Elsevier

Heart Rhythm

Volume 19, Issue 12, December 2022, Pages 2044-2050
Heart Rhythm

Atrial Fibrillation
GJA1 gene polymorphism is a genetic predictor of recurrence after pulmonary vein isolation in patients with paroxysmal atrial fibrillation

https://doi.org/10.1016/j.hrthm.2022.08.024Get rights and content

Background

Atrial fibrillation (AF) and recurrence of AF after pulmonary vein isolation (PVI) have been linked to sinus node dysfunction.

Objective

The purpose of this study was to investigate the association between the heart rate–associated single nucleotide polymorphisms (SNPs) identified in genome-wide association studies and recurrence of AF after PVI.

Methods

In this study, patients with paroxysmal AF who underwent initial PVI, including 522 patients for screening and 172 patients for replication, were recruited and 21 heart rate–associated SNPs identified in genome-wide association studies were genotyped. The association between these SNPs and the recurrence of AF was investigated.

Results

Throughout the follow-up period of 21 ± 12 months, 119 patients with paroxysmal AF (22.8%) exhibited AF recurrences in the screening set. The rate of AF recurrence was significantly associated with the minor allele C of the gap junction alpha-1 protein (GJA1) rs1015451 (additive model: odds ratio 2.07; P = 9.32 × 10−7), but not with other SNPs. This association was confirmed in the replication set (allelic model: odds ratio 1.81; P = 2.70 × 10−2). Multivariate analysis revealed that the recurrence of AF after AF ablation was independently related to the GJA1 SNP rs1015451 additive model, duration of AF >1 year, AF from non–pulmonary vein foci, and thicker interventricular septum.

Conclusion

The GJA1 SNP rs1015451, coding for a gap junction protein (connexin-43), may be considered a novel genetic marker for AF recurrence after PVI.

Introduction

Atrial fibrillation (AF) is the most prevalent type of cardiac arrhythmia and is associated with an increased risk of heart failure, strokes, and all-cause mortality.1 Numerous studies have been conducted to determine the efficacy of radiofrequency catheter ablation (RFCA) in the treatment of AF. According to the meta-analysis by Hakalahti et al,2 RFCA is associated with a considerably higher rate of recurrence-free AF compared with antiarrhythmic drugs. AF ablation is currently established as a therapeutic approach for patients with symptomatic AF, and the scope of its use has broadened. The most frequent RFCA approach for treating paroxysmal AF (PAF) is pulmonary vein (PV) isolation (PVI); however, ∼13%–39% of patients experience AF recurrence after this procedure.3 After RFCA several factors have been linked to an increased risk of AF recurrence, including persistent AF, obesity, sleep apnea, hypertension, diabetes, alcohol intake, duration of AF, size of the left atrium, valvular heart disease, left ventricular dysfunction, dormant PV conduction, and initiation from non-PV foci.4 Several studies have been conducted to determine the association of genetic variations with AF recurrences after RFCA. Among those, the PITX2 gene, which has been shown to be associated with the incidence of AF, has also been linked to the recurrence of AF.5

Sinus node dysfunction has also been associated with an increased incidence and recurrence of AF after RFCA.6,7 Genetic variants at 6 loci have been implicated in sick sinus syndrome,8 while previous genome-wide association studies (GWASs) identified 21 single nucleotide polymorphisms (SNPs) associated with heart rate (HR) during sinus rhythm. Even though several of these HR-associated SNPs have been linked to AF pathogenesis,9 the relationship between these SNPs and the recurrence of AF after RFCA has not been thoroughly studied. We hypothesized that HR-associated SNPs identified in GWASs would be associated with the recurrence of AF after RFCA.

Section snippets

Participants

In this study, 555 consecutive Japanese patients with PAF who underwent an initial RFCA procedure were screened at Hiroshima University Hospital between November 2009 and November 2016. Thirty-three of those patients were excluded because postoperative follow-up was no longer available within 3 months of RFCA, and as such, RFCA and AF recurrence could not continue to be evaluated. Finally, 522 Japanese patients with PAF were included in this study (376 men and 146 women; mean age 64 ± 11

The 21 HR-associated SNPs and recurrence of AF in patients with PAF after RFCA in the screening set

In this study, 119 patients with PAF (22.8%) exhibited late AF recurrences throughout the follow-up period of 21 ± 12 months. The relationship between the 21 HR-associated SNPs identified in the GWASs and the recurrence of AF in patients with PAF after RFCA is displayed in Table 1. After Bonferroni adjustment, the genotypes of the gap junction alpha-1 protein (GJA1) SNP rs1015451 (T>C) were significantly associated with the recurrence of AF. The frequency of the GJA1 SNP rs1015451 minor C

Discussion

In the present study, the GJA1 SNP rs1015451 minor C allele, one of the HR-associated SNPs, increased the rate of AF recurrence after RFCA.

The recurrence of AF after RFCA remains a serious concern. In spite of numerous risk factors, it is difficult to predict whether an AF recurrence will occur before RFCA.4 One of these risk factors, sinus node dysfunction, was reported to increase the rate of AF recurrence after RFCA.6,7 In a previous GWASs analysis, 21 HR-associated SNPs during sinus rhythm

Conclusion

The GJA1 SNP rs1015451 minor allele, coding for a gap junction protein (Cx43), is associated with AF recurrence after RFCA and may be considered as a novel genetic marker of AF recurrence.

Acknowledgments

We thank the members of the clerical and medical staff at Hiroshima University Hospital for their assistance and the ENAGO Group (English editing system) for editing the draft of this manuscript.

References (16)

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Funding Sources: Dr Nakano was supported by Japan Society for the Promotion of Science KAKENHI (grant number 17K09501).

Disclosures: The authors have no conflicts of interest to disclose.

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