Genetic and Molecular Basis of Cardiac Arrhythmias

In recent years, the identification of gene defects in a vast array of monogenic disorders has revolutionized our understanding of the basic mechanisms underlying many disease processes. Mutations in cardiac ion channels, signaling molecules, and structural proteins have been identified as the basis of a wide range of inherited arrhythmia and cardiomyopathy syndromes, including the long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, short QT syndrome, Andersen-Tawil syndrome, progressive cardiac conduction disease, familial atrial fibrillation, and idiopathic ventricular fibrillation. We have also learned that marked clinical and genetic heterogeneity is almost universal across all these syndromes. Individuals carrying the same mutation may have varied disease manifestations, whereas several genes can be responsible for disease pathogenesis. Improved understanding of the pathophysiology of inherited arrhythmia syndromes has not only provided important insights into the underlying molecular and genetic mechanisms and identified novel therapeutic targets but also enabled consideration of more mechanism-based and personalized therapies.