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Reduced functional capacity in patients with Chagas disease: a systematic review with meta-analysis

Abstract

Reduced peak oxygen uptake (VO2peak) is a common clinical finding in progressive Chagas disease. However, the disease stage in which functional impairment is detectable remains uncertain. The present study compared functional capacity between healthy controls and patients with different clinical forms of Chagas disease. A systematic review and meta-analysis (PROSPERO database CRD42017058353) was conducted following a search of the MEDLINE, Web of Science, CINAHL, and LILACS databases from September to December 2017 for articles published in English, Spanish, or Portuguese, with no date restrictions. We included studies that compared the VO2peak between healthy and Chagas disease patients, stratified according to 3 clinical forms [no apparent cardiac disease, non-dilated Chagas heart disease (CHD), and dilated CHD]. Seven cross-sectional studies were included. Chagas disease patients without apparent cardiac disease (n=208) had VO2peak values [mean difference, -1.55ml/kg/min; 95% confidence interval (CI), -4.98ml/kg/min to 1.88ml/kg/min] similar to those of healthy controls (n=105; p=0.38, I2=52%). In non-dilated CHD (n=159), VO2peak was 8.71ml/kg/min lower (95% CI, -13.99 to -3.42ml/kg/min) than in healthy controls (n=59; p=0.001, I2=75%). VO2peak was also significantly lower (mean difference, -9.30ml/kg/min; 95% CI, -11.34 to -7.25ml/kg/min) in dilated CHD patients (n=131) than in healthy controls (n=53; p<0.001, I2=0%). Exercise capacity in Chagas disease patients without apparent cardiac disease is similar to that in healthy controls. Functional impairment in Chagas disease is detectable in the early stages of cardiac involvement, even in the absence of systolic dysfunction and signs of heart failure.

Keywords:
Chagas disease; Functional capacity; Exercise testing; Systematic review

INTRODUCTION

Chagas disease remains a serious public health problem in Latin American countries. Approximately 6-7 million people worldwide are estimated to be infected with Trypanosoma cruzi11. World Health Organization (WHO). Chagas disease (American trypanosomiasis). Geneva: WHO; 2017. Updated 2017 March; cited 2018 March 13. Available from: Available from: http://www.who.int/mediacentre/factsheets/fs340/en/
http://www.who.int/mediacentre/factsheet...
, which is endemic in 21 countries11. World Health Organization (WHO). Chagas disease (American trypanosomiasis). Geneva: WHO; 2017. Updated 2017 March; cited 2018 March 13. Available from: Available from: http://www.who.int/mediacentre/factsheets/fs340/en/
http://www.who.int/mediacentre/factsheet...
, and 80% of the patients do not have access to diagnosis or appropriate treatment22. Dias JCP, Ramos Jr AN, Gontijo ED, Luquetti A, Shikanai-Yasuda MA, Coura JR, et al. II Consenso Brasileiro em Doença de Chagas, 2015. Epidemiol Serv Saúde. 2016;25(n.spe.):7-86., emphasizing the lack of attention to this disease33. Pinheiro E, Brum-Soares L, Reis R, Cubides J-C. Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America. Rev Soc Bras Med Trop. 2017;50(3):296-300..

Recently, the Benznidazole Evaluation for Interrupting Trypanosomiasis trial (BENEFIT)44. Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi Jr A, Rosas F, et al. Randomized Trial of Benznidazole for Chronic Chagas' Cardiomyopathy. N Engl J Med. 2015;373(14):1295-306. showed that parasiticidal treatment does not seem to reduce cardiac damage in Chagas heart disease (CHD), the most severe clinical form of the infection55. Rocha MO, Teixeira MM, Ribeiro AL. An update on the management of Chagas cardiomyopathy. Expert Rev Anti Infect Ther. 2007;5(4):727-43.. In contrast, exercise training has shown positive effects on the overall patient health66. Borghi-Silva A, Trimer R, Mendes RG, Arena RA, Schwartzmann PV. Rehabilitation Practice Patterns for Patients with Heart Failure The South American Perspective. Heart Fail Clin. 2015;11(1):73-82.. The benefits include a significant increase in functional capacity77. Lima MM, Rocha MO, Nunes MC, Sousa L, Costa HS, Alencar MC, et al. A randomized trial of the effects of exercise training in Chagas cardiomyopathy. Eur J Heart Fail. 2010;12(8):866-73.

8. Fialho PH, Tura BR, Sousa AS, Oliveira CR, Soares CC, Oliveira JR, et al. Effects of an exercise program on the functional capacity of patients with chronic Chagas' heart disease, evaluated by cardiopulmonary testing. Rev Soc Bras Med Trop . 2012;45(2):220-4.
-99. Mediano MFF, Mendes FSNS, Pinto VLM, Silva GMS, Silva PS, Carneiro FM, et al. Cardiac rehabilitation program in patients with Chagas heart failure: a single-arm pilot study. Rev Soc Bras Med Trop . 2016;49(3):319-28., respiratory muscle strength99. Mediano MFF, Mendes FSNS, Pinto VLM, Silva GMS, Silva PS, Carneiro FM, et al. Cardiac rehabilitation program in patients with Chagas heart failure: a single-arm pilot study. Rev Soc Bras Med Trop . 2016;49(3):319-28., quality of life77. Lima MM, Rocha MO, Nunes MC, Sousa L, Costa HS, Alencar MC, et al. A randomized trial of the effects of exercise training in Chagas cardiomyopathy. Eur J Heart Fail. 2010;12(8):866-73., and left ventricular ejection fraction (LVEF)99. Mediano MFF, Mendes FSNS, Pinto VLM, Silva GMS, Silva PS, Carneiro FM, et al. Cardiac rehabilitation program in patients with Chagas heart failure: a single-arm pilot study. Rev Soc Bras Med Trop . 2016;49(3):319-28..

Nevertheless, the stage of disease in which reduced functional capacity can be observed remains unclear. Mady et al.1010. Mady C, Ianni BM, Arteaga E, Salemi VM, de Carvalho Frimm C. Maximal functional capacity in patients with Chagas' cardiomyopathy without congestive heart failure. J Card Fail. 2000;6(3):220-4. reported significant reduction in peak oxygen uptake (VO2peak), even in the absence of signs and symptoms of heart failure. In contrast, other studies1111. Molina A, Carrasco H, Milanes J, Molina C, Pacheco JA, Fuenmayor A. Exercise test in chronic Chagas' cardiomyopathy. Its value in the early diagnosis. The behavior of ventricular arrhythmias and conduction disorders due to exercise in the more advanced stages of the disease. Arq Bras Cardiol. 1981;36(2):95-100.,1212. Oliveira FP, Pedrosa RC, Giannella-Neto A. Gas exchange during exercise in different evolutional stages of chronic Chagas' heart disease. Arq Bras Cardiol . 2000;75(6):481-98. reported that reduced functional capacity can be detected only in the advanced stage of the disease, with fatigue and dyspnea during ordinary physical activity as a well-defined marker of poor prognosis1313. Nunes MC, Carmo AA, Rocha MO, Ribeiro AL. Mortality prediction in Chagas heart disease. Expert Rev Cardiovasc Ther. 2012;10(9):1173-84.,1414. Ribeiro AL, Nunes MP, Teixeira MM, Rocha MO. Diagnosis and management of Chagas disease and cardiomyopathy. Nat Rev Cardiol. 2012;9(10):576-89..

As the stage of disease in which reduced functional capacity can be observed may be important in the adoption of cardiac rehabilitation therapies, the present study compared functional capacity between healthy individuals and patients with different clinical forms of Chagas disease.

METHODS

Study design

This systematic review aimed to determine the clinical form of Chagas disease in which reduced functional capacity is detectable. The study was registered in the PROSPERO database CRD42017058353 and edited following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement1515. Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015;313(16):1657-65..

Search strategy and study selection

Potential studies were identified through a systematic search. The databases used were MEDLINE, Web of Science, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Latin American & Caribbean Health Sciences Literature (LILACS) for relevant studies, without date restrictions from inception until December 2017. The search was conducted independently by 2 authors (HSC and MMOL) from September to December 2017. Disagreements were resolved by a third reviewer (PHSF). Search terms included words related to Chagas heart disease, Chagas cardiomyopathy and functional capacity. The following strategy was used for the PubMed search-["Chagas Disease"(Mesh) OR "Chagas heart disease" OR "Chagas Cardiomyopathy"(Mesh)] AND ["Exercise"(Mesh) OR "Exercise Test"(Mesh) OR "functional capacity" OR "oxygen consumption"(Mesh) OR "oxygen uptake" OR "VO2peak"]-and was modified for each database.

Eligibility criteria

Eligibility criteria included studies a) that evaluated patients diagnosed with Chagas disease and defined the criteria; b) that assessed the VO2peak, expressed in ml/kg/min; c) with at least 1 group of patients with Chagas disease and 1 control group; d) written in English, Spanish, or Portuguese.

Those with positive serology for T. cruzi but without signs, symptoms, or evidence of changes on the electrocardiogram or chest radiogram were considered patients with Chagas disease without apparent cardiac disease. Non-dilated CHD patients were defined according to the presence of arrhythmias and intraventricular and atrioventricular conduction disorders with normal ventricular function1616. Andrade JP, Marin Neto JA, Paola AA, Vilas-Boas F, Oliveira GM, Bacal F, et al. I Latin American Guidelines for the diagnosis and treatment of Chagas' heart disease: executive summary. Arq Bras Cardiol . 2011;96(6):434-42.. Patients with ventricular dysfunction (LVEF<50%) and cardiac dilation on echocardiography were considered to have dilated CHD.

Exclusion criteria were review studies, articles in duplicate, animal studies, and those that did not match the objective of this review. There were no restrictions on the year of publication until December 2017. Studies of authors using the same population were excluded, as well as those without adequate statistical analysis.

Quality assessment

The quality assessment was evaluated using the adapted form of the Newcastle Ottawa cohort scale for cross-sectional studies1717. Herzog R, Alvarez-Pasquin MJ, Diaz C, Del Barrio JL, Estrada JM, Gil A. Are healthcare workers' intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review. BMC Public Health. 2013;13:154.. The scale consists of 8 items grouped under 3 topics, namely, selection, comparability and confounders, and outcome.

Outcomes and data analysis

The following data were extracted from the included articles: author, publication year, characteristics of the sample, and VO2peak value and method of measurement.

Chagas disease patients were stratified according to the clinical form of the disease, that is, Chagas disease without apparent cardiac disease, patients with normal left ventricular dimensions and function (non-dilated CHD), and patients with a dilated left ventricle with impaired ventricular systolic function (dilated CHD).

The primary outcome measure was the difference in VO2peak, expressed in ml/kg/min, between healthy individuals and Chagas disease patients (Chagas disease without apparent cardiac disease, non-dilated CHD, and dilated CHD).

The software Review Manager 5.3 (The Nordic Cochrane Centre, Copenhagen, Denmark) was used to conduct meta-analyses for the outcome measures, reported as the mean difference with 95% confidence interval (CI). Heterogeneity was defined as low, moderate, or high according to I2 values (25, 50, or 75%, respectively). A forest plot was used to display the results of the meta-analysis. Data analysis was performed using the fixed-effects model when the results showed low heterogeneity (I2 ≤25%) and the random-effects model when the results showed moderate or high heterogeneity (I2 >25%).

RESULTS

Flow of papers through the review

The electronic search strategy identified 363 studies but 147 (40.5%) were duplicates. After screening titles and abstracts, 187 (51.5%) papers were excluded. Twenty-five articles were review studies, 58 did not perform maximal exercise testing, 26 consisted of a sample without Chagas disease, 24 did not have a healthy control group, 40 conducted animal studies, and 14 articles were not found.

After reading the full text, 16 articles were excluded for failing to meet the objective of the present review, 1 did not define the clinical form of patients with Chagas disease, 1 did not report the sample size, and 3 were by authors who evaluated the same group of study patients in already included studies. Another article did not report VO2peak in ml/kg/min. A total of 7 articles were included in the present review. Figure 1 outlines the flow of papers through the review.

FIGURE 1:
Flow of studies through the review. MEDLINE: Medical Literature Analysis and Retrieval System Online; CINAHL: Cumulative Index to Nursing and Allied Health Literature; LILACS: Latin American & Caribbean Health Sciences Literature.

Participants

Four studies1212. Oliveira FP, Pedrosa RC, Giannella-Neto A. Gas exchange during exercise in different evolutional stages of chronic Chagas' heart disease. Arq Bras Cardiol . 2000;75(6):481-98.,1818. Costa HS, Nunes MC, Souza AC, Lima MM, Carneiro RB, Sousa GR, et al. Exercise-induced ventricular arrhythmias and vagal dysfunction in Chagas disease patients with no apparent cardiac involvement. Rev Soc Bras Med Trop . 2015;48(2):175-80.

19. Rabelo DR, Rocha MO, de Barros MV, Silva JL, Tan TC, Nunes MC. Impaired coronary flow reserve in patients with indeterminate form of Chagas' disease. Echocardiography. 2014;31(1):67-73.
-2020. Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros VC, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11. compared the functional capacity of healthy individuals to patients with Chagas disease without apparent cardiac disease. Three studies1212. Oliveira FP, Pedrosa RC, Giannella-Neto A. Gas exchange during exercise in different evolutional stages of chronic Chagas' heart disease. Arq Bras Cardiol . 2000;75(6):481-98.,2020. Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros VC, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11.,2121. Mady C, Ianni BM, Arteaga E, Salemi VMC, Silva PRS, Cardoso RHA, et al. Maximal functional capacity and diastolic function in patients with cardiomyopathy due to Chagas' disease without congestive heart failure. Arq Bras Cardiol . 1997;69(4):237-41. reported the difference in VO2peak between healthy individuals and patients with non-dilated CHD. Finally, 4 articles1212. Oliveira FP, Pedrosa RC, Giannella-Neto A. Gas exchange during exercise in different evolutional stages of chronic Chagas' heart disease. Arq Bras Cardiol . 2000;75(6):481-98.,2020. Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros VC, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11.,2222. Baião EA, Costa Rocha MO, Lima MM, Beloti FR, Pereira DA, Parreira VF, et al. Respiratory function and functional capacity in Chagas cardiomyopathy. Int J Cardiol. 2013;168(5):5059-61.,2323. Mady C, Cardosa RH, Ianni BM, Arteaga E, Koide NS, Silva PR, et al. Normal maximal functional capacity in patients with congestive heart failure due to Chagas' cardiomyopathy. Arq Bras Cardiol . 1996;67(1):1-4. demonstrated the difference in functional capacity between healthy subjects and patients with dilated CHD. Two studies1212. Oliveira FP, Pedrosa RC, Giannella-Neto A. Gas exchange during exercise in different evolutional stages of chronic Chagas' heart disease. Arq Bras Cardiol . 2000;75(6):481-98.,2020. Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros VC, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11. compared the VO2peak of healthy subjects with more than 1 group with Chagas disease.

Outcomes

The treadmill was used to evaluate VO2peak in 6 studies1818. Costa HS, Nunes MC, Souza AC, Lima MM, Carneiro RB, Sousa GR, et al. Exercise-induced ventricular arrhythmias and vagal dysfunction in Chagas disease patients with no apparent cardiac involvement. Rev Soc Bras Med Trop . 2015;48(2):175-80.

19. Rabelo DR, Rocha MO, de Barros MV, Silva JL, Tan TC, Nunes MC. Impaired coronary flow reserve in patients with indeterminate form of Chagas' disease. Echocardiography. 2014;31(1):67-73.

20. Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros VC, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11.

21. Mady C, Ianni BM, Arteaga E, Salemi VMC, Silva PRS, Cardoso RHA, et al. Maximal functional capacity and diastolic function in patients with cardiomyopathy due to Chagas' disease without congestive heart failure. Arq Bras Cardiol . 1997;69(4):237-41.

22. Baião EA, Costa Rocha MO, Lima MM, Beloti FR, Pereira DA, Parreira VF, et al. Respiratory function and functional capacity in Chagas cardiomyopathy. Int J Cardiol. 2013;168(5):5059-61.
-2323. Mady C, Cardosa RH, Ianni BM, Arteaga E, Koide NS, Silva PR, et al. Normal maximal functional capacity in patients with congestive heart failure due to Chagas' cardiomyopathy. Arq Bras Cardiol . 1996;67(1):1-4. and the cycle ergometer was used in only 1 paper1212. Oliveira FP, Pedrosa RC, Giannella-Neto A. Gas exchange during exercise in different evolutional stages of chronic Chagas' heart disease. Arq Bras Cardiol . 2000;75(6):481-98.. The VO2peak was directly assessed using gas analysis in 3 articles1212. Oliveira FP, Pedrosa RC, Giannella-Neto A. Gas exchange during exercise in different evolutional stages of chronic Chagas' heart disease. Arq Bras Cardiol . 2000;75(6):481-98.,2121. Mady C, Ianni BM, Arteaga E, Salemi VMC, Silva PRS, Cardoso RHA, et al. Maximal functional capacity and diastolic function in patients with cardiomyopathy due to Chagas' disease without congestive heart failure. Arq Bras Cardiol . 1997;69(4):237-41.,2323. Mady C, Cardosa RH, Ianni BM, Arteaga E, Koide NS, Silva PR, et al. Normal maximal functional capacity in patients with congestive heart failure due to Chagas' cardiomyopathy. Arq Bras Cardiol . 1996;67(1):1-4. and estimated by formulas in 4 studies1818. Costa HS, Nunes MC, Souza AC, Lima MM, Carneiro RB, Sousa GR, et al. Exercise-induced ventricular arrhythmias and vagal dysfunction in Chagas disease patients with no apparent cardiac involvement. Rev Soc Bras Med Trop . 2015;48(2):175-80.

19. Rabelo DR, Rocha MO, de Barros MV, Silva JL, Tan TC, Nunes MC. Impaired coronary flow reserve in patients with indeterminate form of Chagas' disease. Echocardiography. 2014;31(1):67-73.
-2020. Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros VC, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11.,2222. Baião EA, Costa Rocha MO, Lima MM, Beloti FR, Pereira DA, Parreira VF, et al. Respiratory function and functional capacity in Chagas cardiomyopathy. Int J Cardiol. 2013;168(5):5059-61..

Quality of papers

The mean Newcastle Ottawa scale score adapted for cross-sectional studies was 7.3 points (range from 6.0 to 9.0). All studies adequately verified the primary outcome and statistically demonstrated the difference between the groups. However, only 1 study reported the sample calculation. The scores according to the Newcastle Ottawa scale and the characteristics of the included studies are summarized in Table 1.

TABLE 1:
Characteristics of included studies that compared the VO2peak between healthy individuals and Chagas disease patients.

VO2peak in patients with Chagas disease without apparent cardiac disease

The mean score for quality was 7.0 points (ranging from 6.0 to 9.0). Only 1 (25%) study evaluated VO2peak directly using gas analysis. One paper used the cycle ergometer and 3 used the treadmill in exercise testing.

No study found significant differences in the VO2peak between healthy individuals and patients with Chagas disease without apparent cardiac disease. The forest plot (Figure 2) showed that patients with Chagas disease without apparent cardiac disease (n=208) had VO2peak values (mean difference -1.55ml/kg/min; 95% CI from -4.98ml/kg/min to 1.88ml/kg/min) similar to those of healthy subjects (n=105) (p=0.38). The heterogeneity of the comparison was moderate (I2 = 52%).

FIGURE 2:
Mean difference in VO2peak between patients with Chagas disease without apparent cardiac disease and healthy controls. SD: standard deviation; 95% CI: 95% confidence interval; VO 2 peak: peak oxygen uptake.

VO2peak in non-dilated CHD patients

The mean score for quality was 7.0 points (ranging from 6.0 to 8.0). Two (66.6%) studies evaluated VO2peak directly using gas analysis. One paper used the cycle ergometer and the other 2 performed exercise testing with a treadmill.

Of the 3 studies included, only 1 (33.3%) reported no significant difference in VO2peak between healthy subjects and dilated CHD patients and 2 (66.6%) showed that the VO2peak was significantly lower in non-dilated CHD patients than in healthy subjects.

The forest plot (Figure 3) showed that VO2peak was 8.71ml/kg/min lower (95% CI -13.99 to -3.42ml/kg/min) in non-dilated CHD patients (n=159) than in healthy subjects (n=59) (p=0.001). The heterogeneity of the comparison was high (I2 = 75%).

FIGURE 3:
Mean difference in VO2peak between non-dilated CHD patients and healthy controls. CHD: Chagas heart disease; SD: standard deviation; 95% CI: 95% confidence interval; VO 2 peak: peak oxygen uptake.

VO2peak in dilated CHD patients

The mean score for quality was 7.0 points (ranging from 6.0 to 9.0). Two (33.3%) studies evaluated VO2peak directly using gas analysis. One (33.3%) paper used the cycle ergometer and 2 (66.6%) performed maximum exercise testing with a treadmill.

All 3 included studies showed that the VO2peak was significantly lower in dilated CHD patients than in healthy subjects. The forest plot (Figure 4) showed that VO2peak was significantly lower (mean difference 9.30ml/kg/min; 95% CI -11.34 to -7.25ml/kg/min) in dilated CHD patients (n=131) than in healthy subjects (n=53) (p<0.001). The analysis was homogeneous (I2 = 0%).

FIGURE 4:
Mean difference in VO2peak between dilated CHD patients and healthy controls. CHD: Chagas heart disease; SD: standard deviation; 95% CI: 95% confidence interval; VO 2 peak: peak oxygen uptake.

DISCUSSION

The VO2peak has been widely used in assessing the functional capacity of patients with Chagas disease and is considered a potential prognostic marker2424. Mady C, Cardoso RH, Barretto AC, da Luz PL, Bellotti G, Pileggi F. Survival and predictors of survival in patients with congestive heart failure due to Chagas' cardiomyopathy. Circulation. 1994;90(6):3098-102.. However, the association between functional impairment and the stage of disease in which it is detectable has been unclear. To our knowledge, this is the first study to systematically determine the stage of Chagas disease at which reduced exercise capacity can be observed. The main findings of the present study were: 1) patients with Chagas disease without apparent cardiac disease have VO2peak values similar to those of healthy individuals and 2) patients with CHD, even with preserved systolic function, showed a significant reduction in functional capacity when compared to healthy individuals.

For patients with Chagas disease without apparent cardiac disease, no study included in this review reported reduced functional capacity in this group of patients compared to that in the healthy subjects. In fact, patients with Chagas disease without apparent cardiac disease have excellent prognosis, similar to that of healthy individuals. However, although VO2peak values are within the normal range, exercise tests in these patients are highly recommended since Chagas patients present a greater number of exercise-induced arrhythmias, both during exercise and the recovery phase1818. Costa HS, Nunes MC, Souza AC, Lima MM, Carneiro RB, Sousa GR, et al. Exercise-induced ventricular arrhythmias and vagal dysfunction in Chagas disease patients with no apparent cardiac involvement. Rev Soc Bras Med Trop . 2015;48(2):175-80..

In patients with non-dilated CHD, 2 studies found a significant decrease in VO2peak compared to that in the healthy subjects, and 1 reported no difference between these groups. The forest plot showed a significant difference in functional capacity between the non-dilated CHD and healthy control groups. The initial phase of Chagas cardiac disease is usually characterized by impairment in electrical stimulus formation and conduction. As shown by electrocardiography, the changes in ventricular function are discrete and segmental, but may indicate subclinical heart disease capable of affecting the functional status. According to Mady et al.1010. Mady C, Ianni BM, Arteaga E, Salemi VM, de Carvalho Frimm C. Maximal functional capacity in patients with Chagas' cardiomyopathy without congestive heart failure. J Card Fail. 2000;6(3):220-4., electrocardiographic changes present from the early stages of disease lead to significant myocardial damage that may reduce exercise capacity. However, we believe that these results should be interpreted with caution, since the meta-analysis showed high heterogeneity. Chagas disease is characterized by great heterogeneity in clinical presentation. With regard to functional capacity, for example, the included studies showed a standard deviation of up to 12ml/kg/min. Furthermore, heterogeneity in the observational studies may be frequent and more common than in interventional studies2525. Stroup DF, Berlin JA, Morton SC, Olkin l, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA . 2000;283(15):2008-12..

In the analysis of patients with dilated CHD, all studies showed significantly lower VO2peak values compared to those in healthy subjects. The forest plot confirmed this result, with homogeneity among the studies. Briefly, patients with dilated CHD have VO2peak values 9.30ml/kg/min lower than healthy patients, equivalent to almost 3 metabolic equivalents (METs). Some findings may suggest the functional impairment at this stage of the disease. The presence of symptoms of heart failure, such as fatigue and dyspnea, may be the most significant. These symptoms limit the patient's ability to exercise2626. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey Jr DE, Drazner MH, et al. 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2013;62(16):1495-1539., especially in association with abnormalities in the structure of skeletal muscle2727. de Oca MM, Torres SH, Loyo JG, Vazquez F, Hernández N, Anchustegui B, et al. Exercise performance and skeletal muscles in patients with advanced Chagas disease. Chest. 2004;125(4):1306-14.. In addition, reduced cardiac output, one of the hallmarks of heart failure2828. Bocchi EA, Braga FGM, Ferreira SMA, Rohde LEP, Oliveira WA, Almeida DR, et al. III Diretriz Brasileira de Insuficiência Cardíaca Crônica. Arq Bras Cardiol . 2009;93(supl 1):3-70., implies lower blood flow to the muscles used during exercise and early lactate accumulation. Respiratory muscle weakness may also reduce functional capacity, as previously reported in patients with heart failure2929. Ribeiro JP, Chiappa GR, Callegaro CC. The contribution of inspiratory muscles function to exercise limitation in heart failure: pathophysiological mechanisms. Rev Bras Fisioter. 2012;16(4):261-7.. Other factors, such as progressive deterioration of ventilatory response3030. Oliveira FP, Pedrosa RC. Ventilatory response during exercise among chronic Chagas cardiopathy patients. Sao Paulo Med J. 2006;124(5):280-4. and chronotropic incompetence2020. Rocha AL, Lombardi F, da Costa Rocha MO, Barros MV, Val Barros VC, Reis AM, et al. Chronotropic incompetence and abnormal autonomic modulation in ambulatory Chagas disease patients. Ann Noninvasive Electrocardiol. 2006;11(1):3-11., can also account for functional impairment. Finally, it may also be possible that the fear of exercise and the discomfort caused by exercise-induced arrhythmias may lead to progressive physical inactivity.

This review had some strengths and limitations. The mean quality score of 7.3 for the included studies was good3131. McPheeters ML, Kripalani S, Peterson NB, Idowu RT, Jerome RN, Potter SA, et al. Quality Improvement Interventions To Address Health Disparities closing the quality gap - revisiting the state of the science [Internet]. Evid Rep Technol Assess. 2012. Available from://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0052248/
from://www.ncbi.nlm.nih.gov/pubmedhealth...
. However, there was a major difference in the mean age among the groups. In addition, few studies were included in each meta-analysis. The heterogeneity among the studies included in the meta-analysis was high for the comparison between non-dilated CHD and healthy individuals. In addition, since there was no restriction on the date of publication, some studies could not be found, especially the oldest ones. Finally, publication bias inherent to systematic reviews was avoided by including studies published in languages other than English.

CONCLUSION

Patients with Chagas disease without apparent cardiac disease have functional capacity similar to that of healthy individuals. In patients with the cardiac form of the disease, even in the absence of systolic dysfunction, functional capacity is markedly decreased, and exercise training should be mandatory in this population.

REFERENCES

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    World Health Organization (WHO). Chagas disease (American trypanosomiasis). Geneva: WHO; 2017. Updated 2017 March; cited 2018 March 13. Available from: Available from: http://www.who.int/mediacentre/factsheets/fs340/en/
    » http://www.who.int/mediacentre/factsheets/fs340/en/
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    Dias JCP, Ramos Jr AN, Gontijo ED, Luquetti A, Shikanai-Yasuda MA, Coura JR, et al. II Consenso Brasileiro em Doença de Chagas, 2015. Epidemiol Serv Saúde. 2016;25(n.spe.):7-86.
  • 3
    Pinheiro E, Brum-Soares L, Reis R, Cubides J-C. Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America. Rev Soc Bras Med Trop. 2017;50(3):296-300.
  • 4
    Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi Jr A, Rosas F, et al. Randomized Trial of Benznidazole for Chronic Chagas' Cardiomyopathy. N Engl J Med. 2015;373(14):1295-306.
  • 5
    Rocha MO, Teixeira MM, Ribeiro AL. An update on the management of Chagas cardiomyopathy. Expert Rev Anti Infect Ther. 2007;5(4):727-43.
  • 6
    Borghi-Silva A, Trimer R, Mendes RG, Arena RA, Schwartzmann PV. Rehabilitation Practice Patterns for Patients with Heart Failure The South American Perspective. Heart Fail Clin. 2015;11(1):73-82.
  • 7
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  • Financial support: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Publication Dates

  • Publication in this collection
    Jul-Aug 2018

History

  • Received
    09 May 2018
  • Accepted
    31 July 2018
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