000095863 001__ 95863
000095863 005__ 20210902121616.0
000095863 0247_ $$2doi$$a10.3389/fphys.2019.01547
000095863 0248_ $$2sideral$$a116391
000095863 037__ $$aART-2020-116391
000095863 041__ $$aeng
000095863 100__ $$0(orcid)0000-0002-1927-1762$$aSampedro-Puente, David Adolfo
000095863 245__ $$aTime Course of Low-Frequency Oscillatory Behavior in Human Ventricular Repolarization Following Enhanced Sympathetic Activity and Relation to Arrhythmogenesis
000095863 260__ $$c2020
000095863 5060_ $$aAccess copy available to the general public$$fUnrestricted
000095863 5203_ $$aBackground 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 IKs phosphorylation kinetics, with its relevance being modulated by the IKs 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.
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 IKs current. Short time lapses in the development of APD oscillations are associated with large oscillatory magnitudes and pro-arrhythmic risk under disease conditions.
000095863 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/DPI2016-75458-R$$9info:eu-repo/grantAgreement/ES/ISCIII/CIBER-BBN-MULTITOOLS2HEART$$9info:eu-repo/grantAgreement/EUR/ERC-2014-StG-638284$$9info:eu-repo/grantAgreement/ES/DGA/LMP124-18$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/T39-17R-BSICoS
000095863 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000095863 590__ $$a4.566$$b2020
000095863 591__ $$aPHYSIOLOGY$$b14 / 81 = 0.173$$c2020$$dQ1$$eT1
000095863 592__ $$a1.32$$b2020
000095863 593__ $$aPhysiology (medical)$$c2020$$dQ2
000095863 593__ $$aPhysiology$$c2020$$dQ2
000095863 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000095863 700__ $$0(orcid)0000-0001-5175-3166$$aFernandez-Bes, Jesús
000095863 700__ $$aSzentandrassy, Norbert
000095863 700__ $$aNanasi, Péter
000095863 700__ $$aTaggart, Peter
000095863 700__ $$0(orcid)0000-0002-1960-407X$$aPueyo, Esther$$uUniversidad de Zaragoza
000095863 7102_ $$15008$$2800$$aUniversidad de Zaragoza$$bDpto. Ingeniería Electrón.Com.$$cÁrea Teoría Señal y Comunicac.
000095863 773__ $$g10 (2020), 1547 [14 pp]$$pFront. physiol.$$tFRONTIERS IN PHYSIOLOGY$$x1664-042X
000095863 8564_ $$s877192$$uhttps://zaguan.unizar.es/record/95863/files/texto_completo.pdf$$yVersión publicada
000095863 8564_ $$s28551$$uhttps://zaguan.unizar.es/record/95863/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
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000095863 951__ $$a2021-09-02-08:44:33
000095863 980__ $$aARTICLE