MECHANICAL INTERACTION OF HETEROGENEOUS CARDIAC MUSCLE SEGMENTSIN SILICO: EFFECTS ONCa2+HANDLING AND ACTION POTENTIAL

Effects of cardiac mechanical heterogeneity on the electrical function of the heart are difficult to assess experimentally, yet they pose a serious (patho-)physiological challenge. Here, we present an in silico study of the effects of mechanical heterogeneity on action potential duration (APD) in mechanically interacting muscle regions and consequent effects on the dispersion of repolarization, a well-established determinant of cardiac arrhythmogenesis. Using a novel mathematical description of ventricular electromechanical activity (virtual muscle), we first assessed how differences in intrinsic contractile properties affect the electrical behavior of cardiac muscle representations. In spite of identical electrophysiological model descriptions in virtual muscle samples, faster muscle models show shorter APD than their slower counterparts. This is a consequence of Ca 2+ -mediated feedback from mechanical to electrical activity in the individual muscle models. This mechano-electric feedback (MEF) is, of course, significantly more complex in native cardiac tissue, as the heterogeneous muscle elements interact both mechanically and electrically. Cardiac mechanical heterogeneity, in its most reduced form, can be represented by a duplex consisting of two mechanically interacting muscle segments. Our in silico model of heterogeneous myocardium therefore consists of two individual virtual muscles that are mechanically interconnected in-series to form a virtual heterogeneous duplex. During isometric contraction of the duplex (i.e. at constant external length), internal mechanical interactions affect Ca 2+ handling and APD of muscle elements, resulting in an increased dispersion of repolarization beyond the intrinsic APD differences. Duplex electromechanical activity is strongly affected by the activation sequence of its elements. Late activation of the faster (subepicardial type) duplex element, postponed by time-lags that correspond to normal transmural activation delays, optimizes duplex contractility and smoothes out intrinsic APD differences, thereby reducing dispersion in repolarization. This smoothing effect is not observed upon delayed activation of the slower (subendocardial type) duplex element. In both settings, changes in repolarization timing follow a nonlinear dependence of APD on activation delay. Furthermore, asynchronous activation of identical elements in a homogeneous duplex causes an impairment of contractile function and increases dispersion of repolarization. This suggests that the normal electrical activation sequence in the heart requires matching mechanical and electrical heterogeneity for optimal cardiac performance. On the subcellular level, our results suggest that mechanical modulation of Ca 2+ handling is a key mechanism of MEF in heterogeneous myocardium, which contributes to the matching of local mechanical and/or electrical activity to global hemodynamic demand.