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Animal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery

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Abstract

Heart failure (HF) with preserved ejection fraction (HFpEF) is currently a preeminent challenge for cardiovascular medicine. It has a poor prognosis, increasing mortality, and is escalating in prevalence worldwide. Despite accounting for over 50% of all HF patients, the mechanistic underpinnings driving HFpEF are poorly understood, thus impeding the discovery and development of mechanism-based therapies. HFpEF is a disease syndrome driven by diverse comorbidities, including hypertension, diabetes and obesity, pulmonary hypertension, aging, and atrial fibrillation. There is a lack of high-fidelity animal models that faithfully recapitulate the HFpEF phenotype, owing primarily to the disease heterogeneity, which has hampered our understanding of the complex pathophysiology of HFpEF. This review provides an updated overview of the currently available animal models of HFpEF and discusses their characteristics from the perspective of energy metabolism. Interventional strategies for efficiently utilizing energy substrates in preclinical HFpEF models are also discussed.

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Fig. 1: Risk factors, species of choice, and key hallmarks of preclinical HFpEF models.
Fig. 2: A systematic overview of glucose, fatty acids and ketone body metabolism in the HFpEF heart.
Fig. 3: Therapeutic approaches targeting metabolic derangement in HFpEF.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 82160278, 81500214, 82370444 and 82070464), the Guangxi Natural Science Foundation (No. 2023GXNSFAA026209) and the Doctoral Foundation of Guangxi University of Science and Technology (No. 20Z23). The elements in Figs. 1, 3 were provided by Freepik (https://www.freepik.com/) and used for a fee. The elements in Fig. 2 were provided by Servier Medical ART (https://smart.servier.com/).

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  1. Department of Pharmacy, School of Medicine, Guangxi University of Science and Technology, Liuzhou, 545005, China

    Si Gao, Xue-ping Liu, Ting-ting Li, Li Chen, Yi-ping Feng, Yu-kun Wang & Xu-dong Jiang

  2. School of Pharmacy, Bengbu Medical College, Bengbu, 233000, China

    Yan-jun Yin

  3. School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, 4102, Australia

    Peter J. Little

  4. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China

    Xiao-qian Wu

  5. Department of Endocrinology, First Affiliated Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Suo-wen Xu

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XJ, SX, and XW conceived this manuscript. SG and XW wrote and edited the manuscript. XL and TL reviewed and made significant revisions to the manuscript. LC organized the table contents. YF, YW, and YY edited the manuscript. PJL provided clinical insights and fine-tuned the English language presentation of the manuscript.

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Correspondence to Xiao-qian Wu, Suo-wen Xu or Xu-dong Jiang.

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Gao, S., Liu, Xp., Li, Tt. et al. Animal models of heart failure with preserved ejection fraction (HFpEF): from metabolic pathobiology to drug discovery. Acta Pharmacol Sin 45, 23–35 (2024). https://doi.org/10.1038/s41401-023-01152-0

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