CALCIUM SENSITIZING AGENTS IN HEART-FAILURE

Congestive heart failure (CHF) is a common cardiovascular disorder tha t is characterised, in part, by a decreased cardiac output reserve. Ac cordingly, there is ongoing interest in the role of positive inotropic agents (e.g. adrenergic agonists and phosphodiesterase type III inhib itors, which mediate their cardiovascular effects via a cyclic adenosi ne monophosphate-dependent mechanism) in the treatment of CHF. However , enthusiasm for positive inotropic therapy in CHF has been dampened b y the results of clinical trials, which have shown that these drugs ar e associated with an increased risk of mortality. Calcium sensitising agents are a heterogeneous group of positive inotropic agents that med iate their cardiovascular actions (at least in part) by increasing the sensitivity of the contractile elements to calcium. Increased sensiti vity to calcium may be related to changes in calcium binding to tropon in C, or to direct effects on the actin-myosin complex. In addition, t he inhibition of phosphodiesterase type III may contribute to the posi tive inotropic action of calcium sensitising agents. Five agents with calcium sensitising properties (pimobendan, levosimendan, MCI-154, EMD -53998 and CGP-48506) have been studied as possible therapies for CHE All of these agents have demonstrated a positive inotropic action in i solated cardiac tissue and in animal models of CHF. In clinical trials , pimobendan, the most extensively studied of these drugs, was well to lerated and was associated with improved exercise tolerance during the first 6 months of therapy; however, it was also associated with a non significant trend towards increased mortality. Because many of the cal cium sensitising agents also inhibit phosphodiesterase type III activi ty, the long term safety of these agents is uncertain. Large-scale sur vival trials are required to determine the long term safety and effica cy of these agents before their role in the treatment of CHF can be de fined.