H. Pouleur

Effect of Enalapril On Myocardial-infarction and Unstable Angina in Patients With Low Ejection Fractions

An association between raised renin levels and myocardial infarction has been reported. We studied the effects of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, on the development of myocardial infarction and unstable angina in 6797 patients with ejection fractions < or = 0.35 enrolled into the two Studies of Left Ventricular Dysfunction (SOLVD) trials. Patients were randomly assigned to placebo (n = 3401) or enalapril (n = 3396) at doses of 2.5-20 mg per day in two concurrent double-blind trials with the same protocol. Patients with heart failure entered the treatment trial (n = 2569) and those without heart failure entered the prevention trial (n = 4228). Follow-up averaged 40 months. In each trial there were significant reductions in the number of patients developing myocardial infarction (treatment trial: 158 placebo vs 127 enalapril, p < 0.02; prevention trial: 204 vs 161 p < 0.01) or unstable angina (240 vs 187 p < 0.001; 355 vs 312, p < 0.05). Combined, there were 362 placebo group patients with myocardial infarction compared with 288 in the enalapril group (risk reduction 23%, 95% CI 11-34%; p < 0.001). 595 placebo group patients developed unstable angina compared with 499 in the enalapril group (risk reduction 20%, 95% CI 9-29%, p < 0.001). There was also a reduction in cardiac deaths (711 placebo, 615 enalapril; p < 0.003), so that the reduction in the combined endpoint of deaths, myocardial infarction, and unstable angina was highly significant (20% risk reduction, 95% CI 14-26%; p < 0.0001). Enalapril treatment significantly reduced myocardial infarction, unstable angina, and cardiac mortality in patients with low ejection fractions.

Baseline Quality of Life as a Predictor of Mortality and Hospitalization in 5,025 Patients With Congestive Heart Failure

This study examined the independent relation of health-related quality of life (HRQL) to mortality and congestive heart failure (CHF)-related hospitalizations in patients with an ejection fraction of < 0.35 followed for a mean of 36.5 months. A brief HRQL questionnaire was administered at baseline to patients randomized to placebo or enalapril in the Studies of Left Ventricular Dysfunction (SOLVD) trial. Participants had an ejection fraction of < 0.35 and either symptomatic CHF (treatment trial, n = 2,465) or asymptomatic CHF (prevention trial, n = 2,560). Baseline assessment of HRQL predicted mortality and CHF-related hospitalizations in symptomatic and asymptomatic patients randomized to enalapril and placebo treatment. Domains that were the stronger univariate predictors of mortality and CHF-related hospitalizations were activities of daily living (relative risk [RR] for mortality: 1.163, p < 0.000; for hospitalization: 1.215, p < 0.000), general health (RR for mortality: 1.205, p < 0.000; for hospitalization: 1.188, p < 0.000), and social functioning (RR for mortality 1.098, p < 0.000; for hospitalization: RR 1.156, p < 0.000). In the multivariate model, activities of daily living (RR for mortality 1.41, p < 0.000; for hospitalization: RR 1.43, p < 0.002), general health (RR for mortality 1.21, p < 0.000; for hospitalization RR 1.16, p < 0.013) and heart failure symptoms (RR for mortality 1.02, p < 0.025; for hospitalization RR 1.03, p < 0.004) were found to be independent risk factors. HRQL independently predicted mortality and CHF-related hospitalizations after adjustment for ejection fraction, age, treatment, and New York Heart Association classification in patients with an ejection fraction of < 0.35, randomized to enalapril and placebo treatment. HRQL provides additional clinical information regarding disease course and outcome that is not captured by traditional indexes of clinical status.

Impaired early left ventricular relaxation in coronary artery disease: effects of intracornary nifedipine.

It has been shown that the maximal rate of left ventricular (LV) relaxation is impaired in patients with coronary artery disease (CAD) under basal conditions. To test the hypothesis that this impaired LV relaxation could be related to viable but metabolically abnormal myocardium, we studied the time course of isovolumic LV pressure fall in 21 patients with CAD and in 13 control subjects under basal conditions. This study was repeated after intracoronary injection of the calcium antagonist nifedipine (N) in 11 patients with CAD and in eight controls. Our data showed that isovolumic pressure fall was biexponential in 20 of 21 CAD patients and in six of 13 controls. Moreover, the time constant of isovolumic pressure fall during the first 40 msec after peak (negative) dP/dt (TJ) was significantly greater in CAD patients than in controls (62 ± 3 vs 44 ± 1 msec, p < 0.002); the time constant of pressure fall during the 40-80 msec after peak (negative) dP/dt (T2) was similar in both groups (42 ± 2 vs 39 ± 2 msec, NS). Thirty seconds after injection of nifedipine, T1 and T2 were significantly prolonged in patients with CAD (14 msec and 16 msec, respectively, p < 0.005) and in controls 12 msec and 14 msec, respectively, p < 0.05), and a negative inotropic effect was observed in both groups (peak (positive) dP/dt −16% in controls and −23% in CAD patients, p < 0.01). At rest, impairment of isovolumic relaxation in CAD patients is mainly limited to the first 40 msec after peak (negative) dP/dt, suggesting a dyssynchronous wall motion. This impairment of LV relaxation is better identified by T1 than by peak (negative) dP/dt in individual patients, and cannot be improved by administration of a calcium antagonist.

Effects of a New Metabolic Modulator, Ranolazine, On Exercise Tolerance in Angina-pectoris Patients Treated With Beta-blocker Or Diltiazem

Summary: Ranolazine (RS 43285) is a new piperazine derivative with anti-ischemic properties attributed to a modulation of myocardial metabolism. Its antianginal action was assessed in 104 patients recruited in a double-blind, crossover, randomized study comparing placebo with a single dose of ranolazine (10, 60, 120, and 240 mg). All patients had chronic stable angina pectoris and remained symptomatic (at least 0.1 mV ST-segment depression and angina during prestudy exercise testing) despite treatment with a β-blocker or with diltiazem. No significant effects of ranolazine on exercise duration or time to angina were observed after the dose of 10, 60, and 120 mg. After the 240 mg dose, however, significant improvement in exercise duration (+13.1% in the combined group, two-tailed p = 0.002; +14.3% in the p-blocker group, p = 0.009; + 11.9% in the diltiazem group, p = 0.06), in time to angina ( + 56.8 s, p = 0.008), and in time to 1 mm ST-segment depression was observed. The cumulative proportion of patients who improved their time to angina by at least 30 s above placebo were 25, 42, 50, and 72% with the doses of 10, 60, 120, and 240 mg, respectively. Sixty-seven percent of the patients with ranolazine plasma levels above 500 ng/ml improved their time to angina against 40% at plasma levels below 500 ng/ml and summed ST-segment depression during exercise and recovery was also significantly reduced at these plasma concentrations. Both heart rate and arterial pressure at rest and at peak exercise were unchanged after ranolazine, 240 mg. It is concluded that a single dose of 240 mg of ranolazine exerts a significant antianginal action in patients already treated with a β-blocker or diltiazem and that the lack of hemodynamic changes supports the hypothesis of a novel mode of action for ranolazine. Further studies are warranted to determine the optimal dosing interval and the maximum effective dose.

Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease.

SummaryTo assess the effects of ranolazine, a new antiischemic drug, on regional myocardium of the left ventricle, left ventricular (LV) hemodynamic and angiographic data were obtained in 15 patients with previous transmural myocardial infarction before and after intravenous infusion of ranolazine (200 or 500 µg/kg body weight). LV angiogram was analyzed by the area method and was divided into six segments. Regional LV segments were classified as normal (perfused by intact coronary vessels, n=20), ischemic (perfused by stenotic vessels but without ECG evidence suggesting myocardial necrosis, n=25), or infarcted (total coronary occlusion and with the ECG evidence for necrosis, n=45). Regional area fractional shortening, peak filling rate, and segmental wall motion during isovolumic relaxation period were analyzed. After ranolazine, regional area fractional shortening was unchanged in all segments. However, regional peak filling rate was decreased in the normal segments (1499±315 to 1368±303 mm2/sec, p<0.05). In the ischemic segments, by constrast, the administration of ranolazine significantly increased the regional peak filling rate (1050±410 to 1133±439 mm/sec, p<0.05) and regional wall lengthening during the isovolumic relaxation period (0.9±4.1% to 2.8±5.7% of end-diastolic segmental area, p<0.05), which indicates an improvement of regional diastolic function. Infarct segments were little affected by ranolazine. Thus, ranolazine improves diastolic function of the noninfarcted myocardium under chronic ischemic conditions and also may exert a mild negative lusitropic effect on the normal myocardium, although the former beneficial effect appears to be more clinically important. This finding supports the hypothesis that chronic myocardial ischemia impairs myocardial diastolic function and also opens new therapeutic perspectives.

Costs and effects of enalapril therapy in patients with symptomatic heart failure: An economic analysis of the studies of left ventricular dysfunction (SOLVD) treatment trial

The clinical results of the Studies of Left Ventricular Dysfunction (SOLVD) Treatment Trial have been published previously, but no evaluation of cost-effectiveness based on the primary data has been reported. The authors used a decision analytic model based on primary data from SOLVD to estimate years of survival (overall, by New York Heart Association Class, and quality-adjusted) and to estimate costs of nonfatal hospitalizations, ambulatory care, therapy with enalapril, and deaths. Clinical and resource utilization data were derived from participants in SOLVD, and cost data were derived from the United States. Therapy with enalapril during the approximate 48-month follow-up period in SOLVD resulted in a gain of 0.16 year of life and savings of dollars 718. During the patients lifetime, a survival benefit of 0.40 year, a cost per year of life saved of dollars 80, and a cost per quality-adjusted life year of dollars 115 with the use of enalapril were projected. The results indicated a net savings and gain in life expectancy during the SOLVD treatment trial. The lifetime projection suggests that therapy with angiotensin-converting enzyme inhibitors, such as enalapril, is extremely attractive when compared with many commonly used interventions in patients with cardiovascular disease or heart failure.

Effects of nitroprusside on venous return and central blood volume in the absence and presence of acute heart failure.

SUMMARYThe effects of nitroprusside (380–760 ug/min) on the systemic venous return, the central blood volume and the equilibrium point between the venous return and cardiac output curves were studied in eight dogs using a right-heart bypass preparation at constant total blood volume. Experiments were performed before and after the production of acute left ventricular failure. During control, nitroprusside infusion shifted the venous return curve, with a reduction in its plateau (3.1 to 2.4 l/min;p < 0.005), the central blood volume fell (−2.4 ± 0.4 ml/kg; p < 0.05) and the cardiac output at equilibrium was reduced (3.1 to 2.4 1/min; p < 0.005). Cardiac failure (produced by acute coronary artery ligation) increased the central blood volume (+6.3 ± 0.6 ml/kg; p < 0.01), leading to a decrease in both the systemic blood volume and the plateau of the venous return curve (3.2 to 2.6 1/min; p < 0.003). The cardiac output at equilibrium was also reduced (3.2 to 1.9 1/min; p < 0.001). In this setting, nitroprusside infusion decreased the central blood volume (−7.4 ml/kg; p < 0.01), but the venous return curve was not altered. The cardiac output curve was markedly shifted upward due to reduced afterload on the failing left ventricle; however, in the absence of a downward shift of the venous return curve, the cardiac output at equilibrium increased from 1.9 to 2.6 1/min (p < 0.05). We conclude that the differing effects of nitroprusside in acute cardiac failure are due primarily to an increased shift of blood from the central circulation in the failure state compared with the normal circulation. This shift counteracts the systemic venodilatation produced by nitroprusside and allows the markedly improved left ventricular function consequent to reduced afterload to be expressed as increased venous return and cardiac output.

Effects of long-term enalapril therapy on left ventricular diastolic properties in patients with depressed ejection fraction. SOLVD Investigators.

BACKGROUND The aim of the present study was to analyze the changes in left ventricular diastolic function that occur in patients with chronic severe left ventricular systolic dysfunction in the absence or presence of prolonged therapy with an angiotensin converting enzyme inhibitor. METHODS AND RESULTS Left ventricular function data (cineangiography plus Millar, frame-by-frame analysis) and right ventricular volumes (radionuclide angiography) were obtained at baseline and after an average follow-up of 12.4 months in 42 patients with a left ventricular ejection fraction of 35% or less. After baseline measurements, the patients were randomized to placebo (n = 16) or enalapril (10 mg BID, n = 26). In the placebo group, the changes in left ventricular function were characterized by increases in end-diastolic (159 +/- 43 to 170 +/- 44 mL/m2) and end-systolic (119 +/- 38 to 128 +/- 49 mL/m2) volumes accompanied by a downward and rightward shift of the diastolic pressure-volume relation. In contrast, decreases in end-diastolic (166 +/- 43 to 156 +/- 47 mL/m2) and end-systolic (125 +/- 43 to 111 +/- 42 mL/m2) volumes accompanied by a slight upward and leftward shift of the diastolic pressure-volume relation were noted in the enalapril group. These changes in left ventricular volumes were significantly different between groups (both P < .005) but were not attended by changes in left ventricular end-diastolic pressure, in time constant of isovolumic pressure decrease, or in right ventricular volumes. However, the chamber stiffness constant beta decreased from 0.044 +/- 0.027 to 0.032 +/- 0.019 mL-1/m2 in the placebo group, whereas it increased insignificantly in the enalapril group (0.040 +/- 0.028 to 0.041 +/- 0.028 mL-1/m2). These changes in chamber stiffness constant beta between baseline and follow-up were significantly different between placebo and enalapril groups (P < .05). Another index of chamber compliance, delta V/delta P, also confirmed the presence of opposite changes in left ventricular chamber compliance in the placebo group and in the enalapril group. The mean diastolic wall stress increased with placebo but not with enalapril (+51 versus -13 kdyn/cm2; P < .04) whereas left ventricular mass and the indexes of left ventricular sphericity tended to improve in the enalapril group. The changes in plasma levels of norepinephrine, atrial natriuretic peptide, and arginine vasopressin were, however, comparable in both groups. CONCLUSIONS The data indicate that in patients with severe systolic left ventricular dysfunction, the progressive left ventricular dilatation was accompanied by a decrease in left ventricular chamber stiffness; enalapril therapy was able to prevent or partially reverse these changes and tended to reduce left ventricular mass and ventricular sphericity. Those changes were suggestive of partial reversal of left ventricular remodeling by enalapril administration.

Assessment of regional left ventricular relaxation in patients with coronary artery disease: importance of geometric factors and changes in wall thickness.

To assess local myocardial relaxation abnormalities in patients with coronary artery disease, local myocardial left ventricular wall stress was computed in nine normal subjects and in 22 patients with coronary artery disease. In normal left ventricles, the rate of decrease in isovolumic local stress was not significantly different from the rate of decrease in isovolumic pressure, and the residual wall stress at the end of isovolumic relaxation was uniformly low. In patients with coronary artery disease, the residual wall stress was increased both in infarcted areas and in non-infarcted areas perfused by stenosed arteries (43 +/- 31 and 30 +/- 19 kdyne/cm2, respectively, vs 9 +/- 5 kdyne/cm2 in normal areas; p less than .001). The rate of decrease in local stress in infarcted areas paralleled the rate of decrease in pressure (48 vs 49 msec; NS), but in ischemic areas the rate of decrease in stress was significantly slower than the rate of decrease in pressure (69 +/- 35 vs 48 +/- 15 msec; p less than .05). It is concluded that in patients with coronary artery disease, indexes based only on the analysis of decreases in isovolumic pressure underestimate the severity of local impairments in relaxation rate and cannot be used to predict the level of residual diastolic wall stress.

Effects of a Cardioselective Beta-1 Partial Agonist (corwin) On Left-ventricular Function and Myocardial-metabolism in Patients With Previous Myocardial-infarction

Corwin is a new selective beta 1 partial agonist, able to stabilize the beta 1 adrenoceptors at approximately 43% of their maximal activity. The aim of the study was to determine the effects of this agent in patients with coronary artery disease (CAD) and previous myocardial infarction (MI). In a first group of 14 patients, corwin increased significantly the peak (+)dP/dt (+35%; p less than 0.005), the global ejection fraction, and the ejection fraction of abnormally contracting segments (from 20 +/- 18 to 26 +/- 19%; p less than 0.02). Corwin also induced significant decreases in mean systolic (-8%; p less than 0.05) and mean diastolic (-38%; p less than 0.001) wall stress and accelerated the relaxation rate. In a second group of 11 patients, a metabolic study indicated that neither myocardial oxygen consumption (15 +/- 7 versus 15 +/- 7 ml/min; difference not significant) nor lactate extraction was modified by the drug. In this group, increases in peak (+)dP/dt, acceleration in ventricular relaxation (-8 ms in time constant of isovolumic pressure decrease; p less than 0.01), and decreases in left ventricular end-diastolic pressure also were noted after administration of corwin, both under basal conditions and during a cold pressor test. In conclusion, corwin is a positive inotrope which, in patients with CAD and left ventricular dysfunction, improves left ventricular systolic and diastolic function without inducing myocardial ischemia.