CALCIUM SENSITIZATION AS NEW PRINCIPLE OF INOTROPIC THERAPY IN END-STAGE HEART-FAILURE

Objective: Due to shortage of donor hearts and increasing waiting-list s of patients with end-stage heart disease, new pharmacological princi ples for bridging therapies are necessary. The positive inotropic effe cts of cAMP-increasing drugs (e.g. catecholamines, phosphodiesterase-i nhibitors) are diminished in the failing myocardium. Hence, we investi gated the usefulness and mechanism of the two calcium sensitizers, lev osimendan and CGP 48506 in preparations from end-stage failing human h earts since the exact mechanism of the positive inotropic effects is n ot yet clearly understood. Methods: Failing human hearts which require d orthotopic heart transplantation due to idiopathic dilated cardiomyo pathy were investigated. Contraction experiments were performed using muscle strips of ventricles. Calcium sensitization was investigated in skinned fibers and phosphodiesterase activity was measured in ventric ular homogenate. In addition, cAMP levels were quantified in myocytes from guinea-pig hearts. Results: In muscle stripes from failing human hearts levosimendan (10 mu mol/l) increased the force of contraction o nly to 112.8 +/- 6.7% of predrug values. In contrast, CCP 48506 increa sed the force of contraction to 311 +/- 59% of predrug values at 100 m u mol/l. The time to peak tension and time of relaxation were increase d to 175 +/- 4% and 205 +/- 15% of control levels at 100 mu mol/l. Ski nned fibers from failing human hearts were sensitized to calcium with an EC50 of 10 mu mol/l. Other mechanisms of action were excluded since CGP 48506 affected neither the activity of phosphodiesterase isoenzym es I-IV in failing human hearts, nor cAMP levels in guinea-pig cardiom yocytes. On the other hand, levosimendan (1 mu mol/l) increased cAMP c ontent from 6.3 +/- 0.3 to 8.1 +/- 0.3 pmol/mg protein. Conclusion: CG P 48506 is an inotropic agent with calcium-sensitizing properties in t he human heart, that is devoid of inhibitory activity on human cardiac phosphodiesterase isoenzymes. It offers, therefore, a new form of pos itive inotropic therapy that can be useful for the bridging treatment of heart failure before transplantation. On the other hand, levosimend an is a calcium sensitizer showing less-effective inotropic effects ac companied by increased cAMP levels. (C) 1998 Elsevier Science B.V. All rights reserved.