本文選題：致心律失常性右室心肌病 + 擴張型心肌病��； 參考：《北京協(xié)和醫(yī)學院》2017年博士論文

【摘要】：背景致心律失常性右室心肌病(ARVC/D)以右室心肌纖維脂肪替換為主要病理特征,以右室心律失常和右室心功能下降為主要臨床表現(xiàn)。相比于其他類型心肌病,ARVC/D以右室心肌受累為主,而左室心肌的病變程度較輕。目前對ARVC/D發(fā)病機制的研究發(fā)現(xiàn),ARVC/D右室心肌的纖維脂肪替換與心肌脂肪酸代謝調(diào)節(jié)紊亂有關(guān)。這說明心肌的能量代謝重塑在疾病發(fā)生過程中發(fā)揮重要作用。但是,目前關(guān)于ARVC/D心肌的葡萄糖底物利用、氨基酸代謝、三羧酸循環(huán)和氧化應激代謝重塑過程,以及與ARVC/D右室心肌受累的關(guān)聯(lián)尚不清楚。目的本研究的目的是探究ARVC/D左室與右室心肌的能量代謝改變,以從代謝角度解析ARVC/D右室心功能下降和右室心律失常的發(fā)生機制,以期為ARVC/D的臨床治療提供新的線索。方法馬松染色檢測非心衰心肌、擴張型心肌病(DCM)和ARVC/D患者的心肌纖維化和心肌細胞體積,并用Image-Pro Plus(IPP)軟件進行定量分析。透射電子顯微鏡觀察心肌細胞內(nèi)脂滴沉積。qPCR檢測心衰心肌標志物腦鈉肽(BNP)的mRNA表達水平。Spearman相關(guān)分析比較超聲心動圖參數(shù)(RVD,LVEDD,LVEF)與心肌BNP的mRNA表達水平高低的相關(guān)性。qPCR檢測7例非心衰心肌、8例DCM和8例ARVC/D患者的左室與右室心肌中參與脂肪酸底物利用、葡萄糖底物利用、谷氨酸代謝、三羧酸循環(huán)和氧化應激相關(guān)轉(zhuǎn)運蛋白、轉(zhuǎn)錄因子、代謝酶的mRNA表達水平。超高效液相色譜質(zhì)譜(UPLC-MS)技術(shù)檢測26例ARVC/D患者的左室與右室心肌中主要代謝中間產(chǎn)物的含量。人線粒體DNA(mtDNA)檢測試劑盒檢測線粒體DNA拷貝數(shù)相對含量。TUNEL凋亡檢測試劑盒檢測心肌細胞凋亡。結(jié)果與DCM患者相比,ARVC/D患者左室擴張(49.50 ± 11.30mm vs.65.50 ±14.50mm,ARVC/D vs.DCM,LVEDD,P0.001)和左室收縮功能障礙(43.50±19.90%vs.22.00±6.90%,ARVC/D vs.DCM,LVEF,P0.001)程度較輕,但右室擴張程度(43.50± 13.00mm vs.27.00±4.30mm,ARVC/D vs.DCM,RVD,P0.001)較重。ARVC/D右室心肌纖維化,肌纖維降解,心肌細胞體積增大,心肌細胞胞漿內(nèi)可見明顯的脂滴沉積。ARVC/D右室心肌BNP的表達水平比DCM右室高12.7倍。ARVC/D和DCM右室BNP的表達水平高低與右室內(nèi)徑(RVD)大小呈正相關(guān)關(guān)系(r=0.692,P=0.003)。ARVC/D左室心肌與DCM左室心肌BNP的表達水平之間沒有顯著差異(P=0.247)。ARVC/D和DCM左室BNP的表達水平高低與左室舒張末內(nèi)徑(LVEDD)(P=0.122)和左室射血分數(shù)(LVEF)(P=0.138)之間也沒有顯著相關(guān)性。與非心衰對照的左室與右室心肌相比,ARVC/D和DCM的左室與右室心肌中參與脂肪酸底物利用(SLC27A1,SLC27A6,FABP3,CPT1B,ACADVL,ACADS,PPARA)、甘油三酯平衡(GPAT2,PNPLA2,PLIN5)、葡萄糖底物利用(SLC2A4,PFKM,PKM,PDHB)、線粒體谷氨酸氧化(SLC1A5、GLUD1)、三羧酸循環(huán)(CS)的重要基因的mRNA表達水平下調(diào)或呈下降趨勢。與DCM右室心肌相比,ARVC/D右室心肌中參與脂肪酸代謝(SLC27A1,SLC27A6,FABP3,CPT1B,ACADVL,ACADS,PPARA)、甘油三酯平衡(GPAT2,PNPLA2,PLIN5)、葡萄糖代謝(SLC2A4,PFKM,PKM,PDHB)、三羧酸循環(huán)(CS)的大部分基因的mRNA表達水平下調(diào)或呈下降趨勢。與DCM左室心肌相比,ARVC/D左室心肌中上述基因的mRNA表達水平?jīng)]有顯著差異。我們發(fā)現(xiàn),參與谷氨酰胺-谷氨酸代謝的酶類,如谷氨酰胺酶(GLS)、谷氨酸-氨連接酶(GLUL)、氨甲酰基-磷酸合成酶(CPS1),和抗氧化酶谷胱甘肽還原酶(GSR)的基因mRNA表達水平只在ARVC/D和DCM右室下調(diào),而在ARVC/D和DCM左室卻沒有顯著改變。此外,ARVC/D右室心肌中尿素循環(huán)代謝中間產(chǎn)物和谷胱甘肽(GSH)含量低于左室(P=0.0013),而氧化型谷胱甘肽(GSSG)含量高于左室(P=0.0039)。與非心衰右室心肌相比,ARVC/D右室心肌線粒體DNA含量下降(P=0.0013)。ARVC/D右室殘余心肌細胞存在顯著的凋亡改變。結(jié)論第一,ARVC/D與DCM左室與右室心肌都存在脂肪酸、葡萄糖、谷氨酸底物利用下降和三羧酸循環(huán)障礙。但是,ARVC/D右室心肌能量代謝受損更加嚴重,產(chǎn)生能量減少,導致ARVC/D右室心功能下降。第二,ARVC/D右室心肌存在谷氨酰胺-谷氨酸代謝障礙和谷胱甘肽代謝穩(wěn)態(tài)失衡,引起右室心肌氧化應激損傷,這可能與ARVC/D右室心肌電生理紊亂和心肌凋亡發(fā)生相關(guān)。
[Abstract]:Background arrhythmogenic right ventricular cardiomyopathy (ARVC/D) is the main pathological feature of right ventricular myocardial fiber fat replacement, with right ventricular arrhythmia and right ventricular function decline as the main clinical manifestation. Compared with other types of cardiomyopathy, ARVC/D is mainly involved in right ventricular myocardium, and left ventricular myocardium is lighter. The pathogenesis of ARVC/D is present. The study found that the replacement of fibrous fat in the right ventricular myocardium of the ARVC/D is related to the disorder of the metabolic regulation of the myocardial fatty acid. This suggests that the remodeling of the energy metabolism of the myocardium plays an important role in the development of the disease. However, the use of glucose substrates, the metabolism of amino acids, the three carboxylic acid cycle and the remodeling process of oxidative stress metabolism are present in the ARVC/D myocardium. The purpose of this study is to explore the energy metabolism changes in the left ventricular and right ventricular myocardium of the ARVC/D in order to analyze the mechanism of ARVC/D right ventricular dysfunction and right ventricular arrhythmia from the metabolic angle, so as to provide new clues for the clinical treatment of ARVC/D. Method Masson staining was used to detect the clinical treatment of the right ventricular myocardium. Myocardial fibrosis and volume of myocardium in patients with non heart failure, dilated cardiomyopathy (DCM) and ARVC/D and quantitative analysis by Image-Pro Plus (IPP) software. Transmission electron microscopy (TEM) observation of lipid droplet deposition in cardiac myocytes,.QPCR detection of cardiac markers of heart failure, BNP,.Spearman correlation analysis and comparison of echocardiography The correlation between RVD, LVEDD, LVEF and the mRNA expression level of myocardial BNP detected in 7 cases of non heart failure myocardium, 8 cases of DCM and 8 cases of ARVC/D patients involved in the use of fatty acid substrates, glucose substrate utilization, glutamate metabolism, three carboxylic acid cycle and oxidative stress related transporters, transcription factors, metabolic enzymes. MRNA expression level. The content of major metabolic intermediates in left ventricular and right ventricular myocardium in 26 patients with ARVC/D was detected by ultra high performance liquid chromatography mass spectrometry (UPLC-MS). Mitochondrial DNA (mtDNA) detection kit was used to detect the relative content of mitochondrial DNA copy number by.TUNEL apoptosis detection kit to detect cardiomyocyte apoptosis. Compared with DCM patients, the results were compared with those of DCM patients. The left ventricular dilatation of ARVC/D patients (49.50 + 11.30mm vs.65.50 + 14.50mm, ARVC/D vs.DCM, LVEDD, P0.001) and left ventricular systolic dysfunction (43.50 + 19.90%vs.22.00 + 6.90%, ARVC/D vs.DCM, LVEF, etc.) were relatively mild, but the right ventricular dilatation degree was more severe than that of the right ventricular myocardium. Muscle fiber degradation, myocardial cell volume increased, the expression level of BNP in.ARVC/D right ventricular myocardium was 12.7 times higher than that of DCM right ventricle,.ARVC/D and DCM right ventricle BNP expression level were positively correlated with right ventricular diameter (RVD) size (r=0.692, P=0.003).ARVC/D left ventricular myocardium and DCM left ventricular myocardium BNP. There was no significant difference between the levels of.ARVC/D and DCM (P=0.247) and left ventricular BNP expression level with left ventricular end diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) (LVEF). Compared with the left ventricular and right ventricular myocardium, the left ventricular and right ventricular myocardium in ARVC/D and DCM were involved in fatty acid bottom. SLC27A1, SLC27A6, FABP3, CPT1B, ACADVL, ACADS, PPARA), triglyceride balance (GPAT2, PNPLA2, PLIN5). The glucose substrate uses (SLC2A4, PFKM), mitochondrial glutamate oxidation, the expression level of the important genes of the three carboxylic acid cycle down or downward trend. The muscles involved in fatty acid metabolism (SLC27A1, SLC27A6, FABP3, CPT1B, ACADVL, ACADS, PPARA), triglyceride balance (GPAT2, PNPLA2, PLIN5), and glucose metabolism (SLC2A4, PFKM, and PLIN5). The expression level of most genes of the three carboxylic acid cycle decreased or declined. There was no significant difference in expression level. We found that the genes involved in glutamine - glutamic acid metabolism, such as glutaminase (GLS), glutamate ammonia ligase (GLUL), aminoformyl phosphate synthetase (CPS1), and antioxidant enzyme glutathione reductase (GSR) gene mRNA expression level only down in the right ventricle of ARVC/D and DCM, and in ARVC/D and DCM left ventricle. In addition, the content of intermediate product of urea metabolism and glutathione (GSH) in ARVC/D right ventricular myocardium was lower than that of left ventricle (P=0.0013), and the content of oxidized glutathione (GSSG) was higher than that of left ventricle (P=0.0039). The mitochondrial DNA content of ARVC/D right ventricular myocardium decreased (P=0.0013).ARVC/D right ventricular remnant myocardium compared with non heart failure right ventricular myocardium. There were significant apoptotic changes in the cell. Conclusion first, both ARVC/D and DCM left ventricular and right ventricular myocardium have fatty acid, glucose, glutamic acid substrate utilization and three carboxylic acid circulation disorder. However, the energy metabolism of ARVC/D right ventricular myocardium is more severely damaged, resulting in reduced energy, resulting in the decrease of ARVC /D right ventricular function. Second, ARVC/D right ventricular myocardium exists. The disorder of glutamine glutamic acid metabolism and the homeostasis of glutathione metabolism may cause oxidative stress injury in the right ventricular myocardium, which may be associated with the electrophysiological disorder of the right ventricular myocardium and the occurrence of myocardial apoptosis in ARVC/D.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R542.2

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