Study On TCM Syndrome Characteristics And Exosome Transcriptome Sequencing Of Persistent Atrial Fibrillation In Coronary Heart Diseas

Part 1:Prognostic of patients with coronary artery disease complicating with atrial fibrillation:a systematic review and meta-analysisObjectives:Our aim was to perform a pairwise meta-analysis to evaluate poor outcomes in patients with coronary artery disease(CAD)complicating with atrial fibrillation(AF).Methods:Pubmed、EMBASE、Scopus、Cochrane Library、CNKI、Wanfang Database、VIP and SinoMed)systematically searched for studies reported poor prognosis of patients with coronary artery disease complicating with atrial fibrillation from inceptions to 17 October,2021.The methodological quality was performed using Newcastle-Ottawa Scale.We pooled hazard risk ratio(HR)using a random-effects model.Publication bias was evaluated using Egger’s test.All analyses were performed using Stata software version 14.Results:Thirty-seven studies were included in the meta-analysis,encompassing a total of 793213 CAD patients with atrial fibrillation.CAD patients with AF presented an independent increased risk of in-hospital mortality(HR 1.41,95%IC 1.32-1.51),long-term mortality(HR 1.51,95%IC 1.37-1.67),long-term MACE(HR 1.72,95%IC 1.20-2.47),long-term heart failure(HR 1.84,95%IC 1.38-2.45),long-term stroke(HR 1.74,95%IC 1.35-2.23)compared to those without AF or without CAD.Instead,risk of long-term myocardial infarction(HR 1.13,95%IC 0.83-1.52)did not differ in CAD patients with and without the AF.Conclusion:Patients with CAD complicating with AF have a worse prognosis than patients without CAD or AF.They have a higher risk of death,long-term MACE,long-term heart failure,and long-term stroke.Part 2 Risk factors of persistent atrial fibrillation and clinical characteristics of coronary heart disease patients complicating with persistent atrial fibrillationObjectives:To explore risk factors of persistent atrial fibrillation(PeAF),the risk factors of patients with PeAF complicating with cerebral infarction and renal insufficiency,and the clinical characteristics of coronary heart disease patients complicating with persistent atrial fibrillation.Methods:(1)A total of 782 patients with AF were selected according to inclusion and exclusion criteria.These patients were divided into PeAF group and paroxysmal atrial fibrillation(PAF)group.IBM SPSS 22.0 statistical software was used to analyze the clinical data.The risk factors of PeAF were evaluated by logistic regression analysis.(2)We divided the patients with PeAF into CAD group and non-CAD group,and compared the clinical data of the two groups.Besides,the patients with PeAF were grouped according to whether they had cerebral infarction or renal insufficiency,the risk factors of PeAF complicating with cerebral infarction and renal insufficiency were evaluated by logistic regression analysis.(3)The general clinical data and laboratory parameters of CAD patients complicating with PeAF and PAF were compared.Results:(1)Compared with PAF group,age,LAD,the proportion of patients with CAD,heart failure,ischemic stroke,diabetes,hyperuricemia,chronic renal insufficiency were higher in PeAF group.Multivariate logistic regression analysis showed LAD≥ 40mm(OR 6.396,95%IC:4.351-9.404)and complicating with CAD(OR 1.556,95%IC:1.089-2.222)were independent risk factors for PeAF.(2)Compared with non-CAD group,the proportion of patients with hypertension,cerebral infarction,carotid atherosclerosis,renal insufficiency were lower,but LAD was higher in CAD group.Compared with patients without cerebral infarction,age,the proportion of patients with carotid atherosclerosis,hypertension,CAD were higher in patients with cerebral infarction,but LVEF was lower in cerebral infarction group.Multivariate logistic regression analysis showed age(OR 1.084,95%IC:1.053-1.115),CAD(OR 1.754,95%IC:1.038-2.966)were independent risk factors for PeAF patients complicating with cerebral infarction,and LVEF(OR 0.957,95%IC:0.924-0.992)was a protective factor.Compared with patients without renal insufficiency,the proportion of patients with hypertension and CAD were higher in renal insufficiency group,LVEF was lower in renal insufficiency group.Multivariate logistic regression analysis showed CAD(OR 1.812,95%IC:1.121-2.928),hypertension(OR 1.890,95%IC:1.024-3.486)were the independent risk factors for PeAF patients complicating with renal insufficiency,and LVEF(OR 0.962,95%IC:0.930-0.996)was a protective factor.(3)Compared with CAD patients complicating with PAF,eosinophils counts and ratio,RDW,MCV,MPV,PLCR,TBIL,DBIL,IDBIL,TP,GLB,y-GT,UA,PT,INR,APTT,LAD were higher in CAD patients complicating with PeAF,and MCHC,PLT,PAB,eGRF,TG,CHO,HDL-C,VLDL,ApoA1,ATⅢ,PTA,TT3,LVEF and heart rate during AF were lower in CAD patients complicating with PeAF.Conclusion:Complicating with CAD and left atrial diameter enlargement are independent risk factors for the progression of paroxysmal AF to persistent AF,and CAD can increase the risk of cerebral infarction and renal insufficiency in patients with PeAF.Part 3 Study on TCM syndromes and clinical characteristics in CAD patients with PeAF Objectives:To summary TCM syndromes of CAD patients with PeAF,and explore the difference physical and chemical parameters among different TCM syndromes.Methods:A total of 282 CAD patients with PeAF were selected according to inclusion and exclusion criteria.We collected clinical symptoms,physical and chemical parameters,of these patients comprehensively,then performed cluster analysis to extract main syndrome.Results:Chest tightness,palpitation,insomnia and fatigue are the most common symptoms of CAD complicating with PeAF,dark red tongue,moss yellow greasy tongue is common tongue image,and thin pulse chord and smooth pulse chord are common pulse conditions.There were four TCM syndromes:Qi and Yin deficiency,and phlegm and blood stasis mutual syndrome,deficiency of liver and kidney,Yin deficiency fire flourishing syndrome,blood stasis and dropsy syndrome.Neutrophils ratio,lymphocyte counts and ratio,RDW,MCHC,uric acid,creatinine,BUN,PA,GLB,DBIL,y-GT,SOD,LDH,NT-proBNP and heart rate were different among the four TCM syndromes.Conclusion:The main TCM syndromes of CAD patients with PeAF were Qi and Yin deficiency,and phlegm and blood stasis mutual syndrome,deficiency of liver and kidney,Yin deficiency fire flourishing syndrome,blood stasis and dropsy syndrome.The basic pathogenesis is Deficiency of both QI and YIN,phlegm and blood stasis,always belong to deficiency in origin and excess in superficiality,deficiency and excess inclusion.The parameters of blood routine,liver function,renal function,and enzymology were different among different TCM syndromes,which provided the basis for the biological foundation of TCM syndrome of CAD with PeAF.Part 4 Transcriptome sequencing of plasma exosomes in CAD patients with AFObjectives:The expression profiles of microRNA,mRNA,lncRNA and circRNA in exosomes of CAD patients with atrial fibrillation and CAD patients with sinus rhythm(SR)were detected to screen the differential expression genes of CAD patients with PAF and CAD patients with sinus rhythm,CAD patients with PeAF and CAD patients with PAF,and to explore the possible mechanism of CAD patients with AF occurrence and development.Methods:Plasma exosomes were isolated from CAD patients with PeAF(n=10),CAD patients with PAF(n=10),CAD patients with SR(n=10),and age-matched healthy volunteers(HV)(n=8).Plasma exosome sequencing technology was used to detect exosome-derived microRNA,mRNA,lncRNA and circRNA.Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were performed.Screening for differentially expressed(DE)genes unique to CAD patients with PeAF.Results:By performing high-throughput sequencing,124 DE miRNAs,1567 DE mRNAs,956 DE lncRNAs,63 DE circRNAs,were detected in the plasma exosomes between CAD patients with SR and HV;69 DE miRNAs,1126 DE mRNAs,1006 DE lncRNAs,62 DE circRNAs,were detected in the plasma exosomes between CAD patients with PAF and SR;126 DE miRNAs,828 DE mRNAs,643 DE lncRNAs,17 DE circRNAs,were detected in the plasma exosomes between CAD patients with PeAF and PAF.Thirty-two miRNAs,186mRNA,1481ncRNA were associated with CAD complicating with PeAF.The expression level of red blood cell-derived exosomes in CAD patients with SR was lower than that in CAD patients with PeAF.The expression level of CD4 T cell-derived exosomes in CAD patients with AF was lower than that in CAD patients with SR,and the proportion of kidney derived exosomes in CAD patients with PAF was lower than that in patients with PeAF and SR.The differential expressed genes of CAD patients with PAF and CAD patients with sinus rhythm are mainly enriched in Biosynthesis of Unsaturated fatty acids,FoxO Signaling Pathway and mTOR signaling Pathway,Neurotrophin signaling Pathway,the differentially expressed genes of CAD patients with PeAF and CAD patients with PAF were mainly concentrated in Taurine and hypotaurine metabolism,Biosynthesis of Unsaturated fatty acids and fatty acid Insulin resistance signaling pathway.Conclusion:This study identified the exosomal RNAs which were closely related to PeAF in coronary heart disease,and elucidated the potential mechanism of the occurrence and development of atrial fibrillation in coronary heart disease.Part 5 Transcriptome sequencing of plasma exosomes in different TCM syndromes of CAD patients with PeAFObjectives:The expression profiles of microRNA,mRNA,lncRNA and circRNA in exosomes of different TCM syndromes of CAD patients with PeAF to explore material basis and scientific connotation of different TCM syndromes.Methods:Plasma exosomes were isolated from CAD patients with PeAF(n=20),5 in each syndrome,and age-matched healthy volunteers(HV)(n=8).Plasma exosome sequencing technology was used to detect exosome-derived microRNA,mRNA,lncRNA and circRNA.GO and KEGG enrichment was used to analyze the unique differentially expressed genes of patients with different TCM syndromes.Results:By performing high-throughput sequencing,13 unique DE miRNAs,6 unique DE mRNAs and 3 unique DE lncRNAs were screened in the plasma exosomes of Patients with Qi and Yin deficiency,and phlegm and blood stasis mutual syndrome;6 unique DE miRNAs,6 unique DE mRNAs and 7 unique DE lncRNAs were screened in the plasma exosomes of Patients with deficiency of liver and kidney syndrome;4 unique DE miRNAs,10 unique DE mRNAs and 6 unique DE lncRNAs were screened in the plasma exosomes of Patients with deficiency of Yin deficiency fire flourishing syndrome;25 unique DE miRNAs,16 unique DE mRNAs and 5 unique DE lncRNAs were screened in the plasma exosomes of Patients with blood stasis and dropsy syndrome.There were differences in expression levels of CD4 T cells,heart,liver,lung,muscle and stomach-derived exosomes among different TCM syndromes.The unique differentially expressed genes of patients with Qi and Yin deficiency,and phlegm and blood stasis mutual syndrome are enriched in biological processes such as response to hormone,response to hypoxia,positive regulation of cell adhesion,as well as lipid and atherosclerosis,Long-term depression signaling pathways.The unique differentially expressed genes of patients with deficiency of liver and kidney syndrome are enriched in biological processes such as negative regulation of cell adhesion,negative regulation of T cell differentiation,as well as Signaling pathways regulating pluripotency of stem cells,Alzheimer disease signaling pathways.The unique differentially expressed genes of patients with deficiency of Yin deficiency fire flourishing syndrome are enriched in biological processes such as positive regulation of ATPase activity and response to starvation,as well as Adrenergic signaling in cardiomyocytes signaling pathway.The unique differentially expressed genes of patients with deficiency of blood stasis and dropsy syndrome are enriched in biological processes such as regulation of autophagy,intrinsic apoptotic signaling pathway,fatty acid derivative metabolic process,as well as PPAR signaling pathway.Conclusion:The unique differentially expressed genes of patients with TCM syndromes represents the material foundation of this syndrome.By analyzing the function of differentially expressed genes,and combined with traditional Chinese medicine theory and related research to explain the biological significance of unique differentially expressed genes in each TCM syndromes.