Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II - Model studies

Ca2+ transients measured in failing human ventricular myocytes exhibit redu ced amplitude, slowed relaxation, and blunted frequency dependence. In the companion article (O'Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin R, Marb an E. Mechanisms of altered excitation-contraction coupling in canine tachy cardia-induced heart, I: experimental studies. Circ Res, 1999;84:562-570), O'Rourke et al show that Ca2+ 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 Ca2+ ATPase and phospholamban are decreased on average by 28% and t hat Na+/Ca2+ exchanger (NCX) protein is increased on average by 104%. In th is article, we present a model of the canine midmyocardial ventricular acti on potential and Ca2+ transient. The model is used to estimate the degree o f functional upregulation and downregulation of NCX and SR Ca2+ ATPase in h eart failure using data obtained from 2 different experimental protocols. M odel estimates of average SR Ca2+ ATPase functional downregulation obtained using these experimental protocols are 49% and 62%, Model estimates of ave rage NCX functional upregulation range are 38% and 75%, Simulation of volta ge-clamp Ca2+ transients indicates that such changes are sufficient to acco unt for the reduced amplitude, altered shape, and slowed relaxation of Ca2 transients in the failing canine heart. Model analyses also suggest that a ltered expression of Ca2+ handling proteins plays a significant role in pro longation of action potential duration in failing canine myocytes.