本文選題：缺血性心肌病 + 氧化應(yīng)激�。� 參考：《鄭州大學(xué)》2016年博士論文

【摘要】：目前國(guó)內(nèi)外大量的研究已應(yīng)用8-羥基脫氧鳥嘌呤(8-OHd G)作為評(píng)估氧化應(yīng)激和DNA氧化損傷指標(biāo)。在DNA氧化損傷中,8-OHd G是最具代表性的氧化損傷產(chǎn)物和敏感生物標(biāo)志物,已成為目前醫(yī)學(xué)研究的熱點(diǎn)。參與人類脫氧核糖核酸(DNA)損傷修復(fù)的基因有130多種,人類8-羥基鳥嘌呤糖苷酶(h OGG1)是其中的一種,h OGG1基因可以對(duì)損傷了的DNA進(jìn)行修復(fù),特異地切除8-OHd G。h OGG1基因第7外顯子第1245位堿基的C/G多態(tài),其326位密碼子或編碼絲氨酸(Ser)或編碼半胱氨酸(Cys),表現(xiàn)出不同酶活性,可能與個(gè)體氧化損傷相關(guān)。多項(xiàng)研究表明,氧化損傷與冠狀動(dòng)脈粥樣硬化性心臟病(CAHD)及其并發(fā)癥明顯相關(guān),同時(shí)脂質(zhì)代謝紊亂是造成動(dòng)脈粥樣硬化的主要因素,可造成活性氧產(chǎn)生增多,形成氧化應(yīng)激,引起血管內(nèi)皮功能紊亂和心血管并發(fā)癥的發(fā)生。冠狀動(dòng)脈粥樣硬化性心臟病,簡(jiǎn)稱冠心病(CHD),缺血性心肌病(ICM)是CHD的一種特殊類型,它是具有一系列臨床表現(xiàn)的一組癥候群,包括心律失常、心臟擴(kuò)大、僵硬、心力衰竭等。長(zhǎng)期心肌缺血更易誘導(dǎo)心肌彌漫性纖維化,最終損害心臟收縮和(或)舒張功能。隨著社會(huì)進(jìn)入人口老齡化階段,ICM發(fā)病率和死亡率呈同步快速增高,500萬(wàn)的美國(guó)心力衰竭人群中,至少有350萬(wàn)不同程度伴有ICM病因的心室收縮和舒張功能不全。目前,ICM的發(fā)病機(jī)制尚未得到確切證實(shí),臨床上的治療手段特異性較差,作為心臟病領(lǐng)域研究的熱點(diǎn)被人們熟知。越來(lái)越多的證據(jù)表明,ICM易受遺傳、環(huán)境因素干擾。目前DNA修復(fù)基因多態(tài)性及其表達(dá)作用和氧化應(yīng)激在ICM中的作用越來(lái)越受到重視。他汀能明顯降低CHD患者心血管事件的發(fā)生率,其作為抗動(dòng)脈粥樣硬化藥物,已經(jīng)成為冠心病的二級(jí)預(yù)防藥物。h OGG1基因Ser326Cys多態(tài)性和血清8-OHd G水平與ICM發(fā)病是否存在關(guān)系,他汀類藥物是否具有抗氧化作用,不同劑量阿托伐他汀抗氧化作用是否存在差異以及其對(duì)ICM患者血清8-OHd G水平和病死率的是否存在影響等,針對(duì)上述研究的報(bào)道較少。本研究擬分為兩部分來(lái)探討:1.h OGG1基因Ser326Cys基因型、血清8-OHd G水平與ICM之間的關(guān)系;2.不同劑量阿托伐他汀對(duì)ICM患者血清8-OHd G水平和病死率的影響。第一部分h OGG1基因Ser326Cys基因型、血清8-OHd G水平與缺血性心肌病之間的關(guān)系目的探討h OGG1基因Ser326Cys基因型和血清8-OHd G水平與ICM的關(guān)系以及ICM的氧化應(yīng)激機(jī)制。方法用病例-對(duì)照研究設(shè)計(jì),選取ICM病例(病例組)和與之年齡、性別匹配,同期住院的冠狀動(dòng)脈造影示冠狀動(dòng)脈正常的對(duì)照各246例,按1:1配對(duì)。運(yùn)用PCR-RFLP技術(shù)檢測(cè)h OGG1基因Ser326Cys單核苷酸多態(tài)性,同時(shí)檢測(cè)血8-OHd G水平及相關(guān)生化指標(biāo)。結(jié)果兩種等位基因頻率分布無(wú)差異(χ2=2.182 P=0.140),三種基因型頻率分布差異有顯著性(χ2=12.388 P=0.002),病例組Cys/Cys基因型頻率明顯高于對(duì)照組,相對(duì)于Ser/Cys基因型,Cys/Cys基因型是發(fā)生ICM的危險(xiǎn)因素(OR=2.22,95%CI:1.40~3.28),將Ser/Ser和Ser/Cys基因型合并計(jì)算,發(fā)現(xiàn)攜帶Cys/Cys基因型者患ICM的風(fēng)險(xiǎn)增加(OR=1.92,95%CI:1.21~2.88)。病例組血8-OHd G水平明顯高于對(duì)照組(P0.05),攜帶Cys/Cys基因型的患者血8-OHd G水平明顯增高(P0.05)。結(jié)論1.h OGG1基因型與ICM存在相關(guān)性,攜帶Cys/Cys基因型的個(gè)體患ICM的風(fēng)險(xiǎn)明顯增加。2.ICM患者的血清8-OHd G水平明顯增高,攜帶h OGG1 Cys/Cys基因型的ICM患者,8-OHd G水平增高明顯。第二部分不同劑量阿托伐他汀對(duì)缺血性心肌病患者血清8-OHd G水平和病死率的影響目的比較40 mg與20 mg阿托伐他汀對(duì)ICM患者血清8-OHd G水平及病死率的影響。方法將病例組246例隨機(jī)分為兩組:阿托伐他汀(輝瑞)20 mg/d治療組124例和40 mg/d治療組122例。兩組患者接受阿托伐他汀治療的同時(shí),根據(jù)病情加用其它藥物。隨訪4年,記錄不良反應(yīng)發(fā)生率。記錄入選對(duì)象的一般臨床資料,進(jìn)行心功能分級(jí)分類,測(cè)定相關(guān)生化指標(biāo)和血清8-OHd G水平,心臟彩色多普勒檢測(cè)心功能指標(biāo)。結(jié)果4年內(nèi),治療組246例患者中有144人完成4年隨訪,其中20 mg治療組70人,40 mg治療組74人,6例中斷治療和隨訪,96例患者隨訪過(guò)程中死亡。隨訪期間,兩組藥物應(yīng)用、藥物性肝炎和橫紋肌溶解發(fā)生和其他不良反應(yīng)方面比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。兩治療組自身治療前后比較,TC、LDL-C均有明顯降低(P0.05)。40 mg治療組較20 mg治療組及40 mg治療組自身治療前后8-OHd G、hs-CRP和BNP降低明顯(P0.05)。研究開始時(shí),兩治療組間心功能各項(xiàng)指標(biāo)比較無(wú)明顯差異(P0.05),研究結(jié)束時(shí),與20 mg治療組比較,40 mg治療組治療后,E峰和E/A比值水平增高明顯,A峰水平降低明顯,差異均有顯著性(P0.05),自身治療前后比較,上述指標(biāo)差異均有顯著性(P0.05)。40 mg組總死亡率雖低于20 mg組總死亡率,但兩組間差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。同一心功能下,應(yīng)用不同劑量阿托伐他汀ICM患者的病死率比較無(wú)明顯差異(P0.05)。結(jié)論1.不同劑量阿托伐他汀的抗氧化作用存在差異,40 mg阿托伐他汀治療組8-OHd G水平降低明顯。2.阿托伐他汀治療ICM安全有效并可改善心臟舒張功能。3.同一心功能下,應(yīng)用不同劑量阿托伐他汀ICM患者的病死率無(wú)明顯差別。
[Abstract]:8- hydroxy deoxyguanine (8-OHd G) has been used as an indicator of oxidative stress and DNA oxidative damage at home and abroad. In DNA oxidative damage, 8-OHd G is the most representative oxidation damage product and sensitive biomarker, and has become a hot spot in medical research. It is involved in the damage repair of human deoxyribonucleic acid (DNA). There are more than 130 genes, and the human 8- hydroxyguanosine glucosidase (H OGG1) is one of them. The H OGG1 gene can repair the damaged DNA and specifically remove the C/G polymorphism of the 1245th base base of the seventh exon of the 8-OHd G.h OGG1 gene. The 326 bit codon or the encoded serine (Ser) or the coded cysteine (Cys) shows different enzyme activities. A number of studies have shown that oxidative damage is associated with coronary atherosclerotic heart disease (CAHD) and its complications, and the disorder of lipid metabolism is the main cause of atherosclerosis, which can cause increased activity of reactive oxygen species, form oxidative stress, cause vascular endothelial dysfunction and cardiovascular disease. The occurrence of complications. Coronary atherosclerotic heart disease (CHD), ischemic cardiomyopathy (ICM) is a special type of CHD. It is a set of syndromes with a series of clinical manifestations, including arrhythmia, heart enlargement, stiffness, heart failure and so on. Long term myocardial ischemia is more likely to induce myocardial diffuse fibrosis and ultimately damage Cardiac contraction and (or) diastolic function. As society enters the aging stage of the population, the incidence and mortality of ICM increase synchronously and rapidly. In 5 million of the people with heart failure in the United States, there are at least 3 million 500 thousand different degrees of ventricular systolic and diastolic dysfunction with the cause of ICM. At present, the pathogenesis of ICM has not been confirmed, clinically. There is a growing number of evidence that ICM is vulnerable to genetic and environmental factors. The role of DNA repair gene polymorphism and its expression and oxidative stress in ICM is becoming more and more important. Statins can significantly reduce the cardiovascular events in patients with CHD. Incidence, as an antiatherosclerotic drug, has become a two level prophylactic drug for coronary heart disease (.H OGG1 gene Ser326Cys polymorphism) and the relationship between serum 8-OHd G level and ICM, statins are antioxidation, different doses of atorvastatin have a difference in oxidation resistance and their effects on ICM patients The effect of serum 8-OHd G level and mortality is less reported. This study is divided into two parts: the 1.h OGG1 gene Ser326Cys genotype, the relationship between serum 8-OHd G level and ICM; 2. the effect of atorvastatin on 8-OHd G level and mortality in ICM patients. The relationship between the Ser326Cys genotype of G1 gene, serum level of 8-OHd G and ischemic cardiomyopathy in order to explore the relationship between the Ser326Cys genotypes of the H OGG1 gene, the relationship between the serum 8-OHd G level and ICM, and the oxidative stress mechanism of ICM. Methods a case control study was designed to select the ICM cases (case group) and the age, sex matching and hospitalization in the same period. Coronary arteriography showed 246 cases of coronary artery normal control, matched by 1:1. The single nucleotide polymorphism of H OGG1 gene Ser326Cys was detected by PCR-RFLP technique, and the serum 8-OHd G level and related biochemical indexes were detected. The frequency distribution of the two alleles was not different (x 2=2.182 P= 0.140), and the difference of frequency distribution of the three genotypes was significant Sex (x 2=12.388 P=0.002), the frequency of Cys/Cys genotype in the case group was significantly higher than that in the control group. Compared with the Ser/Cys genotype, the Cys/Cys genotype was a risk factor for ICM (OR=2.22,95%CI:1.40~3.28). The combined calculation of Ser/Ser and Ser/Cys genotypes showed that the risk of ICM was increased (OR=1.92,95%CI:1.21~2.88) with the Cys/Cys based genotype (OR=1.92,95%CI:1.21~2.88). The level of 8-OHd G in group blood was significantly higher than that in the control group (P0.05), and the level of 8-OHd G in the patients carrying Cys/Cys genotype was significantly higher (P0.05). Conclusion the OGG1 genotype of 1.h is related to ICM, and the risk of ICM is significantly increased in individuals carrying Cys/Cys genotype. The level of 8-OHd G increased significantly in M patients. Second the effect of different doses of atorvastatin on serum 8-OHd G level and mortality in patients with ischemic cardiomyopathy compared the effect of 40 mg and 20 mg atorvastatin on the serum 8-OHd G level and fatality rate of ICM patients. Methods 246 cases of case group were randomly divided into two groups: atorvastatin (Pfizer) 20 mg/d treatment group 124 cases and 122 cases of 40 mg/d treatment group. The two groups were treated with atorvastatin at the same time with other drugs. Follow up for 4 years, record the incidence of adverse reactions. Record the general clinical data of the selected subjects, classify the heart function classification, determine the related biochemical indexes and serum 8-OHd G level, color of heart is more color. In 4 years, 144 of the 246 patients in the treatment group were followed up for 4 years, including 70 in the 20 mg treatment group, 74 in the 40 mg treatment group, 6 with interruption treatment and follow-up, and 96 patients died during the follow-up period. During the follow-up period, the use of drugs, drug-induced liver inflammation and rhabdomyolysis and other adverse reactions were compared during the follow-up period. There was no statistically significant difference (P0.05). Two in the treatment group, before and after the treatment, the TC and LDL-C were significantly decreased (P0.05) in the.40 mg treatment group, the 8-OHd G, hs-CRP and BNP decreased before and after the treatment of the 20 mg group and the 40 mg treatment group. At the end, compared with the 20 mg treatment group, the level of the E peak and the E/A ratio increased significantly after the treatment in the 40 mg treatment group, and the A peak level decreased significantly (P0.05). The differences in the above indexes were significant (P0.05) the total mortality rate of the.40 mg group was lower than the total mortality of the 20 mg group, but there was no statistical difference between the two groups (P) 0.05). Under the same cardiac function, there was no significant difference in the mortality rate of the patients with different doses of atorvastatin ICM (P0.05). Conclusion 1. different doses of atorvastatin had different antioxidative effects, and the level of 8-OHd G in the 40 mg atrovastatin group was significantly lower than that of.2. atrovastatin in the treatment of ICM safe and effective and improved cardiac diastolic function.3 Under the same heart function, there was no significant difference in mortality between different doses of atorvastatin ICM.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R542.2

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