Disclosures MENOPAUSE, ESTROGENS, AND LIPOPROTEIN PARTICLES - - PDF document

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MENOPAUSE, ESTROGENS, AND LIPOPROTEIN PARTICLES

Ronald M. Krauss, Children’s Hospital Oakland Research Institute and UCSF

Disclosures

 Grants: NIH, Quest Diagnostics  Consultant: Quest Diagnostics  Merck Global Atherosclerosis Advisory

Board

Background 1 – What is 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 LDL cholesterol in post-menopause

 Estrogen (and estrogen-progestin) therapy

increase CVD risk in older post-menopausal women, but may be protective if instituted earlier.

Background 2 – What is Not Known

 To what extent does increased LDL-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?

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LDL has been the primary focus of CVD risk reduction

Proportional reduction in event rate (SE)

LDL-C reduction (mmol/L)

n=14,348 events/90,056 pts

CTT Collaborators. Lancet 366:1267, 2005

LDL-C is just one component of an LDL particle

Apoprotein B (ApoB) Cholesterol Phospholipids Triglycerides

LDL-C vs. LDL-Particles (LDL-P) and CVD Risk

Davidson MH, et al. Journal of Clinical Lipidology 5:338, 2011

6% 4% 2% Cumulative incidence of cardiovascular events in subgroups with concordant or discordant levels of LDL-C and LDL-P

From proportional hazards models adjusted for age, sex, and race

n=319 events/6814 pts

LDL Metabolism – Traditional Model

Liver

lipolysis, lipid and apoprotein transfers LDL LDL

Remnants (IDL)

VLDL Eisenberg et al., Biochim Biophys Acta 326: 361-377, 1973

LDL-R

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LDL particles comprise a spectrum of subclasses with differing cholesterol content and CVD risk

Large LDL more cholesterol/particle Medium LDL Small and very small (sdLDL) less cholesterol/particle

Berneis and Krauss, JLR 43:1155, 2002

Adapted from Berneis and Krauss, JLR 43:1155, 2002

Low

Very small VLDL Large LDL

LPL

TG secretion

Major normal pathway Atherogenic dyslipidemia

• f metabolic syndrome, obesity and

insulin resistance

HDL TG

CETP

Chol

TG

V.Small LDL

HL

Small HDL Med

Medium LDL

LPL

Medium VLDL

LDL-R

High

Large VLDL

LPL

Remnants Small LDL

LPL/HL

slower

Origin of LDL subclasses

Lipoprotein subclasses: High-resolution separation and direct quantitation by ion mobility

VLDL IDL

Large LDL Small HDL Large HDL Very Small

HDL

Small Medium d c b a Small Large Medium Small Medium b a

Particle Mass (arbitrary units, derived from particle number)

50 150 250 350 450 550

Lipoprotein Particle Diameter (Å) Musunuru K et al. Arterioscler Thromb Vasc Biol. 2009;29:1975-1980.

Mid- zone

Remnant particles Small LDL Large LDL VLDL

Standard LDL-C assay is a measure of remnant particles as well as “true” LDL

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

VLDL lg med sm IDL lg sm LDL 1 2a 2b 3a 3b 4a 4b 4c

Lg Med Sm Lg Sm Lg Med Sm Very Sm VLDL IDL LDL

r

N=748 men and women not using hormones In stepwise regression, 48% of variance in LDL-C explained by IDL, 2% by LDL particles Remnant particles LDL particles

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Atherogenic Dyslipidemia of Metabolic Syndrome

 Definition  Elevated triglycerides (VLDL remnants)  Reduced HDL cholesterol  LDL-C normal, but increase in sdLDL particles  Prevalence  ~ 20% in persons with ≥ 1 CVD risk factor  ~ 30% in diabetics with ≥ 1 CVD risk factor Halcox et al. Circulation. 2015; 132: A17096

For small LDL particles, LDL-C level misrepresents the number of LDL particles

Larger LDL particles More cholesterol/particle Fewer LDL particles Smaller LDL particles Less cholesterol/particle More LDL particles

100 mg/dL 100 mg/dL

LDL-Cholesterol

Small dense (sd)-LDL-C but not large buoyant (lb)-LDL-C predicts CHD

Hoogeveen et al., ATVB 34:1069, 2014 (n=1158 CVD events/11,419 ~11 yr f/u)

sdLDL-C predicts CHD even when LDL-C < 100 mg/dl

Adjusted for age, sex, and race, smoking, BMI, hypertension, DM, DM medications, and log hs CRP.

Hoogeveen et al., ATVB 34:1069, 2014

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Why are sdLDL associated with increased CVD risk?

 Reduced LDL receptor binding – longer plasma

residence time

 Greater arterial proteoglycan binding  Greater oxidative susceptibility  Association with other risk biomarkers:

 Reduced HDL, increased remnants  Insulin resistance

 Atherogenic components

 Oxidized lipids  ApoCIII

ApoC-III

 Small exchangeable apolipoprotein (MW 10,800) found in

all lipoprotein classes

 ApoCIII 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 apoCIII deficiency associated with reduced

atherosclerosis

 Anti-sense oligo for apoCIII in phase 3 studies

Risk for developing coronary heart disease is associated with “LDL” containing apo-CIII

Mendivil et al., Circulation 124:2065, 2011 Quintiles of LDL concentration

“LDL” apoCIII is mainly in remnants and small LDL fractions

% mass

Rem Large Medium Small VSmall

LDL

Data from Krauss et al., J. Lipid Res 53: 540, 2012

nants

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Med

Medium LDL Medium VLDL

High

Large VLDL

LPL

Remnants Small LDL

CIII CIII CIII CIII CIII CIII CIII CIII CIII CIII CIII CIII

ApoCIII has a key pathologic role in atherogenic dyslipidemia

Reduced hepatic remnant uptake

Blood vessel

plaque

Increased artery binding & direct inflammatory effects

Remnant cholesterol is associated with increased CHD risk

Varbo et al, JACC 61:427–36, 2013

n=75,513 participants; 11,984 IHD cases Odds ratio for 1mmol/L change

Remnant cholesterol* HDL cholesterol LDL cholesterol

*Estimated by total C - LDLC - HDLC

Non-Fasting Triglyceride and CHD Risk

Women’s Health Study

Mora et al. Circulation 118:993, 2008

n=26,330 women (19 983 fasting; 6347 nonfasting)

Hours after meal Increased remnants

Both remnant particles and medium/small LDL are associated with increased CVD & total mortality on statin therapy (JUPITER)

5 10 15 20 25 30 35

% increase in relative risk * * * * * * * Lg Med Sm Lg Sm Lg Med Sm Very Sm VLDL IDL LDL Mora et al. Circulation 2015; 132(23): 2220-9.

* p < 0.05

Remnant particles LDL particles

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High

Large VLDL

LPL

Remnants Small LDL

CIII CIII CIII CIII CIII CIII CIII CIII CIII CIII CIII CIII

Age-related changes in atherogenic lipoprotein particles in women that peak post-menopause

Reduced hepatic remnant uptake

Blood vessel

plaque

Increased artery binding & direct inflammatory effects

INCREASES

HORMONES

Chol content Particle conc.

?

Genetic evidence: ApoC-III mutations reduce non- fasting triglyceride and coronary heart disease risk

Jorgensen et al., NEJM 201:32, 2014

Conclusions(1)

 Greater age-related increases in LDL 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 LDL cholesterol

but this is not accompanied by a decrease in remnants and there is an increase in sdLDL particles.

 Smaller HDL particles are increased by hormones; add to

levels of large HDL that increase slightly with age.

Conclusions (2)

 Age-related increases in apoCIII in women vs.

men, beginning in pre-menopausal years, may contribute to increased levels of atherogenic lipoproteins.

 Therapies aimed at reducing apoCIII levels (e.g.

newer PPAR agonists and anti-sense

• ligonucleotides) may have particular benefit for

reducing CVD risk in post-menopausal women.

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Acknowledgments

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