【作者】 喻松仁；

【导师】 袁肇凯；

【作者基本信息】 湖南中医药大学 ， 中医诊断学， 2014， 博士

【摘要】 [目的]探讨冠心病痰瘀衍变的基本病机,分析脂质代谢异常在冠心病痰瘀衍变的发生和发展过程中的作用,从脂质代谢角度阐释冠心病痰瘀衍变的规律和本质。[方法]1.文献研究系统研究古籍文献,归纳冠心病痰瘀衍变的基本病机;检索中国知网(CNKI)、维普(CQVIP)、万方(WANFANG DATA)、中国生物医学文献数据库(CBM)及Pubmed等数据库收录的有关冠心病痰瘀辨证与血脂变化的文献,提出纳入文献的有关信息,采用Meta分析法进行综合分析,总结和评价脂质代谢的异常改变与冠心病痰瘀病理变化的关系。2.临床研究采用整群随机抽样法,进行多中心、大样本的冠心病中医临床流行病学调查研究;同时检测调查的冠心病患者及健康人血脂、血糖、血液流变学和心脏彩色超声指标,探讨痰瘀辨证在冠心病中证型的分布和冠心病痰瘀衍变的微观指征。3.实验研究复制心肌缺血痰瘀衍变大鼠模型,开展心电图、血脂、血糖、血液流变学、血胰岛素和病理组织学检查,并采用实时荧光定量RT-PCR技术检测脂质代谢相关通路基因表达;运用益气化痰活血法中药治疗心肌缺血大鼠,检测上述指标,探讨冠心病痰瘀衍变与脂质代谢关联性,从脂质代谢的角度阐释冠心病的痰瘀衍变的内在机制。[结果]1.文献研究(1)冠心病痰瘀衍变根本原因在于外为饮食失节所伤,内则脾胃虚弱,运化失职,正气不足,痰浊内生,终致痰凝血瘀胶伏心脉而斑块自成,以心、脾(胃)和血脉为主要病变部位,以“本虚标实”为主要特征,以痰凝和血瘀为其病理关健。(2)对各数据库获取的冠心病痰瘀辨证与血脂变化共10篇文献(末次检索日期为2012年11月30日)应用Meta分析的随机效应模型定量分析,结果表明冠心病血脂含量的异常改变与冠心病的痰瘀病理呈密切的相关性,且由痰到瘀的衍变过程与TC、TG、LDL-C呈现一定的相关性。2.临床研究(1)通过对298例冠心病患者进行中医临床流行病学调查,发现痰瘀相关证组(包括痰凝心脉、痰凝血瘀证)者占64.1%、心肾阳虚者证占7.4%、心肾阴虚证者占9.7%、寒凝心脉证者8.1%、心气虚证者占10.7%,痰瘀证组与非痰瘀证组比较,存在显著性差异。(2)对冠心病病例的相关指标进行检测,发现冠心病痰凝脉证的微观指标以血脂代谢异常较为显著；痰瘀痹阻证则以血液流变学异常及左室射血分数、左心室短轴缩短指数等心脏左室功能改变较为明显。冠心病由健康→非痰非瘀证→痰凝心脉证→痰瘀痹阻证的变化中存在着血糖改变,总体上呈现递增趋势;而“脂质代谢异常”见于CHD痰瘀病理变化的全过程。3.实验研究(1)心肌缺血大鼠由正常→非痰非瘀→痰凝心脉→痰瘀痹阻的病理衍变过程中,存在心电图、血脂、血液流变学的异常改变和胰岛素抵抗现象,脂质代谢通路相关基因PPARγmRNA、INSIG2mRNA、 SCAP mRNA表达异常增高,而SREBP2mRNA表达降低,同时痰瘀痹阻阶段组织形态结构改变明显。(2)对心肌缺血大鼠进行药物治疗后,发现益气化痰活血法(养心通脉片)取得较好效果,一方面在调整脂质代谢的同时,尚能改善血液流变学和胰岛素抵抗现象,另一方面能保护冠状动脉的组织结构,有效改善血管损伤,同时还能改善脂质代谢相关通路基因PPARγmRNA、INSIG2mRNA、SCAPmRNA、 SREBP2mRNA的异常表达,使之趋于正常,从而达到保护心血管系统的作用。[结论]1.痰瘀相关证(包括痰凝心脉、痰凝血瘀证)是冠心病的主要证型,其中“痰凝心脉’’是冠心病发生的关键病机,“痰瘀痹阻”是冠心病发展的必然趋势,且“脂质代谢异常”贯穿于冠心病痰瘀衍变的全过程。2.CHD痰瘀衍变中存在的血液流变学异常、血糖、胰岛素敏感指数降低和组织形态学改变,这可能与脂质代谢或脂质代谢异常诱导的相关通路基因表达异常有关。3.中医益气化痰活血疗法和西医降脂疗法均能改善心肌缺血“痰瘀”病理,表明脂质代谢异常与冠心病痰瘀衍变存在相关性。总之,从课题的研究结果来看,冠心病痰瘀衍变与脂质代谢密切相关,脂质代谢通路相关基因的表达的增强或减弱可能是CHD“痰瘀”衍变发生的内在机制。更多还原

【Abstract】 ObjectivesTo explore the basic pathogenesis of phlegm stasis evolution, analyze the role of abnormal lipid metabolism in the occurrence and development of phlegm stasis evolution of coronary heart diease, and explain the rules and the essences of phlegm stasis evolution from the perspective of lipid metabolism.Methods1Literature ResearchThrough systematic analysis of ancient literature, the basic pathogenesis of phlegm stasis evolution could be summarised; Searching records about changes of phlegm stasis syndrome differentiation and changes of blood lipid from the datatbases collected by Chinese Net of Knowledge and Information (CNKI), VIP (CQVIP), Wan Fang (WANFANG DATA), China biomedical literature database (CBM), and putting forward the information from literature reviewing, using method of Meta analysis to conclude and evaluate the relationship between abnormal changes of lipid metabolism and pathological changes of phlegm stasis.2Clinical StudyBy using cluster random sampling method, conducting multi-centered and large-sampled investigative survey of TCM clinical epidemiology of coronary heart disease; simultaneously detecting blood lipid, blood sugar, blood rheology and cardiac color ultrasound index on both patients suffered from coronary heart disease patients and healthy people, and exploring distribution of the syndrome differentiation of phlegm and micro-indictions of evolution of phlegm stasis in coronary heart diease.3Experimental StudyCopying rat model of myocardial ischemia of phlegm stasis evolution, carrying out electrocardiogram, blood lipid, blood sugar, blood rheology, blood insulin and histopathological examination, and adopting real-time fluorescence quantitative RT-PCR expression to detect the pathway related by genes lipid metabolism; Resorting to benefiting Qi for removing phlegm in treatment of rats suffered from myocardial ischemia, and evaluating the above indications so as to explore the relation between evolution of phlegm stasis of coronary heart diease and lipid metabolism and interpret the intrinsic mechanism of phlegm stasis evolution of coronary heart disease from the angle of the lipid metabolism.Results1Literature Research(1) The fundamental reason for evolution of phlegm stasis of coronary heart diease is caused by improper diet externally and the weakness of the spleen and stomach internally. Malfunctional transfusion, the deficiency of vital qi, and phlegm turbid inside ultimately leads to the accumulation of phlegm and blood stasis gluing to heart pulse and forming patch itself. Heart, spleen (stomach) and blood are the main organs with pathological changes, with "deficiency in origin and excess in superficiality" as the main feature and phlegm and blood stasis being the key pathology.(2) Through access to the database of syndrome differentiation of phlegm stasis of coronary heart diease and blood lipid changes in a total of10documents (last search date November30,2012) and quantitative analysis by the random effect model of Meta analysis, the result showed that there was a close correlation between the pathological changes of coronary heart disease of phlegm stasis and blood fat of coronary heart disease, and showed some correlation between the evolution of phlegm stasis and TC, TG, LDL-C.2Clinical Study(1) Through investigation of the clinical epidemiology of TCM in298cases of patients with coronary heart disease, it has been found that the phlegm stasis correlated syndrome group (including the phlegm, phlegm and blood stasis syndrome of heart pulse) accounted for64.1%, heart kidney yang deficiency syndrome accounted for7.4%, heart and kidney yin deficiency accounted for9.7%, cold coagulation heart vessel syndrome accounted for8.1%, and Qi deficiency accounted for10.7%. There were significant differences between phlegm stasis syndrome group and non Phlegm stasis group.(2) Through detection of the indexes related to coronary heart disease cases, it was found that microscopic indexes of phlegm coagulation heart vessel syndrome with abnormal lipid metabolism is obvious; and phlegm obstruction in the abnormal blood rheology and left ventricular ejection fraction, left ventricular shortening index, left ventricular related functions changed obviously. Coronary heart disease by changes in health and non Sputum Stasis Syndrome, phlegm heart vessel syndrome, phlegm and blood stasis syndrome in a blood glucose change generally showed an increasing trend; and "abnormal lipid metabolism "was common in the whole process of phlegm stasis pathologic changes in CHD.3Experimental Study(1) The pathological change of rat suffered from myocardial ischemia is a process from normal to non Sputum or Stasis, phlegm coagulation and heart pulse, and phlegm stasis blocking, which existed in the electrocardiogram, blood lipids, the abnormal changes of Hemorheology and insulin resistance, and lipid metabolism related genes PPAR y mRNA, INSIG2mRNA, SCAP mRNA indications increased abnormaly, while the indications of SREBP2mRNA decreased, meanwhile, morphology during phlegm stasis blocking phase changed obviously.(2) Through drug treatment for myocardial ischemia rats, it was found that method of benefiting Qi and removing phlegm plus promoting blood circulation (Pills of nourishing heart and circulating pulses) has achieved good effect. On the one hand, it could adjust lipid metabolism, and simultaneously improving the phenomena of blood rheology and insulin resistance. On the other hand it can protect organizational structure of the coronary artery, improve vascular injury, simultaneously improving the abnormal indications of lipid metabolism pathway genes PPAR y mRNA, INSIG2mRNA, SCAPmRNA, SREBP2mRNA, and enable them to be normal so as to protect the functions of cardiovascular system.Conclusion1.The correlated phlegm stasis syndrome (including the phlegm coagulation heart pulse, phlegm and blood stasis syndrome) is the main type of syndrome of coronary heart disease, including "phlegm coagulation heart pulse" being the key to the pathogenesis of coronary heart diease."Phlegm stasis blocking" is the inevitable trend of the development of coronary heart disease, and " abnormal lipid metabolism" went the whole process throughout the phlegm stasis evolution of coronary heart diease.2.Abnormal blood rheology of, blood sugar, decreasing insulin sensitivity index, and the changes of histomorphology existed in phlegm stasis evolution of CHD, which may be related to relevant abnormal pathway genes caused by lipid metabolism or lipid metabolism induced abnormal indications.3.Benefiting Qi and removing phlegm of TCM therapy and Western medical lipid-lowering therapy can improve myocardial ischemia and "phlegm" pathology, which showed that there existed a kind of correlation between abnormal lipid metabolism and phlegm stasis evolution of coronary heart disease.In conclusion, from the researching results of this thesis, it has been found that there was a close relation between phlegm stasis evolution and lipid metabolism, and genes expressions related with lipid metabolism increased or decreased, which may be the mechanism underlying development of evolution of CHD "phlegm stasis".更多还原