www.arquivosonline.com.br Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 101, Nº 5, November 2013

Fig. 1 - Mitral regurgitation assessment using four echocardiographic methods in a patient with idiopathic dilated cardiomyopathy. A) Mitral regurgitation jet area measurement showing an area of 9.01 cm2; B) Vena contracta measurement (0.40 cm), in; C/D) Magnified image of the measure of hemisphere radius, maximum velocity and VTI for calculation of effective regurgitant orifice area and regurgitant volume. In this patient, the effective regurgitant orifice area was 0.14 cm2 and the regurgitant volume was 23.8 ml. Page. 459

Editorial Criteria for Mitral Regurgitation Classification were inadequate for Myocardial Delayed Enhancement by Cardiac Magnetic Resonance Dilated Cardiomyopathy Imaging in Pulmonary Arterial Hypertension: A Marker of Disease Severity Review Article Original Articles Antithrombotic Strategy in the Three First Months following Miniaturized Self-Expanding Drug-Eluting Stent in Small-Caliber Bioprosthetic Heart Valve Implantation Coronary Arteries: Late Effectiveness Case Report Does the Aging Process Significantly Modify the Mean Heart Rate? Acute Coronary Syndromes in 2011 and 2012

Serum Adiponectin and Cardiometabolic Risk in Patients with Acute Sports Events and Acute Coronary Syndrome: Possible Confounding Coronary Syndromes Factors and Bias

Left Ventricular Synchrony and Function in Pediatric Patients with Definitive Pacemakers Eletronic Pages Risk of Ionizing Radiation in Women of Childbearing Age undergoing Radiofrequency Ablation Anatomopathological Session Case 5/2013 - A 73 Year-Old Man with Heart Failure, Preserved Analysis of the Sensitivity and Specificity of Noninvasive Imaging Tests Systolic Function and Associated Renal Failure for the Diagnosis of Renal Artery Stenosis Case Report Triceps Skinfold as a Prognostic Predictor in Outpatient Heart Failure Steal of Blood Flow from the Vertebral Artery to the Internal Thoracic Optimized Treatment and Heart Rate Reduction in Chronic Heart Failure Artery Anastomosed to the Coronary Artery

Mechanical Dyssynchrony is Similar in Different Patterns of Left Viewpoint Bundle-Branch Block Korotkoff Sounds – The Improbable also Occurs REVISTA DA SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Publicada desde 1948

Contents

Editorial

Myocardial Delayed Enhancement by Cardiac Magnetic Resonance Imaging in Pulmonary Arterial Hypertension: A Marker of Disease Severity Carlos Eduardo Rochitte, Susana Hoette, Rogério Souza ...... página 377

Original Articles Coronary Angioplasty with and without Stent Miniaturized Self-Expanding Drug-Eluting Stent in Small-Caliber Coronary Arteries: Late Effectiveness Flavio Roberto Azevedo de Oliveira, Luiz Alberto Piva e Mattos, Alexandre Abizaid, Andrea S. Abizaid, J. Ribamar Costa, Ricardo Costa, Rodolfo Staico, Roberto Botelho, J. Eduardo Souza, Amanda Souza ...... página 379

Cardiogeriatrics Does the Aging Process Significantly Modify the Mean Heart Rate? Marcos Antonio Almeida Santos, Antonio Carlos Sobral Sousa, Francisco Prado Reis, Thayná Ramos Santos, Sonia Oliveira Lima, José Augusto Barreto-Filho ...... página 388

Acute Coronary Artery Disease Serum Adiponectin and Cardiometabolic Risk in Patients with Acute Coronary Syndromes Gustavo Bernardes de Figueiredo Oliveira, João Ítalo Dias França, Leopoldo Soares Piegas ...... página 399

Pediatric Echocardiography Left Ventricular Synchrony and Function in Pediatric Patients with Definitive Pacemakers Michel Cabrera Ortega, Adel Eladio Gonzales Morejón, Giselle Serrano Ricardo ...... página 410

Therapeutic Electrophysiology (Ablation) Risk of Ionizing Radiation in Women of Childbearing Age undergoing Radiofrequency Ablation Gustavo Glotz de Lima, Daniel Garcia Gomes, Caroline Saltz Gensas, Mariana Fernandez Simão, Matheus N. Rios, Leonardo Martins Pires, Marcelo Lapa Kruse, Tiago Luiz Luz Leiria ...... página 418

Arquivos Brasileiros de Cardiologia - Volume 101, Nº 5, November 2013 Systemic Hypertension Analysis of the Sensitivity and Specificity of Noninvasive Imaging Tests for the Diagnosis of Renal Artery Stenosis Flavio Antonio de Oliveira Borelli, Ibraim M. F. Pinto, Celso Amodeo, Paola E. P. Smanio, Antonio M. Kambara, Ana Claudia G. Petisco, Samuel M. Moreira, Ricardo Calil Paiva, Hugo Belotti Lopes, Amanda G. M. R. Sousa ...... página 423

Heart Failure Triceps Skinfold as a Prognostic Predictor in Outpatient Heart Failure Priccila Zuchinali, Gabriela Corrêa Souza, Fernanda Donner Alves, Karina Sanches Machado d’Almeida, Lívia Adams Goldraich, Nadine Oliveira Clausell, Luis Eduardo Paim Rohde ...... página 434

Optimized Treatment and Heart Rate Reduction in Chronic Heart Failure Irineu Blanco Moreno, Carlos Henrique Del Carlo, Antônio Carlos Pereira-Barretto ...... página 442

Mechanical Dyssynchrony is Similar in Different Patterns of Left Bundle-Branch Block Rodrigo Bellio de Mattos Barretto, Leopoldo Soares Piegas, Jorge Eduardo Assef, José Francisco Melo Neto, Thiago Uchoa Resende, Dalmo Antonio Moreira, David Costa LeBihan, Francisco Faustino França, Romeu Sérgio Meneghelo, Amanda Guerra Moraes Rego Sousa ...... página 449

Valvopathy Criteria for Mitral Regurgitation Classification were inadequate for Dilated Cardiomyopathy Frederico José Neves Mancuso, Valdir Ambrosio Moisés, Dirceu Rodrigues Almeida, Wercules Antonio Oliveira, Dalva Poyares, Flavio Souza Brito, Angelo Amato Vincenzo de Paola, Antonio Carlos Camargo Carvalho, Orlando Campos ...... página 457

Review Article

Antithrombotic Strategy in the Three First Months following Bioprosthetic Heart Valve Implantation Andre R. Durães, Milena A. O. Durães, Luis C. L. Correia, Roque Aras ...... página 466

Letter to the Editor

Acute Coronary Syndromes in 2011 and 2012 Juan Sanchis, Antoni Bayes-Genis, Leopoldo Pérez de Isla ...... página 473

Sports Events and Acute Coronary Syndrome: Possible Confounding Factors and Bias Mauro Felippe Felix Mediano, Andrea Silvestre de Sousa, Alejandro Marcel Hasslocher-Moreno ...... página 474

Arquivos Brasileiros de Cardiologia - Volume 101, Nº 5, November 2013 Arquivos Brasileiros de Cardiologia - Eletronic Pages

Anatomopathological Session

Case 5/2013 - A 73 Year-Old Man with Heart Failure, Preserved Systolic Function and Associated Renal Failure Tiago Rodrigues Politi, Paulo Sampaio Gutierrez ...... página *e86

Case Report

Steal of Blood Flow from the Vertebral Artery to the Internal Thoracic Artery Anastomosed to the Coronary Artery Jose Sebastião de Abreu, Nayara Lima Pimentel, Jordana Magalhães Siqueira, Carlos Newton Diógenes Pinheiro, Teresa Cristina Pinheiro Diógenes, José Nogueira Paes Junior ...... página 95

Viewpoint

Korotkoff Sounds – The Improbable also Occurs Bruno Estañol, Guillermo Delgado, Johannes Borgstein ...... página 99

* Indicate manuscripts only in the electronic version. To view them, visit: http://www.arquivosonline.com.br/2013/english/10105/edicaoatual.asp

Arquivos Brasileiros de Cardiologia - Volume 101, Nº 5, November 2013 www.arquivosonline.com.br A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948

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Myocardial Delayed Enhancement by Cardiac Magnetic Resonance Imaging in Pulmonary Arterial Hypertension: A Marker of Disease Severity Carlos Eduardo Rochitte1, Susana Hoette2, Rogério Souza2 Instituto do Coração, InCor, Setor de Ressonância Magnética e Tomografia Computadorizada Cardiovascular1; Unidade de Circulação Pulmonar, Pneumologia, Instituto do Coração do Hospital das Clínicas da FMUSP2, São Paulo, SP - Brazil

The study of Bessa et al.1, published in this issue of from these areas. When images are acquired late (5-10 min Arquivos Brasileiros de Cardiologia, studied 30 patients after contrast injection), the areas in which the myocardium with pulmonary hypertension (PH) using cardiac magnetic is intact do not retain the contrast, but the areas with fibrosis resonance imaging. They evaluated the presence and extent retain the contrast, hence the term delayed enhancement. of delayed enhancement in these patients and correlated In patients with HP, three studies demonstrated the the percentage of delayed enhancement mass with severity presence of delayed enhancement in most patients and markers in pulmonary hypertension. Delayed enhancement delayed enhancement was found mainly in the RV septal was found in 93% of patients with HP in the anterior and attachment zone and in the septal wall3-5. Fibrosis in these inferior septa, in the septal-RV free wall attachment zones, areas can also be found in hypertrophic cardiomyopathy6,7, commonly called delayed enhancement of ventricular unlike other cardiomyopathies such as the Chagas disease8, junction pattern. The delayed enhancement mass was with predominance of fibrosis in the basal and apical left corrected to the left ventricular mass. The percentage of ventricular (LV) inferolateral wall, or viral myocarditis with delayed enhancement was then used for analysis. This diffuse pattern9, among other patterns suggestive of specific study showed a higher percentage of myocardial fibrosis etiologies of cardiomyopathies. In most of these diseases, the in patients with signs of Right Ventricular Failure (RVF), presence of delayed enhancement appears to be associated Functional Class (FC) IV, 6-Minute Walk Test (6MWT) with increased risk of arrhythmias and worse prognosis. < 300 m, Cardiac Index (CI) < 2.0 and right atrial pressure Delayed myocardial enhancement (fibrosis) of ventricular > 15. The presence of RHF, the impairment of FC and the junction pattern appears to be associated with Right 6MWT walking distance and low CI are classic markers Ventricular (RV) overload. An explanation for this preferential of prognosis in HP. The percentage of fibrosis was able to location of delayed enhancement is the overhead sustained by identify patients with RVF (clinical evaluation), FC IV, 6MWT the septum with increased RV afterload. As the RV overload < 300 m and CI < 2.0 L/min.m2 with good accuracy. increases, it dilates and pushes the septum toward the LV, overloading the septal RV attachment zones and the septum Despite some progress in understanding the physiopathology itself. Shehata et al. demonstrated the inverse relationship of the disease and the discovery of new treatments in recent of delayed enhancement mass with Eccentricity Index (EI), decades, pulmonary hypertension is still a disease with poor that is, the higher the septal bulging toward the left ventricle, prognosis2. Non-invasive markers to better assess the severity and consequently the lower the EI, the greater the delayed of the disease and that may help determine which patients enhancement mass10. In experimental studies, these are the require more aggressive treatments are needed. Delayed areas subjected to maximum stress in normal ventricular enhancement is a tool that was initially used to evaluate areas contraction, and these areas are also the first to produce of myocardial fibrosis in patients who have had myocardial natriuretic peptide type A in HP models, reflecting greater infarction. The contrast injected is quickly rinsed in normal mechanical stress. The study of Bessa et al. demonstrated areas, but when there is increased extracellular tissue, such that most patients with HP had delayed enhancement and as in fibrosis, the contrast is retained and is slowly eliminated ventricular junction pattern, confirming the literature data1. An echocardiographic study in patients with HP of a specific etiology associated with schistosomiasis also demonstrated Keywords a relationship of increased pulmonary pressure with disease Magnetic Resonance Secfroscopy/methods; Hypertension, severity, suggesting that in various etiologies of HP, a delayed 11 Pulmonary; Myocardium; Endomyocardial Fibrosis. enhancement of similar pattern may occur (Armstrong) . The strength of this study was that all patients underwent Mailing address: Carlos Eduardo Rochitte • right cardiac catheterization within 72 hours after cardiac Instituto do Coração, InCor, HCFMUSP - Setor de Ressonância Magnética magnetic resonance imaging. Previous studies have shown e Tomografia Computadorizada Cardiovascular, Av. Dr. Enéas de Carvalho Aguiar, 44 - Andar AB, Cerqueira César. Postal Code 05403-000, São Paulo, the relationship of delayed enhancement mass with RV SP - Brazil dysfunction and hemodynamic variables, but this study was E-mail: [email protected] the first to demonstrate the relationship of myocardial fibrosis Manuscript received October 23, 2013; revised manuscript October 23, 2013; accepted October 23, 2013. with clinical, hemodynamic and functional markers. The evaluation of right ventricular function is emerging DOI: 10.5935/abc.20130224 as an independent prognostic marker in HP and the study

377 Rochitte et al. Myocardial Fibrosis in PH – A Severity Marker Editorial of Sheata et al. also demonstrated an inverse correlation comparing other forms of HP, such as those belonging to the of delayed enhancement mass with RV ejection fraction10. other groups of classification (secondary to left ventricular Unfortunately, this study did not evaluate the fibrosis mass dysfunction, diseases of the pulmonary parenchyma, chronic percentage in relation to RV dysfunction. pulmonary thromboembolism, for example) in order to Although this study has evaluated a small number of analyze the existence or not of different patterns of fibrosis. patients with HP and although it is a cross-sectional study Despite these limitations, the manuscript of Bessa et al. is in which it is not possible to show the prognostic role of another original scientific contribution indicating that myocardial delayed enhancement, the fact that the percentage of fibrosis detected by cardiac resonance imaging correlates fibrosis is increased in patients who have markers of worse directly with the severity of disease and possibly with prognosis. prognosis suggests that delayed enhancement may prove to Therefore, another marker of severity of cardiomyopathy be an important noninvasive prognostic marker in patients associated with pulmonary hypertension is reaffirmed and can with HP. It would be interesting if the authors conducted be identified by magnetic resonance imaging. The evaluation of long‑term follow‑up of these patients, so that the prognostic interstitial myocardial fibrosis through myocardial T1 mapping role of delayed enhancement is confirmed and fibrosis may by resonance imaging may bring in the future more information show its prognostic role in HP, thus helping clinical decisions. on the myocardial state and prognosis in this important and The study of Bessa et al. also opens up the possibility of challenging clinical scenario.

References

1. Bessa LG, Junqueira FP, Bandeira ML, Garcia MI, Xavier SS, Lavall ventricular tachycardia events in patients with hypertrophic cardiomyopathy. G, et al. Pulmonary arterial hypertension: Use of delayed contrast- JACC Cardiovasc Imaging.2013;7(3):173-81. enhanced cardiovascular magnetic resonance in risk assessment. Arq Bras Cardiol.2013;Aug 27.pii S0066-782X2013005000069 [Epub ahead of 7. Shiozaki AA, Senra T, Arteaga E, Pita CG, Martinelli Filho M, Avila LF,et al. print]. [myocardial fibrosis in patients with hypertrophic cardiomyopathy and high risk for sudden death]. Arq Bras Cardiol.2010;94(4):535-40. 2. Cicero C, Franchi SM, Barreto AC, Lopes AA. Lack of tight association between quality of life and exercise capacity in pulmonary arterial 8. Mello RP, Szarf G, Schvartzman PR, Nakano EM, Espinosa MM, Szejnfeld hypertension. Arq Bras cardiol.2012;99(4):876-85. D,et al. Delayed enhancement cardiac magnetic resonance imaging can identify the risk for ventricular tachycardia in chronic chagas’ heart disease. 3. Blyth KG, Groenning BA, Martin TN, Foster JE, Mark PB, Dargie HJ, et al. Arq Bras Cardiol.2012;98(5):421-30. Contrast enhanced-cardiovascular magnetic resonance imaging in patients with pulmonary hypertension. Eur Heart J. 2005;26(19):1993-9. 9. Mahrholdt H, Wagner A, Deluigi CC, Kispert E, Hager S, Meinhardt G, et al.. Presentation, patterns of myocardial damage, and clinical course of viral 4. Junqueira FP, Macedo R, Coutinho AC, Loureiro R, De Pontes PV, Domingues myocarditis. Circulation. 2006;114(15):1581-90. RC,et al. Myocardial delayed enhancement in patients with pulmonary hypertension and right ventricular failure: Evaluation by cardiac mri. Br J 10. Shehata ML, Lossnitzer D, Skrok J, Boyce D, Lechtzin N, Mathai SC, et al.. Radiol.2009;82(982):821-6. Myocardial delayed enhancement in pulmonary hypertension: Pulmonary 5. McCann GP, Gan CT, Beek AM, Niessen HW, Vonk Noordegraaf A, van hemodynamics, right ventricular function, and remodeling. AJR Am J Rossum AC. Extent of mri delayed enhancement of myocardial mass is Roentgenol.2011;196(1):87-94. related to right ventricular dysfunction in pulmonary artery hypertension. 11. Armstrong AC, Bandeira AM, Correia LC, Melo HC, Silveira CA, AJR Am J Roentgenol.2007;188(2):349-55. Albuquerque E, et al. Pulmonary artery pressure, gender, menopause, and 6. Shiozaki AA, Senra T, Arteaga E, Martinelli Filho M, Pita CG, Avila LF, et al. pregnancy in schistosomiasis-associated pulmonary hypertension. Arq Bras Myocardial fibrosis detected by cardiac ct predicts ventricular fibrillation/ Cardio.2013;101(2):154-9.

Arq Bras Cardiol. 2013; 101(5):377-378 378 Original Article

Miniaturized Self-Expanding Drug-Eluting Stent in Small Coronary Arteries: Late Effectiveness Flavio Roberto Azevedo de Oliveira, Luiz Alberto Piva e Mattos, Alexandre Abizaid, Andrea S. Abizaid, J. Ribamar Costa, Ricardo Costa, Rodolfo Staico, Roberto Botelho, J. Eduardo Sousa, Amanda Sousa Instituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil

Abstract Background: Small vessels represent a risk factor for restenosis in percutaneous coronary angioplasty (PCA). The Sparrow® self-expanding drug‑eluting stent, which has a lower profile than the current systems, has never been tested in this scenario. Objectives: To evaluate the late effectiveness of the Sparrow® drug-eluting stent, regarding in-stent late lumen loss (LLL). Methods: Patients with ischemia, symptomatic or documented, were submitted to PCA in vessels with reference diameter < 2.75 mm, divided into two groups regarding Sparrow® stent type: group 1: Sparrow® drug-eluting stent (DES), group 2: Sparrow® bare metal stent (BMS). Clinical follow-up duration was 12 months. Evaluation using quantitative coronary angiography (QCA) was performed immediately and at 8 months. A decrease of over 65% of in-stent LLL with DES was estimated to calculate sample size. IBM® SPSS software, release 19 (Chicago, Illinois, USA) was used for the statistical analysis. Results: A total of 24 patients were randomized, 12 in each group. The DES and BMS groups were similar in age (63.25 ± 10.01 vs. 64.58 ± 11.54, p = 0.765), male gender (58.3% vs. 33.3%, p = 0.412), risk factors and all angiographs aspects. Immediate results were satisfactory in both groups. At 8 months in-stent late lumen loss was significantly lower in DES than in BMS group (DES vs. BMS 0.25 ± 0.16 0.97 ± 0.76, p = 0.008). Conclusion: In small-vessel PCA, the Sparrow® DES determined significant reduction in in-stent LLL, when compared to Sparrow® BMS. (Arq Bras Cardiol. 2013;101(5):379-387) Keywords: Angioplasty, Balloon, Coronary; Drug Eluting Stents; Randomized Controlled Trial; Comparative Study.

Introduction restenosis rates in all groups of patients (P), even in patients with small-caliber vessels. Still, restenosis rates remain higher During percutaneous coronary angioplasty (PCA), in smaller-caliber vessels when compared with larger ones7-9. small‑caliber vessels represent higher complexity with increased rates of target-lesion revascularization (TLR) More distal lesions, tortuosity and calcification, common in and more restenosis, when compared with larger-caliber small-caliber vessels, hinder stent navigation in conventional vessels1-5, being related to neointimal hyperplasia (NIH), dilation systems with balloon-expanding stent (BES). which determines late luminal loss (LLL) after PCA. NIH has Stents with thin struts induce lower NIH than the ones the same intensity in vessels of different sizes, with greater with thick struts, even among DES10,11. impact on small-caliber ones, which respond with greater In this context, the Sparrow® self-expanding nitinol lumen loss than larger vessels6. stent (Cardiomind Inc., Sunnyvale, California) appeared, With bare-metal stents (BMS), LLL ranges from 0.8 to dedicated to small-caliber vessels. The BMS version of the 1.0 mm. With drug-eluting stents (DES), LLL is always below Sparrow® self-expanding stent (SES) was evaluated by 12 0.5 mm being smaller (below 0.3 mm) in those DES with Chamié et al , who demonstrated its efficacy and safety. sirolimus, everolimus or biolimus. This greater inhibitory It is mounted on a guide wire system that eliminates the balloon, resulting in 70% lower profile than the conventional power in NIH has resulted in a significant reduction in balloon-stent system. This study is the pioneer to evaluate the impact of LLL when using self-expanding Sparrow® DES compared to Mailing Address: Flavio Roberto Azevedo de Oliveira • the BMS version in small-caliber vessels assessed by QCA Marquês de Tamandaré, Poço da Panela. Postal Code 52061-170, at eight months, which is the primary objective. Secondary Recife, PE - Brazil objectives: (1) comparison between the groups regarding E-mail: [email protected], [email protected] Manuscript received September 10, 2012, revised manuscript September 17, vessel, lumen and stent volumes and the percentage of 2012, accepted April 23, 2013. the stent volume obstruction by means of intracoronary ultrasound (IVUS) immediately after implantation and DOI: 10.5935/abc.20130199 at eight months; (2) description of up to 12 months in

379 Oliveira et al. Self-expanding drug-eluting stent Original Article exchange major adverse cardiac events (MACE - death, Sparrow®). This is a sirolimus-eluting system (6 mg, myocardial infarction, target vessel revascularization (TVR) 60% of the dose of the Cypher® stent) comprising a and stent thrombosis. nitinol SES with a closed-cell design and strut thickness of 67 μm, mounted on a platform that runs on a guide wire (0.014"), incorporated to a matrix of medical grade Methods PLA/PGLA biodegradable copolymers of the SynBiosysTM biodegradable polymer system. This copolymer matrix adds Study design only 8 microns to strut thickness. The result is a very low The present was a prospective randomized, non-blinded profile system, as shown in Figure 1, and up to 70% thinner study (the surgeon was unaware of the type of stent used), than any balloon-stent system (Table 1). carried out at the Instituto Dante Pazzanese de Cardiologia, A flexible guide wire, with 2-3 cm in length, runs along São Paulo (SP), CEP and Conep protocols #3,577 and the stent to allow advancement of the system in the vessel. 14,582 (approved), which evaluated the late effectiveness of There are two radiopaque markers that identify the beginning the Sparrow® DES when compared to the BMS version by and end of the stent in the guide wire system and allow measuring and comparing LLL at eight months through the its precise positioning in the lesion. The compound stent QCA in patients with lesions in small-caliber vessels (reference contains nitinol, which has a thermoelastic expansion diameter ≤ 2.75 mm). property (memory metal). Mechanical locks on the stent The clinical reassessment was scheduled for 30 days, six borders keep it from expanding and attached to the guide months and 12 months after the procedure. QCA assessment wire. A power source (non-sterile external device) is was scheduled immediately before and immediately after the connected to the proximal end of a dilation system sterile PCA and after eight months. Intravascular ultrasound (IVUS) adaptable cable, which controls the stent release through an was also scheduled immediately after stent implantation and electrolysis mechanism with a 0.5 mA current. Initially, the after eight months. distal lock is released and then, the proximal one (Figure 2). The stent system worked with a 0.014" guide wire and Patient selection the balloon was advanced over this system until the lesion, where predilation was performed. Then, the balloon was retreated to a position, proximal to the proximal stent marker Inclusion criteria: and the stent deployment process was initiated through • Age ≥ 18 years. electrolysis, as previously described. Post-procedural dilation • Clinical evidence of ischemia (angina or ischemic was performed after stent release. To prevent trauma to the equivalent) or evidence of ischemia by noninvasive evaluation. stent borders, the balloon was always shorter than the stent. • Target lesion in natural coronary artery with stenosis The same guide wire could also be used to perform IVUS. ≥ 50% and < 100%, analyzed by QCA. Study procedures comprised the following sequence: • Target vessel with reference diameter ≥ 2.0 and ≤ 2.75 mm. electrocardiogram (ECG) before the procedure and at discharge; cardiac enzymes (CK-MB) and troponin I or T, • Target lesion with extension ≤ 20 mm. before and after the procedure, activated clotting time (ACT) after arterial access, at the end of the procedure and Exclusion criteria: before sheath withdrawal; dual antiplatelet therapy with • Female gender during pregnancy. clopidogrel 300 mg and aspirin 100 mg at least 12 hours before the procedure, maintained for at least eight months; • Left ventricular ejection fraction < 30% during the prior use of a 0.6 F sheath and compatible catheter-guides; six months. intravenous heparin (100 U/kg) after sheath placement and • Contraindication to dual antiplatelet use. intracoronary nitroglycerin (100-200 mg); initial angiography • Renal dysfunction (serum creatinine > 2.0 mg/dL). of the vessel in at least two proximal-orthogonal views • Stroke or transient ischemic attack in the previous to allow adequate visualization of the vessel and lesion; six months. evaluation by predilation QCA; ACT with stenting as previously described; sheath withdrawal 3-4 h after the • Life expectancy < 12 months. procedure with ACT < 200 s; discharge after 24 h in cases • Target-lesion located in the left main coronary artery without complications, follow-up visits at 30 days, eight or ostia of the right coronary artery, anterior descending or and 12 months; control angiography at eight months; IVUS circumflex arteries. Bifurcation lesion, with thrombus, or in immediately after stent implantation and after eight months. single remaining vessel. The analysis of the QCA and IVUS were performed offline • Target-lesion involving bifurcation. (QCA using the CMS-GFT® software, release 5.1, Medis, Leiden, the Netherlands, and IVUS using the Echoplaque ® Analyzed device and implantation technique software, Indec Systems, Inc, Mountain View, California, USA). The analyzed device was the sirolimus-eluting Sparrow® In QCA, the following parameters were evaluated: lesion DES (Cardiomind® Inc., Sunnyvale, California, USA), as length, reference vessel diameter (RVD), minimal lumen compared with the BMS version of the same stent (BMS diameter (MLD), percentage of vessel stenosis (PS) calculated

Arq Bras Cardiol. 2013;101(5):379-387 380 Oliveira et al. Self-expanding drug-eluting stent Original Article

2.5 mm stent over balloon: crossover profile of 0.032

Cardiomind Sparrow® stent: crossover profile of 0.014

Guide wire 0.014

Figure 1 - Evidence of low-profile of the Sparrow® stent deployment system (center) compared to a balloon-expanding stent system (top) and an angioplasty guidewire of 0.014” (bottom).

Table 1 - Sparrow® stent specifications

Stent design and material Closed-cell design, diamond-shaped , in nickel-titanium (nitinol) Stent shortening 9-16% Radiopaque coating Platinum coating with 3.5 µm Extension of deployment system in the balloon working segment 170 cm Total extension of the deployment system 190 cm (extensible to 300 cm) Deployment system profile 0.014” Guide tip extension 2-3 cm

A Non-sterile power source B

DEPLOYMENT SYSTEM

Stent Disposable sterile adaptor .014 Stent in a wire Conenction with I. 190 cm the guide wire

Figure 2 - A: Schematic representation showing all the components of the Sparrow® System. B: Sparrow® Stent in its natural form (expanded).

by the formula PS = RD - MLD ÷ RD) x 100, acute luminal 10 mm distal to the stent up to at least 10 mm proximal to gain (ALG) calculated by ALG = post-MLD – pre-DML; LLL the stent, in two acquisitions, the first immediately after the (difference between the late MLD and MLD immediately after implantation and the second after 8 months. For this purpose the procedure). These analyses were performed in-stent and an automated stent traction system at a speed of 0.5 mm / sec in the stent segments 0.5 mm proximal and distal to the stent with a 40 MHz transducer, 2.6-French sheath (Galaxy 2 (analysis of the borders). ouIlab, Boston Scientific Corporation, Natick, Massachusetts, The IVUS images corresponded to the recordings of at least USA) was used. Were programmed Calculations of areas

381 Arq Bras Cardiol. 2013;101(5):379-387 Oliveira et al. Self-expanding drug-eluting stent Original Article and volumes of the vessel, lumen, stent and plaque were Results programmed, as well as the volume of NIH and the stent From January 2009 to April 2010, 24 patients were volume obstruction percentage, according to the protocol included, 12 in each group, and prospectively randomized. already described in literature. Strut apposition to the vessel The clinical characteristics of the patients are shown in wall was also evaluated. Table 2 and disclosed homogeneous groups. The distribution per artery and per segment was similar Study definitions between the groups and the lesion was located in the middle Angiographic success: stent implantation in the target- and distal segments of the vessel in more than 70% of cases lesion with residual stenosis < 30% and TIMI flow 3. in both groups (Table 3). Procedural success: angiographic success without major There were no significant differences between the DES and complications (death, myocardial infarction or in-hospital BMS groups, in this sequence, regarding the volume of contrast emergency revascularization surgery). Stent thrombosis: (133.33 ± 23.87 mL versus 120 ± 34.38 mL, p = 0.282), Academic Research Consortium (ARC) criteria13. Major procedure time (71 ± 9.2 min versus 62 ± 14.82 min, adverse cardiac events (MACE): death (cardiac), nonfatal p = 0.350) and maximum pressure postdilation (15.75 ± 4.67 myocardial infarction (elevation of cardiac enzymes CK-MB versus 15.42 ± 3.12, p = 0.839). or cardiac troponins I and T, up to three times above normal levels until discharge and twice the normal after hospital PCI was successfully performed in all patients. There were discharge or appearance of new Q waves in at least two no MACE or complications until discharge. contiguous ECG leads) and TVR. Binary restenosis: recurrent QCA results of the angiographies performed immediately target lesion ≥ 50% at late control. before and after PCA show that randomization produced similar groups and highlights the homogeneity and immediate Statistical Analysis outcome success between the groups. Lesion extension was The IBM ® SPSS Statistics software, release 19 (Chicago, slightly higher in the group with DES, but not significantly Illinois, USA.) was used for the statistical analyses. Student’s (DES: 15.29 ± 5.55 mm versus BMS: 12.91 ± 3.23 mm, t test was used to compare means between the groups. p = 0.233); stent length (SF 19.92 mm ± 3.60 versus For all compared parameters, p values < 0.05 were BMS: 18.00 ± 2.34 mm, p = 0.139) and implanted stent considered significant. Categorical variables were expressed diameter (DES 2.58 ± 0.25 mm versus 2.66 ± 0.19 mm, as absolute value or proportion. Continuous variables p = 0.368) were not different between groups. were expressed as mean and standard deviation. A level Reference vessel diameter immediately before the procedure of significance of 5% and power of 80% were considered, was similar between the groups (DES = 2.46 + 0.24 mm estimating a LLL decrease with DES of 65% and calculating versus BMS = 2.42 + 0.21 mm, p = 0.680), demonstrating the minimum sample size of 11 patients for each group. a small-caliber vessel scenario.

Table 2 - Main clinical characteristics of the 24 patients treated with Sparrow ® DES and BMS

DES BMS Variables p (n = 12) (n = 12) Male gender, n (%) 7 (58.3%) 4 (33.3%) 0.413 Age in years, mean (SD) 63.25 (10.01) 64.58 (11.54) 0.765 Risk factors for CAD, n (%) Hypertension 12 (100.0) 10 (83.33) 0.460 Diabetes mellitus 5 (41.66) 3 (25.0) 0.665 Hypercholesterolemia 10 (83.33) 9 (75.0) 1.000 Smoking 8 (66.66) 3 (25.0) 0.101 Coronary antecedents CABG surgery 0 0 − PCI 4 (33.33) 3 (25.0) 1.000 Myocardial infarction 4 (33.33) 2 (16.66) 0.637 Clinical presentation Asymptomatic 5 (41.66) 1 (8.33) 0.157 Stable angina 7 (58.33) 11 (91.66) 0.157 Unstable angina 0 0 − DES: drug-eluting stent; BMS: bare-metal stent; SD: standard deviation; CAD: coronary artery disease; CABG: coronary artery bypass graft; PCI: percutaneous coronary intervention.

Arq Bras Cardiol. 2013;101(5):379-387 382 Oliveira et al. Self-expanding drug-eluting stent Original Article

Table 3 - Main qualitative angiographic characteristics of the 24 patients treated with DES and BMS Sparrow ® stents.

DES BMS Variables p (n = 12) (n = 12) Treated vessel ADA 3 (25.0%) 5 (41.66%) 0.665 Cx 2 (16.66%) 2 (16.66%) 1.000 RCA 2 (16.66%) 1 (8.33%) 1.000 Diagonal branch 3 (25.0%) 4 (33.3%) 1.000 Marginal branch 2 (16.66%) 0 0.460 Vessel segment, n (%) Proximal 3 (25%) 2 (16.66%) 1.000 Medial 6 (50%) 6 (50%) 1.000 Distal 3 (25%) 4 (33.3%) 1.000 ADA: anterior descending artery; Cx: circumflex artery; RCA: right coronary artery; DES: drug-eluting stent; BMS: bare-metal stent.

The severity of the lesions included in the study predicted in the study, precluding the provision of full is well demonstrated in the pre-procedural results of information, differently from what occurred with the QCA. MLD (DES = 0.75 + 0.20 mm versus BMS = 0.73 + 0.17 mm, Nevertheless, it was observed that the self-expanding stent p = 0.750) and PS (SF = 69.36 + 6.37 = 69.67% versus showed an increase in volume over time from 14.8% in the BMS + 5.46%, p = 0.905). DES group and 2.5% in the BMS group. There was no strut The immediate results after the procedure measured by malapposition in this group of patients. MLD (DES = 2.46 ± 0.22 mm versus BMS = 2.39 + 0.13 mm, Up to 12 months of evolution, there was no patient loss p = 0.350) and PS (DES = 4.59 ± 3.52% versus to follow-up. All patients used dual antiplatelet therapy BMS = 4.94 + 4.41%, p = 0.869) confirm successful throughout the study, as required by the protocol. There were angiographic procedure in both groups, with similar benefits, no reports of death, nonfatal myocardial infarction or need which is reflected in satisfactory absolute gain in both groups for myocardial revascularization. (DES = 1.71 + 0.28 mm versus BMS = 1.66 + 0.12 mm, p = 0.614), a result of the difference between the Although four patients had binary restenosis in the BMS pre‑procedural and post-procedural MLD. group, the clinical translation of this finding resulted in new At eight months, the parameters analyzed by QCA, as PTCA in three patients, only. Specifically, the patient that had demonstrated in Table 4, showed significant differences occlusive restenosis, was maintained in clinical treatment between the groups regarding the ability to maintain the due to the good evolution. results recorded in the evaluation immediately after the Clinical event compatible with in-stent thrombosis was not procedure, i.e., MLD and PS. These results are reflected in the observed in either group during follow-up. comparison of LLL between groups, the primary objective of this study, which was significantly lower in the group with DES (DES vs BMS = 0.25 + 0.16 vs = 0.97 + 0.76 mm, p = 0.008). Discussion Figure 3 shows study patients’ individual response New research in this area is of relevance because the regarding PS, with the DES group showing more homogeneous small-caliber vessels represent 40-50% of cases of PCA, and and maintenance of the response pattern. this subgroup, although it has been strongly benefited from the advent of DES, still carries a higher risk of restenosis and TVR, The analysis of the 5 mm proximal and distal to the stent when compared with larger-caliber vessel results7,14,15. This study immediately after stent implantation and at eight months, represents the first clinical experience with drug‑eluting SES in as shown in Table 5, disclosed no significant differences small-caliber vessels. between the groups regarding MLD and PS, resulting in LLL with no significant difference. Although the analysis of The primary objective of reducing in-stent LLL in this study the proximal and distal segments to the stent did not show was achieved with Sparrow® DES and the absolute value found significant differences between the groups, there was a trend of 0.25 ± 0.16 mm shows that the performance of this platform of higher LLL in the BMS group compared with DES group, was equivalent to the best results with drug-eluting stents. most markedly in the proximal segment. The patients in our study are also part of a larger cohort, the Technical difficulties in the progression of IVUS catheter multicenter CARE II study16, which included a larger number to an adequate point beyond the stent (including 5 mm of patients and of which initial results, presented at the 2010 distal to it, to include the entire segment of interest) Transcatheter Cardiovascular Therapeutics Congress showed restricted data collection provided by this type of evaluation data similar to those found here.

383 Arq Bras Cardiol. 2013;101(5):379-387 Oliveira et al. Self-expanding drug-eluting stent Original Article

Table 4 - In-stent quantitative coronary angiography variables at eight months

DES BMS Variables p CI (95%) (n = 12) (n = 12) IRD (mm), 8 months mean (SD) 2,44 (0,19) 2,24 (0,42) 0,153 (−0,08; 0,47) MLD (mm), 8 months mean (SD) 2,19 (0,19) 1,42 (0,81) 0,008 (0,14; 0,19) PS (%), 8 months mean (SD) 10,70 (3,95) 39,89(30,89) 0,007 (−0,24; −1,29) LLL (mm) mean (SD) 0,25 (0,16) 0,97 (0,76) 0,008 (−1,19; −0,22) IRD: interpolated reference diameter; MLD: minimum luminal diameter; PS: percentage of stenosis; LLL: late luminal loss; SD: standard deviation; DES: drug-eluting stent; BMS: bare-metal stent

Drug-eluting stent Bare-metal stent % Stenosis % Stenosis % Stenosis % Stenosis

Pre Post Late Pre Post Late

Figure 3 - Demonstration of individual variation in the percentage of stenosis before and after the procedure and at eight months of evolution in the two treatment groups (Sparrow® DES versus Sparrow® BMS), showing greater dispersion and loss of result in the BMS group at the late follow-up.

The CARE II study16, with inclusion criteria similar to were recorded, both involving the proximal border, but those in our study, including the patients in this cohort, they were not isolated cases, reflecting a proliferative involved 137 patients in three groups, comparing Sparrow restenosis process and, therefore, associated with undesired ® DES (group 1) with Sparrow® BMS (group 2) and the proliferation of in-stent NIH. Driver®/Microdriver® bare-metal balloon expandable Safety problems with DES, shown by late and very late stent (group 3). The primary objective was the assessment in-stent thrombosis (low, but greater than that observed with of LLL at eight months by IVUS. At eight months a the BMS), were probably related to chronic inflammatory significantly lower LLL was observed in the DES group, stimulation determined by the durable polymers, which similar to what was found by QCA in our study (0.29 + hinder the re-endothelialization process17-20. In the present 0.45 mm). In the group with Sparrow® DES, the binary study, in-stent thrombosis did not occur during a 12-month restenosis was 6.7% and the incidence of MACE at eight follow-up. The use of bioabsorbable polymers in the months was 6.25%, confirming the results of our study in Sparrow® stent may have contributed to this fact. a larger population. Even in the age of DES, there have been studies showing There was no binary restenosis at the borders in the that the smaller the strut thickness, the lower the LLL11. group of patients with DES, differently from the previously In this context, the Sparrow® stent has an additional described Sirius study report. This may be related to advantage, as it has thinner struts than all other available Sparrow® stent system implantation technique, which stent models. minimizes the chances of barotrauma to the stent borders. These favorable characteristics of the deployment In the group with DES, two cases (16%) of binary restenosis system of the self-expanding Sparrow® stent – thin struts,

Arq Bras Cardiol. 2013;101(5):379-387 384 Oliveira et al. Self-expanding drug-eluting stent Original Article

Table 5 - Quantitative coronary angiography in the 5 mm proximal and distal to the stent immediately after implantation and at eight months

DES BMS Variables p CI (95%) (n = 12) (n = 12) Immediate MLD (mm) Proximal, mean (SD) 2.49 (0.18) 2.43 (0.20) 0.491 (−0.11; 0.23) Distal, mean (SD) 2.51 (0.18) 2.45 (0.20) 0.474 (−0.11; 0.23) PS (%), immediate Proximal, mean (SD) 3.62 (2.77) 3.58 (2.07) 0.971 (−2.11; 2.19) Distal, mean (SD) 2.91 (2.92) 2.88 (1.99) 0.980 (−2.16; 2.21) MLD (mm), 8 months Proximal, mean (SD) 2.21 (0.26) 1.74 (0.79) 0.075 (−0.05; 0.98) Distal, mean (SD) 2.31 (0.28) 1.90 (0.74) 0.104 (−0.094; 0.89) PS (%), 8 months Proximal, mean (SD) 9.41 (7.40) 23.28 (30.72) 0.144 (−33.19; 5.46) Distal, mean (SD) 4.19 (1.50) 16.32 (27.12) 0.154 (−29.37; 5.12) LLL (mm) Proximal, mean (SD) 0.28 (0.19) 0.69 (0.67) 0.064 (−0.84; 0.028) Distal, mean (SD) 0.17 (0.17) 0.54 (0.65) 0.080 (−0.80; 052) MLD: minimum luminal diameter; PS: percentage of stenosis; LLL: late luminal loss; SD: standard deviation; DES: drug-eluting stent; BMS: bare-metal stent.

bioabsorbable polymer, antiproliferative drug from the Conclusions limo family, additional expansion property over time The results of this study allow us to conclude: and deployment technique that minimizes trauma to the borders – may be at the root of its good performance as 1. In patients submitted to percutaneous transluminal demonstrated in our study and ratified by the results of the coronary angioplasty in natural coronary arteries with CARE II study16. reference diameter ≤ 2.75 mm, the use of self-expanding DES Sparrow ® compared with the bare metal version The evaluation by IVUS in this study, as in the CARE of the same stent, resulted in significant reduction of late II16 showed a trend to stent expansion over time, more lumen loss (within eight months after the index procedure). markedly in the group with drug-eluting stents, a finding that motivates further research. 2. Angiographic measurements regarding the immediate outcome after the procedure (percentage of stenosis, The limitations of this study included the small numbers minimal lumen diameter and acute luminal gain) were of patients, which was related to logistical issues regarding satisfactory in both groups with no significant differences the endoprosthesis availability, the randomization, which between them. was not blinded, and the impossibility of IVUS evaluation, an important tool for the assessment of the mechanistic 3. Angiographic measurements regarding the impact performance of stents. of treatment with Sparrow® DES in segments that are 5 mm proximal and distal to the stent showed outcome The subsequent analysis by QCA and IVUS were maintenance at eight months when compared to immediate performed without knowledge of the type of stent used, outcomes (minimal luminal diameter and percent stenosis), which lessens the non-blinded randomization problem. thus demonstrating the absence of angiographic adverse Broad inclusion criteria, without restrictions regarding effects at the stent borders in this group of patients. tortuosity and calcification, in addition to vessel diameter,

may be related to the low rate of IVUS performance in this study. Author contributions The present study paves the way for further research Conception and design of the research: de Oliveira with larger sample sizes and even comparison with other FRA, Mattos LAP, Abizaid A, Staico R, Botelho R, Sousa JE, DES systems, so that the clinical impact of this new device Sousa A; Acquisition of data: de Oliveira FRA, Abizaid A, can be assessed by demonstrating, in a pioneering way, Abizaid AS, Costa JR, Costa R, Staico R, Botelho R, Sousa the performance of the self-expanding Sparrow® stent JE, Sousa A; Analysis and interpretation of the data: de in small‑caliber vessels, validating its efficacy through the Oliveira FRA, Mattos LAP, Sousa JE, Sousa A; Statistical objective parameter of LLL outcome and its safety by the analysis: de Oliveira FRA, Sousa JE; Obtaining funding: de absence of stent thrombosis at 12 months. Oliveira FRA; Writing of the manuscript: de Oliveira FRA,

385 Arq Bras Cardiol. 2013;101(5):379-387 Oliveira et al. Self-expanding drug-eluting stent Original Article

Mattos LAP, Costa JR; Critical revision of the manuscript for Sources of Funding intellectual content: Mattos LAP, Abizaid A, Sousa JE, Sousa There were no external funding sources for this study. A; Clinical monitoring of patients: Abizaid AS. Study Association Potential Conflict of Interest This article is part of the thesis of doctoral submitted by No potential conflict of interest relevant to this article was Flavio Roberto Azevedo de Oliveira, from Instituto Dante reported. Pazzanese de Cardiologia.

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8. Stone GW, Rizvi A, Newman W, Mastali K, Wang JC, Caputo R, et al; SPIRIT 18. Taylor AJ, Gorman PD, Kenwood B, Hudak C, Tashko G, Virmani R. A comparison of four stent designs on arterial injury, cellular proliferation, IV Investigators. Everolimus-eluting versus paclitaxel-eluting stents in neointima formation, and arterial dimensions in an experimental porcine coronary artery disease. N Engl J Med. 2010;362(18):1663-74. model. Catheter Cardiovasc Interv. 2001;53(3):420-5. 9. Leon MB, Mauri L, Popma JJ, Cutlip DE, Nikolsky E, O’Shaughnessy C, et al; 19. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, et ENDEAVOR IV Investigators. A randomized comparison of the ENDEAVOR al. Localized hypersensitivity and late coronary thrombosis secondary zotarolimus-eluting stent versus the TAXUS paclitaxel-eluting stent in de to a sirolimus-eluting stent: should we be cautious? Circulation. novo native coronary lesions12-month outcomes from the ENDEAVOR IV 2004;109(6):701-5. trial. J Am Coll Cardiol. 2010;55(6):543-54. 20. Lockwood NA, Hergenrother RW, Patrick LM, Stucke SM, Steendam R, 10. Briguori C, Sarais C, Pagnotta P, Liistro F, Montorfano M, Chieffo A, et al. Pacheco E, et al. In vitro and in vivo characterization of novel biodegradable In-stent restenosis in small coronary: impact of strut thickness. J Am Coll polymers for application as drug-eluting stent coatings. J Biomater Sci Polym Cardiol. 2002;40(3):403-9. Ed. 2010;21(4):529-52.

Arq Bras Cardiol. 2013;101(5):379-387 386 Oliveira et al. Self-expanding drug-eluting stent Original Article

387 Arq Bras Cardiol. 2013;101(5):379-387 Original Article

Does the Aging Process Significantly Modify the Mean Heart Rate? Marcos Antonio Almeida Santos1,2,3, Antonio Carlos Sobral Sousa2,3, Francisco Prado Reis1, Thayná Ramos Santos1, Sonia Oliveira Lima1, José Augusto Barreto-Filho2,3 Universidade Tiradentes1; Universidade Federal de Sergipe2; Centro de Pesquisas da Clínica e Hospital São Lucas3, Aracaju, SE – Brazil

Abstract Background: The Mean Heart Rate (MHR) tends to decrease with age. When adjusted for gender and diseases, the magnitude of this effect is unclear. Objective: To analyze the MHR in a stratified sample of active and functionally independent individuals. Methods: A total of 1,172 patients aged ≥ 40 years underwent Holter monitoring and were stratified by age group: 1 = 40-49, 2 = 50-59, 3 = 60-69, 4 = 70-79, 5 = ≥ 80 years. The MHR was evaluated according to age and gender, adjusted for Hypertension (SAH), dyslipidemia and non-insulin dependent diabetes mellitus (NIDDM). Several models of ANOVA, correlation and linear regression were employed. A two-tailed p value <0.05 was considered significant (95% CI). Results: The MHR tended to decrease with the age range: 1 = 77.20 ± 7.10; 2 = 76.66 ± 7.07; 3 = 74.02 ± 7.46; 4 = 72.93 ± 7.35; 5 = 73.41 ± 7.98 (p < 0.001). Women showed a correlation with higher MHR (p <0.001). In the ANOVA and regression models, age and gender were predictors (p < 0.001). However, R2 and ETA2 < 0.10, as well as discrete standardized beta coefficients indicated reduced effect. Dyslipidemia, hypertension and DM did not influence the findings. Conclusion: The MHR decreased with age. Women had higher values of MHR, regardless of the age group. Correlations between MHR and age or gender, albeit significant, showed the effect magnitude had little statistical relevance. The prevalence of SAH, dyslipidemia and diabetes mellitus did not influence the results. (Arq Bras Cardiol. 2013;101(5):388- 398) Keywords: Aging; Heart Rate; Electrocardiography, Ambulatory.

Introduction There are several features related to cardiovascular senescence, ranging from decreased left ventricular The aging process, in spite of recent medical advances, compliance due to collagen accumulation and fibrosis still constitutes an inexorable phenomenon. The number of to alterations in the conduction system, with reduction elderly individuals has grown in almost all regions of the world, in pacemaker cells and fatty infiltration, leading to loss particularly where strategies to improve living conditions have of specialized fibers and intrinsic decrease in sinus been implemented1. automatism10,11. Moreover, dynamic histochemical and In recent decades, there has been a change in the age profile immunohistochemical alterations during the aging process of Brazil. Considered for a long time as a young population, are associated with autonomic reactions involved in the 2-5 the number of elderly individuals is progressively increasing . reduction of heart rate in the elderly12, resulting in diagnostic On account of that, large-scale studies have been and therapeutic implications13. performed on the different aspects of the aging issue6-8, There is little scientific literature that aims to measure the understood as a complex and multifactorial process, effect size and relevance of MHR at Holter with advancing comprising biological changes with consequences on quality age. Searching the Medline and Embase databases for of life and general health status9. publications from 2005 on, using the keywords "mean heart rate" and "aging" or "elderly", only one article addressed the issue, albeit indirectly due to its design, as well as its small sample size and specific population14. Mailing Address: Marcos Antonio Almeida Santos • Avenida Gonçalo Prado Rollemberg, 211, Sala 210, São José. The present study aims to investigate the values of Postal Code 49010-410 – Aracaju, SE - Brazil MHR in functionally and mentally active adults and elderly E-mail: [email protected], [email protected] individuals, submitted to physical examination with 24‑hour Manuscript received April 07, 2013, revised manuscript June 03, 2013, accepted June 07, 2013. Holter monitoring. Several and exhaustive statistical analysis models will be used in order to identify, quantify and DOI: 10.5935/abc.20130188 assess the relevance of MHR trends associated with age,

388 Santos et al. Mean heart rate and aging Original Article dependent or not on other factors, including gender and pharmacological survey was carried out in two stages (on the presence of three high prevalence comorbidities among the day of installation and removal of the recording device) and elderly: systemic arterial hypertension (SAH), dyslipidemia by evaluating the compatibility between the anamnesis, the and non-insulin dependent diabetes mellitus (NIDDM). reported diseases and prescribed medications. We also subsequently excluded those whose tests had Methods a recording duration < 22 hours, those with more than 5% of artifacts, atrial fibrillation or dynamic alterations in A cross-sectional, descriptive and analytical study was the ST segment and T wave, high rate of supraventricular carried out. The study complied with the ethical principles or ventricular ectopy (> 10,000/24h), or those who had in the Declaration of Helsinki and the requirements of evidence of abnormal sinus activity, be it of functional the 196/96 National Health Council Resolution, including or organic etiology, manifested by atypical MHR values complementary requirements and was approved by the (< 60 or > 90 bpm). After echocardiography, we selected institutional Research Ethics Committee #100710, on July subjects with ejection fraction (EF) > 50%. The sample 19, 2010. All individuals enrolled in the study consented to selection flowchart is shown in figure 1. participate and signed the free and informed consent form. The resulting sample consisted of 1,172 individuals The sample size, of around a thousand individuals, was and was separated by gender and grouped into five strata previously calculated using the GPower software, based according to the age (in years): 1 = 40-49; 2 = 50-59; on the following parameters: alpha = 0.05, 1-β = 0.80, 3 = 60-69; 4 = 70-79; 5 ≥ 80. There were no missing data. effect = 0.10. Data collection was performed consecutively Anthropometric data were obtained (weight and height) and prospectively and the sample consisted of adult and using an electronic calibrated scale with a maximum elderly individuals of both genders, aged ≥ 40 years, capacity of 200 kg and a ruler for measuring height ranging submitted to Holter monitoring for 24 hours in a cardiology between 1.30 and 2 meters. The Body Mass Index (BMI) reference private practice from July 2010 to December was calculated using the formula: weight (kg) / height (m)2. 2012. The main reason for the examination was routine cardiological assessment in asymptomatic individuals or Sample characterization data were obtained through investigation of nonspecific symptoms, such as palpitations, a sociodemographic questionnaire, as well as reference dizziness or atypical chest pain. to three chronic diseases: systemic arterial hypertension, diabetes mellitus and dyslipidemia. The recording of the electrocardiographic tracing was performed during spontaneous situations occurring outside the The calculations were performed using SPSS platform 20, hospital and medical environment. Every beat that generated with the exception of the homoscedasticity test, and MHR electrical activity at any time of the recording was counted. jackknife estimates were performed in Stata 12. The 95% Confidence Interval (95%CI) was used and a significance The method has been validated by several researchers15,16 value of p < 0.05 (two-tailed). Nonparametric data national17 and international18 cardiology associations. were represented by the total number and percentage. The Holter recorder used in the study was a Cardiolight The chi-square test or Fisher's test were employed when Cardios digital model with Memory Card, which performed appropriate for comparisons between groups. 3-channel continuous recording, subsequently analyzed Parametric variables were described as mean, standard by the CardioSmart Professional CS 540 program. deviation, standard error and interquartile range. Several All recording devices were installed in the same location bootstraps were employed to corroborate the sample values by the same professional and the tests were processed in a of MHR, with 1,000 samples and random counts of the single computer. Moreover, the analysis of the examination 95%CIs for each situation: MHR for the entire sample; MHR and the production of the final report were made by the for gender differences; MHR in five age groups. same cardiologist, experienced in Holter System. The Kolmogorov-Smirnov test was used for exploration Before the enrollment, individuals initially selected by of the normality pattern and Levene's test for equality of the age criterion (≥ 40 years) and under outpatient care, variance. This was carried out both in the whole sample and in were invited for an interview, where cognitive capacity was subgroups divided according to gender or age. In comparisons evaluated, albeit subjectively (understand without difficulty between two independent samples, the mean difference was the content of direct questions related to anamnesis) and calculated by Student's t test. Even though the distribution was functional independence (walking without external aid, pain normal, the same thing was done with the Mann-Whitney or difficulty in walking). test, due to its more conservative characteristic and lower We selected only those individuals that met both probability of Type I error criteria and agreed to take part in the research. Complaints Subsequently, the analysis of MHR between age groups indicating major diseases (history of myocardial infarction, was performed by Kruskal-Wallis (also due to its more angina pectoris, invasive hemodynamic procedure, cardiac conservative characteristic and lower probability of type I surgery and permanent pacing) represented additional error) and three ANOVA models: One-way (age groups), exclusion criteria. 5x2 (age groups and gender) and 5x2x2x2x2 (age groups, We also excluded those who reported using insulin, gender, SAH, dyslipidemia and diabetes mellitus). In the digitalis, antiarrhythmics, beta-blockers or drugs that had a third ANOVA model, the difference between subgroups was direct action on heart rate (such as the nebivolol), and the calculated using Tukey’s post hoc test.

Arq Bras Cardiol. 2013;101(5):388-398 389 Santos et al. Mean heart rate and aging Original Article

2,029 eligible by age criterion

3: refusal to participate 95: functional limitation

247: use of medications 43: cognitive insufficiency (insulin, digoxin, beta-blockers, antiarrhythmics) 24: pacemaker, resynchronizer or cardioverter 188: CHD, previous AMI, PCI, heart surgery 19: artifacts > 5% or recording < 22 h

47: atrial fibrillation 9: alterations of ST-T

25: > 10,000 APCs/24h 129: MHR < 60 ou > 90 bpm

21: > 10,000 VPCs/24h 7:EF < 50%

1,172 individuals

Figure 1 – Sample selection flow chart. CHD: coronary heart disease; AMI: acute myocardial infarction; PCI: percutaneous coronary intervention; APCs: atrial premature complexes; VPCs: ventricular premature complexes; MHR: mean heart rate; EF: ejection fraction

Similarly, models of bivariate, point biserial and partial Results correlation were used, calculating the R2 and ETA2 for MHR The general characteristics of the sample distribution and age, MHR and gender, MHR and diseases, adjusted according to age groups and gender are shown in table 1. and nonadjusted, as well as factors of correlation and The age of the sample ranged between 40 and 100 years, determination for EF and BMI. with a mean of 65.69 ± 11.65 years. Finally, we performed linear regression for MHR in It can be observed that females predominated in the five models. The first two, simplified, involved only the five age groups, but this pattern was not significantly age groups or age. The third was performed using the different between the age groups of the sample population. method of simultaneous input of predictor variables (age group, gender and the three diseases). The fourth With advancing age, there was an increased prevalence was a hierarchical regression divided into two stages, of SAH, diabetes mellitus, dyslipidemia, and number of for age and gender. The fifth was a more complex medications (p < 0.001) and decreased BMI, ejection hierarchical regression, containing the aforementioned fraction and percentage of non-sedentary individuals. variables, entered in three sequential steps. Standardized The mean MHR in the sample population was beta‑coefficients were calculated separately for the two 74.45 ± 7.55 bpm (95% CI = 74.02 to 74.88). In addition hierarchical models. to the narrow confidence interval, the internal validity of

390 Arq Bras Cardiol. 2013;101(5):388-398 Santos et al. Mean heart rate and aging Original Article

Table 1 – Clinical characterization of the sample according to the age groups

AGE RANGE (years) 40-49 50-59 60-69 70-79 ≥ 80 p N = 1172 n(%) n(%) n(%) n(%) n(%) GENDER 0.511 Female 92(7.8) 118(10.1) 255(21.8) 195(16.6) 105(9.0) Male 46(3.9) 63(5.4) 154(13.1) 99(8.4) 45(3.8) COMORBIDITY SAH 33(2.8) 78(6.7) 218(18.6) 175(14.9) 103(8.8) < 0.001 Dyslipidemia 18(1.5) 69(5.1) 164(14) 123(10.5) 59 (5.0) < 0.001 Diabetes 6(0.5) 19(1.6) 52(4.4) 51(4.4) 26(2.2) 0.002 PHYSICAL ACTIVITY < 0.001 Sedentary 89(7.6) 92(7.8) 164(14.0) 167(14.2) 107(9.1) Walking 20(1.7) 41(3.5) 204(17.8) 116(9.9) 32(2.7) Physical exercises 29(2.5) 48(4.1) 41(3.5) 11(0.9) 11(0.9) BMI 27.5 ± 5.2 27.6 ± 3.6 27.2 ± 4.3 26.6 ± 4.4 26.1 ± 4.9 0.003 N. of MEDICATIONS 1.1 ± 1.6 1.1 ± 0.9 1.9 ± 1.8 2.1 ± 1.8 2.7 ± 2.1 0.001 EJECTION FRACTION 71.5 ± 7.6 68.1 ± 5.9 68.7 ± 6.8 67.2 ± 6.7 65.9 ± 7.1 0.003 SAH: systemic arterial hypertension; BMI: body mass index.

these values was corroborated by successive spontaneous In analyses involving the five age groups, different ANOVA bootstrap estimates (95% CI = 74.00 to 74.90) and the use models were employed, as well as the Kruskal-Wallis test of jackknife estimates (95%CI = 74.01 to 74.89). The analysis (Table 5). With regard to the association between higher MHR was also performed in subgroups according to gender, age and female gender, all tests resulted in significant differences. range and the association between them. In all cases, the As for the association between MHR and age group, the One values obtained directly resembled those found by the Way ANOVA and 5x2 (factors = age group and gender) were jackknife and the bootstrap estimates (Table 2). significant. This was not observed with the 5x2x2x2x2x2 ANOVA (previous factors + SAH + dyslipidemia + DM), The median and interquartile ranges of MHR were probably due to the reduction in power caused by the analyzed for the whole sample according to gender and magnification of factors. stratified according to gender and age. The distributions showed typical pattern of normality without outliers or However, in post hoc analysis of the subgroup, Tukey’s atypical values. MHR was higher among women and this test showed differences in MHR, reaching levels of pattern persisted in all age groups; we also identified significance when the comparison was made between a trend decline in MHR with age, regardless of gender non‑contiguous age groups. SAH, dyslipidemia and diabetes (Figure 2A, B, C, D). mellitus had no predictive influence, either separately or in interaction. Due to the multiple comparisons, when The mean MHR was significantly higher in females, both Bonferroni correction was applied, the threshold values for at Student's t test and at the Mann-Whitney test (p < 0.001). the interaction between age group and SAH (p = 0.046) However, the magnitude of this difference was considerably were not considered significant. In situations where there small (d = 0.281). Both tests for comparisons of MHR means was actually a significant difference, the values of R2 and in two independent samples were reapplied regarding ETA2 found in the several models indicated a diminished the presence of DM, dyslipidemia and diabetes, with contribution of the involved variable. Similar phenomenon nonsignificant results. Levene test for homogeneity of variance occurred with the five linear regression models. was satisfactory in all these analyses (Table 3). In the first two models, a simple regression was applied, In order to assess the degree of association between MHR for the age group and for age as discrete variable. In the and some variables bivariate correlation strategies were third, the three comorbidities were added and inserted employed, including point biserial and partial correlation. simultaneously. Hierarchical regression was applied to We calculated the coefficient of correlation and determination, the fourth and fifth models, the first in two stages and individual or adjusted for age, gender, diseases, EF and BMI containing only age and gender, and the second in three (Table 4). Only age, gender and gender adjusted for age were stages, once again including the comorbidities (Table 6). statistically significant (p < 0.001). Despite the significance, Again, in all regression models significance was found for the strength of this association is of very low significance, age range and gender. Nevertheless, the participation of considering that the R and R2 values were less than 0.10. these two variables was limited, given the reduced values of

Arq Bras Cardiol. 2013;101(5):388-398 391 Santos et al. Mean heart rate and aging Original Article

Table 2 – Mean Heart Rate (MHR) values and confidence intervals (CI) according to gender, age and association between gender and age range

Age range MHR (bpm) SD SE 95%CI BOOTSTRAP 95%CI TOTAL 74.45 7.55 0.22 74.02-74.88 74.00-74.90 GENDER Female 75.18 7.49 0.27 74.65-75.72 74.61-75.72 Male 73.07 7.48 0.37 72.34-73.80 72.36-73.81 AGE RANGE 40-49 years 77.20 7.10 0.60 76.00-78.39 75.91-78.42 50-59 years 76.66 7.07 0.52 75.63-77.70 75.55-77.76 60-69 years 74.02 7.46 0.36 73.29-74.74 73.30-74.78 70-79 years 72.93 7.35 0.42 72.09-73.78 72.07-73.80 ≥ 80 years 73.41 7.98 0.65 72.12-74.69 72.21-74.56 GENDER X AGE RANGE 40-49 years Female 78.25 6.83 0.76 76.74-79.75 76.8-79.58 Male 75.08 7.25 1.08 72.96-77.21 73.04-77.04 50-59 years Female 77.63 7.22 0.67 76.31-78.96 76.36-78.25 Male 74.84 6.45 0.92 73.02-76.65 73.27-76.45 60-69 years Female 74.83 7.43 0.46 73.93-75.74 73.94-75.75 Male 72.65 7.34 0.59 71.49-73.81 71.52-73.82 70-79 years Female 73.23 6.99 0.52 72.20-74.26 72.24-74.22 Male 72.33 8.02 0.73 70.88-73.78 70.71-73.95 ≥ 80 years Female 74.19 7.96 0.71 72.78-75.59 72.62-75.72 Male 71.57 7.97 1.09 69.43-73.72 69.24-73.70

Table 3 – Parametric and nonparametric tests for comparisons between the means of MHR in two independent samples, according to gender and comorbidities

Student’s t Levene p Cohen’s d Mann-Whitney p GROUPS: Gender 4.594 0.738 < 0.001 0.281 129.992 < 0.001 SAH 1.726 0.693 0.085 - 160.944 0.069 Dyslipidemia -0.614 0.425 0.539 - 161.495 0.600 Diabetes 0.437 0.243 0.662 - 77.153 0.753 SAH: systemic arterial hypertension; MHR: mean heart rate.

standardized beta coefficients. In the hierarchical models, test (p = 0.892) indicated excellent sample suitability to when analyzing the individual role of comorbidities, it was the models chosen for regression testing. This was also not significant from a statistical point of view. corroborated by analyzing the standardized regression The VIF values around 1 and the computation of residuals involving frequencies of distribution, cumulative the Durbin-Watson equation close to 2, added to the probability and critical values of Z-distribution in successful result of the Cook-Weisberg homoscedasticity scatter plots.

392 Arq Bras Cardiol. 2013;101(5):388-398 Santos et al. Mean heart rate and aging Original Article

Figure 2 – Distribution of Mean Heart Rate (MHR) values. A - Sample population. B - Stratification according to gender. C - Stratification according to age range and gender. D - Chart showing MHR decrease with increasing age, with comparative curve for both genders.

Discussion In the CARLA (Cardiovascular Disease, Living and Ageing) The predominance of women as the age progresses has study, which had a sample of 1,779 individuals, age ranged been probably due to a longer life expectancy in females, between 45 and 83 years and no consistent association was when compared with male elderly individuals19. observed between parameters of heart rate variability and major cardiovascular risk factors22. The three comorbidities assessed in the study (SAH, diabetes and dyslipidemia) showed homogenous distribution and had no Although it is generally considered that sinus automatism influence on MHR behavior. In terms of prevalence, they showed decreases with the aging process12-15, the prognostic value, a similar pattern customarily described in epidemiological studies therapeutic potential and clinical significance have been carried out in other locations in Brazil20,21. questioned in view of varying results and interpretation23,24.

Arq Bras Cardiol. 2013;101(5):388-398 393 Santos et al. Mean heart rate and aging Original Article

Table 4 – Bivariate, point biserial and partial correlation for mean heat rate (MHR) versus age, gender, disease, ejection fraction (EF) and Body Mass Index (BMI)

VARIABLE: MHR R R2 p AGE - 0,198 0,039 < 0,001 GENDER - 0,133 0,017 < 0,001 Gender adjusted for Age - 0. 141 0.019 < 0.001 SAH -0.050 0.0025 0.085 SAH adjusted for Age - 0.002 < 0.0001 0.941 DYSLIPIDEMIA 0.018 0.0003 0.539 Dyslipidemia adjusted for Age 0.048 0.0003 0.100 DIABETES 0.013 0.0001 0.662 Diabetes adjusted for Age 0.048 0.0001 0.695 EJECTION FRACTION (EF) - 0.009 < 0.0001 0.834 EF adjusted for Age - 0.019 0.0003 0.669 BMI 0.002 < 0.0001 0.952 BMI adjusted for Age - 0.011 0.0001 0.709 SAH: systemic arterial hypertension.

In Japan14, the mean values of NN intervals at 24-hour These findings are similar to those found in the present Holter in 15 individuals aged > 65 years were analyzed study. The authors attributed the increase in resting HR in two stages, with a 15-year interval, showing slight in centenarians to the previous effort made when lying shortening of sinus cycle, although reaching statistical on the stretcher, or some emotional expectation before significance (0.976 ± 0.115 x 0.903 ± 0.117, p = 0.0019). the examination. Nevertheless, the authors of this article calculated the The Baltimore Longitudinal Study on Ageing (BLSA)29 difference according to Cohen’s formula and corrected evaluated 69 men and 29 women aged 60 to 85 years. for each year of life, with negligible results (d = 0.0413). Patients were divided into three groups: 59 subjects In Denmark, a study of which sample consisted of aged between 60 and 69 years, 32 aged between 70 and 260 healthy subjects aged between 40 and 79 years, a 79 years, and only 7 members aged ≥ 80 years. All were MHR of 74 ± 18 bpm was obtained25. The lower standard considered "healthy" according to the following criteria: deviation value in this study suggests greater sample absence of systemic disease or overt heart disease, no heart homogeneity, in addition to greater precision due to the abnormalities at physical examination, blood pressure of use of long-term tracings. 160/95 mmHg; ECG with no significant morphological In a case-control study performed in the state of Rio Grande alterations; satisfactory lung function, exercise testing within do Sul, Brazil26, the recording of HR at rest in the control normal limits, no antiarrhythmic and beta-blocker drug group of 5,410 patients with a mean age of 55.4 ± 10.4 years use. The dynamic electrocardiography recordings lasted showed a mean value of 72.1 ± 12.6 bpm. This value was also between 17 and 26 hours. close to the current findings described in Holter monitoring. There was no significant variation in MHR with age. However, dissimilar from the 24-hour ambulatory ECG, However, MHR in women (76.9 ± 8.0) was significantly routine and direct HR measurements are subject to variations higher than that of men (69.8 ± 8.8), with p < 0.001. caused by several types of interference, such as ambient Compared to the present study, and although it temperature, presence of the examiner and the individual’s corroborates our findings, the BLSA showed greater emotional status27. Again, the standard deviation obtained differences regarding gender, which may be due to the from the resting HR was quite higher than that resulting from smaller sample size and greater variability during the the measurement of MHR by 24-hour monitoring. electrocardiographic recording. Another important aspect This aspect of the matter can be illustrated by the of the BLSA study is the excessive proportion of men (70%). analysis of another study28, which used both measurements This fact was due to the enrollment procedure, which was (resting HR and MHR). First, the resting HR of 32 patients voluntary and active on the part of the patients. Additionally, aged 100 to 106 years was compared to that of 89 healthy the measurements obtained in inpatients may result in bias, 30 individuals (aged 63 to 95 years). There was a difference as they may not reflect the natural environment . between the first (76.8 ± 12.7) and the latter (74.9 ± 5.9), The physiopathology of the chronotropic response with statistical significance (p < 0.005). But when the MHR is considered to be complex, multifactorial and not was measured by 24-hour Holter, it was around 72 bpm completely understood. The slight increase in heart rate and there was no significant difference between the groups. may be attributed to transient alterations in blood flow on

394 Arq Bras Cardiol. 2013;101(5):388-398 Santos et al. Mean heart rate and aging Original Article

Table 5 – Parametric and nonparametric tests for comparisons between the means of MHR in five age groups, followed by post hoc evaluation for subgroups

Degrees of freedom Test R2 Eta2 p ANOVA ONE WAY 4 F = 12.962 0.034 0.043 < 0.001 KRUSKAL-WALLIS 4 H = 48.739 0.007 - < 0.001 ANOVA 5X2 0.630 Age group 4 F = 10.421 - 0.035 < 0.001 Gender 1 F = 20.033 - 0.019 < 0.001 Group*Gender 4 F = 39.347 - 0.003 0.572 ANOVA 5X2X2X2X2 0.129 Age group 4 F = 1.899 - 0.007 0.108 Gender 1 F = 4250 - 0.004 0.039 SAH 1 F = 2.278 0.002 0.131 Dyslipidemia 1 F = 1.840 0.002 0.175 Diabetes 1 F = 0.935 0.001 0.334 Group*Gender 4 F = 0.541 0.002 0.706 Group*SAH 4 F = 2.425 0.009 0.046 Group*Dyslipidemia 4 F = 1.528 0.006 0.192 Group*Diabetes 4 F = 1.674 0.006 0.154 POST HOC (Tukey) 40-49 x 50-59 years - - - 0.967 40-49 x 60-69 years - - - < 0.001 40-49 x 70-79 years - - - < 0.001 40-49 x ≥ 80 years - - - < 0.001 50-59 x 60-69 years - - - < 0.001 50-59 x 70-79 years - - - < 0.001 50-59 x ≥ 80 years - - - 0.001 60-69 x 70-79 years - - - 0.291 60-69 x ≥ 80 years - - - 0.905 70-79 x ≥ 80 years - - - 0.967 SAH: systemic arterial hypertension; MHR: mean heart rate. the atrial wall31, progressive reductions in systolic volume with age, regardless of gender and ethnicity, has been or ventricular compliance alterations produced by diastolic demonstrated in other studies with elderly individuals dysfunction32. submitted to 24-hour Holter monitoring27,34,35. Several factors related to the autonomic modulation Further investigations, involving echocardiographic during the aging process, agonist and antagonist ones, may measurements and heart rate variability, may explain the be related to the maintenance of the MHR equilibrium status. phenomenon and confirm some of the hypotheses. The reduced decrease in MHR, substantially lower Among the limitations of this study, one might question than the intrinsic sinus rate decrease14, would eventually the representativeness of the sample, as there was no result from the action of other adaptation mechanisms randomization during the process of participant inclusion of the cardiovascular system in the elderly, such as and the source population consists of patients from a increase in sympathetic tone after a lower myocardial single cardiology referral center. In fact, considering the performance during daily activities, including varying institutional-based sampling, there is potentially a trend degrees of physical exertion. Several studies have identified of predominance of individuals with higher prevalence of a trend of predominant sympathetic modulation over the diseases36. Another factor to be considered is the lack of 23,33 parasympathetic one with advancing age . direct measurement of blood pressure levels and clinical Although the mechanisms responsible for it are not parameters, but the echocardiographic evaluation sought to completely understood, the small decrease in MHR avoid the inclusion of individuals with evident heart disease.

Arq Bras Cardiol. 2013;101(5):388-398 395 Santos et al. Mean heart rate and aging Original Article

Table 6 – Estimates of linear regression for mean heart rate, through simple model with multiple variables and hierarchical model

MHR: REGRESSION MODELS R R2 ADJUSTED STANDARDIZED BETA DURBIN-WATSON*/VIF** p AGE GROUP 0,185 0,034 - 1,944* < 0,001 AGE 0,198 0,038 - 1,943* < 0,001 ENTER: AGE GROUP, GENDER 0,233 0,050 - 1,936* < 0,001 AND COMORBIDITIES Age Group - - - 0,189 1,076** < 0,001 Gender - - - 0,134 1,015** < 0,001 SAH - - -0,017 1,137** 0,581 Dyslipidemia - - 0,033 1,097** 0,275 Diabetes - - 0,011 1,058** 0,716 HIERARCHICAL: AGE(1); GENDER (2) 0,198 (1); 0,242 (2) 0,038 (1); 0,057 (2) - 1,934* Age 0,198 0,038 -0,198 1,001** < 0,001 Gender 0,242 0,057 -0,138 1,001** < 0,001 HIERARCHICAL: AGE GROUP (1); 0,185 (1); 0,230 (2); 0,033 (1); 0,051 (2); - 1,936* < 0,001 GENDER (2); COMORBIDITIES (3) 0,233 (3) 0,050 (3) Age Group - - - 0,185 1,076** < 0,001 Gender - - - 0,137 1,015** < 0,001 SAH - - - 0,017 1,137** 0,581 Dyslipidemia - - 0,033 1,097** 0,275 Diabetes - - 0,011 1,058** 0,716 SAH: systemic arterial hypertension.

Data related to thyroid function were not available in The findings were consistent, reproducible and corroborated approximately 25% of the sample. Although an eventual in several statistical models. thyroid dysfunction may interfere with MHR values, we believe this factor did not have any significant influence on the present study, as the remaining 75% showed normal Author contributions hormone levels and no subjects enrolled in the study Conception and design of the research e Writing of reported the use of thyroid-dysfunction medication. the manuscript: Santos MAA, Sousa ACS, Reis FP, Santos Additionally, the prospective and sequential data TR, Lima SO, Barreto-Filho JA; Acquisition of data: Santos collection, the complete filling out of data, the participants’ MAA, Santos TR; Analysis and interpretation of the data: selection and exclusion criteria and the stringent statistical Santos MAA, Sousa ACS, Reis FP, Barreto-Filho JA; Statistical calculations were relevant measures in minimizing biases. analysis: Santos MAA; Critical revision of the manuscript The distribution of individuals across the age groups and the for intellectual content: Santos MAA, Sousa ACS, Reis FP, expected ratio between men and women in terms of “real Lima SO, Barreto-Filho JA. life” also suggest that the research sample is inserted within the expected population standard. Potential Conflict of Interest No potential conflict of interest relevant to this article was Conclusions reported. MHR decreased with increasing age in both genders. For similar age groups, females had significantly higher MHR values than their male counterparts and this phenomenon Sources of Funding was reproduced in both the total sample and when There were no external funding sources for this study. stratified by age. The prevalence of comorbidities such as hypertension, non-insulin dependent diabetes mellitus and dyslipidemia had no detectable influence on MHR patterns. Study Association Both the association between MHR and age range as the This article is part of the thesis of master and doctoral association between MHR and gender were significant in submitted by Marcos Antonio Almeida Santos from several models of statistical analysis. However, the magnitude Universidade Tiradentes and Universidade Federal of this association in both situations is considerably small. de Sergipe.

396 Arq Bras Cardiol. 2013;101(5):388-398 Santos et al. Mean heart rate and aging Original Article

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Arq Bras Cardiol. 2013;101(5):388-398 397 Original Article

398 Original Article

Serum Adiponectin and Cardiometabolic Risk in Patients with Acute Coronary Syndromes Gustavo Bernardes de Figueiredo Oliveira, João Ítalo Dias França, Leopoldo Soares Piegas Instituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil

Abstract Background: The adipose tissue is considered not only a storable energy source, but mainly an endocrine organ that secretes several cytokines. Adiponectin, a novel protein similar to collagen, has been found to be an adipocyte-specific cytokine and a promising cardiovascular risk marker. Objectives: To evaluate the association between serum adiponectin levels and the risk for cardiovascular events in patients with acute coronary syndromes (ACS), as well as the correlations between adiponectin and metabolic, inflammatory, and myocardial biomarkers. Methods: We recruited 114 patients with ACS and a mean 1.13-year follow-up to measure clinical outcomes. Clinical characteristics and biomarkers were compared according to adiponectin quartiles. Cox proportional hazard regression models with Firth’s penalization were applied to assess the independent association between adiponectin and the subsequent risk for both primary (composite of cardiovascular death/non-fatal acute myocardial infarction (AMI)/non-fatal stroke) and co-primary outcomes (composite of cardiovascular death/non-fatal AMI/non-fatal stroke/ rehospitalization requiring revascularization). Results: There were significant direct correlations between adiponectin and age, HDL-cholesterol, and B-type natriuretic peptide (BNP), and significant inverse correlations between adiponectin and waist circumference, body weight, body mass index, Homeostasis Model Assessment (HOMA) index, triglycerides, and insulin. Adiponectin was associated with higher risk for primary and co-primary outcomes (adjusted HR 1.08 and 1.07/increment of 1000; p = 0.01 and p = 0.02, respectively). Conclusion: In ACS patients, serum adiponectin was an independent predictor of cardiovascular events. In addition to the anthropometric and metabolic correlations, there was a significant direct correlation between adiponectin and BNP. (Arq Bras Cardiol. 2013;101(5):399-409) Keywords: Adiponectin; Metabolic Syndrome X; Insulin Resistance; Acute Coronary Syndrome; Risk Factors.

Introduction of obesity-related diseases, such as diabetes mellitus (DM) and atherosclerosis. Matsuzawa et al12 have assessed the endocrine role of adipocytes and found an abundant Metabolic Syndrome and Adiponectin expression of genes related to the synthesis of several In pre-clinical and clinical conditions, the metabolic bioactive substances, such as adiponectin (Arcp30, AdipoQ, components of cardiovascular risk, such as obesity, insulin apM1 or GBP28), a protein similar to collagen and identified resistance and dyslipidemia, interact in a complex way, as an adipocyte-specific cytokine. being associated with high cardiovascular morbidity and mortality1-11. Visceral obesity plays an increasingly relevant Adiponectin is abundantly expressed in healthy role as a cardiovascular risk factor. In fact, the adipose tissue individuals, has antithrombotic, antiatherogenic and is a storable energy source and an endocrine organ that anti‑inflammatory properties, and is downregulated in obese secretes cytokines, which can contribute to the development individuals. Similarly, adiponectin levels are reduced in male individuals, with type 2 DM, proinflammatory conditions, lipodystrophies, insulin resistance and cardiovascular disease. Inversely, serum adiponectin concentrations are elevated in Mailing Address: Gustavo Bernardes F. Oliveira • women, non-obese individuals, with type 1 DM and in those Av. Dr. Dante Pazzanese, 500. Unidade Coronária, 2.º andar, Unidade undergoing treatment with peroxisome proliferator‑activated Hospitalar III. Postal Code 04012-909, São Paulo, SP - Brazil receptor gamma (PPARγ) agonists13-20. From the prognostic E-mail: [email protected], [email protected] Manuscript received December 07, 2012; revised manuscript June 10, viewpoint, in healthy individuals, adiponectin has been 2013; accepted June 24, 2013. inversely associated with cardiovascular risk, mainly in men, or directly associated with that risk, mainly in the DOI: 10.5935/abc.20130186 elderly21-25. However, studies on chronic heart failure (HF)

399 Oliveira et al. Adiponectin and cardiometabolic risk Original Article or documented cardiovascular disease (CVD) have identified following a 12-hour nocturnal fasting. Insulin resistance hyperadiponectinemia as an independent predictor of was expressed as the HOMA index calculated by using the mortality26-28. Similarly, Cavusoglu et al29 have identified a formula [product of glucose (mg/dL) by insulin (µUI / mL), direct and independent association between adiponectin divided by the constant 405]30,31. Adiponectin and leptin and the risk for acute myocardial infarction (AMI) and were measured by use of ELISA assay. The kits for measuring cardiovascular death in a cohort of men undergoing coronary adiponectin were Human Adiponectin ELISA Kit 96-Well angiography for the diagnostic investigation of chest pain. Plate (Cat. # EZHADP-61K), manufactured by Millipore, Those data suggest that adiponectin might play a different United States. The kits for measuring leptin were DiaSource role in acute clinical scenarios. Thus, this study was aimed KAP2281 Human Leptin ELISA IVD, manufactured by at assessing the association between serum adiponectin DIAsource ImmunoAssays S.A., Belgium. The primary levels and the risk for cardiovascular events in patients outcome comprised cardiovascular death, nonfatal AMI or with acute coronary syndromes (ACSs), and at establishing reinfarction, and nonfatal stroke. The co-primary outcome the correlations between adiponectin and metabolic, comprised primary events and re-hospitalization due inflammatory and myocardial biomarkers. to recurring ischemia or ischemia considered clinically significant requiring revascularization during clinical follow‑up. Cases of AMI were defined by criteria proposed Method for the universal definition of AMI32. Cases of stroke were This study has two components: a) a cross-sectional defined according to World Health Organization (WHO) and analytical component to determine the clinical classical criteria33. The distributions of the continuous characteristics and measures of serum biomarkers of variables were expressed as mean (± standard deviation) patients with ACS on hospital admission; b) a cohort of or median (with interquartile interval), as appropriate, ACS, prospectively included between 2008 and 2010, and the comparisons between the groups were calculated with clinical follow-up for the systematic and prospective by using Student t test or non-parametric (Kruskall-Wallis collection of cardiovascular events. Based on the study test), as appropriate. The distributions of the categorical by Cavusoglu et al29 on a subgroup of patients with variables were expressed as frequencies and percentages, ACS comprising 52.3% of a total of 325 patients and and the comparisons calculated by using chi-square test with all-cause mortality rate of 10.3% in two years of or Fisher exact test, as appropriate. The analysis of the clinical follow-up, the calculation of the sample size was primary and co-primary clinical outcomes was based on the estimated as 112 patients, with significance of α = 0.05 time for the occurrence of the first event. Cox univariate and 1 − β = 0.80. It is worth noting that, due to the lack regression analysis gathered all demographic, metabolic, of studies about adiponectin in patients with ACSs in the inflammatory, anthropometric and angiographic variables, Brazilian population up to the time of the elaboration of and only those univariate predictors with p < 0.10 and this dissertation project, and, thus, scarcity of data on the variables with clinical significance were included in Cox variability of that biomarker measurements, the possibility proportional hazards regression models to determine of inadequate estimation was considered. This study whether adiponectin would be an independent risk included patients of both sexes, over the age of 18 years, predictor. Backward stepwise regression was used for who underwent blood collection within the first 24 hours the models to identify the independent variables of risk from ischemic symptom onset and who provided written for the occurrence of primary and co-primary outcomes, informed consent, in the emergency and coronary units of respectively. Then, Firth’s penalized likelihood method the Instituto Dante Pazzanese de Cardiologia, in the city was used to adjust the potentially overestimated variables of São Paulo. Patients with the following characteristics due to elevated prevalence. The results were expressed were excluded: infectious, inflammatory and neoplastic as hazard ratio and 95% confidence interval (CI), and the diseases; end-stage kidney or liver disease; significant heart discriminatory capacity of the models was expressed by valve disease or heart valve disease precipitating the clinical c-statistic (or c index). Two-tailed tests were used with findings; percutaneous coronary intervention (PCI) or significance level of α = 0.0534,35. coronary artery bypass graft surgery (CABG) in the preceding 30 days; previous and current use of insulin (patients with type 1 DM and those with type 2 DM requiring insulin); and Results use of oral antidiabetic drugs of the thiazolidinedione group. The following parameters were assessed: adiponectin; Characteristics of the Patients leptin; fasting glucose; insulin; Homeostasis Model Assessment (HOMA) index; glycated hemoglobin (HbA1c); Table 1 lists the major characteristics of the 114 patients total cholesterol, LDL- and HDL‑cholesterol; triglycerides; with ACS according to adiponectin quartiles. Their mean ultrasensitive C-reactive protein (us-CRP); leukocytes; (± SD) age was 62 (± 10.5) years, 41.2% were of the fibrinogen; platelets; cardiac troponin I (TnI); CKMB mass; female sex and 82.6%, Caucasians. The prevalence of B-type natriuretic peptide (BNP); and demographic (age, cardiovascular risk factors was significant as follows: arterial sex, ethnicity), anthropometric (weight, body mass index hypertension, 90%; DM, 30%; dyslipidemia, 78%; and and waist circumference) and angiographic (extension/ current tobacco use, 16.4%. The medians (interquartile severity of coronary artery disease [CAD] in patients interval) of the anthropometric parameters were as undergoing coronary angiography) variables. Venous follows: body mass index (BMI) = 27.4 (24.6-30.4) kg / m2 blood samples (10 mL) were collected in the morning and waist circumference = 98 (91-108) cm. Regarding

Arq Bras Cardiol. 2013;101(5):399-409 400 Oliveira et al. Adiponectin and cardiometabolic risk Original Article

Table 1 − Clinical characteristics according to adiponectin quartiles

Characteristics Q1 Q2 Q3 Q4 p Age 60.6 ± 9.4 60.7 ± 9.6 64.3 ± 11.2 64.9 ± 11.8 0.29 Female sex 25% 31% 51.7% 57.1% 0.037 Caucasian ethnicity 71.4% 86.2% 89.7% 85.7% 0.84 ∆t for admission, min 353 ± 45 412 ± 62 482 ± 101 330 ± 65 0.47 Weight, kg 81.8 ± 14.5 77.2 ± 12.8 70.5 ± 13.2 66 ± 13.5 0.0001 BMI, kg/m2 29.6 ± 5.2 28.3 ± 5.0 27.5 ± 4.4 26.4 ± 5.3 0.10 Waist circumference, cm 105.2 ± 11.8 99.2 ± 12.8 97.1 ± 11.4 93.4 ± 12.0 0.004 SBP, mmHg 136 ± 22.6 137 ± 33 147 ± 22.6 142 ± 30.4 0.38 DBP, mmHg 81 ± 18.2 81 ± 17.3 84 ± 13.1 85 ± 16.9 0.72 HR, bpm 73 ± 12 76 ± 16 76 ± 15 83 ± 23 0.61 Killip I 96.3% 89.3% 85.2% 89.3% Killip II/III 3.7% 3.6% 11.1% 10.7% 0.52 Killip IV 0% 7.1% 3.7% 0% Diabetes mellitus 35.7% 24.1% 31% 28.6% 0.81 Dyslipidemia 85.7% 72.4% 82.8% 71.4% 0.48 Previous AMI 60.7% 44.8% 44.8% 39.3% 0.41 Previous PCI 46.4% 37.9% 48.3% 42.9% 0.88 Previous CABG 28.6% 25% 27.6% 17.9% 0.82 Previous stroke 10.7% 3.4% 10.7% 3.7% 0.59 Current smoking 10.7% 13.8% 23.1% 18.5% 0.62 Previous angina 57.1% 58.6% 58.6% 46.4% 0.77 Previous CKF 7.1% 0% 6.9% 14.3% 0.24 SAH 92.9% 82.8% 96.6% 85.7% 0.30 LVEF 0.53 0.49 0.53 0.46 0.66 Moderate/severe LV dysfunction 33.3% 42.3% 19.2% 30.4% 0.35 ∆t: time interval; HR: heart rate; LVEF: left ventricular ejection fraction; SAH: systemic arterial hypertension; BMI: body mass index; CKF: chronic kidney failure; DBP: diastolic blood pressure; SBP: systolic blood pressure; CABG: coronary artery bypass graft surgery; LV: left ventricle.

electrocardiographic (ECG) findings, 97.3% of the patients was on previous use of thiazolidinediones. Regarding the drugs had alterations, the most frequent (30.9%) being ST-segment used during hospitalization to manage ACS, the following stand depression between 0.5 and 1.0 mm. The final diagnosis out: ASA, 99.1%; clopidogrel, 96.5%; beta-blockers, 89.5%; defined 90.3% of the patients with ACS with no persistent ACEI, 88.5%; statins, 98.2%; and low-molecular weight heparin ST-segment elevation. (enoxaparin) for anticoagulation, 93.8%.

Biomarkers in the global sample Procedures Performed during Hospitalization Table 2 shows the values of biomarkers according to Cardiac catheterization for coronary angiography was adiponectin quartiles. The median adiponectin level was performed in 87.7% of the patients. Luminal stenosis ≥ 50% 9,807 (6,113-13,914) ng/mL. characterized significant CAD, which was documented in at least one vessel in 83% of the patients, and in multiple arteries in 38%. Pharmacological Treatment Percutaneous coronary intervention was performed in 47 patients undergoing diagnostic angiography (49%), 76.6% of whom underwent implantation of one coronary stent, and 21.3%, more Medications used before and during hospitalization than one stent. Of the stents implanted, 91% were conventional Previous treatments included the following drugs: acetylsalicylic (non-pharmacological). Coronary artery bypass graft surgery was acid (ASA), 69%; angiotensin-converting-enzyme inhibitors performed in 15.6% of the patients, the left internal thoracic artery (ACEI), 62.2%; beta-blockers, 60.4%; statins, 59.8%; oral being used in 100% of the patients, and grafts being applied to at antidiabetic drugs, 13.2%; and insulin, 1.8%. No patient included least three coronary arteries in two thirds of the patients.

401 Arq Bras Cardiol. 2013;101(5):399-409 Oliveira et al. Adiponectin and cardiometabolic risk Original Article

Table 2 − Biomarkers according to adiponectin quartiles

Biomarkers Q1 Q2 Q3 Q4 p Leptin, ng/mL 4941 ± 4686 5471 ± 5142 7124 ± 7977 4037 ± 4592 0.41 Insulin, µUI/mL 11.36 ± 8.6 10.28 ± 10.1 9.83 ± 5.1 7.80 ± 6.5 0.06 Glucose, mg/dL 117 ± 42 118 ± 59 116 ± 91 110 ± 42 0.67 HbA1c, % 7.1 ± 1.7 6.6 ± 1.5 6.4 ± 1.12 6.4 ± 1.43 0.25 HOMA index 3.35 ± 3.13 2.92 ± 3.15 3.04 ± 3.31 2.23 ± 2.17 0.20 Total cholesterol, mg/dL 182 ± 43 170 ± 37 190 ± 42 191 ± 53 0.32 LDL-cholesterol, mg/dL 107 ±31 104 ± 33 122 ± 40 116 ± 40 0.31 HDL-cholesterol, mg/dL 34 ± 6 34 ± 6 41 ± 8 43 ± 11 0.0001 Triglycerides, mg/dL 221 ± 130 174 ± 127 137 ± 57 149 ± 88 0.03 CKMB mass, ng/mL 12.9 ± 27.4 107.9 ± 394 20.8 ± 45.3 27.1 ± 62.3 0.62 TnI, ng/mL 6.44 ± 12.8 36 ± 99 9.44 ± 17 13.7 ± 26.6 0.65 us-CRP, mg/dL 6.13 ± 15.9 6.2 ± 9.96 3.14 ± 3.73 10.5 ± 21.3 0.89 Leukocytes, /mm3 8689 ± 3189 8978 ± 4480 8446 ± 2921 7620 ± 2118 0.61 Platelets, x103/mm3 239 ± 101 218 ± 511 236 ± 606 226 ± 596 0.61 BNP, pg/mL 120 ± 191 163 ± 222 169 ± 252 437 ± 573 0.21 Fibrinogen, mg/dL 392 ± 88 343 ± 86 354 ± 86 344 ± 83 0.12 Creatinin, mg/dL 1.07 ± 0.33 1.16 ± 0.18 1.06 ± 0.28 1.24 ± 0.68 0.044 BNP: type-B natriuretic peptide; CKMB: creatine kinase, MB fraction; HbA1c: glycated hemoglobin; HOMA: Homeostasis Model Assessment; HDL: high-density lipoprotein; LDL: low-density lipoprotein; us-CRP: ultrasensitive C-reactive protein; TnI: cardiac troponin I.

Clinical Outcomes use of ASA. Adiponectin was consistently an independent Primary outcome was observed in 18.4% of the patients, and predictor of high risk for cardiovascular events in the co-primary outcome, in 21.1%, with a mean 1.13-year clinical models of groups B and D, with borderline significance follow-up in all 114 patients recruited. Thus, follow-up was for group C. performed in 100% of the patients, with no loss to follow-up. The logistic regression analysis showed an almost linear relationship between adiponectin, as a quantitative continuous Adiponectin as a Predictor of Cardiometabolic Risk variable, and the estimate of the probability of risk for primary and co-primary outcomes (Figure 1). The Cox models included the following variables that showed significance for the association with primary and co-primary outcomes: adiponectin; other biomarkers; Correlations Between Adiponectin and Biomarkers clinical characteristics; angiographic variables; and As prespecified, the secondary objective was to study treatments and procedures performed before and the correlations between adiponectin and the different during hospitalization. The models were calculated for biomarkers, and demographic and anthropometric variables. four prespecified groups of interest: overall population Table 7 emphasizes the direct and significant correlation (group A); patients with no DM (group B); patients with between adiponectin and BNP. no ST-segment elevation AMI (group C); and patients with neither DM nor ST-segment elevation AMI (group D) (Tables 3-6). Some of the variables included in the Discussion model for primary outcome were as follows: previous This study of a cohort of patients with ACS on mid/ angina; arterial hypertension; Killip classification; long-term clinical follow-up detected a direct, significant adiponectin; leptin; fasting glucose; creatinine; CKMB and independent association between adiponectin and activity; CKMB mass; TnI; BNP; and urea. After adjusting the risk for relevant cardiovascular clinical outcomes. for those factors, adiponectin was associated with high There was consistent signaling of more evident risk when risk for the primary outcome in the models for groups B patients with DM or ST-segment elevation AMI were excluded. and D. For co-primary outcome, the following variables Cavusoglu et al29 have assessed 325 male patients with stable were included: previous angina; arterial hypertension; angina, unstable angina and non-ST-segment elevation AMI, Killip classification; adiponectin; leptin; fasting glucose; who underwent coronary angiography to determine the creatinine; CKMB activity; heart rate (HR) on admission, prognostic value of serum adiponectin levels. The patients HDL-cholesterol; HOMA index; obesity and in-hospital were followed up for 24 months for the occurrence of

Arq Bras Cardiol. 2013;101(5):399-409 402 Oliveira et al. Adiponectin and cardiometabolic risk Original Article

Table 3 − Cox models for the global population (group A)

Primary and co-primary outcomes Coefficient Hazard ratio 95%CI p Troponin I (per 1) 0.009 1.009 1.002 1.014 0.016 Fasting glucose (per 10) 0.071 1.074 1.021 1.114 0.01

C indices per time intervals

30 days 180 days 365 days 0.7208 0.6641 0.6641

Coefficient Hazard ratio 95%CI p Previous angina 0.987 2.684 0.955 9.038 0.0616 Adiponectin (per 1,000) 0.047 1.048 0.996 1.093 0.0687 Fasting glucose (per 10) 0.054 1.055 0.998 1.099 0.0562

C indices per time intervals

30 days 180 days 365 days 0.6346 0.7719 0.7719

Table 4 − Cox models after excluding the diabetic patients (group B)

Primary and co-primary outcomes Coefficient Hazard ratio 95%CI p Troponin I (per 1) 0.012 1.012 1.004 1.018 0.004

Adiponectin (per 1,000) 0.076 1.079 1.018 1.13 0.014

C indices per time intervals

30 days 180 days 365 days 0.8314 0.7906 0.7906

Coefficient Hazard ratio 95%CI p Previous angina 1.461 4.310 1.17 22.98 0.026 Adiponectin (per 1,000) 0.067 1.070 1.01 1.12 0.023

C indices per time intervals

30 days 180 days 365 days 0.6346 0.7719 0.7719

all-cause death, cardiovascular mortality and AMI. In that Other recent studies have also identified a direct association study, the authors have identified a direct and independent between adiponectin and cardiovascular risk, especially in predictive association between a single baseline adiponectin patients with HF, mainly the elderly26-28. Wannamethee et measurement and the subsequent risk of death and AMI. al28 have prospectively studied the relationship between In the subgroup of non-ST-segment elevation ACS (n = 170), adiponectin levels and mortality in 4,046 male elderly adiponectin remained as an independent risk predictor. (60‑79 years of age), with and without documented CVD

403 Arq Bras Cardiol. 2013;101(5):399-409 Oliveira et al. Adiponectin and cardiometabolic risk Original Article

Table 5 − Cox models after excluding ST-segment elevation AMI (group C)

Primary and co-primary outcomes Coefficient Hazard ratio 95%CI p Fasting glucose (per 10) 0.078 1.081 1.03 1.12 0.005 Adiponectin (per 1,000) 0.05 1.051 0.997 1.098 0.06

C indices per time intervals

30 days 180 days 365 days 0.7039 0.7025 0.7025

Coefficient Hazard ratio 95%CI P Previous angina 1.262 3.53 1.17 13.88 0.023 Adiponectin (per 1,000) 0.050 1.051 0.998 1.096 0.05

C indices per time intervals

30 days 180 days 365 days 0.7368 0.7330 0.7330

Table 6 – Cox models after excluding patients with diabetes and ST-segment elevation AMI (group D)

Primary and co-primary outcomes Coefficient Hazard ratio 95%CI p Previous angina 1.213 3.364 0.89 18.16 0.07 Adiponectin (per 1,000) 0.077 1.080 1.02 1.13 0.012 Troponin I (per 1) 0.038 1.039 1.001 1.075 0.04

C indices per time intervals

30 days 180 days 365 days 0.7994 0.8032 0.8032

Coefficient Hazard ratio 95%CI p Previous angina 1.940 6.96 1.54 65.8 0.009 Adiponectin (per 1,000) 0.069 1.072 1.01 1.12 0.02

C indices per time intervals

30 days 180 days 365 days 0.7390 0.8199 0.8199

and HF. After adjusting for important baseline characteristics, comparing the highest and the lowest tertiles, as well as in men adiponectin remained directly and significantly associated with diagnosed HF (adjusted RR: 2.37, 95%CI: 0.64‑8.79, with total and cardiovascular mortalities in men without CVD p = 0.04; and RR: 3.43 95%CI: 0.54‑21.7, p = 0.008). or HF (adjusted RR: 1.55, 95%CI: 1.19-2.02, p = 0.002; No association was demonstrated in those with diagnosed and RR: 1.53, 95%CI: 1.03‑2.27, p = 0.02), for a trend in CVD, but no HF.

Arq Bras Cardiol. 2013;101(5):399-409 404 Oliveira et al. Adiponectin and cardiometabolic risk Original Article

1,0 Primary outcome Co-primary outcome 0,9 0,8 0,7 0,6 0,5 0,4 0,3 Estimated risk probability 0,2 0,1

10.000 20.000 30.000 40.000

Adiponectin

Figure 1 – Adiponectin values and risk estimation for the outcomes.

Table 7 – Correlations between adiponectin and quantitative variables

Variables Correlation coefficient p BNP 0.221 0.02 BMI – 0.239 0.01 Weight – 0.412 < 0.001 Height – 0.346 < 0.001 Waist circumference – 0.309 0.001 Age 0.236 0.01 BNP: type-B natriuretic peptide; BMI: body mass index.

Our study has some important differences as compared as compared with men in the same age group13,36. In terms with those previously discussed. Ours included patients of of independent risk prediction, this study findings are in a wider age group, no analysis restricted only to the oldest. accordance with those of the most recent literature regarding Similarly, this study was not restricted to the inclusion of male the prognostic value of adiponectin in different clinical individuals21-23,26-29, emphasizing that there was adequate scenarios, either under stable conditions and in populations balance in the sex proportions, with significant female considered healthy or without documented CVD, or representation (41.2%). In fact, the mean adiponectin level under acute clinical conditions or manifest CVD, as in the is approximately 50% greater in women, mainly elderly ones, present study. Some studies have identified an independent

405 Arq Bras Cardiol. 2013;101(5):399-409 Oliveira et al. Adiponectin and cardiometabolic risk Original Article association between adiponectin and higher risk for CAD and instability of atheromatous plaques40. Those mechanisms (nonfatal AMI and fatal CAD) in individuals with no previous include the following: 1) involvement of adiponectin in the documentation, but only in the elderly, with adjusted OR regulation of the necrotic core development; 2) double role of 1.69 (95%CI: 1.23-2.32) for the 5th quintile versus the in the neovascularization process due to pro/antiatherogenic 1st quintile25. However, the Rancho Bernardo study24 has properties; the ability to promote angiogenesis has been reported that adiponectin levels in the 5th quintile stratified proven to be beneficial to prevent ischemia; 3) the inverse by sex were significantly associated with a 44% reduction relationship between adiponectin and the ratio between matrix in OR for the occurrence of CAD, which was eliminated metalloproteinases and the tissue inhibitor of metalloproteinase-1 after adjusting for HDL-cholesterol and/or triglycerides. suggests that adiponectin modulates the stability of atheromatous In the 20-year prospective analysis, higher concentrations of plaques by balancing that relationship; 4) local adiponectin adiponectin were predictive of reduced risk for nonfatal AMI in the intima and adventitia suppresses the expression of only in men. Corroborating that information, a recent study VCAM-1 and ICAM-1 adhesion molecules in vascular walls, on adiponectin and risk of CAD-related events in the context suggesting that adiponectin improves atherosclerosis partially of a meta-analysis of seven prospective studies has reported by inhibiting the expression of those inflammatory molecules an OR for CAD of 0.89 (95%CI: 0.67-1.18), comparing in vivo. Adiponectin has a documented role in the following: men in the 3rd tertile with the 1st tertile, very similar to the endothelial activation; propagation of inflammatory factors findings of that meta-analysis22. Wolk et al37 have assessed through expression of adhesion molecules; monocyte adhesion 499 patients undergoing coronary angiography, 168 of whom to vascular endothelium and migration to the intima; macrophage with ACS, and identified that high adiponectin levels are activation; transformation of macrophages into foam cells; lipid independently associated with a reduced risk of ACS. accumulation in macrophages; proliferation and migration of Of the studied correlations between adiponectin and smooth muscle cells to the intima; and platelet aggregation. other biomarkers, we detected a direct and significant one Other mechanisms involved also include the phenomena of with BNP. Thus, possible interactions like that cannot be oxidation and vascular tone regulation. ruled out, among others identified and non-measurable Of the metabolic variables studied, in addition to factors or variables, which can explain the attenuation of the adiponectin itself, only fasting glucose showed a significant strength of the association with the risk in the global model. direct and independent correlation with cardiovascular That hypothesis is supported by the study by Schnabel et al38, in risk. Our results are comparable to those of several studies which the association of risk and adiponectin remained robust on the prognostic role of hyperglycemia on ACS, especially after adjusting for classical risk factors in the global population AMI. That might either reflect an unbalance of the systems studied. However, after adjusting for BNP, adiponectin lost regulated by adiponectin, as previously discussed, or its independent predictive value. Because of those findings, be influenced by the contra-regulatory mechanisms in patients with manifest CAD, adiponectin seems to have responsible for stress hyperglycemia. However, because a different role. In clinically asymptomatic individuals, high of the associations observed between the biomarkers, adiponectin levels seem to protect against atherosclerotic specifically with adiponectin, and little or no correlation disease; however, when elevated in patients with symptomatic with us-CRP, leukocytes, platelets and fibrinogen, in addition CAD, a direct association with risk for cardiovascular events to maintenance of the association with glycemia even with is observed. That result of direct or paradoxical association the strong effect of association of CKMB mass, reflecting the implies that the beneficial influence of adiponectin in impact of the myocardial necrosis grade, we think that the atherosclerotic disease would be translated into elevations in fasting glucose findings might actually reflect interactions with adiponectin concentrations as a contra‑regulatory mechanism the effects of adiponectin. Similarly, the results demonstrated in response to the excessive and unstable atherosclerotic by adiponectin quartiles suggest and strengthen that glycemia process of the ACS, with a negative net result, despite the levels are directly associated with adiponectin levels, exerting high concentrations of that biomarker. That could indicate an interaction or collinearity effect. unbalance of the entire metabolic homeostatic system, In addition, this study performed serial measurements interfering with cellular bioenergetic processes. of neither adiponectin nor the different biomarkers of It is worth noting that the presence of a strong association metabolism, such as glycemia, insulin, HOMA index and between risk factor and the outcome assessed does not HbA1c. Such serial measurements could provide additional necessarily mean that the risk factor provides a base for an relevant information for better understanding metabolic effective predictive rule. Wang et al39 have shown that, in homeostasis interrelations. individual risk assessment, the use of ten biomarkers added This study found a significant and direct association only a discrete discriminatory capacity to the classical risk between adiponectin and the female sex, presence of factors, with practically overlapping ROC curves and similar comorbidities, chronic kidney failure, current smoking and c indices (0.76 versus 0.77). HDL-cholesterol and creatinine levels. In addition, this Finally, there is the question about the potential mechanisms study found a significant and inverse association between of the increased risk for relevant cardiovascular events. A recent adiponectin and DM, body weight, waist circumference review has assessed the different pathophysiological mechanisms and insulin and triglyceride levels. In fact, the results of adiponectin and has concluded that those associations between the different clinical variables and biomarkers provide relevant information to understand the inflammatory emphasize internal consistency with those previously and atherogenic processes associated with CAD progression reported, and with similar patterns, reinforce the aspect

Arq Bras Cardiol. 2013;101(5):399-409 406 Oliveira et al. Adiponectin and cardiometabolic risk Original Article

of consistency, and indicate similar trends, suggesting and evoke additional investigations to determine the that the results should be considered satisfactory and mechanisms involved in the following: the direct association interpretable. However, as in other observational of adiponectin with greater cardiovascular risk; the significant cross‑sectional studies, there are some limitations, such correlation with BNP; and the potential modulation of that as selection biases, in addition to confounding factors biomarker as a therapeutic target. not completely elucidated, and, thus, without ideal adjustment. However, we emphasize that systematic efforts were planned to minimize those aspects, as follows: Acknowledgements consecutive recruitment of eligible patients; prospective This study received logistic support from the Division and standardized data collection, mainly of clinical events of Translational Epidemiology and from the Clinical since ACS onset and representing 100% of the patients; Analyses Laboratory of the Instituto Dante Pazzanese de adjustment of Cox models for important co-variables, such Cardiologia (IDPC). We are also grateful to the Statistics as age, sex, CAD extension, other metabolic, inflammatory and Epidemiology Laboratory of the IDPC and the Instituto and myocardial necrosis biomarkers, left ventricular Gênese de Análises Científicas. function, coronary revascularization procedures and pharmacological therapy with proven cardiovascular benefit. Considering the unpredictability of the variability Author contributions of the different measures in the population studied, the Conception and design of the research, Analysis and occurrence of non-measured confounding factors, and interpretation of the data, Obtaining funding and Critical the exploratory nature of the hypotheses, the findings revision of the manuscript for intellectual content: Oliveira and conclusions of the study should be considered as GBF, Piegas LS; Acquisition of data and Writing of the suggestive or indicative, supporting their applicability manuscript: Oliveira GBF; Statistical analysis: França JID. to the Brazilian population and contributing to the formulation of new hypotheses. Potential Conflict of Interest Conclusions No potential conflict of interest relevant to this article was reported. The results of this study add information about the potential prognostic role of serum adiponectin levels in patients with ACS. In addition, they support the concept Sources of Funding of metabolic homeostasis as an essential biological process There were no external funding sources for this study. that determines cardiovascular risk. Elevated total serum adiponectin levels were independent and direct predictors of the occurrence of relevant cardiovascular outcomes, such Study Association as re-hospitalization requiring revascularization. The data This article is part of the thesis of Doctoral submitted by discussed emphasize the correlations between adiponectin Gustavo Bernardes de Figueiredo Oliveira, from Universidade and anthropometric, metabolic and myocardial biomarkers, de São Paulo.

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Arq Bras Cardiol. 2013;101(5):399-409 408 Oliveira et al. Adiponectin and cardiometabolic risk Original Article

409 Arq Bras Cardiol. 2013;101(5):399-409 Original Article

Left Ventricular Synchrony and Function in Pediatric Patients with Definitive Pacemakers Michel Cabrera Ortega1, Adel Eladio Gonzales Morejón2, Giselle Serrano Ricardo2 Departamento de Arritmia e Estimulação Cardíaca - Cardiocentro Pediátrico ¨William Soler¨1, Havana, Cuba; Departamento de Ecocardiografia - Cardiocentro Pediátrico ¨William Soler¨ 2, Havana, Cuba

Abstract Background: Chronic right ventricular pacing (RVP) induces a dyssynchronous contraction pattern, producing interventricular and intraventricular asynchrony. Many studies have shown the relationship of RVP with impaired left ventricular (LV) form and function. Objective: The aim of this study was to evaluate LV synchrony and function in pediatric patients receiving RVP in comparison with those receiving LV pacing (LVP). Methods: LV systolic and diastolic function and synchrony were evaluated in 80 pediatric patients with either nonsurgical or postsurgical complete atrioventricular block, with pacing from either the RV endocardium (n = 40) or the LV epicardium (n = 40). Echocardiographic data obtained before pacemaker implantation, immediately after it, and at the end of a mean follow-up of 6.8 years were analyzed. Results: LV diastolic function did not change in any patient during follow-up. LV systolic function was preserved in patients with LVP. However, in children with RVP the shortening fraction and ejection fraction decreased from medians of 41% ± 2.6% and 70% ± 6.9% before implantation to 32% ± 4.2% and 64% ± 2.5% (p < 0.0001 and p < 0.0001), respectively, at final follow-up. Interventricular mechanical delay was significantly larger with RVP (66 ± 13 ms) than with LVP (20 ± 8 ms). Similarly, the following parameters were significantly different in the two groups: LV mechanical delay (RVP: 69 ± 6 ms, LVP: 30 ± 11 ms, p < 0.0001); septal to lateral wall motion delay (RVP: 75 ± 19 ms, LVP: 42 ± 10 ms, p < 0.0001); and, septal to posterior wall motion delay (RVP: 127 ± 33 ms, LVP: 58 ± 17 ms, p < 0.0001). Conclusion: Compared with RV endocardium, LV epicardium is an optimal site for pacing to preserve cardiac synchrony and function. (Arq Bras Cardiol. 2013;101(5):410-417) Keywords: Ventricular Function, Left; Myocardial Contraction; Cardiac Pacing, Artificial; Child; Pacemaker, Artificial.

Introduction permanent LV epicardial pacing concluded that LV function can be preserved by chronic stimulation of the LV (LVP) free Electric stimulation from the right ventricular (RV) apex 9,10 and free wall induce a dyssynchronous contraction pattern wall . In addition, an study of pediatric patients with either characterized by early activation of RV and the interventricular LV dysfunction and RVP or intrinsic left bundle branch block demonstrated the possibility for improvement of LV function septum and delayed activation of the left ventricular (LV) anterior 11 wall. This produces mechanical and electrical interventricular 1 month after single-site LVP . asynchrony, along with intraventricular asynchrony1. Although The present study aimed to evaluate the evolution of LV these detrimental effects are tolerated by most pediatric patients, function and synchrony after endocardial RVP in comparison studies have shown that chronic RV pacing (RVP) is an important with those after epicardial LVP. risk factor for acute and chronic impairment of LV function, structural remodeling of LV, and an increased risk of heart failure2-5. These adverse events occur in 6% and 13% patients Methods after follow-up over approximately 10 years2,5-8. Patients Alternative pacing sites have been investigated to preserve LV synchrony. Two retrospective studies of children with A total of 130 pediatric patients who underwent pacemaker implantation in a single tertiary pediatric cardiology center were prospectively enrolled. The study included all children with either nonsurgical or surgical complete atrioventricular block (CAVB). Children were Mailing Address: Michel Cabrera Ortega • included when paced from both the RV endocardium 100 y Perla, Altahabana, Boyeros 10800, Havana, Cuba (n = 40) and from the left ventricular epicardium (n = 40). E-mail: [email protected] Manuscript received July 06, 2012, revised manuscript October 26, 2012, We excluded the following patients: those aged >18 years accepted November 19, 2012. at pacemaker implantation, those with <95% ventricular pacing, those with ≤1 year of permanent cardiac pacing, DOI: 10.5935/abc.20130189 and those with clinical evidence or history of heart failure

410 Cabrera Ortega et al. LV synchrony and function in paced children Original Article unrelated to CAVB at the time of pacemaker implantation. every patient were made for each observer and the average Table 1 depicts the demographic data of the paced children. of measurements was used for further analysis. Paraesternal The study protocol was approved by the institutional M-mode images were used to measure LV end-diastolic and research ethics committee and written consent was LV end-systolic diameters (LVEDD and LVESD, respectively). obtained from the parents of all patients. LV shortening fraction (LV SF) was calculated according to the formula12: LV SF = LVEDD − LVESD/LVEDD × 100. Pacing LV end-diastolic and LV end-systolic volumes (LVEDV and Pacing lead positions were assigned according to LVESV, respectively) were obtained using Simpson’s biplane implantation protocol data and confirmed by chest X-rays. method, and indexed to body surface area and the ejection LVP unipolar leads were implanted in the apical region, and fraction (EF) calculated. inserted through a left lateral thoracotomy. All endocardial For a comprehensive diastolic evaluation, Doppler tissue pacing leads were placed in the RV apex (RVA). Ventricular imaging (DTI) was undertaken at the lateral and septal pacing (Ventricular Rate Modulated Pacing [VVI/VVIR]) was mitral valve annulus in the apical four-chamber view. the predominant pacing mode. The study excluded patients The peak tissue E-wave (Ea) and A-wave (Aa) velocities who required a change in the pacing site between the were obtained, and the E/Ea ratio was also determined. initiation of pacing and evaluation. LV isovolumic relaxation time was used to assess diastolic function, and it was considered as the period from the end Echocardiography of aortic flow to the beginning of mitral inflow in the apical Echocardiographic evaluations were made before five-chamber view. pacemaker implantation, immediately after, and at regular Myocardial 2D strain was performed to assess ventricular intervals during a mean follow-up period of 6.8 years. synchrony in the four-chamber and long-axis views. Data were obtained in the standard precordial positions with The following parameters were evaluated: an appropriate transducer (5 MHz, Aloka Prosound 5500). Interventricular mechanical delay, measured as the time Two experienced observers, blinded for the ventricular pacing site, performed one- and two-dimensional transthoracic difference between the LV and RV pre-ejection times. echocardiography and Doppler evaluations. All examinations Septal to lateral mechanical delay, calculated as the were performed in line with the recommendations maximum time difference between the earliest and of the Pediatric Council of the American Society of latest peak myocardial systolic velocity of two opposing Echocardiography 12; three measurements in random for segments.

Table 1 - Study population: clinical and pacing data

All patients RV pacing LV pacing Patients 80 40 40 Age (years) 12.5(5.2) 14.6(4.3) 10.3(6.1) Age at first implantation (years) 7.2(4.0) 8.1(3.1) 6.3(4.9) Total duration of pacing (years) 6.8(4.3) 6.3(2.6) 7.2(3.2) Gender (male/female) 80(49/31) 40(26/14) 40(23/17) Structural heart disease 46(57.5) 22(55.0) 24(60.0) Atrial septal defect 3(3.75) - 3(10.0) Ventricular septal defect 5(6.25) 4(10.0) 1(2.5) Tetralogy of Fallot 17(21.25) 8(20.0) 9(22.5) Double outlet right ventricle 9(11.25) 6(15.0) 3(7.5) Subvalvular aortic stenosis 7(8.75) 3(7.5) 4(10.0) Valvular pulmonary stenosis 2(2.5) 1(2.5) 1(2.5) Persistence ductus arteriosus 3(3.75) - 3(7.5) Definitive pacing indications Nonsurgical CAVB 42(52.5) 22(55.0) 20(50.0) Surgical CAVB 38(47.5) 18(45.0) 20(50.0) Stimulation mode DDD/DDDR 9(11.3) 9(22.5) - VVI/VVIR 63(78.7) 23(57.5) 40(100) VDD/VDDR 8(10.0) 8(20.0) - Data are presented as the mean value ± SD or number (%) of patients. CAVB: complete atrioventricular block; DDD: dual chamber pacing and sensing; LV: left ventricular; RV: right ventricular; VDD: ventricular pacing with dual chamber sensing; VVI: ventricular pacing and sensing.

Arq Bras Cardiol. 2013;101(5):410-417 411 Cabrera Ortega et al. LV synchrony and function in paced children Original Article

Septal to posterior wall motion delay (SPWMD), (Table 2). SF in the RVP group was significantly lower than determined as the delay between peak systolic inward before pacing (32 ± 4.2 vs. 41 ± 2.6, p < 0.001) and was motion of the interventricular septum, and the left lower than that in the LVP group (32 ± 4.2 vs. 39 ± 5.2, posterior wall. p < 0.001). The LV EF was normal in children with LVP after LV mechanical delay, measured as the maximum long-term cardiac stimulation, but tended to worsen in the difference between the initial and last peak systolic 2D strain RVAP group (70 ± 6.9 vs. 64 ± 2.5, p < 0.001). A similar in any of the 12 LV segments. tendency has not been observed with LV diastolic function at any pacing site during follow-up (Table 3). Statistics All the echocardiographic parameters reflecting both interventricular and intraventricular dyssynchrony were Data are presented as mean ± standard deviation. affected in patients with RVAP (Table 4). Interventricular For analyzing the differences in continuous variables mechanical delay was significantly larger in the RVAP group between the RVA pacing (RVAP) group and LVP group, (66 ± 13 ms) than in the LVP group (20 ± 8 ms); similarly, t-tests were used. Correlations between variables were septal to lateral wall motion delay (RVP: 75 ± 19 ms; LVP: assessed using Pearson’s correlation (r value). Logistic 42 ± 10 ms, p < 0.0001) and SPWMD (RVAP: 127 ± 33 ms; regression was performed to determine the predictors of LVP: 58 ± 17 ms, p < 0.0001) were altered in patients impaired left ventricular function. Significance was accepted with receiving RVAP but not LVP. In addition, RVAP was at a p value of ≤0.05. The software package Medcalc for associated with global LV dyssynchrony, as evidenced by a Windows (Version 11.3) was used for statistical work up. prolonged LV mechanical delay (69 ± 6 ms) compared with LVP (30 ± 11 ms). Results Five patients developed dilated cardiomyopathy (6.3%). The clinical and echocardiographic data of these patients Patient characteristics are shown in Table 5. Three variables were identified as A total of 80 patients with a mean age of 12.5 ± 5.2 years significant predictors of LV dysfunction: RVAP [odds ratio were evaluated. The demographic data and clinical (OR) = 11.3, p < 0.001], septal to lateral wall mechanical characteristics of study are presented in Table 1. Pacing delay (OR = 12.1, p < 0.001), and septal to posterior indications were postsurgical CAVB (n = 38) and nonsurgical wall motion delay (OR = 11.6, p < 0.001). However, in CAVB (n = 42). In total, 57.5% patients had structural heart those patients receiving RVAP, there was no correlation 2 disease, with 79.2% having undergone surgical correction. between either EF and SPWMD (R = 0.283, p = 0.077) 2 Tetralogy of Fallot was the congenital cardiac disease with or EF and septal to lateral mechanical delay (R = −0.013, the highest rate of postoperative CAVB. Neither the mean p = 0.935) (Figure 1). No correlations were found between age at first implantation nor the duration of pacing showed late LV failure diagnosis, pacing mode, duration of significant differences between the two pacing groups. stimulation, presence of structural heart disease or other All patients with LVP received a single-chamber pacemaker, echocardiographic indices of dyssynchrony. whereas 23 children (57.5%) that were paced from the RVA received VVI/VVIR pacing. Discussion The main finding of our study is that RV apical pacing in Left ventricle: long-term size, function and synchrony. pediatric patients with or without structural heart disease At the end of the follow-up period, LVEDD in patients with produces LV remodeling and dyssynchrony. Moreover, the RVAP increased significantly over both the corresponding research confirms that LVP is a safe site of stimulation when baseline values (40 ± 6.0 vs. 32 ± 3.1, p < 0.001) and the seeking to prevent the dyssynchronous effect of chronic values of the LVP group (40 ± 6.0 vs. 35 ± 4.2, p < 0.001) cardiac pacing.

Table 2 – Evolution of left ventricular systolic function

RVA pacing LV pacing Parameter p value * p value ** p value *** p value **** Before PM implant Last follow-up Before PM implant Last follow-up LVEDD (mm) 32(3.1) 40(6.0) 33(3.6) 35(4.2) <0.001 0.024 0.187 <0.001 LV SF (%) 41(2.6) 32(4.2) 40(4.3) 39(5.2) <0.001 0.351 0.211 <0.001 LV EF (%) 70(6.9) 64(2.5) 70(6.8) 69(3.6) <0.001 0.413 1.000 <0.001

Data are presented as the mean ± SD. EF: ejection fraction; LV: left ventricular; LVEDD: left ventricular end-diastolic diameter; PM: pacemaker; RVA: right ventricular apex; SF: shortening fraction. * RVA pacing before vs. last follow-up. ** LV pacing before vs. last follow-up. *** RVA pacing before vs. LV pacing before. **** RVA pacing last follow-up vs. LV pacing last follow-up.

412 Arq Bras Cardiol. 2013;101(5):410-417 Cabrera Ortega et al. LV synchrony and function in paced children Original Article

Table 3 - Left ventricular diastolic function at last follow-up

Parameter RVAP LVP p LV IVRT (ms) 63(10.5) 65(8.7) 0.356 Ea (cm/s) 19(2.4) 18(3.6) 0.147 Aa (cm/s) 9(2.3) 10(3.1) 0.105 E/Ea 5.1(2.2) 5.3(1.5) 0.636 Data are presented as the mean ± SD. Aa: peak A wave by Doppler tissue imaging; Ea: peak E wave by Doppler tissue imaging; E/Ea: relation between peak E wave by transmitral Doppler flow and peak E by Doppler tissue imaging; LV IVRT: left ventricular isovolumic relaxation time; LVP: left ventricular pacing; RVAP: right ventricular apical pacing.

Table 4 – Echocardiographic measurements of LV synchrony for the study cohort

Parameter RVAP LVP p SPWMD (ms) 127(33) 58(17) <0.001 Septal to lateral wall motion delay (ms) 75(19) 42(10) <0.001 Interventricular mechanical delay (ms) 66(13) 20(8) <0.001 LV mechanical delay (ms) 69(6) 30(11) <0.001 Data are presented as the mean ± SD. LV: left ventricular; LVP: left ventricular pacing; SPWMD: septal to posterior wall motion delay; RVAP: right ventricular apical pacing.

Table 5 – Patients with dilated cardiomyopathy related to ventricular pacing

Age Structural Pacing period Pacing No. Diagnosis Pacing mode LVEDD (mm) LV EF (%) LV SF (%) (years) heart disease (years) site

1. 10 CAVB - 3.6 RV apex DDD 53 44.0 22.0 2. 8 Surgical CAVB VSD 6.2 RV apex VVI 48 48.7 24.5 3. 12 Surgical CAVB TOF 9.5 RV apex DDD 50 48.2 24.3 4. 6 CAVB - 2.8 RV apex VVI 44 52.0 26.5 5. 15 BAVT - 4,6 RV apex VDD 54 42.3 21.0 CAVB: complete atrioventricular block; DDD: dual chamber pacing and sensing; EF: ejection fraction; LV: left ventricle; LVEDD: left ventricular end-diastolic diameter; RV: right ventricle; SF: shortening fraction; TOF: tetralogy of Fallot; VDD: ventricular pacing with dual chamber sensing; VSD: ventricular septal defect; VVI: ventricular pacing and sensing.

Evolution of LV systolic and diastolic function in RV apical the low LV pressure, contraction of the early-activated pacing: myocardium is inefficient. Furthermore, against high LV Endomyocardial biopsies taken from the mid-RV septal pressures, a vigorous late-systolic contraction occurs in region in paced patients have detected histopathological regions with delay. This imposes loading on the earlier abnormalities. These consist of prominent subendocardial activated territories, which undergo paradoxical systolic 16 Purkinje cells with an increase in variable-sized, focal areas stretch . The abnormal contraction pattern of different of dystrophic calcification and myofibrillar disarray13. These regions of LV, results in a redistribution of myocardial strain, 15 findings are the result of stress vectors and myocardial and less effective contraction . Decreases in contractility shearing forces resulting from asynchrony of electrical and relaxation together with histological abnormalities lead ventricular activation, with early activation of myocytes to the detriment of left ventricular function. close to RVA, and delayed activation of cells in remote Clinical data about the deleterious effect of chronic RVP regions1. This heterogeneity in electrical activation of the in children remain controversial, with some researches myocardium is accompanied with changes in the mechanical supporting a negative impact13,17,18, whereas others have activation pattern of LV14. An animal study has demonstrated obtained conflicting results19, 20. The present study found a the presence of rapid early-systolic shortening in early- significant deleterious effect of RV apical pacing on systolic activated regions, with premature relaxation of these sites, LV function, with an incidence of 6.3% in patients with and prestretching of late-activated regions15. Because of dilated cardiomyophathy, which is concordant with previous

Arq Bras Cardiol. 2013;101(5):410-417 413 Cabrera Ortega et al. LV synchrony and function in paced children Original Article

data (6.0%–13.4%)2,5-8. RV apical pacing was a predictive of the diastolic filling parameters on radionuclide left factor for the deterioration of LV function [OR = 11.3, 95% ventriculography, such as time to peak filling rate and confidence interval (CI) = 2.1–63.8, p < 0.001]. Gebauer et negative rate of LV pressure rise in ventricular paced dogs21. al5 evaluated LV function in 82 pediatric patients with either Similarly, Aoyagi et al22, found a prolongation of the LV nonsurgical or postsurgical CAVB. In their research, the only isovolumic relaxation time (IVRT) that was dependent on significant risk factor for the development of LV dilatation the degree of wall motion asynchrony22. Although our and dysfunction was the presence of epicardial RV free data showed a detrimental effect on synchrony in the RVP wall pacing (OR = 14.3, 95% CI = 2.3–78.2, p < 0.001). group, the LV IVRT did not change during follow-up. In Therefore, although epicardial RV free wall stimulation may addition, Kolettis et al23 studied the acute hemodynamic induce more LV dyssynchrony, our findings suggest that status of 20 adult patients with dual-chamber sequential RVAP results in the same degree of asynchronous activation, pacing, determining increased IVRT to be a measure of LV abnormal contraction and decreased pump function. diastolic function deterioration23. Similarly, on the basis of The impact of RV apical stimulation on LV diastolic the hypothesis that RV impairment precedes LV dysfunction, function has not been extensively explored, even in pediatric Dwevedi et al24 found a significant increase in IVRT and populations. Previous research in animal models have deceleration time following 1 month of single-chamber RVP, demonstrated the deterioration of diastolic parameters21,22. which continued to increase progressively until 6 months24. Litwin et al21 for example found a significant alteration They confirm that LV diastolic and systolic functions are

Figure 1 - Correlation between EF and electromechanical delay variables in patient with RVA pacing. A) EF and SLMD. B) EF and SP. EF: ejection fraction, SLMD: septal to lateral mechanical delay, SPWMD: septal to posterior wall motion delay.

414 Arq Bras Cardiol. 2013;101(5):410-417 Cabrera Ortega et al. LV synchrony and function in paced children Original Article deranged in many conditions secondary to involvement of and patients with chronic RVP and LVP. In this study, the the right ventricle24. However, in our study, 57.5% patients RVP group also showed a decreased LV SF. Similarly, the presenting with congenital cardiovascular defects such as systolic LV eccentricity index, and the duration of posterior atrial septal defect, pulmonary stenosis, tetralogy of Fallot septal wall motion delay were significantly longer in this or double-outlet right ventricle, which are conditions that group than in the LVP or control groups10. In addition, improve RV function, diastolic dysfunction was absent and Gebauer et al31 evaluated LV synchrony and function in so was a correlation between the presence of structural 32 patients paced epicardially from the RV free wall, the heart disease and late LV failure. The contradiction with LV apex and the RVA; RV free wall pacing and SPWMD the findings of Dwevedi et al24 could possibly be explained were found to be negative predictors of LVEF31. Of note, because 47.5% of the study population had a corrected Tomaske et al9 showed that a decreased LV EF and greater congenital cardiac defect, and that we excluded patients LV dyssynchrony was associated with children receiving RV with clinical evidence of ventricular dysfunction. Results pacing9. In addition, a significant correlation was established and conclusions from pacing studies in adult patients cannot between decreased LVEF and the severity of mechanical be extrapolated to the pediatric population because of dyssynchrony measured by the septal-to-lateral wall delay differences in comorbid diseases and potential causes of and LV mechanical delay9. ventricular dyssynchrony. Clinical implications Left ventricular dyssynchrony: LVP vs. RVP Our data confirm the benefit of chronic LV pacing on LV We postulate that the sequence of activation is a synchrony and function. The results of our study support the major determinant of cardiac pump function, as previous view that epicardial LVP is the optimal pacing site in pediatric researches have shown25,26. Stimulation from the LV free wall populations; observations in small cohorts support the use induces a prior activation of the LV lateral wall, preventing of an LV pacing site when chronic pacing is indicated in 9,10,31 paradoxical movement of the septum, and resulting in a children . It has also been demonstrated that LV lateral better hemodynamic response when compared with RV wall pacing can be as effective as biventricular pacing in 32,33 pacing27. Moreover, a physiological apex-to-base sequence patients with congestive heart failure . For example, Vanagt is induced, producing a synchronous electrical activation et al. reported the case of a 2-year-old girl with congenital and contraction at the LV circumferential level28. CAVB and heart failure induced by RVP, who recovered LV function following LV apical pacing34. Furthermore, in It has been confirmed in studies in both animals and children with LV dysfunction and dyssynchrony caused by children that LV pumping function approximating to that long-term RVP, small case series have shown improvements of normal ventricular conduction results from pacing at the in function 1 month after single-site LVP11. inferoapical LV septum and the epicardium of LV apex28-30. Alternative sites for pacing have also been investigated35-40. The resultant synchronous contraction is predominantly His-bundle pacing induces a normal physiological sequence because of quick engagement of the impulse into the of activation, and therefore prevents dyssynchrony and LV endocardial layers, and subsequent fast apex-to-base the deleterious effects on LV function35,36; however the conduction along all wall segments of LV30. Mills et al30, anatomical characteristics of this region make this a in their research in dogs with experimental complete AV challenging procedure that could be difficult in a pediatric block, demonstrated that LV apical pacing can produce a population. Alternatively, the RV outflow has been moderate electrical dyssynchrony with normal levels of proposed37,38, although the results are controversial39,40, and myocardial efficiency, contractility and relaxation after 4 30 do not support stimulation from this site in children. In our months of LVP . institution, we advocate the implantation of LV epicardial In our study, indices of dyssynchrony such as septal-to- leads via a left lateral thoracotomy, resulting in stable lateral wall motion delay and SPWMD were identified as thresholds as well as good cosmetic results. predictors of LV dysfunction. This finding demonstrated, once again, the consequences of impairment of normal Study limitations ventricular activation. Apical RVP produces early activation of the RV wall, followed by that of the LV septum and then Because of a lack of diastolic evaluation prior the first implantation, we could not compare the DTI measurement the LV lateral wall30. Early activation of the basal septum before and after permanent pacing; nevertheless, the results induces segmental contraction that is unopposed by the at the last follow-up showed a preserved diastolic function delayed activation of the remaining LV myocardium, which using the DTI echocardiographic method. leads to systolic septal bulging9. Long activation times around the LV circumference (29–49 ms) during RV apical pacing, produces abnormal distribution of mechanical Conclusions work and blood flow, mechanical dyssynchrony, and Chronic RVP was associated with LV remodeling, incoordination of contraction; there is then a consequential dyssynchrony, and systolic dysfunction in our pediatric negative impact on contractility, relaxation, and external population. This is consistent with previous findings. Because 30 efficiency . of the benefits of chronic LV pacing, we believe that it should Research by van Geldorp et al10, compared the be proposed as the optimal site when permanent cardiac ventricular function and synchrony in 18 healthy children stimulation is required in children.

Arq Bras Cardiol. 2013;101(5):410-417 415 Cabrera Ortega et al. LV synchrony and function in paced children Original Article

Author contributions Sources of Funding Conception and design of the research: Ortega MC, There were no external funding sources for this study. Ricardo GS; Acquisition of data, Analysis and interpretation of the data, Statistical analysis and Critical revision of the Study Association manuscript for intellectual content: Ortega MC, Morejón AEG, Ricardo GS; Writing of the manuscript: Ortega MC. This article is part of the thesis of doctoral submitted by Michel Cabrera Ortega, from Cardiocentro Pediátrico ¨William Soler”. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported.

References

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Risk of Ionizing Radiation in Women of Childbearing Age undergoing Radiofrequency Ablation Gustavo Glotz de Lima, Daniel Garcia Gomes, Caroline Saltz Gensas, Mariana Fernandez Simão, Matheus N. Rios, Leonardo Martins Pires, Marcelo Lapa Kruse, Tiago Luiz Luz Leiria Instituto de Cardiologia, Fundação Universitária de Cardiologia, Porto Alegre, RS - Brazil

Abstract Background: The International Commission of Radiology recommends a pregnancy screening test to all female patients of childbearing age who will undergo a radiological study. Radiation is known to be teratogenic and its effect is cumulative. The teratogenic potential starts at doses close to those used during these procedures. The prevalence of positive pregnancy tests in patients undergoing electrophysiological studies and/or catheter ablation in our midst is unknown. Objective: To evaluate the prevalence of positive pregnancy tests in female patients referred for electrophysiological study and/or radiofrequency ablation. Methods: Cross-sectional study analyzing 2,966 patients undergoing electrophysiological study and/or catheter ablation, from June 1997 to February 2013, in the Institute of Cardiology of Rio Grande do Sul. A total of 1490 procedures were performed in women, of whom 769 were of childbearing age. All patients were screened with a pregnancy test on the day before the procedure. Results: Three patients tested positive, and were therefore unable to undergo the procedure. The prevalence observed was 3.9 cases per 1,000 women of childbearing age. Conclusion: Because of their safety and low cost, pregnancy screening tests are indicated for all women of childbearing age undergoing radiological studies, since the degree of ionizing radiation needed for these procedures is very close to the threshold for teratogenicity, especially in the first trimester, when the signs of pregnancy are not evident. (Arq Bras Cardiol. 2013;101(5):418-422) Keywords: Radiation, Ionizing; Women; Fertile Period; Risk Assessment; Catheter Ablation.

Introduction of gestation (Table 1)3. However, it is very difficult and An electrophysiological study (EPS) is an invasive inaccurate to quantify the fetal exposure to radiation, because procedure used for the diagnosis of disturbances in the of the dynamic characteristics of the test, the intermittent rhythm and electrical conduction of the heart. It can be used use of radiation, the different X-ray tube positions, device calibration, and fetal position. Due to this variability, it is to measure atrioventricular conduction intervals, to elucidate not possible to determinate the exact amount of exposure, arrhythmogenic mechanisms, and to evaluate the efficacy which is estimated by anatomical‑mathematical models and of antiarrhythmic agents. It is currently also used to locate in experimental animals (Table 2)4. and map reentrant circuits and ectopic sources in detail, for further treatment with catheter ablation. Thus, it has a Brazilian guidelines and those of the American Heart diagnostic, therapeutic, and prognostic purpose1. Association do not recommend the use of the beta-HCG test in the screening of women of childbearing age undergoing Since the 1970’s, catheters have been positioned in electrophysiological procedures5-7. cardiac chambers by means of fluoroscopy with X-ray emmission2. However, it is known that the exposure of a In the present study, we evaluated the number of female pregnant woman to this radiation can have consequences patients referred for EPS and/or radiofrequency ablation who to the fetus, especially between the 8th and 15th weeks tested positive for a pre-procedural beta-HCG test.

Methods

Mailing Address: Gustavo Glotz de Lima • Cross-sectional study analyzing information from patients Avenida Princesa Isabel, 370, Santana. Postal Code 90620-000, Porto Alegre, undergoing EPS and/or radiofrequency catheter ablation RS – Brazil in the Electrophysiology Laboratory of the Institute of E-mail: [email protected] Cardiology of Rio Grande do Sul, between June 1997 and Manuscript received March 13, 2013; revised manuscript May 24, 2013; accepted June 03, 2013. February 2013. All women of childbearing age underwent the pregnancy test (serum beta-HCG) on the day before DOI: 10.5935/abc.20130192 the procedure.

418 Lima et al. Risk of radiation in women undergoing ablation Original Article

Table 1 - Estimated radiation exposure during imaging tests, based on chest radiography multiples in the anteroposterior (AP) view

Test Dose (mSv) Chest radiography multiples (AP view) Chest radiography AP 0.02 1 Chest radiography in AP and lateral 0.10 5 Invasive diagnostic coronary angiography 7 350 Percutaneous coronary intervention 15 750 Radiofrequency ablation 15 750 Modified Einstein15.

Table 2 - Estimated radiation dose in the fetus during ionizing radiation procedures8-13

Test Estimate (mGy) Range (mGy) References Catheter ablation (1st. trimester) 0.15 0.04-0.20 8.9 Catheter ablation (2nd. trimester) 0.3 9 Catheter ablation (3rd trimester) 0.6 9 Chest angiography for PTE (1st. trimester) 0.02 0.006-0.05 10 Aortic angiography 34 11 Abdominal CT scan (routine) 10 4-60 11, 12, 13 Cerebral angiography 0.06 8 PTE: pulmonary thromboembolism; CT: computed tomography.

The study was approved by the Research Ethics Since the cost of a beta-HCG test in the Single Health System Committee of the Institute of Cardiology of Rio Grande do is of approximately R$ 7.00, we can estimate that approximately Sul/ University Foundation of Cardiology. The database and R$ 1794.00 were necessary to prevent fetal radiation exposure statistical calculations were carried out using the MedCalc® during ablation procedures in their mothers. V.7.3 software program. Categorical variables were expressed Table 3 shows the procedures performed by the Laboratory as absolute numbers and percentages. Continuous variables of Electrophysiology of the Institute of Cardiology of Rio were expressed as mean ± standard deviation. Grande do Sul.

Results Discussion From an initial sample of 2,966 patients, 1,490 were Exposure to ionizing radiation during diagnostic and females, of whom 769 were of childbearing age (10 to 50 therapeutic procedures has dramatically increased in the years, according to the World Health Organization). past years. The mean age of the women undergoing a pregnancy Fetuses are susceptible to teratogenic effects through screening test was 33.6 ± 11.3 years, and the mean time of the complete prenatal period, and are more vulnerable fluoroscopy during ablation was 10.8 ± 9 minutes. in the first trimester of pregnancy. These effects depend A total of 556 ablations and 213 electrophysiological on several variables, including the gestational age, fetal studies were performed in women of childbearing age. mechanisms of cell repair, and level of absorption of the The procedures had been indicated for the investigation of radiation dose. supraventricular tachycardia in most of the cases; 236 cases There is no evidence that a radiation dose lower than of nodal reentry tachycardia and 203 cases of atrioventricular 0.10 Gy is related to severe complications for the fetus14. reentry tachycardia were diagnosed. Specific effects, such as growth restriction, prenatal death, Of the 769 women of childbearing age referred for organ malformation, and intelligence impairment, are related catheter ablation, three had their procedures suspended to doses higher than 0.10-0.20 Gy15-24. because they tested positive for beta-HCG and were In the first weeks of gestation, the secondary effect of in the beginning of pregnancy, which was unknown to radiation may be the induction of abortion8,16-18, which them until the test was performed. Thus, a prevalence of usually results from doses higher than 1 Gy. After 4 weeks, 3.9 cases per 1000 women of childbearing age referred for there may be the risk of organ malformation and overall electrophysiological study was observed. growth retardation.

Arq Bras Cardiol. 2013;101(5):418-422 419 Lima et al. Risk of radiation in women undergoing ablation Original Article

Table 3 - Number of tests performed by gender Despite the ANVISA recommendations, the national guidelines still do not recommend the performance of beta‑HCG Tests performed test in the screening of female patients of childbearing age 6,7 Men 1,476 undergoing EPS and radiofrequency ablation . Women 1,490 Women of childbearing age 769 Limitations Total 2,966 The radiological exposure of each patient in different body positions was not assessed, since the dosimeter is positioned next to the procedure table. This information would permit a more precise quantification of the fetal Deleterious effects on the central nervous system are exposure to radiation. more evident in exposures during the period between the The real cost-effectiveness analysis was not carried out 8th and 15th week of gestation, from the threshold dose of prospectively and thus only an approximate estimate is approximately 0.30 Gy. available. Additionally, the risks considered are those of In relation to the carcinogenic potential, this is present maternal exposure to radiation and not of fetal malformation. both in fetal exposure in the first trimester and in the other 25,26 trimesters . The risk of a fatal cancer is of approximately Conclusion 5 to 15% per Gy8, and the risk of inherited genetic effects is of approximately 0.2 to 1% per Gy25. Calkins et al27 We demonstrated that the risk of exposure to ionizing estimated that the risk of fatal malignancy is of 1 for every radiation of women of childbearing age referred for 1000 patients per hour of fluoroscopy. radiofrequency ablation is significant. The amount of radiation necessary in these procedures is not negligible, especially However, resolution 453 of the National Agency of in the first trimester, when the signs of pregnancy are not Sanitary Surveillance (Agência Nacional de Vigilância Sanitária evident. The real cost-effectiveness analysis could not be – ANVISA) recommends that the dose on the abdominal carried out, but we propose that the pregnancy screening be surface does not exceed 2 mSv during all pregnancy, thus incorporated to the national guidelines and to the routine of making it unlikely that the additional dose on the embryo or electrophysiology laboratories prior to the performance of fetus exceeds approximately 1 mSv in this period28. elective procedures that require fluoroscopy. Currently, a growing interest and concern regarding protective measures and the least possible exposure to Author contributions radioactive effects have been observed. It is believed that new technologies such as electroanatomical mapping and Conception and design of the research and Critical revision intracardiac three-dimensional echocardiography, which of the manuscript for intellectual content: Lima GG, Gomes eliminate the use of radiation, could be used in these DG, Gensas CS, Simão MF, Rios MN, Kruse ML, Leiria TLL, procedures and that they will be introduced gradually2. Pires LM; Acquisition of data: Lima GG, Gomes DG, Gensas CS, Simão MF, Rios MN, Kruse ML, Pires LM; Analysis and In the present study, we observed that half of the women interpretation of the data: Lima GG, Gomes DG, Gensas CS, referred to our service were of childbearing age. Three cases Simão MF, Rios MN; Statistical analysis: Lima GG, Gomes DG, of pregnancy were detected among 769 female patients of Leiria TLL; Writing of the manuscript: Lima GG, Gomes DG, childbearing age. The estimated additional cost for this detection Gensas CS, Simão MF, Rios MN, Leiria TLL, Pires LM. was of approximately R$ 5383.00. These preliminary data raise the discussion about the cost-effectiveness analysis of the measure. This information is important when we compare the Potential Conflict of Interest risks attributed to the use of medications for the treatment of No potential conflict of interest relevant to this article was arrhythmias, such as amiodarone and verapamil, which are reported. known to be potentially teratogenic. Additionally, the screening enables the prevention of radiation exposure and guidance Sources of Funding on the decision-making about the drug therapy. Data in the There were no external funding sources for this study. literature on the cost-effectiveness of performing a beta-HCG test to prevent possible fetal malformations are unknown. The teratogenic effect of radiation in the gestational period Study Association is well established, although few data are available in relation This study is not associated with any post-graduation to exposure during EPS and/or catheter ablation. program.

420 Arq Bras Cardiol. 2013;101(5):418-422 Lima et al. Risk of radiation in women undergoing ablation Original Article

References

1. Gensas CS, Pires LM, Kruse ML, Leiria TL, Gomes DG, Lima GG. Agenesia Force; European Society of Cardiology Committee for Practice Guidelines; da veia cava inferior. Rev Bras Cardiol Invasiva. 2012;20(4):427-30. European Heart Rhythm Association and the Heart Rhythm Society. ACC/ AHA/ESC 2006 guidelines for management of patients with ventricular 2. Pires LM, Leiria TL, Mantovani A, Kruse ML, Ronsoni R, Gensas CS, et arrhythmias and the prevention of sudden cardiac death--executive al. Initial experience of catheter ablation without the use of fluoroscopy. summary: a report of the American College of Cardiology/American Heart Relampa. 2012;25(4):267-72. Association Task Force and the European Society of Cardiology Committee 3. Shaw P, Duncan A, Vouyouka A, Ozsvath K. Radiation exposure and for Practice Guidelines (Writing Committee to Develop Guidelines for pregnancy. J Vasc Surg. 2011;53(1 Suppl):28S-34S. Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European 4. Dauer LT, Thornton RH, Miller DL, Damilakis J, Dixon RG, Marx MV, et Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J. al; Society of Interventional Radiology Safety and Health Committee; 2006;27(17):2099-140. Cardiovascular and Interventional Radiology Society of Europe Standards of Practice Committee. Radiation management for interventions using 15. Einstein AJ. Effects of radiation exposure from cardiac imaging: how good fluoroscopic or computed tomographic guidance during pregnancy: a joint are the data? J Am Coll Cardiol. 2012;59(6):553-65. guideline of the Society of Interventional Radiology and the Cardiovascular 16. Jankowski CB. Radiation and pregnancy: putting the risks in proportion. Am and Interventional Radiological Society of Europe with Endorsement by J Nurs. 1986;86(3):260-5. the Canadian Interventional Radiology Association. J Vasc Interv Radiol. 2012;23(1):19-32. 17. Einstein AJ, Moser KW, Thompson RC, Cerqueira MD, Henzlova MJ. Radiation dose to patients from cardiac diagnostic imaging. Circulation. 5. Buxton AE, Calkins H, Callans DJ, DiMarco JP, Fisher JD, Greene HL, et 2007;116(11):1290-305. al; American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing Committee 18. De Santis M, Di Gianantonio E, Straface G, Cavaliere AF, Caruso A, Schiavon to Develop Data Standards on Electrophysiology). ACC/AHA/HRS 2006 F, et al. Ionizing radiations in pregnancy and teratogenesis: a review of key data elements and definitions for electrophysiological studies and literature. Reprod Toxicol. 2005;20(3):323-9. procedures: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing 19. International Commission on Radiological Protection. Pregnancy and Committee to Develop Data Standards on Electrophysiology). Circulation. medical radiation. Ann ICRP. 2000;30(1):iii-viii,1-43. 2006;114(23);2534-70. 20. Wieseler KM, Bhargava P, Kanal KM, Vaidya S, Stewart BK, Dighe MK. 6. Sosa EA, de Paola A, Gizzi J, Rassi S, Scanavacca M, Pérez A, et al. Indicações Imaging in pregnant patients: examination appropriateness. Radiographics. para estudo eletrofisiológicos e ablação por cateter de arritmias cardíacas. 2010;30(5):1215-29. Recomendações da DAEC da SBC. Arq Bras Cardiol. 1995;64(2):149-51. 21. Streffer C, Shore R, Konermann G, Meadows A, Uma Devi P, Preston Withers 7. Lorga A, Lorga Filho A, D’Ávila A, Rassi A Jr, Paola AV, Pedrosa A, et al; J, et al. Biological effects after prenatal irradiation (embryo and fetus). A Sociedade Brasileira de Cardiologia. Diretrizes para avaliação e tratamento report of the International Commission on Radiological Protection. Ann de pacientes com arritmias cardíacas. Arq Bras Cardiol. 2002;79(supl.5):1-50. ICRP. 2003;33(1-2):5-206.

8. Stabin MG, Blackwell R, Brent RL, Donnelly E, King VA, Lovins K, et al. Fetal 22. American College of Radiology (ACR). Practice Guideline for imaging radiation dose calculations. ANSI N13.54-2008. Washington, DC: American pregnant or potentially pregnant adolescents and women with ionizing National Standards Institute; 2008. radiation. Reston, VA; 2008.

9. Damilakis J, Theocharopoulos N, Perisinakis K, Manios E, Dimitriou P, Vardas 23. Timins JK. Radiation during pregnancy. N J Med. 2001;98(6):29-33. P, et al. Conceptus radiation dose and risk from cardiac catheter ablation 24. Miller RW. Discussion: severe mental retardation and cancer among atomic procedures. Circulation. 2001;104(8):893-7. bomb survivors exposed in utero. Teratology. 1999;59(4):234-5. 10. Winer-Muram HT, Boone JM, Brown HL, Jennings SG, Mabie WC, 25. Otake M, Schull WJ, Lee S. Threshold for radiation-related severe mental Lombardo GT. Pulmonary embolism in pregnant patients: fetal radiation retardation in prenatally exposed A-bomb survivors: a re-analysis. Int J Radiat dose with helical CT. Radiology. 2002;224(2):487-92. Biol. 1996;70(6):755-63. 11. McCollough CH, Schueler BA, Atwell TD, Braun NN, Regner DM, Brown DL, 26. The 2007 Recommendations of the International Commission on Radiological et al. Radiation exposure and pregnancy: when should we be concerned? Protection. ICRP publication 103. Ann ICRP. 2007;37(2‑4):1-332. Radiographics. 2007;27(4):909-17. 27. Calkins H, Niklason L, Sousa J, el-Atassi R, Langberg J, Morady F. 12. Wagner LK, Lester RG, Saldana LR. Exposure of the pregnant patient to Radiation exposure during radiofrequency catheter ablation of accessory diagnostic radiations: a guide to medical management, 2nd ed. Madison, atrioventricular connections. Circulation. 1991;84(6):2376-82. WI: Medical Physics Publishing; 1997. 28. Ministério da Saúde. Agencia Nacional de Vigilância Sanitária. Portaria 13. Hurwitz LM, Yoshizumi T, Reiman RE, Goodman PC, Paulson EK, Frush DP, SVS nº 453, de 1º de junho de 1998: aprova o regulamento técnico que et al. Radiation dose to the fetus from body MDCT during early gestation. estabelece as diretrizes básicas de proteção radiológica em radiodiagnóstico AJR Am J Roentgenol. 2006;186(3):871-6. médico e odontológico, dispõe sobre o uso dos raios-x diagnósticos em todo 14. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, território nacional e dá outras providências. Diário Oficial da União; Brasília; et al; American College of Cardiology/American Heart Association Task 2 de junho; 1998.

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422 Arq Bras Cardiol. 2013;101(5):418-422 Original Article

Analysis of the Sensitivity and Specificity of Noninvasive Imaging Tests for the Diagnosis of Renal Artery Stenosis Flavio Antonio de Oliveira Borelli, Ibraim M. F. Pinto, Celso Amodeo, Paola E. P. Smanio, Antonio M. Kambara, Ana Claudia G. Petisco, Samuel M. Moreira, Ricardo Calil Paiva, Hugo Belotti Lopes, Amanda G. M. R. Sousa

Instituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil

Abstract Background: Aging and atherosclerosis are related to renovascular hypertension in elderly individuals. Regardless of comorbidities, renal artery stenosis is itself an important cause of cardiovascular morbidity and mortality. Objective: To define the sensitivity, specificity, positive predictive value, and negative predictive value of noninvasive imaging tests used in the diagnosis of renal artery stenosis. Methods: In a group of 61 patients recruited, 122 arteries were analized, thus permitting the definition of sensitivity, specificity, and the relative contribution of each imaging study performed (Doppler, scintigraphy and computed tomographic angiography in comparison to renal arteriography). Results: The mean age was 65.43 years (standard deviation: 8.7). Of the variables related to the study population that were compared to arteriography, two correlated with renal artery stenosis, renal dysfunction and triglycerides. The median glomerular filtration rate was 52.8 mL/min/m2. Doppler showed sensitivity of 82.90%, specificity of 70%, a positive predictive value of 85% and negative predictive value of 66.70%. For tomography, sensitivity was 66.70%, specificity 80%, positive predictive value 87.50% and negative predictive value 55.20%. With these findings, we could identify the imaging tests that best detected stenosis. Conclusion: Tomography and Doppler showed good quality and efficacy in the diagnosis of renal artery stenosis, with Doppler having the advantage of not requiring the use of contrast medium for the assessment of a disease that is common in diabetics and is associated with renal dysfunction and severe left ventricular dysfunction. (Arq Bras Cardiol. 2013;101(5):423-433) Keywords: Renal Artery Obstruction / diagnosis; Doppler, Echocardiography; Renal Artery Obstruction / radionuclide imaging; Magnetic Resonance Imaging; Hypertension, Renovascular.

Introduction The identification of a causal relation between arterial stenoses Arterial Hypertension (AH) is a public health problem. and AH has the additional advantage that revascularization Its relation to other diseases such as diabetes mellitus procedures may be decisive for blood pressure control. (DM), heart failure (HF), chronic kidney disease (CKD), No study on the assessment of the sensitivity, specificity, and peripheral obstructive arterial disease (POAD) modifies and positive and negative predictive values of imaging tests for the cardiovascular morbidity and mortality1-3. The growing the diagnosis of renal artery stenosis in the same population is incidence of atherosclerosis in the adult population, the available in the Portuguese language. In a search conducted at presence of arterial obstruction leading to reduced renal the electronic address www.ncbi.nlm.nih.gov, the comparative blood flow and subsequent renovascular hypertension have analysis between diagnostic methods for renal artery stenosis aroused great interest for studies to be conducted in this field. (RAS) was found in few studies published recently4,5. Doppler, renal scintigraphy and computed tomography of the renal arteries were the imaging tests performed and Mailing Address: Flavio Antonio de Oliveira Borelli • compared with the reference standard, i.e, digital renal Alameda dos Jurupis, 410, apto. 111, Indianópolis. Postal Code 04088-001, arteriography. The renin test and magnetic resonance São Paulo, SP - Brazil E-mail: [email protected], [email protected] angiography were also part of the study. However, due to Manuscript received August 11, 2012; revised manuscript November 30, the poor reproducibility of the renin test to predict RAS and 2012; accepted March 14, 2013. because magnetic resonance angiography results were very similar to those of tomography, these two diagnostic methods DOI: 10.5935/abc.20130191 were excluded4-7.

423 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Objective hypotension during treatment with angiotensin converting To define the sensitivity, specificity, positive and negative enzyme inhibitors; refractory or malignant AH with progressive renal failure; elevation of serum creatinine with the use of predictive values of each of the noninvasive imaging tests. angiotensin enzyme inhibitors; asymmetry of renal size or To evaluate if there is a relation between risk factors function; agreement to participate in the study; giving written for atherosclerotic disease and the presence of significant informed consent. obstructions detected on invasive angiography of the renal arteries. Exclusion criteria The exclusion criteria were: history of allergic reaction Methods to iodinated contrast medium; women of childbearing age Prospective cohort study including 61 patients recruited without a negative pregnancy test; inability or refusal to between January 2008 and August 2011. Participants were understand the study and give written informed consent; duly registered and being followed up in our institution. estimated calculation of glomerular filtration lower than The study was approved by the Institutional Research Ethics 30 mL/min/m2; patients with congestive heart failure (CHF); Committee, under number 3592. patients with coagulation disorders; patients with left All volunteers were informed about the nature of the ventricular dysfunction (ejection fraction < 40%); recent study and gave written informed consent. Then, invasive and myocardial infarction (within the 6 months prior to the noninvasive diagnostic tests were performed to determine the beginning of the study); acute coronary syndromes, recent presence or absence or RAS. stroke (within the 6 months prior to the beginning of the study). The flowchart containing the sequence of procedures performed was equally followed for all participants. Diagnostic tests The first stage encompassed history taking, clinical Laboratory tests examination and blood pressure measurement, according to All patients were tested for the following laboratory tests: the standardization of the VI Brazilian Guidelines on Arterial fasting blood glucose, uric acid, sodium and potassium, Hypertension8. Then, the medication used was recorded, and BUN and creatinine, complete blood count, thyroid the patient received additional advice on how to correctly use stimulating hormone (TSH), and lipid profile. Creatinine the antihypertensive drugs. Patients using drugs that could clearance, which was important for the assessment of renal interfere with the renin-angiotensin-aldosterone axis had function impairment and for decision making in other stages these medications replaced by another class, without affecting of the study, was estimated using the Cockcroft Gault formula blood pressure control, with the objective of maintaining their adjusted for body surface and corrected for gender11. blood pressure levels equal to or lower than 140 x 90 mmHg. Diabetic patients on metformin had the medication Noninvasive imaging tests discontinued for at least 48 hours prior to any procedure using Renal artery Doppler iodinated contrast medium. The medication was resumed 72 hours after the use of the iodinated contrast medium, due to A Toshiba high-resolution device with a convex the possibility of renal function impairment9. multi-frequency transducer (3 to 5 MHZ) was used. Images were stored in VHS and included measurements for the Only patients with AH and clinically suspected renovascular detection of renal artery stenosis both direct and indirectly. disease of atherosclerotic etiology who used antihypertensive The origin of both renal arteries was assessed from a cross- medication at the moment of patient selection were included, sectional view of the aorta, in B mode and with color flow, regardless of age, gender, race, religion, socioeconomic seeking to visualize the longest possible extent of the vessel, condition, cardiovascular diseases or other comorbidities, the presence of turbulence and flow abnormalities, observing provided that they met the inclusion criteria but not the the relationship between the systolic and diastolic velocity exclusion criteria. We selected only cases presenting with curves, and the calculation of the renal-aortic ratio (RAR). at least two indicators of a medium or high probability as From this calculation, we were able to define whether the 10 proposed by Pickering (Table 1). Later, all patients underwent arteries were free from stenosis, and to verify the presence the tests selected for the present study. of cases with stenoses affecting more or less than 60% of the vessel diameter, according to criteria described in Table 212. Inclusion criteria The imaging study of the renal arteries was complemented The inclusion criteria were: age between 18 and 80 by the indirect analysis carried out with the patient in the years; clinical picture consistent with atherosclerosis; patients left lateral position and right lateral position. From these with AH (whether controlled or not); stages 2, 3 or resistant recordings, the longitudinal diameter of the kidneys was hypertension; onset of hypertension before 30 years of compared. These images also permitted a better exploration age or after 50 years of age; presence of abdominal or of the distal portion of the renal arteries in which the intrarenal lumbar murmurs; evident atheromatous disease in coronary blood flow was evaluated using Doppler in the segmental or arteries, carotid arteries or peripheral vessels; smokers; pulse interlobar arteries, in three different segments (upper, mid- asymmetry; renal failure not related to other causes; acute and lower); and the acquisition of velocity curves (systolic pulmonary edema with no apparent cause; significant arterial and diastolic) with the objective of analyzing the resistance

Arq Bras Cardiol. 2013;101(5):423-433 424 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Table 1 - Clinical indicators of the probability of renovascular hypertension and investigation proposal

Probability Características clínicas Low Borderline hypertension (0.2%) Non-complicated mild/moderate hypertension

Severe or refractory hypertension Recent onset hypertension below 30 years or above 50 years Presence of abdominal or lumbar murmurs Moderate Radial or carotid pulse asymmetry (5-15%) Moderate hypertension, smokers, or atherosclerosis in other sites (coronary or carotid artery) Undefined renal function deficit Excessive pressure response to ACEI

Severe or refractory hypertension with progressive renal failureHipertensão acelerada ou maligna Alta Accelerated or malignant hypertension (25%) Creatinine increase induced by ACEI* Asymmetric renal size or function ACEI: angiotensin converting enzyme inhibitor.

index (RI), considering that normal values range from 0.56 and When necessary, mapping was repeated after intravenous 0.7, and normal values for the flow acceleration time (AT) injection of furosemide 40 mg, 20 minutes after the when shorter than 70 ms. Tc-99m DTPA injection. Interpretation of the imaging test included the recording Tc-99m DTPA renal scintigraphy of the radiotracer transit time from the abdominal aorta to the kidneys, considering a normal value of up to 6 seconds. Scintigraphic assessments were made using a Millennium Another parameter analyzed was the tracer accumulation VG gamma camera (GE Medical Systems, Milwaukee, USA). time in the kidneys, which reflects the glomerular filtration Angiotensin inhibitors and/or angiotensin II-receptor rate, whose normal value is usually between 3 and 5 minutes, blockers were discontinued for three days prior to the test. followed by the excretion phase which in general lasts For the baseline acquisition of the radioisotope renogram, 20 to 30 minutes. the patients were placed in the supine position, so as to place the gamma-camera next to the kidneys and in direct relation to these organs. An intravenous access large enough to support Computed tomographic angiography of the kidneys and a 7-Gauge or larger needle was established. After proper renal arteries camera calibration, the radiotracer at a dose of 150 uCi/kg The Aquilion® 64 multiple-detector tomographer (Toshiba was injected in bolus until a maximum volume of 1 mL was Medical Systems, Ottawara, Japan) was used in this study. reached. From this moment on, image recording was started. Image acquisition of the arteries started by puncture of a After this initial acquisition, data started to be obtained peripheral vein large enough to permit the administration of using an angiotensin II converting enzyme inhibitor. In the iodinated contrast medium at a rate of at least 3 mL/s. this phase, the administration of technetium-99-labeled Thus, the acquisition of tomographic data was started by the diethylenetriaminepentaacetic acid 150 uCi/kg was repeated record of a single localizer to identify the positioning of the up to the maximum volume of 1 mL. Sixty minutes prior to this segment to be studied. After the specific area of interest to phase, the patients received a Captopril pill at a dose of 50 mg be documented was defined, images were obtained using the and had their blood pressure monitored. The gamma-camera injection of the contrast medium at a dose of 1.50 mL/kg of remained in the same position as in the previous phase, and body weight at a rate of at least 3.50 mL/s. The programming the same intravenous access and technique for radiotracer included the use of 1-mm collimation, with a tube rotation administration were used. time of 500 ms and table speed of 1.50 mm per tube rotation. During image recording, the patients were asked to perform a breath-hold, so as to limit the amount of artifacts resulting from the respiratory movements. Table 2 - Criteria for the identification of the degree of stenosis In order to obtain the volumetric representation of the Degree of stenosis SVP in main renal artery RAR morphology of the kidneys and renal arteries, the increment between anatomical sections, i.e., the distance from one image Normal < 180 cm/s < 3,5 to the next was shorter than the thickness of the cross-sectional < 60% ≥ 180 cm/s < 3,5 views obtained. After acquisition, data were transferred to a > 60% ≥ 180 cm/s ≥ 3,5 work station (Vitrea, Vital Images, California, USA), in which Occlusion Absence of flow Absence of sign the post-processing was carried out, thus permitting the reconstruction of the patient’s anatomy in different planes. SVP: systolic velocity peak; RAR: renal aortic ratio. Semi-objective measurement algorithms were used to measure

425 Arq Bras Cardiol. 2013;101(5):423-433 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article the reference diameters and minimum lumen diameter which, Information regarding sensitivity and specificity, positive in turn, could allow the diagnosis of the presence of stenoses and negative predictive values are presented. and, in positive cases, the estimate of their severity. The agreement level between two diagnostic methods and digital arteriography was analyzed using the Kappa method. Invasive imaging tests Positive values of the diagnostic tests should occur when The gold-standard chosen in this study was the invasive the stenosis diameter was > 60%. assessment of the anatomy of the renal arteries using The significance level of the tests was set at 5%. angiography. Since the vessels are more effectively assessed The analyses were carried out using the Statistical Package by contrasting the target arteries, an iodinated contrast for the Social Sciences (SPSS) 19.0 (SPSS Inc., Chicago IL, medium was used. Because of this procedure, saline 2004) software program. solution was administered before and after the test when renal dysfunction, as characterized by a creatinine clearance between 90 mL/min/1.73m2 and 30 mL/min/1.73m2, was Results present. Saline solution was administered at a dose of 10 Between January 2008 and August 2011, 63 individuals mL/kg of body weight before and after image acquisition, at were recruited. Of these, 61 underwent all tests, except a rate that varied according to the patients’ clinical status and for one patient who did not undergo DTPA radioisotope ventricular function. renogram. Thirty three patients were women; the mean age was 65.43 (± 8.7) years, the mean weight was 71.45 (± 11.83) Digital renal arteriography kg and the mean height was 1.59 (± 0.97) m. Approximately half of the study population had DM and several patients Renal arteriography was performed by the Section of had clinical manifestations of atherosclerosis; however, Interventionist Radiology, using an Axiom Artis 2005 digital the number of participants with smoking habit and POAD angiography equipment (Siemens, Germany), with flat detector was not significant. Patient demographics and their clinical for cardiovascular diagnosis. The procedure started by positioning characteristics are shown in Table 3. the patient in the supine position in the digital hemodynamic laboratory; puncture of the femoral artery after local anesthesia Lipid profile abnormalities were found in more than one with 2% lidocaine without vasoconstrictor was then performed. third of cases. Renal function, as assessed using the adjusted Next, a 5F valved introducer was advanced inside the right Cockcroft Gault formula, showed renal dysfunction in most femoral artery; within which a 0.35 guide wire was introduced; of the cases. a high-flow pigtail catheter was then advanced over the guide The noninvasive imaging tests revealed abnormalities wire. It was used to opacify the abdominal aorta. Then, the suggestive of the presence of significant stenoses in renal renal arteries were selectively catheterized and the arterial, arteries in more than two thirds of the study population. These parenchymatous and venous phases were observed. The contrast results were similar to those found in invasive arteriography. material used was a water-soluble, ionic, low-osmolarity medium. Images were acquired using a digital subtraction filter and stored Sensitivity, specificity, and predictive value of the in a compact disc for further analysis. noninvasive imaging tests After image acquisition, the introducer was removed and The relation between the results obtained with invasive effective local compression was kept for a minimum period and noninvasive imaging tests was analyzed by comparing required. the individual results of each study patient. The initial analysis Based on previous studies, the criterion used for the showed a significant correlation of the results of Doppler and definition of a significant stenosis was an arterial lumen tomography with invasive angiography (Table 4). The results of reduction by at least 60%, since there are data suggesting that the scintigraphic study were not significantly associated with these plaques are those which promote an average systolic those of angiography. gradient higher than 20 mmHg, thus being able to lead to Sensitivity, specificity, positive and negative predictive 13,14 renal tissue ischemia . values of the noninvasive imaging tests, as well as the Kappa value were also defined. Again, arteriography was used as Statistical analysis the reference test. Results of the analyses per patient and per Data were described as absolute (n) and relative (%) vessel are shown in Tables 5 and 6. frequencies for qualitative measures. Mean summary statistics, standard deviation (SD), median and 25th and 75th percentiles Association between risk factors and renal arteriography (Per 25 and Per 75) were used for quantitative measures. findings The effect of the risk factors and other diagnostic tests on As proposed, the association between the presence of the results of the reference test (arteriography) was analyzed. stenoses above 60% and the different risk factors of the The Pearson chi square test or Fisher’s exact test was used to whole population was analyzed. Results are shown in Table 7. analyze the association between qualitative measures and the The presence of abnormal triglyceride levels, renal dysfunction, reference test. Comparison of quantitative measures between high creatinine levels, and decreased glomerular filtration rate the response categories of arteriography was made using the were predictive of the existence of significant obstructive Student’s or Mann-Whitney t test. plaques in at least one of the renal arteries.

Arq Bras Cardiol. 2013;101(5):423-433 426 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Consistency of noninvasive imaging test results was verified minimum gender-required levels. Also, the triglyceride profile by analyzing the results of the interobserver interpretation, in the study population also showed values lower than those i.e., other experienced examiners were asked to quantify the considered atherogenic. This may also be explained by the fact percentage of stenosis in the renal arteries 12 to 18 months that all patients’ plasma lipid levels were under strict control19. after the initial analysis. The results included in the analysis, in turn, were decided by consensus between the two operators, Diagnosis of RAS and the diagnostic tests in case of disagreement regarding the findings. Doppler, CT angiography and magnetic resonance imaging The results presented in Table 8 show a high level of have been exceptionally accepted as tests for the diagnosis of agreement between tests, except for scintigraphy, which diseases of the thoracic and abdominal aorta, as well as for showed intermediate results, albeit significant. those of the infrainguinal vessels. However, this is not valid for the study of the renal arteries. Discussion The analysis of the association between noninvasive tests and digital arteriography shows a clear correlation of Doppler Arteriography remains as the gold-standard test for the and CT angiography with digital arteriography, both in the diagnosis of renal artery stenoses; however, it is still related to analysis per patient and per vessels, all with p values ≤ 0.05. the occurrence of complications, especially in cases of higher This was not observed for scintigraphy. risk and greater number of comorbidities15. The findings of this study demonstrate that the association Analysis of sensitivity, specificity, positive and negative of noninvasive imaging tests may provide important predictive values of the noninvasive diagnostic tests information on the presence of significant renal artery stenosis. Abnormalities found in Doppler and tomography The role of each imaging method used in individuals are frequently accompanied by significant reductions in the with suspected renal artery stenosis was compared. We then arterial lumen; however, some peculiarities of this study proposed a better population selection and the identification deserve special consideration. of the best tests to guide the diagnosis. The study population reproduced many of the aspects associated with the presence of obstructive atheromatous Doppler plaques in the renal arteries described in the literature. Measurements found for the assessment of sensitivity Age above 60 years and white ethnicity – characteristics and specificity of Doppler of the renal arteries in probable found in our study patients, are usually the major predictors RAS showed values of 82.90% and 70%, respectively, which of atherosclerotic disease16. correspond to a positive predictive value of 85% and a negative One of the risk factors commonly associated with predictive value of 66.70%. The Kappa value of 0.523 showed renovascular disease of atherosclerotic origin is cigarette a moderate level of agreement with the reference standard, smoking, especially in the presence of POAD. The present with p < 0.001. study showed a situation different from that seen in the These values make Doppler an interesting diagnostic option literature, because the proportion of smokers or patients with for the investigation of atherosclerotic renovascular disease, POAD was not significant, of 13.1% and 21.3%, respectively. because the test was able to identify stenosis in a population Given that this is a population at a high cardiovascular risk, with RAS, to rule out the disease in patients not having it, a higher incidence of coronary artery disease and carotid artery and to identify it among those with a positive test. This was disease was expected. However, even with the use of different achieved with reasonable safety, and the values found in the methods to identify these diseases, the incidence found was present study corroborate those reported in the literature. low, of 39.3% and 26.2%, respectively. We may conclude that sensitivity, specificity and the Patients were recruited from the Dante Pazzanese Institute positive and negative predictive values make this test an of Cardiology, where anti-tobacco campaigns, frequent use of important diagnostic tool for the investigation of atherosclerotic lipid-lowering drugs and proper dietary guidance are in place, renovascular disease, despite the many limitations regarding the applicability of the method described in the literature20,21. and this may have been the reason for the lower incidence found for those diseases. A meta-analysis on the prevalence of renovascular disease Renal scintigraphy in several risk groups found DM in 20% of their study With low sensitivity and positive predictive values (12.50% population17. The prevalence found in our study is 2.5 times and 45.50%, respectively), and reasonable specificity, but a higher (50.8%). low negative predictive value (70% and 28.60%, respectively), Although hyperlipidemia is frequently identified in the performance of scintigraphy in this population was not as populations with atherosclerotic disease, to date no study has good as that of Doppler, and this was reflected in the finding confirmed that this association is predictive of RAS18. In this of a Kappa value of (-) 0.128. Values lower than zero identify study, high total cholesterol and LDL-cholesterol levels were total disagreement between the findings from scintigraphy not found; the levels verified were strictly within normal limits. and digital renal arteriography This lipid profile may provide this population with a better We should also point out that low significance values were clinical perspective, even considering the fact that 78.7% of found for the other analyses carried out, both for patients and participants showed HDL-cholesterol levels lower than the for arteries.

427 Arq Bras Cardiol. 2013;101(5):423-433 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Table 3 - Descriptive statistics of the population characteristics, categorical variables

Population n % F 33 54.1 Gender M 28 45.9 Black 14 23 Ethnicity White 47 77 No 17 27.9 Age > 60 years Yes 44 72.1 No 53 86.9 Cigarette smoking Yes 8 13.1 Normal 17 27.9 Overweight 26 42.6 BMI range Obesity 1 9 14.8 Obesity 2 9 14.8 No 30 49.2 DM2 Yes 31 50.8 No 41 67.2 TC > 200 mg/dL Yes 20 32.8 No 13 21.3 HDL risk (M < 40/F < 50) Yes 48 78.7 LDL < 100 mg/dL 30 49.2 LDL 100 ≤ LDL ≤ 130 mg/dL 18 29.5

LDL > 130 mg/dL 13 21.3 No 33 54.1 TG > 150 mg/dL Yes 28 45.9 No 24 39.3 AC risk (M > 102/F > 88) Yes 37 60.7 No 48 78.7 POAD Yes 13 21.3 No 37 60.7 CAD Yes 24 39.3 No 45 73.8 Carotid artery disease Yes 16 26.2 No 50 82 Proteinuria Yes 11 18 No 9 14.8 Renal dysfunction Yes 52 85.2 Mean (SD) Median (Per 25; Per 75) Age (years) 65.43 (8.7) 66.0 (59.5;72.5) Weight (kg) 71.45 (11.83) 70.4 (64.0;77.0) Height (m) 1.59 (0.97) 1.59 (1.50;1.68) Body surface (m2) 1.73 (0.16) 1.75 (1.61;1.83) Creatinine (mg/dL) 1.26 (0.47) 1.20 (0.90;1.54) Adjusted Cockcroft Gault (mL/min/1,73 m2) 61.0 (24.6) 52.8 (41.1;74.4) F: female; M: male; BMI: body mass index; DM2: type-2 diabetes mellitus; TC: total cholesterol; HDL: high density lipoproteins; LDL: low density lipoproteins; TG: triglycerides; AC: abdominal circumference; POAD: peripheral obstructive arterial disease; CAD: coronary artery disease; SD: standard deviation; Per 25: 25th percentile; Per 75: 75th percentile.

Arq Bras Cardiol. 2013;101(5):423-433 428 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Table 4 - Association between the diagnostic tests and digital arteriography

Right arteriography Left arteriography Arteriography

Negative Positive Total Negative Positive Total Negative Positive Total P value P value P value (n = 39) (n = 22) (n =61) (n = 32) (n = 29) (n = 61) (n = 20) (n = 41) (n = 61) CT angiography Negative n 36 12 48 0.001 30 7 37 < 0.001 16 13 29 <0.001 % 92.31 54.55 78.69 93.75 24.14 60.66 80.00 31.70 47.50 Positive n 3 10 13 2 22 24 4 28 32 % 7.69 45.45 21.31 6.25 75.86 39.34 20.00 68.29 52.46 Scintigraphy Negative n 32 18 50 1.000F 25 26 51 0.474F 14 35 49 0.155F % 82.05 85.71 83.33 80.65 89.6 85.00 70.00 87.50 81.67 Positive n 7 3 10 6 3 9 6 5 11 % 17.95 14.29 16.67 19.35 10.34 15.00 30.00 12.50 18.33 Doppler Negative n 30 8 38 0.002 29 7 36 < 0.001 14 7 21 i % 76.92 36.36 62.30 90.63 24.14 59.02 70.00 17.10 34.40 Positive n 9 14 23 3 22 25 6 34 40 % 23.08 63.64 37.70 9.38 75.86 40.98 30.00 82.90 65.6 Pearson chi square test.

Table 5 - Sensitivity, positive predictive value (PPV) and Kappa measurement for the diagnostic tests

Agreement (Kappa) Sensitivity (%) PPV (%) Medida Kappa p value Patients (n = 61) Left kidney 75.90 88.00 0.669 < 0.001 Doppler Right kidney 63.60 60.90 0.402 0.002 (n = 61) General 82.90 85.00 0.523 < 0.001 Left kidney 10.30 33.30 -0.092 0.329 Scintigraphy Right kidney 14.30 30.00 -0.420 0.717 (n = 60) General 12.50 45.50 -0.128 0.099 Left kidney 75.90 91.70 0.702 < 0.001 CT angiography Right kidney 45.50 76.90 0.415 0.001 (n = 61) General 68.30 87.50 0.433 < 0.001 Arteries (n = 122)

Doppler (n = 122) 70.60 75.00 0.541 < 0.001

Scintigraphy (n = 120) 12.00 31.60 -0.072 0.453

CT angiography (n = 122) 62.70 86.50 0.579 < 0.001

This diagnostic method is based on the radiotracer arrival, CT angiography accumulation and clearance curves, thus directly depending With superior results, although very close to those found on the degree of the renal structure integrity to identify stenosis using Doppler, CT angiography proved to be a very useful test of a vessel. Therefore, these results do not allow us to consider scintigraphy of the renal arteries as a test indicated for the for the identification of individuals with RAS. The sensitivity, diagnosis of RAS in patients with impaired renal function. specificity, positive and negative predictive values found Thus, we can conclude that scintigraphy is not recommended (68.30%, 80.00%, 87.50% and 55.20%, respectively) showed in populations with renal dysfunction. that this noninvasive imaging test is a very useful diagnostic

429 Arq Bras Cardiol. 2013;101(5):423-433 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Table 6 - Specificity, negative predictive value (NPV) and Kappa measure for the diagnostic tests

Agreement (Kappa) Patients (n = 61) Specificity (%) NPV (%) Kappa measure p value Left kidney 93.80 81.10 0.702 < 0.001 CT angiography (n = 61) Right kidney 92.30 75.00 0.415 0.001 General 80.00 55.20 0.433 < 0.001 Left kidney 80.60 49.00 -0.092 0.329 Scintigraphy (n = 60) Right kidney 82.10 64.00 -0.420 0.717 General 70.00 28.60 -0.128 0.099 Left kidney 90.60 80.60 0.669 < 0.001 Doppler (n = 61) Right kidney 76.90 78.90 0.402 0.002 General 70.00 66.70 0.523 < 0.001 Artéries (n = 122) CT angiography (n = 122) 93.00 77.60 0.579 < 0.0001 Scintigraphy (n = 120) 81.40 56.40 -0.072 0.453 Doppler (n = 122) 83.10 83.10 0.541 < 0.0001 tool. Kappa values showing moderate agreement (0.433) and factor was predictive of the presence of stenosis > 60% in at a significance level of p < 0.001 confirm this statement. least one of the renal arteries, with p ≤ 0.002. Several studies have used this diagnostic method to Plasma triglyceride levels were another risk factor that showed investigate RAS22,23. an association with renal artery stenosis. However, we observed For CT angiography, limitations regarding the use of a an inverse relation to the one usually found. In this population, we contrast medium may be important. In younger populations, found a lower chance of RAS in patients with plasma triglyceride radiation exposure should be considered. levels > 150 mg/dL. Another form of interpreting the results would be to imagine that higher triglyceride levels could bring some protective effective in the development of the obstructive Analysis of the association between risk factors and renal renal plaque. In our study population, these findings reached arteriography a clinical significance level, with p < 0.037, and should thus The relationship between lesions considered greater than a be interpreted. 60% reduction in vessel lumen, as quantified by visual analysis However, it is a fact that the literature does not identify the of the angiogram, was analyzed in order to identify the presence possibility of the development of atherosclerotic disease per se in of an association between risk factors and digital arteriography. populations like this. In the presence of lower triglyceride levels, This analysis permitted the identification of two variables other comorbidities could be present to justify the development – renal dysfunction and plasma triglyceride levels, among the of atherosclerotic disease. risk factors allocated in this study, as being able to establish a Increased plasma triglyceride levels are usually associated with causal relationship between an obstructive plaque in the renal the presence of risk factors such as obesity, metabolic syndrome, artery and the risk factors previously mentioned. pro-thrombotic states, pro-inflammatory states and type-2 DM, Even with the possibility of being represented by any all contributing for an increased risk of cardiovascular diseases. of the variables that identify renal dysfunction, the body The NCEP ATPIII25 identified that levels < 150 mg/dL and surface‑adjusted creatinine clearance corrected by gender was between this value and 200 mg/dL had a smaller participation in the variable chosen to demonstrate the relationship between the assessment of the cardiovascular risk alone. However, values renal dysfunction and the presence of stenosis, because there is > 200 mg/dL (hypertriglyceridemia) are already considered as an an important correlation between its values and cardiovascular independent risk factor for cardiovascular diseases. disease mortality. Thus, identifying renal artery stenosis is We should remember that this population comprised an important condition to minimize the progression of the individuals aware of their morbid condition and who were cardiovascular disease itself. already taking medications that aimed not only to control The findings of the present study identified a median their blood pressure, but also all the risk factors involved in creatinine clearance of 52.8 (41.1; 74.4) mL/min/m2. These atherosclerotic diseases. values correspond to glomerular filtration rates consistent From these findings, we can state that the presence of with stage-3 renal dysfunction, which precisely characterize atherosclerotic disease in other sites, the metabolic syndrome 24 individuals at a higher risk for cardiovascular events . components, and other risk factors that are present in the In this study, 85.2% of the participants had renal dysfunction. population, other than renal dysfunction and triglyceride levels, In the statistical analysis of the quantified measures, this risk did not identify RAS.

Arq Bras Cardiol. 2013;101(5):423-433 430 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Table 7 - Association between risk factors and digital arteriography

Arteriography Total p value Negative (n = 20) Positive (n = 41) n = (61) Male gender n (%) 7 (35) 21 (51.22) 28 (45.9) 0.233 White ethnicity n (%) 17 (85) 30 (73.17) 47 (77.05) 0.302 Age > 60 n (%) 13 (65) 31 (75.61) 44 (72.13) 0.386 Cigarette smoking n (%) 3 (15) 5 (12.2) 8 (13.11) 0.761 Normal BMI n (%) 5 (25) 12 (29.27) 17 (27.87) IMC sobrepeso n (%) 7 (35) 19 (46.34) 26 (42.62) 0.659 BMI obesity 1 n (%) 4 (20) 5 (12.2) 9 (14.75) BMI obesity 2 n (%) 4 (20) 5 (12.2) 9 (14.75) DM2 n (%) 9 (45) 22 (53.66) 31 (50.82) 0.525 TC > 200 mg/dL n (%) 7 (35) 13 (31.71) 20 (32.79) 0.797 HDL risco ( M < 40/F < 50) n (%) 15 (75) 33 (80.49) 48 (78.69) 0.623 LDL < 100 mg/dL n (%) 10 (50) 20 (48.78) 30 (49.18) 100 ≤ LDL ≤130 mg/dL n (%) 4 (20) 14 (34.15) 18 (29.51) 0.373 LDL > 130 mg/dL n (%) 6 (30) 7 (17.07) 13 (21.31) TG > 150 mg/dL n (%) 13 (65) 15 (36.59) 28 (45.9) 0.037 AC risk ( M > 102/F > 88) n (%) 14 (70) 23 (56.1) 37 (60.66) 0.297 POAD n (%) 4 (20) 9 (21.95) 13 (21.31) 0.861 CAD n (%) 8 (40) 16 (39.02) 24 (39.34) 0.942 Carotid artery disease n (%) 3 (15) 13 (31.71) 16 (26.23) 0.164 Proteinuria n (%) 4 (20) 7 (17.07) 11 (18.03) 0.780 Renal dysfunction n (%) 13 (65) 39 (95.12) 52 (85.25) 0.002

Age (years) mean (DP) 62.95 (9.89) 66.63 (7.92) 65.27 (8.61) 0.122t Median (Per 25; Per75) 63.5 (53;70.75) 66 (60.5;73) 65 (59;72)

Height (m) Mean (SD) 1.59 (0.1) 1.59 (0.1) 1.59 (0.1) 0.824M-W Median (Per 25; Per75) 1.62 (1.49;1.65) 1.59 (1.5;1.69) 1.59 (1.5;1.68)

Weight (kg) Meana (SD) 71.97 (13.4) 71.2 (11.15) 71.18 (11.73) 0.945M-W Median (Per 25; Per75) 70 (65.43;82.25) 71 (64;77) 70 (64;77)

2 Body surface (m ) mean (SD) 1.74 (0.18) 1.73 (0.15) 1.73 (0.16) 0.896t Median (Per 25; Per75) 1.72 (1.61;1.81) 1.76 (1.61;1.83) 1.73 (1.61;1.82)

Creatinine mg/dL mean (SD) 0.96 (0.32) 1.41 (0.47) 1.27 (0.47) < 0.001M-W Median (Per 25; Per75) 0.92 (0.7;1.24) 1.3 (1.05;1.8) 1.25 (0.9;1.58)

CG mean (SD) 88.74 (34.21) 56.88 (20.81) 66.63 (29.56) 0.001t Median (Per 25; Per75) 82.78 (59.47;106.73) 55.76 (42.91;66.85) 58.67 (46;82.41)

Adjusted CG mean (SD) 79.09 (28.51) 52.05 (17.08) 60.3 (24.65) 0.001t Median (Per 25; Per75) 72.27 (56.12;104.5) 49.39 (40.04;62.69) 53.98 (43.03;70.68)

CG mean body surface (SD) 78.99 (27.25) 52.23 (17.7) 60.44 (24.39) < 0.001t Median (Per 25; Per75) 77.05 (52.76;101.98) 47.97 (38.35;63.53) 52.75 (41;72.29) Pearson chi square test; t: Student t test; M-W: Mann-Whitney test. BMI: body mass index; DM2: type-2 diabetes mellitus; TC: total cholesterol; HDL: high density lipoproteins; LDL: low density lipoproteins; TG: triglycerides; AC: abdominal circumference; POAD: peripheral obstructive arterial disease; CAD: coronary artery disease; SD: standard deviation; Per 25: 25th percentile; Per 75: 75th percentile; CG: Cockcroft Gault.

431 Arq Bras Cardiol. 2013;101(5):423-433 Borelli et al Sensitivity and specificity of renal artery stenosis Original Article

Table 8 - Agreement between observers of the different noninvasive is operator-dependent. Although tomography is under less imaging tests influence of the physician who conducts the test, it is less Kappa Valor de p frequently available in Brazil.

Arteriography 0.8925 < 0.001 CT angiography 0.9362 < 0.001 Author contributions Conception and design of the research, Analysis and Scintigraphy 0.5140 < 0.001 interpretation of the data and Writing of the manuscript: Doppler 0.9647 < 0.001 Borelli FAO, Pinto IMF, Amodeo C; Acquisition of data: Borelli FAO, Paiva RC, Lopes HB; Statistical analysis and Critical revision of the manuscript for intellectual content: Borelli FAO, Pinto IMF; Examinations of nuclear medicine: Smanio Conclusions PEP; Realization of Doppler renal arteries: Petisco ACG; The findings of the present study demonstrated that it is Performance of all renal arteriography: Kambara AM, Moreira possible to identify the presence of renovascular disease using SM; Infrastructure inpatient and outpatient: Sousa AGMR. an association of noninvasive imaging tests in most of the cases. Sensitivity, specificity, and the positive and negative Potential Conflict of Interest predictive values of Doppler and tomography are satisfactory, unlike what was observed with renal scintigraphy. Renal No potential conflict of interest relevant to this article was dysfunction and low triglyceride levels were the only risk reported. factors associated with the presence of stenosis, as detected by the visual analysis of arteriography. Sources of Funding Finally, considering the investigation process and all the There were no external funding sources for this study. methodology and analyses carried out, Doppler and CT angiography showed a satisfactory correlation with the analysis of the renal artery lumen as seen in the angiogram, unlike in Study Association scintigraphy. However, we should bear in mind that these This article is part of the thesis of doctoral submitted results apply to patients with characteristics similar to those by Flavio Antonio de Oliveira Borelli, from Instituto Dante of this study population, and that Doppler ultrasonography Pazzanese de Cardiologia.

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433 Arq Bras Cardiol. 2013;101(5):423-433 Original Article

Triceps Skinfold as a Prognostic Predictor in Outpatient Heart Failure Priccila Zuchinali1, Gabriela Corrêa Souza2, Fernanda Donner Alves1, Karina Sanches Machado d’Almeida1, Lívia Adams Goldraich1, Nadine Oliveira Clausell2, Luis Eduardo Paim Rohde2 Programa de pós graduação em Ciências da Saúde: Cardiologia e Ciências Cardiovasculares, Universidade Federal do Rio Grande do Sul1; Departamento de Medicina Interna, Universidade Federal do Rio Grande do Sul2, Porto Alegre, RS - Brasil

Abstract Background: Most reports regarding the obesity paradox have focused on body mass index (BMI) to classify obesity and the prognostic values of other indirect measurements of body composition remain poorly examined in heart failure (HF). Objective: To evaluate the association between BMI and other indirect, but easily accessible, body composition measurements associated with the risk of all-cause mortality in HF. Methods: Anthropometric parameters of body composition were assessed in 344 outpatients with a left ventricular ejection fraction (LVEF) of ≤50% from a prospective HF cohort that was followed-up for 30 ± 8.2 months. Survival was evaluated using the Kaplan–Meier method and Cox proportional hazard regression analysis. Results: HF patients were predominantly male, of non-ischemic etiology, and had moderate to severe LV systolic dysfunction (mean LVEF = 32 ± 9%). Triceps skinfold (TSF) was the only anthropometric index that was associated with HF prognosis and had significantly lower values in patients who died (p = 0.047). A TSF ≥ 20 mm was present in 9% of patients that died and 22% of those who survived (p = 0.027). Univariate analysis showed that serum creatinine level, LVEF, and NYHA class were associated with the risk of death, while Cox proportional hazard regression analysis showed that TSF ≥ 20 was a strong independent predictor of all-cause mortality (hazard ratio = 0.36; 95% CI = 0.13–0.97, p = 0.03). Conclusion: Although BMI is the most widely used anthropometric parameter in clinical practice, our results suggested that TSF is a better predictive marker of mortality in HF outpatients. (Arq Bras Cardiol. 2013;101(5):434-441) Keywords: Heart failure; Body mass index; Mortality; Body composition.

Introdution predict fat excess11. Unfortunately, direct measurements of Obesity is defined by excessive body fat and has a long- body mass composition, like dual energy X-ray absorptiometry (DEXA), are not practical and have not been directly related established relationship with cardiovascular disease (CVD) and 12 heart failure (HF)1,2. In the general CVD-free adult population, to survival in HF patients . extremes in body mass index (BMI) have been associated with Data to evaluate the prognostic value of other anthropometric an increased risk of overall mortality3-5. However, there is a and indirect measures of body composition, such as waist growing body of clinical evidence indicating that excess weight circumference (WC), arm muscle circumference (AMC), and might confer a lower risk of adverse clinical events, particularly triceps skinfold (TSF), have been poorly examined in HF patients. in HF patients. This phenomenon has been referred to as the Lavie et al13 have suggested that a high body fat percentage, “obesity paradox” or “reverse epidemiology”6-8. as estimated by TSF measurements, might be an independent Most reports regarding the obesity paradox have used predictor of cardiovascular death or heart transplantation. 9 However, other studies have not reached a consensus regarding BMI to classify obesity . Although BMI is the most common 14-16 method to define overweight and obese populations in the role of these parameters in HF prognosis . epidemiological studies, it clearly does not reflect body Therefore, the aim of the present prospective study composition10, thus depicting a relatively low sensitivity to was to evaluate the association between BMI and several other indirect, but easily accessible, body composition measurements to the risk of HF mortality and hospitalization. Mailing Address: Luis E. Rohde, MD ScD. • Serviço de Cardiologia, Hospital de Clínicas de Porto Alegre - Ramiro Barcelos 2350, sala 2061, Porto Alegre, RS, Brazil 90035-003. Methods E-mail: [email protected] Manuscript received September 11, 2012; revised September 14, 2012; accepted February 2, 2013. Study Design and Population A prospective cohort of HF outpatients followed-up DOI: 10.5935/abc.20130185 at the HF and Transplant Clinic of a university tertiary

434 Zuchinali et al. Triceps skinfold measurement and mortality in heart failure Original Article care hospital in Porto Alegre (RS, Brazil) between May Outcome Evaluation 2008 and December 2009 were enrolled in the present Enrolled patients were followed-up at the HF and study. This cohort included patients with an HF diagnosis, Transplant Outpatient Clinic. At the HF clinic, patients were predominantly with left ventricular systolic dysfunction scheduled to have regular visits at pre-defined intervals of 1–4 [left ventricular ejection fraction (LVEF) < 50%], confirmed months. Follow-up data were directly derived from reviewing by two-dimensional echocardiography. Pregnant women, all electronic clinical data from the institutional records (most patients with significant peripheral edema, and those with patients had several follow-up visits). For patients who were clinical conditions, in which anthropometric measurements not regularly visiting the HF clinic (or were lost to follow-up), were not feasible, were excluded. Signed and informed telephone contact was attempted to obtain relevant clinical consent was obtained from all patients prior to enrollment events based on a structured telephone interview performed and the research protocol was approved by our institutional by trained nurses. For the study participants who we were review committee. unable to contact by phone (approximately 20 patients), we checked their vital status through the State Death Certificate Anthropometric Parameters Database, which contains data on the main cause and date of all deaths in our state. For statistical analysis we used (1) Anthropometric measurements of weight, height, body all-cause mortality and (2) HF-related hospitalizations. surface area (BSA), BMI, WC, arm circumference (AC), AMC, and TSF were collected during the first medical examination. All anthropometric measurements were performed by the Statistical Analysis same trained investigator, a registered nutritionist, to avoid Baseline patient clinical characteristics were expressed as interobserver variability. mean ± SD or number and percentage. Continuous variables were compared using the Student’s t-test or Mann–Whitney BMI, BSA, and Ponderal Index (PI) U test as appropriate, whereas categorical variables were compared using the chi-square test or Fisher’s exact test. BMI was calculated using the Quetelet equation as TSF and BMI were also analyzed according to quintiles of follows: BMI (Quetelet) = weight (kg)/length (m)2. Weight the distribution. Survival curves were constructed using the was measured using a balance scale (Filizola PL180; Filizola, Kaplan–Meier method and compared with the log-rank test. Brazil) with capacity of 180 kg and an accuracy of 100 g. Cox proportional hazard regression analysis was performed For height measurement, we used a vertical wall-mounted to determine independent predictors of survival and included stadiometer. BMI was classified into three categories according at least one anthropometric parameter (either BMI or TSF) to the World Health Organization classification for adults: and clinical predictors of risk [gender, age, New York Heart underweight (<18.5 kg/m²), normal weight (18.5–24.9 kg/m²), Association (NYHA) class, LVEF, and serum creatinine level]. and overweight (>25 kg/m²); and the Pan American Health A two-tailed p value < 0.05 was considered statistically Organization criteria for the elderly: underweight (<23 kg/m²), significant. Statistical analyses were performed using SPSS normal weight (23–28 kg/m²), and overweight (>28 kg/m²)17. 0.5378 0.3964 statistical software ver. 18 for Windows (SPSS, Inc., Chicago, In addition, we calculated BSA as weight × height × IL, USA). 0.024265 and PI as weight/height3.

Waist circumference Results WC was measured at the midpoint between the lowest rib From May 2008 to September 2009, a total of 378 HF and the iliac crest during expiration. Patients were instructed outpatients, who were followed-up at the HF and Transplant to remain in an upright position with weight evenly distributed clinic, agreed to participate in the study and had their on both sides and breathing smoothly to prevent abdominal anthropometric parameters evaluated. We excluded 34 muscle contraction. patients from the protocol because LV function assessment indicated a LVEF > 50%. Triceps Skinfold Baseline clinical characteristics of the remaining study population (n = 344) are listed in Table 1 and stratified by The TSF thickness (in mm) was obtained at the mid-point survival. Overall, HF patients were predominantly male, of the non-dominant arm (between the acromial process and self-reportedly white, of non-ischemic etiology, in NYHA the olecranon) with the arm freely stretched along the body. functional class I–II, and had moderate to severe LV systolic A fold of skin was then pinched with the fingers and a scientific dysfunction (mean LVEF = 32 ± 9%). Most patients were caliper (Cescorf Scientific, Cescorf, Brazil) was applied. hypertensive and 30% had diabetes. The mean follow-up The measurement was repeated three times and the mean of period was 30.3 ± 8.2 months. Patients who died were older, the measurements was used for analysis. had relatively high creatinine levels, low LVEFs, and depicted a trend towards higher NYHA functional class. Arm muscle circumference Nutritional assessment parameters are listed in Table 2. AMC (in cm) was calculated by measuring the AC and the Most HF patients were overweight when classified by BMI. TSF thickness, using the following formula proposed by Jelliffe: There were no significant differences in most anthropometric C2 = C1–3.14*S, where C2 is the muscular circumference, parameters between patients who died and those who C1 is the arm circumference, and S is TSF thickness (in cm)18. survived. In particular, mean BSA and BMI were remarkably

Arq Bras Cardiol. 2013;101(5):434-441 435 Zuchinali et al. Triceps skinfold measurement and mortality in heart failure Original Article

Table 1 - Baseline clinical characteristics of the study population

Total Alive Dead p (n = 344) (n = 288) (n = 56) Age (years) 59 ± 13 59 ± 13 62 ± 11 0.031 Gender (male) 224 (65) 185 (64) 39 (73) 0.54 Ethnicity (Caucasian) 281 (81) 234 (82) 47(85) 0.20 Smoking 43 (12) 35 (13) 8 (17) 0.57 Etiology 0.10 Ischemic 118 (34) 94 (33) 24 (45) Hypertensive 69 (20) 55(19) 14 (26) Idiopathic 57 (17) 53 (18) 4 (7) Alcoholic 38 (11) 32 (11) 6 (11) Other 52 (15) 47 (17) 5 (9) NYHA class 0.08 I-II 286 (83) 244 (84) 42 (75) III-IV 58 (17) 44 (16) 14 (25) Systolic blood pressure (mmHg) 124 ± 22 124 ± 22 125 ± 22 0.83 Creatinine (mg/dL) 1.2 ± 0.5 1.2 ± 0.5 1.4 ± 0.7 0.002 Na (mEq/L) 140 ± 3.4 140 ± 3 140 ± 3 0.31 Left ventricle ejection fraction (%) 32 ± 9 33 ± 9 29 ± 9 0.008 Comorbidities Diabetes Melitus. 104 (30) 81 (29) 23 (42) 0.078 Hypertension 224 (65) 178 (65) 46 (85) 0.004 COPD 27 (7.8) 22 (10) 5(12) 0.078 Angina 52 (15) 44 (18) 8 (19) 0.97 Atrial fibrillation 86 (25) 70 (27) 16 (31) 0.60 Data are expressed as the means ± standard deviation or absolute numbers (%). NYHA: New York Heart Association; COPD: chronic obstructive pulmonary disease.

Table 2 - Anthropometric baseline parameters of the study population

Total Alive Dead p (n = 344) (n = 288) (n = 56) BMI (kg/m²) 26 ± 5 26.7 ± 5.3 26.1 ± 4.8 0.47 Underweight 58 (17) 46 (16) 12 (21) 0.40 Normal 131 (38) 108 (37) 23 (41) Overweight and obesity 155 (45) 134 (46) 21 (37) BMI ≥ 30.4 (superior quintile) 69 (20) 57 (20) 12 (21) 0.45 Ponderal index 16.1± 3.3 16.2 ± 3.4 15.7 ± 2.9 0.26 Body surface area 1.8 ± 0.2 1.8 ± 0.2 1.8 ± 0.2 0.57 Triceps skinfold (mm) 14.3 ± 8 14.6 ± 8.3 12.8 ± 5.5 0.047 TSF ≥ 20 (superior quintile) 68 (20) 63 (22) 5(9) 0.027 Arm muscle circumference (cm) 26.1 ± 3.4 26.2 ± 3.3 25.6 ± 3.5 0.18 Waist circumference (cm) 96 ± 13 95.7 ± 12.6 97.9 ± 13.3 0.24 Data are expressed as the means ± standard deviation or absolute number (%). BMI: Body mass index; TSF: Triceps skinfold.

436 Arq Bras Cardiol. 2013;101(5):434-441 Zuchinali et al. Triceps skinfold measurement and mortality in heart failure Original Article similar in both groups, even when stratified by quintiles of the major independent predictor of overall mortality (HR = 0.36; distribution. TSF was the only anthropometric index that was 95% CI = 0.13–0.97). associated with HF prognosis. Surviving patients had a TSF 10% higher than patients who died. A TSF ≥ 20 mm was observed in only 9% of the HF patients that died during follow-up and Discussion in 22% of those that survived (p = 0.027; Table 2). Despite the growing interest in the obesity paradox, there Data regarding TSF quintiles are presented in Table 3. is still an ongoing debate regarding the most appropriate Patients within the highest TSF quintile were younger, mostly parameter(s) to assess the nutritional status of HF patients. Our females, with lower serum creatinine levels and higher LVEFs. results demonstrated that among numerous anthropometric As expected, patients in the highest TSF quintile had higher indices (BMI, BSA, PI, TSF, WC, and AC), TSF was the only BMIs and WCs (p < 0.001). Figure 1 depicts HF hospitalization parameter that could differentiate survivors from non-survivors rates and overall mortality according to TSF quintiles. in a contemporary “real-world” prospective cohort of HF Our analysis demonstrated that HF patients within the 5th patients. This finding is in agreement with the concept of quintile had approximately a three-fold lower mortality rate reverse epidemiology, as HF patients in the highest TSF quintile than patients in the 2nd, 3rd, and 4th quintiles. No significant had lower overall mortality, even after adjustment for other differences were observed in HF hospitalizations according important clinical predictors of risk. We did not observe a to TSF. In addition, the Kaplan–Meier survival curves stratified dose–response relationship between TSF and mortality, as by TSF progressively diverged over time (Figure 2A), but such only the superior quintile, representing a greater amount of differences were not observed in the BMI-stratified analysis. fat mass, appeared to be an independent protective factor. Table 4 shows univariate analysisand multivariate Cox In addition, unlike other studies, we did not find BMI as an regression analysis results for all-cause mortality, including adequate predictor of HF prognosis. nutritional parameters and other clinical variables. In the The correlation between BMI and HF survival remains univariate analysis, serum creatinine levels, LVEF, and NYHA controversial. Post-hoc analysis of large clinical trials19 class were associated with risk, but TSF was the single best demonstrated that lower BMI was associated with decreased predictor of mortality [hazard ratio (HR) = 0.36; 95% survival. Symptomatic HF patients evaluated in the Candesartan confidence interval (CI) = 0.14–0.91; p = 0.03]. Finally, after in Heart Failure: Assessment of Reduction in Mortality and adjustment for these clinical characteristics, TSF remained a Morbidity trial with either reduced or preserved LV systolic

Table 3 - Comparison of clinical and nutritional characteristics among quintiles of TSF

Q1 (69) Q2 (70) Q3 (68) Q4 (69) Q5 (68) p ≤ 8,1 8,2–10,5 10,6–14,2 14,3–19,9 ≥ 20 Age (years) 63 ± 15 62 ± 9 57 ± 11 59 ± 14 55 ± 13 0.004 Gender (male) 61 (88) 61 (87) 52 (76) 35 (50) 15 (22) <0.001 Etiology 0.06 Ischemic 22 (34) 27 (40) 22 (33) 24 (35) 23 (35) Hypertensive 15 (23) 13 (18) 11 (17) 16 (23) 14 (21) Idiopathic 10 (15) 6 (8) 15 (23) 15 (22) 11 (16) Alcoholic 11 (17) 13 (19) 9 (14) 3 (4) 2 (3) Other 7 (11) 10 (14) 9 (14) 10 (15) 16 (26) NYHA class 0.06 I-II 63 (91) 58 (83) 55 (81) 59 (85) 51 (75) III-IV 6 (9) 12 (17) 13 (19) 10 (14) 17 (25) Systolic blood pressure (mmHg) 120 ± 22 123 ± 20 126 ± 25 128 ± 21 127 ± 22 0.15 Creatinine (mg/dL) 1.4 ± 0.7 1.3 ± 0.4 1.2 ± 0.5 1.0 ± 0.4 1.0 ± 0.4 <0.001 Na (mEq/L) 140 ± 4 141 ± 3 140 ± 3 141 ± 4 140 ± 3 0.42 Left Ventricle Ejection fraction (%) 30 ± 9 31 ± 9 31 ± 8 35 ± 9 35 ± 10 0.004 Body mass index (kg/m²) 22 ± 2 24 ± 3 25 ± 4 26 ± 4 31 ± 6 <0.001 Triceps skinfold (mm) 5.8 ± 1.5 9.5 ± 0.7 12 ± 0.9 17 ± 1.7 27 ± 6 <0.001 Arm muscle circumference (cm) 25 ± 3 26 ± 3 27 ± 3 26 ± 3 26 ± 4 0.95 Waist circumference (cm) 88 ± 9 94 ± 10 97 ± 11 98 ± 13 103 ± 14 <0.001 Data are expressed as means ± standard deviations or absolute numbers (%). NYHA: New York Heart Association.

Arq Bras Cardiol. 2013;101(5):434-441 437 Zuchinali et al. Triceps skinfold measurement and mortality in heart failure Original Article

p=0.69

p=0.027

Figure 1 - HF hospitalization and overall mortality rates according to quintiles of TSF (mm). The p-value represents the difference in the 5th quintile vs. other quintiles.

Triceps Skinfold (mm)

p=0.027

Figure 2 - Kaplan–Meier results for event-free survival curves (freedom from all causes mortality) for: (A) patients in the 5th quintile of triceps skinfold (TSF ≥ 20) vs. all other quintiles (TSF < 20) and (B) patients in the 5th quintile of body mass index (BMI ≥ 30.4) vs. all other quintiles (BMI < 30.4).

438 Arq Bras Cardiol. 2013;101(5):434-441 Zuchinali et al. Triceps skinfold measurement and mortality in heart failure Original Article

Table 4 - Univariate and multivariate Cox regression analysis been proposed to assess nutritional status and appraise different body composition components. TSF thickness 27 Univariate Multivariate measurement allows estimation of body fat content , Variable HR (95% CI) HR (95% CI) while limb circumferences reflect limb muscle and, thus, protein nutritional state. It is important to point out that Age 1.01 (0.99–1.03) TSF thickness measures primarily subcutaneous fat, and Gender (female) 1.29 (0.73–2.29) 0.88 (0.64–1.20) therefore, is insensitive to changes or abnormalities in visceral fat. Body density and body fat can be accurately NYHA class (I and II) 0.54 (0.29–1.00) 0.75 (0.55–1.03) estimated from the sum of TSF measurements28. Previous Creatinine (mg/dL) 1.57 (1.18–2.07) 1.40 (1.00–1.95) studies have compared and validated different body LVEF (%) 0.95 (0.92–0.98) 0.96 (0.93–0.99) composition techniques, such as DEXA, to assess fat mass and have demonstrated an adequate accuracy to estimate TSF (superior quintile) 0.36 (0.14–0.91) 0.36 (0.13–0.97) body fat mass, both for subscapular and TSF thickness29. Waist circumference In particular, TSF has been used more frequently than other 1.01 (0.99–1.03) (cm) sites, because it is easy to access, reproducible, and can 30 Arm muscle measure a wide range of variation among individuals . A 0.95 (0.88–1.02) circumference (cm) recent study compared body composition assessment in 118 hemodialysis patients and reported that TSF was one BMI (superior quintile) 1.06 (0.56–2.01) of the most accurate parameters to estimate total body fat LVEF: left Ventricular ejection fraction; TSF: triceps skin fold; BMI: body mass percentage using DEXA as the reference test31. index ; NYHA: New York Heart Association. Lavie et al13 pioneered evaluation of the prognostic role of body fat percentage based on skinfold measurements in function, underweight patients or those with a low BMI were HF patients and demonstrated that for each 1% absolute independently associated with a substantial increased risk of reduction in percent body fat, major clinical events increased death (almost 70% for BMI < 22.5 kg/m²), but primarily in by >13%. Assessment of other anthropometric parameters, patients without evidence of fluid overload7. Recently, Vara such as WC, has been proposed for HF risk stratification, but 14,15 et al20 described this phenomenon in elderly, hospitalized, HF with inconsistent results . Our results reinforced the concept patients However, although obesity is frequently evaluated by of the obesity paradox and suggested that assessment of a BMI in clinical practice, several investigators have questioned simple anthropometric parameter to measure subcutaneous fat (the TSF) might be adequate to indirectly assess overall the accuracy of BMI to assess different body composition body fat mass. components21-23. For instance, the relationship between BMI and body fat percentage was reportedly influenced by Regarding hospitalization risk, most reports on the ethnicity and age24. In the elderly, BMI might represent a assessment of the obesity paradox opted for analysis of a higher percentage of body fat, while in the relatively young this combined endpoint (death and hospitalization), thereby association is less evident25. Recently, similar to our findings, limiting separate evaluations of these events. Furthermore, several other investigators have questioned the usefulness some studies have found similar results, in which obesity is of BMI as a predictor of mortality or cardiac events10,14,16,26. a predictor of only overall/cardiovascular mortality, but not hospitalization8. One possible explanation for these findings Direct indices of body composition are theoretically the is the fact that patients with greater adiposity are diagnosed best markers to evaluate the prognostic role of nutritional status earlier with HF, which justifies why this group is younger, in different cardiovascular scenarios. Unfortunately, until now, has less degree of cardiac dysfunction, and consequent there were no prospective large-scale studies that evaluated better survival. These patients, however, may have similar the role of these parameters on HF survival. Recently, vulnerability to episodes of HF decompensation than those 12 Oreopoulos et al evaluated the association between direct with normal amounts of fat mass. measurements of body composition by DEXA and prognostic The results of the present study should be evaluated by factors in 140 chronic HF patients and demonstrated that taking into account some methodological limitations. First, we BMI misclassified body fat status in approximately 40% of the used indirect measurements of body composition to evaluate studied patients. Also, a higher lean body mass and/or lower body fat mass. Several studies, however, suggested that TSF fat mass were independently associated with factors that are measurement was apparently an adequate estimation of prognostically beneficial in HF, suggesting that BMI may not body fat27. Second, we acknowledged that anthropometry, be a good indicator of adiposity and may, in fact, be a better particularly skinfold measurement, requires a considerable surrogate for lean body mass in this population, a finding amount of technical skill and meticulousness. In our protocol, 12 that per se might question the obesity paradox . However, all parameters were evaluated by a single trained professional one must also consider that the association of direct body to avoid interobserver variability. Third, we opted to use only composition measurements with surrogate CVD markers may TSF measurements to predict body fat composition30,31 instead 10 not translate into similar data regarding survival . of more complex equations based on multiple skinfolds. Anthropometry is a simple technique that is easily Although this strategy might slightly reduce the accuracy of applied in clinical practice or in large population body composition assessment, we believe that if simplifies the surveys. Numerous anthropometric parameters have clinical applicability of our findings.

Arq Bras Cardiol. 2013;101(5):434-441 439 Zuchinali et al. Triceps skinfold measurement and mortality in heart failure Original Article

Conclusion Zuchinali P; Critical revision of the manuscript for intellectual Our results demonstrated that TSF might be a better content: Clausell NO, Souza GC, Rohde LEP, Zuchinali P. predictor of mortality in HF outpatients and reinforced the Potential Conflict of Interest concept of the obesity paradox. TSF measurement has the No potential conflict of interest relevant to this article was advantages of a simple, practical, and low cost method to reported. assess risk and can be easily implemented in clinical practice, if performed by a trained professional. Sources of Funding There were no external funding sources for this study. Author contributions Conception and design of the research: Souza GC; Acquisition of data: Alves FD, Zuchinali P, Souza GC, Almeida Study Association KSM; Analysis and interpretation of the data: Goldraich LA, This study is not associated with any post-graduation Rohde LEP, Zuchinali P; Statistical analysis: Goldraich LA, program.

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Arq Bras Cardiol. 2013;101(5):434-441 441 Original Article

Optimized Treatment and Heart Rate Reduction in Chronic Heart Failure Irineu Blanco Moreno, Carlos Henrique Del Carlo, Antônio Carlos Pereira-Barretto Instituto do Coração do Hospital das Clínicas da FMUSP, São Paulo, SP - Brazil

Abstract Background: Heart failure (HF) is a syndrome that leads to poor outcome in advanced forms. The neurohormonal blockade modifies this natural history; however, it is often suboptimal. Objective: The aim of this study is to assess at what percentage cardiologists used to treating HF can prescribe target doses of drugs of proven efficacy. Methods: A total of 104 outpatients with systolic dysfunction were consecutively enrolled, all under stabilized treatment. Demographic and treatment data were evaluated and the doses achieved were verified. The findings are shown as percentages and correlations are made between different variables. Results:The mean age of patients was 64.1 ± 14.2 years, with SBP =115.4 ± 15.3, HR = 67.8 ± 9.4 bpm, weight = 76.0 ± 17.0 kg and sinus rhythm (90.4%). As for treatment, 93.3% received a RAS blocker (ACEI 52.9%), all received beta‑blockers (BB), the most often prescribed being carvedilol (92.3%). As for the doses: 97.1% of those receiving an ARB were below the optimal dose and of those who received ACEI, 52.7% received an optimized dose. As for the BB, target doses were prescribed to 76.0% of them. In this group of patients, most with BB target dose, it can be seen that 36.5% had HR ≥ 70 bpm in sinus rhythm. Conclusion:Cardiologists used to treating HF can prescribe target doses of ACEI and BB to most patients. Even though they receive the recommended doses, about one third of patients persists with HR > 70 bpm and should have their treatment optimized. (Arq Bras Cardiol. 2013;101(5):442-448) Keywords: Heart Failure; Heart Rate; Ventricular Dysfunction, Left; Digoxin.

Introduction Experience shows that the HF treatment is not always easy, Heart failure (HF) is a prevalent and potentially progressive as the patients, especially the most severe ones, have reduced syndrome and individuals with HF at advanced stages have high blood pressure levels, a clinical finding that may complicate the morbidity and mortality1,2. The neurohormonal blockade carried prescription of several medications. There is, however, evidence out with adequate doses of drugs can modify its natural history; that HF treatment specialists and HF Clinics can optimize treatment 5,6 however, it is often suboptimal2-4. Data from clinical trials, HF and obtain better results . Few analyses have been carried out on registries and from patients referred for a second opinion show that the quality of HF treatment in Brazil. In InCor, the prescription of 7 often the target doses of drugs with proven efficacy in HF are not drugs was described at the pre-beta-blockers time . prescribed and it is likely that this fact contributes to the possible In search of data on drug prescription and its form, we risk of hypotension, bradycardia and lack of tolerance by patients3,4. proposed to analyze the prescription of drugs of proven In the Euro Heart Survey Programme it was observed that 36.9% efficacy in patients with HF, treated in medical offices, by of patients with HF had a beta-blocker (BB) prescription and only doctors used to treating HF. We aimed to verifying which 17.2% received a combination of diuretics, angiotensin-receptor medications were being prescribed and, among patients inhibitors and beta-blockers4. receiving BB, how many were receiving target doses of the In advanced HF, even when patients are adequately treated, the drugs and clinical features of patients receiving this type of mortality rate is still higher than desired, which suggests that new prescription. We also aimed to answer a more recent question: therapeutic approaches should be investigated or implemented1. how many patients would have a HR > 70 beats per minute while receiving optimized treatment?

Mailing Address: Antônio Carlos Pereira-Barretto • Methods Rua Piave, 103, Morumbi. Postal Code 05620-010, São Paulo, SP - Brazil E-mail: [email protected], [email protected] The aim of the study was to determine how patients with Manuscript received February 04, 2013, revised manuscript July 10, 2013, HF are treated by cardiologists used to treating this syndrome, accepted July 10, 2013. especially if the medication doses tested in large clinical trials can be prescribed to these patients and whether they would DOI: 10.5935/abc.20130201 be well tolerated by patients.

442 Moreno et al. Optimized treatment in heart failure Original Article

To perform this research, we evaluated the treatment of 95% and a variation of ± 3.5 mg in the standard deviation, of patients with HF treated by three cardiologists used taking as basis the standard deviation of the mean dose of to treating this syndrome. From October 2011 to May carvedilol in the SHIFT study8, which was 17.8 mg. Thus, 2012 a total of 104 patients with HF and left ventricular 104 patients were included in the study. systolic dysfunction were consecutively enrolled. Patients The p values ​​ are two-tailed, with a significance level of undergoing HF treatment for more than two months, who <0.05. received a BB and optimized treatment at the time of study enrollment, were included in this cross‑sectional cohort. Demographic data, heart disease etiology, heart rhythm, Results blood pressure, heart rate, weight and drug treatment The main characteristics of the study population are shown data were assessed, verifying the doses prescribed of in Table 1. different drugs. As for the treatment, 93.3% received a renin-angiotensin The inclusion criteria included patients receiving BB, who system blocker and 52.9% an ACE inhibitor and 40.4%, an had an echocardiogram documenting systolic dysfunction ARB; all received beta-blockers, with carvedilol being the with ejection fraction < 45% on a test performed within six most often prescribed medication (92.3%). Spironolactone months prior to study enrollment. was being prescribed to 69.2% of patients and digoxin, to Patients were considered to be adequately managed 16.3% of them. when they were prescribed the three medications that Table 2 shows the mean dose of prescribed drugs. As for the have been proven to modify the natural history of doses, 82.1% of those treated with an ACE inhibitor received HF: Angiotensin-Converting Enzyme (ACE) inhibitor; the target dose and 97.1% of those receiving an ARB received or Angiotensin Receptor Blockers (ARBs) II; BB and a dose that was less than optimal. spironolactone and in those with renal failure, if they received hydralazine and nitrate instead of ACE inhibitor As for the BB, 76.0% of the patients were prescribed target or ARBs. The dose considered correct for ACE inhibitor was doses or higher. In patients over 80 kg, the percentage of patients 20 mg of enalapril 2x/day or equivalent doses of captopril receiving the target dose of 50 mg 2x/day was 21.6%. (150 mg/day) or ramipril (10 mg/day) 2. Regarding the ACE inhibitors, the non-prescription of For ARBs, the correct dose was considered as 150 mg/ day target doses was associated with lower systolic blood pressure of losartan. For candesartan, the target dose was 32 mg/day (112.6 + 14.5 mmHg vs. 122.7 + 15.1 mmHg, p = 0.0003). and for valsartan, 320 mg/day 2. For spironolactone, the Regarding the beta-blockers, the non-prescription of target target dose was 25 mg/day. For beta-blockers, the full dose doses was associated with the etiology of heart disease, with was considered as 25 mg 2x/day for carvedilol to patients up prescription of doses below the target dose in 82% of patients to 80 kg, 50 mg 2x/day for those with more than 80 kg 2. For with Chagas disease. Patients with functional class III and IV bisoprolol, the target dose was considered as 10 mg/day, and also received lower doses of beta-blockers. On the other hand, for metoprolol succinate, 200 mg/day 2. patients with ischemic heart disease received more often the We also identified the percentage and prescription dose of target doses of beta-blockers (Table 1). digoxin, hydrochlorothiazide, furosemide and amiodarone, At the HR analysis of patients in sinus rhythm with medications often prescribed to patients with HF. optimized treatment, it was observed in this population that For the statistical analysis, considering that the most 36.5% had HR > 70 bpm; of these patients, 71.1% received often prescribed medications were enalapril, losartan carvedilol at a dose of 50 mg/day or more (Figure 1). When and carvedilol, equivalent doses were adopted when the comparing the clinical characteristics and pharmacological prescribed medications were not one of those. treatment of patients with HR > or < 70, we found no differences in the degree of cardiac involvement. The EF (37.3 ± 8.9% vs. 37.4 ± 8.34%, p = 0.921) and LVEDD Statistical Analysis (63.8 ± 8.9 vs. 64.7 ± 6.5 mm, p = 0.426) were similar Continuous variables are shown as mean ± standard in both groups. Among the clinical variables, systolic BP deviation and categorical variables as frequencies and differed between the two groups, being lower in the group percentages. The comparison of treatment among patients with HR < 70 bpm (119.2 ± 15.4 vs. 112.8 ± 14.8 mmHg, who reached the target dose of BB was performed using the p = 0.035). Kolmogorov-Smirnov test for normal distribution of continuous variables (Table 1), and all analyzed variables (age, SBP, DBP, HR, ​​weight, LVEF, LVDD, LA) showed a normal distribution Comments using the Kolmogorov-Smirnov test (p > 0.05). Thus, the The patients analyzed in this cross-sectional cohort received Student’s t test was used to compare the means of these optimized treatment from the therapeutic point of view, as variables regarding the “target dose” of BB. In the comparison most were receiving the drugs indicated in the Guidelines for of the characteristics, the chi-square or Fisher’s exact test were the treatment of HF and the target dose was prescribed and used for categorical variables. tolerated by most2,9. The data showed that cardiologists used The sample size was estimated at 98 patients to determine to treating HF can achieve the target doses indicated in the the mean dose of BB (carvedilol) in the population of patients Guidelines for most patients. with HF on optimized treatment, with a confidence interval The data also showed that these results, regarding quality of

Arq Bras Cardiol. 2013;101(5):442-448 443 Moreno et al. Optimized treatment in heart failure Original Article

Table 1 - Clinical characteristics of the study population and comparison between patients who achieved and did not achieve the target dose of beta-blocker

Beta-blocker Total (“target dose”) Characteristics (n = 104) P (K-S) Yes (n = 79) No (n = 25) p* Age (years) 64.1 ± 14.2 0.521 64.5 ± 13.8 63.0 ± 15.7 0.202 Male sex 69 (66.3) - 53 (67.1) 16 (64.0) 0.776 Etiology: Chagas 11 (10.6) - 2 (2.5) 9 (36.0) <0.001 Ischemic 52 (50.0) - 45 (57.0) 7 (28.0) 0.012 Non-ischemic 41 (39.4) - 32 (40.5) 9 (36.0) 0.688 SBP (mmHg) 115.4 ± 15.3 0.985 116.1 ± 14.8 113.2 ± 17.0 0.611 DBP (mmHg) 73.8 ± 10.0 0.539 74.6 ± 9.8 71.4 ± 10.7 0.590 HR (bpm) 67.8 ± 9.4 0.158 67.2 ± 8.6 69.7 ± 11.8 0.340 Weight (kg) 76.0 ± 17.0 0.542 76.9 ± 16.5 73.2 ± 18.6 0.659 AF 10 (9.6) - 9 (11.4) 1 (4.0) 0.445 Class (NYHA): I 17 (16.3) - 14 (17.7) 3 (12.0) 0.757 II 78 (75.0) - 61 (77.2) 17 (68.0) 0.354 III 7 (6.7) - 3 (3.8) 4 (16.0) 0.055 IV 2 (1.9) - 1 (1.3) 1 (4.0) 0.425 FC = III/IV 9 (8.7) - 4 (5.1) 5 (20.0) 0.035 HR ≥70 bpm 43 (41.3) - 31 (39.2) 12 (48.0) 0.438 LVEF (%) 37.3 ± 8.6 0.723 37.7 ± 8.8 36.1 ± 7.9 0.784 LVEDD (mm) 64.3 ± 7.6 0.741 64.2 ± 7.8 64.8 ± 7.0 0.488 LA (mm) 45.8 ± 7.8 0.852 45.6 ± 7.8 46.2 ± 7.8 0.782

SBP: systolic blood pressure; DBP: diastolic blood pressure; HR: heart rate; AF: atrial fibrillation; NYHA: New York Heart Association; FC: functional class; LVEF: left ventricular ejection fraction; LVEDD: left ventricular-end diastolic diameter; LA: left atrial diameter. p*, p value (Student’s t test, Chi-square test or Fisher’s exact test). P (K-S), Kolmogorov-Smirnov test (p > 0.05 = normal distribution).

Table 2 - Percentage of prescription and mean dose of prescribed medications for the treatment of heart failure in the outpatient clinic

Medication n (%) Mean dose (mg/day)

Carvedilol 104 (100.0) 49.8 ± 24.1

Enalapril 55 (52.9) 32.2 ± 27.6

Losartan 42 (40.4) 95.8 ± 48.6

Espironolactona 72 (69.2) 25.7 ± 5.5

Digoxin 17 (16.3) 0.15 ± 0.05

Hydrochlorothiazide 27 (26.0) 32.9 ± 12.6

Furosemide 48 (46.2) 49.6 ± 27.1

Hydralazine 11 (10.6) 172.7 ± 104.6

Nitrates 9 (8.7) 80.00 ± 31.6

Amiodarone 8 (7.7) 115.6 ± 58.2

444 Arq Bras Cardiol. 2013;101(5):442-448 Moreno et al. Optimized treatment in heart failure Original Article

Figure 1 – Patients that met the criteria for further heart rate reduction: 36.5% of patients in sinus rhythm had heart rate (HR) ≥ 70 bpm, who could benefit from further HR reduction.

treatment, were better than those usually described in registries importance of higher doses, with patients showing better and even in some clinical trials4,8,10,11. outcomes when treated with target doses, a more significant 18 In this patient population, the percentage that received a result than with lower doses . renin-angiotensin system blocker was similar to that described Our results showed that it is possible to administrate the in the registries, with more than 90% of patients receiving such target dose to most patients, while demonstrating that Chagas drugs; however, the percentage receiving the target dose was disease was associated with greater difficulty in prescribing higher in our series4,11 . the target doses of beta-blockers. These findings show us that As for the spironolactone, the prescription frequency was physicians used to treating HF can most often prescribe and higher than that observed in the registries and similar to those achieve the target doses of drugs of proven efficacy in HF2,9. observed in the most recent clinical trials4,8,10,12. In the ADHERE It also showed that Chagas disease, probably due to higher Registry, aldosterone blockers were prescribed to 34.6%; in the cardiac impairment and clinical forms, makes it difficult to European registry, to 20.5%, and in the SHIFT study, to 60% of achieve the target doses of these drugs19,20. The higher degree cases, and in our series, to 69.2% of cases4,8,10. of involvement and nonprescription / no tolerance to target As for beta-blockers, all patients were receiving the drug doses may explain the worse outcomes in patients with this 19,20 by selection criteria. The prescribed dose was higher than that disease when they have HF . described in the Registries and even higher than in several There is increasing evidence that the HR can be a good clinical trials of these drugs. Citing two recent studies, in the parameter to indicate the quality of treatment, considering that CIBIS - ELD study the mean prescribed dose of carvedilol was the therapeutic regimen should promote HR reduction, ​​aiming 23.9 mg, and 31% received the target dose of 50 mg/day11. at achieving a HR of around 70 beats per minute or less8,12,21,22. In the SHIFT study, the mean dose was 25.0 mg/day and 26% The presence of HR > 70 bpm would be an indicator of the received the target dose, while in our series the mean dose of need to review the treatment and optimize it. carvedilol was 49.8 mg/day and 76% received the target dose The issue of HR and treatment of HF is a controversial one of 50 mg/day8. and not fully understood, and its interpretation is necessary to The issue of the BB dose is not fully elucidated, but the consider different variables. For instance, in Chagas disease MOCHA and REVERT studies and the analyses of CIBS-II, and in elderly patients, HF is often lower, and thus cannot be CIBIS-III and SENIORS studies indicate that higher doses used as a good indicator of treatment quality. Incidentally, this result in better outcomes with greater reversal of cardiac was one of the results of this study, when we observed that the dilatation and morbimortality reduction13-17. Analysis of data doses of BB prescribed to chagasic patients were lower than from the HF-ACTION study of 2012 again confirmed the those prescribed to nonchagasic ones.

Arq Bras Cardiol. 2013;101(5):442-448 445 Moreno et al. Optimized treatment in heart failure Original Article

In recent years, however, evidence started to appear Study limitations that higher HR would be an important prognostic marker. This pilot observational study demonstrated that cardiologists The BEAUTIFUL and SHIFT studies demonstrated that patients used to treating HF ​​prescribe medications that have been with HR > 70 bpm have a poorer prognosis than patients shown to improve the prognosis of HF, as recommended by the with lower basal HR8,21. Similar results have been reported in Guidelines; however, we do not know how these patients are different databases, such as in the CHARM and DIG studies and treated by most generalists at public health units, and what the in case series22-24. These data leave no doubt that HR should impact is on clinical outcomes (prognosis, HF hospitalizations), be considered an important prognostic factor and should be when comparing the treatment of HF performed by clinicians targeted for treatment, as it has been shown that its reduction and cardiologists. Additional studies are needed to understand with ivabradine resulted in a decrease in hospital admissions due to decompensated HF and from all causes, and reduced the treatment of HF in our country. HF mortality, with no difference in cardiovascular and all-cause mortality. Conclusion In our study, we analyzed the HR in patients after treatment The results of this analysis showed that, in a population optimization and observed that a third of them, even after treated at medical offices, most patients tolerate the drugs of receiving full doses of beta-blockers, persisted with basal proven efficacy in the treatment of HF and the target doses HR > 70 bpm. can be prescribed and are tolerated by most patients. It also This result is similar to that described in several European showed that about one third of patients with optimized HF registries and even clinical trials; there were, however, no treatment remain with HR > 70 bpm, allowing us to conclude Brazilian data on this clinical finding3,4,24,25. that the treatment could be revised and further optimized. When analyzing our series, we tried to verify whether the These findings require further investigations to help in clinical characteristics and those related to the treatment of the planning of new studies in this area, enabling a better patients could explain this finding of HR > 70 bpm. To analyze understanding of HF treatment in the real world and thus the data, we divided the patients into two groups: those assist in the care of patients with this malignant and debilitating with HR > and < 70 bpm. In this comparison, we found no syndrome, in an attempt to reverse this trend. differences that could explain the finding, as the two groups were similar regarding clinical characteristics, as well as the medical treatment received. Moreover, there was no association Author contributions between the prescribed dose of BB and HR of the patient when Conception and design of the research, Acquisition of data undergoing stabilized and optimized drug therapy. Our results and Critical revision of the manuscript for intellectual content: overlap those observed in the SHIFT study, showing that the Moreno IB, Del Carlo CH, Pereira-Barretto AC; Analysis and observed HR was not associated with the dose of BB that interpretation of the data, Statistical analysis and Writing of patients were receiving8,12. the manuscript: Del Carlo CH, Pereira-Barretto AC. Overall, our data and the literature indicate that HF treatment should be individualized. When patients receive treatment Potential Conflict of Interest instructions, physicians should seek to prescribe drugs of proven No potential conflict of interest relevant to this article was efficacy at doses that have shown benefits. We confirmed that the majority of office patients tolerate these doses. reported. Notwithstanding the optimized treatment, patients persisted with HR > 70 bpm, a finding indicative of worse prognosis, Sources of Funding indicating the need for treatment reevaluation and possibly There were no external funding sources for this study. improved optimization, aiming at a reduction in HR. For that purpose, one can prescribe digitalis, increase the dose of beta‑blockers or prescribe ivabradine. Of these drugs, ivabradine Study Association is the one of which effectiveness has been documented, randomly This study is not associated with any post-graduation analyzed in a large clinical trial, the SHIFT study8. program.

References

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448 Arq Bras Cardiol. 2013;101(5):442-448 Original Article

Mechanical Dyssynchrony is Similar in Different Patterns of Left Bundle-Branch Block Rodrigo Bellio de Mattos Barretto, Leopoldo Soares Piegas, Jorge Eduardo Assef, José Francisco Melo Neto, Thiago Uchoa Resende, Dalmo Antonio Moreira, David Costa LeBihan, Francisco Faustino França, Romeu Sérgio Meneghelo, Amanda Guerra Moraes Rego Sousa Instituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil

Abstract Background: Left bundle-branch block (LBBB) and the presence of systolic dysfunction are the major indications for cardiac resynchronization therapy (CRT). Mechanical ventricular dyssynchrony on echocardiography can help identify patients responsive to CRT. Left bundle-branch block can have different morphologic patterns. Objective: To compare the prevalence of mechanical dyssynchrony in different patterns of LBBB in patients with left systolic dysfunction. Methods: This study assessed 48 patients with ejection fraction (EF) < 40% and LBBB consecutively referred for dyssynchrony analysis. Conventional echocardiography and mechanical dyssynchrony analysis were performed, interventricular and intraventricular, with ten known methods, using M mode, Doppler and tissue Doppler imaging, isolated or combined. The LBBB morphology was categorized according to left electrical axis deviation in the frontal plane and QRS duration > 150 ms. Results: The patients’ mean age was 60 ± 11 years, 24 were males, and mean EF was 29% ± 7%. Thirty-two had QRS > 150 ms, and 22, an electrical axis between −30° and +90°. Interventricular dyssynchrony was identified in 73% of the patients, while intraventricular dyssynchrony, in 37%-98%. Patients with QRS > 150 ms had larger left atrium and ventricle, and lower EF (p < 0.05). Left electrical axis deviation associated with worse diastolic function and greater atrial diameter. Interventricular and intraventricular mechanical dyssynchrony (ten methods) was similar in the different LBBB patterns (p = ns). Conclusion: In the two different electrocardiographic patterns of LBBB analyzed, no difference regarding the presence of mechanical dyssynchrony was observed. (Arq Bras Cardiol. 2013;101(5):449-456) Keywords: Bundle-Branch Block; Ventricular Dysfunction; Cardiac Resynchronization Therapy; Stroke Volume.

Introduction complex enlargement, as observed in LBBB, is the most frequent indication for that treatment4-6. However, treatment failure has Heart failure, a clinical syndrome resulting from structural been reported in approximately 30% of the cases in several series3. and/or functional cardiac dysfunction, is known to be the In addition to the already known classic information, end stage of several cardiopathies. Electrocardiographic such as left ventricular dimension and ejection fraction, alterations, such as left bundle-branch block (LBBB), are echocardiography allows the analysis of interventricular common findings in patients with heart failure, mainly in and intraventricular synchronism, which is the focus of the presence of systolic dysfunction1,2. CRT. Different methods, using several echocardiographic Currently, there are several treatment options for heart failure. techniques, have been used to detect and stratify dyssynchrony7,8, enabling predicting those who will have One efficient alternative is cardiac resynchronization therapy3 good results with a certain treatment. (CRT). The indication for implantation of a resynchronizing Left bundle-branch block can have different characteristics pacemaker is based on clinical and electrocardiographic criteria, related to higher morbidity and mortality9,10. The relationship and echocardiographic data. On the electrocardiogram, QRS between different characteristics of LBBB and dyssynchrony assessed on echocardiography is yet to be established, which might contribute to the lack of success of that therapy. Mailing Address: Rodrigo Bellio de Mattos Barretto • Rua Alagoas, 134, apt.º 91, Higienópolis. Postal Code 01242-000, São Paulo, SP - Brazil Objectives E-mail: [email protected], [email protected] Manuscript received November 06, 2012; manuscript revised June 19, 2012; This study aimed at comparing conventional manuscript accepted June 26, 2013. echocardiographic findings and those of ventricular synchrony related to different LBBB morphologies in patients DOI: 10.5935/abc.20130190 with left ventricular systolic dysfunction.

449 Barretto et al. Mechanical dyssynchrony versus LBBB morphologies Original Article

Methods the maximum motion times, measured on tissue Doppler maging, in 12 left ventricular segments > 32 ms, proposed This study was approved by the Committee on Ethics and 7 Research of the Instituto Dante Pazzanese de Cardiologia. by Yu et al ; 7) interval values > 60 ms of the onset of mitral ring systolic motion in four segments measured by use of tissue Doppler imaging, as reported by De Sutter et al20; 8) Study population interval values > 100 ms of the end of mitral ring systolic This study assessed individuals followed up on an motion in four segments measured on tissue Doppler outpatient basis for heart failure treatment, who were imaging, as reported by Perez de Isla et al21, in the Spanish referred to the echocardiography section with systolic Ventricular Asynchrony Registry - RAVE; 9) interval between dysfunction characterized by ejection fraction below the maximum contraction of the anteroseptal and posterior 40%, according to the Simpson’s method. All patients segments > 130 ms measured by use of two-dimensional had sinus rhythm and LBBB11. Patients with the following strain associated with the interval of the septal-to-lateral characteristics were excluded: under the age of 18 years; wall maximum systolic motion on tissue Doppler > 60 ms, wearing a pacemaker; and those who had undergone as demonstrated by Gorcsan et al22 previous valvular surgery or had any degree of aortic valvulopathy. The clinical data concerning functional class, Statistical analysis history and medications used were also assessed. The quantitative variables were described as mean ± standard deviation, and the qualitative ones, as percentages. Electrocardiogram For comparing the different LBBB presentations, the following Twelve-lead electrocardiography was performed. tests were used: Student t test; Wilcoxon test; chi-square The PR intervals and QRS complexes were measured, and test; and Fisher exact test. The JMP8.0® software (Institute the frontal axis characteristics were assessed. The patients Inc., Carry, North Carolina) was used for calculation. were classified into two groups according to the presence The significance level of 5% was adopted. of QRS interval > 150 ms or left electrical axis deviation in the frontal plane, i.e., frontal axis values < –30°. Results Echocardiogram Table 1 shows the clinical characteristics of the 48 patients studied, with approximately 90% of them ® Echocardiogram was performed on a Vivid7 device (GE on beta-blockers and angiotensin-converting-enzyme Vingmed, System VII, Horton, Norway). The images were inhibitors/angiotensin‑receptor blockers. Table 2 shows acquired as digital clips. Then, linear and two-dimensional their electrocardiographic findings. Table 3 shows their measures were taken according to the American Society of echocardiographic variables, with varied degrees of Echocardiography guidelines, using a mean of three consecutive intraventricular dyssynchrony according to the criteria used. cycles on a EchoPAC PC work station, version 6.0.1® (GE Vingmed Ultrasound). Diastolic function was also characterized When patients were compared according to their different according to the American Society of Echocardiography LBBB morphologies, QRS duration > 150 ms and electrical guidelines, and mitral valve regurgitation was quantified12,13. axis in the frontal plane −30° did not relate to differences concerning sex, age, history, functional class or medication Interventricular dyssynchrony was assessed as the used, as shown in Tables 4 and 5. difference between pre-ejection intervals, i.e., from the beginning of the QRS complex to the beginning of the Regarding echocardiographic findings, patients with QRS ventricular ejection into the aortic and pulmonary valves, duration > 150 ms showed greater left ventricular linear using pulsed Doppler; interventricular dyssynchrony was dimensions and volumes, greater left atrial diameters and considered to exist when that value exceeded 40 ms14,15. lower ejection fraction, as shown in Table 4. According to the literature, mechanical intraventricular Patients with left electrical axis deviation in the frontal dyssynchrony has been assessed by use of several plane, < −30°, showed greater left atrial diameters methodologies, whose cutoff points have been described associated with higher grades of left ventricular diastolic as markers of successful CRT. The analysis was performed dysfunction, and greater left ventricular diameter, as according to the following criteria: 1) septal-to-posterior evidenced in Table 5. wall motion delay, in M mode, > 130 ms, as reported The presence of interventricular and intraventricular by Pitzalis et al16; 2) greater interval between maximum dyssynchrony was similar in the two groups of LBBB (longer systolic motion of six left ventricular basal segments > QRS interval duration and left electrical axis deviation in the 110 ms, measured on tissue Doppler, as demonstrated by frontal plane) (Tables 4 and 5). Notabartolo et al17; 3) maximum systolic motion interval between the septum and lateral wall on tissue Doppler > 65 ms, as reported by Gorcsan et al18; 4) presence of Discussion positive criterion of the Saint Mary Hospital score, United The different LBBB presentations assessed do not Kingdom, as reported by Lane et al19; 5) positive criteria allow identifying a dyssynchrony pattern, and their for the presence of dyssynchrony, as established by Cleland prevalences did not differ in the different echocardiographic et al14, in the CARE-HF study; 6) standard deviation of methodologies assessed.

Arq Bras Cardiol. 2013;101(5):449-456 450 Barretto et al. Mechanical dyssynchrony versus LBBB morphologies Original Article

Table 1 – Clinical characteristics of the patients Table 2 – Electrocardiographic (ECG) characteristics

Clinical characteristics/ ECG measures Age (years) 59.9 ± 11.1 Heart rate (bpm) 72.3 ± 14.2 Male sex 50% PR interval (ms) 232.8 ± 58.9 History QRS width (ms) 165.0 ± 28.1 Arterial hypertension 62.4% Frontal ECG axis (º) −2.3 ± 45.8 Coronary artery disease 26.0% Pattern (%) Previous myocardial infarction 22.5% QRS > 150 ms 66.7% Diabetes mellitus 16.5% Frontal ECG axis between −30º and +90º 54.2% Chagas’ disease 6.1% Functional class (NYHA) I 9.5% Despite the limitations of using echocardiography as the method for selecting candidates for pacemaker II 47.6% implantation with evidenced capacity of resynchronization III 42.8% on the PROSPECT study28, most of the methods used Medications used proved to distinguish patients who would benefit from Digitalis 39.6% that therapy. Single center studies have reported several echocardiographic methods that evidenced a better Loop diuretics 81.3% response to that therapy. Spironolactone 79.2% Sweeney et al29 have shown that the conventional Angiotensin-converting-enzyme inhibitor 56.3% electrocardiographic report in patients with LBBB, such Angiotensin receptor blocker 31.3% as QRS duration and the presence of left electrical axis deviation, are not enough to predict individuals who Beta-blocker 89.6% will have echocardiographic improvement after cardiac Calcium channel blocker 6.3% resynchronization by use of pacemaker. However, Nitrate 12.7% electrocardiographic evidence of longer left ventricular NYHA: New York Heart Association. activation time and smaller scar volume characterizes the group of patients with a better response to the resynchronizer. Such measures were not assessed in the present study, and the study by Sweeney et al29 has not However, the LBBB patterns relate to left ventricular compared those electrocardiographic findings with the morphologic and functional alterations, in which longer echocardiographic assessment of mechanical synchrony. QRS complex durations associate with greater left ventricular That relationship can be tested in a further study. dimensions, and the left electrical axis deviation on electrocardiogram relates to greater diastolic dysfunction and greater left atrial dimension. Conclusion Those findings are in accordance with the study by Das In the two different electrocardiographic patterns of LBBB et al23, who have shown that left ventricular ejection fraction analyzed with ten echocardiographic methods, no difference is more impaired when the QRS duration is increased in regarding the presence of mechanical dyssynchrony was patients with LBBB, but it is not associated with left electrical observed. They can, however, be associated with known axis deviation. However, according to Dhingra et al24, the risk patterns, such as a reduced ejection fraction and greater higher incidence of events in patients with LBBB and left diastolic dysfunction grades. electrical axis deviation should be associated with greater diastolic dysfunction, which is known to relate to mortality25. Author contributions Although not all patients meet the criteria proposed Conception and design of the research: Barretto RBM, by the last guidelines for implantation of resynchronizing Piegas LS, Moreira DA, França FF; Acquisition of data: pacemakers5, those indications have been modified, and Barretto RBM, Melo Neto JF, Resende TU; Analysis and most patients studied constitute a group candidate for CRT, interpretation of the data: Barretto RBM, Piegas LS, Assef JE, including patients with ejection fraction < 40%5,26. Findings Melo Neto JF, Resende TU, Moreira DA, França FF; Statistical might indicate lack of relationship between longer QRS analysis and Obtaining funding: Barretto RBM; Writing of intervals in LBBB and the response to that type of treatment27, the manuscript: Barretto RBM, Piegas LS, Assef JE; Critical because the prevalence of mechanical dyssynchrony is similar revision of the manuscript for intellectual content: Barretto regardless of the echocardiographic method used. RBM, Assef JE, LeBihan DC, Meneghelo RS, Sousa AGMR.

451 Arq Bras Cardiol. 2013;101(5):449-456 Barretto et al. Mechanical dyssynchrony versus LBBB morphologies Original Article

Table 3 – Echocardiographic characteristics

Echocardiographic measures M mode Left atrium (mm) 45.5 ± 7.0 Left ventricle, diastole (mm) 74.1 ± 9.8 Left ventricle, systole (mm) 64.3 ± 10.7 Two-dimensional End-diastolic volume (mL) 203.4 ± 79.8 End-systolic volume (mL) 148.5 ± 66.1 Left ventricular ejection fraction (%) 28.7 ± 7.3 Diastolic pattern Grade IA dysfunction 37.5% Grade II dysfunction 31.3% Grade III/IV dysfunction 20.8% Undetermined 10.4% Mitral regurgitation Absent 14.6% Mild 54.2% Moderate 27.1% Severe 4.2% Prevalence of interventricular dyssynchrony Interval between pulmonary and aortic pre-ejective periods > 40 ms 72.9% Prevalence of intraventricular dyssynchrony Criteria Pitzalis et al16 50.0% Notabartolo et al17 39.6% Gorcsan et al18 37.4% Lane et al19 97.9% Cleland et al14 60.4% Yu et al30 60.4% De Sutter et al20 85.4% Criterion I 60.4% Perez de Isla et al21 Criterion II 41.7% Gorcsan et al22 66.0%

Potential Conflict of Interest Study Association No potential conflict of interest relevant to this article was This article is part of the thesis of doctoral submitted reported. by Rodrigo Bellio de Mattos Barretto, from Universidade de São Paulo. Sources of Funding There were no external funding sources for this study.

Arq Bras Cardiol. 2013;101(5):449-456 452 Barretto et al. Mechanical dyssynchrony versus LBBB morphologies Original Article

Table 4 – Comparison of echocardiographic data between patients with different QRS intervals

Echocardiographic measures QRS interval Variable ≤ 150 ms > 150 ms p value (n = 16) (n = 32) M mode Left atrium (mm) 42.2 ± 7.1 47.1 ± 6.5 0.03 Left ventricle, diastole (mm) 71.1 ± 9.5 78.4 ± 8.8 0.001 Left ventricle, systole (mm) 57.9 ± 10.9 64.4 ± 9.26 0.03 Two-dimensional End-diastolic volume (mL) 153.3 ± 69.9 228.6 ± 73.0 0.002 End-systolic volume (mL) 108.3 ± 58.8 168.6 ± 60.8 0.002 Left ventricular ejection fraction (%) 31.8 ± 7.4 27.2 ± 6.8 0.04 Diastolic pattern ns Grade IA dysfunction 12.5% 6.2% Grade II dysfunction 43.8% 59.4% Grade III/IV dysfunction 37.5% 25.0% Undetermined 6.2% 9.4% Mitral regurgitation ns Absent 31.2% 6.2% Mild 50.0% 56.2% Moderate 12.5 34.4% Severe 6.2% 3.1% Prevalence of interventricular dyssynchrony Interval between pulmonary and aortic pre-ejective periods > 40 ms 68.8% 75.0% ns Prevalence of intraventricular dyssynchrony Criteria Pitzalis et al16 61.5% 59.3% ns Notabartolo et al17 56.3% 31.3% ns Gorcsan et al18 50.0% 31.3% ns Lane et al19 100.0% 96.9% ns Cleland et al14 56.3% 62.5% ns Yu et al30 87.5% 62.5% ns De Sutter et al20 87.5% 84.4% ns Criterion I 62.5% 59.4% ns Perez de Isla et al21 Criterion II 43.4% 40.6% ns Gorcsan et al22 50.0% 74.2% ns ns: non-significant, p > 0.05.

453 Arq Bras Cardiol. 2013;101(5):449-456 Barretto et al. Mechanical dyssynchrony versus LBBB morphologies Original Article

Table 5 – Comparison of echocardiographic data between patients with different axis orientation in the frontal plane

Echocardiographic measures Axis in the frontal plane Variable between – 30º and +90º < – 30º p value (n = 26) (n = 22) M mode Left atrium (mm) 42.1 ± 6.3 49.4 ± 5.7 0.0001 Left ventricle, diastole (mm) 71.45 ± 10.5 77.2 ± 8.1 ns Left ventricle, systole (mm) 61.7 ± 11.6 67.4 ± 8.7 ns Two-dimensional End-diastolic volume (mL) 191.2 ± 92.4 217.8 ± 80.8 ns End-systolic volume (mL) 137.9 ± 74.9 161.1 ± 52.7 ns Left ventricular ejection fraction (%) 30.4 ± 7.3 26.8 ± 6.9 ns Diastolic pattern 0,01 Grade IA dysfunction 53.9% 18.2% Grade II dysfunction 23.1% 40.9% Grade III/IV dysfunction 7.7% 36.4% Undetermined 15.4% 4.6% Mitral regurgitation ns Absent 23.1% 4.6% Mild 50.0% 59.1% Moderate 23.1% 31.8% Severe 3.8% 4.6% Prevalence of interventricular dyssynchrony Interval between pulmonary and aortic pre-ejective periods > 40 ms 76.9% 68.2% ns Prevalence of intraventricular dyssynchrony Criteria ns Pitzalis et al16 63.7% 55.6% ns Notabartolo et al17 34.6% 27.3% ns Gorcsan et al18 38.4% 36.4% ns Lane et al19 96.2% 100.0% ns Cleland et al14 61.5% 59.1% ns Yu et al30 76.9% 63.6% ns De Sutter et al20 84.6% 83.4% ns Criterion I 53.9% 66.2% ns Perez de Isla et al21 Criterion II 42.3% 40.9% ns Gorcsan et al22 60.0% 72.7% ns ns: non-significant, p > 0.05.

Arq Bras Cardiol. 2013;101(5):449-456 454 Barretto et al. Mechanical dyssynchrony versus LBBB morphologies Original Article

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Arq Bras Cardiol. 2013;101(5):449-456 456 Original Article

Criteria for Mitral Regurgitation Classification were inadequate for Dilated Cardiomyopathy Frederico José Neves Mancuso1, Valdir Ambrosio Moisés1, Dirceu Rodrigues Almeida1, Wercules Antonio Oliveira2, Dalva Poyares2, Flavio Souza Brito1, Angelo Amato Vincenzo de Paola1, Antonio Carlos Camargo Carvalho1, Orlando Campos1 Disciplina de Cardiologia – EPM/UNIFESP - Escola Paulista de Medicina - Universidade Federal de São Paulo1; Instituto do Sono - EPM/UNIFESP - Escola Paulista de Medicina - Universidade Federal de São Paulo2, São Paulo, SP – Brazil

Abstract Background: Mitral regurgitation (MR) is common in patients with dilated cardiomyopathy (DCM). It is unknown whether the criteria for MR classification are inadequate for patients with DCM. Objective: We aimed to evaluate the agreement among the four most common echocardiographic methods for MR classification. Methods: Ninety patients with DCM were included. Functional MR was classified using four echocardiographic methods: color flow jet area (JA), vena contracta (VC), effective regurgitant orifice area (ERO) and regurgitant volume (RV). MR was classified as mild, moderate or important according to the American Society of Echocardiography criteria and by dividing the values into terciles. The Kappa test was used to evaluate whether the methods agreed, and the Pearson correlation coefficient was used to evaluate the correlation between the absolute values of each method. Results: MR classification according to each method was as follows: JA: 26 mild, 44 moderate, 20 important; VC: 12 mild, 72 moderate, 6 important; ERO: 70 mild, 15 moderate, 5 important; RV: 70 mild, 16 moderate, 4 important. The agreement was poor among methods (kappa = 0.11; p < 0.001). It was observed a strong correlation between the absolute values of each method, ranging from 0.70 to 0.95 (p < 0.01) and the agreement was higher when values were divided into terciles (kappa = 0.44; p < 0.01) Conclusion: The use of conventional echocardiographic criteria for MR classification seems inadequate in patients with DCM. It is necessary to establish new cutoff values for MR classification in these patients. (Arq Bras Cardiol. 2013;101(5):457-465) Key Words: Mitral Valve Insufficiency / classification; Cardiomyopathy, Dilated; Echocardiography / utilization.

Introduction result of a complex phenomenon, with displacement of the Functional mitral regurgitation (MR) is the secondary papillary muscles caused by LV dilation, valve ring dilatation and tethering of the mitral valve1,6-8. Furthermore, in patients MR to left ventricle (LV) dilation1 and it is often shown in with DCM, the left atrium works as a low resistence chamber patients with dilated cardiomyopathy (DCM), where the to which the LV can eject blood9. significant MR occurs in 35-50% of patients with chronic heart failure2. It has already been shown that presence and Although some authors support mitral valve surgery for severity of a functional MR are independently associated patients with significant functional MR and heart failure, with the prognosis in patients with non-ischemic DCM3-5. it is still controversial the suggestion for surgery in these patients10-12. Currently, mitral valve surgery is considered The functional MR pathophysiology is different from that as Class IIb for patients with refractory heart failure and of the MR by primary valvular disease. Functional MR is the significant functional MR13. Doppler echocardiography is the test of choice for the noninvasive assessment of MR mechanism and severity14. It is unknown whether the recommendations of the Mailing Addres: Frederico José Neves Mancuso • American Society of Echocardiography (ASE), together Rua Domiciano Leite Ribeiro, 51, Apto. 13 - bloco 2, Vila Guarani. Postal with the European Society of Cardiology Working Group Code 04317-000, São Paulo, SP - Brazil for evaluation and classification of primary valvular Email: [email protected], [email protected] 14 Manuscript received January 15, 2013; revised manuscript May 10, 2013; insufficiency by Doppler echocardiography are suitable accepted June 07, 2013 for patients with functional MR and DCM. Additionally, the different methods using Doppler echocardiography DOI: 10.5935/abc.20130200 and color flow mapping were validated in clinical studies

457 Manuso et al. Classification of functional mitral regurgitation Original Article for patients showing different causes of primary MR15, but The IM was classified as mild, moderate or important not specifically for patients with DCM. using each of the methods described according to the criteria This study aimed to evaluate the agreement for patients with and cutoff values of the recommendations of the American 14 DCM, among the four most commonly used echocardiographic Society of Echocardiography . MR was also divided into methods for MR classification. terciles (lower, intermediate and higher values) according to the absolute values obtained by each method.

Methods Statistical Analysis Statistical analysis was performed using the SPSS 13.0 Patients software (SPSS Inc., Chicago, Illinois). Continuous data are This study included 90 consecutive outpatients with shown as mean ± PD and categorical data are described non‑ischemic DCM and functional MR of a tertiary center in percentages. Pearson correlation coefficient was used to for treatment of heart failure and cardiomyopathies, of the assess the correlation between the absolute values of the Escola Paulista de Medicina / Universidade Federal de São four methods used for MR quantification. Kappa agreement Paulo, from September 2007 to September 2009. Inclusion test was used to assess the agreement between methods criteria were: age ≥ 18 years old, functional class ≤ III used to classify the MR. Significance values of p < 0.05 (New York Heart Association), medical treatment optimized were considered. for heart failure, sinus rhythm, LV ejection fraction ≤ 0.40 (Simpson method modified) and good quality image. Results Patients with primary valvular disease, hypertension, coronary artery disease (for epidemiology and/or coronary angiography), end stage renal disease or chronic obstructive Clinical Data pulmonary disease were excluded. All participants signed Patient clinical basal characteristics are detailed in Table 1. an informed consent and the institution of ethics committee From the total 90 patients, 60 (67%) showed idiopathic approved the project. dilated cardiomyopathy and 30 (33%) patients showed Chagas cardiomyopathy. Functional class mean was 2.2 ± 0.6. All patients were on beta-blockers (carvedilol 76%, 48 ± 6 mg/day, and Echocardiography metoprolol 24%, 178 ± 43 mg/day), ACE inhibitors (captopril All subjects performed a full two-dimensional 62%, 133 ± 24 mg/day, and enalapril 38%, 31 ± 10 mg/day), echocardiography by using the IE 33 machine (Philips, Andover, and furosemide (97 ± 62 mg/day). Eighty-one (90%) patients Massachusetts), equipped with a 2-5 MHz transducer and were on spironolactone and 20 (22%) were taking digoxin. under continuous electrocardiographic monitoring. Patients were assessed in left lateral decubitus by an echocardiograph Doppler echocardiography qualified-physician, only. LV ejection fraction was calculated using the Simpson method modified. Doppler echocardiography data are described in Table 2. LV ejection fraction average was 0.30 ± 0.07 and 24 (27%) patients showed restrictive filling pattern. The E/e’ ratio was Mitral Regurgitation Echocardiographic Assessment 18.0 ± 7.9 and the mean systolic pulmonary pressure was MR was assessed by four echocardiographic methods that 44 ± 13 mmHg. are part of the recommendations of the American Society 14 of Echocardiography : area of the regurgitant jet (RJ), vena Mitral Regurgitation - Echocardiographic Data contracta (VC), effective regurgitant orifice area (ERO) and The mean values for each method were: RJ: 6.8 ± 4.1 cm2, regurgitant volume (RV) by the converging flow method VC: 0.44 ± 0.15 cm; ERO: 0.14 ± 0.10 cm2, and (PISA). All methods were assessed at the apical window RV: 22.1 ± 15.3 ml (Table 3). The MR jets were central using image zoom. in all patients, as expected. Pearson calculated correlation RJ was measured in the apical 4-chamber view using coefficient (r) indicated a strong correlation between the Nyquist limit of 50-60 cm/s, the color gain adjusted to absolute values of each method, ranging from 0.70 to 0.95 exclude artifacts from non-mobile structures (Figure 1). (p < 0.01) (Figure 2). VC was measured in the apical 4-chamber view as the According to the cutoff values of the recommendations narrowest MR jet, after the orifice (Figure 1). of the American Society of Echocardiography, MR was The converging flow method (proximal isovelocity classified by the RJ method as mild in 26 patients, moderate surface area; PISA) was used to calculate the ERO and RV. in 44 patients and important in 20 patients. Through the PISA radius was measured using the Nyquist limit at which VC, MR was considered mild in 12 patients, moderate in the flow convergence assumed a hemispherical shape 72 patients and important in 6 patients. Through the ERO, (Figure 1). ERO was calculated using the formula: 2 x π x R2 70 patients showed mild MR, 15 patients moderate MR x V aliasing / V peak (R: radius, in cm; V aliasing: proximal and 5 patients important MR. Through the RV, MR was flow convergence velocity in cm/s, V peak: MR maximum mild in 70 patients, moderate in 16 patients and important velocity in cm/s). RV was calculated using the formula: in 4 patients (Figure 3). The agreement among the four ERO x VTI (VTI: MR jet velocity time integral). methods evaluated was poor (kappa = 0.11, p <0.01).

Arq Bras Cardiol. 2013;101(5):457-465 458 Manuso et al. Classification of functional mitral regurgitation Original Article

Figure 1 - Mitral regurgitation assessment using four echocardiographic methods in a patient with idiopathic dilated cardiomyopathy. A) Mitral regurgitation jet area measurement showing an area of 9.01 cm2; B) Vena contracta measurement (0.40 cm), in; C/D) Magnified image of the measure of hemisphere radius, maximum velocity and VTI for calculation of effective regurgitant orifice area and regurgitant volume. In this patient, the effective regurgitant orifice area was 0.14 cm2 and the regurgitant volume was 23.8 ml.

Table 1 – Patient Basal Clinical Features Twenty patients with important MR by the RJ showed the same LV ejection fraction as the other patients (28.04 ± 5.21 N = 90 patients vs. 31.01 ± 7.79, p = 0.11). Age (years) 53 ± 11 The absolute values of each method were divided into terciles: Male (%) 70 30 lower values, 30 intermediate values and 30 higher values (Figure 4). The cutoff values that divided the terciles were different BSA (kg/m²) 1.73 ± 0.17 from the cutoff values of the American Society of Echocardiography. HR (bpm) 69 ± 12 With the cutoff values used to divide into terciles for the MR SBP (mmHg) 109 ± 20 classification in each method, we observed a better agreement DBP (mmHg) 69 ± 14 among the methods (kappa = 0.44, p <0.01). Figure 5 shows the MR classification box-plots according to the cutoff values of the Cardiomyopathy 60 (67%) American Society of Echocardiography and the terciles. Idiopathic Dilated Cardiomyopathy (%) 30 (33%) Discussion Chagas (%) The main finding of this study is the poor ruim agreement Functional Class 2.2 ± 0.6 among the quantitative echocardiographic methods for MR (NYHA) classification in patients with DCM, using the criteria and FC I 7 (8%) cutoff values of the American Society of Echocardiography. FC II 55 (61%) The MR evaluation and classification remains a challenge, FC III 28 (31%) even in patients with primary valvular disease, which has been 15-18 Values expressed as mean ± standard deviation or frequency (%). the reason for recent publications . This is the first study to BSA: body surface area; FC: functional class; HR: heart rate; NYHA: New York address the MR classification by different echocardiographic Heart Association; DBP: diastolic blood pressure; SBP: systolic blood pressure. methods in patients with DCM. A previous study, which

459 Arq Bras Cardiol. 2013;101(5):457-465 Manuso et al. Classification of functional mitral regurgitation Original Article

Table 2 – Doppler echocardiography data included patients with myxomatous or rheumatic etiology MR, unlike our study, showed a good agreement between N = 90 patients the quantitative echocardiographic methods15. LA Diameter 46 ± 6 mm Although we have observed a good correlation between the absolute values of each method, there was a poor agreement LAVi 54 ± 19 ml/m2 in the MR classification. The highest correlation was between LVEDV 273 ± 100 ml the ERO and RV, as expected, since both measures derives LVESV 194 ± 84 ml from PISA method. These findings suggest that the main reason for the poor agreement between the methods is that, although LVEF 30.4 ± 7.4 % the cutoff values of the American Society of Echocardiography E Wave Velocity 79.5 ± 29.7 cm/s are appropriate for patients with primary valvular disease15, A Wave Velocity 65.6 ± 31.9 cm/s they are inadequate for patients with functional MR and DCM. The best agreement observed when using different cutoff values, E/A ratio 1.4 ± 1.5 based on the division into terciles, reinforces this hypothesis. Restrictive filling standard 27 % Further studies are required to establish specific cutoff values for e’ septal Wave Velocity 4.8 ± 1.8 cm/s the classification of functional MR in patients with DCM. E/e’ ratio 18.0 ± 7.9 Functional Mitral Regurgitation: Echocardiographic PASP 44 ± 13 mmHg Assessment Mechanisms Values expressed as mean ± standard deviation or frequency (%). LA: left atrium; LVEF: left ventricle ejection fraction; PASP: pulmonary artery systolic pressure; LAVi: left atrial volume indexed by surface area; LVEDV: left Differences between the pathophysiological mechanisms ventricle end-diastolic volume; LVESV: left ventricle end-systolic volume. of primary and functional MR6,7, as well as particularities of

Table 3 – Mitral regurgitation data (n = 90 patients)

Values Range Jet Area 6.8 ± 4.1 cm2 1.3 – 19 cm2 Vena contracta 0.44 ± 0.15 cm 0.13 – 0.94 cm ERO 0.14 ± 0.10 cm2 0.02 – 0.61 cm2 RV 22.1 ± 15.3 ml 4.5 – 83.4 ml Values expressed as mean ± standard deviation ERO: effective regurgitant orifice area; RV: regurgitant volume.

Figure 2 - Scatter charts for the correlation between absolute values for each of the four methods used for Mitral Regurgitation classification (p < 0.01). RJ: regurgitant jet area; ERO: effective regurgitant orifice area; VC: vena contracta; RV: regurgitant volume.

Arq Bras Cardiol. 2013;101(5):457-465 460 Manuso et al. Classification of functional mitral regurgitation Original Article

Figure 3 – Mitral Regurgitation classification using the four methods described in the study, according to the cutoff values of the American Society of Echocardiography. There was a poor agreement between the methods; kappa: 0.11, p < 0.01. RJ: regurgitant jet area; ERO: effective regurgitant orifice area; VC: vena contracta; RV: regurgitant volume.

echocardiographic techniques may also have contributed classified as moderate in most patients, which may also to the discrepancies in the MR classification observed in have contributed to the observed poor agreement between this study. the methods. ERO and RV by the PISA method may be less The structural changes that occur in the mitral valve accurate in patients with DMC due to non-circular ERO that apparatus are different among patients with MR and those occurs in functional MR, besides the irregular shape of the 16 with primary MR and those with functional MR by DMC. convergence flow zone in these patients . It was recently In functional MR, there is a posterolateral and apical shown that ERO and RV calculated by echocardiography displacement of the papillary muscle, apical tethering are underestimated when compared to these parameters of the valve cusps, and reduced mobility19. Recently, obtained by three-dimensional echocardiography and 22 with the use of three-dimensional transesophageal nuclear magnetic resonance . Therefore, the PISA method echocardiography, Matsumara et al. demonstrated that may underestimate ERO and RV in patients with DCM and PISA geometry is different for patients with DCM, where functional MR, which explains the fact that few patients in the converging flow zone radius is longer in functional our study have important MR presented according to the MR, when compared to the MR per mitral valve prolapse. ERO and RV methods. The authors also observed that PISA method underestimates The evaluation of left atrial and LV dimensions provide the ERO in functional MR16. Previously, an in vitro study important data for the classification of primary MR14. demonstrated that ERO underestimates PISA when this is However, in patients with DCM, the dimensions of these not hemispherical20. These findings, in part, explain the heart chambers do not provide indirect information about poor agreement between the MR classification methods MR severity, since the expansion of these cavities is primarily observed in our study, especially for the exceeding MR by their own cardiomyopathy. classified as mild by ERO and RV. The criteria for the MR classification have not been validated Particular technical aspects of Doppler echocardiography for patients with functional MR and DCM. Although some for each of the methods used for MR quantification should previous studies have considered different cutoff values for MR also be considered. The frequency of the transducer and classification by the ERO method in patients with heart failure, color gain adjustment may influence the RJ, where the these values were chosen arbitrarily23,24. Furthermore, only method is considered less accurate14,21. In patients with DCM, patients with functional MR by ischemic cardiomyopathy were lower LV ejection fraction may also affect the RJ. VC may included in these, condition with MR different mechanisms modify with changes in hemodynamic conditions and it is from those of the nonischemic DCM. Also, MR was classified different at several times in the cardiac cycle21. Furthermore, only as important and not important by these authors23,24, VC intermediate values do not necessarily correspond unlike our study in which MR was classified as mild, moderate to moderate MR, since there is a significant overlap of or important, according to the recommendations of the values with this method14. In our study, VC classified MR American Society of Echocardiography14.

461 Arq Bras Cardiol. 2013;101(5):457-465 Manuso et al. Classification of functional mitral regurgitation Original Article

Figure 4 - Redistribution of absolute values into terciles (30 low values, 30 intermediate values and 30 high values). They are also showing the cutoff values of the American Society of Echocardiography. A better agreement was observed when the values that divided terciles were used for mitral regurgitation classification by each method (kappa: 0.44, p <0.01). RJ: regurgitant jet area; ERO: effective regurgitant orifice area; ASE: American Society of Echocardiography; VC: vena contracta; RV: regurgitant volume.

Finally, the strong correlation finding between absolute conditions, and has been used as one of the criteria for values of each method, associated with the poor agreement response to cardiac resynchronization therapy28. in the MR classification when cutoff values of the American Patients with refractory symptoms of heart failure and Society of Echocardiography are used together with the important MR may be eligible for MR surgical treatment. previous study, which showed a good agreement in the However, clinical studies evaluating mitral valve surgery in these primary MR classification, reinforces the hypothesis that the patients showed controversial results10-12. These findings may cutoff values for MR classification, although appropriate in reflect the difficulty in classifying the MR, which consequently primary mitral valve diseases, are inadequate to classify the makes the selection of appropriate patients for surgery difficult. MR in DCM patients. Findings of this study reinforce the need to integrate the results of multiple echocardiographic methods used in the MR Clinical Implications classification. Moreover, it is necessary to establish new cutoff The MR classification in patients with heart failure and values for MR classification, specific to patients with functional DCM is important, since the MR degree has prognostic MR and DCM, since the correct MR classification is important for and therapeutic value25,26. The functional MR is associated their clinical management. In cases where the two-dimensional with LV volume overload and remodeling26. Additionally, transthoracic echocardiography provides conflicting data for the MR contributes to the increase in LV filling pressures MR assessment, the transesophageal echocardiography is and in pulmonary pressure27. The MR classification has a recommended for a better assessment of the MR degree29. role for therapeutic decisions in the clinical practice. MR Another possibility in cases of disagreement between methods decreases with the clinical treatment of heart failure and is the use of three-dimensional echocardiography, which seems is associated with the improvement in LV hemodynamic to be a promising method for assessment of mitral regurgitation

Arq Bras Cardiol. 2013;101(5):457-465 462 Manuso et al. Classification of functional mitral regurgitation Original Article

Figure 5 - Box plot graphs of the MR classification showing absolute values variation according to the cutoff values of the American Society of Echocardiography and the terciles. A) regurgitant jet area (RJ), B) vena contracta (VC) C) effective regurgitant orifice area (ERO) and D) regurgitant volume (RV).

by measuring the vena contracta three-dimensionally and into terciles was only used to test whether the discrepancy was the regurgitant volume directly, but such measures still need due to the inadequacy of the methods or whether it was due to validation29. A better MR classification can improve the selection the cutoff values recommended for MR classification. A long‑term of patients to surgical treatment of functional MR. In the near prospective study is required, designed specifically for this future, with the MR percutaneous techniques advances, purpose, comparing the MR assessment by other imaging methods treatment indication for invasive functional MR must increase, (angiography or magnetic resonance imaging), in order to establish where it is essential that a reliable MR degree classification is new cutoff values for MR classification in DCM patients. available for patient selection. Conclusion Limitations The echocardiographic criteria for MR classification are A gold standard test for comparison of the MR classification in disagreement with patients with DCM. It is essential such as cardiac angiography or MRI was not used, but actually, to integrate multiple methods in the MR assessment and 18 there is no true gold standard test for the MR assessment , which establish new cutoff values for MR classification for this specific makes the MR classification by echocardiography even harder, population, since the correct MR assessment has therapeutic especially when several methods are available and different and prognostic implications to these patients. MR mechanisms are involved. Furthermore, it is important to observe that variations may occur in the regurgitation intensity with range of hemodynamic or load conditions in the same Author contributions patient, as well as the use of medications that modify these Conception and design of the research: Mancuso FJN, 14 loading/hemodynamics conditions . Moisés VA, Poyares D, Campos O; Acquisition of data: The study could not establish a new cutoff value for MR Mancuso FJN, Almeida DR, Oliveira WA, Brito FS; Analysis classification in this specific population. The division of values and interpretation of the data: Mancuso FJN, Moisés VA,

463 Arq Bras Cardiol. 2013;101(5):457-465 Manuso et al. Classification of functional mitral regurgitation Original Article

Oliveira WA, Campos O; Statistical analysis: Mancuso FJN; Sources of Funding Writing of the manuscript: Campos O; Critical revision of the There were no external funding sources for this study. manuscript for intellectual content: Moisés VA, Almeida DR, Paola AAV, Carvalho ACC, Campos O. Study Association Potential Conflict of Interest This article is part of the thesis of post doctoral submitted No potential conflict of interest relevant to this article was by Frederico José Neves Mancuso, from EPM/UNIFESP - Escola reported. Paulista de Medicina.

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465 Arq Bras Cardiol. 2013;101(5):457-465 Review Article

Antithrombotic Strategy in the Three First Months following Bioprosthetic Heart Valve Implantation Andre R. Durães, Milena A. O. Durães, Luis C. L. Correia, Roque Aras Hospital Ana Nery, Salvador, BA - Brazil

Abstract Introduction Heart valve prosthesis unquestionably improve quality of life The chronic rheumatic heart disease (CRHD) is responsible and survival of patients with severe valvular heart disease, but for at least 200 to 250 thousand premature deaths each the need for antithrombotic therapy to prevent thromboembolic year and is the leading cause of cardiovascular death complications is a major challenge to clinicians and their patients. among children and young adults in developing countries1. Of the articles analyzed, most were retrospective series of cases Heart valve prosthesis (HVP) unquestionably improve quality or historical cohorts obtained from the database. The few of life and survival of patients with severe valvular heart published randomized trials showed no statistical power to assess disease, but the need for antithrombotic therapy to prevent the primary outcome of death or thromboembolic event. In this possible thromboembolic complications remain a major article, we decided to perform a systematic literature review, in challenge to clinicians and their patients2. an attempt to answer the following question: what is the best Since the beginning of its use in the 60s, the bioprosthesis antithrombotic strategy in the first three months after bioprosthetic emerged with the expectation of replacing existing metal heart valve implantation (mitral and aortic)? prosthesis, due to not theoretically requiring permanent oral After two reviewers applying the extraction criteria, we anticoagulation, a fact justified by their predominant tissue found 1968 references, selecting 31 references (excluding composition, thereby reducing the high thrombogenicity of papers truncated, which combined bioprosthesis with the prosthesis used until then. However, these prosthesis had mechanical prosthesis, or without follow-up). a significant negative point: relatively short durability (mean 10-15 years), caused by early structural deterioration that Based on this literature review, there was a low level resulted in the need for reoperations, which, in turn, would of evidence for any antithrombotic therapeutic strategy increase morbidity and mortality3. evaluated. It´s therefore interesting to use aspirin 75 to 100 mg / day as antithrombotic strategy after bioprosthesis The recommendations of the main international replacement in the aortic position, regardless of etiology, for consensuses2,4,5 on antithrombotic therapy after patients without other risk factors such as atrial fibrillation or bioprosthesis implantation demonstrate a low level of previous thromboembolic event. In the mitral position, the evidence (Grade C), which may be explained by the risk of embolism, although low, is more relevant than in the lack of randomized trials and scarcity of prospective aortic position, according to published series and retrospective cohorts representing current diverse therapies, generating cohorts comprised mostly of elderly non-rheumatic patients. considerable variation in behavior between the different services. In Brazil, the main cause of valve disease in The current evidence is limited to have a consistent and children, adolescents and young adults is the CRHD, safe level of evidence regarding the best therapeutic strategy. leading to a high social and economic cost6. In spite of Based on these studies, 75 to 100 mg/day of aspirin is that, the authors of this review do not know any study interesting as antithrombotic strategy after implantation of in the literature that have specifically addressed patients aortic bioprosthesis, regardless of etiology, for patients with with CRHD in relation to any antithrombotic strategy in no other risk factors such as atrial fibrillation or previous the postoperative period of HVP implantation. thromboembolic event. As for mitral bioprosthesis, the risk of embolism, although low, is more relevant than in the aortic Moreover, CRHD has a direct association with poverty 6 position, according to published series and retrospective and poor health , creating a vicious circle of recurrent cohorts - usually elderly non rheumatic patients. pharyngotonsillitis, crossed immune reaction, heart valve involvement, debilitating sequelae, cardiac surgery at an economically active age, costs to the health system and society. In this article, we decided to perform a systematic Keywords review of the literature in an attempt to answer the following Heart Valve Prosthesis Implantation; Fibrinolytic Agents; question: what is the best antithrombotic therapy strategy Platelet Aggregation Inhibitors; Thromboembolism. in the first three months after implantation of bioprosthetic heart valve? Mailing Address: Andre Rodrigues Duraes • Rua Alberto Silva, 439, Itaigara. Postal Code 41815-000, Salvador, BA - Brazil E-mail: [email protected] , [email protected] Review Methodology Manuscript received February 27, 2013, revised manuscript June 10, 2013, accepted on 07/02/13. The Medline, Embase, Cochrane and SciELO databases were reviewed regarding the period between 1970 and DOI: 10.5935/abc.20130202 2012. The terms or keywords used were: heart valve

466 Duraes et al. Antithrombotic strategy after bioprosthetic replacement Review Article prosthesis, bioprosthesis, aspirin or anticoagulants or of bioprosthesis in the aortic position (BAP) and bioprosthesis thromboembolism and bioprosthesis. The search was in the mitral position (BMP). No study had found a sample that limited to articles written in English or Portuguese and that was specific or predominant for patients with CRHD. referred to humans. The articles identified were assessed Most of the selected articles consisted of retrospective by two reviewers. Inclusion criteria were: original articles series or historical cohorts extracted from databases. in English or Portuguese, prospective or retrospective, The few published randomized trials showed no statistical observational or intervention design, preferably having a power to assess the primary outcome of death or control group and sample size > 19 patients. thromboembolic event. The use of several antithrombotic Articles that included patients with metal prosthesis therapies, such as aspirin (ASA), triflusal, ticlopidine or (alone or in conjunction), articles without abstracts, or WAR, isolated or combined, hindered data systematization articles with incomplete or confusing methodology, not to perform a more homogeneous joint analysis. We chose allowing identification of a therapy group, and a control to divide the studies according to the main therapeutic group were excluded. strategy to facilitate result analysis. Table 1 shows the list of studies that had no report on Results the use of any antithrombotic drug strategy after ABP and/or Using the aforementioned methodology, 1,968 references MBP implantation. Tables 2 and 3 show the selected studies were found. Of these, after applying the extraction criteria, that compare WAR with ASA, while Table 4 lists the articles 31 articles were selected. Found there were only three that used ASA or WAR alone, often comparing them with the randomized studies with a total population of 472 patients, follow-up without any specific antithrombotic drug therapy. in whom different levels of anticoagulation or warfarin Therefore, the incidence of thromboembolic events without (WAR) versus antiplatelet agents were tested. Moreover, any specific therapy ranged from 0.011 to 0.900 and 0.01 to two prospective observational studies were found, resulting 2.3% / person-year when evaluating ABP and MBP, respectively, in a sample of 433 patients. The remaining studies were for a follow up ranging from 6-120 months involving publications retrospective and several addressed the combined implantation of the year 1979 to 1995, according to Table 1.

Table 1 – Main comparative studies after bioprosthetic valve implantation with outcome focused on thromboembolic events with no specific antithrombotic therapy

Location and Study design and Conclusion Author-Year N incidence of embolic events Stipulated therapy follow‑up (months) (embolic events) (%/person-year) Cohen et al12 ABP: 0.55* NAT: sinus Rhythm 323 Retrospective; 84 Low incidence; 1979 MBP: 3.9* WAR: AF Fuster et at13 ABP: 0.26# P < 0.01; BPM high risk 302 Retrospective; 120 Not informed 1982 MBP: 0.30# of events; Ionescu et al14 366 Retrospective; 120 MBP: 0.6 Not used Very low risk 1982 Cohn et al 15 663 Retrospective; 108 ABP: 0.07 Not informed - 1984 Joyce et al16 ABP: 0.011-0.024 469 Retrospective; 36.2 Not informed - 1984 MBP: 0.01-0.028 Gallo et al17 ABP: 0.5 189 - Not informed 1985 MBP: 2.3 ABP: 208 pcts Hartz et al18 589 Retrospective; 38 MBP: 209 pts Not informed Low incidence 1986 Total: 0.3 a 0.8 Gonzalez-Lavin et al19 Peak of events between 240 Retrospective; 100 ABP: 0.9 Not used 1988 60‑70 months. Braile et al20 663 Retrospective, 132 MBP: 0.3 - CVA – 0.3% 1991 Babin-Ebell et al21 57 Retrospective. 6 ABP: 0.035–1.75 Not used 1995 p = 0.01 Higher risk for the Orszulak et al22 561 Retrospective; 42 ABP: 1.57 NAT overall; elderly (> 73 years), AF, 1995 decreased EF. N: sample size; AF: atrial fibrillation; ABP: aortic bioprosthesis; MBP: mitral bioprosthesis; NAT: No antithrombotic therapy; EF: ejection fraction; pts: Patients; CVA: cerebrovascular accident; WAR: Warfarin; p: statistical significance; * Embolic events only occurred in patients with AF.

Arq Bras Cardiol. 2013;101(5):466-472 467 Duraes et al. Antithrombotic strategy after bioprosthetic replacement Review Article

Table 2 – Main comparative studies after bioprosthetic valve implantation with outcome focused on thromboembolic events, comparing warfarin with aspirin

Location and incidence of Study design and Author-Year N embolic events Stipulated therapy Conclusion (embolic events) follow‑up (months) (%/person-year) Previous MS and AF are Louagie et al8 MBP 2.01 overall predictors of permanent 100 Retrospective; 70 WAR x ASA 1993 0.5 x 1.3 OA, mechanical prosthesis recommended. ABP: 378 pts WAR 2.9 BPM: WAR reduced events but Blair et al23 748 Retrospective; 3 ASA: 0.8 WAR x ASA X NAT increased bleeding; 1994 NAT: 1.5 ABP: ASA was similar to WAR; MBP: 370 pts High risk of thromboembolism on 0-10/10-90/> 90 d Heras et al9 Warfarin, dipyridamole and the first 10 days; OA ≥ Reduced 816 Retrospective; 99.6 ABP: 41/3.6/1.9 1995 aspirin were used; risk of embolism from 3.9% to MBP: 55/10/2.4 2.5%; ABP and MBP Aramendi et al24 Ti: 137 x WAR 40 x ASA 14 x The first three months are high 168 Retrospective; 38.4 Ticlopidine 0.5 1998 NAT 18 pts risk; Ti was superior to WAR. Warfarin 3 Guerli et al25 249 Prospective; Observational; 3 ABP WAR 141 x ASA 108 pts Similar incidence in both groups; 2004 APB Ramos et al26 Embolism incidence of 18.25%/ 184 Prospective; Observational; 3 MBP ASA 159 and WAR 25 pts 2004 patient-year 18.25 N: sample size; AF: atrial fibrillation; ABP: aortic bioprosthesis; MBP: mitral bioprosthesis; NAT: No antithrombotic therapy; EF: ejection fraction; OA: oral anticoagulation; CVA: cerebrovascular accident; pts: Patients; Ti: Ticlopidine; WAR: Warfarin; ASA: Aspirin; MS: mitral stenosis.

Table 3 – Main comparative studies after bioprosthetic valve implantation with outcome focused on thromboembolic events, comparing warfarin with aspirin

Location and incidence of Study design and Author-Year N embolic events Stipulated therapy Conclusion (embolic events) follow‑up (months) (%/person-year) Aramendi et al27 Prospective, open, ABP 181 pts Triflusal 600 mg Similar reduction in embolism, 193 2005 randomized, multicenter; 3 MBP 10 pts Acenocoumarol INR 2 to 3 and less bleeding with triflusal; Sundt et al28 WAR did not protect against 1151 Retrospective; 3 ABP: 2.4 x 1.9 WAR 624 x ASA 410 pts 2005 events; Colli et al29 69 Randomized; Prospective ABP ASA x WAR No statistical difference 2007 Jamieson et al30 1372 Retrospective; ABP ASA x WAR No statistical difference 2007 Colli et al31 ASA 51 x WAR 36 x NAT 99 Retrospective; MBP No statistical difference 2010 12 pts ElBardissi et al32 861 Retrospective; 3 ABP ASA 728 x WAR 133 pts p = 0.67 2011 Events: Brennan et al7 ASA 12,457 x WAR 2,999 x ASA – 1% 25.656 Retrospective; 3 ABP 2012 ASA + WAR 5,972 pts WAR – 1% Both – 0.6% N: sample size; AF: atrial fibrillation; ABP: aortic bioprosthesis; MBP: mitral bioprosthesis; NAT: No antithrombotic therapy; EF: ejection fraction; OA: oral anticoagulation; CVA: cerebrovascular accident; pts: Patients; p: statistical significance; WAR: Warfarin; ASA: aspirin.

Regarding the comparison between WAR and ASA, alone respectively. More recently, Brennan et al7 demonstrated, or in combination, for patients who had ABP implantation, through a retrospective cohort study with large sample size there was an incidence of thromboembolic events of (25,656 patients), that this is the incidence of 1%/person-year 0.8 to 4.8% / person-year and 0.6 to 3.9% / person-year, for any of the aforementioned therapies.

468 Arq Bras Cardiol. 2013;101(5):466-472 Duraes et al. Antithrombotic strategy after bioprosthetic replacement Review Article

Table 4 – Main comparative studies after bioprosthetic valve implantation with outcome focused on thromboembolic events, comparing warfarin with aspirin alone

Location and incidence of Study design and Author-Year N embolic events Stipulated therapy Conclusion (embolic events) follow‑up (months) (%/person‑year) Gonzalez-Lavin et al33 MBP Group 1: WAR < 6 weeks 206 Bovine pericardial 528 Retrospective; 30.5 1984 Group 1 = 4.6 Group 2 = 0.36 pts; Group 2: > 8 weeks 322 pts bioprosthesis; low risk. Less intensive regimen was Turpie et al34 ABP Group 1: INR 2.5-4.0 108 pts; 210 Randomized; 3 similar for embolic events and 1988 MBP Group 2: INR 2.0-2.25 102 pts had fewer bleeding episodes. High risk of CVA Orszulak et al10 285 Retrospective; MBP 2.5 Not informed (40%/ person‑year) in the 1995 first month; In the first three months there Goldsmith et al35 145 Retrospective; ABP 0.3 ASA was no increased risk of 1998 thromboembolism; Moinuddeen et al36 Early OA was not effective in 185 Retrospective; 3 ABP 2.8 x 2.6 WAR 109 x NAT 76 pts 1998 reducing embolic events Brueck et al37 Retrospective; No benefit of ASA 288 ABP ASA 132 x NAT 156 pts 2007 Observational; 12 versus nothing; Prospective. Low incidence. No benefit of Duraes et al11 184 MBP and ABP ASA 59 x NAT 125 pts Observational ASA versus nothing. N: sample size; AF: atrial fibrillation; ABP: aortic bioprosthesis; MBP: mitral bioprosthesis; NAT: No antithrombotic therapy; EF: ejection fraction; OA: oral anticoagulation; CVA: cerebrovascular accident; pts: Patients; ASA: aspirin.

For those submitted to MBP implantation, Louagie et al8 in the aortic position only, keeping the use of the latter found a low incidence of thromboembolic events (0.5 (WAR) for isolated or combined mitral position (IIa/C and and 1.3%/person-year) when compared WAR and ASA, II/C, respectively) based on recent studies focused on ABP respectively. However, there are Retrospective with an implantation. incidence much higher, reaching levels of 55% / person‑year The Brazilian guideline of valve disease - SBC 201138 in the first 10 days, as Heras et al9 found in 1995. recommends as Class I and level C, bioprosthesis replacement In the same year, Orszulak et al10 showed an incidence in patients who have contraindications to the use of vitamin K of 40% in the first 30 days postoperatively. Finally, more antagonists (VKA), and use these drugs in patients with atrial recently, in 2013, in an article still in press, Duraes et al11 fibrillation (Class I and level of evidence B), or within three prospectively analyzed a cohort of rheumatic patients in months after initial implantation of a bioprosthesis (Class IIb the first three postoperative months after mitral and/or and level of evidence B), not specifying whether in the aortic aortic bioprosthetic implantation, showing a rare incidence and / or mitral position. of embolic events, regardless of being the aortic or mitral Regarding patients with aortic replacement, Brennan bioprosthesis, being even more sporadic in the latter, even et al7, as already mentioned, published an impressive when aspirin is compared with no antiplatelet agent, as retrospective cohort consisting mainly of elderly patients. shown in Tables 2, 3 and 4. In this study, the authors evaluated three antithrombotic strategies (WAR, ASA or both) and found an incidence of embolism similar between the WAR and the ASA alone Discussion group (1% / person-year), occurring significant reduction Current recommendations for antithrombotic therapy in embolic events only when using simultaneous ASA and in the first three months following bioprosthetic valve WAR: 0.6% / person-year, with the number of patients implantation have a low level of evidence, as observed in needed to treat (NNT) of 212, benefit was offset by an the studies selected for this article. The American Heart increase in bleeding rate of almost 3-fold, with the number Association/American College of Cardiology (AHA/ ACC)4 needed to harm (NNH) of 55, being for the most part, recommend the use of ASA as class I and level of evidence according to the authors, gastrointestinal bleeding with no C, alone or in combination with WAR (IIa / C), in accordance increase in bleeding into the central nervous system. with the presence or not of some factor risk (atrial fibrillation, Regarding patients with isolated or combined BMP, the previous thromboembolic event, left ventricular dysfunction, most cited reference in the literature is still byHeras et al9 and hypercoagulability state). The European Society of published in 1995, becoming an important negative paper. Cardiology (ESC)2 and the American College of Chest It was a retrospective and observational study, with database Physicians (ACCP)5 innovated by recommending the use of from the Mayo Clinic. The authors showed a high incidence ASA (instead of WAR) when the replacement is performed of embolic events in the first 90 days, with 55%/person-year

Arq Bras Cardiol. 2013;101(5):466-472 469 Duraes et al. Antithrombotic strategy after bioprosthetic replacement Review Article

in the first 10 days, and 10%/person-year between 10 and or senile valvular heart disease, more prevalent in developed 90 days, postoperatively. In univariate analysis, they observed countries. The first (patients with CRHD) are generally a reduction of 3.9% to 2.5% in the incidence of embolism with younger and thus less likely to have other comorbidities, WAR use. When analyzing the linear rate of embolism in this which are known to increase cardioembolic risk, such same work, it was observed that the benefit of reducing events as severe left ventricular dysfunction, atrial fibrillation with anticoagulation was significant in the first 10 days, with and previous embolic event. Regarding the latter, they no statistical difference (even numerically) within 10 to 90 days are generally elderly patients that commonly have other postoperatively. In the same year, Orszulak et al10 found in diseases or risk factors compatible with aging, such as arterial another retrospective observational cohort, a high incidence hypertension, diabetes and atrial fibrillation, which causes of thromboembolic events - which reached 40% in the first inevitable increase in surgical risk of death and complications, 30 days in the same scenario. These disappointing results may as well as greater probability of embolic events during have discouraged new studies since it seemed clear the need follow-up after surgery and greater risk of bleeding during for the use of WAR in the first months after surgery, especially the instituted anticoagulant therapy. after implantation of BMP. Currently, there are doubts about In short, the best antithrombotic strategy to be adopted the real incidence of embolism events after implantation of in the first three months after aortic and mitral replacement modern biological prosthesis, especially in patients with CRHD, is based mainly on the experience of each service, and and about the best antithrombotic strategy postoperatively. expert opinion - justify the level of evidence C - due to Thus, there is a large gap regarding the actual incidence of scarcity of prospective and randomized controlled trials. embolic events with current biological prosthesis, and there In BAP the use of ASA is similar to the use of WAR in the are no cohorts that specifically address individuals with CRHD elderly patients, and in BMP remains a worldwide trend to following MBP and ABP implantation. WAR use. Patients with CRHD have not been adequately With this lack of impact studies justifies the low level of representative in previous studies to date. evidence the main internationals and Brazilian guidelines. Most studies reported represents individual experiences of Author contributions referral services in cardiac surgery, performed in the last Conception and design of the research: Durães AR; century, during a natural stage of technological development Acquisition of data: Durães AR, Durães MAO; Analysis of prosthesis, different in many aspects of current valve and interpretation of the data: Durães AR, Durães MAO, prosthetic devices - theoretically less thrombogenic. Correia LC, Aras Junior R; Writing of the manuscript: As already said, bioprosthesis have a great advantage over Durães AR, Durães MAO, Aras Junior R; Critical revision mechanical prosthesis, which is the exemption from continuous of the manuscript for intellectual content: Correia LC, use of anticoagulants, in general, the AVK. However, several Aras Junior R. clinical circumstances do increase the probability of an embolic event postoperatively, even in patients with bioprosthesis, Potential Conflict of Interest which is a challenge to the clinician and the patient involved in choosing the best antithrombotic strategy (VKA or ASA, alone No potential conflict of interest relevant to this article was or combined). This decision always takes into account the pros reported. and cons of such conduct, also due to the difficulty in handling these drugs caused by the need for regular monitoring of the Sources of Funding international normalized ratio (INR), which directly influences There were no external funding sources for this study. the risk of bleeding added by this type of drug. Patients with CRHD are generally from low socioeconomic level areas, difficult the management of VKA. Study Association It is also noteworthy the fact that patients affected by this This article is part of the thesis of doctoral submitted by disease are different from the group affected by degenerative André Rodrigues Durães, from Universidade Federal da Bahia.

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472 Arq Bras Cardiol. 2013;101(5):466-472 Letter to the Editor

Acute Coronary Syndromes in 2011 and 2012 Juan Sanchis, Antoni Bayes-Genis, Leopoldo Pérez de Isla Editor Asociado - Revista Española de Cardiología, Madrid, Espanha

Dear Editor, of concern. The 4 most known prognostic scores (TIMI, Nowadays, the invasive approach plays a crucial role in PAMI, CADILLAC and GRACE) were compared in patients 3 the management of acute coronary syndromes, according managed with either primary or rescue coronary angioplasty . to the recommendations in clinical practice guidelines. All 4 scores (particularly TIMI, CADILLAC and GRACE) had This tendency was reflected in some papers published an excellent accuracy to predict mortality at 30 days and in Revista Española de Cardiología in 2011 and 2012. 1 year; prediction of reinfarction or new revascularization, Regarding ST-segment elevation acute coronary syndromes, however, was very poor with any score. regional programs on primary coronary angioplasty have The invasive management has been extended to been developed across Spain. Time delay until reperfusion, populations previously excluded from this treatment, however, remains the main drawback of these programs. such as elderly patients. In a retrospective study on very For instance, Badalona’s experience shows that in only 27% old patients (≥ 85 years) with non-ST-segment elevation of the patients transferred from other hospitals for primary acute coronary syndrome, the invasive approach reduced angioplasty the coronary artery was opened within the time mortality and any ischemic event at 3 years compared limits recommended in the guidelines, i.e. in less than 2 hours with a matched population managed with a conservative from the first medical contact1. Therefore, fibrinolysis should strategy4. Despite the favorable results of the invasive not be ruled out as an alternative treatment in some cases. strategy in any type of acute coronary syndrome, secondary Furthermore, data from cardiac magnetic resonance imaging prevention should not be overlooked. In this sense, the did not evidence significant differences in left ventricular opening of a cardiac catheterization laboratory and the volumes and function between patients treated with primary subsequent increase of coronary intervention procedures angioplasty or pharmaco-invasive strategy (initial fibrinolysis for myocardial infarction, improved mortality at 30 days but followed by routine coronary angioplasty 24 hours later) in not between 30 days and 2 years after adjusting for ACE a single hospital registry2. Prediction of prognosis is a matter inhibitor, beta‑blocker and statin treatment5.

Keywords Acute Coronary Syndrome; Coronary Balloon Angioplasty; Myocardial Infarction.

Mailing Address: Revista Española de Cardiología – Juan Sanchis • Nuestra Sra. de Guadalupe 5, 28028 Madrid, Spain E-mail: [email protected] Manuscript received June 17, 2013, revised Manuscript June 18, 2013, accepted June 20, 2013. DOI: 10.5935/abc.2013218

References

1. Rodríguez-Leor O, Fernández-Nofrerías E, Mauri F, Salvatella N, Carrillo Value of the TIMI, PAMI, CADILLAC, and GRACE Risk Scores in STEACS X, Curos A, et al. Analysis of Reperfusion Delay in Patients With Acute Undergoing Primary or Rescue PCI. Rev Esp Cardiol. 2012;65(3):227-33. Myocardial Infarction Treated With Primary Angioplasty Based on First Medical Contact and Time of Presentation. 2011;64(6):476-83. 4. Villanueva Benito I, Solla Ruíz-I, Paredes-Galán E, Díaz Castro O, Calvo- Iglesias FE, Baz-Alonso JA, et al. Prognostic Impact of Interventional 2. Bodi V, Rumiz E, Merlos P, Nunez J, López-Lereu MP, J Monmeneu JV, et al. Approach in Non-ST Segment Elevation Acute Coronary Syndrome in Very One-Week and 6-Month Cardiovascular Magnetic Resonance Outcome of the Pharmacoinvasive Strategy and Primary Angioplasty for the Reperfusion of ST- Elderly Patients. Rev Esp Cardiol. 2011;64(10):853-61. Segment Elevation Myocardial Infarction. Rev Esp Cardiol. 2011;64(2):111-20. 5. Bosch D, Masia R, Sala J, Vila J, Ramos R, Elosua R, et al. Effect of Opening 3. Méndez-Eirin E, Flores-Ríos X, García-López F, Pérez-Pérez AJ, Estévez- a New Catheterization Laboratory on 30-Day and 2-Year Survival Rates in Loureiro R, Piñón-Esteban P, et al. Comparison of the Prognostic Predictive Myocardial Infarction Patients. Rev Esp Cardiol. 2011;64(2):96-104.

473 Letter to the Editor

Sports Events and Acute Coronary Syndrome: Possible Confounding Factors and Bias Mauro Felippe Felix Mediano, Andrea Silvestre de Sousa, Alejandro Marcel Hasslocher-Moreno Instituto de Pesquisa Clínica Evandro Chagas - Fundação Oswaldo Cruz, Rio de Janeiro, RJ – Brazil

Dear Editor, been described as possible triggers for ACS4,5, making the The relationship between sports events and ACS association between FIFA World Cup and ACS established 1 (Acute Coronary Syndrome) has been the subject of some in the research of Borges et al subject to a number of studies in the literature, with controversial results, and confounding factors and hindering the interpretation of was recently addressed by Borges et al1 in the manuscript results. Defining, as the authors intend, if the World Cup entitled “World Soccer Cup as a Trigger of Cardiovascular could be seen as a direct “trigger” for ACS is not possible Events,” published in volume 6 of 2013 of ABC. The authors or merely if it entails a number of risk conditions already observed a higher incidence of AMI (Acute Myocardial well described in the literature. Furthermore, the use of Infarction) in match days of the FIFA World Cup and, in research findings by observing groups of people to infer particular, on Brazilian games, concluding that this sporting causal relationships in individuals may result in ecological event can act as a “trigger” of AMI in Brazilians. However, fallacy5, since it is not possible to state that all individuals considerations of possible confounding factors and bias who attended the event were exposed the same way. should be made to present to readers a better interpretation Therefore, the study design presented by Borges et al1 does of the data presented. Firstly, the literature describes that, not allow the establishment of a direct association between during sporting events, viewers tend to have numerous risk the occurrence of ACS and the FIFA World Cup, and the behaviors for cardiovascular disease, such as the intake of interpretation of the study results should be performed large amounts of alcohol, consumption of fatty food, and carefully, taking into account the potential confounding use illicit drugs and smoking2,3. These factors have also factors and bias of ecological study.

Keywords Acute coronary syndrome; Football; Alcohlism; Tobacco; Substance- Related Disorders.

Mailing Address: Mauro Felippe Felix Mediano • Rua Antônio Basílio, 519, cobertura 01, Tijuca. Postal Code 20511-190, Rio de Janeiro, RJ, Brasil. E-mail: [email protected] Manuscript received June 22, 2013, revised June 26, 2013, accepted July 25, 2013. DOI: 10.5935.abc.201330219

References

1. Borges DG, Monteiro RA, Schmidt A, Pazin-Filho A. Copa do mundo de 4. Roerecke M, Rehm J. Irregular heavy drinking occasions and risk of ischemic futebol como desencadeador de eventos cardiovasculares. Arq Bras Cardiol. heart disease: a systematic review and meta-analysis. Am J Epidemiol. 2013;100(6):546-52. 2010;171(6):633-44.

2. Leeka J, Schwartz BG, Kloner RA. Sporting events affect spectators’ 5. Mittleman MA, Mostofsky E. Physical, psychological and chemical cardiovascular mortality: it is not just a game. Am J Med. 2010;123(11):972-7. triggers of acute cardiovascular events: preventive strategies. Circulation. 2011;124(3):346-54. 3. Merlo LJ, Hong J, Cottler LB. The association between alcohol-related arrests and college football game days. Drug Alcohol Depend. 2010;106(1):69-71.

474 Mediano et al. Sports Events and Acute Coronary Syndrome Letter to the Editor

Reply We would like to thank our colleagues who sent this letter, “...the exposure may not be uniform (a part of the population which has allowed further discussion on this quite intricate may not be watching the match)”. subject1. Firstly, we agree to the assertions that, over sport However, even with the considerations raised and clarified events, viewers tend to have a number of risk behaviors for above, although we are not able to definitively confirm a cardiovascular diseases, such as the intake of great amounts causal association between the games and the occurrence of alcoholic beverages, eating of fatty food, use of illicit drugs of cardiovascular events, we still can assume that these two and smoking, given that the limitations of our research have factors are related, despite the correction for confounding been addressed in our discussion. However, it is important factors available. Moreover, a simple association, easily to note that the measurement of all possible confounding identifiable and which may be used immediately can be more factors referred to is difficult (illicit drugs, for instance), even useful for health planning than establishing the cause and in prospective studies, as this may be subject to a biased effect relation from the pathophysiological point of view. Until observation2. We stress the limitations of our data, retrieved further information is available and considering everything from a public database, which restricted the availability of data that has been studied in the literature, this information seems to protect the individual’s secrecy rights. Another point to be consistent with most other studies, and we believe that our raised is that these potential confounding factors not available findings should be maintained. in our study may present collinearity with the statement of interests (watching the World Cup and Brazilian matches) and Sincerely, would require a high-cost prospective design to remove all Antonio Pazin Filho the factors raised3,4. Daniel Guilherme Suzuki Borges Regarding the second remark about the problems associated with ecological studies, we believe that they are Rosane Aparecida Monteiro also properly pointed out in our discussion, as one can see that André Schmidt

References

1. Borges DGS, Monteiro RA, Schmidt A, Pazin-Filho A. World soccer cup as 3. Sorlie P, Wei GS. Population-based cohort studies: still relevant? J Am Coll a trigger of cardiovascular events. Arq Bras Cardiol. 2013;100(6):546-52. Cardiol.2011;58(19):2010-3.

2. Levine M, Walter S, Lee H, Haines T, Holbrook A, Moyer V. How to use an 4. Sauerbrei W, Royston P, Binder H. Selection of important variables and article about Harm. JAMA.1994;27(20):1615-9. determination of functional form for continuous predictors in multivariable model building. Stat Med.2007;26(30):5512-28.

Arq Bras Cardiol. 2013;101(5):474-475 475 Anatomopathological Session

Case 5 - A 73 Year-Old Man with Heart Failure, Preserved Systolic Function and Associated Renal Failure Tiago Rodrigues Politi, Paulo Sampaio Gutierrez Instituto do Coração (InCor) HC-FMUSP, São Paulo, SP - Brazil

Male patient, 73 years old, retired metallurgist, born in Laboratory tests showed: potassium = 5.3 mEq/ L, sodium = Alagoas, residing in Sao Paulo, sought medical attention for 135 mEq / L, creatinine = 2.1 mg/dL, hemoglobin = 11.6 g/dL, dyspnea on minimal exertion. hematocrit = 37%, leukocytes = 13,400 / mm ³ and negative At his first visit to Instituto do Coração - Incor (18/June/2004) serology for Chagas disease. he complained of dyspnea that had begun 28 years before, The ECG (June 15, 2004) showed sinus rhythm, 58 bpm initially triggered by great exertion; however, in the last two HR, PR 220 ms, SAQRS (-) 20°, dQRS 86 ms, QT 450 ms,

years it had progressed to dyspnea at minimal exertion and for first-degree atrioventricular block, ST depression in V5 and the last month, it occurred even at rest and with orthopnea. V6 (with flattened or inverted T wave, suggestive of digitalis These symptoms showed slight improvement with furosemide action) (Figure 1). Chest x-ray showed + + / 4 + cardiomegaly. and digoxin. The digoxin dose was decreased to 0.125 mg; the dose He also reported chest pain on exertion, accompanied of 40 mg of furosemide was maintained and 12.5 mg of by sweating and nausea for the last five years before that hydrochlorothiazide were added, together with 40 mg of consultation. The patient underwent a coronary angiography, isosorbide and 100 mg of acetylsalicylic acid daily. which showed a 40% lesion in the anterior descending and Echocardiography (May/2004) showed increased right first diagonal arteries and 50% lesion in the right coronary and left atria, the latter measuring 48 mm, increased septal artery. The left ventricle was normal, with hypertrophic thickness (16 mm), normal left ventricular ejection fraction appearance, and he had pulmonary artery hypertension (66%) and pulmonary hypertension (pulmonary artery (systolic pressure of 50 mmHg). systolic pressure = 65 mmHg). The patient denied current smoking, alcohol New laboratory tests were requested, as well as consumption, arterial hypertension, dyslipidemia and echocardiography, 24-hour Holter assessment and myocardial diabetes mellitus. He underwent gastrectomy for peptic perfusion scintigraphy. However, they were not performed ulcer at 43 years of age and reported anemia requiring because the patient sought emergency medical care due to blood transfusion a month before. the persistence of dyspnea, onset of nausea and vomiting and He had a history of alteration in bowel movement with increased abdominal volume on July 7, 2004. alternating diarrhea and constipation since the age of 69 and Physical examination (July 07, 2004) showed the patient had lost 12 kg in recent months. was in good general health status, slightly pale, heart rate Physical examination showed a patient weighing 54.3 kg, of 64 bpm, blood pressure 90 x 60 mmHg; crackles heard height 1.68 m, BMI 19.2 kg / m², heart rate of 96 bpm, blood at the lung bases; auscultation sounds were arrhythmic, no pressure 92 x 50 mmHg, jugular stasis + +/ 4 + at 45°. murmurs; abdomen: the liver was palpable 5 cm below the Pulmonary auscultation showed crackles at the bases; cardiac costal margin, hardened, extending to the epigastrium; bowel auscultation showed muffled heart sounds and holosystolic sounds were audible and there was no rebound tenderness; murmur at the lower sternal border; the liver was palpable there was no lower-limb edema. three centimeters from the right costal margin and there was Laboratory assessment (07/jul/2004) showed urea = no edema or signs of poor peripheral perfusion. 173 mg/dL, creatinine = 4.4 mg/dL, potassium =5.9 mEq/L, hemoglobin = 11.1 g / dL, hematocrit = 34%, platelets = 284.000/mm³, leukocytes = 6.800/mm³ , normal coagulation, Keywords troponin = 0.82 ng/mL and CK-MB = 12.5 ng/mL. ECG Heart Failure; Renal Insufficiency; Pulmonary Embolism. (July 07, 2004) showed atrial fibrillation with ventricular rate of 60 bpm, ST depression with flattened or inverted T wave, Section Editor: Alfredo José Mansur ([email protected]) suggestive of digitalis action (Figure 2). Associate Editors: Desidério Favarato ([email protected]) The diagnoses of heart failure, digitalis intoxication, chronic Vera Demarchi Aiello ([email protected]) renal failure with acute worsening of renal function and wasting syndrome were attained. Mailing Address: Vera Demarchi Aiello • Digoxin use was discontinued, with volume and dobutamine bloco I, Cerqueira César. Postal Code 05403-000, São Paulo, SP - Brazil E-mail: [email protected], [email protected] being administered. There was improvement in blood pressure, which increased DOI: 10.5935/abc.20130220 to 100 x 60 mmHg, without worsening of dyspnea, and creatine e86 Politi et al. Anatomoclinical Correlation Anatomopathological Session

Figure 1 - ECG – Sinus rhythm, first-degree atrioventricular block, ST depression in V5 and V6 (flattened or inverted T wave, suggestive of digitalis action).

Figure 2 - ECG – Atrial fibrillation, with bradycardia, ST depression with flattened or inverted T wave, suggestive of digitalis action.

decrease. Dobutamine was discontinued on the 3rd day of showed no signs of gastroesophageal reflux or hiatal hernia. hospitalization. The laboratory evolution is shown in Table 1. In the distal third of the esophagus, there were three fine‑caliber Upper digestive endoscopy (July 20, 2011) showed varicose veins, bluish, straight and without red spots. esophageal tract of normal aspect, caliber and extension and The stomach showed good expandability and was reminiscent the gastroesophageal junction 40 cm above the upper arch of the Billroth-II gastrectomy, having usual proportions, with

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Table 1 - Laboratory assessment during hospitalization

7/July 13/July 19/July 21/July Hemoglobin (g/dL) 11,8 8,5 10,1 8,9 Hematocrit (%) 36 26 30 28 MCV (pg) 78 81 77 82 Reticulocytes/mm³ - 32.000 - - Leukocytes/mm³ 7,100 9,700 5,800 4,500 Neutrophils (%) 88 92 60 95 Rods (%) 7 0 0 0 Lymphocytes (%) 7 3 2 1 Monocytes (%) 5 5 6 4 Platelets/mm³ 320,000 188,000 131,000 105,000 Urea (mg/dL) 170 183 250 292 Creatinine (mg/dL) 4.5 3.7 4.5 5.5 Glucose (mg/dL) 74 67 Sodium (mEq/L) 135 135 137 139 Potassium (mEq/L) 5.3 5.5 5.2 5.7 Calcium (mEq/L0) 4.38 Phosphorus (mg/dL) 5.8 Magnesium (mEq/L0) 2.55 Chloride (mEq/L) 112 TSH (µUI/mL) 11.4 Free T4 (ng/dL0) 0.7 AST (U/L) 27 ALT (U/L) 28 AF (U/L) 329 Gamma GT (U/L) 232 Amylase (U/L) 65 DHL (U/L0) 220 CRP (mg/L) 28.4 Total bilirubins (mg/dL) 0,72 0.63 Direct bilirubin (mg/dL) 0,26 0.27 Total proteins (g/dL0) 6.8 Albumin (g/dL) 2.8 Cholesterol (mg/dL0) 101 HDL-C (mg/dL0) 42 LDL-C (mg/dL0) 42 Triglycerides (mg/dL0) 87 INR 1.1 APTT (rel) 0.95 Venous gasometry pH 7.30 7.29

pCO2 (mm Hg) 29 44

pO2 (mm Hg) 37 32

Sat O2 (%) 63.2 47.6

HCO3 (mEq/L) 14 20.5 Base excess (mEq/L) -11 -5.4

e88 Arq Bras Cardiol. 2013;101(5):e86-e94 Politi et al. Anatomoclinical Correlation Anatomopathological Session preserved pleated mucosa with no significant inflammatory Clinical investigation of pulmonary thromboembolism reaction. There were no changes in the anastomotic mouth involves echocardiography, perfusion and ventilation and segments close to the afferent and efferent loops. pulmonary scintigraphy, Doppler of lower limbs, pulmonary In conclusion, there were incipient esophageal varices; normal angiography, and in some cases, pulmonary arteriography, Billtoth II partial gastrectomy and no hemorrhagic lesions. although in the present case only the echocardiography The abdominal ultrasonography (July 11, 2004) had was performed. Therefore, there are no data to support disclosed an enlarged liver, with blunt edges and heterogeneous this diagnosis. texture with multiple nodular images with irregular borders; For the differential diagnosis, systemic diseases that ectasia of hepatic veins and inferior vena cava, with no signs have renal and cardiac involvement (clinical situations of intrahepatic or extrahepatic bile duct dilation and presence that the patient had) were considered, e.g., systemic lupus of voluminous ascites. The spleen was of normal size. Kidney erythematosus and schistosomiasis, in addition to hepatic size was at the lower limit of normal dimensions (right kidney neoplasms which, in this case, should be considered and left kidney measured 8 cm and 9 cm, respectively), with because of the patient's age, history of weight loss in more echogenic texture than the usual and alteration in the recent years and the presence of liver nodules identified corticomedullary ratio - 0.9 cm to the right and 0.9 cm to the by computed tomography. However, there are no data to left. There were no calculi or hydronephrosis, but there were confirm this diagnosis. 1.7-cm simple cortical cysts in the upper pole of the right kidney Systemic lupus erythematosus can affect both renal and and smaller ones, of up to 0.8 cm, in the left kidney. cardiac function and these may present with heart failure, Retroperitoneal visualization was not possible due to such as myocarditis and Libman-Sacks endocarditis, but they excessive intestinal gas. do not cause diastolic heart failure, as in this case5. The high He received packed RBCs on July 13, 2004. On the 19th, pulmonary artery systolic pressure (65 mmHg) makes the he had abdominal distension. On the afternoon of the 21st, possibility of constrictive pericarditis caused by lupus even he underwent CRA, resuscitated through reanimation and more remote. defibrillation techniques; he was submitted to intubation and Schistosomiasis is another cause of cardiac and renal was transferred from the Hospital Auxiliar de Cotoxó to Incor involvement, with manifestations predominantly in ER. The patient developed bradycardia and shock, and after the right heart chambers, pulmonary hypertension and new CRA in asystole, he died at 1 AM on July 22, 2004. even cor pulmonale6. The clinical picture of the patient, with gastrointestinal disorders, portal hypertension, Clinical Aspects hepatomegaly, ascites, and marked weight loss contributes to this diagnosis. However, the chronic form of cor pulmonale This is the case of a 73-year-old patient with hypothyroidism, coronary artery disease, left ventricular hypertrophy, heart consists in a combination of right ventricle hypertrophy and failure with preserved left ventricular ejection fraction and dilation secondary to pulmonary hypertension, neither of exacerbation of chronic renal failure. The patient’s clinical which was identified in the patient. picture had worsened in the last two years that preceded his As the last and main cause of clinical deterioration of the last hospitalization, with progressive symptom worsening. patient, is the evolution of the underlying disease itself, in Among the possible causes for such clinical worsening, this case, diastolic heart failure with preserved left ventricular are: ischemic equivalent, pulmonary thromboembolism and fraction. Diastolic cardiomyopathy is characterized by changes the evolution of the underlying disease, which in this case in ventricular relaxation, with impaired ventricular filling and/ corresponds to diastolic heart failure with preserved left or increased filling pressures and increased dependence 7 ventricular ejection fraction. As for the ischemic equivalent, on the atrial contraction phase . There is an increase in left the patient’s episodes of chest pain were not accompanied atrial pressure and, consequently, in the pulmonary veins and by typical manifestation of myocardial ischemic disease and capillaries, as well as a decrease in stroke volume, signs present additionally, they did not trigger changes in the hemodynamic in this type of heart disease that explain exercise intolerance and balance1. Furthermore, the patient had no predisposing even dyspnea at rest, referred by the patient. The evidence of risk factors for coronary artery disease2 and the coronary diastolic dysfunction can be obtained from the hemodynamic angiography showed no significant coronary lesions. data, levels of natriuretic peptides, echocardiographic and Thus, the hypothesis of an ischemic event is weakened. tissue Doppler data8. Among the main causes of left ventricular Regarding pulmonary thromboembolism, only the diastolic dysfunction are systemic hypertension with left patient's age is a risk factor for pulmonary embolism, as ventricular hypertrophy, aortic stenosis with preserved left observed in epidemiological studies3. Moreover, there ventricular ejection fraction, hypertrophic and restrictive was no clinical history consistent with hypercoagulability cardiomyopathies and coronary artery disease. syndrome with recurrent thrombotic events, although such Hypertensive heart disease can be defined as the result an association can only be ruled out after specific laboratory of overload imposed to the LV by the increase in arterial investigation for the most prevalent types of thrombophilia pressure and peripheral vascular resistance, which causes in the general population, which are factor V Leiden, structural changes in the LV that manifest as hypertrophy hyperhomocysteinemia and antiphospholipid antibody and total stiffness9; however, in this case, the patient did not syndrome, in addition to the less prevalent ones such as have systemic arterial hypertension. As for aortic stenosis, antithrombin III, protein C and S deficiency4. there are no data to support the diagnosis.

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For the diagnosis of left ventricular hypertrophy, the and myocardial infarction occur, although in most cases, the electrocardiogram (ECG) is not a sensitive method, but quite coronary arteries have normal angiographic aspect. There is specific. Still, the findings of the patient in this case do not thickening of the left ventricle, producing usually mild diastolic meet these criteria. Echocardiography is a low-cost procedure dysfunction, with preserved systolic function and mitral and is considered the method of choice for non-invasive regurgitation without clinical significance. The symptomatic diagnosis of increased cardiac mass10. However, in this case, cardiovascular involvement occurs in nearly all male patients, the patient had no criteria for hypertrophic cardiomyopathy whereas the symptoms are mild or absent in females. at the echocardiography. The following are common findings: arterial hypertension, One must also emphasize the differential diagnosis between mitral valve prolapse and congestive heart failure. The patient left ventricular hypertrophy and restrictive cardiomyopathy, of the present case had no skin manifestations, systemic arterial especially with the low-voltage electrocardiogram in the frontal hypertension, or acute myocardial ischemia. plane, present in the latter cardiomyopathy, which favors the Endomyocardial fibrosis, common in tropical countries, storage disease and consequent restriction to ventricular filling11. most often occurs in children and young adults. It is The clinical findings of lower-limb edema and hepatomegaly, characterized by endocardial fibrosis of the inflow tract of as well as the supplementary tests (electrocardiogram and one or both ventricles. Biventricular disease occurs in almost echocardiogram), pointed to predominant RV involvement half the cases; 40% of them have isolated involvement with overload and dilation of both atria and normal LV systolic in the left ventricle and 10%, isolated impairment of function and dimensions. These characteristics corroborate the right ventricle13,15. There is an irregular association the diagnosis of heart disease with diastolic restriction. Among with eosinophilia. LV impairment results in pulmonary the diseases that can cause restrictive cardiomyopathy12 congestion symptoms, while RV involvement may show are storage diseases (hemochromatosis and Fabry disease), characteristics of restrictive cardiomyopathy and also endomyocardial disease (endomyocardial fibrosis) and simulate constrictive pericarditis. Failure of one or both infiltrative diseases (amyloidosis and sarcoidosis). atrioventricular valves often occurs16. Hemochromatosis is characterized by excessive iron Electrocardiographic and echocardiographic findings deposits on parenchymal tissues (heart, liver, gonads, and include: decreased QRS complex voltage, pericardial effusion, pancreas). It can occur as an autosomal recessive or idiopathic apical obliteration and increased endocardial echo reflectivity15. disorder, in association with defects in hemoglobin synthesis The latter findings were not confirmed in this clinical case and, due to ineffective erythropoiesis, chronic liver disease and moreover, the endomyocardial fibrosis does not explain thyroid excessive oral ingestion or parenteral administration of iron and renal involvement shown by the patient. for many years13. Being one of the causes of restrictive cardiomyopathy, Cardiac involvement leads to the combined pattern of sarcoidosis is a systemic granulomatous disease of unknown dilated cardiomyopathy and restrictive cardiomyopathy etiology, characterized by the involvement of various tissues with systolic and diastolic dysfunction. Myocardial damage by noncaseating granulomas17. is mainly attributed to direct toxicity of free iron and not Cardiac involvement is infrequent and primary clinical only the tissue infiltration. Cardiac dilatation occurs with manifestations occur in less than 5% of patients, being increased ventricular thickness. The findings are more characterized by conduction defects, ventricular arrhythmias, prominent in ventricular than in atrial myocardium and syncope and sudden death. The direct myocardial involvement it often affects the cardiac conduction system. In this by granulomas and scar tissue can manifest as dilated or patient, although he showed increased ventricular thickness restrictive cardiomyopathy, with progressive course18. The ECG demonstrated by the echocardiography, there was no is nonspecific and can show T wave abnormalities, blocks or ventricular dilatation or systemic manifestations of the pathological Q waves. Other findings include pericarditis and disease, making this hypothesis unlikely. cor pulmonale. Echocardiography can disclose thinning of the Fabry disease is a genetic disorder with X-linked recessive ventricular wall and increased echogenicity18. Cardiac magnetic inheritance, resulting from abnormalities linked to the resonance is a highly sensitive and specific method for diagnosis. deficiency of the lysosomal enzyme alpha-galactosidase In our case, there were no suggestive alterations, making it A, which is caused by more than 160 mutations14. unlikely that this was the patient's diagnosis. Some of them result in undetectable enzyme activity, And finally, systemic amyloidosis, which is a group of which manifest throughout the body, while others produce diseases that have extracellular deposits of insoluble fibrillar some degree of enzymatic activity resulting in variants proteins consisting of low molecular weight subunits5. with limited involvement only in the myocardium. Clinically, it is classified as5: primary (AL), secondary The disease is characterized by an intracellular accumulation (AA), hereditary and associated with old age (senile). of glycosphingolipids with marked involvement of the skin, AL amyloidosis is caused by the deposition of proteins kidneys and myocardium in the classic form. Involvement derived from light chain fragments, in general, a monoclonal of the vascular endothelium occurs, as well as of conduction immunoglobulin (80.0% of cases). It may occur alone or tissue and heart valves, particularly the mitral valve. in association with multiple myeloma (10.0% of cases). The major clinical manifestations result from the AA amyloidosis can complicate chronic diseases that course accumulation of glycosphingolipids in cell endothelium, with recurrent inflammation. The fibrils consist of fragments with eventual occlusion of small arterioles. Angina pectoris of amyloid protein A, an acute phase protein.

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There is also a hereditary-type amyloidosis (deposition left lung. There was infarction in this territory (Figure 3) and of fibrils derived from transthyretin) and a senile form (also acute infection in this and other areas of the lungs. Pulmonary deposition of transthyretin). In this context, there can be thromboembolism was probably secondary to a clotting amyloid infiltration in the thyroid, leading to hypothyroidism19; disorder, as, in addition to it, there was portal vein thrombosis however, it most commonly occurs concomitantly with goiter, and presence of thrombi that seemed to be recent (i.e., onset not described in the case. Another clinical manifestation, such as in the agonal period) in coronary arterial branches. 5 autonomic neuropathy due to amyloidosis , which courses with The main disease of this patient was hepatocellular orthostatic hypotension, early satiety, change in bowel habits carcinoma (Figure 4), underlying chronic hepatitis (Figure 5). (diarrhea or chronic constipation) were observed in this patient. The neoplasm is the likely cause of the bleeding disorder. AA amyloidosis affects the cardiovascular system in only 5% of In addition to this disease, the patient also had cases and there is no mention of systemic inflammation (although cardiomyopathy, of which predominant clinical picture was serology for hepatitis are not available)20. Therefore, the two atrial fibrillation (which can also be related to pulmonary subtypes of amyloidosis most likely in this case would be AL and thromboembolism, but there were no thrombi in the cardiac senile amyloidosis. There are important differences in the prognosis cavities). The fact that the ventricles did not show marked and rate of evolution between these subtypes: the median survival dilation, contrary to what happens with the atria (Figure 6), after cardiac involvement is, respectively, 11 and 75 months21. suggests that it is a case of restrictive cardiomyopathy. Furthermore, the insidious course of the disease is the Among its possible causes are: amyloidosis, hypertrophic rule for senile amyloidosis, whereas in AL, there is a rapid cardiomyopathy and ischemic heart disease. However, the progression of symptoms and much higher cardiovascular absence of amorphous extracellular deposits, myocardial involvement. In the absence of confirmation of plasma cell fiber disarray and severe obstruction of the coronary arteries dyscrasia, the distinction between them is made through go against such possibilities. Thus, the idiopathic form, with immunohistochemical analysis22. interstitial fibrosis, should be considered. Cardiac involvement in cases of amyloidosis occurs in one The patient also had atherosclerosis, with mild aortic third of patients. Right ventricular failure usually occurs, with little and mild to moderate involvement of the coronary tree, but pulmonary edema, despite elevated filling pressures. There are, with no significant consequences. The kidneys had some however, other alterations including atrial fibrillation, conduction degree of vascular alterations, which may be associated with disorders and electrically inactive areas. Still, high-grade atherosclerosis; kidney failure may have been associated with atrioventricular blocks are uncommon11. Echocardiography is an hepatorenal syndrome. important noninvasive test for the diagnosis of amyloidosis. LV wall thickening with evidence of diastolic dysfunction is the earliest (Dr. Paulo Sampaio Gutierrez) alteration, which can progress to restrictive cardiomyopathy23. Biatrial enlargement and valve thickening may occur19. Anatomopathological diagnosis: The diagnostic investigation includes collecting a urine Main disease: hepatocellular carcinoma related to chronic sample to test for the presence of paraproteins. The detection hepatitis, probably viral. of increased excretion of light chains with maintenance of Relevant secondary disease: restrictive cardiomyopathy. the kappa/lambda ratio, in the absence of the monoclonal chain establishes the diagnosis of amyloidosis20. Although Cause of death: pulmonary thromboembolism (Dr. Paulo not confirmed by tests, the diagnosis of amyloidosis can be Sampaio Gutierrez) achieved through a biopsy24, which can be performed in 25 subcutaneous adipose tissue (sensitivity of 65 to 80%) or in the Comment endomyocardium (up to 97%)26 with demonstration of amyloid deposits in tissues classically stained with Congo red. Therefore, It is difficult in this case, to be sure that the pulmonary due to the clinical picture of the patient and the complementary embolism, which was the final factor triggering death, was tests described, systemic amyloidosis is the most likely diagnosis more related to heart failure or, as it seems likely, considering of this anatomo‑clinical discussion. that such picture was well balanced and that there were no intracavitary thrombi, to hepatocellular carcinoma. There was not enough time to evaluate the hepatic findings in the abdominal ultrasound, which may have contributed to It is noteworthy the lack of a cancer diagnosis during the the case outcome. (Dr. Tiago Rodrigues Politi) patient’s life, corroborating data indicating that autopsies still currently disclose important diagnoses in a significant number of patients with heart disease27. Diagnostic hypothesis Systemic amyloidosis with cardiac and renal involvement. Regarding the heart disease, amyloidosis is a possibility that should be considered in heart failure with restrictive pattern Other diagnoses: hypothyroidism and chronic renal failure. in the elderly. However, the clinical profile of patients with (Dr. Tiago Rodrigues Politi) restrictive idiopathic cardiomyopathy28 showed age variation of 10-90 years, with a mean of 64. Therefore, the patient Necropsy fits into this description, not only regarding age but also The patient had cachexia. The final factor triggering his concerning the atrial fibrillation, detected in 74% of patients. death was pulmonary embolism in the lower lobe of the (Dr. Paulo Sampaio Gutierrez)

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Figure 3 - Histological section of the lower lobe of the left lung with infarction, characterized by destruction of alveolar septa, of which there are only remnants of elastic tissue (yellow arrows). This tissue appears more intact around the small vessels (blue arrows). Verhoeff staining, magnification: 10x.

Figure 4 - Histological section of the liver showing with hepatocarcinoma nodules consisting of cell cords (arrows), with the non-neoplastic tissue in the center, of more intense color and approximately stellar shape. Hematoxylin and eosin staining; magnification: 5x.

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Figure 5 - Histological section of the liver showing the formation of cirrhotic nodules, with darker borders. Masson staining; magnification: 5x.

Figure 6 - Posterior face of the heart. The double line roughly highlights the atrioventricular groove. Note the large atrial dilation, of which height equals or even surpasses that of the ventricles.

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1. Roberts WC, Gardin JM. Location of myocardial infarcts: a confusion of terms 16. Barretto AC, Mady C, Oliveira SA, Arteaga E, Dal Bo C, Ramires JA. Clinical and definitions. Am J Cardiol. 1978;42(5):868-72. meaning of ascites in patients with endomyocardial fibrosis. Arq Bras Cardiol. 2002;78(2):196-9. 2. Uddin SN, Begum F, Malik F, Rahman S. Coronary artery disease in young patients: clinical review and risk facto analysis. Mimensingh Med J. 17. Sharma OP. Diagnosis of cardiac sarcoidosis: an imperfect science, a hesitant 2003;12(1):3-7. art. Chest. 2003;123(1):18-9.

3. Goldhaber SZ. Pulmonary embolism. N Engl J Med. 1998;339(2):93-104. 18. Yazaki Y, Isobe M, Hiramitsu S, Morimoto S, Hiroe M, Omichi C, et al. Comparison of clinical features and prognosis of cardiac sarcoidosis and 4. Fedulo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic idiopathic dilated cardiomyopathy. Am J Cardiol. 1998;82(4):537-40. pulmonary hypertesion. N Engl J Med. 2001;345(20):1465-72. 19. Kimura H, Yamashita S, Ashizawa K, Yokoyama N, Naga-taki S. Thyroid 5. Dember LM, Shepard JA, Nesta F, Stone JR. Case records of the Massachusetts disfunction in patients with amyloid goiter. Clin Endocrinol. 1997;46(6):769-74. General Hospital. Case 15-2005 - An 80-year-old man with shortness of breath, edema, and proteinuria. N Engl J Med. 2005;352 (20): 2111-9. 20. Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR, Pepys MB, et al. Outcome in systemic AL amyloidosis in relation to changes 6. Barbosa MM, Lamounier JA, Lambertucci J. [Cardiopulmonary involvement in concentration of circulating free immunoglobulin light chains following in schistosomiasis]. Arq Bras Cardiol. 1995;65(4):343-8. chemotherapy. Br J Haematol. 2003;122(1):78-84. 7. Aurigemma GP, Gaasch WH. Clinical practice: diastolic heart failure. N Engl 21. Arbustini E, Morbini P, Verga L,. Concardi M, Porcu E, Pilotto A, et al. Light J Med. 2004;351(11):1097-105. and electron microscopy immunohistochemical characterization of amyloid 8. Bocchi EA, Marcondes-Braga FG, Ayub-Ferreira SM, Rohde LE, Oliveira WA, deposits. Amyloid. 1997;4(3):157-70. Almeida DR, et al; Sociedade Brasileira de Cardiologia. III Diretriz brasileira 22. Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic de insuficiência cardíaca crônica. Arq Bras Cardiol. 2009;92(1 supl.1):1-71. amyloidosis presenting with heart failure: a comparison with light chain- 9. Dunn F, Pfeffer M. Left ventricular hypertrophy in hypertension. N Engl J associated amyloidosis. Arch Intern Med. 2005;165(12):1425-9. Med. 1999;340(16):1270-80. 23. Klein AL, Hatle LK, Burstow DJ, Taliercio CP, Seward JB, Kyle RA, et al. 10. Messerli FH. Left ventricular hypertrophy, arterial hypertension and sudden Comprehensive Doppler assessment of right ventricular diastolic function death. J Hypertens. 1990;8(7):S181-6. in cardiac amyloidosis. J Am Coll Cardiol. 1990;15(1):99-108.

11. Murtagh B, Hammill SC, Gertz MA, Kyle R, Tajik A, Grogan M. 24. Swan N, Skinner M, O’Hara CJ. Bone marrow core biopsy specimens in AL Electrocardiographic findings in primary systemic amyloidosis and biopsy- (primary) amyloidosis: a morphologic and immunohistochemical study of proven cardiac involvement. Am J Cardiol. 2005;95(4):535-7. 100 cases. Am J Clin Pathol. 2003;120(4):610-6.

12. Kuperstein R, Feinberg MS, Rosenblat S, Beker B, Eldar M, Schwammenthal 25. Andrews TR, Colon-Otero G, Calamia KT, Menkes DM, Boylan KB, Kyle RA. E. Prevalence, etiology, and outcome of patients with restrictive left Utility of subcutaneous fat aspiration for diagnosing amyloidosis in patients ventricular filling and relatively preserved systolic function. Am J Cardiol. with isolated peripheral neuropathy. Mayo Clin Proc. 2002;77(12):1287-90. 2003;91(12):1517-9. 26. Pellikka PA, Holmes DR Jr, Edwards WD, Nishimura RA, Tajik AJ, Kyle 13. Hoffbrand AV. Diagnosing myocardial iron overload. Eur Heart J. RA. Endomyocardial biopsy in 30 patients with primary amyloidosis and 2001;22(23):2140-1. suspected cardiac involvement. .Arch Intern Med. 1988;148 (3):662-6.

14. Frustaci A, Chimenti C, Ricci R, Natale L, Russo MA, Pieroni M, et al. 27. Saad R, Yamada AT, Pereira da Rosa FH, Gutierrez PS, Mansur AJ. Improvement in cardiac function in the cardiac variant of Fabry´s disease Comparison between clinical and autopsy diagnoses in a Cardiology with galactose-infusion therapy. N Engl J Med. 2001;345(1):25-32. hospital. Heart. 2007;93(11):1414-9.

15. Berensztein CS, Pineiro D, Marcotegui M, Brunoldi R, Blanco MV, Lerman 28. Ammash NM, Seward JB, Bailey KR, Edwards WD, Tajik AJ. Clinical profile J Usefulness of echocardiography and Doppler echocardiography in and outcome of idiopathic restrictive cardiomyopathy. Circulation. endomyocardial fibrosis. J Am Soc Echocardiogr. 2000;13(5):385-92. 2000;101(21):2490-6.

e94 Arq Bras Cardiol. 2013;101(5):e86-e94 Case Report

Steal of Blood Flow from the Vertebral Artery to the Internal Thoracic Artery Anastomosed to the Coronary Artery Jose Sebastião de Abreu1,2,3, Nayara Lima Pimentel4, Jordana Magalhães Siqueira4, Carlos Newton Diógenes Pinheiro5, Teresa Cristina Pinheiro Diógenes3, José Nogueira Paes Junior3 Instituto do Coração SP - Universidade de São Paulo1, São Paulo, SP; Universidade Estadual do Ceará2; Prontocárdio e Clinicárdio3; Faculdade de Medicina da Universidade Federal do Ceará4; Hospital Geral de Fortaleza5, Fortaleza, CE - Brazil

Introduction three months. She reported decreased strength to elevate the left upper limb. She was hypertensive, dyslipidemic and The left vertebral and internal thoracic arteries are branches a smoker. She used calcium antagonists, nitrates, aspirin of the left subclavian artery which, under physiological and statin. Ten years before, she had undergone myocardial conditions, exhibit antegrade flow direction. revascularization with saphenous vein graft to the right On Doppler evaluation, the internal thoracic artery (ITA) coronary artery and from the internal thoracic artery (ITA) flow shows a predominance of systolic component, but when to the anterior descending coronary artery (ADA). anastomosed to the left coronary arteries, the prevalence of the On physical examination she had normal pulmonary diastolic component is usual. This predominance can become auscultation, regular heart rhythm and fourth heart sound, exacerbated and a situation that increases oxygen consumption cervical murmur to the left (++/4+), pulse in the left arm by the myocardium can occur, such as what happens during not palpable without edema. Blood pressure in the right dobutamine stress echocardiography, when the systolic upper limb was 130 x 80 mmHg. component can be suppressed and the diastolic becomes the The electrocardiogram showed mild ventricular only component of the cardiac cycle. The two-dimensional repolarization alteration in the anterolateral wall. and Doppler imaging allows anatomical assessment of arteries She underwent cardiac catheterization, which showed and the verification of normal and pathological flow patterns. occlusion of the saphenous vein graft, severe stenosis Thus, the flow direction reversal of an artery can be compatible (> 80%) in left main coronary artery (LMCA), of ADA, with steal of blood flow and an exacerbation of the diastolic circumflex (Cx), and diagonal (Dg) artery and left subclavian component of the anastomosed internal thoracic artery (AITA) artery (LSA) occlusion; it was not possible to perform proper at Doppler may indicate good functional status of the vessel1-3. assessment of the ITA-ADA conduit (Figure 1A and 1B). Occlusion of the left subclavian artery determines The echocardiogram showed mild left ventricular impairment of blood supply to the left arm, but the steal of hypertrophy and normal basal segmental contraction. blood flow from the left vertebral artery may improve limb The two-dimensional image and Doppler of the anastomosed perfusion. When the subclavian artery occlusion occurs in ITA (AITA), viewed in supraclavicular level, showed good cases with ITA anastomosed to the left coronary arteries, the patency of the conduit through Doppler spectrum with direction of the post-stenotic flow in symptomatic patients exuberant percentage of diastolic component (84%) at rest, is variable and can be reverse in the vertebral and internal well above the commonly found one (Figure 1C and 1D). 4 5 thoracic arteries , have no reverse component , be reverse The vertebral arteries showed normal anatomy and flow 6 only in ITA or, as in our patient, show preferential reverse velocity; however, the flow was retrograde in the left flow from the left vertebral artery to the ITA. vertebral artery (LVA) and showed normal anterograde pattern in the right (Figure 1E and 1F). Case report The attending physician considered that the left coronary system was partially protected by the AITA and the patient A 47-year-old female had had stable angina for was submitted to stenting in the LMCA and Cx and angioplasty approximately three years and increasing angina for the last in the Dg, with consequent cessation of anginal symptoms. Six months after the percutaneous intervention, she underwent dobutamine stress echocardiography, reaching Keywords a maximum heart rate (220 - age) with uneventful outcome Mammary Arteries; Echocardiography, Stress; Angioplasty, and negative result for myocardial ischemia. At peak stress, Balloon, Coronary; Stents. the flow in the AITA became exclusively diastolic, with Mailing Address: Jose Sebastião de Abreu • coronary flow reserve index of 1.8 (Figure 2A and 2B), Rua Dr. José Lourenço, 500/700, Meireles. Postal Code 60115-280, indicating good functional status1,3, while the LVA remained Fortaleza, CE - Brazil entirely with retrograde flow (Figure 2C and 2D). E-mail: [email protected], [email protected] Article received on 11/10/12, revised on 12/04/12, accepted on 3/25/13. Four months after the stress echocardiography, the patient underwent a new intervention for stent implantation DOI: 10.5935/abc.20130216 in the LSA. A subsequent angiogram showed calibrous and e95 Abreu et al. Steal of blood flow to internal thoracic artery Case Report

Figure 1 - Angiography showing stenosis > 80% in the left main coronary artery, left anterior descending artery, circumflex and diagonal arteries (1A), and left subclavian artery (LSA) with occlusion (1B). Supraclavicular recording of two-dimensional image of the anastomosed internal thoracic artery (AITA) emerging from the post-stenotic region of LSA (1C). AITA Doppler imaging showing marked diastolic component (1D), abnormal left vertebral artery with retrograde spectrum (1D) and normal anterograde spectrum in the right artery (1F). fully patent ITA-ADA conduit (Figure 2E and 2F). In a new to the stenotic LSA. In the study by Omeish et al4, it was Doppler assessment, it was observed that the LVA had observed that a patient admitted with acute pulmonary started to show normal antegrade flow. The AITA flow at edema had, at the hemodynamic study, reverse flow in rest showed a decrease in the diastolic component, but it AITA and LVA, and that after stenting in the occluded remained predominantly (58%) within the range expected LSA, the directions of these flows normalized and became for AITA with adequate patency (Figure 2G and 2H). anterograde, concomitant to a successful clinical outcome. The pulse in the left arm became palpable. On the other hand, in the study by Alcocer et al5, it was observed that antegrade flow to AITA was compromised, as in this patient with angina pectoris there was no "compensatory" Discussion steal of blood flow to the region distal to the LSA stenosis. During LSA occlusion in revascularized patients with Vecera et al6 showed, by Doppler assessment, AITA with AITA, distinct variations may occur in flow direction distal reverse flow and the hemodynamic study confirmed the

Arq Bras Cardiol. 2013;101(5):e85-e98 e96 Abreu et al. Steal of blood flow to internal thoracic artery Case Report

Figure 2 – AITA with diastolic predominance at baseline (2A) and 100% diastolic at the end of dobutamine stress echocardiogram (2B). Doppler spectrum of the left vertebral artery (LVA) maintained retrograde (abnormal) at baseline (2C) and during stress (2D). Angiographic view of stent in LSA (2D) and calibrous AITA emerging from the LSA (2F). Subsequent Doppler assessment showing normalization of LVA blood flow direction (2G) and decreased prevalence of diastolic component in the AITA (2H).

suspected LSA occlusion. After LSA angioplasty, the AITA but showed limitations in the assessment of the AITA. flow showed normal anterograde pattern. The two-dimensional Doppler image was of great The case reported herein is the first to show that, in the importance to demonstrate that the diastolic component in presence of LSA occlusion, the steal of blood flow in the LVA the AITA was more pronounced than usual, which suggested can help to increase the antegrade flow of the AITA without to the attending physician that the left coronary system was stenosis and to demonstrate that, the role of two-dimensional partially protected by this AITA, favoring the decision of Doppler image was crucial. performing a percutaneous intervention through stenting The hemodynamic study diagnosed the LSA occlusion, in severely compromised coronary arteries, including the as well as severe stenoses of the coronary arteries, left main coronary artery.

e97 Arq Bras Cardiol. 2013;101(5):e85-e98 Abreu et al. Steal of blood flow to internal thoracic artery Case Report

After the interventional therapy, the patient asymptomatic decision to perform percutaneous intervention for severe evolution and the fact that the dobutamine-stress stenosis of the LMCA and branches of a partially protected echocardiogram was negative for myocardial ischemia left coronary system. corroborated the appropriateness of the interventions. The AITA Doppler assessment showed good functional status of this conduit as, during stress, it was observed Author contributions that the flow became 100% diastolic with a coronary flow Conception and design of the research: Abreu JS; reserve index of 1.8. The two-dimensional Doppler study Acquisition of data, Analysis and interpretation of the performed immediately after stent implantation in LSA data, Writing of the manuscript and Critical revision of the showed that the flow direction in the LVA had normalized manuscript for intellectual content: Abreu JS, Pimentel (anterograde) and that changes had occurred in the AITA NL, Siqueira JM, Diógenes TCP, Paes Junior JN; Performing flow, which demonstrated increased systolic component, procedure (examination): Abreu JS, Pinheiro CND, Paes while still remaining anterograde and with diastolic Junior JN. predominance (58%), which is the Doppler standard usually found in patent AITA3. We emphasize that stress echocardiography, which Potential Conflict of Interest has such widespread use in the evaluation of myocardial No potential conflict of interest relevant to this article was ischemia, is an important tool for the assessment of coronary reported. flow reserve through the graft. Sources of Funding Conclusion There were no external funding sources for this study. In the presence of LSA occlusion, it was inferred that the steal of blood flow from the LVA contributed to the increase in blood supply to the AITA. The two-dimensional Study Association Doppler image was essential to demonstrate that the AITA This study is not associated with any post-graduation was patent and had good functional status, favoring the program.

References

1. Abreu JS, Diógenes TC, Morais JM, Barretto JE, Lobo Fo. JG, Paes Jr JN. 4. Omeish AF, Ghanma IM, Alamlih RI. Successful stenting of total left Avaliação da patência da mamária interna enxertada pelo ecodoppler com subclavian artery occlusion post-coronary artery bypass graft surgery using e sem uso de dobutamina. Arq Bras Cardiol. 1997;69 (supl I):119. dual left vertebral artery and left internal mammary artery protection. J Invasive Cardiol. 2011;23(6):E132-6. 2. Arruda A, Campos Filho O, Ribeiro E, Petrizzo A, Andrade JL, Carvalho 5. Alcocer A, Castillo G, Rivera-Capello JM, González V, Meaney E. Anterograde AC, et al. Avaliação da anastomose de artéria torácica interna esquerda flow compromise of a patent left internal mammary artery graft from a proximal com artéria interventricular anterior pela ecodopplercardiografia. Arq Bras subclavian artery stenosis. Myocardial ischemia not driven by the coronary- Cardiol. 1997;69(6):413-9. subclavian steal syndrome mechanism. Arch Cardiol Mex. 2012;82(2):135-8.

3. Abreu JS, Diógenes TC, Abreu AL, Barreto JE, Morais JM, Abreu ME, et al. 6. Vecera J, Vojtísek P, Varvarovský I, Lojík M, Másová K, Kvasnicka J. Non- Artéria torácica interna enxertada: patência e estado funcional em repouso invasive diagnosis of coronary-subclavian steal: role of the Doppler e após dobutamina. Arq Bras Cardiol. 2008;90(1):37-45. ultrasound. Eur J Echocardiogr. 2010;11(9):E34.

Arq Bras Cardiol. 2013;101(5):e85-e98 e98 Viewpoint

Korotkoff Sounds – The Improbable also Occurs Bruno Estañol1, Guillermo Delgado1, Johannes Borgstein2 Laboratório de Neurofisiologia Clínica - Departamento de Neurologia e Psiquiatria - Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INNSZ) 1, Cidade do México, México; Tergooi Hospital 2, Blaricum, Holanda

Abstract a dog, with the intra-arterial technique and found that BP figures were comparable with both approaches2. Very few discoveries have had such a large impact on He established the maximum value of the systolic BP at and relevance to clinical medicine as the noninvasive 150 mmHg; anything beyond this figure in the adult was measurement of the diastolic blood pressure. A number considered to be abnormal2,3. He introduced the term of gifted physiologists and clinicians were ineffectively in sphygmomanometer, which derives from the Greek word search of a noninvasive method to determine the diastolic “sphygmos,” meaning “pulse”4. The term was, in fact, a pressure. Nonetheless, the quantification of the diastolic BP misnomer, but it is still used in most countries. was not achieved by any of these clinical or physiological researchers, but by an unlikely and unexpected figure: The brilliant Italian physician Scipione Riva-Rocci Nikolai Sergeevich Korotkoff (1874-1920), a young Russian (1863-1937) introduced a bracelet that was connected to army surgeon, working under precarious conditions in a mercury column and, by increasing the pressure until the the hardship of diverse wars. It is easy to dismiss the pulse was obliterated, he was able to measure the systolic 4 achievement of Korotkoff as a serendipitous discovery, BP with great precision . He used the tactile sense of his fingers to detect the moment when the pulse disappeared similar to that of Alexander Fleming in the discovery of or appeared4. This method was accurate, inexpensive and penicillin. However, Nassim N. Taleb's recent black swan soon became highly popular. theory may serve to illustrate his discovery in a new and, perhaps, surprising way. Nevertheless, the diastolic BP could not be precisely determined by this procedure, and when Harvey Cushing introduced Basch's and Riva Rocci's methods into clinical Historical Sketch medicine and surgery only the systolic BP was being Every second throughout the world, someone is assessed3. A number of gifted physiologists and clinicians measuring the systolic and diastolic blood pressure (BP) by were ineffectively in search of a noninvasive method to means of Korotkoff's auscultatory method. It is worth noting determine the diastolic BP5. Nonetheless, the quantification that very few discoveries have had such a large impact of the diastolic BP was not achieved by any of these clinical or on and relevance to clinical medicine as the noninvasive physiological researchers, but by an unlikely and unexpected measurement of the diastolic BP. The systolic and diastolic figure: Nikolai Sergeevich Korotkoff (1874-1920), a young BP had been accurately measured with an intra-arterial Russian army surgeon, working under precarious conditions 6 catheter after Friedrich Goltz (1834-1902) and Justus Gaule in the hardship of diverse wars . He did his amazing feat 6,7 (1849-1939) introduced their ingenious valved device using the Riva-Rocci bracelet and a child's stethoscope . in 18781. Two years later, Bohemian physician Samuel Korotkoff was not a BP researcher and his main concern, S. K. von Basch (1837-1905), former ordinary physician as a war surgeon, was to know if collateral blood supply was to the Mexican Emperor, presented his groundbreaking undiminished, so as to resolve whether a wounded artery apparatus, consisting of a rubber bulb connected to a could be securely ligated when an amputation was likely6. mercury manometer2. He compressed the radial artery with He knew that the onset of the palpable pulse was the systolic the bulb until the pulse was obliterated and, at that point BP and he reasoned that the time of disappearance of the he measured the systolic BP2. The Bohemian physician sound signaled the onset of the laminar flow and, therefore, compared the systolic BP measured with his method in of the relaxation of the arterial wall. He hence proposed that diastolic BP might be estimated by the disappearance of all sounds8. Keywords Some Philosophical Remarks on the Epistemology of the History of Medicine; Arterial Pressure; Sphygmomanometers Unexpected in Science / utilization. It is easy to dismiss the achievement of Korotkoff as Mailing Address: Bruno Estaño • a serendipitous discovery similar to that of Alexander Laboratory of Clinical Neurophysiology, Department of Neurology and Fleming in the discovery of penicillin9. While looking for Psychiatry, National Institute of Medical Sciences and Nutrition Salvador Zubirán (INNSZ). Vasco de Quiroga 15, Tlalpan, Postal Code 14000, one thing, he found something entirely different. However, México D.F., México Nassim N. Taleb's recent black swan theory may serve to E-mail: [email protected] illustrate his discovery in a new and, perhaps, surprising Manuscript received April 1, 2013; revised April 7, 2013; accepted May 20, 2013. way10. In his book, Taleb persuasively argues about finding the unexpected in life and science. Many great discoveries DOI: 10.5935/abc.20130217 and inventions in science and art have been unexpected e99 Estañol e cols. Sons de Korotkoff - O Improvável também ocorre Viewpoint and unpredictable, though easily explained in retrospect. could not yet envision its enormous practical future. In fact, many of these findings have compelled scientists He published his report in a single page to the Imperial to change their theoretical framework to accommodate Military Medical Academy of Saint Petersburg in 19057,8. new facts. It is true that a discovery is made within the In this brief presentation he described his discovery. context of what is already known, and this serves as part In the following month, he made a new presentation. of retrospective explanation: without the Riva Rocci's In 1910 he defended his Ph.D. dissertation on the collaterals bracelet and without the pediatric stethoscope, the young of peripheral circulation8. Subsequently, he worked in Russian surgeon could not have developed his auscultatory different hospitals6,8. He did not publish anything else on method. It is then easy, but probably wrong, to assume that the subject of BP measurement and died of pulmonary the discovery would have been made sooner or later; that tuberculosis, at the early age of 46 years, in 19206,8. similar discoveries may be made simultaneously in different parts of the world (synchronicity) does not entirely confirm this, for the majority of discoveries are not synchronous, Author contributions and we cannot know all the discoveries that remain to Conception and design of the research, Acquisition of be made, even though the facts have been known for data, Analysis and interpretation of the data, Writing of centuries. It has been said that the scientist discovers and the manuscript and Critical revision of the manuscript for the artist invents, but in the case of Laennec, Korotkoff and intellectual content: Estañol B, Delgado G, Borgstein J; others, both concepts are correct. The Russian surgeon Statistical analysis: Delgado G; Obtaining funding: Borgstein J. not only produced an unexpected result but he himself was an unlikely actor in the drama. The odds favored Potential Conflict of Interest that clinicians and physiologists working in the field of BP measurement would come up with the discovery, and it No potential conflict of interest relevant to this article was was improbable, to say the least, that a young surgeon, reported. physically and emotionally overworked, with a large numbers of acute wounded patients, would make such a Sources of Funding momentous discovery. There were no external funding sources for this study. Perhaps it is as simple as observing what everyone has seen, while having some new thoughts about it and it is possible that fatigue played a part in this altered perception. Study Association Nevertheless, at some moment after his discovery, Korotkoff This study is not associated with any post-graduation became keenly aware of its significance, although he program.

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1. Geddes LA. The first accurate measurement of systolic and diastolic blood 6. Gurevich AK. Dr. Nikolay S. Korotkov (1874-1920) -- the discoverer of blood pressure. IEEE Eng Med Biol Mag. 2002;21(3):102-3. pressure measurement tones. J Nephrol. 2006;19 Suppl 10:S115-8.

2. Delgado García G, Estañol Vidal B. [The Emperor’s physician before and 7. Segall HN. Dr N C Korotkoff: discoverer of the auscultatory method for after the Empire]. Gac Med Mex. 2012;148(5):487-96. measuring arterial pressure. Ann Intern Med. 1965;63(1):147-9. 3. Janeway TC. The clinical study of blood-pressure: a guide to the use of the 8. Nabokov AV, Nevorotin AJ. Dr N. S. Korotkov: the low-pitch sounds that sphygmomanometer. New York: D. Appleton and Co; 1904. stand high. Nephrol Dial Transplant. 1998;13(4):1041-3. 4. Roguin A. Scipione Riva-Rocci and the men behind the mercury sphygmomanometer. Int J Clin Pract. 2006;60(1):73-9. 9. Ban TA. The role of serendipity in drug discovery. Dialogues Clin Neurosci. 2006;8(3):335-44. 5. Warfield LM. Studies in auscultatory blood-pressure phenomena. I. The experimental determination of diastolic pressure. Arch Intern Med. 10. Taleb NN. The black swan: the impact of the highly improbable. New York: 1912;10(3):258-67. Random House; 2010.

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