Clinical and Genetic Studies in Inherited Arrhythmia Syndromes

Abstract

Inherited arrhythmia syndromes, or “ion channelopathies”, is a term encompassing a number of different diseases including long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), short QT syndrome (SQTS) and idiopathic ventricular fibrillation (IVF). In inherited arrhythmia syndromes, ventricular arrhythmias originate due to abnormalities with intracellular ion channels, predominantly involving potassium, sodium and calcium handling, due to genetic mutations in genes encoding for channel proteins. The cellular abnormalities in these conditions are typically associated with a structurally normal heart with no evidence of disease macroscopically and the autopsy in the deceased is typically negative. Inherited arrhythmia syndromes are an important cause for sudden cardiac death in the young. There is increasing evidence of genetic and phenotypic heterogeneity amongst inherited arrhythmia syndromes. The yield for genetic testing in inherited arrhythmia syndromes remains at most 60-75% despite significant advances in technology. New genetic testing modalities will provide a significant improvement in the efficacy of genetic testing amongst individuals and families with inherited arrhythmia syndromes. Inherited arrhythmia syndromes can lead to serious cardiac complications including sudden cardiac death. It is possible that there are unidentified clinical, genetic or environmental factors which could predispose patients to higher risk of arrhythmia, including widely available caffeinated energy drinks. The work of this PhD thesis highlights the three critical domains of genetics, risk stratification and triggers for arrhythmia when assessing and managing inherited arrhythmia syndromes. There are a number of unique and important aspects when managing patients and families with inherited arrhythmia syndromes. This includes genetic evaluation, diagnosis, risk stratification, and identification of triggers. The research in this PhD thesis directly addresses a number of these issues and has translational clinical implications for patients and families with inherited arrhythmia syndromes. The ultimate goal of this research is improving assessment and management of these patients and families and prevention of sudden cardiac death.