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

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. Materials and Methods: A representative set of human ventricular computational models coupling cellular electrophysiology, calcium dynamics, β-adrenergic signaling, and mechanics was built. Sympathetic provocation was modeled via phasic changes in β-adrenergic stimulation (β-AS) and mechanical stretch at Mayer wave frequencies within the 0.03-0.15 Hz band.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 3 min. Whereas, the oscillatory response to phasic mechanical stretch is almost immediate, the response to β-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 β-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 Sampedro-Puente et al. Time Course of Low-Frequency Oscillatory Behavior 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. 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.

Characterization of Impaired Ventricular Repolarization by Quantification of QT Delayed Response to Heart Rate Changes in Stress Test

“…1b). This phenomenon is in agreement with recent findings [11] showing that the time for ventricular repolarization adaptation to sympathetic provocation becomes progressively reduced for increasingly higher levels of beta-adrenoceptors' stimulation, as occurs when approaching the stress peak. Electrophysiological simulations including changes in Autonomic Nervous System (ANS) and in HR as those studied here could shed light on this observed behavior.…”

Influence of heart rate correction formulas on QTc interval stability

“…It might also be speculated that in addition to heart rate and QT/RR hysteresis effects, QT interval might also be corrected for other factors such as autonomic status and/or plasma electrolyte and glucose levels 43 , 66 , 67 . In this sense, our “gold standard” individual correction might be further improved.…”

“…Comment should also be made on the fact that we observed both short-term and long-term variations not only of QTc values by the different correction formulas but also, albeit to a much lesser degree, of the individually corrected QTcI values. While direct heart rate influence on the QTcI duration is removed, ventricular repolarisation interval is also under the influence of autonomic nervous system 67 as well as of other regulatory mechanisms, e.g. those responsible for post-prandial effects 43 .…”

De la prueba de esfuerzo a la predicción de muerte súbita cardiaca usando marcadores no invasivos

“…2b). Esto lo relacionamos con los resultados del estudio [6] que muestra que el tiempo de adaptación de la repolarización ventricular a cambios de HR disminuye progresivamente conforme aumentan los niveles de estimulación simpática de los −adrenoreceptores, como seguramente ocurre en la ultima fase de la pruecba de esfuerzo donde se observa este acercamiento.…”