Prevention Of Morbidity And Mortality Of Cardiovascular Disease

For over 25 years, fish and fish oils have been linked to cardiovascular health. This association was first recognised when significantly lower death rates from acute myocardial infarction (Ml) were found among Greenland's Inuit population, despite only moderate differences between the Inuits' blood cholesterol levels and those of other populations (Holub 2002). A high dietary omega-3 fatty acid intake in the form of marine mammals (seal, whale) and various fish were thought responsible for the protective effect (Bang et al 1980). In 1989, results from the first large, randomised, clinical trial investigating the effects of fatty fish consumption on survival and risk of secondary Ml confirmed a link to cardiovascular health (Burr et al 1989). The DART (Diet and Reinfarction study) found a modest intake of 2-3 portions weekly of fatty fish reduced mortality in men who had previously experienced a Ml and produced a relative reduction in total mortality of 29% during the 2-year follow-up, attributed mainly to a reduction in deaths from coronary heart disease (CHD). Increased consumption of fish (RR = 0.66 for 5 or more times per week) was further confirmed in the Nurses Study as significantly reducing risk in both CHD and CHD mortality p^ qqs ^.30

independent of the cardiovascular status (Hu et al 2002).

Various intervention studies have also been conducted to investigate whether similar or superior effects could be obtained with concentrated fish oil supplements. The largest of these is known as the GISSI trial, which involved 11,324 survivors of Ml, and showed that a low-dose fish oil supplement significantly reduced the risk of all-cause death, non-fatal Ml, and non-fatal stroke (Stone 2000). This study was re-analysed and subsequently published again in 2002 (Marchioli et al 2002). This time it specifically showed the reduction in risk of sudden cardiac death was nearly significant at 3 months, accounting for 67% of the overall mortality benefit, became significant at 4 months, and was highly significant at 3.5 years, the end of the study, when it accounted for 59% of the n-3 PUFA advantage in mortality. The reduction observed in all-cause mortality and in cardiovascular mortality resulted mainly from the prevention of sudden cardiac death by the n-3 fatty acids. Meta-analyses In 2002, a high-quality systematic review of 11 RCT on the effect of fish-based dietary or supplemental omega-3 fatty acids on cardiovascular morbidity and mortality in people with CHD found a strongly significant benefit (Bucher et al 2002); however, a 2006 Cochrane review came to a different conclusion (Hooper et al 2006). The review assessed 48 studies that compared at least 6 months of omega-3 fats (vegetable- and fish-based) with placebo or control and used data involving 36 913 participants. Meta-analysis of the studies assessing the effects of increased omega-3 fats on total mortality or combined cardiovascular events found strongly significant statistical heterogeneity. When randomised studies considered to beat medium or high risk of bias were removed, there was no significant effect of omega-3 fats on total mortality; the relative risk was 0.87 (95% confidence interval 0.73 to 1.03, with significant heterogeneity) whereas the cohort studies suggested significant protection, the relative risk was 0.65 (95% confidence interval 0.48 to 0.88, no significant heterogeneity).

It is important to note that until the publication of the DART-2 trial in 2003 (Burr et al 2003), the evidence showed that omega-3 from oily fish or supplements reduced the risks of fatal Ml, sudden death, and overall mortality among people with existing disease. Inclusion of the DART-2 trial in the Cochrane review had a major influence on the conclusion, as removing it produced relative risks similar to those in the Bucher review (fatal Ml: RR 0.70, 95% confidence interval 0.54 to 0.91; sudden death: RR 0.68, 95% confidence interval 0.42 to 1.10; overall mortality: RR0.83 (95% confidence interval 0.75 to 0.91). The DART-2 trial included 3114 men with stable angina and tested the hypothesis that the main benefit of omega-3 fat is derived from its anti-arrhythmic action in the presence of chronic disease. Surprisingly, it did Fish oils 431

not confirm this, showing an excess of sudden and total cardiac deaths most clearly in

participants taking fish oil capsules rather than eating oily fish. Authors of the Cochrane review report that something about the DART-2 study is different from the other included studies; however, further investigation has failed to clarify the issue.

It is possible that, based on this latest review, the effect of omega-3 fats on CVD is smaller than previously thought or that effects in people who have had a Ml are protective of death, but the effects in men with angina and no Ml are not.

Clinical note — The n-3:n-6 fatty acid balance: implications in cardiovascular disease and cancer

In recent years, attention has been drawn to the importance of not only n-3 fatty acid intake but also its relation to concurrent n-6 fatty acid intake. When there is increased n-3 PUFA in the diet and in our bodies, a shift in AA metabolism occurs, which results in the production of metabolites that have beneficial effects on cardiovascular physiology and cancer incidence and promotion (Leaf 2002). For example, when EPA is available to compete with AA, production of thromboxane A2 (a potent vasoconstrictor and platelet activator) is reduced and production of thromboxane B3 results, which is only weakly active. Additionally, several forms of research implicate n-6 PUFAs as stimulating processes that promote human cancer development and progression, whereas n-3 PUFAs have the opposite effect (Weisburger 1997). Once again, competition with AA is thought to be involved, although several other protective mechanisms have also been identified. Overall, it seems that in order to obtain maximal cardiovascular and chemopreventative benefits, intake of n-3 PUFAs should be increased and intake of n-6 PUFAs must be reduced.

It has been estimated that the ratio of n-6 to n-3 essential fatty acids in the Western diet is some 15:1 to 20:1 or higher, whereas the optimal ratio appears to be closer to 2:1 or 1:1 (Leaf 2002, Simopoulos 1999)._

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