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


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.
van Heerebeek
Loek
L
Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
Hamdani
Nazha
N
Handoko
M Louis
ML
Falcao-Pires
Ines
I
Musters
René J
RJ
Kupreishvili
Koba
K
Ijsselmuiden
Alexander J J
AJ
Schalkwijk
Casper G
CG
Bronzwaer
Jean G F
JG
Diamant
Michaela
M
Borbély
Attila
A
van der Velden
Jolanda
J
Stienen
Ger J M
GJ
Laarman
Gerrit J
GJ
Niessen
Hans W M
HW
Paulus
Walter J
WJ
D016022:Case-Control Studies; D048909:Diabetes Complications / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000503:physiopathology; D003971:Diastole; D005260:Female; D005355:Fibrosis; D017127:Glycation End Products, Advanced; D006333:Heart Failure / Q000209:etiology / Q000473:pathology*; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009129:Muscle Tonus; D032383:Myocytes, Cardiac / Q000502:physiology*; D013318:Stroke Volume
D017127:Glycation End Products, Advanced