Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function substudy.

BACKGROUND: The mechanism by which angiotensin-converting enzyme inhibitors reduce mortality rates and disease progression in patients with heart failure is likely mediated in part through prevention of adverse ventricular remodeling. This study examined the effects of the angiotensin-converting enzyme inhibitor captopril and the angiotensin II type 1 receptor antagonist losartan on ventricular volumes and function in elderly patients with heart failure and reduced left ventricular ejection fraction (< or =40%). METHODS: Patients underwent radionuclide ventriculograms (RVG) at baseline and were randomized to either captopril (n = 16) or losartan (n = 13). After 48 weeks, another RVG was obtained. Therapy was then withdrawn for at least 5 days, and the RVG was repeated while the patient was not receiving the drug. RESULTS: At 48 weeks both captopril and losartan significantly reduced left ventricular (LV) end-diastolic volume index (135 +/- 26 to 128 +/- 23 mL/m(2) for losartan, P <.05 vs baseline; 142 +/- 25 to 131 +/- 20 mL/m(2) for captopril, P <.01; mean (SD). Captopril also reduced LV end-systolic volume index (98 +/- 24 to 89 +/- 21 mL/m(2), P <.01 vs. baseline), whereas a nonsignificant trend was observed for the losartan group (97 +/- 23 to 90 +/- 16 mL/m(2), P = not significant). The between-group differences in the changes in LV volumes were not statistically significant. After drug withdrawal, LV end-diastolic volume index remained significantly lower than baseline in the captopril group (P <.01). CONCLUSIONS: Both captopril and losartan prevent LV dilation, representing adverse ventricular remodeling, previously seen with placebo treatment. Reverse remodeling was observed in the captopril group. On the basis of these results, the relative effects on LV remodeling do not provide a rationale for a survival benefit of losartan over captopril.

Ventricular remodeling and the renin angiotensin aldosterone system.

Ventricular remodeling in patients with left ventricular systolic dysfunction is an indolent process that is associated with a poor prognosis. Clinical and experimental data support the central role played by the renin-angiotensin-aldosterone system in the pathophysiology of remodeling. ACE inhibitors improve the natural history of ventricular remodeling and the syndrome of heart failure. Experimental and preliminary clinical data suggest that angiotensin II type I receptor blockade also impacts favorably on remodeling. Some experimental studies suggest a possible synergistic effect when combining ACE inhibitors and angiotensin II type I receptor antagonists. Aldosterone, the regulation of which, in part, is independent of angiotensin II, is a direct mediator of the interstitial component of remodeling, and its blockade has been found to improve clinical outcomes. Future research will more precisely define the mechanism for ventricular remodeling and will yield more effective means of achieving a clinically relevant impact on this process. (c)2000 by CHF, Inc.

Ventricular remodeling and its prevention in the treatment of heart failure.

Ventricular remodeling refers to changes in left ventricular (LV) geometry, mass, and volume in response to myocardial injury or alterations in load. The extent of LV dilatation or remodeling after myocardial infarction (MI) or in patients with heart failure is a strong predictor of both morbidity and mortality. Based on these observations, it is clear that LV remodeling is a maladaptive process. Two classes of drugs appear to inhibit LV remodeling. A large amount of data support the use of angiotensin-converting enzyme (ACE) inhibitors to improve survival and to prevent progressive remodeling. In addition, recent studies suggest that beta-adrenergic blockers have a beneficial effect on both survival and remodeling. These data support a causative role of the renin-angiotensin system and perhaps the sympathetic nervous system in this process. Thus, ACE inhibitors and possibly beta-blockers should be part of the pharmacologic regimen for the treatment of patients with LV dysfunction to prevent progressive LV remodeling.

Ventricular remodeling in a mouse model of myocardial infarction.

We investigated the suitability of studying ventricular remodeling in a mouse model of myocardial infarction (MI). We performed left coronary ligation (n = 22) or a sham procedure (n = 21) on normal C57BL/6J mice. Six weeks later, animals underwent echocardiography and hemodynamic evaluation. Left ventricular (LV) volume at a common distending pressure was calculated from passive pressure-volume curves. The MI group exhibited lower systolic blood pressure (P < 0.05), higher LV end-diastolic pressure (P < 0.05), and lower peak first derivative of LV pressure (dP/dt, P < 0.05) than the sham group. Mice with moderate (< 40%, n = 11) and large (> or = 40%, n = 11) MIs displayed increased LV mass-to-body weight ratio (P < 0.02 and P < 0.01, respectively, vs. sham group), whereas only the large-MI group exhibited increased right ventricular mass-to-body weight ratio (P < 0.01). LV volumes were increased in the moderate-MI group (P = 0.059 vs. sham group) and to a much greater extent in the large-MI group (P < 0.0001 vs. sham group). The moderate- and large-MI groups also exhibited increases in LV end-diastolic diameter (P < 0.03 and P < 0.0001, respectively, vs. sham group) and LV end-systolic diameter (P < 0.01 and P < 0.0001, respectively, vs. sham group) with decreased fractional shortening (P < 0.01 for both). These data demonstrate ventricular remodeling in a mouse model of MI and confirm the feasibility of quantifying indexes of remodeling in vivo and postmortem. This model will be of particular usefulness when applied to transgenic strains.

Divergent effects of angiotensin-converting enzyme inhibition and angiotensin II-receptor antagonism on myocardial cellular proliferation and collagen deposition after myocardial infarction in rats.

There is mechanistic rationale to suggest differential effects of angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 (AT1)-receptor antagonism on ventricular remodeling after myocardial infarction (MI). We compared the effects of ACE inhibition, AT1-receptor antagonism, and their combination on post-MI ventricular remodeling in rats. We induced MI in 62 rats, which then received one of four treatments: (a) placebo; (b) the ACE inhibitor, enalapril; (c) the AT1-receptor antagonist, losartan; and (d) enalapril and losartan in combination. Two weeks after MI, we examined: (a) heart weight (HW)/body weight (BW) ratio; (b) nonmyocyte cellular proliferation in the noninfarct zone by using proliferating cell nuclear antigen staining; and (c) collagen content within the noninfarct zone. Placebo-treated, infarcted rats developed significant increases in HW/BW ratio (p < 0.001), left ventricular (LV) volume (p < 0.01), nonmyocyte cellular proliferation (p < 0.04), and collagen content (p < 0.01) compared with noninfarcted controls. Enalapril, losartan, and combination therapy limited the increase in HW/BW ratio (all p values <0.01 vs. placebo). Enalapril inhibited nonmyocyte proliferation (p < 0.01 vs. placebo), whereas losartan had a smaller effect (p = NS vs. placebo; p < 0.03 vs. enalapril); combined treatment also reduced nonmyocyte cellular proliferation but did not reach statistical significance (p = 0.08 vs. placebo). Enalapril and combination treatment significantly diminished collagen content (both p values <0.01 vs. placebo), whereas losartan did not. Thus, ACE inhibition and AT1-receptor antagonism equally limited myocardial hypertrophy after MI in rats, but ACE inhibition more effectively prevented nonmyocyte cellular proliferation and collagen deposition in the noninfarcted myocardium. Combination therapy was no more effective than was ACE inhibition alone. These data suggest that the myocyte hypertrophic response after MI is strongly influenced by activation of the AT1 receptor, whereas nonmyocyte cellular proliferation and collagen deposition result, in part, from mechanisms separate from AT1-receptor activation.

Acute and long-term effects of the angiotensin-converting enzyme inhibitor, enalapril, on adrenergic activity and sensitivity during exercise in patients with left ventricular systolic dysfunction.

Patients with heart failure and left ventricular systolic dysfunction exhibit increased adrenergic activity but blunted adrenergic responsiveness. We studied patients enrolled in the Studies of Left Ventricular Dysfunction, examining exercise responses of heart rate (HR) and plasma norepinephrine (PNE). Eighty-seven patients were studied before randomization; 65 of these were examined 1 year after randomization to placebo or enalapril. Compared with prevention trial (asymptomatic) patients, patients in the treatment trial (symptomatic) had higher resting HR and PNE levels and less increase in HR with a greater increase in PNE with exercise. Acute administration of enalapril increased the resting HR in patients in the prevention trial only but had no significant effect on PNE. After 1 year of therapy, patients in the prevention trial exhibited no change. Within the treatment trial, the placebo group displayed both a higher peak PNE and increase in PNE with exercise than did the enalapril group, whose HR response was maintained in spite of a reduction of exercise PNE. We conclude that (1) compared with asymptomatic patients, symptomatic patients with reduced left ventricular ejection fraction manifest greater resting and exercise adrenergic activity, with blunted HR response; and (2) in symptomatic patients, 1 year of enalapril treatment effected an augmented HR response to adrenergic stimulation, supporting an interaction between the renin/angiotensin and adrenergic nervous systems. Normalization of adrenergic tone and response likely contributes to the benefits of long-term angiotensin-converting enzyme inhibitor therapy.

Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial.

OBJECTIVES: This clinical trial was performed to determine the safety and clinical impact of titrated metoprolol therapy in patients with heart failure, documented coronary artery disease and a low ejection fraction. BACKGROUND: Despite known cardiodepressant effects, long-term use of beta-adrenergic antagonists appears to be beneficial in patients with idiopathic dilated cardiomyopathy. However, this therapy has not been critically evaluated in patients with heart failure and coronary artery disease. METHODS: In 50 patients with heart failure, known coronary artery disease and an ejection fraction < or = 0.40, we examined the impact of metoprolol therapy in a 6-month double-blind, placebo-controlled randomized trial, assessing the frequency of heart failure exacerbations and changes in symptoms (New York Heart Association functional class), ejection fraction and exercise duration. Placebo-treated patients who completed 6-month follow-up studies then underwent a trial with metoprolol therapy (crossover group). RESULTS: Metoprolol was titrated to a mean maximal dose of 87 mg/day (range 25 to 100) without serious adverse reactions. During double-blind therapy, use of a beta-blocker was associated with a significant reduction in the number of hospital admissions (4% vs. 32%, p < 0.05), overall improved functional class (p = 0.02), increased ejection fraction (4 +/- 7% [mean +/- SD] compared with 0 +/- 6%, p < 0.05) and a greater increase in exercise duration (193 +/- 276 vs. 38 +/- 213 s with placebo, p < 0.01). Crossover outcome paralleled the favorable impact seen during randomized metoprolol therapy. CONCLUSIONS: Cautious use of titrated metoprolol appears to be safe and beneficial when added to standard heart failure therapy in patients with dilated cardiomyopathy associated with coronary artery disease.

Effects of intravenous magnesium sulfate on arrhythmias in patients with congestive heart failure.

Intravenous magnesium is an effective treatment for ventricular tachycardia of some etiologies, and in patients with congestive heart failure low serum magnesium concentrations are associated with frequent arrhythmias and high mortality. This suggests that magnesium administration may decrease the frequency of ventricular arrhythmias in patients with heart failure. We therefore assessed the impact of an intravenous magnesium infusion upon the frequency of ventricular premature depolarizations in 40 patients with New York Heart Association (NYHA) class II to IV heart failure and serum magnesium < or = 2.0 mg/dl. Within 1 week of a baseline 6-hour ambulatory electrocardiographic recording, an infusion of 0.2 mEq/kg of MgSO4 was given over 1 hour and a repeat 6-hour recording was obtained. There was an inverse relationship between the change in magnesium concentration and the change in frequency of premature ventricular depolarizations; premature ventricular depolarizations declined by 134 +/- 207 hr-1 in patients in whom serum magnesium concentration increased > or = 0.75 mg/dl, but increased by 72 +/- 393 hr-1 in patients with a change < 0.75 mg/dl (p < 0.05). For all patients, the frequency of premature ventricular depolarizations was 283 +/- 340 hr-1 pretreatment and 220 +/- 269 hr-1 following magnesium infusion (p = 0.21). Patients with > or = 300 premature ventricular depolarizations hr-1 demonstrated a decrease from 794 +/- 309 to 369 +/- 223 hr-1 (p < 0.001). Intravenous magnesium administration decreased the frequency of couplets from 233 +/- 505 to 84 +/- 140 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)