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研究生:連立明
研究生(外文):Li-Ming Lien
論文名稱:臺灣急性中風照護品質及頸動脈硬化之創新生物標記-血中活化型MMP3
論文名稱(外文):Acute Stroke Care Quality in Taiwan and a Novel Biomarker for Carotid Atherosclerosis -blood active MMP3
指導教授:徐國基徐國基引用關係
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:臨床醫學研究所
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:2010
畢業學年度:99
語文別:英文
論文頁數:133
中文關鍵詞:1
外文關鍵詞:1
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中風是造成國人死亡與成人殘障的首因,有鑑於此,自2006年5月1日開始建立全台灣的中風登錄系統,此登錄系統主要為登錄新發生中風患者的資料,以建立中風患者的描述型資料及管控中風患者的照護品質。儘管各國間健康經濟的情形有所不同,如何改善中風照護的品質仍是全球的優先議題,根據美國心臟學會/中風學會(AHA)對於中風治療的準則依循計畫(GWTG-Stroke),顯示美國790家學術及社區醫院在依據此準則後顯著地改善中風照護品質,然而,GWTG-Stroke是否可類推到不同國家及經濟狀態仍待商榷。台灣中風登錄系統(Taiwan Stroke registry, TSR)利用2006年至2008年登錄的30,599筆中風資料來評估GWTG-Stroke是否可適用於台灣。TSR為衛生署國民健康局所補助39家醫學中心及地區級以上醫院所建立,涵蓋北、中、南、東四區,自2006年5月1日開始,39家醫院的新發生中風個案資料鍵入以網頁建置的台灣中風登錄系統,每一位中風患者登錄資料會以電腦自動進行邏輯確認並請CRO公司進行登錄資料之稽核,利用四個步驟的品質管控以確保登錄資料的可信度,以確保資料登錄的完整性。並以GWTG-Stroke的5項品質指標及1項安全指標來評估TSR中風照護的品質。截至2008年7月31日止,共計有30,599筆中風事件資料登錄於TSR中,其中主要為缺血性中風(74.0%),TOAST分類如下:大血管粥狀硬化(27.7%)、小洞性梗塞(37.7 %)、心源性栓塞(10.9 %)、特殊病因中風(1.5 %)及病因未決中風(22.2 %),這些缺血性中風的患者有23.2%為顱內血管狹窄,5.4%為顱外,僅有1.5%的缺血性中風患者有接受組織型胞漿素活化劑(tPA)的治療,利用描述型資料及比較GWTG-Stroke與TSR結果的表格顯示,發現有2項指標(早期及出院給予抗血栓劑)接近GWTG-Stroke標準,其餘3項指標(靜脈注射組織胞漿素原活化劑、心房纖維顫動患者給予抗凝血劑、降血脂藥物)及1項安全指標均落後於GWTG-Stroke。另一項GWTG-Stroke的重要指標:給予深部靜脈栓塞患者抗凝血劑,則因種族因素而不適用。
急性缺血性中風患者也可能罹患周邊動脈疾病(PAD) 。近來有研究顯示不論是一般族群或是急性缺血性中風患者,低踝臂指數(ABI) 可提高預測未來心血管疾病的發生率,但少有研究針對中風患者罹患周邊動脈疾病(PAD)的盛行率及其相關危險因子做探討,故我們建立世代以研究針對急性缺血性中風患者其罹患PAD的盛行率及相關危險因子做評估,進一步探討PAD對急性缺血性中風之短期預後是否有所影響。PAD中風研究(PAD-Stroke Study)為一前瞻性研究,登錄50歲以上的急性缺血性中風患者,這些患者來自台灣20家醫院,於進入研究時均接受ABI的測量,PAD的定義為ABI <0.9,利用年齡及性別確認急性缺血性中風患者PAD的盛行率及其相關危險因子,患者出院時雷氏修正量表(mRS)分數達3分以上即定義為不良短期預後,在回歸分析時探討那些危險因子將與不良短期預後結合。PAD中風研究總計有1888位患者參與(60.2%為男性;平均年齡為70.2±10.3歲),急性缺血性中風患者PAD盛行率為22.6% (95%CI=20.8%-24.6%),女性中風患者PAD盛行率高於男性,和PAD有關的危險因子包括年齡、性別(女性)、曾有過中風、心臟疾病、尿毒症、頸部血管狹窄、顱內血管狹窄、高密度脂蛋白偏低及目前有抽菸習慣。而調整年齡、性別及一開始的NIHSS分數後,發現有PAD之中風患者不良短期預後的危險性較高,達統計上顯著意義(OR=1.5, 95% CI = 1.1-2.0, p=0.01)。
基質金屬蛋白酶(MMPs)在血管粥狀硬化引起的發炎反應中所扮演的角色近來常被探討,然而,血中MMPs的濃度與頸部動脈粥狀硬化間的關係仍不明朗,所以我們針對台灣社區健康族群評估其血中活化態的MMPs和這些MMPs常見啟動子位置的基因型與頸部斑塊形態的程度以及頸動脈內膜中層厚度間的相關性。社區健康族群研究為2005年時收集了433位自願的健康參與者以健康檢查的方式研究,並測量這些參與者血中的幾項指標,包括利用免疫比濁法測得高敏感度C反應蛋白及利用酵素免疫分析法(ELISA) 測得活化態的MMP-1、MMP-3和MMP-9。斑塊指數(PS)為利用高解析度B模式的頸動脈超音波來測量外頸動脈(ECCA)血管粥狀硬化的程度及嚴重度,PS為頸動脈每個區段的斑塊程度加總後計算,評估位於MMP-1、MMP-3及 MMP-9啟動子位置的基因型和血中活化態的MMPs與頸部動脈血管粥狀硬化的相關性。共收集了433位健康參與者,以PS分為三組:第1組(PS=0, 53.7±10.7 歲, n=238)、第2組(PS=1-3, 59.6±8.3歲, n=154) 及第3組(PS≥4, 68.1±9.7歲, n=41)。結果顯示血中活化態的MMP-3與PS有顯著的劑量效應關係,在這些生化指標中,僅血中活化態MMP-3與PS有關(第1組血中MMP-3 濃度: 5.2±3.3ng/ml, 第2組:6.6±3.9ng/ml以及第3組:9.3±5.8ng/ml; p<0.0001),血中活化態MMP-3及總MMP-3和PS均有顯著的高度相關(p<0.0001),在多類別邏輯斯迴歸分析中顯示血中活化態的MMP-3與PS有關(OR, 1.4; 95% CI, 1.1-1.8; p=0.0038),但與IMT無關,在基因型部份,MMP-3 -1612 6A6A 基因型與PS無關,部分原因可能來自於89%的人MMP-3基因都是6A6A基因型,而MMP-3 -1612 6A6A 基因型與較高的血中活化態MMP-3有關,若MMP-3基因型為6A6A且有頸部斑塊,則血中活化態MMP-3濃度顯著高於其他人。
設置良好的大型中風登錄系統,如台灣中風登錄系統,可提供台灣地區中風患者重要且正確的臨床資料,詳細分析所收集的資料將可做為預防中風及照護的有效策略參考。GWTG-Stroke品質指標,經種族因素修改後,可以是全球性的標準,跨越國家及經濟狀態來評估中風照護品質,以提高品質表現,GWTG-Stroke可納入國家層級推動的中風登錄。PAD在中風患者中並不少見,尤其在老年人、女性、心臟病患者及腦部或頸部大血管疾病患者更為常見,罹患PAD的急性缺血性中風患者在出院時更易有不良短期預後的結果。針對台灣社區健康族群的研究結果顯示,血中活化態的MMP-3與PS有關但與IMT無關,MMP-3 -1612位點為6A6A者與較高血中活化態的MMP-3濃度有關。

Stroke is a leading cause of death and adult disability in Taiwan. A nation-wide stroke registry has been ongoing since May 1, 2006 to collect information and data on patients with new onset of stroke to establish demographic profiles of stroke patients and to monitor quality of stroke prevention and care. Improving quality of stroke care is a global priority despite the diverse healthcare economies across nations. The AHA/ASA Get With the Guidelines-Stroke program (GWTG-Stroke) has shown significant impact in improving quality of stroke care in 790 US academic and community hospitals with broad implications in the country. The generalizability of GWTG-Stroke across national and economic boundaries remains to be tested. The Taiwan Stroke Registry (TSR) with 30,599 stroke admissions between 2006 and 2008 was used to assess the applicability of GWTG-Stroke in Taiwan. Starting May 1, 2006, a web-based Taiwan Stroke Registry system has been in operation for entry of new stroke patients by 39 participating hospitals. Data have been collected prospectively; starting with the admission of new stroke patients. Logic check for typo and inconsistency and web-based and on-site audits by a contract research organization independent of the Registry investigators and participating hospitals have been employed to ensure accuracy of entered data. TSR, sponsored by Taiwan Department of Health engaging 39 academic and community hospitals, covers broadly the entire country with 4 steps of quality control to ensure reliability of entered data. Five GWTG-Stroke performance measures and 1 safety indicator are applied to assess TSR quality of stroke care. By July 31, 2008, 30599 stroke events have been entered into the Registry. The majority had ischemic stroke (74.0%). TOAST classification shows the following distributions: large artery artherosclerosis (27.7%), small vessel occlusion (37.7 %), cardioembolism (10.9 %), specific etiology (1.5 %) and undetermined etiology (22.2 %). Among patients with ischemic stroke, intracranial stenosis constitute 23.2% and extracranial 5.4%. Only 1.5% of ischemic stroke patients received tPA. Demographic and outcome figures are comparable between GWTG-Stroke and TSR. Two indicators (early and discharge antithrombotics) are close to GWTG-Stroke standards while 3 other (IV tPA, anticoagulation for atrial fibrillation, lipid-lowering medication) and 1 safety indicator fall behind. Anticoagulants for deep vein thrombosis, important in GWTG-Stroke, is not applicable because of ethnic factors.
Recent evidence suggests that a low ankle-brachial index (ABI) can improve the accuracy of cardiovascular prediction not only in general populations but also in patients with acute ischemic stroke. However, studies on the prevalence and risk factors of peripheral artery disease (PAD) in acute ischemic stroke patients were rare. This cohort study aimed to determine the prevalence and risk factors of PAD, and to investigate if PAD could affect the short-term outcome in patients with acute ischemic stroke. Patients were consecutively recruited from the PAD-Stroke Study, a prospective registry for admitted acute ischemic stroke cases aged 50 years or older with ABI measurements from 20 hospitals in Taiwan. PAD was defined as the ABI &lt;0.9. The prevalence and its risk factors of PAD in acute ischemic stroke were determined by age and gender. A score of 3 or above on the modified Rankin Scale at discharge was considered as an unfavorable outcome. A regression analysis of factors that might bear weight in determining outcome was made. Of 1888 patients (male, 60.2%; mean age, 70.2±10.3 years), the prevalence of PAD in patients with acute ischemic stroke was 22.6% (95% CI=20.8%-24.6%). Female patients showed a higher prevalence of PAD than male patients (28.3% vs. 18.6%). The factors associated with PAD included age, female gender, an old stroke, heart disease, uremia, carotid stenosis, intracranial stenosis, low high-density lipoprotein cholesterol, and a current smoking habit. An unfavorable outcome at discharge was higher in patients coexisting PAD (OR=1.5, 95% CI = 1.1-2.0, p=0.01) after adjusting for age, gender, and initial NIHSS score.
The involvement of matrix metalloproteinases (MMPs) in atherosclerotic inflammatory response has recently been suggested. However, the relationship between blood levels of MMPs and the extent of carotid atherosclerosis remains uncertain. We assessed blood levels of active MMPs in relation to the extent of carotid plaque formation and intima-media thickness (IMT) in a community population in Taiwan. In this study, we investigated whether the circulating active MMPs and their common promoter low- and high-activity genotypes are related to the extent of carotid plaque formation and intima-media thickness (IMT) in a community population in Taiwan. A total of 433 apparent healthy subjects participating a health screening in 2005 were enrolled. Blood levels of high sensitivity C-reactive protein (hs-CRP), and activity of MMP-1, MMP-3 and MMP-9 were performed by an immunoturbidimetric method and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. Plaque score (PS) was measured by high-resolution B-mode ultrasonography and was used to express the extent and severity of extracranial carotid artery (ECCA) atherosclerosis. The PS was computed by summing up the plaque grades at each segment of the ECCA. We assessed whether the common MMP-1, MMP-3, and MMP-9 promoter low- and high-activity genotypes are related to the circulating active MMPs or carotid atherosclerosis. A total of 433 study subjects were separated into 3 groups based on PS: group 1 (PS=0, 53.7±10.7 years, n=238), group2 (PS=1 to 3, 59.6±8.3 years, n=154) and group 3 (PS≥4, 68.1±9.7 years, n=41). A significant dose-response relationship was found between the blood active MMP-3 and PS. Among the biomarkers, only the activity of MMP-3 was associated with PS (MMP3 level in group 1: 5.2±3.3ng/ml, group 2: 6.6±3.9ng/ml, and group 3: 9.3±5.8ng/ml; p&lt;0.0001). Blood levels of active and total MMP-3 bear a highly significant relationship with PS (both p&lt;0.0001). A multiple ordinal logistic regression analysis revealed that blood levels of active MMP-3 are correlated with PS (OR, 1.4; 95% CI, 1.1 to 1.8; p=0.0038) but not IMT. There is no association between MMP-3 -1612 6A6A genotype and PS, partly because 89% subjects having 6A6A genotype of MMP-3 gene. MMP-3 -1612 6A6A genotype is associated with higher level of blood active MMP3. The blood active MMP-3 in subjects of MMP-3 -1612 6A6A genotype with carotid plaque was significantly higher than that of others.
A well-conducted stroke registry with large sample size as Taiwan Stroke Registry can provide important and accurate data on clinical profiles of stroke in this particular area and ethnic group. Detailed analyses of the data collected will offer insights into developing effective strategies for stroke prevention and care. Results suggest GWTG-Stroke performance measures, with modification for ethnic factors, can be global standards across national and economic boundaries for assessing quality of stroke care and improving performance. GWTG-Stroke can be incorporated into ongoing stroke registries across nations. PAD in acute ischemic stroke patients is not uncommon and is more frequent among older patients, female patients, those with heart disease, and those with either cerebral or cervical large artery disease. Acute ischemic stroke patients suffering from PAD are prone to have an unfavorable functional outcome at discharge. Blood levels of active MMP-3 are associated with the extent of carotid atherosclerosis based on PS but not IMT in this community population in Taiwan and the MMP-3 -1612 6A6A genotype is associated with higher levels of blood active MMP-3.


中文摘要 1
Introduction 8
1. Taiwan Stroke Registry 8
2. Prevalence and Risk Factors of Lower-Extremity Peripheral Arterial Disease in Patients With Acute Ischemic Stroke 11
3. Association of blood active matrix metalloproteinase-3 with carotid plaque score from a community population in Taiwan 12
Materials and Methods 16
1. Taiwan Stroke Registry 16
2. Prevalence and Risk Factors of Lower-Extremity Peripheral Arterial Disease in Patients With Acute Ischemic Stroke 23
3. Association of blood active matrix metalloproteinase-3 with carotid plaque score from a community population in Taiwan 26
Results 31
1. Taiwan Stroke Registry 31
2. Prevalence and Risk Factors of Lower-Extremity Peripheral Arterial Disease in Patients With Acute Ischemic Stroke 35
3. Association of blood active matrix metalloproteinase-3 with carotid plaque score from a community population in Taiwan 37
Discussion 40
1. Taiwan Stroke Registry 40
2. Prevalence and Risk Factors of Lower-Extremity Peripheral Arterial Disease in Patients With Acute Ischemic Stroke 50
3. Association of blood active matrix metalloproteinase-3 with carotid plaque score from a community population in Taiwan 53
Conclusions and Perspectives 62
References 64
Figures 81
Figure 1. Locations of participating hospitals in the Taiwan Stroke Registry 81
Figure 2. Blood active MMP-3 levels between subjects with or without carotid plaque based on different genotypes. 82
Figure 3. The association of blood active MMP-3 and carotid atherosclerosis with the influence from MMP-3 -1612 6A6A genotype and risk factors 83
Tables 84
Table 1. The items and definitions of risk factors in Taiwan Stroke Registry form 84
Table2. Distribution of stroke types in Taiwan Stroke Registry 85
Table 3. Key variables in different stroke types in Taiwan Stroke Registry 86
Table 4. Comparison of the risk factors in different stroke types 87
Table 5. Performance measures in acute stroke care and prevention from 2006 to 2008 in the Taiwan Stroke Registry 88
Table 6. Outcomes based on performance indicators in Taiwan Stroke Registry 89
Table 7. IV tPA Administration in Taiwan Stroke Registry 90
Table 8. Univariate Analysis of Variables Differences among Patients with Acute Ischemic Stroke who have either an Ankle-brachial index (ABI) &lt;0.9 or an ABI ≥0.9 91
Table 9. Comparison of Extracranial and Intracranial Large Artery Stenosis Between ABI&lt;0.9 and ≥0.9 in Patients with Acute Ischemic Stroke 92
Table 11. Univariate Comparison between Favorable and Unfavorable Outcome (mRS≥3) at Discharge in Patients with Acute Ischemic Stroke 94
Table 12. Multivariate Logistic Regression Model for Factors Associated with an Unfavorable Outcome (mRS ≥3) 95
Table 13 Characteristics of study subjects 96
Table 14. Multiple ordinal logistic regression: risk factors associated with carotid plaque score and plaque-free IMT after adjustment for covariates 97
Table 15. Correlation between carotid plaque scores, blood active MMP-3 levels, blood total MMP-3 levels and MMP-3 -1612 5A/6A genotypes 98
Table 16. Literature review of studies correlating blood levels of MMPs and/or promoter common polymorphism of MMPs with carotid atherosclerosis 99
Appendix 100

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