The Quest for the Identification of Genetic Variants in Unexplained Cardiac Arrest and Idiopathic Ventricular Fibrillation

In this issue of PLOS Genetics, Nakano and colleagues from 13 centers in Japan report a candidate gene analysis in unrelated individuals with an unexplained cardiac arrest (UCA) [1]. Cardiac arrest is most often caused by a cardiac arrhythmia named ventricular fibrillation, which, if left untreated, will be lethal within minutes. Moreover, ventricular fibrillation is often the first expression of the disease, implying that patients die suddenly without any warning. It is thus understandable that cardiac arrest is an extremely difficult phenotype, as its victims will not be presymptomatically treated and the vast majority (,85%) will not survive the event. In those few who do survive, the sequelae to cardiac ischemia in coronary artery disease appear to be the predominant cause of the cardiac arrest (i.e., the direct pro-arrhythmic effects of ischemia as well as the indirect pro-arrhythmic effects of successive cardiac remodeling and fibrosis). Several genetic variants that predispose to cardiac arrest in the setting of cardiac ischemia have already been documented [2,3]. In the absence of coronary artery disease or other clear causes (e.g., myocarditis), structural heart disease (e.g., hypertrophic cardiomyopathy) and channelopathies (e.g., long QT syndrome, Brugada syndrome) are now recognized as the most prevalent causes of cardiac arrest, especially in younger individuals [4]. Nevertheless, in some individuals (,5%) the cause of the cardiac arrest remains unexplained: these unexplained cases comprise different, yet unidentified, pathologies (Figure 1). Importantly, UCA appears to have a heritable component in several patients [5], which may thus set their whole family at risk for premature sudden death. A number of UCA cases with documented ventricular fibrillation can be defined as having idiopathic ventricular fibrillation (IVF). This more strict definition is reserved for those patients who survive ventricular fibrillation and in whom all extensive evaluations return normal. The first, and only, breakthrough in defining the genetic underpinnings of IVF was made in 2009 in The Netherlands [5]. Genome-wide haplotype analysis in several related IVF families revealed a conserved haplotype in the DPP6 gene, putatively involved in one of the main cardiac potassium currents: the transient outward current. This discovery has already led to the identification and presymptomatic treatment of dozens of patients at risk for IVF. However, mutations in the DPP6 gene have not yet been implicated in IVF/UCA outside The Netherlands. This continuing lacuna hampers both treatment and cascade screening for the identification and treatment of affected family members and results in both undertreatment and over-treatment with substantial collateral damage (including mortality). Hence, UCA is both an uncommon and a difficult phenotype, and it represents a bothersome black box in current cardiology. Further efforts to delineate its underlying genetic profile will help us to understand this entity and, importantly, will hopefully guide us to the identification of as yet pre-symptomatic but similarly affected family members.