Volume 141, Issue 2, Page E6 (February 2001)

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ABSTRACT

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Parasympathetic dysautonomia precedes left ventricular systolic dysfunction in Chagas disease☆☆☆

Received 7 June 2000; accepted 1 September 2000.

Abstract

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.)

Article Outline

• Abstract

• Methods

• Patients

• Study protocol

• Respiratory sinus arrhythmia

• Heart rate variability

• Statistical analysis

• Results

• Discussion

• References

• Copyright

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 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.

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, enzyme-linked 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 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 contour curve. The general index MN was calculated as the product of P1 · P2 · P3 · 10–3 (Figure 1).

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Fig. 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.

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.

Table I.

Clinical characteristics of controls and patients with Chagas disease


	Controls (n = 38)	Chagas disease (n = 61)	Statistical significance
Age (y)	33 ± 8	38 ± 8	P = .00
Sex (male/female)	33/5	46/15	P = .17
Weight (kg)	71.1 ± 11.4	67.1 ± 9.8	P = .06
Heart rate (beats/min)	69 ± 10	69 ± 7	P = .86
Systolic blood pressure (mm Hg)	118 ± 11	122 ± 12	P = .10
Diastolic blood pressure (mm Hg)	76 ± 10	78 ± 9	P = .12
Cardiothoracic ratio	0.42 ± 0.04	0.43 ± 0.03	P = .67
Mild esophageal motility disturbance (%)	19	11	P = .41
Ejection fraction (%)	68 ± 6	68 ± 7	P = .99
Ejection fraction <55% (%)	0	2	P = 1.00
Left ventricular end-diastolic diameter	5.17 ± 0.07	5.07 ± 0.04	P = .39

Data are mean ± SD when appropriate.

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 1-minute 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 results. Although long-term heart rate variability indexes SDNN and SDANN were not different between groups, patients with Chagas disease had significantly reduced values of short-term heart rate variability indexes rMSSD and pNN50. The proportion of patients with abnormally reduced values of rMSSD was significantly greater in the Chagas disease group than in controls.

Table II.

E/I ratio and 24-hour indexes of heart rate variability in control subjects and patients with Chagas disease and normal left ventricular systolic function


	Controls	Chagas disease	Statistical significance
E/I ratio	1.38 ± 0.02	1.25 ± 0.02	P = .00
Abnormal E/I ratio	0/38	15/61	P = .00
Mean 24-hour R-R interval (msec)	820 ± 113	839 ± 107	P = .54
SDNN (msec)	154 ± 36	143 ± 31	P = .18
SDANN (msec)	140 ± 33	134 ± 32	P = .53
PNN50 (%)*	11 (7-17)	6 (2-12)	P = .00
RMSSD (msec)*	23 (18-27)	17 (13-23)	P = .00
Abnormal rMSSD	4/31	15/42	P = .03
P1	69 ± 10	68 ± 11	P = .22
P2	87 ± 11	88 ± 14	P = .74
P3	118 ± 5	100 ± 4	P = .00
MN	722 ± 28	612 ± 32	P = .03

E/I ratio was measured in 38 controls and 61 patients; 24-hour indexes of heart rate variability were measured in 31 controls and 42 patients. Values were adjusted for covariates (see Methods) and expressed by mean ± SD when appropriate, except *, expressed by medians (interquartile range).

Figure 1 displays two examples of 3-dimensional return maps, one for a patient with Chagas disease and another for a control subject. There is a clear reduction in the maximal transversal axis (P3) of the 3-dimensional distribution obtained from the patient with Chagas disease compared with the healthy subject. P3 is related to the beat-by-beat heart period oscillation, which is significantly reduced in the Chagas disease group (Table II). Although P1 and P2 were not different between the groups, the general index MN was significantly reduced in the Chagas disease group (Table II).

Table III presents the correlation matrix for autonomic indexes for controls and patients with Chagas disease.

Table III.

Pearson correlation coefficient among E/I ratio and selected 24-hour indexes of heart rate variability in controls and patients with Chagas disease


	E/I ratio	Ln RMSSD	Ln PNN50
Ln RMSSD	0.566*
Ln PNN50	0.548*	0.959*
P3	0.535*	0.864*	0.868*
*P < .005.

There was a strong correlation among E/I ratio, rMSSD, pNN50, and P3. However, neither mean E/I ratio nor any of these heart rate variability indexes were significantly correlated to the left ventricular ejection fraction or diameter, to the cardiothoracic index, or to the presence of esophageal radiologic abnormalities.

When those patients with mild esophageal abnormalities were excluded from the study group, vagal test mean values remained significantly reduced in patients with Chagas disease compared with the controls (Table IV).

Table IV.

Vagal indexes in controls and patients with Chagas disease with normal left ventricular systolic function after exclusion of individuals with mild esophageal involvement


	Controls	Chagas disease	Statistical significance
E/I ratio	1.37 ± 0.02	1.25 ± 0.01	P = .00
PNN50 (%)*	14 (8-17)	6 (2-13)	P = .00
RMSSD (msec)*	23 (18-27)	17 (13-23)	P = .01
P3	117 ± 5	101 ± 4	P = .01

E/I ratio was measured in 32 controls and 58 patients; 24-hour indexes of heart rate variability were measured in 26 controls and 39 patients. Values were adjusted for covariates (see Methods) and expressed by mean ± SD when appropriate, except *, expressed by medians (interquartile range).

Discussion

Reduced heart rate variability and abnormalities in respiratory sinus arrhythmia are definite markers of increased risk of death in several conditions, such as heart failure,13 diabetes mellitus,14 and post myocardial infarction.15 Evaluation of respiratory sinus arrhythmia and time domain indices of heart rate variability have scarcely been used to evaluate patients with Chagas disease,16 and the nonlinear 3-dimensional return map has not been used. In this study all three methods were able to detect parasympathetic dysautonomia in patients with Chagas disease without any left ventricular dysfunction.

Many of the studies using respiratory sinus arrhythmia as a marker of vagal influences on the heart have been criticized by the absence of control or adjustment of the index by variables such as age, respiratory rate, and tidal volume.17 In our study all these confounding factors were considered in the analysis.

Although time domain indexes of heart rate variability predominantly reflect vagal modulation to the sinus node,11 in our data only the short-term indexes RMSSD and PNN50 were reduced in patients with Chagas disease. These indexes are almost completely abolished by atropine and are considered measures of parasympathetic heart control.11 Long-term indexes, such as SDNN and SDANN, are not exclusively vagally modulated but can be influenced by other factors, including thermoregulation processes, the renin-angiotensin system, and circadian rhythms.18

Results of the 3-dimensional return map allowed us to understand the mechanism by which time domain indexes of heart rate variability were affected. The 3-dimensional return map sympathetic index P1 was not affected by Chagas disease, indicating that the reduction observed in heart rate variability was not related to any sympathetic changes. The maximal longitudinal axis of the distribution (P2) was similar in patients with Chagas disease and controls, indicating that, besides having the same mean heart rate during 24 hours, they also have the same heart rate dynamic range of variation. Patients with Chagas disease showed a reduction in the maximal beat-to-beat variability during 24 hours, expressed by the maximal transversal axis (P3), which reflects vagal modulation to the sinus node, especially during rest and sleep periods.7

Most previous studies indicated that patients with Chagas disease with normal left ventricular function also had normal autonomic test results.5, 6 Marin-Neto et al19 found significant autonomic dysfunction in the absence of left ventricular dysfunction only in patients with the digestive form of Chagas disease. At variance with these studies, our data support highly significant vagal impairment in patients with Chagas disease independently of the presence of left ventricular dilatation or depressed ejection fraction and even of radiologic esophageal abnormalities.

The reasons for these discordant results may be related to methodologic aspects. All other studies evaluated small numbers of patients, reducing the statistical power to detect subtle autonomic dysfunction. Likewise, the use of less sensitive methods, such as the Valsalva maneuver, might have reduced the ability to detect autonomic abnormalities. Because Marin-Neto et al19 found significant autonomic abnormalities in patients with Chagas disease with normal left ventricular function only when they had the digestive form of the disease, it could be argued that some of our patients could also have undiagnosed digestive involvement. We took special care to select patients without manifestations of digestive involvement and most of them had normal barium esophageal studies. Mild and nonspecific motility abnormalities were occasionally found in a few patients with Chagas disease as well as in control subjects. Autonomic indexes were not correlated with such esophageal abnormalities and reduced heart rate variability and respiratory sinus arrhythmia values were found in the Chagas disease group even when we excluded those patients.

The mechanisms responsible for the observed vagal dysfunction in the absence of left ventricular systolic impairment are not known. Neuronal degeneration and cholinergic terminal nerve destruction20 have been described in experimental and human Chagas disease and may be mediated by inflammatory or immune processes. On the other hand, circulating autoantibodies with partial muscarinic cholinergic agonistic activity have been found in dysautonomic asymptomatic patients with Chagas disease with normal electrocardiograms and chest x-ray films, and it has been hypothesized that it could have provoked vagal dysfunction by desensitization or down-regulation of the muscarinic receptors.21

In conclusion, our data clearly indicate that parasympathetic dysautonomia may precede left ventricular systolic dysfunction in Chagas disease. This finding may have pathophysiologic as well as clinical implications. Although the prognosis of Chagas disease without left ventricular dysfunction is thought to be good,22 as a corollary to other clinical conditions, the presence of cardiac dysautonomia may primarily influence the clinical course of the disease and, more important, may be related to sudden death, a major complication of Chagas disease. This hypothesis deserves to be tested by longitudinal studies.

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Belo Horizonte and Porto Alegre, Brazil

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.

☆☆ Reprint requests: Antonio L. P. Ribeiro, MD, ScD, Rua Companha, 98/101, 30310-770, Belo Horizonte, MG, Brazil. E-mail: antonior@net.em.com.br

PII: S0002-8703(01)63552-X

doi:10.1067/mhj.2001.111406

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