Learning from studying very rare cardiac conditions: the example of short QT syndrome

Abstract

Background: Some congenital heart conditions are very rare. In a climate of limited resources, a viewpoint could be advanced that identifying diagnostic criteria for such conditions and, through empiricism, effective treatments should suffice and that extensive mechanistic research is unnecessary. Taking the rare but dangerous short QT syndrome (SQTS) as an example, this article makes the case for the imperative to study such rare conditions, highlighting that this yields substantial and sometimes unanticipated benefits. Genetic forms of SQTS are rare, but the condition may be under-diagnosed and carries a risk of sudden death. Genotyping of SQTS patients has led to identification of clear ion channel/transporter culprits in < 30% of cases, highlighting a role for as yet unidentified modulators of repolarization. For example, recent exome sequencing in SQTS has identified SLC4A3 as a novel modifier of ventricular repolarization. The need to distinguish "healthy" from "unhealthy" short QT intervals has led to a search for additional markers of arrhythmia risk. Some overlap may exist between SQTS, Brugada Syndrome, early repolarization and sinus bradycardia. Genotype-phenotype studies have led to identification of arrhythmia substrates and both realistic and theoretical pharmacological approaches for particular forms of SQTS. In turn this has increased understanding of underlying cardiac ion channels. In silico and pharmacological data have highlighted risks with abbreviation of refractoriness accompanied by local dispersion of repolarization, and this urges caution with the deployment of K + channel activation as a novel antiarrhythmic approach. The association between abbreviated QT c intervals and primary carnitine deficiency, particularly in patients with concomitant cardiomyopathy illustrates a link between metabolism and electrogenesis, in which the correct identification of causation could, in some cases, lead to dietary intervention that may obviate the need for antiarrhythmic or heart failure drugs. Conclusions: As illustrated here for the SQTS, the detailed study of rare disorders is both directly beneficial for the treatment/management of affected patients and for increasing the understanding of associated underlying cardiac physiology and pharmacology. The pursuit of underlying gene mutations can lead to unanticipated new links between particular genes and cardiac electrophysiology, opening new avenues for research and potential therapeutic intervention.

An Update on the Structure of hERG

“…Additionally, the deactivation kinetics of the channel allow I Kr to influence diastolic depolarization of cardiac pacemaker cells (Ono and Ito, 1995;Mitcheson and Hancox, 1999). Inherited mutations in hERG that attenuate inactivation ("gain of function") result in premature repolarization and shortening of the QT interval (short QT syndrome; SQTS) (Campuzano et al, 2019;Hancox et al, 2019). Loss of function mutations, many (but not all) of which arise from disrupted trafficking of hERG to the cell surface (Anderson et al, 2014), can result in inefficient repolarization and thus an elongation of the QT interval (long QT syndrome; LQTS).…”

In Silico Investigation of CACNA2D1 S755T Mutation Associated With Short QT Syndrome

“…On the other hand, our simulation results clearly suggested that the S755T mutation resulted in a marked decrease in the minimal substrate size required for initiating and maintaining reentry arrhythmias. This highlights that both temporal and spatial vulnerability need to be evaluated to avoid biased conclusions and to understand the overall effects by mutations [31]. In the case of SQTS6, the increased spatial vulnerability in the mutation condition dominated, and eventually contributed to higher risks of developing arrhythmias in SQTS patients.…”

Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome

“…A list of genes and associated mutations that have been linked to congenital SQTS. (The table is modified from [13] and [17], with additional mutations reported in [27][28][29][30]. ♂, inherited from father; ♀, inherited from mother; * truncation mutant.…”