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

International

Journal

of

cardiology ELSEVIER

International Journal of Cardiology 57 (1996) 21-29

Acute effects of digitalis and enalapril on the neurohormonal profile of chagasic patients with severe congestive heart failure Antonio M. Khoury”, Diego F. Davila”‘“, Gabriela Bellabarbab, Jose H. Donis”, Argenis Torres b, Cecilia Lemorvanb, Luis Hernandez”, Walter Bishop’ “Centro Cardiovascular, Universidad de Los Andes, Merida, Venezuela bDepartamento de Fisiopatologia, Universidad de Los Andes, Meriah, Venezuela ‘Departamento de Fisiologia, Universidad de Los Andes, Merida, Venezuela Received 20 February 1996; revised 11 July 1996; accepted 11 July 1996

Abstract Chagasic patients with congestive heart failure are usually treated with digitalis and converting enzyme inhibitors. According to the neurogenic and dysautonomic theories, chagasicpatients would not benefit from thesedrugs. To clarify this controversial issue, we have studied patients with congestive heart failure and suspectedChagas’ 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-chagasicand chagasicpatients. In the chagasicgroup three patients were in functional class III and 3 were in functional class IV. In the non-chagasicgroup five patients were in functional class III and 2 were in functional class IV. Both groups had a marked and quantitatively similar degreeof 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 (22622 1407 to 8652390, P
Chagas; Heart failure; Sympathetic; Parasympathetic;Autonomic; Digitalis; Converting enzyme inhibitors

1. Introduction In Chagas’ heart disease as in most other cardiac *Corresponding author, Apartado diovascular Merida, 5 101, Venezuela.

Postal 590 Centro

Car-

diseases, congestive heart failure is manifested by fluid retention-dependent symptoms and low cardiac output [l-3]. These symptomatic patients are usually treated with digitalis and converting enzyme inhibitors [4]. The proposed mechanisms to explain the benefi-

0167-5273/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved PII SO167-5273(96)02776-3

cial effects of digitalis and converting enzyme inhibitors, in non-chagasic patients, are as follows: current knowledge states that congestive heart failure is, in part, secondary to a marked and relentless activation of the sympathetic and renin-angiotensinaldosterone systems [5,6]. In this context, digitalis would partially restore the capacity of the cardiac mechanoreceptors to modulate the efferent sympathetic activity to the heart and to the periphery [7,8], whereas, converting enzyme inhibitors would directly decrease the activity of the renin-angiotensinaldosterone system [9] and indirectly lower the norepinephrine serum levels, of non-chagasic patients with congestive heart failure [ 10,111. The neurogenic and dysautonomic theories on chagasic heart disease state that chagasic patients have cardiac parasympathetic denervation and abnormally low levels of serum norepinephrine [ 12- 161. Under these circumstances, one would expect digitalis and converting enzyme inhibitors to have no effects on the degree of activation of the sympathetic nervous system and consequently no beneficial therapeutic effects on the clinical manifestations of congestive heart failure [17-191. However, chagasic patients do benefit from these two drugs [20,21]. To clarify this controversial and relevant issue, we have studied the acute effects of digitalis and enalapril on the neurohormonal profile of chagasic patients with congestive heart failure.

ocardiograms. Patients with cardiac diseases, other than suspected Chagas’ heart disease were not included. Specifically, those patients with clinical evidence of high blood pressure, valvular heart disease, coronary artery disease or Diabetes mellitus were excluded. Nineteen normal sedentary subjects were used as controls.

2.2. Clinical criteria for the diagnosis of congestive heart failure The patients included in the study had two or more of the following major criteria: (1) cardiac enlargement as determined by the cardiothoracic ratio (>55%) and/or left ventricular dilatation (diastolic diameter>5.5 cm) by two-dimensional echocardiograms; (2) positive hepato-jugular reflex; (3) bilateral basal pulmonary rates and/or pulmonary congestion on chest X-rays; (4) past medical history of paroxysmal nocturnal dyspnea or pulmonary edema; (5) a third heart sound. A weight loss of at least 5 kg of body weight, while receiving medical treatment was also used, as a major criteria [23-271. This proposal was approved by the Human Research Commission of El Centro Cardiovascular, Universidad de Los Andes, MCrida, Venezuela.

2.3. Neuroendocrine control

2. Methods We studied 13 cardiac medication-free patients, with severe congestive heart failure, who were referred to the emergency department of the University of Los Andes Hospital. All of them came from endemic rural areas of western Venezuela and had dyspnea on minimal efforts or dyspnea at rest plus ankle edema (New York Heart Association, functional classes III-IV [22] 2.1. Clinical protocol After informed consent was obtained, the subjects had their clinical history taken, routine laboratory work up, chest X-rays and two-dimensional ech-

Once admitted to the study, all patients and the normal controls had an intravenous fluid-filled catheter, connected to a three-way stopcock, inserted into an antecubital vein. Blood samples were taken, in the semi-recumbent position and after a resting period of 30 min, in all functional class III patients. In functional class IV patients the resting period was shortened to 15 min, for determinations of plasma renin activity, norepinephrine, aldosterone and serology for Chagas’ disease [28]. The blood samples for renin and aldosterone were placed in prechilled tubes containing 100 ,ul of an 8% solution of ethylenediamine tetraacetic acid and the samples for plasma norepinephrine in tubes containing the former plus 6% glutathione. The tubes were inverted several times and centrifuged within 12 h at 4°C and 3000

A.M. Khoury et al. I International

rev./min. Plasma was stored at -70°C. Renin activity and aldosterone were measured by radioimmunoassay using a commercial available kit (Incstar Corporation, Still Water, MN, USA). Norepinephrine levels were measured by high pressure liquid chromatography and electrochemical detection [29,30]. The blood samples were analyzed in a blind manner. The investigator responsible for this part of the protocol had no knowledge of the clinical diagnosis or functional status of the patients. Interassay coefficients of variations were 6% for plasma aldos-. terone and plasma renin activity and 11.7% for plasma norepinephrine.

2.4. Medical treatment protocol After the baseline blood samples had been taken, all patients received intravenous methyl-digoxin (Boehringer) (0.02 mg/kg) every 6 h for 24 h [31]. Diuretics were used as needed. Six hours after the last dose of digitalis, blood samples were again taken for neurohormonal measurements. Enalapril (Merck Sharp Dohm) (2.5 mg BID) was begun and continued for 96 h [32]. A third set of blood sampled was then obtained (2-2.6 methyl-digoxin half-lives). Oral digoxin was started after this last phase of the medical protocol was completed. The results of the serology test for Chagas’ disease were known, at the end of the study, when all the blood samples had been processed. Plasma levels of digitalis were not measured.

2.5. Statistical analysis On the basis of the serology test for Chagas’ disease, the patients were divided into chagasic and non-chagasic patients. Normal controls and the two groups of patients were compared by means of analysis of variance. The neurohormonal changes induced by digitalis and enalapril were compared within groups and between groups by means of analysis of variance. The possible relationship among the neurohormones and the clinical and echocardiographic variables was studied by means of correlation analysis.

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3. Results 3.1. Clinical radiologic and echocardiographic characteristics The chagasic group included 5 men and 1 woman and the non-chagasic patients 6 men and 1 woman. The two groups were similar in age, baseline heart rate and systemic blood pressure. However, when compared to the normal controls, both groups of patients were significantly older. Three patients were in functional class III and 3 were in functional class IV, in the chagasic group. Five patients were in functional class III and 2 were in functional class IV, in the non-chagasic group. They all had cardiac enlargement on chest X-rays and on two-dimensional echocardiograms. The degree of left ventricular dilatation and depression of the ejection fraction were similar in both groups of patients (Table 1). 3.2. Baseline neurohormonal projile The patients included in the study had a marked activation of the sympathetic and renin-angiotensinaldosterone systems. As can be seen in Table 2, the individual values of the three neuro-hormones vary considerably. Nonetheless, when compared to the normal controls, the non-chagasic and chagasic patients had significantly higher plasma norepinephrine (pg/ml) (normal controls: 109259, MtS.D.; 95% C.I.=-210; 415) and aldosterone (normal controls 93219, M+S.D., 95% C.I.=23; 162). Plasma renin activity (rig/ml per h) was higher than in controls (2.02-+1.10, MtS.D., 95% C.I.=-0.7; 4.57), only in the chagasic patients. The baseline levels of the chagasic patients were not statistically different from those of the non-chagasic patients (Table 2). There was no correlation with any of the clinical or echocardiographic variables included in the investigation. 3.3. Effects of digitalis and enalapril on the clinical status, baseline heart rate and blood pressure. All patients improved their functional status in at least one functional class (NYHA) and had a promi-

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Table 1 Clinical, radiologic and echocardiographic characteristics Characteristics

Non-chagasic patients (n=7)

Chagasic patients (n =6)

Y value

Male Female Age Baseline heart rate (beatslmin) Baseline systolic pressure (mmHg) Baseline diastolic pressure (mmHg) Functional class III IV Cardiothoracic index Two-dimensional echocardiograms Left ventricular diastolic diameter (cm) Left ventricular eiection fraction

6 (86%) 1 (14%) 5429 116216 lllkl4 75513

5 (83%) 1(17%) 47) 10 115516 115216 83t12

NS NS NS NS

5 (71%) 2 (29%) BO.60

3 (50%) 3 (50%) >0.60

5.9kO.39 0.17+0&l

6.49t 1 0.21 kO.06

NS NS

Values,are mean?S.D., except for sex and functional class.

nent weight loss (>5 kg of body weight) during treatment. The baseline heart rate decreasedin the chagasic patients, from 116216 to 88?17 beats/ min. (M-t-S.D., PCO.02). There were no significant changes following enalapril. In the non-chagasic patients, the baseline heart rate also decreasedfrom baseline values (116? 16 to 92t 17, WO.04) (beats/mm). However, following enalapril, there was a non-significant increase (92217 to lOOrt18, NS). The systemic arterial pressure, of both groups of patients, did not change significantly with enalapril or digitalis.

3.4. Esfects of digitalis and enalapril on neurohormonal projile

The chagasic patients had a pronounced and statistically significant reduction in the plasma levels of all three neurohormones,with the acute administration of digitalis (Fig. 1). When compared to the postdigitalis values, plasma aldosterone and norepinephrine showed a further but non-significant reduction, following enalapril. Plasma renin, as expected, increased slightly (Table 3). The non-chagasic patients also had a significant

Table 2 Baseline neurohormonal profile Non-chagasic patients (n =7)

MeantS.D. Confidence Interval (95%)

Chagasic patients (n =6)

NE

PRA

ALDOST

NE

PPA

ALDOST

2698 824 1211 2149 1052 1291 975 1.457?695* 942; 1972

2.33 6.40 6.57 2.20 3.40 9.70

255 326 636 107 918

1570 890 2800 4827 2000 1486

6.30 10.50 16.87 35.57 1.08 -

166 363 518 457 147 -

5.1052.96 5; 10

448?325** 312; 583

2262?1407* 1705; 2818

14213” 9; 19

330?168** 194; 465

NE, plasma norepinephrine (pg/ml); PRA, plasma renin activity (rig/ml per h); ALDOST, plasma aldosterone (pg/ml). *P
A.M. Khoury et al. I International Journul of Cardiology 57 (1996) 21-29

0

25

Norepinephrine ( ml)

500

1000

1500

- 2000

F

ns

- 36

- 2500

3000

3500 - 52

t Fig. 1. Acute. effects of digitalis on the neurohermonal profile. The absolute decrement in the plasma levels of all neurohormones was similar in both groups of patients. Solid bars, chagasic patients. Empty bars, non-chagasic patients.

reduction in the plasma levels of norepinephrine, with digitalis. Plasma renin and aldosterone decreased but did not reach statistical significance. Following enalapril, plasma norepinephrine was higher than postdigitalis, although lower than baseline values (Table 3). Finally, the absolute decrement provoked by digitalis, in the levels of all three neurohormones,was similar in both groups of patients (Fig. 1). Enalapril also induced similar negative changes in plasma aldosterone. However, plasma norepinephrine in-

creased in the non-chagasic patients, whereas the chagasic patients had a further reduction. These opposite changes did reach statistical significance. Plasma renin had the expected positive changes, in both groups of patients (Fig. 2). 4. Discussion We studied patients with suspectedChagas’ disease, who had unequivocal, radiologic and echocar-

Table 3 Effects of digitalis and enalapril on the neurohormonal profile Non-chagasic patient@ =7)

Plasma norepinephrine (pg/ml) Plasma aldosterone (pglml) Plasma renin activity (rig/ml per h)

Chagasic patients+ =6)

Baseline

Digitalis

Enalapril

Baseline

Digitalis

Enalapril

1457k695

625?345* 2102338

924t385 1392207 5.2?4

2262+-1407 3302168 14213

865%390* 155275** 2t1.6***

5712250 91251 3.523.1

448k325

*P
5.1k2.4

l-r-O.26

26

A.M.

550 7

Khoury

et (11. I International

Norepinephrine WmU

Journal

Aldosterone Wml)

of Cardiology

57 (1996)

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Renin (nglmllhr)

400 250 -

Fig. 2. Acute effects of enalapril on the neurohormonal profile. The absolute decrement in plasma levels of aldosterone was similar in both groups of patients. However, plasma norepinephrine increased in the non-chagasic patients, whereas the chagasic patients had a further reduction. Plasma renin had the expected positive changes. Solid bars, chagasic patients. Empty bars, non-chagasic patients.

diographic evidences of severe congestive heart failure and left ventricular systolic dysfunction. To reduce bias and to compare the chagasic patients with a concurrent non-chagasic case control group, we instituted medical treatment, for congestive symptoms, without prior knowledge about the presence or absence of positive serology for Chagas’ disease. Once the serology was known and the medical treatment protocol was completed, the patients were divided in chagasic and non-chagasic patients. Both groups were comparable as to age, sex, functional status, degree of impairment of ventricular function and they all came from the same rural areasof westernVenezuela.We should point out that our institution is the main research center for Chagas’ disease, in this geographical area of Venezuela [ 1,2,33,34]. Furthermore, non-chagasic heart disease, unrelated to atherosclerosis, high blood pressure or valvular heart diseaseis highly prevalent in western Venezuela [35]. These two factors may have influenced the referral of these patients to our institution. Therefore, the most likely etiology for the non-chagasic group, although we did not perform coronary angiography, would be dilated cardiomyopathy. The first phase of our medical protocol was specifically designed to study the acute effects of

digitalis on the neurohormonal profile and on the functional status of the chagasic patients [36]. We found that both groups of patients had a marked and quantitatively similar degree of activation of the sympathetic and renin-angiotensin-aldosterone systems. The absolute decrementin the plasma levels of all three neurohormones, provoked mainly by the acute administration of digitalis, was also similar in the two groups of patients. Furthermore, the clinical status of both groups of patients was also improved by digitalis. Therefore, these results clearly indicate that, the chagasic and non-chagasicpatients included in this study, favorably responded to the acute administration of therapeutic doses of digitalis. Recent clinical trials have conclusively shown that digitalis have beneficial therapeutic effects on the syndrome of congestive heart failure [37,38]. The underlying mechanisms by which digitalis induces these beneficial effects are controversial [7]. However, it has been repeatedly demonstrated that, at therapeutic doses, digitalis directly acts through the cardiac parasympathetic nervous system [39]. In experimental animals, digitalis increase the rate of discharge of cardiac receptors in responseto volume expansion [40,41]. Ganglionic transmission and end organ responseto acetylcholine are also potentiated by digitalis. Thus, at therapeutic doses,digitalis main

A.M. Khoury et al. I International Journal of Cardiology 57 (1996) 21-29

action is to increase cardiac vagal tone. Direct sympathetic effects occur only with toxic doses and are excitatory [39]. In humans, with congestive heart failure, the intravenous administration of digitalis produces a rapid and profound attenuation of peripheral sympathetic activity that precedes the hemodynamic actions of this drug [17]. Moreover, digitalis partially restores the capacity of low pressure cardiac mechanoreceptors, with vagal afferents, to indirectly modulate the efferent sympathetic activity to the heart and to the periphery [42-441. Abnormal high pressure baroreceptor control of heart rate, of decompensated heart failure, is also reversed by digitalis and salt restriction [45]. In this study, autonomic heart rate control, of a group of non-chagasic patients, was assessed by means of several autonomic function tests before and after compensation with digitalis and medical treatment. Following compensation, there was a marked improvement in baroreceptor sensitivity and heart rate responses to atropine and to the Valsalva Maneuver. The authors concluded that compensation, achieved through digitalis and conventional treatment, induces a better sympathetic and parasympathetic control of heart rate. In chagasic patients, with congestive heart failure, the acute effects of digitalis on the hemodynamic profile were initially described in the early 1970s by Manco et al. [46]. In this study, the authors reported direct hemodynamic evidence that digitalis have beneficial therapeutic effects, in chagasic patients with congestive heart failure. These chagasic patients came from Brazilian geographical areas where disturbances of cardiovascular and digestive neural regulation have been consistently described [ 12-141. Therefore, our results complement this early investigation and clearly indicate that digitalis do induce beneficial therapeutic and neurohormonal effects, in chagasic patients with congestive heart failure. The last phase of our medical protocol was designed to study the effects of converting enzyme inhibitors, on the neurohormonal profile of chagasic patients with congestive heart failure. The third set of blood samples was taken 96 h after digitalis had been discontinued. Since this period of time amounts to 2-2.6 biological half-lives for methyl-digoxin, a residual therapeutic effect, if any, would be minimal.

21

Therefore, the observed changes in the neurohormonal profile of our chagasic patients very likely reflect the effects of converting enzyme inhibitors [47-491. In summary, our findings clearly indicate that chagasic patients can indeed derive therapeutic effects from digitalis and converting enzyme inhibitors. Furthermore, the prominent and significant reduction in all three neurohormones suggest that the cardiac autonomic nervous system of these chagasic and non-chagasic patients is responding to the neuromodulatory actions of digitalis.

Acknowledgments Supported in part by ‘Consejo de Desarrollo Cientifico, Humanistic0 Y Tecnologico’ (CDCHTULA). Grants: M-483-94, M-484-94 and BIDCONICIT BTS-37.

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