Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction: A Multiorgan Roadmap
Open accessAbstract
Heart failure (HF) with preserved ejection fraction (EF; HFpEF) accounts for 50% of HF cases, and its prevalence relative to HF with reduced EF continues to rise. In contrast to HF with reduced EF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, an HFpEF treatment strategy is proposed that addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension, and renal insufficiency drive left ventricular remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects left ventricular diastolic dysfunction through macrophage infiltration, resulting in interstitial fibrosis, and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide and cyclic guanosine monophosphate. Systemic inflammation also affects other organs such as lungs, skeletal muscle, and kidneys, leading, respectively, to pulmonary hypertension, muscle weakness, and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial nitric oxide bioavailability by inorganic nitrate-nitrite, myocardial cyclic guanosine monophosphate content by neprilysin or phosphodiesterase 9 inhibition, and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.
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Dysfunction of endothelial cells, induced by hyperglycemia and driven by systemic proinflammatory state, trigger cardiomyocyte dysfunction in HFpEF.
“dysfunction of endothelial cells, induced by hyperglycemia and driven by this systemic proinflammatory state, trigger cardiomyocyte dysfunction in HFpEF.”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [64]
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Artificial intelligence in cardiology
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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., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvaa256 · Cited by 223 · see citing works
Exercise Intolerance in Older Adults With Heart Failure With Preserved Ejection Fraction
Pandey, A., Shah, S. J., Butler, J., Kellogg, D. L., Lewis, G. D., Forman, D. E., Mentz, R. J., Borlaug, B. A., Simon, M. A., Chirinos, J. A., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.07.014 · Cited by 184 · see citing works
Self-citationHaykowsky, M. J., Nicklas, B. J., Brubaker, P. H., Hundley, W. G., Brinkley, T. E., Upadhya, B., Becton, J. T., Nelson, M. D., Chen, H., & Kitzman, D. W. (2018) · JACC: Heart Failure · doi:10.1016/j.jchf.2018.06.002 · Cited by 179 · see citing works
Self-citationObesity-Related Heart Failure With a Preserved Ejection Fraction
Packer, M., & Kitzman, D. W. (2018) · JACC: Heart Failure · doi:10.1016/j.jchf.2018.01.009 · Cited by 172 · see citing works
Self-citationWithaar, C., Lam, C. S. P., Schiattarella, G. G., de Boer, R. A., & Meems, L. M. G. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab389 · Cited by 150 · see citing works
Reddy, Y. N. V., Lewis, G. D., Shah, S. J., Obokata, M., Abou-Ezzedine, O. F., Fudim, M., Sun, J.-L., Chakraborty, H., McNulty, S., LeWinter, M. M., et al. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.11.037 · Cited by 141 · see citing works
Self-citationKosiborod, M. N., Abildstrøm, S. Z., Borlaug, B. A., Butler, J., Christensen, L., Davies, M., Hovingh, K. G., Kitzman, D. W., Lindegaard, M. L., Møller, D. V., et al. (2023) · JACC: Heart Failure · doi:10.1016/j.jchf.2023.05.010 · Cited by 97 · see citing works
Self-citationThe cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF
Withaar, C., Meems, L. M. G., Nollet, E. E., Schouten, E. M., Schroeder, M. A., Knudsen, L. B., Niss, K., Madsen, C. T., Hoegl, A., Mazzoni, G., et al. (2023) · JACC: Basic to Translational Science · doi:10.1016/j.jacbts.2023.05.012 · Cited by 74 · see citing works
Targeting obesity and diabetes to treat heart failure with preserved ejection fraction
Altara, R., Giordano, M., Nordén, E. S., Cataliotti, A., Kurdi, M., Bajestani, S. N., & Booz, G. W. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00160 · Cited by 61 · see citing works
Elsanhoury, A., Nelki, V., Kelle, S., Van Linthout, S., & Tschöpe, C. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.720690 · Cited by 51 · see citing works
Pathophysiology of Heart Failure with Preserved Ejection Fraction
Youn, J.-C., Ahn, Y., & Jung, H. O. (2021) · Heart Failure Clinics · doi:10.1016/j.hfc.2021.02.001 · Cited by 45 · see citing works
Teramoto, K., Nadruz Junior, W., Matsushita, K., Claggett, B., John, J. E., Skali, H., Solomon, S., Cheng, S., & Shah, A. M. (2020) · Hypertension · doi:10.1161/hypertensionaha.120.14833 · Cited by 36 · see citing works
Myocardial Infarction in Heart Failure With Preserved Ejection Fraction
Cunningham, J. W., Vaduganathan, M., Claggett, B. L., John, J. E., Desai, A. S., Lewis, E. F., Zile, M. R., Carson, P., Jhund, P. S., Kober, L., et al. (2020) · JACC: Heart Failure · doi:10.1016/j.jchf.2020.02.007 · Cited by 33 · see citing works
Self-citationAdvances in Machine Learning Approaches to Heart Failure with Preserved Ejection Fraction
Ahmad, F. S., Luo, Y., Wehbe, R. M., Thomas, J. D., & Shah, S. J. (2022) · Heart Failure Clinics · doi:10.1016/j.hfc.2021.12.002 · Cited by 34 · see citing works
Self-citationPandey, A., & Kitzman, D. W. (2021) · JAMA · doi:10.1001/jama.2020.26347 · Cited by 24 · see citing works
Self-citationCosta, K. D., Wong, A. O. T., Mak, S. Y., Roberts, E. G., Keung, W., Correia, C., Walentinsson, A., Christoffersson, J., Cheung, A., Lieu, D. K., et al. (2024) · bioRxiv · doi:10.1101/2024.08.27.609034 · Cited by 5 · see citing works
- Authors
- Shah, S. J., Kitzman, D. W., Borlaug, B. A., van Heerebeek, L., Zile, M. R., Kass, D. A., & Paulus, W. J.
- Affiliations
- Northwestern University (US)
- From Division of Cardiology, Department of Medicine, and the Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.); Sections on Cardiovascular Medicine and Geriatrics, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, (B.A.B.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam...
- ORCID
- Venue
- Circulation
- Published
- 2016-07-05
- Volume
- 134
- Issue
- 1
- Pages
- 73-90
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC4930115
- OpenAlex
- W2462116812
- Cited by
- 1,003
- References
- 158
- Citations by year
- 2026: 88 · 2025: 78 · 2024: 91 · 2023: 82 · 2022: 125 · 2021: 113 · 2020: 124 · 2019: 97 · 2018: 100 · 2017: 81 · 2016: 22
- FWCI
- 82.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001420)
- National Institute on Aging (R01AG018915, P30AG021332)
- National Heart, Lung, and Blood Institute (R01HL114910, R01HL127028, U10HL110262, R01HL119012, R01HL123478, R01HL107577)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- heart failure with preserved ejection fraction, HFpEF phenotypes, left ventricular diastolic dysfunction, coronary microvascular dysfunction, systemic inflammation, macrophage infiltration, myocardial fibrosis, cardiomyocyte hypertrophy, nitric oxide bioavailability, cyclic GMP, pulmonary hypertension, exercise training, sodium retention, diuretics, neprilysin inhibition, spironolactone, statins, caloric restriction, personalized treatment, left ventricular remodeling
- MeSH terms
- Combined Modality Therapy, Coronary Disease, Endothelium, Vascular, Female, Heart Failure, Humans, Hypertension, Hypertension, Pulmonary, Inflammation, Kidney Diseases, Male, Phenotype, Stroke Volume, Signal Transduction, Comorbidity, Muscle Weakness, Precision Medicine
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