Mozaffarian D, Bryson CLJ, et al. Fish intake and risk of incident heart failure. Am Coll Cardiology, 2005;45(12):2015-2021

OBJECTIVES:
Our aim was to investigate the relation between fish consumption and incidence of congestive heart failure (CHF).

BACKGROUND:
The incidence and health burden of CHF are rising, particularly in older persons. Although n-3 fatty acids have effects that could favorably influence risk of CHF, the relation between fish intake and CHF incidence is unknown.

METHODS:
Among 4,738 adults age > or =65 years and free of CHF at baseline in 1989-90, usual dietary intake was assessed using a food frequency questionnaire. In a participant subsample, consumption of tuna or other broiled or baked fish, but not fried fish, correlated with plasma phospholipid n-3 fatty acids. Incidence of CHF was prospectively adjudicated.

RESULTS:
During 12 years' follow-up, 955 participants developed CHF. In multivariate-adjusted analyses,tuna/other fish consumption was inversely associated with incident CHF, with 20% lower risk with intake 1 to 2 times/week (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.64 to 0.99), 31% lower risk with intake 3 to 4 times/week (HR = 0.69, 95% CI = 0.52 to 0.91), and 32% lower risk with intake > or =5 times/week (HR = 0.68, 95% CI = 0.45 to 1.03), compared with intake <1 time/month (p trend = 0.009).

In similar analyses, fried fish consumption was positively associated with incident CHF (p trend = 0.01). Dietary long-chain n-3 fatty acid intake was also inversely associated with CHF (p trend = 0.009), with 37% lower risk in the highest quintile of intake (HR = 0.73, 95% CI = 0.57 to 0.94) compared with the lowest.

CONCLUSIONS:
Among older adults, consumption of tuna or other broiled or baked fish, but not fried fish, is associated with lower incidence of CHF. Confirmation in additional studies and evaluation of potential mechanisms is warranted.

PMID: 15963403

von Schacky, Clemens, et al. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. Annals of Internal Medicine, 1999;130: 554-562.

A recent study has investigated the beneficial effects of fish oil supplementation and atherosclerosis. A randomized, double-blind, placebo-controlled clinical trial involved 162 patients with confirmed atherosclerosis. Half the patients were given 6 grams of fish oils per day for three months while the other half were given 6 grams per day of placebo capsules containing a fatty acid composition resembling that of the average European diet. After three months the dosages were reduced to 3 grams/day for a further 21 months. Angiograms were taken at the start of the trial and at the end of the two-year study period. At the end of the treatment twice as many of the patients in the fish oil group (16) showed regression of their atherosclerotic deposits when compared to the placebo group. Three patients in the placebo group suffered a nonfatal heart attack during the 2-year period as compared to only one in the fish oil group. Seven patients in the placebo group had a cardiovascular event (heart attack or stroke) as compared to only two in the fish oil group. The researchers conclude that fish oil supplementation may be beneficial for atherosclerosis patients and is safe and well-tolerated.

Studer M, Briel M, et al. Effect of Different Antilipidemic Agents and Diets on Mortality, A Systematic Review. Arch Intern Med, 2005;165:725-730

Background: Guidelines for the prevention and treatment of hyperlipidemia are often based on trials using combined clinical end points.
Mortality data are the most reliable data to assess efficacy of interventions. We aimed to assess efficacy and safety of different lipid-lowering interventions based on mortality data.

Methods: We conducted a systematic search of randomized controlled trials published up to June 2003, comparing any lipid-lowering intervention with placebo or usual diet with respect to mortality.

Outcome measures were mortality from all, cardiac, and noncardiovascular causes.

Results: A total of 97 studies met eligibility criteria, with 137,140 individuals in intervention and 138,976 individuals in control groups. Compared with control groups, risk ratios for overall mortality were 0.87 for statins (95% confidence interval [CI], 0.81-0.94), 1.00 for fibrates (95% CI, 0.91-1.11), 0.84 for resins (95% CI, 0.66-1.08), 0.96 for niacin (95% CI, 0.86-1.08), 0.77 for n-3 fatty acids (95% CI, 0.63-0.94), and 0.97 for diet (95% CI, 0.91-1.04).

Compared with control groups, risk ratios for cardiac mortality indicated benefit from statins (0.78; 95% CI, 0.72-0.84), resins (0.70; 95% CI, 0.50-0.99) and n-3 fatty acids (0.68; 95% CI, 0.52-0.90).

Risk ratios for noncardiovascular mortality of any intervention indicated no association when compared with control groups, with the exception of fibrates (risk ratio, 1.13; 95% CI, 1.01-1.27).

Conclusions: Statins and n-3 fatty acids are the most favorable lipid-lowering interventions with reduced risks of overall and cardiac mortality.

Any potential reduction in cardiac mortality from fibrates is offset by an increased risk of death from noncardiovascular causes.

Madsen T, Skou HA, Hansen VE, et al. C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease. Am J Cardiol, 2001; 88(10): 1139-1142.

The acute-phase reactant C-reactive protein (CRP) has emerged as an independent risk factor for coronary artery disease. Experimental and clinical studies provide evidence of anti-inflammatory effects of n-3 polyunsaturated fatty acids (PUFA) derived from fish.

We have studied the effect of marine n-3 PUFA on CRP levels in 269 patients referred for coronary angiography because of clinical suspicion of coronary artery disease. All patients filled out a food questionnaire regarding fish intake.

The n-3 PUFA content of granulocyte membranes was determined and the concentration of CRP in serum was measured using a highly sensitive assay. The results were related to angiographic findings. CRP was significantly higher in patients with significant coronary stenoses than in those with no significant angiographic changes (p <0.001), but the CRP levels were not associated with the number of diseased vessels.

Subjects with CRP levels in the lower quartile had a significantly higher content of docosahexaenoic acid (DHA) in granulocytes than subjects with CRP levels in the upper quartile (p = 0.02), and in a multivariate linear regression analysis, DHA was independently correlated to CRP (R(2) = 0.179; p = 0.003).

The inverse correlation between CRP and DHA may reflect an anti-inflammatory effect of DHA in patients with stable coronary artery disease and suggest a novel mechanism by which fish consumption may decrease the risk of coronary artery disease.

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.

Nestel P, Shige H, et al. The Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid increase systemic arterial compliance in humans Am. J. 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.

Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nut 1991;54:438-463.

Several sources of information suggest that man evolved on a diet with a ratio of omega 6 to omega 3 fatty acids of approximately 1 whereas today this ratio is approximately 10:1 to 20-25:1, indicating that Western diets are deficient in omega 3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. Omega-3 fatty acids increase bleeding time; decrease platelet aggregation, blood viscosity, and fibrinogen; and increase erythrocyte deformability, thus decreasing the tendency to thrombus formation.

In no clinical trial, including coronary artery graft surgery, has there been any evidence of increased blood loss due to ingestion of omega 3 fatty acids.

Many studies show that the effects of omega 3 fatty acids on serum lipids depend on the type of patient and whether the amount of saturated fatty acids in the diet is held constant.
In patients with hyperlipidemia, omega 3 fatty acids decrease low-density-lipoprotein (LDL) cholesterol if the saturated fatty acid content is decreased, otherwise there is a slight increase, but at high doses (32 g) they lower LDL cholesterol; furthermore, they consistently lower serum triglycerides in normal subjects and in patients with hypertriglyceridemia whereas the effect on high-density lipoprotein (HDL) varies from no effect to slight increases.

The discrepancies between animal and human studies most likely are due to differences between animal and human metabolism. In clinical trials eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oils along with antirheumatic drugs improve joint pain in patients with rheumatoid arthritis; have a beneficial effect in patients with ulcerative colitis; and in combination with drugs, improve the skin lesions, lower the hyperlipidemia from etretinates, and decrease the toxicity of cyclosporin in patients with psoriasis.

In various animal models omega 3 fatty acids decrease the number and size of tumors and increase the time elapsed before appearance of tumors.

Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants.

Because omega 3 fatty acids are essential in growth and development throughout the life cycle, they should be included in the diets of all humans.

Omega-3 and omega 6 fatty acids are not interconvertible in the human body and are important components of practically all cell membranes.

Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake.

Yuan J-M, Ross R, Gao Y-T, and Yu M. Fish and Shellfish Consumption in Relation to Death from Myocardial Infarction among Men in Shanghai, China. American Journal of Epidemiology 2001;154(9):809-816

Between 1986 and 1989, 18,244 men aged 45?64 years in Shanghai, China, participated in a prospective study of diet and cancer. All participants completed an in-person, structured interview and provided blood and urine samples. As of September 1, 1998, 113 deaths from acute myocardial infarction were identified.

After analyses were adjusted for age, total energy intake, and known cardiovascular disease risk factors, men who consumed 200 g of fish/shellfish per week had a relative risk of 0.41 (95% confidence interval: 0.22, 0.78) for fatal acute myocardial infarction compared with men consuming <50 g per week.

Similarly, dietary intake of n-3 fatty acids derived from seafood also was significantly associated with reduced mortality from myocardial infarction. Neither dietary seafood nor n-3 fatty acid intake was associated with a reduced risk of death from stroke or ischemic heart disease other than acute myocardial infarction.

However, approximately a 20% reduction in total mortality associated with weekly fish/shellfish intake was observed in the study population (relative risk = 0.79, 95% confidence interval: 0.69, 0.91). These prospective data suggest that eating fish and shellfish weekly reduces the risk of fatal myocardial infarction in middle-aged and older men in Shanghai, China.

Kottke TE, Wu LA, Brekke LN, et al. Preventing Sudden Death with n-3 (Omega-3) Fatty Acids and Defibrillators. Am J Prev Med.,2006;31(4):316-323.

BACKGROUND: Because interventions that prevent and treat events due to cardiovascular disease are applied to different, but overlapping, segments of the population, it can be difficult to estimate their effectiveness if formal calculations are not available.

METHODS: Markov chain analysis, including sensitivity analysis, was used with a hypothetical population resembling that of Olmsted County, MN, aged 30 to 84 in the year 2000 to compare the estimated impact of three interventions to prevent sudden death: (1) raising blood levels of n-3 (omega-3) fatty acids, (2) distributing automated external defibrillators (AEDs), and (3) implanting cardioverter defibrillators (ICDs) in appropriate candidates. The analysis was performed in 2004, 2005, and 2006.

RESULTS: Raising median n-3 fatty acid levels would be expected to lower total mortality by 6.4% (range from sensitivity analysis=1.6% to 10.3%). Distributing AEDs would be expected to lower total mortality by 0.8% (0.2% to 1.3%), and implanting ICDs would be expected to lower total mortality by 3.3% (0.6% to 8.7%). Three fourths of the reduction in total mortality due to n-3 fatty acid augmentation would accrue from raising n-3 fatty acid levels in the healthy population.

CONCLUSIONS: Based on central values of candidacy and efficacy, raising n-3 fatty acid levels would have about eight times the impact of distributing AEDs and two times the impact of implanting ICDs.
Raising n-3 fatty acid levels would also reduce rates of sudden death among the subpopulation that does not qualify for ICDs.

Buckley JD, Burgess S, Murphy KJ, Howe PR. Effects of omega-3 polyunsaturated fatty acids on cardiovascular risk, exercise performance and recovery in Australian Football League (AFL) players. Asia Pac J Clin Nutr. 2005;14 Suppl:S57.

Background:
Long chain omega-3 polyunsaturated fatty acids (LCn-3) can improve cardiovascular (CV) function and reduce the risk of CV disease.
Studies have investigated the potential for these CV benefits to improve athletic performance without success, but none have investigated effects on recovery.

Objectives:
To examine the effect of LC n-3 on exercise performance, recovery, and CV risk in AFL players.

Design:
Twenty-five AFL players completed a five week training program during which they were randomised, double-blind, to consume six g/day of fish oil (FO; n=12, HiDHA(R), Numega Ingredients Pty Ltd) or sunflower oil (C; n=13).

At baseline and after five weeks erythrocyte (RBC) membrane LCn-3 content and fasting serum triglyceride (TG) concentrations were assessed, and players performed two treadmill runs (R1 and R2) to exhaustion separated by five min of recovery.Heart rate (HR) was monitored throughout each treadmill run. R1 assessed running performance while R2 assessed recovery (expressed as % of R1).

Outcomes:
After five weeks, RBC LCn-3 content had increased 47.4 +/- 11.2% in FO (P <0.001) and TG had decreased significantly compared with C (FO, -25.4 +/- 4.9%, C, 4.9 +/- 7.0%; P =0.002).

HR during steady-state submaximal exercise decreased significantly in FO compared with C (FO, -8 +/- 2 bpm, C -2 +/- 2 bpm; P =0.05).

Time to exhaustion during R1 increased in both groups (P <0.001) but by similar amounts (FO, 10.2 +/- 2.2%, C 17.3 +/- 4.3%; P =0.18).

Recovery did not change in either group (FO, -2.6 +/- 10.9%, C -13.5 +/- 6.0%; P =0.87).

Conclusion:
Five weeks of supplementing AFL players with LCn-3 reduced HR during submaximal exercise and fasting TG, reflecting improved CV function and decreased CV risk, but did not enhance endurance exercise performance or recovery.

PMID: 16326521

Virtanen J, Voutilainen S. Mercury, Fish Oils, and Risk of Acute Coronary Events and Cardiovascular Disease, Coronary Heart Disease, and All-Cause Mortality in Men in Eastern Finland. Arteriosclerosis, Thrombosis, and Vascular Biology 2005;25:228.

Objective Mercury has been suggested to have negative effects on cardiovascular health. We investigated the effects of high mercury content in hair on the risk of acute coronary events and cardiovascular and all-cause mortality in men from eastern Finland.

Methods and Results The population-based prospective Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort of 1871 Finnish men aged 42 to 60 years and free of previous coronary heart disease (CHD) or stroke at baseline was used. During an average follow-up time of 13.9 years, 282 acute coronary events and 132 cardiovascular disease (CVD), 91 CHD, and 525 all-cause deaths occurred. Men in the highest third of hair mercury content (>2.03 µg/g) had an adjusted 1.60-fold (95% CI, 1.24 to 2.06) risk of acute coronary event, 1.68-fold (95% CI, 1.15 to 2.44) risk of CVD, 1.56-fold (95% CI, 0.99 to 2.46) risk of CHD, and 1.38-fold (95% CI, 1.15 to 1.66) risk of any death compared with men in the lower two thirds. High mercury content in hair also attenuated the protective effects of high-serum docosahexaenoic acid plus docosapentaenoic acid concentration.

Conclusions High content of mercury in hair may be a risk factor for acute coronary events and CVD, CHD, and all-cause mortality in middle-aged eastern Finnish men. Mercury may also attenuate the protective effects of fish on cardiovascular health.

Mercury may increase the risk of cardiovascular diseases. In this study, high mercury content in hair increased the risk of cardiovascular morbidity and mortality in middle-aged Finnish men and attenuated the beneficial effects of fish oils on cardiovascular health. Regular consumption of fish with high mercury content should be avoided.

Kris-Etherton PM, Harris WS; Appel LJ, for the AHA Nutrition Committee. Omega-3 Fatty Acids and Cardiovascular Disease. New Recommendations From the American Heart Association. Arter,Thromb & Vasc Bio.,2003;23:151-152.

Since the original American Heart Association (AHA) Science Advisory was published in 1996, important new findings have been reported about the benefits of omega-3 fatty acids on cardiovascular disease (CVD).

Omega-3 fatty acids are obtained from two dietary sources: seafood and certain nut and plant oils. Fish and fish oils contain the 20-carbon eicosapentaenoic acid (EPA) and the 22-carbon docosahexaenoic acid (DHA), whereas canola, walnut, soybean, and flaxseed oils contain the 18-carbon alpha-linolenic acid (ALA). ALA appears to be less potent than EPA and DHA.

The evidence supporting the clinical benefits of omega-3 fatty acids derive from population studies and randomized, controlled trials, and new information has emerged regarding the mechanisms of action of these nutrients. These are outlined in a recent Scientific Statement, "Fish Consumption, Fish Oil, Omega-3 Fatty Acids and Cardiovascular Disease."

Simopoulos A. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother, 2002; 56(8): 365-379

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1.

Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established.

Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects.

In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect.

The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences.

These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial.

Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition.

A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries, that are being exported to the rest of the world.

PMID: 12442909

Holguin F, T?ez-Rojo MM, Lazo M, et al. Cardiac Autonomic Changes Associated With Fish Oil vs Soy Oil Supplementation in the Elderly. Chest, 2005;127:1102-1107.

Introduction:
Omega-3 fatty acid levels are associated with decreased risk for sudden death; however, the protective cardiovascular mechanisms of omega-3 are poorly understood.

This study addresses the heart rate variability (HRV) changes in a cohort of elderly subjects randomized to receive either a daily high dose of marine-derived omega-3 fatty acids (fish oil) or a lower daily dose of a plant-derived omega-3 fatty acid (alpha-linolenic acid) in soy oil.

Methods:
A total of 58 elderly nursing home residents were randomized to receive 2 g/d of fish oil capsules vs 2 g/d of soy oil capsules, and were subsequently followed up every other day for a period of 6 months with 6-min measurements of HRV while resting supine.
An initial control period of 2 months without supplementation was allowed to establish an HRV baseline for each participant.

Results:
The average time- and frequency-domain parameters of HRV increased significantly during the supplementation period in both the fish oil and soy oil groups.
In the regression model after adjusting for age and mean heart rate, supplementation with fish oil was associated with a significant increase in the high- and low-frequency components, and SD of normal RR intervals (SDNN), whereas only SDNN increased significantly in the soy oil group.

Conclusions:
Supplementation with 2 g/d of fish oil was well tolerated and was associated with a significant increase in HRV.
Supplementation with 2 g/d of soy oil was associated with a lesser but significant increase in HRV.

Lichtenstein A, Appel L, Brands M, et al. Diet and Lifestyle Recommendations Revision 2006: A Scientific Statement From the American Heart Association Nutrition Committee. Circulation 2006;114:82-96.

AHA Scientific Statement

Improving diet and lifestyle is a critical component of the American Heart Association's strategy for cardiovascular disease risk reduction in the general population.

This document presents recommendations designed to meet this objective.

Specific goals are to consume an overall healthy diet; aim for a healthy body weight; aim for recommended levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides; aim for normal blood pressure; aim for a normal blood glucose level; be physically active; and avoid use of and exposure to tobacco products.

The recommendations are to balance caloric intake and physical activity to achieve and maintain a healthy body weight; consume a diet rich in vegetables and fruits; choose whole-grain, high-fiber foods; consume fish, especially oily fish, at least twice a week; limit intake of saturated fat to <7% of energy, trans fat to <1% of energy, and cholesterol to <300 mg/day by choosing lean meats and vegetable alternatives, fat-free (skim) or low-fat (1% fat) dairy products and minimize intake of partially hydrogenated fats; minimize intake of beverages and foods with added sugars; choose and prepare foods with little or no salt; if you consume alcohol, do so in moderation; and when you eat food prepared outside of the home, follow these Diet and Lifestyle Recommendations.

By adhering to these diet and lifestyle recommendations, Americans can substantially reduce their risk of developing cardiovascular disease, which remains the leading cause of morbidity and mortality in the United States.

Kris-Etherton PM, Harris WS, Appel LJ. AHA Scientific Statement. Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease. Circulation. 2002;106:2747-2757.

Since the first AHA Science Advisory "Fish Consumption, Fish Oil, Lipids, and Coronary Heart Disease," important new findings, including evidence from randomized controlled trials (RCTs), have been reported about the beneficial effects of omega-3 (or n-3) fatty acids on cardiovascular disease (CVD) in patients with preexisting CVD as well as in healthy individuals.

New information about how omega-3 fatty acids affect cardiac function (including antiarrhythmic effects), hemodynamics (cardiac mechanics), and arterial endothelial function have helped clarify potential mechanisms of action. The present Statement will address distinctions between plant-derived (alpha-linolenic acid, C18:3n-3) and marine-derived (eicosapentaenoic acid, C20:5n-3 [EPA] and docosahexaenoic acid, C22:6n-3 [DHA]) omega-3 fatty acids. (Unless otherwise noted, the term omega-3 fatty acids will refer to the latter.)

Evidence from epidemiological studies and RCTs will be reviewed, and recommendations reflecting the current state of knowledge will be made with regard to both fish consumption and omega-3 fatty acid (plant- and marine-derived) supplementation.

This will be done in the context of recent guidance issued by the US Environmental Protection Agency and the Food and Drug Administration (FDA) about the presence of environmental contaminants in certain species of fish.

Hu F, Cho E, et al. Fish and Long-Chain -3 Fatty Acid Intake and Risk of Coronary Heart Disease and Total Mortality in Diabetic Women. Circulation 2003;107:1852-1857.

Background Although several prospective cohort studies have found an inverse association between fish consumption and risk of coronary heart disease (CHD) or sudden cardiac death in the general population, limited data are available among diabetic patients.

Methods and Results We examined prospectively the association between intake of fish and -3 fatty acids and risk of CHD and total mortality among 5103 female nurses with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Between 1980 and 1996 (45 845 person-years of follow-up), we documented 362 incident cases of CHD (141 CHD deaths and 221 nonfatal myocardial infarctions) and 468 deaths from all causes. Compared with women who seldom consumed fish (<1 serving/mo), the relative risks (RRs) (95% CI) of CHD adjusted for age, smoking, and other established coronary risk factors were 0.70 (0.48 to 1.03) for fish consumption 1 to 3 times per month, 0.60 (0.42 to 0.85) for once per week, 0.64 (0.42 to 0.99) for 2 to 4 times per week, and 0.36 (0.20 to 0.66) for 5 or more times per week (P for trend=0.002). Higher consumption of fish was also associated with a significantly lower total mortality (multivariate RR=0.48 [0.29 to 0.80] for 5 times per week [P for trend=0.005]). Higher consumption of long-chain -3 fatty acids was associated with a trend toward lower incidence of CHD (RR=0.69 [95% CI 0.47 to 1.03], P for trend=0.10) and total mortality (RR=0.63 [95% CI, 0.45 to 0.88], P for trend=0.02).

Conclusions A higher consumption of fish and long-chain -3 fatty acids was associated with a lower CHD incidence and total mortality among diabetic women

Jouven X, Charles M, Desnos M, et al. Circulating Nonesterified Fatty Acid Level as a Predictive Risk Factor for Sudden Death in the Population. Circulation 2001;104:756-761.

Background In ischemic conditions, concentration of circulating nonesterified fatty acids (NEFA) is increased and has a proarrhythmic effect that is responsible for ventricular tachyarrhythmias. In nonischemic patients, high NEFA plasma concentration has been shown to be associated with frequent premature ventricular complexes and increased familial risk of cardiovascular disease, but its relation to sudden death has not been studied. We assessed the role of circulating NEFA in sudden death in asymptomatic men in a long-term cohort study.

Methods and Results A total of 5250 men employed by the city of Paris, aged 42 to 53 in 1967 to 1972, free of known ischemic cardiac disease, and included in the Paris Prospective Study I, completed a second annual examination and had fasting plasma circulating NEFA measured. Each subject underwent a physical examination and ECG, provided blood for laboratory tests, and answered questionnaires administered by trained interviewers. Vital status was obtained for each subject from specific inquiries until he retired; after retirement, it was obtained from death certificates. Body mass index, systolic and diastolic blood pressures, tobacco consumption, parental history of sudden death, fasting cholesterol level, and circulating NEFA concentration were independent factors associated with sudden death during follow up (average, 22 years). When adjusted for confounding factors, circulating NEFA concentration remained an independent risk factor for sudden death (relative risk, 1.70; 95% confidence interval, 1.21 to 2.13) but not for fatal myocardial infarction.

Conclusions Circulating NEFA concentration is an independent risk factor for sudden death in middle-aged men. Some form of primary prevention could be envisaged in subjects at high risk of sudden death.

Marchioli R, Barzi F, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results [ ]. Circulation, 2002;105:1897-1903.

BACKGROUND: Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (<3 months) myocardial infarction.

METHODS AND RESULTS: In this study, 11,323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; P=0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; P=0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths.

CONCLUSIONS: The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.

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;112:1945-1952.

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.

White Paper. Heart Health: The Role of Eicosapentaenoic, Docosahexaenoic, & Alpha-Linolenic Acids (EPA, DHA, and ALA)

Source: http://www.crnusa.org/pdfs/CRNo3wg_whitepaper.pdf

Umhau J, K M Dauphinais K, Patel S, et al. The relationship between folate and docosahexaenoic acid in men. European Journal of Clinical Nutrition 2006:60;352?357.

Objective: Docosahexaenoic acid (DHA, 22:6n-3), an essential omega 3 fatty acid, may protect against disorders of emotional regulation as well as cardiovascular disease. Animal studies demonstrate that dietary folate can increase tissue concentrations of DHA, although the literature, to date, includes no human studies examining the possibility that folate status may affect plasma DHA concentrations.

The objective of this study is to determine if the blood concentrations of folate and DHA are correlated in humans.

Design: Retrospective study.

Setting: An American research hospital.

Subjects: A total of 15 normal and 22 hostile and aggressive subjects, with a mean age of 38 years.

Methods: Concentrations of plasma polyunsaturated essential fatty acids and red blood cell folate (RBC folate) were obtained prior to 1996, before American flour was enriched with folate.

Results: RBC folate was significantly correlated with plasma DHA, r=0.57, P=0.005 in the aggressive group. Age, smoking and alcohol consumption did not alter the results. No other essential fatty acids were significantly associated with RBC folate in either group.

Conclusions: The positive relationship between plasma DHA and RBC folate concentrations suggests that these two nutrients should be examined together in order to make the most accurate inferences about their relative contributions to disease pathogenesis.

Our findings present one explanation why some conditions associated with hostility and low DHA status, such as cardiovascular disease and emotional disorders, are also associated with low folate status.

Walser B, Giordano RM, Stebbins CL. Supplementation with omega-3 polyunsaturated fatty acids augments brachial artery dilation and blood flow during forearm contraction. Eur J Appl Physiol. 2006 [Epub ahead of print]

Omega-3 polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have beneficial effects on the heart and vasculature.

We tested the hypothesis that 6 weeks of dietary supplementation with DHA (2.0 g/day) and EPA (3.0 g/day) enhances exercise-induced increases in brachial artery diameter and blood flow during rhythmic exercise.

In seven healthy subjects, blood pressure, heart rate and brachial artery diameter, blood flow, and conductance were assessed before and during the last 30 s of 90 s of rhythmic handgrip exercise (30% of maximal handgrip tension). Blood pressure (MAP), heart rate (HR), and brachial artery vascular conductance were also determined. This paradigm was also performed in six other healthy subjects who received 6 weeks of placebo (safflower oil).

Placebo treatment had no effect on any variable. DHA and EPA supplementation enhanced contraction-induced increases in brachial artery diameter (0.28 +/- 0.04 vs. 0.14 +/- 0.03 mm), blood flow (367 +/- 65 vs. 293 +/- 55 ml min-1) and conductance (3.86 +/- 0.71 vs. 2.89 +/- 0.61 ml min-1 mmHg-1) (P < 0.05). MAP and HR were unchanged.

Results indicate that treatment with DHA and EPA enhances brachial artery blood flow and conductance during exercise. These findings may have implications for individuals with cardiovascular disease and exercise intolerance (e.g., heart failure).

PMID: 16636858

Wendland E, Farmer AJ, Paul G, and A Neil. Effect of alpha-linolenic acid on cardiovascular risks markers: a systematic review. Heart. May, 2005; 10.1136/hrt.2004.053538.

Objective: To determine whether dietary supplementation with alpha-linolenic acid (ALA) can modify established and emerging cardiovascular risk markers.

Design: Systematic review and meta-analysis of randomised controlled trials.

Setting: MEDLINE, Embase, Cochrane register of controlled trials and the metaRegister of controlled trials were searched.

Patients: All studies carried out in humans were included in the review.

Main outcome measures: Total cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, triglyceride, fibrinogen and fasting plasma glucose, changes in body mass index, weight, and systolic and diastolic blood pressure.

Results: Fourteen studies with minimum treatment duration of 4 weeks were included. ALA had a significant effect on three of the 32 outcomes examined in these studies reducing the levels of fibrinogen (0.17 µmol/l [95% CI -0.30 to -0.04], p=0.01) and fasting plasma glucose (0.20 mmol/l [95% CI -0.30 to -0.10], p<0.01), and there was a small but clinically unimportant increase in high-density lipoprotein (0.01 mmol/l [95% CI -0.02 to 0.00], p<0.01)

Treatment with ALA did not significantly modify total cholesterol, triglycerides, weight, body mass index, low-density lipoprotein, diastolic blood pressure, systolic blood pressure, very low-density lipoprotein (VLDL) and apolipoprotein-B.

Conclusions: Although ALA supplementation may causes small decreases in fibrinogen levels and fasting plasma glucose, there appears to be no effect on most cardiovascular risk markers.
Further trials are needed, but dietary supplementation with ALA to reduce cardiovascular disease cannot currently be recommended.

Mozaffarian D, Eric B. Rimm EB. Fish Intake, Contaminants, and Human Health. Evaluating the Risks and the Benefits. J Am Medical Assoc,2006;296(15):1885-1899.

Context: Fish (finfish or shellfish) may have health benefits and also contain contaminants, resulting in confusion over the role of fish consumption in a healthy diet.

Evidence Acquisition: We searched MEDLINE, governmental reports, and meta-analyses, supplemented by hand reviews of references and direct investigator contacts, to identify reports published through April 2006 evaluating (1) intake of fish or fish oil and cardiovascular risk, (2) effects of methylmercury and fish oil on early neurodevelopment, (3) risks of methylmercury for cardiovascular and neurologic outcomes in adults, and (4) health risks of dioxins and polychlorinated biphenyls in fish.

We concentrated on studies evaluating risk in humans, focusing on evidence, when available, from randomized trials and large prospective studies. When possible, meta-analyses were performed to characterize benefits and risks most precisely.

Evidence Synthesis: Modest consumption of fish (eg, 1-2 servings/wk), especially species higher in the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduces risk of coronary death by 36% (95% confidence interval, 20%-50%; P<.001) and total mortality by 17% (95% confidence interval, 0%-32%; P = .046) and may favorably affect other clinical outcomes. Intake of 250 mg/d of EPA and DHA appears sufficient for primary prevention.

DHA appears beneficial for, and low-level methylmercury may adversely affect, early neurodevelopment. Women of childbearing age and nursing mothers should consume 2 seafood servings/wk, limiting intake of selected species.

Health effects of low-level methylmercury in adults are not clearly established; methylmercury may modestly decrease the cardiovascular benefits of fish intake. A variety of seafood should be consumed; individuals with very high consumption (5 servings/wk) should limit intake of species highest in mercury levels. Levels of dioxins and polychlorinated biphenyls in fish are low, and potential carcinogenic and other effects are outweighed by potential benefits of fish intake and should have little impact on choices or consumption of seafood (women of childbearing age should consult regional advisories for locally caught freshwater fish).

Conclusions: For major health outcomes among adults, based on both the strength of the evidence and the potential magnitudes of effect, the benefits of fish intake exceed the potential risks. For women of childbearing age, benefits of modest fish intake, excepting a few selected species, also outweigh risks.

Hu FB, Bronner L, et al. Fish and Omega-3 Fatty Acid Intake and Risk of Coronary Heart Disease in Women. JAMA. 2002;287(14): 1815-1821.

CONTEXT: Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD) in men, but limited data are available regarding women.

OBJECTIVE: To examine the association between fish and long-chain omega-3 fatty acid consumption and risk of CHD in women.

DESIGN, SETTING, AND PARTICIPANTS: Dietary consumption and follow-up data from 84,688 female nurses enrolled in the Nurses' Health Study, aged 34 to 59 years and free from cardiovascular disease and cancer at baseline in 1980, were compared from validated questionnaires completed in 1980, 1984, 1986, 1990, and 1994. MAIN

OUTCOME MEASURES: Incident nonfatal myocardial infarction and CHD deaths.

RESULTS: During 16 years of follow-up, there were 1513 incident cases of CHD (484 CHD deaths and 1029 nonfatal myocardial infarctions). Compared with women who rarely ate fish (<1 per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking, and other cardiovascular risk factors, the multivariable relative risks (RRs) of CHD were 0.79 (95% confidence interval [CI], 0.64-0.97) for fish consumption 1 to 3 times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for 2 to 4 times per week, and 0.66 (95% CI, 0.50-0.89) for 5 or more times per week (P for trend =.001). Similarly, women with a higher intake of omega-3 fatty acids had a lower risk of CHD, with multivariable RRs of 1.0, 0.93, 0.78, 0.68, and 0.67 (P<.001 for trend) across quintiles of intake. For fish intake and omega-3 fatty acids, the inverse association appeared to be stronger for CHD deaths (multivariate RR for fish consumption 5 times per week, 0.55 [95% CI, 0.33-0.90] for CHD deaths vs 0.73 [0.51-1.04]) than for nonfatal myocardial infarction.

CONCLUSION: Among women, higher consumption of fish and omega-3 fatty acids is associated with a lower risk of CHD, particularly CHD deaths.

The Journal of the American Medical Association 2002; 288: 3130-3136

Men who eat fish once a month or more have a reduced risk of ischemic stroke, compared with those who eat fish less often, according to researchers reporting in the December 25 issue of The Journal of the American Medical Association (JAMA).

The authors noted that the effect of fish consumption or long-chain omega-3 polyunsaturated fatty acid (PUFA) intake on risk of stroke remains uncertain. They set out to examine further this relation between fish intake and risk of stroke in men.

Dr Ka He, from the Harvard School of Public Health, Boston, and colleagues, studied more than 43,000 men participating in the Health Professional Follow-up Study (HPFS), a large cohort of men who periodically completed dietary measurements during 12 years of follow-up.

The men aged 40 to 75 years completed a detailed and validated food frequency questionnaire and were free from cardiovascular diseases at baseline in 1986. The researchers determined the relative risk (RR) of stroke by subtype based on the cumulative average fish consumption or long-chain Omega-3 fatty acid intake, ascertained in 1986, 1990, and 1994.

In the 12 year follow-up, 608 participants developed stroke. Among these cases, 377 were confirmed as ischemic stroke, 106 were identified as haemorrhagic stroke, and the remainder could not be classified from the available medical documentation.

"For cumulative average fish consumption, the risk of ischemic stroke was lower among men in each category of fish consumption compared with those who ate fish less than once per month. Even a small amount of fish consumption (1-3 times per month) was associated with a significant reduction of 43 percent in risk of ischemic stroke," wrote the authors.

However no further benefit was observed at higher levels of fish intake. The RR for those who ate fish five or more times per week was 46 percent lower, they said.

Men who consumed fish at least once per month had a 44 percent lower risk of ischemic stroke compared with those who ate fish less than once per month. Risk of haemorrhagic stroke was not significantly associated with fish intake.

Press Release

A new study explains how a diet high in oily fish like salmon and mackerel improves inflammatory conditions, particularly in combination with low doses of aspirin. In a study in the March 7 issue of The Journal of Experimental Medicine, Arita and colleagues identify an anti-inflammatory lipid in humans that is derived from an essential fatty acid in fish oil.

Fatty fish contain large amounts of omega-3 fatty acids--diet-derived essential fatty acids known to benefit patients with cardiovascular disease and arthritis. This research group recently identified a new class of aspirin-triggered bioactive lipids, called resolvins, the activity of which may in part explain the beneficial effects of omega-3 fatty acids. Resolvins are made from the omega-3 fatty acids by cellular enzymes and can reduce inflammation in mice. The main bioactive component of this class of lipids was identified in mice and named resolvin E1.

The researchers have now identified this lipid in plasma taken from volunteers given omega-3 fatty acids and aspirin. Human resolvin E1, the authors show, inhibits both the migration of inflammatory cells to sites of inflammation and the turning on of other inflammatory cells.

This study also reveals a potential pitfall of COX-2 inhibitors, drugs designed to block inflammation, which have been shown to have negative cardiovascular side effects. COX-2 is involved in making resolvin E1 and the authors suggest that inhibition of vascular COX-2 by these inhibitors might block the synthesis of resolvin E1, which would eliminate an important anti-inflammatory pathway. The experiment to prove this idea, however, has yet to be done.

Source: http://www.eurekalert.org/pub_releases/2005-03/joem-eof022405.php

Erkkilä AT, Matthan NR, et al. Higher plasma docosahexaenoic acid is associated with reduced progression of coronary-artery atherosclerosis in women with established coronary artery disease. J. Lipid Res., doi:10.1194/jlr.P600005-JLR200.

Fish, fish oil supplement, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and in some cases alpha-linolenic acid (ALA) intake have been associated with reduced risk of cardiovascular events and death.

The association between n-3 fatty acids in plasma lipids and progression of coronary-artery atherosclerosis was assessed among women with established coronary artery disease (CAD).

A prospective cohort study involved postmenopausal women (n=228) participating in the Estrogen Replacement and Atherosclerosis trial.

Quantitative coronary angiography was performed at baseline and after 3.2±0.6 (mean±SD) years. Women with plasma phospholipid DHA levels above the median, compared to below, exhibited less atherosclerosis progression as expressed by decline in minimum coronary artery diameter (-0.04±0.02 mm and -0.10±0.02 mm, respectively, P=0.007), or increase in percent stenosis (1.34±0.76% and 3.75±0.74%, respectively, P=0.006) and had fewer new lesions [2.0 (0.5-3.5) % of measured segments (95% confidence interval)] and 4.2 (2.8-5.6)%, respectively, P=0.009] after adjustments for cardiovascular risk factors.

Similar results were observed for DHA in the triglycerides. EPA and ALA in plasma lipids were not significantly associated with atherosclerosis progression.

Consistent with higher reported fish intake, higher levels of plasma triglyceride and phospholipid DHA is associated with less progression of coronary atherosclerosis in postmenopausal women with established CAD.

Sands SA, Reid KJ, Windsor SL, and WS Harris. The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes. Lipids, 2005; 40(4): 343-347.

Omega-3 FA are beneficial for cardiovascular health, reducing platelet aggregation, TG levels, and the risk of sudden death from myocardial infarction.

The percentage of EPA + DHA in red blood cells (RBC), also known as the Omega-3 Index, has recently been proposed as a risk marker for death from coronary heart disease (CHD).

The purpose of this study was to begin to explore the factors that can influence RBC EPA + DHA.

We collected information on the number of servings of tuna or nonfried fish consumed per month, as well as on age, gender, ethnicity, smoking status, the presence of diabetes, and body mass index (BMI) in 163 adults in Kansas City who were not taking fish oil supplements.

The average RBC EPA + DHA in this population was 4.9 +/- 2.1%. On a multivariate analysis, four factors significantly and independently influenced the Omega-3 Index: fish servings, age, BMI, and diabetes.

The Index increased by 0.24 units with each additional monthly serving of tuna or nonfried fish (P < 0.0001), and by 0.5 units for each additional decade in age (P < 0.0001).

The Index was 1.13% units lower in subjects with diabetes (P = 0.015) and decreased by 0.3% units with each 3-unit increase in BMI (P = 0.001).

Gender or smoking status had no effect, and the univariate relationship with ethnicity vanished after controlling for fish intake.

Given the importance of n-3 FA in influencing risk for death from CHD, further studies are warranted to delineate the nondietary factors that influence RBC EPA + DHA content.

EPA and DHA play important structural roles as components of cellular membranes. During the normal aging process, cell membranes become more rigid. This can adversely effect the function of tissues throughout the body, including the brain and eyes. There is increased incorporation of EPA and DHA into membrane phospholipids after ingestion of large amounts of marine n-3 fatty acids (Drevon, 1997).
Furthermore, blood cell membranes from animals fed marine n-3 fatty acids demonstrate significantly increased fluidity and flexibility (Hagve et al, 1993; Drevon et al., 1995). These effects may be responsible for the decreased blood viscosity and improved microcirculation observed after feeding marine n-3 fatty acids to animals (Ernst, 1989).

The more unsaturated fatty acids in our diet, the more fluid our cells become. DHA is the most unsaturated of all fatty acids and results in the most fluid cell membranes. Fluid membranes have a greater number of insulin receptors and more responsive receptors, resulting in heightened sensitivity to insulin.

References:
1. Simopoulos, Artemis P., Robinson, J. The Omega Plan, p. 82.) Drevon, CA., et al. 1995. Omega-3 fatty acids ? nutritional aspects. Can J Cardiol. 11(Supp G):47-54.

2. Hagve, TA., et al. 1993. The effect of dietary n-3 fatty acids on osmotic fragility and membrane fluidity of human erythrocytes. Scand J Clin Lab Invest. Suppl 215:75-84.

3. Ernst, E. 1989. Effect of n-3 fatty acids on blood rheulogy. J Internal Med. 225 (Suppl 1): 129-132.

Health Impact Study Finds Seniors Who Take Certain Dietary Supplements Live Longer, More Independent Lives; Savings Estimated to be Billions for U.S. Healthcare System

U.S. Newswire, Health Reporter

WASHINGTON, Nov. 2 /U.S. Newswire/ -- As the American population ages and U.S. healthcare costs skyrocket, taking certain dietary supplements could help seniors live independently longer, and offset healthcare expenditures by billions of dollars, a new study by The Lewin Group finds.

The supplements studied -- omega-3 fatty acids and lutein with zeaxanthin -- have reported savings of $3.1 billion and $2.5 billion respectively over five years, resulting from reduced hospitalizations, physicians' visits, and avoided transitions to dependency, the report shows.

"With healthcare costs for Americans 65 and older expected to reach $16 trillion by the year 2030, the need for innovative and preventative healthcare solutions is clearer than ever," said Elliott Balbert, Dietary Supplement Education Alliance (DSEA) president. "More than 187 million consumers rely on daily use of dietary supplements, and the supplement industry is pleased that this study reinforces the efficacy and health benefits of their usage."

Underscoring the important health and cost benefits of dietary supplements for the U.S. seniors, members of Congress took one step closer to recognizing the role of dietary supplements in the health regimen of Americans, when Rep. Chris Cannon (R-Utah) today announced the creation of a bipartisan caucus on dietary supplements, which he will co-chair with Rep. Frank Pallone (D-N.J.). Cannon introduced H.R. 1545 earlier this year, which would allow supplement costs to be paid by Flexible Spending Accounts (FSAs) and Health Savings Accounts (HSAs).

"As more and more Americans start taking responsibility for their own health, it's important that government acknowledge the positive impact dietary supplements have on disease prevention, and the substantial cost benefits to the healthcare system that result," said Cannon. "Clearly, there's cause for additional research and sound public policy supporting these products, which greatly benefit American consumers and taxpayers alike."

The study's key findings centered upon how omega-3 fatty acids and lutein with zeaxanthin allow seniors to avoid common conditions such as coronary heart disease (CHD) and age-related macular degeneration (AMD), helping them live independently longer and reducing the level of disability associated with these conditions.

The Food and Drug Administration (FDA) has issued a qualified health claim for omega-3 fatty acids and a qualified health claim is currently pending for lutein.

The FDA has acknowledged that consumers will benefit from more information on food labels concerning diet and health and this, in turn, has prompted the agency to establish interim procedures whereby "qualified" health claims can be made for dietary supplements. Health claims characterize a relationship between a substance (specific food component or a specific food) and a disease or health-related condition, and are supported by scientific evidence. All health claims must undergo review by FDA through a petition process.

The Lewin Group's analyses of existing research studied the health effects of the two supplements as they relate to reduction in risk of disease progression for adults over age 65. Using Congressional Budget Office cost accounting rules, Lewin calculated a conservative five-year savings estimate.

Key findings from the study include:

Omega-3 Fatty Acids

In 2002, the American Heart Association, using Federal survey data, estimated that 13 million Americans (or 6.9 percent of the U.S. population) suffer from CHD, which disproportionately affects older Americans.
The average age Americans experience a first heart attack is 65.8 for men and 70.4 for women. In 2000, the U.S. Food and Drug Administration recognized the efficacy of omega-3 fatty acids in dietary supplements for preventing CHD by issuing a qualified health claim.

The Lewin Group estimates potential five-year (2006-2010) savings in health care expenditures resulting from a reduction in the occurrence of CHD among the over age-65 population through daily intake of approximately 1,800 milligrams of omega-3 is $3.1 billion.

Approximately 384,303 hospitalizations and physician fees due to CHD could be avoided over the five-year period.

Lutein with Zeaxanthin

Visual impairment is one of the top four reasons for loss of independence. Age-related diseases of the eye are common (e.g., 35 percent of individuals aged 75 and older have AMD) and costly. For example, 18 percent of all hip fractures among seniors have been attributed to age-related vision loss. The transition to greater dependency, whether through getting more help at home or through moving to a nursing facility, places considerable financial burden on the older person, his or her family, and the health care system.

The Lewin Group estimates five-year (2006-2010) net savings from avoided transitions to dependency associated with a reduction in the relative risk of AMD through daily intake of 6-10 milligrams of lutein with zeaxanthin is $2.5 billion. Across the five year period, approximately 98,219 individuals could avoid the transition to dependence either in the community or a nursing facility that would accompany a loss of central vision resulting from advanced AMD.

"American consumers rely on dietary supplements to improve their overall health and well being, and this study represents a compelling body of evidence that supports what millions of Americans already know," said John Benninger, president-elect of DSEA. "We hope that The Lewin Group's most recent study will help further educate the public and policymakers that supplements are good for health, and good for health policy."

For more information about The Lewin Group's Health Impact Study, please visit http://www.supplementinfo.org.

Source: http://releases.usnewswire.com/GetRelease.asp?id=56082

The Sikh population, and potentially other Asian groups, could significantly reduce their risk of heart disease by increasing the amount of oily fish they eat, according to research released by the Food Standards Agency today.

In the UK, the risk of heart disease among Indian Asians is currently around twice the UK average.

The study, by the University of Reading, found that Sikh men and women consumed less of the fatty acids found mainly in fish oil, and more of those found in vegetable oils, than UK white men and women.

After a moderate intake of fish oil (4g per day for 12 weeks), the levels of beneficial fatty acids in the body increased in the Sikh group to levels similar to the white men and women studied. Results also showed that taking fish oil supplements reduced the risk of heart disease by changing levels of fats in the blood.

Dr Peter Sanderson, Nutrition Scientist at the Agency, said: ?This new research shows that Sikh men and women in the UK, who are at significantly higher than average risk of heart disease, have a low intake of fish. They therefore do not get the protective health benefits of fatty acids found in fish, especially oily fish.

'Eating at least two portions of fish a week, one of which should be oily fish such as salmon or mackerel, could significantly help reduce the risk of heart disease in Asian communities.

In the UK, admission to hospital with heart attack is about double the average in the Asian population, and early death from heart disease is 46% higher for Asian men and 51% higher for Asian women than the UK average.

Diabetes, which is associated with abnormal blood-fat levels, is also four times more likely in the Asian population, and diabetes is known to be linked to an increased risk of heart disease.

Source: http://www.food.gov.uk/news/newsarchive/oilyfish_sikhheartdiseaserisk

CRN ISSUES WHITE PAPER ON THE IMPORTANCE OF OMEGA-3 FATTY ACIDS FOR HEART HEALTH Evidence is Strongest for EPA and DHA Council for Responsible Nutrition

WASHINGTON, D.C., July 20, 2005
The Council for Responsible Nutrition?s (CRN) Omega-3 Working Group (O3WG) today released a white paper highlighting the importance of omega-3 fatty acids, especially EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), for heart health.

Ian Newton, executive director, CRN O3WG, stated, As scientific research builds for the benefit for marine-based omega-3s (EPA and DHA) and consumer interest in these products continues to grow, it is important to educate various audiences on the benefits obtained from the different types of omega-3 fatty acids. The CRN O3WG white paper helps clarify some of the differences.

Two government agencies, including the Food and Drug Administration (FDA) and the Agency for Healthcare Research and Quality (AHRQ), along with the American Heart Association (AHA), have independently reviewed the available evidence and all have reached a similar conclusion: when it comes to omega-3s and heart health, the evidence is strongest for EPA and DHA.

FDA has permitted use of a qualified health claim for dietary supplements and conventional foods containing EPA and DHA, stating, Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease. This health claim does not apply to omega-3 derived from plants such as flax or canola.

AHRQ, which is part of the U.S. Department of Health and Human Services, reviewed the evidence on omega-3s and cardiovascular disease in 2004 and concluded that omega-3 fatty acids help reduce the risk of having a heart attack or dying from heart disease. AHRQ noted that ?the evidence is strongest for fish or fish oil, which are the primary sources of EPA and DHA.

Another omega-3 fatty acid, alpha-linolenic acid (ALA) cannot be synthesized by the body and is therefore an essential fatty acid that must be obtained from the diet. Dietary ALA sources include grains, nuts, and plant oils such as canola and flax seed.

In the body, there is limited conversion of ALA to EPA and DHA. Therefore, to assist in maintaining a healthy heart and reducing the risk of cardiovascular disease, it is critical to obtain EPA and DHA directly from the diet, which means primarily from fatty fish (such as anchovies, sardines and salmon), from dietary supplements containing fish oils or algal oils, or from traditional foods fortified with EPA and DHA.

A number of other countries have established dietary recommendations of 0.3 to 0.5 grams per day for EPA plus DHA.

The American Heart Association and the Dietary Guidelines for Americans both recommend two meals of fatty fish per week for heart health, and this would equate to about 0.5 grams per day of EPA and DHA combined.

Since most North Americans eat very little fish and consume, on average, less than 0.1 grams of EPA and DHA per day, there is a need to take dietary supplements or foods fortified with EPA and DHA to help fill this nutritional gap.

A copy of the CRN O3WG white paper, titled Omega-3 Fatty Acids in Human Health: The Role of Eicosapentaenoic, Docosahexaenoic, and Alpha-Linolenic Acids in Heart Health, is available at http://www.crnusa.org/pdfs/CRNo3wg_whitepaper.pdf.

The Council for Responsible Nutrition (CRN) is one of the dietary supplement industrys leading trade associations. The CRN Omega-3 Working Group (CRN 03WG) consists of representatives from 22 fish and algal-based omega-3 ingredient suppliers and finished product manufacturers. The CRN 03WG was formed to ensure the highest standards are available for product quality and safety from manufacturers and marketers. The group also provides scientific information about the significant health benefits of marine based omega-3 EPA and DHA to ensure greater trade and consumer confidence in these beneficial nutrients.

By Kathleen Doheny
HealthDay Reporter

Daily supplements of fatty acid-rich fish oil may counteract the effects of air pollution on the heart, researchers report.

"The cardiac responses to air pollutants were dramatically reduced in those on fatty acids," said Dr. Fernando Holguin, an assistant professor of medicine at Emory University School of Medicine. He presented the research this week at the American Thoracic Society's annual meeting in San Diego.

Holguin's team tracked the cardiac health of 50 elderly people, all nursing home residents averaging 70 years of age and living in smog-plagued Mexico City.

Each resident received a one-gram oil capsule twice a day (once in the morning and again in the evening) containing omega-3 fatty acids. Half of the group received fish oil capsules and the other half soy oil capsules.

The researchers took ongoing measurements of each participant's cardiac function, focusing specifically on their heart rate variability. Heart-rate variability refers to the heart rate alterations from beat to beat.

"Exposure to the particles of air pollution reduces heart rate variability, and taking the omega-3 fatty acids increased it," Holguin explained. "Increased heart rate variability reduces heart disease risk."

The fish oil was much better at keeping heart rate healthy than was the soy oil, the Emory team found. "Those on soy oil had just marginal protection," Holguin said, while "those on fish oil had a complete abolishment of the effect of the [smog] particles on the heart."

Another expert, Dr. Zi-Jian Xu, a staff cardiologist at Santa Monica-UCLA Medical Center and an assistant clinical professor of medicine at the David Geffen School of Medicine, UCLA, said he is not surprised by the results. "Fish oil has been found to reduce cardiovascular events, mainly heart attack and stroke," he said. "It has also been shown to modestly reduce the risk of another heart attack. The theory is that omega-3 fatty acids can improve cardiovascular health."

The new finding is also consistent with previous research, Xu added.
Holguin advises that people follow the advice of the American Heart Association (AHA) with regards to their daily intake of omega-3 fatty acids.

The AHA currently recommends that individuals with documented heart disease eat about one gram of omega-3 fatty acids a day, preferably from fatty fish.

Source: http://healthinfo.cedars-sinai.edu/healthnews/healthday/050526HD525935.htm

DALLAS, May 27 Eating oily fish like salmon, tuna or bluefish at least twice a week can prevent sudden cardiac death because fatty acids in the fish block dangerous irregular heart rhythms, experts say in a review article in today?s issue of Circulation: Journal of the American Heart Association.

Epidemiologists have known for years that eating fish was associated with reduced risk of cardiovascular disease, but only recently have researchers had laboratory evidence to explain this effect, says review author Alexander Leaf, M.D., Jackson Professor of Clinical Medicine Emeritus, Harvard Medical School, Boston. Leaf and colleagues present a detailed explanation of how omega-3 (n-3) fish oils benefit the heart.

Animal experiments show that fatty acids from n-3 fish oils are stored in the cell membranes of heart cells and can prevent sudden cardiac death or fatal arrhythmias, Leaf says.

Arrhythmias are irregular heart rhythms. Leaf says that studies of individual heart cells demonstrated that the omega-3 essential polyunsaturated fatty acids (n-3 PUFAs) specifically block excessive sodium and calcium currents in the heart. Those excessive electrical discharges cause dangerous and erratic changes in heart rhythm.

The first clinical suggestion that n-3 PUFAs significantly benefited the heart came from a 1989 study in which 2,033 men with heart disease were given dietary advice on fat, fiber or fish. After two years the men who were told to eat fish at least twice a week had a 29 percent reduction in death. There was no benefit in either the fiber or fat groups.

Since about 50 percent to 60 percent of deaths in the setting of coronary heart disease are sudden cardiac death [deaths within one hour of symptoms of a heart attack] attributed to sustained ventricular arrhythmias the authors write, the reduction in deaths reported in this early study is probably evidence of fewer fatal arrhythmias.

This initial study was followed by a series of observational studies and controlled clinical trials. All arrived at the same conclusion: A diet rich in fatty fish reduced fatal heart attacks. But Leaf says that this protection was still not completely understood.

In early animal experiments, researchers demonstrated that animals fed a diet in which 12 percent of the calories came from saturated fat died of sustained ventricular fibrillation, but animals that were also fed n-3 PUFAs did not develop these dangerous arrhythmias when their coronary arteries were tied off.

But then Leaf and other researchers still needed to find out if there were any plausible biochemical or physiological effects of these n-3 fatty acids which could explain their antiarrhythmic action.To do so, they cultured neonatal heart cells from rats and observed them under the microscope. The cells clump together and the clump beats spontaneously, rhythmically and simultaneously just like the whole heart.

Using a video camera, Leaf and his colleagues taped the action of the cells and the effect of different toxic agents on the cells. They discovered that adding n-3 PUFA prevented arrhythmias induced in the cells.

Leaf and his colleagues conclude that n-3 fatty acids have been part of the human diet for some 2-4 million years during which our genes were adapting to our environment, including our diets. They are safe and have been listed on the GRAS list (generally regarded as safe) according to the FDA.

Leaf says that fresh or frozen fish are the best choices but canned tuna can be used if it is packed in water. Tuna packed in oil is not a good choice because the extra oil will extract the beneficial n-3 oil from the fish, he says.

According to a recent American Heart Association scientific statement a dietary approach to increasing omega-3 fatty acid intake is preferable. Still, for patients with coronary artery disease, the dose of omega-3 (about one gram per day) may be greater than what can readily be achieved through diet alone. These individuals, in consultation with their physician, could consider supplements for CHD risk reduction.

The association recommends that individuals with certain cardiovascular conditions consult with their physician about fish oil supplements.

In an accompanying editorial, authors David S. Siscovick, M.D., Rozenn N. Lemaitre, Ph.D., and Dariush Mozaffarian, M.D. say the messages from Leaf and colleagues are clear.

For clinicians, it is time to implement the current American Heart Association dietary guidelines . . . For policymakers, there is a need to consider a new indication for treatment with low-dose n-3 PUFA supplements the prevention of sudden cardiac death in patients with a prior [heart attack]. For researchers, there is a need to continue both clinical studies and studies that explore the mechanism through which n-3 PUFAS influence the risk of sudden cardiac death, they write.

The American Heart Association estimates that sudden cardiac death causes 250,000 deaths in the United States each year.

Co-authors are Jing X. Kang, M.D., Ph.D.; Yong-Fu Xiao, M.D., Ph.D.; and George E. Billman, Ph.D. The study was partly funded by the National Institutes of Health and the American Heart Association.

Source: http://www.americanheart.org/presenter.jhtml?identifier=3012101

Turner R, McLean CH, Silvers KM. Are the health benefits of fish oils limited by products of oxidation? Nutrition Research Reviews, 2006;19:53-62.

Human clinical trials have shown that fish oils reduce the risk of a variety of disorders including CVD. Despite this, results have been inconsistent.

Fish oils are easily oxidised and some fish oils contain higher than recommended levels of oxidised products, but their effects have not been investigated. Recent evidence indicates that dietary oxidised fats can contribute to the development of atherosclerosis and thrombosis.

This review summarizes findings from cellular, animal and human trials that have examined the effects of oxidized lipids and their potential to affect health outcomes, and proposes that oxidized products in fish oils may attenuate their beneficial effects. More research is required to determine the magnitude of negative effects on fish oil on health outcomes in clinical trials.

Pound E, Kang J, Leaf A. Partitioning of polyunsaturated fatty acids, which prevent cardiac arrhythmias, into phospholipid cell membranes
J. Lipid Res., Mar 2001; 42: 346 - 351.

It has been demonstrated in animal studies that polyunsaturated fatty acids (PUFA) prevent ischemia-induced malignant ventricular arrhythmias, a major cause of sudden cardiac death in humans. To learn how these PUFA, at low micromolar concentrations, exert their antiarrhythmic activity, we studied their effects in vitro on the contractions of isolated cardiac myocytes and the conductances of their sarcolemmal ion channels. These fatty acids directly stabilize electrically every cardiac myocyte by modulating the conductances of specific ion channels in their sarcolemma. In this study, we determined the molar ratio of PUFA to the moles of phospholipid (PL) in cell membranes to learn if the ratio is so low as to preclude the possibility that the primary site of action of PUFA is on the packing of the membrane PL. [3H]-arachidonic acid (AA) was used to measure the incorporation of PUFA, and the inorganic phosphorous of the PL was determined as a measure of the moles of PL in the cell membrane. Our results indicate that the mole percent of AA to moles of phospolipid is very low (1.0) at the concentrations that affect myocyte contraction and the conductance of voltage-dependent Na+ and L-type Ca2+ channels in rat cardiomyocytes and in -subunits of human myocardial Na+ channels.

In conclusion, it seems highly unlikely that these fatty acids are affecting the packing of PL within cell membranes as their way of modulating changes in cell membrane ion currents and in preventing arrhythmias in our contractility studies.

Source: J Lipid Res 2001 Mar;42(3):346-51

Parker G, Heruc G, Hilton T, et al. Low levels of docosahexaenoic acid identified in acute coronary syndrome patients with depression. Psychiatry Res, 2006; 141(3): 279-86.

As deficiencies in n-3 PUFAs have been linked separately to depression and to cardiovascular disease, they could act as a higher order variable contributing to the established link between depression and cardiovascular disease.

We therefore examine the relationship between depression and omega-3 polyunsaturated fatty acids (n-3 PUFA), including total n-3 PUFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in patients with acute coronary syndrome (ACS).

Plasma phospholipid levels of n-3 PUFA were measured in 100 patients hospitalized with ACS. Current major depressive episode was assessed by the Composite International Diagnostic Interview (CIDI). Depression severity was assessed by the 18-item Depression in the Medically Ill (DMI-18) measure.

Patients clinically diagnosed with current depression had significantly lower mean total n-3 PUFA and DHA levels. Higher DMI-18 depression severity scores were significantly associated with lower DHA levels, with similar but non-significant trends observed for EPA and total n-3 PUFA levels.

The finding that low DHA levels were associated with depression variables in ACS patients may explain links demonstrated between cardiovascular health and depression, and may have prophylactic and treatment implications.

Leaf A, Kang J, Xiao Y, et al. Clinical Prevention of Sudden Cardiac Death by Omega-3 Polyunsaturated Fatty Acids and Mechanism of Prevention of Arrhythmias by Omega-3 Fish Oils. Circulation, 2003;107:2646-2652

Eating oily fish like salmon, tuna or bluefish at least twice a week can prevent sudden cardiac death because fatty acids in the fish block dangerous irregular heart rhythms, experts explain in a review article in Circulation, a Journal of the American Heart Association.

Epidemiologists have known for years that eating fish was associated with reduced risk of cardiovascular disease, but only recently have researchers had laboratory evidence to explain this effect, writes review author Dr. Alexander Leaf, Jackson Professor of Clinical Medicine Emeritus at Harvard Medical School, Boston. Leaf and colleagues present a detailed explanation of how omega-3 fish oils benefit the heart.

Animal experiments show that fatty acids from omega-3 fish oils are stored in the cell membranes of heart cells and can prevent sudden cardiac death or fatal arrhythmias, Leaf said.

Arrhythmias are irregular heart rhythms. Leaf says that studies of individual heart cells demonstrated that the omega-3 essential polyunsaturated fatty acids (omega-3 PUFAs) specifically block excessive sodium and calcium currents in the heart. Those excessive electrical discharges cause dangerous and erratic changes in heart rhythm.

The first clinical suggestion that omega-3 PUFAs significantly benefited the heart came from a 1989 study in which 2,033 men with heart disease were given dietary advice on fat, fibre or fish. After two years the men who were told to eat fish at least twice a week had a 29 percent reduction in death. There was no benefit in either the fibre or fat groups.

Since about 50 percent to 60 percent of deaths in the setting of coronary heart disease are sudden cardiac death [deaths within one hour of symptoms of a heart attack] attributed to sustained ventricular arrhythmias, the authors write, the reduction in deaths reported in this early study is probably evidence of fewer fatal arrhythmias.

This initial study was followed by a series of observational studies and controlled clinical trials. All arrived at the same conclusion: a diet rich in fatty fish reduced fatal heart attacks. But Leaf says that this protection was still not completely understood.
In early animal experiments, researchers demonstrated that animals fed a diet in which 12 percent of the calories came from saturated fat died of sustained ventricular fibrillation, but animals that were also fed omega-3 PUFAs did not develop these dangerous arrhythmias when their coronary arteries were tied off.

But then Leaf and other researchers still needed to find out if there were any plausible biochemical or physiological effects of these omega-3 fatty acids which could explain their antiarrhythmic action. To do so, they cultured neonatal heart cells from rats and observed them under the microscope. The cells clump together and the clump beats spontaneously, rhythmically and simultaneously just like the whole heart.

Using a video camera, Leaf and his colleagues taped the action of the cells and the effect of different toxic agents on the cells. They discovered that adding omega-3 PUFA prevented arrhythmias induced in the cells.

Leaf and his colleagues conclude that omega-3 fatty acids have been part of the human diet for some 2-4 million years during which our genes were adapting to our environment, including our diets. They are safe and have been listed on the GRAS list (Generally Regarded As Safe) according to the FDA.

The American Heart Association recently stated that a dietary approach to increasing omega-3 fatty acid intake is preferable. Still, for patients with coronary artery disease, the dose of omega-3 (about 1 gram per day) may be greater than what can readily be achieved through diet alone. These individuals, in consultation with their physician, could consider supplements for CHD risk reduction.

In an accompanying editorial, authors DR David S. Siscovick, DR Rozenn N. Lemaitre and DR Dariush Mozaffarian say the messages from Leaf and colleagues are clear. For clinicians, it is time to implement the current American Heart Association dietary guidelines . . . For policymakers, there is a need to consider a new indication for treatment with low-dose omega-3 PUFA supplements the prevention of sudden cardiac death in patients with a prior [heart attack]. For researchers, there is a need to continue both clinical studies and studies that explore the mechanism through which omega-3 PUFAS influence the risk of sudden cardiac death, they write.