Clinical Characteristics Of Tachyarrhythmia Complicated With Depression And The Intervention Mechanism Of Tiaogan Yiqi Dingji Formula

Tachyarrhythmia(premature beat,tachycardia,atrial flutter,atrial fibrillation,etc.)is an important group of cardiovascular diseases,often accompanied by palpitations,chest tightness,dizziness,etc.,which seriously affect the quality of life of patients.If it can’t be treated in time,it may eventually induce cardiomyopathy and develop into heart failure,in which atrial fibrillation can also induce thromboembolism,resulting in increased risk of hospitalization and death.It has caused a great burden to patients and society.Depression is a common psychological comorbidity in patients with cardiovascular disease,and tachyarrhythmia is associated with a higher risk of depressive symptoms.Depression may be associated with increased symptom burden,decreased quality of life,recurrent recurrence,risk of bleeding with oral anticoagulants,risk of cardiovascular and all-cause mortality in patients with tachyarrhythmia.It increases the complexity of management and the risk of poor prognosis in patients with tachyarrhythmia.However,at present,there are still some problems,such as low awareness of tachyarrhythmia complicated with depression,lack of timely and accurate diagnosis,standardized treatment and unsatisfactory treatment effect.Therefore,it is of great clinical significance to explore more excellent methods for the treatment of tachyarrhythmia with depression and to explore the antiarrhythmic and antidepressant effects of Traditional Chinese Medicine(TCM).In view of the clinical experience in the diagnosis and treatment of tachyarrhythmia complicated with depression,combined with the law of the development of TCM pathogenesis,based on the three official prescriptions of court medicine in the Song Dynasty,Taiping Sheng Hui Fang,Sheng Ji Zong Lu,Taiping Huimin Heji Ju Fang,in which the main treatment of palpitation was " Replenish deficiency,soothe nerves and relieving palpitations " and "ten thousand diseases are caused by the liver and the treatment of the liver comes first" said by Qing Dynasty imperial physician Tong Kuoquan,we established the method of "regulating liver and replenishing Qi,nourishing heart and relieving palpitations" and formed Tiaogan Yiqi Dingji Fomula,composed of Nardostachyos Radix et Rhizoma,Agrimonia Herba,etc.to treat tachyarrhythmia complicated with depression.Previous clinical studies had found that this prescription can prevent the recurrence of atrial fibrillation,reduce the attack frequency and shorten the duration,improve the heart rate variability(HRV),improve clinical symptoms in patients,had a significant effect of TCM syndrome,can improve the quality of life,and was safe.In addition,it has the effect of regulating depression-related symptoms.Based on the above research basis,this study intends to systematically analyzed the TCM syndrome distribution and clinical characteristics of tachyarrhythmia patients in patients with tachyarrhythmia,to clarify the wide applicability of Tiaogan Yiqi Dingji Formula in the treatment of tachyarrhythmia with depression.Further,with the help of network pharmacology and animal experiments,the mechanism of this prescription in the treatment of tachyarrhythmia with depression was explored,in order to provide experimental basis for the clinical application of this prescription.This study includes the following parts:Part Ⅰ:Literature reviewThis part reviews the research progress of traditional Chinese and western medicine in the treatment of tachyarrhythmia with depression and the mechanism of tachyarrhythmia and depression.Part Ⅱ:Clinical studiesIt is divided into the following two parts of the study.Study 1:The association between TCM syndrome distribution and depression scale(PHQ-9)score in patients with tachyarrhythmiaObjective:to explore the distribution characteristics of TCM syndrome types and the relationship between the main syndrome type and PHQ-9 score in patients with tachyarrhythmia,so as to provide reference for the clinical treatment of tachyarrhythmia.Methods:302 patients with tachyarrhythmia treated in Xiyuan Hospital,China Academy of Chinese Medical Sciences from March 2021 to February 2022 were collected.The demographic data,medical history,symptoms and signs,results of 24h Holter or electrocardiogram,Patient health questionnaire-9(PHQ-9)and Generalized anxiety disorder-7(GAD-7)were collected.Standardized the collected data into the database and analyzed the collected data to explore the distribution characteristics of TCM syndrome type of patients with tachyarrhythmia and the association between the main syndrome types and the PHQ-9 score.Results:A total of 302 patients with tachyarrhythmia were included in this study,including 120 cases of liver depression and Qi stagnation combined with heart deficiency and timidity syndrome(39.74%),which is the common TCM syndrome type in patients.The mean PHQ-9 score of patients with tachyarrhythmia was 5.39±4.52,of which 148(49.01%)had PHQ-9≥5 and 51(16.89%)had PHQ-9 ≥10.Among the patients with PHQ-9≥5,87(58.8%)was liver depression and Qi stagnation combined with heart deficiency and timidity,and 40(78.4%)was liver depression and Qi stagnation combined with heart deficiency and timidity in patients with PHQ-9≥10.After adjusting for the effects of potential confounding factors such as gender,comorbidity,and GAD-7 score,etc.,female(OR=1.842;95%CI:1.054-3.218),GAD-7 score ≥5(OR=5.043;95%CI:2.774-9.168),and liver depression and Qi stagnation combined with heart deficiency and timidity(OR=3.406;95%CI:1.934-5.998)were associated with PHQ-9 scores ≥5(P<0.05).After adjusting for the effects of potential confounding factors such as gender,comorbidities,and GAD ≥7 score,etc.,GAD-7 ≥5(OR=4.731;95%Cl:2.2499.954)and liver depression and Qi stagnation combined with heart deficiency and timidity(OR=5.193;95%CI:2.381-11.327)were associated with PHQ-9 score ≥10(P<0.05).Conclusion:Liver depression and Qi stagnation combined with heart deficiency and timidity syndrome is a common TCM symptom in patients with tachyarrhythmia,and it is also the main TCM symptom in patients with tachyarrhythmia with depression,and this TCM symptom may be associated with elevated PHQ-9 scores.Study 2:An analysis of the correlation between common TCM syndrome types and heart rate variability in patients with tachyarrhythmiaObjective:A cross-sectional study was conducted to explore the correlation between the common TCM symdrome,liver depression and Qi stagnation combined with heart deficiency and timidity syndrome,and heart rate variability in patients with tachyarrhythmias,in order to provide a reference for the clinical management of tachyarrhythmias.METHODS:105 patients with tachyarrhythmias who visited Xiyuan Hospital,China Academy of Chinese Medical Sciences from March 2021 to February 2022 were collected,who underwent 24h holter within 7 days of data collection and the report included at least "Standard deviation of all normal-to-normal intervals(SDNN)".Patient demographic data,medical history,symptoms and signs,24h holter results(including heart rate variability index SDNN,etc.),PHQ-9 score,and GAD-7 score were collected.Standardized the collected data into the database and statistical analysis of the collected data,to explore the correlation between liver depression and Qi stagnation combined with heart deficiency and timidity syndrome and heart rate variability in patients with tachyarrhythmias.Results:A total of 105 patients were included in this study,and 35 patients(33.33%)was liver depression and Qi stagnation combined with heart deficiency and timidity.Between the two groups of liver stagnation and Qi stagnation combined with heart deficiency and timidity syndrome and non-liver Qi stagnation combined with heart deficiency and timidity syndrome,there was no statistically significant difference in the distribution of baseline data such as gender,age,body mass index(BMI),and comorbidities,P>0.05.The results of Point-biserial correlation analysis showed that liver depression and Qi stagnation combined with heart deficiency and timidity in tachyarrhythmia patients was associated with the decrease of SDNN,rbp=0.273,P<0.05.Conclusion:The liver-depression and Qi stagnation combined with heart deficiency and timidity in tachyarrhythmia patients were correlated with the decrease of HRV.Part III:Network pharmacology study:To investigate the mechanism of Tiaogan Yiqi Dingji Formula in the treatment of tachyarrhythmia with depression based on network pharmacologyObjective:To investigate the material basis and mechanism of Tiaogan Yiqi Dingj i Formula in the treatment of tachyarrhythmia with depression based on network pharmacology,providing research direction for further experimental research.Methods:The active ingredients of Nardostachyos Radix et Rhizoma and Agrimonia Herba,etc.were searched through the BATMAN-TCM platform to predict the targets of the active ingredients of the formula,and the unpredicted active ingredients and their targets were added according to the published literature reports.The GeneCard(https://www.genecards.org/)and DRUGBANK(https://go.drugbank.com/)databases were mined for potential targets for the treatment of tachyarrhythmias,including premature beats,tachycardia,atrial flutter and atrial fibrillation and depression.The shared targets of formula and diseases were screened,and protein-protein interaction(PPI)network maps were constructed using the STRING11.0 database(https://string-db.org/).The results were imported into CytoScape3.8 for visualization,and the Molecular Complex Detection(MCODE)plug-in was used to analyze the interactions and obtain the module,which including the potential core targets.Gene ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis on the potential core targets were performed by Metascape platform(https://metascape.org/).The results were visualized with the help of free online platform for data analysis and visualization(https://www.bioinformatics.com.cn).The network of active ingredient of Tiaogan Yiqi Dingji Formula-potential core target-main signaling pathway was constructed by Cytoscape 3.8 software.Results:The sodium channel protein type 5 subunit alpha(SCN5A),caveolin-3(CAV3),sodium channel subunit beta-1(SCN1B),voltage voltage-dependent L-type calcium channel subunit alpha-1D(CACNA1D),interleukin-10(IL10),tumor necrosis factor(TNF),interleukin-6(IL-6),endothelin-1(EDN1),angiotensinogen(AGT),and ryanodine receptor 2(RYR2)may may be the core target of Tiaogan Yiqi Dingji Formula in the treatment of tachyarrhythmia with depression..The potential core targets were significantly concentrated in the adrenergic signaling in cardiomyocytes,advanced glycation end products(AGE)-receptor for advanced glycation end products(RAGE)signaling pathway,Chagas disease(American trypanosomiasis),renin secretion,fluid shear stress and atherosclerosis,hypoxiainducible factor 1(HIF-1)signaling pathway and complement and coagulation cascades.Conclusion:Tiaogan Yiqi Dingji Formula may exert anti-tachyarrhythmia and anti-depression effects by regulating ion disturbance,anti-inflammation,antioxidative stress and inhibiting renin-angiotensin-aldosterone system.CaMKⅡ/RYR2 signaling pathway is the downstream of adrenergic signaling pathway,which may be related to the anti-arrhythmia and anti-depression effects of Tiaogan Yiqi Dingji Formula.Part Ⅳ:To investigate the intervention mechanism of Tiaogan Yiqi Dingji Formula in the treatment of tachyarrhythmia with depression based on CaMKⅡ/RYR2 signaling pathwayObjective:To explore the intervention effect and mechanism of Tiaogan Yiqi Dingji Formula on tachyarrhythmia with depression,and to lay the experimental foundation for its further clinical application.Methods:A rat model of tachyarrhythmia with depression induced by chronic unpredictable mild stress(CUMS)combined with aconitine was established.60 male Wistar rats were randomly divided into 6 groups(blank control group,aconitine control group,model group,western medicine control group,low and high doses of Chinese medicine)according to the random number table,10 rats in each group.The blank control group and aconitine control group were given 10ml·kg-1·d-1 of pure water gavage daily,and the model group,western medicine control group,and Chinese medicine low and high dose groups were stimulated with one CUMS daily and given 10ml·kg-1·d-1 of pure water,5.2 mg10ml·kg-1·d-1 of metoprolol,16.46 g·kg-1·d-1 of Tiaogan Yiqi Dingji Formula,and 32.92 g·kg-1·d-1 of Tiaogan Yiqi Dingji Formula,respectively gavage for 21 days,once a day.The rats were tested for body weight,sugar-water consumption rate,and heart coefficient,electrocardiogram,and serum adrenocorticotropic hormone(ACTH),corticosterone(CORT)by Elisa,and Calcium/calmodulin-dependent protein kinase(CaMKⅡ),RYR2,p-RYR2(ser2814)protein expression levels in rat myocardial tissue was detected by Western blot.Results:Compared with the blank control group,the model group showed decreased body weight,decreased sugar-water consumption rate,increased arrhythmia score,increased number of premature ventricular beats,increased heart coefficient,increased ACTH and CORT levels,increased CaMKⅡ protein expression levels,and increased p-RYR2(ser2814)/RYR2 levels,and the differences were statistically significant(P<0.05).Compared with the aconitine control group,the model group showed decreased body weight,decreased sugar-water consumption rate,increased heart coefficient,and increased number of premature ventricular beats,and the differences were statistically significant(P<0.05);compared with the model group,the low and high dose groups of Chinese medicine showed increased sugarwater consumption rate,decreased arrhythmia score,decreased number of premature ventricular beats,and decreased CaMKⅡ protein expression level,and the high dose group of Chinese medicine showed increased p-RYR2(ser2814)/RYR2 levels were reduced,and the differences were statistically significant(P<0.05).Conclusion:CUMS may increase susceptibility to tachyarrhythmias in rats.Tiaogan Yiqi Dingji Formula played a dual role of anti-arrhythmia and antidepressant,the mechanism of which may be related to the regulation of CaMKⅡ/RYR2 signaling pathway.