• Ventricular Fibrillation
• Genetic Association Studies

Sudden cardiac arrest (SCA) in young and otherwise healthy individuals remains an intriguing occurrence that warrants in-depth evaluation. In the past decades, the origin of these cardiac arrests has finally been elucidated in many SCA victims. For example, long-QT syndrome (LQTS), Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) were found to coincide with these cases.1 2 CPVT is the subject of the paper by Shimamoto and colleagues from multiple centres in Japan.3

CPVT is one of the rare arrhythmia syndromes, its prevalence is estimated to be approximately 1 in 10 000 individuals, and it associates with bidirectional and polymorphic ventricular tachycardia (VT), ventricular fibrillation (VF), and subsequent syncope and SCA, most often occurring in children, adolescents, and young adults. The hallmark of CPVT is the adrenergic triggering of these arrhythmias and associated symptoms in otherwise healthy individuals without overt structural heart disease and with a normal baseline ECG. Importantly, like other arrhythmia syndromes, CPVT may be inheritable, and may thus affect whole families with a propensity to SCA. In CPVT, genetic testing has a very high yield, and in most indisputable CPVT cases, a pathogenic or likely pathogenic variant in either the cardiac ryanodine receptor gene (RYR2) is identified, or, in less cases, a (usually homozygous) pathogenic or likely pathogenic variant in the cardiac calsequestrin gene (CASQ2). A critical similarity between these two genes and their resultant proteins is that both are pivotal for calcium homeostasis in the cardiac sarcoplasmatic reticulum. The unifying pathophysiological mechanism is the occurrence of spontaneous diastolic calcium release from the ventricular sarcoplasmatic reticulum, resulting in a propensity for delayed after-depolarisations and triggering of polymorphic ventricular ectopy and VT/VF, especially during adrenergic circumstances.1 Although several other genes related to CPVT have been uncovered, the absence of a genetic underpinning of a proposed CPVT …