【作者】 宋庆桥；

【导师】 胡元会；

【作者基本信息】 中国中医科学院 ， 中医内科学， 2010， 博士

【摘要】 背景：随着社会经济的发展和人们生活方式的改变,冠心病心绞痛的发病率逐年提高,已经成为影响人类寿命和生存质量的主要疾病之一。对其进行研究具有重要的社会意义和卫生经济学意义。中医药治疗慢性稳定性心绞痛具有独特的价值,然其证候规律、证候的临床特征、产生机理及预后价值尚缺乏统一认识,有待于进一步研究,为冠心病、心绞痛中医证候的临床诊断、辨证论治提供依据,以利于充分发挥中医药优势。目的：探讨冠心病心绞痛中医常见证候临床表现特征与相关血清蛋白质表达的关系。方法：1.冠心病稳定性心绞痛患者临床中医证候学研究：分析经冠状动脉造影证实的冠心病稳定性心绞痛患者临床证候学特点,包括冠心病心绞痛患者证候要素及常见证候分布特点,观察常见证候及证候要素之间危险因素、冠脉病变程度的差异；采用MDR方法初步构建相关模型,计算冠心病心绞痛患者临床表现与证候要素、常见证候之间的关系。2.冠心病稳定性心绞痛患者相关蛋白质表达与证候关系研究：采用液相蛋白芯片分析方法同步检测冠心病心绞痛患者血清sE-Selectin, sVCAM-1, sICAM-1, MMP-9, MPO, tPAI-1含量,统计证候要素、常见证候之间上述蛋白质表达差异,研究证候要素、常见证候与血清蛋白质表达的关系。结果：1.冠心病稳定性心绞痛患者临床经常出现的证候要素分布为痰147例次、瘀145例次、气虚115例次、阴虚73例次、气滞14例次、阳虚24例次、热22例次、寒4例次；常见证候有气虚血瘀证85例次、痰瘀互结证92例次、阴虚痰阻证56例次、气虚痰阻证86例次、气滞血瘀证14例次、阴虚血瘀证40例次、阳虚痰阻证15、气虚血瘀痰阻证56例次、气阴两虚痰阻证42例次、气阴两虚痰瘀证21例次。不同证候之间,患者冠心病危险因素、冠脉病变程度差异均无显著的统计学意义。2.冠心病心绞痛患者证候要素、常见证候的临床表现特征：寒(头晕、心悸、情志抑郁和脉络形态),准确性,0.884,敏感性,1.000,特异性,0.881,预测准确性, 0.143；气虚,(面色淡白、心痛如刺、唇舌紫暗、腰酸),准确性,0.718,敏感性,0.722,特异性,0.714,预测准确性,0.762；气滞,(善太息、心痛如刺、下肢浮肿、舌质斑点或瘀斑)准确性,0.786,敏感性,1,特异性,0.771,预测准确性,0.241；热,(心悸、唇色紫暗、舌下脉络颜色、脘腹痞闷),准确性,0.704,敏感性,0.909,特异性,0.679,预测准确性,0.253;痰,(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗),准确性,0.762,敏感性,0.748,特异性,0.797,预测准确性,0.902；阳虚,(脘腹痞闷、舌下脉络颜色、唇舌紫暗、心悸)准确性,0.704,敏感性,0.875,特异性,0.681,预测准确性,0.266；阴虚,(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗),准确性,0.728,敏感性,0.795,特异性,0.692,预测准确性,0.586；瘀,(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗)；准确性,0.7476,敏感性,0.731,特异性,0.7869,预测准确性,0.8908；气虚血瘀,(便秘、心悸、舌下脉络形态、体胖多痰)准确性,0.8204,敏感性,0.8947,特异性,0.8128,预测准确性,0.3269；痰瘀互结,(便秘、心悸、舌下脉络形态、体胖多痰),准确性,0.7718,敏感性,1,特异性,0.759,预测准确性,0.1897；阴虚痰阻,(心悸、体胖多痰、便秘、舌下脉络形态)准确性,0.825,敏感性,1.000,特异性,0.818,预测准确性,0.182；气虚痰阻,(心胸胀痛、五心烦热、善太息、情志抑郁),准确性,0.898,敏感性,1.000,特异性,0.895,预测准确性,0.250；气滞血瘀,神疲、心胸胀痛、舌下脉络形态、细脉),准确性,0.854,敏感性,1.000,特异性,0.849,预测准确性,0.189；阴虚血瘀,(心悸、体胖多痰、便秘、脉络),准确性,0.854,敏感性,1.000,特异性,0.849,预测准确性,0.189；阳虚痰阻,(心悸、体胖多痰、便秘、舌下脉络形态),准确性,0.864,敏感性,1.000,特异性,0.859,预测准确性,0.200；气虚血瘀痰阻,(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗),准确性,0.7476,敏感性,0.8529,特异性,0.7267,预测准确性,0.3816；气阴两虚痰阻,(心悸、体胖多痰、舌下脉络形态、便秘)准确性,0.830,敏感性,1.000,特异性,0.816,预测准确性,0.314；气阴两虚痰瘀证,(体胖多痰、心胸胀痛、舌苔色白和面色淡白),准确性,0.811,敏感性,0.950,特异性,0.796,预测准确性,0.333。3.冠心病稳定性心绞痛患者血清sVCAM-1(ln), sICAM-1(ln), MMP-9(ln), MPO(ln), tPAI-1蛋白表达均显著高于健康对照组,p值均<0.01,sE-selectin (In)在稳定性心绞痛患者和健康对照组的表达差异没有显著的统计学意义(p=0.067)。4.相关血清蛋白在冠心病心绞痛各证候要素中表达：tPAI-1在痰、瘀、气虚、阴虚、热证候要素中升高；sVCAM-1在痰、瘀、气虚、气滞、阴虚、热证候要素中升高；sICAM在痰、瘀、气虚、气滞、阴虚、热证候要素中升高；MMP-9在痰、瘀、气虚、气滞、阴虚、热证候要素中升高,sE-Selectin在痰、瘀、气虚、阴虚证候要素中升高；MPO在痰、瘀、气虚、气滞、阳虚、热证候要素中升高。5.相关血清蛋白在冠心病心绞痛常见证候中表达：tPAI-1在气虚血瘀证、痰瘀互结证、阴虚痰阻证、气虚痰阻证、阴虚血瘀证、气虚血瘀痰阻证、气阴两虚痰阻证、气阴虚两虚痰瘀证中表达升高较显著(p<0.01)；sVCAM-1在气虚血瘀证、痰瘀互结证、阴虚痰阻证、气虚痰阻证、阴虚血瘀证、气虚血瘀痰阻证、气阴两虚痰阻证、气阴虚两虚痰瘀证中表达升高较显著(p<0.01)；sICAM在气虚血瘀证、痰瘀互结证、气虚痰阻证、气滞血瘀证、气虚血瘀痰阻证、气阴两虚痰阻证、气阴两虚痰瘀证表达较健康对照组及阳虚痰阻证显著升高(p<0.01)；MMP-9在气虚血瘀证、痰瘀互结证、气虚痰阻证、气滞血瘀证、气虚血瘀痰阻证、气阴两虚痰阻证、气阴两虚痰瘀证表达升高显著(p＜0.01或0.05)；sE-Selectin在气虚血瘀证、痰瘀互结证、气虚痰阻证、阴虚痰阻证、阴虚血瘀证、气虚血瘀痰阻证、气阴两虚痰阻证、气阴两虚痰瘀证显著高于健康对照组和阳虚痰阻证(p＜0.01)；MPO在气虚血瘀证、痰瘀互结证、气虚痰阻证、阴虚痰阻证、阴虚血瘀证、气虚血瘀痰阻证、气阴两虚痰阻证、气阴两虚痰瘀证表达均显著升高(p<0.01)。结论：1.冠心病稳定性心绞痛患者临床常见证候要素痰、瘀、气虚、阴虚、气滞、阳虚、热、寒；常见证候气虚血瘀证、痰瘀互结证、阴虚痰阻证、气虚痰阻证、气滞血瘀证、阴虚血瘀证、阳虚痰阻证、气虚血瘀痰阻证、气阴两虚痰阻证、气阴两虚痰瘀证。2.冠心病心绞痛证候要素临床表现特征：寒(头晕、心悸、情志抑郁和脉络形态),气虚(面色淡白、心痛如刺、唇舌紫暗、腰酸),气滞(善太息、心痛如刺、下肢浮肿、舌质斑点或瘀斑),热(心悸、唇色紫暗、舌下脉络颜色、脘腹痞闷),痰(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗),阳虚(脘腹痞闷、舌下脉络颜色、唇舌紫暗、心悸),阴虚(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗),血瘀(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗)。3.冠心病心绞痛常见证候临床表现特征：气虚血瘀(便秘、心悸、舌下脉络形态、体胖多痰),痰瘀互结(便秘、心悸、舌下脉络形态、体胖多痰),阴虚痰阻(心悸、体胖多痰、便秘、舌下脉络形态),气虚痰阻(心胸胀痛、五心烦热、善太息、情志抑郁),气滞血瘀(神疲、心胸胀痛、舌下脉络形态、细脉),阴虚血瘀(心悸、体胖多痰、便秘、脉络),阳虚痰阻(心悸、体胖多痰、便秘、舌下脉络形态),气虚血瘀痰阻(脘腹痞闷、心悸、舌下脉络颜色、唇舌紫暗),气阴两虚痰阻(心悸、体胖多痰、舌下脉络形态、便秘),气阴两虚痰瘀证(体胖多痰、心胸胀痛、舌苔色白和面色淡白)。4.冠心病稳定性心绞痛患者血清sVCAM-1(ln), sICAM-1(ln), MMP-9(ln), MPO(ln), tPAI-1蛋白均显著高于健康对照组。5.冠心病稳定性心绞痛证候要素中,痰、瘀、气虚、阴虚、热证素的血清tPAI-1、sVCAM-1、sICAM-1、sE-selectin、MMP-9、MPO蛋白表达升高；气滞证素血清sVCAM-1、MMP-9、MPO蛋白表达升高；阳虚证素MPO蛋白表达升高；6.冠心病稳定性心绞痛常见证候中气虚血瘀、痰瘀互结、阴虚痰阻、气虚痰阻、阴虚血瘀证候的血清tPAI-1、sVCAM-1、sICAM-1、sE-selectin、MMP-9、MPO蛋白表达升高；气滞血瘀证候血清sVCAM-1、sICAM-1、MMP-9、MPO蛋白表达升高；气虚血瘀痰阻证、气阴两虚痰阻证、气阴两虚痰瘀证证候tPAI-1、sVCAM-1、sICAM-1、sE-selectin、MMP-9、MPO蛋白表达升高。更多还原

【Abstract】 Background: With the development of social economic and the change of people’s lifestyles, the incidence of angina pectoris increases year by year, and become one of the main diseases which impact on the life expectancy and quality of life. Therefore, it is of great importance on social meaning and health economics meaning to research the disease of angina pectoris. Traditional Chinese medicine plays a unique value in treating chronic stable angina, but the law of syndrome, generation mechanism prognostic value needs to be further researched to give full play to TCM and to provide basis for the syndrome differentiation and clinical diagnosis of angina pectoris.Objective:To discuss the relationship between common clinical manifestation and related serum protein expression in angina pectoris.Methods:1. Clinical syndrome in patients with coronary stable angina cordis: patients with coronary stable angina cordis proved by coronal artery angiography were analyzed the characters of clinical syndrome. The character included syndrome elements, the common syndrome distribution, the risk factor between common syndrome and syndrome elements, the differences of coronary angiographic degree. The relative model was built by using MDR, and then calculated the relationship between clinical manifestation and syndrome of patients with angina pectoris.2. The relationship between protein expression and syndrome in patients with coronary stable angina cordis:the content of Se-Selectin, sVCAM-1, sICAM-1, MMP-9, MPO, tPAI-1 was detected by analysis of liquid protein chip, statisticed the protein differential expressions in syndrome elements and common syndrome, researched the relationship among syndrome elements, common syndrome and protein expression.Results:1.The distribution of common syndrome elements in patients with coronary stable angina cordis shows that 147 cases of phlegm,145 cases of stasis,115 cases of qi deficiency,73 cases of yin deficiency,14 cases of qi stagnation,24 cases of yang deficiency,22 cases of heat,4 cases of cold. The common syndrome shows that 85 cases of qi deficiency and blood stasis,92 cases of phlegm and blood stasis,56 cases of yin deficiency and phlegm obstruction,86 cases of qi deficiency and phlegm obstruction,42 cases of both qi and yin deficiency and phlegm obstruction,21 cases of both qi and yin deficiency and phlegm stasis. Compare with different syndrome, there is no statistically significance in risk factor and coronary angiographic degree.2. The characteristic of syndrome elements and common syndrome in patients with angina pectoris:for cold (dizziness, palpitation, depression, the shape of choroids) the accuracy was 0.884, sensitivity was 1.000, specifty was 0.881 and the predicative accuracy was 0.143; for qi deficiency (pale complexion, stabbing pain in the chest, cyanotic lips and tongue, soreness) the accuracy was 0.718, sensitivity was 0.722, specifty was0.741 and the predicative accuracy was 0.762; for qi stagnation, (preference for sighing, stabbing pain in the chest, edema of both lower limbs, purplish grayish tongue) the accuracy was 0.786, sensitivity was 1, specifty was0.771and the predicative accuracy was 0.241; for heat(palpitation, cyanotic lips and tongue, the color of sublingual vein, abdominal distension) the accuracy was 0.704, sensitivity was 0.909, specifty was0.679and the predicative accuracy was 0.253; for phlegm(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue) the accuracy was 0.762, sensitivity was 0.748, specifty was0.797and the predicative accuracy was 0.902;for yang deficiency(abdominal distension, the color of sublingual vein, cyanotic lips and tongue) the accuracy was 0.704, sensitivity was 0.875, specifty was0.681and the predicative accuracy was 0.266;for yin deficiency(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue) the accuracy was 0.728, sensitivity was 0.795, specifty was0.692and the predicative accuracy was 0.586; for blood stasis(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue) the accuracy was 0.7476, sensitivity was 0.731, specifty was0.7869and the predicative accuracy was 0.8908; for qi deficiency and blood stasis (constipation, palpitation, the shape of choroids, fat body) the accuracy was 0.8204, sensitivity was 0.8947, specifty was0.8128and the predicative accuracy was 0.3269;for phlegm and blood stasis(constipation, palpitation, the shape of choroids, fat body) the accuracy was 0.7718, sensitivity was 1, specifty was0.759and the predicative accuracy was 0.1897; for yin deficiency and phlegm obstruction(constipation, palpitation, the shape of choroids, fat body) the accuracy was 0.825, sensitivity was 1.000, specifty was0.818, the predicative accuracy was 0.182; for qi deficiency and phlegm obstruction(dyspnea chest discomfort, buring sensation of five centers, preference for sighing,depression) the accuracy was 0.898, sensitivity was 1.000, specifty was 0.895 and the predicative accuracy was 0.250; for qi stagnation and blood stasis(dyspnea chest discomfort, buring sensation of five centers, preference for sighing,depression) the accuracy was 0.854, sensitivity was 1.000, specifty was 0.849 and the predicative accuracy was 0.189;for yin-asthenia and blood-stasis(palpitation, overweight and phlegmatic, constipation, thread of thought) the accuracy was 0.854, sensitivity was 1.000, specifty was 0.849 and the predicative accuracy was 0.189;for yang deficiency and phlegm obstruction(palpitation, overweight and phlegmatic, constipation, the shape of choroids) the accuracy was 0.864, sensitivity was 1.000, specifty was 0.859 and the predicative accuracy was 0.200;for qi deficiency and blood stasis and phlegm obstruction(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue) the accuracy was 0.7476, sensitivity was 0.8529, specifty was 0.7267 and the predicative accuracy was 0.3816;for both of qi and yin deficiency and phlegm obstruction(palpitation, overweight and phlegmatic, constipation, the shape of choroids) the accuracy was 0.830, sensitivity was 1.000, specifty was 0.816 and the predicative accuracy was 0.314;for both of deficiency and phlegm stasis(overweight and phlegmatic, dyspnea chest discomfort, whitish tongue fur and pale complexion) the accuracy was 0.811, sensitivity was 0.950, specifty was 0.796 and the predicative accuracy was 0.333.3. The protein expression in sVCAM-1, sICAM-1, MMP-9, MPO, tPAI-1 in patients with coronary stable angina cordis is higher than health(P<0.01). There is no statistically meaning in sE-Selectin in both groups (p=0.067) 4. Protein expression of syndrome elements in patients with coronary stable angina cordis:The expression of tPAI-1 is higher in phlegm, stasis, qi deficiency, yin deficiency, heat; The expression of sVCAM-1 is higher in phlegm, stasis, qi deficiency, qi stagnation, yin deficiency, heat; the expression of sICAM-1 is higher in phlegm, stasis, qi deficiency, qi stagnation, yin deficiency, heat; The expression of MMP-9 is higher in phlegm, stasis, qi deficiency, qi stagnation, yin deficiency, heat; the expression of Se-Selectin is higher in phlegm, stasis, qi deficiency, yin deficiency; The expression of MPO is higher in phlegm, stasis, qi deficiency, qi stagnation, yang deficiency, heat.5. Protein expression of syndrome in patients with coronary stable angina cordis:The expression of tPAI-1 is higher in qi deficiency and blood stasis, phlegm and blood stasis, yin deficiency and phlegm obstruction, qi deficiency and phlegm obstruction, yin deficiency and blood stasis; qi deficiency and blood stasis and phlegm stagnation, both qi and yin deficiency and phlegm obstruction, both qi and yin deficiency and phlegm stasis (P<0.01); The expression of sVCAM-1 is higher in qi deficiency and blood stasis, phlegm and blood stasis, yin deficiency and phlegm obstruction, qi deficiency and phlegm obstruction, yin deficiency and blood stasis, qi deficiency and blood stasis and phlegm stagnation, both qi and yin deficiency and phlegm obstruction, both qi and yin deficiency and phlegm stasis (P<0.01); The expression of sICAM-1 is higher in qi deficiency and blood stasis, phlegm and blood stasis, yin deficiency and phlegm obstruction, qi deficiency and phlegm obstruction, yin deficiency and blood stasis, qi deficiency and blood stasis and phlegm stagnation, both qi and yin deficiency and phlegm obstruction, both qi and yin deficiency and phlegm stasis (P<0.01); The expression of MMP-9 is higher in qi deficiency and blood stasis, phlegm and blood stasis, phlegm and blood stasis, qi deficiency and phlegm obstruction, qi stagnation and blood stasis, qi deficiency and blood stasis and phlegm stagnation, both qi and yin deficiency and phlegm obstruction, both qi and yin deficiency and phlegm stasis (P<0.01or 0.05); The expression of Se-Selectin is higher in qi deficiency and blood stasis, phlegm and blood stasis, qi deficiency and phlegm obstruction, yin deficiency and phlegm obstruction, qi deficiency and blood stasis and phlegm stagnation, both qi and yin deficiency and phlegm obstruction, both qi and yin deficiency and phlegm stasis (P<0.01); The expression of Se-Selectin is higher than health and yang deficiency; The expression of MPO is higher in qi deficiency and blood stasis, phlegm and blood stasis, qi deficiency and phlegm obstruction, yin deficiency and phlegm obstruction, yin deficiency and blood stasis, qi deficiency and blood stasis and phlegm stagnation, both qi and yin deficiency and phlegm obstruction, both qi and yin deficiency and phlegm stasis (P<0.01);Conclusion:1.The common syndrome elements in patients with coronary stable angina cordis can be seen as phlegm, stasis, qi deficiency, yin deficiency, qi stagnation, yang deficiency, heat, cold; while the common syndrome can be seen as qi deficiency and blood stasis, phlegm and blood stasis, qi deficiency and phlegm obstruction, qi stagnation and blood stasis, yin deficiency and blood stasis, yang deficiency and phlegm obstruction, qi deficiency and blood stasis and phlegm obstruction, both of qi and yin deficiency and phlegm obstruction, both of qi and yin deficiency and phlegm stasis.2.The clinical manifestation of syndrome elements in patients with coronary stable angina cordis can be summarized as following: cold(dizziness, palpitation, depression, stabbing pain in the chest, the shape of choroids); qi deficiency(pale complexion, stabbing pain in the chest, cyanotic lips and tongue, sorness); qi stagnation(preference for sighing, stabbing pain in the chest, edema of both lower limbs, purplish grayish tongue);heat (palpitation, cyanotic lips and tongue, the color of sublingual vein, abdominal distension); phlegm(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue);yang deficiency(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue);yin deficiency (abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue);blood stasis(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue);3. The clinical manifestation of syndrome elements in patients with coronary stable angina cordis can be summarized as following: qi deficiency and blood stasis(constipation, fat body, palpitation, the shape of choroids); phlegm and blood stasis(constipation, fat body, palpitation, the shape of choroids);yin deficiency and phlegm obstruction(constipation, fat body, palpitation, the shape of choroids); yin deficiency and blood stasis(constipation, fat body, palpitation, the shape of choroids); qi deficiency and blood stasis and phlegm obstruction(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue); both of qi and yin deficiency and phlegm obstruction(abdominal distension, palpitation, the color of sublingual vein, cyanotic lips and tongue, constipation); both of qi and yin deficiency and phlegm stasis(fat body, stabbing pain in the chest, pale complexion, pale tongue).4. The content of sVCAM-1, sICAM-1, MMP-9, MPO, tPAI-1 in patients with coronary stable angina cordis is higher than health.5. The expression of tPAI-1, sVCAM-1, sICAM-1, sE-Selectin, MMP-9, MPO, in phlegm, stasis, qi deficiency, yin deficiency and heat increase higher; while the expression of sVCAM-1,MMP-9, MPO in qi stagnation increased significantly; MPO in yang deficiency increased.6.The expression of sVCAM-1, sICAM-1, MMP-9, MPO, tPAI-1,sE-Selectin in qi deficiency and blood stasis, phlegm and blood stasis, yin deficiency and phlegm obstruction, qi deficiency and phlegm obstruction, yin deficiency an blood stasis increased; while the expression of sVCAM-1, sICAM-1, MMP-9, MPO in qi stagnation and blood stasis increased higher; the expression of sVCAM-1, sICAM-1, MMP-9, MPO, tPAI-1,sE-Selectin in qi deficiency and blood stasis and phlegm obstruction, both of qi and yin deficiency and phlegm stasis increases higher.更多还原