Effects of omega-3 fatty acids on postprandial triglycerides and monocyte activation.

Epidemiologic studies suggest that elevated postprandial triglycerides (ppTG) are associated with future cardiovascular events. Monocyte activation plays an important role in vascular diseases.  Omega 3 fatty acids (n3 FA) lower fasting TG levels. The effects of n3 FA on ppTG and the role of ppTG for monocyte activation are insufficiently understood. 23 healthy volunteers and 30 non diabetic patients with documented coronary artery disease were subjected to an oral TG tolerance test (OTTT) consisting of 80 g cream fat or to water as control (H2O). Patients were treated with 4 g n3 FA/day or placebo for 3 weeks in a randomized, placebo-controlled, double-blind, crossover study. Relative postprandial TG increase reached its maximum 4 h after fat intake (185.1 plus/minus10.9 percent of baseline). n3 FA reduced fasting TG from 137.1 plus/minus 12.9 to 112.2 plus/minus 8.6 mg/dl (p < 0.05), and maximum ppTG concentrations from 243.6 plus/minus 24.6 to 205.8 plus/minus 17.1 mg/dl (p < 0.05), while relative TG increase (192.8 plus/minus 12.7 percent) was comparable to placebo. Relative monocytopenia and neutrophilia were detected following fat intake, which was unaffected by n3 FA and also detectable in the H2O group. Serum chemotactic cytokine (MCP1 and fractalkine) concentrations and monocyte migration were not affected by fat intake or n3 FA. Monocyte activation markers CD11b and CD14, monocyte subpopulations CD16þCD14high and CD16þCD14low, sICAM serum levels and markers of oxidative stress remained unchanged by fat intake or n3 FA. The postprandial TG increase does not stimulate monocytes beyond their circadian activation patterns. N3 FA reduce fasting TG and the postprandial TG increase. n3 FA may therefore allow to prospectively study whether selected patients benefit from TG lowering independent of LDL and HDL cholesterol. (Authors abstract)

The role of triglycerides (TG) in the pathophysiology and epidemiology of vascular disease is not clear. Mechanistic studies point towards a direct effect of triglyceriderich lipoproteins and chylomicron remnants on the vascular wall. Circulating inflammatory cells, particularly monocyte activation, play an important role in lipid-mediated vascular diseases.  Omega 3 fatty acids (n3 FA) at a higher dose (3 to 4 g daily) are known to lower fasting TG levels by about 30 percent, while their effects on non-fasting, postprandial TG (ppTG) metabolism have not been systematically characterized in non hyperlipidemic patients with coronary artery disease (CAD). N3 FA have been described to have anti-inflammatory effects in blood monocytes. This study aimed to investigate ppTG following treatment with n3 FA and to dissect the effects of ppTG on monocyte activation as a possible mechanism of TG stimulated atherosclerosis using a standardized test protocol in controls and CAD patients. In this study, a standardized oral triglyceride tolerance test (OTTT) increased serum TG by 73percent in healthy controls and 78percent in non-hyperlipidemic patients with coronary artery disease, without affecting cholesterol concentrations. Leukocyte subpopulations and monocyte activation were only mildly affected by the fat intake.  Treating stable, non diabetic, non hyperlipidemic CAD patients with omega 3 fatty acids in a randomized, double-blind, crossover trial decreased not only fasting but also postprandial TG by 18 and 16percent, respectively. Compared to placebo, three weeks treatment with n3 FA did not alter fasting and postprandial leukocyte composition and parameters of monocyte activation and migration.  The analyses do not provide evidence for a stimulatory effect of triglycerides on monocyte activation and migration parameters. The observed parallel postprandial changes after water ingestion likely reflect the circadian regulation of inflammatory status, which may relate to changing levels of cortisol during the day. As with monocyte parameters, cortisol levels were unaffected by n3 FA. Alternatively, several hours fasting in the morning period may be a stressor of similar strength as postprandial hypertriglyceridemia in otherwise normolipidemic individuals. Decrease in glucose and rise in insulin concentrations over time were very mild and within the physiological range of these parameters, making a biologically relevant effect unlikely. The test protocol and the randomized, crossover study now shows that treatment of non-diabetic CAD patients with 4 g/d n3 FA reduces ppTG to a similar extent as fasting TG. Treatment with n3 FA did not change leukocyte composition, activation status or migration of peripheral blood monocytes. Importantly, 90percent of the study patients were on statin treatment and showed LDL-cholesterol serum concentrations <100 mg/dl. It is therefore possible that statin treatment had already reduced the response of circulating inflammatory cells to TG.  In conclusion, the study shows that high dose n3 FA selectively reduce both fasting and postprandial TG in patients with cardiovascular disease on statin treatment. Monocyte activation and migration do not appear to be relevant mechanisms behind possible TG mediated effects on vascular pathophysiology. n3 FA provide an ideal tool to prospectively study whether selected patients benefit from TG lowering independent of LDL and HDL cholesterol.