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

R. Winslow, J. Rice, S. Jafri, E. Marb�n, and B. O'Rourke. Circ. Res. 84 (5): 571--586 (March 1999)


Ca$^2+$ 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, K��b S, Tunin R, Marb�n E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart, I: experimental studies. Circ. Res.. 1999;84:562-570), O'Rourke et al show that Ca$^2+$ 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$^2+$ ATPase and phospholamban are decreased on average by 28\% and that Na$^+$/Ca$^2+$ 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$^2+$ transient. The model is used to estimate the degree of functional upregulation and downregulation of NCX and SR Ca$^2+$ ATPase in heart failure using data obtained from 2 different experimental protocols. Model estimates of average SR Ca$^2+$ 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$^2+$ transients indicates that such changes are sufficient to account for the reduced amplitude, altered shape, and slowed relaxation of Ca$^2+$ transients in the failing canine heart. Model analyses also suggest that altered expression of Ca$^2+$ handling proteins plays a significant role in prolongation of action potential duration in failing canine myocytes.


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