Genetic Susceptibility for Atrial Fibrillation in Patients Undergoing Atrial Fibrillation Ablation.

BACKGROUND: Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS: Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS: Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS: Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Non-pulmonary vein mediated atrial fibrillation: A novel sub-phenotype.

BACKGROUND: Atrial fibrillation (AF) is a mechanistically heterogeneous disorder, and the ability to identify sub-phenotypes ("endophenotypes") of AF would assist in the delivery of personalized medicine. We used the clinical response to pulmonary vein isolation (PVI) to identify a sub-group of patients with non-PV mediated AF and sought to define the clinical associations. METHODS: Subjects enrolled in the Vanderbilt AF Ablation Registry who underwent a repeat AF ablation due to arrhythmia recurrence were analyzed on the basis of PV reconnection. Subjects who had no PV reconnection were defined as "non-PV mediated AF". A comparison group of subjects were identified who had AF that was treated with PVI-only and experienced no arrhythmia recurrence >12 months. They were considered a group enriched for "PV-mediated AF". Univariate and multivariable binary logistic regression analysis was performed to investigate clinical associations between the PV and non-PV mediated AF groups. RESULTS: Two hundred and twenty nine subjects underwent repeat AF ablation and thirty three (14%) had no PV reconnection. They were compared with 91 subjects identified as having PV-mediated AF. Subjects with non-PV mediated AF were older (64 years [IQR 60,71] vs. 60 [52,67], P = 0.01), more likely to have non-paroxysmal AF (82% [N = 27] vs. 35% [N = 32], P<0.001), and had a larger left atrium (LA) (4.2cm [3.6,4.8] vs. 4.0 [3.3,4.4], P = 0.04). In univariate analysis, age (per decade: OR 1.56 [95% CI: 1.04 to 2.33], P = 0.03), LA size (per cm: OR 1.8 [1.06 to 3.21], P = 0.03) and non-paroxysmal AF (OR 8.3 [3.10 to 22.19], P<0.001) were all significantly associated with non-PV mediated AF. However, in multivariable analysis only non-paroxysmal AF was independently associated with non-PV mediated AF (OR 7.47 [95% CI 2.62 to 21.29], P<0.001), when adjusted for age (per decade: OR 1.25 [0.81 to 1.94], P = 0.31), male gender (OR 0.48 [0.18 to 1.28], P = 0.14), and LA size (per 1cm: 1.24 [0.65 to 2.33], P = 0.52). CONCLUSIONS: Non-paroxysmal AF was the only clinical variable found to be independently associated with non-PV mediated AF. We demonstrated that analysis of AF ablation outcomes data can serve as a tool to successfully identify a sub-phenotype of subjects who have non-PV mediated AF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID # NCT02404415.