AUTHOR=Sampedro-Puente David Adolfo , Fernandez-Bes Jesus , Szentandrássy Norbert , Nánási Péter , Taggart Peter , Pueyo Esther 

TITLE=Time Course of Low-Frequency Oscillatory Behavior in Human Ventricular Repolarization Following Enhanced Sympathetic Activity and Relation to Arrhythmogenesis

JOURNAL=Frontiers in Physiology

VOLUME=Volume 10 - 2019

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.01547

DOI=10.3389/fphys.2019.01547

ISSN=1664-042X

ABSTRACT={Background and objectives:} Recent studies in humans and dogs have shown that ventricular repolarization exhibits a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity, which has been related to arrhythmic risk. The appearance of LF-oscillations in ventricular repolarization is, however, not immediate, but it may take up to some minutes. This study seeks to characterize the time-course of the action potential (AP) duration (APD) oscillatory behavior in response to sympathetic provocations, unveil its underlying mechanisms and establish a potential link to arrhythmogenesis under disease conditions. \textbf{Materials and Methods:} A representative set of human ventricular computational models coupling cellular electrophysiology, calcium dynamics, $\beta$-adrenergic signaling and mechanics was built. Sympathetic provocation was modeled via phasic changes in $\beta$-adrenergic stimulation ($\beta$-AS) and mechanical stretch at Mayer wave frequencies within the 0.03-0.15Hz band. \textbf{Results:} Our results show that there are large inter-individual differences in the time-lapse for the development of LF oscillations in APD following sympathetic provocation, with some cells requiring just a few seconds and other cells needing more than three minutes. Whereas the oscillatory response to phasic mechanical stretch is almost immediate, the response to $\beta$-AS is much more prolonged, in line with experimentally reported evidences, thus being this component the one driving the slow development of APD oscillations following enhanced sympathetic activity. If $\beta$-adrenoceptors are priorly stimulated, the time for APD oscillations to become apparent is remarkably reduced, with the oscillation time-lapse being an exponential function of the pre-stimulation level. The major mechanism underlying the delay in APD oscillations appearance is related to the slow $I_{Ks}$ phosphorylation kinetics, with its relevance being modulated by the $I_{Ks}$ conductance of each individual cell. Cells presenting short oscillation time-lapses are commonly associated with large APD oscillation magnitudes, which facilitate the occurrence of pro-arrhythmic events under disease conditions involving calcium-overload and reduced-repolarization-reserve. \textbf{Conclusions:} The time-course of LF oscillatory behavior of APD in response to increased sympathetic activity presents high inter-individual variability, which is associated with different expression and PKA phosphorylation kinetics of the $I_{Ks}$ current. Short time-lapses in the development of APD oscillations are associated with large oscillatory magnitudes and pro-arrhythmic risk under disease conditions.