施德丁類藥物對急性缺血性腦中風病患血液中內皮前驅細胞數量與臨床預後的相關研究

The Effect of Statin Therapy on Endothelial Progenitor Cells and Outcome in Patient with Acute Ischemic Stroke

洪淑華(Shu-Hua Hung)

指導教授 ： 蔡東榮

高雄醫學大學/藥學院/藥學研究所碩士在職專班/碩士(2013年)

摘要

背景：腦中風是全世界主要死因之一，並且是導致成年人長期嚴重生理殘障的主要的原因。動脈粥狀樣硬化與發炎反應在腦血管疾病的致病機轉中扮演重要角色。急性缺血性腦中風後會產生一連串複雜事件，包括腦細胞缺血、發炎反應、神經元壞死和細胞凋亡而造成神經功能障礙，內皮細胞的修復和新生血管可能是缺血性中風後大腦恢復的機轉之一。
內皮前驅細胞(EPCs)會從骨髓釋放到血液中，其特徵在於細胞表面標記物CD34，CD133和血管內皮生長因子受體（VEGF-R）。內皮前驅細胞在動物和人體研究中已被證明會促進新生血管和內皮再生。臨床研究表明，心血管疾病的預後都與內皮前驅細胞的功能障礙和血液中循環內皮前驅細胞的數量呈正相關。
施德丁（statins）類藥物，所謂HMG-CoA還原酶抑制劑，是目前最廣泛用於治療高血脂血症的藥物。許多的研究顯示施德丁類藥物除了具有降膽固醇的功用之外，還具有抗血栓形成與抗發炎反應的作用。臨床研究顯示施德丁類藥物可以降低心血管疾病的發生，包括心肌的梗塞，腦中風和死亡。目前針對急性缺血性中風病患血液中內皮前驅細胞與施德丁類藥物治療的關係尚不清楚。本研究的目的是評估施德丁類藥物對急性缺血性中風患者血液中內皮前驅細胞的影響和預後的關係。
方法： 我們進行一個前瞻性的研究，評估65例急性缺血性中風分病患，包括中風後使用施德丁組(26人)與中風後無使用施德丁組(39人)。缺血性腦中風的脂質治療方案是根據美國中風協會的指導方針，針對糖尿病或高風險的患者如果低密度脂蛋白LDL > 70mg/dl，或非糖尿病患者的低密度脂蛋白> 100 mg/dl則給予施德丁類藥物的降血脂治療。我們使用流式細胞儀(flow cytometry)分別於腦中風後第一天、第七天、以及一個月後來測量病人血液中內皮前驅細胞(CD133+/CD34+及KDR+/CD34+)的表現量，並分析與臨床預後的相關性。另外，我們也收錄了65位年齡與性別相當的人做為對照組。
結果： 急性缺血性中風患者CD133+/ CD34+和KDR+/CD34+細胞數量與對照組相比均顯著降低（P <0.05）。急性缺血性中風患者中大血管病變組與小血管病變組相比，在中風後的CD133+/CD34+細胞數量有顯著減少（p <0.05）。而這兩組間CD133+/ CD34+細胞數量會在中風後皆會逐漸增加。德丁類藥物治療與否對於急性缺血性中風患者血液中內皮前驅細胞的數量並沒有顯著性差異。統計分析顯示，缺血性中風的子類型、CD133+/ CD34+ 與KDR+/CD34+的細胞數量與臨床預後相關。邏輯式回歸分析發現，大血管病變性腦中風（OR= 30.2，95％CI =5.3-171.4，P <0.001），和入院KDR+/CD34+數量低（OR= 0.188，95％CI =0.04-0.86; p = 0.031）與腦中風六個月後的不良預後相關。
討論： 我們的研究發現急性缺血性中風患者血液中內皮前驅細胞的數量比對照組明顯降低，而其中大血管疾病組比較小血管病變組有更顯著的降低。施德丁類藥物治療不影響急性缺血性中風患者後血液中內皮前驅細胞的數量。急性腦中風當時血液中內皮前驅細胞數量較少是預測中風六個月後不良預後的一個獨立危險因子。

關鍵字

急性缺血性腦中風 內皮前驅細胞 預後 施德丁類藥物

並列摘要

Background: Stroke is a major cause of serious morbidity and mortality in the worldwide. Inflammation and oxidative stress play pivotal role in acute ischemic stroke. Acute ischemic stroke (AIS) leads to a complicated cascade of events involving cerebral ischemia, inflammation, neuronal necrosis, and apoptosis of the blood-brain barrier; and neurological dysfunction. Endothelial repair and neo-vascularization are possible recovering from ischemic stroke in the adult brain.
The endothelial progenitors cells (EPCs), released from bone marrow to circulation, characterized by the expression of cell markers CD34, CD133 and vascular endothelial growth factor receptor (VEGF-R). EPCs have been demonstrated in both animal models and humans to contribute to neo-vascularization and re-endothelialization. The clinical studies demonstrated that cardiovascular diseases are associated with dysfunction of EPCs, and the numbers of circulating EPCs is correlated positively with cardiovascular outcome.
Statins, the 3-hydroxy 3-methyl-glutaryl coenzyme-A reductase inhibitors, are originally used for treatment of hypercholesterolemia. The accumulating evidences have suggested that statins possess pleiotropic effects, which include the improvement of endothelial function and an anti-thrombotic effect, independent of their impact on cholesterol-lowering effect. Statin therapy has been shown to reduce cardiovascular events, including myocardial infarction, stroke, and death. In vitro studies, statins have been found to enhance the mobilized and proliferative capacity of EPCs. However, the role of statin therapy on circulating EPCs in patients with AIS has not been well studied. This study aimed to evaluate the relationship among the statin therapy, serial changes of circulating EPCs and outcome in patients after AIS.
Methods: This prospective study evaluated 65 patients with AIS (26 patients with statin therapy and 39 without statin therapy). The circulating level of EPCs (CD133+/CD34+ and KDR+/CD34+) were determined using flow cytometry at different time points (within 48 hours and Day 7, 30 days post-stroke) and analyzed with clinical outcome. EPCs level was also evaluated once in 65 risk control group.
Results: The level of CD133+/CD34+ and KDR+/ CD34+ EPCs were significantly lower in AIS groups when compared to those in the control groups (p<0.05). The level of CD133+/CD34+ EPCs was significantly lower in the large vessel disease group when compared to small vessel disease group on Day 1 after acute stroke (p<0.05). Then, the level of CD133+/CD34+ EPCs was gradually increased thereafter and similar between these two groups on Day 7 after ischemic stroke. The number of circulating EPCs was not significantly different between the patients with and without statin therapy. Statistical analysis revealed that subtype of stroke, diastolic BP, level of CD133+/CD34+ and KDR+/CD34+ EPCs on admission were significantly different between the good and poor outcome groups. After adjustments for covariance using stepwise logistic regression, only subtype of stroke (OR=30.2, 95% CI=5.3-171.4; p<0.001) and KDR+/CD34+ on admission (OR=0.188, 95% CI=0.04-0.86; p=0.031) were independently associated with six-month outcome.
Conclusions: The number of circulating EPCs was significantly lower in the large vessel disease than in the small vessel disease group at acute stage of ischemic stroke. Statins do not significant affect the circulating EPCs in patients after AIS. The lower number of EPCs is an independent risk factor for poor six-month outcome in patients after AIS.

並列關鍵字

acute ischemic stroke endothelial progenitor cells outcome statin

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