【目的】 观察真武汤合桂枝茯苓丸治疗阳虚水泛型慢性心力衰竭（CHF）患者的临床疗效并运用网络药理学探究其作用机 制。【方法】 将64例阳虚水泛型CHF患者随机分为治疗组和对照组，每组各32例。对照组给予西医规范的基础治疗，治疗组 在对照组的基础上加用真武汤合桂枝茯苓丸治疗，疗程为 4 周。观察 2 组患者治疗前后中医证候积分、超声心动图检测指 标、6 min 步行试验（6MWT）距离、明尼苏达心衰生活质量调查问卷（MLHFQ）评分以及血清氨基末端脑钠肽前体 （NT-proBNP）、网膜素1（Omentin-1）水平的变化情况，并比较2组患者的中医证候疗效。使用网络药理学方法从相关数据库 获取真武汤合桂枝茯苓丸的活性成分、靶点与CHF疾病靶点，得到交集靶点后构建交集靶点蛋白质相互作用网络并进行富 集分析，以此预测真武汤合桂枝茯苓丸治疗CHF的作用机制。【结果】（1）治疗4周后，治疗组的总有效率为90.62%（29/32）， 对照组为71.87%（23/32），组间比较（χ2检验），治疗组的中医证候疗效明显优于对照组（P＜0.05）。（2）治疗后，2组患者的气 短/喘息、心悸、畏寒肢冷、面浮肢肿、乏力、唇甲紫暗、面色晦暗、尿少、咳嗽等各项中医证候评分及总积分均较治疗前 降低（P＜0.01），且治疗组对气短/喘息、畏寒肢冷、面浮肢肿、乏力、唇甲紫暗、面色晦暗、尿少等7项中医证候评分及总 积分的降低幅度均明显优于对照组（P＜0.05或P＜0.01）。（3）治疗后，2组患者的左室舒张末期内径（LVEDD）、左室收缩末期 内径（LVESD）均较治疗前降低（P＜0.01），左室射血分数（LVEF）均较治疗前升高（P＜0.01），且治疗组对LVEDD、LVESD的 降低幅度及对LVEF的升高幅度均明显优于对照组（P＜0.01）。（4）治疗后，2组患者的6MWT距离均较治疗前升高（P＜0.01）， MLHFQ积分均较治疗前降低（P＜0.01），且治疗组对6MWT距离的升高幅度及对MLHFQ积分的降低幅度均明显优于对照组 （P＜0.01）。（5）治疗后，2组患者血清 NT-proBNP水平均较治疗前降低（P＜0.01），血清 Omentin-1水平均较治疗前升高（P＜ 0.01），且治疗组对血清NT-proBNP水平的降低幅度及对血清Omentin-1水平的升高幅度均明显优于对照组（P＜0.01）。（6）检 索到真武汤合桂枝茯苓丸中共有106个有效活性成分和818个靶点，以及10 660个CHF的疾病基因，筛选得到了包括NOS3、 TP53、MMP9、VEGFA、IL6、TNF、CASP3等21个网络核心靶点；富集到的通路包含影响肾素分泌、环磷酸鸟苷酸-蛋白激 酶（cGMP-PKG）信号通路、缺氧诱导因子 1（HIF-1）通路、钙信号通路、Th17 细胞分化、晚期糖基化终产物及其受体 （AGE-RAGE）信号通路、胰岛素抵抗等发挥治疗作用。【结论】 真武汤合桂枝茯苓丸对 CHF 的疗效显著，其可通过多成分、 多靶点、多通路的中医药作用机制来发挥抑制机体炎症反应、减轻心脏负荷、改善心室重构等作用，从而能有效改善患者 临床症状，提高患者的生活质量及预后。

Objective To observe the clinical efficacy of Zhenwu Decoction plus Guizhi Fuling Pills in the treatment of patients with chronic heart failure（CHF）of fluid retention due to yang deficiency type， and to explore its therapeutic mechanism by network pharmacology. Methods A total of 64 cases of CHF patients with fluid retention due to yang deficiency type were randomly divided into treatment group and control group，with 32 cases in each group. The control group was given the basic western medicine treatment，and the treatment group was treated with Zhenwu Decoction plus Guizhi Fuling Pills on the basis of treatment for the control group. The course of treatment lasted for 4 weeks. The changes of traditional Chinese medicine（TCM）syndrome scores， echocardiographic parameters， distance of 6-minute walking test（6MWT）， Minnesota Living with Heart Failure Questionnaire （MLHFQ）score，and serum levels of N-terminal pro-brain natriuretic peptide（NT-proBNP）and omentin-1 in the two groups were observed before and after treatment. After treatment， the efficacy for TCM syndrome was compared between the two groups. The active components，component targets and CHF disease targets of Zhenwu Decoction plus Guizhi Fuling Pills were obtained from the relevant databases by using the network pharmacological methods. After the intersection targets were obtained，the intersection target protein-protein interaction network was constructed and the enrichment analysis was carried out to predict the therapeutic mechanism of Zhenwu Decoction plus Guizhi Fuling Pills for CHF. Results（1）After 4 weeks of treatment，the total effective rate of the treatment group was 90.62%（29/32）， and that of the control group was 71.87% （23/32）. The intergroup comparison（tested by chi-square test）showed that the efficacy for TCM syndrome in the treatment group was significantly superior to that in the control group（P＜0.05）.（2）After treatment，the scores of TCM syndromes such as shortness of breath/wheezing，palpitation，aversion to cold and cold limbs，facial edema and edema of limbs，fatigue，darkish-purple lip and nails，gloomy complexion，oliguria and cough as well as the total scores in the two groups were decreased when compared with those before treatment（P＜0.01），and the decrease of the scores of shortness of breath/wheezing， aversion to cold and cold limbs， facial edema and edema of limbs， fatigue，darkish-purple lip and nails，gloomy complexion and oliguria as well as the total scores in the treatment group was superior to that in the control group（P＜0.05 or P＜0.01）.（3）After treatment，the left ventricular enddiastolic diameter（LVEDD）and left ventricular end-systolic diameter（LVESD）in the two groups were decreased when compared with those before treatment（P＜0.01）， and the left ventricular ejection fraction（LVEF）was increased when compared with that before treatment（P＜0.01）. Moreover，the decrease in LVEDD and LVESD and the increase in LVEF in the treatment group were superior to those in the control group（P＜0.01）.（4）After treatment，the 6MWT distance in the two groups was increased（P＜0.01）and the MLHFQ score was decreased （P＜0.01）when compared with that before treatment，and the increase of 6MWT distance and the decrease of MLHFQ score in the treatment group were significantly superior to those in the control group（P＜0.01）.（5）After treatment，the serum NT-proBNP level in the two groups was decreased（P＜0.01）and the serum omentin-1 level was increased when compared with that before treatment（P＜0.01）. The intergroup comparison showed that the decrease of NT-proBNP level and the increase of Omentin-1 level in the treatment group were superior to those in the control group（P＜0.01）.（6）A total of 106 active components and 818 targets of Zhenwu Decoction plus Guizhi Fuling Pills as well as 10 660 disease genes of CHF were obtained. A total of 21 network core targets such as NOS3， TP53， MMP9， VEGFA， IL6， TNF， and CASP3 were screened. The enriched analysis yielded the therapeutic pathways of renin secretion，cyclic guanosine monophosphate-protein kinase（cGMP-PKG）signaling pathway， hypoxia-inducible factor 1（HIF-1）pathway， calcium signaling pathway， Th17 cell differentiation， advanced glycation end products and their receptors（AGE-RAGE）signaling pathway，insulin resistance and so on. Conclusion Zhenwu Decoction plus Guizhi Fuling Pills exert certain effect on CHF. It is effective on inhibiting the inflammatory response， decreasing cardiac load and improving ventricular remodeling through the multicomponent， multi-target and multi-pathway mechanism of Chinese medicine， so as to effectively relieve the clinical symptoms of patients and improve the quality of life and prognosis of the CHF patients.

R259.416

福建省科学技术厅自然科学基金面上项目（编号：2020J01248）