Abstract 131: Differential Regulation of Pitx2 Expression in Pulmonary Vein Muscle Sleeves and Left Atrium with Aging: Implication for Pulmonary Vein Triggers

Introduction: Pitx2, Paired-like homeodomain transcription factor 2, is a homeobox transcription factor that regulates left-right asymmetry during cardiogenesis. Pitx2 insufficiency in the left atrium (LA) has been linked to LA remodeling and arrhythmogenesis in age-related atrial fibrillation (AF). However, the main triggers for AF reside in pulmonary vein muscle sleeves (PVs). Whether Pitx2 insufficiency in PVs also plays a pathogenic role in generating trigger foci remains to be determined. Also, changes in Pitx2 expression in PVs with age remain unclear. We use qRT-PCR and Illumina microarrays to determine age-related changes in Pitx2 expression of PVs in wild type (WT) & heterozygous Pitx2cnull+/- mice, and in humans with or without AF. Methods: PV and LA regions were obtained from 1-23 month-old WT and Pitx2cnull+/- mice. Human PVs were obtained from ~110D human fetal hearts (E110D aborted fetus), two groups of adult donor hearts [20-30s year-old (yo) and 40-50 yo] and two patients with persistent AF. These tissues were used for genetic expression analysis. Results: Pitx2c expression decreases slightly with age in mouse LA and PV tissues. The expression levels of Pitx2c of Pitx2cnull+/- mice in LA are consistently at 55.2±10.5% of WT but at near-equal levels in PVs over four different age groups. In contrast, during human development, Pitx2 expression in PV muscle sleeves first decreases from ~E110D to ~30 yo but increases from 30 to 50 yo. In patients with AF, Pitx2 expression in PVs is only lower by 15% while HCN4 expression is higher by 13.5% when compared to control PVs at >50 yo. Expressions of type 2 Ryanodine receptors and calsequestrin in human PVs increase with age but decrease by ~30% with AF, suggesting impaired calcium handling abilities may play more significant roles than Pitx2 in the generation of PV triggers of AF. Conclusions: Genetic analysis of Pitx2c expression in PV muscle sleeves and LA tissues of WT and Pitx2cnull+/- mice revealed differential expression patterns. In human PVs, Pitx2 expression shows a regulation pattern with age distinct from that in mice, and genes linked to intracellular calcium handling may play a more important role than Pitx2 in generating trigger foci in PVs to initiate AF.