Head to head comparison of semaglutide and colchicine for treating atrial remodeling in post-MI rats with reduced ejection fraction

Abstract Introduction Atrial fibrillation (AF), the most common cardiac arrhythmia, is closely linked to poor clinical outcomes, particularly in patients with heart failure (HF). Inflammation and fibrosis are critical in the development of atrial remodeling, a complex process that ultimately increases AF susceptibility. Current AF therapies are suboptimal and do not effectively target atrial remodeling. Colchicine, a broad-spectrum anti-inflammatory drug approved for various indications, and semaglutide, a GLP-1 receptor agonist approved for diabetes and obesity, may exert direct and indirect cardiac effects. This study evaluates their potential to prevent atrial remodeling in post-MI rats with reduced ejection fraction (EF). Methods Male rats underwent left coronary artery ligation and chronic electrophysiological device implantation including an atrial quadripolar electrode and peripheral ECG leads. After a 1-week recovery, rats with EF≤40% were randomly assigned to receive semaglutide (40 μg/kg/72h SC), colchicine (100 μg/kg/24h IP), or vehicle (saline Q24h IP) for 3 weeks. The doses were selected based on efficacy for other indications in rats. Post-treatment assessments included echocardiography, electrophysiological testing, histology, and Western blot analysis. Results Neither semaglutide nor colchicine improved heart failure parameters, including left ventricular ejection fraction and left atrial diameter. However, semaglutide and, to a lesser extent, colchicine reduced AF inducibility and total AF duration compared to the vehicle (Fig 1). Semaglutide markedly decreased atrial NLRP3 inflammasome expression and fibrosis deposition, whereas colchicine reduced NLRP3 expression but had no effect on fibrosis (Fig 2). An Immunofluorescence analysis revealed that semaglutide prevented connexin 43 lateralization, a feature not observed with colchicine. Western blot analysis showed that colchicine attenuated p38 signaling activation, while semaglutide tended to reduce IL-18 levels, downstream to NLRP3. Conclusions Both semaglutide and colchicine exhibited anti-inflammatory effects in the atria of post-MI rats. However, semaglutide was superior in preventing atrial fibrosis and in reducing AF susceptibility, highlighting its potential anti AF effects beyond the context of diabetes and obesity treatment. Given its beneficial effects on atrial remodeling, semaglutide holds promise as a novel therapeutic strategy for AF prevention, particularly in patients with comorbid heart failure.AF susceptibilty Structural remodeling