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  • Review Article
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Pathophysiological insights into HFpEF from studies of human cardiac tissue

Nature Reviews Cardiology volume 22, pages 90–104 (2025)Cite this article

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Abstract

Heart failure with preserved ejection fraction (HFpEF) is a major, worldwide health-care problem. Few therapies for HFpEF exist because the pathophysiology of this condition is poorly defined and, increasingly, postulated to be diverse. Although perturbations in other organs contribute to the clinical profile in HFpEF, altered cardiac structure, function or both are the primary causes of this heart failure syndrome. Therefore, studying myocardial tissue is fundamental to improve pathophysiological insights and therapeutic discovery in HFpEF. Most studies of myocardial changes in HFpEF have relied on cardiac tissue from animal models without (or with limited) confirmatory studies in human cardiac tissue. Animal models of HFpEF have evolved based on theoretical HFpEF aetiologies, but these models might not reflect the complex pathophysiology of human HFpEF. The focus of this Review is the pathophysiological insights gained from studies of human HFpEF myocardium. We outline the rationale for these studies, the challenges and opportunities in obtaining myocardial tissue from patients with HFpEF and relevant comparator groups, the analytical approaches, the pathophysiological insights gained to date and the remaining knowledge gaps. Our objective is to provide a roadmap for future studies of cardiac tissue from diverse cohorts of patients with HFpEF, coupling discovery biology with measures to account for pathophysiological diversity.

Key points

  • Few studies of cardiac tissue from patients with heart failure with preserved ejection fraction (HFpEF) and comparator groups have been published.

  • Most of these studies were small and showed variability in tissue source, case–control ascertainment and analytical approaches.

  • Cardiac tissue samples from patients with HFpEF show variable degrees of myocardial fibrosis, hypertrophy, microvascular rarefaction, T-tubule disruption, systolic and diastolic dysfunction and impaired metabolism.

  • Only eight candidate pathophysiological pathways have been examined in hypothesis-driven studies of cardiac tissue from patients with HFpEF, and these studies have not led to consensus on its pathophysiology.

  • Only four studies used discovery transcriptomics or proteomic technologies in cardiac tissue from patients with HFpEF and comparators, and showed intriguing, but highly variable, findings.

  • Studies of heart tissue in large and diverse cohorts of patients with HFpEF are urgently needed, with discovery multiomics, appropriate bioinformatic analyses and rigorous validation to address pathophysiological diversity and gain novel therapeutic insights.

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Fig. 1: Structural, functional and metabolic alterations in the myocardium from patients with HFpEF.
Fig. 2: Pathophysiological mechanisms in human HFpEF.
Fig. 3: Studies of tissue samples from patients with HFpEF and comparators.

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Acknowledgements

A.U.F. and K.E.K. are supported by T32 HL007111. B.A.B. is supported by R01 HL128526, R01 HL162828, U01 HL160226 and W81XWH2210245 from the US Department of Defense, and a grant from the Accelerating Medicines Partnership for Heart Failure through the Foundation for the National Institutes of Health (FNIH). S.D. is supported by HL162828 and U01HL160226. K.B.M. is supported by R01 HL149891 and a grant from the Accelerating Medicines Partnership for Heart Failure through the FNIH. Y.W. is supported by HL 148339, DK 117910 and a grant from the Cardiovascular Department, Mayo Clinic, Rochester, MN. M.M.R. is supported by HL162828, U01 HL160226 and a grant from the Accelerating Medicines Partnership for Heart Failure through the FNIH.

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Authors and Affiliations

  1. Department of Cardiovascular Disease, Division of Circulatory Failure, Mayo Clinic, Rochester, MN, USA

    Ahmed U. Fayyaz, Muhammad Eltony, Katlyn E. Koepp, Barry A. Borlaug, Ying Wang & Margaret M. Redfield

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Ahmed U. Fayyaz, Melanie C. Bois & Joesph J. Maleszewski

  3. Mayo Clinic College of Medicine and Science, Library Reference Service, Rochester, MN, USA

    Larry J. Prokop

  4. Mayo Clinic College of Medicine and Science, Computational Biology, Rochester, MN, USA

    Surendra Dasari

  5. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Kenneth B. Margulies

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Contributions

A.U.F., M.E., L.J.P., K.E.K. and M.M.R. researched data for the article. A.U.F. and M.M.R. contributed substantially to discussion of the content and wrote the manuscript. All authors reviewed or edited the manuscript before submission.

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Correspondence to Margaret M. Redfield.

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Nature Reviews Cardiology thanks Michele Senni, Walter J. Paulus and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Review criteria

The review strategy to identify all studies of human myocardial tissue in heart failure with preserved ejection fraction (HFpEF) was performed in accordance with the systematic scoping review guidelines150,151,152. Databases, including Ovid MEDLINER, Ovid EMBASE, Scopus and Web of Science, were searched in English from their inception until 17 August 2022. An experienced librarian (L.J.P.), with input from the rest of the authors, designed and executed the search strategy using controlled vocabulary and keywords for human tissue and HFpEF or diastolic heart failure or dysfunction. Inclusion criteria included: (1) original investigation, (2) study of human cardiac tissue solely or for validation of findings observed in animal models, and (3) tissue obtained from patients with clinical diagnosis of HFpEF or rigorously documented diastolic dysfunction. Use of human cardiac tissue as non-HFpEF comparator was recorded but not required for inclusion. Studies that relied solely on imaging or other non-tissue collection procedures to characterize myocardial properties were excluded. Two investigators (A.U.F. and M.E.) reviewed titles, abstracts and figures from the search results and excluded articles clearly not meeting the predefined eligibility criteria. Three investigators (A.U.F., M.E. and M.M.R.) independently reviewed the remaining studies in detail and excluded those that did not meet the selection criteria or that were restricted to specific heart failure aetiologies (infiltrative or hypertrophic cardiomyopathy). Abstracted data included study type (human-only versus animal model plus human tissue), heart failure diagnostic criteria, ejection fraction criteria for HFpEF diagnosis, and comparator groups (heart failure with reduced ejection fraction (HFrEF) or comparators without heart failure (non-failing comparators)). Within HFpEF, other comparators were noted (Supplementary Box 1). Additionally, group sizes, age, whether both sexes were included, type of tissue (myocardium versus adipose), biopsy site and biopsy acquisition method were recorded. When human tissue studies were performed as part of an animal model-based study, only findings pertinent to the human tissue studies were presented. A total of 6,465 articles were identified from the database search and 14 from other sources (such as authors’ previous knowledge or included in the reference list of identified articles) and 4,083 duplicates were removed (Supplementary Fig. 1a). After title, abstract and figure review, 2,254 articles not meeting the inclusion criteria were excluded. After full-text assessment, another 86 studies did not meet inclusion criteria. Ultimately, 56 studies qualified for inclusion20,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,66,73,78,79,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128, which included 11 (refs. 37,38,42,45,52,55,58,61,64,66,114) identified in cited references or by investigator pre-existing knowledge, and three47,115,124 that were published subsequent to the literature search end-date. The included studies were from 2004 to 2023 (Supplementary Fig. 1b), with 28 (50%) studies published since 2018. Most studies were published in high-impact journals (Supplementary Fig. 1c). Some relevant studies might have been missed by our search and review strategies, and new studies might have emerged during the review and publication process. Our summaries were brief and focused on mechanistic insights and did not detail the strengths and weaknesses of each study.

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Fayyaz, A.U., Eltony, M., Prokop, L.J. et al. Pathophysiological insights into HFpEF from studies of human cardiac tissue. Nat Rev Cardiol 22, 90–104 (2025). https://doi.org/10.1038/s41569-024-01067-1

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