1. HDL Is Commonly Dysfunctional in CVD and Other Inflammatory Conditions
Benjamin J. Ansell, MD FACC
UCLA School of Medicine

2. Potential Mechanistic Links Between Systemic Inflammation and Atherosclerosis
Stimulus
Environmental (infection,
smoking, pollution, diet)
Autoimmune (rheumatic)
Metabolic (diabetes, thyroid)
Oxidative Stress
Reactive oxygen species (ROS)
Myeloperoxidase (MPO)
12-Lipoxygenase
Oxidized
Phospholipids
Direct Vascular
“Chronic Acute Phase”
Dysfunctional HDL
Oxidized LDL

3. Enzymatic and Protein Changes Within HDL During an Acute Phase Reaction
Enzymatic and protein changes within HDL during an acute phase reaction. (Serum amyloid A (SAA), apolipoprotein J (J) and secretory non-pancreatic phospholipase A2 (sPLA2) are present at higher serum concentrations and incorporate into HDL, while the HDL components apolipoprotein A-I (A-I), paraoxonase, platelet activating factor acyl hydrolase (PAF–AH), cholesteryl ester transfer protein (CETP), lecithin:cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) all decrease in concentration within HDL. HDL phospholipid content also falls, along with a reduction in cholesterol esters and an increase in triglycerides, free fatty acids and free cholesterol. A-II, Apolipoprotein A-II.
Rohrer L, et al. Curr Opin Lipidol 2004;15:

4. Assessing HDL Function
Reilly MP, Tall AR. J Clin. Invest. 2007;117:

5. 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.

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

7. CHD Despite High HDL Study: Design
Subjects:
20 adults with stable CHD, HDL-C 84 mg/dL
No hypolipidemic medication, smoking, or diabetes at entry
Controls:
Healthy age and gender-matched controls for each subject
Assessment of HDL function:
Monocyte chemotactic assay (MCA)
Cell-free assay (CFA)
Ansell BJ, Navab M et al. Circulation. 2003;108:

8. 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:

9. 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:

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

11. 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:

12. 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:

13. HDL Function in High-Risk Patients: Controlled Interventional Studies
CHD/risk equivalents (vs. placebo)
Simvastatin– partially improved LDL-induced MCA, CFA
Niacin– partially restored impaired HDL-induced eNO production in DM Patients
D4F – partially improved LDL-induced MCA, CFA in CHD (limited to those with adequate oral absorption)
Fat type – SFA-rich meal increased/PUFA-rich decreased HDL-induced endothelial ICAM-1/VCAM-1
Metabolic syndrome
Multifaceted TLC – improved MCA in MetSyn patients
Rheumatoid arthritis
Atorvastatin – significant decrease in CFA vs. placebo in active RA
Ansell BJ, Navab MN et al. Circulation. 2003;108: Sorrentino SA et al. Circulation 2010;121:
Nicholls, SJ et al. J Am Coll Cardiol 2006;48: Bloedon LT et al J Lipid Res. 2008;49:1344–1352.
Roberts CK et al. J Appl Physiol Charles-Schoeman C et al. J Rheumatol. 2007;34:

14. 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;

15. 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;

16. 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;

17. 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;

18. Christina Charles-Shoeman Naeimeh Kamranpour Rachel Mottahedeh
Alan Fogelman
Mohamad Navab
Srinu Reddy
Brian Van Lenten
Susan Hama
Greg Hough
Alan Wagner
Andrew Watson
Kym Faull
Linda Jin
Julian Whitelegg
Jan Danciger
Gregg Fonarow
Judy Berliner
Linda Demer
Aldons J. Lusis
Diana Shih
Christina Charles-Shoeman
Naeimeh Kamranpour
Rachel Mottahedeh
Ravi Dave
Mike Fishbein
Atherosclerosis Research Unit