Targeting HDL for the Prevention and Management of Cardiovascular Disease.

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Targeting HDL for the Prevention and Management
of Cardiovascular Disease.

• Prof V Blaton KU-Leuven Departm Clin Chem Az St
  Jan Av Ruddershove 10, 8000 Brugge (Be)

XV BCLF Congress Antalya 4-7 September 2007
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HDL cholesterol the missinglink in
cardiovascular riskreduction
HDL the main target in prevention of Coronary
heart events
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HDL an independent Risk Factor
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HDL an independent Risk Factor

• UCF golden standard for separation and
  identification( Goffman and Lindgren )
• Epidemiological data Framingham study
• Cardiovascular risk predictor ( Ridker )
• Mega Prevention Studies (Evidence Based Medicine)
• Intervention Studies Clinical and Experimental
• HDL-C Genetic and environmental origin
• Mass Transfer of cholesterol (C Sirtori )

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350
300
250
292
200
Incidence (per 1000) in 6 years
150
183
100
50
83
78
38
HDL-chol (mmol/L)
35
23
High risk (lt0.9)
13
Lower risk (0.9-1.42)
Lower risk (lt3.48)
High risk (gt5.0)
LDL-chol (mmol/L)
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HDL-C strong CVD risk predictor
95 confidenceinterval
0 1.0 2.0
4.0 6.0
Relative risk for future cardiovascular
events(highest quartile / lowest quartile)
Ridker et al. N Engl J Med 2000 342 836-43
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5-year Inc. MI/death in patients (placebo) with
low LDL-c
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Veterans Affairs HDL Intervention Trial VA-HIT
study

• 1.200 Gemfibrozil mg/day n 1.264 and n1267
  placebo from 1991-1998
• Aim HDL-C increase improve outcome in men with
  CHD, in secundary prevention
• HDL-C lt 40 mg/dl and LDL-C lt140 md/dl
• Duration 5.1 year.

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Exchangable body cholesterol

• Pool 1 rapidly exchanging ( M1),blood liver
  intestine.
• Pool 2 poorly defined (M2) xanthome
• Pool 3 slowly exchanging body cholesterol (M3)

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Atherosclerosis 186 ( 2006 ) 1-11, C Sirtori
HDL and mass transfer of cholesterol
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Adjusted MBmin (g/70kg)
50
25
60
20
120
HDL Cholesterol (mg/dl)
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HDL Raising Leads TO

• Cholesterol mobilization from tissues
• Evidence of atheroma volume reduction

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Low-HDL Genetic Origin
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Genetic and environmental origin of low HDL
cholesterol
Monogenic rare
Polygenic multifactorial
apoA-1 deficiency LCATdeficency Fish eye
disease Tangier Disease ABCA1
frequent
Metabolic syndrome
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Genetic factors associated with low HDL
cholesterol
LCAT
Apo-A-I
ABCA1
Formation and conversion of HDL
Lipid storage disease
Hypertriglyceridemia
HDL deficiency
hormones
Diabetes mellitus
obesity
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HDL- anti-inflammatory Capacity

• CHD is a inflammatory process
• Cytokines are key mediators of inflammation
• Their role in primary atherogenesis is unclear
• HDL has anti-inflammatory functions
• HDL inhibit release of cytokines, inhibit
  adhaesion molecules
• Association between cytokines, hsp-CRP, SAA,SAP
  and HDL in CHD

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HDL inhibition
HDLn HDLs Apo A-I
HDLn HDLre HDLs Apo A-I
( Dr Irena Korita, Tirana University 2007)
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Number and Particle Size determining factor and
Disease related
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HDL subpopulations
APOLIPOPROTEIN COMPOSITION
PARTICLE SHAPE
Discoidal
Spherical
A-I HDL
A-I/A-II HDL
A-II HDL
PARTICLE SIZE
Lipid-poor apoA-I
HDL2a
HDL2b
HDL3c
HDL3b
HDL3a
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Subclasses of serumlipoproteïns Nuclear
Magnetic resonance
Pat. A
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75
Percentile in Populatiion
15
21
16
11
113
20
17
50
29
69
5
1274
6
1
1
25
19
0
2
2
V6
V5
V4
V3
V2
V1
IDL
L3
L2
L1
H5
H4
H3
H2
H1
LDL Partikels (nmol/L)
Grote VLDL (V56)
Grote HDL (H345)
mg/dL TC 162, LDL-C 120, HDL-C 27, TG 113
77
60
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Pat. B
16
38
48
24
75
1597
Percentile in Population
4
32
3
50
8
25
38
5
0
2
2
7
V6
V5
V4
V3
V2
V1
IDL
L3
L2
L1
H5
H4
H3
H2
H1
LDL Partikels (nmol/L)
Grote VLDL (V56)
Grote HDL (H345)
mg/dL TC 183, LDL-C 121, HDL-C 32, TG 210
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Treatment of Low HDL

• Life style
• weight reduction
• Fysical activities
• No Smoking
• Drugs
• Statines
• Fibrates
• Niacin statines
• Inhibition CETP , HDls, Apo-A1 rec, HDLn.
• Gene activation
• - ABCA1 and ABCG1
• Apo-A1
• LCAT

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The effect of statins and fibrates on HDL-C
(mg/dl)
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Fenofibrate
Simvastatin
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Fenofibrate
Pravastatin
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Absolute change of HDL-C (mg/dL)
10
Simvastatin
5
Pravastatin
0
20
10
50
40
30
60
Pre-treatment value of HDL-C (mg/dL)
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HDL-C Percentage Change from Baselineat Week 6
12
10
8
LS mean change from baseline
6
4
2
0
10
20
40
80
Log scale
Dose (mg)
CRESTOR
atorvastatin
simvastatin
pravastatin
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• ABCA1
• ABCG1
• LCAT
• SRB1
• CETP inhibition
• Apo A-I Milano Apo A (I)re

Major Targets to raise HDL-C
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Cascade of lipoprotein metabolisme
H.B. Brewer Ather Throm 2004,24,387
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Torcetrapib Trifluoromethylbenzyl-methoxycarbonyl
-amino-ethylester
Highly effective way to increase HDL via
inhibition of CETP. A DREAM ?
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Effects CETP Inhibitors
Arterioscle Thromb Vasc Biol 200424490-497
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Torcetrapib Large Phase II Study

• 
  HDL-C LDL-c
• Torcet 60 mg placebo 45
  -10
• Torcet 60 mg ATV 10 mg 53 -
  41
• Torcet 60 mg ATV 20 mg 44 -
  50
• Torcet 60 mg ATV 40 mg 50 -
  58
• Torcet 60 mg ATV 80 mg 66 -
  60

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ILLUMINATE STUDY15.000 PATIENTS ??CHD
Torcetrapib 60mg plus atorvastatin 10-80 mg
and alone.
(one year)
HEART FAILURE ANGINA REVASCULARIZATION SYSTOLIC
BLOOD PRESSURE 5mm Vascular effects 2006-2007
82
Total death
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Atorva.
Atorva Torcetrapib.
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The Failure of Torcitrapib

• Was it the Molecule or the Mechanism

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HDL raising gene transfer on atherosclerosis

• Overexpression of transgenes in hepatoctes of
  dyslipemic mice and rabbits
• Gentransport of apo A(I)
• ATP-binding Cassette transport proteine
• ABCA1
• Gentransport of Apo A(I) and LCAT
• Apo A(I) ?HDL and reduction of lesions

Johanna Lievens KU-Leuven 2007
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The unanswered questions

• What regulates concentration and subpopulation of
  HDLs
• What regulates HDL functions
• Cardio protective HDL function and HDL
  concentration
• HDLs subpopulations different in CHD protection
• Relative contribution of cholesterol efflux,
  anti-oxidant, and anti inflammatory to cardio
  protection.
• Overweight smoking and low HDL
• A-I HDLs differ from A-I/A-II HDLs
• Low HDL Atherogenic

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Conclusions HDL Cardioprotective

• HDL particles are cardioprotective
• HDL is an independent risk factor for CVD
• HDL are lifestyle dependent
• HDL are potential therapeutical targets in
  treatment and prevention
• HDL concentration important in diagnosis and
  treatment
• However Unanswered questions