Published online before print December 10, 2007, doi: 10.1161/CIRCULATIONAHA.107.728550
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(Circulation. 2008;117:43-51.)
© 2008 American Heart Association, Inc.
Heart Failure |
Diastolic Stiffness of the Failing Diabetic Heart
Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension
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.
Correspondence to Professor Dr Walter J. Paulus, MD, PhD, ICaR-VU, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands. E-mail wj.paulus{at}vumc.nl
Received July 17, 2007; accepted October 26, 2007.
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.
CLINICAL PERSPECTIVE
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Clinical Summaries
Circulation 2008 117: 1-3.[Extract] [Full Text]
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