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This is a condensed “talk” in 32 slides in a continuous LOOP. Take a seat for 3 minutes

This is a condensed “talk” in 32 slides in a continuous LOOP. Take a seat for 3 minutes and ENJOY!!!. 2001: This is the beginning of the new theory !. Inflammation ! The fire within !.

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This is a condensed “talk” in 32 slides in a continuous LOOP. Take a seat for 3 minutes

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  1. This is a condensed “talk” in 32 slides in a continuous LOOP. Take a seatfor 3 minutes and ENJOY!!!

  2. 2001: This is the beginning of the newtheory! Inflammation! The firewithin!

  3. Inflammation and Atherosclerosis, Libby, Ridker, Maseri, Circulation, 2001, 105, 1135-1143 or P. Libby “Atherosclerosis” THE NEW VIEW, The Scientific American. May, 2002, 48-56

  4. The various stages of plaque developmentin man’slife When to interfere? Biomarkers? FMD response? Othersurrogateendpoints? Waituntilsymptoms?

  5. Lifetimesequence of atheroscleroticprocess Normalvesselappearance Early plaque Obstructive plaque Plaque rupture Plaques increase in number and size Unstable angina Endothelialdysfunctionbegins Acute myocardialinfarction - Cardiacfailure Non-invasive tests normal Invasive tests abnormal Level of vascularinflammation indicators (VCam, Ecam, MCP-1, MIF, IL-6, ox-LDL, CRP?) graduallyrising as severity of diseaseincreases So begin treatmentHERE! Suddendeath Adaptedfrom N. E.J. Med, 2004 Clinicallynon-detectable Clinically evident 10 20 40 ≥ 60 years

  6. In certainregions of France, Jean, goodfood and wine, elsewhere in Western World, Joe, fastfood and sweetdrinks. It shows in longevity!

  7. The french paradox: what is the essential factor? The alcoholor the polyphenols? Orboth? • Jean vs. Joe

  8. There are >500 substancesin wine. 35 have cardiovascularaction, 1 of these is resveratrol...

  9. The multiple mechanisms of the polyphenolstogetherwithindividualactionsform a beneficial cascade on the endothelium.

  10. Multiple mechanisms of action of polyphenols “THE BENEFICIAL CASCADE”VASCULAR RELAXATION (NO stimulation / endothelinreduction)+ANTI-INFLAMMATORY+ANTI-CHOLESTEROLEMIC+ ANTI-THROMBOTIC +ANTI-OXIDANT ACTION=Together: VASCULAR PROTECTIVE and ANTI-ATHEROSCLEROTIC

  11. Variousprocessesinvolved in the dysfunction of the endothelium and the earlyatherosclerotic plaque are the sites where the polyphenolsstop inflammation!

  12. Rwpc’s and atheroscLerosis Phases of leukocyte-endothelialinteraction Role of Monocyte Chemoattractant Protein (MCP-1)and Macrophage Migration Inhibitory Factor (MIF) Leukocyte Chemoattractants of endothelial surface (V-cam, E-cam, MCP-1, MIF etc) Endothelium

  13. Rwpc’s and atherosclerosis Phases of leukocyte-endothelialinteraction RWPC block MCP-1 and MIF and STOP inflammation HERE! Leukocyte Recruitment Slow Rolling Endothelium So block MCP-1, MIF early... …instead of the mechanicalinterventions later

  14. Rwpc’s and atherosclerosis Phases of leukocyte-endothelialinteraction STOP slow rolling beforetheyadhere! Leukocyte Recruitment Slow Rolling Adhesion Endothelium So block MCP-1, MIF early... …instead of the mechanicalinterventions later

  15. Rwpc’s and atheroscLerosis Phases of leukocyte-endothelialinteraction Avoidbirth of a plaque! Leukocyte Recruitment Slow Rolling Adhesion Transmigration Endothelium Selectins MCP-1, MIF Integrins Cholesterol deposition Plaquedevelopment by other proinflammatory molecules, deposits cholesterol

  16. The central role of Macrophage Migration Inhibitory Factor Bernhagen et al., ThrombosisHemostasis. 2013, 109, 391-7

  17. How to stop and clear the plaque... Curtiss, L.K, NEJM 2009, 1144-1146

  18. Resveratrol, one of the polyphenols, to avoidlesiondevelopment as effective as atorvastatin?

  19. The Polyphenolresveratrolprotectsagainstatherosclerosis in hyperlipidemic • apoe3-leiden.cetpmice Control Resveratrol Atorvastatin + Resveratrol Atorvastatin Berbée et al., Nutr. Biochem. 2013; 24(8), 1423-1430

  20. Polyphenolsprotect against atherosclerosis Berbée et al., Nutr. Biochem. 2013; 24(8), 1423-1430

  21. The proven effects of red winepolyphenolsnotonlyon the endotheliumbutalsoonsmoothmusclecell

  22. Protectiveeffects of polyphenolsonbloodvessels (Schini, 2009) Polyphenols ROS P Thrombin PI3K/Akt CA2+ PDGFAB ROS MT1- MMP P NO p38 EDHF T2 VEGF ENDOTHELIAL CELL SMOOTH MUSCLE CELL Vasodilation Vasoconstriction Platelet aggregation Pro- MMP-2 VEGF VEGF expression MMP-2 activity MMP-2 Endothelial dysfunction Angiogenesis ATHEROGENESIS

  23. The Maincharacteristics of the major polyphenolstogether PREVENTIVE AND PROINTEGRITY OF ENDOTHELIUM VIA↑NO Production↓ENDOTHELIN↓V.CAM, E.CAM↓ MCP-1↓ MIF↓ Interleukin 6↓CRP↓ LDL, via ↑ receptor + ↓oxidation↑HDL↑ANTIOXIDANT =PRIMARY PREVENTIONTHERAPEUTIC AND PLAQUE REGRESSION VIA↓ LDL oxidation↓ SMC migration↓ SMC proliferation↓ platelet aggregation↓ VGEF = PLAQUE REGRESSION + ↓ metalloproteinase – action = PLAQUE STABILISATION = SECUNDARY PREVENTION

  24. CLINICAL PROOF: • Concentratesfromspecificfruits and vegetablesplay a significant rolenext to generallifestylechanges. • Usefoodas amedicine!

  25. 7.447 persons; 30% reduction C.V. end points

  26. FRUIT & VEGETABLE CONSUMPTION AND MORTALITY FROM CARDIOVASCulAR DISEASE AND CANCER • A systematicreview and dose-responsemeta-analysis of prospective cohort studies • 833.234 participants, 56.423 deaths, 5-26 years follow-up, 16 studies Conclusion: • Higherconsumption of fruit and vegetables is associatedwithsignificantlylowerrisk of all causemortality! Wang et al. BMJ 2014, 349, G4490

  27. FRUIT & VEGETABLE CONSUMPTION AND MORTALITY FROM CARDIOVASCLUAR DISEASE AND CANCER Dose response relationbetweenconsumption and risk of all-causemortality

  28. FRUIT & VEGETABLE CONSUMPTION AND MORTALITY FROM CARDIOVASCulAR DISEASE • 469.551 participants, 6.893 deaths • The average reduction was 4% for each additional serving of 106gr per day for fruit + vegetables, 6% for fruit alone • Threshold at 5 servings of 106gr a day Conclusion: • Higher consumption of fruit and vegetables is associated with significantly lower risk of cardiovascular mortality! Wang et al. BMJ 2014, 349, G4490

  29. Oneyearconsumption of a RWPC with extra resveratrolimprovesinflammatory markers in patients in primaryprevention of cardiovasculardisease • Prospective, randomized, parallel study in 75 patients for one year • Already on statins for primary prevention for C.A.D. • Then addition of either placebo, or RWPC or RWPC + 8mg resveratrol • Results for RWP + extra resveratrol • Results are consistent withpreviousobservationsbutnowalso prove efficacyduring statin therapy and within1 year follow-up! Tomé-Carneiro in Am. J. Cardiol. April 2012

  30. !MULTIFACTORIAL DISEASE DESERVES A MULTIFACTORIAL SOLUTION! Smoking / Inflammation / Dyslipidaemia / Hypertension / Dysglycaemia Proinflammatorycytokineslead to endothelialdysfunctionand atherosclerosis(e.g. Vcam, MCP-1, MIF, IL-6, TNFα, CD40L, CRP) So No smoking, physical activity 5x week Vegetables, red fruits, nuts, 600gr per day Oilyfish 3x week No red meat! Oliveoil 4 tbs/d Red wine 4 glassesday + or 500mgm In-Vino-Veritas + Lipid core ‘Messenger’ cytokine IL-6 Fibrinogen, PAI-1 Triglyceridemia OX_LDL Atheroma C-reactiveprotein Endothelial Dysfunction So, strictlyadhere to the MediterraneanDietor supplement a varieddietwith “food medicines” such as polyphenols and PUFA’s. EHJ 2010, Oxf. Univ. Press

  31. 6glasses of a specific red wine (~280ml) = 500 à 1000mg polyphenols are neededfordailydose • OR • In 500mg powderedRWPC’sIn-Vino-Veritasfor €1,25/day

  32. This is FANTASTIC! • It is like the birth of a new “vitamin” – justlikeVitamin B6, Vitamin C fromnaturalsources– hithertoignored (exceptby the • Mediterraneanpeople)

  33. In-Vino-Veritas “The Natural Cardiovascular protector”

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