1. Atherosclerosis – A Systemic Complex Disease

2. Agenda What is atherosclerosis? What is the role of endothelial dysfunction in the atherosclerotic process? What is the effect of lipid therapy on atherosclerosis?

3. Agenda What is atherosclerosis? What is the role of endothelial dysfunction in the atherosclerotic process? What is the effect of lipid therapy on atherosclerosis?

4. Atherosclerosis Is a Chronic Inflammatory Disease With LDL-C at the Core Libby P. J Intern Med. 2000;247:349-358. PHASE I: Initiation PHASE II: ProgressionPHASE III: Complication

5. Atherosclerosis Starts at a Young Age 0% 20% 40% 60% 80% 100% <2525-35>35 Donor Age (yr) 22% 47% 70% Nissen S. Am J Cardiol. 2001:87(suppl):15A-20A. Determined by coronary intravascular ultrasound Prevalence of Atherosclerosis (%)

6. Atherosclerosis Frequently Goes Undetected for Years Lumen size does not change significantly— even in the presence of a large lipid core Strong JP, et al. JAMA. 1999;281:727-735. Glagov S, et al. N Engl J Med.1987;316:1371-1375. Media Intima Media Intima Lumen Size of lumen does not change dramatically Vascular wall remodels to accommodate lipid core

7. Kannel WB. Importance of hypertension as a major risk factor in cardiovascular disease. In: Genest J, Koiw E, Kuchel O, Boucher R, Nowaczynski W, Rojo-Ortega JM eds. Hypertension: Physiopathology and Treatment. New York, NY: McGraw-Hill Book Co;1977:888-910. Risk Factors Can Further Confound Atherosclerosis—and Increase CHD Risk X 16 X 4.5 X 9 X 6 X 3 X 4 X 1.6 Framingham Interaction of Risk Factors Smoking Hypertension SBP >195 mm Hg Cholesterol TC >330 mg/dl (8.53 mmol/L)

8. Heart Disease: A Textbook of Cardiovascular Disease. 6th ed. Philadelphia, Pa: W.B.Saunders Co; 2001:995-1009. Miller M. Clin Cardiol. 1999;22(suppl II):II-1-II-6. Hyperlipidemia Initiates the Development of Atherosclerotic Plaque

9. Libby P. J Intern Med. 2000;247:349-358. How Do We Interrupt the Disease Cascade?

10. Stable Plaque Growth Can Lead to Vascular Occlusion STABLE PLAQUE Libby P. Lancet. 1996;348:S4-S7.

11. This high magnification of the atheroma shows numerous foam cells and an occasional cholesterol cleft. Atheromatous Plaque, Histological View

12. What Characterizes Unstable Plaque? Libby P. Circulation. 1995;91:2844-2850.

13. Glagov S, et al. N Engl J Med. 1987;316:1371-1375. Hackett D. Eur Heart J. 1988;9:1317-1323. Libby P. Lancet. 1996;348:S4-S7. Unstable angina Stroke Peripheral ischemia Unstable Plaque Rupture Can Lead to Serious Complications Including MI, Unstable Angina, Stroke, and Peripheral Ischemia Myocardial infarction

14. Stable plaque can cause systemic complications related to vascular narrowing and occlusion, including stable angina, stroke, renal dysfunction, myocardial infarction, and peripheral ischemia Renal dysfunction Stroke Stable angina Myocardial infarction Virmani R et al. Arterioscler Thromb Vasc Biol. 2000;20:1262-1275. Libby P. Circulation. 1995;91:2844-2850. Vascular Occlusion Ultimately Results in Systemic Complications Peripheral ischemia

15. Atherosclerosis (Summary) Starts at a young age and frequently goes undetected for years Multiple risk factors including hyperlipidemia, hypertension, smoking dramatically increase risk for a cardiovascular event Therapies that impact plaque progression and stabilization may play an important role in preventing cardiovascular events

16. Agenda What is atherosclerosis? What is the role of endothelial dysfunction in the atherosclerotic process? What is the effect of lipid therapy on atherosclerosis?

17. NORMAL ENDOTHELIUM ABNORMAL ENDOTHELIUM LDL-C HTN Diabetes Smoking DYSFUNCTION Vascular tone Retard platelet & leukocyte adhesion Inhibit SMC migration/ proliferation Barrier to LDL-C Degrade VLDL-C & chylotriglyceride (lipase) Platelet leukocyte adhesion SMC migration & growth Lipid deposition Clearance Vasoconstriction Dysfunction Endothelial Dysfunction: Imbalance of Normal Vascular Processes Vogel RA. Am J Med. 1999;107:479-487. Forgione MA, et al. J Curr Opin Cardiol. 2000;15:409-415.

18. Methods to Assess Endothelial Function Invasive Measures Quantitative coronary angiography – Changes in coronary artery size – Endothelial-mediated vasodilation with serial intracoronary infusions of increasing dosages of acetylcholine Noninvasive Measures Ultrasound of brachial artery – Changes in brachial artery size – Endothelial-mediated vasodilation with reactive hyperemia Whether brachial artery endothelial function correlates directly with coronary artery endothelial function is an important question that is currently being studied Di Mario C, et al. Am Heart J. 1994;127:514-531. Weldinger F, et al. Am J Cardiol. 2002;89:1025-1029. Corretti M, et al. J Am Coll Cardiol. 2002;39:257-265. Fathi R, et al. Am Heart J. 2001;141:694-703. Gokee N, et al. Circulation. 2002;105:1567-1572. Bae J-H. J Cardiol. 2001;37 Suppl:89-92. Deng YB, et al. Clin Cardiol. 2001;24:291-296. Kuvin J, et al. J Am Coll Cardiol. 2001;38:1843-1849. Kuvin J, et al. Am Heart J. 2001;141:327-328.

19. 500 asymptomatic subjects composite risk factor score calculated for each subject one point for each of the following: – Cholesterol  240mg/dl – Current or former smoker – Current smoker with consumption  10 pack-years – Family history of premature vascular disease – Male gender – Age  50 years 0 P<0.001 Flow- Mediated Dilation (%) 20 15 10 5 0 -5 1234 55 Flow-mediated dilation measured by external ultrasound imaging of the brachial or femoral artery Celermajer DS, et al. J Am Coll Cardiol. 1994;24:1468–1474. Risk Factor Score Risk Factors Are Strongly Related to Endothelial Dysfunction

20. Value taken at 7.7 years follow-up 147 patients admitted after routine diagnostic cath or PTCA Cardiac events include CV death, unstable angina, MI, PTCA, CABG, ischemic stroke, peripheral artery revascularization 4.3% 12% 25% Normal (N=23) Mild–Moderate (N=25) Severe (N=20) Flow-dependent Dilation≥19%10.3–19% Worsening Endothelial Dysfunction Cardiac Event Incidence (%) Adapted from Schachinger V, et al. Circulation. 2000;101:1899–1906. <10.3% Endothelial Dysfunction May Be Associated With Adverse Clinical Outcomes

21. FMD = Flow-Mediated Dilation Adapted from Neunteufl T, et al. Am J Cardiol. 2000;86:207–210. 15% 50% Normal (FMD>10%) Abnormal (FMD<10%) Cardiac Event Incidence (%) P = 0.002 Value taken at 5 years 73 patients admitted with angina pectoris who underwent coronary angiography FMD evaluated by brachial artery ultrasound examination Cardiac events include myocardial infarction, CABG, PTCA Endothelial Dysfunction May Be Associated With Adverse Clinical Outcomes

22. Potential Mechanisms By Which Statins May Affect Endothelial Dysfunction The clinical relevance of these effects has not been established. Data on file, Parke-Davis.

23. 3 months 220 patients Patient population Patients with CHD Atorvastatin 80 mg Pravastatin 40 mg REVERSAL Substudy REVERSing Atherosclerosis with Aggressive Lipid Lowering Brachial reactivity Brachial Artery Reactivity Trial (BART)

24. Endothelial Dysfunction Endothelial dysfunction reflects an imbalance of normal vascular processes Risk factors including hyperlipidemia, hypertension, diabetes and smoking may contribute to endothelial dysfunction and may have an cumulative effect Endothelial dysfunction may be correlated with clinical outcomes Statin therapy may improve endothelial dysfunction

25. Agenda What is atherosclerosis? What is the role of endothelial dysfunction in the atherosclerotic process? What is the effect of lipid therapy on atherosclerosis?

26. Statin Coronary Angiographic Studies Suggest Better Outcomes Due to Plaque Stabilization and Composition DurationDrug/dose in % in Studyn(years)(mg/day)stenosisCV events CCAIT1652 L 36 † 1.7*-28 MAAS1444 S 202.1*— PLAC I2062 P 40— -60* LCAS1712.5F 40 + C0.6*-33 Post-CABG6765.4L 76 + C7.9*-29* *Statistically significant. † Average daily dose. C, cholestyramine; Cp, colestipol; CV, cardiovascular; F, fluvastatin; L, lovastatin; P, pravastatin; S, simvastatin. Blankenhorn DH, et al. Ann Intern Med. 1993;119:969-976. Brown G, et al. N Engl J Med. 1990;323:1289-1298. Herd JA, et al. Am J Cardiol. 1997;80:278-286. Pitt B, et al. J Am Cardiol. 1995;26:1133-1139. The Post Coronary Artery Bypass Graft Trial Investigators, N Engl J Med. 1997;336:153-162. Vos J, et al. Eur Heart J. 1997;18:1081-1089. Waters D, et al. Circulation. 1995;92:2404-2410.

27. New Diagnostic Techniques Are More Sensitive in Determining the True Extent of the Disease Nissen S. Am J Cardiol. 2001;87(suppl):15A-20A.

28. ASAP Study Demonstrated IMT Regression with Atorvastatin 80 mg in FH Patients -0.04-0.0200.020.04 Mean change (mm) Atorvastatin 80 mg Simvastatin 40 mg Reduction Increase Change in carotid intima media thickness (IMT) over 2 years p=0.0017 p=0.0005 Smilde TJ, et al. Lancet. 2001;357:577-581.

29. Marchesi S, et al. J Cardiovasc Pharmacol. 2000: 36:617-621. 0 2 4 6 8 10 12 % Change FMV baseline week 1 week 2week 4 week 8 Atorvastatin Diet *p<0.05 vs diet Changes in brachial artery flow-mediated vasodilation (FMV) over time * * * Statin Therapy Improved Flow-mediated Vasodilation in Hyperlipidemic Women

30. Effects of Lipid Therapy Research suggests that changes in plaque stability and composition, in response to lipid-lowering therapy, may be responsible for reductions of coronary events Statin therapy improved flow-mediated vasodilation in hyperlipidemic women ASAP study demonstrated IMT regression with atorvastatin 80 mg in FH patients compared with FH patients on simvastatin 40 mg Blankenhorn DH, et al. Ann Intern Med. 1993;119:969-976. Brown G, et al. N Engl J Med. 1990;323:1289-1298. Herd JA, et al. Am J Cardiol. 1997;80:278-286. Pitt B, et al. J Am Cardiol. 1995;26:1133-1139. The Post Coronary Artery Bypass Graft Trial Investigators, N Engl J Med. 1997;336:153-162. Vos J, et al. Eur Heart J. 1997;18:1081-1089. Waters D, et al. Circulation.1995;92:2404-2410. Smilde TJ et al. Lancet. 2001;357:577-581. Marchesi S et al. J Cardiovasc Pharmacol 2000: 36:617-621

31. Conclusion Atherosclerosis is a complex systemic disease involving LDL deposition, endothelial dysfunction, and inflammation that may drive the progression of disease Endothelial dysfunction may be predictive of CVD risk Besides their lipid-lowering efficacy statins may provide additional vascular benefits Libby P. J Intern Med. 2000;247:349-358. Schachinger V, et al. Circulation. 2000;101:1899–1906. Marchesi S, et al. J Cardiovasc Pharmacol. 2000: 36:617-621.