The American Journal of Cardiology

Volume 100, Issue 4, Pages.563-746 (15 August 2007)

1. ditorial Board Page A2

2. Contents Pages A4-A6

Coronary Artery Disease

3. Effectiveness of Workload at the Heart Rate of 100 Beats/Min in Predicting Cardiovascular Mortality in Men Aged 42, 48, 54, or 60 Years at Baseline Pages 563-568 Kai P. Savonen, Timo A. Lakka, Jari A. Laukkanen, Tuomas H. Rauramaa, Jukka T. Salonen and Rainer Rauramaa

4. High Molecular Weight Adiponectin as a Predictor of Long-Term Clinical Outcome in Patients With Coronary Artery Disease Pages 569-574 Teruo Inoue, Norihiko Kotooka, Toshifumi Morooka, Hiroshi Komoda, Toshihiko Uchida, Yoshimasa Aso, Toshihiko Inukai, Takehiko Okuno and Koichi Node

5. Accuracy of N-Terminal Pro-Brain Natriuretic Peptide to Predict Mortality in Various Subsets of Patients With Coronary Artery Disease Pages 575-578 Gjin Ndrepepa, Siegmund Braun, Albert Schömig and Adnan Kastrati

6. Time Course of Hemoglobin Concentrations in the Intensive Care Unit in Nonbleeding Patients With Acute Coronary Syndrome Pages 579-582 Marco Previsdomini, Reto Stocker, Roberto Corti, Bernard Cerutti and Andreas Perren 7. Prognostic Significance of Fragmented QRS Complex for Predicting the Risk of Recurrent Cardiac Events in Patients With Q-Wave Myocardial Infarction Pages 583-586 Grzegorz Pietrasik, Ilan Goldenberg, Joanna Zdzienicka, Arthur J. Moss and Wojciech Zareba

8. Usefulness of Noninvasive Cardiac Imaging Using Dual-Source Computed Tomography in an Unselected Population With High Prevalence of Coronary Artery Disease Pages 587-592 Martin Heuschmid, Christof Burgstahler, Anja Reimann, Harald Brodoefel, Ines Mysal, Ellen Haeberle, Ilijas Tsiflikas, Claus D. Claussen, Andreas F. Kopp and Stephen Schroeder

9. Peripheral-Blood Dendritic Cells in Men With Coronary Heart Disease Pages 593-597 Hongyu Shi, Junbo Ge, Weiyi Fang, Kang Yao, Aijun Sun, Rongchong Huang, Qingzhe Jia, Keqiang Wang, Yunzeng Zou and Xuetao Cao

10. Usefulness of Microvolt T-Wave Alternans on Predicting Outcome in Patients With Ischemic Cardiomyopathy With and Without Defibrillators Pages 598-604 Theodore Chow, Sayed Saghir, Cheryl Bartone, Megan Goebel, Julia Schneider, Terri Booth and Paul S. Chan

11. Comparison of the Prognostic Value of the Stress-Recovery Index Versus Standard Electrocardiographic Criteria in Patients With a Negative Exercise Electrocardiogram Pages 605-609 Riccardo Bigi, Lauro Cortigiani, Dario Gregori and Cesare Fiorentini

12. Effects of Triple Antiplatelet Therapy (Aspirin, Clopidogrel, and Cilostazol) on Platelet Aggregation and P-Selectin Expression in Patients Undergoing Coronary Artery Stent Implantation Pages 610-614 Bong-Ki Lee, Seung-Whan Lee, Seong-Wook Park, Se-Whan Lee, Duk-Woo Park, Young-Hak Kim, Cheol Whan Lee, Myeong-Ki Hong, Jae-Joong Kim, Seongsoo Jang, et al.

13. Intravascular Ultrasound Parameters Associated With Stent Thrombosis After Drug-Eluting Stent Deployment Pages 615-620 Teruo Okabe, Gary S. Mintz, Ashesh N. Buch, Probal Roy, Young Joon Hong, Kimberly A. Smith, Rebecca Torguson, Natalie Gevorkian, Zhenyi Xue, Lowell F. Satler, et al. 14. Meta-Analysis of Angiographic Versus Intravascular Ultrasound Parameters of Drug-Eluting Stent Efficacy (from TAXUS IV, V, and VI) Pages 621-626 Esteban Escolar, Gary S. Mintz, Jeffrey Popma, Aleksandra Michalek, Sang Wook Kim, Lazar Mandinov, Joerg Koglin, Gregg Stone, Stephen G. Ellis, Eberhard Grube, et al.

15. Frequency of Stent Fracture as a Cause of Coronary Restenosis After Sirolimus- Eluting Stent Implantation Pages 627-630 Sang-Hee Lee, Jong-Seon Park, Dong-Gu Shin, Young-Jo Kim, Gue-Ru Hong, Woong Kim and Bong-Sup Shim

16. Usefulness of Preprocedural N-Terminal Pro-Brain Natriuretic Peptide in Predicting Angiographic No-Reflow Phenomenon During Stent Implantation in Patients With ST-Segment Elevation Acute Myocardial Infarction Pages 631-634 Seo Na Hong, Youngkeun Ahn, Sun Ho Hwang, Nam Sik Yoon, Sang Rok Lee, Jae Youn Moon, Kye Hun Kim, Young Joon Hong, Hyung Wook Park, Ju Han Kim, et al.

17. Comparison of N-Terminal Pro-Brain Natriuretic Peptide Versus Electrophysiologic Study for Predicting Future Outcomes in Patients With an Implantable Cardioverter Defibrillator After Myocardial Infarction Pages 635-639 Hong Yu, Hanno Oswald, Ajmal Gardiwal, Christoph Lissel and Gunnar Klein

18. Predictors of Aorto–Saphenous Vein Bypass Narrowing Late After Coronary Artery Bypass Grafting Pages 640-645 Josep Rodés-Cabau, Alvaro Facta, Eric Larose, Robert DeLarochellière, Jean- Pierre Déry, Can Manh Nguyen, Louis Roy, Guy Proulx, Onil Gleeton, Gérald Barbeau, et al.

Preventive Cardiology

19. Usefulness of Combining Complement Factor H and C-Reactive Protein Genetic Profiles for Predicting Myocardial Infarction (from the Rotterdam Study) Pages 646-648 Isabella Kardys, Moniek P.M. de Maat, Caroline C.W. Klaver, Dominiek D.G. Despriet, André G. Uitterlinden, Albert Hofman, Paulus T.V.M. de Jong and Jacqueline C.M. Witteman

Arrhythmias and Conduction Disturbances

20. Comparison of Long-Term Follow-Up of Electrocardiographic Features in Brugada Syndrome Between the SCN5A-Positive Probands and the SCN5A- Negative Probands Pages 649-655 Miki Yokokawa, Takashi Noda, Hideo Okamura, Kazuhiro Satomi, Kazuhiro Suyama, Takashi Kurita, Naohiko Aihara, Shiro Kamakura and Wataru Shimizu

21. Incidence of Brugada Electrocardiographic Pattern and Outcomes of These Patients After Intentional Tricyclic Antidepressant Ingestion Pages 656-660 Vikhyat S. Bebarta, Scott Phillips, Aaron Eberhardt, K.J. Calihan, Javier C. Waksman and Kennon Heard

22. Atrial and Ventricular Rate Response and Patterns of Heart Rate Acceleration during Maternal–Fetal Terbutaline Treatment of Fetal Complete Heart Block Pages 661-665 Bettina F. Cuneo, Hui Zhao, Janette F. Strasburger, Marc Ovadia, James C. Huhta and Ronald T. Wakai

23. Angiographic Analysis of the Anatomic Relation of Coronary Arteries to Mitral and Tricuspid Annulus and Implications for Radiofrequency Ablation Pages 666-671 Can Hasdemir, Oguz Yavuzgil, Serdar Payzin, Mehmet Aydin, Cem Ulucan, Meral Kayikcioglu, Levent H. Can, Cuneyt Turkoglu and Hakan Kultursay

24. Quality of Life Within One Year Following Presentation After Transient Loss of Consciousness Pages 672-676 Nynke van Dijk, Mirjam A. Sprangers, Kimberly R. Boer, Nancy Colman, Wouter Wieling and Mark Linzer

Roundtable Discussion

25. The Editor’s Roundtable: Ablation of Atrial Fibrillation Pages 677-683 Vincent E. Friedewald, Robert C. Kowal, Miguel Valderrabano and William C. Roberts

Heart Failure

26. Evidence for the Continued Safety and Tolerability of Fixed-Dose Isosorbide Dinitrate/Hydralazine in Patients With Chronic Heart Failure (the Extension to African-American Heart Failure Trial) Pages 684-689 Clyde W. Yancy, Jalal K. Ghali, Virginia M. Braman, Michael L. Sabolinski, Manuel Worcel, W. Tad Archambault and Joseph A. Franciosa

27. Comparative Effectiveness of Beta-Adrenergic Antagonists (Atenolol, Metoprolol Tartrate, Carvedilol) on the Risk of Rehospitalization in Adults With Heart Failure Pages 690-696 Alan S. Go, Jingrong Yang, Jerry H. Gurwitz, John Hsu, Kimberly Lane and Richard Platt

28. Validation of the Seattle Heart Failure Model in a Community-Based Heart Failure Population and Enhancement by Adding B-Type Natriuretic Peptide Pages 697-700 Heidi T. May, Benjamin D. Horne, Wayne C. Levy, Abdallah G. Kfoury, Kismet D. Rasmusson, David T. Linker, Dariush Mozaffarian, Jeffrey L. Anderson and Dale G. Renlund

Valvular Heart Disease

29. Accuracy of 64-Slice Computed Tomography for the Preoperative Detection of Coronary Artery Disease in Patients With Chronic Aortic Regurgitation Pages 701-706 Hans Scheffel, Sebastian Leschka, André Plass, Robert Vachenauer, Oliver Gaemperli, Elisabeth Garzoli, Michele Genoni, Borut Marincek, Philipp Kaufmann and Hatem Alkadhi

30. Effect of Primary Mitral Regurgitation on Left Ventricular Synchrony Pages 707-711 Thomas S. Denney Jr., Hosakote M. Nagaraj, Steven G. Lloyd, Inmaculada Aban, Cecilia Corros, Frank Seghatol-Eslami, David C. McGiffin, Louis J. Dell’Italia and Himanshu Gupta

Cardiomyopathy

31. Usefulness of Brain Natriuretic Peptide Levels in the Clinical Evaluation of Patients With Hypertrophic Cardiomyopathy Pages 712-714 Josepha Binder, Steve R. Ommen, Horng H. Chen, Michael J. Ackerman, A. Jamil Tajik and Allan S. Jaffe

Congenital Heart Disease

32. Usefulness of Magnetic Resonance Angiography in the Evaluation of Complex Congenital Heart Disease in Newborns and Infants Pages 715-721 Ashwin Prakash, Alejandro J. Torres, Beth F. Printz, Martin R. Prince and James C. Nielsen

Methods

33. Influence of Preparative Procedures on Assay of Platelet Function and Apparent Effects of Antiplatelet Agents Pages 722-727 Nathaniel J. Madsen, Chris E. Holmes, Feliciano A. Serrano, Burton E. Sobel and David J. Schneider

Miscellaneous

34. Cardiac Troponin I in Patients With Acute Lower Limb Ischemia Pages 728-730 Michael Koutouzis, Konstantinos Kontaras, George Sfyroeras, Konstantinos Moulakakis, Savvas Nikolidakis, Vasilios Andrikopoulos and Zenon S. Kyriakides

35. Prevalence and Correlates of Septal Delayed Contrast Enhancement in Patients With Pulmonary Hypertension† Pages 731-735 Javier Sanz, Santo Dellegrottaglie, Mbabazi Kariisa, Roxana Sulica, Michael Poon, Thomas P. O’Donnell, Davendra Mehta, Valentin Fuster and Sanjay Rajagopalan

36. Prevalence and Clinical Significance of Cardiovascular Abnormalities in Patients With the LEOPARD Syndrome Pages 736-741 Giuseppe Limongelli, Giuseppe Pacileo, Bruno Marino, Maria Cristina Digilio, Anna Sarkozy, Perry Elliott, Paolo Versacci, Paolo Calabro, Andrea De Zorzi, Giovanni Di Salvo, et al.

Readers' Comments

37. Patients With Advanced Heart Failure and the Effects of Levosimendan Page 742 Ze-Zhou Song and Jing Ma

38. Reply Pages 742-743 John T. Parissis, Dimitrios Farmakis, Ioannis Praskevaidis, Vassiliki Bistola, Gerasimos Filippatos and Dimitrios T. Kremastinos

39. Impact of Radial Artery Cannulation on Radial Artery Function Pages 743-744 Cristiano O. Cardoso, La Hore C. Rodrigues, Carlos R. Cardoso and Luis Maria C. Yordi

40. Regional Myocardial Performance Index for Diagnosis of Pulmonary Embolism in Patients With Echocardiographic Signs of Pulmonary Hypertension Page 744 Ze-Zhou Song

41. A Novel Method of Two-Dimensional Echocardiographic Tracking Pages 744-745 Ze-Zhou Song

42. Nesiritide in Acute Decompensated Heart Failure: To Use or Not to Use, That Is the Question? Pages 745-746 John R. Kapoor

43. Correction Page 746

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

A2 THE AMERICAN JOURNAL OF CARDIOLOGYா CONTENTS VOL. 100, NO. 4 AUGUST 15, 2007

Coronary Artery Disease Usefulness of Microvolt T-Wave Alternans on Predicting Outcome in Patients With Ischemic Effectiveness of Workload at the Heart Rate of 100 Cardiomyopathy With and Without Beats/Min in Predicting Cardiovascular Mortality in Defibrillators ...... 598 Men Aged 42, 48, 54, or 60 Years Theodore Chow, Sayed Saghir, Cheryl Bartone, at Baseline ...... 563 Megan Goebel, Julia Schneider, Terri Booth, and Kai P. Savonen, Timo A. Lakka, Jari A. Laukkanen, Paul S. Chan Tuomas H. Rauramaa, Jukka T. Salonen, and Rainer Rauramaa Comparison of the Prognostic Value of the Stress- High Molecular Weight Adiponectin as a Predictor Recovery Index Versus Standard of Long-Term Clinical Outcome in Patients With Electrocardiographic Criteria in Patients With a Coronary Artery Disease ...... 569 Negative Exercise Electrocardiogram ...... 605 Teruo Inoue, Norihiko Kotooka, Toshifumi Morooka, Riccardo Bigi, Lauro Cortigiani, Dario Gregori, and Hiroshi Komoda, Toshihiko Uchida, Yoshimasa Aso, Cesare Fiorentini Toshihiko Inukai, Takehiko Okuno, and Koichi Node Effects of Triple Antiplatelet Therapy (Aspirin, Accuracy of N-Terminal Pro-Brain Natriuretic Clopidogrel, and Cilostazol) on Platelet Aggregation Peptide to Predict Mortality in Various Subsets of and P-Selectin Expression in Patients Undergoing Patients With Coronary Artery Disease ...... 575 Coronary Artery Stent Implantation ...... 610 Gjin Ndrepepa, Siegmund Braun, Albert Scho¨mig, and Bong-Ki Lee, Seung-Whan Lee, Seong-Wook Park, Adnan Kastrati Se-Whan Lee, Duk-Woo Park, Young-Hak Kim, Cheol Whan Lee, Myeong-Ki Hong, Jae-Joong Kim, Time Course of Hemoglobin Concentrations in the Seongsoo Jang, Hyun-Sook Chi, and Seung-Jung Park Intensive Care Unit in Nonbleeding Patients With Acute Coronary Syndrome ...... 579 Intravascular Ultrasound Parameters Associated Marco Previsdomini, Reto Stocker, Roberto Corti, With Stent Thrombosis After Drug-Eluting Stent Bernard Cerutti, and Andreas Perren Deployment ...... 615 Teruo Okabe, Gary S. Mintz, Ashesh N. Buch, Prognostic Significance of Fragmented QRS Probal Roy, Young Joon Hong, Kimberly A. Smith, Complex for Predicting the Risk of Recurrent Rebecca Torguson, Natalie Gevorkian, Zhenyi Xue, Cardiac Events in Patients With Q-Wave Myocardial Lowell F. Satler, Kenneth M. Kent, Augusto D. Pichard, Infarction ...... 583 Neil J. Weissman, and Ron Waksman Grzegorz Pietrasik, Ilan Goldenberg, Joanna Zdzienicka, Arthur J. Moss, and Wojciech Zareba Meta-Analysis of Angiographic Versus Intravascular Ultrasound Parameters of Drug-Eluting Stent Efficacy Usefulness of Noninvasive Cardiac Imaging Using (from TAXUS IV, V, and VI)...... 621 Dual-Source Computed Tomography in an Esteban Escolar, Gary S. Mintz, Jeffrey Popma, Unselected Population With High Prevalence of Aleksandra Michalek, Sang Wook Kim, Coronary Artery Disease ...... 587 Lazar Mandinov, Joerg Koglin, Gregg Stone, Martin Heuschmid, Christof Burgstahler, Anja Reimann, Stephen G. Ellis, Eberhard Grube, Keith D. Dawkins, Harald Brodoefel, Ines Mysal, Ellen Haeberle, and Neil J. Weissman Ilijas Tsiflikas, Claus D. Claussen, Andreas F. Kopp, and Stephen Schroeder Frequency of Stent Fracture as a Cause of Coronary Peripheral-Blood Dendritic Cells in Men With Restenosis After Sirolimus-Eluting Stent Coronary Heart Disease ...... 593 Implantation ...... 627 Hongyu Shi, Junbo Ge, Weiyi Fang, Kang Yao, Sang-Hee Lee, Jong-Seon Park, Dong-Gu Shin, Aijun Sun, Rongchong Huang, Qingzhe Jia, Young-Jo Kim, Gue-Ru Hong, Woong Kim, and Keqiang Wang, Yunzeng Zou, and Xuetao Cao Bong-Sup Shim

A4 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 100 AUGUST 15, 2007 Usefulness of Preprocedural N-Terminal Pro-Brain Atrial and Ventricular Rate Response and Patterns Natriuretic Peptide in Predicting Angiographic No- of Heart Rate Acceleration During Maternal–Fetal Reﬂow Phenomenon During Stent Implantation in Terbutaline Treatment of Fetal Complete Heart Patients With ST-Segment Elevation Acute Block ...... 661 Myocardial Infarction ...... 631 Bettina F. Cuneo, Hui Zhao, Janette F. Strasburger, Seo Na Hong, Youngkeun Ahn, Sun Ho Hwang, Marc Ovadia, James C. Huhta, and Ronald T. Wakai Nam Sik Yoon, Sang Rok Lee, Jae Youn Moon, Kye Hun Kim, Young Joon Hong, Hyung Wook Park, Ju Han Kim, Myung Ho Jeong, Jeong Gwan Cho, Angiographic Analysis of the Anatomic Relation of Jong Chun Park, and Jung Chaee Kang Coronary Arteries to Mitral and Tricuspid Annulus and Implications for Radiofrequency Ablation ...666 Comparison of N-Terminal Pro-Brain Natriuretic Can Hasdemir, Oguz Yavuzgil, Serdar Payzin, Peptide Versus Electrophysiologic Study for Mehmet Aydin, Cem Ulucan, Meral Kayikcioglu, Predicting Future Outcomes in Patients With an Levent H. Can, Cuneyt Turkoglu, and Hakan Kultursay Implantable Cardioverter Deﬁbrillator After Myocardial Infarction ...... 635 Quality of Life Within One Year Following Hong Yu, Hanno Oswald, Ajmal Gardiwal, Christoph Lissel, and Gunnar Klein Presentation After Transient Loss of Consciousness ...... 672 Nynke van Dijk, Mirjam A. Sprangers, Kimberly R. Boer, Predictors of Aorto–Saphenous Vein Bypass Nancy Colman, Wouter Wieling, and Mark Linzer Narrowing Late After Coronary Artery Bypass Grafting ...... 640 Roundtable Discussion (CME) Josep Rode´s-Cabau, Alvaro Facta, Eric Larose, Robert DeLarochellie`re, Jean-Pierre De´ry, Can Manh Nguyen, Louis Roy, Guy Proulx, The Editor’s Roundtable: Ablation of Atrial Onil Gleeton, Ge´rald Barbeau, Bernard Noe¨l, Fibrillation ...... 677 Jacques Rouleau, Jean-Roch Boudreault, and Vincent E. Friedewald, Robert C. Kowal, Olivier F. Bertrand Miguel Valderrabano, and William C. Roberts

Preventive Cardiology Heart Failure

Usefulness of Combining Complement Factor H and Evidence for the Continued Safety and Tolerability C-Reactive Protein Genetic Proﬁles for Predicting of Fixed-Dose Isosorbide Dinitrate/Hydralazine in Myocardial Infarction (from the Rotterdam Patients With Chronic Heart Failure (the Extension to Study) ...... 646 African-American Heart Failure Trial) ...... 684 Isabella Kardys, Moniek P.M. de Maat, Clyde W. Yancy, Jalal K. Ghali, Virginia M. Braman, Caroline C.W. Klaver, Dominiek D.G. Despriet, Michael L. Sabolinski, Manuel Worcel, Andre´ G. Uitterlinden, Albert Hofman, W. Tad Archambault, and Joseph A. Franciosa Paulus T.V.M. de Jong, and Jacqueline C.M. Witteman

Arrhythmias and Conduction Comparative Effectiveness of Beta-Adrenergic Disturbances Antagonists (Atenolol, Metoprolol Tartrate, Carvedilol) on the Risk of Rehospitalization in Comparison of Long-Term Follow-Up of Adults With Heart Failure ...... 690 Electrocardiographic Features in Brugada Syndrome Alan S. Go, Jingrong Yang, Jerry H. Gurwitz, John Hsu, Between the SCN5A-Positive Probands and the Kimberly Lane, and Richard Platt SCN5A-Negative Probands ...... 649 Miki Yokokawa, Takashi Noda, Hideo Okamura, Kazuhiro Satomi, Kazuhiro Suyama, Takashi Kurita, Validation of the Seattle Heart Failure Model in a Naohiko Aihara, Shiro Kamakura, and Wataru Shimizu Community-Based Heart Failure Population and Enhancement by Adding B-Type Natriuretic Incidence of Brugada Electrocardiographic Pattern Peptide ...... 697 and Outcomes of These Patients After Intentional Heidi T. May, Benjamin D. Horne, Wayne C. Levy, Tricyclic Antidepressant Ingestion ...... 656 Abdallah G. Kfoury, Kismet D. Rasmusson, Vikhyat S. Bebarta, Scott Phillips, Aaron Eberhardt, David T. Linker, Dariush Mozaffarian, Jeffrey L. Anderson, K.J. Calihan, Javier C. Waksman, and Kennon Heard and Dale G. Renlund

CONTENTS A5 Valvular Heart Disease Prevalence and Correlates of Septal Delayed Contrast Enhancement in Patients With Pulmonary Accuracy of 64-Slice Computed Tomography for the Hypertension ...... 731 Preoperative Detection of Coronary Artery Disease Javier Sanz, Santo Dellegrottaglie, Mbabazi Kariisa, in Patients With Chronic Aortic Regurgitation ....701 Roxana Sulica, Michael Poon, Thomas P. O’Donnell, Hans Scheffel, Sebastian Leschka, Andre´ Plass, Davendra Mehta, Valentin Fuster, and Robert Vachenauer, Oliver Gaemperli, Elisabeth Garzoli, Sanjay Rajagopalan Michele Genoni, Borut Marincek, Philipp Kaufmann, and Hatem Alkadhi Prevalence and Clinical Signiﬁcance of Cardiovascular Abnormalities in Patients With the Effect of Primary Mitral Regurgitation on Left LEOPARD Syndrome ...... 736 Ventricular Synchrony ...... 707 Giuseppe Limongelli, Giuseppe Pacileo, Bruno Marino, Maria Cristina Digilio, Anna Sarkozy, Perry Elliott, Thomas S. Denney, Jr., Hosakote M. Nagaraj, Paolo Versacci, Paolo Calabro, Andrea De Zorzi, Steven G. Lloyd, Inmaculada Aban, Cecilia Corros, Giovanni Di Salvo, Petros Syrris, Michael Patton, Frank Seghatol-Eslami, David C. McGifﬁn, William J. McKenna, Bruno Dallapiccola, and Louis J. Dell’Italia, and Himanshu Gupta Raffaele Calabro Cardiomyopathy Readers’ Comments Usefulness of Brain Natriuretic Peptide Levels in the Patients With Advanced Heart Failure and the Clinical Evaluation of Patients With Hypertrophic Effects of Levosimendan...... 742 Cardiomyopathy ...... 712 Josepha Binder, Steve R. Ommen, Horng H. Chen, Impact of Radial Artery Cannulation on Radial Michael J. Ackerman, A. Jamil Tajik, and Allan S. Jaffe Artery Function ...... 743 Regional Myocardial Performance Index for Congenital Heart Disease Diagnosis of Pulmonary Embolism in Patients With Usefulness of Magnetic Resonance Angiography in Echocardiographic Signs of Pulmonary the Evaluation of Complex Congenital Heart Disease Hypertension ...... 744 in Newborns and Infants ...... 715 A Novel Method of Two-Dimensional Ashwin Prakash, Alejandro J. Torres, Beth F. Printz, Echocardiographic Tracking ...... 744 Martin R. Prince, and James C. Nielsen Nesiritide in Acute Decompensated Heart Failure: Methods To Use or Not to Use, That Is the Question? ...... 745

Inﬂuence of Preparative Procedures on Assay of Correction ...... 746 Platelet Function and Apparent Effects of Antiplatelet Agents ...... 722 Classiﬁeds on pages A14–A16 Nathaniel J. Madsen, Chris E. Holmes, Feliciano A. Serrano, Burton E. Sobel, and Instructions to Authors can be found at the AJC David J. Schneider website: www.AJConline.org

Miscellaneous Full Text: www.ajconline.org Cardiac Troponin I in Patients With Acute Lower Limb Ischemia ...... 728 Michael Koutouzis, Konstantinos Kontaras, Visit our INTERNET Home Page: George Sfyroeras, Konstantinos Moulakakis, Savvas Nikolidakis, Vasilios Andrikopoulos, and http://www.AJConline.org Zenon S. Kyriakides

A6 THE AMERICAN JOURNAL OF CARDIOLOGYா VOL. 100 AUGUST 15, 2007 Effectiveness of Workload at the Heart Rate of 100 Beats/Min in Predicting Cardiovascular Mortality in Men Aged 42, 48, 54, or 60 Years at Baseline

Kai P. Savonen, MDa,*, Timo A. Lakka, DMedSca,b, Jari A. Laukkanen, DMedSca,c, Tuomas H. Rauramaa, MDa, Jukka T. Salonen, DMedScc,d,e, and Rainer Rauramaa, DMedSca,f

The magnitude of work an individual is able to perform at the heart rate (HR) of 100 beats/min (WL100) is a simple, integrated measure of HR at rest, HR response to light dynamic exercise, as well as cardiorespiratory performance. Because a high HR at rest and a low cardiorespiratory performance are previously established risk factors for cardiovascular disease (CVD) mortality, it can be deduced that WL100 is a potential predictor of CVD and coronary heart disease (CHD) mortality. The aim of the present study was to investigate whether WL100 independently predicts CVD and CHD mortality in middle- aged men. The subjects were a representative sample of 1,314 middle-aged men who did not have CHD and did not use HR-lowering medication at baseline. The association of WL100 with CVD and CHD mortality was examined by Cox regression models with backward stepwise selection, including numerous known risk factors for CVD death. During an average follow-up of 11.5 years, there were 51 CVD deaths, of which 35 were due to CHD. In Cox multivariable models, CVD mortality increased by 72% (95% conﬁdence interval and CHD mortality by 89% (95% conﬁdence interval 28% to (0.001 ؍ to 138%, p 27% ؍ 178%, p 0.001) with 1 SD (31 W) decrement in WL100.WL100 improved the predictive power of the adjusted Cox models, including other HR-derived and exercise test variables. In conclusion, WL100 predicts CVD and CHD mortality in men without previous CHD. The association of WL100 with CVD and CHD mortality is not explained by maximal cardiorespiratory performance. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:563–568)

A low workload at a fixed submaximal heart rate (HR), or test and could serve as a useful additional measure to predict a high HR at a fixed submaximal workload, during exercise CVD death. The aim of the present study was to investigate testing has been associated with an increased risk of cardiac whether the association between a low workload at a fixed events in previous population-based studies.1–7 In these submaximal HR and an increased risk of CVD death is studies, however, HR has been Ͼ100 beats/min. A work- evident already at such a low HR level as 100 beats/min. We load that a subject can attain at the HR 100 beats/min hypothesized that WL100 measured during an exercise test (WL100) during exercise testing reflects not only cardiore- on a cycle ergometer predicts CVD mortality in middle- spiratory performance but also HR at rest and how steep the aged men who do not have coronary heart disease (CHD) early HR increase compared with the overall HR increase is. and do not use HR-lowering medication and provides ad- Cardiorespiratory performance1,2,8,9 and HR at rest10–13 are ditional prognostic information beyond other HR-derived known predictors of premature cardiovascular disease and exercise test variables. (CVD) death in apparently healthy individuals. WL100 reflects physiologic responses to early stages of the exercise Methods We studied participants in the Kuopio Ischaemic Heart aKuopio Research Institute of Exercise Medicine, Kuopio; bInstitute of Disease Risk Factor Study, an ongoing population study Biomedicine, Physiology and cSchool of Public Health and Clinical Nu- designed to investigate risk factors for CVD and related trition, University of Kuopio, Kuopio; dInner Savo Health Centre, Suonen- outcomes. The study involved men from east Finland,14 an joki; eOy Jurilab Ltd., Kuopio; and fDepartment of Clinical Physiology and area known for its high prevalence and incidence of CVD.15 Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland. Manu- The subjects are a representative sample of men who lived script received January 26, 2007; revised manuscript received and accepted in the town of Kuopio or neighboring rural communities and March 9, 2007. who were 42, 48, 54, or 60 years of age at baseline between This study was supported by Grants 74/722/2003 from the Ministry of March 1984 and December 1989. Of 3,235 eligible men, Education in Finland, Helsinki; the Finnish Cultural Foundation of North- ern Savo, Kupio; the Foundation of Sports Institutes’ in Finland, Helsinki; 2,682 (83%) participated in the study. Complete data on the Maire Taponen Foundation, Helsinki; the Mehiläinen Research Foun- exercise test variables were available for 2,240 men. WL100 dation, Kupio; and the Paulo Foundation, Helskinki, Finland. could not be recorded or interpolated for 113 men because *Corresponding author: Tel: 358-400-628532; fax: 358-17-2884488. they had either a HR at rest Ͼ100 beats/min or no HR E-mail address: [email protected].fi (K.P. Savonen). values Ͼ100 beats/min during an exercise test. Data on a

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.061 564 The American Journal of Cardiology (www.AJConline.org) prevalent CHD (a history of myocardial infarction or angina and diastolic blood pressure at rest, have been described pectoris diagnosed by a doctor, angina pectoris on effort elsewhere.9,17,19 based on the London School of Hygiene Cardiovascular Deaths were ascertained by computer linkage to the Questionnaire,16 or the use of nitroglycerin for chest pain at National Death Registry using the Finnish social security least once a week), ischemic changes on an electrocardio- number. There were no losses to follow-up. All deaths that gram during an exercise test (a horizontal or downsloping occurred between study enrollment (from March 20, 1984 to ST depression of Ͼ0.5 mm at 80 ms after the J point), or the December 5, 1989) and December 31, 1998 were included. use HR-lowering medication (␤ blockers, digoxin, clonidin, CVD and CHD deaths were coded according to the Inter- methyldopa) were missing for 290 men. Altogether, 523 national Classification of Diseases-9th Edition (ICD-9) men had prevalent CHD or used HR-lowering medication. (codes number 390 to 459 and 410 to 414, respectively) or After these exclusions, the final study sample included (ICD-10) (codes number I00 to I99 and I20 to I25, respec- 1,314 men who did not have previous CHD and did not use tively). CVD and CHD deaths were used as the primary end HR-lowering medication. The study protocol was approved points and all-cause death as the secondary end point, be- by the Research Ethics Committee of the University of cause HR response during exercise primarily reflects car- Kuopio, and complies with the Declaration of Helsinki. diovascular status and most likely predicts CVD mortality. Each participant gave written informed consent. Average follow-up time to any death or the end of follow-up A maximal, symptom-limited exercise test was per- was 11.5 years (range 0.3 to 14.8). A total of 133 deaths formed at baseline using an electrically braked cycle er- (10.1%) occurred during the follow-up period. Of the gometer as previously described.9,17 For 528 men (40%) deaths, 51 (3.9%) were due to CVD and 35 (2.7%) due to examined before June 1986, the testing protocol comprised CHD. of a 3-minute warm-up at 50 W followed by a step-by-step Differences in baseline characteristics between the increase in the workload by 20 W/min. The remaining 786 halves above and below median of WL100 were tested with men (60%) were tested with a linear increase in the work- logistic and linear regression analyses as well as Mann- load by 20 W/min. Whitney U test after adjustment for age and length of HR was recorded from the electrocardiogram at rest, at follow-up. A multiple stepwise linear regression analysis, the end of each 60-second interval during the exercise test, including HR at rest, chronotropic index at HR of 100 and at peak exercise. HR at rest was expressed as the lowest beats/min, maximal HR, and VO2max was used to investigate the determinants of WL . Cox proportional hazards’ HR value, whether measured in the lying position before the 100 regression models were fitted to compute the relative risk of test or while sitting on bicycle at the initiation of the test. death associated with a low WL , expressed as a contin- WL was recorded directly at HR 100 beats/min or inter- 100 100 uous or dichotomous variable. Age, examination year, and polated linearly as a function of HR using HR at rest and the exercise test protocol were forced into the Cox models, and nearest HR value Ͼ100 beats/min. The advantage of this remainder of the variables were chosen by backward step- method for defining WL100 is that the lowest HR values at wise selection (p Ͼ0.1 for removal) from conventional risk the early phase of the exercise test are not required to be Ͻ Ͼ factors, including alcohol consumption, body mass index, 100 beats/min. An exaggerated HR increase 100 beats/ cigarette smoking, CVD history, diabetes, myocardial isch- min at the first workload is an actual phenomenon in indi- emia during exercise test, serum low-density lipoprotein viduals with a limited exercise capacity, particularly if the and high-density lipoprotein cholesterol, and systolic and first workload is not adjusted for the reduced performance. diastolic blood pressure at rest. To detect the best dichoto- Chronotropic index at HR of 100 beats/min was calculated mization cut-off point for WL , the point that maximized Ϫ Ϫ 100 as [(100 HR at rest)/(maximal HR HR at rest)]/ the log-rank test statistics was sought. The additional pre- (workload at HR 100 beats/min/maximal workload).18 dictive value brought by WL beyond other HR-derived Chronotropic index at HR of 100 beats/min quantitatively 100 and exercise test variables was explored by entering WL100 expresses how steep the early increase of HR from rest to into a Cox model that included age, examination year, 100 beats/min is in relation to the overall steepness of HR exercise test protocol, conventional risk factors chosen by increase during the exercise test. A value of roughly 1 stepwise selection, and the HR and exercise test variables in means that the steepness of the early HR increase from rest turn. All tests for statistical significance were 2-sided. Sta- to 100 beats/min is about the same as the HR increase from tistical analyses were performed using SPSS 11.5 for Win- that time point to maximum. Correspondingly, a value Ͼ1 dows (SPSS Inc., Chicago, Illinois). means that the early HR increase is steeper than the HR increase from that time point to maximum. Maximal oxygen Results uptake (VO2max) was defined as the highest value recorded during the 30-second intervals during the exercise test. At baseline, the median (range) age of the men was 52 years Ϯ Ϯ A history of CVD (arrhythmias, cardiomyopathy, clau- (range 42 to 61). The mean SD WL100 was 63 31 W. dication, heart failure, stroke) diagnosed by a doctor was Men with a low WL100 had a lower HDL cholesterol, higher assessed using a self-administered questionnaire. Diabetes systolic and diastolic blood pressure, a lower VO2max,a was defined as fasting blood glucose Ն6.7 mmol/L or the higher maximal HR and HR at rest, a higher chronotropic use of medication for diabetes. The collection of blood index, and a narrower HR reserve than those with a high specimens and the assessment of cigarette smoking, alcohol WL100 (Table 1). They were also more likely to have dia- consumption, body mass index, serum low-density lipopro- betes and less likely to have myocardial ischemia during tein and high-density lipoprotein cholesterol, and systolic exercise than men with a high WL100 (Table 1). HR at rest Coronary Artery Disease/Submaximal Heart Rate and Mortality 565

Table 1 Baseline characteristics in 1,314 men with no history of coronary heart disease and not using heart rate-lowering medication at baseline

Characteristics All Men WL100 Below Median WL100 Above Median p Value for Difference (n ϭ 1314) Value 64 W†† Value 64 W†† Between Groups¶

No. of CVD/CHD/all-cause deaths† 51/35/133 37/26/73 14/9/60 0.002/0.006/0.25 Age (yrs) 52 (42–61) 52 (42–61) 52 (42–61) 0.56 Body mass index (kg/m2) 26.5 Ϯ 3.5 26.6 Ϯ 3.5 26.4 Ϯ 3.2 0.25 Cigarette smoking (cigarette-yrs)§ 144 Ϯ 299 151 Ϯ 319 138 Ϯ 277 0.42 Alcohol consumption (g/wk) 73 Ϯ 110 76 Ϯ 119 70 Ϯ 101 0.33 Cardiovascular disease history (%)* 14.5 13.8 15.1 0.50 Diabetes (%)ʈ 3.7 4.7 2.6 0.04 Serum HDL cholesterol (mmol/L) 1.32 Ϯ 0.29 1.30 Ϯ 0.28 1.35 Ϯ 0.30 0.003 Serum LDL cholesterol (mmol/L) 3.98 Ϯ 0.97 4.02 Ϯ 0.99 3.95 Ϯ 0.95 0.18 Diastolic blood pressure at rest (mm Hg) 88 Ϯ 10 90 Ϯ 10 86 Ϯ 9 Ͻ0.001 Systolic blood pressure at rest (mm Hg) 133 Ϯ 15 135 Ϯ 16 130 Ϯ 14 Ͻ0.001 Maximal oxygen uptake (ml/kg/min) 33.2 Ϯ 7.3 31.9 Ϯ 6.9 34.5 Ϯ 7.5 Ͻ0.001 Myocardial ischemia during exercise test (%)** 13.9 12.0 15.9 0.04 Heart rate at rest (beats/min) 68 Ϯ 10 73 Ϯ 10 63 Ϯ 8 Ͻ0.001 Chronotropic index at heart rate of 100 beats/min‡ 1.13 Ϯ 0.28 1.28 Ϯ 0.29 0.98 Ϯ 0.17 Ͻ0.001 Maximal heart rate (beats/min) 162 Ϯ 17 166 Ϯ 16 158 Ϯ 17 Ͻ0.001 Heart rate reserve (beats/min)# 94 Ϯ 19 93 Ϯ 19 96 Ϯ 19 0.03 Workload at heart rate of 100 beats/min (W) 63 Ϯ 31 38 Ϯ 17 88 Ϯ 19 Ͻ0.001

Data are presented as mean Ϯ SD, median (range) or proportion. * Cardiovascular diseases included arrhytmias, cardiomyopathy, claudication, heart failure, and stroke. † CVD, cardiovascular disease; CHD, coronary heart disease. ‡ Chronotropic index at heart rate of 100 beats/min was calculated as [(100 Ϫ heart rate at rest)/(maximal heart rate Ϫ resting heart rate at rest)]/(workload at heart rate of 100 beats/min/maximal workload).18 § Cigarette-years denotes the lifelong exposure to smoking that was estimated as the product of years smoked and the number of cigarettes smoked daily at the time of examination.19 ʈ Diabetes was defined as fasting glucose Ն6.7 mmol/L or use of medication for diabetes. ¶ Difference in age was tested with Mann-Whitney U test. Differences in cardiovascular disease history, diabetes, myocardial ischemia during exercise test, and number of deaths were tested with logistic regression analysis and in remaining variables with linear regression analysis after adjustment for age. # Heart rate reserve was calculated as maximal heart rate Ϫ heart rate at rest. ** Myocardial ischemia during exercise test was defined as a horizontal or downsloping ST depression of Ն0.5 mm at 80 ms after the J point. †† WL100, workload at heart rate of 100 beats/min. explained 39%, the chronotropic index at HR of 100 beats/ predictors of CHD death were myocardial ischemia during Ͻ Ͻ Ͻ min 21%, VO2max 5%, maximal HR 5%, and all these exercise test (p 0.001), smoking (p 0.001), WL100 50 variables together explained 70% of the variance in WL100. W (relative risk 3.9, 95% CI 1.9 to 8.2, p Ͻ0.001), a high Ͼ Men with a low WL100 were 2 times more likely to die body mass index (p ϭ 0.01), older age (p ϭ 0.03), and CVD of CVD and about 3 times more likely to die of CHD than history (p ϭ 0.05). those with a high WL100 (Table 1). CVD mortality in- In a Cox model that included age, examination year, creased by 72% (95% confidence interval [CI] 27% to exercise test protocol, conventional risk factors chosen by ϭ 138%, p 0.001), CHD mortality by 96% (95% CI 32% to stepwise selection, and the HR-derived and exercise test ϭ 186%, p 0.001), and all-cause mortality by 23% (95% CI variables in turn, a 28 U (1 SD) increase in the chronotropic ϭ 2% to 47%, p 0.03) with a decrement of 31 W (1 SD) in index at HR of 100 beats/min was associated with a 43% WL100 adjusting for age, examination year, and exercise test (95% CI 9% to 88%, p ϭ 0.01) increase in CVD mortality protocol. After further adjustment for conventional risk fac- and a 65% (95% CI 19% to 128%, p ϭ 0.003) increase in tors, CVD mortality increased by 72% (95% CI 27% to CHD mortality; an increment of 10 beats/min (1 SD) in HR 138%, p ϭ 0.001) and CHD mortality by 89% (95% CI 28% at rest was associated with a 39% (95% CI 0 to 92%, p ϭ to 178%, p ϭ 0.001) with a decrement of 31 W in WL , 100 0.05) increase in CHD mortality; a decrement of 7.3 ml/kg/ but no association was found between WL100 and all-cause mortality (Table 2). min (1 SD) in VO2max (which equals to about 2.1 METs) was associated with a 59% (95% CI 0 to 150%, p ϭ 0.05) The best WL100 cut-off point for predicting CVD mor- Ͻ increase in CHD mortality; and a decrement of 46 W (1 SD) tality was 50 W, and 497 men (37.8%) had WL100 50 W. When WL was entered as a dichotomous variable with in maximal workload was associated with a 52% (95% CI 0 100 ϭ conventional risk factors into a backward stepwise Cox to 133%, p 0.05) increase in CHD mortality. WL100 model, the strongest predictors of CVD death were smoking improved the predictive value of all models, except the Ͻ Ͻ (p 0.001), WL100 50 W (relative risk 3.2, 95% CI 1.8 to model predicting CVD mortality that included chronotropic 5.8, p Ͻ0.001), myocardial ischemia during the exercise test index at HR of 100 beats/min. Although the predictive value (p Ͻ0.001), a high body mass index (p ϭ 0.001), older age of WL100 was consistent across the models shown in Table (p ϭ 0.001), and CVD history (p ϭ 0.008). The strongest 3, no other HR-derived or exercise test variable remained a 566 The American Journal of Cardiology (www.AJConline.org)

Table 2 The relative risk for cardiovascular disease, coronary heart disease, and all-cause death in 1,314 men with no history of coronary heart disease and not using heart rate-lowering medication at baseline* Risk Factor Death Due to Death Due to Coronary All-Cause Death Cardiovascular Disease Heart Disease Relative Risk p Value Relative Risk p Value Relative Risk p Value (95% CI) (95% CI) (95% CI) Age (for increment of 1 yr) 1.12 (1.05–1.20) 0.001 1.09 (1.01–1.19) 0.03 1.10 (1.06–1.15) Ͻ0.001 Alcohol consumption Ն91 g/wk (highest fourth vs others) 1.64 (1.13–2.39) 0.009 Body mass index (for increment of 3.5 kg/m2) 1.48 (1.18–1.87) 0.001 1.44 (1.10–1.90) 0.009 1.20 (1.01–1.43) 0.04 Cardiovascular disease history (yes vs no) 2.31 (1.24–4.28) 0.008 2.19 (1.03–4.68) 0.04 Cigarette smoking (for increment of 299 cigarette-years) 1.44 (1.22–1.70) Ͻ0.001 1.43 (1.15–1.76) 0.001 1.45 (1.30–1.61) Ͻ0.001 Myocardial ischemia during exercise test (yes vs no) 3.13 (1.75–5.59) Ͻ0.001 4.29 (2.17–8.49) Ͻ0.001 Serum HDL cholesterol (for decrement of 0.29 mmol/L) 1.22 (1.01–1.47) 0.04 Systolic blood pressure at rest (for increment of 15 mm Hg) 1.32 (1.14–1.53) Ͻ0.001 Workload at heart rate of 100 beats/min (for decrement of 31 W) 1.72 (1.27–2.38) 0.001 1.89 (1.28–2.78) 0.001

* From Cox regression models adjusted for age, examination year, alcohol consumption, body mass index, cigarette smoking, cardiovascular disease history, diabetes, myocardial ischemia during exercise test, serum low-density and high-density lipoprotein cholesterol, systolic and diastolic blood pressure at rest, and exercise test protocol. The relative risks are shown only for variables included in the ﬁnal model after a backward stepwise selection. Except for age, alcohol consumption, cardiovascular disease history, diabetes, and myocardial ischemia during exercise test, the relative risks were calculated for a change of 1 SD, as shown. CI ϭ conﬁdence interval.

Table 3 Workload at heart rate of 100 beats/min and cardiovascular disease and coronary heart disease mortality after adjustment for heart rate and exercise test variables* Heart rate-derived or exercise Cardiovascular Disease Mortality Coronary Heart Disease Mortality Test variable entered into Relative Risk (95% CI) of Relative Risk (95% CI) of adjusted model before WL p Value for Improvement of p Value for Improvement of 100 the Model After Entering CVD Death per Each the Model After Entering CHD Death per Each

WL100 into the Model Increment of 1 SD in WL100 into the Model Increment of 1 SD in WL100 WL100 Heart rate at rest 0.002 1.89 (1.25–2.86) 0.005 2.04 (1.23–3.45) Maximal heart rate 0.004 1.64 (1.16–2.33) Ͻ0.001 2.13 (1.41–3.23) Maximal oxygen uptake 0.006 1.56 (1.12–2.17) 0.002 1.79 (1.22–2.63) Chronotropic index at heart 0.09 1.39 (0.95–2.00) 0.03 1.67 (1.05–2.63) rate of 100 beats/min HR reserve 0.008 1.54 (1.11–2.17) 0.001 1.89 (1.25–2.78) Maximal workload 0.009 1.56 (1.11–2.22) 0.004 1.79 (1.19–2.70)

* Adjusted for risk factors chosen after stepwise selection before the variables in the left column and workload at heart rate of 100 beats/min were entered into the model in turns. significant predictor of death in models that included HR required for risk assessment has ranged from 116 to 160 2,3,5,6 1,4–6 WL100. beats/min and the workload from 100 to 140 W in previous studies, the mean HR to enable the risk assessment Discussion was only 104 beats/min and the mean workload as low as 69 W in the present study. The low level of exercise enables The main finding of the present study was that a low WL100 was associated with increased CVD and CHD mortality in testing of individuals with a limited exercise capacity, and men who did not have a previous CHD or took HR-lowering cardiovascular risks associated with a high-intensity exer- 20,21 medication. The association was independent of other HR- tion can be largely avoided. If necessary, the exercise derived or exercise test variables, and the magnitude of the test can also be repeated frequently, because of a short association was comparable with that of conventional risk recovery period needed. factors. These results are in accordance with the findings of Second, in the previous studies, a high HR at a fixed previous population-based studies investigating the associ- submaximal workload or a low workload at a fixed HR, was ation of submaximal HR and workload with the risk of considered as a surrogate measure of a low cardiorespira- cardiac events.1–7 The present results add, however, 2 im- tory fitness, and the interpretation of the findings was based portant aspects to the previous findings. on this conjecture.1–7 Moreover, the actual maximal cardio- First, the level of exercise used to explore the association respiratory fitness was not measured and thereby could not of a submaximal HR and workload with cardiac events was be included as a covariate in the analysis. In the present 1–6 lower than in the earlier studies. Although the minimum study, a low WL100 was a strong predictor of premature Coronary Artery Disease/Submaximal Heart Rate and Mortality 567

CVD and CHD death, even after adjustment for directly all-cause death. When this effect is considered by adding measured VO2max. Thus, low cardiorespiratory fitness does maximal HR to the stepwise selection as a covariate, both not explain the association of a low workload at a fixed maximal HR and WL100 are chosen among statistically submaximal HR of 100 beats/min with CVD mortality. We significant predictors for all-cause death (data not shown). suggest that a low WL100 concurrently reflects a high HR at Submaximal exercise tests clearly have some benefits rest, an exaggerated HR increase at the beginning of an compared with maximal tests.20,21 However, variables de- exercise test, and a low cardiorespiratory performance. Al- rived from submaximal and maximal tests should be viewed though these variables separately had only a limited predic- as complementary to, instead of opposed to, each other. tive value in the present study, the combined variable WL100 can be measured during a maximal exercise test, as WL100 provided valuable prognostic information. in the present study, or a separate submaximal exercise test. A low stroke volume may be a common denominator for WL100 and myocardial ischemia during exercise test pre- a high HR at rest, an exaggerated HR increase at the be- dicted CVD and CHD deaths independent of each other. ginning of an exercise test, and a low cardiorespiratory This underlines the fact that the predictive value of exercise performance and may at least partly explain the observed testing can be optimized by considering and combining association between WL100 and CVD mortality. However, separate variables measured at different stages of exercise we did not directly assess stroke volume and cannot confirm test and during the recovery period.29,30 our assumption in the present study. Furthermore, it is The strength of the present study is that we have a impossible to say whether a low stroke volume is caused by representative population-based sample of middle-aged an impaired diastolic filling, a weakened systolic perfor- men. Second, the participation rate was high and there were mance, or an increased overall HR level due to an attenuated 22 no losses to follow-up. Third, we have reliable data on vagal activity or a heightened sympathetic activity. mortality, because deaths were ascertained by the National Chronotropic index at the HR of 100 beats/min was a Death Registry using a social security number. Fourth, com- surprisingly strong predictor of CVD and CHD death in the prehensive assessment of health habits and cardiovascular present study. In dogs with a healed myocardial infarction, risk factors allowed us to investigate the independent asso- an increase of HR at the early phase of an exercise stress ciation of WL with CVD mortality. Fifth, cardiorespira- was steeper in dogs that were susceptible to ventricular 100 tory fitness was measured objectively by direct expiratory fibrillation after artificially induced coronary occlusion compared with dogs that were resistant to ventricular fibril- gas analysis instead of using predicted values. lation.23 A steeper increase of HR in susceptible dogs was One limitation of the present study is that only men were accompanied by a greater reduction in cardiac vagal activ- enrolled. Therefore, the generalization of the findings to ity, as indicated by the lower HR variability.23 Unfortu- women should be done with caution. The extent to which nately, maximal performance was not measured; therefore, age, gender, underlying diseases, and regular physical ac- it is impossible know how much of the observed difference tivity influence WL100, or modify its association with CVD in HR response was explained by an unequal maximal mortality deserves further studies. It is possible that part of performance in the 2 groups. In a recent study a higher HR the association is explained by residual confounding due to increase from rest to the workload of 25 W at the onset of other risk factors. However, we adjusted for most important an exercise test was a strong predictor of adverse cardiac risk factors and the results remained similar. It is impossible events and cardiac deaths in patients with CHD.24 The to know whether WL100 changed during the long follow-up investigators suggested that a rapid HR increase was caused period, and how the possible changes could have affected by an excessive vagal withdrawal, reflecting an autonomic our results. In addition, it is impossible to estimate the effect imbalance. The exercise capacity of the subjects with a of the rapidly developed care of acute cardiac events, in- rapid HR increase was lower compared with subjects with a cluding thrombolysis, percutaneous transluminal coronary shallower HR increase, which means that cardiorespiratory angioplasty, and coronary stents, during the follow-up on fitness may explain the observed association to some extent. the predictive value of WL100. The steep HR increase observed in the present study, as indicated by a high chronotropic index at HR 100 beats/min, 1. Lie H, Mundal R, Erikssen J. Coronary risk factors and incidence of may similarly reflect a reduced vagal activity that has been coronary death in relation to physical fitness. Seven-year follow-up associated with an increased risk of CVD death or cardiac study of middle-aged and elderly men. Eur Heart J 1985;6:147–157. 2. Ekelund L-G, Haskell WL, Johnson JL, Whaley FS, Criqui MH, Sheps 25,26 events in population-based studies. Although the mech- DS. Physical fitness as a predictor of cardiovascular mortality in anism of the association is unknown, it has been suggested asymptomatic North American men: the Lipid Research Clinics Mor- that reduced vagal activity makes an individual vulnerable tality Follow-up study. N Engl J Med 1988;319:1379–1384. to fatal ventricular arrhythmias in circumstances that may 3. Slattery ML, Jacobs DR Jr. Physical fitness and cardiovascular disease induce them, such as myocardial ischemia.27,28 mortality: the US Railroad Study. Am J Epidemiol 1988;127:571–580. 4. Hein HO, Suadicani P, Gyntelberg F. Physical fitness or physical A low WL100 did not predict all-cause mortality in the activity as a predictor of ischaemic heart disease? A 17-year follow-up present study, although it was a strong predictor of CVD in the Copenhagen Male Study. J Intern Med 1992;232:471–479. and CHD death. This is easily explained by the inter-rela- 5. Peters RK, Cady LD Jr, Bischoff DP, Bernstein L, Pike MC. Physical fitness and subsequent myocardial infarction in healthy workers. tionship between maximal HR and WL100. The higher a maximal HR, the lower the risk of all-cause death but at the JAMA 1983;249:3052–3056. 6. Sobolski J, Kornitzer M, De Backer G, Dramaix M, Abramowicz M, same time the higher a maximal HR, the lower WL100. Degre S, Denolin H. Protection against ischemic heart disease in the Hence, a high maximal HR as the determinant of a low Belgian Physical Fitness Study: physical fitness rather than physical WL100 dilutes the predictive value of a low WL100 for activity? Am J Epidemiol 1987;125:601–610. 568 The American Journal of Cardiology (www.AJConline.org)

7. Arraiz GA, Wigle DT, Mao Y. Risk assessment of physical activity infarction: a prospective population study in eastern Finnish men. and physical fitness in the Canada Health Survey mortality follow-up Circulation 1991;84:129–139. study. J Clin Epidemiol 1992;45:419–428. 20. Gibbons LW, Blair SN, Kohl HW, Cooper KH. The safety of maximal 8. Sandvik L, Erikssen J, Thaulow E, Erikssen G, Mundal R, Rodahl K. exercise testing. Circulation 1989;80:846–852. Physical fitness as a predictor of mortality among healthy, middle-aged 21. Whaley MH, ed. ACSM’s guidelines for exercise testing and prescrip- Norwegian men. N Engl J Med 1993;328:533–537. tion. 7th Ed. Baltimore, MD: Williams & Wilkins, 2006. 9. Laukkanen JA, Lakka TA, Rauramaa R, Kuhanen R, Venäläinen JM, 22. Janicki JS, Sheriff DD, Robotham JL, Wise RA. Cardiac output during Salonen R, Salonen JT. Cardiovascular fitness as a predictor of mor- exercise: contributions of the cardiac, circulatory and respiratory sys- Arch Intern Med tality in men. 2001;161:825–831. tems. In: Rowell LB, Shepherd JE, ed. Handbook of Physiology. 10. Mensink GBM, Hoffmeister H. The relationship between resting heart Section 12: Exercise: Regulation and integration of multiple systems. rate and all-cause, cardiovascular and cancer mortality. Eur Heart J New York: Oxford University Press, 1996:649–704. 1997;18:1404–1410. 11. Kristal-Boneh E, Silber H, Harari G, Froom P. The association of 23. Billman GE, Hoskins RS. Time-series analysis of heart rate variability resting heart rate with cardiovascular, cancer and all-cause mortality. during submaximal exercise. Circulation 1989;80:146–157. Eight year follow-up of 3527 of male Israeli employees (the CORDIS 24. Falcone C, Buzzi MP, Klersy C, Schwartz PJ. Rapid heart rate increase study). Eur Heart J 2000;21:116–124. at onset of exercise predicts adverse cardiac events in patients with 12. Jouven X, Zureik M, Desnos M, Guerot C, Ducimetiere P. Resting coronary heart disease. Circulation 2005;112:1959–1964. heart rate as a predictive risk factor for sudden death in middle-aged 25. Tsuji H, Larson MG, Venditti FJ Jr, Manders S, Evans JC, Feldman men. Cardiovasc Res 2001;50;373–378. CL, Levy D. Impact of reduced heart rate variability on risk for cardiac 13. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducime- events. The Framingham Heart Study. Circulation 1996;94:2850– tiere P. Heart-rate profile during exercise as a predictor of sudden 2855. death. N Engl J Med 2005;352:1951–1958. 26. Huikuri HV, Mäkikallio TH, Airaksinen KEJ, Seppänen T, Puukka P, 14. Salonen JT. Is there a continuing need for longitudinal epidemiologic Räihä IJ, Sourander LB. Power-law relationship of heart rate variabil- research? The Kuopio Ischaemic Heart Disease Risk Factor Study. ity as a predictor of mortality in the elderly. Circulation 1998;97: Ann Clin Research 1988;20:46–50. 2031–2036. 15. Keys A. Seven Countries: A Multivariate Analysis of Death and 27. Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous system Coronary Heart Disease. Cambridge: Harvard University Press, 1980. and sudden cardiac death: experimental basis and clinical observations 16. Rose GA, Blackburn H, Gillum RF, Prineas RJ. Cardiovascular Survey for post-myocardial infarction risk stratification. Circulation 1992;85 Methods. World Health Organization monograph series no. 56. Ge- Suppl I:I77–I91. neva: World Health Organization, 1982. 28. Schwartz PJ. The autonomic nervous system and sudden death. Eur 17. Lakka TA, Venäläinen JM, Rauramaa R, Salonen R, Tuomilehto J, Salonen JT. Relation of physical activity and cardiorespiratory fitness Heart J 1998;19 Suppl F: F72–F80. to the risk of acute myocardial infarction in men. N Engl J Med 29. Lauer MS. Exercise electrocardiogram testing and prognosis. Novel 1994;330:1549–1554. markers and predictive instruments. Cardiol Clin 2001;19:401– 18. Wilkoff BL, Miller RE. Exercise testing for chronotropic assessment. 414. Cardiol Clin 1992;10:705–717. 30. Froelicher VF, Myers JN. Diagnostic application of exercise testing. 19. Salonen JT, Salonen, R, Seppänen K, Rauramaa R, Tuomilehto J. In: Froehlicher VF, Myers JN. Exercise and the Heart. 5th Ed. Phila-

HDL, HDL2, HDL3 subfractions, and the risk of acute myocardial delphia: W.B. Saunders Co, 2006;226. High Molecular Weight Adiponectin as a Predictor of Long-Term Clinical Outcome in Patients With Coronary Artery Disease

Teruo Inoue, MDa,*, Norihiko Kotooka, MDa, Toshifumi Morooka, MDa, Hiroshi Komoda, MSa, Toshihiko Uchida, MDb, Yoshimasa Aso, MDc, Toshihiko Inukai, MDc, Takehiko Okuno, BScd, and Koichi Node, MDa

Adiponectin is an adipocyte-specific secretory protein that is highly and specifically expressed in adipose tissue, and low plasma levels of adiponectin are associated with coronary artery disease (CAD). It has been suggested that high molecular weight (HMW) adiponectin is more important for vascular protection than total amount of adiponectin. To establish the clinical relevance of HMW adiponectin, we measured its serum levels in 149 patients ,(with CAD. The levels were lower in vasospastic angina pectoris (3.4 ؎ 2.4 ␮g/ml, p <0.01 stable angina pectoris (3.3 ؎ 2.6 ␮g/ml, p <0.001), and healed myocardial infarction (3.8 ؎ 2.9 ␮g/ml, p <0.01) than chest pain syndrome (controls) (6.6 ؎ 5.4 ␮g/ml). The levels were also ,lower in multivessel CAD (3.4 ؎ 2.4 ␮g/dl) compared with single vessel CAD (4.2 ؎ 2.7 ␮g/ml p <0.05) or no organic stenosis (5.1 ؎ 3.5 ␮g/ml, p <0.01). In univariate analysis, diabetes ؍ high-sensitivity C-reactive protein levels (p ,(0.06 ؍ insulin resistance (p ,(0.03 ؍ mellitus (p predicted cardiovascular events during (0.0001 ؍ and low HMW adiponectin levels (p ,(0.0012 7 years of follow-up. However, multivariate analysis showed that only HMW adiponectin levels were an independent predictor of cardiovascular events (relative risk 2.79, 95% confidence In conclusion, serum HMW adiponectin levels may serve as .(0.0014 ؍ interval 1.49 to 5.24, p a predictor of future cardiovascular events in patients with CAD as well as a marker for severity of CAD. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:569–574)

High molecular weight (HMW) adiponectin is more impor- Methods tant for vascular protection than the total amount of adi- 1–4 One hundred forty-nine consecutive patients (106 men and ponectin. Although HMW adiponectin has been difficult Ϯ to detect in the past and only semiquantitative determina- 43 women, aged 63 9 years) were enrolled in the study. tions are available, a novel sandwich enzyme-linked immu- All enrolled patients underwent initial diagnostic coronary nosorbent assay (ELISA) method has been developed to angiography and left ventriculography from April 1997 to accurately determine serum HMW adiponectin levels with- March 1998 for suspicion of chronic CAD and were fol- out requiring any sample pretreatment.5 HMW adiponectin lowed up for a period of 7 years. They included 124 patients levels measured by this ELISA method are closely corre- who had angiographically verified atherosclerotic CAD lated with conventional total adiponectin levels. Hara et al6 (stable effort angina, 80 patients; old myocardial infarction, recently reported that HMW adiponectin levels had better 44 patients) and 25 patients who had no significant organic predictive power for insulin resistance and metabolic syn- coronary artery lesions. All of the patients without organic drome than total adiponectin levels. More recently, we ob- lesions underwent an acetylcholine provocation test. Of served that the HMW adiponectin levels and the HMW-to- these, 13 patients had a positive acetylcholine test and were total adiponectin ratio was lower when coronary artery diagnosed with vasospastic angina, and the remaining 12 disease (CAD) was present in patients with type 2 diabetes patients had a negative test and were diagnosed with chest mellitus.7 However, a relation between HMW adiponectin pain syndrome. The latter group of patients with chest pain levels and the onset of cardiovascular events has not been syndrome served as control subjects (Table 1). Patients were established. In this study, we measured serum HMW adi- excluded if they had an acute myocardial infarction within ponectin levels in patients with CAD without diabetes mel- the previous 3 months, or unstable angina with chest pain litus, and assessed the relation between HMW adiponectin within the previous month. Patients with idiopathic cardio- levels and long-term prognosis as well as disease severity. myopathy, valvular heart disease, congenital heart disease, or other nonischemic heart disease were also excluded. The Saga University institutional review board approved the study protocol, and written informed consent was obtained aDepartment of Cardiovascular and Renal Medicine, Saga University b c from each patient. Faculty of Medicine, Saga; Departments of Cardiology Internal Medi- The angiographic findings were assessed by an investi- cine, Koshigaya Hospital, Dokkyo Medical University, Koshigaya; and dResearch and Development Division, Fujirebio Inc., Tokyo, Japan. Manu- gator who was unaware of the study design. Using the left script received January 26, 2007; revised manuscript received and accepted ventriculogram taken in a 30° right anterior oblique projec- March 12, 2007. tion, left ventricular end-diastolic and end-systolic volumes *Corresponding author: Tel: 81-952-34-2364; fax: 81-952-34-2089. were measured by the area–length method and left ventric- E-mail address: [email protected] (T. Inoue). ular ejection fraction was calculated. Coronary angiograms

Table 1 ponectin in sera. HMW adiponectin levels of a working Patient characteristics (n ϭ 149) standard were determined by human HMW adiponectin Variables purified by affinity for Geratin-Cellulofine (Seikagaku In- dustrial Co., Tokyo, Japan). The sensitivity and upper limit Ϯ Age (yrs) 63 9 (52–74, 63) of the working range of HMW adiponectin levels were 0.18 Men 106 (71%) ␮ Body mass index (kg/m2) 22.6 Ϯ 3.9 (17.8–31.2, 23.2) to 22.05 g/ml. The intra- and interassay variances were No. of coronary arteries narrowed 2.4% to 3.0% and 4.2% to 5.1%, respectively. 0 25 (17%) All patients were assessed for coronary risk factors, in- 1 47 (31%) cluding hypertension, diabetes mellitus, hyperlipidemia, Ͼ1 77 (52%) and smoking habits. The levels of fasting blood glucose, Coronary angioplasty 63 (42%) insulin, total cholesterol, triglyceride, high-density lipopro- Coronary artery bypass grafting 22 (15%) tein-cholesterol, and low-density lipoprotein-cholesterol Medication alone 64 (43%) were measured in the sampled blood. Insulin resistance was Hypertension 75 (50%) assessed using homeostasis model assessment (HOMA-IR)8 Diabetes mellitus 61 (40%) based on the following formula: fasting glucose (milligrams Dyslipidemia 89 (60%) ϫ ␮ Smoker 96 (64%) per deciliter) fasting insulin ( U/mL)/405. High sensi- Use of statins 54 (36%) tivity C-reactive protein (hs-CRP) levels were also mea- Ejection fraction (%) 63 Ϯ 13 (45–76, 65) sured by particle-enhanced technology on the Behring BN II Total cholesterol (mg/dl) 184 Ϯ 39 (138–225, 181) nephelometer (Dade Behring Inc., Newark, Delaware), us- Triglyceride (mg/dl) 71 Ϯ 56 (26–136, 68) ing monoclonal anti-CRP antibodies and a calibrator that High-density lipoprotein-cholesterol 43 Ϯ 12 (31–57, 41) was traceable to World Health Organization Reference Ma- (mg/dl) terial. Low-density lipoprotein-cholesterol 121 Ϯ 31 (82–153, 120) Patient outcomes during 7 years of follow-up were iden- (mg/dl) tified by clinic medical examination or telephone contact. Ϯ Fasting blood glucose (mg/dl) 105 39 (72–134, 93) Information regarding potential cardiovascular events was Insulin resistance index by 2.2 Ϯ 5.8 (0.3–3.2, 1.0) homeostasis model assessment confirmed based on the data source, including charts of High sensitivity C-reactive protein 0.21 Ϯ 0.86 (0.008–2.8, 0.1) hospital days, discharge letters, analysis of coronary angio- (mg/dl) grams or electrocardiograms, and laboratory data. Cardio- High molecular weight adiponectin 3.7 Ϯ 3.1 (1.4–8.3, 2.7) vascular events were defined as cardiovascular death or (␮g/ml) hospitalization caused by nonfatal myocardial infarction, Ϯ refractory angina pectoris, repeated revascularization after Data are shown as mean SD (interquartile range, median value) in coronary angioplasty or coronary artery bypass surgery, continuous variables, or number (percent) in categorical variables. Dyslipidemia was defined as the fasting levels of total cholesterol Ͼ220 new revascularization during medical follow-up, heart fail- mg/dl, triglyceride Ͼ150 mg/dl, high-density lipoprotein cholesterol Ͻ40 ure, serious arrhythmia, or nonfatal cerebrovascular acci- mg/dl, and/or low-density lipoprotein cholesterol Ͼ140 mg/dl, and/or tak- dents. ing lipid-lowering drugs. Data were expressed as the mean Ϯ SD and interquartile range and median value. Comparisons among multiple groups were performed by 1-way analysis of variance. The were visually assessed for all of the atherosclerotic coronary lesions. According to the classification of the American Table 2 Heart Association, the percent diameter stenosis was eval- High molecular weight adiponectin level related factors uated for each lesion and the lesion location was assessed. We assessed the number of affected vessels, considering Yes No p Value that Ͼ50% diameter stenosis was a significant atheroscle- Age Ն63 yrs 4.2 Ϯ 3.4 3.1 Ϯ 2.6 0.03 rotic coronary lesion. Men 3.0 Ϯ 2.2 5.6 Ϯ 4.0 0.0001 Fasting peripheral blood was collected early in the morn- Body mass index Ն23.2 kg/m2 2.9 Ϯ 2.8 4.8 Ϯ 4.2 0.0001 ing on the day of coronary angiography. The blood sample Hypertension 3.9 Ϯ 3.0 3.6 Ϯ 3.1 0.62 was immediately centrifuged at 1,500 g for 15 minutes at Diabetes mellitus 3.4 Ϯ 3.1 4.0 Ϯ 3.0 0.24 Dyslipidemia 3.4 Ϯ 2.7 4.3 Ϯ 3.6 0.08 room temperature. The serum was frozen and stored at Ϯ Ϯ Ϫ80°C until analyzed. The serum HMW adiponectin level Smoker 3.0 2.1 5.1 4.0 0.0001 Total cholesterol; high 4.2 Ϯ 3.4 3.2 Ϯ 2.6 0.06 was measured using a novel sandwich ELISA kit (Fujirebio, Triglyceride; high 3.8 Ϯ 3.3 3.7 Ϯ 2.9 0.91 Tokyo, Japan) based on a monoclonal antibody to human High-density lipoprotein-cholesterol; 3.0 Ϯ 2.5 4.5 Ϯ 3.5 0.002 HMW adiponectin, IH7.5 In brief, 100 ␮l of serum samples low diluted 1:441 were placed in each of 96 wells of a microtiter Low-density lipoprotein-cholesterol; 3.5 Ϯ 2.8 3.9 Ϯ 3.4 0.46 plate coated with IH7 as a capture antibody. IH7 conjugated high with horseradish peroxidase was used as the detection an- Fasting blood glucose; high 3.5 Ϯ 3.2 4.0 Ϯ 2.9 0.39 tibody. The contents of wells were incubated for 30 minutes Insulin resistance index by 3.1 Ϯ 3.0 4.4 Ϯ 3.0 0.008 with tetramethylbenzipine. After the reaction was stopped, homeostasis model assessment; high the absorbance was measured at 450 nm. Using the same Ϯ Ϯ antibody as both capture and detection, this sandwich High-sensitivity C-reactive protein; 3.2 2.8 4.2 2.9 0.01 high ELISA assay system could specifically measure HMW adi- Coronary Artery Disease/High Molecular Weight Adiponectin and Events 571

Figure 1. Comparisons of serum HMW adiponectin level in each basal disease (left) and in each of number of coronary artery narrowed (right). The serum HMW adiponectin level was lower not only in patients with stable effort angina or old myocardial infarction but also in patients with vasospastic angina, compared with the controls. The HMW adiponectin level was lower in patients with multivessel disease, compared with patients with single-vessel disease as well as with no organic stenotic lesions.

Figure 2. Relation between HMW adiponectin levels and left ventricular ejection fraction. There was no significant correlation between HMW adiponectin levels and ejection fraction in all of the patients (left). However, they were correlated in patients with multivessel disease (right). correlation between HMW adiponectin levels and left ven- Results tricular ejection fraction was analyzed by simple linear regression. In addition to comparisons of continuous vari- Characteristcs of all patients are shown in Table 1 and mea- ables, patients were stratified into high and low groups sured variables, including serum HMW adiponectin levels, are Ϯ based on the median of each measured variable. A Cox reported as mean SD, interquartile ranges, and median proportional hazards model was used for predicting the values. All patients were divided into 2 groups according to occurrence of secondary cardiovascular events, using the age (high or low), risk factors (present or absent), or measured parameters as categorical variables. Variables with a p value variables (high or low) and then HMW adiponectin levels were Ͻ0.15 in univariate analyses were entered into the multi- compared between groups. As a result, the HMW adiponectin variate analysis. Kaplan-Meier survival curves were com- levels were lower in the following groups: patients Ͻ63 years, pared between patient groups with low and high HMW men, body mass index Ͼ23.2 kg/m2, smokers, low high-den- adiponectin levels using the log-rank test. A p value Ͻ0.05 sity lipoprotein-cholesterol levels, high HOMA-IR, and high was considered significant. hs-CRP levels (Table 2). 572 The American Journal of Cardiology (www.AJConline.org)

Figure 3. Univariate analysis for the prediction of cardiovascular events by a Cox proportional hazards model. Diabetes, high hs-CRP levels, and low HMW adiponectin levels were signiﬁcant predictors and were used in the multivariate analysis. In addition, smoking habit, high HOMA-IR, and statin use were also entered into the multivariate analysis as these 3 factors had a p value Ͻ0.15 in the univariate analysis.

Although there were no differences in age, gender, and Table 3 body mass index among each disease group, the serum Multivariate analysis for predicting cardiovascular events by Cox HMW adiponectin levels were lower in patients with stable proportional hazard model effort angina (3.3 Ϯ 2.6 ␮g/ml, p Ͻ0.001), old myocardial RR (95% CI) p Value infarction (3.8 Ϯ 2.9 ␮g/ml, p Ͻ0.01), and in patients with Diabetes mellitus 1.39 (0.81–2.38) 0.228 vasospastic angina (3.4 Ϯ 2.4 ␮g/ml, p Ͻ0.01), compared Ϯ ␮ Smoker 1.28 (0.70–2.32) 0.418 with controls (6.6 5.4 g/ml) (Figure 1). No angiographic Insulin resistance index by homeostasis 1.30 (0.76–2.26) 0.340 stenotic lesions were seen in 25 patients (17%) (vasospastic model assessment; high angina and controls), single vessel CAD was observed in 46 Use of statins; no 1.15 (0.69–1.95) 0.593 patients (32%), and multivessel (double and triple vessel) High sensitivity C-reactive protein; high 2.28 (0.92–6.81) 0.094 CAD was observed in 77 patients (51%). HMW adiponectin High molecular weight adiponectin; low 2.79 (1.49–5.24) 0.0014 levels were lower in patients with multivessel disease RR ϭ relative risk; CI ϭ confidence interval. (3.4 Ϯ 2.4 ␮g/ml) compared with patients with single- vessel disease (4.2 Ϯ 2.7 ␮g/ml, p Ͻ0.05), as well as Ϯ ␮ Ͻ with no organic stenotic lesions (5.1 3.5 g/ml, p 0.01) (16%), cerebrovascular accident in 2 (4%), and paroxysmal (Figure 1). These results suggest that low HMW adiponectin atrial fibrillation in 1 (2%). Univariate analysis showed that reflects the severity of CAD. In the limited number of diabetes mellitus (relative risk 1.76, 95% confidence inter- patients with multivessel disease, HMW adiponectin levels ϭ ϭ val 1.12 to 2.69, p 0.03), high hs-CRP levels (relative risk were correlated with left ventricular ejection fraction (R ϭ 0.33, p Ͻ0.005) (Figure 2), although such a correlation was 2.48, 95% confidence interval 1.36 to 3.92, p 0.0012), and low HMW adiponectin levels (relative risk 3.24, 95% absent in all patients (Figure 2). ϭ Of these 149 patients, 63 (42%) underwent coronary confidence interval 1.82 to 5.76, p 0.0001) were signif- angioplasty, 22 (15%) underwent coronary artery bypass icant predictors of cardiovascular events (Figure 3). In mul- grafting, and the remaining 64 (43%) were managed med- tivariate analysis, the only independent predictor of car- ically (Table 1). During a follow-up of 7 years, secondary diovascular events was low HMW adiponectin levels cardiovascular events occurred in 58 patients (39%). Of the (relative risk 2.79, 95% confidence interval 1.49 to 5.24, 50 patients with events, cardiovascular death was present in p ϭ 0.0014) (Table 3). Kaplan-Meier survival curves 5 (9%), nonfatal myocardial infarction in 3 (5%), unstable showed that the cumulative cardiac event rate was 29% angina in 4 (7%), new-onset angina pectoris in 14 (24%), higher in patients with low HMW adiponectin levels than vasospastic angina in 3 (5%), coronary artery bypass sur- in patients with high HMW adiponectin levels (log rank gery in 2 (4%), restenosis in 14 (24%), heart failure in 10 test, p ϭ 0.0046) (Figure 4). Coronary Artery Disease/High Molecular Weight Adiponectin and Events 573

Figure 4. Comparison of Kaplan-Meier survival curves using the log-rank test. Cumulative cardiac event rate was 29% higher in patients with low HMW adiponectin levels (Ͻ2.7 ␮g/ml) than in patients with high HMW adiponectin levels (Ն2.7 ␮g/ml).

Discussion density lipoprotein-cholesterol levels, high HOMA-IR value, and high hs-CRP levels. These results are compatible In this study, serum HMW adiponectin levels were mea- with previously reported data regarding the levels of total sured in consecutive patients who underwent diagnostic adiponectin as well as HMW adiponectin in a broader pop- coronary angiography for CAD, including not only angio- ulation.6,14,15 graphically verified CAD (i.e., vasospastic angina, stable In addition to its profound insulin-sensitizing effects, effort angina, or healed myocardial infarction), but also chest pain syndrome, nominated as the controls. Conse- adiponectin has various antiatherosclerotic actions. Similar quently, the levels were lower in patients with any type of to our results for HMW adiponectin, several clinical studies CAD compared with the controls. In addition, the levels of indicate that total adiponectin levels are decreased in pa- 16,17 HMW adiponectin decreased as the number of arteries with tients with CAD compared with matched controls. Al- CAD increased, and the levels were lowest in patients with though we excluded patients with acute coronary syndrome multivessel CAD. These results suggest that HMW adi- in this study, total adiponectin levels have been reported to ponectin levels are inversely associated with the severity of be lower in patients with acute coronary syndrome, both CAD. The most important finding of this study is that acute myocardial infarction and unstable angina, than in among various risk factors, HMW adiponectin levels were patients with stable CAD.18 In addition, the low adiponectin the most powerful predictor of secondary cardiovascular level is demonstrated to be correlated independently with events during 7 years of follow-up. the development of acute coronary syndrome.18 In the pro- Adiponectin has been demonstrated to link obesity, in- cess of atherogenesis and atherosclerotic progressions, adi- sulin resistance, and cardiovascular diseases. Although clin- ponectin inhibits upregulation of adhesion molecules such ical data on HMW adiponectin levels are lacking, total as intracellular adhesion molecule-1, vascular cell adhesion adiponectin levels have been measured extensively in var- molecule-1 or E-selectin, and subsequent attachment of ious settings. Plasma levels of adiponectin are decreased in leukocytes to vascular endothelial cells.14 Adiponectin also insulin resistance and obesity and synthesis of adiponectin suppresses nuclear factor-␬B activation.19 In addition to increases when insulin sensitivity is improved and weight is these anti-inflammatory actions, adiponectin suppresses lost.9 Low adiponectin serum levels at baseline indepen- proliferation and migration of vascular smooth muscle dently predict future risk of developing type 2 diabetes cells.20,21 Moreover, foam cell transformation of human mellitus in humans.10 Through enhancement of insulin sen- monocyte-derived macrophages is also inhibited by adi- sitivity, adiponectin potentially augments insulin-induced ponectin.22,23 These actions of adiponectin might inhibit inhibition of gluconeogenesis in hepatocytes,11 increases atherogenesis, atherosclerosis progression, plaque instabil- fatty acid combustion in muscle cells,12 causes insulin- ity, or plaque rupture, possibly leading to our results of the stimulated glucose uptake in adipocytes in a paracrine man- low level of HMW adiponectin in CAD and the inverse ner,13 and thereby reduces blood glucose levels. In our association between HMW adiponectin level and severity of limited population of patients with CAD, lower HMW adi- CAD. ponectin levels were associated with younger age, male Because this study included a relatively small number of gender, larger body mass index, smoking habit, lower high- patients, we could only predict overall cardiovascular 574 The American Journal of Cardiology (www.AJConline.org) events but could not use HMW adiponectin levels to predict 10. Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, each event separately. In our study, 20% of the patients Pfeiffer AF. Adiponectin and protection against type 2 diabetes mellitus. Lancet 2003;361:226–228. developed heart failure as an event. Considering the inverse 11. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte- correlation between HMW adiponectin levels and left ven- secreted protein Acrop30 enhances hepatic insulin action. Nat Med tricular function, there appears to be a discrepancy between 2001;7:947–953. HMW adiponectin levels for the prediction of atherosclero- 12. Yamauchi T, Kamon J, Waki Y, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, et al. The fat-derived sis and heart failure. Thus, we should evaluate HMW adi- hormone adiponectin reverses insulin resistance associated with both ponectin levels in a larger cohort to assess its predictive lipoatrophy and obesity. Nat Med 2001;7:941–946. values for each event separately. Although we did not mea- 13. Wu X, Motoshima H, Mahadev K, Stalker TJ, Scalia R, Goldstein BJ. sure total adiponectin levels in the present study, the mea- Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. surement of both HMW and total adiponectin levels should Diabetes 2003;52:1355–1363. be required for precise evaluation of the clinical value of 14. 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Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Miyazaki A, Nakayama H, Horiuchi S. Adiponectin downregulates Chen CL, Tai TY, Chuang LM. Weight reduction increases plasma acyl-coenzyme A: cholesterol acyltransferase-1 in cultured human levels of an adipose-derived anti-inflammatory protein, adiponectin. monocyte-derived macrophages. Biochem Biophys Res Commun 2004; J Clin Endocrinol Metab 2001;86:3815–3819. 317:831–836. Accuracy of N-Terminal Pro-Brain Natriuretic Peptide to Predict Mortality in Various Subsets of Patients With Coronary Artery Disease

Gjin Ndrepepa, MDa,*, Siegmund Braun, MDb, Albert Schömig, MDa,c, and Adnan Kastrati, MDa

The ability of N-terminal pro-brain natriuretic peptide (NT–pro-BNP) to predict mortality in various subsets of patients with coronary artery disease (CAD) is not known. The aim of present study was to investigate the ability of NT–pro-BNP to predict mortality in various subsets of patients with CAD. The study included 1,552 consecutive patients with angiographically proven CAD. Based on receiver-operating characteristic curve analysis, the best NT–pro-BNP level for mortality prediction was 721 ng/L (sensitivity 71.3%, speciﬁcity 71.3%). Patients were divided into 2 groups: the group with NT–pro-BNP level <721 ng/L (1,034 patients) and the group with NT–pro-BNP level >721 ng/L (518 patients). The primary end point of the study was mortality. The median follow-up was 3.6 years (interquartile range 3.3 to 4.6). In total there were 171 deaths: 49 deaths in the group with NT–pro-BNP <721 ng/L and 122 deaths in the group with NT–pro-BNP >721 ng/L (mortality estimates 6.6% vs 29.5%, odds ratio 5.2; 95% conﬁdence intervals 3.9 to 7.0, p <0.001). In 28 subsets of patients, NT–pro-BNP level predicted mortality with odds ratio varying from 2.8 to 7.5. In conclusion, NT–pro-BNP is a reliable predictive marker of mortality in all subsets of patients with CAD. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:575–578)

Brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT–pro-BNP) have an established role in identifying patients with congestive heart failure1 and ample evidence supports a role for them in predicting mortality in patients with acute coronary syndromes (ACSs)2,3 or stable coronary artery disease (CAD).4,5 However, at present no study has tested the power of NT–pro-BNP to predict mortality in various subsets of patients with CAD. We undertook this study to investigate the ability of NT– pro-BNP to predict long-term mortality in patients with stable and unstable CAD.

Methods and Results This study included a series of 1,552 consecutive patients with stable CAD or non–ST-segment elevation ACS who underwent coronary angiography and percutaneous coronary intervention at the Deutsches Herzzentrum and Klini- kum rechts der Isar in Munich between September 1999 and February 2002. Diagnosis of stable CAD was based on the Figure 1. Receiver-operating characteristic curve showing the accuracy of presence of angina symptoms in a patient already diagnosed NT–pro-BNP to predict mortality. AUC ϭ area under curve. with CAD who had no change in their pattern during the preceding 2 months. Unstable angina was diagnosed when increased levels of troponin T (troponin T level Ͼ0.03 anginal pain of Ͼ20 minutes was associated with either ␮ Ն g/L). To be included in the study, all 3 types of CAD had ST-segment depression of 0.1 mV and/or T-wave inver- to have been documented by coronary angiography (coro- sion in 2 continuous leads on the electrocardiogram. Diag- nary stenoses Ն50% lumen obstruction in Ն1 of the 3 major nosis of non–ST-segment elevation acute myocardial infarc- coronary arteries). The complexity of lesions was defined tion was based on the previously mentioned criteria plus according to the modified American College of Cardiology/ American Heart Association grading system. Class B2 and 6 a b C lesions were considered complex. Left ventricular end- Klinik für Herz- und Kreislauferkrankungen; Institut für Laboratori- diastolic pressure was measured before angiography. Global umsmedizin, Deutsches Herzzentrum München, and c1. Medizinische Klinik Klinikum rechts der Isar, Technische Universität München, Munich, left ventricular ejection fraction was determined using the 7 Germany. Manuscript received February 14, 2007; revised manuscript area–length method. Patients with advanced renal disease received and accepted March 8, 2007. (serum creatinine Ͼ2 mg/dl or those on dialysis), acute *Corresponding author: Tel: 49-89-12184016; fax: 49-89-12184593. inflammatory states, or malignancies were excluded. Con- E-mail address: [email protected] (G. Ndrepepa). gestive heart failure was graded according to New York

Table 1 Baseline characteristics Characteristic NT–proBNP (ng/L) p Value Յ721 Ͼ721 (n ϭ 1,034) (n ϭ 518) Age (yrs) 63.9 (57.3; 71.2) 71.5 (63.8; 77.5) Ͻ0.001 Women 189 (18.3%) 178 (34.4%) Ͻ0.001 Diabetes mellitus 240 (23.2%) 166 (32.0%) Ͻ0.001 Body mass index (kg/m2) 27.0 (24.8; 29.3) 26.1 (24.0; 29.0) 0.001 Arterial hypertension 567 (54.8%) 272 (52.5%) 0.38 Current smoker 167 (16.2%) 85 (16.4%) 0.89 Hypercholesterolemia (total Ն240 mg/dl) 501 (48.4%) 209 (40.3%) 0.003 Previous myocardial infarction 367 (35.5%) 234 (45.1%) Ͻ0.001 Previous coronary artery bypass surgery 169 (16.3%) 75 (14.5%) 0.34 Previous coronary balloon angioplasty 522 (50.5%) 211 (40.7%) Ͻ0.001 Atrial fibrillation 17 (1.6%) 66 (12.7%) Ͻ0.001 Heart rate (beats/min) 68 (60; 76) 72 (65; 80) Ͻ0.001 Systolic blood pressure (mm Hg) 150.0 (130.0; 170.0) 149.0 (120.0; 170.0) 0.02 Acute coronary syndrome 262 (25.3%) 231 (44.6%) Ͻ0.001 NYHA class Ͻ0.001 1 298 (28.8%) 207 (40.0%) 2 312 (30.2%) 105 (20.3%) 3 269 (26.0%) 104 (20.1%) 4 155 (15.0%) 102 (19.6%) NT–pro-BNP (ng/L) 200.7 (98.3; 370.5) 1674.5 (1096.0; 3388.8) Ͻ0.001 High-sensitivity C-reactive protein (mg/L) 1.1 (0.8; 1.9) 1.6 (1.1; 4.7) Ͻ0.001 Glomerular filtration rate (ml/min) 74.4 (59.8; 90.7) 59.2 (46.9; 72.4) Ͻ0.001 Coronary artery affected 0.78 Left main 19 (1.8%) 11 (2.1%) Left anterior descendent 401 (38.8%) 211 (40.7%) Left circumflex 238 (23.0%) 125 (24.1%) Right 308 (29.8%) 140 (27.1%) Bypass graft 68 (6.6%) 31 (6.0%) No. of coronary arteries narrowed Ͻ0.001 1 245 (23.6%) 99 (19.1%) 2 323 (31.3%) 165 (31.8%) 3 466 (45.1%) 254 (49.1%) Multivessel coronary disease 789 (76.3%) 419 (80.9%) 0.04 Complex lesions 744 (71.9%) 404 (77.9%) 0.01 LV end-diastolic pressure (mm Hg) 17.0 (12.0; 20.0) 20.0 (14.0; 23.0) Ͻ0.001 LV ejection fraction (%) 62.0 (54.0; 68.0) 48.0 (36.0; 59.0) Ͻ0.001 Therapy at discharge ␤ Blockers 927 (89.7%) 475 (91.7%) 0.20 Statins 891 (86.2%) 448 (86.5%) 0.86 ACE inhibitors 842 (81.4%) 440 (84.9%) 0.09

Data are number of patients (percent) or median (25th; 75th percentiles). ACE ϭ angiotensin-converting enzyme; NYHA ϭ New York Heart Association; LV ϭ left ventricular.

Heart Association classification. For the purpose of this 1,550g for 10 minutes and plasma aliquots were stored frozen study, patients in New York Heart Association class ϾIor at Ϫ80°C until assayed within batches. NT–pro-BNP measure- with a documented history of congestive heart failure were ments were performed on a Roche Elecsys 1010 automated considered to have congestive heart failure. Other cardio- analyzer (Roche Diagnostics, Mannheim, Germany). The mea- vascular risk factors were defined using previously de- suring range is 5 to 35,000 ng/L. High-sensitivity C-reactive scribed criteria.8 Percutaneous coronary intervention protein was measured fully automated with a latex-en- (mostly stent implantation) and periprocedural care were hanced immunoturbidometric assay on a Cobas Integra performed according to the standard criteria. Bare metal (Roche Diagnostics). The upper limit of the reference range stents were used. Antiplatelet therapy consisted of clopi- in healthy adults is 5 mg/L. Troponin T was measured by a dogrel (300 to 600 mg as a loading dose followed by 75 third generation electrochemilumiscence immunoassay on mg/day for Ն4 weeks) and aspirin (200 mg/day adminis- the Elecsys 2010 analyzer (Roche Diagnostics). The lower tered orally and continued indefinitely). detection limit of this assay is 0.01 ␮g/L and the upper limit Detailed description of laboratory measurements has of normal range is 0.03 ␮g/L. Blood count, serum lipids, been previously described.5,8 Briefly, blood samples were and other metabolites were determined immediately after collected before angiography, promptly centrifuged at collection using standard methods. Glomerular filtration Coronary Artery Disease/N-Terminal Pro-Brain Natriuretic Peptide and Mortality 577

Table 2 Number of deaths/total number of patients, probability of mortality in each of the subsets, and the odds ratio associated with having NT–pro-BNP of Յ721 or Ͼ721 ng/L Variable NT–pro-BNP (ng/L) Odds Ratio p Value for (95% CI) Interaction* Յ721 Ͼ721 Deaths/Total (%) Deaths/Total (%) Age Յ66.0 yrs 23/602 (4.6%) 18/171 (13.2%) 2.8 (1.6–5.1) 0.04 Age Ͼ66.0 yrs 26/432 (9.1%) 104/347 (37.4%) 5.3 (3.7–7.6) Men 39/845 (6.8%) 89/340 (32.3%) 6.0 (4.3–8.2) 0.17 Women 10/189 (5.4%) 33/178 (24.1%) 3.7 (1.9–6.9) Diabetes mellitus 19/240 (12.8%) 46/166 (40.9%) 3.7 (2.3–6.0) 0.22 No diabetes 30/794 (4.8%) 76/352 (25.4%) 5.9 (4.1–8.5) Smokers 9/167 (6.5%) 22/85 (28.5%) 5.3 (2.7–10.4) 0.97 Nonsmokers 40/867 (6.6%) 100/433 (30.0%) 5.2 (3.8–7.2) Hypercholesterolemia 22/501 (5.9%) 41/209 (24.2%) 4.5 (2.9–7.2) 0.53 No hypercholesterolemia 27/533 (7.2%) 81/309 (33.2%) 5.6 (3.8–8.1) Body mass index Յ30 kg/m2 37/826 (6.2%) 102/415 (31.2%) 5.8 (4.2–8.0) 0.19 Body mass index Ͼ30 kg/m2 12/208 (8.2%) 20/103 (22.9%) 3.5 (1.8–6.6) Stable coronary artery disease 35/772 (7.3%) 71/287 (32.6%) 5.8 (4.1–8.2) 0.40 Acute coronary syndrome 14/262 (5.6%) 51/231 (26.3%) 4.3 (2.5–7.3) With heart failure 14/205 (11.1%) 75/238 (38.5%) 4.9 (3.0–8.1) 0.41 Without heart failure 35/829 (5.4%) 47/280 (22.3%) 4.0 (2.7–6.0) Previous myocardial infarction 18/367 (8.2%) 62/234 (32.4%) 5.6 (3.6–8.7) 0.51 No previous myocardial infarction 31/667 (6.0%) 60/284 (27.1%) 4.8 (3.3–7.1) LV ejection fraction Յ55% 20/321 (8.1%) 89/353 (30.4%) 4.2 (2.8–6.4) 0.88 LV ejection fraction Ͼ55% 29/713 (5.9%) 33/165 (27.0%) 5.2 (3.4–8.1) With atrial fibrillation 1/17 (7.0%) 26/66 (47.5%) 7.5 (1.6–34.9) 0.54 Without atrial fibrillation 48/1017 (6.6%) 96/452 (26.9%) 4.7 (3.5–6.4) Single-vessel disease 9/245 (4.2%) 24/99 (32.1%) 6.7 (3.5–12.7) 0.40 Multivessel disease 40/789 (7.3%) 98/419 (28.7%) 4.9 (3.6–6.8) C-reactive protein Յ1.2 mg/L 21/599 (4.4%) 28/191 (21.0%) 4.2 (2.5–7.0) 0.57 C-reactive protein Ͼ1.2 mg/L 28/435 (9.2%) 94/327 (24.0%) 4.9 (3.4–7.0) Glomerular filtration rate Յ60 ml/min 16/264 (7.4%) 79/267 (36.7%) 5.2 (3.3–8.3) 0.59 Glomerular filtration rate Ͼ60 ml/min 33/770 (6.3%) 43/251 (22.2%) 4.1 (2.7–6.1)

Data are presented of numbers, probability of mortality (percent), and odds ratio and 95% confidence interval (CI). * Calculated by Breshow-Day test. Abbreviation as in Table 1. rate was calculated using the Cockroft-Gault formula. Lab- the Breslow-Day test. A p value Ͻ0.05 was considered oratory measurements were performed by laboratory per- statistically significant. sonnel unaware of clinical or angiographic outcome. The median follow-up was 3.6 years (interquartile range The primary end point of the study was all-cause mor- 3.3 to 4.6). There were 171 deaths (11%) during follow-up. tality. Clinical follow-up consisted of telephone interviews Receiver-operating characteristic curve analysis showed at 1 month, 1 year, and 3 to 5 years after the index proce- that NT–pro-BNP had an area under curve of 0.764 (95% dure. Follow-up information was performed by medical confidence interval 0.726 to 0.802; Figure 1). The best staff unaware of laboratory measurements. NT–pro-BNP level for prediction of mortality was 721 ng/L Data are presented as median (with 25th and 75th (sensitivity 71.3%, specificity 71.3%). Using this cut-off percentiles) or counts and proportions (percentages). The value, patients were divided into 2 groups: with NT–pro- distribution of the data was analyzed with the 1-sample BNP Յ721 ng/L (1,034 patients) and with NT–pro-BNP Kolmogorov-Smirnov test. Continuous data were compared Ͼ721 ng/L (518 patients). Baseline characteristics of pa- with Wilcoxon rank-sum test. Categorical data were com- tients are shown in Table 1. With the exception of the pared with chi-square test. Receiver-operating characteristic characteristics of arterial hypertension, smokers, previ- curves were constructed to assess the best NT–pro-BNP ous coronary artery bypass surgery, type of coronary level for the prediction of mortality. The area under receiv- artery affected, and therapy at discharge, all other char- er-operating characteristic curve and 95% confidence limits acteristics differed significantly among patients in both were used to assess predictive power for mortality. Proba- groups. bilities of survival in various subsets of patients were esti- There were 49 deaths in the group with NT–pro-BNP mated by applying the Kaplan-Meier method and log-rank Յ721 ng/L and 122 deaths in the group with NT–pro-BNP test, which allowed the calculation of odds ratios (95% Ͼ721 ng/L (probability of mortality 6.6% vs 29.5%, odds confidence intervals) associated with elevated NT–pro-BNP ratio 5.2, 95% confidence intervals 3.9 to 7.0, p Ͻ0.001). level. Heterogeneity in risk prediction was assessed using Risk estimation regarding mortality was assessed in various 578 The American Journal of Cardiology (www.AJConline.org) subgroups of patients (defined by dichotomizing various surement of B-type natriuretic peptide in the emergency diagnosis of clinical characteristics). Discrete characteristics were di- heart failure. N Engl J Med 2002;347:161–167. 2. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, chotomized based on the presence or absence of the condi- McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value tion; continuous characteristics were dichotomized based on of B-type natriuretic peptide in patients with acute coronary syn- median values (age, C-reactive protein) or accepted cutoff dromes. N Engl J Med 2001;345:1014–1021. used to grade conditions (body mass index, glomerular 3. Morrow DA, de Lemos JA, Blazing MA, Sabatine MS, Murphy SA, filtration rate) or define normal and abnormal values (left Jarolim P, White HD, Fox KA, Califf RM, Braunwald E, for the A to ventricular ejection fraction). The number of deaths, the Z Investigators. Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery estimates of mortality in each of subsets, and the odds ratio disease. JAMA 2005;294:2866–2871. associated with being in groups with NT–pro-BNP level Յ or 4. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. Ͼ721 ng/L are shown in Table 2. In all 28 subsets of N-terminal pro-B-type natriuretic peptide and long-term mortality in patients, NT–pro-BNP level predicted increased risk of stable coronary heart disease. N Engl J Med 2005;352:666–675. death with odd ratios varying from 2.8 in patients Ͻ66 years 5. Ndrepepa G, Braun S, Niemoller K, Mehilli J, von Beckerath N, von Beckerath O, Vogt W, Schömig A, Kastrati A. Prognostic value of (median age) to 7.5 in patients with atrial fibrillation. How- N-terminal pro-brain natriuretic peptide in patients with chronic stable ever, the only dichotomized characteristic that showed an angina. Circulation 2005;112:2102–2107. interaction with NT–pro-BNP level in predicting mortality 6. Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, was age, implicating that NT–pro-BNP is a better marker of Topol EJ, Bulle TM. Coronary morphologic and clinical determinants increased risk of death in older than in younger patients of procedural outcome with angioplasty for multivessel coronary dis- ϭ ease. Implications for patient selection. Multivessel Angioplasty Prog- (p 0.04; Table2). nosis Study Group. Circulation 1990;82;1193–1202. 7. Sandler H, Dodge HT. The use of single plane angiocardiograms for Discussion the calculation of left ventricular volume in man. Am Heart J 1968; 75:325–334. In this study we assessed the strength of NT–pro-BNP in 8. Ndrepepa G, Braun S, Mehilli J, von Beckerath N, Vogt W, Schömig predicting long-term mortality in a well-characterized series A, Kastrati A. Plasma levels of N-terminal pro-brain natriuretic pep- of patients with stable CAD and non–ST segment elevation tide in patients with coronary artery disease and relation to clinical ACS. The main finding of this study is that NT–pro-BNP presentation, angiographic severity, and left ventricular ejection fraction. Am J Cardiol 2005;95:553–557. predicts mortality in various subsets of patients with CAD. 9. James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, The finding that NT–pro-BNP is a better predictor of mor- Barnathan ES, Califf R, Topol EJ, Simoons ML, Wallentin L. N-terminal tality in older patients deserves attention, although some pro-brain natriuretic peptide and other risk markers for the separate pre- caution is warranted due to the possible influence of mul- diction of mortality and subsequent myocardial infarction in patients with tiple testing. It is well-known that older patients have a more unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003;108: adverse risk profile due to accumulation of risk with ad- 275–281. vancing age. In contrast, it has sufficiently been confirmed 10. Nakagawa O, Ogawa Y, Itoh H, Suga S, Komatsu Y, Kishimoto I, that elevated NT–pro-BNP levels are independently and Nishino K, Yoshimasa T, Nakao K. Rapid transcriptional activation positively associated with various components of adverse and early mRNA turnover of brain natriuretic peptide in cardiocyte cardiovascular risk.8,9 Apart from being a marker of hemo- hypertrophy. Evidence for brain natriuretic peptide as an “emergency” 10,11 cardiac hormone against ventricular overload. J Clin Invest 1995;96: dynamic burden on the heart and of myocardial isch- 1280–1287. 12,13 emia, elevated levels of NT–pro-BNP may reflect the 11. Talwar S, Squire IB, Downie PF, Mccullough AM, Campton MC, risk from multiple sources being an integrative index of Davies JE, Barnett DB, Ng LL. Profile of plasma N-terminal proBNP increased risk in general. Because of these reasons, NT– following acute myocardial infarction; correlation with left ventricular pro-BNP may be the best known cardiac biomarker that systolic dysfunction. Eur Heart J 2000;21:1514–1521. 12. Goetze JP, Christoffersen C, Perko M, Arendrup H, Rehfeld JF, offers a more complete description of increased risk as that Kastrup J, Nielsen LB. Increased cardiac BNP expression associated associated with advanced age. with myocardial ischemia. FASEB J 2003;17:1105–1107. 13. Bibbins-Domingo K, Ansari M, Schiller NB, Massie B, Whooley MA. 1. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, B-type natriuretic peptide and ischemia in patients with stable coro- Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, et al. for the nary disease: data from the Heart and Soul study. Circulation 2003; Breathing Not Properly Multinational Study Investigators. Rapid mea- 108:2987–2992. Time Course of Hemoglobin Concentrations in the Intensive Care Unit in Nonbleeding Patients With Acute Coronary Syndrome

Marco Previsdomini, MDa,*, Reto Stocker, MDb, Roberto Corti, MDc, Bernard Cerutti, PhDd, and Andreas Perren, MDe

Critically ill patients commonly show a decrease in hemoglobin concentration during their stay in the intensive care unit. The purpose of the present study was to evaluate whether nonbleeding patients with acute coronary syndrome (ACS) show a similar decrease of hemoglobin, and thereby furnish reference values and analyze possible mechanisms. In this retrospective, descriptive study, the charts of all patients with ACS hospitalized between January 2004 and September 2005 were screened with regard to patient characteristics, time course of hemoglobin, as well as clinical parameters, concomitant drug therapy, and fluid balances. One hundred three nonbleeding patients with ACS were analyzed. They showed an average hemoglobin decrease of 1.27 ؎ 1.00 g/dl (p <0.001). The decrease in hemoglobin level was observed during the first 12 to 24 hours; thereafter the hemoglobin concentration remained stable. We found a correlation among decrease of hemoglobin, parameters of stress, such as and white blood cells ,(0.043 ؍ pain (p ,(0.004 ؍ tachycardia (p ,(0.019 ؍ hypertension (p -In conclu .(0.004 ؍ as well as the intravenous administration of nitroglycerin (p ,(0.021 ؍ p) sion, during the first 24 hours in the intensive care unit the hemoglobin concentration of nonbleeding patients with ACS regularly decreases at 1.27 ؎ 1.00 g/dl. Any further decrease in hemoglobin level beyond these values should entail early active search of the bleeding source. We hypothesize that this decrease is due to normalization of the previous stress-induced hemoconcentration and “internal hemodilution” by nitroglycerin. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:579–582)

The natural time course of hemoglobin concentration in sive of the estimated perspiration), total amount of blood sam- patients with acute coronary syndrome (ACS) has not yet plings, daily hemoglobin and white blood cells count, car- been studied. We recently became aware of a decrease in diac markers of ischemia, and the medication given. We hemoglobin concentration in patients with ACS lacking any furthermore recorded hemodynamic data and thoracic pain sign of evident blood loss. The present observational study intensity (visual analog scale). The severity of disease was evaluates this phenomenon and proposes reference values of determined by the Simplified Acute Physiology Score II hemoglobin decrease for nonbleeding patients with ACS. (SAPS II).1 This scoring system, an analog to Apache II, permits classification of severity of disease and attributes a Methods and Results predicted mortality. This retrospective descriptive study was performed in an The therapeutic regimen of our patients was adapted to interdisciplinary 8-bed intensive care unit (ICU) of a re- the clinical situation. At arrival they received 250 mg of gional teaching hospital in southern Switzerland. The inves- acetylsalicylic acid intravenously, followed by 100 mg/day tigation was approved by the local ethics committee. We by mouth. Clopidogrel was given with a loading dose of 300 screened the charts of all patients admitted to our ICU for mg by mouth, followed by 75 mg/day. Four patients were ACS (International Classification of Diseases codes 10: I enrolled in the Electrocardiogram Clarity-Thrombolysis In 20.0, I 21.0 I 21.1, I 21.2, I 21.4) between January 2004 and Myocardiol Infarction (TIMI) 28 study and received the September 2005. Exclusion criteria were active bleeding study drug.2 The dose of unfractioned heparin was tailored (e.g., gastrointestinal bleeding), procedures with possible to augment the activated partial thromboplastin time value blood loss such as coronary angiography and surgery, trans- to 1.5 to 2.3 times the control value. Patients treated with fusion of red blood cells, hemolysis, hemodialysis, and pa- low- molecular-weight heparins received nadroparin 2 ϫ 86 tients with Ͻ2 determinations of hemoglobin. We checked for IU/kg body weight subcutaneously. Tirofiban and thrombo- general patient demographics, total fluid balance (comprehen- lytic agents were applied according to the body weight, following the recommendations of the manufacturers. The analysis was retrospective and the sample size was not Divisions of aMedical Intensive Care and bSurgical Intensive Care and defined on the basis of power consideration. Continuous data cDepartment of Cardiology, University Hospital, Zurich; dDepartment of Ϯ e are reported as means SDs. Categorical data are described as Public Health and Social Welfare; and Intensive Care Unit, Ospedale absolute values and percentages. A paired Student’s t test was Regionale Bellinzona e Valli, Bellinzona, Switzerland. Manuscript received January 3, 2007; revised manuscript received and accepted March used to compare the values of a continuous variable at 2 14, 2007. different time points. A linear fitting was used to check the *Corresponding author: Tel: 41-44-255-22-52; fax: 41-44-255-31-81. strength of the linear correlation between 2 continuous vari- E-mail address: [email protected] (M. Previsdomini). ables. All the analyses were done with S-Plus 7.0 for Win-

Table 1 blood cells, and thoracic pain intensity are reported in Demographic data (n ϭ 103 patients) Table 3. There was an association between the hemoglobin Variable Number course, the decrease of arterial pressure during the ICU stay (0.01 g/dl by decrease of 1 mm Hg, p ϭ 0.019), the decrease Men/women 64/39 in heart rate (0.01 g/dl by decrease of 1 beat/min, p ϭ Age (yrs) 71 Ϯ 13 Ϯ 0.004), the lessening of pain intensity (0.06 g/dl per unit on SAPS II 28 13 ϭ Length of intensive care unit stay (hs) 49 Ϯ 28 the visual analog scale, p 0.043), and the decrease of Intensive care unit mortality 4 (4%) white blood cells during the hospitalization (0.06 g/dl by 3 In-hospital mortality 15 (15%) decrease of 10 /␮l, p ϭ 0.021). Primary diagnosis ACS 16 (16%) Acute non–ST-segment elevation myocardial infarction 49 (48%) Discussion Acute ST-segment elevation myocardial infarction 17 (17%) The present observational study evaluates the time course of Myocardial infarction with cardiac arrest 6 (6%) blood hemoglobin concentrations in a population of non- Subacute myocardial infarction 15 (15%) bleeding patients with ACS with the additional purpose of Continuous data are presented as mean Ϯ SD. providing reference values and evaluating possible affecting factors, considering that these patients are exposed to many drugs that can promote bleeding. Our data indicate that the dows, Enterprise Developer (Insightful Corporation, Seattle, hemoglobin level decreases 1.29 Ϯ 0.79 g/dl during the first Washington). 12 to 24 hours and then remains constant during the remain- We examined the charts of 172 patients with ACS. Sixty- ing stay in the ICU. Theoretically, this might be due to the nine patients were excluded from final evaluation because many blood samples taken at beginning of the hospitaliza- of insufficient hemoglobin assessments (n ϭ 48), too short tion. As described in the past, blood samplings can contrib- length of stay (n ϭ 8), previous procedures with unknown ute to a reduction of hemoglobin concentration, a phenom- blood loss (n ϭ 4), preexistent anemia requiring blood enon referred to as nosocomial or iatrogenic anemia.3,4 transfusions (n ϭ 5), gastric ulcer disease with active bleed- However, the total amount of blood needed for laboratory ing (n ϭ 2), hemolysis (n ϭ 1), and chronic intermittent testing has decreased over the years with improvement in hemodialysis (n ϭ 1). Thus, the analysis concerned 103 techniques and equipment, and in our study it was rather white nonbleeding patients with ACS, 6 of whom with limited, with an average of 52 ml during the entire ICU stay. cardiac arrest, who met the inclusion criteria. General pa- In relation to the assumed mean weight of our patients5 this tient demographics are listed in Table 1. would imply a hemoglobin decrease of 0.13 to 0.15 g/dl The mean hemoglobin concentration at ICU admission (estimated blood volume 7% of body weight),6 which is far was 13.90 Ϯ 1.62 g/dl and decreased during the ICU stay from the value observed in our study. The fluid balance was for 88% of patients. After a decrease of 1.29 Ϯ 0.79 g/dl constant or negative with only 8 exceptions, therefore he- during the first 12 to 24 hours (95% confidence interval 1.12 modilution after correction of fluid deficits can be discarded to 1.46 g/dl, p Ͻ0.001), it remained stable (mean reduction as a reason for the hemoglobin reduction. The mean ICU for the complete ICU stay of 1.27 Ϯ 1.00 g/dl; Figure 1). stay was too short for nutritional, endocrine, renal, or he- The average fluid balance during the entire ICU stay was patic insufficiency to influence the course of hemoglobin Ϫ616 Ϯ 1,465 ml, ϩ 771 ml in the subgroup of patients level. who died (p Ͻ0.001), and blood samplings accounted for Our statistical analysis could not demonstrate a relation 52 Ϯ 18 ml. We found a positive correlation between the between the number and type of platelet-inhibiting and height of the SAPS II score and the global fluid balance anticoagulating drugs and the course of hemoglobin con- (correlation coefficient 0.325, p Ͻ0.001), but there was no centration. This might be due in part to the limited sample evidence of correlation between the fluid balance and the size and the presence of very similar treatment protocols hemoglobin decline (p ϭ 0.150). The decrease in hemoglo- among the patients. The only significant correlation was bin was more important in patients with a higher SAPS II found between the application of systemic thrombolysis and score (ϩ0.02 g/dl per unit of SAPS II, p Ͻ0.001). In the degree of hemoglobin decrease, but this is in the absence contrast, it was less for patients who died during the hos- of a visible blood loss. pitalization (difference of 0.95 g/dl, p Ͻ0.001). About 3/4 of our patients received nitroglycerin intrave- Data concerning the therapeutic regimen are reported in nously during the first hours of hospitalization. Brugger et Table 2. There was no significant relation between the al7 and Arend et al8 described an effect called internal administration of clopidogrel (p ϭ 0.600) or tirofiban (p ϭ hemodilution after the administration of nitrates. The latter 0.646) and the hemoglobin decrease. In contrast, hemoglo- reported an average hemoglobin decrease after administra- bin significantly decreased after systemic thrombolysis tion of intravenous nitroglycerin for 24 hours of 1.48 g/dl, a (Ϫ0.58 g/dl, p ϭ 0.008). Patients receiving nitrates had a value close to our results. mean hemoglobin decrease of 1.43 g/dl during the first 12 to We found a statistical correlation between the amount of 24 hours, whereas those not receiving nitrates had a hemo- hemoglobin decrease, the difference of blood pressure, heart globin decrease of 0.89 g/dl (p ϭ 0.004). The relation rate, pain acuity, and white blood cells between admission between the administration of ␤ blockers and the degree of and discharge. As reported by Patterson et al9 on 29 healthy hemoglobin decrease did not reach a significant level (p ϭ men, acute psychological stress can produce a significant 0.070). Data concerning hemodynamic parameters, white hemoconcentration, probably through a fluid shift from the Coronary Artery Disease/Time Course of Hemoglobin in ACS 581

Figure 1. Time course of hemoglobin concentrations in 103 patients with acute coronary syndrome. The mean hemoglobin concentration at ICU admission was 13.90 Ϯ 1.62 g/dl. After a decrease of 1.29 Ϯ 0.79 g/dl during the first 12 to 24 hours (95% confidence interval 1.12 to 1.46 g/dl, p Ͻ0.001) it remained stable (mean reduction for the complete ICU stay of 1.27 Ϯ 1.00 g/dl). The white lines represent the medians of the observations, whereas the lower and upper extremities of the box represent the first and the third quartiles. The maximum length of each whisker is 1.5 times the interquartile range. Any data value larger than this range is drawn with a horizontal line.

Table 2 score, being more acutely ill at admission, showed more Therapeutic regimens of the study population (n ϭ 103) hemoglobin decline, probably due to the same mechanism. Variable Number The reason why patients who died experienced less hemoglobin decrease, is not completely clear, as their mean Acetylsalicylic acid 96 (93%) positive fluid balance would imply the contrary. On one Clopidogrel 48 (47%) Electrocardiogram clarity-TIMI 28 Study drug 4 (4%) hand they received less nitrates. On the other, their reduced Heparin 101 (98%) decrease in hemoglobin level could represent a sign of Unfractioned heparin 13 (13%) ongoing instability and stress. Considering the small sample Low weight molecular heparin 84 (82%) size, these results might also be due to chance. Tirofiban 13 (13%) Patients receiving blood transfusions were excluded Systemic thrombolysis 17 (17%) from our study. There are few clinical data about the he- Tenecteplase 11 (11%) moglobin threshold for transfusion in patients with cardiac Alteplase 1 (1%) disease.10 Most clinical trials were conducted on patients Streptokinase 5 (5%) undergoing coronary artery bypass.11 For elderly patients Nitroglycerin 79 (77%) with acute myocardial infarction, Wu and al12 reported that ␤ Blocker 70 (68%) blood transfusion was associated with lesser short-term mortality if the hematocrit at admission was Յ30.0% and Table 3 may still be effective with a hematocrit as high as 33.0% on Hemodynamic data, white blood cells and thoracic pain intensity admission. Based on these data, the hemoglobin threshold Variable Admission Discharge for transfusion in patients with ACS is set at most institu- Mean arterial pressure (mm Hg) 98 Ϯ 24 84 Ϯ 14 tions between 8.5 and 10 g/dl. Heart rate (beats/min) 84 Ϯ 22 71 Ϯ 14 Our study has several limits. The retrospective observa- White blood cells (103/␮l) 10.1 Ϯ 3.5 8.9 Ϯ 3.1 tional design implies possible selection bias. For instance, Thoracic pain intensity (visual analog scale) 2.2 Ϯ 2.9 0.0 Ϯ 0.3 28% of the screened patients were discarded from the study Ϯ population because of insufficient hemoglobin assessments. Data are presented as mean SD. In contrast, the scattered measurement of hemoglobin level could also potentially influence the data. One difficulty with vascular to the interstitial space secondary to vasoconstric- such an analysis is the unavoidable decrease in the number tion. After fading of stress, the fluid backflow from the of patients over time, as patients are discharged early, are interstitial space to the vascular bed may explain the de- transferred to other institutions, or die. Although patients crease in hemoglobin level. Patients with a higher SAPS II discharged or transferred could be followed up for a prede- 582 The American Journal of Cardiology (www.AJConline.org) termined time interval, we did not collect these data con- 6. Weiss C, Jelkmann W. Funktionen des Blutes. In: Schmidt und Thews, sidering the bias caused by the different laboratory tech- ed. Physiologie des Menschen. Berlin: Springer Verlag, 1990:422–460. 7. Brugger W, Imhof P, Müller P, Moser P, Reubi F. Effect of nitroglyc- niques. Although no occult blood losses were recognized, erin on blood rheology in healthy subjects. Eur J Clinical Pharmacol one cannot entirely exclude unrecognized gastrointestinal 1985;29:331–336. bleeding as a contributing factor.13 However, there are Ն2 8. Arend SM, Bax JJ, Hermans J, van der Wall EE, Sedney MI. The arguments that make this hypothesis rather improbable: (1) short-term effect of intravenous nitroglycerin on haematocrit; an additional benefit in patients with myocardial ischaemia? Eur Heart J a hemoglobin decease could be noted in as much as 88% of 1994;15:114–119. the examined patients and (2) the rapid onset of hemoglobin 9. Patterson SM, Marsland AL, Manuck SB, Kameneva M, Muldoon decrease with consequently stable values despite continuing MF. Acute hemoconcentration during psychological stress: assessment the previously described therapy. of hemorheologic factors. Int J Behav Med 1998;5:204–212. 10. Hébert CP, Yetisir E, Martin C, Blajchman MA, Wells G, Marshall J, Tweeddale M, Pagliarello G, Schweitzer I. Is a low transfusion thresh- 1. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Phys- old safe in critically ill patients with cardiovascular diseases? Crit iology Score (SAPS II) based on a European/North American multi- Care Med 2001;29:227–234. center study. JAMA 1993;270:2957–2963. 11. Johnson RG, Thurer RL, Kruskall MS, Sirois C, Gervino EG, Crit- 2. Scirica BM, Sabatine MS, Morrow DA, Gibson CM, Murphy SA, chlow J, Weintraub RM. Comparison of two transfusion strategies Wiviott SD, Giugliano RP, McCabe CH, Cannon CP, Braunwald E. after elective operations for myocardial revascularization. J Thorac The role of clopidogrel in early and sustained arterial patency after Cardiovasc Surg 1992;104:307–314. fibrinolysis for ST-segment elevation myocardial infarction: the ECG 12. Wu W-C, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood CLARITY–TIMI 28 Study. J Am Coll Cardiol 2006;48:37–42. transfusion in elderly patients with acute myocardial infarction. N Engl 3. Eyster E. Nosocomial anemia. JAMA 1973;223:73–74. J Med 2001;345:1230–1236. 4. Henry ML. Iatrogenic anemia. Am J Surg 1986;151:362–363. 13. Von Ahsen N, Müller C, Serke S. Important role of non diagnostic 5. Anonymous. Bundesamt für Statistik (2003c), Schweizerische Ge- blood loss and blunted erythropoietic response in the anemia of sundheitsbefragung 2002, Thema 4: Gesundheitszustand. Neuenburg. medical intensive care patients. Crit Care Med 1999;27:2630– Sektion Gesundheit des Bundesamt für Statistik. 2639. Prognostic Significance of Fragmented QRS Complex for Predicting the Risk of Recurrent Cardiac Events in Patients With Q-Wave Myocardial Infarction

Grzegorz Pietrasik, MD, Ilan Goldenberg, MD, Joanna Zdzienicka, MD, Arthur J. Moss, MD, and Wojciech Zareba, MD, PhD*

There are limited data regarding the prognostic value of QRS complex fragmentation, defined as changes in QRS morphology (<120 ms) with different RSR= patterns: additional R waves, notched S wave, or >1R= wave. The purpose of our analysis was to assess the prognostic value of presence of Q waves and QRS fragmentation for predicting recurrent cardiac events, defined as cardiac death, nonfatal myocardial infarction (MI), or unstable angina, whichever occurs first, in 350 patients with first Q-wave MI. In follow-up (2 months on average) electrocardiograms (ECGs), 277 patients (79%) had persistent Q waves and 73 (21%) had resolution of Q waves. Independently of Q waves, presence of QRS complex fragmentation was found in 187 patients (53%). Resolved Q waves on 2-month ECGs was whereas ,(0.007 ؍ associated with worsened prognosis (adjusted hazard ratio [HR] 2.33, p presence of any fragmented QRS did not increase risk of recurrent cardiac events (adjusted ,Among patients for whom Q waves disappeared on 2-month ECGs .(0.79 ؍ HR 0.93, p had over twofold higher risk of recurrent events (37 ؍ patients with QRS fragmentation (n -compared with those without fragmented QRS and persis (0.004 ؍ adjusted HR 2.68, p) tent Q waves. In conclusion, presence of fragmented QRS independently of Q waves was not associated with increased risk of recurrent events in the general population of patients after MI. However, among patients with resolved Q waves, fragmented QRS was associated with increased risk of cardiac events. Fragmented QRS complex should not be neglected in patients with transient Q waves after myocardial infarction. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:583–586)

Q-wave myocardial infarction (MI) compared with non– Methods and Results Q-wave MI has been associated with increased in-hospi- The Multicenter Study of Myocardial Ischemia (MSMI) tal and short-term (Ͻ30 days) mortality.1 Presence of Q waves has been associated with myocardial scarring. Dis- study enrolled 936 patients from 12 centers in the United appearance of Q waves after acute MI has been attributed States, Canada, and Israel. Enrollment began on July 1, to recovery of stunned and/or hibernating myocardium 1988 and ended on May 31, 1991 with follow-up through November 30, 1991. All patients admitted to the coronary and smaller infarct size.2,3 It has been suggested that remnants of viable myocardium are responsible for dis- care unit with documented MI or unstable angina were considered for enrollment. Full details and major results of appearance of Q waves and more frequent angina in this 7 group of patients.4 Prognostic value of Q-wave resolution this study have been previously published. Confirmation of has been previously evaluated, and the loss of Q waves enzyme level elevation was necessary for the diagnosis was not associated with significant changes in mortality of acute MI. Patients were scheduled for enrollment into the or recurrent events.5,6 However, there are limited data study 1 to 6 months after their index coronary event (on regarding prognostic value of fragmentation of the QRS average 2 months after MI), at a time when they were complex, defined as changes in QRS morphology (Ͻ120 considered clinically stable. Patients were ineligible for ms) with different RSR= patterns: additional R waves, enrollment for any of the following prespecified reasons: Ͼ coronary bypass graft surgery after the index coronary notched S wave, or 1R= wave, for the risk of recurrent Ͻ cardiac events among patients with Q-wave MI. event, coronary angioplasty performed 1 month before To evaluate prognostic significance of the fragmented enrollment, major medical co-morbidity, musculoskeletal QRS complex, we compared electrocardiograms (ECG) of disorders that would prevent patients from exercise stress patients who had first Q-wave MI and were followed pro- test, use of cardiac glycosides, complete or incomplete bun- spectively for occurrence of cardiac events. dle branch block or atrial fibrillation, implanted pacemaker, participation in other investigation studies, psychological factors, or physician refusal. Of 936 patients who gave consent, we analyzed 350 patients diagnosed with a first Q-wave MI based on the baseline ECG and clinical history. Heart Research Follow-up Program, Cardiology Division, Department Q waves were classified as presence of classic pathologic of Medicine, University of Rochester Medical Center, Rochester, New Ն York. Manuscript received February 6, 2007; revised manuscript received Q waves (or R waves in leadsV1 to V3)in 2 consecutive and accepted March 8, 2007. leads: anterior (V1 to V4), inferior (leads II, aVF, III), lateral *Corresponding author: Tel: 585-275-5392; fax: 585-273-5283. (V5 to V6, aVL, I), or posterior (V1 to V3). Fragmented QRS E-mail address: [email protected] (W. Zareba). complex was defined as changes in QRS morphology

Table 1 Baseline characteristics of patients by the presence of Q waves Variable Resolved Q Persistent Q p Value Wave Wave (n ϭ 73) (n ϭ 277) Age (yrs) 58 Ϯ 10 58 Ϯ 10 0.88 Women 28 (38%) 47 (17%) Ͻ0.001 Insulin-requiring diabetes 5 (7%) 11 (4%) 0.29 Figure 1. Examples of fragmented QRS complexes. (A) additional R wave; mellitus (B) Rr= pattern; (C) notched S wave; and (D) Ͼ1R=. Hypertension 27 (37%) 95 (34%) 0.67 Smokers 8 (11%) 32 (12%) 0.89 Angina pectoris before the 21 (29%) 81 (29%) 0.999 (Ͻ120 ms) with different RSR= patterns: additional R enrollement waves, notching S wave, or Ͼ1R= wave. Examples of Myocardial infarction fragmented QRS complex are shown in Figure 1. Signifi- therapy cant QRS fragmentation was defined as presence of slurred Thrombolytic therapy for 25 (34%) 142 (51%) 0.01 Ն index event QRS morphology in 2 consecutive leads in the following Coronary angioplasty during 24 (33%) 83 (30%) 0.63 locations: anterior (leads V1 to V4), inferior (leads II, aVF, index event and III), or lateral (leads V5 to V6, aVL, I). Posterior loca- Coronary angioplasty during 3 (4%) 12 (4%) 0.93 tion was not considered, as QRS fragmentation in leads V1 hospital period to V3 was attributed to anterior location. Medical therapy: Patients were categorized based on their 2-month 12-lead Aspirin 55 (75%) 228 (82%) 0.18 ECG at rest into 2 categories: (1) persistent Q wave— ␤-Blocker 38 (52%) 153 (55%) 0.63 presence of significant Q waves or (2) resolved Q wave— Calcium channel blocker 38 (52%) 101 (36%) 0.015 Electrographic findings absence of significant Q waves in comparison to acute phase Ͻ electrocardiography. Subsequently, patients with absent sig- ST-T abnormalities 44 (60%) 255 (92%) 0.001 Left anterior hemiblock 4 (5%) 21 (8%) 0.54 nificant Q waves were divided into those with completely Left posterior hemiblock 0 (0%) 3 (1%) 0.37 normal QRS complex and those with QRS complex frag- QRS (ms) 82 Ϯ 13 82 Ϯ 12 0.870 mentation. Patients were contacted at 4-month intervals throughout the study to determine their clinical status, pharmacologic Among 350 patients diagnosed with Q-wave MI, in 277 and interventional therapy, and the occurrence of study end patients (79%) significant Q waves remained unchanged points. All patients were followed up for Ն6 months to a since the index event. Seventy-three patients (21%) had no maximum of 43 months. The mean duration of follow-up significant Q waves at 2 months post-MI ECG (resolved Q was 686 Ϯ 280 days. waves). Baseline characteristics of patients with resolved The prespecified end points were death due to cardiac and persistent Q waves are presented in Table 1. QRS causes, nonfatal MI, or unstable angina occurring on or fragmentation, independent of presence of Q waves, was before November 30, 1991. The criteria for diagnosing MI identified in 187 patients (53%). Among 73 patients with were the same as those applied to the index coronary event. resolved Q waves, 37 patients (51%) had significant QRS The diagnosis of unstable angina required hospital admis- fragmentation. There was no significant difference in clin- sion to the coronary care unit for increased frequency or ical characteristics between patients with and without QRS duration of typical anginal symptoms and either ischemic fragmentation. ST segment or T-wave changes without elevation of cardiac During a mean follow-up of 686 Ϯ 280 days, there were enzymes. Recurrent cardiac event was defined as cardiac 56 events: 39 (14% event rate) among patients with persis- death, nonfatal MI, or unstable angina, whichever occurred tent Q waves, and 17 (23% event rate) among patients with first. resolved Q waves. Patients with resolved Q waves had a All results are reported as 2-tailed p values. Baseline trend toward higher probability of recurrent cardiac events characteristics were compared using chi-square test for di- as shown in Figure 2 (p ϭ 0.067). In univariate Cox anal- chotomous variables or t test for continuous variables. The ysis, patients with resolved Q waves on 2-month follow-up effect of different electrocardiographic parameters on the ECG had a trend toward 69% higher risk of recurrent end point was examined using Kaplan-Meier survival cardiac events compared with patients in whose Q waves curves and the log-rank statistic was used to compare dif- had persisted (hazard ratio 1.69, 95% confidence interval ferent curves. Multivariate analysis was performed using a 0.96 to 3.03, p ϭ 0.07). After adjustment for clinical pre- Cox proportional hazards regression model. Stepwise selec- dictive covariates—insulin-requiring diabetes, history of tion was used to identify clinical predictors and p Ͻ0.10 angina before enrollment, and ST-T segment abnormali- was used for removing a variable in constructing the base- ties—resolved Q waves were associated with significantly line clinical model. A highly unbalanced variable—the 2.3-fold higher risk of recurrent events (model 1, Table 2). presence of ST-T segment abnormalities—was forced into QRS fragmentation, independent of Q waves, was not the model. Analyses were performed usingSAS software associated with increased frequency of recurrent events: (version 9.1, SAS Institute, Cary, North Carolina). A univariate hazard ratio of QRS fragmentation presence, in- 2-sided p Ͻ0.05 was considered statistically significant. dependently of Q waves was 1.09 (95% confidence interval Coronary Artery Disease/QRS Fragmentation and Cardiac Events 585

Figure 2. Probability of recurrent cardiac event in patients with resolved and persistent Q waves.

Table 2 ates, presence of only QRS fragmentation was associated Risk of recurrent coronary events for different ECG parameters with more than a twofold increase in risk of recurrent Hazard 95% Confidence p events (model 3, Table 2). Ratio Interval Value Model 1 Discussion Resolved Q wave (vs persistent 2.33 1.25–4.17 0.007 Our analysis of patients with Q-wave MI showed that pres- Q wave) ence of persistent Q waves on the ECG in the stable postin- Model 2 Any QRS complex fragmentation 0.93 0.54–1.60 0.79 farction period (2 months after MI on average) is associated (vs absence of QRS with a more favorable prognosis compared with patients fragmentation) with resolved Q waves. In patients with resolved Q waves, Model 3 fragmentation of the QRS complex, identified indepen- Persistent Q wave 1.0 — — dently of the presence of Q waves, was associated with Resolved Q waves with no QRS 1.64 0.61–4.39 0.53 increased risk of cardiac events. The risk of the patients who complex fragmentation had resolved Q waves and did not have QRS complex Resolved Q waves with QRS 2.68 1.38–5.20 0.004 fragmentation was similar to the risk of patients with per- complex fragmentation sistent Q waves. All models are adjusted for diabetes mellitus, angina pectoris before the Presence of QRS complex fragmentation has been pre- enrollment, and ST-T segment changes. viously evaluated. Varriale and Chryssos8 suggested that RSR= complex Ն110 ms, unrelated to right branch bundle block or left 0.64 to 1.84, p ϭ 0.74). After adjustment for insulin-requir- branch bundle block could be associated with myocardial ing diabetes mellitus, history of angina before enrollment, scar. Bayes de Luna9 suggested that abnormalities of the and presence of ST-T segment changes, presence of any second half of the QRS complex (terminal slurring, some- QRS fragmentation was not predictive for recurrent cardiac times with r= in lead V1) during MI might represent necrosis events (model 2, Table 2). in late depolarized basal zones. Similarly, Das et al10 re- Among patients with resolved Q waves, those with frag- cently suggested that significant fragmentation of the QRS mented QRS expressed a higher rate of recurrent events complex Ͻ120 ms was associated with better sensitivity and compared with the remainder of patients with lost Q waves specificity in detecting myocardial scar. Gardner et al11 and those with persistent Q waves (Figure 3). Univariate proposed that fractionated ECGs were associated with dis- hazard ratio of presence of only QRS fragmentation was tortion and separation of individual myocardial fibers by 2.36 (95% confidence interval 1.23 to 4.50, p ϭ 0.009), fibrous tissue in healed post-MI scars. compared with patients with no fragmentation of the QRS In our analysis, QRS fragmentation associated with res- complex (hazard ratio 1.01, 95% confidence interval 0.40 olution of Q waves was predictive of recurrent events. This to 2.56, p ϭ 0.98) and patients with persistent Q waves as could suggest that fragmentation of the QRS complex in a reference group. After adjustment for clinical covari- patients with resolved Q waves represents less stable myo- 586 The American Journal of Cardiology (www.AJConline.org)

Figure 3. Probability of recurrent cardiac events in patients with resolved Q waves with and without QRS fragmentation, and in patients with persistent Q waves. cardium, compared with those with completely resolved Q transmular acute myocardial infarction. Am J Cardiol 1988; waves and who did not have fragmentation of the QRS 61:739–742. complex. 4. Yasuda M, Iida H, Itagane H, Tahara A, Toda I, Akioka K, Teragaki M, Oku H, Tekeuchi K, Takeda T, et al. Significance of Q wave In previous studies, resolution of Q waves was not as- disappearance in the chronic phase following transmural acute myo- sociated with significant changes in mortality, and it has cardial infarction. Jp Circ J 1990;54:1517–1524. been shown that patients with resolved Q waves had smaller 5. Marcus EB, Yano K, MacLean CJ. Regression of Q waves follow- infarcts sizes, more viable myocardium, and more myocar- ing acute myocardial infarction. Am J Epidemiol 1989;129: dial stunning/hibernation.2–6 Presence of QRS fragmenta- 105–111. 6. Wasserman AG, Bren GB, Ross AM, Richardson DW, Hutchinson tion might identify scar within hibernated/viable myocar- RG, Rios JC. Prognostic implications of diagnostic Q waves after dium after resolution of Q waves. To identify the correlation myocardial infarction. Circulation 1982;65:1451–1455. between this electrocardiographic parameter and ischemic 7. Moss AJ, Goldstein RE, Hall WJ, Bigger JT Jr, Fleiss JL, Green- or necrotic myocardial changes, magnetic resonance image berg H, Bodenheimer M, Krone RJ, Marcus FI, Wackers FJ, et al. evaluation would be necessary, which was not available in Detection and significance of myocardial ischemia in stable patients this retrospective study. Current aggressive treatment of MI after recovery from an acute coronary event. JAMA 1992;269: 2379–2385. contributes to faster and more frequent resolution of Q 8. Varriale P, Chryssos BE.The RSR= complex not related to right bundle waves and the clinical and prognostic role of QRS fragmen- branch block diagnostic value as a sign of myocardial scar. Am Heart J tation in such patients would be of interest. 1992;123:369–376. 9. Antonio Bayes De Luna. Electrographic patterns of ischemia, injury 1. Abdulla J, Brendorp B, Torp- Pedersen C, Kober L, for the TRACE and necrosis. In: Antonio Bayes De Luna, ed. Clinical Electrocardi- study group (TRAndolapril Cardiac Evaluation). Does the electrocar- ography: A Textbook. 2nd Edition. Armonk, NY: Futura Publishing diographic presence of Q waves influence the survival of patients with Company, Inc., 1998:141–142. acute myocardial infarction? Eur Heart J 2001;22:1008–1014. 10. Das MK, Khan B, Jacob S, Kumar A, Mahenthiran J. Significance of 2. Voon WC, Chen YW, Hsu CC, Lai WT, Sheu SH. Q wave regression a fragmented QRS complex versus a Q wave in patients with coronary after acute myocardial infarction assessed by Tl-201 myocardial per- artery disease. Circulation 2006;113:2495–2501. fusion SPECT. J Nucl Cardiol 2004;11:165–170. 11. Gardner PI, Ursell PC, Fenoglio JJ Jr, Wit AL. Electrophysiologic and 3. Coll S, Betriu A, de Flores T, Roig E, Sanz G, Mont L, Magrina J, anatomic basis for fractionated electrocardiograms recorded from Serra A, Navarro Lopez F. Significance of Q-wave regression after healed myocardial infarcts. Circulation 1985;72:596–611. Usefulness of Noninvasive Cardiac Imaging Using Dual-Source Computed Tomography in an Unselected Population With High Prevalence of Coronary Artery Disease

Martin Heuschmid, MDa,*, Christof Burgstahler, MDb, Anja Reimann, MDa, Harald Brodoefel, MDa, Ines Mysal, MSa, Ellen Haeberle, MSb, Ilijas Tsiﬂikas, MDa, Claus D. Claussen, MDa, Andreas F. Kopp, MDa, and Stephen Schroeder, MDb

The aim of the present study was to evaluate the diagnostic accuracy of a new dual-source computed tomographic scanner generation with 83-ms temporal resolution in cardiac imaging. Fifty-one unselected consecutive patients (mean age 64 ؎ 10 years) scheduled for invasive coronary angiography because of suspected or known coronary artery disease (CAD) were examined with dual-source computed tomography (DSCT). All coronary segments were analyzed regarding the presence of coronary artery lesions. The findings were compared with invasive coronary angiography. During computed tomographic examination, mean heart rate was 65 ؎ 14 beats/min. Thirteen of 51 patients (25%) did not have sinus rhythm. Mean Agatston score equivalent was 779 (median 358, range 0 to 3,898). Prevalence of CAD was 75%. Based on a coronary segment model, sensitivity was 96%, specificity 87%, positive predictive value 61%, and negative predictive value 99% for the detection of significant lesions (>50% diameter stenosis). The main reason for false-positive results was an overestimation of mild lesions by DSCT. In conclusion, our initial data indicate that DSCT allows a high accuracy to exclude relevant coronary stenosis in unselected patients with a high prevalence of CAD and a relevant number with heart rhythm irregularities. However, overestimation of stenosis, especially in cases of calcifications, is still a limitation. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007; 100:587–592)

Sixteen- and 64-slice multidetector computed tomography coronary angiography because of suspected CAD or sus- (MDCT) has allowed a robust visualization of the entire pected worsening of known CAD. Exclusion criteria were coronary tree and has shown a high negative predictive elevated serum creatinine levels Ͼ1.5 mg/dl, unstable an- value to exclude the presence of significant coronary artery gina, thyroid disease, pregnancy, or patients with previous disease (CAD) in patients with low to intermediate pretest allergic reactions to iodinated contrast agents. Thirty-three probability.1–7 However, various limitations and challenges of/51 (65%) patients were on daily ␤-blocker medication. remain despite all technical innovations in MDCT.8–11 At Additional ␤-blocker medication was not administered. The present, a new scanner generation with 2 x-ray tubes and local ethics committee approved the study protocol, and all detectors (dual-source computed tomography [DSCT]) of- patients gave informed consent to participate in this study. fers an alternative approach to improve temporal resolu- A dual-source computed tomographic (CT) scanner 12–14 tion. Therefore, the purpose of the present study was to (SOMATOM Definition, Siemens Medical Solutions, evaluate the diagnostic accuracy of new DSCT in un- Forchheim, Germany) was used for all CT examinations selected patients with a high prevalence of CAD, irregular with patients in the supine position. To determine the total heart rate, and extensive calcific deposits. Invasive coronary calcium burden, a retrospectively electrocardiographically- angiography was used as reference standard in all patients. gated noncontrast enhanced scan was performed (1.2 mm collimation, 120 kV tube voltage, Electrocardiographically- Methods modulated tube current with maximum of 200 mAeff). Cir- Fifty-one consecutive patients (37 men, 14 women; mean culation time was determined using a test bolus with 20 ml age 64 Ϯ 10 years) were investigated in the present study. of contrast media (400 mg iodine/ml; Imeron 400 Altana, They were recruited from inpatients scheduled for invasive Konstanz, Germany) and a 40-ml saline chaser bolus (flow rate 5 ml/s) with a dual-head injector (CT Stellant; Medrad, Indianola, Pennsylvania). For dual-source CT angiography, a b Departments of Diagnostic Radiology and Cardiology, University the following scan protocol was used: 0.6-mm collimation Hospital Tuebingen, Tuebingen, Germany. Manuscript received December (cardiac mode), 120-kV tube voltage, 330-ms gantry rota- 14, 2006; revised manuscript received and accepted March 15, 2007. *Corresponding author: Tel: 49-7071-298-2087; fax: 49-7071-295- tion time, and pitch 0.2 to 0.43 (automatically adapted to the 845. patients’ heart rate). Tube current for both tubes was 560 E-mail address: [email protected] (M. Heu- mA. For dose reduction, the tube current was electrocardio- schmid). graphically modulated and reduced during the systolic

Table 1 Table 2 Diagnostic accuracy of dual-source computed tomography (DSCT) Patient characteristics (n ϭ 51) Age (yrs) 64 Ϯ 10 Coronary Artery Right Left Left Anterior Left Men/women 37/14 Coronary Main Descending Circumflex Heart rate (beats/min) 65 Ϯ 14 (43–117) Artery Body mass index (kg/m2) 28 Ϯ 4 (19–40) Ն Risk factors 3.4 Ϯ 1.3 Lesions 50% in 35 2 50 22 Total calcium score (Agatston Score Equivalent) 779 Ϯ 996 (0–3898) coronary Calcium score* angiography Right coronary artery 294 Ϯ 437 (0–1,933) Sensitivity (%) 94 100 98 95 Left main 56 Ϯ 105 (0–155) Specificity (%) 91 92 85 85 Left anterior descending 288 Ϯ 386 (0–681) Positive predictive 69 33 63 54 Left circumflex 141 Ϯ 251 (0–1,128) value (%) Total calcium mass (mg calciumhydroxyapatit) 149 Ϯ 191 (0–768) Negative predictive 99 100 99 99 Indication for invasive coronary angiography value (%) Suspicion of coronary artery disease 22/51 (43%) True positive 33 2 49 21 Suspicion of restenosis 29/51 (57%) False positive 15 4 29 18 Prevalence of coronary artery disease 75% True negative 145 45 161 106 False negative 2 0 1 1 Variables are presented as mean Ϯ SD (range). Categorical data are presented with absolute frequencies. Detection of significant coronary lesions using DSCT in comparison * Agaston Score Equivalent. with invasive coronary angiography (per vessel analysis).

diagnostically limited due to motion artifacts; and 6, vascu- phases, but maintained at maximum during the diastolic lar stent. Lesions with a vessel stenosis Ն50% were in- phase of the cardiac cycle. According to the patients’ heart cluded in the analysis. Using a modified classification of the rate, the following electrocardiographic pulsing was American Heart Association, all coronary vessel segments adapted automatically for maximum tube current within the were documented separately (right coronary artery: 1, prox- Ͻ RR interval: 60% to 70% ( 50 beats/min), 55% to 70% (51 imal; 2, middle; 3, distal; and 4, combined posterior de- to 60 beats/min), 35% to 70% (61 to 119 beats/min), and scending and posterolateral branches; 5, left main stem; left Ͼ 20% to 75% ( 120 beats/min). Contrast media (70 ml; in anterior descending: 6, proximal; 7, middle; 8, distal; 9, first patients with coronary artery bypass grafts, 90 ml) was diagonal; 10, second diagonal; left circumflex: 11, proxi- injected intravenously with a flow rate of 5 ml/s followed by mal; 12, distal; and 13, first marginal branch).16 a saline chaser bolus (50 ml, flow rate 5 ml/s). Invasive coronary angiograms were obtained within 1 The standard reconstruction window for noncontrast en- day after DSCT. All angiograms were evaluated by an hanced images was set at 60% of the RR interval using a independent, experienced interventional cardiologist using 3-mm effective slice thickness and 1.5-mm reconstruction quantitative coronary analysis with automated vessel con- increment. For CT angiography, the reconstruction interval tour detection. The angiography catheter was used for cal- with the fewest motion artifacts was determined by recon- ibration (Quantitative Coronary Analysis, Philips, Best, The structing a slice at the level of the middle of the left ven- Netherlands). Lesions with a diameter reduction of Ն50% tricle in 5% increments from 25% to 75% of the RR inter- were considered significant. All coronary vessel segments val. CT angiographic images were reconstructed for were included in the statistical analysis. Coronary angiog- diagnostic evaluation to the time point with the least motion raphy was regarded as the reference standard to detect artifact of the right and left coronary arteries. For CT an- relevant vascular stenosis. In coronary segments with Ͼ1 giographic images, an effective slice thickness of 0.75 mm lesion, the lesion with the most severe diameter reduction and a reconstruction increment of 0.4 mm were chosen. determined the diagnostic accuracy. Coronary calcium deposit were assessed visually and In comparison with invasive coronary angiography, dual- determined quantitatively based on the standard built-in source CT results were analyzed on a segmental basis (each algorithm on an off-line workstation (Syngo Multimodality segment in every vessel), per coronary artery (analysis of Workplace Siemens, Siemens, Erlangen, Germany). For the major coronary vessels), and per patient (evaluating the detection of the total calcium burden, Agatston Score presence of any significant stenosis in a given patient). If a Equivalent as well as the total calcium mass in milligrams segment contained Ͼ1 lesion, the most severe lesion deter- of calciumhydroxyapatite were measured. mined the diagnostic accuracy of the assessment. Categor- All data sets were assessed with a joint reading by 2 ical data were presented with absolute frequencies and per- experienced observers who were not aware of the patients’ centages. Continuous variables are shown as means Ϯ SDs. clinical information or the coronary angiographic findings. All analyses were performed using JMP 5.1 SAS Institute In addition to the original axial slices, multiple planar re- Inc. (Cary, North Carolina). construction, sliding thin-slab maximum intensity projection, and 3-dimensional volume rendering were used de- Results pending on the individual case.15 In terms of artifacts and segment visibility, image quality The patient characteristics are listed in Table 1. DSCT and was graded as follows: 1, excellent; 2, good; 3, diagnostic; invasive coronary angiography were performed without 4, diagnostically limited due to severe calcifications; 5, complications in all 51 patients (Figures 1 and 2). The mean Coronary Artery Disease/Cardiac Dual-Source Computed Tomography 589

Figure 1. Sixty-two-year-old man with suspicion of coronary artery disease (risk factors, smoking, arterial hypertension, familial disposition). Mean heart rate during the CT examination was 60 beats/min. Calcium scoring revealed an Agatston Score Equivalent of 358 and a calcium mass of 69 mg of calciumhydroxyapatite. (A) volume rendering of the coronary arteries. Curved maximum intensity projection (MIP) displays the left anterior descending (LAD) (B) and the left circumﬂex (LC) (D) without vascular stenosis. (C) DSCT of the right coronary artery (RCA) with curved MIP reconstruction. Nonrelevant vascular stenosis and wall irregularity of the distal RCA were conﬁrmed by the invasive coronary angiogram (not displayed). 590 The American Journal of Cardiology (www.AJConline.org)

Figure 2. A 65-year-old man (body mass index 31 kg/m2, mean heart rate 84 beats/min) with known 3-vessel coronary artery disease. Extensive calcified plaques of the coronary tree were measured (Agatston Score Equivalent 854, calcium mass 157 mg of calcium hydroxyapatite). In dual-source CT angiography of the left coronary artery, a stenosis of the left anterior descending [(A) coronary angiography, (C) maximum intensity projection (MIP) image, thin arrows] and an occlusion of the left circumflex [(A) coronary angiography, (B) MIP image, small arrows] were diagnosed. heart rate in dual-source CT examinations was 65 Ϯ 14 age quality. The image quality of 95 segments (15%) was beats/min (median 63, range 43 to 117). Thirteen of 51 impaired due to severe calcifications. Furthermore, motion patients (25%) were not in sinus rhythm during the CT scan. artifacts affected the diagnostic evaluation of 22 segments The mean calcium score (Agatston Score Equivalent) (3.5%). was 779 Ϯ 996 (median 358, range 0 to 3,898) and the mean In coronary angiography, 109 lesions with a diameter calcium mass was 149 Ϯ 191 mg of calciumhydroxyapatite stenosis Ն50% were found. DSCT correctly detected 105 of (median 69, range 0 to 768) (Table 1). 109 of these lesions Ն50%. Due to insufficient image qual- The analysis of image quality was based on a total of 663 ity caused by calcifications and motion artifacts, 4 lesions vessel segments. Thirty-one segments with stents were not were not assessed in DSCT. Sixty-six lesions with a diam- diagnostically assessed and subsequently excluded from the eter stenosis Ͻ50%, according to the reference standard analyses. Therefore, 632 of 663 segments were evaluated invasive coronary angiography, were overestimated by regarding image quality. In summary, 515 of 632 segments DSCT and thus considered as false-positive findings. (81.5%) had acceptable image quality, whereas in 117 seg- On a per-segment basis, sensitivity was 96%, specificity ments (18.5%), the vessel lumen of the coronary segments 87%, positive predictive value was 61%, and negative pre- were insufficiently assessed. Image quality was graded as dictive value 99% (Table 2). A total of 204 vessels were excellent in 147 coronary segments (23.3%) and as good in analyzed. On a per-artery basis, DSCT revealed a sensitivity 226 coronary segments (35.7%). One hundred forty-two of 96%, specificity of 78%, a positive predictive value of segments (22.5%) were considered to have diagnostic im- 68%, and a negative predictive value of 97%. DSCT cor- Coronary Artery Disease/Cardiac Dual-Source Computed Tomography 591 rectly detected significant CAD in 50 of 51 patients. In 1 with a high prevalence of CAD. When comparing these patient, a significant stenosis located in the distal left cir- results to 16- and 64-slice MDCT, the negative predictive cumflex artery was not diagnosed with DSCT. On a per- value is high in all studies, whereas our results have shown patient analysis, sensitivity of DSCT was 97%, specificity a low positive predictive value in DSCT.5,6,27,28 However, 73%, the positive predictive value was 90%, and the nega- we used DSCT in a clinical setting with unselected patients tive predictive value 92%. with high prevalence of disease in conditions that were known to impair image quality. Therefore, our data under- Discussion line that the diagnostic accuracy could be further stabilized by DSCT, allowing a reliable exclusion of CAD. Due to The most important finding of the present study is that different study populations and prevalence of CAD, an image quality in noninvasive cardiac imaging could be exact comparison of our results with the diagnostic accuracy furthermore stabilized by DSCT. The improved image qual- of 64-slice MDCT is difficult.5,6 As indicated by the rela- ity allows also for the examination of patients with higher or tively low positive predictive value in our study, the over- irregular heart rates, as well as of patients with advanced estimation of coronary lesions in case of coronary calcifi- CAD. However, especially as spatial resolution remained cations remained still a limitation of cardiac computed unchanged, coronary calcifications still limit the accuracy of tomography. lesion quantification because of partial volume artifacts. There are some limitations in our study that have to be In patients with increased heart rates (Ͼ80 beats/min) taken into account when interpreting our data. (1) The and arrhythmia (including atrial fibrillation), previous stud- prevalence of CAD was high as all patients had been ies have revealed an impaired image quality with less eval- scheduled for invasive coronary angiography. This pre- uative coronary segments, mainly caused by motion arti- selection might have influenced our results. (2) Because facts due to an insufficient temporal resolution.9,10,17 In stented lesions are still a challenge for DSCT, segments patients with atrial fibrillation or mild heart rate irregulari- with stents were excluded from the analysis. Further ties, image quality could be improved using an “adapted studies should focus on the diagnostic accuracy of DSCT. delay algorithm” with an end-systolic reconstruction win- (3) The number of patients (n ϭ 51) was low, and this dow or manual electrocardiographic editing.18,19 However, was a single center experience. Further studies with mul- despite all technical improvements, high heart rate as well ticenter design are required to evaluate clinical indica- 20 as heart rate irregularities remained a limitation of MDCT. tions of DSCT. In DSCT, temporal resolution is independent of heart rate. The initial clinical experience using DSCT underlined 1. Nieman K, Rensing BJ, van Geuns RJ, Munne A, Ligthart JM, Pat- that the improved temporal resolution resulted in a more tynama M, Krestin GP, Serruys PW, de Feyter PJ. Usefulness of robust image quality within a wide range of heart rates.13,14 multislice computed tomography for detecting obstructive coronary In our study, most patients (65%) were on long-term oral artery disease. Am J Cardiol 2002;89:913–918. ␤-blocker therapy, but no additional ␤ blocker was admin- 2. Kuettner A, Trabold T, Schroeder S, Feyer A, Beck T, Brueckner A, Heuschmid M, Burgstahler C, Kopp AF, Claussen CD. Noninvasive istered before the CT scans. The mean heart rate during detection of coronary lesions using 16-detector multislice spiral com- DSCT scan was 65 beats/min (median 63, range 43 to 119) puted tomography technology: initial clinical results. J Am Coll Car- in our population. diol 2004;44:1230–1237. The optimal time point for image data reconstruction is 3. Nikolaou K, Flohr T, Knez A, Rist C, Wintersperger B, Johnson T, influenced by the heart rate. For 16- and 64-slice MDCT, Reiser MF, Becker CR. Advances in cardiac CT imaging: 64-slice scanner. Int J Cardiovasc Imaging 2004;20:535–540. the best image quality was achieved using mid-diastolic 4. Leschka S, Alkadhi H, Plass A, Desbiolles L, Grunenfelder J, time points in patients with low or moderate heart rate and Marincek B, Wildermuth S. Accuracy of MSCT coronary angiography in end-systolic and early-diastolic intervals in patients with with 64-slice technology: first experience. Eur Heart J 2005;26:1482– high heart rates.20–24 Our results indicate that image recon- 1487. struction windows with best image quality will be toward 5. Raff GL, Gallagher MJ, O’Neill WW, Goldstein JA. Diagnostic accuracy of noninvasive coronary angiography using 64-slice spiral end-systole using DSCT, especially in patients with higher computed tomography. J Am Coll Cardiol 2005;46:552–557. heart rates. 6. Mollet NR, Cademartiri F, van Mieghem CA, Runza G, McFadden EP, In cardiac MDCT, the diagnostic accuracy and image Baks T, Serruys PW, Krestin GP, de Feyter PJ. High-resolution spiral quality is mainly limited by coronary calcifications and computed tomography coronary angiography in patients referred for 25 diagnostic conventional coronary angiography. Circulation 2005;112: motion artifacts. Optimized temporal resolution through 2318–2323. faster gantry rotation speed, as well as multisegmental re- 7. Hendel RC, Patel MR, Kramer CM, Poon M, Hendel RC, Carr JC, construction algorithms, have been conducive to improved Gerstad NA, Gillam LD, Hodgson JM, Kim RJ, et al. ACCF/ACR/ diagnostic accuracy.8,26 Our findings using DSCT in an SCCT/SCMR/ASNC/ NASCI/SCAI/SIR 2006 appropriateness criteria unselected cohort suggest a further stabilization of image for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the American College of Cardiology Foundation quality with 81.5% segments with good and 18.5% coronary Quality Strategic Directions Committee Appropriateness Criteria segments with impaired image quality (15% coronary cal- Working Group, American College of Radiology, Society of Cardio- cifications, 3.5% motion artifacts). However, the proportion vascular Computed Tomography, Society for Cardiovascular Magnetic of segments with impaired image quality due to vascular Resonance, American Society of Nuclear Cardiology, North American calcifications was virtually the same as described by the use Society for Cardiac Imaging, Society for Cardiovascular Angiography 2 and Interventions, and Society of Interventional Radiology. J Am Coll of 16-slice MDCT. Cardiol 2006;48:1475–1497. DSCT revealed a high diagnostic accuracy in the detec- 8. Kuettner A, Beck T, Drosch T, Kettering K, Heuschmid M, Burg- tion of significant coronary lesions in unselected patients stahler C, Claussen CD, Kopp AF, Schroeder S. Diagnostic accuracy 592 The American Journal of Cardiology (www.AJConline.org)

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Hongyu Shi, MDa,b,*, Junbo Ge, MDa, Weiyi Fang, MDb, Kang Yao, MDa, Aijun Sun, PhDa, Rongchong Huang, MDa, Qingzhe Jia, MDa, Keqiang Wang, MBsa, Yunzeng Zou, MDa, and Xuetao Cao, MDc

Accumulating evidence suggests that an imbalance in T-helper type 1 (Th1)/Th2 response with enhanced Th1 immune response has an important role in the process of coronary artery disease (CAD). Dendritic cell (DC) subsets, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), could regulate immune reactions by polarizing naive T-helper cells into Th1 or Th2 effector cells. In this study, total peripheral-blood DCs and mDC and pDC subsets were examined in patients with coronary heart disease. Thirty-two men who underwent and control (21 ؍ coronary angiography for chest pain were divided into the CAD group (n Peripheral-blood DCs and DC .(11 ؍ group (normal coronary angiographic results, n subsets were detected using a 3-color flow cytometry technique. DCs were defined as -Lin1؊HLA-DR؉; mDCs, as Lin1؊HLA-DR؉CD11c؉; and pDCs, as Lin1؊HLA DR؉CD123؉. The absolute number of peripheral-blood DCs was significantly higher in the The mDC fraction in terms of .(0.04 ؍ CAD group compared with the control group (p both percentage and absolute number was also significantly increased in the CAD group compared with the control group (all p <0.05), whereas the pDC fraction was similar between the 2 groups (p >0.05). The mDC/pDC ratio was significantly increased in the In conclusion, total peripheral-blood DCs .(0.01 ؍ CAD group than in the control group (p are significantly higher in patients with CAD because of an increase in mDC subset, which might contribute to enhanced Th1 response in patients with CAD. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:593–597)

Accumulating evidence suggests that an imbalance in T- humans.10 The mDCs (also called DC1), derived from my- helper type 1 (Th1)/Th2 response with enhanced Th1 im- eloid precursors, express cell markers CD11c, CD13, and mune response induced by various antigens, such as oxi- CD33 and produce high levels of interleukin-12 when stim- dized low-density lipoprotein and heat-shock proteins, has ulated with tumor necrosis factor-␣ or CD40 ligand and an important role in the process of coronary artery disease drive a potent Th1-polarized immune response. The pDCs (CAD).1–6 Dendritic cells (DCs) are the most potent anti- (also called DC2) originate from lymphoid precursors and gen-presenting cells, with the unique ability to initiate a can elicit an interleukin-4–independent Th2 polarization of primary immune response to certain antigens by activation naive T cells. mDCs and pDCs are considered to be spe- of “naive” T cells,7 and are actively related to the process of cialized antigen-presenting cells preferentially inducing a atherosclerosis.8 Upon antigen encounter, immature DCs Th1 and Th2 response, respectively.11–13 To see whether the become mature, characterized by decreased phagocytic ac- balance between mDCs and pDCs is altered in patients with tivity and upregulated expression of costimulatory mole- CAD, we examined numbers of peripheral-blood DCs, cules and mature markers, and secrete large amounts of such mDCs, and pDCs in men with CAD and controls without immunostimulatory cytokines as interleukin-12 and further CAD. magnify the T response.9 Two DC subsets, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), were identiﬁed in Methods This investigation was performed with approval of the Eth- aShanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, ics Committee of Zhongshan.Hospital, Fudan University, Fudan University; bShanghai Chest Hospital, Jiaotong University; and People’s Republic of China. Informed consent was obtained cInstitute of Immunology, Second Military Medical University, Shanghai, from all subjects. Thirty-two men who underwent coronary People’s Republic of China. Manuscript received February 5, 2007; re- artery angiography for chest pain from July 2005 to October vised manuscript received and accepted March 19, 2007. 2005 were divided into the CAD group (Ն1 coronary artery This work was supported by the Major State Basic Research Develop- stenosis Ͼ50% detected using coronary angiography, n ϭ ment Program (G2000056903), Beijing; 863 Program of Science and 21) and the control group (normal coronary angiography Technology Ministry (2006AA0ZA406), Beijing, and the Science and ϭ Technology Committee of Shanghai (02 JC14026), Shanghai, Peoples results, n 11). Exclusion criteria for this study included Republic of China. patients with acute myocardial infarction within 2 weeks, *Corresponding author: Tel.: 86-21-6404-1990-2745; fax: 21-6422- troponin-I or troponin-T Ͼ0.1 ng/ml, previous coronary 3006. stent implant, heart failure with New York Heart Associa- E-mail address: [email protected] (J. Ge). tion class III and IV, and chronic or acute infections, auto-

Figure 1. Standardized 3-color flow cytometry assay for percentages of mDCs and pDCs in peripheral blood from a patient with coronary disease. (A) Events excluding debris and dead cells (R1); (B) cells were gated on region R1, a dot blot of lineage marker (x axis) versus HLA-DR (y axis) was used to define the region of LinϪ cells (R2); (C) pDC was defined as LinϪ, HLA-DRϩ, and CD123ϩ (R4); (D) mDC was defined as LinϪ, HLA-DRϩ, and CD11cϩ (R5). FITC ϭ fluorescein isothiocyanate; FSC-H ϭ forward scatter; PE ϭ peripheral. immune diseases, neoplastic disease, advanced liver dis- cells were first stained with monoclonal antibodies, fol- ease, and renal diseases to avoid possible interference of lowed by lysing of erythrocytes. Briefly, blood cells were these conditions on peripheral DCs.14–16 incubated with antigen-presenting cell–, phycoerythrin-, Blood was obtained from all patients while in the recum- peridinin chlorophyll protein–, and fluorescent isothiocya- bent position with a 21-gauge needle using antecubital ve- nate–conjugated monoclonal antibodies for 20 minutes at nipuncture soon after admission. White blood cells, choles- room temperature. Erythrocytes were then lysed with FACS terol, glucose, and creatine kinase were measured according lysing solution (Becton Dickinson). For gating Lin1ϪHLA- to routine protocols. DRϩ cells, whole peripheral-blood cells were stained with Phycoerythrin-conjugated CD11c, phycoerythrin-conju- anti–HLA-DR monoclonal antibody and the lineage cock- gated anti– interleukin-3 receptor a chain (CD123), peri- tail. After washing with FACS flow, stained cells were dinin chlorophyll protein–conjugated anti–HLA-DR, and analyzed using a FACS Caliber flow cytometer and fluorescent isothiocyanate–conjugated lineage cocktail 1 CellQuest Pro software (Becton Dickinson). containing monoclonal antibodies CD3 (T cells), CD14 DCs were defined as cells positive for peridinin chloro- (monocytes/macrophages), CD16 (natural killer cells), phyll protein–conjugated anti–HLA-DR monoclonal anti- CD19 (B cells), and CD56 (natural killer cells) were pur- body and negative for fluorescent isothiocyanate–conju- chased from Becton Dickinson (San Jose, California). Phy- gated Lin1 monoclonal antibodies. The number of total coerythrin-conjugated isotype control murine monoclonal white blood cells in samples was determined using an au- antibodies were also obtained from Becton Dickinson. tomated cell counter. In gated cells, we further defined Peripheral-blood cells obtained from patients in a pro- CD11c and CD123 expression to determine the 2 distinct spective manner were analyzed using 3-color flow cytom- DC lineages. mDCs and pDCs were defined as Lin1ϪHLA- etry. All blood samples were collected in the morning. To DRϩCD11cϩ and Lin1ϪHLA-DRϩCD123ϩ, respectively. minimize selective loss during the preparation procedure, Representative profiles of CD11c and CD123 on peripheral- Coronary Artery Disease/Peripheral Dendritic Cells and CHD 595

Table 1 blood DCs from a patient with CAD are shown in Figure 1. Clinical characteristics Absolute numbers of mDCs and pDCs were calculated from Control Group CAD the white blood cell count multiplied by the proportion of Group each subset within white blood cells. Percentages of mDCs and pDCs were derived from the total number of DCs, (n ϭ 11) (n ϭ 21) Age (yrs) 56 Ϯ 862Ϯ 10 determined using flow cytometric analysis. Risk factors Statistical analyses were performed using unpaired Stu- Hypertension 5 15 dent’s t test or Mann-Whitney U test when indicated and Smoking 9 16 chi-square test to compare differences in the 2 groups. A p Diabetes 2 5 value Ͻ0.05 was considered statistically significant. Corre- Hyperlipidemia* 4 2 lation between variables was analyzed using linear regres- Laboratory findings sion analysis. Total cholesterol (mmol/L 4.0 Ϯ 0.6 4.0 Ϯ 1.0 [mg/dl]) [154 Ϯ 23] [154 Ϯ 38] Low-density lipoprotein 2.1 Ϯ 0.6 2.4 Ϯ 0.9 Results Ϯ Ϯ cholesterol (mmol/L [81 23] [92 35] Clinical characteristics were similar between the CAD and [mg/dl]) control groups, except for more ␤-blocker use in the CAD High-density lipoprotein 1.0 Ϯ 0.2 0.9 Ϯ 0.2 cholesterol (mmol/L [40 Ϯ 8] [35 Ϯ 8] group than the control group (Table 1). [mg/dl]) Total numbers and percentages of DCs and both subsets Triglycerides (mmol/L) 2.0 Ϯ 1.2 1.5 Ϯ 0.7 in both groups are shown in Figure 2. Percentages of DCs Lipoprotein(a) (mg/l) 84 Ϯ 66 171 Ϯ 182 tended to be higher in the CAD group compared with the White blood cells (109/L) 6.5 Ϯ 1.5 6.6 Ϯ 2.2 control group (Figure 2;pϭ 0.07). Total DC number was Lymphocytes (%) 32 Ϯ 15 30 Ϯ 15 significantly higher in the CAD group than the control Medication group (Figure 2;pϽ0.05). Percentage and total number of Aspirin 8 16 the mDC fraction were significantly increased in the CAD ␤ † Blockers 5 17 group compared with the control group (Figure 2;;all p ACE inhibitor/ARB 6 13 Ͻ0.05), whereas the percentage and total;number of the Statins 5 12 pDC fraction were similar between the 2 groups (Figure 2; Fibrates 1 0 Ͼ Calcium, channel blockers 1 6 all p 0.05). mDC/pDC ratio was significantly higher in the CAD group than the control group (Figure 3;pϭ 0.01). * Defined as increase in total cholesterol (Ͼ220 mg/dl or 5.72 mmol/L) There were no relations among diseased vessel numbers and Ͼ or triglycerides ( 200 mg/dl or 2.0 mmol/L). DC, mDC, and pDC numbers (Table 2; all p Ͼ0.05). † p Ͻ0.05 compared with control group. ACE ϭ angiotensin-converting enzyme; ARB ϭ angiotensin II receptor blocker. Discussion In the present study, we observed significantly increased total peripheral DC and mDC numbers and an apparent

Figure 2. Percentages and absolute numbers of peripheral-blood (pb) DCs, mDCs, and pDCs in patients with CAD compared with controls. (A)Percentages and (B) absolute numbers of DCs, mDCs (C, D, respectively), and(E, F, respectively) DCs in peripheral blood of patients with CAD (n ϭ 21) compared with controls (n ϭ 11). Horizontal lines, mean values. 596 The American Journal of Cardiology (www.AJConline.org)

Table 2 Relation between peripheral-blood dendritic cells (DCs) and diseased coronary vessels No. of Diseased Vessels pDCs (%) pDCs mDCs (%) mDCs mDC/pDC Ratio Total DCs (%) A(nϭ 9) 0.05 Ϯ 0.03 0.31 Ϯ 0.16 0.25 Ϯ 0.09 1.56 Ϯ 0.55 5.66 Ϯ 1.88 0.30 Ϯ 0.11 B(nϭ 6) 0.08 Ϯ 0.04 0.55 Ϯ 0.35 0.32 Ϯ 0.11 2.12 Ϯ 0.64 4.65 Ϯ 1.99 0.40 Ϯ 0.14 C(nϭ 6) 0.07 Ϯ 0.04 0.40 Ϯ 0.23 0.31 Ϯ 0.19 1.87 Ϯ 1.00 5.07 Ϯ 1.38 0.38 Ϯ 0.24

All p Ͼ0.05.

numbers were detected, whereas maturation markers or functional activation of circulating DCs were not investigated and warrant further studies. However, this study is the ﬁrst to observe the distribution of DCs and subsets in Chi- nese men with CAD. More detailed studies are required to elucidate the inﬂuences of cardiovascular drugs (e.g., statins and ␤ blockers) on circulating DCs and DC subsets in patients with CAD.

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Theodore Chow, MDa,*, Sayed Saghir, MDa, Cheryl Bartone, BSa, Megan Goebel, BSa, Julia Schneidera, Terri Booth, RNa, and Paul S. Chan, MD, MScb

Microvolt T-wave alternans (MTWA) was proposed as an effective tool to identify high-risk patients with ischemic cardiomyopathy. However, previous studies suggested that the prognostic utility of MTWA may be limited to only patients with normal QRS duration. It therefore was assessed whether MTWA and QRS duration >120 ms independently predict mortality in patients with ischemic cardiomyopathy and whether the prognostic utility of MTWA differs by QRS duration. A total of 768 consecutive patients with ischemic cardiomyopathy (left ventricular ejection fraction <35%) and no history of ventricular arrhythmia were enrolled, of whom 514 (67%) screened MTWA non-negative (positive or indeterminate) and 223 (29%) had a QRS >120 ms on resting electrocardiogram. After multivariable adjustment, a non-negative MTWA test result was associated with a significantly higher risk for all-cause mortality in patients without an implantable cardioverter- ؍ defibrillator (ICD) (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.22 to 4.24, p 0.01) and for all-cause mortality and appropriate ICD shocks in patients with an ICD (HR In contrast, a QRS >120 ms was not associated with .(0.04 ؍ CI 1.07 to 5.41, p 95% ,2.42 all-cause mortality and ICD shocks in patients without (HR 0.96, 95% CI 0.52 to 1.75, p No significant interaction .(0.40 ؍ or with an ICD (HR 1.25, 95% CI 0.76 to 2.08, p (0.88 ؍ In .(0.73 ؍ ICD p ,0.19 ؍ was found between MTWA and QRS >120 ms (non-ICD p conclusion, MTWA, but not QRS duration, predicted mortality outcomes in patients with ischemic cardiomyopathy. Moreover, the prognostic utility of MTWA did not appear to differ by QRS duration. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100: 598–604)

There is growing evidence that microvolt T-wave alternans cardiomyopathy and prolonged QRS duration may require (MTWA) may effectively risk-stratify patients at risk of reassessment.4 We therefore evaluated MTWA and QRS arrhythmias. A recent meta-analysis of MTWA showed that duration as independent predictors of mortality in a large patients with non-negative (positive and indeterminate) cohort of patients with ischemic cardiomyopathy and exam- MTWA study results had a more than threefold risk of ined whether the prognostic utility of MTWA differed sig- arrhythmic events.1 More recent studies showed that nificantly by QRS duration (i.e., whether there was a sig- MTWA was an independent predictor of outcome in pa- nificant interaction between these 2 variables) in patients tients with ischemic cardiomyopathy after adjustment for with and without an implantable cardioverter-defibrillator demographic, clinical, and medication treatment variables.2 (ICD). It was suggested that the presence of a wide QRS may diminish the prognostic utility of MTWA test results.3 Should this be true, the role of MTWA screening to deter- Methods mine sudden cardiac death risk in a patient with ischemic The study design was previously described.2,5 Briefly, consecutive patients with ischemic cardiomyopathy were prospectively enrolled into a large MTWA registry from aThe Lindner Clinical Trial Center, Christ Hospital and Ohio Heart and March 2001 to June 2004. Patients were enrolled from 7 Vascular Center, Cincinnati, Ohio; and bVA Health Services Research and outpatient cardiology clinics of a single specialty cardi- Development and University of Michigan Medical School, Ann Arbor, ology practice (Ohio Heart and Vascular Center, Cincin- Michigan. Manuscript received February 4, 2007; revised manuscript re- nati, Ohio). For this study, only patients with ischemic ceived and accepted March 19, 2007. heart disease (defined as cardiac catheterization with This work was supported in part by Medtronic, Minneapolis, Minne- Ն70% stenosis in Ն1 coronary vessel, documented myo- sota. Dr. Chan is supported by a Cardiovascular Multidisciplinary Research cardial infarction, or history of coronary revasculariza- Training Grant from the National Institutes of Health, Bethesda, Maryland, Յ and by the Ruth L. Kirchstein Research Service Award, Bethesda, Mary- tion) and left ventricular ejection fraction (LVEF) 35% land. None of the sponsors had any involvement in the design, collection, were included. Patients had to be in normal sinus rhythm management, or analysis of the study or in manuscript preparation. for MTWA testing, and those with a previous ventricular *Corresponding author: Tel.: 734-936-8214; fax: 734-761-2939. arrhythmia (including sustained ventricular tachycardia) E-mail address: [email protected] (P.S. Chan). were excluded. The study was approved by the institu-

Table 1 Baseline characteristics of the non–implantable cardioverter-defibrillator cohort stratified by microvolt T-wave alternans (MTWA) and QRS duration Variable ECGϪ/MTWAϪ ECGϩ/MTWAϪ ECGϪ/MTWAϩ ECGϩ/MTWAϩ (n ϭ 146) (n ϭ 33) (n ϭ 141) (n ϭ 56) Mean follow-up 580 Ϯ 325 546 Ϯ 246 552 Ϯ 317 509 Ϯ 306 Age (yrs)*† 63.5 Ϯ 10.5 72.2 Ϯ 10.1 67.6 Ϯ 11.0 74.6 Ϯ 8.0 Men 83% 73% 79% 71% LVEF (%)*† 29.7 Ϯ 5.6 27.9 Ϯ 4.7 28.3 Ϯ 6.6 24.7 Ϯ 6.3 Myocardial infarction 88% 76% 80% 75% Hypertension† 33% 42% 33% 43% Diabetes mellitus 38% 21% 39% 50% Heart failure 61% 76% 68% 75% Peripheral–vascular disease 6% 12% 4% 2% Stroke/transient ischemic attack 12% 15% 16% 25% Atrial fibrillation 12% 15% 17% 16% Renal failure 3% 6% 2% 5% Chronic obstructive pulmonary disease 4% 3% 8% 9% Coronary artery bypass surgery 57% 52% 54% 57% Percutaneous transluminal coronary angioplasty 56% 42% 50% 39% Syncope 16% 15% 13% 27% Abnormal Holter*† 1% 6% 11% 25% Medications Aspirin 76% 76% 78% 73% ACE inhibitors or ARB 86% 79% 81% 86% ␤ blockers 83% 85% 75% 79% Statins 64% 70% 52% 59% Spironolactone 12% 12% 14% 20% Digoxin* 21% 21% 33% 32% Diuretics 58% 70% 62% 71% Class 1 antiarrhythmic 0% 0% 1% 0% Class 3 antiarrhythmic 8% 6% 9% 17%

Values expressed as Ϯ SD or percent. *p Ͻ0.05 comparing MTWAϩ versus MTWAϪ patients. †p Ͻ0.05 comparing QRSϩ versus QRSϪ patients. ACE ϭ angiotensin-converting enzyme; ARB ϭ angiotensin receptor blocker; ECG ϭ electrocardiogram. tional review board at The Christ Hospital (Cincinnati, results were defined as nonsustained ventricular tachy- Ohio), and all patients gave informed consent for registry cardia Ͼ100 beats/min for Ն3 consecutive beats and Ͻ30 participation. seconds. A wide QRS duration was defined as Ͼ120 ms, At baseline enrollment, all patients underwent MTWA but QRS durations Ͼ140 and Ͼ160 ms were also ex- testing using treadmill exercise (Heartwave system, Cam- plored in sensitivity analyses. Finally, the decision for bridge Heart, Inc., Bedford, Massachusetts) with increase in ICD implantation in this cohort was at the discretion of heart rate to a target level of 120 beats/min. Use of ␤ the treating physician. blockers and rate-slowing calcium channel blockers was Because patients with and without ICDs have different held for Ͼ24 hours before testing. Standard criteria were risks for arrhythmic events, study end points, such as used for interpretation of MTWA test results.6 Based on death and ICD shock, would have different clinical sig- previous studies showing no difference in prognostic utility nificance for each group. Therefore, we conducted our between patients who test MTWA indeterminate and posi- analyses separately by ICD status. We defined a primary ϩ ϩ tive (MTWA ),1,2,7 indeterminate and MTWA test results end point of all-cause mortality for the non-ICD group were classified as non-negative. and all-cause mortality and appropriate ICD shock ther- Baseline demographics (age and gender), clinical apy for the ICD group. Secondary end points included characteristics (LVEF, QRS duration, diabetes mellitus, cause-specific mortality using a modified Hinkle-Thaler hypertension, symptomatic heart failure, chronic obstruc- system8 in which arrhythmic deaths were defined as un- tive pulmonary disease, chronic renal insufficiency, pe- witnessed deaths (if stable when last observed within 24 ripheral vascular disease, and history of myocardial hours before death), witnessed instantaneous deaths, se- infarction, stroke, transient ischemic attack, atrial fibril- quelae of cardiac arrest, and appropriate ICD shock ther- lation, unexplained syncope, or revascularization therapy (for the ICD group). Adjudication for all primary and apy), medication treatment (aspirin, angiotensin-convert- secondary end points was performed by investigators ing enzyme inhibitor or angiotensin receptor blocker, ␤ blinded to patient covariates, including MTWA status blocker, digoxin, diuretic, class I or III antiarrhythmic and QRS duration. Clinical follow-up for end points was agent, statin, and spironolactone), ICD status, and Holter achieved using quarterly office visits, telephone contact results were obtained for each patient. Abnormal Holter with the patient, review of office charts, and an annual 600 The American Journal of Cardiology (www.AJConline.org)

Table 2 Baseline characteristics of implantable cardioverter-defibrillator cohort stratified by microvolt T-wave alternans (MTWA) and QRS duration Variable ECGϪ/MTWAϪ ECGϩ/MTWAϪ ECGϪ/MTWAϩ ECGϩ/MTWAϩ (n ϭ 53) (n ϭ 22) (n ϭ 205) (n ϭ 112) Mean follow-up 544 Ϯ 394 525 Ϯ 376 554 Ϯ 319 495 Ϯ 295 Age (yrs)*† 62.6 Ϯ 11.2 69.7 Ϯ 7.9 66.3 Ϯ 9.8 69.4 Ϯ 8.9 Men 79% 86% 88% 86% LVEF*† 27.6 Ϯ 5.6 25.0 Ϯ 7.9 26.7 Ϯ 6.0 24.8 Ϯ 6.0 Myocardial infarction 91% 82% 90% 85% Hypertension* 34% 46% 34% 40% Diabetes mellitus 28% 23% 40% 38% Heart failure 76% 91% 73% 80% Peripheral vascular disease 4% 0% 6% 5% Stroke/transient ischemic attack 6% 14% 17% 16% Atrial fibrillation 13% 32% 14% 15% Renal failure 0% 5% 3% 1% Chronic obstructive pulmonary disease 2% 18% 10% 6% Coronary artery bypass surgery 51% 64% 54% 64% Percutaneous transluminal coronary angioplasty 57% 50% 60% 38% Syncope 15% 18% 15% 15% Abnormal Holter*† 17% 18% 16% 19% Medications Aspirin 79% 86% 78% 71% ACE inhibitors or ARB 91% 91% 84% 85% ␤ blockers 87% 77% 83% 88% Statins 74% 59% 64% 65% Spironolactone 26% 27% 18% 17% Digoxin* 32% 32% 42% 49% Diuretics 70% 77% 63% 71% Class 1 antiarrhythmic 4% 0% 50% 0% Class 3 antiarrhythmic 6% 9% 9% 8%

*pϽ0.05 comparing MTWAϩ versus MTWAϪ patients. † p Ͻ0.05 comparing QRSϩ versus QRSϪ patients. Abbreviations as in Table 1.

Table 3 Summary table of study end points stratified by defibrillator status, microvolt T-wave alternans (MTWA) result, and QRS duration Outcomes ECGϪ/MTWAϪ ECGϩ/MTWAϪ ECGϪ/MTWAϩ ECGϩ/MTWAϩ Nondefibrillator (n ϭ 146) (n ϭ 33) (n ϭ 141) (n ϭ 56) Total deaths 9 (6.2%) 6 (18.2%) 30 (21.3%) 13 (23.2%) Arrhythmic 5 (3.4%) 1 (3.0%) 15 (10.6%) 7 (12.5%) Nonarrhythmic 4 (2.7%) 5 (15.2%) 15 (10.6%) 6 (10.7%) Defibrillator (n ϭ 53) (n ϭ 22) (n ϭ 205) (n ϭ 112) Mortality ϩ defibrillator shocks 4 (7.6%) 4 (18.2%) 37 (18.1%) 22 (19.6%) Arrhythmic 2 (3.8%) 3 (13.6%) 26 (12.7%) 14 (12.5%) Nonarrhythmic 2 (3.8%) 1 (4.6%) 11 (5.4%) 8 (7.1%) query of the National Death Index and was complete for analysis of variance for continuous variables and chi-square mortality end points (100% of 768 patients enrolled) and test for categorical variables. Survival curves for the sub- near-complete for ICD shocks (99.7% of 392 patients groups were constructed using Kaplan-Meier estimates. Un- with ICDs). adjusted relations of MTWA status and QRS duration with The main objective of this study was to assess whether event-free survival were assessed using univariate Cox pro- the prognostic utility of MTWA differed by QRS duration. portional hazards analyses. Given this, our focus was to assess for a significant inter- Separate multivariable Cox proportional hazards models action between MTWA status and QRS duration for the within each ICD group were constructed to assess the in- study’s primary and secondary end points. dependent relation of both MTWA and QRS duration with For each ICD group, patients were categorized into the 4 all-cause mortality and appropriate ICD shock therapy (for subgroups of QRS negative (QRSϪ/MTWAϪ, QRSϩ/ the ICD group). Candidate variables included the previously MTWAϪ, QRSϪ/MTWAϩ, and QRSϩ/MTWAϩ). Baseline described demographic, clinical, medication treatment, and characteristics between MTWAϩ and MTWAϪ patients and Holter testing variables. Covariates associated with survival between QRSϩ and QRSϪ patients were compared using in univariate analyses (p Յ0.10) were entered in a stepwise Coronary Artery Disease/MTWA Predicts Mortality Outcomes 601

Kaplan-Meier Survival Estimates for the Non-ICD Cohort 1.00 0.75 0.50 0.25 0.00

0 10 20 30 40 Months of Follow-up QRS-/MTWA- QRS+/MTWA- QRS-/MTWA+ QRS+/MTWA+

Number at Risk Months 0 10 20 30 35 1) QRS-/MTWA- 146 108 68 30 10 2) QRS+/MTWA- 33 27 14 1 0 3) QRS-/MTWA+ 141 108 60 27 3 4) QRS+/MTWA+ 56 42 20 7 3

Figure 1. Kaplan-Meier survival curves for all-cause mortality in the non-ICD cohort subgroups are plotted for the 4 study subgroups by MTWA result and QRS duration (QRSϪ, QRS Յ120 ms; QRSϩ, QRS Ͼ120 ms). fashion to generate a multivariable Cox regression model characteristics of the study cohort divided according to ICD based on a significance level of p Յ0.05. Age, LVEF, status and into the 4 test categories of QRSϪ/MTWAϪ, MTWA, and QRS duration were included in the final model QRSϩ/MTWAϪ, QRSϪ/MTWAϩ, and QRSϩ/MTWAϩ. regardless of level of significance. Potential clinically In the non-ICD group, patients testing MTWA non- meaningful 2-way interactions between covariates were also negative (compared with those testing MTWAϪ) were examined, including the interaction between MTWA status older, had lower LVEFs, had a greater likelihood of abnor- and QRS duration, to determine whether the prognostic mal Holter results, were more likely to be administered utility seen with MTWA significantly differed by QRS digoxin, and were less likely to be administered statins. duration. Patients with a QRS Ͼ120 ms (compared with those with a Similarly, additional multivariable Cox models within QRS Յ120 ms) were older, had lower LVEFs, and were each ICD group were constructed to evaluate the relation of more likely to have abnormal Holter test results. In the ICD MTWA status and QRS duration (including their interac- group, patients testing MTWA non-negative were older and tion) for arrhythmic and nonarrhythmic mortality. As a more likely to have diabetes and be administered digoxin. sensitivity analysis in all models, different cut-off values to Ͼ Ͼ Ͼ Patients with a QRS 120 ms were older, had lower define a wide QRS duration ( 140 or 160 ms) were also LVEFs, and were more likely to have undergone revascu- used, but these did not alter any study findings (results not larization with angioplasty and coronary artery bypass sur- shown). In all models, the assumption of proportionality for gery. the Cox proportional hazards models was visually assessed using the (log-log [survival]) versus log (survival time) to There were 99 deaths in the cohort (58 in the non-ICD ensure parallelism. group, 41 in the ICD group) and 26 appropriate ICD shocks, For all analyses, the null hypothesis was evaluated at a and their distribution and classification among the 4 subgroups 2-sided significance level of 0.05 with 95% confidence are listed in Table 3. Crude all-cause mortality rates in patients without an ICD were similar among the QRSϩ/MTWAϪ, intervals (CIs) calculated. All analyses were performed us- Ϫ ϩ ϩ ϩ ing SAS, version 9.1 (SAS Institute, Cary, North Carolina). QRS /MTWA , and QRS /MTWA subgroups (range 18% to 23%) and lower in the QRSϪ/MTWAϪ subgroup (6%). Similarly, in patients with an ICD, crude rates for all-cause Results mortality and appropriate ICD shocks were lower in the Ϫ Ϫ Of 768 patients in the cohort, 514 (67%) had a non-negative QRS /MTWA subgroup (8%) compared with the 3 other MTWA test result, 223 (29%) had a QRS Ͼ120 ms, and 392 subgroups (range 18% to 20%). Kaplan-Meier event-free sur- (51%) had an ICD implanted. Mean follow-up for the entire vival curves comparing the 4 subgroups within each ICD cohort was 18 Ϯ 10 months. Tables 1 and 2 list baseline group are shown in Figures 1 and 2. 602 The American Journal of Cardiology (www.AJConline.org)

1.00 Kaplan-Meier Survival Estimates for the ICD Cohort 0.75 0.50 0.25 0.00

0 10 20 30 40 Months of Follow-up QRS-/MTWA- QRS+/MTWA- QRS-/MTWA+ QRS+/MTWA+

Number at Risk Months 0 10 20 30 35 1) QRS-/MTWA- 53 32 26 16 5 2) QRS+/MTWA- 22 15 8 6 3 3) QRS-/MTWA+ 205 150 95 39 9 4) QRS+/MTWA+ 112 75 44 10 1

Figure 2. Kaplan-Meier survival curves for all-cause mortality and appropriate ICD shock therapy in the ICD cohort subgroups are plotted for the 4 study subgroups by MTWA result and QRS duration [QRSϪ, QRS Յ120 ms; QRSϩ, QRS Ͼ120 ms).

Table 4 Adjusted Cox models evaluating microvolt T-wave alternans (MTWA) and QRS duration in predicting mortality events MTWA HR (95% CI) p Value Wide QRS Duration HR (95% CI) p Value Interaction p Value Nondefibrillator All-cause mortality 2.27 (1.22–4.24) 0.01 0.96 (0.52–1.75) 0.88 0.19 Arrhythmic 3.32 (1.31–8.41) 0.01 0.71 (0.27–1.88) 0.95 0.24 Nonarrhythmic 1.77 (0.77–4.08) 0.18 0.98 (0.45–2.17) 0.97 0.12 Defibrillator Mortality ϩ defibrillator shocks 2.42 (1.07–5.41) 0.04 1.25 (0.76–2.08) 0.40 0.73 Arrhythmic 2.05 (0.93–4.55) 0.08 1.33 (0.79–2.24) 0.29 0.73 Nonarrhythmic 2.75 (0.77–9.77) 0.12 1.61 (0.72–3.58) 0.25 0.62

Results are provided separately for the ICD and non-ICD cohorts. Formal tests of Interactions between MTWA and QRS duration are provided for each study end point.

After adjustment for demographic, clinical, and medica- 1.31 to 8.41, p ϭ 0.01), but no prognostic significance was tion treatment variables, patients with a non-negative found for arrhythmic mortality in patients with a prolonged MTWA result had a higher risk of all-cause mortality (haz- QRS duration. Last, neither MTWA nor QRS duration pre- ard ratio [HR] 2.27, 95% CI 1.22 to 4.24, p ϭ 0.01; Table dicted rates of nonarrhythmic mortality. 4). In contrast, QRS duration Ͼ120 ms conferred no prog- In patients with ICDs, multivariable Cox models found nostic utility (HR 0.96, 95% CI 0.52 to 1.75, p ϭ 0.88). that a non-negative MTWA test result (HR 2.42, 95% CI Although a number of interaction terms were examined, 1.07 to 5.41, p ϭ 0.04), but not a QRS Ͼ120 ms (HR 1.25, none reached statistical significance. Importantly, in pa- 95% CI 0.76 to 2.08, p ϭ 0.40), predicted the combined end tients without an ICD, the prognostic utility of a non- point of all-cause mortality and appropriate ICD shock negative MTWA test result did not significantly differ by therapy (Table 4). Again, as with the non-ICD group, the QRS duration (p ϭ 0.19 for interaction between MTWA test prognostic utility of a non-negative MTWA test result was status and QRS duration). not found to differ among patients with a QRS Յ120 and Similarly, patients with a non-negative MTWA result Ͼ120 ms (p for interaction ϭ 0.73). Given the low event had a more than threefold increased risk of an arrhythmic rates, neither MTWA nor QRS duration predicted arrhyth- death than those with an MTWAϪ result (HR 3.32, 95% CI mic or nonarrhythmic events in patients with an ICD, al- Coronary Artery Disease/MTWA Predicts Mortality Outcomes 603 though a non-negative MTWA test result showed a strong QRS duration and found that the predictive power of trend for arrhythmic events (HR 2.05, 95% CI 0.93 to 4.55, MTWA did not differ by QRS duration subgroup. p ϭ 0.08). Although unadjusted results seemed to suggest that the These results suggest that MTWA, but not QRS duration, subgroup of patients with MTWAϪ results with a normal predicts outcomes in patients with and without an ICD. QRS duration had the lowest mortality rate, when we ad- Ϫ Although as listed in Table 3, patients in the QRS / justed for baseline differences between electrocardiogramϪ/ Ϫ MTWA subgroup in both ICD groups had lower crude MTWAϪ and electrocardiogramϩ/MTWAϪ patients in a event rates than the other subgroups, this could simply be multivariable model, no differences were found between attributed to younger age, higher LVEF and rates of coro- MTWAϪ patients who had a normal or prolonged QRS nary revascularization, and lower rates of abnormal Holter duration. Notably, patients who tested MTWAϪ with a Ϫ Ϫ study results in the QRS /MTWA subgroup relative to the normal QRS duration were significantly younger and had ϩ Ϫ QRS /MTWA subgroup. We therefore explored whether higher LVEFs and revascularization rates than those with a normal QRS duration added incremental prognostic utility QRS Ͼ120 ms, and it is likely these differences (and not Ϫ to patients screening MTWA . However, after multivari- QRS duration) accounted for the lower unadjusted mortality able adjustment, QRS Ͼ120 ms was not found to be an rates seen in this subgroup. independent predictor of mortality and appropriate ICD Ϫ Our study had several limitations. As with all cohort shocks in patients testing MTWA (non-ICD patients, HR studies, the potential exists for residual confounding. We 1.50, 95% CI 0.40 to 5.56, p ϭ 0.54; ICD patients, HR 1.44, lacked information about certain covariates, such as lab- 95% CI 0.25 to 8.36, p ϭ 0.68) or ICD and non-ICD oratory data, which may have affected our results. How- patients combined (stratified HR 1.48, 95% CI 0.56 to 3.90, ever, we were able to adjust for a large number of p ϭ 0.43). demographic and clinical characteristics in a manner not previously done before in studies involving MTWA and Discussion QRS duration in patients with ischemic cardiomyopathy. Although our study is the largest to date evaluating the This study found in a population of stable outpatients prognostic utility of QRS duration and MTWA in patients with ischemic cardiomyopathy that MTWA identified with ischemic cardiomyopathy, the relatively modest patients with and without ICDs at significantly higher sample size of each subgroup may have limited our mortality and sudden cardiac death event risk. In con- ability to detect significant differences in cause-specific trast, prolonged QRS duration was found to have no mortality, especially in the ICD cohort, in which event prognostic utility in predicting outcomes in this popula- rates were much lower. Our cohort was also derived from tion. Previous studies provided mixed results for the role several large outpatient cardiology clinics from 1 region of QRS duration in identifying high-risk patients with of the country. Differences in patient risk or practice ischemic cardiomyopathy, but they were limited by their patterns geographically may limit the generalizability of smaller sample sizes (Ͻ200 patients) and inadequate ad- our findings. Last, MTWA is performed only in patients justment for potential confounding.3,9 Our study is the in sinus rhythm, and our results therefore would not largest study to date to examine whether MTWA and apply to the minority of patients (8% to 15%) likely to be QRS duration effectively risk-stratify patients with isch- in atrial fibrillation with ischemic cardiomyopathy.11,12 emic cardiomyopathy, and we were able to examine for potential interactions between MTWA and QRS duration. 1. Gehi AK, Stein RH, Metz LD, Gomes JA. Microvolt T-wave alternans We found no significant interaction between MTWA and for the risk stratification of ventricular tachyarrhythmic events: a all other variables, suggesting that the prognostic utility meta-analysis. J Am Coll Cardiol 2005;46:75–82. of MTWA was not significantly different across QRS 2. Chow T, Kereiakes DJ, Bartone C, Booth T, Schloss EJ, Waller T, Chung E, Menon S, Nallamothu BK, Chan PS. Prognostic utility of duration subgroups. microvolt T-wave alternans in risk stratifying patients with ischemic Our study found no association between QRS duration cardiomyopathy. J Am Coll Cardiol 2006;47:1820–1827. and mortality outcomes, and this was true regardless of 3. Rashba EJ, Osman AF, MacMurdy K, Kirk MM, Sarang S, Peters RW, whether QRS duration Ͼ120, Ͼ140, or Ͼ160 ms was Shorofsky SR, Gold MR. Influence of QRS duration on the prognostic used to define a wide QRS. Other recent studies also value of T wave alternans. J Cardiovasc Electrophysiol 2002;13:770– 775. found no independent association between QRS duration 4. Chan PS, Stein K, Chow T, Fendrick M, Bigger JT, Vijan S. Cost- 9,10 and outcome. Nevertheless, in a previous study in effectiveness of a microvolt T-wave alternans screening strategy for which both MTWA and QRS duration were found to be implantable cardioverter-defibrillator placement in the MADIT-II-eli- predictors for outcomes, it was suggested that the utility gible population. J Am Coll Cardiol 2006;48:112–121. of MTWA screening may be limited to only patients with 5. Chow T, Kereiakes DJ, Bartone C, Booth T, Schloss EJ, Waller T, 3 Chung E, Menon S, Nallamothu BK, Chan PS. Microvolt T-wave a normal QRS duration. However, that study included alternans identifies patients with ischemic cardiomyopathy who benefit both primary and secondary prevention patients (but did from implantable cardioverter-defibrillator therapy. J Am Coll Cardiol not stratify on this variable) and did not formally test for 2007;49:50–58. an interaction between MTWA status and QRS duration. 6. Bloomfield DM, Hohnloser SH, Cohen RJ. Interpretation and classi- In this largest study to date to examine both MTWA and fication of microvolt T wave alternans tests. J Cardiovasc Electro- physiol 2002;13:502–512. QRS duration as independent predictors of all-cause mor- 7. Kaufman ES, Bloomfield DM, Steinman RC, Namerow PB, Costantini tality in patients with ischemic cardiomyopathy, we for- O, Cohen RJ, Bigger JT Jr. “Indeterminate” microvolt T-wave alter- mally tested for an interaction between MTWA status and nans tests predict high risk of death or sustained ventricular arrhyth- 604 The American Journal of Cardiology (www.AJConline.org)

mias in patients with left ventricular dysfunction. J Am Coll Cardiol occurrence of ventricular tachyarrhythmias in patients with implanted 2006;48:1399–1404. cardioverter-defibrillators. J Am Coll Cardiol 2005;46:310–316. 8. Hinkle LE Jr, Thaler HT. Clinical classification of cardiac deaths. 11. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Circulation 1982;65:457–464. Daubert JP, Higgins SL, Brown MW, Andrews ML, for the Multi- 9. Bloomfield DM, Steinman RC, Namerow PB, Parides M, Davidenko center Automatic Defibrillator Implantation Trial II Investigators. Pro- J, Kaufman ES, Shinn T, Curtis A, Fontaine J, Holmes D, et al. phylactic implantation of a defibrillator in patients with myocardial Microvolt T-wave alternans distinguishes between patients likely and infarction and reduced ejection fraction. N Engl J Med 2002;346:877– patients not likely to benefit from implanted cardiac defibrillator ther- 883. apy: a solution to the Multicenter Automatic Defibrillator Implantation 12. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Trial (MADIT) II conundrum. Circulation 2004;110:1885–1889. Domanski M, Troutman C, Anderson J, Johnson G, et al. Amiodarone 10. Buxton AE, Sweeney MO, Wathen MS, Josephson ME, Otterness MF, or an implantable cardioverter-defibrillator for congestive heart failure. Hogan-Miller E, Stark AJ, Degroot PJ. QRS duration does not predict N Engl J Med 2005;352:225–237. Comparison of the Prognostic Value of the Stress-Recovery Index Versus Standard Electrocardiographic Criteria in Patients With a Negative Exercise Electrocardiogram

Riccardo Bigi, PhDa,*, Lauro Cortigiani, MDc, Dario Gregori, PhDd, and Cesare Fiorentini, MDa,b,

To verify whether the stress recovery index (SRI) improves risk stratification in patients with a negative exercise electrocardiogram (ECG) using standard criteria, the SRI was derived in 708 consecutive patients with a negative exercise ECG. All-cause mortality and the combination of death or nonfatal myocardial infarction were target end points. The individual effect of clinical and exercise testing data on outcome was evaluated using Cox regression analysis with separate models for each group of variables. Model validation was performed using bootstrap adjusted by degree of optimism in estimates. Survival analysis was performed using a product-limit Kaplan-Meier method. During a 37-month follow-up, 22 deaths and 40 nonfatal acute coronary syndromes occurred. After adjusting for confounding variables, age (hazard ratio 1.62, 95% confidence interval [CI] 1.14 to 2.31 for interquartile difference), hypertension (hazard ratio 1.74, 95% CI 1.04 to 2.89), and SRI (hazard ratio 0.75, 95% CI 0.65 to 0.86 for interquartile difference) were predictive of death or nonfatal myocardial infarction. Moreover, SRI increased the prognostic power of the model on top of clinical and exercise testing variables and provided significant discrimination of survival. In conclusion, the SRI may help refine the prognostic stratification of patients with a negative exercise test result using standard electrocardiographic criteria. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:605–609)

Heart-rate adjustment of ST-segment depression is a well- syndrome, significant congenital or valvular heart disease, established modality to improve the accuracy of an exercise congestive heart failure, left branch bundle block, chronic electrocardiogram (ECG).1,2 More recently, the stress re- atrial fibrillation, implantable pacemaker, digoxin use, and covery index (SRI) was shown to improve the diagnostic3 prognostically relevant co-morbidity. Informed consent was and prognostic accuracy of standard ST-segment depression obtained from all patients before testing, and the study protocol criteria in general populations,4 as well as in specific clinical was approved by the institutional ethical committee. Complete settings.5–7 We aimed to verify whether the SRI may im- follow-up information was not available for 8 patients; there- prove risk stratification of patients with a negative exercise fore, the present analysis refers to 700 patients. ECG using standard criteria. All patients were in stable clinical condition. Hyperten- sion was defined as systolic blood pressure at rest of Ն140 Methods mm Hg, diastolic blood pressure at rest of Ն90 mm Hg, or treatment with antihypertensive drugs.8 Diabetes mellitus The study cohort consisted of 708 consecutive outpatients was diagnosed according to World Health Organization with a negative exercise ECG that was defined based on the 9 Ն criteria. Hypercholesterolemia was defined as fasting absence of a 0.1-mV ST-segment depression. Patients plasma total cholesterol Ͼ6.2 mmol/L10 or treatment with were tested from December 1998 to January 2001 for eval- cholesterol-lowering drugs. Ejection fraction was obtained uation of chest pain and/or prognostic assessment and pro- using 2-dimensional echocardiography using Simpson’s spectively included in a follow-up program. Of these pa- rule.11 Clinical characteristics of the study population are tients, 198 (28%) had suspected and 510 (72%) had known listed in Table 1. coronary artery disease (CAD) that was defined as previous Patients exercised on a cycle ergometer with 25-W in- myocardial infarction and/or revascularization procedure or cremental loading every 2 minutes. The 12-lead ECG was presence of a Ͼ50% stenosis in Ն1 major epicardial vessel. continuously monitored throughout the test for rhythm, rate, Exclusion criteria were a recent (Ͻ1 month) acute coronary and ST-segment changes. Blood pressure was measured using arm-cuff sphygmomanometry during the last 30 seconds of each work stage. Exercise was continued until chest a Cardiology, Department of Medicine and Surgery, University School pain, repetitive arrhythmias, significant conduction abnor- of Medicine; bCentro Cardiologico Monzino, Milan; cCardiovascular Unit, Ͼ d malities, ST-segment depression 0.3 mV, systolic blood “Campo di Marte” Hospital, Lucca; and Department of Public Health and pressure Ͼ230 mm Hg or a decrease Ͼ20 mm Hg, or Microbiology, University School of Medicine, Turin, Italy. Manuscript received February 6, 2007; revised manuscript received and accepted limiting symptoms (dyspnea, dizziness, fatigue, or cramp in March 20, 2007. legs) occurred. After exercise, patients recovered in a sitting *Corresponding author: Tel.: 39-02-5032-3002; fax: 39-02-5032-3001. position. Total work performed indicated the exercise ca- E-mail address: [email protected] (R. Bigi). pacity of the patient. ST-segment deviation in leads without

Table 1 Clinical characteristics and exercise electrocardiography results Variable All Patients (n ϭ 700) Event (n ϭ 62) No Event (n ϭ 638) Hazard Ratio Age (yrs) 59 (53,64) 62 (57,66) 68 (52,64) 1.85 (1.31–2.61) Men 595 (85%) 53 (85%) 542 (85%) 0.96 (0.47–1.95) Patients with known CAD 510 (72%) 46 (74%) 464 (72%) 1.40 (0.64–3.07) Diabetes mellitus 49 (7%) 5 (8%) 44 (7%) 1.32 (0.53–3.31) Smoker 327 (47%) 31 (50%) 244 (38%) 1.98 (1.20–3.27) Blood pressure Ͼ140/90 mm Hg 277 (40%) 33 (53%) 182 (27%) 2.64 (1.22–5.71) Total cholesterol Ͼ6.2 mmol/L 276 (39%) 18 (29%) 258 (40%) 0.62 (0.36–1.07) Ejection fraction (%) 50 (48,55) 50 (48,55) 50 (48,55) 0.77 (0.61–0.97) Heart rate at rest (beats/min) 73 (63,84) 74 (63,86) 72 (63,84) 1.01 (0.71–1.43) Systolic blood pressure at rest (mm Hg) 130 (120,140) 130 (120,150) 130 (120,140) 1.28 (0.98–1.68) Peak heart rate (beats/min) 136 (120,150) 136 (119,149) 136 (120,151) 0.82 (0.58–1.16) Percent maximal predicted heart rate 85 (74,92) 86 (75,92) 85 (74,92) 1.01 (0.70–1.46) Peak systolic blood pressure (mm Hg) 190 (170,200) 190 (170,210) 190 (170,200) 1.08 (0.80–1.46) Exercise capacity (kpm) 4,087 (2,700,6,000) 4,200 (2,275,6,750) 4,012 (2,700,5,650) 1.08 (0.78–1.50) Exercise time (min) 11 (9,13.5) 11 (9,15) 11 (9,13.5) 1.11 (0.79–1.54) Exercise-induced chest pain 95 (14%) 7 (11%) 88 (14%) 0.96 (0.44–2.11) Maximal ST-segment depression (mV) 0.4 (0,0.7) 0.5 (0,0.8) 0.4 (0,0.7) 1.03 (0.72–1.65) SRI (mV beats/min) Ϫ0.82 (Ϫ2,6.6) Ϫ6(Ϫ16,0) Ϫ0.5 (Ϫ12,7.7) 0.84 (0.71–0.99)

Continuous variables presented as median (first and third quartile). Categorical variables presented as absolute number (percent). Univariate hazard ratios are presented with their 95% confidence intervals; values refer to the effect of interquartile difference for continuous variables and to the category with the highest observed frequency for categorical variables. pathologic Q waves, excluding aVR, was measured 60 ms observed frequency for categorical variables, respectively. after the J point using the end of the PR segment as refer- The individual effect of clinical data, resting ejection frac- ence. Electrocardiographic response was defined as positive tion, and exercise testing results on survival was evaluated in the case of a horizontal or downsloping deviation Ͼ0.1 using Cox proportional hazards regression analysis. The mV compared with the ECG at rest in Ն2 contiguous leads. proportional hazard assumption was checked by plotting Decisions about discontinuing cardioactive drugs before Schoenfeld results against fitted time and varying coeffi- testing and patient management after testing were made cients and using the Grambsh and Therneau test.13 To assess independently by the attending physician, who was unaware whether the provided additional prognostic information, of the study aim. Only exercise testing data reported as part clinical data, ejection fraction at rest, and exercise ECG data of patient care were available as test results. were entered first (model 1), whereas SRI was entered last Details about determination of the SRI were described (model 2). All variables were entered into the model without extensively elsewhere.3,4 Briefly, computer-calculated ST- transformation or cutting off. Nonlinearity was assessed segment amplitudes were obtained with a time constant of using the Wald test comparing higher order models with 12 seconds during exercise and up to 5 minutes during that including only linear terms. In case of nonlinearity, a recovery. At the end of the test, the area subtended to restrictive cubic spline was used to model a nonlinear effect baseline and limited by the ST-segment trend against heart of the covariate. To account for potential risk differences in rate during exercise and recovery was calculated in the lead patients with known CAD compared with those with sus- with the greatest ST-segment shift. The SRI was defined as pected CAD, baseline hazards were assumed different in the difference in absolute values between areas defined by each group of patients and modeled using a CAD-stratified ST-segment depression in the heart-rate domain during ex- Cox model. Selection criteria were the Akaike information ercise and recovery, respectively.3 criterion14 applied backward for each model. Models were Outcome was determined by telephone calls to patients’ cross-validated using a bootstrap technique.15 Multivariable families and primary physicians, with review of outside hazard ratios are presented with their 95% confidence in- records, if necessary. Study end points were all-cause mor- tervals. Areas under the receiver-operating characteristic tality and occurrence of a nonfatal acute coronary syn- curves16 of estimated cumulative hazard functions were drome, diagnosed according to the present international compared with provide evidence of a significant increase in guidelines.12 Patients undergoing revascularization were predictive accuracy of the model after addition of the SRI. censored at the time of the procedure. End points were Cumulative survival curves as a function of time by assessed by an independent noninstitutional review board quartiles of were generated using the Kaplan-Meier method blinded to the study aim. and compared using log-rank test. Estimated percentage of Continuous variables are presented as median with the event rates were derived from Kaplan-Meier estimates to corresponding interquartile difference. Categorical vari- take censoring of data into account. Statistical significance ables are presented as absolute number with corresponding was settled at p Ͻ0.05. The S-Plus (release 2000, Insightful percentages. Univariate hazard ratios refer to the effect of Corporation, Seattle, Washington) statistical package and being in the highest compared with the lowest quartile for Harrell’s Design and Hmisc libraries (Insightful Corpora- continuous variables or in the category with the highest tion) were used for analysis. Coronary Artery Disease/Prognostic Value of Exercise ECG 607

Table 2 Multivariable analysis result Predictor Hazard Ratio Model 1 Age 1.73 (1.21–2.45) Hypertension 1.68 (1.01–2.80) Model 2 Age 1.62 (1.14–2.31) Hypertension 1.74 (1.04–2.89) 0.52 (0.28–0.96)

Values expressed as hazard ratio (95% conﬁdence interval). Values refer to the effect of interquartile difference for continuous variables and to the category with the highest observed frequency for categorical variables.

Results Exercise testing was performed off therapy in 525 patients (75%). Beta-blocker therapy was discontinued for at least 48 hours before testing in all patients. Of those who were tested on therapy, 35 patients were using calcium channel blockers; 17 patients, nitrates; 103 patients, angiotensin- converting enzyme inhibitors; and 20 patients, angiotensin- receptor blockers. Cause for test interruption was muscular Figure 1. Comparison of areas under the receiver-operating characteristic fatigue in 648 patients (92.5%), dyspnea in 14 patients curve (AUCs) by model 1 (0.68, 95% confidence interval 0.57 to 0.80) and (2%), chest pain in 28 patients (4%), and excessive blood model 2 (0.84, 95% confidence interval 0.77 to 0.90) for prediction of pressure increase in 10 patients (1.5%). Exercise testing outcome. The area of model 2 including the SRI was significantly (p ϭ results according to outcome and in the overall study group 0.001) wider, showing superior predictive accuracy. are listed in Table 1. During a median follow-up of 37 months (interquartile difference 24 to 52), 22 patients (3.1%) died, whereas 40 patients (5.7%) were admitted to the hospital because of an acute coronary syndrome. A cardiac cause of death was ascertained in 18 of 22 patients. The yearly event rate was 3%. In addition, 103 patients (14.8%) underwent myocardial revascularization using bypass surgery or percutaneous coronary intervention. Univariate analysis of outcome predictors is listed in Table 1. Multivariable analysis results according to both prognostic models are listed in Table 2. Age, hypertension, and SRI were multivariable predictors of outcome; however, addition of the SRI was associated with improved accuracy of Figure 2. Kaplan-Meier plots associating SRI by quartiles with event the prognostic model, proved by the significant increase in rate. area under the receiver operating characteristic curve (Fig- ure 1). The effect of the SRI on outcome is further demonstrated using survival analysis (Figure 2). The percentage of hensive analysis of heart rate–adjusted ST-segment depres- event rate over time was accurately stratified using the SRI; sion during exercise and recovery yields relevant prognostic in particular, the highest quartile reflected a very favorable discrimination on top of clinical and exercise testing data. outcome, whereas the lowest quartile was associated with The electrocardiographic hallmark of exercise-induced ischemia is horizontal or downsloping ST-segment depres- the highest event rate. Ն To estimate the likelihood of event-free survival in indi- sion 0.1 mV. Intrinsic limitations of this standard criterion 2,17 vidual patients, a nomogram was generated from the fitted for diagnostic and prognostic purposes are well recog- Cox model using the multivariable predictors of outcome nized. Nevertheless, it has been representing the “central (Figure 3). dogma” of exercise electrocardiographic interpretation during the last decades.18 Accordingly, the majority of clinical Discussion studies dealing with the diagnostic and prognostic accuracy of exercise ECG in comparison to different noninvasive Although use of the SRI needs further prospective testing in modalities relied on this standard definition. In particular, other populations, results of the present study confirm the although increasing cardiac risk is known to parallel in- definition of negative exercise ECG crudely based on a creasing exercise-induced ST-segment depression beyond fixed-threshold ST-segment depression to provide unsatis- the threshold of 0.1 mV,19 an evenly favorable interpreta- factory prognostic information. However, a more compre- tion is generally assigned to all deviations less than this 608 The American Journal of Cardiology (www.AJConline.org)

Figure 3. Nomogram for calculating the likelihood of event-free survival in individual patients from multivariate predictors of the fitted Cox model. To derive the likelihood, partial points relative to each predictor are read on the upper scale, their sum is then reported on the total points scale, and the corresponding 1- or 2-year likelihood can be read on the lower scales. cut-off value. This is based on the observation that minor cardial oxygen demand during the recovery phase.25 SRI ST-segment shifts increase sensitivity for angiographic analysis is independent of achievement of a critical thresh- CAD, but with substantial decreases in specificity. How- old of ST-segment depression and therefore is able to con- ever, coronary angiography provides a partial look at CAD vey information throughout the entire spectrum of heart so that the apparent diagnostic mistake, represented by the rate–adjusted ST-segment deviation occurring during the lack of correlation between exercise ECG and coronary different phases of exercise. angiography findings,20 may translate into a prognostic truth A progressive increase in the use of procedures for the because of the inadequacy of the coronary angiogram to diagnosis of CAD during the last decades recently was 21 best describe all aspects of CAD. A prognostic signifi- 26 Յ reported. In particular, the use of imaging stress tests cance of exercise-induced ST-segment shifts 0.1 mV was increased substantially, whereas the use of nonimaging 22 shown previously in symptomatic populations. This was stress tests decreased, although this increase is unlikely to not confirmed in the selected population of asymptomatic be related to an increase in underlying prevalence of the volunteers participating in the Baltimore Longitudinal disease. The economic consequences of that are extraordi- Study of Aging (BLSA).23 However, to the best of our knowledge, no prospective study including a consecutive nary relevant and are going to challenge the sustainability of unselected population of patients was specifically designed reimbursement systems in the coming years. Thus, physi- to address this issue. Moreover, the interpretation of exer- cians will have increasing responsibility to ensure that ex- cise ECG was traditionally based on observations made pensive cardiac procedures are used effectively and effi- during exercise despite the known evidence that those made ciently to maximize their value for improving health.27 during the recovery period provide important information.24 Exercise electrocardiography is a time-honored modality Some years ago, the SRI was suggested to improve the with a favorable clinical profile for assessing CAD. In diagnostic ability of exercise ECG for the detection of particular, it is low cost, generally available, and safe. extensive CAD.3 Afterward, the SRI was shown to add Therefore, any attempt to improve its diagnostic and prog- relevant prognostic information to that obtained from clin- nostic accuracy is expected to have major implications in ical data and standard exercise electrocardiographic analy- term of pay-for-performance measures. sis.3–7 Results of the present study reinforce these findings and extend their clinical relevance to the setting of patients 1. Okin PM, Bergman G, Kligfield P. Heart rate adjustment of the with known or suspected CAD who are able to undergo time-voltage ST segment integral: identification of coronary disease symptom-limited exercise testing with no evidence of sig- and relation to standard and heart rate-adjusted ST segment depression nificant ST-segment depression. The physiologic basis of criteria. J Am Coll Cardiol 1991;18:1487–1492. comparative stress-recovery adjustment of ST-segment de- 2. Okin PM, Kligfield P. Heart rate adjustment of ST segment depression and performance of the exercise electrocardiogram: a critical evalua- 3 pression grounds on earlier observations. In particular, res- tion. J Am Coll Cardiol 1995;25:1726–1735. olution of exercise-induced ST depression was shown to lag 3. Bigi R, Maffi M, Occhi G, Bolognese L, Pozzoni L. Improvement in behind its development given the nonlinear relation to myo- identification of multivessel disease after acute myocardial infarction Coronary Artery Disease/Prognostic Value of Exercise ECG 609

following stress-recovery analysis of ST depression in the heart rate 16. Hanley JA, MCNeil BJ. The meaning and the use of the area under a domain during exercise. Eur Heart J 1994;15:1240–1246. receiver operating characteristic (ROC) curve. Radiology 1982;143: 4. Bigi R, Cortigiani L, Gregori D, Bax JJ, Fiorentini C. Prognostic value 29–36. of combined exercise and recovery electrocardiographic analysis. Arch 17. Lauer M, Froelicher ES, William M, Kligfield P. Exercise testing in Intern Med 2005;165:1253–1258. asymptomatic adults: a statement for professionals from the American 5. Bigi R, Cortigiani L, Gregori D, De Chiara B, Fiorentini C. Exercise Heart Association Council on Clinical Cardiology, Subcommittee on versus recover electrocardiography to predict mortality in patients with Exercise, Cardiac Rehabilitation, and Prevention. Circulation 2005; uncomplicated myocardial infarction. Eur Heart J 2004;25:558–564. 112:771–776. 6. 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Kitagawa G, Sakamoto Y, Ishiguro M. Akaike Information Criterion disease in the United States, 1993–2001. Circulation 2006;113:374– Statistics. Stuttgart: Kluwer, 1987. 379. 15. Efron B, Tibshirani R, Robert J. An Introduction to the Bootstrap. 27. Ayanian J. Rising rates of cardiac procedures in the United States and London: Chapman & Hall, 1993. Canada: too much of a good thing? Circulation 2006;113:333–335. Effects of Triple Antiplatelet Therapy (Aspirin, Clopidogrel, and Cilostazol) on Platelet Aggregation and P-Selectin Expression in Patients Undergoing Coronary Artery Stent Implantation

Bong-Ki Lee, MD, PhDa, Seung-Whan Lee, MD, PhDa, Seong-Wook Park, MD, PhDa,*, Se-Whan Lee, MDa, Duk-Woo Park, MDa, Young-Hak Kim, MD, PhDa, Cheol Whan Lee, MD, PhDa, Myeong-Ki Hong, MD, PhDa, Jae-Joong Kim, MD, PhDa, Seongsoo Jang, MD, PhDb, Hyun-Sook Chi, MD, PhDb, and Seung-Jung Park, MD, PhDa

The purpose of this study was to determine the effect of the addition of cilostazol to aspirin plus clopidogrel on platelet aggregation after intracoronary stent implantation. Twenty patients who underwent coronary stent placement were randomly assigned to therapy with or aspirin plus clopidogrel plus (10 ؍ aspirin plus clopidogrel (dual-therapy group, n A loading dose of clopidogrel (300 mg) and .(10 ؍ cilostazol (triple-therapy group, n cilostazol (200 mg) was administered immediately after stent placement, and clopidogrel (75 mg/day) and cilostazol (100 mg twice daily) were given for 1 month. Platelet aggregation in response to adenosine diphosphate (ADP; 5 and 20 ␮mol/L) or collagen and P-selectin (CD-62P) expression was assayed at baseline, 2 hours, 24 hours, 1 week, and 1 month after stent placement. Inhibition of ADP-induced platelet aggregation was significantly higher in patients receiving triple therapy than those receiving dual therapy from 24 hours after stent placement, and inhibition of collagen-induced platelet aggregation was significantly higher in the triple-therapy group beginning 1 week after stent placement. P-Selectin expression was significantly lower in the triple-therapy than dual-therapy group at 1 week and 30 days. In conclusion, compared with dual antiplatelet therapy, triple therapy after coronary stent placement resulted in more potent inhibition of platelet aggregation induced by ADP and collagen. These findings suggest that triple therapy may be used clinically to prevent thrombotic complications after coronary stent placement. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:610–614)

Cilostazol is a drug with a different mechanism of action (CD-62P) expression in patients undergoing coronary inter- than clopidogrel. Cilostazol inhibited activity of the enzyme vention. cyclic adenosine monophosphate (cAMP) phosphodiesterase in platelets and the production of platelet-derived Methods growth factor in endothelial cells.1 In randomized trials, The 20 patients awaiting elective coronary stent implanta- cilostazol was as effective as ticlopidine2–4 or clopidogrel5 tion were randomly assigned to treatment with aspirin plus in preventing stent thrombosis after coronary stent place- clopidogrel (dual-therapy group, n ϭ 10) or aspirin plus ment, and triple antiplatelet therapy with aspirin and cilosta- clopidogrel plus cilostazol (triple-therapy group, n ϭ 10) zol plus clopidogrel or ticlopidine was more effective in after coronary angiography. All patients received aspirin preventing stent thrombosis than dual therapy with aspirin (200 mg/day) for Ն1 week before coronary intervention. plus clopidogrel or ticlopidine.6 However, less is known Loading doses of clopidogrel (300 mg) and cilostazol (200 about the effects of these treatments on platelet function test mg) were administered immediately after stent placement, results. We therefore compared the effects of triple (aspirin and patients were maintained on clopidogrel 75 mg/day, plus clopidogrel plus cilostazol) and dual therapy (aspirin cilostazol 100 mg twice daily, and aspirin 200 mg/day for plus clopidogrel) on platelet aggregation and P-selectin 30 days. Unfractionated heparin was administered intravenously to all patients before percutaneous coronary intervention to achieve an activated clotting time Ͼ300 seconds. Heparin aDepartments of Medicine and bLaboratory Medicine, Asan Medical therapy was not continued after coronary stent placement. Center, University of Ulsan College of Medicine, Seoul, Korea. Manu- Glycoprotein IIb/IIIa inhibitors were not given, as speciﬁed script received November 22, 2006; revised manuscript received and ac- by the research protocol. Patients with a contraindication to cepted March 13, 2007. antiplatelet agents were excluded, including those with This work was supported by the Cardiovascular Research Foundation, Ͻ ␮ Seoul, Korea, and Grant No. 0412-CR02-0704-0001 from the Korea Health thrombocytopenia ( 100,000 platelets/ L), history of 21 R&D Project, Ministry of Health and Welfare, Seoul, Korea. bleeding diathesis, illicit drug or alcohol abuse, acute myo- *Corresponding author: Tel.: 82-2-3010-3150; fax: 82-2-486-5918. cardial infarction (within 2 weeks), or recent use of an E-mail address: [email protected] (S.-W. Park). antiplatelet agent other than aspirin. The study protocol was

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.070 Coronary Artery Disease/Effect of Triple Antiplatelet Therapy 611 approved by the hospital institutional review board and Table 1 performed in accordance with international ethical regula- Patient characteristics at baseline tions. Participants gave written informed consent. Variable Dual-Therapy Triple-Therapy Blood samples were obtained just before percutaneous Group (n ϭ 10) Group (n ϭ 10) coronary intervention and at 2 hours, 24 hours, 1 week, and Age (yrs) 56.0 Ϯ 10.2 56.6 Ϯ 9.4 1 month after intervention using the double-syringe tech- Men 5 6 nique, in which the first 5 ml of blood was drawn into an Hypertension 5 5 empty syringe, which was discarded. Blood samples were Diabetes mellitus 3 2 drawn into sodium citrate–containing tubes (Vacutainer, Smoker 5 5 Becton-Dickinson, Inc., San Jose, California) for platelet Stent length (mm) 46 Ϯ 24 44 Ϯ 21 aggregation studies and ethylenediaminetetraacetic acid– Platelet count (/␮L) 270,000 Ϯ 51,000 228,000 Ϯ 78,000 containing tubes (Vacutainer) for flow cytometry. Values expressed as mean Ϯ SD or number of patients. Platelet aggregation tests were started within 60 minutes Dual-therapy group treated with aspirin plus clopidogrel. Triple-therapy after blood sampling. People performing platelet aggrega- group treated with aspirin plus clopidogrel plus cilostazol. tion and flow cytometric tests were blinded to patient ran- There were no statistically significant differences between the 2 groups. domization. Platelet-rich plasma was prepared immediately by centrifuging blood samples at 200 g for 10 minutes, and Table 2 platelet-poor plasma was prepared by centrifugation at Mean platelet aggregation over time 1,600 g for 10 minutes. As agonists, we used adenosine diphosphate (ADP) at final concentrations of 5 and 20 ␮M Agonist Dual-Therapy Triple-Therapy p Value ␮ Group Group (mol/L) and collagen at a final concentration of 2 g/ml. (n ϭ 10) (n ϭ 10) Platelet aggregation was assessed at 37° using a PACKS-4 aggregometer (Helena Laboratories Corp., Beaumont, ADP (5 ␮mol/L) Texas) and expressed as maximal percentage of change in Baseline 46.6 Ϯ 14.0 40.9 Ϯ 18.3 0.472 Ϯ Ϯ light transmittance from baseline platelet-rich plasma, using 2 h 40.8 15.2 37.9 19.5 0.693 24 h 34.5 Ϯ 17.0* 20.2 Ϯ 15.1* 0.012 platelet-poor plasma as a reference. Ϯ Ϯ ␮ 7 d 34.5 7.6* 19.3 12.3* 0.004 Blood samples were incubated with ADP 20 Mat 30 d 32.2 Ϯ 7.4* 13.4 Ϯ 9.8* 0.000 room temperature for 10 minutes to stimulate platelet ADP (20 ␮mol/L) activation. Samples were subsequently incubated for 20 Baseline 67.6 Ϯ 13.4 58.4 Ϯ 20.9 0.226 minutes at room temperature with phycoerythrin-conju- 2 h 64.2 Ϯ 11.4 61.5 Ϯ 12.9 0.814 gated anti–P-selectin monoclonal antibody (Pharmingen, 24 h 51.7 Ϯ 14.4* 35.9 Ϯ 18.9* 0.044 San Diego, California), a marker of platelet activation, 7 d 51.3 Ϯ 9.1* 34.2 Ϯ 23.1* 0.045 and Peridinin Chlorophyll Protein-conjugated anti- 30 d 49.4 Ϯ 11.0* 31.2 Ϯ 15.0* 0.008 CD41a (Pharmingen) as control. Each sample was diluted Collagen (2 ␮g/ml) Baseline 66.7 Ϯ 20.0 65.3 Ϯ 15.5 0.753 10-fold in phosphate-buffered solution containing 1% Ϯ Ϯ paraformaldehyde to fix the cells. Platelet surface expres- 2 h 65.3 15.5 60.7 16.4 0.524 24 h 63.9 Ϯ 21.2 51.4 Ϯ 21.7 0.212 sion of P-selectin was analyzed using FACScan flow 7 d 65.4 Ϯ 12.2 31.4 Ϯ 17.9* 0.000 cytometry (Becton-Dickinson, Inc.) within 4 hours of cell 30 d 55.9 Ϯ 13.7 36.5 Ϯ 13.4* 0.007 fixation while the epitopes were still stable. Platelets were identified by their characteristic light-scattering All values expressed as mean Ϯ SD. profiles. Results were expressed as percentage of specific Dual-therapy group treated with aspirin plus clopidogrel; Triple-therapy group treated with aspirin plus clopidogrel plus cilostazol. antibody-positive platelets, defined as those with a fluo- Ͻ Ͼ *p 0.05 compared with respective baseline values using Wilcoxon’s rescence intensity 99% of control platelets. signed-rank test. Continuous variables are presented as mean Ϯ SD and compared using Wilcoxon’s signed-rank test or Mann- Whitney U test. Categorical variables are presented as num- and collagen were similar between the 2 groups. Inhibition ber or percentage and compared using chi-square test or of ADP-induced platelet aggregation gradually increased Fisher’s exact test. Statistical significance is defined as p over time in both groups. At 24 hours after stent placement, Ͻ0.05. platelet aggregation induced by both concentrations of ADP (5 or 20 ␮mol/L) significantly decreased compared with Results baseline in both groups. Beginning 24 hours after stent placement and at all further time points, inhibition of plate- There were no significant differences in patient character- let aggregation induced by both concentrations of ADP was istics between the 2 groups (Table 1). No major adverse significantly higher in patients receiving triple therapy than cardiovascular events, including death, myocardial infarc- in those receiving dual therapy. tion, stroke, or stent thrombosis, occurred during the In the dual-therapy group, there was no inhibition of 1-month study period. In addition, there were no serious collagen-induced platelet aggregation during the 1-month adverse reactions causing drug discontinuation and no ma- study period. However, in the triple-therapy group, collagen- jor bleeding episodes requiring transfusion. induced platelet aggregation was significantly lower 1 week Platelet aggregation profiles are shown in Table 2 and after stent placement than at baseline. Moreover, collagen- Figure 1. At baseline, platelet aggregation induced by ADP induced platelet aggregation was significantly lower at 1 612 The American Journal of Cardiology (www.AJConline.org)

Figure 1. (A to C) Agonist-induced platelet aggregation and (D) percentage of P-selectin expression over 30 days. Percentage of platelet aggregation after stimulation with (A) ADP 5 ␮M, (B) ADP 20 ␮M, or (C) collagen 2 ␮g/ml. (D) Percentage of P-selectin–positive platelets after stimulation with ADP 20 ␮M. All results expressed as mean Ϯ SD. †p Ͻ0.05; ‡p Ͻ0.01 between the 2 groups (compared using Mann-Whitney U test). Black circles, aspirin plus clopidogrel; white circles, aspirin plus clopidogrel plus cilostazol.

Table 3 nificantly lower in the triple therapy group than in the dual Percentage of P-selectin–positive platelets over time after stimulation ␮ therapy group at 1 week and 1 month after stent placement. with adenosine diphosphate 20 mol/L Figure 2 showed individual variability in reduction of ago- Dual-Therapy Group Triple-Therapy Group p Value nist-induced platelet aggregation and P-selectin expression (n ϭ 10) (n ϭ 10) between baseline and 1 month. Most patients in the triple Baseline 81.0 Ϯ 10.2 82.1 Ϯ 6.8 0.693 therapy group showed decreased agonist-induced platelet 2 h 79.2 Ϯ 5.5 73.8 Ϯ 7.1 0.472 aggregation and P-selectin expression at 1 month compared 24 h 76.6 Ϯ 8.4 68.7 Ϯ 6.8 0.293 with baseline activity. 7 d 71.9 Ϯ 9.5 53.2 Ϯ 17.2* 0.042 30 d 73.7 Ϯ 12.9 55.5 Ϯ 13.1* 0.024 Discussion Dual-therapy group treated with aspirin plus clopidogrel; Triple-therapy We showed here that a triple-therapy regimen of cilostazol, group treated with aspirin plus clopidogrel plus cilostazol. clopidogrel, and aspirin showed more potent inhibition of *pϽ0.05 compared with baseline using Wilcoxon’s signed-rank test. ADP-induced platelet aggregation than dual therapy with aspirin and clopidogrel. This difference first appeared 24 week in the triple-therapy group than in the dual-therapy hours after coronary stent placement and was maintained group. Platelet P-selectin expression after ADP (20 ␮M) thereafter, suggesting that clopidogrel and cilostazol had a stimulation is shown in Table 3 and Figure 1. Patients in the rapid and persistent action.7–9 We also found that platelet dual-therapy group showed no decrease in platelet P-selec- P-selectin expression and collagen-induced platelet aggre- tin expression over 1 month. In contrast, platelets from gation were not inhibited by dual antiplatelet therapy with patients in the triple-therapy group showed a significant aspirin and clopidogrel, which agrees with previous find- decrease in P-selectin expression 1 week after stent place- ings.9 However, triple antiplatelet therapy with aspirin, clo- ment versus baseline. In addition, ADP-induced P-selectin pidogrel, and cilostazol inhibited collagen-induced platelet expression was significantly lower in the triple-therapy aggregation and platelet P-selectin expression beginning 1 group than in the dual-therapy group at 1 week and 1 month week after stent placement. P-Selectin, a marker of platelet after stent placement. activation expressed exclusively by activated platelets, pro- In addition, ADP-induced P-selectin expression was sig- motes fibrin deposition, inducing leukocyte accumulation in Coronary Artery Disease/Effect of Triple Antiplatelet Therapy 613

Figure 2. Individual comparison of (Ato C) agonist-induced platelet aggregation and (D) percentage of P-selectin expression over 30 days. Percentage of platelet aggregation after stimulation with (A) ADP 5 ␮M, (B) ADP 20 ␮M, or (C) collagen 2 ␮g/ml. (D) Percentage of P-selectin–positive platelets after stimulation with ADP 20 ␮M. Black circles, aspirin plus clopidogrel; white circles, aspirin plus clopidogrel plus cilostazol. areas of vascular injury and arterial thrombogenesis.10,11 pidogrel may be caused by their ability to increase cAMP Thus, P-selectin may be important during thrombogenesis using different mechanisms of action. The addition of after stent placement, and the addition of cilostazol to the cilostazol to an aspirin plus clopidogrel regimen resulted in conventional dual regimen may decrease thrombotic com- additional suppression of platelet P-selectin expression and plications in patients at high risk of stent thrombosis. A also showed an appreciable decrease of incidence of stent recent clinical study involving 3,012 patients showed that triple thrombosis after coronary stent placement.6,15 This is espe- therapy was more effective than dual therapy in preventing cially important because of the recent finding of resistance stent thrombosis, suggesting that the laboratory findings pre- to aspirin and clopidogrel in a substantial number of patients sented here may be translated to clinical settings.6 undergoing coronary stent placement. This resistance was The exact mechanism of beneficial effects of triple anti- associated with increased risk of stent thrombosis and other platelet therapy remains uncertain. ADP-induced platelet cardiac events.16,17 Thus, the role of cilostazol in patients activation and aggregation may have an important role in with resistance to aspirin and clopidogrel should be clari- the pathogenesis of arterial thrombosis. Although clopi- fied. In addition, several large-scale recent publications and dogrel and cilostazol inhibit ADP-induced platelet aggrega- many clinicians currently use a 600-mg (or even 900-mg) tion using different mechanisms of action, both increase loading dose of clopidogrel, and there are several reports on intracellular cAMP, clopidogrel by inhibiting ADP-induced faster onset of platelet inhibition using a higher loading dose inhibition of adenylate cyclase and cilostazol by inhibiting than a conventional loading dose of 300 mg.18,19 If a higher phosphodiesterase III.12,13 Intracellular cAMP was shown to loading dose of clopidogrel is used in triple therapy, it is correlate with degree of inhibition of platelet aggregation.14 supposed that a more rapid and potent antiplatelet effect Thus, the additive antiplatelet effects of cilostazol and clo- could be achieved. 614 The American Journal of Cardiology (www.AJConline.org)

A few limitations need to be addressed. First, the sample 10. Yokoyama S, Ikeda H, Haramaki N, Yasukawa H, Murohara T, size is small, but we found a significant difference in platelet Imaizumi T. Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates. aggregation between the triple and dual antiplatelet regi- J Am Coll Cardiol 2005;45:1280–1286. mens. Second, study drugs were administered immediately 11. Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, after stent placement, which is not current standard care in Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposi- patients undergoing coronary stent placement. Our study tion is mediated in vivo by P-selectin on adherent platelets. Nature 1992;359:848–851. evaluated serial changes in platelet aggregation after coro- 12. Ryningen A, Olav Jensen B, Holmsen H. Elevation of cyclic AMP nary stent placement and was similar in design to previous decreases phosphoinositide turnover and inhibits thrombin-induced studies.20,21 Third, this study was not designed to show that secretion in human platelets. Biochim Biophys Acta 1998;1394:235– a triple regimen could decrease platelet aggregation in pa- 248. tients who may be at particular risk of adverse events after 13. Defreyn G, Gachet C, Savi P, Driot F, Cazenave JP, Maffrand JP. Ticlopidine and clopidogrel (SR 25990C) selectively neutralize ADP percutaneous coronary intervention, such as those with high inhibition of PGE1-activated platelet adenylate cyclase in rats and platelet reactivity after clopidogrel treatment. To provide a rabbits. Thromb Haemost 1991;65:186–190. rationale for the use of a triple antiplatelet regimen after 14. Kariyazono H, Nakamura K, Shinkawa T, Yamaguchi T, Sakata R, coronary stent placement in patients at high risk of throm- Yamada K. Inhibition of platelet aggregation and the release of P- selectin from platelets by cilostazol. Thromb Res 2001;101:445–453. botic complications, specific tests should be performed in 15. Ahn JC, Song WH, Kwon JA, Park CG, Seo HS, Oh DJ, Rho YM. such patients. For such patients, higher daily dosing regi- Effects of cilostazol on platelet activation in coronary stenting patients mens of clopidogrel could also be beneficial in decreasing already treated with aspirin and clopidogrel. Korean J Intern Med platelet aggregation.22 2004;19:230–236. 16. Muller I, Besta F, Schulz C, Massberg S, Schonig A, Gawaz M. Prevalence of clopidogrel non-responders among patients with stable 1. Okuda Y, Kimura Y, Yamashita K. Cilostazol. Cardiovasc Drug Rev angina pectoris scheduled for elective coronary stent placement. 1993;11:451–465. Thromb Haemost 2003;89:783–787. 2. Park SW, Lee CW, Kim HS, Lee HJ, Park HK, Hong MK, Kim JJ, 17. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Golden- Park SJ. Comparison of cilostazol versus ticlopidine therapy after stent berg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel implantation. Am J Cardiol 1999;84:511–514. resistance is associated with increased risk of recurrent atherothrom- 3. Yoon Y, Shim WH, Lee DH, Pyun WB, Kim IJ, Jang Y, Cho SY. botic events in patients with acute myocardial infarction. Circulation Usefulness of cilostazol versus ticlopidine in coronary artery stenting. 2004;109:3171–3175. Am J Cardiol 1999;84:1375–1380. 18. Price MJ, Coleman JL, Steinhubl SR, Wong GB, Cannon CP, Teirstein 4. Hashiguchi M, Ohno K, Nakazawa R, Kishino S, Mochizuki M, Shiga PS. Onset and offset of platelet inhibition after high-dose clopidogrel T. Comparison of cilostazol and ticlopidine for one-month effective- loading and standard daily therapy measured by a point-of-care assay ness and safety after elective coronary stenting. Cardiovasc Drugs in healthy volunteers. Am J Cardiol 2006;98:681–684. Ther 2004;18:211–217. 19. Montalescot G, Sideris G, Meuleman C, Bal-dit-Sollier C, Lellouche 5. Lee SW, Park SW, Hong MK, Lee CW, Kim YH, Park JH, Kang SJ, N, Steg PG, Slama M, Milleron O, Collet JP, Henry P, Beygui F, Han KH, Kim JJ, Park SJ. Comparison of cilostazol and clopidogrel Drouet L. A randomized comparison of high clopidogrel loading doses after successful coronary stenting. Am J Cardiol 2005;95:859–862. in patients with non-ST-segment elevation acute coronary syndromes: 6. Lee SW, Park SW, Hong MK, Kim YH, Lee BK, Song JM, Han KH, the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Lee CW, Kang DH, Song JK, Kim JJ, Park SJ. Triple versus dual Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. antiplatelet therapy after coronary stenting: impact on stent thrombo- J Am Coll Cardiol 2006;48:931–938. sis. J Am Coll Cardiol 2005;46:1833–1837. 20. Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao T, 7. Tanaka T, Ishikawa T, Hagiwara M, Onoda K, Itoh H, Hidaka H. Bray PF, Kleiman NS. Aspirin and clopidogrel drug response in Effects of cilostazol, a selective cAMP phosphodiesterase inhibitor on patients undergoing percutaneous coronary intervention: the role of the contraction of vascular smooth muscle. Pharmacology 1988;36: dual drug resistance. J Am Coll Cardiol 2006;47:27–33. 313–320. 21. Gurbel PA, Bliden KP, Hayes KM, Yoho JA, Herzog WR, Tantry US. 8. Kunishima T, Musha H, Eto F, Iwasaki T, Nagashima J, Masui Y, So The relation of dosing to clopidogrel responsiveness and the incidence T, Nakamura T, Oohama N, Murayama M. A randomized trial of of high post-treatment platelet aggregation in patients undergoing aspirin versus cilostazol therapy after successful coronary stent im- coronary stenting. J Am Coll Cardiol 2005;45:1392–1396. plantation. Clin Ther 1997;19:1058–1066. 22. Beckerath NVB, Kastrati AK, Wieczoreck AW, Pogatsa-Murray 9. Gurbel PA, Malinin AI, Callahan KP, Serebruany VL, O’Connor CM. GPM, Sibbing DS, Schoemig AS. A double-blind randomized com- Effect of loading with clopidogrel at the time of coronary stenting on parison between two different clopidogrel maintenance doses after platelet aggregation and glycoprotein IIb/IIIa expression and platelet- percutaneous coronary intervention (ISAR-CHOICE 2 Trial). Eur leukocyte aggregate formation. Am J Cardiol 2002;90:312–315. Heart J 2006;27:abstract 5039. Intravascular Ultrasound Parameters Associated With Stent Thrombosis After Drug-Eluting Stent Deployment

Teruo Okabe, MDa, Gary S. Mintz, MDb, Ashesh N. Buch, MDa, Probal Roy, MDa, Young Joon Hong, MDa, Kimberly A. Smith, BSa, Rebecca Torguson, BSa, Natalie Gevorkian, MDa, Zhenyi Xue, MSa, Lowell F. Satler, MDa, Kenneth M. Kent, MDa, Augusto D. Pichard, MDa, Neil J. Weissman, MDa, and Ron Waksman, MDa,*

Drug-eluting stent (DES) thrombosis (ST) can be devastating. The study aim was to evaluate intravascular ultrasound (IVUS) predictors for DES thrombosis by comparing IVUS studies after implantation in 13 patients with 14 DES thrombosis lesions with a group of controls (30 lesions in 27 patients) matched for history of chronic renal failure and type of DES. Five patients (38%) discontinued dual antiplatelet therapy at the time of ST. There were 3 in-stent restenosis lesions (21%) treated using DESs in the ST group compared with 0 in the control group (p <0.05). Compared with the control group, IVUS ,studies in the ST group showed a smaller minimum stent area (4.6 ؎ 1.1 vs 5.6 ؎ 1.7 mm2 In the ST group, 11 of 14 stents had a minimum stent area <5.0 mm2 .(0.0489 ؍ p Minimum stent area in patients .(0.0392 ؍ compared with 12 of 30 in the control group (p who stopped clopidogrel therapy and developed ST (5.30 ؎ 1.15 mm2) tended to be larger compared with that in patients who developed ST while using clopidogrel (4.24 ؎ 0.96 ,Within the 5-mm-long proximal and distal reference segments analyzed .(0.091 ؍mm2,p the ST group had larger proximal reference maximum plaque burdens and smaller minimum lumen areas, along with a tendency toward similar ﬁndings in the distal reference segments. In conclusion, IVUS ﬁndings at the time of DES implantation in patients who subsequently developed ST showed a smaller minimum stent area (especially in patients who developed ST while using clopidogrel) and more residual disease at the stent edges. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:615–620)

Drug-eluting stents (DESs) decrease angiographic and clin- setts) from April 2003 to September 2006 at our institution ical restenosis compared with bare-metal stents.1–5 How- were included in this study. Baseline demographic and ever, DESs may increase the risk of stent thrombosis (ST) procedural variables were recorded and entered prospec- compared with bare-metal stents.1,2,6 ST after bare-metal tively into our database by a dedicated data coordinating stent or DES implantation may have devastating conse- center. The occurrence of cardiac events or need for re- quences, including death and acute myocardial infarc- peated coronary revascularization was recorded and adjudi- tion.3,7–9 Predictors of DES thrombosis included primary cated by source documentation. We identified retrospec- stent implantation in patients with acute myocardial infarc- tively 13 patients with 14 lesions who underwent intravascular tion, renal failure,9,10 bifurcation lesions, number of de- ultrasonography at the time of DES deployment (Cypher 11 ployed stents, stent length,8,9,11 treatment of in-stent reste- lesions, Taxus 3 lesions) and subsequently developed ST. nosis,12 minimum stent area,13,14 residual reference segment We selected as the control group 27 patients (30 lesions; stenosis,14 reaction to the polymer,15 and discontinuation of Cypher 26 lesions, Taxus 4 lesions) who underwent similar antiplatelet therapy.8,9,16,17 We identified intravascular ultra- IVUS-guided DES deployment without ST. These were sound (IVUS) parameters predictive of ST after DES de- then matched with the ST group for stent type and presence ployment. of chronic renal failure, a known predictor of ST. Data for this study came from our database under the Health Insurance Methods Portability and Accountability Act of 1996 waiver, and the Institutional Review Board approved the study. All patients treated with sirolimus-eluting (Cypher; Cordis, Patients were treated with a single or multiple DESs. Johnson & Johnson, Miami Lakes, Florida) and paclitaxel- eluting stents (Taxus; Boston Scientific, Natick, Massachu- Intraprocedural anticoagulation included unfractionated heparin or bivalirudin with or without glycoprotein IIb/IIIa inhibitors. Activated clotting time was maintained at Ͼ250 seconds during the procedure. Type of stent and use of other aCardiovascular Research Institute, Washington Hospital Center, b devices were at the discretion of the operator. All patients Washington, DC; and Cardiovascular Research Foundation, New York, Ͼ New York. Manuscript received January 24, 2007; revised manuscript were given aspirin 325 mg/day for 24 hours before the received and accepted March 7, 2007. procedure, which was continued indefinitely, and a 300- to *Corresponding author: Tel.: 202-877-2812; fax: 202-877-2715. 600-mg loading dose of clopidogrel followed by 75 mg E-mail address: [email protected] (R. Waksman). twice daily for Ն6 months.

Coronary angiograms were analyzed using a validated Table 1 edge-detection system (CAAS QCA for Research, Pie Med- Clinical characteristics ical Imaging B.V., Maastricht, The Netherlands). The ref- Variable ST Control p Value erence diameter and minimum luminal diameter were mea- (n ϭ 13) (n ϭ 27) sured before and after the procedure. Angiographic Age (yrs) 57.5 Ϯ 10.4 65.3 Ϯ 12.0 0.043 percentage of diameter stenosis was defined as (1 Ϫ [min- ϫ Men 5 (38%) 20 (74%) 0.029 imum luminal diameter/reference diameter]) 100. Each Hypertension* 10 (77%) 23 (85%) 0.5 lesion was classified according to the modified American Hypercholesterolemia† 11 (85%) 21 (78%) 0.6 College of Cardiology/American Heart Association classi- Diabetes mellitus 5 (38%) 8 (30%) 0.6 fication. Family history of coronary artery 6 (46%) 5 (19%) 0.067 We used 1 of 2 commercially available systems: Atlantis disease SR (Boston Scientific Corp./SCIMED, Minneapolis, Min- Current smoker 6 (46%) 6 (22%) 0.12 nesota) or Eagle Eye (Volcano Therapeutics, Inc., Rancho Stable angina pectoris 10 (77%) 17 (63%) 0.4 Cordova, California). IVUS images were recorded after Acute coronary syndrome 3 (23%) 10 (37%) 0.4 administration of nitroglycerin 150 to 200 ␮g. The ultra- Previous myocardial infarction 4 (31%) 4 (15%) 0.2 Previous coronary artery bypass 4 (31%) 3 (11%) 0.13 sound catheter was advanced Ͼ5 mm beyond the stent and Ͼ surgery pulled back to a point 5 mm proximal to the stent using Previous percutaneous coronary 4 (31%) 8 (30%) 0.9 motorized transducer pullback at 0.5 or 1.0 mm/s. All IVUS intervention images were recorded on s-VHS videotapes or compact Chronic renal failure 1 (8%) 3 (11%) 0.7 discs for off-line analysis. Dialysis dependent 1 (8%) 0 (0%) 0.3 Lesions were divided into 5 sections as proximal and Glycoprotein IIb/IIIa inhibitor use 5 (38%) 1 (4%) 0.004 distal reference segments, proximal and distal stent edges, * Defined as history of hypertension diagnosed and/or treated with and stent body. Edge dissection, stent malapposition, and medication or currently being treated with diet and/or medication by a plaque prolapse were evaluated. Cross-sectional area mea- physician. surements of the external elastic membrane, stent area, † Includes patients with a previously documented diagnosis of lumen area, plaque and media (plaque and media ϭ external hypercholesterolemia. elastic membrane Ϫ lumen area), and plaque burden (plaque and media/external elastic membrane) were performed ev- Table 2 ery 1 mm in both the stented segment and 5-mm-long Angiographic and procedural characteristics reference sites proximal and distal to the stent edge using Variable ST Control p Value TapeMeasure 4.2.16C (Indec Systems, Inc., Mountain (n ϭ 13) (n ϭ 27) View, California). When side branches were located near the proximal or distal stent edge, reference segment analysis Lesion location ended at the side branch. Stent length was measured using Left anterior coronary artery 10 (71%) 18 (60%) 0.5 automatic pullback. Volumes were determined using Simp- Left circumflex 1 (7%) 4 (13%) 0.5 son’s rule and also reported as mean areas. Maximum cross- Right coronary 3 (22%) 8 (27%) 0.7 ACC/AHA type B2/C 12 (85%) 21 (70%) 0.26 sectional area plaque burden and the smallest lumen area Ostial lesion 2 (14%) 2 (7%) 0.4 within each 5-mm-long reference segment were also reported. Bifurcation 7 (50%) 9 (30%) 0.20 ST was defined as angiographically documented partial In-stent restenosis 3 (21%) 0 (0%) 0.0275 or total stent occlusion or ST-elevation or non–ST-elevation Chronic total occlusion 1 (7%) 1 (3%) 0.6 myocardial infarction in the territory of the treated vessel Thrombus 0 (0%) 4 (13%) 0.5 when ST could not be excluded definitively. ST was divided Ulceration 3 (21%) 4 (13%) 0.5 into 3 categories of (1) acute (Յ24 hours after DES deploy- Maximum balloon diameter (mm) 3.07 Ϯ 0.28 3.22 Ϯ 0.31 0.14 ment), (2) subacute (24 hours to 30 days after DES deploy- Maximum inflation pressure (atm) 15.5 Ϯ 3.1 17.1 Ϯ 3.6 0.17 Ϯ Ϯ ment), and (3) late (Ͼ30 days after DES deployment). Total stent number 1.1 0.4 1.3 0.5 0.4 Statistical analysis was performed using SAS, version ACC/AHA ϭ American College of Cardiology/American Heart 9.1 (SAS Institute Inc., Cary, North Carolina). Continuous Association. variables were reported as mean Ϯ 1 SD and compared using Student’s t test unless data were not normally distributed, in which case Mann-Whitney test was used. Categor- tein IIb/IIIa inhibitors (Table 1). Acute coronary syndromes ical variables were reported as frequencies and compared and thrombus-containing or ulcerated angiographic lesion using chi-square statistics. A p value Ͻ0.05 was considered characteristics were not significantly different between the 2 significant. We had full access to the data and take respon- groups (Tables 1 and 2). However, there were 3 in-stent sibility for its integrity. We have read and agree to the restenosis cases in the ST group compared with 0 in the manuscript as written. control group (p ϭ 0.0275). Three patients had acute, 5 patients had subacute, and 5 Results patients had late ST. Acute and subacute ST occurred a median of 6.4 days (range 3 hours to 16 days) from proce- Baseline clinical characteristics were similar between ST dures. However, none had shown ST during the procedure. and non-ST patients, although patients with ST were less Late ST occurred at 6.7 months (range 1.8 to 14.4). Dis- often men, younger, and more often treated with glycopro- continuation of clopidogrel therapy was documented in 5 Coronary Artery Disease/Stent Thrombosis After DES Deployment 617

Table 3 of 30 in the control group (p ϭ 0.0392). Figure 2 shows Quantitative coronary angiographic analysis the relation between minimum stent area and time from Variable ST Control p Value DES deployment to ST. Minimum stent area in patients (n ϭ 14) (n ϭ 30) who stopped clopidogrel therapy and developed ST (5.30 Ϯ 1.15 mm2) tended to be larger compared with that in Pre-reference 2.43 Ϯ 0.5 2.70 Ϯ 0.62 0.17 patients who developed ST while using clopidogrel (4.24 diameter (mm) Ϯ 2 ϭ Pre-minimum luminal 1.03 Ϯ 0.55 1.25 Ϯ 0.56 0.2 0.96 mm ,p 0.091). However, minimum stent area diameter (mm) was similar regardless of whether patients developed Pre-diameter stenosis (%) 57.1 Ϯ 21.2 53.0 Ϯ 17.3 0.5 acute, subacute, or late ST (analysis of variance p ϭ 0.4). Post-reference diameter 2.75 Ϯ 0.47 3.03 Ϯ 0.55 0.12 Within the 5-mm-long proximal and distal reference seg- (mm) ments analyzed, although vessel sizes (external elastic Post-minimum luminal 2.27 Ϯ 0.22 2.46 Ϯ 0.38 0.07 membrane areas) were similar in the 2 groups, the ST group diameter (mm) had larger proximal reference maximum plaque burdens and Post-diameter stenosis (%) 16.4 Ϯ 8.4 18.0 Ϯ 9.7 0.6 smaller minimum lumen areas, along with a tendency toward similar findings in distal reference segments. In the ST Table 4 group, there were 2 edge dissections, no case of acute stent Intravascular ultrasound analysis after drug-eluting stent deployment malapposition, and 1 patient with plaque prolapse. Con- versely, there were no edge dissections, 2 acute stent malap- Variable ST Control p Value ϭ ϭ positions, and 6 patients with plaque prolapse in the control (n 14) (n 30) group (p ϭ NS for all comparisons). Figures 3 and 4 show Stent expansion (%) 91 Ϯ 25 90 Ϯ 19 0.9 representative cases of ST. Edge dissection 2 0 0.2 Acute stent malapposition 0 2 0.8 Plaque prolapse 1 6 0.5 Discussion Proximal reference segment 2 Ϯ Ϯ This study showed that lesions causing ST after DES de- Mean EEM area (mm ) 14.7 4.6 14.2 5.2 0.8 ployment have small minimum stent areas and more refer- Mean lumen area (mm2) 5.6 Ϯ 1.6 6.91 Ϯ 2.5 0.11 Smallest lumen area (mm2) 4.7 Ϯ 1.1 6.0 Ϯ 2.3 0.0669 ence segment disease, especially in patients who developed Largest plaque burden 0.66 Ϯ 0.08 0.56 Ϯ 0.10 0.0018 ST while using clopidogrel. Proximal stent edge Previous studies reported that stent underexpansion was EEM area (mm2) 14.9 Ϯ 4.5 16.2 Ϯ 5.1 0.4 1 of the mechanical causes of ST after bare-metal stent Stent area (mm2) 6.1 Ϯ 1.5 7.0 Ϯ 2.1 0.17 implantation.18 Because DESs significantly decreased late Stented segment loss, aggressive DES expansion was believed to be less Mean EEM area (mm2) 13.3 Ϯ 3.8 14.2 Ϯ 4.4 0.5 necessary than after bare-metal stent implantation. For ex- 2 Minimum stent area (mm ) 4.6 Ϯ 1.1 5.6 Ϯ 1.7 0.0489 ample, Sonoda et al13 reported that the minimum stent area Stent length (mm) 26.2 Ϯ 9.3 24.5 Ϯ 13.9 0.7 3 Ϯ Ϯ that best separated Cypher restenosis from no restenosis was EEM volume (mm ) 346.5 160.4 356.3 250.4 0.8 5.0 mm2, smaller than the 6.5 mm2 that best separated Stent volume (mm3) 150.2 Ϯ 63.3 165.8 Ϯ 95.4 0.6 Distal stent edge bare-metal stent restenosis from no restenosis. However, the EEM area (mm2) 10.7 Ϯ 3.0 12.0 Ϯ 4.6 0.3 current analysis is the second to show that DES underex- Stent area (mm2) 5.6 Ϯ 1.6 6.8 Ϯ 2.2 0.079 pansion is a common finding after ST in DES-treated pa- Distal reference segment tients. In the current study, the number of ST lesions with a Mean EEM area (mm2) 9.4 Ϯ 3.4 10.3 Ϯ 4.7 0.5 minimum stent area Ͻ5.0 mm2 was significantly higher Mean lumen area (mm2) 4.8 Ϯ 1.7 6.2 Ϯ 3.4 0.062 compared with the control group (Figure 1). Smallest lumen area (mm2) 4.3 Ϯ 1.7 5.3 Ϯ 2.1 0.12 The 2 basic causes of small minimum stent area are stent Largest plaque burden 0.53 Ϯ 0.15 0.45 Ϯ 0.14 0.14 underexpansion and a small vessel. In the present study, EEM ϭ external elastic membrane. both seemed to be important. Stent expansion (minimum stent area/average of proximal and distal reference lumen area) averaged 91%, but the SD was large at 25%. There patients (38%); 2 in the subacute ST group (1 patient had would have to be 100% stent expansion to achieve a min- stopped all antiplatelet therapy because of a surgical proce- imum stent area of 5.0 mm2 in a 2.5-mm reference lumen dure) and 3 in the late ST group. vessel. There was a moderate difference in quantitative Procedure characteristics (Table 2) and quantitative cor- coronary angiographic reference diameters between the 2 onary angiographic analysis (Table 3) did not show differ- groups, perhaps because of the higher prevalence of women ences between the 2 groups except that ST lesions tended to in the ST group or, alternatively, that more ST patients were have smaller final minimum lumen diameters (p ϭ 0.07). women because of their smaller vessel sizes. Younger IVUS analyses are listed in Table 4. Throughout the women were reported to have smaller vessel sizes compared entire analysis length (stent and reference segments), exter- with men.19 However, IVUS showed no difference in ex- nal elastic membrane did not differ between the groups. ternal elastic membrane areas between the 2 groups. This Minimum stent area was significantly smaller in the ST indicates that ST did not necessarily occur in smaller ves- group. Figure 1 shows the histogram of the minimum stent sels, but in vessels that were more diffusely diseased with a area between the 2 groups. In the ST group, 11 of 14 stents larger plaque burden. had a minimum stent area Յ5.0 mm2 compared with 12 Cheneau et al18 reported more stent edge dissections in 618 The American Journal of Cardiology (www.AJConline.org)

Figure 1. The distribution of minimum stent area after DES deployment in each group. Left, ST group; right, control. Each division of the x axis means a width of 0.5 mm2. Eleven lesions in the ST group (79%) had minimum stent area Ͻ5.0 mm2 compared with 12 lesions in the control group (40%; p Ͻ0.05).

patients who stopped using clopidogrel versus those who still using clopidogrel, thus suggesting that optimal stent expansion does not compensate for lack of dual antiplatelet therapy and dual antiplatelet therapy does not compensate for stent underexpansion. The present study included 3 patients who underwent Cypher deployment for bare-metal stent restenosis (Table 2). Waters et al12 suggested that DES treatment of bare-metal stent restenosis could be 1 of the factors associated with ST in patients discontinuing antiplatelet therapy. In the present study, 2 patients prematurely discontinued antiplatelet therapy at the time of ST (11 and 16 days after the procedure). Minimum stent area in these 3 Figure 2. Relation between minimum stent area and interval from DES patients measured 4.0, 4.54, and 2.94 mm2. deployment to occurrence of ST (days). Black circles, patient not using Stent length, number of stents,8,9,11 primary stenting in clopidogrel at time of ST thrombosis; white diamonds, using clopidogrel. patients with acute myocardial infarction, renal failure,9,10 Ϯ 2 Minimum stent area of patients without clopidogrel (5.30 1.15 mm ) and bifurcation lesions8,9 were all identified as predictors of tended to be larger than those for patients using clopidogrel (4.24 Ϯ 0.96 mm2,pϭ 0.091). ST in reported previous studies. However, these were not confirmed in the current study, presumably because of small patient numbers and their possible interaction with stent bare-metal stent–treated patients who developed ST com- underexpansion, which cannot be assessed. Longer stents pared with controls. Fujii et al14 reported that 67% of ST (or lesions treated with more stents) were not associated after DES deployment was associated with residual refer- with the smaller minimum stent area than shorter stents (or ence segment stenosis (peristent lumen area Ͻ4.0 mm2, lesions treated with only 1 stent) in the ST group. plaque burden Ͼ70%). In the present analysis, ST in DES- Finally, other possible IVUS-detectable predictors of ST treated patients was associated with smaller peristent lu- after DES implantation are acute and late acquired stent mens and larger plaque burdens, but not with edge dissec- malapposition, plaque prolapse, and strut fracture. Acute tions. However, both edge dissections and untreated stent malapposition and plaque prolapse were not more significant peristent edge disease can affect inflow and out- common in ST patients than controls in the present study. flow, which can contribute to ST. A greater edge plaque We did not have intravascular ultrasonography at the time burden was also shown to be a risk factor for edge restenosis of ST and therefore could not determine whether any of the after both bare-metal stent and DES implantation.20 Thus, it STs were associated with them. Several previous studies may be important to cover the entire diseased segment to reported that acute21,22 and late15,23 stent malapposition, decrease both edge restenosis and ST. plaque prolapse,24,25 nonuniform strut distribution,26 or strut Premature discontinuation of clopidogrel therapy was fracture27 could occur and be part of the reason for major reported to be perhaps the most significant predictor for ST adverse cardiovascular events, including ST. However, in DESs.8,9,16,17 Five of these ST patients had stopped clo- some studies denied associations between ST and stent pidogrel therapy, 1 of whom also stopped aspirin therapy. malapposition or plaque prolapse.28,29 Minimum stent area at the time of ST tended to be larger in The main limitation of this study was the number of Coronary Artery Disease/Stent Thrombosis After DES Deployment 619

Figure 3. A 74-year-old black woman with a diagnosis of stable angina underwent Cypher stent (2.5 ϫ 28 mm) deployment into the left anterior descending artery. Left upper panel, final angiogram at the procedure. White arrows, (a) The proximal reference; (b) minimum stent area (MSA); and (c) the distal reference segment. Lower panels, IVUS images after Cypher deployment from proximal (left side) to distal (right side). Right upper panel, Coronary angiogram of this patient 125 days later. Although dissection occurred at the distal reference site (white arrows) on IVUS, the procedure was finished because the lumen was not obstructed by the flap and blood flow was not impaired. This patient was readmitted to our hospital 125 days later because of suspicion of recent myocardial infarction, when she was using both aspirin and clopidogrel. EEM ϭ cross-sectional area of external elastic membrane; LA ϭ luminal area; P&M area ϭ plaque plus media area.

Figure 4. The Taxus stent (3.0 ϫ 24 mm) was deployed into the left anterior descending artery of a 47-year-old black woman with hypertension and hypercholesterolemia with a diagnosis of stable angina. She had a history of percutaneous coronary intervention and bypass surgery. Left upper panel, final angiogram at the procedure. White arrows, (a) the proximal reference, (b) MSA, and (c) distal reference segment. Lower panels, IVUS images after Taxus deployment from proximal (left side) to distal (right side). Right upper panel, coronary angiogram of this patient 54 days later. Abbreviations as in Figure 3. 620 The American Journal of Cardiology (www.AJConline.org) patients with ST and that it was a retrospective single-center eluting stents after discontinuation of antiplatelet therapy. Catheter experience. Controls were matched for only DES type and Cardiovasc Interv 2005;65:520–524. 13. Sonoda S, Morino Y, Ako J, Terashima M, Hassan AH, Bonneau HN, presence of chronic renal failure. However, there were no Leon MB, Moses JW, Yock PG, Honda Y, Kuntz RE, Fitzgerald PJ, significant differences in other factors associated with ST, for the SIRIUS Investigators. Impact of final stent dimensions on such as reference diameter, bifurcation lesions, residual long-term results following sirolimus-eluting stent implantation: serial dissection, stent length, and acute coronary syndrome. ST intravascular ultrasound analysis from the SIRIUS trial. J Am Coll patients were more frequently treated with glycoprotein Cardiol 2004;43:1959–1963. IIb/IIIa inhibitors. Patients were not matched for bifurcation 14. Fujii K, Carlier SG, Mintz GS, Yang YM, Moussa I, Weisz G, Dangas G, Mehran R, Lansky AJ, Kreps EM, et al. Stent underexpansion and lesion location, gender, or clinical presentation; however, residual reference segment stenosis are related to stent thrombosis after there was no difference between groups in these variables. sirolimus-eluting stent implantation: an intravascular ultrasound study. We did not perform a multivariate analysis because of the J Am Coll Cardiol 2005;45:995–998. small patient numbers in this study. 15. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD. Localized hyper- sensitivity and late coronary thrombosis secondary to a sirolimus- 1. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin eluting stent. Should we be cautious? Circulation 2004;109:701–705. M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, 16. Jeremias A, Sylvia B, Bridges J, Kirtane AJ, Bigelow B, Pinto DS, Ho Falotico R, for the RAVEL Study Group. Randomized study with the KK, Cohen DJ, Garcia LA, Cutlip DE, Carrozza JP Jr. Stent throm- sirolimus-coated Bx velocity balloon-expandable stent in the treatment bosis after successful sirolimus-eluting stent implantation. Circulation of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for 2004;109;1930–1932. coronary revascularization. N Engl J Med 2002;346:1773–1780. 17. McFadden EP, Stabile E, Regar E, Cheneau E, Ong AT, Kinnaird T, 2. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, Suddath WO, Weissman NJ, Torguson R, Kent KM, et al. Late O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein thrombosis in drug-eluting coronary stents after discontinuation of PS, Jaeger JL, Kuntz RE, for the SIRIUS Investigators. Sirolimus- antiplatelet therapy. Lancet 2004;364:1519–1521. eluting stents versus standard stents in patients with stenosis in a native 18. 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Sakurai R, Ako J, Morino Y, Sonoda S, Kaneda H, Terashima M, JK, Kim JJ, Weissman NJ, Fearnot NE, Park SW, Park SJ, for the Hassan AH, Leon MB, Moses JW, Popma JJ, et al, for the SIRIUS ASian Paclitaxel-Eluting Stent Clinical Trial. Paclitaxel coating Trial Investigators. Predictors of edge stenosis following sirolimus- reduces in-stent intimal hyperplasia in human coronary arteries: a eluting stent deployment (a quantitative intravascular ultrasound anal- serial volumetric intravascular ultrasound analysis from the ASian ysis from the SIRIUS trial). Am J Cardiol 2005;96:1251–1253. Paclitaxel-Eluting Stent Clinical Trial (ASPECT). Circulation 21. Alfonso F, Suarez A, Angiolillo DJ, Sabate M, Escaned J, Moreno R, 2003;107:517–520. Hernandez R, Banuelos C, Macaya C. Findings of intravascular ultra- 5. Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerck- sound during acute stent thrombosis. Heart 2004;90:1455–1459. ens U, Russell ME. 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T, Costa RA, Moussa I, Dangas GD, Mehran R, et al. Nonuniform strut 9. Kuchulakanti PK, Chu WW, Torguson R, Ohlmann P, Rha SW, distribution correlates with more neointimal hyperplasia after siroli- Clavijo LC, Kim SW, Bui A, Gevorkian N, Xue Z, et al. Correlates mus-eluting stent implantation. Circulation 2004;110:3430–3434. and long-term outcomes of angiographically proven stent thrombo- 27. Sianos G, Hofma S, Ligthart JM, Saia F, Hoye A, Lemos PA, Serruys sis with sirolimus- and paclitaxel-eluting stents. Circulation 2006; PW. Stent fracture and restenosis in the drug-eluting stent era. Cathet 113:1108–1113. Cardiovasc Interv 2006;61:111–116. 10. Park DW, Park SW, Park KH, Lee BK, Kim YH, Lee CW, Hong MK, 28. Hong MK, Mintz GS, Lee CW, Park DW, Park KM, Lee BK, Kim Kim JJ, Park SJ. Frequency of and risk factors for stent thrombosis YH, Song JM, Han KH, Kang DH, et al. Late stent malapposition after after drug-eluting stent implantation during long-term follow-up. 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Meta-Analysis of Angiographic Versus Intravascular Ultrasound Parameters of Drug-Eluting Stent Efficacy (from TAXUS IV, V, and VI)

Esteban Escolar, MDa, Gary S. Mintz, MDb, Jeffrey Popma, MDc, Aleksandra Michalek, MDa, Sang Wook Kim, MD, PhDa, Lazar Mandinov, MD, PhDd, Joerg Koglin, MD, PhDd, Gregg Stone, MDb, Stephen G. Ellis, MDe, Eberhard Grube, MDf, Keith D. Dawkins, MDg, and Neil J. Weissman, MDa,*

Both quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) are currently used to assess in-stent restenosis. This study aimed to use standardized imaging and clinical follow-up to compare QCA parameters with several IVUS parameters to evaluate their strengths and weaknesses for detecting in-stent restenosis in a drug-eluting stent population. A subset of patients from the TAXUS IV, V, and VI studies was evaluated. The subset, which included 216 TAXUS-treated patients and 191 bare-metal stent–treated patients, had complete IVUS and QCA performed at baseline and follow-up. As expected, all QCA and IVUS parameters were consistent with less intimal hyperplasia in TAXUS patients than controls. The overall incidence of QCA binary restenosis was 14.0%, which was 9.3% in TAXUS-treated patients and 19% in bare-metal stent–treated Regression analysis showed that QCA late lumen loss and percentage .(0.0008 ؍ patients (p of diameter stenosis correlated only moderately with the various IVUS measures of neointimal hyperplasia for the combined group of patients (TAXUS ؉ bare-metal stent), as well as for the TAXUS-treated and bare-metal stent–treated patients separately. However, in general, correlations within the control (bare-metal stent) group tended to be stronger than within the TAXUS group. The strongest correlation was between QCA percentage of diameter stenosis and IVUS percentage of intimal hyperplasia in the overall group and the control group. The strongest IVUS predictor of QCA binary restenosis at 9 months was and p <0.001. In 0.91 ؍ maximum percentage of intimal hyperplasia, with an overall C conclusion, the QCA and IVUS parameters used to evaluate drug-eluting stent efﬁcacy showed a moderate correlation with IVUS percentage of intimal hyperplasia, reliably predicting QCA binary in-stent restenosis. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:621–626)

Drug-eluting stents (DESs) have dramatically decreased, timal hyperplasia and therefore directly quantify the in-stent but not totally eliminated, in-stent restenosis. The primary restenosis process. Using angiographic and IVUS data from quantitative end point for assessing the effectiveness of the Treatment of denovo coronary disease using a single DESs typically has been quantitative coronary angiography pAclitaXel eluting stent studies (TAXUS) randomized con- (QCA); specifically, measures of late loss, follow-up diam- trolled trials, we compared multiple angiographic and IVUS eter stenosis, and binary restenosis.1 However, these angio- measures of restenosis to better understand the relative graphic measures are surrogates for intimal hyperplasia (the strengths and weaknesses of these parameters. biologic process of in-stent restenosis). Conversely, intravascular ultrasound (IVUS) can visualize and measure in- Methods Patient population and protocol: The TAXUS trials aCardiovascular Research Institute/Medstar Research Institute, Wash- that used the polymer-based paclitaxel-eluting TAXUS Ex- ington Hospital Center, Washington, DC; bCardiovascular Research Foun- press stent (Boston Scientific, Natick, Massachusetts) in de dation, New York, New York; cDepartment of Cardiology, Brigham and novo lesions (TAXUS IV, V de novo, and VI) were de- Women’s Hospital, Boston; dBoston Scientific Corp, Natick, Massachu- scribed previously.2 All 3 studies were double-blind ran- setts; eThe Cleveland Clinic Foundation, Cleveland, Ohio; fHeart Center, domized controlled trials. The institutional review board at g Siegburg, Germany; and Southampton University Hospital, Southampton, each participating center approved each of the 3 studies, and United Kingdom. Manuscript received October 31, 2006; revised manu- consecutive eligible patients signed informed written con- script received March 4, 2007, and accepted March 20, 2007. *Corresponding author: Tel.: 202-877-0223; fax: 202-877-0206. sent. For the purpose of this report, we analyzed only E-mail address: [email protected] (N.J. Weissman). patients with complete angiographic and volumetric IVUS data at both time of implantation and 9-month follow-up. Dr. Mandinov and Dr. Koglin are full-time employees of Boston The current analysis therefore includes a subset of 216 Scientific Corporation, Marlborough, Massachusetts. TAXUS-treated patients (68 from TAXUS IV, 104 from

Figure 1. Illustration of IVUS measurement of maximal intimal hyperplasia (IH) thickness. Once the lumen and the stent are traced, the software detects the centroid of the stent and constructs 180 lines through this centroid. The computer calculates the maximal distance between the lumen border and stent, the maximum IH thickness. Average distance between the lumen border and stent represents the mean IH thickness. CSA ϭ cross-sectional area.

Figure 2. Illustration of IVUS measurement of percentage of neointimal free length of stent (%NFLS). The number of cross-sectional image slices (1 mm apart) with no detectable neointimal hyperplasia using IVUS is divided by total length of the stent. Abbreviations: EEM ϭ external elastic membrane; IH ϭ intimal hyperplasia.

TAXUS V, and 44 from TAXUS VI) and 191 bare-metal ameter stenosis at follow-up), and late lumen loss (calcu- stent–treated control patients (68 from TAXUS IV, 84 from lated as minimal lumen diameter after the procedure Ϫ TAXUS V, and 39 from TAXUS VI). follow-up minimal lumen diameter) were calculated.3 Angiography analysis: Independent QCA analysis was IVUS protocol and analysis: After intracoronary admin- performed at the angiographic core laboratory by a techni- istration of nitroglycerin 0.1 to 0.2 mg, IVUS imaging was cian who was unaware of patients’ clinical outcomes. A performed using a motorized transducer pullback system (0.5 single angiographic core laboratory was used for all patients mm/s) and commercial catheters (Atlantis SR, Boston Scien- in this report. The in-stent analysis encompassed only the tific, Maple Grove, Minnesota, or Eagle Eye or Avanar F/X, segment covered by the stent, whereas the in-lesion analysis Volcano Corp., Rancho Cordova, California). Images were also included 5-mm segments proximal and distal to the stored on s-VHS tapes or compact disc in Digital Imaging and stent edge. Minimal lumen and reference diameters were Communications in Medicine (DICOM) format. measured after the procedure and at follow-up. Percentage Quantitative volumetric IVUS analysis was performed at of diameter stenosis, restenosis rate (defined as Ͼ50% dian independent core laboratory by a technician who was Coronary Artery Disease/Imaging Assessment of DES Efficacy 623

Table 1 Selected baseline patient characteristics Variable TAXUS Control p Value TAXUS IV TAXUS V TAXUS VI p* Value IV, V, VI IV, V, VI (TAXUS ϩ control) (TAXUS ϩ control) (TAXUS ϩ control) (n ϭ 216) (n ϭ 191) (n ϭ 36) (n ϭ 188) (n ϭ 83) Baseline clinical characteristic Age (yrs) 62.7 Ϯ 10.3 62.9 Ϯ 10.1 0.83 62.7 Ϯ 10.2 62.1 Ϯ 10.5 64.6 Ϯ 9.6 0.18 Women 55 (25.5%) 64 (33.5%) 0.08 35 (25.7%) 62 (33%) 22 (26.5%) 0.31 Diabetes mellitus 62 (28.7%) 45 (23.6%) 0.26 31 (22.8%) 61 (32.4%) 15 (18.1%) 0.02 Requiring medication 44 (20.4%) 25 (13.1%) 0.06 22 (15.9%) 38 (20%) 15 (18.2%) 0.59 Requiring insulin 18 (8.3%) 20 (10.5%) 0.49 8 (5.9%) 26 (13.8%) 4 (4.8%) 0.01 Hypertension requiring 146 (67.4%) 127 (66.5%) 0.91 102 (75%) 120 (63.6%) 51 (61.4%) 0.04 medication Hyperlipidemia 155 (71.8%) 126 (65.8%) 0.23 93 (68.2%) 130 (69%) 58 (69.9%) 0.96 requiring medication Current smoking 51 (23.7%) 37 (19.6%) 0.33 29 (21.3%) 39 (20.7%) 21 (25%) 0.71 Previous myocardial 69 (32.1%) 53 (27.9%) 0.33 37 (27.2%) 58 (30.6%) 28 (33.7%) 0.59 infarction Clinical presentation Unstable angina pectoris 65 (30.1%) 62 (32.5%) 0.66 42 (30.9%) 69 (36.7%) 16 (19.3%) 0.015 Stable angina pectoris 122 (56.7%) 103 (54%) 0.54 75 (55%) 96 (51%) 56 (68%) 0.03 Lesion characteristics Left anterior descending 97 (44.7%) 81 (42.6%) 0.66 67 (49%) 71 (37.8%) 42 (50.4%) 0.01 Lesion type A 17 (7.9%) 12 (6.3%) 0.56 15 (11.1%) 13 (6.9%) 1 (1.2%) 0.0148 B1 65 (30.2%) 36 (18.8%) 0.008 55 (40.7%) 29 (15.5%) 17 (20.5%) 0.0001 B2 74 (34.4%) 83 (43.5%) 0.06 49 (36.3%) 76 (40.4%) 32 (38.6%) 0.76 C 59 (27.4%) 60 (31.4%) 0.38 16 (11.9%) 70 (37.2%) 33 (39.8%) 0.0001 Total stent length (mm) 27.37 Ϯ 12.02 26.83 Ϯ 11.8 0.59 18.53 Ϯ 5.03 28.15 Ϯ 12.74 27.18 Ϯ 3.94 0.0001

Values expressed as mean Ϯ SD or number (percent). * p Value for baseline comparison across all studies. unaware of patients’ clinical outcomes. A single IVUS core length of each stent that was free of IVUS-detectable neo- laboratory was used for all patients in this report. With the intima divided by the total length of the stent (Figure 2). use of computerized planimetry (TapeMeasure, Indec Sys- Statistical analysis: Continuous variables are presented tems, Mountain View, California), stent and lumen edges as mean Ϯ 1 SD. Factorial design analyses using 2-way were manually traced. Stent, lumen, and intimal hyperplasia analysis of variance testing treatment and study interaction (stent Ϫ lumen) areas were measured every 1 mm within the for each QCA and IVUS parameter were performed show- stented segment. Volumes were calculated using Simpson’s ing no significant interaction p values for all variables. This rule. Percentage of intimal hyperplasia was defined as inti- justifies the pooling and comparison of TAXUS and bare- mal hyperplasia volume divided by stent volume. Maximum metal stents using simple t test. percentage of intimal hyperplasia was defined as the largest Adjusted R-square by correlation based on partial corre- percentage of intimal hyperplasia (intimal hyperplasia area lation for the overall population was performed. For corre- divided by stent area) at any point within the length of the lation assessment in the TAXUS and bare-metal stent group stent. IVUS binary restenosis was defined as maximum only, partial correlation was sought by adjusting for study. Ͼ percentage of intimal hyperplasia 50%. Minimum lumen Statistical significance was set at p Ͻ0.05. area was defined as the smallest lumen area within the length of the stent. Angiographic diameter stenosis is a comparison of 2 Results linear dimensions with a goal of obtaining a surrogate mea- There were some minor differences in baseline clinical sure of intimal hyperplasia thickness within the stent. Inti- characteristics among the 3 TAXUS trials (Table 1). Mean mal hyperplasia thickness on IVUS therefore was also mea- IVUS stent areas were equal in the TAXUS arms among the sured to determine its relative value. TapeMeasure software 3 studies (7.80 Ϯ 1.87 in TAXUS IV, 7.70 Ϯ 2.41 in automatically places 180 lines passing through the centroid TAXUS V, and 7.90 Ϯ 1.7 mm2 in TAXUS VI; p ϭ 0.22). of the mass of the lumen contour and the entire stent Percentages of intimal hyperplasia were also similar in the circumference. Intimal hyperplasia thickness was measured TAXUS arms among the 3 studies (11.12 Ϯ 12.32% in as the distance between the lumen and stent along each of TAXUS IV, 13.77 Ϯ 12.75% in TAXUS V, and 11.03 Ϯ these lines (Figure 1). Maximal, mean, and minimal intimal 11.48% in TAXUS VI; p ϭ 0.31). Percentage of neointimal hyperplasia thicknesses were calculated.4,5 Percentage of free length of the stent was shorter in the TAXUS arm of neointimal free length of the stent was measured as the TAXUS V compared with TAXUS IV and VI (40.31 Ϯ 624 The American Journal of Cardiology (www.AJConline.org)

Table 2 Quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) analysis at 9-month follow-up TAXUS IV, V, VI Control IV, V, VI p Value* (n ϭ 216) (n ϭ 191) QCA (in-stent) Minimum lumen diameter (mm) 2.24 Ϯ 0.6 1.84 Ϯ 0.64 0.0001 Late lumen loss (mm) 0.41 Ϯ 0.56 0.86 Ϯ 0.51 0.0001 Diameter stenosis (%) 17.93 Ϯ 18.75 34.91 Ϯ 18.12 0.0001 IVUS (in-stent) Mean stent CSA (mm2) 7.51 Ϯ 2.27 8.01 Ϯ 2.44 0.03 Minimum lumen CSA (mm2) 5.34 Ϯ 2.28 4.58 Ϯ 2.34 0.0010 Mean lumen CSA (mm2) 6.58 Ϯ 2.29 5.7 Ϯ 2.25 0.0001 IH volume (%) 12.49 Ϯ 12.42 29.54 Ϯ 14 Ͻ0.0001 Mean IH CSA (mm2) 0.93 Ϯ 0.99 2.32 Ϯ 1.35 Ͻ0.0001 Maximum IH thickness (mm) 0.47 Ϯ 0.35 0.77 Ϯ 0.31 Ͻ0.0001 Mean IH thickness (mm) 0.11 Ϯ 0.12 0.27 Ϯ 0.15 Ͻ0.0001 NFLS (%) 48.8 Ϯ 35.98 13.4 Ϯ 22.14 Ͻ0.0001

* p Value for treatment comparison between TAXUS and control based on pooled data. CSA ϭ cross-sectional area; IH ϭ intimal hyperplasia; NFLS ϭ neointimal free length of stent.

Table 3 Table 4 Correlation between quantitative coronary angiography (QCA) late Correlation between quantitative coronary angiography (QCA) lumen loss (LLL) and intravascular ultrasound (IVUS) measures of percentage of diameter stenosis (DS) and intravascular ultrasound intimal hyperplasia (IVUS) measures of intimal hyperplasia IVUS parameter R Correlating QCA LLL p Value IVUS Parameter R Correlating QCA p Value to the IVUS Parameter %DS to IVUS Parameter Intimal hyperplasia (%) Intimal hyperplasia (%) Overall 0.59 Ͻ0.0001 Overall 0.52 Ͻ0.0001 TAXUS 0.57 Ͻ0.0001 TAXUS 0.49 Ͻ0.0001 Control 0.63 Ͻ0.0001 Control 0.56 Ͻ0.0001 Neointimal free lenght of stent (%) Neointimal free lenght of stent (%) Overall Ϫ0.36 Ͻ0.0001 Overall Ϫ0.23 Ͻ0.0001 TAXUS Ϫ0.38 Ͻ0.0001 TAXUS Ϫ0.26 0.0002 Control Ϫ0.32 Ͻ0.0001 Control Ϫ0.24 0.002 Mean intimal hyperplasia thickness Mean intimal hyperplasia thickness Overall 0.55 Ͻ0.0001 Overall 0.45 Ͻ0.0001 TAXUS 0.57 Ͻ0.0001 TAXUS 0.44 Ͻ0.0001 Control 0.56 Ͻ0.0001 Control 0.46 Ͻ0.0001 Maximum intimal hyperplasia Maximum intimal hyperplasia thickness thickness Overall 0.52 Ͻ0.0001 Overall 0.43 Ͻ0.0001 TAXUS 0.47 Ͻ0.0001 TAXUS 0.39 Ͻ0.0001 Control 0.61 Ͻ0.0001 Control 0.49 Ͻ0.0001

sures of intimal hyperplasia were smaller in TAXUS-treated 33.65% vs 57.24 Ϯ 37% in TAXUS IV and 59.57 Ϯ ϭ patients (Table 2). Almost half the length of the stent was 34.11% in TAXUS VI; p 0.0019). Maximum intimal free of neointima in the TAXUS-treated group compared hyperplasia thickness was greater in the TAXUS arm of Ϯ Ϯ with 13.4% neointima-free length in the bare-metal stent TAXUS V compared with TAXUS IV (0.52 0.31 vs 0.40 controls. 0.33 mm; p ϭ 0.01), but was similar between TAXUS V and VI. QCA and IVUS parameters were similar among the QCA versus IVUS correlations: Regression analysis 3 bare-metal stent control groups. Baseline characteristics showed that QCA late lumen loss (Table 3) and percentage of the TAXUS- and bare-metal stent–treated groups were of diameter stenosis (Table 4) correlated only moderately similar (Table 1). with the various IVUS measures of neointimal hyperplasia QCA reference vessel diameter was smaller for the for the combined group of patients (TAXUS ϩ bare-metal TAXUS group than the bare-metal stent group (2.75 Ϯ 0.45 stent), as well as for the TAXUS-treated and bare-metal vs 2.87 Ϯ 0.54 mm; p ϭ 0.01), although baseline minimal stent–treated patients separately. However, correlations lumen diameters were similar. At follow-up, QCA minimal within the control (bare-metal stent) group tended in general lumen diameter, late lumen loss, and percentage of diameter to be stronger than within the TAXUS group. The strongest stenosis in TAXUS-treated patients were all consistent with correlation was seen between QCA percentage of diameter less intimal hyperplasia (Table 2). Also at follow-up, IVUS stenosis and IVUS percentage of intimal hyperplasia in the mean and minimum lumen areas were larger and all mea- overall group and the control group. Coronary Artery Disease/Imaging Assessment of DES Efﬁcacy 625

Table 5 Overall (TAXUS ϩ bare-metal stent) intravascular ultrasound predictors for 9-month quantitative coronary angiography binary restenosis Parameter Control TAXUS Overall C p Value In-Stent C p Value In-Stent C p Value In-Stent Statistic (%DS Ͼ50) Statistic (%DS Ͼ50) Statistic (%DS Ͼ50) Maximum IH thickness 0.829 0.7392 22.73% 0.843 0.5613 8.87% 0.856 0.5206 15.3% % IH 0.860 0.6498 24.1% 0.849 0.6905 9.23% 0.876 0.6552 16.1% Minimum Lumen CSA 0.794 0.0001 22.16% 0.689 0.0002 8.49% 0.777 Ͻ0.0001 14.9% % Neointimal free 0.636 0.5999 24.1% 0.763 0.5136 9.23% 0.740 0.3467 16.1% length of stent Maximum % IH 0.929 Ͻ0.0001 22.16% 0.883 0.0279 8.49% 0.917 Ͻ0.0001 14.9%

DS ϭ diameter stenosis; other abbreviations as in Table 2.

IVUS predictors of QCA binary restenosis: The over- the rate of IVUS binary restenosis was also higher than all incidence of QCA binary restenosis was 14.0%, which angiographic binary restenosis. Using this measure, fewer was 9.3% in TAXUS-treated patients and 19.0% in bare- patients would be required to detect a difference between 2 metal stent–treated patients (p ϭ 0.0008). The strongest DESs. As an example, using this IVUS definition of binary predictor of QCA binary restenosis at 9 months was IVUS restenosis to compare a DES with a bare-metal stent (based maximum percentage of intimal hyperplasia, with an overall on differences in percentage of intimal hyperplasia Ͼ50% C ϭ 0.91 and p Ͻ0.001 (Table 5). between TAXUS and bare-metal stent), it would be necessary to have only 42 patients per group to detect a difference QCA predictors of IVUS binary restenosis: The over- with a statistical power of 80% and confidence interval of all incidence of IVUS binary restenosis (maximum percent- 95%. In the same-case scenario, but using angiographic age of intimal hyperplasia Ͼ50%) was 30%, which was binary restenosis as a surrogate end point, 129 patients per 15% in TAXUS-treated patients and 46% in bare-metal stent–treated patients (p Ͻ0.0001). None of the QCA pa- group would be necessary. If the intention is to compare 2 rameters tested had the power to predict IVUS binary different DESs, using the IVUS definition of binary reste- restenosis. nosis (and assuming an absolute difference between the groups of 10% as an extrapolation from the differences between Cypher [Cordis Corporation, Miami, Florida] Discussion and TAXUS stents in the Randomized Comparison Be- Although they assess the same biologic process, the present tween CYPHER and TAXUS Stents [REALITY] and study showed only a moderate relation between QCA and Sirolimus-Eluting Stent Compared with Paclitaxel-Elut- IVUS parameters of stent restenosis. The current meta- ing Stent for Coronary Revascularization [SYRTAX] analysis combined angiographic and IVUS data from studies10), it would be necessary to have 189 patients per the TAXUS trials. Use of a standardized angiographic and group to show a statistical difference with a power of IVUS acquisition protocol and single core angiographic and 80% and confidence interval of 95% with IVUS. If an IVUS laboratories across the trials provided the consistency angiographic definition of binary restenosis is used to necessary for meta-analysis. compare 2 different DESs with these same assumptions, QCA late lumen loss is the end point used most often in 640 patients per group would be necessary. randomized clinical DES trials.6–8 However, it represents In recent clinical trials, most DES restenoses were the difference between 2 minimal lumen diameter measure- focal.11,12 Focal in-stent restenosis is the result of focal ments at 2 different times; the axial location of the minimal accumulation of neointimal hyperplasia. Thus, maximum lumen diameter at each time point is variable. Thus, it is not percentage of intimal hyperplasia should have a high a true measure of maximum intimal hyperplasia thickness degree of accuracy to detect focal in-stent restenosis. within the stent. Accordingly, this analysis showed that late Conversely, classic IVUS measures of in-stent restenosis, lumen loss correlated with maximum intimal hyperplasia percentage of intimal hyperplasia volume (often called thickness with an r value of only 0.52 overall, 0.47 for the net volume obstruction), minimize the impact of the TAXUS stents and 0.61 for bare-metal stents. A previ- more common focal intimal hyperplasia accumulation. ously reported QCA analysis from TAXUS IV showed a This was also shown by the analysis of percentage of good relation between target lesion revascularization neointimal free length of the stent. In the TAXUS group, and late lumen loss, but only if late lumen loss was almost half the stent was free of IVUS-detectable intimal Ͼ0.6 mm.9 hyperplasia. Stents have been compared on the basis of their angio- The present study was a retrospective subanalysis of the graphic restenosis rates, easily differentiating DESs from TAXUS IV, V, and VI studies. There were some differences control bare-metal stents.1,7,8 However, a comparison of in study populations among the protocols; however, given different DESs may be more problematic because there is the objective of this substudy, those differences did not often little difference in QCA restenosis rates. IVUS per- affect our analysis. IVUS was also conducted in only a centage of intimal hyperplasia as a continuous variable was subset of angiographic patients and thus there was the po- higher than QCA percentage of diameter stenosis. Similarly, tential for selection bias. 626 The American Journal of Cardiology (www.AJConline.org)

Acknowledgment: We thank Peter Lam, PhD, Boston Sci- 7. Lansky AJ, Costa RA, Mintz GS, Tsuchiya Y, Midei M, Cox DA, entific Corp., Maple Grove, Minnesota, for assistance with O’Shaughnessy C, Applegate RA, Cannon LA, Mooney M, et al, for statistical analyses. the DELIVER Clinical Trial Investigators. Non-polymer-based paclitaxel-coated coronary stents for the treatment of patients with de novo coronary lesions: angiographic follow-up of the DELIVER clinical 1. Mauri L, Orav EJ, Kuntz RE. Late loss in lumen diameter and binary trial. Circulation 2004;109:1948–1954. restenosis for drug-eluting stent comparison. Circulation 2005;111: 8. Moses JW, Leonv MB, Popma JJ, Fitzgerald PJ, Holmes DR, 3435–3442. O’Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein 2. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann PS, Jaeger JL, Kuntz RE, for the SIRIUS Investigators. Sirolimus- JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME. eluting stents versus standard stents in patients with stenosis in a native A polymer-based paclitaxel-eluting stent in patients with coronary coronary artery. N Engl J Med 2003;349:1315–1323. artery disease. N Engl J Med 2004;350:221–231. 9. Ellis SG, Popma JJ, Lasala JM, Koglin JJ, Cox DA, Hermiller J, 3. van der Zwet PM, Reiber JH. A new approach for the quantification of O’Shaughnessy C, Mann JT, Turco M, Caputo R, et al. Relationship complex lesion morphology: the gradient field transform: basic prin- between angiographic late loss and target lesion revascularization after ciples and validation results. J Am Coll Cardiol 1994;24:216–224. coronary stent implantation analysis from the TAXUS-IV trial. JAm 4. Hoffmann R, Mintz GS, Pichard AD, Kent KM, Satler LF, Leon MB. Coll Cardiol Intimal hyperplasia thickness at follow-up is independent of stent size, 2005;45:1193–1200. a serial intravascular ultrasound study. Am J Cardiol 1998;82:1168– 10. Silber S. Cypher versus Taxus: are there differences? J Interv Cardiol 1172. 2005;18:441–446 5. Hoffmann R, Mintz GS, Haager PK, Bozoglu T, Grube E, Gross M, 11. Colombo A, Orlic D, Stankovic G, Corvaja N, Spanos V, Montor- Beythien C, Mudra H, vom Dahl J, Hanrath P. Relation of stent design fano M, Liistro F, Carlino M, Airoldi F, Chieffo A, Di Mario C. and stent surface material to subsequent in-stent intimal hyperplasia in Preliminary observations regarding angiographic pattern of reste- coronary arteries determined by intravascular ultrasound. Am J Car- nosis after rapamycin-eluting stent implantation. Circulation 2003; diol 2002;89:1360–1364. 107:2178–2180. 6. Mintz GS, Hong MK, Raizner AE, Lee CW, Kim JJ, Escolar E, 12. Weissman NJ, Koglin J, Cox DA, Hermiller J, O’Shaughnessy C, Fearnot NE, Park SW, Park SJ, Weissman NJ. Intravascular ultrasound Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, et al. Polymer- assessment of neointima distribution and the length of stent that was based paclitaxel-eluting stents reduce in-stent neointimal tissue prolif- free of intravascular ultrasound-detectable intimal hyperplasia in pa- eration: a serial volumetric intravascular ultrasound analysis from the clitaxel-eluting stents. Am J Cardiol 2005;95:107–109. TAXUS-IV trial. J Am Coll Cardiol. 2005;45:1201–5. Frequency of Stent Fracture as a Cause of Coronary Restenosis After Sirolimus-Eluting Stent Implantation

Sang-Hee Lee, MD, Jong-Seon Park, MD, PhD*, Dong-Gu Shin, MD, PhD, Young-Jo Kim, MD, PhD, Gue-Ru Hong, MD, PhD, Woong Kim, MD, and Bong-Sup Shim, MD

Stent fracture (SF) was suggested as a cause of restenosis after sirolimus-eluting stent (SES) implantation. This study was performed to evaluate the incidence and characteristics of SF to determine its contribution to restenosis in patients with in-stent restenosis (ISR) after SES implantation. From May 2003 to February 2006, SESs were used for percutaneous coronary intervention in 868 patients with 1,109 coronary narrowings. Follow-up coronary angiography was performed in 366 patients (42%), and 26 ISR lesions were observed. These patients were enrolled in this study. SF was divided into 3 types as avulsion, collapse, and partial based on the findings of fluoroscopy, coronary angiography, and intravascular ultrasound study. Of 26 patients with ISR lesions, SF was identified in 10. SF types were avulsion (5 patients), collapse (2 patients), and partial (3 patients). SF was identified at the midshaft (7 patients) and overlap sites (3 patients) of stents. SF was not observed in the 30 patients with ISR after bare-metal Bx Velocity stent implantation. Four patients with SF were treated with paclitaxel-eluting stents. In conclusion, SF is 1 of the leading causes of ISR after SES implantation. Careful fluoroscopic examination is necessary at the time of follow-up angiography to identify this problem. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:627–630)

The use of sirolimus-eluting stents (SESs) has proved to Korea. All patients had clinical indications for percutaneous be an effective approach to the prevention of neointimal coronary intervention with angiographic coronary diameter hyperplasia. They are commonly used in the treatment of stenosis Ն50%. All patients were asked to return for a patients with coronary artery stenosis.1–3 However, reste- follow-up angiogram 9 months after stent implantation. nosis is 1 of the most common complications associated Angiography was performed in 366 patients with or without with SES implantation, although it is dramatically de- symptoms. All patients in this study had ISR after SES creased compared with bare-metal stents (BMSs). Many implantation. Patients who had restenosis at the stent edge mechanisms to explain the occurrence of in-stent reste- or the diffuse proliferative type were excluded from the nosis (ISR) were suggested, including stent underexpan- study because most reported SFs were observed in the sion, polymer disruption during delivery, and drug resis- middle of the stents, with neointimal proliferation confined tance.4 Recently, several cases of stent failure associated within the stent. We analyzed angiographic and fluoro- with stent fracture (SF) were reported. SF was suggested scopic images of 30 ISRs from 108 lesions after BMS (Bx to be an unusual cause of restenosis after SES implanta- Velocity, Johnson & Johnson) implantation from March tion.5 Most reported cases of SF were observed in the 2000 to January 2004 and compared them with ISR lesions midportion of the implanted SES with focal ISR.5,6 These in patients with SES. Preprocedural and clinical character- findings suggest a potential correlation between SF and istics are listed in Table 1. The study protocol followed focal type of ISR. The objective of the present study was ethical guidelines of the 1975 Declaration of Helsinki and to determine the incidence and characteristics of SF and was approved by the institutional ethics committees at its contribution to ISR by analyzing ISR lesions after SES Yeungnam University Hospital. All patients provided in- implantation. formed consent. Stent implantation procedures were performed according Methods to standard interventional techniques using the femoral ar- From May 2003 to February 2006, a total of 868 consecu- tery. For scheduled procedures, all patients received aspirin tive patients were successfully treated using an SES 200 mg/day and clopidogrel 75 mg/day or ticlopidine 500 (Cypher stent; Johnson & Johnson, Miami Lakes, Florida) mg/day before the procedure. For patients undergoing an for 1,109 lesions at Yeungnam University Hospital, Daegu, emergency procedure, a loading dose of aspirin 200 mg and clopidogrel 300 mg was provided. Lesions were predilated using optimal balloon dilatation according to the operator’s judgment. We attempted to include all segments with ste- Division of Cardiology, Department of Internal Medicine, Yeung-nam Ն University Hospital, Daegu, Korea. Manuscript received January 8, 2007; nosis 20% as the target lesion for stent placement. Length revised manuscript received and accepted March 15, 2007. and number of stents required were determined by operator *Corresponding author: Tel.: 82-53-620-3847; fax: 82-53-654-8386. visual estimation. After the procedure, patients received E-mail address: [email protected] (J.-S. Park). ticlopidine 500 mg/day or clopidogrel 75 mg/day for 6

Table 1 SF site on IVUS; (2) partial type, defined as the absence of Clinical characteristics of study patients stent struts in Ն1⁄3 of the vessel wall on IVUS; and (3) Variable SES BMS p Value collapse type, defined as a folded and compacted inner and o (n ϭ 26) (n ϭ 30) outer wall of the stent found in a bended segment with Ͼ45 as observed using fluoroscopy. All images were interpreted Age (yrs) 58 Ϯ 11 60 Ϯ 9 0.414 by 2 interventional cardiologists. Men 22 (84%) 23 (77%) 0.517 Ϯ Diabetes mellitus 9 (33%) 5 (17%) 0.138 Continuous variables were reported as mean SD. Vari- Hypertension* 12 (46%) 9 (30%) 0.273 able categories were expressed as frequencies. Student’s t Dyslipidemia† 12 (46%) 13 (43%) 0.938 test or nonparametric analysis using Mann-Whitney U test Smoker 11 (42%) 13 (43%) 0.921 was used to analyze continuous variables for comparisons Previous myocardial infarction 5 (19%) 4 (13%) 0.555 between groups. Chi-square test or Fisher’s exact test was Diagnosis at index procedure used for comparisons of categorical variables expressed as Stable angina pectoris 10 (38%) 12 (40%) frequencies. SPSS, version 12.0 (SPSS Inc., Chicago, Illi- Unstable angina pectoris 6 (23%) 9 (30%) nois) was used for data analysis. A p value Ͻ0.05 was Acute myocardial infarction 9 (33%) 9 (30%) 0.681 considered statistically significant. Follow-up duration (mo) 14 Ϯ 912Ϯ 9 0.531 Ն * Defined as systolic blood pressure 140 mm Hg or diastolic blood Results pressure Ն90 mm Hg or use of antihypertensive treatment. † Defined as total cholesterol level Ͼ240 mg/dl or use of cholesterol- From March 2000 to February 2006, there were 1,109 and lowering treatment. 109 eligible lesions treated with SESs and BMSs, respectively. Based on follow-up angiography, 26 SES and 30 months and aspirin 200 mg/day indefinitely. No patient BMS ISR lesions, with or without symptoms, were identi- underwent atherectomy procedures, such as rotational or fied and enrolled in this study. Baseline clinical data did not directional atherectomy. differ between the 2 groups. Mean follow-up was 14 Ϯ 9 Three coronary angiograms were obtained for each pa- months for the SES group and 12 Ϯ 9 for the BMS group tient; before percutaneous coronary intervention, immedi- (Table 1). Of 26 cases of ISR lesions associated with SESs, ately after percutaneous coronary intervention, and at fol- SF was identified in 10. Detailed characteristics of each are low-up. Angiographic follow-up study at 9 months was listed in Table 2. Table 3 lists angiographic and fluoroscopic recommended for all patients. If clinical evidence of myo- features of the 10 patients with SF. SF was diagnosed based cardial ischemia developed at any time during follow-up, on fluoroscopic (n ϭ 7) and intravascular ultrasonographic hospital admission and coronary angiography were recom- findings (n ϭ 3). Three SFs detected using fluoroscopy were mended. At least 2 orthogonal projections were obtained confirmed using IVUS. SF types included avulsion (n ϭ 5), after intracoronary injection of nitroglycerin 200 ␮g and collapse (n ϭ 2), and partial (n ϭ 3). The SF was found in were included in the analysis. Quantitative coronary angio- the midsegment of the stent (n ϭ 7) in patients who had 1 graphic analysis was performed using the computer-assisted stent implanted. Three SFs were observed in patients with automated edge detection method (CASS System II, Pie multiple stents implanted. Mean stent length was 58.74 Ϯ Medical Imaging, Maastricht, The Netherlands) by 2 ob- 8.04 mm. SFs were observed in the middle of the lesion and servers. Mean reference vessel diameter, minimal luminal overlapping segments; SF types were avulsion in 2 and diameter, lesion length, ISR length, and percentage of di- partial in 1 patient. ameter stenosis were analyzed in all patients. Angiographic features of 10 patients with ISR with SF Intravascular ultrasonography (IVUS) was performed in were compared with those of 16 patients with ISR without 14 patients (54%) with SESs and not performed in patients SF (Table 4). Percutaneous coronary intervention–related with BMSs. For the IVUS, a 2.5-Fr 40-MHz Coronary factors, such as lesion site, stent length, diameter, and max- Imaging Catheter (Atlantis SR pro, Boston Scientific, imal implantation pressure, were not significantly different Natick, Massachusetts) was used. Before placing the IVUS in comparisons between groups. catheter distal to the stent, intracoronary nitroglycerin 200 Angiographic and fluoroscopic features of restenosis ␮g was administered. The catheter was slowly pulled back were compared between 26 SES and 30 BMS cases. Table using the automatic motorized transducer pullback (0.5 5 lists procedural and angiographic characteristics of the 2 mm/s) beginning approximately 10 mm distal to the stent groups. Reference vessel diameters and stents used were and continuing to the aorto-ostial junction. Ultrasound im- similar for both groups. However, lesion lengths and stent ages were recorded on a compact disc for off-line review lengths were longer and maximal inflation pressures were and analysis. lower in the SES group compared with the BMS group. The Angiographic restenosis was defined as Ն50% stenosis most frequent restenosis types were focal in the SES group diameter on the follow-up angiogram. Restenosis pattern (81%) and diffuse in the BMS group (60%). SF was ob- was classified as focal (Ͻ10 mm), diffuse (Ն10 mm), or served in 10 of 26 patients (38%) in the SES group; how- total occlusion based on follow-up angiographic findings. ever, there was no SF observed in the BMS group. There SF types were classified as avulsion, partial, or collapse was no significant difference in the clinical presentation of with fluoroscopy and IVUS (Figure 1). Definitions of SF ISR between the 2 groups. types included (1) avulsion type, defined as 2 fractured Five of 10 patients with SF had clinical symptoms fol- segments of the stent separated completely, as observed lowed by percutaneous coronary intervention. One patient using fluoroscopy, and/or stent struts were absent from the was treated with cutting balloon angioplasty and had recur- Coronary Artery Disease/Stent Fracture and Restenosis After SES 629

Figure 1. Examples of 3 different types of stent fracture. (A) Avulsion type shows 2 fractured stent segments displaced on the ﬂuoroscopic image (c).On IVUS, no stent struts were observed (d). (B) Partial fracture shows minimal strut damage on ﬂuoroscopy (c) and partial absence of struts (arrowheads) on IVUS (d). (C) The collapse type shows a folded stent at a high angular segment (c). It does not show a strut-free gap in the stented segment. PCI ϭ percutaneous coronary intervention.

Table 2 Characteristics of ten patients with stent fracture Patient No. Age (yrs) Targeted Coronary Artery Stent Diameter (mm) ϫ Length (mm) Fracture Type 1 50 Right 3.5 ϫ 23/3.0 ϫ 23 Partial 2 50 Left anterior descending 2.75 ϫ 33/2.5 ϫ 33 Avulsion 3 78 Right 2.5 ϫ 23 Collapse 4 72 Left anterior descending 2.5 ϫ 28 Partial 5 66 Left circumﬂex 3.0 ϫ 23 Avulsion 6 52 Right 2.5 ϫ 33 Collapse 7 52 Left anterior descending 2.75 ϫ 23/2.5 ϫ 33 Avulsion 8 63 Right 2.75 ϫ 33 Avulsion 9 58 Left anterior descending 2.75 ϫ 33 Avulsion 10 65 Right 3.0 ϫ 28 Partial rent restenosis at follow-up angiography. Four patients were ISR occurs in Ͻ10% of patients undergoing coronary treated with a paclitaxel-eluting stent. Currently, follow-up intervention using an SES, as reported in many clinical angiography performed in 3 patients showed that the stent trials.7,8 Recently, SF was suggested as a cause of restenosis was patent in all paclitaxel-eluting stents. after drug-eluting stent placement.9 Although SF is usually identiﬁed at routine follow-up coronary angiography, in Discussion patients without angina, it can lead to an acute coronary In the present study, SF was found with a high incidence in syndrome.5,6 A study showed that patients with ISR had ISR lesions after SES implantation. SF was not observed in more cases of focal restenosis after implantation with SESs ISR lesions treated with BMSs, Bx Velocity stents. Repeated compared with patients receiving paclitaxel-eluting stents.10 coronary intervention of these ISR lesions using paclitaxel-eluting This suggests that veiled focal problems with the stent or stents showed favorable clinical and angiographic results. lesion may contribute to the development of focal resteno- 630 The American Journal of Cardiology (www.AJConline.org)

Table 3 Table 5 Angiographic and fluoroscopic features of ten patients with stent fracture Comparison of angiographic findings and clinical presentations between sirolimus-eluting stents (SESs) and bare metal stents (BMSs) Variables n ϭ 10 Variable SESs BMSs p Value Diagnostic method (n ϭ 26) (n ϭ 30) Fluoroscopy 7 IVUS 3 Quantitative angiography Fluoroscopy and IVUS 3 Reference diameter (mm) 2.99 Ϯ 0.28 3.04 Ϯ 0.44 0.638 Stent fracture types Minimal luminal 0.17 Ϯ 0.12 0.27 Ϯ 0.18 0.017 Avulsion 5 diameter (mm) Collapse 2 Lesion length (mm) 26.80 Ϯ 9.89 16.56 Ϯ 6.50 Ͻ0.001 Partial 3 Used stent diameter (mm) 2.92 Ϯ 0.32 3.08 Ϯ 0.51 0.163 Fractured stent in coronary artery Used stent length (mm) 32.7 Ϯ 12.21 18.16 Ϯ 6.36 Ͻ0.001 Left anterior descending 4 Maximal pressure (atm) 11 Ϯ 313Ϯ 5 0.544 Right 5 Overlapping stent 6 (23%) 0 (0%) Left circumflex 1 Restenosis type Fractured segment in Focal 21 (81%) 9 (30%) Proximal 0 Diffuse 3 (12%) 8 (60%) Mid 7 Total occlusion 2 (7%) 3 (10%) Ͻ0.001 Distal 0 Stent fracture 10 (36%) 0 (0%) Overlap site of multiple stents 3 Clinical presentation at follow-up study Myocardial infarction 4 (15%) 1 (3%) Table 4 Unstable angina pectoris 3 (12%) 8 (27%) Comparison of angiographic features between patients with and without Stable angina pectoris 16 (61%) 15 (50%) stent fracture (SF) Silent ischemia 3 (12%) 6 (20%) 0.184 SF No SF p Value (n ϭ 10) (n ϭ 16) implantation. In addition, we did not compare the SF inci- Restenosis site Left anterior descending 4 8 dence of SESs with that of the paclitaxel-eluting stents. Right 5 5 Left circumflex 1 2 1. Tanimoto S, Daemen J, Tsuchida K, Garcia-Garcia HM, de Jaegere P, Left main 0 1 0.716 van Domburg RT, Serruys PW. Two-year clinical outcome after coronary stenting of small vessels using 2.25-mm sirolimus- and pacli- Total stent length (mm) 35.92 Ϯ 12.75 30.73 Ϯ 11.8 0.301 Ϯ Ϯ taxel-eluting stents: insight into the RESEARCH and T-SEARCH Stent diameter (mm) 2.90 0.35 2.93 0.31 0.779 registries. Catheter Cardiovasc Interv 2006;69:94–103. Ϯ Ϯ Maximum pressure (atm) 10.40 2.60 11.31 2.75 0.409 2. Lee CW, Park KH, Kim YH, Hong MK, Kim JJ, Park SW, Park SJ. Restenosis type Clinical and angiographic outcomes after placement of multiple over- Focal 8 (80%) 13 (81.2%) lapping drug-eluting stents in diffuse coronary lesions. Am J Cardiol Diffuse 0 3 (18.7%) 2006;98:918–922. Total occlusion 2 (20%) 0 0.79 3. Chieffo A, Stankovic G, Bonizzoni E, Tsagalou E, Iakovou I, Mon- torfano M, Airoldi F, Michev I, Sangiorgi MG, Carlino M, Vitrella G, Colombo A. Early and mid-term results of drug-eluting stent implantation in unprotected left main. Circulation 2005;111:791–795. sis. We analyzed fluoroscopic, angiographic, and intravas- 4. Cowley MJ. Drug-eluting stent restenosis: incidence, predictors, mecha- cular ultrasonographic images in detail, focusing on the nisms, and treatment. J Interv Cardiol 2006;19(Suppl):S47–S53. presence of an SF. We found that 44% of SFs were identi- 5. Park JS, Shin DG, Kim YJ. Fractured DES with a patent coronary fied in focal or totally occluded ISR lesions. Therefore, artery: clinical implications. J Invasive Cardiol 2007;19:E43–E45. results of the present study suggest that SF is 1 of the 6. Surmely JF, Kinoshita Y, Dash D, Matsubara T, Terashima M, Ehara M, Ito T, Nasu K, Takeda Y, Tanaka N, Suzuki T, Katoh O. Stent strut leading causes of focal ISR after SES implantation. fracture-induced restenosis in a bifurcation lesion treated with the To determine the effect of the neointima, we compared crush stenting technique. Circ J 2006;70:936–938. SF in restenotic lesions in both SESs and Bx Velocity 7. Schampaert E, Cohen EA, Schluter M, Reeves F, Traboulsi M, Title BMSs. We found no SF in restenotic lesions of patients with LM, Kuntz RE, Popma JJ. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small BMSs. This finding suggests that the lack of stent protection native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43: by the neointima at an early stage of stent implantation may 1110–1115. have significant consequences. Alternatively, the production 8. Popma JJ, Leon MB, Moses JW, Holmes DR Jr, Cox N, Fitzpatrick M, process of drug coating may potentially weaken the stent Douglas J, Lambert C, Mooney M, Yakubov S, Kuntz RE. Quantitative metal. We cannot conclude that any 1 factor is the key assessment of angiographic restenosis after sirolimus-eluting stent implantation in native coronary arteries. Circulation 2004;110:3773–3780. element for SF after SES implantation. However, we spec- 9. Min PK, Yoon YW, Moon Kwon H. Delayed strut fracture of siroli- ulate that multiple factors, including poor neointimal hyper- mus-eluting stent: a significant problem or an occasional observation? plasia, stent design, and cardiac movement, contribute to the Int J Cardiol 2006;106:404–406. development of SF. 10. Corbett SJ, Cosgrave J, Melzi G, Babic R, Biondi-Zoccai GG, Godino C, Morici N, Airoldi F, Michev I, Montorfano M, et al. Patterns of Our study had several limitations. Follow-up coronary restenosis after drug-eluting stent implantation: insights from a con- angiography was not performed in all patients. Therefore, temporary and comparative analysis of sirolimus- and paclitaxel-elut- we could not determine the true incidence of SF after SES ing stents. Eur Heart J 2006;27:2330–2337. Usefulness of Preprocedural N-Terminal Pro-Brain Natriuretic Peptide in Predicting Angiographic No-Reflow Phenomenon During Stent Implantation in Patients With ST-Segment Elevation Acute Myocardial Infarction

Seo Na Hong, MD, Youngkeun Ahn, MD*, Sun Ho Hwang, MD, Nam Sik Yoon, MD, Sang Rok Lee, MD, Jae Youn Moon, MD, Kye Hun Kim, MD, Young Joon Hong, MD, Hyung Wook Park, MD, Ju Han Kim, MD, Myung Ho Jeong, MD, Jeong Gwan Cho, MD, Jong Chun Park, MD, and Jung Chaee Kang, MD

The no-reflow phenomenon after primary percutaneous coronary intervention (PCI) is associated with larger infarct size, worse functional recovery, and higher incidence of complication after acute ST-elevation myocardial infarction (STEMI). The aim of this study was to assess the relation between preprocedural N-terminal pro–brain-type natriuretic peptide (NT–pro-BNP) and angiographic no-reflow phenomenon. We measured preprocedural serum NT–pro-BNP level in 159 consecutive patients with acute STEMI aged 63 ؎ 12 years; 72% men) before PCI. Angiographic no-reflow after PCI was defined) as Thrombolysis In Myocardial Infarction (TIMI) flow grade <3. Baseline characteristics, and normal-reflow (67 ؍ including time from chest pain onset, between the no-reflow (n were similar. NT–pro-BNP was significantly higher in the no-reflow group (92 ؍ groups (n ,Also .(0.005 ؍ than the normal reflow group (1,982 ؎ 3,314 vs 415 ؎ 632 pg/ml; p high-sensitivity C-reactive protein, monocytes, and troponin-T were significantly higher in the no-reflow group than the normal-reflow group. In the no-reflow group, NT–pro-BNP pg/ml) than 3,495 ؎ 2,290 ;41 ؍ was much higher in patients with TIMI flow grade 0 (n pg/ml), but without significant 2,340 ؎ 1,575 ;26 ؍ those with TIMI grade 1 or 2 (n difference. The area under the receiver-operating characteristic curve for NT–pro-BNP was 0.78, and the optimal cut-off value identified using receiver-operating characteristic curve analysis was 500 pg/ml. At the standard cut-off value of >500 pg/ml, increased NT–pro- BNP showed a high probability of no-reflow phenomenon (odds ratio 4.42, 95% confidence In conclusion, preprocedural NT–pro-BNP may be a .(0.028 ؍ interval 1.15 to 17.00, p strong predictor of the development of no-reflow phenomenon after PCI in patients with acute STEMI. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:631–634)

Early reperfusion after coronary occlusion in patients with (NT–pro-BNP). BNP and NT–pro-BNP increase after acute acute myocardial infarction (MI) is associated with a better MI and unstable angina pectoris and are strong predictors of prognosis.1 Reperfusion therapy for patients with acute MI mortality in patients with acute coronary syndromes.6 We using primary percutaneous coronary intervention (PCI) investigated the relation between preprocedural NT–pro- was shown to improve the clinical outcome compared with BNP and angiographic no-reflow phenomenon during stent thrombolysis.2 However, despite the achievement of opti- implantation in patients with acute MI. mal epicardial coronary artery patency, 30% to 40% of patients showed the no-reflow phenomenon,3 which is as- Methods and Results sociated with larger infarct size, worse functional recovery, and higher incidence of complications.4 Several mechanisms One hundred fifty-nine consecutive patients with acute ST- responsible for no reflow were identified in experimental mod- elevation MI (STEMI) who underwent PCI were enrolled. Ͼ els, including extravascular compression, microvascular vaso- Inclusion criteria were prolonged chest pain ( 30 minutes), Ͼ Ն constriction, and platelet/leukocyte capillary plugging.5 Brain- ST-segment elevation 2mmin 2 adjacent leads on type natriuretic peptide (BNP) is a neurohormone synthesized standard electrocardiogram, and more than twofold increase Ͼ and released from the cardiac ventricles in response to in- in serum creatine kinase. Cardiac symptoms lasting 30 creased wall tension6 and produced as a prohormone, pro- minutes that occurred within 48 hours before the onset of BNP, that is enzymatically cleaved into BNP and the amino- infarction were defined as preinfarction angina.7 We ex- terminal portion of the prohormone, N-terminal pro-BNP cluded patients with left main disease, severe chronic heart failure, severe valvular heart disease, Killip class ՆIII on admission, cardiogenic shock, and calculated creatinine Ͻ 2 The Heart Center of Chonnam National University Hospital, Gwangju, clearance 80 ml/min/m . All clinical data were collected South Korea. Manuscript received January 15, 2007; revised manuscript prospectively. received and accepted March 20, 2007. Peripheral blood samples for serum NT–pro-BNP were *Corresponding author: Tel.: 82-62-220-4764; fax: 82-62-223-3105. obtained before PCI using direct venipuncture of the ante- E-mail address: [email protected] (Y. Ahn). cubital vein after the patient had rested in the supine posi-

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.075 632 The American Journal of Cardiology (www.AJConline.org) tion for 30 minutes. Blood samples were collected in tubes Table 1 without anticoagulant. Samples were centrifuged and serum Baseline clinical, lesion, and procedural characteristics was stored frozen in aliquots at Ϫ70°C within 30 minutes. Variable Normal Reflow No-Reflow p Value Serum NT–pro-BNP was measured using an electrochemi- (n ϭ 92) (n ϭ 67) luminescence sandwich immunoassay method for NT–pro- Age (yrs) 60 Ϯ 364Ϯ 3 0.083 BNP with an Elecsys 2010 analyzer (Roche Diagnostics, Men 67 (73%) 48 (71%) 0.887 Mannheim, Germany). This electrochemiluminescence Hypertension 40 (43%) 27 (41%) 0.883 sandwich immunoassay is a type of photon detection assay Diabetes 21 (23%) 11 (16%) 0.442 using polyclonal antibodies (a biotinylated antibody and a Smoker 49 (53%) 31 (46%) 0.519 ruthenium derivative–labeled antibody) in a 2-voltage elec- Hyperlipidemia 41 (45%) 19 (29%) 0.123 tric field. It has high sensitivity and specificity and a large Left ventricular ejection 58 Ϯ 753Ϯ 1 0.104 detection range. The analytic range of the NT–pro-BNP fraction (%) assay extends from 5 to 35,000 ng/L. The reference value is Previous ischemic heart 7 (8%) 0 (0%) 0.095 disease variable according to age and gender. In our institute, ref- Ͻ Ͻ Preinfarction angina 30 (33%) 19 (28%) 0.643 erence values are 88 pg/ml in men and 153 pg/ml in Physical findings women. Systolic blood pressure 140 Ϯ 23 132 Ϯ 22 0.131 Cardiac enzymes, fibrinogen, lipid profiles, and high- (mm Hg) sensitivity C-reactive protein were also measured before Diastolic blood pressure 88 Ϯ 14 81 Ϯ 13 0.052 PCI in all patients. (mm Hg) All patients received oral aspirin (300 mg) and clopi- Heart rate (beats/min) 73 Ϯ 14 74 Ϯ 13 0.711 dogrel (300 mg) immediately after admission and intra- Electrocardiographic findings 0.107 Anterior wall infarction 35 (38%) 33 (49%) venous heparin (5,000 U) before PCI. Heparin was con- Inferior wall infarction 49 (53%) 32 (48%) tinued as an intravenous infusion (25,000 U/day) for the Creatinine (mg/dl) 0.9 Ϯ 0.2 1.0 Ϯ 0.3 0.644 subsequent 72 hours and adjusted to achieve a target Monocyte (/mm3) 533 Ϯ 329 748 Ϯ 439 0.013 activated partial thromboplastin time of 2.0 to 3.0 times C-Reactive protein (mg/dl) 1.0 Ϯ 1.5 3.0 Ϯ 4.3 0.009 control levels. Troponin-T (ng/ml) 1.3 Ϯ 3.0 4.9 Ϯ 6.5 0.001 All patients underwent coronary angiography using a Creatine kinase-MB (U/L) 98 Ϯ 89 102 Ϯ 123 0.864 common technique. All stenotic lesions were predilated and Homocysteine (␮mol/L) 7.3 Ϯ 3.3 11.3 Ϯ 9.8 0.181 Fibrinogen (mg/dl) 278 Ϯ 83 347 Ϯ 112 0.035 stents were deployed at 10 to 16 atmospheres. Angiograms Ϯ Ϯ were analyzed using a validated quantitative coronary an- Low-density lipoprotein 121 32 106 27 0.028 cholesterol (mg/dl) giographic system (Philips H5000, Philips Medical Sys- Lipoprotein(a) (mg/dl) 28 Ϯ 30 32 Ϯ 31 0.613 tems, Andover, Massachusetts, or Allura DCI program, Hemoglobin A1c (%) 6.1 Ϯ 1.1 6.2 Ϯ 1.0 0.847 Philips Medical System, Best, The Netherlands). Target coronary artery 0.200 Angiographic no reflow after PCI was defined as Throm- Left anterior descending 35 (38%) 33 (49%) bolysis In Myocardial Infarction (TIMI) flow grade Ͻ3 Left circumflex 20 (22%) 6 (9%) during stent implantation without evidence of dissection, Right 37 (40%) 28 (42%) stenosis, or vasospasm. ACC/AHA classification 0.439 B 34 (37%) 32 (38%) All metric variables were described as mean Ϯ SD. 1 B2 21 (23%) 25 (33%) Differences in metric variables between groups were ana- C 37 (40%) 21 (29%) lyzed using Student’s t test. Correlations between NT–pro- Initial TIMI flow 0.590 BNP and other parameters were described using Pearson’s 0 49 (53%) 34 (51%) correlation. The prediction power of NT–pro-BNP for no- 1 9 (10%) 5 (7%) reflow phenomenon was calculated using multivariate lo- Abciximab use 43 (47%) 24 (36%) 0.264 gistic regression analysis. All statistical processes were per- Time from pain to PCI (min) 220 Ϯ 138 227 Ϯ 145 0.412 formed using SPSS-PC 11.0 (SPSS-PC Inc., Chicago, Stent diameter (mm) 3.2 Ϯ 0.2 3.3 Ϯ 0.3 0.116 Ϯ Ϯ Illinois). A p value Ͻ0.05 was considered significant. Stent length (mm) 25.9 5.0 27.0 4.8 0.361 Baseline clinical characteristics are listed in Table 1. ACC/AHA ϭ American College of Cardiology/American Heart High-sensitivity C-reactive protein, troponin-T, monocytes, Association. and fibrinogen were significantly higher in the no-reflow group than the normal-reflow group, and low-density lipoprotein was (n ϭ 41) and those with TIMI grade 1 or 2 (n ϭ 26; Figure significantly lower in the no-reflow group compared with the 2). normal-reflow group. No significant differences in age, gender, Groups were divided into 2 subgroups according to time coronary risk factors, global left ventricular systolic function, from pain to PCI. NT–pro-BNP was significantly higher in renal function, distribution of target vessel, use of intravenous patients with no reflow than those with normal reflow in or intracoronary abciximab, or physical findings on admission both subgroups (p ϭ 0.026 in patients with Ͻ180 min- were observed between groups. utes, p ϭ 0.008 in patients with Ͼ180 minutes; Figure 3). NT–pro-BNP was 1,982 Ϯ 3,314 pg/ml in the no-reflow NT–pro-BNP correlated positively with age, troponin-T, group and 415 Ϯ 632 pg/ml in the normal reflow group (p high-sensitivity C-reactive protein, and homocysteine ϭ 0.005; Figure 1). In the no-reflow group, NT–pro-BNP and negatively with ejection fraction (r ϭ 0.261, p ϭ was not different between patients with TIMI flow grade 0 0.016; r ϭ 0.379, p ϭ 0.001; r ϭ 0.366, p ϭ 0.001; r ϭ Coronary Artery Disease/NT–pro-BNP and No-Reflow Phenomenon 633

Table 2 Correlation between N-terminal pro–brain-type natriuretic peptide and multiple variables Variable Correlation (r) p Value Age 0.261 0.016 Ejection fraction Ϫ0.466 0.001 Troponin-T 0.379 0.001 C-reactive protein 0.366 0.001 Homocysteine 0.371 0.036 Fibrinogen 0.147 0.373 Monocytes 0.185 0.090 Creatinine 0.158 0.149

Table 3 Independent predictive factors for no-reflow phenomenon Figure 1. The difference in NT–pro-BNP in patients with no reflow and Parameters Odds Ratio 95% Confidence p Value normal reflow (p ϭ 0.005). Interval Age 1.033 0.977–1.092 0.252 Hypertension 0.706 0.168–2.960 0.634 Diabetes 1.945 0.497–7.611 0.339 Smoker 0.637 0.109–2.404 0.506 Hyperlipidemia 1.774 0.428–7.357 0.429 Ejection fraction 0.971 0.912–1.034 0.362 Monocyte 2.396 0.316–18.183 0.398 C-reactive protein 1.350 0.296–1.034 0.698 Troponin T 1.197 1.019–1.406 0.032 NT–pro-BNP (Ͼ500 pg/ml) 5.844 1.149–17.000 0.028

ciximab use. NT–pro-BNP also was significantly higher in patients with no reflow than those with normal reflow in both subgroups (4,838 Ϯ 8,250 vs 115 Ϯ 93 pg/ml, p ϭ 0.019 in patients with abciximab use; 1,731 Ϯ 2,060 vs 577 Ϯ 738, p ϭ 0.003 in patients without abciximab use). Figure 2. The difference in NT–pro-BNP according to TIMI flow grade in The area under the receiver-operating characteristic the no-reflow group (p ϭ NS). curve for NT–pro-BNP was 0.78, and the optimal cut-off value identified using receiver-operating characteristic analysis was 500 pg/ml. Multivariate logistic regression analyses of the association between the angiographic no-reflow phenomenon and multiple parameters are listed in Table 3. At the standard cut-off value of Ͼ500 pg/ml, increased NT–pro-BNP showed a high probability of no-reflow phenomenon (odds ratio 4.42, 95% confidence interval 1.15 to 17.00, p ϭ 0.028). In multivariate analysis, NT–pro-BNP was an independent predictor of no-reflow phenomenon, along with troponin-T.

Discussion Rapid restoration of coronary flow to the jeopardized myocardium has become an essential part of therapy after acute MI. Despite an open infarct-related artery, breakdown of Figure 3. The difference in NT–pro-BNP according to time from pain to ϭ Ͻ ϭ obstruction to coronary microvasculature can markedly de- PCI (p 0.026 in patients with 180 minutes, p 0.008 in patients with crease blood flow to the infarct zone. This effect is known Ͼ180 minutes). Black bars, no reflow; white bars, normal reflow. as the no-reflow phenomenon.8,9 This phenomenon is important because it correlates with infarct size and provides 0.371, p ϭ 0.036; r ϭϪ0.466, and r ϭ 0.001, respec- useful prognostic information. Various pharmacologic in- tively; Table 2). terventions and catheter-based devices have been applied to Groups were divided into 2 subgroups according to ab- prevent this no-reflow phenomenon.8,9 634 The American Journal of Cardiology (www.AJConline.org)

This study showed that NT–pro-BNP can be a useful ventricular function, and survival after acute myocardial infarction. predictor of no-reflow phenomenon in patients with acute N Engl J Med 1993;329:1615–1622. 2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intra- STEMI. We excluded patients with a specific situation that venous thrombolytic therapy for acute myocardial infarction: a quan- affected NT–pro-BNP. titative review of 23 randomized trials. Lancet 2003;361:13–20. Many clinical trials showed that NT–pro-BNP increased 3. Morishima I, Sone T, Okumura K, Tsuboi H, Kondo J, Mukawa H, in patients with acute coronary syndrome and was a pow- Matsui H, Toki Y, Ito T, Hayakawa T. Angiographic no-reflow phe- erful predictor of both short- and long-term mortality.10–12 nomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first We recently reported that NT–pro-BNP was a valuable acute myocardial infarction. J Am Coll Cardiol 2000;36:1202–1209. screening test for coronary artery disease in patients with a 4. Stone GW, Peterson MA, Lansky AJ, Dangas G, Mehran R, Leon MB. normal electrocardiogram, echocardiogram, and cardiac en- Impact of normalized myocardial perfusion after successful angio- zymes.13 In addition, NT–pro-BNP predicted in-stent reste- plasty in acute myocardial infarction. J Am Coll Cardiol 2002;39:591– nosis in patients with preserved left ventricular function and 597. Circulation 14 5. Rezkalla SH, Kloner RA. No-reflow phenomenon. 2002; normal troponin I levels. 105:656–662. Recent study showed that BNP level obtained on admis- 6. James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong sion is a powerful independent predictor of short-term and P, Barnathan ES, Califf R, Topol EJ, Simoons ML, Wallentin L. angiographic success after PCI in patients with STEMI. The N-Terminal pro-brain natriuretic peptide and other risk markers for the no-reflow phenomenon can be predicted in patients with separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease. Circulation 2003; STEMI on the basis of high serum BNP values on admis- 108:275–281. sion.15 The no-reflow phenomenon remains an independent 7. Thompson PL, Meredith I, Amerena J, Campbell TJ, Sloman JG, predictor of death in a wide group of patients treated with Harris PJ. Effect of pravastatin compared with placebo initiated within PCI, not only those with STEMI. Data from this study15 24 hours of onset of acute myocardial infarction or unstable angina: the Pravastatin in Acute Coronary Treatment (PACT) trial. Am Heart J made us conclude that the no-reflow phenomenon in pa- 2004;148:e1–e8. tients with STEMI was diagnosed almost 5 times more often 8. Reffelmann T, Kloner RA. The no-reflow phenomenon: basic science in the group with higher serum baseline BNP, and mean and clinical correlates. Heart 2002;87:162–168. baseline serum BNP in the no-reflow phenomenon subgroup 9. Ito H. No-reflow phenomenon and prognosis in patients with acute was approximately 3 times higher than in the population myocardial infarction. Nat Clin Pract Cardiovasc Med 2006;3:499– 506. without no reflow. 10. Omland T, de Lemos JA, Morrow DA, Antman EM, Cannon CP, Hall There are several limitations to this study. First, we C, Braunwald E. Prognostic value of N-terminal pro-atrial and pro- excluded patients who had possible factors to increase NT– brain natriuretic peptide in patients with acute coronary syndromes. pro-BNP levels. Therefore, in this study population, the Am J Cardiol 2002;89:463–465. percentage of no reflow after primary PCI in patients with 11. Omland T, Persson A, Ng L, O’Brien R, Karlsson T, Herlitz J, Harrford M, Caidahl K. N-Terminal pro-B-type natriuretic peptide and STEMI was higher compared with other studies. Second, long-term mortality in acute coronary syndromes. Circulation 2002; we measured NT–pro-BNP from peripheral-blood samples 106:2913–2918. before PCI using direct venipuncture of the antecubital vein 12. Heeschen C, Hamm CW, Mitrovic V, Lantelme NH, White HD, for after patient had rested in the supine position for 30 minutes. the Platelet Receptor Inhibition in Ischemic Syndrome Management Because NT–pro-BNP levels change dynamically during (PRISM) Investigators. N-Terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary the time course of acute coronary syndrome, although the syndromes. Circulation 2004;110:3206–3212. time from chest pain to PCI was similar between groups, the 13. Hong SN, Yoon NS, Ahn Y, Lim SY, Kim YS, Yun KH, Kang DK, time from chest pain to blood sampling was very influential Lee SH, Lee YS, Kim KH, et al. N-Terminal pro-B-type natriuretic in determining NT–pro-BNP levels in this study. Third, we peptide predicts significant coronary artery lesion in the unstable angina patients with normal electrocardiogram, echocardiogram, and did not elucidate the exact underlying mechanism to the link cardiac enzymes. Circ J 2005;69:1472–1476. between NT–pro-BNP and the no-reflow phenomenon. 14. Hong SN, Ahn Y, Yoon NS, Lee KH, Kim YS, Hwang SH, Lee SR, Fourth, segmentary hypoenhancement assessed using mag- Kim KH, Park HW, Hong YJ, et al. Usefulness of serum N-terminal netic resonance imaging reflecting microvasculature ob- pro-brain natriuretic peptide to predict in-stent restenosis in patients struction can be present in almost 90% of patients treated with preserved left ventricular function and normal troponin I levels. 16 Am J Cardiol 2007;99:1051–1054. using primary PCI. Because angiographic TIMI flow score 15. Grabowski M, Filipiak KJ, Karpinski G, Wretowski D, Rdzanek A, only addresses the issue of large epicardial vessel patency, Huczek Z, Horszczaruk GJ, Kochman J, Rudowski R, Opolski G. successful PCI associated with an epicardial TIMI 3 flow Serum B-type natriuretic peptide levels on admission predict not only score is not precisely predictive of microvascular perfusion short-term death but also angiographic success of procedure in patients recovery. Therefore, angiographic no reflow does not cor- with acute ST-elevation myocardial infarction treated with primary angioplasty. Am Heart J 2004;148:655–662. relate with cardiac magnetic resonance imaging no reflow. 16. Di Bella G, Aquaro GD, Strata E, Deiana M, De Marchi D, Lombardi M, Pingitore A. Simultaneous visualization of myocardial scar, no- 1. The GUSTO Angiographic Investigators. The effect of tissue plasmin- reflow phenomenon, ventricular and atrial thrombi by cardiac mag- ogen activator, streptokinase, or both on coronary-artery patency, netic resonance. Int J Cardiol 2007;115:e10–e11. Comparison of N-Terminal Pro-Brain Natriuretic Peptide Versus Electrophysiologic Study for Predicting Future Outcomes in Patients With an Implantable Cardioverter Defibrillator After Myocardial Infarction

Hong Yu, MD†, Hanno Oswald, MD†, Ajmal Gardiwal, MD, Christoph Lissel, MD, and Gunnar Klein, MD*

The aim of the study was to examine the predictive value of N-terminal pro-brain natriuretic peptide (NT–pro-BNP) versus electrophysiologic study in patients with implantable cardioverter–defibrillators (ICDs) after myocardial infarction (MI). We prospectively studied 99 consecutive patients with a history of MI who underwent ICD implantation for primary or secondary prevention of sudden cardiac death. An electrophysiologic study was performed in all patients. Venous blood samples for NT–pro-BNP measurement were obtained at the beginning of the study. The primary end point was ventricular tachycardia or ventricular fibrillation (VT/VF) and the secondary end point was a composite of death, hospitalization for heart failure, or MI. On multivariate Cox regression analysis, NT–pro- BNP level at or greater than median (497 ng/L) was the only significant predictor for NT–pro-BNP ,(0.001 ؍ Along with amiodarone use (p .(0.047 ؍ VT/VF occurrence (p levels higher than median were also associated with a higher risk of composite clinical Kaplan-Meier analysis showed that patients with NT–pro-BNP level at .(0.036 ؍ events (p or greater than median had a higher risk of experiencing VT/VF and composite clinical events than patients with NT–pro-BNP levels less than median (log-rank p <0.05). In conclusion, assay of NT–pro-BNP, which is easy to perform and widely available, is superior to electrophysiologic study for prediction of future outcomes in predominantly secondary prophylactic ICD recipients after MI. In the era of primary prophylactic ICD implantation without preimplantation electrophysiologic study, higher NT–pro-BNP levels might help to improve risk-adjusted concomitant antiarrhythmic therapy and device selection. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:635–639)

New serum biomarkers have emerged recently as a more Methods promising and more feasible method to identify various patient populations at high risk for various cardiac events. Patients with a history of MI who underwent ICD implan- Notably, B-type natriuretic peptide or N-terminal pro-brain tation had to meet the American College of Cardiology/ natriuretic peptide (NT–pro-BNP) levels have prognostic American Heart Association criteria for ICD implantation 4 significance in patients with congestive heart failure1,2 and (class I to IIb). Patients were excluded if cardiac events have been measured in relation to implantable cardioverter– occurred within 72 hours of an acute MI or if they had defibrillator (ICD) therapies.3 To our knowledge, it is un- undergone cardiac surgery or had electrolyte abnormalities clear if NT–pro-BNP is superior to electrophysiologic study or a proarrhythmic drug effect. for prediction of arrhythmic events (i.e., ventricular tachy- Enrollment began in March 2003 and ended in March cardia/ventricular fibrillation [VT/VF]) or nonarrhythmic 2004. At entry into the study, clinical characteristics were events in patients with an ICD after myocardial infarction collected through medical record review and interrogation (MI). Thus, we performed this prospective cohort study to of the patients. Congestive heart failure severity was cate- test the predictive value of NT–pro-BNP measurement ver- gorized according to New York Heart Association class at sus electrophysiologic study in patients with predominantly baseline interview. Left ventricular ejection fraction was secondary prophylactic ICDs. determined by echocardiography or left ventricular angiography. For analysis of NT–pro-BNP, venous blood was collected after 30 minutes of supine rest from all patients at the beginning of the study. NT–pro-BNP was measured Department of Cardiovascular Medicine, Hannover Medical School, using an electrochemiluminescence immunoassay (ECLIA; Hannover, Germany. Manuscript received January 28, 2007; revised manu- Roche Diagnostics, Mannheim, Germany).2 script received and accepted March 13, 2007. *Corresponding author: Tel: 49-511-5326523; fax: 49-511-5328475. Electrophysiologic studies were performed in the nonse- E-mail address: [email protected] (G. Klein). dated, postabsorptive state after all antiarrhythmic agents had been discontinued for Ն5 drug half-lives (except in the † Drs. Yu and Oswald have contributed equally to this manuscript. case of amiodarone). Assessment of sinus and atrioventric-

Table 1 Baseline characteristics of study subjects Variable All NT-pro-BNP at or Above Median NT-pro-BNP Less Than Median (n ϭ 99) (n ϭ 50) (n ϭ 49) Men 85 (86%) 42 (84%) 43 (88%) Age (yrs) 68 Ϯ 969Ϯ 867Ϯ 9 Ejection fraction (%) 36 Ϯ 13 31 Ϯ 10* 40 Ϯ 13* New York Heart Association class I 12 (12%) 5 (10%) 7 (14%) II 55 (56%) 28 (56%) 27 (56%) III 32 (32%) 17 (34%) 15 (31%) Permanent atrial ﬁbrillation 12 (12%) 7 (14%) 5 (10%) QRS width (ms) 144 Ϯ 38 149 Ϯ 39 140 Ϯ 37 Medications Angiotensin-converting enzyme inhibitors 79 (80%) 38 (76%) 41 (84%) ␤/blocker 73 (74%) 35 (70%) 38 (78%) Diuretics 51 (52%) 31 (62%)* 20 (41%)* Spironolactone 19 (19%) 12 (24%) 7 (14%) Sotalol 35 (35%) 20 (40%) 15 (31%) Amiodarone 20 (20%) 13 (26%) 7 (14%) ICD Primary prophylaxis 9 (9%) 5 (10%) 4 (8%) Secondary prophylaxis 90 (91%) 44 (88%) 45 (92%) Follow-up (days) 556 Ϯ 122 532 Ϯ 130 580 Ϯ 108 Electrophysiologic study Inducible 78 (79%) 37 (74%) 41 (84%) Noninducible 21 (21%) 13 (26%) 8 (16%)

*pϽ0.05. ular node and His-Purkinje function were performed, in- Table 2 cluding sinus node recovery time, atrioventricular node Univariate analysis for prediction of ventricular tachycardia or block cycle length, atrioventricular node effective refractory ventricular fibrillation period, ventriculoatrial block cycle length, and His-ventricular conduction time. Programmed ventricular stimulation Variable Hazard Ratio (95% confidence interval) was performed with Յ3 extrastimuli at 3 basic drive cycle lengths (600, 500, and 400 ms) starting at the right ventric- Diuretics* 2.8 (1.141–7.087) ular apex and outflow tract. Coupling intervals of extra- Sotalol* 2.4 (1.085–5.276) † stimuli were decreased in 20-ms intervals until coupling NT–pro-BNP at or above median* 2.4 (1.067–5.323) intervals of 190 ms or refractoriness were reached or a Permanent atrial fibrillation 2.3 (0.887–5.723) sustained ventricular arrhythmia was induced. Only patients Spironolactone 1.3 (0.485–3.438) New York Heart Association class 1.1 (0.632–2.071) with inducible sustained monomorphic VT were considered ␤ blocker 1.1 (0.425–2.712) inducible. Electrophysiologic study (inducible) 1.0 (0.344–3.012) Patients were monitored for ICD therapies (only sus- QRS width 1.0 (0.997–1.108) tained VT/VF episodes treated by antitachycardia pacing or Ejection fraction 1.0 (0.926–1.005) shock were included) and composite clinical events (death, Amiodarone 0.7 (0.247–2.093) hospitalization for heart failure, or MI) during routine fol- Angiotensin-converting enzyme 0.6 (0.232–1.768) low-up visits every 6 months. Hospitalization for heart * Significant difference. failure was defined by New York Heart Association class IV † Significant difference in multivariate analysis. (pulmonary edema) or ankle edema, making intravenous diuretic treatment necessary. Myocardial infarction was defined according to American College of Cardiology/Amer- of continuous variables and categoric variables, respec- ican Heart Association guidelines. Appropriate device ther- tively. A Cox regression model was built stepwise, and the apy for sustained VT/VF was confirmed by 2 p value for entering and staying in the model was set at 0.05. electrophysiologists (H.Y., G.K.) by analysis of stored elec- To test for a hazard ratio and its 95% confidence interval, trograms as previously described.5 Sotalol and amiodarone univariate analysis was performed for each variable. Mul- were added during follow-up when patients experienced tivariate Cox regression was performed to identify indepen- recurrent VT/VF episodes or inadequate ICD discharges as dent predictors for future outcomes. Along with NT–pro- a result of atrial fibrillation. BNP at or greater than median, age, gender, left ventricular All data were reported as mean Ϯ SD for continuous ejection fraction, New York Heart Association class, QRS variables and number of patients with percentages for cat- width, permanent atrial fibrillation, electrophysiologic egoric variables. Student t test or Mann-Whitney tests and study, and medications were used for analysis. Kaplan- chi-square or Fisher’s exact tests were used for comparison Meier analysis was used for survival comparison between Coronary Artery Disease/NT–Pro-BNP Versus EP in Patients With ICD 637

Figure 1. Kaplan-Meier curves for freedom from VT or VF occurrence (A) NT–pro-BNP at or above median (497 ng/L) and NT–pro-BNP lower than median and (B) inducibility and noninducibility at electrophysiologic study. independent risk predictors identified by Cox regression antitachycardia pacing with shock(s) in 6, and shock(s) in analysis. A p value Ͻ0.05 was considered statistically sig- 14. The mean number of shocks for each patient was 2. nificant. All statistical analyses were performed using SPSS Mean time to delivered ICD therapy was 529 Ϯ 128 days. version 14.0 (SPSS Inc., Chicago, Illinois). Twenty-one patients (21%) reached the combined clinical end point (death, hospitalization for heart failure, or MI) and 5 patients (5%) died. Results Table 2 shows the results of the Cox regression analyses Table 1 shows the baseline clinical and demographic fea- for VT/VF occurrence. On univariate analysis, diuretics, tures of all the patients and in both NT–pro-BNP subgroups. sotalol, and NT–pro-BNP were significant predictors for Median NT–pro-BNP level at inclusion was 497 ng/L. Pa- VT/VF (p ϭ 0.024, p ϭ 0.027, and p ϭ 0.033, respectively). tients with NT–pro-BNP levels at or greater than median Multivariate analysis including age, gender, left ventricular had lower ejection fractions and received a higher propor- ejection fraction, New York Heart Association class, QRS tion of diuretics. Indication for ICD therapy was a primary width, permanent atrial fibrillation, NT–pro-BNP, electro- prophylactic indication in 9% (left ventricular ejection frac- physiologic study findings, and drugs listed in Table 2 tion Յ35% as a result of previous MI, nonsustained VT and showed that only NT–pro-BNP at or greater than median inducible at electrophysiologic study) and secondary pro- (497 ng/L; p ϭ 0.047) was an independent risk predictor for phylactic indication in 91% (successful resuscitation of VT/VF occurrence. Kaplan-Meier analysis showed that pa- VT/VF or recurrent sustained VT with or without syncope). tients with NT–pro-BNP levels at or greater than median Single-chamber devices were seen in 69% of cases, 27% (497 ng/L) had a significantly higher probability of VT/VF had dual-chamber devices, and 4% had biventricular ICDs occurrence (Figure 1; log-rank p ϭ 0.035). Electrophysi- for a primary prophylactic purpose. The lowest VT detec- ologic study findings did not predict the occurrence of tion zone was 170 Ϯ 15 beats/min. VT/VF (Figure 1; log-rank p ϭ 0.973). An electrophysiologic study was performed in all pa- Univariate and multivariate analyses revealed that NT– tients: 78 had inducible sustained monomorphic VT, 4 had pro-BNP and amiodarone use were significantly associated polymorphic VT or VF, and 17 had normal findings. Pa- with a higher risk of occurrence of the composite clinical tients with previous spontaneous sustained ventricular end point (p ϭ 0.023 and p ϭ 0.001 in univariate analysis; tachyarrhythmias were more likely to have a positive elec- p ϭ 0.036 and p ϭ 0.001 in multivariate analysis, respec- trophysiologic study finding (85% vs. 56%; p ϭ 0.046). tively). Kaplan-Meier analysis showed that patients with Appropriate ICD therapies were delivered in 23 of the 99 NT–pro-BNP levels at or greater than median (497 ng/L) enrolled patients (23%), with antitachycardia pacing in 3, had a greater likelihood of experiencing composite clinical 638 The American Journal of Cardiology (www.AJConline.org)

Figure 2. Kaplan-Meier curves for freedom from composite of death, hospitalization for heart failure, or MI (A) NT–pro-BNP at or above median (497 ng/L) and NT–pro-BNP lower than median and (B) with and without amiodarone use. events (Figure 2; log-rank p ϭ 0.002). Neither univariate describe an association between higher BNP levels and nor multivariate analysis indicated any significant relation VT/VF occurrence in a mixed population of primary and between electrophysiologic study and the occurrence of secondary ICD recipients with and without MI. They found composite clinical events. Kaplan-Meier analysis showed that BNP above median (573 ng/L in their study) was a that patients with amiodarone use had a significantly higher significant predictor for ICD therapy in 345 consecutive likelihood of clinical events (Figure 2; log-rank p ϭ 0.001). patients undergoing first-time ICD implantation. Patients with BNP levels higher than median had a 2.2-fold in- Discussion creased risk for VT/VF events. This is in accordance with our data showing a 2.4-fold increased risk for VT/VF oc- To our knowledge, this is the first study to demonstrate that currence for patients with an ICD with NT–pro-BNP levels determination of preimplantation NT–pro-BNP is more ef- higher than the median level. fective for the prediction of outcomes in patients with ICDs Regarding ventricular arrhythmia burden, our study after MI than invasive electrophysiologic study. shows that patients with increased NT–pro-BNP are at Electrophysiologic study has been considered a gold higher risk for VT/VF. This appears to be reasonable, as standard and widely used to assess the risk of recurrent VT BNP is released as a response of the heart to intraventricular or sudden cardiac death.6–8 However, the results regarding pressure or stretch, which in turn causes electrophysiologic its predictive value in different studies have not always been abnormalities like slowing of intraventricular conduction, consistent. Electrophysiologic study was not performed rou- triggering after-depolarizations and ventricular ectopic tinely in the Multicenter Automatic Defibrillator Implanta- beats.9,18–21 Moreover, recent studies in mild to moderate tion Trial (MADIT II), mainly because of a high 2-year false and severe heart failure identified BNP as an independent negative rate for risk prediction in the Multicenter Unsus- 1,22 tained Tachycardia Trial (MUSTT).8 In addition, the pre- risk factor for sudden death. However, neither study dictive value of electrophysiologic study and NT–pro-BNP specified arrhythmic death as an outcome. Nonarrhythmic measurement has never been compared in primary or sec- causes of sudden death, such as pulmonary emboli, ruptured ondary prevention studies. aneurysms, MIs, hyperkalemia, and electromechanical dis- BNP is mainly synthesized and released from ventricular sociation could have been underestimated in these studies. myocytes as a 76–amino acid N-terminal fragment (i.e., In contrast to determination of ejection fraction and elec- N-terminal BNP) and a 32–amino acid active hormone (i.e., trophysiologic study, measurement of NT–pro-BNP is easy, BNP) in response to myocyte stretch and transmural pres- reproducible, and widely available. Measurement of NT– sure load.9 BNP increases natriuresis and diuresis by inhi- pro-BNP levels might be helpful in allocating patients to an bition of renal sodium reabsorption10 and relaxes vascular empiric antiarrhythmic medication to prevent ICD shocks smooth muscle, thereby reducing ventricular afterload and and thereby improve quality of life.23–27 In addition, these preload.11,12 In addition, BNP inhibits the renin–angiotensi- patients might also benefit from device settings with anti- n–aldosterone system and the central and peripheral sym- tachycardia pacing for fast VT to reduce painful shocks.27 pathoadrenergic system.13–15 Recently, the results of the Alternans Before Cardioverter Our data show that NT–pro-BNP is an independent pre- Defibrillator (ABCD) trial suggested that microvolt T-wave dictor for VT/VF occurrence and combined clinical events alternans is a promising new risk-stratification tool.28 When in patients with an ICD after MI. This agrees with the combined with electrophysiologic study, it may be effective findings of various previous studies in heart failure and in ruling out approximately 17% of patients for primary acute coronary syndrome.16,17 Verma et al3 were the first to ICD therapy with an acceptably low risk (1.2% in 12 Coronary Artery Disease/NT–Pro-BNP Versus EP in Patients With ICD 639 months) of an unprotected event in this group. Further uretic factor in mild essential hypertension. Circulation 1989;80: studies have to show if NT–pro-BNP measurement helps to 893–902. 13. Floras JS. Sympathoinhibitory effects of atrial natriuretic factor in improve patient selection for primary prophylactic ICD normal humans. Circulation 1990;81:1860–1873. therapy beyond microvolt T-wave alternans. 14. Brunner-La Rocca HP, Kaye DM, Woods RL, Hastings J, Esler MD. Our study has apparent limitations. The incidence of ICD Effects of intravenous brain natriuretic peptide on regional sympa- therapies seems to be lower (23.1%) in a 18-month fol- thetic activity in patients with chronic heart failure as compared with healthy control subjects. J Am Coll Cardiol 2001;37:1221–1227. low-up than in other secondary prevention trials (39% to 15. Atarashi K, Mulrow PJ, Franco-Saenz R. Effect of atrial peptides on 29,30 65.4%). This difference may be a result of (1) optimal aldosterone production. J Clin Invest 1985;76:1807–1811. medical therapy, including ␤-blocker therapy, amiodarone, 16. Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, and sotalol in our study; and (2) inclusion of a broader range Glazer RD, Tognoni G, Cohn JN. Changes in brain natriuretic peptide of patients in the other secondary prevention trials. How- and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107: 3 ever, our results are similar to those of Verma et al (18%), 1278–1283. who also enrolled patients with ICD implantation for mixed 17. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. primary and secondary prevention. Another potential limi- N-terminal pro-B-type natriuretic peptide and long-term mortality in tation is that we included patients with predominantly sec- stable coronary heart disease. N Engl J Med 2005;352:666–675. 18. Whang W, Mittleman MA, Rich DQ, Wang PJ, Ruskin JN, Tofler GH, ondary prophylactic ICD indication (88.9%). Thus, it is Muller JE, Albert CM. Heart failure and the risk of shocks in patients beyond the scope of this study to determine the prognostic with implantable cardioverter defibrillators: results from the Triggers value of NT–pro-BNP, electrophysiologic study, or other Of Ventricular Arrhythmias (TOVA) study. Circulation 2004;109: clinical variables for the primary prophylactic ICD population. 1386–1391. 19. 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Josep Rodés-Cabau, MD*, Alvaro Facta, MD, Eric Larose, MD, Robert DeLarochellière, MD, Jean-Pierre Déry, MD, Can Manh Nguyen, MD, Louis Roy, MD, Guy Proulx, MD, Onil Gleeton, MD, Gérald Barbeau, MD, Bernard Noël, MD, Jacques Rouleau, MD, Jean-Roch Boudreault, MD, and Olivier F. Bertrand, MD, PhD

The objective of this study was to evaluate the clinical and angiographic factors associated with significant saphenous vein graft (SVG) atherosclerosis progression at mid-term follow-up in a series of unselected coronary patients who had previously received a coronary artery bypass graft (CABG). A total of 123 SVGs from 86 patients who underwent cardiac catheterization twice, 15 ؎ 12 months apart, were included in the study. None of the SVGs presented any >50% diameter stenosis (DS) lesion or underwent any intervention at baseline. All SVGs were divided into 3 segments and each SVG segment was scored from 0 to 3 depending on the presence of lesions, with percent DS ranging from 0% to 19% (score 0), 20% to 29% (score 1), 30% to 39% (score 2), and >40% (score 3). The SVG atherosclerotic burden score (ABS) was calculated by adding the score obtained for each of the 3 SVG segments. Significant progression was defined as >10% increase in lesion percent DS or >0.6 mm decrease in minimal lumen diameter between baseline and follow-up studies. Mean age of the study population was 66 ؎ 9 years, and most of the patients were receiving statin therapy with mean low-density lipoprotein cholesterol of 85 ؎ 26 mg/dl. Significant angiographic progression occurred in >1 SVG in 41 patients (48%). On multivariate analysis, the variables associated with SVG atherosclerosis progression were SVG ABS (odds ratio [OR], 1.52 for each increase of 1 point in SVG ABS; 95% confidence interval [CI] 1.1 to 2.29) and high-density lipoprotein (HDL) cholesterol (OR 1.38 for each decrease of 5 mg/dl in HDL cholesterol levels, 95% CI 1.09 to 1.85). Twenty-two patients (26%) had a cardiac event at follow-up related to SVG disease progression. The percent DS of the SVG segment at baseline was associated with SVG disease progression leading to a cardiac event (OR 3.67 for each increase of 5% in percent DS, 95% CI 2.11 to 6.38). In conclusion, simple clinical and angiographic variables such as HDL cholesterol, ABS, and lesion severity remain independent predictors of significant SVG atherosclerosis progression in mild to moderately diseased SVGs despite mean low-density lipoprotein levels <90 mg/dl. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:640–645)

The Post Coronary Artery Bypass Graft (CABG) Trial1 low-up in this subset of patients,3,4 but few data are avail- demonstrated that aggressive lipid-lowering therapy signif- able regarding the factors involved in SVG disease progres- icantly decreased saphenous vein graft (SVG) disease pro- sion and cardiac events in such patients in the current era, gression. The Post-CABG Trial included patients in stable especially regarding SVGs without significant atheroscle- condition, and in approximately half of them, CABG had rotic disease at the time of baseline cardiac catheterization. been performed within Ͻ5 years. Currently, most of the This study evaluates the clinical and angiographic factors coronary patients with previous CABG are receiving inten- associated with substantial SVG atherosclerosis progression sive lipid-lowering treatment, but SVG disease progression at mid-term follow-up in a series of consecutive unselected continues to occur despite the achievement of low low- coronary patients with a previous CABG, focusing in those density lipoprotein (LDL) cholesterol levels. Also, “real- SVGs with no significant disease at baseline angiographic world” patients who have previously received a CABG who study. need to undergo cardiac catheterization are frequently diag- Ͼ nosed with an acute coronary syndrome 7 years after Methods 2,3 intervention. Many studies have shown a very high rate of Patients: We evaluated all patients with a previous cardiac events and death at mid-term and long-term fol- CABG, including SVGs who had undergone cardiac catheterization twice between 2001 and 2005 in our center. Only Ն Interventional Cardiology Laboratories, Quebec Heart Institute–Laval patients with 1 SVG without significant angiographic dis- Hospital, Laval, Quebec, Canada. Manuscript received January 11, 2007; ease at the baseline procedure were included. Significant revised manuscript received and accepted March 13, 2007. angiographic disease was defined as the presence of any *Corresponding author: Tel: 418-656-8711; fax: 418-656-4544. lesion with Ն50% diameter stenosis (DS) in the SVG. None E-mail address: [email protected] (J. Rodés-Cabau). of the patients had any intervention at any segment of the

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.080 Coronary Artery Disease/Predictors of SVG Atherosclerosis Progression 641 studied SVG(s) at baseline. Cardiac catheterizations were Table 1 performed by radial or femoral approach using standard Clinical and angiographic characteristics of the study population ϭ techniques. The following criteria were required for base- (n 86) line and follow-up angiographic studies to be considered Variable Value comparable: (1) the same sized catheters had to be used in Ϯ Ն Mean age (yrs) 66 9 both studies; (2) catheter size had to be 5Fr; (3) the Men 62 (72%) projections showing the worst SVG disease severity had to Body mass index (kg/m2) 28 Ϯ 4 be comparable between studies (Ͻ10° difference in projec- Current tobacco use 4 (5%) tion angle); and (4) use of intracoronary nitroglycerin had to Hypertension 65 (76%) be the same in both studies. Only patients with comparable Hypercholesterolemia 69 (80%) baseline and follow-up angiographic studies were included. Diabetes mellitus 38 (44%) Clinical characteristics including cardiovascular risk fac- Previous myocardial infarction 39 (45%) Ϯ tors, lipid levels within the 3 months of the procedure, and Ejection fraction (%) 53 14 Time from bypass surgery (yrs) 8 Ϯ 6 medication were recorded for all patients. The study proto- Time between baseline and follow-up angiography (mos) 15 Ϯ 12 col was performed in accordance with the institutional eth- Lipid levels (mg/dL) ics committee, and all patients gave informed consent for Total cholesterol 163 Ϯ 38 the procedures. LDL cholesterol 85 Ϯ 26 HDL cholesterol 43 Ϯ 11 Angiographic analysis: Quantitative coronary angio- Triglycerides 159 Ϯ 90 graphic (QCA) analyses were performed for baseline and Clinical indication for baseline angiography follow-up studies with the Medis QCA system (Medis Med- Stable angina pectoris 32 (37%) ical Imaging Systems, Nuenen, The Netherlands). All SVGs Acute coronary syndrome 54 (63%) were divided into 3 segments (proximal, middle, and distal) Unstable angina pectoris 38 (44%) of approximately the same length. QCA measurements were Myocardial infarction 16 (19%) performed for each SVG segment and included the minimal Current medications lumen diameter, the maximal percent DS and the reference Aspirin 84 (98%) Clopidogrel 22 (26%) diameter of the segment. Based on percent DS, each SVG Angiotensin converting enzyme inhibitor/angiotensin 44 (51%) segment was scored from 0 to 3 depending on the presence receptor antagonist of lesions, with percent DS ranging from 0% to 19% (score Lipid-lowering medication 76 (88%) 0), 20% to 29% (score 1), 30% to 39% (score 2), and Ն 40% ␤ blocker 63 (73%) (score 3). The SVG atherosclerotic burden score (ABS) was Angiographic SVG measurements (369 segments) calculated by adding the score obtained for each of the 3 Baseline segments. Reference diameter (mm) 3.51 Ϯ 0.92 Minimal lumen diameter (mm) 2.91 Ϯ 0.78 QCA measurements were performed offline by 1 inves- Ϯ tigator unaware of clinical data. The intraobserver mean SD Percent diameter stenosis 16 10 Follow-up for differences in repeated measurements of 30 SVG seg- Reference diameter (mm) 3.49 Ϯ 0.2 ments was 0.16 mm for the minimal lumen diameter and Minimal lumen diameter (mm) 2.75 Ϯ 0.79 2.96% for the percent DS. A difference Ͼ3 times the mean Percent diameter stenosis 20 Ϯ 13 SD for differences in repeated measurements was consid- SVG atherosclerotic burden score (123 SVGs) ered significant. Significant SVG segment disease progres- Baseline sion was defined by a decrease in minimal lumen diameter Median score 1 (0–2) Ն0.6 mm and/or an increase Ն10% in percent DS between 0 51 (41%) 1–2 49 (40%) baseline and follow-up studies. Significant atherosclerotic Ͼ Ն 2 23 (19%) progression of a SVG was defined as the presence of 1 Follow-up SVG segment with a significant angiographic progression Median score 1.5 (0–3) based on the aforementioned criteria. In cases of complete 0 45 (37%) occlusion of the SVG at follow-up, the mean value of the 1–2 35 (28%) QCA measurements of the 3 SVG segments at baseline was Ͼ2 43 (35%) used for analysis. Statistical analysis: Qualitative variables were expressed as percentages and numerical variables as mean hibiting differences between groups with a p value Ͻ0.20 in values with their SD or as median values with their 25% to the univariate analysis were included in the multivariate 75% interquartile range. Comparison of numerical variables analysis. The area under the receiver-operating characteris- was performed using the Student’s t test or Wilcoxon rank tic curve was used to determine the best cutoff point re- test depending on variable distribution, and the chi-square garding the baseline SVG percent DS for the prediction of test or Fisher’s exact test was used to compare qualitative cardiac events related to significant SVG progression at variables. A stepwise logistic regression analysis was used follow-up. Differences were considered statistically signif- to determine the independent predictive factors of signifi- icant at p values Ͻ0.05. The data were analyzed using the cant SVG angiographic progression and cardiac events re- statistical package program SAS version 9.1.3 (SAS, Cary, lated to SVG progression at follow-up. The variables ex- North Carolina). 642 The American Journal of Cardiology (www.AJConline.org)

Table 2 Comparison of clinical and angiographic characteristics between patients with and without signiﬁcant angiographic SVG disease progression Variable Angiographic Progression p Value Yes (n ϭ 41) No (n ϭ 45) Mean age (yrs) 67 Ϯ 965Ϯ 9 0.47 Men 33 (80%) 29 (64%) 0.15 Body mass index (kg/m2) 28 Ϯ 528Ϯ 4 0.57 Current tobacco use 2 (5%) 2 (4%) 1.00 Hypertension 31 (76%) 34 (76%) 1.00 Hypercholesterolemia 33 (80%) 36 (80%) 1.00 Diabetes mellitus 16 (39%) 22 (49%) 0.39 Prior myocardial infarction 20 (49%) 21 (47%) 0.76 Ejection fraction (%) 54 Ϯ 14 52 Ϯ 12 0.57 Time from last bypass surgery (yrs) 9 Ϯ 57Ϯ 6 0.13 Time between baseline and follow-up angiography (mo) 17 Ϯ 14 13 Ϯ 10 0.09 Lipid levels (mg/dl) Total cholesterol 158 Ϯ 36 166 Ϯ 40 0.42 LDL cholesterol 84 Ϯ 26 85 Ϯ 27 0.84 HDL cholesterol 40 Ϯ 10 46 Ϯ 12 0.03 Triglycerides 161 Ϯ 110 156 Ϯ 73 0.85 Indication for baseline angiography 0.11 Stable angina pectoris 13 (32%) 19 (42%) Acute coronary syndrome 28 (68%) 26 (58%) Current medications Aspirin 40 (98%) 44 (98%) 1.00 Clopidogrel 10 (24%) 12 (27%) 1.00 Angiotensin converting enzyme inhibitor/angiotensin 21 (51%) 23 (51%) 1.00 receptor antagonist Lipid-lowering medication 34 (83%) 42 (93%) 0.18 ␤ blocker 30 (73%) 33 (73%) 1.00 Baseline angiographic SVG measurements All segments (n ϭ 369) 198 171 Reference diameter (mm) 3.67 Ϯ 1.00 3.32 Ϯ 0.77 0.04 Minimal lumen diameter (mm) 2.98 Ϯ 0.87 2.83 Ϯ 0.66 0.29 Percent diameter stenosis 18 Ϯ 11 14 Ϯ 8 0.009 Segments with stenosis progression 75 171 Reference diameter (mm) 3.68 Ϯ 1.03 3.32 Ϯ 0.77 0.05 Minimal lumen diameter (mm) 2.91 Ϯ 1.02 2.83 Ϯ 0.66 0.50 Percent diameter stenosis 21 Ϯ 13 14 Ϯ 8 Ͻ0.001 Baseline SVG ABS 66 57 All SVGs Median score 1 (0–3) 0 (0–2) 0.006 0 21 (32%) 30 (53%) 1–2 28 (42%) 21 (37%) 0.009 Ͼ2 17 (26%) 6 (11%) SVGs with angiographic progression 50 57 Median score 1 (0–3) 0 (0–2) Ͻ0.001 0 14 (28%) 30 (53%) 1–2 20 (40%) 21 (37%) 0.002 Ͼ2 16 (32%) 6 (11%)

Results 38 patients, and non–ST elevation myocardial infarction A total of 151 consecutive patients with previous coro- in 16 patients. Clinical indications for a second study nary bypass surgery including SVGs underwent 2 cardiac were stable angina in 40 patients, unstable angina in 36 catheterizations between 2001 and 2005 in our institu- patients, and non–ST elevation myocardial infarction in tion. Among them, 42 patients were excluded because 10 patients. The clinical and angiographic characteristics they did not have any SVG without significant disease at of the study population are shown in Table 1. SVG baseline study, and 23 patients were excluded because reference diameter decreased from 3.51 Ϯ 0.92 mm at baseline and follow-up angiographic studies were not baseline to 3.49 Ϯ 0.92 mm at follow-up (p ϭ NS), and comparable. The final study population consisted of 86 minimal lumen diameter decreased from 2.91 Ϯ 0.78 to patients with 123 SVGs with no significant disease at 2.75 Ϯ 0.79 mm (p Ͻ0.0001). The median SVG ABS baseline study. Clinical indications for initial angiogra- increased from 1 (interquartile range 0 to 2) at baseline to phy were stable angina in 32 patients, unstable angina in 1.5 (interquartile range 0 to 3) at follow-up (p Ͻ0.0001). Coronary Artery Disease/Predictors of SVG Atherosclerosis Progression 643

Figure 1. Example of a 72-year-old patient who had undergone bypass surgery 9 years before baseline angiography. The patient was initially admitted because of unstable angina, and coronary angiography demonstrated a signiﬁcant lesion in the native coronary artery as the culprit lesion. At that time, a SVG anastomosed to a diagonal branch of the left anterior descending artery (A) had a 34% DS lesion in the midportion of the vein graft (white arrow). Ten months after initial angiography, the patient was readmitted because of a non–ST elevation myocardial infarction. Coronary angiography (B) showed a signiﬁcant progression of the disease in the midportion of the vein graft anastomosed to the diagonal branch (white arrow) with a 72% DS lesion at that point responsible for the clinical event.

Saphenous veing graft angiographic progression: between 30% and 49% DS (n ϭ 28), the incidence of Forty-one ofthe 86 patients (48%) showed significant an- cardiac events related to SVG disease progression at fol- giographic progression in Ն1 SVG between baseline and low-up was 68% versus 5% in the 58 patients with no SVG follow-up studies. The clinical and angiographic character- lesions Ն30% (p Ͻ0.0001). istics of these patients compared with those who did not show any significant SVG progression are shown in Table 2. Discussion In the multivariate analysis, the variables independently associated with SVG angiographic progression were high- The results of this study showed that, in the current era, density lipoprotein (HDL) cholesterol levels at baseline most patients with previous CABG and Ն1 patent SVG (odds ratio [OR] 1.38 for each decrease of 5 mg/dl in HDL after a mean follow-up of 8 years after the operation were level, 95% confidence interval [CI] 1.09 to 1.85; p ϭ 0.031) receiving intensive lipid-lowering therapy with a mean LDL and SVG ABS (OR 1.52 for each increase of 1 point in cholesterol level Ͻ90 mg/dl. In these patients, HDL cho- ABS, 95% CI 1.1 to 2.29, p ϭ 0.045). lesterol levels and vein graft atherosclerotic burden were the Twenty-two patients (26%) had a cardiac event after a 2 independent factors associated with significant SVG ath- mean follow-up of 20 Ϯ 15 months related to a significant erosclerosis progression of mild to moderately diseased progression of the disease in Ն1 SVG segment (Figure 1), SVGs at mid-term follow-up as evaluated by angiography. and complete occlusion of the SVG occurred in 2 patients. Also, SVG maximum percent DS at baseline was the only Eight of the 22 patients had a myocardial infarction and 19 independent predictor of clinical events related to SVG patients underwent target SVG revascularization. The clin- disease progression, with a percent DS Ն30% the best ical and angiographic characteristics of these patients com- cutoff point to determine SVG disease progression leading pared with those with no clinical events related to SVG to a clinical event at midterm follow-up. disease progression are shown in Table 3. In the multivar- Consistent with the results of this study, previous studies iate analysis, the only variable associated with SVG disease have demonstrated a positive correlation between the pres- progression leading to a cardiac event was the percent DS at ence and severity of SVG atherosclerosis as evaluated by baseline (odds ratio 3.67 for each increase of 5% in percent angiography and the occurrence of significant SVG disease DS, 95% CI 2.11 to 6.38, p Ͻ0.001). The area under the progression and cardiac events at mid- and long-term fol- receiver-operating characteristic curve for baseline percent low-up. 5–8 Domanski et al5 evaluated the prognostic factors DS was 0.903, and the best baseline cutoff point to predict for atherosclerosis SVG progression in the patients included SVG progression associated with a cardiovascular event at in the Post CABG Trial,1 showing that the maximum per- midterm follow-up was 30% DS, with a sensitivity of 82% cent DS of the graft was the most important independent and a specificity of 96%. In the presence of SVG lesions prognostic factor for SVG atherosclerosis progression.5 The 644 The American Journal of Cardiology (www.AJConline.org)

Table 3 Comparison of clinical and angiographic characteristics between patients with and without SVG disease progression leading to a clinical event at follow-up Variable Patients With SVG Disease Progression Patients With No SVG Disease p Value Leading to a Clinical Event Progression Leading to a Clinical Event (n ϭ 22) (n ϭ 64) Mean age (yrs) 66 Ϯ 10 66 Ϯ 9 0.99 Male gender 18 (82%) 44 (69%) 0.28 Body mass index (kg/m2) 28 Ϯ 428Ϯ 4 0.87 Current tobacco use 2 (9%) 2 (3%) 0.27 Hypertension 18 (82%) 47 (73%) 0.57 Hypercholesterolemia 20 (91%) 49 (77%) 0.22 Diabetes mellitus 12 (55%) 26 (41%) 0.32 Prior myocardial infarction 9 (41%) 31 (48%) 0.48 Ejection fraction (%) 53 Ϯ 12 53 Ϯ 13 0.91 Time from bypass surgery (yrs) 9 Ϯ 58Ϯ 6 0.18 Time between baseline and follow-up angiography (mo) 20 Ϯ 15 13 Ϯ 10 0.07 Lipid levels (mg/dl) Total cholesterol 157 Ϯ 36 164 Ϯ 39 0.55 LDL cholesterol 81 Ϯ 26 85 Ϯ 27 0.65 HDL cholesterol 41 Ϯ 12 44 Ϯ 11 0.36 Triglycerides 151 Ϯ 89 160 Ϯ 91 0.77 Indication for baseline angiography 0.10 Stable angina pectoris 5 (23%) 27 (42%) Acute coronary syndrome 17 (77%) 37 (58%) Current medications Aspirin 22 (100%) 62 (97%) 1.00 Clopidogrel 7 (32%) 15 (23%) 0.57 Angiotensin converting enzyme inhibitor/angiotensin 11 (50%) 33 (52%) 1.00 receptor antagonist Lipid-lowering medication 18 (82%) 58 (91%) 0.27 ␤-blocker 15 (68%) 48 (75%) 0.58 Clinical events related to SVG disease progression Myocardial infarction 8 (36%) — Target vessel revascularization 19 (86%) — Baseline angiographic SVG measurements All segments 93 276 Reference diameter (mm) 3.74 Ϯ 1.13 3.43 Ϯ 0.82 0.15 Minimal lumen diameter (mm) 2.84 Ϯ 0.97 2.93 Ϯ 0.71 0.53 Percent diameter stenosis 24 Ϯ 12 14 Ϯ 8 Ͻ0.001 Segments leading to a clinical event at follow-up 26 276 Reference diameter (mm) 3.59 Ϯ 0.85 3.43 Ϯ 0.82 0.43 Minimal lumen diameter (mm) 2.29 Ϯ 0.66 2.93 Ϯ 0.71 Ͻ0.001 Percent diameter stenosis 36 Ϯ 914Ϯ 8 Ͻ0.001 Baseline SVG ABS All SVGs 31 92 Median score 3 (1–5) 0.5 (0–1) Ͻ0.001 0 5 (16%) 46 (50%) 1–2 10 (32%) 39 (42%) Ͻ0.001 Ͼ2 16 (52%) 7 (8%) SVGs leading to a clinical event at follow-up 22 92 Median score 3.5 (2–5) 0.5 (0–1) Ͻ0.001 0 2 (9%) 46 (50%) 1–2 6 (27%) 39 (42%) Ͻ0.001 Ͼ2 14 (64%) 7 (8%) present study provides the additional information that global SVG minimal lumen diameter, was associated with a more atherosclerotic burden of the SVG as measured by a simple than twofold increase in the risk of cardiac death or myo- angiographic score might also be a useful marker of signif- cardial infarction at 3-year follow-up, suggesting that an- icant SVG disease progression at midterm follow-up. These giographic changes in SVGs are appropriate surrogate results highlight the concept that the presence of measurable markers for clinical outcomes. Also consistent with the angiographic stenoses in the SVGs might be a marker of an results of the present study are previous reports identifying accelerated atherosclerotic process. In addition, Knatterud the presence of moderate lesions in the SVG as an important et al6 demonstrated that significant angiographic progres- predictor of clinical events at mid-term follow-up. Ellis et sion of SVG disease, defined as a reduction of Ն0.6 mm in al7 reported a series of 103 patients who underwent suc- Coronary Artery Disease/Predictors of SVG Atherosclerosis Progression 645 cessful coronary angioplasty of severe SVG lesions and tions were included in the study. This might lead to an showed that cardiac events after the first year and Յ3 years overestimation of the incidence of angiographic SVG pro- after the intervention were mostly related to the presence of gression and cardiac events related to SVG progression at moderate SVG lesions (30% to 50% DS) not treated at follow-up. Also, the presence of nonsignificant lesions at baseline coronary angiography. Incidences of cardiac events the first cardiac catheterization might have influenced the were 45% for the lesions between 40% and 50% DS, 18% decision to perform the second one in some cases. However, for lesions between 30% and 40%, and 2% for lesions the 26% cardiac event rate at approximately 2 years of Ͻ30%. In our study population, approximately 2/3 of the follow-up related to SVG progression in the present study is Ն patients with SVG lesions 30% had a cardiac event related similar to those reported in previous studies with similar to SVG disease progression at a mean follow-up of approx- patients subsets.3,7,8 imately 2 years, compared with only 5% of the patients without such lesions. In the same way, Le May et al8 demonstrated that the presence of moderate SVG lesions Acknowledgment: We thank Serge Simard, MSc, for sta- treated medically was associated with a mortality rate of tistical analysis. 25% at 2-year follow-up compared with 10% in patients without such lesions. 1. The Post Coronary Artery Bypass Graft Trial Investigators. The effect The present study has demonstrated that, in the current of aggressive lowering of low-density lipoprotein cholesterol levels era, most coronary patients with previous bypass surgery and low-dose anticoagulation on obstructive changes in saphenous- and patent SVGs after a mean follow-up of 8 years after the vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162. operation are receiving intensive lipid-lowering therapy 2. Chen L, Théroux P, Lespérance J, Shabani F, Thibault B, De Guise P. with mean LDL levels Ͻ90 mg/dl, which are even lower Angiographic features of vein grafts versus ungrafted coronary arteries in patients with unstable angina and previous bypass surgery. JAm than those obtained in the aggressive treatment group of the Coll Cardiol 1996;15:1493–1499. 1 Post CABG Trial. However, mean HDL cholesterol levels 3. Keely EC, Velez CA, O’Neill W, Safian RD. Long-term clinical of our study population were Ͻ45 mg/dl, much lower than outcome and predictors of major adverse cardiac events afer percuta- those that would be recommended for such a high-risk neous interventions on saphenous vein grafts. J Am Coll Cardiol coronary population. HDL cholesterol has very well known 2001;38:659–665. antiatherogenic effects, such as the reversal of LDL trans- 4. Mehta RH, Honeycutt E, Shaw LK, Glower D, Harrington RA, Sketch MH. Clinical correlates of long-term mortality after percutaneous port from the vessel wall back to the liver, the inhibition of interventions of saphenous vein grafts. Am Heart J 2006;152:801– lipoprotein oxidation, and the further inhibition of plaque 806. expansion by improving the stability of existing plaques.9 5. Domanski MJ, Borkowf CB, Campeau L, Knatterud GL, White C, Also, there is a strong association between HDL cholesterol Hoogwerf B, Rosenberg Y, Geller NL. Prognostic factors for athero- levels and the risk of development and progression of native sclerosis progression in saphenous vein grafts. J Am Coll Cardiol coronary heart disease.10,11 Neitzel et al12 showed that HDL 2000;36:1877–1883. 6. Knatterud GL, White C, Geller NL, Campeau L, Forman SA, Doman- levels were significantly lower in patients who underwent ski M, Forrester JS, Gobel FL, Herd A, Hickey A, et al. Angiographic repeat operation or died 6 to 12 years after bypass surgery changes in saphenous vein grafts are predictors of clinical outcomes. compared with a control group of 535 survivors who did not Am Heart J 2003;145:262–269. require another revascularization during the same period. 7. Ellis SG, Brener SJ, DeLuca S, Tuzcu M, Raymond RE, Whitlow PL, Also, low HDL cholesterol level was found to be an inde- Topol E. Late myocardial ischemic events after saphenous vein graft intervention: importance of initially “nonsignificant” vein graft le- pendent prognostic factor for significant atherosclerosis sions. Am J Cardiol 1997;79:1460–1464. 1 SVG progression in the Post CABG Trial. The present 8. Le May MR, Labinaz M, Marquis JF, Laramée LA, O’Brien ER, study has shown that in the era of intensive lipid-lowering Williams WL, Jelley JL, Woodend K, Higginson LA. Predictors of therapy with the achievement of very low LDL cholesterol long-term outcome after stent implantation in a saphenous vein graft. levels in most of the patients, low HDL cholesterol level Am J Cardiol 1999;83:681–686. remains an important factor involved in the progression of 9. Libby P. Managing the risk of atherosclerosis: the role of high-density lipoprotein. Am J Cardiol 2001;88(suppl):3N–8N. SVG atherosclerosis at midterm follow-up in mild to mod- 10. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High erately diseased SVGs. density lipoprotein as a protective factor against coronary heart dis- Even though most patients with a clinically evident car- ease. Am J Med 1977;62:707–714. diac event at follow-up after baseline angiography would 11. Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sortie PD, Catellier have undergone cardiac catheterization, we can not rule out D, Patsch W. Coronary heart disease prediction from lipoprotein cho- the possibility that we may have missed some patients with lesterol levels, triglycerides, lipoprotein (a), apolipoprotein A-1 and B, and HDL density subfractions. Circulation 2001;104:1108–1113. silent ischemic events related to SVG angiographic progres- 12. Neitzel G, Barboriak J, Pintar K, Qureshi I. Atherosclerosis in aorto- sion who did not undergo angiography at follow-up. Con- coronary bypass grafts: morphological study and risk factor analysis 6 versely, only patients who underwent 2 cardiac catheteriza- to 12 years after surgery. Arteriosclerosis 1986;594–600. Usefulness of Combining Complement Factor H and C-Reactive Protein Genetic Profiles for Predicting Myocardial Infarction (from the Rotterdam Study)

Isabella Kardys, MDa, Moniek P.M. de Maat, PhDb, Caroline C.W. Klaver, MD, PhDa,c,e, Dominiek D.G. Despriet, MDa,c,e, André G. Uitterlinden, PhDa,d, Albert Hofman, MD, PhDa, Paulus T.V.M. de Jong, MD, PhDa,e,f, and Jacqueline C.M. Witteman, PhDa,*

Complement factor H (CFH) is an important regulator of the complement cascade. Binding of C-reactive protein (CRP) to CFH augments the ability of CFH to downregulate the effect of complement in atherosclerotic lesions. The CFH Tyr402His polymorphism has been suggested to influence the ability of CFH to bind CRP. We hypothesized that the combined presence of unfavorable CRP and CFH genetic profiles is associated with risk of myocardial infarction (MI). The Rotterdam Study is a population-based cohort study in 7,983 men and women aged >55 years. The CFH Tyr402His (rs1061170) polymorphism was determined (His402 allele 37%), and using 3 tagging polymorphisms (rs1130864, rs1205, and ;CCG ؍ CCC, 4 ؍ TCC, 3 ؍ CTC, 2 ؍ rs3093068), CRP haplotypes were inferred (1 frequencies of 33%, 32%, 30%, and 6%, respectively). Participants were grouped by CFH genotype (TyrTyr [reference], TyrHis, and HisHis) and CRP haplotype (haplotype 1 homozygotes [reference], haplotype 2 carriers, haplotype 3 carriers, and haplotype 4 carriers), which resulted in a total of 12 groups. CFH His402 homozygotes who were also CRP haplotype 3 carriers had an age- and gender-adjusted hazard ratio of 5.9 (95% confidence interval 2.1 to 16.5) to develop MI compared with the reference group. In conclusion, this population-based study suggests that the combined presence of unfavorable CFH and CRP genetic profiles is associated with risk of MI. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:646–648)

Recently, the complement factor H (CFH) gene and the failure to show a consistent association.8–10 In view of the C-reactive protein (CRP) gene have received attention with biologic effect of CRP on the ability of CFH to downregu- regard to coronary heart disease risk. CFH is a plasma late the effect of complement, we investigated whether the protein essential in the regulation of the alternative comple- combined presence of unfavorable genetic CFH and CRP ment pathway1 and has been suggested to play a part in profiles was associated with risk of MI in the Rotterdam complement inhibition in atherosclerotic lesions.2 Binding Study. of CRP to CFH augments the ability of CFH to downregulate the effect of complement.3,4 The His402allele of the Methods and Results functional CFH Tyr402His polymorphism (rs1061170) has been suggested to influence the ability of CFH to bind The Rotterdam Study is a population-based cohort study aimed at studying chronic diseases in elderly participants. CRP,1 and has recently been found to be associated with 5 Objectives and methods of the Rotterdam Study have been risk of myocardial infarction (MI) in the Rotterdam Study. 11 CRP level is a consistent risk factor for cardiovascular described in detail elsewhere. Briefly, the Rotterdam Study cohort included 7,983 men and women aged Ն55 disease.6 Steady-state CRP level has been found to be in- years (78% of the eligible population) living in a well- fluenced by CRP haplotypes.7–9 However, the association between CRP haplotypes and coronary heart disease re- defined suburb of the city of Rotterdam, The Netherlands. mains controversial. Few studies have been performed on Baseline data were collected from 1990 to 1993. A trained this topic so far, and lack of power may play a part in their interviewer visited all subjects at home and collected information using a computerized questionnaire, and established cardiovascular risk factors were measured at the research aDepartments of Epidemiology and Biostatistics, bHematology, cOph- center in 7,129 participants, as previously described in de- thalmology, and dInternal Medicine, Erasmus Medical Center, Rotterdam ; tail.5 DNA was available for 6,571 participants. The medi- eDepartment of Molecular and Clinical Ophthalmogenetics, Netherlands cal ethics committee of Erasmus Medical Center, Rotter- Institute for Neuroscience, Amsterdam; and fDepartment of Ophthalmol- dam, The Netherlands, approved the study. Participants ogy, Academic Medical Center, Amsterdam, The Netherlands. Manuscript gave written informed consent and permission to retrieve received February 16, 2007; revised manuscript received and accepted information from treating physicians. March 15, 2007. Follow-up started at the baseline examination and, for This study was supported by Grant 948-00-016 from the Research Institute for Diseases in the Elderly (RIDE) of the Netherlands Organiza- the present study, lasted until January 1, 2005. Information tion for Health Research and Development (ZonMw), The Hague, The on fatal and nonfatal cardiovascular end points was obtained Netherlands. from general practitioners and letters and discharge reports *Corresponding author: Tel: 31-10-4087488; fax: 31-10-4089382. from medical specialists.5 Two research physicians inde- E-mail address: [email protected] (J.C.M. Witteman). pendently coded all reported events according to the Inter-

Table 1 Baseline characteristics (n ϭ 5178) Variable Value Age (yrs) 69.1 Ϯ 9.2 Women 3293 (63.0%) Body mass index (kg/m2) 26.2 Ϯ 3.7 Systolic blood pressure (mm Hg) 139 Ϯ 22 Diastolic blood pressure (mm Hg) 74 Ϯ 11 Total cholesterol mmol/L 6.6 Ϯ 1.2 mg/dl 257 Ϯ 47 High-density lipoprotein cholesterol mmol/L 1.4 Ϯ 0.4 Figure 1. CFH genotype, CRP haplotype, and risk of MI. †p Ͻ0.05; R ϭ mg/dl 55 Ϯ 16 reference; 2* ϭ haplotype 2 carriers; 3* ϭ haplotype 3 carriers; 4* ϭ C-reactive protein (mg/L)* 1.80 (0.86–3.49) haplotype 4 carriers. Participants with haplotype 2 and 3 (2–3) were present Diabetes mellitus 508 (9.9%) in both the 2* and 3* group. Participants with haplotype 2 and 4 (2–4) were Smokers present in both the 2* and 4* group. Participants with haplotype 3 and 4 Never 1879 (37.4%) (3–4) were present in both the 3* and 4* group. Current 1134 (22.6%) Former 2012 (40.0%) Hypertension (history) 1673 (33.2%) erties as previously mentioned. In addition, we determined Ϯ CRP haplotypes by genotyping the participants for the hap- Values of continuous variables are expressed as mean SD. Categorical lotype tagging SNPs 1184 CϾT (rs1130864), 2042 CϾT variables are expressed as count (percentage). Valid percentages may vary Ͼ 9,13 for some counts because of missing values in the variables. (rs1205) and 2911 C G (rs3093068). We chose to de- * Median and interquartile range because of skewed distribution. termine CRP haplotypes to make use of the common variation across the entire CRP gene. CRP haplotypes were Table 2 inferred using the program PHASE (University of Wash- Complement factor H genotype, C-reactive protein haplotype, and risk ington, Seattle, Washington), which implements a Bayesian of myocardial infarction statistical method for reconstructing haplotypes from population genotype data.14 Complement C-Reactive Protein Cases/Subjects Hazard Ratio (95% For the analysis, participants were grouped according to Factor H Haplotype Confidence Genotype Interval) CFH genotype (TyrTyr [reference], TyrHis, and HisHis) and CRP haplotype (haplotype 1 homozygotes [reference], TyrTyr 1–1 4/200 1.0 (reference) haplotype 2 carriers, haplotype 3 carriers, and haplotype 4 2* 52/1141 2.3 (0.8–6.4) carriers), which resulted in 12 groups. Participants homozy- 3* 60/1097 2.8 (1.0–7.7)† † gous for the common CFH Tyr genotype and the most 4* 14/233 3.2 (1.0–9.7) frequent CRP haplotype 1 were used as the reference group. TyrHis 1–1 13/245 2.8 (0.9–8.7) 2* 60/1255 2.5 (0.9–6.8) Cox proportional-hazards analysis was used to determine 3* 59/1163 2.7 (1.0–7.4) the relative risks of MI associated with combinations of 4* 8/277 1.6 (0.5–5.2) Tyr402His genotype and CRP haplotype, adjusted for age HisHis 1–1 3/76 2.1 (0.5–9.5) and gender. The proportional hazards assumption was tested 2* 24/374 3.4 (1.2–9.8)† (by drawing log Ϫ log plots of the survival function). All 3* 39/355 5.9 (2.1–16.5)† analyses were performed using SPSS version 11.0 (SPSS, 4* 9/84 5.1 (1.6–16.5)† Chicago, Illinois). Participants with haplotype 2 and 3 (2 to 3) were present in both the 2* Genotyping was successful for the 4 SNPs within the and 3* group. Participants with haplotype 2 and 4 (2 to 4) were present in CRP and CFH genes in 5,946 participants. After excluding both the 2* and 4* group. Participants with haplotype 3 and 4 (3 to 4) were participants with history of MI, coronary artery bypass present in both the 3* and 4* group. grafting, or percutaneous transluminal coronary angio- * Carrier of the numbered haplotype listed. plasty, 5,178 participants were left for analysis. A total of † p Ͻ0.05. 277 MIs occurred during a median follow-up time of 12 years (interquartile range, 9 to 13 ). Chi-square tests showed national Classification of Diseases, 10th edition (ICD-10).12 that genotype distributions were in Hardy-Weinberg equi- In case of disagreement, consensus was reached. A medical librium in the full cohort. The population frequency of the expert in cardiovascular disease whose judgment was con- His402 allele was 37%; genotype frequencies were 41%, sidered final reviewed all events. In identifying incident MIs 45%, and 14% for TyrTyr, TyrHis, and HisHis, respec- (ICD code I21), all available information, which included tively. The probability of the CRP haplotypes estimated by electrocardiography, cardiac enzyme levels, and clinical PHASE was Ն0.999 in all participants. Haplotypes were judgment of the treating specialist, was used. coded as 1 to 4 in order of decreasing frequency in the Participants were genotyped for the Tyr402His population (coding from 1184 C/T, 2042 C/T, and 2911 (1277TϾC, rs1061170) single-nucleotide polymorphism C/G: haplotype 1 ϭ CTC, haplotype 2 ϭ TCC, haplotype 3 (SNP) of the CFH gene, as described previously.13 This ϭ CCC, and haplotype 4 ϭ CCG). Frequencies of haplo- SNP was chosen because of its suggested functional prop- types 1, 2, 3, and 4 were 33%, 32%, 30%, and 6%, respec- 648 The American Journal of Cardiology (www.AJConline.org) tively. These 4 haplotypes described 99.9% of our popula- solidate the findings. The results would be strengthened if tion. confirmed by another, independent, study. Our study may Baseline characteristics of the study population are stimulate other research groups to investigate this associa- shown in Table 1. Hazard ratios for developing MI are tion. displayed in Table 2. The reference group had the lowest risk of MI. Within CFH TyrTyr homozygotes, risk in- 1. Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, creased in carriers of CRP haplotypes 2, 3, and 4. A similar Lopez-Trascasa M, Sanchez-Corral P. The human complement factor increase in risk was seen within CFH HisHis homozygotes. H: functional roles, genetic variations and disease associations. Mol Immunol 2004;41:355–367. Within CRP haplotype 2, haplotype 3, and haplotype 4 2. Oksjoki R, Jarva H, Kovanen PT, Laine P, Meri S, Pentikainen MO. carriers, CFH HisHis homozygotes carried the highest rel- Association between complement factor H and proteoglycans in early ative risks. Although within the CRP haplotype 1–1 ho- human coronary atherosclerotic lesions: implications for local regula- mozygotes, CFH HisHis homozygosity also resulted in an tion of complement activation. Arterioscler Thromb Vasc Biol 2003; increased relative risk, this was not statistically significant. 23:630–636. 3. Fearon DT. Regulation by membrane sialic acid of beta1H-dependent This may have been caused by lack of power. The risk decay-dissociation of amplification C3 convertase of the alternative pattern is illustrated in Figure 1. Additional adjustment for complement pathway. Proc Natl Acad SciUSA1978;75:1971–1975. body mass index, systolic and diastolic blood pressure, total 4. Mold C, Kingzette M, Gewurz H. C-reactive protein inhibits pneumo- and high-density lipoprotein cholesterol, diabetes mellitus, coccal activation of the alternative pathway by increasing the interac- and smoking did not materially change the risk estimates. tion between factor H and C3b. J Immunol 1984;133:882–885. 5. Kardys I, Klaver CC, Despriet DD, Bergen AA, Uitterlinden AG, Hofman A, Oostra BA, Van Duijn CM, de Jong PT, Witteman JC. A Discussion common polymorphism in the complement factor H gene is associated with increased risk of myocardial infarction: the Rotterdam Study. The results of the present study suggest that the combined J Am Coll Cardiol 2006;47:1568–1575. presence of unfavorable genetic CFH and CRP profiles is 6. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley associated with MI. To our knowledge, our study is the first A, Lowe GD, Pepys MB, Gudnason V. C-reactive protein and other to investigate this association. A combined effect of CFH circulating markers of inflammation in the prediction of coronary heart and CRP genetic profiles has previously been found for disease. N Engl J Med 2004;350:1387–1397. age-related macular degeneration.15 These findings support 7. Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, Rieder M, Liu K, Williams OD, Iribarren C, Lewis EC, et al. Polymorphisms 4 the previously suggested biologic effect of CRP on CFH. within the c-reactive protein (CRP) promoter region are associated CFH has the ability to downregulate the effect of comple- with plasma CRP levels. Am J Hum Genet 2005;77:64–77. ment in atherosclerotic lesions.2 CRP is capable to enhance 8. Miller DT, Zee RY, Suk Danik J, Kozlowski P, Chasman DI, Lazarus this effect: it has been shown that binding of CRP to CFH R, Cook NR, Ridker PM, Kwiatkowski DJ. Association of common is the mechanism by which the CRP-dependent alternative CRP gene variants with CRP levels and cardiovascular events. Ann Hum Genet 2005;69:623–638. 4 pathway, induced by damaged tissue, is counterarrested. 9. Kardys I, de Maat MP, Uitterlinden AG, Hofman A, Witteman JC. The Tyr402His SNP is located within the cluster of amino C-reactive protein gene haplotypes and risk of coronary heart disease: acids implicated in the binding of CRP, and the His402allele the Rotterdam Study. Eur Heart J 2006;27:1331–1337. may diminish the binding properties for CRP because of the 10. Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, Durda JP, substitution of a positively charged histidine for a non- Cushman M, Bis JC, Zeng D, Lin D, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and 1 charged hydrophobic tyrosine. The decrease in comple- cardiovascular events. JAMA 2006;296:2703–2711. ment inhibition, combined with enhanced activation of the 11. Hofman A, Grobbee DE, de Jong PT, van den Ouweland FA. Deter- classical complement pathway by increased CRP levels, minants of disease and disability in the elderly: the Rotterdam Elderly may underlie the large increase in risk of MI. Study. Eur J Epidemiol 1991;7:403–422. Strengths of the present study include its large size, 12. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th Revision. Geneva, Swit- population-based design, coverage of 99.9% of the variation zerland: WHO, 1992. in the CRP gene, occurrence of 277 incident MIs, and 13. Nickerson D. Seattle SNPs: NHLBI program for genomic applications. thorough follow-up procedure. Nevertheless, some aspects Seattle: UW-FHCRC. Available at http://pga.gs.washington.edu. Ac- of this study warrant further consideration. First, although cessed February 16, 2007. haplotyping was performed for the CRP gene, we deter- 14. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet mined only 1 SNP in the CFH gene. It remains to be 2001;68:978–989. investigated whether this SNP is the true underlying variant 15. Despriet DD, Klaver CC, Witteman JC, Bergen AA, Kardys I, de Maat and does not represent a marker in complete or partial MP, Boekhoorn SS, Vingerling JR, Hofman A, Oostra BA, Uitterlin- linkage disequilibrium. Still, the Tyr402His SNP is a cred- den AG, Stijnen T, et al. Complement factor H polymorphism, com- ible candidate because the substitution of a positively plement activators, and risk of age-related macular degeneration. JAMA 2006;296:301–309. charged histidine for a noncharged hydrophobic tyrosine 16. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, could have functional implications for the CFH protein, and Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, et furthermore, haplotype reconstruction has implicated this al. A common haplotype in the complement regulatory gene factor H SNP in relation to complement-mediated pathogenesis of (HF1/CFH) predisposes individuals to age-related macular degenera- age-related macular degeneration.16,17 tion. Proc Natl Acad SciUSA2005;102:7227–7232. 17. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning Another aspect that merits attention is the fact that our AK, Sangiovanni JP, Mane SM, Mayne ST, et al. Complement factor findings are based on 1 single cohort. We did not have an H polymorphism in age-related macular degeneration. Science 2005; independent reproducibility cohort at our disposal to con- 308:385–389. Comparison of Long-Term Follow-Up of Electrocardiographic Features in Brugada Syndrome Between the SCN5A-Positive Probands and the SCN5A-Negative Probands

Miki Yokokawa, MD, Takashi Noda, MD, PhD, Hideo Okamura, MD, Kazuhiro Satomi, MD, PhD, Kazuhiro Suyama, MD, PhD, Takashi Kurita, MD, PhD, Naohiko Aihara, MD, Shiro Kamakura, MD, PhD, and Wataru Shimizu, MD, PhD*

To investigate changes of electrocardiographic parameters with aging and their relation to the presence of SCN5A mutation in probands with Brugada syndrome (BS), we measured several electrocardiographic parameters prospectively during long-term follow-up (10 ؎ 5 ؎ years) in 8 BS probands with SCN5A mutation (SCN5A-positive group, all men; age 46 10 years) and 36 BS probands without SCN5A mutation (SCN5A-negative group, all men; age 46 ؎ 13 years). Throughout the follow-up period, depolarization parameters, such as P-wave (lead II), QRS (leads II, V2,V5), S-wave durations (leads II, V5), and PQ interval (leads II) were all significantly longer and S-wave amplitude (II, V5) was significantly deeper in the SCN5A-positive group than in the SCN5A-negative group. The SCN5A- positive group showed a significantly longer corrected QT interval (lead V2) and higher ST amplitude (lead V2) than those in the SCN5A-negative group. The depolarization parameters increased with aging during the follow-up period in both groups; however, the PQ interval (lead II) and QRS duration (lead V2) were prolonged more prominently and the QRS axis deviated more to the left with aging in the SCN5A-positive group than in the SCN5A-negative group. In conclusion, conduction slowing was more marked and more progressively accentuated in Brugada probands with SCN5A mutation than in those without SCN5A mutation. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007; 100:649–655)

Brugada syndrome (BS) is characterized by a ST-segment related BS.13 However, progressive changes of the depolar- elevation in the right precordial leads V1 to V3 and is ization and repolarization parameters on the electro- associated with sudden cardiac death (SCD) secondary to a cardiogram (ECG) with aging during long-term follow-up rapid polymorphic ventricular tachycardia (VT) or ventric- in relation to the SCN5A mutation have not been fully ular ﬁbrillation (VF).1–9 It has been suggested that a tran- evaluated. In the present study, we prospectively measured sient outward current-mediated action potential notch and a several electrocardiographic parameters during long-term loss of action potential dome in the epicardium of the right follow-up periods and compared them between patients ventricular outﬂow tract (RVOT) give rise to a transmural with BS with and without SCN5A mutation. voltage gradient, resulting in ST-segment elevation in the right precordial lead in BS.8 Conversely, the SCN5A gene encoding the cardiac sodium channel has been reported to Methods 10 be linked to BS, and mild conduction abnormalities and The study population consisted of 44 probands with BS 5,11 12 QRS prolongation have been described. Smits et al admitted to the National Cardiovascular Center in Suita, have compared these electrocardiographic parameters be- Japan, due to history of aborted SCD, syncope, or evalua- tween SCN5A mutation carriers and those who do not carry tion of electrocardiographic abnormality, who could be pro- the mutation. Probst et al13 meticulously studied aging- spectively followed up for Ͼ5 years (average 10 Ϯ 5 years) associated electrocardiographic parameters in SCN5A- at regular outpatient clinics in our hospital. All probands were men, and their age on admission (i.e., at early period) Division of Cardiology, Department of Internal Medicine, National ranged from 20 to 72 years (mean 46 Ϯ 12 years). BS was Cardiovascular Center, Suita, Osaka, Japan. Manuscript received February diagnosed when a type 1 coved-type ST-segment elevation 6, 2007; revised manuscript received and accepted March 15, 2007. (Ն0.2 mV at J point) was observed in Ͼ1 of the right Dr. Shimizu was supported by the Uehara Memorial Foundation, To- precordial leads (V1 to V3) in the presence or absence of a kyo; the Hoansha Research Foundation, Osaka; Japan Research Foundation sodium channel blocker in conjunction with 1 of the fol- for Clinical Pharmacology, Tokyo; Ministry of Education, Culture, Sports, lowing: (1) documented VF or polymorphic VT, (2) a fam- Science and Technology Leading Project for Biosimulation, Tokyo; and Ͻ health sciences research grants (H18-Research on Human Genome-002) ily history of SCD at 45 years of age, type 1 ECG in from the Ministry of Health, Labor and Welfare, Tokyo, Japan. family members, (3) inducibility of VF or polymorphic VT *Corresponding author: Tel: 81-6-6833-5012; fax: 81-6-6872-7486. with programmed electrical stimulation, and (4) history of E-mail address: [email protected] (W. Shimizu). aborted cardiac arrest with or without documentation of VF,

Table 1 SCN5A mutations, common variants and promotor haplotype Coding* No. of Patients Type Coding No. of Patients Type

SCN5A Positive Group SCN5A Negative Group (n ϭ 8) (n ϭ 36) Mutation A735V 1 Missense P1719fsX1786 1 Frameshift L276Q 1 Missense V1764fsX1786 1 Frameshift L136P 1 Missense R367H 2 Missense T1709M 1 Missense Common variant H558R 1 Missense H558R 4 Missense Promotor haplotype AA 5 AA 12 AB 2 AB 4 BB 0 BB 1

* The numbers and letters refer to the amino acid coding of the mutant channel protein. AA ϭ haplotype A (common alleles) homozygotes; AB ϭ haplotype A/haplotype B (minor alleles) heterozygotes; BB ϭ haplotype B homozygotes. See detail in Bezzina et al.14 syncopal episodes of unknown origin, or nocturnal agonal 2-way repeated-measures analysis of variance (ANOVA) respiration.4 followed by the Scheffe multiple-comparison test. Compar- We divided the 44 Brugada probands into 2 groups isons of changes in each parameter between the SCN5A- according to the presence or absence of an SCN5A coding positive group and the SCN5A-negative group were made region mutation: SCN5A-positive group (n ϭ 8) and using 1-way ANOVA followed by Scheffe test. Compari- SCN5A-negative group (n ϭ 36). sons of the clinical, electrophysiologic, and follow-up data The standard 12-lead ECGs were recorded at least every between the SCN5A-positive group and the SCN5A-nega- 6 months prospectively at regular outpatient clinics with a tive group were made using chi-square test or 1-way paper speed of 25 mm/s and an amplitude of 10 mm/mV. ANOVA followed by Scheffe test. A p value Ͻ0.05 was The ECGs were magnified to 150%, and several electrocar- considered significant. diographic parameters were measured manually by an investigator (MY) blinded to clinical and genetic information. As depolarization parameters, P-wave duration (lead II), PQ Results interval (lead II), QRS duration (leads II, V2, and V5), The SCN5A mutations, which were identified at a coding S-wave duration and amplitude (leads II, V5), and QRS axis region in the SCN5A-positive group, are shown in Table 1. were measured. Conversely, corrected QT interval (QTc, Five missense mutations and 2 frameshift mutations were leads II, V , and V ), corrected JT interval (JTc, leads II, V , 2 5 2 identified. A missense mutation, R367H, was identified in 2 and V ), and ST amplitude at the J point and 40 ms after 5 unrelated Brugada probands. The common variant and theJ point (STJ and STJ40, lead V ) were measured as 2 SCN5A promoter haplotype14 in both groups are also shown repolarization parameters. The absolute values of these parameters and the change of each parameter between early in Table 1. There were no significant differences in the and late periods were compared between the 8 probands in frequency of the common variant and the promoter haplo- the SCN5A-positive group and the 36 in the SCN5A-neg- type between the 2 groups. ative group. The comparison of the clinical and electrophysiologic In all patients, we screened SCN5A mutation in all 28 characteristics between the 8 SCN5A-positive probands and exons of SCN5A gene by a direct sequencing method using the 36 SCN5A-negative probands are shown in Table 2. an ABI 3700 system (Applied Biosystems, Foster City, There were no significant differences in the age on admis- California). An SCN5A mutation was defined when the sion, when the clinical diagnosis of BS was made, between mutation was not identified in any of the 100 control sub- the 2 groups. No significant differences were observed in jects. We also screened the SCN5A promoter haplotype, the incidence of spontaneous type 1 ECG, documented VF which we have recently identified in an Asian population,14 until the early period, family history of SCD, implantation in 7 recent SCN5A-positive probands and 17 SCN5A-neg- of implantable cardioverter defibrillator, complete right ative probands. bundle branch block (RBBB) at the early period and the Numeric values were expressed as means Ϯ SD. Com- latest follow-up period (i.e., late period), and late potentials. parisons of each electrocardiographic parameter between The HV interval during the electrophysiologic study was the SCN5A-positive group and the SCN5A-negative group significantly longer in the SCN5A-positive group than in the and between the early and the late periods were made using SCN5A-negative group. There were no significant differ- Arrhythmias and Conduction Disturbances/Electrocardiographic Features in Brugada Syndrome 651

Table 2 Clinical and electrophysiologic characteristics and follow-up Characteristic SCN5A-Positive Group SCN5A-Negative Group p Value (n ϭ 8) (n ϭ 36) Clinical characteristics Age on admission (yrs) 46 Ϯ 10 46 Ϯ 13 0.938 Spontaneous type 1 ECG 6 (75%) 25 (69%) 0.755 Documented VF until early period 2 (25%) 17 (47%) 0.251 Family history of SCD 3 (38%) 4 (11%) 0.065 ICD implantation 8 (100%) 26 (72%) 0.090 Complete RBBB at early period 1 (13%) 2 (5%) 0.481 Complete RBBB at late period 1 (13%) 6 (17%) 0.771 Late potentials 7/7 (100%) 24/33 (73%) 0.117 Electrophysiologic characteristics Induction of VF 5/8 (63%) 25/33 (76%) 0.658 Mode (triple/double/single) 1/3/1 12/11/2 – HV interval (ms) 65Ϯ5(nϭ7) 41Ϯ8(nϭ27) Ͻ0.001 Follow-up Follow-up period (yrs) 10 Ϯ 510Ϯ 4 0.993 Arrhythmic events during follow-up periods 4/8 (50%) 12/36 (33%) 0.375 Previous VF 2/2 (100%) 8/17 (47%) 0.156 No previous VF 2/6 (33%) 4/19 (21%) 0.539

EPS ϭ electrophysiological study; HV ϭ His-ventricular interval; ICD ϭ implantable cardioverter-deﬁbrillator.

ences in the frequency and mode of VF induction between amplitude (lead V2) and STJ40 amplitude (lead V2) did not the 2 groups. change throughout the follow-up period in both groups, but Figure 1 illustrates the standard 12-lead ECGs at early were significantly greater in the SCN5A-positive group than and late periods during the follow-up period in representa- in the SCN5A-negative group at the early and late periods. tive patients with BS in the SCN5A-positive group (Figure Even if we eliminated probands with BS with complete 1) and the SCN5A-negative group. Table 3 shows compos- RBBB (1 SCN5A-positive proband and 2 SCN5A-negative ite data of the electrocardiographic parameters at the early probands at the early period, 1 SCN5A-positive proband and late periods in the 8 SCN5A-positive probands and 36 and 6 SCN5A-negative probands at the late period), the SCN5A-negative probands during the follow-up period. main results and statistical differences were not significant. As depolarization parameters, the P-wave duration (lead Table 4 depicts comparison of the change of the electro- II), PQ interval (lead II), and QRS duration (lead II) signif- cardiographic parameters from early to late periods between icantly increased with aging from early to late periods in the SCN5A-positive group and the SCN5A-negative group. both groups and were all significantly longer in the SCN5A- The changes in PQ interval (lead II) and QRS duration positive group than in the SCN5A-negative group at both (lead V2) were significantly longer in the SCN5A-positive early and late periods. The QRS duration (lead V2)inthe group than in the SCN5A-negative group. The change in SCN5A-positive group and the S-wave duration (leads II QRS axis was greater (i.e., deviated more to the left) in the and V5) in the SCN5A-negative group significantly in- SCN5A-positive group than in the SCN5A-negative group. creased with aging. The QRS duration (leads V2 and V5) There were no significant differences in the duration of and the S-wave duration (leads II and V5) were significantly follow-up period and the incidence of arrhythmic events longer, and the S-wave amplitude (leads II and V5) was during the follow-up period between the 2 groups (Table 2). significantly deeper in the SCN5A-positive group at early Because a history of documented VF (until the early period) and late periods. The QRS axis was not different between was proven to be the strongest predictor for subsequent the 2 groups at the early period; however, it was signifi- arrhythmic events, arrhythmic events were compared be- cantly smaller (i.e., deviated to the left) at the late period in tween the 2 groups separately in probands with previous VF the SCN5A-positive group. and those without previous VF, but no significant differ- As a repolarization parameter, the corrected QT interval ences were observed (Table 2). (lead V2) was significantly prolonged from the early period to the late period in the SCN5A-positive group, and was Discussion significantly longer in the SCN5A-positive group than in the SCN5A-negative group at the early and late periods. How- The present study includes what is, to our knowledge, the ever, the QTc intervals (leads II and V5) did not change longest follow-up of changes of electrocardiographic pa- from the early period to the late period in both groups and rameters in SCN5A-positive probands and SCN5A-negative were not different between groups at the early and late probands with BS. periods. Conversely, no JTc intervals (leads II, V2, and V5) Mild conduction abnormalities, such as widening of changed from the early period to the late period in both the P wave, prolongation of QRS duration and PQ and groups, and the JTc interval (lead V2) at the late period was HV intervals, and higher incidence of RBBB, have been significantly longer in the SCN5A-positive group. The STJ described in patients with BS, especially those with 652 The American Journal of Cardiology (www.AJConline.org)

Figure 1. Standard 12-lead ECG at early and late periods during follow-up in representative cases of BS. A,inanSCN5A-positive proband (follow-up period,

7 years), the P-wave (lead II), QRS (lead V2), and S-wave (lead V5) durations and PQ interval (lead II) were prolonged even at the early period (47 years of age, a). The S-wave amplitude (lead V5) was also deep, and the QRS axis deviated to the left. The QTc interval (lead V2) was borderline prolonged. At the late period (b), all these parameters further increased. B, in an SCN5A-negative proband (follow-up period, 9 years), the P-wave (lead II), QRS (lead V2), and S-wave (lead V5) durations, PQ interval (lead II), and QTc interval (lead V2) were less prolonged compared with those in an SCN5A-positive proband ϭ at the early period (51 years of age, a). At the late period (b), these parameters did not change signiﬁcantly. V5-dS S-wave duration in lead V5. Arrhythmias and Conduction Disturbances/Electrocardiographic Features in Brugada Syndrome 653

Table 3 Electrocardiographic parameters during follow-up period ECG Parameter (leads) Early Period Late Period SCN5A- SCN5A- p Value SCN5A- SCN5A- p Value Positive Group Negative Group Positive Group Negative Group (n ϭ 8) (n ϭ 36) (n ϭ 8) (n ϭ 36) Heart rate (beats/min) 66 Ϯ 11 64 Ϯ 10 0.924 60 Ϯ 667Ϯ 12 0.194 P-wave duration (II) (ms) 137 Ϯ 21 110 Ϯ 12 Ͻ0.001 155 Ϯ 19† 119 Ϯ 16† Ͻ0.001 PQ interval (II) (ms) 227 Ϯ 31 179 Ϯ 18 Ͻ0.001 257 Ϯ 22* 190 Ϯ 22† Ͻ0.001 QRS duration (II) (ms) 125 Ϯ 22 102 Ϯ 18 Ͻ0.001 142 Ϯ 41‡ 111 Ϯ 19‡ Ͻ0.001 Ϯ Ϯ Ͻ Ϯ Ϯ Ͻ QRS duration (V2) (ms) 135 15 110 13 0.001 157 28* 115 16 0.001 Ϯ Ϯ Ͻ Ϯ Ϯ Ͻ QRS duration (V5) (ms) 130 28 101 15 0.001 147 42 108 17 0.001 S-wave duration (II) (ms) 65 Ϯ 38 35 Ϯ 24 Ͻ0.001 77 Ϯ 54 43 Ϯ 26‡ Ͻ0.001 Ϯ Ϯ Ͻ Ϯ Ϯ Ͻ S-wave duration (V5) (ms) 69 40 37 19 0.001 78 50 49 17* 0.001 S-wave amplitude (II) (mV) 0.37 Ϯ 0.23 0.23 Ϯ 0.24 0.005 0.43 Ϯ 0.24 0.21 Ϯ 0.17 Ͻ0.001 Ϯ Ϯ Ͻ Ϯ Ϯ † Ͻ S-wave amplitude (V5) (mV) 0.83 0.47 0.34 0.25 0.001 0.88 0.48 0.47 0.27 0.001 QRS axis (°) 44 Ϯ 81 49 Ϯ 43 0.954 10 Ϯ 76‡ 43 Ϯ 41 0.001 QTc interval (II) (ms) 409 Ϯ 37 396 Ϯ 28 0.535 432 Ϯ 40 410 Ϯ 34 0.164 Ϯ Ϯ Ϯ ‡ Ϯ Ͻ QTc interval (V2) (ms) 427 51 392 37 0.038 471 38 405 38 0.001 Ϯ Ϯ Ϯ Ϯ QTc interval (V5) (ms) 401 43 389 29 0.593 408 39 398 36 0.746 JTc interval (II) (ms) 279 Ϯ 32 290 Ϯ 30 0.554 292 Ϯ 44 293 Ϯ 34 0.100 Ϯ Ϯ Ϯ Ϯ JTc interval (V2) (ms) 285 39 279 35 0.960 316 42 283 38 0.044 Ϯ Ϯ Ϯ Ϯ JTc interval (V5) (ms) 265 26 286 30 0.108 262 42 283 32 0.105 Ϯ Ϯ Ϯ Ϯ STJ amplitude (V2) (mV) 0.42 0.19 0.29 0.13 0.014 0.37 0.23 0.24 0.17 0.011 Ϯ Ϯ Ͻ Ϯ Ϯ STJ40 amplitude (V2) (mV) 0.38 0.14 0.23 0.12 0.001 0.34 0.17 0.21 0.15 0.006 Data are presented as means Ϯ SD. *pϽ0.001 versus early period. † p Ͻ0.01 versus early period. ‡ p Ͻ0.05 versus early period. ECG ϭ electrocardiographic; JTc ϭ corrected JT; QTc ϭ corrected QT; STJ amplitude ϭ ST amplitude at J point; STJ 40 amplitude ϭ ST amplitude 40 ms after J point.

Table 4 Comparison of the change of electrocardiographic parameters during follow-up Change in ECG Parameter SCN5A-Positive Group SCN5A-Negative Group p Value (leads) (n ϭ 8) (n ϭ 36) Heart rate (beats/min) Ϫ7 Ϯ 10 3 Ϯ 13 0.046 P-wave duration (II) (ms) 19 Ϯ 12 9 Ϯ 13 0.077 PQ interval (II) (ms) 30 Ϯ 22 11 Ϯ 14 0.004 QRS duration (II) (ms) 17 Ϯ 22 8 Ϯ 15 0.163 Ϯ Ϯ QRS duration (V2) (ms) 22 20 6 11 0.003 Ϯ Ϯ QRS duration (V5) (ms) 17 29 8 14 0.161 S-wave duration (II) (ms) 12 Ϯ 17 8 Ϯ 13 0.423 Ϯ Ϯ S-wave duration (V5) (ms) 9 15 12 14 0.604 S-wave amplitude (II) (mV) 0.06 Ϯ 0.10 Ϫ0.02 Ϯ 0.14 0.152 Ϯ Ϯ S-wave amplitude (V5) (mV) 0.05 0.27 0.13 0.18 0.331 QRS axis (°) Ϫ34 Ϯ 55 Ϫ6 Ϯ 16 0.010 QTc interval (II) (ms) 22 Ϯ 32 15 Ϯ 34 0.562 Ϯ Ϯ QTc interval (V2) (ms) 44 49 13 40 0.064 Ϯ Ϯ QTc interval (V5) (ms) 6 37 9 30 0.845 JTc interval (II) (ms) 13 Ϯ 27 3 Ϯ 28 0.339 Ϯ Ϯ JTc interval (V2) (ms) 31 48 5 38 0.094 Ϫ Ϯ Ϫ Ϯ JTc interval (V5) (ms) 3 29 3 29 0.990 Ϫ Ϯ Ϫ Ϯ STJ amplitude (V2) (mV) 0.05 0.18 0.05 0.12 0.949 Ϫ Ϯ Ϫ Ϯ STJ40 amplitude (V2) (mV) 0.04 0.16 0.02 0.11 0.642 Abbreviations as in Table 3.

SCN5A mutation.5,11 Smits et al12 observed significantly tions. Age-dependent variability in the conduction pa- longer PQ and HV intervals at baseline and a larger rameters was evidenced in SCN5A-positive patients with increase in PQ and QRS intervals after administration of BS.13,15 Moreover, this concept has been mechanistically sodium channel blockers in patients with BS with investigated in vivo in heterozygous SCN5A mice, which SCN5A mutations than in those without SCN5A muta- showed progressive impairment with aging of atrial and 654 The American Journal of Cardiology (www.AJConline.org) ventricular conduction associated with myocardial rear- events. We recently used 87-lead body surface ECGs and rangements and fibrosis.16 Meregalli et al17 showed pro- reported that a corrected recovery time, another repolariza- longation of S-wave duration in leads II and III after tion parameter, was significantly longer in the right precor- administration of sodium channel blockers. Their group dial body surface ECGs, reflecting the potentials of the suggested that these electrocardiographic signs included RVOT, than in other body surface ECGs.26 Similarly, in the reciprocal changes in the inferior leads, mirroring the present study, the longest QTc interval was observed in lead 17,18 conduction slowing in the RVOT, which may V2 in most patients with BS with SCN5A mutation, who progress with aging and relate to the pathogenesis of BS. usually also had a coved-type ST-segment elevation and a In the present study, the P-wave, QRS, S-wave durations, terminal negative T wave. The fact that the QTc interval in and PQ intervals were all significantly longer, and the lead V2 was significantly longer in the SCN5A-positive S-wave amplitude was significantly deeper in the patients than in the SCN5A-negative patients at the early SCN5A-positive group than in the SCN5A-negative and late periods can be explained by more frequent and group. In addition, the PQ interval and QRS duration in higher coved-type ST-segment elevation with a terminal lead V2 were more markedly prolonged, and the QRS negative T wave in the SCN5A-positive patients. The QTc axis deviated more to the left with aging in the SCN5A- interval in lead V2 was significantly prolonged from the positive group than in the SCN5A-negative group during early period to the late period in the SCN5A-positive pa- the follow-up period. The results of previous clinical tients; however, the JTc interval in lead V2 did not change studies and the present study suggest that progressive from the early period to the late period, suggesting that the depolarization abnormalities (i.e., conduction slowing) significant QTc prolongation in lead V2 with aging occurred with aging may play a key role in the pathogenesis of BS. mainly as a result of a significant prolongation of the QRS It has been argued recently that arrhythmic events may duration in lead V . occur when a sufficient degree of cell damage has been 2 There are several limitations to the present study. First, reached as a result of the severity of ion channel protein because a small number of patients with BS with SCN5A mutation. Frustaci et al19 showed that myocyte apoptosis at mutation could be included in a single-center study, a larger the right and left ventricular myocardium was significantly number of patients with SCN5A mutation will be required higher in patients with BS with SCN5A mutations than in control subjects on histologic study. They suggested that to make a definitive conclusion. Second, the study population included 44 Brugada probands who could be prospec- abnormalities in the function of sodium channels may lead Ϯ to cellular damage because intracellular sodium homeosta- tively followed up for average of 10 5 years in our sis has a relevant role in myocellular function.19 Experimen- hospital. Therefore, the probands represent a severely af- tally, Aiba et al20 used a high-resolution optical mapping fected population, but not a consecutively referred popula- 27 system in a pharmacologic BS model and demonstrated that tion. Third, Veltmann et al recently reported the preva- depolarization abnormalities (i.e., conduction slowing) is lence of fluctuations between diagnostic and nondiagnostic required for the maintenance of VF in BS, although the ECGs in patients with BS, which may influence the mea- initiating premature beats were a result of a phase 2 reentry surement of some electrocardiographic parameters, espe- mechanism. These histologic and experimental studies also cially QT, JT interval, and ST amplitude, and should be support that progressive conduction abnormalities with ag- taken into account. However, the influence of the fluctua- ing may explain why an initial VF episode appears at tions on depolarization parameters such as QRS duration is middle to older ages, usually 40 to 50 years, in BS. It is expected to be less pronounced. generally accepted that SCN5A mutation is not associated with a higher risk of cardiac events, suggesting that genetic 1. Brugada P, Brugada J. Right bundle branch block, persistent ST analysis is a useful diagnostic parameter but is not helpful segment elevation and sudden cardiac death: a distinct clinical and 7 electrocardiographic syndrome: a multicenter report. J Am Coll Car- for risk stratification. Similarly, in the present study, the diol 1992;20:1391–1396. presence of SCN5A mutation did not predict subsequent 2. Brugada J, Brugada P. Further characterization of the syndrome of arrhythmic events (Table 2). Most clinical studies have right bundle branch block, ST segment elevation, and sudden cardiac reported that induction of VF by programmed electrical death. J Cardiovasc Electrophysiol 1997;8:325–331. stimulation did not predict the clinical outcome or clinical 3. Brugada J, Brugada R, Brugada P. Right bundle-branch block and 6,21,22 ST-segment elevation in V1 through V3. A marker for sudden death in severity in patients with BS. If the progressive con- patients without demonstrable structural heart disease. Circulation duction slowing with aging often observed in patients with 1998;97:457–460. BS, especially SCN5A-positve patients, are really linked to 4. Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, VF appearance, conduction parameters, such as QRS wid- Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, ening, late potentials, or inducibility of VF, may still have a Towbin JA. Study Group on the Molecular Basis of Arrhythmias of the potential to predict new or subsequent cardiac events.23 A European Society of Cardiology. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation 2002;106:2514– much larger patient population is required to make a defin- 2519. itive conclusion regarding the predictive value of SCN5A 5. Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, mutation and the conduction parameters for cardiac events. Corrado D, Gussak I, Lemarec H, Nademanee K, Perez Riera AR, et Several clinical studies have suggested a localized QT al. Brugada syndrome: report of the second consensus conference: prolongation, a repolarization parameter, in the right pre- endorsed by the Heart Rhythm Society and the European Heart 24,25 Rhythm Association. Circulation 2005;111:659–670. cordial leads (mainly lead V2) in patients with BS. 6. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Castro Hevia et al25 have suggested that a QTc Ͼ460 ms in Giordano U, Bloise R, Giustetto C, De Nardis R, Grillo M, Ronchetti lead V2 was a significant risk factor for subsequent cardiac E, Faggiano G, Nastoli J. Natural history of Brugada syndrome: Arrhythmias and Conduction Disturbances/Electrocardiographic Features in Brugada Syndrome 655

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Incidence of Brugada Electrocardiographic Pattern and Outcomes of These Patients After Intentional Tricyclic Antidepressant Ingestion

Vikhyat S. Bebarta, MDa,*, Scott Phillips, MDb, Aaron Eberhardt, MDc, K.J. Calihand, Javier C. Waksman, MD, DABTb, and Kennon Heard, MDb

Brugada syndrome is a genetic dysfunction of the myocardial sodium channel that leads to ventricular dysrhythmias. The electrocardiographic (ECG) pattern of Brugada syndrome is occasionally seen after tricyclic antidepressant (TCA) ingestion; however, the outcome and complication risk for these patients is not clear. The objective of our study was to describe the incidence of Brugada ECG pattern (BEP) and serious complications of these patients in a large case series of intentional TCA ingestions. We also compared the proportion of complications of patients with BEP versus those without BEP. We evaluated 402 TCA ingestions, of which 9 (2.3%) were associated with the development of BEP. We compared the adverse outcomes of all TCA ingestions versus TCA ingestions with BEP. A increase in the adverse outcomes in the BEP group was found: seizures (relative risk [RR] 4; 95% conﬁdence interval [CI] 1.5 to 10.8), widened QRS (RR 4.8; 95% CI 1.8 to 12.9), and hypotension (RR 3.9; 95% CI 2.1 to 7.4). To reduce confounding ingestants, we also compared all patients with an isolated TCA ingestion versus those with BEP. A signiﬁcant increase in adverse outcomes was again found with the BEP group: seizures (RR 3; 95% CI 1.1 to 8.6), widened QRS (RR 4.8; 95% CI 1.5 to 15.1), and hypotension (RR 3.4; 95% CI 1.9 to 22.3). No deaths or dysrhythmias were found in the BEP group. In conclusion, BEP after TCA ingestion is rare, and death or dysrhythmias did not occur. However, patients with BEP are likely at increased risk for TCA-induced complications. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:656–660)

Brugada syndrome is associated with sudden death and is ingestions. In addition, we aimed to compare the incidence believed to be mediated by a genetic myocardial sodium of adverse outcomes in the patients with BEP versus TCA channel dysfunction that leads to slow inward current.1,2 ingestions without BEP. Patients with Brugada syndrome have a characteristic electrocardiogram (ECG). Type 1 Brugada electrocardiographic Methods pattern (BEP) is similar to a right bundle branch block with downsloping ST-segment elevation in leads V1 to V3 (Fig- This was a retrospective cohort study in which we reviewed ure 1). Type IA antidysrhythmics can unmask BEP in some previously collected medical records of patients with inten- patients. Interestingly, overdose of medications with type tional TCA ingestions.9,10 Patients were collected through a IA antidysrhythmic effects, such as tricyclic antidepressants previous multicenter study of 9 participating medical cen- (TCAs), cocaine, and antipsychotic agents, has been asso- ters.9 ciated with BEP.3–8 However, the clinical significance of Patients were included in the study if they presented with the BEP after ingestion of these medications has not been a history of intentional antidepressant ingestion and had a clearly defined. Goldgran-Toledano et al3 suggested that the measurable serum or urine TCA level. Patients were ex- BEP may be a marker for death or poor outcome in a small cluded if neither a measurable TCA level nor interpretable series of patients with TCA and thioridazine overdose, al- ECG was available for review. The patient records were though no difference in mortality was found between collected from November 1990 to March 1993. The original groups. The objective of our study was to describe the study was approved by the institutional review board at prevalence of BEP in a large case series of intentional TCA participating hospitals and present study was approved at the coordinating center. Trained reviewers used a standardized data collection aDivision of Medical Toxicology, Department of Emergency Medicine, form (DCF) to extract the data from the medical chart. Each b Wilford Hall Medical Center, San Antonio, Texas; University of Colorado reviewer used the DCF to collect the following information Health Sciences Center, Rocky Mountain Poison and Drug Center, Denver, on each subject: age, gender, ethnicity, antidepressant(s) Colorado; cDepartment of Emergency Medicine, Denver Health Medical Center, Denver, Colorado; and dAurora Women’s Care Clinic, Aurora, involved in the ingestion, and coingestants. The form spe- Colorado. Manuscript received December 14, 2006; revised manuscript cifically recorded the co-ingestion of the following drugs received and accepted March 13, 2007. known to adversely affect myocardial sodium channels: *Corresponding author: Tel: 210-481-0040; fax: 702-442-7921. quinine, propafenone, flecainide, chloroquine, procain- E-mail address: [email protected] (V.S. Bebarta). amide, mexiletine, disopyramide, diphenhydramine, co-

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.077 Arrhythmias and Conduction Disturbances/Brugada ECG Pattern and Antidepressants 657

Figure 1. Example of BEP. caine, amantadine, propoxyphene, propranolol, mesorid- azine, carbamazepine, and phenytoin. Laboratory confirmation of TCA ingestion and detection of other ingestants was performed by serum or urine testing (or both) at a central laboratory (Analyitox, Englewood, Colorado) using Ն1 confirmatory method (thin-layer chromatography, gas chromatography, or high-performance liquid chromatography). The results were recorded on the DCF. Determi- nation of coingestants was based on a combination of laboratory testing and history extracted from the medical record. If eitherdocumented a coingestant, the ingestant was recorded on the DCF. All ECGs were reviewed by 1 abstractor and classified as BEP or non-BEP. BEP was defined as RSR= (i.e., incomplete right bundle branch block pattern) in leads V1 to V3 with downsloping ST elevation and T-wave inversion. This pattern is referred to as type 1 and is the most common BEP.2 A picture of the BEP was on the DCF. Patients were Figure 2. Flow diagram of patients involved in the study. classified as having the BEP if any ECG in the record showed a BEP pattern. The primary author (V.S.B.), who they were entered into a spreadsheet for analysis. The re- was blinded to the clinical outcomes, reevaluated ECGs viewers were blinded to the study objective. classified as BEP by the reviewers to ensure accuracy. The The following outcomes were recorded for each subject: primary author and abstractors agreed on all BEP ECGs. mortality, dysrhythmia (i.e., wide-complex tachycardia, The reviewers were trained in data extraction on an ventricular tachycardia, ventricular fibrillation, Torsade de initial sample of charts and were provided feedback. The Pointes, atrial fibrillation, atrial flutter, or second- or third- reviewers reviewed ECGs with and without BEP before the degree block), widened QRS (Ͼ120 ms), hypotension (i.e., initiation of the study to improve their diagnostic ability in systolic blood pressure Ͻ90 mm Hg), seizure, endotracheal identifying BEP. We also had ongoing meetings to answer intubation, and intensive care unit admission. We also re- questions and had continuous monitoring of the collected corded the following TCA-induced clinical effects: tachy- data. All definitions for study variables and clinical out- cardia, central nervous system depression, and presence of a comes were predefined. After the DCFs were completed, R wave Ͼ3 mm in lead aVR. 658 The American Journal of Cardiology (www.AJConline.org)

Table 1 Baseline characteristics between patients with a TCA ingestion, isolated TCA ingestion, and patients with a BEP Characteristics All TCA Ingestions All TCA Ingestions All Ingestions All Isolated TCA Without BEP With BEP Ingestions Median age (yrs) 33 33 31 28 TCA level (ng/ml) 355 352 792 485 Male gender 180/402 (45%) 176/402 (44%) 4/9 (45%) 47/118 (39%)

Table 2 Table 3 TCA ingested for patients with and without BEP Measured outcomes of two patient groups, all TCA ingestions compared with those with BEP TCA Ingested BEP Non-BEP (n ϭ 9) (n ϭ 393) Outcome BEP Proportion Non-BEP Proportion Relative Risk (n ϭ 9) (n ϭ 393) (95% CI) Amitriptyline 0 177 Doxepin 1 60 Seizures 0.33 0.08 4.0 (1.5–10.8) Nortriptyline 4 52 Wide QRS 0.33 0.07 4.8 (1.8–12.9) Imipramine 3 49 Hypotension 0.56 0.14 3.9 (2.1–7.4) Desipramine 0 29 ICU admission 0.89 0.81 1.1 (0.9–1.4) Clomipramine 0 12 Intubation 0.67 0.52 1.3 (0.8–2.1) Trimipramine 0 5 Dysrhythmia 0 0.025 – Amoxapine 0 5 Death 0 0.015 – Maprotiline 0 2 ϭ Unidentiﬁed 1 2 ICU intensive care unit.

creased risk of seizures, widened QRS, and hypotension Proportions of patients with each outcome were calcu- (Table 3). The proportions of patients with dysrhythmias lated for patients with and without BEP. We used the exact requiring intubation and ICU admission were similar be- approximation to determine the 95% confidence interval tween the 2 groups. To remove the confounding effect of (CI) for these proportions. We compared the incidence of coingestants, non-BEP isolated TCA ingestions were com- the following outcomes between patients with and without pared with those in patients with BEP. A similar finding of BEP: mortality, dysrhythmia, seizures, widened QRS, hy- increased risk of seizures (relative risk [RR] 3.0; 95% CI 1.1 potension, endotracheal intubation, and intensive care unit to 8.6), widened QRS (RR 4.8; 95% CI 1.5 to 5.1), and admission. The proportions of outcomes were compared hypotension (RR 3.4; 95% CI 1.9 to 22.3) was found in the using Fisher’s exact test. BEP group. To attempt to determine if co-ingestion confounded our No patients who developed BEP ingested a type 1A or results, we performed an additional analysis comparing the 1C antidysrhythmic agent. One patient with BEP co-in- outcomes for all patients with BEP (n ϭ 9) versus those gested thioridazine and another ingested perphenazine. The without BEP with isolated TCA ingestion (n ϭ 115). There other co-ingestions for patients with BEP were propranolol, were insufficient patients with BEP with isolated TCA in- chloral hydrate, clonazepam, lorazepam, alprazolam, salicy- gestion (n ϭ 3) to compare them with patients with isolated lates, butalbital, caffeine, ethanol, ethanol alone (n ϭ 3), TCA ingestion without BEP. and nothing (n ϭ 3).

Results Discussion Six hundred eighteen cases of antidepressant ingestions BEP after TCA ingestion in our study was unusual; Ͻ3% of were reviewed. Four hundred two patients had a measurable patients developed a BEP. In addition, no patients devel- TCA level and an interpretable ECG. All patients with BEP oped dysrhythmias or died. We found that the patients with had a detectable TCA level (Figure 2). The groups of all BEP after TCA ingestion were more likely to have hypo- TCA ingestions, isolated TCA ingestions, BEP, and all tension and a widened QRS and may be more likely to have non-BEP TCA ingestions had similar baseline characteris- seizures than those without BEP. The increased risk of the tics (Table 1). The median TCA level was higher in the BEP widened QRS in the patients with BEP was not merely a group. The frequency of TCA-induced clinical effects in the result of the characteristic pattern of the BEP, as only 3 of isolated TCA group were tachycardia (52%; n ϭ 60), cen- 9 patients with BEP had a wide QRS. No patients with BEP tral nervous system depression (79%; n ϭ 92), and right- died or developed dysrhythmias, but the small sample size axis deviation of the terminal 40 ms of the QRS complex limits our ability to detect these outcomes. identified by a Ն3-mm R wave in lead aVR (61%; n ϭ 72). In this report, most mixed and isolated TCA ingestions Table 2 lists the specific TCA ingested in the BEP and involved amitriptyline. However, we found no cases of BEP non-BEP groups. after amitriptyline overdose. Interestingly, nortriptyline was Overall, 2.3% of TCA ingestions (9 of 402) were asso- found in 44% of BEP cases, but only 13% of all ingestions. ciated with the development of a BEP. Compared with the Imipramine was also represented more in the BEP group patients without BEP, the patients with BEP had an in- (33% vs 12%). These findings suggest that there may be Arrhythmias and Conduction Disturbances/Brugada ECG Pattern and Antidepressants 659 inherent differences in the propensity of each TCA to cause graphic pattern similar to that observed in Brugada syn- BEP. drome, but without the risk of dysrhythmias.18 This would The BEP pattern observed in our patients is unlikely to explain why developing a BEP after TCA ingestion does not have occurred as a result of coingestants. Only two patients portend a high risk of sudden death or ventricular dysrhyth- had coingestants that have been reported to alter intracar- mia as seen with Brugada syndrome. diac conduction, and the support for perphenazine-induced There are several limitations to the internal and external wide-complex tachycardia is limited to 1 case report.6 We validity of this study. The lack of mortality in the BEP cannot exclude thioridazine as a cause of BEP in the second group may be a result of the small sample size. Another patient. Many toxicologists consider the cardiac effects of limitation is that our BEP diagnosis is based on a single thioridazine similar to those of the TCAs.11,12 ECG. The findings of BEP may be transient, and our pa- We found a modest association between BEP and sei- tients did not have ongoing electrocardiographic monitor- zures, hypotension, and prolonged QRS duration. It is pos- ing. This may result in misclassification bias. In addition, sible that this association could be a result of confounding although some ECGs were collected before sodium bicar- by coingestants. As noted earlier, thioridazine produces bonate administration, and a few may have received it cardiac effects similar to TCAs and has been associated before electrocardiography was performed. However, so- with dysrhythmias and hypotension in overdose. One of the dium bicarbonate administration may not mitigate TCA- patients ingested propranolol, which could account for hy- induced BEP.19 potension and QRS widening, and several patients ingested We were unable to adjust for treatment variation, co- ethanol and sedatives that could account for altered mental ingestions, and co-morbidity. It is possible that the pa- status. tients with BEP received substandard treatment, had dif- Goldgran-Toledano et al3 have reported a case series similar to ours and suggested a relation between BEP and ferent co-ingestions, or may have had more co-morbid adverse outcome after TCA overdose. They evaluated 98 conditions. mixed TCA ingestions and found that 15% of patients had The results of this study may not be generalized to other BEP. There are several possible explanations for the higher populations. First, the TCA prescribing pattern has changed incidence of BEP in this study. It is possible that they used since these data were collected (1990 to1993). Most patients different definitions of BEP or that their electrocardio- are now taking much lower doses of TCAs. If BEP occurs graphic assessment was not blinded to outcome, which as a dose-dependent effect of TCA toxicity, the lower doses could lead to bias. It is also possible that they studied a of TCA may make BEP less common. Second, there group with more severe poisonings. However, the 2.4% has been a substantial increase in the number of selective overall mortality rate was similar to the mortality of TCA serotonin reuptake inhibitor medications available. These ingestions in our study (1.4%), and only 1 of the deaths in newer agents may have more or less propensity to cause their study was a patient with BEP. This suggests that there sodium channel blockade than other agents. Also, the me- was no significant difference in poisoning severity between dian TCA level is higher in the BEP group, which could the 2 studies. Our findings do not support the suggestion of suggest that this group is potentially more intoxicated; how- Goldgran-Toldedano et al3 that BEP is a marker of an ever, the range is wide and TCA levels have not been clearly increased risk of death from TCA poisoning. linked to TCA-induced complications.20 The mechanism of BEP after intentional TCA ingestion Genetic or electrophysiology testing for Brugada syn- is unclear. Brugada syndrome is believed to originate from drome in our patients with BEP would have been preferred a structural change in the myocardial sodium channel that but was not obtained. This testing can be logistically and produces altered opening. This dysfunction is reflected in financially challenging to obtain in a patient with transient the ECG pattern and can be induced in some patients with BEP without significant clinical effects. a type IA antidysrhythmic drug.1 Tricyclic antidepressants In summary, we found a modest association between also have a similar effect on cardiac sodium channels as a BEP and several TCA-related complications (widened type IA antidysrhythmic agent.13,14 One possibility is that QRS interval, hypotension, and seizures). The low inci- these patients have Brugada syndrome and a large TCA dence of death and ventricular dysrhythmias prevents us ingestion induced a BEP in these susceptible patients. This from drawing conclusions about these complications. Al- could imply that these patients have the high mortality though BEP may be a reflection of TCA toxicity and the associated with Brugada syndrome, which we did not ob- resultant poisoned sodium channels, it is an uncommon serve. The incidence of death or ventricular fibrillation with finding and may be a predictor of clinically significant Brugada syndrome ranges from 4% to 8% depending on the outcomes. presenting symptoms and electrophysiology testing15–17 When the subjects from our study and the study of Gold- 1. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR. 3 gram-Toldedano et al are combined, 1 death and no other The Brugada syndrome: clinical, electrophysiologic and genetic as- ventricular dysrhythmias occurred in Ͼ500 TCA ingestions, pects. J Am Coll Cardiol 1999;33:5–15. which indicates a lower risk of serious complications than 2. Brugada J, Brugada R, Brugada P. Right bundle-branch block and that associated with Brugada syndrome. ST-segment elevation in leads V1 through V3: a marker for sudden Another possibility for BEP after TCA ingestion is that death in patients without demonstrable structural heart disease. Circu- lation 1998;97:457–460. TCAs block myocardial sodium channels in the right ven- 3. Goldgran-Toledano D, Sideris G, Kevorkian JP. Overdose of cyclic tricle (similar to the slowed sodium channels in patients antidepressants and the Brugada syndrome. N Engl J Med 2002;346: with Brugada syndrome) resulting in an electrocardio- 1591–1592. 660 The American Journal of Cardiology (www.AJConline.org)

4. Babaliaros VC, Hurst JW. Tricyclic antidepressants and the Brugada 12. Buckley NA, Whyte IM, Dawson AH. Cardiotoxicity more common in syndrome: an example of Brugada waves appearing after the admin- thioridazine overdose than with other neuroleptics. J Toxicol Clin istration of desipramine. Clin Cardiol 2002;25:395–398. Toxicol 1995;33:199–204. 5. Sanders P, Farouque O, Cehic DA, Young GD. An unusual cause of 13. Pentel PR, Benowitz NL. Tricyclic antidepressant poisoning: manage- arrhythmic syncope: the Brugada syndrome. AustNZJMed1999;29: ment of arrhythmias. Med Toxicol 1986;1:101–121. 737–738. 14. Sasyniuk BI, Jhamandas V, Valois M. Experimental amitriptyline 6. Bolognesi R, Tsialtas D, Vasini P, Conti M, Manca C. Abnormal intoxication: treatment of cardiac toxicity with sodium bicarbonate. ventricular repolarization mimicking myocardial infarction after het- Ann Emerg Med 1986;15:1052–1059. erocyclic antidepressant overdose. Am J Cardiol 1997;79:242–245. 15. Brugada J, Brugada R, Brugada P. Determinants of sudden cardiac 7. Tada H, Sticherling C, Oral H, Morady F. Brugada syndrome mim- death in individuals with the electrocardiographic pattern of Brugada icked by tricyclic antidepressant overdose. J Cardiovasc Electro- syndrome and no previous cardiac arrest. Circulation 2003;108:3092– physiol 2001;12:275. 3096. 8. Rouleau F, Asfar P, Boulet S, Dube L, Dupuis JM, Alquier P, Victor 16. Eckardt L, Probst V, Smits JP, et al. Long-term prognosis of individ- J. Transient ST segment elevation in right precordial leads induced by uals with right precordial ST-segment-elevation Brugada syndrome. psychotropic drugs: relationship to the Brugada syndrome. J Cardio- vasc Electrophysiol 2001;12:61–65. Circulation 2005;111:257–263. 9. Phillips S, Brent J, Kulig K, Heiligenstein J, Birkett M. Fluoxetine 17. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol 2006; versus tricyclic antidepressants: a prospective multicenter study of 29:1130–1159. antidepressant drug overdoses. The Antidepressant Study Group. 18. Niemann JT, Bessen HA, Rothstein RJ, Laks MM. Electrocardio- J Emerg Med 1997;15:439–445. graphic criteria for tricyclic antidepressant cardiotoxicity. Am J Car- 10. Revicki DA, Palmer CS, Phillips SD, Reblando JA, Heiligenstein JH, diol 1986;57:1154–1159. Brent J, Kulig K. Acute medical costs of ﬂuoxetine versus tricyclic 19. Bebarta VS, Waksman JW. Brugada pattern after large amitriptyline antidepressants: a prospective multicentre study of antidepressant drug overdose not responsive to sodium bicarbonate. J Toxicol Clin Toxicol overdoses. Pharmacoeconomics 1997;11:48–55. 2004;42:734. 11. Copetti R, Proclemer A, Pillinini PP. Brugada-like ECG abnormalities 20. Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning: during thioridazine overdose. Br J Clin Pharmacol 2005;59:608. cardiovascular toxicity. Toxicol Rev 2005;24:205–214. Atrial and Ventricular Rate Response and Patterns of Heart Rate Acceleration during Maternal–Fetal Terbutaline Treatment of Fetal Complete Heart Block

Bettina F. Cuneo, MDa,b,*, Hui Zhao, PhDc, Janette F. Strasburger, MDd, Marc Ovadia, MDb, James C. Huhta, MDe, and Ronald T. Wakai, PhDc

Terbutaline is used to treat fetal bradycardia in the setting of complete heart block (CHB); however, little is known of its effects on atrial and ventricular beat rates or patterns of heart rate (HR) acceleration. Fetal atrial and ventricular beat rates were compared before and after transplacental terbutaline treatment (10 to 30 mg/day) by fetal echocardiography in 17 fetuses with CHB caused by immune-mediated damage to a normal conduction system or a congenitally malformed conduction system associated with left (8 ؍ isoimmune, n) While receiving terbutaline, 9 of the 17 fetuses underwent .(9 ؍ atrial isomerism (LAI, n fetal magnetocardiography (fMCG) to assess maternal HR and rhythm, patterns of fetal HR acceleration, and correlation between fetal atrial and ventricular accelerations (i.e., AV correlation). Maternal HR and fetal atrial and ventricular beat rates increased with terbutaline. However, terbutaline’s effects were greater on the atrial pacemaker(s) in fetuses with isoimmune CHB and greater on the ventricular pacemaker(s) in those with LAI- associated CHB. Patterns of fetal HR acceleration also differed between isoimmune and LAI CHB. Finally, despite increasing HR, terbutaline did not restore the normal coordi- nated response between atrial and ventricular accelerations in isoimmune or LAI CHB. In conclusion, the pathophysiologic heterogeneity of CHB is reﬂected in the differing effect of terbutaline on the atrial and ventricular pacemaker(s) and varying patterns of HR acceleration. However, regardless of the cause of CHB, terbutaline augments HR but not AV correlation, suggesting that its effects are determined by the conduction system defect rather than the autonomic control of the developing heart. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:661–665)

Fetal complete heart block (CHB) is a rare condition, oc- fetal electrocardiography technique with the capacity for curring in approximately 1 of 15,000 pregnancies. Fetal beat-to-beat analysis over many hours—we observed pat- CHB that occurs in association with maternal immunoglob- terns of HR accelerations, the atrial and ventricular pace- ulin-G Sjögren antibodies (i.e., isoimmune CHB) is be- maker response, and the ventricular rate response to atrial lieved to be a result of immune-mediated ﬁbrosis disrupting accelerations (i.e., AV correlation) during terbutaline treat- continuity between the atrium and the atrioventricular (AV) ment in fetuses with isoimmune and LAI-associated CHB. bundle relatively late in cardiogenesis,1–3 whereas CHB Our results lead us to postulate a mechanism for the ob- associated with congenital cardiac malformations such as served difference in acceleration patterns between isoim- left atrial isomerism (LAI) is believed to result from malde- mune and LAI CHB as it relates to the nature and timing of velopment of the conduction system early in cardiogenesis, the conduction system defect. probably during pattern formation of the specialized versus working myocardium.4–7 With such morphologic and etio- logic heterogeneity, it might be expected that the electro- Methods physiologic characteristics of the atrial and ventricular pace- We reviewed the perinatal cardiology database from 2 large makers in fetuses with CHB would differ in response to perinatal centers for fetuses presenting with CHB between pharmacologic heart rate (HR) augmentation with a ␤ ago- 1996 and 2006 that received terbutaline to augment ventric- nist such as terbutaline.8–10 Using the technique of fetal ular rate. After the initial diagnosis, fetuses were evaluated magnetocardiography (fMCG)—the only high-resolution by echocardiography (Sequoia; Siemens, Mountain View, California) performed at the referring perinatal center every week. At each visit, atrial and ventricular rates were mea- aRush Medical College, Chicago, Illinois; bThe Heart Institute for c sured by Doppler interrogation of the outﬂow tracts (ven- Children, Chicago, Illinois; Department of Medical Physics, University of tricular rate) or M-Mode of the atrium (atrial rate). Mean Wisconsin, Madison, Wisconsin; dMedical College of Wisconsin, Milwau- kee, Wisconsin; and eUniversity of South Florida College of Medicine, St. atrial and ventricular rates were averaged from 10 consec- Petersburg, Florida. Manuscript received January 4, 2006; revised manu- utive cycle lengths. Charts were reviewed for perinatal and script received and accepted March 13, 2007. neonatal outcome, gestational age at diagnosis, onset of *Corresponding author: Tel: 708-684-5580; fax: 708-684-4068. terbutaline treatment, fMCG and delivery, duration of ter- E-mail address: [email protected] (B.F. Cuneo). butaline treatment, and whether the infant was paced. Pre-

Table 1 Clinical and outcome of 17 fetuses with CHB Case No. Gestational Age Gestational Age Duration Gestational Age QRS Gestational Age Outcome at Diagnosis at Terbutaline of Terbutaline at fMCG Duration at Delivery (wks) Treatment (wks) (wks) (wks) (ms) (wks) Isoimmune CHB 1 24 24 13 29 56 37 PM, alive 2 19 23 12 24 68 35 PM, alive 3 19 25 12 30 46 37 PM, alive 4 24 24 14 25 49 37 PM, alive 5 24 26 13 32 46 39 PM, alive 6 19 21 14 ND ND 36 PM, neonatal death 7 22 28 7.5 ND ND 36.5 PM, alive 8 30 34 4 ND ND 38 PM, alive Mean Ϯ SD 22.6 Ϯ 3.8 25.6 Ϯ 4.0 11.2 Ϯ 3.6* 28 Ϯ 3.4 36.9 Ϯ 1.2* LAI CHB 9 20 28 9 31 55 37 PM, alive 10 20 25 9 29 61 34 PM, neonatal death 11 25 29 6 31 60 35 PM, neonatal death 12 19 35 3 38 55 38 PM, neonatal death 13 32 32 1 ND ND 33 PM, neonatal death 14 23 31 2 ND ND 33 PM, neonatal death 15 22 35 1 ND ND 35 PM, neonatal death 16 19 22 8 ND ND 30 PM, neonatal death 17 27 28 7 ND ND 36 PM, neonatal death Mean Ϯ SD 23 Ϯ 4.4 29.4 Ϯ 4.3 5.1 Ϯ 3.4* 32.2 Ϯ 4.0 34.6 Ϯ 2.4*

*pϽ0.05. ND ϭ not done; PM ϭ pacemaker. treatment maternal HR was measured during obstetric tributed data. We compared differences in the atrial and visits. ventricular responses to terbutaline between fetuses with When echocardiography demonstrated a decrease in the isoimmune CHB and those with LAI CHB by Wilcoxon mean fetal HR to Ͻ56 beats/min, mothers were given ter- 2-sample test, a nonparametric equivalent to the indepen- butaline 2.5 to 7.5 mg orally every 4 to 6 hours (total daily dent 2-sample t test. Differences in gestational age at de- dose 10 to 30 mg). We chose to start terbutaline treatment livery and onset of treatment, as well as duration of tur- because of reports suggesting poor outcome of fetuses with butaline treatment were compared between LAI CHB and HR Ͻ56 beats/min11 Because we anticipated treatment over isoimmune CHB by t test. Data are reported as means Ϯ many weeks, the dose of terbutaline was titrated to maintain SD. A p value Ͻ0.05 was considered significant. a maternal HR at rest between 95 and 115 beats/min. Ter- In the 9 fetuses studied by fMCG, we also qualitatively butaline was not well tolerated at higher doses due to fre- evaluated patterns of fetal HR acceleration and the correla- quent maternal complaints of palpitations. During the tion between fetal atrial and ventricular accelerations.12 course of treatment, no mother developed pulmonary edema or glucose intolerance. Mothers with fetal isoimmune CHB Results also received oral dexamethasone (4 mg/day until 30 weeks, and then the dose was tapered by 1 mg every other week) Seventeen fetuses diagnosed at 19 to 23 weeks with CHB from the time of diagnosis until 36 weeks’ gestation or received terbutaline for mean ventricular rates Ͻ56 beats/ delivery. min (Table 1). Two fetuses with isoimmune CHB (patients Nine of the 15 terbutaline-treated fetuses underwent 1 and 4) initially had pericardial effusions and ascites that fMCG at 20 to 37 weeks of age at the Division of Medical resolved during treatment. Four fetuses with LAI CHB Physics at the University of Wisconsin in Madison using a (patients 13 through 16) developed hydrops before terbutal- 37-channel biomagnetometer in a specially constructed low ine was given; the hydrops did not improve despite an permeability room, as previously described.12 QRS duration increased fetal HR. All infants were born alive at 33 to 39 was measured from the signal-averaged fMCG. Five to 10 weeks’ gestation. Only duration of terbutaline treatment and tracings each of 10 to 15–minute duration were recorded gestational age at delivery were different between fetuses from multiple probe positions then digitized and band-pass with isoimmune CHB and LAI CHB. filtered (1 to 80 Hz). Maternal HR (mean and range) and Sixteen infants received dual-chamber pacemakers and rhythm were also measured during fMCG. epicardial leads within 24 hours of birth; 1 with isoimmune Before the beginning of terbutaline treatment, mean beat CHB is still not paced at 9 months of age; 88% of patients rates of the fetal atrial and ventricular pacemakers and with isoimmune CHB survived compared with only 11% of maternal HRs were measured by echocardiography (fetuses) those with LAI CHB. or auscultation (mothers) and compared with posttreatment The mean atrial and ventricular rates after terbutaline values by Wilcoxon signed-rank test for nonnormally dis- treatment differed significantly from pretreatment rates in Arrhythmias and Conduction Disturbances/Terbutaline Therapy for Fetal Complete Heart Block 663

Table 2 Effects of terbutaline on maternal heart rate and fetal atrial and ventricular rates (mean Ϯ SD) in fetal CHB Rate No. of Patients Pre-Terbutaline Beat Rate Post-Terbutaline Beat Rate p Value Fetal atrium 17 121.6 Ϯ 13.3 133.6 Ϯ 16.9 Ͻ0.001 Fetal ventricle 17 52.5 Ϯ 2.3 63.4 Ϯ 8.9 Ͻ0.001 Maternal 9 74.5 Ϯ 6.7 98.2 Ϯ 10.2 0.008

Table 3 Differences in atrial and ventricular rate response (mean Ϯ SD) to terbutaline between fetuses with isoimmune and LAI CHB Rate Isoimmune CHB Beat Rate LAI-CHB Beat Rate p Value (n ϭ 8) (n ϭ 9) Baseline atrial 128.3 Ϯ 9.9 115 Ϯ 13.5 0.06 Post-terbutaline atrial 143.9 Ϯ 14.6 123.3 Ϯ 12.5 Ͻ0.01 Baseline ventricular 51.7 Ϯ 2.6 53.3 Ϯ 1.7 0.23 Post-terbutaline ventricular 58.6 Ϯ 5.0 68.1 Ϯ 9.6 0.03 fetuses and mothers (Table 2). There was no difference It has been shown previously in fetal CHB that, if the between pretreatment atrial or ventricular rates between baseline ventricular rate is Ͼ55 beats/min, accelerations in fetuses with LAI CHB and isoimmune CHB, but the atrial atrial and ventricular rates are correlated. In the current and ventricular rates after terbutaline treatment differed series, terbutaline restored fetal ventricular rate to Ͼ55 significantly between isoimmune and LAI CHB (Table 3). beats/min, but AV correlation did not normalize in isoim- Specifically, the ventricular rate response to terbutaline was mune or LAI CHB (Figure 2). greater for the 9 fetuses with LAI CHB, whereas the atrial rate response was higher for those 8 with isoimmune CHB. Discussion Mean fetal HR was maintained at Ͼ60 beats/min during the 6 to 12 weeks of terbutaline treatment in 4 of 6 The most important finding of this study is that distinct fetuses, but in 2 fetuses, mean fetal HR decreased back to electrophysiologic patterns of fetal HR acceleration, reflect- 55 to 56 beats/min at 33 to 35 weeks’gestation. Because ing the underlying pathology of the conduction system dys- the maternal HR was 120 beats/min and there were no function, are seen after HR perturbation with terbutaline. clinical findings of fetal heart failure, the dose of ter- These patterns can be summarized as follows. When the butaline was not increased. conduction system is structurally normal but damaged by Terbutaline was well tolerated by all mothers and con- maternal antibodies late in cardiogenesis (i.e., isoimmune tinued until delivery. During treatment, 5 of 9 mothers had CHB), terbutaline increases fetal HR, but with a pattern of premature atrial (n ϭ 4) or ventricular heart beats that wavelike accelerations with gradual relaxation to baseline comprised Ͻ1% of the recorded beats during fMCG and level. In fetuses in which conduction system development is were considered benign. Maternal tachyphylaxis was ob- altered presumably early in cardiogenesis (i.e., LAI CHB), served in 2 mothers, necessitating an increased dose of terbutaline reveals low-amplitude oscillations plus abrupt terbutaline at 32 and 34 weeks’gestation. transitions between 9 to 10 beat accelerations and baseline At terbutaline-augmented HRs to Ͼ55 beats/min in the or it merely increases fetal HR without distinct accelera- fetus with isoimmune CHB, the HR acceleration patterns tions. were almost wavelike, with a gradual return to baseline. In Previous data and data from this study show that ter- contrast, terbutaline affected fetal HR pattern in LAI CHB butaline, a ␤-2 agonist, increases atrial and ventricular rates in 1 of 2 ways. In 3 fetuses, the ventricular rate was higher, in the setting of CHB.8–10 Because the atrial and ventricular but the acceleration pattern was monotonously flat with no responses to HR perturbation vary, it appears that terbutal- oscillations. In the other 2 fetuses, accelerations were sus- ine, by exerting a differential effect on primary and subsid- tained and high in amplitude or the HR oscillated between iary pacemakers, acts locally and does not influence neural the baseline and an accelerated rate 9 to 10 beats faster than control of HR. We postulate that the robust increase in the baseline before decreasing back to baseline level (Figure 1). atrial (i.e., primary) pacemaker but not the ventricular (i.e., Despite the different coupling intervals of the accelerated subsidiary) pacemakers in isoimmune CHB reflect the beats, the QRS morphology and duration of these beats pathologic findings of disease in the AV node. Alterna- remained normal and did not differ between isoimmune and tively, the faster ventricular rate seen in fetuses with LAI LAI CHB. The QRS was narrow with a normal duration CHB implies preservation of the components of the distal (Figure 1), which we interpreted as indicating that the sub- conduction system serving in the subsidiary pacemaker role, sidiary pacemaker was located in the proximal portion of with developmental anomalies of the sinus node responsible the conduction system (AV node–His bundle). Because a for the lower baseline atrial rate and atrial rate response to ventricular escape rhythm is unlikely at these rates and with terbutaline. such morphology, these observations suggest that the accel- In addition to the differential effects on mean atrial and erated rhythm originated at or near the AV junction. ventricular rate, the HR patterns of acceleration in response 664 The American Journal of Cardiology (www.AJConline.org)

Figure 1. Heart rates during terbutaline treatment in fetuses with isoimmune and LAI CHB. (A) Image from a 29-week fetus with isoimmune CHB. There is a gradual increase in rate, with a slow return to baseline in a wavelike pattern of acceleration. (B) Image from a 29-week fetus with LAI CHB. The accelerations are much more frequent, short-lived, and of higher amplitude and rate than in (A), and oscillate between several different rates. (C) Image from a 31-week fetus with LAI CHB showing a concentrated area of rapid and high-amplitude oscillations, which abruptly ends. (D) The fMCG during the period of intense oscillations presented in (C). Note the QRS morphology is the same even at the shorter coupling intervals, and the PP interval does not vary. The bottom tracing is the maternal signal and the top 2 tracings are the fetal signals.

atrial atrial 150 150

100 100 fetal heartfetal rate (bpm) fetal heartfetal rate (bpm) ventricular 50 50 ventricular

0 100 200 300 400 500 600 0 100 200 300 400 500 600 time (sec) time (sec)

Figure 2. An example of AV correlation during atrial accelerations in CHB. Right, image from a 29-week untreated fetus with a isoimmune CHB and mean fetal HR of 65 beats/min. Note there is good AV correlation: ventricular accelerations (bottom tracing) follow atrial acceleration (top tracing). Left,in comparison, there is a flat ventricular response to atrial accelerations in this 29-week fetus with isoimmune CHB on terbutaline to maintain a mean fetal HR of 62 beats/min. This impaired AV correlation was also seen with LAI CHB (not shown). Arrhythmias and Conduction Disturbances/Terbutaline Therapy for Fetal Complete Heart Block 665 to terbutaline also differ. Whereas the mechanism of HR 1. Buyon JP, Hiebert R, Copel J, Craft J, Friedman D. Autoimmune- acceleration—␤-1 stimulation or reflex mechanism of re- associated congenital heart block: Demographics, mortality, morbidity and recurrence rates obtained from national neonatal lupus registry. ␤ 13 sponse to -2 vasodilation —appears straightforward, the J Am Coll Cardiol 1998;31:1658–1666. mechanism for the different patterns of HR acceleration in 2. Ho SY, Esscher E, Anderson RH, Michaelsson MSO. Anatomy of response to terbutaline is more complex. We postulate the congenital complete heart block and relation to maternal anti-Ro an- existence of a nodal pacemaker, quite proximal to the AV tibodies. Am J Cardiol 1986;58:291–294. Ͼ 3. Bharati S, Swerdlow MA, Vitullo D, Chiemmongoltip P, Lev M. node within the AV junction, with a ventricular rate of 55 Neonatal lupus with congenital atrioventricular block and myocarditis. beats/min. In the case of isoimmune heat block, ongoing PACE 1987;10:1056–1070. inflammation or fibrosis results in a more distal “locus of 4. Dickinson DF, Wilkinson JL, Anderson KR, Smith A. The cardiac automaticity” within the conduction axis. These more distal conduction system in situs ambiguous. Circulation 1979;59:879– ␤ 885. subsidiary pacemakers may have fewer -receptors, abnor- 5. Ho SY, Fagg N, Anderson RH, Cook A, Allan L. Disposition of the mal innervation, or different underlying channel expression atrioventricular conduction tissues in the heart with isomerism of the patterns, rendering them unable to sustain a faster rate. This atrial appendages: its relation to congenital complete AV Block. JAm is seen by fewer, less frequent, and lower velocity acceler- Coll Cardiol 1992;20:904–910. 6. Bharati S, Lev M. The course of the conduction system in dextrocar- ations in the terbutaline-treated fetus with isoimmune CHB. dia. Circulation 1978;57:163–171. These data suggest that the prognosis for isoimmune 7. Moorman AF, Christoffels VM, Anderson RH. Anatomic substrates CHB is extremely favorable and that aggressive transpla- for cardiac conduction. Heart Rhythm 2005;8:875–886. cental therapy with terbutaline in this population is justified: 8. Yoshida H, Iwamoto M, Sakakibara H, Shigeta H, Hirahara F, Sato K. hydrops was reversed in 2 of 2 fetuses with isoimmune Treatment of fetal congenital complete heart block with maternal administration of beta-sympathomimetics. Gynecol Obstet Invest CHB who received terbutaline for fetal ventricular rates 2001;52:142–144. Ͻ55 beats/min. However, the prognosis of those with LAI 9. Groves AM, Allan LD, Rosenthal E. Therapeutic trial of sympatho- AV block even with terbutaline remains very bleak: hydrops mimetics in three cases of complete heart block in the fetus. Circula- progressed relentlessly in 4 fetuses in this group despite tion 1995;92:3394–3396. 10. Jaeggi ET, Fouron JC, Silverman ED, Ryan G, Smallhorn J, Horn- terbutaline augmentation of ventricular rate. This suggests berger LK. Transplacental fetal treatment improves the outcome of that the fetus with LAI CHB and hydrops will require more prenatally diagnosed complete heart block without structural heart innovative and extreme therapy to survive. disease. Circulation 2004;110:1542–1548. 11. Enronen M, Siren MK, Ekblad H, Tikanoja T, Julkunen H, Paavilainen T. Short and long term outcome of children with congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000;106: Acknowledgment: We thank D. Woodrow Benson MD, 86–91. PhD, who was supported by NIH grant HL69712, for crit- 12. Wakai TR, Leuthold AC, Martin CB. Atrial and ventricular fetal ical reading of the manuscript and valuable suggestions. We heart rate patterns in isolated congenital complete heart block detected by magnetocardiography. Am J Obstet Gynecol 1998;179: thank Mary Maier for fMCG data acquisition; Nana Aba 258–260. Mensah-Brown, MS; for fMCG data analysis; and Rita 13. Gabbe SG, Nelson LM, Paul RH. Fetal heart rate response to acute Allen, BA, for manuscript preparation. hemorrhage. Obstet Gynecol 1977;49:247–251. Angiographic Analysis of the Anatomic Relation of Coronary Arteries to Mitral and Tricuspid Annulus and Implications for Radiofrequency Ablation

Can Hasdemir, MDa,*, Oguz Yavuzgil, MDa, Serdar Payzin, MDa, Mehmet Aydin, MDb, Cem Ulucan, MDa, Meral Kayikcioglu, MDa, Levent H. Can, MDa, Cuneyt Turkoglu, MDa, and Hakan Kultursay, MDa

Coronary artery (CA) narrowings and/or occlusions after radiofrequency ablation (RFA) have been reported. The aim of this study was to describe the in vivo topographic anatomy of CAs and their anatomic relation to the mitral and tricuspid annulus using selective coronary angiography. Fifty consecutive patients undergoing RFA for narrow QRS complex tachycardia were included in the study. Multipolar electrode catheters were inserted into the right atrial appendage, His bundle region, distal coronary sinus (CS), and right ventricle. A mapping catheter was placed across the subeustachian isthmus (SEI). Selective coronary angiography was performed. The maximum and minimum distances between the distal CAs and the mapping catheter located along the mitral and tricuspid annulus were measured during systole and diastole and in right and left anterior oblique projections. The large (>1.5 mm) distal right CA was <5 mm from the mapping catheter in the SEI in 4 patients (8%). The large posterolateral branch of the right CA was <2 mm from the CS Os-middle cardiac vein in 10 patients (20%). The large left circumﬂex CA was <2 mm from the ﬂoor or ceiling of the CS in 7 patients (14%) and <2 mm from the CS catheter at the lateral and anterolateral mitral annulus in 12 patients (24%). RFA was canceled in 2 patients because of the close proximity (<2 mm) of the distal CA to the ablation site. In conclusion, large CAs are frequently located in close proximity to the common ablation sites. Coronary angiography should be considered in children and adults who may develop any signs or symptoms suggestive of acute CA occlusion until larger controlled series are available. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:666–671)

Acute coronary artery (CA) narrowings and/or occlusions population. The study protocol was approved by the Ege have been previously reported after radiofrequency ablation University School of Medicine Institutional Review Board. (RFA) for atrial arrhythmias.1–14 To date, a paucity of data Patients were studied in the fasting state under sedation exists about the frequency and topographic anatomy of CAs with intravenous midazolam and fentanyl. Multipolar elec- located in close proximity to the posteroseptal region, sub- trode catheters were inserted percutaneously into the right eustachian isthmus (SEI), and coronary sinus (CS) and its femoral vein, the left femoral vein, and the right subclavian branches in patients undergoing RFA for atrial arrhythmias. vein and positioned under fluoroscopic guidance in the right The aim of this study was to describe the in vivo topo- atrial appendage, His bundle region, distal CS/great cardiac graphic anatomy of distal CAs and their anatomic relation- vein, and right ventricle. Mapping catheter was placed (at ship to common ablation sites using selective coronary 6:00 to 7:00 o’clock position) across the SEI with an atrial- angiography. to-ventricular electrographic ratio of 0.5 to 1. The fluoroscopic angles of the right anterior oblique (RAO) and the Methods left anterior oblique (LAO) projections were selected in Fifty-four consecutive patients who underwent electro- each patient based on the orientation of the interventricular physiologic study and RFA for narrow QRS complex tachy- septum, as determined by the direction of the electrode cardia were prospectively included in the study. Patients catheter recording His bundle activation. The angle of the were excluded if they had undergone CA bypass graft sur- LAO projection was set first so that the tip of the His bundle gery (n ϭ 4). The remaining 50 patients form the study catheter (and therefore the basal portion of the interventricular septum) was oriented perpendicular to this plane. The angle in the RAO projection was then set almost perpendicular to the LAO plane, allowing visualization of the a Department of Cardiology, Ege University School of Medicine, Izmir, entire CS catheter. Left-sided accessory pathways and atrial Turkey; bTepecik Teaching and Research Hospital, Izmir, Turkey. Manu- script received February 21, 2006; revised manuscript received and ac- tachycardias (ATs) were approached by transseptal punc- cepted March 13, 2007. ture. *Corresponding author: Tel: 90-232-390-4001; fax: 90-232-343-5392. Selective coronary angiography procedures were per- E-mail address: [email protected] (C. Hasdemir). formed through the right femoral artery with right and left

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.082 Arrhythmias and Conduction Disturbances/RF Ablation and Relocation of Coronary Arteries 667

Judkins catheters. Coronary angiographic procedures were Atrioventricular reentrant tachycardia (AVRT) was present performed in the same fluoroscopic angles of the RAO and in 23 patients (46%), atrioventricular nodal reentrant tachy- LAO projections as selected in the electrophysiologic study. cardia in 20 (40%), focal AT in 5 (10%), and isthmus- Images were taken in each projection for 5 to 10 seconds dependent atrial flutter in 2 (4%). Coronary artery disease after each injection of radiographic contrast agent to visu- (nonocclusive) was present in 4 patients (8%), hypertensive alize the entire coronary venous system (particularly the CS heart disease in 9 (18%), rheumatic heart disease in 4 (8%), and its branches) in the venous phase (i.e., levophase) of and repaired secundum-type atrial septal defect in 1 (2%). A coronary angiograms. Venous phase images were used for total of 35 patients (70%) did not have any structural heart localization of the ostium of the CS and middle cardiac vein. disease. None of the patients had an anomalous CA. All images were transferred to a dedicated workstation In patients with right-dominant CAs (n ϭ 39, 78%), the (AXIOM Artis FC; Siemens Medical Solutions, Erlangen, distances between the distal right CA (vessel diameter 2.4 Ϯ Germany) for analysis. CA diameters were calculated by 0.8 mm, range 0.8 to 4.2) and the distal end of the mapping comparison with the reference angiographic catheter. catheter in the SEI were 11.5 Ϯ 7.0 mm on RAO images in Coronary arterial circulation was defined as right-domi- systole, 5.2 Ϯ 4.0 mm on RAO images in diastole, 8.9 Ϯ 5.7 nant, left-dominant, and co-dominant.15 The coronary arte- mm on LAO images in systole, and 4.1 Ϯ 3.5 mm on LAO rial circulation was considered right-dominant when the images in diastole. The maximum distance was Յ5mm terminal portion of the right CA supplied the atrioventricular nodal artery and the posterior descending and postero- (range 0 to 4.7) in 4 patients (8%) with a large distal right lateral left ventricular branches. The coronary arterial cir- CA (range 1.6 to 2.8 mm; Figure 1). The distances between culation was considered left-dominant when the terminal the posterolateral branch of the right CA (vessel diameter Ϯ portion of the left circumflex CA supplied the atrioventric- 1.6 0.6 mm, range 0.4 to 3.4) and the CS Os-middle Ϯ ular nodal artery and the posterior descending and postero- cardiac vein were 3.8 3.1 mm on RAO images in systole, Ϯ Ϯ lateral left ventricular branches. The coronary arterial cir- 1.8 2.1 mm on RAO images in diastole, 2.3 2.4 on culation was considered co-dominant when the posterior LAO images in systole, and 1.2 Ϯ 1.9 mm on LAO images descending artery was supplied by the right CA and the in diastole. The maximum distance was Յ5 mm (range 0 to posterolateral branch was supplied by the left circumflex 5 mm) in 14 patients (28%) and Յ2 mm (range 0 to 2 mm) CA. in 10 patients (20%) with a large (range 1.5 to 3.4 mm) Every patient underwent transthoracic echocardiography posterolateral branch (Figure 2). In these patients, the shape before electrophysiologic study for the evaluation of valves, of the posterolateral branch of the right CA was sharply atrial size, and ventricular function. Previous electrophysi- curved (i.e., inverted u–shaped) in 9 patients (64%) and ologic study reports were reviewed for previous ablation broad-based in 5 patients (36%; Figure 3). sites. In patients with a left-dominant CA (n ϭ 9, 18%), the All images were reviewed in the arterial and venous distances between the left circumflex CA (vessel diameter phases of coronary angiograms in each projection. After 2.5 Ϯ 0.3 mm, range 2.0 to 2.9) and the floor or the ceiling determining the course of the distal CAs and their anatomic of CS were 2.5 Ϯ 3.4 mm in RAO images in systole, Ͻ2.0 relation to the tricuspid annulus at the SEI and mitral an- mm on RAO images in diastole, 1.7 Ϯ 1.8 mm on LAO nulus (i.e., CS and great cardiac vein), the following mea- images in systole, and Ͻ2.0 mm on LAO images in diastole. surements were made: (1) the distance between the distal The maximum distance was Յ5 mm (range 0 to 4.6 mm) in right CA (in right-dominant cases) and the distal end of the 8 patients (16%) and Յ2 mm (range 0 to 1.8 mm) in 7 mapping catheter in the SEI, (2) the distance between the patients (14%) with a large (range 2.0 to 2.9 mm) left uppermost part of the posterolateral branch of the right or circumflex CA (Figure 4). In these patients, the left circum- the left circumflex CA and the ostium of the middle cardiac flex CA was located along the floor of the CS in 5 patients vein and the floor of the CS, (3) the distance between the (55%) and along the ceiling of the CS in 4 patients (45%; distal left circumflex CA (in left-dominant cases) and the Figure 5). floor or the ceiling of the CS, and (4) the distance between In patients with a co-dominant CA (n ϭ 2, 4%), the left the left circumflex CA and the great cardiac vein (lateral– circumflex CA was close to the mitral annulus (1.4 mm) in anterolateral mitral annulus). All measurements were made 1 patient. during systole and diastole and in RAO and LAO projec- Յ tions. The size of the CA was categorized as large (vessel A large (range 2.0 to 2.9 mm) left circumflex CA was 5 diameter Ն1.5 mm) or small (vessel diameter Ͻ1.5 mm). mm (maximum distance) away from the CS catheter at the The proximity of the CA was considered “very close” if the lateral and anterolateral mitral annulus in 15 patients (30%; ϭ distance between the mapping or CS catheter and the CA 8 left-dominant, 6 right-dominant, and 1 co -dominant), Յ was Յ2 mm (including measurements made during systole and 2 mm in 12 patients (24%). and diastole and measurements made in RAO and LAO RFA was canceled in 2 patients as a result of the close projections), and “close” if the distance was Յ5 mm. Values proximity of the distal CA to the ablation site. The first are expressed as ranges and means Ϯ SD. patient had counterclockwise isthmus-dependent atrial flutter (Figure 1). The distal end of the ablation catheter in the SEI was in close proximity to the distal right CA. The Results second patient had a posteroseptal accessory pathway lo- The study population consisted of 50 patients (21 men and cated on the floor of the CS around the ostium of the middle 29 women; mean age 41 Ϯ 18 years; range 14 to 79). cardiac vein (Figure 2). 668 The American Journal of Cardiology (www.AJConline.org)

Figure 1. Selective coronary angiography of the right CA (RCA) in LAO and RAO projections. (A,B) The distal tip of the mapping catheter is in close proximity to the distal RCA (vessel diameter 2.1 mm) during diastole in LAO and RAO projections, respectively. (C,D) The distal tip of the mapping catheter moves away from the distal RCA during systole in LAO (distance 0.7 mm) and RAO (distance 2.1 mm) projections, respectively.

Figure 2. Selective coronary angiography of the right CA (RCA) in LAO and RAO projections. (A) Distal tip of the mapping catheter is in close proximity to the posterolateral branch (vessel diameter 1.6 mm) of the RCA during diastole in LAO projection. (B) Distal tip of the mapping catheter is compressing the posterolateral branch of the RCA (arrow) during diastole in RAO projection. (C,D) The distal tip of the mapping catheter moves away from the posterolateral branch of the RCA during systole in LAO (distance 1.1 mm) and RAO (distance 1.1 mm) projections, respectively. CS ϭ coronary sinus. Arrhythmias and Conduction Disturbances/RF Ablation and Relocation of Coronary Arteries 669

Figure 3. Selective coronary angiography of the right CA (RCA) in LAO projections. (A) The arrow shows an inverted U–shaped posterolateral branch of the RCA. (B) The arrow shows a broad-based posterolateral branch of the RCA.

Figure 4. Selective coronary angiography of the left circumflex() and left anterior descending CA in LAO and RAO projections. (A) Coronary angiography shows a dominant left circumflex CA located along the ceiling of the CS. (B,C) The distal tip of the mapping catheter is in close proximity to the left circumflex CA (arrows) in shallow LAO and standard RAO projections, respectively. (D) The arrow shows the indentation of the left circumflex CA (vessel diameter 2.5 mm) created by the compression of the distal tip of the mapping catheter.

Discussion RFA for atrial arrhythmias has been reported to be Ͻ0.1% based on a recent study of a prospective catheter ablation Acute CA narrowings and/or occlusions have been previ- registry.22 The low incidence of CA damage can be caused ously reported after RFA for atrioventricular reentrant tachycardia, atrioventricular nodal reentrant tachycardia, by the heat-sink effect of flowing blood and the surrounding 23 isthmus-dependent atrial flutter, and atrial fibrillation.1–14 fatty tissue. The most common sites of this complication were the pos- High-risk ablation sites (e.g., CS Os-middle cardiac vein, teroseptal region, lateral mitral annulus, SEI, and inside the floor or ceiling of CS, and SEI) are ablation sites for several CS. Location of the arrhythmogenic focus, ablation sites types of common arrhythmias, such as atrioventricular re- very close to the CA (distance Յ2 mm), tissue architecture entrant tachycardia caused by posteroseptal (including the (e.g., nonuniform muscle trabeculae, thinner fatty tissue in permanent form of junctional reciprocating tachycardia), the atrioventricular groove), and unfavorable anatomic vari- left posterior and posterolateral accessory pathways, isth- ation of CAs place patients at greater risk of CA dam- mus-dependent atrial flutter, focal atrial tachycardia, and age.14,16–21 Despite the close proximity of the ablation sites atrial fibrillation.24–28 In recent years, CS became a common to CAs, the incidence of acute myocardial infarction after target for focal atrial tachycardia and atrial fibrillation ab- 670 The American Journal of Cardiology (www.AJConline.org)

Figure 5. Coronary angiography of the left circumflex(LCx)and left anterior descending CA in LAO and RAO projections. (A,B) Coronary angiography shows the dominant left circumflex LCx CA located along the floor of the CS in LAO and RAO projections, respectively. (C,D) Coronary angiography shows the dominant left circumflex CA located along the ceiling of the CS in the LAO and RAO projections, respectively. lations. It has been found that the musculature of the CS catheter and the index CA can be better delineated using- serves as a critical component of the reentry circuit in intravascular ultrasonography. Most of our study population approximately 25% of patients with atypical flutter after (90%) were adults. There was no control group in the study ablation for atrial fibrillation. The CS may also generate that showed any deleterious effects of RFA at high-risk sites focal atrial arrhythmias that may play a role in triggering in patients who underwent RFA without coronary angiog- and/or maintaining atrial fibrillation.26 In addition, mitral raphy. isthmus ablations (including ablations within the CS) for AF may also increase the risk of CA damage.28 Based on our 1. Solomon AJ, Tracy CM, Swartz JF, Reagan KM, Karasik PE, Fletcher findings, coronary angiography might be considered in RD. Effect on coronary artery anatomy of radiofrequency catheter these patients. ablation of atrial insertion sites of accessory pathways. J Am Coll Cardiol 1993;21:1440–1444. One other aspect of CA damage during RFA is related to 2. Chatelain P, Zimmermann M, Weber R, Campanini C, Adamec R. age, as most reported cases are in children (range 5 weeks Acute coronary occlusion secondary to radiofrequency catheter abla- to 12 years of age).1–13 The higher incidence of acute CA tion of a left lateral accessory pathway. Eur Heart J 1995;16:859–861. occlusions among children can be explained by their smaller 3. Khanal S, Ribeiro PA, Platt M, Kuhn MA. Right coronary artery occlusion as a complication of accessory pathway ablation in a 12- hearts and thinner myocardial, interstitial, and epicardial year-old treated with stenting. Catheter Cardiovasc Interv 1999;46: fatty tissue. In 1 recent autopsy study, the distance from the 59–61. endocardial surface of the atrioventricular valve annulus 4. Bertram H, Bokenkamp R, Peuster M, Hausdorf G, Paul T. Coronary and adventitia of the adjacent CA was measured in 10 artery stenosis after radiofrequency catheter ablation of accessory normal pediatric heart specimens at 11 locations around the atrioventricular pathways in children with Ebstein’s malformation. 29 Circulation 2001;103:538–543. right and left atrioventricular grooves. The study showed 5. Strobel GG, Trehan S, Compton S, Judd VE, Day RW, Etheridge SP. that the endocardium-to-CA distance varied by age and Successful pediatric stenting of a nonthrombotic coronary occlusion as location, with the shortest distances in the region of the a complication of radiofrequency catheter ablation. Pacing Clin Elec- ostium of the CS and the greatest distances in the right trophysiol 2001;24:1026–1028. anteroseptal area. Excluding right anteroseptal measure- 6. Weiss C, Becker J, Hoffmann M, Willems S. Can radiofrequency Ͻ current isthmus ablation damage the right coronary artery? Histopatho- ments, in the 5 patients 7 years of age, the endocardium- logical findings following the use of a long (8 mm) tip electrode. to-CA distances were Յ4 mm in 76% and Յ5 mm in 96%. Pacing Clin Electrophysiol 2002;25:860–862. As a result of these studies and our findings, RFA should be 7. Ouali S, Anselme F, Savoure A, Cribier A. Acute coronary occlusion performed with great caution regarding CA damage, partic- during radiofrequency catheter ablation of typical atrial flutter. J Car- diovasc Electrophysiol 2002;13:1047–1049. ularly at high-risk ablation sites in all patients, and partic- 8. Paul T, Kakavand B, Blaufox AD, Saul JP. Complete occlusion of the ularly in children. left circumflex coronary artery after radiofrequency catheter ablation The exact distance between the distal end of the ablation in an infant. J Cardiovasc Electrophysiol 2003;14:1004–1006. Arrhythmias and Conduction Disturbances/RF Ablation and Relocation of Coronary Arteries 671

9. de Paola AA, Leite LR, Arfelli E. Mechanical reperfusion of acute 19. Sanchez-Quintana D, Ho SY, Cabrera JA, Farre J, Anderson RH. right coronary artery occlusion after radiofrequency catheter ablation Topographic anatomy of the inferior pyramidal space: relevance to and long-term follow-up angiography. J Invas Cardiol 2003;15:173– radiofrequency catheter ablation. J Cardiovasc Electrophysiol 2001; 175. 12:210–217. 10. Duong T, Hui P, Mailhot J. Acute right coronary artery occlusion in an 20. Becker AE. Left atrial isthmus: anatomic aspects relevant for linear adult patient after radiofrequency catheter ablation of a posteroseptal catheter ablation procedures in humans. J Cardiovasc Electrophysiol accessory pathway. J Invas Cardiol 2004;16:657–659. 2004l;15:809–812. 11. Blaufox AD, Saul JP. Acute coronary artery stenosis during slow 21. Wittkampf FH, van Oosterhout MF, Loh P, Derksen R, Vonken EJ, pathway ablation for atrioventricular nodal reentrant tachycardia in a Slootweg PJ, Ho SY. Where to draw the mitral isthmus line in catheter child. J Cardiovasc Electrophysiol 2004;15:97–100. ablation of atrial fibrillation: histological analysis. Eur Heart J 2005; 12. Raio N, Cohen TJ, Daggubati R, Marzo K. Acute right coronary artery 26:689–695. occlusion following radiofrequency catheter ablation of atrial flutter. 22. Scheinman MM, Huang S. The 1998 NASPE prospective catheter J Invas Cardiol 2005;17:92–93. ablation registry. Pacing Clin Electrophysiol 2000;23:1020–1028. 13. Takahashi Y, Jais P, Hocini M, Sanders P, Rotter M, Rostock T, 23. Lustgarten DL, Bell S, Hardin N, Calame J, Spector PS. Safety and Sacher F, Jais C, Clementy J, Haissaguerre M. Acute occlusion of the efficacy of epicardial cryoablation in a canine model. Heart Rhythm left circumflex coronary artery during mitral isthmus linear ablation. 2005;2:82–90. J Cardiovasc Electrophysiol 2005;16:1104–1107. 24. Gaita F, Haissaguerre M, Giustetto C, Fischer B, Riccardi R, Richiardi 14. Sun Y, Arruda M, Otomo K, Beckman K, Nakagawa H, Calame J, Po E, Scaglione M, Lamberti F, Warin JF. Catheter ablation of permanent S, Spector P, Lustgarten D, Herring L, Lazzara R, Jackman W. Cor- junctional reciprocating tachycardia with radiofrequency current. JAm onary sinus–ventricular accessory connections producing posterosep- Coll Cardiol 1995;25:648–654. tal and left posterior accessory pathways: incidence and electrophys- 25. Badhwar N, Kalman JM, Sparks PB, Kistler PM, Attari M, Berger M, iological identification. Circulation 2002;106:1362–1367. Lee RJ, Sra J, Scheinman MM. Atrial tachycardia arising from the 15. Baim DS, Grossman W. Coronary angiography. In: Baim DS, Gross- coronary sinus musculature: electrophysiological characteristics and man W, eds. Grossman’s Cardiac Catheterization, Angiography, and long-term outcomes of radiofrequency ablation. J Am Coll Cardiol Intervention. Philadelphia: Lippincott Williams & Wilkins, 2000:232– 2005;46:1921–1930. 234. 26. Chugh A, Oral H, Good E, Han J, Tamirisa K, Lemola K, Elmouchi D, 16. Bokenkamp R, Wibbelt G, Sturm M, Windhagen-Mahnert B, Bertram Tschopp D, Reich S, Igic P, et al. Catheter ablation of atypical atrial H, Hausdorf G, Paul T. Effects of intracardiac radiofrequency current flutter and atrial tachycardia within the coronary sinus after left atrial application on coronary artery vessels in young pigs. J Cardiovasc ablation for atrial fibrillation. J Am Coll Cardiol 2005;46:83–91. Electrophysiol 2000;11:565–571. 27. Lemola K, Mueller G, Desjardins B, Sneider M, Case I, Good E, Han 17. Aoyama H, Nakagawa H, Pitha JV, Khammar GS, Chandrasekaran K, J, Tamirisa K, Tschopp D, Reich S, et al. Topographic analysis of the Matsudaira K, Yagi T, Yokoyama K, Lazzara R, Jackman WM. coronary sinus and major cardiac veins by computed tomography. Comparison of cryothermia and radiofrequency current in safety and Heart Rhythm 2005;2:694–699. efficacy of catheter ablation within the canine coronary sinus close to 28. Jais P, Hsu LF, Rotter M, Sanders P, Takahashi Y, Rostock T, Sacher the left circumflex coronary artery. J Cardiovasc Electrophysiol 2005; F, Hocini M, Clementy J, Haissaguerre M. Mitral isthmus ablation for 16:1218–1226. atrial fibrillation. J Cardiovasc Electrophysiol 2005;16:1157–1159. 18. Waki K, Saito T, Becker AE. Right atrial flutter isthmus revisited: 29. Al-Ammouri I, Perry JC. Proximity of coronary arteries to the atrio- normal anatomy favors nonuniform anisotropic conduction. J Cardio- ventricular valve annulus in young patients and implications for abla- vasc Electrophysiol 2000;11:90–94. tion procedures. Am J Cardiol 2006;97:1752–1755. Quality of Life Within One Year Following Presentation After Transient Loss of Consciousness

Nynke van Dijk, MD, PhDa,b,*, Mirjam A. Sprangers, PhDc, Kimberly R. Boer, MScb, Nancy Colman, MDd, Wouter Wieling, MD, PhDa, and Mark Linzer, MDe

The purpose of this study was to examine (1) changes in quality of life (QoL) within 1 year after presentation with transient loss of consciousness (TLOC) and (2) which factors are predictive of these changes. This study was part of the Fainting Assessment Study (FAST), which assessed diagnostic strategies in patients with TLOC. Adult patients presenting to Academic Medical Center, Amsterdam, The Netherlands, with TLOC were included in the study. QoL was assessed with the generic Short Form 36 and the disease-speciﬁc Syncope Functional Status Questionnaire at presentation and 1 year of follow-up. Of 468 included patients, 82% completed questionnaires at presentation and 72% after 1-year follow-up. QoL improved on 7 of 8 subscales of the Short Form 36 and on all summary scales of the Syncope Functional Status Questionnaire. Older age, recurrence, higher level of co-morbidity, and a neurologic or psychogenic diagnosis were predictive of poorer QoL. In conclusion, QoL in patients with TLOC improves signiﬁcantly over time. Physicians should particularly pay attention to patients who are older, have recurrent episodes, a neurologic or psychogenic diagnosis, and a higher level of co-morbidity because these patients are vulnerable to a relatively poorer QoL. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:672–676)

Transient loss of consciousness (TLOC) can be a symptom ary 2000 and May 2002 were included. Patients were eli- of various disorders, from benign (vasovagal syncope) to gible for inclusion if they had Ն1 episode of TLOC in the lethal (cardiac arrhythmias).1 However, even if the cause of 12 months before presentation. TLOC was defined as self- TLOC is benign, morbidity can be considerable and epi- limiting, transient, short-lived episodes of loss of conscious- sodes can have a major effect on quality of life (QoL).2–4 ness not due to head trauma.5 Patients Ͻ18 years of age and The objective of this study was to examine the extent to patients with a known cause for their episodes were ex- which QoL changes 1 year after presentation with TLOC. cluded. Patients were excluded from this QoL study when Although we expected QoL to improve, this study also they had a lack of Dutch proficiency or physical or mental aimed to determine the extent to which sociodemographic incapability to complete the questionnaires. The study was and clinical factors, particularly the influence of different approved by the medical ethical committee of the Academic clinical diagnoses, are predictive of changes in QoL during Medical Center Amsterdam. All patients gave informed 1-year follow-up. consent. Generic QoL was measured using the self-administered Methods short form 36 (SF-36), which measures generic health con- This study was part of the Fainting Assessment Study cepts relevant across age, disease, and treatment groups. (FAST), which assessed diagnostic strategies in patients The 36-item questionnaire yields 8 scale scores (physical presenting with TLOC. Methods and outcomes of this study functioning, role functioning physical, bodily pain, general have been described in detail elsewhere.4 In FAST, patients health, vitality, social functioning, role functioning emo- presenting with TLOC to the Academic Medical Center tional, and mental health) and a score for reported health Amsterdam (Amsterdam, The Netherlands) between Febru- transition comparing present health with 1 year previously. The scores can be summarized into 2 scales, the physical and mental component summaries. All raw scale scores are Departments of aInternal Medicine, bClinical Epidemiology Biostatis- linearly converted to a scale of 0 to 100. Higher scores 4,6 tics and Bioinformatics, cMedical Psychology, and dCardiology, Academic indicate higher levels of functioning or well-being. Trans- Medical Center, University of Amsterdam, Amsterdam, The Netherlands; lation, validation, and norming of the Dutch-language ver- and eDepartment of Medicine, University of Wisconsin, Madison, Wiscon- sion were performed by Aaronson et al.7 sin. Manuscript received February 23, 2007; revised manuscript received Disease-specific QoL was measured using the Syncope and accepted March 20, 2007. Functional Status Questionnaire (SFSQ), which consists of This research was financially supported by Grant NHS 99/181 from the 11 yes/no questions to assess how syncope interferes with a Netherlands Heart Foundation, The Hague, The Netherlands, and an un- restricted educational grant from Medtronic, Inc., Heerlen, The Nether- patient’s life and three 8-point Likert-scale questions that lands. assess fear and worry with respect to syncope. To calculate *Corresponding author: Tel: 31-20-566-6948; fax: 31-20-691-2683. the impairment score the number of areas in which syncope E-mail address: [email protected] (N. van Dijk). interfered with a patient’s life (range 0 to 11) is divided by

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.085 Arrhythmias and Conduction Disturbances/Quality of Life in Patients With TLOC 673 the number of applicable areas and then multiplied by 100, over 1 year for patients who perceived their general health resulting in a score between 0 and 100, with 100 represent- to be “somewhat better” and for patients who perceived ing impairment in all areas. The 3 Likert-scale questions their health to be “somewhat worse” than 1 year previously were averaged to calculate a fear/worry score scaled from 0 on the health transition item of the SF-36 was calculated to to 100, with 100 indicating maximum fear and worry. The obtain the minimally important difference.11 The effect size Syncope Dysfunction Score (SDS) is the average impair- of the change in QoL over 1-year follow-up was calculated 4,8 Ϫ 12,13 ment score and fear/worry score. This questionnaire was as meanbaseline meanfollow-up ⁄SDbaseline, with 0.2 repre- translated into Dutch through the forward–backward meth- senting a small effect, 0.5 a moderate effect, and 0.8 a large od; 2 bilingual native Dutch speakers translated the ques- effect.14 A p value Ͻ0.05 was considered statistically sig- tionnaire into Dutch and discussed and adjusted the differ- nificant. ences. The Dutch questionnaire was translated back into To identify sociodemographic and clinical factors pre- English by a bilingual native-American speaker, the differ- dictive of change in QoL (mental and physical component ences were discussed, and the translated version was ad- summaries of the SF-36 and SDS of the SFSQ), univariate justed. general linear analyses were performed with the scale score Protocol called for patients to undergo an initial evalua- at 1-year follow-up as a dependent variable; the scale score tion consisting of a medical history, physical examination, of the same scale at presentation was entered as a covariate. and electrocardiography. If no diagnosis was obtained after The physical and mental component summaries were used initial evaluation, patients were to undergo echocardiogra- in this analysis to simplify interpretation of results and to phy, 24-hour Holter monitoring, and exercise electrocardi- decrease risk of type I errors. ography. In the remaining undiagnosed patients, additional Predefined, literature-based3,4,7,15,16 candidate predictive history taking and autonomic function testing (standing test, factors were age, gender, duration of syncopal problems in carotid sinus massage, and head-up tilt) were performed.9 months, lifetime episodes, number of syncope and presyn- At 1- and 2-year follow-ups, patients were sent a question- cope episodes in the year before presentation, Charlson naire regarding their clinical follow-up with respect to re- co-morbidity index, number of recurrent episodes in the currences and other cardiovascular events. If unreturned, the year after presentation, and clinical diagnosis (grouped per patient, a family member, or the general physician was diagnostic category, i.e., no diagnosis, cardiac, reflex syn- contacted by telephone, if they could not be traced; the cope, neurologic, and psychiatric). Distribution of continu- medical insurance company was contacted to document ous predictors was graphically assessed, and in case of whether the patient was still alive. After Ն2 year follow-up, nonlinearity, a log transformation was performed when pos- an expert panel made a final diagnosis based on all available sible; otherwise variables were categorized. Duration of clinical information. Co-morbid conditions were derived syncopal problems in months was successfully transformed, from the medical records and are presented as the Charlson and the Charlson co-morbidity score was categorized result- co-morbidity index, which is a weighted index to classify ing in 4 categories (0, 1, 2, and Ն3 points). Number of co-morbid conditions, taking into account the seriousness lifetime syncopal episodes (1 vs Ն2), number of episodes in and number of conditions.10 the previous year (1 vs Ն2), number of presyncopal epi- All patients received the QoL questionnaires (SF-36 and sodes (0 vs Ն1), and number of recurrences (0 vs Ն1) were SFSQ) for the first time at the first presentation to our dichotomized. hospital with TLOC. Patients were requested to return the A p value Ͻ0.1 in the univariate analysis was used as a questionnaire by mail. Patients who completed the question- criterion for inclusion in the multivariate general linear naires at baseline were sent the questionnaires again at 1 main effects model for that particular outcome measurement year after initial presentation. Nonrespondents received a (mental component summary, physical component sum- written reminder 2 and 4 weeks after sending the first mary, or SDS) including baseline values of the dependent questionnaire. variable. A forward method was used for variable selection. Different patients entered the QoL questionnaires 2 times Because none of the factors was strongly correlated with into a SPSS (SPSS, Inc., Chicago, Illinois) database. Dif- other factors or outcome (r Ͼ0.2), no interaction terms were ferences in data entry were checked and corrected according added. In the multivariate model factors were considered to the original data. Analysis was performed using SPSS independently predictive of change in QoL during 1-year 11.5. Sociodemographic and clinical data were expressed as follow-up if the p value was Ͻ0.05. percentages for categorical data, means Ϯ SDs for normally distributed, and medians (quartiles) for non-normally dis- Results tributed continuous data. Differences between respondents and nonrespondents at baseline and 1-year follow-up were From February 2000 until May 2002, 503 patients were tested using chi-square test for categorical variables and included in FAST. Thirty-five patients were excluded from Student’s t test or Mann-Whitney U test (where appropriate) the QoL component of this study due to language problems for continuous data. The scale scores of the 2 questionnaires (n ϭ 14) or a physical or mental inability to complete the were calculated according to the manuals6,8 and expressed questionnaires (n ϭ 21). Of the remaining 468 patients, 385 as means Ϯ SDs. Results of the yes/no questions of the (82%) completed the questionnaires and were included in SFSQ were expressed as proportions. the analyses. Respondents were older than nonrespondents, Changes in QoL from baseline to follow-up were as- had syncopal episodes for a longer period, and had more sessed using paired t test for continuous data and McNemar lifetime syncopal episodes (Table 1). test for categorical data. Means change in SF-36 and SFSQ At 1-year follow-up, 12 patients were excluded from 674 The American Journal of Cardiology (www.AJConline.org)

Table 1 Characteristics of FAST patients in respondents versus nonrespondents at baseline and after one-year follow-up Variables Baseline Follow-up Respondents Nonrespondents p Value Respondents Nonrespondents p Value (n ϭ 385) (n ϭ 83) (n ϭ 268) (n ϭ 105) Age 52 Ϯ 19 46 Ϯ 19 Ͻ0.01* 53 Ϯ 18 46 Ϯ 19 Ͻ0.01* Men 58% 49% 0.17 63% 41% Ͻ0.01* Highest educational level Elementary school 7.6% 20% 0.23 8.4% 9.3% 0.59 High school 18% 17% 18% 20% Lower vocational education 16% 8.6% 16% 12% Intermediate vocational education 27% 23% 25% 33% College 23% 20% 24% 20% University 9.0% 11% 8.4% 12% Months of syncopal problems 18 (2–96) 6.0 (0.3–36) Ͻ0.01* 24 (2–120) 12 (4–72) 0.69 Lifetime number syncopal episodes 3 (2–10) 2 (1–5) 0.01* 3 (1–10) 4 (2–13) 0.08 Syncopal episodes last 12 mo 2 (1–3) 1 (1–3) 0.13 1 (1–3) 2 (1–4) Ͻ0.01* Presyncopal episodes/mo 0 (0–2) 0 (0–4) 0.44 0 (0–2) 0 (0–2) 0.59 Injury due to syncope 34% 30% 0.46 32% 38% 0.28 Charlson co-morbidity index 0 (0–1) 0 (0–1) 0.40 0 (0–1) 0 (0–0.5) 0.32 Previous consultation for TLOC 66% 60% 0.41 64% 71% 0.20 Recurrences during follow-up 34% 38% 0.55 Diagnosis after 2-yr follow-up No diagnosis 9.9% 18% 0.16 7.5% 13% 0.02* Reﬂex syncope 75% 72% 77% 74% Cardiac syncope 6.5% 4.8% 8.2% 1.0% Neurological 2.6% 3.6% 3.0% 1.9% Psychogenic pseudosyncope 6.0% 1.2% 4.9% 9.5% Metabolic 0.3% 0.0% 0.0% 1.0%

Values are means Ϯ SDs, percentages of patients, or medians (quartiles). * Significant at p Ͻ0.05. follow-up due to death (n ϭ 10), severe dementia (n ϭ 1), morbidity, having Ͼ1 episode at presentation, and recurrent and detention (n ϭ 1). Of the remaining 373 original re- episodes remained independently predictive of less im- spondents, 268 (72%) filled in the QoL questionnaires at provement in physical component summary in the multivar- 1-year follow-up. These respondents were older, more iate model (Table 3). likely to be men, and had fewer episodes of TLOC in the From univariate analyses, Ͼ1 episode at presentation, year before presentation than nonrespondents. Further, re- recurrences during follow-up, and patient diagnostic cate- spondents at 1-year follow-up more often had a cardiac gory were added to the multivariate model for change in diagnosis, whereas nonrespondents more often had no or a mental component summary. Only recurrences and cause of psychological diagnosis for their episodes (Table 1). episodes predicted less improvement in mental component QoL scores at baseline and after 1-year follow-up are summary. listed in Table 2. Compared with baseline, QoL improved From univariate analyses, gender, number of episodes in significantly on all subscales of the SF-36, except for gen- the entire period and in the year before presentation, and eral health, and improved on all summary scales of the recurrences were added to the multivariate model for SFSQ. Effect sizes were small. On the health transition change in SDS. Only the presence of recurrences remained question of the SF-36 at follow-up, 19% of patients per- independently predictive of less improvement on the SDS in ceived their health to be worse, 32% to be equal, and 49% the multivariate model. to be better compared with the moment of presentation. Minimally important differences based on groups of pa- Discussion tients perceiving their health to be a little better/worse for the subscales of the SF-36 were 1.3 to 22 and 2.6 to 16 for Our results demonstrate that the mean QoL of patients the summary scales of the SFSQ. Mean difference between presenting with TLOC improves significantly after 1-year presentation and 1-year follow-up was larger than the min- follow-up on almost all scales of the SF-36 and SFSQ. imally important difference on 6 of the 8 scales of the SF-36 Although effect sizes are small, changes are larger than the for those patients who indicated they had improved minimally important difference on 6 of the 8 scale scores of (Table 2). the SF-36. Almost 50% of patients reported their health to From univariate analyses, age, having Ͼ1 episode at have improved in the year after presentation, and only 19% presentation, period of complaints, co-morbidity, and hav- reported it to have worsened. QoL of patients over a period ing recurrences were added to the multivariate model for of 1 year improves less in patients with older age, recurrent change in physical component summary. Older age, co- episodes, a higher level of co-morbidity, and being diag- Arrhythmias and Conduction Disturbances/Quality of Life in Patients With TLOC 675

Table 2 Quality of life at presentation and after one-year follow-up Variable Baseline 1-yr Follow-up p Effect Size‡ MID QOL Improved MID QOL Worse Qol Dutch Reference (n ϭ 268) (n ϭ 268) Value (n ϭ 65) (n ϭ 38) Population7

SF-36* Physical functioning 68 Ϯ 28 72 Ϯ 29 Ͻ0.01 0.14 1.3 Ϯ 16§ Ϫ4.0 Ϯ 20 83 Ϯ 23 Role physical 46 Ϯ 45 61 Ϯ 43 Ͻ0.01 0.33 14 Ϯ 42§ Ϫ8.8 Ϯ 37 77 Ϯ 36 Bodily pain 64 Ϯ 28 71 Ϯ 29 Ͻ0.01 0.25 5.8 Ϯ 25§ Ϫ8.1 Ϯ 33 75 Ϯ 23 General health 55 Ϯ 23 57 Ϯ 25 0.08 0.10 2.2 Ϯ 14 Ϫ9.5 Ϯ 15 71 Ϯ 21 Vitality 50 Ϯ 26 57 Ϯ 26 Ͻ0.01 0.27 5.5 Ϯ 25§ Ϫ6.7 Ϯ 19 69 Ϯ 19 Social functioning 68 Ϯ 28 76 Ϯ 27 Ͻ0.01 0.29 5.0 Ϯ 23§ Ϫ7.2 Ϯ 30 84 Ϯ 22 Role emotional 65 Ϯ 43 71 Ϯ 40 0.04 0.15 16 Ϯ 45 Ϫ22 Ϯ 48 83 Ϯ 33 Mental health 67 Ϯ 22 72 Ϯ 20 Ͻ0.01 0.23 4.8 Ϯ 16§ Ϫ1.8 Ϯ 23 77 Ϯ 17 Physical component summary 44 Ϯ 11 46 Ϯ 12 Ͻ0.01 0.21 0.7 Ϯ 7.9§ Ϫ2.2 Ϯ 8.1 49 Ϯ 10 Mental component summary 44 Ϯ 13 47 Ϯ 11 Ͻ0.01 0.26 5.6 Ϯ 11 Ϫ5.6 Ϯ 12 52 Ϯ 10 SFSQ† Impairment score 32 Ϯ 32 26 Ϯ 34 Ͻ0.01 0.19 Ϫ12 Ϯ 28 6.6 Ϯ 35 Fear/worry score 39 Ϯ 28 27 Ϯ 25 Ͻ0.01 0.43 Ϫ16 Ϯ 25 Ϫ2.6 Ϯ 26 SDS 37 Ϯ 26 27 Ϯ 25 Ͻ0.01 0.38 Ϫ15 Ϯ 20 2.9 Ϯ 23

Values are means Ϯ SDs. * SF-36 scores range from 0 to 100; 100 indicates perfect health. † SFSQ scores range from 0 to 100; 0 indicates no impairment due to syncope. ‡ Effect size: 0.2 ϭ small; 0.5 ϭ moderate; 0.8 ϭ large. § Difference between baseline and 1-year follow-up larger than MID. MID ϭ minimally important difference (mean difference in patients perceiving their health to be little better/worse than 1 year previously).

Table 3 Sociodemographic and clinical factors predictive of changes in scores of the Short Form 36 (physical component score, and mental component score) and Syncope Functional Status Questionnaire (syncope dysfunction score) over one-year follow-up Signiﬁcant Factors in the Univariate Model Mean Difference 95% CI (mean p Value in (multivariate model) difference) Multivariate Model PCS Age Ϫ1.2 per 10 yrs Ϫ1.9 to Ϫ0.51 Ͻ0.01* Ͼ1 episode in yr before presentation Ϫ4.9 Ϫ8.6 to Ϫ1.1 0.01* 2 log mo of complaints (change for every doubling of period) 0.29 Ϫ0.03 to 0.62 0.08 Charlson index score (vs 0) 1 Ϫ2.0 Ϫ5.2 to 1.2 0.21 Ն2 Ϫ6.6 Ϫ10.8 to Ϫ2.5 Ͻ0.01* Recurrence of episodes (0 vs Ն1) Ϫ5.2 Ϫ7.6 to Ϫ2.8 Ͻ0.01* MCS Ͼ1 episode in yr before presentation Ϫ0.075 Ϫ2.7 to 2.6 0.96 Recurrence of episodes Ϫ3.1 Ϫ5.8 to Ϫ0.38 0.03* Diagnostic category (vs no diagnosis) Reﬂex syncope Ϫ5.7 Ϫ11.1 to Ϫ0.4 0.04* Cardiac Ϫ4.5 Ϫ11.3 to 2.3 0.19 Neurologic Ϫ11.3 Ϫ20.3 to Ϫ2.3 0.01* Psychogenic Ϫ11.2 Ϫ19.1 to Ϫ3.3 Ͻ0.01* SDS Male gender Ϫ5.3 Ϫ11.1 to 0.6 0.08 Ͼ1 episode before presentation 0.68 Ϫ7.1 to 8.5 0.86 Ͼ1 episode in year before presentation 2.4 Ϫ4.7 to 9.5 0.50 Recurrence of episodes (0 vs Ն1) 9.4 3.5 to 15 Ͻ0.01*

Mean differences are the changes in PCS/MCS or SDS at follow-up for every step of change in the predictive variable in the multivariate model. * Significant at p Ͻ0.05. CI ϭ confidence interval; MCS ϭ mental component score; PCS ϭ physical component score. nosed with a neurologic or psychogenic cause of these longer period of syncopal problems and a larger number of episodes. episodes. Because a longer period of having symptoms and a Although the response rates at baseline and 1-year fol- larger number of episodes are predictive of worse QoL, QoL of low-up are high,17 respondents differed from nonrespondents patients with TLOC in the general population may be less on these occasions. At the 2 moments, respondents were older impaired than QoL of patients in this study. Further, our study and more severely affected than nonrespondents, having a was conducted in an academic medical center, with some 676 The American Journal of Cardiology (www.AJConline.org) patients presenting with their first syncopal episode and others 2. Linzer M, Pontinen M, Gold DT, Divine GW, Felder A, Brooks WB. being referred. This could also have led to the inclusion of Impairment of physical and psychosocial function in recurrent syn- more severely affected patients. Therefore, generalizability of cope. J Clin Epidemiol 1991;44:1037–1043. 3. Rose MS, Koshman ML, Spreng S, Sheldon R. The relationship results could be somewhat impaired. between health-related quality of life and frequency of spells in pa- To study whether statistically significant changes are tients with syncope. J Clin Epidemiol 2000;53:1209–1216. also clinically meaningful, we used effect size and mini- 4. van Dijk N, Sprangers MA, Colman N, Boer KR, Wieling W, Linzer mally important difference. Effect sizes Ͼ0.5 SD are usu- M. Clinical factors associated with quality of life in patients with ally considered clinically meaningful,18 although others transient loss of consciousness. J Cardiovasc Electrophysiol 2006;17: 998–1003. have suggested that effect sizes of 0.2 to 0.3 can be con- 5. Thijs RD, Wieling W, Kaufmann H, van Dijk G. Defining and clas- 19 sidered an important clinical change. In our study no sifying syncope. Clin Auton Res 2004;14(suppl 1):i4–i8. effect size was Ͼ0.5, but almost all are Ͼ0.2, indicating that 6. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health Survey the differences could be considered clinically meaningful. Manual and Interpretation Guide. Boston, MA: The Health Institute, The small effect size can be explained by the large SDs of New England Medical Center, 1993. the scale scores of the 2 questionnaires. However, when 7. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R, Sprangers MA, te Velde A, Verrips E. Translation, addressing minimally important differences, differences in validation, and norming of the Dutch language version of the SF-36 scores between baseline and 1-year follow-up are larger Health Survey in community and chronic disease populations. J Clin than the minimally important difference in 6 of the 8 scale Epidemiol 1998;51:1055–1068. scores of the SF-36. This indicates that the differences are 8. Linzer M, Gold DT, Pontinen M, Divine GW, Felder A, Brooks WB. clinically meaningful. In our calculation of the minimally Recurrent syncope as a chronic disease: preliminary validation of a important difference, we used results from the health tran- disease-specific measure of functional impairment. J Gen Intern Med 1994;9:181–186. sition question, which asked patients to report on the dif- 9. Brignole M, Alboni P, Benditt D, Bergfeldt L, Blanc JJ, Bloch Thom- ference in QoL between baseline and 1-year follow-up, sen PE, van Dijk JG, Fitzpatrick A, Hohnloser S, Janousek J, et al. which could have been influenced by recollection bias. Guidelines on management (diagnosis and treatment) of syncope. Eur As described by Baron-Esquivias et al16 and in agree- Heart J 2001;22:1256–1306. ment with our previous findings, patients’ QoL at presenta- 10. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of tion and after follow-up is strongly associated with presence classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383. of recurrent episodes. This indicates that prevention of re- 11. Guyatt GH, Osoba D, Wu AW, Wyrwich KW, Norman GR. Methods currences by adequate diagnosis and treatment could have a to explain the clinical significance of health status measures. Mayo major influence on QoL of patients. Clin Proc 2002;77:371–383. QoL of patients diagnosed with psychiatric pseudosyn- 12. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting cope or neurologic conditions is worse than that of patients changes in health status. Med Care 1989;27(suppl):S178–S189. 13. Deyo RA, Diehr P, Patrick DL. Reproducibility and responsiveness of with other diagnoses or no diagnosis at all. The nature of the health status measures. Statistics and strategies for evaluation. Control disorders can explain part of this; patients diagnosed with Clin Trials 1991;12(suppl):142S–158S. psychiatric pseudosyncope may feel stigmatized and there- 14. Cohen J. Statistical Power Analysis for the Behavioral Sciences, 2nd fore have worse QoL. The seriousness and long-term nature Ed. Hillsdale, NJ: Lawrence Erlbaum Associates, 1988. of neurologic disorders could explain the impaired QoL in 15. Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S. Risk factors these patients, although we did not expect it to be much for syncope recurrence after a positive tilt-table test in patients with syncope. Circulation 1996;93:973–981. worse than in patients diagnosed with, e.g., cardiac condi- 16. Baron-Esquivias G, Gomez S, Aguilera A, Campos A, Romero N, tions. We expected that the uncertainty of remaining undi- Cayuela A, Valle JI, Redondo M, Pedrote A, Burgos J, Martinez A, agnosed could have led to a lower QoL, whereas exclusion Errazquin F. Short-term evolution of vasovagal syncope: influence of a possible serious condition might have reassured these on the quality of life. Int J Cardiol 2005;102:315–319. patients of the benign nature of their episodes, especially at 17. Edwards P, Roberts I, Clarke M, DiGuiseppi C, Pratap S, Wentz R, 1-year follow-up. It is unknown which part of the improve- Kwan I. Increasing response rates to postal questionnaires: systematic review. BMJ 2002;324:1183–1185. ment is a treatment effect and which part is the natural 18. Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in history of patients with TLOC. health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003;41:582–592. 1. Kapoor WN, Karpf M, Wieand S, Peterson JR, Levey GS. A prospec- 19. Revicki DA, Cella D, Hays RD, Sloan JA, Lenderking WR, Aaronson tive evaluation and follow-up of patients with syncope. N Engl J Med NK. Responsiveness and minimal important differences for patient 1983;309:197–204. reported outcomes. Health Qual Life Outcomes 2006;4:70. The Editor’s Roundtable: Ablation of Atrial Fibrillation

Vincent E. Friedewald, MDa,*, Robert C. Kowal, MD, PhDb, Miguel Valderrabano, MDc, and William C. Roberts, MDd

Acknowledgment stroke risk by a similar degree. AF is more prevalent among European-Americans than African-Americans and is This CME activity is supported by an educational grant slightly more frequent in men than women. In this Editor’s from Biosense Webster, Inc, Diamond Bar, California. Roundtable, the panel discusses current concepts of AF, with emphasis on the technique, indications, limitations, Disclosure outcomes, and future of ablation therapy. Dr. Friedewald has no relevant financial relationships to disclose. Dr. Kowal has received honoraria for speaking for Discussion Medtronic, Minneapolis, Minnesota. Dr. Valderrabano has Dr. Friedewald: What is radiofrequency ablation (RFA)? no relevant financial relationships to disclose. Dr. Roberts Dr. Valderrabano: RFA is a procedure designed to has received honoraria for speaking from Astrazeneca, Wil- eliminate AF by destroying atrial tissue. The procedure has mington, Delaware; Merck, North Wales, Pennsylvania; many variants, most of them creating lesions in the left atrial Schering Plough, Kenilworth, New Jersey; Pfizer, New (LA) wall in the area of the pulmonary venous ostia and York, New York; and Novartis, East Hanover, New Jersey. adjacent LA wall. Haissaguerre and others4 have shown that most initiating extra beats of paroxysmal AF originate in a Objectives pulmonary vein. Ablating foci in the pulmonary vein(s) Upon completion of the activity, the physician should be eliminates AF paroxysms in nearly 70% of cases. Ablation able to: also electrically isolates the wall of the pulmonary vein from the LA wall. The procedure is technically complex and 1. Describe the mechanistic rationale for an invasive carries the potential for fatality when performed improperly. curative procedure for atrial fibrillation. Dr. Roberts: What does the word “ablation” mean? 2. Select patients who are candidates for radiofrequency Dr. Valderrabano: According to Stedman’s Medical ablation. Dictionary,5 ablation is defined as “removal of a body part 3. Explain the major risks and benefits of radiofrequency or the destruction of its function, as by a surgical procedure, ablation to patients. morbid process, or noxious substance.” As it pertains to this 4. Take appropriate measures to reduce the complica- technique, ablation is the destruction of electrically con- tions associated with radiofrequency ablation. ducting tissue in the wall of the pulmonary veins adjacent to the LA wall. Introduction Dr. Kowal: Patients referred for ablation too often ex- Atrial fibrillation (AF) is the most common cardiac arrhyth- pect the procedure to “fix” the problem to be a minor one, mia requiring treatment.1 In 2001, 2.3 million persons in the but it is a complex one. Furthermore, the pathophysiology USA were estimated to have AF, and the number projected of AF differs from patient to patient. The 45-year-old pa- to have AF by 2050 is 5.6 million. The prevalence of AF tient with weekly, 30-minute episodes of paroxysmal AF is increases markedly with age, occurring in 9% of persons very different from the 70-year-old patient who has had AF age Ն80 years. AF is an independent risk factor for stroke, continuously for 6 months. which is usually caused by thromboembolism from the left Dr. Friedewald: How do they differ? atrial appendage, increases stroke risk by 4 to 5 times, and Dr. Kowal: The mechanisms of AF in each are different. is responsible for 15% to 20% of all strokes.2,3 All forms Most early 20th century models of AF involved firing from (paroxysmal, persistent, and permanent) of AF increase focal sites. Those concepts later evolved into a model of continuous undulation of activation referred to as reentry, where there is no single responsible site of impulse origi- aAssistant Editor, American Journal of Cardiology; Clinical Professor, nation. Thus, for many years it was believed that ablation of Department of Internal Medicine, the University of Texas Medical School a single site to terminate AF would be ineffective. Now, at Houston, Houston, Texas; Visiting Professor, University of Notre Dame, paroxysmal AF is believed to be generated and sustained Notre Dame, Indiana; bBaylor University Medical Center, Dallas, Texas; from a few, specialized sites of rapid electrical discharge. In cDirector, Division of Cardiac Electrophysiology, Methodist DeBakey some patients with long-duration persistent AF, the mech- d Heart Center, Houston, Texas; Editor-in-Chief, American Journal of Car- anism is even more complex, driven by focal sites of reen- diology; Executive Director, Baylor Heart and Vascular Institute, Baylor try, because when the atrium fibrillates, the molecular and University Medical Center; Dean, A. Webb Roberts Center for CME of Baylor Health Care System, Dallas, Texas. Manuscript received May 10, genetic programs of atrial tissue actually change. This con- 2007; revised manuscript received and accepted May 11, 2007. cept is that AF begets AF, and the more often AF occurs, the This manuscript is based on a meeting of the authors on April 10, 2007. more select ion channels are down-regulated and the more *Corresponding author: Tel 512-264-1611; fax 512-264-7034. LA wall fibrosis develops, with atrial cells assuming differ- E-mail address: [email protected] (V.E. Friedewald). ent microscopic appearances. In the future, ablative proce-

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.05.020 678 The American Journal of Cardiology (www.AJConline.org) dures might be tailored according to the different underlying gitudinal and circumferential arrays—not in a continuous mechanisms of the AF. array as in normal atrial myocardial tissue. Dr. Friedewald: How do recurrent episodes of AF have Dr. Roberts: Microscopically, pulmonary vein walls an adverse effect on the structure of the LA wall? look different from atrial walls. Dr. Kowal: When this change occurs, episodes of AF Dr. Kowal: But clearly there is electrical activity in the episodes last for relatively long periods. Classically, the pulmonary vein wall. paroxysmal episodes of AF lengthen in duration and in- Dr. Friedewald: Do other types of supraventricular ar- crease in frequency over time, until eventually they do not rhythmias also originate in the pulmonary veins? terminate spontaneously. As the duration of AF lengthens, Dr. Kowal: Yes, regular atrial tachycardias also origi- the myocardial cells in the LA wall are altered ultrastruc- nate in pulmonary vein sites, and can be ablated. turally, fibrous tissue increases in the LA wall, and protein Dr. Friedewald: How often are AF foci located outside synthesis in the LA wall is altered. AF in non-human ani- the walls of the pulmonary veins? mals for 48 hours shortens the refractory periods and alters Dr. Kowal: In paroxysmal AF, 20% to 25% of the foci the ability to shuttle calcium in and out of the sarcoplasmic are in locations other than the pulmonary veins, a much reticulum. These are the electrical changes that are believed higher percent than in persistent or permanent AF. to accompany fibrosis and stretch-related responses that Dr. Friedewald: What are the known triggers of parox- change atrial myocytes, making continuous AF more likely ysmal AF? or reverting back to AF after conversion to sinus rhythm. Dr. Valderrabano: There is a wide spectrum of causes, Dr. Roberts: How do you classify the different forms of including a cholinergic mechanism, especially when AF AF? occurs after meals and at nighttime, but it is uncommon. Dr. Kowal: AF is divided into paroxysmal and persis- Dr. Friedewald: What are the roles of alcohol and fa- tent; and permanent and chronic. Paroxysmal AF refers to tigue as AF triggers? episodes that start and terminate spontaneously, usually Dr. Kowal: Both are clear antecedent triggers. So is within 48 hours. Persistent AF refers to a form of AF that exercise. In most patients, however, there are no identifiable requires some type of intervention for termination—elec- triggers of AF, which may occur at any time. trical cardioversion, chemical cardioversion, or ablative ter- Dr. Friedewald: What is the most common form of AF mination. Permanent AF refers to the arrhythmia in patients ablation? who, despite antiarrhythmic drug therapy and attempts at Dr. Valderrabano: Currently, pulmonary vein isolation cardioversion, do not convert to sinus rhythm or very rap- is the most common form of AF ablation. idly revert to AF after cardioversion to sinus rhythm. The Dr. Friedewald. What are the complications of ablation patient who is cardioverted from AF to sinus rhythm and for AF? then within a few days—despite receiving antiarrhythmic Dr. Valderrabano. The most serious complication is a drugs—reverts again to AF also has permanent AF. fistula between the atrium and the esophagus, a potentially Dr. Valderrabano: All of these mechanisms, however, lethal complication of a treatment for a non-life–threatening are only guesses when we try to apply them to individual disease. I inject a contrast material into the esophagus to patients. A 40-year-old patient with paroxysmal AF gener- first identify its location and then avoid “burning” close to ally responds well to pulmonary vein isolation, and we it. Some electrophysiologists, however, do not do esopha- therefore assume that in that patient we are eliminating gograms. electrical corridors or foci in the pulmonary veins. Because Dr. Kowal: Unfortunately, the real complication rate of an 80-year-old patient with persistent AF does not respond AF ablation is unknown because so many of the patients as well to that approach, we assume that he has another come from other parts of the country, making follow-up mechanism, but there are no mapping studies that prove this difficult. assumption. There is a huge gap between practice and sci- Dr. Friedewald: You used the term “non-lethal condi- ence in AF. tion,” but the risk of sudden cardiac death is increased in Dr. Roberts: Why are pulmonary veins the foci for AF? patients with AF. Dr. Kowal: Unfortunately, there are no adequate non- Dr. Valderrabano: We know from epidemiological human animal models of pulmonary vein focal triggers of studies that AF carries an increased risk of dying in general, AF that we can study. Examination of sleeves of myocar- based on Framingham data and other studies. dium extending into the pulmonary veins has shown that Dr. Kowal: There are at least 2 potential mechanisms for they are electrically different, with shorter action potentials, sudden death due to AF. One mechanism is that patients making them more electrically susceptible after depolariza- with AF have an ability to produce long–short coupling tion. The connections between the cells are fewer, so there intervals that could lead to a stimulus entering a scar zone is discontinuous conduction, and all of these factors, when for reentrant ventricular tachycardia or even ventricular combined, are arrhythmogenic. We do not understand why fibrillation, especially in patients with heart failure and in firing from a site causes AF in some patients, regular tachy- the presence of hypokalemia or hyperkalemia. There also cardias in others, and no rhythm changes in others. may be an increase in the baseline adrenergic tone when AF Dr. Roberts: Are there myocardial fibers in the walls of develops, something that could establish a proarrhythmic pulmonary veins? state in the ventricle of susceptible individuals. Dr. Kowal: There are sleeves of electrically active mus- Dr. Roberts: Among the 1,000 electrophysiologists in cular tissue running into the pulmonary veins in both lon- the USA, how many perform ablation procedures? Roundtable Discussion/Ablation of Atrail Fibrillation 679

Dr. Valderrabano: Perhaps 200 electrophysiologists in especially in the first few weeks, due to the trauma of the the USA. ablation lesions created in the LA wall. Dr. Roberts: And there are 2 to 3 million people with Dr. Kowal: I agree with that approach. The ablation AF? procedure is not indicated for the sole purpose of stopping Dr. Valderrabano: Yes, but not all of them are candi- anticoagulants, which is the reason some patients want it dates for an ablation. performed. According to American College of Cardiology/ Dr. Roberts: Who is a candidate for ablation? American Heart Association/European Society of Cardiol- Dr. Valderrabano: The best candidate is the young ogy guidelines for AF, the procedure is viewed as a second- person with paroxysmal AF and a structurally normal heart. line therapy for use when antiarrhythmic drugs have failed.6 Dr. Kowal: And an LA cavity that is not excessively That is in contrast to ablation for supraventricular tachycar- enlarged. dia and atrial flutter, in which it is offered as a first-line Dr. Friedewald: Who are not candidates for ablation? therapy, because the success of ablation for those dysrhyth- Dr. Valderrabano: Patients with massive LA dilatation, mias is very high and the procedure in them is very safe. LA clots, and AF due to valvular heart disease are poor Dr. Friedewald: Why are the drugs for AF so dangerous candidates for ablation. and so often ineffective? Dr. Kowal: Advanced age carries the risk for more Dr. Valderrabano: Because we do not understand AF complications, and patients with co-morbid conditions, such very well. We understand the drugs from the molecular as sleep apnea, chronic obstructive lung disease, and obe- standpoint, such as which ion channels they block and how sity, are usually poor candidates for ablation. they block them. How these effects translate to intact tissue Dr. Roberts: Nonvalvular AF is rare in individuals age in humans, however, is unclear. Consequently, drugs for AF Ͻ50 years, and most often occurs at age Ͼ70 years. are, in my view, truly “pathetic.” Dr. Valderrabano: That is correct, in part because with Dr. Kowal: Not only are the drugs not very efficacious, aging there is more structural disease—scar tissue, fibrosis, they also carry significant risk. Some manufacturers are hypertrophy—and we believe the mechanism is different working on atrial-specific drugs, but most of these drugs from AF in younger patients with normal hearts. The young also affect ventricular repolarization and conduction, so respond best to ablation. they are proarrhythmic in the ventricle. Other drugs, such as Dr. Roberts: How many ablation procedures have you amiodarone, have liver, thyroid, lung, and ocular toxicities, which are not acceptable to most people, especially young, done? otherwise healthy patients. Dr. Valderrabano: About 260. Dr. Friedewald: You said success following ablation Dr. Kowal: About 130. was 75% to 80%. When do you declare “success”? Dr. Roberts: How many procedures does it take to Dr. Kowal: Success is the procedure’s ability to prevent become proficient? AF, including prevention in cases when combined with a Dr. Valderrabano: Probably about 60 procedures. drug that had not been effective before the procedure. Suc- Dr. Roberts: How long does it take you to do a proce- cess also applies to patients whose burden drops to only dure? rare, short-lived episodes compared to much longer-lived Dr. Valderrabano: Four to 5 hours for most cases. and frequent episodes before the ablation. Dr. Roberts: What do you tell the patient before the Dr. Valderrabano: If we look at success in terms of procedure? absolute freedom from AF in week-long monitoring, it is Dr. Kowal: I explain that the procedure to electrically low. If we define success in terms of patient satisfaction, isolate the pulmonary veins has a 70% to 75% success rate. however, it is quite decent. In addition to the standard vascular complications of any Dr. Friedewald: Patient satisfaction means fewer symp- electrophysiology study, there is about a 1% risk each of toms. What are the symptoms of AF? stroke, perforation with tamponade, and pulmonary vein Dr. Kowal: The classic symptoms are palpitations, light- stenosis—which is probably higher than the actual current headedness, near-syncope—rarely outright syncope—and risk—plus less frequent risks for damage to adjacent struc- dyspnea with exertion. It is also very common for patients tures, such as the esophagus and pulmonary bronchus. to describe vague feelings, such an indescribable sense of There is also the risk for AF recurrence, especially during doom. Some patients with AF are “in tune” with every the first week after the procedure, because these lesions heartbeat. They check their pulse many times a day and often cause pericarditis that can independently trigger AF. It claim to be constantly going in and out of AF. Ambulatory is not uncommon for patients to have Ն3 episodes of AF monitoring, however, shows that they are not. I would like during the first week after the procedure, and then never to write a prescription for some patients not to take their have AF again. I also tell patients with paroxysmal AF that pulse. we will not know whether the procedure is successful until Dr. Roberts: The frequency of systemic hypertension, a month or 2 later, and for patients with persistent AF, the especially systolic hypertension, increases with age. Since cure may not occur until 4 or more months later. Done the LA cavity increases in size in both hypertension and in properly, it is a time-consuming discussion. AF, if hypertension were better controlled than the current Dr. Roberts: How do you administer anticoagulants? 30% control rate, would there be fewer cases of AF? Dr. Valderrabano: Not everybody with AF needs war- Dr. Valderrabano: That is a reasonable assumption. In farin, but everybody after an atrial ablation needs warfarin many patients I see for AF ablation, I see high LA pressures for at least 3 months because there is a risk of stroke, and large P waves in the absence of significant mitral 680 The American Journal of Cardiology (www.AJConline.org) regurgitation. This indicates a stiff left ventricle with high 80 years, it might be justified for this purpose. The proce- LA pressures, even with undiagnosed hypertension. In some dure, however, would have to be improved, and we would such patients I have begun antihypertensive treatment after need long-term outcome trials to determine whether we the procedure. There may also be a role for treating AF with could safely lessen the incidence of persistent AF after age angiotensin-converting enzyme inhibitors by modifying the 70 by such a prophylactic approach. milieu of the LA wall. Dr. Friedewald: Does a patient with an acute myocar- Dr. Kowal: Angiotensin-converting enzyme inhibitors dial infarction have a worse prognosis if they had prior and angiotensin receptor blockers reduce the recurrence risk persistent AF? of AF, probably because of their role in altering LA remod- Dr. Roberts: I do not know the answer. Is the outcome eling. among patients with coronary bypass operations worse Dr. Roberts: How often is the first episode of AF part of when they develop AF—which is common after this oper- a serious event, such as a stroke? ation—compared to those who stay in sinus rhythm? Dr. Valderrabano: In the absence of some other abnor- Dr. Valderrabano: Postoperative AF is a distinct entity mality, such as hypertension or a plaque in the aortic arch, due to pericardial inflammation caused by the right atrial I do not believe that a single episode of AF, lasting a few cannula inserted during coronary bypass surgery. I am not hours, is enough to generate a clot that would become an aware of any studies correlating postoperative AF with embolus. surgical outcome or future paroxysmal AF beyond the im- Dr. Kowal: My sense is that people who present with a mediate postoperative period. stroke and AF have had asymptomatic AF that had been Dr. Roberts: In 1900, the average age of death in the going on for quite a while. It is surprising how many USA was 47 years, the average age of death in 2000 was 77 persons with AF have no symptoms. Those are the people in years, and the average age of death in 2100 will probably be most danger for a stroke, because they have no warning 100ϩ years. Since AF clearly increases with age, this is system. going to be a very common condition in 2100. Dr. Valderrabano: And those are the people who are Dr. Kowal: What we do not know is whether the patients not candidates for ablation. who have AF have been selected out by age 100 years. Dr. Roberts: Because they are not symptomatic? Dr. Valderrabano: The prevalence of AF plateaus in Dr. Valderrabano: Correct. What ablation does best is older years, so I do not anticipate an epidemic of AF during eliminate symptoms, not eliminate the risk of stroke. the next 100 years. Dr. Roberts: The entity lipomatous hypertrophy of the Dr. Friedewald: Is the overall incidence of AF increas- atrial septum occurs in some obese patients, who also have ing because of the aging population? fat in other portions of the heart as well. Is there any data on Dr. Kowal: The aging population is part of the reason, weight loss as a therapy for atrial arrhythmias? but there is also an independent increase in the frequency Dr. Valderrabano: Not that I am aware of. of AF in the general population. Today, for any given age Dr. Kowal: I do not know the answer but I believe group, there is a higher prevalence of AF than there was weight loss should be encouraged for patients with AF, 20 years ago, and we do not know the reason for the because their symptoms will lessen with decreased body increase. weight. Dr. Roberts: I have not seen any studies of AF fre- Dr. Valderrabano: Weight loss also lowers blood pres- quency in the metabolic syndrome, but I wonder if the sure, which in turn reduces LA pressure and favorably metabolic syndrome is a factor for the increased prevalence affects AF control. of AF, with the escalating frequency of obesity. Dr. Roberts: Does not almost everyone with AF have a Dr. Kowal: That is possible and needs to be studied. It dilated left atrium? is also possible we are diagnosing AF in young people more Dr. Kowal: Some younger patients with paroxysmal AF often, since we can do something about it. A genetic pre- do not have LA dilatation. disposition to AF also accounts for more patients with AF in Dr. Friedewald: How often do young persons with par- young patients than we found in the past. oxysmal AF eventually develop persistent AF? Dr. Friedewald: What is the role of antiarrhythmic Dr. Kowal: The conversion from paroxysmal AF to drugs in patients you ablate for AF? persistent AF is about 30% at 3 years. It is not entirely Dr. Valderrabano: I prefer to do the ablation on patients age-related, however. I did a successful ablation on an who have been receiving at least 1 antiarrhythmic drug, and 80-year-old woman—a competitive athlete—with true par- I like to continue the antiarrhythmic medication for at least oxysmal AF, so AF is not necessarily permanent with ad- 2 to 3 months after the procedure. vanced age. Dr. Friedewald: What antiarrhythmics do you use? Dr. Friedewald: Is prevention of future persistent AF an Dr. Valderrabano: That depends on the patient and indication for ablation of paroxysmal AF? whether there is or is not structural heart disease. For Dr. Valderrabano: That would be a theoretical promise younger patients, I start with propafenone or flecainide and that I would have a hard time selling to a patient who was continue it after the procedure. satisfied with medical control of paroxysmal AF. Dr. Roberts: What medication do you use for the Dr. Kowal: You bring up a good point, however, from 75-year-old patient who presents with the first episode of the public policy point of view. If ablation of paroxysmal AF? AF in persons age 50 to 60 years reduces by 50% the Dr. Valderrabano: More than age, the medication used number of people who develop persistent AF by age 70 to is determined by whether there is structural heart disease Roundtable Discussion/Ablation of Atrail Fibrillation 681 present. If there is minor left ventricular hypertrophy, the diologists should be more proactive in referring them for LA cavity only mildly dilated, and no myocardial isch- ablation evaluation? emia—documented by a negative stress test—I start with Dr. Kowal: Absolutely, yes. propafenone, a fairly safe drug. Dr. Valderrabano: All physicians need to be more Dr. Kowal: For patients with coronary arterial disease aware that many young patients with AF can be cured with and an ejection fraction that is not profoundly depressed, ablation. sotalol is a reasonable choice. Patients with left ventricular Dr. Friedewald: How often is paroxysmal AF part of the dysfunction, however, are a real challenge, and our options preexcitation syndrome, and how does that impact the type for those patients are amiodarone and dofetilide. If there is of procedure you perform? a defibrillator in place, sotolol also may be given to them. Dr. Kowal: In those patients, particularly younger pa- Dr. Friedewald: What ␤ blocker do you use for con- tients, when we ablate the accessory pathway, the incidence trolling the ventricular rate in AF? of AF drops dramatically. I would not do pulmonary vein Dr. Valderrabano: I start with 25 to 50 mg of atenolol, isolation in someone who has not had the accessory path- depending on the patient size and the heart rate during way ablated first. episodes of AF. After ablation, I give a minimum dose of 25 Dr. Friedewald: What is atypical atrial flutter, which is mg atenolol for women and 50 mg for men. reported as a complication of ablation? Dr. Roberts: What is the current approach to rate control Dr. Kowal: I’ll start by defining typical atrial flutter, versus conversion to sinus rhythm? which accounts for about 95% of the atrial flutter that we Dr. Kowal: In the minimally symptomatic patient aged see in patients without instrumentation to their atria. This is Ͼ65 years, a mortality benefit does not occur from an a short supraventricular reentrant tachycardia involving the approach of repeatedly trying to maintain sinus rhythm with tricuspid annulus, usually in a counterclockwise direction repeated use of antiarrhythmic drugs and cardioversion ver- when looking from the ventricle back to the atrium. This is sus an approach with rate control and anticoagulation. That a well-defined circuit that is relatively easy to ablate. being said, patients are better off in sinus rhythm than in AF Atypical atrial flutter refers to a rapid atrial reentrant whenever possible. Atrioventricular junction ablation and rhythm that occurs in sites other than the tricuspid annulus. pacemaker implantation is a good procedure for reducing Classic examples would be atrial flutter in the region of a symptoms in patients with AF who are drug refractory, have residual scar from a prior right atriotomy to fix an atrial poor rate control, and are not good candidates for ablation septal defect or around the mitral annulus in a patient with for pulmonary vein isolation. a surgically-produced Maze procedure in the past. Dr. Valderrabano: They should also be on warfarin. Dr. Friedewald: Does atypical flutter have the same Dr. Roberts: What about the patient with hypertrophic electrocardiographic appearance as typical flutter? cardiomyopathy and AF? That is a dangerous combination, Dr. Kowal: Its electrocardiographic appearance varies is it not? considerably, and it can be quite difficult to determine its Dr. Valderrabano: There are data supporting the effi- origin on that basis alone, especially when there have been cacy of ablation in such patients, but I have no personal extensive lesions that affect the P-wave morphology. Inter- experience. estingly, these tachycardias can cause more symptoms than Dr. Kowal: There are also data indicating that success AF, because they may have persistent, rapid ventricular rates decrease as left ventricular hypertrophy increases. rates. Dr. Friedewald: There are more than 2 million persons Dr. Roberts: Why is atrial flutter so much less common in the USA with AF, but in 2002, only 5,000 people re- than AF? ceived ablation. It appears that a lot of patients who might Dr. Kowal: I do not know. People used to say that atrial benefit are not receiving ablation. Are a lot of patients being flutter was not a stable rhythm, but we have learned in the referred and rejected, or is the main reason that they are last 15 years that it can be a very stable rhythm. Patients can simply not being referred for possible ablation? have atrial flutter for months. Dr. Kowal: It is a combination of both factors, but Dr. Friedewald: Patients with atrial flutter, however, clearly there are huge numbers of patients who would ben- tend to be more symptomatic than patients with AF? efit who are never evaluated by an electrophysiologist. Dr. Valderrabano: Yes. That is due to the conduction Dr. Friedewald: Why not? rate. The atrioventricular node more readily conducts flutter Dr. Kowal: There are many reasons, including educa- than AF because in AF it gets bombarded irregularly at 400 tion, skepticism, access, and reimbursement. beats/min, whereas in atrial flutter the atrioventricular node Dr. Valderrabano: We also do not have enough elec- can get stuck in a 2:1 conduction pattern with fast ventric- trophysiologists who know how to do the procedure, be- ular rates. cause it is so involved and requires a lot of training. Dr. Friedewald: It is difficult to understand why more Dr. Friedewald: Are you so saturated with patients that atrial flutter patients are not routinely referred for an elec- you cannot handle any more? trophysiology evaluation and possible ablation. Dr. Valderrabano: No, we could take more patients. Dr. Valderrabano: We need a lot more physician edu- Dr. Kowal: I agree, we can take more patients, and we cation about atrial flutter. I teach the fellows and residents have made our systems more efficient so we can accommo- that I want to know about any case of atrial flutter, because date more patients. we can treat it with ablation. Dr. Friedewald: Because there appear to be so many Dr. Kowal: Atrial flutter ablation is so successful that it more patients who might benefit, do you suggest that car- should be performed before giving an antiarrhythmic drug, 682 The American Journal of Cardiology (www.AJConline.org) but that is often not what occurs in practice. Many atrial Dr. Friedewald: Do you know of any specifically? flutter patients, unfortunately, are treated with amiodarone. Dr. Kowal: Some companies are looking at atrial-spe- Dr. Roberts: Can atrial flutter ablation be performed cific drugs targeting AF. In the past, such drugs have been quickly? disappointing. If we can restrict a drug’s effects to the atria, Dr. Kowal: Yes, reasonably quickly, depending on the then a lot of the complications and side effects may be thickness of the tissue. It is a much less complex procedure minimized. than AF ablation. Dr. Roberts: Pharmaceutical companies are a little hes- Dr. Roberts: How often does AF ablation involve sites itant about introducing such drugs, are they not? outside the left atrium? Dr. Kowal: Yes, mostly because of ventricular proar- Dr. Kowal: Some people have non-pulmonary vein foci. rhythmias and side effects. I do not believe we can hang our These other sites are located in the wall bordering the hopes on a drug. For future ablation, there may be an easier coronary ostium, coronary sinus wall, superior vena caval technology to isolate the pulmonary veins more quickly, wall, and occasionally the lateral LA wall. The common more safely, more efficaciously, and more reproducibly. feature of all these sites is a venous structure connecting There will be more advances in technology allowing better into myocardium. There is something about such structural identification of sites driving AF outside of the pulmonary interfaces that is proarrhythmic. veins. Dr. Roberts: Can these sites be ablated without entering Dr. Valderrabano: Another advance would allow us to the left side of the heart? delineate the mechanisms of AF in each patient before the Dr. Kowal: Yes, when the source can be determined to procedure so that we can design a procedure that is more be on the right side of the heart. mechanistically sound. Currently, we are doing that in only Dr. Valderrabano: It is difficult to be certain that a a gross fashion. I also believe the procedure is going to specific case of AF originates in the right atrial wall. become more uniform across centers worldwide. The best Dr. Roberts: Do you routinely anticoagulate patients outcomes at present are where large numbers of patients are with persistent AF? being treated with ablation, because ablation demands a lot Dr. Kowal: Yes, and I also anticoagulate patients with of technical expertise. With advances in technology the paroxysmal AF who have other significant risk factors, procedure is going to become more standardized and such as left ventricular hypertrophy, poorly-controlled achieve comparable results everywhere. hypertension, prior transient ischemic attacks or stroke, Dr. Friedewald: Thank you. diabetes mellitus, coronary artery disease, and chronic heart failure. Dr. Friedewald: Since there are so many unanswered Needs Assessment: The need for this activity for cardi- questions about the long-term outcome, is there a registry ologists and other healthcare specialists in cardiovascular 1,3,6 where patients who have had ablation are being followed? medicine is based on the following : Dr. Kowal: Through our physician group and the hos- 1. AF is a common condition that is increasing in fre- pital—because other groups in the hospital perform the quency in all age groups. procedure—we are in the process of developing a registry to 2. Untreated AF carries serious complications, including follow these patients. sudden death. Dr. Valderrabano: We have a very similar situation. I 3. Many patients with AF do not respond well to med- started a registry at The Methodist Hospital, and we are ical therapy. trying to extend it to the rest of Houston. Some major 4. Radiofrequency ablation is curative in many patients institutions, such as the Mayo Clinic and The Cleveland with AF. Clinic, have registries, but we need “real-world” data from other than major centers to study efficacy and complica- Target Audience: This activity is designed for cardiol- tions, because we need to learn how to optimize this pro- ogists and all other health care specialists caring for patients cedure. with acute and chronic coronary heart disease. Dr. Kowal: There is a concerted effort in the field of CME Credit: The A. Webb Roberts Center for Continu- electrophysiology to try to get more such multicenter ing Medical Education of Baylor Health Care System, Dal- studies to look at outcomes, complications, success rates, las, designates this educational activity for a maximum of and potential benefits that we have never looked at be- 0.5 AMA PRA Category 1 Credit.™ Physicians should only fore. For example, Doug Packer at the Mayo Clinic is claim credit commensurate with the extent of their partici- starting a multicenter trial that will look at the more pation in the activity. difficult patients with AF who have risk factors for stroke The A. Webb Roberts Center for Continuing Medical and mortality. Education for Baylor Health Care System, Dallas, is accred- Dr. Friedewald: Because the ablation procedure is con- ited by the Accreditation Council for Continuing Medical stantly evolving acquiring sufficient numbers of patients Education to provide continuing medical education for necessary for accurate outcome studies is difficult. physicians. Dr. Kowal: Yes. Someone presents a new approach at every major meeting on this topic. CME Instructions: After reading this article, go online Dr. Friedewald: What is the future for AF ablation? at www.AJConline.org to register, complete a post-test with Dr. Kowal: There may be some promising things on the a minimum score of 80%, complete an evaluation and print drug front. a certificate. Roundtable Discussion/Ablation of Atrail Fibrillation 683

Combination of Media: Print and Internet 3. Rosamund W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase Computer Requirements: Windows 2000, Pentium 3 N, Ho M, Howard V, Kissela B, et al. Heart disease and stroke statis- or greater, 512 RAM, 80 gigabytes storage tics—2007 update. Circulation 2007;115:e69–e171. 4. Haissaguerre M, Jasi P, Shah DC, Takahashi A, Hocini M, Quiniou G, Estimated Time to Complete: 1 hour Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous Release Date: August 2007 initiation of atrial fibrillation by ectopic beats originating in the pulmo- Termination Date: August 2008 nary veins. N Engl J Med 1998;339:659–666. 5. Stedman’s Medical Dictionary, 25th Ed. Baltimore, MD: Williams and 1. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Wilkins, 1990. Singer DE. Prevalence of diagnosed atrial fibrillation in adults. JAMA 6. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen 2001;285:2370–2375. KA, Halperin JL, Le Heuzey J-Y, Kay GN, Lowe JE, et al. ACC/AHA/ 2. Halperin JL, Hart RG. Atrial fibrillation and stroke: new ideas, persist- ESC 2006 Guidelines for the management of patients with atrial fibril- ing dilemmas. Stroke 1988;19:937–941. lation. Circulation. 2006;114:700–752. Evidence for the Continued Safety and Tolerability of Fixed-Dose Isosorbide Dinitrate/Hydralazine in Patients With Chronic Heart Failure (the Extension to African-American Heart Failure Trial)

Clyde W. Yancy, MDa, Jalal K. Ghali, MDb, Virginia M. Bramanc, Michael L. Sabolinski, MDc, Manuel Worcel, MDc, W. Tad Archambault, PhDd, and Joseph A. Franciosa, MDe,*

The benefits of fixed-dose combination isosorbide dinitrate plus hydralazine (ID/H) in African-Americans with heart failure (HF) were established by the African-American Heart Failure Trial (A-HeFT), which was terminated early because of a significant survival benefit of ID/H. The Extension to A-HeFT trial (X-A-HeFT), designed to make ID/H available for ethical reasons after A-HeFT termination, afforded an opportunity to further observe responsiveness and compliance with ID/H. In total 198 patients completing the A-HeFT took ID/H for an additional 209 ؎ 116 days. Their age (57 ؎ 13 years), cause and duration of HF, and HF medications were not different from all A-HeFT patients. New York Heart Association class at X-A-HeFT baseline was >III in 51% of patients versus 100% of all patients at A-HeFT baseline, remained unchanged in most patients, improved in 24%, and worsened in only 9% during X-A-HeFT. The average number of ID/H tablets taken during X-A-HeFT was 3.7 ؎ 1.8 per day with compliance averaging 87 ؎ 25%. The most common adverse events, headache (34%) and dizziness (16%), were less than in patients taking ID/H in A-HeFT, with only 6% discontinuations for adverse events. The 6% annualized mortality rate in X-A-HeFT was the same as for ID/H in A-HeFT. There were no statistically significant differences in baseline characteristics or outcomes in X-A-HeFT patients analyzed according to their A-HeFT randomization. In conclusion, these results confirm the good compliance, tolerability, and responsiveness, with low mortality and improved symptoms, during treatment with ID/H observed in A-HeFT. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:684–689)

The excess burden of heart failure (HF) and different re- primary objective of X-A-HeFT was to observe clinical sponsiveness of African-American patients to HF treat- responses, tolerability, and compliance to continued treatments prompted the African-American Heart Failure Trial ment with ID/H. (A-HeFT), which compared fixed-dose combination isosorbide dinitrate plus hydralazine (ID/H) or placebo added with Methods standard therapy of HF, including ␤ blockers and angioten- The design and overall results of A-HeFT have been pub- sin-converting enzyme inhibitors, in 1,050 self-declared Af- 4,5 rican-Americans with symptomatic HF.1–5 The benefits of lished. In brief, A-HeFT was a double-blinded, random- ID/H in African-Americans with HF were clearly estab- ized, placebo-controlled study of African-American patients lished by A-HeFT, which was terminated early because of with stable symptomatic HF while on standard therapy, including but not limited to angiotensin-converting enzyme significantly higher mortality in the placebo group versus ␤ the ID/H group.5 Because of this truncation of A-HeFT inhibitors, blockers, diuretics, and/or digoxin. Patients due to clear benefits of ID/H, it was deemed ethically had to have left ventricular (LV) dysfunction defined as LV ejection fraction Յ35% or LV internal end-diastolic diam- necessary to make ID/H available to any former A-HeFT Ͼ Ͻ patients, and the Extension to A-HeFT trial (X-A-HeFT) eter 6.5 cm plus LV ejection fraction 45%. Eligible was designed. Because the mean duration of treatment ex- patients were randomized to ID/H or placebo, 3 times/day, posure in A-HeFT was 10 months, X-A-HeFT offered an with titration to targets of ID 120 mg/day and H 225 mg/day opportunity to observe additional exposure to ID/H. The (i.e., 2 tablets 3 times/day). All patients were to be treated and followed for a maximum of 18 months or until the last patient randomized had completed 6 months of treatment aBaylor University Medical Center, Heart and Vascular Institute, Dal- and follow-up, whichever occurred first. The primary effi- las, Texas; bWayne State University School of Medicine, Detroit, Michi- cacy end point consisted of a composite score calculated gan; cNitroMed, Inc., Lexington, Massachusetts; dVirtu Stat, Ltd., North from change from baseline in 6-month quality of life mea- Wales, Pennsylvania; and eMt. Sinai School of Medicine and Weill Cornell surement, death from any cause, and first hospitalization Medical College, New York, New York. Manuscript received January 27, for HF. 2007; revised manuscript received and accepted March 19, 2007. This work was supported by NitroMed, Inc., Lexington, Massachusetts. Patients in X-A-HeFT: All investigator sites and their *Corresponding author: Tel: 212-879-2366; fax 212-879-2238. patients who completed A-HeFT or were still active, i.e., E-mail address: [email protected] (J.A. Franciosa). were at least in the prerandomization stabilization phase of

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.086 Heart Failure/Continued Responsiveness to Isosorbide Dinitrate/Hydralazine 685

Table 1 Baseline characteristics of patients Characteristic All Patients Patients on ID/H Patients on Placebo p Value (n ϭ 198) in A-HeFT in A-HeFT (ID/H vs placebo in A-HeFT) (n ϭ 84) (n ϭ 109) Age (yrs) 57 Ϯ 13 57 Ϯ 12 57 Ϯ 13 0.7887 Women 84 (43%) 43 (51%) 39 (36%) 0.0277 Cause of HF* 0.6417 Ischemic 48 (25%) 26 (26%) 22 (24%) Idiopathic 49 (25%) 17 (20%) 32 (29%) Hypertension 74 (38%) 34 (41%) 40 (37%) Other 22 (12%) 11 (13%) 11 (10%) Previous myocardial infarction 58 (29%) 19 (23%) 37 (34%) 0.0856 Hypertension 186 (94%) 83 (99%) 98 (90%) 0.0111 Diabetes mellitus 81 (41%) 38 (45%) 41 (38%) 0.2856 Weight (kg) 98 Ϯ 27 95 Ϯ 26 98 Ϯ 34 0.4308 Heart rate (beats/minute)* 73 Ϯ 12 74 Ϯ 14 72 Ϯ 11 0.3081 Systolic blood pressure (mm Hg)* 126 Ϯ 18 125 Ϯ 17 127 Ϯ 20 0.4099 Diastolic blood pressure (mm Hg)* 76 Ϯ 11 75 Ϯ 10 76 Ϯ 11 0.5252 HF status Duration (yrs)* 4.9 Ϯ 4.9 5.2 Ϯ 5.7 4.7 Ϯ 4.1 0.4645 NYHA class 0.0200 I 15 (8%) 3 (4%) 12 (11%) II 82 (41%) 47 (56%) 34 (31%) III 99 (50%) 34 (40%) 61 (56%) IV 2 (1%) 0 (%) 2 (2%)

*nϭ 193 for all patients.

Table 2 Course of patients during A-HeFT Characteristic All Patients Patients on ID/H Patients on Placebo p Value (n ϭ 193) in A-HeFT in A-HeFT (ID/H vs placebo in A-HeFT) (n ϭ 84) (n ϭ 109) Hospitalizations for HF 17 (9%) 7 (8%) 10 (%) 0.8047 Unscheduled clinic visits for HF 2 (1%) 0 (0%) 2 (2%) 0.5058 Change in NYHA class 0.4812 Improved 79 (41%) 37 (44%) 42 (38%) Unchanged 112 (58%) 47 (56%) 65 (60%) Worsened 2 (1%) 0 (0%) 2 (2%) Change in LV ejection fraction (units)* 3.3 Ϯ 8.6 4.7 Ϯ 8.3 1.9 Ϯ 8.8 0.0677 Change in LV internal diastolic dimension (cm)† Ϫ0.08 Ϯ 1.11 Ϫ0.20 Ϯ 0.89 0.03 Ϯ 1.28 0.2425 Compliance (%) 86 Ϯ 32 89 Ϯ 32 83 Ϯ 32 0.2638 Most frequent adverse events Headache 59 (31%) 38 (46%) 21 (19%) Ͻ0.0001 Dizziness 35 (18%) 28 (34%) 7 (7%) Ͻ0.0001 Pain 30 (16%) 14 (17%) 16 (15%) 0.8414 Hypotension 13 (7%) 13 (16%) 0 (%) Ͻ0.0001 Dyspnea 19 (10%) 3 (4%) 16 (15%) 0.0131

*nϭ 127 for all patients; † n ϭ 128 for all patients.

A-HeFT at its premature termination, were offered enroll- Study design and procedures: At their last A-HeFT ment in X-A-HeFT. To be eligible for X-A-HeFT partici- study visit after discontinuing the blinded study drug or as pation, the center had to obtain institutional review board soon as possible thereafter at the investigator’s discretion, approval and patients had to provide written informed con- eligible patients were enrolled in X-A-HeFT. Investigators sent. Patients had to have New York Heart Association and their patients remained blinded to patients’ A-HeFT (NYHA) class I to IV HF symptoms while receiving stable randomization at time of enrollment in and throughout the standard HF therapy. The same inclusion/exclusion criteria course of X-A-HeFT. It should be noted that many centers from A-HeFT also had to be satisfied, e.g., patients could and their patients had completed participation in A-HeFT not be pregnant, have uncontrolled hypertension, symptom- well before its premature termination and start-up of X-A- atic hypotension, or any condition that might jeopardize the HeFT. Thus, only 56 A-HeFT centers chose to participate in evaluation of safety, and could not be further selected ac- X-A-HeFT. For those who did participate, enrollment into cording to HF duration, cause, or severity.4,5 X-A-HeFT was delayed to allow for retrieval of patients 686 The American Journal of Cardiology (www.AJConline.org) who had completed A-HeFT earlier and to allow for institutional review board approval. Average time between end of A-HeFT and start of X-A-HeFT was 191 Ϯ 156 days (range 30 to 852). Enrolled patients underwent baseline assessments including demographic information, medical history, cause of HF, NYHA class, recording of all concomitant medications, physical examination, electrocardiogram, and laboratory measurements. A patient was then dispensed open-label ID/H and started on 1 tablet (containing ID 20 mg plus H 37.5 mg) 3 times per day. The patient was instructed to take the first dose within the next 12 hours and to continue taking the subsequent doses 3 times per day, at approximately 9 A.M., 3 P.M., and 9 P.M. This approximately 12-hour nitrate-free interval and the known effects of hydralazine likely pre- Figure 1. Compliance with ID/H (black bars) or placebo (hatched bars) vented nitrate tolerance.5 A telephone call or clinic visit was treatment according to A-HeFT randomization. No differences are statis- scheduled within 2 weeks when the patient was instructed to tically significant. increase the dose of study medication to 2 tablets 3 times per day if the study drug was being well tolerated (to achieve the target maintenance dose of ID 120 mg/day and H 225 mg/day). Patients were to be treated and followed up to 12 months or until ID/H received US Food and Drug Administration approval, whichever came first. Patients were seen every 3 months with observations including history and physical examination, adverse events, concomitant medications, and NYHA class. At each visit patients returned the study medication and tablet counts were performed to measure patient compliance. Primary end points were compliance with the study drug measured by counts of tablets dispensed and returned at each visit and safety and tolerability indicated by the frequency of adverse events. Secondary end points included change in NYHA class and clinical outcomes of death and Figure 2. Survival by Kaplan-Meier analysis according to A-HeFT ran- hospitalizations for HF. Although not prespecified as an domization. end point or adjudicated, hospitalizations for HF were captured as serious adverse events of worsening HF. Statistical analysis: Detailed statistical methods of A- HeFT have been reported elsewhere.4,5 Because X-A-HeFT was an open-label study, statistical methods used were descriptive, and sample size estimates are not relevant. This intention-to-treat analysis includes those eligible patients who were enrolled and received Ն1 dose of ID/H. The primary analysis used only available data and no imputa- tions were performed. Data were analyzed at study end for compliance measurements, with study end defined as completion of a final visit or the occurrence of death anytime after enrollment. Percent compliance was calculated as 100 times the ratio of numbers of tablets consumed to that prescribed (consumed ϭ issued Ϫ returned). Because A- HeFT treatment and course could have affected X-A-HeFT Figure 3. Changes in distribution in NYHA classes I (black bars),II results, patients were also grouped and compared according (hatched bars), III (dotted bars), and IV (cross-hatched bars);pՅ0.05 for to their A-HeFT randomization, i.e., ID/H or placebo. change in distribution from baseline to end of study.

Results randomized, 84 (44%) to ID/H and 109 (56%) to placebo. In Patients and their disposition: The ﬁrst patient was total 158 patients (80%) completed X-A-HeFT. Reasons for enrolled in X-A-HeFT in August 2004, and 198 patients not completing the study included withdrawal because of were enrolled and received Ն1 dose of ID/H. Of these 5 had adverse events in 12 (6%), loss to follow-up in 4 (2%), and not yet been randomized in A-HeFT, whereas 193 had been death in 8 (4%). The study was terminated in July 2005, Heart Failure/Continued Responsiveness to Isosorbide Dinitrate/Hydralazine 687

Table 3 Most common adverse events Characteristic All Patients Patients on ID/H in Patients on Placebo p Value (n ϭ 193) A-HeFT in A-HeFT (ID/H vs placebo (n ϭ 82) (n ϭ 111) in A-HeFT) Adverse events in Ն5% of all patients Headache, any 66 (34%) 26 (32%) 40 (36%) NS Dizziness 31 (16%) 14 (17%) 17 (15%) NS Exacerbation of HF 24 (12%) 12 (15%) 12 (11%) NS Chest pain 19 (10%) 12 (15%) 7 (6%) NS Pain 17 (9%) 8 (10%) 9 (8%) NS Respiratory infection 14 (7%) 8 (10%) 6 (5%) NS Dyspnea 13 (7%) 9 (11%) 4 (4%) NS Hypotension 12 (6%) 5 (6%) 7 (6%) NS Light headedness 5 (6%) 3 (4%) 7 (6%) NS Bronchitis 10 (5%) 3 (4%) 7 (6%) NS Serious adverse events in Ն2% of all patients Exacerbation of HF 19 (10%) 11 (13%) 8 (7%) NS Pneumonia 7 (4%) 4 (5%) 3 (3%) NS Cardiac arrest 6 (3%) 0 (0%) 6 (5%) Ͻ0.05 Chest pain 4 (2%) 0 (0%) 4 (4%) NS Syncope 4 (2%) 2 (2%) 2 (2%) NS Bronchitis 4 (2%) 2 (2%) 2 (2%) NS subsequent to approval of ID/H by the US Food and Drug significant differences according to A-HeFT treatment (Fig- Administration. Average study duration per patient was ure 1). 232 Ϯ 106 days, or about 7.6 months. Clinical outcomes: During X-A-HeFT 9% of patients Baseline patient characteristics: Demographic charac- were hospitalized for HF and 4% died, with no statistically teristics and HF status of patients at baseline are presented significant differences according to A-HeFT randomization. in Table 1. Overall annualized morality rate was also low at 6%, and Kaplan-Meier survival curves according to A-HeFT ran- Experience of X-A-HeFT patients in A-HeFT: As pre- domization are shown in Figure 2. sented in Table 2, X-A-HeFT patients showed no statisti- Changes in HF symptoms, as indicated by change in cally significant differences between groups in clinical out- NYHA class, are shown in Figure 3. Overall most patients comes or compliance with the treatment regimen during were unchanged, with 24% showing improved NYHA class A-HeFT. and only 9% showing worsened NYHA class during X-A- Adverse events in X-A-HeFT patients on their study HeFT. The greatest improvement in X-A-HeFT occurred in drugs during A-HeFT were as expected in this patient pop- patients in NYHA class III at baseline compared with other ulation, with headache, dizziness, and hypotension occur- classes (p Ͻ0.001). Of patients with class III at baseline, ring in a higher percentage of patients taking ID/H during 42% improved 1 to 2 classes, whereas only 1 patient (1%) A-HeFT and dyspnea occurring in a higher percentage of showed deterioration to class IV. These differences may patients taking placebo (Table 2). There were no differences relate to the fact that at baseline a higher percentage of observed between groups in frequency or type of serious patients treated with placebo in A-HeFT were in NYHA adverse events during A-HeFT. class III to IV and a lower percentage were in class I to II Dosing experience with ID/H: At their first follow-up (Table 1). 76% of patients reported the study drug being well tolerated Adverse events: The most common adverse events oc- with an average of only 19 Ϯ 24 days required to reach the curring during X-A-HeFT in all patients and in patients target dose, achieved by 67% of patients. Maintenance grouped according to A-HeFT randomization are presented doses averaged 3.7 Ϯ 1.8 tablets per day, equivalent to ID in Table 3. As expected, the most common adverse events 74 mg plus H 138 mg. Study drug was decreased in 22% of were headache and dizziness, which occurred overall at patients during titration and in 40% during maintenance. about the same frequency as in the X-A-HeFT patients who Although most patients in X-A-HeFT had received placebo took ID/H during A-HeFT. There were no statistically sig- during A-HeFT and were therefore new to ID/H in X-A- nificant differences between groups by A-HeFT randomiza- HeFT, there were no significant differences in dosing during tion in these same adverse events during X-A-HeFT. X-A-HeFT according to A-HeFT randomization. Study drug exposure and compliance: Total days on Discussion ID/H averaged 209 Ϯ 116 in all patients, with compliance averaging 87 Ϯ 25% during that time and no significant This experience of former A-HeFT patients receiving ID/H differences between groups according to A-HeFT treatment. again or anew for about 7 months confirms the overall Throughout X-A-HeFT compliance remained high with no A-HeFT experience. Average annual mortality of 6% and 688 The American Journal of Cardiology (www.AJConline.org) low rate of hospitalizations for HF in X-A-HeFT are virtu- vivors of A-HeFT and, hence, may represent selected good ally the same as in patients receiving ID/H in A-HeFT.5 The responders to ID/H and a lower-risk cohort of patients percentage of patients improving their NYHA class in X-A- originally taking placebo in A-HeFT. The population is HeFT was roughly comparable to the percentage of these further limited in that not all A-HeFT investigative sites and same patients improving on ID/H in A-HeFT. Further, pa- only a small portion of A-HeFT completers, i.e., 21%, tients enrolled in X-A-HeFT, i.e., A-HeFT survivors, were agreed to participate in X-A-HeFT. Some patients may have by definition at lower risk. The hospitalization rate for HF in declined participation because of difficulty complying with these patients during A-HeFT was essentially the same as in or tolerating their A-HeFT study drug. This may also have X-A-HeFT and did not differ by A-HeFT treatment during contributed to the low incidence of adverse events observed A-HeFT or X-A-HeFT. We also confirmed the safety and in X-A-HeFT. In addition, compliance in X-A-HeFT may tolerability of ID/H during X-A-HeFT because only 6% of have been favorably affected by the sponsor’s provision of patients were discontinued for adverse events and the per- study drug because ID/H was not yet approved for use in centage of patients reporting headache or dizziness was HF. Given the relatively small number of patients in the somewhat lower during X-A-HeFT than in all ID/H-treated present study, we did not analyze results in subgroups. patients in A-HeFT. However, such analyses have been reported recently for the These results demonstrate good compliance with the entire A-HeFT population and found consistent beneficial prescribed regimen of ID/H during the renewed exposure. effects of ID/H in subgroups by age, gender, baseline blood The 68% of patients achieving maintenance doses of ID/H pressure, history of chronic renal insufficiency, presence of of 3.8 tablets per day in A-HeFT was essentially the same as diabetes mellitus, and cause of HF.13 the 65% and 3.7 tablets, respectively, in X-A-HeFT. The We attempted to address some of these concerns by 87% compliance rate in X-A-HeFT was somewhat higher than comparing patients who entered X-A-HeFT according to the 80% rate of ID/H-treated patients in A-HeFT, further in- their A-HeFT treatment. Those X-A-HeFT patients treated dicating good tolerability. In addition, compliance in X-A- with placebo in A-HeFT had slightly less reversal of LV HeFT was not different between patients taking ID/H in A- remodeling, slightly more hospitalizations for HF, and HeFT and those for whom ID/H was a new treatment. slightly less improvement in NYHA class during A-HeFT Citing experience in the Vasodilator Heart Failure Trials than those treated with ID/H. These variables are known to (V-HeFT), current guidelines for HF management raise adversely affect survival in HF.14–16 Although we could not concerns over the continued efficacy of ID plus H because show any statistically significant differences in these vari- of frequent adverse effects and difficult compliance with a ables in our small sample, the slight but concordant differ- multiple-dose treatment regimen.6–8 In V-HeFT, using the ences may suggest that patients treated with placebo in individual components of ID plus H and requiring up to 16 A-HeFT were at higher risk for events during X-A-HeFT. tablets/day, headache occurred in about 75% and dizziness The present experience expands exposure of African- in Ͼ65% of patients. Total daily doses of I and H targeted Americans with HF to ID/H and confirms the safety, toler- in V-HeFT were also higher than in A-HeFT. In contrast, in ability, and compliance associated with this treatment, thus A-HeFT, requiring up to 6 tablets/day of ID/H, headache supporting efforts to get more African-Americans on this occurred in about 50% and dizziness in about 1/3 of patients therapy recommended by all current guidelines.6,17,18 taking ID/H, and these same adverse effects occurred in even fewer patients on ID/H in X-HeFT, i.e., about 1/3 of 1. Yancy CW. Heart failure in African Americans: a cardiovascular patients reporting headache and a little over 15% reporting enigma. J Card Fail 2000;6:183–186. dizziness. Nevertheless, the observed compliance rate of 2. Yancy CW, Strong M. The natural history, epidemiology, and prognosis of heart failure in African Americans. Congest Heart Fail 2004; 87% in X-A-HeFT was in the range of 85% to 90% con- 10:15–18. sidered successful in programs designed to increase medi- 3. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in cation compliance of patients with HF.9 This experience response to therapy for heart failure: analysis of the Vasodilator-Heart with ID/H may have important implications regarding the Failure Trials. J Card Fail 1999;5:178–187. necessary doses of ID plus H and possibly the use of generic 4. Franciosa JA, Taylor AL, Cohn JN, Yancy CW, Ziesche S, Olukotun A, Ofili E, Ferdinand K, Loscalzo J, Worcel W, for the A-HeFT individual components of ID plus H. Investigators. African-American Heart Failure Trial (A-HeFT): ratio- Another important finding of X-A-HeFT was the low nale, design, and methodology. J Card Fail 2002;8:128–135. rate of hospitalizations for HF. Hospitalization for condi- 5. Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand tions sensitive to ambulatory care are considered “prevent- K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN, for the African-American Heart Failure Trial Investigators. Combination of able” hospitalizations, and HF is among the most common isosorbide dinitrate and hydralazine in blacks with heart failure. causes of these, especially in African-Americans.10 Given N Engl J Med 2004;351:2049–2057. the burden of hospitalization for HF, increasing incidence of 6. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats HF, expected growth in the elderly population, and expected TG, Jessup M, Konstam MA, Mancini DM, Michl K, et al. American increase in the percentage of African-Americans in popula- College of Cardiology; American Heart Association Task Force on Ͻ Ͼ Practice Guidelines; American College of Chest Physicians; Interna- tions 65 and 65 years of age, the imperative to decrease tional Society for Heart and Lung Transplantation; Heart Rhythm hospitalizations for HF is substantial.10 Observations from Society. ACC/AHA 2005 guideline update for the diagnosis and man- A-HeFT already suggest a health economic benefit of ID/H agement of chronic heart failure in the adult: a report of the American from fewer hospitalizations and emergency room visits for HF, College of Cardiology/American Heart Association Task Force on 11,12 Practice Guidelines (Writing Committee to Update the 2001 Guide- which are also more prevalent in African-Americans. lines for the Evaluation and Management of Heart Failure): developed A major limitation of this study is its lack of concurrent in collaboration with the American College of Chest Physicians and controls. Further, patients enrolled in X-A-HeFT were sur- the International Society for Heart and Lung Transplantation: endorsed Heart Failure/Continued Responsiveness to Isosorbide Dinitrate/Hydralazine 689

by the Heart Rhythm Society. Circulation 2005;112(suppl):e154– 13. Taylor AL, Ziesche S, Yancy CW, Carson P, Ferdinand K, Taylor M, e235. Adams K, Olukotun AY, Ofili E, Tam W, et al, on behalf of the 7. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, African-American Heart Failure Trial Investigators. Early and sus- Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, et al. tained benefit on event-free survival and heart failure hospitalization Effect of vasodilator therapy on mortality in chronic congestive heart from fixed-dose combination of isosorbide dinitrate/hydralazine: con- failure: results of a Veterans Administration Cooperative Study. sistency across subgroups in the African-American Heart Failure Trial. N Engl J Med 1986;314:1547–1552. Circulation 2007;115:1747–1753. 8. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith 14. Goldberg RJ, Spencer FA, Farmer C, Meyer TE, Pezzella S. Incidence R, Dunkman WB, Loeb H, Wong M, et al. A comparison of enalapril and hospital death rates associated with heart failure: a community- with hydralazine-isosorbide dinitrate in the treatment of chronic con- wide perspective. Am J Med 2005;118:728–734. N Engl J Med gestive heart failure. 1991;325:303–310. 15. Jong P, Vowinckel E, Liu PP, Gong Y, Tu JV. Prognosis and deter- 9. Rich MW, Gray DB, Beckham V, Wittenberg C, Luther P. Effect of a minants of survival in patients newly hospitalized for heart failure: a multidisciplinary intervention on medication compliance in elderly population-based study. Arch Intern Med 2002;162:1689–1694. patients with congestive heart failure. Am J Med 1996;101:270–276. 10. Laditka JN, Laditka SB. Race, ethnicity and hospitalization for six 16. Gottdiener JS, McClelland RL, Marshall R, Shemanski L, Furberg CD, chronic ambulatory care sensitive conditions in the USA. Ethn Health Kitzman DW, Cushman M, Polak J, Gardin JM, Gersh BJ, Aurigemma 2006;11:247–263. GP, Manolio TA. Outcome of congestive heart failure in elderly 11. Angus DC, Linde-Zwirble WT, Tam SW, Ghali JK, Sabolinski ML, persons: influence of left ventricular systolic function. The Cardiovas- Villagra VG, Winkelmayer WC, Worcel M, for the African-American cular Health Study. Ann Intern Med 2002;137:631–639. Heart Failure Trial (A-HeFT) Investigators. Cost-effectiveness of 17. Adams KF, Lindenfeld J, Arnold JMO, Baker DW, Barnard DH, fixed-dose combination of isosorbide dinitrate and hydralazine therapy Baughman KL, Boehmer JP, Deedwania P, Dunbar SP, Elkayam U, et for blacks with heart failure. Circulation 2005;112:3745–3753. al. HFSA 2006 comprehensive heart failure practice guideline. J Card 12. Hugli O, Braun JE, Kim S, Pelletier AJ, Camargo CA Jr. United States Fail 2006;12(suppl):e1–e122. emergency department visits for acute decompensated heart failure, 18. Puckrein G. BiDil: from another vantage point. Health Aff (Millwood) 1992 to 2001. Am J Cardiol 2005;96:1537–1542. 2006;25(suppl):w368–374. Comparative Effectiveness of Beta-Adrenergic Antagonists (Atenolol, Metoprolol Tartrate, Carvedilol) on the Risk of Rehospitalization in Adults With Heart Failure

Alan S. Go, MDa,b,*, Jingrong Yang, MAa, Jerry H. Gurwitz, MDc, John Hsu, MD, MBA, MSCEa, Kimberly Lane, MPHd,e, and Richard Platt, MD, MScd,e

Placebo-controlled randomized trials have demonstrated the efficacy of selected ␤ blockers on outcomes in chronic heart failure (HF), but the relative effectiveness of different ␤ blockers in usual clinical care is poorly understood. We compared 12-month risk of rehospitalization for HF associated with receipt of different ␤ blockers in 7,883 adults hospitalized for HF within 2 large health plans between January 1, 2001 and December 31, 2002. Beta-blocker use was ascertained from electronic pharmacy databases and readmissions within 12 months were identified from hospital discharge databases. Extended Cox regression was used to examine the association between receipt of different ␤ blockers and risk of readmission for HF after adjustment for potential confounders. During follow-up, there were 3,234 person-years of exposure to ␤ blockers (39.3% atenolol, 42.0% metoprolol tartrate, 12.3% carvedilol, and 6.4% other). Crude 12-month rates of readmissions for HF were high overall (42.6 per 100 person-years). After adjustment for potential confounders, cumulative exposure to each ␤ blocker, and propensity to receive carvedilol compared with atenolol, adjusted risks of readmission were not significantly different for metoprolol tartrate (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.05) or for carvedilol (adjusted hazard ratio 0.92, 95% confidence interval 0.74 to 1.14). In conclusion, in a contemporary cohort of high-risk patients hospitalized with HF, we found that adjusted risks of rehospitalization for HF within 12 months were not significantly different in patients receiving atenolol, shorter-acting metoprolol tartrate, or carvedilol. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:690–696)

There have been few head-to-head randomized comparisons evaluated in future randomized trials, but any outcome within the available set of ␤ blockers that have examined differences by ␤-blocker type could have important re- clinical outcomes, and existing comparative ␤-blocker trials source, drug access, and policy implications. To address this have primarily involved carvedilol and shorter-acting meto- issue, we analyzed risk of rehospitalization for HF associ- prolol tartrate.1 In addition, few published clinical outcomes ated with receipt of different types of ␤ blockers in a studies exist in large populations in typical medical settings contemporary sample of adults hospitalized for HF. We of the comparative effectiveness of different ␤ blockers, hypothesized that adjusted readmission rates for HF would including atenolol, in patients with heart failure (HF).2 vary among different ␤ blockers. Given that many ␤ blockers are already in generic formu- lations, it is highly unlikely that they will be systematically Methods Study sample: Patients were identified from Kaiser Per- manente of Northern California (Oakland, California), a aDivision of Research, Kaiser Permanente of Northern California, Oak- b large integrated health care delivery system providing care land, and Departments of Epidemiology, Biostatistics, and Medicine, Ͼ University of California, San Francisco, San Francisco, California; and for 3.2 million patients, and Harvard Pilgrim Health Care cMeyers Primary Care Institute, University of Massachusetts Medical (Boston, Massachusetts), a not-for-profit network-based School and Fallon Foundation, Worcester, and dChanning Laboratory, health plan providing care to Ͼ900,000 members. The study Brigham and Women’s Hospital, and Department of Ambulatory Care and was approved by institutional review boards at collaborating Prevention, Harvard Medical School, and eHarvard Pilgrim Health Care, institutions and waiver of informed consent was obtained Boston, Massachusetts. Manuscript received August 2, 2006; revised given the nature of the study. manuscript received and accepted March 13, 2007. We identified adults hospitalized between January 1, This research was conducted by Kaiser Permanente of Northern Cali- 2001 and December 31, 2002 with a primary discharge fornia and Harvard Pilgrim Health Care under contract to the Agency for diagnosis of HF (International Classification of Diseases, Healthcare Research and Quality (Contract HHSA29020050033I), Rock- Ninth Edition codes 398.91, 402.01, 402.11, 402.91, 404.01, ville, Maryland. The authors are responsible for its content. No statement may be construed as the official position of the Agency for Healthcare 404.03, 404.11, 404.13, 404.91, 404.93, 428.0, 428.1, Research and Quality of the U.S. Department of Health and Human 428.20, 428, 21, 428.22, 428.23, 428.30, 428.31, 428.32, Services. 428.33, 428.40, 428.41, 428.42, 428.43, and 428.9). These *Corresponding author: Tel: 510-891-3553; fax: 510-891-2853. codes have a positive predictive value Ͼ95% for clinical HF E-mail address: [email protected] (A.S. Go). using Framingham criteria derived from medical records

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. www.AJConline.org doi:10.1016/j.amjcard.2007.03.084 Heart Failure/Comparative Effectiveness of Beta Blockers in Heart Failure 691 review.3 We excluded patients if they were Ͻ18 years old, Terminology codes and data sources available upon re- had a length of stay Ͻ24 hours, died during the index quest). Previous cardiovascular disease included acute cor- hospitalization, or did not have continuous membership and onary syndrome, angina pectoris, percutaneous coronary a pharmacy benefit for Ն12 months before the admission intervention, coronary artery bypass grafting, stroke or tran- date and Ն12 months after discharge or until censoring sient ischemic attack, and peripheral arterial disease.5 We during the first year after discharge. Of all initially identified used a previously validated approach6 to identify diabetes patients, 27% were excluded for Ն1 criterion. mellitus based on a primary hospital discharge diagnosis for diabetes mellitus or diabetic complication, Ն2 outpatient Exposure to beta blockers: Time-dependent exposure diagnoses of diabetes, and/or a filled prescription for an to ␤ blockers was identified from pharmacy databases dur- antidiabetic medication. Hypertension was based on having ing the 12 months before and after the index hospitalization, Ն2 outpatient diagnoses of hypertension or 1 outpatient including acebutolol, atenolol, bisoprolol, carvedilol, labe- diagnosis plus Ն1 filled prescription for an antihypertensive talol, metoprolol succinate, metoprolol tartrate, nadolol, medication.5 Dyslipidemia was defined as an outpatient pindolol, propranolol, sotalol, and timolol. These agents diagnosis for dyslipidemia or receipt of a lipid-lowering represented all oral ␤ blockers used within the open formu- medication.5 End-stage renal disease was identified by re- laries of the participating sites during the study period. We ceipt of renal replacement therapy or diagnosed chronic used data on filled outpatient prescriptions for ␤ blockers renal failure. We also identified chronic lung disease, and estimated the timing and duration of receipt of ␤ block- chronic liver disease, atrial fibrillation or atrial flutter, sys- ers based on estimated daily supply per prescription and temic cancer, and diagnosed dementia, psychiatric disorder, refill patterns. For any 2 consecutive prescriptions, we ex- or depression.5 We used data from filled outpatient prescrip- amined the time (in days) between the projected end date of tions to assign previous and postdischarge receipt of other the first prescription and the date of the next filled prescrip- cardiovascular medications that might influence outcomes tion. Given that dose adjustment is not uncommon, we including angiotensin-converting enzyme inhibitors, angio- allowed a “grace period” of 14 days between prescriptions. tensin II receptor blockers (ARBs), digoxin, diuretics, ni- Thus, if the time between the projected end date of the first trates, hydralazine, aldosterone receptor antagonists, cal- prescription and the fill date of the next prescription was cium channel blockers, ␣-adrenergic receptor antagonists, Յ14 days, we considered that subject continually receiving statins, and other lipid-lowering agents. We used the same ␤-blocker therapy. If the refill interval was Ͼ14 days, then approach as described above for ␤ blockers to characterize the subject was considered off ␤-blocker therapy starting time-dependent exposure to these medications. the day after the projected end date of the first prescription until the date of the next filled prescription, if any. For Statistical analysis: All analyses were performed using patients with Ͼ1 ␤-blocker prescription filled on the same SAS 9.0 (SAS Institute, Cary, North Carolina). We com- day, we used the prescription with the longest estimated pared baseline characteristics between groups of interest daily supply. Concurrent use of multiple ␤ blockers for HF using Student’s t test or Wilcoxon rank-sum test for con- is not clinically indicated,4 so if a patient filled a prescrip- tinuous variables and chi-square test for categorical vari- tion for a different ␤ blocker before the projected end date ables. For rate calculations and subsequent multivariable for an existing ␤-blocker prescription, the patient was con- modeling, we used the following categories for ␤-blocker sidered off the previous ␤ blocker as of the fill date of the exposure: atenolol, metoprolol tartrate, carvedilol, other ␤ later prescription for the different ␤ blocker. We also clas- blockers, and no ␤ blocker. Although use of long-acting sified total duration (in days) of exposure to each ␤ blocker metoprolol succinate was an a priori interest, it was included during the 12 months before and up to 12 months after the in the category of “other ␤ blockers” because too few index hospitalization by using the methods described above members received this agent. Age- and gender-adjusted and subtracting the total number of hospital days during this rates (per 100 person-years) of rehospitalization for HF period because hospitalized patients would receive medica- during the first 12 months after discharge by ␤-blocker tions from the hospital and not their own supply. exposure were calculated using Poisson regression with generalized estimating equations to account for clustering Rehospitalization for HF: Readmissions for HF during effects within subjects for exposure to specific ␤ blockers the 12 months after discharge were identified from hospital and for repeated nonfatal hospitalizations for HF. discharge databases using the same methods described for As an observational study of treatment and outcomes in identifying the cohort. Consecutive hospitalizations for HF clinical practice, there is a concern about treatment selection occurring within 3 days of each other were considered a bias. Because our primary goal was to examine differences single clinical episode. in readmission rates in patients with HF receiving different Covariates: Sociodemographic characteristics included types of ␤ blockers rather than a treatment versus no treat- age, gender, and insurance type identified from administra- ment comparison, the concern of treatment selection bias is tive databases. To account for possible temporal trends in somewhat attenuated. However, physicians might differen- HF severity, treatment, or outcomes, we also included cal- tially prescribe ␤ blockers for patients with more severe HF endar year and index hospitalization length of stay. We used (i.e., type of ␤ blocker received might be nonrandom), so hospital discharge diagnoses/procedures and ambulatory di- we calculated the likelihood of receiving carvedilol (the agnoses during the 12 months before the index hospitaliza- most specific ␤ blocker for HF in our analysis) using a tion to identify relevant co-morbidity (International Classi- propensity score method and assigned each patient into a fication of Diseases, Ninth Edition and Current Procedural decile of propensity score.7 We included all characteristics 692 The American Journal of Cardiology (www.AJConline.org)

Table 1 Baseline characteristics of 7,883 adults hospitalized with heart failure between January 1, 2001 and December 31, 2002 overall and between those receiving or not receiving a ␤ blocker at discharge and/or during follow-up Characteristic Overall On ␤ Blocker Off ␤ Blocker p Value (n ϭ 7,883) (n ϭ 5,385) (n ϭ 2,498) (␤ blocker vs no ␤ blocker) Age (yrs), mean Ϯ SD 74 Ϯ 12 73 Ϯ 12 75 Ϯ 12 Ͻ0.001 Age group (yrs) Ͻ0.001 Ͻ50 328 (4.2%) 237 (4.4%) 91 (3.6%) 50–64 1,402 (18%) 1,024 (19%) 378 (15%) 65–74 2,064 (26%) 1,483 (28%) 581 (23%) 75–84 2,743 (35%) 1,826 (34%) 917 (37%) Ն85 1,346 (17%) 815 (15%) 531 (21%) Women 3,946 (50%) 2,649 (49%) 1,297 (52%) Ͻ0.001 Calendar year of entry Ͻ0.001 2001 4,096 (52%) 2,655 (49%) 1,441 (58%) 2002 3,787 (48%) 2,730 (51%) 1,057 (42%) Insurance type 0.002 Medicare choice 5,875 (75%) 3,940 (73%) 1,935 (78%) Commercial 1,773 (23%) 1,275 (24%) 498 (20%) Self-pay 115 (1.5%) 84 (1.6%) 31 (1.2%) Medi-Cal/Medicaid 117 (1.5%) 84 (1.6%) 33 (1.3%) Other 3 (0%) 2 (0%) 1 (0%) Index length of stay (d), median (interquartile range) 3 (2–5) 3 (2–5) 3 (2–5) 0.002 Previous cardiovascular disease Acute coronary syndrome 1,050 (13%) 892 (17%) 158 (6.3%) Ͻ0.001 Angina pectoris 2,901 (37%) 2,215 (41%) 686 (28%) Ͻ0.001 Percutaneous coronary intervention 237 (3.0%) 206 (3.8%) 31 (1.2%) Ͻ0.001 Coronary artery bypass grafting 617 (7.8%) 513 (9.5%) 104 (4.2%) Ͻ0.001 Ischemic stroke or transient ischemic attack 300 (3.8%) 219 (4.1%) 81 (3.2%) 0.075 Peripheral arterial disease 456 (5.8%) 311 (5.8%) 145 (5.8%) 0.96 Diabetes mellitus 3,394 (43%) 2,414 (45%) 980 (39%) Ͻ0.001 Hypertension 4,284 (54%) 3,162 (59%) 1,122 (45%) Ͻ0.001 Dyslipidemia 2,947 (37%) 2,298 (43%) 649 (26%) Ͻ0.001 End-stage renal disease or chronic kidney disease 371 (4.7%) 267 (5.0%) 104 (4.2%) 0.121 Chronic lung disease 1,743 (22%) 944 (18%) 799 (32%) Ͻ0.001 Chronic liver disease 137 (1.7%) 91 (1.7%) 46 (1.8%) 0.63 Atrial ﬁbrillation or ﬂutter 1,927 (24%) 1,274 (24%) 653 (26%) 0.017 Systemic cancer 762 (9.7%) 487 (9.0%) 275 (11%) 0.006 Diagnosed dementia or psychiatric disorder 341 (4.3%) 193 (3.6%) 148 (5.9%) Ͻ0.001 Diagnosed depression 869 (11%) 593 (11%) 276 (11%) 0.96 Medications at baseline ␤ Blockers Acebutolol 2 (0%) 2 (0%) 0 (0%) 0.34 Atenolol 1,646 (21%) 1,618 (30%) 28 (1.1%) Ͻ0.001 Metoprolol tartrate 1,057 (13%) 1,024 (19%) 33 (1.3%) Ͻ0.001 Metoprolol succinate 3 (0%) 3 (0.1%) 0 (0%) 0.24 Carvedilol 244 (3.1%) 237 (4.4%) 7 (0.3%) Ͻ0.001 Bisoprolol 1 (0%) 1 (0%) 0 (0%) 0.50 Propranolol 77 (1.0%) 76 (1.4%) 1 (0%) Ͻ0.001 Sotalol 62 (0.8%) 60 (1.1%) 2 (0.1%) Ͻ0.001 Labetalol 24 (0.3%) 24 (0.4%) 0 (0%) Ͻ0.001 Pindolol 2 (0%) 2 (0%) 0 (0%) 0.34 Nadolol 11 (0.1%) 11 (0.2%) 0 (0%) 0.024 Timolol NA NA NA NA Angiotensin-converting enzyme inhibitor 2,863 (36%) 2,075 (39%) 788 (32%) Ͻ0.001 ARB 693 (8.8%) 512 (9.5%) 181 (7.2%) Ͻ0.001 Digoxin 1,507 (19%) 984 (18%) 523 (21%) 0.005 Diuretic 4,466 (57%) 3,083 (57%) 1,383 (55%) 0.12 Nitrate 1,883 (24%) 1,452 (27%) 431 (17%) Ͻ0.001 Hydralazine 499 (6.3%) 372 (6.9%) 127 (5.1%) 0.002 Aldosterone receptor antagonist 414 (5.3%) 271 (5.0%) 143 (5.7%) 0.20 Calcium channel blocker 1,903 (24%) 1,350 (25%) 553 (22%) 0.005 ␣-Adrenergic receptor antagonist 871 (11%) 644 (12%) 227 (9.1%) Ͻ0.001 Statin 2,342 (30%) 1,864 (35%) 478 (19%) Ͻ0.001 Other lipid-lowering therapy 52 (0.7%) 45 (0.8%) 7 (0.3%) 0.005 Heart Failure/Comparative Effectiveness of Beta Blockers in Heart Failure 693

Table 2 Baseline characteristics of 5,385 adults with heart failure between January 1, 2001 and December 31, 2002 and who received a ␤ blocker at discharge and/or during follow-up stratified by type of ␤* blocker received Characteristic Atenolol Metoprolol Tartrate Carvedilol Other (n ϭ 2,138) (n ϭ 2,250) (n ϭ 632) ␤ Blocker (n ϭ 365) Age (yrs), mean Ϯ SD 74 Ϯ 12 73 Ϯ 12‡ 68 Ϯ 13§ 77 Ϯ 11§ Age group (yrs) §§ Ͻ50 65 (3.0%) 99 (4.4%) 62 (9.8%) 8 (2.2%) 50–64 381 (18%) 438 (20%) 169 (27%) 35 (9.6%) 65–74 593 (28%) 614 (27%) 184 (29%) 87 (24%) 75–84 741 (35%) 755 (34%) 184 (29%) 145 (40%) Ն85 358 (17%) 344 (15%) 33 (5.2%) 90 (25%) Women 1,146 (54%) 1,096 (49%)‡ 210 (33%)‡ 197 (54%) Insurance type §‡ Medicare choice 1,593 (75%) 1,634 (73%) 378 (60%) 305 (84%) Commercial 405 (19%) 483 (22%) 198 (31%) 41 (11%) Self-pay 108 (5.1%) 101 (4.5%) 42 (6.6%) 14 (3.8%) Medi-Cal/Medicaid 32 (1.5%) 30 (1.3%) 14 (2.2%) 5 (1.4%) Other 0 (0%) 2 (0.1%) 0 (0%) 0 (0%) Index length of stay (days), median (interquartile range) 4 (3–6) 4 (3–6) 4 (3–6) 4 (3–6) Previous cardiovascular disease Acute coronary syndrome 343 (16%) 439 (20%)† 76 (12%)† 34 (9.3%)§ Angina pectoris 891 (42%) 956 (43%) 238 (38%) 130 (36%)§ Percutaneous coronary intervention 86 (4.0%) 88 (3.9%) 20 (3.2%) 12 (3.3%) Coronary artery bypass grafting 202 (9.4%) 231 (10%) 60 (9.5%) 20 (5.5%)† Ischemic stroke or transient ischemic attack 92 (4.3%) 94 (4.2%) 15 (2.4%)† 18 (4.9%) Peripheral arterial disease 114 (5.3%) 137 (6.1%) 37 (5.9%) 23 (6.3%) Diabetes mellitus 941 (44%) 1,016 (45%) 297 (47%) 160 (44%) Hypertension 1,375 (64%) 1,292 (57%)§ 272 (43%)§ 223 (61%) Dyslipidemia 911 (43%) 990 (44%) 268 (42%) 129 (35%)‡ End-stage renal disease or chronic kidney disease 92 (4.3%) 142 (6.3%)‡ 12 (1.9%)‡ 21 (5.8%) Chronic lung disease 338 (16%) 412 (18%)† 124 (20%)† 70 (19%) Chronic liver disease 31 (1.4%) 31 (1.4%) 16 (2.5%) 13 (3.6%)‡ Atrial fibrillation or flutter 508 (24%) 548 (24%) 123 (20%)† 95 (26%) Systemic cancer 204 (9.5%) 204 (9.1%) 49 (7.8%) 30 (8.2%) Diagnosed dementia or psychiatric disorder 87 (4.1%) 79 (3.5%) 17 (2.7%) 10 (2.7%) Diagnosed depression 243 (11%) 241 (11%) 69 (11%) 40 (11%) Medications at baseline, no. (%) Angiotensin-converting enzyme inhibitor 807 (38%) 864 (38%) 268 (42%)† 136 (37%) ARB 199 (9.3%) 198 (8.8%) 86 (14%)‡ 29 (7.9%) Digoxin 306 (14%) 419 (19%)§ 193 (31%)§ 66 (18%) Diuretic 1,214 (57%) 1,254 (56%) 393 (62%)† 222 (61%) Nitrate 576 (27%) 639 (28%) 155 (25%) 82 (23%) Hydralazine 132 (6.2%) 161 (7.2%) 52 (8.2%) 27 (7.4%) Aldosterone receptor antagonist 67 (3.1%)‡ 105 (4.7%)§ 84 (13%) 15 (4.1%) Calcium channel blocker 569 (27%) 583 (26%)§ 97 (15%) 101 (28%) ␣-Adrenergic receptor antagonist 272 (13%) 274 (12%)§ 47 (7.4%) 51 (14%) Statin 752 (35%) 800 (36%) 196 (31%) 116 (32%) Other lipid-lowering therapy 16 (0.7%) 15 (0.7%) 9 (1.4%) 5 (1.4%) Duration of previous ␤-blocker usage (d), median (interquartile range) Atenolol 323 (172–451) 0 (0–0)§ 0 (0–0)§ 0 (0–0)§ Metoprolol Tartrate 0 (0–0) 255 (111–358)§ 0 (0–0)‡ 0 (0–0)§ Carvedilol 0 (0–0) 0 (0–0) 254 (111–349)§ 0 (0–0) Other ␤ blockers 0 (0–0) 0 (0–0) 0 (0–0)† 297 (143–412)§

* Baseline deﬁned as the ﬁrst date of known exposure to ␤ blockers at or after discharge from the index hospitalization. † p Ͻ0.05; ‡ p Ͻ0.01; § p Ͻ0.001 versus atenolol. listed in Table 1 in the propensity score logistic regression ously reported to be associated with receipt of HF therapies model. or adverse outcomes in patients with HF. For all models, we We conducted multivariable extended Cox regression used a “sandwich” estimate of the variance/covariance ma- models to evaluate the relation between ␤-blocker type and trix to obtain SEs accommodating the clustering of obser- HF rehospitalization after adjustment for potential con- vations on subjects.8 We conducted a sensitivity analysis in founders. We included covariates based on variables previ- a subset of patients at 1 site who had documented left 694 The American Journal of Cardiology (www.AJConline.org) ventricular systolic dysfunction (ejection fraction Ͻ40% or moderate to severely decreased systolic function by qualitative assessment) and were receiving concurrent digoxin and ␤-blocker therapy because these were most likely to represent symptomatic patients with systolic HF.

Results Baseline characteristics in overall cohort and in those receiving versus not receiving beta blockers: During 2001 and 2002, we identified 7,883 eligible survivors of a hospitalization for HF. There was a high prevalence of previous cardiovascular disease and documented vascular risk factors, chronic lung disease, and atrial fibrillation/ flutter in cohort members. Within 30 days before admission, 40% of patients re- Figure 1. Age- and gender-adjusted rate of rehospitalization for HF by type ceived a ␤ blocker, with the most commonly used being of ␤ blocker received during the first 12 months after discharge in 7,883 atenolol and metoprolol tartrate, and relatively few patients adults hospitalized for HF between January 1, 2001 and December 31, receiving metoprolol succinate, carvedilol, or other ␤ block- 2002. Rates were calculated using Poisson regression with generalized ers (Table 1). Overall, 68% of patients received a ␤ blocker estimating equations (p ϭ 0.006, metoprolol tartrate vs atenolol; p ϭ at discharge and/or during the 12 months after discharge 0.007, carvedilol vs atenolol; p ϭ 0.429, other ␤ blockers vs atenolol; Ͻ from the index hospitalization. Patients receiving a ␤ p 0.001, no blockers vs atenolol). blocker were younger and less likely to be women, to be identified early in the study period, to have Medicare insur- Table 3 ance coverage, and to have lung disease, cancer, and de- Multivariable association between receipt of selected ␤ blockers on mentia or psychotic disorders. Conversely, patients receiv- 12-month rate of rehospitalization for heart failure in patients discharged ing a ␤ blocker were more likely to have previously alive from a hospitalization for heart failure between January 1, 2001 diagnosed cardiovascular disease, diabetes, hypertension, and December 31, 2002 known dyslipidemia, and atrial fibrillation or flutter (Table Type of ␤ Blocker Rehospitalization for HF Adjusted Hazard 1). Receipt of ␤ blockers after discharge was also associated Ratio (95% Confidence Interval)* with use of ␤ blockers before admission and previous use of angiotensin-converting enzyme inhibitors, ARBs, nitrates, hy- Atenolol Reference dralazine, aldosterone receptor antagonists, calcium channel Metoprolol tartrate 0.95 (0.85–1.06) ␣ Carvedilol 0.92 (0.74–1.14) blockers, -adrenergic receptor antagonists, and statins or Other ␤ blocker 1.31 (1.09–1.57) other lipid-lowering agents. No ␤ blocker 1.12 (1.03–1.22) Baseline characteristics by type of beta blocker re- * Models adjusted for time-varying individual ␤-blocker use, total du- ceived: At discharge from the index hospitalization or dur- ration of exposure to each ␤ blocker from 12 months before index hospi- ing follow-up, 5,385 cohort members received Ն1 ␤ talization throughout follow-up, health plan, age, gender, calendar year of entry, time-varying Medicare insurance coverage, index hospitalization blocker. Table 2 presents the distribution of baseline char- ␤ length of stay, previous hospitalization for HF, cardiovascular history, acteristics of treated patients by type of blocker. The other co-existing illnesses, time-varying use of other cardiovascular med- primary comparisons were metoprolol tartrate versus ateno- ications, and decile of baseline propensity score for receiving carvedilol. lol and carvedilol versus atenolol. Compared with patients receiving atenolol, minimal differences were noted for patients receiving metoprolol tartrate, who were slightly pared with metoprolol tartrate or carvedilol (Figure 1). younger and men; more likely to have a history of acute Compared with receipt of atenolol, readmission rate for HF coronary syndrome and kidney and lung diseases; receive was significantly higher for periods off ␤ blockers. digoxin, nitrates, and aldosterone receptor antagonists; but After adjustment for potential confounders, there was no less likely to have hypertension or receive calcium channel significant difference in relative risk of rehospitalization for blockers. However, those receiving carvedilol were more metoprolol tartrate or carvedilol compared with receipt of likely to be younger and men, to have commercial insurance atenolol (Table 3). Of note, there were higher adjusted risks coverage, and to have a lower prevalence of previous acute of rehospitalization associated with receiving other ␤ block- coronary syndrome, stroke or transient ischemic attack, hy- ers or not receiving ␤ blockers. In a sensitivity analysis of pertension, kidney disease, atrial fibrillation/flutter, and ␣ 664 patients with known left ventricular systolic function baseline calcium channel blocker or -adrenergic receptor and receiving concurrent digoxin and ␤-blocker therapy, antagonists. In contrast, those receiving carvedilol were readmission rates compared with receipt of atenolol were more likely to receive ARBs, digoxin, hydralazine, and not significantly different for metoprolol tartrate (adjusted aldosterone receptor antagonists at baseline. hazard ratio 0.93, 95% confidence interval 0.58 to 1.49) or Comparative effectiveness of beta blockers: The age- carvedilol (adjusted hazard ratio 1.18, 95% confidence in- and gender-adjusted rate of rehospitalization for HF was terval 0.70 to 2.01), which is consistent with findings for the significantly lower for periods exposed to atenolol com- overall cohort. Heart Failure/Comparative Effectiveness of Beta Blockers in Heart Failure 695

Discussion systolic HF and concurrent digoxin and ␤-blocker use was consistent with results in the overall cohort. Data were not Within a large cohort of older adults recently hospitalized systematically available on selected relevant drugs includ- with HF, we examined the comparative effectiveness of ing over-the-counter aspirin and nonsteroidal anti-inflam- different ␤ blockers in treated patients. We found that 68% matory drugs, other lifestyle factors (e.g., smoking and of the cohort received a ␤ blocker at discharge and/or during the first 12 months after discharge, with the most frequently alcohol use, diet and physical activity patterns), and other used ␤ blockers in our population being atenolol, shorter- potentially relevant clinical characteristics (e.g., body mass acting metoprolol tartrate, and carvedilol, respectively. In index and level of systolic or diastolic blood pressure). We patients with HF receiving ␤ blockers, there were notable studied insured patients so our findings would not be com- differences in demographic and clinical characteristics in pletely generalizable to uninsured patients or other clinical patients receiving different ␤ blockers, with carvedilol- settings. As with any observational study of drug effective- treated patients being significantly younger and having a ness outside a randomized trial setting, it is vulnerable to lower co-morbidity burden but also receiving HF-related residual confounding and/or treatment selection bias. To therapies more frequently than those receiving atenolol or mitigate this, we relied on several different methods. First, metoprolol tartrate. we focused only on patients receiving ␤ blockers at dis- Rehospitalization for HF within the first 12 months oc- charge and during follow-up, which removes a major treat- curred in nearly 54% of the cohort—highlighting the large ment selection bias. Second, we identified and statistically burden and resource utilization in this population despite adjusted for key potential confounding variables, including frequent use of various pharmacologic agents. Compared patient characteristics, type of medical insurance, longitu- with receipt of atenolol, the age- and gender-adjusted rate of dinal use of other cardiovascular medications, and cumula- rehospitalization for HF was significantly higher for meto- tive duration of exposure to different ␤ blockers. Third, we prolol tartrate and carvedilol. However, these differences further attempted to decrease residual selection bias using were no longer significant after adjustment for potential propensity score methods.7 Despite these efforts, we cannot confounding variables, baseline predicted likelihood of re- rule out the effects of residual unmeasured confounding. ceiving carvedilol, and cumulative exposure to each ␤ Although a recent analysis from the Organized Program blocker. Although information on left ventricular systolic to Initiate Lifesaving Treatment in Hospitalized Patients function was unavailable in the entire cohort, analysis of a with Heart Failure (OPTIMIZE-HF) registry reported that subgroup of patients with documented systolic HF being short-term (60- to 90-day) mortality rates were lower in treated with digoxin and ␤ blockers showed similar results, selected hospitalized patients with HF discharged on carve- which support our findings observed for the overall cohort. dilol, metoprolol succinate, or bisoprolol compared with Our study had several strengths including the relatively patients not receiving ␤ blockers,2 the present study is the large sample of patients receiving ␤ blockers, geographic first evaluation, to our knowledge, of the comparable lon- diversity, and comprehensive longitudinal data on other gitudinal effectiveness between different individual ␤ relevant prescription medications and coexisting illnesses blockers in a relatively unselected, high-risk elderly popu- and an important clinical outcome of rehospitalization for lation after hospitalization for HF within usual care settings. HF. However, our study had several limitations. We in- Given that HF remains the leading cause of hospitalization cluded an incomplete spectrum of type of ␤ blockers used in Medicare beneficiaries and the high associated costs of and detailed prescription information was not available. We prescription medications in this population, our study pro- also did not have information on patient symptoms or side vides important insights because we observed similar ad- ␤ effects of -blocker therapy. Despite the size of our HF justed rates of short-term rehospitalization for HF with cohort and geographic diversity, we found that only a se- receipt of atenolol or metoprolol tartrate as with carvedilol, ␤ lected number of blockers was used in each health plan which is approved by the US Food and Drug Administration population. Specifically, atenolol, shorter-acting metoprolol for the treatment of mild to severe HF. However, our results ␤ tartrate, and carvedilol were the 3 primary blockers pre- should be interpreted cautiously and additional observa- scribed, whereas longer-acting metoprolol succinate and tional studies and possible randomized comparisons should bisoprolol were used in very few patients. This precluded be performed that include a broad set of generic and brand- our evaluation of the comparable effectiveness of these name ␤ blockers and examine mortality and HF hospital- agents in our populations with HF. We implemented meth- izations. If our observations are confirmed, it would have ods to assign time-dependent exposure to medications based important clinical and policy implications for optimizing on our previous work using data from filled prescription and treatment and outcomes in high-risk patients with HF. refill patterns from outpatient pharmacy databases but could not confirm actual drug adherence. However, previous studies have demonstrated a strong association between these Acknowledgment: We thank Jim Livingston, MBA, Inna measurements of drug adherence and related physiologic Dashevsky, and Ning Hernandez for their expert technical outcomes. For the entire cohort, uniform data were unavail- assistance on this study. able on left ventricular systolic function, which is an important prognostic variable and related to current treatment ␤ 1. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath recommendations for use of blockers (i.e., decreased left P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, et al. ventricular ejection fraction Ͻ40%).4 However, our sensi- Comparison of carvedilol and metoprolol on clinical outcomes in tivity analysis in the subgroup of patients with documented patients with chronic heart failure in the Carvedilol Or Metoprolol 696 The American Journal of Cardiology (www.AJConline.org)

European Trial (COMET): randomised controlled trial. Lancet 2003; Guidelines (Writing Committee to Update the 2001 Guidelines for 362:7–13. the Evaluation and Management of Heart Failure): developed in 2. Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M, collaboration with the American College of Chest Physicians and Greenberg BH, O’Connor CM, Sun JL, Yancy C, Young JB. Carvedilol the International Society for Heart and Lung Transplantation: en- use at discharge in patients hospitalized for heart failure is associated dorsed by the Heart Rhythm Society. Circulation 2005;112(suppl): with improved survival: an analysis from Organized Program to Initiate e154–e235. Lifesaving Treatment in Hospitalized Patients with Heart Failure 5. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney (OPTIMIZE-HF). Am Heart J 2007;153(suppl):e81–e11. disease and the risks of death, cardiovascular events, and hospitaliza- 3. Lee WY, Capra AM, Jensvold NG, Gurwitz JH, Go AS. Gender and tion. N Engl J Med 2004;351:1296–1305. risk of adverse outcomes in heart failure. Am J Cardiol 2004;94:1147– 6. Selby JV, Ray GT, Zhang D, Colby CJ. Excess costs of medical care for 1152. patients with diabetes in a managed care population. Diabetes Care 4. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, 1997;20:1396–1402. Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, et al. 7. Rubin DB. Estimating causal effects from large data sets using propen- ACC/AHA 2005 guideline update for the diagnosis and management sity scores. Ann Intern Med 1997;127:757–763. of chronic heart failure in the adult: a report of the American College 8. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the of Cardiology/American Heart Association Task Force on Practice Cox Model. New York: Springer, 2000. Validation of the Seattle Heart Failure Model in a Community- Based Heart Failure Population and Enhancement by Adding B-Type Natriuretic Peptide

Heidi T. May, MSPHa, Benjamin D. Horne, PhD, MPHa,*, Wayne C. Levy, MDc, Abdallah G. Kfoury, MDa,b, Kismet D. Rasmusson, FNPa,b, David T. Linker, MDc, Dariush Mozaffarian, MD, DrPHd, Jeffrey L. Anderson, MDa,b, and Dale G. Renlund, MDa,b

Management of heart failure (HF) remains complex with low 5-year survival. The Seattle Heart Failure Model (SHFM) is a recently described risk score derived predominantly from clinical trial populations that may enable the prediction of survival in patients with HF. This study sought to validate the SHFM in an independent, nonclinical trial-based HF -from the hospital-based Intermountain Heart Collabora (4,077 ؍ population. Patients (n tive Study registry with a diagnosis of HF were evaluated using prospectively collected data mean ؎ SD follow-up 4.4 ؎ 3.1 years). The SHFM was used to calculate a risk score for) each patient. Receiver-operating characteristic area under the curve provided SHFM predictive ability for a composite end point of survival free from death, transplantation, or left ventricular assist device implantation. Addition of creatinine, serum urea nitrogen, diabetes status, and B-type natriuretic peptide (BNP) to the SHFM was also evaluated. Patient age averaged 67 ؎ 13 years and 61% were men. Area under the curves were 0.70 (95% confidence interval 0.66 to 0.70), 0.67 (95% confidence interval 0.66 to 0.69), 0.67 (95% confidence interval 0.065 to 0.68), and 0.66 (95% confidence interval 0.63 to 0.67) for 1-, 2-, 3-, and 5-year survivals, respectively. Area under the curves were slightly attenuated implantable cardioverter-defibrillator recipients ,(1,339 ؍ in patients >75 years of age (n -BNP added signifi .(1,634 ؍ and patients with an ejection fraction >40% (n ,(693 ؍ n) cantly to the model (area under the curve ؉0.06). BNP was found to add additional predictive ability at 1 year (area under the curve change ؉0.05) and nominally at 5 years area under the curve change ؉0.02). In conclusion, the SHFM predicts survival in patients) with HF in a hospital-based population, with areas under the curve similar to those from data on which models were initially fit. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:697–700)

It is unlikely that the incidence of heart failure (HF) will Methods decrease. In fact, the reverse is true. The risk of developing of HF within 6 years of a myocardial infarction is substan- The primary objective of this study was to validate the tive, with approximately 25% of men and 50% of women utility of the SHFM for prediction of survival (free from being affected.1 The recently described Seattle Heart Failure death, transplantation, or left ventricular assist device im- Model (SHFM) is a risk score that provides an estimation of plantation) in a hospitalized HF patient population at 1, 2, mean 1-, 2-, and 3-year survivals using commonly obtained and 3 years. A second objective was to determine the predictive ability of the SHFM for 5-year survival. Exploratory clinical, pharmacologic, device, and laboratory informa- Ͼ tion.2 It was developed and validated in outpatient-based objectives included assessment of the model in patients 75 ϭ participants with HF from 4 clinical trials and 2 observa- years of age (n 1,339), implantable cardioverter-defibril- ϭ tional registries. However, its applicability has not yet been lator (ICD) recipients (n 693), and patients with an Ͼ ϭ determined in a large hospital-based population or specific ejection fraction (EF) 40% (n 1,634). To further in- subsets of patients. This study evaluated the validity of the crease the predictability of the SHFM, addition of serum SHFM in an independent, nonclinical trial, hospital-based urea nitrogen, creatinine, diabetes status (fasting glucose Ͻ Ͼ HF population. levels 100, 100 to 125, and 125 mg/dl or a clinical diagnosis of diabetes mellitus), and B-type natriuretic peptide (BNP) to the model was evaluated. Study patients (n ϭ 4,077) were drawn from the cardiac aLDS Hospital, Intermountain Medical Center, and bUniversity of c catheterization registry of the Intermountain Heart Collab- Utah, Salt Lake City, Utah; University of Washington, Seattle, Washing- orative Study. The population studied included consecutive ton; and dBrigham and Women’s Hospital, Harvard Medical School, Bos- ton, Massachusetts. Manuscript received January 26, 2007; revised manu- patients with HF undergoing coronary angiography at LDS script received and accepted March 19, 2007. Hospital (Salt Lake City, Utah) from 1993 to 2005. HF was *Corresponding author: Tel: 801-408-5442; fax: 801-408-8655. defined as a decrease in left ventricular function character- E-mail: [email protected] (B.D. Horne). ized by an EF Յ40% or a physician-reported clinical HF

Table 1 Baseline characteristics of patients with heart failure enrolled in the catheterization registry of the Intermountain Heart Collaborative Study (n ϭ 4,077) Characteristic Result Age (yrs) 67.0 (range 19–96) Men 2,792 (61.4%) Average follow-up (yrs) 4.4 Ϯ 3.1 (range 0.4–12.2) New York Heart Association class (n ϭ 1,268) I 17 (1.4%) II 308 (24.4%) III 685 (54.1%) IV 258 (20.4%) EF (%) 45.0 Ϯ 17.8 Ischemic cause 2,714 (59.7%) Systolic blood pressure (mm Hg) 133.1 Ϯ 21.7 Medications Loop diuretic 2,196 (48.2%) Figure 1. Percentage of patients with an event (death, transplantation, or Potassium-sparing diuretic 188 (4.1%) left ventricular assist device implantation) at 1 year in each decile of the ␤ Blocker 3,516 (77.2%) SHFM. Angiotensin receptor blocker 300 (6.6%) Angiotensin-converting enzyme inhibitor 2,127 (46.7%) Allopurinol 8 (0.2%) Statin 1,908 (41.9%) (missing n ϭ 2,701, 66.2%), EF (missing n ϭ 1,018, ICD 542 (13.3%) 25.0%), and total cholesterol (missing n ϭ 807, 19.8%) Laboratory were estimated using multiple imputation (intercooled Sodium (mEq/L) 139.8 Ϯ 2.1 STATA 7.0, STATA Corp., College Station, Texas). Addi- Creatinine (mg/dl) 1.47 Ϯ 1.13 tional analyses for comparison assigned missing York Heart Total cholesterol (mg/dl) 173.3 Ϯ 53.5 Ϯ Association class data as class III and the other 4 variables Uric acid (mg/dl) 6.5 2.4 had missing values assigned from York Heart Association Hemoglobin (g/dl) 13.5 Ϯ 2.1 White blood cells 9.0 Ϯ 4.2 class-specific means of patients with full data. Percent lymphocytes 18.3 Ϯ 10.6 Deaths were determined by telephone survey, hospital Creatinine (mg/dl)* 1.2 (0.9–1.5) records, and Utah State Health Department records (death Serum urea nitrogen (mg/dl)* 21.0 (16.0–31.0) certificates) and were verified through Social Security death BNP (pg/ml) (n ϭ 544)* 602.0 (258.0–1260.0) records. Patients not listed as deceased in any registry were * Median (interquartile range). considered to be alive. Heart transplantation and left ventricular assist device implantation were determined by review of hospital records. Ϯ diagnosis (i.e., American College of Cardiology/American Variables are summarized as means SDs for continu- Heart Association stage B/C). All patients evaluated were ous variables and frequencies for discrete variables. Calcu- discharged alive from the index hospitalization. This study lation of the SHFM used the variables, variable beta coef- was approved by the hospital institutional review board. ficients, and methods as previously described.2 Deciles of At the time of study entry (i.e., at angiography), patient predicted versus actual survival were plotted against each demographic information was collected including age, gen- other and Pearson correlation coefficients were determined der, HF etiology, New York Heart Association class, blood at each time point. Receiver operator characteristic curves pressure, and when available EF, as determined by left were used to determine areas under the curve for prediction ventriculography or (in its absence) by echocardiography. of survival. Two-tailed p values at ␣ ϭ 0.05 were desig- Of those who had an EF measurement, there were 1,425 nated as nominally significant. patients with an EF Յ40%. Documentation was made re- To evaluate the predictive ability of additional variables garding whether the patient had a biventricular pacer, an (serum urea nitrogen, creatinine, diabetes status, and BNP) ICD, or a biventricular ICD. Discharge medications were in addition to the SHFM, a new SHFM was created from our also recorded, including statins, ␤-adrenergic receptor data. Logistic regression was used to develop the risk scores blockers, angiotensin-converting enzyme inhibitors or an- at 1 year and 5 years. Regression models entered the SHFM giotensin receptor blockers, and diuretics. Laboratory as- variables and serum urea nitrogen (continuous variable), sessments made during the index hospitalization were creatinine (continuous variable), diabetes status (glucose stored electronically for future use. Diabetes status was categories: normal Ͻ100 mg/dl, intermediate 100 to 125 categorized as normal (fasting glucose level Ͼ100 mg/dl), mg/dl, and diabetes Ͼ125 mg/dl or a clinical diagnosis of intermediate (100 to 125 mg/dl), or diabetic (Ͼ125 mg/dl) diabetes mellitus), and BNP (continuous variable). Each or a clinical diagnosis of diabetes mellitus. Missing values variable was multiplied by its associated beta coefficient for York Heart Association class (missing n ϭ 2,939, and the products were summed to determine a patient’s risk 72.1%), lymphocytes (missing n ϭ 1,416, 34.7%), uric acid score. Heart Failure/Validation of Seattle Heart Failure Model 699

Table 2 Events, areas under the curve, and 95% confidence intervals for implementation of the Seattle Heart Failure Model at one and two, three, and five years 1-yr End Point 2-yr End Point 3-yr End Point 5-yr End Point Event* 917 (20.2%) 1,207 (26.5%) 1,428 (31.4%) 1,774 (39.0%) Areas under the curve 0.70 0.67 0.67 0.66 95% Confidence Intervals 0.68–0.72 0.66–0.69 0.65–0.68 0.64–0.68

* Composite end point of death, transplantation, and left ventricular assist device implantation.

survivals, respectively. The SHFM model was evaluated in patients Ͼ75 years old (n ϭ 1,339), those with an EFϾ40% (n ϭ 1,634), and those who had received an ICD (n ϭ 693) at 1, 2, 3, and 5 years (Table 3). To determine the added predictive ability of serum creatinine, serum urea nitrogen, diabetes, and BNP, a newly derived risk score based on the SHFM variables was performed. As expected, when only the SHFM variables were entered, areas under the curve at 1 and 5 years were higher (Table 4) than those resulting from implementation of the original SHFM coefﬁcients. As with the SHFM, addition of creatinine did not substantively add to the model, as did serum urea nitrogen and diabetes status (area under the curve change ϩ0.01); however, BNP did add considerable predictive ability at 1 year (area under the curve change ϩ0.05) and modest ability at 5 years (area under the curve change ϩ0.02; Table 4). To determine whether the increased area under the curve in the SHFM containing BNP could be ascribed to the addition of Figure 2. Percentage of patients with an event (death, transplantation, or BNP or to a randomly better selected population, we as- left ventricular assist device implantation) at 5 years in SHFM deciles. sessed the SHFM and our SHFM-derived risk score only in patients who had a BNP measurement (Table 4). Area under Results the curve changes were actually increased (SHFM 1 year ϩ0.07 and 5 years ϩ0.04, derived from SHFM 1 year Patient demographics are presented in Table 1. Compared ϩ0.06 and 5 years ϩ0.03) when BNP was added. Such with the derivation cohort in the Prospective Randomized results show that the area under the curve increases seen in Amlodipine Survival Evaluation (PRAISE) in which the the SHFM plus BNP can be ascribed to the addition of BNP SHFM was developed, our population had more women, and not the selected subset of this cohort. Instead of mod- higher average EFs, fewer patients with ischemic cause, eling the parameter of interest (e.g., serum urea nitrogen) higher average systolic blood pressure, and several medica- with all other SHFM variables, we also evaluated the orig- ␤ tion usage differences, in particular higher use of blockers inal SHFM score as a single variable (SHFM ϫ 1 ϩ pa- and statins. rameter of interest ϫ beta coefﬁcient), which resulted in During 13,902.1 person-years of follow-up, 2,142 events similar additions to the areas under the curve for serum urea occurred (1,974 deaths, 100 transplantation, and 68 left nitrogen, creatinine, or diabetes status, although this method ventricular assist device implantations). The SHFM was attenuated the additional predictive ability of BNP highly predictive of 1-year event rate (Figure 1). Predicted (ϩ0.034). Individual predictive abilities for BNP for 1- and 1-year survivals were 93.2% in decile 1 and 53.3% in decile 5-year survivals were 0.67 and 0.63, respectively. 10 (average 79.7%), with a correlation of 0.99 to actual survival. Predicted 2-year survivals were 87.2% in decile 1 Discussion and 47.5% in decile 10 (average 73.0%), with a correlation of 0.99 to actual survival. Predicted survivals at year 3 were In this cohort of nonclinical trial, hospital-based patients 83.8% in decile 1 and 42.9% in decile 10 (average 67.9%), with HF, we successfully validated the SHFM at 1 year, 2 with a correlation of 0.99 to actual survival. Results of the years, and 3 years. Areas under the curve determined from implementation of the SHFM in our cohort are presented in our population were similar to those previously published.2 Table 2. Because the SHFM was originally developed in patients The ability of the SHFM to predict survival was main- who were clinical trial participants, who are generally tained at 5 years (Table 2). Predicted 5-year survivals were healthier, its applicability within a large health care system 78.0% in decile 1 and 34.6% in decile 10 (average 60.4%), to potentially sicker patients had not been elucidated. Al- with a correlation of 0.98 to actual survival. Figure 2 dis- though the SHFM has been previously validated in a cohort plays percent actual events occurring in each decile at 5 of clinic patients with HF (n ϭ 148) and a consecutive set years. In the subset of patients with full data for lympho- of patients with HF seen by cardiologists participating in the cytes, uric acid, EF, and total cholesterol (n ϭ 2,121), areas Italian Heart Failure Registry (n ϭ 872), its validation under the curve were 0.70 and 0.66 for 1- and 5-year within a hospital-based cohort was unknown. This study 700 The American Journal of Cardiology (www.AJConline.org)

Table 3 Seattle Heart Failure Model areas under the curve and 95% confidence intervals for one-, two-, three, and five-year survival in subsets of patients (Ͼ75 years of age, ejection fraction Ͼ40%, and implantable cardioverter-defibrillator implantation) 1 yr 2 yrs 3 yrs 5 yrs Age Ͼ75 yrs (n ϭ 1,339) 0.68 (0.65–0.72) 0.66 (0.62–0.69) 0.65 (0.62–0.68) 0.64 (0.61–0.68) EF Ͼ40% (n ϭ 1,634) 0.66 (0.62–0.69) 0.63 (0.60–0.67) 0.62 (0.59–0.66) 0.62 (0.59–0.59) ICD Implantation (n ϭ 693) 0.62 (0.56–0.69) 0.63 (0.57–0.68) 0.62 (0.57–0.67) 0.64 (0.59–0.69)

Table 4 and thus require further validation. Thus, the excellent pre- Areas under the curve (95% confidence intervals) for risk scores based dictive ability of the SHFM was shown repeatedly with only on the SHFM variables derived within our population, with added modest attenuations between subgroups, as with different variables creatinine, serum urea nitrogen, diabetes status, and BNP to populations, and provides valuable information regarding determine their added predictive ability (SHFM vs derived SHFM in those patients with a BNP measurement) short-term (1-year), intermediate-term (2- and 3-year), and long-term (5-year) survivals. 1-yr Event 5-yr Event This study shares the limitations of all observational, SHFM derived 0.73 (0.71–0.75) 0.71 (0.69–0.73) nonrandomized studies; however, it was large and prospec- SHFM ϩ creatinine 0.74 (0.72–0.75) 0.72 (0.70–0.73) tive in patient ascertainment and follow-up. This registry SHFM ϩ blood urea nitrogen 0.74 (0.72–0.76) 0.72 (0.71–0.74) may not be entirely representative of a general HF popula- SHFM ϩ diabetes status* 0.74 (0.72–0.45) 0.72 (0.70–0.73) tion because it captured only those patients undergoing BNP measurement (n ϭ 544) angiography. However, the primary objective of this study SHFM 0.71 (0.66–0.76) 0.69 (0.65–0.74) was to validate the SHFM in a different population (hospi- SHFM derived 0.72 (0.67–0.77) 0.70 (0.65–0.74) talized patients with HF) than previously studied for whom SHFM ϩ BNP 0.78 (0.73–0.82) 0.73 (0.69–0.78) full SHFM data tend to be available and for whom inter- * Glucose levels Ͻ100, 100 to 125, and Ͼ125 mg/dl or clinical diag- ventions can be implemented. The SHFM maintained its nosis of diabetes mellitus. predictive ability despite this population restriction. Elec- tronic data or discharge medication compliance was not confirms the applicability of the SHFM in many HF popu- verified through medical charts, although verification of the lations, particularly an independent hospital-based cohort. risk score would not have been validated if the data were not Because patients with HF require continual monitoring reliable and accurate. Some patients did not have informa- through physician visits and diagnostic testing, this population regarding some components of the SHFM and that tion could potentially better represent the general HF pop- information was therefore estimated. However, when modulation to which the SHFM should be applied. els were constructed using patients with a full dataset, areas Previously, the SHFM had been tested only in patients under the curve were similar to those in patients who had with 3 years of follow-up. We showed that the SHFM could estimations for missing data. be extended to 5-year prediction with a predictive ability similar to that of 2- and 3-year survivals. Although slightly 1. American Heart Association. Heart and stroke statistical update—2006 attenuated, results among subgroups (age Ͼ75 years, update. Circulation 2006;113(suppl):e85–e151. Ͼ 2. Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp EF 40%, and ICD implantation) of this study population AB, Anand I, Maggioni A, Burton P, Sullivan MD, et al. The Seattle had fairly good predictive ability. Such attenuations could Heart Failure Model: prediction of survival in heart failure. Circulation be attributed to a decrease in power due to a smaller sample 2006;113:1424–1433. Accuracy of 64-Slice Computed Tomography for the Preoperative Detection of Coronary Artery Disease in Patients With Chronic Aortic Regurgitation

Hans Scheffel, MDa, Sebastian Leschka, MDa, André Plass, MDb, Robert Vachenauer, MDb, Oliver Gaemperli, MDc, Elisabeth Garzoli, MDa, Michele Genoni, MDb, Borut Marincek, MDa, Philipp Kaufmann, MDc,d, and Hatem Alkadhi, MDa,*

We studied the diagnostic accuracy of 64-slice computed tomography for the diagnosis of significant coronary artery disease (CAD) compared with conventional coronary angiography (CA) in patients with chronic aortic regurgitation (AR) referred for elective aortic (valve surgery. Fifty consecutive patients with chronic AR (38 men, mean age 54 ؎ 14 years scheduled for valve surgery underwent 64-slice computed tomographic (CT) coronary angiography and CA. Significant stenosis was defined as a luminal diameter decrease Mean heart rate during CT scanning was 65.5 ؎ 7.4 beats/min. Mean Agatston .50%< score was 136 ؎ 278 (range 0 to 1207); prevalence of significant CAD in the study population was 26% (13 of 50 patients). Thirteen of 742 segments (1.8%) in 3 patients were (9 ؍ considered nondiagnostic with computed tomography because of motion artifacts (n In a patient-based analysis taking nonevaluative segments as falsely .(4 ؍ or calcium (n positive, sensitivity, specificity, and positive and negative predictive values of computed tomography were 100%, 95%, 87%, and 100%, respectively. Preoperative CA could have been avoided in 70% of patients (35 of 50), CA would have been performed to confirm the CT diagnosis in 26% (13 of 50), and unnecessary CA would have been performed in 4% (2 of 50) on the basis of false-positive CT ratings. In conclusion, 64-slice CT coronary angiography provides high diagnostic accuracy for diagnosing significant CAD in patients with chronic AR and may be used as a filter test before valve surgery to decide whether CA should be performed. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:701–706)

Multidetector row computed tomographic (CT) coronary tions to iodinated contrast media (n ϭ 4), renal insufficiency angiography represents an emerging noninvasive technique (creatinine level Ͼ120 ␮mol/L, n ϭ 3), hemodynamic for imaging the coronary artery tree. Using 64-slice CT instability (n ϭ 1), and lack of sinus rhythm (n ϭ 3). coronary angiography, several studies have demonstrated Two patients denied written informed consent. Thus, the that it enables the diagnosis of coronary artery disease final study population comprised 50 patients (38 men, 12 (CAD) and, more importantly, reliably allows exclusion of women; mean age 54 Ϯ 14 years, range 35 to 83). Patient CAD.1,2 In this study we evaluated the diagnostic accuracy demographics are presented in Table 1. CT scans and CA of 64-slice CT coronary angiography to preoperatively de- were performed within 11.3 Ϯ 7.8 days (range 1 to 30). The tect significant CAD in patients undergoing elective valve institutional committee on human research has approved the surgery for chronic aortic regurgitation (AR). study, and written informed consent was obtained from all 50 patients. Patients with prescan heart rates Ͼ70 beats/min Methods received intravenous ␤-blocker therapy (metoprolol tartrate From April 2005 to May 2006, we screened 63 consecutive 5 to 15 mg, Lopresor, Daiichi Sankyo, Switzerland) imme- patients with AR scheduled for valve surgery. Thirteen diately before the CT scan. Patients’ mean body mass index 2 patients were excluded because of previous allergic reac- was 25.45 Ϯ 4.55 kg/m (range 16.4 to 36.9). All scans were performed using a 64-slice CT scanner (Somatom Sensation 64, Siemens Medical Solutions, Forchheim, Ger- aInstitute of Diagnostic Radiology, bClinic for Cardiovascular Surgery, many). A native scan was performed for calcium scoring and cCardiovascular Center, University Hospital Zurich, and dCenter for with the following parameters: detector collimation 32 ϫ Integrative Human Physiology, University of Zurich, Zurich, Switzerland. 0.6 mm, slice collimation 64 ϫ 0.6 mm by means of a Manuscript received January 31, 2007; revised manuscript received and z-flying focal spot, gantry rotation time 330 ms, pitch 0.2, accepted March 15, 2007. tube potential 120 kV, and tube current time product 150 This research was supported by the National Center of Competence in Research, Computer Aided and Image Guided Medical Interventions of the effective mAs. Thereafter, CT coronary angiographic data Swiss National Science Foundation, Zurich, Switzerland. were acquired using the same parameters except a higher *Corresponding author: Tel: 41-44-255-3662; fax: 41-44-255-4443. tube current time product of 700 effective mAs. Electrocar- E-mail address: [email protected] (H. Alkadhi). diographic pulsing for decreasing radiation dose was ap-

Table 1 planar reformations, and thin-slab maximum intensity pro- Patient demographics (n ϭ 50) jections on a per-segment basis. First, 2 independent and Age (yrs) 54 Ϯ 14 (35–83) blinded readers judged the image quality of all coronary Men 38 artery segments as being diagnostic or not. Second, the 2 Angina pectoris 11 (22%) observers assessed all coronary artery segments for the Hypertension (increased levels Ͼ140/90 mm Hg) 20 (40%) presence of hemodynamically significant stenoses. Signifi- Hypercholesteremia (increased levels Ͼ200 mg/dl) 21 (42%) cant stenosis was defined as luminal diameter narrowing Diabetes mellitus 2 (4%) Ͼ50%. Vessel diameters were measured on reconstructions Smoker/ex-smoker 18 (36%) perpendicularly oriented to the vessel centerline using elec- Body mass index Ͼ30 kg/m2 6 (12%) Aortic root morphology tronic calipers. For any disagreement in data analysis, con- Tricuspid valve 16 (32%) sensus agreement was achieved. Bicuspid valve 34 (68%) CA was performed according to standard techniques. Dilatation 41 (82%) Vascular access was obtained through a femoral approach Surgery with Seldinger technique and a 6Fr or 7Fr catheter. Multiple Biological aortic valve replacement 16 (32%) views were stored on a CD-ROM. Angiograms were eval- Mechanical aortic valve replacement 7 (14%) uated by 1 experienced reader who was blinded to results Composite graft 27 (54%) from 64-slice CT coronary angiography. Coronary artery Coronary artery bypass graft 10 (20%) segments were defined according to the same recommenda- CA tions mentioned above.3 Each vessel segment was scored as 0 37 (74%) being significantly stenosed, defined as a diameter decrease 1 4 (8%) Ͼ 2 3 (6%) 50% or not. Coronary artery analysis was performed in all 3 6 (12%) vessels with a luminal diameter of Ն1 mm, excluding those vessels distal to complete occlusions. Quantitative variables CAD was defined as 1-vessel disease; 2-vessel disease; and 3-vessel were expressed as mean Ϯ SD and categorical variables as disease. frequencies or percentages. To evaluate the ability of computed tomography to diagnose CAD we performed a seg- plied in all patients with full tube current applied at 60% of ment-based, vessel-based, and patient-based analysis of the the RR interval. In each patient, images were first recon- data. Interobserver agreement for the 2 readers of coronary structed at 60% and 70% of the RR interval. If considered artery stenoses detection and assessment of image quality necessary, additional images were reconstructed in 5% steps were interpreted according to guidelines of Landis and of the RR interval within the full tube current window. A Koch4 by using the clustered data. Sensitivity, specificity, bolus of iodixanol 90 ml (Visipaque 320, 320 mg/ml, GE positive predictive value, and negative predictive value Healthcare, Buckinghamshire, United Kingdom) followed were calculated from chi-square tests of contingency, and by 30-ml saline solution was continuously injected into a 95% confidence intervals were calculated from binomial left antecubital vein through an 18-gauge catheter at a flow expression on a per-segment basis. CA was considered the rate of 5 ml/s. Bolus tracking was performed with a region standard of reference. Intermodality agreements between of interest placed into the ascending aorta with a threshold computed tomography and CA were expressed by ␬ statis- of 100 HU. Datasets were retrospectively reconstructed tics. Statistics were calculated on a segment-based, vessel- synchronized to electrocardiography during mid- to end- based, and patient-based (presence of Ն1 significant coro- diastole at 60% to 70% of the RR interval. Estimated radi- nary artery stenosis or absence of any significant stenosis in ation doses were calculated using commercially available each patient) analysis. As previously suggested,5 the pa- software (WinDose, Institute of Medical Physics, Erlangen, tient-based analysis was also performed including all pa- Germany) and revealed values of 1.1 to 1.5 mSv for calcium tients censoring any nonevaluative coronary segment by scoring and 8.8 to 13.6 mSv for CT coronary angiography computed tomography as positive, because every patient for men and women, respectively. Reconstructed images with any nonevaluative segment would undergo CA in clin- were transferred to an external workstation (Leonardo, Sie- ical practice. mens Medical Solutions). Mean Agatston score was calculated with a detection threshold of 130 HU by using semi- Results automated software (Syngo Calcium Scoring, Siemens Medical Solutions). Computed tomography and CA were successfully per- For analysis of CT coronary angiographic data, coronary formed in all patients without complications. Average heart arteries were segmented according to recommendations of rate during scanning was 65.5 Ϯ 7.4 beats/min (range 45 to the American Heart Association3: The right coronary artery 76). Seven patients (14%) were under oral ␤-blocker med- was defined to include segments 1 to 4, the left main and left ication at the time of the CT scan. Six patients (12%) with anterior descending arteries to include segments 5 to 10, and increased heart rate (mean 76 Ϯ 3.4 beats/min, range 71 to the left circumflex artery to include segments 11 to 15. All 81) received intravenous ␤ blockers before the scan. segments with a diameter of Ն1 mm at their origin were With CT coronary angiography, a total of 742 segments included. Segments distal to an occluded vessel would be in 50 patients was evaluated. Interobserver agreement for excluded from analysis. determining diagnostic image quality was excellent (␬ ϭ All reconstructed images were evaluated and classified 0.91). Image quality was rated as being diagnostic in 98.2% by 2 independent readers using axial-source images, multi- (729 of 742) and nonevaluative in 1.8% (13 of 742) of the Valvular Heart Disease/Coronary Artery Disease in Chronic Aortic Regurgitation 703

† segments. The 13 nonevaluative segments (segment 4, n ϭ 3; segment 7, n ϭ 1; segment 9, n ϭ 2; segment 10, n ϭ 1; segment 13, n ϭ 4; and segment 14, n ϭ 2) were found in

Agreement 3 patients (6%), in whom 1 patient had significant CAD according to CA and computed tomography, whereas significant stenoses were absent in the other 2 patients. Causes for nonevaluative segments were extensive calcifications (n ϭ 4) or motion artifacts (n ϭ 9). No problems occurred with regard to the signal-to-noise ratio in any patient. No segment distal to an occluded vessel had to be excluded from analysis. CA identified 45 coronary artery stenoses with a diameter narrowing Ͼ50% in 13 patients (26%; Table 1). Single- vessel disease was present in 4 patients (8%), 2-vessel disease in 3 (6%), and 3-vessel disease in 6 (12%). Signif- icant coronary artery stenoses could be excluded in 37 nic aortic regurgitation compared with invasive patients (74%). Calcium scoring scans revealed calcified vessel wall de- true positive. posits in 16 patients (32%). Thirteen of these 16 patients ϭ (81.2%) had significant coronary artery stenoses (as determined by CA), whereas 3 patients (18.8%) had calcifications without significant stenoses. No patient had significant stenoses but no calcifications. The mean Agatston score in all patients was 136 Ϯ 278 (range 0 to 1207), whereas the

true negative; TP mean Agatston score in the patients with signiﬁcant steno-

ϭ ses was 481 Ϯ 366 (range 96 to 1207) and that in those without significant stenoses was 37 Ϯ 12 (range 0 to 73). The prevalence and degree of coronary calcification in our study population were too low to allow a systematic statistical evaluation of a threshold above which a CT coronary angiographic examination would not be justified. Table 2 presents the diagnostic accuracy of 64-slice CT coronary angiography for the diagnosis of significant CAD. The ␬ value for coronary artery stenosis detection with positive predictive value; TN computed tomography was 0.84, indicating an excellent ϭ interobserver agreement. Sixty-four–slice CT coronary angiography correctly recognized 42 of the 45 significant stenoses (93.3%). With computed tomography, 4 false-positive ratings occurred because of overestimation of severity of stenoses in the presence of wall irregularities on the TP TN FP FN Sensitivity (%) Specificity (%) PPV (%) NPV (%)coronary Intermodality angiogram. Computed tomography misclassified 3 segments as being not significantly stenosed resulting in 3 false-negative ratings. Causes of false ratings were massive calcifications in 5 segments (4 false positive, 1 false nega- No. of Patients

negative predictive value; PPV tive) and motion artifacts in 2 segments (0 false positive, 2

ϭ false negative). The 3 false-negative ratings occurred in the mid right coronary artery (segment 2), distal right coronary artery (segment 3), and distal left anterior descending artery (%) (segment 8), respectively, and the 4 false positive ratings in of Disease the distal right coronary artery (segment 3), distal left an-

values. terior descending artery (segment 8), second diagonal

␬ false positive; NPV branch (segment 10), and distal left circumflex artery (seg- ϭ ment 14), respectively. On a segment-based analysis, overall sensitivity, which was the number of patients having coronary artery stenosis identified by CT coronary angiography divided by the number of patients with CAD defined by CA and the patients falsely defined as having no stenosis at computed tomogra- false negative; FP

ϭ phy, was 81.8% (95% conﬁdence interval 48.2 to 97.7).

Agreement represented by Specificity, which was defined as the number of patients FN Values in parentheses represent* 95% Statistical confidence analysis intervals. † including the 13 nonevaluative segments as FP ratings. Right coronary arteryLeft main arteryLeft anterior descending arteryLeft circumflex artery 18.0 18.0 22.0 0 50 50 9 50 8 50 39 40 9 2 0 1 38 0 50 1 1 0 100 (66.4–100) 88.9 (51.8–99.7) 2 0 95.1 (83.5–99.4) 97.6 (87.1–99.7) 85.7 (57.2–98.2) 81.8 (48.2–97.7) 100 86.7 (—) (69.3–96.2) 99.6 (97.6–100) 100 98.2 (91.0–100) (94.9–99.6) 92.3 (64.0–99.8) 100 (92.9–100) 99.1 (96.9–99.9) 0.87 0.88 100 (—) 0.82 100 (92.9–100) 1.00

Table 2 Diagnostic accuracy of 64-slicecoronary computed angiography tomographic coronary angiography for theVariable diagnosis of signiﬁcant coronary stenoses in patients with chro Patient-based analysisPatient-based analysis*Coronary-based analysis Prevalence 26.0Segment-based analysis 26.0 14.5 50 50 200 13 6.2 13 26 37 167 35having 729 0 4 2 no 42 0 3 0 coronary 680 100 (75.3–100) 89.6 (72.7–97.8) 100 (75.3–100) 4 97.7artery 100 (94.1–99.4) (90.5–100) 94.6 (81.8–99.3) 3 88.9 (51.8–99.7) 10086.7stenosis (75.3–100)(59.5–98.3) 81.8 (48.2–97.7) 97.6 (87.1–99.7) 100 100(90.0–100) (90.5–100) 97.4 (86.5–99.9) byCT 0.86 90.0 (55.5–99.8) 0.90 1.00 coronary 95.0 (83.7–99.4) angiog- 0.92 704 The American Journal of Cardiology (www.AJConline.org)

Figure 1. A 36-year-old man with severe chronic AR. Invasive CA demonstrates normal left (A) and right (B) coronary arteries without stenoses. Sixty-four–slice CT coronary angiography demonstrates normal left anterior descending (curved multiplanar reformations) (C) and left circumﬂex (curved multiplanar reformations) (D) arteries and a normal right coronary artery (thin maximum intensity projections) (E) without stenoses.

Figure 2. A 55-year-old man with moderate chronic AR. Invasive CA demonstrates proximal occlusion of the right coronary artery (A) and significant stenoses of the proximal segment of the left anterior descending (arrow, B) and of the proximal intermediary artery (arrow, C). Sixty-four–slice CT CA similarly demonstrates proximal occlusion of the right coronary artery (transverse multiplanar reformations) (D) and significant stenoses of the proximal left anterior descending (curved multiplanar reformations) (arrow, E) and proximal intermediary (curved multiplanar reformations) (arrow, F) arteries. The left circumflex artery showed vessel wall irregularities without significant stenoses at catheter angiography (C) and computed tomography (curved multiplanar reformations) (G). Note filling of the sinus node artery at invasive CA and computed tomography (asterisk, A and D) before occlusion of the right coronary artery, and the short myocardial bridging segment of the left anterior descending artery (arrowhead, E) immediately distal to the stenosis as depicted with computed tomography. raphy divided by the number of patients without CAD On a patient-based analysis, 64-slice CT coronary an- defined by CA and the patients falsely defined as having giography correctly demonstrated absence of significant stenosis at computed tomography, was 97.4% (95% confi- coronary stenosis in all 37 patients (Figure 1). In all 13 dence interval 86.5 to 99.9). Positive predictive value, patients with Ն1 significant stenosis, computed tomography which was defined as the number of patients having coro- correctly identified significant CAD (Figure 2). Thus, sen- nary artery stenosis identified by CT coronary angiography sitivity, specificity, positive predictive value, and negative divided by the number of patients with CAD defined by CA predictive value were 100% on a per-patient analysis. If all and the patients falsely defined as having stenosis at com- 13 nonevaluative segments were considered falsely posi- puted tomography, was 90.0% (95% confidence interval tive, unnecessary CA would have been performed in 2 55.5 to 99.8). Negative predictive value, which was defined patients. Computed tomography would then have a sensi- as the number of patients having no coronary artery stenosis tivity of 100% (95% confidence interval 75.3 to 100), a identified by CT coronary angiography divided by the num- specificity of 94.6% (95% confidence interval 81.8 to 99.3), ber of patients without CAD defined by CA and the patients a positive predictive value of 86.7% (95% confidence in- falsely defined as having no stenosis at computed tomogra- terval 59.5 to 98.3), and a negative predictive value of 100% phy, was 95.0% (95% confidence interval 83.1 to 99.4). The (95% confidence interval 90.0 to 100; Table 2). Intermodal- intermodality agreement was excellent (␬ ϭ 0.92). ity agreement was perfect on a patient-based analysis when On a vessel-based analysis, overall sensitivity was 89.6% using only evaluative segments (␬ ϭ 1.00) and excellent (95% confidence interval 72.7 to 97.8), specificity was when considering nonevaluative segments as falsely posi- 97.7% (95% confidence interval 94.1 to 99.4), positive tive (␬ ϭ 0.90). predictive value was 88.9% (95% confidence interval 51.8 to 99.7), and negative predictive value was 97.6% (95% Discussion confidence interval 87.1 to 99.7). Overall agreement between computed tomography and CA on a vessel-based The prevalence of significant CAD in our population was analysis was excellent (␬ ϭ 0.86). Sensitivity was higher in 32% (16 of 50 patients), which is slightly lower than the the left main and left anterior descending arteries (100% in prevalence of 37% reported in the literature.6 This preva- the 2 arteries) compared with the sensitivity in the right lence of concomitant CAD is lower than that of concomitant coronary artery and left circumflex artery (88.9% and CAD in patients with aortic stenosis.7–9 85.7%, respectively). In contrast, specificity and negative Holmstrom et al10 assessed the diagnostic accuracy of predictive value were excellent in all vessels. 8-detector row CT coronary angiography for the diagnosis Valvular Heart Disease/Coronary Artery Disease in Chronic Aortic Regurgitation 705 of CAD in 23 patients with severe aortic stenosis. The the aortic root including the aortic valve that can be per- investigators found a low sensitivity of 63%, a specificity of formed with a similar accuracy compared with echocardi- 96%, a positive predictive value of 52%, and a negative ography.19 Knowledge of the presence of a significant CAD predictive value of 98% compared with CA; however, 38% will probably lead to bypass and aortic valve replacement of the segments in their study had to be excluded because of surgery in 1 session offering an advantage of CT angiogra- extensive calcifications. Gilard et al11 investigated the ac- phy or CA compared with other imaging modalities such as curacy of 16-detector row CT coronary angiography in 55 electrocardiography and stress testing. patients with aortic stenosis undergoing valve surgery. The following study limitations have to be acknowl- These investigators found a sensitivity of 100%, a specific- edged. First, only patients scheduled for elective valve sur- ity of 80%, a positive predictive value of 55%, and a gery have been included in our study, which may represent negative predictive value of 100% for the detection of an inclusion bias. Second, only patients with chronic but not significant coronary stenoses. However, lumen assessment with acute AR have been included. Similarly, we did not was impaired particularly in patients with a high calcium include patients with infective endocarditis as an underlying load (i.e., an Agatston score Ͼ1,000), indicating the modal- cause of AR. Third, CT coronary angiography is associated ity to strongly rely on the prevalence and extent of CAD in with substantial irradiation. However, we have decreased the specific population.12 Most recently, Meijboom et al13 the applied radiation dose by applying electrocardiographic studied the diagnostic performance of 64-slice CT coronary pulsing for dose-decreasing purposes in all patients. This angiography for the preoperative detection of significant approach may at least in part have contributed to the fact coronary stenoses in 70 patients with various valvular dis- that some of the 9 nonevaluative coronary segments were orders referred for cardiac valve surgery, of whom 9 pa- caused by motion artifacts in the reconstruction intervals tients had AR. The investigators found an excellent overall with full tube output. sensitivity of 100%, a specificity of 92%, a positive predictive value of 82%, and a negative predictive value of 100% 1. Leber AW, Knez A, von Ziegler F, Becker A, Nikolaou K, Paul S, for the noninvasive technique. However, the diagnostic ac- Wintersperger B, Reiser M, Becker CR, Steinbeck G, Boekstegers P. curacy of 64-slice CT coronary angiography for the group Quantification of obstructive and nonobstructive coronary lesions by of patients with AR has not been calculated, most probably 64-slice computed tomography: a comparative study with quantitative because of the small cohort. coronary angiography and intravascular ultrasound. J Am Coll Cardiol 2005;46:147–154. We found in 50 patients with chronic AR a perfect 2. Leschka S, Alkadhi H, Plass A, Desbiolles L, Grunenfelder J, agreement between computed tomography and CA on a Marincek B, Wildermuth S. Accuracy of MSCT coronary angiography patient-based analysis when including only evaluative seg- with 64-slice technology: first experience. Eur Heart J 2005;26:1482– ments into the analysis. All 13 patients with significant 1487. CAD were correctly diagnosed with the noninvasive tech- 3. Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, Griffith LS, McGoon DC, Murphy ML, Roe BB. A reporting system on patients nique. In contrast, 13 segments (1.8%) had to be excluded evaluated for coronary artery disease. Report of the Ad Hoc Commit- from analysis, all being distal vessel segments with calcifi- tee for Grading of Coronary Artery Disease, Council on Cardiovascu- cations and motion artifacts. On an intent-to-diagnose basis lar Surgery, American Heart Association. Circulation 1975;51:5–40. and taking into consideration that not completely evaluative 4. Landis JR, Koch GG. The measurement of observer agreement for CT examinations would lead to CA in clinical practice, the categorical data. Biometrics 1977;33:159–174. diagnostic accuracy on a per-patient level revealed a sensi- 5. Garcia MJ, Lessick J, Hoffmann MH. Accuracy of 16-row multidetector computed tomography for the assessment of coronary artery tivity of 100%, specificity of 95%, positive predictive value stenosis. JAMA 2006;296:403–11. of 87%, and negative predictive value of 100%. This rep- 6. Pathak R, Padmanabhan VT, Tortolani AJ, Ong LY, Hall MH, Pizza- resents a drawback of the noninvasive method that might be rello RA. Angina pectoris and coronary artery disease in isolated, overcome with the new generation of dual-source CT scan- severe aortic regurgitation. Am J Cardiol 1986;57:649–651. ners providing a higher temporal resolution.14,15 First expe- 7. Graboys TB, Cohn PF. The prevalence of angina pectoris and abnormal coronary arteriograms in severe aortic valvular disease. Am rience has indicated dual-source computed tomography to Heart J 1977;93:683–686. be a technique that provides a high diagnostic accuracy in 8. Morrison GW, Thomas RD, Grimmer SF, Silverton PN, Smith DR. patients with extensive calcifications while obviating the Incidence of coronary artery disease in patients with valvular heart need for heart rate control.16 However, the prognosis of disease. Br Heart J 1980;44:630–637. patients with CAD is not significantly affected by stenoses 9. Timmermans P, Willems JL, Piessens J, De Geest H. Angina pectoris and coronary artery disease in severe aortic regurgitation. Am J Car- in small vessels and correct lesion identification will have diol 1988;61:826–829. only little impact on revascularization strategies for prog- 10. Holmstrom M, Sillanpaa MA, Kupari M, Kivisto S, Lauerma K. nosis improvement.17,18 Eight-row multidetector computed tomography coronary angiography Regarding the preoperative diagnostic workup of pa- evaluation of significant coronary artery disease in patients with severe tients with chronic AR, CA could have been avoided in 70% aortic valve stenosis. Int J Cardiovasc Imaging 2006;22:703–710. 11. Gilard M, Cornily JC, Pennec PY, Joret C, Le Gal G, Mansourati J, of our patients (35 of 50) when performing computed to- Blanc JJ, Boschat J. Accuracy of multislice computed tomography in mography instead. In 26% (13 of 50), CA would have been the preoperative assessment of coronary disease in patients with aortic performed to confirm the CT diagnosis of Ն1 significant valve stenosis. J Am Coll Cardiol 2006;47:2020–2024. stenosis, and in 4% (2 of 50) an unnecessary CA would have 12. Hoffmann U, Shapiro M. Coronary multidetector computed tomogra- been performed on the basis of false-positive ratings with phy: a new standard for preoperative risk assessment? J Am Coll Cardiol 2006;47:2025–2026. computed tomography. An additional important preopera- 13. Meijboom WB, Mollet NR, Van Mieghem CA, Kluin J, Weustink AC, tive impact of computed tomography in this group of pa- Pugliese F, Vourvouri E, Cademartiri F, Bogers AJ, Krestin GP, de tients is the potential morphologic/anatomic assessment of Feyter PJ. Pre-operative computed tomography coronary angiography 706 The American Journal of Cardiology (www.AJConline.org)

to detect signiﬁcant coronary artery disease in patients referred for 17. Califf RM, Phillips HR III, Hindman MC, Mark DB, Lee KL, Behar cardiac valve surgery. J Am Coll Cardiol 2006;48:1658–1665. VS, Johnson RA, Pryor DB, Rosati RA, Wagner GS, et al. Prognostic 14. Flohr TG, McCollough CH, Bruder H, Petersilka M, Gruber K, Suss C, value of a coronary artery jeopardy score. J Am Coll Cardiol 1985;5: Grasruck M, Stierstorfer K, Krauss B, Raupach R, et al. First perfor- 1055–1063. mance evaluation of a dual-source CT (DSCT) system. Eur Radiol 18. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, 2006;16:256–268. Douglas JS, Ferguson TB Jr, Fihn SD, Fraker TD Jr, Gardin JM, et 15. Achenbach S, Ropers D, Kuettner A, Flohr T, Ohnesorge B, Bruder H, al. ACC/AHA 2002 guideline update for the management of pa- Theessen H, Karakaya M, Daniel WG, Bautz W, Kalender WA, tients with chronic stable angina—summary article: a report of the Anders K. Contrast-enhanced coronary artery visualization by dual- American College of Cardiology/American Heart Association Task source computed tomography—initial experience. Eur J Radiol 2006; Force on practice guidelines (Committee on the Management of 57:331–335. Patients With Chronic Stable Angina). J Am Coll Cardiol 2003;41: 16. Scheffel H, Alkadhi H, Plass A, Vachenauer R, Desbiolles L, Gaem- 159–168. perli O, Schepis T, Frauenfelder T, Schertler T, Husmann L, et al. 19. Alkadhi H, Wildermuth S, Plass A, Bettex D, Baumert B, Leschka S, Accuracy of dual-source CT coronary angiography: First experience in Desbiolles LM, Marincek B, Boehm T. Aortic stenosis: comparative a high pre-test probability population without heart rate control. Eur evaluation of 16-detector row CT and echocardiography. Radiology Radiol 2006;16:2739–2747. 2006;240:47–55. Effect of Primary Mitral Regurgitation on Left Ventricular Synchrony

Thomas S. Denney, Jr., PhDe, Hosakote M. Nagaraj, MDa, Steven G. Lloyd, MD, PhDa, Inmaculada Aban, PhDb, Cecilia Corros, MDa, Frank Seghatol-Eslami, MDa, David C. McGifﬁn, MDc, Louis J. Dell’Italia, MDa,d, and Himanshu Gupta, MDa,*

Mitral regurgitation (MR) promotes left ventricular (LV) dilatation and eccentric remodeling. In the presence of LV dyssynchrony and heart failure, cardiac resynchronization therapy decreases the severity of MR. Whether primary MR can cause LV dyssynchrony is unknown. We investigated whether moderate to severe primary MR causes LV dyssynchrony in the presence of LV dilation and an ejection fraction (EF) >55%. We studied 37 normal subjects and 22 patients with moderate to severe MR and no coronary artery disease. Electrocardiographically gated cine and tagged cardiac magnetic resonance imaging was performed. Two-dimensional, maximum-circumferential shortening strain and time-to-peak strain (TTPS) were computed using harmonic-phase analysis of tagged magnetic resonance imaging. LV dyssynchrony was assessed by comparing TTPS delay of various LV quadrants and TTPS dispersion among the contralateral quadrants in patients with MR and normal subjects. Statistical comparison was done using a generalized linear model for repeated measurements. LV end-diastolic and LV end-systolic volumes were signiﬁcantly larger in patients with MR versus normal subjects (207 ؎ 11 vs 130 ؎ 4 and 5vs47؎ 2 ml, p <0.001). LVEF did not differ in patients with MR and normal ؎ 73 subjects. The difference in the TTPS among various quadrants and the dispersion among the contralateral quadrants of the LV myocardium was similar between patients with MR and normal subjects. In conclusion, moderate to severe MR does not cause LV dyssynchrony in patients with LV dilatation and normal LVEF. Thus, cardiac resynchronization therapy in the absence of LV dyssynchrony may not decrease the severity of MR. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:707–711)

Mitral regurgitation (MR) is a commonly diagnosed clinical method for the assessment of LV dyssynchrony.7 In the entity that is associated with significant morbidity and mor- present study, patients with moderate to severe MR with tality.1–3 Cardiac resynchronization therapy (CRT) in pa- eccentric LV remodeling, LV ejection fraction (EF) Ͼ55%, tients with heart failure has been shown to decrease the and no evidence of myocardial ischemia had cine magnetic severity of MR.4,5 This may be due to electrical and me- resonance imaging and magnetic resonance imaging tissue chanical synchronization that causes increased mitral valve tagging. We demonstrate that moderate to severe MR with leaflet cooptation.4–6 However, it is unknown if MR on its eccentric LV remodeling does not cause LV dyssynchrony own contributes to left ventricular (LV) dyssynchrony in- in patients with normal LVEF. Thus, CRT in the absence of dependent of LV dysfunction. Regional measurements of LV dyssynchrony may not decrease the severity of MR. the timing and magnitude of myocardial shortening using tagged magnetic resonance imaging is an established Methods The study was approved by the institutional review board of aDepartment of Medicine, Division of Cardiology, bDepartment of the University of Alabama at Birmingham and informed Biostatistics, School of Public Health, cDepartment of Surgery, University consent was obtained from all participants. Normal volun- of Alabama at Birmingham, and dBirmingham Department of Veteran teers (n ϭ 37) with no history of heart disease formed the Affairs, Department of Medicine, Division of Cardiology, Birmingham, control cohort. The MR group (n ϭ 22) included patients and eDepartment of Electrical and Computer Engineering, Auburn Univer- with moderate to severe MR. MR on echocardiogram was sity, Auburn, Alabama. Manuscript received December 5, 2006; revised classified as moderate to severe based on the ratio of MR manuscript received and accepted March 20, 2007. area to left atrial area Ն0.40 (or 40%).8 The severity This study was supported by Grants R01HL60707 and R01HL54816 of MR was also confirmed by magnetic resonance from the National Institutes of Health (Bethesda, Maryland) to Dr. imaging.9,10 To exclude any confounding factors of ische- Dell’Italia and Grant P50HL077100 from the Specialized Center for Clin- mia patients with MR and negative coronary angiographic ically Oriented Research in Cardiac Dysfunction. Dr. Lloyd was supported in part by the American College of Cardiology Foundation/GE Healthcare or nuclear stress testing results were included for the Career Development Award in Cardiovascular Imaging. Dr. Corros was a study. fellow sponsored by the Sociedad Española de Cardiologia. Magnetic resonance imaging was performed on a 1.5-T *Corresponding author: Tel: 205-934-7078; fax: 205-934-9730. magnetic resonance imaging scanner (GE, Milwaukee, Wis- E-mail address: [email protected] (H. Gupta). consin) optimized for cardiac application. Electrocardio-

Figure 1. Tagged magnetic resonance images of a normal volunteer at LV midlevel at end-diastole (A) and end-systole (B). (C) The end-systole image is overlaid with a map of regional maximum shortening (0% shortening is mapped to blue, 25% shortening is mapped to yellow).

Table 1 Table 2 Baseline parameters in patients with mitral regurgitation and normal Magnetic resonance imaging parameters in patients with mitral subjects regurgitation and normal subjects Variable Normal MR MRI Variable Normal MR p Value (n ϭ 37) (n ϭ 22) (n ϭ 37) (n ϭ 22) Age (yrs) 39 Ϯ 11 53 Ϯ 10 LV end-diastolic volume (ml) 130 Ϯ 4 207 Ϯ 11 Ͻ0.001 Men 16 (44%) 13 (60%) LV end-systolic volume (ml) 47 Ϯ 273Ϯ 5 Ͻ0.001 Hypertension 1 (3%) 6 (28%) LV stroke volume (ml) 83 Ϯ 3 134 Ϯ 7 Ͻ0.001 Diabetes mellitus 0 1 (5%) Right ventricular end-diastolic 127 Ϯ 5 147 Ϯ 8NS Body surface area (m2) 1.97 Ϯ 0.22 1.84 Ϯ 0.46 volume (ml) Heart rate (beats/min) 73 Ϯ 11 69 Ϯ 13 Right ventricular end-systolic 59 Ϯ 368Ϯ 5NS Mean systolic blood pressure (mm Hg) 125 118 volume (ml) Mean diastolic blood pressure (mm Hg) 75 74 Right ventricular stroke 70 Ϯ 379Ϯ 5NS volume (ml) Right ventricular EF (%) 55 Ϯ 154Ϯ 2NS graphically gated breath-hold steady-state free precision LVEF (%) 64 Ϯ 164Ϯ 1NS LV mass (g) 115 Ϯ 6 141 Ϯ 8 0.01 technique was used to obtain standard (2-, 3-, and 4-cham- ϫ Ϯ Ϯ ber short-axis) views using the following parameters: slice 2 posterior wall thickness/ 0.32 0.01 0.26 0.0 0.001 ϫ LV end-diastolic dimension thickness of the imaging planes 8 mm, field of view 44 Ϯ Ϯ ϫ ␣ ϭ LV end-diastolic volume/LV 1.21 0.06 1.49 0.0 0.006 44, scan matrix 256 128., flip angle 45°, repetition/ mass (ml/g) echo times 3.8/1.6). Fast gradient echocardiographic sequence with a 2-dimensional spatial modulation of magne- MRI ϭ magnetic resonance imaging. tization tagging preparation was done using exactly the same slice prescription as above. GE Advantage Worksta- timeframes after the timeframe closest to end-systole. These tion with Mass Medis 2.0 (Lieden, The Netherlands) soft- 5 timeframes around end-systole constituted a search win- ware with semiautomated contour detection was used for dow over which the peak strain and TTPS were computed. quantifying LV and right ventricular volumes, LVEF, and The LV wall in each image was divided into 4 sectors right ventricular EF.11–13 Severity of MR on magnetic res- starting at the anterior right ventricular insertion point. In onance images was based on previously published criterion each timeframe in the search window, the median 2-dimen- for the intensity and width of the regurgitant jet.9,10,14,15 sional, maximum-shortening strain was computed in each Two-dimensional, maximum-shortening strain was com- sector over the basal, middle, and apical thirds of the LV. puted in each image using the harmonic-phase analysis.16,17 This procedure produced 12 strain values (4 sectors and 3 Two-dimensional, maximum-shortening strain is the maxi- levels) per timeframe for each subject. In each sector and mum contraction at a given point and is approximately level, a quadratic polynomial was fitted to the strains versus circumferential in orientation. Peak 2-dimensional myocar- timeframe data. The peak strain was defined as the maxi- dial strain and time-to-peak strain (TTPS) were computed mum magnitude fitted strain. End-systole was determined for each subject. The TTPS was defined as the time at which from cine -magnetic resonance imaging. The raw images the peak strain was attained.16,17 The local strain of tissue is were visually inspected before processing and found to have measured based on the spatial frequency of the tag lines as no significant difference in wall motion between the various shown in Figure 1. For strain analysis, LV wall contours LV quadrants. Therefore it is unlikely that the true peak were semiautomatically drawn using custom-written soft- strain occurred outside the defined time window for calcu- ware on each short-axis slice 2 timeframes before and 2 lating the peak strain. Valvular Heart Disease/Primary Mitral Regurgitation and LV Synchrony 709

Table 3 Peak strains in all four quadrants at all three levels in patients with mitral regurgitation and normal subjects Level Quadrant Normal MR p Value (n ϭ 37) (n ϭ 22) Midventricle Anterior 0.17 Ϯ 0.003 0.19 Ϯ 0.004 0.007 Septal 0.16 Ϯ 0.003 0.16 Ϯ 0.005 0.261 Inferior 0.17 Ϯ 0.004 0.17 Ϯ 0.005 0.177 Lateral 0.20 Ϯ 0.005 0.20 Ϯ 0.003 0.232 Base Anterior 0.16 Ϯ 0.003 0.17 Ϯ 0.004 0.023 Septal 0.14 Ϯ 0.006 0.14 Ϯ 0.003 0.785 Inferior 0.17 Ϯ 0.003 0.16 Ϯ 0.006 0.243 Lateral 0.19 Ϯ 0.003 0.19 Ϯ 0.004 0.507 Apex Anterior 0.21 Ϯ 0.004 0.21 Ϯ 0.003 0.232 Septal 0.19 Ϯ 0.004 0.19 Ϯ 0.005 0.807 Inferior 0.19 Ϯ 0.003 0.19 Ϯ 0.006 0.367 Lateral 0.21 Ϯ 0.002 0.21 Ϯ 0.003 0.201

tiple readings per participant, analyses were done using a generalized linear model for repeated measurements with the PROC MIXED procedure in SAS (SAS Institutes, Cary, North Carolina). It was assumed that the differences in the TTPS between the 2 groups, if present, would depend on the myocardial slice and sector location. All statistical tests were performed using a 5% level of signiﬁcance.

Results Twenty-two patients with MR (13 men, mean 53 Ϯ 10 years of age) and 37 normal subjects (16 men, mean 39 Ϯ 11 years of age) were included in this study. Baseline characteristics and clinical parameters are presented in Table 1. All participants in the MR group were ruled out for ischemic heart disease as a cause for MR with cardiac catheterization (n ϭ 10) or maximal exercise stress test with myocardial perfusion imaging (n ϭ 15). All participants with MR had normal QRS duration on surface 12-lead electrocardiogram (QRS duration Ͻ100 ms, 2 patients in the MR group had incomplete right branch bundle block). Magnetic resonance imaging and 2-dimensional echocardiography confirmed moderate to severe MR in all participants in the MR group. Magnetic resonance imaging LV volumes and functional parameters in the MR and normal groups are listed in Table 2. Figure 2. Absolute TTPS for all 4 quadrants of the –left ventricle: anterior Patients with MR had a Ͼ50% increase in LV end- (Ant), septal (Sept), inferior (Inf), and lateral (Lat) at the LV midventricle (A), base (B), and apex (C) in the MR compared with normal group. TTPS diastolic volume. Patients with MR had a significant difference among various quadrants was not significant (p ϭ NS) indicat- increase in LV mass with eccentric LV remodeling in ing the absence of LV dyssynchrony in the MR group. addition to well-preserved LVEF with a larger LV stroke volume compared with controls. Right ventricular vol- The baseline characteristics of the 2 groups described by umes and function did not differ in patients with MR and categorical variables were compared using chi-squared tests normal subjects. Tagged magnetic resonance imaging– and Fisher’s exact test, where applicable. For continuous derived TTPS parameters are shown in Figure 2. The variables, we used the t test or nonparametric Wilcoxon test peak strain values were different in the anterior walls of for comparing 2 independent variables. To investigate the the left ventricle at basal and midventricular levels com- difference between normal participants and patients with pared with controls (Table 3). The TTPS dispersion be- MR for LV dyssynchrony, the range of TTPS difference tween the contralateral quadrants (lateral/septal and an- among the quadrants of the LV wall and the TTPS disper- terior/inferior) quadrants at all the 3 levels is presented in sion among lateral/septal and anterior/inferior quadrants at 3 Figure 3. Patients with MR did not demonstrate signifi- different locations were analyzed. Because there were mul- cant LV dyssynchrony despite significant LV dilatation. 710 The American Journal of Cardiology (www.AJConline.org)

Figure 3. TTPS dispersion among contralateral quadrants in the MR (gray bars) compared with normal (black bars) group at the LV mid, base, and apex levels. The TTPS dispersion among septal/lateral (A) and anterior/inferior (B) quadrants in the MR versus normal groups was not signiﬁcant (p ϭ NS) indicating the absence of LV dyssynchrony in the MR group.

Discussion tients had LVEFs Ͼ55%, which precluded testing this hypothesis. In the presence of LV dyssynchrony and heart failure, CRT To our knowledge this is the first study to demonstrate results in reversal of LV remodeling and in improvements in that in patients with severe MR, significant LV remodeling, the severity of MR.5,6,18–20 Thus, it has been suggested that and preserved systolic function there is no evidence of LV primary MR can cause LV dyssynchrony. However, these dyssynchrony. Thus, our results suggest that CRT may be studies could not differentiate the effect of CRT on changes ineffective in decreasing the severity of MR in such patients in LV chamber geometry versus severity of MR on LV and that, in patients with MR and LV dysfunction with dyssynchrony. The major finding of this study is that there concomitant dyssynchrony, MR may just be a surrogate is no evidence of LV dyssynchrony in patients with mod- indicator of CRT’s efficacy in reverse LV remodeling rather erate to severe MR with a dilated left ventricle and normal than the target for therapy. LVEF, militating against a causal relation between MR and LV dyssynchrony. 1. Rosenhek R, Rader F, Klaar U, Gabriel H, Krejc M, Kalbeck D, To determine whether MR may be contributing to LV Schemper M, Maurer G, Baumgartner H. Outcome of watchful waiting dyssynchrony, we enrolled participants with moderate to in asymptomatic severe mitral regurgitation. Circulation 2006;113: severe MR with Ͼ50% increase in LV end-diastolic and 2238–2244. end-systolic volumes with normal LVEF (mean 64%). Tis- 2. Grigioni F, Avierinos JF, Ling LH, Scott CG, Bailey KR, Tajik AJ, Frye RL, Enriquez-Sarano M. Atrial fibrillation complicating the sue Doppler imaging in echocardiography has been used to course of degenerative mitral regurgitation: determinants and long- 4,11,21 assess LV dyssynchrony where LV dyssynchrony is term outcome. J Am Coll Cardiol 2002;40:84–92. defined by maximum delay between peak systolic velocities 3. Tribouilloy CM, Enriquez-Sarano M, Schaff HV, Orszulak TA, Bailey of the septal to lateral LV segments Ն65 ms (referred to as KR, Tajik AJ, Frye RL. Impact of preoperative symptoms on survival the septal-to-lateral delay).22,23 In this study, we evaluated after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications. Circulation 1999;99:400–405. LV dyssynchrony in patients with MR and normal subjects 4. Yu CM, Chau E, Sanderson JE, Fan K, Tang MO, Fung WH, Lin H, by measuring the difference in TTPS within myocardial Kong SL, Lam YM, Hill MR, Lau CP. Tissue Doppler echocardio- segments and between contralateral myocardial quadrants graphic evidence of reverse remodeling and improved synchronicity from tagged magnetic resonance imaging.7 In our patients by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438–445. with MR compared with normals, there was no difference in 5. Abraham WT. Cardiac resynchronization therapy. Prog Cardiovasc TTPS among the various quadrants of the LV segments. Dis 2006;48:232–238. Furthermore, TTPS dispersion among the contralateral 6. Sutton MG, Plappert T, Hilpisch KE, Abraham WT, Hayes DL, Chin- quadrants from LV base to apex did not differ in patients choy E. Sustained reverse left ventricular structural remodeling with with MR and the normal control population. cardiac resynchronization at one year is a function of etiology: quantitative Doppler echocardiographic evidence from the Multicenter In- The severity of MR and the magnitude of ventricular Sync Randomized Clinical Evaluation (MIRACLE). Circulation 2006; dyssynchrony can change during exercise.24 Effects of such 113:266–272. dynamic changes in MR and its association with dyssyn- 7. Lardo AC, Abraham TP, Kass DA. Magnetic resonance imaging chrony were not evaluated because these variables were assessment of ventricular dyssynchrony: current and emerging con- beyond the scope of the present study. In our MR group cepts. J Am Coll Cardiol 2005;46:2223–2228. 8. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, there was significant LV remodeling as indicated by a 60% Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski increase in LV end-diastolic volume and eccentric LV hy- H, et al. Recommendations for evaluation of the severity of native pertrophy. However, we cannot rule out the possibility that valvular regurgitation with two-dimensional and Doppler echocardi- more extensive LV remodeling with systolic dysfunction ography. J Am Soc Echocardiogr 2003;16:777–802. 9. Kon MW, Myerson SG, Moat NE, Pennell DJ. Quantification of would result in LV dyssynchrony. This may be true when regurgitant fraction in mitral regurgitation by cardiovascular magnetic the LVEF decreases to low normal (i.e., 50%), which would resonance: comparison of techniques. J Heart Valve Dis 2004;13:600– be indicative of LV dysfunction in primary MR. Our pa- 607. Valvular Heart Disease/Primary Mitral Regurgitation and LV Synchrony 711

10. Hundley WG, Li HF, Willard JE, Landau C, Lange RA, Meshack BM, 18. St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio Hillis LD, Peshock RM. Magnetic resonance imaging assessment of DB, Leon AR, Loh E, Kocovic DZ, Fisher WG, Ellestad M, et al. the severity of mitral regurgitation: comparison with invasive tech- Effect of cardiac resynchronization therapy on left ventricular size and niques. Circulation 1995;92:1151–1158. function in chronic heart failure. Circulation 2003;107:1985–1990. 11. Westenberg JJ, Lamb HJ, van der Geest RJ, Bleeker GB, Holman ER, 19. Yu CM, Bleeker GB, Fung JW, Schalij MJ, Zhang Q, van der Wall EE, Schalij MJ, de Roos A, van der Wall EE, Reiber JH, Bax JJ. Assess- Chan YS, Kong SL, Bax JJ. Left ventricular reverse remodeling but ment of left ventricular dyssynchrony in patients with conduction not clinical improvement predicts long-term survival after cardiac delay and idiopathic dilated cardiomyopathy: head-to-head compari- resynchronization therapy. Circulation 2005;112:1580–1586. son between tissue Doppler imaging and velocity-encoded magnetic 20. Linde C, Leclercq C, Rex S, Garrigue S, Lavergne T, Cazeau S, resonance imaging. J Am Coll Cardiol 2006;47:2042–2048. McKenna W, Fitzgerald M, Deharo JC, Alonso C, et al. Long-term 12. Rajappan K, Livieratos L, Camici PG, Pennell DJ. Measurement of benefits of biventricular pacing in congestive heart failure: results from ventricular volumes and function: a comparison of gated PET and the MUltisite STimulation in cardiomyopathy (MUSTIC) study. JAm cardiovascular magnetic resonance. J Nucl Med 2002;43:806–810. Coll Cardiol 2002;40:111–118. 13. Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ. Reduc- 21. Bordachar P, Lafitte S, Reuter S, Sanders P, Jais P, Haissaguerre M, tion in sample size for studies of remodeling in heart failure by the use Roudaut R, Garrigue S, Clementy J. Echocardiographic parameters of of cardiovascular magnetic resonance. J Cardiovasc Magn Reson ventricular dyssynchrony validation in patients with heart failure using 2000;2:271–278. J Am Coll Cardiol 14. Westenberg JJ, Danilouchkine MG, Doornbos J, Bax JJ, van der Geest sequential biventricular pacing. 2004;44:2157– RJ, Labadie G, Lamb HJ, Versteegh MI, de Roos A, Reiber JH. 2165. Accurate and reproducible mitral valvular blood flow measurement 22. Bleeker GB, Kaandorp TA, Lamb HJ, Boersma E, Steendijk P, de with three-directional velocity-encoded magnetic resonance imaging. Roos A, van der Wall EE, Schalij MJ, Bax JJ. Effect of posterolateral J Cardiovasc Magn Reson 2004;6:767–776. scar tissue on clinical and echocardiographic improvement after car- 15. Westenberg JJ, Doornbos J, Versteegh MI, Bax JJ, van der Geest RJ, diac resynchronization therapy. Circulation 2006;113:969–976. de Roos A, Dion RA, Reiber JH. Accurate quantitation of regurgitant 23. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk volume with MRI in patients selected for mitral valve repair. Eur P, van der Wall EE, Schalij MJ. Left ventricular dyssynchrony predicts J Cardiothorac Surg 2005;27:462–467. response and prognosis after cardiac resynchronization therapy. JAm 16. Osman NF, Kerwin WS, McVeigh ER, Prince JL. Cardiac motion Coll Cardiol 2004;44:1834–1840. tracking using CINE harmonic phase (HARP) magnetic resonance 24. Lafitte S, Bordachar P, Lafitte M, Garrigue S, Reuter S, Reant P, Serri imaging. Magn Reson Med 1999;42:1048–1060. K, Lebouffos V, Berrhouet M, Jais P, et al. Dynamic ventricular 17. Osman NF ME, Prince JL. Imaging heart motion using harmonic phase dyssynchrony: an exercise-echocardiography study. J Am Coll Cardiol MRI. IEEE Trans Med Imaging 2000;19:186–202. 2006;47:2253–2259. Usefulness of Brain Natriuretic Peptide Levels in the Clinical Evaluation of Patients With Hypertrophic Cardiomyopathy

Josepha Binder, MD, Steve R. Ommen, MD*, Horng H. Chen, MD, Michael J. Ackerman, MD, PhD, A. Jamil Tajik, MD, and Allan S. Jaffe, MD

Hypertrophic cardiomyopathy (HC) is associated frequently with heart failure symptoms and diastolic dysfunction. Although the influence of brain natriuretic peptide (BNP) levels in the management of patients with systolic dysfunction is evolving, there are few data on the role of BNP in the management of patients with HC. BNP was compared with clinical and echocardiographic variables, including measures of diastolic filling, in 217 patients with HC. BNP values were correlated with New York Heart Association classification, echocardiographic estimates of diastolic filling pressure, and right ventricular systolic pressure even after adjusting for age, gender, renal function, and body habitus. However, the overlap of the BNP levels in these respective categories was notable. BNP values did not correlate with objective measures of exercise capacity, and serial BNP values did not track changes in clinical status. In conclusion, BNP levels in patients with HC are associated with similar subjective and objective measures as have been observed in patients with left ventricular systolic dysfunction, but these correlations are relatively weak and do not allow the precise characterization of clinical status. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:712–714)

Several studies have reported the elevation of brain natriuretic cally included spectral Doppler analysis (Table 2). LV wall peptide (BNP) levels in hypertrophic cardiomyopathy (HC), stress was estimated using the formula (systolic blood pres- especially in obstructive HC.1–4 Plasma BNP levels were re- sure ϫ LV outflow tract gradient at rest ϫ LV end-diastolic lated to the presence and magnitude of heart failure symptoms dimension)/mean LV wall thickness. Diastolic function was in patients with HC, but the association of BNP levels with classified in 3 categories: normal filling pressure was de- measures of diastolic dysfunction was less clear in this group fined by normal left atrial volume index, E/A ratio Ͼ0.75 to than in many others.5,6 The present study was designed to 1.5 and E/e= ratio Ͻ15 or by E/A ratio Յ0.75 and E/E= ratio correlate clinical status and echocardiographic parameters as Ͻ15. Intermediate increased filling pressure was defined as the standard parameters of diastolic function to plasma levels E/A ratio Ͼ0.75, deceleration time Ͼ160 ms, and Ն2ofthe of BNP in a large population of patients with HC. following parameters: increased left atrial volume index, E/e= ratio Ͼ12, decrease in E/A ratio by 0.5 during the Methods and Results Valsalva maneuver, pulmonary vein diastolic flow velocity Ͼ This was a retrospective study of 217 patients with HC who 2 times pulmonary vein systolic velocity, pulmonary vein Ͼ also had documented measurements of BNP. The clinical atrial reversal velocity 0.35 m/s, or pulmonary vein atrial diagnosis of HC was based on the echocardiographic dem- reversal flow duration exceeding mitral A-wave flow dura- onstration of left ventricular (LV) hypertrophy in the ab- tion by Ͼ30 ms. Severe diastolic dysfunction was defined sence of other disease processes known to promote hyper- by Ն2 of the following parameters: E/A ratio Ͼ1.5, decel- trophy. The protocol was approved by the Mayo Foundation eration time Ͻ160 ms, or E/e= ratio Ͼ15. Patients who did Institutional Review Board. not meet these criteria because of coexistent atrial fibrilla- Data collected from medical records are listed in Table 1. tion or lack of complete data were classified as having Creatinine clearance was calculated using the Cockcroft- indeterminate diastolic function and excluded from analysis. Gault equation: glomerular filtration rate ϭ [(140 Ϫ age) ϫ Descriptive statistics are reported as mean Ϯ SD for weight in kilograms]/(creatinine ϫ 72)]. Samples for the continuous variables and as frequencies and percentages for determination of BNP were obtained, immediately placed nominal and ordinal variables. Because BNP values are on crushed ice, and run Ͻ2 hours after collection with the known to be dependent on age and gender, the BNP values Biosite assay (Biosite Inc., San Diego, California). were indexed to the normal range for each patient.7 The All the echocardiographic variables were measured ac- natural logarithms of these indexed values were used to cording to the recommendations of the American Society of create a normal distribution for statistical analysis. Univar- Echocardiography and were taken from the original mea- iate associations were assessed using Pearson’s correlation surement at the time of the echocardiography and specifi- coefficients for continuous variables and analysis of variance for categorical variables. Variables with significant univariate associations, defined as p Ͻ0.05, with BNP were Mayo Clinic College of Medicine, Rochester, Minnesota. Manuscript received February 7, 2007; revised manuscript received and accepted entered into multiple linear regression. March 13, 2007. Demographic and clinical variables are listed in Table 1. *Corresponding author: Tel: 507-284-8260; fax: 507-266-0103. The mean BNP value was 209 Ϯ 232 pg/ml (range 4 to E-mail address: [email protected] (S.R. Ommen). 1,540), and the mean normalized BNP value was 3.3 Ϯ 4

Table 1 Demographic and clinical characteristics of 217 patients with hypertrophic cardiomyopathy and brain natriuretic peptide measurement Variable Value BNP (pg/ml) 209 Ϯ 232 BNP indexed to normal range 3.3 Ϯ 4 Log-normalized BNP index 0.67 Ϯ 1.1 Age (yrs) 54.9 Ϯ 15.8 Body surface area (m2) 2.00 Ϯ 0.3 Body mass index 30.2 Ϯ 7 Creatinine clearance (ml/min/m2) 95.2 Ϯ 40.9 Men 127 (59%) Family history of sudden death 34 (16%) Family history of HC 60 (28%) LV outflow tract obstruction at rest 122 (56%) Previous surgical myectomy 73 (33%) Figure 1. Relation between NYHA functional class and measured BNP NYHA class values. I 65 (30%) II 58 (27%) III 87 (40%) IV 7 (3%) Diastolic function Normal filling pressure 78 (36%) Increased filling pressure 139 (64%)

Table 2 Echocardiographic characteristics of 217 patients with HC and brain natriuretic peptide measurement Variable Value Mitral regurgitation grade 0 65 (30%) 1 120 (55%) 2 26 (12%) Figure 2. Relation between Doppler-estimated LV ﬁlling pressure and 3 6 (3%) measured BNP values. LV outﬂow tract gradient at rest (mm Hg) 28.7 Ϯ 29.6 Septal thickness (mm) 17.8 Ϯ 5.5 LV mass index (g/m2) 145.8 Ϯ 47.9 LV ejection fraction (%) 71.1 Ϯ 47.9 Left atrial volume index (ml/m2) 44.4 Ϯ 17.7 E-wave velocity (m/s) 0.88 Ϯ 0.29 A-wave velocity (m/s) 0.78 Ϯ 0.33 E/A ratio 1.32 Ϯ 0.76 DT (ms) 232.8 Ϯ 61.9 e= velocity (m/s) 0.056 Ϯ 0.019 E/e= ratio 17.3 Ϯ 8.4 Right ventricular systolic pressure (mm Hg) 37.3 Ϯ 12 Calculated wall stress (mm Hg ϫ mm/mm) 469.0 Ϯ 152

times the upper limit of normal (range 0.8 to 42.8). BNP values were significantly higher in patients with New York Figure 3. Relation between Doppler-estimated right ventricular systolic Ͻ Heart Association (NYHA) class III or IV symptoms com- pressure (RVSP) and measured BNP values (p 0.0001). pared with less symptomatic patients (4.7 Ϯ 6vs2.3Ϯ 3 times the upper limit of normal, p ϭ 0.0001). Figure 1 displays the relation and considerable overlap between mea- Variables with significant univariate relations with BNP ϭ sured BNP values and clinical NYHA classification. were limited to age (p 0.04), LV outflow tract gradient at Echocardiographic variables are listed in Table 2. BNP rest (p ϭ 0.0005), septal wall thickness (p Ͻ0.0001), LV values correlated with the severity of diastolic function. mass index (p Ͻ0.0001), left atrial volume index BNP values were 2.0 Ϯ 0.8 versus 2.3 Ϯ 0.6 versus 4.0 Ϯ (p Ͻ0.0001), mitral A-wave velocity (p ϭ 0.007), E/A ratio 0.4 times the upper limit of normal among patients with (p ϭ 0.0004), mitral annular e= velocity (p Ͻ0.0001), E/e= mild, intermediate, and severe dysfunction, respectively ratio (p Ͻ0.0001), calculated LV wall stress (p ϭ 0.01), and (p Ͻ0.0001; Figure 2). right ventricular systolic pressure (p Ͻ0.0001) (Figure 3). 714 The American Journal of Cardiology (www.AJConline.org)

Multivariate analysis adjusting for gender, creatinine as tissue Doppler imaging,9 has improved the noninvasive clearance, and body surface area showed that age (p ϭ estimation of filling pressures, and in the present study, 0.003), septal thickness (p ϭ 0.01), mitral annular e= veloc- diastolic function was clearly associated with symptom ity (p ϭ 0.03), and right ventricular systolic pressure class. Although it has been demonstrated that increased (p Ͻ0.0001) were the only independent variables. When diastolic filling pressures should correlate with increased overall diastolic function grade, which incorporates multi- ventricular stretch and in turn increases in measured BNP ple echocardiographic parameters, was substituted into the and observed symptoms,6 the present data clearly confirm model, age (p ϭ 0.02), gender (p ϭ 0.02), septal thickness complex and incompletely understood interactions in pa- (p ϭ 0.01), diastolic grade (p ϭ 0.01), and right ventricular tients with HC, because calculated wall stress was only systolic pressure (p Ͻ0.0001) were the only variables with weakly associated with BNP levels and did not enter the independent relations to the log-normalized indexed BNP multivariate models. The relative roles of variably increased 2 value (overall fit of model: r ϭ 0.37, p Ͻ0.0001). wall thickness and intramyocardial fibrosis as modulators of Objective measurements of peak oxygen consumption BNP secretion warrant further evaluation. Likewise, out- were available in 103 patients. The mean peak oxygen comes data may be helpful in ultimately determining Ϯ consumption was 21.1 6mlO2/kg/min. There was close whether there is any role for BNP assessment in the eval- correlation between NYHA functional class and peak oxy- uation and management of patients with HC. In summary, gen consumption. Patients in NYHA classes I and II Ϯ BNP is correlated with symptom status and diastolic filling achieved 72 18% of age- and gender-predicted peak pressures in patients with HC, even after adjustment for oxygen consumption, whereas those in classes III and IV Ϯ ϭ confounding demographic and echocardiographic variables. achieved 60 17% (p 0.0004). After adjusting for age However, the clinical utility of determination of BNP is not and gender, BNP measurements did not correlate with peak readily apparent. oxygen consumption measurements. Fifty-six patients had Ն2 clinical evaluations that in- 1. Hasegawa K, Fujiwara H, Doyama K, Miyamae M, Fujiwara T, Suga S, cluded BNP measurements. The evaluations were on aver- Mukoyama M, Nakao K, Imura H, Sasayama S. Ventricular expression age 300 days apart (range 5 to 732). BNP was decreased of brain natriuretic peptide in hypertrophic cardiomyopathy. Circulation (improved) at the second evaluation in 33 patients (59%) 1993;88:372–380. and increased in the remainder. The mean change in mea- 2. Nishigaki K, Tomita M, Kagawa K, Noda T, Minatoguchi S, Oda H, sured BNP values was a decrease by 10 pg/ml (range Ϫ447 Watanabe S, Morita N, Nakao K, Fujiwara H. Marked expression of ϩ plasma brain natriuretic peptide is a special feature of hypertrophic to 1,650). There were no significant associations between obstructive cardiomyopathy. J Am Coll Cardiol 1996;28:1234–1242. the change in BNP levels and any of the other serial mea- 3. Maron BJ, Tholakanahalli VN, Zenovich AG, Casey SA, Duprez D, surements, including symptom class, diastolic filling pres- Aeppli DM, Cohn JN. Usefulness of B-type natriuretic peptide assay in sure, and right ventricular systolic pressure. the assessment of symptomatic state in hypertrophic cardiomyopathy. Circulation 2004;109:984–989. 4. Ogino K, Ogura K, Kinugawa T, Osaki S, Kato M, Furuse Y, Kinugasa Discussion Y, Tomikura Y, Igawa O, Hisatome I, Shigemasa C. Neurohumoral The utility of BNP as a marker of clinical severity in HC has profiles in patients with hypertrophic cardiomyopathy: differences to hypertensive left ventricular hypertrophy. Circ J 2004;68:444–450. been suggested, but not conclusively demonstrated, by other 5. Mottram PM, Leano R, Marwick TH. Usefulness of B-type natriuretic studies using BNP to distinguish between obstructive and peptide in hypertensive patients with exertional dyspnea and normal left nonobstructive forms of HC or the relation of BNP to ventricular ejection fraction and correlation with new echocardiographic NYHA classification.1–4 The present study was unique in indexes of systolic and diastolic function. Am J Cardiol 2003;92:1434– that it used rigorously defined criteria to assess LV diastolic 1438. 6. Troughton RW, Prior DL, Pereira JJ, Martin M, Fogarty A, Morehead filling pressure and included subsets of patients with objec- A, Yandle TG, Richards AM, Starling RC, Young JB, et al. Plasma tively measured exercise capacity and/or serial BNP deter- B-type natriuretic peptide levels in systolic heart failure: importance of minations. The overall results suggest that although there is left ventricular diastolic function and right ventricular systolic function. a statistical association between noninvasive measures of J Am Coll Cardiol 2004;43:416–422. filling and measured BNP, there are complex interactions 7. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, that are not readily apparent. Likewise, the clinical utility of Burnett JC, Jr.Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol 2002;40:976–982. BNP in the management of HC is doubtful, because there 8. Nishimura RA, Appleton CP, Redfield MM, Ilstrup DM, Holmes DR Jr, were no clear relations to changes in subjective assessment Tajik AJ. Noninvasive Doppler echocardiographic evaluation of left of clinical status nor to objective measures of exercise ventricular filling pressures in patients with cardiomyopathies: a simul- capacity. taneous Doppler echocardiographic and cardiac catheterization study. It has been demonstrated that the assessment of diastolic J Am Coll Cardiol 1996;28:1226–1233. 9. Nagueh SF, Lakkis NM, Middleton KJ, Spencer WH III, Zoghbi WA, function in HC is more complex and in fact that the stan- Quinones MA. Doppler estimation of left ventricular filling pressures in dard, traditional assessment of mitral inflow does not apply patients with hypertrophic cardiomyopathy. Circulation 1999;99:254– to patients with HC.8 The addition of newer modalities, such 261. Usefulness of Magnetic Resonance Angiography in the Evaluation of Complex Congenital Heart Disease in Newborns and Infants

Ashwin Prakash, MDa,b,*, Alejandro J. Torres, MDa, Beth F. Printz, MD, PhDa,b, Martin R. Prince, MD, PhDb, and James C. Nielsen, MDc

This study evaluated the quality of the visualization of extracardiac thoracic vessels by magnetic resonance angiography (MRA) in young infants with congenital heart disease. Echocardiography is often sufﬁcient in evaluating CHD in young infants. Cardiac catheterization is needed in some instances to evaluate extracardiac thoracic vessels. Extracar- diac thoracic vessels can be accurately evaluated using MRA in adults and older children, but image quality in small infants may be limited. Twenty-nine magnetic resonance angiographic scans were performed at a single institution on 28 infants aged <3 months (median 6 days, range 1 to 90 days) with complex CHD in whom imaging was inconclusive by echocardiography. A blinded observer at a different institution graded (from 0 to 3) the quality of the visualization of the main, branch, lobar, and second-generation pulmonary arteries; lobar pulmonary veins; aortopulmonary collaterals; vena cavae; thoracic aorta and its branches; patent ductus arteriosus; and visceral sidedness. The results of MRA were compared with those of x-ray angiography and surgical inspection, when available. The mean image quality grade was >2 for all structures except the second-generation pulmonary arterial branches, for which it was 2. The median total scan duration was 9 minutes and cardiac (25 ؍ range 3 to 46). Findings were concordant with surgical inspection (n) in all subjects. There were no complications. In conclusion, MRA (8 ؍ catheterization (n is excellent for the visualization of extracardiac thoracic vessels in young infants with CHD and can be used as an alternative to cardiac catheterization when echocardiography is inconclusive. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:715–721)

Three-dimensional contrast-enhanced magnetic resonance Methods angiography (MRA) is a noninvasive technique that has Study population: All infants aged Ͻ3 months with been shown to be accurate in the delineation of vascular CHD who underwent contrast-enhanced MRA at Morgan anatomy in adults and older children and may be used Stanley Children’s Hospital of New York Presbyterian from instead of x-ray angiography.1–5 However, the routine use of March 2004 to February 2005 were included in this retro- this technique in young infants (aged Ͻ3 months) has been spective study. The primary diagnosis for each subject is limited by technical problems, including low image signal- listed in Table 1. The Columbia University Institutional to-noise ratio, artifacts related to respiratory motion, hypo- Review Board gave permission for the review of existing thermia, bolus timing, and the lack of adequately sized data. The decision to perform MRA and/or cardiac cathe- receiver coils. The effects of these technical limitations on terization was made by the patient’s cardiologist on a case- the quality of the visualization of individual thoracic vessels by-case basis. and on the diagnostic accuracy of MRA in this age group Magnetic resonance angiographic protocol: Magnetic are not known. To define the role of MRA in the evaluation resonance angiographic studies were performed using a of these infants, it is important to systematically assess the 1.5-T whole-body scanner (Signa EXCITE; General Elec- quality of the visualization and diagnostic accuracy of MRA tric, Milwaukee, Wisconsin), using a commercially avail- related to each thoracic vascular structure of interest in this able 4-element head-imaging coil. All infants were sedated, patient population. We evaluated the image quality of the paralyzed, and mechanically ventilated during the examina- pulmonary arterial bed and other extracardiac thoracic ves- tions. MRA was performed in the coronal orientation using sels by MRA in newborns and young infants with congen- the following imaging parameters: field of view 200 mm, ital heart disease (CHD). matrix 192 (phase) and 256 (frequency), slice thickness 2 mm, echo time 1.1 ms, repetition time 3.4 to 3.7 ms, flip angle 40°, receiver band width 31.3 kHz, number of signal averages 1, sequential phase ordering, number of dynamics aDivision of Pediatric Cardiology and bDepartment of Radiology, Co- c 3, and acquisition time 25 to 35 s/dynamic. Gadopentate lumbia University College of Physicians and Surgeons; and Division of dimeglumine (Magnevist; Berlex Laboratories, Seattle, Pediatric Cardiology, Mount Sinai School of Medicine, New York, New Washington) (0.4 to 0.5 mmol/kg) followed by a normal York. Manuscript received January 5, 2007; revised manuscript received 3 and accepted March 7, 2007. saline flush (1 cm /kg) was manually injected in a periph- *Corresponding author: Tel: 212-305-8261; fax: 212-305-4429. eral or central vein in the upper or lower extremity at a rate E-mail address: [email protected] (A. Prakash). of approximately 0.5 to 1 cm3/s. After the suspension of

Table 1 were graded separately. The aortopulmonary collaterals Primary cardiac diagnoses were graded as a group in each subject. Diagnosis n Comparison with findings of x-ray angiography and Single ventricle physiology 10 surgical inspection: The specific diagnostic questions at Pulmonary venous anomaly 4 referral for each magnetic resonance angiographic scan Scimitar syndrome 4 were determined from the official magnetic resonance an- Tetralogy of Fallot, pulmonary atresia 5 giographic report. Subjects in whom specific confirmation Left pulmonary artery sling 2 of the diagnostic question by x-ray angiography or surgical Situs inversus, coarctation of aorta 1 inspection (performed within 3 months of MRA) was avail- Truncus arteriosus with isolated left pulmonary artery 1 able were identified. For these subjects, the magnetic reso- Tetralogy of Fallot, absent pulmonary valve 1 nance angiographic diagnoses for each anatomic segment in question were recorded by an observer who is an expert in Table 2 the magnetic resonance imaging of CHD (AP). For all Image quality grading scale subjects, the magnetic resonance angiographic diagnosis of Grade Description the anatomic segment in question preceded the catheterization or surgical procedure. X-ray angiographic images for 0 Structure not seen due to poor image quality these subjects were reviewed by an expert in congenital 1 Structure seen with indistinct margins, image quality cardiac catheterization (AJT), and all vascular diagnoses insufficient for diagnosis were recorded. The findings of surgical inspection were 2 Structure seen with indistinct margins, image quality obtained from the official operative reports. The accuracy of sufficient for diagnosis but not for measurement 3 Structure seen with distinct margins, image quality magnetic resonance angiographic diagnosis related to the sufficient for diagnosis and measurement diagnostic question at referral was thus determined. In ad- A Structure absent dition, official magnetic resonance angiographic, x-ray angiographic, and surgical reports were carefully searched for any other diagnostic discrepancies, which were recorded. mechanical ventilation, imaging was initiated approxi- Results mately 5 to 10 seconds after the start of the injection, taking Subjects and diagnostic questions: Twenty-nine con- into consideration the site of the intravenous line and the trast-enhanced magnetic resonance angiographic scans were length of tubing. Three sets of images (dynamics) were performed on 28 infants aged Ͻ3 months (median 6 days, obtained, with ventilator breaths delivered for approxi- range 1 to 90 days; median weight 3 kg, range 2.1 to 3.9) mately 5 seconds between each period of apnea. The num- during the 1-year study period. The results of MRA in the 4 ber of dynamics obtained during each period of apnea was patients with scimitar syndrome have been reported previ- based on the infant’s ability to tolerate apnea and varied ously.6 All subjects had undergone echocardiography before from 1 to 2. Oxygen saturation, blood pressure, respiratory MRA. The diagnostic questions at referral for MRA are rate, and heart rate were monitored noninvasively through- listed in Table 3. out the procedure. MRA and sedation: All subjects tolerated the suspen- Magnetic resonance angiographic image analysis for sion of respiration for a median of 25 seconds (range 20 to image quality: Magnetic resonance angiographic images 48) without significant desaturation or change in heart rate. were electronically deidentified and transferred to a blinded The median total duration of scanning was 9 minutes (range observer (JCN) who was an expert in the magnetic reso- 3 to 46). There were no complications. nance imaging of CHD at a different institution (Mount Magnetic resonance angiographic image quality: Im- Sinai Medical Center). This blinded observer performed all age quality grades for analyzed structures are listed in Table image analyses using a commercially available computer 4. Overall magnetic resonance angiographic image quality workstation and software (Advantage Windows 4.0; Gen- was excellent in every subject. The mean image quality eral Electric). Cardiac and extracardiac vascular anatomy grade was Ͼ2 for all structures except the second-genera- was defined and graded by constructing user-defined sub- tion pulmonary arterial branches, for which it was 2. The volume maximal-intensity projections and multiplanar re- image quality grade was Ն2 (adequate for diagnosis) for formatted images from the 3-dimensional data sets. The every structure in every subject except for the second- quality of the visualization of the pulmonary arterial bed, generation pulmonary arterial branches. The image quality pulmonary and systemic veins, thoracic aorta and its grade was Ͻ2 (inadequate for diagnosis) for the second- branches, aortopulmonary collaterals, patent ductus arterio- generation pulmonary arterial branches in only 1 subject sus, and the sidedness of the abdominal viscera was as- with tetralogy of Fallot with pulmonary atresia and severely sessed semiquantitatively using the grading scale listed in hypoplastic native pulmonary arteries. Examples of maxi- Table 2. The pulmonary artery branch to each lung and mum intensity projections reconstructed from magnetic res- further branches to each lobe of the lung were graded onance angiographic data sets are shown in Figures 1 to 4. separately, and the second-generation branches for each lung were graded as a group. The pulmonary vein branches Comparison with findings of x-ray angiography and draining each lung lobe were graded separately. The sub- surgical inspection: The results of x-ray angiography (n ϭ clavian, carotid, and internal mammary arteries on each side 8) and/or surgical inspection (n ϭ 25) were available for 23 Congenital Heart Disease/MRA of Heart Disease in Infancy 717

Table 3 Accuracy of magnetic resonance angiographic assessment of referral diagnostic questions Anatomic Segment for Which MRA Evaluation No. of MRA Scans Diagnostic Conﬁrmation of Anatomic No. of Scans in Which MRA Was Requested Segment by Angiography/Surgery Diagnosis Was Concordant Available (n) With Angiography/Surgery (n) Pulmonary artery anatomy 20 16 16 Pulmonary venous anatomy 12 11 11 Aortopulmonary collaterals 13 9 9 Anatomy of aortic arch, its branches, or ductus arteriosus 7 6 6 Surgical psuedoaneurysm 2 2 2 Systemic venous anatomy 3 2 2 Airway compression 1 1 1

Table 4 collaterals. The presence of “dual” blood supply to individ- Image quality grades ual lung segments via collaterals and native pulmonary Structure Analyzed Image Quality No. of Scans arteries was not assessed by MRA. Grade in Which Indications for cardiac catheterization: Although the Structure Was Mean Ϯ SD Range Present diagnostic questions at referral were accurately answered by MRA, in 6 of 28 subjects, additional cardiac catheterization PAs was performed before surgery. The purpose of catheteriza- Main PA 3 Ϯ 0 3–3 26 tion was diagnostic in 3 subjects (to conﬁrm the anatomy Proximal PA branches 3 Ϯ 0 3–3 29 Ϯ and lung-segment distribution of the aortopulmonary col- Lobar PA branches 2.8 0.6 2–3 29 laterals in 2 subjects with tetralogy of Fallot with pulmonary Second-generation PA branches 2 Ϯ 0.6 0–3 29 PVs atresia and to measure pulmonary artery pressure in 1 sub- Lobar pulmonary veins 2.9 Ϯ 0.1 2–3 29 ject with scimitar syndrome, ventricular septal defect, and Anomalous PV conﬂuence 3 Ϯ 0 3–3 3 left pulmonary artery sling). In the other 3 subjects, cathe- Anomalous vertical PV 3 Ϯ 0 3–3 4 terization was performed for interventional procedures Aortopulmonary collateral arteries 2.7 Ϯ 0.5 2–3 6 (stenting of pulmonary vein stenosis in 1 subject, decom- Superior vena cavae pression of the left atrium in 1 subject with hypoplastic left Right sided 3 Ϯ 0 2–3 26 heart syndrome, and embolization of an aortopulmonary Left sided 3 Ϯ 0 2–3 10 collateral in 1 subject with scimitar syndrome). Inferior vena cava 3 Ϯ 0 3–3 28 Aorta and branches Adverse effects: No immediate adverse effects were Ascending aorta 3 Ϯ 0 3–3 29 noted after the injection of contrast medium. Clinical and Transverse aortic arch 3 Ϯ 0 3–3 27 laboratory data for a period of Ն72 hours were available after Isthmus 3 Ϯ 0 3–3 27 25 of 29 scans in subjects who remained admitted to the Thoracic descending aorta 3 Ϯ 0 3–3 29 Ϯ hospital. None of these subjects demonstrated an increase in Carotid and subclavian arteries 3 0 3–3 29 serum creatinine, abnormal hepatic function, or other adverse Internal mammary arteries 2.9 Ϯ 0.3 2–3 29 Patent ductus arteriosus 2.9 Ϯ 0.3 2–3 13 effects during this period. Three of 29 subjects were discharged Visceral sidedness home soon after the magnetic resonance imaging scans, and Stomach 3 Ϯ 0 3–3 29 although laboratory data were unavailable, none had a clinical Liver 3 Ϯ 0 3–3 29 adverse event on follow-up. In 1 subject, the magnetic reso- Spleen 3 Ϯ 0 3–3 24 nance imaging scan was performed emergently before cardiac surgery. This patient died in the operating room. PA ϭ pulmonary artery; PV ϭ pulmonary vein.

Discussion and 28 subjects, respectively. Comparisons of the diagnostic findings of MRA with those of x-ray angiography and The present study demonstrates the utility of MRA in young surgical inspection, as related to the diagnostic questions at infants with complex CHD in whom echocardiographic referral, are listed in Table 3. The diagnostic questions at evaluation is incomplete or inconclusive. Because echocar- referral were accurately answered by MRA in each subject. diography provides excellent visualization of intracardiac No discrepancies were noted between the official magnetic anomalies, the referral question was frequently related to the resonance angiographic, x-ray angiographic, and operative extracardiac thoracic vasculature. MRA is especially suited reports. For the aortopulmonary collaterals, the number and for the evaluation of these anomalies, especially when they sites of origin of all collaterals were accurately assessed by occur in combination with each other. After a single intra- MRA. The distribution of branches from the collaterals to venous injection of contrast medium, a 3-dimensional data individual lung lobes was accurately assessed by MRA in 7 set of the entire vasculature can be obtained rapidly. of 9 subjects; in 2 of 9 subjects, there were minor discrep- The present report is the first to systematically study the ancies between MRA and x-ray angiography in the delin- quality of the visualization of individual extracardiac vascular eation of the lobar lung distribution of the aortopulmonary structures in a group of infants aged Ͻ3 months with complex 718 The American Journal of Cardiology (www.AJConline.org)

Figure 1. Maximum-intensity projections (MIPs) from a newborn infant with heterotaxy (asplenia) syndrome, functionally single ventricle, double-outlet right ventricle, pulmonary stenosis, and total anomalous pulmonary venous return showing (A) right superior vena cava (RSVC) and left superior vena cava (LSVC) with a small bridging vein; (B) levocardia with a midline transverse liver; and (C) conﬂuence of right upper (RU), right lower (RL), left upper (LU), and left lower (LL) pulmonary veins behind the left atrium draining superiorly via a vertical vein (VV). A sagittal MIP (D) shows drainage of the VV into the LSVC.

CHD. Image quality was excellent for the diagnosis and mea- periods of apnea are well tolerated by intubated infants. The surement of anomalies involving the main, proximal branch, contrast was injected manually with the “best-estimate” and lobar pulmonary arteries; the systemic and pulmonary method used for the timing of imaging. Although real-time veins; the aorta and its branches; and the aortopulmonary imaging sequences are now commercially available to allow collateral arteries and for the determination of abdominal vis- the timing of contrast bolus, we prefer the best-estimate ceral situs. Image quality grade for the second-generation pul- method in small infants because of their rapid heart rates monary arteries was lower on average, and they were not and relatively fast circulation times. The manual injection of well visualized in 1 subject with tetralogy of Fallot, pulmo- contrast has the advantage of allowing direct monitoring of nary atresia, and hypoplastic native pulmonary arteries. the subject and communication with the respiratory thera- The acquisition parameters used in this series were cho- pist during the suspension of respiration. In our experience, sen to provide adequate spatial resolution while maintaining the site of injection (upper or lower extremity) and the type acceptable signal-to-noise characteristics on the basis of our of venous line (central or peripheral) do not affect the institutional experience, the scanning platform used, and the quality of imaging significantly, although this was not eval- work of others.7 The field of view and imaging matrix were uated critically in this study. We also believe that a rapid adjusted to maximize resolution while balancing signal-to- injection rate (0.5 to 1 cm3/s) is important to allow scanning noise characteristics. Parallel-processing techniques such as during the “first pass” of the contrast medium because of the sensitivity encoding were purposefully not used to maxi- fast circulation time in small infants, especially in the pres- mize the signal-to-noise ratio and because relatively long ence of intracardiac shunts. The elimination of respiratory Congenital Heart Disease/MRA of Heart Disease in Infancy 719

Figure 2. Maximum-intensity projections (MIPs) from a newborn infant with hypoplastic left-sided cardiac syndrome after stage 1 palliation with a right ventricle–to–pulmonary artery conduit. Axial (A), sagittal (B), and coronal (C) MIPs show a large psuedoaneurysm (arrow) anterior to the right ventricle–to–pulmonary artery conduit (arrowhead). The reconstructed aortic arch and the aortopulmonary anastomosis are also well seen in a sagittal plane (D). LPA ϭ left pulmonary artery; RPA ϭ right pulmonary artery. motion is important in this group of patients because even in infants. Accurate diagnoses of the often complex cardiac slight blurring can make the visualization of small structures and vascular anomalies in this patient group require imaging difficult in these small-sized subjects. However, this re- quality of an order that is often limited by the inherently low quires endotracheal intubation and paralysis with close signal-to-noise ratio related to their small body size. To an monitoring by either an anesthesiologist or an intensivist. extent, the signal-to-noise ratio can be improved with the These resources may not be available at all institutions, and use of a higher dose of contrast. In this reported cohort, hence the decision to use intubation and paralysis should be failure to obtain diagnostic images on MRA would have individualized. The median total scanning duration was 9 necessitated cardiac catheterization and angiography with minutes, showing that in most infants, the referral question exposure to radiation and iodinated contrast media, which can be answered rapidly using MRA. Additional functional has been shown to be more nephrotoxic than gadolinium- assessment, including the quantification of ventricular func- based agents.8 Hence, a decision to use high-dose (0.4 to 0.5 tion and the measurement of blood flow, can be performed mmol/kg) gadolinium was made to maximize the signal-to- using magnetic resonance imaging. However, in most sub- noise ratio and image quality. The safety of high-dose ga- jects in this series, these data were provided by echocardi- dolinium-based contrast has been shown by several inves- ography alone or were not thought to be clinically relevant. tigators.9–21 Most of the subjects were closely monitored in The optimal dose for MRA of complex CHD in infants the intensive care unit after MRA, and in this small cohort, aged Ͻ3 months is unknown. Dose-finding studies are very no adverse effects of the higher dose were noted. However, difficult to perform in this patient population because of larger prospective dose-finding studies are needed to deter- ethical and logistic reasons. This is true for most drugs used mine the optimal dose of gadolinium in this patient popu- 720 The American Journal of Cardiology (www.AJConline.org)

Figure 3. Oblique coronal maximum-intensity projections from a newborn infant with functionally single ventricle showing the right (A) and left (B) pulmonary arteries and branches to the upper (U), middle (M), and lower (L) lobes.

Figure 4. Maximum-intensity projections (MIPs) from a newborn infant with situs inversus totalis. A coronal MIP (A) shows dextrocardia, left-sided liver, left-sided superior vena cava (arrow), right-sided innominate vein (arrowhead), hypoplastic ascending aorta (AO), normal-sized main pulmonary artery (MPA), and a large patent ductus arteriosus (PDA). A sagittal MIP (B) shows a hypoplastic aortic arch (arrowhead) and a large PDA. lation. Until such data are available, the dose used should be This study was limited by its retrospective design, relatively individualized to balance the risk of using a higher dose small sample size, and heterogenous patient population. The against the risk for requiring cardiac catheterization if im- image quality grading score was semiquantitative and hence aging is suboptimal with a lower dose. somewhat subjective in nature. Larger prospective studies Because of the retrospective nature of this study, a direct comparing MRA directly with reference techniques such as comparison of the ﬁndings on MRA with other reference cardiac catheterization will help determine the accuracy of this techniques was possible only in a subset of subjects in technique in speciﬁc diagnostic subgroups. whom no discrepancies in diagnosis were noted on surgical ϭ ϭ inspection (n 25) or on cardiac catheterization (n 8). 1. Greil GF, Powell AJ, Gildein HP, Geva T. Gadolinium-enhanced Larger prospective studies are required to evaluate the ac- three-dimensional magnetic resonance angiography of pulmonary and curacy of MRA compared with reference techniques. systemic venous anomalies. J Am Coll Cardiol 2002;39:335–341. Congenital Heart Disease/MRA of Heart Disease in Infancy 721

2. Geva T, Greil GF, Marshall AC, Landzberg M, Powell AJ. Gadolinium- 13. Yoshikawa K, Davies A. Safety of ProHance in special populations. enhanced 3-dimensional magnetic resonance angiography of pulmonary Eur Radiol 1997:7(suppl):246–250. blood supply in patients with complex pulmonary stenosis or atresia: 14. Frank J, Choyke P, Girton M, Morrison P, Diggs R, Skinner M. comparison with X-ray angiography. Circulation 2002;106:473–478. Gadopentate dimeglumine clearance in renal insufficiency in rabbits. 3. Prasad SK, Soukias N, Hornung T, Khan M, Pennell DJ, Gatzoulis Invest Radiol 1990;25:1212–1216. MA, Mohiaddin RH. Role of magnetic resonance angiography in the 15. Jau P, Bonnet JL, Joly P, Barth P, Habib G, Djiane P, Bory M, Bernard diagnosis of major aortopulmonary collateral arteries and partial PJ. Study of early myocardial infarction by nuclear magnetic reso- anomalous pulmonary venous drainage. Circulation 2004;109:207– nance imaging with gadolinium Dota injection. Arch Mal Coeur Vaiss 214. 1991;84:195–200. 4. Masui T, Seelos KC, Kersting-Sommerhoff BA, Higgins CB. Abnor- 16. Remy-Jardin M, Bahepar J, Lafitte JJ, Dequiedt P, Ertzbischoff O, malities of the pulmonary veins: evaluation with MR imaging and Bruzzi J, Delannoy-Deken V, Duhamel A, Remy J. Multi-detector row comparison with cardiac angiography and echocardiography. Radiol- CT angiography of pulmonary circulation with gadolinium-based con- ogy 1991;181:645–649. trast agent: prospective evaluation in 60 patients. Radiology 2006;238: 5. Valsangiacomo ER, Levasseur S, McCrindle BW, MacDonald C, 1022–1035. Smallhorn JF, Yoo SJ. Contrast-enhanced MR angiography of pulmo- 17. Remy-Jardin M, Dequiedt P, Etzbischoff O, Tillie-Leblond I, Bruzzi J, nary venous abnormalities in children. Pediatr Radiol 2003;33:92–98. Duhamel A, Remy J. Safety and effictiveness of gadolinium-enhanced 6. Khan MA, Torres AJ, Printz BF, Prakash A. usefulness of magnetic multi-detector row spiral CT angiography of the chest: preliminary resonance angiography for diagnosis of scimitar syndrome in early results in 37 patients with contraindications to iodinated contrast infancy. Am J Cardiol 2006;96:1313–1316. 7. Tsai-Goodman B, Geva T, Odegard KC, Sena LM, Powell AJ. Clinical agents. Radiology 2005;235:819–826. role, accuracy, and technical aspects of cardiovascular magnetic res- 18. Haustein J, Laniado M, Niendorf HP, Louton T, Beck W, Planitzer J, onance imaging in infants. Am J Cardiol 2004;94:69–74. Schoffel M, Reiser M, Kaiser W, Schomer W. Triple-dose versus 8. Prince MR, Arnoldus C, Frisoli JK. Nephrotoxicity of high-dose gad- standard-dose gadopentetate dimeglumine: a randomized study in 199 olinium compared with iodinated contrast. J Magn Reson Imaging patients. Radiology 1993;186:855–860. 1996;6:162–166. 19. Haussler MD, Rummeny EJ, Raufhake C, Blasius S, Lindner N, 9. Shellock FG, Kanal E. Safety of magnetic resonance imaging contrast Daldrup HE, Reimer P, Peters PE. High dosage Gd-DTPA-BMA agents. J Magn Reson Imaging 1999;10:477–484. (Gadodiamid) administration in diagnosis and therapeutic monitoring 10. Niendorf H, Dinger J, Haustein J, Cornelius I, Alhassan A, Clauss W. of malignant bone tumors. Radiology 1996;32:148–152. Tolerance data of Gd-DTPA: a review. Eur J Radiol 1991;13:15–20. 20. Runge RM, Kirsch JE, Thomas GS. High-dose Applications of gado- 11. Oksendal A, Hals P. Biodistribution and toxicity of MR imaging linium chelates in magnetic resonance imaging. Magn Reson Med contrast media. J Magn Reson Imaging 1993;3:157–165. 1991;22:358–363. 12. Niendorf H, Haustein J, Cornelius I, Alhassan A, Claus W. Safety of 21. Rosioreanu A, Hon M, Imbriano L, Mueller R, Katz DS. High-dose gadolinium-DTPA: extended clinical experience. Magn Reson Med intravenous gadolinium for renal computed tomographic angiography. 1991;22:222–228. J Vasc Interv Radiol 2004;15:517–519. Influence of Preparative Procedures on Assay of Platelet Function and Apparent Effects of Antiplatelet Agents

Nathaniel J. Madsen, MDa, Chris E. Holmes, MD, PhDb,c, Feliciano A. Serrano, MDa, Burton E. Sobel, MDa,c, and David J. Schneider, MDa,c,*

Previous studies have shown that anticoagulants alter platelet reactivity and the apparent effects of antiplatelet agents. This study was conducted to identify the impact of methods of preparation of blood samples on an assay of platelet function and the effects of antiplatelet agents. The activation of platelets was identified with the use of flow cytometry in response to thrombin (1 and 10 nmol/L), adenosine diphosphate (0.2 and 1 ␮mol/L), platelet activating factor (1 nmol/L), and convulxin (1 and 10 ng/ml). Antiplatelet effects were assessed after the addition in vitro of tirofiban (50 ng/ml) and cangrelor (10 nmol/L). Results were compared in whole blood and platelet-rich plasma (PRP) anticoagulated with corn trypsin inhibitor (32 ␮g/ml, a specific inhibitor of factor XIIa). The fraction of young platelets was quantified with thiazole orange, which identifies ribonucleic acid. The activation of platelets was consistently less in PRP compared with whole blood. Activation in ,PRP was 23 ؎ 15% that in whole blood for thrombin, 65 ؎ 26% for adenosine diphosphate for platelet activating factor, and 49 ؎ 25% for convulxin (p <0.01 for each 20% ؎ 40 comparison). The fraction of young platelets in PRP was 39 ؎ 11% that in whole blood (p <0.001). The effects of antiplatelet agents varied with agonist and antiplatelet agent but were generally greater in PRP compared with whole blood (p <0.05). In conclusion, platelet reactivity is lower and the effects of antiplatelet agents are greater and potentially mis- leading in PRP compared with whole blood. The accuracy of platelet function testing may be improved by performance in whole blood. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:722–727)

Platelets are pivotal in atherogenesis, thrombosis complicat- written informed consent. Whole blood (10 ml) was ob- ing atherosclerotic plaque rupture, and complications after tained by peripheral venipuncture from healthy subjects coronary intervention.1–5 We have found previously that the (n ϭ 22) or from a coronary guide catheter in the ascending determination of platelet reactivity before percutaneous cor- aorta from 10 patients who underwent cardiac catheteriza- onary intervention differentiates patients at high compared tion for symptomatic coronary artery disease. Blood was with low risk for subsequent cardiac events.5 Previous stud- anticoagulated with corn trypsin inhibitor (32 ␮g/ml, a ies have demonstrated that the biochemical conditions used specific inhibitor of factor XIIa; Haematologic Technolo- for the assay of platelet function can alter platelet reactivity gies, Inc., Essex Junction, Vermont). PRP was prepared by and the apparent effect of antiplatelet agents.6–12 We hy- the centrifugation (at 190g for 15 minutes) of whole blood. pothesized that centrifugation, commonly used to prepare For the isolation of washed platelets, blood was antico- platelet-rich plasma (PRP), would lead to the selective loss agulated with acid citrate dextrose (0.085 mol/L trisodium of more reactive platelets. Young platelets appear to belong citrate, 0.071 mol/L citric acid 0.071, 0.1 mol/L glucose, pH 13 to the group of more reactive platelets. The objectives of 4.5, 1:5 v/v). Washed platelets were prepared from PRP this study were to determine whether platelet reactivity is with the use of centrifugation (at 1,100g for 15 minutes). altered by the method of preparation of blood samples and Platelet pellets were washed with modified Tyrode’s buffer whether altered platelet reactivity is associated with changes (0.138 mol/L sodium chloride (NaCl), 2.7 mmol/L potas- in the proportion of young platelets in the samples and the extent of inhibition of antiplatelet agents. sium chloride (KCl), 0.4 mmol/L sodium phosphate dibasic (NaH2PO4), 12 mmol/L sodium carbonate (NaHCO3), 2 mmol/L magnesium chloride (MgCl ), 0.01 mol/L 4-[2- Methods 2 hydroxyethyl]-1-piperazineethanesulfonic acid [HEPES], The protocol was approved by the Institutional Review 0.1% glucose, 0.2% bovine serum albumin, pH 7.45) con- Board of the University of Vermont. All subjects provided taining 300 ␮l acid citrate dextrose and 50 U/ml unfractionated heparin and subsequently suspended in modified Ty- rode’s buffer. a b c Cardiology Unit, Hematology and Oncology Unit, and Cardiovas- To determine whether differences in platelet reactivity in cular Research Institute, Department of Medicine, University of Vermont, Burlington, Vermont. Manuscript received February 2, 2007; revised whole blood compared with PRP reflected, at least in part, manuscript received and accepted March 22, 2007. dissimilar platelet counts in the 2 preparations, we adjusted *Corresponding author: Tel: 802-656-8953; fax: 802-656-8969. the platelet count in PRP by adding platelet-poor plasma. E-mail address: [email protected] (D.J. Schneider). Platelet poor plasma (prepared by centrifuging PRP at

21,000g for 2 minutes) was added to PRP to generate a platelet count in PRP that equaled that in whole blood. Aliquots of 5 ␮l of whole blood or PRP that were anticoagulated with corn trypsin inhibitor were added to microcentrifuge tubes containing fluorochrome-labeled li- gands, HEPES-Tyrode’s buffer (5 mmol/L HEPES, 137 mmol/L NaCl, 2.7 mmol/L NaHCO3, 0.36 mmol/L NaH2PO4, 2 mmol/L CaCl2, and 5 mmol/L glucose, pH 7.4) as previously described.5,12,14 Selected platelet agonists were used to activate platelets (1 and 10 nmol/L thrombin [Haematologic Technologies, Inc.], 0.2 and 1 ␮mol/L adenosine diphosphate [ADP; BioData, Horsham, Pennsylva- nia], 1 nmol/L platelet activating factor [Sigma-Aldrich Corporation, St. Louis, Missouri], and 1 and 10 ng/ml convulxin [Pentapharm, Basel, Switzerland]). Antiplatelet effects were assessed after the addition in vitro of tirofiban (50 ng/ml) and cangrelor (10 nmol/L). Platelets were identified with the use of a phycoerthrin- Figure 1. Comparison of reactivity of platelets in whole blood, of platelets Cy5-conjugated anti-CD42b. The activation of glycoprotein in PRP, and of washed platelets from 4 healthy subjects. Platelet activation IIb/IIIa was detected with the use of fluorescein isothiocya- in response to 1 nmol/L thrombin and 0.2 ␮mol/L ADP was determined in nate–conjugated PAC-1, and the surface expression of P- each preparation by assay of the binding of PAC-1 (binds to activated selectin was identified with the use of phycoerythrin-con- glycoprotein IIb/IIIa) with the use of flow cytometry. Results are the jugated anti-CD62 (Becton, Dickinson and Company, San percentage activation in PRP or washed platelets compared with whole blood (i.e., PRP/whole blood ϫ 100). Values are means Ϯ SDs. *p Ͻ0.05, Jose, California). Glycine-proline-arginine-proline (Calbio- **p Ͻ0.001 compared with whole blood. chem, San Diego, California) was added to tubes in which thrombin was used as an agonist to prevent the polymeriza- 0 tion of endogenous fibrinogen.15 Lower concentrations of cence intensity exceeded 10 . Flow cytometric analysis was the agonists were used because we have found that they performed within 45 minutes. effectively discriminate interindividual differences of plate- Values are means Ϯ SDs. Differences between whole let reactivity.5 After 15 minutes, platelets were fixed and blood and PRP were identified with the use of paired Stu- erythrocytes lysed by the addition of 100 ␮l Optilyse-C dent’s t tests. Significance was defined as p Ͻ0.05. solution (Immunotech, Westbrook, Massachusetts). Sam- ples were diluted with 1.5 ml HEPES-Tyrode’s buffer after Results a second 15-minute incubation to facilitate analysis by flow Platelet activation (PAC-1 binding) in response to ADP and cytometry. All assays were performed in duplicate. thrombin (i.e., platelet reactivity) was less in PRP and Flow cytometric analysis was performed with the use of washed platelet preparations compared with that in whole a Beckman Coulter Epics Elite (Beckman Coulter, Inc., blood (Figure 1). Differences were more pronounced with Miami, Florida). Platelets were identified on the basis of thrombin than ADP. size and binding of the fluorochrome-labeled antibody We postulated that 1 mechanism potentially contributing CD42b. Control samples were used to define a threshold to differences in platelet reactivity when assessed in PRP above which activation-dependent binding occurred. To as- compared with whole blood was the relatively greater loss sess non-activation-dependent protein association with of more reactive platelets during the preparation of PRP. We platelets, fluorescein isothiocyanate–conjugated and phyco- quantified the number of young platelets because we pos- erthrin-conjugated nonimmune immunoglobulin-G were tulated that they would represent more reactive platelets,13 used. We chose to quantify activation as the percentage of referred to by some as “vanguard platelets.”18 Furthermore, platelets activated rather than by mean fluorescence inten- we anticipated that more young platelets would be present sity because we have shown previously that the quantifica- in blood from patients with coronary artery disease. Thus, tion of percentage platelets activated discriminates interin- we repeated our analysis with blood from patients with dividual differences in platelet reactivity, identifies the coronary artery disease and quantified the proportions of prognostic implications of platelet reactivity, and correlates young platelets in whole blood and PRP. Blood was taken with quantification with mean fluorescence intensity.5,16 from 10 patients who underwent cardiac catheterization. Thiazole orange (Sigma-Aldrich Corporation) was used Similar to the results in healthy subjects, platelet reactivity as previously described to identify young platelets, which was less in PRP compared with whole blood (Figure 2 and characteristically contain ribonucleic acid.17 Aliquots of Table 1). Again, the magnitude of difference in platelet blood or PRP (5 ␮l) were incubated for 15 minutes in the reactivity between whole blood and PRP varied with respect absence of agonist in HEPES-Tyrode’s buffer, thiazole or- to the agonist used (Figure 2). Differences between whole ange (1 ␮g/ml), and a peridinin chlorophyll protein–conju- blood and PRP were apparent when activation was iden- gated antibody to glycoprotein IIIa (CD61; Becton, Dick- tified with PAC-1 (reflecting the activation of glycopro- inson and Company) that was used to identify platelets. tein IIb/IIIa) or anti-CD62 (reflecting platelet-surface ex- Platelets were identified as positive if their mean fluores- pression of P-selectin). The proportion of young platelets 724 The American Journal of Cardiology (www.AJConline.org)

Figure 3. Comparison of the proportion of young platelets in whole blood and PRP from 10 patients with coronary artery disease who underwent cardiac catheterization. Young platelets were identified by the presence of ribonucleic acid with the use of thiazole orange. On the left, the proportion of young platelets in each preparation is shown. On the right, the percentage of young platelets compared with that in whole blood is shown. Values are means Ϯ SDs. *p Ͻ0.001 compared with whole blood. Figure 2. Comparison of platelet reactivity in whole blood and PRP from 10 patients with coronary artery disease who underwent cardiac catheterization. Platelet activation in response to 1 nmol/L thrombin, 0.2 ␮mol/L ADP, 1 nmol/L platelet activating factor (PAF), and 1 ng/ml convulxin was determined in each preparation by assay of the binding of PAC-1 (binds to activated glycoprotein [GP] IIb/IIIa) and anti-CD62 (identifies the surface expression of P-selectin) with the use of flow cytometry. Results are the percentage activation in PRP compared with whole blood. Values are means Ϯ SDs. *p Ͻ0.05, **p Ͻ0.001 compared with whole blood (applies to both bars in each pair).

Table 1 Activation of platelets in whole blood and platelet-rich plasma from patients (n ϭ 10) with coronary artery disease Percentage of Platelets Activated Agonist PAC-1 p Value Anti-CD62 p Value Thrombin, 1 nm/L Whole blood 35.0 Ϯ 32.8 27.7 Ϯ 28.7 PRP 10.8 Ϯ 14.2 0.006 8.2 Ϯ 11.2 0.018 Figure 4. Comparisons in samples from 5 healthy subjects of platelet (plt) ADP, 0.2 ␮m reactivity in whole blood, PRP, and PRP in which the platelet count has Whole blood 37.0 Ϯ 17.9 5.4 Ϯ 4.8 been adjusted to equal that in whole blood. Platelet activation in response PRP 26.4 Ϯ 19.0 0.005 4.2 Ϯ 4.9 0.142 to 1 nmol/L thrombin, 0.2 ␮mol/L ADP, 1 nmol/L platelet activating factor PAF, 1 nm (PAF), and 1 ng/ml convulxin was determined in each preparation by assay Whole blood 20.0 Ϯ 13.4 11.5 Ϯ 6.4 of the binding of PAC-1 (binds to activated glycoprotein IIb/IIIa) with the PRP 11.6 Ϯ 10.7 Ͻ0.001 4.6 Ϯ 4.2 0.001 use of ﬂow cytometry. The proportion of young platelets was identiﬁed Convulxin, 1 ng/ml with the use of thiazole orange. Results are the percentage activation in Whole blood 4.6 Ϯ 3.2 1.8 Ϯ 1.2 PRP or PRP with adjusted platelet count compared with whole blood PRP 1.9 Ϯ 1.6 0.001 1.2 Ϯ 0.8 0.01 (i.e., PRP/whole blood ϫ 100). Values are means Ϯ SDs. Results in PRP No agonist and PRP with adjusted platelet count were similar. Whole blood 0.6 Ϯ 0.4 0.03 0.4 Ϯ 0.3 0.06 PRP 0.2 Ϯ 0.2 0.2 Ϯ 0.1

PAF ϭ platelet activating factor. blood by the addition of platelet-poor plasma from the same subject. Adjustment of the platelet count did not affect the decreased platelet reactivity seen in PRP compared with was less in PRP compared with that in whole blood (p whole blood (Figure 4). Ͻ0.001; Figure 3). To determine whether the apparent effects of antiplatelet A second factor potentially contributing to differences in agents would be altered by their assessment in PRP com- platelet reactivity when assessed in whole blood compared pared with whole blood, we spiked blood in vitro with with PRP could be dissimilar platelet counts in the 2 prep- cangrelor, a P2Y12 antagonist, and tiroﬁban, a glycoprotein arations. To assess the contribution of platelet count, IIb/IIIa antagonist. We chose concentrations of each anti- we adjusted the platelet count in PRP to equal that in whole platelet agent that would be associated with submaximal Methods/Platelet Function Testing in Whole Blood 725

Table 2 Activation of platelets in whole blood and platelet-rich plasma with higher concentrations of agonists in the absence and presence of antiplatelet agents (n ϭ 13 healthy subjects) Percentage of Platelets Activated Agent PAC-1 p Value Anti-CD62 p Value vs WB vs WB No antiplatelet agent Thrombin 10 nm/L WB 89.1 Ϯ 5.3 96.1 Ϯ 1.1 PRP 83.7 Ϯ 7.3 0.027 90.1 Ϯ 7.1 0.021 PRP* 73.2 Ϯ 14.6 0.007 83.6 Ϯ 12.7 0.01 ADP 1 ␮mol/L WB 75.5 Ϯ 12.0 37.6 Ϯ 12.5 PRP 64.1 Ϯ 16.3 0.001 30.4 Ϯ 13.0 0.015 PRP* 58.4 Ϯ 18.1 Ͻ0.001 28.2 Ϯ 11.3 0.005 Convulxin 10 ng/ml WB 92.3 Ϯ 10.3 85.8 Ϯ 14.8 PRP 70.5 Ϯ 30.3 0.011 63.1 Ϯ 29.4 0.005 PRP* 80.0 Ϯ 20.0 0.011 74.7 Ϯ 18.9 0.008 Figure 5. Comparison of the extent of inhibition of platelet activation Tirofiban 50 ng/ml (PAC-1 binding) in whole blood (WB), PRP, and PRP in which the platelet Thrombin 10 nmol/L count has been adjusted to approximate that in whole blood from 13 WB 48.6 Ϯ 13.3 94.9 Ϯ 1.9 healthy subjects. Blood was spiked in vitro with tirofiban (50 ng/ml) and PRP 31.1 Ϯ 15.7 Ͻ0.001 87.5 Ϯ 7.6 0.024 cangrelor (10 nmol/L) to induce submaximal inhibition. Platelet activation PRP* 28.5 Ϯ 13.1 Ͻ0.001 87.4 Ϯ 5.8 Ͻ0.001 in response to 10 nmol/L thrombin, 1 ␮mol/L ADP, and 10 ng/ml con- ADP 1 ␮mol/L vulxin was determined in each preparation by assay of the binding of WB 20.3 Ϯ 15.0 23.7 Ϯ 9.3 PAC-1 (binds to activated glycoprotein IIb/IIIa) with the use of flow PRP 13.7 Ϯ 9.2 0.015 20.2 Ϯ 10.2 0.007 cytometry. The extent of inhibition was calculated with the following PRP* 11.8 Ϯ 8.3 0.005 19.6 Ϯ 7.0 0.005 formula: 1 Ϫ (effect with antiplatelet agent/effect without antiplatelet Convulxin 10 ng/L agent) ϫ 100. Values are means Ϯ SDs. *p Ͻ0.05, **p Ͻ0.01 compared WB 47.8 Ϯ 18.5 73.6 Ϯ 25.4 with whole blood (applies to both bars in each pair). PRP 26.4 Ϯ 21.3 0.003 52.8 Ϯ 30.1 0.001 PRP* 23.8 Ϯ 17.8 Ͻ0.001 57.9 Ϯ 28.4 0.007 Cangrelor 10 nmol/L identify greater inhibition and lower residual platelet func- Thrombin 10 nmol/L tion and hence overestimate the efficacy. WB 82.4 Ϯ 8.0 92.3 Ϯ 4.4 PRP 64.2 Ϯ 20.6 0.012 79.2 Ϯ 18.6 0.024 Discussion PRP* 47.7 Ϯ 26.7 0.005 61.1 Ϯ 24.3 0.003 ADP 1 ␮mol/L Our results demonstrate that the method of preparation of WB 38.4 Ϯ 15.4 9.3 Ϯ 4.2 blood samples for in vitro testing affects the assessment of PRP 29.4 Ϯ 17.1 0.086 10.4 Ϯ 5.3 0.143 platelet reactivity and the assessment of effects of antiplate- PRP* 27.1 Ϯ 18.4 0.026 9.7 Ϯ 4.4 0.461 let agents. Platelet reactivity is consistently less when as- Convulxin 10 ng/ml sessed in PRP compared with that in minimally altered WB 80.2 Ϯ 15.5 65.5 Ϯ 26.6 PRP 51.1 Ϯ 30.4 Ͻ0.001 45.8 Ϯ 25.8 Ͻ0.001 whole blood. The effects of antiplatelet agents tend to be PRP* 57.6 Ϯ 28.8 0.003 53.8 Ϯ 25.1 0.003 overestimated in PRP compared with whole blood. Differ- ences between results obtained in whole blood and PRP * PRP with platelet count adjusted to approximate that in WB. varied with respect to the agonist used to induce activation WB ϭ whole blood. and the antiplatelet agent. In particular, assessment of the effect of a P2Y12 antagonist, cangrelor, on ADP-induced activation was similar in PRP and whole blood. The results were similar when activation was identified by the activa- inhibition. The activation of platelets was induced by higher tion (change in conformation) of glycoprotein IIb/IIIa or the concentrations of agonists (10 nmol/L thrombin, 1 ␮mol/L surface expression of P-selectin. ADP, and 10 ng/ml convulxin). The activation of platelets Multiple factors may contribute to the greater platelet in the absence and presence of the 2 antiplatelet agents was reactivity observed in whole blood. One such factor appears greater in whole blood compared with PRP (Table 2). In to be the relatively greater loss of more reactive platelets addition, the percentage inhibition was greater in PRP for during preparation of PRP. Consistent with this hypothesis, each condition and antagonist except the inhibition of ADP- we found that the fraction of young platelets was approxi- induced activation of platelets by cangrelor (Figure 5). Ad- mately 60% less in PRP than that in whole blood from the justment of the platelet count did not affect the differences same subject. Our observation that the extent of inhibition is noted (Table 2 and Figure 5). Thus, whether the effects of greater in PRP is also consistent with this observation. If antiplatelet agents were evaluated as percentage inhibition PRP consistently reduced platelet reactivity, the extent of or as residual platelet function, assessment in PRP tended to inhibition should be similar in PRP and whole blood. The 726 The American Journal of Cardiology (www.AJConline.org) greater extent of inhibition observed in PRP suggests that it that may contribute is that testing platelet function in PRP requires less antiplatelet effect to inhibit platelets in PRP may reflect the effect of the agent on a subset of all platelets than whole blood. that is enriched with less reactive platelets. For some agents, We chose to quantify the fraction of young platelets in their ability to inhibit may be unaffected by the prevalence samples because we postulated that the combination of of more reactive platelets. Our results suggest that P2Y12 centrifugation and the exposure of platelets to multiple antagonists may fall into this group. For other agents, their foreign surfaces would predispose to the loss of more reac- ability to inhibit may be greater when the subset of less tive platelets. Vanguard platelets have been described as the reactive platelets is enriched. Our results suggest that gly- first wave of platelets that adhere after damage to the en- coprotein IIb/IIIa antagonists fall into this group.23 dothelium, as demonstrated by their adhesion in vitro to collagen.18 Although a surface epitope to identify vanguard platelets has not been identified, recent evidence demon- Acknowledgment: We thank Grace Sullivan, BS, and strates that young platelets are more reactive13 and seem Heidi Taatjes, BS, for their expert technical assistance. likely to be a constituent of vanguard platelets. Accordingly, the study of platelets that have been separated with the use 1. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, of centrifugation in vitro is a study of a subset of platelets Littman DR, Weber C, and Ley K. Circulating activated platelets present in vivo. Moreover, the subset appears to be skewed exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat with respect to loss of the more reactive platelets. Med 2003;9:61–67. Our results are consistent with those in previous studies 2. Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986;315:983–989. demonstrating that conditions in which platelet function is 3. Thaulow E, Erikssen J, Sandvik L, Stromorken H, Cohn PF. Blood tested can alter not only platelet function but also the ap- platelet count and function are related to total and cardiovascular death parent effects of antiplatelet agents. We have found previ- in apparently healthy men. Circulation 1991;84:613–617. ously that anticoagulants necessary to prevent clotting in 4. Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity vitro alter platelet reactivity.12 In particular, agents that and prognosis in survival of myocardial infarction. N Engl J Med chelate calcium, such as sodium citrate, may increase plate- 1990;322:1549–1554. 5. Kabbani SS, Watkins MW, Ashikaga T, Terrien EF, Holoch PA, Sobel 12 let reactivity. BE, Schneider DJ. Platelet reactivity characterized prospectively. A The antiplatelet effects of glycoprotein IIb/IIIa inhibi- determinant of outcome 90 days after percutaneous coronary interven- tors, particularly eptifibatide, are augmented when tested in tion. Circulation 2001;104:181–186. blood treated with calcium chelators. For eptifibatide, this 6. Nylander S, Johansson K, Van Giezen JJ, Lindahl TL. Evaluation of artifact led to initially inadequate dosing in clinical stud- platelet function, a method comparison. Platelets 2006;17:49–55. 19 7. Gritters M, Grooteman MP, Schoorl M, Schoorl M, Bartels PC, Schef- ies. Similarly, the inhibitory effects of P2Y12 antagonists fer PG, Teerlink T, Schalkwijk CG, Spreeuwenberg M, Nube MJ. have been shown to be greater when tested in blood treated Citrate anticoagulation abolishes degranulation of polymorphonuclear with calcium chelators.8 The results of the present study cells and platelets and reduces oxidative stress during hemodialysis. extend previous observations demonstrating that anticoagu- Nephrol Dial Transplant 2006;21:153–159. lants affect the assessment of platelet reactivity and alter the 8. Labarthe B, Theroux P, Angioi M, Ghitescu M. Matching the evalu- apparent efficacy of platelet antagonists. ation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol Consistent with previous reports, we found that the in- 2005;46:638–645. hibition of P2Y12 decreases the activation of platelets in- 9. Marciniak SJ Jr, Jordan RE, Mascelli MA. Effect of Ca2ϩ chelation duced by convulxin that mimics the effects of collagen20,21 on the platelet inhibitory ability of the GPIIb/IIIa antagonists abcix- and by thrombin.22 The release of platelet stores of ADP imab, eptifibatide and tirofiban. Thromb Haemost 2001;85:539–543. appears to participate in the activation of platelets induced 10. Kereiakes DJ, Lorenz T, Young JJ, Kukielka G, Mueller MN, Nanni- azzi-Alaimo L, Phillips DR. Differential effects of citrate versus by these agonists, and so P2Y12 antagonists blunt the acti- PPACK anticoagulation on measured platelet inhibition by abciximab, vation of platelets induced by diverse agonists. eptifibatide and tirofiban. J Thromb Thrombolysis 2001;12:123–127. Platelet activation was identified with the use of flow 11. Rebello SS, Huang J, Faul JD, Lucchesi BR. Role of extracellular cytometry, whereas platelet aggregometry is commonly ionized calcium in the in vitro assessment of GPIIb/IIIa receptor used for in vitro testing. We have found previously that the antagonists. J Thromb Thrombolysis 2000;9:23–28. assessment of the extent of inhibition exhibited by 1 group 12. Schneider DJ, Tracy PB, Mann KG, Sobel BE. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997; of antiplatelet agents (glycoprotein IIb/IIIa antagonists) 96:2877–2883. with the use of flow cytometry paralleled the extent of 13. Thattaliyath B, Cykowski M, Jagadeeswaran P. Young thrombocytes inhibition determined with the use of platelet aggregom- initiate the formation of arterial thrombi in zebrafish. Blood 2005;106: etry.14 Nevertheless, results obtained with 1 technique can- 118–124. not necessarily be extrapolated to other techniques. 14. Schneider DJ, Herrmann HC, Lakkis N, Aguirre F, Lo MW, Yin KC, Aggarwal A, Kabbani SS, DiBattiste PM. Increased concentrations of The centrifugation of platelets required to prepare tirofiban in blood and their correlation with inhibition of platelet washed platelets has been shown previously to increase the aggregation after greater bolus doses of tirofiban. Am J Cardiol 2003; spontaneous activation of platelets and decrease platelet 91:334–336. reactivity.23 Our results with washed platelets are consistent 15. Achyuthan KE, Dobson JV, Greenberg CS. Gly-Pro-Arg-Pro modifies with these observations and consistent with the likelihood the glutamine residues in the alpha- and gamma-chains of fibrinogen: that the preparation of platelets to create PRP leads to the inhibition of transglutaminase cross-linking. Biochim Biophys Acta 1986;872:261–268. greater loss of more reactive platelets. 16. Schneider DJ, Baumann PQ, Holmes MB, Taatjes DJ, Sobel BE. Time Our results suggest that testing antiplatelet effects in and dose dependent augmentation of inhibitory effects of abciximab by vitro with PRP may overestimate their efficacy. One factor aspirin. Thromb Haemost 2001;85:309–313. Methods/Platelet Function Testing in Whole Blood 727

17. Robinson M, MacHin S, Mackie I, Harrison P. In vivo biotinylation the Gq-coupled TXA2 receptor is required for ERK2 activation in studies: speciﬁcity of labelling of reticulated platelets by thiazole collagen-induced platelet aggregation. FEBS Lett 2004;556: orange and mepacrine. Br J Haematol 2000;108:859–864. 227–235. 18. Patel D, Vaananen H, Jirouskova M, Hoffmann T, Bodian C, Coller 21. Larson MK, Chen H, Kahn ML, Taylor AM, Fabre JE, Mortensen RM, BS. Dynamics of GPIIb/IIIa-mediated platelet-platelet interactions in Conley PB, Parise LV. Identiﬁcation of P2Y12-dependent and -inde- platelet adhesion/thrombus formation on collagen in vitro as revealed pendent mechanisms of glycoprotein VI-mediated Rap1 activation in by videomicroscopy. Blood 2003;101:929–936. platelets. Blood 2003;101:1409–1415. 19. Phillips DR, Teng W, Arfsten A, Nannizzi-Alaimo L, White MM, 22. Kim S, Foster C, Lecchi A, Quinton TM, Prosser DM, Jin J, Cattaneo Longhurst C, Shattil SJ, Randolph A, Jakubowski JA, Jennings LK, M, Kunapuli SP. Protease-activated receptors 1 and 4 do not stimulate Scarborough RM. Effect of Ca2ϩ on GP IIb-IIIa interactions with G(i) signaling pathways in the absence of secreted ADP and cause integrelin: enhanced GP IIb-IIIa binding and inhibition of platelet human platelet aggregation independently of G(i) signaling. Blood aggregation by reductions in concentration of ionized calcium in 2002;99:3629–3636. plasma anticoagulated with citrate. Circulation 1997;96:1488–1494. 23. Schoenfeld H, Muhm M, Doepfmer U, Exadaktylos A, Radtke H. 20. Roger S, Pawlowski M, Habib A, Jandrot-Perrus M, Rosa JP, Platelet activity in washed platelet concentrations. Anesth Analg 2004; Bryckaert M. Costimulation of the Gi-coupled ADP receptor and 99:17–20. Cardiac Troponin I in Patients With Acute Lower Limb Ischemia

Michael Koutouzis, MD, Konstantinos Kontaras, MD, George Sfyroeras, MD, Konstantinos Moulakakis, MD, Savvas Nikolidakis, MD, Vasilios Andrikopoulos, MD, and Zenon S. Kyriakides, MD, PhD*

The presence, cause, and clinical signiﬁcance of elevated cardiac troponin I in patients with acute lower limb ischemia is yet unknown. Forty-six patients (20 men [43%]; mean age .years, range 42 to 92) with acute lower limb ischemia were enrolled in this study 10 ؎ 72 Serial creatine kinase (CK), CK isoenzyme MB (CK-MB), and troponin I measurements were obtained in all consecutive patients. Peak levels were evaluated for each patient. Twenty-four patients (52%) had elevated peak troponin I levels (>0.2 ng/ml) during their hospitalization. Patients were divided into 3 groups according to their peak troponin I levels: 11 patients (24%) had peak troponin I levels >1 ng/ml (the high troponin I group), 13 (28%) had levels of 0.2 to 1 ng/ml (the intermediate troponin I group), and the remaining 22 (48%) had peak troponin I levels <0.2 ng/ml (the low troponin I group). The peak CK in the 3 (0.04 ؍ levels were 10,263 ؎ 16,513, 1,294 ؎ 1,512, and 934 ؎ 1,045 IU/ml (p ,different troponin I subgroups, respectively, and the peak CK-MB levels were 143 ؎ 170 Troponin I was positively correlated with CK .(0.04 ؍ and 38 ؎ 43, respectively (p ,31 ؎ 38 -The mean length of hospital .(0.009 ؍ p ,0.38 ؍ and CK-MB (R (0.017 ؍ p ,0.35 ؍ R) ization was 8.3 ؎ 6.2 days for the whole study group and did not vary among the 3 troponin There were no differences .(0.762 ؍ I groups (10.5 ؎ 10.9 vs 8.6 ؎ 4.9 vs 7.2 ؎ 4.0 days, p in mortality during hospitalization among the 3 groups (4 of 11 vs 1 of 13 vs 4 of 22 In conclusion, patients with acute lower limb ischemia often have .(0.22 ؍ patients, p elevated cardiac troponin I levels. Elevated troponin I levels were not associated with the duration of hospitalization or with in-hospital mortality in this group of patients. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:728–730)

The aim of this study was to investigate the presence, cause, The patients were examined by the same cardiologist to and clinical significance of elevated troponin I in patients identify possible causes that may have led to elevated car- with acute lower limb ischemia. diac troponin I levels due to primary cardiac causes. Cardiac echocardiographic studies were performed Ͻ6 hours after Methods and Results hospitalization. Transesophageal echocardiographic studies were performed in some of the patients according to the car- Patients presenting with acute lower limb ischemia to the diologist’s discretion. All but 3 patients (all from the high emergency department of our hospital were recruited for the Ͻ Ͻ troponin I group) underwent surgical revascularization 6 study. The onset of symptoms was 24 hours from presen- hours after admission. The type of surgical procedure per- tation to the emergency department. Patients with end-stage formed was decided on the basis of the patient’s history and renal disease, sepsis, acute or recent myocardial infarction, the findings of the clinical examination and angiography. pulmonary embolism, myocarditis or pericarditis, acute se- The Red Cross General Hospital ethics committee ap- vere heart failure, and severe hypotension (systolic blood Ͻ proved the protocol of this study. pressure 70 mm Hg) on admission were excluded from Blood samples were obtained on admission for the base- the study. Fifty patients were initially evaluated. Four line measurements of common biochemical markers. The met the exclusion criteria and did not participate in the serum levels of creatine kinase (CK), CK isoenzyme MB study. The remaining 46 patients constituted the study Ϯ (CK-MB), and troponin I were evaluated every 6 hours for population. The mean age of the study group was 74 10 the first 2 days of hospitalization and daily for the rest of the years (range 44 to 92) and 20 were men (43%). All hospital stay. The peak level for each parameter entered patients were examined by the same group of vascular the statistical analysis. Troponin I was measured using the surgeons, and once the clinical diagnosis of acute limb Straus II fluorometric enzyme immunoassay (Dade Behring, ischemia was made, informed consent was obtained. Elec- Newark, Delaware) by technologists unaware of the clinical trocardiography and baseline measurements of common data. CK and CK-MB were measured using the Abbott biochemical serum levels and hemoglobin were performed. AXSYM system (Abbott Laboratories, Abbott Park, Illi- nois) using microparticle enzyme immunoassay. Ϯ Red Cross General Hospital, Athens, Greece. Manuscript received Continuous parameters are reported as mean SD and October 24, 2006; revised manuscript received and accepted March 7, categorical variables as percentages. To compare differences 2007. among the 3 groups, 1-way analysis of variance was used. *Corresponding author: Tel: 30-210-6414-705; fax: 30-210-6414587. Student’s t test or the U test was used for continuous variables E-mail address: [email protected] (Z.S. Kyriakides). between 2 groups, as appropriate. Categorical variables were

Table 1 Clinical, laboratory, and surgical parameters of the study population Variable All patients Troponin I Level (ng/ml) (n ϭ 46) Ͼ1 0.2–1 Ͻ0.2 (n ϭ 11) (n ϭ 13) (n ϭ 22) Cardiovascular risk factors Age 72 Ϯ 10 75 Ϯ 12 74 Ϯ 11 75 Ϯ 19 Men 20 (43%) 2 (18%) 7 (54%) 10 (45%) Hypertension 35 (79%) 9 (82%) 9 (69%) 17 (77%) Diabetes melitus 13 (28%) 4 (36%) 3 (23%) 6 (27%) Hypercholesterolemia 34 (74%) 8 (73%) 8 (61%) 13 (60%) Previous myocardial infarction 17 (37%) 6 (55%) 4 (31%) 7 (32%) Smoking (previous or current) 41 (89%) 10 (91%) 12 (92%) 19 (86%) Atrial fibrillation/atrial flutter Permanent 12 (26%) 3 (27%) 3 (23%) 6 (27%) Paroxysmal 2 (4%) 0 (0%) 2 (15%) 0 (0%) Persistent 2 (4%) 1 (9%) 1 (8%) 0 (0%) Echocardiographic findings Ejection fraction (%) 52 Ϯ 11 53 Ϯ 951Ϯ 11 51 Ϯ 9 Left-ventricular hypertrophy 24 (52%) 7 (64%) 6 (46%) 10 (45%) Diastolic dysfunction 37 (80%) 7 (64%) 11 (85%) 19 (73%) Segmental wall motion abnormalities 10 (22%) 2 (18%) 5 (38%) 3 (14%) Atrial enlargement 17 (43%) 4 (36%) 6 (46%) 5 (23%) Blood markers Hemoglobin on admission (g/dl) 13 Ϯ 212Ϯ 213Ϯ 213Ϯ 2 Peak serum creatinine (mg/dl) 1.4 Ϯ 1.4 1.6 Ϯ 0.8 1.0 Ϯ 0.3 1.2 Ϯ 1.4 Acute ischemia cause Atherothrombotic 32 (70%) 9 (82%) 8 (61%) 15 (68%) Embolic 14 (30%) 2 (18%) 2 (15%) 10 (45%) Treatment Medical 3 (7%) 3 (27%) 0 (0%) 0 (0%) Surgical 43 (93%) 8 (73%) 13 (100%) 22 (100%) Type of procedure Embolectomy 20 (46%) 4 (50%) 5 (39%) 11 (50%) Thrombectomy/endarterectomy 6 (14%) 2 (25%) 1 (8%) 3 (14%) Bypass grafting 14 (33%) 2 (25%) 4 (31%) 8 (36%) Above knee 11 (24%) 2 (25%) 3 (23%) 6 (27%) Below knee 3 (7%) 0 (0%) 1 (8%) 2 (9%) Time from symptom onset to procedure (h) 13.0 Ϯ 5.7 13.1 Ϯ 7.3 11.6 Ϯ 5.2 13.8 Ϯ 6.1

There were no significant differences between the three subgroups of the study population. compared using the chi-square test or Fisher’s exact test. levels were 143 Ϯ 170, 38 Ϯ 31, and 38 Ϯ 43 IU/ml, Spearman’s correlation test was performed to examine re- respectively (p ϭ 0.04), in the 3 groups. lations between variables. A p value Ͻ0.05 was considered Peak troponin I levels were correlated with peak CK significant. (R ϭ 0.35, p ϭ 0.017) and peak CK-MB (R ϭ 0.38, p ϭ Twenty-four patients (52%) had elevated peak troponin I 0.009) levels. levels (Ͼ0.2 ng/ml) during their hospitalization. Patients The mean duration of hospitalization for the whole study were divided into 3 groups according their peak troponin I population was 8.3 Ϯ 6.2days. No differences in the dura- levels: the high troponin I group had peak levels Ͼ1 ng/ml tion of hospitalization were identified among the 3 different (n ϭ 11 [24%]), the intermediate group had levels of 0.2 to troponin I groups (10.5 Ϯ 10.9 vs 8.6 Ϯ 4.9 vs 7.2 Ϯ 4.0 1 ng/ml (n ϭ 13 [28%]), and the low or normal troponin I days, p ϭ 0.762). group had peak levels Ͻ0.2 ng/ml (n ϭ 22 [48%]). Nine patients (19.5%) died during their hospitalization: 4 The clinical and laboratory characteristics, as well as the (36%) from the high troponin I group, 1 (9%) from the surgical procedure profiles of the study population and its intermediate troponin I group, and 4 (18%) from the low subgroups, are listed in Table 1. There were no significant troponin I group. There were no differences in mortality differences among the 3 subgroups of the study population. during hospitalization among the 3 subgroups (p ϭ 0.22). Peak CK levels varied significantly among the 3 tro- Ϯ ponin I subgroups: 10,263 16,513 IU/ml in the high Discussion troponin I group, 1,294 Ϯ 1,512 IU/ml in the intermediate troponin I group, and 934 Ϯ 1,045 IU/ml in the The main finding of this study was that serum troponin I normal troponin I group (p ϭ 0.04). The peak CK-MB elevation is common in patients with acute lower limb 730 The American Journal of Cardiology (www.AJConline.org) ischemia. Peak troponin I levels were strongly correlated with fact favors the hypothesis that inflammation is critical for peak CK and CK-MB levels. There were no differences in troponin elevation in this group of patients. The fact that no cardiovascular risk factors, cause of the limb ischemia (em- coronary angiographic or myocardial perfusion studies were bolic or thrombotic), or echocardiographic changes among the performed in these patients, because of their clinical status, 3 different troponin I subgroups. It seems that the elevation could be a possible limitation of this study. The exact of troponin I is not correlated with revascularization, be- mechanism of troponin elevation in patients with acute limb cause it was also elevated in all 3 patients with acute lower ischemia is an issue for further investigation. limb ischemia who did not undergo surgical revasculariza- In conclusion, cardiac troponin I is often elevated in tion. In contrast, there were no differences in the duration of patients with acute limb ischemia, without primary cardiac hospitalization or in in-hospital mortality among the differ- source. Elevated troponin I levels were not associated with ent peak troponin I subgroups. the duration of hospitalization and in hospital mortality in Recently, Rittoo et al1 demonstrated that patients with this group of patients. acute limb ischemia due to embolism who underwent surgical revascularization had troponin T elevations. The pro- 1. Rittoo D, Stahne M, Lindesay C, Grocott E, Hickey N, Downing R. portion of patients with elevated peak troponin values was Prognostic significance of raised cardiac troponin T in patients present- similar to that found in our study (44% and 52%, respec- ing with acute limb ischemia. Eur J Vasc Endovasc Surg 2006;32:500– 503. tively), although we also enrolled patients with acute lower 2. Missov E, Calzolari C, Pau B. Circulating cardiac troponin I in severe limb ischemia due to thrombosis. This favors the hypothesis congestive heart failure. Circulation 1997;96:2953–2958. that the limb ischemia itself was responsible for the cardiac 3. Spies C, Haude V, Fitzner R, Schroder K, Overbeck M, Runkel N, troponin elevation. Schaffartzik W. Serum cardiac troponin I as a prognostic marker in Patients with troponin I elevations did not have symp- early sepsis. Chest 1998;21:1410–1416. 4. Jackson I, Stewart A. Best evidence topic report: use of troponin in the toms, signs, or electrocardiographic findings of acute myo- diagnosis of myocardial conduction after blunt chest trauma. Emer Med cardial ischemia. This suggests that the troponin elevations J 2005;22:193–195. were unlikely to be due to primary myocardial events. There 5. Katritsis DG, Hossein-Nia M, Anastasakis A, Poloniecki J, Holt DW, are 4 possible mechanisms causing cardiac troponin eleva- Camm AJ, Ward DE, Rowland E. Myocardial injury induced by radio- tion, other than acute coronary syndromes: (1) subendocar- frequency and low energy ablation: a quantitative study of CK isoforms, CK-MB, and troponin T concentrations. Pacing Clin Electrophysiol 2 dial injury due to increased wall stress ; (2) toxic heart 1998;21:1410–1416. injury due to endogenous substances in circulation, espe- 6. Garre L, Alvarez A, Rubio M, Pellegrini A, Caridi M, Berardi A, cially in critically ill patients3; (3) mechanical cardiac injury Lazzaro C, Blanco P, Menehem C, Diaz M. Use of cardiac troponin T due to direct trauma4 or secondary to iatrogenic causes5,6; rapid assay in the diagnosis of a myocardial injury secondary to elec- 7 trical cardioversion. Clin Cardiol 1997;20:619–621. and (4) cardiotropic viral infections. 7. Smith SC, Ladenson JH, Mason JW, Jaffe AS. Elevations of cardiac Cardiac troponin T is well correlated with serum C-re- troponin I associated with myocarditis. Experimental and clinical cor- active protein in patients with acute limb ischemia.1 This relates. Circulation 1997;95:163–168. Prevalence and Correlates of Septal Delayed Contrast Enhancement in Patients With Pulmonary Hypertension†

Javier Sanz, MDa,*, Santo Dellegrottaglie, MDa,b, Mbabazi Kariisa, MPHa, Roxana Sulica, MDa, Michael Poon, MDa,c, Thomas P. O’Donnell, PhDd,†, Davendra Mehta, MD, PhDa, Valentin Fuster, MD, PhDa, and Sanjay Rajagopalan, MDa,e

Using cardiac magnetic resonance, the presence of myocardial delayed contrast enhancement (DCE) has been described in the ventricular septum at the level of the right ventricular insertion points in patients with pulmonary hypertension (PH). The aim of this study was to investigate the prevalence, extent, and correlates of this finding. Septal DCE was evaluated in 55 patients with known or suspected PH of various causes. The extent of DCE was estimated visually with an insertion enhancement score (range 0 to 4) and quantified as DCE mass. The results were correlated with cine magnetic resonance and right-sided cardiac catheterization. Predictors of DCE were investigated using multivariate analysis. PH at rest was present in 42 patients (group 1) and absent in 13 (group 2). DCE was noted in 41 patients (97%) in group 1 and 3 (23%) in group 2 (p <0.0001). The extent of DCE was higher in group 1 than group 2 (median insertion enhancement score 3 vs 0, median DCE mass 8.7 vs 0 g, respectively; p <0.0001 for both). The extent of DCE showed moderate to to 0.73) with pulmonary pressures and with right 0.5 ؍ good univariate correlations (r ventricular volumes, mass, and ejection fractions. In multivariate analysis, systolic pulmonary pressure was the only predictor of DCE. In conclusion, the presence of septal DCE at the right ventricular insertion points is common in PH of different causes, and the level of systolic pulmonary pressure elevation appears to be the main determinant of this finding. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:731–735)

The presence of pulmonary hypertension (PH) has negative aims were to investigate the prevalence, extent, and corre- prognostic implications.1 Morbidity and mortality associ- lates of septal DCE in the RV insertion points in subjects ated with PH are largely related to right ventricular (RV) with PH from a variety of causes and to provide insights pressure overload and dysfunction, with secondary right- into potential determinants of this finding. sided heart failure.2 In patients with PH, magnetic resonance is a useful tool in the evaluation of biventricular structure Methods and function.3–5 This modality can also accurately demonstrate myocardial fibrosis in various diseases that predomi- The study population consisted of 72 patients referred for nantly involve the left ventricle. With the possible exception cardiac magnetic resonance evaluation of known or sus- of cardiac amyloidosis,6 delayed contrast enhancement pected PH (September 2004 to March 2006) who addition- (DCE) after the administration of gadolinium-based contrast ally underwent right-sided cardiac catheterization. All pa- agents has been shown to correspond to myocardial necrosis tients gave informed consent for the procedures, and the and/or fibrosis.7 The presence of DCE in the ventricular study was approved by the institutional review board. Cri- septum at the level of the RV insertion points was recently teria of exclusion from the analysis were time interval Ͼ described in patients with pulmonary arterial hypertension between magnetic resonance and catheterization 3 months or PH secondary to chronic thromboembolic disease.8,9 Our and DCE in areas other than the septal RV insertion points and adjacent septum (such as DCE with a typical ischemic or infiltrative pattern). The underlying cause of PH was 2,10 aThe Zena and Michael A. Wiener Cardiovascular Institute and Marie- determined after comprehensive diagnostic workup. Dis- Josee and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai ease duration was estimated as the time from symptom School of Medicine, New York, New York; bInstitute of Cardiology, onset (as recorded on the medical record) or, if unknown, as Department of Cardiovascular Sciences, Federico II University, Naples, the time since the diagnosis of PH was first established. Italy; cDepartment of Cardiology, Cabrini Medical Center, New York, New Magnetic resonance studies were performed with a 1.5-T York; dSiemens Corporate Research, Princeton, New Jersey; and eDavis magnet (Magnetom Sonata; Siemens Medical Solutions, Heart & Lung Research Institute, Ohio State University, Columbus, Ohio. Erlangen, Germany) using a phased-array surface coil and Manuscript received November 21, 2006; revised manuscript received and electrocardiographic gating. At the time of the examina- accepted March 7, 2007. *Corresponding author: Tel: 212-241-6054; fax: 212-534-2683. tions, all subjects were in sinus rhythm. Cine views cover- E-mail address: [email protected] (J. Sanz). ing the 2 ventricles from base to apex were acquired using a standard steady-state free precession sequence. Subse- † Conflict of interest: Dr. O’Donnell is an employee of Siemens Cor- quently, the patients received an intravenous bolus of 0.125 porate Research, Princeton, New Jersey. mmol/kg11 of gadopentate dimeglumine (Magnevist; Berlex

Table 1 Comparison between patients with (group 1) and without (group 2) pulmonary hypertension at rest Variable PH at Rest No PH at Rest p Value n ϭ 42 (76%) n ϭ 13 (24%) Age (yrs) 48 (11) 51 (22) NS Women 21 (50%) 12 (92%) 0.006 Disease duration (mos) 5 (20) 0.8 (4.5) NS Cause Pulmonary arterial hypertension 20 (48%) 4 (31%) 0.001 Left-sided heart disease 5 (12%) 4 (31%) NS Lung disease 3 (7.1%) 3 (23%) NS Chronic thromboembolic disease 1 (2.4%) 0 (0%) N/A Sarcoidosis 14 (33%) 1 (7.6%) 0.001 Right-sided cardiac catheterization Pulmonary wedge pressure (mm Hg) 10 (8) 9 (4) NS Systolic pulmonary pressure (mm Hg) 71 Ϯ 19 31 Ϯ 9 Ͻ0.0001 Mean pulmonary pressure (mm Hg) 44 Ϯ 12 18 Ϯ 4 Ͻ0.0001 RV end-diastolic pressure (mm Hg) 8 (12) 4 (2) 0.01 Cardiac index (L/min ϫ m2) 2.9 (1.3) 3.7 (1.2) 0.03 PVRI (Wood units ϫ m2) 9.5 (9) 2.5 (1.9) 0.03 Mixed venous oxygen saturation (%) 62 Ϯ 12 72 Ϯ 6 0.002 Cardiac magnetic resonance LV end-diastolic volume index (ml/m2) 70 (29) 66 (17) NS LV end-systolic volume index (ml/m2) 28 (16) 25 (11) NS LV ejection fraction (%) 58 (18) 62 (14) NS LV mass index (g/m2) 52 (15) 46 (10) NS RV end-diastolic volume index (ml/m2) 109 (43) 77 (9) Ͻ0.0001 RV end-systolic volume index (ml/m2) 63 (41) 35 (9) Ͻ0.0001 RV ejection fraction (%) 37 Ϯ 13 53 Ϯ 10 0.0002 RV mass index (g/m2) 32 (15) 15 (1.4) Ͻ0.0001

LV ϭ left ventricular; N/A ϭ not applicable; PVRI ϭ pulmonary vascular resistance index.

Laboratories, LLC, Montville, New Jersey) followed by 20 was quantified using prototype software (VPT; Siemens ml of saline. After 5 to 10 minutes, contiguous short-axis Corporate Research, Princeton, New Jersey). Myocardial views matching the cine images were acquired using a regions were considered enhanced if the signal intensity was phase-sensitive inversion-recovery fast gradient-echo se- Ն3 SDs above the mean value of normal myocardium.16,17 quence for the evaluation of DCE.12 Typical breath-hold Because of the lower resolution of the single-shot technique, times ranged from 8 to 14 seconds. In patients with an quantitative analyses were restricted to the phase-sensitive inability to perform such breath-holds or when severe mo- sequence. tion artifacts occurred, DCE images were repeated with a Right-sided cardiac catheterization was performed with a single-shot inversion-recovery steady-state free precession Swan-Ganz catheter following standard procedures. Quan- sequence during free breathing.13 tified variables included pulmonary capillary wedge pres- Cine images were postprocessed using specialized soft- sure, mean and systolic pulmonary artery pressures, RV ware (Argus; Siemens Medical Solutions). Biventricular end-diastolic pressure, cardiac index (thermodilution), pul- endocardial and epicardial contours were traced manually to monary vascular resistance index, and mixed venous oxy- obtain end-diastolic and end-systolic volume indexes, ejec- gen saturation. Subsequently, upper-extremity exercise was tion fractions, and mass indexes (indexes being defined as performed for 5 minutes or until the heart rate increased by the specific parameter divided by the body surface area). For Ն30%. Exercise was considered adequate if the output (in the computation of mass, the septum was considered part of triplicate) increased by Ն30%. For the purpose of analysis, the left ventricle,14 whereas papillary muscles and trabecu- subjects were categorized as those with or without PH at lations were included as part of the cavity.15 DCE image rest (groups 1 and 2, respectively), defined as mean pulmo- analysis was blinded to the patients’ clinical information. nary pressure Ͼ25 mm Hg.2,10 Group 2 included patients DCE extent was first semiquantified visually using an in- with normal pressures and those with exercise-induced PH sertion enhancement score: 0 ϭ no DCE, 1 ϭ DCE confined (mean pulmonary pressure Ͼ30 mm Hg with exercise).2,10 to the insertion point, and 2 ϭ DCE extending into the Categorical variables are expressed as percentages and septum contiguous to the insertion point. The definition of continuous variables as mean Ϯ SD for those normally insertion point was based on previous work by Blyth et al.9 distributed or otherwise as medians and interquartile ranges This scoring system was separately applied to the anterior (IQRs). Departures from normality were detected with the and inferior RV insertion points and added to obtain a total Shapiro-Wilk statistic. Differences between groups 1 and 2 score (range 0 to 4). Two investigators reviewed the cine or between patients in group 2 with and without exercise- images and all available DCE images and assigned this induced PH were assessed with the chi-square test, Fisher’s score to each patient by consensus. In addition, DCE mass exact test, Student’s t test, or the Mann-Whitney U test as Miscellaneous/Delayed Enhancement in Pulmonary Hypertension 733

Figure 1. Representative examples of myocardial DCE involving the septal right ventricular insertion points and various values of insertion enhancement scores. The bottom row displays DCE images. The top row shows still frames from the cine loops in matching slice positions. The cine images were used to help differentiate true DCE from nearby nonmyocardial structures, such as cavity or epicardial fat. The left ventricle (LV) and right ventricle (RV) are labeled in (A) for reference. (A, B) Insertion enhancement score ϭ 1 (inferior insertion point; arrow). (C, D) Insertion enhancement score ϭ 2 (both insertion points; arrows). (E, F) Insertion enhancement score ϭ 3 (isolated inferior insertion point and anterior insertion point extending into the anterior septum; arrows). (G, H) Insertion enhancement score ϭ 4 (both insertion points are involved, with extension into the anterior and inferior septum; arrows).

examinations was 0 days (mean 10.6, range 0 to 83). The single-shot sequence was used in 9 subjects (all in group 1) because of significant breathing artifacts during conventional DCE imaging. Table 1 list the underlying diseases leading to PH1 and the results of the cardiac catheterization and magnetic resonance. As expected, pulmonary hemody- namics and RV status were significantly impaired in patients in group 1. Among the patients in group 2, 6 had exercise-induced PH and 7 normal pressures at rest and Figure 2. Differences in mean DCE extent quantified as (A) insertion during exercise The former had a higher median age (62 vs enhancement score (IES) or (B) DCE mass in patients with and without PH 40 years), mean pulmonary pressure (21 vs 16 mm Hg), and at rest (groups 1 and 2, respectively). Error bars, SDs. pulmonary vascular resistance index (3.8 vs 1.9 Wood units ϫ m2) and lower mixed venous oxygen saturation (68% vs 75%) and cardiac index (3.3 vs 4.5 L/min ϫ m2)(pϽ0.05 appropriate. Differences between PH subgroups according for all). to cause were compared using the Kruskal-Wallis test or DCE was present in 44 of the patients (80%): 41 (97%) in analysis of variance. Correlations between the extent of group 1 and 3 (23%) in group 2 (p Ͻ0.0001). In group 2, DCE DCE and hemodynamic or cardiac parameters were ex- was seen in 2 patients (33%) with exercise-induced PH and in plored with Spearman’s rho (r) coefficients. Parameters 1 (14%) subject with normal pressures (p ϭ 0.56). DCE typ- significantly associated with the presence of DCE on uni- ically involved the midmyocardium, particularly in the basal variate analysis were entered into a multivariate model segments. If only 1 insertion point was involved, this was more using stepwise logistic regression analysis. All tests were 2 frequently the inferior point. The median insertion enhance- tailed, and a p value Ͻ0.05 was considered significant. ment score was significantly higher in group 1 than group 2 (3 Analyses were performed with SAS version 9.1 (SAS In- [IQR 1.5] vs 0 [IQR 1], p Ͻ0.0001). Diffuse DCE involvement stitute Inc., Cary, North Carolina). of the septum (score ϭ 4) was observed in 11 patients (26%) in group 1. Examples of different insertion enhancement scores Results are shown in Figure 1. Similarly, group 1 had a higher median DCE mass than group 2 (8.7 [IQR 5.9] vs 0 [IQR 0.4] g, After the exclusion of 10 patients with time intervals be- respectively, p Ͻ0.0001). These differences are illustrated in tween cardiac magnetic resonance and catheterization Ͼ3 Figure 2. Patients in group 1 were subsequently categorized months, 5 patients with DCE in other areas (4 with previous into subgroups (pulmonary arterial hypertension, left-sided myocardial infarctions and 1 with diffuse cardiac sarcoid- cardiac disease, lung disease, and sarcoidosis; see Table 1)to osis), and 2 patients who refused to receive contrast agents, explore potential differences in DCE extent according to un- the final study population consisted of 55 patients. They derlying cause. The respective DCE mass values were 7.4 (IQR were predominantly women (33 [60%]), with a mean age of 8.2), 0.9 (IQR 9), 2.7 (IQR 3.9) and 7.7 (IQR 6.1) g (p ϭ 0.15). 50 years (range 29 to 88). The median time interval between The correlations between DCE extent and parameters 734 The American Journal of Cardiology (www.AJConline.org)

Table 2 cause DCE with time. However, this could not be ascer- Correlates of delayed contrast enhancement extent (Spearman’s tained from this investigation, partly because of sample size correlation coefficients) considerations. In addition, 1 patient with normal pressures Variable IES DCE Mass showed DCE in the RV insertion points, as described also in n ϭ 55 (100%) n ϭ 46 (84%) other clinical scenarios.18 Thus, this DCE pattern appears to Age NS NS be a sensitive but relatively nonspecific marker for the Disease duration NS NS presence of PH. Right-sided cardiac catheterization Regarding DCE extent, absolute quantification using an Pulmonary wedge pressure NS NS objective analytic method seems to be preferable. However, Systolic pulmonary pressure 0.55* 0.72* we also developed and validated a simple visual score that Mean pulmonary pressure 0.56* 0.72* can be easily implemented in clinical practice without the RV end-diastolic pressure 0.32 0.32 need for a more time-consuming analysis, and that also Cardiac index Ϫ0.33 Ϫ0.30 demonstrated good correlations with RV functional param- Pulmonary vascular resistance index 0.56* 0.61* Ϫ Ϫ eters and hemodynamic variables. The amount of DCE Mixed venous oxygen saturation 0.37 0.29 correlated well with the degree of RV and hemodynamic Cardiac magnetic resonance LV end-diastolic volume index NS NS impairment. These results are similar to those reported by 9 LV end-systolic volume index NS 0.33 Blyth et al in 25 patients with pulmonary arterial hyper- LV ejection fraction Ϫ0.28 Ϫ0.32 tension or chronic thromboembolic disease. Our results ex- LV mass index NS 0.46 tend these observations to a larger series of patients includ- RV end-diastolic volume index 0.40 0.60* ing other PH causes. When we compared different patient RV end-systolic volume index 0.47 0.55* subgroups, we did not find significant differences in the RV ejection fraction Ϫ0.50* Ϫ0.51 extent of DCE, and the pattern was virtually identical re- RV mass index 0.51* 0.73* gardless of cause. Our findings thus suggest that DCE is Only correlation coefficients with p values Ͻ0.05 are shown. mostly related to the presence of PH rather than a disease- *pϽ0.0001. specific phenomenon. However, in view of the small num- IES ϭ insertion enhancement score; other abbreviation as in Table 1. ber of patients, we cannot reliably rule out some influence of the underlying disease on the response of the myocardium to the pressure overload. Somewhat surprisingly, there was obtained from right-sided cardiac catheterization or cine no association in this study between estimated disease du- imaging are listed in Table 2. These were generally better ration and either DCE presence or extent. This finding likely for absolute rather than visual DCE quantification, although reflects the difficulty of ascertaining true disease duration the 2 methods were highly correlated (r ϭ 0.78, p Ͻ0.0001). for a disorder in which diagnosis is often challenging and Pulmonary pressures and resistance and RV mass index delays are common.19 were the variables most strongly correlated with DCE ex- One limitation of our study is that coronary disease was tent. There was an inverse but nonsignificant correlation not systematically ruled out as a potential alternative cause between age and DCE mass (r ϭϪ0.27, p ϭ 0.07). On of DCE. However, the pretest likelihood in many patients univariate analysis, predictors of DCE were male gender; was very low (i.e., young women) and the pattern of DCE systolic and mean pulmonary pressures; RV end-diastolic was seen consistently regardless of cause. Because of the pressure; pulmonary vascular resistance index; mixed oxy- heterogeneity of therapies in a population with multiple gen saturation; and RV volumes, ejection fraction, and underlying diseases and the limited number of patients in mass. In a multivariate model, only systolic pulmonary each subgroup, the study was not powered to evaluate the pressure remained significantly associated with the presence potential influence of different medications on myocardial of DCE (odds ratio estimate 1.23, confidence interval 1.08 fibrosis. We used a phase-sensitive technique for DCE im- to 1.40, p ϭ 0.002). aging that is less common than the conventional inversion- recovery technique, but the 2 methods have shown excellent 12 Discussion agreement. Finally, a time interval of 3 months between tests was selected as an arbitrary cutoff. Although pulmo- The main findings of this investigation are as follows: (1) nary pressures may substantially change during this period DCE in the septum at the level of the RV insertion points is (and this might explain the few disagreements between the extremely common in patients with chronic PH of different presence and absence of PH and DCE), it is unlikely that the causes; (2) the extent of DCE correlates with the degree of amount of DCE experiences substantial variations in short hemodynamic and RV morphofunctional impairment; and periods of time. Therefore, we assumed that measurements (3) in multivariate analysis, systolic pulmonary pressure is within 3 months were as representative of the chronic de- the only predictor of DCE. gree of PH as same-day catheterization. In this study, the prevalence of DCE was very high in patients with confirmed PH at rest. There were also 2 sub- 1. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domen- jects with exercise-induced PH and DCE, which may reflect ighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, et al. Clinical an early stage of the disease already accompanied by myo- classification of pulmonary hypertension. J Am Coll Cardiol 2004;43: 5S–12S. cardial fibrosis. It could therefore be speculated that exer- 2. Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam cise-induced PH alone, or simply higher mean pulmonary T, Olschewski H, Peacock A, Pietra G, Rubin LJ, et al. Guidelines on pressure (even within normal limits), might be enough to diagnosis and treatment of pulmonary arterial hypertension. The Task Miscellaneous/Delayed Enhancement in Pulmonary Hypertension 735

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Giuseppe Limongelli, MD, PhDa,e,*, Giuseppe Pacileo, MDa, Bruno Marino, MDb, Maria Cristina Digilio, MDc,d, Anna Sarkozy, MDc,d, Perry Elliott, MDe, Paolo Versacci, MDb, Paolo Calabro, MDa, Andrea De Zorzi, MDc,d, Giovanni Di Salvo, MD, PhDa, Petros Syrris, PhDe, Michael Patton, MA, MB, ChB, MScf, William J. McKenna, MDe, Bruno Dallapiccola, MDc,d, and Raffaele Calabro, MDa

The aim of this study was to characterize cardiovascular involvement in a large number of patients with LEOPARD syndrome. Twenty-six patients (age range 0 to 63 years, median age at the time of the study evaluation 17 years) underwent clinical and genetic investigations. Familial disease was ascertained in 9 patients. Nineteen patients (73%) showed electrocardiographic abnormalities. Left ventricular (LV) hypertrophy was present in 19 patients (73%), including 9 with LV outﬂow tract obstructions; right ventricular hypertrophy was present in 8 patients (30%). Valve (57%) and coronary artery (15%) anomalies were also observed. Single patients showed LV apical aneurysm, LV noncompaction, ,(isolated LV dilation, and atrioventricular canal defect. During follow-up (9.1 ؎ 4.5 years 2 patients died suddenly, and 2 patients had cardiac arrest. These patients had LV hypertrophy. Despite the limited number of subjects studied, genotype-phenotype correlations were observed in familial cases. In conclusion, most patients with LEOPARD syndrome showed LV hypertrophy, often in association with other valvular or congenital defects. A spectrum of underrecognized cardiac anomalies were also observed. Long-term prognosis was benign, but the occurrence of 4 fatal events in patients with LV hypertrophy indicates that such patients require careful risk assessment and, in some cases, consideration for prophylaxis against sudden death. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100:736–741)

LEOPARD syndrome (LS; Online Mendelian Inheritance in and molecular studies have shown that PTPN11 mutations Man #151100; www.ncbi.nlm.nih.gov/sites/entrez?dbϭ account for about 50% and 90% of patients affected by OMIM) is a rare inherited disease characterized by a spectrum Noonan syndrome and LS, respectively.6–9 The nature and of somatic abnormalities.1–3 In 1971, Gorlin et al1 proposed the clinical importance of cardiovascular phenotypes associated well-known acronym LEOPARD (lentigines, electrocardio- with LS remain uncertain, because few patients with the dis- graphic abnormalities, ocular hypertelorism, pulmonary steno- ease have undergone comprehensive cardiac evaluations. The sis, abnormalities of the genitalia, retardation of growth, deaf- aim of this study was to characterize cardiovascular involve- ness). Subsequently, Voron et al2 suggested diagnostic criteria ment in large number of patients with clinical and molecular to facilitate clinical recognition of the disease. To date, 200 diagnoses of LS. cases have been described. Digilio et al4 showed that LS is allelic to Noonan syndrome (Online Mendelian Inheritance in Man #163950), because the 2 conditions are related to specific Methods different mutations of the PTPN11 gene.5 Subsequent clinical This was an observational study involving 3 Italian centers and 2 centers in the United Kingdom. Twenty-six European-derived patients referred to these institutions aSecond University of Naples, Monaldi Hospital, Naples; Departments since 1990 were enrolled in the study. Informed consent of bPediatrics and cExperimental Medicine and Pathology, University “La was obtained for all participants according to a protocol Sapienza,” Rome; dIRCCS-CSS, San Giovanni Rotondo and CSS-Mendel proposed by the ethics committee at Monaldi Hospital Institute, Rome, Italy; eDepartment of Cardiology, The Heart Hospital, (Naples, Italy) and approved by the other institutions. University College of London; and fMedical Genetics, St. George’s Hos- Phenotypical examination for major and minor dysmor- pital, University of London, London, United Kingdom. Manuscript re- phisms was performed by 2 clinical geneticists (MCD, MP). ceived October 11, 2006; revised manuscript received and accepted March Based on specific facial anomalies, patients were classified 13, 2007. as mild dysmorphic (hypertelorism, ear anomalies) and full This work was supported in part by grants from the Italian Ministry of Health (RC 2004, RC 2005, Rome, Italy). Dr. Dallapiccola was supported dysmorphic (hypertelorism, palpebral ptosis, epicanthal by the Italian Ministry of Instruction, University and Research, Rome, folds, and ear anomalies). Anthropometric measurements, Italy. behavioral pure-tone audiometry and/or auditory brainstem *Corresponding author: Tel: 39-0817062852; fax: 39-0817062683. response, renal ultrasonography, and radiologic studies E-mail address: [email protected] (G. Limongelli). were also performed.

The diagnosis of LS was based on multiple lentigines, with Ն3 cardinal features outlined by Voron et al.2 When lentiginosis is absent, 3 other features in patients and immediate relatives with LS are diagnostic. In children and young patients without lentigines, LS was diagnosed in presence of Ն3 of the following clinical criteria: congenital heart defect, café au lait spots, sensorineural deafness, hy- potonia or delayed motor development, distinct facial anomalies (Ն3 of the dysmorphic facial features found in LS, i.e., hypertelorism, downslanting palpebral fissures, palpebral ptosis, ear anomalies), or 1 parent affected by LS.10 Family screening was performed in all the patients. Rela- tives were studied when available. Clinical investigation was performed using a common protocol defined by the investigators, including rest electrocardiography; M-mode, 2-dimensional, and Doppler echocardiography; 24-hour electrocardiographic (ECG) monitoring; and upright symptom-limited exercise testing. Integrated M-mode and 2-dimensional echocardiographic studies were performed to determine wall thickness, chamber dimensions, and cardiac function, following the Amer- ican Society of Echocardiography’s11 recommendations. Different sonographers acquired the images. The images were recorded and analyzed off-line by a single investigator blinded to patients’ identities. Three different measurements were repeated for each parameter, and the average was calculated. Patients underwent symptom-limited exercise treadmill tests using the Bruce protocol. Blood pressure response to exercise was considered abnormal when systolic blood pressure failed to increase by Ͼ25 mm Hg from baseline or with a Ͼ10 mm Hg decrease from the maximum blood pressure during exercise. Patients underwent 24-hour Holter ECG monitoring to reveal conduction, rhythm, and repolarization abnormalities. Nonsustained ventricular tachycardia was defined as Ն3 consecutive ventricular beats at rate of Ն120 beats/min, lasting for Ͻ30 seconds. Left ventricular (LV) hypertrophy was diagnosed when LV wall thickness in diastole was Ͼ2 SDs from the mean corrected for age, gender, and body surface area.12 The thickest place on the LV wall was the maximal wall thickness, expressed as a Z score relative to the normal distribution adjusted for age- and growth-related changes. Right ventricular hypertrophy was diagnosed when Ն2 right ventricular wall measurements exceeded 2 SDs from the mean recorded in normal subjects.13 An LV outflow tract gradient Ͼ30 mm Hg was considered to represent significant LV outflow tract obstruction. The diagnosis of valve abnormalities was assessed using classic echocardiographic criteria. Coronary artery dilation was shown by measuring coronary artery diameter in the parasternal short-axis view. The whole PTPN11 gene coding region was screened for mutation, including the 15 coding exons and exon-intron boundaries. Polymerase chain reaction fragments were initially screened with single-strand conformation polymorphism analysis of abnormal fragment migration, followed by the direct sequencing of fragments with abnormal mi- Figure 1. Patient 1. (A) Multiple lentigines. (B) Echocardiography showing hypertrophic cardiomyopathy. (C) Coronary artery angiography showing gration patterns. ϭ ϭ Data are presented as the numbers of subjects with partic- dilation of both coronary arteries. AO aorta; LCA left coronary artery; RCA ϭ right coronary artery. ular cardiovascular defect and/or abnormalities and/or events. 738 The American Journal of Cardiology (www.AJConline.org)

Table 1 Patient characteristics and genotype results ID FHLS Age LS Age CHD Skin Dysmorphisms ECG LVH RVH PS MVA AVA CA Other PTPN11 Diagnosed Diagnosed Mutation (yrs) (yrs) 1* 0 12 1 mo ML Full ϩϩ(obs) 0 0 0 ϩϩ / Arg498Lcu 2* 0 18 9 ML Full ϩϩ 0 ϩ 0 0 0 LVS Tyr279Cys 3* ϩ (F1)† 1 2 d Caf Full ϩϩ(obs) ϩϩ 0 0 0 / Arg498Trp 4* ϩ (F1) 29 17 ML Full ϩϩϩ00 ϩ 0 / Arg498Trp 5* 0 7 1 mo ML, large nevi Full ϩ 0 ϩϩϩ 0 ϩ LVK and Tyr279Cys LVS 6 ϩ (F2)† 17 13 ML, caf None ϩϩ(obs) 0 0 0 0 0 / Negative 7 ϩ (F2) 24 16 ML Mild ϩϩ 0 0 0 0 0 / Negative 8 ϩ (F2) 39 31 ML Mild ϩϩ 000 0ϩ / Negative 9 ϩ (F2) 62 54 ML Mild ϩϩ(obs) 0 0 0 0 0 / Negative 10* 0 2 6 d ML Full ϩϩ(obs) 0 0 ϩ 0 0 / Thr468Mct 11* 0 2 4 ML Full 0 ϩ 00ϩϩϩ / Thr468Mct 12 0 3 9 ML, caf Full ϩϩ(obs) ϩϩϩ 0 0 / Negative 13* 0 5 3 ML, caf Full 0 ϩ (obs) 0 0 ϩ 0 0 / Tyr279Cys 14* 0 19 9 ML, caf Full ϩϩ(obs) 0 ϩϩ ϩ 0 AVCD Thr468Mct 15 0 14 13 ML, caf Full ϩϩϩϩϩ0 0 / Thr468Pro 16* 0 33 17 ML, caf Full ϩϩ(obs) ϩ 0 ϩ 0 0 / Negative 17* 0 14 10 ML, caf Full ϩ 000ϩϩ0 / Negative 18* 0 3 8 ML, caf Mild 0 0 0 0 0 0 0 / Thr468Mct 19* 0 4 1 ML, caf Full 0 0 0 0 0 0 0 NCLV Tyr279Cys 20* ϩ (F3)† 1 mo 1 ML, caf Full 0 0 0 0 0 0 0 LVE Thr468Mct 21* ϩ (F3) 1 mo 1 ML, caf Full 0 0 0 0 ϩ 0 0 / Thr468Mct 22* ϩ (F3) 18 32 ML, caf Full 0 0 0 0 0 0 0 LVK Thr468Mct 23* 0 10 3 ML, caf Full 0 ϩϩ0 0 0 0 / Negative 24 0 5 14 ML Full ϩϩ(obs) ϩ 0 ϩϩ0 VSDs Negative 25 0 16 2 ML, large nevi Mild ϩϩ 0 0 0 0 0 / Negative 26 0 54 54 ML Mild ϩϩ(obs) 0 0 0 0 0 / Negative

* Patients included in previous publications.5,7,8,10,14 † Patients 3, 6, and 21 were the index patients for family 1 (F1), family 2 (F2), and family 3 (F3). Arg ϭ arginine; AVA ϭ aortic valve anomalies; AVCD ϭ atrioventricular canal defect; CA ϭ coronary anomalies; caf ϭ cafe au lait spot; CHD ϭ congenital heart defect; Cys ϭ cysteine; ECG ϭ electrocardiogram; FHLS ϭ family history of LS; LVE ϭ LV enlargement; LVH ϭ LV hypertrophy; LVK ϭ LV kinesis abnormalities; LVS ϭ LV shape abnormalities; Met ϭ methionine; MVA ϭ mitral valve anomalics; NCLV ϭ noncompacted left ventricle; obs ϭ obstruction of the LV outﬂow tract; Pro ϭ proline; PS ϭ pulmonary stenosis; Thr ϭ threomine; Tyr ϭ tyrosine; Trp ϭ tryptophan; VSDs ϭ multiple ventricular septal defects.

Patients 3, 6, and 20 were the index patients for families 1, 2, percentile 1.25, 75th percentile 15.5; Table 1). A detailed and 3, respectively. The frequency of each variable is reported description of the cardiovascular phenotype is reported in as mean Ϯ 2 SDs. Qualitative data were compared using the following. Fisher’s exact test or the chi-square test. Continuous variables Nineteen patients (73%) had LV hypertrophy. Seven were compared using Student’s t test. A threshold of p Յ0.05 patients had significant LV outflow tract obstructions (37%) was accepted as statistically significant. due to systolic anterior movement of the mitral valve, and 1 patient had a mid-LV obstruction. The patterns of LV hy- Results pertrophy were asymmetric in 15 patients, concentric in 1 The study cohort comprised 26 subjects (7 male and 19 patient, and apical in 3 patients (Figure 1). Ten patients had female subjects; age range 0 to 63 years, median age at the abnormal diastolic function, 9 with abnormal relaxation and time of the study evaluation 17 years). The median age at 1 with a restrictive filling pattern. Dyspnea, ECG abnormal- the diagnosis of LS was 13 years (range 0 to 62, 25th ities, and diastolic dysfunction were significantly more fre- percentile 3.25, 75th percentile 18.7). Familial disease was quent in patients with LV hypertrophy (Table 2). Noteworthy, ascertained by the investigators in 9 patients; the others (17 family history of sudden death, significant cardiovascular patients [65%]) had sporadic cases. Multiple lentigines symptoms, and arrhythmias were not observed in patients (Figure 1) and structural heart defects were the most com- without LV hypertrophy. Eight patients (30%) had right mon features in the 26 patients (96%), followed by facial ventricular hypertrophy (Table 1), associated with isolated dysmorphism (92%), short stature (65%), retarded growth LV hypertrophy in 2 patients, with LV hypertrophy and (50%), sensorineural deafness (23%), and genital abnormal- pulmonary stenosis in 2 patients and only with pulmonary ities (4%). Some patients have been previously reported, as stenosis in 1 patient. Right midventricular stenosis due to a listed in Table 1.5,7,8,10,14 The median age at the diagnosis of hypertrophied moderator band with muscle bundles was the cardiac abnormalities was 9 years (range 0 to 54, 25th reported in a single patient. Miscellaneous/Cardiovascular Abnormalities in LEOPARD Syndrome 739

Table 2 Comparison between patients with and without left ventricular hypertrophy ID Age at Male BSA FHCHD FHSD Dyspnoca Abnormal MWT LA Diastolic Atrial NSVT Diagnosis (yrs) Electrocardiagraphic (mm) Dimension Dysfunction Fibrillation Findings (mm) Patients with LV hypertrophy (n ϭ 19) 11mo ϩ 1000 ϩ 22 26 0 0 0 29 ϩ 1.7 ϩ 00 ϩ 33 30 ϩ 0 ϩ 3 2 d 0 0.3 ϩ 00 ϩ 17 14 ϩ 00 4 17 0 1.4 ϩ 00 ϩ 13 30 ϩ 00 613 ϩ 1.3 ϩϩ ϩ ϩ 36 41 ϩ 00 7 16 0 1.9 ϩϩ ϩ ϩ 28 41 ϩϩϩ 8 31 0 1.9 ϩϩ ϩ ϩ 27 43 ϩϩϩ 9 54 0 1.6 ϩϩ 0 ϩ 14 52 ϩ 00 10 6 d 0 0.7 0 0 0 ϩ 11 22 0 0 0 11 4 ϩ 1.1 0 0 0 0 11 28 0 0 0 12 9 0 1.3 0 0 ϩϩ16 31 ϩ 00 13 3 0 0.6 0 0 0 0 12 22 0 0 0 14 9 0 1.7 0 0 0 ϩ 21 40 0 ϩ 0 15 13 ϩ 1.1 ϩ 00 ϩ 17 27 0 ϩ 0 16 17 0 1.3 0 ϩϩ ϩ 18 35 0 0 ϩ 23 3 0 0.5 0 0 ϩϩ10 18 0 0 0 24 14 0 1.5 0 0 ϩϩ22 36 ϩ 0 ϩ 25 2 0 1.5 0 0 ϩϩ41 34 0 0 0 26 54 0 1.5 0 0 ϩϩ15 48 ϩ 00 Patients without LV hypertrophy (n ϭ 7) 5 1 mo 0 1.4 0 0 0 ϩ 10 32 0 0 0 17 10 1 1.2 0 0 0 ϩ 10 31 0 0 0 18 8 0 1.3 0 0 0 0 9 27 0 0 0 19 1 1 0.9 0 0 0 0 7 25 0 0 0 20 1 0 0.6 ϩ 0 0 0 6 20 0 0 0 21 1 0 1 ϩ 0 0 0 7 24 0 0 0 22 32 0 1.9 ϩ 0 0 0 9 34 0 0 0

BSA ϭ body surface area; FHCHD ϭ family history of congenital heart defect; FHSD ϭ family history of sudden death; LA ϭ left atrial; MWT ϭ maximal wall thickness; NSVT ϭ nonsustained ventricular tachycardia.

Nineteen patients (73%) had ECG abnormalities. Left or biventricular hypertrophy were the most common anomalies (46%), often associated with Q waves (19%), prolonged QTc intervals (23%), and repolarization (42%) abnormalities. Conduction defects were observed in 6 patients (23%) and P-wave abnormalities in 5 patients (19%). Most patients with ECG abnormalities had LV hypertrophy (89%), right ventricular hypertrophy (39%), pulmonary valve abnormalities (33%), aortic valve abnormalities (28%), and other associated cardiac defects (Table 1). Pulmonary stenosis was observed in 6 patients (23%): isolated valvular, isolated infundibular, and valvular and infundibular in 2 patients. Patient 5 had a dysplastic pulmonary valve. Mild aortic regurgitation was present in 6 patients (23%), 2 patients had concomitant discrete subaor- tic stenosis, and 1 patient had aortic valve dysplasia. Eleven Figure 2. Increased maximal wall thickness (MWT) Z score after the patients (38%) had morphologic mitral valve prolapse of 1 appearance of multiple lentigines. or both leaﬂets. Coronary abnormalities were present in 4 patients (15%): the left ventricle) and/or abnormalities of the segmental wall patient 1 had dilations of the main left coronary artery (4.6 motion (Table 1). Single patients had an apical aneurysm of mm), the anterior descending artery (5 mm), and the right the left ventricle, a noncompacted left ventricle, isolated LV coronary artery (5 mm) (Figure 1); patient 5 had a dilation enlargement, an atrioventricular canal defect, and multiple of the right coronary artery (4.9 mm); and patients 8 and 11 ventricular septal defects (Table 1). had dilations of the main left coronary artery (4.5 and 4 mm, Cross-sectional follow-up data were available at an av- respectively). Three patients (11%) had abnormalities of LV erage of 110.2 Ϯ 54 months (9.1 Ϯ 4.5 years; range 1 to 15 shape (2 of them showing the so-called ballerina shape of years) after the earliest cardiovascular examination. During 740 The American Journal of Cardiology (www.AJConline.org)

Table 3 Clinical characteristics of the patients at risk for fatal events ID FHSD QTc (ms) MWT (mm) MWT Z LVOT Gradient (mm Hg) ABPR AF NSVT Outcome Score 2 No 408 33 13.9 8 No No Yes SD 3 Yes 475 17 15.2 90 No No No SD 6 Yes 446 36 16.4 15 No No No ICD (pp), alive 7 Yes 416 28 11.6 10 No Yes Yes ICD (pp), app shock, alive 16 Yes 490 18 8.7 12 No Yes Yes CA, ICD (sp)/PMK, alive

ABPR ϭ abnormal blood pressure response during exercise; AF ϭ atrial fibrillation; app ϭ appropriate; CA ϭ cardiac arrest; ICD ϭ implantable cardioventer-defibrillator; LVOT ϭ LV outflow tract gradient; PMK ϭ pacemaker; pp ϭ primary prevention; QTc ϭ rate-corrected QT interval; SD ϭ sudden death; sp ϭ secondary prevention; other abbreviations as in Table 2. follow-up, 5 patients (26%) showed increased LV hypertro- Previous studies have reported that the appearance or phy (maximal wall thickness Z score) 16.6 Ϯ 6 months after worsening of LV hypertrophy was often concomitant with lentigines appeared, while no differences were observed for the first manifestation of multiple lentigines.3 In this study, LV outflow gradient and global systolic and diastolic func- we observed a worsening of the hypertrophic process at the tion (Figure 2). first manifestation of lentigines in 5 patients. In contrast, we Patients 2 and 15 underwent pulmonary valvulotomy noted that the onset of LV hypertrophy preceded multiple with right ventricular outflow tract muscular band resection, lentigines in most of our cohort. Indeed, recent studies patient 16 had a right ventricular outflow tract muscular suggest that LV hypertrophy and other features, such as café band resection, and patient 14 had a total repair of an au lait spots and deafness, may precede multiple lentigi- atrioventricular canal defect. Patient 9 received a DDD nes.10 In our study, the rate of electrocardiographic LV pacemaker for complete atrioventricular block. Patient 16 hypertrophy was higher than in previous studies and agrees received an implantable cardioverter-defibrillator pace- with echocardiographic findings.1–3 A high percentage of maker after cardiac arrest. Patients 6 and 7 received im- patients with LV hypertrophy had prolonged QTc intervals plantable cardioverter-defibrillators for the primary preven- (23%), including 2 patients with fatal events. The signifi- tion of sudden death, and in the latter, we observed an cance and potential clinical impact of a prolonged QTc appropriate discharge (ventricular fibrillation) after 18 interval in LS needs further investigation. months. Two patients died suddenly (patients 2 and 3). As recently suggested, pulmonary stenosis is less fre- Clinical characteristics of the patients with adverse out- quent than LV hypertrophy in patients with LS.6–7 In con- comes are listed in Table 3. trast, abnormalities of the aortic and mitral valves have Sixteen patients (61%; 13 of the index patients [65%]) probably been underestimated.6,7 Sporadic cases describe carried missense mutations in the PTPN11 gene (Table 1). vascular and coronary artery abnormalities in patients with Among patients with PTPN11 mutations, 3 (18%; 2 of the LS.13,16 We showed coronary artery abnormalities in 4 pa- index patients [10%]) had mutations involving amino acid tients, confirmed by coronary angiography in 2 of them. LV Arg498Leu, 5 (31%; 38% of the index patients) had muta- noncompaction and dilated cardiomyopathy were previ- tions involving amino acid Tyr279Cys, and 8 (50%; 6 of the ously noted in patients with Noonan syndrome.17,18 How- index patients [30%]) had mutations involving amino acid ever, these cardiac abnormalities have not been reported in Thr468Met. Because of sample size, there was no signifi- LS before, widening the spectrum of cardiovascular anom- cant correlation between specific PTPN11 mutations and alies associated with the syndrome. cardiac phenotype. Long-term prognosis seems benign in patients with LS with only mild cardiac abnormalities. In contrast, patients Discussion with LV hypertrophy may develop significant symptoms This is the first systematic analysis of cardiovascular phe- and arrhythmias during follow-up. Nevertheless, we ob- notype in large cohort of patients with LS. Since the original served 4 fatal events in our study population. Sporadic cases description, ECG abnormalities and pulmonary stenosis reported sudden death in patients with LS associated with have been part of the clinical picture of the disease, while LV hypertrophy.3,19 In contrast, several studies described LV hypertrophy and other cardiac defects have been suc- the clinical outcomes and investigated risk assessment in cessively characterized.1–3,15 patients with familial hypertrophic cardiomyopathy.20 LV hypertrophy, mainly asymmetric (79%), was the Whether the molecular mechanisms are different, patho- most common cardiac anomaly in our series. Apical and logic and clinical findings may be similar in familial hyper- concentric hypertrophy, not previously reported, were ob- trophic cardiomyopathy and LV hypertrophy associated to served in our study population (16% and 5%, respectively). LS.21,22 Because a specific risk stratification is not yet avail- LV outflow tract obstructions and abnormal mitral filling able in LS, our patients received implantable cardioverter- patterns were found in about half of the patients examined. defibrillators after algorithms recommended in patients with As previously shown, right ventricular hypertrophy was familial hypertrophic cardiomyopathy.20 It is interesting to present in about 30% of patients with LS, associated with underscore an appropriate shock in a patient who received LV hypertrophy and pulmonary stenosis.15 an implantable cardioverter-defibrillator for the primary Miscellaneous/Cardiovascular Abnormalities in LEOPARD Syndrome 741 prevention of sudden death. These data, in accordance with 7. Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio previous observations, seem to suggest that patients with LS VM, Di Ciommo V, Marino B, Pizzuti A, Dallapiccola B. Correlation between PTPN1 gene mutations and congenital heart defects in with LV hypertrophy carry a relatively higher risk for ad- Noonan and LEOPARD syndromes. J Med Genet 2003;40:704–708. verse events during follow-up. 8. Sarkozy A, Conti E, Digilio MC, Marino B, Marini E, Pacileo G, As previously shown, Tyr279Cys and Thr468Met oc- Wilson M, Calabrò R, Pizzuti A, Dalla Piccola B. Clinical and mo- curred in most of the patients studied.5,7–9 We failed to identify lecular analysis of 30 patients with multiple lentigines and LEOPARD a significant correlation between cardiovascular features syndrome. J Med Genet 2004;41:e68. and specific PTPN11 mutations. To date, the genetic mech- 9. Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Laombe D, Layet V, et al. PTPN11 mutations in anisms responsible for cardiac features in PTPN11-negative patients with LEOPARD syndrome: a French multicentric experience. patients are still unknown. Recently, Kalidas et al23 ex- J Med Genet 2004;41:e117. cluded a role for PTPN11 gene by linkage analysis in 2 10. Digilio MC, Sarkozy A, de Zorzi A, Pacileo G, Limongelli G, Man- families without PTPN11 mutations, supporting the hypoth- ganelli R, Calabro’ R, Marino B, Dalla Piccola B. LEOPARD syn- esis of a heterogenous genetic background in LS. We found drome: clinical diagnosis in the first year of life. Am J Med Genet 2006;140A:740–746. LV hypertrophy and ECG abnormalities in all the affected 11. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereaux R, members of family 1 (Arg498Trp) and family 2 (PTPN11 Feigenbaum H, Gutgessell H, Reichek N, Sahn D, Schnittger I. Rec- negative). The expression of the cardiac phenotype was ommendation for quantitation of the left ventricle by two-dimensional severe in the 2 families, with an apparently greater risk for echocardiography. American Society of Echocardiography Committee fatal events. In family 3 (Thr468Met), we observed mild, on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358–367. isolated ventricular enlargement of the left ventricle in pa- 12. Feigenbaum H. Echocardiographic measurements and normal values. tient 21 and LV wall motion abnormalities in patient 23, In: Echocardiography. Philadelphia, Pennsylvania: Lea & Febiger; suggesting an incomplete or, eventually, age-related pheno- 1994:658. typic expression of dilated cardiomyopathy. 13. McKenna WJ, Kleinebenne A, Nihoyannopoulos P, Foale R. Echo- We must underscore that the frequency of PTPN11 mu- cardiographic measurement of right ventricular wall thickness in hy- tations does not reflect the real prevalence of PTPN11 gene pertrophic cardiomyopathy: relation to clinical and prognostic features. J Am Coll Cardiol 1988;11:351–358. 5,7–9 in previous studies. Nevertheless, in the present study, 14. Pacileo G, Calabro P, Limongelli G, Santoro G, Digilio M, Sarkozy A, patients were referred to a third-level cardiovascular center Marino B, Dallapiccola B, Calabro R. Diffuse coronary dilation in a for a complete cardiovascular screening, whereas in previ- young patient with LEOPARD syndrome. Int J Cardiol 2006;112:e35– ous investigations, patients were referred mainly to a med- e37. ical genetics unit. 15. Sutton MJ, Tajik AJ, Giuliani ER, Gordon H, Daniel WF. Hypertro- phic obstructive cardiomyoapthy and lentiginosis: a little known neu- roectodermal syndrome. Am J Cardiol 1981;47:214–217. 16. Yagubyan M, Panneton JM, Lindor NM, Conti E, Sarkozy A, Pizzuti Acknowledgment: We thank the patients and families who A. LEOPARD syndrome: a new polyaneurysm association and an participated in this study. update on the molecular genetics of the disease. J Vasc Surg 2004;39: 897–900. 17. Yu CM, Chow LT, Sanderson JE. Dilated cardiomyopathy in Noon- 1. Gorlin RJ, Anderson RC, Moller JH. The LEOPARD (multiple len- an’s syndrome. Int J Cardiol 1996;56:83–85. tigines) syndrome revisited. Birth Defect Orig Artic Ser 1971;7:110– 18. Amann G, Sherman FS. Myocardial dysgenesis with persistent sinu- 115. Pediatr Pathol 2. Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines syndrome. soids in a neonate with Noonan’s phenotype. 1992;12: Case report and review of the literature. Am J Med 1976;60:447–456. 83–92. 3. Sommerville J, Bonham-Carter RE. The heart in lentiginosis. Br 19. Woywodt A, Welzel J, Haase H, Duerholz A, Wiegand U, Potratz J, Heart J 1972;34:58–66. Sheikhzadeh A. Cardiomyopathic Lentiginosis/LEOPARD syndrome 4. Digilio MC, Conti E, Sarkozy A, Manganelli R, Dottorini T, Marino B, presenting as sudden cardiac arrest. Chest 1998;113:1415–1417. Pizzuti A, Dallapiccola B. Grouping of multiple-lentigines/LEOPARD 20. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004; and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 363:1881–1891. 2002;71:389–394. 21. Limongelli G, Hawkes L, Calabro’ R, McKenna WJ, Syrris P. Muta- 5. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, tion screening of the PTPN11 gene in hypertrophic cardiomyopathy. Kremer H, van der Burgt I, Crosby AH, Ian A, Jeffery S, et al. Eur J Med Genet 2006;49:426–430. Mutations in PTPN11, encoding the protein tyrosine phospatase 22. Burch M, Mann JM, Sharland M, Shinebourne EA, Parton MA, SHP-2, cause Noonan syndrome. Nat Genet 2002;30:123–126. McKenna WJ. Myocardial disarray in Noonan syndrome. Br 6. Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Heart J 1992;68:586–588. Brunner HG, Bertola DR, Crosby A, Ion A, et al. PTPN11 mutations 23. Kalidas K, Shaw AC, Crosby AH, Newbury-Ecob R, Greenhalgh L, in Noonan syndrome: molecular spectrum, genotype-phenotype cor- Temple IK, Law C, Patel A, Patton MA, Jeffery S. Genetic heteroge- relation, and phenotypic heterogeneity. 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Patients With Advanced Heart advantages offered by levosimendan in so on, the mechanisms of which need to Failure and the Effects of patients with advanced heart failure? be further elucidated. Levosimendan Similarly, the differences between RV We read with great interest the report systolic and diastolic function at base- Ze-Zhou Song, MM by Parissis et al,1 whose study con- line and after levosimendan administra- Jing Ma, MM firmed that tissue Doppler imaging tion between the 2 study groups were Hangzhou, China 10 January 2007 maximal systolic tricuspid annular ve- not described. Was there a relation between the differences in RV systolic locity, right ventricular (RV) early dia- 1. Parissis JT, Paraskevaidis I, Bistola V, stolic velocity, and the ratio of early to and diastolic function at baseline and Farmakis D, Panou F, Kourea K, Nikolaou M, late diastolic velocity increased signifi- after levosimendan administration in Filippatos G, Kremastinos D. Effects of levo- cantly after levosimendan administra- the 2 study groups and further therapeu- simendan on right ventricular function in patic advantages offered by levosimendan tients with advanced heart failure. Am J Car- tion and that levosimendan beneficially diol 2006;98:1489–1492. modulated neurohormonal and inflam- in patients with advanced heart failure? 2. López-Candales A, Rajagopalan N, Saxena N, matory status by decreasing B-type na- This requires further evaluation. Gulyasy B, Edelman K, Bazaz R. Right ven- triuretic peptide levels and altering the Second, an echocardiographic study tricular systolic function is not the sole deter- ratio of interleukin-6 to interleukin-10 by López-Candales et al2 confirmed that minant of tricuspid annular motion. Am J Car- diol 2006;98:973–977. in favor of the latter. This suggests that maximal tricuspid annular plane sys- levosimendan may offer further thera- tolic excursion not only is determined doi:10.1016/j.amjcard.2007.01.008 peutic advantages in patients with ad- by RV systolic function but also ap- Reply: vanced heart failure by improving sys- pears to depend on left ventricular systolic and diastolic RV function. The tolic function. Tricuspid annular plane Right ventricular (RV) function has methods and interpretation of the re- systolic excursion Ͻ2.0 cm is associ- been shown to bear additive prognostic sults, however, raise several concerns. ated with some degree of either RV or significance in patients with advanced First, Parissis et al1 reported that the heart failure due to left ventricular left ventricular dysfunction, whereas a 1 2 study groups (the levosimendan group value Ͼ2.0 cm suggests normal biven- dysfunction. Novel echocardiographic markers on the basis of tissue Doppler and the placebo group) were well bal- tricular systolic function. Also, it is not imaging seem to have better diagnostic anced with respect to baseline features confirmed that maximal velocity during accuracy in evaluating RV systolic and and concomitant medications. How- early diastole, maximal velocity during diastolic function compared with con- ever, left ventricular diastolic function atrial contraction, and their ratio to the ventional echocardiography, as well as parameters (e.g., E, A, and E-wave de- tricuspid annulus not only are deter- good correlation with the gold-standard celeration time; the E/A ratio; maximal mined by RV systolic and diastolic velocity during early diastole, maximal technique of RV radionuclide ventricu- function but also appear to depend on lography.2 In our recently published velocity during atrial contraction, and left ventricular systolic and diastolic their ratio to the mitral annulus) were study,3 we assessed the effects of levo- function. RV systolic and diastolic simendan on a wide spectrum of con- not included in the baseline parameters. functional parameters evaluated by tis- It is well known that marked diastolic ventional and tissue Doppler imaging sue Doppler imaging in the study by echocardiographic markers of RV func- dysfunction typically displaces the pres- 1 Parissis et al, therefore, could not action in patients hospitalized for acute sure-volume relation in an upward di- curately reflect changes in RV systolic rection, resulting in increased left ven- exacerbation of chronic heart failure and diastolic function after levosimen- secondary to left ventricular dysfunc- tricular end-diastolic, left atrial, and dan infusion. That is to say, markedly pulmonary capillary wedge pressures, tion. Levosimendan is a powerful inodi- improved RV systolic and diastolic even leading to RV dysfunction. In this lator that acts as a promoter of intracel- functional parameters evaluated by tis- study, all the patients studied had left lular calcium sensitization to cardiac sue Doppler imaging in this study could ventricular dysfunction, but was there a myofilaments as well as an opener of not confirm that levosimendan increases significant difference in left ventricular adenosine triphosphate–sensitive potas- RV contractility and decreases pulmo- diastolic functional condition between sium channels, causing peripheral arte- the 2 study groups? Was there a relation nary arterial pressure and pulmonary rial and venous dilatation.4 This bio- between left ventricular diastolic func- vascular resistance. logic action is responsible for the tional condition and further therapeutic Despite this question, it is confirmed drug-induced reduction of peripheral that levosimendan may offer further vascular resistance and cardiac after- therapeutic advantages in patients with load. Thus, levosimendan can lead to a advanced heart failure who undergo the significant increase of cardiac output *Letters (from the United States) concerning a optimization of oral medications, in- particular article in The American Journal of Car- through its combined positive inotropic 4 diology௡ must be received within 2 months of the cluding improved New York Heart As- and peripheral vasodilatory properties. article’s publication, and should be limited (with sociation class, modulated neurohormon- According to these observations, we an- rare exceptions) to 2 double-spaced typewritten al and inflammatory status, decreased swer the comments of Drs. Song and pages. Two copies must be submitted. systolic pulmonary arterial pressure, and Ma5 as follows.

First, in our study,3 we refrained 3. Parissis JT, Paraskevaidis I, Bistola V, fortable and cost effective and to result from reporting parameters of left ven- Farmakis D, Panou F, Kourea K, Nikolaou M, in shorter hospital stays. Filippatos G, Kremastinos D. Effects of levo- 1 tricular diastolic function. On one hand, simendan on right ventricular function in pa- However, Burstein et al’s report all patients had advanced left-sided tients with advanced heart failure. Am J Car- raises an important question about radial heart failure, with ejection fractions diol 2006;98:1489–1492. artery “quality” after cannulation. Be- Ͻ35% and concomitant diastolic dys- 4. Parissis J, Filippatos G, Farmakis D, Adamo- cause of likely vasomotor dysfunction, function, with elevated ratios of early poulos S, Paraskevaidis I, Kremastinos D. Le- the radial artery presents impaired func- vosimendan for the treatment of acute heart diastolic transmitral peak flow velocity failure syndromes. Exp Opin Pharmacother tion as assessed by flow-mediated dila- to early diastolic tissue velocity at the 2005;6:2741–2751. tion. Other investigators have shown that lateral mitral annulus (E/e=). In addi- 5. Song Z-Z, Ma J. Patients with advanced heart previous puncture of the radial artery is tion, we have previously shown the failure and the effects of levosimendan. Am J related to more intimal hyperplasia and Cardiol 2007;99:000–000. 3 beneficial effects of levosimendan on 6. Parissis JT, Panou F, Farmakis D, Adamopou- reduced early graft patency. Indeed, this indexes of left ventricular diastolic los S, Filippatos G, Paraskevaidis I, Venetsa- change in radial artery functional status function in patients with acutely decom- nou K, Lekakis J, Kremastinos DT. Effects of should be considered before its cannula- pensated chronic heart failure.6 levosimendan on markers of left ventricular tion. In a randomized clinical trial, Desai Second, it was stressed in our study3 diastolic function and neurohormonal activa- et al4 demonstrated worse vessel patency tion in patients with advanced heart failure. that apart from the direct effects of Am J Cardiol 2005;96:423–426. with the saphenous vein than the radial levosimendan on RV function, also 7. Leather HA, Ver Eycken K, Segers P, Herijgers artery at 1-year follow-up (13.6% vs shown in animal models,7 the favorable P, Vandermeersch E, Wouters PF. Effects of 8.2%, p ϭ 0.009) in patients who under- impact of levosimendan on indexes levosimendan on right ventricular function and went CABG.4 In a secondary analysis ventriculovascular coupling in open chest pigs. 5 of RV function might have resulted Crit Care Med 2003;31:2339–2343. from that trial, radial artery graft use was partly from the improvement of left 8. Kerbaul F, Rondelet B, Demester JP, Fesler P, strongly protective against graft occlusion ventricular systolic and diastolic func- Huez S, Naeije R, Brimioulle S. Effects of at 1 year, after adjustment for all covari- tion. Moreover, the observed decrease levosimendan versus dobutamine on pressure ates, with a larger protective effect seen in in systolic pulmonary arterial pressure load-induced right ventricular failure. Crit women. Care Med 2006;34:2814–2819. may be related to the amelioration of Currently, optional methods of vascu- left ventricular function and to the doi:10.1016/j.amjcard.2007.01.007 lar access have been pursued. The tran- vasodilating effects of the drug on pul- sulnar approach has been proposed as an monary vasculature.3 The levosimen- alternative method of vascular access for dan-induced enhancement of RV con- Impact of Radial Artery diagnostic and coronary intervention. In tractility and improvement of RV filling Cannulation on Radial the PCVI-CUBA study, Aptecar et al6 led pressures are additional advantages of Artery Function a randomized trial in 431 patients who the drug in the management of patients We congratulate Burstein et al1 on underwent the TRA or the transulnar ap- with acute heart failure due to left ven- their meticulous report on the transradial proach. The 2 approaches obtained simi- tricular dysfunction. approach (TRA) and flow-mediated dila- lar rates of success and acute complica- Although there are recent experi- tion. In a very interesting study, the in- tions. The transulnar approach might be mental data indicating that levosimen- vestigators demonstrated that radial can- considered an alternative technique for dan beneficially affects isolated RV nulation and sheath insertion result in cardiac intervention in an attempt to pre- dysfunction,8 the relevant clinical expe- immediate and persistent alteration of serve the radial artery. rience is limited and may be a field for flow-mediated dilation, suggesting severe In summary, we think that all these future research. vasomotor dysfunction. Also, they spec- factors must be considered when select- ulated that the TRA should be avoided in ing a method of vascular access to per- John T. Parissis, MD patients who will likely undergo coronary form cardiac catheterization for patients Dimitrios Farmakis, MD artery bypass grafting (CABG). who are likely candidates for CABG. In- Ioannis Praskevaidis, MD In patients in whom CABG is re- terventional cardiologists are in responsi- Vassiliki Bistola, MD quired, graft integrity, graft–native ves- ble for choosing the most adequate vas- Gerasimos Filippatos, MD sel mismatch, adequate risk factors con- cular approach for coronary angiography Dimitrios T. Kremastinos, MD trol, and aspirin maintenance are crucial but also should preserve potential vessels Athens, Greece 22 January 2007 for late vessel patency. Together, these that can be used in CABG. Because radial factors contribute to the benefits of arterial grafts seem to present better pa- 1. Meluzin J, Spinarova L, Hude P, Krejci J, CABG for coronary revascularization, tency than saphenous vein grafts, it may Kincl V, Panovsky R, Dusek M. Prognostic especially in patients with diabetes and be reasonable to avoid the radial approach importance of various echocardiographic right left ventricular dysfunction. and conserve this vessel for future use ventricular parameters in patients with symp- TRA is an attractive and safe ap- during CABG. New studies should focus tomatic heart failure. J Am Soc Echocardiogr 2005;18:435–444. proach for cardiac catheterization and on this topic. 2. Meluzin J, Spinarova L, Bakala J, Toman J, intervention. Compared with the trans- Cristiano O. Cardoso Krejci J, Hude P, Kara T, Soucek M. Pulsed femoral approach, the TRA presents La Hore C. Rodrigues Doppler tissue imaging of the velocity of tri- fewer vascular complications, mainly in cuspid annular motion: a new, rapid, and non- Carlos R. Cardoso invasive method of evaluating right ventricular patients who require anticoagulation Luis Maria C. Yordi 2 systolic function. Eur Heart J 2001;22:340– and full antiplatelet therapy. Addition- Porto Alegre, Brazil 348. ally, the TRA seems to be more com- 28 February 2007 744 The American Journal of Cardiology (www.AJConline.org)

1. Burstein JM, Gidrewicz D, Hutchison SJ, Hsiao et al1 described in the abstract 1. Hsiao SH, Yang SH, Wang WC, Lee CY, Lin Holmes K, Jolly S, Cantor WJ. Impact of ra- that 100 patients with echocardio- SK, Liu CP. usefulness of regional myocardial dial artery cannulation for coronary angiogra- performance index to diagnose pulmonary em- phy and angioplasty on radial artery function. graphic signs of PH were enrolled in bolism in patients with echocardiographic signs Am J Cardiol 2007;99:457–459. this study after informed consent was of pulmonary hypertension. Am J Cardiol 2006; 2. Agostoni P, Biondi-Zoccai GG, de Benedictis obtained and that PE was found in 50 98:1652–1655. ML, Rigattieri S, Turri M, Anselmi M, Vas- patients by multidetector-row computed 2. Nootens M, Wolfkiel CJ, Chomka EV, Rich S. sanelli C, Zardini P, Louvard Y, Hamon M. tomography of the chest. That is to say, Understanding right and left ventricular sys- Radial versus femoral approach for percutane- tolic function and interactions at rest and with ous coronary diagnostic and interventional 50 patients with PE (the PE group) all exercise in primary pulmonary hypertension. procedures; Systematic overview and meta- had echocardiographic signs of PH, de- Am J Cardiol 1995;75:374–377. analysis of randomized trials. J Am Coll Car- fined by the investigators as (1) pulmo- doi:10.1016/j.amjcard.2007.03.012 diol 2004;44:349–356. nary arterial systolic pressure (PASP) 3. Kamiya H, Ushijima T, Kanamori T, Ikeda C, Ͼ40 mm Hg and (2) evidence of RV Nakagaki C, Ueyama K, Watanabe G. Use of A Novel Method the radial artery graft after transradial cathe- dilation or dysfunction. However, the terization: is it suitable as a bypass conduit? average value of PASP in the PE group of Two-Dimensional Ann Thorac Surg 2003;76:1505–1509. was 40 mm Hg in Table 1, were the Echocardiographic Tracking 4. Desai ND, Cohen EA, Naylor CD, Fremes SE. PASP value of 50 patients all Ͼ40 mm I read with great interest the study by A randomized comparison of radial-artery and 1 saphenous-vein coronary bypass grafts. N Engl Hg which were not well described in the Ogawa et al, which confirmed that J Med 2004;351:2302–2309. study by Hsiao et al1? If not, was there there was excellent agreement between 5. Desai ND, Naylor CD, Kiss A, Cohen EA, a contrary description or slip of the pen the 2-dimensional tracking and manual Feder-Elituv R, Miwa S, Radhakrishnan S, between the abstract and Table 1? methods for left ventricular (LV) wall Dubbin J, Schwartz L, Fremes SE. Impact of ϭ patient and target-vessel characteristics on ar- A mechanism of ventricular interac- thickness (r 0.99) and percentage terial and venous bypass graft patency: insight tion in PH can be described as follows2: wall thickness (%WT) (r ϭ 0.97); that from a randomized trial. Circulation 2007;115: (1) at rest, cardiac function is character- the mean differences in LV wall thick- 684–691. ized by RV systolic overload due to PH ness and %WT were 0.1 Ϯ 0.4 mm and 6. Aptecar E, Pernes JM, Chabane-Chaouch M, and diastolic overload with tricuspid re- 0 Ϯ 5.4%, respectively; and that aver- Bussy N, Catarino G, Shahmir A, Bougrini K, Dupouy P. Transulnar versus transradial artery gurgitation, whereas the left ventricle age %WT was significantly decreased approach for coronary angioplasty: the PCVI- has diastolic underloading and reduced in regions of hypokinetic or akinetic CUBA study. Catheter Cardiovasc Interv compliance, LV systolic performance wall motion compared with those of 2006;67:711–720. remains preserved; and (2) during exer- normal motion (18 Ϯ 4% and 4 Ϯ 4% doi:10.1016/j.amjcard.2007.02.045 cise, RV systolic performance further vs 39 Ϯ 10%, p Ͻ0.001), suggesting worsens, with a reduction in stroke vol- that this 2-dimensional tracking method ume and the ejection fraction, and con- can be used for the noninvasive, auto- Regional Myocardial Performance sequently LV stroke volume decreases mated quantitation of LV wall motion Index for Diagnosis of Pulmonary because of underfilling, and heart rate in 2-dimensional echocardiography. The Embolism in Patients With becomes the mechanism by which car- methods and interpretation of the re- Echocardiographic Signs of diac output increases. It is likely that the sults, however, raise several concerns. Pulmonary Hypertension extent of RV and LV dysfunction was It is well known that segmental myo- I read with great interest the report well related to pulmonary arterial pres- cardial motion is complex, with 3 sep- by Hsiao et al,1 which confirmed that sure. In Hsiao et al’s study,1 PASP in arate components: radial motion, longi- the right ventricular (RV) myocardial the PH group was significantly higher tudinal motion, and rotational motion. performance index (MPI) was signifi- than that in the PE group, which could In addition, segmental myocardial cantly higher in patients with pulmo- have caused the discordance of the motion could be affected by cardiac nary embolism (PE) than in others; that changes in LV and RV dysfunction and global motion and adjacent myocar- patients without PE had concordant further affected the sensitivity and spec- dial motion. changes in the RV and left ventricular ificity of the V index identifying PE. In the study by Ogawa et al,1 how- (LV) MPIs; that in patients with acute Therefore, the sensitivity and specificity ever, segmental LV wall motion, in- PE, the RV MPI became higher but the of the V index in identifying PE with cluding normokinetic, hypokinetic, aki- LV MPI was relatively constant; that the same level of PASP in PH and PE netic, and dyskinetic, was evaluated by using the RV MPI divided by the LV needs to be studied further. In addition, means of visual estimation by an expe- MPI (the V index), PE could be distin- in Hsiao et al’s study,1 the duration of rienced examiner without knowledge of guished in patients with echocardio- PH in the PH and PE groups was not the study patients. Therefore, the visual graphic signs of pulmonary hypertension well described, which could have caused estimation of regional wall motion could (PH); and that by receiver-operating the discordance of the changes in LV be more subjective, less reproducible, characteristic curve analysis, a V index and RV dysfunction and further af- and even more inaccurate, even though Ͼ1.2 identified PE with sensitivity of fected the sensitivity and specificity of it was performed by an experienced ex- 82% and specificity of 83%, suggesting the V index in identifying PE. This is- aminer. It is well known that the accu- that the V index is a useful parameter to sue requires further study. racy of ultrasonic strain and strain rate assess the possibility of PE in patients measurements to evaluate segmental with echocardiographic signs of PH. Ze-Zhou Song, MM myocardial motion has been validated, The methods and interpretation of the Hangzhou, China and ranges of normal values have been results, however, raise several concerns. 5 March 2007 recently established in healthy volun- Readers’ Comments 745 teers.2 Furthermore, deformation in- compared with conventional manual mea- angioplasty. J Am Coll Cardiol 2003;41:810– dexes derived from ultrasonic strain and surement and agreement of LV wall 819. 6. Becker M, Hoffmann R, Kühl HP, Grawe H, strain rate measurements appear to be motion score assessment by the present Katoh M, Kramann R, Bücker A, Hanrath P, less affected by global cardiac motion automated system of 2-dimensional Heussen N. Analysis of myocardial deforma- and segmental tethering than myocar- tracking and visual estimation by an tion based on ultrasonic pixel tracking to de- dial velocities.3,4 A study by Kukulski expert? termine transmurality in chronic myocardial et al5 confirmed the ability of ultrasonic In the study by Ogawa et al,1 infarction. Eur Heart J 2006;27:2560–2566. strain indexes to differentiate acutely whether coronary arteriography was doi:10.1016/j.amjcard.2007.03.030 ischemic myocardium not only from performed and whether the segmental normal but also from dysfunctional LV wall motion condition, including myocardium, and a study by Becker et normokinetic, hypokinetic, akinetic, Nesiritide in Acute Decompensated al6 confirmed that the frame-to-frame and dyskinetic, was closely related to Heart Failure: To Use or Not to tracking of acoustic markers in 2-di- the results of coronary arteriography is Use, That Is the Question? mensional echocardiographic images not described, which could affect the I applaud the editors for publishing for the analysis of myocardial deforma- precise assessment of ischemic myocar- Onwuanyi and Taylor’s1 review on acute tion allows discrimination between dif- dium. In addition, it is well known that decompensated heart failure (HF). The in- ferent transmurality states of myocar- myocardial dyssynergy and abnormally vestigators state that “emerging data from dial infarction, which certify the value segmental LV wall motion may depend meta-analyses have shown that nesiritide of ultrasonic strain and strain rate mea- not only on ischemia but also on the use is associated with a significant in- surements to evaluate the segmental increase in afterload. In the study by crease in serum creatinine, a known 1 motion of ischemic myocardium. There- Ogawa et al, however, the aferload marker of poor outcome in acute HF. fore, the agreement between 2-dimen- condition of patients, for example, sys- There are also data suggesting a trend sional tracking and ultrasonic strain and tolic blood pressure, were not de- toward increased 30-day mortality in ne- strain rate measurements to evaluate scribed, which could affect the precise siritide-treated patients.”2–4 However, segmental myocardial motion and the assessment of ischemic myocardium. further elaboration on these 2 issues is ability of 2-dimensional tracking to dif- Could these factors affect the precise essential when considering the clinical ferentiate ischemic myocardium not assessment of visual estimation by an safety of nesiritide in acute decompen- only from normal but also from dys- experienced examiner and even the re- sated HF. functional myocardium and discrimina- sults such that this 2-dimensional track- Several studies have documented the tion by 2-dimensional tracking between ing method can be used for the nonin- safety of nesiritide in patients with kid- different transmurality states of myo- vasive, automated quantitation of LV cardial infarction, and so on, need to be ney disease hospitalized with heart fail- wall motion? 5,6 further evaluated. ure. The meta-analysis referenced in It is well known that hypertension, the review, however, raised questions Ze-Zhou Song, MM hypercholesterolemia, diabetes, chronic about the adverse renal effects of ne- Hangzhou, China obstructive pulmonary disease, Graves’ siritide on the basis of a risk for serum 19 March 2007 2 disease, and so on, could affect LV or creatinine elevation. Of note, this anal- right ventricular myocardial segments 1. Ogawa K, Hozumi T, Sugioka K, Matsumura ysis used US Food and Drug Adminis- and global function to some extent. In Y, Nishiura M, Kanda R, Abe Y, Takemoto Y, tration data and drug sponsor docu- their study, however, Ogawa et al1 did Yoshiyama M, Yoshikama J. Usefulness of ments along with data from published automated quantitation of regional left ventric- not describe relevant histories of these trials. Furthermore, higher than cur- ular wall motion by a novel method of two- rently recommended doses of nesiritide diseases along with the clinical baseline dimensional echocardiographic tracking. Am J characteristics of the patients. Is there a Cardiol 2006;98:1531–1537. were used, and changes in diuretic dos- relation of segmental LV wall motion, 2. Kowalski M, Kukulski T, Jamal F, D’Hooge J, age were limited because of study de- including normokinetic, hypokinetic, Weidemann F, Rademakers F. Can natural sign. These limitations should be kept strain and strain rate quantify regional myocar- in mind when drawing conclusions. and akinetic motion, by visual estima- dial deformation? A study in healthy subjects. tion by an experienced examiner and Ultrasound Med Biol 2001;27:1087–1097. Neurohormonal antagonism results in 2-dimensional tracking to relevant his- 3. Urheim S, Edvardsen T, Torp H, Angelsen B, similar acute elevations in serum creat- tories of these diseases? How did the Smiseth O. Myocardial strain by Doppler inine, with the maintenance of renal echocardiography: validation of a new method function in the long term.7,8 No evi- investigators discriminate abnormally to quantify regional myocardial function. Cir- segmental LV wall motion in patients culation 2000;102:1158–1164. dence exists to suggest that increased caused either by ischemic heart disease 4. Kukulski T, Jamal F, D’Hooge J, Bijnens B, serum creatinine associated with nesirit- or by these diseases? Two-dimensional De Scheerder I, Sutherland GR. Acute isch- ide leads to worse outcomes. Thus, the tracking could exactly evaluate segmen- emic changes in systolic and diastolic events significance of the observed elevations during clinical coronary angioplasty: a com- tal LV wall motion according to the parison of regional velocity, strain rate and is unclear. study by Ogawa et al,1 and then is in strain measurement. J Am Soc Echocardiogr With regard to the trend toward in- ischemic heart disease or in these dis- 2002;15:1–12. creased mortality with nesiritide noted eases? In contrast, could the relevant 5. Kukulski T, Jamal F, Herbots L, D’hooge J, by the investigators, there were also Bijnens B, Hatle L, Scheerder ID, Sutherland history of these diseases affect the GR. Identification of acutely ischemic myocar- several notable limitations to this meta- 4 precise measurement of LV wall thick- dium using ultrasonic strain measurements: a analysis. Broad ranges of nesiritide ening in parasternal short-axis views clinical study in patients undergoing coronary doses, again some higher than currently 746 The American Journal of Cardiology (www.AJConline.org) recommended, were used in the few 1. Onwuanyi A, Taylor M. Acute decompensated 7. Bakris GL, Weir MR. Angiotensin-converting studies included in the analysis. In ad- heart failure: pathophysiology and treatment. enzyme inhibitor–associated elevations in se- Am J Cardiol 2007;99(suppl):25D–30D. rum creatinine: is this a cause for concern? dition, decreased 30-day survival ap- 2. Sackner-Bernstein JD, Skopicki HA, Aaron- Arch Intern Med 2000;160:685–693. pears to have been related to significant son KD. Risk of worsening renal function 8. Epstein BJ. Elevations in serum creatinine imbalances in baseline characteristics with nesiritide in patients with acutely de- concentration: concerning or reassuring? compensated heart failure. Circulation 2005; Pharmacotherapy 2004;24:697–702. between the groups, which were not ac- 9. Scios, Inc. Natrecor label update. Mountain counted for in the meta-analysis. Fi- 111:1487–1491. 3. Fonarow GC, Adams KF Jr, Abraham WT, View, California: Scios, Inc., 2005. nally, longer term outcomes were not Yancy CW, Boscardin WJ. Risk stratification doi:10.1016/j.amjcard.2007.04.006 assessed. When all available trial data for in-hospital mortality in acutely decompen- were used, the adverse 6-month out- sated heart failure. JAMA 2005;293:572–580. Correction comes with nesiritide were not seen.9 4. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson KD. Short-term risk of death after There is an error in “Role of C-reac- No significant differences were ob- treatment with nesiritide for decompensated tive protein in coronary risk reduction: served between the groups at 6 heart failure. JAMA 2005;293:1900–1905. focus on primary prevention,” by Antonio months (hazard ratio 1.05, 95% con- 5. Butler J, Emerman C, Peacock WF, Mathur M. Gotto Jr., in the March 1, 2007, issue fidence interval 0.81 to 1.36).9 Thus, VS, Young JB; VMAC Study Investigators. of the American Journal of Cardiology. well-designed trials to assess out- The efficacy and safety of B-type natriuretic On page 721, the second sentence peptide (nesiritide) in patients with renal insuf- comes are needed to fully address ficiency and acutely decompensated conges- in paragraph 3, column 1 should read these disparate results before drawing tive heart failure. Nephrol Dial Transplant as follows: “Because populations tend conclusions about nesiritide. 2004;19:391–399. to be heterogeneous, one cannot as- 6. Yancy CW. Nesiritide is safe for CHF patients sume that these values are constant with renal insufficiency: retrospective results for every individual and across all John R. Kapoor, MD, PhD from the Follow Up Serial Infusions of Nesirit- subgroups.52–54” Stanford, California ide (FUSION) trial (abstr). J Card Fail 2004; 2 April 2007 10(suppl):S114. doi:10.1016/j.amjcard.2007.04.007