Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
Basic Res Cardiol. 2020 Feb 25;115(2):21. doi: 10.1007/s00395-020-0778-2.
Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial 'Ischemia and No Obstructive Coronary Artery disease' (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. DM (streptozotocin), HC (high-fat diet) and CKD (renal embolization) were induced in 10 female swine (DM + HC + CKD), while 12 healthy female swine on a normal diet served as controls (Normal). After 5 months, at a time when coronary atherosclerosis was still negligible, myocardial perfusion, metabolism, and function were studied at rest and during treadmill exercise. DM + HC + CKD animals showed hyperglycemia, hypercholesterolemia, and impaired kidney function. During exercise, DM + HC + CKD swine demonstrated perturbations in myocardial blood flow and oxygen delivery, necessitating a higher myocardial oxygen extraction-achieved despite reduced capillary density-resulting in lower coronary venous oxygen levels. Moreover, myocardial efficiency was lower, requiring higher oxygen consumption for a given level of myocardial work. These perturbations in myocardial oxygen balance were associated with lower myocardial lactate consumption, stroke volume, and LVdP/dt, suggestive of myocardial ischemia and dysfunction. Further analyses showed a reduction in adenosine-recruitable coronary flow reserve, but this was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained; the latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. However, isolated small arteries displayed selective blunting of endothelium-dependent vasodilation in response to bradykinin in DM + HC + CKD swine, suggesting that changes in coronary microvascular function rather than in structure contributed to the perturbations in myocardial oxygen delivery. In conclusion, common comorbidities in swine result in CMD, in the absence of appreciable atherosclerosis, which is severe enough to produce perturbations in myocardial oxygen balance, particularly during exercise, resembling key features of INOCA.
患有缺血性心脏病的合并症，包括糖尿病（DM）、高胆固醇血症（HC）和慢性肾病（CKD），与冠状动脉微血管功能障碍（CMD）有关。越来越多的证据表明，CMD 可能导致心肌“缺血但无阻塞性冠状动脉疾病”（INOCA）。在本研究中，我们通过一种具有多种合并症的新型猪模型来测试 CMD 导致心肌灌注和氧输送紊乱的假设。DM（链脲佐菌素）、HC（高脂肪饮食）和 CKD（肾栓塞）诱导 10 头雌性猪（DM+HC+CKD），而 12 头正常饮食的健康雌性猪作为对照组（正常）。5 个月后，当冠状动脉粥样硬化仍可忽略不计时，在休息和跑步机运动期间研究了心肌灌注、代谢和功能。DM+HC+CKD 动物表现出高血糖、高胆固醇血症和肾功能受损。在运动过程中，DM+HC+CKD 猪表现出心肌血流和氧输送的紊乱，需要更高的心肌氧摄取-尽管毛细血管密度降低-导致冠状静脉氧水平降低。此外，心肌效率较低，为给定水平的心肌做功需要更高的耗氧量。这些心肌氧平衡的紊乱与较低的心肌乳酸消耗、每搏量和 LVdP/dt 相关，提示存在心肌缺血和功能障碍。进一步的分析显示，腺苷可诱导的冠状动脉血流储备减少，但这仅是由于基础冠状动脉血流增加所致，而每克心肌的最大冠状动脉血流保持不变；后者与不变的小动脉壁/腔比、小动脉密度和小动脉周围胶原含量一致。然而，在 DM+HC+CKD 猪中，孤立的小动脉对缓激肽的内皮依赖性血管扩张反应选择性减弱，表明冠状动脉微血管功能的变化而不是结构的变化导致了心肌氧输送的紊乱。总之，猪的常见合并症导致 CMD，而没有明显的动脉粥样硬化，这足以导致心肌氧平衡紊乱，尤其是在运动期间，类似于 INOCA 的关键特征。
