1. 2001: This is the beginning of the new theory!

2. Inflammation and Atherosclerosis, Libby, Ridker, Maseri, Circ., 2001, 105, 1135-1143

3. The various stages of plaque development and when to interfere

4. Sequence of atherosclerotic process Normal vessel appearance Early plaqueObstructive plaquePlaque rupture Endothelial dysfunction begins Plaques increase in number and size Unstable angina Non-invasive tests normal Invasive tests abnormal Acute myocardial infarction - Cardiac failure Sudden death Level of vascular inflammation indicators (VCam, Ecam, MCP-1, MIF, IL-6, ox-LDL, CRP?) gradually rising as severity of disease increases So begin treatment HERE! Clinically non- detectable Clinically evident 10 20 40 ≥ 60 years

5. In certain regions of France, good food and wine, elsewhere in Western World, Fastfood and sweet drinks. It shows in longevity!

6. The french paradox what is the essential factor?

8. Multiple mechanisms form a beneficial cascade

10. Visuals of the various processes involved in the initiation of an atherosclerotic plaque and where the polyphenols stop inflammation

11. Rwpc’s and atherosclerosis Phases of leukocyte-endothelial interaction IIEndothelium Leukocyte Chemoattractants of endothelial surface (V- cam, E-cam, MCP-1, MIF etc)

12. Rwpc’s and atherosclerosis Phases of leukocyte-endothelial interaction IIILeukocyte Endothelium Recruitment Slow Rolling RWPC block MCP-1 and MIF and STOP inflammation HERE So block MCP-1, MIF early... …instead of the mechanical interventions later

13. Rwpc’s and atherosclerosis Phases of leukocyte-endothelial interaction IVLeukocyte Endothelium Recruitment Slow Rolling Adhesion So block MCP-1, MIF early... …instead of the mechanical interventions later

14. Rwpc’s and atherosclerosis Phases of leukocyte-endothelial interaction VLeukocyte Endothelium Plaque development by other proinflammatory molecules Recruitment Slow Rolling Selectins MCP-1, MIF Selectins MCP-1, MIF Adhesion Transmigration

15. Resveratrol, one of the polyphenols can avoid lesion development as effective as atorvastatin

16. The polyphenol Resveratrol protects against atherosclerosis in hyperlipidemic APOE3-Leiden.CETP mice Berbée JF et al. J. Nutr. Biochem. 2013;24(8):1423-1430 Control Atorvastatin Resveratrol Atorvastatin + Resveratrol

18. The proven effects of red wine polyphenols on the endothelium and smooth muscle cell

19. Thrombin Protective effects of Polyphenols on blood vessels (Schini, 2009) ROSROS CA 2+ PI3K/AktPI3K/Akt PP ROSROS VasodilationVasoconstriction Platelet aggregation VEGF expression MMP-2 activity Endothelial dysfunction Polyphenols ENDOTHELIAL CELL NO EDHF PDGF AB p38 P P VEGF Pro- MMP-2 T2 MT1- MMP SMOOTH MUSCLE CELL Angiogenesis ATHEROGENESIS

20. And in tabular form…

22. Food supplements play a significant role next to general lifestyle changes.

23. Smoking / Inflammation / Dyslipidaemia / Hypertension / Dysglycaemia Proinflammatory cytokines which ultimately lead to atherosclerosis (e.g. Vcam, Ecam, MCP-1, MIF, IL-6, TNFα, CD40L, CRP) No smoking, physical activity 5x week Red fruits, nuts, vegetables 600gr per day Oily fish 3x week or 6:1 EPA/DHA Olive oil 4 tblsp/day or oleuropein+hydroxyl tyrosol Red wine 4 glasses day or 500mgm In Vino Veritas Fibrinogen, PAI-1 Triglyceridemia OX_LDL C-reactive protein Endothelial Dysfunction Atheroma Lipid core ‘Messenger’ cytokine IL-6 And dark chocolate?

24. Let food be the medicine