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Fish Consumption and Acute Coronary Syndrome: A Meta-Analysis

  • Sylvie S.L. Leung Yinko
    Affiliations
    Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada

    Division of Clinical Epidemiology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
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  • Ken D. Stark
    Affiliations
    Department of Kinesiology, University of Waterloo, Waterloo, Ontario, Canada
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  • George Thanassoulis
    Affiliations
    Division of Clinical Epidemiology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada

    Division of Cardiology, McGill University Health Centre, Montreal, Quebec, Canada
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  • Louise Pilote
    Correspondence
    Requests for reprints should be addressed to Louise Pilote, MD, MPH, PhD, Division of Clinical Epidemiology, McGill University Health Centre, 687 Pine Avenue, West V-Building, Montreal, QC H3A 1A1, Canada.
    Affiliations
    Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada

    Division of Clinical Epidemiology, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada

    Division of General Internal Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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      Abstract

      Background

      Findings on the association between fish consumption and acute coronary syndrome are inconsistent. We assessed the role of fish consumption in acute coronary syndrome by conducting a dose-response meta-analysis.

      Methods

      We conducted a literature search of MEDLINE and Embase databases from 1966 to June 2013 for prospective cohort and case-control studies that evaluated the association between fish consumption and acute coronary syndrome among general populations without cardiovascular disease history. Additional studies were identified via hand search of references of relevant articles. Estimates of relative risk (RR) were pooled using random-effects model. Sex and age effects were also evaluated.

      Results

      Our search retrieved 11 prospective cohort and 8 case-control studies, totaling 408,305 participants. Among prospective cohort studies, the highest category of fish consumption (ie, ≥4 times per week) was associated with the greatest risk reduction in acute coronary syndrome (RR 0.79; 95% confidence interval [CI], 0.70-0.89). In dose-response analysis, each additional 100-g serving of fish per week was associated with a 5% reduced risk (RR per serving 0.95; 95% CI, 0.92-0.97). Subgroup analysis and meta-regression suggested that the risk reduction did not differ across sex or age groups. No heterogeneity was observed among prospective cohort (P = .73) and case-control (P = .29) studies. There was no evidence of publication bias.

      Conclusion

      Our meta-analysis demonstrated that there is an inverse association between fish consumption and the risk of acute coronary syndrome. Fish consumption appears beneficial in the primary prevention of acute coronary syndrome, and higher consumption is associated with greater protection.

      Keywords

      Clinical Significance
      • Fish consumption is beneficial for the primary prevention of acute coronary syndrome.
      • Each additional 100-g serving of fish per week is associated with a 5% reduced risk of acute coronary syndrome.
      • Age and sex do not appear to influence the association between fish consumption and acute coronary syndrome.
      Fish, especially fatty fish, are a rich source of omega-3 fatty acids. Omega-3 fatty acids are polyunsaturated fatty acids, consisting of eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6), which have been shown to have anti-inflammatory, antithrombotic, and antiarrhythmic effects; improve blood lipid profile, and help in vascular relaxation and plaque stability.
      • Kris-Etherton P.M.
      • Harris W.S.
      • Appel L.J.
      Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.
      Yet, controversy exists as to the efficacy of omega-3 fatty acids in preventing cardiovascular diseases, and recent meta-analyses have indicated that omega-3 fatty acid supplements are not associated with cardiovascular disease risk reduction.
      • Kotwal S.
      • Jun M.
      • Sullivan D.
      • et al.
      Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis.
      • Rizos E.C.
      • Ntzani E.E.
      • Bika E.
      • et al.
      Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.
      Conversely, it appears that fish, as opposed to omega-3 fatty acid supplements, may be beneficial to cardiovascular health, and the distinction between fish versus omega-3 fatty acid intake requires further exploration.
      Evidence from meta-analyses indicate the cardioprotective effects of fish consumption in relation to different end points such as cerebrovascular diseases, heart failure, and overall cardiovascular mortality,
      • Chowdhury R.
      • Stevens S.
      • Gorman D.
      • et al.
      Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis.
      • Djousse L.
      • Akinkuolie A.O.
      • Wu J.H.
      • et al.
      Fish consumption, omega-3 fatty acids and risk of heart failure: a meta-analysis.
      • He K.
      • Song Y.
      • Daviglus M.L.
      • et al.
      Fish consumption and incidence of stroke: a meta-analysis of cohort studies.
      • Larsson S.C.
      • Orsini N.
      Fish consumption and the risk of stroke: a dose-response meta-analysis.
      • Mozaffarian D.
      • Rimm E.B.
      Fish intake, contaminants, and human health: evaluating the risks and the benefits.
      but none of these reviews have assessed the role of fish consumption in the primary prevention of acute coronary syndrome. Findings from observational studies, including long-term prospective cohort and case-control studies, have not been consistent, with some studies, but not all, reporting an association between fish consumption and acute coronary syndrome. A systematic review and quantitative analysis of these studies is therefore needed to clarify the association between fish consumption and acute coronary syndrome.
      The aim of this study was to investigate the association between fish consumption and acute coronary syndrome by conducting a dose-response meta-analysis. As a secondary objective, we evaluated whether this association varied according to sex and age.

      Methods

      The Meta-analysis Of Observational Studies in Epidemiology (MOOSE) protocol
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • et al.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      was followed throughout the design, implementation, analysis, and reporting of this systematic review and meta-analysis study.

      Study Selection

      We conducted a literature search of MEDLINE and Embase databases from 1966 to June 2013 for studies that evaluated the association between fish consumption and acute coronary syndrome, using search terms for fish (“fish” OR “fish meat” OR “seafood”) in combination with those for acute coronary syndrome (“acute coronary syndrome” OR “myocardial infarction” OR “heart infarction” OR “heart infarct”) (see Supplementary Figure 1, available online for details of search strategy). References of relevant articles were hand searched to identify additional studies. Studies were included if they met the following criteria:
      • Prospective cohort or case-control study design.
      • Fish consumption as exposure of interest.
      • Acute coronary syndrome as outcome of interest.
      • The most adjusted relative risk (RR) and 95% confidence interval (CI) were reported.
      • The study population consisted of general adult populations without preexisting disease or without a previous acute coronary syndrome event.
      • For dose-response analysis, the number of cases and participants or person-years for each category of fish consumption were reported (or data were available to calculate them).
      We restricted studies to those published in English or French. If a study reported a measure of association and 95% CI for men and women, the results were treated as 2 separate studies in the meta-analysis. For studies that reported results only by different types of acute coronary syndrome (eg, fatal and nonfatal myocardial infarction) or by different types of fish (eg, low- and high-fat fish), the RRs were pooled. Finally, if data were shared or duplicated in more than one study, the first published or most detailed one was included in the analysis.

      Data Extraction

      Relevant data were independently extracted by 2 reviewers using a predesigned data collection form. Disagreements were resolved by consensus through discussion, or upon consultation of a third reviewer. The collected data included first author’s last name, year of publication, country where the study was conducted, duration and person-years of follow-up, sample size and proportion of men and women, mean and range of age, type and number of acute coronary syndrome events, method used to assess fish consumption, categories of fish consumption, most adjusted RR and corresponding 95% CI for each category of fish consumption, and the variables included in the multivariable model.

      Quality Assessment

      Quality assessment was performed using the Newcastle Ottawa Scale, which is one of the most comprehensive tools available for assessing the quality of nonrandomized studies (cohort and case-control studies) in meta-analyses.

      Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed on June 10, 2013.

      Scores range from 0 to 9, with a higher score indicating better methodological quality. Studies with a score ≥7 were considered as being of higher quality.

      Statistical Analysis

      As some studies reported category of consumption in frequency, we first standardized these intake levels by converting frequency into grams per day, using 100 g as a standard portion size for fish, as per dietary guidelines. The mean or median fish intake per category of each study was then used to categorize the levels of intake into 5 standardized intervals, namely “less than once per month” (the reference category), “1 to <4 times per month,” “1 to <2 times per week,” “2 to <4 times per week,” and “≥4 times per week.” We assumed that the reported reference exposure category from all studies represented a level of intake that was similar to the standardized reference category. When a range of intake was reported rather than the mean or median, the midpoint value of the upper and lower boundaries of the category was used as the average intake. If the highest level of intake was open ended (eg, ≥5 times per week), we assumed that that boundary had the same magnitude as the closest category. If a study did not report the lower boundary of the lowest category of fish consumption, it was considered to be zero. Additionally, if the mean or median or average amount of fish consumption from 2 or more categories of a single study fell into the same standardized category of fish intake, the estimates were pooled. Dose-response meta-analysis was conducted using generalized least-squares method for trend estimation of summarized dose-response data.
      • Greenland S.
      • Longnecker M.P.
      Methods for trend estimation from summarized dose-response data, with applications to meta-analysis.
      Restricted cubic splines with 3 knots at fixed percentiles were used to examine potential nonlinear relationship between fish consumption and acute coronary syndrome. Potential departure from a linear relationship was assessed by testing the null hypothesis that the coefficient of the second spline is equal to 0. Furthermore, we conducted subgroup analysis and meta-regression to investigate the effect of sex and age on the potential association between fish consumption and acute coronary syndrome.
      The DerSimonian and Laird random-effects model,
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      which considers both within- and between-study variation, was used to calculate summary estimates and 95% CIs for each category of fish consumption. Heterogeneity among studies was assessed by using the I2 statistic test.
      • Higgins J.P.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      Potential publication bias was assessed by using funnel plots, Egger’s regression asymmetry test
      • Egger M.
      • Davey Smith G.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      and Begg’s rank correlation test.
      • Begg C.B.
      A measure to aid in the interpretation of published clinical trials.
      All statistical analyses were conducted using STATA, version 12.1 (StataCorp, College Station, Tex).

      Results

      Literature Search

      The initial search identified 1185 potentially relevant articles (276 from MEDLINE and 909 from Embase). Among them, 246 were duplicates. Two additional articles were identified via hand search. After initial screening, based on titles and abstracts, 37 articles remained. After full-text assessment, 18 articles were excluded for various reasons. Thus, the final set of studies consisted of 19 studies (Figure 1).
      Figure thumbnail gr1
      Figure 1Flow diagram of selection of studies on fish consumption and acute coronary syndrome*.

      Study Characteristics

      The combined studies included 11 prospective cohort
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • et al.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      • Bjerregaard L.J.
      • Joensen A.M.
      • Dethlefsen C.
      • et al.
      Fish intake and acute coronary syndrome.
      • Daviglus M.L.
      • Stamler J.
      • Orencia A.J.
      • et al.
      Fish consumption and the 30-year risk of fatal myocardial infarction.
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • et al.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      • Hu F.B.
      • Bronner L.
      • Willett W.C.
      • et al.
      Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      • Kuhn T.
      • Teucher B.
      • Kaaks R.
      • Boeing H.
      • Weikert C.
      • Buijsse B.
      Fish consumption and the risk of myocardial infarction and stroke in the German arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Germany).
      • Morris M.C.
      • Manson J.E.
      • Rosner B.
      • et al.
      Fish consumption and cardiovascular disease in the physicians' health study: a prospective study.
      • Mozaffarian D.
      • Lemaitre R.N.
      • Kuller L.H.
      • et al.
      Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study.
      • Yamagishi K.
      • Iso H.
      • Date C.
      • et al.
      Fish, omega-3 polyunsaturated fatty acids, and mortality from cardiovascular diseases in a nationwide community-based cohort of Japanese men and women the JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) Study.
      • Yuan J.M.
      • Ross R.K.
      • Gao Y.T.
      • Yu M.C.
      Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China.
      and 8 case-control
      • Gramenzi A.
      • Gentile A.
      • Fasoli M.
      • et al.
      Association between certain foods and risk of acute myocardial infarction in women.
      • Lockheart M.S.
      • Steffen L.M.
      • Rebnord H.M.
      • et al.
      Dietary patterns, food groups and myocardial infarction: a case-control study.
      • Martinez-Gonzalez M.A.
      • Fernandez-Jarne E.
      • Serrano-Martinez M.
      • et al.
      Mediterranean diet and reduction in the risk of a first acute myocardial infarction: an operational healthy dietary score.
      • Oliveira A.
      • Lopes C.
      • Rodriguez-Artalejo F.
      Adherence to the Southern European Atlantic Diet and occurrence of nonfatal acute myocardial infarction.
      • Panagiotakos D.B.
      • Pitsavos C.
      • Zampelas A.
      • et al.
      Fish consumption and the risk of developing acute coronary syndromes: the CARDIO2000 study.
      • Sasazuki S.
      Case-control study of nonfatal myocardial infarction in relation to selected foods in Japanese men and women.
      • Tavani A.
      • Pelucchi C.
      • Negri E.
      • et al.
      n-3 Polyunsaturated fatty acids, fish, and nonfatal acute myocardial infarction.
      • Wennberg M.
      • Bergdahl I.A.
      • Hallmans G.
      • et al.
      Fish consumption and myocardial infarction: a second prospective biomarker study from northern Sweden.
      studies, totaling 408,305 participants (398,177 for prospective cohort and 10,128 for case-control studies), with 47.1% being male. The mean age was 55.8 years (age range 20-84 years). There were 8517 cases of acute coronary syndrome. The majority of the studies were from the US (5 studies) and Japan (3 studies). The remaining were from various European countries, and one study was from China. Among prospective cohort studies, the average follow-up time was 11.2 years, ranging from 4 to 30 years (Table 1, Table 2).
      Table 1Characteristics of Included Cohort Studies on Fish Consumption and Acute Coronary Syndrome
      First Author, Year of Publication (Country)Years & Duration of Follow-UpNumber of ParticipantsMean Age (Range), YearsNumber of Cases (Outcome)Dietary Assessment ToolCategories of Fish ConsumptionCovariates
      Ascherio, 1995 (US)
      • Ascherio A.
      • Rimm E.B.
      • Stampfer M.J.
      • et al.
      Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men.
      1986-1992

      6
      44,895 men57.5 (40-75)547 (nonfatal MI)Self-administered FFQ<1/mo, 1-3/mo, 1/wk, 2-3/wk, 4-5/wk, ≥6/wkAge, BMI, smoking, alcohol consumption, history of hypertension, history of diabetes, history of hypercholesterolemia, family history of MI before 60 years, profession, intake of n-3 fatty acids
      Bjerregaard, 2010 (Denmark)
      • Bjerregaard L.J.
      • Joensen A.M.
      • Dethlefsen C.
      • et al.
      Fish intake and acute coronary syndrome.
      1993-2003

      7.6
      25,573 men

      28,653 women
      56 (50-64)854 (nonfatal MI)Self-administered FFQ0-24 g/d, 25-35 g/d, 36-47 g/d, 48-64 g/d, >64 g/d (men); 0-22 g/d, 23-31 g/d, 32-41 g/d, 42-54 g/d, >55 g/d (women)Education, smoking, alcohol intake, BMI, history of diabetes, systolic blood pressure, serum cholesterol, physical activity, dietary intake of fruits and vegetables, total energy intake, dietary intake of SFA, MUFA and PUFA, menopausal status
      Daviglus, 1997 (US)
      • Daviglus M.L.
      • Stamler J.
      • Orencia A.J.
      • et al.
      Fish consumption and the 30-year risk of fatal myocardial infarction.
      1957-1959

      30
      1822 men47.6 (40-55)293 (fatal MI)Questionnaire-based interview by nutritionists0 g/d, 1-17 g/d, 18-34 g/d, ≥35 g/dAge, education, religion, systolic pressure, serum cholesterol, number of cigarettes smoked, BMI, diabetes, electrocardiographic abnormalities, intake of energy, cholesterol, SFA, MUFA, PUFA, total protein, carbohydrate, alcohol, iron, thiamine, riboflavin, niacin, vitamin C, beta carotene and retinol
      de Goede, 2010 (Netherlands)
      • de Goede J.
      • Geleijnse J.M.
      • Boer J.M.
      • et al.
      Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake.
      1993-2007

      11.3
      9604 men

      11,738 women
      42.1 (20-65)64 (fatal MI)

      252 (nonfatal MI)
      Self-administered FFQ<3.3 g/d, 3.3-7.3 g/d, 7.4-14 g/d, >14 g/dAge, sex, BMI, total energy intake, ethanol intake, smoking, SES, vitamin or mineral supplement use, use of drugs for hypertension or hypercholesterolemia, family history of cardiovascular diseases, SFA intake, fruit and vegetable intake
      Hu, 2002 (US)
      • Hu F.B.
      • Bronner L.
      • Willett W.C.
      • et al.
      Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.
      1980-1994

      16
      84,688 women46.5 (34-59)1029 (nonfatal MI)Self-administered FFQ<1/mo, 1-3/mo, 1/wk, 2-4/wk, ≥5/wkAge, time periods, smoking, BMI, alcohol intake, menopausal status, postmenopausal hormone use, vigorous to moderate activity, use of aspirin, multivitamin use, vitamin E supplement use, history of hypertension, hypercholesterolemia, diabetes, intake of trans fat, ratio PUFA:SFA, dietary fiber
      Iso, 2006 (Japan)
      • Iso H.
      • Kobayashi M.
      • Ishihara J.
      • et al.
      Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I.
      1990-2001

      10
      19,985 men

      21,593 women
      49.5 (40-59)198 (total MI)Self-administered FFQmedian 23 g/d, 51 g/d, 78 g/d, 114 g/d, 180 g/dAge, sex, smoking, alcohol intake, BMI, history of hypertension and diabetes, medication use for hypercholesterolemia, education, sports at leisure time, dietary intake of fruits, vegetables, SFA, MUFA, n-6 PUFA, cholesterol and total energy, public health centers
      Kuhn, 2013 (Germany)
      • Kuhn T.
      • Teucher B.
      • Kaaks R.
      • Boeing H.
      • Weikert C.
      • Buijsse B.
      Fish consumption and the risk of myocardial infarction and stroke in the German arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Germany).
      1994-1998

      8.1
      20,292 men

      28,023 women
      50.5 (35-65)605 (total MI)Self-administered FFQ<7.5 g/d, 7.5-14.5 g/d, 14.5-21.5 g/d, 21.5-31.1 g/d, >31.1 g/dAge, sex, study centers, energy intake, alcohol intake, BMI, waist circumference, physical activity, education, smoking, diabetes
      Morris, 1995 (US)
      • Morris M.C.
      • Manson J.E.
      • Rosner B.
      • et al.
      Fish consumption and cardiovascular disease in the physicians' health study: a prospective study.
      1982-1988

      4
      21,185 men62 (40-84)281 (total MI)Self-administered FFQ<1/wk, 1/wk, 2-4/wk, ≥5/wkAge, level of fish consumption, aspirin and beta-carotene assignment, smoking, alcohol consumption, obesity, diabetes, vigorous exercise, parental history of MI before 60, history of hypertension, history of hypercholesterolemia, vitamin supplement use, SFA intake
      Mozaffarian, 2003 (US)
      • Mozaffarian D.
      • Lemaitre R.N.
      • Kuller L.H.
      • et al.
      Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study.
      1989-2000

      9.3
      1526 men

      2384 women
      72.7 (≥65)363 (nonfatal MI)Self-administered FFQ picture-sort version1/mo, 1-3/mo, 1/wk, 2/wk, ≥3/wkAge, sex, education, diabetes, smoking, pack-years of smoking, tuna/other fish and fried fish/fish sandwich consumption, BMI, systolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, C-reactive protein, intake of SFA, alcohol, beef/pork, fruits and vegetables
      Yamagishi, 2008 (Japan)
      • Yamagishi K.
      • Iso H.
      • Date C.
      • et al.
      Fish, omega-3 polyunsaturated fatty acids, and mortality from cardiovascular diseases in a nationwide community-based cohort of Japanese men and women the JACC (Japan Collaborative Cohort Study for Evaluation of Cancer Risk) Study.
      1988-2003

      12.7
      22,881 men

      35,091 women
      56.1 (40-79)329 (fatal MI)Self-administered FFQMedian 20 g/d, 33 g/d, 45g/d, 62 g/d, 86 g/d (men); 21 g/d, 33 g/day, 46g/d, 62 g/d, 85 g/d (women)Age, sex, history of hypertension and diabetes, smoking, alcohol consumption, BMI, mental stress, walking, sports, education, total energy, dietary intake of cholesterol, SFA, n-6 PUFA, vegetables and fruits
      Yuan, 2001 (China)
      • Yuan J.M.
      • Ross R.K.
      • Gao Y.T.
      • Yu M.C.
      Fish and shellfish consumption in relation to death from myocardial infarction among men in Shanghai, China.
      1986-1989

      12
      18,244 men55.8 (45-64)113 (fatal MI)Questionnaire-based interview<30 g/wk, 30-<60 g/wk, 60-<100 g/wk, 100-<150 g/wk, ≥150 g/wkAge, total energy intake, level of education, BMI, smoking, number of cigarettes smoked, number of alcoholic drinks consumed, history of diabetes, history of hypertension
      BMI = body mass index; FFQ = food frequency questionnaire; MI = myocardial infarction; MUFA = monounsaturated fatty acid; PUFA = polyunsaturated fatty acid; SES = socioeconomic status; SFA = saturated fatty acid.
      Table 2Characteristics of Included Case-Control Studies on Fish Consumption and Acute Coronary Syndrome
      First Author, Year of Publication (Country)YearsNumber of ParticipantsMean Age (Range), YearsNumber of Cases (Outcome)Dietary Assessment ToolCategories of Fish ConsumptionCovariates
      Gramenzi, 1990 (Italy)
      • Gramenzi A.
      • Gentile A.
      • Fasoli M.
      • et al.
      Association between certain foods and risk of acute myocardial infarction in women.
      1983-1989936 women49 (21-69)287 (total MI)Questionnaire-based interview<1/wk, 1/wk, >1/wkAge, area of residence, education, smoking, hyperlipidemia, diabetes, hypertension, BMI, intake of carrots, green vegetables, fresh fruit, meat, ham and salami, butter, total fat score, coffee consumption, alcohol consumption
      Lockheart, 2007 (Norway)
      • Lockheart M.S.
      • Steffen L.M.
      • Rebnord H.M.
      • et al.
      Dietary patterns, food groups and myocardial infarction: a case-control study.
      1995-1997211 men and women62.4 (45-75)106 (total MI)Interview using FFQMedian 32 g/d, 99 g/d (low-fat); 12 g/d, 52 g/d (high-fat)Age, marital status, education, family history of heart disease, smoking, energy intake
      Martinez-Gonzalez, 2002 (Spain)
      • Martinez-Gonzalez M.A.
      • Fernandez-Jarne E.
      • Serrano-Martinez M.
      • et al.
      Mediterranean diet and reduction in the risk of a first acute myocardial infarction: an operational healthy dietary score.
      1999-2001277 men

      65 women
      61.6 (<80)171 (total MI)Self-administered FFQ<60 g/d, >77 g/dAge, sex, hospital, smoking, BMI, high blood pressure, high blood cholesterol, diabetes, leisure-time physical activity, SES, intake of olive oil, fiber, fruits, vegetables, alcohol, meat/meat products and white bread/rice/pasta
      Oliveira, 2010 (Portugal)
      • Oliveira A.
      • Lopes C.
      • Rodriguez-Artalejo F.
      Adherence to the Southern European Atlantic Diet and occurrence of nonfatal acute myocardial infarction.
      1999-20031460 men

      1556 women
      52 (33-69)820 (nonfatal MI)Interview using FFQMedian <35.5 g/d, ≥35.5 g/d (excluding cod); <13.5 g/d, ≥13.5 g/d (cod)Sex, age, education, total energy intake, intake of fruit, refined cereals and white meat, smoking, regular physical activity, family history of MI, BMI, menopause, hormone replacement therapy
      Panagiotakos, 2005 (Greece)
      • Panagiotakos D.B.
      • Pitsavos C.
      • Zampelas A.
      • et al.
      Fish consumption and the risk of developing acute coronary syndromes: the CARDIO2000 study.
      2000-20011562 men

      364 women
      60.1 (49-75)848 (nonfatal ACS)Questionnaire-based interviewNever, <150 g/wk, 150-300 g/wk, >300 g/wkAge, sex, smoking, hypertension, hypercholesterolemia, HDL cholesterol, LDL cholesterol, diabetes, physical inactivity, BMI, food items consumed
      Sasazuki, 2001 (Japan)
      • Sasazuki S.
      Case-control study of nonfatal myocardial infarction in relation to selected foods in Japanese men and women.
      1996-19981340 men

      506 women
      59.5 (40-79)458 (nonfatal MI)Questionnaire-based interview<2/wk, 2-3/wk, ≥4/wkSmoking, alcohol use, sedentary job, leisure-time physical activity, hyperlipidemia, hypertension, diabetes, angina pectoris, obesity, tofu consumption, fruit consumption
      Tavani, 2001 (Italy)
      • Tavani A.
      • Pelucchi C.
      • Negri E.
      • et al.
      n-3 Polyunsaturated fatty acids, fish, and nonfatal acute myocardial infarction.
      1995-1999675 men

      310 women
      60 (25-79)507 (nonfatal MI)Interview using FFQ<1/wk, 1-<2/wk, ≥2/wkAge, sex, education, BMI, cholesterol, smoking, coffee, alcohol, meat, vegetables, fruit, calorie intakes, physical activity, hyperlipidemia, diabetes, hypertension, family history of MI in first-degree relatives
      Wennberg, 2011 (Sweden)
      • Wennberg M.
      • Bergdahl I.A.
      • Hallmans G.
      • et al.
      Fish consumption and myocardial infarction: a second prospective biomarker study from northern Sweden.
      1987-1999648 men

      218 women
      58.7 (34-77)392 (total MI)Self-administered FFQ<1/mo, 1/mo-<1/wk, 1-2/wk, >2/wkApolipoprotein B/apolipoprotein A-I, smoking, systolic blood pressure, diabetes, education, consumption of fruit and vegetables, consumption of wine, consumption of strong beer, level of physical activity
      ACS = acute coronary syndrome; BMI = body mass index; FFQ = food frequency questionnaire; MI = myocardial infarction; MUFA = monounsaturated fatty acid; PUFA = polyunsaturated fatty acid; SES = socioeconomic status; SFA = saturated fatty acid.

      Fish Consumption and Acute Coronary Syndrome

      Among prospective cohort studies, a significant association was observed between fish consumption and a reduced risk of acute coronary syndrome (Table 3, Figure 2). The highest category of fish consumption (ie, ≥4 times per week) was associated with the greatest risk reduction in acute coronary syndrome (RR 0.79; 95% CI, 0.70-0.89). No evidence of heterogeneity was found (I2 = 0.0%, P = .73). Although most of the studies (9 of 11) were of high quality, we conducted an analysis to exclude the studies of low quality, and obtained similar results. Because all except 2 studies reported hazard ratios as measures of association, we performed a separate analysis for these studies. The results were similar, with the highest category of fish consumption being associated with a 21% reduced risk of acute coronary syndrome (hazard ratio 0.79; 95% CI, 0.69-0.90). In sensitivity analysis excluding the largest study, we also found a significant reduction in the risk of acute coronary syndrome (RR 0.76; 95% CI, 0.66-0.88). Furthermore, the results did not differ according to country.
      Table 3Pooled Measures of Acute Coronary Syndrome According to Category of Fish Consumption
      RR (95% CI) per Category of Fish Consumption
      <Once per Month1 to <4 Times per Month1 to <2 Times per Week2 to <4 Times per Week≥4 Times per Week
      Prospective cohort1.000.82 (0.72-0.92)0.85 (0.72-1.01)0.83 (0.71-0.96)0.79 (0.70-0.89)
       Highest quality studies1.000.84 (0.74-0.95)0.81 (0.73-0.91)0.84 (0.73-0.95)0.79 (0.70-0.89)
       Hazard ratio only1.000.83 (0.73-0.95)0.81 (0.72-0.90)0.81 (0.70-0.95)0.79 (0.69-0.90)
       Largest study excluded1.000.82 (0.72-0.92)0.85 (0.72-1.01)0.80 (0.67-0.96)0.76 (0.66-0.88)
      Case-control1.000.76 (0.67-0.87)0.84 (0.64-1.10)0.73 (0.49-1.09)
      CI = confidence interval; RR = relative risk.
      Figure thumbnail gr2
      Figure 2Meta-analysis of prospective and case-control studies on fish consumption and acute coronary syndrome comparing the highest (≥4 times per week) to lowest (less than once per month) category of intake.
      Among case-control studies, fish consumption also appeared to reduce the risk of acute coronary syndrome (RR 0.76; 95% CI, 0.67-0.87 for 1 to <2 times per week), but the association was nonsignificant for the highest versus lowest category. Similar to prospective cohort studies, little heterogeneity was observed (I2 = 20.2%, P = .29). Generally, the case-control studies were of poorer quality, and only 2 studies were considered as being of high quality, with their score being 7 each. In sensitivity analysis, no substantial change was seen after excluding the largest study.

      Dose-Response Analysis

      Eight prospective cohort studies provided sufficient data to conduct a dose-response analysis. It was found that each additional 100-g serving of fish per week was associated with a risk reduction in acute coronary syndrome by 5% (RR 0.95; 95% CI, 0.92-0.97). We did not find evidence for a nonlinear relationship (P = .92).

      Effect of Sex and Age

      There were 6 studies (5 prospective cohort and 1 case-control studies) that were conducted among men only, and 4 studies (2 prospective cohort and 2 case-control studies) that were among women only. The subgroup analysis of prospective cohort studies of men versus women did not support a sex difference in the association between fish intake and acute coronary syndrome (RR 0.84; 95% CI, 0.70-1.01 and RR 0.80; 95% CI, 0.61-1.06 for men and women, respectively). There was also no evidence that the association differed by sex according to meta-regression (RR 0.95; 95% CI, 0.56-1.64).
      In additional meta-regression analyses where we included age as a continuous variable, there was no significant effect of age on the association between fish consumption and acute coronary syndrome. However, there was only modest variation in age across the included studies, with most studies having a mean age in the range of 47 to 62 years.

      Publication Bias

      No evidence of publication bias was found among the prospective cohort and case-control studies. This was supported by funnel plots, which did not show presence of asymmetry (Supplementary Figure 2, available online), as well as the Egger’s test (P = .60) and the Begg’s test (P = .44).

      Discussion

      Our meta-analysis demonstrated that there is an inverse association between fish consumption and the risk of acute coronary syndrome. We observed a greater risk reduction with increasing fish intake, and with each additional 100-g serving per week, the risk of acute coronary syndrome was further reduced by 5%.
      This study represents an updated investigation of the role of fish consumption in acute coronary syndrome. While several meta-analyses of observational studies have evaluated the effect of fish consumption on different cardiovascular outcomes,
      • Bouzan C.
      • Cohen J.T.
      • Connor W.E.
      • et al.
      A quantitative analysis of fish consumption and stroke risk.
      • Konig A.
      • Bouzan C.
      • Cohen J.T.
      • et al.
      A quantitative analysis of fish consumption and coronary heart disease mortality.
      • Whelton S.P.
      • He J.
      • Whelton P.K.
      • Muntner P.
      Meta-analysis of observational studies on fish intake and coronary heart disease.
      • Xun P.
      • Qin B.
      • Song Y.
      • et al.
      Fish consumption and risk of stroke and its subtypes: accumulative evidence from a meta-analysis of prospective cohort studies.
      • Zheng J.
      • Huang T.
      • Yu Y.
      • et al.
      Fish consumption and CHD mortality: an updated meta-analysis of seventeen cohort studies.
      none of them have specifically examined acute coronary syndrome as an outcome. The landmark DART (Diet and Reinfarction) trial demonstrated that fish consumption was beneficial for the secondary prevention of myocardial infarction, with ≥2 servings of fish per week being associated with reduced cardiovascular mortality risk.
      • Burr M.L.
      • Fehily A.M.
      • Gilbert J.F.
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).
      Yet, the benefits of omega-3 fatty acid supplements in the secondary prevention of cardiovascular diseases remain controversial in light of recent meta-analyses that have combined the evidence from randomized controlled trials and found no association.
      • Kotwal S.
      • Jun M.
      • Sullivan D.
      • et al.
      Omega 3 fatty acids and cardiovascular outcomes: systematic review and meta-analysis.
      • Rizos E.C.
      • Ntzani E.E.
      • Bika E.
      • et al.
      Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.
      Additionally, there is also a need to distinguish between primary versus secondary prevention. We explored the relationship between fish and acute coronary syndrome among generally healthy populations, as opposed to clinical trials. Our findings from prospective cohort studies confirm that fish consumption is beneficial in the primary prevention of acute coronary syndrome.
      The potential differential effect of omega-3 fatty acids from fish versus supplements has previously been highlighted. It has been suggested that the bioavailability and functioning of nutrients obtained from foods compared with supplements may differ.
      • Kris-Etherton P.M.
      • Hill A.M.
      N-3 fatty acids: food or supplements?.
      A 6-week experimental study comparing salmon to fish oil capsules found that EPA and DHA from dietary fish were more effectively incorporated into plasma lipids, leading to higher plasma concentrations of omega-3 fatty acids.
      • Visioli F.
      • Rise P.
      • Barassi M.C.
      • et al.
      Dietary intake of fish vs. formulations leads to higher plasma concentrations of n-3 fatty acids.
      In another study where participants were randomly assigned to the consumption of oily fish or omega-3 fatty acid capsules providing the same amount of EPA and DHA, EPA content in erythrocytes was found to increase more rapidly in the fish group.
      • Harris W.S.
      • Pottala J.V.
      • Sands S.A.
      • Jones P.G.
      Comparison of the effects of fish and fish-oil capsules on the n 3 fatty acid content of blood cells and plasma phospholipids.
      Thus, while omega-3 fatty acids have been shown to favorably impact markers of cardiovascular diseases, whether they come from a complex food matrix such as fish, or are in an isolated form, could possibly explain why differences are observed between fish and omega-3 fatty acid supplements.
      It has also been indicated that adherence to high omega-3 fatty acid diets in nutritional interventions may be poor.
      • Patterson A.C.
      • Metherel A.H.
      • Hanning R.M.
      • Stark K.D.
      The percentage of DHA in erythrocytes can detect non-adherence to advice to increase EPA and DHA intakes.
      It is plausible that one of the reasons why fish have a cardioprotective effect relative to supplements is that adherence to fish consumption may be higher. Fish can be included in the diet as a high-quality protein food and contain a wide array of other valuable nutrients including vitamins (A, D, B3, B6, B12) and minerals (calcium, phosphorus, selenium, iron, magnesium, potassium, iodine). These nutrients have diverse properties that are beneficial to the overall health. Higher vitamin D levels have also been linked to reduced acute coronary syndrome mortality and morbidity.
      • Dror Y.
      • Giveon S.M.
      • Hoshen M.
      • et al.
      Vitamin D levels for preventing acute coronary syndrome and mortality: evidence of a nonlinear association.
      Hence, when considering omega-3 fatty acid intake for cardiovascular benefits, a diet-based approach including fish, rather than supplements, may be warranted.
      Most of the studies included in this meta-analysis used food frequency questionnaires to assess fish consumption. Although fish consumption is a recognized proxy for omega-3 fatty acid intake, blood concentrations of omega-3 fatty acids may reflect dietary intake more strongly.
      • Harris W.S.
      The omega-3 index as a risk factor for coronary heart disease.
      Some studies have suggested that low blood levels of omega-3 fatty acids may be associated with an increased risk of acute coronary syndrome.
      • Block R.C.
      • Harris W.S.
      • Reid K.J.
      • et al.
      EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls.
      • Harris W.S.
      • Reid K.J.
      • Sands S.A.
      • Spertus J.A.
      Blood omega-3 and trans fatty acids in middle-aged acute coronary syndrome patients.
      • Joensen A.M.
      • Overvad K.
      • Dethlefsen C.
      • et al.
      Marine n-3 polyunsaturated fatty acids in adipose tissue and the risk of acute coronary syndrome.
      The omega-3 index, which is the sum of EPA and DHA in erythrocyte membranes, expressed as a percentage of total erythrocyte fatty acids, is a novel biomarker of blood concentrations of omega-3 fatty acids.
      • von Schacky C.
      The Omega-3 Index as a risk factor for cardiovascular diseases.
      The omega-3 index has been indicated as a reliable biomarker for assessing long-term omega-3 fatty acid intake, and fish consumption has been shown to strongly correlate with higher omega-3 index.
      • Salisbury A.C.
      • Amin A.P.
      • Harris W.S.
      • et al.
      Predictors of omega-3 index in patients with acute myocardial infarction.
      It has also been shown that men are better able to increase blood levels of omega-3 fatty acids with dietary advice on fish intake, likely because men consume larger portion sizes than women, which may not be captured by dietary assessment with food frequency questionnaires.
      • Patterson A.C.
      • Metherel A.H.
      • Hanning R.M.
      • Stark K.D.
      The percentage of DHA in erythrocytes can detect non-adherence to advice to increase EPA and DHA intakes.
      This study summarizes the evidence from observational studies but presents with some limitations. Our meta-analysis consisted of studies that adjusted for many important confounders, including socioeconomic status and various lifestyle behaviors such as different dietary factors, physical activity, and smoking. However, residual confounding is still possible, given that fish consumption may be associated with healthier lifestyle behaviors that are difficult to measure. Another limitation is that we had a relatively small sample of studies, which cannot eliminate the possibility of publication bias. Whether the association between fish consumption and acute coronary syndrome differed by sex was inconclusive, possibly due to our small number of studies. We also did not find an age effect, but this could be due to the narrow age range. It would have been equally interesting to evaluate whether the association differed by type of fish or acute coronary syndrome, but we did not have enough studies to conduct these analyses.
      In conclusion, fish consumption appears to be beneficial in the primary prevention of acute coronary syndrome. An inverse association between fish consumption and the risk of acute coronary syndrome was observed. A dose-response relationship was found between fish consumption and the reduced risk of acute coronary syndrome. Future studies are needed to further investigate whether sex differences and age effects exist. Moreover, more research is required to elucidate whether this association varies according to the type of fish.

      Acknowledgments

      We acknowledge Jin Choi for his help with data extraction.

      Appendix

      Figure thumbnail fx1
      Supplementary Figure 1Search strategies for studies on fish consumption and acute coronary syndrome.
      Figure thumbnail fx2
      Supplementary Figure 2Funnel plot of studies on fish consumption and acute coronary syndrome.

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