Disclosures. Background 1 What is Known MENOPAUSE, ESTROGENS, AND LIPOPROTEIN PARTICLES. Background 2 What is Not Known 10/2/2017

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1 Disclosures MENOPAUSE, ESTROGENS, AND LIPOPROTEIN PARTICLES Grants: NIH, Quest Diagnostics Consultant: Quest Diagnostics Merck Global Atherosclerosis Advisory Board Ronald M. Krauss, Children s Hospital Oakland Research Institute and UCSF Background 1 What is Known Background 2 What is Not Known Premenopausal women are protected from CVD vs. men of the same age; risk is similar to that of men ten years younger. Protection is lost in post-menopausal years. CVD risk has been attributed in part to increased cholesterol in post-menopause Estrogen (and estrogen-progestin) therapy increase CVD risk in older post-menopausal women, but may be protective if instituted earlier. To what extent does increased -C explain the increase in CVD risk in post-menopause? Is there evidence that estrogen effects on lipids and lipoproteins reverse atherogenic changes in post-menopause? 1

has been the primary focus of CVD risk reduction -C is just one component of an particle Proportional reduction in event rate (SE) Apoprotein B (ApoB) Cholesterol Phospholipids

-Particles (-P) and CVD Risk Metabolism Traditional Model Cumulative incidence of cardiovascular events in subgroups with concordant or discordant levels of -C and -P lipolysis, lipid

2 has been the primary focus of CVD risk reduction -C is just one component of an particle Proportional reduction in event rate (SE) Apoprotein B (ApoB) Cholesterol Phospholipids Triglycerides -C reduction (mmol/l) n=14,348 events/90,056 pts CTT Collaborators. Lancet 366:1267, C vs. -Particles (-P) and CVD Risk Metabolism Traditional Model Cumulative incidence of cardiovascular events in subgroups with concordant or discordant levels of -C and -P lipolysis, lipid and apoprotein transfers 6% V Remnants (IDL) 4% Liver -R 2% From proportional hazards models adjusted for age, sex, and race n=319 events/6814 pts Davidson MH, et al. Journal of Clinical Lipidology 5:338, 2011 Eisenberg et al., Biochim Biophys Acta 326: ,

particles comprise a spectrum of subclasses with differing cholesterol content and CVD risk Origin of subclasses more cholesterol/particle and very small (sd) less cholesterol/particle Berneis and

3 particles comprise a spectrum of subclasses with differing cholesterol content and CVD risk Origin of subclasses more cholesterol/particle and very small (sd) less cholesterol/particle Berneis and Krauss, JLR 43:1155, 2002 TG secretion Low Med High V Very small V LPL LPL Major normal pathway -R LPL LPL/HL TG V. V Remnants slower HL Chol TG CETP Atherogenic dyslipidemia of metabolic syndrome, obesity and insulin resistance Adapted from Berneis and Krauss, JLR 43:1155, 2002 Lipoprotein subclasses: High-resolution separation and direct quantitation by ion mobility Standard -C assay is a measure of remnant particles as well as true Particle Mass (arbitrary units, derived from particle number) Very d c b a b a IDL Remnant particles V V Midzone Lipoprotein Particle Diameter (Å) Musunuru K et al. Arterioscler Thromb Vasc Biol. 2009;29: r N=748 men and women not using hormones Remnant particles particles V Lg med sm Med Sm IDL lg Lg sm Sm Lg 2b Med Sm 4a 4b Very Sm lg 1 2a 3a 3b 4c V IDL In stepwise regression, 48% of variance in -C explained by IDL, 2% by particles 3

Atherogenic Dyslipidemia of Metabolic Syndrome Definition Elevated triglycerides (V remnants) Reduced cholesterol -C normal, but

particles, -C level misrepresents the number of particles 100 mg/dl -Cholesterol 100 mg/dl r particles More cholesterol/particle Fewer

2015; 132: A17096 dense (sd)--c but not large buoyant (lb)--c predicts CHD sd-c predicts CHD even when -C < 100 mg/dl Adjusted for age,

4 Atherogenic Dyslipidemia of Metabolic Syndrome Definition Elevated triglycerides (V remnants) Reduced cholesterol -C normal, but increase in sd particles Prevalence ~ 20% in persons with 1 CVD risk factor ~ 30% in diabetics with 1 CVD risk factor For small particles, -C level misrepresents the number of particles 100 mg/dl -Cholesterol 100 mg/dl r particles More cholesterol/particle Fewer particles er particles Less cholesterol/particle More particles Halcox et al. Circulation. 2015; 132: A17096 dense (sd)--c but not large buoyant (lb)--c predicts CHD sd-c predicts CHD even when -C < 100 mg/dl Adjusted for age, sex, and race, smoking, BMI, hypertension, DM, DM medications, and log hs CRP. (n=1158 CVD events/11,419 ~11 yr f/u) Hoogeveen et al., ATVB 34:1069, 2014 Hoogeveen et al., ATVB 34:1069,

Insulin resistance Atherogenic components Oxidized lipids Apo ApoC-III exchangeable apolipoprotein (MW 10,800) found in all lipoprotein classes Apo in apob-containing lipoproteins is associated with

5 Why are sd associated with increased CVD risk? Reduced receptor binding longer plasma residence time Greater arterial proteoglycan binding Greater oxidative susceptibility Association with other risk biomarkers: Reduced, increased remnants Insulin resistance Atherogenic components Oxidized lipids Apo ApoC-III exchangeable apolipoprotein (MW 10,800) found in all lipoprotein classes Apo in apob-containing lipoproteins is associated with CHD risk Reduces lipolysis and receptor-mediated clearance of apob-containing lipoproteins Increases arterial proteoglycan binding of apob-containing lipoproteins Direct pro-inflammatory properties Human apo deficiency associated with reduced atherosclerosis Anti-sense oligo for apo in phase 3 studies Risk for developing coronary heart disease is associated with containing apo- apo is mainly in remnants and small fractions % mass Quintiles of concentration Rem V nants Mendivil et al., Circulation 124:2065, 2011 Data from Krauss et al., J. Lipid Res 53: 540,

6 Apo has a key pathologic role in atherogenic dyslipidemia Remnant cholesterol is associated with increased CHD risk Remnant cholesterol V cholesterol High Med V LPL Remnants Blood vessel cholesterol Reduced hepatic remnant uptake Increased artery binding & direct inflammatory effects plaque Estimated by total C - C - C n=75,513 participants; 11,984 IHD cases Odds ratio for 1mmol/L change Varbo et al, JACC 61:427 36, 2013 Non-Fasting Triglyceride and CHD Risk Women s Health Study Both remnant particles and medium/small are associated with increased CVD & total mortality on statin therapy (JUPITER) Increased remnants % increase in relative risk Remnant particles particles Lg Med Sm Lg Sm Lg Med Sm Very Sm Hours after meal n=26,330 women ( fasting; 6347 nonfasting) Mora et al. Circulation 118:993, 2008 p < 0.05 V IDL Mora et al. Circulation 2015; 132(23):

7 Age-related changes in atherogenic lipoprotein particles in women that peak post-menopause Genetic evidence: ApoC-III mutations reduce nonfasting triglyceride and coronary heart disease risk High V Reduced hepatic remnant uptake HORMONES Chol content Particle conc. LPL Remnants Blood vessel INCREASES Increased artery binding & direct inflammatory effects? plaque Jorgensen et al., NEJM 201:32, 2014 Conclusions(1) Conclusions (2) Greater age-related increases in cholesterol in women vs. men are mainly due to atherogenic remnant lipoprotein particles. These particles reach levels higher than those in men in the post-menopausal years. Thus, remnant lipoprotein particles may contribute to increased CVD risk in older women and loss of premenopausal CVD protection compared to men of similar age. Hormone therapy in post-menopause reduces cholesterol but this is not accompanied by a decrease in remnants and there is an increase in sd particles. er particles are increased by hormones; add to levels of large that increase slightly with age. Age-related increases in apo in women vs. men, beginning in pre-menopausal years, may contribute to increased levels of atherogenic lipoproteins. Therapies aimed at reducing apo levels (e.g. newer PPAR agonists and anti-sense oligonucleotides) may have particular benefit for reducing CVD risk in post-menopausal women. 7

8 Acknowledgments NIH U19 grant David Waters Mohammed Saad Patricia Blanche Laura Holl Steven Hulley Joel Simon Michael Caulfield Richard Reitz Julia Larsen 8

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