HEMODYNAMIC, NEUROHUMORAL, AND MYOCARDIAL ENERGETIC EFFECTS OF PIMOBENDAN, A NOVEL CALCIUM-SENSITIZING COMPOUND, IN PATIENTS WITH MILD-TO-MODERATE HEART-FAILURE

In contrast to cyclic AMP-dependent positive inotropes, the calcium-sensitizer and partial phosphodiesterase (PDE) inhibitor pimobendan may induce beneficial effects in heart failure. However, its effect on relaxation, myocardial energetics and neurohormones are unknown. Twelve patients with heart failure, New York Heart Association (NYHA) classification II-III, due to ischemic cardiomyopathy, were studied for 1 h after they received 5 mg pimobendan intravenously (i.v.). Pimobendan progressively reduced systemic resistance and left ventricular end-diastolic pressure (LVEDP) (22 and 50%, respectively) and improved isovolumetric contractility and relaxation parameters by 30% (all p < 0.05 vs. control). LV end-diastolic and end-systolic volumes (LVEDV, LVESV) decreased significantly by 20 and 19%, respectively. Cardiac output (CO) increased by 17% due to a simultaneous increase in heart rate (HR) from 75 +/- 3 to 86 +/- 5 beats/min (mean +/- SEM, p < 0.05). Pimobendan did not change coronary hemodynamics, but myocardial O-2 extraction and consumption were decreased significantly by 18 and 20%, respectively. Catecholamines, angiotensin II (AII), and aldosterone levels did not change significantly. In contrast, arterial and coronary venous renin increased significantly from 57 +/- 17 and 53 +/- 14.7 mu M/h at control to 69 +/- 20 and 69 +/- 20 mu M/h, respectively, 60 min after pimobendan administration. Simultaneously, cardiac renin uptake at baseline (0.449 +/- 0.185 mu mol/min) changed to release (-0.071 +/- 0.145 mu mol/min, p < 0.05). Serious side effects did not occur. Thus, pimobendan had progressive positive inotropic and lusitropic effects, diminished preload and afterload despite modest stimulation of plasma renin activity (PRA), and reduced systemic vascular resistance. Despite its clear positive inotropic and chronotropic properties, pimobendan still caused significant improvement of myocardial energetics and thus may be useful during acute exacerbations of heart failure caused by ischemic heart disease.