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研究生:余榮敏
研究生(外文):Jung-Min
論文名稱:DNA鍵結物對冠狀動脈繞道心臟手術病患之臨床分析研究
論文名稱(外文):Clinical Analysis and Implication of Hydrophobic DNA Adducts Levels in Patients Undergoing Coronary Artery Bypass Grafting Surgery
指導教授:蔡宗博蔡宗博引用關係李 輝
學位類別:博士
校院名稱:中山醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:124
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1. 研究背景:
根據世界衛生組織西元2005年統計資料顯示,心臟血管疾病及惡性腫瘤是人類因疾病死亡原因的首位。從流行病學研究中得知癌症與心臟血管疾病有相同的危險因子,例如抽菸。已知香煙中的多環芳香烴(polycyclic aromatic hydrocarbons;PAH)致癌物(benzo[a]pyrene;BaP)會經體內的代謝產生高活性的中間代謝物,攻擊DNA形成DNA鍵結物,造成DNA傷害,過去研究指出,心臟組織中可偵測出高量之DNA鍵結物,且似乎與動脈粥狀硬化(Atherosclerosis) 的形成有關。為了解台灣冠狀動脈心臟病 (CAD)患者心臟血管組織中DNA鍵結物含量與抽煙量之相關性,以及DNA鍵結物含量對冠狀動脈繞道心臟手術 (CABG) 病患之臨床影響。

2. 材料與方法:
自1999年11月至2002年12月,本研究隨機收集73位CABG病患。以32P-postlabeling分析CABG病患者主動脈組織中的DNA鍵結物含量,以RFLP (restriction fragment length polymorphism) 分析CYP1A1的基因型,以PCR (polymerase chain reaction) 分析GSTM1的基因型,以Reverse transcription (RT)-PCR分析CYP1A1 mRNA。在DNA鍵結物含量對CABG手術病患之臨床影響方面,則分析病患術前病史,術中相關參數,術後合併症及癒後。

3. 研究結果:
結果發現男性抽菸患者之DNA鍵結物含量 (269.97±66.52 adducts/108 nucleotides) 顯著高於男性不抽煙患者 (104.54±26.97 adducts/108 nucleotides ; P = 0.052),且DNA鍵結物含量與總抽菸量呈顯著線性正相關 (r = 0.462 ; P = 0.013)。同樣以32P-postlabeling分析DNA鍵結物含量,結果發現不吸菸女性之DNA鍵結物含量(245.67±64.88 adducts/108 nucleotides)顯著高於不吸菸男性(104.54±26.97 adducts/108 nucleotides; P = 0.034)。CYP1A1及GSTM1基因型與DNA鍵結物含量並無統計上的意義,但CYP1A1 mRNA表現似乎與抽菸量呈正相關 (r = 0.512; P = 0.043)。進一步分析DNA鍵結物含量CABG病患之臨床影響,以DNA鍵結物含量200 adducts/108 nucleotides為界線,分為二組比較。在手術前病史及心臟功能狀態中,DNA鍵結物含量(p < 0.001),慢性阻塞性肺病(p = 0.001),不穩定型心絞痛(p = 0.012),冠狀動脈(支架)整形術(p =0.033),心肌梗塞病史(p = 0.018),以及左心室射出分率(LVEF)(p = 0.049),顯示出統計上的差異。分析手術中的病人參數時,發現肺動脈平均壓有顯著的差異(p < 0.001)。在手術後的癒後方面,雖然在死亡率及術後心血管疾病再發生率上,無明顯差異。但是在手術後的併發症(p = 0.013)及感染率(p = 0.034)上,則有較高發生的機會。

4. 討論:
這些結果顯示,香菸中之致癌物可能是抽菸引起心臟血管組織形成DNA鍵結物的主要貢獻者。因此推測環境污染物對心臟血管組織同樣會造成DNA傷害,且女性對於環境致癌物有較高的感受性。本研究又發現CYP1A1及GSTM1基因型不會影響DNA鍵結物之含量,由以上之結果獲知,抽菸之台灣心臟血管組織中的DNA鍵結物形成主要與抽菸有關,但是環境致癌物在不抽菸之心臟血管組織中所形成之DNA鍵結物含量並不低於抽菸者,這結果暗示不僅抽菸是引起心臟血管疾病之主因,同時環境污染物暴露亦是重要的危險因子。且女性較男性有較高之DNA鍵結物形成,顯示環境污染物暴露可能是台灣女性罹患心臟血管疾病的主要危險因子,且較不抽菸男性有較高的罹患心臟血管疾病之危險。在DNA鍵結物含量對CABG病患之臨床影響上,DNA鍵結物對基因的傷害,發炎反應的產生,表現在感受性較高的心血管系統內皮細胞上,促進冠狀動脈粥狀硬化的產生,以及增加對CABG病患手術住院過程中,心肺功能的影響與合併症的發生。


1. Background:
CAD and cancer are the leading causes of death in the modern society. Cigarette smoking is the common risk factor of these two diseases. Therefore, it is conceivable that atherosclerosis and carcinogenesis may share a common genotoxic mechanism of exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs). In our previous studies, using 32P-postlabeling assay to detect theDNA adducts level in lung cancer patients, we found no definite correlation between smoking amount and the DNA adducts level. However, The DNA adducts level of female lung cancer was higher than male in non-smoking patients. This suggested a higher susceptibility to DNA damage in female than male. Lung is the first defense line for the environmental exogenous compounds. Nevertheless, several reports showed that the DNA adducts level of cardiovascular system is higher than lung and other body tissues. In this study, we analyzed the more vulnerable tissue- aorta, to determine the correlation between DNA adducts level and gender; smoking amount; polymorphisms and expression of metabolic enzymes in the CAD patients.
Recent research has shown that inflammation plays a key role in CAD and other manifestations of atherosclerosis. These studies highlight the role of inflammation in the pathogenesis of atherosclerotic CAD. It will recount the evidence that atherosclerosis, the main cause of CAD, is an inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, propagate, and activate lesions in the arterial tree. Inflammation also participates in the local, myocardial, and systemic complications of atherosclerosis. Therefore, It is reasonable to assume that the PAH-DNA adducts level may influence various physiological parameters to play a role in clinical coronary artery bypass grafting (CABG) patients’ perioperative courses. We analyze CAD patients’ characteristics and perioperative parameters to clarify the correlations between DNA adducts levels and clinical manifestations in the CABG patients

2. Materials and methods:
From Nov.1999 to Dec. 2002, 73 pieces of aorta tissue were collected randomly from CAD patients during CABG in Chung Shan Medical University Hospital. The specimens were stored at temperature -80℃ immediately after harvesting from patients. Due to very limited specimens available for laboratory processing, 44 specimens were analyzed for PAH-adducts levels, 30 for polymorphisms of genotype CYP1A1 and GSTM1, and 29 for CYP1A1 mRNA expression levels.
Analysis of hydrophobic DNA adducts was performed by 32P-postlabelling method. The analysis of CYP1A1 genetic polymorphism was performed by RFLP (restriction fragment length polymorphism) method. The analysis of GSTM1 genetic polymorphism was performed by the specific primer and the GSTM1 PCR (polymerase chain reaction) product. Reverse transcription (RT)-PCR was used to analyze the CYP1A1 mRNA. With retrospective review of the CABG patients charts, Further analyses of patients’ characteristics and perioperative parameters was performed to clarify the correlations between DNA adducts levels and clinical manifestations in the CABG patients.

3. Results:
32P-Psotlabeling assay data showed that a linear relationship (r = 0.462 ; P = 0.013) was observed between DNA adducts levels and total cigarettes smoked in CABG patients. DNA adducts levels in non-smoking female (245.67±64.88 adducts/108 nucleotides) CABG patients were also found significantly higher than those of male (104.54±26.97 adducts/108 nucleotides; P = 0.034). The genetic polymorphisms of CYP1A1 and GSTM1 in the aorta tissue were not associated with PAH-DNA adducts levels by PCR-RFLP data, but the CYP1A1 mRNA levels by RT-PCR were found correlated with the cigarette consumptions (r = 0.512; P = 0.043). For the correlation between DNA addults levels and CABG, The patients were grouped according to their DNA adducts levels by 200 DNA adducts/108 nucleotides (group I < 200, group II ≧200). Among the data of pre-operative patient’s demography and cardiac status: the DNA adducts values (p < 0.001), chronic obstructive pulmonary disease (p = 0.001), percutaneous transluminal coronary angioplasty or stenting (p =0.033), unstable angina (p = 0.012), myocardial infarction history (p = 0.018) and left ventricular ejection fraction (p = 0.049) showed statistically significant different between the two groups. The pulmonary artery mean pressure (p < 0.001) was significant higher in group II among the intrao-perative parameters. Among the follow up of post-operative patient’s events: complications (p = 0.013) and infections (p = 0.034) were also noted with statistical significant higher in group II.

4. Discussion:
Compared DNA adducts levels between CAD and lung cancer patients, more than 3 folds were found in aorta tissues than lung tissue. High susceptibility to DNA damage can be considered in cardiovascular system. These results suggested that cigarette smoking may be responsible for the adducts levels in CAD patients. In addition, environmental carcinogen exposure may play a more important role in DNA adducts formation in non-smoking female CAD patients than in non-smoking male patients.
These results implicate that, atherosclerotic inflammatory process in CAD patients were manifested in local, myocardium, and systemic responses. The DNA adducts level are correlated with myocardial infarction attack risk and pulmonary vascular dysfunction. The genotoxic mechanism of hydrophobic DNA adducts is more possible to be expressed as inflammation process in the systemic and pulmonary endothelium of blood vessels. This effect can be further observed in the peri-operative complications and infections of patients undergoing CABG surgery. More detailed researches for mechanism of DNA adducts induced injury, will be necessary to establish a biological model to seek more perfect biomarks for prevention, treatment, follow-up of CAD patients and improvement of surgical results of CABG patients.


CONTENTS
ABSTRACT 4
1. LITERATURE REVIEW AND BACKGOUND 7
1.1. Coronary Artery Disease (CAD) and Atherosclerosis 7 1.1.1. The Pathophysiology of Chronic CAD 7
1.1.1.1. Lesion Formation 7
1.1.1.2. The Therapy of Chronic CAD: Perspective for the Future 10
1.1.2. The Pathophysiology of Acute Coronary Syndromes (ACS) 12
1.1.2.1. Lesion Formation 12
1.1.2.2. Treatment of the ACS: Perspective on the Future 15
1.1.3. Endothelium and Reactive Oxygen Species 18
1.2. DNA Adducts and Atherosclerosis 19
1.3. Coronary Artery Bypass Grafting (CABG) Surgery for CAD 23
1.3.1. For Prognosis 23
1.3.2. For Symptom Relief 24
1.4. Motivation and Purpose 25
2. PATIENTS, MATERIALS AND METHODS 27
2.1. Specimens Collection 27
2.2. Reagents 27
2.2.1. DNA and RNA Extraction 27
2.2.2. Analysis of Hydrophobic DNA -Adducts: 32P-postlabelling 28
2.2.3. CYP1A1 and GSTM1 Genetic Polymorphism Analysis 28
2.2.4. The RT-PCR Analysis of CYP1A1 28
2.3. DNA and RNA Extraction from Aorta Tissue 29
2.4. Analysis of Hydrophobic DNA -Adducts: 32P-postlabelling 34
2.5. CYP1A1 Genetic Polymorphism Analysis 35
2.6. GSTM1 Genetic Polymorphism Analysis 36
2.7. The RT-PCR Analysis of CYP1A1 36
2.8. Patients and Clinical Parameters 37
2.9. Statistical Analysis 38
3. RESULTS 41
3.1. The Correlation between DNA Adducts Levels and Cigarettes
Consumption 41
3.2. The Correlation between DNA Adducts Levels and CYP1A1, GSTM1 Genotypes 42
3.3. The Correlation between CYP1A1 Gene Expression and Cigarettes Consumption 43
3.4. Gender and Environmental Effect on DNA Adducts Levels and CYP1A1 Expression for Non-smoking CABG Patients 43
3.5. Clinical Results of CABG Patients and DNA Adducts Levels 43
4. DISCUSSION 47
4.1. The Correlation between DNA Adducts Levels and Cigarettes
Consumption 47
4.2. The Correlation between DNA Adducts Levels and CYP1A1, GSTM1 Genotypes 49
4.3. The Correlation between CYP1A1 Gene Expression and Cigarettes
Consumption 51
4.4. Gender and Environmental Effect on DNA Adducts Levels and CYP1A1 Expression for Non-smoking CABG Patients 54
4.5. Clinical Analysis of CABG Patients and DNA Adducts Levels 57
5. CONCLUSIONS 61
6. REFERENCES 63
7. TABALES AND FIGURES 81
8. APPENDICES 99
9. 中文摘要 122
ABSTRACT


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