同型半胱氨酸与急性脑梗死的关系研究
|
摘要
目的研究同型半胱氨酸与急性脑梗死的关系;探讨叶酸、甲钴胺及维生素B6的应用对急性脑梗死伴高同型半胱氨酸血症(HHcy)的影响。
方法系统地收集2007年1月至2008年12月我院神经科首发急性脑梗死住院患者544例,所有患者均经头颅CT/MRI确诊为急性脑梗死;对其按照性别、叶酸水平、tHcy水平及TOAST分型进行系统分层研究;将Hcy与叶酸、维生素B12、超敏C反应蛋白及血脂、肌酐等行相关分析及多元线性回归分析:TOAST 3型中具有颞窗而获得大脑中动脉血流参数的病人有192例,对Hcy及脑血管危险因素与大脑中动脉血流动力学参数的关系进行分析。急性脑梗死伴HHcy患者被随机分为治疗组和对照组,两组给予急性脑梗死的标准治疗,治疗组在标准治疗的基础上给予叶酸、甲钴胺和维生素B6口服3个月。分别检测发病72小时内、2周和3个月时的的tHcy、叶酸和维生素B12;终点事件为两组神经功能评分、生活指数及卒中或心血管事件的发生。
结果544例急性脑梗死患者按性别分组后,两组间tHcy水平无明显差异;当tHcy＞15umol/l时,患者叶酸水平和维生素B12较低;按TOAST分型后,在1型和2型脑梗死中tHcy水平明显升高。而且tHcy水平与维生素B12、叶酸呈负相关,与肌酐呈正相关;Hcy水平与颈总动脉内膜厚度无明显相关;TOAST 3型脑梗死患者tHcy水平与MCA血流动力学参数的无明显相关性。168例急性脑梗死伴HHcy患者,治疗组应用叶酸、甲钴胺后tHcy水平明显下降;治疗组和对照组在恢复期两组tHcy水平均有下降;治疗组和对照组在三个月时的NIHSS、mRS分级及BI指数无差异,两组卒中复发率及血管性事件的发生率无明显差异。
结论tHcy与血叶酸、维生素B12及肌酐相关;TOAST 1型和2型脑梗死急性期Hcy水平升高明显;Hcy与脑梗死患者的颈动脉内膜厚度及大脑中动脉的血流动力学无明显相关;叶酸和甲钴胺及维生素B6能够降低tHcy水平,但不能改善急性脑梗死的预后。
Objective To investigate the relationship between homocysteine and acute cerebral infarction, and to explore the effects of treatment of folate,methylcobalamin and vitamin B6 in the acute cerebral infarction patients with hyperhomocysteinemia(HHcy).
Methods 544 acute cerebral infarction patients identified by brain MRI/CT were collected between January 2007 to December 2008.The patients were stratified according with their gender,serum folate,tHcy and TOAST respectively;correlation analysis and multiple linear regression analysis were used to determine the relationship between tHcy and HsCRP,serum lipid,folate,vitamin B12,creatinine,et al.There were 192 of TOAST 3 CI patients with adequate temporal acoustical window to analysis the relationship of MCA blood flow parameters and Hcy, vascular risk factors.168 acute cerebral infarction patients with HHcy were randomized divided into the treatment group and control group,all the patients in this two group were treated with the standard treatment program of cerebral infarction;the treatment group,in additional was also treated with folic acid,mecobalamin and vitamin B6 at least three month,the level of plasma Hcy,folate,vitamin B12 in this two group were inspected in two weeks and 3 months.The primary efficacy end points included NIHSS,BI,mRS and recurrence rate of stroke or vascular event at 3 month,。
Results:No significant differences in the level of tHcy was found between the two groups divided by sex;the folic acid and vitamin B12 levels were significantly lower in patients with the level of tHcy＞15μmol/l.level of tHcy was negatively correlated with folate,vitamin B12,and positively correlated with creatinine were found;level of were not correlated with IMT in patients of cerebral infaction.There were higher tHcy levels in patients of TOAST 1 and 2.There was no relationship identified between the level of tHcy and the middle cerebral artery hemodynamics in patients of TOAST 3;the level of tHcy in 168 patients with the level of tHcy＞15μmol/L were decreased after 3 month.But more decreased were observed in patients of the treatment group.There were no difference in the Score of NIHSS,BI index and mRS in patients between the treatment and control group after 3 months.
Conclusion:level of tHcy was correlated with folate,vitamin B12 and creatinine;higher tHcy level was observed in patients of TOAST 1 and 2;there was no relationship were found between the tHcy and the carotid intima-media thickness,and the hemodynamics of the brain MCA.Obviously effect of treatment of folate and vitamin B12 in decrease tHcy were found in patients of treatment group,but there was no difference were observed in the prognosis in this two groups.
方法系统地收集2007年1月至2008年12月我院神经科首发急性脑梗死住院患者544例,所有患者均经头颅CT/MRI确诊为急性脑梗死;对其按照性别、叶酸水平、tHcy水平及TOAST分型进行系统分层研究;将Hcy与叶酸、维生素B12、超敏C反应蛋白及血脂、肌酐等行相关分析及多元线性回归分析:TOAST 3型中具有颞窗而获得大脑中动脉血流参数的病人有192例,对Hcy及脑血管危险因素与大脑中动脉血流动力学参数的关系进行分析。急性脑梗死伴HHcy患者被随机分为治疗组和对照组,两组给予急性脑梗死的标准治疗,治疗组在标准治疗的基础上给予叶酸、甲钴胺和维生素B6口服3个月。分别检测发病72小时内、2周和3个月时的的tHcy、叶酸和维生素B12;终点事件为两组神经功能评分、生活指数及卒中或心血管事件的发生。
结果544例急性脑梗死患者按性别分组后,两组间tHcy水平无明显差异;当tHcy＞15umol/l时,患者叶酸水平和维生素B12较低;按TOAST分型后,在1型和2型脑梗死中tHcy水平明显升高。而且tHcy水平与维生素B12、叶酸呈负相关,与肌酐呈正相关;Hcy水平与颈总动脉内膜厚度无明显相关;TOAST 3型脑梗死患者tHcy水平与MCA血流动力学参数的无明显相关性。168例急性脑梗死伴HHcy患者,治疗组应用叶酸、甲钴胺后tHcy水平明显下降;治疗组和对照组在恢复期两组tHcy水平均有下降;治疗组和对照组在三个月时的NIHSS、mRS分级及BI指数无差异,两组卒中复发率及血管性事件的发生率无明显差异。
结论tHcy与血叶酸、维生素B12及肌酐相关;TOAST 1型和2型脑梗死急性期Hcy水平升高明显;Hcy与脑梗死患者的颈动脉内膜厚度及大脑中动脉的血流动力学无明显相关;叶酸和甲钴胺及维生素B6能够降低tHcy水平,但不能改善急性脑梗死的预后。
Objective To investigate the relationship between homocysteine and acute cerebral infarction, and to explore the effects of treatment of folate,methylcobalamin and vitamin B6 in the acute cerebral infarction patients with hyperhomocysteinemia(HHcy).
Methods 544 acute cerebral infarction patients identified by brain MRI/CT were collected between January 2007 to December 2008.The patients were stratified according with their gender,serum folate,tHcy and TOAST respectively;correlation analysis and multiple linear regression analysis were used to determine the relationship between tHcy and HsCRP,serum lipid,folate,vitamin B12,creatinine,et al.There were 192 of TOAST 3 CI patients with adequate temporal acoustical window to analysis the relationship of MCA blood flow parameters and Hcy, vascular risk factors.168 acute cerebral infarction patients with HHcy were randomized divided into the treatment group and control group,all the patients in this two group were treated with the standard treatment program of cerebral infarction;the treatment group,in additional was also treated with folic acid,mecobalamin and vitamin B6 at least three month,the level of plasma Hcy,folate,vitamin B12 in this two group were inspected in two weeks and 3 months.The primary efficacy end points included NIHSS,BI,mRS and recurrence rate of stroke or vascular event at 3 month,。
Results:No significant differences in the level of tHcy was found between the two groups divided by sex;the folic acid and vitamin B12 levels were significantly lower in patients with the level of tHcy＞15μmol/l.level of tHcy was negatively correlated with folate,vitamin B12,and positively correlated with creatinine were found;level of were not correlated with IMT in patients of cerebral infaction.There were higher tHcy levels in patients of TOAST 1 and 2.There was no relationship identified between the level of tHcy and the middle cerebral artery hemodynamics in patients of TOAST 3;the level of tHcy in 168 patients with the level of tHcy＞15μmol/L were decreased after 3 month.But more decreased were observed in patients of the treatment group.There were no difference in the Score of NIHSS,BI index and mRS in patients between the treatment and control group after 3 months.
Conclusion:level of tHcy was correlated with folate,vitamin B12 and creatinine;higher tHcy level was observed in patients of TOAST 1 and 2;there was no relationship were found between the tHcy and the carotid intima-media thickness,and the hemodynamics of the brain MCA.Obviously effect of treatment of folate and vitamin B12 in decrease tHcy were found in patients of treatment group,but there was no difference were observed in the prognosis in this two groups.
引文
[l]Grand Challenges to reduce stroke[J].The Lancet Neurology,2008,7:1.
[2]Lonn E,Yusuf S,Arnold MJ,et al.Homocysteine lowering with acid and B vitamins in vascular disease[J].N Engl J Med,2006,354:1567-72.
[3]Bonaa KH,Njolstad I,Uelan PM,et al.Homocysteine lowering and cardiovascular events after acute myocardial infarction[J].N Engl J Med,2006,354:1578-88.
[4]SpenceJD,HowardVJ,ChamblessLE,et al.Vitamin Intervention for Stroke Prevention (VISP)trialrational-and-design[J].Neuroepidemiology,2001,20:16-25.
[5]Hao L,Ma J,et al.High prevalence of hyperhomocysteinemia in Chinese adults is associated with low folate,vitamin B12,and vitamin B6 status[J].J Nutr,2007,137:407-413.
[6]RogersJD,Sanchez-SaffonA,Frol B,Diaz-Arrastia R.Elevated plasma homocysteine levels in patients treated with ldopa[J].Arch Neurol 2003,60:59-64.
[7]Stanger 0,Weger M.Interactions of homoeysteine,nitric oxide,folate and radicals in the progressivdy dma endothdium[J].Clin Chem Lab Med,2003,41(1-1):1444-1454.
[8]Kartal Ozer N,Neigs Y,Aytan N.Molecularmechanisms of cholesterol Or homocy steine effect in the development of atheroselerosis:role of vitaminE [J].Bio-factors,2003,19(1-2):63-70.
[9]Beltowiski J.Protein homocysteinylation:a new mechanism of atherogenesis[J]?Postepy Hig Med Dosw,2005,59:392-404.
[10]Upchuch GR,Welch GN,Fabian AJ,et al.Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase[J].J Bio Chem,1997,272:17012-17017.
[11]Ling Q,Hajjar KA.inhibition of endothielial cell thromboresistance by homocy-steine[J],J Nutr,2000,130:373-376.
[12]Lee Me,Wang H.Homocysteine and hypomethylation.A novel link to vascular disease [J].Trends Cardiovasc Med,1999,9:49-54.
[13]VirginaJ.Howard,MSPH;ElizabethG.Sides,MED,et al.Changes in Plasema Homocye-steine in the Acute Phase After Stroke[J].Stroke,2002;33,473-478
[14]Lindgren A,Brattstrom L,Norving B,Hultberg B,Andersson A,Johansson BB.Plasma homocysteine in the acute and convalescentphases after stroke[J].Stroke.1995,26:795 - 800.
[15]Annthony S Wierzbicki.Homocysteine and cardiovascular disease:a review of the evidence[J].Diabetes Vasc Disease Rec,2007,4:143-149.
[16]F.Perini.E,Galloni.l,Bolgan · G,et al.Elevated plasma homocysteine in acute stroke was not associated with severity and outcome:stronger association with small artery disease[J].Neurol Sci,2005,26:310-318.
[17]乔兴茂,王雷,姜文洲,等.C反应蛋白与缺血性脑卒中的相关性研究[J].实用临床医学,2005,6:20-21.
[18]Aysen Akalin,Ozkan Alatas and Omer Colak.Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type2diabetic patients[J].European Journal of Endocrinology.2008,158:47-52.
[19]Chambers JC,Obeid OA,Kooner JS.Physiological increments in plasma homocystei -ne ind -uce vascular endothelial dysfunction in nor-mal human subjects[J].Arterioscler Thromb Vasc Biol,1999,19(12):2922-2927.
[20]Coull BM,Malionow MR,Beamer N,et al.Elevated plasma homocysteine concentrat -ion as a possible independent risk factor for stroke[J].Stroke,1990,21:57-2-576.
[21]Boysen G,Brander T,Christensen H,et al,Homocysteine and risk of recurrent stroke[J].Stroke,2003,34(5):1258-1261.
[22]Ueland PM,Nygard O,Vollset SE,et al.The.Hordaland Homocysteine Studies[J].Lipids.2001,36:33-39.
[23]J David Spence.Homocysteine-lowering therapy:a role in stroke prevention[J].Lancet Neurol,2007,6:830-838.
[24]Ebbesen LS.Hyperhomocysteinemia,thrombosis and vascular biology[J].Cell Mol Biol,2004,50:917-30.
[25]Howard VJ,Sides EG,Newman GC,et al.Changes in plasma homocyst(e) ine in the acute phase after stroke[J].Stroke,2002,33:473-78.
[26]AmarencoP,Lavallee P,Touboul PJ.Statins and stroke prevention[J].Cerebrovasc Dis,2004,17:81-88.
[27]Annemaris D.Wijnhoud,Peter J.Koudstaal,Diederik W.J.Dippel,Relations of Transcranial blood flow dopper parameters with major vascular risk factors study in patients with recent TIA or Nodisabling Ischemic Stroke[J].Journal of Clinical Ultrasound,2006,34(2):70-76.
[28]Homcysteine Studies Collaboration.Homocysteine and risk of ischemic heart disease and stroke:a meta-analysis[J].JAMA,2002,288(16):2015-2022.
[29]Stanger 0,Fowler B,Herimann W.Folate therapy and in-stent restenosis.N Engl J Med [J],2004,351(12):1259-1260.
[30]GraceY.-H.Ho,ohn W.Eikelboom,Graeme J.Hankey,etal.Methyleneterahydrofolate Reduct-ase Polymorphisms and Homocysteine-Lowering Effect of Vitamin Therapy in Singaporean Stroke Patients[J].Stroke,2006,37:456-400.
[31]Loscalzo J.Homocysteine trialsclear outcomes for comlex reason[J].N Engl Med,2006,354 (15):1629-1632.
[32]Bazzano LA;Reynoldx K;Holder KN.Effect of folic acid supplementation on risk of cardiovascular diseases:a meta-analysis of randomized controlled trials[J].JAMA,2006,296(22):2720-2726.
[33]MRC Vitamin Research Group.Prevention of neural tube defects:results of the Medical Research Council Vitamin Study[J].Lancet,1991,338:131-137.
[34]Yang Q,Botto LD,Erickson JD,Berry RJ,Sambell C,Johansen H,Friedman JM:improvement in stroke mortality in Canada and the united states,1990 to 2002[J].Circulation,2006,113:1335-1343.
[35]Wang X,Qin X,Demirtas H,Li J,Mao G,Huo Y,Sun N,Liu L,Xu X:Efficacy of folic acid supplementation in stroke prevention:A meta-analysis [J].Lancet,2007,369:1876-1882.
[36]Wald D,Law M,Morris J:Homocysteine and cardiovascular disease:Evidence on causality from a meta-analysis[J].BMJ,2002,325:1202.
[37]Toole J,Malinow M,Chambless L,et al.Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke,myocardial infarction,and death:The vitamin intervention for stroke prevention (visp)randomized controlled trial[J].JAMA,2004,291:565-575.
[38]Bazzano L,Reynolds K,Holder K,et al.Effect of folic acid supplementation on risk of cardiovascular diseases:A meta-analysis of randomized controlled-trials[J].JAMA,2006,296:2720-2726.
[39]VITAT0PS Trial Study Group:The vitatops (vitamins to prevent stroke)trial:Rationale and design of an international,large,simple,randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke[J].Cerebrovasc Dis,2002,13:120-126.
[40]Eva Lonn.Homocysteine in the prevention of ischemic heart disease,stroke and venous thro-mboembolism:therapeutic target or just another distraction? Curr Opin Hematol [J].2007,14:481-487.
[41]Haynes WG.Hyperhomocysteinaemia,vascular function and atherosclerosis effects of vitamins[J].Cardiovasc Drugs Ther,2002,16:391-399.
[42]Baik HW,Russell RM.Vitamin B12 deficiency in the elderly[J].Annu Rev Nutr,1999,19:357-377.
[43]Chanson A,Cardinault N,Rock E.Decreased plasma folate concentration in young and elderly healthy subjects after a shortterm supplementation with isotretoin [J].J Eur AcadDermatol Venereol,2008,22(1):94-100.
[44]Lindsay H.Allen.Folate and Vitamin B12 Status in the Americas[J].Nutrition Reviews,2004,62(6):29-33.
[45]Forges T,Monnier Barbarino P,Alberto JM.Impact of folate and homocysteine metabolism on human reproductive health[J].Hum Reprod Update,2007,13(3)225-238.
[46]Van Oijen MG,Laheij RJ,Janson JB,et al.The predictive value of vitamin B12 concentrations and hyperhomocysteienaemia for cardiovascular disease[J].Neth Heart J,2007,15(6):291-294.
[47]Koseoglu E;Karaman Y;Relations between homocysteine,folate and vitamin B12 in vascular dementia and in Alzheimer disease[J].Clin Biochem.2007,40(12):859-863.
[48]GarciaG;Trejos J;Restrepo B;Landazuri P;Homocysteine,folate and vitamin B12 in Colombian patients with coronary disease[J].Arq Bras Cardiol,2007,89(2):71-76.
[49]Garibotto G,Sofia A,Valli A,et al.Causes of hyperhomocysteinemia in patients with chronic kidney diseases[J].Semin Nephrol,2006,26(1):3-7.
[50]Bostom A;Brosnan JT;Hall B;Nadeau MR;Selhub J.Net uptake of plasma homocysteine by the rat kidney in vivo[J].Atherosclerosis,1995,116(1):59-62.
[51]Ubbink JR,Vermaak WJ,van der Merwe A,et al.Vitamin B-12,vitaminB-6,and folate nutritional status in men with hyperhomocysteinemia [J].Am J Clin Nutr,1993,57:47.
[52]Finkelstein JD.The metabolism of homocysteine:pathways and regulation[J].Eur J Pediatrics.1998,15(2):40-44.
[53]MC Quilian BM,BeibyJP,Nidorf M,et al.Hyperhomocysteinemia but not the C677T mutation of methylenetetro hydrofolate reductase is an independent risk determinant of carotid wall thickening[J],Circulation,1999,99(9):2383—2388.
[54]Aminbakhsh A,Mancini GB.Carotid intima-media thickness measuremen-ts:what defines an abnormality? A systematic review[J].Clin Invest Med,1999,22:149-57.
[55]Wang H,Fan D,Zhang H,et al.Serum level of homocysteine is correlated to carotid artery atherosclerosis in Chinese with ischemic stroke[J].Neurol Res,2006,28(1):25-30.
[56]Nakhai Pour HR;Grobbee DE;Bots ML;MullerM;van der Schouw YT;Julius Center for Health Sciences and Primary Care,University Medical Center Utrecht,Utrecht,The Netherlands[J].J Hum Hypertens,2007,21 (12):942-948.
[57]Linnebank M,MoskauS,Farmand S,et al.Homocysteine and carotid intima-media thickness in a german population:lack of clinical relevance[J].Stroke,2006,37(11):2840-2842
[58]de Bree A,Mennen LI,Zureik M,et al.Homocysteine is not associated with arterial thickness and stiffness in healthy middle-aged French volunteers[J].Int J Cardiol,2006,113 (3):332-340.
[59]Hofmann MA,Lalla E,Lu Y,et al.Hyperhomocysteinemia enhances vascular inflamma -tion and accelerates atherosclerosis in a murine model[J].J Clin Invest,2001,107:675-687.
[60]Grolimund P,Seiler RW,Aaslid R,et al.Evaluation of cerebrovascular disease by combined extracranial and transcranial Doppler sonography.Experience in 1,039 patients[J].Stroke,1987,18:1018.
[61]Grolimund P,Seiler RW.Age dependence of the flow velocity in the basal cerebral arteries a transcranial Doppler ultrasound study[J].Ultrasound Med Biol,1988,14:191.
[62]Casas JP,Bautista LE,Smeeth L.Homocysteine and stroke:evidence on a causal link from mendelian randomisation[J].Lancet,2005,365(9455):224-232。
[63]Virtanen JK,Voutilainen S,Happonen P,et al.Serum homocysteine,folate and risk of stroke:Kuopio Ischaemic Heart Disease Risk Factor(KIHD) Study[J].Eur J Cardiovasc Prev Rehabil,2005,12(4):369-375.
[64]Haapaniemi E,Helenius J,Soinne L.Serial measurements of plasma homocysteine levels in early and late phases of ischemic stroke[J].Eur J Neurol,2007,14(1):12-17.
[65]Usman Khan,Carollyn Carollyn,Lalit Kalra,et al.Homocysteine and Its Relation ship to Stroke Subtypes in a UK Black Population[J].Stroke,2008,39:2943-29 -49.
[66]阮少川,肖卫民,苗海峰,等.血浆同型半胱氨酸水平与不同类型脑梗死的关系.广东医学[J].2006,27(8):1120-1121.
[67]MagedY.Z.Youssef,OlusegunA.Mojiminiyi,NabilaA.Abdella.Plasma concentration -s of C-reactive protein and total homocysteine in relation to the severity and risk factors for cerebrovasvular disease[J].Transtional Research,2007,150(3):158-163.
[68]P.Dusitanond,J.W.Eikelboom,G.J.Hankey,et al.Homocysteine-Lowering Treatment With Folic Acid,Cobalamin,and Pyridoxine Does Not Reduce Blood Markersof Inflammation,Endothelial Dysfunction,orHypercoagulability in Patients With Previous Transient Ischemic Attack or Stroke[J].Stroke.2005;36:144-146.
[69]G.H.Schernthaner,C.Plank,E.Minar,et al.No effect of homocysteine- lowering therapy on vascular inflammation and haemostasis in peripheral arterial occlusive disease[J].European Journal of Clinical Investigation,2006,36:333-339.
[70]Senaratne MPJ,Griffiths J,Nagendran J.Elevation of plasma homocysteine levels associated with acute myocardial infarction[J].Clin Invest Med.2000,23:220-226.
[71]Egerton W,Silberberg J,Crooks R,et al.Serialmeasures of plasma homocyst (e)ine after acute myocardial infarct ion[J].Am J Cardiol.1996;77:759-761.
[72]Schnyder G,Roffi M,Pin R,et al.Decreased rate of coronary restenosis after lowering of plasma homocysteine levels[J].N Engl J Med.2001,345(22):1593-1600.
[73]Lange H,Suryapranata H,De Luca G.Folate therapy and in-stent restenosis after coronary stenting[J].N Engl J Med.2004,350 (26):2673-2681.
[74]Dusitanond P;Eikelboom JW;Hankey GJ,et al.Homocysteine-lowering treatment with folic acid,cobalamin,and pyridoxine does not reduce blood markers of inflammation,endothelial dysfunction,or hypercoagulability in patients with previous transient ischemic attack or stroke:a randomized substudy of the VITAT0PS trial[J].Stroke.2005,36 (1):144-146.
[75]Stampfer MJ,Malinow MR,Willet WC,et al.A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians[J].JAMA.1992,268:877-881.
[76]Hankey GJ,Algra A,Chen C,et al.VITATOPS,the VITAmins TO prevent stroke trial:rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke [J].Int J Stroke,2007,2 (2):144-150.
[77]Petty GW,Brown RD Jr,Whisnant JP,et al.Survival and recurrence after first cerebral infarction:a population-based study in Rochester,Minnesota,1975 throughl989[J],Neurology,1998,50(1):208-216.
[78]Ubbink JR,Vermaak WJ,et al.Vitamin B12,vitaminB6,and folate nutritional status in men with hyperhomocysteinemia[J].Am J Clin Nutr.1993,57:47.
[2]Lonn E,Yusuf S,Arnold MJ,et al.Homocysteine lowering with acid and B vitamins in vascular disease[J].N Engl J Med,2006,354:1567-72.
[3]Bonaa KH,Njolstad I,Uelan PM,et al.Homocysteine lowering and cardiovascular events after acute myocardial infarction[J].N Engl J Med,2006,354:1578-88.
[4]SpenceJD,HowardVJ,ChamblessLE,et al.Vitamin Intervention for Stroke Prevention (VISP)trialrational-and-design[J].Neuroepidemiology,2001,20:16-25.
[5]Hao L,Ma J,et al.High prevalence of hyperhomocysteinemia in Chinese adults is associated with low folate,vitamin B12,and vitamin B6 status[J].J Nutr,2007,137:407-413.
[6]RogersJD,Sanchez-SaffonA,Frol B,Diaz-Arrastia R.Elevated plasma homocysteine levels in patients treated with ldopa[J].Arch Neurol 2003,60:59-64.
[7]Stanger 0,Weger M.Interactions of homoeysteine,nitric oxide,folate and radicals in the progressivdy dma endothdium[J].Clin Chem Lab Med,2003,41(1-1):1444-1454.
[8]Kartal Ozer N,Neigs Y,Aytan N.Molecularmechanisms of cholesterol Or homocy steine effect in the development of atheroselerosis:role of vitaminE [J].Bio-factors,2003,19(1-2):63-70.
[9]Beltowiski J.Protein homocysteinylation:a new mechanism of atherogenesis[J]?Postepy Hig Med Dosw,2005,59:392-404.
[10]Upchuch GR,Welch GN,Fabian AJ,et al.Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase[J].J Bio Chem,1997,272:17012-17017.
[11]Ling Q,Hajjar KA.inhibition of endothielial cell thromboresistance by homocy-steine[J],J Nutr,2000,130:373-376.
[12]Lee Me,Wang H.Homocysteine and hypomethylation.A novel link to vascular disease [J].Trends Cardiovasc Med,1999,9:49-54.
[13]VirginaJ.Howard,MSPH;ElizabethG.Sides,MED,et al.Changes in Plasema Homocye-steine in the Acute Phase After Stroke[J].Stroke,2002;33,473-478
[14]Lindgren A,Brattstrom L,Norving B,Hultberg B,Andersson A,Johansson BB.Plasma homocysteine in the acute and convalescentphases after stroke[J].Stroke.1995,26:795 - 800.
[15]Annthony S Wierzbicki.Homocysteine and cardiovascular disease:a review of the evidence[J].Diabetes Vasc Disease Rec,2007,4:143-149.
[16]F.Perini.E,Galloni.l,Bolgan · G,et al.Elevated plasma homocysteine in acute stroke was not associated with severity and outcome:stronger association with small artery disease[J].Neurol Sci,2005,26:310-318.
[17]乔兴茂,王雷,姜文洲,等.C反应蛋白与缺血性脑卒中的相关性研究[J].实用临床医学,2005,6:20-21.
[18]Aysen Akalin,Ozkan Alatas and Omer Colak.Relation of plasma homocysteine levels to atherosclerotic vascular disease and inflammation markers in type2diabetic patients[J].European Journal of Endocrinology.2008,158:47-52.
[19]Chambers JC,Obeid OA,Kooner JS.Physiological increments in plasma homocystei -ne ind -uce vascular endothelial dysfunction in nor-mal human subjects[J].Arterioscler Thromb Vasc Biol,1999,19(12):2922-2927.
[20]Coull BM,Malionow MR,Beamer N,et al.Elevated plasma homocysteine concentrat -ion as a possible independent risk factor for stroke[J].Stroke,1990,21:57-2-576.
[21]Boysen G,Brander T,Christensen H,et al,Homocysteine and risk of recurrent stroke[J].Stroke,2003,34(5):1258-1261.
[22]Ueland PM,Nygard O,Vollset SE,et al.The.Hordaland Homocysteine Studies[J].Lipids.2001,36:33-39.
[23]J David Spence.Homocysteine-lowering therapy:a role in stroke prevention[J].Lancet Neurol,2007,6:830-838.
[24]Ebbesen LS.Hyperhomocysteinemia,thrombosis and vascular biology[J].Cell Mol Biol,2004,50:917-30.
[25]Howard VJ,Sides EG,Newman GC,et al.Changes in plasma homocyst(e) ine in the acute phase after stroke[J].Stroke,2002,33:473-78.
[26]AmarencoP,Lavallee P,Touboul PJ.Statins and stroke prevention[J].Cerebrovasc Dis,2004,17:81-88.
[27]Annemaris D.Wijnhoud,Peter J.Koudstaal,Diederik W.J.Dippel,Relations of Transcranial blood flow dopper parameters with major vascular risk factors study in patients with recent TIA or Nodisabling Ischemic Stroke[J].Journal of Clinical Ultrasound,2006,34(2):70-76.
[28]Homcysteine Studies Collaboration.Homocysteine and risk of ischemic heart disease and stroke:a meta-analysis[J].JAMA,2002,288(16):2015-2022.
[29]Stanger 0,Fowler B,Herimann W.Folate therapy and in-stent restenosis.N Engl J Med [J],2004,351(12):1259-1260.
[30]GraceY.-H.Ho,ohn W.Eikelboom,Graeme J.Hankey,etal.Methyleneterahydrofolate Reduct-ase Polymorphisms and Homocysteine-Lowering Effect of Vitamin Therapy in Singaporean Stroke Patients[J].Stroke,2006,37:456-400.
[31]Loscalzo J.Homocysteine trialsclear outcomes for comlex reason[J].N Engl Med,2006,354 (15):1629-1632.
[32]Bazzano LA;Reynoldx K;Holder KN.Effect of folic acid supplementation on risk of cardiovascular diseases:a meta-analysis of randomized controlled trials[J].JAMA,2006,296(22):2720-2726.
[33]MRC Vitamin Research Group.Prevention of neural tube defects:results of the Medical Research Council Vitamin Study[J].Lancet,1991,338:131-137.
[34]Yang Q,Botto LD,Erickson JD,Berry RJ,Sambell C,Johansen H,Friedman JM:improvement in stroke mortality in Canada and the united states,1990 to 2002[J].Circulation,2006,113:1335-1343.
[35]Wang X,Qin X,Demirtas H,Li J,Mao G,Huo Y,Sun N,Liu L,Xu X:Efficacy of folic acid supplementation in stroke prevention:A meta-analysis [J].Lancet,2007,369:1876-1882.
[36]Wald D,Law M,Morris J:Homocysteine and cardiovascular disease:Evidence on causality from a meta-analysis[J].BMJ,2002,325:1202.
[37]Toole J,Malinow M,Chambless L,et al.Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke,myocardial infarction,and death:The vitamin intervention for stroke prevention (visp)randomized controlled trial[J].JAMA,2004,291:565-575.
[38]Bazzano L,Reynolds K,Holder K,et al.Effect of folic acid supplementation on risk of cardiovascular diseases:A meta-analysis of randomized controlled-trials[J].JAMA,2006,296:2720-2726.
[39]VITAT0PS Trial Study Group:The vitatops (vitamins to prevent stroke)trial:Rationale and design of an international,large,simple,randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke[J].Cerebrovasc Dis,2002,13:120-126.
[40]Eva Lonn.Homocysteine in the prevention of ischemic heart disease,stroke and venous thro-mboembolism:therapeutic target or just another distraction? Curr Opin Hematol [J].2007,14:481-487.
[41]Haynes WG.Hyperhomocysteinaemia,vascular function and atherosclerosis effects of vitamins[J].Cardiovasc Drugs Ther,2002,16:391-399.
[42]Baik HW,Russell RM.Vitamin B12 deficiency in the elderly[J].Annu Rev Nutr,1999,19:357-377.
[43]Chanson A,Cardinault N,Rock E.Decreased plasma folate concentration in young and elderly healthy subjects after a shortterm supplementation with isotretoin [J].J Eur AcadDermatol Venereol,2008,22(1):94-100.
[44]Lindsay H.Allen.Folate and Vitamin B12 Status in the Americas[J].Nutrition Reviews,2004,62(6):29-33.
[45]Forges T,Monnier Barbarino P,Alberto JM.Impact of folate and homocysteine metabolism on human reproductive health[J].Hum Reprod Update,2007,13(3)225-238.
[46]Van Oijen MG,Laheij RJ,Janson JB,et al.The predictive value of vitamin B12 concentrations and hyperhomocysteienaemia for cardiovascular disease[J].Neth Heart J,2007,15(6):291-294.
[47]Koseoglu E;Karaman Y;Relations between homocysteine,folate and vitamin B12 in vascular dementia and in Alzheimer disease[J].Clin Biochem.2007,40(12):859-863.
[48]GarciaG;Trejos J;Restrepo B;Landazuri P;Homocysteine,folate and vitamin B12 in Colombian patients with coronary disease[J].Arq Bras Cardiol,2007,89(2):71-76.
[49]Garibotto G,Sofia A,Valli A,et al.Causes of hyperhomocysteinemia in patients with chronic kidney diseases[J].Semin Nephrol,2006,26(1):3-7.
[50]Bostom A;Brosnan JT;Hall B;Nadeau MR;Selhub J.Net uptake of plasma homocysteine by the rat kidney in vivo[J].Atherosclerosis,1995,116(1):59-62.
[51]Ubbink JR,Vermaak WJ,van der Merwe A,et al.Vitamin B-12,vitaminB-6,and folate nutritional status in men with hyperhomocysteinemia [J].Am J Clin Nutr,1993,57:47.
[52]Finkelstein JD.The metabolism of homocysteine:pathways and regulation[J].Eur J Pediatrics.1998,15(2):40-44.
[53]MC Quilian BM,BeibyJP,Nidorf M,et al.Hyperhomocysteinemia but not the C677T mutation of methylenetetro hydrofolate reductase is an independent risk determinant of carotid wall thickening[J],Circulation,1999,99(9):2383—2388.
[54]Aminbakhsh A,Mancini GB.Carotid intima-media thickness measuremen-ts:what defines an abnormality? A systematic review[J].Clin Invest Med,1999,22:149-57.
[55]Wang H,Fan D,Zhang H,et al.Serum level of homocysteine is correlated to carotid artery atherosclerosis in Chinese with ischemic stroke[J].Neurol Res,2006,28(1):25-30.
[56]Nakhai Pour HR;Grobbee DE;Bots ML;MullerM;van der Schouw YT;Julius Center for Health Sciences and Primary Care,University Medical Center Utrecht,Utrecht,The Netherlands[J].J Hum Hypertens,2007,21 (12):942-948.
[57]Linnebank M,MoskauS,Farmand S,et al.Homocysteine and carotid intima-media thickness in a german population:lack of clinical relevance[J].Stroke,2006,37(11):2840-2842
[58]de Bree A,Mennen LI,Zureik M,et al.Homocysteine is not associated with arterial thickness and stiffness in healthy middle-aged French volunteers[J].Int J Cardiol,2006,113 (3):332-340.
[59]Hofmann MA,Lalla E,Lu Y,et al.Hyperhomocysteinemia enhances vascular inflamma -tion and accelerates atherosclerosis in a murine model[J].J Clin Invest,2001,107:675-687.
[60]Grolimund P,Seiler RW,Aaslid R,et al.Evaluation of cerebrovascular disease by combined extracranial and transcranial Doppler sonography.Experience in 1,039 patients[J].Stroke,1987,18:1018.
[61]Grolimund P,Seiler RW.Age dependence of the flow velocity in the basal cerebral arteries a transcranial Doppler ultrasound study[J].Ultrasound Med Biol,1988,14:191.
[62]Casas JP,Bautista LE,Smeeth L.Homocysteine and stroke:evidence on a causal link from mendelian randomisation[J].Lancet,2005,365(9455):224-232。
[63]Virtanen JK,Voutilainen S,Happonen P,et al.Serum homocysteine,folate and risk of stroke:Kuopio Ischaemic Heart Disease Risk Factor(KIHD) Study[J].Eur J Cardiovasc Prev Rehabil,2005,12(4):369-375.
[64]Haapaniemi E,Helenius J,Soinne L.Serial measurements of plasma homocysteine levels in early and late phases of ischemic stroke[J].Eur J Neurol,2007,14(1):12-17.
[65]Usman Khan,Carollyn Carollyn,Lalit Kalra,et al.Homocysteine and Its Relation ship to Stroke Subtypes in a UK Black Population[J].Stroke,2008,39:2943-29 -49.
[66]阮少川,肖卫民,苗海峰,等.血浆同型半胱氨酸水平与不同类型脑梗死的关系.广东医学[J].2006,27(8):1120-1121.
[67]MagedY.Z.Youssef,OlusegunA.Mojiminiyi,NabilaA.Abdella.Plasma concentration -s of C-reactive protein and total homocysteine in relation to the severity and risk factors for cerebrovasvular disease[J].Transtional Research,2007,150(3):158-163.
[68]P.Dusitanond,J.W.Eikelboom,G.J.Hankey,et al.Homocysteine-Lowering Treatment With Folic Acid,Cobalamin,and Pyridoxine Does Not Reduce Blood Markersof Inflammation,Endothelial Dysfunction,orHypercoagulability in Patients With Previous Transient Ischemic Attack or Stroke[J].Stroke.2005;36:144-146.
[69]G.H.Schernthaner,C.Plank,E.Minar,et al.No effect of homocysteine- lowering therapy on vascular inflammation and haemostasis in peripheral arterial occlusive disease[J].European Journal of Clinical Investigation,2006,36:333-339.
[70]Senaratne MPJ,Griffiths J,Nagendran J.Elevation of plasma homocysteine levels associated with acute myocardial infarction[J].Clin Invest Med.2000,23:220-226.
[71]Egerton W,Silberberg J,Crooks R,et al.Serialmeasures of plasma homocyst (e)ine after acute myocardial infarct ion[J].Am J Cardiol.1996;77:759-761.
[72]Schnyder G,Roffi M,Pin R,et al.Decreased rate of coronary restenosis after lowering of plasma homocysteine levels[J].N Engl J Med.2001,345(22):1593-1600.
[73]Lange H,Suryapranata H,De Luca G.Folate therapy and in-stent restenosis after coronary stenting[J].N Engl J Med.2004,350 (26):2673-2681.
[74]Dusitanond P;Eikelboom JW;Hankey GJ,et al.Homocysteine-lowering treatment with folic acid,cobalamin,and pyridoxine does not reduce blood markers of inflammation,endothelial dysfunction,or hypercoagulability in patients with previous transient ischemic attack or stroke:a randomized substudy of the VITAT0PS trial[J].Stroke.2005,36 (1):144-146.
[75]Stampfer MJ,Malinow MR,Willet WC,et al.A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians[J].JAMA.1992,268:877-881.
[76]Hankey GJ,Algra A,Chen C,et al.VITATOPS,the VITAmins TO prevent stroke trial:rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke [J].Int J Stroke,2007,2 (2):144-150.
[77]Petty GW,Brown RD Jr,Whisnant JP,et al.Survival and recurrence after first cerebral infarction:a population-based study in Rochester,Minnesota,1975 throughl989[J],Neurology,1998,50(1):208-216.
[78]Ubbink JR,Vermaak WJ,et al.Vitamin B12,vitaminB6,and folate nutritional status in men with hyperhomocysteinemia[J].Am J Clin Nutr.1993,57:47.