冠状动脉微栓塞时微循环储备血流再分布研究与定向开放初步探讨

Coronary microvascular dysfunction seriously affects the prognosis of patients with coronary heart disease. Coronary microvascular obstruction is an important factor that results in coronary microvascular dysfunction. The classical theory considers that perfusion in coronary microcirculation can be recovered after coronary microvascular spasm is relieved. However, our pre-experiment found that coronary microvascular obstruction was not ameliorated after drug treatment used to relieve coronary microvascular spasm in mouse model of coronary thrombotic microembolism. We proposed the hypothesis of redistribution and oriented opening of reserved flow in coronary microcirculation. That is to say, when the coronary microembolism is happened, some potential microvessels and capillaries are oriented opened and reserved flow in coronary microcirculation is redistributed. By using large animal model of coronary thrombotic microembolism which is more consistent with the clinical practice and different doses of autologous thrombus, we plan to observe the effects of coronary microembolism on the number and distribution of opened microvessels, the changes of microcirculatory blood flow, and the myocardial viability. We plan to investigate the influence of the drugs with different mechanisms of action on the opening of three microcirculatory channels（circuitous channel, thoroughfare channel, and arterio-venous shunt） and the myocardial viability. We plan to preliminarily probe the mechanisms of oriented opening of microcirculatory vessels by means of corresponding antagonists with possible mechanism of opening circuitous channel. Our study is significant for illustrating the mechanism and clinical treatment of coronary microvascular dysfunction including coronary no-reflow phenomenon.

冠脉微循环障碍严重影响冠心病患者的预后，冠脉微栓塞是导致冠脉微循环障碍的重要因素。经典理论认为解除微小动脉痉挛后可恢复冠脉微循环血流，但我们预实验发现在小鼠冠脉自体微血栓栓塞模型中，被栓塞微动脉接受解除微小动脉痉挛的药物治疗后仍处于栓塞状态。我们提出"冠脉微栓塞微循环储备血流再分布与定向开放"假说，即：冠脉发生微栓塞时，部分潜在的微血管及毛细血管定向开放，微循环储备血流发生再分布。拟采用更加符合临床实际的大动物冠脉自体微血栓栓塞模型，通过不同剂量的自体血栓，观察冠脉微栓塞对微循环血管开放数量及分布，微循环血流量的变化和对心肌活性的作用；观察不同作用机制的药物对微循环三种通路（迂回通路、直捷通路、动静脉短路）开放的影响及对心肌活性的作用；选择开放迂回通路为主的可能机制，应用相应的阻断剂，初步探讨微循环血管定向开放的机制，对阐明冠脉微循环障碍机制及临床治疗无复流现象等微循环障碍性疾病具有意义。

冠脉微循环障碍所致的冠脉无复流/慢血流严重影响冠心病患者的预后，冠脉微栓塞是导致冠脉微循环障碍的重要因素。经典理论认为解除栓塞后微小动脉痉挛后可恢复冠脉微循环血流，但我们预实验中发现在大鼠冠脉自体微血栓栓塞模型中，被栓塞微动脉接受解除微小动脉痉挛的药物治疗后仍处于栓塞状态，但心肌血流却明显改善。因此我们提出冠脉微栓塞后可能的微循环储备血流理论，即：心脏存在潜在的储备微血管床，心脏微循环存在储备血流，并受自身代偿以及药物干预的调节。正式实验中采用冠脉微栓塞法构建更加符合临床实际的小型猪冠脉慢血流模型，通过观察微栓塞后冠脉血流及病理过程的演变发现：（1）微栓塞后导致慢血流所产生的病理学变化与缺血-再灌注有相似点，但并不完全相同，炎症反应在慢血流形成后心肌损伤与重构中扮演了重要角色；（2）微栓塞导致的冠脉慢血流虽然能够逐渐恢复，但需要较长过程，血流的变化和心功能的变化是不能匹配的：冠脉血流虽能逐渐恢复，但心功能损害则出现不可逆的病理生理学变化；（3）近期血流的自我恢复是靠储备微血管床开放实现代偿，涉及到各种自身调解的机制；但代偿功能有限的，血流恢复程度会达到相对稳态（平台期）；微血管血流储备容量决定恢复的程度；而CFR（冠脉血流储备)和HRM(冠脉微循环血流阻力）是反映微血管储备的敏感指标；（4）远期冠脉血流完全恢复是靠心肌中新生微血管网再生（病理学染色证实）实现的；（5）及时的药物干预时间点（近期干预）增加微循环储备血流容量，使血流快速恢复，药物实现的冠脉微循环水平的血运重建是改善预后的重要原因。.本模型与临床PCI过程中微栓塞导致的慢血流现象的病理生理学机制是类似的，本模型通过探讨冠脉微循环储备血流实现自身代偿过程中神经体液及代谢性调解的病理生理学过程进一步阐明微栓塞后冠脉慢血流的理论机制，为我们提供了更加合适的药物干预时间和干预靶点，这也将为临床冠脉无复流、慢血流等冠脉微循环障碍疾病的防治提供指导性意见。