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