Rome, Italy - One of the possible ways in which long-chain omega-3 fatty acids play a role in decreasing cardiovascular events is by entering advanced atherosclerotic plaques. According to the results of a new study, investigators were able to show that the incorporation of eicosapentaenoic acid (EPA) into advanced plaque was associated with a decreased expression of various matrix metalloproteinases (MMPs) involved in causing plaque instability, as well as with decreased plaque inflammation.

These are results of the Omacor Carotid Endarterectomy Intervention (OCEAN) study, presented here this week at the International Symposium on Atherosclerosis by Dr Philip Calder (University of Southampton, UK).

"By increasing the availability of omega-3 fatty acids, they appear in advanced atherosclerotic plaques, indicated in this study by the carotid artery, and this results in lower numbers of macrophages, foam cells, and T cells, as well as the lower expression of inflammatory markers," said Calder. "Histologically, this results in a plaque that appears to be less inflamed and more stable. This may contribute to reduced mortality in patients consuming omega-3 fatty acids, for example, in the GISSI Prevenzione trial."

Less inflamed and more stable

Calder and his group previously published data in which surgical patients were randomized to placebo, vegetable oil, and omega-3 fatty acids. Patients supplemented with omega-3 fatty acids before surgery were more likely to have stable plaques and less likely to have unstable plaques, said Calder, noting that the more stable plaque contained more EPA and docosahexaenoic acid (DHA) than unstable plaque. Patients treated with omega-3 fatty acids also had lower macrophage infiltration into the plaque with more EPA and DHA.

Presenting the OCEAN findings, Calder said that patients identified for carotid endarterectomy were randomized to treatment with 2 g/day of omega-3 fatty acids or placebo. Patients remained in the trial until surgery, which, historically, was an average of 40 to 50 days after first being identified for endarterectomy. After surgery, the investigators obtained the plaque and studied the morphology, histology, and cellular infiltration using immunohistochemistry, as well as the expression of MMPs, cytokines, and adhesion molecules at the mRNA level.

In total, 112 patients were randomized to therapy, with 50 patients in the placebo arm and 45 patients in the active-therapy arm completing the study. Average patient age was 75 years and a majority were men. Patients were typically overweight and former or current smokers and had hypertension. Calder noted that lipid measurements were typically good, likely because patients were well treated, with 85% taking statins and 80% taking aspirin.

Investigators report that EPA and DHA were rapidly taken up into the plaque. There was a significant 100% increase in EPA content in the plaque in patients supplemented with omega-3 fatty acids, but only a 10% nonsignificant increase in the uptake of DHA in the atherosclerotic plaque. The number of foam cells was significantly lower in those treated with fatty acids vs those randomized to placebo.

Calder noted that a combined mean score, a composite summed measure that includes the size of the lipid core, number of foam cells, and number of macrophages in the plaque and the cap, as well as the overall density of inflammation in the plaque and cap, was lower among patients treated with omega-3 fatty acids. The mean score was significantly negatively correlated with plaque EPA, he reported.
 
"In other words, the more EPA in the plaque, the less inflamed and more stable it is," said Calder.

In addition, investigators measured mRNA levels for seven MMPs. Three of the seven—MMP-9, MMP-7, and MMP-12—were significantly decreased in patients supplemented with omega-3 fatty acids. Intercellular adhesion molecule 1 (ICAM-1), an adhesion molecule involved in the recruitment of monocytes into the vessel wall, and the inflammatory cytokine interleukin-6 were also lower in patients taking fatty acids.

What does it all mean?

Dr Heiner Bucher (University Hospital Basel, Switzerland), who moderated the session, told heartwire that the investigators should be commended for taking advantage of delays in the healthcare system to carry out this study. As noted by Calder, investigators were somewhat hindered, as a delay of 40 to 50 days from the time of referral for surgery until the procedure is the norm in the hospital. Instead, patients underwent surgery 21 days after referral, limiting the amount of time they were on omega-3 fatty acids.

Bucher called the study and its findings intriguing in that it attempts to show a mechanistic benefit with omega-3 fatty acids, long shown to have cardioprotective benefits in epidemiological and case-control studies. He does, however, have reservations about the clinical implications of such findings.

"We are moving now to surrogate end points, like carotid thickening and plaque stabilization, but I still don't know how this translates into clinical benefit," said Bucher. "The piece that we're missing is how much of a decline in carotid thickening or improvement in plaque stabilization results in hard clinical end points, like improved survival or reduced cardiovascular events."