Autonomic nervous system dysfunction in children with severe tetanus: dissociation of cardiac and vascular sympathetic control.

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.

Autonomic nervous system dysfunction in children with severe tetanus: dissociation of cardiac and vascular sympathetic control

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 + or - 11.77 bpm (mean + or - SD) for heart rate (P<0.01) and 38.60 + or - 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 + or - bpm (P<0.05) and blood pressure of 10.24 + or - 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 + or - mmHg (P<0.05), but the heart rate continued to be elevated (27.80 + or - 0 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

Heart rate responses to a muscarinic agonist in rats with experimentally induced acute and subacute chagasic myocarditis.

We administered arecoline to rats, with experimentally induced chagasic myocarditis, in order to study the sinus node sensitivity to a muscarinic agonist. Sixteen month old 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 arecoline as a bolus injection at the following doses: 5. 0, 10.0, 20.0, 40.0, and 80.0 microg/kg. Heart rate was recorded before, during and after each dose of arecoline. 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 animals studied during the acute stage (349 +/- 68 bpm, mean +/- SD), was higher than that of the controls (250 +/- 50 bpm, p < 0.005). The heart rate changes were expressed as percentage changes over baseline values. A dose-response curve was constructed for each group of animals. Log scales were used to plot the systematically doubled doses of arecoline and the induced-heart rate changes. The slope of the regression line for the acutely infected animals (r = - 0.99, b =1.78) was not different from that for the control animals (r = - 0.97, b = 1.61). The infected animals studied during the subacute stage (r = - 0.99, b = 1.81) were also not different from the age-matched controls (r = - 0.99, b = 1.26, NS). Consequently, our results show no pharmacological evidence of postjunctional hypersensitivity to the muscarinic agonist arecoline. Therefore, these results indirectly suggest that the postganglionic parasympathetic innervation, of the sinus node of rats with autopsy proved chagasic myocarditis, is not irreversibly damaged by Trypanosoma cruzi.

Cardiac afferents and neurohormonal activation in congestive heart failure.

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.

Effect of human immunodeficiency virus type 1 on intracellular activation and superoxide production by neutrophils.

The immunopathogenesis of AIDS is associated with the development of opportunistic infections by intracellular pathogens that can invade and reproduce freely because of impaired cellular functions. Neutrophils from asymptomatic human immunodeficiency virus (HIV) type 1-infected persons and from symptomatic patients with AIDS were found to retain normal phagocytosis activity while producing significantly less superoxide than neutrophils from HIV-1-negative subjects, when stimulated through Fc receptors or protein kinase C. After priming with a synthetic HIV-1 envelope peptide and stimulation via the Fc receptor, the neutrophils from HIV-1-negative controls had suppressed superoxide production, reduced phosphorylation of two unidentified cellular proteins, and increased expression of a third phosphoprotein. These results suggest that HIV-1 can produce direct functional damage of neutrophils through binding of envelope components to the cell membrane.

Heart rate changes during the Valsalva maneuver in patients with isolated aortic insufficiency

To determine the possible relationship between left ventricular dilatation and heart rate changes provoked by the Valsalva maneuver (Valsava ratio), we studied 9 patients with isolated chronic aortic insufficiency. Left ventricular systolic function was assessed by two dimensional echocardiography and cardiac catheterization. All patients were asymptomatic (functional class I of the New York Heart Association). The left ventricular internal diameters and volumes were significantly increased in all patients. The asymptomatic patients had either normal or slightly depressed ejection fraction (EF>0.40). The Valsalva ratio of these asymptomatic patients showed no significant correlation with the left ventricular volumes or with the left ventricular ejection fraction. In other words, parasympathetic heart rate control, as expressed by the Valsalva ratio, was normal in the asymptomatic patients with left ventricular dilatation and preserved left ventricular ejection fraction. Therefore, left ventricular dilatation may not be the major mechanism responsible for the abnormal parasympathetic heart rate control of patients with acquired heart disease.

Heart rate changes during the Valsalva maneuver in patients with isolated aortic insufficiency.

To determine the possible relationship between left ventricular dilatation and heart rate changes provoked by the Valsalva maneuver (Valsalva ratio), we studied 9 patients with isolated chronic aortic insufficiency. Left ventricular systolic function was assessed by two-dimensional echocardiography and cardiac catheterization. All patients were asymptomatic (functional class I of the New York Heart Association). The left ventricular internal diameters and volumes were significantly increased in all patients. The asymptomatic patients had either normal or slightly depressed ejection fraction (EF > 0.40). The Valsalva ratio of these asymptomatic patients showed no significant correlation with the left ventricular volumes or with the left ventricular ejection fraction. In other words, parasympathetic heart rate control, as expressed by the Valsalva ratio, was normal in the asymptomatic patients with left ventricular dilatation and preserved left ventricular ejection fraction. Therefore, left ventricular dilatation may not be the major mechanism responsible for the abnormal parasympathetic heart rate control of patients with acquired heart disease.

Acute effects of digitalis and enalapril on the neurohormonal profile of chagasic patients with severe congestive heart failure.

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.

Heart rate responses to intravenous serotonin in rats with acute chagasic myocarditis.

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.

Heart rate responses to intravenous serotinin in rats with acute chagasic myocarditis

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 mug/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.

Plasma norepinephrine, myocardial damage and left ventricular systolic function in Chagas' heart disease.

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.

Cardiac sympathetic-parasympathetic balance in rats with experimentally-induced acute chagasic myocarditis.

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.

Plasma renin activity in chagasic patients with and without congestive heart failure.

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.

Apical left ventricular aneurysms and cardiac parasympathetic innervation in Chagas' heart disease.

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.

Cardiac autonomic control mechanisms in Chagas' heart disease. Therapeutic implications.

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?.

Cardiac parasympathetic innervation in Chagas' heart disease.

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.

Electrocardiographic abnormalities and left ventricular systolic function in Chagas' heart disease.

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)

Cardiac parasympathetic abnormalities: Cause or consequence of chagas heart disease?

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.

[Behavior of the ST segment, during isometric exercise, in chagasic patients with apical aneurysm of the left ventricle]. / Comportamiento del segmento ST, durante el ejercicio isométrico, de pacientes chagásicos con aneurisma apical ventricular izquierdo.

In order to study the ST-segment changes during isometric exercise (IE) we have reviewed the hemodynamic and cineangiographic protocols of 13 with Chaga's disease patients. On the basis of the electrocardiogram (EKG) and the left ventricular cineangiogram, the chagasic patients were divided in two groups. Chagas' group I: 6 patients with left ventricular apical aneurysm, Chagas' II: 7 patients with multiple left ventricular dyskinetic segment and occasional premature ventricular contractions. Fourteen subjects with normal left ventricular cineangiograms and normal EKG's were used as controls. The IE was performed by all chagasic and control subjects 31.9 +/- 18 (M +/- SD) months after the cardiac catheterization. The IE was performed at 25% of maximum voluntary capacity for 5 minutes. The precordial leads (V1-V6) were simultaneously recorded, in the standing position, immediately before and after the IE. The ST-segment changes were assessed by measuring the distance of the 'J point, of the ST-segment, to the baseline in three consecutive sinus beats. Immediately before the IE, 5 patients of Chagas' group I (86%) has ST-segment elevation (leadas V1-V2). In the control group, only 2 subjects (14%) had ST-segment elevation, (P less than 0.007). After IE, the control subjects "normalized" their ST-segment elevation, whereas it persisted elevated in the 5 Chagas' group I patients (P less than 0.003). These results suggest that in chagasic patients, the ST-segment changes observed during isometric exercise could be related to the presence of left ventricular apical aneurysm.