Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases1–3. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10−68; rs9388451, P = 5.1 × 10−17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10−14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (Ptrend = 6.1 × 10−81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction4–7 can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development8. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Background-Coronary spasm can cause myocardial ischemia and angina in patients with and those without obstructive coronary artery disease. However, provocation tests using intracoronary acetylcholine administration are rarely performed in clinical routine in the United States and Europe. Thus, we assessed the clinical usefulness, angiographic characteristics, and safety of intracoronary acetylcholine provocation testing in white patients with unobstructed coronary arteries. Methods and Results-From September 2007 to June 2010, a total of 921 consecutive patients (362 men, mean age 62±12years) who underwent diagnostic angiography for suspected myocardial ischemia and were found to have unobstructed coronary arteries (no stenosis ≥50%) were enrolled. The intracoronary acetylcholine provocation testing was performed directly after angiography according to a standardized protocol. Three hundred forty-six patients (35%) reported chest pain at rest, 222 (22%) reported chest pain on exertion, 238 (24%) reported a combination of effort and resting chest pain, and 41 (4%) presented with troponin-positive acute coronary syndrome. The overall frequency of epicardial spasm (>75% diameter reduction with angina and ischemic ECG shifts) was 33.4%, and the overall frequency of microvascular spasm (angina and ischemic ECG shifts without epicardial spasm) was 24.2%. Epicardial spasm was most often diffuse and located in the distal coronary segments (P<0.01

Sudden cardiac death (SCD) in an athlete is a rare yet highly visible tragedy that generates significant media attention and discussion among medical personnel, sports communities, and laypersons alike. The incidence of SCD is greater in athletes compared with their nonathletic counterparts due to the increased risk associated with strenuous exercise in the context of a quiescent cardiac abnormality. Numerous structural, electrical, and acquired cardiovascular abnormalities are capable of causing SCD, many of which can be identified during life and managed by lifestyle modifications, pharmacotherapy, and device therapy. Strategies for the prevention of SCD, including pre-participation cardiovascular screening, are endorsed by sports governing bodies, but mandatory pre-participation cardiovascular screening remains rare. Evaluation of athletes poses diagnostic difficulties, particularly differentiating between physiological adaptation to exercise, known as athlete's heart, and cardiomyopathic processes capable of causing SCD. This paper provides a detailed review regarding the etiology of SCD in young athletes and provides insight into the challenges and dilemmas faced when evaluating athletes for underlying pathological conditions.

BACKGROUND Use of anti-arrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. Recent studies have demonstrated a role for NOS1AP gene variants in modulating QT interval in healthy subjects and modification of the severity of presentation and the risk of arrhythmias in LQTS. METHODS We carried out an association study using 167 SNPs spanning the NOS1AP gene in 58 Caucasian patients experiencing dLQTS and 87 Caucasian controls from the DARE Study. RESULTS Association analysis identified one polymorphism significantly associated with dLQTS (rs10800397: p=3.7×10−4; OR=3.3, 99.95% CI=1.0–10.8). The associations were more pronounced in the subgroup of amiodarone users, in which three SNPs including rs10800397 were significantly associated (most significant SNP rs10919035: p=3.0×10−4; OR=5.5, 99.95% CI=1.1–27.9). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone-dLQTS cases versus 173 controls (meta-analysis of both studies: OR=2.81; p=2.4×10−4; 95% CI=1.62–4.89). Analysis of QTc among 74 controls from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 controls from the BRIGHT cohort (top SNP DARE rs12734991 in meta-analysis: mean [SD] increase in QTc interval per C allele=9.1 [3.2]ms; p=1.7×10−4). CONCLUSIONS Our results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. We suggest that common variation in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.