The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction
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AIMS: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like glucagon-like peptide receptor agonist (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide (Lira) and the SGLT2i dapagliflozin (Dapa). METHODS AND RESULTS: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high-fat diet (HFD) for 12 weeks. After 8 weeks HFD, angiotensin II (ANGII), was administered for 4 weeks via osmotic mini pumps. HFD + ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling, and metabolic dysregulation with inflammation. The multiple hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement, lung congestion, and elevated blood pressures. Treatment with Lira attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapa treatment improved glucose handling, but had mild effects on the HFpEF phenotype. CONCLUSIONS: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and the development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for the treatment of HFpEF.
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The murine model of HFpEF has several similarities with human HFpEF.
“We have shown previously that a murine model of HFpEF has several similarities with human HFpEF.27,28”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [28]
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Mitochondrial Dysfunction in HFpEF: Potential Interventions Through Exercise
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Are fat and sugar just as detrimental in old age?
Valencia, A. P., Nagaraj, N., Osman, D. H., Rabinovitch, P. S., & Marcinek, D. J. (2021) · GeroScience · doi:10.1007/s11357-021-00390-6 · Cited by 17 · see citing works
Pugliese, N. R., Paneni, F., Tricò, D., Bacca, A. V., De Biase, N., Dalpiaz, H., Mengozzi, A., Virdis, A., Ghiadoni, L., Taddei, S., et al. (2025) · Cardiovascular Diabetology · doi:10.1186/s12933-025-02778-6 · Cited by 16 · see citing works
Yang, Z., Tian, R., Zhang, X., Cai, J., She, Z., & Li, H. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.1120085 · Cited by 16 · see citing works
Non-coding RNAs in the pathophysiology of heart failure with preserved ejection fraction
Jalink, E. A., Schonk, A. W., Boon, R. A., & Juni, R. P. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1300375 · Cited by 16 · see citing works
Aidara, M. L., Walsh‐Wilkinson, É., Thibodeau, S.-È., Labbé, E.-A., Morin-Grandmont, A., Gagnon, G., Boudreau, D. K., Arsenault, M., Bossé, Y., & Couët, J. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00462.2023 · Cited by 16 · see citing works
Cersosimo, A., Salerno, N., Sabatino, J., Scatteia, A., Bisaccia, G., Rosa, S. D., Dellegrottaglie, S., Bucciarelli‐Ducci, C., Torella, D., & Leo, I. (2024) · Cardiovascular Diabetology · doi:10.1186/s12933-024-02181-7 · Cited by 16 · see citing works
Sharma, A., Blasio, M. J. D., & Ritchie, R. H. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15820 · Cited by 16 · see citing works
Do obesity and visceral adiposity promote heart failure with reduced ejection fraction?
Packer, M. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf645 · Cited by 16 · see citing works
Güven, B., Sun, Q., Wagg, C. S., de Oliveira, A. A., Silver, H. L., Persad, K. L., Onay-Beşi̇kçi̇, A., Vu, J., Oudit, G. Y., & Lopaschuk, G. D. (2023) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.123.001791 · Cited by 15 · see citing works
Beyond Weight Loss: the Emerging Role of Incretin-Based Treatments in Cardiometabolic HFpEF
Capone, F., Nambiar, N., & Schiattarella, G. G. (2024) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000001117 · Cited by 15 · see citing works
Kobak, K. A., Zarzycka, W., King, C. J., Borowik, A., Peelor, F. F., Baehr, L. M., Leutert, M., Rodríguez‐Mias, R. A., Villén, J., Bodine, S. C., et al. (2025) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2024.11.006 · Cited by 14 · see citing works
Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction
Troy, A. M., Normukhamedova, D., Grothe, D., Momen, A., Zhou, Y., McFadden, M. J., Husain, M., Billia, F., & Cheng, H. M. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00733.2023 · Cited by 14 · see citing works
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Clinical Update in Heart Failure with Preserved Ejection Fraction
Krittanawong, C., Britt, W., Rizwan, A. M., Siddiqui, R., Khawaja, M., Khan, R., Joolharzadeh, P., Newman, N. A., Rivera, M. R. R., & Tang, W. H. W. (2024) · Current Heart Failure Reports · doi:10.1007/s11897-024-00679-5 · Cited by 17 · see citing works
Walsh‐Wilkinson, É., Aidara, M. L., Morin-Grandmont, A., Thibodeau, S.-È., Gagnon, J., Genest, M., Arsenault, M., & Couët, J. (2022) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00044.2022 · Cited by 14 · see citing works
Zheng, Q., Li, H., Jiang, Y., Yang, P., Yin, G., Yang, L., Li, S., & Sun, L. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114760 · Cited by 13 · see citing works
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Zheng, W., Qi, Q., Li, J., He, C., & Fan, H. (2025) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-025-01917-z · Cited by 17 · see citing works
Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications
Ye, M., Feng, S., Xu, Z., He, W., Liu, C., & Zhu, W. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156460 · Cited by 14 · see citing works
Liraglutide Protects Against Diastolic Dysfunction and Improves Ventricular Protein Translation
Rutledge, C. A., Enriquez, A., Redding, K., Lopez, M. A., Mullett, S. J., Gelhaus, S. L., Jurczak, M. J., Goetzman, E. S., & Kaufman, B. A. (2023) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-023-07482-9 · Cited by 13 · see citing works
The immunology of heart failure with preserved ejection fraction
Smart, C. D., & Madhur, M. S. (2023) · Clinical Science · doi:10.1042/cs20230226 · Cited by 15 · see citing works
- Authors
- Withaar, C., Meems, L. M. G., Markousis-Mavrogenis, G., Boogerd, C. J., Silljé, H. H. W., Schouten, E. M., Dokter, M. M., Voors, A. A., Westenbrink, B. D., Lam, C. S. P., & de Boer, R. A.
- Affiliations
- University Medical Center Groningen (NL)
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
- Royal Netherlands Academy of Arts and Sciences (NL)
- ORCID
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-09-01
- Volume
- 117
- Issue
- 9
- Pages
- 2108-2124
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC8318109
- OpenAlex
- W3082464276
- Cited by
- 223
- References
- 88
- Citations by year
- 2026: 30 · 2025: 47 · 2024: 48 · 2023: 43 · 2022: 37 · 2021: 15 · 2020: 3
- FWCI
- 15.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cardiovascular Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc)
- Funders
- Netherlands Heart Foundation Senior Clinical Scientist Grant (2019T064)
- Rosalind Franklin Fellowship
- Novo Nordisk
- Mouse Clinic for Cancer and Aging
- Netherlands Organization for Scientific Research (917.13.350)
- Netherlands Heart Foundation (2014-40, 2017-21, 2017-11, 2018-30)
- leDucq Foundation
- European Research Council (CoG 818715)
- European Union’s Horizon2020 research and innovation program
- Marie Skłodowska-Curie (751988)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- heart failure with preserved ejection fraction, liraglutide, dapagliflozin, GLP-1 receptor agonists, SGLT2 inhibitors, high-fat diet, angiotensin II, obesity, type 2 diabetes, cardiac hypertrophy, myocardial fibrosis, atrial enlargement, pulmonary congestion, natriuretic peptides, mouse model, cardiac function
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, Angiotensin II, Animals, Benzhydryl Compounds, Blood Glucose, Disease Models, Animal, Female, Fibrosis, Gene Expression Regulation, Glucosides, Mice, Inbred C57BL, Myocardium, Signal Transduction, Ventricular Function, Left, Hypertrophy, Left Ventricular, Ventricular Remodeling, Mice, Heart Failure, Diastolic, Incretins, Diet, High-Fat
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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