1. CHD Prevention in the Elderly: Should All Older Adults Be Treated? Lew Kuller, Dr.P.H., M.D., Graduate School of Public Health Professor, Department of Epidemiology

2. Pathophysiology of Vascular Disease Risk Factor Conditions Oxidative Stress Endothelium/Stem Cells/ Other Targets Dyslipidemia ↑Blood Pressure Heredity Smoking Diabetes Other Xanthine oxidase NADH/NADPH oxidase Uncoupled eNOS NF-KB Chemokines Growth factors Chemoattractni proteins Adhesion motcculcs ACE/Ang

3. Clinical Sequelae Structural Alterations Functional Alterations ↓Bioavailable NO (endothclial dynfunction) Reduced diliation or constriction Inflammation Procoagant Vascular surface Abnormal tone smc growth Inflammatory cell Infiltration Plaque growth Negative remodeling ↓Fibrinolysia ↓Platelet aggregation ↑inflammation Death Myocardial Infarction Stroke Ischemia Congestive heart failure Pepine CJ. Why vascular biology matters Am J Cartiol 2001 88(Suppl)):5K.9K

4. Lifetime Risk of a First Coronary Heart Disease Event, Excluding Angina Pectoris Lifetime Risk (Percent) Age (years)

5. Incidence of Myocardial Infarction by Age and Sex per 1000 Person-Years* (CHS) Rate Age (years) Rates were significantly higher in men than in women and strongly associated with age in both men and women

6. Incident Stroke by Age and Sex Women Men Age-Sex Group Rate per 1000 person-years

7. Prevalence (per 100) of CHF by Age (Years) and Gender CHF Prevalence (%) Age (years) Kitxman DW, Ganfin JM, Cottdiner Js, Hoinen R, Aurigenums G, Atarino ik, Lyles M, Cushman M, Enrigid M, for the CHS Research Group. Importance of heart failure with operserved systolic function in patients >=65 years of age. Am J Cartiol 2001; 57: 413-419

8. Systolic Function by Gender Among Participants with CHF MenWomen Kitxman DW, Ganfin JM, Cottdiner Js, Hoinen R, Aurigenums G, Atarino ik, Lyles M, Cushman M, Enrigid M, for the CHS Research Group. Importance of heart failure with operserved systolic function in patients >=65 years of age. Am J Cartiol 2001; 57: 413-419

9. Vascular Aging Athero - Plaques - Stenosis - Calcification - Rupture Sclerosis - Degeneration of elastin - Changes in collagen - Wall thickening - Arterial dilation

10. I. Measures of subclinical atherosclerosis and vascular disease are good surrogate measures. A.Subclinical measures are strongly correlated with extent of atherosclerosis. B.Traditional cardiovascular risk factors, LDLc, HDLc, smoking, and blood pressure are primary determinants of subclinical atherosclerosis such as coronary calcium scores. C.Measures of subclinical disease are powerful independent predictors of clinical disease. D.Change in risk factor levels are related to change in extent of subclinical disease over time. E.Changes in measure of subclinical disease are related to change in risk of disease.

11. Prevalence of Subelinical Disease in Men and Women by Age (Excluding Clinical Disease) – Cardiovascular Health Study Age (Years) Prevalence(%) N=223N=174N=234N=202N=320N=292N=257N=224N=44N=41 N=number with subclinical disease

12. Distribution of Specific Events in the CHS by Category of Subclinical and No disease (WOMEN) Average 2.4 Years Follow-up N=2 0 24 15 24 7 42 16 17 7 Category Incidence Rate (%) N = Number of events

13. CVD Mortality in CHS Participants With a Low AAI by Presence or Absence of CVD Risk Factors: Participants Without Prevalent CVD at Baseline (RR=2.54)(RR=2.27) 6 Yr Mortality Percent

14. Risk of Incident CV Events: Lower Extremity Arterial Disease Relative Risk Author Population Cutpoint M W Criqui,1992 624 LRC 0.8 or less 3.3 2.5 Leng,1996 1,592 Edinburgh 0.9 or less 1.9 Newman,1997 1,537 SHEP 0.9 or less 3.0 2.7 Newman,1999 4,268 CHS 0.9 or less 2.6 2.3

15. Relative risk * of Myocardial Infaretion as a Function of the Common-Carotid-Artery and Internal-Carotid Artery Intima-Media Thickness Expressed as Quintiles and as a Continuous Variable Relative Risk Maximal CCA IMTMaximal ICA IMTMaximal CCA & ICA IMT * Adjusted for age, sex & other risk factors

16. Unadjusted Relative risk of Myocardial Infarction as a Function of the Common-Carotid-Artery and Internal-Carotid Artery Intima-Media Thickness Expressed as Quintiles and as a Continuous Variable Relative Risk Maximal CCA & ICA IMTMaximal ICA IMTMaximal CCA IMT CCA: common Carotid Artery,ICA:internal Carotid Artery, IMT: Intima Media Thickness

17. Risk of Incident CV Events Associated with Carotid Disease Relative Risk Author Definition of disease M W Salonin,1991 CCA-Avg. IMT>1.0 mm 2.2 Chambless,1997 Average IMT>1.0 mm 1.9 5.1 Hodis,1998 CCA- Avg. IMT,75% 7.7 O’Leary,1999 CCA/ICA Max. IMT,80% 3.7

18. Associations Between the Incidence of Myocardial Infarctions and the Risk Factors Considered for Multivariate Analysis Variable Adjusted RR* * Adjusted for???

19. CHD Event Rate by Number of Subclinical Measures Rate 1)AAI 2)ECG 3)Common Carotid MIT>80% 4)Carotid Stenosis

20. Prevalence of Subclinical Disease by Diabetic Status (Excludes Clinical Disease) NN% Prevalent Diabetes at Baseline39729474 New* Diabetes at Baseline40529773 Total Diabetic80258873 NonDiabetic180497754 Subclinical *WHO criteria

21. Figure 4. Diabetes Status and Presence of Subclinical/clinical CVD at Baseline and Incidence of Specific Events Among Men and Women in the CHS Diabetes Status Rate Incident CHDIncident StrokeIncident CHF

22. Diabetes Status and Presence of Subclinical CVD at Baseline and Incidence of Specific Events Among Men and Women in the CHS Relative Risk Diabetes Status – Outcome: Death DS = Diabetes Status

23. Multivariate Associations of CVD Risk Factors with Incident CHD Among Diabetics 1.??-4.??0.65-1.650.97-1.641.00-1.290.97-1.160.65-5.060.94-1.09 CVD Risk Factors

24. Median CAC Scores for two populations: EBT Nashville* and ACE-CHS by age in men and women

25. ACE-CHS Median coronary artery calcification score by age in men and women n=614

26. Distribution of CAC Scores in Men % Coronary Artery Calcification Score Newman AB, Naydeck ???, Sutton-Tyttell K, Feldnun A, Edmundowice D, Kuller H Coronary artery Calcification in older adults to age 99. Prevalence and risk factors. Circulation 2001;104:2679-2684

27. Distribution of CAC Scores in Men Coronary Artery Calcification Score Newman AB, Naydeck ???, Sutton-Tyttell K, Feldnun A, Edmundowice D, Kuller H Coronary artery Calcification in older adults to age 99. Prevalence and risk factors. Circulation 2001;104:2679-2684

28. Calcium Score and Confirmed CHD Calcium ScoreNCHD(%)No CHD (%) 0-100835(6)78(94) 100-400401(3)39(97) 400-600163(19)13(81) >600186(33)12(67) Total15715(10)152(90) *Odds ratio=7

29. Median (Interquartile Range) of LDL Measures by Age <75, Race and Sex* in the CHS Study mg/dl * Data weighted by the reciprocal of the sampling probabilities

30. Figure 1. Odds Ratio of MI and Angina by quartiles of LDL, particles and size, as Compared to Super Healthy in CHS Women Only, Adjusted for Age&Race Odds Ratio Quartile Variable CHS

31. LDL Particles by sex and disease status GENDER Female Male 95% CILDL Particles nmol/L 170 63 228 111 246 169 191 243 Super healthy no subclinical dis subclinical disease angina or m

32. LDL Size by sex and disease status GENDER Female Male 95% CILDL Particles nmol/L 170 63 228 111 246 169 191 243 Super healthy no subclinical dis subclinical disease angina or m

33. Figure 3. Odds Ratio of MI and Angina vs. Super Healthy by Quartiles of HDLc Measured by NMR and CHS Laboratory for Men and Women Adjusted for Age and Race Odds Ratio Quartile Variable CHS Women Men

34. Multiple Logistic Regression Model of Relationship of NMR Measures and Angina, MI vs Super Healthy: Men & Women Odds Ratio Step 1: Age, Race Step 2:Step1+DBP, SBP, Educ, Waist Circ,Somking Step 3: Step2+Creatinine, CRP, LDL, HDL, Trig, Insulin LDL Particles, 100 nmol/L CHS

35. Summary 1.Total LDLc, number of LDL particles and LDL size predict risk of coronary heart disease in older women but not men 2.Number of LDL particles is a stronger predictor of CHD among women, independent of LDLc levels or measure of other cardiovascular risk factors 3.Large LDL (L3) by NMR is the most common LDL fraction among older women and does not predict risk of CHD 4.Large HDLc, but not small HDL, predicts CHD in both men and women

36. Relationship of NMR Lipoprotein to Coronary Calcium Scores Among Older Women in the Cardiovascular Health Study (CHS) – Age 80 (Agatston units.) Coronary Calcium Score NMR Lipoproteins LDL

37. Relationship of NMR Lipoprotein to Coronary Calcium Scores Among Older Women in the Cardiovascular Health Study (CHS) – Age 80 (Agatston units.) Coronary Calcium Score NMR Lipoproteins VLDL

38. Relationship of NMR Lipoprotein to Coronary Calcium Scores Among Older Women in the Cardiovascular Health Study (CHS) – Age 80 (Agatston units.) Coronary Calcium Score NMR Lipoproteins HDL

39. Relationship of Coronary Calcium, by Agatston Score, in the Cooper Clinic Cohort (6 year follow-up) to Combined Fatal and nonFatal CHD Outcome (n=17,256;461 events, 17 deaths) Adjusted Relative Risk* MI/CHD Death * Adjusted for age, gender, BMI, smoking habit, BIP, cholesterol, diabetes Final Program & Abstracts: AHA – 42 Anrnual Conference on Cardiiovascular Disease Epidemiology and Prevention. April 23-26, 2002, Honolulu,HA

40. SIMVASTATIN: VASCULAR EVENT by AGE & SEX Baseline Feature STATIN (10269) PLACEBO (10267) Age group(years) <658381093 65-69516677 70-74550628 >=75138208 Sex Male16762148 Female388458 ALL PATIENTS2042 (19.9%) 2608 (25.4%) 0.4 0.6 0.8 1.0 1.2 1.4 Het X = 4.4 Het X = 0.4 24% SE 2.6 Reduction (2P<0.00001) Risk ratio and 95%CI STATIN better STATIN worse

41. SHEP/Control Long Term Outcome CV Event-Free Survival K-M Estimate Years Since Subclinical Disease Measurement

42. 8 Post LDLc by and 2 EBCT Coronary Calcium Score: Nonhormone Users, n=78 (Agatston units) LDLc(mmHg) P=.07 Coronary Calcium Score(%)