辛伐他汀对慢性心力衰竭大鼠左室重构的影响

目的:探讨辛伐他汀对慢性心力衰竭大鼠心肌纤维化及心肌超微结构的影响.方法:利用腹主动脉缩窄法建立雄性Wistar大鼠心衰模型,随机分为心衰假手术组、模型组和辛伐他汀组.观察各组大鼠左心室肌质量指数(LVMI),H-E和Massion染色观察左心室心肌形态结构变化,电镜下观察左心室心肌的超微结构,SP免疫组织化学检测左心室心肌中结缔组织生长因子(CTGF)表达情况,RT-PCR测定各组大鼠左心室心肌CTGF mRNA水平.结果:与假手术组相比,模型组LVIM、心肌胶原容积分数(CVF)、CTGF蛋白及mRNA表达明显上升.与模型组相比,辛伐他汀组LVMI、CVF、CTGF蛋白及mRNA表达均明显下降.光镜和电镜结果显示,辛伐他汀组心肌损害程度较模型组明显减轻.结论:辛伐他汀能显著改善慢性心力衰竭大鼠心肌肥厚,逆转心肌纤维化和超微结构的异常方面,其机制可能与下调CTGF的表达有关.     

Morphological aspects of heart remodeling in chronic heart failure

Intraoperative biopsy specimens of the right atrium auricula from patients at different stages of chronic heart failure (CHF) were studied using the methods of light and electron microscopy. Marked heteromorphism of cardiomyocytes (CMC) was demonstrated which was found to be correlated to CHF progression. CMC showing the signs of hypertrophy and organelle hyperplasia, sarcomere discomplexation, myofibril fragmentation were identified, as well as CMC containing numerous pinocytotic vesicles, caveolae, distended T-system tubules. Apoptotic CMC and interstitial cells were also shown. No significant correlation between the myocardial cell apoptosis and CHF stage was established.     

Integrin expression during reverse remodeling in the myocardium of heart failure patients

BackgroundThe main anchoring proteins of myocardial cells with each other and with the extracellular matrix are integrins present in the membranes of myocardial cells. These integrins are important for maintaining the architecture of the myocardial tissue and the mechanotransduction in the heart. Heart failure leads to various alterations in the myocardium, such as changes in morphology, and in expression of mRNAs, miRNAs, and proteins. Left ventricular assist device (LVAD) support in heart failure patients has been described to induce reverse remodeling of the myocardium and thus to (some degree of) reversal of the aforementioned alterations. In this study, we evaluated whether changes in expression of integrins α-1, -3, -5, -6, -7, -10, -11 and β-1, -3, -5 and -6 play a role during reverse remodeling.MethodsThree-step immunoperoxidase staining procedures were applied on frozen heart tissue sections to locate the various integrins tested. Integrin mRNA expression was established by standard Q-PCR procedures.ResultsIt was shown that mRNA expression of several integrins changes significantly during LVAD support, however without subsequent changes in immunohistochemical detectable quantities. Various integrins showed different locations within the myocardium.ConclusionLVAD-induced reversed remodeling did not result in significant integrin protein expression, although changes in integrin mRNA expression suggested an adaptation to unloading.     

Remodeling myocardium and skeletal muscle in chronic heart failure

The spread and progression of chronic heart failure (CHF) is viewed presently from the standpoint of remodeling the myocardium and skeletal peripheral vessels. However, it is not clear yet, if such remodeling is a common adaptive mechanism in CHF for the myocardium and skeletal muscle. The study aim was to investigate the morphological changes in the myocardium and their interrelations with the skeletal muscle condition in CHF patients. For this purpose the biopsy materials of the left ventricle and pectoral muscles obtained from 36 patients with CHF (functional classes I-IV according to NYHA) of various etiologies as well as biopsy materials of the rectus abdominal muscle obtained from 8 patients without CHF were examined by light and electron microscopy. It was established that the development and progression of CHF is accompanied by similar changes in the morphology of the myocardium and skeletal muscle at the tissue, cellular and subcellular levels. As CHF aggravates, the manifestations of hypertrophy and heteromorphism of tissue fibers equally progress in the myocardium and skeletal muscle. A reliable correlation was detected between changes of cellular-stromal ratio in the myocardium and in the skeletal muscle (r = 0.57; p < 0.05).     

心脏收缩力调节对慢性心力衰竭兔心室肌电重构的影响

目的:观察心脏收缩力调节(cardiac contractility modulation, CCM)对慢性心力衰竭兔心室肌电重构的影响并探讨其可能的机制。方法:30只新西兰大白兔随机分为3组:假手术组、心衰组(采用升主动脉根部套扎法建立兔慢性心力衰竭模型)和心衰+CCM刺激组(模型制作成功后给予4周的CCM治疗)。电生理记录仪测定QTc和心室有效不应期(ventricular effective refrective period, VERP);采用RT-qPCR和Western blot检测心室肌Kv1.4、Kv4.3和缝隙连接蛋白43 (connexin 43, Cx43)的mRNA和蛋白的表达水平。结果:(1)实验第12周末,心衰兔QTc显著延长(P<0.05);实验第16周末,与心衰组相比,心衰+CCM组经4周CCM刺激后QTc显著缩短(P<0.05)。实验第16周末,与假手术组相比,心衰组、心衰+CCM组VERP显著延长(P<0.05);与心衰组相比,CCM可缩短心衰模型兔的VERP(P<0.05)。(2)与假手术组相比,心衰组心肌组织中Kv1.4、...     

不同年龄小鼠缺血性心力衰竭后心室重塑程度的比较

 目的：研究不同年龄小鼠缺血性心衰后心室重塑程度的变化。方法：选择3月龄和18月龄的雄性C57BL/6J小鼠共100只,每个月龄组50只,在2组中分别随机选取 40只,结扎左冠状动脉定量控制心梗面积,建立稳定缺血性心衰模型,每组其余10只作为假手术组,于术后8周行心脏超声评价各组心功能变化;称量全心脏及左心室重量并计算左心室质量指数(LVMI);免疫组化检测心肌Ⅰ、Ⅲ型胶原表达,Masson染色检测心肌纤维化的程度并计算心肌间质胶原分数(CVF)。结果：与低龄组相比,老龄组心脏破裂率（18% vs 10%）和心力衰竭死亡率（22% vs 10%）均高于低龄组(P＜0.05);老龄组心室腔明显增大,心率较快,左室短轴收缩功能障碍更明显（P＜0.05）;老龄组LVMI明显增加（P＜0.05）;老龄组CVF、Ⅰ型胶原的表达以及Ⅰ/Ⅲ型胶原的比值显著高于低龄组（P＜0.05）。结论：老龄小鼠缺血性心衰后心肌胶原分布异常,心室重塑程度更重,心功能降低更明显。     

miRNAs与心肌重塑及心衰的研究进展

心衰是几乎所有心血管疾病的终末表现和主要致死原因。心肌重塑是心衰的中间表型,心衰的发生必然伴随着完整的或者是部分的心脏重塑过程。心肌重构和心衰的分子机制仍不十分清楚。最近,越来越多的研究表明,miRNAs参与了这一病程,通过调控相关靶基因的表达影响心肌肥厚、心肌纤维化、心衰的发生和发展。本文结合病人和动物模型的最新研究结果,对miRNAs在心肌重塑及心衰中的作用做一综述,并对miRNAs在心脏疾病临床治疗中应用前景给予展望。     

Evidence of cardiocyte apoptosis in myocardium of dogs with chronic heart failure.

It is often speculated that progressive deterioration of left ventricular function in heart failure is due to ongoing loss of viable cardiocytes. In this study, we examined the possibility that cardiocyte loss in heart failure may be due, in part, to apoptosis, an active process of gene-directed cellular self-destruction. Studies were performed in left ventricular tissue obtained from 10 dogs with chronic heart failure produced by multiple intracoronary microembolizations (left ventricular ejection fraction 27 +/- 1%) and from 5 normal dogs. Evidence for cardiocyte apoptosis was based on transmission electron microscopy criteria and on in situ immunohistochemical labeling of nuclear DNA fragmentation. There was no evidence of apoptotic cardiocytes in normal dogs. Features of cardiocyte apoptosis were observed in dogs with heart failure primarily in regions bordering old infarcts. Electron microscopic features of cardiocyte apoptosis included (1) intact sarcolemma and inner organelles in the presence of compaction and segregation of nuclear chromatin into sharply delineated masses that about the nuclear envelope, (2) intact sarcolemma in the presence of cytoplasm shrinkage, blebbing, and nuclear fragmentation, and (3) intact sarcolemma in the presence of complete disorganization of inner organelles and disappearance of nucleolemma. A count of all of the apoptotic bodies positively labeled for nuclear DNA fragments showed that 11% were of cardiocyte origin confirmed by positive labeling with striated muscle antimyosin antibody. We conclude that morphological and biochemical features of cardiocyte apoptosis exist in the left ventricular myocardium of dogs with chronic heart failure.     

慢性心衰大鼠心脏CGRP免疫阳性细胞的形态与分布

目的研究慢性心衰(CHF)大鼠心脏降钙素基因相关肽(CGRP)免疫阳性细胞的分布变化规律。方法以阿霉素(ADR)制备慢性心衰模型,采用免疫组织化学方法结合医学图像分析系统对CHF大鼠心脏CGRP免疫阳性细胞的形态分布变化进行观察。结果显示正常组CGRP免疫阳性细胞主要以圆形和椭圆形为主,CHF组细胞以指环形为主;CHF时CGRP免疫阳性细胞的数密度和面密度明显降低(P<0.05)。结论CHF时CGRP免疫阳性细胞形态和数量与正常时相比,均有明显变化,与CHF的发生、发展密切相关。     

MMP-7、MMP-10和TIMP-4在心力衰竭心室重构中的表达

目的:应用细胞因子抗体芯片技术筛选与心力衰竭心室重构关系密切的基质蛋白酶。方法:从本院的心脏病组织库中挑选6例病理诊断明确和各方面资料比较齐全的致心律失常性右室心肌病引起心力衰竭的心脏病标本(来源于心脏移植的受体),与年龄、性别和种族等因素相匹配的正常对照心脏组织(来源于心脏移植的供体)进行细胞因子抗体芯片分析,筛选在致心律失常性右室心肌病引起的心力衰竭中差异表达的基质蛋白酶,并应用酶联免疫分析和免疫组织化学的方法加以验证。结果:在所筛选的17种基质金属蛋白酶中,只有MMP-7和MMP-10在致心律失常性右室心肌病引起心力衰竭中高表达,而在4种基质金属蛋白酶内源性组织抑制剂中,只有TIMP-4 低表达。经酶联免疫分析和免疫组织化学的方法证实,不仅在致心律失常性右室心肌病引起心力衰竭的心肌,在缺血性心肌病和扩张性心肌病引起的心力衰竭心肌中也发现MMP-7和MMP-10 的高表达及TIMP-4的低表达。结论:心肌组织中MMP-7和MMP-10的高表达及TIMP-4的低表达在不同心肌病引起的心力衰竭心室重构分子机制中可能发挥重要的作用。     

半乳糖凝聚素-3在心肌梗死后心室重构和心力衰竭中作用的研究进展

心力衰竭作为多种心血管疾病的共同归宿和主要死因,早期诊断和有效干预是提高患者预后结果和转归的重要手段。半乳糖凝聚素-3(Gal-3)是近年来出现的一种新的生物标志物,与心肌纤维化及心力衰竭相关,在心力衰竭的诊断及治疗中具有参考价值,可有望作为心力衰竭治疗的一个新靶点。     

有氧运动抑制心梗后心力衰竭大鼠左室重塑及交感神经重塑

目的:探讨长期有氧运动对心梗后心力衰竭(心衰)大鼠模型左心室及交感神经重塑(结构重塑与功能重塑)的影响,为心衰的机制研究及康复治疗提供科学依据和有效方法。方法:健康雄性Wistar大鼠通过结扎冠状动脉前降支建立心梗后心衰模型,术后4周随机分为假手术安静组(S组)、心衰安静组(H组)和心衰运动组(HE组)。HE组进行10周跑台训练,S组和H组保持安静状态。超声心动术检测心脏结构与功能,即左室舒张期内径(LVIDd)、左室收缩期内径(LVIDs)、左室舒张期前壁厚度(LVAWDd)、左室收缩期前壁厚度(LVAWDs)、左室舒张期后壁厚度(LVPWDd)、左室收缩期后壁厚度(LVPWDs)、缩短分数(FS)和左室射血分数(LVEF);Masson染色进行心脏组织病理学观察并获得心肌胶原容积分数(CVF);高压液相色谱法检测心肌和血浆去甲肾上腺素(NE)水平;经皮下引导电极连续采集心电信号,对自主神经功能参数——心率变异性(HRV)进行频域分析,包括总功率谱(TP)、归一化低频功率谱(LFn)、归一化高频功率谱(HFn)和LF/HF比值;实时荧光定量PCR检测心肌I型胶原(Col-I)、III型胶原(Col-III)、心房钠尿因子(ANF)、α-肌球蛋白重链(α-MHC)、β-肌球蛋白重链(β-MHC)和肌质网Ca2+-ATP酶(SERCA2a)mRNA表达,Western blotting法检测心肌神经生长因子(NGF)及其受体(Trk A)和酪氨酸羟化酶(TH)蛋白表达。结果:(1)与S组比较,H组体重(BW)、LVIDd、FS、LVEF、TP、HFn、α-MHC和SERCA2a的mRNA,NGF、Trk A和TH的蛋白表达降低(P0.05);左室重量(LVW)、左室质量指数(LVMI)、LVAWDd、LVAWDs、LVPWDd、LVPWDs、CVF、血浆和心肌NE含量、LFn、LF/HF、ANF、β-MHC、Col-I和Col-III的mRNA表达升高(P0.05)。(2)与H组比较,HE组LVW、LVMI、LVIDd、FS、LVEF、TP、HFn、α-MHC和SERCA2a的mRNA,NGF、Trk A和TH的蛋白表达升高(P0.05);CVF、血浆和心肌NE含量、LFn、LF/HF、ANF、β-MHC、Col-I和Col-III的mRNA表达降低(P0.05)。结论:长期有氧运动可抑制心梗后心衰大鼠左室重塑与交感神经重塑,心功能和自主调节改善。     

Adrenomedullin and endothelin-1 are related to inflammation in chronic heart failure

Background:  Adrenomedullin (ADM) and endothelin-1 (ET-1) are novel promising peptide biomarkers in chronic heart failure (CHF). According to recent studies among their pleiotropic effect they play roles in the regulation of inflammation. The aim of the study was to measure the above mentioned two vasoactive peptides in parallel in a well characterized population of patients with CHF, and study their associations with inflammatory markers. Materials and methods:  A total of 186 patients (138 male, 48 female) with <45% left ventricular ejection fraction (LVEF), and without acute inflammatory disease, were enrolled. Plasma midregional-proADM (MR-proADM) and C-terminal-proET-1 (CT-proET-1) were determined by a novel sandwich immunoluminomertic assay. Results:  Increased MR-proADM and CT-proET-1 plasma levels were measured in patients with severe CHF (NYHA III-IV) as compared to the group of NYHA I-II (p<0.0001). MR-proADM and CT-proET-1 levels showed significant negative correlation with serum albumin and prealbumin levels (p≤0.0001), while positive correlations were found with levels of CRP, TNF-alpha, soluble TNF receptors and IL-6 (p≤0.0001). In multiple linear regression models after adjustments for several potential confounders (disease severity [LV-EF, NYHA classes, NT-proBNP], ion and water homeostasis [sodium and presence of peripheral oedema], renal function [serum creatine]) the relationship between ADM and albumin, CRP, soluble TNF receptors and between ET-1 and CRP, TNF receptors and IL-6 remained significant. Conclusions:  Vasoregulation and inflammation may be connected in heart failure patients independently of the disease severity. The observed link may contribute to the understanding of the complex pathomechanism in CHF. Received 14 August 2008; returned for revision 31 October 2008; received from final revision 9 November 2008; accepted by C. Kasserra 18 November 2008     

慢性心力衰竭时心肌组织中CGRP的含量变化及mRNA表达

目的探讨心肌组织降钙素基因相关肽(CGRP)含量变化及mRNA的表达与慢性心力衰竭(CHF)发生、发展的关系。方法以阿霉素(ADR)制备慢性心衰模型,采用放射免疫学方法和逆转录聚合酶链反应进行检测。结果CHF时,心肌组织中CGRP含量为34.82±3.01,高于正常心肌组织中CGRP的含量24.77±3.84,差异具有统计学意义;而CGRP的mRNA表达降低。结论心肌组织中CGRP含量变化及其mRNA的表达调控,与CHF的发生、发展密切相关。     

Aerobic exercise improves the inflammatory profile correlated with cardiac remodeling and function in chronic heart failure rats

OBJECTIVE:

The aim of the present study was to evaluate the effect of 8 weeks of aerobic exercise training on cardiac functioning and remodeling and on the plasma levels of inflammatory cytokines in chronic heart failure rats.

METHODS:

Wistar rats were subjected to myocardial infarction or sham surgery and assigned to 4 groups: chronic heart failure trained (n = 7), chronic heart failure sedentary (n = 6), sham trained (n = 8) and sham sedentary (n = 8). Four weeks after the surgical procedures, the rats were subjected to aerobic training in the form of treadmill running (50 min/day, 5 times per week, 16 m/min). At the end of 8 weeks, the rats were placed under anesthesia, the hemodynamic variables were recorded and blood samples were collected. Cardiac hypertrophy was evaluated using the left ventricular weight/body weight ratio, and the collagen volume fraction was assessed using histology.

RESULTS:

The chronic heart failure trained group showed a reduction in left ventricular end-diastolic pressure, a lower left ventricular weight/body weight ratio and a lower collagen volume fraction compared with the chronic heart failure sedentary group. In addition, exercise training reduced the plasma levels of TNF-α and IL-6 and increased the plasma level of IL-10.

CONCLUSION:

An 8-week aerobic exercise training program improved the inflammatory profile and cardiac function and attenuated cardiac remodeling in chronic heart failure rats.     

Association of right ventricular dysfunction and Cheyne-Stokes respiration in patients with chronic heart failure

Cheyne-Stokes respiration (CSR) is present in up to 40% of patients with congestive heart failure (CHF) and is an independent risk factor for increased overall mortality. We examined whether CSR is associated with right ventricular (RV) dysfunction in CHF patients. Parameters of RV function were assessed by two-dimensional echocardiography and tissue velocity imaging in 42 patients (aged 23-75 years) with a left ventricular (LV) ejection fraction below 40%. Respiratory polygraphy revealed CSR with an central apnea-hypopnea index (CAHI) >10 h-1 in 13 of the 42 patients (31%). Demographic characteristics did not differ among the patient groups. The velocity of the tricuspid annular systolic motion (TASM), a parameter reflecting systolic RV function, was significantly reduced in CHF patients with CSR (10.5 +/- 2.3 cm s-1) compared with those without CSR (15.0 +/- 5.1 cm s-1, P = 0.004), and was inversely associated with the CAHI (y = 15.2-0.2x; r = 0.46, P = 0.003). The RV dimensions were significantly increased and the fractional RV area changes significantly reduced in CHF patients with CSR (33 +/- 17 versus 48 +/- 20%; P = 0.04). Doppler parameters of pulmonary artery flow indicate higher pulmonary artery pressures in CSR patients compared with patients without CSR, which is also reflected by an increased RV free-wall thickness in CSR patients (6.5 +/- 1.1 vs. 5.3 +/- 1.3 mm; P = 0.05). Parameters of systolic LV function, forced expiratory volume in 1 s (FEV1), and PaO2 and PaCO2 were not different among patients with or without CSR. In conclusion, CSR is associated with depressed systolic RV function and increased RV dimensions in CHF patients. Future studies will show whether optimized treatment of CSR will improve RV function.     

实时三维超声心动图左心室重构指数评价冠心病患者左心室重构的研究

目的探讨实时三维超声心动图（RT-3DE）测量左心室重构指数（LVRI）评价冠心病患者左心室重构的价值。方法根据冠状动脉造影结果,将病变组分为左旋支或/和右冠支病变组（LCX/RCA组）24例,其中男性18例,女性6例,年龄38～76岁,平均年龄54.2岁;单纯左前降支病变组（LAD组）21例,其中男性16例,女性5例,年龄35～78岁,平均年龄53.5岁;包含LAD病变的双支或多支病变组（多支组）27例,其中男性20例,女性7例,年龄39～80岁,平均年龄56.2岁;正常对照组22例,其中男性17例,女性5例,年龄32～79岁,平均年龄55.2岁。行RT-3DE,应用软件自动测量左心室舒张末期容积（LVEDV）、舒张末期心外膜容积（LVEDVepi）、左心室射血分数（LVEF）;再计算左心室质量[LVM=1.05×（LVEDVepi-LVEDV）]、LVRI（LVM/LVEDV）,并采用二维超声心动图（2DE）双平面Simpson测量并计算上述各值。比较RT-3DE和2DE测量LVRI在组间的差异、组内的差异和相关性,以及LVRI与LVEDV、LVEF的相关性;并比较观察者间及观察者内两种方法测量LVRI的一致性和重复性。结果正常对照组、LCX/RCA组、LAD组、多支组两种方法测量的LVRI呈显著递减（P〈0.05或P〈0.01）。前两组两种方法间的LVRI差异无统计学意义（P〉0.05）,后两组有统计学意义（P〈0.05或P〈0.01）。相关性分析表明：①除多支组内两种方法间的LVRI无显著相关性（P〉0.05）外,余3组内均呈显著相关性（P〈0.01）;②病变组同种方法测量的LVRI与LVEDV呈显著负相关性、LVEF呈显著正相关性（P〈0.01）,但正常组内无显著相关性（P〉0.05）。RT-3DE测量的LVRI观察者间及观察者内一致性和重复性较2DE好。结论来源于RT-3DE的LVRI优于2DE,更能作为临床评价冠心病患者左心室重构的指标。     

兔舒张性心衰和收缩性心衰模型建立及间质重构的比较

目的 比较兔舒张性心衰（DHF）和收缩性心衰（SHF）模型间心功能和间质重构的差异。方法 采用腹主动脉缩窄术建立DHF模型,用腹主动脉缩窄术联合破主动脉瓣术建立SHF模型,用心超和血流动力学检测心功能,用羟脯氨酸法测定心肌胶原含量,天狼猩红染色（PSR）测定胶原面积(CA)、容积分数（CVF）及Ⅰ/Ⅲ型胶原的面积比值。结果 与对照（control）组相比,DHF组心肌明显肥厚,僵硬度增加,心室舒张功能异常但射血分数（EF值）正常,间质胶原含量、面积、容积分数及Ⅰ/Ⅲ型面积比值均显著升高;SHF组心腔明显扩大,心室收缩功能异常,间质胶原含量、面积及容积分数明显升高,但Ⅰ/Ⅲ型面积比值下降（P<0.05或P<0.01）。结论 成功构建了可以代表不同临床类型两种不同心衰模型,为以后的实验研究提供了技术支持。