New Therapies Based on New Insights in Inherited Arrhythmia Syndromes

Abstract

Inherited arrhythmia syndromes are caused by mutations in genes generally encoding ion channel (subunits). This knowledge has led to a recent increase in the therapeutic armentarium for these disease entities, frequently aimed to directly target the molecular defect. Indeed, the genetic basis has become the basis for therapy choices in a number of disease entities. In the long QT syndrome the genetic substrate determines the risk, age window and triggers of cardiac events. Therapeutic decisions as to life style measurements to be taken (among others avoiding specific triggers) and the age of start treatment are genotype-dependent. Also the pharmacological therapy bears gene-specific elements. In catecholaminergic Ventricular tachycardia (CPVT) mutations in the Ryanodine receptor gene (RyR2) are responsible for a leaky RyR protein. Studies in isolated bilayers containing RyR2 receptors indicated that flecainide blocks the RyR protein effectively. Subsequent studies in a CASQ2 knockout mouse model, mimicking human CPVT, shows a strong antiarrhythmic effect of flecainide. Finally, also in CPVT patients, with either a pathogenic RyR2 or CASQ2 mutation and not suffciemtly protected by b-blockers, flecainide demonstrated a potent antiarrhythmic effect. This development clearly underscores the importance of unravelling the genetic basis of these arrhythmia syndromes. It is hoped and believed that patients with far more prevalent arrhythmias will also benefit from this exciting development.