动脉粥样硬化斑块逆转治疗和挑战

1、动脉粥样硬化斑块逆转治疗和挑战动脉粥样硬化伴随一生的风险泡沫细胞脂纹中期损伤粥样硬化纤维斑块复合性病变/破裂内皮功能失调10岁开始30岁开始40岁开始脂质沉积为主平滑肌细胞和胶原血栓出血Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S.动脉粥样硬化累及全身血管床冠状动脉疾病脑血管疾病外周动脉疾病3.8%11.9%3.3%24.7%19.2%7.4%29.9%3.8%11.8%3.3%CAPRIE Steering Committee. Lancet 1996;348:1329-1339动脉粥样硬化斑块 能逆转 还是不能逆转 挑战 我们用PA

2、S疗法挑战 抗氧化剂-普罗布考抗血小板聚集-阿司匹林 降血脂-阿托伐他汀来自动脉硬化的经典学说PAS 三联的组成ProbucolAspirinStatins汀类药物可以改善血管功能，降脂的功能PAS疗法的理论基础来自动脉硬化的经典学说内皮损伤学说氧化应激学说 血栓形成学说8LDL内皮损伤管腔单核细胞巨噬细胞泡沫细胞内膜oxLDL细胞增殖、退化活性氧ROSSR-A脂核在血管粘附分子-1(VCAM-1)和细胞间粘附分子-1(ICAM-1)的作用下，粘附到血管内皮上；单核细胞趋化蛋白-1的介导下，穿越血管内皮细胞9血中胆固醇由LDL携带运输ox-LDL结合慢结合快LDL-RSR-A表达减少功能下调表

3、达增加功能上调Daniel S, et al. Nature Medicine. 2002 Nov; 8(11):1211-7 LDL颗粒被吞饮, 然后进入溶酶体。在溶酶体中, LDL被水解释放出游离胆固醇。游离胆固 醇可掺入细胞浆膜中, 被细胞膜所利用或转换成其他物质。而LDL受体则可再循环 细胞内游离的胆固醇增多抑制受体的合成和表达细胞 内游离胆固醇含量增加则抑制LDL受体的合成和表达, 反之亦然。 LDL表面多不饱和脂肪酸双链断裂和ApoB形成共轭双烯ROS活性氧簇化学修饰LDL-C动脉粥样硬化X 高血脂与动脉粥样硬化形成之间存在中间环节：化学修饰内皮损伤诱发血栓形成示意图 胶原与vWF

4、因子结合 与糖蛋白（GPIb)血小板激活TXA2血栓血小板聚集Pollack CV, et al. The Journal of Emergency Medicine. 2008(34)4: 417-42835 X 109血小板粘附在内皮细胞受损的胶原上，释放ADP和TXA2,然后引起血小板激活、聚集，血栓形成。 粘附磷脂酶 A2被激活裂解膜磷脂游离花生四稀酸环氧化酶PGH2PGC2TXA2血栓素合成酶花生四烯酸途径血小板释放内源性ADP通过血小板膜上的ADP受体引起聚集 凝血酶IIa凝血酶原II纤维蛋白原纤维蛋白血小板间的聚集是两个血小板的膜上糖蛋白纤维蛋白原暴露在Ca2+参与纤维蛋白原结合

5、才能连接血小板 。抑制血栓的形成抑制氧化的LDL-C 的形成减少OX-LDL底物形成抗氧化抑制MMPs降血脂抗血小板聚集 导致动脉粥样硬化心血管事件的三个主要环节传统疗法Our study on PAS therapy 2008 -2011, CHD were selected by coronary angiography or coronary CTA.All cases were divided into two groups; control group 65 (AS) aspirin 100mg/d and , Atrovastatin 20mg/d .PAS group 85(AP

6、S) probucol, 0.5g/d, aspirin100mg/d and Atrovastatin 20mg /d. And all cases were followed up for 1 year, examined the coronary plaque reversal through Coronary angiography or coronary CTA AS group (65case) Comparison of vascular plaque stenosis before and after therapy （ xs，mm） indicators Beforether

7、apy after therapydifference（d） tp Vascular stenosis0.68士0.180.53士0.190.15士0.113.13p0.01 In AS group, vascular stenosis was decreased by about 15% after treatment. PASgroup（84case） Comparison of vascular plaque stenosis before and after therapy （ xs，mm Xs） indicatorsBeforetherapy after therapy differ

8、ence （d） tp Vascular stenosis0.71士0.250.47士0.410.24士0.194.59p0.01In PAS group, vascular stenosis was decreased by 24% after treatment. Comparison of vascular plaque stenosis AS and PAS therapy （Xs） indicatorsAS groupPAS group （d）tpVascular stenosis 0.15士0.110.24士0.190.09士0.243.76p0.01 Comparing PAS

9、group and AS group, PAS group had more 9% plaque reversalPlaque reversal吴世艳1.jpg动脉粥样硬化Probucol与他汀联合治疗对斑块稳定性的影响【背景资料】 92名冠心病患者分别给予:A组 n=31 Atrovastatin 10mg,QdP组 n=30 Probucol 250mg,BidA+P组 n=31 Atrovastatin 10mg,Qd+Probucol 250mg,Bid 疗程8周【试验发布】日本68届循环年会报告【研究单位】 Tadateru Takayama Nihon University Sch

10、ool of Medicine, Tokyo, Japanprobucol单用或与他汀联用均显著提高斑块稳定性Tadateru T. Presented on 68th Scientific Sessions of Japanese Circulation Society. Mar 27-29,2004,Tokyo,Japan.30*P=NS90* P0.05与基线相比斑块回声强度增加比例(%)更有效稳定斑块之乐组 (500mg/d)阿托伐他汀组 (10mg/d)之乐+阿托伐他汀组 P+S research unit Department of Cardiovascular Medicine,

11、 Osaka University Graduate School of Medicine, Japan.【 study design multi-centered, randomised, case-control study 410 patients with FH were randomisely grouped into probucol group (307 cases), non-probucol group (103 cases) Follow-up for 15 years (average), 20 years (maximum) Study time: 1984-2005

12、indicators cardiovascular events: include acute myocardial infarction, pectoris angina, heart failure, TIA or atherosclerosis induced peripheral arterial disease Probucol, secondary prevention for cardiovascular events in high risk patients Journal of Atherosclerosis and Thrombosis, 2008; 15:292-303

13、.POSITIVE研究Probucol, effective decrease in cardiovascular events之乐组非之乐组HR= 0.13讲义P0.00110080604020010501520未出现事件患者百分比随访时间%（年）Journal of Atherosclerosis and Thrombosis, 2008; 15:292-303.POSITIVE研究Although PAS therapy brought us good prospectus. But we still have some problems to investigate.Such as: Why combination therapy of atorvastatin and antioxidants make effects in plaque reversal? what is the mec