UC San Diego

Transmural differences in the expression patterns of many ion channels distinguish myocytes isolated from the ventricular endocardium, epicardium and midmyocardium of several species. Modifications to ion channel function, e.g. by accessory subunits, phosphoregulation or congenital abnormalities, may alter cellular electrical activity in a myocyte subtype specific manner, increasing dispersion of repolarization. However, in well-coupled myocardial tissue, repolarization gradients are thought to be minimized by electrotonic coupling. Advances in molecular biology have yielded a wealth of quantitative information on the structure, function and regulation of cardiac ion channels. As the consequences of congenital "ion channelopathies" are often explored in isolated expression systems, it is difficult to establish a connection between the molecular mechanisms of ion channel defects and their clinical phenotypes. Furthermore, the ability to obtain high resolution measurements of electrophysiological phenomena in vivo is extremely limited. Thus, the objective was to develop and validate computational multiscale models to investigate the hypotheses that 1) transmural heterogeneities in the molecular mechanisms underlying cellular electrical activity influence patterns of activation and recovery in well-coupled myocardial tissue, and 2) heritable ion channel mutations amplify these heterogeneities and contribute to potentially life-threatening arrhythmogenesis. In this work, we integrated biophysically detailed ionic models into geometrically accurate 3D finite element models of cardiac conduction. These models predicted that 1) intrinsic cellular heterogeneities are attenuated in well-coupled myocardial tissue by electrotonic coupling; 2) autonomic-mediated amplification of spatial heterogeneities link a molecular level genetic mutation in KCNQ1 with proarrhythmic cellular events and T-Wave abnormalities; 3) sustained components of I_Kv43 and I_NaL play a major role in shaping the cardiac action potential; and 4) increased dispersion of repolarization resulting from an SCN5A mutation permits pause-dependent episodes of polymorphic ventricular tachycardia. These findings suggest that, despite electrotonic interactions that minimize repolarization gradients, ion channel mutations may amplify intrinsic cellular heterogeneities thus creating an electrically unstable substrate. Multiscale computational modeling is a powerful tool to integrate the molecular mechanisms of ion channel regulation into the native, complex environment of the cardiac ventricular myocyte and intact myocardial tissue, thus bridging the gap between congenital defects and clinical phenotypes