2001: This is the beginning of the new

theory!

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

or

P. Libby “Atherosclerosis” THE NEW VIEW, The Scientific American. May, 2002, 48-56

The various stages of plaque development

and when to interfere

Sequence of atherosclerotic process

Normal vessel appearance Early plaque Obstructive plaque Plaque 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

Adapted from N. E.J. Med, 2004

In certain regions of France, good food and wine,

elsewhere in Western World, Fastfood and sweet drinks.

It shows in longevity!

The french paradoxwhat is the essential factor?

Jean vs. Joe

6 glasses of a specific* red wine (~280ml) = 500 à 1000mg polyphenols are needed for daily dose

*) Château Petrus… = EXPENSIVE!

` …or 2 capsules? IT IS YOUR CHOICE!

Multiple mechanisms form a beneficial cascade

“THE BENEFICIAL CASCADE”

VASCULAR RELAXATION (NO stimulation / endothelin reduction)

+ANTI-INFLAMMATORY

+ANTI-CHOLESTEROLEMIC

+ ANTI-THROMBOTIC

+ANTI-OXIDANT ACTION

=Together:

VASCULAR PROTECTIVE and ANTI-ATHEROSCLEROTIC

MULTIPLE MECHANISMS OF ACTION OF POLYPHENOLS

Visuals of the various processes involved in the

initiation of an atherosclerotic plaque and

where the polyphenols stop inflammation

Rwpc’s and atherosclerosisPhases of leukocyte-endothelial interaction II

Endothelium

Leukocyte

Chemoattractants of endothelial surface (V-cam, E-cam, MCP-1, MIF etc)

Rwpc’s and atherosclerosisPhases of leukocyte-endothelial interaction III

Leukocyte

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

Rwpc’s and atherosclerosisPhases of leukocyte-endothelial interaction IV

Leukocyte

Endothelium

Recruitment

Slow RollingAdhesion

So block MCP-1, MIF early...

…instead of the mechanical interventions later

STOP slow rolling before they adhere!

Rwpc’s and atherosclerosisPhases of leukocyte-endothelial interaction V

Leukocyte

Integrins

Endothelium

Plaque development by other proinflammatory molecules

Recruitment

Slow Rolling

Selectins MCP-1, MIF

AdhesionTransmigration

Cholesterol deposition

Avoid birth of a plaque!

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

atorvastatin

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

POLYPHENOLS* PROTECT AGAINST ATHEROSCLEROSIS

Berbée et al., accepted for publication December 2012

* This was tested with the polyphenol Resveratrol

The proven effects of red wine polyphenols on the

endothelium and smooth muscle cell

Thrombin

Protective effects of Polyphenols on blood vessels (Schini, 2009)

ROS

CA2+ PI3K/AktPP

ROS

VasodilationVasoconstrictionPlatelet aggregation

VEGF expressionMMP-2 activity

Endothelial dysfunction

Polyphenols

ENDOTHELIAL CELL

NO EDHF

PDGFAB

p38P

VEGF

VEGF

Pro-

MMP-2MMP-2

T2

MT1-MMP

SMOOTH MUSCLE CELL

Angiogenesis

ATHEROGENESIS

And in tabular form…

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 PREVENTION

THERAPEUTIC AND PLAQUE REGRESSION VIA

↓ LDL oxidation↓ SMC migration↓ SMC proliferation↓ platelet aggregation↓ VGEF

= PLAQUE REGRESSION

+ ↓ metallo proteinase – action

= PLAQUE STABILISATION

= SECUNDARY PREVENTION

THE MAIN CHARACTERISTICS

Food supplements play a significant role next to

general lifestyle changes.

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/DHAOlive oil 4 tblsp/day

or oleuropein+hydroxyl tyrosol

Red wine 4 glasses day or 500mgm In Vino Veritas

Fibrinogen, PAI-1TriglyceridemiaOX_LDL

C-reactive

protein

Endothelial Dysfunction

Atheroma

Lipid core

‘Messenger’ cytokine

IL-6

A MULTIFACTORIAL DISEASE DESERVES A MULTIFACTORIAL SOLUTION

So, strictly adhere to the Mediterranean Diet or supplement a varied diet with food medicines such as polyphenols and PUFA’s. EHJ 2010, Oxf. Univ. Press

So

And dark chocolate?

Let food be the medicine