| 1 Knowledge map analysis of research related to sick sinus syndromeOBJECTIVE:To sort out the development of research on sick sinus syndrome(SSS)at domestic and international level in recent years,to dig out the countries,institutions and individual scholars with rich achievements or important influences in sick sinus syndrome research,as well as the topics,frontiers and hot spots of research,etc.,and to visualize the patterns of research on sick sinus syndrome in recent years in international,domestic and Chinese Medicine(CM)communities.It provides suggestions for research and clinical practitioners to develop research directions and select literature.It also provides reference information for academic exchange and cooperation such as the introduction of domestic and foreign personnel and study visits.METHODS:The Web of Science(WoS)core collection database was searched for studies on the topic of sick sinus syndrome,the China National Knowledge Infrastructure(CNKI)database was searched for studies on the topic of "sick sinus syndrome",and the CNKI database was searched for studies on the topic of "sick sinus syndrome" and "Chinese Medicine".The search results were imported into CiteSpace software for processing,and descriptive statistical analysis,co-occurrence analysis,cluster analysis,and burst analysis were applied to analyze the time,country,institution,scholars,keywords,and categoryof the relevant studies,and to draw the overall publication(cited)result,country-collaboration network,country-keyword association,institution-collaboration network,all scholars.The knowledge maps of international,domestic and domestic Chinese Medicine research on SSS were composed by analyzing the information of overall research publication(cited)result,national cooperation network map,national-keyword association map,institutional cooperation network graph,all scholars cooperation network graph,top scholars cooperation network map,scholars cooperation network clustering map,keyword co-occurrence map,keyword burst map,keyword time zone(perspective)map,domain co-occurrence map,etc.,and finally building a comprehensive knowledge map of domestic and foreign research on SSS.RESULTS:From macroscopic to microscopic,the knowledge map was divided into three perspectives:international,national,and CM,as well as five levels:overall,country,institution,scholar,and keyword.The international research perspective complements the category level.Firstly,in the international perspective,at the overall level,the total number of SSS-related studies per year has slightly increased in the past 30 years,and the frequency of citations has shown a clear trend of increase.At the national level,there is a situation of one over many strong countries,with the United States ranking first in the total number of studies,and the total number is much larger than other countries,while China and Japan are in the second and third places.Most countries cooperate closely.There are also some countries that prefer independent research,such as Germany,Italy,Canada,Belgium,etc.Compared with China and the United States,China started later,but the number of studies showed a rapid growth trend and surpassed the United States in 2017.The scope of research in the United States is more comprehensive,with a balance of clinical and basic research,with clinical research being the main focus.Research in China is dominated by basic research and less clinical research.At the institutional level,Aarhus University School of Medicine,Manchester University,and Mayo Medical Center are the institutions with the most published SSS-related research.China was listed by the University of Hong Kong and Chang Gung University,with no institutions from the mainland in the top 20.Institutional collaborations are clearly influenced by geography,with mainly collaborations within the same continent or country,and fewer international collaborations across continents.Aarhus University School of Medicine,although with the highest total number of studies,is more independent and collaborates less with other institutions.JC NIELSEN,KENNETH A ELLENBOGEN,and HR ANDERSEN are the three most published scholars in the field of SSS.In terms of frequency of citations,HR ANDERSEN,GA LAMAS,and M ROSENQVIST ranked in the top three,while M SANTINI,CP LAU,GA LAMAS,and HF TSE ranked in the top 20 worldwide for both total number of published studies and frequency of citations.8 clusters were obtained by cluster analysis of scholars and research topics.The tags(representative scholars)were sinus node disease(KENNETH A ELLENBOGEN),insertable cardiac monitor(HEART ASSOC AHA AMER),bradyarrhythmias(LUIGI PADELETTI),and complications(JENS COSEDIS NIELSEN),pacemaker mode(SANA M AL-KHATIA),pacemaker(SOREN HOJBERG),atrial fibrillation(BOYOUNG JOUNG),septal pacing(DL HAYES).After 2007,there has been an explosion of research on SSS,bradyarrhythmias,complications,and pacemaker mode.In particular,the study of sinus complications remains a major international research hotspot at the moment.At the keyword level,keywords such as heart failure,long term follow up,atrioventricular block,dual chamber,randomized trial,long qt syndrome,bundle branch block,etc.,are still prominent keywords in international research.Sinoatrial node,association,mutation,spacemaker implantation,and predictor,remain burst keywords until 2022.The keyword time zone plot shows that the development pattern of SSS-related research internationally is from macro to micro,and from a preference for clinical to a parallel development of clinical and basic research.Through the perspective of expression keyword,discovery mechanism and ion channel are an important direction of research in recent years.At the level of category co-occurrence,CARDIOVASCULAR SYSTEM&CARDIOLOGY,ENGINEERING,GENERAL&INTERNAL MEDICINE are in the top three.Then there is the perspective of domestic SSS-related studies.At the overall level,the number of related studies published showed an overall trend of increasing first and then decreasing.At the institutional level,Guang’anmen Hospital of the China Academy of Chinese Medical Sciences was the institution that published the most relevant studies,with Beijing University of Chinese Medicine and Xinjiang Renmin Hospital in second and third place.Studies were conducted relatively independently between different institutions,with a lack of cooperation.At the scholar level,the number of scholars involved in SSS-related studies in China is high,mostly independent,and several research teams exist.Three scholars,Ruxiu Liu,Fangzheng Wang,and Shu Zhang,are the most published scholars in the field of SSS in China.Only one category was obtained by cluster analysis,and the label was "phase analysis",whose representative scholars were Fangzheng Wang,Shu Zhang,Wei Hua and Keping Chen.At the keyword level,the frequency and centrality of arrhythmia,sinus node,and atrial fibrillation were higher.Chinese Medicine,Xinbao pill,famous doctors’ experience,atrial fibrillation,and safety are still burst keywords when it comes to 2022.The time zone plot suggests that the pattern of domestic research on SSS is to introduce concepts and improve understanding first,then pursue efficacy,and in recent years,more emphasis on safety.The time zone plot through the highlighted keyword "experience of famous doctors" revealed that the keywords were connected with Chinese medical masters,Zhiming Liu,Tongyang Huoxue,heart-kidney co-treatment,arrhythmia,Chinese Medicine treatment,palpitations,heart failure,.Finally,from the perspective of domestic CM practitioners,at the overall level,the overall research on SSS by domestic CM practitioners showed a trend of first increase and then decrease.At the institutional level,Guang’anmen Hospital of the China Academy of Chinese Medical Sciences is still the institution with the highest number of published studies,while Beijing University of Chinese Medicine and Tianjin First Central Hospital are the second and third,with a lack of cooperation between different institutions.Perspective analysis of research at Guang’anmen Hospital of the China Academy of Chinese Medical Sciences on topics such as Chinese Medicine,experience of famous doctors,Chinese Medicine masters,Zhiming Liu,heart-kidney co-treatment,benefitting qi and warming yang,promoting yang and activating blood,heart-kidney yang deficiency,combination of disease and evidence,animal models,systematic evaluation,and review.At the scholars’ level,the total size of domestic research SSS is fair,most of them are independent studies,and there are fewer large teams.Three scholars,Ruxiu Liu,Zhiming Liu,and Jinfeng Liu,are the most published scholars in the field of SSS in Chinese Medicine in China.Only one cluster was obtained from the cluster analysis,and the label was "Zhiming Liu".At the keyword level,the frequency and centrality of keywords such as sinus node,CM,CM treatment,palpitation,arrhythmia,heart-kidney yang deficiency,heart-yang deficiency,Radix Glycyrrhizae Preparata,Aconitum carmichaeli Debx,Aconitum carmichaeli Debx,and experience of famous doctors were high.The time zone plot suggests that the research of SSS in CM is gradually comprehensive,especially the type of identification,from treating heart-zangxiang alone to treating heart and kidney together.Heart function,data mining,heart rate,Xinfukang,and famous doctors’ experience are still prominent keywords when it comes to 2022.Chinese medicine master Zhiming Liu studied the Four Books and Five Classics and other Chinese classics in traditional Chinese private schools,and he also enjoys reading and reciting ancient texts in his spare time.The Zhou Yi is at the top of the Four Books and Five Classics,has had a profound impact on all aspects of China,and Chinese medicine is no exception.Among the many traditional Chinese medical practitioners,Professor Liu Zhiming highly esteems the academic views of Jingyue Zhang,who attaches great importance to the idea of "the same source of medicine and Yi".Therefore,the influence of Zhou Yi should be taken into account in the inheritance of traditional Chinese medicine by tracing its origin.In the Zhou Yi,the role of Yang is emphasized among Yin and Yang,and the Qian divinatory trigram,in which all six lines are Yang,is put in the first place.Under its influence,Chinese medicine has emphasized the significance of yang in life since the Yellow Emperor’s Classic of Internal Medicine,and the Su Wen-Shengqi Tongtian Theory,as well as Jing Yue’s commentary,liken yang to the sun in nature,and if the sun operates regularly,everything will thrive and prosper,and vice versa.By analogy with medicine,if yang energy is normal,the body is peaceful,while the opposite produces disease.There are two types of Yang diseases:Yang deficiency and Yang stagnant.Professor Liu Zhiming often says:"The role of Yang Qi is to movement" and"Movement is supplementary".In Chinese medicine,there are two main aspects of yang energy:"warmth" and "movement".Insufficient Yang movement,poor operation and sluggish pulse are called Yang stagnant(Yu).Therefore,The key mechanism of the SSS is Yang Yu.Therefore,the treatment should be a combination of "TongYang" and Huoxue(Activate Blood).The Zangfu is identified by the heart and kidney.The normal relationship between heart and kidney is described as "water and fire are mutually beneficial",and Su Wen-Wuzang Shengcheng points out that the kidney is the master of the heart,so the heart and kidney are treated together.Therefore,Prof.Liu Zhiming emphasizes that the disease mechanism is based on the stagnant of the heart and kidney yang,and especially emphasizes that the yang energy is used to movement,and that it can only be fully utilized by ensuring that the yang energy "keeps moving and passes through without obstruction".Therefore,he proposed the idea of "Yang energy does not come from tonic,but movement" and "Take fluency as the condition goes well " and "Take movement as tonic",and often "warm and move at the same time,treating the heart and kidneys together" when treating the symptoms.Chief Liu Ruxiu has been exploring the use of Chinese medicine to treat SSS in clinical practice since 1991,and has hosted several projects of the National Natural Science Foundation of China and the Chinese Academy of Chinese Medicine Sciences,and has conducted many studies in both clinical and basic aspects simultaneously,which have confirmed the safety and effectiveness of Tong Yang and Huoxue formula in treating SSS.CONCLUSION:International research attention on SSS is increasing year by year.At the national level,the United States remains the country with the most research strength and influence,with China in second place with strong potential for growth.At the institutional level,international institutions emphasize collaboration,with Aarhus University School of Medicine,University of Manchester,and Mayo Medical Center being the most internationally influential institutions.At the domestic level,independent research is preferred,with Guang’anmen Hospital of the China Academy of Chinese Medical Sciences having the most research results and the strongest influence.At the scholar level,JC NIELSEN,KENNETH A ELLENBOGEN,HR ANDERSEN,HR ANDERSEN,GA LAMAS,M ROSENQVIST,M SANTINI,CP LAU,GA LAMAS,and HF TSE are the famous scholars who study sinus internationally,and domestic Ruxiu Liu,Fangzheng Wang,and Shu Zhang are the scholars with the most research results,while the CM community has the most research results from Ruxiu Liu,Zhiming Liu,and Jinfeng Liu.At the keyword level,the hotspot of international research is clinical,and in recent years,it has developed into both clinical and basic research.Domestic Western Medical research is mainly influenced by international research,while CM research is a major feature and advantage.At the category level,SSS research is not only limited to medicine,but also emphasizes the combination with engineering and the development of multidisciplinary integrated research.2 Effect of Tongyang Huoxue Formula(TYHX)intervention on knockdown/over-expression ofβ-tubulin on cell number and calcium ion concentration in injury sinus node cells of mammary rabbitsOBJECTIVE:To investigate the effects of the intervention of TYHX Formula to knock down or overexpress β-tubulin in damaged sinus node cells of mammary rabbits on cell number and calcium ion concentration using ischemia-reperfusion conditions to damage sinus node cells.METHODS:Mammary rabbit sinus node cells were selected for the study,isolated,cultured and identified.The drug non-toxic concentration of TYHX Formula was screened.According to whetherβ-tubulin was knocked down or overexpressed in the sinus node cells and whether TYHX Formula was added to intervene or not,they were divided into control group,model group,TYHX Formula group,TYHX Formula+β-tubulin knockdown group and TYHX Formula+β-tubulin overexpression group.The number of sinus node cells in each group was observed by inverted microscope,and the calcium ion concentration in the injury sinus node cells of mammary rabbits was detected by flow cytometry,and the calcium ion fluorescence intensity in the injury sinus node cells of mammary rabbits was detected by confocal.RESULTS:After ischemia-reperfusion injury(model group),sinus node cells of mammary rabbits showed decreased cell number,increased intracellular calcium ion concentration(P<0.05),and increased calcium ion fluorescence intensity,suggesting intracellular calcium overload and apoptosis or cell death after sinus node cell injury.The sinus node cell number increased,intracellular calcium ion concentration decreased(P<0.05)and calcium ion fluorescence intensity decreased(P<0.001)in the TYHX Formula group,suggesting that TYHX Formula could interfere with sinus node cell injury,reduce intracellular calcium overload,and decrease apoptosis or death of sinus node cells in mammary rabbits.Compared with the TYHX Formula+β-tubulin knockdown group,there were fewer cells,higher intracellular calcium ion concentration(P<0.05),and higher calcium ion fluorescence intensity(P<0.001),suggesting that knockdown of β-tubulin reduced the intervention of TYHX Formula on sinus node cells,and the effect of reducing intracellular calcium overload was affected,and cells still suffered from apoptosis or death.Compared with the TYHX Formula+βtubulin overexpression group,the number of cells increased,the intracellular calcium ion concentration was lower(P<0.05),and the calcium ion fluorescence intensity was higher(P<0.001),suggesting that overexpression of β-tubulin enhanced the intervention of TYHX Formula on the sinus node of mammary rabbits,and the effect of reducing intracellular calcium overload increased,and the death or apoptosis of sinus node cells decreased.CONCLUSION:TYHX Formula can protect the sinus node cells and reduce the calcium overload injury of sinus node cells in mammary rabbits caused by ischemia-reperfusion,and this treatment mechanism may be related to β-tubulin.3 Effect of Tongyang Huoxue Formula intervention on knockdown/overexpression of β-tubulin in injury sinus node cells of lactating rabbits on calcium transport moleculesOBJECTIVE:To investigate the effect of knockdown or overexpression of β-tubulin on the mRNA and protein expression of SERCA2a and RyR2 on the sarcoplasmic reticulum and NCX1.1 and Cav 1.3 calcium transport molecules on the cell membrane in mammary rabbit sinus node cells injured by ischemia-reperfusion conditions by using TYHX Formula intervention.METHODS:Mammary rabbit sinus node cells were selected for the study,isolated,cultured and identified.According to whether β-tubulin was knocked down or overexpressed in the sinus node cells and whether TYHX Formula was added,the cells were divided into control group,model group,TYHX Formula group,TYHX Formula+β-tubulin knockdown group and TYHX Formula+βtubulin overexpression group.mRNA expression of calcium transport molecules was detected by Real-time PCR and protein expression of calcium transport molecules was detected by Western Blot.RESULTS:Real-time PCR results showed that the relative mRNA expression of RyR2(n=7,P<0.001)was elevated and the relative mRNA expression of SERCA2a(n=7,P<0.01),NCX1.1(n=7,P<0.001),Cav 1.3(n=7,P<0.001)in the model group compared with the control group decreased.Compared with the model group,the relative expression of RyR2 mRNA was decreased in the TYHX Formula group(n=7,P<0.001),and the relative expression of SERCA2a(n=7,P<0.01),NCX1.1(n=7,P<0.001),and Cav1.3(n=7,P<0.001)mRNAs were increased.The relative expression of RyR2 mRNA was elevated(n=7,P<0.001)and the relative expression of SERCA2a(n=7,P<0.01),NCX1.1(n=7,P<0.001),and Cav1.3(n=7,P<0.01)was decreased in the TYHX Formula+Knockdown group compared with the TYHX Formula group.The relative mRNA expression of RyR2(n=7,P<0.01)was decreased and the relative mRNA expression of SERCA2a(n=7,P<0.001),NCX1.1(n=7,P<0.05)and Cav1.3(n=7,P<0.001)was increased in the TYHX Formula+β-tubulin overexpression group compared with the TYHX Formula group.Western Blot results showed that the relative protein expression of RyR2(n=3,P<0.001)was elevated and that of SERCA2a(n=3,P<0.01),NCX1.1(n=3,P<0.001),and Cav1.3(n=3,P<0.05)was decreased in the model group compared with the control group.Compared with the model group,the relative expression of RyR2 protein was decreased in the TYHX Formula group(n=3,P<0.001),and the relative expression of SERCA2a(n=3,P<0.01),NCX 1.1(n=3,P<0.01),and Cav 1.3(n=3,P<0.01)was increased.The relative expression of RyR2 protein was elevated(n=3,P<0.001)and the relative expression of SERCA2a(n=3,P<0.001),NCX1.1(n=3,P<0.01)and Cav1.3(n=3,P<0.01)was decreased in the TYHX Formula+Knockdown group compared with the TYHX Formula group.The relative protein expression of RyR2(n=3,P<0.001)was decreased and that of SERCA2a(n=3,P<0.01),NCX1.1(n=3,P>0.05),and Cav 1.3(n=3,P>0.05)was increased in the TYHX Formula+β-tubulin overexpression group compared with the TYHX Formula group.CONCLUSION:The TYHX Formula can protect the sinus node cells and reduce intracellular calcium overload in mammary rabbits,and this therapeutic mechanism may be related to RyR2,SERCA2a,NCX1.1,Cav1.3 calcium transport molecules and achieved through β-tubulin. |
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