**5.1 n-3 and n-6 PUFA**

Every cooking oils or foods generally include several kinds of fatty acids. **Table 3** shows the amounts of different fatty acids in several commercially available oils and foods. In the US, people use soybean oil very frequently for cooking, and its dominant fatty acid is n-6 PUFA (50%), along with MUFA (25%). Olive oil, a very popular oil in the Mediterranean Sea area, is a well-known representative with


Instead of ratio of n-6 to n-3, ω-3 index, based on measurements of EPA and DHA in red blood cells, was proposed as a marker for previous consumption of fish for last 120 days [137, 138]. The ω-3 index >8% has been proposed as optimal for cardioprotection. The average ω-3 index in Japanese is 9–11%. By contrast, the average in the US people is 4–5% and only <10% of individuals have the ω-3 index >8% [139], which reflects well the difference of fish consumption between Japan

*Effects and Issues of Diet Fat on Cardiovascular Metabolism*

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

**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

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

and the US.

**87**

consumption of fish intake in diet.

#### **Table 3.**

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

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 with that in mackerel, respectively.

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 fatty acids.

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 consume more n-3 PUFAs.

Instead of ratio of n-6 to n-3, ω-3 index, based on measurements of EPA and DHA in red blood cells, was proposed as a marker for previous consumption of fish for last 120 days [137, 138]. The ω-3 index >8% has been proposed as optimal for cardioprotection. The average ω-3 index in Japanese is 9–11%. By contrast, the average in the US people is 4–5% and only <10% of individuals have the ω-3 index >8% [139], which reflects well the difference of fish consumption between Japan and the US.
