· Jose Sebastião de Abreu, Nayara Lima Pimentel, Jordana Magalhães Siqueira, Carlos Newton...

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

EditorialMyocardial Delayed Enhancement by Cardiac Magnetic Resonance

Imaging in Pulmonary Arterial Hypertension: A Marker of Disease Severity

Original ArticlesMiniaturized Self-Expanding Drug-Eluting Stent in Small-Caliber

Coronary Arteries: Late Effectiveness

Does the Aging Process Significantly Modify the Mean Heart Rate?

Serum Adiponectin and Cardiometabolic Risk in Patients with Acute

Coronary Syndromes

Left Ventricular Synchrony and Function in Pediatric Patients with

Definitive Pacemakers

Risk of Ionizing Radiation in Women of Childbearing Age undergoing

Radiofrequency Ablation

Analysis of the Sensitivity and Specificity of Noninvasive Imaging Tests

for the Diagnosis of Renal Artery Stenosis

Triceps Skinfold as a Prognostic Predictor in Outpatient Heart Failure

Optimized Treatment and Heart Rate Reduction in Chronic Heart Failure

Mechanical Dyssynchrony is Similar in Different Patterns of Left

Bundle-Branch Block

Criteria for Mitral Regurgitation Classification were inadequate for

Dilated Cardiomyopathy

Review ArticleAntithrombotic Strategy in the Three First Months following

Bioprosthetic Heart Valve Implantation

Case ReportAcute Coronary Syndromes in 2011 and 2012

Sports Events and Acute Coronary Syndrome: Possible Confounding

Factors and Bias

Eletronic Pages

Anatomopathological SessionCase 5/2013 - A 73 Year-Old Man with Heart Failure, Preserved

Systolic Function and Associated Renal Failure

Case ReportSteal of Blood Flow from the Vertebral Artery to the Internal Thoracic

Artery Anastomosed to the Coronary Artery

ViewpointKorotkoff Sounds – The Improbable also Occurs

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

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

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 SeverityCarlos 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 EffectivenessFlavio 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 SyndromesGustavo 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 PacemakersMichel 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 AblationGustavo 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


Systemic Hypertension

Analysis of the Sensitivity and Specificity of Noninvasive Imaging Tests for the Diagnosis of Renal Artery StenosisFlavio 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 FailurePriccila 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 FailureIrineu Blanco Moreno, Carlos Henrique Del Carlo, Antônio Carlos Pereira-Barretto..................................................................................................................................................................página 442

Mechanical Dyssynchrony is Similar in Different Patterns of Left Bundle-Branch BlockRodrigo 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 CardiomyopathyFrederico 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 ImplantationAndre R. Durães, Milena A. O. Durães, Luis C. L. Correia, Roque Aras..................................................................................................................................................................página 466

Letter to the Editor

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

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


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 FailureTiago 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 ArteryJose 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 OccursBruno 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

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Editorial

Myocardial Delayed Enhancement by Cardiac Magnetic Resonance Imaging in Pulmonary Arterial Hypertension: A Marker of Disease SeverityCarlos 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

Mailing address: Carlos Eduardo Rochitte •Instituto do Coração, InCor, HCFMUSP - Setor de Ressonância Magnética e Tomografia Computadorizada Cardiovascular, Av. Dr. Enéas de Carvalho Aguiar, 44 - Andar AB, Cerqueira César. Postal Code 05403-000, São Paulo, SP - BrazilE-mail: [email protected] received October 23, 2013; revised manuscript October 23, 2013; accepted October 23, 2013.

DOI: 10.5935/abc.20130224

The study of Bessa et al.1, published in this issue of Arquivos Brasileiros de Cardiologia, studied 30 patients with pulmonary hypertension (PH) using cardiac magnetic resonance imaging. They evaluated the presence and extent of delayed enhancement in these patients and correlated the percentage of delayed enhancement mass with severity markers in pulmonary hypertension. Delayed enhancement was found in 93% of patients with HP in the anterior and inferior septa, in the septal-RV free wall attachment zones, commonly called delayed enhancement of ventricular junction pattern. The delayed enhancement mass was corrected to the left ventricular mass. The percentage of delayed enhancement was then used for analysis. This study showed a higher percentage of myocardial fibrosis in patients with signs of Right Ventricular Failure (RVF), Functional Class (FC) IV, 6-Minute Walk Test (6MWT) < 300 m, Cardiac Index (CI) < 2.0 and right atrial pressure > 15. The presence of RHF, the impairment of FC and the 6MWT walking distance and low CI are classic markers of prognosis in HP. The percentage of fibrosis was able to identify patients with RVF (clinical evaluation), FC IV, 6MWT < 300 m and CI < 2.0 L/min.m2 with good accuracy.

Despite some progress in understanding the physiopathology of the disease and the discovery of new treatments in recent decades, pulmonary hypertension is still a disease with poor prognosis2. Non-invasive markers to better assess the severity of the disease and that may help determine which patients require more aggressive treatments are needed. Delayed enhancement is a tool that was initially used to evaluate areas of myocardial fibrosis in patients who have had myocardial infarction. The contrast injected is quickly rinsed in normal areas, but when there is increased extracellular tissue, such as in fibrosis, the contrast is retained and is slowly eliminated

from these areas. When images are acquired late (5-10 min after contrast injection), the areas in which the myocardium is intact do not retain the contrast, but the areas with fibrosis retain the contrast, hence the term delayed enhancement.

In patients with HP, three studies demonstrated the presence of delayed enhancement in most patients and delayed enhancement was found mainly in the RV septal attachment zone and in the septal wall3-5. Fibrosis in these areas can also be found in hypertrophic cardiomyopathy6,7, unlike other cardiomyopathies such as the Chagas disease8, with predominance of fibrosis in the basal and apical left ventricular (LV) inferolateral wall, or viral myocarditis with diffuse pattern9, among other patterns suggestive of specific etiologies of cardiomyopathies. In most of these diseases, the presence of delayed enhancement appears to be associated with increased risk of arrhythmias and worse prognosis. Delayed myocardial enhancement (fibrosis) of ventricular junction pattern appears to be associated with Right Ventricular (RV) overload. An explanation for this preferential location of delayed enhancement is the overhead sustained by the septum with increased RV afterload. As the RV overload increases, it dilates and pushes the septum toward the LV, overloading the septal RV attachment zones and the septum itself. Shehata et al. demonstrated the inverse relationship of delayed enhancement mass with Eccentricity Index (EI), that is, the higher the septal bulging toward the left ventricle, and consequently the lower the EI, the greater the delayed enhancement mass10. In experimental studies, these are the areas subjected to maximum stress in normal ventricular contraction, and these areas are also the first to produce natriuretic peptide type A in HP models, reflecting greater mechanical stress. The study of Bessa et al. demonstrated that most patients with HP had delayed enhancement and ventricular junction pattern, confirming the literature data1. An echocardiographic study in patients with HP of a specific etiology associated with schistosomiasis also demonstrated a relationship of increased pulmonary pressure with disease severity, suggesting that in various etiologies of HP, a delayed enhancement of similar pattern may occur (Armstrong)11.

The strength of this study was that all patients underwent right cardiac catheterization within 72 hours after cardiac magnetic resonance imaging. Previous studies have shown the relationship of delayed enhancement mass with RV dysfunction and hemodynamic variables, but this study was the first to demonstrate the relationship of myocardial fibrosis with clinical, hemodynamic and functional markers.

The evaluation of right ventricular function is emerging as an independent prognostic marker in HP and the study

KeywordsMagnetic Resonance Secfroscopy/methods; Hypertension,

Pulmonary; Myocardium; Endomyocardial Fibrosis.

377

Editorial

Rochitte et al.Myocardial Fibrosis in PH – A Severity Marker

References

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

of Sheata et al. also demonstrated an inverse correlation of delayed enhancement mass with RV ejection fraction10. Unfortunately, this study did not evaluate the fibrosis mass percentage in relation to RV dysfunction.

Although this study has evaluated a small number of patients with HP and although it is a cross-sectional study in which it is not possible to show the prognostic role of delayed enhancement, the fact that the percentage of fibrosis is increased in patients who have markers of worse prognosis suggests that delayed enhancement may prove to be an important noninvasive prognostic marker in patients with HP. It would be interesting if the authors conducted long-term follow-up of these patients, so that the prognostic role of delayed enhancement is confirmed and fibrosis may show its prognostic role in HP, thus helping clinical decisions. The study of Bessa et al. also opens up the possibility of

comparing other forms of HP, such as those belonging to the other groups of classification (secondary to left ventricular dysfunction, diseases of the pulmonary parenchyma, chronic pulmonary thromboembolism, for example) in order to analyze the existence or not of different patterns of fibrosis.

Despite these limitations, the manuscript of Bessa et al. is another original scientific contribution indicating that myocardial fibrosis detected by cardiac resonance imaging correlates directly with the severity of disease and possibly with prognosis. Therefore, another marker of severity of cardiomyopathy associated with pulmonary hypertension is reaffirmed and can be identified by magnetic resonance imaging. The evaluation of interstitial myocardial fibrosis through myocardial T1 mapping by resonance imaging may bring in the future more information on the myocardial state and prognosis in this important and challenging clinical scenario.

1. Bessa LG, Junqueira FP, Bandeira ML, Garcia MI, Xavier SS, Lavall G, et al. Pulmonary arterial hypertension: Use of delayed contrast-enhanced cardiovascular magnetic resonance in risk assessment. Arq Bras Cardiol.2013;Aug 27.pii S0066-782X2013005000069 [Epub ahead of print].

2. Cicero C, Franchi SM, Barreto AC, Lopes AA. Lack of tight association between quality of life and exercise capacity in pulmonary arterial hypertension. Arq Bras cardiol.2012;99(4):876-85.

3. Blyth KG, Groenning BA, Martin TN, Foster JE, Mark PB, Dargie HJ, et al. Contrast enhanced-cardiovascular magnetic resonance imaging in patients with pulmonary hypertension. Eur Heart J. 2005;26(19):1993-9.

4. Junqueira FP, Macedo R, Coutinho AC, Loureiro R, De Pontes PV, Domingues RC,et al. Myocardial delayed enhancement in patients with pulmonary hypertension and right ventricular failure: Evaluation by cardiac mri. Br J Radiol.2009;82(982):821-6.

5. McCann GP, Gan CT, Beek AM, Niessen HW, Vonk Noordegraaf A, van Rossum AC. Extent of mri delayed enhancement of myocardial mass is related to right ventricular dysfunction in pulmonary artery hypertension.AJR Am J Roentgenol.2007;188(2):349-55.

6. Shiozaki AA, Senra T, Arteaga E, Martinelli Filho M, Pita CG, Avila LF, et al. Myocardial fibrosis detected by cardiac ct predicts ventricular fibrillation/

ventricular tachycardia events in patients with hypertrophic cardiomyopathy. JACC Cardiovasc Imaging.2013;7(3):173-81.

7. Shiozaki AA, Senra T, Arteaga E, Pita CG, Martinelli Filho M, Avila LF,et al. [myocardial fibrosis in patients with hypertrophic cardiomyopathy and high risk for sudden death]. Arq Bras Cardiol.2010;94(4):535-40.

8. Mello RP, Szarf G, Schvartzman PR, Nakano EM, Espinosa MM, Szejnfeld D,et al. Delayed enhancement cardiac magnetic resonance imaging can identify the risk for ventricular tachycardia in chronic chagas’ heart disease. Arq Bras Cardiol.2012;98(5):421-30.

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 myocarditis. Circulation. 2006;114(15):1581-90.

10. Shehata ML, Lossnitzer D, Skrok J, Boyce D, Lechtzin N, Mathai SC, et al.. Myocardial delayed enhancement in pulmonary hypertension: Pulmonary hemodynamics, right ventricular function, and remodeling. AJR Am J Roentgenol.2011;196(1):87-94.

11. Armstrong AC, Bandeira AM, Correia LC, Melo HC, Silveira CA, Albuquerque E, et al. Pulmonary artery pressure, gender, menopause, and pregnancy in schistosomiasis-associated pulmonary hypertension. Arq Bras Cardio.2013;101(2):154-9.

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Original Article

Miniaturized Self-Expanding Drug-Eluting Stent in Small Coronary Arteries: Late EffectivenessFlavio 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 SousaInstituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil

Mailing Address: Flavio Roberto Azevedo de Oliveira •Marquês de Tamandaré, Poço da Panela. Postal Code 52061-170,Recife, PE - BrazilE-mail: [email protected], [email protected] received September 10, 2012, revised manuscript September 17, 2012, accepted April 23, 2013.

DOI: 10.5935/abc.20130199

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.

IntroductionDuring percutaneous coronary angioplasty (PCA),

small-caliber vessels represent higher complexity with increased rates of target-lesion revascularization (TLR) and more restenosis, when compared with larger-caliber vessels1-5, being related to neointimal hyperplasia (NIH), which determines late luminal loss (LLL) after PCA. NIH has the same intensity in vessels of different sizes, with greater impact on small-caliber ones, which respond with greater lumen loss than larger vessels6.

With bare-metal stents (BMS), LLL ranges from 0.8 to 1.0 mm. With drug-eluting stents (DES), LLL is always below 0.5 mm being smaller (below 0.3 mm) in those DES with sirolimus, everolimus or biolimus. This greater inhibitory power in NIH has resulted in a significant reduction in

restenosis rates in all groups of patients (P), even in patients with small-caliber vessels. Still, restenosis rates remain higher in smaller-caliber vessels when compared with larger ones7-9.

More distal lesions, tortuosity and calcification, common in small-caliber vessels, hinder stent navigation in conventional dilation systems with balloon-expanding stent (BES).

Stents with thin struts induce lower NIH than the ones with thick struts, even among DES10,11.

In this context, the Sparrow® self-expanding nitinol stent (Cardiomind Inc., Sunnyvale, California) appeared, dedicated to small-caliber vessels. The BMS version of the Sparrow® self-expanding stent (SES) was evaluated by Chamié et al12, who demonstrated its efficacy and safety. It is mounted on a guide wire system that eliminates the balloon, resulting in 70% lower profile than the conventional balloon-stent system.

This study is the pioneer to evaluate the impact of LLL when using self-expanding Sparrow® DES compared to the BMS version in small-caliber vessels assessed by QCA at eight months, which is the primary objective. Secondary objectives: (1) comparison between the groups regarding vessel, lumen and stent volumes and the percentage of the stent volume obstruction by means of intracoronary ultrasound (IVUS) immediately after implantation and at eight months; (2) description of up to 12 months in

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

exchange major adverse cardiac events (MACE - death, myocardial infarction, target vessel revascularization (TVR) and stent thrombosis.

Methods

Study designThe present was a prospective randomized, non-blinded

study (the surgeon was unaware of the type of stent used), carried out at the Instituto Dante Pazzanese de Cardiologia, São Paulo (SP), CEP and Conep protocols #3,577 and 14,582 (approved), which evaluated the late effectiveness of the Sparrow® DES when compared to the BMS version by measuring and comparing LLL at eight months through the QCA in patients with lesions in small-caliber vessels (reference diameter ≤ 2.75 mm).

The clinical reassessment was scheduled for 30 days, six months and 12 months after the procedure. QCA assessment was scheduled immediately before and immediately after the PCA and after eight months. Intravascular ultrasound (IVUS) was also scheduled immediately after stent implantation and after eight months.

Patient selection

Inclusion criteria:• Age ≥ 18 years.• Clinical evidence of ischemia (angina or ischemic

equivalent) or evidence of ischemia by noninvasive evaluation. • Target lesion in natural coronary artery with stenosis

≥ 50% and < 100%, analyzed by QCA.• Target vessel with reference diameter ≥ 2.0 and ≤ 2.75 mm.• Target lesion with extension ≤ 20 mm.

Exclusion criteria:• Female gender during pregnancy.• Left ventricular ejection fraction < 30% during the prior

six months.• Contraindication to dual antiplatelet use. • Renal dysfunction (serum creatinine > 2.0 mg/dL).• Stroke or transient ischemic attack in the previous

six months.• Life expectancy < 12 months.• Target-lesion located in the left main coronary artery

or ostia of the right coronary artery, anterior descending or circumflex arteries. Bifurcation lesion, with thrombus, or in single remaining vessel.

• Target-lesion involving bifurcation.

Analyzed device and implantation techniqueThe analyzed device was the sirolimus-eluting Sparrow®

DES (Cardiomind® Inc., Sunnyvale, California, USA), as compared with the BMS version of the same stent (BMS

Sparrow®). This is a sirolimus-eluting system (6 mg, 60% of the dose of the Cypher® stent) comprising a 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 PLA/PGLA biodegradable copolymers of the SynBiosysTM biodegradable polymer system. This copolymer matrix adds only 8 microns to strut thickness. The result is a very low profile system, as shown in Figure 1, and up to 70% thinner than any balloon-stent system (Table 1).

A flexible guide wire, with 2-3 cm in length, runs along the stent to allow advancement of the system in the vessel. There are two radiopaque markers that identify the beginning and end of the stent in the guide wire system and allow its precise positioning in the lesion. The compound stent contains nitinol, which has a thermoelastic expansion property (memory metal). Mechanical locks on the stent borders keep it from expanding and attached to the guide wire. A power source (non-sterile external device) is connected to the proximal end of a dilation system sterile adaptable cable, which controls the stent release through an electrolysis mechanism with a 0.5 mA current. Initially, the distal lock is released and then, the proximal one (Figure 2).

The stent system worked with a 0.014" guide wire and 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 and the stent deployment process was initiated through electrolysis, as previously described. Post-procedural dilation was performed after stent release. To prevent trauma to the stent borders, the balloon was always shorter than the stent. The same guide wire could also be used to perform IVUS.

Study procedures comprised the following sequence: electrocardiogram (ECG) before the procedure and at discharge; cardiac enzymes (CK-MB) and troponin I or T, before and after the procedure, activated clotting time (ACT) after arterial access, at the end of the procedure and before sheath withdrawal; dual antiplatelet therapy with clopidogrel 300 mg and aspirin 100 mg at least 12 hours before the procedure, maintained for at least eight months; use of a 0.6 F sheath and compatible catheter-guides; intravenous heparin (100 U/kg) after sheath placement and intracoronary nitroglycerin (100-200 mg); initial angiography of the vessel in at least two proximal-orthogonal views to allow adequate visualization of the vessel and lesion; evaluation by predilation QCA; ACT with stenting as previously described; sheath withdrawal 3-4 h after the procedure with ACT < 200 s; discharge after 24 h in cases without complications, follow-up visits at 30 days, eight and 12 months; control angiography at eight months; IVUS immediately after stent implantation and after eight months.

The analysis of the QCA and IVUS were performed offline (QCA using the CMS-GFT® software, release 5.1, Medis, Leiden, the Netherlands, and IVUS using the Echoplaque ® software, Indec Systems, Inc, Mountain View, California, USA).

In QCA, the following parameters were evaluated: lesion length, reference vessel diameter (RVD), minimal lumen diameter (MLD), percentage of vessel stenosis (PS) calculated

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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).

Guide wire 0.014

2.5 mm stent over balloon: crossover profile of 0.032

Cardiomind Sparrow® stent: crossover profile of 0.014

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

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

by the formula PS = RD - MLD ÷ RD) x 100, acute luminal gain (ALG) calculated by ALG = post-MLD – pre-DML; LLL (difference between the late MLD and MLD immediately after the procedure). These analyses were performed in-stent and in the stent segments 0.5 mm proximal and distal to the stent (analysis of the borders).

The IVUS images corresponded to the recordings of at least

10 mm distal to the stent up to at least 10 mm proximal to the stent, in two acquisitions, the first immediately after the implantation and the second after 8 months. For this purpose an automated stent traction system at a speed of 0.5 mm / sec with a 40 MHz transducer, 2.6-French sheath (Galaxy 2 ouIlab, Boston Scientific Corporation, Natick, Massachusetts, USA) was used. Were programmed Calculations of areas

Conenction withthe guide wire

Disposable sterileadaptor

Non-sterile power source

DEPLOYMENT SYSTEM

I..014 Stent in a wire

190 cm

Stent

A B

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

Variables DES (n = 12)

BMS(n = 12) p

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.

and volumes of the vessel, lumen, stent and plaque were programmed, as well as the volume of NIH and the stent volume obstruction percentage, according to the protocol already described in literature. Strut apposition to the vessel wall was also evaluated.

Study definitionsAngiographic success: stent implantation in the target-

lesion with residual stenosis < 30% and TIMI flow 3. Procedural success: angiographic success without major complications (death, myocardial infarction or in-hospital emergency revascularization surgery). Stent thrombosis: Academic Research Consortium (ARC) criteria13. Major adverse cardiac events (MACE): death (cardiac), nonfatal myocardial infarction (elevation of cardiac enzymes CK-MB or cardiac troponins I and T, up to three times above normal levels until discharge and twice the normal after hospital discharge or appearance of new Q waves in at least two contiguous ECG leads) and TVR. Binary restenosis: recurrent target lesion ≥ 50% at late control.

Statistical AnalysisThe IBM ® SPSS Statistics software, release 19 (Chicago,

Illinois, USA.) was used for the statistical analyses. Student’s t test was used to compare means between the groups. For all compared parameters, p values < 0.05 were considered significant. Categorical variables were expressed as absolute value or proportion. Continuous variables were expressed as mean and standard deviation. A level of significance of 5% and power of 80% were considered, estimating a LLL decrease with DES of 65% and calculating the minimum sample size of 11 patients for each group.

ResultsFrom January 2009 to April 2010, 24 patients were

included, 12 in each group, and prospectively randomized. The clinical characteristics of the patients are shown in Table 2 and disclosed homogeneous groups.

The distribution per artery and per segment was similar between the groups and the lesion was located in the middle and distal segments of the vessel in more than 70% of cases in both groups (Table 3).

There were no significant differences between the DES and BMS groups, in this sequence, regarding the volume of contrast (133.33 ± 23.87 mL versus 120 ± 34.38 mL, p = 0.282), procedure time (71 ± 9.2 min versus 62 ± 14.82 min, p = 0.350) and maximum pressure postdilation (15.75 ± 4.67 versus 15.42 ± 3.12, p = 0.839).

PCI was successfully performed in all patients. There were no MACE or complications until discharge.

QCA results of the angiographies performed immediately before and after PCA show that randomization produced similar groups and highlights the homogeneity and immediate outcome success between the groups. Lesion extension was slightly higher in the group with DES, but not significantly (DES: 15.29 ± 5.55 mm versus BMS: 12.91 ± 3.23 mm, p = 0.233); stent length (SF 19.92 mm ± 3.60 versus BMS: 18.00 ± 2.34 mm, p = 0.139) and implanted stent diameter (DES 2.58 ± 0.25 mm versus 2.66 ± 0.19 mm, p = 0.368) were not different between groups.

Reference vessel diameter immediately before the procedure was similar between the groups (DES = 2.46 + 0.24 mm versus BMS = 2.42 + 0.21 mm, p = 0.680), demonstrating a small-caliber vessel scenario.

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

Variables DES(n = 12)

BMS (n = 12) p

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 is well demonstrated in the pre-procedural results of MLD (DES = 0.75 + 0.20 mm versus BMS = 0.73 + 0.17 mm, p = 0.750) and PS (SF = 69.36 + 6.37 = 69.67% versus BMS + 5.46%, p = 0.905).

The immediate results after the procedure measured by MLD (DES = 2.46 ± 0.22 mm versus BMS = 2.39 + 0.13 mm, p = 0.350) and PS (DES = 4.59 ± 3.52% versus BMS = 4.94 + 4.41%, p = 0.869) confirm successful angiographic procedure in both groups, with similar benefits, which is reflected in satisfactory absolute gain in both groups (DES = 1.71 + 0.28 mm versus BMS = 1.66 + 0.12 mm, p = 0.614), a result of the difference between the pre-procedural and post-procedural MLD.

At eight months, the parameters analyzed by QCA, as demonstrated in Table 4, showed significant differences between the groups regarding the ability to maintain the results recorded in the evaluation immediately after the procedure, i.e., MLD and PS. These results are reflected in the 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).

Figure 3 shows study patients’ individual response regarding PS, with the DES group showing more homogeneous and maintenance of the response pattern.

The analysis of the 5 mm proximal and distal to the stent immediately after stent implantation and at eight months, as shown in Table 5, disclosed no significant differences between the groups regarding MLD and PS, resulting in LLL with no significant difference. Although the analysis of the proximal and distal segments to the stent did not show significant differences between the groups, there was a trend of higher LLL in the BMS group compared with DES group, most markedly in the proximal segment.

Technical difficulties in the progression of IVUS catheter to an adequate point beyond the stent (including 5 mm distal to it, to include the entire segment of interest) restricted data collection provided by this type of evaluation

predicted in the study, precluding the provision of full information, differently from what occurred with the QCA.

Nevertheless, it was observed that the self-expanding stent showed an increase in volume over time from 14.8% in the DES group and 2.5% in the BMS group. There was no strut malapposition in this group of patients.

Up to 12 months of evolution, there was no patient loss to follow-up. All patients used dual antiplatelet therapy throughout the study, as required by the protocol. There were no reports of death, nonfatal myocardial infarction or need for myocardial revascularization.

Although four patients had binary restenosis in the BMS group, the clinical translation of this finding resulted in new PTCA in three patients, only. Specifically, the patient that had occlusive restenosis, was maintained in clinical treatment due to the good evolution.

Clinical event compatible with in-stent thrombosis was not observed in either group during follow-up.

DiscussionNew research in this area is of relevance because the

small-caliber vessels represent 40-50% of cases of PCA, and this subgroup, although it has been strongly benefited from the advent of DES, still carries a higher risk of restenosis and TVR, when compared with larger-caliber vessel results7,14,15. This study represents the first clinical experience with drug-eluting SES in small-caliber vessels.

The primary objective of reducing in-stent LLL in this study was achieved with Sparrow® DES and the absolute value found of 0.25 ± 0.16 mm shows that the performance of this platform was equivalent to the best results with drug-eluting stents.

The patients in our study are also part of a larger cohort, the multicenter CARE II study16, which included a larger number of patients and of which initial results, presented at the 2010 Transcatheter Cardiovascular Therapeutics Congress showed data similar to those found here.

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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.

Bare-metal stentDrug-eluting stent

Late LatePost PostPre Pre

% Stenosis

% S

tenos

is

% S

tenos

is

% Stenosis

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


BMS(n = 12) p CI (95%)

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

The CARE II study16, with inclusion criteria similar to those in our study, including the patients in this cohort, involved 137 patients in three groups, comparing Sparrow ® DES (group 1) with Sparrow® BMS (group 2) and the Driver®/Microdriver® bare-metal balloon expandable stent (group 3). The primary objective was the assessment of LLL at eight months by IVUS. At eight months a significantly lower LLL was observed in the DES group, similar to what was found by QCA in our study (0.29 + 0.45 mm). In the group with Sparrow® DES, the binary restenosis was 6.7% and the incidence of MACE at eight months was 6.25%, confirming the results of our study in a larger population.

There was no binary restenosis at the borders in the group of patients with DES, differently from the previously described Sirius study report. This may be related to Sparrow® stent system implantation technique, which minimizes the chances of barotrauma to the stent borders. In the group with DES, two cases (16%) of binary restenosis

were recorded, both involving the proximal border, but they were not isolated cases, reflecting a proliferative restenosis process and, therefore, associated with undesired proliferation of in-stent NIH.

Safety problems with DES, shown by late and very late in-stent thrombosis (low, but greater than that observed with the BMS), were probably related to chronic inflammatory stimulation determined by the durable polymers, which hinder the re-endothelialization process17-20. In the present study, in-stent thrombosis did not occur during a 12-month follow-up. The use of bioabsorbable polymers in the Sparrow® stent may have contributed to this fact.

Even in the age of DES, there have been studies showing that the smaller the strut thickness, the lower the LLL11. In this context, the Sparrow® stent has an additional advantage, as it has thinner struts than all other available stent models.

These favorable characteristics of the deployment system of the self-expanding Sparrow® stent – thin struts,

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


BMS(n = 12) p CI (95%)

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 limo family, additional expansion property over time and deployment technique that minimizes trauma to the borders – may be at the root of its good performance as demonstrated in our study and ratified by the results of the CARE II study16.

The evaluation by IVUS in this study, as in the CARE II16 showed a trend to stent expansion over time, more markedly in the group with drug-eluting stents, a finding that motivates further research.

The limitations of this study included the small numbers of patients, which was related to logistical issues regarding the endoprosthesis availability, the randomization, which was not blinded, and the impossibility of IVUS evaluation, an important tool for the assessment of the mechanistic performance of stents.

The subsequent analysis by QCA and IVUS were performed without knowledge of the type of stent used, which lessens the non-blinded randomization problem.

Broad inclusion criteria, without restrictions regarding tortuosity and calcification, in addition to vessel diameter, may be related to the low rate of IVUS performance in this study.

The present study paves the way for further research with larger sample sizes and even comparison with other DES systems, so that the clinical impact of this new device can be assessed by demonstrating, in a pioneering way, the performance of the self-expanding Sparrow® stent in small-caliber vessels, validating its efficacy through the objective parameter of LLL outcome and its safety by the absence of stent thrombosis at 12 months.

ConclusionsThe results of this study allow us to conclude:1. In patients submitted to percutaneous transluminal

coronary angioplasty in natural coronary arteries with reference diameter ≤ 2.75 mm, the use of self-expanding DES Sparrow ® compared with the bare metal version of the same stent, resulted in significant reduction of late lumen loss (within eight months after the index procedure).

2. Angiographic measurements regarding the immediate outcome after the procedure (percentage of stenosis, minimal lumen diameter and acute luminal gain) were satisfactory in both groups with no significant differences between them.

3. Angiographic measurements regarding the impact of treatment with Sparrow® DES in segments that are 5 mm proximal and distal to the stent showed outcome maintenance at eight months when compared to immediate outcomes (minimal luminal diameter and percent stenosis), thus demonstrating the absence of angiographic adverse effects at the stent borders in this group of patients.

Author contributionsConception and design of the research: de Oliveira

FRA, Mattos LAP, Abizaid A, Staico R, Botelho R, Sousa JE, Sousa A; Acquisition of data: de Oliveira FRA, Abizaid A, Abizaid AS, Costa JR, Costa R, Staico R, Botelho R, Sousa JE, Sousa A; Analysis and interpretation of the data: de Oliveira FRA, Mattos LAP, Sousa JE, Sousa A; Statistical analysis: de Oliveira FRA, Sousa JE; Obtaining funding: de Oliveira FRA; Writing of the manuscript: de Oliveira FRA,

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15. Wong P, Lau KW, Lim YL, Oesterle SN. Stent placement for non-STRESS/BENESTENT lesions: a critical review. Catheter Cardiovasc Interv. 2000;51(2):223-33.

16. Abizaid A, Botelho R, Verheye S, Meredith I, Costa R, Staico R, et al. [Poster]. CARE II 8 month follow-up results with the CardioMind® 0.014” Sparrow® Sirolimus-eluting Nitinol Stent System J Am Coll Cardiol. 2010;56(13):B53.

17. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern. Circulation. 2007;115(11):1440-55.

18. Taylor AJ, Gorman PD, Kenwood B, Hudak C, Tashko G, Virmani R. A comparison of four stent designs on arterial injury, cellular proliferation, neointima formation, and arterial dimensions in an experimental porcine model. Catheter Cardiovasc Interv. 2001;53(3):420-5.

19. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation. 2004;109(6):701-5.

20. Lockwood NA, Hergenrother RW, Patrick LM, Stucke SM, Steendam R, Pacheco E, et al. In vitro and in vivo characterization of novel biodegradable polymers for application as drug-eluting stent coatings. J Biomater Sci Polym Ed. 2010;21(4):529-52.

References

Mattos LAP, Costa JR; Critical revision of the manuscript for intellectual content: Mattos LAP, Abizaid A, Sousa JE, Sousa A; Clinical monitoring of patients: Abizaid AS.

Potential Conflict of InterestNo potential conflict of interest relevant to this article was

reported.

Sources of FundingThere were no external funding sources for this study.

Study AssociationThis article is part of the thesis of doctoral submitted by

Flavio Roberto Azevedo de Oliveira, from Instituto Dante Pazzanese de Cardiologia.

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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

Mailing Address: Marcos Antonio Almeida Santos •Avenida Gonçalo Prado Rollemberg, 211, Sala 210, São José.Postal Code 49010-410 – Aracaju, SE - BrazilE-mail: [email protected], [email protected] received April 07, 2013, revised manuscript June 03, 2013, accepted June 07, 2013.

DOI: 10.5935/abc.20130188

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.

IntroductionThe aging process, in spite of recent medical advances,

still constitutes an inexorable phenomenon. The number of elderly individuals has grown in almost all regions of the world, particularly where strategies to improve living conditions have been implemented1.

In recent decades, there has been a change in the age profile of Brazil. Considered for a long time as a young population, the number of elderly individuals is progressively increasing2-5.

On account of that, large-scale studies have been performed on the different aspects of the aging issue6-8, understood as a complex and multifactorial process, comprising biological changes with consequences on quality of life and general health status9.

There are several features related to cardiovascular senescence, ranging from decreased left ventricular compliance due to collagen accumulation and fibrosis to alterations in the conduction system, with reduction in pacemaker cells and fatty infiltration, leading to loss of specialized fibers and intrinsic decrease in sinus automatism10,11. Moreover, dynamic histochemical and immunohistochemical alterations during the aging process are associated with autonomic reactions involved in the reduction of heart rate in the elderly12, resulting in diagnostic and therapeutic implications13.

There is little scientific literature that aims to measure the effect size and relevance of MHR at Holter with advancing age. Searching the Medline and Embase databases for 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.

The present study aims to investigate the values of MHR in functionally and mentally active adults and elderly individuals, submitted to physical examination with 24-hour Holter monitoring. Several and exhaustive statistical analysis models will be used in order to identify, quantify and assess the relevance of MHR trends associated with age,

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dependent or not on other factors, including gender and presence of three high prevalence comorbidities among the elderly: systemic arterial hypertension (SAH), dyslipidemia and non-insulin dependent diabetes mellitus (NIDDM).

MethodsA cross-sectional, descriptive and analytical study was

carried out. The study complied with the ethical principles in the Declaration of Helsinki and the requirements of the 196/96 National Health Council Resolution, including complementary requirements and was approved by the institutional Research Ethics Committee #100710, on July 19, 2010. All individuals enrolled in the study consented to participate and signed the free and informed consent form.

The sample size, of around a thousand individuals, was previously calculated using the GPower software, based on the following parameters: alpha = 0.05, 1-β = 0.80, effect = 0.10. Data collection was performed consecutively and prospectively and the sample consisted of adult and elderly individuals of both genders, aged ≥ 40 years, submitted to Holter monitoring for 24 hours in a cardiology reference private practice from July 2010 to December 2012. The main reason for the examination was routine cardiological assessment in asymptomatic individuals or investigation of nonspecific symptoms, such as palpitations, dizziness or atypical chest pain.

The recording of the electrocardiographic tracing was performed during spontaneous situations occurring outside the hospital and medical environment. Every beat that generated electrical activity at any time of the recording was counted. The method has been validated by several researchers15,16 national17 and international18 cardiology associations.

The Holter recorder used in the study was a Cardiolight Cardios digital model with Memory Card, which performed 3-channel continuous recording, subsequently analyzed by the CardioSmart Professional CS 540 program. All recording devices were installed in the same location by the same professional and the tests were processed in a single computer. Moreover, the analysis of the examination and the production of the final report were made by the same cardiologist, experienced in Holter System.

Before the enrollment, individuals initially selected by the age criterion (≥ 40 years) and under outpatient care, were invited for an interview, where cognitive capacity was evaluated, albeit subjectively (understand without difficulty the content of direct questions related to anamnesis) and functional independence (walking without external aid, pain or difficulty in walking).

We selected only those individuals that met both criteria and agreed to take part in the research. Complaints indicating major diseases (history of myocardial infarction, angina pectoris, invasive hemodynamic procedure, cardiac surgery and permanent pacing) represented additional exclusion criteria.

We also excluded those who reported using insulin, digitalis, antiarrhythmics, beta-blockers or drugs that had a direct action on heart rate (such as the nebivolol), and the

pharmacological survey was carried out in two stages (on the day of installation and removal of the recording device) and by evaluating the compatibility between the anamnesis, the reported diseases and prescribed medications.

We also subsequently excluded those whose tests had a recording duration < 22 hours, those with more than 5% of artifacts, atrial fibrillation or dynamic alterations in the ST segment and T wave, high rate of supraventricular or ventricular ectopy (> 10,000/24h), or those who had evidence of abnormal sinus activity, be it of functional or organic etiology, manifested by atypical MHR values (< 60 or > 90 bpm). After echocardiography, we selected subjects with ejection fraction (EF) > 50%. The sample selection flowchart is shown in figure 1.

The resulting sample consisted of 1,172 individuals and was separated by gender and grouped into five strata according to the age (in years): 1 = 40-49; 2 = 50-59; 3 = 60-69; 4 = 70-79; 5 ≥ 80. There were no missing data.

Anthropometric data were obtained (weight and height) using an electronic calibrated scale with a maximum capacity of 200 kg and a ruler for measuring height ranging between 1.30 and 2 meters. The Body Mass Index (BMI) was calculated using the formula: weight (kg) / height (m)2.

Sample characterization data were obtained through a sociodemographic questionnaire, as well as reference to three chronic diseases: systemic arterial hypertension, diabetes mellitus and dyslipidemia.

The calculations were performed using SPSS platform 20, with the exception of the homoscedasticity test, and MHR jackknife estimates were performed in Stata 12. The 95% Confidence Interval (95%CI) was used and a significance value of p < 0.05 (two-tailed). Nonparametric data were represented by the total number and percentage. The chi-square test or Fisher's test were employed when appropriate for comparisons between groups.

Parametric variables were described as mean, standard deviation, standard error and interquartile range. Several bootstraps were employed to corroborate the sample values of MHR, with 1,000 samples and random counts of the 95%CIs for each situation: MHR for the entire sample; MHR for gender differences; MHR in five age groups.

The Kolmogorov-Smirnov test was used for exploration of the normality pattern and Levene's test for equality of variance. This was carried out both in the whole sample and in subgroups divided according to gender or age. In comparisons between two independent samples, the mean difference was calculated by Student's t test. Even though the distribution was normal, the same thing was done with the Mann-Whitney test, due to its more conservative characteristic and lower probability of Type I error

Subsequently, the analysis of MHR between age groups was performed by Kruskal-Wallis (also due to its more conservative characteristic and lower probability of type I error) and three ANOVA models: One-way (age groups), 5x2 (age groups and gender) and 5x2x2x2x2 (age groups, gender, SAH, dyslipidemia and diabetes mellitus). In the third ANOVA model, the difference between subgroups was calculated using Tukey’s post hoc test.

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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

2,029 eligible by age criterion

95: functional limitation

25: > 10,000 APCs/24h

47: atrial fibrillation

188: CHD, previous AMI, PCI, heart surgery

247: use of medications (insulin, digoxin, beta-blockers,

antiarrhythmics)

129: MHR < 60 ou > 90 bpm

9: alterations of ST-T

19: artifacts > 5% or recording < 22 h

24: pacemaker, resynchronizer or

cardioverter

7:EF < 50%

43: cognitive insufficiency

3: refusal to participate

1,172 individuals

21: > 10,000 VPCs/24h

Similarly, models of bivariate, point biserial and partial correlation were used, calculating the R2 and ETA2 for MHR and age, MHR and gender, MHR and diseases, adjusted and nonadjusted, as well as factors of correlation and determination for EF and BMI.

Finally, we performed linear regression for MHR in five models. The first two, simplified, involved only the age groups or age. The third was performed using the method of simultaneous input of predictor variables (age group, gender and the three diseases). The fourth was a hierarchical regression divided into two stages, for age and gender. The fifth was a more complex hierarchical regression, containing the aforementioned variables, entered in three sequential steps. Standardized beta-coefficients were calculated separately for the two hierarchical models.

ResultsThe general characteristics of the sample distribution

according to age groups and gender are shown in table 1. The age of the sample ranged between 40 and 100 years, with a mean of 65.69 ± 11.65 years.

It can be observed that females predominated in the five age groups, but this pattern was not significantly different between the age groups of the sample population. With advancing age, there was an increased prevalence of SAH, diabetes mellitus, dyslipidemia, and number of medications (p < 0.001) and decreased BMI, ejection fraction and percentage of non-sedentary individuals.

The mean MHR in the sample population was 74.45 ± 7.55 bpm (95% CI = 74.02 to 74.88). In addition to the narrow confidence interval, the internal validity of

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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 bootstrap estimates (95% CI = 74.00 to 74.90) and the use of jackknife estimates (95%CI = 74.01 to 74.89). The analysis was also performed in subgroups according to gender, age range and the association between them. In all cases, the values obtained directly resembled those found by the jackknife and the bootstrap estimates (Table 2).

The median and interquartile ranges of MHR were analyzed for the whole sample according to gender and stratified according to gender and age. The distributions showed typical pattern of normality without outliers or atypical values. MHR was higher among women and this pattern persisted in all age groups; we also identified a trend decline in MHR with age, regardless of gender (Figure 2A, B, C, D).

The mean MHR was significantly higher in females, both at Student's t test and at the Mann-Whitney test (p < 0.001). However, the magnitude of this difference was considerably small (d = 0.281). Both tests for comparisons of MHR means in two independent samples were reapplied regarding the presence of DM, dyslipidemia and diabetes, with nonsignificant results. Levene test for homogeneity of variance was satisfactory in all these analyses (Table 3).

In order to assess the degree of association between MHR and some variables bivariate correlation strategies were employed, including point biserial and partial correlation. We calculated the coefficient of correlation and determination, individual or adjusted for age, gender, diseases, EF and BMI (Table 4). Only age, gender and gender adjusted for age were statistically significant (p < 0.001). Despite the significance, the strength of this association is of very low significance, considering that the R and R2 values were less than 0.10.

In analyses involving the five age groups, different ANOVA models were employed, as well as the Kruskal-Wallis test (Table 5). With regard to the association between higher MHR and female gender, all tests resulted in significant differences. As for the association between MHR and age group, the One Way ANOVA and 5x2 (factors = age group and gender) were significant. This was not observed with the 5x2x2x2x2x2 ANOVA (previous factors + SAH + dyslipidemia + DM), probably due to the reduction in power caused by the magnification of factors.

However, in post hoc analysis of the subgroup, Tukey’s test showed differences in MHR, reaching levels of significance when the comparison was made between non-contiguous age groups. SAH, dyslipidemia and diabetes mellitus had no predictive influence, either separately or in interaction. Due to the multiple comparisons, when Bonferroni correction was applied, the threshold values for the interaction between age group and SAH (p = 0.046) were not considered significant. In situations where there was actually a significant difference, the values of R2 and ETA2 found in the several models indicated a diminished contribution of the involved variable. Similar phenomenon occurred with the five linear regression models.

In the first two models, a simple regression was applied, for the age group and for age as discrete variable. In the third, the three comorbidities were added and inserted simultaneously. Hierarchical regression was applied to the fourth and fifth models, the first in two stages and containing only age and gender, and the second in three stages, once again including the comorbidities (Table 6). Again, in all regression models significance was found for age range and gender. Nevertheless, the participation of these two variables was limited, given the reduced values of

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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, when analyzing the individual role of comorbidities, it was not significant from a statistical point of view.

The VIF values around 1 and the computation of the Durbin-Watson equation close to 2, added to the successful result of the Cook-Weisberg homoscedasticity

test (p = 0.892) indicated excellent sample suitability to the models chosen for regression testing. This was also corroborated by analyzing the standardized regression residuals involving frequencies of distribution, cumulative probability and critical values of Z-distribution in scatter plots.

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DiscussionThe predominance of women as the age progresses has

been probably due to a longer life expectancy in females, when compared with male elderly individuals19.

The three comorbidities assessed in the study (SAH, diabetes and dyslipidemia) showed homogenous distribution and had no influence on MHR behavior. In terms of prevalence, they showed a similar pattern customarily described in epidemiological studies carried out in other locations in Brazil20,21.

In the CARLA (Cardiovascular Disease, Living and Ageing) study, which had a sample of 1,779 individuals, age ranged between 45 and 83 years and no consistent association was observed between parameters of heart rate variability and major cardiovascular risk factors22.

Although it is generally considered that sinus automatism decreases with the aging process12-15, the prognostic value, therapeutic potential and clinical significance have been questioned in view of varying results and interpretation23,24.

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.

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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 Holter in 15 individuals aged > 65 years were analyzed in two stages, with a 15-year interval, showing slight shortening of sinus cycle, although reaching statistical significance (0.976 ± 0.115 x 0.903 ± 0.117, p = 0.0019). Nevertheless, the authors of this article calculated the difference according to Cohen’s formula and corrected for each year of life, with negligible results (d = 0.0413).

In Denmark, a study of which sample consisted of 260 healthy subjects aged between 40 and 79 years, a MHR of 74 ± 18 bpm was obtained25. The lower standard deviation value in this study suggests greater sample homogeneity, in addition to greater precision due to the use of long-term tracings.

In a case-control study performed in the state of Rio Grande do Sul, Brazil26, the recording of HR at rest in the control group of 5,410 patients with a mean age of 55.4 ± 10.4 years showed a mean value of 72.1 ± 12.6 bpm. This value was also close to the current findings described in Holter monitoring. However, dissimilar from the 24-hour ambulatory ECG, routine and direct HR measurements are subject to variations caused by several types of interference, such as ambient temperature, presence of the examiner and the individual’s emotional status27. Again, the standard deviation obtained from the resting HR was quite higher than that resulting from the measurement of MHR by 24-hour monitoring.

This aspect of the matter can be illustrated by the analysis of another study28, which used both measurements (resting HR and MHR). First, the resting HR of 32 patients aged 100 to 106 years was compared to that of 89 healthy individuals (aged 63 to 95 years). There was a difference between the first (76.8 ± 12.7) and the latter (74.9 ± 5.9), with statistical significance (p < 0.005). But when the MHR was measured by 24-hour Holter, it was around 72 bpm and there was no significant difference between the groups.

These findings are similar to those found in the present study. The authors attributed the increase in resting HR in centenarians to the previous effort made when lying on the stretcher, or some emotional expectation before the examination.

The Baltimore Longitudinal Study on Ageing (BLSA)29 evaluated 69 men and 29 women aged 60 to 85 years. Patients were divided into three groups: 59 subjects aged between 60 and 69 years, 32 aged between 70 and 79 years, and only 7 members aged ≥ 80 years. All were considered "healthy" according to the following criteria: absence of systemic disease or overt heart disease, no heart abnormalities at physical examination, blood pressure of 160/95 mmHg; ECG with no significant morphological alterations; satisfactory lung function, exercise testing within normal limits, no antiarrhythmic and beta-blocker drug use. The dynamic electrocardiography recordings lasted between 17 and 26 hours.

There was no significant variation in MHR with age. However, MHR in women (76.9 ± 8.0) was significantly higher than that of men (69.8 ± 8.8), with p < 0.001.

Compared to the present study, and although it corroborates our findings, the BLSA showed greater differences regarding gender, which may be due to the smaller sample size and greater variability during the electrocardiographic recording. Another important aspect of the BLSA study is the excessive proportion of men (70%). This fact was due to the enrollment procedure, which was voluntary and active on the part of the patients. Additionally, the measurements obtained in inpatients may result in bias, as they may not reflect the natural environment30.

The physiopathology of the chronotropic response is considered to be complex, multifactorial and not completely understood. The slight increase in heart rate may be attributed to transient alterations in blood flow on

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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 or ventricular compliance alterations produced by diastolic dysfunction32.

Several factors related to the autonomic modulation during the aging process, agonist and antagonist ones, may be related to the maintenance of the MHR equilibrium status.

The reduced decrease in MHR, substantially lower than the intrinsic sinus rate decrease14, would eventually result from the action of other adaptation mechanisms of the cardiovascular system in the elderly, such as increase in sympathetic tone after a lower myocardial performance during daily activities, including varying degrees of physical exertion. Several studies have identified a trend of predominant sympathetic modulation over the parasympathetic one with advancing age23,33.

Although the mechanisms responsible for it are not completely understood, the small decrease in MHR

with age, regardless of gender and ethnicity, has been demonstrated in other studies with elderly individuals submitted to 24-hour Holter monitoring27,34,35.

Further investigations, involving echocardiographic measurements and heart rate variability, may explain the phenomenon and confirm some of the hypotheses.

Among the limitations of this study, one might question the representativeness of the sample, as there was no randomization during the process of participant inclusion and the source population consists of patients from a single cardiology referral center. In fact, considering the institutional-based sampling, there is potentially a trend of predominance of individuals with higher prevalence of diseases36. Another factor to be considered is the lack of direct measurement of blood pressure levels and clinical parameters, but the echocardiographic evaluation sought to avoid the inclusion of individuals with evident heart disease.

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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* < 0,001ENTER: AGE GROUP, GENDERAND COMORBIDITIES 0,233 0,050 - 1,936* < 0,001

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** < 0,001HIERARCHICAL: AGE GROUP (1);GENDER (2); COMORBIDITIES (3)

0,185 (1); 0,230 (2); 0,233 (3)

0,033 (1); 0,051 (2); 0,050 (3) - 1,936* < 0,001

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 approximately 25% of the sample. Although an eventual 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 hormone levels and no subjects enrolled in the study reported the use of thyroid-dysfunction medication.

Additionally, the prospective and sequential data collection, the complete filling out of data, the participants’ selection and exclusion criteria and the stringent statistical calculations were relevant measures in minimizing biases. The distribution of individuals across the age groups and the expected ratio between men and women in terms of “real life” also suggest that the research sample is inserted within the expected population standard.

ConclusionsMHR decreased with increasing age in both genders.

For similar age groups, females had significantly higher MHR values than their male counterparts and this phenomenon was reproduced in both the total sample and when stratified by age. The prevalence of comorbidities such as hypertension, non-insulin dependent diabetes mellitus and dyslipidemia had no detectable influence on MHR patterns. Both the association between MHR and age range as the association between MHR and gender were significant in several models of statistical analysis. However, the magnitude of this association in both situations is considerably small.

The findings were consistent, reproducible and corroborated in several statistical models.

Author contributionsConception and design of the research e Writing of

the manuscript: Santos MAA, Sousa ACS, Reis FP, Santos TR, Lima SO, Barreto-Filho JA; Acquisition of data: Santos MAA, Santos TR; Analysis and interpretation of the data: Santos MAA, Sousa ACS, Reis FP, Barreto-Filho JA; Statistical analysis: Santos MAA; Critical revision of the manuscript for intellectual content: Santos MAA, Sousa ACS, Reis FP, Lima SO, Barreto-Filho JA.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of master and doctoral submitted by Marcos Antonio Almeida Santos from Universidade Tiradentes and Universidade Federal de Sergipe.

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References

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

Mailing Address: Gustavo Bernardes F. Oliveira •Av. Dr. Dante Pazzanese, 500. Unidade Coronária, 2.º andar, Unidade Hospitalar III. Postal Code 04012-909, São Paulo, SP - BrazilE-mail: [email protected], [email protected] received December 07, 2012; revised manuscript June 10, 2013; accepted June 24, 2013.

DOI: 10.5935/abc.20130186

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

Metabolic Syndrome and Adiponectin In pre-clinical and clinical conditions, the metabolic

components of cardiovascular risk, such as obesity, insulin resistance and dyslipidemia, interact in a complex way, being associated with high cardiovascular morbidity and mortality1-11. Visceral obesity plays an increasingly relevant role as a cardiovascular risk factor. In fact, the adipose tissue is a storable energy source and an endocrine organ that secretes cytokines, which can contribute to the development

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 expression of genes related to the synthesis of several bioactive substances, such as adiponectin (Arcp30, AdipoQ, apM1 or GBP28), a protein similar to collagen and identified as an adipocyte-specific cytokine.

Adiponectin is abundantly expressed in healthy individuals, has antithrombotic, antiatherogenic and anti-inflammatory properties, and is downregulated in obese 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 women, non-obese individuals, with type 1 DM and in those undergoing treatment with peroxisome proliferator-activated receptor gamma (PPARγ) agonists13-20. From the prognostic viewpoint, in healthy individuals, adiponectin has been inversely associated with cardiovascular risk, mainly in men, or directly associated with that risk, mainly in the elderly21-25. However, studies on chronic heart failure (HF)

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

or documented cardiovascular disease (CVD) have identified hyperadiponectinemia as an independent predictor of mortality26-28. Similarly, Cavusoglu et al29 have identified a direct and independent association between adiponectin and the risk for acute myocardial infarction (AMI) and cardiovascular death in a cohort of men undergoing coronary angiography for the diagnostic investigation of chest pain. Those data suggest that adiponectin might play a different role in acute clinical scenarios. Thus, this study was aimed at assessing the association between serum adiponectin levels and the risk for cardiovascular events in patients with acute coronary syndromes (ACSs), and at establishing the correlations between adiponectin and metabolic, inflammatory and myocardial biomarkers.

MethodThis study has two components: a) a cross-sectional

and analytical component to determine the clinical characteristics and measures of serum biomarkers of patients with ACS on hospital admission; b) a cohort of ACS, prospectively included between 2008 and 2010, with clinical follow-up for the systematic and prospective collection of cardiovascular events. Based on the study by Cavusoglu et al29 on a subgroup of patients with ACS comprising 52.3% of a total of 325 patients and with all-cause mortality rate of 10.3% in two years of clinical follow-up, the calculation of the sample size was estimated as 112 patients, with significance of α = 0.05 and 1 − β = 0.80. It is worth noting that, due to the lack of studies about adiponectin in patients with ACSs in the Brazilian population up to the time of the elaboration of this dissertation project, and, thus, scarcity of data on the variability of that biomarker measurements, the possibility of inadequate estimation was considered. This study included patients of both sexes, over the age of 18 years, who underwent blood collection within the first 24 hours from ischemic symptom onset and who provided written informed consent, in the emergency and coronary units of the Instituto Dante Pazzanese de Cardiologia, in the city of São Paulo. Patients with the following characteristics were excluded: infectious, inflammatory and neoplastic diseases; end-stage kidney or liver disease; significant heart valve disease or heart valve disease precipitating the clinical findings; percutaneous coronary intervention (PCI) or 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 use of oral antidiabetic drugs of the thiazolidinedione group. The following parameters were assessed: adiponectin; leptin; fasting glucose; insulin; Homeostasis Model Assessment (HOMA) index; glycated hemoglobin (HbA1c); total cholesterol, LDL- and HDL-cholesterol; triglycerides; ultrasensitive C-reactive protein (us-CRP); leukocytes; fibrinogen; platelets; cardiac troponin I (TnI); CKMB mass; B-type natriuretic peptide (BNP); and demographic (age, sex, ethnicity), anthropometric (weight, body mass index and waist circumference) and angiographic (extension/severity of coronary artery disease [CAD] in patients undergoing coronary angiography) variables. Venous blood samples (10 mL) were collected in the morning

following a 12-hour nocturnal fasting. Insulin resistance was expressed as the HOMA index calculated by using the formula [product of glucose (mg/dL) by insulin (μUI / mL), divided by the constant 405]30,31. Adiponectin and leptin were measured by use of ELISA assay. The kits for measuring adiponectin were Human Adiponectin ELISA Kit 96-Well Plate (Cat. # EZHADP-61K), manufactured by Millipore, United States. The kits for measuring leptin were DiaSource KAP2281 Human Leptin ELISA IVD, manufactured by DIAsource ImmunoAssays S.A., Belgium. The primary outcome comprised cardiovascular death, nonfatal AMI or reinfarction, and nonfatal stroke. The co-primary outcome comprised primary events and re-hospitalization due to recurring ischemia or ischemia considered clinically significant requiring revascularization during clinical follow-up. Cases of AMI were defined by criteria proposed for the universal definition of AMI32. Cases of stroke were defined according to World Health Organization (WHO) classical criteria33. The distributions of the continuous variables were expressed as mean (± standard deviation) or median (with interquartile interval), as appropriate, and the comparisons between the groups were calculated by using Student t test or non-parametric (Kruskall-Wallis test), as appropriate. The distributions of the categorical variables were expressed as frequencies and percentages, and the comparisons calculated by using chi-square test or Fisher exact test, as appropriate. The analysis of the primary and co-primary clinical outcomes was based on the time for the occurrence of the first event. Cox univariate regression analysis gathered all demographic, metabolic, inflammatory, anthropometric and angiographic variables, and only those univariate predictors with p < 0.10 and variables with clinical significance were included in Cox proportional hazards regression models to determine whether adiponectin would be an independent risk predictor. Backward stepwise regression was used for the models to identify the independent variables of risk for the occurrence of primary and co-primary outcomes, respectively. Then, Firth’s penalized likelihood method was used to adjust the potentially overestimated variables due to elevated prevalence. The results were expressed as hazard ratio and 95% confidence interval (CI), and the discriminatory capacity of the models was expressed by c-statistic (or c index). Two-tailed tests were used with significance level of α = 0.0534,35.

Results

Characteristics of the PatientsTable 1 lists the major characteristics of the 114 patients

with ACS according to adiponectin quartiles. Their mean (± SD) age was 62 (± 10.5) years, 41.2% were of the female sex and 82.6%, Caucasians. The prevalence of cardiovascular risk factors was significant as follows: arterial hypertension, 90%; DM, 30%; dyslipidemia, 78%; and current tobacco use, 16.4%. The medians (interquartile interval) of the anthropometric parameters were as follows: body mass index (BMI) = 27.4 (24.6-30.4) kg / m2 and waist circumference = 98 (91-108) cm. Regarding

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electrocardiographic (ECG) findings, 97.3% of the patients had alterations, the most frequent (30.9%) being ST-segment depression between 0.5 and 1.0 mm. The final diagnosis defined 90.3% of the patients with ACS with no persistent ST-segment elevation.

Biomarkers in the global sampleTable 2 shows the values of biomarkers according to

adiponectin quartiles. The median adiponectin level was 9,807 (6,113-13,914) ng/mL.

Pharmacological Treatment

Medications used before and during hospitalizationPrevious treatments included the following drugs: acetylsalicylic

acid (ASA), 69%; angiotensin-converting-enzyme inhibitors (ACEI), 62.2%; beta-blockers, 60.4%; statins, 59.8%; oral antidiabetic drugs, 13.2%; and insulin, 1.8%. No patient included

was on previous use of thiazolidinediones. Regarding the drugs used during hospitalization to manage ACS, the following stand out: ASA, 99.1%; clopidogrel, 96.5%; beta-blockers, 89.5%; ACEI, 88.5%; statins, 98.2%; and low-molecular weight heparin (enoxaparin) for anticoagulation, 93.8%.

Procedures Performed during HospitalizationCardiac catheterization for coronary angiography was

performed in 87.7% of the patients. Luminal stenosis ≥ 50% characterized significant CAD, which was documented in at least one vessel in 83% of the patients, and in multiple arteries in 38%. 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 than one stent. Of the stents implanted, 91% were conventional (non-pharmacological). Coronary artery bypass graft surgery was performed in 15.6% of the patients, the left internal thoracic artery being used in 100% of the patients, and grafts being applied to at least three coronary arteries in two thirds of the patients.

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%

0.52Killip II/III 3.7% 3.6% 11.1% 10.7%

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.

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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 OutcomesPrimary outcome was observed in 18.4% of the patients, and

co-primary outcome, in 21.1%, with a mean 1.13-year clinical follow-up in all 114 patients recruited. Thus, follow-up was performed in 100% of the patients, with no loss to follow-up.

Adiponectin as a Predictor of Cardiometabolic RiskThe Cox models included the following variables that

showed significance for the association with primary and co-primary outcomes: adiponectin; other biomarkers; clinical characteristics; angiographic variables; and treatments and procedures performed before and during hospitalization. The models were calculated for four prespecified groups of interest: overall population (group A); patients with no DM (group B); patients with 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 model for primary outcome were as follows: previous angina; arterial hypertension; Kil l ip classification; adiponectin; leptin; fasting glucose; creatinine; CKMB activity; CKMB mass; TnI; BNP; and urea. After adjusting for those factors, adiponectin was associated with high risk for the primary outcome in the models for groups B and D. For co-primary outcome, the following variables were included: previous angina; arterial hypertension; Killip classification; adiponectin; leptin; fasting glucose; creatinine; CKMB activity; heart rate (HR) on admission, HDL-cholesterol; HOMA index; obesity and in-hospital

use of ASA. Adiponectin was consistently an independent predictor of high risk for cardiovascular events in the models of groups B and D, with borderline significance for group C.

The logistic regression analysis showed an almost linear relationship between adiponectin, as a quantitative continuous variable, and the estimate of the probability of risk for primary and co-primary outcomes (Figure 1).

Correlations Between Adiponectin and BiomarkersAs prespecified, the secondary objective was to study

the correlations between adiponectin and the different biomarkers, and demographic and anthropometric variables. Table 7 emphasizes the direct and significant correlation between adiponectin and BNP.

DiscussionThis study of a cohort of patients with ACS on mid/

long-term clinical follow-up detected a direct, significant and independent association between adiponectin and the risk for relevant cardiovascular clinical outcomes. There was consistent signaling of more evident risk when patients with DM or ST-segment elevation AMI were excluded. Cavusoglu et al29 have assessed 325 male patients with stable angina, unstable angina and non-ST-segment elevation AMI, who underwent coronary angiography to determine the prognostic value of serum adiponectin levels. The patients were followed up for 24 months for the occurrence of

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

Primary and co-primary outcomes

Coefficient Hazard ratio 95%CI pTroponin 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



0.6346 0.7719 0.7719

all-cause death, cardiovascular mortality and AMI. In that study, the authors have identified a direct and independent predictive association between a single baseline adiponectin measurement and the subsequent risk of death and AMI. In the subgroup of non-ST-segment elevation ACS (n = 170), adiponectin remained as an independent risk predictor.

Other recent studies have also identified a direct association between adiponectin and cardiovascular risk, especially in patients with HF, mainly the elderly26-28. Wannamethee et al28 have prospectively studied the relationship between adiponectin levels and mortality in 4,046 male elderly (60-79 years of age), with and without documented CVD

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



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



0.7208 0.6641 0.6641


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




0.6346 0.7719 0.7719

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




Adiponectin (per 1,000) 0.05 1.051 0.997 1.098 0.06



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



0.7368 0.7330 0.7330

and HF. After adjusting for important baseline characteristics, adiponectin remained directly and significantly associated with total and cardiovascular mortalities in men without CVD or HF (adjusted RR: 1.55, 95%CI: 1.19-2.02, p = 0.002; and RR: 1.53, 95%CI: 1.03-2.27, p = 0.02), for a trend in

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



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



0.7994 0.8032 0.8032


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



0.7390 0.8199 0.8199

comparing the highest and the lowest tertiles, as well as in men with diagnosed HF (adjusted RR: 2.37, 95%CI: 0.64-8.79, p = 0.04; and RR: 3.43 95%CI: 0.54-21.7, p = 0.008). No association was demonstrated in those with diagnosed CVD, but no HF.

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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.

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

Primary outcome

10.000 20.000 30.000 40.000

1,00,9

0,80,7

0,60,5

0,40,3

0,20,1

Co-primary outcomeEs

timat

ed ri

sk p

roba

bilit

y

Adiponectin

Our study has some important differences as compared with those previously discussed. Ours included patients of a wider age group, no analysis restricted only to the oldest. Similarly, this study was not restricted to the inclusion of male individuals21-23,26-29, emphasizing that there was adequate balance in the sex proportions, with significant female representation (41.2%). In fact, the mean adiponectin level is approximately 50% greater in women, mainly elderly ones,

as compared with men in the same age group13,36. In terms of independent risk prediction, this study findings are in accordance with those of the most recent literature regarding the prognostic value of adiponectin in different clinical scenarios, either under stable conditions and in populations considered healthy or without documented CVD, or under acute clinical conditions or manifest CVD, as in the present study. Some studies have identified an independent

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association between adiponectin and higher risk for CAD (nonfatal AMI and fatal CAD) in individuals with no previous documentation, but only in the elderly, with adjusted OR of 1.69 (95%CI: 1.23-2.32) for the 5th quintile versus the 1st quintile25. However, the Rancho Bernardo study24 has reported that adiponectin levels in the 5th quintile stratified by sex were significantly associated with a 44% reduction in OR for the occurrence of CAD, which was eliminated after adjusting for HDL-cholesterol and/or triglycerides. In the 20-year prospective analysis, higher concentrations of adiponectin were predictive of reduced risk for nonfatal AMI only in men. Corroborating that information, a recent study on adiponectin and risk of CAD-related events in the context of a meta-analysis of seven prospective studies has reported an OR for CAD of 0.89 (95%CI: 0.67-1.18), comparing men in the 3rd tertile with the 1st tertile, very similar to the findings of that meta-analysis22. Wolk et al37 have assessed 499 patients undergoing coronary angiography, 168 of whom with ACS, and identified that high adiponectin levels are independently associated with a reduced risk of ACS.

Of the studied correlations between adiponectin and other biomarkers, we detected a direct and significant one with BNP. Thus, possible interactions like that cannot be ruled out, among others identified and non-measurable factors or variables, which can explain the attenuation of the strength of the association with the risk in the global model. That hypothesis is supported by the study by Schnabel et al38, in which the association of risk and adiponectin remained robust after adjusting for classical risk factors in the global population studied. However, after adjusting for BNP, adiponectin lost its independent predictive value. Because of those findings, in patients with manifest CAD, adiponectin seems to have a different role. In clinically asymptomatic individuals, high adiponectin levels seem to protect against atherosclerotic disease; however, when elevated in patients with symptomatic CAD, a direct association with risk for cardiovascular events is observed. That result of direct or paradoxical association implies that the beneficial influence of adiponectin in atherosclerotic disease would be translated into elevations in adiponectin concentrations as a contra-regulatory mechanism in response to the excessive and unstable atherosclerotic process of the ACS, with a negative net result, despite the high concentrations of that biomarker. That could indicate unbalance of the entire metabolic homeostatic system, interfering with cellular bioenergetic processes.

It is worth noting that the presence of a strong association between risk factor and the outcome assessed does not necessarily mean that the risk factor provides a base for an effective predictive rule. Wang et al39 have shown that, in individual risk assessment, the use of ten biomarkers added only a discrete discriminatory capacity to the classical risk factors, with practically overlapping ROC curves and similar c indices (0.76 versus 0.77).

Finally, there is the question about the potential mechanisms of the increased risk for relevant cardiovascular events. A recent review has assessed the different pathophysiological mechanisms of adiponectin and has concluded that those associations provide relevant information to understand the inflammatory and atherogenic processes associated with CAD progression

and instability of atheromatous plaques40. Those mechanisms include the following: 1) involvement of adiponectin in the regulation of the necrotic core development; 2) double role in the neovascularization process due to pro/antiatherogenic properties; the ability to promote angiogenesis has been proven to be beneficial to prevent ischemia; 3) the inverse relationship between adiponectin and the ratio between matrix metalloproteinases and the tissue inhibitor of metalloproteinase-1 suggests that adiponectin modulates the stability of atheromatous plaques by balancing that relationship; 4) local adiponectin in the intima and adventitia suppresses the expression of VCAM-1 and ICAM-1 adhesion molecules in vascular walls, suggesting that adiponectin improves atherosclerosis partially by inhibiting the expression of those inflammatory molecules in vivo. Adiponectin has a documented role in the following: endothelial activation; propagation of inflammatory factors through expression of adhesion molecules; monocyte adhesion to vascular endothelium and migration to the intima; macrophage activation; transformation of macrophages into foam cells; lipid accumulation in macrophages; proliferation and migration of smooth muscle cells to the intima; and platelet aggregation. Other mechanisms involved also include the phenomena of oxidation and vascular tone regulation.

Of the metabolic variables studied, in addition to adiponectin itself, only fasting glucose showed a significant direct and independent correlation with cardiovascular risk. Our results are comparable to those of several studies on the prognostic role of hyperglycemia on ACS, especially AMI. That might either reflect an unbalance of the systems regulated by adiponectin, as previously discussed, or be influenced by the contra-regulatory mechanisms responsible for stress hyperglycemia. However, because of the associations observed between the biomarkers, specifically with adiponectin, and little or no correlation with us-CRP, leukocytes, platelets and fibrinogen, in addition to maintenance of the association with glycemia even with the strong effect of association of CKMB mass, reflecting the impact of the myocardial necrosis grade, we think that the fasting glucose findings might actually reflect interactions with the effects of adiponectin. Similarly, the results demonstrated by adiponectin quartiles suggest and strengthen that glycemia levels are directly associated with adiponectin levels, exerting an interaction or collinearity effect.

In addition, this study performed serial measurements of neither adiponectin nor the different biomarkers of metabolism, such as glycemia, insulin, HOMA index and HbA1c. Such serial measurements could provide additional relevant information for better understanding metabolic homeostasis interrelations.

This study found a significant and direct association between adiponectin and the female sex, presence of comorbidities, chronic kidney failure, current smoking and HDL-cholesterol and creatinine levels. In addition, this study found a significant and inverse association between adiponectin and DM, body weight, waist circumference and insulin and triglyceride levels. In fact, the results between the different clinical variables and biomarkers emphasize internal consistency with those previously reported, and with similar patterns, reinforce the aspect

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AcknowledgementsThis study received logistic support from the Division

of Translational Epidemiology and from the Clinical Analyses Laboratory of the Instituto Dante Pazzanese de Cardiologia (IDPC). We are also grateful to the Statistics and Epidemiology Laboratory of the IDPC and the Instituto Gênese de Análises Científicas.

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interpretation of the data, Obtaining funding and Critical revision of the manuscript for intellectual content: Oliveira GBF, Piegas LS; Acquisition of data and Writing of the manuscript: Oliveira GBF; Statistical analysis: França JID.



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Study Association

This article is part of the thesis of Doctoral submitted by Gustavo Bernardes de Figueiredo Oliveira, from Universidade de São Paulo.

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Original Article

Left Ventricular Synchrony and Function in Pediatric Patients with Definitive PacemakersMichel 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

Mailing Address: Michel Cabrera Ortega •100 y Perla, Altahabana, Boyeros 10800, Havana, CubaE-mail: [email protected] Manuscript received July 06, 2012, revised manuscript October 26, 2012, accepted November 19, 2012.

DOI: 10.5935/abc.20130189

AbstractBackground: 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.

permanent LV epicardial pacing concluded that LV function can be preserved by chronic stimulation of the LV (LVP) free wall9,10. In addition, an study of pediatric patients with either LV dysfunction and RVP or intrinsic left bundle branch block demonstrated the possibility for improvement of LV function 1 month after single-site LVP11.

The present study aimed to evaluate the evolution of LV function and synchrony after endocardial RVP in comparison with those after epicardial LVP.

Methods

PatientsA 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 included when paced from both the RV endocardium (n = 40) and from the left ventricular epicardium (n = 40). We excluded the following patients: those aged >18 years at pacemaker implantation, those with <95% ventricular pacing, those with ≤1 year of permanent cardiac pacing, and those with clinical evidence or history of heart failure

IntroductionElectric stimulation from the right ventricular (RV) apex

and free wall induce a dyssynchronous contraction pattern characterized by early activation of RV and the interventricular septum and delayed activation of the left ventricular (LV) anterior wall. This produces mechanical and electrical interventricular asynchrony, along with intraventricular asynchrony1. Although these detrimental effects are tolerated by most pediatric patients, studies have shown that chronic RV pacing (RVP) is an important 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 after follow-up over approximately 10 years2,5-8.

Alternative pacing sites have been investigated to preserve LV synchrony. Two retrospective studies of children with

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unrelated to CAVB at the time of pacemaker implantation. Table 1 depicts the demographic data of the paced children. The study protocol was approved by the institutional research ethics committee and written consent was obtained from the parents of all patients.

PacingPacing lead positions were assigned according to

implantation protocol data and confirmed by chest X-rays. LVP unipolar leads were implanted in the apical region, and inserted through a left lateral thoracotomy. All endocardial pacing leads were placed in the RV apex (RVA). Ventricular pacing (Ventricular Rate Modulated Pacing [VVI/VVIR]) was the predominant pacing mode. The study excluded patients who required a change in the pacing site between the initiation of pacing and evaluation.

EchocardiographyEchocardiographic evaluations were made before

pacemaker implantation, immediately after, and at regular intervals during a mean follow-up period of 6.8 years. Data were obtained in the standard precordial positions with an appropriate transducer (5 MHz, Aloka Prosound 5500). Two experienced observers, blinded for the ventricular pacing site, performed one- and two-dimensional transthoracic echocardiography and Doppler evaluations. All examinations were performed in line with the recommendations of the Pediatric Council of the American Society of Echocardiography 12; three measurements in random for

every patient were made for each observer and the average of measurements was used for further analysis. Paraesternal M-mode images were used to measure LV end-diastolic and LV end-systolic diameters (LVEDD and LVESD, respectively). LV shortening fraction (LV SF) was calculated according to the formula12: LV SF = LVEDD − LVESD/LVEDD × 100. LV end-diastolic and LV end-systolic volumes (LVEDV and LVESV, respectively) were obtained using Simpson’s biplane method, and indexed to body surface area and the ejection fraction (EF) calculated.

For a comprehensive diastolic evaluation, Doppler tissue imaging (DTI) was undertaken at the lateral and septal mitral valve annulus in the apical four-chamber view. The peak tissue E-wave (Ea) and A-wave (Aa) velocities were obtained, and the E/Ea ratio was also determined. LV isovolumic relaxation time was used to assess diastolic function, and it was considered as the period from the end of aortic flow to the beginning of mitral inflow in the apical five-chamber view.

Myocardial 2D strain was performed to assess ventricular synchrony in the four-chamber and long-axis views. The following parameters were evaluated:

Interventricular mechanical delay, measured as the time difference between the LV and RV pre-ejection times.

Septal to lateral mechanical delay, calculated as the maximum time difference between the earliest and latest peak myocardial systolic velocity of two opposing 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 Atrial septal defectVentricular septal defectTetralogy of FallotDouble outlet right ventricleSubvalvular aortic stenosisValvular pulmonary stenosisPersistence ductus arteriosus

46(57.5)3(3.75)5(6.25)

17(21.25)9(11.25)7(8.75)2(2.5)

3(3.75)

22(55.0)-

4(10.0)8(20.0)6(15.0)3(7.5)1(2.5)

-

24(60.0)3(10.0)1(2.5)

9(22.5)3(7.5)

4(10.0)1(2.5)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.

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Septal to posterior wall motion delay (SPWMD), determined as the delay between peak systolic inward motion of the interventricular septum, and the left posterior wall.

LV mechanical delay, measured as the maximum difference between the initial and last peak systolic 2D strain in any of the 12 LV segments.

StatisticsData are presented as mean ± standard deviation.

For analyzing the differences in continuous variables between the RVA pacing (RVAP) group and LVP group, t-tests were used. Correlations between variables were assessed using Pearson’s correlation (r value). Logistic regression was performed to determine the predictors of impaired left ventricular function. Significance was accepted at a p value of ≤0.05. The software package Medcalc for Windows (Version 11.3) was used for statistical work up.

Results

Patient characteristicsA total of 80 patients with a mean age of 12.5 ± 5.2 years

were evaluated. The demographic data and clinical characteristics of study are presented in Table 1. Pacing indications were postsurgical CAVB (n = 38) and nonsurgical CAVB (n = 42). In total, 57.5% patients had structural heart disease, with 79.2% having undergone surgical correction. Tetralogy of Fallot was the congenital cardiac disease with the highest rate of postoperative CAVB. Neither the mean age at first implantation nor the duration of pacing showed significant differences between the two pacing groups. All patients with LVP received a single-chamber pacemaker, whereas 23 children (57.5%) that were paced from the RVA received VVI/VVIR pacing.

Left ventricle: long-term size, function and synchrony.At the end of the follow-up period, LVEDD in patients with

RVAP increased significantly over both the corresponding baseline values (40 ± 6.0 vs. 32 ± 3.1, p < 0.001) and the values of the LVP group (40 ± 6.0 vs. 35 ± 4.2, p < 0.001)

(Table 2). SF in the RVP group was significantly lower than before pacing (32 ± 4.2 vs. 41 ± 2.6, p < 0.001) and was lower than that in the LVP group (32 ± 4.2 vs. 39 ± 5.2, p < 0.001). The LV EF was normal in children with LVP after long-term cardiac stimulation, but tended to worsen in the RVAP group (70 ± 6.9 vs. 64 ± 2.5, p < 0.001). A similar tendency has not been observed with LV diastolic function at any pacing site during follow-up (Table 3).

All the echocardiographic parameters reflecting both interventricular and intraventricular dyssynchrony were affected in patients with RVAP (Table 4). Interventricular mechanical delay was significantly larger in the RVAP group (66 ± 13 ms) than in the LVP group (20 ± 8 ms); similarly, septal to lateral wall motion delay (RVP: 75 ± 19 ms; LVP: 42 ± 10 ms, p < 0.0001) and SPWMD (RVAP: 127 ± 33 ms; LVP: 58 ± 17 ms, p < 0.0001) were altered in patients with receiving RVAP but not LVP. In addition, RVAP was associated with global LV dyssynchrony, as evidenced by a prolonged LV mechanical delay (69 ± 6 ms) compared with LVP (30 ± 11 ms).

Five patients developed dilated cardiomyopathy (6.3%). The clinical and echocardiographic data of these patients are shown in Table 5. Three variables were identified as significant predictors of LV dysfunction: RVAP [odds ratio (OR) = 11.3, p < 0.001], septal to lateral wall mechanical delay (OR = 12.1, p < 0.001), and septal to posterior wall motion delay (OR = 11.6, p < 0.001). However, in those patients receiving RVAP, there was no correlation between either EF and SPWMD (R2 = 0.283, p = 0.077) or EF and septal to lateral mechanical delay (R2 = −0.013, p = 0.935) (Figure 1). No correlations were found between late LV failure diagnosis, pacing mode, duration of stimulation, presence of structural heart disease or other echocardiographic indices of dyssynchrony.

DiscussionThe main finding of our study is that RV apical pacing in

pediatric patients with or without structural heart disease produces LV remodeling and dyssynchrony. Moreover, the research confirms that LVP is a safe site of stimulation when seeking to prevent the dyssynchronous effect of chronic cardiac pacing.

Table 2 – Evolution of left ventricular systolic function

ParameterRVA pacing LV pacing

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.

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Evolution of LV systolic and diastolic function in RV apical pacing:

Endomyocardial biopsies taken from the mid-RV septal region in paced patients have detected histopathological abnormalities. These consist of prominent subendocardial Purkinje cells with an increase in variable-sized, focal areas of dystrophic calcification and myofibrillar disarray13. These findings are the result of stress vectors and myocardial shearing forces resulting from asynchrony of electrical ventricular activation, with early activation of myocytes close to RVA, and delayed activation of cells in remote regions1. This heterogeneity in electrical activation of the myocardium is accompanied with changes in the mechanical activation pattern of LV14. An animal study has demonstrated the presence of rapid early-systolic shortening in early-activated regions, with premature relaxation of these sites, and prestretching of late-activated regions15. Because of

the low LV pressure, contraction of the early-activated myocardium is inefficient. Furthermore, against high LV pressures, a vigorous late-systolic contraction occurs in regions with delay. This imposes loading on the earlier activated territories, which undergo paradoxical systolic stretch16. The abnormal contraction pattern of different regions of LV, results in a redistribution of myocardial strain, and less effective contraction15. Decreases in contractility and relaxation together with histological abnormalities lead to the detriment of left ventricular function.

Clinical data about the deleterious effect of chronic RVP in children remain controversial, with some researches supporting a negative impact13,17,18, whereas others have obtained conflicting results19, 20. The present study found a significant deleterious effect of RV apical pacing on systolic LV function, with an incidence of 6.3% in patients with dilated cardiomyophathy, which is concordant with previous

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

No. Age (years) Diagnosis Structural

heart diseasePacing period

(years)Pacing

site Pacing mode LVEDD (mm) LV EF (%) LV SF (%)

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.

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.

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data (6.0%–13.4%)2,5-8. RV apical pacing was a predictive factor for the deterioration of LV function [OR = 11.3, 95% confidence interval (CI) = 2.1–63.8, p < 0.001]. Gebauer et al5 evaluated LV function in 82 pediatric patients with either nonsurgical or postsurgical CAVB. In their research, the only significant risk factor for the development of LV dilatation and dysfunction was the presence of epicardial RV free wall pacing (OR = 14.3, 95% CI = 2.3–78.2, p < 0.001). Therefore, although epicardial RV free wall stimulation may induce more LV dyssynchrony, our findings suggest that RVAP results in the same degree of asynchronous activation, abnormal contraction and decreased pump function.

The impact of RV apical stimulation on LV diastolic function has not been extensively explored, even in pediatric populations. Previous research in animal models have demonstrated the deterioration of diastolic parameters21,22. Litwin et al21 for example found a significant alteration

of the diastolic filling parameters on radionuclide left ventriculography, such as time to peak filling rate and negative rate of LV pressure rise in ventricular paced dogs21. Similarly, Aoyagi et al22, found a prolongation of the LV isovolumic relaxation time (IVRT) that was dependent on the degree of wall motion asynchrony22. Although our data showed a detrimental effect on synchrony in the RVP group, the LV IVRT did not change during follow-up. In addition, Kolettis et al23 studied the acute hemodynamic status of 20 adult patients with dual-chamber sequential pacing, determining increased IVRT to be a measure of LV diastolic function deterioration23. Similarly, on the basis of the hypothesis that RV impairment precedes LV dysfunction, Dwevedi et al24 found a significant increase in IVRT and deceleration time following 1 month of single-chamber RVP, which continued to increase progressively until 6 months24. 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.

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deranged in many conditions secondary to involvement of the right ventricle24. However, in our study, 57.5% patients presenting with congenital cardiovascular defects such as atrial septal defect, pulmonary stenosis, tetralogy of Fallot or double-outlet right ventricle, which are conditions that improve RV function, diastolic dysfunction was absent and so was a correlation between the presence of structural heart disease and late LV failure. The contradiction with the findings of Dwevedi et al24 could possibly be explained because 47.5% of the study population had a corrected congenital cardiac defect, and that we excluded patients with clinical evidence of ventricular dysfunction. Results and conclusions from pacing studies in adult patients cannot be extrapolated to the pediatric population because of differences in comorbid diseases and potential causes of ventricular dyssynchrony.

Left ventricular dyssynchrony: LVP vs. RVPWe postulate that the sequence of activation is a

major determinant of cardiac pump function, as previous researches have shown25,26. Stimulation from the LV free wall induces a prior activation of the LV lateral wall, preventing paradoxical movement of the septum, and resulting in a better hemodynamic response when compared with RV pacing27. Moreover, a physiological apex-to-base sequence is induced, producing a synchronous electrical activation and contraction at the LV circumferential level28.

It has been confirmed in studies in both animals and children that LV pumping function approximating to that of normal ventricular conduction results from pacing at the inferoapical LV septum and the epicardium of LV apex28-30. The resultant synchronous contraction is predominantly because of quick engagement of the impulse into the LV endocardial layers, and subsequent fast apex-to-base conduction along all wall segments of LV30. Mills et al30, in their research in dogs with experimental complete AV block, demonstrated that LV apical pacing can produce a moderate electrical dyssynchrony with normal levels of myocardial efficiency, contractility and relaxation after 4 months of LVP30.

In our study, indices of dyssynchrony such as septal-to-lateral wall motion delay and SPWMD were identified as predictors of LV dysfunction. This finding demonstrated, once again, the consequences of impairment of normal ventricular activation. Apical RVP produces early activation of the RV wall, followed by that of the LV septum and then the LV lateral wall30. Early activation of the basal septum induces segmental contraction that is unopposed by the delayed activation of the remaining LV myocardium, which leads to systolic septal bulging9. Long activation times around the LV circumference (29–49 ms) during RV apical pacing, produces abnormal distribution of mechanical work and blood flow, mechanical dyssynchrony, and incoordination of contraction; there is then a consequential negative impact on contractility, relaxation, and external efficiency30.

Research by van Geldorp et al10, compared the ventricular function and synchrony in 18 healthy children

and patients with chronic RVP and LVP. In this study, the RVP group also showed a decreased LV SF. Similarly, the systolic LV eccentricity index, and the duration of posterior septal wall motion delay were significantly longer in this group than in the LVP or control groups10. In addition, Gebauer et al31 evaluated LV synchrony and function in 32 patients paced epicardially from the RV free wall, the LV apex and the RVA; RV free wall pacing and SPWMD were found to be negative predictors of LVEF31. Of note, Tomaske et al9 showed that a decreased LV EF and greater LV dyssynchrony was associated with children receiving RV pacing9. In addition, a significant correlation was established between decreased LVEF and the severity of mechanical dyssynchrony measured by the septal-to-lateral wall delay and LV mechanical delay9.

Clinical implicationsOur data confirm the benefit of chronic LV pacing on LV

synchrony and function. The results of our study support the view that epicardial LVP is the optimal pacing site in pediatric populations; observations in small cohorts support the use of an LV pacing site when chronic pacing is indicated in children9,10,31. It has also been demonstrated that LV lateral wall pacing can be as effective as biventricular pacing in patients with congestive heart failure32,33. For example, Vanagt et al. reported the case of a 2-year-old girl with congenital CAVB and heart failure induced by RVP, who recovered LV function following LV apical pacing34. Furthermore, in children with LV dysfunction and dyssynchrony caused by long-term RVP, small case series have shown improvements in function 1 month after single-site LVP11.

Alternative sites for pacing have also been investigated35-40. His-bundle pacing induces a normal physiological sequence of activation, and therefore prevents dyssynchrony and the deleterious effects on LV function35,36; however the anatomical characteristics of this region make this a challenging procedure that could be difficult in a pediatric population. Alternatively, the RV outflow has been proposed37,38, although the results are controversial39,40, and do not support stimulation from this site in children. In our institution, we advocate the implantation of LV epicardial leads via a left lateral thoracotomy, resulting in stable thresholds as well as good cosmetic results.

Study limitationsBecause of a lack of diastolic evaluation prior the first

implantation, we could not compare the DTI measurement before and after permanent pacing; nevertheless, the results at the last follow-up showed a preserved diastolic function using the DTI echocardiographic method.

Conclusions Chronic RVP was associated with LV remodeling ,

dyssynchrony, and systolic dysfunction in our pediatric population. This is consistent with previous findings. Because of the benefits of chronic LV pacing, we believe that it should be proposed as the optimal site when permanent cardiac stimulation is required in children.

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1. van Geldorp IE, Vanagt WY, Prinzen FW, Delhass T. Chronic ventricular pacing in children: toward prevention of pacing-induced heart disease. Heart Fail Rev. 2011;16(3):305-14.

2. Moak JP, Barron KS, Hougen TJ, Wiles HB, Balaji S, Sreeram N, et al. Congenital heart block: development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol. 2001;37(1):238-42.

3. Tantengco MV, Thomas RL, Karpawich PP. Left ventricular dysfunction after long-term right ventricular apical pacing in the young. J Am Coll Cardiol. 2001;37(8):2093-100.

4. Karpawich PP, Mital S. Comparative left ventricular function following atrial, septal, and apical single chamber heart pacing in the young. Pacing Clin Electrophysiol. 1997;20(8 Pt 1):1983-8.

5. Gebauer RA, Tomek V, Salameh A, Marek J, Chaloupecký V, Gebauer R, et al. Predictors of left ventricular remodeling and failure in right ventricular pacing in the young. Eur Heart J. 2009;30(9):1097-104.

6. Kim JJ, Friedman RA, Eidem BW, Cannon BC, Arora G, Smith O, et al. Ventricular function and long-term pacing in children with congenital complete atr ioventr icular block. J Cardiovasc Electrophysiol. 2007;18(4):373-7.

7. Vatasescu R, Shalganov T, Paprika D, Kornyei L, Prodan Z, Bodor G, et al. Evolution of left ventricular function in pediatric patients with permanent right ventricular pacing for isolated congenital heart block: a medium term follow-up. Europace. 2007;9(4):228-32.

8. Chiesa P, Cuesta A, Dutra S, Matto S, Morales J, Giudice J, et al. Miocardiopatía dilatada en la edad pediátrica por marcapasos con estimulación en el ápex del ventrículo derecho. Arch Pediatr Urug. 2008;79(2):125-38.

9. Tomaske M, Breithardt OA, Bauersfeld U. Preserved cardiac synchrony and function with single-site left ventricular epicardial pacing during mid-term follow-up in paediatric patients. Europace. 2009;11(9):1168-76.

10. van Geldorp IE, Vanagt WY, Bauersfeld U, Tomaske M, Prinzen FW, Delhaas T. Chronic left ventricular pacing preserves left ventricular function in children. Pediatr Cardiol. 2009;30(2):125-32.

11. Tomaske M, Breithardt OA, Balmer C, Bauersfeld U. Successful cardiac resynchronization with single-site left ventricular pacing in children. Int J Cardiol. 2009;136(2):136-43.

12. Lai WW, Geva T, Shirali GS, Frommelt PC, Humes RA, Brook MM, et al; Task Force of the Pediatric Council of the American Society of Echocardiography; Pediatric Council of the American Society of Echocardiography. Guidelines and standards for performance of pediatric echocardiogram: a report from the task force of the pediatric council of the American Society of Echocardiography. J Am Soc Echocardiogr. 2006;19(12):1413-30.

13. Karpawich PP, Rabah R, Hass E. Altered cardiac histologic following apical right ventricular pacing in patients with congenital atrioventricular block. Pacing Clin Electrophysiol. 1999;22(9):1372-7.

14. Tops LF, Schalij MJ, Bax JJ. The effect of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol. 2009;54(9):764-76.

15. Badke FR, Boinay P, Covell JW. Effects of ventricular pacing on regional left ventricular performance in the dog. Am J Physiol. 1980;238(6):H858-67.

16. Prinzen FW, Hunter WC, Wyman BT, McVeigh E. Mapping of regional myocardial strain and work during ventricular pacing: experimental study using magnetic resonance imaging tagging. J Am Coll Cardiol. 1999;33(6):1735-42.

17. Tantengco MV, Thomas RL, Karpawich PP. Left ventricular dysfunction after long-term right ventricular apical pacing in the young. J Am Coll Cardiol. 2001;37(8):2093-100.

18. Thambo JB, Bordachar P, Garrigue S, Laffite S, Sanders P, Reuter S, et al. Detrimental ventricular remodeling in patients with congenital heart block and chronic right ventricular apical pacing. Circulation. 2004;110(25):3766-72.

19. Sagar S, Jahangir A, Friedman PA. Long-term right ventricular apex pacing in patients with congenital AV block does not have a detrimental effect on ventricular function. Circulation. 2004;110(3):345-6.

20. Shalganov TN, Paprika D, Vatasescu R, Kardoss A, Mihalcz A, Kornyei L, et al. Mid-term echocardiographic follow up of left ventricular pacing in pediatrics patients with and without structural heart disease. Cardiovasc Ultrasound. 2007;5:13.

21. Litwin SE, Gorman G, Huang SK. Effect of different pacing modes on left ventricular relaxation in closed chested dogs. Pacing Clin Electrophysiol. 1989;12(7 Pt 1):1070-6.

22. Aoyagi T, Iizuka M, Takahashi T, Ohya T, Serizawa T, Momomura S, et al. Wall motion asynchrony prolongs time constant of left ventricular relaxation. Am J Physiol. 1989;257(3 Pt 2):H883-90.

23. Kolettis TM, Kyriakides ZS, Tsiapras D, Popov T, Paraskevaides IA, Kremastinos DT. Improved left ventricular relaxation during short-term right ventricular outflow tract compared to apical pacing. Chest. 2000;117(1):60-4.

24. Dwivedi SK, Bansal S, Puri A, Makharia MK, Narain VS, Saran RK, et al. Diastolic and systolic right ventricular dysfunction precedes left ventricular dysfunction in patients paced from right ventricular apex. Indian Pacing Electrophysiol J. 2006;6(3):142-52.

25. Rinzen FW, Peschar M. Relation between the pacing induced sequence of activation and left ventricular pump function in animals. Pacing Clin Electrophysiol. 2002;25(4 Pt 1):484-98.

26. Puggioni E, Brignole M, Gammage M, Soldati E, Bongiorni MG, Simantirakis EN, et al. Acute comparative effect of right and left ventricular pacing in patients with permanent atrial fibrillation. J Am Coll Cardiol. 2004;43(2):234-8.

27. Little WC, Reeves RC, Arciniegas J, Katholi RE, Rogers EW. Mechanism of abnormal interventricular septal motion during delayed left ventricular activation. Circulation. 1982;65(7):1486-91.

References

Author contributionsConception and design of the research: Ortega MC,

Ricardo GS; Acquisition of data, Analysis and interpretation of the data, Statistical analysis and Critical revision of the manuscript for intellectual content: Ortega MC, Morejón AEG, Ricardo GS; Writing of the manuscript: Ortega MC.

Potential Conflict of InterestNo potential conflict of interest relevant to this article

was reported.

Sources of Funding


Study Association

This article is part of the thesis of doctoral submitted by Michel Cabrera Ortega, from Cardiocentro Pediátrico ¨William Soler”.

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28. Peschar M, de Swart H, Michels KJ, Reneman RS, Prinzen FW. Left ventricular septal and apex pacing for optimal pump function in canine hearts. J Am Coll Cardiol. 2003;41(7):1218-26.

29. Vanagt WY, Verbeek XA, Delhaas T, Mertens L, Daenen WJ, Prinzen FW. The left ventricular apex is the optimal site for pediatric pacing: correlation with animal experience. Pacing Clin Electrophysiol. 2004;27(6 Pt 2):837-43.

30. Mills RW, Cornelussen RN, Mulligan LJ, Strik M, Rademakers LM, Skadsberg ND, et al. Left ventricular septal and left ventricular apical pacing chronically maintain cardiac contractile coordination, pump function and efficiency. Circ Arrhythm Electrophysiol. 2009;2(5):571-9.

31. Gebauer RA, Tomek V, Kubus P, Razek V, Matejka T, Salameh A, et al. Differential effects on the site of permanent epicardial pacing on the left ventricular synchrony and function in the young: implications for lead placement. Europace. 2009;11(12):1654-9.

32. Blanc JJ, Bertault-Valls V, Fatemi M, Gilard M, Pennec PY, Etienne Y. Midterm benefits of left univentricular pacing in patients with congestive heart failure. Circulation. 2004;109(12):1741-4.

33. Touiza A, Etienne Y, Gilard M, Fatemi M, Mansourati J, Blanc JJ. Long-term left ventricular pacing: assessment and comparison with biventricular pacing in patients with severe congestive heart failure. J Am Coll Cardiol. 2001;38(7):1966-70.

34. Vanagt WY, Prinzen FW, Delhaas T. Reversal of pacing induced heart failure by left ventricular apical pacing. N Engl J Med. 2007;357(25):2637-8.

35. Deshmukh P, Casavant DA, Romanyshyn M, Anderson K. Permanent, direct His-bundle pacing: A novel approach to cardiac pacing in patients with normal His-Purkinje activation. Circulation. 2000;101(8):869-77.

36. Zanon F, Baracca E, Aggio S, Pastore G, Boaretto G, Cardano P, et al. A feasible approach for direct his-bundle pacing using a new steerable catheter to facilitate precise lead placement. J Cardiovasc Electrophysiol. 2006;17(1):29-33.

37. Hillock RJ, Stevenson IH, Mond HG. The right ventricular outflow tract: a comparative study of septal, anterior wall, and free wall pacing. Pacing Clin Electrophysiol. 2007;30(8):942-7.

38. Mond HG, Hillock RJ, Stevenson IH, McGavigan AD. The right ventricular outflow tract: the road to septal pacing. Pacing Clin Electrophysiol. 2007;30(4):482-91.

39. Kipta A, Steinwender C, Kammler J, Leisch F, Hofmann R. Long-term outcomes in patients with atrioventricular block undergoing septal ventricular lead implantation compared with standard apical pacing. Europace. 2008;10(5):574-9.

40. de Cock CC, Meyer A, Kamp O, Visser CA. Hemodynamic benefits of right ventricular outflow tract pacing: comparison with right ventricular apex pacing. Pacing Clin Electrophysiol. 1998;21(3):536-41.

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

Mailing Address: Gustavo Glotz de Lima •Avenida Princesa Isabel, 370, Santana. Postal Code 90620-000, Porto Alegre, RS – BrazilE-mail: [email protected] Manuscript received March 13, 2013; revised manuscript May 24, 2013; accepted June 03, 2013.

DOI: 10.5935/abc.20130192

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.

IntroductionAn electrophysiological study (EPS) is an invasive

procedure used for the diagnosis of disturbances in the rhythm and electrical conduction of the heart. It can be used to measure atrioventricular conduction intervals, to elucidate arrhythmogenic mechanisms, and to evaluate the efficacy of antiarrhythmic agents. It is currently also used to locate and map reentrant circuits and ectopic sources in detail, for further treatment with catheter ablation. Thus, it has a diagnostic, therapeutic, and prognostic purpose1.

Since the 1970’s, catheters have been positioned in cardiac chambers by means of fluoroscopy with X-ray emmission2. However, it is known that the exposure of a pregnant woman to this radiation can have consequences to the fetus, especially between the 8th and 15th weeks

of gestation (Table 1)3. However, it is very difficult and inaccurate to quantify the fetal exposure to radiation, because of the dynamic characteristics of the test, the intermittent use of radiation, the different X-ray tube positions, device calibration, and fetal position. Due to this variability, it is not possible to determinate the exact amount of exposure, which is estimated by anatomical-mathematical models and in experimental animals (Table 2)4.

Brazilian guidelines and those of the American Heart Association do not recommend the use of the beta-HCG test in the screening of women of childbearing age undergoing electrophysiological procedures5-7.

In the present study, we evaluated the number of female patients referred for EPS and/or radiofrequency ablation who tested positive for a pre-procedural beta-HCG test.

MethodsCross-sectional study analyzing information from patients

undergoing EPS and/or radiofrequency catheter ablation in the Electrophysiology Laboratory of the Institute of Cardiology of Rio Grande do Sul, between June 1997 and February 2013. All women of childbearing age underwent the pregnancy test (serum beta-HCG) on the day before the procedure.

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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.

The study was approved by the Research Ethics Committee of the Institute of Cardiology of Rio Grande do Sul/ University Foundation of Cardiology. The database and statistical calculations were carried out using the MedCalc® V.7.3 software program. Categorical variables were expressed as absolute numbers and percentages. Continuous variables were expressed as mean ± standard deviation.

ResultsFrom an initial sample of 2,966 patients, 1,490 were

females, of whom 769 were of childbearing age (10 to 50 years, according to the World Health Organization).

The mean age of the women undergoing a pregnancy screening test was 33.6 ± 11.3 years, and the mean time of fluoroscopy during ablation was 10.8 ± 9 minutes.

A total of 556 ablations and 213 electrophysiological studies were performed in women of childbearing age. The procedures had been indicated for the investigation of supraventricular tachycardia in most of the cases; 236 cases of nodal reentry tachycardia and 203 cases of atrioventricular reentry tachycardia were diagnosed.

Of the 769 women of childbearing age referred for catheter ablation, three had their procedures suspended because they tested positive for beta-HCG and were in the beginning of pregnancy, which was unknown to them until the test was performed. Thus, a prevalence of 3.9 cases per 1000 women of childbearing age referred for electrophysiological study was observed.

Since the cost of a beta-HCG test in the Single Health System is of approximately R$ 7.00, we can estimate that approximately R$ 1794.00 were necessary to prevent fetal radiation exposure during ablation procedures in their mothers.

Table 3 shows the procedures performed by the Laboratory of Electrophysiology of the Institute of Cardiology of Rio Grande do Sul.

DiscussionExposure to ionizing radiation during diagnostic and

therapeutic procedures has dramatically increased in the past years.

Fetuses are susceptible to teratogenic effects through the complete prenatal period, and are more vulnerable in the first trimester of pregnancy. These effects depend on several variables, including the gestational age, fetal mechanisms of cell repair, and level of absorption of the radiation dose.

There is no evidence that a radiation dose lower than 0.10 Gy is related to severe complications for the fetus14. Specific effects, such as growth restriction, prenatal death, organ malformation, and intelligence impairment, are related to doses higher than 0.10-0.20 Gy15-24.

In the first weeks of gestation, the secondary effect of radiation may be the induction of abortion8,16-18, which usually results from doses higher than 1 Gy. After 4 weeks, there may be the risk of organ malformation and overall growth retardation.

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

Test Estimate (mGy) Range (mGy) ReferencesCatheter 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.

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Table 3 - Number of tests performed by gender

Tests performed

Men 1,476

Women 1,490

Women of childbearing age 769

Total 2,966

Deleterious effects on the central nervous system are more evident in exposures during the period between the 8th and 15th week of gestation, from the threshold dose of approximately 0.30 Gy.

In relation to the carcinogenic potential, this is present both in fetal exposure in the first trimester and in the other trimesters25,26. The risk of a fatal cancer is of approximately 5 to 15% per Gy8, and the risk of inherited genetic effects is of approximately 0.2 to 1% per Gy25. Calkins et al27 estimated that the risk of fatal malignancy is of 1 for every 1000 patients per hour of fluoroscopy.

However, resolution 453 of the National Agency of Sanitary Surveillance (Agência Nacional de Vigilância Sanitária – ANVISA) recommends that the dose on the abdominal surface does not exceed 2 mSv during all pregnancy, thus making it unlikely that the additional dose on the embryo or fetus exceeds approximately 1 mSv in this period28.

Currently, a growing interest and concern regarding protective measures and the least possible exposure to radioactive effects have been observed. It is believed that new technologies such as electroanatomical mapping and intracardiac three-dimensional echocardiography, which eliminate the use of radiation, could be used in these procedures and that they will be introduced gradually2.

In the present study, we observed that half of the women referred to our service were of childbearing age. Three cases of pregnancy were detected among 769 female patients of childbearing age. The estimated additional cost for this detection 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 risks attributed to the use of medications for the treatment of arrhythmias, such as amiodarone and verapamil, which are known to be potentially teratogenic. Additionally, the screening enables the prevention of radiation exposure and guidance on the decision-making about the drug therapy. Data in the 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 is well established, although few data are available in relation to exposure during EPS and/or catheter ablation.

Despite the ANVISA recommendations, the national guidelines still do not recommend the performance of beta-HCG test in the screening of female patients of childbearing age undergoing EPS and radiofrequency ablation6,7.

LimitationsThe 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 exposure to radiation.

The real cost-effectiveness analysis was not carried out prospectively and thus only an approximate estimate is available. Additionally, the risks considered are those of maternal exposure to radiation and not of fetal malformation.

ConclusionWe demonstrated that the risk of exposure to ionizing

radiation of women of childbearing age referred for radiofrequency ablation is significant. The amount of radiation necessary in these procedures is not negligible, especially in the first trimester, when the signs of pregnancy are not evident. The real cost-effectiveness analysis could not be carried out, but we propose that the pregnancy screening be incorporated to the national guidelines and to the routine of electrophysiology laboratories prior to the performance of elective procedures that require fluoroscopy.

Author contributionsConception and design of the research and Critical revision

of the manuscript for intellectual content: Lima GG, Gomes DG, Gensas CS, Simão MF, Rios MN, Kruse ML, Leiria TLL, Pires LM; Acquisition of data: Lima GG, Gomes DG, Gensas CS, Simão MF, Rios MN, Kruse ML, Pires LM; Analysis and interpretation of the data: Lima GG, Gomes DG, Gensas CS, Simão MF, Rios MN; Statistical analysis: Lima GG, Gomes DG, Leiria TLL; Writing of the manuscript: Lima GG, Gomes DG, Gensas CS, Simão MF, Rios MN, Leiria TLL, Pires LM.


reported.


Study AssociationThis study is not associated with any post-graduation

program.

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2. Pires LM, Leiria TL, Mantovani A, Kruse ML, Ronsoni R, Gensas CS, et al. Initial experience of catheter ablation without the use of fluoroscopy. Relampa. 2012;25(4):267-72.

3. Shaw P, Duncan A, Vouyouka A, Ozsvath K. Radiation exposure and pregnancy. J Vasc Surg. 2011;53(1 Suppl):28S-34S.

4. Dauer LT, Thornton RH, Miller DL, Damilakis J, Dixon RG, Marx MV, et al; Society of Interventional Radiology Safety and Health Committee; Cardiovascular and Interventional Radiology Society of Europe Standards of Practice Committee. Radiation management for interventions using fluoroscopic or computed tomographic guidance during pregnancy: a joint guideline of the Society of Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe with Endorsement by the Canadian Interventional Radiology Association. J Vasc Interv Radiol. 2012;23(1):19-32.

5. Buxton AE, Calkins H, Callans DJ, DiMarco JP, Fisher JD, Greene HL, et al; American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology). ACC/AHA/HRS 2006 key data elements and definitions for electrophysiological studies and procedures: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology). Circulation. 2006;114(23);2534-70.

6. Sosa EA, de Paola A, Gizzi J, Rassi S, Scanavacca M, Pérez A, et al. Indicações para estudo eletrofisiológicos e ablação por cateter de arritmias cardíacas. Recomendações da DAEC da SBC. Arq Bras Cardiol. 1995;64(2):149-51.

7. Lorga A, Lorga Filho A, D’Ávila A, Rassi A Jr, Paola AV, Pedrosa A, et al; Sociedade Brasileira de Cardiologia. Diretrizes para avaliação e tratamento de pacientes com arritmias cardíacas. Arq Bras Cardiol. 2002;79(supl.5):1-50.

8. Stabin MG, Blackwell R, Brent RL, Donnelly E, King VA, Lovins K, et al. Fetal radiation dose calculations. ANSI N13.54-2008. Washington, DC: American National Standards Institute; 2008.

9. Damilakis J, Theocharopoulos N, Perisinakis K, Manios E, Dimitriou P, Vardas P, et al. Conceptus radiation dose and risk from cardiac catheter ablation procedures. Circulation. 2001;104(8):893-7.

10. Winer-Muram HT, Boone JM, Brown HL, Jennings SG, Mabie WC, Lombardo GT. Pulmonary embolism in pregnant patients: fetal radiation dose with helical CT. Radiology. 2002;224(2):487-92.

11. McCollough CH, Schueler BA, Atwell TD, Braun NN, Regner DM, Brown DL, et al. Radiation exposure and pregnancy: when should we be concerned? Radiographics. 2007;27(4):909-17.

12. Wagner LK, Lester RG, Saldana LR. Exposure of the pregnant patient to diagnostic radiations: a guide to medical management, 2nd ed. Madison, WI: Medical Physics Publishing; 1997.

13. Hurwitz LM, Yoshizumi T, Reiman RE, Goodman PC, Paulson EK, Frush DP, et al. Radiation dose to the fetus from body MDCT during early gestation. AJR Am J Roentgenol. 2006;186(3):871-6.

14. Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M, et al; American College of Cardiology/American Heart Association Task

Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association and the Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death--executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J. 2006;27(17):2099-140.

15. Einstein AJ. Effects of radiation exposure from cardiac imaging: how good are the data? J Am Coll Cardiol. 2012;59(6):553-65.

16. Jankowski CB. Radiation and pregnancy: putting the risks in proportion. Am J Nurs. 1986;86(3):260-5.

17. Einstein AJ, Moser KW, Thompson RC, Cerqueira MD, Henzlova MJ. Radiation dose to patients from cardiac diagnostic imaging. Circulation. 2007;116(11):1290-305.

18. De Santis M, Di Gianantonio E, Straface G, Cavaliere AF, Caruso A, Schiavon F, et al. Ionizing radiations in pregnancy and teratogenesis: a review of literature. Reprod Toxicol. 2005;20(3):323-9.

19. International Commission on Radiological Protection. Pregnancy and medical radiation. Ann ICRP. 2000;30(1):iii-viii,1-43.

20. Wieseler KM, Bhargava P, Kanal KM, Vaidya S, Stewart BK, Dighe MK. Imaging in pregnant patients: examination appropriateness. Radiographics. 2010;30(5):1215-29.

21. Streffer C, Shore R, Konermann G, Meadows A, Uma Devi P, Preston Withers J, et al. Biological effects after prenatal irradiation (embryo and fetus). A report of the International Commission on Radiological Protection. Ann ICRP. 2003;33(1-2):5-206.

22. American College of Radiology (ACR). Practice Guideline for imaging pregnant or potentially pregnant adolescents and women with ionizing radiation. Reston, VA; 2008.

23. Timins JK. Radiation during pregnancy. N J Med. 2001;98(6):29-33.

24. Miller RW. Discussion: severe mental retardation and cancer among atomic bomb survivors exposed in utero. Teratology. 1999;59(4):234-5.

25. Otake M, Schull WJ, Lee S. Threshold for radiation-related severe mental retardation in prenatally exposed A-bomb survivors: a re-analysis. Int J Radiat Biol. 1996;70(6):755-63.

26. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP. 2007;37(2-4):1-332.

27. Calkins H, Niklason L, Sousa J, el-Atassi R, Langberg J, Morady F. Radiation exposure during radiofrequency catheter ablation of accessory atrioventricular connections. Circulation. 1991;84(6):2376-82.

28. Ministério da Saúde. Agencia Nacional de Vigilância Sanitária. Portaria SVS nº 453, de 1º de junho de 1998: aprova o regulamento técnico que estabelece as diretrizes básicas de proteção radiológica em radiodiagnóstico médico e odontológico, dispõe sobre o uso dos raios-x diagnósticos em todo território nacional e dá outras providências. Diário Oficial da União; Brasília; 2 de junho; 1998.

References

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Original Article

Analysis of the Sensitivity and Specificity of Noninvasive Imaging Tests for the Diagnosis of Renal Artery StenosisFlavio 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

Mailing Address: Flavio Antonio de Oliveira Borelli • Alameda dos Jurupis, 410, apto. 111, Indianópolis. Postal Code 04088-001, São Paulo, SP - BrazilE-mail: [email protected], [email protected] Manuscript received August 11, 2012; revised manuscript November 30, 2012; accepted March 14, 2013.

DOI: 10.5935/abc.20130191

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.

IntroductionArterial Hypertension (AH) is a public health problem.

Its relation to other diseases such as diabetes mellitus (DM), heart failure (HF), chronic kidney disease (CKD), and peripheral obstructive arterial disease (POAD) modifies the cardiovascular morbidity and mortality1-3. The growing incidence of atherosclerosis in the adult population, the presence of arterial obstruction leading to reduced renal blood flow and subsequent renovascular hypertension have aroused great interest for studies to be conducted in this field.

The identification of a causal relation between arterial stenoses and AH has the additional advantage that revascularization procedures may be decisive for blood pressure control.

No study on the assessment of the sensitivity, specificity, and positive and negative predictive values of imaging tests for the diagnosis of renal artery stenosis in the same population is available in the Portuguese language. In a search conducted at the electronic address www.ncbi.nlm.nih.gov, the comparative analysis between diagnostic methods for renal artery stenosis (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 compared with the reference standard, i.e, digital renal arteriography. The renin test and magnetic resonance angiography were also part of the study. However, due to the poor reproducibility of the renin test to predict RAS and because magnetic resonance angiography results were very similar to those of tomography, these two diagnostic methods were excluded4-7.

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

Objective To define the sensitivity, specificity, positive and negative

predictive values of each of the noninvasive imaging tests.To evaluate if there is a relation between risk factors

for atherosclerotic disease and the presence of significant obstructions detected on invasive angiography of the renal arteries.

Methods Prospective cohort study including 61 patients recruited

between January 2008 and August 2011. Participants were duly registered and being followed up in our institution. The study was approved by the Institutional Research Ethics Committee, under number 3592.

All volunteers were informed about the nature of the study and gave written informed consent. Then, invasive and noninvasive diagnostic tests were performed to determine the presence or absence or RAS.

The flowchart containing the sequence of procedures performed was equally followed for all participants.

The first stage encompassed history taking, clinical examination and blood pressure measurement, according to the standardization of the VI Brazilian Guidelines on Arterial Hypertension8. Then, the medication used was recorded, and the patient received additional advice on how to correctly use the antihypertensive drugs. Patients using drugs that could interfere with the renin-angiotensin-aldosterone axis had these medications replaced by another class, without affecting blood pressure control, with the objective of maintaining their blood pressure levels equal to or lower than 140 x 90 mmHg.

Diabetic patients on metformin had the medication discontinued for at least 48 hours prior to any procedure using iodinated contrast medium. The medication was resumed 72 hours after the use of the iodinated contrast medium, due to the possibility of renal function impairment9.

Only patients with AH and clinically suspected renovascular disease of atherosclerotic etiology who used antihypertensive medication at the moment of patient selection were included, regardless of age, gender, race, religion, socioeconomic condition, cardiovascular diseases or other comorbidities, provided that they met the inclusion criteria but not the exclusion criteria. We selected only cases presenting with at least two indicators of a medium or high probability as proposed by Pickering10 (Table 1). Later, all patients underwent the tests selected for the present study.

Inclusion criteriaThe inclusion criteria were: age between 18 and 80

years; clinical picture consistent with atherosclerosis; patients with AH (whether controlled or not); stages 2, 3 or resistant hypertension; onset of hypertension before 30 years of age or after 50 years of age; presence of abdominal or lumbar murmurs; evident atheromatous disease in coronary arteries, carotid arteries or peripheral vessels; smokers; pulse asymmetry; renal failure not related to other causes; acute pulmonary edema with no apparent cause; significant arterial

hypotension during treatment with angiotensin converting enzyme inhibitors; refractory or malignant AH with progressive renal failure; elevation of serum creatinine with the use of angiotensin enzyme inhibitors; asymmetry of renal size or function; agreement to participate in the study; giving written informed consent.

Exclusion criteriaThe exclusion criteria were: history of allergic reaction

to iodinated contrast medium; women of childbearing age without a negative pregnancy test; inability or refusal to understand the study and give written informed consent; estimated calculation of glomerular filtration lower than 30 mL/min/m2; patients with congestive heart failure (CHF); patients with coagulation disorders; patients with left ventricular dysfunction (ejection fraction < 40%); recent myocardial infarction (within the 6 months prior to the beginning of the study); acute coronary syndromes, recent stroke (within the 6 months prior to the beginning of the study).

Diagnostic testsLaboratory testsAll patients were tested for the following laboratory tests:

fasting blood glucose, uric acid, sodium and potassium, BUN and creatinine, complete blood count, thyroid stimulating hormone (TSH), and lipid profile. Creatinine clearance, which was important for the assessment of renal function impairment and for decision making in other stages of the study, was estimated using the Cockcroft Gault formula adjusted for body surface and corrected for gender11.

Noninvasive imaging testsRenal artery DopplerA Toshiba high-resolution device with a convex

multi-frequency transducer (3 to 5 MHZ) was used. Images were stored in VHS and included measurements for the detection of renal artery stenosis both direct and indirectly. The origin of both renal arteries was assessed from a cross-sectional view of the aorta, in B mode and with color flow, seeking to visualize the longest possible extent of the vessel, the presence of turbulence and flow abnormalities, observing the relationship between the systolic and diastolic velocity curves, and the calculation of the renal-aortic ratio (RAR). From this calculation, we were able to define whether the arteries were free from stenosis, and to verify the presence of cases with stenoses affecting more or less than 60% of the vessel diameter, according to criteria described in Table 212.

The imaging study of the renal arteries was complemented by the indirect analysis carried out with the patient in the left lateral position and right lateral position. From these recordings, the longitudinal diameter of the kidneys was compared. These images also permitted a better exploration of the distal portion of the renal arteries in which the intrarenal blood flow was evaluated using Doppler in the segmental or interlobar arteries, in three different segments (upper, mid- and lower); and the acquisition of velocity curves (systolic and diastolic) with the objective of analyzing the resistance

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Table 2 - Criteria for the identification of the degree of stenosis

Degree of stenosis SVP in main renal artery RAR

Normal < 180 cm/s < 3,5

< 60% ≥ 180 cm/s < 3,5

> 60% ≥ 180 cm/s ≥ 3,5

Occlusion Absence of flow Absence of sign

SVP: systolic velocity peak; RAR: renal aortic ratio.

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

Probability Características clínicas

Low(0.2%)

Borderline hypertensionNon-complicated mild/moderate hypertension

Moderate(5-15%)

Severe or refractory hypertensionRecent onset hypertension below 30 years or above 50 years

Presence of abdominal or lumbar murmursRadial or carotid pulse asymmetry

Moderate hypertension, smokers, or atherosclerosis in other sites (coronary or carotid artery)Undefined renal function deficit

Excessive pressure response to ACEI

Alta(25%)

Severe or refractory hypertension with progressive renal failureHipertensão acelerada ou malignaAccelerated or malignant hypertensionCreatinine 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 0.7, and normal values for the flow acceleration time (AT) when shorter than 70 ms.

Tc-99m DTPA renal scintigraphy Scintigraphic assessments were made using a Millennium

VG gamma camera (GE Medical Systems, Milwaukee, USA). Angiotensin inhibitors and/or angiotensin II-receptor

blockers were discontinued for three days prior to the test. For the baseline acquisition of the radioisotope renogram,

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 a 7-Gauge or larger needle was established. After proper camera calibration, the radiotracer at a dose of 150 uCi/kg was injected in bolus until a maximum volume of 1 mL was reached. From this moment on, image recording was started.

After this initial acquisition, data started to be obtained using an angiotensin II converting enzyme inhibitor. In this phase, the administration of technetium-99-labeled diethylenetriaminepentaacetic acid 150 uCi/kg was repeated up to the maximum volume of 1 mL. Sixty minutes prior to this phase, the patients received a Captopril pill at a dose of 50 mg and had their blood pressure monitored. The gamma-camera remained in the same position as in the previous phase, and the same intravenous access and technique for radiotracer administration were used.

When necessary, mapping was repeated after intravenous injection of furosemide 40 mg, 20 minutes after the Tc-99m DTPA injection.

Interpretation of the imaging test included the recording of the radiotracer transit time from the abdominal aorta to the kidneys, considering a normal value of up to 6 seconds. Another parameter analyzed was the tracer accumulation time in the kidneys, which reflects the glomerular filtration rate, whose normal value is usually between 3 and 5 minutes, followed by the excretion phase which in general lasts 20 to 30 minutes.

Computed tomographic angiography of the kidneys and renal arteries

The Aquilion® 64 multiple-detector tomographer (Toshiba Medical Systems, Ottawara, Japan) was used in this study.

Image acquisition of the arteries started by puncture of a peripheral vein large enough to permit the administration of the iodinated contrast medium at a rate of at least 3 mL/s. Thus, the acquisition of tomographic data was started by the record of a single localizer to identify the positioning of the segment to be studied. After the specific area of interest to be documented was defined, images were obtained using the injection of the contrast medium at a dose of 1.50 mL/kg of body weight at a rate of at least 3.50 mL/s. The programming included the use of 1-mm collimation, with a tube rotation 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.

In order to obtain the volumetric representation of the morphology of the kidneys and renal arteries, the increment between anatomical sections, i.e., the distance from one image to the next was shorter than the thickness of the cross-sectional views obtained. After acquisition, data were transferred to a work station (Vitrea, Vital Images, California, USA), in which the post-processing was carried out, thus permitting the reconstruction of the patient’s anatomy in different planes. Semi-objective measurement algorithms were used to measure

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the reference diameters and minimum lumen diameter which, in turn, could allow the diagnosis of the presence of stenoses and, in positive cases, the estimate of their severity.

Invasive imaging testsThe gold-standard chosen in this study was the invasive

assessment of the anatomy of the renal arteries using angiography. Since the vessels are more effectively assessed by contrasting the target arteries, an iodinated contrast medium was used. Because of this procedure, saline 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 present. Saline solution was administered at a dose of 10 mL/kg of body weight before and after image acquisition, at a rate that varied according to the patients’ clinical status and ventricular function.

Digital renal arteriography Renal arteriography was performed by the Section of

Interventionist Radiology, using an Axiom Artis 2005 digital angiography equipment (Siemens, Germany), with flat detector for cardiovascular diagnosis. The procedure started by positioning the patient in the supine position in the digital hemodynamic laboratory; puncture of the femoral artery after local anesthesia with 2% lidocaine without vasoconstrictor was then performed. Next, a 5F valved introducer was advanced inside the right femoral artery; within which a 0.35 guide wire was introduced; a high-flow pigtail catheter was then advanced over the guide wire. It was used to opacify the abdominal aorta. Then, the renal arteries were selectively catheterized and the arterial, parenchymatous and venous phases were observed. The contrast material used was a water-soluble, ionic, low-osmolarity medium. Images were acquired using a digital subtraction filter and stored in a compact disc for further analysis.

After image acquisition, the introducer was removed and effective local compression was kept for a minimum period required.

Based on previous studies, the criterion used for the definition of a significant stenosis was an arterial lumen reduction by at least 60%, since there are data suggesting that these plaques are those which promote an average systolic gradient higher than 20 mmHg, thus being able to lead to renal tissue ischemia13,14.

Statistical analysisData were described as absolute (n) and relative (%)

frequencies for qualitative measures. Mean summary statistics, standard deviation (SD), median and 25th and 75th percentiles (Per 25 and Per 75) were used for quantitative measures.

The effect of the risk factors and other diagnostic tests on the results of the reference test (arteriography) was analyzed. The Pearson chi square test or Fisher’s exact test was used to analyze the association between qualitative measures and the reference test. Comparison of quantitative measures between the response categories of arteriography was made using the Student’s or Mann-Whitney t test.

Information regarding sensitivity and specificity, positive and negative predictive values are presented.

The agreement level between two diagnostic methods and digital arteriography was analyzed using the Kappa method.

Positive values of the diagnostic tests should occur when the stenosis diameter was > 60%.

The significance level of the tests was set at 5%. The analyses were carried out using the Statistical Package

for the Social Sciences (SPSS) 19.0 (SPSS Inc., Chicago IL, 2004) software program.

ResultsBetween January 2008 and August 2011, 63 individuals

were recruited. Of these, 61 underwent all tests, except for one patient who did not undergo DTPA radioisotope renogram. Thirty three patients were women; the mean age was 65.43 (± 8.7) years, the mean weight was 71.45 (± 11.83) kg and the mean height was 1.59 (± 0.97) m. Approximately half of the study population had DM and several patients had clinical manifestations of atherosclerosis; however, the number of participants with smoking habit and POAD was not significant. Patient demographics and their clinical characteristics are shown in Table 3.

Lipid profile abnormalities were found in more than one third of cases. Renal function, as assessed using the adjusted Cockcroft Gault formula, showed renal dysfunction in most of the cases.

The noninvasive imaging tests revealed abnormalities suggestive of the presence of significant stenoses in renal arteries in more than two thirds of the study population. These results were similar to those found in invasive arteriography.

Sensitivity, specificity, and predictive value of the noninvasive imaging tests

The relation between the results obtained with invasive and noninvasive imaging tests was analyzed by comparing the individual results of each study patient. The initial analysis showed a significant correlation of the results of Doppler and tomography with invasive angiography (Table 4). The results of the scintigraphic study were not significantly associated with those of angiography.

Sensitivity, specificity, positive and negative predictive values of the noninvasive imaging tests, as well as the Kappa value were also defined. Again, arteriography was used as the reference test. Results of the analyses per patient and per vessel are shown in Tables 5 and 6.

Association between risk factors and renal arteriography findings

As proposed, the association between the presence of stenoses above 60% and the different risk factors of the whole population was analyzed. Results are shown in Table 7. The presence of abnormal triglyceride levels, renal dysfunction, high creatinine levels, and decreased glomerular filtration rate were predictive of the existence of significant obstructive plaques in at least one of the renal arteries.

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Consistency of noninvasive imaging test results was verified by analyzing the results of the interobserver interpretation, i.e., other experienced examiners were asked to quantify the percentage of stenosis in the renal arteries 12 to 18 months after the initial analysis. The results included in the analysis, in turn, were decided by consensus between the two operators, in case of disagreement regarding the findings.

The results presented in Table 8 show a high level of agreement between tests, except for scintigraphy, which showed intermediate results, albeit significant.

Discussion Arteriography remains as the gold-standard test for the

diagnosis of renal artery stenoses; however, it is still related to the occurrence of complications, especially in cases of higher risk and greater number of comorbidities15.

The findings of this study demonstrate that the association of noninvasive imaging tests may provide important information on the presence of significant renal artery stenosis. Abnormalities found in Doppler and tomography are frequently accompanied by significant reductions in the arterial lumen; however, some peculiarities of this study deserve special consideration.

The study population reproduced many of the aspects associated with the presence of obstructive atheromatous plaques in the renal arteries described in the literature.

Age above 60 years and white ethnicity – characteristics found in our study patients, are usually the major predictors of atherosclerotic disease16.

One of the risk factors commonly associated with renovascular disease of atherosclerotic origin is cigarette smoking, especially in the presence of POAD. The present study showed a situation different from that seen in the literature, because the proportion of smokers or patients with POAD was not significant, of 13.1% and 21.3%, respectively.

Given that this is a population at a high cardiovascular risk, a higher incidence of coronary artery disease and carotid artery disease was expected. However, even with the use of different methods to identify these diseases, the incidence found was low, of 39.3% and 26.2%, respectively.

Patients were recruited from the Dante Pazzanese Institute of Cardiology, where anti-tobacco campaigns, frequent use of lipid-lowering drugs and proper dietary guidance are in place, and this may have been the reason for the lower incidence found for those diseases.

A meta-analysis on the prevalence of renovascular disease in several risk groups found DM in 20% of their study population17. The prevalence found in our study is 2.5 times higher (50.8%).

Although hyperlipidemia is frequently identified in populations with atherosclerotic disease, to date no study has confirmed that this association is predictive of RAS18. In this study, high total cholesterol and LDL-cholesterol levels were not found; the levels verified were strictly within normal limits. This lipid profile may provide this population with a better clinical perspective, even considering the fact that 78.7% of participants showed HDL-cholesterol levels lower than the

minimum gender-required levels. Also, the triglyceride profile in the study population also showed values lower than those considered atherogenic. This may also be explained by the fact that all patients’ plasma lipid levels were under strict control19.

Diagnosis of RAS and the diagnostic testsDoppler, CT angiography and magnetic resonance imaging

have been exceptionally accepted as tests for the diagnosis of diseases of the thoracic and abdominal aorta, as well as for those of the infrainguinal vessels. However, this is not valid for the study of the renal arteries.

The analysis of the association between noninvasive tests and digital arteriography shows a clear correlation of Doppler and CT angiography with digital arteriography, both in the analysis per patient and per vessels, all with p values ≤ 0.05. This was not observed for scintigraphy.

Analysis of sensitivity, specificity, positive and negative predictive values of the noninvasive diagnostic tests

The role of each imaging method used in individuals with suspected renal artery stenosis was compared. We then proposed a better population selection and the identification of the best tests to guide the diagnosis.

Doppler Measurements found for the assessment of sensitivity

and specificity of Doppler of the renal arteries in probable RAS showed values of 82.90% and 70%, respectively, which correspond to a positive predictive value of 85% and a negative predictive value of 66.70%. The Kappa value of 0.523 showed a moderate level of agreement with the reference standard, with p < 0.001.

These values make Doppler an interesting diagnostic option for the investigation of atherosclerotic renovascular disease, because the test was able to identify stenosis in a population with RAS, to rule out the disease in patients not having it, and to identify it among those with a positive test. This was achieved with reasonable safety, and the values found in the present study corroborate those reported in the literature.

We may conclude that sensitivity, specificity and the positive and negative predictive values make this test an important diagnostic tool for the investigation of atherosclerotic renovascular disease, despite the many limitations regarding the applicability of the method described in the literature20,21.

Renal scintigraphyWith low sensitivity and positive predictive values (12.50%

and 45.50%, respectively), and reasonable specificity, but a low negative predictive value (70% and 28.60%, respectively), the performance of scintigraphy in this population was not as good as that of Doppler, and this was reflected in the finding of a Kappa value of (-) 0.128. Values lower than zero identify total disagreement between the findings from scintigraphy and digital renal arteriography

We should also point out that low significance values were found for the other analyses carried out, both for patients and for arteries.

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

Population n %

Gender F 33 54.1

M 28 45.9

Ethnicity Black 14 23

White 47 77

Age > 60 yearsNo 17 27.9

Yes 44 72.1

Cigarette smoking No 53 86.9

Yes 8 13.1

BMI range

Normal 17 27.9

Overweight 26 42.6

Obesity 1 9 14.8

Obesity 2 9 14.8

DM2 No 30 49.2

Yes 31 50.8

TC > 200 mg/dL No 41 67.2

Yes 20 32.8

HDL risk (M < 40/F < 50) No 13 21.3

Yes 48 78.7

LDL

LDL < 100 mg/dL 30 49.2

100 ≤ LDL ≤ 130 mg/dL 18 29.5

LDL > 130 mg/dL 13 21.3

TG > 150 mg/dL No 33 54.1

Yes 28 45.9

AC risk (M > 102/F > 88) No 24 39.3

Yes 37 60.7

POADNo 48 78.7

Yes 13 21.3

CAD No 37 60.7

Yes 24 39.3

Carotid artery diseaseNo 45 73.8

Yes 16 26.2

ProteinuriaNo 50 82

Yes 11 18

Renal dysfunctionNo 9 14.8

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.

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Table 4 - Association between the diagnostic tests and digital arteriography

Right arteriography Left arteriography ArteriographyNegative Positive Total

P valueNegative Positive Total

P valueNegative Positive Total

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

Sensitivity (%) PPV (%)Agreement (Kappa)

Medida Kappa p valuePatients (n = 61)

Doppler (n = 61)

Left kidney 75.90 88.00 0.669 < 0.001Right kidney 63.60 60.90 0.402 0.002

General 82.90 85.00 0.523 < 0.001

Scintigraphy(n = 60)

Left kidney 10.30 33.30 -0.092 0.329Right kidney 14.30 30.00 -0.420 0.717

General 12.50 45.50 -0.128 0.099

CT angiography(n = 61)

Left kidney 75.90 91.70 0.702 < 0.001Right kidney 45.50 76.90 0.415 0.001

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, accumulation and clearance curves, thus directly depending on the degree of the renal structure integrity to identify stenosis of a vessel. Therefore, these results do not allow us to consider scintigraphy of the renal arteries as a test indicated for the diagnosis of RAS in patients with impaired renal function. Thus, we can conclude that scintigraphy is not recommended in populations with renal dysfunction.

CT angiography

With superior results, although very close to those found using Doppler, CT angiography proved to be a very useful test for the identification of individuals with RAS. The sensitivity, specificity, positive and negative predictive values found (68.30%, 80.00%, 87.50% and 55.20%, respectively) showed that this noninvasive imaging test is a very useful diagnostic

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

Patients (n = 61) Specificity (%) NPV (%)Agreement (Kappa)

Kappa measure p value

CT angiography (n = 61)

Left kidney 93.80 81.10 0.702 < 0.001

Right kidney 92.30 75.00 0.415 0.001

General 80.00 55.20 0.433 < 0.001

Scintigraphy (n = 60)

Left kidney 80.60 49.00 -0.092 0.329

Right kidney 82.10 64.00 -0.420 0.717

General 70.00 28.60 -0.128 0.099

Doppler (n = 61)

Left kidney 90.60 80.60 0.669 < 0.001

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 a significance level of p < 0.001 confirm this statement.

Several studies have used this diagnostic method to investigate RAS22,23.

For CT angiography, limitations regarding the use of a contrast medium may be important. In younger populations, radiation exposure should be considered.

Analysis of the association between risk factors and renal arteriography

The relationship between lesions considered greater than a 60% reduction in vessel lumen, as quantified by visual analysis of the angiogram, was analyzed in order to identify the presence of an association between risk factors and digital arteriography.

This analysis permitted the identification of two variables – renal dysfunction and plasma triglyceride levels, among the risk factors allocated in this study, as being able to establish a causal relationship between an obstructive plaque in the renal artery and the risk factors previously mentioned.

Even with the possibility of being represented by any of the variables that identify renal dysfunction, the body surface-adjusted creatinine clearance corrected by gender was the variable chosen to demonstrate the relationship between renal dysfunction and the presence of stenosis, because there is an important correlation between its values and cardiovascular disease mortality. Thus, identifying renal artery stenosis is an important condition to minimize the progression of the cardiovascular disease itself.

The findings of the present study identified a median creatinine clearance of 52.8 (41.1; 74.4) mL/min/m2. These values correspond to glomerular filtration rates consistent with stage-3 renal dysfunction, which precisely characterize individuals at a higher risk for cardiovascular events24.

In this study, 85.2% of the participants had renal dysfunction. In the statistical analysis of the quantified measures, this risk

factor was predictive of the presence of stenosis > 60% in at least one of the renal arteries, with p ≤ 0.002.

Plasma triglyceride levels were another risk factor that showed an association with renal artery stenosis. However, we observed an inverse relation to the one usually found. In this population, we found a lower chance of RAS in patients with plasma triglyceride 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 renal plaque. In our study population, these findings reached a clinical significance level, with p < 0.037, and should thus be interpreted.

However, it is a fact that the literature does not identify the possibility of the development of atherosclerotic disease per se in populations like this. In the presence of lower triglyceride levels, other comorbidities could be present to justify the development of atherosclerotic disease.

Increased plasma triglyceride levels are usually associated with the presence of risk factors such as obesity, metabolic syndrome, pro-thrombotic states, pro-inflammatory states and type-2 DM, all contributing for an increased risk of cardiovascular diseases. The NCEP ATPIII25 identified that levels < 150 mg/dL and between this value and 200 mg/dL had a smaller participation in the assessment of the cardiovascular risk alone. However, values > 200 mg/dL (hypertriglyceridemia) are already considered as an independent risk factor for cardiovascular diseases.

We should remember that this population comprised individuals aware of their morbid condition and who were already taking medications that aimed not only to control their blood pressure, but also all the risk factors involved in atherosclerotic diseases.

From these findings, we can state that the presence of atherosclerotic disease in other sites, the metabolic syndrome components, and other risk factors that are present in the population, other than renal dysfunction and triglyceride levels, did not identify RAS.

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Table 7 - Association between risk factors and digital arteriography

Arteriography Totalp 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)

0.659IMC sobrepeso n (%) 7 (35) 19 (46.34) 26 (42.62)

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)

0.373100 ≤ LDL ≤130 mg/dL n (%) 4 (20) 14 (34.15) 18 (29.51)

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)

Body surface (m2) 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.

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Table 8 - Agreement between observers of the different noninvasive imaging tests

Kappa Valor de p

Arteriography 0.8925 < 0.001

CT angiography 0.9362 < 0.001

Scintigraphy 0.5140 < 0.001

Doppler 0.9647 < 0.001

Conclusions The findings of the present study demonstrated that it is

possible to identify the presence of renovascular disease using an association of noninvasive imaging tests in most of the cases.

Sensitivity, specificity, and the positive and negative predictive values of Doppler and tomography are satisfactory, unlike what was observed with renal scintigraphy. Renal dysfunction and low triglyceride levels were the only risk factors associated with the presence of stenosis, as detected by the visual analysis of arteriography.

Finally, considering the investigation process and all the 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 scintigraphy. However, we should bear in mind that these results apply to patients with characteristics similar to those of this study population, and that Doppler ultrasonography

is operator-dependent. Although tomography is under less influence of the physician who conducts the test, it is less frequently available in Brazil.

Author contributionsConception and design of the research, Analysis and

interpretation of the data and Writing of the manuscript: 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 PEP; Realization of Doppler renal arteries: Petisco ACG; Performance of all renal arteriography: Kambara AM, Moreira SM; Infrastructure inpatient and outpatient: Sousa AGMR.



Sources of Funding


Study Association

This article is part of the thesis of doctoral submitted by Flavio Antonio de Oliveira Borelli, from Instituto Dante Pazzanese de Cardiologia.

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Triceps Skinfold as a Prognostic Predictor in Outpatient Heart FailurePriccila 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

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.E-mail: [email protected] Manuscript received September 11, 2012; revised September 14, 2012; accepted February 2, 2013.

DOI: 10.5935/abc.20130185

AbstractBackground: 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.

IntrodutionObesity is defined by excessive body fat and has a long-

established relationship with cardiovascular disease (CVD) and heart failure (HF)1,2. In the general CVD-free adult population, extremes in body mass index (BMI) have been associated with an increased risk of overall mortality3-5. However, there is a growing body of clinical evidence indicating that excess weight might confer a lower risk of adverse clinical events, particularly in HF patients. This phenomenon has been referred to as the “obesity paradox” or “reverse epidemiology”6-8.

Most reports regarding the obesity paradox have used BMI to classify obesity9. Although BMI is the most common method to define overweight and obese populations in epidemiological studies, it clearly does not reflect body composition10, thus depicting a relatively low sensitivity to

predict fat excess11. Unfortunately, direct measurements of body mass composition, like dual energy X-ray absorptiometry (DEXA), are not practical and have not been directly related to survival in HF patients12.

Data to evaluate the prognostic value of other anthropometric and indirect measures of body composition, such as waist circumference (WC), arm muscle circumference (AMC), and triceps skinfold (TSF), have been poorly examined in HF patients. Lavie et al13 have suggested that a high body fat percentage, as estimated by TSF measurements, might be an independent predictor of cardiovascular death or heart transplantation. However, other studies have not reached a consensus regarding the role of these parameters in HF prognosis14-16.

Therefore, the aim of the present prospective study 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.

Methods

Study Design and PopulationA prospective cohort of HF outpatients followed-up

at the HF and Transplant Clinic of a university tertiary

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care hospital in Porto Alegre (RS, Brazil) between May 2008 and December 2009 were enrolled in the present study. This cohort included patients with an HF diagnosis, predominantly with left ventricular systolic dysfunction [left ventricular ejection fraction (LVEF) < 50%], confirmed by two-dimensional echocardiography. Pregnant women, patients with significant peripheral edema, and those with clinical conditions, in which anthropometric measurements were not feasible, were excluded. Signed and informed consent was obtained from all patients prior to enrollment and the research protocol was approved by our institutional review committee.

Anthropometric ParametersAnthropometric measurements of weight, height, body

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 same trained investigator, a registered nutritionist, to avoid interobserver variability.

BMI, BSA, and Ponderal Index (PI)BMI was calculated using the Quetelet equation as

follows: BMI (Quetelet) = weight (kg)/length (m)2. Weight was measured using a balance scale (Filizola PL180; Filizola, Brazil) with capacity of 180 kg and an accuracy of 100 g. For height measurement, we used a vertical wall-mounted stadiometer. BMI was classified into three categories according to the World Health Organization classification for adults: underweight (<18.5 kg/m²), normal weight (18.5–24.9 kg/m²), and overweight (>25 kg/m²); and the Pan American Health Organization criteria for the elderly: underweight (<23 kg/m²), normal weight (23–28 kg/m²), and overweight (>28 kg/m²)17. In addition, we calculated BSA as weight0.5378 × height0.3964 × 0.024265 and PI as weight/height3.

Waist circumferenceWC was measured at the midpoint between the lowest rib

and the iliac crest during expiration. Patients were instructed to remain in an upright position with weight evenly distributed on both sides and breathing smoothly to prevent abdominal muscle contraction.

Triceps SkinfoldThe TSF thickness (in mm) was obtained at the mid-point

of the non-dominant arm (between the acromial process and the olecranon) with the arm freely stretched along the body. A fold of skin was then pinched with the fingers and a scientific caliper (Cescorf Scientific, Cescorf, Brazil) was applied. The measurement was repeated three times and the mean of the measurements was used for analysis.

Arm muscle circumferenceAMC (in cm) was calculated by measuring the AC and the

TSF thickness, using the following formula proposed by Jelliffe: C2 = C1–3.14*S, where C2 is the muscular circumference, C1 is the arm circumference, and S is TSF thickness (in cm)18.

Outcome EvaluationEnrolled patients were followed-up at the HF and

Transplant Outpatient Clinic. At the HF clinic, patients were scheduled to have regular visits at pre-defined intervals of 1–4 months. Follow-up data were directly derived from reviewing all electronic clinical data from the institutional records (most patients had several follow-up visits). For patients who were not regularly visiting the HF clinic (or were lost to follow-up), telephone contact was attempted to obtain relevant clinical events based on a structured telephone interview performed by trained nurses. For the study participants who we were unable to contact by phone (approximately 20 patients), we checked their vital status through the State Death Certificate Database, which contains data on the main cause and date of all deaths in our state. For statistical analysis we used (1) all-cause mortality and (2) HF-related hospitalizations.

Statistical Analysis Baseline patient clinical characteristics were expressed as

mean ± SD or number and percentage. Continuous variables were compared using the Student’s t-test or Mann–Whitney U test as appropriate, whereas categorical variables were compared using the chi-square test or Fisher’s exact test. TSF and BMI were also analyzed according to quintiles of the distribution. Survival curves were constructed using the Kaplan–Meier method and compared with the log-rank test. Cox proportional hazard regression analysis was performed to determine independent predictors of survival and included at least one anthropometric parameter (either BMI or TSF) and clinical predictors of risk [gender, age, New York Heart Association (NYHA) class, LVEF, and serum creatinine level]. A two-tailed p value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS statistical software ver. 18 for Windows (SPSS, Inc., Chicago, IL, USA).

ResultsFrom May 2008 to September 2009, a total of 378 HF

outpatients, who were followed-up at the HF and Transplant clinic, agreed to participate in the study and had their anthropometric parameters evaluated. We excluded 34 patients from the protocol because LV function assessment indicated a LVEF > 50%.

Baseline clinical characteristics of the remaining study population (n = 344) are listed in Table 1 and stratified by survival. Overall, HF patients were predominantly male, self-reportedly white, of non-ischemic etiology, in NYHA functional class I–II, and had moderate to severe LV systolic dysfunction (mean LVEF = 32 ± 9%). Most patients were hypertensive and 30% had diabetes. The mean follow-up period was 30.3 ± 8.2 months. Patients who died were older, had relatively high creatinine levels, low LVEFs, and depicted a trend towards higher NYHA functional class.

Nutritional assessment parameters are listed in Table 2. Most HF patients were overweight when classified by BMI. There were no significant differences in most anthropometric parameters between patients who died and those who survived. In particular, mean BSA and BMI were remarkably

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Table 1 - Baseline clinical characteristics of the study population

Total(n = 344)

Alive(n = 288)

Dead(n = 56) p

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(n = 344)

Alive(n = 288)

Dead(n = 56) p

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.

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similar in both groups, even when stratified by quintiles of the distribution. TSF was the only anthropometric index that was 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 in 22% of those that survived (p = 0.027; Table 2).

Data regarding TSF quintiles are presented in Table 3. Patients within the highest TSF quintile were younger, mostly females, with lower serum creatinine levels and higher LVEFs. As expected, patients in the highest TSF quintile had higher BMIs and WCs (p < 0.001). Figure 1 depicts HF hospitalization rates and overall mortality according to TSF quintiles. Our analysis demonstrated that HF patients within the 5th quintile had approximately a three-fold lower mortality rate than patients in the 2nd, 3rd, and 4th quintiles. No significant differences were observed in HF hospitalizations according to TSF. In addition, the Kaplan–Meier survival curves stratified by TSF progressively diverged over time (Figure 2A), but such differences were not observed in the BMI-stratified analysis.

Table 4 shows univariate analysisand multivariate Cox regression analysis results for all-cause mortality, including nutritional parameters and other clinical variables. In the univariate analysis, serum creatinine levels, LVEF, and NYHA class were associated with risk, but TSF was the single best predictor of mortality [hazard ratio (HR) = 0.36; 95% confidence interval (CI) = 0.14–0.91; p = 0.03]. Finally, after adjustment for these clinical characteristics, TSF remained a

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

Q1 (69)≤ 8,1

Q2 (70)8,2–10,5

Q3 (68)10,6–14,2

Q4 (69)14,3–19,9

Q5 (68)≥ 20 p

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.

major independent predictor of overall mortality (HR = 0.36; 95% CI = 0.13–0.97).

DiscussionDespite the growing interest in the obesity paradox, there

is still an ongoing debate regarding the most appropriate parameter(s) to assess the nutritional status of HF patients. Our results demonstrated that among numerous anthropometric indices (BMI, BSA, PI, TSF, WC, and AC), TSF was the only parameter that could differentiate survivors from non-survivors in a contemporary “real-world” prospective cohort of HF patients. This finding is in agreement with the concept of reverse epidemiology, as HF patients in the highest TSF quintile had lower overall mortality, even after adjustment for other important clinical predictors of risk. We did not observe a dose–response relationship between TSF and mortality, as only the superior quintile, representing a greater amount of fat mass, appeared to be an independent protective factor. In addition, unlike other studies, we did not find BMI as an adequate predictor of HF prognosis.

The correlation between BMI and HF survival remains controversial. Post-hoc analysis of large clinical trials19 demonstrated that lower BMI was associated with decreased survival. Symptomatic HF patients evaluated in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity trial with either reduced or preserved LV systolic

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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.

p=0.027

p=0.69

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).

p=0.027

Triceps Skinfold (mm)

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Table 4 - Univariate and multivariate Cox regression analysis

Variable UnivariateHR (95% CI)

MultivariateHR (95% CI)

Age 1.01 (0.99–1.03)

Gender (female) 1.29 (0.73–2.29) 0.88 (0.64–1.20)

NYHA class (I and II) 0.54 (0.29–1.00) 0.75 (0.55–1.03)

Creatinine (mg/dL) 1.57 (1.18–2.07) 1.40 (1.00–1.95)

LVEF (%) 0.95 (0.92–0.98) 0.96 (0.93–0.99)

TSF (superior quintile) 0.36 (0.14–0.91) 0.36 (0.13–0.97)

Waist circumference (cm) 1.01 (0.99–1.03)

Arm muscle circumference (cm) 0.95 (0.88–1.02)

BMI (superior quintile) 1.06 (0.56–2.01)

LVEF: left Ventricular ejection fraction; TSF: triceps skin fold; BMI: body mass index ; NYHA: New York Heart Association.

function, underweight patients or those with a low BMI were independently associated with a substantial increased risk of death (almost 70% for BMI < 22.5 kg/m²), but primarily in patients without evidence of fluid overload7. Recently, Vara et al20 described this phenomenon in elderly, hospitalized, HF patients However, although obesity is frequently evaluated by BMI in clinical practice, several investigators have questioned the accuracy of BMI to assess different body composition components21-23. For instance, the relationship between BMI and body fat percentage was reportedly influenced by ethnicity and age24. In the elderly, BMI might represent a higher percentage of body fat, while in the relatively young this association is less evident25. Recently, similar to our findings, several other investigators have questioned the usefulness of BMI as a predictor of mortality or cardiac events10,14,16,26.

Direct indices of body composition are theoretically the best markers to evaluate the prognostic role of nutritional status in different cardiovascular scenarios. Unfortunately, until now, there were no prospective large-scale studies that evaluated the role of these parameters on HF survival. Recently, Oreopoulos et al12 evaluated the association between direct measurements of body composition by DEXA and prognostic factors in 140 chronic HF patients and demonstrated that BMI misclassified body fat status in approximately 40% of the studied patients. Also, a higher lean body mass and/or lower fat mass were independently associated with factors that are prognostically beneficial in HF, suggesting that BMI may not be a good indicator of adiposity and may, in fact, be a better surrogate for lean body mass in this population, a finding that per se might question the obesity paradox12. However, one must also consider that the association of direct body composition measurements with surrogate CVD markers may not translate into similar data regarding survival10.

Anthropometry is a simple technique that is easily applied in clinical practice or in large population surveys. Numerous anthropometric parameters have

been proposed to assess nutritional status and appraise different body composition components. TSF thickness measurement allows estimation of body fat content27, while limb circumferences reflect limb muscle and, thus, protein nutritional state. It is important to point out that TSF thickness measures primarily subcutaneous fat, and therefore, is insensitive to changes or abnormalities in visceral fat. Body density and body fat can be accurately estimated from the sum of TSF measurements28. Previous studies have compared and validated different body composition techniques, such as DEXA, to assess fat mass and have demonstrated an adequate accuracy to estimate body fat mass, both for subscapular and TSF thickness29. In particular, TSF has been used more frequently than other sites, because it is easy to access, reproducible, and can measure a wide range of variation among individuals30. A recent study compared body composition assessment in 118 hemodialysis patients and reported that TSF was one of the most accurate parameters to estimate total body fat percentage using DEXA as the reference test31.

Lavie et al13 pioneered evaluation of the prognostic role of body fat percentage based on skinfold measurements in HF patients and demonstrated that for each 1% absolute reduction in percent body fat, major clinical events increased by >13%. Assessment of other anthropometric parameters, such as WC, has been proposed for HF risk stratification, but with inconsistent results14,15. Our results reinforced the concept of the obesity paradox and suggested that assessment of a simple anthropometric parameter to measure subcutaneous fat (the TSF) might be adequate to indirectly assess overall body fat mass.

Regarding hospitalization risk, most reports on the assessment of the obesity paradox opted for analysis of a combined endpoint (death and hospitalization), thereby limiting separate evaluations of these events. Furthermore, some studies have found similar results, in which obesity is a predictor of only overall/cardiovascular mortality, but not hospitalization8. One possible explanation for these findings is the fact that patients with greater adiposity are diagnosed earlier with HF, which justifies why this group is younger, has less degree of cardiac dysfunction, and consequent better survival. These patients, however, may have similar vulnerability to episodes of HF decompensation than those with normal amounts of fat mass.

The results of the present study should be evaluated by taking into account some methodological limitations. First, we used indirect measurements of body composition to evaluate body fat mass. Several studies, however, suggested that TSF measurement was apparently an adequate estimation of body fat27. Second, we acknowledged that anthropometry, particularly skinfold measurement, requires a considerable amount of technical skill and meticulousness. In our protocol, all parameters were evaluated by a single trained professional to avoid interobserver variability. Third, we opted to use only TSF measurements to predict body fat composition30,31 instead of more complex equations based on multiple skinfolds. Although this strategy might slightly reduce the accuracy of body composition assessment, we believe that if simplifies the clinical applicability of our findings.

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2. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, et al. Obesity and the risk of heart failure. N Engl J Med. 2002;347(5):305-13.

3. Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. 1999;341(15):1097-105.

4. Haslam DW, James WP. Obesity. Lancet. 2005;366(9492):1197-209.

5. Zheng W, McLerran DF, Rolland B, Zhang X, Inoue M, Matsuo K, et al. Association between body-mass index and risk of death in more than 1 million Asians. N Engl J Med. 2011;364(8):719-29.

6. Arena R, Lavie CJ. The obesity paradox and outcome in heart failure: is excess bodyweight truly protective? Future Cardiol. 2010;6(1):1-6.

7. Kenchaiah S, Pocock SJ, Wang D, Finn PV, Zornoff LA, Skali H, et al. Body mass index and prognosis in patients with chronic heart failure: insights from the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) program. Circulation. 2007;116(6):627-36.

8. Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS, Jadbabaie F, et al. The obesity paradox body mass index and outcomes in patients with heart failure. Arch Intern Med. 2005;165(1):55-61.

9. Shirley S, Davis LL, Carlson BW. The relationship between body mass index/body composition and survival in patients with heart failure. J Am Acad Nurse Pract. 2008;20(6):326-32.

10. Lavie CJ, Milani RV, Ventura HO, Romero-Corral A. Body composition and heart failure prevalence and prognosis: getting to the fat of the matter in the “obesity paradox”. Mayo Clin Proc. 2010;85(7):605-8.

11. Romero-Corral A, Somers VK, Sierra-Johnson J, Thomas RJ, Bailey KR, Collazo-Clavell ML, et al. Accuracy of body mass index to diagnose obesity in the US adult population. Int J Obes. 2008;32(6):959-66.

12. Oreopoulos A, Ezekowitz JA, McAlister FA, Kalantar-Zadeh K, Fonarow GC, Norris CM, et al. Association between direct measures of body

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13. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol. 2003;91(7):891-4.

14. Testa G, Cacciatore F, Galizia G, Della-Morte D, Mazzella F, Langellotto A, et al. Waist circumference but not body mass index predicts long-term mortality in elderly subjects with chronic heart failure. J Am Geriatr Soc. 2010;58(8):1433-40.

15. Clark AL, Fonarow GC, Horwich TB. Waist circumference, body mass index, and survival in systolic heart failure: the obesity paradox revisited. J Card Fail. 2011;17(5):374-80.

16. Gastelurrutia P, Lupón J, Domingo M, Ribas N, Noguero M, Martinez C, et al. Usefulness of body mass index to characterize nutritional status in patients with heart failure. Am J Cardiol. 2011;108(8):1166-70.

17. Wold Health Organization (WHO). Anales da 36ª Reunión del Comité Asesor de Investigaciones en salud. Encuesta multicentrica: salud, bien estar y envejecimiento (SABE) en América Latina y el Caribe; mayo 2001. Washington (DC); 2001.

18. Jelliffe DB. The Assessment of the nutritional status of the community - (with special reference to field surveys in developing regions of the world). Monogr Ser World Health Organ. 1996;53:3-271.

19. Kapoor JR, Heidenreich PA. Obesity and survival in patients with heart failure and preserved systolic function: a U-shaped relationship. Am Heart J. 2010;159(1):75-80.

20. Casas Vara A, Santolaria F, Fernandez-Bereciartúa A, Gonzalez-Reimers E, Garcia-Ochoa A, Martinez-Riera A. The obesity paradox in elderly patients with heart failure: analysis of nutritional status. Nutrition. 2012;28(6):616-22.

21. Romero-Corral A, Somers VK, Sierra-Johnson J, Jensen MD, Thomas RJ, Squires RW, et al. Diagnostic performance of body mass index to detect obesity in patients with coronary artery disease. Eur Heart J. 2007;28(17):2087-93.

References

ConclusionOur results demonstrated that TSF might be a better

predictor of mortality in HF outpatients and reinforced the concept of the obesity paradox. TSF measurement has the advantages of a simple, practical, and low cost method to assess risk and can be easily implemented in clinical practice, if performed by a trained professional.

Author contributionsConception and design of the research: Souza GC;

Acquisition of data: Alves FD, Zuchinali P, Souza GC, Almeida KSM; Analysis and interpretation of the data: Goldraich LA, Rohde LEP, Zuchinali P; Statistical analysis: Goldraich LA,

Zuchinali P; Critical revision of the manuscript for intellectual content: Clausell NO, Souza GC, Rohde LEP, Zuchinali P.



Sources of Funding


Study Association

This study is not associated with any post-graduation program.

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22. Romero-Corral A, Lopez-Jimenez F, Sierra-Johnson J, Somers VK. Differentiating between body fat and lean mass: how should we measure obesity? Nat Clin Pract Endocrinol Metab. 2008;4(6):322-3.

23. Salinas AM, Coca A. Ergo-anthropometric assessment [letter reply]. Mayo Clin Proc. 2009;84(10):941-2.

24. Deurenberg P. Universal cut-off BMI points for obesity are not appropriate. Br J Nutr. 2001;85(2):135-6.

25. Poirier P. Adiposity and cardiovascular disease: are we using the right definition of obesity? Eur Heart J. 2007;28(17):2047-8.

26. Tarastchuk JC, Guérios EE, Bueno Rda R, Andrade PM, Nercolini DC, Ferraz JG, et al. Obesity and coronary intervention: should we continue to use body mass index as a risk factor? Arq Bras Cardiol. 2008;90(5):284-9.

27. Woodrow G. Body composition analysis techniques in the aged adult: indications and limitations. Curr Opin Clin Nutr Metab Care. 2009;12(1):8-14.

28. Durnin JV, Womersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br J Nutr. 1974;32(1):77-97.

29. Goran MI, Driscoll P, Johnson R, Nagy TR, Hunter G. Cross-calibration of body-composition techniques against dual-energy X-ray absorptiometry in young children. Am J Clin Nutr. 1996;63(3):299-305.

30. Wang J, Thornton JC, Kolesnik NS, Pierson RN Jr. Anthropometry in body composition: an overview. Ann N Y Acad Sci. 2000;904:317-26.

31 Bross R, Chandramohan G, Kovesdy CP, Oreopoulos A, Noori N, Golden S, et al. Comparing body composition assessment tests in long-term hemodialysis patients. Am J Kidney Dis. 2010;55(5):885-96.

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

Mailing Address: Antônio Carlos Pereira-Barretto •Rua Piave, 103, Morumbi. Postal Code 05620-010, São Paulo, SP - Brazil E-mail: [email protected], [email protected] received February 04, 2013, revised manuscript July 10, 2013, accepted July 10, 2013.

DOI: 10.5935/abc.20130201

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.

IntroductionHeart failure (HF) is a prevalent and potentially progressive

syndrome and individuals with HF at advanced stages have high morbidity and mortality1,2. The neurohormonal blockade carried out with adequate doses of drugs can modify its natural history; however, it is often suboptimal2-4. Data from clinical trials, HF registries and from patients referred for a second opinion show that often the target doses of drugs with proven efficacy in HF are not prescribed and it is likely that this fact contributes to the possible risk of hypotension, bradycardia and lack of tolerance by patients3,4. In the Euro Heart Survey Programme it was observed that 36.9% of patients with HF had a beta-blocker (BB) prescription and only 17.2% received a combination of diuretics, angiotensin-receptor inhibitors and beta-blockers4.

In advanced HF, even when patients are adequately treated, the mortality rate is still higher than desired, which suggests that new therapeutic approaches should be investigated or implemented1.

Experience shows that the HF treatment is not always easy, as the patients, especially the most severe ones, have reduced blood pressure levels, a clinical finding that may complicate the prescription of several medications. There is, however, evidence that HF treatment specialists and HF Clinics can optimize treatment and obtain better results5,6. Few analyses have been carried out on the quality of HF treatment in Brazil. In InCor, the prescription of drugs was described at the pre-beta-blockers time7.

In search of data on drug prescription and its form, we proposed to analyze the prescription of drugs of proven efficacy in patients with HF, treated in medical offices, by doctors used to treating HF. We aimed to verifying which medications were being prescribed and, among patients receiving BB, how many were receiving target doses of the drugs and clinical features of patients receiving this type of prescription. We also aimed to answer a more recent question: how many patients would have a HR > 70 beats per minute while receiving optimized treatment?

MethodsThe aim of the study was to determine how patients with

HF are treated by cardiologists used to treating this syndrome, especially if the medication doses tested in large clinical trials can be prescribed to these patients and whether they would be well tolerated by patients.

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To perform this research, we evaluated the treatment of patients with HF treated by three cardiologists used to treating this syndrome. From October 2011 to May 2012 a total of 104 patients with HF and left ventricular systolic dysfunction were consecutively enrolled. Patients undergoing HF treatment for more than two months, who 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, blood pressure, heart rate, weight and drug treatment data were assessed, verifying the doses prescribed of different drugs.

The inclusion criteria included patients receiving BB, who had an echocardiogram documenting systolic dysfunction with ejection fraction < 45% on a test performed within six months prior to study enrollment.

Patients were considered to be adequately managed when they were prescribed the three medications that have been proven to modify the natural history of HF: Angiotensin-Converting Enzyme (ACE) inhibitor; or Angiotensin Receptor Blockers (ARBs) II; BB and spironolactone and in those with renal failure, if they received hydralazine and nitrate instead of ACE inhibitor or ARBs. The dose considered correct for ACE inhibitor was 20 mg of enalapril 2x/day or equivalent doses of captopril (150 mg/day) or ramipril (10 mg/day) 2.

For ARBs, the correct dose was considered as 150 mg/ day of losartan. For candesartan, the target dose was 32 mg/day and for valsartan, 320 mg/day 2. For spironolactone, the target dose was 25 mg/day. For beta-blockers, the full dose was considered as 25 mg 2x/day for carvedilol to patients up to 80 kg, 50 mg 2x/day for those with more than 80 kg 2. For bisoprolol, the target dose was considered as 10 mg/day, and for metoprolol succinate, 200 mg/day 2.

We also identified the percentage and prescription dose of digoxin, hydrochlorothiazide, furosemide and amiodarone, medications often prescribed to patients with HF.

For the statistical analysis, considering that the most often prescribed medications were enalapril, losartan and carvedilol, equivalent doses were adopted when the prescribed medications were not one of those.

Statistical Analysis Continuous variables are shown as mean ± standard

deviation and categorical variables as frequencies and percentages. The comparison of treatment among patients who reached the target dose of BB was performed using the 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 using the Kolmogorov-Smirnov test (p > 0.05). Thus, the Student’s t test was used to compare the means of these variables regarding the “target dose” of BB. In the comparison of the characteristics, the chi-square or Fisher’s exact test were used for categorical variables.

The sample size was estimated at 98 patients to determine the mean dose of BB (carvedilol) in the population of patients with HF on optimized treatment, with a confidence interval

of 95% and a variation of ± 3.5 mg in the standard deviation, taking as basis the standard deviation of the mean dose of carvedilol in the SHIFT study8, which was 17.8 mg. Thus, 104 patients were included in the study.

The p values are two-tailed, with a significance level of <0.05.

ResultsThe main characteristics of the study population are shown

in Table 1. As for the treatment, 93.3% received a renin-angiotensin

system blocker and 52.9% an ACE inhibitor and 40.4%, an ARB; all received beta-blockers, with carvedilol being the most often prescribed medication (92.3%). Spironolactone was being prescribed to 69.2% of patients and digoxin, to 16.3% of them.

Table 2 shows the mean dose of prescribed drugs. As for the doses, 82.1% of those treated with an ACE inhibitor received the target dose and 97.1% of those receiving an ARB received a dose that was less than optimal.

As for the BB, 76.0% of the patients were prescribed target doses or higher. In patients over 80 kg, the percentage of patients receiving the target dose of 50 mg 2x/day was 21.6%.

Regarding the ACE inhibitors, the non-prescription of target doses was associated with lower systolic blood pressure (112.6 + 14.5 mmHg vs. 122.7 + 15.1 mmHg, p = 0.0003).

Regarding the beta-blockers, the non-prescription of target doses was associated with the etiology of heart disease, with prescription of doses below the target dose in 82% of patients with Chagas disease. Patients with functional class III and IV also received lower doses of beta-blockers. On the other hand, patients with ischemic heart disease received more often the target doses of beta-blockers (Table 1).

At the HR analysis of patients in sinus rhythm with optimized treatment, it was observed in this population that 36.5% had HR > 70 bpm; of these patients, 71.1% received carvedilol at a dose of 50 mg/day or more (Figure 1). When comparing the clinical characteristics and pharmacological 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 (63.8 ± 8.9 vs. 64.7 ± 6.5 mm, p = 0.426) were similar in both groups. Among the clinical variables, systolic BP differed between the two groups, being lower in the group with HR < 70 bpm (119.2 ± 15.4 vs. 112.8 ± 14.8 mmHg, p = 0.035).

CommentsThe patients analyzed in this cross-sectional cohort received

optimized treatment from the therapeutic point of view, as most were receiving the drugs indicated in the Guidelines for the treatment of HF and the target dose was prescribed and tolerated by most2,9. The data showed that cardiologists used to treating HF can achieve the target doses indicated in the Guidelines for most patients.

The data also showed that these results, regarding quality of

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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

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

Total Beta-blocker

(“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).

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treatment, were better than those usually described in registries and even in some clinical trials4,8,10,11.

In this patient population, the percentage that received a renin-angiotensin system blocker was similar to that described in the registries, with more than 90% of patients receiving such drugs; however, the percentage receiving the target dose was higher in our series4,11 .

As for the spironolactone, the prescription frequency was higher than that observed in the registries and similar to those observed in the most recent clinical trials4,8,10,12. In the ADHERE Registry, aldosterone blockers were prescribed to 34.6%; in the European registry, to 20.5%, and in the SHIFT study, to 60% of cases, and in our series, to 69.2% of cases4,8,10.

As for beta-blockers, all patients were receiving the drug by selection criteria. The prescribed dose was higher than that described in the Registries and even higher than in several clinical trials of these drugs. Citing two recent studies, in the CIBIS - ELD study the mean prescribed dose of carvedilol was 23.9 mg, and 31% received the target dose of 50 mg/day11. In the SHIFT study, the mean dose was 25.0 mg/day and 26% received the target dose, while in our series the mean dose of carvedilol was 49.8 mg/day and 76% received the target dose of 50 mg/day8.

The issue of the BB dose is not fully elucidated, but the MOCHA and REVERT studies and the analyses of CIBS-II, CIBIS-III and SENIORS studies indicate that higher doses result in better outcomes with greater reversal of cardiac dilatation and morbimortality reduction13-17. Analysis of data from the HF-ACTION study of 2012 again confirmed the

importance of higher doses, with patients showing better outcomes when treated with target doses, a more significant result than with lower doses18.

Our results showed that it is possible to administrate the target dose to most patients, while demonstrating that Chagas disease was associated with greater difficulty in prescribing the target doses of beta-blockers. These findings show us that physicians used to treating HF can most often prescribe and achieve the target doses of drugs of proven efficacy in HF2,9. It also showed that Chagas disease, probably due to higher cardiac impairment and clinical forms, makes it difficult to achieve the target doses of these drugs19,20. The higher degree of involvement and nonprescription / no tolerance to target doses may explain the worse outcomes in patients with this disease when they have HF19,20.

There is increasing evidence that the HR can be a good parameter to indicate the quality of treatment, considering that the therapeutic regimen should promote HR reduction, aiming at achieving a HR of around 70 beats per minute or less8,12,21,22. The presence of HR > 70 bpm would be an indicator of the need to review the treatment and optimize it.

The issue of HR and treatment of HF is a controversial one and not fully understood, and its interpretation is necessary to consider different variables. For instance, in Chagas disease and in elderly patients, HF is often lower, and thus cannot be used as a good indicator of treatment quality. Incidentally, this was one of the results of this study, when we observed that the doses of BB prescribed to chagasic patients were lower than those prescribed to nonchagasic ones.

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.

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In recent years, however, evidence started to appear that higher HR would be an important prognostic marker. The BEAUTIFUL and SHIFT studies demonstrated that patients with HR > 70 bpm have a poorer prognosis than patients with lower basal HR8,21. Similar results have been reported in different databases, such as in the CHARM and DIG studies and in case series22-24. These data leave no doubt that HR should be considered an important prognostic factor and should be targeted for treatment, as it has been shown that its reduction with ivabradine resulted in a decrease in hospital admissions due to decompensated HF and from all causes, and reduced HF mortality, with no difference in cardiovascular and all-cause mortality.

In our study, we analyzed the HR in patients after treatment optimization and observed that a third of them, even after receiving full doses of beta-blockers, persisted with basal HR > 70 bpm.

This result is similar to that described in several European HF registries and even clinical trials; there were, however, no Brazilian data on this clinical finding3,4,24,25.

When analyzing our series, we tried to verify whether the clinical characteristics and those related to the treatment of patients could explain this finding of HR > 70 bpm. To analyze the data, we divided the patients into two groups: those with HR > and < 70 bpm. In this comparison, we found no 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 between the prescribed dose of BB and HR of the patient when undergoing stabilized and optimized drug therapy. Our results overlap those observed in the SHIFT study, showing that the observed HR was not associated with the dose of BB that patients were receiving8,12.

Overall, our data and the literature indicate that HF treatment should be individualized. When patients receive treatment instructions, physicians should seek to prescribe drugs of proven efficacy at doses that have shown benefits. We confirmed that the majority of office patients tolerate these doses.

Notwithstanding the optimized treatment, patients persisted with HR > 70 bpm, a finding indicative of worse prognosis, indicating the need for treatment reevaluation and possibly 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 is the one of which effectiveness has been documented, randomly analyzed in a large clinical trial, the SHIFT study8.

Study limitationsThis pilot observational study demonstrated that cardiologists

used to treating HF prescribe medications that have been shown to improve the prognosis of HF, as recommended by the Guidelines; however, we do not know how these patients are treated by most generalists at public health units, and what the impact is on clinical outcomes (prognosis, HF hospitalizations), when comparing the treatment of HF performed by clinicians and cardiologists. Additional studies are needed to understand the treatment of HF in our country.

ConclusionThe results of this analysis showed that, in a population

treated at medical offices, most patients tolerate the drugs of proven efficacy in the treatment of HF and the target doses can be prescribed and are tolerated by most patients. It also showed that about one third of patients with optimized treatment remain with HR > 70 bpm, allowing us to conclude that the treatment could be revised and further optimized. These findings require further investigations to help in the planning of new studies in this area, enabling a better understanding of HF treatment in the real world and thus assist in the care of patients with this malignant and debilitating syndrome, in an attempt to reverse this trend.

Author contributionsConception and design of the research, Acquisition of data

and Critical revision of the manuscript for intellectual content: Moreno IB, Del Carlo CH, Pereira-Barretto AC; Analysis and interpretation of the data, Statistical analysis and Writing of the manuscript: Del Carlo CH, Pereira-Barretto AC.



Sources of Funding


Study Association


1. Barretto AC, Del Carlo CH, Cardoso JN, Morgado PC, Munhoz RT, Eid MO, e cols. Re-hospitalizações e morte por insuficiência cardíaca. Índices ainda alarmantes. Arq Bras Cardiol. 2008;91(5):335-41.

2. Bocchi EA, Marcondes-Braga FG, Ayub-Ferreira SM, Rohde LE, Oliveira WA, Almeida DR, et al.; Sociedade Brasileira de Cardiologia. III Diretriz brasileira de insuficiência cardíaca crônica. Arq Bras Cardiol. 2009;93(1 supl.1):1-71.

3. Komajda M, Lapuerta P, Hermans N, Gonzalez-Juanatey JR, van Veldhuisen DJ, Erdmann E, et al. Adherence to guidelines is a predictor of outcome in chronic heart failure: the MAHLER survey. Eur Heart J. 2005;26(16):1653-9.

4. Komajda M, Follath F, Swedberg K, Cleland J, Aguilar JC, Cohen-Solal A, et al; Study Group on Diagnosis of the Working Group on Heart Failure of the European Society of Cardiology. The EuroHeart Failure Survey programme--a survey on the

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10. Fonarow GC, Heywood T, Heidenreich PA, Lopatin M, Yancy CW; ADHERE Scientific Advisory Committee and Investigators. Temporal trends in clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 to 2004: findings from Acute decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2007;153(6):1021-8.

11. Düngen HD, Apostolovic S, Inkrot S, Tahirovic E, Töpper A, Mehrhof F, et al; CIBIS-ELD investigators and Project Multicentre Trials in the Competence Network Heart Failure. Titration to target dose of bisoprolol vs carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail. 2011;13(6):670-80.

12. Swedberg K, Komajda M, Bohm M, Borer J, Robertson M, Tavazzi L, et al; SHIFT investigators. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of betablocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol. 2012;59(22):1938-45.

13. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation. 1996;94(11):2807-16.

14. Colucci WS, Kolias TJ, Kirkwood FA, Adams KF, Armstrong WF, Ghali JK, Gottlieb SS, et al; REVERT Study Group. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with toprol-XL (REVERT) trial. Circulation. 2007;116(1):49-56.

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17. Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J, et al; SENIORS Investigators. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J. 2005;26(3):215-25.

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21. Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807-16.

22. Castagno D, Skali H, Takeuchi M, Swedberg K, Yusuf S, Granger CB, et al; CHARM Investigators. Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program. J Am Coll Cardiol. 2012;59(20):1785-95.

23. The effect of digoxin on mortality and morbidity in patients with heart fai lure. The Digitalis Investigation Group. N Engl J Med. 1997;336(8):525-33.

24. Cullington D, Goode KM, Clark AL, Cleland JG. Heart rate achieved or beta-blocker dose in patients with chronic heart failure: which is the better target? Eur J Heart Fail. 2012;14(7):737-47.

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Original Article

Mechanical Dyssynchrony is Similar in Different Patterns of Left Bundle-Branch BlockRodrigo 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 SousaInstituto Dante Pazzanese de Cardiologia, São Paulo, SP - Brazil

Mailing Address: Rodrigo Bellio de Mattos Barretto •Rua Alagoas, 134, apt.º 91, Higienópolis. Postal Code 01242-000, São Paulo, SP - BrazilE-mail: [email protected], [email protected] received November 06, 2012; manuscript revised June 19, 2012; manuscript accepted June 26, 2013.

DOI: 10.5935/abc.20130190

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.

IntroductionHeart failure, a clinical syndrome resulting from structural

and/or functional cardiac dysfunction, is known to be the end stage of several cardiopathies. Electrocardiographic alterations, such as left bundle-branch block (LBBB), are common findings in patients with heart failure, mainly in the presence of systolic dysfunction1,2.

Currently, there are several treatment options for heart failure. One efficient alternative is cardiac resynchronization therapy3

(CRT). The indication for implantation of a resynchronizing pacemaker is based on clinical and electrocardiographic criteria, and echocardiographic data. On the electrocardiogram, QRS

complex enlargement, as observed in LBBB, is the most frequent indication for that treatment4-6. However, treatment failure has been reported in approximately 30% of the cases in several series3.

In addition to the already known classic information, such as left ventricular dimension and ejection fraction, echocardiography allows the analysis of interventricular and intraventricular synchronism, which is the focus of CRT. Different methods, using several echocardiographic techniques, have been used to detect and stratify dyssynchrony7,8, enabling predicting those who will have good results with a certain treatment.

Left bundle-branch block can have different characteristics related to higher morbidity and mortality9,10. The relationship 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.

ObjectivesThis s tudy a imed at compar ing convent iona l

echocardiographic findings and those of ventricular synchrony related to different LBBB morphologies in patients with left ventricular systolic dysfunction.

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

MethodsThis study was approved by the Committee on Ethics and

Research of the Instituto Dante Pazzanese de Cardiologia.

Study populationThis study assessed individuals followed up on an

outpatient basis for heart failure treatment, who were referred to the echocardiography section with systolic dysfunction characterized by ejection fraction below 40%, according to the Simpson’s method. All patients had sinus rhythm and LBBB11. Patients with the following characteristics were excluded: under the age of 18 years; wearing a pacemaker; and those who had undergone previous valvular surgery or had any degree of aortic valvulopathy. The clinical data concerning functional class, history and medications used were also assessed.

ElectrocardiogramTwelve-lead electrocardiography was performed.

The PR intervals and QRS complexes were measured, and the frontal axis characteristics were assessed. The patients were classified into two groups according to the presence of QRS interval > 150 ms or left electrical axis deviation in the frontal plane, i.e., frontal axis values < –30°.

EchocardiogramEchocardiogram was performed on a Vivid7® device (GE

Vingmed, System VII, Horton, Norway). The images were acquired as digital clips. Then, linear and two-dimensional measures were taken according to the American Society of Echocardiography guidelines, using a mean of three consecutive cycles on a EchoPAC PC work station, version 6.0.1® (GE Vingmed Ultrasound). Diastolic function was also characterized according to the American Society of Echocardiography guidelines, and mitral valve regurgitation was quantified12,13.

Interventricular dyssynchrony was assessed as the difference between pre-ejection intervals, i.e., from the beginning of the QRS complex to the beginning of the ventricular ejection into the aortic and pulmonary valves, using pulsed Doppler; interventricular dyssynchrony was considered to exist when that value exceeded 40 ms14,15. According to the literature, mechanical intraventricular dyssynchrony has been assessed by use of several methodologies, whose cutoff points have been described as markers of successful CRT. The analysis was performed according to the following criteria: 1) septal-to-posterior wall motion delay, in M mode, > 130 ms, as reported by Pitzalis et al16; 2) greater interval between maximum systolic motion of six left ventricular basal segments > 110 ms, measured on tissue Doppler, as demonstrated by 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 positive criterion of the Saint Mary Hospital score, United Kingdom, as reported by Lane et al19; 5) positive criteria for the presence of dyssynchrony, as established by Cleland et al14, in the CARE-HF study; 6) standard deviation of

the maximum motion times, measured on tissue Doppler maging, in 12 left ventricular segments > 32 ms, proposed by Yu et al7; 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) interval values > 100 ms of the end of mitral ring systolic motion in four segments measured on tissue Doppler imaging, as reported by Perez de Isla et al21, in the Spanish Ventricular Asynchrony Registry - RAVE; 9) interval between the maximum contraction of the anteroseptal and posterior segments > 130 ms measured by use of two-dimensional strain associated with the interval of the septal-to-lateral wall maximum systolic motion on tissue Doppler > 60 ms, as demonstrated by Gorcsan et al22

Statistical analysisThe quantitative variables were described as mean ±

standard deviation, and the qualitative ones, as percentages. For comparing the different LBBB presentations, the following tests were used: Student t test; Wilcoxon test; chi-square test; and Fisher exact test. The JMP8.0® software (Institute Inc., Carry, North Carolina) was used for calculation. The significance level of 5% was adopted.

ResultsTable 1 shows the clinical characteristics of the

48 patients studied, with approximately 90% of them on beta-blockers and angiotensin-converting-enzyme inhibitors/angiotensin-receptor blockers. Table 2 shows their electrocardiographic findings. Table 3 shows their echocardiographic variables, with varied degrees of intraventricular dyssynchrony according to the criteria used.

When patients were compared according to their different LBBB morphologies, QRS duration > 150 ms and electrical axis in the frontal plane −30° did not relate to differences concerning sex, age, history, functional class or medication used, as shown in Tables 4 and 5.

Regarding echocardiographic findings, patients with QRS duration > 150 ms showed greater left ventricular linear dimensions and volumes, greater left atrial diameters and lower ejection fraction, as shown in Table 4.

Patients with left electrical axis deviation in the frontal plane, < −30°, showed greater left atrial diameters associated with higher grades of left ventricular diastolic dysfunction, and greater left ventricular diameter, as evidenced in Table 5.

The presence of interventricular and intraventricular dyssynchrony was similar in the two groups of LBBB (longer QRS interval duration and left electrical axis deviation in the frontal plane) (Tables 4 and 5).

DiscussionThe different LBBB presentations assessed do not

allow identifying a dyssynchrony pattern, and their prevalences did not differ in the different echocardiographic methodologies assessed.

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However, the LBBB patterns relate to left ventricular morphologic and functional alterations, in which longer QRS complex durations associate with greater left ventricular dimensions, and the left electrical axis deviation on electrocardiogram relates to greater diastolic dysfunction and greater left atrial dimension.

Those findings are in accordance with the study by Das et al23, who have shown that left ventricular ejection fraction is more impaired when the QRS duration is increased in patients with LBBB, but it is not associated with left electrical axis deviation. However, according to Dhingra et al24, the higher incidence of events in patients with LBBB and left electrical axis deviation should be associated with greater diastolic dysfunction, which is known to relate to mortality25.

Although not all patients meet the criteria proposed by the last guidelines for implantation of resynchronizing pacemakers5, those indications have been modified, and most patients studied constitute a group candidate for CRT, including patients with ejection fraction < 40%5,26. Findings might indicate lack of relationship between longer QRS intervals in LBBB and the response to that type of treatment27, because the prevalence of mechanical dyssynchrony is similar regardless of the echocardiographic method used.

Despite the limitations of using echocardiography as the method for selecting candidates for pacemaker implantation with evidenced capacity of resynchronization on the PROSPECT study28, most of the methods used proved to distinguish patients who would benefit from that therapy. Single center studies have reported several echocardiographic methods that evidenced a better response to that therapy.

Sweeney et al29 have shown that the conventional electrocardiographic report in patients with LBBB, such as QRS duration and the presence of left electrical axis deviation, are not enough to predict individuals who will have echocardiographic improvement after cardiac resynchronization by use of pacemaker. However, electrocardiographic evidence of longer left ventricular 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 compared those electrocardiographic findings with the echocardiographic assessment of mechanical synchrony. That relationship can be tested in a further study.

ConclusionIn the two different electrocardiographic patterns of LBBB

analyzed with ten echocardiographic methods, no difference regarding the presence of mechanical dyssynchrony was observed. They can, however, be associated with known risk patterns, such as a reduced ejection fraction and greater diastolic dysfunction grades.

Author contributionsConception and design of the research: Barretto RBM,

Piegas LS, Moreira DA, França FF; Acquisition of data: Barretto RBM, Melo Neto JF, Resende TU; Analysis and interpretation of the data: Barretto RBM, Piegas LS, Assef JE, Melo Neto JF, Resende TU, Moreira DA, França FF; Statistical analysis and Obtaining funding: Barretto RBM; Writing of the manuscript: Barretto RBM, Piegas LS, Assef JE; Critical revision of the manuscript for intellectual content: Barretto RBM, Assef JE, LeBihan DC, Meneghelo RS, Sousa AGMR.

Table 1 – Clinical characteristics of the patients

Clinical characteristics/

Age (years) 59.9 ± 11.1

Male sex 50%

History

Arterial hypertension 62.4%

Coronary artery disease 26.0%

Previous myocardial infarction 22.5%

Diabetes mellitus 16.5%

Chagas’ disease 6.1%

Functional class (NYHA)

I 9.5%

II 47.6%

III 42.8%

Medications used

Digitalis 39.6%

Loop diuretics 81.3%

Spironolactone 79.2%

Angiotensin-converting-enzyme inhibitor 56.3%

Angiotensin receptor blocker 31.3%

Beta-blocker 89.6%

Calcium channel blocker 6.3%

Nitrate 12.7%

NYHA: New York Heart Association.

Table 2 – Electrocardiographic (ECG) characteristics

ECG measures

Heart rate (bpm) 72.3 ± 14.2

PR interval (ms) 232.8 ± 58.9

QRS width (ms) 165.0 ± 28.1

Frontal ECG axis (º) −2.3 ± 45.8

Pattern (%)

QRS > 150 ms 66.7%

Frontal ECG axis between −30º and +90º 54.2%

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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%

Perez de Isla et al21Criterion I 60.4%

Criterion II 41.7%

Gorcsan et al22 66.0%


reported.


Study Association

This article is part of the thesis of doctoral submitted by Rodrigo Bellio de Mattos Barretto, from Universidade de São Paulo.

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


VariableQRS interval

p value≤ 150 ms(n = 16)

> 150 ms(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%


Interval between pulmonary and aortic pre-ejective periods > 40 ms 68.8% 75.0% ns


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

Perez de Isla et al21Criterion I 62.5% 59.4% ns

Criterion II 43.4% 40.6% ns


ns: non-significant, p > 0.05.

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


VariableAxis in the frontal plane

p valuebetween – 30º and +90º(n = 26)

< – 30º(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%


Interval between pulmonary and aortic pre-ejective periods > 40 ms 76.9% 68.2% ns


Criteria ns

Pitzalis et al16 63.7% 55.6% ns

Notabartolo et al17 34.6% 27.3% 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

Perez de Isla et al21Criterion I 53.9% 66.2% ns

Criterion II 42.3% 40.9% ns


ns: non-significant, p > 0.05.

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17. Notabartolo D, Merlino JD, Smith AL, DeLurgio DB, Vera FV, Easley KA, et al. Usefulness of the peak velocity difference by tissue Doppler imaging technique as an effective predictor of response to cardiac resynchronization therapy. Am J Cardiol. 2004;94(6):817-20.

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References

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Criteria for Mitral Regurgitation Classification were inadequate for Dilated CardiomyopathyFrederico 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

Mailing Addres: Frederico José Neves Mancuso •Rua Domiciano Leite Ribeiro, 51, Apto. 13 - bloco 2, Vila Guarani. Postal Code 04317-000, São Paulo, SP - BrazilEmail: [email protected], [email protected] Manuscript received January 15, 2013; revised manuscript May 10, 2013; accepted June 07, 2013

DOI: 10.5935/abc.20130200

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.

IntroductionFunctional mitral regurgitation (MR) is the secondary

MR to left ventricle (LV) dilation1 and it is often shown in patients with dilated cardiomyopathy (DCM), where the significant MR occurs in 35-50% of patients with chronic heart failure2. It has already been shown that presence and severity of a functional MR are independently associated with the prognosis in patients with non-ischemic DCM3-5.

The functional MR pathophysiology is different from that of the MR by primary valvular disease. Functional MR is the

result of a complex phenomenon, with displacement of the papillary muscles caused by LV dilation, valve ring dilatation and tethering of the mitral valve1,6-8. Furthermore, in patients with DCM, the left atrium works as a low resistence chamber to which the LV can eject blood9.

Although some authors support mitral valve surgery for patients with significant functional MR and heart failure, it is still controversial the suggestion for surgery in these patients10-12. Currently, mitral valve surgery is considered as Class IIb for patients with refractory heart failure and 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 American Society of Echocardiography (ASE), together with the European Society of Cardiology Working Group for evaluation and classification of primary valvular insufficiency by Doppler echocardiography14 are suitable for patients with functional MR and DCM. Additionally, the different methods using Doppler echocardiography and color flow mapping were validated in clinical studies

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for patients showing different causes of primary MR15, but not specifically for patients with DCM.

This study aimed to evaluate the agreement for patients with DCM, among the four most commonly used echocardiographic methods for MR classification.

Methods

PatientsThis study included 90 consecutive outpatients with

non-ischemic DCM and functional MR of a tertiary center for treatment of heart failure and cardiomyopathies, of the Escola Paulista de Medicina / Universidade Federal de São Paulo, from September 2007 to September 2009. Inclusion criteria were: age ≥ 18 years old, functional class ≤ III (New York Heart Association), medical treatment optimized for heart failure, sinus rhythm, LV ejection fraction ≤ 0.40 (Simpson method modified) and good quality image. Patients with primary valvular disease, hypertension, coronary artery disease (for epidemiology and/or coronary angiography), end stage renal disease or chronic obstructive pulmonary disease were excluded. All participants signed an informed consent and the institution of ethics committee approved the project.

EchocardiographyAll subjects performed a ful l two-dimensional

echocardiography by using the IE 33 machine (Philips, Andover, Massachusetts), equipped with a 2-5 MHz transducer and under continuous electrocardiographic monitoring. Patients were assessed in left lateral decubitus by an echocardiograph qualified-physician, only. LV ejection fraction was calculated using the Simpson method modified.

Mitral Regurgitation Echocardiographic Assessment MR was assessed by four echocardiographic methods that

are part of the recommendations of the American Society of Echocardiography14: area of the regurgitant jet (RJ), vena contracta (VC), effective regurgitant orifice area (ERO) and regurgitant volume (RV) by the converging flow method (PISA). All methods were assessed at the apical window using image zoom.

RJ was measured in the apical 4-chamber view using Nyquist limit of 50-60 cm/s, the color gain adjusted to exclude artifacts from non-mobile structures (Figure 1). VC was measured in the apical 4-chamber view as the narrowest MR jet, after the orifice (Figure 1).

The converging flow method (proximal isovelocity surface area; PISA) was used to calculate the ERO and RV. PISA radius was measured using the Nyquist limit at which the flow convergence assumed a hemispherical shape (Figure 1). ERO was calculated using the formula: 2 x π x R2 x V aliasing / V peak (R: radius, in cm; V aliasing: proximal flow convergence velocity in cm/s, V peak: MR maximum velocity in cm/s). RV was calculated using the formula: ERO x VTI (VTI: MR jet velocity time integral).

The IM was classified as mild, moderate or important using each of the methods described according to the criteria and cutoff values of the recommendations of the American Society of Echocardiography14. MR was also divided into terciles (lower, intermediate and higher values) according to the absolute values obtained by each method.

Statistical AnalysisStatistical analysis was performed using the SPSS 13.0

software (SPSS Inc., Chicago, Illinois). Continuous data are shown as mean ± PD and categorical data are described in percentages. Pearson correlation coefficient was used to assess the correlation between the absolute values of the four methods used for MR quantification. Kappa agreement test was used to assess the agreement between methods used to classify the MR. Significance values of p < 0.05 were considered.

Results

Clinical DataPatient clinical basal characteristics are detailed in Table 1.

From the total 90 patients, 60 (67%) showed idiopathic 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 metoprolol 24%, 178 ± 43 mg/day), ACE inhibitors (captopril 62%, 133 ± 24 mg/day, and enalapril 38%, 31 ± 10 mg/day), and furosemide (97 ± 62 mg/day). Eighty-one (90%) patients were on spironolactone and 20 (22%) were taking digoxin.

Doppler echocardiographyDoppler 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 18.0 ± 7.9 and the mean systolic pulmonary pressure was 44 ± 13 mmHg.

Mitral Regurgitation - Echocardiographic Data The mean values for each method were: RJ: 6.8 ± 4.1 cm2,

VC: 0.44 ± 0.15 cm; ERO: 0.14 ± 0.10 cm2, and RV: 22.1 ± 15.3 ml (Table 3). The MR jets were central in all patients, as expected. Pearson calculated correlation coefficient (r) indicated a strong correlation between the absolute values of each method, ranging from 0.70 to 0.95 (p < 0.01) (Figure 2).

According to the cutoff values of the recommendations of the American Society of Echocardiography, MR was classified by the RJ method as mild in 26 patients, moderate in 44 patients and important in 20 patients. Through the VC, MR was considered mild in 12 patients, moderate in 72 patients and important in 6 patients. Through the ERO, 70 patients showed mild MR, 15 patients moderate MR and 5 patients important MR. Through the RV, MR was mild in 70 patients, moderate in 16 patients and important in 4 patients (Figure 3). The agreement among the four methods evaluated was poor (kappa = 0.11, p <0.01).

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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.

Twenty patients with important MR by the RJ showed the same LV ejection fraction as the other patients (28.04 ± 5.21 vs. 31.01 ± 7.79, p = 0.11).

The absolute values of each method were divided into terciles: 30 lower values, 30 intermediate values and 30 higher values (Figure 4). The cutoff values that divided the terciles were different from the cutoff values of the American Society of Echocardiography. With the cutoff values used to divide into terciles for the MR classification in each method, we observed a better agreement among the methods (kappa = 0.44, p <0.01). Figure 5 shows the MR classification box-plots according to the cutoff values of the American Society of Echocardiography and the terciles.

DiscussionThe main finding of this study is the poor ruim agreement

among the quantitative echocardiographic methods for MR classification in patients with DCM, using the criteria and cutoff values of the American Society of Echocardiography. The MR evaluation and classification remains a challenge, even in patients with primary valvular disease, which has been the reason for recent publications15-18. This is the first study to address the MR classification by different echocardiographic methods in patients with DCM. A previous study, which

Table 1 – Patient Basal Clinical Features

N = 90 patients

Age (years) 53 ± 11

Male (%) 70

BSA (kg/m²) 1.73 ± 0.17

HR (bpm) 69 ± 12

SBP (mmHg) 109 ± 20

DBP (mmHg) 69 ± 14

Cardiomyopathy 60 (67%)

Idiopathic Dilated

Cardiomyopathy (%) 30 (33%)

Chagas (%)Functional Class (NYHA) 2.2 ± 0.6

FC I 7 (8%)

FC II 55 (61%)

FC III 28 (31%)

Values expressed as mean ± standard deviation or frequency (%).BSA: body surface area; FC: functional class; HR: heart rate; NYHA: New York Heart Association; DBP: diastolic blood pressure; SBP: systolic blood pressure.

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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.

included patients with myxomatous or rheumatic etiology MR, unlike our study, showed a good agreement between the quantitative echocardiographic methods15.

Although we have observed a good correlation between the absolute values of each method, there was a poor agreement in the MR classification. The highest correlation was between the ERO and RV, as expected, since both measures derives from PISA method. These findings suggest that the main reason for the poor agreement between the methods is that, although the cutoff values of the American Society of Echocardiography are appropriate for patients with primary valvular disease15, they are inadequate for patients with functional MR and DCM. The best agreement observed when using different cutoff values, based on the division into terciles, reinforces this hypothesis. Further studies are required to establish specific cutoff values for the classification of functional MR in patients with DCM.

Functional Mitral Regurgitation: Echocardiographic Assessment Mechanisms

Differences between the pathophysiological mechanisms of primary and functional MR6,7, as well as particularities of

Table 2 – Doppler echocardiography data

N = 90 patients

LA Diameter 46 ± 6 mm

LAVi 54 ± 19 ml/m2

LVEDV 273 ± 100 ml

LVESV 194 ± 84 ml

LVEF 30.4 ± 7.4 %

E Wave Velocity 79.5 ± 29.7 cm/s

A Wave Velocity 65.6 ± 31.9 cm/s

E/A ratio 1.4 ± 1.5

Restrictive filling standard 27 %

e’ septal Wave Velocity 4.8 ± 1.8 cm/s

E/e’ ratio 18.0 ± 7.9

PASP 44 ± 13 mmHg

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 ventricle end-diastolic volume; LVESV: left ventricle end-systolic volume.

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.

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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 to the discrepancies in the MR classification observed in this study.

The structural changes that occur in the mitral valve apparatus are different among patients with MR and those with primary MR and those with functional MR by DMC. In functional MR, there is a posterolateral and apical displacement of the papillary muscle, apical tethering of the valve cusps, and reduced mobility19. Recently, with the use of three-dimensional transesophageal echocardiography, Matsumara et al. demonstrated that PISA geometry is different for patients with DCM, where the converging flow zone radius is longer in functional MR, when compared to the MR per mitral valve prolapse. The authors also observed that PISA method underestimates the ERO in functional MR16. Previously, an in vitro study demonstrated that ERO underestimates PISA when this is not hemispherical20. These findings, in part, explain the poor agreement between the MR classification methods observed in our study, especially for the exceeding MR classified as mild by ERO and RV.

Particular technical aspects of Doppler echocardiography for each of the methods used for MR quantification should also be considered. The frequency of the transducer and color gain adjustment may influence the RJ, where the method is considered less accurate14,21. In patients with DCM, lower LV ejection fraction may also affect the RJ. VC may modify with changes in hemodynamic conditions and it is different at several times in the cardiac cycle21. Furthermore, VC intermediate values do not necessarily correspond to moderate MR, since there is a significant overlap of values with this method14. In our study, VC classified MR

classified as moderate in most patients, which may also have contributed to the observed poor agreement between the methods. ERO and RV by the PISA method may be less accurate in patients with DMC due to non-circular ERO that occurs in functional MR, besides the irregular shape of the convergence flow zone in these patients16. It was recently shown that ERO and RV calculated by echocardiography are underestimated when compared to these parameters obtained by three-dimensional echocardiography and nuclear magnetic resonance22. Therefore, the PISA method may underestimate ERO and RV in patients with DCM and functional MR, which explains the fact that few patients in our study have important MR presented according to the ERO and RV methods.

The evaluation of left atrial and LV dimensions provide important data for the classification of primary MR14. However, in patients with DCM, the dimensions of these heart chambers do not provide indirect information about MR severity, since the expansion of these cavities is primarily by their own cardiomyopathy.

The criteria for the MR classification have not been validated for patients with functional MR and DCM. Although some previous studies have considered different cutoff values for MR classification by the ERO method in patients with heart failure, these values were chosen arbitrarily23,24. Furthermore, only patients with functional MR by ischemic cardiomyopathy were included in these, condition with MR different mechanisms from those of the nonischemic DCM. Also, MR was classified only as important and not important by these authors23,24, unlike our study in which MR was classified as mild, moderate or important, according to the recommendations of the American Society of Echocardiography14.

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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 values of each method, associated with the poor agreement in the MR classification when cutoff values of the American Society of Echocardiography are used together with the previous study, which showed a good agreement in the primary MR classification, reinforces the hypothesis that the cutoff values for MR classification, although appropriate in primary mitral valve diseases, are inadequate to classify the MR in DCM patients.

Clinical Implications The MR classification in patients with heart failure and

DCM is important, since the MR degree has prognostic and therapeutic value25,26. The functional MR is associated with LV volume overload and remodeling26. Additionally, the MR contributes to the increase in LV filling pressures and in pulmonary pressure27. The MR classification has a role for therapeutic decisions in the clinical practice. MR decreases with the clinical treatment of heart failure and is associated with the improvement in LV hemodynamic

conditions, and has been used as one of the criteria for response to cardiac resynchronization therapy28.

Patients with refractory symptoms of heart failure and important MR may be eligible for MR surgical treatment. However, clinical studies evaluating mitral valve surgery in these patients showed controversial results10-12. These findings may reflect the difficulty in classifying the MR, which consequently makes the selection of appropriate patients for surgery difficult.

Findings of this study reinforce the need to integrate the results of multiple echocardiographic methods used in the MR classification. Moreover, it is necessary to establish new cutoff values for MR classification, specific to patients with functional MR and DCM, since the correct MR classification is important for their clinical management. In cases where the two-dimensional transthoracic echocardiography provides conflicting data for MR assessment, the transesophageal echocardiography is recommended for a better assessment of the MR degree29. Another possibility in cases of disagreement between methods is the use of three-dimensional echocardiography, which seems to be a promising method for assessment of mitral regurgitation

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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 the regurgitant volume directly, but such measures still need validation29. A better MR classification can improve the selection of patients to surgical treatment of functional MR. In the near future, with the MR percutaneous techniques advances, treatment indication for invasive functional MR must increase, where it is essential that a reliable MR degree classification is available for patient selection.

LimitationsA gold standard test for comparison of the MR classification

such as cardiac angiography or MRI was not used, but actually, there is no true gold standard test for the MR assessment18, which makes the MR classification by echocardiography even harder, especially when several methods are available and different 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 patient, as well as the use of medications that modify these loading/hemodynamics conditions14.

The study could not establish a new cutoff value for MR classification in this specific population. The division of values

into terciles was only used to test whether the discrepancy was due to the inadequacy of the methods or whether it was due to the cutoff values recommended for MR classification. A long-term prospective study is required, designed specifically for this purpose, comparing the MR assessment by other imaging methods (angiography or magnetic resonance imaging), in order to establish new cutoff values for MR classification in DCM patients.

ConclusionThe echocardiographic criteria for MR classification are

in disagreement with patients with DCM. It is essential to integrate multiple methods in the MR assessment and establish new cutoff values for MR classification for this specific population, since the correct MR assessment has therapeutic and prognostic implications to these patients.

Author contributionsConception and design of the research: Mancuso FJN,

Moisés VA, Poyares D, Campos O; Acquisition of data: Mancuso FJN, Almeida DR, Oliveira WA, Brito FS; Analysis and interpretation of the data: Mancuso FJN, Moisés VA,

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2. Allen LA, Felker GM. Advances in the surgical treatment of heart failure. Curr Opin Cardiol. 2008;23(3):249-53.

3. Koelling TM, Aaronson KD, Cody RJ, Bach DS, Armstrong WF. Prognostic significance of mitral regurgitation and tricuspid regurgitation in patients with left ventricular systolic dysfunction. Am Heart J. 2002;144(3):524-9.

4. Trichon BH, Felker GM, Shaw LK, Cabell CH, O’Connor CM. Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure. Am J Cardiol. 2003;91(5):538-43.

5. Patel JB, Borgeson DD, Barnes ME, Rihal CS, Daly RC, Redfield MM. Mitral regurgitation in patients with advanced systolic heart failure. J Card Fail. 2004;10(4):285-91.

6. Otsuji Y, Handschumacher MD, Schwammenthal E, Jiang L, Song JK, Guerrero JL, et al. Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation. 1997;96(6):1999-2008.

7. Kwan J, Shiota T, Agler DA, Popovic ZB, Qin JX, Gillinov MA, et al. Geometric differences of the mitral apparatus between ischemic and dilated cardiomyopathy with significant mitral regurgitation: real-time three-dimensional echocardiography study. Circulation. 2003;107(8):1135-40.

8. Kirkpatrick JN, Vannan MA, Narula J, Lang RM. Echocardiography in heart failure: applications, utility, and new horizons. J Am Coll Cardiol. 2007;50(5):381-96.

9. Bach DS. Nonischemic mitral regurgitation and left ventricular dysfunction. In: Lang RM. (editor). Dynamic echocardiography. St Louis, MO: Saunders Elsevier; 2010. p. 81-3.

10. Bolling SF, Deeb GM, Brunsting LA, Bach DS. Early outcome of mitral valve reconstruction in patients with end-stage cardiomyopathy. J Thorac Cardiovasc Surg. 1995;109(4):676-82.

11. Wu AH, Aaronson KD, Bolling SF, Pagani FD, Welch K, Koelling TM. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction. J Am Coll Cardiol. 2005;45(3):381-7.

12. DiSalvo TG, Acker MA, Dec GW, Byrne JG. Mitral valve surgery in advanced heart failure. J Am Coll Cardiol. 2010;55(4):271-82.

13. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al; American College of Cardiology Foundation; American Heart Association. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53(15):e1-e90. Erratum in: J Am Coll Cardiol. 2009;54(25):2464.

14. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003;16(7):777-802.

15. Pinheiro AC, Mancuso FJ, Hemerly DF, Kiyose AT, Campos O, de Andrade JL, et al. Diagnostic value of color flow mapping and Doppler echocardiography in the quantification of mitral regurgitation in patients with mitral valve prolapse or rheumatic heart disease. J Am Soc Echocardiogr. 2007;20(10):1141-8.

16. Matsumara Y, Fukuda S, Tran H, Greenberg NL, Agler DA, Wada N, et al. Geometry of the proximal isovelocity surface area in mitral regurgitation by 3-dimensional color Doppler echocardiography: difference between functional mitral regurgitation and prolapse regurgitation. Am Heart J. 2008;155(2):231-8.

17. Marsan NA, Westenberg JJ, Ypenburg C, Delgado V, van Bommel RJ, Roes SD, et al. Quantification of functional mitral regurgitation by real-time 3D echocardiography: comparison with 3D velocity-encoded cardiac magnetic resonance. JACC Cardiovasc Imaging. 2009;2 (11):1245-52.

18. Biner S, Rafique A, Rafii F, Tolstrup K, Noorani O, Shiota T, et al. Reproducibility of proximal isovelocity surface area, vena contracta, and regurgitant jet area for assessment of mitral regurgitation severity. JACC Cardiovasc Imaging. 2010;3(3):235-43.

19. He S, Fontaine AA, Schwammenthal E, Yoganathan AP, Levine RA. Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies. Circulation. 1997;96(6):1826-34.

20. Utsunomiya T, Ogawa T, Doshi R, Patel D, Quan M, Henry WL, et al. Doppler color flow “proximal isovelocity surface area” method for estimating volume flow rate: effects of orifice shape and machine factors. J Am Coll Cardiol. 1991;17(5):1103-11. Erratum in: J Am Coll Cardiol. 1993;21(6):1537.

21. Kizilbash AM, Willett DL, Brickner ME, Heinle SK, Grayburn PA. Effects of afterload reduction on vena contracta width in mitral regurgitation. J Am Coll Cardiol. 1998;32(2):427-31.

22. Hamada S, Altiok E, Frick M, Almalla M, Becker M, Marx N, et al. Comparison of accuracy of mitral valve regurgitation volume determined by three-dimensional transesophageal echocardiography versus cardiac magnetic resonance imaging. Am J Cardiol. 2012;110(7):1015-20.

23. Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation. 2001;103(13):1759-64.

24. Grigioni F, Detaint D, Avierinos JF, Scott C, Tajik J, Enriquez-Sarano M. Contribution of ischemic mitral regurgitation to congestive heart failure after myocardial infarction. J Am Coll Cardiol. 2005;45(2):260-7.

25. Blondheim DS, Jacobs LE, Kotler MN, Costacurta GA, Parry WR. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J. 1991;122(3 Pt 1):763-71.

26. Junker A, Thayssen P, Nielsen B, Andersen PE. The hemodynamic and prognostic significance of echo-Doppler-proven mitral regurgitation in patients with dilated cardiomyopathy. Cardiology. 1993;83(1-2):14-20.

References

Oliveira WA, Campos O; Statistical analysis: Mancuso FJN; Writing of the manuscript: Campos O; Critical revision of the manuscript for intellectual content: Moisés VA, Almeida DR, Paola AAV, Carvalho ACC, Campos O.



Sources of Funding


Study Association

This article is part of the thesis of post doctoral submitted by Frederico José Neves Mancuso, from EPM/UNIFESP - Escola Paulista de Medicina.

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27. Enriquez-Sarano M, Rossi A, Seward JB, Bailey KR, Tajik AJ. Determinants of pulmonary hypertension in left ventricular dysfunction. J Am Coll Cardiol 1997;29(1):153-9.

28. Breithardt OA, Sinha AM, Schwammenthal E, Bidaoui N, Markus KU, Franke A, et al. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol. 2003;41(5):765-70. Erratum in J Am Coll Cardiol. 2003;41(10):1852.

29. Tarasoutchi F, Montera MW, Grinberg M, Barbosa MR, Piñeiro DJ, Sánchez CR, et al; Sociedade Brasileira de Cardiologia. Diretriz brasileira de valvopatias - SBC 2011. / I Diretriz Interamericana de Valvopatias - SIAC 2011. Arq Bras Cardiol. 2011;97(5 supl. 3):1-67.

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

KeywordsHeart Valve Prosthesis Implantation; Fibrinolytic Agents;

Platelet Aggregation Inhibitors; Thromboembolism.

Mailing Address: Andre Rodrigues Duraes •Rua Alberto Silva, 439, Itaigara. Postal Code 41815-000, Salvador, BA - BrazilE-mail: [email protected] , [email protected] received February 27, 2013, revised manuscript June 10, 2013, accepted on 07/02/13.

DOI: 10.5935/abc.20130202

AbstractHeart valve prosthesis unquestionably improve quality of life

and survival of patients with severe valvular heart disease, but the need for antithrombotic therapy to prevent thromboembolic complications is a major challenge to clinicians and their patients. Of the articles analyzed, most were retrospective series of cases or historical cohorts obtained from the database. The few published randomized trials showed no statistical power to assess the primary outcome of death or thromboembolic event. In this article, we decided to perform a systematic literature review, in an attempt to answer the following question: what is the best antithrombotic strategy in the first three months after bioprosthetic heart valve implantation (mitral and aortic)?

After two reviewers applying the extraction criteria, we found 1968 references, selecting 31 references (excluding papers truncated, which combined bioprosthesis with mechanical prosthesis, or without follow-up).

Based on this literature review, there was a low level of evidence for any antithrombotic therapeutic strategy evaluated. It´s therefore interesting to use aspirin 75 to 100 mg / day as antithrombotic strategy after bioprosthesis replacement in the aortic position, regardless of etiology, for patients without other risk factors such as atrial fibrillation or previous thromboembolic event. In the mitral position, the risk of embolism, although low, is more relevant than in the aortic position, according to published series and retrospective cohorts comprised mostly of elderly non-rheumatic patients.

The current evidence is limited to have a consistent and safe level of evidence regarding the best therapeutic strategy. Based on these studies, 75 to 100 mg/day of aspirin is interesting as antithrombotic strategy after implantation of aortic bioprosthesis, regardless of etiology, for patients with no other risk factors such as atrial fibrillation or previous thromboembolic event. As for mitral bioprosthesis, the risk of embolism, although low, is more relevant than in the aortic position, according to published series and retrospective cohorts - usually elderly non rheumatic patients.

IntroductionThe chronic rheumatic heart disease (CRHD) is responsible

for at least 200 to 250 thousand premature deaths each year and is the leading cause of cardiovascular death among children and young adults in developing countries1. Heart valve prosthesis (HVP) unquestionably improve quality of life and survival of patients with severe valvular heart disease, but the need for antithrombotic therapy to prevent possible thromboembolic complications remain a major challenge to clinicians and their patients2.

Since the beginning of its use in the 60s, the bioprosthesis emerged with the expectation of replacing existing metal prosthesis, due to not theoretically requiring permanent oral anticoagulation, a fact justified by their predominant tissue composition, thereby reducing the high thrombogenicity of the prosthesis used until then. However, these prosthesis had a significant negative point: relatively short durability (mean 10-15 years), caused by early structural deterioration that resulted in the need for reoperations, which, in turn, would increase morbidity and mortality3.

The recommendations of the main international consensuses 2,4,5 on ant i thrombot ic therapy a f ter bioprosthesis implantation demonstrate a low level of evidence (Grade C), which may be explained by the lack of randomized trials and scarcity of prospective cohorts representing current diverse therapies, generating considerable variation in behavior between the different services. In Brazil, the main cause of valve disease in children, adolescents and young adults is the CRHD, leading to a high social and economic cost6. In spite of that, the authors of this review do not know any study in the literature that have specifically addressed patients with CRHD in relation to any antithrombotic strategy in the postoperative period of HVP implantation.

Moreover, CRHD has a direct association with poverty and poor health6, creating a vicious circle of recurrent 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 review of the literature in an attempt to answer the following question: what is the best antithrombotic therapy strategy in the first three months after implantation of bioprosthetic heart valve?

Review MethodologyThe Medline, Embase, Cochrane and SciELO databases

were reviewed regarding the period between 1970 and 2012. The terms or keywords used were: heart valve

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prosthesis, bioprosthesis, aspirin or anticoagulants or thromboembolism and bioprosthesis. The search was limited to articles written in English or Portuguese and that referred to humans. The articles identified were assessed by two reviewers. Inclusion criteria were: original articles in English or Portuguese, prospective or retrospective, observational or intervention design, preferably having a control group and sample size > 19 patients.

Articles that included patients with metal prosthesis (alone or in conjunction), articles without abstracts, or articles with incomplete or confusing methodology, not allowing identification of a therapy group, and a control group were excluded.

ResultsUsing the aforementioned methodology, 1,968 references

were found. Of these, after applying the extraction criteria, 31 articles were selected. Found there were only three randomized studies with a total population of 472 patients, in whom different levels of anticoagulation or warfarin (WAR) versus antiplatelet agents were tested. Moreover, two prospective observational studies were found, resulting in a sample of 433 patients. The remaining studies were retrospective and several addressed the combined implantation

of bioprosthesis in the aortic position (BAP) and bioprosthesis in the mitral position (BMP). No study had found a sample that was specific or predominant for patients with CRHD.

Most of the selected articles consisted of retrospective series or historical cohorts extracted from databases. The few published randomized trials showed no statistical power to assess the primary outcome of death or thromboembolic event. The use of several antithrombotic therapies, such as aspirin (ASA), triflusal, ticlopidine or WAR, isolated or combined, hindered data systematization to perform a more homogeneous joint analysis. We chose to divide the studies according to the main therapeutic strategy to facilitate result analysis.

Table 1 shows the list of studies that had no report on the use of any antithrombotic drug strategy after ABP and/or MBP implantation. Tables 2 and 3 show the selected studies that compare WAR with ASA, while Table 4 lists the articles that used ASA or WAR alone, often comparing them with the follow-up without any specific antithrombotic drug therapy.

Therefore, the incidence of thromboembolic events without any specific therapy ranged from 0.011 to 0.900 and 0.01 to 2.3% / person-year when evaluating ABP and MBP, respectively, for a follow up ranging from 6-120 months involving publications 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

Author-Year N Study design and follow-up (months)

Location andincidence of embolic events

(%/person-year)Stipulated therapy Conclusion

(embolic events)

Cohen et al12

1979 323 Retrospective; 84 ABP: 0.55*MBP: 3.9*

NAT: sinus RhythmWAR: AF Low incidence;

Fuster et at13

1982 302 Retrospective; 120 ABP: 0.26#

MBP: 0.30# Not informed P < 0.01; BPM high risk of events;

Ionescu et al14

1982 366 Retrospective; 120 MBP: 0.6 Not used Very low risk

Cohn et al 15

1984 663 Retrospective; 108 ABP: 0.07 Not informed -

Joyce et al16

1984 469 Retrospective; 36.2 ABP: 0.011-0.024MBP: 0.01-0.028 Not informed -

Gallo et al17

1985 189 - ABP: 0.5MBP: 2.3 Not informed

Hartz et al18

1986 589 Retrospective; 38ABP: 208 pctsMBP: 209 pts

Total: 0.3 a 0.8Not informed Low incidence

Gonzalez-Lavin et al19

1988 240 Retrospective; 100 ABP: 0.9 Not used Peak of events between 60-70 months.

Braile et al20

1991 663 Retrospective, 132 MBP: 0.3 - CVA – 0.3%

Babin-Ebell et al21

1995 57 Retrospective. 6 ABP: 0.035–1.75 Not used

Orszulak et al22

1995 561 Retrospective; 42 ABP: 1.57 NAT overall;p = 0.01 Higher risk for the elderly (> 73 years), AF, 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.

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


Location and incidence of embolic events (%/person-year)

Stipulated therapy Conclusion (embolic events)

Louagie et al81993 100 Retrospective; 70 MBP 2.01 overall

0.5 x 1.3 WAR x ASA

Previous MS and AF are predictors of permanent

OA, mechanical prosthesis recommended.

Blair et al23

1994 748 Retrospective; 3

ABP: 378 ptsWAR 2.9ASA: 0.8NAT: 1.5

MBP: 370 pts

WAR x ASA X NAT BPM: WAR reduced events but

increased bleeding;ABP: ASA was similar to WAR;

Heras et al91995 816 Retrospective; 99.6

0-10/10-90/> 90 dABP: 41/3.6/1.9MBP: 55/10/2.4

Warfarin, dipyridamole and aspirin were used;

High risk of thromboembolism on the first 10 days; OA ≥ Reduced risk of embolism from 3.9% to

2.5%;

Aramendi et al24

1998 168 Retrospective; 38.4ABP and MBPTiclopidine 0.5

Warfarin 3

Ti: 137 x WAR 40 x ASA 14 x NAT 18 pts

The first three months are high risk; Ti was superior to WAR.

Guerli et al25

2004 249 Prospective; Observational; 3 ABP WAR 141 x ASA 108 pts Similar incidence in both groups;

Ramos et al26

2004 184 Prospective; Observational; 3APBMBP18.25

ASA 159 and WAR 25 pts Embolism incidence of 18.25%/patient-year

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




Aramendi et al27

2005 193 Prospective, open, randomized, multicenter; 3

ABP 181 ptsMBP 10 pts

Triflusal 600 mg Acenocoumarol INR 2 to 3

Similar reduction in embolism, and less bleeding with triflusal;

Sundt et al28

2005 1151 Retrospective; 3 ABP: 2.4 x 1.9 WAR 624 x ASA 410 pts WAR did not protect against events;

Colli et al29

2007 69 Randomized; Prospective ABP ASA x WAR No statistical difference

Jamieson et al30

2007 1372 Retrospective; ABP ASA x WAR No statistical difference

Colli et al31

2010 99 Retrospective; MBP ASA 51 x WAR 36 x NAT 12 pts No statistical difference

ElBardissi et al32

2011 861 Retrospective; 3 ABP ASA 728 x WAR 133 pts p = 0.67

Brennan et al72012 25.656 Retrospective; 3 ABP ASA 12,457 x WAR 2,999 x

ASA + WAR 5,972 pts

Events:ASA – 1%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 or in combination, for patients who had ABP implantation, there was an incidence of thromboembolic events of 0.8 to 4.8% / person-year and 0.6 to 3.9% / person-year,

respectively. More recently, Brennan et al7 demonstrated, through a retrospective cohort study with large sample size (25,656 patients), that this is the incidence of 1%/person-year for any of the aforementioned therapies.

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




Gonzalez-Lavin et al33

1984 528 Retrospective; 30.5 MBPGroup 1 = 4.6 Group 2 = 0.36

Group 1: WAR < 6 weeks 206 pts; Group 2: > 8 weeks 322 pts

Bovine pericardial bioprosthesis; low risk.

Turpie et al34

1988 210 Randomized; 3 ABPMBP

Group 1: INR 2.5-4.0 108 pts; Group 2: INR 2.0-2.25 102 pts

Less intensive regimen was similar for embolic events and had fewer bleeding episodes.

Orszulak et al10

1995 285 Retrospective; MBP 2.5 Not informedHigh risk of CVA

(40%/ person-year) in the first month;

Goldsmith et al35

1998 145 Retrospective; ABP 0.3 ASAIn the first three months there

was no increased risk of thromboembolism;

Moinuddeen et al36

1998 185 Retrospective; 3 ABP 2.8 x 2.6 WAR 109 x NAT 76 pts Early OA was not effective in reducing embolic events

Brueck et al37

2007 288 Retrospective; Observational; 12 ABP ASA 132 x NAT 156 pts No benefit of ASA

versus nothing;

Duraes et al11 184 Prospective.Observational MBP and ABP ASA 59 x NAT 125 pts Low incidence. No benefit of

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 found a low incidence of thromboembolic events (0.5 and 1.3%/person-year) when compared WAR and ASA, respectively. However, there are Retrospective with an incidence much higher, reaching levels of 55% / person-year in the first 10 days, as Heras et al9 found in 1995.

In the same year, Orszulak et al10 showed an incidence of 40% in the first 30 days postoperatively. Finally, more recently, in 2013, in an article still in press, Duraes et al11 prospectively analyzed a cohort of rheumatic patients in the first three postoperative months after mitral and/or aortic bioprosthetic implantation, showing a rare incidence of embolic events, regardless of being the aortic or mitral bioprosthesis, being even more sporadic in the latter, even when aspirin is compared with no antiplatelet agent, as shown in Tables 2, 3 and 4.

DiscussionCurrent recommendations for antithrombotic therapy

in the first three months following bioprosthetic valve implantation have a low level of evidence, as observed in the studies selected for this article. The American Heart Association/American College of Cardiology (AHA/ ACC)4 recommend the use of ASA as class I and level of evidence C, alone or in combination with WAR (IIa / C), in accordance with the presence or not of some factor risk (atrial fibrillation, previous thromboembolic event, left ventricular dysfunction, and hypercoagulability state). The European Society of Cardiology (ESC)2 and the American College of Chest Physicians (ACCP)5 innovated by recommending the use of ASA (instead of WAR) when the replacement is performed

in the aortic position only, keeping the use of the latter (WAR) for isolated or combined mitral position (IIa/C and II/C, respectively) based on recent studies focused on ABP implantation.

The Brazilian guideline of valve disease - SBC 201138 recommends as Class I and level C, bioprosthesis replacement in patients who have contraindications to the use of vitamin K antagonists (VKA), and use these drugs in patients with atrial fibrillation (Class I and level of evidence B), or within three months after initial implantation of a bioprosthesis (Class IIb and level of evidence B), not specifying whether in the aortic and / or mitral position.

Regarding patients with aortic replacement, Brennan et al7, as already mentioned, published an impressive retrospective cohort consisting mainly of elderly patients. 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 group (1% / person-year), occurring significant reduction in embolic events only when using simultaneous ASA and WAR: 0.6% / person-year, with the number of patients needed to treat (NNT) of 212, benefit was offset by an increase in bleeding rate of almost 3-fold, with the number needed to harm (NNH) of 55, being for the most part, according to the authors, gastrointestinal bleeding with no increase in bleeding into the central nervous system.

Regarding patients with isolated or combined BMP, the most cited reference in the literature is still byHeras et al9 published in 1995, becoming an important negative paper. It was a retrospective and observational study, with database from the Mayo Clinic. The authors showed a high incidence of embolic events in the first 90 days, with 55%/person-year

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1. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet. 2012; 379(9819):953-64.

2. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G, Baumgartner H, et al. tGuidelines on the management of valvular heart disease (version 2012): The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg. 2012;42(4):S1-44.

3. Nowell J, Wilton E, Markus H, Jahanngiri M. Antithrombotic therapy following bioprosthetic aortic valve replacement. Eur J Cardiothorac Surg. 2007;31(4):578-85.

4. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr., Faxon DP, Freed MD. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force

References

in the first 10 days, and 10%/person-year between 10 and 90 days, postoperatively. In univariate analysis, they observed a reduction of 3.9% to 2.5% in the incidence of embolism with WAR use. When analyzing the linear rate of embolism in this same work, it was observed that the benefit of reducing events with anticoagulation was significant in the first 10 days, with no statistical difference (even numerically) within 10 to 90 days postoperatively. In the same year, Orszulak et al10 found in another retrospective observational cohort, a high incidence of thromboembolic events - which reached 40% in the first 30 days in the same scenario. These disappointing results may have discouraged new studies since it seemed clear the need for the use of WAR in the first months after surgery, especially after implantation of BMP. Currently, there are doubts about the real incidence of embolism events after implantation of modern biological prosthesis, especially in patients with CRHD, and about the best antithrombotic strategy postoperatively. Thus, there is a large gap regarding the actual incidence of embolic events with current biological prosthesis, and there are no cohorts that specifically address individuals with CRHD following MBP and ABP implantation.

With this lack of impact studies justifies the low level of evidence the main internationals and Brazilian guidelines. Most studies reported represents individual experiences of referral services in cardiac surgery, performed in the last century, during a natural stage of technological development of prosthesis, different in many aspects of current valve prosthetic devices - theoretically less thrombogenic.

As already said, bioprosthesis have a great advantage over mechanical prosthesis, which is the exemption from continuous use of anticoagulants, in general, the AVK. However, several clinical circumstances do increase the probability of an embolic event postoperatively, even in patients with bioprosthesis, which is a challenge to the clinician and the patient involved in choosing the best antithrombotic strategy (VKA or ASA, alone or combined). This decision always takes into account the pros and cons of such conduct, also due to the difficulty in handling these drugs caused by the need for regular monitoring of the international normalized ratio (INR), which directly influences 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.

It is also noteworthy the fact that patients affected by this disease are different from the group affected by degenerative

or senile valvular heart disease, more prevalent in developed countries. The first (patients with CRHD) are generally younger and thus less likely to have other comorbidities, which are known to increase cardioembolic risk, such as severe left ventricular dysfunction, atrial fibrillation and previous embolic event. Regarding the latter, they are generally elderly patients that commonly have other diseases or risk factors compatible with aging, such as arterial hypertension, diabetes and atrial fibrillation, which causes inevitable increase in surgical risk of death and complications, as well as greater probability of embolic events during follow-up after surgery and greater risk of bleeding during the instituted anticoagulant therapy.

In short, the best antithrombotic strategy to be adopted in the first three months after aortic and mitral replacement is based mainly on the experience of each service, and expert opinion - justify the level of evidence C - due to scarcity of prospective and randomized controlled trials. In BAP the use of ASA is similar to the use of WAR in the elderly patients, and in BMP remains a worldwide trend to WAR use. Patients with CRHD have not been adequately representative in previous studies to date.

Author contributionsConception and design of the research: Durães AR;

Acquisition of data: Durães AR, Durães MAO; Analysis and interpretation of the data: Durães AR, Durães MAO, Correia LC, Aras Junior R; Writing of the manuscript: Durães AR, Durães MAO, Aras Junior R; Critical revision of the manuscript for intellectual content: Correia LC, Aras Junior R.


reported.


Study AssociationThis article is part of the thesis of doctoral submitted by

André Rodrigues Durães, from Universidade Federal da Bahia.

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on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008; 118(15):e523-e661.

5. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH,American College of Chest Physicians. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.2012;141(2 Suppl):e576S-e600S.

6. Barbosa PJB, Müller RE, Latado AL, Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Pediatria. Sociedade Brasileira de Reumatologia. Diretrizes brasileiras para diagnóstico, tratamento e prevenção da febre reumática. Arq Bras Cardiol.2009;93(3 supl.4):1-18.

7. Brennan JM, Edwards FH, Zhao Y , O Brien`S, Booth ME, Dokholyan RS, et al. Early anticoagulation of bioprosthetic aortic valves in older patients: results from the Society of Thoracic Surgeons Adult Cardiac Surgery National Database. J Am Coll Cardiol. 2012; 60(11):971-7.

8. L o u a g i e Y A , J a m a r t J , h t t p : / / w w w. n c b i . n l m . n i h . g o v /pubmed?term=Eucher%20P%5BAuthor%5D&cauthor=true&cauthor_uid=8215671Buche M, Schoevaerdts JC. Mitral valve Carpentier-Edwards bioprosthetic replacement, thromboembolism, and anticoagulants. Ann Thorac Surg. 1993;56(4):931-6.

9. Heras M, Chesebro JH, Fuster V, Penny WJ, Grill DE, Bailey KR, et al. High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol. 1995;25(5):1111-9.

10. Orszulak TA, Schaff HV, Pluth JR , Danielson GK, Riga FJ, Jestrup DM, et al.The risk of stroke in the early postoperative period following mitral valve replacement. Eur J Cardiothorac Surg. 1995;9(11):615-9.

11. Duraes AR, Duraes MAO, Correia LC , Fernandes MAS, Aras Jr R. Impact of aspirin use on the incidence of thromboembolic events after bioprosthesis replacement in patients with rheumatic disease. Rev Bras Cir Cardiovasc. 2013; (ahead of print)).

12. Cohen LH, Koster JK, Mee RB, Collins JJ Jr. Long-term follow-up of the Hancock bioprosthetic heart valve: a 6-year review. Circulation. 1979; 60(2 Pt 2):87-92.

13. Fuster V, Pumphrey CW, McGoon MD, Chesebra JH, Pluth JR, McGoon DC, et al. Systemic thromboembolism in mitral and aortic Starr-Edwards prosthesis: a 10-19 year follow-up. Circulation. 1982;66(Pt 2):1157-61.

14. Ionescu MI, Smith DR, Hasan SS, Chidambaram M, Tandon AP. Clinical durability of the pericardial xenograft valve: ten years experience with mitral replacement. Ann Thorac Surg. 1982;34(3):265-77.

15. Cohn LH. The long-term results of aortic valve replacement. Chest. 1984;85(3):387-96.

16. Joyce LD, Nelson RM. Comparison of porcine valve xenografts with mechanical prosthesis. A 7 1/2 year experience. J Thorac Cardiovasc Surg. 1984; 88(1):102-13.

17. Gallo I, Artinano E, Nistal F. Four- to seven-year follow-up of patients undergoing Carpentier-Edwards porcine heart valve replacement. Thorac Cardiovasc Surg. 1985; 3(6)3:347-51.

18. Hartz RS, Fisher EB, Finkelmeier B, De Boer A, Sanders JH Jr, Moran JM, et al. An eight-year experience with porcine bioprosthetic cardiac valves. J Thorac Cardiovasc Surg. 1986;91(6):910-7.

19. Gonzalez-Lavin L, Amini S, Gonzalez-Lavin J, McGrath LB, Fernandez J, Graf D. Instantaneous risk of events following aortic valve replacement with pericardial valves: a ten-year experience. Tex Heart Inst J. 1988;15(1):31-4.

20. Braile DM, Ardito RV, Greco OT, Lorga AM. IMC bovine pericardial valve: 11 years. J Card Surg. 1991;6(4 Suppl):580-8.

21. Babin-Ebell J, Schmidt W, Eigel P, Elert O. Aortic bioprosthesis without early anticoagulation--risk of thromboembolism. Thorac Cardiovasc Surg. 1995;43(4):212-4.

22. Orszulak TA, Schaff HV, Mullany CJ , Anderson BJ, Ilstrup DM, Puga FJ, et al.Risk of thromboembolism with the aortic Carpentier-Edwards bioprosthesis. Ann Thorac Surg. 1995;59(2):462-8.

23. Blair KL, Hatton AC, White WD, Smith LR, Lowe JE, Wolfe WG, et al. Comparison of anticoagulation regimens after Carpentier-Edwards aortic or mitral valve replacement. Circulation. 1994;90(5Pt 2):214-9.

24. Aramendi JL, Agredo J, Llorente A, Lavirarte C, Pijoan J. Prevention of thromboembolism with ticlopidine shortly after valve repair or replacement with a bioprosthesis. J Heart Valve Dis. 1988;7(6):610-4.

25 Gherli T, Colli A, Fragnito C, Nicolini F, Borrello B, Saccani S, et al. Comparing warfarin with aspirin after biological aortic valve replacement: a prospective study. Circulation. 2004;110(5):496-500.

26. Ramos AI, Magalhaes HM, Maldonado M, Togna DJ, Meneghelo ZM, Arnoni AS, et al. Incidence of intracardiac thrombus and thromboembolism in the first three months after bioprosthetic valve implantation. Arq Bras Cardiol. 2004;83 (Spec N.):46-52.

27. Aramendi JI, Mestres CA, Martinez-Leon J, Campos V, Munoz G, Navas C. Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (trac): prospective, randomized, co-operative trial. Eur J Cardiothorac Surg. 2005;27(5):854-60.

28. Sundt TM, Zehr KJ, Dearani JA, Daly RC, Mullany CJ, McGregor CG, et al.Is early anticoagulation with warfarin necessary after bioprosthetic aortic valve replacement? J Thorac Cardiovasc Surg. 2005;129(5):1024-31.

29. Colli A, Mestres CA, Castella M , Gherli T. Comparing warfarin to aspirin (WoA) after aortic valve replacement with the St. Jude Medical Epic heart valve bioprosthesis: results of the WoA Epic pilot trial. J Heart Valve Dis. 2007;16(6):667-71.

30. Jamieson WR, Moffatt-Bruce SD, Skarsgard P, Hadi MA, Ye J, Fradet GJ, et al. Early antithrombotic therapy for aortic valve bioprosthesis: is there an indication for routine use? Ann Thorac Surg. 2007;83:549-56.

31. Colli A, D’Amico R, Mestres CA, Pomar JL, Camara ML, Ruyra X, et al. Is early antithrombotic therapy necessary after tissue mitral valve replacement? J Heart Valve Dis. 2010;19(4):405-11.

32. ElBardissi AW, DiBardino DJ, Chen FY , Yamashita MH, Cohn LH. Is early antithrombotic therapy necessary in patients with bioprosthetic aortic valves in normal sinus rhythm? J Thorac Cardiovasc Surg.139(5):1137-45.

33. Gonzalez-Lavin L, Tandon AP, Chi S , Blair TC, McFaddon PM, Lewis B, et al. The risk of thromboembolism and hemorrhage following mitral valve replacement. A comparative analysis between the porcine xenograft valve and Ionescu-Shiley bovine pericardial valve. J Thorac Cardiovasc Surg. 1984;87(3):340-51.

34. Turpie AG, Gunstensen J, Hirsh J , Nelson H, Gent M. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet. 1988;1(8597):1242-5.

35. Goldsmith I, Lip GY, Mukundan S, Rosin MD. Experience with low-dose aspirin as thromboprophylaxis for the Tissuemed porcine aortic bioprosthesis: a survey of five years’ experience. J Heart Valve Dis. 1998;7(5):574-9.

36. Moinuddeen K, Quin J, Shaw R , Dewar M, Tellides G, Kopf G, et al. Anticoagulation is unnecessary after biological aortic valve replacement. Circulation. 1998;98(Suppl.19);II95-8.

37. Brueck M, Kramer W, Vogt P, Steinert N, Roth P, Gorlach G, et al. Antiplatelet therapy early after bioprosthetic aortic valve replacement is unnecessary in patients without thromboembolic risk factors. Eur J Cardiothorac Surg. 2007;32(1):108-12.

38. Tarasoutchi F, Montera MW, Grinberg M, Barbosa MR, Piñeiro DJ, Sánchez CRM; et al. Sociedade Brasileira de Cardiologia. Diretriz brasileira de valvopatias - SBC 2011 / I Diretriz Interamericana de Valvopatias - SIAC 2011. Arq Bras Cardiol. 2011; 97(5 supl. 1): 1-67.

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

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

KeywordsAcute Coronary Syndrome; Coronary Balloon Angioplasty;

Myocardial Infarction.

References

DOI: 10.5935/abc.2013218

Dear Editor,Nowadays, the invasive approach plays a crucial role in

the management of acute coronary syndromes, according to the recommendations in clinical practice guidelines. This tendency was reflected in some papers published in Revista Española de Cardiología in 2011 and 2012. Regarding ST-segment elevation acute coronary syndromes, regional programs on primary coronary angioplasty have been developed across Spain. Time delay until reperfusion, however, remains the main drawback of these programs. For instance, Badalona’s experience shows that in only 27% of the patients transferred from other hospitals for primary angioplasty the coronary artery was opened within the time limits recommended in the guidelines, i.e. in less than 2 hours from the first medical contact1. Therefore, fibrinolysis should not be ruled out as an alternative treatment in some cases. Furthermore, data from cardiac magnetic resonance imaging did not evidence significant differences in left ventricular volumes and function between patients treated with primary angioplasty or pharmaco-invasive strategy (initial fibrinolysis followed by routine coronary angioplasty 24 hours later) in a single hospital registry2. Prediction of prognosis is a matter

of concern. The 4 most known prognostic scores (TIMI, PAMI, CADILLAC and GRACE) were compared in patients managed with either primary or rescue coronary angioplasty3. All 4 scores (particularly TIMI, CADILLAC and GRACE) had an excellent accuracy to predict mortality at 30 days and 1 year; prediction of reinfarction or new revascularization, however, was very poor with any score.

The invasive management has been extended to populations previously excluded from this treatment, such as elderly patients. In a retrospective study on very old patients (≥ 85 years) with non-ST-segment elevation acute coronary syndrome, the invasive approach reduced mortality and any ischemic event at 3 years compared with a matched population managed with a conservative strategy4. Despite the favorable results of the invasive strategy in any type of acute coronary syndrome, secondary prevention should not be overlooked. In this sense, the opening of a cardiac catheterization laboratory and the subsequent increase of coronary intervention procedures for myocardial infarction, improved mortality at 30 days but not between 30 days and 2 years after adjusting for ACE inhibitor, beta-blocker and statin treatment5.

1. Rodríguez-Leor O, Fernández-Nofrerías E, Mauri F, Salvatella N, Carrillo X, Curos A, et al. Analysis of Reperfusion Delay in Patients With Acute Myocardial Infarction Treated With Primary Angioplasty Based on First Medical Contact and Time of Presentation. 2011;64(6):476-83.

2. Bodi V, Rumiz E, Merlos P, Nunez J, López-Lereu MP, J Monmeneu JV, et al. One-Week and 6-Month Cardiovascular Magnetic Resonance Outcome of the Pharmacoinvasive Strategy and Primary Angioplasty for the Reperfusion of ST-Segment Elevation Myocardial Infarction. Rev Esp Cardiol. 2011;64(2):111-20.

3. Méndez-Eirin E, Flores-Ríos X, García-López F, Pérez-Pérez AJ, Estévez-Loureiro R, Piñón-Esteban P, et al. Comparison of the Prognostic Predictive

Value of the TIMI, PAMI, CADILLAC, and GRACE Risk Scores in STEACS Undergoing Primary or Rescue PCI. Rev Esp Cardiol. 2012;65(3):227-33.

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 Approach in Non-ST Segment Elevation Acute Coronary Syndrome in Very Elderly Patients. Rev Esp Cardiol. 2011;64(10):853-61.

5. Bosch D, Masia R, Sala J, Vila J, Ramos R, Elosua R, et al. Effect of Opening a New Catheterization Laboratory on 30-Day and 2-Year Survival Rates in Myocardial Infarction Patients. Rev Esp Cardiol. 2011;64(2):96-104.

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

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] received June 22, 2013, revised June 26, 2013, accepted July 25, 2013.

KeywordsAcute coronary syndrome; Football; Alcohlism; Tobacco;

Substance- Related Disorders.

1. Borges DG, Monteiro RA, Schmidt A, Pazin-Filho A. Copa do mundo de futebol como desencadeador de eventos cardiovasculares. Arq Bras Cardiol. 2013;100(6):546-52.

2. Leeka J, Schwartz BG, Kloner RA. Sporting events affect spectators’ cardiovascular mortality: it is not just a game. Am J Med. 2010;123(11):972-7.

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.

4. Roerecke M, Rehm J. Irregular heavy drinking occasions and risk of ischemic heart disease: a systematic review and meta-analysis. Am J Epidemiol. 2010;171(6):633-44.

5. Mittleman MA, Mostofsky E. Physical, psychological and chemical triggers of acute cardiovascular events: preventive strategies. Circulation. 2011;124(3):346-54.

References

DOI: 10.5935.abc.201330219

Dear Editor,The relationship between sports events and ACS

(Acute Coronary Syndrome) has been the subject of some studies in the literature, with controversial results, and was recently addressed by Borges et al1 in the manuscript entitled “World Soccer Cup as a Trigger of Cardiovascular Events,” published in volume 6 of 2013 of ABC. The authors observed a higher incidence of AMI (Acute Myocardial Infarction) in match days of the FIFA World Cup and, in particular, on Brazilian games, concluding that this sporting event can act as a “trigger” of AMI in Brazilians. However, considerations of possible confounding factors and bias should be made to present to readers a better interpretation of the data presented. Firstly, the literature describes that, during sporting events, viewers tend to have numerous risk behaviors for cardiovascular disease, such as the intake of large amounts of alcohol, consumption of fatty food, and use illicit drugs and smoking2,3. These factors have also

been described as possible triggers for ACS4,5, making the association between FIFA World Cup and ACS established in the research of Borges et al1 subject to a number of confounding factors and hindering the interpretation of results. Defining, as the authors intend, if the World Cup could be seen as a direct “trigger” for ACS is not possible or merely if it entails a number of risk conditions already well described in the literature. Furthermore, the use of research findings by observing groups of people to infer causal relationships in individuals may result in ecological fallacy5, since it is not possible to state that all individuals who attended the event were exposed the same way. Therefore, the study design presented by Borges et al1 does not allow the establishment of a direct association between the occurrence of ACS and the FIFA World Cup, and the interpretation of the study results should be performed carefully, taking into account the potential confounding factors and bias of ecological study.

474


Mediano et al.Sports Events and Acute Coronary Syndrome

ReplyWe would like to thank our colleagues who sent this letter,

which has allowed further discussion on this quite intricate subject1. Firstly, we agree to the assertions that, over sport events, viewers tend to have a number of risk behaviors for cardiovascular diseases, such as the intake of great amounts of alcoholic beverages, eating of fatty food, use of illicit drugs and smoking, given that the limitations of our research have been addressed in our discussion. However, it is important to note that the measurement of all possible confounding factors referred to is difficult (illicit drugs, for instance), even in prospective studies, as this may be subject to a biased observation2. We stress the limitations of our data, retrieved from a public database, which restricted the availability of data to protect the individual’s secrecy rights. Another point to be raised is that these potential confounding factors not available in our study may present collinearity with the statement of interests (watching the World Cup and Brazilian matches) and would require a high-cost prospective design to remove all the factors raised3,4.

Regarding the second remark about the problems associated with ecological studies, we believe that they are also properly pointed out in our discussion, as one can see that

“...the exposure may not be uniform (a part of the population may not be watching the match)”.

However, even with the considerations raised and clarified above, although we are not able to definitively confirm a causal association between the games and the occurrence of cardiovascular events, we still can assume that these two factors are related, despite the correction for confounding factors available. Moreover, a simple association, easily identifiable and which may be used immediately can be more useful for health planning than establishing the cause and effect relation from the pathophysiological point of view. Until further information is available and considering everything that has been studied in the literature, this information seems consistent with most other studies, and we believe that our findings should be maintained.

Sincerely,Antonio Pazin Filho

Daniel Guilherme Suzuki BorgesRosane Aparecida Monteiro

André Schmidt

1. Borges DGS, Monteiro RA, Schmidt A, Pazin-Filho A. World soccer cup as a trigger of cardiovascular events. Arq Bras Cardiol. 2013;100(6):546-52.

2. Levine M, Walter S, Lee H, Haines T, Holbrook A, Moyer V. How to use an article about Harm. JAMA.1994;27(20):1615-9.

3. Sorlie P, Wei GS. Population-based cohort studies: still relevant? J Am Coll Cardiol.2011;58(19):2010-3.

4. Sauerbrei W, Royston P, Binder H. Selection of important variables and determination of functional form for continuous predictors in multivariable model building. Stat Med.2007;26(30):5512-28.

References

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


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

KeywordsHeart Failure; Renal Insufficiency; Pulmonary Embolism.

Section Editor: Alfredo José Mansur ([email protected])

Associate Editors: Desidério Favarato ([email protected])

Vera Demarchi Aiello ([email protected])

Mailing Address: Vera Demarchi Aiello •bloco I, Cerqueira César. Postal Code 05403-000, São Paulo, SP - BrazilE-mail: [email protected], [email protected]

Male patient, 73 years old, retired metallurgist, born in Alagoas, residing in Sao Paulo, sought medical attention for dyspnea on minimal exertion.

At his first visit to Instituto do Coração - Incor (18/June/2004) he complained of dyspnea that had begun 28 years before, initially triggered by great exertion; however, in the last two years it had progressed to dyspnea at minimal exertion and for the last month, it occurred even at rest and with orthopnea. These symptoms showed slight improvement with furosemide and digoxin.

He also reported chest pain on exertion, accompanied by sweating and nausea for the last five years before that consultation. The patient underwent a coronary angiography, which showed a 40% lesion in the anterior descending and first diagonal arteries and 50% lesion in the right coronary artery. The left ventricle was normal, with hypertrophic appearance, and he had pulmonary artery hypertension (systolic pressure of 50 mmHg).

The pat ient denied current smoking , a lcohol consumption, arterial hypertension, dyslipidemia and diabetes mellitus. He underwent gastrectomy for peptic ulcer at 43 years of age and reported anemia requiring blood transfusion a month before.

He had a history of alteration in bowel movement with alternating diarrhea and constipation since the age of 69 and had lost 12 kg in recent months.

Physical examination showed a patient weighing 54.3 kg, height 1.68 m, BMI 19.2 kg / m², heart rate of 96 bpm, blood pressure 92 x 50 mmHg, jugular stasis + +/ 4 + at 45°. Pulmonary auscultation showed crackles at the bases; cardiac auscultation showed muffled heart sounds and holosystolic murmur at the lower sternal border; the liver was palpable three centimeters from the right costal margin and there was no edema or signs of poor peripheral perfusion.

Laboratory tests showed: potassium = 5.3 mEq/ L, sodium = 135 mEq / L, creatinine = 2.1 mg/dL, hemoglobin = 11.6 g/dL, hematocrit = 37%, leukocytes = 13,400 / mm ³ and negative serology for Chagas disease.

The ECG (June 15, 2004) showed sinus rhythm, 58 bpm HR, PR 220 ms, SAQRS (-) 20°, dQRS 86 ms, QT 450 ms, first-degree atrioventricular block, ST depression in V5 and V6 (with flattened or inverted T wave, suggestive of digitalis action) (Figure 1). Chest x-ray showed + + / 4 + cardiomegaly.

The digoxin dose was decreased to 0.125 mg; the dose of 40 mg of furosemide was maintained and 12.5 mg of hydrochlorothiazide were added, together with 40 mg of isosorbide and 100 mg of acetylsalicylic acid daily.

Echocardiography (May/2004) showed increased right and left atria, the latter measuring 48 mm, increased septal thickness (16 mm), normal left ventricular ejection fraction (66%) and pulmonary hypertension (pulmonary artery systolic pressure = 65 mmHg).

New laboratory tests were requested, as well as echocardiography, 24-hour Holter assessment and myocardial perfusion scintigraphy. However, they were not performed because the patient sought emergency medical care due to the persistence of dyspnea, onset of nausea and vomiting and increased abdominal volume on July 7, 2004.

Physical examination (July 07, 2004) showed the patient was in good general health status, slightly pale, heart rate of 64 bpm, blood pressure 90 x 60 mmHg; crackles heard at the lung bases; auscultation sounds were arrhythmic, no murmurs; abdomen: the liver was palpable 5 cm below the costal margin, hardened, extending to the epigastrium; bowel sounds were audible and there was no rebound tenderness; there was no lower-limb edema.

Laboratory assessment (07/jul/2004) showed urea = 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, troponin = 0.82 ng/mL and CK-MB = 12.5 ng/mL. ECG (July 07, 2004) showed atrial fibrillation with ventricular rate of 60 bpm, ST depression with flattened or inverted T wave, suggestive of digitalis action (Figure 2).

The diagnoses of heart failure, digitalis intoxication, chronic renal failure with acute worsening of renal function and wasting syndrome were attained.

Digoxin use was discontinued, with volume and dobutamine being administered.

There was improvement in blood pressure, which increased to 100 x 60 mmHg, without worsening of dyspnea, and creatine DOI: 10.5935/abc.20130220

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Politi et al.Anatomoclinical Correlation

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

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 hospitalization. The laboratory evolution is shown in Table 1.

Upper digestive endoscopy (July 20, 2011) showed esophageal tract of normal aspect, caliber and extension and the gastroesophageal junction 40 cm above the upper arch

showed no signs of gastroesophageal reflux or hiatal hernia. In the distal third of the esophagus, there were three fine-caliber varicose veins, bluish, straight and without red spots. The stomach showed good expandability and was reminiscent 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

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preserved pleated mucosa with no significant inflammatory reaction. There were no changes in the anastomotic mouth and segments close to the afferent and efferent loops. In conclusion, there were incipient esophageal varices; normal Billtoth II partial gastrectomy and no hemorrhagic lesions.

The abdominal ultrasonography (July 11, 2004) had disclosed an enlarged liver, with blunt edges and heterogeneous texture with multiple nodular images with irregular borders; ectasia of hepatic veins and inferior vena cava, with no signs of intrahepatic or extrahepatic bile duct dilation and presence of voluminous ascites. The spleen was of normal size. Kidney size was at the lower limit of normal dimensions (right kidney and left kidney measured 8 cm and 9 cm, respectively), with more echogenic texture than the usual and alteration in the corticomedullary ratio - 0.9 cm to the right and 0.9 cm to the left. There were no calculi or hydronephrosis, but there were 1.7-cm simple cortical cysts in the upper pole of the right kidney and smaller ones, of up to 0.8 cm, in the left kidney.

Retroperitoneal visualization was not possible due to excessive intestinal gas.

He received packed RBCs on July 13, 2004. On the 19th, he had abdominal distension. On the afternoon of the 21st, he underwent CRA, resuscitated through reanimation and defibrillation techniques; he was submitted to intubation and was transferred from the Hospital Auxiliar de Cotoxó to Incor ER. The patient developed bradycardia and shock, and after new CRA in asystole, he died at 1 AM on July 22, 2004.

Clinical Aspects This is the case of a 73-year-old patient with hypothyroidism,

coronary artery disease, left ventricular hypertrophy, heart failure with preserved left ventricular ejection fraction and exacerbation of chronic renal failure. The patient’s clinical picture had worsened in the last two years that preceded his last hospitalization, with progressive symptom worsening.

Among the possible causes for such clinical worsening, are: ischemic equivalent, pulmonary thromboembolism and the evolution of the underlying disease, which in this case corresponds to diastolic heart failure with preserved left ventricular ejection fraction. As for the ischemic equivalent, the patient’s episodes of chest pain were not accompanied by typical manifestation of myocardial ischemic disease and additionally, they did not trigger changes in the hemodynamic balance1. Furthermore, the patient had no predisposing risk factors for coronary artery disease2 and the coronary angiography showed no significant coronary lesions. Thus, the hypothesis of an ischemic event is weakened.

Regarding pulmonary thromboembolism, only the patient's age is a risk factor for pulmonary embolism, as observed in epidemiological studies3. Moreover, there was no clinical history consistent with hypercoagulability syndrome with recurrent thrombotic events, although such an association can only be ruled out after specific laboratory investigation for the most prevalent types of thrombophilia in the general population, which are factor V Leiden, hyperhomocysteinemia and antiphospholipid antibody syndrome, in addition to the less prevalent ones such as antithrombin III, protein C and S deficiency4.

Clinical investigation of pulmonary thromboembolism involves echocardiography, perfusion and ventilation pulmonary scintigraphy, Doppler of lower limbs, pulmonary angiography, and in some cases, pulmonary arteriography, although in the present case only the echocardiography was performed. Therefore, there are no data to support this diagnosis.

For the differential diagnosis, systemic diseases that have renal and cardiac involvement (clinical situations that the patient had) were considered, e.g., systemic lupus erythematosus and schistosomiasis, in addition to hepatic neoplasms which, in this case, should be considered because of the patient's age, history of weight loss in recent years and the presence of liver nodules identified by computed tomography. However, there are no data to confirm this diagnosis.

Systemic lupus erythematosus can affect both renal and cardiac function and these may present with heart failure, such as myocarditis and Libman-Sacks endocarditis, but they do not cause diastolic heart failure, as in this case5. The high pulmonary artery systolic pressure (65 mmHg) makes the possibility of constrictive pericarditis caused by lupus even more remote.

Schistosomiasis is another cause of cardiac and renal involvement, with manifestations predominantly in the right heart chambers, pulmonary hypertension and even cor pulmonale6. The clinical picture of the patient, with gastrointestinal disorders, portal hypertension, hepatomegaly, ascites, and marked weight loss contributes to this diagnosis. However, the chronic form of cor pulmonale consists in a combination of right ventricle hypertrophy and dilation secondary to pulmonary hypertension, neither of which was identified in the patient.

As the last and main cause of clinical deterioration of the patient, is the evolution of the underlying disease itself, in this case, diastolic heart failure with preserved left ventricular fraction. Diastolic cardiomyopathy is characterized by changes in ventricular relaxation, with impaired ventricular filling and/or increased filling pressures and increased dependence on the atrial contraction phase7. There is an increase in left atrial pressure and, consequently, in the pulmonary veins and capillaries, as well as a decrease in stroke volume, signs present in this type of heart disease that explain exercise intolerance and even dyspnea at rest, referred by the patient. The evidence of diastolic dysfunction can be obtained from the hemodynamic data, levels of natriuretic peptides, echocardiographic and tissue Doppler data8. Among the main causes of left ventricular diastolic dysfunction are systemic hypertension with left ventricular hypertrophy, aortic stenosis with preserved left ventricular ejection fraction, hypertrophic and restrictive cardiomyopathies and coronary artery disease.

Hypertensive heart disease can be defined as the result of overload imposed to the LV by the increase in arterial pressure and peripheral vascular resistance, which causes structural changes in the LV that manifest as hypertrophy and total stiffness9; however, in this case, the patient did not have systemic arterial hypertension. As for aortic stenosis, there are no data to support the diagnosis.

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For the diagnosis of left ventricular hypertrophy, the electrocardiogram (ECG) is not a sensitive method, but quite specific. Still, the findings of the patient in this case do not meet these criteria. Echocardiography is a low-cost procedure and is considered the method of choice for non-invasive diagnosis of increased cardiac mass10. However, in this case, the patient had no criteria for hypertrophic cardiomyopathy at the echocardiography.

One must also emphasize the differential diagnosis between left ventricular hypertrophy and restrictive cardiomyopathy, especially with the low-voltage electrocardiogram in the frontal plane, present in the latter cardiomyopathy, which favors the storage disease and consequent restriction to ventricular filling11.

The clinical findings of lower-limb edema and hepatomegaly, as well as the supplementary tests (electrocardiogram and echocardiogram), pointed to predominant RV involvement with overload and dilation of both atria and normal LV systolic function and dimensions. These characteristics corroborate the diagnosis of heart disease with diastolic restriction. Among the diseases that can cause restrictive cardiomyopathy12 are storage diseases (hemochromatosis and Fabry disease), endomyocardial disease (endomyocardial fibrosis) and infiltrative diseases (amyloidosis and sarcoidosis).

Hemochromatosis is characterized by excessive iron deposits on parenchymal tissues (heart, liver, gonads, and pancreas). It can occur as an autosomal recessive or idiopathic disorder, in association with defects in hemoglobin synthesis due to ineffective erythropoiesis, chronic liver disease and excessive oral ingestion or parenteral administration of iron for many years13.

Cardiac involvement leads to the combined pattern of dilated cardiomyopathy and restrictive cardiomyopathy with systolic and diastolic dysfunction. Myocardial damage is mainly attributed to direct toxicity of free iron and not only the tissue infiltration. Cardiac dilatation occurs with increased ventricular thickness. The findings are more prominent in ventricular than in atrial myocardium and it often affects the cardiac conduction system. In this patient, although he showed increased ventricular thickness demonstrated by the echocardiography, there was no ventricular dilatation or systemic manifestations of the disease, making this hypothesis unlikely.

Fabry disease is a genetic disorder with X-linked recessive inheritance, resulting from abnormalities linked to the deficiency of the lysosomal enzyme alpha-galactosidase A, which is caused by more than 160 mutations14. Some of them result in undetectable enzyme activity, which manifest throughout the body, while others produce some degree of enzymatic activity resulting in variants with limited involvement only in the myocardium. The disease is characterized by an intracellular accumulation of glycosphingolipids with marked involvement of the skin, kidneys and myocardium in the classic form. Involvement of the vascular endothelium occurs, as well as of conduction tissue and heart valves, particularly the mitral valve.

The major clinical manifestations result from the accumulation of glycosphingolipids in cell endothelium, with eventual occlusion of small arterioles. Angina pectoris

and myocardial infarction occur, although in most cases, the coronary arteries have normal angiographic aspect. There is thickening of the left ventricle, producing usually mild diastolic dysfunction, with preserved systolic function and mitral regurgitation without clinical significance. The symptomatic cardiovascular involvement occurs in nearly all male patients, whereas the symptoms are mild or absent in females. The following are common findings: arterial hypertension, mitral valve prolapse and congestive heart failure. The patient of the present case had no skin manifestations, systemic arterial hypertension, or acute myocardial ischemia.

Endomyocardial fibrosis, common in tropical countries, most often occurs in children and young adults. It is characterized by endocardial fibrosis of the inflow tract of one or both ventricles. Biventricular disease occurs in almost half the cases; 40% of them have isolated involvement in the left ventricle and 10%, isolated impairment of the right ventricle13,15. There is an irregular association with eosinophilia. LV impairment results in pulmonary congestion symptoms, while RV involvement may show characteristics of restrictive cardiomyopathy and also simulate constrictive pericarditis. Failure of one or both atrioventricular valves often occurs16.

Electrocardiographic and echocardiographic findings include: decreased QRS complex voltage, pericardial effusion, apical obliteration and increased endocardial echo reflectivity15. The latter findings were not confirmed in this clinical case and, moreover, the endomyocardial fibrosis does not explain thyroid and renal involvement shown by the patient.

Being one of the causes of restrictive cardiomyopathy, sarcoidosis is a systemic granulomatous disease of unknown etiology, characterized by the involvement of various tissues by noncaseating granulomas17.

Cardiac involvement is infrequent and primary clinical manifestations occur in less than 5% of patients, being characterized by conduction defects, ventricular arrhythmias, syncope and sudden death. The direct myocardial involvement by granulomas and scar tissue can manifest as dilated or restrictive cardiomyopathy, with progressive course18. The ECG is nonspecific and can show T wave abnormalities, blocks or pathological Q waves. Other findings include pericarditis and cor pulmonale. Echocardiography can disclose thinning of the ventricular wall and increased echogenicity18. Cardiac magnetic resonance is a highly sensitive and specific method for diagnosis. In our case, there were no suggestive alterations, making it unlikely that this was the patient's diagnosis.

And finally, systemic amyloidosis, which is a group of diseases that have extracellular deposits of insoluble fibrillar proteins consisting of low molecular weight subunits5. Clinically, it is classified as5: primary (AL), secondary (AA), hereditary and associated with old age (senile). AL amyloidosis is caused by the deposition of proteins derived from light chain fragments, in general, a monoclonal immunoglobulin (80.0% of cases). It may occur alone or in association with multiple myeloma (10.0% of cases). AA amyloidosis can complicate chronic diseases that course with recurrent inflammation. The fibrils consist of fragments of amyloid protein A, an acute phase protein.

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There is also a hereditary-type amyloidosis (deposition of fibrils derived from transthyretin) and a senile form (also deposition of transthyretin). In this context, there can be amyloid infiltration in the thyroid, leading to hypothyroidism19; however, it most commonly occurs concomitantly with goiter, not described in the case. Another clinical manifestation, such as autonomic neuropathy due to amyloidosis5, which courses with orthostatic hypotension, early satiety, change in bowel habits (diarrhea or chronic constipation) were observed in this patient.

AA amyloidosis affects the cardiovascular system in only 5% of cases and there is no mention of systemic inflammation (although serology for hepatitis are not available)20. Therefore, the two subtypes of amyloidosis most likely in this case would be AL and senile amyloidosis. There are important differences in the prognosis and rate of evolution between these subtypes: the median survival after cardiac involvement is, respectively, 11 and 75 months21.

Furthermore, the insidious course of the disease is the rule for senile amyloidosis, whereas in AL, there is a rapid progression of symptoms and much higher cardiovascular involvement. In the absence of confirmation of plasma cell dyscrasia, the distinction between them is made through immunohistochemical analysis22.

Cardiac involvement in cases of amyloidosis occurs in one third of patients. Right ventricular failure usually occurs, with little pulmonary edema, despite elevated filling pressures. There are, however, other alterations including atrial fibrillation, conduction disorders and electrically inactive areas. Still, high-grade atrioventricular blocks are uncommon11. Echocardiography is an important noninvasive test for the diagnosis of amyloidosis. LV wall thickening with evidence of diastolic dysfunction is the earliest alteration, which can progress to restrictive cardiomyopathy23. Biatrial enlargement and valve thickening may occur19.

The diagnostic investigation includes collecting a urine sample to test for the presence of paraproteins. The detection of increased excretion of light chains with maintenance of the kappa/lambda ratio, in the absence of the monoclonal chain establishes the diagnosis of amyloidosis20. Although not confirmed by tests, the diagnosis of amyloidosis can be achieved through a biopsy24, which can be performed in subcutaneous adipose tissue (sensitivity of 65 to 80%)25 or in the endomyocardium (up to 97%)26 with demonstration of amyloid deposits in tissues classically stained with Congo red. Therefore, due to the clinical picture of the patient and the complementary tests described, systemic amyloidosis is the most likely diagnosis of this anatomo-clinical discussion.

There was not enough time to evaluate the hepatic findings in the abdominal ultrasound, which may have contributed to the case outcome. (Dr. Tiago Rodrigues Politi)

Diagnostic hypothesisSystemic amyloidosis with cardiac and renal involvement.Other diagnoses: hypothyroidism and chronic renal failure.

(Dr. Tiago Rodrigues Politi)

NecropsyThe patient had cachexia. The final factor triggering his

death was pulmonary embolism in the lower lobe of the

left lung. There was infarction in this territory (Figure 3) and acute infection in this and other areas of the lungs. Pulmonary thromboembolism was probably secondary to a clotting disorder, as, in addition to it, there was portal vein thrombosis and presence of thrombi that seemed to be recent (i.e., onset in the agonal period) in coronary arterial branches.

The main disease of this patient was hepatocellular carcinoma (Figure 4), underlying chronic hepatitis (Figure 5). The neoplasm is the likely cause of the bleeding disorder.

In addition to this disease, the patient also had cardiomyopathy, of which predominant clinical picture was atrial fibrillation (which can also be related to pulmonary thromboembolism, but there were no thrombi in the cardiac cavities). The fact that the ventricles did not show marked dilation, contrary to what happens with the atria (Figure 6), suggests that it is a case of restrictive cardiomyopathy. Among its possible causes are: amyloidosis, hypertrophic cardiomyopathy and ischemic heart disease. However, the absence of amorphous extracellular deposits, myocardial fiber disarray and severe obstruction of the coronary arteries go against such possibilities. Thus, the idiopathic form, with interstitial fibrosis, should be considered.

The patient also had atherosclerosis, with mild aortic and mild to moderate involvement of the coronary tree, but with no significant consequences. The kidneys had some degree of vascular alterations, which may be associated with atherosclerosis; kidney failure may have been associated with hepatorenal syndrome.

(Dr. Paulo Sampaio Gutierrez)

Anatomopathological diagnosis:Main disease: hepatocellular carcinoma related to chronic

hepatitis, probably viral.

Relevant secondary disease: restrictive cardiomyopathy.

Cause of death: pulmonary thromboembolism (Dr. Paulo Sampaio Gutierrez)

CommentIt is difficult in this case, to be sure that the pulmonary

embolism, which was the final factor triggering death, was more related to heart failure or, as it seems likely, considering that such picture was well balanced and that there were no intracavitary thrombi, to hepatocellular carcinoma.

It is noteworthy the lack of a cancer diagnosis during the patient’s life, corroborating data indicating that autopsies still currently disclose important diagnoses in a significant number of patients with heart disease27.

Regarding the heart disease, amyloidosis is a possibility that should be considered in heart failure with restrictive pattern in the elderly. However, the clinical profile of patients with restrictive idiopathic cardiomyopathy28 showed age variation of 10-90 years, with a mean of 64. Therefore, the patient fits into this description, not only regarding age but also concerning the atrial fibrillation, detected in 74% of patients. (Dr. Paulo Sampaio Gutierrez)

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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.

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.

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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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References

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Case Report

Steal of Blood Flow from the Vertebral Artery to the Internal Thoracic Artery Anastomosed to the Coronary ArteryJose 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

Mailing Address: Jose Sebastião de Abreu •Rua Dr. José Lourenço, 500/700, Meireles. Postal Code 60115-280, Fortaleza, CE - BrazilE-mail: [email protected], [email protected] Article received on 11/10/12, revised on 12/04/12, accepted on 3/25/13.

KeywordsMammary Arteries; Echocardiography, Stress; Angioplasty,

Balloon, Coronary; Stents.

DOI: 10.5935/abc.20130216

IntroductionThe left vertebral and internal thoracic arteries are branches

of the left subclavian artery which, under physiological conditions, exhibit antegrade flow direction.

On Doppler evaluation, the internal thoracic artery (ITA) flow shows a predominance of systolic component, but when anastomosed to the left coronary arteries, the prevalence of the diastolic component is usual. This predominance can become exacerbated and a situation that increases oxygen consumption by the myocardium can occur, such as what happens during dobutamine stress echocardiography, when the systolic component can be suppressed and the diastolic becomes the only component of the cardiac cycle. The two-dimensional and Doppler imaging allows anatomical assessment of arteries and the verification of normal and pathological flow patterns. Thus, the flow direction reversal of an artery can be compatible with steal of blood flow and an exacerbation of the diastolic component of the anastomosed internal thoracic artery (AITA) at Doppler may indicate good functional status of the vessel1-3.

Occlusion of the left subclavian artery determines impairment of blood supply to the left arm, but the steal of blood flow from the left vertebral artery may improve limb perfusion. When the subclavian artery occlusion occurs in cases with ITA anastomosed to the left coronary arteries, the direction of the post-stenotic flow in symptomatic patients is variable and can be reverse in the vertebral and internal thoracic arteries4, have no reverse component5, be reverse only in ITA6 or, as in our patient, show preferential reverse flow from the left vertebral artery to the ITA.

Case reportA 47-year-old female had had stable angina for

approximately three years and increasing angina for the last

three months. She reported decreased strength to elevate the left upper limb. She was hypertensive, dyslipidemic and a smoker. She used calcium antagonists, nitrates, aspirin and statin. Ten years before, she had undergone myocardial revascularization with saphenous vein graft to the right coronary artery and from the internal thoracic artery (ITA) to the anterior descending coronary artery (ADA).

On physical examination she had normal pulmonary auscultation, regular heart rhythm and fourth heart sound, cervical murmur to the left (++/4+), pulse in the left arm not palpable without edema. Blood pressure in the right upper limb was 130 x 80 mmHg.

The electrocardiogram showed mild ventricular repolarization alteration in the anterolateral wall. She underwent cardiac catheterization, which showed occlusion of the saphenous vein graft, severe stenosis (> 80%) in left main coronary artery (LMCA), of ADA, circumflex (Cx), and diagonal (Dg) artery and left subclavian artery (LSA) occlusion; it was not possible to perform proper assessment of the ITA-ADA conduit (Figure 1A and 1B).

The echocardiogram showed mild left ventricular hypertrophy and normal basal segmental contraction. The two-dimensional image and Doppler of the anastomosed ITA (AITA), viewed in supraclavicular level, showed good patency of the conduit through Doppler spectrum with exuberant percentage of diastolic component (84%) at rest, well above the commonly found one (Figure 1C and 1D). The vertebral arteries showed normal anatomy and flow velocity; however, the flow was retrograde in the left vertebral artery (LVA) and showed normal anterograde pattern in the right (Figure 1E and 1F).

The attending physician considered that the left coronary system was partially protected by the AITA and the patient was submitted to stenting in the LMCA and Cx and angioplasty in the Dg, with consequent cessation of anginal symptoms.

Six months after the percutaneous intervention, she underwent dobutamine stress echocardiography, reaching a maximum heart rate (220 - age) with uneventful outcome and negative result for myocardial ischemia. At peak stress, the flow in the AITA became exclusively diastolic, with coronary flow reserve index of 1.8 (Figure 2A and 2B), indicating good functional status1,3, while the LVA remained entirely with retrograde flow (Figure 2C and 2D).

Four months after the stress echocardiography, the patient underwent a new intervention for stent implantation in the LSA. A subsequent angiogram showed calibrous and

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Abreu et al.Steal of blood flow to internal thoracic artery


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 Doppler assessment, it was observed that the LVA had started to show normal antegrade flow. The AITA flow at rest showed a decrease in the diastolic component, but it remained predominantly (58%) within the range expected for AITA with adequate patency (Figure 2G and 2H).

The pulse in the left arm became palpable.

DiscussionDuring LSA occlusion in revascularized patients with

AITA, distinct variations may occur in flow direction distal

to the stenotic LSA. In the study by Omeish et al4, it was observed that a patient admitted with acute pulmonary edema had, at the hemodynamic study, reverse flow in AITA and LVA, and that after stenting in the occluded LSA, the directions of these flows normalized and became anterograde, concomitant to a successful clinical outcome.

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" steal of blood flow to the region distal to the LSA stenosis. Vecera et al6 showed, by Doppler assessment, AITA with reverse flow and the hemodynamic study confirmed the

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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 flow showed normal anterograde pattern.

The case reported herein is the first to show that, in the presence of LSA occlusion, the steal of blood flow in the LVA can help to increase the antegrade flow of the AITA without stenosis and to demonstrate that, the role of two-dimensional Doppler image was crucial.

The hemodynamic study diagnosed the LSA occlusion, as well as severe stenoses of the coronary arteries,

but showed limitations in the assessment of the AITA. The two-dimensional Doppler image was of great importance to demonstrate that the diastolic component in the AITA was more pronounced than usual, which suggested to the attending physician that the left coronary system was partially protected by this AITA, favoring the decision of performing a percutaneous intervention through stenting in severely compromised coronary arteries, including the left main coronary artery.

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1. Abreu JS, Diógenes TC, Morais JM, Barretto JE, Lobo Fo. JG, Paes Jr JN. Avaliação da patência da mamária interna enxertada pelo ecodoppler com e sem uso de dobutamina. Arq Bras Cardiol. 1997;69 (supl I):119.

2. Arruda A, Campos Filho O, Ribeiro E, Petrizzo A, Andrade JL, Carvalho AC, et al. Avaliação da anastomose de artéria torácica interna esquerda com artéria interventricular anterior pela ecodopplercardiografia. Arq Bras Cardiol. 1997;69(6):413-9.

3. Abreu JS, Diógenes TC, Abreu AL, Barreto JE, Morais JM, Abreu ME, et al. Artéria torácica interna enxertada: patência e estado funcional em repouso e após dobutamina. Arq Bras Cardiol. 2008;90(1):37-45.

4. Omeish AF, Ghanma IM, Alamlih RI. Successful stenting of total left subclavian artery occlusion post-coronary artery bypass graft surgery using dual left vertebral artery and left internal mammary artery protection. J Invasive Cardiol. 2011;23(6):E132-6.

5. Alcocer A, Castillo G, Rivera-Capello JM, González V, Meaney E. Anterograde flow compromise of a patent left internal mammary artery graft from a proximal subclavian artery stenosis. Myocardial ischemia not driven by the coronary-subclavian steal syndrome mechanism. Arch Cardiol Mex. 2012;82(2):135-8.

6. Vecera J, Vojtísek P, Varvarovský I, Lojík M, Másová K, Kvasnicka J. Non-invasive diagnosis of coronary-subclavian steal: role of the Doppler ultrasound. Eur J Echocardiogr. 2010;11(9):E34.

References

After the interventional therapy, the patient asymptomatic evolution and the fact that the dobutamine-stress echocardiogram was negative for myocardial ischemia corroborated the appropriateness of the interventions. The AITA Doppler assessment showed good functional status of this conduit as, during stress, it was observed that the flow became 100% diastolic with a coronary flow reserve index of 1.8. The two-dimensional Doppler study performed immediately after stent implantation in LSA showed that the flow direction in the LVA had normalized (anterograde) and that changes had occurred in the AITA flow, which demonstrated increased systolic component, while still remaining anterograde and with diastolic predominance (58%), which is the Doppler standard usually found in patent AITA3.

We emphasize that stress echocardiography, which has such widespread use in the evaluation of myocardial ischemia, is an important tool for the assessment of coronary flow reserve through the graft.

ConclusionIn 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 Doppler image was essential to demonstrate that the AITA was patent and had good functional status, favoring the

decision to perform percutaneous intervention for severe stenosis of the LMCA and branches of a partially protected left coronary system.

Author contributionsConception and design of the research: Abreu JS;

Acquisition of data, Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Abreu JS, Pimentel NL, Siqueira JM, Diógenes TCP, Paes Junior JN; Performing procedure (examination): Abreu JS, Pinheiro CND, Paes Junior JN.



Sources of Funding


Study Association


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Korotkoff Sounds – The Improbable also OccursBruno 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

Mailing Address: Bruno Estaño •Laboratory of Clinical Neurophysiology, Department of Neurology and Psychiatry, National Institute of Medical Sciences and Nutrition Salvador Zubirán (INNSZ). Vasco de Quiroga 15, Tlalpan, Postal Code 14000, México D.F., MéxicoE-mail: [email protected] received April 1, 2013; revised April 7, 2013; accepted May 20, 2013.

KeywordsHistory of Medicine; Arterial Pressure; Sphygmomanometers

/ utilization.

DOI: 10.5935/abc.20130217

AbstractVery few discoveries have had such a large impact on

and relevance to clinical medicine as the noninvasive measurement of the diastolic blood pressure. A number of gifted physiologists and clinicians were ineffectively in search of a noninvasive method to determine the diastolic pressure. Nonetheless, the quantification of the diastolic BP was not achieved by any of these clinical or physiological researchers, but by an unlikely and unexpected figure: Nikolai Sergeevich Korotkoff (1874-1920), a young Russian army surgeon, working under precarious conditions in the hardship of diverse wars. It is easy to dismiss the achievement of Korotkoff as a serendipitous discovery, similar to that of Alexander Fleming in the discovery of penicillin. However, Nassim N. Taleb's recent black swan theory may serve to illustrate his discovery in a new and, perhaps, surprising way.

Historical SketchEvery second throughout the world, someone is

measuring the systolic and diastolic blood pressure (BP) by means of Korotkoff's auscultatory method. It is worth noting that very few discoveries have had such a large impact on and relevance to clinical medicine as the noninvasive measurement of the diastolic BP. The systolic and diastolic BP had been accurately measured with an intra-arterial catheter after Friedrich Goltz (1834-1902) and Justus Gaule (1849-1939) introduced their ingenious valved device in 18781. Two years later, Bohemian physician Samuel S. K. von Basch (1837-1905), former ordinary physician to the Mexican Emperor, presented his groundbreaking apparatus, consisting of a rubber bulb connected to a mercury manometer2. He compressed the radial artery with the bulb until the pulse was obliterated and, at that point he measured the systolic BP2. The Bohemian physician compared the systolic BP measured with his method in

a dog, with the intra-arterial technique and found that BP figures were comparable with both approaches2. He established the maximum value of the systolic BP at 150 mmHg; anything beyond this figure in the adult was considered to be abnormal2,3. He introduced the term sphygmomanometer, which derives from the Greek word “sphygmos,” meaning “pulse”4. The term was, in fact, a misnomer, but it is still used in most countries.

The brilliant Italian physician Scipione Riva-Rocci (1863-1937) introduced a bracelet that was connected to a mercury column and, by increasing the pressure until the pulse was obliterated, he was able to measure the systolic BP with great precision4. He used the tactile sense of his fingers to detect the moment when the pulse disappeared or appeared4. This method was accurate, inexpensive and soon became highly popular.

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 medicine and surgery only the systolic BP was being assessed3. A number of gifted physiologists and clinicians were ineffectively in search of a noninvasive method to determine the diastolic BP5. Nonetheless, the quantification of the diastolic BP was not achieved by any of these clinical or physiological researchers, but by an unlikely and unexpected figure: Nikolai Sergeevich Korotkoff (1874-1920), a young Russian army surgeon, working under precarious conditions in the hardship of diverse wars6. He did his amazing feat using the Riva-Rocci bracelet and a child's stethoscope6,7.

Korotkoff was not a BP researcher and his main concern, as a war surgeon, was to know if collateral blood supply was undiminished, so as to resolve whether a wounded artery could be securely ligated when an amputation was likely6. He knew that the onset of the palpable pulse was the systolic BP and he reasoned that the time of disappearance of the sound signaled the onset of the laminar flow and, therefore, of the relaxation of the arterial wall. He hence proposed that diastolic BP might be estimated by the disappearance of all sounds8.

Some Philosophical Remarks on the Epistemology of the Unexpected in Science

It is easy to dismiss the achievement of Korotkoff as a serendipitous discovery similar to that of Alexander Fleming in the discovery of penicillin9. While looking for one thing, he found something entirely different. However, Nassim N. Taleb's recent black swan theory may serve to illustrate his discovery in a new and, perhaps, surprising way10. In his book, Taleb persuasively argues about finding the unexpected in life and science. Many great discoveries and inventions in science and art have been unexpected

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Estañol e cols.Sons de Korotkoff - O Improvável também ocorre


1. Geddes LA. The first accurate measurement of systolic and diastolic blood pressure. IEEE Eng Med Biol Mag. 2002;21(3):102-3.

2. Delgado García G, Estañol Vidal B. [The Emperor’s physician before and after the Empire]. Gac Med Mex. 2012;148(5):487-96.

3. Janeway TC. The clinical study of blood-pressure: a guide to the use of the sphygmomanometer. New York: D. Appleton and Co; 1904.

4. Roguin A. Scipione Riva-Rocci and the men behind the mercury sphygmomanometer. Int J Clin Pract. 2006;60(1):73-9.

5. Warfield LM. Studies in auscultatory blood-pressure phenomena. I. The experimental determination of diastolic pressure. Arch Intern Med. 1912;10(3):258-67.

6. Gurevich AK. Dr. Nikolay S. Korotkov (1874-1920) -- the discoverer of blood pressure measurement tones. J Nephrol. 2006;19 Suppl 10:S115-8.

7. Segall HN. Dr N C Korotkoff: discoverer of the auscultatory method for measuring arterial pressure. Ann Intern Med. 1965;63(1):147-9.

8. Nabokov AV, Nevorotin AJ. Dr N. S. Korotkov: the low-pitch sounds that stand high. Nephrol Dial Transplant. 1998;13(4):1041-3.

9. Ban TA. The role of serendipity in drug discovery. Dialogues Clin Neurosci. 2006;8(3):335-44.

10. Taleb NN. The black swan: the impact of the highly improbable. New York: Random House; 2010.

References

and unpredictable, though easily explained in retrospect. In fact, many of these findings have compelled scientists to change their theoretical framework to accommodate new facts. It is true that a discovery is made within the context of what is already known, and this serves as part of retrospective explanation: without the Riva Rocci's bracelet and without the pediatric stethoscope, the young Russian surgeon could not have developed his auscultatory method. It is then easy, but probably wrong, to assume that the discovery would have been made sooner or later; that 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, and we cannot know all the discoveries that remain to be made, even though the facts have been known for centuries. It has been said that the scientist discovers and the artist invents, but in the case of Laennec, Korotkoff and others, both concepts are correct. The Russian surgeon not only produced an unexpected result but he himself was an unlikely actor in the drama. The odds favored that clinicians and physiologists working in the field of BP measurement would come up with the discovery, and it was improbable, to say the least, that a young surgeon, physically and emotionally overworked, with a large numbers of acute wounded patients, would make such a momentous discovery.

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. Nevertheless, at some moment after his discovery, Korotkoff became keenly aware of its significance, although he

could not yet envision its enormous practical future. He published his report in a single page to the Imperial Military Medical Academy of Saint Petersburg in 19057,8. In this brief presentation he described his discovery. In the following month, he made a new presentation. In 1910 he defended his Ph.D. dissertation on the collaterals of peripheral circulation8. Subsequently, he worked in different hospitals6,8. He did not publish anything else on the subject of BP measurement and died of pulmonary tuberculosis, at the early age of 46 years, in 19206,8.

Author contributionsConception and design of the research, Acquisition of

data, Analysis and interpretation of the data, Writing of the manuscript and Critical revision of the manuscript for intellectual content: Estañol B, Delgado G, Borgstein J; Statistical analysis: Delgado G; Obtaining funding: Borgstein J.


reported.


Study AssociationThis study is not associated with any post-graduation

program.

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