Calcium sensitization as new principle of inotropic therapy in end-stage heart failure?1

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Abstract
Objective: Due to shortage of donor hearts and increasing waiting-lists of patients with end-stage heart disease, new pharmacological principles for bridging therapies are necessary. The positive inotropic effects of cAMP-increasing drugs (e.g. catecholamines, phosphodiesterase-inhibitors) are diminished in the failing myocardium. Hence, we investigated the usefulness and mechanism of the two calcium sensitizers, levosimendan and CGP 48506 in preparations from end-stage failing human hearts since the exact mechanism of the positive inotropic effects is not yet clearly understood. Methods: Failing human hearts which required orthotopic heart transplantation due to idiopathic dilated cardiomyopathy were investigated. Contraction experiments were performed using muscle strips of ventricles. Calcium sensitization was investigated in skinned fibers and phosphodiesterase activity was measured in ventricular homogenate. In addition, cAMP levels were quantified in myocytes from guinea-pig hearts. Results: In muscle stripes from failing human hearts levosimendan (10 μmol/l) increased the force of contraction only to 112.8±6.7% of predrug values. In contrast, CGP 48506 increased the force of contraction to 311±59% of predrug values at 100 μmol/l. The time to peak tension and time of relaxation were increased to 175±4% and 205±15% of control levels at 100 μmol/l. Skinned fibers from failing human hearts were sensitized to calcium with an EC50 of 10 μmol/l. Other mechanisms of action were excluded since CGP 48506 affected neither the activity of phosphodiesterase isoenzymes I–IV in failing human hearts, nor cAMP levels in guinea-pig cardiomyocytes. On the other hand, levosimendan (1 μmol/l) increased cAMP content from 6.3±0.3 to 8.1±0.3 pmol/mg protein. Conclusion: CGP 48506 is an inotropic agent with calcium-sensitizing properties in the human heart, that is devoid of inhibitory activity on human cardiac phosphodiesterase isoenzymes. It offers, therefore, a new form of positive inotropic therapy that can be useful for the bridging treatment of heart failure before transplantation. On the other hand, levosimendan is a calcium sensitizer showing less-effective inotropic effects accompanied by increased cAMP levels.

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