Nestel P, Shige H, et al. The n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans. American Journal of Clinical Nutrition 2002;76:326-330

Background: n-3 Fatty acids influence vascular function, but the effect of individual fatty acids on systemic arterial compliance (SAC) has not been reported. SAC, which reflects arterial elasticity, is emerging as a new cardiovascular risk factor and appears to predict future cardiovascular events.

Objective: We tested whether the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) improve SAC in dyslipidemic subjects.

Design: Thirty-eight dyslipidemic subjects were randomly assigned to receive 3 g EPA/d (n = 12), 3 g DHA/d (n = 12), or a placebo (n = 14) in a 7-wk parallel, double-blind trial. Arterial functions were measured at the beginning and end of the interventions. Plasma lipids and plasma fatty acids were also measured.

Results: Consumption of the n-3 fatty acids significantly increased SAC, whereas consumption of the placebo did not (P = 0.043; repeated-measures analysis of variance across the 3 groups); the increase was 36% with EPA and 27% with DHA. The major components contributing to the increase in SAC (systolic and pulse pressures and total vascular resistance) tended to decrease but not significantly. Plasma total and VLDL triacylglycerol were significantly lower in the n-3 fatty acid groups (P = 0.026 and 0.006, respectively; repeated-measures analysis of variance) than in the placebo group.

Conclusion: EPA and DHA increase SAC and tend to reduce pulse pressure and total vascular resistance, effects that may reduce the risk of adverse cardiovascular events.

Woodman RJ, Mori TA, t al. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Am J Clin Nutr, 2002; 76: 1007-1015.

BACKGROUND: n-3 Fatty acids lower blood pressure, improve lipids, and benefit other cardiovascular disease risk factors. Effects on glycemia in patients with type 2 diabetes are uncertain.

OBJECTIVE: We determined whether purified eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on glycemic control, including insulin sensitivity and stimulated insulin secretion; 24-h ambulatory blood pressure; and serum lipids in type 2 diabetic patients with treated hypertension.

DESIGN: In a double-blind, placebo-controlled trial of parallel design, 59 subjects were randomly assigned to consume 4 g EPA, DHA, or olive oil/d for 6 wk while continuing to consume their usual diet.

RESULTS: Thirty-nine men and 12 postmenopausal women with a mean (+/- SE) age of 61.2 +/- 1.2 y completed the study. In comparison with the change from baseline in fasting glucose in the olive oil group, fasting glucose in the EPA and DHA groups increased 1.40 +/- 0.29 mmol/L (P = 0.002) and 0.98 +/- 0.29 mmol/L (P = 0.002), respectively. Neither EPA nor DHA had significant effects on glycated hemoglobin, fasting insulin or C-peptide, insulin sensitivity or secretion, or blood pressure. Serum triacylglycerols in the EPA and DHA groups decreased 19% (P = 0.022) and 15% (P = 0.022), respectively. There were no significant changes in serum total, LDL, or HDL cholesterol, although HDL(2) cholesterol in the EPA and DHA groups increased 16% (P = 0.026) and 12% (P = 0.05), respectively. HDL(3) cholesterol decreased 11% (P = 0.026) with EPA supplementation.

CONCLUSIONS: EPA and DHA had similar benefits on lipids but adverse effects on short-term glycemic control in hypertensive diabetic patients. The overall implications for cardiovascular disease require long-term evaluation.

Niu K, Hozawa A, Kuriyama S, et al. Dietary long-chain n-3 fatty acids of marine origin and serum C-reactive protein concentrations are associated in a population with a diet rich in marine products. Am J Clin Nutr, 2006;84(1):223-229.

Background: Several studies have reported that the intake of n-3 polyunsaturated fatty acids (PUFAs) or fish is inversely associated with serum C-reactive protein (CRP) concentrations, but few studies have evaluated the relations between serum CRP concentrations and consumption of n-3 PUFAs derived from marine products in populations with a diet rich in marine products. Therefore, it is still unclear whether a greater consumption of n-3 PUFAs is associated with lower serum CRP concentrations.

Objective: The aim of this study was to investigate the relations between n-3 PUFA intake and serum CRP concentration in the Japanese, who have a diet rich in marine products.

Design: We designed a cross-sectional survey of 401 men and 570 women aged 70 y who were living in Japan. CRP concentrations were measured, and subjects whose serum CRP concentrations were 10.0 mg/L were excluded. Dietary intake was assessed with a self-administered diet-history questionnaire.

Results: After adjustment for several predictors of inflammation, the odds ratio of high CRP (1.0 mg/L) for increasing quartiles of total n-3 PUFA and eicosapentaenoic acid + docosahexaenoic acid were 1.0, 0.72, 0.57, and 0.44 (P for trend = 0.01) and 1.0, 0.91, 0.76, and 0.54 (P for trend = 0.03), respectively.

Conclusions: Greater intake of n-3 PUFAs derived from marine products, as measured with a self-administered questionnaire, was independently related to a lower prevalence of high CRP concentrations in this older Japanese population with a diet rich in marine products. Our findings suggest that even very high intakes of n-3 PUFAs may lower serum CRP concentrations.

Carpentier YA, Portois L, Malaisse WJ. n3 Fatty acids and the metabolic syndrome. Am J Clin Nutr, 2006;83(6):S1499-1504S.

The metabolic syndrome is defined as the coexistence of 3 or more components, some of which indicate alterations in glucose and lipid metabolism.

The prevalence of the metabolic syndrome is rapidly increasing in relation to obesity, and it is considered to be an important predictor of cardiovascular disease.

Increased intakes or supplements of n3 marine fatty acids may improve defects in insulin signaling and prevent alterations in glucose homeostasis and the further development of type 2 diabetes. This is largely mediated through a reduction in fatty acid accumulation in muscle and liver.

n3 Polyunsaturated fatty acids (n3 PUFAs) reduce plasma triacylglycerols and improve the lipoprotein profile by decreasing the fraction of atherogenic small, dense LDL. However, n3 PUFAs do not lower LDL cholesterol. These effects are likely mediated through the activity of transcription factors relating to expression of genes involved in lipid oxidation and synthesis.

Other pleiotrophic effects of n3 PUFAs may contribute to decreasing the burden of the metabolic syndrome, such as modulating inflammation, platelet activation, endothelial function, and blood pressure.

Although studies comparing the effect of both major n3 PUFAs are limited, docosahexaenoic acid appears at least as efficient as eicosapentaenoic acid in correcting several risk factors.

The use of n3 PUFAs should be considered in more global strategies including changes in lifestyle, such as adhering to a healthy Mediterranean type of diet and practicing regular physical exercise.

Geelen A, Brouwer IA, Schouten EG, et al. Effects of n3 fatty acids from fish on premature ventricular complexes and heart rate in humans. Am J Clin Nutr., 2005;81(2):416-420.

Background: A large body of evidence suggests that n3 fatty acids from fish prevent fatal heart disease. They may be an effective and safe alternative to drug treatment for reducing the risk of arrhythmia and sudden cardiac death.

Objective: We investigated the effect of n3 fatty acids on heart rate and premature ventricular complexes (PVCs), a common form of arrhythmia that may trigger arrhythmias that are more life-threatening.

Design: Patients (n = 84) with 1440 PVCs/24 h in a previous Holter recording were randomly assigned to receive 1.5 g/d of either n?3 fatty acids or placebo. Two 24-h Holter recordings were made at baseline, and 2 were made after an intervention of 14 wk.

Results: Treatment did not significantly affect the number of PVCs. The number decreased in the fish-oil group by 867/24 h more than it decreased in placebo group (95% CI: ?3187, 1453).

However, the mean 24-h heart rate was significantly affected, decreasing in the fish-oil group by a mean of 2.1 beats/min more than it decreased in the placebo group (95% CI: ?3.9, ?0.3).

Conclusions: Supplementation with 1.5 g n3 fatty acids/d from fish does not substantially suppress the number of PVCs in a patient population with frequent PVCs.

However, n3 fatty acids decreased heart rate by 2.1 beats/min, a significant decrease that predicts a lower risk of sudden death.

Mozaffarian D, Geelen A, Brouwer IA, et al. Effect of Fish Oil on Heart Rate in Humans. A Meta-Analysis of Randomized Controlled Trials Circulation, 2005, doi:10.1161/CIRCULATIONAHA.105.556886. Published online before print September 19, 2005.

Background--The effect of fish oil on heart rate (HR), a major risk factor for sudden death, is not well established. We calculated this effect in a meta-analysis of randomized, double-blind, placebo-controlled trials in humans.

Methods and Results--Randomized trials of fish oil that evaluated HR were identified through MEDLINE (1966 through January 2005), hand-searching of references, and contact with investigators for unpublished results.

Two investigators independently extracted trial data. A pooled estimate was calculated from random-effects meta-analysis.

Predefined stratified meta-analyses and meta-regression were used to explore potential heterogeneity. Of 197 identified articles, 30 met inclusion criteria. Evidence for publication bias was not present.

In the overall pooled estimate, fish oil decreased HR by 1.6 bpm (95% CI, 0.6 to 2.5; P=0.002) compared with placebo.

Between-trial heterogeneity was evident (Q test, P<0.001).

Fish oil reduced HR by 2.5 bpm (P<0.001) in trials with baseline HR 69 bpm (median) but had little effect (0.04-bpm reduction; P=0.56) in trials with baseline HR <69 bpm (P for interaction=0.03).
Fish oil reduced HR by 2.5 bpm (P<0.001) in trials with duration 12 weeks but had less effect (0.7-bpm reduction; P=0.27) in trials with duration <12 weeks (P for interaction=0.07).

HR reduction with fish oil intake did not significantly vary by fish oil dose (range, 0.81 to 15 g/d), type of HR measure, population age, population health, parallel versus crossover design, type of control oil, or study quality by Delphi criteria (P for interaction >0.25 for each).

Conclusions--In randomized controlled trials in humans, fish oil reduces HR, particularly in those with higher baseline HR or longer treatment duration.

These findings provide firm evidence that fish oil consumption directly or indirectly affects cardiac electrophysiology in humans.
Potential mechanisms such as effects on the sinus node, ventricular efficiency, or autonomic function deserve further investigation.

Zampelas A, Panagiotakos DB, et al. Fish Consumption Among Healthy Adults Is Associated With Decreased Levels of Inflammatory Markers Related to Cardiovascular Disease. J Am Coll Cardiol, 2005;46:120-124

OBJECTIVES: The aim of this work was to investigate the association between fish consumption and levels of various inflammatory markers among adults without any evidence of cardiovascular disease.

BACKGROUND: Fish consumption has been associated with reduced risk of coronary heart disease, but the mechanisms have not been well understood or appreciated.

METHODS: The ATTICA study is a cross-sectional survey that enrolled 1,514 men (age 18 to 87 years) and 1,528 women (age 18 to 89 years) from the Attica region, Greece. Of them, 5% of men and 3% of women were excluded due to a history of cardiovascular disease.
Among others, C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, serum amyloid A (SAA), and white blood cells (WBC) were measured, and dietary habits (including fish consumption) were evaluated using a validated food frequency questionnaire.

RESULTS: A total of 88% of men and 91% of women reported fish consumption at least once a month. Compared to non-fish consumers, those who consumed >300 g of fish per week had on average 33% lower CRP, 33% lower IL-6, 21% lower TNF-alpha, 28% lower SAA levels, and 4% lower WBC counts (all p < 0.05).
Significant results were also observed when lower quantities (150 to 300 g/week) of fish were consumed. All associations remained significant after various adjustments were made.

CONCLUSIONS: Fish consumption was independently associated with lower inflammatory markers levels, among healthy adults.
The strength and consistency of this finding has implications for public health and should be explored further.

Lopez-Garcia E, Schulze MB, et al. Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women. J Nutr, 2004;134(7):1806-1811

We evaluated the hypothesis that intake of (n-3) fatty acids is inversely associated with biomarkers of inflammation and endothelial activation.

We conducted a cross-sectional study of 727 women from the Nurses' Health Study I cohort, aged 43-69 y, apparently healthy at time of a blood draw in 1990. Dietary intake was assessed by a validated FFQ in 1986 and 1990.

C-reactive protein (CRP) levels were 29% lower among those in the highest quintile of total (n-3) fatty acids, compared with the lowest quintile; interleukin-6 (IL-6) levels were 23% lower, E-selectin levels 10% lower, soluble intracellular adhesion molecule (sICAM-1) levels 7% lower, and soluble vascular adhesion molecule (sVCAM-1) levels 8% lower.

The intake of alpha-linolenic acid was inversely related to plasma concentrations of CRP (beta = -0.55, P = 0.02), Il-6 (beta = -0.36, P = 0.01), and E-selectin (beta = -0.24, P = 0.008) after controlling for age, BMI, physical activity, smoking status, alcohol consumption, and intake of linoleic acid (n-6) and saturated fat.

Long-chain (n-3) fatty acids (eicosapentaenoic and docosahexaenoic) were inversely related to sICAM-1 (beta = -0.11, P = 0.03) and sVCAM-1 (beta = -0.17, P = 0.003).

Total (n-3) fatty acids had an inverse relation with CRP (beta = -0.44, P = 0.007), IL-6 (beta = -0.26, P = 0.009), E-selectin (beta = -0.17, P = 0.004), sICAM-1 (beta = -0.07, P = 0.02), and sVCAM-1 (beta = -0.10, P = 0.004).

These associations were not modified by intake of vitamin E, dietary fiber, trans fatty acids, or by the use of postmenopausal hormone therapy.

In conclusion, this study suggests that dietary (n-3) fatty acids are associated with levels of these biomarkers reflecting lower levels of inflammation and endothelial activation, which might explain in part the effect of these fatty acids in preventing cardiovascular disease.

PMID: 15226473

Lopez-Garcia E, Schulze M, et al. Consumption of (n-3) Fatty Acids Is Related to Plasma Biomarkers of Inflammation and Endothelial Activation in Women. J. Nutr, 2004; 134:1806-1811

We evaluated the hypothesis that intake of (n-3) fatty acids is inversely associated with biomarkers of inflammation and endothelial activation.

We conducted a cross-sectional study of 727 women from the Nurses? Health Study I cohort, aged 43?69 y, apparently healthy at time of a blood draw in 1990. Dietary intake was assessed by a validated FFQ in 1986 and 1990.

C-reactive protein (CRP) levels were 29% lower among those in the highest quintile of total (n-3) fatty acids, compared with the lowest quintile; interleukin-6 (IL-6) levels were 23% lower, E-selectin levels 10% lower, soluble intracellular adhesion molecule (sICAM-1) levels 7% lower, and soluble vascular adhesion molecule (sVCAM-1) levels 8% lower.

The intake of -linolenic acid was inversely related to plasma concentrations of CRP (?= ?0.55, P = 0.02), Il-6 (?= ?0.36, P = 0.01), and E-selectin (?= ?0.24, P = 0.008) after controlling for age, BMI, physical activity, smoking status, alcohol consumption, and intake of linoleic acid (n-6) and saturated fat.

Long-chain (n-3) fatty acids (eicosapentaenoic and docosahexaenoic) were inversely related to sICAM-1 (?= ?0.11, P = 0.03) and sVCAM-1 (?= ?0.17, P = 0.003).

Total (n-3) fatty acids had an inverse relation with CRP (?= ?0.44, P = 0.007), IL-6 (?= ?0.26, P = 0.009), E-selectin (?= ?0.17, P = 0.004), sICAM-1 (?= ?0.07, P = 0.02), and sVCAM-1 (?= ?0.10, P = 0.004).

These associations were not modified by intake of vitamin E, dietary fiber, trans fatty acids, or by the use of postmenopausal hormone therapy.

In conclusion, this study suggests that dietary (n-3) fatty acids are associated with levels of these biomarkers reflecting lower levels of inflammation and endothelial activation, which might explain in part the effect of these fatty acids in preventing cardiovascular disease.

Cleland LG, Caughey GE, James MJ, Proudman SM. Reduction of cardiovascular risk factors with longterm fish oil treatment in early rheumatoid arthritis. J Rheumatol,2006;33(10):1973-1979.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased risk for cardiovascular (CV) events through multiple factors. Fish oil has been shown to reduce symptoms in RA and to reduce CV risk. We assessed the effect of an antiinflammatory dose of fish oil on CV risk factors within a program of combination chemotherapy for patients with early RA.

METHODS: Patients who chose not to take fish oil (n = 13) were compared with patients who achieved a sustained elevation of eicosapentaenoic acid (EPA) in plasma phospholipid fatty acids (> 5% total fatty acids) while taking fish oil over a 3-year period (n = 18). We examined cellular content of arachidonic acid (AA), synthesis of thromboxane A2 and prostaglandin E2, use of nonsteroidal antiinflammatory drugs (NSAID), traditional CV lipid risk factors, and disease activity at 3 years.

RESULTS: At 3 years, AA (as a proportion of AA plus long-chain n-3 fatty acids that can compete with AA for cyclooxygenase metabolism) was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in subjects taking fish oil. Serum thromboxane B2 was 35% lower and lipopolysaccharide-stimulated whole-blood prostaglandin E2 was 41% lower with fish oil ingestion compared to no fish oil. NSAID use was reduced by 75% from baseline with fish oil (p < 0.05) and by 37% without fish oil (NS). Favorable changes in fasting blood lipids were seen with, but not without fish oil. Remission at 3 years was more frequent with fish oil use (72%) compared to no fish oil (31%).

CONCLUSION: Fish oil reduces cardiovascular risk in patients with RA through multiple mechanisms.