Semaglutide reduces volume overload and atrial remodelling in a novel experimental model of cardiometabolic HFpEF
Abstract
Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent cardiometabolic syndrome linked to obesity, type 2 diabetes, and hypertension. Recent trials, including STEP-HFpEF1 and SUMMIT2, demonstrate that glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve outcomes in obese HFpEF. However, as GLP-1RAs induce substantial weight loss, it remains unclear whether benefits reflect weight reduction alone or direct modification of HFpEF pathophysiology. To determine whether semaglutide improves cardiac and systemic features of HFpEF in a novel preclinical model of obesity and volume overload. Male wild-type mice were fed a high-fat diet (HFD; 36% fat) for 16 weeks to induce obesity. Hypertension was induced at week 10 via uninephrectomy with deoxycorticosterone acetate (DOCA; 2.4 mg/day, s.c.) and 0.9% saline drinking water (1K/DOCA/salt). Semaglutide (0.04 mg/kg) or vehicle was administered every second day for 42 days. Blood pressure was measured by tail-cuff plethysmography, body composition by EchoMRI, and cardiac tissue analysed for histopathology and mRNA expression. 1K/DOCA/salt + HFD increased blood pressure within 14 days compared with controls; semaglutide attenuated this rise (141 ± 10 vs. 120 ± 17 and 112 ± 14 mmHg; P < 0.05; n = 7–10). Free water content was elevated in 1K/DOCA/salt + HFD mice versus controls (0.37 ± 0.17 vs. 0.13 ± 0.06; P < 0.001) and tended to decrease with semaglutide (P = 0.059). Left atrial weight was increased in 1K/DOCA/salt + HFD mice (6.03 ± 0.23 vs. 4.14 ± 1.17 mg; P < 0.05) and reduced by semaglutide (5.56 ± 0.30 mg; P < 0.05). Semaglutide improved haemodynamic and structural features of cardiometabolic HFpEF, attenuating hypertension, volume expansion, and atrial remodelling. These findings support GLP-1 receptor agonism as a therapeutic strategy targeting systemic and cardiac drivers of HFpEF.J Thomas HFpEFFor image description, please refer to the figure legend and surrounding text.