Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility

Odening, Katja E.; Bódi, Ilona; Franke, Gerlind; Rieke, Raphaela; Medeiros, Anna Ryan de; Perez-Feliz, Stefanie; Fürniss, Hannah E; Mettke, Lea; Michaelides, Konstantin; Lang, Corinna N.; Steinfurt, Johannes; Pantulu, Naga Deepa; Ziupa, David; Menza, Marius; Zehender, Manfred; Bugger, Heiko; Peyronnet, Rémi; Behrends, Jan C.; Doleschall, Zoltán; Hausen, Axel zur; Bode, Christoph; Jolivet, Geneviève; Brunner, Michael

doi:10.1093/eurheartj/ehy761

Cited by 36 publications

(48 citation statements)

References 14 publications

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“…SQT1 transgenic animals exhibited shortened QT c intervals, altered QT c -rate adaptation and abbreviated ventricular and atrial APs and ERP. Alterations in T wave height were not reported [107]. Increased regional AP dispersion was seen in SQT1 rabbits (consistent with reported localised alterations in δV seen in silico [67]).…”

Section: Insights From Preclinical Sqts Studies Into Arrhythmia Substsupporting

confidence: 85%

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Learning from studying very rare cardiac conditions: the example of short QT syndrome

Hancox

Whittaker

Zhang

et al. 2019

J Congenit Heart Dis

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Background: Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous short QT syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in < 30% of cases, highlighting a role for as yet unidentified modulators of repolarization. For example, recent exome sequencing in SQTS has identified SLC4A3 as a novel modifier of ventricular repolarization. The need to distinguish "healthy" from "unhealthy" short QT intervals has led to a search for additional markers of arrhythmia risk. Some overlap may exist between SQTS, Brugada Syndrome, early repolarization and sinus bradycardia. Genotype-phenotype studies have led to identification of arrhythmia substrates and both realistic and theoretical pharmacological approaches for particular forms of SQTS. In turn this has increased understanding of underlying cardiac ion channels. In silico and pharmacological data have highlighted risks with abbreviation of refractoriness accompanied by local dispersion of repolarization, and this urges caution with the deployment of K + channel activation as a novel antiarrhythmic approach. The association between abbreviated QT c intervals and primary carnitine deficiency, particularly in patients with concomitant cardiomyopathy illustrates a link between metabolism and electrogenesis, in which the correct identification of causation could, in some cases, lead to dietary intervention that may obviate the need for antiarrhythmic or heart failure drugs. Conclusions: As illustrated here for the SQTS, the detailed study of rare disorders is both directly beneficial for the treatment/management of affected patients and for increasing the understanding of associated underlying cardiac physiology and pharmacology. The pursuit of underlying gene mutations can lead to unanticipated new links between particular genes and cardiac electrophysiology, opening new avenues for research and potential therapeutic intervention.

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Section: Insights From Preclinical Sqts Studies Into Arrhythmia Substsupporting

confidence: 85%

“…Very recently, a transgenic rabbit model of SQT1 has been reported in which the human N588K hERG mutation has been expressed [107]. SQT1 transgenic animals exhibited shortened QT c intervals, altered QT c -rate adaptation and abbreviated ventricular and atrial APs and ERP.…”

Section: Insights From Preclinical Sqts Studies Into Arrhythmia Substmentioning

confidence: 99%

Learning from studying very rare cardiac conditions: the example of short QT syndrome

Hancox

Whittaker

Zhang

et al. 2019

J Congenit Heart Dis

View full text Add to dashboard Cite

show abstract

“…17 While the I Ca,L decrease and I Ks increase may contribute to the shorter QT and action potentials, the I K1 decrease may partially reverse the SQT1 phenotype. However, it must be noted that the observed I K1 decrease and change in I K1 reversal potential were not associated with alterations in resting membrane potential, 12 making potential effects on AP repolarization less likely. The authors also report increased mechanical dispersion and alterations in diastolic relaxation in N588K rabbits (in the absence of cardiac fibrosis), demonstrating the complexities of ion channel dysfunction on the whole-heart level.…”

mentioning

confidence: 84%

“…Indeed, the authors elegantly demonstrate the strength of using rabbits to mimic SQT1: N588K rabbits display similar in vivo and ex vivo features to human mutation carriers, including short QT and T wave alterations, reduced QT adaptation to heart rate, shortened atrial and ventricular refractory periods, and increased atrial and ventricular arrhythmia susceptibility. 12 Quinidine, which was shown to correct the QT interval and effectively suppress ventricular arrhythmias in SQT1 patients, 4,13 reversed AP and QT shortening in N588K rabbits, substantiating its anti-arrhythmic potential. Cellular measurements demonstrated that N588K rabbits reproduce the augmented I Kr amplitude and AP shortening previously seen in cell expression systems, computer simulations, and hiPSC-CMs.…”

mentioning

confidence: 84%

“…In their study in the current issue of European Heart Journal, Odening and colleagues present the generation and first assessment of rabbits overexpressing human HERG-N588K in cardiomyocytes. 12 Benefits of rabbits include their relative anatomical, electrical, and mechanical similarities to the human hearts. Indeed, the authors elegantly demonstrate the strength of using rabbits to mimic SQT1: N588K rabbits display similar in vivo and ex vivo features to human mutation carriers, including short QT and T wave alterations, reduced QT adaptation to heart rate, shortened atrial and ventricular refractory periods, and increased atrial and ventricular arrhythmia susceptibility.…”

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confidence: 99%

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