Trans Fatty Acid and Coronary Artery Disease　– Lessons From Seven Countries Study –

The Seven Countries Study was the first to show true differences in prevalence, incidence and mortality for coronary artery disease (CAD) among populations with different geographical, ethnic, and cultural characteristics.¹ Ancel Keys, the leader of the study, coordinated the program in 7 countries, the United States, Finland, The Netherlands, Italy, Yugoslavia, Greece and Japan (Tanushimaru and Ushibuka), working from the Laboratory of Physical Hygiene, School of Public Health, University of Minnesota, Minneapolis, USA.²

Article p 2017

The effect of the average intake of different fatty acids and antioxidants in relation to population CAD mortality rates could be investigated using the results of chemical analyses carried out in 1987.^3–5 Of the different fatty acids, the population’s average intake of saturated fatty acids was the most associated with 25-year CAD mortality rates. The intake of trans fatty acids was also strongly associated with 25-year CAD mortality rates.³ The intake of trans fatty acids was the highest in The Netherlands (8 g/day). CAD such as angina pectoris and myocardial infarction are common conditions in The Netherlands.³

Elaidic acid is the major trans fat found in hydrogenated vegetable oils and occurs in small amounts in caprine and bovine milk (very roughly 0.1% of the fatty acids)⁶ and some meats. It is the trans isomer of oleic acid. The name of the elaidinization reaction comes from elaidic acid. Elaidic acid increases plasma CETP activity, which lowers high-density lipoprotein cholesterol.⁷

The Seven Countries Study group already found strong positive associations between 25-year death rates from CAD and average intake of the 4 major saturated fatty acids, lauric, myristic, palmitic, and stearic acids (r>0.8, P<0.001); the trans fatty acid elaidic acid (r=0.78, P<0.001); and dietary cholesterol (r=0.55, P<0.05) (Table).³ Although linoleic acid is related to endothelial dysfunction and attenuates endothelium-derived relaxing factor, this acid is not associated with serum cholesterol and coronary death rates.^3,8,9 Interpreted in the light of experimental and clinical studies, the results of these cross-cultural analyses suggest that dietary saturated and trans fatty acids and dietary cholesterol are important determinants of differences in population rates of CAD death.

Table. Correlation Between Nutrients (Energy %) and Serum Cholesterol, and Death Rates in 16 Cohorts (Seven Countries Study: 25-Year Follow-up)

(25-year mortality)	SFA	CHOL	CAD	CAN	ALL
C12:0	0.83†	0.84†	0.84†	0.07	0.25
C14:0	0.88†	0.81†	0.86†	0.07	0.28
C16:0	0.97†	0.62*	0.81†	−0.13	0.35
C18:0	0.97†	0.60*	0.84†	−0.04	0.45
SFA	–	0.71**	0.88†	−0.05	0.36
C18:1C	0.05	0.17	−0.08	−0.51*	−0.30
C18:1T	0.84†	0.70**	0.78†	0.20	0.22
C18:2CC	0.30	−0.06	0.00	−0.27	−0.31
EPA+DHA (log)	−0.51*	−0.26	−0.36*	0.27	0.01
DIET CHOL	0.62*	0.46	0.55*	0.33	0.29
PROTEIN	−0.05	−0.16	0.02	0.00	−0.11
FAT	0.80†	0.62*	0.60*	−0.29	0.05
CARBOH	−0.58*	−0.46	−0.43	0.31	0.05
ALC (log)	−0.74**	−0.59*	−0.66*	0.00	−0.25
ENERGY	0.29	0.09	0.28	−0.14	0.52*
SERUM CHOL	0.71**	–	0.73**	−0.04	0.07

*P<0.05; **P<0.01; ^†P<0.001. ALL, all-cause deaths; CAD, coronary artery disease; CAN, cancer; C12:0, lauric acid; C14:0, myristic acid; C16:0, palmitic acid; C18:0, stearic acid; C18:1C, oleic acid; C18:1T, elaidic acid; C18:2CC, linoleic acid; DHA, docosahexaenoic acid; DIET CHOL, dietary cholesterol; EPA, eicosapentaenoic acid: SFA, saturated fatty acid. (Modified from Kromhout D, et al.³)

We have previously cautioned that the incidence of CAD has not increased in our cohort (Tanushimaru) for a couple of decades.¹⁰ The varied composition of the Japanese diet has probably prevented CAD. However, careful surveillance is needed in the future because of the increasing intake of fat, especially saturated fatty acids and trans fatty acids, with the potential for a modern epidemic of CAD in Japan. It is very serious problem that serum trans fatty acids were elevated in the young generation with CAD and/or metabolic syndrome.¹¹ The guidelines of public organization in Western countries (WHO, FDA etc) propose an upper limit for the intake of trans fatty acids (<1% of daily total energy intake).¹²

Recently, the FDA took steps to further reduce trans fats and remove artificial trans fats in processed foods. However, the Japanese government has not taken any countermeasures against the problem. We should expand out understanding of the risks from trans fatty acids.

References

• 1.    Keys  A,  Aravanis  C,  Blackburn  HW,  Van Buchem  FSP,  Buzina  R,  Djordjevic  BS, et al. Epidemiological studies related to coronary heart disease: Characteristics of men aged 40–59 in Seven Countries. Acta Med Scand 1967; 460(Suppl 180): 1–392.
• 2.    Keys  A. Coronary heart disease in seven countries. Circulation 1970; 41(Suppl 1): 1–211.
• 3.    Kromhout  D,  Menotti  A,  Bloemberg  B,  Aravanis  C,  Blackburn  H,  Buzina  R, et al. Dietary saturated and trans fatty acids, cholesterol and 25-year mortality from coronary heart disease: The Seven Countries Study. Prev Med 1995; 24: 308–315.
• 4.    Hertog  MGI,  Kromhout  D,  Aravanis  C,  Blackburn  H,  Buzina  R,  Fidanza  F, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the Seven Countries Study. Arch Intern Med 1995; 155: 381–386.
• 5.    Kromhout  D,  Bloemberg  BPM,  Feskens  EJM,  Hertog  MGI,  Menotti  A,  Blackburn  H; for the Seven Countries Study Group. Alcohol, fish, fiber and antioxidant vitamins do not explain population differences in coronary heart disease mortality. Int J Epidemiol 1996; 25: 753–759.
• 6.    Alonso  L,  Fontecha  J,  Lozada  L,  Fraga  MJ,  Juárez  M. Fatty acid composition of caprine milk: Major, branched-chain, and trans fatty acids. J Dairy Sci 1999; 82: 878–884.
• 7.    Abbey  M,  Nestel  PJ. Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet. Atherosclerosis 1994; 106: 99–107.
• 8.    Satoh  K. Linoleic acid: A novel mechanism of endothelial cell dysfunction. Circ J 2013; 77: 2702–2703.
• 9.    Wei  J,  Takeuchi  K,  Watanabe  H. Linoleic acid attenuates endothelium-derived relaxing factor production by suppressing cAMP-hydrolyzing phosphodiesterase activity. Circ J 2013; 77: 2823–2830.
• 10.    Adachi  H,  Hino  A. Trends in nutritional intake and serum cholesterol levels over 40 years in Tanushimaru, Japanese men. J Epidemiol 2005; 15: 85–89.
• 11.    Mori  K,  Ishida  T,  Yasuda  T,  Hasokawa  M,  Monguchi  T,  Sasaki  M, et al. Serum trans-fatty acid concentration is elevated in young patients with coronary artery disease in Japan. Circ J 2015; 79: 2017–2025.
• 12.   WHO. Diet, nutrition and the prevention of chronic diseases. World Health Organ Tech Rep Ser 2003; 916: i–viii, 1–149.