Wataru Hayashida

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 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.

Role of Endogenous Endothelin-1 in Experimental Renal Hypertension in Dogs

BACKGROUND Endothelin-1, a vasoconstrictive peptide released by endothelium, may be involved in the pathophysiology of hypertension. The goal of the present study was to evaluate the role of endogenous endothelin-1 in renal hypertension in dogs. The model of hypertension consisted of silk tissue wrapping of the left kidney, which produced hypertension associated with perinephritis after 6 to 8 weeks. METHODS AND RESULTS Thirty-two anesthetized open chest dogs were studied randomly: 8 dogs with perinephritic hypertension received the nonpeptidic ETA-ETB receptor antagonist bosentan (group 1); 8 other hypertensive dogs received the vehicle solution (group 2); 8 healthy dogs received bosentan (group 3); and 8 healthy dogs received the vehicle solution (group 4). Bosentan was injected as an intravenous bolus (3 mg/kg) followed by a 1-hour infusion at a rate of 7 mg.kg-1.h-1. In hypertensive dogs, bosentan produced a similar decrease (P = .0001) of both left ventricular systolic and mean aortic pressures, which averaged 38 mm Hg (-22% and -24%, respectively). These parameters remained unchanged with the vehicle solution. Left ventricular end-diastolic and left atrial pressures also declined significantly with bosentan (P = .0005 and P < .05, respectively). Left ventricular lengths tended to decrease. The other cardiovascular parameters (heart rate, peak [+]dP/dt, time constant of relaxation, and coronary vascular resistance) did not change significantly. In healthy dogs, bosentan decreased mean aortic pressure by 19 mm Hg (P = .004). Vehicle solution had no effect. Plasma endothelin-1 levels, similar under basal conditions in healthy and hypertensive dogs, increased 30-fold with bosentan (P = .0001). CONCLUSIONS Specific endothelin-1 receptor antagonism markedly lowers blood pressure in experimental hypertension but is less effective on blood pressure of healthy animals. This suggests that endothelin-1 plays a role in the pathophysiology of hypertension but contributes to a lesser extent to the maintenance of normal blood pressure. This role of endothelin-1 is unrelated to its plasma levels. The increase of plasma endothelin-1 with bosentan, due either to a displacement of endothelin-1 from its receptor or to a feedback mechanism, does not prevent this blood pressure reduction.

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 endothelin-1 at pathophysiologic concentrations on coronary perfusion and mechanical function of normal and postischemic myocardium.

We assess hemodynamic, vascular, and hormonal effects of endothelin-1 (ET-1) at pathophysiologic levels on normal and ischemic myocardium. Thirty conscious chronically instrumented dogs were studied before, during, and after a 10-min coronary artery occlusion (CAO) performed either during ET-1 infusion (2.5 ng/ kg min, n = 15) or during placebo infusion (n = 15). ET-1 infusion produced an increase in plasma ET-1 (from 1.3 ± 0.1 to 11.5 ± 1.1 pAf, p < 0.0001) during CAO (pathophysiologic value). Left anterior descending artery (LAD) blood flow (measured by Doppler flow probe) decreased similarly during CAO with ET-1 or placebo (p = 0.0001, NS, ET-1 vs. placebo). Both endocardial and epicardial blood flows in ischemic regions also decreased (p = 0.0001) during CAO but were threefold greater with ET-1 than with placebo (endocardium 42 ± 7 vs. 14 ± 2 ml/min/100 g, p = 0.003). No significant difference in myocardial blood flows between groups was observed in control regions. CAO produced increases (p < 0.005) in heart rate (HR), mean aortic pressure (AOP), and ventricular pressures but no change in atrial pressures. The changes in these parameters were comparable in the ET-1 and placebo groups. Despite the greater residual flow during CAO, however, ET-1 decreased the function of the ischemic zone during reperfusion as assessed by systolic shortening (p < 0.05). Atrial natriuretic factor (ANF), unchanged during CAO with placebo, increased from 38.3 ± 6.1 to 53.3 ± 10 pM with ET-1 (p = 0.02). Thus, ET-1, at pathophysiologic levels, increases collateral blood flow in ischemic myocardium without affecting perfusion of normal myocardium. It decreases postischemic myocardial recovery and directly stimulates ANF release.

Diastolic properties in canine hypertensive left ventricular hypertrophy: effects of angiotensin converting enzyme inhibition and angiotensin II type-1 receptor blockade.

OBJECTIVE Angiotensin II has been suggested to be involved in the pathogenesis of diastolic dysfunction in left ventricular hypertrophy (LVH). The purpose of this study was to asses the effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on LV diastolic function in 16 normal control dogs and 20 LVH dogs with perinephritic hypertension. METHODS LV hemodynamics was studied before and after intravenous injection of enalaprilat (0.25 mg/kg) or L-158,809 (0.3 mg/kg). The hemodynamic data were analyzed in relation to the changes in myocardial blood flow (measured by radioactive microspheres) and in the circulating angiotensin II and norepinephrine levels. RESULTS AND CONCLUSIONS At baseline, significant increases were observed for LV/body weight ratio as well as LV systolic and end-diastolic pressure in the LVH dogs (all P < 0.01 vs. the control group). In addition, LV relaxation time constant was prolonged and the chamber and myocardial stiffness constants were increased (P < 0.01) in the LVH dogs, suggesting an impairment of LV diastolic function. Administration of enalaprilat or L-158,809 improved LV stiffness constants in the LVH dogs (P < 0.05). The diastolic LV pressure-diameter relation shifted downwards in the LVH dogs whereas diastolic distensibility was not altered in the control dogs. Although the circulating angiotensin II levels were significantly decreased by enalaprilat in the LVH dogs, they did not correlate with the changes in the stiffness constants. Furthermore, the alterations of LV diastolic properties in the LVH group could not be attributed to myocardial perfusion, which was rather decreased by administration of enalaprilat and L-158,809. These results suggest that angiotensin II, particularly at the local level, is involved in the pathogenesis of diastolic dysfunction in pressure-overload LVH. The data also support the concept that ACE inhibitors and angiotensin II receptor blockers are potentially beneficial in the treatment of the hypertrophied heart.

Load-sensitive diastolic relaxation in hypertrophied left ventricles

We studied effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on left ventricular (LV) diastolic relaxation in 11 normal control dogs and 16 LV hypertrophied (LVH) dogs with perinephritic hypertension. At baseline, LV systolic and end-diastolic pressures and end-systolic elastance were increased in the LVH group (all P < 0.01 vs. the control group). LV relaxation time constant was also prolonged (P < 0.01), suggesting impaired LV diastolic relaxation in this model of LVH. Before and after the administration of enalaprilat (0.25 mg/kg) and L-158,809 (0.30 mg/kg), LV relaxation was assessed over a wide range of LV loading conditions during vena caval occlusion. LV relaxation time constant was insensitive to load reduction in the control group, which was not affected by enalaprilat or L-158,809. In contrast, LV unloading caused a significant prolongation of the relaxation time constant in the LVH group. This load-sensitive LV relaxation abnormality was significantly improved by enalaprilat or L-158,809. These results support the concept that angiotensin II is involved in the pathogenesis of diastolic dysfunction in pressure-overloaded LVH and also suggest that angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor antagonists are potentially beneficial in the treatment of the hypertrophied heart.We studied effects of enalaprilat and L-158,809, an angiotensin II type-1 receptor antagonist, on left ventricular (LV) diastolic relaxation in 11 normal control dogs and 16 LV hypertrophied (LVH) dogs with perinephritic hypertension. At baseline, LV systolic and end-diastolic pressures and end-systolic elastance were increased in the LVH group (all P < 0.01 vs. the control group). LV relaxation time constant was also prolonged ( P < 0.01), suggesting impaired LV diastolic relaxation in this model of LVH. Before and after the administration of enalaprilat (0.25 mg/kg) and L-158,809 (0.30 mg/kg), LV relaxation was assessed over a wide range of LV loading conditions during vena caval occlusion. LV relaxation time constant was insensitive to load reduction in the control group, which was not affected by enalaprilat or L-158,809. In contrast, LV unloading caused a significant prolongation of the relaxation time constant in the LVH group. This load-sensitive LV relaxation abnormality was significantly improved by enalaprilat or L-158,809. These results support the concept that angiotensin II is involved in the pathogenesis of diastolic dysfunction in pressure-overloaded LVH and also suggest that angiotensin-converting enzyme inhibitors and angiotensin II type-1 receptor antagonists are potentially beneficial in the treatment of the hypertrophied heart.