Donald M. Lloyd-Jones, MD, ScM MESA Steering Committee February 2, 2005

1. Association of Lipoprotein Particle Number and Size with Subclinical Coronary Atherosclerosis in MESA Donald M. Lloyd-Jones, MD, ScM MESA Steering Committee February 2, 2005

2. Lipids and CVD Risk Total cholesterol Cholesterol subfractions (LDL/HDL/TG) Lipoproteins/Apoproteins Lipoprotein particle size/number

3. LDL Size and Risk for CHD • Controversy regarding importance of LDL size • Quebec CV Study • Men with mean LDL <25.6 nm had OR of 2.2 for 5-year IHD • Independent of other RFs and lipid measures • PHS Nested Case-Control • Cases had smaller LDL diameter • BUT, adjustment for RFs and lipids attenuated to non-significance

4. Abdominal obesity  Hypertriglyceridemia  Low HDL cholesterol  Increased cholesterol/HDL cholesterol ratio  Normal or marginally elevated LDL cholesterol  Insulin resistance  Hyperinsulinemia  Glucose intolerance and type 2 diabetes  Elevated fibrinogen and PAI-1 levels  Impaired tolerance to dietary fat  Altered endothelial reactivity  Abnormalities Associated with Small, Dense LDL

5. LDL Particle Number • Increasing interest in LDL particle number as determinant of risk and ?target of therapy • 2 kinds of people • High LDLc – tend to have higher LDLp number and larger LDL size • Low to moderate LDLc – May have low or high LDLp number • And it matters which you have

6. LDLp and LDLc in FOS

7. LDLp, LDL size and Risk of IHD

8. LDL and Risk for CHD in CHS

9. Background Subclinical CAD Lipoprotein particle n/size ? Incident clinical CVD events

10. ERA-JUMP Study • Post-WWII birth cohort of Japanese men (n=100) and American men (n=100) in Pittsburgh area • Marked differences in CAC (13% vs 47%) • Despite similar LDL, higher BP, more smoking • Japanese men had substantially lower levels of small LDL and higher levels of large HDL, findings that appeared to explain in part the large difference in prevalence of CAC

11. Prevalence of CAC by Sex and Ethnicity * * * * * Men Women *P<0.05 compared with whites of same sex.

12. Adjusted ORs for Factors Associated with CAC, Men White African A Hispanic Chinese Age, 10 yrs Waist, 10 cm LDL-C, 30 mg/dL HDL-C, 10 mg/dL SBP, 20 mm/Hg Ex-Smokers Current Smokers Diabetes Hypertension Chol Rx AUC (%) 80 78 79 72 Also adjusted for education, triglycerides, and alcohol. *p< 0.05, ** p<0.01, ***p<0.001.

13. Objective • To examine the association between lipoprotein particle number and size and subclinical coronary atherosclerosis (as represented by CAC) • To determine whether LDL particle number is associated with CAC in different sex-race groups • Does controlling for LDL particle number attenuate ethnic differences in CAC?

14. Hypotheses • Higher LDL particle number will be associated with the presence and extent of CAC. • Smaller LDL size, larger HDL size, and larger VLDL size will be associated with the presence of CAC (CAC score >0), and will be associated with the extent of CAC (higher CAC score) among those with CAC. • Adjustment for differences in lipoprotein particle numbers and particle sizes will attenuate the known differences that have been observed across ethnic groups in the MESA cohort.

15. MESA Study Sample • The Multi-Ethnic Study of Atherosclerosis (MESA) is an NHLBI-sponsored multi-center longitudinal cohort study investigating prevalence, correlates, and progression of subclinical cardiovascular disease (CVD). • 6 U.S. field centers recruited 6,814 healthy men and women (~50% each sex) free of clinical CVD from 4 racial/ethnic groups, ages 45-84 yrs. • 34% White • 28% African American • 22% Hispanic • 12% Chinese

16. NMR and Lipoproteins

17. Methods • NMR lipoprotein analysis from blood drawn at Exam 1 • Coronary artery calcium (CAC) measured at Exam 1 (phantom-adjusted mean of CAC score from 2 scans) • LR analyses • Dependent variable CAC score >0

18. Prevalence of CAC by Sex and Ethnicity * * * * * Men Women *P<0.05 compared with whites of same sex.

19. Age-Adjusted LDL Values †P<0.05 compared with whites of same sex.

20. OR for Presence of CACAll Participants

21. Lipoprotein Variables Associated with CACAll Participants • Adjusted for age, sex, race • LDLc, LDLp, lLDL, sLDL, LDL size • VLDLc, VLDLp, lVLDL, mVLDL, sVLDL, VLDL size • HDLc, HDLp, lHDL, HDL size

22. Base Multivariable ModelAll Participants

23. Cholesterol Subclass and CACAll Participants Adjusted for age, sex, race, BMI, SBP, antiHTN use, diabetes, smoking, statin use

24. Lipoprotein Variables Associated with CACAll Participants • Significant MV*-adjusted covariates • LDLp, sLDL, LDL size • VLDLp, mVLDL, sVLDL, VLDL size • HDLp, lHDL, mHDL Adjusted for age, sex, race, BMI, SBP, antiHTN use, diabetes, smoking, statin use

25. Lipoproteins and CAC by SexAll Men • Men – MV associations • VLDLp (10 nmol/L): OR 1.04 (1.00-1.08; P=0.04) • sVLDL (10 nmol/L): OR 1.09 (1.01-1.18; P=0.02) • VLDL size (10 nm): OR 0.98 (0.96-1.00; P=0.03) • Essentially all P>0.20 for LDL, HDL particle numbers and mean sizes

26. Lipoproteins and CAC by SexAll Women • Women – MV associations • VLDL numbers and size all NS • LDLp (100 nmol/L): OR 1.05 (1.02-1.09; P=0.004) • sLDL (100 nmol/L): OR 1.15 (1.02-1.31; P=0.03) • LDL size (nm): OR 0.85 (0.72-1.00; P=0.04) • HDLp (nmol/L): OR 0.98 (0.96-0.99; P=0.04)

27. Lipoprotein Variables Associated with CACby Sex and Ethnicity *Adjusted for age, BMI, SBP, BP meds, diabetes, smoking, statin

28. Lipoprotein Variables Associated with CACby Sex and Ethnicity *Adjusted for age, BMI, SBP, BP meds, diabetes, smoking, statin

29. Lipoprotein Variables Associated with CACby Sex and Ethnicity *Adjusted for age, BMI, SBP, BP meds, diabetes, smoking, statin

30. Lipoprotein Variables Associated with CACby Sex and Ethnicity *Adjusted for age, BMI, SBP, BP meds, diabetes, smoking, statin

31. Subgroups • Associations of CAC with cholesterol and lipoprotein variables tended to be stronger in women than men • No lipoprotein variables knocked out differences between races in models • Similar findings in younger (<65) compared with older (65) • Except HDLp only significant in old

32. Is LDLp independent of LDLc? • In models with both LDLc and LDLp, LDLc consistently dominated • BUT r=0.836 • Stratified MV analysis: LDLp • In those with LDLc 100: P=0.10 • In those with LDLc <100: P=0.01

33. Metabolic Syndrome • Analyses restricted to individuals with metabolic syndrome (NCEP criteria) • N=2541 (37.3%) • Lipid measures associated with CAC: • TC, LDL (W>>M); not HDL or TG • Lipoprotein variables associated with CAC • VLDLp, sVLDL, VLDL size, HDL size all weak • NO LDL variables!!! • Except LDLp in women

34. Summary • Highly significant MV associations for some lipoprotein particle number/size variables in all participants • Minimally adjusted • MV-adjusted • Major differences in patterns of association of lipoprotein variables in strata • Sex, ethnicity, metabolic syndrome

35. Questions • Is NMR measurement of lipoprotein particle number/size useful in prediction of subclinical atherosclerosis? • Do lipoprotein subclasses play a role in CAC development? • Results of C-IMT data? • Is CAC truly representing coronary atherosclerosis the way we think it is? • What environmental or genetic factors are influencing ethnic-specific determinants of calcification, and of lipid-CAC associations? • Is there some selection bias in the MESA population?