Preclinical short QT syndrome models: Studying the phenotype and drug-screening

Abstract

Cardiovascular diseases are the main cause of sudden cardiac death (SCD) in developed and developing countries. Inherited cardiac channelopathies are linked to 5-10% of SCDs, mainly in the young. Short QT syndrome (SQTS) is a rare inherited channelopathy, which leads to both atrial and ventricular tachyarrhythmias, syncope, and even SCD. International European Society of Cardiology guidelines include as diagnostic criteria: (i) QTc ≤ 340 ms on electrocardiogram, (ii) QTc ≤ 360 ms plus one of the follwing, an affected short QT syndrome pathogenic gene mutation, or family history of SQTS, or aborted cardiac arrest, or family history of cardiac arrest in the young. However, further evaluation of the QTc ranges seems to be required, which might be possible by assembling large short QT cohorts and considering genetic screening of the newly described pathogenic mutations. Since the mechanisms underlying the arrhythmogenesis of SQTS is unclear, optimal therapy for SQTS is still lacking. The disease is rare, unclear genotype-phenotype correlations exist in a bevy of cases and the absence of an international short QT registry limit studies on the pathophysiological mechanisms of arrhythmogenesis and therapy of SQTS. This leads to the necessity of experimental models or platforms for studying SQTS. Here, we focus on reviewing preclinical SQTS models and platforms such as animal models, heterologous expression systems, human-induced pluripotent stem cell-derived cardiomyocyte models and computer models as well as three-dimensional engineered heart tissues. We discuss their usefulness for SQTS studies to examine genotype-phenotype associations, uncover disease mechanisms and test drugs. These models might be helpful for providing novel insights into the exact pathophysiological mechanisms of this channelopathy and may offer opportunities to improve the diagnosis and treatment of patients with SQT syndrome.