Atrial fibrillation (AF) affects over 33 million individuals worldwide1 and has a complex heritability.2 We conducted the largest meta-analysis of genome-wide association studies for AF to date, consisting of over half a million individuals including 65,446 with AF. In total, we identified 97 loci significantly associated with AF including 67 of which were novel in a combined-ancestry analysis, and 3 in a European specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait loci (eQTL) analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Renal insufficiency dramatically increases the risk of infection complicating pacemaker or ICD surgery. This association should be part of the risk-benefit consideration prior to device implantation. Additional study of more extensive perioperative antibiotic therapy in this subset of patients is warranted.

Background: Atrial fibrillation (AF) has been associated with myocardial oxidative stress, and antioxidant agents have demonstrated antiarrhythmic benefit in humans. We compared serum markers of oxidation and associated inflammation in individuals with or without AF. Methods: Serum markers of oxidative stress and inflammation were compared in a cross-sectional, case-control design study of 40 male individuals, with or without persistent or permanent AF, who were matched for age, sex, diabetes, and smoking status, known confounding variables for the measurement of oxidative stress. We used derivatives of reactive oxidative metabolites (DROMs) and ratios of oxidized to reduced glutathione (E h GSH) and cysteine (E h CySH) to quantify oxidative stress. We also measured inflammatory markers, including high-sensitivity C-reactive protein, interleukins 1␤ and 6, and tumor necrosis factor ␣. Results: Univariate, conditional logistical regression analysis showed that oxidative stress but not inflammatory markers were statistically associated with AF (P <0.05). The increase in the odds ratios for AF for E h GSH, E h CySH, and DROMs were 6.1 (95% CI, 1.3-28.3; P ‫؍‬ 0.02), 13.6 (95% CI, 2.5-74.1; P ‫؍‬ 0.01), and 15.9 (95% CI, 1.7-153.9; P ‫؍‬ 0.02), respectively. There was a stronger correlation between E h GSH and E h CySH (r ‫؍‬ 0.66) than between E h GSH and DROMs (r ‫؍‬ 0.41). In multivariate analysis corrected for statins and other AF

BACKGROUND Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous. OBJECTIVES We sought to define the prevalence of mutations in the RNA splicing protein, RBM20, in a large cohort with DCM, and to determine if genetic variation in RBM20 is associated with clinical outcomes. METHODS Subjects included in the GRADE (Genetic Risk Assessment of Defibrillator Events) study were at least 18 years of age, had an ejection fraction of ≤ 30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in DCM subjects; two common polymorphisms in RBM20, rs942077 and rs35141404, were genotyped in all GRADE subjects. RESULTS 1465 subjects were enrolled in the GRADE study and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 ± 13 years, 64% were male and the mean follow up was 24.2 ± 17.1 months after ICD placement. RBM20 mutations were identified in eight subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared to non-mutation carriers. Three of eight subjects (37.5%) with RBM20 mutations had atrial fibrillation (AF) whereas 19 (7.4%) subjects without mutations had AF (p= 0.02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele OR 0.62, 95% CI 0.44–0.86, p=0.006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele OR 0.58, p=0.047). CONCLUSIONS Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers.

Background: Heart failure (HF) is a morbid and heritable disorder for which the biological mechanisms are incompletely understood. We therefore examined genetic associations with HF in a large national biobank, and assessed whether refined phenotypic classification would facilitate genetic discovery. Methods: We defined all-cause HF among 488,010 participants from the UK Biobank and performed a genome-wide association analysis. We refined the HF phenotype by classifying individuals with left ventricular dysfunction and without coronary artery disease (CAD) as having nonischemic cardiomyopathy (NICM), and repeated a genetic association analysis. We then pursued replication of lead HF and NICM variants in independent cohorts, and performed adjusted association analyses to assess whether identified genetic associations were mediated through clinical HF risk factors. In addition, we tested rare, loss-of-function mutations in 24 known dilated cardiomyopathy (DCM) genes for association with HF and NICM. Finally, we examined associations between lead variants and left ventricular structure and function among individuals without HF using cardiac magnetic resonance imaging (n=4,158) and echocardiographic data (n=30,201). Results: We identified 7,382 participants with all-cause HF in the UK Biobank. Genome-wide association analysis of all-cause HF identified several suggestive loci (P < 1×10 −6), the majority linked to upstream HF risk factors, i.e. CAD (CDKN2B-AS1 and MAP3K7CL) and atrial fibrillation (PITX2). Refining the HF phenotype yielded a subset of 2,038 NICM cases. In contrast to all-cause HF, genetic analysis of NICM revealed suggestive loci that have been implicated in DCM (BAG3, CLCNKA-ZBTB17). DCM signals arising from our NICM analysis replicated in independent cohorts, persisted after HF risk factor adjustment, and were associated with indices of left ventricular dysfunction in individuals without clinical HF. Additionally, analyses of loss-offunction variants implicated BAG3 as a disease-susceptibility gene for NICM (loss-of-function variant carrier frequency=0.01%, OR=12.03, P=3.62×10 −5). Conclusions: We found several distinct genetic mechanisms of all-cause HF in a national biobank that reflect well-known HF risk factors. Phenotypic refinement to a NICM subtype appeared to facilitate the discovery of genetic signals that act independent of clinical HF risk factors, and which are associated with subclinical left ventricular dysfunction.

CIED procedures that utilized an antibacterial envelope had a high rate of CIED implantation success (>99%). Although the follow-up to date is short, there was also a low rate of infection (<0.50%) in this population at high risk for CIED infection.

Background-Little is known about long-term outcomes of patients who survive inhospital cardiac arrest.