Abstract

OBJECTIVES: A vast amount of systematic reviews examined the relation between fish consumption and coronary heart disease (CHD), but less is known about the relation with stroke or total cardiovascular disease (CVD). Reviews examining dose response relationships are old, and excluded results from the majority of available studies.
Though dietary recommendations typically include the advice to include fatty fish in order to reduce CHD risk, no review systematically described differences in effect between fatty fish and lean fish.

• To review all prospective studies which published information about total fish, or specific types of fish, in relation with total CVD, CHD, and stroke.
• To define the amount of consumption found to be related with possible effects on the different CVD end points.
• To define possible effect modification by confounders.

DATA SOURCE: The Pubmed database was searched (No start date - Dec 13, 2010) for relevant articles using the keyword fish, omega 3, polyunsaturated fat, or seafood, combined with prospective, cohort, follow-up, or longitudinal and a fair amount of other keywords. The exact search term is described Here.
Prospective studies published in the English language were included. Reference lists were searched for additional articles.
RESULTS: 86 articles were found which provided information about 46 different cohorts. Of these, 0 articles were excluded. Results are described when any evidence for an association - as defined in the Methods - was found. In addition, data about total fish, fatty fish, and lean fish is described.

• Total CVD.
  -Data about total fish was provided by 15 cohorts, including 13,137 cases. Significant protective effects were found in 4 (sub)cohorts, 3 of which were of small size. Inconclusive evidence was found for an association with CVD risk (RR = 0.94). Effect sizes were similar for intakes of 1, 2, and ≥ 3 servings/week. Suggestive evidence was found for a protective effect against CVD mortality (RR = 0.84).
  -Data about fatty fish was provided by 1 cohort, and no association was found. Data about lean fish was not provided.
• CHD.
  -Data about total fish was provided by 37 cohorts, including 23,801 cases. Significant protective effects were found in 10 (sub)cohorts, 7 of which were of small size. Inconclusive evidence was found for an association with CHD risk (RR = 0.88). Effect sizes were similar for intakes of 2, and ≥ 3 servings/week. Protective effects were stronger among US cohorts (n = 11; RR = 0.86), and Asian cohorts (n = 8; RR = 0.85), than among European cohorts (n = 17; RR = 0.95). Inconclusive evidence was found for an association with CHD mortality (RR = 0.88), and heart failure (RR = 0.86). Consumption of 2-3 servings fish week possibly protects against nonfatal myocardial infarction (RR = 0.78 to 0.80).
  -Data about fatty fish was provided by 8 cohorts, and data about lean fish was provided by 5 cohorts. No evidence was found for a difference in effect.
  -Data about dried or salted fish was provied by 2 Asian cohorts. Protective effects were found in both cohorts. Suggestive evidence was found that consumption of dried/salted fish ≥ 3 times/week protects against CHD risk (RR = 0.74).
• Stroke.
  -Data about total fish was provided by 22 cohorts, including 21,290 cases. Significant protective effects were found in 6 (sub)cohorts, 3 of which were of moderate-very large size. Consumption of fish possibly protects against total stroke risk (RR = 0.87). Effect sizes were identical for intakes of 2 and ≥ 3 servings/week. Protective effects were found in US cohorts (n = 8; RR = 0.77), and Asian cohorts (n = 6; RR = 0.87), but not in European cohorts (n = 7; RR = 0.96). Protective effects among US cohorts were caused by a decrease in ischemic stroke, while protective effects in Asian cohorts were caused by a decrease in hemorrhagic stroke. Protective effects were found in female cohorts (n = 9; RR = 0.80), but not in male cohorts (n = 11; RR = 0.99).
  -Data about fatty fish was provided by 4 cohorts, and data about lean fish was provided by 3 cohorts. Inconclusive evidence was found for a difference in effect.

CONCLUSION: High fish consumption possibly protects against stroke risk. Consumption of 2-3 servings fish week possibly protects against nonfatal myocardial infarction. And suggestive evidence was found for a protective effect against total CVD mortality. Inconclusive evidence was found for an association between fish consumption and total CVD risk, CHD risk, CHD mortality, and risk of heart failure. Examination of a possible dose response effect shows effects against total CVD risk, total CVD mortality, CHD risk, CHD mortality, and stroke risk were similar for intakes of 2 and ≥ 3 servings fish/week.
Stratified analysis shows, effects against CHD risk, and stroke risk are stronger for/restricted to US/Asian populations. In addition, the evidence for a protective effect against stroke risk is restricted to women. Fish possibly protects against ischemic stroke in US cohorts, while it protects against hemorrhagic stroke in Asian cohorts.
Inconclusive evidence was found for a difference in effect between fatty fish and lean fish consumption. Suggestive evidence was found for a protective effect of dried/salted fish against CHD risk, but this association was only examined in 2 Asian cohorts. Little is know about effects from specific types of fish.
LIMITATIONS: Given the large amount of articles found from the literature, it is remarkable how little data is provided about subtypes of fish (e.g., fatty fish, fried fish), or specific types of fish (e.g., tuna, mackerel). Advisory committees worldwide recommend intake of (fatty) fish for prevention of CVD/CHD risk, while absolutely no data is available about effects from salmon, mackerel, or sardines.

Introduction.

The "dietary guidelines for Americans, 2010" report advices consumption of 2 servings of seafood/week at 4 oz per serving, because moderate evidence shows this to be associated with reduced cardiac mortality from CHD or sudden death in persons with and without CVD. The type of seafood chosen, should provide at least 250 mg of long-chain n-3 fatty acids per day (US Department of Agriculture and US Department of Health and Human Services).
Evidence from prospective studies was discussed on page D3-34 of the report, and is defined as follows:

Fatty fish intake decreased CVD incidence/risk in 10 prospective studies, according to the USDA. Findings according to the USDA report are put into the following table and compared to findings as they were presented in the articles referred to.

Summary of results:

• The study by Turunen (2008) should not have been included by the USDA. Fishermen were identified when they entered the "Professional Fishermen Register" between 1980-2002, and causes of death were linked with Finland's national causes-of-death from 1980-2005. In addition, 88 fishermen and 94 spouses completed a FFQ in 2004-2005, but data about fish (oil) intake was not linked to any health outcome.
• Fish or N-3 fatty acids from fish, decreased CVD incidence/risk at the recommended level of consumption in only 2 out of 10 cohorts (Virtanen 2008; Mozaffarian 2005). Actually, both authors examined the same cohort: "The Health Professionals Follow-up Study".
• Fatty fish consumption was examined in only 3 out of 10 cohorts (Levitan 2009; Virtanen 2008; Streppel 2008).
• Fatty fish consumption was related to decreased CVD incidence/risk in only one out of these 3 cohorts (Streppel 2008).
• Fatty fish consumption was related to decreased CVD incidence/risk at the recommended level of intake in 0 cohorts.

Conclusion: In "the dietary guidelines for Americans report, 2010", the USDA briefly describes results from prospective cohort studies. Effects from fatty fish intake on CVD incidence/risk would have been described in 10 cohorts, and the USDA suggests a consistent protective effect against CVD incidence/risk was found.
But fatty fish intake was examined in only 3 out of 10 cohorts, and in no case was a significant protective effect found at the recommended level of intake.

|Additional references:
Albert CM. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med. 2002 Apr 11;346(15):1113-8. Full text
Iso H. 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. Circulation. 2006 Jan 17;113(2):195-202. Full text
Järvinen R. Intake of fish and long-chain n-3 fatty acids and the risk of coronary heart mortality in men and women. Br J Nutr. 2006 Apr;95(4):824-9. Abstract
Lemaitre RN. n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr. 2003 Feb;77(2):319-25. Full text
Levitan EB. Fish consumption, marine omega-3 fatty acids, and incidence of heart failure: a population-based prospective study of middle-aged and elderly men. Eur Heart J. 2009 Jun;30(12):1495-500. Full text
Mozaffarian D. Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men. Circulation. 2005 Jan 18;111(2):157-64. Full text
Streppel MT. Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study. Eur Heart J. 2008 Aug;29(16):2024-30. Full text
Turunen AW. Mortality in a cohort with high fish consumption. Int J Epidemiol. 2008 Oct;37(5):1008-17. Full text
US Department of Agriculture and US Department of Health and Human Services. Report of the Dietary Guidelines Advisory Committee on the dietary guidelines for Americans, 2010. June 15, 2010. Available at: Link. Accessed on May 6, 2011.
Virtanen JK. Fish consumption and risk of major chronic disease in men. Am J Clin Nutr. 2008 Dec;88(6):1618-25. Full text
Yamagishi K. 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. J Am Coll Cardiol. 2008 Sep 16;52(12):988-96. Abstract|

Methods.

Defining fish consumption: "Total fish" included data about fish consumption with or without seafood/shellfish, or without using a definition for fish. Preferably, the definition excluded seafood/shellfish.
Data about "omega-3 fatty acids" was included as a surrogate for fish consumption, if these fatty acids reflected (primarily) non-supplemental dietary intakes; were defined as "marine omega-3 fatty acids", "omega-3 fatty acids from fish (oil)", or "dietary fish oil"; and did not include omega-3 from other dietary sources.
Preferably, fish consumption was chosen over consumption of marine omega-3 fatty acids.
Conversions for different units of consumption: Four systematic reviews provided data about conversion of grams to servings. In 2005, authors from two of these reviews (Bouzan C; König A) assumed that 100 g of fish was equivalent to one serving. In 2004, He K. published two systematic reviews. In both cases, the assumption was made that 105 g of fish was equivalent to one serving, based on the derived average portion size in the Health Professionals Follow-Up Study.
For my own systematic reviews, 105 g of fish was converted to one serving/portion. And for frequency intakes per week, the assumption was made that consumption of fish once/week is equal to consumption of one serving fish/week.
Dose response methodology: Fish consumption was categorized into standardized levels of intake. If one of these standardized levels of intake fell into two categories of intake in a single study, the average RR from these two categories was found to reflect the RR for this standardized level of intake. If > 1 standardized levels of intake fell into the same category of intake in a single study. The RR for this category was found to reflect the RR for all these standardized levels of intake. Studies were considered if they included ≥ 3 different levels of consumption. Studies examining fish oil as a proxy for fish consumption were not included.
Data from the author "Hirayama T.": Dr. Hirayama examined the effects of a small amount of food groups in relation to a large amount of mortality end points in a Japanese cohort of very large size. An extended review of his work was published as a book in 1990 (Hirayama T [10]). Data about this cohort is seldom included in current systematic reviews about the relations mentioned. Dr. Hirayama published a lot of articles stating that vegetables and meats were related to several disease end points, adjusted for age and sex. However, the book included one page showing effects after multivariate analysis including cigarette smoking, meat, green-yellow vegetables, and alcohol. This analysis showed that a large amount of previously published effects completely changed when these variables were taken into account.
Since a) Dr. Hirayama himself only published sex-, and age-adjusted results in the English language, while results following multivariate analysis often were completely different b) the results were published as a book and not in a peer-reviewed journal, and c) Dr. Hirayama was the only researcher examining this cohort, results from his cohort are debatable. Results will be presented including effects from his work, but his work will not be included when the evidence for a possible effect is judged.

|Additional references:
Bouzan C. A quantitative analysis of fish consumption and stroke risk. Am J Prev Med. 2005 Nov;29(4):347-52. Abstract
He K. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation. 2004 Jun 8;109(22):2705-11. Full text
He K. Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke. 2004 Jul;35(7):1538-42. Full text
König A. A quantitative analysis of fish consumption and coronary heart disease mortality. Am J Prev Med. 2005 Nov;29(4):335-46. Abstract|

Fish and total cardiovascular disease (CVD).

Background: In the past, several systematic reviews were published relating fish consumption to CHD or stroke, but Wang C (2004) was the only author to examine the relation with total cardiovascular disease. CVD mortality was the end point considered in this review.
The author found data about 5 cohorts (Daviglus ML [2], Dolecek TA [11], Albert CM [15], Gillum RF [17], Nagata C [23]). Significant protective effects were found in the smallest 2 of these cohorts (Daviglus ML [2], Dolecek TA [11]). Available data about 2 other cohorts was missing (Hu FB [14], Salonen JT [16]), and data about 4 additional cohorts was published following the publication of this review (Folsom AR [29], Chang-Claude J [30], Yamagishi K [36], Tomassalo C [45]).

|Additional reference:
Wang C. Effects of omega-3 fatty acids on cardiovascular disease. Evid Rep Technol Assess (Summ). 2004 Mar;(94):1-8. Full text (pages 64, 72-73)|

Results:
Total CVD risk. Data about total fish consumption and total cardiovascular disease was provided by 15 cohorts, including 13,137 + X cases (no amount of cases was defined in one cohort (Gillum RF [17]).
Significant protective effects were found in 3 cohorts (Daviglus ML [2], Dolecek TA [11], Yamagishi K [36]), two of which were of (very) small size (2, 11). And in one subcohort of very small size (Tomassalo C [45]). These analysis' included 2,894 cases (22% of all cases).
A small, significantly increased risk was found in another cohort, including 3,163 cases (Yen AM [40]). The CVD prevalence was extremely high in the latter cohort (14% in 2.81 years time). This was probably caused by the wide definition for CVD used. The average RR could be calculated from 13 cohorts: RR = 0.94. The protective effect became slightly stronger after excluding the debatable results from Yen AM: RR = 0.91.
Total CVD mortality. Restricting the evidence to mortality end points, left 11 cohorts available for analysis. These included 6,121 cases.
All protective effects described for CVD risk were attributed to mortality end points, including 2,894 cases (47% of all cases). The average RR could be calculated from 10 cohorts: RR = 0.84.

Intermediate levels of consumption: For CVD risk, effects were somewhat stronger at higher levels of consumption. Average RR's for intakes of < 1, 1, 2, and ≥ 3 servings/week were 0.95, 0.90, 0.88, and 0.91, respectively. For CVD mortality, corresponding RR's were 1.00, 0.93, 0.90, and 0.89. A more detailed analysis can be found here.
Effect modification: No effect modification was found by gender (Gillum RF [17], Nagata C [23], Yamagish K [36]) omega-6 fat intake (Virtanen JK [14], income, or BMI (Tomasallo C [45]).
Subjects with prevalent disease: Data about women with diabetes was available from 2 cohorts. A nonsignificant protective effect was found in one cohort (Hu FB [14]), but no association was found in the other cohort (Folsom AR [29]).
No significant association was found in one cohort among subjects with prevalent CHD (Erkkilä AT [28]).

Conclusion. For CVD risk significant protective effects were found in 4 out of 15 cohorts, 3 of which were of small size. Inconclusive evidence was found for an association between high total fish consumption and total cardiovascular disease risk (- 6%). Stratified analysis by level of consumption showed that effect sizes were similar at intakes of 1, 2, and ≥ 3 servings/week.
For CVD mortality significant protective effects were found in 4 out of 11 cohorts, 3 of which were of small size. Suggestive evidence was found for a protective effect of high total fish consumption against cardiovascular disease mortality (- 16%). Effects were similar for intakes of 2 and ≥ 3 servings/wk.

Fish and coronary heart disease (CHD).

Background: Several randomized trials examined the association between fish oil consumption and CHD. Fewer randomized trials examined the relation with fish consumption. In two trials subjects were randomly allocated to a dietary advice to increase consumption of fatty fish to ≥ 2 portions/week. Both trials included men from the UK only (The DART study, and the DART II study).
The DART study included men with a history of MI. After 2 years of follow-up, fish advice significantly decreased risk of death from heart disease (Burr ML [9]), but no long-term benefit was found (Ness AR [9]). The DART II study included men with angina. Fish advice nonsignificantly increased risk of death from heart disease (Burr ML [25]).
In the past, several systematic reviews were published relating fish consumption to CHD. But lot's of cohorts were excluded from analysis, or not found by the authors, biasing associations towards a protective effect. Results from these systematic reviews are discussed briefly:

• He K. 2004: Examined the relation with CHD death. 11 cohorts were included, and 7 studies (including data about 5 additional cohorts) were excluded. A total of 3,032 CHD deaths were included. 7 cohorts were not identified/discussed (Hirayama T [10], Dolecek TA [11], Knekt P [13], Gillum RF [17], Pietinen P [18], Whiteman D [21], Nagata C [23]). A strong protective effect was found: RR = 0.62 (0.45-0.82) for consumption ≥ 5 times/week vs < once/month.
• Wang C. 2004: Examined the relation with CHD death. 15 cohorts were included. One cohort was excluded (Norell SE [5]), and 9 cohorts were not identified/discussed (Vollset SE [3], Hirayama T [10], Knekt P [13], Soinio M [16], Gillum RF [17], Yuan JM [19], Whiteman D [21], Nagata C [23], Erkkilä AT [28]).
  The authors of this review stated that among the large cohort studies, only the Physician's Health Study [15] failed to report a significant beneficial effect of fish consumption. But findings in their own tables contradict this statement. Tables 3.31 and 3.32 show results from prospective studies relating omega-3 fatty acids or fish to cardiac death (pages 65-66). Among the studies larger than the Physician's Health Study, no significant effects at any level of consumption were found in 3 cohorts (Fraser GE [8]; Pietinen P [18]; Egeland GM. 2001). Actually, a significant protective effect of high vs low consumption among the larger cohorts was found in only one cohort (Hu FB [14].
  Since a cod liver oil supplement was consumed in one of the cohorts (Egeland GM. 2001), this result was not included in my review examining dietary fish consumption.
• König A. 2005: This review only included articles identified by Wang C. (2004) in the review mentioned above. And the authors wanted to describe the dose-response relationship for fish consumption and CHD death. Studies that limited attention to populations with particular risk/protective factors were excluded a priori, such as smokers and vegetarians. In addition, several other cohorts were excluded from the analysis, leaving only 6 out of 15 original cohorts (Kromhout D [1], Ascherio [14], Daviglus ML [2], Albert CM [15], Hu FB [14], Mozaffarian D [24]), and one subcohort (Oomen CM [2]), including a total of 1,927 cases.
  The authors of this review found that one servings of fish/week significantly decreased risk of CHD death (- 17%) relative to no consumption, and that each additional serving per week decreased risk incrementally by 3.9%.
• Mozaffarian D. 2006: Examined the relation with CHD mortality. Both randomized trials and cohort studies were included. 14 cohorts examining fish intake were included And 14 cohorts were not identified/discussed (Vollset SE [3], Rodriguez BL [4], Norell SE [5], Hirayama T [10], Järvinen R [13], Salonen JT [16], Gillum RF [17], Pietinen P [18], Whiteman D [21], Nagata C [23], Erkkilä AT [28], Chang-Claude J [30], Ness AR [31], Nakamura Y [32]).
  The authors of this review found a significant protective effect from consumption of 1-2 servings fish/week (- 36%). Within the 14 cohorts included by the authors, a significant protective effect was found in 9 (sub)cohorts. But for "The Health Professionals Follow-up Study" [14] the authors chose to include a more recent publication in which a significant protective effect was found (Mozaffarian D. 2005; 218 cases), while an older publication about this cohort including more cases found absolutely no effect (Ascherio A. 1995; 264 cases). Also, for one of the randomized trials included [9], the authors chose to include data from an older publication in which a strong protective effect was found after 2 years of follow-up (Burr ML. 1989; 194 cases), while a more recent publication showed that no effect was found after > 10 years of follow-up (Ness AR. 2002; 738 cases).
  Noticeable is the fact that within the 14 cohorts excluded by the authors, significant protective effects were found in only 2 (sub)cohorts, and that significantly increased risks were found in 2 other cohorts.

|Additional references:
Egeland GM. Cod liver oil consumption, smoking, and coronary heart disease mortality: three counties, Norway. Int J Circumpolar Health. 2001 Apr;60(2):143-9. Abstract
He K. Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation. 2004 Jun 8;109(22):2705-11. Full text
König A. A quantitative analysis of fish consumption and coronary heart disease mortality. Am J Prev Med. 2005 Nov;29(4):335-46. Abstract
Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18;296(15):1885-99. Full text.
Wang C. Effects of omega-3 fatty acids on cardiovascular disease. Evid Rep Technol Assess (Summ). 2004 Mar;(94):1-8. Full text |

Coronary heart disease risk: Data about total fish consumption was provided by 37 cohorts, including 23,801 cases.
Significant protective effects were found in 4 cohorts (Daviglus ML [2], Dolecek TA [11], Kromhout D [12], Bernstein AM [14]), 3 of which were of (very) small size (2, 11, 12).
Significant protective effects were also found in 6 subcohorts: IHD among women only, and hypertensive heart disease among men only (Hirayama T [10]), women only (Järvinen R [13]), MI only (Yuan JM [19]), IHD death only (Mozaffarian D [24], de Goede J [34]), or "referents" only (Tomasallo C [45]). Four of these cohorts were of (very) small size also (13, 19, 24, 45). These analysis' included 6,393 cases (27% of all cases).
A significantly increased risk was found in one vegetarian cohort of very small size, including 60 cases (Chang-Claude J [30]).
The average RR could be calculated from 31 cohorts: RR = 0.88. Excluding the debatable results from Hirayama T [10], did not change the effect size.
Intermediate levels of consumption: Protective effects were stronger among higher levels of consumption (RR's are 0.95, 0.95, 0.89, and 0.90 for intakes < 1, 1, 2, and ≥ 3 servings/week, respectively). A more detailed analysis can be found here.
Effect modification: A detailed analysis can be found here. Briefly, stratified analysis showed the following effects:

• Protective effects were somewhat stronger among women (RR = 0.84) than among men (RR = 0.90).
• Protective effects were stronger among US (RR = 0.86) and Asian (RR = 0.85) cohorts, than among European (RR = 0.95) cohorts.
• No (consistent) effect modification was found by other factors.

Coronary heart disease mortality: Data about total fish consumption was provided by 33 cohorts, including 15,347 cases.
Significant protective effects were found in 6 cohorts (Daviglus ML [2], Dolecek TA [11], Kromhout D [12], Hu FB [14], Mozaffarian D [24], de Goede J [34]), 4 of which were of (very) small size (2, 11, 12, 24).
Significant protective effects were also found in 4 subcohorts: IHD among women only, and hypertensive heart disease among men only (Hirayama T [10]), women only (Järvinen R [13]), MI only (Yuan JM [19]), or "referents" only (Tomasallo C [45]). Three of these cohorts were of (very) small size also (13, 19, 45). These analysis' included 3,715 cases (24% of all cases).
A significantly increased risk was found in one vegetarian cohort of very small size, including 60 cases (Chang-Claude J [30]).
Protective effects were stronger for higher levels of consumption (1.00, 0.93, 0.90, and 0.90 for < 1, 1, 2, and ≥ 3 servings/wk, respectively). The average RR could be calculated from 29 cohorts: RR = 0.88. Excluding the debatable results from Hirayama T [10], did not change the effect size.

Subjects with prevalent diabetes: In one cohort, a significant protective effect was found among normoglycemic subjects (MR = 0.29), but not among glucose intolerant subjects (MR = 1.1; Feskens EJ [12]). In another cohort, risk tended to increase among men with diabetes (RR = 1.9), but not among men without diabetes (RR = 1.1; Morris MC [15]). In a third cohort, the protective effect was stronger among diabetic women (RR = 0.38), than among nondiabetic (RR = 0.78; Hu FB [14]).
But no significant effects were found among diabetic subjects in 2 cohorts (Ascherio A [14], Soinio M [16]. And no effect modification by prevalent diabetes was found in 2 other cohorts (Mozaffarian D [24], Folsom AR [29]).
Subjects with prevalent heart disease: One cohort included subjects with CAD only (Erkkilä AT [28]), and another cohort included subjects with suspected CAD only (Manger MS [46]). No associations were found with CHD risk or CHD mortality at any level of consumption.

Nonfatal MI: Data about total fish consumption was provided by 7 cohorts, including 2,787 cases.
Significant protective effects were found in 2 cohorts of moderate-large size (Hu FB [14], Iso H [33]), including 1,225 cases (44% of all cases). And a nonsignificant protective effect was found in a third cohort, which was of very small size (Mozaffarian D [24]). No (non)significantly increased risks were found. The average RR = 0.79.
Intermediate levels of consumption: Protective effects were stronger among higher levels of consumption (RR's are 0.88, 0.87, 0.80, and 0.78 for intakes < 1, 1, 2, and ≥ 3 servings/week). A more detailed analysis can be found here.
No (non)significantly increased risks were found at any level of consumption in any cohort. (non)significant protective effects were as follows:

• 14) Ascherio A (1995). Nonsignificant at 1-3 servings/month, and significant at 2-3 servings/wk.
• 14) Hu FB (2002). Nonsignificant at intake 1-3 times/month, and significant at intake 1-4 times/wk.
• 24) Mozaffarian D (2003). The trend showed a nonsignificant protective effect, but no associations were found at any level of intake.
• 33) Iso H (2006). Significant at 12 servings/wk.

Overlapping effects were found at intake 2-3 servings/wk in 2 cohorts of moderate-large size (Ascherio A [14], Hu FB [14]). These cohorts included 1,583 cases (57% of all cases).

Heart failure: Data about total fish consumption was provided by 6 cohorts, including 4,319 cases. A significant protective effect was found in one cohort of very small size, but with a very high prevalence of heart failure (> 20% of the population). No other significant associations were found, but all RR's were < 1. The average RR = 0.86.

Conclusion: High total fish consumption significantly decreased CHD risk in 10 out of 37 cohorts. But most cohorts were of small size, and protective effects were often restricted to subcohorts. Inconclusive evidence was found for an association between high vs low consumption of total fish and CHD risk, but the average effect size (- 12%) does not exclude the possibility of a small protective effect. Stratified analysis shows any small protective effect might be restricted to US and Asian populations.
High total fish consumption significantly decreased CHD mortality in 10 out of 33 cohorts. But most cohorts were of small size, and protective effects were sometimes restricted to subcohorts. Inconclusive evidence was found for an association between high vs low consumption of total fish and CHD mortality, but the average effect size (- 12%) does not exclude the possibility of a small protective effect. For both CHD risk and CHD mortality, effect sizes were stronger for higher levels of consumption, but similar for intakes of 2 and ≥ 3 servings/week.
High total fish consumption significantly decreased risk of nonfatal MI in 2 cohorts of moderate-large size, but these cohorts included only a minority of all cases. Suggestive evidence was found that high vs low consumption of total fish is protective against nonfatal MI (- 21%). Analysis of intermediate levels of consumption showed significant protective effects against nonfatal MI were found in 2 cohorts of moderate-large size at intake 2-3 servings/wk. These cohorts included the majority of all cases. Consumption of 2-3 servings fish/wk possibly protects against nonfatal MI (- 20 to 22%).
High total fish consumption significantly decreased risk of heart failure in 1 out of 6 cohorts. Inconclusive evidence was found for an association between high vs low consumption of total fish and risk of heart failure, but the average effect size (- 14%) does not exclude the possibility of a small protective effect.

Fish and stroke.

Background: In the past, at least 3 systematic reviews were published relating fish consumption to stroke. Results from these systematic reviews are discussed briefly:

• He K. 2004: Examined the relation with stroke risk. 8 cohorts were included with 3,491 stroke events. Three cohorts were not identified/discussed (Lapidus L [6], Kinjo Y [10], Nagata C [23]).
  The authors found a significant protective effect against stroke risk based on the relative risk (RR = 0.69; 95% CI = 0.54-0.88), but not on the P-value (P = 0.06) for consumption ≥ 5 times/week vs < once/month.
• Wang C. 2004: Examined the relation with stroke risk. 9 cohorts were included. In one of these cohorts, the association with total omega-3 fatty acids, rather than marine omega-3 fatty acids was examined (Seino F. 1997), so these results were not included in my review. Three cohorts were not identified/discussed (Lapidus L [6], Nagata C [23], Sauvaget C [27]).
  The authors of this review stated that inconsistent findings were done (pages 70-71, 73).
• Bouzan C. 2005: This review only included articles identified by Wang C. (2004) in the review mentioned above. And the authors wanted to describe the dose-response relationship for fish consumption and stroke risk. 4 cohorts, and 1 case-control study were included, and 4 cohorts were excluded (Keli SO [1], Kinjo Y [10], Morris MC [15], Yuan JM [19]), in addition to the cohort examining total omega-3 fatty acids mentioned above (Seino F. 1997). Three cohorts were not identified/discussed (Lapidus L [6], Nagata C [23], Sauvaget C [27]).
  The authors found that one serving/week of fish decreased stroke risk by 12%. And that any increment of one additional serving/week, decreased risk by an additional 2%.

|Additional references:
Bouzan C. A quantitative analysis of fish consumption and stroke risk. Am J Prev Med. 2005 Nov;29(4):347-52. Abstract
He K. Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke. 2004 Jul;35(7):1538-42. Full text
Seino F. Dietary lipids and incidence of cerebral infarction in a Japanese rural community. J Nutr Sci Vitaminol (Tokyo). 1997 Feb;43(1):83-99. Abstract
Wang C. Effects of omega-3 fatty acids on cardiovascular disease. Evid Rep Technol Assess (Summ). 2004 Mar;(94):1-8. Full text|

Results:
Total stroke risk. Data about total fish consumption was provided by 22 cohorts, including 21,290 cases.
Significant protective effects were found in 4 cohorts (Kinjo Y [10], Mozaffarian D [24], Sauvaget C [27], Larsson SC [42]), and in two subcohorts among white women, and black men/women (Gillum RF [17]). These analysis' included 15,156 cases (71% of all cases).
A significantly increased risk was found in two other cohorts (Wennberg M [22] among men only, and Ness AR [31]).
The average RR could be calculated from 21 cohorts: RR = 0.87. One cohort attributed greatly to the total amount of cases (Kinjo Y [10]), but exclusion of this cohort from the analysis did not change the effect size materially: RR = 0.88.
Ischemic stroke risk. Data about total fish consumption was provided by 10 cohorts, including 8,382 cases.
Significant protective effects were found in 2 US cohorts (He K [14], Mozaffarian D [24]), including 914 cases (11% of all cases). The RR, but not the trend was significant in one of these cohorts (He K [14]). No (non)significantly increased risks were found. The average RR = 0.91.
Hemorrhagic stroke risk. Data about total fish consumption was provided by 10 cohorts, including 6,250 cases.
Significant protective effects were found in 2 Asian cohorts (Kinjo Y [10], Sauvaget C [27]), including 5,127 cases (82% of all cases). No (non)significantly increased risks were found. The average RR = 0.89.

Intermediate levels of consumption: Protective effects seemed get stronger with increasing levels of consumption (RR = 0.98, 0.94, 0.93, and 0.89 for < 1, 1, 2, and ≥ 3 servings fish/wk, respectively. But these effects depended on data from one single cohorts (Kinjo Y [10]). After exclusion of this cohort, all effects became stronger (RR = 0.97, 0.89, 0.86, and 0.86 for < 1, 1, 2, and ≥ 3 servings fish/week, respectively. A more detailed analysis can be found here.
Effect modification: A detailed analysis can be found here. Briefly, stratified analysis showed the following effects:

• Data about men was available from 11 cohorts (3,929 cases). A significantly increased risk was found in 1 cohort (Wennberg M [22]). No other associations were found. The average RR = 0.99.
  Data about women was available from 9 cohorts (4,309 cases). Significant protective effects were found in 2 cohorts (Gillum RF [17], Larsson SC [42]), including 1,931 cases (45% of all cases). And nonsignificant protective effects were found in another 2 cohorts (Iso H [14], Iso H [36]), including 1,588 cases (37% of all cases). The average RR = 0.80.
• Protective effects were found among US cohorts (RR = 0.77) and Asian cohorts (RR = 0.87), but not among European cohorts (RR = 0.96).
• Protective effects among US cohorts were found against ischemic stroke risk, while protective effects among Asian cohorts were found against hemorrhagic stroke risk.
• No consistent effect modification was found by other factors.

Subjects with prevalent disease. In one cohort, a significant protective effect was found against total stroke risk. And this effect was not modified by diabetes or prevalent CHD (Mozaffarian D [2005]).

Conclusion: Significant protective effects against total stroke risk were found in 6 out of 22 cohorts, 3 of which were of moderate-very large size. These cohorts included 71% of all cases. High fish consumption possibly protects against total stroke risk (- 13%). Effect sizes were identical for intakes of 2 and ≥ 3 servings/week. Stratified analysis showed that the evidence for a protective effect was restricted to Asian/US cohorts only, and women only.
Stratified analysis shows that the protective effect against total stroke risk among US cohorts is possibly caused by a protective effect against ischemic stroke risk, while the protective effect against total stroke risk among Asian cohorts is possibly caused by a protective effect against hemorrhagic stroke risk.