不稳定性心绞痛方证对应及证候动态变化研究

【作者】 孙晓伟；

【导师】 王阶；

【作者基本信息】 北京中医药大学 ， 中西医结合临床， 2010， 博士

【摘要】 在中医学与现代医学的发展过程中,形成了辨证论治与辨病治疗的临床诊疗模式。病证结合已经成为目前中医研究的主要模式,方证对应是中医提高临床疗效的关键,将方剂与证候相结合进行研究,架起理法方药之间的桥梁,探求方剂与证候间的内在联系与规律,有利于提高辨证论治水平与临床疗效,因此病证结合方证对应是中西医结合研究的良好切入点。开展病证方结合方证对应研究,有助于丰富与完善中医理论体系与诊疗方法,对揭示经典方剂的作用机理及证候的本质都具有重要的意义。冠心病是危害人类健康的一个主要疾病,已成为人群的主要死亡原因之一,因此冠心病的防治目前仍是医学研究的焦点之一。不稳定性心绞痛是冠心病的一个主要类型,属于现代医学急性冠脉综合症的范畴,其病情变化较快、凶险,需要及时诊治,现代医学已经形成了一套规范的诊疗标准。中医药在治疗冠心病方面具有一定的优势,在明确诊断疾病的基础上进行中医辨证治疗,能进一步提高疗效、提高生活质量、改善预后。本研究在病证结合的基础上,选择明确诊断的不稳定性心绞痛患者,采用经典名方血府逐瘀胶囊和生脉胶囊进行方证对应与不对应干预治疗,采集多时点的临床信息,从多方面阐释方证对应的作用机理,并探讨方证对应干预下的证候动态变化。目的探讨不稳定性心绞痛方证对应与不对应干预下的疗效及证候的动态变化,阐释方证对应的机理及证候的动态变化特征。方法入选88例经冠脉造影明确诊断的冠心病不稳定性心绞痛患者,血瘀证和气阴两虚证各44例,采用随机、双盲、双模拟的研究方法,分别用血府逐瘀胶囊和生脉胶囊进行方证对应与不对应干预治疗,收集治疗前、治疗后1周、2周、3周、4周的症状、中医证候、实验室指标及SAQ等相关信息。试验结束后：①进行两种干预方法的疗效比较,包括心绞痛疗效、心电图疗效、主要症状体征疗效、中医证候疗效、实验室指标疗效、生活质量疗效；②探讨不稳定性心绞痛在两种方法干预下证候的动态变化,应用生存分析和重复测量资料的方差分析方法,研究主要包括症状、证候要素频数、证候要素积分、证候要素组合及生物学标记物的动态变化特征。③探讨证候要素与生物学标记物之间的关系。结果1.疗效观察：试验过程中脱落6例,纳入统计分析的共有82例。①心绞痛疗效：血瘀证方证对应与不对应治疗有效率分别为80.95%、50.00%,方证对应优于不对应(P<0.05)；气阴两虚证方证对应与不对应治疗有效率分别为76.19%、55.00%,疗效无统计学意义(P>0.05)；总体方证对应与不对应治疗有效率分别为78.57%、52.50%,方证对应优于不对应(P<0.05)。②心电图疗效：方证对应与不对应治疗改善心电图总有效率为分别为73.81%、57.5%,比较无统计学意义(P>0.05)。③主要症状体征疗效：方证对应治疗在改善胸闷、心悸、倦怠乏力、气短、自汗优于不对应治疗(P<0.05),而在改善胸痛、畏寒肢冷、腰膝酸软、不寐等症状两种方法无差别(P>0.05)。④中医证候疗效：血瘀证方证对应与不对应治疗有效率分别为85.71%、50.00%,方证对应优于不对应(P<0.05)；气阴两虚证方证对应与不对应治疗有效率分别为80.95%、45.00%,方证对应优于不对应(P<0.05)；两证总体方证对应与不对应治疗有效率分别为83.33%47.50%,方证对应优于不对应(P<0.05)。⑤生物学标记物变化：hs-CRP、Hcy、MPO. MMP9、ET在血瘀证组方证对应治疗后下降(P＜0.05或P＜0.01),不对应治疗下降无统计学意义(P>0.05),对应治疗优于不对应(P<0.05)；在气阴两虚证组方证对应与不对应治疗后均有所下降(P<0.05或P<0.01),但两种方法差异无统计学意义(P＜0.05)；两个证型总体治疗后较治疗前均下降(P<0.05或P<0.01),且治疗后比较方证对应优于不对应(P<0.05)。PAF、PAG、BNP在血瘀证、气阴两虚证及总体治疗后均降低(P＜0.05或P<0.01),但治疗后各组间方证对应与不对应比较均无统计学意义(P＞0.05)。血脂四项：血瘀证、气阴两虚证及总体治疗后较治疗前比较,无论方证对应还是不对应差异均有统计学意义,TG、TC、LDL-C均下降(P<0.05), HDL-C均升高(P<0.05),但治疗后组间方证对应与不对应比较差异无统计学意义(P>0.05)。⑥SAQ疗效：各组治疗后AS、AF、TS、DP积分升高较治疗前比较差异具有统计学意义(P<0.05或P<0.01),两证总体方证对应与不对应治疗后比较亦有统计学意义(P<0.05)。各组PL积分治疗前后及治疗后组间比较差异均无统计学意义(P>0.05)。2.证候动态变化：①症状变化：方证对应时,胸闷、心悸、自汗、气短症状消失的时间早于不对应治疗(P<0.05),而胸痛等其他症状消失时间无差别(P>0.05)；②证候要素频数变化：方证对应时,血瘀证、气虚证消失的时间要早于不对应治疗(P<0.05),而阴虚证的消失时间两种方法无统计学意义(P＞0.05)；③证候要素积分变化：方证对应时,血瘀证、气虚证、阴虚证积分下降要早于不对应治疗(P<0.05或P<0.01),血瘀证在治疗1周、气虚证、阴虚证在治疗2周后与治疗前比较即有统计学意义；不对应治疗时,血瘀证在治疗3周、气虚证、阴虚证在治疗4周后与治疗前比较才有统计学意义；④证候要素组合变化：方证对应时,在治疗过程中,2证组合逐渐增多,3证组合逐渐减少,而不对应治疗时2证组合逐渐减少,3证组合逐渐增多。⑤生物学标记物的变化：方证对应时,hs-CRP、Hcy、ET、MPO、MMP9在治疗1周后水平下降即有统计学意义(P<0.01),而方证不对应时MPO、MMP9治疗2周、hs-CRP、Hcy, ET治疗3周时水平下降才有统计学意义(P<0.01)。3.证候要素与生物学标记物关系：血瘀证与PAF关系最为密切,提示血瘀可能与血小板活化有关；气虚证与BNP、PAG关系密切,提示气虚与心功能不全及血小板聚集有关；阴虚证与Hey、BNP、ET有一定关系,但三者的诊断贡献度均较小；气滞证与ET、MPO关系密切,提示气滞可能与内皮功能受损及炎症反应有关；痰浊证与TC、hs-CRP、TG关系最为密切,提示痰浊与血脂紊乱及炎症反应有关；热蕴证与hs-CRP、MMP9最为密切,提示热蕴可能与炎症反应有关；阳虚证与BNP密切相关,提示阳虚可能与心功能不全有关；寒凝证与BNP正相关,与Hey、MMP9负相关,提示寒凝可能与心功能不全有关,与炎症反应关系不大。结论1.不稳定性心绞痛在方证对应干预治疗时,心绞痛总疗效、症状如胸闷、心悸、气短、倦怠乏力、自汗疗效,中医证候疗效,部分生物学标记物如hs-CRP、Hey、MPO、MMP9、ET疗效,SAQ疗效,方证对应治疗均优于不对应治疗。2.不稳定性心绞痛在方证对应干预时,胸闷、心悸、自汗、气短症状消失时间,血瘀证、气虚证两证候要素消失时间,血瘀证、气虚证、阴虚证积分下降时间,方证对应治疗要早于不对应治疗；在方证对应治疗时,证候要素组合朝着简单组合发展,在不对应治疗时朝着复杂组合发展；方证对应治疗时,部分生物学标记物下降时间要早于不对应。3.证候要素与某些生物学标记物有一定的关系,可以为辨证提供参考依据。更多还原

【Abstract】 During the development process of traditional chinese medicine (TCM) and modern medicine, clinical pattern of diagnosis and treatment about syndrome differentiation and treatment in TCM and treatment based on disease differentiation in modern medicine formed. Currently, the study on combination of disease and syndrome which lies in syndrome differentiation in TCM binding disease diagnosis in modern medicine has become the main pattern of syndrome. Combination of disease and syndrome with prescription corresponding to syndrome is the key of clinical effect. Combination of prescription and syndrome, putting up a bridge between principle-method-recipe-medicines,exploration of the internal relations of them, which can improve the level of clinical syndrome differentiation and treatment. Therefore, prescription corresponding to syndrome is the best starting point of integrative chinese and western medicine study. Carrying out the study of combination of disease and syndrome and prescription corresponding to syndrome contributes to enrich and perfect the theoretical system and treatment methods of TCM,which is of great significance for revealing the mechanism of the classic prescription and the essence of syndrome.Coronary heart disease(CHD)is one of the main disease harmful to human health, which has become one of the leading causes of death, so prevention and treatment of CHD is still the focus of medical research. Unstable angina (UA), one of the major types of CHD, belongs to the scope of acute coronary syndrome(ACS).UA has characteristics of changing fast and danger, which should be diagnosed and treated timely. Modern medicine has become a series of standard for diagnosis and treatment, and TCM in treating CHD has its own advantages. With a clear diagnosis plus TCM treatment, it can further improve the efficacy, quality of life and improve prognosis. In this study, on the basis of combination of disease and syndrome, patients with UA who were diagnosed by coronary angiography(CAG) were selected to take part in this trial. Using the classic formula Xuefuzhuyu capsules and Shengmai capsules to interference UA with prescription corresponding to syndrome or non-corresponding, collecting clinical information multiple timepoint, to explain the mechanism of prescription corresponding to syndrome and to explore the dynamic change of syndrome under the guide of theory.PurposeTo observe the effect and dynamic change of syndrome factors of UA intervened with prescription corresponding to syndrome or non-corresponding, and to explain the mechanism of prescription corresponding to syndrome and the dynamic change characteristics of syndrome. Methods88 cases with UA diagnosed by CAG were studied. including blood stasis group(44 cases), deficiency of both Qi and Yin group(44 cases). Using a randomized, double-blind, double dummy research methods, Xuefuzhuyu capsules and Shengmai capsules were administrated to intervene with patients. Clinical information were collected before and after treatment 1 week,2 weeks,3 weeks,4 weeks, including symptoms, signs, TCM syndrome and laboratory objective markers. After the test:①To compare the efficacy of two interventions, including angina pectoris, the main symptoms and signs, ECG effects, curative effect of TCM, laboratory markers of efficacy, quality of life effects;②To observe the dynamic change of syndrome of patients with UA in two interventional ways, using survival analysis and repeated measures analysis of variance methods, mainly including symptoms frequency, syndrome factor frequency, syndrome factor points, syndrome factors combination and biological markers③To explore the relationship between syndrome factors and biological markers.Results1. Comparison of therapeutic effects:During experimental period, six cases fell off, a total of 82 cases were involved into statistical analysis.①angina pectoris:the effective rate of prescription corresponding to syndrome and non-corresponding in blood stasis group was 80.95%,50.00%, respectively, the former was better than the latter(P＜0.05); the effective rate of prescription corresponding to syndrome and non-corresponding in deficiency of both Qi and Yin group was 76.19%,55.00%, respectively, there was no statistical significance (P>0.05); the total effective rate in prescription corresponding to syndrome and non-corresponding group was 78.57%,52.50%, respectively, the former is better than the latter (P＜0.05).②ECG effects:the effective rate of prescription corresponding to syndrome and non-corresponding in the whole group was 73.81%,57.5%, respectively, there was no statistical significance (P>0.05).③main symptoms and signs:the improvement of chest distress, palpitations, shortness of breath, malaise and fatigue, spontaneous perspiration in prescription corresponding to syndrome group was better than non-corresponding group (P＜0.05), but in improving the chest pain, aversion to cold, soreness of loins and knees, insomnia in the two group, there were no statistical significance(P>0.05).④TCM syndrome: the effective rate of prescription corresponding to syndrome and non-corresponding in blood stasis group was 85.71%,50.00%, respectively, while in deficiency of both Qi and Yin the rate was 80.95%,45.00%, respectively,the former is better than the latter (P＜0.05); the total effective rate in the whole group was 83.33%,47.50%, respectively, also, the former is better (P＜0.05).⑤biological markers:The level of hs-CRP, Hey, MPO, MMP9, ET in the blood stasis group treated with prescription corresponding to syndrome decreased after treatment (P<0.05 or P＜0.01), but they did not decrease in non-corresponding group (P>0.05),the former is better than the latter; while in deficiency of both Qi and Yin group all the five markers decreased despite of prescription corresponding to syndrome or not(P<0.05 or P<0.01)after treatment, but there were no ststistical significance between two kinds of methods; when comparison of all cases,these markers in those who were treated with prescription corresponding to syndrome decreased more than those treated with non-corresponding(P<0.05). The level of PAF, PAG, BNP after treatment in all groups were lower than that before treatment(P<0.05 or P＜0.01), but there were no statistical significance among the groups after treatment (P>0.05). Four Items of Blood-lipid Tests:there were statistical significance in lowering the level of TG, TC, LDL-C (P＜0.05), and increasing the level of HDL-C before and after treatment in each group (P<0.05), but there was no statistical significance between the two groups after treatment(P>0.05).⑥SAQ:before and after treatment in each group, AS, AF, TS, DP points decreased, there were statistical significance (P<0.05 or P<0.01), when added into all, points lowerd more in those who were treated with prescription corresponding to syndrome than those treated with non-corresponding (P＜0.05). PL points did not lower in each group before and after treatment (P>0.05).2. Dynamic changes of syndrome:①symptoms:the disappearance time of chest distress, palpitations, spontaneous perspiration, shortness of breath symptoms in prescription corresponding to syndrome group was earlier than non-corresponding group(P<0.05), while there were no statistical significance about disappearance time of chest pain and other symptoms in non-corresponding group(P>0.05);②frequency of syndrome factors:when treated with prescription corresponding to syndrome, the onset time about blood stasis and Qi deficiency was earlier than non-corresponding (P＜0.05), while the onset time about Yin deficiency of two kinds of methods was not statistically significant(.P>0.05);③points of syndrome factors:when treated with prescription corresponding to syndrome, the onset time of syndrome points reduction about blood stasis, Qi deficiency, Yin deficiency was earlier than non-corresponding (P＜0.05 or P＜0.01), after treatment of 1 week in blood stasis and 2 weeks in Qi deficiency and Yin deficiency there were statistical significance, while it was as well after treatment of 3 weeks in blood stasis and 4 weeks in Qi deficiency and Yin deficiency when treated with non-corresponding,④combination of syndrome factors:when treated with prescription corresponding to syndrome, the combination of two syndromes gradually increased while the combination of three syndromes gradually decreased. when treated with non-corresponding, the change trend of combination of syndromes is contrary to that.⑤biological markers:when treated with prescription corresponding to syndrome, the level of hs-CRP, Hey, ET, MPO, MMP9 decreased after treatment of 1 week that is statistically significant (P<0.01), while treated with non-corresponding, the level of MPO, MMP9 fell after 2 weeks, and the level of hs-CRP, Hey, ET did after treatment for 3 weeks only, which showed statistical significance (P<0.01).3. The relationship between syndrome factors and biological markers:Blood stasis syndrome and PAF was closely related which suggests the main pathology of blood stasis is platelet activation. Qi deficiency related BNP, PAG which suggests cardiac insufficiency and platelet aggregation. Yin deficiency was related to Hey, BNP and ET, but the degree of relation was minor and had little value for diagnosis. Qi stagnation was associated with ET, MPO which suggests inflammatory reaction and impaired endothelial function. Turbid phlegm well correlated TC, hs-CRP, TG. which implicate hyperlipemia and inflammatory reaction. Heat deposition was correlated with hs-CRP, MMP9 which hint inflammatory reaction. And also, Yang deficiency closely related to BNP which suggests cardiac insufficiency. Cold coagulation was associated with BNP, Hey, MMP9 which suggest cardiac insufficiency and inflammatory reaction.Conclusion1. Unstable angina treated with prescription corresponding to syndrome, the overall effect of angina, the effect of symptoms of chest distress, palpitations, shortness of breath, spontaneous perspiration, the effect of TCM syndrome, the effect of some biological marker such as hs-CRP, Hey, MPO,MMP9, ET, and SAQ efficacy were better than non-corresponding treatment.2. Unstable angina treated with prescription corresponding to syndrome, the onset time of some symptoms such as chest distress, palpitations, spontaneous perspiration,shortness of breath, the disappearance time of syndrome factors such as blood stasis and Qi deficiency, the falling time of syndrome points of blood stasis,Qi deficiency and Yin deficiency were earlier than non-corresponding treatment. Combination of syndromes changed toward to simple trend when intervention with prescription corresponding to syndrome while varied toward to a complicated trend when intervention with non-corresponding. The onset time of some biological markers was earlier in prescription corresponding to syndrome treatment than non-corresponding treatment.3. Syndrome factor has close relationship with some certain biological markers which can provide reference for the diagnosis.更多还原