骨髓间质干细胞移植对香猪急性心肌梗死后心肌结构和心功能的影响

目的 移植自体骨髓间质干细胞(BMSCs)到香猪急性心肌梗死区内,研究移植BMSCs对心肌结构和心功能的影响. 方法将24只贵州香猪采用计算器随机法分为实验组(n＝12)和对照组(n＝12),抽取香猪自体骨髓,经体外分离出BMSCs并培养和经5-氮胞苷(5-azacytidine)转化,利用结扎左前降支(LAD)的方法建立急性心肌梗死动物模型,经LAD和梗死区多点注射的方法将实验组香猪注射BMSCs(细胞总数2×106个),对照组注射等量的细胞培养液.3周和6周后,用超声心动图(UCG)观察两组移植后心肌结构和心功能改变的情况. 结果实验组左心室射血分数、左心室短轴缩短率和室壁增厚率明显高于对照组;左心室室壁、室间隔厚度和心室腔的大小在两组之间也存在明显差别,实验组室壁和室间隔厚度明显大于对照组,而心室腔小于对照组. 结论 BMSCs梗死区心肌移植后可减轻心室重构的进程,减轻心肌的变薄程度,使心室腔未明显扩大.BMSCs移植还可增加心肌的收缩力,改善心功能.     

骨髓基质干细胞治疗兔缺血心肌的初步实验研究

目的通过建立兔自体骨髓移植模型,验证骨髓基质干细胞(MSCs)移植到缺血心肌后是否在心肌的微环境中可以向心肌细胞分化,探讨其对缺血心肌心功能的影响。方法将13只新西兰大白兔分为实验组(7只)和对照组(6只),实验组于心肌梗死前后缘上、中、下各3点分别注射被5溴-2脱氧尿苷(BrdU)标记的自体MSCs(3×106cells/30μl);对照组注射同等量的磷酸盐缓冲液(PBS)。移植4周后通过激光共聚焦显微镜验证移植后的MSCs是否向心肌细胞分化,并用心脏彩色超声心动图和多导生理记录仪测定缺血心肌的心功能。结果移植4周后,MSCs向心肌细胞分化,表达出α-肌小节肌动蛋白(-αsarcomeric actin)和存在于闰盘中的连接蛋白43(connexin 43),自体MSCs能够增加局部心肌组织中血管数量。实验组心肌左心室收缩功能明显比对照组增强[左心室射血分数(LVEF):0.51±0.07 vs.0.43±0.06,左心室侧壁运动幅度(LVLWMD):1.75±0.42mm vs.1.09±0.28mm,左心室收缩期室壁增厚率(LVΔT):0.19%±0.05%vs.0.11%±0.04%,左心室收缩压(LVSP):113.1±6.3 mmHg vs.99.5±5.1 mmHg,左心室舒张期末压(LVEDP):11.5±2.1 mmHg vs.14.3±3.1mmHg,左心室压力增高最大速率(+dp/dtmax):4 618.3±365.2mmHg/s vs.3 268.1±436.9 mmHg/s,左心室压力下降最大速率(-dp/dtmax):3 008.8±346.7mmHg/s vs.2 536.9±380.4 mmHg/s,P<0.05]。结论自体MSCs移植到兔缺血心肌后可以向心肌细胞分化,提高缺血心肌的心功能,对治疗心肌缺血具有较好的前景。     

杂交技术在冠状动脉外科中的应用

目的总结29例杂交技术治疗冠心病的临床疗效。方法2000年1月~2005年4月,29例冠心病接受杂交技术进行心肌血管化。均为男性,年龄(62.8±9.7)岁。其中合并高血压23例,糖尿病5例,慢性阻塞性肺病2例,陈旧性心肌梗死14例。二支病变10例,三支病变19例。左室射血分数0.576±0.108。结果29例接受33根移植物,其中左乳内动脉(left internalm amm ary artery,LIMA)27支,大隐静脉6支。共植入支架41个。平均每例心肌血管化2.5支。全组无死亡,无住院并发症。LIMA血流量(45±14)m l/m in。胸腔引流量(274±197)m l,2例(6.9%)接受输血。ICU时间(1.9±0.1)d。术后住院4~11 d,平均7.5 d。29例随访0.5~5.1年,(2.2±0.9)年,无远期死亡和心肌梗死。术后心功能NYHA分级Ⅰ级25例,Ⅱ级4例。冠脉造影共4例,大隐静脉桥血管闭塞1例,支架内再狭窄2例。结论杂交技术治疗冠心病中期疗效满意,适用于高危病人,其长期效果有待进一步评价。     

内皮素A受体拮抗剂BQ123对前列腺癌PC-3M细胞增殖与凋亡的影响

目的:观察内皮素A受体拮抗剂BQ123对转移性前列腺癌(PCa)PC-3M细胞株增殖与凋亡的影响,初步探讨内皮素A受体拮抗剂对转移性PCa细胞的体外抗肿瘤效应。方法:实验分为两组,对照组为PC-3M细胞及含灭活小牛血清的F12/RMPI1640培养液;实验组为PC-3M细胞加入等量的1μmol/LBQ123。采用四甲基偶氮唑蓝(MTT)比色法、划痕损伤实验、细胞迁移实验观察BQ123对人PCaPC-3M细胞株增殖的抑制效应,利用Annexin V-FITC/PI染色和流式细胞术检测BQ123诱导PC-3M细胞凋亡的作用及其与细胞周期的关系。结果:MTT比色法结果显示BQ123随着作用时间的增加,对PC-3M的抑制率分别为24h22.32%、48h44.88%和72h64.47%,表现出良好的时效关系(P<0.05),划痕损伤实验结果提示:实验组PC-3M细胞的迁移距离分别为12h(103.42±75.63)μm、24h(243.75±121.53)μm和48h(422.07±36.01)μm,均低于对照组的12h(162.93±19.87)μm、24h(317.19±43.19)μm和48h(692.74±40.84)μm(P<0.05)。细胞迁移实验中实验组穿入下室的PC-3M细胞为(79.2±9.58)个,亦明显少于对照组的(92.6±5.94)个(P<0.05);Annexin V-FITC/PI双染色法的结果显示对照组PC-3M细胞凋亡率为(9.38±1.37)%,实验组PC-3M细胞凋亡率为(15.03±0.93)%,差异有统计学意义(P<0.05),细胞周期实验的结果显示实验组各期细胞比例与对照组相比差异不显著(P>0.05)。结论:BQ123对PCaPC-3M细胞株的生长、迁移和侵袭能力均有明显的抑制作用,且可以诱导PC-3M细胞凋亡,可为PCa治疗的研究提供一种新的思路。     

小肠黏膜下层-骨髓间充质干细胞移植治疗陈旧性心肌梗死

目的探讨自体骨髓间充质干细胞(MSCs)-小肠黏膜下层(SIS)支架复合物移植于陈旧性心肌梗死区域后细胞的存活、支架的降解情况及其对心功能的影响。方法将16只黑山羊按随机数字表法分为两组,每组8只。实验组:建立心肌梗死模型,抽取自体骨髓,经体外分离MSCs,进行培养、传代、BrdU标记、与SIS支架复合,并于心肌梗死6周时将MSCs-SIS复合物补片移植至陈旧性心肌梗死区;对照组:建立心肌梗死模型。于移植后6周行超声心动图、HE染色及免疫组织化学检测。结果 MSCs-SIS植入心肌梗死区2周时在补片区可见大量炎性细胞浸润;6周时淋巴细胞浸润消失,SIS部分降解,移植区见大量移植细胞存活。MSCs-SIS植入体内后6周时,实验组每搏输出量(42.81±4.91mlvs.37.06±4.75ml)、射血分数(59.20%±5.41%vs.44.56%±4.23%)、室壁增厚率(54.51%±8.60%vs.43.36%±8.91%)、舒张期E峰(54.85±6.35cm/svs.43.14±4.81cm/s)显著高于对照组(P0.05),左心室收缩期末容积(29.75±5.98mlvs.46.25±6.68ml)、舒张期末容积(72.55±8.13mlvs.83.31±8.61ml)显著低于对照组(P0.05)。结论 SIS作为支架移植MSCs有利于移植细胞存活,对陈旧性心肌梗死后心功能有明显的改善作用。     

异丙酚对急性心肌梗死大鼠心脏功能的影响

目的 观察异丙酚对急性心肌梗死大鼠血液动力学影响的量-效关系以及心肌梗死范围和心肌超微结构的变化。方法 将急性心肌梗死模型的大鼠随机分为5组（n=8）,对照组（Ⅰ）,其余大鼠分别持续静脉输注30（Ⅱ）、45（Ⅲ）、60（Ⅳ）、75（Ⅴ）mg·kg-1·h-1异丙酚30min。测定输注异丙酚30min血药浓度,观察血液动力学、心肌梗死范围和心肌超微结构的变化。结果 血药浓度为（3.4±0.9）～（12.9±2.4）μg/ml时,平均动脉压（MAP）、心率（HR）、左室收缩压（LVSP）、左室内压力变化最大速率（±dp/dtmax）、心肌耗氧指数（MOCI）均呈剂量依赖性下降（P<0.05）,左心室舒张末压（LVEDP）无明显变化（P>0.05）,心肌梗死面积为23.7％～29.2％（P>0.05）,心肌超微结构无显著性差异。结论 在血药浓度（3.4±0.9）～（12.9±2.4）μg/ml范围内,异丙酚对血液动力学及心收缩功能呈剂量依赖性抑制,对心肌梗死范围和心肌细胞超微结构无明显影响。     

脑利钠肽在评价功能性单心室患者TCPC后心功能中的价值及意义

目的探讨脑利钠肽(BNP)在评价功能性单心室患者行全腔静脉-肺动脉连接术(TCPC)后心功能中的价值及其意义。方法选择2004年4~11月间连续在我科随访的TCPC后患者11例(TCPC组),男7例,女4例;年龄8.2±4.1岁;随访时间2.1±1.6年。按照改良R oss标准对临床心功能评分。采集外周静脉血3m l,用酶标免疫法测定血浆BNP浓度。其中6例同期用磁共振成像(M R I)测定心功能,对BNP做相关因素分析。9人健康儿童作为正常对照(对照组)。结果(1)TCPC组血浆BNP水平为400pg/m l(IQR 200-690),较对照组的110 pg/m l(IQR 90-190)增高(P=0.003);(2)M R I测定结果:TCPC组6例患者舒张期末容量指数为65.76±8.65 m l/m2,收缩期末容量指数为31.90±6.36 m l/m2,心搏出量指数为39.09±11.76 m l/m2,射血分数(EF)为0.52±0.06,心脏指数(C I)为2.38±0.58 L/m in.m2,心肌质量指数为103.49±21.57 g/m2,心肌质量/心室舒张期末容量为1.57±0.24;(3)TCPC组BNP水平与手术时年龄呈明显正相关(r=0.632,P=0.041);BNP水平与上述M R I指标、R oss评分、性别、年龄、脉搏血氧饱和度(SpO2)及主心室类型等因素无关。结论TCPC后近2年神经内分泌系统仍处于应激状态,BNP增高可能与TCPC后特有的血流动力学状态有关;血浆BNP水平不能作为正确评估TCPC后心功能状态的指标。     

犬急性心肌梗死早期冠状动脉旁路移植术对左室壁运动的影响

目的 探讨犬急性心肌梗死早期冠状动脉旁路移植术对室壁运动的影响及其在唤醒冬眠心肌中的意义.方法 结扎犬冠状动脉前降支制备心肌梗死模型(30只).按手术日期随机分组,分别在心肌梗死后1、2、4、6周行冠状动脉旁路移植术作为实验组,其中第2周4只,其余每组6只;对每个实验组分别设立心肌梗死对照组(不进行冠状动脉旁路移植术),每组2只.实验组在冠状动脉旁路移植术前及冠状动脉旁路移植术8周后开胸利用多巴酚丁胺超声负荷试验结合组织多普勒成像技术标记冬眠心肌,并测定室壁运动记分;对照组在相同时间点同样的方法标记冬眠心肌并测定室壁运动记分.每只犬处死后分别测定心肌梗死面积.结果 每个实验组各存活4只,对照组均存活.1、2周实验组较4、6周实验组及对照组梗死区心肌室壁运动记分的变化明显减小(0.03±0.06,0.05 ±0.09,0.23 ±0.08,0.27±0.06,0.32 ±0.05,P＜0.05),所有实验组较对照组心肌室壁运动记分的变化明显减小(1.195±0.09,1.25±0.18,1.30±0.18,1.36 ±0.11,1.65 ±0.17,P＜0.05),所有实验组较对照组唤醒更多的冬眠心肌(0.27 ±0.12,0.22±0.04,0.31±0.09,0.23±0.03,0.03 ±0.04,P＜0.05).1、2周实验组较4、6周实验组及对照组心肌梗死范围明显减小[(20.75±2.63)％,(21.25±2.5)％,(27.25±1.71)％,(27.75±2.22)％,(26.50±0.71)％,(29.00±1.41)％,(27.00±1.41)％,(28.50±0.71)％,P＜0.05)].结论 犬急性心肌梗死早期冠状动脉旁路移植可以明显改善心肌室壁运动,唤醒更多的冬眠心肌,尤其2周内行冠状动脉旁路移植术可以最大限度地减少梗死心肌对室壁运动的影响,并可以减少心肌梗死范围.     

两步冷冻法对周围神经雪旺细胞生物活性的影响

目的探讨两步冷冻法不同冷冻温度对周围神经雪旺细胞(Schwanncell,SC)生物活性的影响。方法雌性SD大鼠80只,切取双侧坐骨神经2cm,随机分为8组,每组10只20条坐骨神经。1组为新鲜对照组,不作任何处理;另7组为实验组,采用两步冷冻法分别降温至-20、-30、-40、-50、-60、-70和-80℃,保存2h后转入液氮中(-196℃)保存48h,取出后在37℃水浴箱中快速复温1min,消化收集各组SC,经Calceim-AM荧光染色,作流式细胞仪分析,求出各组细胞平均荧光强度,再经共聚焦显微镜直接观察SC荧光强度,进一步判断SC的生物活性。结果经流式细胞仪检测各组SC荧光强度为新鲜对照组242.5220±9.5684,-20℃组168.6770±10.2070,-30℃组214.9920±8.3291,-40℃组235.5260±9.2805,-50℃组222.4340±8.5155,-60℃组217.4090±9.5157,-70℃组132.3760±13.4597,-80℃组108.1320±16.0331;-40℃组荧光强度较其它实验组强,差异有统计学意义(P<0.01)。共聚焦显微镜观察各组SC生物活性,并作荧光强度分析:新鲜对照组143.7000±5.5678,-20℃组119.7000±5.1651,-30℃组121.3000±4.3474,-40℃组139.7000±5.0122,-50℃组121.0000±4.5461,-60℃组118.4000±4.9261,-70℃组81.2000±5.1164,-80℃组79.0000±5.7164;新鲜对照组SC生物活性较各实验组强,-40℃组SC生物活性较其它实验组强,差异均有统计学意义(P<0.01)。结论两步冷冻法均能较好保存SC生物活性,以-40℃组SC生物活性最好。     

骨骼肌卫星细胞梗死心肌移植的细胞因子分泌及血管再生作用

目的　研究骨骼肌卫星细胞梗死心肌移植的胰岛素样生长因子(IGF)-1、碱性纤维母细胞生长因子(bFGF)分泌及血管再生的作用。方法　骨骼肌卫星细胞经结扎的冠状动脉左前降支远端灌注移植入梗死区，2、4、8周后取标本，应用免疫组化学方法检测细胞因子表达及梗死区血管密度。结果　骨骼肌卫星细胞移植2、4、8周后梗死区IGF-1和bFGF表达分别为81.68±3.34、96.87±7.78、90.43±7.36及81.87±3.58、65.66±4.57、74.20±6.41，明显高于对照组(P＜0.01)；同时，移植2、4、8周后梗死区血管密度高于对照组(P＜0.05)。结论　骨骼肌卫星细胞梗死心肌移植除有心肌再生外，尚可通过细胞因子分泌对梗死心肌起到积极作用。     

Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs

BACKGROUND: Global and regional shape changes that occur within the left ventricular wall after myocardial infarction have been termed infarct expansion. A potential mechanism for this postinfarction remodeling is activation of the matrix metalloproteinases. Accordingly, the present study examined the effects of matrix metalloproteinase inhibition on left ventricular global geometry after myocardial infarction in pigs. METHODS: Myocardial infarction was created in pigs by means of occlusion of the first and second obtuse marginal branches of the circumflex coronary artery, resulting in a uniform left ventricular free wall infarct size of 21% +/- 2%. At 5 days after infarction, the pigs were randomized to undergo broad-spectrum matrix metalloproteinase inhibition (n = 9; PD166793, 20 mg. kg(-1). d(-1) by mouth) or myocardial infarction alone (n = 8). Ten pigs served as noninfarction control animals. Left ventricular end-diastolic area, determined by means of echocardiography, was measured 8 weeks after infarction. RESULTS: Left ventricular end-diastolic area increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and myocardial infarction only groups compared to reference control animals (3.7 +/- 0.2 cm(2)), but was reduced with broad-spectrum matrix metalloproteinase inhibition compared to myocardial infarction alone (4.5 +/- 0.2 vs 4.9 +/- 0.2 cm(2), respectively; P <.05). Regional radial stress within the infarct region increased in both infarction groups when compared to values obtained from reference control animals (599 +/- 152 g/cm(2)), but was attenuated in the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition group compared to the myocardial infarction alone group (663 +/- 108 vs 1242 +/- 251 g/cm(2), respectively; P <.05). Similarly, regional myocardial stiffness increased in both the myocardial infarction plus broad-spectrum matrix metalloproteinase inhibition and the myocardial infarction only groups compared with that observed in reference control animals (14 +/- 1 rkm, P <.05) but was lower with broad-spectrum matrix metalloproteinase inhibition than with myocardial infarction alone (42 +/- 6 vs 68 +/- 10 rkm, respectively; P <.05). CONCLUSIONS: Matrix metalloproteinase inhibition reduced postinfarction left ventricular dilation, reduced regional myocardial wall stress, and modified myocardial material properties. These unique findings suggest that increased myocardial matrix metalloproteinase activation after infarction contributes directly to the left ventricular remodeling process.     

Local myocardial overexpression of growth hormone attenuates postinfarction remodeling and preserves cardiac function

BACKGROUND: Ventricular remodeling with chamber dilation and wall thinning is seen in postinfarction heart failure. Growth hormone induces myocardial hypertrophy when oversecreted. We hypothesized that localized myocardial hypertrophy induced by gene transfer of growth hormone could inhibit remodeling and preserve cardiac function after myocardial infarction. METHODS: Rats underwent direct intramyocardial injection of adenovirus encoding either human growth hormone (n = 9) or empty null vector as control (n = 9) 3 weeks after ligation of the left anterior descending coronary artery. Analysis of the following was performed 3 weeks after delivery: hemodynamics, ventricular geometry, cardiomyocyte fiber size, and serum growth hormone levels. RESULTS: The growth hormone group had significantly better systolic cardiac function as measured by maximum left ventricular pressure (73.6 +/- 6.9 mm Hg versus control 63.7 +/- 7.8 mm Hg, p < 0.05) and maximum dP/dt (2845 +/- 453 mm Hg/s versus 1949 +/- 605 mm Hg/s, p < 0.005), and diastolic function as measured by minimum dP/dt (-2520 +/- 402 mm Hg/s versus -1500 +/- 774 mm Hg/s, p < 0.01). Ventricular geometry was preserved in the growth hormone group (ventricular diameter 12.2 +/- 0.7 mm versus control 13.1 +/- 0.4 mm, p < 0.05; borderzone wall thickness 2.0 +/- 0.2 mm versus 1.5 +/- 0.1 mm, p < 0.001), and was associated with cardiomyocyte hypertrophy (6.09 +/- 0.63 microm versus 4.66 +/- 0.55 microm, p < 0.005). Local myocardial expression of growth hormone was confirmed, whereas serum levels were undetectable after 3 weeks. CONCLUSIONS: Local myocardial overexpression of growth hormone after myocardial infarction resulted in cardiomyocyte hypertrophy, attenuated ventricular remodeling, and improved systolic and diastolic cardiac function. The induction of localized myocardial hypertrophy presents a novel therapeutic approach for the treatment of ischemic heart failure.     

TNFR gene-modified mesenchymal stem cells attenuate inflammation and cardiac dysfunction following MI

OBJECTIVES: To investigate the protective effect of tumor necrosis factor receptor (TNFR) gene modified mesenchymal stem cells (MSCs) transplantation against inflammation and cardiac dysfunction following acute myocardial infarction (AMI). DESIGN: MSCs were extracted from the tibias and femurs of rats and transfected with recombinant adeno-associated viral (rAAV) expressing EGFP (enhanced green fluorescent protein) or p75 (human 75 kilodalton) TNFR at multiplicity of infection of 10(5) particles/cell. Rats with AMI induced by occlusion of the left coronary artery were randomized to MSCs-TNFR transplantation group, MSCs-EGFP transplantation group and MI control group. RESULTS: The effects of MSCs-TNFR transplantation on cardiac inflammation and left ventricular dysfunction were observed after 2 weeks of MI. We found that: 1) MSCs-TNFR transplantation attenuated protein production and gene expression of inflammatory cytokines TNF-, IL-1beta and IL-6; 2) MSCs-TNFR transplantation inhibited cardiomyocytes apoptosis and 3) MSCs-TNFR transplantation improved left ventricular function. CONCLUSIONS: The experimental data show that transplantation with rAAV-TNFR transfected MSCs improves left ventricular function following MI through anti-apoptotic and anti-inflammatory mechanisms.     

Cardiomyocyte transplantation does not reverse cardiac remodeling in rats with chronic myocardial infarction

BACKGROUND: Several reports have documented the potential benefits of cell transplantation as an alternative to cardiac transplantation. This study was designed to investigate whether cardiomyocyte transplantation is effective in rats with chronic myocardial infarction. METHODS: Syngeneic Lewis rats were used in this study. Chronic myocardial infarction was induced in rats by ligating the left anterior descending artery. Four weeks later, after left ventricular (LV) dysfunction with akinetic regions was confirmed by echocardiography, the rats were randomized into two groups: a group that received fetal cardiomyocyte transplantation (TX group; n = 11); and a group that received an intramyocardial injection of culture medium only (control group; n = 12). RESULTS: Four weeks after treatment, the TX group had smaller end-systolic dimension (LVDs) (7.5 +/- 0.9 vs 8.9 +/- 0.8 mm, p < 0.01) and better fractional shortening (FS) (26.2 +/- 5.9 vs 17.7% +/- 5.1%, p < 0.01) than the control group. However, there were no differences in LV end-diastolic dimension, LVDs, and FS between baseline and post-treatment values in the TX group. In addition, plasma levels of atrial natriuretic peptide were not significantly different between the two groups 4 weeks after treatment. In microscopic examination, small amounts of transplanted cardiomyocytes were found only in the periinfarct area, not in the center of scar area, and a thicker ventricular wall in the infarct area was detected in the TX group. CONCLUSIONS: Fetal cardiomyocyte transplantation prevented, but did not reverse, cardiac remodeling that was accompanied with heart failure in myocardial infarction rats. Further investigation is warranted for optimal clinical application to the failing heart.     

Mechanism of higher incidence of ischemic mitral regurgitation in patients with inferior myocardial infarction: quantitative analysis of left ventricular and mitral valve geometry in 103 patients with prior myocardial infarction

OBJECTIVE: The mechanism of higher incidence of ischemic mitral regurgitation in patients with inferior compared with anterior myocardial infarction despite less global left ventricular remodeling and dysfunction is controversial. We hypothesized that inferior myocardial infarction causes left ventricular remodeling, which displaces posterior papillary muscle away from its normal position, leading to ischemic mitral regurgitation. METHODS: In 103 patients with prior myocardial infarction (61 anterior and 42 inferior) and 20 normal control subjects, we evaluated the grade of ischemic mitral regurgitation on the basis of the percentage of Doppler jet area, left ventricular end-diastolic and end-systolic volumes, midsystolic mitral annular area, and midsystolic leaflet-tethering distance between papillary muscle tips and the contralateral anterior mitral annulus, which were determined by means of quantitative echocardiography. RESULTS: Global left ventricular dilatation and dysfunction were significantly less pronounced in patients with inferior myocardial infarction (left ventricular end-systolic volume: 52 +/- 18 vs 60 +/- 24 mL, inferior vs anterior infarction, P<.05; left ventricular ejection fraction: 51% +/- 9% vs 42% +/- 7%, P <.0001). However, the percentage of mitral regurgitation jet area and the incidence of significant regurgitation (percentage of jet area of 10% or greater) was greater in inferior infarction (percentage of jet area: 10.1% +/- 7.5% vs 4.4% +/- 7.0%, P =.0002; incidence: 16/42 (38%) vs 6/61 (10%), P <.0001). The mitral annulus (area = 8.2 +/- 1.2 cm2 in control subjects) was similarly dilated in both inferior and anterior myocardial infarction (9.7 +/- 1.7 vs. 9.5 +/- 2.3 cm2, no significant difference), and the anterior papillary muscle-tethering distance (33.8 +/- 2.6 mm in control subjects) was also similarly and mildly increased in both groups (35.2 +/- 2.4 vs 35.2 +/- 2.8 mm, no significant difference). However, the posterior papillary muscle-tethering distance (33.3 +/- 2.3 mm in control subjects) was significantly greater in inferior compared with anterior myocardial infarction (38.3 +/- 4.1 vs 34.7 +/- 2.9 mm, P =.0001). Multiple stepwise regression analysis identified the increase in posterior papillary muscle-tethering distance divided by body surface area as an independent contributing factor to the percentage of mitral regurgitation jet area (r2 = 0.70, P <.0001). CONCLUSIONS: It is suggested that the higher incidence and greater severity of ischemic mitral regurgitation in patients with inferior compared with anterior myocardial infarction can be related to more severe geometric changes in the mitral valve apparatus with greater displacement of posterior papillary muscle caused by localized inferior basal left ventricular remodeling, which results in therapeutic implications for potential benefit of procedures, such as infarct plication and leaflet or chordal elongation, to reduce leaflet tethering.     

TNFR gene-modified mesenchymal stem cells attenuate inflammation and cardiac dysfunction following MI

Objectives. To investigate the protective effect of tumor necrosis factor receptor (TNFR) gene modified mesenchymal stem cells (MSCs) transplantation against inflammation and cardiac dysfunction following acute myocardial infarction (AMI). Design. MSCs were extracted from the tibias and femurs of rats and transfected with recombinant adeno-associated viral (rAAV) expressing EGFP (enhanced green fluorescent protein) or p75 (human 75 kilodalton) TNFR at multiplicity of infection of 10⁵ particles/cell. Rats with AMI induced by occlusion of the left coronary artery were randomized to MSCs-TNFR transplantation group, MSCs-EGFP transplantation group and MI control group. Results. The effects of MSCs-TNFR transplantation on cardiac inflammation and left ventricular dysfunction were observed after 2 weeks of MI. We found that: 1) MSCs-TNFR transplantation attenuated protein production and gene expression of inflammatory cytokines TNF-α, IL-1β and IL-6; 2) MSCs-TNFR transplantation inhibited cardiomyocytes apoptosis and 3) MSCs-TNFR transplantation improved left ventricular function. Conclusions. The experimental data show that transplantation with rAAV-TNFR transfected MSCs improves left ventricular function following MI through anti-apoptotic and anti-inflammatory mechanisms.     

Angiogenic growth factors and/or cellular therapy for myocardial regeneration: a comparative study

BACKGROUND: Locally delivered angiogenic growth factors and cell implantation have been proposed for patients with myocardial infarcts without a possibility of percutaneous or surgical revascularization. The goal of this study was to compare the effects of these techniques in an experimental model of myocardial infarct. METHODS: Left ventricular myocardial infarction was created in 27 sheep by ligation of 2 coronary arteries. Three weeks after creation of the infarct, animals were randomized into 4 groups. In group 1, sheep received a culture medium injection to the infarct area (control group); group 2 underwent autologous myoblast implantation; group 3 received vascular endothelial growth factor; and group 4 received injection of both vascular endothelial growth factor and myoblasts. Evaluation included serum troponin IC levels, echocardiography (2-dimensional and color kinesis), and immunohistologic studies for quantitative analysis of capillaries (3 months after surgery). RESULTS: Four animals died of refractory ventricular fibrillation during myocardial infarction; 2 died after surgery because of stroke and 2 because of infections. Serum troponin increased to 45.6 +/- 4.7 ng/mL at postinfarction day 2. Echocardiography at 3 months showed a significant limitation of left ventricular dilation in the cell group (57 +/- 11.1 mL) and in the cell plus vascular endothelial growth factor group (58.6 +/- 6.6 mL: control group, 74.4 +/- 11.2 mL; vascular endothelial growth factor group, 68.1 +/- 3.4 mL). Color kinesis echography showed important improvements of regional fractional area change in the cell group (from 13.6% +/- 0.8% to 21.1% +/- 1.5%) and in the cell plus vascular endothelial growth factor group (from 12.8% +/- 0.9% to 18.7% +/- 2.3%). The number of capillaries increased in the peri-infarct region of the vascular endothelial growth factor group (1036 +/- 75: control group, 785 +/- 31; cell group, 830 +/- 75; cell plus vascular endothelial growth factor group, 831 +/- 83). CONCLUSIONS: In the cell therapy groups, regional ventricular contractility improved and heart dilatation was limited compared with either vascular endothelial growth factor or control; thus, postischemic remodeling was reduced. Angiogenesis was demonstrated in the vascular endothelial growth factor group, without improvement of ventricular function and remodeling. To improve local conditions for cell survival, further studies are warranted on prevascularization of myocardial scars with angiogenic therapy.     

Functional remodelling and left ventricular dysfunction after repeated ischaemic episodes. A chronic experimental porcine model.

This experimental study was set up to investigate left ventricular function and remodelling after repeated ischaemic episodes using magnetic resonance imaging (MRI). A significant reduction in mortality due to coronary heart disease (CHD) has been explained by both a decline in the incidence of acute myocardial infarction (AMI) and an improved post-AMI survival rate, suggesting a change in the natural history of CHD. Experimental intracoronary microembolization can induce different ischaemic patterns and the functional impact of repeated ischaemic episodes different from occlusion of central epicardial arteries can be studied. In this study repeated intracoronary microembolizations were performed in 20 domestic pigs. After 129 d, MRI was performed for assessment of left ventricular volume, mass and wall stress. Six pigs underwent serial MRI at baseline, immediately after embolization and at the end of the observation period. Microembolizations induced acute myocardial infarct expansion and increased left ventricular wall stress preceding chronic remodelling. End systolic and end diastolic volumes increased from 15.1 +/- 2.7 cm3 to 41.3 +/- 11.5 cm 3 (p < 0.002), and from 52.0 +/- 6.7 cm3 to 81.1 +/- 9.2 cm3 (p < 0.0007), respectively. End systolic wall stress increased from and 17.5 +/- 2.7 to 29.7 +/- 6.2 N/m2 (p < 0.001). Left ventricular filling pressures and cardiac index were unchanged. Histological examination revealed a diffuse pattern of perivascular fibrosis covering 12 +/- 3% of the left ventricular wall. This study demonstrates that repeated ischaemic episodes different from confined regional myocardial infarctions induce acute infarct expansion and chronic left ventricular remodelling in pigs. Serial assessment of absolute left ventricular volumes and mass is important during acute/chronic remodelling.     

Effects of chronic cardiomyoplasty on ventricular remodeling in a goat model of chronic cardiac dilatation: part 2

BACKGROUND: Reduction of ventricular dilatation, rather than direct improvement of pump function, has been suggested to be the main working mechanism of dynamic cardiomyoplasty (CMP). This working mechanism was examined in the goat using a chronic cardiac dilatation model induced by the creation of a cervical arteriovenous shunt and submitted to passive and active CMP. METHODS: Fourteen female goats underwent surgical creation of a shunt between the left carotid artery and the jugular vein. Seven goats had no additional operation (control group). The other 7 goats (CMP group) underwent CMP approximately 8 weeks after the creation of the shunt. The wrapped left latissimus dorsi muscle was left unstimulated for 2 weeks, and subsequently stimulated electrically for a 3-month period, using a 1:4 muscle-to-heart contraction ratio. Hemodynamic measurements included heart catheterization and determination of left ventricular (LV) pressure-volume relations by means of the conductance catheter method at baseline, after 8 weeks (only in the CMP group), and after 5 months. Transthoracic echocardiography was performed just before opening the AV shunt and every 2 weeks thereafter. RESULTS: Significant ventricular enlargement, as well as persistent increase in filling pressures, were observed after 8 weeks. Animals in the control group dilated further beyond 2 months (LV end-diastolic diameter from 39 +/- 2 to 67 +/- 6 mm). In contrast, the ongoing LV dilatation process was stopped by passive CMP, and LV end-diastolic diameter significantly decreased after electrical activation of the wrapped skeletal muscle (from 63 +/- 7 to 42 +/- 6 mm). Cardiomyoplasty also significantly increased the slope of the end-systolic pressure-volume relation (elastance) when compared with pre-CMP values (from 0.9 +/- 0.2 to 1.7 +/- 0.5 mm Hg/mL), which indicated an improvement of the LV contractile state. No significant hemodynamic effects could be observed at the tuned stimulation settings on a beat-to-beat basis during electrical muscle stimulation. CONCLUSIONS: The contribution of CMP to LV dimension and contractility appeared to be either passive or active, and this study suggests the importance of stimulating the latissimus dorsi muscle to enhance the girdling effects of the wrapped latissimus dorsi muscle and to improve LV contractility.     

Helical myofiber orientation after myocardial infarction and left ventricular surgical restoration in sheep

OBJECTIVES: It has been proposed that successful left ventricular surgical restoration should restore normal helical myofiber orientation. A magnetic resonance imaging technique, magnetic resonance diffusion tensor imaging, has been developed to measure myocyte orientation. By using magnetic resonance diffusion tensor imaging, this study tested the hypothesis that (1) myocyte orientation is altered after anteroapical myocardial infarction and (2) left ventricular surgical restoration restores normal helix angles. METHODS: Thirteen sheep underwent anteroapical myocardial infarction (25% of left ventricular mass). Ten weeks later, animals underwent either aneurysm plication (n = 8) or sham operations (n = 5). Six weeks after this operation, hearts were excised, perfusion fixed in diastole, and underwent magnetic resonance diffusion tensor imaging. Hearts from normal sheep (n = 5) were also harvested and imaged. Primary eigenvectors of the diffusion tensors from magnetic resonance diffusion tensor imaging were resolved into helix angles relative to a local wall coordinate system. Transmural samples of the helix angles were compared at the border zone of the aneurysm or repair (or a comparable distance from the base in normal sheep), 1 cm below the valves, and halfway between. RESULTS: The helical myofiber orientation did not change after myocardial infarction. However, aneurysm plication caused myofibers in the anterior border zone to rotate counterclockwise (-35.6 +/- 10.5 degrees , P = .028) and those in the lateral border zone to rotate clockwise (34.4 +/- 8.1 degrees , P = .031). CONCLUSIONS: Surgical restoration alters myocyte orientation adjacent to the surgical repair. However, myofiber orientation is not abnormal after myocardial infarction, and thus surgical restoration techniques intent on restoring normal helix angles might not be warranted.