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Cardiomyocyte Stiffness in Diastolic Heart Failure
Open accessAbstract
BACKGROUND: Heart failure with preserved left ventricular (LV) ejection fraction (EF) is increasingly recognized and usually referred to as diastolic heart failure (DHF). Its pathogenetic mechanism remains unclear, partly because of a lack of myocardial biopsy material. Endomyocardial biopsy samples obtained from DHF patients were therefore analyzed for collagen volume fraction (CVF) and sarcomeric protein composition and compared with control samples. Single cardiomyocytes were isolated from these biopsy samples to assess cellular contractile performance. METHODS AND RESULTS: DHF patients (n=12) had an LVEF of 71+/-11%, an LV end-diastolic pressure (LVEDP) of 28+/-4 mm Hg, and no significant coronary artery stenoses. DHF patients had higher CVFs (7.5+/-4.0%, P<0.05) than did controls (n=8, 3.8+/-2.0%), and no conspicuous changes in sarcomeric protein composition were detected. Cardiomyocytes, mechanically isolated and treated with Triton X-100 to remove all membranes, were stretched to a sarcomere length of 2.2 microm and activated with solutions containing varying [Ca2+]. Compared with cardiomyocytes of controls, cardiomyocytes of DHF patients developed a similar total isometric force at maximal [Ca2+], but their resting tension (F(passive)) in the absence of Ca2+ was almost twice as high (6.6+/-3.0 versus 3.5+/-1.7 kN/m2, P<0.001). F(passive) and CVF combined yielded stronger correlations with LVEDP than did either alone. Administration of protein kinase A (PKA) to DHF cardiomyocytes lowered F(passive) to control values. CONCLUSIONS: DHF patients had stiffer cardiomyocytes, as evident from a higher F(passive) at the same sarcomere length. Together with CVF, F(passive) determined in vivo diastolic LV dysfunction. Correction of this high F(passive) by PKA suggests that reduced phosphorylation of sarcomeric proteins is involved in DHF.
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“Increased Fpassive has been observed in HFpEF patient biopsies, and increased cardiac stiffening is associated with aging.38,39”
From The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF (2023) · cites this paper as [39]
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Metadata
- Authors
- Borbély, A., van der Velden, J., Papp, Z., Bronzwaer, J. G. F., Edes, I., Stienen, G. J. M., & Paulus, W. J.
- Affiliations
- From the Laboratory for Physiology (A.B., J.v.d.V., J.G.F.B., G.J.M.S., W.J.P.), Institute for Cardiovascular Research, VUMC, Amsterdam, the Netherlands, and the Division of Clinical Physiology (A.B., Z.P., I.E.), Institute of Cardiology, UDMHSC, Debrecen, Hungary.
- Amsterdam Cardiovascular Sciences (NL)
- Venue
- Circulation
- Published
- 2005-02-15
- Volume
- 111
- Issue
- 6
- Pages
- 774-781
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2140058582
- Cited by
- 536
- References
- 44
- Citations by year
- 2026: 13 · 2025: 19 · 2024: 21 · 2023: 24 · 2022: 25 · 2021: 28 · 2020: 37 · 2019: 20 · 2018: 28 · 2017: 32 · 2016: 35 · 2015: 30 · 2014: 35 · 2013: 24 · 2012: 20
- FWCI
- 14.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- 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, cardiomyocyte stiffness, passive tension, collagen volume fraction, sarcomeric proteins, protein kinase A, sarcomere length, diastolic dysfunction, left ventricular end-diastolic pressure, myocardial fibrosis
- MeSH terms
- Aged, Aged, 80 and over, Calcium, Diastole, Female, Heart Failure, Hemodynamics, Humans, Male, Middle Aged, Myocardium, Stroke Volume, Ventricular Function, Left, Ventricular Pressure, Cyclic AMP-Dependent Protein Kinases, Myocytes, Cardiac
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