| Objective:Firstly,to find the independent high-risk factors from the traditional and unconventional risk factors of CAS,and to explore the potential effects on the asymmetric distribution of CAS;secondly,to explore the high-risk constitution of AS through Meta-analysis;thirdly,to evaluate the efficacy of Dingjifang recipe intervened in CAS patients who have highrisk constitution,and to evaluate the influence of Dingjifang recipe on the risk factors,and the risk of CCVD,thereby accomplishing the purpose of "Treating Different Disease with the Same Method" and "Balance the Body to Improve the Progress of the Disease";finally,to explore the mechanisms of bile acid metabolism in CAS patients who have high-risk constitution intervened with Dingjifang recipe.Methods:(1)Case-control study: CAS inpatients(case group)and inpatients without CAS(no CAS group)were enrolled.Traditional and unconventional risk factors of CAS were collected from both groups,and the independent high-risk factors were confirmed among them by single factor contrast and multivariate analysis.Patients were divided into left-side CAS group,right-side CAS group,and bilateral CAS group according to the location of CAS.The potential high-risk factors which had an effect on the asymmetric distribution of CAS were identified in the subgroups.(2)Meta analysis: the databases including CNKI,WANFANG date,VIP datebase,China Biology Medicine disc,and Pubmed were searched.All literatures related to TCM constitution and AS were collected.Literatures were screened,extracted,and evaluated independently by 2 investigators.R language package 4.0.0 and Reviewer Manager 5.3 were used to analyze the extracted data.(3)Randomized controll trial: CAS cases with the high risk constitution of Blood-stasis were screened and randomly assigned into 2 groups,the Dingjifang recipe group received Dingjifang recipe united anti-arteriosclerosis foundational medicine,the foundational intervention group only accepted anti-arteriosclerosis foundational medicine,and the intervention period was 6 months.The effect of indicators were the degree of CAS,the clinical performance of Blood-stasis constitution,the plasma arteriosclerosis index,the transformation of Blood-stasis constitution,and the SF-36.The hazard factor and risk assessment index were Apo B/Apo A1 and the 10-year risk of CCVD.To comprehensively evaluate the changes in the efficacy of CAS intervened by Dingjifang recipe.(4)The plasma was collected from the Dingjifang recipe group,the foundational intervention group before and after intervention,and the patients without CAS,each with 15 cases.The bile acid metabolite changes were analyzed through LC-MS/MS.The data were analyzed by Analyst 1.6.3 and SIMCA 14.1 software to perform peak extraction and metabolite identification,and multiple supervised statistical methods were used to screen out bile acid differential metabolites.The differential bile acid metabolites were submitted to the KEGG database for analyzing the relevant pathways.Results:1.Case-control study:(1)884 cases were finally enrolled in the CAS group,890 cases were finally enrolled in the no CAS group.(2)Comparison of traditional risk factors between the two groups: age,male,TG,LDL-C,SBP,smoking were high risk factors of CAS(P<0.05).(3)Comparison of unconventional risk factors between the two groups:Apo B/ApoA1,alcohol consumption,Mb were high risk factors of CAS(P<0.05).(4)Comparison of traditional risk factors among the subgroups:SBP and age were high risk factors of the bilateral CAS(P<0.05),and male was an protective factor of the right-sided CAS(P<0.05).(5)Comparison of unconventional risk factors among the subgroups:Apo B/Apo A1 were high risk factors of the bilateral CAS(P<0.05),and alcohol consu-mption an d were protective factors of the right-sided CAS(P<0.05).(6)The 10-year CCVD risk values of CAS patients and the proportion of CAS patients at high risk were both significantly higher than those of patients without CAS(P<0.05);the 10-year CCVD risk values of the bilateral CAS patients and the proportion of bilateral CAS patients at high risk were significantly higher than those in the unilateral CAS patients(P<0.05).2.Meta analysis:(1)A total of 10 studies(6 cross-sectional studies and 4 case-control studies)were included.(2)The total sample capacity of the cross-sectional studies was 1650 patients.The proportions of each TCM constitution among the AS patients were arranged from large to small: Phlegm-dampness constitution > Qi-deficiency constitution > Bl-ood-stasis constitution > Yang-deficiency constitution > Damp-heat constitution >Gentleness constitution > Yin-deficiency constitution > Qi-stagnation constitution >Special constitution.(3)The total sample capacity of the case-control studies was 800 patients,and 426 patients in the AS group and 374 patients in the no AS group.The OR of Phlegm-dampness constitution people of developing AS was 3.16,it was statistically significant(P<0.05);the OR of Qi-deficiency constitution people of developing AS was 0.47,it was not statistically significant(P>0.05),the OR of Blood-stasis constitution people of developing AS was 3.78,it was statistically significant(P<0.05).3.Randomized controll trial:(1)47 cases were enrolled in the Dingjifang recipe group,5 cases fell off,42 cases completed the test;47 cases were enrolled in the foundational intervention group,3 cases fell off,44 cases completed the test.(2)Effect on the degree of CAS: the overall response rate of the Dingjifang recipe group(52.38℅)was significantly higher than that of the foundational intervention group(31.82℅)(P<0.05),among them,the Dingjifang recipe group was more effective in Blood-stasis constitution(Qi-Yin Deficiency Syndrome)(the overall response rate was 76.93℅);the plaque area reduced significantly after intervention in the Dingjifang recipe group(P<0.05);there was no significant difference between the two groups before and after intervention in CIMT(P>0.05).(3)Effect on the Blood-stasis constitution manifestations: the overall response rate of the Dingjifang recipe group(45.23℅)was significantly higher than that of foundational intervention group(15.91℅)(P<0.05),among them,the Dingjifang recipe group was more effective in Blood-stasis constitution(Qi-Yin Deficiency Syndrome)(the overall response rate was 61.53℅);three single symptoms of "Sublingual varicosity" "dark circles" and "chest tightness and chest prick" improved significantly better after intervention with the Dingjifang recipe(P<0.05).(4)Effect on the plasma arteriosclerosis index: Dingjifang recipe could significantly reduced the plasma arteriosclerosis index in the people with Blood-stasis constitution(QiYin Deficiency Syndrome)(5)Effect on the SF-36 scores: the improvement of SF-36 scores in the Dingjifang recipe group was significant after intervention(P<0.017),and it was mainly reflected in the BP and RP(P<0.017).(6)Effect on the Blood-stasis transformation: the Dingjifang recipe group had an effect of transforming the Blood-stasis constitution,the conversion scores of Qi-deficiency and Yin-deficiency constitution were abated significantly(P<0.05).(7)Effect on the Apo B/Apo A1: after intervention,the ratio was significantly abated in the Dingjifang recipe group(P<0.05),it was mainly reflected in the people with Blood-stasis constitution(Qi-Yin Deficiency Syndrome)(P<0.05).(8)Effect on the 10-year risk of CCVD: after intervention,the Dingjifang recipe group had a significant lower risk than the foundational intervention group(P<0.05),but there was no significant difference before and after intervention in either group(P>0.05);the risk of people with Blood-stasis constitution(Non Qi-Yin Deficiency Syndrome)increased significantly after intervention in the foundational intervention group which compared with the before intervention and the Dingjifang recipe group(P<0.05).4.Bile acid metabolomics:(1)A number of 11 differential metabolites were distinguished between before and after intervention in the Dingjifang recipe group wherein the number of downregulated metabolites was 10 such as CA、DCA、HCA and so on.TCA was upregulated metabolite.(2)A number of 8 upregulated metabolites were distinguished between before and after intervention in the foundational intervention group such as GCA,DCA,GDCA and so on.(3)A number of 11 differential metabolites were distinguished between the Dingjifang recipe group before intervention and the no CAS group wherein the number of upregulated metabolites was 10 such as UCA,CDCA,CA and so on.TCA was downregulated metabolite.(4)A number of 6 differential metabolites were identified between the Dingjifang recipe group after intervention and the no CAS group wherein the number of upregulated metabolites was 3 such as CDCA,CDCA-3Gln,UDCA.Tβ-MCA,THCA,and GHCA were downregulated metabolites.(5)The differential bile acid metabolites among the groups involved in 5 KEGG pathways such as bile circulation,glycolipid biochemical metabolism,and taurine metabolism.Conclusions:1.Case-control study: firstly,ApoB/Apo A1 may contribute to the CAS and the location distribution of CAS;secongly,the CAS patients,especially the bilateral CAS patients,have a high 10-year risk of CCVD.2.Meta analysis: Phlegm-dampness constitution is the main constitution of AS,and Blood-stasis constitution is the important high risk constitution of developing AS.3.Randomized controll trial: firstly,Dingjifang recipe could improve the performence of Blood-stasis constitution,reduce the degree of CAS,and improve the QOL;secondly,Dingjifang recipe could reduce the Apo B/Apo A1,and control the 10-year risk of CCVD.thirdly,"combination of syndrome and constitution" enhance the intervention effect of Dingjifang recipe.4.Bile acid metabolomics: Dingjifang recipe could reduce the concentrations of bile acid metabolites in CAS people with Blood-stasis constitution and may inhibit AS through the specific pathway such as Taurine and hypotaurine metabolism. |
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