Heart Rate Variability and Chagas Heart Disease

Heart Rate; Chagas Cardiomyopathy, Amiodarone/Therapeutic Use; Ventricular Dysfunction

We believe that the present study is relevant, which investigated the effect of exercise training on heart rate variability (HRV) in patients with Chagas heart disease¹. However, there are some issues in this study, which should be further discussed.

The use of amiodarone in approximately 80% of patients may have decreased their autonomic response², affecting the validity of HRV parameters.

Furthermore, low-ejection fraction (mean, 37%) may have acted as a confounding factor, and this finding may need to be investigated by inclusion of a control group without Chagas heart disease but with similar ejection fraction; inclusion of a control group with Chagas heart disease but with ejection fraction close to normal; or better yet, the inclusion of both groups.

A small sample size (37 subjects divided into two groups) masks potential differences; for a power of 80% and a two‑tailed alpha of 0.05, we estimate that the effect size ("d") of a large magnitude (d = 0.95) would be required to be detectable.

In fact, even when calculating the sample size, underpowering has been one of the major obstacles in clinical studies³. Although we did not consider a very high standard deviation (which would lead to greater difficulties), the effective post hoc power to detect intergroup differences considering a SDNN value of 0.15 would be only 7.3%, according to our calculations.

Moreover, we believe that, instead of the separate use of paired tests and tests for independent samples to answer the original question, other models (e.g., panel data or mixed models) are better adjusted to the experimental design and to the proposed objectives.

References

• ¹
  Nascimento BR, Lima MM, Nunes Mdo C, de Alencar MC, Costa HS, Pinto Filho MM, et al. Efeitos do treinamento físico sobre a variabilidade da frequência cardíaca na cardiopatia chagásica. Arq Bras Cardiol. 2014;103(2):201-8.
• ²
  Malik M, Camm AJ, Janse MJ, Julian DJ, Frangin JA, Schwartz PJ. Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (the European Myocardial Infarct Amiodarone Trial). J Am Coll Cardiol. 2000;35(5):1263-75.
• ³
  Vickers AJ. Underpowering in randomized trials reporting a sample size calculation. J Clin Epidemiol. 2003;56(8):717-20.

Reply

Thank you for your comments on the article titled “Effects of exercise training on heart rate variability in Chagas heart disease”¹. Herein, we would like to address some concerns raised by the reviewers.

Our study mainly aimed to evaluate changes in heart rate variability (HRV) in response to a physical training program in patients with Chagas cardiomyopathy in comparison with a control group that was physically inactive. In this context, the effects of amiodarone on HRV are known^2,3, particularly in patients with ectopic foci of arrhythmia, which is an underlying complication commonly observed in patients with Chagas heart disease, and we acknowledge that these effects could be a confounding factor. However, the percentage of patients taking the medication was high and statistically similar between the groups (77.8% and 84.2%, p = 0.62), suggesting that these effects were probably balanced and decreased the possibility of interferences in the differences in the delta values of HRV indices at the end of the study. In addition, drug withdrawal during the study would be unethical, and consequently, we would not be able to otherwise obtain the required data. However, the bias introduced by the use of drugs acting on the cardiac rhythm-widely used for the treatment of left ventricular dysfunction-should always be considered in HRV studies.

With regard to the non-inclusion of patients with ventricular dysfunction caused by other etiologies and the noninclusion of patients with Chagas heart disease with preserved ejection fraction, the presence of autonomic dysfunction has been reported in a large number of patients with Chagas heart disease, even in the absence of heart disease⁴. Similarly, decreased HRV in patients with ventricular dysfunction caused by other etiologies (with diagnostic and prognostic validation)⁵ as well as their positive response to exercise have been reported⁶. The inclusion of the above-mentioned groups would undoubtedly provide valuable information to our findings, including the results of HRV among patients with the indeterminate form of the disease. However, we believe that this result is not essential to answer the central question of this study, which is whether the prognostic benefit of physical training in patients with Chagas heart disease-largely demonstrated in previous studies-evaluated with HRV indices would be mediated by changes in the autonomic system. For this reason, we only recruited patients with a similar underlying condition and those who were physically inactive during the study period as controls.

With respect to the power of the study to detect differences between groups, the example used would apply when comparing the SDNN parameter between the groups, or within the same group, in different periods. However, the variable of interest used to calculate the sample size was the variation in the SDNN parameter (∆SDNN), which was compared between the groups. In the absence of a study with similar design to compare individuals with Chagas heart disease, we considered previous data on heart disease due to other etiologies⁷. Therefore, to detect ∆SDNN differences of 10–15 ms between the groups with 㬠 error of 20%, samples sizes of <40 patients would be sufficient even when considering the large dispersion values observed. Therefore, we believe that underpowering in relation to this reference index did not occur.

Finally, we evaluated longitudinal data in two different periods in this study. The aforementioned analytical methods (panel data and mixed models) would be more appropriate in longitudinal studies with multiple observations. However, the use of paired tests (Student’s t test and Wilcoxon test) and the comparison of changes (delta values) between the groups with two measures are methodologically appropriate for the present experimental design⁸.

We appreciate the comments and criticism of the authors and hope we have adequately addressed the issues raised.

Sincerely Yours,

Bruno Ramos Nascimento

Marcia Maria Oliveira Lima

Manoel Otávio da Costa Rocha

Antonio Luiz Pinho Ribeiro.

References

• ¹
  Nascimento BR, Lima MM, Nunes Mdo C, de Alencar MC, Costa HS, Pinto Filho MM, et al. Efeitos do treinamento físico sobre a variabilidade da frequência cardíaca na cardiopatia chagásica. Arq Bras Cardiol. 2014;103(2):201-8.
• ²
  Rohde LE, Polanczyk CA, Moraes RS, Ferlin E, Ribeiro JP. Effect of partial arrhythmia suppression with amiodarone on heart rate variability of patients with congestive heart failure. Am Heart J. 1998;136(1):31-6.
• ³
  Malik M, Camm AJ, Janse MJ, Julian DG, Frangin GA, Schwartz PJ. Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (The European Myocardial Infarct Amiodarone Trial). J Am Coll Cardiol. 2000;35(5):1263-75.
• ⁴
  Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros Vda C, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11.
• ⁵
  Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen M, et al. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). Circulation. 1998;98(15):1510-6.
• ⁶
  Selig SE, Carey MF, Menzies DG, Patterson J, Geerling RH, Williams AD, et al. Moderate-intensity resistance exercise training in patients with chronic heart failure improves strength, endurance, heart rate variability, and forearm blood flow. J Card Fail. 2004;10(1):21-30.
• ⁷
  Murad K, Brubaker PH, Fitzgerald DM, Morgan TM, Goff DC Jr, Soliman EZ, et al. Exercise training improves heart rate variability in older patients with heart failure: a randomized, controlled, single-blinded trial. Congest Heart Fail. 2012;18(4):192-7.
• ⁸
  Locascio JJ, Atri A. An overview of longitudinal data analysis methods for neurological research. Dement Geriatr Cogn Dis Extra. 2011;1(1):330-57.

Carta-resposta

Agradecemos pelos comentários feitos sobre nosso artigo intitulado Efeitos do treinamento físico sobre a Variabilidade da Frequência Cardíaca na cardiopatia chagásica¹ e gostaríamos de esclarecer alguns pontos levantados pelos prezados colegas.

Nosso artigo teve como objetivo principal avaliar as mudanças dos índices de Variabilidade da Frequência Cardíaca (VFC) em resposta a um programa de treinamento físico aeróbico em pacientes com miocardiopatia chagásica, em comparação com grupo semelhante, mantido inativo fisicamente. Nesse contexto, são conhecidos os efeitos da amiodarona sobre a VFC^2,3, especialmente em pacientes com focos ectópicos de arritmia – condição de base comumente observada na cardiopatia chagásica – e este poderia ser um fator de confusão. Entretanto, a proporção de pacientes em uso da medicação era alta e estatisticamente semelhante entre os grupos (77,8% e 84,2%; p = 0,62), sugerindo que seu efeito fosse provavelmente balanceado e reduzindo a chance de ter havido interferência na diferença entre os deltas dos índices de VFC ao final do estudo. Além disso, seria antiética a suspensão da droga para a realização do estudo e, dessa forma, o dado não poderia ser obtido de outra maneira. Contudo, o viés introduzido pela utilização de drogas com efeito sobre o ritmo – amplamente utilizadas na disfunção ventricular esquerda – deve ser sempre ponderado em estudos de VFC.

Sobre a não inclusão de pacientes com disfunção ventricular de outras etiologias e de pacientes chagásicos com fração de ejeção preservada, consideramos que já se demonstrou, na literatura, de forma consistente, a presença de disfunção autonômica em uma considerável proporção de pacientes chagásicos, mesmo na ausência de cardiopatia⁴ e, da mesma forma, já é bem estabelecida a redução dos índices de VFC em pacientes com disfunção ventricular de outras etiologias (com validação diagnóstica e prognóstica)⁵, assim como sua resposta positiva ao treinamento físico⁶. A inclusão dos grupos citados sem dúvida agregaria informações adicionais aos nossos achados, como a resposta da VFC em pacientes com forma indeterminada, mas, em nossa opinião, não seria imprescindível para a resposta à pergunta central do presente estudo: se o benefício prognóstico do treinamento físico, na cardiopatia chagásica, já amplamente demonstrado em estudos prévios, seria ou não mediado por alterações no sistema autonômico, avaliado por meio dos índices de VFC. Por esse motivo, utilizamos como controle apenas pacientes com condição de base semelhante, mantidos inativos durante o programa.

Sobre o poder do estudo para detectar diferenças entre os grupos, o exemplo utilizado se aplicaria na comparação do parâmetro SDNN entre os grupos ou dentro do mesmo grupo, em momentos diferentes. No entanto, a variável de interesse do estudo, utilizada para o cálculo amostral, foi a variação do índice (∆SDNN), comparado entre os grupos. Na falta de estudo comparativo com desenho semelhante entre chagásicos, consideramos dados prévios com cardiopatias de outras etiologias⁷. Assim, para se detectarem diferenças do ∆SDNN entre 10 e 15 ms entre os grupos, com erro 㬠 = 20%, amostras inferiores a 40 pacientes seriam suficientes, mesmo com as medidas de dispersão alargadas encontradas. Dessa forma, consideramos que não tenha havido underpowering do estudo em relação a esse índice de referência.

Finalmente, no presente estudo avaliamos dados longitudinais observados em dois momentos diferentes. Os métodos analíticos citados (panel data e mixed models) seriam realmente mais adequados em estudos longitudinais com múltiplas observações, mas a utilização de testes pareados (t de Student e Wilcoxon) e a comparação das variações (deltas) entre os grupos são metodologicamente adequadas para o presente delineamento, com duas medidas⁸.

Agradecemos os comentários e críticas dos autores, e esperamos ter esclarecido adequadamente as questões levantadas.

Atenciosamente,

Bruno Ramos Nascimento

Marcia Maria Oliveira Lima

Manoel Otávio da Costa Rocha

Antonio Luiz Pinho Ribeiro.

Publication Dates

• Publication in this collection
  Jan 2015

History

• Received
  09 Oct 2014
• Reviewed
  13 Nov 2014
• Accepted
  13 Nov 2014