le hdl-c, où en est-on aujourd’hui ? par john chapman
DESCRIPTION
Le HDL-c, où en est-on aujourd’hui ? par John ChapmanTRANSCRIPT
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 ?:
Inflammation - macrophages - T lymphocytes - mast cells
Lipid-richcore
Thin-cap atherosclerotic plaqueThe rupture-prone or high-risk plaque = Killer #1high-risk plaque = Killer #1
Courtesy: Erling FalkCourtesy: Erling Falk
Thin cap
Atherosclerotic Plaque Development:
From Healthy Vessel to Clinical CVD
Genetic/Genomic Genetic/Genomic DeterminantsDeterminants
Environmental Environmental ModifiersModifiers
Healthy Vascular
State
Traditional Risk FactorsNovel Risk
Factors
Subclinical Subclinical AtherosclerosisAtherosclerosis
Clinical Clinical CardiovascularCardiovascular
DiseaseDisease
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
Haz
ard
Rat
io
4040 6060 8080
HDL-C (mg/dL)
N = 302,430
3030 5050 7070
www.escardio.org/guidelines
ESC/EAS Guidelines for the managementof dyslipidaemias
The Task Force for the management of dyslipidaemias of theEuropean Society of Cardiology (ESC) and the EuropeanAtherosclerosis Society (EAS)
Developed with the special contribution of: European Association for CardiovascularPrevention & 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):1769–1818Atherosclerosis 2011 Jul;217(1):3-46
www.escardio.org/guidelines
SCORE charts with HDL-C for use in high risk regions: HDL-C= 1.4 mmol/L (56
mg/dL)
46912
571014
681115
791318
8111520
3468
3579
46811
56913
681115
2345
2346
3457
3468
45710
0011
0111
0111
111 2
1112
1223
1234
2235
2345
2356
4 5 6 7 8
Smokers
681013
681114
791215
8101317
9111418
3456
3457
3467
4568
4579
2234
2234
2234
2345
2345
0000
0000
0001
000 1
0011
1111
1112
1112
1122
1122
4 5 6 7 8
Women
Total Cholesterol (mmol/L)
Age
65
60
55
50
40
Men
Non-smokers Smokers
7111521
9121723
10141926
11162229
13182534
571014
681216
7101419
8111622
10131825
3569
45811
56912
681115
791317
1112
1112
1122
112 3
1223
2346
2357
3468
45710
46811
4 5 6 7 8
Non-smokers
180160140120
180160140120
180160140120
180160140120
180160140120
3457
3457
3468
4568
4679
1223
1223
2234
2234
2334
1112
1112
1122
1122
1123
0000
0000
0000
0000
0000
0011
0011
0111
0111
1111
4 5 6 7 8
Syst
olic
blo
od p
ress
ure
(mm
Hg)
European Heart Journal 2011;32 (14):1769–1818Atherosclerosis 2011 Jul;217(1):3-46
www.escardio.org/guidelines
SCORE charts with HDL-C for use in high risk regions: HDL-C= 0.8 mmol/L (32
mg/dL)
681116
791318
8111521
9131824
11152128
46811
57913
681115
791318
8111521
3457
3469
45710
56912
681115
0111
1112
1112
112 2
1123
2235
2345
2357
3468
4579
4 5 6 7 8
Smokers
10131722
11141924
12162026
14182228
15192531
56811
57912
681013
791114
7101216
3456
3457
3468
4568
4679
0011
0111
0111
111 1
1111
1223
1223
2233
2234
2334
4 5 6 7 8
Women
Total Cholesterol (mmol/L)
Age
65
60
55
50
40
Men
Non-smokers Smokers
10141926
12162230
14192534
16222939
19263445
7101419
8121622
10141925
12162230
14192635
57913
681115
791318
8111521
10141925
1122
1123
1223
123 3
2235
3468
45710
46812
571014
691217
4 5 6 7 8
Non-smokers
180160140120
180160140120
180160140120
180160140120
180160140120
57911
67912
681013
791215
8101316
2345
3346
3456
3467
4568
1223
2233
2234
2234
2345
0000
0000
0001
0001
0011
1111
1112
1112
1122
1122
4 5 6 7 8
Syst
olic
blo
od p
ress
ure
(mm
Hg)
European Heart Journal 2011;32 (14):1769–1818Atherosclerosis 2011 Jul;217(1):3-46
What is HDL-C ?
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
What are the building blocks of HDL particle structure ?
Lipid-free apoAI
The HDL Building Block
Plasma HDL subpopulations :
symmetrical cage-like structure with 4 apoAI copies per particle
Huang et al, Nature Struct Mol Biol, 2011
Correlational network of proteins in HDL subfractions Davidson et al, ATVB 2009
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
HDL Lipids = HDL Lipidome
CeramidesSphingolipidsGlycosphingolipids PhospholipidsDi- and TriacylglycerolsCholesteryl estersModified lipids (oxidized, glycated)LysolipidsFree fatty acids
Lipidomics technology
Analytical platform = Liquid chromatography, electrospray ionisation triple quadrapole mass spectrometer
(LC ESI-MS/MS)
Lipid extraction• 10L plasma
• Single phase CHCl3/MeOH
Lipid Quantification• Stable isotope dilution
• Multiple reaction monitoring
Camont et al, ATVB 2013
HDL in 2014
Lipidome
CVD protection
HDLFunctionality
ProteomeProteome
What is the origin of HDL-C ?
Courtesy of Dr H.B. Brewer
Kontush A, Chapman MJ, Nature CPCM 2008
Lipids60%
Protein40%
Protein45%
Lipids55%
Lipids35%
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
VLDLIDLLDL
CETPCE
CE
FC, CE
TG
TG
What are the major physiological, clinically-
relevant functions of HDL ?
23
23
Cholesterol efflux from cells to HDL particles
Extracellular space Cell membrane
FC
FC
FC
FC
ABCA1
Diffusion
SR-B1
Diffusion
SR-B1ABCG1
Diffusion
SR-B1ABCG1
Lipid-poor ApoA-I
Discoidal HDL
Small spherical HDL
Large spherical HDL
LCAT
LCAT
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
HomozygousProband
LAD
Mixed Plaque
Homozygous Familial ApoA-I Deficiency
Homozygous Familial ApoA-I Deficiency
Santos RD et al, J Lipid Res 2008;49:349-357.
Is HDL-C an informative biomarker
of HDL function ?
Is HDL-C an informative biomarker
of HDL function ?
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 »
• Khera et al, NEJM 2011, 364: 127-135
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
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
• Is HDL particle function conserved in
metabolic syndrome (prediabetes)
and type 2 diabetes ?
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.
CEVLDLTG
Chronic inflammation
Oxidativestress
Hyperglycemia
IL-6; TNFα
HL
A-I
A-I
TG
SAA
A-IFunctionallydeficient HDL
Cholesterol efflux capacity Antioxidative activity Anti-inflammatory activity Antiapoptotic activity Vasodilatory activity
Normalfunctional
HDL
A-I
PON1
SAA + altered expression of HDL proteins(CRP)
CE
CETP
TG
PON1
Liver
Altered proteome + lipidome
Do elevated levels of HDL-C reduce CV
risk ?
- Epidemiological data- Experimental animal studies
- Genetic CETP deficiency
Low HDL-C Levels Are Associated With High CHD Risk BUT:
Elevated HDL-C Levels Are Cardioprotective
HDL-CHDL-C
Rela
tive r
isk f
or
incid
en
t C
HD
Rela
tive r
isk f
or
incid
en
t C
HD
mmol/Lmmol/Lmg/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
1.01.03939
1.21.24848
1.41.45656
1.71.76565
2.12.18181
0.80.83131
0.90.93838
1.11.14343
1.21.24949
1.61.66262
ARIC
• Raise HDL-C !
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
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
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
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)
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
Dal – OUTCOMES•Dalcetrapib + statin vs Statin
•ACS patients
•HDL-C +30%
•No effect on LDL-C
•Stopped for futility
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
Kingwell and Chapman, Circulation 2013
Plaque cholesterol efflux : rHDL
Potential mechanisms of rHDL action
Kingwell and Chapman, Circulation 2013
Kingwell and Chapman, Circulation 2013
Ongoing HDL Infusion Trials
Oral DESIGN N Primary endpoint Expected
RVX-208
2b
Placebo vs RVX-208 Coronary artery disease
324 % change in coronary atheroma volume (IVUS)
2013
EvacetrapibACCELERATE
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
AnacetrapibREVEAL
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 agentsOngoing clinical trials involving oral HDL- raising agents
apoB
Macrophage
VLDL
SR-BI
Liver
CE,FC
ABCA1
A-I
PL FC
LDLLCATCE
apoB
Peripheraltissues
Bile acidsCholesterol
CETP
HDL metabolism: Impact of potent CETP inhibition
CELDL-R
FC
FC
CE
HDL3 TG
CE CECE
E
EE
HDL
HDL2AI
AI
Preß-HDL
apoE-HDL
ABCA-1 SR-B1 ABCG-1
Decreased apoA-I/HDL catabolism
Atherogenic lipoproteins (VLDL, IDL, LDL)
Liver
CETPinhibitors
SR-B1Bile
HDL2HDL3Pre-HDL
Macrophage within Atherosclerotic Plaque
ApoA-I synthesis
HDL infusion
Lipid-freeapoA-I
LCAT
LCAT
CETP
miR-33
ASOs:
-CETP
-apoCIII
miR-33
ASOs:
-CETP
-apoCIII
HDLisolation
Eder & coll.1951
LCATreactionGlomset
1962
HDLapolipoprotein
familiesAlaupovic
1971
HDLand RCTMiller &
Miller1975
HDL-C& CV riskGordon & coll.1977
HDL-Cassay
Albers & coll.1982
ABCA1& low HDL-C
AssmannGenestHaydenSchmitz
1999
HDLdysfunctionFogelman
& coll.1995
SR-BIreceptorKrieger & coll.1996
Doublebelt
modelSegrest & coll.1999
Atherosclerosis regressionby rHDLin manNissen & coll.2003
Trefoilmodel
Davidson & coll.2008
Clinical trials
of HDL-raising
therapies
HDLheterogeneity
Chapman & coll. Nichols & coll.
1981
CETPZilversmit
& coll.Barter & coll.
1977-82
ApoA-I sequence
Jackson & coll.Brewer & coll.
1975-78
ABCG1& HDL
Tall & coll.2004
CETPdeficiencyMabuchi
& coll.1985
ApoA-IMilanoSirtori & coll.1980
Familial HDL
deficiencySchaefer
& coll.1977-78
MacrophageRCT
Rader & coll.2003
Cholesterolefflux to HDL
OramPhillips
Rothblat1981-82
Pre-betaHDLs
Fielding & coll.Asztalos & coll.
1987-93
Kontush A, Chapman MJ, High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics. Wiley & Sons, NY, 2012.
HDL :TIMELINES