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

Studies of both message and expressed protein levels in patients and animal 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, specifically 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 observed in failing myocytes. To do this, we have developed a computer model of the normal and failing canine myocyte that describes properties of both membrane 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 mechanism of AP prolongation in canine HF is reduction of Ca²⁺-dependent inactivation of L-type Ca²⁺ current in response to reduced SR Ca²⁺ levels. These reduced SR Ca²⁺ levels are, in turn, a consequence of HF-induced down regulation of the SR Ca²⁺-ATPase, and up regulation of the Na⁺-Ca²⁺ exchanger. The hypothesis that intracellular Ca²⁺ cycling has important influences on AP duration changes in HF is supported by a measured close correlation between AP duration and Ca²⁺ transient amplitude when myocytes are stimulated from rest.