Editorial
The Ratio of Circulating Eicosapentaenoic Acid to Arachidonic Acid Ratio in the Community-Dwelling Japanese Population
2023 Volume 30 Issue 6 Pages 587-588
Details
2023 Volume 30 Issue 6 Pages 587-588
See article vol. 30: 589-600
Fatty acids have different physiological functions depending on their carbon-chain length and presence or absence and position of double bonds. Polyunsaturated fatty acids (PUFAs) with two or more double bonds are categorized as n-3 PUFAs and n-6 PUFAs according to the position of their double bond. Since these are essential fatty acids and must be obtained from exogenous sources such as daily diet, circulating levels reflect intake relatively well. The principal n-3 PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both of which are found in fish oil. Arachidonic acid (AA) is one of the n-6 PUFAs and is obtained from meat, fish, and eggs. EPA is associated with anti-inflammation and anti-hemagglutination. Conversely, AA is a precursor to mediators associated with inflammation and aggregation.
Dyersburg and Bang et al.1) reported that Greenlandic Inuit, who have a low incidence of myocardial infarction, primarily consume seal and whale, which are extremely high in n-3 PUFAs and have high levels of circulating EPA and low levels of AA. Conversely, Danes, who have high incidences of myocardial infarction compared to Greenlandic Inuit, had low levels of circulating EPA and high levels of AA. Many subsequent experimental, clinical, and observational studies have reported a possible cardiovascular disease (CVD) protective role for n-3 PUFAs. Recently, several double-blind, randomized, controlled trials (RCT) were conducted to examine the association between EPA-only or both EPA and DHA supplementation and primary or secondary prevention of CVD in Western populations, whose fish intake is lower than that of the Japanese. Of these large RCTs, the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT)2) with high-dose (4 g/day) supplementation of EPA-only showed a preventive effect. This trial was based on the Japan EPA Lipid Intervention Study (JELIS)3), which demonstrated that EPA supplementation was effective in the secondary prevention of CVD at an RCT of 1.8 g/day of EPA in statin-treated Japanese patients with a fish-eating culture. However, other recent large RCTs found no association, and the differences in the results of these RCTs are under discussed.
Furthermore, many patient-based studies in Japan with high cardiovascular risk have reported that those with higher circulating EPA/AA ratio, which is circulating EPA level divided by circulating AA level, have a lower risk of CVD4). Although there are not many reports on the general population, the Hisayama Study5) reported a higher risk of developing CVD in participants with HS-CRP ≥ 1.0 mg/L and a circulating EPA/AA ratio of ＜0.29 compared to ＞0.59.
Honda et al.6) reported that circulating EPA/AA ratio significantly decreased from 0.40 in 2002 to 0.32 in 2012 in 4251 participants aged 40 years or older in the Hisayama Study. The difference in this ratio was more pronounced among the younger age groups in their 40s and 50s. Considering the fatty acid, the 2002 geometric mean circulating EPA level was 59.0 µg/mL and circulating AA level was 147.6 µg/mL. These values were similar to the median circulating EPA level of 59.5 µg/mL, circulating AA level of 136.8 µg/mL, and EPA/AA ratio of 0.43 in the INTERMAP/INTERLIPID study7) conducted from 1996 to 1998 in Sapporo, Toyama, Shiga, and Wakayama among men and women aged 40–59.
The decrease in the circulating EPA/AA ratio over the 10 years in the Hisayama Study6) is not due to a decrease in circulating EPA levels in the numerator but because the increase in circulating AA levels in the denominator exceeded the increase in circulating EPA. Circulating AA levels by age groups were also consistently higher in 2012 than in 2002. For DHA, a fatty acid abundant in fish oil, the circulating DHA/AA ratio similarly decreased in the 2012 survey compared to the 2002 survey due to an increase in AA. Honda et al. suggested that the increased meat intake of the Japanese may be one of the factors contributing to the increase in circulating AA levels. In fact, in the 2006 National Health and Nutrition Survey8), fish and meat intakes were reversed, with meat being consumed more frequently since then. Whereas, Honda et al. also suggested the possibility of increased circulating AA levels other than increased meat intake. Circulating fatty acid levels have been reported to change with lipid-lowering drug usage, smoking, alcohol consumption, physical activity, and body mass index. In the Hisayama Study by Honda et al.6), the percentage of participants using lipid-lowering drugs was higher in 2012 (22.9%) than in 2002 (9.9%). However, the decrease in the circulating EPA/AA ratio from 2002 to 2012 was seen independently of lipid-lowering drug use.
The circulating EPA/AA ratio in the 2012 Hisayama Study6) was 0.32, a decrease from the 2002 study but still higher than 0.06 for Japanese Americans who had a Western lifestyle in Hawaii in the late 1990s7). Studies of Japanese Americans from Japan, Hawaii, and California, who are genetically similar but have very different lifestyles, have reported a higher risk of coronary artery disease in those whose lifestyles are more accustomed to Western culture9). As lifestyles, including diet, and treatments have changed over time, disease patterns will likely change accordingly. Therefore, the evolution of the circulating EPA/AA ratio in the Japanese population requires continued attention and observation. The report by Honda et al. of circulating EPA/AA ratios at different time points for the same community residents added one more insight for future CVD prevention.
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