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 sensitivity to Ca 2+ . Presently used inotropic agents act by increasing the intracellular concentration of Ca 2+ in cardiac myocytes by either cAMP-dependent or cAMP-independent mechanisms. There is concern that elevation of cAMP and/or cytosolic Ca 2+ might be proarrhythmic and increase mortality in patients with congestive heart failure (CHF). Ca 2+ sensitization represents a new approach to the treatment of CHF. Drugs that sensitize the contractile proteins to Ca 2+ enhance myocardial contractility without changes in the cytosolic Ca 2+ concentration. Ca 2+ sensitization can be achieved by an increased affinity of troponin-C for Ca 2+ (pimobendan), by stabilization of the Ca 2+ -induced conformational change of troponin-C (levosimendan) or by direct interference with the myosin-actin interaction (MCI-154, EMD 53998, and EMD 57033). Ca 2+ sensitization reduces the risk for Ca 2+ overload and has a favorable effect on myocardial oxygen consumption. Inhibition of cardiac relaxation is a possible adverse effect of Ca 2+ sensitizers owing to an expected higher level of contractile tension during diastole. However, most of the reported Ca 2+ sensitizers have additional phosphodiesterase (PDE) III-inhibitory activity, which is associated with a positive lusitropic effect, but from the standpoint of mortality PDE inhibition might not be beneficial in the long run. Most Ca 2+ sensitizers have a hemodynamic profile characteristic of inodilators. Clinical data on Ca 2+ sensitizers are yet very sparse but ongoing clinical trials are awaited.