Christian van Eyll

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.

Effects of D-nebivolol and L-nebivolol on left ventricular systolic and diastolic function: comparison with D-L-nebivolol and atenolol.

Summary: (D-L) Nebivolol is a new β1-selective adrenoceptor blocker which in normal individuals preserves rest and exercise hemodynamics. We assessed the effects of the enantiomers (L- and D-nebivolol) on left ventricular (LV) systolic and diastolic function and compared their effects with those of the racemic mixture. LV angiography (+Millar) was performed before and after intravenous (i.v.) infusion of either D- or L-nebivolol (1.25–2.5 mg, n = 22) in patients with ischemic heart disease and previous myocardial infarction. Neither L- nor D-nebivolol produced significant changes in heart rate (HR), peak (+) dP/dt, (dP/dt) DP40, cardiac index (CI) or ejection fraction (EF). Diastolic distensibility, evaluated from the shift of the pressure-volume data at the time of mitral valve opening, did not improve after D- or L-enantiomers administration. In contrast, both D-L-nebivolol 2.5 mg (n = 9) and atenolol 15 mg (n = 9) significantly reduced HR and peak (+) dP/dt, but in comparison to atenolol D-L nebivolol improved EF (+ 4% after D-L nebivolol vs. −4% after atenolol; p < 0.05 D-L nebivolol vs. atenolol) and maintained cardiac output CO, (+ 2% vs. −21%; p < 0.05 between groups). Moreover, unlike any of the other drugs in the study, the racemate shifted the diastolic pressure-volume data downward, suggesting improved LV distensibility. The beneficial effects of nebivolol on LV systolic and diastolic function appears to require the presence of both D- and L-enantiomers.

Force-velocity-length relations in hypertrophic cardiomyopathy: Evidence of normal or depressed myocardial contractility

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.

Medium-term effects of beta-blockade on left ventricular mechanics: a double-blind, placebo-controlled comparison of nebivolol and atenolol in patients with ischemic left ventricular dysfunction.

The aim of this study was to compare the effects on left ventricular function and exercise tolerance of a selective beta-antagonist (atenolol) with those of another selective beta 1-antagonist with vasodilator properties (nebivolol) in patients with ischemic left ventricular dysfunction but no overt congestive heart failure. Beta blockers are widely used in ischemic heart disease, but their effects on left ventricular mechanics and exercise tolerance are poorly defined in the subgroup of patients with significant systolic dysfunction but without clinical evidence of ischemia or congestive heart failure. Angiographic and symptom-limited exercise data were obtained at baseline and after an 8-10-week double-blind treatment with placebo (n = 10), 50 mg atenolol daily (n = 10), or 2.5 mg (n = 10) or 5 mg (n = 10) nebivolol daily. When compared to placebo, both atenolol and nebivolol reduced resting heart rate and improved left ventricular ejection fraction (from 33.9 to 39.2% with atenolol and from 36.5 to 40.8% with nebivolol, both P < .05) while lowering mean systolic wall stress. Only nebivolol, however, produced a parallel downward shift of the pressure-volume relationship during early diastolic filling and improved the early peak filling rate when compared to placebo (+ 10%, P < .05). When compared to baseline, maximal exercise duration increased by 7 and 13 seconds with placebo and atenolol, respectively (both NS vs baseline), and increased by 44 seconds with nebivolol (P = .0077 vs baseline). Both atenolol and nebivolol decreased maximal exercise heart rate; the reduction was more pronounced with atenolol. Prolonged beta 1-adrenoceptor blockade leads to a significant increase in left ventricular ejection fraction in patients with ischemic left ventricular dysfunction. The dissociation between the changes in resting left ventricular function and the changes in exercise duration suggests that in this clinical setting, the changes in systolic function may have less impact on functional capacity than an improvement in diastolic distensibility during the rapid filling phase.

Hemodynamic and cardiac effects of the selective T-type and L-type calcium channel blocking agent mibefradil in patients with varying degrees of left ventricular systolic dysfunction.

OBJECTIVES This study sought to assess the hemodynamic and cardiac effects of two dose levels of mibefradil in patients with varying degrees of ischemic left ventricular dysfunction. BACKGROUND Mibefradil is a new, selective T-type and L-type calcium channel blocking agent. Because L-type channel blockade may depress myocardial performance, an invasive hemodynamic study was performed to assess the safety of this agent. METHODS We performed an open label study, examining the effects of two intravenous doses of mibefradil, selected to produce plasma levels comparable to those measured after oral administration of 50 mg (dose 1: 400 ng/ml) or 100 mg (dose 2: 800 ng/ml) of the drug. Variables studied included the indexes of left ventricular function and neurohormone levels. Patients were stratified according to ejection fraction (EF) (> or = 40%, n = 26; < 40%, n = 24) and the presence (n = 15) or absence (n = 35) of heart failure. RESULTS In patients with preserved systolic function, dose 1 had no clinically significant hemodynamic effects, but dose 2 decreased mean aortic pressure and systemic vascular resistance (-8.5 mm Hg, -12%, both p < 0.01) and also reduced end-systolic stress and volume, thus improving EF (52% to 58%, p < 0.01). Heart rate tended to decrease. In patients with depressed EF, heart rate decreased significantly with both doses. The effects of dose 1 mimicked those observed after dose 2 in patients with preserved EF. Dose 2 (plasma levels 1,052 +/- 284 ng/ml) still decreased left ventricular systolic wall stress and improved EF (24.0% to 28.5%, p < 0.05) but also significantly depressed the maximal first derivative of left ventricular pressure. Examination of individual pressure-volume loops in two patients with heart failure showed a clear rightward shift of the loop despite a decrease in systolic pressure, suggesting negative inotropy. Neurohormone levels were unchanged at both dose levels and in all subgroups. CONCLUSIONS Intravenous mibefradil was well tolerated and produced an overall favorable cardiovascular response. However, high plasma concentrations might produce myocardial depression in patients with heart failure, and caution should be exerted in this setting.

Regional remodeling and nonuniform changes in diastolic function in patients with left ventricular dysfunction: Modification by long-term enalapril treatment☆

OBJECTIVES The purpose of the present study was to assess the process of late regional remodeling and the changes in regional diastolic function at the base and apex of the left ventricle in patients with chronic systolic dysfunction. BACKGROUND Remodeling has been suggested to play an important role in the progression of left ventricular dysfunction and heart failure. However, the regional difference in the process of late remodeling and its relation to diastolic function remain unclear. METHODS In 32 patients with previous myocardial infarction and left ventricular ejection fraction < or = 35%, left ventricular hemodynamic and angiographic data were studied before and 1 year after randomization to conventional therapy with placebo (n = 12) or enalapril, 10 mg twice daily (n = 20). Left ventricular regional wall dynamics were analyzed in the basal and apical regions by the area method. RESULTS In the placebo group, left ventricular end-diastolic and end-systolic regional areas increased significantly over time at the base but were unchanged at the apex. At the base, the diastolic left ventricular pressure-regional area relation shifted rightward and the regional stiffness constant decreased (6.9 +/- 4.3 to 5.0 +/- 3.1 x 10(-3) mm-2, p < 0.05), indicating an increase in regional distensibility. At the apex, however, the diastolic pressure-regional area relation shifted upward slightly, and the regional stiffness constant increased from 11.5 +/- 4.4 to 14.4 +/- 5.6 x 10(-3) mm-2 (p = 0.08). The regional peak filling rate was maintained at the base but decreased at the apex (1,014 +/- 436 to 762 +/- 306 mm2/s, p < 0.05); further, the changes in regional peak filling rate during follow-up were inversely related to the changes in the regional stiffness constant (r = -0.78, p < 0.001) at the apex. In contrast, in the enalapril group, end-diastolic and end-systolic regional areas significantly decreased over time both at the base and at the apex. Diastolic pressure-regional area relations shifted leftward, but the regional stiffness constant and regional peak filling rate did not change significantly either at the base or at the apex. CONCLUSIONS These findings suggest that in patients with severe systolic left ventricular dysfunction, there was a regional difference in the process of late remodeling between the base and apex of the left ventricle, which was associated with nonuniform changes in regional diastolic function in the placebo group. The data also suggest that the nonuniform progression of regional remodeling and diastolic dysfunction was prevented by long-term enalapril treatment.

Effects of intravenous epinine administration on left ventricular systolic performance, coronary hemodynamics, and circulating catecholamines in patients with heart failure.

Summary Twenty-six patients with mild to moderate heart failure were studied to determine the effects of epinine infusion (at a rate producing plasma levels similar to those measured after oral administration of 100 mg of the prodrug ibopamine) on left ventricular (LV) function (14 patients), and coronary flow and circulating catecholamines (12 patients). The only significant hemodynamic change at an infusion rate of 0.5 μg/kg/min was a 9% (p < 0.05) decrease in systemic vascular resistance (SVR). At an infusion rate of 1 μg/kg/min (mean free epinine plasma levels 14.3 ± 3.7 ng/ml), heart rate (HR), dP/dtmax (1,405 ± 255 to 1,490 ± 320 mm Hg, NS), (dP/dt)/DP40, and the relaxation rate remained unchanged, but the ejection fraction (EF) increased from 32 to 38% (p < 0.001), cardiac output (CO) increased, and SVR decreased by 22% (p < 0.05). In a separate group of 12 patients, epinine infusion at rates of 0.5–1 μg/kg/min produced no significant changes in coronary blood flow or myocardial oxygen uptake. At these infusion rates, arterial norepinephrine (NE) and dopamine (DA) levels decreased slightly and arterial and coronary sinus epinephrine increased. In conclusion, epinine, at concentrations similar to those achieved during therapeutic use of ibopamine, had negligible effect on myocardial contractility and relaxation rate in heart failure patients. Cardiac pump function was improved by a decrease in SVR rather than by inotropic stimulation. The data also suggest that these low concentrations of epinine may modulate the sympathetic nervous system, but further studies are needed to determine whether this effect could have clinical significance.

Cardiac and hemodynamic effects of intravenous dofetilide in patients with heart failure

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.

Effects of prolonged nisoldipine administration on the "hibernating" myocardium.

To assess the effects of nisoldipine on chronically underperfused myocardial areas (“hibernating myocardium”), the global and regional left ventricular (LV) function was analyzed before and after 2 months of double-blind monotherapy with nisoldipine (10 mg twice daily) or placebo in 17 patients with a previous anterior myocardial infarction. The baseline LV ejection fraction ranged from 34 to 51%, and no patient had heart failure. Compared to placebo, nisoldipine significantly lowered the LV systolic pressure and end-diastolic pressure (-3 vs. +6 mmHg with placebo; p < 0.01) and the LV pressure at the time of mitral valve opening (-2.0 ± 3.4 vs. + 3.5 ± 3.0 mm Hg; p < 0.01). Despite this reduction in driving pressure, the global LV early peak filling rate improved only with nisoldipine and this improvement was related to a selective increase in the expansion rate of the anterior areas, from 1,010 ± 360 to 1,339 ± 496 mm2/s (p < 0.001). The time to regional peak filling rate (-8%; p < 0.01), the asynchrony of diastolic wall motion, and the regional ejection fraction (33 ± 10 to 38 ± 12%; p < 0.001) also improved in the anterior areas with nisoldipine but not with placebo. In contrast, in the inferior control zones, the regional ejection fraction and filling rate remained unchanged, both when compared to baseline and to placebo. In conclusion, prolonged nisoldipine therapy had no significant effect on the normal myocardium but improved systolic and diastolic function in hypokinetic areas. The functional improvement in such areas might be related to improved perfusion, to a greater sensitivity to afterload reduction, or to an effect of nisoldipine on myocardial calcium handling.

Impaired Regional Diastolic Distensibility in Coronary-artery Disease - Relations With Dynamic Left-ventricular Compliance

The regional left ventricular distensibility and its relations with the dynamic left ventricular chamber compliance were studied in 11 normal subjects and in 30 patients with coronary artery disease. The regional peak filling rates were calculated from angiographic data in eight ventricular segments and used as an index of regional distensibility. A depressed global peak filling rate was observed in only 30% of the patients with angina pectoris, but regional abnormalities in peak filling rate were detected in 75% of these patients. A relation between alterations in regional peak filling rate and left ventricular compliance was evident in these patients. Despite comparable end diastolic volume and pressure (10 +/- 2 mm Hg vs. 10 +/- 3 in normal subjects; not significant), the patients with angina pectoris, whose ventricle had at least three segments with a reduced peak filling rate, had indeed significant increases in mean left ventricular filling pressure (14 +/- 4 mm Hg vs. 8 +/- 3 in normal subjects; p less than 0.01) and upward shifts of their left ventricular pressure-volume relation during rapid filling. Conversely, an increase in regional peak filling rate produced by intravenous administration of the calcium antagonist nicardipine in a subgroup of patients with poor diastolic function was accompanied by a reduction in mean left ventricular filling pressure and by a downward shift of the early diastolic left ventricular pressure-volume relation. It is concluded that even in the absence of clinical signs of ischemia and of a previous myocardial infarction, large areas with impaired distensibility are frequently present in patients with angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)