Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death1. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 1 0,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 1 2.53 and P = 1.5 × 10−29. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.

Background-Despite the success of catheter ablation of cavotricuspid isthmus-dependent atrial flutter (AFL), important postablation outcomes are ill-defined. The purpose of our study was to analyze long-term outcomes after catheter ablation of cavotricuspid isthmus-dependent AFL. Methods and Results-A meta-analysis was performed of articles reporting clinical outcomes after catheter ablation of AFL published between January 1988 and July 2008. The analysis included 158 studies comprising 10 719 patients (79% men, 59.8Ϯ0.5 years old, 46% left atrial enlargement, 46% heart disease, 42% with history of atrial fibrillation, 14.3Ϯ0.4 months of follow-up). The overall acute success rate adjusted for reporting bias was 91.1% (95% CI, 89.5 to 92.4), 92.7% (95% CI, 90.0 to 94.8) for 8-to 10-mm tip/or irrigated radiofrequency catheters, and 87.9% (95% CI, 84.2 to 90.9) for 4-to 6-mm tip catheters (PϾ0.05). Atrial flutter recurrence rates were significantly reduced by use of 8-to 10-mm tip or irrigated radiofrequency catheters (6.7% versus 13.8%, PϽ0.05) and by use of bidirectional cavotricuspid isthmus block as a procedural end point (9.3% versus 23.6%, PϽ0.05). The AFL recurrence rate did not increase over time. The overall occurrence rate of atrial fibrillation after AFL ablation was 33.6% (95% CI, 29.7 to 37.3) but was 52.7% (95% CI, 47.8 to 57.6) in patients with a history of atrial fibrillation before ablation and 23.1% (95% CI, 17.5 to 29.9) in those without atrial fibrillation before ablation (PϽ0.05). The incidence of atrial fibrillation increased over time in both groups; however, 5 years after ablation, the incidence of atrial fibrillation was similar in those with and without atrial fibrillation before ablation. The acute complication rate was 2.6% (95% CI, 2 to 3). The mortality rate during follow-up was 3.3% (95% CI, 2.4 to 4.5). Antiarrhythmic drug use after ablation was 31.6% (95% CI, 25.6 to 37.8

Objectives This study tested the hypothesis that response to antiarrhythmic drugs (AADs) is modulated by 3 common loci associated with atrial fibrillation (AF). Background Recent genome wide association studies (GWAS) have identified 3 loci, on chromosomes 4q25 (near PITX2), 16q22 (in ZFHX3), and 1q21 (in KCNN3), that associate with either typical or lone AF. These findings indicate that variable mechanisms contribute to AF susceptibility, and suggest that response to therapy may be genotype-dependent. Methods We studied 478 and 198 Caucasian patients respectively in the discovery cohort and validation cohort, prospectively enrolled in the Vanderbilt AF Registry. Response was defined prospectively as successful rhythm control if the patient remained on the same AAD therapy for a minimum of 6 months with ≥ 75% reduction in symptomatic AF burden. We also evaluated AF recurrence by 12 lead ECG at 3, 6 and 12 months. Symptomatic patients were also given 24-48-hour Holter monitor or 30-days event recorder when AF recurrence was not captured by 12 lead ECG. Results In the discovery cohort, 399 (83%) were successfully rhythm-controlled. Multiple clinical variables (including age, hypertension, lone AF) failed to significantly predict response to AADs. By contrast single nucleotide polymorphism (SNP) rs10033464 at 4q25 was an independent predictor of successful rhythm control in patients with Typical AF carrying the ancestral allele (wild type) vs. carriers of variant allele (odds ratio [OR] 4.7, [95% confidence interval [CI] 1.83-12, P=0.0013. In the validation cohort, 143 (72%) patients met the criteria for successful rhythm control and rs10033464 was again an independent predictor of successful rhythm control, OR: 1.5, 95% CI: 1.02-3.06, P = 0.04. This SNP (rs10033464) was an independent predictor of AF recurrence in the discovery (39% AF recurrence) and validation cohort (38% AF recurrence); OR: 3.27, 95% CI: 1.7–6, P<0.001 and OR: 4.3, 95% CI: 1.98–9.4, P<0.001 respectively. Conclusions These results suggest that a common SNP on chromosome 4q25 associated with AF modulates response to AAD therapy and points to a potential role for stratification of therapeutic approaches by genotype.

Atrial fibrillation (AF) is more common in those with obstructive sleep apnea (OSA) than in unaffected individuals and recurs more frequently in the presence of severe OSA after electrical cardioversion and AF ablation. However, it is unknown whether severity of OSA influences the efficacy of anti-arrhythmic drug (AAD) therapy in patients with OSA and AF. This study examined the impact of OSA severity on treatment of symptomatic AF with AADs. We studied 61 patients (62 ± 15 years; 21 women) treated with AADs for symptomatic AF who had overnight polysomnography. Rhythm control was prospectively defined as successful if a patient remained on the same AAD therapy for a minimum of 6 months with ≥75% reduction in symptomatic AF burden. Twenty-four patients (40%) had severe OSA. Thirty patients (49%) were rhythm controlled with AADs. Non-responders to AADs were more likely to have severe OSA than milder disease (52% vs 23%; p < 0.05); those with severe OSA were less likely to respond to AADs than participants with non-severe OSA (39% vs 70%; p = 0.02). Non-responders had higher apnea-hypopnea indices than responders (34 ± 25 vs 22 ± 18 events/hour; p = 0.05), but there were no differences between these groups in minimum oxygen saturation or % time spent in REM sleep. In conclusion, patients with severe OSA are less likely to respond to AAD therapy for AF than those with milder forms of OSA.