Clínica y genética en el síndrome de QT largo

Medeiros-Domingo, Argelia; Iturralde-Torres, Pedro; Ackerman, Michael J.

doi:10.1157/13108280

Cited by 57 publications

(24 citation statements)

References 120 publications

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“…The clinical manifestations of LQTS can be variable, ranging from asymptomatic patients diagnosed through family screening, to SCD, syncope, convulsions, malignant ventricular arrhythmias, VF, and typically torsade de pointes [82,83,84,85,86,87]. SD usually occurs in healthy children and teenagers and in physically or emotionally stressful situations.…”

Section: Long Qt Syndromementioning

confidence: 99%

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Fernández-Falgueras

Sarquella-Brugada

Brugada

et al. 2017

Biology

113

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Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). This review focuses on cardiac channelopathies, which are characterized by lethal arrhythmias in the structurally normal heart, incomplete penetrance, and variable expressivity. Arrhythmias in these diseases result from pathogenic variants in genes encoding cardiac ion channels or associated proteins. Due to a lack of gross structural changes in the heart, channelopathies are often considered as potential causes of death in otherwise unexplained forensic autopsies. The asymptomatic nature of channelopathies is cause for concern in family members who may be carrying genetic risk factors, making the identification of these genetic factors of significant clinical importance.

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Section: Long Qt Syndromementioning

confidence: 99%

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Fernández-Falgueras

Sarquella-Brugada

Brugada

et al. 2017

Biology

113

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“…5 The estimated genotype-to-phenotype correlation of 60–75% depends on the location of the mutation on the ion channel. 6 In general, mutations in the pore-forming regions have been linked to more severe phenotypes, but large variations in penetrance are seen even among family members carrying the same mutation. 7 The incidence of LQTS is estimated to be 1:1000 individuals, 45% of whom are diagnosed with LQTS type 2 (LQT2).…”

Section: Introductionmentioning

confidence: 99%

Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation

Matsa

Rajamohan

Dick

et al. 2011

European Heart Journal

356

286

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AimsCongenital long QT syndromes (LQTSs) are associated with prolonged ventricular repolarization and sudden cardiac death. Limitations to existing clinical therapeutic management strategies prompted us to develop a novel human in vitro drug-evaluation system for LQTS type 2 (LQT2) that will complement the existing in vitro and in vivo models.Methods and resultsSkin fibroblasts from a patient with a KCNH2 G1681A mutation (encodes IKr potassium ion channel) were reprogrammed to human induced pluripotent stem cells (hiPSCs), which were subsequently differentiated to functional cardiomyocytes. Relative to controls (including the patient's mother), multi-electrode array and patch-clamp electrophysiology of LQT2–hiPSC cardiomyocytes showed prolonged field/action potential duration. When LQT2–hiPSC cardiomyocytes were exposed to E4031 (an IKr blocker), arrhythmias developed and these presented as early after depolarizations (EADs) in the action potentials. In contrast to control cardiomyocytes, LQT2–hiPSC cardiomyocytes also developed EADs when challenged with the clinically used stressor, isoprenaline. This effect was reversed by β-blockers, propranolol, and nadolol, the latter being used for the patient's therapy. Treatment of cardiomyocytes with experimental potassium channel enhancers, nicorandil and PD118057, caused action potential shortening and in some cases could abolish EADs. Notably, combined treatment with isoprenaline (enhancers/isoprenaline) caused EADs, but this effect was reversed by nadolol.ConclusionsFindings from this paper demonstrate that patient LQT2–hiPSC cardiomyocytes respond appropriately to clinically relevant pharmacology and will be a valuable human in vitro model for testing experimental drug combinations.

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“…guinea-pig myocytes, arterially perfused canine and rabbit left ventricular wedge preparations), as well as in vivo toxicity studies in monkeys, dogs, and mouse. 8 However, a particular limitation of the mouse is the reliance on different ion channels relative to human (mouse, I to , I K , slow1 , I K , slow2 , I SS ; human, I Ks , I Kr ) during the cardiac action potential. 9 Lack of predictive translation of such models towards human behaviour 4 has led to the development of a multitude of functionally relevant, humanized in vitro models for LQTS via use of induced pluripotency technologies.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

Matsa

Dixon

Medway

et al. 2013

European Heart Journal

111

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AimsLong-QT syndromes (LQTS) are mostly autosomal-dominant congenital disorders associated with a 1:1000 mutation frequency, cardiac arrest, and sudden death. We sought to use cardiomyocytes derived from human-induced pluripotency stem cells (hiPSCs) as an in vitro model to develop and evaluate gene-based therapeutics for the treatment of LQTS.Methods and resultsWe produced LQTS-type 2 (LQT2) hiPSC cardiomyocytes carrying a KCNH2 c.G1681A mutation in a IKr ion-channel pore, which caused impaired glycosylation and channel transport to cell surface. Allele-specific RNA interference (RNAi) directed towards the mutated KCNH2 mRNA caused knockdown, while leaving the wild-type mRNA unaffected. Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K+ currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations).ConclusionsThese findings provide in vitro evidence that allele-specific RNAi can rescue diseased phenotype in LQTS cardiomyocytes. This is a potentially novel route for the treatment of many autosomal-dominant-negative disorders, including those of the heart.

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Clínica y genética en el síndrome de QT largo

Cited by 57 publications

References 120 publications

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances

Drug evaluation in cardiomyocytes derived from human induced pluripotent stem cells carrying a long QT syndrome type 2 mutation

Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes

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