AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Targeting the Sympathetic-Adipocyte-PAI-1 Axis to Prevent Arrhythmogenic Remodeling in Atrial Fibrillation
By Ullah MK, O'Donnell C, Mikhailov A et al.
Background Atrial fibrillation (AF) is strongly associated with aging, and AF itself accelerates the biological aging of atrial tissue. Sympathetic nerve activity is a critical driver of AF, and epicardial adipose tissue containing the atrial ganglionated plexi (GPs) has been implicated in its pathogenesis. Whether sympathetic stimulation promotes aging of atrial adipocytes and a pro-remodeling adipokine secretome remains unknown. Objective To determine whether sympathetic activation induces aging-associated reprogramming of atrial adipocytes, generates a pro-arrhythmic paracrine signal, and whether this can be attenuated by targeting Gαs or by inhibiting senescence regulator PAI-1. Methods Adipocytes isolated from canine atrial fat pads (n=4-5) were treated with isoproterenol (ISO, 10 μM, 7 days), a β-adrenergic receptor agonist. Senescence regulators and adipokine transcripts were quantified by RT-qPCR. The PAI-1 protein level was determined by ELISA. Conditioned media from control and ISO-treated adipocytes were applied to endothelial cells to assess paracrine alterations, including expression of SA-β-Gal and key senescence regulators. In rapid atrial pacing (RAP) canine model of AF (n=3), Gαs-inhibitory peptide-expressing plasmid was injected into atrial fatpads (±myocardium), and atrial fibrosis was quantified after 10 weeks of RAP. Control RAP animals received scrambled plasmids or no gene therapy (n=7). Results In RAP canine model, sympathetic nerve sprouting extended into atrial fat pads and GPs. β-Adrenergic receptor stimulation of isolated adipocytes upregulated p16, p21, p53, TBX5, and PAI-1, reduced ADIPOQ, and increased Leptin expression, consistent with a senescence and pro-inflammatory phenotype. ISO treatment also elevated secreted PAI-1 protein levels in adipocyte cultured medium (ELISA). Conditioned media from ISO-treated adipocytes promoted endothelial senescence, showing a quantitative increase in SA-β-Gal-positive cells, and upregulated inflammatory (IL-6, TNFα, CXCL10), pro-survival (BCL2), and endogenous PAI-1 expression in endothelial cells. Notably, pharmacological inhibition of PAI-1 with TM5441 attenuated expression of senescence regulators in Iso-activated adipocytes. In vivo Gαs inhibition significantly attenuated the expression of RAP-induced senescence regulators and fibrosis, particularly in the left atrial appendage (10% vs 17% in RAP controls, p<0.05). Conclusions Sympathetic stimulation drives senescence-like reprogramming of atrial adipocytes and their secretome, linking autonomic tone to an aged fat-pad phenotype that promotes endothelial remodeling. PAI-1 emerges as a key mediator of this pro-inflammatory secretome and other senescence regulators. Targeting Gαs signaling or PAI-1 in atrial GPs represents a novel strategy to blunt adipocyte-driven arrhythmogenic remodeling in AF.