The DOI matches its Crossref record, with a small difference in title or year; 98 of the 99 references it cites were found in a registry or an index.
A Novel Paradigm for Heart Failure With Preserved Ejection Fraction
Open accessAbstract
Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.
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“The lessened secretion of inflammatory adipocytokines might act to alleviate coronary endothelial inflammation with secondary beneficial effects on microvascular rarefaction and myocardial fibrosis, 2 important mechanisms in the pathogenesis of HFpEF.46–48”
From Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity (2025) · cites this paper as [48]
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“Obesity and diabetes create a pro-inflammatory state and promote endothelial and coronary microvascular dysfunction. 1,7,8”
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“Obesity, diabetes, and HF result in pro-inflammatory states, 7,31-34 and each are risk factors for infectious disease complications, an important cause of morbidity and mortality in these patient groups.”
In the citing paper
“Inflammation due to sarcopenic obesity results in reduced NO, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) activity in cardiomyocytes, leading to LV hypertrophy and stiffness [120].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [120]
In the citing paper
“Inhibition of systemic metabolic inflammation with glucose-lowering drugs is thought to enhance endothelial and cardiomyocyte function”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [70]
In the citing paper
“Indirectly, through a paracrine endothelial signaling, hyperglycemia causes a mitochondrial hyper-production of superoxide, with impaired activation of endothelial nitric oxide synthase.”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [67]
In the citing paper
“As a result, the impaired bioavailability in nitric oxide impairs its downstream cGMP protein kinase G (PKG) pathway in cardiomyocytes which become hypertrophied and stiffened [65,67].”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [67]
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Cites
Pfeffer, M. A., Braunwald, E., Moyé, L. A., Basta, L., Brown, E. J., Cuddy, T. E., Davis, B. R., Geltman, E. M., Goldman, S., Flaker, G. C., et al. (1992) · New England Journal of Medicine · doi:10.1056/nejm199209033271001 · Cited by 5,911
NAD(P)H Oxidase: Role in Cardiovascular Biology and Disease
Griendling, K. K., Sorescu, D., & Ushio-Fukai, M. (2000) · Circulation Research · doi:10.1161/01.res.86.5.494 · Cited by 2,886
Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure
Cohn, J. N., Archibald, D. G., Ziesche, S., Franciosa, J. A., Harston, W. E., Tristani, F. E., Dunkman, W. B., Jacobs, W., Francis, G. S., Flohr, K. H., et al. (1986) · New England Journal of Medicine · doi:10.1056/nejm198606123142404 · Cited by 2,400
Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure
Taylor, A. L., Ziesche, S., Yancy, C., Carson, P., D'Agostino, R., Ferdinand, K., Taylor, M., Adams, K., Sabolinski, M., Worcel, M., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa042934 · Cited by 1,773
Patterns of left ventricular hypertrophy and geometric remodeling in essential hypertension
Ganau, A., Devereux, R. B., Roman, M. J., SIMONE, G. D., Pickering, T. G., Saba, P. S., Vargiu, P., Simongini, I., & LARAGH, J. H. (1992) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(92)90617-v · Cited by 1,594
Zile, M. R., Baicu, C. F., & Gaasch, W. H. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032566 · Cited by 1,577
Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction
Lam, C. S. P., Roger, V. L., Rodeheffer, R. J., Borlaug, B. A., Enders, F., & Redfield, M. M. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2008.11.051 · Cited by 1,345
Torre-Amione, G., Kapadia, S., Benedict, C., Oral, H., Young, J. B., & Mann, D. L. (1996) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(95)00589-7 · Cited by 1,211
Solomon, S. D., Zile, M. R., Pieske, B. M., Voors, A. A., Shah, A. M., Kraigher‐Krainer, E., Shi, V. C., Bransford, T. L., Takeuchi, M., Gong, J., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61227-6 · Cited by 1,171
Flagged first, then by citations
1 of the 99 references couldn’t be matched to a known paper.
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Items 1,001–1,005 of 1,005
Impact of dietary nitrate on age-related diastolic dysfunction
Rammos, C., Hendgen-Cotta, U. B., Totzeck, M., Pohl, J., Lüdike, P., Flögel, U., Deenen, R., Köhrer, K., French, B. A., Gödecke, A., et al. (2016) · European Journal of Heart Failure · doi:10.1002/ejhf.535 · Cited by 31
Coronary microvascular dysfunction
Sucato, V., Novo, G., Saladino, A., Evola, S., & Galassi, A. R. (2020) · Minerva Cardioangiologica · doi:10.23736/s0026-4725.20.05070-7 · Cited by 30
De Marco, C., Claggett, B. L., de Denus, S., Zile, M. R., Huynh, T., Desai, A. S., Sirois, M. G., Solomon, S. D., Pitt, B., Rouleau, J. L., et al. (2021) · ESC Heart Failure · doi:10.1002/ehf2.13153 · Cited by 29
Mechanotransductive receptor Piezo1 as a promising target in the treatment of fibrosis diseases
Xu, Y., Huang, Y., Cheng, X., Hu, B., Jiang, D., Wu, L., Peng, S., & Hu, J. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1270979 · Cited by 24
Chaar, D., Dumont, B. L., Vulesevic, B., Neagoe, P.-E., Räkel, A., White, M., & Sirois, M. G. (2022) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2022.05.026 · Cited by 22
Metadata
- Authors
- Paulus, W. J., & Tschöpe, C.
- Affiliations
- Amsterdam Cardiovascular Sciences (NL)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Paulus, Walter J.
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 62
- Issue
- 4
- Pages
- 263-271
- ISSN
- 0735-1097 (ISSN-L)
- OpenAlex
- W164205712
- Cited by
- 3,564
- References
- 99
- Citations by year
- 2026: 351 · 2025: 334 · 2024: 320 · 2023: 298 · 2022: 331 · 2021: 364 · 2020: 348 · 2019: 253 · 2018: 225 · 2017: 228 · 2016: 222 · 2015: 148 · 2014: 117 · 2013: 19
- FWCI
- 28.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- European Commission
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- heart failure with preserved ejection fraction, systemic inflammation, comorbidities, nitric oxide bioavailability, protein kinase G, cardiomyocyte hypertrophy, diastolic dysfunction, left ventricular stiffness, interstitial fibrosis, cardiac remodeling, Laplace law, obesity, diabetes mellitus, chronic obstructive pulmonary disease, salt-sensitive hypertension
- MeSH terms
- Animals, Coronary Circulation, Endothelium, Vascular, Heart Failure, Humans, Inflammation, Microcirculation, Myocardium, Stroke Volume, Comorbidity, Ventricular Remodeling
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