Genetic susceptibility to atrial fibrillation is associated with atrial electrical remodeling and adverse post-ablation outcome

Objectives: This study sought to assess the atrial electrophysiological properties and post-ablation outcomes in patients with atrial fibrillation (AF) with and without the rs2200733 single nucleotide variant. Background: The phenotype associated with chromosome 4q25 of the AF-susceptibility locus remains unknown. Methods: In this study, 102 consecutive patients (ages 61 ± 9 years, 64% male) with paroxysmal or persistent AF were prospectively recruited prior to ablation. Patients were genotyped for rs2200733 and high-density left atrial (LA) electroanatomic maps were created using a multipolar catheter during distal coronary sinus (CS) pacing at 600 ms. Voltage, conduction velocity (CV), CV heterogeneity, and fractionated signals of 6 LA segments were determined. Arrhythmia recurrence was assessed by continuous device (51%) and Holter monitoring. Results: Overall, 41 patients (40%) were single nucleotide variant carriers (38 heterozygous, 3 homozygous). A mean of 2,239 ± 852 points per patient were collected. Carriers had relatively increased CV heterogeneity (45.7 ± 7.5% vs. 35.9 ± 2.3%; p < 0.001), complex signals (9.4 ± 2.9% vs 6.0 ± 1.2%; p = 0.008), regional LA slowing, or conduction block (31.7 ± 8.2% vs. 17.9 ± 1.9%; p = 0.013) particularly in the posterior and lateral walls. There were no differences in CV, voltage, atrial refractoriness, or sinus node function. At follow-up (median: 27 months; range 19 to 31 months), carriers had lower arrhythmia-free survival (51% vs. 80%; p = 0.003). On multivariable analysis, carrier status was independently associated with CV heterogeneity (p = 0.001), complex signals (p = 0.002), and arrhythmia recurrence (p = 0.019). Conclusions: These data provide the first evidence that the rs2200733-tagged haplotype alters LA electrical remodeling and is a determinant of long-term outcome following AF ablation. The molecular mechanisms underpinning these changes warrant further investigation.