Effects of MCI-154, a Calcium Sensitizer, on Left Ventricular Systolic and Diastolic Function in Pacing-Induced Heart Failure in the Dog

Abstract

Background MCI-154 is a positive inotropic agent that increases the myofilament response to Ca 2+ . Whether MCI-154 has beneficial effects on left ventricular dysfunction in chronic heart failure is not known. We examined the effects of MCI-154 on left ventricular systolic and diastolic function in pacing-induced heart failure in dogs. Methods and Results We studied eight anesthetized dogs before and 2 to 4 weeks after rapid right ventricular pacing. Left cineventriculograms with simultaneous left ventricular pressures (tip manometer) were obtained before and during intravenous administration of MCI-154 (1.0 μg·kg −1 ·min −1 for 15 minutes) in the control and heart-failure states. Left ventricular volume dynamics was derived from frame-by-frame (20-ms) analyses of left ventricular angiograms. In heart failure, left ventricular contractility as assessed by shifts of the end-systolic pressure-volume ratio, evaluated by inferior vena cava occlusion, was improved by MCI-154 (+1.94 mm Hg/mL, P <.05) to an extent similar to that in the control state (+2.47 mm Hg/mL, P <.05). MCI-154 also accelerated left ventricular relaxation, assessed by the time constant of isovolumic pressure decay (T 1/2 ), in both states. The absolute decrease in T 1/2 with MCI-154 in heart failure was significantly greater than in the control state (−8.2 versus −3.1 ms, P <.05). In heart failure, MCI-154 shifted the left ventricular diastolic pressure-volume relation clearly downward, suggesting increased diastolic distensibility. Conclusions MCI-154 improved not only left ventricular systolic function but also diastolic relaxation and distensibility in a chronic heart failure model.