New pharmacologic interventions to increase cardiac contractility: challenges and opportunities.

Abstract

The most extensively studied inotropic agents in patients with heart failure are phosphodiesterase (PDE) 3 inhibitors, which increase contractility by raising intracellular cyclic adenosine monophosphate content. In clinical trials, the inotropic benefits of these agents have been outweighed by an increase in sudden cardiac death. Here, I review recent findings that help explain what are likely to be distinct mechanisms involved in the beneficial and adverse effects of PDE3 inhibition. The proapoptotic consequences of PDE3 inhibition are becoming more apparent. Moreover, it has also become clear that individual PDE3 isoforms in cardiac myocytes are selectively regulated to interact with different proteins in different intracellular compartments. The beneficial and adverse effects of PDE3 inhibition may thus be attributable to the inhibition of different isoforms in different intracellular domains. In particular, PDE3A1 has been shown to interact directly with sarcoplasmic/endoplasmic reticulum Ca ATPase (SERCA2) in the sarcoplasmic reticulum through a phosphorylation of a site in its unique N-terminal domain, making it possible that this isoform can be selectively targeted to increase intracellular Ca cycling. Conventional PDE3 inhibitors target several functionally distinct isoforms of these enzymes. Isoform-selective and/or compartment-selective targeting of PDE3, through its protein-protein interactions, may produce the inotropic benefits of PDE3 inhibition without the adverse consequences.