葡萄籽原花青素抗颈动脉粥样硬化效应的临床研究
BENEFICIAL EFFECTS OF GRAPE SEED PROANTHOCYANIDIN EXTRACT ON CAROTID ATHEROSCLEROSIS
作者：曹爱红 导师：高海青
山东大学 临床医学（药学方向）
摘 要
随着我国人口的老龄化，以动脉粥样硬化为基础的缺血性心脑血管疾病的发病率逐步升高，目前已经成为我国人群的主要死亡原因之一。据预测，到2050年动脉粥样硬化将成为世界范围内的首位死亡原因。动脉粥样硬化的防治一直是心血管领域的一个研究热点。
国内外大量动物实验已经证实葡萄籽原花青素（grape seed proanthocyanidin extract,GSPE）具有极强的抗炎、抗氧化、保护血管内皮等作用，显示出明显的抗动脉粥样硬化效应。然而，有关GSPE干预颈动脉粥样硬化的临床研究尚未见报道。
通过临床研究观察应用GSPE干预后对患者颈动脉粥样硬化的治疗效果，并探讨其可能的作用机制，为寻求新的动脉粥样硬化防治药物提供科学依据。
1. 研究对象
选择经彩色多普勒超声检查确诊存在颈动脉粥样硬化的患者157例，随机分为两组：GSPE组和对照组。对照组81例，给予生活方式干预；GSPE组76例，在相同的生活方式干预的基础上，口服葡萄多酚胶囊（天津市尖峰天然产物研究开发有限公司，原花青素OPC含量：100mg/粒）每次两粒，每天两次。整个随访持续24个月。
2. 病史采集及体格检查
所有患者均详细记录年龄、性别、吸烟史、既往史、心脑血管疾病家族史等基本信息，并记录心率、血压，测量身高、体重并计算指数（body mass index,BMI）,并进行心电图等常规检查及系统的体格检查。
3. 血清学检查
所有受试者均于治疗前治疗后6、12、24个月取空腹静脉血，测定血清胆固醇（total cholesterol ,TC）、甘油三酯（triglyceride,TG）、高密度脂蛋白-胆固醇（high density lipoprotein cholesterol,HDL-C）、低密度脂蛋白-胆固醇（low density lipoprotein cholesterol,LDL-C）浓度（mmol/L）及高敏C反应蛋白(high-sensitive C-reactive protein,hs-CRP)水平（mg/L）.
4. 颈动脉超声检查
采用高分辨率彩色多普勒超声检测所有患者在治疗前及治疗后第6、12、24个月平均最大颈动脉中膜厚度（mean maximum carotid intima-media thickness,MMCIMT）、斑块积及斑块稳定性的改变。
5. 统计学处理
采用SPSS13.0统计软件进行统计分析，计量资料以均数±标准差（x¯±s）表示，组间比较采用两样本t检验，组内比较采用配对t检验。计数资料采用百分率表示，比较用卡方检验。P<0.05为差异有统计学意义。
研究结果如下：
1. 共157例患者完成24个月的随访，对照组81例，GSPE组76例。两组患者治疗前在性别、年龄、体重指数、血压、血液生化指标及既往病史等方面无显著性差异。
2. 治疗前两组TC、TG、LDL-C及HDL-C水平无显著差异。治疗后GSPE组患者TC、TG、LDL-C水平均下降，但组内差异无统计学意义；HDL-C水平治疗6个月显著升高（P<0.05)。
3. 治疗前两组hs-CRP水平无显著性差异，治疗6个月GSPE组hs-CRP即显著下降，较治疗前降低2.44mg/L（P<0.05),，而对照组hs-CRP呈现升高趋势，12个月后显著升高（P<0.05)。治疗6个月后两组hs-CRP水平即出现显著性差异（P<0.55）。
4. 治疗前两组患者MMCIMT、斑块积分比较，差异无统计学意义（P>0.05）。治疗后GSPE组患者MMCIMT显著变薄、斑块积分显著减少。GSPE组治疗12个月患者MMCIMT较治疗前减小6.2%（P<0.05），治疗6个月斑块积分减小10.9%（P<0.05），且随着治疗时间的延长，患者MMCIMT和斑块积分进一步降低。对照组患者MMCIMT和斑块积分随着时间的延长逐渐增加。组间比较，治疗6个月两组患者MMCIMT比较P<0.05，两组斑块积分比较P<0.01。
5. 两组治疗前不稳定斑块数相比较，差异无统计学意义（P>0.05)。治疗后，GSPE组的总斑块数及不稳定斑块数均减少，对照组总斑块数及不稳定斑块数均增加。
葡萄籽原花青素具有显著的抗动脉粥样硬化效应，可显著降低动脉粥样硬化患者颈动脉内中膜厚度，稳定、减小甚至消退斑块，且随着时间的延长，GSPE的抗动脉粥样硬化效应越明显。GSPE还可降低心脑血管事件的发生率。
GSPE的这种抗动脉粥样硬化效应的产生不依赖于血脂的变化，可能与其抗炎、抗氧化、消除氧自由基的作用相关。GSPE可能成为动脉粥样硬化尤其是无症状动脉粥样硬化患者的一种新的治疗药物，成为动脉粥样硬化一级预防的新选择。
关键词 葡萄籽原花青素 动脉粥样硬化 颈动脉B超
Abstract
Atherosclerosis is the main underlying cause of ischemic vascular diseases and is predicted to become the leading cause of global mortality by 2050. Atherosclerotic plaques indicate the occurrence of ischemia events,and how to deal with it is a difficult task for clinical physician. Animal studies have indicated that grape seed proanthocyanidin extract (GSPE) exerts an antiatherogenic effect by inducing regression of atherosclerotic plaques. Whether GSPE can reverse the atherosclerotic progression and reduce the incidence rate of cardiovascular events in clinical use have not been reported by now.
The aim of this study is to observe the effect of GSPE on carotid atherosclerosis in clinical use and investigate the possible mechanism,providing a scientific basis for new treatments of atherosclerosis.
1. Study population
Consecutive 157 nonhypercholesterolemic patients diagnosed with asymptomatic carotid artery plaques or abnormal CIMT based on carotid ultrasonography were randomly assigned to control group（n=81) or GSPE group（n=76).In control group,all patients were enrolled in a lifestyle intervention. The patients in GSPE group received GSPE 400mg/day(200mg bid) in addition to the same lifestyle intervention. The whole study lasted 24 months.
2. History investigation and physical examination
A full clinical history and physical examination of all patients were performed by a specialized physician. The following information was collected: age,sex,BMI(body mass index),blood pressure,current medications and history of hypertension or diabetes mellitus.
3. Laboratory analyses
Peripheral blood samples were collected in the early morning before breakfast at the beginning of the study and follow-up period. Serum total cholesterol(TC),triglyceride (TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol (HDL-C) and high-sensitive C-reactive protein (hs-CRP) levels were assessed by standard techniques in the hospital laboratory. Assessments were performed at baseline,as well as at months 6,12 and 24 after the first infusion.
4. Carotid B-Mode Ultrasound examination
High-resolution B-mode ultrasonography of the carotid artery was performed with an ultrasound scanner(iE33,Philips) equipped with a linear array 5-to7-MHz transducer . The effects of GSPE were monitored by blinded,serial assessments of mean maximum carotid intima-media thickness(MMCIMT) and the plaque score.
5. Statistical Analysis
Numerical data are expressed as mean ±SD ( x¯±s ). The significance of the differences in various parameters within each group between baseline and after treatment was tested using a paired Student test. The significance of the differences between groups in these parameters was tested by an unpaired Student's test. Categorical date was summarized as percentages and compared using chi-square analysis. All analyses were carried out by SPSS 13.0 software. All P values were two-tailed and statistical significance was set at P<0.05.
Result as following:
1. All 157 patients completed the protocol. There was no significant difference in all baseline demographic parameters between the two groups'.
2. There was no significant between groups on serum lipid profile at baseline .In GSPE group,serum TC,TG and LDL-C level all decreased after treatment (P>0.05). In control groups ,there was no significant change on lipid profile during follow-up .Between-group comparison,significant difference of serum HDL-C level appeared after 12 months (P<0.05).
3. GSPE resulted in significant reductions in serum hs-CRP concentration during follow-up .Serum hs-CRP concentration significantly increased in control group after 12 months ( P<0.05 ).Significant difference of serum hs-CRP levels between the two groups appears after 6 months treatment ( P<0.05 ).
4. After treatment,GSPE result in significant reduction in MMCIMT progression (3.3% decrease after 6 months,6.2% decrease after 12 months and 9.4% decrease after 24 months ) and plaque score (10.9% decrease after 6 months ,24.1% decrease after 12 months and 33.1% decrease after 24 months ). While MMCIMT and plaque score was stable and even increased with the time going on in control group. The group of plaques and unstable also decreased after treatment of GSPE.
GSPE can inhibit the development of carotid intima-media thickness,regress the carotid plaque and promote the stabilization of carotid plaque,and as the treatment of prolonged ,the antiatherosclerosis effect of GSPE was more apparent ,At lease .after treatment of 24 months,GSPE can reduce the cardiovascular event significantly .In the light of our results ,we can speculate that GSPE could be an effective therapeutic candidate for the primary programs for the asymptomatic patient with atherosclerotic lesion .Future in vivo studies are required to investigate the mechanism.
Key words Grape seed proanthocyanidin extract (GSPE) Atherosclerosis Carotid plaque
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