To evaluate the plausibility of the results of the
trial, it is important to try to identify which biologic factors
modified by the Mediterranean diet may have been cardioprotective.
Two major biologic factors were modified by the
intervention:
1) the antioxidant vitamins, alpha-tocopherol and
ascorbic acid, which were increased in the plasma of the study
patients (3,5);
2) the plasma fatty acid profile, with a noticeable
increase in omega-3 fatty acids and a decrease in omega-6 fatty
acids in the study group (3,5).
Other factors such as the
antioxidant flavonoids (12) and minerals, arginine, glutamine
and methionine (13-15) and vitamins of the B group including
folic acid (16,17) probably played important roles but were not
measured in the study.
Favorable effects of omega-3 fatty acids were reported in
association with elevation of their plasma levels (18), for
instance, antiarrhythmogenic effect (19-21).
A low fat diet
enriched in monounsaturated fatty acids (22,23) is also characteristic
of the Mediterranean diet, and its favorable effects
have been extensively discussed (24).
In fact, several lines of evidence indicate that the major
mechanisms leading to acute arterial manifestations--in particular,
sudden death, unstable angina and myocardial infarction-in
various conditions including heart transplantation
(25-28) are localized inflammation and immune-mediated
processes with macrophage infiltration (29) preceded or followed,
or both, by lipid modification (oxidation) and accumulation.
These initiating events eventually lead to lesion hemorrhage,
plaque ulceration and rupture and, ultimately,
occlusive or subocclusive coronary thrombosis (10,11). Some
of these processes were apparently prevented in the study
patients of the Lyon trial.
The next question therefore should be whether certain
nutriments of the Mediterranean diet are able to prevent or
reduce plaque inflammation.
Recent studies in humans (30,31)
have shown a direct influence of dietary fatty acids on the fatty
acid composition of arterial lesions. Rapp et al. (30) reported
the incorporation of dietary omega-3 fatty acids in obstructive
arterial lesions within some days after starting supplementation.
The striking feature of their study conducted in humans
was the rapidity with which the atherosclerotic lesions were loaded with omega-3 fatty acids. The arterial lesions at risk of
rupture are known to be lipid-rich, young and not very fibrotic
or very stenotic (25-27).
Incorporation of new fatty acids at a
rapid rate by means of dietary changes in young and dangerous
lesions is thus conceivable in patients who have consumed an
alpha-linolenic-rich diet.
This possibility may explain why in
recent dietary trials, beneficial effects in dieters were apparent
within a few weeks after start of the trial (2-4).
Omega-3 fatty
acids may have an anti-inflammatory and stabilizing effect on
the lipid-rich lesions because they have been shown in various
animal models (32,33) and in humans (34-37) to interfere with
the many secretory and proinflammatory properties of leukocytes.
They prevent the development of atherosclerotic lesions
in rabbits and mice by modulating macrophage secretory
activities (32,33), whereas the activated lesion macrophages
seem to be the main determinants of plaque inflammation and
rupture in humans (26,29).
Thus, loading plaque with omega-3
fatty acids, as occurs in patients with high intake and high
plasma levels of omega-3 fatty acids (30,31), can induce local
anti-inflammatory activity.
Oxidized lipids are also thought to play a major role in
arterial complications by stimulating macrophages, injuring
endothelial cells and promoting leukocyte coagulant activity
and platelet reactivity (38). The nature of the substrate for
lipid peroxidation, mainly the polyunsaturated fatty acids, is a
dominant influence in determining the rate of peroxidation, in
association with the content of antioxidants (38).
The importance
of the fatty acid composition of lipids in determining
their susceptibility to oxidation was impressively demonstrated
by recent studies (39,40) comparing lipoproteins enriched in
either linoleate or oleate in both animal models and humans:
Lipids enriched in oleate were remarkably resistant to oxidation.
The study group in the Lyon study had a plasma fatty acid
profile extremely favorable for protecting circulating or tissue
lipids against oxidation; oleic acid intake was increased, linoleic
acid intake was decreased (3,5) and similar profiles were
observed in plasma (3,5).
Also, antioxidant defenses were
reinforced with higher plasma levels of antioxidant vitamins
(3,5). This effect probably protected against uncontrolled lipid
oxidation (38), suppressed leukocyte production of reactive
oxygen species (41) and inhibited monocyte function (42). In
addition, the ratio of arachidonic acid to eicosopentanoic acid
in the plasma (see Ref 3) was also extremely favorable for
obtaining an antithrombotic effect through an improved balance
in the generation of prostacyclin and thromboxane
(43,44).
This is a major point because lesion ulceration and
plaque disruption eventually culminate in thrombotic occlusion,
which is thought to determine the acuteness of the clinical
presentation (11).
We conclude that the present data support the view that
comprehensive dietary modifications can rapidly induce a
multitude of significant biologic changes at various cellular and
molecular levels. These changes are probably capable of
interfering with the pathogenesis of acute coronary events.
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