The Diagnosis Value Of ST2 And Hs-CRP In Patients With Acute Coronary Syndrome And The Mechanisms Of Left Ventricular Remodeling After Acute Myocardial Infarction

Coronary atherosclerotic heart disease (coronary heart disease, CHD) is one of the highest morbidity and mortality in world, and is the first cause of death in men over 45 years of age in most countries and the second cause of death in women next to the tumor. CHD has seriously influenced on the human life expectancy and quality of life. Virchow first reported that CHD was essentially an inflammatory hypothesis. Recent years, a large number of studies have confirmed that atherosclerosis is a chronic (auto)-inflammatory disease. Inflammation not only directly involved in the pathophysiologic changes of atherosclerotic plaque rupture, but also involved in the occurrence and development of coronary heart disease. On the basis of atherosclerotic lesions, plaque rupture and surface thrombosis result in complete or incomplete occlusion of distal vascular of lesions; this would show as acute coronary syndrome (ACS) in clinic. How to identify vulnerable patients early and accurately before the acute cardiovascular events and conduct positive and effective intervention has become an urgent issue.Inflammatory markers are increasingly used to monitor the condition of patients with ACS, and have higher clinical value in predicting the rupture of vulnerable plaque. Serological markers may not only reflect the high-risk patients, but also have the possibility to develop non-invasive tests for detection of plaque vulnerability; therefore, it can be popularized, and have good predictive value. Therefore, it is more important to explore novel and more meaningful risk factors to prevent the risk of coronary heart disease. CRP, as an inflammatory factor, is considered closely related to the incidence, development and prognosis of coronary artery disease, and has high sensitivity and accuracy in predicting the stability of the plaque. High-sensitivity C-reactive protein (hs-CRP), with high sensitivity to detect concentrations as low as 0.15mg/L, can enhance the prediction of prognosis and treatment of CHD. Now, hs-CRP which is considered to be an independent risk factor in cardiovascular disease can be regarded as an important indicator to determine the prognosis of CHD, moreover, hs-CRP in patients without clinical evidence of CHD, has a strong early warning role to the occurrence of future cardiovascular events and provides a simple and economical method for screening high-risk patients. C-reactive protein (CRP), the classic acute-phase protein, initiates macrophages and neutrophils to produce interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor-2 (TNF-2) and stimulates the liver to synthesize; furthermore, Hatanaka et al found the expression of CRP in the blood vessels of atherosclerosis and infarcted myocardium. Thus we can infer that CRP, mediated immune response of certain antigen, participates in neutrophil activation and adhesion induced by complement activation to participate in the formation of atherosclerosis. Hong et al found plasma hs-CRP levels in patients with multiple vulnerable plaques were higher than those in patients without multiple vulnerable plaques, suggesting that hs-CRP can be used as independent predictor of multiple vulnerable plaques. Some scholars have analyzed the relationship between the CRP levels and the prognosis of patients with coronary heart disease, and found that hs-CRP has prognostic value. Another study showed that CRP can also transit OX40/OX40L signaling pathway, or both mutual influences to promote each other to participate in the inflammatory response in vivo.Understanding of the processes that initiate and maintain inflammation has increased with the characterization of new disease pathways in the adaptive and innate immune systems. One such pathway is the receptor-ligand pair OX40-OX40 ligand (OX40L), which has shown association with atherosclerosis in both mouse and human. OX40L, originally termed glycoprotein 34 kDa (GP34), and its cognate receptor OX40 belong to the TNF and TNF receptor superfamilies, respectively. OX40 is preferentially expressed by activated CD4+ T cells, whereas OX40L is mainly expressed in the surface of activated antigen presenting cells, such as dendritic cells, B lymphocytes, endothelial cells, macrophages and some tissue cells including heart, skeletal muscle, testis and lung. Microarray analyses identified OX40L as the key molecule expressed by TSLP-activated DCs, as it enables them to trigger allergic inflammatory Th2 immune responses. OX40 binding to OX40L, by inhibiting apoptosis, plays an extremely important role for the promotion of activated CD4+T cell survival, proliferation and the generation of memory T cells. Interruption of the OX40-OX40L pathway attenuates atherogenesis in LDL receptor-deficient mice. Attributable to the immunoregulatory role of this pathway, interactions between OX40 and OX40L have the potential to enhance inflammatory responses in atherosclerotic plaque.Risk stratification of patients admitted with ACS is increasingly dependent on measurement of prognostically significant biomarkers, serum ST2 may be such a biomarker. It has been known for several years that ST2, an IL-1 receptor (IL-1R) family member, is basally expressed by cardiomyocytes. ST2 has 2 primary isoforms regulated by different promoters. The transmembrane ST2 isoform (ST2L) is a membrane-bound isoform with 3 extracellular IgG domains, a single transmembrane domain, and an intracellular SIR domain homologous to TLRs and other IL-1Rs. The soluble ST2 isoform (sST2) lacks the transmembrane and intracellular domains. Both ST2L and sST2 are biomechanically induced in cardiomyocytes. Furthermore, elevations of serum sST2 predict worse prognosis in patients with chronic heart failure and those with acute myocardial infarction.The mechanisms by which ST2 signaling may affect myocardial pathophysiology have not yet been identified, in part because over a decade of searching had not yet yielded a functional ligand for ST2. However, using a structural bioinformatics approach, Schmitz et al. recently identified a novel IL-1-related sequence from a dog brain cDNA library. This protein, now called IL-33, proved to be a functional ligand of ST2L capable of activating NF-κB, the common signaling pathway of IL-1R/TLRs. ST2L acts as a ligand for free IL-33 that exerts antihypertrophic, antifibrotic, and antiapoptotic effects on cardiac fibroblasts and myocytes in settings associated with increased mechanical strain or ischemia/reperfusion injury. sST2 in contrast, acts as a soluble decoy receptor for IL-33, effectively decreasing the IL-33 concentration available for ST2L binding. Accordingly, imbalances in the IL-33/ST2 system would theoretically attenuate the cardioprotective effects of IL-33.In human studies, serum sST2 is elevated early after acute myocardial infarction (AMI) and correlates with creatine kinase and (inversely with) left ventricular ejection fraction (LVEF). Serum sST2 correlates with N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients admitted with ST segment elevation myocardial infarction and predicts subsequent 30-day mortality and heart failure. Additionally, serum sST2 is elevated and is of predictive value in acutely dyspneic patients with and without decompensated acute heart failure, and in chronic heart failure. That sST2 predicts adverse cardiovascular outcome, and is related to LVEF after AMI, suggests that it may have a role in adverse left ventricular (LV) remodeling, but this has yet to be evaluated.In our study, we determinated the expression levels of serum soluble ST2 (sST2), high sensitive C-reactive protein (hs-CRP) and plasma OX40L, drawing blood from local coronary plaque, femoral artery and ulnar vein to research their effect in cardiovascular response to injury. Meanwhile, the correlation among them and the correlation between them and the coronary artery stenoses in patients were assessed by us. We examined the relationships between serum sST2 and parameters of LV function in patients admitted with AMI, and discussed the role of ST2 in left ventricular remodeling after AMI. The research contents and main results of this dissertation are as follows:1. The level of serum soluble ST2, hs-CRP and plasma OX40L at peripheral blood and local coronary plaque in patients with acute coronary syndromeObjective:ST2 is a member of the interleukin-1 receptor family that is up-regulated in conditions associated with increased myocardial strain. ST2 has been shown to be independently predictive of adverse outcome in patients with acute coronary syndrome (ACS), but its expression of local coronary plaque has not been established. Methods:A total number of 130 patients with coronary artery disease (CAD) and 50 healthy subjects were involved in the study over a 12 month period, including 90 patients with ACS,40 with stable angina (SA) undergoing percutaneous coronary angiography. Concentrations of sST2, hs-CRP and OX40L at local coronary plaque, femoral artery and ulnar vein were assessed.Results:Patients with CAD were significantly older (P< 0.01), and had more diabetic patients than the control group (P=0.001). Lipoprotein (a), fibrinogen, bilirubin and Gensini score were significantly high in the CAD group (P<0.05). The concentrations of sST2, hs-CRP and OX40L were established significantly higher in patients with ACS compared with controls or SA (P<0.01). The sST2 levels had the trend of increase from local coronary plaque to femoral artery to ulnar vein (P<0.01). Elevated sST2 level of local coronary plaque (sST2c) was associated with ACS with an area under receiver operating characteristic (ROC) curve of 0.845 (95% CI 0.773-0.917; P<0.001). sST2c levels from ACS patients showed a positive correlation with levels of hs-CRPc and OX40Lc (P<0.001). A positive correlation was observed between the number of complex lesions and sST2c (P< 0.001),but there were not significant correlation with stenosis severity.Conclusions:sST2 levels of local coronary plaque were significantly elevated in ACS and were more sensitive to the inflammatory response of cardiovascular injury. It represented an interesting novel pathophysiologic pathway.2. The relation between sST2 and hs-CRP and left ventricular function in patients after acute myocardial infarctionObjective:Serum sST2 levels are elevated early after acute myocardial infarction (AMI), we would research the correlation between sST2 and left ventricular function in patients after acute myocardial infarction.Methods:50 patients with acute myocardial infarction patients and 50 healthy subjects were involved in this study from December 2008 to April 2010. We drew blood from ulnar vein when admission of patients, before undergoing coronary angiography and drug application. All patients were examined by echocardiography, detected the left ventricle ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septum thickness (IVST), left ventricular fractional shortening (LVFS) and left ventricular posterior wall thickness (LVPWT).Results:Serum sST2 and hs-CRP correlated significantly inversely with LV ejection fraction and left ventricular fractional shortening (P<0.001), and correlated with change in LV end diastolic diameter and left ventricular end systolic diameter (P <0.001).Conclusions:Measurement of sST2 and hs-CRP early after AMI assists in the prediction of LV functional, and serum sST2 and hs-CRP may be an importance biomarker in ventricular remodeling after AMI.3. The quantification of ST2 and hs-CRP expression in myocardial tissues in the rat model of acute myocardial infarctionObjective:ST2, an interleukin-1 receptor family member, as a gene may markedly induce by mechanical strain in cardiac myocytes and participate in the acute myocardial response to stress and injury.Methods:60 adult female Wistar rats, weight (250±20) g. Myocardial infarction models were established by anterior descending coronary artery ligation. Rats were randomized to operated group (1 hour,4 hour,6 hour,12 hour, 1day,3 days,1 week, 2 weeks,3 weeks and 4 weeks) and sham-operated group. Cardiac tissue was extracted RNA using Trizol. The amounts of mRNA for ST2 and hs-CRP were determinated by real-time RT-PCR method, and normalized withβ-actin.Results:After normalized withβ-actin, the mRNA levels of ST2 were significantly increased 1 hours after AMI compared with the sham-operated group (P<0.01), and reached peak at 12h-1d, hs-CRP mRNA also was significantly increased, and reached peak at 3d, but there was not significant correlation with ST2 mRNA expression.Conclusions:ST2 and hs-CRP released in response to myocardial infarction, and was transcriptionally regulated in the heart after MI.4. The histological changes of ST2 and hs-CRP in the rat model of acute myocardial infarction Objective:Observation the histological changes of ST2 in acute myocardial infarction of rats to study the expression of ST2 and hs-CRP in myocardial tissue of acute myocardial infarction.Methods:60 adult female Wistar rats, weight (250±20) g. Myocardial infarction models were established by anterior descending coronary artery ligation. Rats were randomized to operated group (1 hour,4 hour,6 hour,12 hour, 1day,3 days,1 week, 2 weeks,3 weeks and 4 weeks) and sham-operated group. The heart was fixed by formalin, paraffin-embedded and made paraffin sections. We detected the expression of ST2 and hs-CRP in myocardial tissue by applications of immunofluorescence and immunohistochemical.Results:ST2 and hs-CRP were found to deposit in the cardiac tissue, and accorded with the response of ventricular remodeling.Conclusions:ST2 and hs-CRP play an important role in leading to ventricular remodeling after acute myocardial infarction.