Hemodynamic effects of vasodilators and long-term response in heart failure

Hemodynamic responses to vasodilators are commonly assessed when starting long-term vasodilator treatment in patients with chronic left ventricular failure, although the relation between short- and long-term responses is not established. Thus, short- and long-term hemodynamic responses to placebo and vasodilators (isosorbide dinitrate, minoxidil and enalapril or captopril) were measured and long-term clinical efficacy was assessed by changes in exercise capacity after 1 to 5 months of vasodilator administration (plus digitalis and diuretic agents) in 46 patients with New York Heart Association functional class II to IV heart failure caused by cardiomyopathy. There were no significant changes in hemodynamics or exercise capacity during placebo treatment. After initial doses and during long-term administration of vasodilator drugs, hemodynamics were significantly improved. After long-term vasodilator treatment, maximal oxygen uptake during exercise increased by 2.9 +/- 5.7 ml/min per kg from a control value of 14.1 +/- 5.6 ml/min per kg (p less than 0.01), and exercise duration also increased by 1.8 +/- 3.5 minutes (p less than 0.01). Changes in maximal oxygen uptake, however, did not correlate with short-term changes in pulmonary wedge pressure (correlation coefficient [r] = -0.14), cardiac index (r = -0.01) or systemic vascular resistance (r = -0.20). Long-term hemodynamic changes also failed to correlate with changes in exercise capacity. Baseline hemodynamics, cardiac dimensions and left ventricular ejection fraction before vasodilator administration all failed to correlate with baseline exercise capacity or with long-term changes in exercise capacity. Thus, hemodynamic measurements at initiation or during follow-up of vasodilator therapy do not relate to long-term clinical efficacy assessed by exercise capacity in patients with chronic left ventricular failure. Therefore, the rationale for making invasive hemodynamic measurements before initiating long-term vasodilator therapy for heart failure is questioned.     

Enalapril in patients with chronic heart failure: a placebo-controlled, randomized, double-blind study

A number of studies have shown short-term hemodynamic and symptomatic improvement in patients with congestive heart failure treated with angiotensin converting-enzyme inhibitors. The long-term efficacy of the oral long-acting converting-enzyme inhibitor enalapril remains to be established in controlled studies. We evaluated this drug in 36 patients with New York Heart Association functional class II to III heart failure who were clinically stable on digoxin and diuretic therapy. After baseline assessment of symptoms, exercise capacity, and results of echocardiographic examination and right heart catheterization, patients were randomly assigned to treatment with 5 mg enalapril twice daily (n = 18) or placebo (n = 18) in a double-blind fashion. The two groups had similar clinical, echocardiographic, and hemodynamic characteristics before treatment. After 3 months of treatment, the enalapril group showed a significant improvement as judged by subjective patient impression, functional class, and exercise duration (9.3 +/- 5.7 vs 17.6 +/- 5.6 min; p less than .001). Diuretic dosage was reduced in six patients and increased in one patient, one patient had died and another had been withdrawn from the study. In the placebo group there was no significant change with respect to patient impression, functional class, or exercise duration; diuretic dosage was increased in seven patients and four patients had died. Echocardiographic left ventricular dimensions were significantly reduced and left ventricular shortening fraction significantly increased in the enalapril group but were unchanged in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quality of life among 5,025 patients with left ventricular dysfunction randomized between placebo and enalapril: The studies of left ventricular dysfunction

Objectives. This study was performed to assess the quality of life of patients with left ventricular dysfunction for up to 2 years after randomization to enalapril or placebo.Background. Previous reports have documented that survival of patients with congestive heart failure can be extended by the angiotensin-converting enzyme inhibitor enalapril. However, it is unknown whether enalapril has a long-term favorable impact on the quality of life in patients with heart failure.Methods. A brief quality of life questionnaire assessing the quality of life was administered at baseline and at 6 weeks, 1 year and 2 years of follow-up to patients randomized to placebo or enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). Participants had an ejection fraction ≤ 0.35, no other serious illnesses and either symptomatic heart failure (treatment trial, n = 2,465) or asymptomatic left ventricular dysfunction (prevention trial, n = 2,560).Results. Among the 14 scales of quality of life, better scores at one or more follow-up intervals were noted in 6 scales in the treatment trial and in 1 scale in the prevention trial among patients assigned to enalapril. Consistent superiority with enalapril at two consecutive follow-up intervals was noted in the treatment trial for social functioning and dyspnea but for no scale in the prevention trial. However, an average of 40% of quality of life responses were missing at 2 years of follow-up because of death or failure to complete the questionnaire. In the treatment trial, survivors with more severe heart failure were less likely to complete the questionnaire.Conclusions. Modest benefits in quality of life for ≥ 1 year occurred when patients with left ventricular dysfunction and symptomatic heart failure were treated with enalapril. No apparent beneficial or adverse effect on quality of life was observed with enalapril in asymptomatic patients with left ventricular dysfunction.     

Comparison of enalapril and captopril in the treatment of chronic heart failure

The long-term effect of enalapril (group 1) and captopril (group 2) on clinical symptomatology and left ventricular function was evaluated in 29 patients with severe congestive heart failure (13 ischemic and 12 dilated cardiomyopathy, four valvular heart disease). During the 6-month observation period, five patients died (two on enalapril and three on captopril therapy = 6-month mortality rate 18%). Nine patients showed no beneficial effect of enalapril or captopril on clinical and hemodynamic findings (= nonresponders). The initial findings on these nine patients were, however, not significantly different from the clinical and hemodynamic findings on the patients who improved. Enalapril had to be discontinued in two patients because of side effects (progressive renal failure and gastrointestinal symptoms, respectively). A total of 22 patients completed the study, 11 treated with enalapril (mean dosage 25 +/- 10 mg/day) and 11 treated with captopril (mean dosage 77 +/- 26 mg/day). After 6 months there was a significant improvement according to the New York Heart Association (NYHA) classification, from 2.4 to 1.9 in group 1 (p less than 0.01) and from 2.7 to 1.9 in group 2 (p less than 0.001). The cardio-thoracic ratio (chest x-ray) decreased significantly from 0.59 to 0.56 (p less than 0.001) in group 1 and from 0.56 to 0.53 (p less than 0.001) in group 2. Physical working capacity (bicycle ergometry) showed a significant increase in both groups from 61% to 81% in group 1 (p less than 0.01) and from 66% to 83% in group 2 (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mild systolic dysfunction in heart failure (left ventricular ejection fraction >35%): Baseline characteristics,prognosis and response to therapy in the vasodilator in heart failure trials (V-HeFT)

Objectives. This analysis sought to evaluate the clinical characteristics and outcome in heart failure with mild systolic dysfunction.Background. Although heart failure with mild systolic dysfunction occurs commonly, this is an understudied area because clinical trials have usually excluded patients with ejection fraction >35%.Methods. The 422 patients with left ventricular ejection fraction ⩽35% were compared with 172 with a left ventricular ejection fraction > 35% in the Vasodilator in Heart Failure Trial (V-HeFT I), whereas in V-HeFT-II 554 patients with a left ventricular ejection fraction ⩽ 35% were compared with 218 patients with a left ventricular ejection fraction > 35% for mortality and clinical care. For a left ventricular ejection fraction >35%, treatment with hydralazine/isosorbide dinitrate was compared with prazosin and placebo therapy in V-HeFT I, and hydralazine/isosorbide dinitrate was compared with enalapril in V-HeFT II for mortality, clinical course and change in physiologic variables: ejection fraction, plasma norepinephrine levels, ventricular tachycardia and echocardiographic variables.Results. In both studies, patients with a left ventricular ejection fraction > 35% differed principally in hypertensive history, higher functional capacity and radiographic and echocardiographic cardiac dimension from patients with a left ventricular ejection fraction ⩽35%, and plasma norepinephrine levels differed in V-HeFT II (p < 0.01). Patients with a left ventricular ejection fraction >35% had a lower cumulative mortality than those with a left ventricular ejection fraction ⩽35% (p < 0.0001) and less frequent hospital admissions for heart failure (p < 0.014, V-HeFT I; p < 0.005, V-HeFT II). Although cumulative mortality and morbidity did not differ between treatment groups in V-HeFT I, enalapril decreased overall mortality versus hydralazine/isosorbide dinitrate (p < 0.035) in V-HeFT II. For physiologic variables in V-HeFT II, enalapril decreased ventricular tachycardia at follow-up (p < 0.05).Conclusion. In V-HeFT, heart failure with mild systolic dysfunction was associated with different characteristics and a more favorable prognosis than heart failure with more severe systolic dysfunction. Enalapril decreased overall mortality and sudden death compared with hydralazine/isosorbide dinitrate. Prospective trials are needed to address therapy for heart failure with mild systolic dysfunction.     

Acute and long-term effects of enalapril on the cardiovascular response to exercise and exercise tolerance in patients with congestive heart failure

Enalapril is a recently developed angiotensin-converting enzyme inhibitor that improves cardiac function at rest in patients with congestive heart failure. This study investigated the acute effects of enalapril on the cardiovascular response to exercise, and then evaluated the long-term effects of enalapril on exercise capacity and functional status during a 12 week placebo-controlled trial in patients with heart failure. Ten patients underwent hemodynamic monitoring while at rest and during incremental bicycle exercise before and after 5 to 10 mg of enalapril orally. At rest, enalapril decreased mean blood pressure 13% (p less than 0.01) and systemic vascular resistance 20% (p less than 0.05) and increased stroke volume index 21% (p less than 0.01). During maximal exercise, enalapril decreased systemic vascular resistance and increased both cardiac and stroke volume indexes. Enalapril acutely increased exercise duration (p less than 0.05) and maximal oxygen consumption (p less than 0.001). These 10 patients and an additional 13 patients were then randomized to either placebo or enalapril treatment and followed up for 12 weeks. Of the 11 patients assigned to active treatment, 73% considered themselves improved compared with 25% of the patients assigned to placebo treatment (p less than 0.02). During long-term treatment, exercise capacity increased in patients receiving enalapril (p less than 0.001) but was unchanged in patients receiving placebo (intergroup difference, p less than 0.05). During long-term treatment, no adverse effects of enalapril occurred. Thus, enalapril improves cardiac function at rest and during exercise. Compared with placebo, maintenance therapy with enalapril results in symptomatic improvement and increased exercise capacity.     

Minoxidil in patients with chronic left heart failure: contrasting hemodynamic and clinical effects in a controlled trial

Minoxidil, a potent predominant arterial dilator, improves hemodynamics over the short term in patients with heart failure. In random double-blind fashion 17 patients with chronic left heart failure were given minoxidil (nine patients) or placebo (eight patients) in addition to digoxin and diuretics for 3 months. Cardiac index and heart rate increased and mean arterial pressure and systemic vascular resistance fell within 4 hr of minoxidil administration. Right heart and pulmonary arterial pressures were unchanged over the short term but rose after long-term minoxidil. After 3 months of minoxidil treatment, systemic vascular resistance was still reduced (11.7 +/- 6.3[SD] vs 17.1 +/- 3.1 U at baseline; p less than .05). Hemodynamics were similar at baseline and remained unchanged during placebo treatment. Mean left ventricular ejection fraction rose from 29.6 +/- 17.7% to 42.7 +/- 22.3% (p less than .05) after 3 months of minoxidil treatment (this result was influenced largely by responses in two patients), and remained unchanged (at 25.1 +/- 16.6%) after 3 months of placebo. Exercise duration and maximal oxygen uptake during exercise were unchanged during minoxidil or placebo treatment. Total clinical events, including increased need for diuretics, angina, ventricular arrhythmias, worsening heart failure, and death were all more frequent during minoxidil vs placebo administration (21 vs seven total events; p less than .01). Thus, despite improving hemodynamics and left ventricular function, long-term minoxidil administration was associated with a poorer clinical course in patients with chronic left ventricular failure. Furthermore, this experience demonstrates that improvement of left ventricular function alone cannot be reliably interpreted as proof of clinical efficacy of therapeutic interventions in patients with heart failure.     

Clinical studies of enalapril treatment for patients with severe congestive heart failure.

The clinical efficacy of enalapril was investigated in 21 patients with severe heart failure. For each subject, the following parameters were compared before and one month after enalapril maintenance treatment. NYHA functional class, Killip's class, cardiothoracic ratio (CTR), left ventricular (LV) function estimated by echocardiography and gated equilibrium radionuclide angiography, Holter ECG recordings, serum digoxin concentration (SDC), plasma remin activity, plasma aldosterone concentration, plasma norepinephrine concentration (PNE), etc. Short- and long-term hemodynamic responses to enalapril were also studied, with simultaneous measurement of enalapril concentration by radioimmunoassay. After maintenance therapy, patients showed a significant improvement as judged by NYHA functional class, Killip's class, and CTR. The LV fractional shortening and the ejection fraction significantly increased. The frequency of ventricular tachycardia showed a significant tendency to decrease after the therapy. The SDCs were unchanged, which indicates no pharmacokinetic drug interaction between digoxin and enalapril. Hemodynamic assessment showed a reduction in systemic vascular resistance, a reduction in mean blood pressure, and an increase in the cardiac index. No major side effects were observed during the study period. According to a multivariate analysis, the coefficient of determination of PNE was the highest for the final global improvement rating. This may reflect the neurohormonal improvement of congestive heart failure by enalapril therapy. In conclusion, enalapril is recommended for treating patients with severe CHF.     

Long-term effects of the angiotensin-converting enzyme inhibitor enalapril on chronic heart failure. Examination by 123I-MIBG imaging

To examine the long-term effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril on chronic heart failure, 10 patients (7 men and 3 women, mean age: 62 +/- 11 years) with chronic stable heart failure, classified as New York Heart Association (NYHA) functional class 2-3 for more than 3 months, and a left ventricular ejection fraction less than 45% were treated with 2.5-5.0 mg of enalapril once a day for 3-15 months (mean 7 months). The causes of heart failure were old myocardial infarction (n = 7), hypertension (n = 2), and atrial fibrillation (n = 1). Radioiodinated metaiodobenzyl guanidine (123I-MIBG) imaging, radionuclide angiography, and treadmill exercise test were performed before and after the treatment. With enalapril treatment, (1) left ventricular ejection fraction (LVEF) increased significantly from 38.3 +/- 6.9% to 47.5 +/- 14.7%; (2) sub-maximal exercise time increased significantly from 205 +/- 112 to 272 +/- 120 seconds; (3) the heart to mediastinum (H/M) ratio of 123I-MIBG increased significantly (early image: 1.99 +/- 0.38 versus 2.20 +/- 0.50; delayed image: 1.86 +/- 0.44 versus 2.09 +/- 0.51); and (4) the washout rate of 123I-MIBG decreased slightly from 29.1 +/- 9.1% to 25.4 +/- 7.0%. The improvement rate of LVEF was significantly correlated with the improvement rates of the H/M ratio and washout rate after treatment with enalapril. Thus, the long-term effects of enalapril can be observed in the cardiac sympathetic nervous system, and 123I-MIBG imaging appears to be useful for evaluating the therapeutic effects of enalapril on the cardiac sympathetic nervous system in patients with chronic heart failure.     

Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. SOLVD Investigators.

BACKGROUND. In patients with heart failure, activation of the renin-angiotensin system is common and has been postulated to provide a stimulus for further left ventricular (LV) structural and functional derangement. We tested the hypothesis that chronic administration of the angiotensin converting enzyme (ACE) inhibitor enalapril prevents or reverses LV dilatation and systolic dysfunction among patients with depressed ejection fraction (EF) and symptomatic heart failure. METHODS AND RESULTS. We examined subsets of patients enrolled in the Treatment Trial of Studies of Left Ventricular Dysfunction (SOLVD). Fifty-six patients with mild to moderate heart failure underwent serial radionuclide ventriculograms, and 16 underwent serial left heart catheterizations, before and after randomization to enalapril (2.5-20 mg/day) or placebo. At 1 year, there were significant treatment differences in LV end-diastolic volume (EDV; p less than 0.01), end-systolic volume (ESV; p less than 0.005), and EF (p less than 0.05). These effects resulted from increases in EDV (mean +/- SD, 136 +/- 27 to 151 +/- 38 ml/m2) and ESV (103 +/- 24 to 116 +/- 24 ml/m2) in the placebo group and decreases in EDV (140 +/- 44 to 127 +/- 37 ml/m2) and ESV (106 +/- 42 to 93 +/- 37 ml/m2) in the enalapril group. Mean LVEF increased in enalapril patients from 0.25 +/- 0.07 to 0.29 +/- 0.08 (p less than 0.01). There was a significant treatment difference in LV end-diastolic pressure at 1 year (p less than 0.05), with changes paralleling those of EDV. The time constant of LV relaxation changed only in the placebo group (p less than 0.01 versus enalapril), increasing from 59.2 +/- 8.0 to 67.8 +/- 7.2 msec. Serial radionuclide studies over a period of 33 months showed increases in LV volumes only in the placebo group. Two weeks after withdrawal of enalapril, EDV and ESV increased to baseline levels but not to the higher levels observed with placebo. CONCLUSIONS. In patients with heart failure and reduced LVEF, chronic ACE inhibition with enalapril prevents progressive LV dilatation and systolic dysfunction (increased ESV). These effects probably result from a combination of altered remodeling and sustained reduction in preload and afterload.     

Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography

To impact on the development of clinical congestive heart failure as a complication of doxorubicin therapy, left ventricular ejection fraction was monitored with serial resting radionuclide angiocardiography in 1,487 patients with cancer over a seven-year period in both university and community hospital environments. A high-risk subset of 282 patients was selected for retrospective analysis of their clinical outcome. High-risk patients were identified by one or two of the following three criteria: decline of 10 percent or more in absolute left ventricular ejection fraction from a normal baseline to 50 percent or less; high cumulative dose of doxorubicin (more than 450 mg/m2); abnormal baseline left ventricular ejection fraction (less than 50 percent). Clinical congestive heart failure occurred in 46 (16 percent) during the treatment period, and in an additional three patients (1.3 percent) at last follow-up examination 11.8 +/- 14.2 months following discontinuation of doxorubicin. Total cumulative dosages of doxorubicin that precipitated congestive heart failure (75 to 1,095 mg/m2) and those that did not (30 to 880 mg/m2) varied widely. Decline of 10 percent or more in absolute left ventricular ejection fraction to a value of 50 percent or less preceded administration of the final dose of doxorubicin that precipitated clinical congestive heart failure in the majority of patients in whom congestive heart failure developed. Clinical congestive heart failure improved in 87 percent given routine therapy with digitalis, diuretics, and/or vasodilators. Criteria for monitoring left ventricular ejection fraction and discontinuing doxorubicin were formulated. The occurrence of clinical congestive heart failure was compared in those patients whose management was concordant with proposed criteria (Group A) and in those whose management was not (Group B). Group A had a lower incidence of congestive heart failure compared with Group B (2.9 percent versus 20.8 percent, p less than 0.001) and had only mild congestive heart failure that resolved with treatment (n = 2) and no deaths due to congestive heart failure. Multivariate analysis with proportional-hazards regression (Cox's model) demonstrated a fourfold reduction in the incidence of congestive heart failure independent of other clinical predictor variables in those patients whose management was concordant with proposed guideline criteria. The incidence, persistence, late development, predictability, and reversibility of clinical congestive heart failure were comparable in university and community hospital settings.(ABSTRACT TRUNCATED AT 400 WORDS)     

Beneficial clinical effect of very early enalapril treatment in patients with acute left ventricular failure complicating myocardial infarction

Acute myocardial infarction (AMI) leads to left ventricular dysfunction, the extent of which predicts mortality. We studied the effect of very early enalapril treatment in patients with left ventricular failure (Killip classification II-III) resulting from AMI. In a double-blind randomized trial, patients on conventional treatment were started on placebo (PL, n = 15) or 2.5 mg enalapril (EN, n = 15) twice daily as early as 24 to 30 h after AMI and were followed up over a period of 21 days. One patient died in each treatment group. There were three dropouts in the placebo group (progressive heart failure requiring antiotensin-converting enzyme inhibition) and one dropout in the enalapril group (malignant ventricular arrhythmias). Plasma atrial natriuretic peptide (ANP) and norepinephrine decreased similarly in both groups from elevated baseline concentrations. The patients with the highest baseline ANP levels died in both groups: EN: 579 fmol/ml (mean 65.3 ± 34.4 fmol/ml), PL: 403 fmol/ml (mean 63.5 ± 37.6 fmol/ml). Killip classification improved in 9 of 13 patients on enalapril but only in 5 of 11 patients on placebo. On echocardiography an increase in fractional shortening (FS) (3.2 ± 7.5%, p < 0.05) was found with enalapril only. Patients on placebo required more diuretics, and plasma aldosterone increased threefold. Thus, very early enalapril treatment may help prevent left ventricular failure after AMI. Extremely high initial plasma ANP concentrations may predict an unfavorable outcome.     

Effects of enalapril in heart failure: a double blind study of effects on exercise performance,renal function,hormones, and metabolic state.

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.     

Safety and efficacy of valsartan versus enalapril in heart failure patients

Although a cornerstone in the treatment of heart failure, angiotensin-converting enzyme inhibitors are under-used, partly due to side effects. If proven at least similarly efficacious to angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers may replace them due to their superior tolerability. We aimed to compare the efficacy and safety of valsartan and enalapril in heart failure patients stabilised on an angiotensin-converting enzyme inhibitor. We randomised 141 patients (mean 68 years, 74% males) with stable mild/moderate heart failure and left ventricular ejection fraction 0.45 or less, to valsartan 160 mg q.d. (n=70) or enalapril 10 mg b.i.d. (n=71) for 12 weeks. Changes in 6-min-walk test (primary efficacy variable), patients' wellbeing and left ventricular size and function did not differ significantly between the treatment groups. Valsartan was significantly non-inferior to enalapril in walk test distance change: least-square means treatment difference +1.12 m (95% confidence interval -21.9 to 24.1), non-inferiority P<0.001. Left ventricular size (P<0.001) and function (P=0.048) improved significantly only in the valsartan group. Fewer patients experienced adverse events in the valsartan group (50%) than in the enalapril group (63%), although statistically non-significant. Valsartan is similarly efficacious and safe to enalapril in patients with stable, mild/moderate heart failure, previously stabilised on an angiotensin-converting enzyme inhibitor and directly switched to study medication.     

Lack of long-term ventricular arrhythmia reduction by enalapril in heart failure

Previous studies have indicated that angiotensin-converting enzyme inhibitors may reduce the frequency of ventricular arrhythmias in patients with heart failure. These reports were mostly small and of short duration. We prospectively studied 734 patients recruited in 11 universities for 1 year who were enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) to determine the long-term effects of enalapril and placebo on the frequency and complexity of ventricular arrhythmias in patients with symptomatic (treatment trial) or asymptomatic (prevention trial) heart failure and depressed left ventricular function (ejection fraction ≤35%). Five hundred fifty-three patients from the prevention trial and 181 from the treatment trial of SOLVD underwent ambulatory electrocardiographic monitoring at baseline, and then at 4 and 12 months of double-blind therapy with either placebo or enalapril (2.5 to 10 mg twice daily). The prospectively defined primary analysis was by intent-to-treat and revealed no significant differences in ventricular premature complexes between the placebo and enalapril groups at baseline (87 ± 13 vs 84 ± 13/hour), 4 months (100 ± 15 vs 85 ± 12/hour), or 12 months (80 ± 12 vs 90 ± 14/hour). Likewise, there was no difference between the placebo and enalapril groups in runs of nonsustained ventricular tachycardia: baseline (8.3 ± 4.1 vs 1.9 ± 0.4 runs/day), 4 months (16 ± 12 vs 7.2 ± 4.1 runs/day), or after 12 months of blinded therapy (11 ± 7.0 vs 6.1 ± 4.4 runs/day). Over the 1 -year trial, an equal number of patients in the placebo and enalapril groups developed new ventricular arrhythmias or had comparable reductions in ventricular arrhythmias which had been present at baseline. Our conclusion is that enalapril has no antiarrhythmic effect in a spectrum of patients with heart failure representing New York Heart Association classes I to III. These observations are consistent with the absence of any observed effect of enalapril on sudden death or hospitalization for arrhythmias in the 6,797 patients enrolled in SOLVD.     

Increased myocardial [123I]-metaiodobenzylguanidine uptake after enalapril treatment in patients with chronic heart failure.

OBJECTIVE: To assess non-invasively the effect of enalapril on cardiac sympathetic neuronal uptake function in patients with congestive heart failure, by using [123I]-metaiodobenzylguanidine (MIBG), which is a noradrenaline analogue. Cardiac MIBG uptake was visualised by single photon emission tomography (SPET). In addition, plasma noradrenaline concentration, indicating systemic sympathetic activity, was measured to see whether it was related to cardiac MIBG uptake. DESIGN: Consecutive patients were treated with enalapril and served as their own controls. SETTING: Cardiac unit of a tertiary care centre. PATIENTS: 23 Patients with chronic, mild to moderate, stable congestive heart failure, and a left ventricular ejection fraction less than 40%. Heart failure was caused by ischaemic heart disease or was idiopathic. INTERVENTIONS: Cardiac MIBG SPET was performed and plasma noradrenaline concentration was measured before and after 6 weeks treatment with enalapril. MAIN OUTCOME MEASURES: Cardiac uptake of MIBG was measured by using the left ventricular cavity and a venous blood sample as a reference. RESULTS: Cardiac uptake of MIBG increased significantly after enalapril treatment, indicating improved cardiac neuronal uptake function. Plasma noradrenaline concentration did not decrease significantly. Cardiac MIBG uptake was not related to plasma noradrenaline concentration. CONCLUSIONS: Cardiac MIBG SPET can be used to assess changes in cardiac sympathetic neuronal uptake function caused by pharmacological intervention. Enalapril seemed to improve cardiac sympathetic neuronal uptake function but did not significantly affect plasma noradrenaline concentrations in a group of patients with predominantly moderate heart failure. These results accord with the hypothesis that restoration of cardiac neuronal uptake of noradrenaline is one of the beneficial effects of enalapril in such patients.     

Preserved ventricular pump function after a marked reduction of left ventricular mass.

OBJECTIVES. This study was designed to evaluate the long-term effects of combination therapy with an angiotensin-converting enzyme inhibitor and a beta-adrenergic blocking agent on the relation between the decrease in arterial pressure at rest and during exercise and the decrease in left ventricular mass. BACKGROUND. A variety of antihypertensive drugs including angiotensin-converting enzyme inhibitors and beta-blockers have been shown to reduce ventricular hypertrophy, although little is known about combination therapy and the time course of such a reduction. METHODS. Twenty-one patients with previously untreated essential hypertension were treated with a low dose combination of 50 mg of atenolol and 10 mg of enalapril once daily for 39 months. Cardiovascular findings were assessed by two-dimensionally guided M-mode echocardiography in the pretreatment phase and after 6 and 39 months of combination therapy. RESULTS. Combination therapy reduced arterial pressure at rest from 161/108 to 130/86 mm Hg (p less than 0.001) and exercise arterial pressure at 100 W from 192/112 to 167/95 mm Hg (p less than 0.001). After 6 months of treatment, significant decreases in interventricular septal thickness (9%, p less than 0.001), posterior wall thickness (9%, p less than 0.001) and left ventricular mass index (16%, p less than 0.001) were demonstrated on the echocardiogram. After 39 months of therapy, reductions in these values were 28% (p less than 0.001), 29% (p less than 0.001) and 40% (p less than 0.001), respectively. CONCLUSIONS. Long-term treatment with combination therapy of atenolol and enalapril produced significant reductions in arterial pressure at rest and during exercise accompanied by a marked reduction of left ventricular mass. However, whereas arterial pressure decreased immediately and remained unchanged, left ventricular mass decreased more gradually and continued to decrease throughout the treatment period of greater than 3 years. Despite this marked reduction in left ventricular mass, left ventricular pump function was well preserved during rest and exercise.     

Effects of enalapril in heart failure: a double blind study of effects on exercise performance, renal function, hormones, and metabolic state

Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.     

Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure

Renal function was evaluated in 104 patients with severe chronic heart failure whom we treated with captopril or enalapril. Seventy patients showed no change or an improvement in renal function (group A), and 34 patients developed functional renal insufficiency (group B). Before converting-enzyme inhibition, group B patients received higher doses of furosemide (p less than 0.02) and had lower central venous pressures (p less than 0.05) than group A patients. After 1 to 3 months of converting-enzyme inhibition, an excessive reduction in left ventricular filling pressure (to less than 15 mm Hg) or mean arterial pressure (to less than 60 mm Hg) was noted in 28 of 34 (82%) patients in group B but in only 22 of 70 patients in group A (31%) (p less than 0.001). At the end of the study, drug-induced azotemia resolved after a reduction in the dosage of diuretics, despite unaltered treatment with captopril and enalapril. Hence, the deterioration of renal function after converting-enzyme inhibition in heart failure is not a toxic or immunologic reaction to therapy but results from specific hemodynamic events that can be ameliorated by sodium repletion.     

Overtreatment of hypertension in the elderly?

In a representative population sample of 619 70-year-old people, 26% were taking antihypertensive treatment. Twenty per cent (n = 32) of them showed no signs of cardiovascular disease and had a blood pressure of less than 175/95 mmHg. Treatment was withdrawn in 25 of the 32 patients. Casual blood pressure, blood pressure during isometric exercise and left ventricular morphology and function were studied repeatedly over 2 years, using non-invasive methods. A significant increase in mean systolic and diastolic blood pressures was observed in the 14 patients who completed the study. No change was observed with respect to left ventricular morphology and left ventricular diastolic function. A statistically significant decrease in left ventricular fractional shortening, but no clinical signs of congestive heart failure were observed. Withdrawal of antihypertensive treatment in elderly patients free from signs of cardiovascular disease may thus be attempted without harmful effects on cardiovascular function.