Research Priorities for Heart Failure With Preserved Ejection Fraction: National Heart, Lung, and Blood Institute Working Group Summary
Open accessAbstract
Heart failure with preserved ejection fraction (HFpEF), a major public health problem that is rising in prevalence, is associated with high morbidity and mortality and is considered to be the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. To address this challenging syndrome, the National Heart, Lung, and Blood Institute convened a working group made up of experts in HFpEF and novel research methodologies to discuss research gaps and to prioritize research directions over the next decade. Here, we summarize the discussion of the working group, followed by key recommendations for future research priorities. There was uniform recognition that HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF. It was recognized that advances in the understanding of basic mechanisms and the roles of inflammation, macrovascular and microvascular dysfunction, fibrosis, and tissue remodeling are needed and ideally would be obtained from (1) improved animal models, including large animal models, which incorporate the effects of aging and associated comorbid conditions; (2) repositories of deeply phenotyped physiological data and human tissue, made accessible to researchers to enhance collaboration and research advances; and (3) novel research methods that take advantage of computational advances and multiscale modeling for the analysis of complex, high-density data across multiple domains. The working group emphasized the need for interactions among basic, translational, clinical, and epidemiological scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers. A network of collaborative centers to accelerate basic, translational, and clinical research of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress. This resource would facilitate comprehensive, deep phenotyping of a multicenter HFpEF patient cohort with standardized protocols and a robust biorepository. The research priorities outlined in this document are meant to stimulate scientific advances in HFpEF by providing a road map for future collaborative investigations among a diverse group of scientists across multiple domains.
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Obesity and diabetes create a pro-inflammatory state and promote endothelial and coronary microvascular dysfunction.
“Obesity and diabetes create a pro-inflammatory state and promote endothelial and coronary microvascular dysfunction. 1,7,8”
From Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials (2024) · cites this paper as [1]
The Adipose tissue pathophysiology section says excess adipose tissue causes systemic inflammation and impaired nitric-oxide signaling. The Cardiac pathophysiology section links microvascular inflammation to coronary microvascular dysfunction, but describes that link as a belief needing further study. The paper identifies diabetes as an HFpEF risk factor; these passages do not establish that diabetes itself causes the stated inflammatory and vascular changes. (LLM, conf=0.83)
Experimental — accuracy not yet measuredObesity is a major risk factor for the development and progression of heart failure with preserved ejection fraction.
“Obesity is a major risk factor for heart failure (HF) with preserved ejection fraction (HFpEF). 1,2”
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Heart Failure With Preserved Ejection Fraction: A Review
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Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF
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Discovery of Titin and Its Role in Heart Function and Disease
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What’s wrong with my experiment?: The impact of hidden variables on neuropsychopharmacology research
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Right Heart Phenotype in Heart Failure With Preserved Ejection Fraction
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The role of epicardial adipose tissue remodelling in heart failure with preserved ejection fraction
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Pathophysiology of Heart Failure with Preserved Ejection Fraction
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Hernández, J. M., Shen, E. Y., Ko, C. Y., Hourani, Z., Spencer, E. R., Smoliarchuk, D., Bossuyt, J., Granzier, H. L. M., Bers, D. M., & Hegyi, B. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae070 · Cited by 42 · see citing works
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Chao, C., Kato, N., Scott, C. G., López-Jiménez, F. A., Lin, G., Kane, G. C., & Pellikka, P. A. (2022) · Journal of the American Society of Echocardiography · doi:10.1016/j.echo.2022.06.013 · Cited by 40 · see citing works
Takvorian, K. S., Wang, D., Courchesne, P. L., Vasan, R. S., Benjamin, E. J., Cheng, S. C., Larson, M. G., Levy, D. A., & Ho, J. E. (2022) · Circulation Heart Failure · doi:10.1161/circheartfailure.121.009446 · Cited by 42 · see citing works
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Diabetes and Excess Aldosterone Promote Heart Failure With Preserved Ejection Fraction
Hegyi, B., Hernández, J. M., Ko, C. Y., Hong, J., Shen, E. Y., Spencer, E. R., Smoliarchuk, D., Navedo, M. F., Bers, D. M., & Bossuyt, J. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.122.027164 · Cited by 37 · see citing works
Periodontal Status, C-Reactive Protein, NT-proBNP, and Incident Heart Failure
Molinsky, R. L., yuzefpolskaya, M., Norby, F. L., Yu, B., Shah, A. M., Pankow, J. S., Ndumele, C. E., Lutsey, P. L., Papapanou, P. N., Beck, J. D., et al. (2022) · JACC Heart Failure · doi:10.1016/j.jchf.2022.05.008 · Cited by 35 · see citing works
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Ostrominski, J. W., Vaduganathan, M., Claggett, B. L., de Boer, R. A., Desai, A. S., Dobreanu, D., Hernandez, A. F., Inzucchi, S. E., Jhund, P. S., Kosiborod, M., et al. (2022) · European Journal of Heart Failure · doi:10.1002/ejhf.2652 · Cited by 36 · see citing works
Abudureyimu, M., Yang, M., Wang, X., Luo, X., Ge, J., Hu, P., Zhang, Y., & Ren, J. T. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-0983-0 · Cited by 33 · see citing works
Reddy, Y. N. V., Stewart, G. M., Obokata, M., Koepp, K. E., & Borlaug, B. A. (2021) · European Journal of Heart Failure · doi:10.1002/ejhf.2093 · Cited by 33 · see citing works
The future of heart failure with preserved ejection fraction
Heinzel, F. R., & Shah, S. J. (2022) · Herz · doi:10.1007/s00059-022-05124-8 · Cited by 33 · see citing works
Bakhshi, H., Michelhaugh, S. A., Bruce, S. A., Seliger, S. L., Qian, X., Ambale‐Venkatesh, B., Varadarajan, V., Bagchi, P., Lima, J. A. C., & deFilippi, C. R. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104490 · Cited by 35 · see citing works
Vistnes, M., Erusappan, P. M., Sasi, A., Nordén, E. S., Bergo, K. K., Romaine, A., Lunde, I. G., Zhang, L., Olsen, M. B., Øgaard, J., et al. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad078 · Cited by 31 · see citing works
Endothelial-Mesenchymal Transition in Heart Failure With a Preserved Ejection Fraction
Valero‐Muñoz, M., Oh, A., Faudoa, E., Bretón‐Romero, R., El-Adili, F., Bujor, A. M., & Sam, F. (2021) · Circulation Heart Failure · doi:10.1161/circheartfailure.121.008372 · Cited by 31 · see citing works
Left Atrial Myopathy in Heart Failure With Preserved Ejection Fraction
Omote, K., & Borlaug, B. A. (2021) · Circulation Journal · doi:10.1253/circj.cj-21-0795 · Cited by 30 · see citing works
Impaired Right Atrial Reserve Function in Heart Failure with Preserved Ejection Fraction
Kagami, K., Harada, T., Yoshida, K., Amanai, S., Kato, T., Wada, N., Adachi, T. K., & Obokata, M. (2022) · Journal of the American Society of Echocardiography · doi:10.1016/j.echo.2022.03.006 · Cited by 30 · see citing works
Harada, T., Yamaguchi, M., Omote, K., Iwano, H., Mizuguchi, Y., Amanai, S., Yoshida, K., Kato, T., Kurosawa, K., Nagai, T., et al. (2022) · Circulation Cardiovascular Imaging · doi:10.1161/circimaging.121.013495 · Cited by 30 · see citing works
Shi, Y., Dong, G., Liu, J., Xiong, S., Liu, C., Yang, C., Wang, Q., & Qiao, W. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.854501 · Cited by 30 · see citing works
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Nrf2-Keap1 in Cardiovascular Disease: Which Is the Cart and Which the Horse?
Dhyani, N., Tian, C., Gao, L., Rudebush, T., & Zucker, I. H. (2024) · Physiology · doi:10.1152/physiol.00015.2024 · Cited by 30 · see citing works
Cardiovascular, Kidney, Liver, and Metabolic Interactions in Heart Failure: Breaking Down Silos
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Biomarkers of HFpEF: Natriuretic Peptides, High-Sensitivity Troponins and Beyond
Morfino, P., Aimo, A., Castiglione, V., Vergaro, G., Emdin, M., & Clerico, A. (2022) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd9080256 · Cited by 31 · see citing works
Non-invasive assessment of HFpEF in mouse models: current gaps and future directions
Villalba‐Orero, M., García‐Pavía, P., & Lara‐Pezzi, E. (2022) · BMC Medicine · doi:10.1186/s12916-022-02546-3 · Cited by 29 · see citing works
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Functional Roles of Furin in Cardio-Cerebrovascular Diseases
Wichaiyo, S., Koonyosying, P., & Morales, N. P. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.3c00325 · Cited by 27 · see citing works
Wang, N., Rueter, P., Ng, M., Chandramohan, S., Hibbert, T., O’Sullivan, J., Kaye, D. M., & Lal, S. (2024) · European Journal of Heart Failure · doi:10.1002/ejhf.3271 · Cited by 27 · see citing works
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Rieger, A. C., Bagno, L., Salerno, A. G., Florea, V., Rodriguez, J. E., Rosado, M., Turner, D., Dulce, R. A., Takeuchi, L. M., Kanashiro‐Takeuchi, R. M., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2019835118 · Cited by 27 · see citing works
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Lifestyle interventions in cardiometabolic HFpEF: dietary and exercise modalities
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Circulating Non-Coding RNAs as Indicators of Fibrosis and Heart Failure Severity
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- Authors
- Shah, S. J., Borlaug, B. A., Kitzman, D. W., McCulloch, A. D., Blaxall, B. C., Agarwal, R., Chirinos, J. A., Collins, S., Deo, R. C., Gladwin, M. T., Granzier, H., Hummel, S. L., Kass, D. A., Redfield, M. M., Sam, F., Wang, T. J., Desvigne-Nickens, P., & Adhikari, B. B.
- Affiliations
- Northwestern University (US)
- Mayo Clinic (US)
- Wake Forest University Health Sciences (US)
- University of California San Diego (US)
- Christ Hospital (US)
- Indiana University Indianapolis (US)
- University of Pennsylvania (US)
- Vanderbilt University (US)
- Brigham and Women's Hospital (US)
- University of Pittsburgh (US)
- University of Arizona (US)
- University of Michigan (US)
- Johns Hopkins University (US)
- Boston University (US)
- National Institutes of Health (US)
- ORCID
- Venue
- Circulation
- Published
- 2020-03-24
- Volume
- 141
- Issue
- 12
- Pages
- 1001-1026
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC7101072
- OpenAlex
- W3012616651
- Cited by
- 436
- References
- 114
- Citations by year
- 2026: 53 · 2025: 74 · 2024: 74 · 2023: 67 · 2022: 99 · 2021: 49 · 2020: 19
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG018915, R01AG045551, R01AG058969, P30AG021332, U24AG059624)
- National Heart, Lung, and Blood Institute (R01HL128526, R61HL146390, R01HL118524, U01HL125175, R01HL127028, R01HL144657, R01HL104106, R01HL126638, U10HL110262, R01HL149423, DP2HL123228, R35HL135827, P01HL103455, R01HL117153, R01HL140731, P01HL094307, R01HL132551, U01HL125205, R01HL133695, R01HL121510, R01HL107577, R56HL136730, R01HL134321, R01HL125886, R01HL098032, T32HL110849)
- National Cancer Institute (K12CA090625)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103056, P50DK096418)
- 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 › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- heart failure with preserved ejection fraction, research priorities, research gaps, animal models, inflammation, microvascular dysfunction, macrovascular dysfunction, fibrosis, tissue remodeling, biorepository, multiscale modeling, translational research
- MeSH terms
- Heart Failure, Humans, Research, Stroke Volume, United States, National Heart, Lung, and Blood Institute (U.S.)
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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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