Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction
Abstract
BACKGROUND: The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. METHODS AND RESULTS: We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-β. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-β, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-β resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. CONCLUSIONS: Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.
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Microvascular rarefaction and fibrosis are likely triggered by microvascular endothelial inflammation.
“The last two alterations are likely triggered by microvascular endothelial inflammation [70].”
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 [70]
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- Authors
- Westermann, D., Lindner, D., Kasner, M., Zietsch, C., Savvatis, K., Escher, F., von Schlippenbach, J., Skurk, C., Steendijk, P., Riad, A., Poller, W., Schultheiss, H.-P., & Tschöpe, C.
- Affiliations
- Leiden University Medical Center (NL)
- From the Department of Cardiology and Pneumology (D.W., D.L., M.K., C.Z., K.S., F.E., J.v.S., C.S., A.R., W.P., H.-P.S., C.T.), Charité, Universititäts-Medizin Berlin, Campus Benjamin Franklin, Berlin, Germany, and Department of Cardiology (P.S.), Leiden University Medical Center, Leiden, The Netherlands.
- ORCID
- Venue
- Circulation Heart Failure
- Published
- 2011-01
- Volume
- 4
- Issue
- 1
- Pages
- 44-52
- ISSN
- 1941-3289 (ISSN-L)
- 1941-3297
- OpenAlex
- W2131184290
- Cited by
- 644
- References
- 55
- Citations by year
- 2026: 32 · 2025: 48 · 2024: 53 · 2023: 50 · 2022: 57 · 2021: 58 · 2020: 49 · 2019: 37 · 2018: 45 · 2017: 49 · 2016: 35 · 2015: 42 · 2014: 30 · 2013: 21 · 2012: 17
- FWCI
- 12.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Heart Failure (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Keywords
- heart failure with preserved ejection fraction, cardiac inflammation, extracellular matrix remodeling, diastolic dysfunction, myocardial fibrosis, collagen deposition, MMP-1, TGF-beta, myofibroblasts, endomyocardial biopsy, left ventricular systolic function
- MeSH terms
- Adult, Aged, Biopsy, Cells, Cultured, Collagen, Extracellular Matrix, Female, Fibroblasts, Fibrosis, Heart, Heart Failure, Humans, Inflammation, Male, Middle Aged, Myocardium, Stroke Volume, Case-Control Studies, Transforming Growth Factor beta, Ventricular Function, Left, Extracellular Matrix Proteins, Disease Progression, Matrix Metalloproteinase 1
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