprotein (LDL) cholesterol, ezetimibe/simvastatin vs atorvastatin vs scar size, location, and transmurality effect on left ventricular remodeling with simvastatin for reduction in level of, 1706 healed MI, 1109 LVEDP. See Left ventricular end-diastolic pressure Left ventricular apical ballooning syndrome, women with, incidence, clinical findings, and outcome of, 182 Magnesium therapy, for acute management of rapid atrial fibrillation, meta-analysis Left ventricular assist device support of, 1726 myocarditis recovery and, 1755 Magnetic resonance imaging ventricular arrhythmias during, 1151 contrast-enhanced Left ventricular basal ballooning phenotype, isolated, of transient cardiomyopathy in total scar burden effect on response to CRT and, 657 young women, 1451 with and without right bundle branch block after alcohol septal ablation for Left ventricular contractile asynchrony, in patients with type 2 diabetes mellitus with obstructive hypertrophic cardiomyopathy, 563 and without clinically evident heart disease, 1482 (Readers’ Comments), first-pass perfusion, invasive fractional flow reserve for assessment of hemody- Reply, 1483 namic significance of epicardial coronary artery stenosis vs, 1090 Left ventricular contractile reserve, in idiopathic dilated cardiomyopathy as of left ventricular volumes after MI, comparison of two- and three-dimensional determined by dipyridamole stress echocardiography, independent echocardiography for follow-up vs, 300 prognostic value of coronary flow reserve and, 1154 of right ventricular function in adults with repaired tetralogy of Fallot, echocardi- Left ventricular dysfunction ography vs, 1593 advanced, myocardial infarction prognosis by location and type with, 642 of subclinical atherosclerosis, Framingham risk score and, 310 asymptomatic diastolic, in ambulatory patients with CAD, 1643 Marathon runner(s). See also Sports Left ventricular end-diastolic pressure, AQ interval measurements and prediction of, 119 exercise-induced hypertension, endothelial dysfunction, and coronary artery dis- predicting by echocardiography, 1776 (Reader’s Comment) ease in, 743 Left ventricular function Marfan syndrome, beta blockers in children with, 406 chronic afterload increase in patients with congenital left-sided obstructive le- Maron, Barry Joel, MD, a conversation with, 1334 (Interview) sions and, 1582 Medical education preserved, and normal troponin I levels, usefulness of N-terminal pro-BNP se- growing chronic illnesses among elderly patients, physician workforce and, 1476 rum levels to predict in-stent restenosis, 1051 (Editorial) preserved systolic, heart failure with non–ST-elevation ACS and, 1351 physician knowledge of national cholesterol guidelines before and after an inter- and structure, comparison of changes in obese otherwise healthy adults with vs active curriculum, 1234 without obstructive sleep apnea, 1298 Medical history, of mitral valve prolapse diagnosis, 129 systolic and diastolic, in children after anthracycline infusions, 974 MELAS syndrome, cardiac involvement in adults with m.3243AG gene mutation Left ventricular hypertrabeculation/noncompaction, diagnosis of, contrast vs and, 264 conventional echocardiography and, 145 (Reader’s Comments) Men Left ventricular mass access-related bleeding complications with PCI in women using the radial vs assessment by real-time three-dimensional echocardiography, 1180 (Readers’ femoral artery compared to, 1216 Comments) bone mineral and body composition changes after CABG, 585

three-dimensional echocardiography, number of component views and accuracy with Brugada syndrome, ECG at higher V1 to V2 recording in, 53

of, 1321 heart value survival score vs peak VO2 prognosis predictions in women vs, 399 Left ventricular remodeling lower pre-hospital case fatality of women after MI, and survival benefit compared after reperfused AMI, plasma brain natriuretic peptide relation to serum indexes with, 1481 (Readers’ Comments) of collagen type I turnover and, 651 Meta-analysis with healed MI, left ventricular scar size, location, and transmurality effect on, cardiac function before and after surgery for pectus excavatum, 1762 1109 cardiovascular event risk with celecoxib, 91 predictors of, after reperfused AMI, 1024 (Readers’ Comments) intravascular ultrasound of coronary atherosclerotic volume in patients with glo- reverse merular filtration rates Յ60 vs Ͼ60 ml/min/1.73 m2, 813 left ventricular lead placement in CRT, diastolic dyssynchrony and, 239 magnesium therapy for acute management of rapid atrial fibrillation, 1726 prediction of, qualitative observation of left ventricular multiphasic septal randomized trials of drug-eluting stents vs bare metal stents in patients with motion and septal-to-lateral apical shuffle after CRT and, 966 diabetes mellitus, 1399 Lepirudin, smart infusion technology and administration of, 1002 Metabolic syndrome Leukocyte count, after primary angioplasty, myonecrosis, myocardial perfusion and, cardiovascular disease risk and, 382 (Editor’s Roundtable) 1067 clinical impact of, and additive effect with smoking on subsequent cardiac Levosimendan, for acute heart failure syndromes, clinical criteria for assessing events after acute myocardial infarction of, 885 response to, 146 (Reader’s Comments) coronary artery calcium and uric acid in men asymptomatic for myocardial isch- Lifestyle intervention, type 2 diabetes mellitus and cardiovascular disease prevention emia and with vs without, 41 and, 726 definition comparisons of Adult Treatment Panel III and International Diabetes Life support, advanced cardiac, elective high-risk PCI supported by, 771 Federation for, 541 Lipid-modifying drugs. See also Statins impact on atherosclerotic burden and cardiovascular prognosis, 1623 discontinuation in United States in recent clinical practice of, 530 non-clinically diagnosed diabetic patients with ACS and, clinical outcomes of, preoperative, influence on postoperative outcome in patients undergoing CABG, 667 785 Metastases, to liver, carcinoid heart disease without, 292

18 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 Metoprolol, heart rate variability in symptomatic patients with mitral valve prolapse Myocardial deformation analysis for assessment of fetal myocardial performance, and, 1568 993 Metoprolol XL, in patients with transposition of great arteries and systemic right Myocardial function, segmental, medical therapy for heart failure effect in patients ventricular dysfunction, 704 with ischemic cardiomyopathy on, 1741 MI. See Myocardial infarction Myocardial infarction Microvascular perfusion, myocardial blush grade after primary or rescue PCI and, acute (See Acute myocardial infarction) 1671 with advanced left ventricular dysfunction, prognosis by location and type of, Mitral regurgitation 642 chronic, due to mitral valve prolapse, annular-to-leaflet mismatch and reductive anterior wall, size of myocardial scar and persistence of ST-segment elevation annuloplasty need in patients undergoing mitral repair for, 1434 after healing of, 1106 isolated, and isolated aortic regurgitation, and both, prevalence and clinical cor- baseline plasma myeloperoxidase levels as independent predictor at two years in relates of, in adults aged 21 to 35 years, CARDIA Study, 830 patients presenting with ACS of, usefulness of, 1364 in vitro validation of real-time three-dimensional color Doppler echocardiography conduction disturbances and repolarization duration after, 163 for direct measurement of proximal isovelocity surface area in, 1440 COPD impact on outcomes after, 636 Mitral valve prolapse early-onset, polymorphisms in paraoxonase and endothelial nitric oxide synthase annular-to-leaflet mismatch and the need for reductive annuloplasty in patients genes and, 1100 undergoing mitral repair for chronic mitral regurgitation due to, 1434 fatal acute, restrictive diastolic filling pattern and apoptosis in, 307 historical review of diagnosis, 129 healed, left ventricular scar size, location, and transmurality effect on left ventric- link among anxiety disorders, inheritance and, 1350 (Readers’ Comments) ular remodeling with, 1109 metoprolol effect on heart rate variability in symptomatic patients with, 1568 high-risk patients with acute ST-segment elevation, protection of distal emboliza- Mitral valve replacement, long-term outcome after repeated balloon mitral valvotomy tion in, (PREMIAR Trial), 357 in patients with restenosis after previous balloon valvotomy vs, 1571 increased creatine kinase-MB after PCI and prediction of, 616 Mitral valvotomy, repeated balloon, long-term outcome after mitral valve lower pre-hospital case fatality after, and survival benefit for women compared replacement in patients with restenosis after previous balloon valvotomy with men, 1481 (Readers’ Comments) vs, 1571 non–ST-segment elevation, glycoprotein IIb/IIIa inhibitor timing and outcomes Mnemonics, CAMELOT tales about, 878 (Readers’ Comments) among patients undergoing PCI, in the CRUSADE Initiative, 1389 Mortality. See also Death periprocedural, after PCI, N-terminal pro-BNP assessment of, 344 among fibrinolytic-treated patients with acute STEMI presenting with cardiogenic QT interval changing capacity and ventricular fibrillation after, 296 shock, impact of initial heart rate and systolic pressure on, 793 relation of family history of, and the presence of coronary arterial calcium in among statin and nonstatin users, cross-sectional or longitudinal comparison of, various age and risk factor groups, 825 1179 (Readers’ Comments) ST-segment elevation (See ST-segment elevation myocardial infarction) anemia effect on hemorrhagic complications following PCI and, 1513 two- vs three-dimensional echocardiography with MRI for follow-up of left ven- body mass index relation in patients with known or suspected CAD and, 1485 tricular volumes after, 300 heart failure, chronic kidney disease and, 393 in women, baseline high vs baseline low levels of high-sensitivity CRP and immediate thrombolytic therapy vs delayed primary angioplasty for AMI and, prediction of, 1500 1384 Myocardial ischemia obesity and, 876 (Readers’ Comments) coronary angiographic lesions association with increased left atrial dimension

one-year, usefulness of ST depression with T-wave inversion in leads V4 to V6 during exercise tolerance tests among patients with unknown coronary in non–ST-elevation ACS, Electrocardiographic Analysis of the Global Use heart disease and, 1187 of Strategies to Open Occluded Coronary Arteries IIB Trial, 934 coronary artery calcium and uric acid in men with vs without metabolic syn- risk, clinical and echocardiographic markers in patients with atrial fibrillation of, drome and asymptomatic for, 41 1733 different thresholds of ramp and standard Bruce protocol exercise tests in pa- risk-adjusted analysis of PCI by American College of Cardiology/American Heart tients with positive exercise stress tests and angiographically demon- Association Guidelines recommendations, 189 strated coronary arterial narrowing, 921 short- and long-term, impact of admission hyperglycemia and diabetes mellitus during dobutamine stress echocardiography in asymptomatic patients with diabe- after AMI in the PCI era on, 1674 tes mellitus and no prior history of coronary events, 1193 six-month, effect of no re-flow during primary PCI for AMI on, 442 Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) with suspected CVD, usefulness of CBC-derived risk score in prediction of, 169 Study, on high-dose atorvastatin benefits in patients Ն65 years of age troponin levels below the diagnostic cut-off level for AMI in predicting progno- with ACS, 632 sis in unselected patients admitted to the coronary care unit, usefulness Myocardial perfusion, leukocyte count, myonecrosis and relation with outcomes of, 1357 after primary angioplasty of, 1067 two- and five-year, comparison of left ventricle ejection fraction and exercise Myocardial perfusion imaging capacity after AMI as predictors of, 436 for determining lesion significance in patients with multivessel coronary disease, MRI. See Magnetic resonance imaging comparison between angiography and fractional flow reserve vs, 896 Multidetector computed tomography. See Computed tomography electrocardiographically gated SPECT, value in symptomatic postmenopausal Multislice computed tomography. See Computed tomography women of, 1096 Mutations Myocardial perfusion reserve, in postmenopausal women with angina pectoris, Ala490Pro, in HERG gene, autosomal dominant long QT syndrome and, 1737 estradiol-drospirenone hormone treatment and, 1648 m.3243AϾG MELAS, cardiac involvement in adults with, 264 Myocardial scar, size of, and persistence of ST-segment elevation after healing of in sarcomeric protein genes anterior wall MI, 1106 sporadic hypertrophic cardiomyopathy in Japanese patients Ͻ40 years and, Myocarditis, percutaneous left ventricular assist device as bridge to recovery from, 1755 1745 Myonecrosis

Myeloperoxidase, baseline plasma levels of, usefulness as independent predictor of aspirin effects on platelet TXA2 synthesis in STEMI patients and, 19 MI at two years in patients presenting with ACS, 1364 leukocyte count, myocardial perfusion and, relation with outcomes after primary Myocardial blush grade, relation to microvascular perfusion and myocardial infarct angioplasty of, 1067 size after primary or rescue PCI, 1671 postprocedural markers of, measuring aspirin resistance, clopidogrel responsive- Myocardial bridge, adjacent nontunneled left anterior descending coronary artery ness in patients undergoing PCI and, 1518 compared with coronary artery size in, 1653 Myopathy, skeletal, fatal and widespread, simvastatin therapy and, 1171

SUBJECT INDEX 19 Natriuretic peptides Patent foramen ovale brain, relation to serum indexes of collagen type I turnover and left ventricular five-year experience with percutaneous closure of, 1316 remodeling after reperfused AMI, 651 in patients with paradoxical embolism, outcomes after transcatheter closure of, B-type (See also N-Terminal Pro-BNP) 1312 levels before and after exercise, relation to functional capacity in patients Patients, CAD risk score based on information reported by, 1236 with idiopathic dilated cardiomyopathy, 1279 PCI. See Percutaneous coronary intervention preimplantation levels, predicting CRT response and, 242 Pectus excavatum, cardiac function before and after surgery for, 1762 Neointimal hyperplasia Pediatric cardiology. See also Children after coronary artery stenting, gender differences and, 491 good books appearing in 2006 on, 745 coverage of sirolimus-eluting stents three months after implantation, optical co- Percutaneous coronary intervention herence tomography of, 1033 access-related bleeding complications in women vs men using the radial vs Neonates. See Infants femoral artery for, 1216 Neurofibromatosis, pulmonary hypertension in, 1177 for acute STEMI, FilterWire EZ safety and efficacy in, 911 New York Heart Association functional class, association of natural history end for AMI, usefulness of unfractionated heparin in patients not receiving glycopro- points in heart failure and, 549 tein IIb/IIIa inhibitors after, 202 Niacin extended release/lovastatin, safety of lovastatin alone, atorvastatin alone, anemia and hemorrhagic complications and mortality following, 1513 pravastatin alone, and simvastatin alone compared with, 379 CABG for ischemic cardiomyopathy vs, 37 Nicorandil, intravenous, and preexisting angina pectoris effect on short- and long- for CAD, obstructive sleep apnea and, 26 term outcomes in patients with first acute STEMI, 1203 computed tomographic angiography guided, usefulness of, 871 (Editorial) Nitric oxide metabolism, in adults with cyanotic congenital heart disease, 691 cost-minimization analysis of the Angio-Seal vascular closure device following, Nitric oxide synthase, endothelial, early-onset MI and gene polymorphisms in, 1100 766 Nitroprusside, slow coronary flow after successful stent implantation and, 916 elective high-risk, supported by extracorporeal life support, 771 Non-human cardiology, good books appearing in 2006 on, 745 gender differences with drug-eluting stents in, 626 Noninferiority, meaning and clinical measurement of, 284 (Editorial) glycoprotein IIb/IIIa inhibitor use timing and outcomes among non–ST-segment Noninvasive imaging, fractional flow reserve for myocardial ischemia evaluation vs elevation MI patients undergoing, in CRUSADE Initiative, 1389 quantitative coronary angiography and/or, 450 good books appearing in 2006 on, 745 N-Terminal Pro-BNP guideline-recommended, CABG vs medical therapy only vs, in the REACH Inter- active infective endocarditis and prognostic value of, 1425 national Registry, 1212 in hospitalized patients with heart failure, prognostic significance of BUN vs, immediate (ad hoc) vs staged, outcomes following, 446 1143 increased creatine kinase-MB after, myocardial infarction prediction and, 616 periprocedural myocardial injury after PCI assessed with, 344 measuring aspirin resistance, clopidogrel responsiveness, and postprocedural serum levels, in predicting in-stent restenosis in patients with preserved left myonecrosis markers in patients undergoing, 1518 ventricular function and normal troponin I levels, 1051 N-terminal pro-BNP assessment of periprocedural myocardial injury after, 344 in patients with AMI, body mass index impact on outcomes after, 903 Obesity predictors and outcomes of emergency department visits within 30 days after, mortality correlation to, 876 (Readers’ Comments) 197 otherwise healthy adults with vs without obstructive sleep apnea and, compari- prednisone after, efficacy and safety of lower-dose vs higher-dose, the IM- son of cardiac structural and functional changes in, 1298 PRESS-LD study, 1082 Omacor prerandomization anticoagulant switching with bleeding and, 1687 effects on serum lipids and clinical outcome, 145 (Reader’s Comments) fish oil composition of, and GISSI Trial, 1483 (Readers’ Comments) primary Omega-3 fatty acids for AMI, effect on six-month mortality of no re-flow during, 442 blood levels, in middle-aged acute coronary artery disease patients, 154 for AMI, time to treatment impact on myocardial reperfusion and infarct size hepatocyte triglyceride reduction through hyperinsulinemia, cytokines and adipo- with, in the EMERALD Trial, 1680 cytokines by, 146 (Reader’s Comments) baseline platelet count impact in AMI patients undergoing, the CADILLAC relation to dietary factors known to reduce CAD risk, 1230 trial, 1055 Optical coherence tomography, of neointimal coverage of sirolimus-eluting stents, primary or rescue, relation of myocardial blush grade to microvascular perfusion three months after implantation, 1033 and myocardial infarct size after, 1671 Osteoprotegerin, coronary calcium and aortic plaque in the Dallas Heart Study and, risk-adjusted mortality analysis of, American College of Cardiology/American 513 Heart Association Guidelines for, 189 Oxygen uptake routine fractional flow reserve assessment influence on decision making during, delayed pulmonary, after heart transplantation, relation of etiology of heart failure 504 before heart transplantation and, 1745 in saphenous vein grafts, prediction of distal embolization during, 603 heart value survival score prognosis predictions in men vs women compared to, shortening time to infarct artery patency in STEMI patients using, 1360 399 with a single remaining vessel, 470 noninvasive measurement of cardiac output at rest and during exercise with Syntax score to predict clinical outcome in CAD patients with three-vessel lu- heart failure and, 404 men obstruction undergoing, 1072 trends in, American College of Cardiology–National Cardiovascular Data Registry Pacemaker leads, superior vena cava syndrome induced by, 1765 report on, 329 Paclitaxel-eluting stents trilayer metal phosphorylcholine-coated zotarolimus-eluting stent for, 1403 angiographic analysis of late luminal loss in sirolimus-eluting stents vs, 593 ultrasonic strain measurements to predict regional wall motion recovery in pa- clinical trials comparing sirolimus-eluting stents to, lessons for the future, 424 tients with AMI after, usefulness of, 754 (Editorial) Percutaneous transluminal coronary angioplasty, trends in operator and hospital sirolimus-eluting stents vs bare metal stents in patients with STEMI, three-year procedure volume and outcomes, 339 comparison of, RESEARCH and T-SEARCH Registries, 1027 Pericardial effusions, in patients undergoing pericardiocentesis, diagnostic value of PAIVS. See Pulmonary atresia with intact ventricular septum the biochemical composition of, 1294 Paramedics, shortening time to infarct artery patency in STEMI patients and, 1360 Pericardiocentesis, diagnostic value of the biochemical composition of pericardial Paraoxonase, early-onset MI and gene polymorphisms in, 1100 effusions in patients undergoing, 1294

20 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 Peripheral arterial disease Pulmonary vein frequency of abnormal cardiac ﬁndings in echocardiography with and without, isolation, circumferential ablation in permanent atrial ﬁbrillation with, 1425 499 primary stenosis in children of, 568

in patients with diabetes mellitus, relation of increased hemoglobin A1c levels to severity of, 1468 QT interval, changing capacity after MI with or without cardiac arrest, 296 Pharmacology, cardiac, good books appearing in 2006 on, 745 Phased-array imaging, intraluminal, in type B aortic dissection, intravascular ultrasound and transesophageal echocardiography vs, 270 Radial artery Pheochromocytoma, President Eisenhower and, 1325 access-related bleeding complications with PCI in women vs men using the Physical activity, Doppler measures of diastolic function and, 1629 femoral artery vs, 1216 Physical examination function after cannulation for coronary angiography and angioplasty, 457 Rancho Bernardo study cardiac, good books appearing in 2006 on, 745 atherosclerosis assessment confounders in, 876 (Readers’ Comments) estimation of right atrial pressure by internal medicine residents using hand- coronary artery calcium association with carotid intimal media thickness in, 227 carried ultrasound vs, 1614 coronary heart disease association with endothelin-1 in, 486 Physiology, cardiac, good books appearing in 2006 on, 745 IL-6 and CRP as predictors of subclinical carotid atherosclerosis and, 98 Plaques Randomized Argentine Clopidogrel Stent (RACS) trial, of long-term vs short-term aortic, osteoprotegerin relation to coronary artery calcium in Dallas Heart Study clopidogrel with coronary stenting, 349 and, 513 Ranitidine, antiplatelet effects of aspirin and, 124 coronary Ranolazine, for chronic angina pectoris, gender comparison of efficacy and safety intravascular ultrasound assessment of temporal changes in volume of, 5 of, 11 noncalcified, in patients with zero and low coronary artery calcium, 64-slice Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital (RESEARCH) computed tomographic angiography of, 1183 registry, paclitaxel- and sirolimus-eluting stents vs bare metal stents in rupture of, coronary culprit lesions with, serial intravascular ultrasonic study patients with STEMI, three-year comparison of, 1027 of outcomes following bare metal stent implantation in patients with an- REduction of Atherothrombosis for Continued Health (REACH) Registry, guideline- gina pectoris, 1394 recommended PCI vs CABG vs medical therapy only in, 1212 size relation to necrotic core in patients with acute coronary syndrome as Regadenoson, in stress myocardial perfusion imaging, 1619 (Editorial) determined by intravascular ultrasonic imaging radiofrequency, 790 Remodeling. See Left ventricular remodeling Platelet counts, baseline, in AMI patients undergoing primary PCI, the CADILLAC Renin-angiotensin system inhibition, type 2 diabetes mellitus development and, trial, 1055 1006 Postmenopausal women. See Women, postmenopausal Repolarization, duration after MI with conduction disturbances, 163 Pravastatin Restenosis platelet inhibition by aspirin and clopidogrel in patients with coronary stent after previous balloon valvotomy, long-term outcome after mitral valve replace- thrombosis and, 353 ment or repeated balloon mitral valvotomy in patients with, 1571 safety of lovastatin/extended release niacin vs, 379 angiographic, after drug-eluting stent implantation for aorto-ostial coronary artery Prednisone, comparison of efficacy and safety of lower-dose to higher-dose, after disease, results and predictors of, 760 PCI, the IMPRESS-LD study, 1082 in-stent, in patients with preserved left ventricular function and normal troponin I PREMIAR (Protection of Distal Embolization in High-Risk Patients with Acute ST- levels, usefulness of N-terminal pro-BNP serum levels to predict, 1051 Segment Elevation Myocardial Infarction) Trial, 357 in unstable angina pectoris with sirolimus-eluting stenting and, a SIRIUS sub- Procainamide, safety and efficacy comparison of propafenone vs amiodarone for study, 1044 conversion of recent onset atrial fibrillation vs, 1721 Rhabdomyolysis, fatal and widespread, after simvastatin therapy, 1171 Propafenone, safety and efficacy comparison of procainamide vs amiodarone for Right bundle branch block. See Bundle branch block conversion of recent onset atrial fibrillation vs, 1721 Right ventricle Protection of Distal Embolization in High-Risk Patients with Acute ST-Segment infarction, survival in shock due to left ventricular pump failure after PCI for Elevation Myocardial Infarction (PREMIAR) Trial, 357 STEMI vs, 431 PTCA. See Percutaneous transluminal coronary angioplasty multislice computed tomography measurement of volumes before and after atrial Pulmonary arterial flow discordance, usefulness to pulmonary embolism septal defect closure of, 1458 identification, 579 Right ventricular dysfunction, systemic, effect of beta blockers in patients with Pulmonary artery. See Transposition of the great arteries transposition of great arteries and, 704 Pulmonary atresia with intact ventricular septum, fetal, determinants of outcome in, Right ventricular function 699 echocardiography vs MRI in adults with repaired tetralogy of Fallot for assess- Pulmonary embolism ment of, 1593 acute and structure, comparison of changes in obese otherwise healthy adults with vs differentiation between acute coronary syndromes on the basis of negative T without obstructive sleep apnea, 1298 waves and, 817 Rosuvastatin multidetector spiral computed tomography according to age and gender for alone or with ezetimibe, efficacy and safety of, in EXPLORER Study, 673 diagnosis of, usefulness of, 1303 alternate day dosing in patients previously intolerant to statin therapy, 291 acute massive, catheter-tip embolectomy in management of, 415 effects of high doses of atorvastatin on subpopulations of high-density lipopro- acute submassive, gender-related differences in risk-to-benefit ratio of thrombol- teins vs, 681 ysis for, 103 in South-Asian patients at risk of CAD, atorvastatin vs, from the IRIS Trial, 1538 embolectomy outcome, 421 pulmonary arterial flow discordance in identification of, usefulness of, 579 Saphenous vein grafts Pulmonary hypertension aortocoronary, long-term patency of, relation of polymorphisms in five genes to, arterial, transition from intravenous epoprostenol to intravenous treprostinil in 1087 stable pediatric patients with, 696 prediction of distal embolization during PCI in, 603 in neurofibromatosis, 1177 Scar tissue, contrast-enhanced MRI of response to CRT and, 657 prognostic importance of, in patients with heart failure, 1146 Screening for Heart Attack Prevention and Education (SHAPE), cost and Pulmonary valve stenosis, fetal, determinants of outcome in, 699 effectiveness of, 1013 (Editorial)

SUBJECT INDEX 21 SEAS study, simvastatin and ezetimibe in aortic stenosis, 970 Statins. See also Atorvastatin; Endostatin; Lovastatin; Pravastatin; Rosuvastatin; Selective serotonin reuptake inhibitors, antiplatelet effect of clopidogrel and, 1025 Simvastatin (Readers’ Comments) for acute coronary syndrome, 213 (Editor’s Roundtable) Sepsis, complication in patients with cardiogenic shock following AMI, age at death and use of, 1181 (Readers’ Comments), Reply, 1182 microbiological profile of, from the SHOCK Study, 802 alternate day rosuvastatin dosing in patients previously intolerant to, 291 Sideris septal occluder device, for closure of atrial septal defect, late migration into AMI in patients with vs without aortic valve sclerosis, in Heart and Soul Study, the left atrium with mitral valve obstruction, 1479 1128 Simvastatin coenzyme Q10 and myopathic symptoms in patients treated with, 1409 coronary and abdominal aortic arterial calcium and, from CATZ Study, 1714 early treatment effect at standard doses on long-term clinical outcomes in pa- CRP in coronary artery disease and, 149 tients with AMI, 1523 and ezetimibe inflammation hypothesis and its potential relevance to therapy with, 732 in aortic stenosis, SEAS study, 970 intravascular ultrasound assessment of temporal changes in coronary plaque for reduction of CRP and LDL cholesterol levels, simvastatin monotherapy vs volume and, 5 atorvastatin monotherapy vs, 1706 mortality among users and non-users of, cross-sectional or longitudinal compar- fatal and widespread skeletal myopathy confirmed morphologically years after ison of, 1179 (Readers’ Comments) initiation of, 1171 platelet inhibition by aspirin and clopidogrel in patients with coronary stent monotherapy vs atorvastatin monotherapy vs ezetimibe/simvastatin combination thrombosis and, 353 for reduction of CRP and LDL cholesterol levels, 1706 safety and efficacy in Asians, 410 safety of lovastatin/extended release niacin vs, 379 survival in patients with nonischemic dilated cardiomyopathy and, in the Beta Single-photon emission computed tomography Blocker Evaluation of Survival Trial (BEST), 1448 for determining lesion significance in multivessel coronary disease, comparison STEMI. See ST-segment elevation myocardial infarction between angiography and fractional flow reserve vs, 896 Stenosis early rest-type vs stress-type of atypical chest pain in emergency department, aortic, simvastatin and ezetimibe in, SEAS study, 970 electrocardiographic exercise test vs, 1662 association of multiple inflammatory markers with carotid intima-media thickness Single remaining vessel, PCI with, 470 and, from the Framingham Heart Study, 1598 primary pulmonary vein, in children, 568 Sinus of Valsalva aneurysms, retrospective study of 47 years of a single center Stents. See also Coronary stenting experience and systematic overview of published reports, 1159 bare metal (See Bare metal stents) Sinus rhythm Carbofilm-coated, aspirin alone vs aspirin plus ticlopidine or clopidogrel after comparison of usefulness of CRT in patients with heart failure and, vs patients implantation of, 1062 with atrial fibrillation and heart failure, 1252 drug-eluting endothelial cell function during atrial fibrillation and after restoration of, 1258 for aorto-ostial coronary artery disease, results and predictors of angio- maintenance after electrical cardioversion for atrial fibrillation, effect of candesar- graphic restenosis and long-term adverse cardiac events after, 760 tan and various inflammatory markers on, 1544 Axxess Plus trial, for treatment of bifurcation lesions, 1691 Sirolimus-eluting stents comparison of CABG in patients with diabetes mellitus and, 779 angiographic analysis of late luminal loss in paclitaxel-eluting stents vs, 593 in coronary arteries, late thrombosis in, 1039 clinical trials comparing paclitaxel-eluting stents to, lessons for the future, 424 FDA’s Public Health Notification impact on the adoption of, 1227 (Editorial) gender differences in PCI with, 626 optical coherence tomography evaluation of neointimal coverage of, three late stent thrombosis and, 1020 (Editorial) months after implantation, 1033 overlapping heterogenous, outcome of, 364 paclitaxel-eluting stents vs bare metal stents in patients with STEMI, three-year thrombosis due to, frequency, etiology, treatment, and outcomes during one comparison of, RESEARCH and T-SEARCH Registries, 1027 year of follow-up, 465 safety and effect on restenosis in unstable angina pectoris patients, a SIRIUS drug-eluting and bare-metal, overlapping heterogenous, outcome of, 364 substudy, 1044 drug-eluting vs bare metal SIRolImUS-eluting stent (SIRIUS) substudy, safety and effect on restenosis in acute myocardial infarction risk and, 621 unstable angina pectoris with sirolimus-eluting stenting, 1044 angiographic and ultrasound analysis of luminal loss and neointimal volume, Sleep apnea, obstructive in TAXUS II trial, 607 CAD and PCI outcomes with, 26 coronary arterial late angiographic stent thrombosis frequency in the first six comparison of cardiac structural and functional changes in obese otherwise months with, 774 healthy adults with vs without, 1298 effectiveness compared in large (Ն3.5 mm) coronary arteries, 599 Sleep-related breathing disorder, acute atrial overdrive pacing and, 573 impact on later frequency of AMI and death, 333 Slow coronary flow, nitroprusside effect after successful stent implantation on, 916 meta-analysis of randomized trials in patients with diabetes mellitus of, 1399 Smoking nitroprusside effect on slow coronary flow after successful implantation of, 916 additive effect of metabolic syndrome and, on subsequent cardiac events after paclitaxel-eluting (See Paclitaxel-eluting stents) AMI, 885 sirolimus-eluting (See Sirolimus-eluting stents) crack cocaine, cardiac arrest and, 822 zotarolimus-eluting, trilayer metal phosphorylcholine-coated, PCI using, 1403 Soluble intercellular adhesion molecule-1, relation between soluble homocysteine, Stress echocardiography fibrinogen levels and race/ethnicity in women without cardiovascular dipyridamole disease and, 1246 evaluation of patients Ն65 years of age with known or suspected CAD, SPECT. See Single-photon emission computed tomography prognostic implications of, 1491 Sports in idiopathic dilated cardiomyopathy, independent prognostic value of con- endurance, major adverse cardiac events during, 849 tractile and coronary flow reserve as determined by, 1154 evaluation of chest barriers for protection against sudden death due to commotio dobutamine cordis, 857 for CAD diagnosis in women, 714 exercise-induced hypertension, CAD, and endothelial cell dysfunction in a mara- evaluation of patients Ն65 years of age with known or suspected CAD, thon runner and, 743 prognostic implications of, 1491 SRV, PCI with, 470 myocardial ischemia during, in asymptomatic patients with diabetes mellitus SSRI, antiplatelet effect of clopidogrel and, 1025 (Readers’ Comments) and no prior history of coronary events, 1193

22 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007 risk assessment before noncardiac vascular surgery in patients with left ven- Tetralogy of Fallot, repaired tricular ejection fraction Ͻ35%, value of myocardial viability estimation cardiopulmonary exercise to predict long-term prognosis in adults with, useful- using, 1555 ness of, 1462 real-time three-dimensional, ultrasound contrast agent and image quality in, 275 echocardiographic vs cardiac MRI for assessing right ventricular function in safety of, transesophageal atrial pacing and, 584 (Readers’ Comments) adults with, 1593 Stress myocardial perfusion imaging, new generation of coronary vasodilators in, Thrombolysis, immediate, for AMI, comparison of mortality beneﬁt of delayed 1619 (Editorial) primary angioplasty vs, 1384 Stress tests Thrombosis carotid ultrasound in CAD prediction using, usefulness of, 1196 coronary arterial late angiographic stent, frequency in the ﬁrst six months with diabetes mellitus prognosis assessment, and cardiac imaging in patients with, bare metal stents vs drug-eluting stents, 774 1016 (Editorial) coronary stent, statins and platelet inhibition by clopidogrel with, 353 ramp and standard Bruce protocol, different thresholds of myocardial ischemia with drug-eluting stents, frequency, etiology, treatment, and outcomes during in patients with positive exercise stress tests and angiographically dem- one year of follow-up, 465 onstrated coronary arterial narrowing, 921 good books appearing in 2006 on, 745 Stroke late acute ischemic, mechanism of troponin elevations in patients with, 867 of coronary arteries with drug-eluting stents, 1039 acute ischemic, troponin elevation in, 108 drug-eluting stents and, 1020 (Editorial)

intraatrial block and, 49 Thromboxane A2, inhibition of platelet synthesis in STEMI patients of, aspirin and ST-segment elevation, persistence after healing of anterior wall MI, myocardial scar myonecrosis and, 19 size and, 1106 Thrombus ST-segment elevation myocardial infarction giant floating aortic, in transesophageal echocardiography, 739 acute left ventricular, contrast echocardiography assessment after AMI for, 1667 with cardiogenic shock, impact of initial heart rate and systolic blood pres- Ticlopidine, aspirin plus clopidogrel or, vs aspirin alone after Carbofilm-coated sure on relation of age and mortality among fibrinolytic-treated patients, stent implantation, 1062 793 Tilt-table test, for discriminating adolescents with or without chronic fatigue, FilterWire EZ in, safety and efficacy of, 911 usefulness of an abnormal cardiovascular response during, 997 first, effect of intravenous nicorandil and preexisting angina pectoris on Tissue Doppler imaging. See Doppler imaging, tissue short- and long-term outcomes in patients with, 1203 Trandolapril, as add-on therapy in patients taking verapamil SR, factors influencing hemoglobin admission levels in patients presenting with cardiogenic shock and, blood pressure response to, INVEST Study, 1549 prognostic value of, 1201 Transesophageal atrial pacing, stress echocardiography safety and, 584 (Readers’ myocardial blush grade relation to infarct size after primary or rescue PCI for, Comments) 1671 Trans fatty acids, blood levels of, in middle-aged acute CAD patients, 154

myonecrosis and aspirin effects on platelet TXA2 synthesis in, 19 Transposition of the great arteries, effect of beta blockers on systemic right paclitaxel- and sirolimus-eluting stents vs bare metal stents in patients with, ventricular dysfunction with, 704 three-year comparison, RESEARCH and T-SEARCH Registries, 1027 Treprostinil, intravenous, transition of stable pediatric patients with pulmonary previously occluded noninfarct vessels in, impact of, 429 (Readers’ Comments) arterial hypertension from intravenous epoprostenol to, 696 shortening time to infarct artery patency in patients with, 1360 Triglycerides, hepatocyte, omega-3 fatty acids reduction through hyperinsulinemia, survival in shock due to right ventricular infarction vs left ventricular pump fail- cytokines, and adipocytokines of, 146 (Reader’s Comments) ure after PCI for, 431 Troponin Studies, methodological mechanism of elevations in patients with acute ischemic stroke, 867 mortality among statin users and nonstatin users, cross-sectional or longitudinal negative, prognostic value of myocardial contrast echocardiography in patients comparison in, 1179 (Readers’ Comments) presenting to hospital with acute chest pain and, 1369 statin use and age at death, 1181 (Readers’ Comments), Reply, 1182 normal, and non–ST-segment elevation chest pain, risk categories for prognostic Superior vena cava syndrome, endocardial deﬁbrillator and pacemaker leads and, assessment of, 797 1765 usefulness of levels below the diagnostic cut-off level for AMI in predicting Survival prognosis in unselected patients admitted to the coronary care unit, 1357 long-term, with heart failure and ventricular conduction delays treated with CRT, Troponin I, normal, in patients with preserved left ventricular function, N-terminal 232 pro-BNP serum levels and predicting in-stent restenosis with, 1051 lower pre-hospital case fatality of women compared with men after MI and, 1481 Troponin T, elevation in acute ischemic stroke, 108 (Readers’ Comments) Turner’s syndrome, coronary artery disease and, 741 shock due to right ventricular infarction vs left ventricular pump failure after PCI T wave

for STEMI and, 431 inversion in leads V4 and V6 with ST depression, usefulness in one-year mortal- Syncope, unexplained, neurocardiogenic mechanisms of idiopathic dilated ity prediction, in Electrocardiographic Analysis of the Global Use of Strat- cardiomyopathy and, 558 egies to Open Occluded Coronary Arteries IIB Trial, 934 SYNERGY trial, racial differences among high-risk patients with non–ST-elevation negative, differentiation between acute pulmonary embolism and acute coronary ACS, 315 syndromes on the basis of, 817 Syntax score, for predicting clinical outcome in CAD patients with three-vessel lumen obstruction undergoing PCI, 1072 Ultrasound Systemic hypertension, evolving deﬁnition of, 1168 (Editorial) angiographic outcomes of late lumen loss and neointimal growth in Taxus and Systolic heart failure, diastolic heart failure and unstable angina pectoris vs, 460 bare metal stents vs, in TAXUS II Trial, 607 carotid Taxus-Stent Evaluated at Rotterdam Cardiology Hospital (T-SEARCH) registry of subclinical atherosclerosis, Framingham risk score and, 310 paclitaxel- and sirolimus-eluting stents vs bare metal stents in patients with usefulness with stress testing in CAD prediction, 1196 STEMI, three-year comparison of, 1027 of coronary artery in myocardial bridge size compared with adjacent nontunneled Taxus stents left anterior descending coronary artery, 1653 angiographic and ultrasound outcomes of late lumen loss and neointimal growth hand-carried, estimation of right atrial pressure by internal medicine residents in bare metal stents vs, in TAXUS II Trial, 607 using physical examination vs, 1614 clinical trials comparing Cypher stents to, lessons for the future, 424 (Editorial) intravascular (See Intravascular ultrasound)

SUBJECT INDEX 23 strain measurements using, in prediction of regional wall motion recovery with Wave reﬂections, relation of habitual cocoa consumption to aortic stiffness and AMI after PCI, 754 central hemodynamics in healthy individuals and, 1473 Uric acid, coronary artery calcium in men asymptomatic for myocardial ischemia Weight loss and with vs without metabolic syndrome and, 41 effects on epicardial fat after bariatric surgery, echocardiography of, 1242 reduction in predicted coronary heart disease risk after bariatric surgery for, 222 Valve calciﬁcation, cytokines, bone resorption and, 1024 (Readers’ Comments) White blood cells, heart rate recovery after exercise and, 707 Valvular heart disease, good books appearing in 2006 on, 745 Women Vascular angiography, good books appearing in 2006 on, 745 baseline high vs baseline low levels of high-sensitivity CRP, and characteristics Vascular surgery, noncardiac, in patients with left ventricular ejection fraction Ͻ35%, value of myocardial viability estimation using dobutamine stress of future MI in, 1500 echocardiography in risk assessment before, 1555 cardiovascular disease in, good books appearing in 2006 on, 745 Vasodilation, anger provocation effect on endothelium-dependent and -independent, comparison of access-related bleeding complications with PCI in men using the 860 radial vs femoral artery vs, 1216 Ventricular arrhythmias, during left ventricular assist device support, 1151 dobutamine stress echocardiography for coronary artery disease diagnosis in, Ventricular dysfunction. See Left ventricular dysfunction; Right ventricular 714

dysfunction heart value survival score vs peak VO2 prognosis predictions in men vs, 399 Ventricular fibrillation left ventricular apical ballooning syndrome incidence, clinical findings, and out- after myocardial infarction with and without cardiac arrest, 296 come of, 182 chest barriers for protection against sudden death due to, 857 lower pre-hospital case fatality after MI, and survival benefit of men compared Ventricular remodeling. See Left ventricular remodeling with, 1481 (Readers’ Comments) Ventricular septal defects postmenopausal perimembranous, transcatheter closure of, in infants and children using the Am- with angina pectoris, estradiol-drospirenone hormone treatment and myocar- platzer perimembranous ventricular septal defect occluder, 984 dial perfusion reserve in, 1648 Ͻ subaortic, at 1 year of age, development of aortic cuspal prolapse and aortic estrogen/progestin therapy, and coronary calcium progression in, 374 regurgitation in, 1588 symptomatic, value of electrocardiographically gated single-photon emission Ventricular septation, for double-inlet left ventricular repair, late post-operative computed tomographic myocardial perfusion scintigraphy in, 1096 cardiopulmonary responses in Fontan procedure vs, 1757 risk-to-benefit ratio of thrombolysis for acute submassive pulmonary embolism Verapamil SR, trandolapril add-on therapy in patients taking, factors influencing in, 103 blood pressure response to, INVEST Study, 1549 Turner’s syndrome, CAD and, 741 Vitamin D, atorvastatin effects in patients with acute ischemic heart disease on without cardiovascular disease, relation between soluble ICAM-1, homocysteine, levels of, 903 and fibrinogen levels and race/ethnicity in, 1246 VO2. See Oxygen uptake young, isolated left ventricular basal ballooning phenotype of transient cardiomy- Wall motion recovery, regional, ultrasonic strain measurements in patients with AMI opathy of, 1451 after PCI, usefulness of ultrasonic strain measurements in prediction of, 754 Warfarin, aspirin plus, after ACS, aspirin plus clopidogrel vs, 1637 Zotarolimus-eluting stents, trilayer metal phosphorylcholine-coated, PCI using, 1403

24 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 99 JUNE 15, 2007