Sudden Cardiac Death - A Current Perspective - US Cardiology 2006

Sudden Cardiac Death - A Current Perspective - US Cardiology 2006

David S Rosenbaum
This article was published in US Cardiology 2006
Published: November 2005
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Heart disease is the leading cause of death in the US with 700,000 deaths annually, of which 460,000 are attributable to sudden cardiac death (SCD).1,2 SCD is usually attributed to ventricular fibrillation (VF). Despite recent reductions in cardiac mortality from other causes, the incidence of SCD remains high with minimal decline in the last decade. The large majority of patients who suffer life-threatening ventricular arrhythmias have advanced left ventricular (LV) systolic dysfunction. Coronary artery disease is the most common predisposing condition in developed countries, accounting for up to 75% to 80% of all cases.3 Non-ischemic cardiomyopathy and other cardiomyopathic disorders account for 10% to 15% of cases.4 Inflammatory disorders (i.e. myocarditis), structural heart disease (i.e. valvular or congenital heart disease), and infiltrative disorders (i.e. sarcoidosis) account for about 3% to 5% of cases.4 There are also comparatively rare but important heritable disorders that can cause SCD in the absence of structural abnormalities of the left ventricle. These include the long QT syndrome (LQTS), Brugada syndrome, and arrhythmogenic right ventricular dysplasia (ARVD), which account for approximately 1% to 2% of cases.3,4

Identifying Patients at Risk for SCD Genetic Markers of SCD

Genetically inherited disorders should be considered when evaluating patients with syncope or unexplained loss of consciousness and family history of SCD. These patients are often relatively young and have no overt evidence of structural heart disease. For example, the LQTS is a monogenetic disorder associated with prolonged ventricular repolarization, malignant ventricular arrhythmias, typically torsades de pointes, and SCD. In this subset of patients, genetic screening is currently available to identify patients at risk for SCD. Linkage analysis in the early 1990s heralded the identification of several mutations responsible for LQTS phenotypes. LQT1 is due to a mutation in KCNQ1, the alpha subunit of the potassium ion channel, and responsible for cardiac slowly activated delayed rectifying potassium current (IKs).5 LQT2 is associated with mutation in the human ether-a-go-go gene (HERG), the protein responsible for rapidly activated delayed rectifying potassium current (IKr).6 LQT5 and LQT6 are due to mutation in KCNE1, the beta subunit of IKs, and KCNE2, the beta subunit of IKr respectively.7 Mutation in SCN5a, the alpha subunit of the cardiac sodium channel, is responsible for LQT3 and LQT4 is due to mutation in ankyrin B, a cytoskeletal protein that anchors ion channels to cell membrane.8,9 Brugada syndrome is characterized by electro-cardiogram (ECG) features of ST elevation in right precordial leads with right bundle branch pattern, and is caused by mutation in SCN5a.10 More recently, mutation in genes encoding the ryanodine receptor, or calsequestrin, was identified as the cause of catecholaminergic polymorphic ventricular tachycardia.11,12
Although these monogenic disorders would appear to be straightforward causes of SCD (i.e. besides carrying a mutated ion channel the patient is otherwise normal), they have revealed a great deal about the complexities and challenges associated with predicting a particular clinical phenotype from a patient’s genotype. Identification of abnormal genotype may not be sufficient to identify patients at risk for SCD. For example, significant proportions of genetically documented LQTS patients, referred to as ‘silent gene carriers’, never develop symptoms.13 This phenomenon of variable penetrance is widespread in inheritable disorders and thought to be due to environmental factors and genetic polymorphisms that co-exist in patients with abnormal genotypes.14

Inherited cardiomyopathic disorders can also cause SCD in young individuals and, particularly, athletes. Hypertrophic cardiomyopathy, a rare form of cardiomyopathy, is familial in over 90% of cases, with over 200 mutations reported in genes encoding for beta-myosin heavy chain, myosin light chain, cardiac troponin T, troponin I, myosin binding protein C, and actin.15 Dilated cardiomyopathy (DCM), also referred to as non-ischemic cardiomyopathy, a more commonly observed form of primary myocardial disease and LV dilatation, is associated with inherited mutations in cytoskeletal proteins (desmin, taffazin, D-sarcoglan, metavinculin) and sarcomere proteins (troponin I, troponin T).15 Genetic testing, although not frequently used in patients with DCM, may become a useful tool when more data is available. ARVD is a rare disorder characterized by fibro-fatty infiltration of the right ventricle and malignant ventricular arrhythmias.ARVD has been associated with inherited mutations in desmoplakin, plakophilin-2, plakoglobin, and ryanodine receptor.16 To date, the clinical utility of genetic screening for these disorders is not known. Therefore, diagnosis and therapy is typically guided by the pattern and severity of the clinical presentation. The signal averaged ECG has known utility in detecting RV conduction abnormality associated with ARVD.

Although there have been some recent advances in understanding the genetic basis for coronary vascular disease,17 the genetic basis for susceptibility to SCD in patients with coronary disease remains elusive. Recent epidemiological studies have demonstrated an interesting clustering of SCD in families where parents or siblings experience SCD.18,19 In the Paris Prospective Study I, the relative risk for SCD was 2.54 with maternal history of SCD, 1.82 with paternal history of SCD, and 9.4 if SCD was present in both parents.18 In the Seattle Kings County study, incidence of SCD was 50% higher if first degree relatives had SCD or myocardial infarction (MI).19 Although a few genetic polymorphisms based on limited genetic screening that confer increased susceptibility to SCD are currently known,20,21 a more comprehensive screening for candidate genes is necessary to identify the genetic basis for susceptibility to SCD in patients with coronary disease.

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