左西孟旦和米力农治疗对心力衰竭患者血管内皮因子、心室重构及心功能的影响

目的探讨并对比左西孟旦和米力农对心力衰竭患者血管内皮因子、心室重构及心功能的影响。方法将2016年6月至2018年6月医院收治的80例急性失代偿期心力衰竭患者随机分为左西孟旦组和米力农组,每组各40例。治疗前和治疗7d采用超声心动图检测心功能参数[左心室收缩末期内径(left ventricular end systolic diameter,LVESD)、左心室舒张末期内径(left ventricular end diastolic diameter,LVEDD)、左心室射血分数(left ventricular ejection fractions,LVEF)],检测血清N-末端前体脑钠肽(N-terminal pro-B-type natriuretic peptid,NT-pro BNP)、血管内皮生长因子(vascular endothelial growth factor,VEGF)、白介素6(Interleukin-6,IL-6)、肿瘤坏死因子α(tumor necrosis factor-α,TNF-α),治疗结束后2个月行6min步行实验(6-minute walk test,6MWT),记录两组不良反应。结果左西孟旦组治疗后LVESD值低于米力农组,LVEF值高于米力农组,差异有统计学意义(P <0.05),但两组治疗后LVEDD值比较,差异无统计学意义(P>0.05);左西孟旦组治疗后NT-pro BNP水平低于米力农组,6MWT距离长于米力农组,差异有统计学意义(P<0.05);左西孟旦组治疗后VEGF水平高于米力农组,IL-6、TNF-α水平低于米力农组,差异有统计学意义(P<0. 05),两组不良反应发生率比较,差异无统计学意义(P>0. 05)。结论左西孟旦、米力农均可用于治疗心力衰竭患者心室重构,改善心功能,但短期效果而言,左西孟旦优于米力农。     

miR-30a在心肌梗死大鼠心肌纤维化中的作用机制及对心功能的影响

目的探讨miR-30a在大鼠心肌梗死后对心肌纤维化的作用机制及对心功能的影响。方法构建携带大鼠miR-30a基因的载体,在HEK293细胞中包装病毒载体r AAV9-miR-30a及阴性对照r AAV9-miR-30a-NC,提取纯化后通过冠脉注射方法分别传导PBS缓冲液、r AAV9-miR-30-NC和r AAV9-miR-30a至大鼠心脏,再建立大鼠心肌梗死模型,分别设为PBS组、miR-30-NC组和miR-30a组,同时设立假手术组(sham组)。用心脏彩色多普勒超声检测心功能指标,包括短轴缩短率(FS)及左室射血分数(LVEF);Masson染色观察心肌胶原容积分数(CVF);免疫组化法检测Ⅰ、Ⅲ型胶原表达;实时荧光定量PCR(real-time PCR)检测心肌miR-30a及TGF-β1和CTGF mRNA表达;蛋白印迹法(Western blot)检测TGF-β1及CTGF蛋白的表达。结果 miR-30a组心功能较PBS组及miR-30-NC组显著改善(P0.05)。miR-30a组的心肌CVF及Ⅰ、Ⅲ胶原表达水平、Ⅰ/Ⅲ型胶原比值较PBS组及miR-30-NC组显著降低(P0.01);miR-30a组心肌TGF-β1 mRNA及蛋白表达水平与PBS组及miR-30-NC组比较显著下降(P0.001);CTGF mRNA及蛋白表达水平较PBS组及miR-30-NC组显著降低(P0.001)。结论 miR-30a过表达能下调心肌梗死后心肌TGF-β1、CTGF mRNA及蛋白水平,从而减少心肌胶原产生,抑制心肌纤维化,进而改善心功能。     

可溶性TGFβRⅡ对大鼠心肌梗死后心功能的影响

目的: 观察可溶性转化生长因子βⅡ型受体(sTGFβRⅡ)对大鼠心肌梗死(MI)后心功能的影响,并探讨其可能机制。方法: 结扎左冠状动脉前降支,建立SD大鼠MI模型,3 d后存活大鼠进行实验,随机分为MI组、pAd-sTGFβRⅡ组(携带TGFβRⅡ胞外区基因即sTGFβRⅡ的重组腺病毒载体转染)和空载体组,并另设假手术组。4周后,超声心动图检测各组大鼠心率(HR)、左心室舒张末期直径(LVEDD)、左心室收缩末期直径(LVESD)和射血分数(EF)的变化,取心肌冰冻切片在荧光显微镜下观察sTGFβRⅡ基因在心肌组织中的表达,天狼星红-饱和苦味酸染色法检测Ⅰ、Ⅲ型胶原的表达,RT-PCR和免疫组化法分别检测基质金属蛋白酶9(MMP-9)mRNA和蛋白的表达,明胶酶谱法分析MMP-9的活性。结果: (1)与假手术组比较,MI组和空载体组HR、LVEDD、LVESD、Ⅰ和Ⅲ型胶原、MMP-9 mRNA和蛋白表达量及其活性均明显增加(P<0.01),EF明显下降(P<0.01)。(2)与MI组比较,pAd-sTGFβRⅡ组HR、LVEDD和LVESD明显减小(P<0.01),EF明显升高(P<0.01);Ⅰ和Ⅲ型胶原、MMP-9 mRNA和蛋白表达量及其活性均明显下降(P<0.01),但仍高于假手术组。结论: sTGFβRⅡ干预能够改善MI后心功能,抑制TGF-β介导的MMP-9表达可能是其机制之一。     

急性心肌梗死后早期血浆心肌纤维化相关指标的变化

目的:观察急性心肌梗死早期内源性松弛素(H2RLX)和Ⅰ型前胶原C端末端肽（PICP）、 转化生长因子（TGF-β1）的的表达。方法:入选41名急性心肌梗死患者和冠脉血管正常的对照组10名。心肌梗死后 3 d、7 d分别抽静脉血,用ELISA方法检测H2RLX和PICP、 TGF-β1,对照组在入选后抽静脉血检测H2RLX和PICP、 TGF-β1。结果:(1)心肌梗死后3 d H2RLX与对照组比较,没有显著差异。梗死后3 d和7 d的H2RLX水平没有明显变化。(2) 梗死后3 d PICP 水平显著高于对照组, PICP在梗死后7 d的水平显著低于梗死后3 d的水平。(3) 梗死后3 d TGF-β1与梗死后7 d TGF-β1保持在较高水平,两个时点的TGF-β1水平均明显高于对照组。(4) 梗死后7 d松弛素水平和心肌梗死组的空腹血糖呈正相关。结论:在心肌梗死早期血浆中没有内源性松弛素表达的增加,但心肌胶原形成及前纤维化因子表达增加。     

雌激素对急性心肌梗死前后去卵巢大鼠干细胞及心功能的影响

目的去卵巢大鼠发生急性心肌梗死前后,应用雌激素干预,观察其外周血干细胞的变化及其对心功能的影响。方法将30只SD雌性大鼠分为正常对照组、急性心肌梗死组、去卵巢心肌梗死组、去卵巢雌激素替代组及去卵巢雌激素治疗组。用流式细胞术检测各组CD90 细胞的百分率;用POWERLAB4.12系统测量左室收缩末压(LVESP)、左室舒张末压(LVEDP)、 dp/dtmax及-dp/dtmax。结果去卵巢心肌梗死组外周血CD90 细胞的百分率显著低于急性心肌塞组及去卵巢雌激素替代组(P<0.01);而去卵巢雌激素替代组心梗后第1天外周血CD90 细胞的百分率即显著升高(P<0.05),第3天达峰值,且数值较高。去卵巢雌激素治疗组与去卵巢心肌梗死组相比较,仅在心梗后7d外周血CD90 细胞的百分率才开始升高;但与去卵巢雌激素替代组相比,心梗术后7d内各时点均较低。各组LVESP均有所下降,以急性心肌梗死组为著;而LVEDP均有升高,以去卵巢心肌梗死组及去卵巢雌激素治疗组最明显(P<0.01)。结论去卵巢大鼠在心肌梗死之前应用雌激素替代治疗,外周血CD90 细胞的百分率较高,且心功能明显优于去卵巢大鼠在心肌梗死后应用雌激素替代治疗。     

抑制HMGB1对心肌梗死大鼠模型心肌纤维化的影响及机制研究

目的:探讨抑制高迁移率族蛋白B1(HMGB1)对心肌梗死(MI)大鼠心肌纤维化的影响及机制.方法:15只雄性SD大鼠随机分为正常组、模型组、HMGB1抑制组,每组5只,结扎冠状动脉缺血30 min再灌注法构建MI模型,HE染色观察心肌组织病理变化,Masson染色观察心肌组织纤维化程度,Western blot检测Ⅰ型...     

当归对大鼠心肌梗死后心肌纤维化的影响及机制

目的： 观察转化生长因子-β1(TGF-β₁)、巨噬细胞在心肌梗死后心肌纤维化发生发展过程中的变化及当归的治疗作用，探讨心肌梗死后心肌纤维化的发生及当归的干预机制。 方法： 结扎SD大鼠冠脉前降支复制心肌梗死模型，随机分为假手术（sham）组、心肌梗死（MI）组和心肌梗死当归（MI+angelica）组。术后24 h开始给药，MI+angelica组腹腔注射当归（20 mL·kg^-1·d^-1，相当于生药10 g·kg^-1·d^-1），sham组和MI组腹腔注射等量生理盐水。于术后1、2、4周记录左室血流动力学改变，检测非梗死区心肌胶原含量、TGF-β₁及巨噬细胞的变化。 结果： ① MI组和MI+angelica组非梗死区心肌TGF-β₁及巨噬细胞阳性表达显著高于sham组（P<0.01），以1周的阳性表达为最高，但MI+angelica组低于MI组（P<0.01）；② 术后各时点MI组心功能受损，于术后2周和4周心肌胶原含量明显高于sham组（P<0.01）；术后4周MI+angelica组心功能损害轻于MI组，心肌胶原含量低于MI组（P< 0.01）。 结论： 当归通过抑制巨噬细胞在非梗死区的浸润、下调TGF-β₁的表达，阻断促纤维化发生的环节，减轻心肌梗死后非梗死区反应性胶原的过度沉积，防治心肌梗死后心肌纤维化，改善心脏功能。     

过继转输急性心肌梗死大鼠脾细胞介导心肌损伤

目的 :探讨自身免疫反应在急性心肌梗死 (AMI)后心肌损伤中的作用。方法 :复制AMI大鼠模型和假手术作对照 ,6周后将 10 0× 10 6 ～ 15 0× 10 6 脾细胞过继转输给同源近交大鼠 ;4周后检测受者大鼠血流动力学、组织病理和抗肌球蛋白重链 (MHC)抗体。结果 :AMI大鼠和转输大鼠 (AMI T组 ) (8 2 2只 )血清中检测到抗MHC抗体 ,假手术大鼠和转输大鼠(Sham T组 ) (0 2 0只 )均为阴性 (P <0 0 5 ) ;AMI T组 (n =10 )大鼠发生心脏特异性炎症反应和心功能受损 ,Sham T组心脏无异常变化。结论 :AMI T大鼠发生了淋巴细胞介导心肌损伤和心功能下降 ,心肌自身免疫反应可能是AMI后心室重塑的新颖机制。     

大鼠急性心肌梗死区域miRNA-29和miRNA-21的动态变化与心功能的关系

目的 探讨大鼠急性心肌梗死后早期梗死区域miRNA-29和miRNA-21的动态变化与心功能的关系.方法 SD雄性大鼠25只,结扎冠状动脉前降支,建立大鼠心肌梗死模型,分为术后7、14、21、28 d组和假手术组(对照组),每组各5只.彩色超声心动图检测大鼠左室射血分数(LVEF)、左室短轴缩短率(LVFS)和左室舒张末期内径(LVIDd).石蜡切片,苏木精-伊红(HE)和Masson染色.Western blotting检测大鼠心肌梗死后梗死区的胶原纤维I(I)和弹性蛋白(E)的变化.实时荧光定量聚合酶链法检测大鼠心肌梗死区域miRNA-29和miRNA-21的水平.结果 大鼠心肌梗死后,心功能下降,2周时LVEF和LVFS下降至最低,后缓慢升高(P<0.05);胶原I逐渐升高(P<0.01),弹性蛋白E逐渐降低(P<0.05).而且较对照组,心肌梗死区miRNA-29于第1周上升明显,第2周迅速下降(P<0.01);miRNA-21第2周明显上升,后逐渐下降(P<0.01).结论 miRNA-29和miRNA-21表达升高可能在急性心肌梗死早期的心功能降低中起重要作用.     

单核/巨噬细胞调控心梗后心肌纤维化的研究进展

<正>急性心肌梗死(acute myocardial infarction,AMI)是一种严重的缺血性心脏病,持续的心肌缺血可导致心肌细胞大量凋亡或坏死而丢失。心肌纤维化(myocardial fibrosis,MF)是指在心肌的正常组织结构中胶原纤维过量积聚、心脏组织中胶原浓度显著升高或胶原成分发生激剧改变,导致心脏僵硬度增加、心功能下降。MF是心肌梗死的主要病理生理学过程,可导致心脏重构(cardiac remodeling),并逐渐发展为慢性心力衰竭(chronic heart failure,CHF)^[1]。     

Livin基因修饰的骨髓间充质干细胞移植治疗对急性心肌梗死大鼠心功能的影响

 目的: 探讨livin修饰的骨髓间充质干细胞(MSCs)移植改善急性心肌梗死大鼠心功能的作用及livin和促凋亡蛋白caspase-3、caspase-7、caspase-9在感染后的表达情况。方法: 通过全骨髓培养法分离培养骨髓间充质干细胞,感染携带livin基因的重组腺病毒后用流式检测其对MSCs凋亡的影响。通过Western blot法分别检测livin、caspase-3、caspase-7和caspase-9的蛋白表达情况。采用冠状动脉左前降支结扎法建立心肌梗死模型,然后实验分4组进行:无胎牛血清的DMEM组;单纯干细胞治疗组(MSCs组);空载腺病毒转染干细胞组(rAd-control/MSCs)组;livin基因转染干细胞组(rAd-livin/MSCs组)。1个月后采用生理仪记录各组大鼠左室收缩压(LVSP)、左室舒张末压(LVEDP)、左室内压最大上升速率(+dp/dt_max)和左室内压最大下降速率(-dp/dt_max)来评价大鼠心功能。结果: rAd-livin/MSCs组凋亡率较MSCs组和rAd-control/MSCs组显著降低(P<0.05);rAd-livin/MSCs组抗凋亡蛋白livin明显上升(P<0.05),促凋亡蛋白caspase-3、caspase-7及caspase-9表达显著下降(P<0.05);细胞移植后1个月,rAd-livin/MSCs组心功能比MSCs组改善更明显(P<0.05)。结论: rAd-livin感染MSCs后可促进抗凋亡蛋白livin的表达,同时降低促凋亡蛋白caspase-3、caspase-7和caspase-9的表达及细胞凋亡率。rAd-livin/MSCs移植能进一步改善心肌梗死大鼠心功能。     

睾酮对大鼠心肌梗塞后心肌肥大的影响

本文应用立体形态定量技术,观察睾酮(T)对心肌梗塞后心肌肥大的影响。实验分为:假手术组(S组)、心肌梗塞组(MI组)。心肌梗塞后睾酮治疗组(MIT组)。结果证明,与S组相比,MI及MIT组大鼠心肌细胞核密度明显减少,尤其以MIT组变化显著,MIT组平均核长度明显增加;MI组的 dp/dt max明显降低,T值延长,MIT组的上两指标无显著差异。MI后血浆T总浓度与平均每核心肌细胞体积呈显著正相关关系。提示:睾酮确实促进了MI后心肌肥大,从而促进了心功能的恢复。     

HIF-1α基因对心肌梗死后心肌细胞凋亡和心功能影响的实验研究

目的：探讨腺病毒介导的低氧诱导因子-1α(HIF-1α)在急性心肌梗死(AMI)后对兔心肌细胞凋亡及心功能的影响。方法:复制兔AMI模型，随机分为4组，分别给心肌内注入腺病毒介导的HIF-1α基因(Ad-HIF-1α)、不含HIF-1α基因腺病毒颗粒(Ad-blank)、HIF-1α核酶基因(Rz-HIF-1α)，假手术组(sham)为对照，各组动物分别在处死前应用Maclab/8s多功能生理仪记录不同时段心功能参数，末端原位标记（TUNEL）法检测心肌细胞凋亡。结果: 凋亡细胞在sham组基本不存在，Rz-HIF-1α组最多，Ad-HIF-1α组少于Ad-blank组。1 d凋亡细胞最多，随着时间的延长，凋亡细胞逐渐减少，56 d仍有少量凋亡细胞存在。心功能参数sham组最高，Rz-HIF-1α组最低，Ad-HIF-1α组高于Ad-blank组。结论: 腺病毒介导的HIF-1α基因治疗能明显减少心肌细胞凋亡，增强心功能，给予HIF-1α核酶基因则增加细胞凋亡，恶化心功能。     

心肌梗塞后泵功能的恢复及其机制的实验研究

造成大鼠不同范围的心肌梗塞(MI)后,动态观察不同时期的静息和容量负荷状态下泵功能恢复的规律及其代偿机制。结果证明:(1)梗塞范围(IS)小于左室的46%时,泵功能都有自动恢复的可能性。IS越小,恢复越快、越好。IS超过46%时未见恢复;(2)在IS相同的条件上,静息状态的泵功能远较负荷状态的泵功能恢复得好;(3)MI后,泵功能代偿机制的代偿效应与IS呈反比。如IS超过46%,任何代偿机制均难以发挥效应。     

Arterial blood gases,muscle fiber diameter and intercapillary distance in cardiac hypertrophy of rats with an old myocardial infarction

In rats with a myocardial infarction due to ligation of the left coronary artery a marked right ventricular hypertrophy developed after 41/2 weeks. At this time no difference against control animals was observed in arterial , , pH, ideal alveolar , and alveolar-arterial O₂ pressure difference, as measured in unanesthetized animals at normoxia. In histological sections of the heart stained by PAS reaction capillaries and muscle fibers were counted, and the mean intercapillary distance and muscle fiber diameter were estimated. In the right ventricle of the rats with myocardial infarction both increased when compared with control animals or with sham-operated rats. Fibercapillary ratio was the same in all three groups. Similar results were obtained in the remaining undamaged tissue of the left ventricle of rats with a myocardial infarction when compared with the left ventricle of control or sham-operated rats. Findings concerning intercapillary distance suggest that also in the myocardium which remains intact during the development of the infarction and later hypertrophies, tissue oxygen transport might be impaired, particularly during a stress situation. Results in the right ventricle of rats with myocardial infarction show an opposite trend against rats exposed chronically to simulated high altitude, where in the hypertrophied right ventricle a shorter intercapillary distance occurs and therefore an improvement of tissue oxygen transport might be expected.Dedicated to Professor Dr. Adolf Faller, University of Fribourg, Switzerland, on his 65th birthdayPresented in part at the IXth World Conference of the European Society for Microcirculation, Antwerp, July 5–9, 1976     

Substrate stiffness-regulated matrix metalloproteinase output in myocardial cells and cardiac fibroblasts: Implications for myocardial fibrosis

Cardiac fibrosis, an important pathological feature of structural remodeling, contributes to ventricular stiffness, diastolic dysfunction, arrhythmia and may even lead to sudden death. Matrix stiffness, one of the many mechanical factors acting on cells, is increasingly appreciated as an important mediator of myocardial cell behavior. Polydimethylsiloxane (PDMS) substrates were fabricated with different stiffnesses to mimic physiological and pathological heart tissues, and the way in which the elastic modulus of the substrate regulated matrix-degrading gelatinases in myocardial cells and cardiac fibroblasts was explored. Initially, an increase in cell spreading area was observed, concomitant with the increase in PDMS stiffness in both cells. Later, it was demonstrated that the MMP-2 gene expression and protein activity in myocardial cells and cardiac fibroblasts can be enhanced with an increase in PDMS substrate stiffness and, moreover, such gene- and protein-related increases had a significant linear correlation with the elastic modulus. In comparison, the MMP-9 gene and protein expressions were up-regulated in cardiac fibroblasts only, not in myocardial cells. These results implied that myocardial cells and cardiac fibroblasts in the myocardium could sense the stiffness in pathological fibrosis and showed a differential but positive response in the expression of matrix-degrading gelatinases when exposed to an increased stiffening of the matrix in the microenvironment. The phenomenon of cells sensing pathological matrix stiffness can help to increase understanding of the mechanism underlying myocardial fibrosis and may ultimately lead to planning cure strategies.     

再灌注对于实验性心肌梗塞家兔心功能的影响

开胸、全麻家兔在冠状动脉左室支结扎后随机分为两组:组Ⅰ,连续观察4小时不给与任何处理(n=9),组Ⅱ,冠脉结扎1小时后去除结扎线并继续观察3小时(n=10)。冠脉结扎前。后及再灌注后,同步、连续记录心电图、平均动脉压、左心室内压及心室内压变化速率。观察结束后处死动物测定心肌梗塞范围并取电镜标本。结果表明,冠脉结扎1小时引起上述各项指标显著抑制,与结扎前数值相比均具有显著性差异。再灌注后,组Ⅱ动物的心脏功能进一步下降,与组Ⅰ对应数据相比均具有显著性差异,且该组动物均伴有心肌内出血。比较两组动物的梗塞范围无统计学差异。再灌注的损害作用可能不仅仅是由于细胞水肿、出血等因素限制了冠脉血流的恢复;另外,毛细血管内及细胞中胞饮空泡的部分恢复可能促进了一些有害的大分子代谢产物的转运。     

Effects of rhBNP on myocardial fibrosis after myocardial infarction in rats

Purpose: We aimed to observe the effects and mechanism of rhBNP treatment on myocardial fibrosis (MF) after myocardial infarction (MI). Methods: SPF rats were separated into 3 groups: normal, MI (ligation of left coronary artery), and MI + rhBNP (recombinant human brain natriuretic peptide). Rats in MI + rhBNP group were given 30 μg/kg for 2 days before modeling and for 4 weeks after modeling. mRNA levels and the expression levels of TGF-β1 (transforming growth factor) and CTGF (connective tissue growth factor) in 3 groups were analyzed using the RT-qPCR and western blotting analysis, respectively. Furthermore, myocardial volume fraction (CVF) was analyzed using the Sirius Red F3B (SR) while the percentage of type I and III collagen in 3 groups were analyzed using the immunohistochemical staining. Results: Compared with the normal group, the levels of TGF-β1, CTGF, CVF, type I and III collagen were higher in MI group. However, mRNA levels of TGF-β1 and CTGF were significantly decreased in MI + rhBNP compared to MI groups. Expression of TGF-β1 was lower while that of CTGF was higher in MI + rhBNP group than that in MI group. Besides, CVF, and type I and III collagen were lower in MI + rhBNP group compared with MI group. Conclusion: rhBNP could significantly decrease the TGF-β1 and CTGF levels in post-MI so as to inhibit the type I and III collagen deposition in MF of post-MI. rhBNP will be benefit for the improvement of MF.