Abstract-Ca2ϩ 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, Kääb S, Tunin R, Marbán E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart, I: experimental studies. Circ Res. 1999;84:562-570 Key Words: excitation-contraction coupling Ⅲ heart failure Ⅲ midmyocardial ventricular action potential Ⅲ Ca 2ϩ transient R ecent studies using the canine tachycardia pacinginduced model of heart failure 1-8 demonstrate that changes in cellular electrophysiological and excitationcontraction (E-C) coupling processes are qualitatively similar to those observed in cells isolated from failing human heart. In human heart failure, I K1 current density measured at hyperpolarized membrane potentials is reduced by Ϸ50%, 9,10 and density of the transient outward current I to1 is reduced by Ϸ75% in subepicardial 11 and Ϸ40% in midmyocardial ventricular cells 9 and is unchanged in subendocardial ventricular cells. 11 The magnitude of I K1 is reduced by Ϸ40%, and that of I to1 by Ϸ70% in failing canine midmyocardial cells. 5 Expression of proteins involved in E-C coupling is also altered in human heart failure. Sarcoplasmic reticulum (SR) Ca 2ϩ ATPase mRNA level, 12-16 protein level, 12,17,18 and uptake rate 19 are reduced by Ϸ50% in end-stage heart failure. Na ϩ /Ca 2ϩ exchanger (NCX) mRNA levels are increased by Ϸ55% to 79%, 12,20 and NCX protein levels increase 36% to 160%. 12,20 -22

This study employs two modeling approaches to investigate short-term interval-force relations. The first approach is to develop a low-order, discrete-time model of excitation-contraction coupling to determine which parameter combinations produce the degree of postextrasystolic potentiation seen experimentally. Potentiation is found to increase 1) for low recirculation fraction, 2) for high releasable fraction, i.e., the maximum fraction of Ca(2+) released from the sarcoplasmic reticulum (SR) given full restitution, and 3) for strong negative feedback of the SR release on sarcolemmal Ca(2+) influx. The second modeling approach is to develop a more detailed single ventricular cell model that simulates action potentials, Ca(2+)-handling mechanisms, and isometric force generation by the myofilaments. A slow transition from the adapted state of the ryanodine receptor produces a gradual recovery of the SR release and restitution behavior. For potentiation, a small extrasystolic release leaves more Ca(2+) in the SR but also increases the SR loading by two mechanisms: 1) less Ca(2+)-induced inactivation of L-type channels and 2) reduction of action potential height by residual activation of the time-dependent delayed rectifier K(+) current, which increases Ca(2+) influx. The cooperativity of the myofilaments amplifies the relatively small changes in the Ca(2+) transient amplitude to produce larger changes in isometric force. These findings suggest that short-term interval-force relations result mainly from the interplay of the ryanodine receptor adaptation and the SR Ca(2+) loading, with additional contributions from membrane currents and myofilament activation.

Ventricular myocardium comprises at least three electrophysiologically distinct cell types: epicardial, endocardial and M cells. Epicardial and M cells, but not endocardial cells, display action potentials with a notched or spike-and-dome morphology: the result of a prominent, transient, outward current-mediated phase 1. M cells are distinguished from endocardial and epicardial cells by the ability of their action potential to disproportionately prolong in response to a slowing down of rate and/or in response to agents with class III actions. This intrinsic electrical heterogeneity contributes to the inscription of the electrocardiogram (ECG) as well as to the development of a variety of cardiac arrhythmias. Heterogeneous response of the three cell types to pharmacological agents and/or pathophysiological states results in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of re-entrant arrhythmias, including Torsade de Pointes, commonly associated with the long-QT syndrome (LQTS), and the polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF) encountered in the Brugada syndrome. Despite an abundance of experimental data describing the heterogeneity of cellular electrophysiology that exists across the ventricular wall, relatively few computer models have been developed to investigate the physiological and pathophysiological consequences of such electrical heterogeneity. As computer power increases and numerical algorithms improve, three-dimensional computer models of ventricular conduction that combine physiological membrane kinetics with realistic descriptions of myocardial structure and geometry will become more feasible. With sufficient detail and accuracy, these models should illuminate the complex mechanisms underlying the initiation and maintenance of Torsade de Pointes and other arrhythmias.