Emerging therapeutic targets in the short QT syndrome

Jules C Hancox*, Dominic G Whittaker, Chunyun Du, A Graham Stuart, Henggui Zhang

*Corresponding author for this work

Research output: Contribution to journalReview article (Academic Journal)

15 Citations (Scopus)
189 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)439-451
Number of pages13
JournalExpert Opinion on Therapeutic Targets
Volume22
Issue number5
Early online date8 May 2018
DOIs
Publication statusPublished - May 2018

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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