Mechanisms linking T‐wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome

Liu, Weiqing; Kim, Tae Yun; Huang, Xiaodong; Liu, Michael B.; Koren, Gideon; Choi, Bum‐Rak; Qu, Zhilin

doi:10.1113/jp275492

Cited by 45 publications

(53 citation statements)

References 65 publications

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“…Since phase-2 EADs cannot propagate into PVCs in tissue [19–22], this raises question on how are EADs linked to arrhythmias under LQTS and many other diseased conditions where Ca 2+ may not be overloaded. In recent studies [22, 64], we demonstrated how phase-2 EADs and tissue-scale dynamical instabilities interact to result in PVCs and arrhythmias under LQTS, linking mechanistically phase-2 EADs to arrhythmogenesis.…”

Section: Discussionmentioning

confidence: 99%

Determinants of early afterdepolarization properties in ventricular myocyte models

Huang

Song

2018

PLoS Comput Biol

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Early afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf-homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development.

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Section: Discussionmentioning

confidence: 99%

Determinants of early afterdepolarization properties in ventricular myocyte models

Huang

Song

2018

PLoS Comput Biol

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“…Clinically, the disease phenotype of LQT2 and the onset of characteristic TdP arrhythmia or VT-like arrhythmia have been reported to be due to sudden arousal, exercise, sudden emotional or acoustic triggers or at rest during sleep, and are preceded by a pause in R-R interval with a transient dramatic rise in the QT interval immediately before the TdP [7,11,48]. T-wave alternans, T-wave liability (beat-to-beat variation) or oscillation in the ECG have been reported to be a precursor to lethal arrhythmia and major cardiac events in humans and in rabbit LQT2 models [49,50]. On clinical examination our symptomatic patient developed non-sustained ventricular tachycardia on a 24 h Holter recording while on beta-blocker bisoprolol and was implanted with an implantable cardioverter-defibrillator (ICD).…”

Section: What Is Causing Arrhythmogenic Events In Lqt2?mentioning

confidence: 99%

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

Shah

Prajapati

Penttinen

et al. 2020

Cells

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Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers from the same family. When comparing asymptomatic and symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium current density, and arrhythmicity on adrenaline exposure were similar, but a difference in Ca2+ transients was observed. The major differences were, however, observed at aggregate level with increased susceptibility to arrhythmias on exposure to adrenaline or potassium channel blockers on CM aggregates derived from the symptomatic individual. The effect of this mutation was modeled in-silico which indicated the reactivation of an inward calcium current as one of the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major phenotype characteristics observed in LQT2 mutation carriers and strong phenotype differences between LQT2 asymptomatic vs. symptomatic were revealed at CM-aggregate level.

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“…Therefore, T peakend -the length from the beginning of the T wave (T p ) to the end (T e ) on ECG-that reflect the transmural dispersion of repolarization was suggested to use as an indicator of arrhythmic risk, although, no clear consensus about the value of this parameter has been reached so far (Antzelevitch, 2008;Barbhaiya et al, 2013;Meijborg et al, 2014). Of note, dispersion of repolarization was recently identified (experimentally and by computational modeling) as cause for triggered activity/EAD formation, further enhancing the need to assess dynamic dispersion of repolarization noninvasively (Liu et al, 2018).…”

Section: Proarrhythmia Ecg Markers For Temporal Instability Of Repolamentioning

confidence: 99%

Transgenic Rabbit Models in Proarrhythmia Research

et al. 2020

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Drug-induced proarrhythmia constitutes a potentially lethal side effect of various drugs. Most often, this proarrhythmia is mechanistically linked to the drug's potential to interact with repolarizing cardiac ion channels causing a prolongation of the QT interval in the ECG. Despite sophisticated screening approaches during drug development, reliable prediction of proarrhythmia remains very challenging. Although drug-induced long-QT-related proarrhythmia is often favored by conditions or diseases that impair the individual's repolarization reserve, most cellular, tissue, and whole animal model systems used for drug safety screening are based on normal, healthy models. In recent years, several transgenic rabbit models for different types of long QT syndromes (LQTS) with differences in the extent of impairment in repolarization reserve have been generated. These might be useful for screening/prediction of a drug's potential for long-QT-related proarrhythmia, particularly as different repolarizing cardiac ion channels are impaired in the different models. In this review, we summarize the electrophysiological characteristics of the available transgenic LQTS rabbit models, and the pharmacological proof-of-principle studies that have been performed with these models-highlighting the advantages and disadvantages of LQTS models for proarrhythmia research. In the end, we give an outlook on potential future directions and novel models.

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Mechanisms linking T‐wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome

Cited by 45 publications

References 65 publications

Determinants of early afterdepolarization properties in ventricular myocyte models

Determinants of early afterdepolarization properties in ventricular myocyte models

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

Transgenic Rabbit Models in Proarrhythmia Research

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