MODELING THE CELLULAR BASIS OF ALTERED EXCITATION-CONTRACTION COUPLING IN HEART-FAILURE

Ca transients measured in failing human ventricular myocytes exhibit r educed amplitude and slowed relaxation [Beuckelmann, D.J., Nabauer, M. , Erdmann, E., 1992. Intracellular calcium handling in isolated ventri cular myocytes from patients with terminal heart failure. Circulation 85, 1046-1055; Gwathmey, J.K., Copelas, L., MacKinnon, R., Schoen, F.J ., Feldman, M.D., Grossman, W., Morgan, J.P., 1987. Abnormal intracell ular calcium handling in myocardium from patients with end-stage heart failure. Circ. Res. 61, 70-76; Kaab, S., Nuss, H. B., Chiamvimonvat, N., O'Rourke, H., Pak, P.H., Kass, D.A., Marban, E., Tomaselli, G.F., 1996. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ. Res. 78(2) ; Li, H.G., Jones, D.L., Yee, R., Klein, G.J., 1992. Electrophysiologi c substrate associated with pacing-induced heart failure in dogs: pote ntial value of programmed stimulation in predicting sudden death. J. A m. Cell. Cardiol. 19(2), 444-449; Vermeulen, J.T., McGuire, M.A., Opth of, T., Colonel, R., Bakker, J.M.T.d., Klopping, C., Janse, M.J., 1994 . Triggered activity and automaticity in ventricular trabeculae of fai ling human and rabbit hearts. Cardiovasc. Res. 28, 1547-1554.] and blu nted frequency dependence [Davies, C.H., Davia, K., Bennett, J.G., Pep per, J.R., Poole-Wilson, P.A., Harding, S.E., 1995. Reduced contractio n and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation, 92, 2540-2549; Hasenfuss, G ., Reinecke, H., Studer, I:., Meyer, M.. Pieske, B., Holtz, J., Holuba rsch, C., Posival, H., Just, H., Drexler, H., 1994. Relation between m yocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and nonfailing human myocardium. Circ. Res. 75, 434-442; Ha senfuss, G., Reinecke, H., Studer, R., Pieske, B., Meyer, M., Drexler, H., Just, H., 1996. Calcium cycling proteins and force-frequency rela tionships in heart failure. Basic Res. Cardiol. 9, 17-22; Monte, F.D., O'Gara, P., Poole-Wilson, P.A., Yacoub, M., Harding, S.E., 1995. Cell geometry and contractile abnormalities of myocytes from failing human left ventricle. Cardiovasc. Res. 30, 281-290; Philips, P.J., Gwatkmey , J.K., Feldman, M.D.. Schoen, F.J., Grossman, W., Morgan, J.P., 1990. Post-extrasystolic potentiation and the force-frequency relationships : differential augmentation of myocardial contractility in working myo cardium from patients with end-stage heart failure. J. Mol. Cell. Card iol. 22, 99-110; Pieske, B., Hasenfuss, G., Holubarsch, C., Schwinger, R., Bohm, M., Just, H., 1992. Alterations of the force-frequency rela tionship in the failing human heart depend on the underlying cardiac d isease. Basic Res. Cardiol. 87, 213-221]. Analyses of protein levels i n these failing hearts reveal that the SR Ca-ATPase is down-regulated on average by 50% and that the Na/Ca exchanger is up-regulated on aver age by a factor of two. In this paper, we test the hypothesis that thi s altered pattern of expression of Ca handling proteins is sufficient to account for changes in excitation-contraction coupling properties m easured experimentally at the cellular level. To do this, we present a n integrated model of excitation-contraction coupling in the guinea pi g ventricular cell. The model is used to determine the effects of SR C a-ATPase down-regulation and Na/Ca exchanger up-regulation on action p otential duration, Ca transient shape and amplitude, and isometric for ce. Model analyses demonstrate that changes in Ca handling proteins pl ay a direct and critical role in prolongation of action potential dura tion, and in reduction of contractile force in heart failure. (C) 1998 Elsevier Science Ltd. All rights reserved.