Common atrial fibrillation risk alleles at 4q25 predict recurrence after catheter-based atrial fibrillation ablation
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and affects 2–5 million adults in the United States1 for an annual direct health-care cost of more than 6.5 billion dollars.2 It is thought that the majority of patients with AF possess a combination of common and rare genetic variants that predispose to its development, which clinically manifests in the presence of acquired cardiac or systemic disease.3 This is termed “typical” AF and is estimated to represent between 70% to greater than 95% of all AF cases.4, 5, 6, 7 To examine the potential of genetic screening toward addressing the health-care burden imposed by AF, it is necessary to determine the role of common genetic risk markers in modulating response to therapies, such as AF ablation, in patients with typical AF.
Over the last decade, genome-wide association studies have identified many common genetic variants associated with AF.8, 9, 10 The strongest association is mapped to 2 common AF susceptibility single nucleotide polymorphisms (SNPs) on chromosome 4q25. This locus is near the paired-like homeodomain transcription factor 2 (PITX2) gene, which regulates development of the pulmonary vein (PV) myocardium and left to right symmetry.11 Approximately 25% of individuals of European ancestry have been found to carry the 4q25 AF risk allele, and accumulating evidence suggests that these individuals demonstrate impaired clinical response to a variety of AF therapies, including antiarrhythmic drugs (AADs) and catheter-based AF ablation.12, 13 Recently, in a population of predominately lone AF, risk allele carriers at chromosome 4q25 demonstrated impaired response to catheter ablation.13 To address the ability of genetic risk markers to predict clinical response to AF ablation in the majority of patients with AF, we sought to test the hypothesis that common AF susceptibility alleles on chromosome 4q25 (rs2200733, rs10033464) conferred an increased risk for AF recurrence after catheter-based ablation in patients with typical AF.
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Study population
Three hundred seventy-two patients enrolled in the Vanderbilt AF Registry underwent 474 catheter-based AF ablations from February 2004 to December 2011 (Figure 1). The Vanderbilt AF Registry is a prospective clinical and genetic database.14 Eligible ablation records were from Caucasian patients who underwent a de novo or repeat catheter-based AF ablation and were followed up for at least 3 months. Records from de novo segmental PV isolation procedures, surgical AF ablation, and hybrid
Patient characteristics
Complete baseline patient characteristics and procedural details are listed in Table 1, Table 2. The final study cohort consisted of 311 unique patients. Two hundred thirty-eight patients underwent only 1 ablation and 73 patients underwent 2 or more.
Samples were successfully genotyped at a call rate of≥99% for both SNPs. Complete haplotype and minor allele frequencies are listed in Table 1. Risk allele carriers at rs2200733 were more likely to have lone AF and demonstrated a graded effect with
Discussion
In this study, we demonstrated that the 4q25 AF risk allele rs2200733 independently predicted recurrence of AT/AF after catheter ablation. Our findings are from a highly generalizable, nonselected group of patients with AF ablation, with predominately typical AF undergoing both de novo and repeat procedures. This extends the finding that common genetic variation at the 4q25 AF risk loci modulates clinical response to AF ablation in patients with lone AF to the majority of patients with AF who
Conclusions
The 4q25 AF risk polymorphism rs2200733 predicts impaired clinical response to catheter ablation in multivariable analysis among a highly generalizable population of patients undergoing de novo and repeat AF ablation. Overall, our findings demonstrate that a 4q25 AF risk allele may hold promise as an objectively measured patient characteristic that can be used as a clinical tool for selecting patients for AF ablation.
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This study was supported by American Heart Association Established Investigator (0940116N) and Clinical Research Program (11CRP7420009) Awards and National Institutes of Health grants U19 HL65962, HL092217, and UL1 RR024975.