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Le HDL-c, où en est-on aujourd’hui ? par John Chapman
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. 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. 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
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
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. What are the major
physiological, clinically-
relevant functions of HDL ?
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
27. Is HDL-C an informative biomarker
of HDL function ?
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. 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. • Is HDL particle function conserved in
metabolic syndrome (prediabetes)
and type 2 diabetes ?
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
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. 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
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.