Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour

[EN] In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).The Giles Laboratory acknowledges funding from the Canadian Institutes for Health Research. The computational work in Spain, was funded from the Ministerio de Economia, Industria y Competitividad of Spain (DPI2016-75799-R) and AEI/FEDER, UE, and the Programa Prometeu (PROMETEU/2016/088) de la Conselleria d'Educacio, Formacio/Ocupacio, Generalitat ValencianaTrenor Gomis, BA.; Cardona-Urrego, KE.; Saiz Rodríguez, FJ.; Noble, D.; Giles, W. (2017). Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour. The Journal of Physiology. 595(21):6599-6612. https://doi.org/10.1113/JP2736516599661259521Anderson, M. E., Al-Khatib, S. M., Roden, D. M., & Califf, R. M. (2002). Cardiac repolarization: Current knowledge, critical gaps, and new approaches to drug development and patient management. American Heart Journal, 144(5), 769-781. doi:10.1067/mhj.2002.125804ANTZELEVITCH, C. (2005). Modulation of Transmural Repolarization. Annals of the New York Academy of Sciences, 1047(1), 314-323. doi:10.1196/annals.1341.028Antzelevitch, C. (2012). 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