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 ef fects of two dose levels of mibefradil in patients with varying degree s of ischemic left ventricular dysfunction. Background. Mibefradil is a new, selective T-type and L-type calcium channel blocking agent. Bec ause L-type channel blockade may depress myocardial performance, an in vasive hemodynamic study was performed to assess the safety of this ag ent. Methods. We performed an open label study, examining the effects of two intravenous doses of mibefradil, selected to produce plasma lev els comparable to those measured after oral administration of 50 mg (d ose 1:400 ng/ml) or 100 mg (dose 2:800 ng/ml) of the drug. Variables s tudied included the indexes of left ventricular function and neurohorm one levels. Patients were stratified according to ejection fraction (E F) (greater than or equal to 40%, n = 26; <40%, n = 24) and the presen ce (n = 15) or absence (n = 35) of heart failure. Results. In patients with preserved systolic function, dose 1 had no clinically significan t hemodynamic effects, but dose 2 decreased mean aortic pressure and s ystemic 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,vith depressed EF, heart rate decreased significantly with both doses. The effects o f dose 1 mimicked those observed after dose 2 in patients with preserv ed 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 o f left ventricular pressure. Examination of individual pressure-volume loops in two patients with heart failure showed a clear rightward shi ft of the loop despite a decrease in systolic pressure, suggesting neg ative inotropy. Neurohormone levels were unchanged at both dose levels and in all subgroups. Conclusions. Intravenous mibefradil was well to lerated and produced an overall favorable cardiovascular response. How ever, high plasma concentrations might produce myocardial depression i n patients with heart failure, and caution should be exerted in this s etting.