养心汤对室性早搏患者（气血亏虚型）的血清miRNA-1和尿代谢组学的影响
|
摘要
目的：通过观察养心汤对室性早搏(气血亏虚型)患者的临床疗效及对室性早搏患者的血清miRNA-1和尿代谢组学的影响,初步探讨室性早搏患者的发病机制及探寻其相关代谢组学标志物。
方法：本研究将入选的100例室性早搏患者随机分为治疗组和对照组,在治疗原发疾病的基础上,对照组常规服用慢心律150mg,日3次口服；治疗组口服慢心律150mg,日3次口服,并同时给予养心汤150ml,日2次口服,治疗四周为一疗程。观察治疗前后的中医症候、24h室性早搏数QT离散度的变化。从上述患者中随机抽取治疗组和对照组各10例,测定治疗前后的血清miRNA-1。另从研究观察患者中随机抽取治疗组和对照组各10例,另选取健康志愿者10例,采用UPLC-TOF/MS代谢组学技术观察室性早搏患者用药前后尿代谢物成分的变化,采用主成分分析(PCA)、偏最小二乘判别分析(PLS-DA)和正交校正的偏最小二乘判别分析(OPLS-DA),寻找室性早搏患者的相关代谢组学标志物。
结果：
1、治疗组临床症状改善总有效率达89.79%,对照组有效率为60.42%,与对照组比较有统计学意义(P<0.05)。
2、治疗组室性早搏控制总有效率达79.59%,对照组室性早搏治疗有效率达62.5%,与对照组比较疗效显著(P<0.05)。
3、治疗组在治疗后中医症状积分明显下降(P<0.01),对照组在治疗后中医症状积分亦有下降趋势与疗前比较P<0.05,与对照组比较,治疗组疗后中医症状积分下降更明显(P<0.01)。
4、治疗组和对照组在治疗后患者的QT离散度均有明显下降,有统计学意义,治疗组在治疗后QT离散度下降较对照组更为显著,两者比较有统计学意义(P<0.05)。
5、治疗组和对照组在治疗前miRNA-1水平表达较高,作治疗后均有不同程度的下降(P<0.05)。治疗组疗后与对照组疗后比较miRNA-1下降更明显(P<0.05)。
6、室性早搏患者的尿中羧酸酯、酰基辅酶A脱氢酶、异戊酸、酰基肉碱比正常组有明显降低；经治疗后,治疗组和对照组均有一定上升,治疗组在治疗后上调的更明显。
结论：
1、养心汤能改善气血亏虚型室性早搏患者的临床症状。
2、养心汤能减少气血亏虚型室性早搏患者的室性早搏次数,缩短室性早搏患者的QT离散度。
3、养心汤能降低室性早搏患者血清中miRNA-1的水平,并对气血亏虚型室性早搏患者尿中的羧酸酯、酰基辅酶A脱氢酶、异戊酸、酰基肉碱代谢产物具有调节作用。
Objective:Through investigating the clinical efficancy of Yang Xin Tang to the patients with ventricular premature beats in Syndrome of asthenia of Qi and blood and effects to serum miRNA-1and urine metabolomics of patients with ventricular premature beats,preliminary study the pathogenesis of patients with ventricular premature beats and explore its metabolomics markers.
Methods:In this study,100patients with ventricular premature beats were randomly divided into treatment and control groups,and four weeks of a course of treatment,observing TCM symptoms before and after treatment,24h ventricular premature beats, and QT dispersion changes. The patients from the first part were randomly selected treatment group and control group10cases,determinating serum miRNA-1before and after treatment. The patients from the first part randomly selected treatment group and control group10cases, and the other10cases were selected from healthy volunteers,observing ventricular premature contraction in patients with medication changes in the composition by using urinary metabolites before and after UPLC-TOF/MS metabolomics techniques, and looking for ventricular premature beats in patients with metabolic group markers by the use of principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal correction partial least squares discriminant analysis (OPLS-DA).
Results:1. the treatment group to improve the total effective rate was89.79%, the control group was60.42%, and it was statistically significant compared with control group(P<0.05).2.the treatment group, ventricular premature beats control the total effective rate was79.59%,in the control group of ventricular premature beats treatment rate of62.5%compared with the control group a significant effect (P<0.05).3.the treatment group after treatment, TCM syndrome score decreased significantly (P<0.01), the control group after treatment, TCM syndromes integral is also a downward trend and treatment, P<0.05, treatment and control groups after the treatment of TCM symptom scores decreased more significantly (P<0.01).4.treatment and control groups in the treatment of patients with QT dispersion have decreased significantly, with statistical significance, the treatment group after treatment, QT dispersion decreased compared with the control group is more significant, both statistically significant (P<0.05).5. treatment and control groups before treatment miRNA-1level higher expression, in varying degrees after treatment decreased (P<0.05). The treatment group after treatment of miRNA-1decreased more significantly compared with the control group after treatment(P<0.05).6.Urine metabolomics studies have shown that:the tryptophan in the urine of patients with ventricular premature beats, carboxylic esters, acyl-coenzyme A dehydrogenase, isovaleric acid was significantly reduced than the normal group.after treatment, the treatment group was increased more obviously than control group.
Conclusion:1.Yang Xin Tang can significantly improve clinical sympto-ms in patients with ventricular premature beats.2.Yang Xin Tang can significantly reduce the incidence of premature ventricular beats and shorten the QT dispersion in patients with ventricular premature beats.3.Yang Xin Tang can significantly reduce the level of serum of miRNA-1of patients with ventricular premature beats.5. Yang Xin Tang can interfere with some urine metabolomics markers in patients with ventricular premature beats.
方法：本研究将入选的100例室性早搏患者随机分为治疗组和对照组,在治疗原发疾病的基础上,对照组常规服用慢心律150mg,日3次口服；治疗组口服慢心律150mg,日3次口服,并同时给予养心汤150ml,日2次口服,治疗四周为一疗程。观察治疗前后的中医症候、24h室性早搏数QT离散度的变化。从上述患者中随机抽取治疗组和对照组各10例,测定治疗前后的血清miRNA-1。另从研究观察患者中随机抽取治疗组和对照组各10例,另选取健康志愿者10例,采用UPLC-TOF/MS代谢组学技术观察室性早搏患者用药前后尿代谢物成分的变化,采用主成分分析(PCA)、偏最小二乘判别分析(PLS-DA)和正交校正的偏最小二乘判别分析(OPLS-DA),寻找室性早搏患者的相关代谢组学标志物。
结果：
1、治疗组临床症状改善总有效率达89.79%,对照组有效率为60.42%,与对照组比较有统计学意义(P<0.05)。
2、治疗组室性早搏控制总有效率达79.59%,对照组室性早搏治疗有效率达62.5%,与对照组比较疗效显著(P<0.05)。
3、治疗组在治疗后中医症状积分明显下降(P<0.01),对照组在治疗后中医症状积分亦有下降趋势与疗前比较P<0.05,与对照组比较,治疗组疗后中医症状积分下降更明显(P<0.01)。
4、治疗组和对照组在治疗后患者的QT离散度均有明显下降,有统计学意义,治疗组在治疗后QT离散度下降较对照组更为显著,两者比较有统计学意义(P<0.05)。
5、治疗组和对照组在治疗前miRNA-1水平表达较高,作治疗后均有不同程度的下降(P<0.05)。治疗组疗后与对照组疗后比较miRNA-1下降更明显(P<0.05)。
6、室性早搏患者的尿中羧酸酯、酰基辅酶A脱氢酶、异戊酸、酰基肉碱比正常组有明显降低；经治疗后,治疗组和对照组均有一定上升,治疗组在治疗后上调的更明显。
结论：
1、养心汤能改善气血亏虚型室性早搏患者的临床症状。
2、养心汤能减少气血亏虚型室性早搏患者的室性早搏次数,缩短室性早搏患者的QT离散度。
3、养心汤能降低室性早搏患者血清中miRNA-1的水平,并对气血亏虚型室性早搏患者尿中的羧酸酯、酰基辅酶A脱氢酶、异戊酸、酰基肉碱代谢产物具有调节作用。
Objective:Through investigating the clinical efficancy of Yang Xin Tang to the patients with ventricular premature beats in Syndrome of asthenia of Qi and blood and effects to serum miRNA-1and urine metabolomics of patients with ventricular premature beats,preliminary study the pathogenesis of patients with ventricular premature beats and explore its metabolomics markers.
Methods:In this study,100patients with ventricular premature beats were randomly divided into treatment and control groups,and four weeks of a course of treatment,observing TCM symptoms before and after treatment,24h ventricular premature beats, and QT dispersion changes. The patients from the first part were randomly selected treatment group and control group10cases,determinating serum miRNA-1before and after treatment. The patients from the first part randomly selected treatment group and control group10cases, and the other10cases were selected from healthy volunteers,observing ventricular premature contraction in patients with medication changes in the composition by using urinary metabolites before and after UPLC-TOF/MS metabolomics techniques, and looking for ventricular premature beats in patients with metabolic group markers by the use of principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal correction partial least squares discriminant analysis (OPLS-DA).
Results:1. the treatment group to improve the total effective rate was89.79%, the control group was60.42%, and it was statistically significant compared with control group(P<0.05).2.the treatment group, ventricular premature beats control the total effective rate was79.59%,in the control group of ventricular premature beats treatment rate of62.5%compared with the control group a significant effect (P<0.05).3.the treatment group after treatment, TCM syndrome score decreased significantly (P<0.01), the control group after treatment, TCM syndromes integral is also a downward trend and treatment, P<0.05, treatment and control groups after the treatment of TCM symptom scores decreased more significantly (P<0.01).4.treatment and control groups in the treatment of patients with QT dispersion have decreased significantly, with statistical significance, the treatment group after treatment, QT dispersion decreased compared with the control group is more significant, both statistically significant (P<0.05).5. treatment and control groups before treatment miRNA-1level higher expression, in varying degrees after treatment decreased (P<0.05). The treatment group after treatment of miRNA-1decreased more significantly compared with the control group after treatment(P<0.05).6.Urine metabolomics studies have shown that:the tryptophan in the urine of patients with ventricular premature beats, carboxylic esters, acyl-coenzyme A dehydrogenase, isovaleric acid was significantly reduced than the normal group.after treatment, the treatment group was increased more obviously than control group.
Conclusion:1.Yang Xin Tang can significantly improve clinical sympto-ms in patients with ventricular premature beats.2.Yang Xin Tang can significantly reduce the incidence of premature ventricular beats and shorten the QT dispersion in patients with ventricular premature beats.3.Yang Xin Tang can significantly reduce the level of serum of miRNA-1of patients with ventricular premature beats.5. Yang Xin Tang can interfere with some urine metabolomics markers in patients with ventricular premature beats.
引文
[1]陆一.仲景方用于心律失常治验[J].中华中医药学刊,2008,26(9)：1873-1874.
[2]韩向东,陈长勋.苦参碱的心血管药理研究进展[J].中药新药与临床药理,2006,17(1)：73-75.
[3]王雪芳,刘艳明.苦参碱对低钙诱发豚鼠心律失常的电生理影响[J].中国中医基础医学杂志,2011,16(6)：633-639.
[4]陈彩霞,张宏艳.人参皂甙Re对异丙肾上腺素致家兔室性心律失常的保护作用[J].中国当代儿科杂志,2009,11(5)：384-388.
[5]周玉萍.《实用中西医结合心律失常学》[M].中医古籍出版社 2001：81-82.
[6]徐智,曹宏宇.小檗碱对犬心肌梗塞后自发性室颤的防治作用[J].中国药理学报,1989,10(4)：320-324.
[7]黄伟民,干以庆,任建英,等.黄连素治疗室性快速心律失常[J].中华心血管病杂志,1990,18(3)：155-156.
[8]张华,马兰香,杨星吕,等.葛根素对大鼠心肌细胞离子通道的影响[J].第四军医大学学报,2006,27(3)：249-251.
[9]罗助荣,盖晓波,郑卫星,等.葛根素对冠心病凝血纤溶活性和内皮功能的影响[J].中华实用中西医杂志,1999,12：1982-1983.
[10]于海波,徐长庆,单宏丽等.丹参酮Ⅱ-A对大鼠心室肌细胞膜钾电流的影响[J].哈尔滨医科大学学报,2002,36(2)：112-114.
[11]张毅.《心律失常中西医诊疗学》[M].中国中医药出版社,2001,9：660.
[12]周文斌,尹克春,陈力.心悸的中医辨证施治体会[J].广东医学,2005,26(7)：1001-1002.
[13]李晓,赵华.罗铃主任治疗心悸病的经验[J].云南中医中药杂志,2001,22(4)：4.
[14]赵华,李晓.罗铨主任运用生脉散为主辨治老年心悸的经验[J].云南中医中药杂志,2002,23(1)：4.
[15]张会珍,赵志国,张一听.许古民教授辨治心悸的临床经验[J].河北中医药学报,2006,21(4)：28-29.
[16]李宏.辨证治疗心律火常56例[J].河南中医,2004,24(12)：30.
[17]祝光礼.室性心律失常的分型辨治体会[J].浙江中医杂志,2002(12)：513-514.
[18]崔长琮.稳心颗粒对家兔左心室内、外膜电生理特性的影响[J].世界中医药,2007,2(5)：304-305.
[19]孙淑梅,陈清启,张雪娟.量子共振检测稳心颗粒与心律平治疗室性早搏100例临床研究[J].中西医结合心脑血管病杂志,2007,5(8)：681-682.
[20]李宁,吴相锋,马克娟等.参松养心胶囊对心室肌细胞钾通道的影响[J].疑难病杂志,2007,6(3)：133-137.
[21]黄从新.室性早搏和非持续性室性心动过速的临床意义.中华心律失常学杂志,2009,13(2)：121-123.
[22]Franze MR, Mechano. electric feedback in human heart[J]. Cardiovase Res,1996,32:15.
[23]王文广,吴杰,张存泰.心肌缺血时钙调蛋白信号转导途径的变化与对心脏的影响[J].中国心脏起搏与心电生理杂志,2005,19(4)：313.
[24]冯志强.同步记录无损伤心内、外膜心肌MAP对比研究[J].中国现代医生,2006,46(31)：49.
[25]罗廷福,文琼秀,游建林,龚武田.不同剂量辛伐他汀对慢性缺血性心脏病合并阵发性心房纤颤C反应蛋白及心电图的影响研究[J].实用心脑肺血管病杂志,2011,11(7)：1106-1108
[26]Gondo N,Kumagai K,Nakashima H,et al. Angiotensin-Ⅱ provokes cesium-induced ventricular tachyarrhythmias[J]. Cardiovasc-Res,2001,49(2): 381-390.
[27]袁桂清.果糖二磷酸钠对各种缺血缺氧损伤的保护和治疗效果显著[J].中华医学杂志,2002,82(14)：965
[28]罗小岚,赵水平,赵延恕.非器质性心脏病频发室性早搏的治疗策略[J].中国全科医学,2009,12(3)：426-7.
[29]Higham PD, Campbell RW.QT dispention [J].Br Heart J,1994 71(5):508-510.
[30]Day CP, Mc Comb JM, Campbell RWF.QT dispersion:an in-dieation of arrhythmia risk in patients with long QT intervals[J]. Br Heart J. 1990,63:342
[31]张春芳.QT离散度在急性心肌梗死中的临床意义,基层医学论坛2010年第14卷增刊：6-7.
[32]侯毅.高血压病患者QTd离散度与伴左心室肥厚及室性心律失常的关系.临床内科杂志,2002,19(2)：148-149.
[33]杨生春.扩张型心肌病患者QTd与室性心律失常关系.吉林医学.2000,21(1)：9-10.
[34]Davey p.QT interval and mortality from coronary artery disease.Prog Cardiovasc Dis,2000,42(5):359-384.
[35]Barr CS, Naas A, Freman M, et al. QT dispersion and suddenunexpected death in chronic heart failure.Lancet,1994,343-327.
[36]许智韬,王伟,田清等.高血压患者左室肥厚与QT离散度分析.心脏杂志.2001,13(3)：239-240.
[37]侯毅.高血压病患者QTc离散度与伴左室肥厚及恶性室性心律失常的关系.临床内科杂志,2002,19(2)：148-149.
[38]王影,张斌,孙东芸,等.高血压左室肥厚的QT离散度及左室Tei指数的研究.临床心电学杂志,2007,16(3)：195-197.
[39]何贵新,何劲松,莫云秋,等.急性心肌梗死静脉溶栓前后QT间期离散度观察.心电学杂,2005,24：148.
[40]戴明卜,赵冬梅,支忠继,等.阿替洛尔对扩张型心肌病QT间期离散度及室性心律失常的影响.临床荟萃,2009,24：1728-1730.
[41]朱晋坤,方颖,毛华,等.安体舒通对慢性充血性心力衰竭患者QT离散度的影响.临床心电学杂志,2006,15(4)：278-280.
[42]张丽环,徐佳俊,蔡丽萍,等.胺碘酮对恶性心律失常QT离散度的影响.临床心电学杂志,2007,16：115-116.
[43]Salloum F N, Yin C,Kukreja R C.Role of miRs in cardiac preconditioning[J]. J Cardiovasc Pharmacol,2010,56(6):581-588.
[44]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function [J]. Cell,2004,116:281-297
[45]Xu P, Vernooy SY,Guo M, et al. The drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism [J]. Curr Biol,2003,13:790-795.
[46]Kristen MN, Glen JW. MicroRNAs and cancer:past, present, and potential future [J]. Mol Cancer Ther,2008,7:3655-3660.
[47]DivakaranVMann DL.The emerging role of microRNAs in cardiac remode-ling and heart failure [J]. Circ Res,2008,103:1072-1083.
[48]Walker MD. Role of microRNA in pancreatic cells:where more is less[J]. Diabetes,2008,57:2567-2568.
[49]FlyntAS,LaiEC.Biological principles of microRNA-mediated regula-tion:shared themes amid diversity.Nat Rev Genet,2008,9:831-842.
[50]吴敏,韩召军miRNA研究方法进展[J].生物技术通讯,2005,16(5).
[51]陈军莹.niRNA在肿瘤研究中的进展[J].重庆医学,2010,39(22).
[52]Lagos-QuintanaM,R auhutR,Yalcin A,et al.Identification of tissue-specific microRNAs from mouse[J].Curr B iol,2002,12(9):735.
[53]HE L, Thomson J M,Hemann M T,et al. A microRNA polycistron as a potential human oncogene[J].Nature,2005,435(7043):828-833.
[54]Zhang B,Pan X,Cobb G P,et al.microRNAs as oncogenes and tumor suppressors[J].Dev Biol,2007,302(1):1-12.
[55]Esau C,Davis S,Murray S F,et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting[J].Cell Metab,2006,3 (2):87-98.
[56]Calin G A,Ferracin M,Cimmino A,et al. AmicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia[J].N Engl J Med,2005,353(17):1793-1801.
[57]Calin G A,Croce C M. MicroRNA signatures in human cancers[J].Nat Rev Cancer,2006,6(11):857-866.
[58]Osada H,Takahashi T. MicroRNAs in biological processes and carcinogenesis[J].Carcinogenesis,2007,28(1):2-12.
[59]Lu J,Getz G,Miska E A,et al. MicroRNA expression profiles classify human cancers [J].Nature,2005,435(7043):834-838.
[60]Calin G A,Croce C M. MicroRNAs and chromosomal abnormalities in cancer cells [J].Oncogene,2006,25(46):6202-6210.
[61]Lagos-QuintanaM,R auhutR,Yalcin A,et al.Identification of tissue-specific microRNAs from mouse[J].Curr B iol,2002,12(9):735.
[62]Van Rooij E,Sutherland LB, Qi X, et al.Control of stress-dependent cardiac growth and gene expression by a microRNA[J]. Science,2007,316: 575-579
[63]van Rooij E,Sutherland LB,Liu N,et al. A signature pattern of stress responsive microRNAs that can evoke cardiac hypertrophy and heart failure [J]. Proc Natl Acad Sci USA,2006,103:18255-18260.
[64]Saved D,Hong C,Chen IY,et al.MicroRNAs play an essential role in the development of cardiac Hypertrophy[J]. Circ Res,2007,100:416-424.
[65]Care A,Catalucci D,Felicetti F,et al.MicroRNA-133 controls cardiac hypertrophy [J]. Nat Med,2007,13:613-618.
[66]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure[J]. Circulation,2007,116: 258-267.
[67]Ikeda S,He A,Kong SW,et al. MicroRNA-1 negatively regulates expression of the Hypertrophv-associated calmodulin and Mef2a genes [J].Mol Cell Biol,2009,29:2193-2204.
[68]Ji R,Cheng Y,ue J,et al.MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation [J]. Circ Res,2007,100:1579-1588.
[69]Yang B,Lin H,Xiao J,et al. The muscle-specific microRNA miR-1 regulates cardiac arrhvthmogenic potential by targeting GJA1 and KCNJ2 [J]. Nat Med,2007,13:486-491.
[70]TangY,Zheng J,Sun Y,etal. MicroRNA-1 regulates cardiomyocyte apoptosis by targeting Bcl-2[J]. IntHeart J,2009,50(3):377-387.
[71]ChengY,Tan N,Yang J,A translational study of circulating cell-freemicroRNA-1 in acutemyocardial infarction[J]. Clin Sci(Lond),2010, 119(2):87-95.
[72]韦书永强,黄颖.体外反搏对AMI患者血浆微小RNA-1表达水平的影响[J].新医学,2011,42(10)：674-676.
[73]Terentyev D,Belevych A E,Terentyeva R,et al.miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2[J].Circ Res,2009 Feb 27; 104(4):514-21.
[74]Nicholson J K,Lindon J C,Holmes E.Metabonomics:understanding the metabolic responses of living systems to pathophysiological stimuli via muhi-variate statistical Analysis of biological NMR spectroscopic data.Xenobiotica.1999,29(11):1181.
[75]Gennan JB,Bauman DE,Burrrin DG,et al.Metabolomics in the opening decade of the 21st Century:building the roads to individualized heal th[J].Nutn,2004,134(10):2729.
[76]Kim HK,Choi YH, Erkelens C,et al. Metabolic fingerprinting of Ephedra species using 1H-NMR spectroscopy and principal component analysis. Chem Pharm Bull (Tokyo).2005,53(1):105-9.
[77]Nicholson J K,Holmes E. The Handbook of Metabonomics and Metablomics [J].Amsterdam:Elsevier,2007,6(11):112.
[78]Serge Rezzi,Ziad Ramadan,Francois-pierre J Martin,Laurent B Fay,Peter van B laderen,John C Lindon,Jeremy K Nicholson, Sunil Kochhar [J].Proteome Rues,2007,6(11):4469.
[79]Serge Rezzi,Ziad Ramadan Laurent B,Fay,Sunil Kochhar[J].Proteome Res,2007,6(2):513.
[80]Robertson D G,Reily M D,Baker Jd.Metabonomics in pharmaceutical discovery and development[J].Proteome Research,2007,6(2):526.
[81]Schnackenberg LK, Beger RD. Monitoring the health to disease continuum with global metabolic profiling and systems biology. Pharmacogenomics. 2006,7(7):1077-86.
[82]Kan CW, Fredlake CP, Doherty EA,Barron AE. DNA sequencing and geno-typeing in miniaturized electrophoresis systems. Electrophoresis,2004, 25(21-22):3564-88.
[83]MayrM, Chung Y, Mayr U, et al.Proteomic and metabolomic analyses of atherosclerotic vessels from apolipoprotein E-deficient mice reveal alterations in inflammation, oxidative stress, and energy metabolis-m.Arterioscle Thromb Vase Biol,2005,25:2135-2142.
[84]车庆明,黄新立,李艳梅,等.黄岑苷的药物代谢产物研究[J].中国中药杂志,2001,26(11)：768-769.
[85]汤喜兰,徐国良,李冰涛,等.花椒水提物给药大鼠.尿液代谢组学研究[J].中国实验方剂学杂志,2010,16(5)：127.
[86]张磊艺,杨景云,王立波.银杏叶提取物对糖尿病大鼠脂质代谢及肠道正常菌群的影响[J].中国微生态学杂志,2004,16(3)：1471.
[87]Rainy K,Serkova N J,Agarwal R. Silibinin feeding alters the metabolic profile in TRAMP prostatic tumors:1 H-NMRS-based metabolomics study[J].Cancer Res,2009,69(9):3731.
[88]陈文学,廖维靖,刘华,等.当归对人鼠缺血.性脑损伤代谢物的影响.中国康复医学杂志,2006,21(10)：879-882.
[89]赵剑宁,颜贤忠,彭双清.基于代谢组学技术研究中药关木通的肾毒性作用[J].世界科学技术一中医药现代化,2007,9(5)：54-59.
[90]樊夏雷,刘文英,王广基等.基于GC/TOF/MS的关木通肾毒性代谢组学研究[J].毒理学杂志,2007,21(4)：323.
[91]Chen Minjun.Ni Yan,Duan Hongquan,et al. Mass SPectronetrybased Metabqlic Profiling of Rat Urine Associated with General Toxicity Induced by Multiglycoside of Tripterygium Wilfordii Hook F[J].Chemical Research in Toxicology,2007:288-294.
[92]李建新,华京,何翠翠.中药毒性的代谢组学研究(Ⅰ)：雷公藤甲素的肾脏毒性[J].亚太传统医药,2007,3(7)：41-45.
[93]蒋宁,周文霞,张永祥.应用代谢组学方法研究比较六味及八味地黄汤的作用机制[J].中药药理与临床,2007,23(5)：451.
[94]罗和古.基于代谢组学的逍遥散方证相关的机理研究[D].北京：北京中医药学,2007.
[95]Xie B,Gong T,Gao R,et al. Development of rat urinary HPLC-UV profiling for metabonomic study on Liuwei Di-huang Pills[J].J Pham Biomed Anal, 2009,49(2):492-7.
[96]周明眉,刘平,贾伟.基于代谢网络变化的中药整体效应评价方法研究[J].世界科学技术-中医药现代化,2006,8(6)：113-119.
[97]Li L,Wang JN,Ren JX,et al.Metabonomics anlay-sis of the urine of rats with Qi deficiency and blood stasis syndrome based on NMR techniques [J]. Chinese Science Bulletin,2007,52(22):3068-3073.
[98]LU Yi-hong,HAO Hai-ping,WANG Guang-ji,et al.Matabolomics approach to the biochemical differentiation of traditional Chinese medicine syndrome types of hypertension.Chinese Journal of Clinical Pharmacology Therapeutics,2007,12 (10):1144-1150.
[99]郑丽红.脾气虚证唾液代谢组学的初步研究.广州中医药大学硕士学位论文,2007：5.
[100]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础.世界科学技术-中医药现代化,2009,11(1)：127-133.
[101]M in jun Chen L Liping Zhao Jianjiang; et al.M etabonomic study of aristelochic acid induced nephrotoxicity in rate[J].Journal of proteme Research,2006,5(4):995-1002.
[102]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究.中华中医药学刊,2009,27(6)：1267-1269.
[103]罗和古,丁杰,岳广欣,等.大鼠肝郁脾虚证的代谢组学研究.中西医结合学报,2007,5(3)：307-313.
[104]徐舒,陈合兵,李洪,等.“肝郁证”大鼠模型的建立及代谢组学的初步研究.中华中医药杂志,2009,24(6)：787-791
[105]刘树民,卢芳,王喜军,等.基与代谢组学的热病证候模型评价方法研究.中国药理学通报,2009,25(4)：549-551.
[106]简维雄,黄献乎,陈清华,等.基于气相色谱-质谱的大鼠心血瘀阻证血浆代谢组学研究.中华中医药学刊,2009,27(4)：796-798.
[107]Griffiths Jones S, Crocock RJ, Donnen SV, Baternam A, Enright AJ. rniRBase:microRNA sequences, Largets and gene nomenclature[J].Nucleic Acids Res,2006,34(supple 1):140-144.
[108]Prasad G N,Ramasamy S,Thomas J M, et al.Enhanced external counterpul-sation(EECP)therapy:current evidence for clinical practice and who will benefit? [J].Indian Heart J,2010,62 (4):296-302.
[109]徐倩,周亚滨.养心颗粒对冠心病快速型心律失常模型兔血浆一氧化氮及前列环素含量的影响[J].中西医结合心脑血管病杂志2008,1(1)：41.
[110]冯妍,周亚滨.养心颗粒对冠心病快速性心律失常模型心肌组织Ca2+-Mg2+-ATPase活性的影响[J].中医药信息.2008,25(2)：60-62.
[2]韩向东,陈长勋.苦参碱的心血管药理研究进展[J].中药新药与临床药理,2006,17(1)：73-75.
[3]王雪芳,刘艳明.苦参碱对低钙诱发豚鼠心律失常的电生理影响[J].中国中医基础医学杂志,2011,16(6)：633-639.
[4]陈彩霞,张宏艳.人参皂甙Re对异丙肾上腺素致家兔室性心律失常的保护作用[J].中国当代儿科杂志,2009,11(5)：384-388.
[5]周玉萍.《实用中西医结合心律失常学》[M].中医古籍出版社 2001：81-82.
[6]徐智,曹宏宇.小檗碱对犬心肌梗塞后自发性室颤的防治作用[J].中国药理学报,1989,10(4)：320-324.
[7]黄伟民,干以庆,任建英,等.黄连素治疗室性快速心律失常[J].中华心血管病杂志,1990,18(3)：155-156.
[8]张华,马兰香,杨星吕,等.葛根素对大鼠心肌细胞离子通道的影响[J].第四军医大学学报,2006,27(3)：249-251.
[9]罗助荣,盖晓波,郑卫星,等.葛根素对冠心病凝血纤溶活性和内皮功能的影响[J].中华实用中西医杂志,1999,12：1982-1983.
[10]于海波,徐长庆,单宏丽等.丹参酮Ⅱ-A对大鼠心室肌细胞膜钾电流的影响[J].哈尔滨医科大学学报,2002,36(2)：112-114.
[11]张毅.《心律失常中西医诊疗学》[M].中国中医药出版社,2001,9：660.
[12]周文斌,尹克春,陈力.心悸的中医辨证施治体会[J].广东医学,2005,26(7)：1001-1002.
[13]李晓,赵华.罗铃主任治疗心悸病的经验[J].云南中医中药杂志,2001,22(4)：4.
[14]赵华,李晓.罗铨主任运用生脉散为主辨治老年心悸的经验[J].云南中医中药杂志,2002,23(1)：4.
[15]张会珍,赵志国,张一听.许古民教授辨治心悸的临床经验[J].河北中医药学报,2006,21(4)：28-29.
[16]李宏.辨证治疗心律火常56例[J].河南中医,2004,24(12)：30.
[17]祝光礼.室性心律失常的分型辨治体会[J].浙江中医杂志,2002(12)：513-514.
[18]崔长琮.稳心颗粒对家兔左心室内、外膜电生理特性的影响[J].世界中医药,2007,2(5)：304-305.
[19]孙淑梅,陈清启,张雪娟.量子共振检测稳心颗粒与心律平治疗室性早搏100例临床研究[J].中西医结合心脑血管病杂志,2007,5(8)：681-682.
[20]李宁,吴相锋,马克娟等.参松养心胶囊对心室肌细胞钾通道的影响[J].疑难病杂志,2007,6(3)：133-137.
[21]黄从新.室性早搏和非持续性室性心动过速的临床意义.中华心律失常学杂志,2009,13(2)：121-123.
[22]Franze MR, Mechano. electric feedback in human heart[J]. Cardiovase Res,1996,32:15.
[23]王文广,吴杰,张存泰.心肌缺血时钙调蛋白信号转导途径的变化与对心脏的影响[J].中国心脏起搏与心电生理杂志,2005,19(4)：313.
[24]冯志强.同步记录无损伤心内、外膜心肌MAP对比研究[J].中国现代医生,2006,46(31)：49.
[25]罗廷福,文琼秀,游建林,龚武田.不同剂量辛伐他汀对慢性缺血性心脏病合并阵发性心房纤颤C反应蛋白及心电图的影响研究[J].实用心脑肺血管病杂志,2011,11(7)：1106-1108
[26]Gondo N,Kumagai K,Nakashima H,et al. Angiotensin-Ⅱ provokes cesium-induced ventricular tachyarrhythmias[J]. Cardiovasc-Res,2001,49(2): 381-390.
[27]袁桂清.果糖二磷酸钠对各种缺血缺氧损伤的保护和治疗效果显著[J].中华医学杂志,2002,82(14)：965
[28]罗小岚,赵水平,赵延恕.非器质性心脏病频发室性早搏的治疗策略[J].中国全科医学,2009,12(3)：426-7.
[29]Higham PD, Campbell RW.QT dispention [J].Br Heart J,1994 71(5):508-510.
[30]Day CP, Mc Comb JM, Campbell RWF.QT dispersion:an in-dieation of arrhythmia risk in patients with long QT intervals[J]. Br Heart J. 1990,63:342
[31]张春芳.QT离散度在急性心肌梗死中的临床意义,基层医学论坛2010年第14卷增刊：6-7.
[32]侯毅.高血压病患者QTd离散度与伴左心室肥厚及室性心律失常的关系.临床内科杂志,2002,19(2)：148-149.
[33]杨生春.扩张型心肌病患者QTd与室性心律失常关系.吉林医学.2000,21(1)：9-10.
[34]Davey p.QT interval and mortality from coronary artery disease.Prog Cardiovasc Dis,2000,42(5):359-384.
[35]Barr CS, Naas A, Freman M, et al. QT dispersion and suddenunexpected death in chronic heart failure.Lancet,1994,343-327.
[36]许智韬,王伟,田清等.高血压患者左室肥厚与QT离散度分析.心脏杂志.2001,13(3)：239-240.
[37]侯毅.高血压病患者QTc离散度与伴左室肥厚及恶性室性心律失常的关系.临床内科杂志,2002,19(2)：148-149.
[38]王影,张斌,孙东芸,等.高血压左室肥厚的QT离散度及左室Tei指数的研究.临床心电学杂志,2007,16(3)：195-197.
[39]何贵新,何劲松,莫云秋,等.急性心肌梗死静脉溶栓前后QT间期离散度观察.心电学杂,2005,24：148.
[40]戴明卜,赵冬梅,支忠继,等.阿替洛尔对扩张型心肌病QT间期离散度及室性心律失常的影响.临床荟萃,2009,24：1728-1730.
[41]朱晋坤,方颖,毛华,等.安体舒通对慢性充血性心力衰竭患者QT离散度的影响.临床心电学杂志,2006,15(4)：278-280.
[42]张丽环,徐佳俊,蔡丽萍,等.胺碘酮对恶性心律失常QT离散度的影响.临床心电学杂志,2007,16：115-116.
[43]Salloum F N, Yin C,Kukreja R C.Role of miRs in cardiac preconditioning[J]. J Cardiovasc Pharmacol,2010,56(6):581-588.
[44]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function [J]. Cell,2004,116:281-297
[45]Xu P, Vernooy SY,Guo M, et al. The drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism [J]. Curr Biol,2003,13:790-795.
[46]Kristen MN, Glen JW. MicroRNAs and cancer:past, present, and potential future [J]. Mol Cancer Ther,2008,7:3655-3660.
[47]DivakaranVMann DL.The emerging role of microRNAs in cardiac remode-ling and heart failure [J]. Circ Res,2008,103:1072-1083.
[48]Walker MD. Role of microRNA in pancreatic cells:where more is less[J]. Diabetes,2008,57:2567-2568.
[49]FlyntAS,LaiEC.Biological principles of microRNA-mediated regula-tion:shared themes amid diversity.Nat Rev Genet,2008,9:831-842.
[50]吴敏,韩召军miRNA研究方法进展[J].生物技术通讯,2005,16(5).
[51]陈军莹.niRNA在肿瘤研究中的进展[J].重庆医学,2010,39(22).
[52]Lagos-QuintanaM,R auhutR,Yalcin A,et al.Identification of tissue-specific microRNAs from mouse[J].Curr B iol,2002,12(9):735.
[53]HE L, Thomson J M,Hemann M T,et al. A microRNA polycistron as a potential human oncogene[J].Nature,2005,435(7043):828-833.
[54]Zhang B,Pan X,Cobb G P,et al.microRNAs as oncogenes and tumor suppressors[J].Dev Biol,2007,302(1):1-12.
[55]Esau C,Davis S,Murray S F,et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting[J].Cell Metab,2006,3 (2):87-98.
[56]Calin G A,Ferracin M,Cimmino A,et al. AmicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia[J].N Engl J Med,2005,353(17):1793-1801.
[57]Calin G A,Croce C M. MicroRNA signatures in human cancers[J].Nat Rev Cancer,2006,6(11):857-866.
[58]Osada H,Takahashi T. MicroRNAs in biological processes and carcinogenesis[J].Carcinogenesis,2007,28(1):2-12.
[59]Lu J,Getz G,Miska E A,et al. MicroRNA expression profiles classify human cancers [J].Nature,2005,435(7043):834-838.
[60]Calin G A,Croce C M. MicroRNAs and chromosomal abnormalities in cancer cells [J].Oncogene,2006,25(46):6202-6210.
[61]Lagos-QuintanaM,R auhutR,Yalcin A,et al.Identification of tissue-specific microRNAs from mouse[J].Curr B iol,2002,12(9):735.
[62]Van Rooij E,Sutherland LB, Qi X, et al.Control of stress-dependent cardiac growth and gene expression by a microRNA[J]. Science,2007,316: 575-579
[63]van Rooij E,Sutherland LB,Liu N,et al. A signature pattern of stress responsive microRNAs that can evoke cardiac hypertrophy and heart failure [J]. Proc Natl Acad Sci USA,2006,103:18255-18260.
[64]Saved D,Hong C,Chen IY,et al.MicroRNAs play an essential role in the development of cardiac Hypertrophy[J]. Circ Res,2007,100:416-424.
[65]Care A,Catalucci D,Felicetti F,et al.MicroRNA-133 controls cardiac hypertrophy [J]. Nat Med,2007,13:613-618.
[66]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure[J]. Circulation,2007,116: 258-267.
[67]Ikeda S,He A,Kong SW,et al. MicroRNA-1 negatively regulates expression of the Hypertrophv-associated calmodulin and Mef2a genes [J].Mol Cell Biol,2009,29:2193-2204.
[68]Ji R,Cheng Y,ue J,et al.MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation [J]. Circ Res,2007,100:1579-1588.
[69]Yang B,Lin H,Xiao J,et al. The muscle-specific microRNA miR-1 regulates cardiac arrhvthmogenic potential by targeting GJA1 and KCNJ2 [J]. Nat Med,2007,13:486-491.
[70]TangY,Zheng J,Sun Y,etal. MicroRNA-1 regulates cardiomyocyte apoptosis by targeting Bcl-2[J]. IntHeart J,2009,50(3):377-387.
[71]ChengY,Tan N,Yang J,A translational study of circulating cell-freemicroRNA-1 in acutemyocardial infarction[J]. Clin Sci(Lond),2010, 119(2):87-95.
[72]韦书永强,黄颖.体外反搏对AMI患者血浆微小RNA-1表达水平的影响[J].新医学,2011,42(10)：674-676.
[73]Terentyev D,Belevych A E,Terentyeva R,et al.miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2[J].Circ Res,2009 Feb 27; 104(4):514-21.
[74]Nicholson J K,Lindon J C,Holmes E.Metabonomics:understanding the metabolic responses of living systems to pathophysiological stimuli via muhi-variate statistical Analysis of biological NMR spectroscopic data.Xenobiotica.1999,29(11):1181.
[75]Gennan JB,Bauman DE,Burrrin DG,et al.Metabolomics in the opening decade of the 21st Century:building the roads to individualized heal th[J].Nutn,2004,134(10):2729.
[76]Kim HK,Choi YH, Erkelens C,et al. Metabolic fingerprinting of Ephedra species using 1H-NMR spectroscopy and principal component analysis. Chem Pharm Bull (Tokyo).2005,53(1):105-9.
[77]Nicholson J K,Holmes E. The Handbook of Metabonomics and Metablomics [J].Amsterdam:Elsevier,2007,6(11):112.
[78]Serge Rezzi,Ziad Ramadan,Francois-pierre J Martin,Laurent B Fay,Peter van B laderen,John C Lindon,Jeremy K Nicholson, Sunil Kochhar [J].Proteome Rues,2007,6(11):4469.
[79]Serge Rezzi,Ziad Ramadan Laurent B,Fay,Sunil Kochhar[J].Proteome Res,2007,6(2):513.
[80]Robertson D G,Reily M D,Baker Jd.Metabonomics in pharmaceutical discovery and development[J].Proteome Research,2007,6(2):526.
[81]Schnackenberg LK, Beger RD. Monitoring the health to disease continuum with global metabolic profiling and systems biology. Pharmacogenomics. 2006,7(7):1077-86.
[82]Kan CW, Fredlake CP, Doherty EA,Barron AE. DNA sequencing and geno-typeing in miniaturized electrophoresis systems. Electrophoresis,2004, 25(21-22):3564-88.
[83]MayrM, Chung Y, Mayr U, et al.Proteomic and metabolomic analyses of atherosclerotic vessels from apolipoprotein E-deficient mice reveal alterations in inflammation, oxidative stress, and energy metabolis-m.Arterioscle Thromb Vase Biol,2005,25:2135-2142.
[84]车庆明,黄新立,李艳梅,等.黄岑苷的药物代谢产物研究[J].中国中药杂志,2001,26(11)：768-769.
[85]汤喜兰,徐国良,李冰涛,等.花椒水提物给药大鼠.尿液代谢组学研究[J].中国实验方剂学杂志,2010,16(5)：127.
[86]张磊艺,杨景云,王立波.银杏叶提取物对糖尿病大鼠脂质代谢及肠道正常菌群的影响[J].中国微生态学杂志,2004,16(3)：1471.
[87]Rainy K,Serkova N J,Agarwal R. Silibinin feeding alters the metabolic profile in TRAMP prostatic tumors:1 H-NMRS-based metabolomics study[J].Cancer Res,2009,69(9):3731.
[88]陈文学,廖维靖,刘华,等.当归对人鼠缺血.性脑损伤代谢物的影响.中国康复医学杂志,2006,21(10)：879-882.
[89]赵剑宁,颜贤忠,彭双清.基于代谢组学技术研究中药关木通的肾毒性作用[J].世界科学技术一中医药现代化,2007,9(5)：54-59.
[90]樊夏雷,刘文英,王广基等.基于GC/TOF/MS的关木通肾毒性代谢组学研究[J].毒理学杂志,2007,21(4)：323.
[91]Chen Minjun.Ni Yan,Duan Hongquan,et al. Mass SPectronetrybased Metabqlic Profiling of Rat Urine Associated with General Toxicity Induced by Multiglycoside of Tripterygium Wilfordii Hook F[J].Chemical Research in Toxicology,2007:288-294.
[92]李建新,华京,何翠翠.中药毒性的代谢组学研究(Ⅰ)：雷公藤甲素的肾脏毒性[J].亚太传统医药,2007,3(7)：41-45.
[93]蒋宁,周文霞,张永祥.应用代谢组学方法研究比较六味及八味地黄汤的作用机制[J].中药药理与临床,2007,23(5)：451.
[94]罗和古.基于代谢组学的逍遥散方证相关的机理研究[D].北京：北京中医药学,2007.
[95]Xie B,Gong T,Gao R,et al. Development of rat urinary HPLC-UV profiling for metabonomic study on Liuwei Di-huang Pills[J].J Pham Biomed Anal, 2009,49(2):492-7.
[96]周明眉,刘平,贾伟.基于代谢网络变化的中药整体效应评价方法研究[J].世界科学技术-中医药现代化,2006,8(6)：113-119.
[97]Li L,Wang JN,Ren JX,et al.Metabonomics anlay-sis of the urine of rats with Qi deficiency and blood stasis syndrome based on NMR techniques [J]. Chinese Science Bulletin,2007,52(22):3068-3073.
[98]LU Yi-hong,HAO Hai-ping,WANG Guang-ji,et al.Matabolomics approach to the biochemical differentiation of traditional Chinese medicine syndrome types of hypertension.Chinese Journal of Clinical Pharmacology Therapeutics,2007,12 (10):1144-1150.
[99]郑丽红.脾气虚证唾液代谢组学的初步研究.广州中医药大学硕士学位论文,2007：5.
[100]王广基,阿基业,严蓓,等.代谢组学研究冠心病中医分型的体内物质基础.世界科学技术-中医药现代化,2009,11(1)：127-133.
[101]M in jun Chen L Liping Zhao Jianjiang; et al.M etabonomic study of aristelochic acid induced nephrotoxicity in rate[J].Journal of proteme Research,2006,5(4):995-1002.
[102]朱萱萱,王广基,阿基业,等.冠心病中医辨证分型的代谢组学研究.中华中医药学刊,2009,27(6)：1267-1269.
[103]罗和古,丁杰,岳广欣,等.大鼠肝郁脾虚证的代谢组学研究.中西医结合学报,2007,5(3)：307-313.
[104]徐舒,陈合兵,李洪,等.“肝郁证”大鼠模型的建立及代谢组学的初步研究.中华中医药杂志,2009,24(6)：787-791
[105]刘树民,卢芳,王喜军,等.基与代谢组学的热病证候模型评价方法研究.中国药理学通报,2009,25(4)：549-551.
[106]简维雄,黄献乎,陈清华,等.基于气相色谱-质谱的大鼠心血瘀阻证血浆代谢组学研究.中华中医药学刊,2009,27(4)：796-798.
[107]Griffiths Jones S, Crocock RJ, Donnen SV, Baternam A, Enright AJ. rniRBase:microRNA sequences, Largets and gene nomenclature[J].Nucleic Acids Res,2006,34(supple 1):140-144.
[108]Prasad G N,Ramasamy S,Thomas J M, et al.Enhanced external counterpul-sation(EECP)therapy:current evidence for clinical practice and who will benefit? [J].Indian Heart J,2010,62 (4):296-302.
[109]徐倩,周亚滨.养心颗粒对冠心病快速型心律失常模型兔血浆一氧化氮及前列环素含量的影响[J].中西医结合心脑血管病杂志2008,1(1)：41.
[110]冯妍,周亚滨.养心颗粒对冠心病快速性心律失常模型心肌组织Ca2+-Mg2+-ATPase活性的影响[J].中医药信息.2008,25(2)：60-62.