Computational models of the failing myocyte: relating altered gene expression to cellular function

Studies of both, message and expressed protein levels in patients and anima l models of heart failure (HF) have demonstrated reduced message levels of genes encoding outward potassium (K+) currents in end-stage HF. These same studies have also shown altered expression of calcium-handling proteins, sp ecifically down regulation of the sarcoplasmic reticulum (SR) Ca2+-ATPase, and up regulation of the Na+- Ca2+ exchanger. We have tested the hypothesis that this minimal model of end-stage HF can account for action potential ( AP) prolongation, and reduced Ca2+ transient amplitude and decay rate obser ved in failing myocytes. To do this, we have developed a computer model of the normal and failing canine myocyte that describes properties of both mem brane currents as well as intracellular calcium cycling. Model simulations closely reproduce AP and Ca2+ transient properties measured experimentally in failing myocytes. Simulations also indicate that the predominant mechani sm of AP prolongation in canine BF is reduction of Ca2+-dependent inactivat ion of L-type Ca2+ current in response to reduced SR Ca2+ levels. These red uced SR Ca2+ levels are, in turn, a consequence of HF-induced down regulati on of the SR Ca2+-ATPase, and up regulation of the Na+-Ca2+ exchanger. The hypothesis that intracellular Ca2+ cycling has important influences on AP d uration changes in HF is supported by a measured close correlation between AP duration and Ca2+ transient amplitude when myocytes are stimulated from rest.