Calcium sensitising agents in heart failure.

Congestive heart failure (CHF) is a common cardiovascular disorder that is characterised, in part, by a decreased cardiac output reserve. Accordingly, there is ongoing interest in the role of positive inotropic agents (e.g. adrenergic agonists and phosphodiesterase type III inhibitors, which mediate their cardiovascular effects via a cyclic adenosine monophosphate-dependent mechanism) in the treatment of CHF. However, enthusiasm for positive inotropic therapy in CHF has been dampened by the results of clinical trials, which have shown that these drugs are associated with an increased risk of mortality. Calcium sensitising agents are a heterogeneous group of positive inotropic agents that mediate their cardiovascular actions (at least in part) by increasing the sensitivity of the contractile elements to calcium. Increased sensitivity to calcium may be related to changes in calcium binding to troponin C, or to direct effects on the actin-myosin complex. In addition, the inhibition of phosphodiesterase type III may contribute to the positive 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 CHF. All of these agents have demonstrated a positive inotropic action in isolated cardiac tissue and in animal models of CHF. In clinical trials, pimobendan, the most extensively studied of these drugs, was well tolerated and was associated with improved exercise tolerance during the first 6 months of therapy; however, it was also associated with a nonsignificant trend towards increased mortality. Because many of the calcium sensitising agents also inhibit phosphodiesterase type III activity, the long term safety of these agents is uncertain. Large-scale survival trials are required to determine the long term safety and efficacy of these agents before their role in the treatment of CHF can be defined.