复合bFGF的PCL/PLGA肝素化支架在心肌血运重建中应用的实验研究
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摘要
目的:冠心病严重威胁着人类的健康,冠状动脉搭桥术和经皮冠脉介入治疗挽救了大量冠心病患者的生命。但是,约12%的患者因弥漫性冠脉血管病变、搭桥远端靶血管直径偏小以及二次手术缺乏桥血管等原因不适合上述治疗;而基于心肌窦状隙理论衍生的激光打孔方式,经动物实验及临床尸检证实,2周后孔道血栓化完全闭塞。本文在缺血部位室壁产生直径3.0mm的透壁孔道,同时植入具有良好力学弹性并复合碱性成纤维细胞生长因子(basic fibroblast growthfactor,bFGF)的肝素缓释抗凝支架,以尝试支撑孔道开放,抑制凝血途径激活,诱导血管再生,改善周围心肌血流灌注及心脏功能。
     方法:(1)通过静电纺丝法、溶剂挥发铸膜法、熔融挤塑法,优化工艺,制作复合bFGF的肝素化PCL/PLGA双层支架。
     (2)进行机械打孔、支架植入的可行性及损伤性评价。
     (3)在小型猪心梗模型基础上,设立对照组、单纯孔道组、孔道-空白支架组和孔道-肝素化支架组,在肝素缓释抗凝的前提下,进行孔道的长期开放性研究。
     (4)在机械打孔联合肝素化支架孔道开放的前提下,设立空白支架组、肝素化支架组和复合bFGF的肝素化支架组,通过在肝素化支架内同步复合bFGF,研究二者能否发挥协同作用,进一步促进缺血区域血流灌注及心功能的改善。
     结果:(1)力学测试PCL/PLGA支架具有良好的抗压强度,扫描电镜观察无明显变形,支架肝素含量25mg,bFGF含量15μg。
     (2)机械打孔及支架植入操作简便,无恶性心律失常、出血、栓塞等情况发生;
     在CVP、MAP、HR稳定的前提下,通过对左室短轴缩短率的分析,打孔及支架植入前后心功能无显著差异(P>0.05)。
     (3)单纯孔道及空白支架植入6周后均发生闭塞,而肝素化支架孔道保持开放,扫描电镜观察管腔内皮化,并且周围新生血管密度显著增加,心肌灌注核素扫描质量缺损百分率、左室短轴缩短率均较其它组显著改善(P<0.05)。
     (4)复合bFGF的肝素化支架组细胞因子VEGF、vWF、TGF-β3、IL-1β表达增强,并且新生血管密度、灌注质量缺损百分率与空白及肝素化支架组存在显著差别(P<0.05);复合bFGF的肝素化支架组及肝素化支架组左室短轴缩短率均较空白支架组显著改善(P<0.001),但前两组间比较,无显著统计学差异,但提示心功能有进一步改善的趋势(P=0.058)。
     结论:(1)复合bFGF的肝素化PCL/PLGA支架具有良好的抗压强度,能够耐受心肌的反复挤压。
     (2)肝素化处理后的支架通过缓释抗凝保持孔道长期开放,并且诱导部分管壁内皮化,增加血流灌注,改善心脏功能。
     (3)复合的肝素和bFGF能够协同发挥生物学作用,促进周围血管新生,增加心肌血流灌注,显示心功能有进一步改善的趋势。
Objective.Coronary artery disease remains the leading cause of morbidity and mortality in the world.Approximately 12%of patients with coronary artery disease,because of unfavorable characteristics such as diffuse coronary atherosclerosis,small distal vessels or lack of suitable bridge vessels,are not amenable to coronary artery bypass grafting(CABG) or percutaneous coronary intervention(PCI).In this setting,transmyocardial laser revascularization(TMLR) derived from the idea of myocardial sinusoids has been explored, however,histologic observations in experimental specimens and clinical postmortem studies have demonstrated initial thrombus and eventually entire obliteration of the channels.The objective of this study,by producing transmural channels of 3.0mm in diameter and then implanting heparinized bFGF-incorporating PCL/PLGA stentts,is to investigate the potentiality of channel patency and new vessels density,and further study the concomitant efficacy in improving myocardial perfusion and function.
     Methods.
     (1) By electrospinning technology,solvent casting and surface spraying,a kind of novel heparinized bFGF-incorporating PCL/PLGA bilayer stent was fabricated.
     (2) Evaluate the feasibility of transmyocardial drilling revascularization(TMDR) and stent implantation,and the potential injury to the heart.
     (3) After myocardial infarction model,the miniswines were grouped:Control Group, TMDR Group,TMDR with Blank Stentt Group(TMDR-BS group) and TMDR with Heparinized Stent Group(TMDR-HS Group),and investigated the channel patency and myocardial perfusion improvement.
     (4) Based on the long-term patency of the heparinized channel,the miniswines were grouped:TMDR with Blank Stent Group(TMDR-BS Group),TMDR with Heparinized Stentt Group(TMDR-HS Group),and TMDR with Heparinized bFGF-incorporating Stentt Group(TMDR-HBS Group),and evaluated whether heparinized bFGF-incorporating stent could further enhance myocardial perfusion and function by the biologically synergetic role of bFGF and heparin.
     Results.
     (1) Each PCL/PLGA stent,with 25mg heparin and 15μg bFGF,could keep original shape and maintain control-release of heparin and bFGF for 4 weeks.
     (2) Both TMDR and stent implantation were accomplished readily,without any side effects,such as embolism,bleeding,and hemodynamic abnormality.
     (3) In TMDR and TMDR-BS group,the channels were occluded 6 weeks later. However,heparinized stent could keep the channel patent and induce luminal endothelialization.In TMDR-HS group,the neovascular density significantly increased, mass defect percentage(MDP%) of myocardial perfusion and fractional shortening(FS%) in TMDR-HBS group also revealed significant improvements compared with other groups (P<0.05).
     (4) In TMDR-HBS group,pro-angiogenic factors ofVEGF、vWF、TGF-β3、IL-1βmarkedly expressed.Vascular density and MDP%significantly increased compared with TMDR-BS and TMDR-HS group(P<0.05).FS%in both TMDR-HBS and TMDR-HS group significantly improved compared with TMDR-BS group(P<0.001),however,there existed a trend towards improvement between TMDR-HBS and TMDR-HS group (P=0.058),although no statistical difference was revealed.
     Conclusions.PCL/PLGA bilayer stent could withstand recurrent crushing in vivo and maintain original contour.The stent with heparinized procedure could keep the channel open and promote luminal endothelialization by continuous anticoagulation.The control-released heparin and bFGF promoted neovascular formation and collateral development,and further improved cardiac function by increasing blood flow perfusion of ischemic "hibernated" myocardium.
引文
[1]Mukher jee D,Bhatt DL,Roe MT,et al.Direct myocardial revascularization and angiogenesis-how many patients might be eligible[J].Am J Cardiol,1999,84(5):598-600.
    [2]Sen PK,Udwadia Te,Kinare SG,et al.Transmyocardial acupuncture,a new approach to myocardial revascularization[J].J Thorac Cardiaovasc Surg,1965,50(2):181-189.
    [3]Hardy RJ,James FG,Millard RW,et al.Regional myocardial blood flow and cardiac mechanics in dog hearts with CO_2 laser induced intramyocardial revascularization[J].Basic Res Cardiol,1990,85(2):179-197.
    [4]Kohmoto T,Fisher PE,Gu A,et al.Physiology,histology,and 2-week morphology of acute transmyocardial channels made with a CO2 laser[J].Ann Thorac Surg,1997,63(5):1275-1283.
    [5]Gassler N,Wintzer HO,Stubbe HM,et al.Transmyocardial laser revascularization histological features in human nonresponder myocardium[J].Circulation,1997,95(2):371-375.
    [6]Malekan R,Reynolds C,Narula N,et al.Angiogenesis in transmyocardial laser revascularization.A nonspecific response to injury[J].Circulation,1998,98(19Suppl):Ⅱ 62-66.
    [7]Chu VF,Giaid A,Kuang JQ,et al.Angiogenesis in transmyocardial revascularization:comparison of laser versus mechanical punctures[J].Ann Thorac Surg,1999,68(2):301-307.
    [8]Li W,Tanaka K,Chiba Y,et al.Role of MMPs and plasminogen activators in angiogenesis after transmyocardial laser revascularization in dogs[J].Am J Physiol Circ Physiol,2003,284(1):23-30.
    [9]孙磊,甘志华,徐莘香等.人工合成聚己内酯体内降解的研究[J].中国生物医学工程学报,1999,16(2):169-174.
    [10]Sun H,Mei L,Song C,et al.The in vivo degradation,absorption and excretion of PCL-based implant[J].Biomaterials,2006,27(9):1735-1740.
    [11]Lemoine D,Francois C,Kedzewicz F,et al.Stability study of nanoparticles of poly(epsilon-caprolactone),poly(D,L-lactide) and poly(lactide-co-glycolide)[J].Biomaterials,1996,17(22):2191-2197.
    [12]Vaz CM,van Tui jl S,Bouten CV,et al.Design of scaffolds for blood vessel tissue engineering using a multi-layering electrospinning technique[J].Acta Biomater,2005,1(5):575-82.
    [13]艾合麦提,陈统一,陈中伟.新型生物降解材料聚己酸内酯的理化性能研究[J].上海生物医学工程杂志,1999,20(4):6-9.
    [14]朱光明.形态记忆聚合物及其应用[M].北京:化学工业出版社,2002:120-122.
    [15]Walter PJ.Are the channels too small in transmyocardial laser revascularization[J].Tex Heart Inst,2002,29(2):154.
    [16]Cooley DA,Frazier OH,Kadipasaoglu KA,et al.rransmyocardial laser revaculari-zation:anatomic evidence of long-term channel patency[J].Texas Heart Inst,1994,21(3):220-224.
    [17]Domkowski PW,Biswas SS,Steenbergen C,et al.Histological evidence of angiogenesis 9 months after transmyocardial laser revascularization[J].Circulation,2001,103(3):469-471.
    [18]Mack CA.Channel patency and neovascularization after transmyocardial revasculari zation using an excimer laser,results and comparisons to nonlased channels.[J].Circu-lation,1997,96(9 Suppl):Ⅱ 65-69.
    [19]Whittaker P,Rakusan K,Kloner RA,et al.Transmural channels can protect ischemic tissue:assessment of long-term myocardial response to laser-and needle-made channels[J].Circulation,1996,93(1):143-152.
    [20]Hughes GC,Kypson AP,Annex BH,et al.Induction of angiogenesis after TMR:a comparison of Holmium:YAG,CO2,and excimer lasers[J].Ann Thorac Surg,2000,70:504-509.
    [21]Mueller XM,Tevaearai HT,Chaubert P,et al.Does laser injury induce a different neovascularisation pattern from mechanical or ischaemic injuries[J].HEART,2001,85(6),697-701.
    [22]Resnick,N,Yahav H,Khachigian LM,et al.Endothelial gene regulation by laminar shear stress[J].Adv Exp Med Biol,1997,430:155-164.
    [23]Folkow B.Structure and function of the arteries in hypertension[J].Am Heart J,1987,114(4):938-948.
    [24]Whittaker CP.Transmyocardial revascularization:the fate of myocardial channels[J].Ann rhorac Surg,1999,68(6):2376-2382.
    [25]Horvath KA,Belkind N,Wu I,et al.Functional comparison of transmyocardial revascularization by mechanical and laser means[J].Ann Thorac Surg,2001,72(6):1997-2002.
    [26]Krabatsch T,Tambeur L,Lieback E,et al.Transmyocardial laser revascularization in the treatment of end-stage coronary artery disease[J].Ann Thorac Cardiovasc Surg, 1998,4(2):64-71.
    [27] Pearlman JD, Hibberd MG, Chuang ML, et al. Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis[J]. Nat Med, 1995,1(10): 1085-9.
    [28] Unger EF, Banai S, Shou, et al. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model[J]. Am J Physiol, 1994,266(4): 1588-1595.
    [29] Zheng J, Shin JH, Xaymardan M, et al. Platelet-derived growth factor improves cardiac function in a rodent myocardial infarction model[J]. Coron Artery Dis, 2004,15(1): 59-64.
    [30] Whalen GF, Shing Y, Folkman J. The fate of intravenously administered bFGF and the effect of heparin[J]. Growth Factors, 1989,1(2):157-164.
    [31] Laham RJ, Post M, Rezaee M, et al. Transendocardial and transepicardial intramyocardial fibroblast growth factor-2 administration: myocardial and tissue distribution[J]. Drug Metab Dispos, 2005, 33(8):1101-1107.
    [32] Sellke FW, Laham RJ, Edelman ER, et al. Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results [J]. Ann Thorac Surg, 1998,65(6): 1540- 1544.
    [33] Yamamoto M, Ikada Y, Tabata Y. Controlled release of growth factors based on biodegradation of gelatin hydrogel[J]. J Biomater Sci Polym Ed, 2001, 12(1): 77-88.
    [34] Nillesen ST, Geutjes PJ, Wismans R, et al. Increased angiogenesis and blood vessel maturation in acellular collagen-heparin scaffolds containing both FGF_2 and VEGF[J]. Biomaterials, 2007, 28(6):1123-1131.
    [35] Thompson JA, Anderson KD, DiPietro JM, et al. Site-directed neovessel formation in vivo[J]. Science, 1988, 9;241 (4871):1349-1352.
    [36] Miyoshi M, Kawazoe T, Igawa HH, et al. Effects of bFGF incorporated into a gelatin sheet on wound healing[J]. J Biomater Sci Polym Ed, 2005, 16 (7): 893-907.
    [37] Fujita M, Ishihara M, Morimoto Y, et al. Efficacy of photocrosslinkable chitosan hydrogel containing fibroblast growth factor-2 in a rabbit model of chronic myocardial infarction[J]. J Surg Res, 2005,126(1):27-33.
    [38] He W, Yong T, Teo WE, et al. Fabrication and endothelialization of collagen-blended biodegradable polymer nanofibers: potential vascular graft for blood vessel tissue engineering[J]. Tissue Eng, 2005,11(9-10): 1574-1588.
    [39] Ma Z, He W, Yong T, et al. Grafting of gelatin on electrospun poly(caprolactone) nanofibers to improve endothelial cell spreading and proliferation and to control cell Orientation[J]. Tissue Eng, 2005,11(7-8): 1149-1158.
    [40] Chung HJ, Kim HK, Yoon JJ, et al. Heparin immobilized porous PLGA micro-spheres for angiogenic growth factor delivery[J]. Pharm Res, 2006, 23 (8): 1835-1841.
    [41] Jeon O, Kang SW, Lim HW, et al. Long-term and zero-order release of basic fibroblast growth factor from heparin-conjugated poly(L-lactide-co-glycolide) nanospheres and fibrin gel[J]. Biomaterials, 2006, 27(8):1598-1607.
    [42] Schumacher B, Pecher P, von Specht BU, et al. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease[J]. Circulation, 1998, 97(7):645-650.
    [43] Edelman ER, Nugent MA, Karnovsky MJ. Perivascular and intravenous adminis- tration of basic fibroblast growth factor: vascular and solid organ deposition[J]. Proc Natl Acad Sci USA, 1993, 90(4):1513 - 1517.
    [44] Rajanayagam MA, Shou M, Thirumurti V, et al. Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs[J]. J Am Coll Cardiol, 2000, 35(2):519-526.
    [45] Fearon WF, Ikeno F, Bailey LR, et al. Evaluation of high-pressure retrograde coronary venous delivery of FGF-2 protein[J]. Catheter Cardiovasc Interv, 2004, 61(3): 422-428.
    [46] von Degenfeld G, Raake P, Kupatt C, et al. Selective pressure-regulated retroinfusion of fibroblast growth factor-2 into the coronary vein enhances regional myocardial blood flow and function in pigs with chronic myocardial ischemia[J]. J Am Coll Cardiol, 2003, 42(6):1120-1128.
    [47] Laham R, Rezaee M, Post M, et al. Intrapericardial administration of basic fibroblast growth factor: myocardial and tissue distribution and comparison with intracoronary and intravenous administration[J]. Catheter Cardiovasc Interv, 2003, 58(3):375 - 81.
    [48] Laham RJ, Rezaee M, Post M, et al. Intrapericardial delivery of fibroblast growth factor-2 induces neovascularization in a porcine model of chronic myocardial ischemia[J]. J Pharmacol Exp Ther, 2000, 292(2):795-802.
    [49] Pecher P, Schumacher BA. Angiogenesis in ischemic human myocardium:clinical results after 3 years[J]. Ann Thorac Surg, 2000, 69(5): 1414-1419.
    [50] Sakakibara Y, Tambara K, Sakaguchi G, et al. Toward surgical angiogenesis using slow-released basic fibroblast growth factor[J]. Eur J Cardio-thoracic Surgery, 2003, 24(1): 105-112.
    [51] Gospodarowicz D, Cheng J. Heparin protects basic and acidic FGF from inactivation[J]. J Cell Physiol, 1986,128(3):475-484.
    [52] Kardami E, Detillieux K, Ma X, et al. Fibroblast growth factor-2 and cardioprotection[J]. Heart Fail Rev, 2007,12(3-4) :267-277.
    [53] Ruel M, Laham RJ, Parker JA, et al. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein[J]. J Thorac Cardiovasc Surg, 2002,124(1): 28-34.
    [54] Elcin AE, Elcin YM. Localized angiogenesis induced by human vascular endothelial growth factor- activated PLGA sponge [J]. Tissue Eng, 2006,12 (4): 959-968.
    [55] Pitt CG, Gratzl MM, Kimmel GL, et al. Aliphatic polyesters II. The degradation of poly (DL-lactide), poly(epsilon-caprolactone), and their copolymers in vivo. Biomaterials, 1981, 2(4):215-220.
    [56] Wei G, Jin Q, Giannobile WV, et al. Nano-fibrous scaffold for controlled delivery of recombinant human PDGF-BB[J]. J Control Release, 2006,112(1): 103-110.
    [57] Aguado M, Lambert P. Controlled-release vaccine-biodegradable polylactide/ polyglycolide(PL/PG) microspheres as antigen vehicles[J]. Immunobiol, 1992,184(2-3) :113-125.
    [58] Ma G, Song C, Sun H, et al. A biodegradable levonorgestrel-releasing implant made of PCL/F68 compound as tested in rats and dogs[J]. Contraception, 2006, 74(2):141-147.
    [59] Webber WL, Lago F, Thanos C, et al. Characterization of soluble, salt-loaded, degradable PLGA films and their release of tetracycline[J]. J Biomed Mater Res, 1998, 41(1): 18-29.
    [60] Bretland AJ, Lawry J, Sharrard RM. A study of death by anoikis in cultured epithelial cells adhesion-prevented cellular death[J]. Cell Prolif, 2001, 34(4): 199-210.
    [61] Grayson AC, Voskerician G, Lynn A, et al. Differential degradation rates in vivo and in vitro of biocompatible poly (lactic acid) and poly(glycolic acid) homo-and co-polymers for a polymeric drug-delivery microchip[J]. J Biomater Sci Polym Ed, 2004,15(10): 1281- 1304.
    [62] Fujita M. Heparin and angiogenic therapy [J]. European Heart Journal, 2000, 21(4) :270-4.
    [63] Noishiki Y, Miyata T. A simple method to heparinize biological materials[J].J Biomed Mater Res, 1986, 20(3):337-46.
    [64] Tsai CC, Chang Y, Sung HW, et al. Effects of heparin immobilization on the surface characteristics of a biological tissue fixed with a naturally occurring crosslinking agent (genipin): an in vitro study[J]. Biomaterials, 2001, 22(6):523-533.
    [65] Bonan R, Bhat K, Lefevre T, et al. Coronary artery stenting after angioplasty with self-expanding parallel wire metallic stents[J]. Am Heart J, 1991,121(5):1522-1530.
    [66] Pieper JS, Hafmans T, van Wachem PB, et al. Loading of collagen-heparan sulfate matrices with bFGF promotes angiogenesis and tissue generation in rats[J].J Biomed Mater Res, 2002, 62(2): 185-194.
    [67] Saksela O, Moscatelli D, Sommer A, et al. Endothelial cell-derived heparan sulfate binds basic fibroblast growth factor and protects it from proteolytic degradation[J]. J Cell Biol, 1988,107(2):743-751.
    [68] Klagsbrun M. Mediators of angiogenesis: the biological significance of basic fibroblast growth factor (bFGF)-heparin and heparan sulfate interactions[J].Semin Cancer Biol, 1992, 3(2):81-87.
    [69] Zittermann SI, Issekutz AC. Endothelial growth factors VEGF and bFGF differentially enhance monocyte and neutrophil recruitment to inflammation[J]. J Leukoc Biol,2006,80(2):247-257.
    [70] Martin TA, Harding KG, Jiang WG. Regulation of angiogenesis and endothelial cell motility by matrix-bound fibroblasts[J]. Angiogenesis, 1999, 3(1):69-76.
    [71] Anghelina M, Krishnan P, Moldovan L, et al. Monocytes/macrophages cooperate with progenitor cells during neovascularization and tissue repair: conversion of cell columns into fibrovascular bundles[J].Am J Pathol, 2006,168(2): 529-541.
    [72] Blotnick S, Peoples GE, Freeman MR, et al. T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblasts: differential production and release by CD4+ and CD8+ T cells[J]. Proc Natl Acad Sci U S A, 1994, 91(8):2890-2894.
    [73] Zhou X, Deng Y, Xie L. A study on the mechanism of bFGF promoting endothelial cells to adhere to polyurethane material [J]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 2002,19(3):386-388.
    [74] Vlodavsky I, Folkman J, Sullivan R, et al. Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix [J]. Proc Natl Acad Sci U S A, 1987,84(8) :2292-2296.
    [75] Pintucci G, Moscatelli D, Saponara F, et al. Lack of ERK activation and cell migration in FGF-2-deficient endothelial cells[J]. FASEB J, 2002,16 (6): 598-600.
    [76] Lazarous DF, Shou M, Stiber JA, et al. Pharmacodynamics of basic fibroblast growth factor: route of administration determines myocardial and systemic distribution[J]. Cardiovasc Res, 1997, 36(1):78-85.
    [77] Uchida Y, Yanagisawa-Miwa A, Nakamura F, et al. Angiogenic therapy of acute myocardial infarction by intrapericardial injection of basic fibroblast growth factor and heparin sulfate: an experimental study [J]. Am Heart J, 1995, 130(6) : 1182-1188.
    [78] Teng CJ, Luo J, Chiu RJ, et al.Mssive mechanical loss of microspheres with direct intramyocardial injection in the beating heart:implications for cellular cardiomyoplasty[J]. J Thorac Cardiovasc Surg, 2006,132(3): 628-632.
    [79] Asplund B, Sperens J, Mathisen T, et al. Effects of hydrolysis on a new biodegradable co-polymer [J]. J Biomater Sci Polym Ed, 2006, 17(6): 615-630.
    [80] Yamamoto N, Kohmoto T, Roethy W, et al. Histologic evidence that basic fibroblast growth factor enhances the angiogenic effects of transmyocardial laser revascularization[J]. Basic Res Cardiol, 2000, 95(1): 55-63.
    [81] Biswas SS, Hughes GC, Scarborough JE, et al. Intramyocardial and intracoronary basic fibroblast growth factor in porcine hibernating myocardium: a comparative study[J]. J Thorac Cardiovasc Surg, 2004,127(1): 34-43.
    [82] Lopez JJ, Edelman ER, Stamler A, et al. Basic fibroblast growth factor in a porcine model of chronic myocardial ischemia: a comparison of angiographic, echocardiographic and coronary flow parameters[J]. J Pharmacol Exp Ther, 1997, 282(1):385-390.
    [83] Baffour R, Garb JL, Kaufman J, et al. Angiogenic therapy for the chronically ischemic lower limb in a rabbit model[J]. J Surg Res, 2000, 93(2): 219-229.
    [84] Doi K, Matsuda T. Enhanced vascularization in a microporous polyurethane graft impregnated with basic fibroblast growth factor and heparin[J]. J Biomed Mater Res, 1997, 34(3):361-370.
    [1]Allen KB,Dowling RD,Fudge TL,et al.Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina[J].N Engl J Med,1999,341(14):1029-1036.
    [2]Allen KB,Dowling RD,Angell WW,et al.Transmyocardial revascularization:5-year follow-up of a prospective,randomized multicenter trial[J].Ann Thorac Surg,2004,77(4):1228-1234.
    [3]Krabatsch T,Tambeur L,Lieback E,et al.Transmyocardial laser revascularization in the treatment of end-stage coronary artery disease[J].Ann Thorac Cardiovasc Surg,1998,4(2):64-71.
    [4]Whittaker CP.Transmyocardial revascularization:the fate of myocardial channels[J].Ann Thorac Surg,1999,68(6):2376-2382.
    [5]Lutter G,Schwarzkopf J,Lutz C,et al.Histologic findings of transmyocardial laser channels after two hours[J]. Ann Thorac Surg, 1998,65(5): 1437-1439.
    [6] Cooley DA, Frazier OH, Kadipasaoglu KA, et al. Transmyocardial laser revacularization:anatomic evidence of long-term channel patency[J]. Texas Heart Inst, 1994, 21(3):220-224.
    [7] Domkowski PW, Biswas SS, Steenbergen C, et al. Histological evidence of angiogenesis 9 months after transmyocardial laser revascularization[J]. Circulation, 2001,103(3):469-471.
    [8] Mack CA. Channel patency and neovascularization after transmyocardial revascularization using an excimer laser, results and comparisons to nonlased channels[J]. Circulation, 1997, 96(9 Suppl):II 65-69.
    [9] Kohmoto T, Fisher PE, Gu A, et al. Does blood flow through holmium:YAG transmyocardial laser channels[J]. Ann Thorac Surg, 1996, 61(3):861-868.
    [10] Gassier N, Wintzer HO, Stubbe HM, et al. Transmyocardial laser revascularization histological features in human nonresponder myocardium[J]. Circulation, 1997, 95(2):371-375.
    [11] Fischer PE, Khomoto T, Derosa CM, et al.Histologic analysis of transmyocardial channels: comparison of CO_2 and Holmium: YAG lasers [J]. Ann Thorac Surg, 1997, 64(2):466-472.
    [12] Malekan R. Angiogenesis in transmyocardial laser revascularization. A nonspecific response to injury[J]. Circulation, 1998, 98(19 Suppl):II 62-66.
    [13] Chu VF, Giaid A, Kuang JQ, et al. Angiogenesis in transmyocardial revascularization: comparison of laser versus mechanical punctures[J]. Ann Thorac Surg, 1999, 68(2):301-307.
    [14] Walter PJ. Are the channels too small in transmyocardial laser revascularization[J]. Tex Heart Inst, 2002, 29(2): 154.
    [15] Li W, Chiba Y, Kimura T, et al. Transmyocardial laser revascularization induced angiogenesis correlated with the expression of matrix metalloproteinases and platelet-derived endothelial cell growth factor[J]. Eur J Cardiothorac Surg,2001,19(2):156-63.
    [16] Hamman BL, White CH, Cheung EH, et al. Transmyocardial laser revascularization causes sustained VEGF secretion. Semin Thorac Cardiovasc Surg. 2006,18(1):43-45.
    [17] Li W, Tanaka K, Chiba Y, et al. Role of MMPs and plasminogen activators in angiogenesis after transmyocardial laser revascularization in dogs[J]. Am J Physiol Heart Circ Physiol, 2003, 284(1):23-30.
    [18] Ay I, Sugimori H, Finklestein SP. Intravenous basic fibroblast growth factor (bFGF) decreases DNA fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats[J]. Brain Res Mol Brain Res, 2001, 87(1):71-80.
    [19] Jiang ZS, Padua RR, Ju H, et al. Acute protection of ischemic heart by FGF-2: involvement of FGF-2 receptors and protein kinase C[J]. Am J Physiol Heart Circ Physiol, 2002, 282(3):1071-1080.
    [20] Chu VF, Giaid A, Kuang JQ, et al. Angiogenesis in transmyocardial revascularization: comparison of laser versus mechanical punctures[J]. Ann Thorac Surg, 1999, 68(2):301-307.
    [21] Galinanes M, Loubani M, Sensky PR, et al. Efficacy of transmyocardial laser revascularization and thoracic sympathectomy for the treatment of refractory angina[J]. Ann Thorac Surg, 2004, 78(1):122-128.
    [22] Hughes GC, Baklanov DV, Biswas SS,et al. Regional cardiac sympathetic innervation early and late after transmyocardial laser revascularization[J].J Card Surg, 2004, 19(1) :21-27.
    [23] Asai T, Yamamoto S, Ishino K, et al. Time-dependent regional myocardial denervation as a nonspecific response to transmyocardial laser revascularization[J]. Ann Thorac Surg, 2005, 80(4):1362-1369.
    [24] Horvath KA, Aranki SF, Cohn LH, et al. Sustained angina relief 5 years after transmyocardial laser revascularization with a CO_2 laser[J]. Circulation, 2001,104(12 Suppl 1):I 81-84.
    [1]Mukherjee D,Bhatt DL,Roe MT,et al.Direct myocardial revascularization and angiogenesis-how many patients might be eligible[J].Am J Cardiol,1999,84(5):598-600.
    [2]Henry TD,Annex BH,McKendall GR,et al.The VIVA trial vascular endothelial growth factor in ischemia for vascular angiogenesis[J].Circulation,2003,107(10):1359-1365.
    [3]Simons M,Annex BH,Laham RJ,et al.Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2 double-Blind,randomized,controlled clinical trial[J].Circulation,2002,105(7):788-793.
    [41]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 progression of atherosclerosis[J].Circulation,1998,98(20):2108.
    [5]Lazarous DF,Shou M,Stiber JA,et al.Pharmacodynamic of basic fibroblast growth factor:route of administration determines myocardial and systemic distribution[J].Cardiovasc Res,1997,36(1):78-85.
    [6]Rajanayagam MAS,Shou M,Thirumurti V,et al.Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs[J]. J Am Coll Cardiol, 2000, 35(2):519-526.
    [7] Mazue G, Bertolero F, Garofano L, et al. Experience with the preclinical assessment of basic fibroblast growth factor (bFGF)[J]. Toxicol Lett, 1992, 64-65:329-338.
    [8] Sato K, Wu T, Laham RJ, et al. Efficacy of Intracoronary or intravenous VEGF165 in a pig model of chronic myocardial ischemia[J]. J Am Coll Cardiol, 2001, 37 (2):616-623.
    [9] Lopez JJ, Laham RJ, Stamler A, et al. VEGF administration in chronic myocardial ischemia in pigs[J]. Cardiovasc Res, 1998, 40(2):272 - 281.
    [10] Devlin GP, Fort S, Yu E, et al. Effect of a single bolus of intracoronary basic fibroblast growth factor on perfusion in an ischemic porcine model [J]. Can J Cardiol, 1999,15(6):676-682.
    [11] Voisine P, Li J, Bianchi C, et al. Effects of L-arginine on fibroblast growth factor 2 - induced angiogenesis in a model of endothelial dysfunction[J]. Circulation, 2005, 112(suppl I):202-207.
    [12] Banai S, Jaklitsch MT, Shou M, et al. Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs[J]. Circulation, 1994, 89(5):2183 - 2189.
    [13] Laham RJ, Rezaee M, Post M, et al. Intrapericardial delivery of fibroblast growth factor-2 induces neovascularization in a porcine model of chronic myocardial ischemia[J]. J Pharmacol Exp Ther, 2000, 292(2):795- 802.
    [14] Sellke FW, Laham RJ, Edelman ER, et al. Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results [J]. Ann Thorac Surg 1998, 65(6) :1540- 1544.
    [15] Biswas SS, Hughes GC, Scarborough JE, et al. Intramyocardial and intracoronary basic fibroblast growth factor in porcine hibernating myocardium:a comparative study[J].J Thorac Cardiovasc Surg, 2004,127(1): 34-43.
    [16] Schumacher BA, Pecher P, Specht BU, et al. Induction of neoangiogenesis in ischemic myocardium by human growth factors:first clinical results of a new treatment of coronary heart disease[J]. Circulation, 1998, 97(7):645-650.
    [17] Pecher P, Schumacher BA. Angiogenesis in ischemic human myocardium: clinical results after 3 years [J]. Ann Thorac Surg, 2000, 69 (5): 1414-1419.
    [18] Post MJ, Laham R, Sellke FW, et al. Therapeutic angiogenesis in cardiology using protein formulations. Cardiovasc Res, 2001, 49(3):522-531.
    [19] Harada K, Grossman W, Friedman M, et al. Basic Fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts[J]. Clinical Invest, 1994,94(2):623-630.
    [20] Laham RJ, Sellke FW, Edelman ER, et al. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery results of a phase I randomized, double-Blind, placebo-controlled trial[J]. Circulation, 1999,100(18):1865-1871.
    [21] Sakakibara Y, Tambara K, Sakaguchi G, et al. Toward surgical angiogenesis using slow-released basic fibroblast growth factor[J]. Eur J Cardio-thoracic Surgery, 2003, 24(1):105-112.
    [22] Teng CJ, Luo J, Chiu RJ, et al.Mssive mechanical loss of microspheres with direct intramyocardial injection in the beating heart:implications for cellular cardiomyoplasty[J]. J Thorac Cardiovasc Surg, 2006,132(3): 628-632.
    [23] Dow J, Simkhovich BZ, Keddes L, et al. Washout of transplated cells from the heart:a potential new hurdle for cell transplantation therapy[J]. Cardiovasc Res, 2005, 67(2):301-307.
    [24] Yamamoto N, Kohmoto T, Roethy W, et al. Histologic evidence that basic fibroblast growth factor enhances the angiogenic effects of transmyocardial laser[J]. Basic Res Cardiol, 2000, 95(1):55-63.
    [1]Gensini GG,Bruto da Costa BC.The coronary collateral circulation in living man[J].Am J Cardiol,1969,24(3):393-400.
    [2]Saito Y,Yasuno M,Ishida M,et al.Importance of coronary collaterals for restoration of left ventricular function after intracoronary thrombolysis[J].Am J Cardiol,1985,55(11):1259-1263.
    [3]Conway EM,Collen D,Carmeliet P.Molecular mechanisms of blood vessel growth[J].Cardiovasc Res,2001,49(3):507-521.
    [4]Ferrara N.Role of vascular endothelial growth factor in the regulation of angiogenesis[J].Kidney Int,1999,56(3):794-814.
    [5]Drake CJ,LaRue A,Ferrara N,et al.VEGF regulates cell behavior during vasculogenesis[J].Dev Biol,2000,224(2):178-188.
    [6]Asahara T,Takahashi T,Masuda H,et al.VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells[J].EMBO J,1999,18(14):3964-3972.
    [7]Kimura H,Weisz A,Kurashima Y,et al.Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide:control of hypoxia-inducible factor-1activity by nitric oxide[J].Blood,2000,95(1):189-197.
    [8]Suri C,McClain J,Thurston G,et al.Increased vascularization in mice overexpressing angiopoietin-1[J].Science,1998,282(5388):468-471.
    [9]Shyy YJ,Hsieh HJ,Usami S,et al.Fluid shear stress induces a biphasic response of human monocyte chemotactic protein 1 gene expression in vascular endothelium[J].Proc Natl Acad Sci U S A,1994,91(11):4678-4682.
    [10] Klagsbrun M. The fibroblast growth factor family: structural and biological properties[J]. Prog Growth Factor Res, 1989,1(4):207-235.
    [11] Ware JA, Simons M. Angiogenesis in ischemic heart disease[J]. Nat Med, 1997, 3 (2): 158-164.
    [12] Folkman J. The role of angiogenesis in tumor growth [J]. Semin Cancer Biol, 1992, 3(2): 65-71.
    [13] Senger DR. Molecular framework for angiogenesis: a complex web of interactions between extravasated plasma proteins and endothelial cell proteins induced by angiogenic cytokines[J]. Am J Pathol, 1996,149(1) :1-7.
    [14] Yamada H, Yamada E, Hackett SF, et al. Hyperoxia causes decreased expression of vascular endothelial growth factor and endothelial cell apoptosis in adult retina[J].J Cell Physiol, 1999,179(2):149-156.
    [15] Anchorage dependence, integrins, and apoptosis[J]. Cell, 1994, 77(4): 477-478.
    [16] Gospodarowicz D, Jones KL, Sato G. Purification of a growth factor for ovarian cells from bovine pituitary glands [J]. Proc Natl Acad Sci U S A. 1974;71(6):2295-2299.
    [17] Miyataka M, IshikawaK, Katori R. Basic fibroblast growth factor increased regional myocardial blood flow and limited infarct size of acutely infarcted myocardium in dogs[J]. Angiology, 1998, 49(5):381-390.
    [18] Nozaki K, Finklestein SP, Beal MF. Basic fibroblast growth factor protects against hypoxia-ischemia and NMDA neurotoxicity in neonatal rats[J].J Cereb Blood Flow Metab, 1993, 13(2):221-228.
    [19] Liu L, Pasumarthi KB, Padua RR, et al. Adult cardiomyocytes express functional high-affinity receptors for basic fibroblast growth factor [J]. Am J Physiol,1995, 268(5):1927-1938.
    [20] Lin TN, Te J, Lee M, et al. Induction of basic fibroblast growth factor (bFGF) expression following focal cerebral ischemia[J]. Brain Res Mol Brain Res, 1997,49(1-2) : 255-265.
    [21] Cohen MV, Vernon J, Yaghdjian V, et al. Longitudinal changes in myocardial basic fibroblast growth factor (FGF-2) activity following coronary artery ligation in the dog[J]. J Mol Cell Cardiol, 1994, 26(5):683-690.
    [22] Nugent MA, Karnovsky MJ, Edelman ER. Vascular cell-derived heparan sulfate shows coupled inhibition of basic fibroblast growth factor binding and mitogenesis in vascular smooth muscle cells[J].Circ Res,1993,73(6):1051-1060.
    [23]Lindner V,Reidy MA.Expression of basic fibroblast growth factor and its receptor by smooth muscle cells and endothelium in injured rat arteries.An en face study[J].Circ Res,1993,73(3):589-595.
    [24]Ferrari G,Minozzi MC,Toffano G,et al.Basic fibroblast growth factor promotes the survival and development of mesencephalic neurons in culture[J].Dev Biol,1989,133(1):140-147.
    [25]Pesenti E,Sola F,Mongelli N,et al.Suramin prevents neovascularisation and tumour growth through blocking of basic fibroblast growth factor activity[J].Br J Cancer,1992,66(2):367-372.
    [26]Yasuda T,Grinspan J,Stern J,et al.Apoptosis occurs in the oligodendroglial lineage,and is prevented by basic fibroblast growth factor[J].J Neurosci Res,1995,40(3):306-317.
    [27]Niswander L,Martin GR.FGF-4 and BMP-2 have opposite effects on limb growth[J].Nature,1993,361(6407):68-71.
    [28]Padua RR,Sethi R,Dhalla NS,et al.Basic fibroblast growth factor is cardioprotective in ischemia-reperfusion injury[5].Mol Cell Biochem,1995 23,143(2):129-135.
    [29]Hasegawa T,Kimura A,Miyataka M,et al.Basic fibroblast growth factor increases regional myocardial blood flow and salvages myocardium in the infarct border zone in a rabbit model of acute myocardial infarction[J].Angiology,1999,50(6):487-495.
    [30]周兰,常英姿,丘宗萌,等.碱性成纤维细胞生长因子对缺血/再灌注大鼠心脏的保护作用[J].基础医学与临床,1997,17(4):273-275.
    [31]Cuevas P,Carceller F,Lozano RM,et al.Protection of rat myocardium by mitogenic and non-mitogenic fibroblast growth factor during post-ischemic reperfusion[J].Growth Factors,1997,15(1):29-40.
    [32]Kent KC,Mii S,Harrington EO,et al.Requirement for protein kinase C activation in basic fibroblast growth factor-induced human endothelial cell proliferation[5].Circ Res,1995,77(2):231-238.
    [33]刘秀华,庞永政,唐朝枢等.碱性成纤维细胞生长因子对乳鼠心肌细胞缺氧复氧损伤的影响[J].生理学报,1997,49(4):455-458.
    [34] Cuevas P, Carceller F, Reimers D, et al. Fibroblast growth factor-1 inhibits medial smooth muscle cells apoptosis afterballoon injury[J]. Neurol Res, 2000, 22(2):185-188.
    [35] Tamatani M, Ogawa S, Nunez G, et al. Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide[J].Cell Death Differ, 1998, 5(10):911-919.
    [36] Kazama H, Yonehara S. Oncogenic K-Ras and basic fibroblast growth factor prevent Fas-mediated apoptosis in fibroblasts through activation of mitogen-activated protein kinase[J].J Cell Biol, 2000,148(3):557-566.
    [37] Lindner V, Lappi DA, Baird A, et al. Role of basic fibroblast growth factor in vascular lesion formation[J]. Circ Res, 1991, 68(1):106-113.
    [38] Hughes SE, Crossman D, Hall PA. Expression of basic and acidic fibroblast growth factors and their receptor in normal and atherosclerotic human arteries[J]. Cardiovasc Res, 1993, 27(7):1214-1219.
    [39] Unger EF, Banai S, Shou M, et al. Basic fibroblast growth factor enhances myocardial collateral flow in a canine model[J]. Am J Physiol, 1994, 266 (4): 1588-1595.
    [40] Wempe F, Lindner V, Augustin HG. Basic fibroblast growth factor (bFGF) regulates the expression of the CC chemokine monocyte chemoattractant protein-1 (MCP-1) in autocrine-activated endothelial cells[J]. Arterioscler Thromb Vasc Biol, 1997,17(11):2471-2478.
    [41] Kolomoets NM. Endothelial dysfunction and its clinical significance (new trend in cardiology)[J]. Voen Med Zh, 2001, 322(5):29-35, 96.
    [42] Huang Z, Chen K, Huang PL, et al. bFGF ameliorates focal ischemic injury by blood flow-independent mechanisms in eNOS mutant mice [J]. Am J Physiol, 1997, 272(3): 1401-1405.
    [43] Pinsky DJ, Aji W, Szabolcs M, et al. Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture[J]. Am J Physiol, 1999,277(3): 1189-1199.
    [44] Stefanelli C, Pignatti C, Tantini B, et al. Nitric oxide can function as either a killer molecule or an antiapoptotic effector in cardiomyocytes [J].Biochim Biophys Acta, 1999,1450(3):406-413.
    [45] Jiang ZS, Yang YZ, Zhao W, et al. Basic fibroblast growth factor increases nitric oxide and endothelin production in rat aorta[J]. Sheng Li Xue Bao, 2000, 52 (3): 211-214.
    [46]Murphy PR,Limoges M,Dodd F,et al.Fibroblast growth factor-2 stimulates endothelial nitric oxide synthase expression and inhibits apoptosis by a nitric oxide-dependent pathway in Nb2 lymphoma cells[J].Endocrinology,2001,142(1):81-88.
    [47]Schumacher B,Pecher P,von Specht BU,et al.Induction of neoangiogenesis in ischemic myocardium by human growth factors:first clinical results of a new treatment of coronary heart disease[J].Circulation,1998,97(7):645-650.
    [48]Cuevas P,Reimers D,Giménez-Gallego G.Loss of basic fibroblast growth factor in the subcommissural organ of old spontaneously hypertensive rats[J].Neurosci Lett,1996,221(1):25-28.

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