Congenital short QT syndrome: Landmarks of the newest arrhythmogenic cardiac channelopathy

Pérez‐Riera, Andrés Ricardo; Paixão-Almeida, Adail; Barbosa‐Barros, Raimundo; Yanowitz, Frank G.; Baranchuk, Adrián; Dubner, Sérgio; Chagas, Antônio Carlos Palandri

doi:10.5603/cj.a2013.0052

Cited by 21 publications

(14 citation statements)

References 30 publications

(27 reference statements)

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“…Currently, 3 genes encoding potassium channels, KCNH2 (for SQTS1), KCNQ1 (for SQTS2), KCNJ2 (for SQTS3), and 3 more genes encoding calcium channels, CACNA1C (for SQTS4), CACNB2 (for SQTS5), and CACNA2D1 (for SQTS6) are identified and linked to SQTS. The genetic analysis, however, does not identify any genetic cause in up to 40% of SQTS cases . Additionally, overlap syndrome, SQTS with Brugada syndrome, has been reported .…”

mentioning

confidence: 98%

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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confidence: 98%

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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“…Furthermore to determine the probability of that diagnosis we used probability scoring proposed by Gollob. Gollob et al [11] published a systematic review based on a comprehensive analysis in order to develop diagnostic criteria for congenital SQTS to facilitate clinical evaluation of suspected cases [12]. The score was established on the basis of clinical, electrocardiographic, and genetic criteria as follows:…”

Section: Discussionmentioning

confidence: 99%

“…Crucially and in opposite to the more common long QT syndrome, very short and uniform QT/QTc intervals (QTc interval ≤330 ms with the exception of the calcium-dependent variants 4 and 5) are observed. Moreover, some minor ECG abnormalities, such as: -absent or minimal ST segments, -interval from J point to T wave peak (Jp-Tp) measured in the precordial lead with the T wave of greatest amplitude <120 ms, -possible tall T waves with narrow base similar to the T wave found in hyperkalemia ("desert tent T waves"), -early repolarization pattern [5], -prolongation of T peak -T end interval, -presence of prominent U waves, -and very frequent paroxysmal AF [4].…”

Section: Introductionmentioning

confidence: 99%

31-year old man with Short QT syndrome

Wiśniowska‐Śmiałek

Rubiś

Holcman

et al. 2016

Journal of Rare Cardiovascular Diseases

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Short QT (SQTS) syndrome is a rare inherited autosomal dominant cardiac channelopathy associated with malignant ventricular and atrial arrhythmias. It is the severest form of the major channelopathies, with cardiac arrest or sudden cardiac death (SCD) as the most common presentation. We report a case of a young patient in whom ventricular fibrillation was the first manifestation of the disease. JRCD 2016; 2 (7): 1-1

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“…Congenital SQT can either be caused to excessive repolarization capacity (SQT1-3), or due to decreased depolarization capacity (SQT4-7), and is associated with high risk for sudden cardiac death and therefore implantable cardioverter-defibrillator (ICD) implantation is indicated [8, 9]. However, pharmacotherapy may be beneficial in patients that are unsuitable for ICD therapy (e.g.…”

Section: Introductionmentioning

confidence: 99%

PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function KIR2.1 channels, but increases channel protein expression

et al. 2017

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BackgroundThe inward rectifier potassium current IK1 contributes to a stable resting membrane potential and phase 3 repolarization of the cardiac action potential. KCNJ2 gain-of-function mutations V93I and D172N associate with increased IK1, short QT syndrome type 3 and congenital atrial fibrillation. Pentamidine-Analogue 6 (PA-6) is an efficient (IC50 = 14 nM with inside-out patch clamp methodology) and specific IK1 inhibitor that interacts with the cytoplasmic pore region of the KIR2.1 ion channel, encoded by KCNJ2. At 10 μM, PA-6 increases wild-type (WT) KIR2.1 expression in HEK293T cells upon chronic treatment. We hypothesized that PA-6 will interact with and inhibit V93I and D172N KIR2.1 channels, whereas impact on channel expression at the plasma membrane requires higher concentrations.MethodsMolecular modelling was performed with the human KIR2.1 closed state homology model using FlexX. WT and mutant KIR2.1 channels were expressed in HEK293 cells. Patch-clamp single cell electrophysiology measurements were performed in the whole cell and inside-out mode of the patch clamp method. KIR2.1 expression level and localization were determined by western blot analysis and immunofluorescence microscopy, respectively.ResultsPA-6 docking in the V93I/D172N double mutant homology model of KIR2.1 demonstrated that mutations and drug-binding site are >30 Å apart. PA-6 inhibited WT and V93I outward currents with similar potency (IC50 = 35.5 and 43.6 nM at +50 mV for WT and V93I), whereas D172N currents were less sensitive (IC50 = 128.9 nM at +50 mV) using inside-out patch-clamp electrophysiology. In whole cell mode, 1 μM of PA-6 inhibited outward IK1 at −50 mV by 28 ± 36%, 18 ± 20% and 10 ± 6%, for WT, V93I and D172N channels respectively. Western blot analysis demonstrated that PA-6 (5 μM, 24 h) increased KIR2.1 expression levels of WT (6.3 ± 1.5 fold), and V93I (3.9 ± 0.9) and D172N (4.8 ± 2.0) mutants. Immunofluorescent microscopy demonstrated dose-dependent intracellular KIR2.1 accumulation following chronic PA-6 application (24 h, 1 and 5 μM).Conclusions1) KCNJ2 gain-of-function mutations V93I and D172N in the KIR2.1 ion channel do not impair PA-6 mediated inhibition of IK1, 2) PA-6 elevates KIR2.1 protein expression and induces intracellular KIR2.1 accumulation, 3) PA-6 is a strong candidate for further preclinical evaluation in treatment of congenital SQT3 and AF.

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Congenital short QT syndrome: Landmarks of the newest arrhythmogenic cardiac channelopathy

Abstract: Congenital or familial short QT syndrome is a genetically heterogeneous cardiac channelopathy without structural heart disease that has a dominant autosomal or sporadic pattern of trans- (Cardiol J 2013; 20, 5: 464-471)

Cited by 21 publications

References 30 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

31-year old man with Short QT syndrome

PA-6 inhibits inward rectifier currents carried by V93I and D172N gain-of-function KIR2.1 channels, but increases channel protein expression

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