Cardiac Lymphatic Dysfunction Causes Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs In Vivo
Cardiac Lymphatic Dysfunction Causes Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs In Vivo
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DOI：
10.1161/atvbaha.119.312396
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发表时间：
2019-04-01
影响因子：
8.7
通讯作者：
Shimokawa, Hiroaki
中科院分区：
文献类型：
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作者：
Amamizu, Hirokazu;Matsumoto, Yasuharu;Shimokawa, Hiroaki
目的-我们以前已经证明冠状动脉外膜炎症在冠状动脉血管运动异常的发病机制中起重要作用，包括药物洗脱支架（DES）诱导的冠状动脉过度收缩反应。重要的是，外膜还含有淋巴管，其可以通过运输外渗的液体和炎性细胞来防止炎症。因此，我们的目的是研究冠状动脉外膜淋巴管在DES诱导的冠状动脉过度收缩反应在猪体内模型的发病机制中的作用。方法和结果-我们进行了2项实验研究。方案1：15只猪分为3组，分别置入DES和裸金属支架。还检查了距离支架植入20 mm的非支架植入部位。在方案2中，将12只猪分为2组，在2周后结扎或不结扎淋巴管，然后植入DES（n=6）。我们在DES植入后4周进行冠状动脉造影，随后进行免疫组织学分析。在方案1中，4周后仅DES边缘的淋巴管数量和口径较大。在方案2中，与外膜炎症、Rho激酶激活和较少的外膜淋巴管形成相关的淋巴管结扎组中冠状动脉过度收缩反应进一步增强。重要的是，这些炎症相关变化与增强的冠状动脉血管收缩反应之间存在显著相关性。结论：这些结果提供了证据，心脏淋巴管功能障碍在猪体内冠状动脉血管收缩反应的发病机制中起重要作用。
Objective- We have previously demonstrated that coronary adventitial inflammation plays important roles in the pathogenesis of coronary vasomotion abnormalities, including drug-eluting stent (DES)-induced coronary hyperconstricting responses. Importantly, the adventitia also harbors lymphatic vessels, which may prevent inflammation by transporting extravasated fluid and inflammatory cells. We thus aimed to examine the roles of coronary adventitial lymphatic vessels in the pathogenesis of DES-induced coronary hyperconstricting responses in a porcine model in vivo. Approach and Results- We performed 2 experimental studies. In protocol 1, 15 pigs were divided into 3 groups with or without DES and with bare metal stent. Nonstented sites 20 mm apart from stent implantation also were examined. In the protocol 2, 12 pigs were divided into 2 groups with or without lymphatic vessels ligation followed by DES implantation at 2 weeks later (n=6 each). We performed coronary angiography 4 weeks after DES implantation, followed by immunohistological analysis. In protocol 1, the number and the caliber of lymphatic vessels were greater at only the DES edges after 4 more weeks. In protocol 2, coronary hyperconstricting responses were further enhanced in the lymphatic vessels ligation group associated with adventitial inflammation, Rho-kinase activation, and less adventitial lymphatic vessels formation. Importantly, there were significant correlations among these inflammation-related changes and enhanced coronary vasoconstricting responses. Conclusions- These results provide evidence that cardiac lymphatic vessel dysfunction plays important roles in the pathogenesis of coronary vasoconstrictive responses in pigs in vivo.