Replies to post #102280 on Amarin Corp Plc (AMRN)
03/12/17 6:23 PM
TBARS do not measure CVD risk accurately...So what if they lower Vit E. If you think Vit E is going to protect you fron CVD events...Well go ahead.. --JL
Another method of determining oxidative stress is to measure the disappearance of antioxidants, such as alpha-tocopherol [vitamin E], from the blood. Because the majority of plasma tocopherols are found in plasma lipids, which have been shown to decrease in the critically ill, any measure of plasma tocopherols in the critically ill population should be indexed to total cholesterol.
Our hypothesis was that n-3 FA supplementation might improve the endothelial dysfunctional state in the present population with advanced CHD, and this might be evaluated by the presently measured soluble markers. The finding of lower values of the hemostatic markers vWF, and sTM in group I at baseline, and the significant reductions in sTM and t-PAag in group II during the study period would fit this hypothesis.
However, the finding of higher values of the inflammatory markers sE-sel and sVCAM-1 in group I at baseline, and the significant increasing change in these markers in group II during the study period, was unexpected. All over, the findings seem to indicate that supplementation with highly concentrated n-3 FA to patients with coronary atherosclerotic disease decreases the hemostatic activity of the endothelium, whereas the inflammatory activity might be increased.
Concerning the changes in t-PAag, this may possibly be linked to the simultaneous changes in triglycerides. Triglycerides have been demonstrated to stimulate cultured endothelial cells to release plasminogen activator inhibitor-1 (PAI-1).22 Thus, a reduction in triglycerides may lead to reduced PAI-1 secretion. It is also suggested that in steady-state conditions t-PAag mainly reflects the level of PAI-1,23 as the t-PAag method used determines both t-PA and PAI-1. Accordingly, the t-PAag reductions obtained during n-3 FA supplementation might reflect reduced endothelial secretion of PAI-1 along with the reduction in triglycerides.
Concerning the markers of inflammation, our results are not in accordance with some previously published studies. However, it should be emphasized that our study was performed as a clinical trial in patients with atherosclerotic disease and not in isolated cells. We are not aware of previous studies on soluble inflammatory factors that have been performed in a population readily comparable with ours. However, similar results, that is, an increase in sE-sel and sVCAM-1 after supplementation with n-3 FA, were recently described by Seljeflot et al26 in a population of healthy individuals at high risk for atherosclerotic disease states.
Finally, moderate beneficial effects with n-3 FA have been demonstrated in different inflammatory diseases such as rheumatoid arthritis,29 30 and clinical benefit of n-3 FA has also been reported in patients with psoriasis.31
On the other hand, Blok et al32 reported in a prospective trial that fish oil supplementation did not affect the concentrations of circulating cytokines. Furthermore, they found the ex vivo production of cytokines (interleukin-Iß, tumor necrosis factor-a, and interleukin-Ra), after endotoxin stimulation of whole blood, to be significantly increased during fish oil supplementation. However, the observed increase was not significantly different from that in the placebo group.
The reason for the apparent discrepancy is not clear. However, it is well known that polyunsaturated fatty acids are prone to peroxidation and that generated free radicals and oxidized LDL may both be cytotoxic.33 Various authors have suggested the possible deleterious effects of n-3 FA supplementation because of their increased susceptibility to oxidation,34 35 36 although contradictory results have been reported.15
This could also be discussed along with the decreased levels of vitamin E after n-3 FA supplementation encountered in the present study. This finding is in accordance with what we have recently reported in another study26 and also with the results from Hau et al,37 suggesting a consumption of antioxidants caused by an increased level of oxidation after n-3 FA supplementation.
Increased TBARS values after long-term supplementation with n-3 FA, as evidenced by the differences between the groups at baseline and the differences in changes between the groups during the study period, further supports the hypothesis of increased peroxidation.
In conclusion, we could demonstrate that high-dosage n-3 FA supplementation decreases circulating t-PAag and sTM and increases sE-sel and sVCAM-1 in blood from patients with CHD. In addition to reduced levels of hemostatic markers of atherosclerosis, these results might indicate a proinflammatory response that could be adverse, possibly brought about by an increased peroxidation as demonstrated by a consumption of vitamin E and increased TBARS.
Background: Although the replacement of dietary saturated fat with unsaturated fat has been advocated to reduce the risk of cardiovascular disease, diets high in polyunsaturated fatty acids (PUFAs) could increase lipid peroxidation, potentially contributing to the pathology of atherosclerosis.
Objective: The objective of this study was to examine indexes of in vivo lipid peroxidation, including free F2-isoprostanes, malondialdehyde (MDA), and thiobarbituric acid reacting substances (TBARS), in the plasma of postmenopausal women taking dietary oil supplements rich in oleate, linoleate, and both eicosapentaenoic acid and docosahexaenoic acid.
Design: Fifteen postmenopausal women took 15 g sunflower oil/d, providing 12.3 g oleate/d; safflower oil, providing 10.5 g linoleate/d; and fish oil, providing 2.0 g EPA/d and 1.4 g DHA/d in a 3-treatment crossover trial.
Results: Plasma free F2-isoprostane concentrations were lower after fish-oil supplementation than after sunflower-oil supplementation (P = 0.003). When plasma free F2-isoprostane concentrations were normalized to plasma arachidonic acid concentrations, significant differences among the supplements were eliminated. Plasma MDA concentrations were lower after fish-oil supplementation than after sunflower-oil supplementation (P = 0.04), whereas plasma TBARS were higher after fish-oil supplementation than after sunflower oil (P = 0.003) and safflower oil (P = 0.001) supplementation. When plasma MDA concentrations were normalized to plasma PUFA concentrations, significant differences were eliminated, but TBARS remained higher after fish-oil supplementation than after sunflower oil (P = 0.01) and safflower-oil (P = 0.0003) supplementation.
The objective of this study was to test the predictive value of an oxidative stress biomarker in 634 patients from the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT).
During the three-year study, there were 51 major vascular events such as fatal/nonfatal myocardial infarction, 149 hospitalizations for nonfatal vascular events, and 139 patients underwent a major vascular procedure. At baseline, patients with TBARS levels in the highest quartile had a relative risk (RR) of 3.30 (95% confidence interval [CI] 1.47 to 7.42; p = 0.038) for major vascular events, RR of 4.10 (95% CI 2.55 to 6.60; p < 0.0001) for nonfatal vascular events, and RR of 3.84 (95% CI 2.56 to 5.76; p < 0.0001) for major vascular procedures. The effect of TBARS on events and procedures was also seen in a multivariate model adjusted for inflammatory markers (C-reactive protein, soluble intercellular adhesion molecule-1, interleukin-6), and other risk factors (age, low-density lipoprotein, high-density lipoprotein, total cholesterol, triglycerides, body mass index, and blood pressure). This analysis showed an independent effect of TBARS on major vascular events (p = 0.0149), nonfatal vascular events (p < 0.0001), major vascular procedures (p < 0.001), and all vascular events and procedures (p < 0.0001).
Eicosapentaenoic acid (EPA) is one of the major dietary polyunsaturated fatty acids and induces apoptosis in several cancer cells. In this study, the EPA induced lipid peroxidation and response of antioxidative enzymes have been investigated in rat pheochromocytoma PC12 cells to elucidate the mechanisms of apoptosis induced by the polyunsaturated fatty acid EPA. We have analyzed superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities and glutathione (GSH) contents in PC12 cells after exposure to different concentrations of EPA. Lipid peroxidation was shown to increase in the presence of EPA as an indication of the oxidative damage. Lipid peroxidation was enhanced by EPA in a dose-dependent manner, and the loss of cell viability was partially reversed by vitamin E. In the case of antioxidant enzyme activities, SOD and GPX activities and GSH contents increased significantly at 50 micromol/L EPA and were respectively 2.41-fold (p < 0.01), 3.49-fold (p < 0.05), and 1.43-fold (p < 0.05) higher than controls. The CAT activity at 10 micromol/L had the highest value and was increased by 25.83% (p < 0.05) compared to control. The results suggest that in PC12 cells the mechanism of apoptosis induced by EPA may be partly due to lipid peroxidation.
To determine if the ratio of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in fish oil had an effect on plasma lipid responses, we randomly fed eight normolipidemic men three 36%-fat diets containing primarily butter, EPA-rich pollock oil, or DHA-rich tuna or salmon-blend oils. Plasma EPA and DHA reflected the amounts in the diets. Compared with values for the butter diet, very-low-density lipoprotein (VLDL) triglycerides decreased equally (71-78%) with all diets; low-density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B decreased 26% and 13%, respectively, on the tuna and salmon-blend oil [DHA:EPA of 2:1] but did not change (-1%) and increased 19% with the pollock diet [high EPA]; high-density lipoprotein cholesterol (HDL-C) and lipoproteins A-I and A-II decreased with all diets but more with the pollock diet than with the tuna and salmon diets. The 23-31% decrease in total cholesterol on the tuna and salmon diets resulted mostly from decreased LDL-C whereas the 16% decrease on pollock oil resulted mostly from a decrease in HDL-C.
Results: Fifty-six men aged 48.8 ± 1.1 y completed the study. Relative to those in the olive oil group, triacylglycerols fell by 0.45 ± 0.15 mmol/L (˜20%; P = 0.003) in the DHA group and by 0.37 ± 0.14 mmol/L (˜18%; P = 0.012) in the EPA group. Neither EPA nor DHA had any effect on total cholesterol. LDL, HDL, and HDL2 cholesterol were not affected significantly by EPA, but HDL3 cholesterol decreased significantly (6.7%; P = 0.032). Although HDL cholesterol was not significantly increased by DHA (3.1%), HDL2 cholesterol increased by ˜29% (P = 0.004). DHA increased LDL cholesterol by 8% (P = 0.019). Adjusted LDL particle size increased by 0.25 ± 0.08 nm (P = 0.002) with DHA but not with EPA.
It has been suggested that serum HDL cholesterol is better maintained with DHA-enriched than with EPA-enriched oils (38). The present data and previous findings (19) support this hypothesis. We observed that the increase in HDL cholesterol was due to a 29% increase in HDL2 cholesterol. Increased HDL2 cholesterol was reported previously by our group after daily consumption of fish or fish oils by subjects with type 2 diabetes or at risk of heart disease (23, 37). In contrast, Grimsgaard et al (19) surmised that both EPA and DHA increase HDL2 cholesterol because both fatty acids increased the ratio of HDL cholesterol to apo A-I. DHA increased HDL cholesterol and EPA decreased apo-AI, suggesting an increased surface-to-core ratio of the HDL particle and a redistribution of the HDL subclasses toward the larger HDL2 particles (41). The mechanisms by which DHA increases HDL cholesterol are not known, but may be related to alterations in lipid transfer protein activity, which decreases after n-3 fatty acid supplementation (41). In epidemiologic terms, the increase in HDL2 cholesterol could have a marked effect on the incidence of cardiovascular disease, given that HDL2 cholesterol may be the subfraction of HDL cholesterol that may be most protective against coronary heart disease (42).
In Cox multivariate survival models adjusted for age and examination year, serum HDL cholesterol of less than 1.09 mmol/l (42 mg/dl) was associated with a 3.3-fold risk of acute myocardial infarction (95% confidence intervals [CI], 1.7-6.4), serum HDL2, cholesterol of less than 0.65 mmol/l (25 mg/dl) was associated with a 4.0-fold risk of acute myocardial infarction (95% CI, 1.9-8.3), and serum HDL3 cholesterol of less than 0.40 mmol/l (15 mg/dl) was associated with a 2.0-fold (95% CI, 1.1-4.0) risk of acute myocardial infarction.
OBJECTIVE:
To evaluate which HDL subfraction, HDL2 or HDL3 exerts the greater preventive effect on the Cu(2+)-induced LDL oxidation.
METHODS:
LDL was incubated for 6 h with 2.5 microM Cu2+ in phosphate-buffered saline alone, or in the presence of HDL2 or HDL3 at various protein concentrations. Each sample was subjected to agarose gel electrophoresis, and the amount of lipid hydroperoxide in each sample of LDL was measured.
RESULTS:
There was no significant difference in the levels of LPO between the LDL and LDL + HDL2 cases, whereas a significant reduction was apparent with LDL + HDL3. Both HDL2 and HDL3 significantly inhibited oxidative modification of LDL, as assessed by electrophoretic mobility, in a concentration dependent manner, but this effect was much more pronounced with HDL3.
A decrease in HDL-C of >0.1 mmol/L was associated with a 56 % increase in major adverse cardiovascular events compared with unchanged HDL-C levels. The results were consistent across subgroups based on age, gender, presence of diabetes, primary and secondary prevention.
This study addressed whether purified EPA and DHA have different effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men. We found that DHA, but not EPA, improved serum lipid status, in particular a small increase in HDL cholesterol and a significant increase in the HDL2-cholesterol subfraction, without adverse effects on fasting glucose concentrations. Neither EPA nor DHA affected total cholesterol and both fatty acids reduced triacylglycerols and increased fasting insulin concentrations to a similar extent. DHA supplementation significantly increased LDL cholesterol; however, this was associated with an increase in LDL particle size, which may represent a shift to a less atherogenic LDL particle.
The benefits of n-3 fatty acids have to be weighed against the potential for impaired glucose tolerance, particularly in patients with type 2 diabetes (20–22), although no adverse effect has been seen in healthy volunteers or in hypertensive (25) or dyslipidemic patients (24). We showed in patients with type 2 diabetes that, under carefully controlled dietary conditions, n-3 fatty acids can lead to a deterioration in glycemic control (23). This effect, however, was prevented by a moderate exercise program.
Both EPA and DHA supplementation increased fasting insulin, but only EPA increased fasting glucose. These results are consistent with a differential effect of EPA and DHA on glucose responses in humans. In contrast, lower doses of EPA (900 and 1800 mg/d) did not change fasting plasma glucose or glycated hemoglobin concentrations in patients with type 2 diabetes (53, 54).
Mechanisms underlying the putative adverse effects of n-3 fatty acids on glycemic control include an increase in hepatic glucose output, which may be related to an elevated flux of gluconeogenic precursors to the liver, increased plasma glucagon concentrations, changes in hepatic insulin or glucagon sensitivity, or decreased insulin secretion rates (20–22). The mechanisms responsible for the increase in fasting glucose after EPA but not after DHA supplementation are not known, but may be because EPA increases hepatic glucose production or decreases hepatic insulin secretion more than does DHA.
Nonsmoking treated hypertensive diabetic men and postmenopausal women, aged 40–75 years, were stratified by sex, age, and BMI and randomized to receive 4 g/day purified EPA, DHA, or olive oil (placebo) for 6 weeks in a double-blinded trial. LDL particle diameter was determined by gradient gel electrophoresis (2).
At baseline there were no significant differences among the olive oil, EPA, and DHA groups in plasma LDL cholesterol level and LDL particle size (25.69 ± 0.13 nm, 26.0 ± 0.16 nm, and 25.74 ± 0.16 nm, respectively). Relative to placebo, LDL particle size was decreased by 0.12 ± 0.10 nm (P = 0.49) with EPA and increased by 0.26 ± 0.10 nm (P = 0.02) with DHA after adjusting for multiple comparisons.
These data support our previous study in overweight hypercholesterolemic subjects, in whom LDL particle size increased after supplementation with DHA but not EPA (2).
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