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We investigated whether ranolazine therapy improves exercise-induced angina pectoris and myocardial ischemia compared with placebo or with standard doses of atenolol in patients who had chronic angina and evaluated the effects on hemodynamics at rest and during exercise. In this trial, 158 patients who had symptom-limited exercise discontinued beta-blocker therapy and were randomized into a double-blind, 3-period, crossover study of 400 mg of immediate-release ranolazine 3 times daily, 100 mg/day of atenolol, or placebo, each administered for 1 week. Exercise tests were administered at the end of each treatment period. Therapy with ranolazine or atenolol produced statistically significant improvement in all 3 exercise end points compared with placebo. Compared with atenolol therapy, ranolazine therapy resulted in significantly longer total exercise duration and was statistically indistinguishable from atenolol for time to onset of angina and ST-segment depression. Except for a modest increase in systolic blood pressure at peak exercise during ranolazine therapy, hemodynamic measurements did not differ significantly during ranolazine and placebo therapies. In contrast, atenolol significantly decreased blood pressure, heart rate, and rate-pressure product at rest and during exercise compared with placebo or ranolazine. In conclusion, ranolazine therapy prolonged exercise duration and decreased exercise-induced ischemia and angina with quantitative effects equal to or greater than those with atenolol. Unlike atenolol, the anti-ischemic and antianginal effects of ranolazine occurred without decreases in blood pressure, heart rate, or rate-pressure product.

This study assesses the effects of dofetilide, a new selective Ikr blocker with class III properties, on left ventricular function and hemodynamics of heart failure and compares these effects with those of placebo and amiodarone. Because available antiarrhythmic drugs may depress myocardial performance, an invasive hemodynamic study was performed to assess the safety of this agent. Hemodynamic and angiographic data were obtained at baseline and after 30 minutes of double-blind infusion of dofetilide (8 microg/kg; n = 12), placebo (n = 12), or amiodarone (5 mg/kg; n = 6) in heart failure patients (New York Heart Association class II or III, ejection fraction <35%). Intravenous dofetilide preserved the inotropic indexes and the end-systolic volume index despite a slight but significant decrease in heart rate, whereas intravenous amiodarone increased end-diastolic and end-systolic volume indexes. Amiodarone induced a negative inotropic effect illustrated by a rightward shift of the pressure-volume loop and a reduction in pressure-derived indexes of contractility. Intravenous dofetilide acutely prolonged QT interval more than intravenous amiodarone; however, dofetilide did not slow the overall relaxation rate and reduced QT dispersion. In an acute setting, compared with intravenous amiodarone, intravenous dofetilide preserves cardiac function offering a hemodynamic advantage to treat arrhythmias in patients with impaired left ventricular function.

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.

When the heart faces a hemodynamic challenge (pressure or volume overload, myocardial infarction, etc.), mechanical, neurohormonal, and metabolic changes occur and impact on the myocytes, the fibroblasts, and the microcirculation. These changes immediately modify the function of the heart but also trigger gene expression and protein synthesis, leading after days and months to a remodeled heart in which not only the geometry of the cavity is changed but the composition of the wall has also become markedly abnormal. The remodeling process is infinitely complex, because all factors involved interact in a complex way and because the genetic responses may vary between species and between individuals. Moreover, we still ignore the role (or even the existence) of many growth factors involved in the process. To illustrate this complexity, one can use 2 classic models: pressure-overload hypertrophy and acute myocardial infarction. In both situations, experimental models can be designed so that angiotensin II and aldosterone are elevated and in both types of models the use of an angiotensin-converting enzyme inhibitor favorably influences hypertrophy and survival. Interestingly, however, intense interstitial fibrosis leading to an increase in diastolic stiffness is present in the pressure overload models, whereas increased diastolic distensibility and cardiac dilation are observed in models of myocardial infarction. This clearly indicates that in addition to the renin-angiotensin system other factors interact in the remodeling process and modulate the effects of angiotensin-converting enzyme inhibition on ventricular remodeling.

Left ventricular function and neurohormonal status in patients with heart failure remaining symptomatic during therapy with angiotensin-converting enzyme inhibitors were assessed, and the effects of dopaminergic receptor stimulation in this setting were determined. Neurohormonal and left ventricular function (radionuclide angiography) data were obtained in 19 patients with symptomatic ischemic heart failure. Measurements were repeated after 4 to 6 weeks of therapy with the dopamine agonist ibopamine (100 mg, 3 times/day) or placebo administered in a double-blind, randomized, parallel group design. At baseline, despite therapy with enalapril, the angiotensin II levels (mean 39.4 pg/ml; p < 0.01 vs controls) were significantly increased, as were plasma norepinephrine (497 +/- 240 pg/ml; p < 0.01 vs controls), endothelin-1, atrial natriuretic peptide and arginine vasopressin. Moreover, in comparison with pretreatment values, left ventricular ejection fraction had decreased substantially (-9.1%) in patients with plasma norepinephrine > or = 600 pg/ml, but not in those with lower values of norepinephrine. With ibopamine, plasma norepinephrine decreased from 516 +/- 241 to 391 +/- 208 pg/ml (n = 8; p < 0.025 vs placebo), whereas it increased with placebo. In conclusion, the neurohormonal control provided by an angiotensin-converting enzyme inhibitor is reduced in a large subset of patients during prolonged therapy; ibopamine appears to be a potentially useful drug to improve neurohormonal control in this setting.

Left ventricular (LV) diastolic filling is impaired in hearts with healed myocardial infarction. Possible hemodynamic parameters related to impaired LV filling include left atrial pressure, time constant of isovolumic relaxation, chamber stiffness and wall motion asynchrony. Previous studies demonstrated univariate correlations between each of these parameters and LV filling. The current study was designed to compare relative importance of these parameters in patients with a myocardial infarction. Left ventriculograms with simultaneous LV pressure measurement were analyzed in 15 patients with a myocardial infarction and in 10 control subjects. Every frame of the left ventriculogram was divided into 8 segments and the volume of each segment was obtained frame-by-frame by planimetry and area-length method. Asynchrony was quantitated as the sum of areas of discrepancy between each segmental and global volume-time curve. Patients with myocardial infarction had greater asynchrony (20 +/- 2 vs 10 +/- 1%, p < 0.01), greater atrial filling fraction (46 +/- 4 vs 35 +/- 5%, p < 0.05) and slower peak early filling rate (2.5 +/- 0.1 vs 4.1 +/- 0.4 end-diastolic volume/s, p < 0.01) than the control subjects. Multiple regression analyses with hemodynamic variables (asynchrony, LV pressure at mitral valve opening, time constant of LV isovolumic pressure decrease and LV chamber stiffness constant) showed that asynchrony and LV pressure at mitral valve opening were significant determinants of LV filling in patients with myocardial infarction, whereas LV pressure at mitral valve opening was the only significant determinant in control subjects.

The double-blind, placebo-controlled, multinational trial Xamoterol in Severe Heart Failure randomized 290 patients treated with captopril and 217 treated with enalapril to xamoterol or placebo. At the end of the 100-day follow-up period, the cumulative probability of survival in patients with coronary artery disease or with dilated cardiomyopathy decreased in the captopril group (90.3%) when compared with the enalapril group (97.2%). The excess mortality in the captopril group could not be related to the indexes of the severity of heart failure, such as baseline exercise duration, functional class, cardiothoracic ratio, ejection fraction or dose of diuretic drugs. Furthermore, the excess in mortality was seen in all subsets of patients examined as well as across countries. Examination of the dosing regimen used, however, suggests that insufficient daily dosage of captopril or the inadequate schedule of administration, or both, might be responsible for different degrees of angiotensin-converting enzyme inhibition between the enalapril and captopril groups and hence for the difference in mortality. It is important in future clinical trials to determine to what extent complete circadian angiotensin-converting enzyme inhibition is necessary to provide the full benefit of this therapy in heart failure.

The effects of balloon inflation on myocardial perfusion and metabolism were studied during aortic valvuloplasty in 17 patients with aortic stenosis, including 6 with associated coronary artery disease. Coronary sinus flow and blood samples were obtained before and during the first inflation, and 5 to 10 minutes after the last inflation. During inflation, coronary blood flow decreased (272 +/- 111 standard deviation to 166 +/- 92 ml/min; p less than 0.05), myocardial oxygen uptake fell and transcardiac lactate handling shifted from extraction to production (35 +/- 54 to -41 +/- 48 mumol/min; p less than 0.01). At the end of the procedure, aortic valve area had increased from 0.51 +/- 0.22 to 0.81 +/- 0.48 cm2 (p less than 0.002). Coronary sinus flow increased slightly above control values (+6%; difference not significant) and myocardial oxygen and lactate uptakes were back to control values. However, myocardial alanine production had increased from -3.6 to -6.6 mumol/min (p less than 0.05) and glutamine production was reduced or replaced by extraction (-3.3 +/- 2.1 to 3.5 +/- 3.8 mumol/min; p less than 0.05). Recovery of coronary flow, oxygen and lactate uptakes was not significantly different in patients with or without coronary artery disease, although the former patients tended to have less glutamine extraction and less improvement in their ejection fraction at the end of the procedure. Thus, aortic balloon valvuloplasty produces brief episodes of low-flow ischemia. Recovery of oxidative metabolism is almost immediate after deflation and no detrimental effect seems to persist at the end of the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of the calcium antagonists nicardipine and nisoldipine on left ventricular (LV) metabolism were analyzed in 32 patients with angina pectoris. Measurements were made at a fixed heart rate under the basal state and during a cold pressor test (CPT). After administration of the drugs, coronary blood flow increased significantly and the mean aortic pressure decreased by 10% (p less than 0.01) in the basal state and by 11% (p less than 0.01) during CPT. Despite the reduction in pressure-rate product, myocardial oxygen consumption was unchanged in the basal state (18 +/- 4 vs 19 +/- 4 ml/min, difference not significant) and during CPT (21 +/- 5 vs 21 +/- 5 ml/min, difference not significant); this discrepancy between a reduced pressure-rate product and an unchanged oxygen consumption was also noted when nicardipine was given after propranolol (0.1 mg/kg; 12 patients). Both agents also increased LV lactate uptake, particularly during CPT (+13 mumol/min, p less than 0.05 vs control CPT) and reduced LV glutamine production. In 10 patients in whom 14C-lactate was infused, the chemical LV lactate extraction ratio increased more than the 14C-lactate extraction ratio after administration of the drugs, indicating a reduction in LV lactate production. The data are consistent with the hypothesis that nicardipine and nisoldipine improve perfusion and aerobic metabolism in chronically ischemic areas, resulting in an augmented oxygen consumption and in a reduced lactate production.

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.

The incidence of ventricular arrhythmias after myocardial infarction was compared in a double blind study of disopyramide (33 patients), aprindine (34 patients) and placebo (31 patients). Total ventricular arrhythmias were less frequent in the aprindine group than in the disopyramide group (P less than 0.05) or than in the combined disopyramide and placebo groups (P less than 0.05). The incidence of life-threatening arrhythmias and of ventricular arrhythmias in high risk patients was also reduced by aprindine compared to disopyramide (P less than 0.001) or placebo (P less than 0.001). It is concluded that aprindine is effective in reducing ventricular arrhythmias and that further investigations on its preventive use after the onset of myocardial infarction are justified.

To determine if the calcium antagonist nicardipine protects the myocardium against ischemia, myocardial lactate, hypoxanthine and prostanoid function was studied in 12 patients during percutaneous transluminal coronary angioplasty (PTCA). Values were obtained before balloon inflation and during 4 minutes after deflation. Intracoronary injection of 0.2 mg of nicardipine distal to the stenosis was done randomly before the first or second inflation; the other inflation served as a control. One minute after deflation, coronary sinus flow levels were similar during the nicardipine and control procedure (161 +/- 61 vs 159 +/- 72 ml/min); lactate (-9 +/- 21% vs -17 +/- 21%, p less than 0.025) and hypoxanthine production (-107 +/- 85% vs -218 +/- 153%, p less than 0.05) were less severe after nicardipine pretreatment than after control. All patients reverted to lactate extraction 4 minutes after inflation plus nicardipine infusion, whereas lactate was still produced 4 minutes after control inflation. No significant changes in thromboxane B2 or prostacyclin levels were observed in the coronary sinus 1 minute after inflation, but higher arterial thromboxane B2 values were observed after control inflation than after inflation with nicardipine infusion (median values 169 vs 78 pg/ml, p less than 0.05). In conclusion, intracoronary infusion of nicardipine reduced signs of ischemia and alterations in prostanoid handling after coronary occlusion. The mechanisms of myocardial protection appeared unrelated to coronary sinus blood flow changes or to a systemic effect of nicardipine.

To assess myocardial contractility in patients with hypertrophic cardiomyopathy (HC), force-velocity-length relations were analyzed during left ventricular (LV) ejection. LV pressure, volume and wall stress data in 15 patients with HC were analyzed and compared with values from 32 normal subjects. Patients with HC had a greater LV mass than did normal subjects (272 versus 96 g/m2, p less than 0.001), elevated LV end-diastolic pressure (17.5 versus 9.8 mm Hg, p less than 0.01) and impaired LV relaxation compared with those of normal subjects. Patients with HC also had a greater ejection fraction (84 +/- 7 versus 74 +/- 8%, p less than 0.01) and mean velocity of shortening than did normal subjects. However, in patients with HC, end-systolic stress (60 +/- 29 versus 187 +/- 61 kdyne/cm2, p less than 0.001) was significantly lower. End-systolic volume and stress data were linearly related in normal subjects (r = 0.88), and values from patients with HC fell either within the lowest part of the 95% confidence interval of this normal relation or outside it in the zone of depressed contractility (11 patients with HC). In addition, the slopes of the relations between end-systolic wall stress and ejection fraction or mean velocity of shortening were abnormal in patients with HC; the slope of the stress-volume trajectory during late ejection was also depressed in 12 patients with HC (average slope 2.6 versus 5.5 kdyne/cm5/m2, p less than 0.001). Thus, there is no evidence of a hypercontractile state in patients with HC; their high values of ejection phase indexes may be explained by a reduction in myocardial afterload.