Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Genetic risk factors for common and rare cardiac rhythm disorders

Sudden cardiac death (SCD) is defined by abrupt and unexpected death due to a cardiac cause, most often attributed to sustained ventricular arrhythmias. Knowledge about the molecular pathways involved in SCD is necessary in order to develop preventive strategies and novel therapies. Insight into these pathways may be gained by dissecting the genetic underpinnings of SCD. This thesis has accordingly focused on the identification of genes predisposing to SCD in the setting of the rare Mendelian arrhythmia disorders as well as to SCD in the setting of myocardial ischemia that underlies a significant part of SCD in the older segment of the general population

Prognosis among survivors of primary ventricular fibrillation in the percutaneous coronary intervention era

Background Sudden cardiac death (SCD) constitutes one of the most prevalent modes of death and is mainly caused by primary ventricular fibrillation (VF), that is, VF in the acute setting of a first acute myocardial infarction (MI). Current guidelines for secondary prevention of SCID are based on data from the thrombolysis era. We analyzed follow-up data of a large group of primary VF survivors to determine prognosis and risk of SCID in patients who received contemporary MI treatment. Methods Patients in this study were included in the ongoing Dutch multicenter primary VF study between December 1999 and April 2007. Primary VF was defined as VF during the first ST-elevation myocardial infarction (STEMI). Patients surviving the first 30 days were analyzed in this study. Data on mortality, cause of death, hospitalization, and implantable cardioverter-defibrillator (ICD) implantation were retrieved from national databases. In addition, data on left ventricular ejection fraction and medication use during follow-up were retrieved. Results In total, 341 primary VF patients (cases) and 292 STEMI patients without VF (controls) were included in the study. Demographic and infarct characteristics were comparable between both groups. The median follow-up was 3.33 years for cases and 3.69 for controls (P = .02). The left ventricular ejection fraction post-STEMI was 45.1% versus 46.5% (P=.342). During follow-up, 19 cases died versus 24 controls. Cox regression analysis showed no significant difference in survival between cases and controls (relative risk 0.59, 95% CI 0.15-2.30). Implantable cardioverter-defibrillators were implanted in 22 cases and 2 controls (P <.001), but only 2 cases and I control patient received appropriate ICD shocks. p-Blocker use during follow-up was 84.4% in cases versus 76.2% in controls (P = .049). Of cases, 2.5% were rehospitalized for acute MI versus 10.1% of controls (P <.001). The numbers of admissions for acute coronary syndromes and chest pain were not different between groups. Conclusions in conclusion, patients who survive the first month after primary VF have a similar prognosis as patients with a STEMI without VF. This is the first study to address this question in the modern era of reperfusion therapy. Implantable cardioverter-defibrillator treatment in primary VF patients without residual ischemia or other risk factors can be safely withheld. (Am Heart J 2009; 158:467-72.

Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia

OBJECTIVES: The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. BACKGROUND: A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks of the cardiomyocyte. METHODS: The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed using CAR haploinsufficient (CAR(+/-)) mice. RESULTS: In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR(+/-) mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR(+/-) hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR(+/-) myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5. CONCLUSIONS: CAR is a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease

Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis

AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation. We found a rare missense variant (p.Arg1898His; R1898H) in SCN5A in one patient. We generated induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs) from the patient's peripheral blood mononuclear cells. The variant was then corrected (R1898R) using Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 technology, allowing us to study the impact of the R1898H substitution in the same cellular background. Whole-cell patch clamping revealed a 36% reduction in peak sodium current (P = 0.002); super-resolution fluorescence microscopy showed reduced abundance of NaV1.5 (P = 0.005) and N-Cadherin (P = 0.026) clusters at the intercalated disc. Subsequently, we sequenced SCN5A in an additional 281 ARVD/C patients (60% male, 34.8 ± 13.7 years, 52% desmosomal mutation-carriers). Five (1.8%) subjects harboured a putatively pathogenic SCN5A variant (p.Tyr416Cys, p.Leu729del, p.Arg1623Ter, p.Ser1787Asn, and p.Val2016Met). SCN5A variants were associated with prolonged QRS duration (119 ± 15 vs. 94 ± 14 ms, P < 0.01) and all SCN5A variant carriers had major structural abnormalities on cardiac imaging. CONCLUSIONS: Almost 2% of ARVD/C patients harbour rare SCN5A variants. For one of these variants, we demonstrated reduced sodium current, Nav1.5 and N-Cadherin clusters at junctional sites. This suggests that Nav1.5 is in a functional complex with adhesion molecules, and reveals potential non-canonical mechanisms by which Nav1.5 dysfunction causes cardiomyopathy

Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction.

Sudden cardiac death from ventricular fibrillation during acute myocardial infarction is a leading cause of total and cardiovascular mortality. To our knowledge, we here report the first genome-wide association study for this trait, conducted in a set of 972 individuals with a first acute myocardial infarction, 515 of whom had ventricular fibrillation and 457 of whom did not, from the Arrhythmia Genetics in The Netherlands (AGNES) study. The most significant association to ventricular fibrillation was found at 21q21 (rs2824292, odds ratio = 1.78, 95% CI 1.47-2.13, P = 3.3 x 10(-10)). The association of rs2824292 with ventricular fibrillation was replicated in an independent case-control set consisting of 146 out-of-hospital cardiac arrest individuals with myocardial infarction complicated by ventricular fibrillation and 391 individuals who survived a myocardial infarction (controls) (odds ratio = 1.49, 95% CI 1.14-1.95, P = 0.004). The closest gene to this SNP is CXADR, which encodes a viral receptor previously implicated in myocarditis and dilated cardiomyopathy and which has recently been identified as a modulator of cardiac conduction. This locus has not previously been implicated in arrhythmia susceptibility