| Obstructive sleep apnea hypopnea syndrome(OSAHS)has a high incidence,which can initiate or aggravate hypertension,arrhythmia,coronary heart disease,chronic heart failure,diabetes,obesity,insulin resistance and stroke.OSAHS increases the risk of cardiovascular disease morbidity and mortality.OSAHS is an independent risk factor for the occurrence and development of atrial fibrillation.If paroxysmal atrial fibrillation occurs frequently,it can progress to persistent atrial fibrillation over time.Paroxysmal atrial fibrillation combined with OSASH currently lacks effective treatments.Radiofrequency ablation and surgery have obvious limitations and poor compliance.At present,there are serious shortcomings in the compliance rate of AF treatment.The basic treatment principles such as maintaining sinus rhythm,controlling ventricular rate and anticoagulation strength are far from meeting the standard.Atrial fibrillation treatment has the problems of reversion and maintenance of sinus rhythm,easy recurrence,high cost of surgery and unpredictable risks.Combined with traditional Chinese medicine treatment at the early stage of the disease is expected to improve the overall efficacy of atrial fibrillation,relieve symptoms,reduce the recurrence rate,slow the progression of comorbidities,and improve the prognosis.Traditional Chinese medicine can reduce the side effects of drugs and has good safety.Meanwhile,it has a positive effect on reducing the mortality and disability of paroxysmal atrial fibrillation combined with OSAHS,improving the quality of life of patients,reducing the cost of treatment,and promoting the harmonious development of society and economy.N-of-1 randomized controlled trial is a randomized,multi-cycle,two-phase cross-designed research scheme that applies the principle of randomized control to a single case.Paroxysmal atrial fibrillation,being a chronic,recurrent disease that requires long-term treatment,is suitable for N-of-1 randomized controlled trial.A N-of-1 randomized controlled trial can evaluate the efficacy of a certain drug compared to a placebo or another drug by repeatedly performing multiple cross-controlled studies on the same individual,and by observing the patient’s response to the intervention.It aims to decide the best treatment for the patient.The individualized treatment concept of N-of-1 randomized controlled trials is similar to TCM syndrome differentiationTraditional Chinese medicine prescriptions exert their therapeutic effects by acting on multiple targets and multiple pathways,and it is difficult to clarify the mechanism of action by traditional research.With the rapid development and widespread application of bioinformatics,network pharmacological methods have been used to systematically reflect the correlations between multi-component,multi-target,multi-path and complex diseases of traditional Chinese medicine compounds.Network pharmacology,as a discipline that uses the holistic view of network balance to understand the interaction between drugs and the body,has pioneered a new model of complex network relationships between multiple targets and multiple diseases.Network pharmacology has important application value in the research of the pathogenesis of complex diseases and therapeutic targets,and it has similarities with the overall view of Chinese medicine.Therefore,the purpose of this study is to predict the mechanism of Tiaoganyiqidingji formula for the treatment of paroxysmal atrial fibrillation combined with OSAHS by network pharmacological methods.It is hoped to provide a reference for in-depth basic experimental research and clinical rational application of traditional Chinese medicine compound treatment of paroxysmal atrial fibrillation combined with OSAHS.This study includes three parts:the first part is a literature review:traditional review from two aspects of research progress in integrated traditional Chinese and western medicine for OSAHS-associated atrial fibrillation,and a N-of-1 randomized controlled trial in the field of traditional Chinese medicine.a systematic review of the impact of OSAHS on the risk of atrial fibrillation in patients with coronary heart disease,and found that OSAHS can increase the risk of atrial fibrillation in patients with coronary heart disease.The more severe OSAHS,the greater the risk of AF.The second part is a clinical study of Tiaoganyiqidingji formula in the treatment of paroxysmal atrial fibrillation combined with OSAHS.A randomized,double-blind,N-of-1 randomized controlled trial study design was conducted.A total of 16 patients with paroxysmal atrial fibrillation and OSAHS were included.Three rounds of two-phase cross-controls were performed using Tiaoganyiqidingji formula and placebo for a total of 23 weeks.The study aims to explore the efficacy of Tiaoganyiqidingji formula in preventing the recurrence of AF,reducing the frequency of the occurrence of AF,shortening the duration of AF,improving clinical symptoms.Meanwhile,this study was used to explore research methods applicable to the evaluation of traditional Chinese medicine for paroxysmal atrial fibrillation combined with OSAHS.The third part is the mechanism of Tiaoganyiqidingji formula in the treatment of paroxysmal atrial fibrillation combined with OSAHS.Based on the network pharmacology method,"herb component-target-signaling pathway-disease" systematically explains the mechanism of Tiaoganyiqidingji formula in the treatment of paroxysmal atrial fibrillation combined with OSAHSPart Ⅰ:A systematic review of the impact of OSAHS on the risk of atrial fibrillation in patients with coronary heart diseaseObjective:To systematically evaluate the impact of OSAHS on the risk of atrial fibrillation in patients with coronary heart disease.Methods:Computer retrieval of China Knowledge Infrastructure Project(CNKI),Wanfang Data Knowledge Service Platform(WanFang),Vipu Journal Resource Integration Service Platform(VIP),China Biomedical Literature Service System(SinoMed),PubMed,EMbase and the Cochrane Library.Cohort studies on the relationship between OSAHS and the risk of atrial fibrillation after coronary heart disease or coronary artery bypass grafting were conducted in Chinese and foreign databases above,and the retrieval time is from the beginning of the database construction to July 2,2018.The two researchers independently retrieved the literature,extracted the data,and assessed the quality of the literature included in the study.Meta-analysis was performed using RevMan 5.3 software.Results:A total of 11 cohort studies were included,including 709 patients with OSAHS and 975 patients with non-OSAHS.The results showed that OSAHS significantly increased the risk of atrial fibrillation in patients with coronary heart disease[OR=3.00,95%CI(2.31,3.90),P<0.000 01].The results of the subgroup analysis showed that:①The risk of atrial fibrillation in patients with coronary heart disease and OSAHS diagnosed by polysomnography(PSG)increased[OR=3.24,95%CI(2.26,4.65),P<0.000 01],of which patients with heart disease combined with moderate to severe OSAHS have a higher risk of atrial fibrillation[OR=5.60,95%CI(3.28,9.56),P<0.000 01];②patients with coronary heart disease and high-risk OSAHS assessed by the Berlin Questionnaire(BQ)also had an increases risk of atrial fibrillation than patients with coronary heart disease and low-risk OSAHS[OR=2.21,95%CI(1.50,3.26),P<0.001].Conclusion:OSAHS significantly increases the risk of atrial fibrillation in patients with coronary heart disease,and the more severe OSAHS,the greater the risk of atrial fibrillationPart Ⅱ:A N-of-1 randomized controlled trial of Tiaoganyiqidingji formula in the Treatment of Paroxysmal Atrial Fibrillation Combined with Obstructive Sleep Apnea Hypopnea SyndromeObjective:To carry out a N-of-1 randomized controlled trial to explore the efficacy of Tiaoganyiqidingji formula in preventing the recurrence of AF,reducing the frequency of AF,shortening the duration of AF and improving clinical symptoms Meanwhile,this study was used to explore research methods applicable to the evaluation of traditional Chinese medicine for paroxysmal atrial fibrillation combined with OSAHSMethods:The study was designed using a series of single-case randomized controlled trials.It uses its own case as a control,and adopts a randomized,double-blind,three-round,two-phase cross-controlled design.A total of 16 subjects were included,and cross-contrast the test drug(Tiaoganyiqidingji formula)with the placebo on the same subject.Each subject will receive three cycles of treatment cycles,and each cycle of treatment cycles is 8 weeks,including Tiaoganyiqidingji formula and placebo treatment phases.The first three weeks of each treatment phase is the treatment period,and the second one is the elution period.The treatment period is 23 weeks.The test and control drugs were used in a randomized double-blind order.Collect disease information and efficacy indicators at the end of 3w,7w,11w,15w,19w,and 23w,including the frequency of AF,the duration of AF,clinical symptoms,TCM syndrome scores,the efficacy of TCM syndromes,heart rate variability,quality of life scoresResults:(1)Compared with the control period,the frequency and duration of atrial fibrillation(atrial fibrillation load)decreased significantly in subjects 4,subjects 10,and 11 during the treatment period,and the difference has statistical significance(P<0.05),the atrial fibrillation load of the remaining subjects in the treatment period was lower than that in the control period,but the difference has no statistical significance(P>0.05).Compared with before treatment,the atrial fibrillation load was significantly reduced in all subjects during the treatment period,and the difference has statistical significance(P=0.049).Compared with before treatment,the atrial fibrillation load was reduced in all subjects during the control period.However,the difference has no statistical significance(P=0.115).(2)Compared with before treatment,the time-domain indicators of heart rate variability SDNN,SDANN,rMSSD,and triangle index were all increased after the test drug treatment,and the difference has statistical significance(P<0.05).Compared with before treatment,PNN50 during treatment has a tendency to increase,but the difference has no statistical significance(P>0.05).(3)The clinical symptom efficacy results of each cycle of treatment period and the control period of all cases show that the clinical symptom efficacy in the treatment period is better than that in the control period,and the difference is statistically significant(P=0.002)(4)Compared with before treatment,the TCM syndrome scores of all cases in each round of treatment and control period were reduced.After combining the TCM syndrome scores of each period of 13 subjects in each round,compared with the control period,the TCM syndrome scores of Case 1,Case 2,Case 6,Case 7,Case 9,Case 10,and Case 12 were all in the treatment period significantly reduced,and the difference has statistical significance(P<0.05)(5)Compared with the control period,the curative effect of TCM symptoms of Cases 1,2,6,7,9,10 and 12 in the treatment period is better than that in the control period,and the difference has statistical significance(P<0.05).(6)Compared with the control period,the case 3,case 4,case 5,case 8,case 12,case 13,case 14,and case 15 quality of life scores in the treatment period increased,and the difference has statistical significance(P<0.05)(7)Subjects who completed all the tests performed polysomnographic monitoring and found that compared with before treatment,the indicators related to polysomnography after treatment,AHI,ODI,total number of sleep apnea/hypnea,mean apnea/low ventilation time reduced,but the difference has no statistical significance(P>0.05).The minimum SaO2 did not increase significantly after treatment,and the difference has no statistical significance(P>0.05).Conclusion:Tiaoganyiqidingji formula can prevent recurrence of AF,reduce the frequency of AF and shorten the duration of AF,improve heart rate variability,effectively improve clinical symptoms,reduce TCM syndrome scores,improve the efficacy of TCM symptoms,improve quality of life.Tiaoganyiqidingji formula has no significant effect on hematuria and liver and kidney function,has no toxic side effects,and has good safety.Part Ⅲ:Exploring the mechanism of Tiaoganyiqidingji formula in the treatment of paroxysmal atrial fibrillation combined with OSAHS based on network pharmacologyObjective:To predict the potential targets and signaling pathways of Tiaoganyiqidingji formula for the treatment of paroxysmal atrial fibrillation combined with OSAHS by network pharmacological methods,and explore the mechanism of Tiaoganyiqidingji formula on the treatment of paroxysmal AF with OSAHS.It is hoped to provide a reference for in-depth basic experimental research and clinical rational application of traditional Chinese medicine compound treatment of paroxysmal atrial fibrillation combined with OSAHSMethods:Firstly,the TCMSP database and the BATMAN-TCM analysis platform were used to retrieve and obtain herb component and candidate targets of the 11 Chinese herbal medicine Ziziphi Spinosae Semen(Suanzaoren),Nardostachys Chinensis Batal(Gansong),Corydalis Rhizoma(Yanhusuo),Agrimony(Xianhecao),Tribulus terrestris(Jili),Concha Ostreae(Muli),radix glycyrrhizae(Gancao),Codonopsis pilosula(Dangshen),Radix Paeoniae Alba(Baishao),Radix Ophiopogonis(Maidong),cassia twig(Guizhi)in Tiaoganyiqidingji formula.Then using "paroxysmal atrial fibrillation" and "obstructive sleep apnea hypopnea syndrome" as key words,the disease gene database Genecards was searched for paroxysmal atrial fibrillation combined with OSAHS disease-related targets.Herb component targets and paroxysmal atrial fibrillation combined with OSAHS disease-related targets were intersected to obtain the potential target of Tiaoganyiqidingji formula for the treatment of paroxysmal atrial fibrillation combined with OSAHS,and then combined with the STRING database and Cytoscape 3.7.1 software to construct and analyze potential protein-protein interaction networks.The drug target network of Tiaoganyiqidingji formula with the disease target network of paroxysmal atrial fibrillation combined with OSAHS was mapped to build a "drug candidate component-potential target-disease" interaction network to obtain drug candidate component of Tiaoganyiqidingji formula treatment of paroxysmal atrial fibrillation combined with OSAHS and its potential targets.The topological analysis was performed on the potential target interaction network of Tiaoganyiqidingji formula for the treatment of paroxysmal atrial fibrillation combined with OSAHS to determine the key therapeutic targets.The potential functional targets were analyzed by GO and KEGG pathway enrichment analysis to predict signaling pathways.Finally,a "drug component-key therapeutic target-signaling pathway" network for the treatment of paroxysmal atrial fibrillation combined with OSAHS by Tiaoganyiqidingji formula was constructed.Results:(1)There are 214 active components in the Chinese herbal medicine from Tiaoganyiqidingji formula,which act on 422 candidate targets.There are 8,5,50,9,11,89,18,7,8,5 active components coming from Ziziphi Spinosae Semen(Suanzaoren),Nardostachys Chinensis Batal(Gansong),Corydalis Rhizoma(Yanhusuo),Agrimony(Xianhecao),Tribulus terrestris(Jili),radix glycyrrhizae(Gancao),Codonopsis pilosula(Dangshen),Radix Paeoniae Alba(Baishao),Radix Ophiopogonis(Maidong),cassia twig(Guizhi),respectively.Meanwhile,these are also the effective components for the treatment of paroxysmal atrial fibrillation combined with OSAHS(2)A total of 232 targets related to paroxysmal atrial fibrillation combined with OSAHS disease were retrieved by searching the disease gene database(3)214 active components of Tiaoganyiqidingji formula can act on 422 candidate targets,which are mapped with 232 paroxysmal atrial fibrillation combined with OSAHS disease-related targets to obtain 189 active components from Tiaoganyiqidingji formula acting on 55 therapeutic targets related to paroxysmal atrial fibrillation combined with OSAHS(4)Topological analysis of the interaction network of potential therapeutic targets from Tiaoganyiqidingji formula for the treatment of paroxysmal atrial fibrillation combined with OSAHS,to obtain eight key therapeutic targets,such as interleukin-6(IL6),tumor necrosis factor(TNF),and vascular endothelial growth factor-α(VEGFA),protein kinase-1(AKT1),mitogen-activated protein kinase-3(MAPK3),interleukin-1B(IL1B),insulin(INS),cell tumor antigen p53(TP53)(5)Through GO functional annotation and KEGG pathway enrichment analysis of potential therapeutic targets,a total of 65 biological processes,14 molecular function-related processes,10 cell component expression processes,and 92 signaling pathways were found.Among them,the mechanism of Tiaoganyiqidingji formula in the treatment of paroxysmal atrial fibrillation combined with OSAHS may be mainly related to the positive regulation of the MAPK cascade response,the positive regulation of the NO biosynthesis process,the response to hypoxia,and RNA polymerase Ⅱ.Positive regulation of promoter transcription,positive regulation of Ⅰ-kappaB kinase/NF-kappaB signal,positive regulation of cell proliferation,and other biological processes.The signaling pathways are related to regulation of tumor necrosis factor(TNF)signaling pathway,hypoxia-inducible factor(HIF-1)signaling pathway,phosphatidylinositol 3 kinase-protein Kinase B(PI3K-Akt)signaling pathway,and mitogen-activated protein kinase(MAPK)signaling pathway are related.Conclusions:The 189 main components in Tiaoganyiqidingji formula can act on 55 paroxysmal atrial fibrillation combined with OSAHS disease-related targets.Among them,IL6,TNF,VEGFA,AKT1,MAPK3,IL1B,INS,TP53 are key therapeutic targets of Tiaoganyiqidingji formula in the treatment of paroxysmal atrial fibrillation combined with OSAHS.TNF signaling pathway,PI3K-Akt signaling pathway,HIF-1 signaling pathway,and MAPK signaling pathway are the main signaling pathway. |
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