臺灣博碩士論文加值系統

中 文 摘 要
國人的主要死亡原因之一為心臟血管疾病及腦血管疾病。心臟血管疾病或腦血管疾病，從致病機轉的角度分析，與慢性次臨床性發炎及脂肪細胞激素作用有所關聯。代謝症候群視為多重代謝障礙群集發生在同一人身上，代謝症候群有較高之大小血管疾病之發生率及死亡率，但臨床報告上仍與多個因素有相關。研究指出週邊血液白血球數目與冠狀動脈嚴重程度，心臟血管疾病與腦血管疾病的死亡率等皆有相關，而且這些相關白血球數目在正常範圍內就可以發現其統計上的意義。顯示週邊血液白血球數目，的確是缺血性心臟病的一個重要危險因子。週邊血液的白血球包含有多型核白血球、單核球、淋巴球和其他白血球等組成。每一種白血球都有其特殊之抗發炎及免疫的功能，另外也有證據指出，各類的白血球在動脈硬化的慢性發炎中也有其扮演的角色。由於過去研究著重於總白血球數目與代謝症候群和動脈硬化等疾病之相關研究。但是在白血球或各分類白血球與動脈硬化的病理機轉仍不甚清楚，而且文獻上對於分析各分類白血球與缺血性動脈硬化疾病的報告仍然是相當的少。
有相當多之研究報告指出，脂肪細胞所分泌的細胞激素在調整胰島素敏感度的過程中，以及在引起心臟血管疾病，胰島素阻抗性、糖尿病、血脂不良、發炎、動脈硬化的致病機轉中扮演著重要的角色。然而脂肪細胞誘導胰島素阻抗性的機轉、以及脂肪細胞激素在糖尿病的致病成因仍然存在著許多的未知。
因此本研究假設1) 代謝症候群與國人缺血性冠狀動脈疾病有關，可以早期預測缺血性冠狀動脈疾病之發生。2)週邊血液白血球如各分類白血球與代謝症候群，及各組成成分和缺血性動脈硬化的血管疾病有關聯。3) 脂肪細胞激素與國人代謝症候群及心臟血管疾病之關係密切。
本研究乃針對假設，進行一橫切面相關性研究觀察，研究結果發現：
1. 冠狀動脈疾病很難早期診斷，病人是否合併代謝症候群不會影響冠狀動脈疾病發生率，但是國人糖尿病合併冠狀動脈疾病與白蛋白尿是否發生有關。
2. 週邊血液總白血球、中性球、單核球、及淋巴球數目在糖尿病合併心血管疾病病人有較無心血管疾病者顯著增加。
3. 週邊血液總白血球、中性球、單核球、及淋巴球數目與代謝症候群之血壓、血糖、血脂、及肥胖有關聯性。
4. 週邊血液總白血球、中性球、單核球、及淋巴球數目及代謝症候群與心臟血管疾病發生有密切關聯。
5. 前瞻性觀察研究更發現基礎週邊血液總白血球、中性球、單核球、及淋巴球數目及中性球與淋巴球的比例與糖尿病在4年內是否發生心臟血管疾病有關，為心臟血管疾病發生之危險因子。
6. 在基因方面，發現CYP2J2基因多型性變化與年齡層小於等於65歲與吸菸者對心臟血管疾病有顯著之關連。而ABCA 1 R219K多型性變化與心臟血管疾病與脂質代謝的情形，並沒有相關性。這樣的結果也發現在日本與美國最近的研究成果。
因此，研究之結果將可對冠狀動脈疾病之可能遺傳因素及機轉有進一步之探討，提供預防及治療冠狀動脈疾病之基礎研究資料。

Abstract
At the beginning of the 21st century, cardiovascular disease accounts for nearly half of all death in the developed world, it is the top one that ranks in the mortality in the western countries. In Taiwan, it ranks the number two in the mortality rate in 2004. By 2020, it is predicted that cardiovascular disease will claim 25 million lives annually and that coronary artery disease (CAD) will surpass infectious disease as the world’s number one leading cause of death and disability. As the trend is spreading and shifting to the developing countries. Specially in Taiwan, it is a red light to warn us to try every effort to combat this challenge of cardiovascular disease and to prevent it becoming worse.
There is increasing evidences that subclinical inflammation, metabolic syndrome, and adipocytokines play a central role in cardiovascular disease, obesity, glucose intolerance, type 2 diabetes mellitus (T2DM), and metabolic syndrome. The traditional risk factors are often congregated in a individual as metabolic syndrome, such as hyperstension, hyperglycemia, dyslipidemia, and obesity, and these risk factors make the atherosclerotic change to become worse and even ruptured of the blood vessels. Subjects with metabolic syndrome are known to have increased risk of cardiovascular disease, while the role of metabolic syndrome in the prediction of ischemic coronary artery disease still inconclusive.
There is a significant positive association between the white blood cells counts with the severity of carotid atherosclerosis, cardiovascular disease, and mortality from coronary heart and cerebrovascular diseases even within the normal range. The relationship between leukocyte counts and ischemic vascular diseases has been observed in prospective and retrospective cohort studies, as well as in case-control studies, and persists after adjustment for multiple risk factors, including smoking. There are so many abundant evidences that relative leukocytosis associated with high blood pressure, obesity, high serum triglycerides, and metabolic syndrome (MetS). Thus, there is a reason to believe that leukocyte is not simply a marker of chronic inflammation, but directly contributes to the pathogenesis of MetS and atherosclerosis.
The peripheral circulating white cells compose of polymorphonuclear cells, monocytes and lymphocytes, each cell possess unique biological function and contributes to inflammation and immune response. There are evidences indicate that all the differential white cells involved in the pathogenesis of chronic inflammation as the genesis of atherosclerosis. The causal relevance of the association between peripheral leukocyte and MetS or atherosclerosis, however, remains uncertain because it is not clear to what extent the association of the total or subtypes of leukocyte counts with atherosclerosis risk merely reflects the impacts of established risk factors, the extent of existing atherosclerosis, or both and relative few studies have examined counts of specific types of leukocyte in association with specific components of MetS and atherosclerosis.
Cytochrome P450 Epoxygenase (CYP 2J2) was found to influence the risk of the coronary artery disease. The procedures depend upon the CYP 2J2 gene expression which is relative to the productions of epoxyeicosatrienoic acid (EETs) and have been found the functions of anti-inflammation, anti-thrombotic, anti-oxidative, anti-apoptosistic effects and dilation of smooth muscle cells. There is also well known that the inflammation culprit is the lipoprotein metabolisms and genetic variations in gene regulating lipid metabolism affects the plasma lipid levels and correlated to the risk of cardiovascular disease. ATP-binding cassette transporter 1 (ABCA 1) have shown to affect the plasma HDL-C level. The contribution to us is promoting the “Efflux” of LDL-C from the intracellular and peripheral tissue and macrophage to apolipoprotein receptor and secretion with bile outside the human body.
The rationale of the present studies were 1) the components of metabolic syndrome are related to the ischemic coronary artery disease could be the indicator of presence of coronary artery disease. 2) the compartments of peripheral leukocyte, especially neutrophil, lymphocyte, and monocyte counts are related to the components of MetS and atherosclerotic diseases. 3) The percentage (%) of lymphocytes is the accessible prognosis maker in patients with CABG. 4) Genetic variations of CYP 2J2 and ABCA1 genes are related to the components of metabolic syndrome and cardiovascular disease. To clarify these, we conducted a cross-sectional observational study in Chinese with type 2 diabetes mellitus to observe the factors of chronic inflammation in the association with ischemic cardiovascular disease in a regional hospital.
Subjects with T2DM who enrolled in a diabetes disease management program were studied. The definition and criteria of MetS we used were modified from those outlined by the criteria of WHO and NCEP-ATP III.
The major findings are:
1) A considerable proportion of T2DM patients have silent CAD. A diabetic patient with incipient or overt nephropathy should be examined for the presence of CAD. The definition of metabolic syndrome may be modified for early detection of CAD in patients with T2DM.
2) Peripheral total and differential leukocyte counts are related to the risk of ischemic cardiovascular disease in patients with type 2 diabetes mellitus.
3) Peripheral total and differential leukocyte counts are related to the componenets of metabolic syndrome.
4) Peripheral toal and differential leukocyte counts are associated with risk of ischemic cardiovascular disease .
5) Peripheral total and differential leukocyte counts are related to the mortality of patients receiving coronary artery bypass surgery.
6) Genetic variations of CYP2J2 gene is associated with cardiovascular diseases in the age less than 65-year-old and smoking patients are increased the risk of the CAD.
In Conclusions：Our results show that the silent CAD in T2DM patients, the micro/macro albuminuria is the risk factor. And metabolic syndrome, peripheral total and differential leukocyte counts and leukocytes/lymphocytes ratio in T2DM patients and genetic variations of CYP 2J2 genetic polymorphisms in the age less than 65-year-old and smoking patients are increased the risk of cardiovascular disease. But the ABCA1 R219 genetic polymorphisms didn’t relate to the plasma HDL-C levels and severity of CAD in our study and the same result as Japanese’s.

目 錄

致謝 9
中文摘要 10
英文摘要(Abstract) 13
關鍵字 18
縮寫表 19
第一章 緒論、文獻探討與研究目的 20
第一節、研究背景 21
第二節、冠狀動脈疾病 23
第三節、代謝症候群與冠狀動脈疾病 29
第四節、週邊血液白血球數與冠狀動脈疾病 32
第五節、心臟生化指標 34
第六節、CYP 2J2與ABCA1基因變異與冠狀動脈疾病 39
第七節、研究目的 46
第二章 無症狀的冠狀動脈疾病、代謝症候群與第二型糖尿病的關係 49
第一節、前言 50
第二節、材料與方法 53


第三節、結果 57
第四節、討論 59
圖與表
Figure 1 Diagnostic procedure of silent coronary artery disease in patients with type 2 diabetes mellitus 65
Table 1 Clinical characteristics of subjects with type 2 diabetes mellitus 66
Table 2 Prevalence of metabolic syndrome, types of diabetic treatment, and smoking status in patients studied 67
Table 3 Correlation and logistic regression analysis of silent coronary artery disease with clinical characteristics in subjects studied 68
第三章 週邊血液總白血球與各分類白血球數與缺血性冠狀動脈疾病在糖尿病人的研究 69
第一節、前言 70
第二節、材料與方法 72


第三節、結果 78
第四節、討論 81
圖與表
Table 1 Clinical characteristics of subjects with type 2 diabetes mellitus grouped by the number of components of metabolic syndrome 87
Table 2 Prevalence of metabolic syndrome, cerebrovascular and coronary artery disease categorized according to leukocyte counts quartiles 88
Figure 1 Univariate and multivariate analysis of quartile 4 versus 1 white blood cell subtypes on metabolic syndrome 89
Figure 2 Comparison of the receiver operating characteristic curves with specification of area under curve in risk of metabolic syndrome and
ischemic vascular disease with leukocyte counts 91


第四章 心臟生化指標：白血球與其分類對心臟冠狀動脈繞
道手術預後的分析 92
第一節、前言 93
第二節、材料與方法 95
第三節、結果 98
第四節、討論 99
圖與表
Table 1 Clinical characteristics of subjects coronary arterial disease 101
Table 2 Spearman correlation analysis of peripheral total and differential leukocyte count 102
Table 3 Analysis peripheral total and differential leukocyte counts vs. each operation day 103
Table 4 Total WBC vs. each leukocyte counts by each day 104
Table 5 Association peripheral total and differential leukocyte counts and EF and Killip 105


Table 6 Analysis peripheral total and differential
leukocyte counts by Killips status 106
Figure 1 Total WBC vs. each leukocyte counts by each day 107
第五章 基因CYP 2J2的多型性變化對心臟冠狀動脈疾病危險性的分析 108
第一節、前言 109
第二節、材料與方法 111
第三節、結果 113
第四節、討論 115
圖與表
圖一、CYP2J2 Promotor DNA序列和Alu I限制酶辨識切割位點 119
圖二、CYP2J2 Alu I 電泳結果 120
Table 1 Clinical characteristics of study subjects 121
Table 2 CYP2J2 G-50T genotypes and allele frequencies of CAD patients and controls 122
Table 3 Comparison of CYP2J2 genotypes in patients


studied stratified by age groups 123
Table 4 Comparison of CYP2J2 genotypes in patients studied stratified by age groups (smoker) 124
Table 5 Comparison of CYP2J2 genotypes in patients studied stratified by age groups (non-smoker) 125
第六章 基因ABCA1 R219K 的多型性變化對心臟冠狀動脈疾病危險性的分析 126
第一節、前言 127
第二節、材料與方法 132
第三節、結果 134
第四節、討論 135
圖與表
Figure 1 Macrophage and foam cells express growth factors and proteinases 129
Figure 2 HDL and reverse cholesterol transport 129
Figure 3 HDL metabolism in Tangier disease 130
Figure 4 ABC A1基因 SNP位置 130


Figure 5 ABCA1 R219K 基因分析與電泳結果 133
Figure 6 Model for gene-environment interaction 136
表一、對照組和冠狀動脈心臟疾病組的臨床資料分析 137
表二、在男性對照組和冠狀動脈心臟疾病組的臨床資料分析 138
表三、在女性對照組和冠狀動脈心臟疾病組的臨床資料分析 139
表四、男性冠狀動脈心臟疾病組ABCA1 R219K各基因型與臨床資料比較 140
表五、女性冠狀動脈心臟疾病組ABCA1 R219K各基因型與臨床資料比較 141
表六、男性健康對照組ABCA1 R219K各基因型與臨床資料比較 142
表七、女性健康對照組ABCA1 R219K各基因型與臨床資料比較 143
第七章 總結論 144


參考文獻 149
附件
已刊登之論文 201

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