1 / 32

“OXIDATION” OF LDL AND ROLE OF “OXIDIZED LDL” IN ATHEROSCLEROSIS

“OXIDATION” OF LDL AND ROLE OF “OXIDIZED LDL” IN ATHEROSCLEROSIS. Question? How is LDL “oxidized”?. Oxidative stress Endothelial cells Smooth muscle cells Radicals (oxygen, sulfur) Lipoxygenase Metal ion dependent oxidation of lipids Lipid Oxidized LDL. Inflammation

vieiral
Télécharger la présentation

“OXIDATION” OF LDL AND ROLE OF “OXIDIZED LDL” IN ATHEROSCLEROSIS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. “OXIDATION” OF LDL AND ROLE OF “OXIDIZED LDL” IN ATHEROSCLEROSIS

  2. Question? How is LDL “oxidized”?

  3. Oxidative stress • Endothelial cells • Smooth muscle cells • Radicals (oxygen, sulfur) • Lipoxygenase • Metal ion dependent • oxidation of lipids • Lipid Oxidized LDL • Inflammation • Activation of macrophages • Myeloperoxidase activity • Metal ion independent • oxidation of lipids and protein • Lipid Oxidized LDL • Phospholipase activity • Prostaglandin synthesis • Platelet activation • Aldehyde-type substitution • of lysine residues in the absence of lipid peroxidation and apo B-100 fragmentation MDA-modified LDL Total “oxidized LDL” = lipid oxidized LDL + MDA-modified LDL Our mAb-4E6 recognizes all forms of “oxidized LDL”

  4. Question? How could “oxidized LDL” contribute to atherothrombosis?

  5. Shear stress Homocystein Monocyte Platelet LDL VCAM-1 ICAM-1 Fibronectin E-selectin Adhesion Aggregation Coagulation Adhesion PAI-1  tPA  NO thrombin  TF  Infiltration ENDOTHELIUM Macrophage proliferation MCP-1 M-CSF MM-LDL INTIMA Macrophage MPO PLA2 SR bFGF PLA2 Extracellular lipid pool Foam Cell Apoptotic M Ox-LDL SMC migration & proliferation SR Thrombosis PDGF Thrombosis TF SMC migration SMC MEDIA Mertens and Holvoet. FASEB J. 2001;15:2073-84

  6. ASSOCIATION OF CARDIOVASCULAR RISK AND DISEASE WITH OXIDIZED LDL

  7. OxLDL was measured with a mAb4E6-based ELISA. Previously, we have detected elevated levels of oxidized LDL in the plasma of middle-aged (40-60 Y) CAD patients. We have isolated ‘oxidized LDL’ from the plasma of those patients and shown that it is minimally oxidized, explaining why we detect it in the blood. HOLVOET et al., CIRC 1998, 98 (15);1487. HOLVOET et al., ATVB 2001, 21 (5); 844.

  8. 100 80 P<0.001 OXLDL 60 Sensitivity Tot-C/HDL-C 40 20 0 0 20 40 60 80 100 100-Specificity Holvoet et al. ATVB 2001;20:698-702

  9. Global Risk Assessment Score (GRAS): based on age, gender, total cholesterol, HDL cholesterol, systolic blood pressure, diabetes mellitus and smoking American Heart Association American College of Cardiology

  10. 100 P<0.001 80 OXLDL 60 Sensitivity GRAS 40 20 0 0 20 40 60 80 100 100-Specificity Holvoet et al. ATVB 2001;20:698-702

  11. Is circulating oxLDL elevated in persons with high CHD risk prior to events?

  12. We have measured oxidized LDL in 3,033 samples from the population-based Health ABC cohort. Participants (aged 70-79 Y) were recruited from a random sample of White and Black Medicare eligible adults living in the Memphis, TN and the Pittsburgh, PA vicinities from March 1997 – June 1998.

  13. BASELINE 385 persons had CHD (n=385): MI, angina, coronary angioplasty, or coronary artery bypass surgery According to ATPIII, 1113 persons had CHD risk equivalents: non-coronary forms of clinical atherosclerotic disease, diabetes, and/or a 10-year risk for CHD events greater than 20% by Framingham scoring (= high risk) All other persons (n=1524) were considered to be at low risk Holvoet et al. ATVB 2003; 23:1444-1448

  14. Odds ratio for established CHD for persons in the highest quintile of oxLDL compared with those in the lowest quintile and adjusted for age, gender, race, smoking and LDL-C: 2.4 (95% CI: 1.6-3.5) Odds ratio for high CHD risk status for persons in the highest quintile of oxLDL compared with those in the lowest quintile and adjusted for age, gender, race, smoking and LDL-C: 3.0 (95% CI: 2.3-4.0) Holvoet et al. ATVB 2003; 23:1444-1448

  15. THE METABOLIC SYNDROME, OXIDIZED LDL AND CARDIOVASCULAR RISK

  16. Relation between metabolic syndrome and oxLDL 2.6 (95% CI: 2.1-3.2) OxLDL (% LDL) ** 2.0 (95% CI: 1.6-2.5) OxLDL (mg/dl) * 1 4 0 2 3 5 6 Odds Ratio (95% CI) * Odds ratios for high oxLDL for subjects with MS compared with subjects without MS adjusted for age, sex, ethnicity, smoking and LDL-C. ** Adjusted for age, sex, ethnicity, smoking. Holvoet et al. Diabetes 2004; 53: 1068

  17. Question: Does oxidized LDL predict risk for myocardial infarction in the Health ABC cohort?

  18. Relative Risk of Myocardial Infarction 1.9 (95% CI: 1.1-3.5) Oxidized LDL * 2.0 (95% CI: 1.4-2.9) Metabolic Syndrome 0 1 2 3 4 5 6 Relative Risk (95% CI) * RR for MI compared with subjects in the lowest quintile of oxLDL and adjusted for age, sex, ethnicity, smoking, LDL-C and the metabolic syndrome. Holvoet et al. Diabetes 2004; 53: 1068

  19. Is circulating oxLDL associated with subclinical CVD?

  20. Ox-LDL in MESA Paul Holvoet, Nancy Jenny, Pam Schreiner, Russ Tracy, David Jacobs for the Multi-Ethnic Study of Atherosclerosis Study Group

  21. AA CA

  22. All Mean (SD) = 0.99 ± 0.73 mg/dl

  23. Men Women Mean (SD) = 0.94 ± 0.68 mg/dl Mean (SD) = 1.07 ± 0.79 mg/dl

  24. White AA Mean (SD) = 0.93 ± 0.66 mg/dl Mean (SD) = 1.12 ± 0.83 mg/dl CA Hispanic Mean (SD) = 1.06 ± 0.82 mg/dl Mean (SD) = 0.89 ± 0.53 mg/dl

  25. Ox-LDL levels by Risk Factor Quartile (1) Cont.

  26. Ox-LDL levels by Risk Factor Quartile (2)

  27. Ox-LDL values in Persons with Subclinical CVD Compared to values in those without Data are mean±SD; n = 859 participants not missing any of the variables in the table. (1)Adjusted for age, gender, and race. (2) Additionally adjusted for total cholesterol, HDL-cholesterol, triglycerides, IL-6, fibrinogen, and smoking.

  28. Ox-LDL values in Persons with Subclinical CVD Compared to values in those without Data are mean±SD; n = 859 participants not missing any of the variables in the table. (1)Adjusted for age, gender, and race. (2) Additionally adjusted for total cholesterol, HDL-cholesterol, triglycerides, IL-6, fibrinogen, and smoking.

  29. Ox-LDL values in Persons with Subclinical CVD Compared to values in those without Data are mean±SD; n = 859 participants not missing any of the variables in the table. (1)Adjusted for age, gender, and race. (2) Additionally adjusted for total cholesterol, HDL-cholesterol, triglycerides, IL-6, fibrinogen, and smoking.

  30. Sub-clinical CVD and oxidized LDL 1.6 ** 1.4 ** * 0: 147 white, 77 black, ** 1.2 58 Chinese, 109 Hispanic 1.0 1: 143 white, 63 black, 0.8 Oxidized LDL (mg/dl) 24 Chinese, 56 Hispanic 0.6 2-3: 103 white, 34 black, 0.4 11 Chinese, 34 Hispanic 0.2 0 White AA CA Hispanic Number of subclinical diseases present

  31. Conclusions • MESA is the first study to describe ox-LDL levels in a multi-ethnic cohort with comprehensive measures of subclinical atherosclerosis • the distributions were highly skewed, and suggest the need for sex- and race-specific cut-points of ox-LDL for CVD risk prediction • We confirmed a relationship of ox-LDL with established CVD risk factors, especially metabolic syndrome, and have extended these findings to younger men and women, and different ethnic groups • lipidemia, inflammation, gender, ethnicity, and smoking status statistically explained over 40 % of the variation in ox-LDL • We have established an association with several independent measures of subclinical atherosclerosis • the attenuation of subclinical CVD association by adjustment for CVD risk factors is consistent with a causal role for ox-LDL intermediate between traditional risk factors and atherosclerosis

  32. Acknowledgement Dieuwke De Keyzer Rozenn Quarck Gregor Theilmeier Peter Verhamme Wim Verreth Hilde Bernar Els Deridder Michèle Landeloos

More Related