WILL CALCIUM SENSITIZERS PLAY A ROLE IN THE TREATMENT OF HEART-FAILURE

This review summarizes some of the problems with inotropic agents and describes the new concept of increasing cardiac myofilament sensitivit y to Ca2+. Presently used inotropic agents act by increasing the intra cellular concentration of Ca2+ in cardiac myocytes by either cAMP-depe ndent or cAMP-independent mechanisms. There is concern that elevation of cAMP and/or cytosolic Ca2+ might be proarrhythmic and increase mort ality in patients with congestive heart failure (CHF). Ca2+ sensitizat ion represents a new approach to the treatment of CHF. Drugs that sens itize the contractile proteins to Ca2+ enhance myocardial contractilit y without changes in the cytosolic Ca2+ concentration. Ca2+ sensitizat ion can be achieved by an increased affinity of troponin-C for Ca2+ (p imobendan), by stabilization of the Ca2+-induced conformational change of troponin-C (levosimendan) or by direct interference with the myosi n-actin interaction (MCI-154, EMD 53998, and EMD 57033). Ca2+ sensitiz ation reduces the risk for Ca2+ overload and has a favorable effect on myocardial oxygen consumption. Inhibition of cardiac relaxation is a possible adverse effect of Ca2+ sensitizers owing to an expected highe r level of contractile tension during diastole. However, most of the r eported Ca2+ sensitizers have additional phosphodiesterase (PDE) III-i nhibitory activity, which is associated with a positive lusitropic eff ect, but from the standpoint of mortality PDE inhibition might not be beneficial in the long run. Most Ca2+ sensitizers have a hemodynamic p rofile characteristic of inodilators. Clinical data on Ca2+ sensitizer s are yet very sparse but ongoing clinical trials are awaited.