【摘要】：背景與目的心力衰竭(heart failure,HF)是全球心血管疾病死亡的主要原因,也是人類社會(huì)的一個(gè)主要健康問(wèn)題[1]。與晚期惡性腫瘤相比,心衰的發(fā)病率、住院率和死亡率更高[2],尤其是以老年患者多見(jiàn)[3],心衰患者院外的平均預(yù)期生存時(shí)間大約是5.5年[4],對(duì)于年齡≥65歲的慢性心衰患者,一年的死亡率大約是25%-40%[5-11],兩年的死亡率是22%-52.9%[12,13]。因此,慢性心衰是一個(gè)全球性的衛(wèi)生保健服務(wù)難題。慢性心力衰竭(chronic heart failure,CHF)是各種不同病因引起心臟疾病進(jìn)展的最終階段,隨著人們對(duì)慢性心力衰竭的深入研究,已經(jīng)發(fā)現(xiàn)心室重構(gòu)(ventricular remodeling,VR)是心衰進(jìn)展的重要病理生理基礎(chǔ)。研究發(fā)現(xiàn),免疫信號(hào)素4D(Semaphorin4D,Sema4D)為I型跨膜糖蛋白分子,主要表達(dá)于T細(xì)胞、B細(xì)胞、血小板、內(nèi)皮細(xì)胞、心肌細(xì)胞等,在各種炎癥因子刺激下,細(xì)胞表面Sema4D活化為可溶性Sema4D(sSema4D),與其受體plexin-B1結(jié)合,通過(guò)細(xì)胞表面Met結(jié)構(gòu)的酪氨酸激酶使下游的相關(guān)信號(hào)分子發(fā)生磷酸化,參與新生血管產(chǎn)生、組織膠原纖維化形成、血栓形成、動(dòng)脈粥樣硬化性疾病等�；|(zhì)金屬蛋白酶14(Matrix metalloproteinases-14),即膜型基質(zhì)金屬蛋白酶1(membrane-type 1 matrix metalloproteinases,MMT1-MMP),是基質(zhì)金屬蛋白酶類的亞家族成員,以活性酶形式表達(dá)于細(xì)胞膜表面,可降解細(xì)胞外基質(zhì)中的Ⅰ、Ⅲ型膠原纖維和纖維連接蛋白,參與心肌纖維化的發(fā)生和心力衰竭的進(jìn)展。有研究顯示Sema4D可在膜型基質(zhì)金屬蛋白酶1(MT1-MMP)的作用下成為可溶性Sema4D(sSema4D),發(fā)揮相應(yīng)的生物學(xué)功能[16],目前對(duì)于二者關(guān)系的研究尚少見(jiàn)。有研究發(fā)現(xiàn),在心衰患者中s Sema4D和MMP14的水平是升高的,但二者是否與老年慢性心衰心室重構(gòu)有關(guān)尚未見(jiàn)報(bào)道。本研究通過(guò)測(cè)定老年慢性心力衰竭患者血清sSema4D、MMP14水平變化和觀察超聲心動(dòng)圖的相關(guān)指標(biāo),探討sSema4D、MMP14與老年慢性心力衰竭心室重構(gòu)的相關(guān)性,為慢性心力衰竭提供新的治療靶點(diǎn)。方法選取2014年08月至2015年12月在鄭州大學(xué)第一附屬醫(yī)院老年心血管科住院的慢性心衰患者116例,包括擴(kuò)張型心肌病(dilated cardiomyopathy,DCM)32例、冠心病(coronary heart disease,CHD)49例、房顫(atrial fibrillation,AF)35例。按照紐約心功能分級(jí)法(NYHA分級(jí))分為心功能II級(jí)組(n=28)、心功能III級(jí)組(n=58)、心功能IV級(jí)組(n=30)。另選取鄭大一附院門(mén)診保健科健康體檢者35例作為正常對(duì)照組。酶聯(lián)免疫吸附法檢測(cè)血清sSema4D、MMP14、B型利鈉肽原(proBNP)、超敏C反應(yīng)蛋白(hs-CRP)水平;彩色多普勒超聲心動(dòng)儀檢測(cè)左心房?jī)?nèi)徑(LAD)、右心室內(nèi)徑(RVD)、左心室射血分?jǐn)?shù)(LVEF)、左心室舒張末期內(nèi)徑(LVDd)、左心室短軸縮短率(LVFS)。采用SPSS21.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析,計(jì)量資料以x±S表示,兩組間比較采用t檢驗(yàn)。單因素方差分析進(jìn)行多組間的比較,Bonferroni法用于組間兩兩比較,簡(jiǎn)單線性相關(guān)分析采用Pearson法。多因素相關(guān)性采用多元(重)回歸分析。以P0.05為檢驗(yàn)標(biāo)準(zhǔn),差異有統(tǒng)計(jì)學(xué)意義。結(jié)果1.慢性心衰組心功能II級(jí)、III級(jí)、IV級(jí)患者血清sSema4D、MMP14、proBNP水平均較正常對(duì)照組升高(F為175.496、325.862、77.403,P0.001),且不同心功能分級(jí)組間兩兩比較,差異有統(tǒng)計(jì)學(xué)意義(P0.05)。2.慢性心衰治療前血清sSema4D、MMP14、proBNP水平較正常對(duì)照組升高(t分別是15.65、28.95、34.54,P0.001),且治療前三者水平均高于治療后(t分別是7.95、26.64、22.28,P0.001),差異有統(tǒng)計(jì)學(xué)意義。3.慢性心衰組左心室舒張末期內(nèi)徑、左房直徑、右室直徑較正常對(duì)照組增大(t分別為22.43、18.83、3.34,P0.01),左心室射血分?jǐn)?shù)、左室短軸縮短率較正常對(duì)照組下降(t分別為-38.23、-29.40,P0.001),差異均有統(tǒng)計(jì)學(xué)意義。4.DCM、CHD、AF三組間血清sSema4D、MMP14、pro-BNP水平比較差異無(wú)統(tǒng)計(jì)學(xué)意義(F分別為0.243、0.247、0.284,P0.05)。5.多因素回歸分析顯示血漿sSema4D、MMP14、hsCRP對(duì)左室舒張末期內(nèi)徑的影響有統(tǒng)計(jì)學(xué)意義(P0.05),但是pro-BNP的影響沒(méi)有統(tǒng)計(jì)學(xué)意義(P0.05)。且血清sSema4D對(duì)左室舒張末期內(nèi)徑擴(kuò)大的貢獻(xiàn)最大(β=0.268,P=0.019),MMP14次之(β=0.234,P=0.037)6.相關(guān)分析結(jié)果顯示sSema4D與MMP14的表達(dá)水平呈正相關(guān)(r=0.462,P0.05),與左心室舒張末期內(nèi)徑、pro-BNP呈正相關(guān)(r分別為0.643、0.464,P0.001),與左室射血分?jǐn)?shù)呈負(fù)相關(guān)(r=-0.554,P0.001);MMP14與左心室舒張末期內(nèi)徑、pro-BNP呈正相關(guān)(r分別為0.541、0.365,P0.001),與左室射血分?jǐn)?shù)呈負(fù)相關(guān)(r=-0.462,P0.001)。結(jié)論1.老年慢性心力衰竭患者血清sSema4D、MMP14水平升高。2.老年慢性心力衰竭患者血清s Sema4D蛋白與MMP14蛋白水平、左心室舒張末期內(nèi)徑呈正相關(guān)。3.血清sSema4D可能與慢性心衰心室重構(gòu)有關(guān)。4.血清sSema4D、MMP14是老年慢性心衰進(jìn)展的一個(gè)危險(xiǎn)因素;或可成為治療慢性心力衰竭的一個(gè)新靶點(diǎn)。
[Abstract]:BACKGROUND AND OBJECTIVE Heart failure (HF) is a major cause of death from cardiovascular diseases worldwide and a major health problem in human society. About 5.5 years [4], the one-year mortality rate is about 25% - 40% [5-11], and the two-year mortality rate is 22% - 52.9% [12,13]. In the final stage, with the in-depth study of chronic heart failure, ventricular remodeling (VR) has been found to be an important pathophysiological basis for the progress of heart failure. Cells, etc., stimulated by various inflammatory factors, Sema4D on the cell surface is activated as soluble Sema4D (sSema4D), which binds to its receptor plexin-B1, phosphorylates downstream signal molecules through the Met-structured tyrosine kinase on the cell surface, participates in angiogenesis, collagen fibrosis, thrombosis, and atherosclerotic diseases. Matrix metalloproteinases-14, or membrane-type 1 matrix metalloproteinases (MMT1-MMP), are subfamily members of matrix metalloproteinases. They are expressed on the surface of cell membrane in the form of active enzymes and can degrade collagen type I and type III fibers and fibronection in extracellular matrix. Receptor proteins are involved in the development of myocardial fibrosis and heart failure. Studies have shown that Sema4D can be soluble under the action of matrix metalloproteinase 1 (MT1-MMP) and play a corresponding biological role [16]. At present, the relationship between them is rare. The relationship between sSema4D, MMP14 and ventricular remodeling in elderly patients with chronic heart failure has not been reported. Methods 116 patients with chronic heart failure, including 32 patients with dilated cardiomyopathy (DCM), 49 patients with coronary heart disease (CHD) and 35 patients with atrial fibrillation (AF), were enrolled in the Department of Geriatric Cardiology, First Affiliated Hospital of Zhengzhou University from August 2014 to December 2015. According to the New York Heart Function Grading (NYHA), the patients were divided into three groups: Heart Function Grade II (n = 28), Heart Function Grade III (n = 58) and Heart Function Grade IV (n = 30). Thirty-five healthy subjects were selected as normal control group. Serum sSema4D, MMP14, proBNP, hs-CRP were detected by ELISA. Level; Left atrial diameter (LAD), right ventricular diameter (RVD), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd) and left ventricular short-axis shortening rate (LVFS) were measured by color Doppler echocardiography. SPSS21.0 software was used for statistical analysis. The measurement data were expressed as X 65 Bonferroni method was used to compare between groups. Pearson method was used to analyze the simple linear correlation. Multivariate (heavy) regression analysis was used to analyze the multivariate correlation. The levels of serum sSema4D, MMP14 and proBNP were higher in the control group than in the control group before treatment (t was 15.65, 28.95, 34.54, P 0.001), and the levels of sSema4D, MMP14 and proBNP before treatment were higher than those after treatment (t was 7.95, respectively). Left ventricular end-diastolic diameter, left atrial diameter and right ventricular diameter in chronic heart failure group were larger than those in normal control group (t 22.43, 18.83, 3.34, P 0.01, respectively). Left ventricular ejection fraction and left ventricular short axis shortening rate were lower than those in normal control group (t - 38.23, - 29.40, P 0.001, respectively). There was no significant difference in serum sSema4D, MMP14, pro-BNP levels among the three groups (F 0.243, 0.247, 0.284, P 0.05). 5. Multivariate regression analysis showed that plasma sSema4D, MMP14, and hsCRP had statistically significant effects on left ventricular end-diastolic diameter (P 0.05), but the effect of pro-BNP had no statistical significance (P 0.05). Serum sSema4D had the greatest contribution to the enlargement of left ventricular end-diastolic diameter (beta = 0.268, P = 0.019), followed by MMP14 (beta = 0.234, P = 0.037) 6. Correlation analysis showed that sSema4D was positively correlated with the expression of MMP14 (r = 0.462, P 0.05), positively correlated with left ventricular end-diastolic diameter, pro-BNP (r = 0.643, 0.464, P 0.001), and negatively correlated with left ventricular ejection fraction. MMP14 was positively correlated with left ventricular end-diastolic diameter (r = 0.541, 0.365, P 0.001), and negatively correlated with left ventricular ejection fraction (r = - 0.462, P 0.001). Conclusion 1. Serum levels of sSema4D and MMP14 were elevated in elderly patients with chronic heart failure. Serum sSema4D may be associated with ventricular remodeling in chronic heart failure. 4. Serum sSema4D and MMP14 may be a risk factor for the progression of chronic heart failure in the elderly, or may be a new target for chronic heart failure.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R541.6

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