富路韩颖哈尔滨医科大学附属第一医院心内科.ppt

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1、富路韩颖哈尔滨医科大学附属第一医院心内科 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望 The First Clinical College of Harbin Medical UniversityCardiac Contractility交感神经系统在心力衰竭中的作用交感神经系统在心力衰竭中的作用Peripheral PerfusionSympathetic ActivationApoptosis、Necrosis、Fibrosis、Hypertrophy -

2、Adrenergic desensitization Sympathetic RemodelingCardiac RemodelingVicious Cycle The First Clinical College of Harbin Medical University 研究背景研究背景Androgen beneficial?deleterious?女女 性性CHF发病率发病率死亡率死亡率 男男 性性Estrogenic protection The First Clinical College of Harbin Medical University研究背景研究背景Deficiencies

3、 in DHEAS,TT,eFT and IGF-1 were Deficiencies in DHEAS,TT,eFT and IGF-1 were seen across all age categories in men with CHFseen across all age categories in men with CHFDHEAS,TT and eFT were inversely related to DHEAS,TT and eFT were inversely related to NYHA class irrespective of causeNYHA class irr

4、espective of causeMen with CHF and normal level of all anabolic Men with CHF and normal level of all anabolic hormones had the best 3-year survival rate(83%)hormones had the best 3-year survival rate(83%)compared with those with deficencies in 1(74%),compared with those with deficencies in 1(74%),2(

5、55%),or all 3(27%)anabolic endocrine axes2(55%),or all 3(27%)anabolic endocrine axes The First Clinical College of Harbin Medical University雄激素的神经保护作用？雄激素的神经保护作用？男性的心脏交感神经活性高于女性男性的心脏交感神经活性高于女性雄鼠心梗后交感神经激活诱发的心律失常雄鼠心梗后交感神经激活诱发的心律失常明显更重于雌鼠明显更重于雌鼠 雄激素参与神经系统发育过程雄激素参与神经系统发育过程睾酮减轻睾酮减轻缺氧缺血性脑损伤时大脑缺氧缺血性脑损伤时大脑皮

6、质神经细胞凋亡皮质神经细胞凋亡 睾酮可以使运睾酮可以使运动神经元、骨动神经元、骨盆自主神经元盆自主神经元体积增大，改体积增大，改善突触形成和善突触形成和突触传递的可突触传递的可塑性塑性 睾酮可以激睾酮可以激活胆碱乙酰活胆碱乙酰基转移酶和基转移酶和酪氨酸羟化酪氨酸羟化酶酶，影响，影响NE的合成、贮的合成、贮存和释放存和释放 The First Clinical College of Harbin Medical University 实验目的实验目的 观察内源性雄激素缺乏及生理剂量睾酮观察内源性雄激素缺乏及生理剂量睾酮补充治疗对慢性心力衰竭雄鼠心脏交感神补充治疗对慢性心力衰竭雄鼠心脏交感神经重构

7、的作用经重构的作用实验方法实验方法Wistar雄鼠雄鼠60只只（20020g）去势去势/假去势术假去势术后后1w1w给予异丙肾给予异丙肾340mg/kg,340mg/kg,共共2 2次次正常组ControlS-Cas+PlaCas+PlaCas+TesCas+Tes+Flu术术后后予花生油予花生油2g/kg,2g/kg,1 1次次/2d,/2d,共共8 8周周术术后后予花生油予花生油2mg/kg,2mg/kg,1 1次次/2d,/2d,共共8 8周周术术后后予睾酮予睾酮2mg/kg,2mg/kg,1 1次次/2d,/2d,共共8 8周周术术后后予睾酮予睾酮2mg/kg,2mg/kg,1 1次次

8、/2d,/2d,氟他胺氟他胺3030mg/kg，1次次/2d,共共8 8周周血流动力学血流动力学心肌心肌NE血浆血浆NE免疫组化免疫组化THNGFWesternTHNGF是NE合成的限速酶，其阳性表达可代表交感神经在心脏中的分布。是神经营养因子家族的代表，对交感神经的生长、分化、存活、突触功能调控都有重要作用实实 验验 结结 果果 The First Clinical College of Harbin Medical University血流动力学结果血流动力学结果组别组别 例数例数HR,beats/min LVSDP,mmHg LVEDP,mmHg Left ventricular dP/

9、dt,mmHg/s Control 1036729 109.68.8 5.32.6 4587.6566.8 S-cas+Pla 941425*87.59.3 *18.92.5 *3352.0639.9 *Cas+Pla 842522*82.49.1*23.72.7 *3064.3594.7*Cas+Tes 1040821 92.39.6 *16.83.1 *3467.7435.0 *Cas+Tes+Flu 940426 88.710.1 *17.52.9 *3212.0618.6 *与与Control组比较，组比较，*P0.05；与；与Cas+HF+P组比较，组比较，P0.05。表表1 1 各

10、组大鼠各组大鼠血流动力学血流动力学指标比较指标比较 The First Clinical College of Harbin Medical University血浆及心肌血浆及心肌NE*与正常组比较，与正常组比较，*P0.05 与与Cas+HF+P组比较，组比较，P0.05 The First Clinical College of Harbin Medical University 心肌心肌 TH免疫组化染色免疫组化染色 正常组正常组S-cas+PlaS-cas+Pla组组组组Cas+PlaCas+Pla组组Cas+TesCas+TesCas+Tes+FluCas+Tes+Flu组组 Th

11、e First Clinical College of Harbin Medical University心肌心肌 TH免疫组化染色免疫组化染色*与正常组比较，与正常组比较，*P0.05 与与Cas+HF+P组比较，组比较，P0.05每组大鼠观察两张切片，每每组大鼠观察两张切片，每张切片计数张切片计数5个（个（200）阳性率评定标准阳性率评定标准为结合表达为结合表达面积和染色强度综合判定。面积和染色强度综合判定。The First Clinical College of Harbin Medical University 心肌心肌 NGF免疫组化染色免疫组化染色 正常组正常组S-cas+Pla

12、S-cas+Pla组组组组Cas+PlaCas+Pla组组Cas+TesCas+Tes组组Cas+Tes+FluCas+Tes+Flu组组 The First Clinical College of Harbin Medical University心肌心肌 NGF免疫组化染色免疫组化染色 与正常组比较，与正常组比较，*P0.05 与与Cas+HF+P组比较，组比较，P0.05每组大鼠观察两张切片，每每组大鼠观察两张切片，每张切片计数张切片计数5个（个（200）阳性率评定标准阳性率评定标准为结合表达为结合表达面积和染色强度综合判定。面积和染色强度综合判定。*The First Clinical

13、 College of Harbin Medical University心肌心肌TH Western Blot 与正常组比较，与正常组比较，*P0.05；与；与Cas+HF+P组比较，组比较，P0.05TH60kDaGAPDH36kDaControlS-cas+Pla Cas+Pla Cas+Tes Cas+Tes+Flu*The First Clinical College of Harbin Medical University心肌心肌NGF Western Blot 与正常组比较，与正常组比较，*P0.05；与；与Cas+HF+P组比较，组比较，P0.05NGF13kDaGAPDH36

14、kDaControlS-cas+Pla Cas+Pla Cas+Tes Cas+Tes+Flu*讨讨 论论 The First Clinical College of Harbin Medical University心衰时心肌坏死、纤维瘢痕形成心衰时心肌坏死、纤维瘢痕形成心脏交感神经心脏交感神经轴索受其影响而出现功能障碍轴索受其影响而出现功能障碍心衰时血浆心衰时血浆NE作用于心肌细胞作用于心肌细胞心肌中心肌中NGF的含的含量降低量降低交感神经分布减少交感神经分布减少THTH、NGFNGF，心脏交感神经分布密度心脏交感神经分布密度交感神经失支配交感神经失支配交感神经失支配交感神经失支配动动 物

15、物心衰交感神经重构心衰交感神经重构血浆血浆NE 水平水平，心肌心肌NE含量含量心肌心肌心肌心肌NENE耗竭耗竭耗竭耗竭释放释放 NE再摄取再摄取NE TH，NE合成合成心心衰衰交交感感神神经经过过度度激激活活心肌心肌NE耗竭耗竭触触发发反反应应迟迟钝钝 The First Clinical College of Harbin Medical University本研究显示本研究显示心肌心肌NENE含量含量THTH、NGFNGF阳性神经密度阳性神经密度心肌心肌THTH、NGFNGF蛋白表达蛋白表达 去势去势生理睾酮替代生理睾酮替代心脏交感神经重构心脏交感神经重构 The First Clinic

16、al College of Harbin Medical UniversityAndrogen signal transductionTTarget cell Nongenomic effectsT5-reductasearomataseDHTTE2ARER/Genomic effectsCell functionGrowthDifferentiationProliferationapoptosis本实验中应用本实验中应用AR阻断剂未能阻断睾酮的神经保护作用阻断剂未能阻断睾酮的神经保护作用 The First Clinical College of Harbin Medical Univers

17、ity结结 论论 在慢性心力衰竭雄性大鼠，内源性睾酮水平下降加在慢性心力衰竭雄性大鼠，内源性睾酮水平下降加在慢性心力衰竭雄性大鼠，内源性睾酮水平下降加在慢性心力衰竭雄性大鼠，内源性睾酮水平下降加重了心功能不全，并加重心脏交感神经重构；重了心功能不全，并加重心脏交感神经重构；重了心功能不全，并加重心脏交感神经重构；重了心功能不全，并加重心脏交感神经重构；生理剂量睾酮替代治疗可以改善大鼠的心功能和心生理剂量睾酮替代治疗可以改善大鼠的心功能和心生理剂量睾酮替代治疗可以改善大鼠的心功能和心生理剂量睾酮替代治疗可以改善大鼠的心功能和心脏交感神经重构。脏交感神经重构。脏交感神经重构。脏交感神经重构。这为睾

18、酮补充治疗男性慢性心衰的临床这为睾酮补充治疗男性慢性心衰的临床可行性提供了理论依据。可行性提供了理论依据。12 The First Clinical College of Harbin Medical UniversityLu Fu,Ying HanLu Fu,Ying Han Cardiovascular Department,First Affiliated Cardiovascular Department,First Affiliated Hospital,Harbin Medical University,ChinaHospital,Harbin Medical University

19、,China The effects of testosterone upon cardiac sympathetic function in rats with induced heart failure The First Clinical College of Harbin Medical UniversityCardiac ContractilityThe sympathetic system in CHFPeripheral PerfusionSympathetic ActivationApoptosis、Necrosis、Fibrosis、Hypertrophy -Adrenerg

20、ic desensitization Sympathetic RemodelingCardiac RemodelingVicious Cycle The First Clinical College of Harbin Medical UniversityBackgroundAndrogen beneficial?deleterious?FemalesCHFmorbiditymortality MalesEstrogenic protection The First Clinical College of Harbin Medical UniversityBackgroundDeficienc

21、ies in DHEAS,TT,eFT and IGF-1 were Deficiencies in DHEAS,TT,eFT and IGF-1 were seen across all age categories in men with CHFseen across all age categories in men with CHFDHEAS,TT and eFT were inversely related to DHEAS,TT and eFT were inversely related to NYHA class irrespective of causeNYHA class

22、irrespective of causeMen with CHF and normal level of all anabolic Men with CHF and normal level of all anabolic hormones had the best 3-year survival rate(83%)hormones had the best 3-year survival rate(83%)compared with those with deficencies in 1(74%),compared with those with deficencies in 1(74%)

23、,2(55%),or all 3(27%)anabolic endocrine axes2(55%),or all 3(27%)anabolic endocrine axes The First Clinical College of Harbin Medical UniversityNeuroprotective effects of testosterone This hormone has been linked to an increase in neuronal somal size,neuritic growth,plasticity and synaptogenesis in b

24、oth motoneurons of the spinal nucleus of the bulbocavernosus and several populations of pelvic autonomic neurons Males have higher sympathetic cardiac autonomic activity than females.Post-infarction arrhythmias induced by sympathetic activation are more severe in male than female rats.Testosterone a

25、ctivates choline acetyltransferase and tyrosine hydroxylase(TH)and influences NE metabolism,storage,and release Testosterone is involved with nervous system development.Some research has shown that androgen has a neuroprotection against hypoxia-ischemia brain damage.The First Clinical College of Har

26、bin Medical University Aim The current study was designed to determine whether castration with or without testosterone replacement resulted in changes in cardiac sympathetic nerve activity in rats with induced heart failure.Methods60 Wistar male rats（20020g）1w after castration/sham-castration,rats r

27、eceived a subcutaneous injection of isoproterenol at 340 mg/kg,a total of two injections ControlS-Cas+PlaCas+PlaCas+TesCas+Tes+Flupeanut oil 2g/kg,1/d,for 8 weekspeanut oil 2g/kg,1/d,for 8 weekstestosterone 2mg/kg,1/d,for 8 weekstestosterone 2mg/kg,flutamide 25mg/kg,1/d,for 8 weeksMyocardial NEplasm

28、a NEImmunohisto-chemistry THNGFWestern Blot analysis THNGFresting hemodyna-micsResults The First Clinical College of Harbin Medical UniversityResults of resting hemodynamics *P0.05 vs control group；P0.05 vs Cas+Pla group。Table 1 results of resting hemodynamics group nHR,beats/min LVSDP,mmHg LVEDP,mm

29、Hg Left ventricular dP/dt,mmHg/s Control 1036729 109.68.8 5.32.6 4587.6566.8 S-cas+Pla 941425*87.59.3 *18.92.5 *3352.0639.9 *Cas+Pla 842522*82.49.1*23.72.7 *3064.3594.7*Cas+Tes 1040821 92.39.6 *16.83.1 *3467.7435.0 *Cas+Tes+Flu 940426 88.710.1 *17.52.9 *3212.0618.6 *The First Clinical College of Har

30、bin Medical Universitythe plasma and cardiac NE contents*P0.05 vs control group P0.05 vs Cas+Pla group The First Clinical College of Harbin Medical University Immunohistochemical staining for TH Control groupS-cas+Pla groupS-cas+Pla groupCas+PlaCas+Pla groupCas+Tes groupCas+Tes groupCas+Tes+Flu grou

31、pCas+Tes+Flu group The First Clinical College of Harbin Medical Universitythe TH-positive nerve cell density*The density of TH-labeled nerve fibers was quantitatively estimated from 10 randomly selected fields at a magnification of 200.The nerve density was measured on tracings by computerized plani

32、metry.*P0.05 vs control group P0.05 vs Cas+Pla group The First Clinical College of Harbin Medical University Immunohistochemical staining for NGFControl groupgroupS-cas+Pla groupS-cas+Pla groupCas+Pla groupCas+Pla groupCas+Tes groupCas+Tes groupCas+Tes+Flu groupCas+Tes+Flu group The First Clinical C

33、ollege of Harbin Medical Universitythe NGF-positive nerve cell density 与正常组比较，与正常组比较，*P0.05 与与Cas+HF+P组比较，组比较，P0.05*The density of TH-labeled nerve fibers was quantitatively estimated from 10 randomly selected fields at a magnification of 200.The nerve density was measured on tracings by computerize

34、d planimetry.The First Clinical College of Harbin Medical University the expression of TH protein *P0.05 vs control group；P0.05 vs Cas+Pla group。TH60kDaGAPDH36kDaControlS-cas+Pla Cas+Pla Cas+Tes Cas+Tes+Flu*The First Clinical College of Harbin Medical Universitythe expression of NGF protein *P0.05 v

35、s control group；P0.05 vs Cas+Pla group。NGF13kDaGAPDH36kDaControlS-cas+Pla Cas+Pla Cas+Tes Cas+Tes+Flu*DiscussionDiscussion The First Clinical College of Harbin Medical UniversityMyocardial ischaemia and cell deathcardiac cardiac sympathetic nerve fiber dysfunctionsympathetic nerve fiber dysfunctionP

36、lasma NE affects myocardiumNGF the density of cardiac sympathetic nerve TH、NGF，the density of cardiac sympathetic nervescardiac sympathetic remodelingcardiac sympathetic remodeling Sympathetic Remodeling in CHFplasma NE，myocardial NEexhaust of myocardial NEexhaust of myocardial NENE releaseNE reupta

37、ke THNE synthesis exhaust of exhaust of myocardial NEmyocardial NEover-activation ofcardiac sympathetic nervous system The First Clinical College of Harbin Medical UniversityWhat the reasearch tell usWhat the reasearch tell usmyocardial NE contentTH/NGF positive nerve densityTH/NGF protein expressio

38、nCastrationCastrationTestosterone Testosterone replacementreplacementCardiac sympathetic remodeling The First Clinical College of Harbin Medical UniversityAndrogen signal transductionTTarget cell Nongenomic effectsT5-reductasearomataseDHTTE2ARER/Genomic effectsCell functionGrowthDifferentiationProli

39、ferationapoptosisFlutamide failed to block the testosterone-induced neuroprotective effects on the cardiac sympathetic nervous system in castrated rats with heart failure The First Clinical College of Harbin Medical UniversityConclusions E Endogenous testosterone deprivation in rats significantly nd

40、ogenous testosterone deprivation in rats significantly worsened cardiac function and sympathetic function during worsened cardiac function and sympathetic function during pathophysiological changes associated with heart failurepathophysiological changes associated with heart failure；T Testosterone r

41、eplacement reversed these adverse effects.estosterone replacement reversed these adverse effects.Therefore,androgens may play an important role in modulating Therefore,androgens may play an important role in modulating pathophysiological changes in the cardiac sympathetic nervous system that pathoph

42、ysiological changes in the cardiac sympathetic nervous system that result from heart failure and our findings suggest the potential for beneficial result from heart failure and our findings suggest the potential for beneficial effects of testosterone in the treatment of this condition.effects of testosterone in the treatment of this condition.12 The First Clinical College of Harbin Medical University