10/2/2017 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 To what extent does increased LDL-C explain CVD vs. men of the same age; risk is similar to the increase in CVD risk in post-menopause? that of men ten years younger. Protection is lost in post-menopausal years. CVD risk has been attributed in part to Is there evidence that estrogen effects on increased LDL cholesterol in post-menopause lipids and lipoproteins reverse atherogenic Estrogen (and estrogen-progestin) therapy changes in post-menopause? increase CVD risk in older post-menopausal women, but may be protective if instituted earlier. 1
10/2/2017 LDL has been the primary focus of CVD risk LDL-C is just one component of an LDL particle reduction Proportional reduction in event rate (SE) Apoprotein B (ApoB) Cholesterol Phospholipids Triglycerides LDL-C reduction (mmol/L) n=14,348 events/90,056 pts CTT Collaborators. Lancet 366:1267, 2005 LDL Metabolism – Traditional Model LDL-C vs. LDL-Particles (LDL-P) and CVD Risk Cumulative incidence of cardiovascular events in subgroups lipolysis, lipid and with concordant or discordant levels of LDL-C and LDL-P apoprotein transfers Remnants LDL LDL 6% VLDL (IDL) Liver LDL-R 4% 2% From proportional hazards models adjusted for age, sex, and race Eisenberg et al., Biochim Biophys Acta 326: 361-377, 1973 n=319 events/6814 pts Davidson MH, et al. Journal of Clinical Lipidology 5:338, 2011 2
10/2/2017 LDL particles comprise a spectrum of subclasses Origin of LDL subclasses with differing cholesterol content and CVD risk Very LPL Large small LDL VLDL Large LDL TG secretion more cholesterol/particle Medium Medium LPL VLDL LDL Low Med Major normal pathway Medium LDL LDL-R High Large LPL LPL/HL Small Small and very small Remnants TG V.Small VLDL slower LDL LDL (sdLDL) HL Chol TG less cholesterol/particle CETP Small HDL Atherogenic dyslipidemia HDL of metabolic syndrome, obesity and insulin resistance Berneis and Krauss, JLR 43:1155, 2002 Adapted from Berneis and Krauss, JLR 43:1155, 2002 Standard LDL-C assay is a measure of Lipoprotein subclasses: High-resolution separation remnant particles as well as “true” LDL and direct quantitation by ion mobility N=748 men and women not using hormones (arbitrary units, derived from particle number) Medium 0.8 Large Large b LDL Remnant particles Small LDL 0.7 a LDL particles Small 0.6 LDL Particle Mass 0.5 Remnant HDL particles 0.4 Small r HDL IDL a Very Small 0.3 Small b VLDL VLDL Large 0.2 HDL Medium Small c 0.1 d Medium Large 0 VLDL lg Lg Med Sm med sm Lg IDL lg Sm sm LDL 1 Lg 2a Med Sm 2b 3a 3b 4a Very Sm 4b 4c Mid- zone VLDL IDL LDL 50 150 250 350 450 550 Lipoprotein Particle Diameter (Å) In stepwise regression, 48% of variance in LDL-C explained by IDL, 2% by LDL particles Musunuru K et al. Arterioscler Thromb Vasc Biol. 2009;29:1975-1980. 3
10/2/2017 Atherogenic Dyslipidemia of For small LDL particles, LDL-C level Metabolic Syndrome misrepresents the number of LDL particles Definition Elevated triglycerides (VLDL remnants) Reduced HDL cholesterol LDL-C normal, but increase in sdLDL particles Prevalence LDL-Cholesterol 100 mg/dL 100 mg/dL ~ 20% in persons with ≥ 1 CVD risk factor ~ 30% in diabetics with ≥ 1 CVD risk factor Larger LDL particles Smaller LDL particles Less cholesterol/particle More cholesterol/particle More LDL particles Fewer LDL particles Halcox et al. Circulation. 2015; 132: A17096 Small dense (sd)-LDL-C sdLDL-C predicts CHD even when but not large buoyant (lb)-LDL-C predicts CHD LDL-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, 2014 4
10/2/2017 Why are sdLDL associated with ApoC-III increased CVD risk? Reduced LDL receptor binding – longer plasma Small exchangeable apolipoprotein (MW 10,800) found in all lipoprotein classes residence time ApoCIII in apoB-containing lipoproteins is associated with Greater arterial proteoglycan binding CHD risk Greater oxidative susceptibility Reduces lipolysis and receptor-mediated clearance of Association with other risk biomarkers: apoB-containing lipoproteins Reduced HDL, increased remnants Increases arterial proteoglycan binding of apoB-containing lipoproteins Insulin resistance Direct pro-inflammatory properties Atherogenic components Human apoCIII deficiency associated with reduced Oxidized lipids atherosclerosis ApoCIII Anti-sense oligo for apoCIII in phase 3 studies “LDL” apoCIII is mainly in remnants and Risk for developing coronary heart disease is associated with “LDL” containing apo-CIII small LDL fractions % mass Quintiles of LDL concentration Rem Large Medium Small VSmall nants LDL Data from Krauss et al., J. Lipid Res 53: 540, 2012 Mendivil et al., Circulation 124:2065, 2011 5
10/2/2017 ApoCIII has a key pathologic role Remnant cholesterol is associated with in atherogenic dyslipidemia increased CHD risk Remnant cholesterol* Medium Medium VLDL LDL HDL cholesterol Med CIII CIII CIII High CIII CIII CIII CIII Large LPL Small Remnants VLDL LDL LDL cholesterol CIII CIII CIII CIII CIII Blood vessel Reduced Increased artery binding & hepatic remnant uptake plaque direct inflammatory effects *Estimated by total C - LDLC - HDLC Odds ratio for 1mmol/L change n=75,513 participants; 11,984 IHD cases Varbo et al, JACC 61:427–36, 2013 Both remnant particles and medium/small LDL are Non-Fasting Triglyceride and CHD Risk associated with increased CVD & total mortality on statin Women’s Health Study therapy (JUPITER) Remnant LDL particles particles 35 * Increased remnants % increase in relative risk * * * 30 * * 25 20 * 15 10 5 0 Lg Med Sm Lg Sm Lg Med Sm Very Sm Hours after meal VLDL IDL LDL * p < 0.05 n=26,330 women (19 983 fasting; 6347 nonfasting) Mora et al. Circulation 2015; 132(23): 2220-9. Mora et al. Circulation 118:993, 2008 6
10/2/2017 Age-related changes in atherogenic lipoprotein Genetic evidence: ApoC-III mutations reduce non- particles in women that peak post-menopause fasting triglyceride and coronary heart disease risk HORMONES CIII Chol content CIII Particle conc. CIII High CIII CIII CIII CIII Large LPL Small Remnants VLDL LDL CIII CIII CIII CIII CIII Blood vessel ? INCREASES Reduced Increased artery binding & hepatic remnant uptake plaque direct inflammatory effects Jorgensen et al., NEJM 201:32, 2014 Conclusions(1) Conclusions (2) Greater age-related increases in LDL cholesterol in women vs. Age-related increases in apoCIII in women vs. men are mainly due to atherogenic remnant lipoprotein men, beginning in pre-menopausal years, may particles. contribute to increased levels of atherogenic These particles reach levels higher than those in men in the lipoproteins. post-menopausal years. Thus, remnant lipoprotein particles may contribute to increased CVD risk in older women and loss of premenopausal CVD Therapies aimed at reducing apoCIII levels (e.g. protection compared to men of similar age. newer PPAR agonists and anti-sense Hormone therapy in post-menopause reduces LDL cholesterol oligonucleotides) may have particular benefit for but this is not accompanied by a decrease in remnants and there is an increase in sdLDL particles. reducing CVD risk in post-menopausal women. Smaller HDL particles are increased by hormones; add to levels of large HDL that increase slightly with age. 7
10/2/2017 Acknowledgments NIH U19 grant Michael Caulfield David Waters Richard Reitz Mohammed Saad Julia Larsen Patricia Blanche Laura Holl Steven Hulley Joel Simon 8
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