Statin的短期治療可以改善川崎症後期合併冠狀動脈異常病童的血管內膜功能異常和動脈血管硬化; Does Statin Therapy Improve Endothelial Dysfunction and Arterial Stiffness in the Long Term Follow-up Patients of Kawasaki Disease Complicating with Coronary Arterial Abnormality

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题名:	Statin的短期治療可以改善川崎症後期合併冠狀動脈異常病童的血管內膜功能異常和動脈血管硬化;Does Statin Therapy Improve Endothelial Dysfunction and Arterial Stiffness in the Long Term Follow-up Patients of Kawasaki Disease Complicating with Coronary Arterial Abnormality
作者:	黃士銘;Shih-Ming Huang
贡献者:	中國醫藥大學：臨床醫學研究所碩士班
关键词:	川崎症;血管內膜功能異常;進行性血管炎;冠狀動脈異常;血脂異常;Kawasaki disease;endothelial dysfunction;progressive arterial wall inflammation;lipid profile abnormality
日期:	2007-07-09
上传时间:	2009-08-12 14:23:37 (UTC+8)
摘要:	題目：Statin治療是否可以改善川崎症後期合併冠狀動脈異常病童的血管內膜功能異常和動脈血管硬化。研究背景：川崎症是一種好發在亞洲兒童的全身性血管炎，距第一個發生案例至今已有將近30年了。目前研究發現這些病人在年輕時就有早發性血管粥狀硬化的傾向發生。一些研究也顯示在川崎症急性期併發冠狀動脈異常的病人在後期仍有低度進行性血管發炎、血管內膜功能異常及動脈血管硬化的情況發生。此外，血脂肪的代謝異常也被認為是川崎症多年後造成血管內膜功能異常及動脈血管硬化的原因之一。藉由測量血液高敏感度CRP來評量慢性血管發炎、藉由測量臂動脈血流擴張程度和頸動脈內膜中層厚度來評量血管內膜功能及藉由測量臂踝脈波傳遞速度、動脈血管硬化指數和臂踝血壓指數來評量評估動脈血管硬化程度,這些方法已經被用來當作衡量心血管異常的指標。Statins, hydroxymethylglutaryl coenzyme A 還原酶抑制劑，已經被證實不僅可以降低LDL-C，同時可以改善成人的血管粥狀硬化和血管內膜的功能異常。然而， statin對於治療後期川崎症併發冠狀動脈異常的兒童在改善血脂肪異常、慢性血管發炎、血管內膜功能異常和動脈血管硬化方面尚未被評估過。研究目的：本實驗的研究目的就是為了證明statin治療是否可以改善併發冠狀動脈異常川崎症後期病童的血脂肪異常、慢性血管發炎、血管內膜功能異常及動脈血管硬化。研究方法: 本實驗分為兩部份。第一部份乃比較11名川崎症合併冠狀動脈異常病童與11名健康且年齡、性別相符沒有川崎症兒童的各種周邊動脈異常測量值的差異。第二部份再比較這11名川崎症合併冠狀動脈異常病童服藥前後的周邊動脈異常的改變。這些實驗組的兒童每日睡前口服一次simvastatin 10 mg 持續3個月。服用藥物前及服用藥物後每個月皆要接受血脂肪、高敏感性CRP檢測及頸動脈內膜中層厚度、右臂動脈血流擴張程度、臂踝脈波傳遞速度、動脈血管硬化指數和臂踝血壓指數檢查，直到3個月研究期間結束。初步的藥物效果評估乃比較川崎症兒童服用藥物前及服用藥物後每個月血中脂肪、高敏感性CRP、頸動脈內膜中層厚度、右臂動脈血流擴張程度、臂踝脈波傳遞速度、動脈血管硬化指數和臂踝血壓指數的變化，且和健康的對照組兒童比較是否有顯著差異和改善。至於藥物的安全性乃藉由每個月監控肌肉酵素（CPK）、肝功能(AST/ALT)及是否有臨床症狀產生。實驗結果：[第一部份] 川崎症組與健康組不管在性別、年齡、身體質量指數和血壓方面皆沒有顯著的差別。在服用藥物前，川崎症實驗組有較正常對照組有較高的高敏感性CPR、較高的動脈血管硬化指數、較快的臂踝脈波傳遞速度和較低的臂動脈血流擴張程度。至於在血脂肪、動脈內膜中層厚度和臂踝血壓指數則沒有顯著的不同。[第二部份]川崎症病童經過3個月的statin治療後，血脂肪方面皆有顯著的改善，除了TG沒有顯著地下降之外。高敏感度CRP經過3個月的治療後也有顯著下降，但改善後仍高於正常兒童。在血管內膜功能和動脈血管硬化方面，臂動脈血流擴張程度、動脈內膜中層厚度、臂踝脈波傳遞速度、動脈血管硬化指數和臂踝血壓指數皆有顯著地改善。動脈內膜中層厚度、臂踝脈波傳遞速度和臂踝血壓指數皆有改善至與正常對照組比較沒有顯著差別，但臂動脈血流擴張程度和動脈血管硬化指數改善後仍和正常對照組有顯著的差異。在3個月的研究療程中，在CPK、AST和ALT方面並沒有明顯的變化，而且並沒有臨床副作用症狀產生。研究結論：在川崎症合併有冠狀動脈異常的兒童發病多年後依然可以發現有慢性血管發炎、血管內膜功能異常及動脈血管硬化的情況發生。在合併有冠狀動脈異常長期追蹤的川崎症兒童，短期的statin治療可以顯著地改善且正常化血脂肪、慢性血管發炎、血管內膜功能異常及動脈血管硬化的情況，而且沒有肌肉或肝功能異常等副作用的產生，雖然在我們的研究中長期的安全性仍未知。我們的研究結果也強調當血管粥狀硬化過程尚為可逆時，在合併冠狀動脈異常的川崎症兒童早期服用statin治療或許可以避免未來早發性血管粥狀硬化傾向的發生。 Topic: Does Statin Therapy Improve Endothelial Dysfunction and Arterial Stiffness in the Long Term Follow-up Patients of Kawasaki Disease Complicating with Coronary Arterial Abnormality Background: Kawasaki disease (KD), a systemic vasculitis with predilection for Asian children, has been noted for almost 40 years since its first description in 1967. Latest concern falls on the possibility of its predisposition to premature atherosclerosis in young adulthood. Several studies showed evidences of ongoing low grade inflammation, endothelia dysfunction and arterial stiffness in those KD patients complicating with coronary arterial abnormality (CAA) even late after their acute phases. Besides, their abnormalities in lipoprotein metabolism are also believed to be determinant factors for the persistent endothelial dysfunction and arterial stiffness many years later. Many tools have been used to assess the arterial dysfunction in adults, which include: chronic vascular inflammation measured by high-sensitive CRP (hs-CRP), endothelial dysfunction measured by flow-mediated dilation (FMD) of the brachial artery & intima-media thickness (IMT) and arterial stiffness measured by brachial-ankle pulse wave velocity (baPWV), arterial stiffness index (ASI) and ankle brachial pressure index (ABI). Long term medication of statin, a HMG CoA reductase inhibitor, have been proven effective in reducing LDL-C levels and improving the endothelial dysfunction in adult patients of atherosclerosis. However, its efficacy in treating late KD children complicating with CAA has not yet been evaluated. Objective: This study was designed to determine whether statin therapy (simvastatin) improve lipoprotein abnormalities, chronic vascular inflammation, arterial stiffness and endothelial dysfunction in children of KD complicating with CAA at their long term follow-up. Methods: This study is divided into two parts. Part one study included 11 KD children complicating with CAA as study group and 11 healthy age- and gender-matched children as control group. Part two study compared the arterial dysfunctional parameters on these 11 KD patients before and after they received the simvastatin therapy 10 mg single dose per day at bedtime for three months. Lipid profiles (LDL-C, HDL-C, TG, TC), hs-CRP, IMT, ASI, baPWV, ABI and FMD were performed during each visit at baseline and every month until finishing three months therapy. The primary efficacy outcome was the change from baseline in lipid profiles, hs-CRP, IMT, ASI, baPWV, ABI and FMD after three months of treatment. The principal safety was monitored every month by muscle-related enzyme (CPK), liver enzyme (AST and ALT) measurements and relevant clinical complaints, especially muscle cramps. Results: Part one study: There are no significant difference between the KD patients and normal control group in the demographic data including gender, age, body mass index and blood pressure. However, the KD group had significantly higher hs-CPR (0.430 ± 0.225 vs. 0.045 ± 0.028 mg/L, p < 0.001) and ASI (4.82 ± 0.86 vs. 2.96 ± 0.89, p < 0.001), faster baPWV (1261 ± 117 vs 1070 ± 173 cm/sec, p = 0.006) and decreased FMD (6.12 ± 1.61 vs. 13.11 ± 1.00 %, p < 0.001) than the normal control. There were no significant difference in lipid profiles, IMT and ABI. Part two study: After three months of statin treatment on the KD patients, there were 9.4 % decreased in TC level, 12.4 % decreased in LDL-C level and 7.3 % increased in HDL-C level. All were statistically significant. Serum hs-CRP level decreased from 0.430 ± 0.225 mg/L to 0. 209 ± 0.098 (p = 0.001). The final hs-CRP level were still significantly higher than that of normal control. There were also 7.5 % decreased of IMT, 10.2 % decreased of baPWV, 22.2 % decreased of ASI, 7.3 % increased of ABI, and 68.6 % increased of FMD. The IMT, baPWV and ABI values had improved to a level closer to that of normal control, but ASI and FMD values remained worse than the normal control. There were neither significant changes in ALT, AST and CK levels nor any adverse effects related to the drug. CONCLUSIONS: Chronic vascular inflammation, endothelium dysfunction and arterial stiffness persist in the KD patients complicating with CAA at their long term follow-up. We find that a 3-month medication of statin therapy can significantly improve their lipoprotein abnormalities, chronic vascular inflammation, endothelial dysfunction and arterial stiffness. No adverse effect was found.
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