| With the increasingly serious aging of China,the incidence of Bradycardiac arrhythmia(BA)is gradually increasing.Western medicine represented by atropine and isoproterenol can increase heart rate in a short time,but it is not suitable for long-term use.As an effective strategy for BA treatment,pacemaker implantation is expensive and requires lifelong follow-up,which affects the quality of life of patients to varying degrees.Some patients are not suitable for or refuse to accept such treatment.Therefore,it is urgent to find new effective strategy in the field of traditional Chinese medicine and provide patients with alternative clinical options.Professor Weng weiliang conducts clinical exploration on the basis of his teacher Guo Shikui's treatment of BA with aromatherapy carries out principle of warming Yang,regulating qi and activating blood.Therefore,summarizing the clinical experience of professor Weng in the treatment of BA,digging the core prescription--Yuanjiang prescription,and clarifying the therapeutic characteristics and mechanism of clinical application will be positive for traditional Chinese medicine in BA drug treatment.The specific research plan is shown in the picture and text summaryObjectivesTo analyze the effective population of bradycardiac arrhythmia(BA)treated by Weng Weiliang using the methods of warming yang,regulating qi and activating blood.Then to identify the characteristics of beneficiary population and establish BA curative effect prediction model of traditional Chinese medicine intervention.To data mine the core composition of recipe(Yuanjiang prescription)from treatments of effective population,as well as to explore the possible pharmacological mechanism of Yuanjiang prescription.So as to provide an objective molecular biological basis for the clinical application of Yuanjiang prescription.Methods1.Clinical research section1.1 Clinical data collection of patients treated by Weng Weiliang.197 BA patients of case observation study were selected from Weng weiliang outpatient clinic of Xiyuan hospital of Chinese academy of traditional Chinese medicine among January 2016 and June 2016.Analyze and compare the changes of heart rate and relevant clinical characteristics of patients before and after treatment,and divide the effective/ineffective group.1.2 Characteristics mining of effective population and establishment of curative effect prediction modelUse Chi-square test and cross sectional analysis to determine the effective population characteristics of the method of warming yang,regulating qi and activating blood circulation in the treatment of BA.Carry out Interaction analysis on the univariate significant variables obtained from previous analysis,and then screen the model by discriminant analysis.Finally,establish a probabilistic prediction model of curative effect,to predict whether the method of warming Yang,regulating qi and activating blood circulation is effective or ineffective in treating BA patients.1.3 Core composition of recipe data mining from treatments of effective populationUse the social network analysis method to ensure medication frequency statistics and prescription mining.Clear and definite the core composition of the recipe,name it as Yuanjiang prescription1.4 Case analysis for long-term dynamic diagnosis and treatmentLong-term follow-up was conducted for BA patients treated with Profession Weng.Based on the long-term follow-up data,use semi-quantitative analysis to summarize the influencing factors of curative effect fluctuation.Optimize the clinical treatment plan through the analysis and summary of the correlation between curative effect and medical record.2.Experiment research section2.1 Network pharmacological analysis of Yuanjiang prescription on the treatment of BAObtain the components and candidate targets of 6 core drugs of Yuanjiang prescription,which were mapped with the candidate targets of BA disease,and 50 drug-disease common genes were obtained.Use cytoscape software to construct the candidate target network of drug-candidate component-BA,and analyze the correlation between drug components and disease action targets.Conduct GO and KEGG pathways enrichment analysis by Clue GO plug-in to explore the drug targets,pathways and main drug components of Yuanjiang prescription.2.2 Comparative study between two methods in establishing a sick sinus node damage model in ratEstablish sick sinus syndrome(SSS)model by the methods of ischemia-reperfusion injury and sodium hydroxide injury.The achievement ratio,heart rate(HR),sinoatrial node recovery time(SNRT),sinoatrial conduction time(SACT)were recorded after 2 weeks.The right auricle and the superior vena cava were used as marks to orient the tissue for histology study.2 important protein HCN4 and SCN5A were further explored by western blot method.And the calcium concentration was calculated.2.3 Explore pharmacological mechanism of Yuanjiang prescription on SSSEstablish ischemia-reperfusion injury SSS model.Separate the model rats into model group,atropine group,xinbao pill group,Yuanjiang group.The heart rates of rats in each group were compared with those in the control group before and after administration.Use S1S2 overspeed inhibition stepwise increasing method to measure the changes of sinus conduction time and recovery time of sinus node.Use Western blot and calcium content colorimetry to verify the network pharmacological prediction targets and the key proteins in the pathological process of SSS.Results1.Results of clinical research section1.1 Result of the clinical effect analysis of weng weiliang on patients with BA(1)There were significant differences in patients' total cardiac number(Before administration 76158.57±12405.13,after administration 81276.63±12002.26),average heart rate(Before administration 55.12±9.25,after administration 58.57±8.94),minimum heart rate(Before administration 35.18±5.06,after administration 40.27±6.35),maximum RR interval(Before administration 2.3±0.84,after administration 1.9±0.87),and the number of>2s cardiac arrest within 24 hours(Before administration 106.59±328.32,after administration 33.84±129.5)before and after treatment.Since the total number of heart beats,the average heart rate,and the average rank of the minimum heart rate were greater than those before treatment,it suggested that the heart rate was significantly increased after treatment for 2 months.The mean rank of the longest RR interval and the number of>2s in 24 hours were less than those before treatment,suggesting that the RR interval was shortened and the number of strokes decreased after 2 months of treatment.Based on the results of efficacy analysis,197 cases of BA patients treated by Professor Weng were divided into effective group(143 cases)and ineffective group(54 cases).(2)In early diagnosis and treatment records,there are a total of 162 cases(162/197)that doctors have clearly suggested patients to accept pacemaker implantation.A descriptive statistical analysis was performed on 162 patients who met the criteria of pacemaker implantation.After the first treatment,a total of 61 patients(61/162)Holter results indicated that the minimum heart rate of>40/min,which did not meet the standards of pacemaker implantation according to the evaluation of objective indicators.1.2 Results of characteristics mining of effective population and curative effect prediction modelAccording to the division of the effective and ineffective groups,(1)intergroup rank sum test was conducted according to the change of heart rate.The results indicated that the minimum heart rate(35.67±5.20)and maximum heart rate(84.08±20.01)of the effective patients were significantly different from the minimum heart rate(33.48±4.17)and maximum heart rate(91.72±21.08)of the ineffective patients.(2)Chi-square test and cross-sectional analysis were performed on 7 common concomitant diseases including coronary heart disease,hypertension,diabetes,myocarditis,atrial fibrillation,atrial premature and ventricular premature.The results indicated that the efficacy of BA patients associated with the following concomitant diseases is influenced:(a)coronary heart disease associated with hypertension,(b)atrial fibrillation associated with premature beat,and(c)hypertension associated with atrial premature.(3)according to the analysis of different types of BA characteristics,the results suggest that atrioventricular block is an independent risk factor affecting the efficacy.Discriminant analysis was used to establish a probability model for predicting whether the method of warming Yang,regulating qi and activating blood circulation was effective or ineffective in treating BA patients:y=-0.2X1+0.07X2+0.16X3-0.65X4-1.12X5-0.71X6-0.75X7-0.91X8(X1=Duration of medication at first visit,X2=average heart rate,X3=minimum heart rate,X4=coronary heart disease,X5=atrial fibrillation,X6=ventricular premature,X7=sino-auriculau heart-block,X8=atrioventricular block).1.3 Result of core composition of Yuanjiang prescription.The result shows that the core composition of Yuanjiang prescription are rhizoma galangae,rhizoma corydalis,radix curcumae,rhizoma zingiberis,cortex cinnamomi,piper longum.1.4 Results of case analysis for long-term dynamic diagnosis and treatmentAccording to the semi-quantitative analysis,the influencing factors that need to be paid attention to are summarized as follows:(1)Gradually reducing the dosage and frequency of drugs are more conducive to the discontinuation of drugs in BA patients after the onset of treatment.(2)In 60%of typical medical cases,benefiting qi drugs were stopped first,which had no obvious influence on the heart rate index of patients.(3)For patients with BA,the minimum effective dose of honey ephedra is usually 3-6g.(4)Sophora sophora and rhizoma coptidis are commonly used as adjuvant drugs.Although these two drug were relatively cold,the correlation analysis results with the curative effect suggest that the drug has no effect of reducing heart rate and does not affect the overall therapeutic effect of the prescription.2.Results of experiment research section2.1 Network pharmacological results of Yuanjiang prescription on the treatment of BAThe prediction results of network pharmacology suggested that the regulation of renin secretion pathway and cAMP signaling pathway was mainly through the action of the prescription on 50 action targets including SCN5A,CAV1,KCNH2,CHRM and PRL.The effect of the drug is mainly related to octadecenoic acid,cubeb oil,eugenene,coumarene,piperine,berberine and other drug components.There are 14 active components among the total 20 components of piper longum in the treatment of BA,which act on a total of 7 disease targets.There are 6 active components among the total 11 components of rhizoma zingiberis in the treatment of BA,which act on a total of 24 disease targets.There are 13 active components among the total 25 components of rhizoma galangae in the treatment of BA,which act on a total of 48 disease targets.There are 6 active components among the total 10 components of cortex cinnamomi in the treatment of BA,which act on a total of 23 disease targets.There are 39 active components among the total 51 components of rhizoma corydalis in the treatment of BA,which act on a total of 37 disease targets.There are 11 active components among the total 68 components of radix curcumae in the treatment of BA,which act on a total of 46 disease targets.2.2 Results of comparative study between two methods in establishing a sick sinus node damage model in ratThe death ratio of modeling was 16.6%(2/12)in the IRIG,33.3%(5/15)in the ISHG.The HRs significantly decreased after operation in the IRIG and ISHG compared with pre-operation(P<0.01).The HR was reduced by above 30%in these 2 groups after modeling,while the reduction was better maintained in IRIG.SNRT and SACT were significantly prolonged compared with pre-modeling in 2 groups(P<0.01).Morphology results showed blurry in structure and boundaries with pale cytoplasm.IRIG and ISHG modeling influenced the calcium concentration and damage the sinus node function by decrease the expression of HCN4 and SCN5A.2.3 Results of pharmacological mechanism of Yuanjiang prescription on SSS(1)Effects of Yuanjiang prescription on heart rate of model ratsAfter 14 days of administration with Yuanjiang prescription,heart rate comparison among groups are as follow:Compared with the Control group,the Model group's heart rate was significantly reduced(p<0.05).Compared with Model group,the heart rates of Atropine group,xinbao pill group and YJ group were significantly increased(p<0.01).Compared with xinbaowan group,the heart rate of rats in the Model group,Atropine group and YJ group were significantly increased(p<0.05).The results indicated that after 14 days administration,Yuanjiang prescription could significantly increase the heart rate of rats,and the effect was better than that of the positive control drug xinbao pill group.(2)Effects of Yuanjiang prescription on electrophysiology of model ratsAfter 14 days of administration with Yuanjiang prescription,SNRT comparison among groups are as follow:Compared with the Control group,the SNRT of Model group,xinbao pill group and Atropine group were significantly prolonged(p<0.01).Compared with Model group,SNRT of rats in each group were significantly shorten(p<0.05).Compared with that in xinbao pill group,the SNRT of rats in the Atropine grou and YJ group were significantly shorten(p<0.01).SACT comparison among groups are as follow:Compared with the control group,the SACT in each group were significantly prolonged(p<0.01).Compared with Model group,SACT of rats in each group were significantly shorten(p<0.01).compared with xinbao pill group,SACT of rats in Atropine group and Yuanjing group were significantly shorten in all groups(p<0.01)(3)Effects of Yuanjiang prescription on protein expression and intracellular calcium ions of model ratsAfter 14 days of administration with Yuanjiang prescription,compared with control group,the expressions of HCN4 protein in sinus node area of rats in the Model group,Atropine group,xinbao pill group and Yuanjiang prescription were significantly decreased.Compared with Model group,Yuanjiang prescription could increase the expression of HCN4 protein in sinus node area of rats.Compared with the normal group,SCN5A protein expression in sinus node area of Model rats was significantly decreased.Yuanjiang prescription could increase the expression of SCN5A protein in sinus node area of rats.Compared with the normal group,CHRM2 protein expression in sinus node area of Model rats was significantly increased.Compared with Model group,Yuanjiang prescription could reduce the expression of CHRM2 protein in sinus node area of rats.Compared with control group,the CHR protein expression in sinus node area of rats in Model,Atropine,XB and Yuanjiang prescription groups was significantly decreased,and the CHR protein expression in each group increased after administration.After 14 days of administration with Yuanjiang prescription,comparison of intracellular calcium ion concentration between groups are as follow:compared with Control group,the intracellular calcium concentration in rats in the Model group,Atropine group and YJ group are significantly decreased(p<0.05).Conclusion1.Professor Weng has achieved remarkable efficacy in treating BA with methods of warming Yang,activating blood circulation and regulating qi.According to the analysis of the characteristics of the effective and ineffective population,low minimum heart rate,high maximum heart rate and atrioventricular block are the risk factors affecting the efficacy.The curative effect was not significantly affected by the simple concomitant disease,but the curative effect was not good in the patients with more than one concomitant disease like coronary heart disease,hypertension,atrial fibrillation and premature ventricular.The application of discriminant analysis method to establish a predictive model for judging curative effect can provide a reference for the characteristics of the beneficiary population of BA accepted by TCM treatment in the future2.Based on the data statistical method of social network analysis,effective BA prescriptions of professor Weng were data mined with real diagnosis and treatment data.The core prescription was named as Yuanjiang prescription.To some extent,it reflects professor Weng 's understanding of the pathogenesis of BA and his thoughts on its differentiation and treatment.3.Semi-quantitative analysis was used to analyze the individual long-term diagnosis and treatment scheme,and the diagnosis and treatment experience and rules of each patient were summarized one by one.Finally,by summarizing the rules of individual cases,the clinical diagnosis and treatment experience of famous old Chinese medicine physician can be effectively explored,and the clinical decision-making can be provided.It provides new ideas for the analysis of dynamic treatment schemes of Chinese medicine and the inheritance of experience of Chinese medicine physician.4.Ischemia reperfusion injury and sodium hydroxide injury could construct stable SSS models which could represent clinic pathological damage.IRIG and ISHG modeling might damage the sinus node function by influencing the K+channel,which impaired the driving ability of SAN and leading to apoptosis.5.Yuanjiang prescription can effectively increase heart rate and improve electrophysiological level of sinus node area in SSS model rats by shortening sinus atrial conduction time and recovery time of sinus atrial node.Yuanjiang prescription may adjust the autonomic nerve function and blood sinus node area,improve the adrenaline and thyroxine nerve body fluids such as hormone levels,increase CRH protein expression,cut CHRM2 protein expression,increase the intracellular calcium ion concentration,thus improve SCN5A and HCN4 myocardial excitability of the ion channels,trigger pathology right move or extend the sinoatrial node cells of the action potential,thus improve the heart rate. |
PDF Full Text Request