M. F. Rousseau

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.

Cardiovascular effects of AR-L115 BS in conscious dogs with and without chronic congestive heart failure.

AR-L115 BS is a phenyl-imidazo-pyridine derivative that combines positive inotropic and vasodilator properties. To analyze the mechanisms of action of AR-L115 in the presence or absence of heart failure, we administered it intravenously to conscious dogs (seven normals and eight with a volume-overload heart failure). In normals, at a plasma level around 1,000 ng/ml, AR-L115 BS increased left ventricular (LV) peak (+) dP/dt (+48%: p < 0.02) and heart rate (+29 beats/min: p < 0.05) without altering significantly cardiac filling pressures or cardiac output. The mean aortic pressure and the systemic vascular resistances (-20%: p < 0.02) were reduced, but plasma renin activity (PRA) was unchanged. In heart failure, the same plasma level increased peak (+) dP/dt by 36% (p < 0.01), but heart rate stayed unchanged. Mean aortic pressure, systemic vascular resistances (-20%: p < 0.01), and LV end-diastolic pressure (-9.1 mm Hg: p < 0.01) all dropped significantly, while cardiac output increased slightly: PRA did not rise significantly. After β-blockade, the increases in peak (+) dP/dt and the changes in systemic vascular resistances were markedly reduced. In conclusion, AR-L115 BS has strong positive inotropic and vasodilator effects, both of which are partially dependent on the level of the sympathetic tone in the intact animal. These combined properties improve hemodynamics in heart failure: this improvement is already significant at relatively low plasma levels, at which deleterious changes in heart rate or PRA are absent.

Effects of Dobutamine and Sulmazol (ar-l115 Bs) On Myocardial-metabolism and Coronary, Femoral, and Renal Blood Flows - a Comparative-study in Normal Dogs and in Dogs With Chronic Volume Overload

We compared the hemodynamic and metabolic effects of dobutamine and sulmazol (AR-L115 BS) in normal dogs and in dogs with chronic volume overload. In both cases, the doses of dobutamine and sulmazol were adapted to produce comparable increases in two indices of inotropic state, peak (+) left ventricular dP/dt and dP/dt normalized by a developed pressure of 40 mm Hg. In normal dogs, both drugs had similar effects on myocardial oxygen consumption, myocardial high-energy phosphate stores, and renal or femoral blood flows; in addition, mean aortic pressure (129 ± 8 to 114 ± 10 mm Hg; p < 0.002), the renal vascular resistance (−18%; p < 0.005), and the coronary vascular resistance (−30%; p < 0.05) were all decreased significantly during sulmazol administration. In chronic volume overload, the changes in renal and femoral blood flows and in myocardial high-energy phosphate stores induced by dobutamine or sulmazol were again similar. However, sulmazol still decreased mean aortic pressure (−20 ± 5 mm Hg; p < 0.002) and markedly reduced the left ventricular filling pressure (−40%; p < 0.006), while these parameters were not significantly modified after dobutamine. Myocardial oxygen consumption was unchanged after sulmazol but increased slightly with dobutamine. Finally, the frequency of ventricular premature beat was unchanged by sulmazol but increased after dobutamine. In conclusion, sulmazol is likely to be superior to dobutamine to stimulate a failing left ventricle when clinical status is characterized by markedly elevated filling pressures. It might also be superior when the coronary vascular reserve is reduced or in the presence of ventricular arrhythmias.

Validation Of An Index Of Left Ventricular Contractility In Man By Means Of A Simple Model Of The Left Ventricle And Of The Vascular Bed

Previous studies in patients with heart disease have shown that the stress-volume relation was linear during late ejection and that the slope of this linear portion (SLSV) could easily be determine...