Arrhythmia Predisposition : Between Rare Disease Paradigms and Common Ion Channel Gene Variants

Cardiac side effects, such as QT prolongation or occurrence of Torsade de pointes (TdP), from widely used cardiac and non-cardiac drugs are still a major challenge for physicians. Recent advances in knowledge on the physiology of myocardial repolarization have made it clear that alterations of ion channel genes are associated with diverse in vitro effects that may tune normal repolarization to critical edges where ventricular arrhythmia occurs. The extent to which genetic factors (aside from “typical” ion channel gene mutations) are associated with susceptibility to TdP remains to be determined and is addressed in this review. Future research must: 1) identify all relevant genes for repolarization; 2) determine the extent to which the variability of the QT interval and of the response to action potential prolongation is genetically controlled; 3) investigate the role of functionally relevant single nucleotide polymorphisms/haplotype constellations to the contribution to repolarization; and 4) integrate identified genetic factors with other known factors for TdP risk, according to their relative importance, in a network algorithm for arrhythmogenesis. Gaining an understanding of the current genetic and genomic data of patients with drug-induced arrhythmia are the first steps to overcoming the hurdles associated with unexpected cardiac side effects of a variety of drugs.