Mechanisms of Altered Excitation-Contraction Coupling in Canine Tachycardia-Induced Heart Failure, II: Model Studies

Ca transients measured in failing human ventricular myocytes exhibit reduced amplitude, slowed relaxation, and blunted frequency dependence. In the companion article (O'Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin R, Marban E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart, Iexperimental studies. Circ Res. 1999;84:562-570), O'Rourke et al show that Ca transients recorded in myocytes isolated from canine hearts subjected to the tachycardia pacing protocol exhibit similar responses. Analyses of protein levels in these failing hearts reveal that both SR Ca ATPase and phospholamban are decreased on average by 28% and that Na exchanger (NCX) protein is increased on average by 104%. In this article, we present a model of the canine midmyocardial ventricular action potential and Ca transient. The model is used to estimate the degree of functional upregulation and downregulation of NCX and SR Ca ATPase in heart failure using data obtained from 2 different experimental protocols. Model estimates of average SR Ca ATPase functional downregulation obtained using these experimental protocols are 49% and 62%. Model estimates of average NCX functional upregulation range are 38% and 75%. Simulation of voltage-clamp Ca transients indicates that such changes are sufficient to account for the reduced amplitude, altered shape, and slowed relaxation of Ca transients in the failing canine heart. Model analyses also suggest that altered expression of Ca handling proteins plays a significant role in prolongation of action potential duration in failing canine myocytes. (Circ Res. 1999;84:571-586.)