24 October, 2016: 

The benefits of the Mediterranean diet in regard to cardiovascular health and metabolic risk factors in postmenopausal women are well recognized [1, 2]. Seafood is considered as one of the major components of the Mediterranean diet. So could one make a clear link between a regular consumption of fish and cardiovascular benefits? Most of us would say 'yes, certainly', but a recent publication challenges this common perception. The newest data come from a prospective cohort study of US women participating in the Women's Health Initiative from 1993 to 2014 [3]. A total of 39,876 women who were aged ≥ 45 years and free of cardiovascular disease at baseline provided dietary data on food frequency questionnaires. Analyses used Cox proportional hazards models to evaluate the association between fish and energy-adjusted omega-3 polyunsaturated fatty acid intake and the risk of major cardiovascular disease, defined as a composite outcome of myocardial infarction, stroke, and cardiovascular death. The final analytic sample included 38,392 women (mean age 55 years). During 713,559 person-years of follow-up, 1941 cases of incident major cardiovascular disease were confirmed. Tuna and dark fish (mackerel, salmon, sardines, bluefish, and swordfish) intake was not associated with the risk of incident major cardiovascular disease (p-trend > 0.05). Neither α-linolenic acid nor marine omega-3 fatty acid intake was associated with major cardiovascular disease or with individual cardiovascular outcomes (all p-trend > 0.05). There was no effect modification by age, body mass index, or baseline history of hypertension.

Comment

This recent study seems to break a sort of a myth, which associates regular intake of fish with improved cardiovascular health. Such an association is biologically plausible because fish or omega-3 fatty acids in adequate amounts can be anti-inflammatory, hypotriglyceridemic, anti-thrombotic, ventricular anti-arrhythmic, endothelium relaxant, and possibly anti-atherogenic [4]. A 2003 expert panel from the American Heart Association [5] stated: 'Intake of fish has been associated with a reduced risk of CVD. The benefits of fish seem to result, at least in part, from omega-3 fatty acids. Women who do not eat fish might consider non-marine sources of omega-3 fatty acids, such as flaxseed oil, walnut oil, canola oil, soybean oil, or walnuts. However, there is less evidence supporting a cardiovascular benefit from these sources of omega-3 fatty acids.' This guideline was preceded by a much more detailed publication on the cardiovascular merits of fish and fish oil [6]. Based on all the available clinical data, the usual recommendation has been to eat fish, especially oily fish, at least twice weekly [7]. But now we are faced with a large study which tells us a different story [3]. Is this the only study that points at such a surprising conclusion? In fact, other previous publications were in line with the message of neutral effects, as discussed by Rhee and colleagues [3]. The Iowa Women’s Health Study cohort comprised 41,836 women aged 55–69 years recruited via a baseline questionnaire mailed in 1986 [8]. Among 127 food frequency items, there were four fish and seafood questions. During follow-up of 442,965 person-years in women without heart disease at baseline, 4653 deaths occurred; there was an inverse age- and energy-adjusted association between total mortality and fish intake, with a relative risk of 0.82 (95% CI 0.74–0.91). However, adjustment for multiple other risk factors attenuated all associations to statistically non-significant levels. Absence of a significant, independent association between fish intake and coronary heart disease or stroke mortality or for estimated marine omega-3 fatty acid intake was recorded as well. In comparison, plant-derived α-linolenic acid was inversely associated with mortality after multivariable adjustment. To note, a meta-analysis evaluating long-chain omega-3 polyunsaturated fatty acids and risk of stroke [9] showed that, while the overall results in eight prospective studies (5238 stroke events among 242,076 participants) yielded a relative risk of 0.90 (95% CI 0.81–1.01) for the highest versus lowest category of intake, the results in women were a little better (relative risk 0.80, 95% CI 0.65–0.99).

In conclusion, there are some inconsistencies in regard to cardioprevention by fish, fish oil or omega-3. These could be explained by the differences between the various studies. The effects in men may not be the same as in women; clinical studies are methodologically superior to observational ones and are less subject to bias; high risk, at-risk, or optimal risk individuals are probably reacting differently to the diet; the total amount of fish or omega-3 ingested, frequency of eating and duration of follow-up may have an impact, as may the concomitant dietary components; last, but not least, the protective outcomes may vary according to the population examined in terms of ethnicity. So perhaps the best way to reduce the risk for cardiovascular disease is to implement as many as possible lifestyle and diet health advices, rather than follow just one or a few of them.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Hernández-Angeles C, Castelo-Branco C. Cardiovascular risk in climacteric women: focus on diet. Climacteric 2016;19:215-21
   http://www.ncbi.nlm.nih.gov/pubmed/27112972 
2. Garcia M, Bihuniak JD, Shook J, Kenny A, Kerstetter J, Huedo-Medina TB. The effect of the traditional Mediterranean-style diet on metabolic risk factors: a meta-analysis. Nutrients 2016;8:168
   http://www.ncbi.nlm.nih.gov/pubmed/26999195 
3. Rhee JJ, Kim E, Buring JE, Kurth T. Fish consumption, omega-3 fatty acids, and risk of cardiovascular disease. Am J Prev Med 2016 Sep 16. Epub ahead of print
   http://www.ncbi.nlm.nih.gov/pubmed/27646568 
4. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747–57
   http://www.ncbi.nlm.nih.gov/pubmed/12438303 
5. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. American Heart Association scientific statement. Arterioscler Thromb Vasc Biol 2004;24:e29-50
   http://www.ncbi.nlm.nih.gov/pubmed/15003974
6. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-57 http://www.ncbi.nlm.nih.gov/pubmed/12438303
7. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115:1481-501 
   http://www.ncbi.nlm.nih.gov/pubmed/17309915 
8. Folsom AR, Demissie Z. Fish intake, marine omega-3 fatty acids, and mortality in a cohort of postmenopausal women. Am J Epidemiol 2004; 160:1005-1010 http://www.ncbi.nlm.nih.gov/pubmed/15522857 
9. Larsson SC, Orsini N, Wolk A. Long-chain omega-3 polyunsaturated fatty acids and risk of stroke: A meta-analysis. Stroke 2011;42:3621-23 
   http://www.ncbi.nlm.nih.gov/pubmed/23179632