细胞生长因子、C-反应蛋白与冠状动脉病变程度及侧支循环关系的研究
|
摘要
目的 检测稳定型心绞痛（SAP）患者血清血管内皮细胞生长因子（VEGF）水平及碱性成纤维细胞生长因子（bFGF）、C-反应蛋白（CRP）水平的变化，探讨冠心病（CHD）患者VEGF、bFGF、CRP与冠状动脉病变严重程度的关系，并分析了VEGF、bFGF与侧支循环的关系。
方法 检测 62例经冠状动脉造影证实有一支或一支以上主要冠状动脉狭窄≥50%的稳定型心绞痛（SAP）患者及20例冠状动脉造影正常者血清VEGF、bFGF、CRP水平，VEGF、bFGF采用酶联免疫吸附法（ELISA）检测，血清CRP水平采用免疫浊度法测定，用冠状动脉病变血管的数量和Gensini积分系统评价冠状动脉病变的严重程度，CHD组又按Gensini积分高低又分为A组（29例，Gensini积分＜30）和B组（33例，Gensini积分≥30），以Rentrop法对侧支循环进行分级，比较CHD各亚组之间以及CHD组与正常对照组患者血清 VEGF、bFGF、CRP水平的差异，分析VEGF、bFGF、CRP与冠状动脉病变程度以及VEGF、bFGF侧支循环的关系。
结果 CHD组患者血清VEGF、bFGF、CRP平均水平明显高于正常对照组(P <0.01) ；CHD组双支和三支血管病变亚组血清VEGF、bFGF、CRP平均水平较单支病变组显著增高（P <0.01）, 三支血管病变亚组血清bFGF、CRP平均水平较双支病变组显著增高（P <0.05），CHD组中Gensini积分B组血清VEGF、bFGF、CRP水平显著高于A组（P <0.01），且CHD组血清VEGF、bFGF水平与冠状动脉硬化积分呈显著正相关性（r=0.548 ,P =0.010 VS r=0.289，P=0.024），CHD组中有侧支循环形成组血清VEGF、bFGF平均浓度显著高于无侧支循环形成组（P<0.01），三支血管病变组侧支循环形成率高于双支和单支病变组（P<0.05），Gensini积分B组侧支循环形成率显著高于A组。
结论 稳定型心绞痛（SAP）患者血清 VEGF、bFGF、CRP水平高于正常对照组；SAP患者血清VEGF、bFGF与冠状动脉病变程度呈正相关，CRP与冠状动脉病变程度有一定关系；血清VEGF、bFGF可能参与了CHD的发病过程，VEGF、bFGF
既有促进侧支循环形成的作用，又在动脉粥样硬化的发展过程中起着一定的作用。血清VEGF、bFGF的检测有助于临床病情的分析。
Objective To study the correlation of serum vascular endothelial growth factor(VEGF), basic fibroblast growth factor (bFGF) and CRP with the severity of coronary atherosclerosis and coronary collateral development in patients with stable coronary heart disease(SAP)
Methods Subjects included 82 patients undergoing diagnostic coronary angiography, 20 of whom had normal coronary arteries (control group). The lesion severity of the remaining 62 patients(CHD group) with stable coronary heart disease demonstrable coronary atherosclerosis(vessle stenosis≥50%) were evaluated by the Gensini scores and the number of significantly lesion coronary vessles. Two groups were divided according to Gensini scores, namely mild atherosclerosis group(Group A,n=29,Gensini score＜30)and severe atherosclerosis group(Group B, n =33, Gensini score ≥30). And the angiographic coronary collateral scores were noted by Rentrop Class. Blood samples were taken before angiography , and levels of serum vascular endothelial growth factor(VEGF),basic fibroblast growth factor(bFGF) and were measured by enzyme-linked immunosorbent assay(ELISA). These levels were then compared between groups.
Results Serum vascular endothelial growth factor(VEGF),basic fibroblast growth factor (bFGF) and CRP in CHD group were significantly higher than the control groups(P<0.01).Serum VEGF ,bFGF and CRP level in 2 or 3 vessels lesion group and Gensini score group B were elevated as compared with that of 1 vessel lesion group and and Gensini score group A group respectively(P<0.01). Serum bFGF and CRP level in 3 vessels lesion group and Gensini were higher than 2 vessel lesion group (P<0.05).Both the serum VEGF and bFGF concentrations were positively
correlated with the Gensini score(r=0.548,P=0.0100 vs r=0.289, P=0. 0240 respectively). The mean serum VEGF and bFGF concentration was higher in patients with collateral circulation than in those patients without collateral circulation(P<0.01).The collateral circulation occurrence rate in 2 or 3 vessle disease group was higher than that of 1 vessle disease.
Conclusion The serum VEGF , bFGF concentration had correlation with the severity of coronary atherosclerosis and coronary collateral.CRP had certain relation with the severity of coronary atherosclerosis. VEGF and bFGF might enhance lateral circulation development and doubtly regulate the development of atherosclersis.
方法 检测 62例经冠状动脉造影证实有一支或一支以上主要冠状动脉狭窄≥50%的稳定型心绞痛（SAP）患者及20例冠状动脉造影正常者血清VEGF、bFGF、CRP水平，VEGF、bFGF采用酶联免疫吸附法（ELISA）检测，血清CRP水平采用免疫浊度法测定，用冠状动脉病变血管的数量和Gensini积分系统评价冠状动脉病变的严重程度，CHD组又按Gensini积分高低又分为A组（29例，Gensini积分＜30）和B组（33例，Gensini积分≥30），以Rentrop法对侧支循环进行分级，比较CHD各亚组之间以及CHD组与正常对照组患者血清 VEGF、bFGF、CRP水平的差异，分析VEGF、bFGF、CRP与冠状动脉病变程度以及VEGF、bFGF侧支循环的关系。
结果 CHD组患者血清VEGF、bFGF、CRP平均水平明显高于正常对照组(P <0.01) ；CHD组双支和三支血管病变亚组血清VEGF、bFGF、CRP平均水平较单支病变组显著增高（P <0.01）, 三支血管病变亚组血清bFGF、CRP平均水平较双支病变组显著增高（P <0.05），CHD组中Gensini积分B组血清VEGF、bFGF、CRP水平显著高于A组（P <0.01），且CHD组血清VEGF、bFGF水平与冠状动脉硬化积分呈显著正相关性（r=0.548 ,P =0.010 VS r=0.289，P=0.024），CHD组中有侧支循环形成组血清VEGF、bFGF平均浓度显著高于无侧支循环形成组（P<0.01），三支血管病变组侧支循环形成率高于双支和单支病变组（P<0.05），Gensini积分B组侧支循环形成率显著高于A组。
结论 稳定型心绞痛（SAP）患者血清 VEGF、bFGF、CRP水平高于正常对照组；SAP患者血清VEGF、bFGF与冠状动脉病变程度呈正相关，CRP与冠状动脉病变程度有一定关系；血清VEGF、bFGF可能参与了CHD的发病过程，VEGF、bFGF
既有促进侧支循环形成的作用，又在动脉粥样硬化的发展过程中起着一定的作用。血清VEGF、bFGF的检测有助于临床病情的分析。
Objective To study the correlation of serum vascular endothelial growth factor(VEGF), basic fibroblast growth factor (bFGF) and CRP with the severity of coronary atherosclerosis and coronary collateral development in patients with stable coronary heart disease(SAP)
Methods Subjects included 82 patients undergoing diagnostic coronary angiography, 20 of whom had normal coronary arteries (control group). The lesion severity of the remaining 62 patients(CHD group) with stable coronary heart disease demonstrable coronary atherosclerosis(vessle stenosis≥50%) were evaluated by the Gensini scores and the number of significantly lesion coronary vessles. Two groups were divided according to Gensini scores, namely mild atherosclerosis group(Group A,n=29,Gensini score＜30)and severe atherosclerosis group(Group B, n =33, Gensini score ≥30). And the angiographic coronary collateral scores were noted by Rentrop Class. Blood samples were taken before angiography , and levels of serum vascular endothelial growth factor(VEGF),basic fibroblast growth factor(bFGF) and were measured by enzyme-linked immunosorbent assay(ELISA). These levels were then compared between groups.
Results Serum vascular endothelial growth factor(VEGF),basic fibroblast growth factor (bFGF) and CRP in CHD group were significantly higher than the control groups(P<0.01).Serum VEGF ,bFGF and CRP level in 2 or 3 vessels lesion group and Gensini score group B were elevated as compared with that of 1 vessel lesion group and and Gensini score group A group respectively(P<0.01). Serum bFGF and CRP level in 3 vessels lesion group and Gensini were higher than 2 vessel lesion group (P<0.05).Both the serum VEGF and bFGF concentrations were positively
correlated with the Gensini score(r=0.548,P=0.0100 vs r=0.289, P=0. 0240 respectively). The mean serum VEGF and bFGF concentration was higher in patients with collateral circulation than in those patients without collateral circulation(P<0.01).The collateral circulation occurrence rate in 2 or 3 vessle disease group was higher than that of 1 vessle disease.
Conclusion The serum VEGF , bFGF concentration had correlation with the severity of coronary atherosclerosis and coronary collateral.CRP had certain relation with the severity of coronary atherosclerosis. VEGF and bFGF might enhance lateral circulation development and doubtly regulate the development of atherosclersis.
引文
1 Esser S,Lampugnani MG,Corada M,et al .Vascular endothelialgrowth factor induces VE-adherin tyrosine phosphorylation inendothelial cells.J Cell Sci,1998 ,111 (Pt13) :1853-1856
2 Ramos MA ,Kuzuya M, Esaki T ,et al .Induction of macrophage VEGF in response to oxidaized LDL and VEGF accumulation in human atheroscleroticlesion.ArteriosclerThromVascBiol,1998,18:1188-1196
3 Inoue M, Itoh H , Ueda M,et al.Vascular endothelial growth factor(VEGF) expression in human coronary atherosclerotic lesions：possible pathophysiological significance of VEGF in progress of atherosclerosis.Circulation , 1998 ,98 :2108-2116
4 Flugelman MY,Virmani R,Correa R,et al.Smooth muscle cell abundance and fibroblast growth factors in coronary lesions of patients with nonfatal unstable angina:a clue to the mechanism of transformation from the stable to the unstable clinical state. Circulation. 1993, 8:2493-2500
5 Nabel EG, Yang ZY, Plautz G, et al. Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo. Nature. 1993,362:844-846.
6 Edelman ER,Nugent MA,Smith LT,et al.Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries. J Clin Invest.1992,89:465-473.
7 Gensini GG.A more meaningful scoring system for determining the severity of coronary heart disease[J].AmJ Cardiol,1983,51:606-612.
8 Rentrop,KP,Cohen,M,Blanke H, Philips, RA.Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty ballon in human subjects[J] J Am Coll Cardiol,1985,5;587-592
9 Ferrara N Henzel WJ.Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothilial cell .Biophs Res commun .1989 Jun 15,161(2):851-857
10 Hyder S Murthy L ,Stancel G.Progestin regulation of vascular
endothelial growth factor in human breast cancer cells. Cancer Res,1998,58 (2):392-395
11 Sa G, etal Activation of cytosolic phospholipase A2 by basic fibroblast growth factor via a 42P mitogen-activated protein kinase-dependent phosphorylation pathway endothelial cells.JBC , 1995,270:2360-2365
12 Cummins P.Fibroblast and transforming growth factor expression in the cardiacmyocyte.Cardio-vascular Res,1993,27:1150-1154
13 ORNITZ, D.M.& ITOH,N.Fibroblast growth factors. Genome Biol. 2001,2,3005.1-3005.12.
14 Ogawa H , Suefuji H , Soejima H. Increased blood vascular endothelial growth factor levels in patients with acute myocardial infarction[J]. Cardiology , 2000 , 93 (122) : 93-99
15 Selo Y,Imaiy,Suzki s et al .Serum leveles of VEGF in patients with acute myocardial infarct undergoing reperfusion therapy.Clin Sci Colch,1997,92(5):453-457
16 Katinioti AA， Tousoulis D, et al .Basic fibroblast growth factor changes in response to coronary antioplasty in patients with stable angina.[J].Int J cardiol .2002 Aug,84(2-3):195-199
17 Risau W. Mechanisms of angiogenesis. Nature,1997,386 (6626) : 671-674
18 Ito WD,Arras M,Winkerler B ,etal.Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion [ J ]. Circ Res. 1997 ,80:829-837.
19 Arras M,Ito WD ,Scholz D,et al.Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb[J]. J Clin Invest ,1998 ,101 :40-50.
20 ChenYX,Nakashima Y,Tanaka K,Shiraishi S,Nakagama, Sueishi K. Immunohistochemical expression of vascular endothelial growth factor/vascular permeability factor in atherosclerotic intimas of human coronary arteries. Arterioscler Thromb Vasc Biol , 1999 , 19 (1) : 131-139
Christophy Heeschen, MD; Steanie Dimmeler, PhD;et al Prognostic significance of angiogenic growth factor serum levels in patients with acute coronary syndromes[J].circulation.2003,107:524-530
22 Ridker PM ,Glynn RJ ,Hennken CH. C-reactive protein adds to the predictive value of total and HDL cholerol in determining risk of first myocarical infarction. Circulation ,1998 ,97∶2007 —2011
23 Harb TS , Zareba W, Moss AJ , et al . Association of C - reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction[J ] . AMJ Cardiol ,2002,89 : 216 - 221
24 Allen PB , Russell PT , Frank K, et al . Elevated C - reactive protein values and atherosclerosis in sudden coronary death : Association with different pathologies[J ] . Circulation ,2002 ,17 :2019 - 2029
25. Mori T, Sasaki J Serum glycoproteins and severity of coronary atherosclerosis. Am Heart J. 1995 Feb,129(2):234-238.
26. Mezaki T,Matsubara T,Plasma levels of soluble Thrombomodulin, C-reactive protein, and serum amyloid A protein in the atherosclerotic coronary circulation Jpn Heart J. 2003 Sep,44(5): 601-612.;
27 Kodama ,K, Kusuoka，H，SakaiA，et al,Collateral channels that develop after an acute myocardial infarction prevent subsequen left ventricular dilation.J Am Coll Cardiol,1996 ,27; 1133-1139.
28 Schaper W, Buschmann I. Arteriogenesis ,the good and bad of it .Cardiovasc Res , 1999 ,43 :835-837.
29 Chaper W,Sharma H,Quinkler H etal.Molecular biologic concepts of coronary anastomoses.J Am Coll Cardiol , 1990 ,15 :513-518.
30 Kumar S , West D ,Shahabuddin S ,et al. Angiogenesis factor from
human myocardial infarcts. Lancet ,1983 ,13 :364-368.
31 Fleisch Billinger M,Eberli, FR,Garachemani AR ,Meier B ,Seiler Physiologically assessed coronary collateral flow and intra- coronary growth factor concentrations in patients with 1-3 vessel coronary artery disease. Circulation,1999,100(9):1945-1950
2 Ramos MA ,Kuzuya M, Esaki T ,et al .Induction of macrophage VEGF in response to oxidaized LDL and VEGF accumulation in human atheroscleroticlesion.ArteriosclerThromVascBiol,1998,18:1188-1196
3 Inoue M, Itoh H , Ueda M,et al.Vascular endothelial growth factor(VEGF) expression in human coronary atherosclerotic lesions：possible pathophysiological significance of VEGF in progress of atherosclerosis.Circulation , 1998 ,98 :2108-2116
4 Flugelman MY,Virmani R,Correa R,et al.Smooth muscle cell abundance and fibroblast growth factors in coronary lesions of patients with nonfatal unstable angina:a clue to the mechanism of transformation from the stable to the unstable clinical state. Circulation. 1993, 8:2493-2500
5 Nabel EG, Yang ZY, Plautz G, et al. Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo. Nature. 1993,362:844-846.
6 Edelman ER,Nugent MA,Smith LT,et al.Basic fibroblast growth factor enhances the coupling of intimal hyperplasia and proliferation of vasa vasorum in injured rat arteries. J Clin Invest.1992,89:465-473.
7 Gensini GG.A more meaningful scoring system for determining the severity of coronary heart disease[J].AmJ Cardiol,1983,51:606-612.
8 Rentrop,KP,Cohen,M,Blanke H, Philips, RA.Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty ballon in human subjects[J] J Am Coll Cardiol,1985,5;587-592
9 Ferrara N Henzel WJ.Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothilial cell .Biophs Res commun .1989 Jun 15,161(2):851-857
10 Hyder S Murthy L ,Stancel G.Progestin regulation of vascular
endothelial growth factor in human breast cancer cells. Cancer Res,1998,58 (2):392-395
11 Sa G, etal Activation of cytosolic phospholipase A2 by basic fibroblast growth factor via a 42P mitogen-activated protein kinase-dependent phosphorylation pathway endothelial cells.JBC , 1995,270:2360-2365
12 Cummins P.Fibroblast and transforming growth factor expression in the cardiacmyocyte.Cardio-vascular Res,1993,27:1150-1154
13 ORNITZ, D.M.& ITOH,N.Fibroblast growth factors. Genome Biol. 2001,2,3005.1-3005.12.
14 Ogawa H , Suefuji H , Soejima H. Increased blood vascular endothelial growth factor levels in patients with acute myocardial infarction[J]. Cardiology , 2000 , 93 (122) : 93-99
15 Selo Y,Imaiy,Suzki s et al .Serum leveles of VEGF in patients with acute myocardial infarct undergoing reperfusion therapy.Clin Sci Colch,1997,92(5):453-457
16 Katinioti AA， Tousoulis D, et al .Basic fibroblast growth factor changes in response to coronary antioplasty in patients with stable angina.[J].Int J cardiol .2002 Aug,84(2-3):195-199
17 Risau W. Mechanisms of angiogenesis. Nature,1997,386 (6626) : 671-674
18 Ito WD,Arras M,Winkerler B ,etal.Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion [ J ]. Circ Res. 1997 ,80:829-837.
19 Arras M,Ito WD ,Scholz D,et al.Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb[J]. J Clin Invest ,1998 ,101 :40-50.
20 ChenYX,Nakashima Y,Tanaka K,Shiraishi S,Nakagama, Sueishi K. Immunohistochemical expression of vascular endothelial growth factor/vascular permeability factor in atherosclerotic intimas of human coronary arteries. Arterioscler Thromb Vasc Biol , 1999 , 19 (1) : 131-139
Christophy Heeschen, MD; Steanie Dimmeler, PhD;et al Prognostic significance of angiogenic growth factor serum levels in patients with acute coronary syndromes[J].circulation.2003,107:524-530
22 Ridker PM ,Glynn RJ ,Hennken CH. C-reactive protein adds to the predictive value of total and HDL cholerol in determining risk of first myocarical infarction. Circulation ,1998 ,97∶2007 —2011
23 Harb TS , Zareba W, Moss AJ , et al . Association of C - reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction[J ] . AMJ Cardiol ,2002,89 : 216 - 221
24 Allen PB , Russell PT , Frank K, et al . Elevated C - reactive protein values and atherosclerosis in sudden coronary death : Association with different pathologies[J ] . Circulation ,2002 ,17 :2019 - 2029
25. Mori T, Sasaki J Serum glycoproteins and severity of coronary atherosclerosis. Am Heart J. 1995 Feb,129(2):234-238.
26. Mezaki T,Matsubara T,Plasma levels of soluble Thrombomodulin, C-reactive protein, and serum amyloid A protein in the atherosclerotic coronary circulation Jpn Heart J. 2003 Sep,44(5): 601-612.;
27 Kodama ,K, Kusuoka，H，SakaiA，et al,Collateral channels that develop after an acute myocardial infarction prevent subsequen left ventricular dilation.J Am Coll Cardiol,1996 ,27; 1133-1139.
28 Schaper W, Buschmann I. Arteriogenesis ,the good and bad of it .Cardiovasc Res , 1999 ,43 :835-837.
29 Chaper W,Sharma H,Quinkler H etal.Molecular biologic concepts of coronary anastomoses.J Am Coll Cardiol , 1990 ,15 :513-518.
30 Kumar S , West D ,Shahabuddin S ,et al. Angiogenesis factor from
human myocardial infarcts. Lancet ,1983 ,13 :364-368.
31 Fleisch Billinger M,Eberli, FR,Garachemani AR ,Meier B ,Seiler Physiologically assessed coronary collateral flow and intra- coronary growth factor concentrations in patients with 1-3 vessel coronary artery disease. Circulation,1999,100(9):1945-1950