Michel F. Rousseau

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.

Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study

BACKGROUND In the studies of left ventricular dysfunction (SOLVD), enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolic dysfunction during the trial. We did a 12-year follow-up of SOLVD to establish if the mortality reduction with enalapril among patients with heart failure was sustained, and whether a subsequent reduction in mortality would emerge among those with asymptomatic ventricular dysfunction. METHODS Of the 6797 patients previously enrolled in the SOLVD prevention and treatment trials, we ascertained the subsequent vital status of 5165 individuals who were alive when the trials had been completed. Follow-up was done through direct contacts in Belgium and linkages with national death registries and federal beneficiary or historic tax summary files in the USA and Canada. FINDINGS Follow-up was 99.8% (6784/6797) complete. In the prevention trial, 50.9% (1074/2111) of the enalapril group had died compared with 56.4% (1195/2117) of the placebo group (generalised Wilcoxon p=0.001). In the treatment trial, 79.8% (1025/1285) of the enalapril group had died compared with 80.8% (1038/1284) of the placebo group (generalised Wilcoxon p=0.01). The reductions in cardiac deaths were significant and similar in both trials. When data for the prevention and treatment trials were combined, the hazard ratio for death was 0.90 for the enalapril group compared with the placebo group (95% CI 0.84-0.95, generalised Wilcoxon p=0.0003). Enalapril extended median survival by 9.4 months in the combined trials (95% CI 2.8-16.5, p=0.004). INTERPRETATION Treatment with enalapril for 3-4 years led to a sustained improvement in survival beyond the original trial period in patients with left ventricular systolic dysfunction, with an important increase in life expectancy.

Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy.

OBJECTIVES We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure (CHF). BACKGROUND In the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone receptor antagonist, significantly reduced mortality in patients with severe CHF. However, the mechanism of action and neurohormonal impact of this therapy remain to be clarified. METHODS The effects of spironolactone (25 mg/day; n = 54) or placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET-1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a subgroup of 107 patients (New York Heart Association functional class III to IV; mean ejection fraction 25%) at study entry and at three and six months. RESULTS Compared with the placebo group, plasma levels of BNP (-23% at 3 and 6 months; p = 0.004 and p = 0.05, respectively) and N-proANF (-19% at 3 months, p = 0.03; -16% at 6 months, p = 0.11) were decreased after spironolactone treatment. Over time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin II increased significantly in the spironolactone group at three and six months (p = 0.003 and p = 0.001, respectively). As expected, a significant increase in aldosterone levels was observed over time in the spironolactone group (p = 0.001). CONCLUSIONS Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides (which decrease) and aldosterone and AII (which increase). The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and/or compliance, whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms. Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting.

Diagnostic value of history and maximal exercise electrocardiography in men and women suspected of coronary heart disease.

Coronary arteriographic data have been compared in 278 patients (231 males and 47 females) with the ECG response to a maximal exercise test and with the history (myocardial infarction - MI, typical or atypical angina pectoris - AP). The sensitivity and specificity of exercise ECG were similar in males and females. False negative ECG responses were frequent in males (40%) and false positive ECG responses were frequent in females (38%). This difference between sexes was essentially due in our patients to the higher prevalence of CHD in males (80%) than in females (43%). In the absence of a previous MI, a history of typical AP was associated with coronary heart disease (CHD) in 94% of males and 62% of females. Atypical AP was rarely associated with CHD (18% in males; 11% in females). When typical AP was associated with an abnormal exercise ECG, CHD was highly probable in males (98%) and present in 75% of females. In presence of atypical AP with a normal exercise ECG, CHD was unlikely in males (11%) and in females (8%). We conclude that exercise ECG has limited value for the diagnosis of CHD. In men with typical AP, exercise ECG often confirms the diagnosis but a negative ECG exercise does not rule out CHD because of the high incidence of fales negative responses. In males and females with atypical AP, an abnormal response to exercise is difficult to interpret owing to a high incidence of false positive responses.

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 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.

Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary artery disease on cardiac hormonal activation.

Cardiac natriuretic peptides are activated in heart failure. However, their diagnostic and prognostic values have not been compared under the routine conditions of an outpatient practice.

Prognostic value of myocardial viability by delayed-enhanced magnetic resonance in patients with coronary artery disease and low ejection fraction : impact of revascularization therapy.

OBJECTIVES The purpose of this study was to evaluate the impact of myocardial viability assessment by delayed-enhanced cardiac magnetic resonance (DE-CMR) and of revascularization therapy on survival in patients with coronary artery disease (CAD) and low ejection fraction (EF). BACKGROUND Prior studies have shown that DE-CMR predicts recovery of left ventricular (LV) dysfunction after revascularization. METHODS The authors prospectively evaluated survival of 144 consecutive patients (130 males, age 65 ± 11 years) with CAD and LV dysfunction (EF: 24 ± 7%) undergoing DE-CMR. Eighty-six patients underwent complete revascularization of dysfunctional myocardium (79 coronary artery bypass grafting, 7 percutaneous coronary intervention), whereas 58 patients remained under medical treatment. RESULTS Over the 3-year median follow-up, 49 patients died. Three-year survival was significantly worse in medically treated patients with dysfunctional viable than with nonviable myocardium (48% vs. 77% survival, p = 0.02). By contrast, in revascularized patients, survival was similar whether myocardium was viable or not (88% and 71% survival, respectively, p = NS). Hazard of death of viable myocardium remaining under medical treatment versus complete revascularization was 4.56 (95% confidence interval [CI]: 1.93 to 10.8). Cox multivariate analysis indicated that interaction of revascularization and viability provided significant additional value (chi-square test = 13.1, p = 0.004) to baseline predictors of survival (New York Heart Association functional class, wall motion score, and peripheral artery disease). More importantly, in 43 pairs of propensity score-matched patients, hazard of death (hazard ratio: 2.5 [95% CI: 1.1 to 6.1], p = 0.02) remained significantly higher for medically treated patients rather than for those with fully revascularized viable myocardium. CONCLUSIONS Without revascularization, presence of dysfunctional viable myocardium by DE-CMR is an independent predictor of mortality in patients with ischemic LV dysfunction. This observation may be useful for pre-operative selection of patients for revascularization.

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.

log(TG)/HDL-C is related to both residual cardiometabolic risk and β-cell function loss in type 2 diabetes males.

BackgroundT2DM is associated with atherogenic dyslipidemia (AD), defined as decreased HDL-C plus raised triglycerides (TG). AD confers increased risk for CAD, even when LDL-C is at target. AD is rarely assessed due to lack of screening methods consensus.AimTo establish the prevalence and severity of AD from log(TG)/HDL-C in T2DM males, and to determine how it relates to cardiometabolic phenotype, glucose homeostasis, micro- and macrovascular complications, and 10-year UKPDS CV risk.Methods585 T2DM males divided according to quintiles (Q) of log(TG)/HDL-C. AD prevalence defined as HDL-C <40 mg.dL-1 plus TG ≥150 mg.dL-1. β-cell function assessed with HOMA.ResultsMean HDL-C and TG were 44 (13) and 204 (155) mg.dL-1. AD prevalence was 35%. AD correlated with lower β-cell function, with accelerated loss of insulin secretion, and with poorer HbA1c levels. AD was related to a high prevalence of CAD, and also to 10-year absolute CAD risk.Conclusionslog(TG)/HDL-C is a simple means to estimate AD and the residual CV risk it confers in T2DM. AD closely associates with major cardiometabolic and glucose homeostasis determinants and poorer metabolic control. The ratio also relates to macroangiopathy prevalence and ranks future CAD risk, and is well-suited to capture non-LDL-related macrovascular residual risk and major glycemic determinants.