Abstract 15812: Oxidative Stress Promotes Susceptibility to Atrial Fibrillation in Pitx2 Deficient Mice

Abstract

Introduction: The strongest genetic risk factor for atrial fibrillation (AF) is variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene Pitx2 . Mice deficient in Pitx2 ( Pitx2 +/- ) have increased AF susceptibility, although the mechanism(s) remains controversial. Recent evidence indicates that with cardiac injury, Pitx2 encodes an antioxidant gene program that promotes repair. Isolevuglandins (IsoLGs) are highly reactive lipid peroxidation products that mediate a major component of oxidative stress-related injury. We used a small molecule scavenger of IsoLGs to test the hypothesis that oxidative stress is enhanced in the setting of Pitx2 deficiency to cause AF susceptibility. Methods: Pitx2 +/- and Pitx2 +/+ (wild type littermate control) mice were treated orally with either vehicle or the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) starting at weaning. At age 16-18 weeks, animals underwent transesophageal atrial pacing, echocardiography, and tissue harvest or flow cytometry to measure atrial inflammation. Results: Pitx2 +/- mice demonstrated a significant increase in inducible AF burden compared to control mice (242.9±105.3 vs 23.6±11 sec; n=7, 14; P <0.05). There was also a trend for an increased incidence of sustained AF (71.4% vs 21.4; P=0.055). Flow cytometry revealed that there was no increase in the number of total leukocytes in the atria of Pitx2 +/- mice compared to control atria, nor were differences present in selected populations of immune cells (including CD3, CD19, NK1.1, F4/80, Ly6G, or CD11b/MHCII positive cells). For Pitx2 +/- mice treated with 2-HOBA, there was trend for a reduction in AF burden (39.6±14.4 sec; n=11; P =0.075) as well as sustained AF (27.2%), while the drug had no effect in control mice. Based on cardiac histology (n=5, 5) and echocardiography (n=11, 14), no major histologic, structural, or functional abnormalities were identified in Pitx2 +/- mice. Conclusions: The reduction in AF burden by the IsoLG scavenger 2-HOBA supports the hypothesis that enhanced oxidative stress is responsible for AF susceptibility in the setting of Pitx2 deficiency. These results suggest a potential role for genotype-specific AF therapy (in 4q25 variant carriers) using IsoLG scavengers.