动脉粥样硬化斑块逆转治疗和挑.ppt

动脉粥样硬化斑块逆转的 治疗和挑战,吉林大学第二医院心内科 孟晓萍,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PAS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,Probucol Aspirin Statins,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,8,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-R,SR-A,表达减少 功能下调,表达增加 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,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: 417-428,35 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,PGH2,PGC2,TXA2,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才能连接血小板 。,抑制氧化的 LDL-C 的形成,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(APS) 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）,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）,In PAS group, vascular stenosis was decreased by 24% after treatment.,Comparison of vascular plaque stenosis AS and PAS therapy （,Xs）,Comparing PAS group and AS group, PAS group had more 9% plaque reversal,Plaque 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,Qd P组 n=30 Probucol 250mg,Bid A+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 School of Medicine, Tokyo, Japan,probucol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=NS,90*,* 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, 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 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.,POSITIVE研究,Probucol, effective decrease in cardiovascular events,之乐组,非之乐组,HR= 0.13（0.05-0.34） P0.001,100,80,60,40,20,0,10,5,0,15,20,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 mechanism behi