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We have studied the cardiac chronotropic responses to the Valsalva maneuver and to dynamic exercise of twenty chronic chagasic patients with normal left ventricular function and no segmental wall abnormalities by two-dimensional echocardiogram. The absolute increase in heart rate of the patients (Δ = 21.5 ± 10 bpm, M±SD) during the maneuver was significantly diminished when compared to controls (Δ = 31.30 ± 70, M±SD, p = 0.03). The minimum heart rate (58.24 ± 8.90 vs. 62.80 ± 10, p = 0.68) and the absolute decrease in heart rate at the end of the maneuver (Δ = 38.30 ± 13 vs. Δ = 31.47 ± 17, p = 0.10) were not different from controls. The initial heart rate acceleration during dynamic exercise (Δ = 12 ± 7.55 vs. Δ = 19 ± 7.27, M±SD, p = 0.01) was also diminished, but the heart rate recovery during the first ten seconds was more prominent in the sero-positive patients (Median: 14, Interquartile range: (9.75-17.50 vs. 5(0-8.75, p = 0.001). The serum levels of muscarinic cardiac auto-antibodies were significantly higher in the chagasic patients (Median: 34.58, Interquartile Range: 17-46.5, Optical Density) than in controls (Median: 0, Interquartile Range: 0-22.25, p = 0.001) and correlated significantly and directly (r = 0.68, p = 0.002) with early heart rate recovery during dynamic exercise. The results of this investigation indirectly suggest that, the cardiac muscarinic auto-antibodies may have positive agonist effects on parasympathetic heart rate control of chagasic patients.

Background: Children with scorpion envenomation have massive sympathetic activation and variable degrees of left ventricular systolic dysfunction., Objective: To evaluate a rescue protocol for children with severe left ventricular dysfunction secondary to scorpion envenomation., Methods: Four children, after scorpion envenomation, were subjected to a rescue protocol for acute left ventricular dysfunction: Endotracheal intubation and respiratory assistance, electrocardiograms, chest x-Ray, echocardiograms and blood samples for norepinephrine and troponin I serum levels. Samples and echocardiograms were repeated at 12, 24 and 48 hours. Intravenous medications: Dobutamine: 4-6 microg/kg/min. Amiodarone: 3 mg/kg during a 2 hour period. Maintenance: 5 mg/kg/day. Furosemide: 0.5 mg/kg/dose. Diuretics were given when the systemic blood pressure was above percentile fifty. Amiodarone, Dobutamine and Furosemide were administered during the first 48 hours. Beta-adrenergic blockers and angiotensin converting enzyme were given, at 48 hours after admission, once the left ventricular Ejection fraction > 0.35 and the clinical status had improved., Results: On admission, norepinephrine was 1,727.50 +/-794.96 pg/ml, troponin I 24.53 +/- 14.09 ng/ml and left ventricular ejection fraction 0.20 +/- 0.056. At twelve hours, norepinephrine and troponin I serum levels were down to half of the initial values and the ejection fraction increased to 0.32 +/- 0.059. During the next 24 and 48 hours, the ejection fraction rose to 0.46 +/- 0.045, (p<0.01) and norepinephrine and troponin diminished to 526.75 +/- 273.73 (p < 0.02) and 2.20 +/- 2.36 (p<0.02) respectively., Conclusion: Amiodarone, by acting as a neuromodulator, is very likely responsible for the early and progressive decrease of serum norepinephrine.

The medical records of ten pediatric patients with a clinical diagnosis of tetanus were reviewed retrospectively. The heart rate and blood pressure of all tetanus patients were measured noninvasively every hour during the first two weeks of hospitalization. Six of ten tetanus patients presented clinical evidence of sympathetic hyperactivity (group A) and were compared with a control group consisting of four children who required mechanical ventilation for diseases other than tetanus (group B). Heart rate and blood pressure simultaneously and progressively increased to a maximum by day 7. The increase over baseline was 43.70 +/- 11.77 bpm (mean +/- SD) for heart rate (P<0.01) and 38.60 +/- 26.40 mmHg for blood pressure (P<0.01). These values were higher and significantly different from those of the control group (group B) at day 6, which had an average heart rate increase over baseline of 19.35 +/- 12.26 bpm (P<0.05) and blood pressure of 10.24 +/- 13.30 mmHg (P<0.05). By the end of the second week of hospitalization, in group A the increase of systolic blood pressure over baseline had diminished to 9.60 +/- 15.37 mmHg (P<0.05), but the heart rate continued to be elevated (27.80 +/- 33.92 bpm, P = NS), when compared to day 7 maximal values. The dissociation of these two cardiovascular variables at the end of the second week of hospitalization suggests the presence of asymmetric cardiac and vascular sympathetic control. One possible explanation for these observations is a selective and delayed action of tetanus toxin on the inhibitory neurons which control sympathetic outflow to the heart.

Cardiac chambers have afferent connections to the brainstem and to the spinal cord. Vagal afferents mediate depressor responses and become activated by volume expansion, increased myocardial contractility and atrial natriuretic factor. Sympathetic afferents, on the contrary, are activated by metabolic mediators, myocardial ischemia and cardiac enlargement. These opposite behaviors may lead to activation or suppression of the sympathetic nervous system and of the renin-angiotensin-aldosterone system. As cardiac diseases progress, the heart dilates, plasma norepinephrine increases, atrial natriuretic factor is released and the renin-angiotensin-aldosterone system is suppressed to maintain water and sodium excretion. This dissociation of the neurohormonal profile of cardiac patients, may be explained by coactivation of sympathetic afferents, by cardiac dilatation, and of vagal afferents by atrial natriuretic factor. In more advanced stages, atrial natriuretic factor suppression of the renin-angiotensin-aldosterone system is overridden by overt sympathetic activation and sodium and water retention ensues. Digitalis, angiotensin-converting enzyme inhibitors and beta-blockers selectively decrease cardiac adrenergic drive. A common mechanism of action, to all three groups of drugs, would be attenuation of sympathetic afferents and partial normalization of vagal afferents. Consequently, heart size and cardiac afferents emerge as the key factors to understand the pathophysiology and treatment of the syndrome of congestive heart failure., (Copyright 2000 Harcourt Publishers Ltd.)

This study involves a review of the records of 64 children referred to the University of los Andes Hospital with the diagnosis of scorpion envenomation. The patients were divided into group 1 (local manifestations, 42.4%) and group 2 (systemic manifestations, 7.8%). Seven of these patients had severe cardiorespiratory complications, came from distinct geographical zones and received antivenin. Our results indicate that poisonous and extremely dangerous scorpions predominate in certain geographical zones within the state of Merida, Venezuela.

Chagasic patients with congestive heart failure are usually treated with digitalis and converting enzyme inhibitors. According to the neurogenic and dysautonomic theories, chagasic patients would not benefit from these drugs. To clarify this controversial issue, we have studied patients with congestive heart failure and suspected Chagas' heart disease. All patients received intravenous methyl-digoxin for 24 h and oral enalapril for 96 h. Blood samples for plasma norepinephrine, aldosterone and renin were taken at baseline, after acute digitalization and following enalapril. Based on the serology for Chagas' disease, the patients were divided into non-chagasic and chagasic patients. In the chagasic group three patients were in functional class III and 3 were in functional class IV. In the non-chagasic group five patients were in functional class III and 2 were in functional class IV. Both groups had a marked and quantitatively similar degree of neurohormonal activation. All patients improved at least one functional class and lost more than 5 kg of body weight with treatment. The chagasic patients had a statistically significant reduction in plasma norepinephrine (2262 +/- 1407 to 865 +/- 390, P < 0.008, pg/ml, M +/- S.D.), plasma aldosterone (330 +/- 168 to 155 +/- 75, P < 0.01, pg/ml, M +/- S.D.) and plasma renin activity (14 +/- 13 to 2 +/- 1.6 ng/ml per h, M +/- S.D., P < 0.05), with digitalis. Following enalapril, norepinephrine and aldosterone there was a further but non-significant reduction, when compared to postdigitalis values. These results indicated that chagasic patients do benefit from digitalis and enalapril. Furthermore, the prominent and significant reduction in all three neurohormones suggest that the parasympathetic and sympathetic systems of these chagasic and non-chagasic patients, are responding to the neuromodulatory effects of digitalis and enalapril.

We administered serotonin to rats with experimentally induced chagasic myocarditis in order to study the Bezold-Jarisch reflex. Sixteen 4-month old Wistar rats were inoculated with 200,000 T. cruzi parasites ("Y" strain). Between days 18 and 21 (acute stage), 8 infected rats and 8 age-matched controls received intravenous serotonin as a bolus injection at the following doses: 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 14.0 micrograms/kg. Heart rate was recorded before, during and after each dose of serotonin. The remaining 8 infected animals and 8 controls were subjected to the same experimental procedure during the subacute stage, i.e., days 60 to 70 after inoculation. The baseline heart rate of the infected animals studied during the acute stage (327 +/- 62 beats/min, mean +/- SD) was higher than that of the controls (248 +/- 52, P < 0.01). The heart rate changes were expressed as percent changes to correct for the higher baseline heart rate of the infected animals. A dose-response curve was constructed for each group of animals. The slope for the acutely infected animals (r = -0.95, b = -3.98) was not different from that for the control animals (r = -0.92, b = -3.50). The infected animals studied during the subacute stage (r = -0.92, b = -4.33) were not different from the age-matched controls (r = -0.87, b = -4.03). These results suggest that the afferent and efferent pathways which mediate the Bezold-Jarisch reflex are functionally preserved in rats with histologically proved chagasic myocarditis.

The functional status of the sympathetic nervous system in Chagas' heart disease is still the subject of intense controversy. To determine the nature of the abnormalities of the sympathetic nervous system, we measured the plasma norepinephrine concentration of chagasic patients with varying degrees of myocardial damage. Thirty-six patients with positive serology for Chagas' disease were studied. Twenty patients were in Functional Class I (New York Heart Association), 10 were in Functional Class II and six were in Functional Classes III-IV. Cardiac catheterization was performed in 24 patients. The asymptomatic patients had a plasma norepinephrine concentration (121 +/- 37 pg/ml, mean +/- S.D.) not different from normal controls (103 +/- 59 pg/ml). The symptomatic patients, however, had a significantly elevated plasma norepinephrine concentration (665 +/- 354 pg/ml, P < 0.001). The baseline heart rate of the asymptomatic and symptomatic patients directly correlated with the plasma norepinephrine concentration (r = 0.69, P < 0.0001). The symptomatic patients had larger ventricular volumes, higher left ventricular end-diastolic pressures and lower ejection fractions than the asymptomatic patients and normal controls. The plasma norepinephrine concentration correlated linearly with the left ventricular end-diastolic volume (r = 0.77, P < 0.0001), and non-linearly with the ejection fraction (r = -0.70, P < 0.0001) and the left ventricular end-diastolic pressure (r = 0.53, P < 0.007). These results indicate that, in Chagas' heart disease as in most other cardiac diseases, sympathetic nervous system activation is a late and compensatory phenomenon. In other words, sympathetic activation is very likely related to the progressive impairment of left ventricular function.

To clarify the mechanism responsible for the transient sinus tachycardia in rats with acute chagasic myocarditis, we have examined the cardiac sympathetic-parasympathetic balance of 29 rats inoculated with 200,000 parasites (Trypanosoma cruzi). Sixteen infected animals and 8 controls were studied between days 18 and 21 after inoculation (acute stage). The remaining 13 infected animals and 9 controls were studied between days 60 and 70 after inoculation (sub-acute stage). Under anesthesia (urethane 1.25 g/kg), all animals received intravenous atenolol (5 mg/kg) and atropine (10 mg/kg). Acute stage: The baseline heart rate of the infected animals was significantly higher than that of the controls (P < 0.0001). The magnitude of the negative chronotropic response to atenolol was 4 times that of the controls (P < 0.00001). This response correlated with the baseline heart rate (r = -0.72, P < 0.001). The heart rate responses to the beta-blocker and to atropine, of the infected animals studied during the sub-acute stage, were not different from controls. These findings suggest that cardiac sympathetic activity is transiently enhanced and cardiac parasympathetic activity is not impaired, in rats with acute chagasic myocarditis. The transient predominance of cardiac sympathetic activity could explain, in part, the sinus tachycardia observed in the acute stage of experimentally-induced chagasic myocarditis.

Chagasic patients with advanced heart disease have fluid retention-dependent symptoms. Since fluid retention is mostly dependent on the renin-angiotensin-aldosterone system, chagasic patients with congestion related symptoms should have activation of the renin-angiotensin-aldosterone system. The purpose of this investigation was to determine the plasma renin activity baseline values of chagasic patients with and without congestive heart failure. Twenty-eight patients with positive serology for Chagas' disease were studied. Nineteen patients were asymptomatic (functional class I New York Heart Association) and nine were symptomatic (functional classes II-IV). Cardiac catheterization and ventricular cineangiography were performed on 20 patients. The symptomatic patients had significantly higher plasma renin activity levels (4.11 +/- 1.03 ng/ml/h) than the asymptomatic patients (1.08 +/- 0.11 ng/ml/h, P < 0.001) and the normal sedentary controls (1.65 +/- 0.22 ng/ml/h, P < 0.05, mean +/- S.E.). The plasma renin activity baseline values of the asymptomatic and symptomatic patients correlated directly with the baseline heart rate (r = 0.77, P < 0.0001). The symptomatic patients had larger ventricular volumes, moderately depressed ejection fractions and increased left ventricular end-diastolic pressures. The plasma renin activity baseline values also correlated directly with the left ventricular diastolic pressures (r = 0.70, P < 0.0006) and with the left ventricular diastolic (r = 0.66, P < 0.001) and systolic volumes (r = 0.67, P < 0.001). These results indicate that chagasic patients with fluid retention-dependent symptoms and hemodynamic evidence of left ventricular systolic dysfunction have activation of the renin-angiotensin-aldosterone system.

Left ventricular apical aneurysms are present in Chagasic patients who have normal cardiac parasympathetic innervation. Cardiac parasympathetic abnormalities are found, in later stages of the disease, when diffuse myocardial damage and ventricular dilatation are already present. The apical region of the left ventricle is also affected in several acute and chronic non-Chagasic cardiac diseases. Therefore, thinning of the left ventricular apex, with aneurysm formation, may be a non-specific myocardial sequelae, secondary to myocardial damage.

According to the neurogenic theory of Chagas' heart disease, the cardiac parasympathetic abnormalities of chagasic cardiac patients are due to a selective destruction of the cardiac parasympathetic neurons. Trypanosoma cruzi would selectively destroy the cardiac vagal neurons, during the acute stage of the disease. However, these cardiac parasympathetic abnormalities are found mainly in chagasic patients who are in very advanced stages of the disease. Furthermore, the extent of cardiac parasympathetic involvement correlates with the degree of left ventricular dilation. Cardiac parasympathetic abnormalities, and a reciprocal sympathetic hyperactivity are also present in non-chagasic cardiac patients. Modern medical treatment, with sympatholytic drugs, prevents ventricular dilatation and prolongs life in these non-chagasic cardiac patients. Consequently, if chagasic cardiac patients have ventricular dilatation-related parasympathetic abnormalities; it is of the utmost importance to ask: first, do they also have a progressive activation of their neurohumoral systems?; and second, would they benefit from sympatholytic drugs?.

Trypanosoma cruzi is thought to selectively destroy the postganglionic cardiac vagal neurons of chagasic cardiac patients. This theory is based on morphologic and functional evidences obtained from chagasic individuals who were in very advanced stages of the disease. We have studied chagasic patients who were in both the early and late stages of the disease. Our findings and the review of the available literature suggest that myocardial damage and mild left ventricular dilatation precede the cardiac parasympathetic abnormalities. Furthermore, we have found a strong correlation between the degree of left ventricular dilatation and the extent of cardiac parasympathetic impairment. Consequently, we propose that the cardiac parasympathetic abnormalities arise as a compensating mechanism for the progressive left ventricular dilatation.

In chagasic patients, the electrocardiogram becomes abnormal very late in the course of the disease. Most clinical studies concerning cardiac autonomic function of chagasic patients have been carried out in this very late stage of the disease. The purpose of this study was to assess accurately the left ventricular systolic function of chagasic patients with abnormal electrocardiograms. We performed left ventricular contrast cineangiography in 44 patients with positive complement fixation test for Chagas' disease and abnormal electrocardiograms. On the basis of the electrocardiographic abnormalities found in the electrocardiogram taken the night before the hemodynamic procedure, we divided our patients into three subgroups; those with rhythm disturbances, those with ventricular conduction abnormalities, and those with rhythm disturbances plus ventricular conduction abnormalities. The chagasic patients with only cardiac rhythm disturbances, had left ventricular volumes and ejection fractions which were similar to those of controls. On the other hand, the left ventricular volumes of the chagasic patients with ventricular conduction defects, although slightly larger, were still not different from those of controls. Finally, the chagasic patients, with cardiac rhythm disturbances and left ventricular conduction defects, had the largest left ventricular volumes (P less than 0.05), and the lowest ejection fractions (P less than 0.001) of all three subgroups. These findings clearly indicate that chagasic patients, in this very late stage of the disease, have a very variable degree of left ventricular systolic dysfunction. Furthermore, our results show a distinct tendency for the left ventricular volumes to increase, and for the ejection fraction to decrease; when the electrocardiogram becomes progressively more abnormal, and "mixed" electrocardiographic abnormalities appear.(ABSTRACT TRUNCATED AT 250 WORDS)

Chagasic patients may have a normal or abnormal response of heart rate to atropine. To determine if this response to atropine is related to the degree of left ventricular dysfunction, we studied 33 patients with a positive complement fixation test for Chagas' disease. Eleven subjects, with atypical chest pain and negative complement fixation test, were used as controls (sero-negative). Left ventricular wall motion and the left ventricular volumes were determined by ventricular cineangiography. Coronary arteriography was also performed. The sero-negative subjects had normal left ventricular wall motion and the left ventricular diastolic volume was 88 +/- 24 ml/m2. The response of heart rate to atropine was 50 +/- 8 (mean +/- SD) (range 40-65 beats/min). On the basis of the response to atropine, the chagasic patients were divided into groups with a normal response (greater than 40 beats/min) and those with an abnormal response (less than 40 beats/min). Sixty five per cent of those with a normal response had left ventricular apical aneurysms. The left ventricular end-diastolic volume was not significantly different from the sero-negative subjects (96 +/- 26 ml/m2). Six patients (30%) had a left ventricular diastolic volume between 110 and 140 ml/m2. Sixty two per cent of those chagasic subjects with an abnormal response had diffuse left ventricular hypokinesis, and the left ventricular end-diastolic volume was 192 +/- 49 ml/m2 (P less than 0.01). The response of heart rate and the left ventricular diastolic volume were inversely correlated in the chagasic patients (r = -0.88, P less than 0.01). Our results indicate that myocardial damage and the degree of left ventricular dilatation are more severe in chagasic patients with an abnormal response of their heart rate to atropine. Furthermore, the inverse correlation between these two variables is highly indicative of a relationship between the response of heart rate to atropine and the degree of left ventricular dysfunction.

The mechanisms by which Trypanosoma cruzi causes cardiomyopathy are unknown but are the subject o f several hypotheses. In this paper, Diego Davila, Osman Rossell and Jose Donis discuss the aetiology of cardiac failure in Chagas disease and suggest that parasympathetic abnormalities are a consequence of, rather than the cause of, the progressive cardiac enlargement seen in these patients.