Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension

Loek van Heerebeek, Nazha Hamdani, M Louis Handoko, Ines Falcao-Pires, René J Musters, Koba Kupreishvili, Alexander J J Ijsselmuiden, Casper G Schalkwijk, Jean G F Bronzwaer, Michaela Diamant, Attila Borbély, Jolanda van der Velden, Ger J M Stienen, Gerrit J Laarman, Hans W M Niessen, Walter J Paulus

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)43-51
Number of pages9
JournalCirculation
Volume117
Issue number1
DOIs
Publication statusPublished - 1 Jan 2008

Cite this

van Heerebeek, Loek ; Hamdani, Nazha ; Handoko, M Louis ; Falcao-Pires, Ines ; Musters, René J ; Kupreishvili, Koba ; Ijsselmuiden, Alexander J J ; Schalkwijk, Casper G ; Bronzwaer, Jean G F ; Diamant, Michaela ; Borbély, Attila ; van der Velden, Jolanda ; Stienen, Ger J M ; Laarman, Gerrit J ; Niessen, Hans W M ; Paulus, Walter J. / Diastolic stiffness of the failing diabetic heart : importance of fibrosis, advanced glycation end products, and myocyte resting tension. In: Circulation. 2008 ; Vol. 117, No. 1. pp. 43-51.
@article{8f4636d6c29744b38481fbe2f92965f9,
title = "Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension",
abstract = "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.",
keywords = "Case-Control Studies, Diabetes Complications, Diabetes Mellitus, Diastole, Female, Fibrosis, Glycation End Products, Advanced, Heart Failure, Heart Ventricles, Humans, Male, Middle Aged, Muscle Tonus, Myocytes, Cardiac, Stroke Volume, Journal Article",
author = "{van Heerebeek}, Loek and Nazha Hamdani and Handoko, {M Louis} and Ines Falcao-Pires and Musters, {Ren{\'e} J} and Koba Kupreishvili and Ijsselmuiden, {Alexander J J} and Schalkwijk, {Casper G} and Bronzwaer, {Jean G F} and Michaela Diamant and Attila Borb{\'e}ly and {van der Velden}, Jolanda and Stienen, {Ger J M} and Laarman, {Gerrit J} and Niessen, {Hans W M} and Paulus, {Walter J}",
year = "2008",
month = "1",
day = "1",
doi = "10.1161/CIRCULATIONAHA.107.728550",
language = "English",
volume = "117",
pages = "43--51",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

van Heerebeek, L, Hamdani, N, Handoko, ML, Falcao-Pires, I, Musters, RJ, Kupreishvili, K, Ijsselmuiden, AJJ, Schalkwijk, CG, Bronzwaer, JGF, Diamant, M, Borbély, A, van der Velden, J, Stienen, GJM, Laarman, GJ, Niessen, HWM & Paulus, WJ 2008, 'Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension' Circulation, vol. 117, no. 1, pp. 43-51. https://doi.org/10.1161/CIRCULATIONAHA.107.728550

Diastolic stiffness of the failing diabetic heart : importance of fibrosis, advanced glycation end products, and myocyte resting tension. / van Heerebeek, Loek; Hamdani, Nazha; Handoko, M Louis; Falcao-Pires, Ines; Musters, René J; Kupreishvili, Koba; Ijsselmuiden, Alexander J J; Schalkwijk, Casper G; Bronzwaer, Jean G F; Diamant, Michaela; Borbély, Attila; van der Velden, Jolanda; Stienen, Ger J M; Laarman, Gerrit J; Niessen, Hans W M; Paulus, Walter J.

In: Circulation, Vol. 117, No. 1, 01.01.2008, p. 43-51.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Diastolic stiffness of the failing diabetic heart

T2 - importance of fibrosis, advanced glycation end products, and myocyte resting tension

AU - van Heerebeek, Loek

AU - Hamdani, Nazha

AU - Handoko, M Louis

AU - Falcao-Pires, Ines

AU - Musters, René J

AU - Kupreishvili, Koba

AU - Ijsselmuiden, Alexander J J

AU - Schalkwijk, Casper G

AU - Bronzwaer, Jean G F

AU - Diamant, Michaela

AU - Borbély, Attila

AU - van der Velden, Jolanda

AU - Stienen, Ger J M

AU - Laarman, Gerrit J

AU - Niessen, Hans W M

AU - Paulus, Walter J

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - Diabetes Complications

KW - Diabetes Mellitus

KW - Diastole

KW - Female

KW - Fibrosis

KW - Glycation End Products, Advanced

KW - Heart Failure

KW - Heart Ventricles

KW - Humans

KW - Male

KW - Middle Aged

KW - Muscle Tonus

KW - Myocytes, Cardiac

KW - Stroke Volume

KW - Journal Article

U2 - 10.1161/CIRCULATIONAHA.107.728550

DO - 10.1161/CIRCULATIONAHA.107.728550

M3 - Article

VL - 117

SP - 43

EP - 51

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 1

ER -