Le HDL-c, où en est-on aujourd’hui ? par John Chapman

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Le HDL-c, où en est-on aujourd’hui ? par John Chapman

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  • John thought the animation could go to save time (on the other hand it probably adds clarity)
    Throuhgout the slides “cholesterol ester” should be “cholesteryl ester)
  • Key points
    At least four different processes promote the efflux of excess cholesterol from cells, with different HDL types acting as the acceptor particle.
    The relative importance of these four processes is uncertain. It may vary between different cell types and according to physiological circumstances.1
    Background
    There are at least four different processes that promote the efflux of cholesterol from cells to HDLs:
    ABCA1 promotes a net efflux of cholesterol from cells to lipid-free ApoA-I in the extracellular space 2,3,4,5
    ABCG1 promotes a net efflux of cholesterol from cells to large spherical HDLs in the extracellular space 2,3,4,5
    A net efflux of cholesterol to HDLs depends on the presence of a cholesterol concentration gradient from the cell to the HDL particle. Such a gradient is generated by the LCAT-mediated esterification of cholesterol, which also promotes formation of spherical HDL 2,3,5
    SR-B1 mediates bidirectional transfer of cholesterol between cells and HDLs,2,4,5 but a net efflux to HDL depends on a cholesterol concentration gradient.1
    Abbreviations
    ABCA1=ATP binding cassette A1; ABCG1=ATP binding cassette G1; Apo=apolipoprotein; HDL=high-density lipoprotein; LCAT=lecithin:cholesterol acyltransferase; SR-B1=scavenger receptor type B1; UC=unesterified cholesterol (will be changed to FC following redraw)
    References
    1Barter P, Rye KA. High density lipoprotein cholesterol: the new target. A handbook for clinicians. 3rd ed. Birmingham, UK: Sherborne Gibbs, 2007.
    2von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2001;21:13–27.
    3Barter PJ. Hugh Sinclair Lecture: The regulation and remodelling of HDL by plasma factors. Atherosclerosis Supplements 2002;3:39–47.
    4Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest. 2006;116:3090–3100.
    5Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med. 2008;263:256–273.
  • Le HDL-c, où en est-on aujourd’hui ? par John Chapman

    1. 1. M. John Chapman BSc, Ph.D., D.Sc., FESC Past-President, European Atherosclerosis Society Research Professor, University of Pierre and Marie Curie Director Emeritus, Dyslipidemia and Atherosclerosis Research, INSERM UMR1166 Pitié-Salpetriere University Hospital, Paris, France 17eme Journee d’Endocrinologie, Metabolisme & Nutrition, Hopital de la Pitie-Salpetriere 2014 Le HDL-C : Ou en est-on aujourd’hui ?:
    2. 2. Inflammatio n - macrophages - T lymphocytes - mast cells Lipid- rich core Thin-cap atherosclerotic plaque The rupture-prone or high-risk plaque = Killer #1high-risk plaque = Killer #1 Courtesy: Erling FalkCourtesy: Erling Falk Thin cap
    3. 3. Atherosclerotic Plaque Development: From Healthy Vessel to Clinical CVD Genetic/GenomicGenetic/Genomic DeterminantsDeterminants EnvironmentalEnvironmental ModifiersModifiers Healthy Vascular State Traditional Risk Factors Novel Risk Factors SubclinicalSubclinical AtherosclerosisAtherosclerosis ClinicalClinical CardiovascularCardiovascular DiseaseDisease
    4. 4. The Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000 Coronary Heart Disease and HDL-C 0.80.8 1.01.0 1.51.5 2.02.0 2.52.5 3.03.0 3.53.5 HazardRatio 4040 6060 8080 HDL-C (mg/dL) N = 302,430 3030 5050 7070
    5. 5. www.escardio.org/guidelines ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Developed with the special contribution of: European Association for Cardiovascular Prevention & Rehabilitation† Authors/Task Force Members: Željko Reiner* (ESC Chairperson) (Croatia) Alberico L. Catapano* (EAS Chairperson)* (Italy), Guy De Backer (Belgium), Ian Graham (Ireland), Marja-Riitta Taskinen (Finland), Olov Wiklund (Sweden), Stefan Agewall (Norway), Eduardo Alegria (Spain), M. John Chapman (France), Paul Durrington (UK), Serap Erdine (Turkey), Julian Halcox (UK), Richard Hobbs (UK), John Kjekshus (Norway), Pasquale Perrone Filardi (Italy), Gabriele Riccardi (Italy), Robert F. Storey (UK), David Wood (UK). European Heart Journal 2011;32 (14):1769–1818 Atherosclerosis 2011 Jul;217(1):3-46
    6. 6. www.escardio.org/guidelines SCORE charts with HDL-C for use in high risk regions: HDL-C= 1.4 mmol/L (56 mg/dL) 4 6 9 12 5 7 10 14 6 8 11 15 7 9 13 18 8 11 15 20 3 4 6 8 3 5 7 9 4 6 8 11 5 6 9 13 6 8 11 15 2 3 4 5 2 3 4 6 3 4 5 7 3 4 6 8 4 5 7 10 0 0 1 1 0 1 1 1 0 1 1 1 1 1 1 2 1 1 1 2 1 2 2 3 1 2 3 4 2 2 3 5 2 3 4 5 2 3 5 6 4 5 6 7 8 Smokers 6 8 10 13 6 8 11 14 7 9 12 15 8 10 13 17 9 11 14 18 3 4 5 6 3 4 5 7 3 4 6 7 4 5 6 8 4 5 7 9 2 2 3 4 2 2 3 4 2 2 3 4 2 3 4 5 2 3 4 5 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 1 1 1 1 1 1 1 1 1 2 1 1 1 2 1 1 2 2 1 1 2 2 4 5 6 7 8 Women Total Cholesterol (mmol/L) Age 65 60 55 50 40 Men Non-smokers Smokers 7 11 15 21 9 12 17 23 10 14 19 26 11 16 22 29 13 18 25 34 5 7 10 14 6 8 12 16 7 10 14 19 8 11 16 22 10 13 18 25 3 5 6 9 4 5 8 11 5 6 9 12 6 8 11 15 7 9 13 17 1 1 1 2 1 1 1 2 1 1 2 2 1 1 2 3 1 2 2 3 2 3 4 6 2 3 5 7 3 4 6 8 4 5 7 10 4 6 8 11 4 5 6 7 8 Non-smokers 180 160 140 120 180 160 140 120 180 160 140 120 180 160 140 120 180 160 140 120 3 4 5 7 3 4 5 7 3 4 6 8 4 5 6 8 4 6 7 9 1 2 2 3 1 2 2 3 2 2 3 4 2 2 3 4 2 3 3 4 1 1 1 2 1 1 1 2 1 1 2 2 1 1 2 2 1 1 2 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 1 1 0 1 1 1 0 1 1 1 1 1 1 1 4 5 6 7 8 Systolicbloodpressure(mmHg) European Heart Journal 2011;32 (14):1769–1818 Atherosclerosis 2011 Jul;217(1):3-46
    7. 7. www.escardio.org/guidelines SCORE charts with HDL-C for use in high risk regions: HDL-C= 0.8 mmol/L (32 mg/dL) 6 8 11 16 7 9 13 18 8 11 15 21 9 13 18 24 11 15 21 28 4 6 8 11 5 7 9 13 6 8 11 15 7 9 13 18 8 11 15 21 3 4 5 7 3 4 6 9 4 5 7 10 5 6 9 12 6 8 11 15 0 1 1 1 1 1 1 2 1 1 1 2 1 1 2 2 1 1 2 3 2 2 3 5 2 3 4 5 2 3 5 7 3 4 6 8 4 5 7 9 4 5 6 7 8 Smokers 10 13 17 22 11 14 19 24 12 16 20 26 14 18 22 28 15 19 25 31 5 6 8 11 5 7 9 12 6 8 10 13 7 9 11 14 7 10 12 16 3 4 5 6 3 4 5 7 3 4 6 8 4 5 6 8 4 6 7 9 0 0 1 1 0 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 2 2 3 1 2 2 3 2 2 3 3 2 2 3 4 2 3 3 4 4 5 6 7 8 Women Total Cholesterol (mmol/L) Age 65 60 55 50 40 Men Non-smokers Smokers 10 14 19 26 12 16 22 30 14 19 25 34 16 22 29 39 19 26 34 45 7 10 14 19 8 12 16 22 10 14 19 25 12 16 22 30 14 19 26 35 5 7 9 13 6 8 11 15 7 9 13 18 8 11 15 21 10 14 19 25 1 1 2 2 1 1 2 3 1 2 2 3 1 2 3 3 2 2 3 5 3 4 6 8 4 5 7 10 4 6 8 12 5 7 10 14 6 9 12 17 4 5 6 7 8 Non-smokers 180 160 140 120 180 160 140 120 180 160 140 120 180 160 140 120 180 160 140 120 5 7 9 11 6 7 9 12 6 8 10 13 7 9 12 15 8 10 13 16 2 3 4 5 3 3 4 6 3 4 5 6 3 4 6 7 4 5 6 8 1 2 2 3 2 2 3 3 2 2 3 4 2 2 3 4 2 3 4 5 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 1 1 1 1 1 1 1 1 1 2 1 1 1 2 1 1 2 2 1 1 2 2 4 5 6 7 8 Systolicbloodpressure(mmHg) European Heart Journal 2011;32 (14):1769–1818 Atherosclerosis 2011 Jul;217(1):3-46
    8. 8. What is HDL-C ?
    9. 9. NY-160626.038/020131YlsjoLS1 HDLHDL2a2aHDLHDL2b2b HDLHDL3c3cHDLHDL3b3bHDLHDL3a3a PARTICLE SIZEPARTICLE SIZE APOLIPOPROTEIN COMPOSITIONAPOLIPOPROTEIN COMPOSITION DiscoidalDiscoidal apoA-I HDLapoA-I HDL apoA-I/A-II HDLapoA-I/A-II HDL Lipid-poor apoA-ILipid-poor apoA-I HDL-C = Sum of cholesterol content in all plasma HDL particle subpopulations
    10. 10. What are the building blocks of HDL particle structure ?
    11. 11. Lipid-free apoAI The HDL Building Block
    12. 12. Plasma HDL subpopulations : symmetrical cage-like structure with 4 apoAI copies per particle Huang et al, Nature Struct Mol Biol, 2011
    13. 13. Correlational network of proteins in HDL subfractions Davidson et al, ATVB 2009
    14. 14. Kumpula et al. (2008) Chem Phys Lipids 155: 57-62 Molecular models of plasma HDL % Chemical Composition HDL2 HDL3 PL 30 24 FC 3 1 CE 27 23 TG 4 2 PRN 34 51 6 nm ApoAI
    15. 15. HDL Lipids = HDL Lipidome Ceramides Sphingolipids Glycosphingolipids Phospholipids Di- and Triacylglycerols Cholesteryl esters Modified lipids (oxidized, glycated) Lysolipids Free fatty acids
    16. 16. Lipidomics technology Analytical platform = Liquid chromatography, electrospray ionisation triple quadrapole mass spectrometer (LC ESI-MS/MS) Lipid extraction • 10µL plasma • Single phase CHCl3/MeOH Lipid Quantification • Stable isotope dilution • Multiple reaction monitoring
    17. 17. Camont et al, ATVB 2013
    18. 18. HDL in 2014 Lipidome CVD protection HDL Functionality Proteome
    19. 19. What is the origin of HDL-C ?
    20. 20. Courtesy of Dr H.B. Brewer
    21. 21. Kontush A, Chapman MJ, Nature CPCM 2008 Lipids 60% Protein40% Protein 45% Lipids 55% Lipids 35% HDL3a Heterogeneity and Intravascular Metabolism of HDL particles HDL2b HDL3c HDL3b HDL2a Pre-β-HDL FC, PL ABCA1 HDL3 Lipid-free A-I HDL2 FC, CE PLTP HL EL Hepatocyte A-I LCAT LCAT Peripheral cell SR-BI CE FC FC CE Intestine ABCG1 FC, PL HDL-R LDL-R VLDL IDL LDL CETP CE CE FC, CE TG TG
    22. 22. What are the major physiological, clinically- relevant functions of HDL ?
    23. 23. 23 23 Cholesterol efflux from cells to HDL particles Extracellular space Cell membrane FC FC FC FC ABCA1 Diffusion SR-B1 Diffusion SR-B1 ABCG1 Diffusion SR-B1 ABCG1 Lipid-poor ApoA-I Discoidal HDL Small spherical HDL Large spherical HDL LCAT LCAT
    24. 24. HDL apoAI VLDL/LDL CECE Liver Bile CECE CETP SR-B1SR-B1 LDL-RLDL-R CECE FCFC FCFC (1) (2) (3) (3) SR-B1SR-B1 LCAT Extrahepatic tissuesExtrahepatic tissues Arterial wallArterial wall FCFC ABCA1, ABCG1,ABCA1, ABCG1, SR-B1SR-B1 Reverse cholesterol transport
    25. 25. Homozygous Proband LAD Mixed Plaque Homozygous Familial ApoA-I Deficiency
    26. 26. Homozygous Familial ApoA-I Deficiency Santos RD et al, J Lipid Res 2008;49:349-357.
    27. 27. Is HDL-C an informative biomarker of HDL function ?
    28. 28. Cholesterol efflux capacity, HDL-C and Atherosclerosis • « Cholesterol efflux capacity from macrophages has a strong inverse association with both carotid IMT and the likelihood of angiographic CAD, independently of HDL-cholesterol » •
    29. 29. Relationship between genetic variants of HDL and CV risk Meta-analysis : genetic variations in genes that raise the concentration of HDL-C are not associated with a decrease in CV risk. Genes which increase HDL-C concentration may not increase HDL function…. Voight et al; Lancet 2012 It is essential that we stop regarding HDL-C as protective and focus more on the protective functions of HDL
    30. 30. • Is HDL particle function conserved in metabolic syndrome (prediabetes) and type 2 diabetes ?
    31. 31. NY-160626.038/020131YlsjoLS1 Abnormal Metabolism and Defective Function of HDL in Diabetic Dyslipidemia CE Kontush A, Chapman MJ. Pharmacol Rev 2006; Curr. Diabetes Rep. 2008;8:51-59. CE VLDL TG Chronic inflammation Oxidative stress Hyperglycemia IL-6; TNFα HL A-I A-I TG SAA A-I Functionally deficient HDL ↓ Cholesterol efflux capacity ↓ Antioxidative activity ↓ Anti-inflammatory activity ↓ Antiapoptotic activity ↓ Vasodilatory activity Normal functional HDL A-I PON1 SAA + altered expression of HDL proteins (CRP) CE CETP TG PON1 Liver Altered proteome + lipidome
    32. 32. Do elevated levels of HDL-C reduce CV risk ?
    33. 33. - Epidemiological data - Experimental animal studies - Genetic CETP deficiency
    34. 34. Low HDL-C Levels Are Associated With High CHD Risk BUT: Elevated HDL-C Levels Are Cardioprotective HDL-CHDL-C RelativeriskforincidentCHDRelativeriskforincidentCHD mmol/Lmmol/L mg/dLmg/dL Adjusted for age and race, 10-year follow-up; N=12,339.Adjusted for age and race, 10-year follow-up; N=12,339. Sharrett AR et al.Sharrett AR et al. CirculationCirculation. 2001.. 2001. 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1 2 3 4 5 WomenWomen 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1 2 3 4 5 MenMen 1.01.0 3939 1.21.2 4848 1.41.4 5656 1.71.7 6565 2.12.1 8181 0.80.8 3131 0.90.9 3838 1.11.1 4343 1.21.2 4949 1.61.6 6262 ARIC
    35. 35. • Raise HDL-C !
    36. 36. The Failures : Niacin AIM-HIGH •ER-Niacin vs Placebo ( +niacin) •CVD patients •High TG / low HDL-C •LDL-C at entry : 40-80 mg/dl •Stopped at 3 years :futility HPS2 – THRIVE •n = 25,673 : High CV risk •ER Niacin + LRPT vs Placebo •Stopped at 3.9 years (median) •XS myopathy (Chinese subjects) •No reduction in MACE
    37. 37. The Failures: CETP inhibitors ILLUMINATE •Torcetrapib + Atorvastatin vs Atorvastatin •HDL-C +72% ; LDL-C -25% •Increase in CVD events ( +25% ) in active arm •Off-target toxicity •Increase in BP (5mmHg) Dal – OUTCOMES •Dalcetrapib + statin vs Statin •ACS patients •HDL-C +30% •No effect on LDL-C •Stopped for futility
    38. 38. The Successes : rHDL infusion • rHDL / apoAI Milano infusion • IVUS • Coronary plaque regression • JAMA 2003 • Symptomatic PAD • rHDL / CSL 111 • Atherectomy • Lipid / macrophage plaque content • Circ Res 2008
    39. 39. Kingwell and Chapman, Circulation 2013 Plaque cholesterol efflux : rHDL
    40. 40. Potential mechanisms of rHDL action Kingwell and Chapman, Circulation 2013
    41. 41. Kingwell and Chapman, Circulation 2013 Ongoing HDL Infusion Trials
    42. 42. Oral DESIGN N Primary endpoint Expected RVX-208 2b Placebo vs RVX-208 Coronary artery disease 324 % change in coronary atheroma volume (IVUS) 2013 Evacetrapib ACCELERATE 3 Placebo vs evacetrapib Cardiovascular diseases 11,000 Time to first occurrence of composite CV endpoint (Death, MI, stroke, coronary Revascularization, or Hospitalization for UA) 2015 Anacetrapib REVEAL 3 Placebo vs anacetrapib Atherosclerotic cardiovascular disease 30,000 Major coronary events (Coronary death, MI or coronary revascularization procedure) 2017 Ongoing clinical trials involving oral HDL- raising agents
    43. 43. apoB Macrophage VLDL SR-BI Liver CE,FC ABCA1 A-I PL FC LDLLCAT CE apoB Peripheral tissues Bile acids Cholesterol CETP HDL metabolism: Impact of potent CETP inhibition CE LDL-R FC FC CE HDL3 TG CE CECE E E E HDL HDL2 AI AI Preß- HDL apoE-HDL
    44. 44. ABCA-1 SR-B1 ABCG-1 Decreased apoA-I/HDL catabolism Atherogenic lipoproteins (VLDL, IDL, LDL) Liver CETP inhibitors SR-B1Bile HDL2 HDL3Preβ-HDL Macrophage within Atherosclerotic Plaque ApoA-I synthesis HDL infusion Lipid-free apoA-I LCAT LCAT CETP miR-33 ASOs: -CETP -apoCIII miR-33 ASOs: -CETP -apoCIII
    45. 45. HDL isolation Eder & coll. 1951 LCAT reaction Glomset 1962 HDL apolipoprotein families Alaupovic 1971 HDL and RCT Miller & Miller 1975 HDL-C & CV risk Gordon & coll. 1977 HDL-C assay Albers & coll. 1982 ABCA1 & low HDL-C Assmann Genest Hayden Schmitz 1999 HDL dysfunction Fogelman & coll. 1995 SR-BI receptor Krieger & coll. 1996 Double belt model Segrest & coll. 1999 Atherosclerosis regression by rHDL in man Nissen & coll. 2003 Trefoil model Davidson & coll. 2008 Clinical trials of HDL- raising therapies HDL heterogeneity Chapman & coll. Nichols & coll. 1981 CETP Zilversmit & coll. Barter & coll. 1977-82 ApoA-I sequence Jackson & coll. Brewer & coll. 1975-78 ABCG1 & HDL Tall & coll. 2004 CETP deficiency Mabuchi & coll. 1985 ApoA-I Milano Sirtori & coll. 1980 Familial HDL deficiency Schaefer & coll. 1977-78 Macrophage RCT Rader & coll. 2003 Cholesterol efflux to HDL Oram Phillips Rothblat 1981-82 Pre-beta HDLs Fielding & coll. Asztalos & coll. 1987-93 Kontush A, Chapman MJ, High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics. Wiley & Sons, NY, 2012. HDL : TIMELINES

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