Genomics, heart failure and sudden cardiac death

Abstract

Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD rates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lower-risk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD.

Fig. 1

Mechanistic pathways through which genetic variations in susceptible individuals could affect mechanisms of initiation of arrhythmogenesis, propagation, and conduction of aberrant electrical impulses and transitions between potentially lethal ventricular tachyarrhythmias leading to SCD. Potential and documented elements of potential risk are depicted for three broad categories: (1) those that lead to atherosclerosis and overt coronary artery disease and the likelihood of myocardial infarction and ischemic arrhythmias; (2) those involved in electrogenesis and myocardial conduction pathways; and (3) those that may influence initiation of triggering events and perpetuation of an arrhythmia. Adapted from Spooner PM, Albert C, Benjamin EJ, Boineau R, Elston RC, et al (2001) Sudden cardiac death genes, and arrhythmogenesis: consideration of new population and mechanistic approaches from a National Heart, Lung, and Blood Institute workshop, part II. Circulation 103:2447–2452, by permission of the American Heart Association 2007