## Abstract

Lower rates of coronary heart disease (CHD) and other cardiovascular disease in the Japanese population compared with the US and other Western populations suggest the possibility of genetic differences that confer some protection from such disease in Japanese people. However, lifestyle changes in Japan in recent decades have been accompanied by the increasing prevalence of hypercholesterolaemia and diabetes, and recent data indicate an increase in prevalence of ischaemic heart disease. Studies in Japan have indicated a strong relationship between hypercholesterolaemia and CHD. Close attention must be devoted to what appears to be a growing risk for cardiovascular disease in the Japanese population.

## Introduction

Although it is increasing, the prevalence of coronary heart disease (CHD) in the Japanese population remains lower than that in the US and other Western populations. However, with changes in Japanese lifestyle since World War II, the prevalence of such risk factors as hypercholesterolaemia and diabetes has increased, possibly predicting further increases in the incidence of CHD and other cardiovascular disease in Japan.

## East/West differences?

It is well known that there are lower rates of cardiovascular mortality and CHD mortality among Japanese men, even those living in Hawaii, than among US Caucasians. There may be genetic differences between Japanese people and Western people that underlie some of the observed differences in risk. However, it is also the case that the prevalence of CHD risk factors has increased and continues to increase in Japan, and it is likely that rates of CHD and other cardiovascular disease will therefore increase. Fig. 1 shows mortality due to CHD, heart failure and other diseases of the heart from 1990 to 1998 in white men in the US, male Japanese Americans living in Hawaii and male Japanese living in Japan as reported by Sekikawa et al.1 The relatively small percentage of mortality attributed to CHD and the large proportion attributed to heart failure in Japanese men likely represent some degree of misclassification of CHD deaths as heart failure deaths.

Fig. 1

Cardiovascular mortality from 1990 to 1998 in Japanese and US men. (Adapted with permission from Sekikawa et al.1)

Fig. 1

Cardiovascular mortality from 1990 to 1998 in Japanese and US men. (Adapted with permission from Sekikawa et al.1)

## Risk factors

While total cholesterol levels have been decreasing in the US population, a marked increase in the Japanese population began in the 1980s, such that by the later part of the decade, mean levels in Japanese women exceeded those in US adults. These increases appear to be associated with the marked increase in ischaemic heart disease mortality observed in Japanese men and women in the early 1990s. Fig. 2 shows mean serum total cholesterol levels in American people and Japanese people by decade of life according to 1972–1976 data from the US and 1980 data from Japan. Japanese men and women who were around 20 years of age at the time of the study had higher cholesterol levels than did their US counterparts.2 This age group is now around 40 years of age and there is concern that the elevated cholesterol levels may be associated with increased cardiovascular disease as this segment of the population ages. Also shown in Fig. 2 is the distribution of Japanese adults with total cholesterol levels ⩾5.69 mmol/l (220 mg/dl) by decade of age in surveys performed in 1980, 1990 and 2000.3 In addition to an increasing prevalence of elevated total cholesterol between 1980 and 1990 for each decade of age, these data also suggest a high prevalence of elevated cholesterol in older, post-menopausal women.

Fig. 2

Top: Mean serum total cholesterol levels according to age in Japanese (1980) and US (1972–1976) populations. (Adapted with permission from Sekimoto et al.2) Bottom: Proportion of individuals in Japan with total cholesterol ⩾5.69 mmol/l (220 mg/dl) by decade of age (from 30s to 70s) in surveys in 1980 (’80), 1990 (’90) and 2000 (’00). (Data from the Ministry of Health, Labour and Welfare.3)

Fig. 2

Top: Mean serum total cholesterol levels according to age in Japanese (1980) and US (1972–1976) populations. (Adapted with permission from Sekimoto et al.2) Bottom: Proportion of individuals in Japan with total cholesterol ⩾5.69 mmol/l (220 mg/dl) by decade of age (from 30s to 70s) in surveys in 1980 (’80), 1990 (’90) and 2000 (’00). (Data from the Ministry of Health, Labour and Welfare.3)

The frequency of diabetes is also increasing in Japan, with survey data indicating a doubling of the prevalence of diabetes between 1980 and 2000 (Fig. 3).4 According to Ministry of Health, Labour and Welfare statistics, the estimated population of diabetic patients in Japan is expected to increase from 6.9 million in 1997 to 10.8 million in 2010. These changes in cardiovascular risk profiles likely represent changes in lifestyle in Japanese society, including consumption of increasing amounts of animal products and reduced physical activity.

Fig. 3

Increase in prevalence of diabetes in Japan between 1980 and 2000. (Data from the Ministry of Health, Labour and Welfare.4)

Fig. 3

Increase in prevalence of diabetes in Japan between 1980 and 2000. (Data from the Ministry of Health, Labour and Welfare.4)

## Association of cardiovascular risk and hypercholesterolaemia

Studies in Japan have shown a strong relationship between hypercholesterolaemia and cardiovascular risk. In a 13-year cohort study of cause-specific mortality reported by Okamura et al.,5 9215 community-dwelling individuals aged at least 30 years without a history of cardiovascular disease were stratified according to baseline serum total cholesterol levels of

$${<}$$
4.14, 4.14–5.16, 5.17–6.20 and ⩾6.21 mmol/l (
$${<}$$
160, 160–200, 200–240 and ⩾240 mg/dl). Overall, 1206 deaths occurred during follow-up, of which 462 were attributed to cardiovascular disease and 79 to CHD. Total cholesterol levels
$$>$$
6.21 mmol/l (240 mg/dl) were significantly associated with coronary mortality; the relative risk for coronary mortality in this group was 2.93 (95% confidence interval [CI], 1.52–5.63) compared with the reference group defined by total cholesterol of 4.14–5.16 mmol/l (160–200 mg/dl). No significant relationship between total cholesterol and stroke was observed. On multivariate analysis, the attributable risk percentage of hypercholesterolaemia for CHD mortality was 66%.

The Japan Lipid Intervention Trial was a 6-year nationwide study in which 47,294 subjects without CHD and 5127 patients with CHD, all with serum total cholesterol ⩾5.69 mmol/l (220 mg/dl), received open-label treatment with simvastatin 5–10 mg under standard clinical conditions.6,7 Subjects were men aged 35–70 years and post-menopausal women aged ⩽70 years. In the primary prevention cohort, simvastatin treatment reduced total cholesterol by 18.4%, low-density lipoprotein cholesterol (LDL-C) by 26.8% and triglycerides by 16.1%, and increased high-density lipoprotein cholesterol (HDL-C) by 4.5% (average changes during treatment). In the secondary prevention cohort, simvastatin treatment reduced total cholesterol by 19.8%, LDL-C by 28.6% and triglycerides by 15.9%, and increased HDL-C by 4.7% (average changes during treatment). In the primary prevention cohort, relative risk of CHD according to lipid values during treatment was significantly increased, with the following:

• Total cholesterol ⩾6.21 mmol/l (240 mg/dl)

• 6.21–6.70 mmol/l (240–259 mg/dl) (relative risk, 2.63; 95% CI, 1.68–4.12)

• ⩾6.70 mmol/l (260 mg/dl) (relative risk, 4.03, 95% CI, 2.55–6.38)

Reference, 5.17–5.66 mmol/l (200–219 mg/dl)

• LDL-C ⩾4.14 mmol/l (160 mg/dl)

• 4.14–4.63 mmol/l (160–179 mg/dl) (relative risk, 2.59; 95% CI, 1.62–4.15)

• ⩾4.65 mmol/l (180 mg/dl) (relative risk, 5.71; 95% CI, 3.64–8.97)

Reference, 3.10–3.59 mmol/l (120–139 mg/dl)

• Triglycerides ⩾3.39 mmol/l (300 mg/dl) (relative risk, 2.16; 95% CI, 1.38–3.37)

Reference, 3.10–3.59 mmol/l (120–139 mg/dl)

• HDL-C

$${<}$$
1.03 mmol/l (40 mg/dl) (relative risk, 1.45; 95% CI, 1.01–2.07)

Reference, 1.03–1.26 mmol/l (40–49 mg/dl)

In the secondary prevention cohort, there was a trend for total cholesterol ⩾6.21 mmol/l (240 mg/dl) (relative risk, 1.65; 95% CI, 0.92–2.94) vs 4.65–5.15 mmol/l (180–199 mg/dl) and HDL-C

$${<}$$
1.03 mmol/l (40 mg/dl) (relative risk, 1.60; 95% CI, 0.99–2.58) (reference, 1.03–1.26 mmol/l (40–49 mg/dl)) to predict CHD events; LDL-C ⩾3.62 mmol/l (140 mg/dl) significantly increased relative risk (3.62–4.11 mmol/l [140–159 mg/dl], relative risk, 1.95; 95% CI, 1.06–3.58; ⩾4.14 mmol/l [160 mg/dl], relative risk, 2.27; 95% CI, 1.19–4.32) vs 2.59–3.06 mmol/l (100–119 mg/dl). In the primary prevention cohort, each 0.26 mmol/l (10 mg/dl) decrease in average total cholesterol, LDL-C and triglycerides reduced CHD risk by 11.3%, 15.8% and 1.2%, and each 0.26 mmol/l (10 mg/dl) increase in HDL-C reduced risk by 37.5%. In the secondary prevention cohort, each 0.26 mmol/l (10 mg/dl) decrease in average LDL-C reduced relative risk of CHD by 8.0% (95% CI, 3.8–12.0) and each 0.26 mmol/l (10 mg/dl) increase in HDL-C reduced relative risk by 28.3% (95% CI, 13.9–40.3).

## Conclusion

The prevalence of coronary disease is increasing in the Japanese population, although it remains lower than in the US and other Western populations. Nevertheless, the prevalence of lipid risk factors in younger Japanese people is now similar to that in the US population, and there has been a continuous increase in the frequency of diabetes in Japan. As in Western populations, hypercholesterolaemia is associated with increased CHD risk. There is thus concern regarding what coming years will bring in terms of continued increases in coronary disease.

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