Emerging therapeutic targets in the short QT syndrome

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.

KEYWORDS:

• Atrial fibrillation
• atrial-selective
• CACNA1C
• CACNA2D1 CACNB2b hERG
• KCNH2
• KCNJ2
• KCNQ1
• Kir2.1
• short QT syndrome
• SLC4A3
• sudden death
• ventricular fibrillation

Article highlights

• The short QT syndrome (SQTS) is a rare condition associated with atrial and ventricular arrhythmias and a risk of sudden death. Implantable devices and antiarrhythmic pharmacology are used to treat the syndrome.

• There are 8 successfully genotyped variants, involving gain-of-function mutations to K⁺ ion channel genes (SQT1-3) or loss-of-function mutations to Ca²⁺ channel subunit genes (SQT4-6), to a Na⁺ channel gene (SQT7) and to an anion exchanger (SQT8).

• Information from patients and in vitro and in silico experiments indicates important roles for abbreviated refractoriness, dispersion of repolarisation and a shortened wavelength for re-entry in arrhythmia substrates in the SQTS.

• A combination K⁺ current inhibition during the action potential plateau, with sodium channel inhibition, collectively resulting in delaying repolarisation and refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry in the SQTS. In vitro and in silico data point to the feasibility of genotype-specific pharmacology, though selective agents against each known target are not yet in clinical use.

• Approximately three-quarters of genotyped cases have not yielded mutations in ion channel target genes. Exome or genome sequencing may thus be warranted to identify the underlying culprits in SQTS cases where targeted ion genotyping is unsuccessful. This is likely to reveal new modulators of repolarisation and potentially new intervention points to target in the SQTS.

This box summarizes key points contained in the article.

Acknowledgments

JCH also acknowledges a University of Bristol Research Fellowship.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

JH received research funding from the British Heart Foundation (FS/14/5/30533, PG/15/106/31915) and SADS UK. HZ received research funding from the British Heart Foundation (FS/14/5/30533). GS receives research funding from SADS UK.