Abstract
Spatial dispersion of repolarization is known to play an important role in arrhythmogenesis. Electrotonic modulation of repolarization by the activation sequence has been observed in some species and tissue preparations, but to varying extents. Our study sought to determine the mechanisms underlying species- and tissue-dependent electrotonic modulation of repolarization in ventricles. Epi-fluorescence optical imaging of whole rat hearts and pig left ventricular wedges were used to assess epicardial spatial activation and repolarization characteristics. Experiments were supported by computer simulations using realistic geometries. Tight coupling between activation times (AT) and action potential duration (APD) were observed in rat experiments but not in pig. Linear correlation analysis found slopes of −1.03 ± 0.59 and −0.26 ± 0.13 for rat and pig, respectively (p < 0.0001). In rat, maximal dispersion of APD was 11.0 ± 3.1 ms but dispersion of repolarization time (RT) was relatively homogeneous (8.2 ± 2.7, p < 0.0001). However, in pig no such difference was observed between the dispersion of APD and RT (17.8 ± 6.1 vs. 17.7 ± 6.5, respectively). Localized elevations of APD (12.9 ± 8.3%) were identified at ventricular insertion sites of rat hearts both in experiments and simulations. Tissue geometry and action potential (AP) morphology contributed significantly to determining influence of electrotonic modulation. Simulations of a rat AP in a pig geometry decreased the slope of AT and APD relationships by 70.6% whereas slopes were increased by 75.0% when implementing a pig AP in a rat geometry. A modified pig AP, shortened to match the rat APD, showed little coupling between AT and APD with greatly reduced slope compared to the rat AP. Electrotonic modulation of repolarization by the activation sequence is especially pronounced in small hearts with murine-like APs. Tissue architecture and AP morphology play an important role in electrotonic modulation of repolarization.
Highlights
Regional variations of the action potential duration (APD) are perhaps the best characterized form of electrophysiological heterogeneity in the heart
Optical images from the epicardial surface of the rat ventricles and the pig left ventricular myocardium were obtained to investigate the relationship between the activation sequence and the spatial distribution of Action potential duration at 80% of repolarization (APD80)
The longest APD80 of 58.4 ms was observed at the pacing location and the shortest of 35.7 ms lay close to the site of the latest activation time (AT)
Summary
Regional variations of the action potential duration (APD) are perhaps the best characterized form of electrophysiological heterogeneity in the heart It has been reported in a wide range of species that spatial gradients of APD exist from base to apex and in the transmural plane of healthy myocardium (Wan et al, 2000; Antzelevitch, 2005). Such variations in APD serve to co-ordinate repolarization time (RT) of tissue to maintain normal functioning of the heart and are determined at a cellular level by the density of transmembrane ionic currents in various regions of the heart (Nerbonne and Kass, 2005). These APD gradients are the most pronounced at the pacing site, at the tissue www.frontiersin.org
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