**5.2 Epidemiology and history regarding health benefits of fish oil (n-3 PUFAs)**

As shown in **Table 1**, the guidelines from AHA/ACC, ADA, and AACE recommend 2 servings of fatty fish per week for the general population. A typical serving of fish can range from 3 to 6 ounces (about 85–170 g), depending on the type of fish and its preparation. Most adult Americans eat only 7–13 g/day of fish, and Japanese who are 20 years and older eat 73 g/day of fish, based on a 2013 national survey [140]. Because of the difference of daily intake of fatty food, the percent of calorie from total fat is higher among Americans than Japanese, except for n-3 PUFA, which is only 30% higher in Japanese [119, 141]. Reason for the relatively small difference in fat calorie from n-3 FUFA is that in Americans, the intake of red meat and poultry as a source of n-3 PUFA is much higher among Americans. When comparing percent of calories from EPA and DHA between Japanese and Americans, this parameter is almost four times higher in Japanese [140, 141]. The percent of calories from EPA and DHA and their concentration in the blood reflects baseline consumption of fish intake in diet.

Epidemiological data of Greenlanders from almost half century ago [142] and WHO study [143] have shown that fish consumption was independently, significantly, and inversely associated with all-cause and CHD mortality. In 1999, the GISSI-P study, the first RCT of dietary supplementation with n-3 fatty acid, showed significant reduction in the risk of the major CV events by 10% [144]. Based on the results of this RCT and positive observational studies, since 2000, the European Medicines Agency (EMA) has authorized n-3 fatty acid medicines for use after a heart attack in several EU countries, at a dose of 1 g per day. In 2002, the second AHA Science Advisory "Fish Consumption, Fish Oil, Lipids, and Coronary Heart Disease" concluded that individuals at risk for CHD benefit from the consumption of plant- and marine-derived n-3 fatty acids (1 g of EPA + DHA per day) [145].

However, since the 1990s at almost the same time as US and EU recommendations, conflicting data have been substantially reported showing no correlation between n-3 fatty acid consumption and CV events [146–154]. The Cochran metaanalysis in 2004 including 48 RCTs (36,913 participants) and 41 cohort analyses has concluded that consumption of n-3 fats did not show a reduction in the risk of total mortality or combined CV events [155]. Until the positive results in the REDUCE-IT study in 2019 [156], all major RCTs with n-3 fatty acids [157–162] except JELIS study (**Table 4**) [163], which were conducted in Japan with open-blind design. These negative results in observational studies and RCTs were enough to result in label changes in for n-3 supplements in Europe. In 2016, the ESC/EAS guidelines concluded that it was unclear whether n-3 fatty acids had beneficial effects on CV events [39]. Furthermore, 2 years later in 2018, EMA concluded that omega-3 fatty acid medicines are not effective in preventing further CV events in subjects with a history of myocardial infarction and that n-3 fatty acid supplements would no longer be authorized for secondary prevention [164]. Results of the ASCEND study [162], which was published several months before this recommendation, had substantially affected this EMA decision. The ASCEND study, which has been the largest double-blind omega-3 RCT, evaluated MACE for 7.4 years in 15,480 subjects

MUFA making up more than 70% of all fatty acids. Both soybean oil and olive oil include SFA at about 15% of all fat. It should be noted that mackerel, which people believe is a very rich source of fish oil (=n-3 PUFA), contains more than twice as much SFA and MUFA compared to n-3 PUFA. Bluefin tuna (nonoily tuna) and salmon contain only one-tenth and one-third the amount of n-3 PUFA compared

*Amounts of different fatty acids contained in several cooking oils, butter and foods.*

Rapeseed oil 100 g 100 g 7.4 g 63 g 9 g 18 g Soybean oil 100 g 100 g 16 g 23 g 6.8 g 50 g Olive oil 100 g 100 g 14 g 73 g 0.8 9.8 g Mackerel 100 g 17 g 4.6 g (27%) 5 g (8.5%) 2.1 g (12%) 0.4 g (2.4%) Butter 100 g 81 g 51 g (63%) 21 g (26%) 0.3 g (0.3%) 2.2 g (2.7%) Peanuts 100 g 56 g 11 g (20%) 26 g (46%) 0 g (0%) 17 g (30%) *Figures in parenthesis (%) are the percent of calories from each fatty acid compared to the total amount of fat.*

**Fat SFA MUFA PUFA n-3 PUFA n-6**

From this table, it is easily understandable that saturated fat is not synonymous with fat from animal food and likewise unsaturated fat is not synonymous with plant food. When compared gram for gram, olive oil has 7 times SFA of the trimmed beef sirloin. Furthermore, the oily fish, mackerel, which are advised to eat, has more than two times SFA of the beef sirloin. Therefore, it is not unexpected that results in clinical studies with pharmaceutical drugs with highly purified EPA differ from those of epidemiological studies with variable fish consumption. When reading manuscripts of nutritional studies with interventions involving fatty acid(s), it is important to consider which oils or food stuffs are added to modify the specific

The ratio of n-6 to n-3 fatty acids in the diet of early humans was estimated to be

1:1 [131]. The ratio in the diet of the US today has risen to 10:1 because of the combination of reduced n-3 fatty acid intake and the widespread use of vegetable oils rich in linoleic acid (n-6). As shown in **Table 3**, all listed foods and oils have much higher content of n-6 compared with that of n-3 except mackerel. It has been proposed that while n-3 fatty acids have anti-inflammatory effects, n-6 fatty acids have pro-inflammatory effects. This is based on data that oxylipins synthesized from n-6 PUFA have more inflammatory, vasoconstrictive, and proliferative effects compared with a metabolite derived from n-3 PUFA, although there are notable exceptions [132]. Because enzymes generating inflammatory metabolites from n-6 PUFA are inhibited by EPA and DHA from n-3 PUFA, increases in tissue concentration of EPA and DHA tend to shift the activity toward anti-inflammatory status. This is the rationale for using the ratio of n-6 to n-3 PUFA (n-6/n-3) in the blood as a potential risk marker for CV diseases, cancer, and some other chronic inflammatory diseases such rheumatoid arthritis, and bronchial asthma [133]. However, it is difficult to predict the appropriate cut-off value of n-6/n-3. Furthermore, blood concentration of n-6/n-3 does not reflect the amount of oral intake of n-3 and n-6 PUFAs [134–136]. At present, a general consensus is that high linoleic acid (n-6 PUFA) in the diet or circulation is not associated with higher in vivo or ex vivo proinflammatory responses, and that those individuals consuming the highest level of α-linolenic acid (n-3 PUFA) had the lowest inflammatory status [136]. Therefore, the oral intake of linoleic acid should not be restricted and it is unnecessary to

with that in mackerel, respectively.

*New Insights into Metabolic Syndrome*

fatty acids.

**Table 3.**

consume more n-3 PUFAs.

**86**


**Table 4.** *Comparison*

 *of RCTs of n-3 PUFA [156–163].* with diabetes living in England. The n-3 supplements had no effects not only on CV events but also on mortality of other chronic diseases such as cancer and COPD. The authors also commented on the issue of cost of n-3 supplements, because up to 31% of all British people were using them. The authors clearly concluded that the recommendation of n-3 in guidelines in major meetings should be drastically

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

*DOI: http://dx.doi.org/10.5772/intechopen.93261*

Compared with the clear negative opinion against effects of n-3 fatty acids from EMA, the USFDA has accepted the potential medical benefit of n-3 fatty acids for secondary prevention. In 2017, the most recent AHA Science Advisory still concluded that treatment with omega-3 PUFA supplements is reasonable for secondary prevention, stating that a potentially modest reduction in CHD mortality (10%) in this clinical population would justify treatment with a relatively safe therapy [165]. The Cochran review in 2018 (included 79 RCTs, 112,059 participants) concluded that increasing n-3 saturated fat intake made little difference to all-cause mortality and CHD mortality, which did not support the recommendation in the 2017 AHA Science Advisory of the use of n-3 fat supplements for patients with CHD [166]. Despite the inconsistent recommendation between EMA and FDA, all guidelines

support an indication for reducing TG by n-3 supplements. Furthermore, they positively advise intake of fish, a rich source of marine- or plant-derived omega-3 fatty acid. The positive effects of fish consumption on CHD have been mostly attributed to n-3 PUFA (EPA and DHA); however, fish is also an excellent source of bioactive peptides which have shown beneficial activities for cholesterol-lowering, hypotensive effects through ACE inhibition, or inhibitory action for atherosclerosis, inflammation, or oxidation [167]. Supplements containing fish oil are very popular among people living in the US, being used by 7.8% of the population [168]. The reason for the popularity of n-3 supplements in the US reflects a typical lifestyle not to eat fish often (one serving of fish/week) as well as a general belief in beneficial effects of omega-3 oil for health. The commercially available n-3 supplements do not contain fish peptides but usually include at least some amount of other ingredi-

ents that are potentially harmful for health such as SFA, mercury, etc.

**5.3 Reasons for inconsistent data of omega-3 fatty acids for coronary heart**

reduction of CV events so far. **Table 4** shows comparison of previous RCTs

Most of the RCTs with n-3 supplements generally have not shown a significant

The dosage is another important factor. Findings in two Cochran review manuscripts showed no dose dependency of n-3 fatty acids [155, 166]. It is of note that the absolute amount of fish intake was very small in some studies, which tends to make the correlation between n-3 fatty acids and CV events less clear. In some studies in cultures where eating fish is not common, the participants who belonged to the

extreme example is a study to compare subjects who consumed no fish to subjects who ate fish once a week [148]. The JPHC study, conducted in Japan, showed clear

–3 servings/week, and one

group with the highest intake of fish consumed just 2

–163, 169]. Inconsistent data in RCTs as well as observational studies of n-3 supplements could be attributed to statin use, dose of n-3 fatty acid, or TG and HDL values at baseline. The statin use was very low in two positive studies (GISSI-P [144] and GISSI-HF [169]), which mainly recruited subjects two decades ago, before the wide-spread use of stains. One study showed that although among statinusers coronary vascular events were not reduced with n-3 fatty acid supplements, the events significantly decreased in statin nonusers [170]. This suggests that statin treatment modified the effects of n-3 fatty acids on the incidence of major cardio-

corrected [162].

**disease**

vascular events.

**89**

[144, 156

with diabetes living in England. The n-3 supplements had no effects not only on CV events but also on mortality of other chronic diseases such as cancer and COPD. The authors also commented on the issue of cost of n-3 supplements, because up to 31% of all British people were using them. The authors clearly concluded that the recommendation of n-3 in guidelines in major meetings should be drastically corrected [162].

Compared with the clear negative opinion against effects of n-3 fatty acids from EMA, the USFDA has accepted the potential medical benefit of n-3 fatty acids for secondary prevention. In 2017, the most recent AHA Science Advisory still concluded that treatment with omega-3 PUFA supplements is reasonable for secondary prevention, stating that a potentially modest reduction in CHD mortality (10%) in this clinical population would justify treatment with a relatively safe therapy [165]. The Cochran review in 2018 (included 79 RCTs, 112,059 participants) concluded that increasing n-3 saturated fat intake made little difference to all-cause mortality and CHD mortality, which did not support the recommendation in the 2017 AHA Science Advisory of the use of n-3 fat supplements for patients with CHD [166].

Despite the inconsistent recommendation between EMA and FDA, all guidelines support an indication for reducing TG by n-3 supplements. Furthermore, they positively advise intake of fish, a rich source of marine- or plant-derived omega-3 fatty acid. The positive effects of fish consumption on CHD have been mostly attributed to n-3 PUFA (EPA and DHA); however, fish is also an excellent source of bioactive peptides which have shown beneficial activities for cholesterol-lowering, hypotensive effects through ACE inhibition, or inhibitory action for atherosclerosis, inflammation, or oxidation [167]. Supplements containing fish oil are very popular among people living in the US, being used by 7.8% of the population [168]. The reason for the popularity of n-3 supplements in the US reflects a typical lifestyle not to eat fish often (one serving of fish/week) as well as a general belief in beneficial effects of omega-3 oil for health. The commercially available n-3 supplements do not contain fish peptides but usually include at least some amount of other ingredients that are potentially harmful for health such as SFA, mercury, etc.
