Abstract
BACKGROUND AND AIMS Heart failure with preserved ejection fraction (HFpEF) remains a therapeutic challenge. GLP-1 receptor agonists (GLP-1RAs) show clinical promise, and the prevailing hypothesis is that their benefits are primarily driven by weight loss and the downstream benefits of improved functional status. We investigated the weight loss-independent effects of low-dose GLP-1RA therapy in a clinically relevant rodent model of severe cardiometabolic HFpEF.
METHODS Ten-week-old male ZSF1 obese rats with spontaneous HFpEF were treated with low-dose semaglutide (30 nmol/kg twice weekly, n=6) or vehicle for 16 weeks. Comprehensive assessments included body weight, 2-D echocardiography, invasive hemodynamics, exercise capacity as well as cardiac and hepatic fibrosis and lipid deposition. The study utilized advanced multi-omics approaches, including single-cell RNA sequencing of the heart and liver, as well as cardiac, hepatic and plasma proteomics, to explore underlying mechanisms.
RESULTS In ZSF1 obese rats, low-dose semaglutide in the absence of weight loss, significantly improved cardiac function, exercise tolerance, and attenuated fibrosis in the heart and liver. Interestingly, semaglutide therapy reduced cardiac and hepatic lipid content as well as lipid droplets in cardiac myocytes and hepatocytes. Mechanistically, multi-omics analyses of cardiac and hepatic tissues revealed that semaglutide exerted these benefits by improving cardiac metabolism, interfering with pro-fibrotic and pro-hypertrophic signals, and by reducing systemic inflammation.
CONCLUSIONS Low-dose semaglutide provides significant cardioprotective, hepatoprotective, and metabolic benefits in HFpEF independent of weight loss. Our findings support the investigation of lower GLP-1RA dosing in HFpEF and other cardiovascular conditions, including in non-obese patients, to expand the clinical utility of these potent drugs.
Authors and Affiliations
Mahmoud H. Elbatreek, Ph.D.¹˒⁹, Zhen Li, Ph.D.², Xiaoman Yu, M.S.², Natalie D. Gehred, Ph.D.³, Tatiana Gromova, Ph.D.³, Jingshu Chen, Ph.D.⁴, Naoto Muraoka, Ph.D.⁴, Martin Jensen, Ph.D.⁴, Vinay Kartha, Ph.D.⁴, Chris Carrico, Ph.D.⁴, Timothy D. Allerton, Ph.D.⁵, Michael E. Bowdish, M.D.¹, Joanna Chikwe, M.D.¹, Sanjiv J. Shah, M.D.⁶, Kathleen C. Woulfe, Ph.D.⁷, Timothy A. McKinsey, Ph.D.⁷, Edwin Yoo, M.D., Ph.D.⁸, David J. Polhemus, M.D., Ph.D.⁸, Thomas M. Vondriska, Ph.D.³, Traci T. Goodchild, Ph.D.¹, and David J. Lefer, Ph.D.¹*
¹ Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
² School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
³ Departments of Anesthesiology & Perioperative Medicine, Medicine and Physiology, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA
⁴ Gordian Biotechnology, South San Francisco, CA
⁵ Vascular Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA
⁶ Northwestern University Medicine, Feinberg School of Medicine, Chicago, IL
⁷ Department of Medicine, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora
⁸ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
⁹ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
\* Corresponding author: David J. Lefer