Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension
Open accessAbstract
BACKGROUND: Excessive diastolic left ventricular stiffness is an important contributor to heart failure in patients with diabetes mellitus. Diabetes is presumed to increase stiffness through myocardial deposition of collagen and advanced glycation end products (AGEs). Cardiomyocyte resting tension also elevates stiffness, especially in heart failure with normal left ventricular ejection fraction (LVEF). The contribution to diastolic stiffness of fibrosis, AGEs, and cardiomyocyte resting tension was assessed in diabetic heart failure patients with normal or reduced LVEF. METHODS AND RESULTS: Left ventricular endomyocardial biopsy samples were procured in 28 patients with normal LVEF and 36 patients with reduced LVEF, all without coronary artery disease. Sixteen patients with normal LVEF and 10 with reduced LVEF had diabetes mellitus. Biopsy samples were used for quantification of collagen and AGEs and for isolation of cardiomyocytes to measure resting tension. Diabetic heart failure patients had higher diastolic left ventricular stiffness irrespective of LVEF. Diabetes mellitus increased the myocardial collagen volume fraction only in patients with reduced LVEF (from 14.6+/-1.0% to 22.4+/-2.2%, P<0.001) and increased cardiomyocyte resting tension only in patients with normal LVEF (from 5.1+/-0.7 to 8.5+/-0.9 kN/m2, P=0.006). Diabetes increased myocardial AGE deposition in patients with reduced LVEF (from 8.8+/-2.5 to 24.1+/-3.8 score/mm2; P=0.005) and less so in patients with normal LVEF (from 8.2+/-2.5 to 15.7+/-2.7 score/mm2, P=NS). CONCLUSIONS: Mechanisms responsible for the increased diastolic stiffness of the diabetic heart differ in heart failure with reduced and normal LVEF: Fibrosis and AGEs are more important when LVEF is reduced, whereas cardiomyocyte resting tension is more important when LVEF is normal.
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Fibrosis and advanced glycation end products are more importantly represented when LVEF is reduced.
“Otherwise, fibrosis and advanced glycation end products (AGEs) were more importantly represented when left ventricular ejection fraction (LVEF) was reduced [68].”
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 [68]
Raised LV diastolic stiffness is peculiar of HFpEF, predominantly due to increased resting tension of hypertrophied cardiomyocytes from a deficit in phosphorylation of the N2B region of titin by protein kinase A.
“In line with this pathophysiological mechanism, a past bioptic study in diabetic patients demonstrated that a raised LV diastolic stiffness was peculiar of HFpEF, predominantly due to the increased resting tension of hypertrophied cardiomyocytes since a deficit in phosphorylation of the N2B region of titin by protein kinase A.”
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 [68]
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- Authors
- van Heerebeek, L., Hamdani, N., Handoko, M. L., Falcao-Pires, I., Musters, R. J., Kupreishvili, K., Ijsselmuiden, A. J. J., Schalkwijk, C. G., Bronzwaer, J. G. F., Diamant, M., Borbély, A., van der Velden, J., Stienen, G. J. M., Laarman, G. J., Niessen, H. W. M., & Paulus, W. J.
- Affiliations
- From the Departments of Physiology (L.v.H., N.H., M.L.H., I.F-P., R.J.M., A.B., J.v.d.V., G.J.M.S., W.J.P.), Cardiology (J.G.F.B.), Endocrinology (M.D.), and Pathology and Surgery (K.K, H.W.M.N.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, the Netherlands; Department of Cardiology (A.J.J.I, G.J.L.), Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands; and Department of Internal Medicine (C.G.S.), University of Maastricht, Maastricht, the Netherlands.
- Maastricht University (NL)
- ORCID
- Venue
- Circulation
- Published
- 2008-01
- Volume
- 117
- Issue
- 1
- Pages
- 43-51
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2014051267
- Cited by
- 723
- References
- 52
- Citations by year
- 2026: 20 · 2025: 33 · 2024: 37 · 2023: 37 · 2022: 44 · 2021: 43 · 2020: 53 · 2019: 30 · 2018: 46 · 2017: 45 · 2016: 41 · 2015: 45 · 2014: 52 · 2013: 37 · 2012: 46
- FWCI
- 16.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (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
- diabetic heart failure, diabetes mellitus, myocardial fibrosis, collagen deposition, advanced glycation end products, left ventricular ejection fraction, endomyocardial biopsy, cardiomyocytes
- MeSH terms
- Diabetes Mellitus, Diastole, Female, Fibrosis, Heart Failure, Heart Ventricles, Humans, Male, Middle Aged, Muscle Tonus, Stroke Volume, Case-Control Studies, Glycation End Products, Advanced, Myocytes, Cardiac, Diabetes Complications
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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