Metformin and sulodexide restore cardiac microvascular perfusion capacity in diet-induced obese rats
Authors: Judith van Haare
Jurgen W G E van Teeffelen
M Eline Kooi
Mark J Post
Marc van Bilsen
Hans Vink
Dennis Koehn
Jos Slenter
Hanneke Cobelens
Gustav J Strijkers
Journal: Cardiovascular diabetology (2017)
Discipline: CLINICAL MEDICINE
Keywords: Cardiac function; Endothelial dysfunction; Glycocalyx; Metformin; Myocardial perfusion
Affiliations: Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Department of Radiology and Nuclear Medicine, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands., Biomedical Engineering and Physics, Academic Medical Center, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands., Pie Medical Imaging, P.O. Box 1132, 6201 BC, Maastricht, The Netherlands., Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. ., Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. .

Abstract:  Background: Disturbances in coronary microcirculatory function, such as the endothelial glycocalyx, are early hallmarks in the development of obesity and insulin resistance. Accordingly, in the present study myocardial microcirculatory perfusion during rest and stress was assessed following metformin or sulodexide therapy in a rat model of diet-induced obesity. Additionally, the effect of degradation of the glycocalyx on myocardial perfusion was assessed in chow-fed rats. Methods: Rats were fed a high fat diet (HFD) for 8 weeks and were divided into a group without therapy, and groups that received the anti-diabetic drug metformin or the glycocalyx-stabilizing drug sulodexide in their drinking water during the last 4 weeks of the feeding period. Myocardial microvascular perfusion was determined using first-pass perfusion MRI before and after adenosine infusion. The effect of HFD on microcirculatory properties was also assessed by sidestream darkfield (SDF) imaging of the gastrocnemius muscle. In an acute experimental setting, hyaluronidase was administered to chow-fed control rats to determine the effect of enzymatical degradation of the glycocalyx on myocardial perfusion. Results: HFD-rats developed central obesity and insulin sensitivity was reduced as evidenced by the marked reduction in insulin-induced phosphorylation of Akt in both cardiac and gastrocnemius muscle. We confirmed our earlier findings that the robust increase in myocardial perfusion in chow-fed rats after an adenosine challenge (+56%, p = 0.002) is blunted in HFD rats (+8%, p = 0.68). In contrast, 4-weeks treatment with metformin or sulodexide partly restored the increase in myocardial perfusion during adenosine infusion in HFD rats (+81%, p = 0.002 and +37%, p = 0.02, respectively). Treating chow-fed rats acutely with hyaluronidase, to enzymatically degrade the glyocalyx, completely blunted the increase in myocardial perfusion during stress. Conclusions: In early stages of HFD-induced insulin resistance myocardial perfusion becomes compromised, a process that can be countered by treatment with both metformin and sulodexide. The adverse effect of acute glycocalyx degradation and protective effect of long-term sulodexide administration on myocardial perfusion provides indirect evidence, suggesting a role for the glycocalyx in preserving coronary microvascular function in pre-diabetic animals. 

Retracted: No

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