Role of Dysfunctional HDL in Cardiovascular Disease Benjamin

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

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

Functional Versus Dysfunctional HDL § Functional Versus Dysfunctional HDL Zheng C, Aikawa, M. JACC. 2012; 60: 2380 -83.

IDEAL Increased MCE Risk at Very High HDL-C van der Steeg, WA et al. J Am Coll Cardiol. 2008; 51: 634 -642.

HDL-C Does Not Predict MACE in ACS: Results of 3 -Year Clinical Follow-Up N-184 Treatment-naive Paneni F et al. Int J Cardiol. 2012; 158: 158 -160.

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.

Correlation Between MCA and Cholesterol Efflux Corr. = 0. 760 (P<0. 001). Navab M et al. Ann Med. 2005; 37: 173 -178.

Inflammatory/Anti-inflammatory Properties: HDL Inflammatory Index HII Anti-inflammatory Proinflammatory 1. 0 LDL + HDL

CHD Despite High HDL Study: Monocyte Chemotaxis Assay (MCA) HDL Inflammatory Index (HII) 1. 40 1. 37 Subjects: • 20 adults with stable CHD, HDL-C 84 mg/d. L • Mean LDL-C 108 mg/d. L • No lipid medication, smoking, or diabetes 1. 20 1. 00 0. 80 P<0. 001 0. 60 0. 35 0. 40 0. 20 0 Patients Controls Ansell BJ, Navab MN et al. Circulation. 2003; 108: 2751 -2756.

CHD Despite High HDL Study: Cell-Free Assay (CFA) 1. 60 Relative Fluorescence 1. 40 1. 20 P<0. 001 1. 00 0. 80 0. 60 0. 40 0. 20 0. 00 Patients Controls Ansell BJ, Navab M et al. Circulation. 2003; 108: 2751 -2756.

Impaired HDL Vasodilatory Effect in DM Sorrentino SA et al. Circulation 2010; 121; 110 -122.

MCA in Patients with Varying Degrees of Glycemia 1. 6 HDL effect on LDL-induced monocyte chemotaxis in artery wall coculture MCA 1. 2 . 8 . 4 0 Control IGT Well-Controlled Poorly-Controlled Type 2 DM Navab, MN et al. Diabetes. 2009; 58: 2711 -2717.

Proinflammatory HDL in Systemic Lupus Erythematosus/Rheumatoid Arthritis HII (≥ 1. 0 proinflammatory) P=. 001 3. 0 P=. 016 2. 5 2. 0 1. 5 1. 0 0. 5 0. 0 SLE RA Proinflammatory HDL (%) P<. 0001 Control Group Mc. Mahon M et al. Arthritis Rheum. 2006; 54: 2541 -2549. P<. 0001 1. 0 0. 8 0. 6 P=. 003 44. 7 P=. 006 0. 4 20. 1 0. 2 4. 1 0. 0 SLE RA Control

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: 2640 -2646.

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: 2371 -79.

Myeloperoxidase (MPO) § ↑Leukocytes and/or activity release MPO § MPO nitration and/or chlorination of apo. A-1 at Tyr-192 and Tyr-166. leads to a loss of normal conformation of apo. A-1 at “hinge” region s impairs binding with ABCA 1 (macrophage lipid efflux) s impedes HDL’s binding to hepatic receptor SRB-1 s upregulates expression of NFκβ and CAM’s Shao B et al. J Biol Chem. 2005; 280: 5983 -5993. Underti A et al. J Biol Chem. 2009; 284: 30825– 30835.

Nitrated and Chlorinated HDL is Impaired in Endothelial Cell Repair Pan B et al. Free Rad Med Biol. 2013 Epub ahead of print.

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 Apo A-1 Phospholipid monolayer Antioxidant Enzymes Apo A-1 Ansell BJ et al. Current Opinion in Lipidology. 2007: 18; 427 -434.

Anti-Inflammatory HDL Antioxidant Enzymes e. g. PON-1, PAF-AH, LCAT Apo A-1 Phospholipid monolayer Systemic inflammation, e. g. coronary disease, diabetes, metabolic syndrome, surgery, infection, rheumatologic diseases Antioxidant Enzymes Apo A-1 Ansell BJ et al. Current Opinion in Lipidology. 2007: 18; 427 -434.

Anti-Inflammatory HDL Antioxidant Enzymes e. g. PON-1, PAF-AH, LCAT Apo A-1 Phospholipid monolayer Systemic inflammation, e. g. coronary disease, diabetes, metabolic syndrome, surgery, infection, rheumatologic diseases ↑s. PLA-A 2 Oxidized Phospholipids Acute Phase Proteins Antioxidant Enzymes Myeloperoxidase Apo A-1 Chemically modified Apo A-1 Ansell BJ et al. Current Opinion in Lipidology. 2007: 18; 427 -434.

Anti-Inflammatory HDL Antioxidant Enzymes Pro-Inflammatory HDL Systemic inflammation, e. g. coronary disease, diabetes, metabolic syndrome, surgery, infection, rheumatologic diseases Oxidized Phospholipids ↑s. PLA-A 2 e. g. PON-1, PAF-AH, LCAT Apo A-1 Acute Phase Proteins Phospholipid monolayer ABCA 1 Antioxidant Enzymes Myeloperoxidase Apo A-1 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; 427 -434.