Parasympathetic dysautonomia precedes left ventricular systolic dysfunction in Chagas disease Antonio L. P. Ribeiro, MD, ScD,a Ruy S. Moraes, MD, ScD,b,d Jorge P. Ribeiro, MD, ScD,b,d Elton L. Ferlin, BSc EE,c Rosália M. Torres, MD,a Enilce Oliveira, MD,a and Manoel O. C. Rocha, MD, ScDa Belo Horizonte and Porto Alegre, Brazil
Background Parasympathetic dysautonomia is an established feature of advanced Chagas cardiomyopathy. However, in the absence of cardiac involvement, the presence of vagal dysfunction remains controversial. In a cross-sectional study, we compared patients with Chagas disease without cardiac involvement and healthy individuals by three different methods to determine whether vagal dysfunction is present in the early phase of Chagas disease.
Methods Sixty-one patients with Chagas disease without cardiac involvement and 38 controls were submitted to respiratory sinus arrhythmia test and 24-hour Holter monitoring. Vagal heart influences were assessed by the expiratory/inspiratory (E/I) ratio, time-domain indexes of heart rate variability (HRV), and by the quantification of a 3-dimensional return map.
Results The two groups were comparable in terms of left ventricular ejection fraction and left ventricular end-diastolic dimension. Compared with the control group, patients with Chagas disease had significantly lower values of the E/I ratio (mean ± SD: 1.38 ± 0.02 and 1.25 ± 0.02, P < .004) and short-term indexes of HRV (median [interquartile range]—rMSSD: 23 [18-27] and 17 [13-23], P = .00; pNN50: 11 [7-17] and 6 [2-12], P = .00). P3, a beat-to-beat HRV index derived from the 3-dimensional return map, also was significantly reduced in the Chagas disease group (mean ± SD: 118 ± 5 vs 100 ± 4, P = .00). None of these indexes of vagal heart control were significantly correlated with left ventricular function or to the presence of esophageal radiologic abnormalities.
Conclusion Parasympathetic dysautonomia is an independent and early phenomenon in Chagas disease and may precede left ventricular systolic dysfunction. (Am Heart J 2001;141:260-5.)
Chagas disease is a major endemic condition in Latin America, where close to 20 million persons are infected.1 Recently, Chagas disease has become also a potential health problem in Europe and the United States, where thousands of Latin American immigrants are now living.2 The natural history of Chagas disease was described in the beginning of the century, but there are many obscure and controversial aspects. Although sudden death is mainly a complication of advanced cardiac involvement, it can be the first manifestation of the disease. Bestetti et al3 found that one fifth of the patients dying suddenly from Chagas disease were From the aHospital das Clínicas and School of Medicine, Federal University of Minas Gerais, Belo Horizonte, the bCardiology and cBiomedical Engineering Divisions, Hospital de Clínicas de Porto Alegre, and the dDepartment of Medicine, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil. Supported by grants from Fundação de Amparo à Pesquisa do Estado do Minas Gerais, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul, Coordenadoria de Aperfeiçoamento do Ensino Superior, Conselho Nacional de Pesquisa, and Programa de Incentivo de Núcleos de Excelência. Submitted June 7, 2000; accepted September 1, 2000. Reprint requests: Antonio L. P. Ribeiro, MD, ScD, Rua Companha, 98/101, 30310770, Belo Horizonte, MG, Brazil. E-mail:
[email protected] Copyright © 2001 by Mosby, Inc. 0002-8703/2001/$35.00 + 0 4/1/111406 doi:10.1067/mhj.2001.111406
asymptomatic and some of them had normal electrocardiograms just before death. The mechanisms involved in sudden death in Chagas disease are controversial, but it has been argued that structural cardiac abnormalities, ventricular arrhythmias, and autonomic disturbances may play a role.4 Autonomic involvement is a well-established feature of advanced Chagas cardiomyopathy, in which anatomic denervation and functional abnormalities have been extensively described.5 For some authors,6 vagal and sympathetic autonomic disturbances are always a late phenomena in Chagas disease and may not occur in early phases. Indeed, Davila et al6 proposed that ventricular enlargement and neurohumoral activation preceded autonomic dysfunction, which would be a late consequence of heart failure, as in many other cardiac diseases. Several methods are currently available to evaluate cardiac autonomic dysfunction and some of them are very sensitive in detecting early involvement.7 Thus, in this cross-sectional study, we used three different methods to compare patients with Chagas disease without cardiac or esophageal involvement and healthy individuals to test the hypothesis that vagal dysfunction is present in the early phase of Chagas disease.
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Methods Patients Patients were referred from blood banks or primary care units to the Chagas Disease Outpatient Reference Center of the Federal University of Minas Gerais, Brazil, to evaluate suspected or confirmed infection with Tripanossoma cruzi. Consecutive patients between 15 and 50 years old with a definite serologic status for Chagas disease and absence of heart and digestive involvement detected in a first medical interview were recruited. A definite serologic status for Chagas disease was defined by the presence of two or more different positive reactions to T cruzi (indirect immunofluorescence, enzymelinked immunosorbent assay, indirect hemagglutination, or complement fixation) in patients at risk of infection. Those who agreed to participate and signed a written informed consent were submitted to a standard screening protocol that included medical history, physical examination, electrocardiogram, laboratory and chest x-ray examinations. Exclusion criteria were (1) any cardiac symptoms or abnormalities in the cardiovascular physical examination, (2) abnormal electrocardiogram or chest x-ray film, (3) any evidence of cardiovascular disease, diabetes, thyroid dysfunction, chronic obstructive pulmonary disease, renal or hepatic failure, anemia, or any significant systemic disease, (4) alcoholism, (5) pregnancy, and (6) the use of any drug with cardiovascular or metabolic effects. A control group of healthy volunteers (between the ages of 15 and 50 years) with no risk or serologic evidence of Chagas disease was also submitted to the same evaluation.
Study protocol The study protocol was approved by the Ethical Committee of the Hospital das Clínicas of the Federal University of Minas Gerais. Patients and controls were evaluated by one of the investigators (A. L. P. R.), without knowledge of the individuals’ serologic status. Each one had a 2-dimensional echo Doppler cardiogram (Siemens Sonoline CF) with M-mode measurements performed according to the American Society of Echocardiography.8 Most of the patients with Chagas disease (56/61 individuals) and some of the controls (16/38) also had a barium contrast esophageal radiologic study. Patients and controls also participated in respiratory sinus arrhythmia and heart rate variability evaluations.
Respiratory sinus arrhythmia Patients came to the laboratory in the morning, after fasting for at least 2 hours. Respiratory sinus arrhythmia was assessed in a quiet room with controlled temperature (25°C ± [SD] 3°C). No caffeine-containing beverages, cigarettes, and medications were allowed for 12 hours before the study. Subjects were sitting and breathed into a mouthpiece connected to a water-sealed spirometer (Collins DSII) with a noseclip. Subjects were instructed to breathe at 6 cycles per minute with the help of a metronome, heart rate was recorded with an electrocardiogram (Hewllet-Packard 1504), and tidal volume was measured. The quantification procedure was performed accordingly to the Grossman et al9 peak-valley respiratory sinus arrhythmia estimation, with use of both respiratory and heart period data. In brief, the minimal inspiratory heart period and the maximal expiratory heart period were
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obtained for each respiratory cycle. For each respiratory cycle, an expiratory/inspiratory (E/I) ratio was calculated. The E/I ratio is a well-established index of the respiratory sinus arrhythmia, which is closely related to the vagal control of the heart.10 The mean E/I ratio for a patient was the sum of the individual E/I ratio for each breath divided by the number of breaths occurring during the measurement period. To minimize the effect of the differences in the tidal volume achieved by each subject, the mean E/I ratio value was normalized with use of the mean tidal volume recorded during the same maneuver. Each individual value was classified as normal or abnormal according to age-related reference values defined by Smith.10
Heart rate variability Twenty-four-hour Holter monitoring was performed with a portable three-channel cassette tape recorder (Del Mar Avionics model 423). Subjects were encouraged to continue with their normal everyday activities during the recordings, with the avoidance of physical exercise or drugs that could interfere with autonomic function. Analysis of heart rate variability was performed when at least 18 hours of good-quality tracings and 85% or more sinus rhythm beats were available. Because of technical reasons, only 73 tapes (recording time [mean ± SD] 22.7 ± 1.4 hours) of 31 control subjects and 42 patients with Chagas disease were studied. The recordings were analyzed on a Del Mar 750A Innovator scanner (Del Mar Avionics, Irvine, Calif) by a semiautomatic technique. This software allows detection of normal beats, artifacts, and ectopies to create a time series of normal R-R intervals, with a resolution of 2.4 milliseconds.11 The following time-domain indexes were calculated12: SD of R-R intervals (SDNN), SD of mean R-R intervals calculated in 5-minute intervals (SDANN), percentage of number of pairs of R-R intervals differing by more than 50 milliseconds (PNN50), and square root of the mean of sum of squares of differences between adjacent R-R intervals (rMSSD). After age adjustment, the values of SDNN, SDANN, and rMSSD were classified as normal or abnormal according to reference values defined by the Task Force of the European Society of Cardiology and North American Society for Pacing and Electrophysiology.12 For each 24-hour heart rate time series, a 3-dimensional return map was constructed plotting RRn versus difference between adjacent R-R intervals ([RRn + 1] – [RRn]) versus counts as previously described.7 This nonlinear method has been shown to quantify parasympathetic as well as sympathetic modulation to the sinus node and it is capable of detecting early autonomic dysfunction in diabetic patients in a reproducible way.7 In short, normal R-R intervals were plotted on the x axis against the difference between adjacent R-R intervals on the y axis. Whenever superimposition of points occurred, the number of superimposed points was expressed on the z axis, normalized by the maximum density. A set of indices was calculated to quantify the 3-dimensional images. P1 was calculated as 100 minus the double of the mean slope between 10% and 90% of maximum density, in the plane that intersects the distribution in its maximum concentration of points, perpendicular to RRn. To calculate P2 and P3, 3-dimensional images were displayed as 10 equally spaced contour curves: P2 was calculated as the maximal longitudinal length and P3 as the maximal transversal length of the outermost
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Figure 1
Representative example of 24-hour 3-dimensional return maps in a control subject (1) and a patient with Chagas disease and normal left ventricular function (2). Three-dimensional distributions (a) and contour curves (b). P1 was measured at maximum density along the plane depicted; P1 = (100 – 2 · Mean slope); Mean slope = Tangent of the angle θ. P2 = Maximal longitudinal range and P3 = Maximal transversal range.
contour curve. The general index MN was calculated as the product of P1 · P2 · P3 · 10–3 (Figure 1).
Statistical analysis This study was designed to have an 80% statistical power in detecting abnormal respiratory sinus arrhythmia in 30% of the patients with Chagas disease in a 2-sided test at 5% significance, considering a 2:1 ratio of Chagas disease and control patients. When necessary, logarithmic transformation of nonnormal or heteroscedatic data was performed to allow subsequent analysis. Baseline features and autonomic indexes of the two groups were compared with use of the unpaired Student t and exact Fisher tests. Age and tidal volume were significantly correlated with respiratory sinus arrhythmia and the individual values of the E/I ratio were adjusted for these variables. Similarly, time domain heart rate variability indexes were adjusted for age and mean 24-hour R-R interval. Pearson’s correlation coefficient was used to measure correlation between variables and, when multiple comparisons were made, the Bonferroni correction was applied. To ensure that the presence of esophageal radiologic abnormalities were not responsible for the observed reduction in vagal indexes, post hoc statistical analysis was performed after exclusion of those patients who exhibited esophageal mild motility disorders.
Results The study population consisted of 61 patients with Chagas disease and 38 control subjects who completed the screening protocol and showed no heart involvement or systemic disease. Clinical, radiologic, and echocardiographic characteristics of the study sample are shown in Table I. Patients with Chagas disease were slightly older than control subjects. Contrast barium esophageal radiologic study disclosed mild motility disorders in 6 control subjects and in 3 patients with Chagas disease; they were subtle abnormalities, with 1minute retention of the barium meal in the esophagus, without significant dilatation. The ejection fraction was normal in almost all patients; only one patient with Chagas disease had a slightly reduced value (0.50%). There were no differences in the cardiothoracic index and the left ventricular end-diastolic diameter between the groups. Table II presents the results of autonomic tests for patients with Chagas disease and controls. Patients had significantly reduced respiratory sinus arrhythmia as assessed by the adjusted mean E/I ratio and only patients with Chagas disease had age-related abnormal test
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Table I. Clinical characteristics of controls and patients with Chagas disease
Age (y) Sex (male/female) Weight (kg) Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Cardiothoracic ratio Mild esophageal motility disturbance (%) Ejection fraction (%) Ejection fraction
