Carnitine deficiency induces a short QT syndrome

Roussel, Julien; Labarthe, François; Thireau, Jérôme; Ferro, Fabio; Farah, Charlotte; Roy, Jérôme; Horiuchi, Masahisa; Tardieu, M.; Lefort, Bruno; Benoist, J.-F.; Lacampagne, Alain; Richard, Sylvain; Fauconnier, Jérémy; Babuty, Dominique; Guennec, J.-Y. Le

doi:10.1016/j.hrthm.2015.07.027

Cited by 51 publications

(40 citation statements)

References 24 publications

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“…This is perhaps not surprising upon consideration of the molecular mechanisms involved, because loss-of-function mutations in the inward currents, which tips the net current in the outward direction, are observed in both SQTS and Brugada syndrome. Acquired causes are more common, including electrolyte abnormalities of hyperkalaemia or hypercalcaemia, myocardial ischaemia, acidosis or carnitine deficiency [35], [36]. Hyperthermia can also cause a shortened QT interval, as can drugs such as digitalis, acetylcholine, catecholamines or K ATP activators.…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological mechanisms of long and short QT syndromes

Tse

Chan

Keung

et al. 2017

IJC Heart & Vasculature

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The QT interval on the human electrocardiogram is normally in the order of 450 ms, and reflects the summated durations of action potential (AP) depolarization and repolarization of ventricular myocytes. Both prolongation and shortening in the QT interval have been associated with ventricular tachy-arrhythmias, which predispose affected individuals to sudden cardiac death. In this article, the molecular determinants of the AP duration and the causes of long and short QT syndromes (LQTS and SQTS) are explored. This is followed by a review of the recent advances on their arrhythmogenic mechanisms involving reentry and/or triggered activity based on experiments conducted in mouse models. Established and novel clinical risk markers based on the QT interval for the prediction of arrhythmic risk and cardiovascular mortality are presented here. It is concluded by a discussion on strategies for the future rational design of anti-arrhythmic agents.

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Section: Introductionmentioning

confidence: 99%

Electrophysiological mechanisms of long and short QT syndromes

Tse

Chan

Keung

et al. 2017

IJC Heart & Vasculature

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“…Hyperthermia can also cause a shortened QT interval, as can drugs such as digitalis, acetylcholine, catecholamines, or ATP‐sensitive K + channel activators. Short QT intervals have also been associated with epilepsy, particularly during the ictal and postictal states …”

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confidence: 99%

“…Short QT intervals have also been associated with epilepsy, particularly during the ictal and postictal states. [14][15][16] In spite of rapid advances in understanding the mechanisms and genetic bases of SQTS, much less is known about the appropriate treatments for SQTS patients. Because of the high risk of SCD, it has been recommended to implant ICD in patients with a strong family history of SCD and evidence of short QTc interval.…”

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confidence: 99%

Modeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes

El‐Battrawy

Liu

Cyganek

et al. 2018

JAHA

107

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BackgroundShort QT syndrome (SQTS), a disorder associated with characteristic ECG QT‐segment abbreviation, predisposes affected patients to sudden cardiac death. Despite some progress in assessing the organ‐level pathophysiology and genetic changes of the disorder, the understanding of the human cellular phenotype and discovering of an optimal therapy has lagged because of a lack of appropriate human cellular models of the disorder. The objective of this study was to establish a cellular model of SQTS using human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs).Methods and ResultsThis study recruited 1 patient with short QT syndrome type 1 carrying a mutation (N588K) in KCNH2 as well as 2 healthy control subjects. We generated hiPSCs from their skin fibroblasts, and differentiated hiPSCs into cardiomyocytes (hiPSC‐CMs) for physiological and pharmacological studies. The hiPSC‐CMs from the patient showed increased rapidly activating delayed rectifier potassium channel current (IK r) density and shortened action potential duration compared with healthy control hiPSC‐CMs. Furthermore, they demonstrated abnormal calcium transients and rhythmic activities. Carbachol increased the arrhythmic events in SQTS but not in control cells. Gene and protein expression profiling showed increased KCNH2 expression in SQTS cells. Quinidine but not sotalol or metoprolol prolonged the action potential duration and abolished arrhythmic activity induced by carbachol.ConclusionsPatient‐specific hiPSC‐CMs are able to recapitulate single‐cell phenotype features of SQTS and provide novel opportunities to further elucidate the cellular disease mechanism and test drug effects.

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“…Under treatment with L-carnitine, no further syncopal episodes occurred and her QT interval returned to normal. The association between PCD and short-QT syndrome was recently reported in a very few patients [17,18]. The relationship between PCD, a short QT syndrome and arrhythmias was studied by Roussel et al in a mouse model of carnitine deficiency induced by long-term subcutaneous perfusion of MET88 [17].…”

Section: Discussionmentioning

confidence: 96%