- 學位論文
降血脂藥物HMG-CoA 抑制劑Atorvastatin停藥對於高血脂病人血中Soluble CD40 Ligand濃度之影響及脂肪細胞激素Adiponectin與Resistin血清濃度在HMG-CoA 抑制劑Atorvastatin治療前後之變化
Effects on Soluble CD40L and Adipocytokines after Therapy and Withdrawal of Atorvastatin in Patients with Hypercholesterolemia
摘要
研究背景：最近的文獻研究發現Soluble CD40L，與高膽固醇病人體內容易發生高血栓及凝血狀況有關，而且可能參與動脈粥狀硬化斑的不穩定性，而造成臨床上病人發生急性冠心症（acute coronary syndrome）; 也有文獻提出Soluble CD40L 可以作為急性冠心症病人的預後指標。另外，兩種新的脂肪細胞激素，包括adiponectin與resistin，最近也被發現可能具有直接參與動脈粥狀硬化過程的角色。抗血脂藥物statin，除了已經被證實可以有效降低膽固醇血清值，更可以發揮多重的（pleiotropic effects）血管保護作用。而statin 的治療如果突然被中斷（statin withdrawal），在基礎實驗中發現血管的保護作用會消失，在臨床上也發現急性冠心症的病人若突然戒斷其statin 治療，會增加心肌梗塞的機會。有關statin withdrawal 的系列研究，曾經在文獻中討論過high sensitivity-CRP以及NO的角色，可是對於stain withdrawal對於sCD40L的影響，回顧文獻研究目前仍然沒有資料。另一方面，有關statin類藥物對於高血脂病人體內脂肪細胞激素的影響，也沒有文獻資料可尋。 研究設計：總共有32位高膽固醇血症的患者接受完整三個月Atorvastatin 每天10mg口服治療。在加入治療前，收集其基礎值的血清樣本，並於接受完三個月atorvastatin治療後，再次收集其血清樣本。所有血清樣本皆分析其血脂電泳並以ELISA方式檢查其sCD40L, adiponectin以及resistin之濃度。病人在停用atorvastatin後之連續三天，回診接受抽血並比較血清中血脂濃度與sCD40L之血清濃度。 實驗結果：在經過三個月口服降膽固醇藥物atorvastatin治療後，病人的血中總膽固醇、低密度脂蛋白膽固醇以及sCD40L呈現明顯的降低(255.44 ± 32.12 vs. 184.44 ± 23.18 mg/dl, 178.09 ± 32.12 vs. 122.12 ± 23.18 mg/dl, and 1.93 ± 1.13 vs. 1.30 ± 0.97 ng/ml, respectively, 所有p值<0.05). 在停用atorvastatin 的最初第一天與第二天，雖然sCD40L 的血清值平均值有回升的情況(1.79 ± 1.39 vs. 1.30 ± 0.97 ng/ml, p值=0.098; 1.75 ± 1.11 vs. 1.30 ± 0.97 ng/ml, p值=0.077, respectively)，但是和停藥當天相比，並沒有達到統計學上的有意義。直到第三天，sCD40L的血清值才達到有意義的差異(1.89 ± 1.28 vs. 1.30 ± 0.97 ng/ml, p=0.023)。值的注意的是，總膽固醇以及低密度脂蛋白的血中濃度在statin停藥後三天並沒有顯著差異。所有在statin withdrawal期間所得到的sCD40L數值都要來的比治療前的基礎值要低。至於兩種脂肪細胞激素，adiponectin以及resistin，在三個月atorvastatin的治療前後，並沒有發現有顯著的改變 (4.48 ± 2.16 vs. 4.43 ± 2.37 μg/ml, 15.76 ± 8.03 vs. 15.48 ± 8.26 ng/ml, respectively). 研究結論： 對於血中總膽固醇、低密度脂蛋白膽固醇以及sCD40L，與過去文獻研究結果一致地，可以明顯地在投與降膽固醇藥物治療後，呈現降低的情況。在statin停藥後，sCD40L在最初兩天便已經有升高的情況，而在第三天達到統計學上的顯著差異。所有在statin withdrawal期間所得到的sCD40L數值都要來的比治療前的基礎值低，沒有所謂的反彈現象。Statin藥物的治療在這一類高血脂病人，對於兩種最近發現可能參與動脈粥狀硬化過程的的脂肪細胞激素adiponectin 與resistin來說，並沒有血清測量值上顯著的影響。
並列摘要
Background: Enhanced soluble CD40 ligand (sCD40L) has been found participating in the prothrombotic status in patients with hypercholesterolemia and plaque instability in acute coronary syndrome. Two novel adipocytokines, including adiponectin and resistin, were recently found also involved in inflammation of vasculature, and play direct and reciprocal vascular roles in atherosclerosis. Statin has pleiotropic effects on atherosclerosis process beyond lipid lowering, and withdrawal of statin therapy could abrogate vascular protection action and even increase the incidence of thrombotic vascular events in patients with statin therapy. The changes of sCD40L after abrupt cessation of statin therapy remain unknown, and there are still not data available about the influence of statin treatment on two adipocytokines. Methods: Total of thirty-two patients with hyperlipidemia received statin (atorvastatin, 10 mg/day) therapy for 3 months. The serum levels of lipid profiles, sCD40L, adiponectin and resistin were assessed before and immediately after 3 months of statin therapy. In addition, the serum level of sCD40L in all patients was measured on the 3 consecutive days after statin withdrawal. The serum levels of SCD40L, adiponectin and resistin were measured by ELISA method. Results: After 3 months of statin therapy, the total cholesterol, low-density lipoprotein cholesterol (LDL-chol) as well as sCD40L were significantly reduced (255.44 ± 32.12 vs. 184.44 ± 23.18 mg/dl, 178.09 ± 32.12 vs. 122.12 ± 23.18 mg/dl, and 1.93 ± 1.13 vs. 1.30 ± 0.97 ng/ml, respectively, all p value <0.05). The level of sCD40L was found to have the tendency of increase toward baseline on the first and second days after withdrawal of statin therapy (1.79 ± 1.39 vs. 1.30 ± 0.97 ng/ml, p=0.098; 1.75 ± 1.11 vs. 1.30 ± 0.97 ng/ml, p=0.077 , respectively) but not reach significant difference until the third day (1.89 ± 1.28 vs. 1.30 ± 0.97 ng/ml, p=0.023). However, the total cholesterol and LDL-chol did not show any increase during the 3 day period of statin withdrawal. No significant difference of both adiponectin and resistin could be demonstrated between before and after the 3-month treatment of statin (4.48 ± 2.16 vs. 4.43 ± 2.37 μg/ml, 15.76 ± 8.03 vs. 15.48 ± 8.26 ng/ml, respectively). Conclusion: The serum level of sCD40L, total cholesterol and LDL-chol were significantly decreased after 3 months of statin therapy. The serum level of sCD40L reelevated toward baseline level, while the lipid profiles remained unchanged during 3 days period of statin withdrawal. This indicates that the pleiotropic effects of statin on sCD40L was abrogated, and was independent on serum cholesterol level. Serum level of adiponectin and resistin did not show any significant change after statin therapy in this study.