冠状动脉粥样硬化斑块易损性对心肌灌注的影响及机制研究

Recently, many studies indicated that regional myocardial perfusion mismatched with the coronary artery stenosis severity although atherosclerotic coronary arterial stenosis is a main pathophysiology mechanism for the myocardial perfusion abnormality. Our previous studies found that the vulnerability of the plaque, not the size, was the independent predictor for the development of cardiac events. And.the inflammatory response was the main factor involving the development of vulnerable plaque. Some in vitro studies also confirmed that inflammatory factors could increase coronary vascular resistance thereby contributing to the impairment of the microcirculation function. Since the inflammation plays important role in both vulnerable plaque and microcirculation perfusion abnormality, we hypothesized that besides epicardial coronary arterial stenosis, vulnerability of the plaque is also a crucial factor influencing the downstream myocardial perfusion. In order to test the hypothesis in animal models of coronary atherosclerosis disease, this study will be performed as follows,1) The relationship between plaque vulnerability in epicardial coronary artery and the downstream myocardial perfusion will be determined with comprehensive imaging. Myocardial contrast echocardiography (MCE) combined with adenosine stress test will be used to quantify regional myocardial perfusion and myocardial flow reserve function. And plaque vulnerability will be determined by intravascular ultrasound with virtual imaging in vivo and then assessed by histology. 2) The pathophysiology mechanism of vulnerable plaque leading to downstream myocardial perfusion abnormality in the inflammation route will be further explored by revealing the role of local inflammatory factors in regulating downstream myocardial perfusion, and by analyzing the inflammation infiltration in the coronary plaque.

虽然动脉粥样硬化斑块引起冠状动脉狭窄是导致下游心肌缺血的主要机制，但是斑块所致冠脉狭窄的程度与下游心肌灌注之间却往往呈现不匹配现象。我们的前期研究发现斑块的稳定性而非其大小影响着心血管事件的发生，而炎症反应是促进斑块向不稳定性进展的重要机制。体外实验研究证实炎症介质通过增加小动脉阻力，亦是引起微循环灌注异常的重要因素。基于炎症在斑块易损性以及心肌灌注调节中均起着重要作用，我们推测冠脉斑块除了通过狭窄程度影响心肌灌注之外，易损斑块亦可能通过炎症细胞与介质进一步影响下游局部心肌灌注。为证明这一假设，本研究将利用心肌造影超声心动图对心肌微循环灌注进行多参数定量分析，结合血管内超声虚拟组织成像深入探讨斑块各项易损性特征对局部心肌血流灌注的影响及程度；并且，通过评估斑块的炎症状态，分析局部炎症介质对微循环小动脉以及下游心肌灌注的调控作用，阐明易损斑块通过炎症调控引起下游心肌灌注异常的病理生理机制。

在成功建立冠状动脉粥样硬化斑块的动物模型的基础上，完成了腺苷负荷前后超声心动图斑点追踪分析以及心肌造影，以分析斑块稳定性对心肌功能及病变下游心肌灌注的影响。对病变部位冠状动脉进行 Mac-2染色，检测斑块内巨噬细胞浸润程度及血清中TNF-α的表达，分析并阐明活动性炎症参数与心肌造影超声心动图参数的相关性。研究发现，静息及腺苷负荷状态下，实验组的左室前间隔和后壁心肌造影A值、β值及A x β值较对照组均显著下降。在腺苷负荷状态下，不稳定斑块组A值与β值及A x β值较稳定斑块组显著下降。在左室长轴心肌斑点追踪应变分析中，腺苷负荷状态下，实验组的纵向应变较对照组显著下降；且在实验组中，不稳定斑块组纵向应变较稳定斑块组亦显著降低。实验组血基础上TNF-α水平显著高于对照组。免疫组化分析发现斑块内有不同程度的巨噬细胞浸润，平均巨噬细胞浸润率为35.2%（范围20.5%-48.0%）。相关分析结果显示，斑块内巨噬细胞浸润率与血清TNF-α水平呈显著正相关（r = 0.63, P = 0.003；）。另外，斑块内巨噬细胞浸润率还分别与腺苷负荷状态下左室前间隔及后壁心肌造影A × β值呈显著负相关（r = -0.74, P ＜ 0.001；r = -0.72, P ＜ 0.001）。通过研究，我们明确了冠状动脉粥样硬化斑块易损性特征与下游心肌灌注的关系。我们研究结果还显示随着斑块内巨噬细胞浸润程度逐渐加重，其下游支配区域的心肌血流灌注量也随之降低。