Effect of ω-3 fatty acid supplementation on endothelial function, endogenous fibrinolysis and platelet activation in patients with a previous myocardial infarction: a randomised controlled trial.

OBJECTIVE: The mechanisms through which ω-3 fatty acids reduce adverse cardiac events remain uncertain. We aimed to investigate the effect of ω-3 fatty acid supplementation on endothelial vasomotor function, endogenous fibrinolysis, and platelet and monocyte activation in patients with coronary heart disease. DESIGN: Randomised, double-blind, placebo-controlled, cross-over trial. SETTING: Academic cardiac centre. PARTICIPANTS: 20 male patients with a previous myocardial infarction. INTERVENTION: ω-3 Fatty acid supplementation (2 g/day for 6 weeks) versus olive oil placebo. OUTCOME MEASURES: Peripheral blood was taken for analysis of platelet and monocyte activation, and forearm blood flow (FBF) was assessed in a subset of 12 patients during intrabrachial infusions of acetylcholine, substance P and sodium nitroprusside. Stimulated plasma tissue plasminogen activator (t-PA) concentrations were measured during substance P infusion. RESULTS: All vasodilators caused dose-dependent increases in FBF (p<0.0001). ω-3 Fatty acid supplementation did not affect endothelium-dependent vasodilation with acetylcholine and substance P compared with placebo (p=0.5 and 0.9). Substance P caused a dose-dependent increase in plasma t-PA concentrations (p<0.0001), which was not affected by ω-3 fatty acid supplementation (p=0.9). ω-3 Fatty acids did not affect platelet-monocyte aggregation, platelet P-selectin or CD40L, or monocyte CD40. CONCLUSIONS: We have demonstrated that dietary supplementation with ω-3 fatty acids does not affect endothelial vasomotor function, endothelial t-PA release, or platelet and monocyte activation in patients with coronary heart disease. Cardiac benefits conferred by ω-3 fatty acids in coronary heart disease are unlikely to be mediated through effects on these systems.

Effect of ω-3 fatty acid supplementation on endothelial function, endogenous fibrinolysis and platelet activation in male cigarette smokers.

OBJECTIVE: The effects of ω-3 fatty acids on endothelial function, fibrinolysis and platelet function are uncertain. We investigated the effects of ω-3 fatty acid supplementation on endothelial vasomotor function, endogenous fibrinolysis, and platelet and monocyte activation in healthy cigarette smokers; a group at increased risk of myocardial infarction. DESIGN, SETTING, PARTICIPANTS: Twenty cigarette smokers were recruited into a randomised, double-blind, placebo-controlled, crossover trial of ω-3 fatty acid supplementation. INTERVENTION: ω-3 fatty acid supplements (2 g/day) or placebo for a 6-week period. MAIN OUTCOME MEASURES: Peripheral blood was taken for analysis of platelet and monocyte activation, and forearm blood flow (FBF) was assessed in a subset of 12 smokers during intrabrachial infusions of acetylcholine, substance P and sodium nitroprusside. Stimulated plasma tissue plasminogen activator (t-PA) concentrations were measured during substance P infusion. RESULTS: All vasodilators caused dose-dependent increases in FBF (p<0.0001). Compared with placebo, ω-3 fatty acid supplementation led to greater endothelium-dependent vasodilatation with acetylcholine and substance P (p=0.0032 and p=0.056). Substance P caused a dose-dependent increase in plasma t-PA concentrations (p<0.0001) that was greater after ω-3 fatty acid supplementation compared with placebo (8.8±2.3 IU ml(-1) vs 3.6±1.1 IU ml(-1); p=0.029). ω-3 fatty acids did not affect platelet-monocyte aggregation, platelet P-selectin or CD40L, or monocyte CD40. CONCLUSIONS: We have demonstrated for the first time that ω-3 fatty acids augment acute endothelial t-PA release and improve endothelial vasomotor function in cigarette smokers. Improved endogenous fibrinolysis and endothelial function may represent important mechanisms through which ω-3 fatty acids confer potential cardiovascular benefits.

Dietary intervention with oil rich fish reduces platelet-monocyte aggregation in man.

BACKGROUND: Dietary intake of fish rich in omega-3 fatty acids is associated with a reduction in cardiovascular events. The mechanisms for this are uncertain and previous studies investigating effects on platelet function have produced inconsistent results. Platelet-monocyte aggregation is a sensitive marker of platelet activation and may contribute to the initiation and progression of atherothrombosis. This study assessed the effect of dietary intervention with oily fish on platelet-monocyte aggregation in healthy subjects. METHODS: Fourteen subjects had their diet supplemented with 500 g of oil-rich fish per week for 4 weeks. A control group of 14 subjects received no dietary intervention over a 4-week period. Platelet-monocyte aggregates were assessed with flow cytometry. RESULTS: Dietary intervention with fish led to an increase in omega-3 fatty acids in plasma phospholipids (14.2+/-3.4% versus 5.8+/-1.3%, P<0.001). In contrast to the control group, platelet-monocyte aggregates were reduced by 35% following dietary intervention with oily fish (16.0+/-9.0% versus 24.8+/-10.9%, P<0.01), and returned to basal levels 4 weeks after discontinuation of supplementation. There was an inverse correlation between platelet-monocyte aggregation and plasma omega-3 fatty acid concentrations (r=-0.421, P=0.006). There were no changes in the plasma markers of platelet activation, soluble P-selectin or soluble CD40 ligand. CONCLUSIONS: We have demonstrated, for the first time, that dietary intervention with oil-rich fish reduces platelet-monocyte aggregation in man. Our results suggest that reduced platelet activation provides a potential mechanism through which fish oils confer their cardiovascular preventative benefits.

Do oxidized fatty acids activate coagulation factor VII during post-prandial lipemia in women?

Factor VII is activated to VIIa within hours after dietary fat, irrespective of its fatty acid composition. Edible oils contain oxidized material (hydroxy fatty acids, HOFA). Twenty-five fasting women, aged 38 (10) years, consumed 30 g walnut oil containing 26 (6) mg HOFA. Blood was collected 2-hourly to measure plasma triglycerides and plasma lipid HOFA by gas chromatography/mass spectrometry. VII and sTF-dependent VIIa were quantified at 0, 6 and 24 h. Increased plasma triglycerides and HOFA (areas under the curve 0-8 h, AUC) were related r = 0.83, p < 0.001. VIIa increased from 2.6 (1.4) to 4.2 (1.9) ng/mL at 6 h (p < 0.001). Plasma VII remained constant. VIIa (6 h) was related to plasma triglycerides- and HOFA-AUC: r = 0.38 and 0.53, respectively (both p < 0.05). Plasma VIIa was also related to body weight, fasting triglycerides, HOFA and VII. Only HOFA-AUC and body weight related to VIIa (6 h) in stepwise regression analysis (p = 0.007 and 0.038, respectively). Oxidized, not normal, fat activates VII and could increase coronary risk in humans.

Dietary hydroxy fatty acids are absorbed in humans: implications for the measurement of 'oxidative stress' in vivo.

Lipid peroxidation products formed in vivo or originating from the diet may lead to atherosclerosis. However, little is known about the absorption of these products in man. We studied the absorption of fat (30 g) containing 14-15 mg [U-13C]-labeled hydroxy or dihydroxy triglycerides in two groups of six apparently healthy women aged 40 +/- 2 years. Post-prandial 13C-labeled hydroxy fatty acid concentration increased in a pattern somewhat different from that of plasma triglycerides, with peak levels being reached between 4 and 6 h. However, the amount of 13C-labeled oxidized fat absorbed (area under the curve of plasma concentrations from 0 to 8 h) was related to that of plasma triglycerides: 13C hydroxy vs TG (r = 0.88, p <.02), and 13C dihydroxy vs TG (r = 0.85, p <.05). 13C monohydroxy triglycerides appeared to be absorbed to a greater extent than those of 13C dihydroxy triglycerides. Although low levels of 13C hydroxy lipids could be detected in fasting plasma after 24 h, concentrations were very low. Dietary lipid oxidation products are absorbed. The measurement of hydroxy fatty acids in plasma total lipids may not be a valid marker of lipid peroxidation in vivo when subjects are not fasting.