摘要
目的:近年发现交感神经的异常生长与室性心律失常发生有关,但其机制不明确,组织重构是发生折返性心律失常的重要基础。本试验目的在于了解交感神经生长是否可以直接对心室组织重构产生影响。方法:20只日本大耳白名兔随机分入神经生长因子组(NGF组)、假手术组与健康组,NGF组开胸注射NGF,假手术组开胸注射生理盐水作为对照,术后13天取心肌标本观察交感神经密度,并测定心肌羟脯氨酸、肿瘤坏死因子(TNF-a)含量,以了解交感神经生长对炎性细胞因子表达、细胞外胶原沉积的影响。结果:1.注射EGF的试验兔左室新生交感神经数量明显增多,酷氨酸羟化酶染色阳性神经密度(间隔54±14,游离壁59+22)及生长相关蛋白43阳性神经密度(间隔15±6,游离壁39+16)较假手术组明显增加.(酪氨酸羟化酶阳性密度:间隔46±13,游离壁16+10;生长相关蛋白43阳性神经密度:间隔8±5,游离壁9+4)2.NGF组心室羟脯氨酸含量较假手术组明显增加(间隔:058±0.13 vs0.37+0.13μg/mg;游离壁:0.65±0.26 vs 0.43±0.14μg/mg),NGF组TNF-a表达较假手术组有明显增加(间隔:86.7±35.4 vs 33.1+9.5 pg/mg;游离壁:86.7+354 vs32.8+11.4 pg/mg)。结论:伴随心室交感神经的生长,左室的炎症因子表达及胶原沉积增加,说明交感神经的异常生长可以直接影响心肌组织重构,促进室性心律失常基质发生。
Objective: It is considered that sympathetic nerve sprouting plays an important role in sudden cardiac death.However mechanisms of inducing arrhythmia by sympathetic nervesprouting are still unknown.Structural remodeling are basic arrhythmogenesis changes in patiesnts suffer from sudden cardiac death.This study was designed to determine weather sympathetic nervesprouting could also induce structural remodeling. Methods: Twenty Japanese white rabbits are randomized into three groups.Sympathetic nerve sprouting was induced by injection of nerve growthfactor(NGF)into myocardium and sham operation served as controls.Thirteen days after operation.Immunocytochemical staining for Tyrosine hydroxyase(TH)and growth-associated protein-43(GAP43)wasperformed to study the density of sympathetic nerves in myocardium.TNF-a level was measured by ELISA.Hydroxyproline content was detected by alkaline hydrolysis method. Results: 1.Densityof nerve fibers immunopositive to TH and GAP-43 was significantly higher in NGF group than those of controls. 2.Cardiac collagen content as well as TNF-a level in NGF infused rabbits increasedsignificantly compared to controls or healthy subjects. Conclusions: Rabbits with cardiac sympathetic nerve sprouting manifested higher expression of inflammation factor and increased collagenaccumulation.The findings suggest that sympathetic nerve sprouting could cause ventricular arrhythmia by promote cardiac structural remodeling.
引文
[1]Marron K,Wharton J,Sheppard MN,et al.Distribution,morphology,and neurochemistry of endocardial and epicardial nerve arborization in the human heart.Ciculation 1995;92:2343-2351
[2]CHEN P S,CHEN L S,CAO JM,et al.Sympathetic nerve sprouting,electrical remodeling and the mechanisms of sudden cardiac death.Cardiovasc Res,2001,50(2):409-416
[3]YANOWITZ F,PRESTON J B,ABILDSKOV J A.Functional distribution of right and left stellate innervation to the ventricles.Production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone.Circ Res,1966,18(4):416-428.
[4]Ji-Min Cao,Michael C Fishbein,Jan B.Han,et al.Relationship between regional cardiac hyperinnervation and ventricular arrhythmis.Circulation.2000;101:1960-1969
[5]T.Nakata,K.Miyarnoto,A.Doi,et al.Cardiac death prediction and impaired cardiac sympathetic innervation asecssed by metaiodobenzylguanidine in patients with failing and non-failing hearts J.Nucl.Cardiol.1998;5:579-590
[6]Ji-Min Cao,Lan S.Chen,Bruce H.Ken Knight,et al.Nerve Sprouting and Sudden Cardiac Death.Circ Res.2000;86:816-821
[7]Moshe Swiss,Shengmei Zhou,Ignacio Gonzalez-Gonez,et al.Long-term aubthexhold electrical stimilation of the left stellate ganglion and a canine model of sudden cardiac death.JACC 2004;43:868-864
[8]Sybil T.Lockhart,Gian G,Turrigiano,Susan J,Birren.Nerve growth factor modulates sy m patic transmission between syapathetic neurons and cardiac myocytea J,Neuroeci 1997:17(24):9573-9582
[9]REN C,WANG F,LI G,et al.Nerve sprouting suppressesmyocardial I(to)and I(K1)channels and increases severity toventricular fibrillation in rat.Auton Neurosci,2008,144(1-2):22-29.
[10]FF Di Mola,H Friess,Zw Zhu,et al.Nerve grouth factor and Trk high affinity receptor(Trk A)gene expression in inflammatory bowel disease.Gut 2000;46:670-678
[11]Micera A,Vignei E,Pickholtz D,et al.Nerve grouth factor displays stimulatory effects on human skin and lung fibroblasts,demonstrating a direct role for this factor in tissue repair.Proc Natl Acad Sci USA 2001:98;6162-6167.
[12]Joseph Francjs,Zhi-Hua Zhang,Robert M.Weiss,et al.Neuralegulation of the proinflammatory cytokine response to acute myocardial infarction.Am J Physiol Heart Circ Physiol2004;287:H791-797
[13]Peng J,Gurantz D,Tran V,Cowling RT,Greenberg BH.Tumor necrosis factor-alpha-induced AT1 receptor upregulation enhances angiontensinⅡ-mediated cardiac fibroblast responses that favor fibrosis.Circ Res.2002;91:11119-1126.
[14]Sia YT,Parker TG,Tsoporis JN,Liu P,Adam A,Rouleau JL.Long-term effects of carvedilol on left ventrictular function,remodeling,and expression of cardiac cytokines after large myocardial infarction in the rat.J Cardivoasc Pharmacol.2002;39:73-87.
[15]Puhakka M,Magga J,Hietakorpi S,Penttila I,Uusimaa P,Risteli P,Risteli J,Peuhkurinen K.Interleukin-6 and tumor necrosis factor alpha in relation to myocardial infarct size and collagen formation.J Cardiac Failure.2003;9:325-332.
