Cellular mechanisms of heart failure

In cardiac myocytes, contraction is triggered by a transient increase in intracellular Ca2+ levels. Depolarization causes Ca2+ entry through L-type Ca2+ channels, which in turn triggers release of Ca2+ from the sarcoplasmic reticulum (SR). This process is referred to as Ca2+-induced Ca2+ release (CICR). Following release, Ca2+ is recycled into the SR by the SR Ca2+ ATPase (SERCA) and extruded from the cell by the Na+-Ca2+ exchanger (NCX). During heart failure, cellular Ca2+ transients become smaller and slower, leading to reduced contractile function. The precise mechanisms underlying this deficit remain unclear. One possibility is that reduced Ca2+ release results from decreased Ca2+ content in the SR. This decrease may result from decreased SERCA funct ion, increased NCX activity, and/or increased leak of Ca2+ from the SR. It has also been proposed that alterations in L-type Ca2+ current (ICa-L) could lead to reduced CICR in failure. Such alterations may involve local loss of L-type channels, a reduc ed ability of ICa-L to trigger Ca2+ release, or alterations in the inactivation characteristics of ICa-L. In the current project, we will characterize alterations in SR functions and ICa-L that underlie reduced contractility in a mouse model of heart fail ure following myocardial infarction. Changes in Ca2+ homeostasis might also be the initial triggering event for heart failure. One candidate trigger is altered SR function. In our study, we will examine both proposed triggers of heart failure, and the mec hanisms that underlie attenuated contractility in this condition. We hypothesize that alterations in Ca2+ homeostasis contribute to both processes, and may therefore be an important therapeutic target.