1、第五届中-日心血管论坛,Masakazu Yamagishi , MD, FACC Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, JAPAN,危险因素的强化干预对冠状动脉疾病的进展或消退的作用,申明,本研究曾得到Kowa和Shionogi制药公司的赞助.,KFC,McD,Olympics in Tokyo,Changes in Cholesterol Levels in Japan and US,Increased PCI Even Universi
2、ty Hospital,2003,2004,2005,2006,2007,2008,左主干病变,经皮冠脉介入治疗前,经皮冠脉介入治疗,经皮冠脉介入治疗,经皮冠脉介入治疗,经皮冠脉介入治疗,再狭窄,再狭窄,再狭窄,再-再狭窄,冠脉搭桥,日本金泽市心脏研究所成员,横浜栄共済病院,富山赤十字病院,石川県立中央病院,福井県立病院,金沢循環器病院,福井循環器病院,加賀市民病院,金沢社保病院,小松市民病院,芳珠記念病院,KKR北陸病院,舞鶴共済病院,済生会金沢病院,高岡市民病院,金沢大学附属病院,厚生連高岡病院,Subjects,左主干病变：随访,0,200,400,600,800,1000,1200,P
3、=N.S.,Kaplan-Meier法,0,20,40,60,80,100,(%),（天）,SYNTAX试验,主要不良事件主要发生在SYNTAX积分高患者行PCI后,COURAGE 研究(血运重建和强化药物的临床评价),强化药物治疗,0,1,3,7,5,6,2,4,1.0,0.6,0.9,0.7,0.5,0.8,0,无任何原因死亡或心梗发生的存活率,年,危险比, 1.05; 95%可信区间 (0.87-1.27); p=0.62,(Boden WE. et al.: NEJM 2007:356: 1503),日本-急性冠脉综合征,普伐他汀 和阿托伐他汀在急性冠脉综合征日本人群的评估,Takes
4、hi Kimura (Kyoto University) Takeshi Morimoto (Kyoto University) Izumi Miki (Kyoto University) Saeko Minematsu (Kyoto University) Takafumi Hiro (Yamaguchi University) Hiroko Kanou（Yamaguchi University) Katsumi Miyauchi (Juntendo University) Natsuko Yamamoto（Juntendo University) Yoshihisa Nakagawa (T
5、enri Hospital) Yukio Ozaki (Fujita Health University) Masakazu Yamagishi (Kanazawa University) Tetsu Yamaguchi (Toranomon Hospital) Satoshi Saito (Nihon University) Kazuo Kimura (Yokohama City University Medical Center) Hiroyuki Daida (Juntendo University) Masunori Matsuzaki (Yamaguchi University)fo
6、r the JAPAN-ACS Investigators,终点 : % 远离靶病变5mm以上的位置斑块变化体积百分比 纳入标准 : 诊断为急性冠脉综合征的患者同时在IVUS指导下成功进行了PCI 研究起止时间 : 2005.11.1. 2007.10.31. ( 注册时间: - 2006.10.31.) 项目负责人: Masunori Matsuzaki 秘书: Hiroyuki Daida, Takeshi Kimura 参加人员 : Katsumi Miyauchi, Yoshihisa Nakagawa, Masakazu Yamagishi, Yukio Ozaki, Takafum
7、i Hiro,PCI IVUS,72 小时后,8 - 12 个月,IVUS,普伐他汀 4mg/day,阿托伐他汀 20mg /day,知情同意书,随机给予,Circ J 2006；70：16241628,急性冠脉综合征,研究方案,根据性别、有无糖尿病 和入院时胆固醇水平进 行危险分层,血脂指标的变化,低密度脂蛋白胆固醇,甘油三酯,高密度脂蛋白胆固醇,非高密度脂蛋白胆固醇,(%),( ): 患者数目, meanSD 双样本 t-检验 (两组间), 单样本 t检验 (each group) * : p 0.01, * : p 0.001,高密度脂蛋白胆固醇,40mg/dL 基线水平,-40,-30
8、,-20,-10,0,10,20,30,-35.8 22.9,-36.2 19.5,*,p=0.9,-30.1 20.8,-30.5 18.9,21.2 75.5,16.2 59.9,9.9 23.5,8.0 21.4,*,*,*,*,*,*,*,20.6 24.6,10.8 25.3,*,*,(39),(46),p=0.08,(124),(125),(124),(124),(124),(125),(122),(123),p=0.6,p=0.5,p=0.9,(Hiro T et al JACC 2009),术前,术后,ID # 008 64岁，男性 基线 (mm3) 斑块容积=84.6 血管容
9、积=168.8 管腔容积=84.2 随访(mm3) 斑块容积=71.8 血管容积=163.7 管腔容积=91.8 变化百分比 斑块容积=-15.1 % 血管容积=-3.0% 管腔容积=+9.0%,(Hiro T et al JACC 2009),斑块容积的变化,均值标准差 单样本 t-检验,阿托伐他汀(n=127),p=0.5,p=0.5,斑块容积变化的百分比,斑块容积百分比的变化,标准化的斑块容积变化,p=0.3,(mm3),斑块容积变化的均值,-18.1 14.2,*,-16.9 13.9,*,-6.26 6.15,*,-5.73 6.26,*,-9.82 8.58,*,-8.75 8.2
10、0,*,(Hiro T et al JACC 2009),ESTABLISH （ATV 20 mg）,JAPAN-ACS,（PTV 4 mg）（ATV 20 mg）,ESTABLISH （）,逆转 （普伐他汀 40 mg）,逆转 （阿托伐他汀 80 mg）,ASTEROID* (RSV 40mg),A-PLUS (),(mg/dL),LDL-C（mean value）,-20,-10,0,10,60,80,100,120,Overseas, Chronic Phase,JAPAN、Acute Phase（ACS）,*标准化的总的斑块容积,ASTEROID: JAMA 2006,295:1556
11、-1565 ESTABLISH: Circulation 2004,110:1061-1068. REVERSAL: JAMA 2004;291:1071-1080 JAPAN-ACS: 72th JCS Late Breaking Clinical Trials A-PLUS: Circulation 2004,110;3372-3377,(%),R2=0.7617,R2=0.8807,低密度脂蛋白水平和斑块消退,体積変化率（平均値）,血管内超声检测罗伐他汀日本冠状动脉粥样硬化人群中作用的研究,COSMOS,Hiroyuki Daida Juntendo University Tadater
12、u Takayama Nihon University Takafumi Hiro Yamaguchi University Masakazu Yamagishi Kanazawa University Atsushi Hirayama Nihon University Satoshi Saito Nihon University Tetsu Yamaguchi Toranomon Hospital Masunori Matsuzaki Yamaguchi Universityon behalf of COSMOS investigators,ClinicalTrials.gov Identi
13、fier: NCT00329160, Sponsors and Collaborators: AstraZeneca Shionogi, Phase: Phase IV,研究方案,就诊周数:,-1 -8,筛选,00,728,832,936,1040,1144,1248,1352,1456,1560,1664,1768,1872,1976,624,520,416,312,28,14,血管内超声/冠脉造影 血脂水平 超敏C-反应 蛋白,血管内超声/冠脉造影 血脂水平 超敏C-反应蛋白,血脂水平,血脂水平 超敏C反应蛋白,血脂水平,罗伐他汀2.5 - 20 mg,Takayama T et al.
14、Circ. J 2007;71 (2) :271-275,从 2.5 mg/day开始,如果低密度脂蛋白胆固醇仍高于80 mg/dL， 剂量逐渐增加至 20 mg/day,1) 20-75 岁 2) 冠心病需行PCI的患者 3) 高胆固醇血症A) 未干预的人群: 低密度脂蛋白胆固醇 B) 曾接受过治疗的患者: 140mg/dL 或总胆固醇220mg/dL 低密度脂蛋白胆固醇 100mg/dL或 总胆固醇180mg/dL 4) PCI病变: 75%, 靶病变: 50%狭窄,血脂指标的变化,-4.8,+19.8,-38.6,-47.5,-50,0,50,(%),甘油三酯(mg/dL),高密度脂蛋白
15、 胆固醇(mg/dL),低密度脂蛋白 胆固醇 (mg/dL),LDL-C/ HDL-C 比,p0.0001,p=0.1639,p0.0001,p0.0001,140.2 82.9,47.1 55.2,147.8 130.3,3.12 1.56,基线 随访,p value : 随访 vs. 基线水平,变化百分比的平均值,n=126,Case: 53岁 女性 右冠#2,基线,随访(76周),病例报告,冠脉容积指标的变化,(%),斑块容积,管径容积,血管容积,p0.0001,p=0.4673,p0.0001,-10,-5,0,5,10,+7.25,-5.07,+0.76,变化百分比均值,n=126,
16、Takayama T et al. Circ. J 2009 in press,低密度脂蛋白胆固醇水平和斑块容积变化百分比的关系,糖尿病患者斑块容积负向变化,-6,-3,0,25 n=69,25 n=57,基线体重指数,6.5 n=32,6.5 n=94,基线糖化血红蛋白,-6.10*,-3.82,-6.53*,-0.78,p=0.3682,p=0.0454,变化百分比均值,(%),*：p0.02 (follow-up vs. baseline),LDL-C,Vascular events,Hypertension DM Smoking Stress,LDL-C and Other Risk
17、Factors,HDL-C,Change in Lipid Parameters,-4.8,+19.8,-38.6,-47.5,-50,0,50,(%),TG (mg/dL),HDL-C (mg/dL),LDL-C (mg/dL),LDL-C/ HDL-C ratio,p0.0001,p=0.1639,p0.0001,p0.0001,140.2 82.9,47.1 55.2,147.8 130.3,3.12 1.56,Baseline Follow-up,p value : follow-up vs. baseline,Mean % Change,n=126,(Takayama T et al
18、. Circ. J 2009 in press),liver,macrophage,LDLR,ABCG1,ABCA1,VLDL,LDL,SR-BI,SR-BI,ABCA1,apoA-I,HDL,pre- HDL,CETP,CD36,Nissen S et al. NEJM 2007（改）,Enhanced LDL-C Extraction Through SR-B1 by Serum From CETP Deficiency,0,10,20,30,with anti-SRBI antibody (750:1),3H-cholesterol efflux (%),withoutanti-SRBI
19、 antibody,net efflux,CETP欠損症 Homozygotes (n=3),CETP欠損症 Heterozygotes (n=5),Controls (n=10),Miwa K, Kawashiri M, Yamagishi M et al.: Clin Chem Acta 2009,LDL-C,Vascular events,Hypertension DM Smoking Stress,LDL-C and Other Risk Factors,HDL-C,再会於金沢,金沢城,兼六園,主計町茶屋街,The 5th China-Japan Cardiovascular Foru
20、m,Masakazu Yamagishi , MD, FACC Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, JAPAN,Impact of Aggressive Treatment for Risk Factors on Progression or Regression of Coronary Artery Disease,Disclosure,There is nothing for disclosure except modest suppo
21、rts from Kowa and Shionogi Pharmaceutical Companies.,Left Main Lesion,Before PCI,PCI,PCI,PCI,PCI,PCI,Restenosis,Restenosis,Restenosis,Re-restenosis,CABG,Members of Kanazawa Heart,横浜栄共済病院,富山赤十字病院,石川県立中央病院,福井県立病院,金沢循環器病院,福井循環器病院,加賀市民病院,金沢社保病院,小松市民病院,芳珠記念病院,KKR北陸病院,舞鶴共済病院,済生会金沢病院,高岡市民病院,金沢大学附属病院,厚生連高岡病
22、院,LMCA：Follow-up,0,200,400,600,800,1000,1200,P=N.S.,Kaplan-Meier法,0,20,40,60,80,100,(%),（days）,SYNTAX Trial,Mace more frequently occurs in patients with high SYNTAX scores after PCI.,COURAGE (Clinical outcomes utilizing revascularization and aggressive drug evaluation) Study,Aggressive medical treat
23、ment,0,1,3,7,5,6,2,4,1.0,0.6,0.9,0.7,0.5,0.8,0,Survival Free of Death from Any Cause and Myocardial Infarction,年,Hazzard ratio, 1.05; 95% CI (0.87-1.27); p=0.62,(Boden WE. et al.: NEJM 2007:356: 1503),JAPAN-ACS,Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome,Takeshi Kimu
24、ra (Kyoto University) Takeshi Morimoto (Kyoto University) Izumi Miki (Kyoto University) Saeko Minematsu (Kyoto University) Takafumi Hiro (Yamaguchi University) Hiroko Kanou（Yamaguchi University) Katsumi Miyauchi (Juntendo University) Natsuko Yamamoto（Juntendo University) Yoshihisa Nakagawa (Tenri Ho
25、spital) Yukio Ozaki (Fujita Health University) Masakazu Yamagishi (Kanazawa University) Tetsu Yamaguchi (Toranomon Hospital) Satoshi Saito (Nihon University) Kazuo Kimura (Yokohama City University Medical Center) Hiroyuki Daida (Juntendo University) Masunori Matsuzaki (Yamaguchi University)for the J
26、APAN-ACS Investigators,End point : % change in plaque volume at sites 5 mm apart from the culprit lesions Inclusion Criteria : Patients who have been diagnosed as acute coronary syndrome and with successful PCI by IVUS guidance Study period : 2005.11.1. 2007.10.31. ( Enrollment : - 2006.10.31.) Stud
27、y chair : Masunori Matsuzaki Secretary : Hiroyuki Daida, Takeshi Kimura Working member : Katsumi Miyauchi, Yoshihisa Nakagawa, Masakazu Yamagishi, Yukio Ozaki, Takafumi Hiro,PCI IVUS,72 hours,8 - 12 months,IVUS,Pitavastatin 4mg/day,Atorvastatin 20mg /day,Informed consent,Randomized,Circ J 2006；70：16
28、241628,Acute Coronary Syndrome,Study Protocol,stratified by: gender diabetes mellitus TC level on admission,Change in Lipid Parameters,LDL-C,TG,HDL-C,Non-HDL-C,(%),( ): number of patients, meanSD 2 sample t-test (between groups), 1 sample t-test (each group) * : p 0.01, * : p 0.001,HDL-C,40mg/dL at
29、baseline,-40,-30,-20,-10,0,10,20,30,-35.8 22.9,-36.2 19.5,*,p=0.9,-30.1 20.8,-30.5 18.9,21.2 75.5,16.2 59.9,9.9 23.5,8.0 21.4,*,*,*,*,*,*,*,20.6 24.6,10.8 25.3,*,*,(39),(46),p=0.08,(124),(125),(124),(124),(124),(125),(122),(123),p=0.6,p=0.5,p=0.9,(Hiro T et al JACC 2009),Before,After,ID # 008 64y.o.
30、 male Baseline (mm3) Plaque Volume=84.6 Vessel Volume=168.8 Lumen Volume=84.2 Follow Up (mm3) Plaque Volume=71.8 Vessel Volume=163.7 Lumen Volume=91.8 % Change Plaque Volume=-15.1 % Vessel Volume=-3.0% Lumen Volume=+9.0%,(Hiro T et al JACC 2009),Illustration of Change in Plaque Volume,meanSD 1 sampl
31、e t-test,Atorvastatin (n=127),p=0.5,p=0.5,% Change in Plaque Volume,Change in % Plaque Volume,Change in Normalized Plaque Volume,p=0.3,(mm3),Mean Change in Plaque Volume,-18.1 14.2,*,-16.9 13.9,*,-6.26 6.15,*,-5.73 6.26,*,-9.82 8.58,*,-8.75 8.20,*,(Hiro T et al JACC 2009),ESTABLISH （ATV 20 mg）,JAPAN
32、-ACS,（PTV 4 mg）（ATV 20 mg）,ESTABLISH （）,REVERSAL （PRV 40 mg）,REVERSAL （ATV 80 mg）,ASTEROID* (RSV 40mg),A-PLUS (),(mg/dL),LDL-C（mean value）,-20,-10,0,10,60,80,100,120,Overseas, Chronic Phase,JAPAN、Acute Phase（ACS）,*normalized total plaque volume,ASTEROID: JAMA 2006,295:1556-1565 ESTABLISH: Circulatio
33、n 2004,110:1061-1068. REVERSAL: JAMA 2004;291:1071-1080 JAPAN-ACS: 72th JCS Late Breaking Clinical Trials A-PLUS: Circulation 2004,110;3372-3377,(%),R2=0.7617,R2=0.8807,LDL-C Levels and Plaque Regression,体積変化率（平均値）,COronary atherosclerosis Study Measuring effects Of rosuvastatin using intravascular
34、ultrasound in Japanese Subjects,COSMOS,Hiroyuki Daida Juntendo University Tadateru Takayama Nihon University Takafumi Hiro Yamaguchi University Masakazu Yamagishi Kanazawa University Atsushi Hirayama Nihon University Satoshi Saito Nihon University Tetsu Yamaguchi Toranomon Hospital Masunori Matsuzak
35、i Yamaguchi Universityon behalf of COSMOS investigators,ClinicalTrials.gov Identifier: NCT00329160, Sponsors and Collaborators: AstraZeneca Shionogi, Phase: Phase IV,Study Protocol,Visit: Week:,-1 -8,Screening,00,728,832,936,1040,1144,1248,1352,1456,1560,1664,1768,1872,1976,624,520,416,312,28,14,IVU
36、S/CAG Lipid Levels hsCRP,IVUS/CAG Lipid Levels hsCRP,Lipid Levels,Lipid Levels hsCRP,Lipid Levels,Rosuvastatin 2.5 - 20 mg,Takayama T et al. Circ. J 2007;71 (2) :271-275,Treatment started with 2.5 mg/day, and if LDL-C80 mg/dL was not achieved, the dosage was titrated to 20 mg/day,1) 20-75 years old
37、2) Patients with CHD who required PCI 3) HypercholesterolemiaA) Untreated patients: LDL-C B) Prior use patients: LDL-C140mg/dL or TC220mg/dL 100mg/dL or TC180mg/dL 4) PCI lesion: 75%, target lesion: 50% stenosis,Patient Flow,214 subjects enrolled,Completed study n=126,IVUS not analyzable, Lost to fo
38、llow up, Withdrew consent and others n=87,Rosuvastatin 2.5 - 20 mg/day n=213,Did not receive study drug n=1,Change in Lipid Parameters,-4.8,+19.8,-38.6,-47.5,-50,0,50,(%),TG (mg/dL),HDL-C (mg/dL),LDL-C (mg/dL),LDL-C/ HDL-C ratio,p0.0001,p=0.1639,p0.0001,p0.0001,140.2 82.9,47.1 55.2,147.8 130.3,3.12
39、1.56,Baseline Follow-up,p value : follow-up vs. baseline,Mean % Change,n=126,Case: 53y/o female RCA#2,Baseline,Follow up(76W),Case Presentation,Change in Coronary Artery Volume Parameters,(%),Plaque volume,Lumen volume,Vessel volume,p0.0001,p=0.4673,p0.0001,-10,-5,0,5,10,+7.25,-5.07,+0.76,Mean % Cha
40、nge,n=126,Takayama T et al. Circ. J 2009 in press,Relationship Between LDL-C level and % Change in Plaque Volume,Impaired Change in Plaque Volume in DM,-6,-3,0,25 n=69,25 n=57,BMI at baseline,6.5 n=32,6.5 n=94,HbA1c at baseline,-6.10*,-3.82,-6.53*,-0.78,p=0.3682,p=0.0454,Mean % Change,(%),*：p0.02 (follow-up vs. baseline),LDL-C,Vascular events,Hypertension DM Smoking Stress,LDL-C and Other Risk Factors,HDL-C,再会於金沢,
