Genomics in Sudden Cardiac Death

Abstract

Abstract-Sudden cardiac death (SCD) remains a public health problem of major magnitude. Contrary to earlier expectations, and despite decreased overall cardiac mortality, SCD rates appear to be rising in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. With the exception of the implantable defibrillator, there are few effective approaches to SCD prevention and even fewer clues concerning patient phenotypes predisposed to life-threatening arrhythmias. Clinical variables such as ejection fraction predict mortality but are not sensitive enough to identify many high SCD risk patients. The predictive power of autonomic dysregulation and markers such as lipid levels, hypertension, diabetes, and smoking is quite low in subclinical heart disease, the population in which the majority of SCDs occur. This review addresses advances in genomic science applicable to the SCD public health problem in both rare and common forms of heart disease. These include novel bioinformatic approaches to both identify candidate genes/pathways and identify previously unknown functional genetic elements, as well as methods to comprehensively screen these elements. We also discuss the possibility of applying high-density genome-wide SNP analyses to examine genetic contributions to arrhythmia susceptibility in community-based, case-control studies of common forms of SCD. The development of novel strategies to identify contributors to susceptibility in common cardiac phenotypes is most likely to lead to new and relevant therapeutic targets for SCD.

Epidemiology of Sudden Cardiac Death: Clinical and Research Implications

“…It is likely that some proportion of these patients eventual develop structural heart disease if they survive their sudden cardiac arrest or this event is successfully prevented by an intervention (Figure 4). Besides the relatively rare genetic diseases such as long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia, patients with autopsynegative sudden cardiac death (no genetic abnormalities identified) may comprise a larger part of this subgroup than previously anticipated (9). In fact, while this may not be true in all populations, Behr and co-workers estimated the incidence to be as high as 11/100,000, in a nationwide epidemiological survey of unexpected sudden cardiac death in England, UK, among healthy individuals aged 16-64 years (14,15).…”

“…Thirdly, an accurate estimate of sudden cardiac death incidence requires prospective ascertainment of cases. Studies that have used retrospective death-certificate based methodology to identify cases of sudden cardiac death are likely to significantly overestimate sudden cardiac death incidence by as much as 200-300 percent (9). Therefore the US estimates published by the US Centers for Disease Control and Prevention (400-450,000 per year) (10) are likely to be a significant overestimate (5).…”

“…Also the incidence is likely to be lower if older age groups, who experience most sudden cardiac deaths were included in this analysis. Subjects with sudden unexplained death have also been termed as having idiopathic ventricular fibrillation or sudden arrhythmic death syndromes (6,9,10,15). It is possible that some proportion of these patients had heritable monogenic disorders such as the long QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (6,(20)(21)(22)(23)(24).…”

“…These studies provide evidence of a significant genetic contribution to sudden cardiac death and the next logical step is to identify specific gene defects that could be used for screening and identification of the high-risk patient. Significant advances are continuously being made in gene-finding technology, but some basic issues will need to be resolved before we can perform a search for candidate genes (9). Most patients that suffer sudden cardiac death have multiple associated co-morbidities such as coronary artery disease, DM, obesity and heart failure, each one of which may have genetic risk that could be unrelated to the genetic risk of sudden cardiac death (Figure 8).…”

Primary prevention with the ICD in clinical practice: not as straightforward as the guidelines suggest?

“…[37][38][39] Recent studies indicate that genetic factors are strongly involved in sudden death risk caused by common diseases, such as coronary artery disease. 40,41 It is to be expected that these developments will guide the way to the development of additional genetic risk markers helping us to safely withhold ICD therapy in patients at alleged risk, as well as identify future sudden death victims among patients with heart disease.…”