Emerging therapeutic targets in the short QT syndrome |
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Authors: | Jules C Hancox Dominic G Whittaker Chunyun Du A Graham Stuart Henggui Zhang |
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Institution: | 1. School of Physiology, Pharmacology and Neuroscience, Medical Sciences Building, University Walk, Bristol, United Kingdom;2. Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom;3. Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom;4. School of Biomedical Sciences, University of Leeds, Leeds, United Kingdom;5. Cardiology, Bristol Heart Institute, University of Bristol, Bristol, United Kingdom |
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Abstract: | Introduction: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K+ channel inhibitors. A combination of K+ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K+ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8. |
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Keywords: | Atrial fibrillation atrial-selective CACNA1C CACNA2D1 CACNB2b hERG KCNH2 KCNJ2 KCNQ1 Kir2 1 short QT syndrome SLC4A3 sudden death ventricular fibrillation |
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