关于心肌梗死后心力衰竭患者血浆中miRNA表达及基于ECHO的心肌能量消耗的研究
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摘要
研究背景
心力衰竭是发达国家导致住院和死亡的主要病因,它是以左心室重塑、扩张为特点,同时伴随着胚胎基因的激活所导致的一系列病理学改变,是各种心脏疾病发展的终末阶段。随着我国人口老龄化、急性心肌梗死(AMI)诊疗方式的提高令生存率的增加和心衰患者寿命的延长,以致心衰患病率逐年增加。心衰的治疗策略虽然在近十余年里发生了根本性变化,从关注短期血流动力学改善转而针对心肌重构机制,防止和延缓重构的发展,取得了明显的成效,明显降低了心衰的死亡率和住院率,但由于心脏病及相并危险因素的不断增加,其5年病死率仍与恶性肿瘤相仿,因此,探索寻找新的治疗靶点,进一步减少患者病死率,成为心衰治疗的主要研究方向。
MicroRNA (miRNA)是近年来发现的小分子调节RNA,由约22个内源性非编码的核苷酸组成,可以和与之互补的信使RNA (mRNA)结合抑制其翻译或促进其降解,对mRNA的稳定及翻译效率起到重要的调控作用,从而实现对基因表达的负性调节效果。1993年Lee等在新小杆线虫和果蝇中发现了第一个miRNA并命名为lin-4；2000年Reomhart等在对线虫发育调控的研究中发现了let-7从而拉开了miRNA的研究序幕。MiRNA不仅参与调控机体的多种生理过程,如细胞的新陈代谢、增殖分化、生长凋亡等,而且在众多疾病的发生发展中起重要的调控作用。2006年Van Rooij E等首次观察到miRNA在心脏疾病的发生发展过程中有着重要调节作用,近年来miRNA在心血管疾病中的心肌肥厚与纤维化、心力衰竭、心律失常、心肌细胞凋亡和血管再生等研究领域均取得了一些重要进展,使得miRNA成为国际心血管研究领域的一个热点。
尤其值得注意的是,几乎所有关于人类心脏疾病miRNA功能的研究均来自心力衰竭患者。冠心病心力衰竭是由于泵功能的衰竭导致心脏不能够提供足够的器官血流灌注,经常是病理性心肌肥厚或扩张和致命性终末阶段。心肌细胞肥大是心肌细胞对于各种形式的血流压力超负荷、内分泌紊乱、心肌损伤及心肌结构或收缩蛋白遗传突变的主要反应；病理性心肌肥厚导致心功能受损是心力衰竭及心源性猝死的主要预测因子：所以研究其潜在的分子学机制及寻求新的治疗靶点十分重要。心肌肥厚表现为细胞内信号转导和转录调节激活所引起的心肌细胞的增大和间质蛋白合成的增加。2006年至今越来越多的研究关注miRNA与心肌肥厚-心力衰竭的关系。细胞培养实验通过过表达或敲除细胞中某些miRNA未影响心衰的发生发展,证实了多种miRNA参与心肌肥厚的病理过程。例如,发现MiR-21在心脏压力负荷增加时持续表达,体外细胞培养显示其调节心肌生长以及主要心肌细胞胚胎基因激活的作用；而心肌纤维化也是心脏对于损伤的反应,表现为miRNA对肌细胞外基质的调节。压力超负荷或心肌梗死后心脏成纤维细胞将会分泌更多的细胞外基质蛋白,从而导致心肌纤维化,心肌收缩力下降,心室壁顺应性减退、而出现心力衰竭；同时研究发现心肌梗死后组织miR-21升高并证实miR-21可以促进成纤维细胞分泌胶原纤维,相反心肌梗死后miR-29表达明显下调,因此抑制miR-21或上调miR-29的表达均会抑制心肌纤维化,改善心功能。这些研究显示了miRNA在调节心肌肥厚、纤维化和心力衰竭过程中起着重要作用,提示了miRNA表达谱的差异亦可以预测疾病和疾病所处的发展阶段,同时也提示miRNA很可能成为心脏疾病潜在的治疗靶点。显然,我们很难在人类心力衰竭的起始阶段取得患者的心肌组织进行研究,而已有的研究几乎都是小样本量的研究,在动物心肌组织进行取样分析并不能推广到临床用途,所以探求miRNA新的研究途径显得十分必要。
2008年Mitchell PS等的一项关于癌症标志物的研究中发现,血浆中miRNA能以稳定的形式存在,避免内源性RNA酶的降解,同年Shlomit G等同样观察到miRNA可以在血浆和其他体液中稳定存在,并且表达谱随不同病理生理状态而改变。正是由于这些非细胞性miRNA在循环中的稳定性,我们可以十分简便地获得外周静脉血并提取血浆来代替心肌组织研究心力衰竭时特异性表达的miRNA。由于外周静脉血的获取十分简便而且病人的接受性较好,使得miRNA在心力衰竭乃至整个心血管疾病的研究可以获得足够的样本量,突破样本量不足导致的假阳性,而且更符合真是世界的情况。
众所周知,心肌梗死不仅导致心肌细胞坏死、凋亡,还累及血管床和心肌外胶原组织,复杂的病理生理、病理解剖而导致心室重构,引起心功能不全：目前与缺血性心肌损伤、心肌保护及修复相关的miRNA表达及功能的研究主要集中在心肌梗死后不同阶段心力衰竭的动物模型上,而较少关于心力衰竭患者中miRNA表达的相关研究。针对上述情况,本研究将入选心肌梗死引起的不同类型心力衰竭患者,包括急性心肌梗死引起的急性心力衰竭患者,陈旧性心肌梗死伴发的慢性心力衰竭患者,以及冠状动脉造影显示冠脉正常的正常者,分别抽取其外周静脉血,通过miRNA array分析各组间miRNA表达谱的差异,筛选出差异显著的几种miRNA,进而筛选不同类型急性心力衰竭可能的特异性血清miRNA,探索新的心力衰竭标志物,并筛选出一些新的心力衰竭miRNA调控通路,为心力衰竭寻找到新的治疗靶点。
心肌梗死作为冠心病的一种,近年来发病率呈逐年上升趋势,随着急性心肌梗死治疗手段的进步,尤其是再灌注治疗方法的应用使其早期死亡率不断降低,但转而变成了越来越多急性心肌梗死患者发展为不同程度的心力衰竭。众所周知,血管紧张素转换酶抑制剂(ACEI)能阻断肾素-血管紧张素-醛固酮系统(RAAS),从而抑制心肌重构,有效地提高心力衰竭患者的生存率、改善症状、降低再住院率。心肌梗死后心力衰竭患者血压往往不高或偏低,培哚普利因其降压作用相对较温和,是临床上应用较为广泛的一种ACEI类药物,多项大规模临床试验均证实其在抑制心肌重构、降低远期死亡率方面作用显著。多数研究均从阻断RAAS系统、抑制心肌重构方面研究培哚普利对于心肌梗死后心力衰竭患者预后的影响,但目前尚无从心肌能量消耗方面研究其对心力衰竭患者的影响。2003年Vittorio Palmieri等提出心肌能量消耗全新的的超声指标MEE(myocardial energy expenditure).因其无创、临床易操作、易广泛推广、价格相对低廉,多普勒超声心动图方法评估心肌能量消耗近来得到了深入的研究。本研究将从基于ECHO的心肌能量消耗指标出发,观察不同时期心肌梗死患者及不同剂量培哚普利治疗12个月对心肌梗死后心力衰竭患者超声心动图各指标的变化,并探讨其临床意义。同时,由于心肌梗死后出现了心肌收缩力下降,心室顺应性降低,而陈旧性心肌梗死所致心室重塑等因素,心肌能量消耗水平存在差异,通过无并发心衰的急性心梗,陈旧性心梗与冠脉正常患者的超声心电图各指标及MEE的水平探讨心梗患者的心肌能量消耗情况,为针对缺血心肌能量代谢治疗提供依据。
第一部分心肌梗死后心力衰竭患者血浆中miRNA表达差异
目的采用血浆miRNA array方法分析心肌梗死不同阶段心力衰竭组患者与正常对照组间miRNA表达谱的差异,筛选出与心衰有关的外周血miRNA谱为探索新的心力衰竭标志物及进一步寻找心力衰竭的治疗靶点提供基础。
方法选择急性心肌梗死患者25例,其中合并心力衰竭患者15例做为AMHF组,心功能正常患者10例做为AMNHF组,陈旧性心肌梗死后心力衰竭患者10例做为OMHF组,行冠脉造影检查结果正常的心功能正常者10例做为NHF组。采集其外周静脉血并离心得到血浆,对分同组别的血浆miRNA Array检测。
结果AMHF组与AMNHF组比较,miRNA上调大于1.5倍的有19种,下调大于1.5倍的有25种。AMHF组与OMHF组比较,miRNA上调大于1.5倍的有13种,下调大于1.5倍的有43种。AMNHF组与NHF组比较,miRNA上调大于1.5倍的有38种,下调大于1.5倍的有48种。
结论基于外周静脉血血浆的miRNA array分析方法可以筛选出心肌梗死引起的心力衰竭患者及正常对照组间的miRNA表达谱的差异,筛选出与心衰有关的外周血miRNA为探索新的心力衰竭标志物及进一步寻找心力衰竭的治疗靶点提供基础。
第二部分心肌梗死后心力衰竭患者经不同剂量培哚普利治疗后其心肌能量消耗水平的变化及其意义
目的探讨心肌梗死后并心力衰竭患者给予不同剂量培哚普利治疗12个月后经无创超声心动图评估的心脏结构指标及心肌能量消耗(MEE)水平变化及其意义。方法选取心肌梗死后不同程度心力衰竭患者63例,分别给予培哚普利治疗,根据长期口服剂量水平分为常规剂量组(N,培哚普利4mg)和靶剂量组(H,培哚普利8mg)。治疗前及治疗12个月后分别用多普勒成像技术测量心脏结构指标、左室收缩功能指标(左室短轴缩短率LVFS,左室射血分数LVEF),计算左室收缩末周向室壁应力(cESS)、MEE。入组前及治疗后分别于清晨采集外周静脉血,检测NT-proBNP及血肌酐。
结果治疗前两组间基线资料各指标比较差异均无统计学意义(P>0.05)。治疗后两组间比较,H组心脏结构指标(左室收缩末期内径LVIDs、左室质量指数LVMI)、心肌能量消耗指标(cESS、MEE)及IgNT-proBNP小于N组,收缩功能指标(LVFS、LVEF)高于N组,差异具有统计学意义(P<0.05)。与治疗前比较,H组治疗后心脏结构指标、心肌能量消耗指标及IgNT-proBNP均明显降低,收缩功能指标明显升高；N组除PWTs、LVFS外其他各指标间变化均有统计学意义(P<0.05)。双变量相关分析显示,MEE与IgNT-proBNP呈正相关关系(P<0.01)。
结论心肌梗死后心力衰竭患者经过12个月不同剂量培哚普利治疗,均抑制了心肌重构,改善了左室收缩功能,降低了NT-proBNP及心肌能量消耗水平；高剂量培哚普利治疗较低剂量能更明显地抑制心肌重构,改善左室收缩功能,降低NT-proBNP及心肌能量消耗水平。
第三部分心肌梗死不同时期患者心肌能量消耗变化及意义
目的探讨多普勒超声指标心肌能量消耗(MEE)在心肌梗死不同时期患者中的变化及临床意义。
方法选取经冠状动脉造影确诊为心肌梗死且无心力衰竭患者51例,其中急性心肌梗死(AMI)组28例,陈旧性心肌梗死(OMI)组23例；选取同时期行冠状动脉造影正常的患者30例作为正常对照(NOR)组。所有入选患者均用多普勒超声技术测量心脏结构指标、左心室收缩功能指标LVEF等,应用公式计算左心室收缩末周向室壁应力(cESS)及MEE；检测血浆N端前体脑钠肽(NT-proBNP);探讨MEE与左室收缩功能及NT-proBNP相关性。
结果AMl组1gNT-proBNP. MEE大于OMI组(P<0.05)；与NOR组比较,AMI组和OMI组中cESS.MEE及1gNT-proBNP指标水平均明显升高(P<0.05)。相关性分析示：MEE与LgNT-proBNP间呈正相关关系,与LVFS、LVEF呈负相关关系。
结论心肌梗死组患者MEE均高于正常对照组；急性心肌梗死组患者MEE高于陈旧性心肌梗死组患者；MEE与左室收缩功能指标呈明显负相关关系。MEE能有效地评估不同时期心肌梗患者的心功能状态。
Background
Heart failure is one of major causes of hospitalization and death in developed countries, characterized by left ventricular remodeling and expansion, accompanied by series of pathological changes caused by the activation of embryonic genes. It is the end stage of the development of various heart diseases. Despite of the increased survival rate of patients with acute myocardial infarction (AMI) and life extension of patients with heart failure, the prevalence of heart failure is increasing every year because of the aging of our population. Despite of fundamental changes in treatment strategies for heart failure, turning from short-term hemodynamic improvement to preventing and delaying the development of reconstruction, thereby heart failure mortality and hospitalization rates reduced, the5-year mortality of heart failure was still similar with malignant tumors. Therefore it is one of main research directions in heart failure treatment to find out new therapeutic targets for further reduction of the mortality.
MicroRNAs (miRNAs) are recently discovered small molecule modulators, consisting of about22non-coding nucleotides. They could negatively regulate gene expression by inhibiting translation or promoting degradation of their complementary messenger RNA (mRNA). In1993, Lee et al found in a new Caenorhabditis and Drosophila the first miRNA and named it lin-4. In2000, Reomhart et al discovered let-7in the study of regulation of nematodes growth and thus began the miRNA research prelude. MiRNAs are not only involved in regulating various of physiological processes, such as cell metabolism, proliferation and differentiation, growth and apoptosis, they also play important regulatory role in the development of many diseases. In2006, the Van Rooij E observed miRNAs had an important role during the development of heart disease. miRNA has become a hot topic of the international field in cardiovascular research in recent years because of some important progress in cardiac hypertrophy and fibrosis, heart failure, arrhythmias, cardiac myocyte apoptosis and vascular regeneration.
Almost all studies of miRNA function in human heart disease were in patients with heart failure. Heart failure, a common and fatal end stage of pathological cardiac hypertrophy, is due to the the failure of pump function, which makes the heart not be able to provide adequate organ perfusion. Myocardial cell hypertrophy is the main reaction of myocardial cells to various forms of blood pressure overload, endocrine disorders, myocardial injury and genetic mutations of cardiac structure or contractile proteins. Pathological cardiac hypertrophy leading to impaired cardiac function is a major predictor of heart failure and sudden cardiac death. Therefore, it is important to find out the potential molecular mechanisms and seek new therapeutic targets. Cardiac hypertrophy has the performance of myocardial cells hypertrophy and stromal protein synthesis increasement caused by the activation of intracellular signal transduction and transcriptional regulation. Since2006, ther have been more and more study in therelationship between miRNA and cardiac hypertrophy or heart failure. The cell culture experiments by miRNA over-expression or knockout have confirmed the involvement of miRNA in the pathological process of myocardial hypertrophy. MiR-21expresses persistently with cardiac pressure overload, and has been proved to regulate cardiac growth and activate mainly embryonic gene of myocardial cells in vitro. Myocardial fibrosis is also one response of the heart to injury, with the performance of regulation of extracellular matrix by miRNAs. Fibroblasts with pressure overload or myocardial infarction will secrete more extracellular matrix proteins, leading to myocardial fibrosis, decreased ventricular wall compliance or heart failure. It has been found that miR-21could promote collagen fibers secretion by fibroblasts after myocardial infarction, and miR-29expression was significantly lowered, so the inhibition of miR-21or up-regulation of miR-29can both inhibit myocardial fibrosis. These studies showed that miRNAs play important roles in regulating cardiac hypertrophy, fibrosis and heart failure, and the differences in miRNA expression profiles can predict diseases and stage of diseases development. They also indicate that the miRNA is likely to be potential therapeutic target of heart disease. Obviously, it is difficult to study in the initial stage of human heart failure with cardiac tissue from patients, only some small sample size studys were reported, so it is very necessary to explore new research path of miRNA.
In2008, Mitchell PS found in a study on cancer markers that miRNA could exist in plasma with stable forms to avoid degradation by endogenous RNA enzyme. In the same year, Shlomit G also observed that miRNA could exist in plasma and other body fluids stably, and their expression will change in different pathophysiological states. It is just because of the stability of these non-cell miRNA in circulation, we can easily obtain peripheral blood samples and extract plasma instead of the myocardial tissue to study miRNAs expressing specificly in heart failure. Peripheral venous blood is very easy to get, so we can sufficient sample size in the study of miRNAs in heart failure and oher cardiovascular diseases, avoiding false-positive induced by insufficient sample size.
Our study will include patients in different stages of heart failure caused by myocardial infarction, including patients with acute heart failure caused by acute myocardial infarction, patients with chronic heart failure caused by old myocardial infarction, and narmal patients with normal coronary arteries confirmed by coronary angiography. External peripheral venous blood were obtained. The differences of miRNA expression profiles between groups were analysed by miRNA array, several miRNA with most obvious changes were found out, and then the specific serum miRNA for heart failure may be determined. It will be helpful for exploring new heart failure markers, miRNA regulatory pathways and new therapeutic targets for heart failure.
Myocardial infarction, as a kind of coronary heart disease, showed an increasing trend in the incidence rate recent years. With the advances in the treatment of acute myocardial infarction, the patients' mortality rates were continously lowering, more and more patients with acute myocardial infarction change into heart failure in different degrees. Angiotensin-converting enzyme inhibitors (ACEI) can block the renin-angiotensin-aldosterone system (RAAS) with inhibition of myocardial remodeling, improvement in survival rate and symptoms, and reduction in rehospitalization rates. Perindopril is widely used as a clinical ACEI drugs for its relatively mild antihypertensive effect, because the blood pressure of patients with heart failure after myocardial infarction are often not high or even low. A number of large clinical trials have confirmed its significant role in inhibition of myocardial remodeling and reduction in long-term mortality. Most related studies in perindopril for the prognosis of patients with heart failure after myocardial infarction were about blocking the RAAS system, inhibiting myocardial remodeling. There is still no related study in myocardial energy consumption aspects. In2003, Vittorio Palmieri suggested a totally new ultrasound index MEE (myocardial energy expenditure) for myocardial energy consumption evaluation. Because it's non-invasive, easy to operate, easy to be widely spreaded, and relatively inexpensive, Doppler echocardiographic assessment of myocardial energy consumption has recently been in-depth studied. Our study will be based on ECHO myocardial energy consumption indicators, the changes of any echocardiography indicators were observed for patients with myocardial infarction or patients with different doses of perindopril treatment for12months after myocardial infarction, and their clinical significance will be studied.
Part one A subset circulating microRNAs are differently expressed in patients with myocardial infarction
Objective Analyzing the miRNA expression profile differences between patients with myocardial infarction (with or without heart failure) and normal control group using plasma of miRNA array. Specific miRNAs would be choosing to explore the new circulating markers for myocardial infarction and heart failure.
Method15patients with heart failure and10patients without heart failure after acute myocardial infarction were recruited as AMHF and AMNHF group. We selected10patients with heart failure after old myocardial infarction as OMHF group.10patients with normal coronary angiography results were recruited as NHF group. The plasma of peripheral venous blood had been get for miRNA the Array detection.
Result There was19miRNAs upregulated and25miRNAs downregulated more than1.5times between AMHF group and AMNHF group. Compared to NHF group, the AMNHF group had38miRNAs upregulated48miRNAs downregulated more than1.5times. There was13miRNAs upregulated and43miRNAs downregulated more than1.5times between AMHF group and OMHF group.
Conclusion There was significant differences in miRNA expression profiles between the patients with different stages of heart failure after myocardial infarction and normal control group using miRNA array analysis method which was based on peripheral blood plasma. Specific miRNAs would be choosing to explore the new circulating markers for myocardial infarction and heart failure.
Part two The significance of changes of myocardial energy expenditure in patients with heart failure after myocardial infarction using different dose of Perindopril
Objective To investigate the significance and difference of myocardial energy expenditure in patients with heart failure after myocardial infarction using different dose of Perindopril.
Method63patients with heart failure after myocardial infarction were recruited and treated with different dose of Perindopril in next12months. We divided them into two groups:N group(4mg Perindopril) and H group(8mg Perindopril). The Doppler imaging was used to measure the structural and systolic functional parameters. Then, the circumferential end-systolic wall stress (cESS) and myocardial energy expenditure (MEE) were calculated by the corresponding formulas. Biochemical indicator including serum creatinine and plasma NT-proBNP were detected on the next morning before and after treatment.
Results There was no significant difference between the two groups before treatment. After12months treatment with Perindopril, H group had lower LA, LV, RA, RV, LVIDs, AD, cESS,1gNT-proBNP, MEE and higher LVFS, LVEF than N group. Compared to before treatment, after12months of treatment H group had higher LVFS and LVEF, and lower LA, LV, RA, RV, AD, LVIDs, LVMI,1gNT-proBNP and MEEm. There was significant difference between the before and after treatment of N group except for PWTs、LVET、LVSV and LVFS. Bivariate analysis confirmed that MEE was significant correlated with1gNT-proBNP(r=0.513, P<0.01).
Conclusion After12months of treatment with Perindopril, the patients with heart failure after myocardial infarction had less myocardial remodeling, better left ventricular systolic function and lower level of NT-proBNP and myocardial energy expenditure. Target dose of perindopril treatment had better results than the conventional dose.
Part three The significance of changes of myocardial energy expenditure in patients at different periods after myocardial infarction
Objective To investigate the significance and difference of myocardial energy expenditure in patients after acute and old myocardial infarction.
Method51patients without heart failure after acute and old myocardial infarction were recruited. At the same time, we recruited30patients with normal coronary angiography results as control group. All of them were divided into three groups: AMI group(n=28), OMI group (n=23) and NOR group(n=30). The Doppler imaging was used to measure the structural and systolic functional parameters. Then, the circumferential end-systolic wall stress (cESS) and myocardial energy expenditure (MEE) were calculated by the corresponding formulas. Plasma NT-proBNP were detected on the next morning after admission.
Results The LgNT-proBNP and MEE were significantly higher in AMI group than that in OMI group (P<0.05). Compared to NOR group, cESS, MEE, and LgNT-proBNP were significantly higher in AMI and OMI group respectively (P<0.05).Bivariate analysis confirmed that MEE was significantly positively correlated with LgNT-proBNP, but negtively correlated with LVFS and LVEF.
Conclusion The myocardial energy expenditure level in patients with myocardial infarction is higher than those with normal coronary angiography. Compared to patients with acute myocardial infarction, those with old myocardial infarction had higher myocardial energy expenditure. MEE is an effective indicator for evaluating the cardiac function of patients at different periods after myocardial infarction, and significantly correlated with left ventricular systolic function parameters.
心力衰竭是发达国家导致住院和死亡的主要病因,它是以左心室重塑、扩张为特点,同时伴随着胚胎基因的激活所导致的一系列病理学改变,是各种心脏疾病发展的终末阶段。随着我国人口老龄化、急性心肌梗死(AMI)诊疗方式的提高令生存率的增加和心衰患者寿命的延长,以致心衰患病率逐年增加。心衰的治疗策略虽然在近十余年里发生了根本性变化,从关注短期血流动力学改善转而针对心肌重构机制,防止和延缓重构的发展,取得了明显的成效,明显降低了心衰的死亡率和住院率,但由于心脏病及相并危险因素的不断增加,其5年病死率仍与恶性肿瘤相仿,因此,探索寻找新的治疗靶点,进一步减少患者病死率,成为心衰治疗的主要研究方向。
MicroRNA (miRNA)是近年来发现的小分子调节RNA,由约22个内源性非编码的核苷酸组成,可以和与之互补的信使RNA (mRNA)结合抑制其翻译或促进其降解,对mRNA的稳定及翻译效率起到重要的调控作用,从而实现对基因表达的负性调节效果。1993年Lee等在新小杆线虫和果蝇中发现了第一个miRNA并命名为lin-4；2000年Reomhart等在对线虫发育调控的研究中发现了let-7从而拉开了miRNA的研究序幕。MiRNA不仅参与调控机体的多种生理过程,如细胞的新陈代谢、增殖分化、生长凋亡等,而且在众多疾病的发生发展中起重要的调控作用。2006年Van Rooij E等首次观察到miRNA在心脏疾病的发生发展过程中有着重要调节作用,近年来miRNA在心血管疾病中的心肌肥厚与纤维化、心力衰竭、心律失常、心肌细胞凋亡和血管再生等研究领域均取得了一些重要进展,使得miRNA成为国际心血管研究领域的一个热点。
尤其值得注意的是,几乎所有关于人类心脏疾病miRNA功能的研究均来自心力衰竭患者。冠心病心力衰竭是由于泵功能的衰竭导致心脏不能够提供足够的器官血流灌注,经常是病理性心肌肥厚或扩张和致命性终末阶段。心肌细胞肥大是心肌细胞对于各种形式的血流压力超负荷、内分泌紊乱、心肌损伤及心肌结构或收缩蛋白遗传突变的主要反应；病理性心肌肥厚导致心功能受损是心力衰竭及心源性猝死的主要预测因子：所以研究其潜在的分子学机制及寻求新的治疗靶点十分重要。心肌肥厚表现为细胞内信号转导和转录调节激活所引起的心肌细胞的增大和间质蛋白合成的增加。2006年至今越来越多的研究关注miRNA与心肌肥厚-心力衰竭的关系。细胞培养实验通过过表达或敲除细胞中某些miRNA未影响心衰的发生发展,证实了多种miRNA参与心肌肥厚的病理过程。例如,发现MiR-21在心脏压力负荷增加时持续表达,体外细胞培养显示其调节心肌生长以及主要心肌细胞胚胎基因激活的作用；而心肌纤维化也是心脏对于损伤的反应,表现为miRNA对肌细胞外基质的调节。压力超负荷或心肌梗死后心脏成纤维细胞将会分泌更多的细胞外基质蛋白,从而导致心肌纤维化,心肌收缩力下降,心室壁顺应性减退、而出现心力衰竭；同时研究发现心肌梗死后组织miR-21升高并证实miR-21可以促进成纤维细胞分泌胶原纤维,相反心肌梗死后miR-29表达明显下调,因此抑制miR-21或上调miR-29的表达均会抑制心肌纤维化,改善心功能。这些研究显示了miRNA在调节心肌肥厚、纤维化和心力衰竭过程中起着重要作用,提示了miRNA表达谱的差异亦可以预测疾病和疾病所处的发展阶段,同时也提示miRNA很可能成为心脏疾病潜在的治疗靶点。显然,我们很难在人类心力衰竭的起始阶段取得患者的心肌组织进行研究,而已有的研究几乎都是小样本量的研究,在动物心肌组织进行取样分析并不能推广到临床用途,所以探求miRNA新的研究途径显得十分必要。
2008年Mitchell PS等的一项关于癌症标志物的研究中发现,血浆中miRNA能以稳定的形式存在,避免内源性RNA酶的降解,同年Shlomit G等同样观察到miRNA可以在血浆和其他体液中稳定存在,并且表达谱随不同病理生理状态而改变。正是由于这些非细胞性miRNA在循环中的稳定性,我们可以十分简便地获得外周静脉血并提取血浆来代替心肌组织研究心力衰竭时特异性表达的miRNA。由于外周静脉血的获取十分简便而且病人的接受性较好,使得miRNA在心力衰竭乃至整个心血管疾病的研究可以获得足够的样本量,突破样本量不足导致的假阳性,而且更符合真是世界的情况。
众所周知,心肌梗死不仅导致心肌细胞坏死、凋亡,还累及血管床和心肌外胶原组织,复杂的病理生理、病理解剖而导致心室重构,引起心功能不全：目前与缺血性心肌损伤、心肌保护及修复相关的miRNA表达及功能的研究主要集中在心肌梗死后不同阶段心力衰竭的动物模型上,而较少关于心力衰竭患者中miRNA表达的相关研究。针对上述情况,本研究将入选心肌梗死引起的不同类型心力衰竭患者,包括急性心肌梗死引起的急性心力衰竭患者,陈旧性心肌梗死伴发的慢性心力衰竭患者,以及冠状动脉造影显示冠脉正常的正常者,分别抽取其外周静脉血,通过miRNA array分析各组间miRNA表达谱的差异,筛选出差异显著的几种miRNA,进而筛选不同类型急性心力衰竭可能的特异性血清miRNA,探索新的心力衰竭标志物,并筛选出一些新的心力衰竭miRNA调控通路,为心力衰竭寻找到新的治疗靶点。
心肌梗死作为冠心病的一种,近年来发病率呈逐年上升趋势,随着急性心肌梗死治疗手段的进步,尤其是再灌注治疗方法的应用使其早期死亡率不断降低,但转而变成了越来越多急性心肌梗死患者发展为不同程度的心力衰竭。众所周知,血管紧张素转换酶抑制剂(ACEI)能阻断肾素-血管紧张素-醛固酮系统(RAAS),从而抑制心肌重构,有效地提高心力衰竭患者的生存率、改善症状、降低再住院率。心肌梗死后心力衰竭患者血压往往不高或偏低,培哚普利因其降压作用相对较温和,是临床上应用较为广泛的一种ACEI类药物,多项大规模临床试验均证实其在抑制心肌重构、降低远期死亡率方面作用显著。多数研究均从阻断RAAS系统、抑制心肌重构方面研究培哚普利对于心肌梗死后心力衰竭患者预后的影响,但目前尚无从心肌能量消耗方面研究其对心力衰竭患者的影响。2003年Vittorio Palmieri等提出心肌能量消耗全新的的超声指标MEE(myocardial energy expenditure).因其无创、临床易操作、易广泛推广、价格相对低廉,多普勒超声心动图方法评估心肌能量消耗近来得到了深入的研究。本研究将从基于ECHO的心肌能量消耗指标出发,观察不同时期心肌梗死患者及不同剂量培哚普利治疗12个月对心肌梗死后心力衰竭患者超声心动图各指标的变化,并探讨其临床意义。同时,由于心肌梗死后出现了心肌收缩力下降,心室顺应性降低,而陈旧性心肌梗死所致心室重塑等因素,心肌能量消耗水平存在差异,通过无并发心衰的急性心梗,陈旧性心梗与冠脉正常患者的超声心电图各指标及MEE的水平探讨心梗患者的心肌能量消耗情况,为针对缺血心肌能量代谢治疗提供依据。
第一部分心肌梗死后心力衰竭患者血浆中miRNA表达差异
目的采用血浆miRNA array方法分析心肌梗死不同阶段心力衰竭组患者与正常对照组间miRNA表达谱的差异,筛选出与心衰有关的外周血miRNA谱为探索新的心力衰竭标志物及进一步寻找心力衰竭的治疗靶点提供基础。
方法选择急性心肌梗死患者25例,其中合并心力衰竭患者15例做为AMHF组,心功能正常患者10例做为AMNHF组,陈旧性心肌梗死后心力衰竭患者10例做为OMHF组,行冠脉造影检查结果正常的心功能正常者10例做为NHF组。采集其外周静脉血并离心得到血浆,对分同组别的血浆miRNA Array检测。
结果AMHF组与AMNHF组比较,miRNA上调大于1.5倍的有19种,下调大于1.5倍的有25种。AMHF组与OMHF组比较,miRNA上调大于1.5倍的有13种,下调大于1.5倍的有43种。AMNHF组与NHF组比较,miRNA上调大于1.5倍的有38种,下调大于1.5倍的有48种。
结论基于外周静脉血血浆的miRNA array分析方法可以筛选出心肌梗死引起的心力衰竭患者及正常对照组间的miRNA表达谱的差异,筛选出与心衰有关的外周血miRNA为探索新的心力衰竭标志物及进一步寻找心力衰竭的治疗靶点提供基础。
第二部分心肌梗死后心力衰竭患者经不同剂量培哚普利治疗后其心肌能量消耗水平的变化及其意义
目的探讨心肌梗死后并心力衰竭患者给予不同剂量培哚普利治疗12个月后经无创超声心动图评估的心脏结构指标及心肌能量消耗(MEE)水平变化及其意义。方法选取心肌梗死后不同程度心力衰竭患者63例,分别给予培哚普利治疗,根据长期口服剂量水平分为常规剂量组(N,培哚普利4mg)和靶剂量组(H,培哚普利8mg)。治疗前及治疗12个月后分别用多普勒成像技术测量心脏结构指标、左室收缩功能指标(左室短轴缩短率LVFS,左室射血分数LVEF),计算左室收缩末周向室壁应力(cESS)、MEE。入组前及治疗后分别于清晨采集外周静脉血,检测NT-proBNP及血肌酐。
结果治疗前两组间基线资料各指标比较差异均无统计学意义(P>0.05)。治疗后两组间比较,H组心脏结构指标(左室收缩末期内径LVIDs、左室质量指数LVMI)、心肌能量消耗指标(cESS、MEE)及IgNT-proBNP小于N组,收缩功能指标(LVFS、LVEF)高于N组,差异具有统计学意义(P<0.05)。与治疗前比较,H组治疗后心脏结构指标、心肌能量消耗指标及IgNT-proBNP均明显降低,收缩功能指标明显升高；N组除PWTs、LVFS外其他各指标间变化均有统计学意义(P<0.05)。双变量相关分析显示,MEE与IgNT-proBNP呈正相关关系(P<0.01)。
结论心肌梗死后心力衰竭患者经过12个月不同剂量培哚普利治疗,均抑制了心肌重构,改善了左室收缩功能,降低了NT-proBNP及心肌能量消耗水平；高剂量培哚普利治疗较低剂量能更明显地抑制心肌重构,改善左室收缩功能,降低NT-proBNP及心肌能量消耗水平。
第三部分心肌梗死不同时期患者心肌能量消耗变化及意义
目的探讨多普勒超声指标心肌能量消耗(MEE)在心肌梗死不同时期患者中的变化及临床意义。
方法选取经冠状动脉造影确诊为心肌梗死且无心力衰竭患者51例,其中急性心肌梗死(AMI)组28例,陈旧性心肌梗死(OMI)组23例；选取同时期行冠状动脉造影正常的患者30例作为正常对照(NOR)组。所有入选患者均用多普勒超声技术测量心脏结构指标、左心室收缩功能指标LVEF等,应用公式计算左心室收缩末周向室壁应力(cESS)及MEE；检测血浆N端前体脑钠肽(NT-proBNP);探讨MEE与左室收缩功能及NT-proBNP相关性。
结果AMl组1gNT-proBNP. MEE大于OMI组(P<0.05)；与NOR组比较,AMI组和OMI组中cESS.MEE及1gNT-proBNP指标水平均明显升高(P<0.05)。相关性分析示：MEE与LgNT-proBNP间呈正相关关系,与LVFS、LVEF呈负相关关系。
结论心肌梗死组患者MEE均高于正常对照组；急性心肌梗死组患者MEE高于陈旧性心肌梗死组患者；MEE与左室收缩功能指标呈明显负相关关系。MEE能有效地评估不同时期心肌梗患者的心功能状态。
Background
Heart failure is one of major causes of hospitalization and death in developed countries, characterized by left ventricular remodeling and expansion, accompanied by series of pathological changes caused by the activation of embryonic genes. It is the end stage of the development of various heart diseases. Despite of the increased survival rate of patients with acute myocardial infarction (AMI) and life extension of patients with heart failure, the prevalence of heart failure is increasing every year because of the aging of our population. Despite of fundamental changes in treatment strategies for heart failure, turning from short-term hemodynamic improvement to preventing and delaying the development of reconstruction, thereby heart failure mortality and hospitalization rates reduced, the5-year mortality of heart failure was still similar with malignant tumors. Therefore it is one of main research directions in heart failure treatment to find out new therapeutic targets for further reduction of the mortality.
MicroRNAs (miRNAs) are recently discovered small molecule modulators, consisting of about22non-coding nucleotides. They could negatively regulate gene expression by inhibiting translation or promoting degradation of their complementary messenger RNA (mRNA). In1993, Lee et al found in a new Caenorhabditis and Drosophila the first miRNA and named it lin-4. In2000, Reomhart et al discovered let-7in the study of regulation of nematodes growth and thus began the miRNA research prelude. MiRNAs are not only involved in regulating various of physiological processes, such as cell metabolism, proliferation and differentiation, growth and apoptosis, they also play important regulatory role in the development of many diseases. In2006, the Van Rooij E observed miRNAs had an important role during the development of heart disease. miRNA has become a hot topic of the international field in cardiovascular research in recent years because of some important progress in cardiac hypertrophy and fibrosis, heart failure, arrhythmias, cardiac myocyte apoptosis and vascular regeneration.
Almost all studies of miRNA function in human heart disease were in patients with heart failure. Heart failure, a common and fatal end stage of pathological cardiac hypertrophy, is due to the the failure of pump function, which makes the heart not be able to provide adequate organ perfusion. Myocardial cell hypertrophy is the main reaction of myocardial cells to various forms of blood pressure overload, endocrine disorders, myocardial injury and genetic mutations of cardiac structure or contractile proteins. Pathological cardiac hypertrophy leading to impaired cardiac function is a major predictor of heart failure and sudden cardiac death. Therefore, it is important to find out the potential molecular mechanisms and seek new therapeutic targets. Cardiac hypertrophy has the performance of myocardial cells hypertrophy and stromal protein synthesis increasement caused by the activation of intracellular signal transduction and transcriptional regulation. Since2006, ther have been more and more study in therelationship between miRNA and cardiac hypertrophy or heart failure. The cell culture experiments by miRNA over-expression or knockout have confirmed the involvement of miRNA in the pathological process of myocardial hypertrophy. MiR-21expresses persistently with cardiac pressure overload, and has been proved to regulate cardiac growth and activate mainly embryonic gene of myocardial cells in vitro. Myocardial fibrosis is also one response of the heart to injury, with the performance of regulation of extracellular matrix by miRNAs. Fibroblasts with pressure overload or myocardial infarction will secrete more extracellular matrix proteins, leading to myocardial fibrosis, decreased ventricular wall compliance or heart failure. It has been found that miR-21could promote collagen fibers secretion by fibroblasts after myocardial infarction, and miR-29expression was significantly lowered, so the inhibition of miR-21or up-regulation of miR-29can both inhibit myocardial fibrosis. These studies showed that miRNAs play important roles in regulating cardiac hypertrophy, fibrosis and heart failure, and the differences in miRNA expression profiles can predict diseases and stage of diseases development. They also indicate that the miRNA is likely to be potential therapeutic target of heart disease. Obviously, it is difficult to study in the initial stage of human heart failure with cardiac tissue from patients, only some small sample size studys were reported, so it is very necessary to explore new research path of miRNA.
In2008, Mitchell PS found in a study on cancer markers that miRNA could exist in plasma with stable forms to avoid degradation by endogenous RNA enzyme. In the same year, Shlomit G also observed that miRNA could exist in plasma and other body fluids stably, and their expression will change in different pathophysiological states. It is just because of the stability of these non-cell miRNA in circulation, we can easily obtain peripheral blood samples and extract plasma instead of the myocardial tissue to study miRNAs expressing specificly in heart failure. Peripheral venous blood is very easy to get, so we can sufficient sample size in the study of miRNAs in heart failure and oher cardiovascular diseases, avoiding false-positive induced by insufficient sample size.
Our study will include patients in different stages of heart failure caused by myocardial infarction, including patients with acute heart failure caused by acute myocardial infarction, patients with chronic heart failure caused by old myocardial infarction, and narmal patients with normal coronary arteries confirmed by coronary angiography. External peripheral venous blood were obtained. The differences of miRNA expression profiles between groups were analysed by miRNA array, several miRNA with most obvious changes were found out, and then the specific serum miRNA for heart failure may be determined. It will be helpful for exploring new heart failure markers, miRNA regulatory pathways and new therapeutic targets for heart failure.
Myocardial infarction, as a kind of coronary heart disease, showed an increasing trend in the incidence rate recent years. With the advances in the treatment of acute myocardial infarction, the patients' mortality rates were continously lowering, more and more patients with acute myocardial infarction change into heart failure in different degrees. Angiotensin-converting enzyme inhibitors (ACEI) can block the renin-angiotensin-aldosterone system (RAAS) with inhibition of myocardial remodeling, improvement in survival rate and symptoms, and reduction in rehospitalization rates. Perindopril is widely used as a clinical ACEI drugs for its relatively mild antihypertensive effect, because the blood pressure of patients with heart failure after myocardial infarction are often not high or even low. A number of large clinical trials have confirmed its significant role in inhibition of myocardial remodeling and reduction in long-term mortality. Most related studies in perindopril for the prognosis of patients with heart failure after myocardial infarction were about blocking the RAAS system, inhibiting myocardial remodeling. There is still no related study in myocardial energy consumption aspects. In2003, Vittorio Palmieri suggested a totally new ultrasound index MEE (myocardial energy expenditure) for myocardial energy consumption evaluation. Because it's non-invasive, easy to operate, easy to be widely spreaded, and relatively inexpensive, Doppler echocardiographic assessment of myocardial energy consumption has recently been in-depth studied. Our study will be based on ECHO myocardial energy consumption indicators, the changes of any echocardiography indicators were observed for patients with myocardial infarction or patients with different doses of perindopril treatment for12months after myocardial infarction, and their clinical significance will be studied.
Part one A subset circulating microRNAs are differently expressed in patients with myocardial infarction
Objective Analyzing the miRNA expression profile differences between patients with myocardial infarction (with or without heart failure) and normal control group using plasma of miRNA array. Specific miRNAs would be choosing to explore the new circulating markers for myocardial infarction and heart failure.
Method15patients with heart failure and10patients without heart failure after acute myocardial infarction were recruited as AMHF and AMNHF group. We selected10patients with heart failure after old myocardial infarction as OMHF group.10patients with normal coronary angiography results were recruited as NHF group. The plasma of peripheral venous blood had been get for miRNA the Array detection.
Result There was19miRNAs upregulated and25miRNAs downregulated more than1.5times between AMHF group and AMNHF group. Compared to NHF group, the AMNHF group had38miRNAs upregulated48miRNAs downregulated more than1.5times. There was13miRNAs upregulated and43miRNAs downregulated more than1.5times between AMHF group and OMHF group.
Conclusion There was significant differences in miRNA expression profiles between the patients with different stages of heart failure after myocardial infarction and normal control group using miRNA array analysis method which was based on peripheral blood plasma. Specific miRNAs would be choosing to explore the new circulating markers for myocardial infarction and heart failure.
Part two The significance of changes of myocardial energy expenditure in patients with heart failure after myocardial infarction using different dose of Perindopril
Objective To investigate the significance and difference of myocardial energy expenditure in patients with heart failure after myocardial infarction using different dose of Perindopril.
Method63patients with heart failure after myocardial infarction were recruited and treated with different dose of Perindopril in next12months. We divided them into two groups:N group(4mg Perindopril) and H group(8mg Perindopril). The Doppler imaging was used to measure the structural and systolic functional parameters. Then, the circumferential end-systolic wall stress (cESS) and myocardial energy expenditure (MEE) were calculated by the corresponding formulas. Biochemical indicator including serum creatinine and plasma NT-proBNP were detected on the next morning before and after treatment.
Results There was no significant difference between the two groups before treatment. After12months treatment with Perindopril, H group had lower LA, LV, RA, RV, LVIDs, AD, cESS,1gNT-proBNP, MEE and higher LVFS, LVEF than N group. Compared to before treatment, after12months of treatment H group had higher LVFS and LVEF, and lower LA, LV, RA, RV, AD, LVIDs, LVMI,1gNT-proBNP and MEEm. There was significant difference between the before and after treatment of N group except for PWTs、LVET、LVSV and LVFS. Bivariate analysis confirmed that MEE was significant correlated with1gNT-proBNP(r=0.513, P<0.01).
Conclusion After12months of treatment with Perindopril, the patients with heart failure after myocardial infarction had less myocardial remodeling, better left ventricular systolic function and lower level of NT-proBNP and myocardial energy expenditure. Target dose of perindopril treatment had better results than the conventional dose.
Part three The significance of changes of myocardial energy expenditure in patients at different periods after myocardial infarction
Objective To investigate the significance and difference of myocardial energy expenditure in patients after acute and old myocardial infarction.
Method51patients without heart failure after acute and old myocardial infarction were recruited. At the same time, we recruited30patients with normal coronary angiography results as control group. All of them were divided into three groups: AMI group(n=28), OMI group (n=23) and NOR group(n=30). The Doppler imaging was used to measure the structural and systolic functional parameters. Then, the circumferential end-systolic wall stress (cESS) and myocardial energy expenditure (MEE) were calculated by the corresponding formulas. Plasma NT-proBNP were detected on the next morning after admission.
Results The LgNT-proBNP and MEE were significantly higher in AMI group than that in OMI group (P<0.05). Compared to NOR group, cESS, MEE, and LgNT-proBNP were significantly higher in AMI and OMI group respectively (P<0.05).Bivariate analysis confirmed that MEE was significantly positively correlated with LgNT-proBNP, but negtively correlated with LVFS and LVEF.
Conclusion The myocardial energy expenditure level in patients with myocardial infarction is higher than those with normal coronary angiography. Compared to patients with acute myocardial infarction, those with old myocardial infarction had higher myocardial energy expenditure. MEE is an effective indicator for evaluating the cardiac function of patients at different periods after myocardial infarction, and significantly correlated with left ventricular systolic function parameters.
引文
[1]顾东风,黄广勇,何江.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003；31(1)：03-06.
[2]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function. Cell, 2004,116:281-297.
[3]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by micro-RNA-10b in breast cancer. Nature,2007,449:682-688.
[4]Van Rooij E, Sutherland LB,L iu N, et al. A signature patttern of stress-responsive Micro-RNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA,2006,103:18255-18260.
[5]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure. Circulation,2007,116:258-267.
[6]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heart disease. Physiol Genomics,2007,31:367-373.
[7]Thum T, Catalucci D, Bauersachs J. MicroRNAs:novel regulators in cardiac development and disease. Cardiovasc Res,2008,79:562-570.
[8]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105:10513-10518.
[9]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3:e3148.
[10]Tijsen AJ, Creemers EE, Moeland PD, et al. miR-423-5p as a circulating biomarker for heart failure. Circ Res,2010,106:1035-1039.
[11]Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature,2008,456:980-984.
[12]Nicolosi GL, Golcea S, Ceconi C, et al. Effects of perindopril on cardiac remodelling and prognostic value of pre-discharge quantitative echocardiographic parameters in elderly patients after acute myocardial infarction:the PREAMI echo sub-study. Eur Heart J,2009,30(13):1656-1665.
[13]Bertrand ME, Fox KM, Remme WJ, et al. Angiotensin-converting enzyme inhibition with perindopril in patients with prior myocardial infarction and/or revascularization:a subgroup analysis of the EUROPA trial. Arch Cardiovasc Dis,2009,102(2):89-96.
[14]Palmieri V, Bella JN, Arnett DK, Oberman A, et al. Associations of aortic and mitral regurgitation with body composition and myocardial energy expenditure in adults with hypertension:the hypertension genetic epidemiology network study. Am Heart J,2003,145:1071-1077.
[15]Vittorio P, Mary JR, Jonathan NB, et al. Prognostic implications of relatios of left ventricular systolic dysfunction with body composition and myocardial energy expenditure:The Strong Heart Study. J Am Soc Echocardiogr,2008,21(1):66-71.
[16]沈安娜,杜志勇,王鹏,等.多普勒超声心动图检测慢性心力衰竭患者心肌生物能量消耗水平的变化及临床意义[J].中华心血管病杂志,2010,38(3)：209-21
[1]顾东风,黄广勇,何江.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003；31(1)：03-06.
[2]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function. Cell, 2004,116:281-297.
[3]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by micro-RNA-10b in breast cancer. Nature,2007,449:682-688.
[4]Van Rooij E, Sutherland LB,L iu N, et al. A "signature patttern of stress-responsive Micro-RNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA,2006,103:18255-18260.
[5]Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific miRNAs from mouse. Curr Biol,2002,12:735-739
[6]Ji R, Cheng Y, Yue J, et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res,2007,100:1579-1588
[7]Chen JF, Mandel EM, Thomson JM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet,2006,38:228-233.
[8]Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRN A-1-2. Cell,2007,129:303-317.
[9]Yang B, Lin H, Xiao J, et al. Themuscle-specific microRNA miR-1 regulates cardiac arrhyth-mogenic potential by targeting GJA1 and KCNJ2. NatMed,2007,13:486-489.
[10]Xiao J, Yang B, Lin H, et al. Mesenchymal stem cells transfected with HCN2 genes by Lenti V can be modified to be cardiac pacemaker cells.J Cell Physiol,2007,212:285-288.
[11]Xu C, Lu Y, Lin H, et al. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis via targeting HSP60/HSP70 and caspase-9 in cardiomyocytes. J Cell Sci,2007,120:3045-3052.
[12]Wang S, Aurora A, Johnson B, et al. An endothelial-specific microRNA governs vascular integrity and angiogenesis. Dev Cell,2008,15:261-271.
[13]Cheng Y, Ji R, Yue J, et al. MicroRNAs are aberrantly expressed in hypertrophic heart:do they play a role in cardiac hypertrophy?Am J Pathol,2007,170:1831-1840.
[14]Tatsuguchi M, Seok HY, Callis TE, et al. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol,2007,42:1137-1141.
[15]van Rooij E, Sutherland LB, Qi X, et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science,2007,316:575-579.
[16]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[17]Sayed D, Hong C, Chen IY, et al. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res,2007,100:416-424.
[18]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[19]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure. Circulation,2007,116:258-267.
[20]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heart disease. Physiol Genomics,2007,31:367-373.
[21]Thum T, Catalucci D, Bauersachs J. MicroRNAs:novel regulators in cardiac development and disease. Cardiovasc Res,2008,79:562-570.
[22]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105:10513-10518.
[23]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3:e3148.
[24]Tijsen AJ, Creemers EE, Moeland PD, et al. miR-423-5p as a circulating biomarker for heart failure. Circ Res,2010,106:1035-1039.
[25]Fukushima Y, Nakanishi M, Nonogi H, et al. Assessment of Plasma miRNAs in Congestive Heart Failure. Circulation Journal,2010,10:1253-1257.
[26]Corsten MF, Dennert R, Jochems S, et al. Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease. Circulation,2010,10:1161-1179.
[27]Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature,2008,456:980-984.
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[1]顾东风,黄广勇,何江.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003；31(1)：03-06.
[2]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function. Cell, 2004,116:281-297.
[3]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by micro-RNA-10b in breast cancer. Nature,2007,449:682-688.
[4]Van Rooij E, Sutherland LB,L iu N, et al. A signature patttern of stress-responsive Micro-RNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA,2006,103:18255-18260.
[5]Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific miRNAs from mouse. Curr Biol,2002,12:735-739
[6]Ji R, Cheng Y, Yue J, et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res,2007,100:1579-1588
[7]Chen JF, Mandel EM, Thomson JM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet,2006,38:228-233.
[8]Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell,2007,129:303-317.
[9]Yang B, Lin H, Xiao J, et al. Themuscle-specific microRNA miR-1 regulates cardiac arrhyth-mogenic potential by targeting GJA1 and KCNJ2. NatMed,2007,13:486-489.
[10]Xiao J, Yang B, Lin H, et al. Mesenchymal stem cells transfected with HCN2 genes by Lenti V can be modified to be cardiac. pacemaker cells.J Cell Physiol,2007,212:285-288.
[11]Xu C, Lu Y, Lin H, et al. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis via targeting HSP60/HSP70 and caspase-9 in cardiomyocytes. J Cell Sci,2007,120:3045-3052.
[12]Wang S, Aurora A, Johnson B, et al. An endothelial-specific microRNA governs vascular integrity and angiogenesis. Dev Cell,2008,15:261-271.
[13]Cheng Y, Ji R, Yue J, et al. MicroRNAs are aberrantly expressed in hypertrophic heart:do they play a role in cardiac hypertrophy?Am J Pathol,2007,170:1831-1840.
[14]Tatsuguchi M, Seok HY, Callis TE, et al. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol,2007,42:1137-1141.
[15]van Rooij E, Sutherland LB, Qi X, et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science,2007,316:575-579.
[16]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[17]Sayed D, Hong C, Chen IY, et al. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res,2007,100:416-424.
[18]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[19]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure. Circulation,2007,116:258-267.
[20]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heart disease. Physiol Genomics,2007,31:367-373.
[21]Thum T, Catalucci D, Bauersachs J. MicroRNAs:novel regulators in cardiac development and disease. Cardiovasc Res,2008,79:562-570.
[22]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105:10513-10518.
[23]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3:e3148.
[24]Tijsen AJ, Creemers EE, Moeland PD, et al. miR-423-5p as a circulating biomarker for heart failure. Circ Res,2010,106:1035-1039.
[25]Fukushima Y, Nakanishi M, Nonogi H, et al. Assessment of Plasma miRNAs in Congestive Heart Failure. Circulation Journal,2010,10:1253-1257.
[26]Corsten MF, Dennert R, Jochems S, et al. Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease. Circulation,2010,10:1161-1179.
[27]Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature,2008,456:980-984.
[2]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function. Cell, 2004,116:281-297.
[3]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by micro-RNA-10b in breast cancer. Nature,2007,449:682-688.
[4]Van Rooij E, Sutherland LB,L iu N, et al. A signature patttern of stress-responsive Micro-RNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA,2006,103:18255-18260.
[5]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure. Circulation,2007,116:258-267.
[6]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heart disease. Physiol Genomics,2007,31:367-373.
[7]Thum T, Catalucci D, Bauersachs J. MicroRNAs:novel regulators in cardiac development and disease. Cardiovasc Res,2008,79:562-570.
[8]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105:10513-10518.
[9]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3:e3148.
[10]Tijsen AJ, Creemers EE, Moeland PD, et al. miR-423-5p as a circulating biomarker for heart failure. Circ Res,2010,106:1035-1039.
[11]Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature,2008,456:980-984.
[12]Nicolosi GL, Golcea S, Ceconi C, et al. Effects of perindopril on cardiac remodelling and prognostic value of pre-discharge quantitative echocardiographic parameters in elderly patients after acute myocardial infarction:the PREAMI echo sub-study. Eur Heart J,2009,30(13):1656-1665.
[13]Bertrand ME, Fox KM, Remme WJ, et al. Angiotensin-converting enzyme inhibition with perindopril in patients with prior myocardial infarction and/or revascularization:a subgroup analysis of the EUROPA trial. Arch Cardiovasc Dis,2009,102(2):89-96.
[14]Palmieri V, Bella JN, Arnett DK, Oberman A, et al. Associations of aortic and mitral regurgitation with body composition and myocardial energy expenditure in adults with hypertension:the hypertension genetic epidemiology network study. Am Heart J,2003,145:1071-1077.
[15]Vittorio P, Mary JR, Jonathan NB, et al. Prognostic implications of relatios of left ventricular systolic dysfunction with body composition and myocardial energy expenditure:The Strong Heart Study. J Am Soc Echocardiogr,2008,21(1):66-71.
[16]沈安娜,杜志勇,王鹏,等.多普勒超声心动图检测慢性心力衰竭患者心肌生物能量消耗水平的变化及临床意义[J].中华心血管病杂志,2010,38(3)：209-21
[1]顾东风,黄广勇,何江.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003；31(1)：03-06.
[2]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function. Cell, 2004,116:281-297.
[3]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by micro-RNA-10b in breast cancer. Nature,2007,449:682-688.
[4]Van Rooij E, Sutherland LB,L iu N, et al. A "signature patttern of stress-responsive Micro-RNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA,2006,103:18255-18260.
[5]Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific miRNAs from mouse. Curr Biol,2002,12:735-739
[6]Ji R, Cheng Y, Yue J, et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res,2007,100:1579-1588
[7]Chen JF, Mandel EM, Thomson JM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet,2006,38:228-233.
[8]Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRN A-1-2. Cell,2007,129:303-317.
[9]Yang B, Lin H, Xiao J, et al. Themuscle-specific microRNA miR-1 regulates cardiac arrhyth-mogenic potential by targeting GJA1 and KCNJ2. NatMed,2007,13:486-489.
[10]Xiao J, Yang B, Lin H, et al. Mesenchymal stem cells transfected with HCN2 genes by Lenti V can be modified to be cardiac pacemaker cells.J Cell Physiol,2007,212:285-288.
[11]Xu C, Lu Y, Lin H, et al. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis via targeting HSP60/HSP70 and caspase-9 in cardiomyocytes. J Cell Sci,2007,120:3045-3052.
[12]Wang S, Aurora A, Johnson B, et al. An endothelial-specific microRNA governs vascular integrity and angiogenesis. Dev Cell,2008,15:261-271.
[13]Cheng Y, Ji R, Yue J, et al. MicroRNAs are aberrantly expressed in hypertrophic heart:do they play a role in cardiac hypertrophy?Am J Pathol,2007,170:1831-1840.
[14]Tatsuguchi M, Seok HY, Callis TE, et al. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol,2007,42:1137-1141.
[15]van Rooij E, Sutherland LB, Qi X, et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science,2007,316:575-579.
[16]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[17]Sayed D, Hong C, Chen IY, et al. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res,2007,100:416-424.
[18]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[19]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure. Circulation,2007,116:258-267.
[20]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heart disease. Physiol Genomics,2007,31:367-373.
[21]Thum T, Catalucci D, Bauersachs J. MicroRNAs:novel regulators in cardiac development and disease. Cardiovasc Res,2008,79:562-570.
[22]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105:10513-10518.
[23]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3:e3148.
[24]Tijsen AJ, Creemers EE, Moeland PD, et al. miR-423-5p as a circulating biomarker for heart failure. Circ Res,2010,106:1035-1039.
[25]Fukushima Y, Nakanishi M, Nonogi H, et al. Assessment of Plasma miRNAs in Congestive Heart Failure. Circulation Journal,2010,10:1253-1257.
[26]Corsten MF, Dennert R, Jochems S, et al. Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease. Circulation,2010,10:1161-1179.
[27]Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature,2008,456:980-984.
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[1]顾东风,黄广勇,何江.中国心力衰竭流行病学调查及其患病率.中华心血管病杂志,2003；31(1)：03-06.
[2]Bartel DP. MicroRNAs:genomics, biogenesis, mechanism, and function. Cell, 2004,116:281-297.
[3]Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by micro-RNA-10b in breast cancer. Nature,2007,449:682-688.
[4]Van Rooij E, Sutherland LB,L iu N, et al. A signature patttern of stress-responsive Micro-RNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA,2006,103:18255-18260.
[5]Lagos-Quintana M, Rauhut R, Yalcin A, et al. Identification of tissue-specific miRNAs from mouse. Curr Biol,2002,12:735-739
[6]Ji R, Cheng Y, Yue J, et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ Res,2007,100:1579-1588
[7]Chen JF, Mandel EM, Thomson JM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet,2006,38:228-233.
[8]Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell,2007,129:303-317.
[9]Yang B, Lin H, Xiao J, et al. Themuscle-specific microRNA miR-1 regulates cardiac arrhyth-mogenic potential by targeting GJA1 and KCNJ2. NatMed,2007,13:486-489.
[10]Xiao J, Yang B, Lin H, et al. Mesenchymal stem cells transfected with HCN2 genes by Lenti V can be modified to be cardiac. pacemaker cells.J Cell Physiol,2007,212:285-288.
[11]Xu C, Lu Y, Lin H, et al. The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis via targeting HSP60/HSP70 and caspase-9 in cardiomyocytes. J Cell Sci,2007,120:3045-3052.
[12]Wang S, Aurora A, Johnson B, et al. An endothelial-specific microRNA governs vascular integrity and angiogenesis. Dev Cell,2008,15:261-271.
[13]Cheng Y, Ji R, Yue J, et al. MicroRNAs are aberrantly expressed in hypertrophic heart:do they play a role in cardiac hypertrophy?Am J Pathol,2007,170:1831-1840.
[14]Tatsuguchi M, Seok HY, Callis TE, et al. Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol,2007,42:1137-1141.
[15]van Rooij E, Sutherland LB, Qi X, et al. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science,2007,316:575-579.
[16]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[17]Sayed D, Hong C, Chen IY, et al. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res,2007,100:416-424.
[18]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133 controls cardiac hypertrophy. Nat Med,2007,13:613-618.
[19]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart:a clue to fetal gene reprogramming in heart failure. Circulation,2007,116:258-267.
[20]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heart disease. Physiol Genomics,2007,31:367-373.
[21]Thum T, Catalucci D, Bauersachs J. MicroRNAs:novel regulators in cardiac development and disease. Cardiovasc Res,2008,79:562-570.
[22]Mitchell PS, Parkin RK, Kroh EM, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A,2008, 105:10513-10518.
[23]Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One,2008,3:e3148.
[24]Tijsen AJ, Creemers EE, Moeland PD, et al. miR-423-5p as a circulating biomarker for heart failure. Circ Res,2010,106:1035-1039.
[25]Fukushima Y, Nakanishi M, Nonogi H, et al. Assessment of Plasma miRNAs in Congestive Heart Failure. Circulation Journal,2010,10:1253-1257.
[26]Corsten MF, Dennert R, Jochems S, et al. Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease. Circulation,2010,10:1161-1179.
[27]Thum T, Gross C, Fiedler J, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature,2008,456:980-984.