Introduction

2. Introduction • High LDL-C and low HDL-C are associated with the risk for coronary heart disease (CHD) • However, dyslipidemia has a much weaker relationship to the risk of stroke than CHD • Stroke mortality is higher than CHD in Japan

3. Oxidized LDL Explains many aspects of biological response to LDL Is accumulated in atheroma Associates with therisk of metabolic syndrome Introduction (cont)

4. LOX-1 A receptor for (oxidatively) modified LDL From animal studies; thought to be involved in the pathogenesis of endothelial dysfunction, atherosclerosis, and myocardial infarction Introduction (cont)

5. What do you think is the better method to measure cholesterol-related parameters, if determination of LDL cholesterol concentration is ineffective for risk stratification? Question

6. Study Population 2295 community-dwelling participants (1094 men and 1201 women) in Japan without past history of CHD or stroke A mean 11-year follow-up period Materials and Methods

7. Endpoint First event of stroke or CHD, i.e., myocardial infarction, coronary artery bypass surgery, or angioplasty Sudden deaths of unknown origin, which occurred within 24 hours Materials and Methods (cont)

8. Materials and Methods (cont) LOX-1 ligand (LAB) sLOX-1 Determine both LOX-1 ligand containing ApoB (LAB) and sLOX-1 concentrations in sera collected from the participants at the start of follow-up. Measurement of receptor Receptor-based assay Figure 1. To detect modified LDL including oxidized LDL, a receptor-based assay, which measures binding activity rather than absolute amount of certain epitopes, was performed. Measurement of sLOX-1 might assess expression level of LOX-1.

9. What would be agood strategy for risk stratification of CHD and stroke, if you have measured LOX-1 ligand and sLOX-1? Question

10. Results LAB: LOX-1 ligand containing ApoB sLOX-1: soluble LOX-1 released from plasma membrane LAB quartiles sLOX-1 quartiles aData are mean (SD) unless noted otherwise.bHypertension was defined as systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg, or use of antihypertensive agents. cDiabetes was defined as fasting serum glucose > 7.0 mmol/L (126 mg/dL), use of antidiabetic agents, or both. dAlcohol drinking was defined as consuming at least 1 drink per week.

11. Results LAB quartiles High LAB confers an increased risk of ischemic stroke. Model 1 adjusted for age, sex, BMI, smoking, drinking, hypertension, diabetes, and use of lipid-lowering agents; model 2 as model 1 with the addition of non-HDL cholesterol. LAB: LOX-1 ligand containing ApoB

12. Results LOX index = LAB x sLOX-1 LOX index (x106) quartiles Low LOX index is associated with lower risk of ischemic stroke. High LOX index is a risk of CHD. Model 1 adjusted for age, sex, BMI, smoking, drinking, hypertension, diabetes, and use of lipid-lowering agents; model 2 as model 1 with the addition of non-HDL cholesterol.

13. The authors have recently reported that there was no association between low density lipoprotein cholesterol (LDL-C) and the incidence of ischemic stroke in the same cohort. Why could LOX index predict the risk of ischemic stroke, while LDL-C cholesterol could not? Question

14. Experiments Indicate LOX index measured by activity-based assay successfully predicted the risk of ischemic stroke The hazard ratio was >3, as large as that for hypertension LOX index also predicted the risk of CHD Discussion

15. Hypothesis LOX-1 ligand might have a role in promoting ischemic stroke that is not conferred by LDL-C alone LOX-1 promotes thrombosis in animal models, which can cause ischemic stroke Discussion (cont)

16. Clinical Implications LOX index appears to supply the missing link between ischemic stroke and cholesterol-related parameters LOX index might be used as a therapeutic index in prophylaxis of stroke and CHD LOX-1 antagonist therapy might be effective in preventing ischemic stroke and CHD Discussion (cont)

17. Take-Home Message LOX index predicts the risk of ischemic stroke as strongly as hypertension does Discussion (cont)