European Heart Journal (1992) 13,966-970
Chagas cardiomyopathy and captopril
R. R. ROBERTl*t, E. E. MARTINEZf, J. L. ANDRADEf, V. L. ARAUJOf, F. S. BRITOf, O. P. PORTUGALf AND
S. F. H O R O W I T Z *
KEY WORDS: Chagas, cardiomyopathy, captopril, arrhythmias.
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^Division of Cardiology, Escola Paulista de Medicina, Rua Botucatu 611 Sao Paulo, SP, 04023 Brazil and the
*Division of Cardiology, Beth Israel Medical Center, First Ave. at 16th St. New York, 10003 New York, U.S.A.
Chagas disease is a leading cause ofheartfailure in Latin America. Sudden death occurs in approximately 40% of patients
with heartfailure due to Chagas disease. We report a single blind, cross-over trial of prolonged treatment with captopril and
placebo in 18 Chagas disease patients with class IV NYHA heart failure. Ventricular dimensions, neurohormones,
electrolytes and ventricular arrhythmias were analysed in 11 men and seven women receiving stable doses of digoxin and
frusemide who were randomly divided into two intervention groups. Group I patients were given increasing doses of
captopril up to 150 mg. day~' maintainedfor 6 weeks, group II received the placebo. A 24 h Holter, 2-D echocardiogram,
urinary catecholamines, plasma renin and electrolyte determinations were performed at the end of each phase. After a
2-week washout period, the two groups crossed over and another period of 6 weeks was observed. Ventricular arrhythmias
were analysed by either Mann-Whitney or the Wilcoxon test. Remaining data were assessed by the Student t-test. A
significant reduction in heart rate and urinary catecholamine levels, and enhanced plasma levels of renin, together with a
reduction in ventricular couplets wasfound in the captopril-treated group. We conclude that captopril has a beneficial effect
on neurohormones with a subsequently reduced heart rate and diminished incidence of ventricular arrhythmias in patients
with Chagas disease. This effect might result in a reduction of mortality caused by the disease, suggesting the need for
further investigations.
Introduction
Chagas' disease is a prominent cause of cardiac death in
Latin America1'1. Severe congestive heart failure with massive cardiac enlargement is a common finding in infected
patients. Once heart failure develops, life expectancy is
reduced to a few years'21. Similar to other dilated cardiomyopathies, sudden death occurs in approximately 40%
of patients with heart failure;due to Chagas disease121.
" In some infected persons sudden death is the first manifestation of illness'31. Studies in cardiomyopathy patients
other than those of Chagas disease, who suffered sudden
cardiac death while wearing an ambulatory ECG monitor
have demonstrated that the mechanism of death is an
acute ventricular tachyarrhythmia in approximately 80%
of cases'4-51. The incidence of sudden death is increased in
patients with marked left ventricular dysfunction and
ventricular arrhythmias'4'6-71. Because there has been no
definitive study of the impact of antiarrhythmic drug
treatment on survival of patients with heart failure and
ventricular arrhythmias, the role of therapy with
antiarrhythmic drugs remains uncertain at present17"91.
Previous reports'3101 have emphasized the importance
of structural factors (such as myocardial fibrosis) in
predisposing to re-entry phenomena, critical to the development of ventricular ectopic rhythms. Areas of myocardial fibrosis and the presence of left ventricular apical
aneurysms are common findings in hearts of patients who
die of Chagas disease'"1.
Submitted for publication on 3 April 1991, and in revised form September
1991.
Correspondence- Dr Steven F. Horowitz, Beth Israel Medical Center, First Ave
at 16th St. 8th Dazian, New York, NY (212)42045-60, U.S.A.
0I95-668X/92/070966+05 $03.00/0
However, recent evidence points to potentially reversible arrhythmogenic factors in patients with congestive
heart failure: factors such as electrolyte abnormalities,
activation of neurohormonal mechanisms and drug
therapy for heart failure. Due to its ability to promote
cation repletion and to reduce circulating levels of
potentially arrhythmogenic neurohormones, captopril
may prevent the occurrence of complex ventricular
tachyarrhythmias'121 and death from chronic heart failure.
A single blind, cross-over trial of prolonged treatment
with captopril and placebo in patients with severe congestive heart failure due to Chagas disease is reported
here. The effects of the drug on ventricular function,
neurohormones, electrolytes and ventricular arrhythmias
were analysed.
Methods
PATIENT POPULATION
Eleven men and seven women ranging in age from
23-60 years (mean 43 years), who had suffered from congestive heart failure due to Chagas disease for more than 6
months, were selected for the study protocol. All patients
were in NYHA class III or IV and all had shown a positive radioimmunoassay result for Chagas disease. Other
cardiomyopathy aetiologies were excluded by clinical
history and echocardiography.
STUDY PROTOCOL
Written informed consent was obtained from every
patient. Patients were randomly divided into two groups.
Group I consisted of five men and four women, group II
© 1992 The European Society of Cardiology
Chagas cardiomyopathy and captopril 967
consisted of six men and three women. Initially, stable
doses of digoxin (0-25 mg. day"1) and frusemide (mean
dose 104 mg. day"1) were given for a period of at least 2
weeks without potassium supplementation. At the end of
this period patients were admitted to the hospital and the
following measurements were made:
Patients
I
II
III
IV
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
XVI
(years)
33
35
32
29
37
42
52
60
39
56
60
34
35
59
39
Sex
NYHA
M
IV
III
III
III
III
M
F
F
M
F
M
M
F
M
M
III
III
III
III
IV
IV
IV
III
III
M
IV
M
F
F
(cm)
(kg)
166
176
163
158
165
155
156
172
147
146
165
148
174
162
158
680
66-5
58-5
650
68-5
500
540
530
480
630
57-5
48-5
620
57-5
56-5
Results
Patients' age, sex, NYHA functional class for heart failure, height and body weight at the start of the study are
presented in Table 1.
CLINICAL OUTCOME
Of the 18 patients selected, 15 completed the study.
Three patients were excluded, all in thefirst2 weeks before
Patients from group I received incremental doses of
treatment with either the placebo or captopril. Three
captopril, starting with 12-5mgt.i.d., increasing to
patients had to be admitted to hospital to receive intra50 mg t.i.d. over a 1 week period. This was maintained at venous frusemide, one during captopril treatment and the
50mgt.i.d. for 6 weeks. During a 7-week follow-up other while receiving the placebo. One patient developed
period, patients were seen once a week. At the end of this symptomatic hypotension that disappeared when the dose
period they were admitted to the hospital and all of the of captopril was reduced to 37-5mg.day" 1 . Another
above-mentioned measurements were repeated. Both patient had postural dizziness without demonstrable
captopril and the placebo were discontinued for a wash- hypotension that ameliorated after reducing the dose of
out period of 2 weeks and all tests were performed again. captopril to 75 mg . day"1.
Then, the two groups were crossed over for another
period of 7 weeks, after which all measurements were performed for the last time. Due to the severity of the chronic HEART RATE AND BLOOD PRESSURE
During treatment with captopril, heart rate was sigheart failure (CHF) in this group of patients we chose a
nificantly
lower than during treatment with the placebo
regimen of matching placebo in a single-blind fashion so
(69
±12
vs
79 ±19 beats, min"1 respectively, P<005).
those whose clinical condition worsened could be identThere
was
no
significant difference in systolic and diastolic
ified. Ideally, a longer time interval would have allowed us
arterial
blood
pressure during treatment with captopril or
to note the beneficial haemodynamic effects of captopril;
placebo
(Table
2).
however, we used the shortest time interval during which
captopril effects could be observed and tolerated by
patients in the placebo group who were receiving no ECHOCARDIOGRAPHY
There were no significant differences in left ventricular
vasodilator therapy.
end diastolic or systolic dimensions or left ventricular
fractional shortening, when comparing the effects of
captopril vs those of the placebo (Table 2).
STATISTICAL ANALYSIS
We compared the two groups using the Student t-test
for independent values'161; renin values were first con- RENAL AND HORMONAL EFFECTS
verted to logarithms'171. For the comparative analysis of
During treatment with captopril urinary excretion of
the incidence of ventricular tachyarrhythmias, the Mann- norepinephrine was significantly lower than during treatWhitney test"61 was used; when no difference was seen ment with the placebo (40-7±2-9 vs 56-8±7-8 ug.ml" 1 .
we performed a paired t-test or the Wilcoxon'181 paired 24h "' respectively, P < 005) (Table 3).On the other hand,
test, comparing the placebo with the captopril phases. the plasma renin level with captopril was significantly
Differences were considered significant at P<005.
higher than that seen during treatment with the placebo
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(i) Arterial blood pressure, heart rate, body weight
and height.
(ii) 2-D echocardiogram recording with measurement of systolic and diastolic left ventricular
dimensions.
(iii) Twenty-four-hour ambulatory ECG recording
using the Medilog system to determine the total
frequency of ventricular premature complexes
(VPC), the incidence of ventricular couplets
(VC) and the incidence of episodes of nonsustained ventricular tachycardia (NSVT).
(iv) Venous blood samples were taken in the morning
after patients had been supine for 2 h and after they
had fasted overnight to determine serum levels of
sodium, potassium, magnesium'131 and plasma
renin activity measured by radioimmunoassay'141.
(v) Total urinary excretion of catecholamines in
24 h determined by liquid chromatography1151.
(vi) The body-urea nitrogen (BUN), plasma creatinine and white blood cell (WBC) count were also
determined.
Table 1
968 R. R. Roberti etal
Table 2
Basal
Captoprir
Basal
Placebo
101 ± 15
72±12
76±11
65 ±10
56±11
16±8
99±10
70±8
69±12'
65±11
54± 12
20±U
98±13
74±12
77 ±20
66±11
56±12
15±7
98±18
68±7
79 ±19*
66±12
56±U
16±7
SBP ^systolic blood pressure (mmHg), DBP = diastolic blood
pressure (mmHg), HR = heart rate (beats, min" 1 ), LVEDD = left
ventricular end diastolic dimension (mm), LVESD = left ventricular
end systolic dimension (mm), LVFS = left ventricular fraction
shortening values (%). 'Indicates significant differences between
captopril and placebo phases, f < 0 0 5 , values are expressed in
mean±SD.
Basal
BUN
Crcatinine
RBC
WBC
Hb
Captopril
40±13
37±13
0-9±0-3 0-9±0-3
4-4±0-5 4-3 ±0-3
60±l-5 6-2±23
12-8±ll 12-5± 10
Basal
Placebo
36±1O
35±10
0-9±0-2 0-9±0-3
4-3±0-5 4-2±0-5
6-5 ± 2 0 6-6 ± 2 0
12-3±l-4 12-2±I-8
Values are expressed as mean±SD. No significant differences were
observed. BUN = body urea nitrogen (mg%). Creatinine is
expressed in mg.dl" 1 . RBC = red blood cells (million . c m - \
WBC => white blood cells (thousand . cm" 3 ), Hb = Haemoglobin
Table 5
Basal
Captopril
Basal
Placebo
328
406
87
320
222*
41
286
392
68
451
422
317
Table 3
VPC
Basal
Captopril
Basal
Placebo
vc
NSVT
Renin
8-6 ±7-6
Norepinephrine 42± 18
Sodium
138±2
Potassium
40±0-3
Magnesium
1 9±01
28-5 ±32* 13 5± 15
40±ll*
46±18
138±2
138±2
4-2 ±0-6 4-2±0-4
l-9±01
l-9±0-l
13-3±21*
56 ±30*
137±3
4-3±0-3
1 -9 ± 0-1
Values are expressed as mean ± SD. 'Indicates significant differences
between captopril and placebo phases, P<005.
Values for renin werefirstconverted to logarithms, here expressed in
Hg.ml~'.h~'. Norepinephrine is expressed in ug.ml-'. 24 h~'.
Sodium and potassium are expressed in mEq. 1"' while magnesium is
expressed in mg%.
Values are expressed as means. 'Significant difference between
captopril and placebo phases, P<005. VPC = ventricular premature complexes per 24 h, VC = ventricular couplets per 24 h,
NSVT = episodes of non-sustained ventricular tachycardia per 24 h.
when they were using the placebo (422 vs 222 VC. 24 h" 1 ,
/><005)(Table5).
Discussion
In the present study, captopril induced significant
reductions in urinary norepinephrine excretion, heart rate
(26-8±8-6 vs 13-4±5-6 ug.ml" . h" respectively, and in the number of ventricular couplets in 24 h, together
f<0-05) (Table 3). Although plasma levels of potassium with a significant elevation of plasma renin levels.
were higher during the treatment with captopril the differSeveral previous studies have shown captopril to
ence did not reach statistical significance (4-0 ±0-4 vs replenish low levels of potassium and magnesium in
1
4-3 ±0-6 mEq . I" ) (Table 3). Mean values for sodium patients with CHF(12'">201. However, similar to other puband magnesium are also listed in Table 3, but differences lications'21"23' plasma levels of potassium and magnesium
did not reach levels of statistical significance also. BUN, were not significantly elevated by captopril in the patients
creatinine, WBC, red blood cell count (RBC) and haemo- of this study. This may have been related to total body
globin levels did not show statistical differences when potassium depletion due to baseline frusemide therapy
treatment with captopril or with the placebo were without potassium supplementation. Clearly, captopril
compared (Table 4).
therapy would suppress any potassium loss; however, the
short study interval time might explain the inability to
detect potassium repletion.
THE 24 H ECG MONITORING
Recent studies have shown that elevated levels of plasma
In the baseline assessment, before treatment with either
captopril or placebo, ventricular premature complexes norepinephrine may indicate a poor prognosis'24'. The most
(VPC) and/or ventricular couplets occurred in 80% of striking finding of our study was that captopril induced a
subjects, whereas non-sustained ventricular tachycardia reduction in plasma norepinephrine, suggesting a poten(NSVT) occurred in 73% of patients (Table 5). No signifi- tially beneficial effect on the natural history of severe forms
cant difference was seen in the incidence of VPC or in the of Chagas disease. Under these circumstances angiotensin
number of episodes of NSVT (Table 5) when the treat- II increases central sympathetic discharge'25', increases
ments with captopril or placebo were compared. On the norepinephrine release from sympathetic nerve terminals'261
other hand, the number of ventricular couplets was sig- and inhibits re-uptake of norepinephrine'27'. As there was
nificantly lower in patients using captopril compared to no significant change in arterial blood pressure, we believe
1
1
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SBP
DBP
HR
LVEDD
LVESD
LVFS
Table 4
Chagas cardiomyopathy and captopril 969
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the decrease in heart rate, also seen in other studies'20*281, of captopril on the occurrence of sudden death and/or
may be due to a lessening of risk of heart failure or other overall mortality in severe CHF due to Chagas' disease.
angiotensin Il-sympathetic interactions.
Elevated plasma renin levels have also been shown to be
associated with a poor prognosis in CHF129'. The observed References
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