Relevance of Na+-Ca2+ exchange in heart failure

Altered expression and activity of the sarcolemmal Na+-Ca2+ exchange protein may play a key role for altered contractile function and arrhythmogenesis in hypertrophy and heart failure. To date, a majority of studies reported increased expression and function of the exchanger in human heart failure as well as in animal models. Whether overexpression of the exchanger in heart failure may be beneficial or detrimental is still controversial. This is partially related to the fact that the functional consequences of an altered expression are hard to predict because altered expression does not necessarily mean altered function. Exchanger activity depends on its thermodynamic properties which depend on [Ca]i, [Na]i, and on the action potential predicting the operation mode of the exchanger. Assuming that forward-mode which is believed to be the preferred operation mode in the nonfailing myocyte promoting Ca2+ extrusion and Na+ entry would be increased in failing myocytes with increased NCX abundance in sarcolemmal membranes this might promote SR Ca2+ depletion and induce contractile systolic dysfunction. On the other hand, increased forward-mode activity might prevent cytoplasmic Ca2+ overload and preserve diastolic function. Vice versa, increased reverse-mode Na+-Ca2+ exchange with increased Ca2+ influx may contribute to sarcoplasmic reticulum Ca2+ load and may compensate for decreased expression and activity of SERCA. This in turn may be associated with increased spontaneous SR Ca2+ release followed by arrhythmogenic transient inward currents. Moreover, both operation modes may be increased depending on the phase of the action potential. After all, expression and activity of the ex-changer in heart failure have to be considered with the concomitant changes such as alterations in intracellular Na+ or altered expression and activity of the SERCA which strongly impact on cytoplasmic Ca2+. Moreover, since distinct functional phenotypes with respect to NCX expression and function have been described we have to learn more about heterogeneity in heart failure. In this regard, it will be important to identify conditions and external stimuli that lead to induction of specific gene programs which presumably induce distinct functional phenotypes.