Semaglutide Reverses Ectopic Lipid Accumulation, Impaired Myocardial Perfusion Reserve, and Diastolic Dysfunction in a Mouse Model of Cardiometabolic Heart Disease
Skacel TP, Saleh NR, Pavelec CM, Quach K, Bradley LA, Bresticker JE
JACC Basic to Translational Science (2026)
In a pair-fed mouse design that isolates weight-independent effects, semaglutide reversed obesity-induced cardiometabolic heart disease — reducing proinflammatory epicardial adipose, ectopic lipid, and myocardial fibrosis, and restoring myocardial perfusion reserve and diastolic strain — while pair-fed controls matched for reduced caloric intake did not.
Skacel and colleagues at the University of Virginia Cardiovascular Research Center used multiparametric cardiovascular magnetic resonance to dissect semaglutide's cardiac effects from its appetite-suppression-mediated caloric-reduction effects. Mice were placed on a high-fat, high-sucrose diet to induce a cardiometabolic-heart-disease phenotype, then either treated with semaglutide or pair-fed to match the reduced dietary intake observed in semaglutide-treated animals. The CMR protocol assessed epicardial adipose tissue volume and composition, myocardial fat fraction, adenosine myocardial perfusion reserve, systolic strain, and diastolic function; myocardial fibrosis was assessed histologically.
Semaglutide treatment reduced proinflammatory epicardial adipose tissue, reduced ectopic myocardial lipid accumulation, improved adenosine myocardial perfusion reserve, and reversed impairments in both systolic and diastolic strain. Myocardial fibrosis was also reduced. Crucially, pair-fed control mice (matched for the reduced caloric intake) did not show these reversals, indicating the cardiac protective effect of semaglutide is not solely attributable to reduced energy intake or to weight loss alone.
The study was funded by NHLBI R01HL162872 / R01HL181257, an NIGMS MSTP grant, and an American Heart Association predoctoral fellowship. Authors reported no relationships relevant to the paper.
This is a preclinical mouse study; the mouse cardiometabolic-heart-disease model (high-fat, high-sucrose diet) is an established but reductive surrogate for the human HFpEF / diabetic-cardiomyopathy phenotype, and the conclusions do not translate directly to clinical HFpEF outcome trial readouts.
The pair-feeding control isolates caloric intake but does not isolate the meal-frequency or post-prandial glycemic-excursion differences between semaglutide-treated and pair-fed animals — semaglutide-treated mice may have a flatter glycemic profile per kcal consumed, which could mediate part of the "weight-independent" effect through a glycemia pathway rather than a direct cardiac GLP-1 receptor pathway. The abstract does not report sample sizes per arm or effect sizes with confidence intervals.
The CMR pipeline was performed at the University of Virginia using a research-grade high-field scanner; image quality and analysis pipelines may not generalise to clinical CMR practice. Fibrosis was histologically confirmed but the quantification method is not detailed in the abstract. Abstract-only extraction.
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