Dose-Related Hemodynamic and Electrocardiographic Effects of the Calcium Promoter BAY y 5959 in the Presence or Absence of Congestive Heart Failure

Objectives. The aim of this study was to assess the cardiovascular effects of BAY y 5959, calcium promoter modulating myocardial calcium channels, in the presence or absence of congestive heart failure. Background. There is still clinical need for short-term administration of intravenous positive inotropes. BAY y 5959 was developed as new approach to increase myocardial performance by selectively enhancing calcium influx in the myocytes. Methods. Forty-one patients (21 without and 20 with congestive heart failure) were studied in an open label, dose-ranging study. Hemodynamic variables (including left ventricular [LV] angiography) and plasm samples were obtained at baseline and after 20 min of intravenous infusion of BAY y 5959 at doses ranging from 0.25 to 4.5 μg/kg body weight per min. Results. In both study groups, BAY y 5959 produced dose-dependent increases in the indexes of inotropic state, without affecting isovolumetric relaxation rate. The magnitude of the response was comparable in patients with or without heart failure (average 38% increase in maximal first derivative of LV pressure [dP/dt max] at plasm levels of 100 μg/liter). BAY y 5959 also induced mild but statistically significant bradycardi and significantly decreased end-systolic volume while producing leftward shift of the pressure-volume loop. Mean aortic pressure was unaffected at doses up to 3.0 μg/kg per min, and cardiac index improved in patients with heart failure at doses of 2.0 μg/kg per min (+23%, p < 0.05). However, at dose of 4.5 μg/kg per min, mean aortic pressure and LV systolic wall stress increased, suggesting systemic vasoconstriction. The QT interval was also prolonged significantly at most doses. Conclusions. BAY y 5959 exhibits positive inotropic effects in patients with and without heart failure. The optimal response— combining bradycardia, reduced preload and improved cardiac output—appeared to be achieved at dose of not, vert, similar2.0 μg/kg per min. The impact of QT prolongation with regard to potential antiarrhythmic or proarrhythmic effects is unclear at this time.