Diabetes Mellitus-Induced Microvascular Destabilization in the Myocardium

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• 作者：Rabea Hinkel ; DVM^a ; ^b ; ^c ; Andrea Hoewe ; DVM^a ; Simone Renner ; DVM^d ; ^e ; Judy Ng ; PhD^a ; Seungmin Lee ; PhD^a ; Katharina Klett ; DVM^a ; ^c ; Veronika Kaczmarek ; MD^a ; ^c ; Alessandra Moretti ; PhD^a ; ^b ; Karl-Ludwig Laugwitz ; MD^a ; ^b ; Philipp Skroblin ; PhD^f ; Manuel Mayr ; MD^f ; Hendrik Milting ; MD^g ; Andreas Dendorfer ; MD^h ; Bruno Reichart ; MD^h ; Eckhard Wolf ; DVM^d ; ^e ; Christian Kupatt ; MD^a ; ^b ; ^h ; ^{christian.kupatt@tum.de}
• 关键词：angiogenesis ; chronic myocardial ischemia ; gene therapy ; thymosin β4
• 刊名：Journal of the American College of Cardiology
• 出版年：2017
• 出版时间：17 January 2017
• 年：2017
• 卷：69
• 期：2
• 页码：131-143
• 全文大小：3409 K
• 卷排序：69

文摘

Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors.ObjectivesThis study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus.MethodsThe 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 adeno-associated virus (rAAV) (5 × 1012 viral particles encoding vascular endothelial growth factor-A [VEGF-A] or thymosin beta 4 [Tβ4]) 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.ResultsDiabetic 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.Tβ4 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.Tβ4 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%).ConclusionsDiabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV.Tβ4 in a translational large animal model of hibernating myocardium.