AUTHOR=Hwang Inseok , Kwon Oh-Seok , Hong Myunghee , Yang Song-Yi , Park Je-Wook , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Pak Hui-Nam 

TITLE=Association of ZFHX3 Genetic Polymorphisms and Extra-Pulmonary Vein Triggers in Patients With Atrial Fibrillation Who Underwent Catheter Ablation

JOURNAL=Frontiers in Physiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.807545

DOI=10.3389/fphys.2021.807545

ISSN=1664-042X

ABSTRACT=<p><bold>Background:</bold> The <italic>ZFHX3</italic> gene (16q22) is the second most highly associated gene with atrial fibrillation (AF) and is related to inflammation and fibrosis. We hypothesized that <italic>ZFHX3</italic> is associated with extra-pulmonary vein (PV) triggers, left atrial (LA) structural remodeling, and poor rhythm outcomes of AF catheter ablation (AFCA).</p><p><bold>Methods:</bold> We included 1,782 patients who underwent a <italic>de novo</italic> AFCA (73.5% male, 59.4 ± 10.8 years old, 65.9% paroxysmal AF) and genome-wide association study and divided them into discovery (<italic>n</italic> = 891) and replication cohorts (<italic>n</italic> = 891). All included patients underwent isoproterenol provocation tests and LA voltage mapping. We analyzed the <italic>ZFHX3</italic>, extra-PV trigger-related factors, and rhythm outcomes.</p><p><bold>Result:</bold> Among 14 single-nucleotide polymorphisms (SNPs) of <italic>ZFHX3</italic>, rs13336412, rs61208973, rs2106259, rs12927436, and rs1858801 were associated with extra-PV triggers. In the overall patient group, extra-PV triggers were independently associated with the <italic>ZFHX3</italic> polygenic risk score (PRS) (OR 1.65 [1.22–2.22], <italic>p</italic> = 0.001, model 1) and a low LA voltage (OR 0.74 [0.56–0.97], <italic>p</italic> = 0.029, model 2). During 49.9 ± 40.3 months of follow-up, clinical recurrence of AF was significantly higher in patients with extra-PV triggers (Log-rank <italic>p</italic> &lt; 0.001, HR 1.89 [1.49–2.39], <italic>p</italic> &lt; 0.001, model 1), large LA dimensions (Log-rank <italic>p</italic> &lt; 0.001, HR 1.03 [1.01–1.05], <italic>p</italic> = 0.002, model 2), and low LA voltages (Log-rank <italic>p</italic> &lt; 0.001, HR 0.73 [0.61–0.86], <italic>p</italic> &lt; 0.001, model 2) but not the <italic>ZFHX3</italic> PRS (Log-rank <italic>p</italic> = 0.819).</p><p><bold>Conclusion:</bold> The extra-PV triggers had significant associations with both <italic>ZFHX3</italic> genetic polymorphisms and acquired LA remodeling. Although extra-PV triggers were an independent predictor of AF recurrence after AFCA, the studied AF risk SNPs intronic in <italic>ZFHX3</italic> were not associated with AF recurrence.</p>