How To Prevent A Heart Attack

Transcription

1 Atherosclerosis Timeline Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Plaque Rupture Cholesterol Accumulation - Inflammation Decades Modified from Stary HC et al, Circulation 92:1355, 1995 Thrombosis Seconds Normal Asymptomatic Atherosclerosis Symptomatic Atherosclerosis: Angina Myocardial Infarction Stroke

2 Cholesterol Transport and Atherosclerosis Atherogenic Transport Liver VLDL, LDL Cholesterol Core Arterial Wall HDL Bile Franceschini, 1999 Antiatherogenic Transport

3 CHD Prevention through Plaque Stabilization Atherogenic Transport Liver VLDL, LDL Today Cholesterol Core Arterial Wall Franceschini, 1999 Antiatherogenic Transport

4 The Statins First generation O H 3 C CH 3 O HO H O O CH 3 HO O O O H 3 C O H 3 C CH 3 H CH 3 H 3 C CH 3 HO O H COOH OH CH 3 HMG-CoA H 3 C H 3 C HO Lovastatin Simvastatin Pravastatin Second generation Third generation HO COOH OH HO COOH OH HO COOH OH F Fluvastatin CH 3 N CH 3 F N HN CH 3 O CH 3 F N H 3 C N CH 3 CH 3 N SO 2 CH 3 Atorvastatin Rosuvastatin

5 Statins and Cardiovascular Disease A Meta-analysis Relative Risk Reduction (%) S, WOSCOPS, CARE, AFCAPS/TexCAPS, LIPID, HPS, LIPS, PROSPER, ASCOT-LLA n= Major Coronary Events Stroke All-cause Mortality Cheung et al, BJCP 57:640,2004

6 Proportion with event (%) Statins and CHD Heart Protection Study high-risk subjects HPS Collaborative Group, Lancet 360:7,2002 Years of follow-up Placebo -27% Simvastatin 898 unavoided coronary events (vs 1212 on placebo)

7 Liver CHD Prevention through Plaque Stabilization Atherogenic Transport VLDL, LDL Today Cholesterol Core Arterial Wall Bile Franceschini, 1999 HDL Tomorrow? Antiatherogenic Transport

8 HDL Metabolism and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PL CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney

9 HDL-therapy Small Molecules target PPARα, CETP, ABCA1, others mode of action administration use plasma HDL raising oral chronic Franceschini et al, 2002

10 HDL-therapy Small Molecules target PPARα, CETP, ABCA1, others mode of action administration use plasma HDL raising oral chronic Franceschini et al, 2002

11 Fibrates and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PC CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney

12 Fibrates in Secondary Prevention The VA-HIT Study CHD Events (%) coronary patients < 74 y HDL-C <40 mg/dl; TG <300 mg/dl; LDL-C <140 mg/dl Gemfibrozil (1200 mg/d) for 5.1 years HDL-C: +6%; LDL-C: = Placebo -22% Gemfibrozil Years Rubins et al, NEJM 341:410,1999

13 HDL-therapy Small Molecules target PPARα, CETP, ABCA1, others mode of action administration use plasma HDL raising oral chronic Franceschini et al, 2002

14 CETP Inhibitors and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PC CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney

15 CETP Inhibitors and Antiatherogenic Cholesterol Transport Liver LDL-R SR-BI TG HDL 3 CE LCAT ApoA-I ABCA1 Arterial Wall Macrophage VLDL,LDL CETP C,PC CE nhdl TG HL,EL Franceschini et al, 2002 HDL 2 Kidney

16 Torcetrapib in Volunteers 100 CETP Inhibition (%) Clark et al, ATVB 24:490, mg/day 240 mg/day Time after dose (hrs)

17 Torcetrapib in Low-HDL Patients HDL Cholesterol (mg/dl) Placebo Treatment LDL Cholesterol (mg/dl) mg/day 240 mg/day 120 mg/day 240 mg/day Brousseau et al, NEJM 350:1505,2004 Torcetrapib

18 HDL-therapy target Small Molecules PPARα, CETP, ABCA1, others Synthetic HDL plaque mode of action administration use plasma HDL raising oral chronic plaque stabilization parental acute/subacute Franceschini et al, 2002

19 Plasma vs. Synthetic HDL Unesterified Cholesterol Phospholipids (PCs, SM, etc.) Phosphatidylcholine (DPPC) CE,TG ApoA-I Plasma HDL Franceschini et al, 2003 ApoA-II Apolipoprotein (ApoA-I, ra-i M /A-I M ) Synthetic HDL

20 Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS Nissen et al, JAMA 290:2292, 2003

21 Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS 47 patients, 5 weekly injections of ra-i M /A-I M shdl (15 or 45 mg/kg) Vessel Area Lumen Area Atheroma Area Primary end-point: change in total atheroma volume Nissen et al, JAMA 290:2292, 2003

22 Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS 0.5 Atheroma Volume (% change) Placebo Nissen et al, JAMA 290:2292, 2003 n=21 n=15 n=36 shdl (15 mg/kg) shdl (45 mg/kg) n=11 n=36 shdl all

23 Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS 47 patients, 5 weekly injections of ra-i M /A-I M shdl (15 or 45 mg/kg) Vessel Area Lumen Area Atheroma Area Secondary end-point: change in the most severely diseased 10-mm segment Nissen et al, JAMA 290:2292, 2003

24 Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS Atheroma Volume (% change) Most Severely Diseased 10-mm Segment Nissen et al, JAMA 290:2292, 2003 Placebo shdl

25 Regression of Coronary Atherosclerosis by ra-i M /A-I M shdl in Patients with ACS -34% Nissen et al, JAMA 290:2292, 2003

26 Soft Plaque Regression by ra-i M /A-I M shdl in Rabbits shdl (1.0 g ra-i M /A-I M ) infusion over 90 min through IVUS catheter Chiesa et al, Circ Res 90:974, 2002 Saline (3 days) shdl (3 days) Oil Red O Stain

27 Liver CHD Prevention through Plaque Stabilization Atherogenic Transport VLDL, LDL Today Cholesterol Core Arterial Wall Bile Franceschini, 1999 HDL Tomorrow Antiatherogenic Transport

28 Regression of Coronary Atherosclerosis LDL-lowering or shdl-therapy? Atheroma Volume (change, %) Pravastatin (LDL-C mg/dl) 18 months Atorvastatin (LDL-C mg/dl) 5 weeks ra-i M /A-I M shdl Nissen et al, JAMA 290:2292, 2003 Nissen et al, JAMA 291:1071, 2004