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Hinkel, Rabea; Höwe, Andrea; Renner, Simone; Ng, Judy; Lee, Seungmin; Klett, Katharina; Kaczmarek, Veronika; Moretti, Alessandra; Laugwitz, Karl-Ludwig; Skroblin, Philipp; Mayr, Manuel; Milting, Hendrik; Dendorfer, Andreas; Reichart, Bruno; Wolf, Eckhard; Kupatt, Christian (2017): Diabetes Mellitus-Induced Microvascular Destabilization in the Myocardium. In: Journal of the American College of Cardiology, Vol. 69, No. 2: pp. 131-143
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Abstract

BACKGROUND Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors. OBJECTIVES This study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus. METHODS The authors obtained myocardial samples from patients with end-stage heart failure at time of transplant, with or without diabetes mellitus. Diabetic (db) and wild-type (wt) pigs were used to analyze myocardial vascularization and function. Chronic ischemia was induced percutaneously (day 0) in the circumflex artery. At day 28, recombinant adenoassociated virus (rAAV) (5 x 10(12) viral particles encoding vascular endothelial growth factor-A [VEGF-A] or thymosin beta 4 [T beta 4]) was applied regionally. CD31_capillaries per high power field (c/hpf) and NG2_pericyte coverage were analyzed. Global myocardial function (ejection fraction [EF] and left ventricular end-diastolic pressure) was assessed at days 28 and 56. RESULTS Diabetic human myocardial explants revealed capillary rarefaction and pericyte loss compared to nondiabetic explants. Hyperglycemia in db pigs, even without ischemia, induced capillary rarefaction in the myocardium (163 +/- 14 c/hpf in db vs. 234 +/- 8 c/hpf in wt hearts;p < 0.005), concomitant with a distinct loss of EF (44.9% vs. 53.4% in nondiabetic controls;p<0.05). Capillary density further decreased in chronic ischemic hearts, as did EF (both p<0.05). Treatment with rAAV. T beta 4 enhanced capillary density and maturation in db hearts less efficiently than in wt hearts, similar to collateral growth. rAAV. VEGF-A, though stimulating angiogenesis, induced neither pericyte recruitment nor collateral growth. As a result, rAAV. T beta 4 but not rAAV. VEGF-A improved EF in db hearts (34.5 +/- 1.4%), but less so than in wt hearts (44.8 +/- 1.5%). CONCLUSIONS Diabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV. T beta 4 in a translational large animal model of hibernating myocardium. (C) 2017 by the American College of Cardiology Foundation.