Molecular Insights into the Short QT Syndrome.

Srikanth Perike,Mark Mccauley

doi:10.19102/icrm.2018.090302

Abstract

Short QT syndrome (SQTS) is a myocardial conduction disorder characterized by a short QT interval on electrocardiogram and predisposition to familial atrial fibrillation and/or sudden cardiac death. Genetic SQTS is primarily caused by one or more cardiac ion channelopathies, in which either impaired depolarization currents, or enhanced repolarization currents, shorten cardiac action potential duration. Given that QT interval duration is not always predictive of arrhythmia burden and risk of death in SQTS, there is a need to understand the molecular mechanisms of the condition to improve risk prognostication and potential pharmacologic treatment. In the last decade, several computational advances and in vitro preclinical studies have provided insight into the molecular mechanisms underlying congenital SQTS. In this review, we discuss recent findings in SQTS molecular mechanisms and correlate these advances with clinical guidelines for SQTS diagnosis and treatment.

Highlights

Short QT syndrome (SQTS) is a genetic cardiac channelopathy with a predisposition to life-threatening atrial and ventricular arrhythmias
Despite patients presenting with normal cardiac anatomy, SQTS is characterized on electrocardiogram (ECG) by short QT intervals, representing cardiac
The group found that an N588K-hERG mutation in SQTS 1 (SQT1) initiates and maintains ventricular reentry, which increases the generation of reentrant spiral waves and stabilizes scroll waves in anatomical three-dimensional (3D) ventricular tissue.[20]

Summary

Introduction

Short QT syndrome (SQTS) is a genetic cardiac channelopathy with a predisposition to life-threatening atrial and ventricular arrhythmias. The group found that an N588K-hERG mutation in SQT1 initiates and maintains ventricular reentry, which increases the generation of reentrant spiral waves and stabilizes scroll waves in anatomical three-dimensional (3D) ventricular tissue.[20] On the other hand, in SQT3, the gain-of-function KIR 2.1 D172N mutation increases IK1 ionic currents and increases arrhythmia risk due to enhanced tissue vulnerability, a reduced ventricular effective refractory period, and altered membrane excitability.[21] Rice et al developed a related myocyte contraction model primarily based on a cross-bridge cycling model of cardiac muscle contraction.[22] This model simulates a wide variety of experimental cardiac muscle characteristics such as steady-state force-sarcomere length, force-calcium, and sarcomere length-calcium relations.[22] At present, there is little information available regarding impaired cardiac contractile functions in SQTS patients To address this limitation, Adeniran et al coupled cardiac muscle contraction and ventricular cell models; SQTS mutations were simulated at the single-cell level and evaluated with respect to the potential electromechanical consequences.[23] They built experimental cellular data into predictions for mechanical activity in two-dimensional and 3D human ventricular tissue models, and these geometrical changes were incorporated into the electrophysiological computations.[24] They found that shortening of the action potential in SQTS is associated with reduced ventricular mechanical function.

Short QT syndrome in experimental models

Diagnosis of short QT syndrome in human patients

Short QT syndrome pharmacotherapy

Level of Evidence C

Level of Other Studies Evidence Supporting

Conclusions