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