Please use this identifier to cite or link to this item: http://hdl.handle.net/10995/92495
Title: R-From-T as a Common Mechanism of Arrhythmia Initiation in Long QT Syndromes
Authors: Liu, M. B.
Vandersickel, N.
Panfilov, A. V.
Qu, Z.
Issue Date: 2019
Publisher: Lippincott Williams and Wilkins
Citation: Liu M. B. R-From-T as a Common Mechanism of Arrhythmia Initiation in Long QT Syndromes / M. B. Liu, N. Vandersickel, A. V. Panfilov, Z. Qu. — DOI 10.1161/CIRCEP.119.007571 // Circulation: Arrhythmia and Electrophysiology. — 2019. — Vol. 12. — Iss. 12. — e007571.
Abstract: Background: Long QT syndromes (LQTS) arise from many genetic and nongenetic causes with certain characteristic ECG features preceding polymorphic ventricular tachyarrhythmias (PVTs). However, how the many molecular causes result in these characteristic ECG patterns and how these patterns are mechanistically linked to the spontaneous initiation of PVT remain poorly understood. Methods: Anatomic human ventricle and simplified tissue models were used to investigate the mechanisms of spontaneous initiation of PVT in LQTS. Results: Spontaneous initiation of PVT was elicited by gradually ramping up ICa,L to simulate the initial phase of a sympathetic surge or by changing the heart rate, reproducing the different genotype-dependent clinical ECG features. In LQTS type 2 (LQT2) and LQTS type 3 (LQT3), T-wave alternans was observed followed by premature ventricular complexes (PVCs). Compensatory pauses occurred resulting in short-long-short sequences. As ICa,L increased further, PVT episodes occurred, always preceded by a short-long-short sequence. However, in LQTS type 1 (LQT1), once a PVC occurred, it always immediately led to an episode of PVT. Arrhythmias in LQT2 and LQT3 were bradycardia dependent, whereas those in LQT1 were not. In all 3 genotypes, PVCs always originated spontaneously from the steep repolarization gradient region and manifested on ECG as R-on-T. We call this mechanism R-from-T, to distinguish it from the classic explanation of R-on-T arrhythmogenesis in which an exogenous PVC coincidentally encounters a repolarizing region. In R-from-T, the PVC and the T wave are causally related, where steep repolarization gradients combined with enhanced ICa,L lead to PVCs emerging from the T wave. Since enhanced ICa,L was required for R-from-T to occur, suppressing window ICa,L effectively prevented arrhythmias in all 3 genotypes. Conclusions: Despite the complex molecular causes, these results suggest that R-from-T is likely a common mechanism for PVT initiation in LQTS. Targeting ICa,L properties, such as suppressing window ICa,L or preventing excessive ICa,L increase, could be an effective unified therapy for arrhythmia prevention in LQTS. © 2019 Circulation: Arrhythmia and Electrophysiology. All rights reserved.
Keywords: ARRHYTHMIAS, CARDIAC
GENOTYPE
HEART
HEART RATE
LONG QT SYNDROME
BETA ADRENERGIC RECEPTOR BLOCKING AGENT
POTASSIUM CHANNEL
SODIUM CHANNEL
ACTION POTENTIAL
ARRHYTHMOGENESIS
ARTICLE
BRADYCARDIA
CARDIAC MUSCLE CELL
CARDIOPULMONARY EXERCISE TEST
COMPUTER MODEL
DEPOLARIZATION
ELECTROCARDIOGRAPHY
GENE MUTATION
GENOTYPE
HEART ARRHYTHMIA
HEART PACING
HEART RATE
HEART REPOLARIZATION
HEART VENTRICLE
HUMAN
LONG QT SYNDROME
LONG QT SYNDROME 1
LONG QT SYNDROME 2
LONG QT SYNDROME 3
MATHEMATICAL MODEL
POLYMORPHIC VENTRICULAR TACHYCARDIA
PRIORITY JOURNAL
QT INTERVAL
R WAVE
SINUS RHYTHM
T WAVE
TACHYCARDIA
ELECTROCARDIOGRAPHY
GENETICS
HEART MUSCLE CONDUCTION SYSTEM
LONG QT SYNDROME
PATHOPHYSIOLOGY
PHYSIOLOGY
ACTION POTENTIALS
ELECTROCARDIOGRAPHY
GENOTYPE
HEART CONDUCTION SYSTEM
HEART RATE
HEART VENTRICLES
HUMANS
LONG QT SYNDROME
URI: http://hdl.handle.net/10995/92495
Access: info:eu-repo/semantics/openAccess
SCOPUS ID: 85076566728
WOS ID: 000503199500006
PURE ID: 11728822
ISSN: 1941-3149
DOI: 10.1161/CIRCEP.119.007571
metadata.dc.description.sponsorship: National Institutes of Health, NIH: R01 HL139829, T32 GM008042, R01 HL134709, F30 HL132449
This work was supported by National Institutes of Health grants R01 HL134709, R01 HL139829, T32 GM008042, and F30 HL132449.
Appears in Collections:Научные публикации, проиндексированные в SCOPUS и WoS CC

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