Dietary intervention with oil rich fish reduces platelet-monocyte aggregation in man
Introduction
Consumption of fish oil may protect against cardiovascular disease [1]. Data from observational studies suggest that fish intake is inversely associated with fatal coronary heart disease [2], and randomized controlled trials of dietary fish or fish oil supplementation after myocardial infarction demonstrate a reduction in mortality [3], [4]. These effects are believed to be due to the high amounts of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present in fish oil. EPA and DHA must be obtained from dietary sources and recent guidelines from the American Heart Association recommend the consumption of oily fish at least twice weekly for individuals with and without coronary heart disease [5]. However, not all randomised controlled trials have shown a benefit [6], and the underlying mechanisms through which cardiac protection might be conferred remain uncertain.
The effects of fish oil on platelet function and thrombosis are controversial. Although fish oils were originally thought to act by reducing platelet aggregation through effects on eicosanoid metabolism [7], subsequent studies have produced contradictory results [8]. Alternative mechanisms of action have been proposed including effects on arrhythmias, inflammation, endothelial function and atherosclerotic plaque stability [9], [10], [11], [12]. Indeed, it has been suggested that there is little evidence for a major antithrombotic effect of fish oils at the moderate doses shown to reduce mortality in the secondary prevention trials [13].
Most previous studies investigating the effects of fish oils on platelet function have relied on in vitro platelet aggregometry and plasma assays of soluble markers of platelet activation [8]. These techniques are poorly suited to the detection of potentially subtle effects induced by dietary changes. Reproducibility is unsatisfactory and the tests are difficult to standardize [14]. Platelet aggregometry can only measure ex vivo changes in platelet reactivity to a single external stimulus, and sample manipulation required for both methods leaves them particularly vulnerable to artefactual in vitro activation.
Modern flow cytometric techniques allow platelets to be analyzed directly in their physiological environment of whole blood with minimal sample manipulation. Circulating platelet-monocyte aggregates, formed by the binding of activated platelets to leukocytes via a P-selectin dependent mechanism [15], can be readily measured in this way and have emerged as a highly sensitive marker of platelet activation [16]. The adhesion of activated platelets to monocytes also has important functional consequences, and can induce the expression of cytokines, chemokines, adhesion molecules and tissue factor [17]. Consistent with these biological effects, circulating platelet-monocyte aggregates appear to promote atherosclerotic lesion formation and are increased in stable coronary heart disease and acute coronary syndromes [18], [19].
We therefore investigated whether supplementing the diet of healthy individuals with a moderate intake of oil-rich fish would reduce platelet activation and platelet-monocyte aggregation.
Section snippets
Study participants and design
Twenty-eight healthy male volunteers aged between 21 and 28 years were enrolled into the study. Exclusion criteria included those taking regular medication, those with clinical evidence of atherosclerotic vascular disease, hypertension, diabetes mellitus, hypercholesterolemia, an intercurrent illness likely to be associated with an acute phase inflammatory response, and renal or hepatic insufficiency. Ethical approval was obtained from the Lothian Research Ethics Committee and all subjects
Baseline characteristics
Baseline characteristics were similar between the fish supplementation and control groups (Table 1). Study participants were young and there were no differences in body mass index, smoking status, or lipid profile.
Effect of fish intervention on plasma phospholipid fatty acid composition
The plasma phospholipid fractions of omega-3 and omega-6 fatty acids did not differ between groups at baseline. Dietary intervention with fish led to an increase in the percentage of total omega-3 fatty acids (14.2 ± 3.4% versus 5.8 ± 1.3%, P < 0.001), EPA (5.2 ± 2.1% versus 1.0 ± 0.3%, P <
Discussion
We have demonstrated, for the first time, that dietary intervention with oil-rich fish is associated with a reversible reduction in platelet-monocyte aggregation in man. There was an inverse correlation between platelet-monocyte aggregation and the plasma levels of EPA and DHA, consistent with the effects being related to the omega-3 content of oily fish. Our results suggest that reduced platelet activation could represent an important mechanism through which dietary fish confer their putative
Conclusion
We have demonstrated that dietary intervention with moderate amounts of oil-rich fish can reduce platelet-monocyte aggregation in man. Platelet-monocyte aggregates are sensitive markers of platelet activation and contribute to the initiation and progression of atherosclerosis. This could represent a previously unreported mechanism through which fish oils might confer their potential cardiovascular benefits. Most previous studies assessing the effects of fish oils on platelet function have used
Acknowledgements
We would like to thank Shona Johnstone for technical assistance with flow cytometry, and Lianne Milligan for performing analysis of the weighed food records. JD was supported by a British Heart Foundation Project Grant (PG/2003/009).
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