(15-01-11) Higher EPA Content in Carotid Artery Plaque May Improve Lesion Stability

Many investigators have sought a better understanding of the mechanisms
underlying the diverse effects of omega-3 long-chain polyunsaturated fatty
acids (n-3 LC-PUFAs) and how such mechanisms might interact in complex
conditions. In cardiovascular disease, n-3 LC-PUFAs have anti-thrombotic, anti-
inflammatory, anti-arrhythmic and vasoreactive properties among others that are
likely to contribute to the overall cardioprotective properties associated with
their consumption. The importance of inflammatory responses to atherosclerosis
and plaque stability has provided new insights into how n-3 LC-PUFAs can affect
what is happening in the arteries, particularly regarding the stability of
atherosclerotic plaque (Figure). Rupture of a plaque can and frequently does
lead to potentially fatal thrombus (clot) formation.

Several reports have shown that n-3 LC-PUFAs inhibit inflammatory signaling
pathways and reduce the production of inflammatory mediators that promote
plaque rupture. They also modify plaque angiogenesis, helping to improve plaque
stability. Previous research reported that dietary n-3 LC-PUFAs are
incorporated into atherosclerotic plaque leading to altered plaque morphology
suggestive of greater lesion stability. Investigators from the first report of
n-3 LC-PUFAs and plaque stability conducted another randomized controlled trial
to elaborate on the details of plaque morphology and inflammation and improve
the assessment of plaque stability. Their findings are described in this
report.

Patients awaiting carotid endarterectomy were recruited from 2 hospitals in
the U.K. and randomized to consume either 1.5 g n-3 LC-PUFAs providing 0.8 and
0.7 g/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from
fatty acid ethyl esters, respectively, or 1.6 g/day of oleic acid for at least
7 days prior to surgery. Participants were excluded if they ate more than 2
meals of oily fish per week or took n-3 PUFA supplements of any kind. There
were 61 and 60 participants in the treatment and control groups, whose average
ages were 71 and 74 years, respectively. Data were obtained from 53 control and
47 treatment patients. The median time until surgery was 21 days (range 7 to
102). Carotid plaques were obtained from the common carotid artery and 2 mm
sections taken for biochemical analysis, histology and immunohistochemistry.

The investigators scored the plaque section closest to the bifurcation for
size of the lipid core, number of foam cells, hemorrhage, inflammation and cap
inflammation. An average of these scores was used as a summary score to
represent plaque inflammation and instability, the study?s primary outcome. In
addition, the researchers classified the plaque according to the classic and
modified version of the American Heart Association?s (AHA) ?Stary? system in
which Type VI plaque is the most severe.

A comparison between the n-3 LC-PUFA-treated and control groups showed a
significant increase in the plasma phospholipids of all n-3 LC-PUFAs as well as
significant decreases in the n-6 PUFAs linoleic, eicosatrienoic and arachidonic
acids. In the carotid plaque phospholipids, only EPA was significantly
increased by an average of 100%, from 0.4 ? 0.2 to 0.8 ? 0.4 in the control and
n-3 LC-PUFA groups, respectively (Table). There was no significant change in
DHA, linoleic or arachidonic acid content of the plaque phospholipids. While
other studies have reported increased incorporation of EPA rather than DHA, an
early study observed relatively more DHA than EPA in advanced human
atherosclerotic plaques.

As for the plaques, the summary score of 7 characteristics did not differ
between the 2 groups (15 vs 14) in the control and treated groups, respectively
(Table). However, the number of foam cells in the plaques was significantly
lower in the n-3 LC-PUFA group. The distribution of plaque morphology as
assessed by the classic and modified AHA criteria did not differ between the
groups in any category.

The investigators also assessed the messenger RNA levels in the plaques for
several matrix metalloproteinases (MMP), interleukin-6, intercellular adhesion
molecule-1 and tissue inhibitor-2 of MMPs and observed significantly lower
levels of MMP-7, -9 and -12 and the tissue inhibitor of MMP, TIMP-2, in the n-3
LC-PUFA-treated plaques. Interleukin-6 and intercellular adhesion molecule-1
mRNA levels were also significantly lower in the treated group, findings
consistent with reduced inflammatory activity.

It is noted, however, that the primary outcome?scores for plaque inflammation
and stability?did not differ with n-3 LC-PUFA treatment from controls. Unlike
the previous report from this group, the duration of n-3 LC-PUFA consumption
prior to surgery was shorter in the present study, median of 21 vs 42 days, a
difference that likely contributed to the differences in the two studies?
findings. The treatment was long enough to enable a 100% increase in plaque EPA
content, indicating that plaques are dynamic and responsive to their fatty acid
environment, even in the advanced stages. The investigators reported
significant inverse correlations between plaque EPA content and plaque
inflammation and instability, which might suggest less inflammation and greater
plaque stability with higher EPA levels. However, their evidence for improved
plaque stability remains indirect, but highly suggestive.

Support for this interpretation was reported in studies of EPA-fed mice with
apoE- or LDL-receptor-deficiencies. EPA suppressed the formation of
atherosclerotic lesions, decreased the infiltration of macrophages into
plaques, increased collagen and smooth muscle cells and reduced the mRNA
content of MMP-2 and -9. On the other hand, a study of nearly 500 men reported
that plasma phospholipid EPA was inversely associated with carotid and femoral
intima media thickness, but was not associated with plaque occurrence. In
Japanese patients with acute myocardial infarction, serum (log)EPA and (log)DHA
levels were inversely correlated with soft plaque scores, a finding suggestive
of less vulnerable plaque. If these investigators are correct, higher intakes
of n-3 LC-PUFAs could contribute to a lower risk of nonfatal myocardial
infarction by reducing the inflammatory effects associated with atherosclerotic
plaque and by increasing their stability, making them less prone to fatal
rupture.

Sources:
Cawood AL, Ding R, Napper FL, Young RH, Williams JA, Ward MJ, Gudmundsen O,
Vige R, Payne SP, Ye S, Shearman CP, Gallagher PJ, Grimble RF, Calder PC.
Eicosapentaenoic acid (EPA) from highly concentrated n−3 fatty acid ethyl
esters is incorporated into advanced atherosclerotic plaques and higher plaque
EPA is associated with decreased plaque inflammation and increased stability.
Atherosclerosis 2010;212:252?259.[PubMed]

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