冠心病易损患者早期预警及“瘀毒”临床表征的研究

【作者】 曲丹；

【导师】 陈可冀； 徐浩；

【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】 动脉粥样硬化(atherosclerosis,AS)及冠心病(coronary heart disease,CHD)观念的革新为中医药学创新病因学说的提出,带来了治疗理念更新的契机。中医学认为,瘀血是CHD最重要的病机之一,贯穿于CHD发生发展的始终,而导致易损斑块破裂合并血栓形成过程中所涉及的血管内皮损伤、组织坏死及炎症介质等病理产物均与中医“毒”邪密切相关。针对急性心血管事件(acute cardiovascular event,ACE)的危害性和发病特点,课题组紧密结合临床实践,提出“瘀毒致变”是引发ACE的关键病理机转,以期创新中医治法,明确干预时机,早期识别CHD高危患者,提高防治水平。易损斑块是导致急性心血管病事件的主要原因。然而,随着研究的深入,发现导致心血管事件的斑块并不一定是易损斑块,可能还与全身整体因素有关,称之为易损患者更为合适,所以应进一步优化心血管危险评估方案,及早干预易损患者以防止ACE的发生。本课题基于临床流行病学的前瞻性队列研究,结合随访ACE发生情况,对稳定期CHD患者的个人史、体质特点、症状、体征、辨证分型、理化检查指标、治疗情况等进行多因素分析,探索性建立易损患者的早期预警模型,并应用ROC曲线评价效能,其结果为“瘀毒”的宏观、微观表征提供依据。中医证候是患者个体、疾病以及社会、心理等综合因素相互作用、相互影响的外在表征,对于构建基于整体观、系统论的预警体系具有重要意义。在疾病发生、发展过程中,随着邪正的轻重盛衰而发生相应的证候变化,随之诊断和治疗也发生了变化。所以,研究证候的演变规律是证候研究中最为关键、核心的问题。本课题探索性应用多因子降维(multifactor dimensionality reduction,MDR)数据挖掘方法,分析CHD稳定期患者发生心血管事件的证候演变规律,寻找哪种证候之间的演变更容易引发近期心血管事件,其结果为“瘀毒”的动态表征提供依据。研究一：构建冠心病易损患者的早期预警模型目的：探索性构建冠心病易损患者的早期预警模型,应用ROC曲线评价效能方法：2007年10月至2010年3月,选择中日友好医院稳定期CHD患者,且完成了1年随访者共397例,结合随访1年后发生ACE情况,对患者的临床资料进行多因素分析。结果：脑卒中病史患者59例,其中11例发生心血管事件,占18.6%,事件组与非事件组比较具有显著性差异(P=0.043)；缺乏身体锻炼的患者58例,其中有12例发生心血管事件,占20.7%，事件组与非事件组比较具有显著性差异(P=0.015)；关于理化检查指标,我们根据临床研究需要将其进行分层研究,结果发现hs-CRP≥1mg/L、ApoA1＜1.1g/L的患者更易发生心血管事件(P=0.005和P=0.015)；从心绞痛特点的分析中发现,自发性心绞痛、发作性质为绞痛、发作部位在背部者对ACE的发生有明显影响,P值分别为0.009、0.017、0.011；中医主症胸闷,兼症口臭在事件组与非事件组间比较具有显著性差异(P=0.011、0.039)。将这些指标又进行了二分类Logistic回归,结果显示：脑卒中病史、锻炼身体、ApoA1分层、hs-CRP分层、症状胸闷具有统计学意义(P<0.05),其中锻炼身体、指标ApoA1分层与心血管事件成负相关(OR值依次0.376、0.459),脑卒中病史、胸闷、hs-CRP分层为正相关(OR值依次2.479、2.218、2.405)。而症状口臭、心绞痛性质是绞痛、心绞痛发作部位在背部、心绞痛类型为自发性心绞痛,经分析均无统计学意义(P均>0.05)。建立预警方程：Logit(p)=-2.319-0.779 (ApoA1分层)-0.978锻炼身体+0.908脑卒中病史+0.877(hs-CRP分层)+0.797胸闷。应用ROC曲线评价效能,其评价指标的结果为：AUC=0.744,敏感度=81.4%,特异度=62.2%,Youden指数=0.436,阳性似然比=2.153,阴性似然比=0.299,阳性预报值=0.218,阴性预报值=0.964。结论：脑卒中病史、缺乏锻炼身体、平素经常胸闷为CHD稳定期患者“瘀毒”的宏观表征之一；hs-CRP≥1mg/L、ApoA1＜1.1g/L为“瘀毒”的微观表征之一,值得进一步研究。研究二：冠心病稳定期患者发生急性心血管事件的证候分布特点及演变规律的研究目的：探索性分析冠心病稳定期患者发生急性心血管事件的证候分布特点及演变规律方法：完成两年随访的患者共303例,根据入选时间进行半年、一年复查,记录患者的证候情况,两年随访主要记录事件的发生情况。去除资料不完整及1年内发生事件的患者。首先应用频数分布法,观察事件组与非事件组患者的证候分布特点；再应用MDR数据挖掘方法,探索性分析CHD稳定期患者发生ACE的证候演变规律。结果：频数分布图显示CHD稳定期患者以血瘀证最为常见。实证方面,事件组与非事件组的气滞、寒痰(第二时段)均呈现降低的变化,而血瘀与痰热则有不同趋势,血瘀证在非事件组与事件组呈现相反的演变趋势,而痰热证在事件组呈现逐渐增加,在非事件组则是先增加再减少,第二时段呈现相反的变化；虚证方面,阴虚、气虚的变化趋势基本相同,而阳虚的变化两组则呈现相反的方向。提示血瘀、痰热、阳虚可能为发生心血管事件的主要因素。然后应用MDR数据挖掘方法,进一步探讨CHD患者的证候演变规律,结果显示：证候由气虚向痰热、阳虚向痰热的转化,易引发心血管事件。其中血瘀随着病程的变化并未成为导致心血管事件的必要条件,而其他证候如化痰热则为主要机转,提示蕴热可能是发病的关键之一结论：证候由气虚向痰热或阳虚向痰热的转化,可作为CHD稳定期患者“瘀毒”动态表征之一,值得进一步研究。更多还原

【Abstract】 As updating of atherosclerosis and coronary heart disease concept,it provides a good opportunity to innovate pathogenesis theory of coronary heart diease(CHD).In view of TCM,blood-stasis is considered as the basic pathogenesis of CHD, it penetrates from beginning to the end. While inflammatory reaction results in rupturing of vulnerable atherosclerotic plaque, such as vascular endothelial dysfunction of injury, tissue necrosis and migration and activation of inflammatory mediator. TCM views that it is close with the pathogenic toxin theory. According to the dangers and characteristics of acute cardiovascular events, a hypothesis of "blood-stasis& toxin causing catastrophe" was put forward by the research group in close connection with clinical practice. It provides a new way to innovate the treatment method, clear opportunity to intervene high-risk patients with CHD and improve prevention level.Vulnerable plaque is the main reason of leading to acute cardiovascular events (ACE). However, with the further study, we find that the plaque which causes cardiovascular event is not always vulnerable plaque, it may be concerned with the whole systemic factors, so it could be better to name them as vulnerable patient better. We should further optimize the assessment of cardiovascular risk programs and intervene vulnerable patients earlier, in order to lower the occurrence of ACE. Combined of ACE follow-up, we use prospective study and clinical epidemiological methods to analyze the clinical data collected from stable patients of CHD, the data including past history, characteristic of onset, symptoms, TCM syndrome-differentiation, examination, drugs therapy and intervention therapeutic method is discussed,based on which to build the early warning model for vulnerable patients.Then the model is applied to verify the effectiveness by the method of ROC curves, and the result will be probed into the clinical manifestation of blood-stasis& toxin in the accepts of macro and micro characteristics.Syndrome of TCM is the external representation of the interaction between the individual patients, disease, social and psychological factors.It is very important to build early-warning system based on the overall and systemic concept. In the process of the disease, syndrome is changed along with Xie Zheng, and it leads the diagnosis and treatment changing. Therefore, the study of the evolution of syndrome is the most critical and core in the syndrome research. We decide to explore applications MDR (multi-factor dimensionality reduction) data mining methodology to analyze the syndrome evolution of the stable CHD patients with ACE, and try to find which syndrome easily triggering ACE in the near future, the result will be probed into the clinical manifestation of blood-stasis& toxin in the acceptance of the dynamic characterization.Clinical studyⅠ:Building early warning model for vulnerable patient of CHDObjective:To build early warning model for vulnerable patient of CHD, and it is applied to verify the effectiveness by the method of ROC curveMethod:From September 2007 to March 2010,397 stable CHD cases finished one year follow-up in China-Japan Friendship Hospital are enrolled, combined with ACE follow-up one year,the clinical data collected are analyzed.Results:Among 397 stable CHD patients, cases with the stroke-history is 59 patients, while 11 cases(18.6%) with ACE, there was significant difference between ACE and non-ACE (P=0.043);the patients who lacking physical exercises are 58 cases,while 12 cases with ACE(20.7%),there was significant difference between ACE and non-ACE groups (P=0.015);Concerning biochemical examinations, we stratify them into two levels, the results show that hs-CRP>lmg/L,ApoA1＜1.1g/L are more frequent in patients with ACE (P=0.005,P=0.015); From the characteristic of angina pectoris, we find that spontaneous angina,colic,the painful location in back are more frequent in patients with ACE(P=0.009,0.017,0.011);Symptoms, including suffocating and halitosis, are significant difference between two groups(P=0.011,0.039).By binary Logistic regression,the results show that the stroke-history,physical exercises,ApoAl,hs-CRP,suffocating are significant differenence between two groups (respectively, P＜0.05). Lack of physical exercises, ApoA1 show protective trends for ACE (OR=0.376,0.459),while combining stroke history, hs-CRP, suffocating appear predictive trends to ACE (OR=2.479,2.405,2.218).The other factors, including halitosis,spontaneous angina,colic,the location of angina pectoris in back, are not related to the risk of ACE (P>0.05)Early warning model:Logit(p)=-2.319-0.779ApoAl-0.978 physical exercises +0.908 stroke-history+0.877hs-CRP+0.797 suffocating.Then we apply the method of ROC curve to verify the effectiveness of the model, the results show that AUC=0.744, sensitivity=81.40%, specificity=62.20%, Youden index=0.436, positive likelihood=2.153, negative likelihood=0.29, positive predictive=0.218, negative predictive=0.964.Conclusion:Stroke-history,lack of physical exercises,suffocating which are probably the Clinical macro manifestation of "blood-stasis& toxin"; hs-CRP≥1mg/L and ApoA1＜1.1g/L are probably the Clinical micro manifestation of "blood-stasis& toxin". These conclusions need to be demonstrated by further study.Clinical studyⅡ:The syndrome distribution and dynamic evolution of stable CHD patients with ACEObjective:To analyze the syndrome distribution and dynamic evolution of stable CHD patients with ACE Method:303 cases finished 2-year follow-up are enrolled. According to the time of taking part in the research, the patients should finish the records of syndromes in half a year and one year, and the situations of events are recorded in 2-year follow-up. The patients with incomplete data and ACE happened within a year will be removed. First, we use frequency distribution method to analyze the characteristic of syndromes distribution; Then, we use MDR data mining methodology to analyze the syndrome change of the stable CHD patients with ACE.Results:Frequency distribution map shows that blood-stasis is the main syndrome of stable CHD patients. In the acceptance of excess, Qizhi syndrome and phlegm-cold (secondary phrase) show the same descending trends, but the blood-stasis and phlegm-heat show the different trends. Blood-stasis syndrome performs opposite direction of changing between two groups, and phlegm-heat shows gradually increasing trend in ACE group and first increasing then decreasing in the non-ACE group, the secondary phrase appears opposite changes. In the acceptance of deficiency, deficiency-yin and deficiency-qi show the same trends, while deficiency-yang performs opposite direction of changing. The results remind us that the blood-stasis, phlegm-heat and deficiency-yang may be the most important factors to lead ACE. Then we apply MDR data mining methodology to analyze the syndrome change of the stable CHD patients with ACE, The results show that the trends of deficiency-qi to phlegm-heat and deficiency-yang to phlegm-heat trigger ACE more easily. We find that the changes of blood-stasis with the course of disease, which is not the necessary condition for ACE, while the transformation from other syndromes to phlegm-heat is the pathogenesis hinge, these conclusions remind us that the accumulated heat is the key phenomenia to ACE, it needs further studies.Conclusion:The trends of syndrome from deficiency-qi to phlegm-heat and from deficiency-yang to phlegm-heat are probably the clinical dynamic manifestations of "blood-stasis& toxin".This conclusion is worth demonstrated by further studies.更多还原