I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Klinikum der Universität München, Munich, Munich, Germany.
I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany.
J Am Coll Cardiol. 2017 Jan 17;69(2):131-143. doi: 10.1016/j.jacc.2016.10.058.
Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors.
This study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus.
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 adeno-associated virus (rAAV) (5 × 10 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.
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.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%).
Diabetes 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.
糖尿病会导致微循环稀疏，并可能损害缺血心肌对促血管生成因子的反应性。
本研究旨在探讨微血管不稳定是否会影响糖尿病患者的器官功能和治疗性血管新生。
作者从接受心脏移植的终末期心力衰竭患者的心脏组织中获取样本，包括有糖尿病和无糖尿病的患者。使用糖尿病（db）和野生型（wt）猪来分析心肌血管生成和功能。经皮在回旋支动脉中诱导慢性缺血（第 0 天）。第 28 天，局部应用重组腺相关病毒（rAAV）（5×10 病毒颗粒，编码血管内皮生长因子-A [VEGF-A]或胸腺肽-β4 [Tβ4]）。分析 CD31+毛细血管/高倍视野（c/hpf）和 NG2+周细胞覆盖率。在第 28 天和第 56 天评估整体心肌功能（射血分数 [EF]和左心室舒张末期压）。
与非糖尿病患者的心肌组织相比，糖尿病患者的心肌组织中毛细血管稀疏，周细胞缺失。db 猪的高血糖症，即使没有缺血，也会导致心肌中的毛细血管稀疏（db 猪的毛细血管密度为 163±14 c/hpf，wt 猪的毛细血管密度为 234±8 c/hpf；p<0.005），同时 EF 明显下降（非糖尿病对照组的 EF 为 44.9%，db 猪为 44.8%；p<0.05）。慢性缺血性心脏中的毛细血管密度进一步降低，EF 也降低（均 p<0.05）。与 wt 心脏相比，rAAV.Tβ4 处理在 db 心脏中对毛细血管密度和成熟的增强作用效率较低，类似于侧支生长。虽然 rAAV.VEGF-A 能刺激血管生成，但既不能募集周细胞，也不能促进侧支生长。结果，rAAV.Tβ4 而非 rAAV.VEGF-A 能改善 db 心脏的 EF（34.5±1.4%），但效果不如 wt 心脏（44.8±1.5%）。
糖尿病使心脏的微血管不稳定，通过翻译大型动物冬眠心肌模型中的 rAAV.Tβ4 影响治疗性血管新生的幅度。
