| BackgroundHeart 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 infarctionObjective 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 PerindoprilObjective 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 infarctionObjective 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. |
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