Objectives This study aimed to identify the genetic defect in a family with idiopathic ventricular fibrillation (IVF) manifesting in childhood and adolescence. Background Although sudden cardiac ...death in the young is rare, it frequently presents as the first clinical manifestation of an underlying inherited arrhythmia syndrome. Gene discovery for IVF is important as it enables the identification of individuals at risk, because except for arrhythmia, IVF does not manifest with identifiable clinical abnormalities. Methods Exome sequencing was carried out on 2 family members who were both successfully resuscitated from a cardiac arrest. Results We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without electrocardiographic or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another 2 were resuscitated from out-of-hospital cardiac arrest with documented VF at ages 10 and 16 years, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.F90L) in the CALM1 gene encoding calmodulin. This mutation was also carried by 1 of the siblings who died suddenly, from whom DNA was available. The mutation was present in the mother and in another sibling, both asymptomatic but displaying a marginally prolonged QT interval during exercise. Conclusions We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that F90 mediates the direct interaction of CaM with target peptides. Our approach highlights the utility of exome sequencing in uncovering the genetic defect even in families with a small number of affected individuals.
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 NaV 1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV 1.5. 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.
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 SCD 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 SCD 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 1 control patient received appropriate ICD shocks. β-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.
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