Contrast-enhanced MRI of murine myocardial infarction - part I

The use of contrast agents has added considerable value to the existing cardiac MRI toolbox that can be used to study murine myocardial infarction, as it enables detailed in vivo visualization of the molecular and cellular processes that occur in the infarcted and remote tissue. A variety of non-targeted and targeted contrast agents to study myocardial infarction are available and under development. Manganese, which acts as a calcium analogue, can be used to assess cell viability. Traditionally, low-molecular-weight Gd-containing contrast agents are employed to measure infarct size in a late gadolinium enhancement experiment. Gd-based blood-pool agents are used to study the vascular status of the myocardium. The use of targeted contrast agents facilitates more detailed imaging of pathophysiological processes in the acute and chronic infarct. Cell death was visualized by contrast agents functionalized with annexin A5 that binds specifically to phosphatidylserine accessible on dying cells and with an agent that binds to the exposed DNA of dead cells. Inflammation in the myocardium was depicted by contrast agents that target cell adhesion molecules expressed on activated endothelium, by contrast agents that are phagocytosed by inflammatory cells, and by using a probe that targets enzymes excreted by inflammatory cells. Cardiac remodeling processes were visualized with a contrast agent that binds to angiogenic vasculature and with an MR probe that specifically binds to collagen in the fibrotic myocardium. These recent advances in murine contrast-enhanced cardiac MRI have made a substantial contribution to the visualization of the pathophysiology of myocardial infarction, cardiac remodeling processes and the progression to heart failure, which helps to design new treatments. This review discusses the advances and challenges in the development and application of MRI contrast agents to study murine myocardial infarction.     

Transdisciplinary approach to the follow-up of patients after myocardial infarction

OBJECTIVES: To compare conventional and transdisciplinary care in a tertiary outpatient clinic for patients after their first acute myocardial infarction. METHODS: One hundred fifty-three patients with acute myocardial infarction were randomized at hospital discharge and followed-up to compare conventional (n=75) and transdisciplinary care (n=78). They were submitted to a clinical evaluation, received a dietary plan, and were re-evaluated twice in 60-180 days by a nurse, dietitian and physician, when new clinical and laboratory data were collected. The primary outcome was clinical improvement, as evaluated by an index including reduction of body weight, lowering of blood pressure, smoking cessation, increase in physical activity and compliance with medication. RESULTS: The groups were similar at baseline: 63.4% were men, 89.9% had an acute myocardial infarction with ST-segment-elevation, 32.7% were diabetic, and 72.2% were hypertensive. The clinical improvement index was similar between the studied groups: in 33.3 % (transdisciplinary care) vs. 30.4 % (conventional care) of patients, the improvement was very good (P=1.000). Rates of re-hospitalization and death (p=0.127) were similar between transdisciplinary and conventional care. Compliance with diet was higher for transdisciplinary care (50.0%) vs. conventional care (26.1%) (p=0.007), as was compliance with visits (73.3 vs. 40.3%, respectively, p<0.001). CONCLUSIONS: Compliance with diet and visits was higher for transdisciplinary care vs. conventional care; however, the transdisciplinary approach did not provide more clinical benefits than the conventional approach after patients' first acute myocardial infarction in this setting.     

几种基于中华小型猪心脏磁共振延时增强图像的心肌梗死体积定量算法的初步比较

目的心脏磁共振(CMR)心肌成像应用钆对比剂延迟强化(LGE)显示冠心病心肌梗死(MI)的价值已得到公认。近年来涌现出多种MI体积的定量方法,但是一直没能达成共识。笔者对比了定量MI体积计算的若干方法在中华小型猪MI模型的应用,以期得到准确度最高的定量MI体积计算方法。方法猪龄3个月中华小型猪6只,行冠状动脉结扎,制作MI模型,1个月后行磁共振扫描(可认为是陈旧MI),随后即取心做TTC染色。运用数学软件MATLAB(2011b)编程对LGE图像先手动勾勒心内膜和心外膜,然后行不同信号强度(SI)阈值(5种倍数标准差:2s、3s、4s、5s、6s)分割,提取MI体积,并与病理切片得到的MI体积进行比较。结果病理切片得到的MI体积为(12.24±4.34)cm3。随着SI阈值增大,5种半自动定量算法得到的MI体积分别为(24.04±6.10)cm3、(17.76±6.41)cm3、(14.29±5.88)cm3、(11.70±5.24)cm3、(9.56±4.73)cm3。采用相关分析显示,TTC染色结果与半自动定量方法得到的结果两两之间的相关系数分别为0.807、0.917、0.952、0.967、0.962。结论 5s半自动定量方法在中华小型猪MI模型MI体积计算中与TTC染色结果相关性好,且无统计学差异。5s是一种行之有效的MI定量方法。     

Effects of renal impairment on cardiac remodeling and clinical outcomes after myocardial infarction

How renal function influences post-acute myocardial infarction (AMI) cardiac remodeling and outcomes remains unclear. This study evaluated the impact of levels of renal impairment on drug therapy, echocardiographic parameters, and outcomes in patients with AMI undergoing percutaneous coronary intervention (PCI). A total of 611 patients diagnosed with AMI underwent successful PCI, and two echocardiographic examinations were performed within 1 year after AMI. Patients were categorized according to Group 1: severely impaired estimated glomerular filtration rate (eGFR)<30, Group 2: mildly impaired 30≤eGFR<60, Group 3: potentially at risk 60≤eGFR<90 and normal eGFR≥90 ml/min/1.73 m2. During the 5-year follow-up period, the primary endpoints were cardiovascular mortality and outcomes. Patients with worse renal function (eGFR<30) were older and had a higher prevalence of hypertension and diabetes, but relatively few were smokers or had hyperlipidemia. Despite more patients with lesions of the left anterior descending artery, those with worse renal function received suboptimal guideline-directed medical therapy (GDMT). Notably, patients with worse renal function presented with worse left ventricular function at baseline and subsequent follow-up. Kaplan-Meier analysis revealed increased cardiovascular death, development of heart failure, recurrent AMI and revascularization in patients with worse renal function. Notably, as focusing on patients with ST elevation MI, the similar findings were observed. In multivariable Cox regression, impaired renal function showed the most significant hazard ratio in cardiovascular death. Collectively, in AMI patients receiving PCI, outcome differences are renal function dependent. We found that patients with worse renal function received less GDMT and presented with worse cardiovascular outcomes. These patients require more attention.     

Monitoring dynamic alterations in calcium homeostasis by T (1)-weighted and T (1)-mapping cardiac manganese-enhanced MRI in a murine myocardial infarction model

Manganese has been used as a T(1)-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn(2+)) enter viable myocardial cells via voltage-gated Ca(2+) channels, manganese-enhanced MRI is sensitive to the viability and inotropic state of the heart. In spite of the established importance of Ca(2+) regulation in the heart both before and after myocardial injury, monitoring strategies to assess Ca(2+) homeostasis in affected cardiac tissues are limited. This study implements a T(1)-mapping method to obtain quantitative information both dynamically and over a range of MnCl(2) infusion doses. To optimize the current Mn(2+) infusion protocols, we performed both dose-dependent and temporal washout studies. A non-linear relationship between infused MnCl(2) solution dose and increase in left ventricular wall relaxation rate (DeltaR(1)) was observed. Control mice also exhibited significant Mn(2+) clearance over time, with a decrease in DeltaR(1) of approximately 50% occurring in just 2.5 h. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. With the use of the measured relationship between infused Mn(2+) dose, DeltaR(1), and inductively coupled plasma mass spectrometry data analysis provided a means of estimating the absolute heart Mn concentration in vivo. We show that this technique has the sensitivity to observe or monitor potential alterations in Ca(2+) handling in vivo because of the physiological remodeling after myocardial infarction. Left ventricular free wall DeltaR(1) values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than in healthy tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future treatment or evaluation of disease progression.     

血管紧张素（1-7）对兔急性心肌梗死再灌注血清一氧化氮水平及心肌微血管完整性的影响

目的探讨血管紧张素(1-7)[Ang-(1-7)]对急性心肌梗死再灌注血清一氧化氮(NO)水平及心肌微血管完整性的影响。方法新西兰雄性大白兔30只,随机分成以下3组:假手术组、缺血再灌注(I-R)对照组和Ang-(1-7)治疗组,每组10只。Ang-(1-7)治疗组经置入式微量泵持续颈静脉给予Ang-(1-7)(25μg.kg-1.h-1)3d。假手术组和I-R对照组经微量泵只给予等量的生理盐水。每组均在3d预处理后,冠状动脉左前降支结扎2h,再灌注2h。测定缺血前、后和再灌注2h时血清NO含量及光镜下心肌灶性出血发生率的变化,并采用氯化三苯四唑(TTC)染色观察心肌梗死范围。结果心肌缺血前Ang-(1-7)治疗组NO已显著升高(P<0.01);心肌缺血后2h时,各组NO均比缺血前显著降低(P<0.01),但Ang-(1-7)治疗组比I-R对照组显著增高(P<0.01);再灌注2h后,各组NO均比缺血2h时进一步降低,但Ang-(1-7)治疗组仍比I-R对照组显著增高(P<0.01)。心肌灶性出血发生率在I-R对照组为65.00%,而Ang-(1-7)治疗组为27.50%(P<0.01)。心肌梗死面积在I-R对照组为(28.70±5.45)%,而Ang-(1-7)治疗组为(15.46±4.32)%(P<0.01)。结论静脉持续给予Ang-(1-7)能提高急性心肌梗死再灌注时血清NO水平,可保护心肌微血管的完整性。     

APO(a) variants and lipoprotein(a) in men with or without myocardial infarction

The lipoprotein Lp(a) with high plasma concentration is an independent genetic determinant for cardiovascular diseases. It was investigated as a quantitative factor of risk for myocardial infarction. A total of 345 Italian subjects, 127 Cases and 218 Controls, were studied. Lipids and lipoproteins were compared. Cases had atherogenic traits, such as lower HDL cholesterol and higher triglycerides than Controls. In particular, they had Lp(a) concentrations over the risk threshold, (median, 27 mg/dl in Cases vs 17 mg/dl in Controls; P = 0.0075, Mann-Whitney test) which confirmed the association of this parameter with the disease. Two main functional variants of the apo(a) gene, KringleIV and penta-nucleotide repeat, (PNR) were analyzed. Allele and genotype frequency distributions differed between Cases and Controls. Lp(a) concentrations differed according to PNR genotypes in Controls: subjects having alleles >8 showed lower Lp(a). This was not found in Cases. They had a higher prevalence of the smaller KringleIV alleles, the high Lp(a)-expressing ones. In Cases, genotypes consisting of two small KringleIV alleles were prevalently associated to PNR 8/9 and 8/10, thus preventing Lp(a) lowering. The putative apo(a) enhancer within LINE1 in the apo(a)-plasminogen intergenic region was investigated for functional polymorphisms. No variants that could be associated to the Lp(a) variability were found.     

白细胞介素6基因-572C/G多态性与心肌梗塞易感性的关联研究

目的观察白细胞介素6（interleukin 6，IL6）基因-572C／G多态性在中国人群中的分布频率、与心肌梗塞（myocardial infarction，MI）易感性的关系、对MI患者冠脉病变程度的影响以及初步对该位点基因变异进行功能性分析。方法应用聚合酶链反应．限制性片段长度多态性方法对232例MI患者和260名正常对照者IL6基因-572C／G多态性进行了分析，观察了该基因多态性对冠脉病变程度及外周血单核细胞（peripheral blood mononuclear cells，PBMC）产生IL6能力的影响。结果中国汉族人群存在IL6基因-572C／G多态性；两组人群基因型、等位基因频率差异存在统计学意义，MI组CG＋GG基因型频率、G等位基因频率均显著高于对照组（P〈0．01）；基因型频率的相对风险分析发现，G等位基因携带者息MI的风险是CC基因型的1．68倍（95％CI：1．17—2．41，P〈0．01）；-572C／G多态性在单支、双支、三支冠脉病变组间的分布差异无统计学意义（P〉0．05）；G等位基因携带者氧化低密度脂蛋白刺激24h PBMC产生IL6的能力明显高于CC基因型（P〈0．05）。结论IL6基因-572G等位基因可能是中国汉族人MI的易感因子，这可能与携带该等位基因的人群存在IL6水平的高表达有关。     

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。     

Incidence and mortality rates of myocardial infarction in Chinese workers aged 40–59 in relation to coronary risk factors

Summary Some 2045 male Chinese industrial workers aged 40–59 years living in the city of Wuhan in the People's Republic of China were examined for coronary risk factors in the year 1983. The investigation included a patient history, clinical examination, and ECG and laboratory tests, with special attention to serum lipids. After 5 years, a follow-up investigation of the study group was carried out. The results were compared to the similarly designed German GRIPS project.In comparison to the German population, significantly lower levels for total-, LDL-, and VLDL-cholesterol, apolipoprotein B, triglycerides, uric acid, body mass index, and diastolic blood pressure were found in China. The percentage of smokers, however, was remarkably higher in China than in the Federal Republic of Germany.During the 5 year observation period in the Chinese sample, four subjects suffered from sudden death and four from nonfatal myocardial infarction; in the German study group three times as many fatal myocardial infarction and cases of sudden death and 7.5 times as many nonfatal myocardial infarctions were recorded. Nonfatal coronary heart disease and peripheral vascular disease were also observed less often in China. The incidence of cerebrovascular diseases was 1.5 times higher in China than in Germany.Whereas in Germany, total-, and LDL-cholesterol values were the major distinguishing parameters between infarction and reference groups, in China these values have thus far had no significant influence on the level of risk. Instead in the Chinese incidence group, significantly higher levels for blood pressure, body mass index, uric acid, and the ratio LDL/HDL-cholesterol were found.     

Manganese-enhanced MRI of acute cardiac ischemia and chronic infarction in pig hearts: kinetic analysis of enhancement development

To assess infarction development in pig hearts, Mn-enhanced and Gd-enhanced MRI were used. In domestic pigs (25-35 kg, n = 37), the first and second diagonal branches of the left anterior descending coronary artery were ligated to induce acute ischemia and infarction (ischemia+reperfusion) or chronic infarction of increasing duration (3- 28 days). Ex vivo experiments were performed on hearts perfused in the Langendorff mode with a 50:50 mixture of blood and Krebs-Henseleit buffer using a spin-echo sequence on a 7 T Bruker imaging system. Signal acquisition from the heart and two reference test tubes (H(2)O and H(2)O + 10 mM CuSO(4)) was gated by the left ventricular pressure wave. T(1)-weighted images of six 8 mm short-axis slices (2 mm interslice gaps) were obtained before and after the addition of 0.2 mM MnCl(2) every 5 min over a 30-45 min period. Signal intensities were normalized to those of the H(2)O reference and fitted by a monoexponential function. The rates of intensity increase and maximal increases were significantly lower in the ischemic/infarcted areas and showed a trend to rise on infarction progression. In vivo Gd-enhanced MRI (3 T Siemens scanner) and in vivo/ex vivo near-infrared imaging confirmed major Mn-enhanced MRI findings. Triphenyltetrazolium chloride staining revealed necrotic areas in all chronic infarctions and no necrosis after acute ischemia. We conclude that MnCl(2) highlights ischemic areas because of the low collateral flow characteristic of pig hearts, whereas in the infarcted areas with substantial perfusion, scar tissue components are important for contrast distribution.     

自体骨髓间充质干细胞移植梗死心肌猪的心功能变化

背景：干细胞移植可改善缺血性心肌血供并改善心功能。 目的：进一步验证自体骨髓间充质干细胞在心肌梗死后的应用及效果评价。 方法：15只健康太湖梅山猪通过冠脉栓塞建立心肌梗死模型。随机分为3组,每组5只,其中2组分别在心肌梗死后3 h,2周行自体骨髓干细胞移植,模型组不移植细胞。行心脏超声观察心脏功能各指标的改变;并在不同时间点检测血清血管内皮生长因子值;在实验终点取大体标本并通过免疫组织化学检测移植细胞在心肌内定植及分化情况,检测心肌血管密度。 结果与结论：心肌梗死3 h组与模型组比较,射血分数、左室舒张期内径、左室收缩期内径各项心功能指标及心肌血管密度、不同时间点血清血管内皮生长因子水平差异无显著性意义。心肌梗死后2周移植组与模型组相比,心功能指标均有改善,心肌血管密度大于模型组,血清血管内皮生长因子水平明显高于较移植前(P < 0.05)。提示不同时间点心肌微环境对于骨髓来源的间充质干细胞分化及定植的影响,心肌梗死后急性期内局部微环境不利于移植细胞的存活,在瘢痕修复早期行骨髓干细胞移植对骨髓干细胞的分化和定植以及对心功能的改善有较好的效果。     

Insertion /deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme and parental history of myocardial infarction

Bøhn M, Berge KE, Bakken A, Erikssen J, Berg K. Insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme and parental history of myocardial infarction.
Clin Genet 1993: 44: 298–301. © Munksgaard, 1993
One hundred and eighty-one male and 48 female myocardial infarction (MI) survivors and 172 male and 194 female controls were studied with respect to a possible association between premature parental MI (before age 61 years in mothers and/or before age 56 years in fathers) and an insertion/deletion (I/D) polymorphism in the gene encoding angiotensin I-converting enzyme (ACE). In the total series, the frequency of premature parental MI was 14% in the DD (homozygotes for the deletion (D) allele) genotypic group, 10.6% in the ID (heterozygotes) genotypic group and 6.1% in the II (homozygotes for the insertion (I) allele) genotypic group. In all males (male MI survivors and male controls combined), and in the total series, there was a significant excess of DD individuals as compared to II individuals among those with a parental history of premature MI (odds ratio 3.1 (p = 0.03) and 3.1 (p = 0.009), respectively). The ACE polymorphism may be an important genetic marker of MI risk and contribute to clustering of premature MI in families.     

冠心病患者血清hs-CRP和血浆脂联素检测的临床意义

目的：探讨了冠心病患者血清hs-CRP和血浆脂联素水平的变化及意义。方法：应用免疫比浊法和ELISA对68例冠心病患者进行测定，其中稳定型心绞痛31例，不稳定型心绞痛30例，急性心肌梗死7例，进行了血清hs-CRP和血浆脂联素水平测定，并与35名正常健康人作比较。结果：冠心病患者在治疗前血清hs-CRP水平非常显著地高于正常人组（P〈0．01），而血清脂联素水平则显著地低于正常人组（P〈0．01），急性心肌梗死组和不稳定型心绞痛组又高于稳定型心绞痛组（P〈0．01）。经治疗后一个月血清hs-CRP与正常人比较无显著性差异（P〉0．05）而脂联素水平与正常人比较仍有显著性差异（P〈0．05）。结论：检测冠心病患者血清hs-CRP和血浆脂联素水平对冠心病的发生、发展以及疗效和预后均有重要的临床价值。     

冠心病患者血清hs-CRP和E-Selectin检测的临床意义

目的:探讨了冠心病患者血清超敏C反应蛋白(hs-CRP)和E-选择素(E-Selectin)水平的变化及意义.方法:应用免疫比浊法检测hs-CRP,ELISA法检测E-Selectin水平对58例冠心病患者进行了血清hs-CRP,E-Selectin水平检测.其中稳定型心绞痛25例,不稳定型心绞痛20例,急性心肌梗死13例,并以35名正常健康人作比较.结果:冠心病患者血清hs-CRP和E-Selectin水平明显高于正常人组(P＜0.01),急性心肌梗死组和不稳定型心绞痛组有明显高于稳定型心绞痛组(P＜0.01),冠心病组血清hs-CRP、E-Selectin水平与冠状动脉狭窄程度无明显相关性(P＞0.05).结论:血清hs-CRP和E-Selectin水平的变化与冠心病的发生、发展有关,但与冠状动脉狭窄程度无关.