Attenuation of cardiovascular remodeling in DOCA-salt rats by the vasopeptidase inhibitor, omapatrilat

Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and angiotensin-converting enzyme with similar potency. The aim of this study was to investigate whether omapatrilat prevents or reverses cardiovascular remodeling and hypertension in deoxycorticosterone acetate (DOCA)-salt rats. Male Wistar rats (313 +/- 2 g, n = 114) were uninephrectomized (UNX) with or without further treatment with DOCA and 1% NaCl in the drinking water. Compared with UNX control rats, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, perivascular and interstitial cardiac fibrosis and inflammation, endothelial dysfunction, and the prolongation of ventricular action potential duration within four weeks. The administration of omapatrilat (40 mg/kg/day po) for two weeks commencing two weeks after surgery attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation. In contrast, omapatrilat treatment did not lower systolic blood pressure nor improve endothelial dysfunction. This study concludes that the renin-angiotensin-aldosterone, natriuretic peptide, and bradykinin systems are directly involved in the pathogenesis of cardiovascular remodeling in the DOCA-salt model of hypertension in rats, which may be independent of their effects on blood pressure.     

Sustained cardiomyocyte apoptosis and left ventricular remodelling after myocardial infarction in experimental diabetes

Aims/hypothesis Diabetes is known to reduce survival after myocardial infarction. Our aim was to examine whether diabetes is associated with enhanced cardiomyocyte apoptosis and thus interferes with the post-infarction remodelling process in myocardium in rat.Methods Four weeks after intravenous streptozotocin (diabetic groups) or citrate buffer (controls) injection, myocardial infarction was produced by ligation of left descending coronary artery. Level of cardiomyocyte apoptosis was quantified by TUNEL and caspase-3 methods. Collagen volume fraction and connective tissue growth factor were determined under microscope. Left ventricular dimensions were evaluated by echocardiography and planimetry.Results The number of apoptotic cardiomyocytes was equally high in diabetic and non-diabetic rats after 1 week from infarction. At 12 weeks after infarction the number of apoptotic cells was higher in the diabetic as compared to non-diabetic rats both in the border zone of infarction and in non-infarcted area. Correspondingly, left ventricular end diastolic diameter, relative cardiac weight, connective tissue growth factor-expression and fibrosis were increased in diabetic compared with non-diabetic rats with myocardial infarction.Conclusion/interpretation Sustained cardiomyocyte apoptosis, left ventricular enlargement, increased cardiac fibrosis and enhanced profibrogenic connective tissue growth factor expression were detected after myocardial infarction in experimental diabetes. Apoptotic myocyte loss could be an important mechanism contributing to progressive dilatation of the heart and poor prognosis after myocardial infarction in diabetes.Abbreviations STZ streptozotozin - MI myocardial infarction - CTGF connective tissue growth factor - LV left ventricular - LVEDD LV end-diastolic diameter - BNP B-type natriuretic peptide     

Right ventricular cardiomyocyte apoptosis in patients with acute myocardial infarction of the left ventricular wall

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p <0.001). RV apoptosis significantly correlated with such parameters of global adverse remodeling as cardiac diameter to LV free wall thickness (R = +0.57, p = 0.050). RV apoptosis was significantly higher in five cases (42%) with infarct involving the ventricular septum and an adjacent small area of the RV walls (median 1.0%, interquartile range 0.8 to 2.2 vs median 0.5%, interquartile range 0.2 to 1.0, p = 0.048, p <0.001 vs controls). The association between apoptotic rate in the right ventricle and cardiac remodeling was apparent even after exclusion of cases with RV AMI involvement (R = +0.82, p = 0.023 for diameter to LV wall thickness ratio and R = -0.91, p = 0.002 for RV free wall thickness). In conclusion, patients with cardiac remodeling after AMI had a significant increase in RV apoptosis even when ischemic involvement of the RV wall was not apparent.     

辛伐他汀对心肌梗死大鼠心室重构的影响

目的采用超声心动图检测评价辛伐他汀对改善大鼠心肌梗死(MI)后心室重构的作用。方法34只大鼠分3组:(1)MI组:仅结扎左冠状动脉前降支(LAD);(2)治疗组:结扎LAD,并用辛伐他汀40 mg.kg-1.d-1进行灌胃;(3)假手术组:开胸,但不结扎LAD。超声心动图检查心脏结构和功能,逆转录-聚合酶链式反应(RT-PCR)测定梗死区和非梗死区肿瘤坏死因子(TNF)-αmRNA表达,免疫印迹法和免疫组织化学染色法测定TNF-α蛋白的产生。结果超声心动图显示,MI组与假手术组比较,左心室舒张末期内径(LVEDd)显著增大,分别为(7.5±0.4)mm和(4.5±0.3)mm,短轴缩短率〔FS,分别为(20.5±2.5)%和(51.6±3.1)%〕和射血分数〔EF,分别为(41.4±4.3)%和(85.2±3.7)%〕明显降低(均为P<0.05)。与MI组比较,辛伐他汀显著减轻左心室扩张,改善左心室功能(P<0.05)。MI组TNF-αmRNA表达和蛋白质的产生较假手术组增加(均为P<0.01),而治疗组TNF-αmRNA表达和蛋白质的产生比MI组明显下降(P<0.05)。TNF-αmRNA表达和蛋白质生成与心功能下降呈正相关,辛伐他汀减轻TNF-α基因表达,改善心功能。结论辛伐他汀改善大鼠MI后心室的不良重塑,其机制可能与降低非梗死区和梗死区心肌内TNF-α基因表达和蛋白质合成有关。     

Comparison of the effects of an angiotensin-converting enzyme inhibitor and a vasopeptidase inhibitor after myocardial infarction in the rat

OBJECTIVES: The goal of this study was to compare the effects of the vasopeptidase inhibitor omapatrilat and the angiotensin-converting enzyme inhibitor (ACEI) captopril in the postmyocardial infarction (MI) rat model. BACKGROUND; The cardioprotective effects of ACEIs after MI are thought to be partially due to an increase in bradykinin (BK). Vasopeptidase inhibitors inhibit both ACE and neutral endopeptidase (NEP), further reduce BK metabolism and increase natriuretic peptides, which may result in better cardioprotective effects than with ACEIs after MI. METHODS: Myocardial infarction was induced in 514 Wistar male rats by ligation of the anterior coronary artery. Rats surviving 4 h after MI (n = 282) were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, neurohumoral, hemodynamic, ventricular remodeling, morphometry, immunohistochemistry and cardiac cytokine expression were measured. RESULTS: Omapatrilat and captopril resulted in similarly improved survival, cardiac hemodynamics and reduced cardiac fibrosis and hypertrophy after MI. The pattern of left ventricular (LV) remodeling differed, omapatrilat causing less attenuation of the rightward shift of the LV pressure-volume relation at lower filling pressures than captopril. Both interventions reduced messenger ribonucleic acid expression of the profibrotic cytokine transforming growth factor-beta(1); neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha). Expression of TNF-alpha was in cardiomyocytes. Both medications reduced circulating endothelin-1, angiotensin II and catecholamines, but only omapatrilat increased atrial natriuretic peptides. CONCLUSIONS: This study indicates that both omapatrilat and captopril markedly improve post-MI survival, cardiac function and cardiac remodeling in the rat. It would appear that the addition of NEP inhibition to those of ACEIs does not result in significant further benefit after MI.     

Hypercholesterolemia exacerbates ventricular remodeling in the rat model of myocardial infarction

BackgroundDetrimental left ventricular (LV) remodeling is exacerbated in hypercholesterolemic patients with myocardial infarction; however, this could result from either larger infarcts or more extensive remodeling itself in this population. Therefore, we sought to investigate whether high cholesterol feeding exacerbates LV remodeling and heart failure in rats with myocardial infarction independently from its influence on infarct size.Methods and ResultsMyocardial infarction was induced by permanent ligation of left coronary artery in rats fed normal and high-cholesterol diet and the animals were followed for 8 weeks. Hypercholesterolemic rats were matched with normocholesterolemic animals for infarct size 24 hours after infarction and exhibited more pronounced LV dilation at 8 weeks after infarction (LV systolic/diastolic diameter 8.1 ± 0.2/10.2 ± 0.3 versus 6.7 ± 0.2/8.9 ± 0.2, respectively, measured by echocardiography, P < .05 each). Pressure-volume curves obtained in isolated Langendorff-perfused hearts revealed higher diastolic LV volumes (1677 ± 102 versus 1385 ± 46 μL/kg body weight, P < .05) and hemodynamic examination demonstrated higher LV end-diastolic pressure (21.8 ± 0.7 versus 18.7 ± 1.0 mm Hg, P < .05) in hypercholesterolemic rats compared with normocholesterolemic animals.ConclusionIn a rat model of myocardial infarction, LV remodeling and heart failure are more pronounced in rats fed high-cholesterol diet in comparison to animals fed normal chow. This effect is independent from effect of hypercholesterolemia on infarct size.     

再灌注心律失常对急性心肌梗死患者心肌细胞凋亡和左室重构的影响

目的探讨急性心肌梗死（AMI）患者再灌注心律失常（RA）、心肌细胞凋亡和左室功能的关系。方法156例经急诊再灌注治疗的AMI患者,分为RA组58例（24小时内出现RA）,非再灌注心律失常（Non．RA）组98例。应用ELISA方法,分别检测再灌注治疗成功后即刻、7天和2—4周血清细胞凋亡信号分子Fas／APO-1水平,并在1周、6个月和1年做心脏彩超,检测左室射血分数（LVEF）和左室舒张末期内径（LVEDD）。结果（1）RA组血管开通时间较Non-RA组晚,且前降支病变较Non-RA组发生率高（P〈0．05）。（2）再灌注治疗成功后即刻,RA组血清Fas／APO-1浓度明显高于Non-RA组[（13．82±4．36）μg/L与（8．19±3．56）μg/L,P〈0．05]。（3）再灌注治疗成功后第7天,两组患者血清Fas／APO-1浓度达高峰,2—4周时明显下降,与第7天比较差异有统计学意义[RA组（10．91±3．65）μg/L与（14．26±4．98）μg/L,P〈0．05;Non-RA组（4．69±1．87）μg/L与（12．19±3．25）μg/L,P〈0．01],且2—4周时RA组Fas／APO-1浓度明显高于Non．RA组[（10．91±3．65）μg/L与（4．69±1．87）μg/L,P〈0．01]。（4）AMI再灌注治疗成功后1周,RA组与Non-RA组比较,LVEF和LVEDD差异无统计学意义[LVEF（47．7±9．6）％与（49．2±8．9）％,P〉0．05;LVEDD（59．7±10．3）mm与（57．4±12．4）mm,P〉0．05]。（5）AMI再灌注治疗成功1年后,Non-RA组LVEF明显高于自身急性期和RA组[分别为（59．5±9．2）％、（49．2±8．9）％和（49．9±10．1）％,P〈0．05],LVEDD虽然无显著性变化（P〉0．05）,但有增加趋势。结论心肌缺血严重患者易发生RA,且与心肌缺血所诱发心肌细胞凋亡有关,影响左室功能的恢复,促进心室重构。     

抑郁对急性心肌梗死大鼠心室重构的影响

目的 观察抑郁对急性心肌梗死(AMI)大鼠心室重构及血流动力学的影响.方法实验大鼠46只,随机分为四组:假手术组(n=10),梗死模型组(n=12)、抑郁模型组(n=12)、路优泰组(每天90 mg/kg)(n=12).4 w后用Open-field法观察各组大鼠行为学变化以及血流动力学测定和病理及光镜下心肌组织切片观察.结果①行为学观察:与假手术组相比,抑郁模型组,水平穿越格数、竖立次数、理毛时间,均减少,中央格停留时间、粪便粒数均增加(P＜0.01);与抑郁模型组相比,梗死模型组、路优泰组水平穿越格数、竖立次数、理毛时间明显增加,中央格停留时间、粪便粒数明显减少(P＜0.05,P＜0.01).②心室重构指标测定:与假手术组相比,梗死模型组、抑郁模型组、路优泰组,心率、左心室舒张末压、左、右室相对重量、室间隔厚度明显增加,主动脉收缩压、主动脉舒张压、左心室收缩压、左心室内压最大上升及下降速率明显减少(P＜0.05,P＜0.01).与抑郁模型组相比,梗死模型组、路优泰组,主动脉收缩压、左心室收缩压、左心室内压最大上升及下降速率明显增加,心率、左心室舒张末压、左、右室相对重量、室间隔厚度减少(P＜0.05,P＜0.01),且抑郁组大鼠光镜下心肌损伤最为严重.结论 AMI后抑郁可加重心肌梗死后心室重构过程,对血流动力学、心功能均有极为不利影响.     

NADPH氧化酶在大鼠心梗后心室重构中作用的研究

目的探讨NADPH氧化酶在大鼠心肌梗塞后心室重构中的作用。方法取体重150～220 g雄性Sprague-Dawley（SD）大鼠,通过结扎或不结扎冠状动脉前降支分为手术（O）组和假手术（S）组。每组再随机分为两个亚组,术后第二天开始分别给予NADPH氧化酶抑制剂夹竹桃麻素(15 mg·kg^-1·d^-1,A)和等量安慰剂（P）灌胃5周。5周后处死大鼠,术前和处死前均称体重（BW）并做心脏超声检查获取左心室射血分数（LVEF）,处死后取出心脏称心脏重量（HW）、左心室重量（LVW）、用ELISA法测定左心室非梗塞区心肌组织胶原蛋白Ⅰ和Ⅲ含量、用TUNEL法测定非梗塞区心肌细胞凋亡指数,并观察非梗塞区心肌细胞凋亡指数和LVEF的关系。结果 （1）共86只雄性SD大鼠用于实验,最终得假手术组（SP组）6只、假手术干预组（SA组）6只、心梗组（OP组）7只和心梗干预组（OA组）6只。（2）SP组、OP组、OA组和SA组的BW分别为（314.17±20.67）g、（296.71±36.63）g、（298.00±57.06）g和（329.83±24.64）g,组间差异无统计学意义。SP组和SA组的HW分别为（646.17±85.44）mg和（648.67±63.11）mg,组间差异无统计学意义;OP组和OA组分别为（1144.14±59.46）mg和（884.00±97.14）mg,与SA组和SP组的差异有统计学意义（P相似文献   

急性心肌梗死与左室重构

急性心肌梗死(AMI)后左室发生细胞学,分子学及细胞间质的变化,进而引起左室在大小、形态、组织结构和功能状态的改变,此即目前许多研究所提及的AMI后的左室重构.AMI后左室的重构贯穿于整个病程的始终,成为影响AMI患者近远期预后的主要原因之一.     

氯沙坦对急性心肌梗死后心室重构的影响

目的:研究氯沙坦对急性心肌梗死后心室重构的影响。方法:符合入选标准的120例急性心肌梗死患者被随机均分为三组:氯沙坦组(A组)。卡托普利组(B组),常规治疗组(C组),分别于治疗前,治疗后6个月进行超声心动图检查。结果:对照组常规治疗后.左室舒张末容积(LVEDV)、左室射血分数(LVEF)、每搏量(SV)均进一步恶化(P<0.05),A、B组的LVEDV、LVEF、SV较C组则无显著恶化(P<0.05～<0.01).A组又好于B组(P<0.05)。结论:氯沙坦能明显改善急性心肌梗死后心室重构。     

T3预处理对小鼠心肌梗死后心室重构的影响

目的 探讨三碘甲状腺原氨酸（triiodothyronine,T3）预处理对小鼠心肌梗死（myocardial infarction,MI）后心室重构的影响。方法 采用随机数字法将24只昆明小鼠分为4组,分别为：假手术组（Sham组）、手术组（MI组）、手术+T3组(MI+T3组)、手术+T3+PI3K/Akt信号通路抑制剂LY294002组（MI+T3+LY294002组),每组6只。连续三天腹腔注射生理盐水、T3（2ug?100g-1?d-1）和LY294002（2mg?100g-1?d-1）进行预处理,每天一次。结扎左冠状动脉前降支诱导小鼠发生急性心肌梗死。手术4周后,称量并记录小鼠体重、全心重和左室重量;采用TUNEL染色法检测小鼠非梗死区心肌细胞凋亡情况;采用CD31免疫荧光染色检测梗死边缘区血管新生情况;采用Masson染色检测梗死后心肌梗死面积及纤维化程度。结果 手术后,与Sham组小鼠的心重/体重（6.5±0.6）和左室质量/体重（4.1±0.4）相比,MI组（8.3±0.5、5.4±0.2）明显增加(P＜0.05),造模成功;与MI组小鼠的心肌细胞凋亡（28.0±4.0）、新生血管密度（42.22±3.33）、心肌梗死面积（30.0±1.3）、纤维化程度（30.67±1.33）相比,MI+T3组分别为（11.0±5.0、57.78±6.67、22.0±4.6、24.0±2.33）(P＜0.05);与MI+T3组相比, MI+T3+LY294002组小鼠的心肌细胞凋亡增加（36.0±5.0）、新生血管密度减少（41.11±4.44）、心肌梗死面积增加（37.0±3.3）、纤维化程度加重（37.33±4.0）(P＜0.05)。结论 T3在心肌梗死后可通过PI3K/Akt信号通路发挥抑制凋亡、促进血管新生、减少心肌纤维化和抗心室重构的作用。     

急性心肌梗死后螺内酯干预对左室重构的影响

目的　探讨急性心肌梗死(AMI)患者应用螺内酯干预对于左室重构(LVRM)的影响。方法　4家医院共入选AMI患者88例,采用多中心、随机、对照的方法,对46例AMI患者在常规治疗的基础上加用螺内酯40mg/d(螺内酯组),对照组(n=42)常规治疗。在6个月干预期内检测两组血清Ⅲ型前胶原氨基端肽(PⅢNP)、脑钠肽(BNP)及超声心动图,以评价左室纤维化、左室功能和左室容积。结果　88例中,急性前壁心肌梗死患者43例,螺内酯组23例、对照组20例;急性下壁心肌梗死患者45例,螺内酯组23例、对照组22例。急性前壁心肌梗死组在治疗3、6个月时螺内酯组与对照组相比,血清PⅢNP和BNP明显降低[PⅢNP分别为( 260 .2±59. 9 )ng/L比( 328 .0±70 .3 )ng/L, P=0 .001, ( 197 .1±46 .3 )ng/L比( 266. 7±52 .4 )ng/L, P<0. 001 ,BNP分别为( 347 .4±84 .0)ng/L比(430 .1±62 .9)ng/L, P<0 .001, (243 .7±79. 7)ng/L比(334. 6±62. 8)ng/L, P<0. 001]。治疗6个月时螺内酯组较对照组左室舒张末期内径、左室收缩末期内径明显降低[分别为(51. 0±5 .5)mm比(55. 6±4 .5)mm, P=0 .005, (35 .7±4 .6)mm比(39 .1±5 .6)mm, P=0 .046]。急性下壁心肌梗死组在治疗6个月时螺内酯组与对照组相比血清PⅢNP、BNP水平无统计学意义,(P>0 05),并且左     

贝那普利联合阿托伐他汀钙对急性心肌梗死后心室重构的影响及机制探讨

目的:观察贝那普利及阿托伐他汀钙对急性心肌梗死（AMI）后心室重构的影响。方法: 将符合标准AMI的患者74例随机分为对照组和观察组各37例。观察组在基础治疗基础上加用贝那普利及阿托伐他汀钙,对照组仅加贝那普利基础治疗,坚持服用24周,不能耐受贝那普利的改为替米沙坦。分析3 d和24周超声心动图的观察指标。结果: 观察组的左室收缩末期容积（LVESV）和左室舒张末期容积（LVEDV ）的下降幅度明显高与对照组;左室射血分数(LVEF)和左室快速充盈E波最大流速（VE）和心房充盈A 波最大流速(VA)比值（VE/VA）也明显高于对照组;左室心肌重量指数（LVMI）增高幅度显著小于对照组(均P<005)。结论: 贝那普利及阿托伐他汀钙抑制AMI后心室重构,改善心功能效应明显好于单用贝那普利。     

急性心肌梗死早期左室重构与发病时间

目的 采用心肌静息门控单光子发射计算机体层摄影术（ＧＳＰＥＣＴ）研究了急性心肌梗列死（ＡＭＩ）早期左室的重构特点。方法 ＡＭＩ患者３７例,根据发病时间分作四个亚组,第一亚组（１６例）,第二亚组（７例）,第三亚组（１１例）和第四亚组（３例）,患者发病时间分别为≤３小时,〉３小时￣≤６小时,〉６小时￣≤１２小时和〉１２小时。患者入院后即注射显影剂＾９９ｍ锝甲氧基异丁基异腈,２小时后采用双探头ＧＳＰＥＣ