wwwlipidorg - PDF document

www.lipid.org www.lipid.orgEPIDEMIOLOGYITSEVOLUTIONINTOTARGET www.lipid.org www.lipid.orgWHATDIFFERENTIATESPARTICLESFROMOTHERLIPOPROTEINS?APPEARSPRIMARILYANTIATHEROGENIC. www.lipid.org

www.lipid.orgPotential Antiatherogenic Actions of HDLChapman MJ, et al. CurrMed ResOpin.AssmannG, et al. AnnuRevMed. Antiapoptotic Transport Activity Vasodilatory Apo A-I www.lipid.org

www.lipid.orgPARTICLESPRODUCED? www.lipid.org www.lipid.org HDL BIOGENESIS www.lipid.org www.lipid.org Zhang, Y. et al. Because adipose inflammation is a hallmark of central obesityand

type 2 diabetes mellitus, loss of adipocyte lipidation of HDL may contribute directly to lower HDL-C levels in these inflammatory, www.lipid.org www.lipid.orgEarly case-control studies

(1950s) in the US and Israel showed that patients with CAD tend to have lower HDL levels than The Tromso Heart Study showed that CAD patients have HDL levels 35% lower than controls and

that patients with low HDL are 3 times more likely to develop CAD than those with elevated Low HDL is associated with significant disability and the loss of ability to execute daily li

ving activities among patients over 65 years of age. Among the elderly, low HDL predicts risk for future MI and stroke better than LDL.CAD, coronary artery disease; LDL, low-density lip

oprotein; MI, myocardial infarction.HDL as CAD Risk Factor www.lipid.org www.lipid.orgSevere premature atherosclerotic disease in the proximal left main coronary arteryFor every 1 mg/dL

drop in HDL-C, risk for NIDDM Low HDL Portends1.GoldbourtU et al. ArteriosclerThrombVascBiol1997;17:107-13.2.Qeverling-RijnsburgerAWE et al. 3.Burke AP et al. 4.Shah P et al. 5.Pearson

T et al. Am J Epidemiol6.Sasongkoet al. Diabetes care 2011; 34: 474-479.7.Stern MP et al. www.lipid.org www.lipid.orgControls (N = 601)Hypertension *Significantly different fr

om controls (CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. GenestJJ et al. Am J Cardiol. 1991;67:1185-1189. www.

lipid.org www.lipid.orgEPIDEMIOLOGY www.lipid.org www.lipid.org 10-1415-1920-2425-29HDL-C (mg/dL) Men WomenMiller M & Zahn M. CurrOpinCardiol occurs in occurs in ~ National Health And

Nutrition Examination Survey III: Distribution of Low HDL-C Bottom Tertile of www.lipid.org www.lipid.org BruckertE EurHeart J SupplMean HDL-cholesterol in mmol/L (M) by country and p

revalence (P) of low HDL-cholesterol adjusted for eight confounding factors by country; low HDL-cholesterol was defined as mmol/L (40mg/dL) in men mmol/L (50mg/dL) in women. www.lipid.o

rg www.lipid.org Prevalence (%) of different severities of obesity in the Pan-European Survey of low HDL-cholesterol (excludes 3% of the overall population for whom obesity status was n

ot recorded)BruckertE EurHeart J Suppl www.lipid.org www.lipid.org Prevalence of low HDL-cholesterol, hypertriglyceridaemia, or both according to receipt or not of lipEuropean Survey of

low HDL-cholesterol.BruckertE EurHeart J Suppl www.lipid.org 5.0015.0020.0025.0030.0012345 CVD Mortality Rate (per 1000 person years) www.lipid.org 1.6 HDL TertilesCVD Mortality Rate

(per 1000 person years) 0.370.220.202.01.7 www.lipid.org 2.004.006.008.0012.0014.0016.0018.001.09 HDL TertilesCVD Mortality Rate (per 100 person years) 0.800.550.362.82.79.66.44.91513

www.lipid.org 0.501.001.502.002.503.003.504.004.505.0012345 1 2 3 4 HDL QuintileCVD Mortality Rate (per 1000 person years) 0.90.20.20.50.21.21.00.80.30.72.21.41.10.70.42.71.81.41.21.24.

94.72.12.11.7 www.lipid.org 1.002.003.004.005.006.007.008.0012345 1 2 3 4 HDL QuintileCVD Mortality Rate (per 1000 person years) 2.81.91.21.81.23.72.62.42.11.95.72.93.52.52.75.74.63.93.

52.97.35.45.55.04.4 www.lipid.org www.lipid.orgRelative risk of CHD for sex-specific lipid factor quintiles with adjustment for age and race in ARIC women and men N=12,339, 10-Sharrett

AR, et al. 2001;104:1108-1113.Women mg/dL39 48 56 65 81 3138 43 49 62 HDL-C Cholesterol (mmol/L) HDL-C Cholesterol (mmol/L)H

DL-C Provides Substantial CHD Prediction: ARIC www.lipid.org www.lipid.orgSignificantassociationfoundbetweenlevelsafteradjustmentforIncidence of CHD Per 1000 SubjectsOver a 6-year Peri

od According to HDL-C Level*PROCAM: Prospective Cardiovascular Münster study.The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity

and mortality has not been determined. PROCAM* Results at 6 Years of Follow-up www.lipid.org www.lipid.org CastelliWP. Can J Cardiol. Jul 1988;4 SupplA:5A-10A.Risk of Coronary Artery Di

sease in Men Aged 50-70 by LDL and HDL Cholesterol Levels www.lipid.org www.lipid.orgAbbott RD, et al. Arteriosclerosis. May-Jun 1988;8(3):207-211. 23-4647-5556-6667-139Rate per 100/12

years124-21112 Year Incidence of Myocardial InfarctionFramingham Cohort-Women www.lipid.org www.lipid.orgTo evaluate if apoB and apoA-I add predictive information of cardiac risk -fata

l myocardial infarction -up and above TC, TG, and LDL-C98,722 males and 76,831 females, –;&#x-277;&#x.100;80 yearsconsecutively referred 1985–1996, no diagnosis or treatment known

, 67 months mean follow upFatal myocardial infarctionmales 864, females 359 www.lipid.org www.lipid.org Risk ratio0.30.80.41.0 1.201.571.81Women 0.70.90.30.41.00.50.70.90.80.6 § §‡ AMOR

IS, Fatal Myocardial Infarction www.lipid.org www.lipid.orgApolipoprotein A-I (g/L) Risk ratio0.30.80.41.0 1.241.431.57Women § 0.70.90.30.41.00.50.70.90.80.6 *§ AMORIS, Fatal Myocardial

Infarction www.lipid.org 4.0 3.6 2.3 1.7 4.1 3.1 1.8 1.7 2.3 1.6 1.1 1.2 1.4 0.8 1.1 1.0 0.01.02.03.04.05.0 1.121.301.421.65 0.901.101.391.80 www.lipid.org 9.1 5.7 6.7 3.9 8.7 5.1 2.5

5.1 7.0 7.0 3.8 5.2 5.8 4.3 4.5 1.0 0.02.04.06.08.010.0 1.241.431.571.83 0.811.061.281.71Women www.lipid.org www.lipid.org McQueen M et al. Odds ratio (95% CI)Decile Median (SD dista

nc ApoB/ApoA-I 0.43 0.78 0.85 04 1.28TC/HDL-C 2.74 3.37 3.82 6.21 7. Risk of MI for increasing decile medians

(adjusted for age, sex and region) of ratios of apoB/ApoA-I and TC/HDL-CLipids, Lipoproteins & Apolipoproteins as Markers of risk of MI in52 Countries in The INTERHEART Study www.lipid

.org Risk factorOdds ratio adjusted for all (99% CI)ApoB/ApoA-1 (fifth quintile 3.87 (3.39-4.42)3.25 (2.81-3.76)Current smoking2.95 (2.72-3.20)2.87 (2.58-3.19)Diabetes3.08 (2.77-3.42)2.

37 (2.07-2.71)Hypertension2.48 (2.30-2.68)1.91 (1.74-2.10)Abdominal obesity 2.22 (2.03-2.42)1.62 (1.45-1.80)Psychosocial 2.51 (2.15-2.93)2.67 (2.21-3.22)Vegetable and fruits daily0.70 (

0.64-0.77)0.70 (0.62-0.79)Exercise 0.72 (0.65-0.79)0.86 (0.76-0.97)Alcohol intake0.79 (0.73-0.86)0.91 (0.82-1.02)All combined129.2 (90.2-185.0)129.2 (90.2-185.0)Yusuf S. European Societ

y of Cardiology Congress 2004; August 28-September 1, 2004; Munich, Germany.INTERHEART: Risk of Acute MI Associated with Risk Factorsin the Overall Population www.lipid.org www.lipid.or

g)27.627.6 n.s.Total cholesterol (mg/dl)259.6243.3 0.001HDL cholesterol (mg/dl)46.8 51.8 0.00375.664.83Systolic BP (mmHg)139.0136.6n.s.Diastolic BP (mmHg)84.984.5 n.s.Regular smoker %53

.928.00.0001Physical activity %25.735.60.05Diabetes %8.43.10.0096Education ()74.273.7n.s.Lp-PLA (ng/ml)292.3 263.40.0013(mg/L)2.491.54 0.0001geometric means calculated from the log-tran

sformed distributionKoenig et al. AHA 2003. Age-Adjusted Baseline Characteristics of 934 men, Aged 45-64 YearsParticipating in the MONICA Augsburg Survey 1984/85With Follow-up 1998 www.

lipid.org www.lipid.org 11.75 35-4445+HDL Cholesterol (mg/dL)Present (n=471) Trend p PekkanenJ, Linn S, HeissG, et al. N EnglJ Med. Jun 14 11.2CHD Mortality and HDL CholesterolLRC Men

10 Year Follow up www.lipid.orgHDL-C = high-density lipoprotein cholesterol; CVD = cardiovascular disease; LDL-C = low-densTC = total cholesterol; RR = relative risk; CI = confidence in

terval.Relative risks are adjusted for age at baseline as a continuous variable values indicated better prediction of CVD mortality by that lipid level when added to age-only model.Meas

ured by an increase of 0.78 mmol/L (30 mg/dL).Measured by an increase of 0.26 mmol/L (10 mg/dL).forFractions:ResearchProgramCui Y et al. Comparison of lipid levels in predic RR (95% CI)

for addition to modelNon-HDL-C*1.19 (1.13 to 1.26)24.3LDL-C*1.11 (1.02 to 1.22)5.0TC1.16 (1.08 to 1.23)14.4HDL-C†0.77 (0.69 to 0.86)23.2WomenNon-HDL-C1.15 (1.06 to 1.25)8.3LDL-C1.08 (0.

96 to 1.22)1.8TC1.10 (0.99 to 1.22)2.8HDL-C0.77 (0.69 to 0.88)18.5 www.lipid.org www.lipid.org Hazard Ratio for Ischemic Heart Disease (IHD) as a Function of High-Density Lipoprotein (H

DL) Cholesterol in Quintiles in the Copenhagen City Heart Study Frikke-Schmidt, R. et al. JAMA www.lipid.org www.lipid.org Hazard Ratios for Coronary Heart Disease Across Fifthsof Usual

Lipids or Apolipoproteins Di AngelantonioE, SarwarN, Perry P, et al. JAMA. Nov 11 2009;302(18):1993-2000. Quintile Mean (SD Distance From Overall Mean) Hazard Ratio www.lipid.org www.l

ipid.org Hazard Ratios for Coronary Heart Disease or Ischemic Stroke Across Quintiles of Usual Triglyceride, HDL-C, and Non–HDL-C Levels TriglycerideNon-HDL-CTriglycerideNon-HDL-C Hazar

d RatioUsual Mean Level, mg/dL Hazard RatioUsual Mean Level, mg/dLHazard RatioUsual Mean Level, mg/dLHazard RatioUsual Mean Level, mg/dLHazard RatioUsual Mean Level, mg/dLHazard RatioUs

ual Mean Level, mg/dLDi AngelantonioE, SarwarN, Perry P, et al. JAMA. Nov 11 2009;302(18):1993-2000. www.lipid.org www.lipid.org Hazard Ratios for Coronary Heart Disease Across Fifths o

f Non-HDL-Cby Levels of HDL-C and Fifths of HDL-C by Levels of Non-HDL-C Hazard Ratio Hazard Ratio Usual Mean Non-HDL-C Level, mg/dL Usual Mean HDL-C Level, mg/dL Non-HDL-C by levels of

HDL-C HDL-C by levels of Non-HDL-CDi AngelantonioE, SarwarN, Perry P, et al. JAMA. Nov 11 2009;302(18):1993-2000. www.lipid.org www.lipid.org Shahar, E. et al. Multivariable-adjusted r

isk functions of incident ischemic stroke among men in relation to LDL-C, HDL-C, apoB, and triglycerides (TG) www.lipid.org www.lipid.org Willey, J. Z. et al. Continuous Variables and

Risk of Ischemic Stroke www.lipid.org www.lipid.orgWestern Collaborative Group StudyBelgian Interuniversity Research on Nutrition ThefollowingotherobservationalstudiesalsoconfirmlowHDLa

sanimportantindependentCADriskfactor:HDL as CAD Risk Factor www.lipid.org www.lipid.org*95% confidence intervals for adjusted CHD = coronary heart disease; HDL-C = high-density lipoprot

ein cholesterol% Change in Risk per FHSLRCFCPPTMRFITFHSLRCFMenWomen HDL-C Levels in Various Clinical Trials -10 Gordon DJ, et al. www.lipid.org www.lipid.org Foody, J. M. et al. 2000;1

02:III-90-III-94.Survival and HCL-C. Adjusted for age, HTN, DM, body mass index,TC, TG, LVEF, disease extent, and ITA use www.lipid.org www.lipid.org Event-free survival and HDL-C. Adju

sted for age, HTN, DM,body mass index, TC, TG, LVEF, disease extent, and ITA useFoody, J. M. et al. 2000;102:III-90-III-94. www.lipid.org www.lipid.org 0.03.83.011.3 Targetlesion revasc

ularization or major cardiac eventMeanHDL-C of 55 mg/dL(�40 mg/dLin men and �45 mg/dLin women)MeanHDL-C of 32 mg/dL(in men and in women)Wolfram RM. Am J Cardiol.2006;98:71

1-717. 0 to 30 Days�30 Days to 1 YearPost Drug-Eluting Stent Implantation 60708090100 Survival Probability, %60120180240300360 HDL-C 1 mg/dLEvents -FreeSurvivalDeathImpact of Low

HDL-C on Clinical Outcomes www.lipid.org Relative Risk of CHDLowHigh Higher the Level of HDL-C, Lower the Risk of CHD www.lipid.org www.lipid.orgCOMPLICATIONS/EXCEPTIONSTHATCOMESHDL,B

ETTER? www.lipid.org www.lipid.org Unadjusted Rates of the Combined Primary End deGoma, E. M. et al. J Am CollCardiol Event rate (%) www.lipid.org www.lipid.org Adjusted Odds Ratios for

the Combined Primary End Point More EventsdeGoma, E. M. et al. J Am CollCardiol www.lipid.org www.lipid.org Wim A. van der Steeg, et al. J Am CollCardiol2008;51:634–42.European Prospec

tive Investigation into Cancer and Nutrition -Norfolk Study Incremental Decrease in End Points Through Aggressive Lipid Lowering HDL Size (nm)high values of plasma HDL-C and HDL parti

cle size can confer increased risk of atherosclerotic disease. epidemiological observation parallels the findings of some previous animal studies , there is no clear biological explanat

ion of how HDL can become www.lipid.org www.lipid.org Robins, S. J. et al. ArteriosclerThrombVascBiol2011;31:1208-1214.The Prevalence of IR by the 4th Quartile of HOMA-IR is Shown acro

ss Quartiles of Fasting Plasma HDL-C and across Quartiles of Fasting Plasma Triglycerides for Men and Women www.lipid.org www.lipid.org Unadjusted Kaplan-Meier Curves Showing the Cumula

tive Incidence of CHD Events in the Entire Study Sample (N=2910) with and without IR and with Lower or Higher Values of Fasting Plasma HDL-C (A) and with Lower or Higher Values of Plasm

a Triglycerides (TG) (B) Robins, S. J. et al. ArteriosclerThrombVascBiol2011;31:1208-1214. www.lipid.org www.lipid.orgPlasma TG (mmol/L) 0.01.02.03.04.05.0 R = -0.48; SnidermanAD et al

.Am J Cardiol. www.lipid.org www.lipid.org 3.04.05.0T2&#x 1.5;怀 50th IHD, ischemic heart disease.SnidermanAD et al.Am J Cardiol. www.lipid.org www.lipid.orgAtherogenicity of Triglycer

ides and Etiology of Abnormal Lipid MetabolismAdapted from Bays H, et al. Expert Opin Pharmacother. Small, denseHDL-P Small, denseLDL-P pHDL-CVisceralFFA ? LDL-C Non–HDL-C Apo B LDL P #

www.lipid.org www.lipid.org 1000120014001600180020406080100100120140160180 010020030040010001200140016001800LDL Particles (nmol/L)LDL Cholesterol (mg/dL)HDL Cholesterol (mg/dL)Trigly

cerides (mg/dL)LDL ParticlesLDL CholesterolLDL ParticlesLDL CholesterolAmer J Cardiol Relations of LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides www.l

ipid.org www.lipid.org 304050607080 HDL-C Levels Lovastatin 35–39 mg/dl �40 mg/dl AFCAPS/TexCAPS: Risk Reduction by HDL-C Tertile at Baseline www.lipid.org www.lipid.org 0.250.2

00.150.100.05 35 mg/dLHDL-C Decrease in minimum lumen diameter (mm) Fluvastatin for interaction = 0.01Ballantyne CM et al. Lipoprotein and Coronary Atherosclerosis Study (LCAS)

Benefit of Statin Therapy in Patients With Low HDL-CLRC Men 10 Year Follow up www.lipid.org www.lipid.org Mean LDL = 131 mg/dL.Below Tertile*Above Tertile* 25% CHD Event Rate and HDL-C

Levels in the Heart Collaborative Group. www.lipid.org www.lipid.org*CHD death, nonfatal MI, and stroke. 0.40.60.811.21.41.6 Pravastatin BetterPlacebo Better 0.88 Primary End Point* b

y Tertiles of LDL-C and HDL-C Shepherd J et al. www.lipid.org www.lipid.org•Patients with stable coronary disease (N=143) received gemfibrozil + niacin + cholestyramine or placebo–Base

line LDL-C 128 mg/dL•Group with greatest HDL-C increase had greatest chance of being CV event –HDL-C increase was a significant predictor of event-free survival even after adjustment fo

r LDL-C changes ( DevendraGP, et al. J CardiovascPharmacolTher. Dec Post-hoc Analysis of AFREGS www.lipid.org www.lipid.orgAngiographicEffectsMetaAnalysis,Trials'%s = 3.0 –0.076

(%HDL-C) + 0.06 (%= 0.96; PS+N=simvastatin + niacinHATS (HDL -Atherosclerosis Treatment in original study. Brown BG, et al. CurrOpinLipidol www.lipid.org www.lipid.orgLDL-C mg/dL Nicho

lls SJ, et al. Regression of Coronary Atherosclerosis Associated with On-Treatment Levels of LDL-C and www.lipid.org www.lipid.orgPercentage increase in HDL-C and percentage relative r

isk reduction in CHD: data from 17 prospective, randomized trials combining a total of 44,170 patients Alsheikh-Ali AA, et al. AHA Scientific Sessions, 2004. HDL-C and CHD Risk: Meta A

nalysis www.lipid.org www.lipid.org Barter P, et al. Low HDL-C was Associated with Higher CV Events in Patients with LDL-C 70 mg/dLPost-hoc Analysis of TNT www.lipid.org www.lipid.org J

afri H, et al. Ann Intern MedBlack circles indicate patients who are receiving statin interventions, and green circles indicate patients who are receiving a nonstatin control.Associatio

ns Between HDL-C and Cardiovascular Outcomes: Statin Treatment Does Not Alter Inverse Relationship www.lipid.org www.lipid.orgIncidence rates per 100 person years of exposure for the JU

PITER primary endpoint according to on-treatment concentrations of HDL-C and on treatment concentrations of ApoA1 RidkerPM, GenestJ, BoekholdtSM, et al. Lancet. Jul 31 2010;376(9738):33

3-339. www.lipid.org www.lipid.org •Electronic medical record study of 1,512 high-risk •Low HDL-C present in 66% of overall patients–Most prevalent (79%) in Alsheikh-Ali AA, et al. Am J

Cardiol. Low HDL-C defined as 40 mg/dL in men and 50 mg/dL in womenDocumented CHDOr CHD Risk Equivalents and Controlled LDL-C www.lipid.org www.lipid.orgCOMESHDL,PIECESNOTALWAYSTOGETHE

RNEATLY www.lipid.org www.lipid.orgTangier disease (deletion of nucleotides 3283 & 3284) produces a premature stop codon, resulting in the expression of a nonfunctional Up to one half o

f the cases of familial hypoalphalipoproteinemiaare due to a mutation in the gene for ABCA1The R219K variant of ABCA1 is associated with increased ABCA1 expression, higher mean serum HD

L levels, and lower frequency of CAD in Dutch men1.Remaleyet al. ProcNatlAcadSciUSA2.CleeSM et al. 2001;103:1198-205. www.lipid.org www.lipid.org Table 2. Summary of Data Available on

CETP Genotypes, CETP Phenotypes, Lipid Levels, and JAMA Characteristics of Participants of Danish Descent in the3 Studies Conducted in Copenhagen, Denmark www.lipid.org www.lipid.org Pl

asma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen General Population StudyJAMA www.lipid.org

www.lipid.org JAMA www.lipid.org www.lipid.orgAPOPROTEIN www.lipid.org www.lipid.orgsignificantly decreases the ability of apoA-I to bind fibroblasts and promote lipid effluxresults in

about a 4-fold reduction of serum HDL and increased risk for premature CADPatients with apoA-I(Lys 0) have low HDL due to enhanced ApoA-I (L178P) leads to endothelial dysfunction, incr

eased arterial wall thickness, and premature CADApoprotein A-I Mutations1.Huang W et al. ArteriosclerThrombVascBiol2.Miller M, et al. ArteriosclerThrombVascBiol3.Tilly-KeisiM et al. Art

eriosclerThrombVascBiol4.HovinghGK et al. J Am CollCardiol www.lipid.org www.lipid.orgEffect of APOA1 genotype and genotype combinations on HDL cholesterol levels and theoretically pred

icted and observed risks of J ClinEndocrinolMetab www.lipid.org www.lipid.org Effect of APOA1 genotype and genotype combinations onapoA-I levels and theoretically predicted and observed

risks ofJ ClinEndocrinolMetab www.lipid.org www.lipid.orgIntravenous injections of HDL and apoA-I prevent atherogenesis in rabbits fed high-cholesterol dietsIntravenous injection of HD

L in rabbits with established atherosclerotic disease results in significant slowing in rates of Transgenic apoE-deficient mice overexpressing human apoA-I have elevated serum HDL level

s and resistance to atherosclerosisMice with an LDL receptor deficiency fed an atherogenicdiet experience a dramatic 70% decrease in aortic atheromatousplaque burden within 4 weeks afte

r being injected with an adenovirus that The residual plaque in treated animals also has fewer foam cells, has a lower density of macrophages, and is more fibrotic, possibly rendering i

t more stable.Apoprotein A-I and Atherosclerosis1.BadimonJ et al. J ClinInvest2.Miyazaket al. ArteriosclerThrombVascBiol3.BadimonJ et al. 1992;86(supplIII):86-94.4.Plumb A et al. ProcNa

tlAcadSciUSA 1994;91:9607-11.5.PasztyC et al. J ClinInvest 6.Benoit P et al. 7.TangiralaR et al. 1999;100:1816-22. www.lipid.org www.lipid.org Total CholesterolLDL CholesterolHDL Choles

terolTriglyceridesApoA-ISirtoriCR, et al. Circulation. Apr17 2001;103(15):1949-1954. www.lipid.org www.lipid.org 0.60.70.80.91.0 Average IMT (mm) A-ILow-HDL SirtoriCR, et al. Circulatio

n. Apr17 2001;103(15):1949-1954. www.lipid.org www.lipid.org C www.lipid.org www.lipid.orgRoma P, Gregg RE, Meng MS, et al. J Clin Invest. Apr 1993; Dimer Has A Long Half-Life www.lipi