OMEGA, a Randomized, Placebo-Controlled Trial to Test the Effect of Highly Purified Omega-3 Fatty Acids on Top of Modern Guideline-Adjusted Therapy After Myocardial Infarction Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil. n-3 fatty acids do not enhance LDL susceptibility to oxidation in hypertriacylglycerolemic hemodialyzed subjects. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Effect of fish-oil-enriched margarine on plasma lipids, low-density-lipoprotein particle composition, size, and susceptibility to oxidation. Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study. Fish and n-3 fatty acids for the prevention of fatal coronary heart disease and sudden cardiac death. Randomized controlled trial of gamma-linolenic acid and eicosapentaenoic acid in peripheral arterial disease. Plasma fatty acid composition and incident heart failure in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Do fish oils prevent restenosis after coronary angioplasty? Fish intake and risk of incident atrial fibrillation. Supplementation of postmenopausal women with fish oil does not increase overall oxidation of LDL ex vivo compared to dietary oils rich in oleate and linoleate. Controlled trial of fish oil for regression of human coronary atherosclerosis. HARP Research Group. Prevention of Fatal Arrhythmias in High-Risk Subjects by Fish Oil n-3 Fatty Acid Intake Effect of eicosapentaenoic acid on restenosis rate, clinical course and blood lipids in patients after percutaneous transluminal coronary angioplasty. Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study. Lack of benefit of dietary advice to men with angina: results of a controlled trial Omega-3 Fatty Acid Supplementation Does Not Reduce Risk of Atrial Fibrillation After Coronary Artery Bypass Surgery: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Peroxidation of LDL from combined-hyperlipidemic male smokers supplied with omega-3 fatty acids and antioxidants. Effects of n-3 polyunsaturated fatty acids on left ventricular function and functional capacity in patients with dilated cardiomyopathy. N-3 fatty acids do not prevent restenosis after coronary angioplasty: results from the CART study. Coronary Angioplasty Restenosis Trial. Fatty acid-binding protein-2 genotype influences lipid and lipoprotein response to eicosapentaenoic acid supplementation in hypertriglyceridemic subjects. Long‐term effects of n‐3 polyunsaturated fatty acids on haemostatic variables and bleeding episodes in patients with coronary artery disease Randomized, Double-Blind, Placebo-Controlled Trial of Fish Oil and Mustard Oil in Patients with Suspected Acute Myocardial Infarction: The Indian Experiment of Infarct Survival—4 Effect of fish oil on ventricular tachyarrhythmia and death in patients with implantable cardioverter defibrillators: the Study on Omega-3 Fatty Acids and Ventricular Arrhythmia (SOFA) randomized trial. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Administration of dietary fish oil capsules in healthy middle-aged Japanese men with a high level of fish consumption Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial Reduction in the rate of early restenosis after coronary angioplasty by a diet supplemented with n-3 fatty acids. Essential fatty acids and cardiovascular disease: the Edinburgh Artery Study Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. n-3 fatty acids and cardiovascular events after myocardial infarction.
Background — There is no r and omized , double-blind trial testing the prognostic effect of highly purified omega-3 fatty acids in addition to current guideline -adjusted treatment of acute myocardial infa rct ion . Methods and Results — OMEGA is a r and omized , placebo-controlled , double-blind , multicenter trial testing the effects of omega-3-acid ethyl esters-90 ( 1 g/d for 1 year ) on the rate of sudden cardiac death in survivors of acute myocardial infa rct ion , if given in addition to current guideline -adjusted treatment . Secondary end points were total mortality and nonfatal clinical events .  Patients ( n=3851 ; female , 25.6 % ; mean age , 64.0 years ) were r and omized in 104 German centers 3 to 14 days after acute myocardial infa rct ion from October 2003 until June 2007 .  Acute coronary angiography was performed in 93.8 % and acute percutaneous coronary intervention in 77.8 % of all patients . During a follow-up of 365 days , the event rates were ( omega and control groups ) as follows : sudden cardiac death , 1.5 % and 1.5 % ( P=0.84 ) ; total mortality , 4.6 % and 3.7 % ( P=0.18 ) ; major adverse cerebrovascular and cardiovascular events , 10.4 % and 8.8 % ( P=0.1 ) ; and revascularization in survivors , 27.6 % and 29.1 % ( P=0.34 ) . Conclusions — Guideline -adjusted treatment of acute myocardial infa rct ion results in a low rate of sudden cardiac death and other clinical events within 1 year of follow-up , which could not be shown to be further reduced by the application of omega-3 fatty acids . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00251134 BACKGROUND Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease . We aim ed to test the hypothesis that long-term use of eicosapentaenoic acid ( EPA ) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish . METHODS 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999 . Patients were r and omly assigned to receive either 1800 mg of EPA daily with statin ( EPA group ; n=9326 ) or statin only ( controls ; n=9319 ) with a 5-year follow-up . The primary endpoint was any major coronary event , including sudden cardiac death , fatal and non-fatal myocardial infa rct ion , and other non-fatal events including unstable angina pectoris , angioplasty , stenting , or coronary artery bypass grafting . Analysis was by intention-to-treat . The study was registered at Clinical Trials.gov , number NCT00231738 . FINDINGS At mean follow-up of 4.6 years , we detected the primary endpoint in 262 ( 2.8 % ) patients in the EPA group and 324 ( 3.5 % ) in controls-a 19 % relative reduction in major coronary events ( p=0.011 ) . Post-treatment LDL cholesterol concentrations decreased 25 % , from 4.7 mmol/L in both groups . Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events . Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group . Sudden cardiac death and coronary death did not differ between groups . In patients with a history of coronary artery disease who were given EPA treatment , major coronary events were reduced by 19 % ( secondary prevention subgroup : 158 [ 8.7 % ] in the EPA group vs 197 [ 10.7 % ] in the control group ; p=0.048 ) . In patients with no history of coronary artery disease , EPA treatment reduced major coronary events by 18 % , but this finding was not significant ( 104 [ 1.4 % ] in the EPA group vs 127 [ 1.7 % ] in the control group ; p=0.132 ) . INTERPRETATION EPA is a promising treatment for prevention of major coronary events , and especially non-fatal coronary events , in Japanese hypercholesterolaemic patients OBJECTIVES To investigate the impact of apolipoprotein E ( apoE ) genotype on the response of the plasma lipoprotein profile to eicosapentaenoic acid ( EPA ) versus docosahexaenoic acid ( DHA ) intervention in humans . METHODS AND RESULTS 38 healthy normolipidaemic males , prospect ively recruited on the basis of apoE genotype ( n=20 E3/E3 and n=18 E3/E4 ) , completed a double-blind placebo-controlled cross-over trial , consisting of 3 x 4 week intervention arms of either control oil , EPA-rich oil ( ERO , 3.3 g EPA/day ) or DHA-rich oil ( DRO , 3.7 g DHA/day ) in r and om order , separated by 10 week wash-out periods . A significant genotype-independent 28 % and 19 % reduction in plasma triglycerides in response to ERO and DRO was observed . For total cholesterol ( TC ) , no significant treatment effects were evident ; however a significant genotype by treatment interaction emerged ( P=0.045 ) , with a differential response to ERO and DRO in E4 carriers . Although the genotype x treatment interaction for LDL-cholesterol ( P=0.089 ) did not reach significance , within DRO treatment analysis indicated a 10 % increase in LDL ( P=0.029 ) in E4 carriers with a non-significant 4 % reduction in E3/E3 individuals . A genotype-independent increase in LDL mass was observed following DRO intervention ( P=0.018 ) . Competitive uptake studies in HepG2 cells using plasma very low density lipoproteins ( VLDL ) from the human trial , indicated that following DRO treatment , VLDL(2 ) fractions obtained from E3/E4 individuals result ed in a significant 32 % ( P=0.002 ) reduction in LDL uptake relative to the control . CONCLUSIONS High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers , which appears to be due to an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup Recent data suggest that treatment with n-3 fatty acids could enhance the susceptibility of plasma low-density-lipoprotein ( LDL ) to oxidation .  Twelve hypertriacylglycerolemic , hemodialyzed patients were treated with 2.5 g n-3 fatty acids/d for 2 mo . Treatment was then withdrawn for 2 mo ( washout phase ) . Plasma total cholesterol and LDL cholesterol increased significantly ( 9 % and 28 % ) and plasma triacylglycerols decreased significantly after the n-3 phase compared with baseline and washout values . LDL susceptibility to oxidation was tested by oxidation of LDL particles with 2,2'-azobis ( 2-amidinopropane ) dihydrochloride ( AAPH ) . No significant changes were observed for the lag phase and the peroxidation rate . The vitamin E content of LDL also did not change significantly . The results thus suggest that a daily dosage of 2.5 g n-3 fatty acids does not enhance LDL susceptibility to oxidation , while retaining its hypotriacylglycerolemic effect BACKGROUND Results of epidemiologic studies and clinical trials indicate that moderate doses of n-3 fatty acids reduce the risk of cardiovascular disease and may improve prognosis . OBJECTIVE The objective was to evaluate the effect of a high-dose ethylester concentrate of n-3 fatty acids administered early after an acute myocardial infa rct ion ( MI ) on subsequent cardiac events and serum lipids . DESIGN Three hundred patients with acute MI were r and omly assigned to a daily dose of either 4 g highly concentrated n-3 fatty acids or corn oil , administered in a double-blind manner over 12 - 24 mo . Median follow-up time was 1.5 y. Clinical follow-up , including the drawing of blood sample s , was performed after 6 wk of treatment and later at 0.5-year intervals . RESULTS Forty-two ( 28 % ) patients in the n-3 group and 36 ( 24 % ) in the corn oil group experienced at least one cardiac event ( cardiac death , resuscitation , recurrent MI , or unstable angina ) . No significant difference in prognosis was observed between groups for single or combined cardiac events . Total cholesterol concentrations decreased in both groups , with no significant intergroup differences . On average , the monthly increase in HDL cholesterol was 1.11 % in the n-3 group and 0.55 % in the corn oil group ( P = 0.0016 ) . Triacylglycerol concentrations decreased by 1.30%/mo in the n-3 group , whereas they increased by 0.35%/mo in the corn oil group ( P < 0.0001 ) . CONCLUSION No clinical benefit of a high-dose concentrate of n-3 fatty acids compared with corn oil was found despite a favorable effect on serum lipids We investigated the effect of incorporating n-3 polyunsaturated fatty acids ( PUFAs ) into the diet on the lipid-class composition of LDLs , their size , and their susceptibility to oxidation . Forty-seven healthy volunteers incorporated 30 g sunflower-oil ( SO ) margarine/d into their habitual diet during a 3-wk run-in period and then used either SO or a fish-oil-enriched sunflower oil ( FO ) margarine for the following 4 wk . Plasma concentrations of total cholesterol , triacylglycerols , HDL cholesterol , LDL cholesterol , and apolipoproteins A-I and B did not differ significantly between the groups during intervention . The FO margarine increased the concentration of n-3 very-long-chain PUFAs in the LDL particles , showing 93 % ( P < or = 0.0001 ) , 8 % ( P = 0.05 ) , and 35 % ( P = < 0.0001 ) increases in eicosapentaenoic acid , docosapentaenoic acid , and docosahexaenoic acid , respectively , in the FO group compared with 3 % , 7 % , and 7 % , respectively , in the SO group during the intervention . The cholesterol content of the LDL particles increased in the FO group [ total cholesterol : 6 % ( P = 0.008 ) ; cholesterol ester : 12 % ( P = 0.014 ) ] , although it was not significantly different from that in the control group , whereas the other lipid classes and the size of the LDL particles remained unchanged in both groups . A reduction in the alpha-tocopherol content in LDL ( 6 % , P = 0.005 ) was observed in the FO group . Ex vivo oxidation of LDL induced with Cu2 + showed a significantly reduced lag time ( from 91 to 86 min , P = 0.003 ) and lower maximum rate of oxidation ( from 10.5 to 10.2 nmol x mg(-1 ) x min(-1 ) , P = 0.003 ) after intake of the FO margarine . The results indicate that consumption of the FO compared with the SO margarine had no effect on LDL size and lipid composition and led to minor changes in LDL a-tocopherol content and oxidation resistance BACKGROUND The lipid-modulatory effects of high intakes of the fish-oil fatty acids eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) are well established and likely to contribute to cardioprotective benefits . OBJECTIVES We aim ed to determine the effect of moderate EPA and DHA intakes ( < 2 g EPA+DHA/d ) on the plasma fatty acid profile , lipid and apolipoprotein concentrations , lipoprotein subclass distribution , and markers of oxidative status . We also aim ed to examine the effect of age , sex , and apolipoprotein E ( APOE ) genotype on the observed responses . DESIGN Three hundred twelve adults aged 20 - 70 y , who were prospect ively recruited according to age , sex , and APOE genotype , completed a double-blind placebo-controlled crossover study . Participants consumed control oil , 0.7 g EPA+DHA/d ( 0.7FO ) , and 1.8 g EPA+DHA/d ( 1.8FO ) capsules in r and om order , each for an 8-wk intervention period , separated by 12-wk washout periods . RESULTS In the group as a whole , 8 % and 11 % lower plasma triacylglycerol concentrations were evident after 0.7FO and 1.8FO , respectively ( P < 0.001 ) : significant sex x treatment ( P = 0.038 ) and sex x genotype x treatment ( P = 0.032 ) interactions were observed , and the greatest triacylglycerol-lowering responses ( reductions of 15 % and 23 % after 0.7FO and 1.8FO , respectively ) were evident in APOE4 men . Furthermore , lower VLDL-cholesterol ( P = 0.026 ) and higher LDL-cholesterol ( P = 0.010 ) , HDL-cholesterol ( P < 0.001 ) , and HDL2 ( P < 0.001 ) concentrations were evident after fish-oil intervention . CONCLUSIONS Supplements providing EPA+DHA at doses as low as 0.7 g/d have a significant effect on the plasma lipid profile . The results of the current trial , which used a prospect i ve recruitment approach to examine the responses in population subgroups , are indicative of a greater triacylglycerol-lowering action of long-chain n-3 polyunsaturated fatty acids in males than in females Large observational studies , r and omized clinical trials , and experimental studies have evaluated the effects of fish and n-3 fatty acid consumption on  fatal coronary heart disease ( CHD ) and sudden cardiac death ( SCD )  , clinical ly defined events that most often share the final common pathway of fatal ventricular arrhythmia . These different study design s , each having complementary strengths and limitations , provide strong concordant evidence that modest consumption of fish or fish oil ( 1 - 2 servings/wk of oily fish , or approximately 250 mg/d of EPA+DHA ) substantially reduces the risk of CHD death and SCD . Pooled analysis of prospect i ve cohort studies and r and omized clinical trials demonstrates the magnitude and dose-response of this effect , with 36 % lower risk of CHD death comparing 0 and 250 mg/d of EPA+DHA consumption ( P < 0.001 ) , but then little additional benefit with higher intakes . Reductions in risk are even larger in observational studies utilizing tissue biomarkers of n-3 fatty acids that more accurately measure dietary consumption . The concordance of findings from different studies also suggests that effects of fish or fish oil on CHD death and SCD do not vary depending on presence or absence of established CHD . The strength and consistency of the evidence , and the magnitude of this effect are each notable . Because more than one-half of all CHD deaths and two-thirds of SCD occur among individuals without recognized heart disease , modest consumption of fish or fish oil , together with smoking cessation and regular moderate physical activity , should be among the first-line treatments for prevention of CHD death and SCD BACKGROUND AND AIMS epidemiological studies suggest polyunsaturated fatty acids protect against the development of atherosclerosis . The aim of this study was to perform a r and omized controlled trial of gamma-linolenic and eicosapentaenoic acids in patients with lower limb atherosclerosis . Main outcome measures were : cholesterol and lipoprotein concentrations ; haemostatic and rheological variables ; the ankle brachial pressure index ; walking distance ; and cardiovascular events and death . METHODS 120 men and women with stable intermittent claudication were r and omized to 2 years treatment with either a combination of gamma-linolenic and eicosapentaenoic acids , or placebo . RESULTS 39 ( 65.0 cent ) of those taking fatty acids and 36 ( 60.0 cent ) of those taking placebo completed the trial . Lipid concentrations did not differ significantly during the trial . In those taking fatty acids , haematocrit was significantly higher than in the placebo group after 6 months ( 46.1 cent compared with 44.6 cent , P < /= 0.01 ) , and systolic blood pressure was significantly lower after 2 years ( 150|mmHg compared with 161.8|mmHg , < /= 0.05 ) . There was no difference in walking distance , but there was a small reduction in non-fatal coronary events in the fatty acid group ( 10 cent compared with 15 cent , P > 0.05 ) . CONCLUSIONS a combination of polyunsaturated fatty acids produced a statistically significant reduction in systolic blood pressure , but no other significant benefits on risk factors . The trend towards fewer coronary events in those taking fatty acids warrants further investigation BACKGROUND Some previous prospect i ve studies showed that dietary intake of omega3 polyunsaturated fatty acids was associated with lower risk of heart failure ( HF )  , but no study has examined the association between plasma fatty acids and HF . METHODS We included 3,592 white participants from the Minneapolis field center of the Atherosclerosis Risk in Communities ( ARIC ) Study , aged 45 to 64 at baseline ( 1987 - 1989 ) , initially free of coronary heart disease , stroke , and HF and who had cholesterol ester and phospholipid plasma fatty acids measured . Participants were followed through 2003 , and incident HF was defined by a hospital discharge or death including a HF International Classification of Diseases code . RESULTS During the 14.3-year follow-up , we identified 197 cases of HF ( 110 for men and 87 for women ) . After adjustment for age and other confounders , higher saturated fatty acids , especially myristic ( 14:0 ) acid , were associated positively with incident HF in both men and women . Higher arachidonic ( 20:3,omega6 ) and long-chain omega3 polyunsaturated fatty acids , especially docosahexaenoic ( 22:6,omega3 ) acid , were associated inversely with HF in women but not in men . Neither plasma alpha-linolenic nor eicosapentaenoic acid was associated with incident HF . CONCLUSIONS In both men and women , greater levels of saturated fatty acids may increase risk of HF . In women , arachidonic acid and long-chain omega3 polyunsaturated fatty acids may decrease risk of HF BACKGROUND The omega-3 polyunsaturated fatty acids derived from fish oils have been shown to modulate many factors believed to affect the pathogenesis of atherosclerosis . Because certain features of restenosis following angioplasty mimic some of the early changes of atherogenesis , some research ers have suggested that fish oil might prevent restenosis following angioplasty . We report the effects of omega-3 fatty acids on the rate of restenosis following percutaneous intraluminal coronary angioplasty ( PTCA ) . METHODS AND RESULTS From August 1989 through September 1992 , 551 patients were r and omized to start receiving a daily dietary supplement of ten 1.0-g capsules containing 80.6 % ethyl esters of omega-3 fatty acids providing 4.1 g eicosapentaenoic acid ( EPA ) and 2.8 g docosahexaenoic acid ( DHA ) for 6 months or an equal amount of an ethyl ester of corn oil .  Four hundred seventy subjects who were well matched for risk factors completed successful angioplasty of one or multiple lesions in native coronary vessels and constituted the study cohort , of whom 447 were evaluable at 6 months after PTCA . The criteria for restenosis were that the quantitative coronary angiography at 6 months show a > 30 % increase in narrowing at the stenosis site or loss of at least half of the gain achieved at the time of PTCA and final restenosis with < 50 % luminal diameter remaining . In 93 % of the patients , the end point was determined by angiography and in all except 1 % of these by quantitative coronary angiography . Compliance with the fish oil supplement was good as judged by incorporation of EPA and DHA in plasma and red blood cell phospholipids . The restenosis rate among analyzable patients was 46 % for corn oil and 52 % for fish oil ( P = .37 ) . The addition of 200 mg alpha-tocopherol for all subjects during the study had no effect on restenosis rates . CONCLUSIONS This was the largest of such trials to date , and a supplement of 8 g/d of omega-3 fatty acids failed to prevent the usual high rate of restenosis after PTCA . No adverse effects were attributable to this large daily supplement of omega-3 fatty acids BACKGROUND Atrial fibrillation ( AF ) is the most common arrhythmia in clinical practice and is particularly common in the elderly . Although effects of fish intake , including potential antiarrhythmic effects , may favorably influence risk of AF , relationships between fish intake and AF incidence have not been evaluated . METHODS AND RESULTS In a prospect i ve , population -based cohort of 4815 adults > or = age 65 years , usual dietary intake  was assessed at baseline in 1989 and 1990 . Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids , whereas consumption of fried fish or fish s and wiches ( fish burgers ) did not . AF incidence was prospect ively ascertained on the basis of hospital discharge records and annual electrocardiograms . During 12 years ' follow-up , 980 cases of incident AF were diagnosed . In multivariate analyses , consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF , with 28 % lower risk with intake 1 to 4 times per week ( HR=0.72 , 95 % CI=0.58 to 0.91 , P=0.005 ) , and 31 % lower risk with intake > or = 5 times per week ( HR=0.69 , 95 % CI=0.52 to 0.91 , P=0.008 ) , compared with < 1 time per month ( P trend=0.004 ) . Results were not material ly different after adjustment for preceding myocardial infa rct ion or congestive heart failure . In similar analyses , fried fish/fish s and wich consumption was not associated with lower risk of AF . CONCLUSIONS Among elderly adults , consumption of tuna or other broiled or baked fish , but not fried fish or fish s and wiches , is associated with lower incidence of AF . Fish intake may influence risk of this common cardiac arrhythmia Although replacement of dietary saturated fat with monounsaturated and polyunsaturated fatty acids ( MUFA and PUFA ) has been advocated for the reduction of cardiovascular disease risk , diets high in PUFA could increase low density lipoprotein ( LDL ) susceptibility to oxidation , potentially contributing to the pathology of atherosclerosis . To investigate this possibility , 15 postmenopausal women in a blinded crossover trial consumed 15 g of sunflower oil ( SU ) providing 12.3 g/day of oleate , safflower oil ( SA ) providing 10.5 g/day of linoleate , and fish oil ( FO ) providing 2.0 g/day of eicosapentaenoate ( EPA ) and 1.4 g/day of docosahexaenoate ( DHA ) . During CuSO(4)-mediated oxidation , LDL was depleted of alpha-tocopherol more rapidly after FO supplementation than after supplementation with SU ( P = 0.0001 ) and SA ( P = 0.05 ) . In LDL phospholipid and cholesteryl ester fractions , loss of n-3 PUFA was greater and loss of n-6 PUFA less after FO supplementation than after SU and SA supplementation ( P < 0.05 for all ) , but loss of total PUFA did not differ . The lag phase for phosphatidylcholine hydroperoxide ( PCOOH ) formation was shorter after FO supplementation than after supplementation with SU ( P = 0.0001 ) and SA ( P = 0.006 ) , whereas the lag phase for cholesteryl linoleate hydroperoxide ( CE18:2OOH ) formation was shorter after FO supplementation than after SU ( P = 0.03 ) but not SA . In contrast , maximal rates of PCOOH and CE18:2OOH formation were lower after FO supplementation than after SA ( P = 0.02 and 0.0001 , respectively ) and maximal concentrations of PCOOH and CE18:2OOH were lower after FO supplementation than after SA ( P = 0.03 and 0.0006 , respectively ) . Taken together , our results suggest that FO supplementation does not increase the overall oxidation of LDL ex vivo , especially when compared with SA supplementation . Consequently , health benefits related to increased fish consumption may not be offset by increased LDL oxidative susceptibility.-- Higdon , J. V. , S. H. Du , Y. S. Lee , T. Wu , and R. C. W and er . Supplementation of postmenopausal women with fish oil does not increase overall oxidation of LDL ex vivo compared to dietary oils rich in oleate and linoleate . J. Lipid Res . 2001 . 42 : 407 - -418 OBJECTIVES This r and omized clinical trial tested whether fish oil supplements can improve human coronary atherosclerosis .  BACKGROUND Epidemiologic studies of population s whose intake of oily fish is high , as well as laboratory studies of the effects of the polyunsaturated fatty acids in fish oil , support the hypothesis that fish oil is antiatherogenic . METHODS Patients with angiographically documented coronary heart disease and normal plasma lipid levels were r and omized to receive either fish oil capsules ( n = 31 ) , containing 6 g of n-3 fatty acids , or olive oil capsules ( n = 28 ) for an average duration of 28 months . Coronary atherosclerosis on angiography was quantified by computer-assisted image analysis . RESULTS Mean ( + /- SD ) baseline characteristics were age 62 + /- 7 years , plasma total cholesterol concentration 187 + /- 31 mg/dl ( 4.83 + /- 0.80 mmol/liter ) and triglyceride levels 132 + /- 70 mg/dl ( 1.51 + /- 0.80 mmol/liter ) . Fish oil lowered triglyceride levels by 30 % ( p = 0.007 ) but had no significant effects on other plasma lipoprotein levels . At the end of the trial , eicosapentaenoic acid in adipose tissue sample s was 0.91 % in the fish oil group compared with 0.20 % in the control group ( p < 0.0001 ) . At baseline , the minimal lumen diameter of coronary artery lesions ( n = 305 ) was 1.64 + /- 0.76 mm , and percent narrowing was 48 + /- 14 % . Mean minimal diameter of atherosclerotic coronary arteries decreased by 0.104 and 0.138 mm in the fish oil and control groups , respectively ( p = 0.6 between groups ) , and percent stenosis increased by 2.4 % and 2.6 % , respectively ( p = 0.8 ) . Confidence intervals exclude improvement by fish oil treatment of > 0.17 mm , or > 2.6 % . CONCLUSIONS Fish oil treatment for 2 years does not promote major favorable changes in the diameter of atherosclerotic coronary arteries Background — The long-chain n-3 fatty acids in fish have been demonstrated to have antiarrhythmic properties in experimental models and to prevent sudden cardiac death in a r and omized trial of post – myocardial infa rct ion patients . Therefore , we hypothesized that these n-3 fatty acids might prevent potentially fatal ventricular arrhythmias in high-risk patients . Methods and Results — Four hundred two patients with implanted cardioverter/defibrillators ( ICDs ) were r and omly assigned to double-blind treatment with either a fish oil or an olive oil daily supplement for 12 months . The primary end point , time to first ICD event for ventricular tachycardia or fibrillation ( VT or VF ) confirmed by stored electrograms or death from any cause , was analyzed by intention to treat . Secondary analyses were performed for “ probable ” ventricular arrhythmias , “ on-treatment ” analyses for all subjects who had taken any of their oil supplements , and “ on-treatment ” analyses only of those subjects who were on treatment for at least 11 months . Compliance with double-blind treatment was similar in the 2 groups ; however , the noncompliance rate was high ( 35 % of all enrollees ) . In the primary analysis , assignment to treatment with the fish oil supplement showed a trend toward a prolonged time to the first ICD event ( VT or VF ) or of death from any cause ( risk reduction of 28 % ; P=0.057 ) . When therapies for probable episodes of VT or VF were included , the risk reduction became significant at 31 % ; P=0.033 . For those who stayed on protocol for at least 11 months , the antiarrhythmic benefit of fish oil was improved for those with confirmed events ( risk reduction of 38 % ; P=0.034 ) . Conclusions — Although significance was not achieved for the primary end point , this study provides evidence that for individuals at high risk of fatal ventricular arrhythmias , regular daily ingestion of fish oil fatty acids may significantly reduce potentially fatal ventricular arrhythmias In order to study the effects of eicosapentaenoic acid ( Maxepa ) , Maxepa placebo and aspirin/dipyridamole combination on the clinical course and restenosis rate of atherosclerotic lesions after percutaneous transluminal coronary angioplasty 79 men and 29 women were r and omly divided into three treatment groups and restudied angiographically within one year of the procedure . Angina recurred less in the Maxepa group than in the other groups , although not statistically so . Restenosis rate was significantly reduced in the Maxepa group ( 11 % ) compared to the placebo group ( 30 % ) but , while less , was not significantly lower than in the aspirin/dipyridamole group ( 17 % ) . Maxepa treatment appears to reduce restenosis rate of coronary artery lesions after percutaneous transluminal coronary angioplasty and may be an acceptable and equally effective alternative therapy to aspirin/dipyridamole Objective To investigate whether dietary supplementation with B vitamins or omega 3 fatty acids , or both , could prevent major cardiovascular events in patients with a history of ischaemic heart disease or stroke . Design Double blind , r and omised , placebo controlled trial ; factorial design . Setting Recruitment throughout France via a network of 417 cardiologists , neurologists , and other physicians . Participants 2501 patients with a history of myocardial infa rct ion , unstable angina , or ischaemic stroke . Intervention Daily dietary supplement containing 5-methyltetrahydrofolate ( 560 μg ) , vitamin B-6 ( 3 mg ) , and vitamin B-12 ( 20 μg ) or placebo ; and containing omega 3 fatty acids ( 600 mg of eicosapentanoic acid and docosahexaenoic acid at a ratio of 2:1 ) or placebo . Median duration of supplementation was 4.7 years . Main outcome measures Major cardiovascular events , defined as a composite of non-fatal myocardial infa rct ion , stroke , or death from cardiovascular disease . Results Allocation to B vitamins lowered plasma homocysteine concentrations by 19 % compared with placebo , but had no significant effects on major vascular events ( 75 v 82 patients , hazard ratio , 0.90 ( 95 % confidence interval 0.66 to 1.23 , P=0.50 ) ) . Allocation to omega 3 fatty acids  increased plasma concentrations of omega 3 fatty acids by 37 % compared with placebo , but also had no significant effect on major vascular events ( 81 v 76 patients , hazard ratio 1.08 ( 0.79 to 1.47 , P=0.64 ) ) . Conclusion This study does not support the routine use of dietary supplements containing B vitamins or omega 3 fatty acids for prevention of cardiovascular disease in people with a history of ischaemic heart disease or ischaemic stroke , at least when supplementation is introduced after the acute phase of the initial event . Trial registration Current Controlled Trials IS RCT N41926726 Subjects with the metabolic syndrome ( MetS ) have enhanced oxidative stress and inflammation . Dietary fat quality has been proposed to be implicated in these conditions . We investigated the impact of four diets distinct in fat quantity and quality on 8-iso-PGF2α ( a major F2-isoprostane and oxidative stress indicator ) , 15-keto-13,14-dihydro-PGF2α ( 15-keto-dihydro-PGF2α , a major PGF2α metabolite and marker of cyclooxygenase-mediated inflammation ) and C-reactive protein ( CRP ) . In a 12-week parallel multicentre dietary intervention study ( LIPGENE ) , 417 volunteers with the MetS were r and omly assigned to one of the four diets : two high-fat diets ( 38 % energy ( % E ) ) rich in SFA or MUFA and two low-fat high-complex carbohydrate diets ( 28 % E ) with ( LFHCC n-3 ) or without ( LFHCC ) 1·24 g/d of very long chain n-3 fatty acid supplementation . Urinary levels of 8-iso-PGF2α and 15-keto-dihydro-PGF2α were determined by RIA and adjusted for urinary creatinine levels . Serum concentration of CRP was measured by ELISA . Neither concentrations of 8-iso-PGF2α and 15-keto-dihydro-PGF2α nor those of CRP differed between diet groups at baseline ( P>0·07 ) or at the end of the study ( P>0·44 ) . Also , no differences in changes of the markers were observed between the diet groups ( 8-iso-PGF2α , P = 0·83 ; 15-keto-dihydro-PGF2α , P = 0·45 ; and CRP , P = 0·97 ) . In conclusion , a 12-week dietary fat modification did not affect the investigated markers of oxidative stress and inflammation among subjects with the MetS in the LIPGENE study Objective : To see whether mortality among men with angina can be reduced by dietary advice . Design : A r and omized controlled factorial trial . Setting : Male patients of general practitioners in south Wales . Subjects : A total of 3114 men under 70 y of age with angina . Interventions : Subjects were r and omly allocated to four groups : ( 1 ) advised to eat two portions of oily fish each week , or to take three fish oil capsules daily ; ( 2 ) advised to eat more fruit , vegetables and oats ; ( 3 ) given both the above types of advice ; and ( 4 ) given no specific dietary advice .  Mortality was ascertained after 3–9 y. Results : Compliance was better with the fish advice than with the fruit advice . All-cause mortality was not reduced by either form of advice , and no other effects were attributable to fruit advice . Risk of cardiac death was higher among subjects advised to take oily fish than among those not so advised ; the adjusted hazard ratio was 1.26 ( 95 % confidence interval 1.00 , 1.58 ; P=0.047 ) , and even greater for sudden cardiac death ( 1.54 ; 95 % CI 1.06 , 2.23 ; P=0.025 ) . The excess risk was largely located among the subgroup given fish oil capsules . There was no evidence that it was due to interactions with medication . Conclusion : Advice to eat more fruit was poorly complied with and had no detectable effect on mortality . Men advised to eat oily fish , and particularly those supplied with fish oil capsules , had a higher risk of cardiac death . This result is unexplained ; it may arise from risk compensation or some other effect on patients ' or doctors ' behaviour . Sponsorship : British Heart Foundation , Seven Seas Limited , Novex Pharma Limited , The Fish Foundation Background —Omega-3 polyunsaturated fatty acids ( n-3 PUFA ) have been reported to reduce the risk of sudden cardiac death presumed to be due to fatal ventricular arrhythmias , but their effect on atrial arrhythmias is unclear . Methods and Results — Patients ( n=108 ) undergoing coronary artery bypass graft surgery were r and omly assigned to receive 2 g/d n-3 PUFA or placebo ( olive oil ) for at least 5 days before surgery ( median , 16 days ; range , 12 to 21 days ) . Phospholipid n-3 PUFA were measured in serum at study entry and at surgery and in right atrial appendage tissue at surgery . Echocardiography was used to assess left ventricular function and left atrial dimensions .  Postoperative continuous ECG monitoring ( Lifecard CF ) for 5 days or until discharge , if earlier , was performed with a daily 12-lead ECG and clinical review if patients remained in the hospital beyond 5 days . Lifecard recordings were analyzed for episodes of atrial fibrillation ( AF ) ≥30 seconds ( primary outcome ) . Clinical AF , AF burden ( % time in AF ) , hospital stay , and intensive care/high dependency care stay were measured as secondary outcomes . One hundred three patients completed the study ( 51 in the placebo group and 52 in the n-3 PUFA group ) . There were no clinical ly relevant differences in baseline characteristics between groups . n-3 PUFA levels were higher in serum and right atrial tissue in the active treatment group . There was no significant difference between groups in the primary outcome of AF ( 95 % confidence interval [ CI ] , −6 % to 30 % , P=0.28 ) in any of the secondary outcomes or in AF-free survival . Conclusions —Omega-3 PUFA do not reduce the risk of AF after coronary artery bypass graft surgery . Clinical Trial Registration —www.ukcrn.org.uk . Identifier : 4437 The effects of marine omega-3 polyunsaturated fatty acids ( FAs ) and antioxidants on the oxidative modification of LDL were studied in a r and omized , double-blind , placebo-controlled trial . Male smokers ( n = 41 ) with combined hyperlipidemia were allocated to one of four groups receiving supplementation with omega-3 FAs ( 5 g eicosapentaenoic acid and docosahexaenoic acid per day ) , antioxidants ( 75 mg vitamin E , 150 mg vitamin C , 15 mg beta-carotene , and 30 mg coenzyme Q10 per day ) , both omega-3 FAs and antioxidants , or control oils . LDL and human mononuclear cells were isolated from the patients at baseline and after 6 weeks of supplementation . LDL was subjected to cell-mediated oxidation by the patients ' own mononuclear cells , as well as to Cu(2+)-catalyzed and 2,2'-azobis-(2-amidinopropane hydrochloride ) (AAPH)-initiated oxidation . Extent of LDL modification was measured as lag time , the formation rate of conjugated dienes ( CDs ) , the maximum amount of CDs formed , formation of lipid peroxides , and the relative electrophoretic mobility of LDL on agarose gels . Dietary supplementation with omega-3 FAs increased the concentration of total omega-3 FAs in LDL and reduced the concentration of vitamin E in serum . The omega-3 FA-enriched LDL particles were not more susceptible to Cu(2+)-catalyzed , AAPH-initiated , or autologous cell-mediated oxidation than control LDL . In fact , enrichment with omega-3 FAs significantly reduced the formation rate of CDs when LDL was subjected to AAPH-induced oxidation . Supplementation with moderate amounts of antioxidants significantly increased the concentration of vitamin E in serum and increased the resistance of LDL to undergo Cu(2+)-catalyzed oxidation , measured as increased lag time , reduced formation of lipid peroxides , and reduced relative electrophoretic mobility compared with control LDL . Supplementation with omega-3 FAs/antioxidants  showed oxidizability of LDL similar to that of control LDL and omega-3 FA-enriched LDL . In conclusion , omega-3 FAs neither rendered the LDL particles more susceptible to undergo in vitro oxidation nor influenced mononuclear cells ' ability to oxidize autologous LDL , whereas moderate amounts of antioxidants protected LDL against oxidative modification OBJECTIVES This study was design ed to test the effects of n-3 polyunsaturated fatty acids ( PUFAs ) on left ventricular ( LV ) systolic function in chronic heart failure ( HF ) due to nonischemic dilated cardiomyopathy ( NICM ) . BACKGROUND One hundred thirty-three patients with NICM and minimal symptoms on st and ard therapy were r and omized to 2 g of n-3 PUFAs or placebo .  LV function and functional capacity were assessed prospect ively by echocardiography and cardiopulmonary exercise testing at baseline and at 12 months after r and omization . METHODS Patients with chronic HF due to NICM and minimal symptoms while receiving evidence -based therapy were enrolled . LV function and functional capacity were assessed prospect ively by echocardiography , cardiopulmonary exercise test , and New York Heart Association functional class at baseline and at 12 months after r and omization to either 2 g of n-3 PUFAs or placebo . RESULTS At 12 months after r and omization , the n-3 PUFAs group and the placebo group differed significantly ( p < 0.001 ) in regard to : 1 ) LV ejection fraction ( increased by 10.4 % and decreased by 5.0 % , respectively ) ; 2 ) peak VO(2 ) ( increased by 6.2 % and decreased by 4.5 % , respectively ) ; 3 ) exercise duration ( increased by 7.5 % and decreased by 4.8 % , respectively ) ; and 4 ) mean New York Heart Association functional class ( decreased from 1.88 ± 0.33 to 1.61 ± 0.49 and increased from 1.83 ± 0.38 to 2.14 ± 0.65 , respectively ) . The hospitalization rates for HF were 6 % in the n-3 PUFAs and 30 % in the placebo group ( p = 0.0002 ) . CONCLUSIONS In patients with NICM and minimal symptoms in response to evidence -based medical therapy , n-3 PUFAs treatment increases LV systolic function and functional capacity and may reduce hospitalizations for HF . Given these promising results , larger studies are in order to confirm our findings OBJECTIVES The aim of the study was to investigate whether omega-3 fatty acids ( n-3 FA ) reduce the occurrence of restenosis  after percutaneous transluminal coronary angioplasty . BACKGROUND Meta-analyses have shown significant reduction of restenosis after coronary angioplasty upon supplementation with n-3 FA . METHODS In a prospect i ve , placebo-controlled , double-blind study , 500 patients were r and omly allocated to treatment with n-3 FA ( Omacor , Pronova AS , Oslo , Norway ) 5.1 g/day or corn oil ( placebo ) starting at least two weeks prior to elective coronary angioplasty .  The treatment was continued until restenosis evaluation by quantitative coronary angiography after six months . Stenosis was defined as a minimal luminal diameter ( MLD ) < 40 % of the reference diameter . Successful coronary angioplasty was defined as > or = 20 % acute gain in MLD and a residual stenosis < 50 % . Restenosis was defined as > or = 20 % late loss of diameter and stenosis > 50 % or an increase in stenosis of > or = 0.7 mm . Three-hundred ninety-two patients fulfilled the criteria for initial stenosis and successful coronary angioplasty , and , except four patients who died , none were lost for follow-up . RESULTS Restenosis occurred in 108/266 ( 40.6 % ) of the treated stenoses in the Omacor group and in 93/263 ( 35.4 % ) in the placebo group ( odds ratio [ OR ] 1.25 , 95 % confidence interval [ CI ] [ 0.87 - 1.80 ] p = 0.21 ) . In the Omacor group one or more restenoses occurred in 90/196 ( 45.9 % ) patients as compared with 86/192 ( 44.8 % ) in the placebo group ( OR 1.05 , 95 % CI [ 0.69 - 1.59 ] p = 0.82 ) . CONCLUSIONS Supplementation with 5.1 g n-3 FA/day for six months , initiated at least two weeks prior to coronary angioplasty did not reduce the incidence of restenosis OBJECTIVE The blood lipid-lowering effects of eicosapentaenoic acid ( EPA ) on hypertriglyceridemic subjects with different fatty acid-binding protein-2 ( FABP2 ) genotypes have not , to our knowledge , been previously studied . METHODS Twenty-three FABP2 Ala54 and 23 Thr54 carriers with hypertriglyceridemia ( triacylglycerol level > 200mg/dL ) were enrolled in this study . Participants took 2 g of pure EPA daily for 8 wk . Fasting blood lipid and lipoprotein profiles were determined and changes from baseline were measured . RESULTS Blood lipids and lipoprotein responses of the FABP2 genotypes differed after EPA supplementation . Changes from baseline for triacylglycerol ( 19.2 % decrease for Ala54 and 60.5 % for Thr54 , P<0.001 ) , very low-density lipoprotein ( 20.0 % decrease for Ala54 and 60.5 % for Thr54 , P<0.001 ) , apolipoprotein CIII ( 22.8 % decrease for Ala54 and 36.4 % for Thr54 , P<0.01 ) , and high-density lipoprotein cholesterol ( 17.6 % increase for Ala54 and 30.7 % for Thr54 , P<0.01 ) differed significantly between the two carrier groups . However , changes in total cholesterol , low-density lipoprotein cholesterol , and apolipoprotein B were not significant . EPA supplementation increased plasma EPA in Ala54 and Thr54 carriers . Although EPA supplementation increased the level of plasma EPA in both carrier groups , this effect was more pronounced in the Thr54 carriers . CONCLUSION Therefore , EPA consumption has more favorable effects on blood lipids of hypertriglyceridemics with Thr54 genotype rather than those with Ala54 . The level of plasma EPA increases after EPA supplementation . Because the FABP2 Thr54 polymorphism appears to be prevalent in hypertriglyceridemic subjects , increasing EPA intake in these subjects could be an effective strategy for reducing blood triacylglycerol concentration The long-term effects of fish-oil supplementation on haemostatic parameters and bleeding episodes were investigated in patients undergoing coronary artery bypass surgery . They were investigated before and 9 months after the operation . Following r and omization post-operatively , 260 patients received 4 g  fish-oil concentrate  per day , whereas 251 patients comprised the control group .  All patients received either aspirin ( 300 mg/day ) or warfarin ( international normalized ratio aim ed at 2.5–4.2 ) . Compliance was affirmed by determination of serum phospholipid fatty acids . No excess of bleeding episodes could be attributed to the use of fish oil , given in addition to either aspirin or warfarin . The supplementation of fish oil did not affect the bleeding time or plasma levels of beta-thromboglobulin , whereas an increase in the platelet count after the operation was slightly less pronounced in the fish-oil group . Apart from a small increase in PAI-1 antigen of borderline significance , no long-term effects by fish oil on parameters of coagulation and fibrinolysis were seen In a r and omized , placebo-controlled trial , the effects of treatment with fish oil ( eicosapentaenoic acid , 1.08 g/day ) and mustard oil ( alpha-linolenic acid , 2.9 g/day ) were compared for 1 year in the management of 122 patients ( fish oil , group A ) , 120 patients ( mustard oil , group B ) , and 118 patients ( placebo , group C ) with suspected acute myocardial infa rct ion ( AMI ) . Treatments were administered about ( mean ) 18 hours after the symptoms of AMI in all three groups . The extent of cardiac disease , rise in cardiac enzymes , and lipid peroxides were comparable among the groups at entry into the study . After 1 year total cardiac events were significantly less in the fish oil and mustard oil groups compared with the placebo group ( 24.5 % and 28 % vs. 34.7 % , p > 0.01 ) . Nonfatal infa rct ions were also significantly less in the fish oil and mustard oil groups compared with the placebo group ( 13.0 % and 15.0 % vs. 25.4 % , p > 0.05 ) . Total cardiac deaths showed no significant reduction in the mustard oil group ; however , the fish oil group had significantly less cardiac deaths compared with the placebo group ( 11.4 % vs. 22.0 % , p > 0.05 ) . Apart from the decrease in the cardiac event rate , the fish oil and mustard oil groups also showed a significant reduction in total cardiac arrhythmias , left ventricular enlargement , and angina pectoris compared with the placebo group . Reductions in blood lipoproteins in the two intervention groups were modest and do not appear to be the cause of the benefit in the two groups . Diene conjugates showed a significant reduction in the fish oil and mustard oil groups , indicating that a part of the benefit may be caused by the reduction in oxidative stress . The findings of this study suggest that fish oil and mustard oil , possibly due to the presence of n-3 fatty acids , may provide rapid protective effects in patients with AMI . However , a large study is necessary to confirm this suggestion CONTEXT Very-long-chain n-3 polyunsaturated fatty acids ( omega-3 PUFAs ) from fish are thought to reduce risk of sudden death , possibly by reducing susceptibility to cardiac arrhythmia . OBJECTIVE To study the effect of supplemental fish oil vs placebo on ventricular tachyarrhythmia or death . DESIGN , SETTING , AND PATIENTS The Study on Omega-3 Fatty acids and ventricular Arrhythmia ( SOFA ) was a r and omized , parallel , placebo-controlled , double-blind trial conducted at 26 cardiology clinics across Europe . A total of 546 patients with implantable cardioverter-defibrillators ( ICDs ) and prior documented malignant ventricular tachycardia ( VT ) or ventricular fibrillation ( VF ) were enrolled between October 2001 and August 2004 . Patients were r and omly assigned to receive 2 g/d of fish oil ( n = 273 ) or placebo ( n = 273 ) for a median period of 356 days ( range , 14 - 379 days ) . MAIN OUTCOME MEASURE Appropriate ICD intervention for VT or VF , or all-cause death . RESULTS The primary end point occurred in 81 ( 30 % ) patients taking fish oil vs 90 ( 33 % ) patients taking placebo ( hazard ratio [ HR ] , 0.86 ; 95 % confidence interval [ CI ] , 0.64 - 1.16 ; P = .33 ) . In prespecified subgroup analyses , the HR was 0.91 ( 95 % CI , 0.66 - 1.26 ) for fish oil vs placebo in the 411 patients who had experienced VT in the year before the study , and 0.76 ( 95 % CI , 0.52 - 1.11 ) for 332 patients with prior myocardial infa rct ions . CONCLUSION Our findings do not indicate evidence of a strong protective effect of intake of omega-3 PUFAs from fish oil against ventricular arrhythmia in patients with ICDs . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00110838 BACKGROUND Several epidemiological and experimental studies suggest that n-3 polyunsaturated fatty acids ( PUFA ) can exert favourable effects on atherothrombotic cardiovascular disease , including arrhythmias . We investigated whether n-3 PUFA could improve morbidity and mortality in a large population of patients with symptomatic heart failure of any cause . METHODS We undertook a r and omised , double-blind , placebo-controlled trial in 326 cardiology and 31 internal medicine centres in Italy . We enrolled patients with chronic heart failure of New York Heart Association class II-IV , irrespective of cause and left ventricular ejection fraction , and r and omly assigned them to  n-3 PUFA 1 g daily ( n=3494 ) or placebo ( n=3481 ) by a concealed , computerised telephone r and omisation system . Patients were followed up for a median of 3.9 years ( IQR 3.0 - 4.5 ) . Primary endpoints were time to death , and time to death or admission to hospital for cardiovascular reasons . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00336336 . FINDINGS We analysed all r and omised patients . 955 ( 27 % ) patients died from any cause in the n-3 PUFA group and 1014 ( 29 % ) in the placebo group ( adjusted hazard ratio [ HR ] 0.91 [ 95.5 % CI 0.833 - 0.998 ] , p=0.041 ) . 1981 ( 57 % ) patients in the n-3 PUFA group and 2053 ( 59 % ) in the placebo group died or were admitted to hospital for cardiovascular reasons ( adjusted HR 0.92 [ 99 % CI 0.849 - 0.999 ] , p=0.009 ) . In absolute terms , 56 patients needed to be treated for a median duration of 3.9 years to avoid one death or 44 to avoid one event like death or admission to hospital for cardiovascular reasons . In both groups , gastrointestinal disorders were the most frequent adverse reaction ( 96 [ 3 % ] n-3 PUFA group vs 92 [ 3 % ] placebo group ) . INTERPRETATION A simple and safe treatment with n-3 PUFA can provide a small beneficial advantage in terms of mortality and admission to hospital for cardiovascular reasons in patients with heart failure in a context of usual care The nutritional effects of fish oil , which is rich in the n-3 polyunsaturated fatty acids , have been reported . In this r and omized , placebo-controlled , double-blind , crossover study , we evaluated the effects of dietary fish oil capsules on the hematological parameters of healthy middle-aged Japanese men with a high level of fish oil consumption . Over a 4-week period , subjects were administered five fish oil or olive oil ( placebo ) capsules with every meal ( 1,260 mg eicosapentaenoic acid and 540 mg docosahexaenoic acid/day ) . There was a 4-week washout period between the treatment phases . The results did not demonstrate a decrease in plasma triacylglycerol , cholesterol , low-density lipoprotein cholesterol , and whole-blood viscosity . Further , no changes in the fatty acid composition of plasma and erythrocyte phospholipids were noted . These results suggested that the supplementation of fish oil might be effective only for those subjects who have a lower level of fish oil consumption BACKGROUND N-3 polyunsaturated fatty acids ( PUFAs ) from oily fish protect against death from cardiovascular disease . We aim ed to assess the hypothesis that incorporation of n-3 and n-6 PUFAs into advanced atherosclerotic plaques increases and decreases plaque stability , respectively . METHODS We did a r and omised controlled trial of patients awaiting carotid endarterectomy . We r and omly allocated patients control , sunflower oil ( n-6 ) , or fish-oil ( n-3 ) capsules until surgery . Primary outcome was plaque morphology indicative of stability or instability , and outcome measures were concentrations of EPA , DHA , and linoleic acid in carotid plaques ; plaque morphology ; and presence of macrophages in plaques . Analysis was per protocol . FINDINGS 188 patients were enrolled and r and omised ; 18 withdrew and eight were excluded . Duration of oil treatment was 7 - 189 days ( median 42 ) and did not differ between groups . The proportions of EPA and DHA were higher in carotid plaque fractions in patients receiving fish oil compared with those receiving control ( absolute difference 0.5 [ 95 % CI 0.3 - 0.7 ] , 0.4 [ 0.1 - 0.6 ] , and 0.2 [ 0.1 - 0.4 ] g/100 g total fatty acids for EPA ; and 0.3 [ 0.0 - 0.8 ] , 0.4 [ 0.1 - 0.7 ] , and 0.3 [ 0.1 - 0.6 ] g/100 g total fatty acids for DHA ; in plaque phospholipids , cholesteryl esters , and triacylglycerols , respectively ) . Sunflower oil had little effect on the fatty acid composition of lipid fractions . Fewer plaques from patients being treated with fish oil had thin fibrous caps and signs of inflammation and more plaques had thick fibrous caps and no signs of inflammation , compared with plaques in patients in the control and sunflower oil groups ( odds ratio 0.52 [ 95 % CI 0.24 - 0.89 ] and 1.19 [ 1.02 - 1.57 ] vs control ; 0.49 [ 0.23 - 0.90 ] and 1.16 [ 1.01 - 1.53 ] vs sunflower oil ) . The number of macrophages in plaques from patients receiving fish oil was lower than in the other two groups . Carotid plaque morphology and infiltration by macrophages did not differ between control and sunflower oil groups . INTERPRETATION Atherosclerotic plaques readily incorporate n-3 PUFAs from fish-oil supplementation , inducing changes that can enhance stability of atherosclerotic plaques . By contrast , increased consumption of n-6 PUFAs does not affect carotid plaque fatty-acid composition or stability over the time course studied here . Stability of plaques could explain reductions in non-fatal and fatal cardiovascular events associated with increased n-3 PUFA intake To determine the safety and benefit of n-3 fatty acid therapy in the prevention of early restenosis after coronary angioplasty , we conducted a r and omized , unblinded study comparing a conventional antiplatelet regimen ( 325 mg of aspirin and 225 mg of dipyridamole per day ; control group ) with a similar regimen supplemented with 3.2 g of eicosapentaenoic acid per day ( treatment group ) . Treatment began seven days before angioplasty and continued for six months afterward . All angiographic analyses were blinded and performed by a method that was vali date d by comparison with quantitative coronary angiography . In 82 male patients , 103 coronary lesions were dilated . Both groups had similar base-line clinical and angiographic characteristics . The incidence of early vessel restenosis , as determined on a second angiogram three to four months after angioplasty , was 36 percent in the control group and 16 percent in the treatment group ( P = 0.026 ) . The incidence of restenosis per patient was also significantly lower in the treatment group ( 46 vs. 19 percent ) . Both multiple logistic regression and Mantel-Haenszel statistical analyses demonstrated a significant independent benefit of treatment with n-3 fatty acids . No important bleeding complications developed in the treated patients . These results , in a male population at relatively high risk for restenosis , suggest that a dietary supplement of n-3 fatty acids , administered for one week before and for six months after coronary angioplasty , is safe and reduces the occurrence of early restenosis after that procedure . Whether this beneficial effect also applies to other population s is unknown The aim of this study was to determine whether plasma and red cell fatty acid levels were associated with cardiovascular disease , and whether any association was independent of other major risk factors . Over 1100 subjects were examined in a r and om sample survey of the general population ( the Edinburgh Artery Study ) .  Fatty acids were measured in three plasma fractions ( triglyceride , cholesteryl ester and phospholipid ) and in red cell phospholipids . Fatty acid levels in groups with cardiovascular disease ( myocardial infa rct ion ( MI ) , angina and lower limb disease ) were compared with a no disease group . In the cholesteryl ester and phospholipid fractions there were significantly lower levels of eicosapentaenoic acid in the MI group on univariate analysis ( p,0.05 ) , but not when adjusted for age , sex , smoking and systolic blood pressure using logistic regression . In the red cell fraction , alpha-linolenic acid was significantly lower in those with stroke ( p,0.01 ) and lower limb disease ( p,0.05 ) . Linoleic acid was significantly raised in the triglyceride fraction in those with MI , probably reflecting recent dietary changes . There were significant increases in dihomo-gamma-linolenic acid in the phospholipid and red cell fractions in those with MI , and in the phospholipid fraction in the stroke group . These results do not support the hypothesis that n-6 fatty acids are protective against cardiovascular disease , although there may be some beneficial effects of the n-3 fatty acid , alpha-linolenic acid . Results from cross-sectional surveys must , however , be interpreted with caution because the presence of disease may affect dietary intake Since the first AHA Science Advisory “ Fish Consumption , Fish Oil , Lipids , and Coronary Heart Disease,”1 important new findings , including evidence from r and omized 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.2 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 ( α-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 review ed , 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 . # # # Coronary Heart Disease As review ed by Stone,1 three prospect i ve epidemiological studies within population s reported that men who ate at least some fish weekly had a lower coronary heart disease ( CHD ) mortality rate than that of men who ate none.3–6 ⇓ ⇓ ⇓ More recent evidence that fish consumption favorably affects CHD mortality , especially nonsudden death from myocardial infa rct ion ( MI ) , has been reported in a 30-year follow-up of the Chicago Western Electric Study .7 Men who consumed 35 g or more of fish daily compared with those who consumed none had a relative risk of death from CHD of 0.62 and a relative risk of nonsudden death from MI of 0.33 . In an BACKGROUND Results from prospect i ve cohort studies and r and omized , controlled trials have provided evidence of a protective effect of n-3 fatty acids against cardiovascular diseases . We examined the effect of the marine n-3 fatty acids eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) and of the plant-derived alpha-linolenic acid ( ALA ) on the rate of cardiovascular events among patients who have had a myocardial infa rct ion . METHODS In a multicenter , double-blind , placebo-controlled trial , we r and omly assigned 4837 patients , 60 through 80 years of age ( 78 % men ) , who had had a myocardial infa rct ion and were receiving state-of-the-art antihypertensive , antithrombotic , and lipid-modifying therapy to receive for 40 months one of four trial margarines : a margarine supplemented with a combination of EPA and DHA ( with a targeted additional daily intake of 400 mg of EPA-DHA ) , a margarine supplemented with ALA ( with a targeted additional daily intake of 2 g of ALA ) , a margarine supplemented with EPA-DHA and ALA , or a placebo margarine . The primary end point was the rate of major cardiovascular events , which comprised fatal and nonfatal cardiovascular events and cardiac interventions . Data were analyzed according to the intention-to-treat principle , with the use of Cox proportional-hazards models . RESULTS The patients consumed , on average , 18.8 g of margarine per day , which result ed in additional intakes of 226 mg of EPA combined with 150 mg of DHA , 1.9 g of ALA , or both , in the active-treatment groups . During the follow-up period , a major cardiovascular event occurred in 671 patients ( 13.9 % ) . Neither EPA-DHA nor ALA reduced this primary end point ( hazard ratio with EPA-DHA , 1.01 ; 95 % confidence interval [ CI ] , 0.87 to 1.17 ; P=0.93 ; hazard ratio with ALA , 0.91 ; 95 % CI , 0.78 to 1.05 ; P=0.20 ) . In the prespecified subgroup of women , ALA , as compared with placebo and EPA-DHA alone , was associated with a reduction in the rate of major cardiovascular events that approached significance ( hazard ratio , 0.73 ; 95 % CI , 0.51 to 1.03 ; P=0.07 ) . The rate of adverse events did not differ significantly among the study groups . CONCLUSIONS Low-dose supplementation with EPA-DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infa rct ion and who were receiving state-of-the-art antihypertensive , antithrombotic , and lipid-modifying therapy . ( Funded by the Netherl and s Heart Foundation and others ; Clinical Trials.gov number , NCT00127452 . )
INTRODUCTION Cardiovascular disease remains the commonest health problem in developed countries , and residual risk after implementing all current therapies is still high .
The use of marine omega-3 fatty acids ( DHA and EPA ) has been recommended to reduce cardiovascular risk by multiple mechanisms .
OBJECTIVES To up date the current evidence on the influence of omega-3 on the rate of cardiovascular events .