Myocardial Stiffness in Patients With Heart Failure and a Preserved Ejection Fraction: Contributions of Collagen and Titin
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Background—: The purpose of this study was to determine whether patients with heart failure and a preserved ejection fraction (HFpEF) have an increase in passive myocardial stiffness and the extent to which discovered changes depend on changes in extracellular matrix fibrillar collagen and cardiomyocyte titin. Methods and Results—: Seventy patients undergoing coronary artery bypass grafting underwent an echocardiogram, plasma biomarker determination, and intraoperative left ventricular epicardial anterior wall biopsy. Patients were divided into 3 groups: referent control (n=17, no hypertension or diabetes mellitus), hypertension (HTN) without (–) HFpEF (n=31), and HTN with (+) HFpEF (n=22). One or more of the following studies were performed on the biopsies: passive stiffness measurements to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay), collagen assays (biochemistry or histology), or titin isoform and phosphorylation assays. In comparison with controls, patients with HTN(–)HFpEF had no change in left ventricular end-diastolic pressure, myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers of inflammation (C-reactive protein, soluble ST2, tissue inhibitor of metalloproteinase 1). In comparison with both control and HTN(–)HFpEF, patients with HTN(+)HFpEF had increased left ventricular end-diastolic pressure, left atrial volume, N-terminal propeptide of brain natriuretic peptide, total, collagen-dependent, and titin-dependent stiffness, insoluble collagen, increased titin phosphorylation on PEVK S11878(S26), reduced phosphorylation on N2B S4185(S469), and increased biomarkers of inflammation. Conclusions—: Hypertension in the absence of HFpEF did not alter passive myocardial stiffness. Patients with HTN(+)HFpEF had a significant increase in passive myocardial stiffness; collagen-dependent and titin-dependent stiffness were increased. These data suggest that the development of HFpEF depends on changes in both collagen and titin homeostasis.
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Cardiac myocytes isolated from HFpEF patients and experimental models exhibit prolonged relaxation, diminished contraction velocity, a decrease in β-adrenergic response, and increased myocardial stiffness.
“Cardiac myocytes isolated from HFpEF patients and experimental models exhibit prolonged relaxation, diminished contraction velocity, a decrease in β-adrenergic response, and increased myocardial stiffness.45,46”
From Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial (2024) · cites this paper as [45]
The Introduction reports slowed or incomplete left-ventricular relaxation in HFpEF, and the Discussion reports increased passive myocardial stiffness in patient tissue and cites earlier findings of increased stiffness in isolated cardiomyocytes. It does not establish prolonged relaxation in isolated myocytes, diminished contraction velocity, or a decreased β-adrenergic response. No page numbers are available in our copy. (LLM, conf=0.87)
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Heart Failure With Preserved Ejection Fraction
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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., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.041886 · Cited by 436 · see citing works
Myocardial Gene Expression Signatures in Human Heart Failure With Preserved Ejection Fraction
Hahn, V. S., Knutsdottir, H., Luo, X., Bedi, K., Margulies, K. B., Haldar, S. M., Stolina, M., Yin, J., Khakoo, A. Y., Vaishnav, J., et al. (2021) · Circulation · doi:10.1161/circulationaha.120.050498 · Cited by 291 · see citing works
Borovac, J. A., D'Amario, D., Bozic, J., & Glavas, D. (2020) · World Journal of Cardiology · doi:10.4330/wjc.v12.i8.373 · Cited by 195 · see citing works
Packer, M., Lam, C. S. P., Lund, L. H., Maurer, M. S., & Borlaug, B. A. (2020) · European Journal of Heart Failure · doi:10.1002/ejhf.1902 · Cited by 185 · 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
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
Inflammation in Heart Failure With Preserved Ejection Fraction
Gomberg-Maitland, M., Shah, S. J., & Guazzi, M. (2016) · JACC Heart Failure · doi:10.1016/j.jchf.2015.11.013 · Cited by 38 · see citing works
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 · see citing works
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 · 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
- Zile, M. R., Baicu, C. F., S. Ikonomidis, J., Stroud, R. E., Nietert, P. J., Bradshaw, A. D., Slater, R., Palmer, B. M., Van Buren, P., Meyer, M., M. Redfield, M., A. Bull, D., L. Granzier, H., & LeWinter, M. M.
- Affiliations
- University of Vermont (US)
- From Division of Cardiology, Department of Medicine, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (M.R.Z., C.F.B., A.D.B.); Division of Cardiothoracic Surgery, Department of Surgery, Medical University of South Carolina, and RHJ Department of Veterans Affairs Medical Center, Charleston, SC (J.S.I., R.E.S.); Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC (P.J.N.); Department of Cellular and...
- ORCID
- Venue
- Circulation
- Published
- 2015-04-07
- Volume
- 131
- Issue
- 14
- Pages
- 1247-1259
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC4390480
- OpenAlex
- W2159549492
- Cited by
- 681
- References
- 79
- Citations by year
- 2026: 57 · 2025: 66 · 2024: 52 · 2023: 46 · 2022: 66 · 2021: 72 · 2020: 79 · 2019: 61 · 2018: 52 · 2017: 62 · 2016: 42 · 2015: 25
- FWCI
- 43.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 CX000415, I01 BX000487)
- National Institutes of Health (UL1TR000062)
- National Heart, Lung, and Blood Institute (U10HL110342, R01HL118524, R01HL089944, U10HL110262, R01HL06288, R01HL123478, R56HL123478, R01HL115988, U10HL110302, R01HL122744)
- National Center for Advancing Translational Sciences
- 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 › Cardiomyopathy and Myosin Studies
- Keywords
- heart failure with preserved ejection fraction, myocardial stiffness, titin, collagen, extracellular matrix, hypertension, titin phosphorylation, inflammatory markers, left ventricular end-diastolic pressure, left atrial volume, coronary artery bypass grafting, left ventricular biopsy
- MeSH terms
- Aged, Biopsy, Collagen, Compliance, Diastole, Elasticity, Female, Heart Failure, Heart Ventricles, Humans, Hypertension, Inflammation, Male, Middle Aged, Myocardium, Phosphorylation, Protein Processing, Post-Translational, Stroke Volume, Biomarkers, Protein Isoforms, Diabetes Complications, Connectin
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