1. Role of Dysfunctional HDL in Cardiovascular Disease
Benjamin J. Ansell, MD FACC
UCLA School of Medicine

2. Benjamin J. Ansell, MD Honoraria: Aegeron Stocks, Stock Options,
Other Ownership Interest: Amgen, Bruin Pharma Off Label: None

3. Functional Versus Dysfunctional HDL
Zheng C, Aikawa, M. JACC.2012; 60:

4. IDEAL Increased MCE Risk at Very High HDL-C
van der Steeg, WA et al. J Am Coll Cardiol. 2008;51:

5. HDL-C Does Not Predict MACE in ACS: Results of 3-Year Clinical Follow-Up
Treatment-naive
Paneni F et al. Int J Cardiol. 2012; 158:

6. Assessing HDL Anti-Inflammatory Function: Methods
Ability of HDL to alter LDL-induced monocyte chemotactic activity (MCA) in a human artery wall coculture.
Ability of HDL to alter oxidized phospholipid-induced fluorescence in a cell-free assay (CFA).
Navab M et al. J. Lipid Res. 2000:41:1495–1508.

7. Correlation Between MCA and Cholesterol Efflux
Corr. = (P<0.001).
Navab M et al. Ann Med.2005;37:

8. Inflammatory/Anti-inflammatory Properties: HDL Inflammatory Index
Proinflammatory
HII
1.0
LDL
LDL + HDL

9. CHD Despite High HDL Study: Monocyte Chemotaxis Assay (MCA)
1.37
1.40
Subjects:
20 adults with stable CHD, HDL-C 84 mg/dL
Mean LDL-C 108 mg/dL
No lipid medication, smoking, or diabetes
1.20
1.00
0.80
HDL Inflammatory Index (HII)
P<0.001
0.60
0.35
0.40
0.20
Patients
Controls
Ansell BJ, Navab MN et al. Circulation. 2003;108:

10. CHD Despite High HDL Study: Cell-Free Assay (CFA)
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.40
1.60
P<0.001
Relative Fluorescence
Patients
Controls
Ansell BJ, Navab M et al. Circulation. 2003;108:

11. Impaired HDL Vasodilatory Effect in DM
Sorrentino SA et al. Circulation 2010;121;

12. MCA MCA in Patients with Varying Degrees of Glycemia 1.6 1.2 .8 .4 IGT
HDL effect on LDL-induced monocyte chemotaxis in artery wall coculture
1.6
1.2
MCA .8 .4
Control
IGT
Well-Controlled
Type 2 DM
Poorly-Controlled
Type 2 DM
Navab, MN et al. Diabetes. 2009;58:

13. HII (≥1.0 proinflammatory) Proinflammatory HDL (%)
Proinflammatory HDL in Systemic Lupus Erythematosus/Rheumatoid Arthritis
P<.0001
P=.001
P<.0001
1.0
3.0
P=.016
0.8
P=.003
2.5
2.0
0.6
44.7
HII (≥1.0 proinflammatory)
Proinflammatory HDL (%)
P=.006
1.5
0.4
1.0
20.1
0.2
0.5
4.1
0.0
0.0
SLE RA
Control
SLE RA
Control
Group
McMahon M et al. Arthritis Rheum. 2006;54:

14. The Antioxidative Index of HDL Isolated from Patients with Crohn’s Disease and Controls
van Leuven, S. I. et al. J. Lipid Res. 2007;48:

15. Impaired Efflux Capacity of HDL from Patients on Chronic Hemodialysis
% Efflux With/out Activation of ABC Transporters by LXR Agonist to HDL
N=57
Effect blunted by statin treatment
Yamamoto, S et al. J Amer Coll Cardiol. 2012; 60:

16. Myeloperoxidase (MPO)
↑Leukocytes and/or activity release MPO
MPO nitration and/or chlorination of apoA-1 at Tyr-192 and Tyr-166. leads to a loss of normal conformation of apoA-1 at “hinge” region
impairs binding with ABCA1 (macrophage lipid efflux)
impedes HDL’s binding to hepatic receptor SRB-1
upregulates expression of NFκβ and CAM’s
Shao B et al. J Biol Chem. 2005;280:
Underti A et al. J Biol Chem. 2009; 284:30825–30835.

17. Nitrated and Chlorinated HDL is Impaired in Endothelial Cell Repair
Pan B et al. Free Rad Med Biol Epub ahead of print.

18. Systemic inflammation,
Anti-Inflammatory HDL
Systemic inflammation,
e.g. coronary disease, diabetes, metabolic syndrome, surgery, infection, rheumatologic diseases
Antioxidant
Enzymes
e.g. PON-1, PAF-AH, LCAT
Antioxidant
Enzymes
Apo A-1
Phospholipid
monolayer
Apo A-1
Ansell BJ et al. Current Opinion in Lipidology. 2007:18;

19. Systemic inflammation,
Anti-Inflammatory HDL
Systemic inflammation,
e.g. coronary disease, diabetes, metabolic syndrome, surgery, infection, rheumatologic diseases
Antioxidant
Enzymes
e.g. PON-1, PAF-AH, LCAT
Antioxidant
Enzymes
Apo A-1
Phospholipid
monolayer
Apo A-1
Ansell BJ et al. Current Opinion in Lipidology. 2007:18;

20. Systemic inflammation,
Anti-Inflammatory HDL
Systemic inflammation,
e.g. coronary disease, diabetes, metabolic syndrome, surgery, infection, rheumatologic diseases
Antioxidant
Enzymes
e.g. PON-1, PAF-AH, LCAT
Oxidized
Phospholipids
↑sPLA-A2
Antioxidant
Enzymes
Apo A-1
Myeloperoxidase
Acute Phase
Proteins
Phospholipid
monolayer
Apo A-1
Chemically modified Apo A-1
Ansell BJ et al. Current Opinion in Lipidology. 2007:18;

21. Systemic inflammation,
Anti-Inflammatory HDL
Systemic inflammation,
e.g. coronary disease, diabetes, metabolic syndrome, surgery, infection, rheumatologic diseases
Pro-Inflammatory HDL
Antioxidant
Enzymes
e.g. PON-1, PAF-AH, LCAT
Oxidized
Phospholipids
↑sPLA-A2
Antioxidant
Enzymes
Apo A-1
Myeloperoxidase
Acute Phase
Proteins
Phospholipid
monolayer
Apo A-1
ABCA1
Chemically modified Apo A-1
Impaired Cholesterol Efflux
Increased LDL Oxidation
Enhanced Thrombosis,
ECM Degradation
Ansell BJ et al. Current Opinion in Lipidology. 2007:18;