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Genetics in sudden cardiac death

ESC Congress 2010

This was a very interesting session which was co-chaired by William J. McKenna (London, UK) and myself. It addressed the role of gene variants in modulating surrogate markers as well as the risk of sudden cardiac death itself in the context of primary arrhythmia syndromes, of ischemia, and in victims of out-of-hospital sudden death.

Sudden cardiac death (SCD) accounts for 15-20% of all natural deaths in adults in the US and Western Europe, and up to 50% of all cardiovascular deaths. Ventricular fibrillation (VF) is the most common underlying cardiac arrhythmia. It arises through multiple mechanisms, depending on the underlying cardiac pathology. Considerable progress has been made in the understanding of the genetic, molecular and electrophysiological basis of SCD in the last decade, in particular in the uncommon (monogenic) familial arrhythmia syndromes. However, the overwhelming majority (~80%) of SCDs in adults are caused by myocardial ischemia or acute myocardial infarction (MI).

Stefan Kääb (Munich, Germany) presented a talk on genetic variants modulating electrocardiogram markers as surrogates for sudden cardiac death risk. He emphasized the need for improved risk stratification and a better understanding of systems biology of arrhythmias leading to SCD. In the context of state of the art genotyping technology, ECG-signatures may be looked at as quantitative traits that contain heritable components and serve as biomarkers for cardiac arrhythmias. Genome wide association studies have helped to identify novel genetic markers that modulate major ECG markers such as heart rate, PR, QRS and QT-interval and are pointing research towards more functional studies to elucidate pathophysiology and pathways (Milan et al. Heart Rhythm 2010;7:1141-48). Linking information on genetic contribution to ECG markers with genetic contribution to SCD may improve risk stratification in the future.

Peter Schwartz (Pavia, IT) presented the state of the art on the search for modifier genes for clinical severity in the primary arrhythmia syndromes focusing on the Long QT Syndrome (LQTS) as the only one with adequate data. He provided conceptual insights on methodological aspects and on legitimate clinical implications. He also presented the first study (Crotti et al, Circulation 2009;120:1657-63) which provided solid evidence for modifier genes in LQTS. This study, based on 500 members of 25 South African families including 205 carriers of the same mutation causing LQT1, demonstrated that the presence of common genetic variants of the NOS1AP gene can double the risk of sudden cardiac death. This opens the road for a more refined risk stratification based on the synergistic role of disease-causing mutations and common polymorphisms.

Arthur Wilde (Amsterdam, NL) addressed the role of genetic susceptibility in acute ischemia. Indeed, a familial history of sudden death is a strong predictor of ventricular fibrillation in the setting of a first myocardial infarction. A genome wide association study in the AGNES population (patients with first MI complicated by ventricular fibrillation (cases) vs uncomplicated first MI) has identified a novel locus close to the gene encoding the CAR (coxackie adenovirus receptor gene) on chr21q21 (Bezzina et al, Nature Genetics 2010;42(8):688). Further studies are underway to get insight into the pathophysiological mechanisms underlying this interesting, rather unexpected link.

Xavier Jouven (Paris, FR) and his group initially described the genetic susceptibility for sudden cardiac death ten years ago in the general population, which has been confirmed in patients hospitalized for ischemic heart disease. Since then, a candidate gene approach has been used to test the different mutations that have already been described in rare diseases, both in patients after survived cardiac arrest as well as in the general population. Since the vast majority of subjects who die suddenly do not reach hospital, and patients hospitalized after out-of-hospital cardiac arrest represent only a small sample of sudden cardiac death patients, genome-wide association studies (GWAS) should be done in all sudden cardiac death cases.

Different studies have been launched of which the biggest ones (> 1000 subjects recruited) are CABS (Cardiac Arrest Blood Study) in Seattle, ORSUD in Oregon, and CARTAGENE in Europe. CARTAGENE (cardiac arrest and genetic) collected blood from mobile units in 13 areas including the main cities in France. 1200 sudden death cases have been recruited to date and the genetic analysis is performed in Munich, Germany. These different cohort studies and others collaborate within the CHARGE consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology; to collect many more cases due to a high heterogeneity of the phenotype.

Chairmen's comment

The recognition by the speakers in this session that a family history of sudden death was a strongly associated risk factor underscores the search for genetic determinants of SCD. Successful research is traditionally hypothesis-driven. The use of genome wide association studies to delineate genetic markers for sudden death, however, has been successful in identifying pathways to explore new biology outside of our current concepts of pathogenesis of arrhythmia and ischaemia. Though in general, not ready for clinical application, these studies will undoubtedly lead to better understanding of disease pathogenesis.




Genetics in sudden cardiac death

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.