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Role of Dysfunctional HDL in Cardiovascular Disease
Benjamin J. Ansell, MD FACC UCLA School of Medicine
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Benjamin J. Ansell, MD Honoraria: Aegeron Stocks, Stock Options,
Other Ownership Interest: Amgen, Bruin Pharma Off Label: None
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Functional Versus Dysfunctional HDL
Zheng C, Aikawa, M. JACC.2012; 60:
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IDEAL Increased MCE Risk at Very High HDL-C
van der Steeg, WA et al. J Am Coll Cardiol. 2008;51:
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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:
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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.
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Correlation Between MCA and Cholesterol Efflux
Corr. = (P<0.001). Navab M et al. Ann Med.2005;37:
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Inflammatory/Anti-inflammatory Properties: HDL Inflammatory Index
Proinflammatory HII 1.0 LDL LDL + HDL
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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:
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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:
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Impaired HDL Vasodilatory Effect in DM
Sorrentino SA et al. Circulation 2010;121;
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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:
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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:
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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:
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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:
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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.
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Nitrated and Chlorinated HDL is Impaired in Endothelial Cell Repair
Pan B et al. Free Rad Med Biol Epub ahead of print.
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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;
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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;
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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;
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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;
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