Presentation is loading. Please wait.

Presentation is loading. Please wait.

HDL Is Commonly Dysfunctional in CVD and Other Inflammatory Conditions

Similar presentations


Presentation on theme: "HDL Is Commonly Dysfunctional in CVD and Other Inflammatory Conditions"— Presentation transcript:

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


Download ppt "HDL Is Commonly Dysfunctional in CVD and Other Inflammatory Conditions"

Similar presentations


Ads by Google