Exercise Training in Chagas' Cardiomyopathy: Trials are Welcome for this Neglected Heart Disease

This editorial refers to ‘A randomized trial of the effects of exercise training in Chagas cardiomyopathy' by Márcia M.O. Lima et al., published in this issue on pages 866–873. In this issue of the European Journal of Heart Failure Lima et al. report the results of an exercise training trial for Chagas cardiomyopathy, a neglected endemic disease in underdeveloped countries in Latin America and a new threat to developed countries.1 Chagas disease causes the highest burden of any parasitic disease in the Western hemisphere. Chagas disease, caused by the parasite Trypanosoma cruzi, affects an estimated 8million people in the Americas.2 Migration of Latin Americans to the USA, Canada, and Europe has modified Chagas disease epidemiology. European countries are now facing some neglected diseases they are not used to dealing with.3 The most common feature of Chagas disease is chronic Chagas cardiomyopathy, which can present as conduction system abnormalities, brady- and tachyarrhythmias, biventricular dilated cardiomyopathy, apical aneurysm, and thrombus formation in the aneurysm or remodelled ventricles. Translating into clinical practice, the main manifestations of Chagas disease are heart failure, arrhythmias, sudden death, and embolism. In endemic regions or in cardiac centres receiving patients from endemic regions, Chagas' cardiomyopathy is the cause of heart failure in 8.1–28% of cases.4,5 In an estimated population of over 41million, chronic Chagas heart disease was responsible for 8% of deaths caused by heart failure or diseases associated with heart failure.5 It has now been shown by Lima et al. in a single centre prospective controlled randomized trial that 12 weeks of exercise training can improve exercise capacity and health-related quality of life in chronic Chagas cardiomyopathy compared with an inactive control group.1 Although the authors did not measure maximum oxygen consumption directly and included only a limited number of patients over a short-term follow-up, the elegant demonstration of an increase in exercise time, 6min walk test distance, calculated oxygen consumption, and quality of life in chronic Chagas cardiomyopathy advances research in the management of this important and neglected disease. Lima et al. not only demonstrate that exercise training is effective, but also that it is feasible and without significant adverse events. Even in the context of neutral results for mortality and positive results for health-related quality of life from HF-ACTION trial, the strengths of this trial are attractive considering the specific mechanisms involved in the pathophysiology of chronic Chagas cardiomyopathy.6–8 Although the pathogenesis of chronic Chagas disease is not completely understood, the aetiology of chagasic heart disease is likely multifactorial7,9 (Figure Figure 1). Parasite persistence, inflammatory response, autoimmunity, damage to the parasympathetic system causing sympathetic over activity, and microvascular abnormalities, have all been studied extensively as possible pathogenic mechanisms.7 Most researchers in the field now agree that chronic low-grade parasite persistence drives tissue damage and the autoimmune component of Chagas cardiomyopathy.7 In fact, reactivation of Chagas infection after heart transplantation has reinforced evidence for a potential role of parasite persistence in the development of Chagas heart disease.10 In general, histology of cardiac tissue from patients with chronic Chagas cardiomyopathy, combined with non-invasive investigations provide evidence of persistent myocarditis, inflammatory infiltrate oedema, contraction-band necrosis and myocytolysis, focal and diffuse areas of myocellular hypertrophy, and fibrosis that can affect the conduction system.11 Trypanosoma cruzi antigen can be detected using specific and sensitive techniques. Co-infection has recently been reported in Chagas cardiomyopathy, but its impact on outcome remains unknown.9 Regarding the influence of specific mechanisms involved in Chagas disease on exercise training prescription, one would consider the quite common persistent myocarditis as a concern. In general, an exercise training programme or cardiac rehabilitation should probably be withheld in patients with myocarditis.12 It has been shown that exercise may increase viral replication in animal models determining effects on cytolysis, immune response, inflammation, and necrosis.12,13 Ventricular arrhythmias could determine sudden death as a consequence of inflammation, oedema, myocardial necrosis, and fibrosis in active or healed myocarditis.12 In contrast, Lima et al. did not report any adverse effects of exercise training during a short-term follow-up.1 However, despite the provocative results establishing the feasibility and physiological benefits of exercise training in Chagas cardiomyopathy in this single-centre prospective randomized trial, the safety and benefit on hard endpoints should now be tested in a large multiple-centre prospective randomized trial with strategies to guarantee adherence to treatment. Accepted mechanisms in neurogenic theory to explain Chagas cardiomyopathy, such as sympathetic over-activity, could also influence the exercise training response. However, in the Lima study response of heart rate, systemic blood pressure, calculated maximum oxygen consumption, and 6min walking test distance was comparable to results of exercise training in other aetiologies with low use of β-blockers.1,14 Also, these results do not support parasympathetic denervation as an important mechanism in the pathogenesis of Chagas cardiomyopathy, or a mechanism jeopardizing exercise prescription in Chagas cardiomyopathy. One very important issue in Chagas cardiomyopathy is the appropriate selection of patients for exercise training and other therapies. Lima et al. selected patients with Stages B2 and C according to the classification of the Latin America Guidelines for the Diagnosis and Treatment of Chagasic Cardiomyopathy. These Guidelines classify Chagas cardiomyopathy into acute and chronic phases. The acute phase is associated with high level parasitaemia, and mild, non-specific symptoms in the majority of individuals. These can include fever, chills, nausea, vomiting, diarrhoea, rash, and meningeal irritation. Moreover, a raised inflammatory lesion at the site of parasite entry (chagoma), unilateral periorbital oedema (Romaña sign), conjunctivitis, lymphadenopathy, and hepatosplenomegaly have all been described in patients with acute Chagas disease. Patients can also present with acute myocarditis. After 8–12 weeks, infected individuals pass into the chronic phase, in which parasites are no longer detectable by peripheral blood microscopy and diagnosis relies on demonstration of anti-T. cruzi antibodies. Infection is life-long in the absence of successful treatment. Over a period of decades, 20–30% of infected individuals develop specific patterns of heart end-organ damage. The chronic phase is classified as Phase A (positive serology without structural heart disease, corresponding to old indeterminate form), Phase B (structural heart disease but with normal right and left ventricular ejection fraction by any method), Phase B2 (structural heart disease but with abnormal right or left ventricular ejection fraction without symptoms of heart failure), Phase C (structural heart disease, abnormal right or left ventricular ejection fraction and symptoms of systolic heart failure), and Phase D (refractory heart failure requiring specialized interventions). Baseline characteristics of patients included in the Lima study indicate that the majority were in Phase B2 based on calculated maximum oxygen consumption, left ventricular ejection fraction of 36–37%, left ventricular end-diastolic diameter of 64 mm by echocardiogram, and brain natriuretic peptide of 89–129 pg/mL. In addition, higher serum levels of brain natriuretic peptide have been reported in Chagas heart disease with heart failure.15 In this context, the results from Lima are applicable to early stage Chagas cardiomyopathy. New studies should be developed in more advanced stages of Chagas cardiomyopathy to test safety and efficacy since this disease presents a worse prognosis compared with other aetiologies.16 The morbidity and mortality associated with Chagas' heart disease make it necessary to develop and maintain programmes to control the vector, eliminate transmission, and perform clinical trials. In general, recommendations for management of chronic Chagas' disease heart failure are supported by level of evidence C, derived from case series and the opinions of specialists.17 Use of specific anti-T. cruzi drugs in Chagas cardiomyopathy is a polemic issue.18 Medical treatment has been extrapolated from trials that included other aetiologies.17,19 Left bundle branch block is not common in Chagas' cardiomyopathy for cardiac resynchronization therapy. Treatment of acute decompensated chagasic heart failure is also based on results obtained in other aetiologies; however, levosimendan has been used successfully in this aetiology.20,21 Alternative surgical procedures to heart transplantation have shown disappointing long-term results despite early benefits.22,23 Heart transplantation is indicated for selected patients, presenting better results than ischaemic and idiopathic dilated cardiomyopathy aetiology.24 Ventricular assist device implantation has been performed successfully.25 Bone marrow stem cell treatment has been tested in selected patients with small improvements in cardiac function.26 However, challenges in the management of chronic Chagas cardiomyopathy have not been properly addressed and specific trials for chronic Chagas cardiomyopathy are now both welcome and necessary. Conflict of interest: none declared.

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