高血压前期“隐证”人群的代谢组学辨证指标研究

Traditional Chinese medicine（TCM）intervention can effectively prevent the occurrence of hypertension in pre-hypertension (PHT) population. Currently, PHT people with hidden syndrome are accounted for almost 30% of PHT population, and the feature of “disease and syndrome unidentifiable” become the “bottle neck” of applying TCM intervention on these people. Studies have shown that different syndromes of hypertension have significantly different metabolomic features; our previous studies also showed that PHT with different typical syndromes presented distinctive metabolomic features, as well as PHT with hidden syndrome also appeared syndrome-related metabolomic features from microcosmic view. We hypothesize that each PHT syndrome has its distinctively endogenous small-molecule metabolomes, based on which a series of microcosmic syndrome differentiation indexes can be developed and applied for microcosmic differentiation on hidden syndrome of PHT. In this project, with the studies on metabolomics features of PHT with typical syndromes, the metabolomics microcosmic syndrome differentiation patterns of PHT would be developed and applied for syndrome classification of PHT with hidden syndrome. Further, the metabolomics microcosmic syndrome differentiation pattern of PHT will be validated by clinical trials with blood pressure detection and metabolomics studies. It would be the first time of applying metabolomics methods to study hidden syndrome and developing microcosmic syndrome differentiation indexes based on distinctive metabolomic features, which would be especially practical in promoting clinical efficacy of PHT treatment of TCM. This study would also provide innovational model and method for TCM theories and practices on syndrome differentiation and “pre-disease treatment”.

中医药干预是预防高血压前期（PHT）人群发生高血压的有效手段。目前PHT“隐证”人群占PHT总体比例近30%，“既无病可辨又无证可辨”成为这类人群临床用药的“瓶颈”。已有研究表明，高血压的不同证候有明显不同的代谢组学特征；我们前期也初步发现PHT的不同证候存在差异性代谢组学特征，PHT隐证在微观上同样表现出与证候相关的代谢组学特征。我们推测：PHT的“证”具有内在的、可相互区分的特征小分子内源性物质群，以此建立的辨证指标可用于隐证的“微观辨证”。本课题拟通过对PHT典型证候代谢物组特征的研究，建立PHT证候的代谢物组微观判别模式，研究PHT隐证的中医微观辨证指标，并采用临床试验对此进行验证。本研究将首次应用代谢组学方法对隐证人群进行研究并找出其“辨证”的特征指标，为提高PHT临床疗效提供新的手段，并为发展中医辨证和“治未病”理论提供创新的研究模式和方法。

研究发现，高血压患者中隐证占23.0%，基本隐证约占25%，这些人少有症状表现，但血压升高，属于无症状高血压，中医辨证时“无证可辨”的隐证。隐证为判断疾病的发展与中医预防带来难点，事实上，隐证人群虽外在症状不显，但内在的病理变化已悄然发生。有研究表明，高血压无症状期存在小动脉玻璃样病变、交感活性增强以及内皮功能异常等病理证。因此，隐证人群很可能存在向典型证候发展倾向，研究隐证的人群典型证候倾向可以为疾病防治带来新的思路。.本课题旨在研究能否通过建立高血压不同证型的代谢组学辨证指标，以指导高血压隐证人群的辨证治疗。研究过程中，我们建立了高血压人群数据库、证候数据库和生物样本库，获取高血压典型证和隐证的血清学样本。研究了典型证候高血压人群的代谢组学特征，通过靶向和非靶向代谢组学研究，我们初步确定了高血压痰湿壅盛证生物标志物5种，高血压肝阳上亢证生物标志物5种，其中棕榈酸为共同差异代谢物。对高血压痰湿壅盛证与高血压肝阳上亢证100例受试者9个差异代谢物浓度进行中心化、标准化后，采用Fisher判别分析方法，建立判别模型。以高血压证候类型为因变量，9种代谢物为自变量建立模型，得到一个判别函数（P=0.033）和公式。我们采用了交叉验证法中的刀切法检验了判别函数的效果。所建立的判别函数对原始已分组个案分类的正确率为71.0%，在进行交叉验证后，对已分组个案分类的正确率为60%。利用建立的判别模型对高血压隐证组进行高血压体质微观判别，能判别出高血压痰湿壅盛证倾向和高血压肝阳上亢证倾向。.本研究采用代谢组学方法筛选出高血压痰湿证与肝阳上亢证的特征代谢物，并尝试以此建立判别模型，对高血压隐证人群的证候倾向做出预判，取得了初步的结果。虽然模型稳定性、准确率还不高，临床验证也仅进行了极少部分，但可以看出这一研究思路是可行的，有望为中医微观辨证开辟新的研究领域。