Differential Effects of the <i>β</i>‐Adrenoceptor Blockers Carvedilol and Metoprolol on SQT1‐ and SQT2‐Mutant Channels

Bódi, Ilona; Franke, Gerlind; Pantulu, Naga Deepa; Wu, Kezhong; Perez-Feliz, Stefanie; Bode, Christoph; Zehender, Manfred; Hausen, Axel zur; Brunner, Michael; Odening, Katja E.

doi:10.1111/jce.12178

Cited by 10 publications

(16 citation statements)

References 34 publications

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“…This finding highlighted the ability of iPSC‐CMs to recapitulate not only the phenotype but also the drug responses of the disorder. Furthermore, another study tested the effects of 2 widely used β‐blockers, carvedilol and metoprolol, on p.N588K‐HERG and p.V307L‐KCNQ1 channels expressed in mammalian cells . It was found that metoprolol is more potent than carvedilol in inhibiting both mutant K + channel currents.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, another study tested the effects of 2 widely used b-blockers, carvedilol and metoprolol, on p.N588K-HERG and p.V307L-KCNQ1 channels expressed in mammalian cells. 39 It was found that metoprolol is more potent than carvedilol in inhibiting both mutant K + channel currents. This suggests that metoprolol may be a new candidate drug for treating SQTS.…”

Section: Discussionmentioning

confidence: 99%

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

El‐Battrawy

Liu

Cyganek

et al. 2018

JAHA

117

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

El‐Battrawy

Liu

Cyganek

et al. 2018

JAHA

117

View full text Add to dashboard Cite

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“…10,11 This point is noteworthy, since such replications are not always observed. This point also deserves to be mentioned since Bodi et al 9 have used an interesting novel technology to record the cardiac potassium currents. They have used the Port-a-Patch technology (Nanion Technologies, Munich, Germany) 12 that does not depend on glass micropipettes but makes use of borosilicate microchips containing a micron-sized aperture that allows formation of stable "giga-seals" with cells and records in the whole-cell configuration.…”

Section: This Study In Jcementioning

confidence: 97%

“…The study by Bodi and colleagues, 9 published in this issue of the Journal of Cardiovascular Electrophysiology, investigated the effects of 2 widely used beta-blockers, carvedilol and metoprolol, on SQTS1 p.N588K-KCNH2 and SQTS2 p.V307L-KCNQ1 mutant potassium channels In vitro 20 In vitro 21 c.s. Carvedilol 9 In vitro Metroprolol 9 In vitro Nifekalant 21 c.s. Doxepin 22 In vitro Propafenone 20 In vitro Quinidine 7 In vitro 20 In vitro 23 In vitro/c.s.…”

Section: This Study In Jcementioning

confidence: 99%

“…16 Taken together, these results demonstrate that the pharmacology of β-blockers, and in particular their antiarrhythmic properties, may not only encompass their well-described β-adrenergic receptor antagonistic properties, 17 but also their cardiac ion channel-blocking features as well. This work by Bodi et al 9 adds a significant piece of information in the quest to more efficiently treat SQTS patients. However, one has to mention a few caveats in attempting to translate these results to clinical practice.…”

Section: This Study In Jcementioning

confidence: 99%

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β‐Blockers in Congenital Short‐QT Syndrome as Ion Channel Blockers

Abriel

Rougier

2013

Cardiovasc electrophysiol

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German Cardiac Society Working Group on Cellular Electrophysiology state-of-the-art paper: impact of molecular mechanisms on clinical arrhythmia management

et al. 2018

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Cardiac arrhythmias remain a common challenge and are associated with significant morbidity and mortality. Effective and safe rhythm control strategies are a primary, yet unmet need in everyday clinical practice. Despite significant pharmacological and technological advances, including catheter ablation and device-based therapies, the development of more effective alternatives is of significant interest to increase quality of life and to reduce symptom burden, hospitalizations and mortality. The mechanistic understanding of pathophysiological pathways underlying cardiac arrhythmias has advanced profoundly, opening up novel avenues for mechanism-based therapeutic approaches. Current management of arrhythmias, however, is primarily guided by clinical and demographic characteristics of patient groups as opposed to individual, patient-specific mechanisms and pheno-/genotyping. With this state-of-the-art paper, the Working Group on Cellular Electrophysiology of the German Cardiac Society aims to close the gap between advanced molecular understanding and clinical decision-making in cardiac electrophysiology. The significance of cellular electrophysiological findings for clinical arrhythmia management constitutes the main focus of this document. Clinically relevant knowledge of pathophysiological pathways of arrhythmias and cellular mechanisms of antiarrhythmic interventions are summarized. Furthermore, the specific molecular background for the initiation and perpetuation of atrial and ventricular arrhythmias and mechanism-based strategies for therapeutic interventions are highlighted. Current "hot topics" in atrial fibrillation are critically appraised. Finally, the establishment and support of cellular and translational electrophysiology programs in clinical rhythmology departments is called for to improve basic-science-guided patient management.

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Differential Effects of the β‐Adrenoceptor Blockers Carvedilol and Metoprolol on SQT1‐ and SQT2‐Mutant Channels

Cited by 10 publications

References 34 publications

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

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

β‐Blockers in Congenital Short‐QT Syndrome as Ion Channel Blockers

German Cardiac Society Working Group on Cellular Electrophysiology state-of-the-art paper: impact of molecular mechanisms on clinical arrhythmia management

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