Possible involvement of apoptotic death of myocytes in left ventricular remodeling after myocardial infarction

Pathophysiological roles of apoptosis in post-infarction left ventricular (LV) remodeling have not been well characterized. This study showed that TUNEL- or cleaved caspase-3-positive myocytes were identified late after ligation of the left coronary artery in rats, suggesting that apoptotic myocyte death contributed to the morphological change associated with LV remodeling.     

氟伐他汀对大鼠心肌梗死后心室重塑的影响

目的:探讨羟甲基戊二酰辅酶A还原酶抑制剂氟伐他汀对SD大鼠心肌梗死后心室重塑的过程及心功能的影响。方法:SD大鼠冠状动脉前降支结扎形成心肌梗死,24h后存活的大鼠随机分成心肌梗死(AMI)对照组和氟伐他汀治疗组,治疗组予以氟伐他汀20mg·kg^-1·d^-1灌胃给药,对照组予以蒸馏水灌胃;另设假手术组。8周后进行心脏超声、血液动力学检测判定心脏功能和进行心脏形态学分析;同时检测血浆总胆固醇(Tch)、肌酐(Cr)、天冬氨酸氨基转移酶(AST),NO₂^-/NO₃^-、谷胱甘肽过氧化物酶(glutathioneperioxidase,GSH-PX)以及血浆、心肌脂质过氧化物(LPO)水平。结果:氟伐他汀组血浆Tch水平与AMI组比较没有显著性差异,平均主动脉压和心率差别无显著性,显著降低了左室舒张末压和减少了肺相对重量(P＜0.05);减少了右室相对重量、左室后壁厚度、肺相对重量和心肌纤维化(P＜0.05,P<0.01);降低了血浆和心肌的LPO的水平,抑制NO₂^-/NO₃^-的过度表达,增加了GSH-PX的表达(P＜0.05);血浆Cr和AST水平无显著差别(P＞0.05)。结论:氟伐他汀改善大鼠AMI后心室重塑,相对延缓心力衰竭的进展;氟伐他汀抗氧化机制可能参与这个过程。     

氟伐他汀对心肌梗死大鼠心室重塑的影响

心室重塑是心力衰竭基本病理改变过程,急性心肌梗死(acute myocard ial infarction,AM I)后心室重塑是指左心室大小、形状和组织结构的变化过程,亦即梗死区室壁心肌的梗死扩展和非梗塞区室壁心肌的反应性肥厚、伸长,致左心室进行性扩张和变形伴心功能降低的过程,一般在心肌梗死后24 h内出现。近年来,羟甲基戊二酰辅酶A还原酶抑制剂———他汀类药物的非调脂作用备受重视。本研究用氟伐他汀干预SD大鼠AM I模型的心室重塑作用并探讨其可能的相关机制。1材料与方法1·1心肌梗死模型的建立和分组:雄性SD大鼠50只(中国科学院上海动物中心提…     

The effects of peptide-based modification of alginate on left ventricular remodeling and function after myocardial infarction

Adverse cardiac remodeling and dysfunction after myocardial infarction (MI) is associated with (BioLineRx, BL-1040 myocardial implant) excessive damage to the extracellular matrix. Biomaterials, such as the in situ-forming alginate hydrogel, provide temporary support and attenuate these processes. Here, we tested the effects of decorating alginate biomaterial with cell adhesion peptides, containing the sequences RGD and YIGSR, or a non-specific peptide (RGE), in terms of therapeutic outcome soon after MI. The biomaterial (i.e., both unmodified and peptide-modified alginate) solutions retained the ability to flow after cross-linking with calcium ions, and could be injected into 7-day infarcts, where they underwent phase transition into hydrogels. Serial echocardiography studies performed before and 60 days after treatment showed that alginate modification with the peptides reduced the therapeutical effects of the hydrogel, as revealed by the extent of scar thickness, left ventricle dilatation and function. Histology and immunohistochemistry revealed no significant differences in blood vessel density, scar thickness, myofibroblast or macrophage infiltration or cell proliferation between the experimental groups BioLineRx BL-1040 myocardial implant. Our studies thus reveal that the chemical and physical traits of the biomaterial can affect its therapeutical efficacy in attenuating left ventricle remodeling and function, post-MI.     

长期TCV116干预对心肌梗死后心室重塑及心功能的影响

目的:研究长期新型血管紧张素Ⅱ1型受体阻断剂TCV116干预对心肌梗死(MI)后心肌重塑及心功能的影响。方法:通过结扎冠状动脉左前降支复制大鼠MI模型,1周后将大鼠随机分为:(1)MI对照组;(2)MITCV116治疗组(2mg.kg^-1·d^-1):另设假手术组及假手术TCV116组。22周后检测:(1)血流动力学参数如平均动脉压(MAP)、左室收缩压(LVSP)、室内压最大上升和下降速率(dp／dt_max)和左室舒张末压(LVEDP)及心脏形态学指标如左室相对重量(LVW／BW)和左室腔相对面积(LVCA／BW);(2)室间隔存活心肌中β肌球蛋白重链(βMHC)、B型钠尿肽(BNP)、转化生长因子β₁(TGF-β₁)、I型和III型胶原(collagenI、III)基因的mRNA表达;(3)存活率。结果:MI对照组与MITCV116治疗组间总体MI范围无显著差异(34%±14％vs33%±13%,P>0.05)。MI对照组LVW／BW和LVCA／BW显著高于假手术组(P<0.01),βMHC、BNP、TGF-β₁、collagenI和III基因的mRAN表达显著大于假手术组(P<0.01);同时MAP、LVSP、dp／dt_max显著低于和LVEDP显著高于假手术组(P<0.01),也伴随着生存时间显著缩短(P<0.05)。TCV116治疗组,LVW／BW和LVCA／BW与MI对照组比无显著差异,βMHC、BNP、TGF-β₁、collagenI和III基因的mRNA表达低于MI对照组(P<0.05或P<0.01);与此同时,MAP、LVSP、dp／dt_max显著高于及LVEDP显著低于MI对照组(P<0.05或P<0.01),并伴随着生存时间的延长(P<0.05)。结论:长期血管紧张素II1型受体阻断剂干预能显著改善心肌梗死后大鼠心室重塑及心功能。     

氟伐他汀对大鼠心肌梗死后左室功能、肌球蛋白重链基因表达及胶原重建的影响

目的：观察羟甲基戊二酰辅酶A还原酶抑制剂氟伐他汀对大鼠急性心肌梗死(AMI)后左室功能、肌球蛋白重链（α、β MHC）基因转录mRNA表达及胶原重建的影响。 方法： 雌性SD大鼠AMI术后6 h随机分为：①AMI对照组；②氟伐他汀组；③假手术组。 直接灌胃给药8周后行高频多普勒超声、血流动力学、左室心肌α、β MHC的mRNA、非梗死区胶原容积分数(CVF)及Ⅰ/Ⅲ胶原的免疫组化测定。 结果： AMI组E峰、E峰减速度、E/A、左室舒张末压(LVEDP)、β MHC mRNA、非梗死区CVF及Ⅰ/Ⅲ胶原比值明显高于假手术组，左室短轴速短率（FS）、射血分数（EF）、平均动脉压（MAP）和α MHC mRNA 显著低于假手术组。氟伐他汀组的E峰、E峰减速度、E/A、LVEDP、β MHC mRNA、非梗死区CVF及I/Ⅲ胶原比值明显低于AMI组，FS、EF、MAP和α MHC mRNA显著高于AMI组。 结论： 氟伐他汀对心梗后左室功能、肌球蛋白链基因mRNA表达及胶原重建可产生有益的影响。     

Swimming exercise training prior to acute myocardial infarction attenuates left ventricular remodeling and improves left ventricular function in rats

The effect of exercise training prior to acute myocardial infarction (AMI) on left ventricular (LV) remodeling is poorly understood. This study investigated the protective effect of 3 weeks of swimming exercise training prior to AMI on cardiac morphology and function. Male Sprague-Dawley rats (n = 35) were randomly assigned to 3 groups: swimming training (n = 14, 90 min, 5 days/wk, 3 wk), sedentary (n =14), and controls (n = 7, no exercise, no MI). At the end of the training/sedentary period, rats were subjected to AMI (ExMI and SedMI) induced by surgical ligation of the left coronary artery. Thereafter, the rats remained sedentary for a 4-wk recovery period. Trans-thoracic echocardiography was performed in each group at the end of the exercise/sedentary period (pre-AMI), 24 hr after AMI, and following recovery (4 wk after AMI). No differences were observed in LV dimensions and function pre-AMI among the 3 groups; however, LV-end systolic diameter (LVESD) and LV-end systolic area (LVES-area) were significantly lower in the prior trained rats, 24 hr post-AMI with no additional change 4 wk post-AMI, during remodeling. Both LV-shortening fraction (SF%) and fractional area change (FAC%) were higher in the trained animals 4 wk post-AMI (39+/-12% vs 23+/-8%; p 0.002, and 48+/-14% vs. 38+/-9%; p 0.07, respectively). In conclusion, 3 wk of swimming exercise training prior to AMI significantly attenuated LV remodeling and improved LV function, despite no changes in LV dimensions or systolic function at the end of the exercise session. The data suggest that even a short-term training period is sufficient to induce cardiac protection.     

晚期再灌注预加依那普利减少实验性心肌梗塞后的左室重构

目的:研究晚期再灌注以及晚期再灌注预加血管紧张素转化酶抑制剂依那普利对心肌梗塞后左室重构的影响。方法:通过结扎冠状动脉建立兔的心梗模型,心梗组行永久冠脉结扎,晚期再灌注组于结扎冠脉3h后解除结扎行再灌注,晚期再灌注预加依那普利组在晚期再灌注的基础上于心梗后早期加用依那普利治疗。于术后7周进行血液动力学参数测定及取出动物的心脏行形态学检查。结果:晚期再灌注组膨展指数低于心梗组,但梗塞面积、左室容积、左室重量以及血液动力学指标无明显改善;而晚期再灌注预加依那普利组膨展指数、左室容积、左室重量均低于心梗组,血液动力学指标也有所改善。结论:晚期再灌注可以减少梗塞膨展,但对心梗后晚期左室重构无明显影响;晚期再灌注预加依那普利有利于减少左室重构,改善心功能。     

Changes in protease inhibitors after acute myocardial infarction.

Plasma levels of fibrinogen, alpha1-antitrypsin, alpha2-macroglobulin, antithrombin III, and C1 inactivator were measured serially for 10 days in 11 patients after acute myocardial infarction. Both fibrinogen and alpha1-antitrypsin rose markedly to reach peak levels 5-7 days after infarction while C1 inactivator levels rose slowly with the highest observed mean level on the 10th postinfarction day. Neither antithrombin III nor alpha2-macroglobulin changed significantly after myocardial infarction. No relationship between C1 inactivator levels and either fibrinogen or alpha1-antitrypsin was found in a study of 30 patients with a variety of disorders while fibrinogen and alpha1-antitrypsin levels were significantly correlated.     

Microvascular integrity as a predictor of left ventricular remodeling after acute anterior wall myocardial infarction.

The purpose of this study was to investigate the relation of microvascular integrity and ventricular remodeling after acute myocardial infarction. Twenty-six patients with first acute anterior myocardial infarction were studied before discharge with myocardial contrast echocardiography (MCE). Opacification index (OI) and wall motion index were calculated in the left anterior descending artery territory and left ventricular diastolic volume was measured at baseline and during a 9-month follow-up. In total 26 patients, the regional wall motion improved but the left ventricular volume and global function was not changed significantly at follow-up. When the patients were divided into 3 groups according to opacification index (> or = 0.75, 0.5 approximately 0.75, < or = 0.5) at baseline, functional recovery was not observed and significant left ventricular dilatation was developed in patients with < or = 0.5 OI. Among the baseline echo-parameters such as ejection fraction, wall motion score, left ventricular volume and opacification index, the best predictor for long term left ventricular dilatation was the opacification index by multivariate analysis. In patients with acute anterior wall infarction the assessment of microvascular integrity by MCE at acute stage provides useful information regarding recovery of dysfunctional regional wall motion and ventricular remodeling.     

联合应用培哚普利和氯沙坦改善心肌梗死后左室重构和心功能的临床研究

目的:观察培哚普利和氯沙坦联合治疗对于急性前壁心肌梗死患者左室重构、心功能和血清Ⅲ型前胶原肽(PⅢNP)水平的影响。方法:急性前壁心肌梗死患者,随机分为培哚普利组、氯沙坦组和培哚普利+氯沙坦组。入院后行急诊冠脉造影和介入治疗,术后分别给予:培哚普利2-4mg/d;氯沙坦25-50mg/d;或二者联合。所有患者常规给予抗血小板、抗凝、他汀类调脂药等。3个月后超声心动图检测左室大小、左室容量和左室射血分数。酶免法和放免法测定血液脑钠肽(BNP)、C反应蛋白(CRP)和PⅢNP水平。结果:3组患者的基础临床特征无显著区别。与基础值相比,3个月后,所有患者均表现出血液中CRP水平下降、BNP和PⅢNP水平上升,且有不同程度的左室扩大和左心功能下降。与培哚普利组和氯沙坦组相比,联合用药组患者CRP、BNP和PⅢNP水平显著降低,且左室扩张和射血功能障碍程度均减轻。血清PⅢNP水平与CRP水平及左室舒张末期容积指数均呈显著正相关(r=0.597,r=0.543,均P0.01),与左室射血分数呈显著负相关(r=-0.565,P0.01)。结论:急性前壁心肌梗死患者,早期联合培哚普利和氯沙坦治疗可以进一步改善左室重构和心功能,其机制可能与抑制胶原合成、抑制心肌纤维化有关。     

氟伐他汀对大鼠心肌梗死后左室重构及caspase-3表达的影响

目的：观察氟伐他汀对大鼠心肌梗死后左室重构及凋亡基因caspase-3的影响。 方法： 复制心肌梗死动物模型，实验分为4组，Ⅰ组假手术组，Ⅱ组假手术+氟伐他汀组，Ⅲ组模型组，Ⅳ组模型+氟伐他汀组。Ⅱ和Ⅳ组术后给氟伐他汀10 mg·kg^-1·d^-1共4周，观察左室结构及心动超声变化，心肌羟脯氨酸含量及caspase-3表达。 结果： Ⅳ组心肌超微结构和左室重构指标改善程度明显高于Ⅲ组，羟脯氨酸含量及免疫组化caspase-3阳性细胞明显少于Ⅲ组（P<0.05），RT-PCR caspase-3 mRNA表达也明显少于Ⅲ组（P<0.05）。 结论： 氟伐他汀能改善大鼠心梗后左室重构，并下调凋亡基因caspase-3表达，抑制细胞凋亡。     

卡维地洛缓解兔心肌梗死后心室重构

冠心病患者发生心力衰竭最常见的始动因素是心肌梗死(myocardial infarction,MI),由梗死心肌触发的一系列体液及细胞外基质的改变等因素将导致心脏结构异常,即心室重构.研究表明,MI后心室重构是发生心室功能障碍和心力衰竭的重要原因.因此,抑制心室重构已成为心血管领域备受关注的课题.本实验旨在研究卡维地洛对心室重构的影响.     

Early, selective growth hormone administration may ameliorate left ventricular remodeling after myocardial infarction

Left ventricular (LV) remodeling after myocardial infarction (MI) may lead to congestive heart failure, disability and death. It consists of expansion of the infarct zone and dilatation of the non-infarcted myocardium, causing shape distortion and ventricular enlargement. Experimental studies have shown that treatment with growth hormone (GH) stimulates cardiac repair, resulting in increased infarct zone collagen scar formation and possibly enhanced proteinosynthesis. These actions may ameliorate the process of LV remodeling. We hypothesize that these beneficial effects may be more prominent, if GH is delivered selectively in the infarct area, during the early phase of acute MI. Experimental and clinical studies are necessary to validate this hypothesis.     

心肌梗死大鼠心室重塑的动态观察

目的：探讨大鼠心肌梗死（MI）后细胞因子TGF—β1及心室重塑指标动态变化及其与重塑的关系。方法：结扎冠脉左前降支建立心肌梗死（MI）模型并设立假手术对照组。术后3天、1周、4周和24周检测血流动力学和组织形态学及胚胎基因（B肌球蛋白重链），Ⅰ、Ⅲ型胶原和TGF—β1的mRNA水平。结果：与假手术组相比，MI组血流动力学改变明显。心肌梗死后第3天胚胎基因β-MHC、胶原、TGF-β1都上升，一直持续到第4周。梗死区Ⅰ、Ⅲ型胶原在第4周仍然比非梗死区高，即使在第24周非梗死区的胶原水平仍然高于假手术组。TGF—β1在第1周达到高峰后逐渐下降到第24周时非梗死区与假手术组相比有统计学差异（P〈0．01），相关性分析提示梗死区TGF-β1与Ⅰ、Ⅲ型胶原、β-MHC存在相关；非梗死区TGF-β1与Ⅰ、Ⅲ型胶原存在相关。结论：TGF—β1参与心室重塑病理生理过程并且可能是心室重塑的病因之一。     

Two-dimensional speckle-tracking echocardiography assessment of left ventricular remodeling in patients after myocardial infarction and primary reperfusion

Introduction

Left ventricular remodeling (LVR) is the most prognostically important consequence of acute myocardial infarction (AMI). The aim of the study was to assess the value of speckle tracking echocardiography in the prediction of left ventricular remodeling in patients after AMI and primary coronary angioplasty (PCI).

Material and methods

Eighty-eight patients (F/M = 31/57 patients; 63.6 ±11 years old) with coronary artery disease (CAD) and successful PCI were enrolled and divided into group I with ST-elevation myocardial infarction or non-ST elevation myocardial infarction and group II with stable angina pectoris. Conventional and speckle tracking echocardiography was performed 3 days (baseline), 30 days and 90 days after PCI. Patients were divided into 2 groups based on the presence of LVR (increase of LV end-diastolic and/or end-systolic volume > 20%) at 3 months follow-up.

Results

At initial presentation, 2-chamber longitudinal strain (9.4 ±3.5% vs. –11.6 ±3.6%, p < 0.04) and 4-chamber transverse strain (10.4 ±8.2% vs. 15.6 ±8%, p < 0.003) were lower in the LVR+ group compared to the LVR– group. LV wall motion score index did not differ between the two groups. After 30 days, circumferential apical and basal strain (–15.58 ±8.9% vs. –25.53 ±8.8%, p < 0.001; –15.02 ±5.6 vs. –19.78 ±6.3, p < 0.008), radial apical strain (9.96 ±8.4% vs. 14.15 ±5.5%, p < 0.03), 4-chamber longitudinal strain (–8.7 ±5.8% vs. –13.47 ±3.9%, p < 0.005), 4-chamber transverse strain (10.5 ±8.1% vs. 16.7 ±8.3%, p < 0.03), apical rotation (3.84 ±2.5° vs, 5.66 ±3.2°, p < 0.04) and torsion (6.15 ±4.1° vs. 8.98 ±4.6°, p < 0.03) were significantly decreased in the LVR+ group compared to the LVR– group. According to ROC analysis, circumferential apical strain > –15.92% (sensitivity 93%, specificity 59%, positive predictive value 90%) was the most powerful predictor of remodeling after primary PCI in AMI.

Conclusions

Our results suggest that impaired indices of LV deformation detected 3 days and 30 days after AMI may provide important predictive value in LV remodeling and patients’ follow-up.     

Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction

A key component of cardiac remodeling after acute myocardial infarction (MI) is the inflammatory response, which modulates cardiac tissue repair. The purpose of this study was to investigate the relationship between the monocytic inflammatory response and left ventricular remodeling after MI using mice deficient in CC chemokine receptor 2 (CCR2), the primary receptor for the critical regulator of CC chemokine ligand 2. Immunohistochemical analysis revealed rapid infiltration of macrophages into infarcted tissue within 7 days in wild-type (WT) mice. However, this process was greatly impaired in CCR2-deficient (CCR2(-/-)) mice. Echocardiography demonstrated beneficial effects of CCR2 deficiency on left ventricular remodeling at 7 and 28 days after MI. In situ zymography showed augmented gelatinolytic activity in WT mice within 7 days after MI, whereas gelatinolytic activity was barely detectable in CCR2(-/-) mice. Moreover, the distribution of gelatinolytic activity in serial sections was very similar to the distribution of macrophages rather than neutrophils. Expression of matrix metalloproteinases and tumor necrosis factor-alpha mRNAs was up-regulated in infarcted regions from WT mice compared to CCR2(-/-) mice at 3 days after MI. Direct inhibition of CCR2 functional pathway might contribute to the attenuation of left ventricular remodeling after MI.     

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。