DIRECT MYOCARDIAL EFFECTS OF OPC-18790 IN HUMAN HEART-FAILURE - BENEFICIAL-EFFECTS ON CONTRACTILE AND DIASTOLIC FUNCTION DEMONSTRATED BY INTRACORONARY INFUSION WITH PRESSURE-VOLUME ANALYSIS

Objectives. We sought to determine the precise myocardial effects of O PC-18790 as demonstrated by intracoronary administration. Background. Although previous studies have determined the cardiovascular effects o f a novel intravenous inotrope, OPC-18790, the observed benefits on co ntractile and diastolic function may have been confounded by the marke d changes in peripheral loading associated with this drug when given i ntravenously. Methods. Eight heart failure patients received intracoro nary OPC-18790 at 31.25 mu g/min for 20 min, and then at 62.5 mu g/min for another 20 min. Hemodynamic variables and pressure-volume indexes using the conductance catheter method were determined at baseline and then after the two doses. Results. There were no significant effects on heart rate, cardiac output or loading conditions, including afterlo ad as determined by systemic vascular resistance and arterial elastanc e (E-a) and preload as determined by end-diastolic volume (EDV). There were significant increases in end-systolic elastance (E-es) from 0.74 +/- 0.11 to 0.90 +/- 0.16 mm Hg/ml at 31.25 mu g/min and to 1.37 +/- 0.33 mm Hg/ml at 62.5 mu g/min (p < 0.05 by analysis of variance [ANOV A]). Diastolic function improved, as determined by the time constant f or isovolumetric relaxation tau, which decreased significantly from ba seline to 31.25 mu g/min (94 +/- 9 to 79 +/- 9 ms, p < 0.05), and did not shorten further at 62.5 mu g/min (78 +/- 8 ms, p = NS), There were significant decreases in right atrial pressure (9 +/- 1 to 7 +/- 1 mm Hg, p < 0.01 by ANOVA) and mean pulmonary artery wedge pressure (21 /- 3 to 16 +/- 2 mm Hg, p < 0.05 by ANOVA), This fall in filling press ures was not accompanied by any change in EDV. Inspection of the diast olic portion of the pressure-volume curve confirmed a downward shift c onsistent with pericardial release in five of the eight patients. Conc lusions. Intracoronary administration of OPC-18790 demonstrates that t he direct myocardial effects of this agent include a modest increase i n inotropy and improvement in diastolic function, both of which occur without increases in heart rate, indicating that this agent may be ben eficial for the intravenous treatment of congestive heart failure. (C) 1998 by the American College of Cardiology.