Fat and Protein Intakes and Risk of Intraparenchymal Hemorrhage among Middle-aged Japanese

Hiroyasu Iso1,, Shinichi Sato2, Akihiko Kitamura2, Yoshihiko Naito2, Takashi Shimamoto2 and Yoshio Komachi2

1 Department of Public Health Medicine, Institute of Community Medicine, University of Tsukuba, Ibaraki-ken, Japan.
2 Osaka Medical Center for Health Science and Promotion, Osaka, Japan.

Received for publication September 21, 2001; accepted for publication July 23, 2002.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The authors examined the relation between low intakes of saturated fat and animal protein and risk of intraparenchymal hemorrhage in a 14-year prospective study (ending in 1997) of 4,775 Japanese aged 40–69 years who undertook a single 24-hour dietary recall. Compared with the highest quartile of energy-adjusted saturated fat intake (median, 17 g/day), multivariate relative risks, after adjustment for age, sex, community, total energy intake, and known cardiovascular risk factors, were 0.77 (95% confidence interval (CI): 0.42, 1.42) for the second quartile (12 g/day), 0.66 (95% CI: 0.34, 1.25) for the third quartile (8 g/day), and 0.30 (95% CI: 0.12, 0.71) for the lowest quartile (5 g/day); p for trend = 0.005. An inverse relation was observed among both hypertensives and nonhypertensives; the respective relative risks with a one standard deviation increase in saturated fat intake (15.4 g/day) were 0.72 (95% CI: 0.52, 1.00) and 0.36 (95% CI: 0.14, 0.95). Intake of animal protein tended to correlate inversely with risk; the relative risk with a one standard deviation increase in animal protein intake (17.6 g/day) was 0.79 (95% CI: 0.61, 1.02); p = 0.07. Results are similar to those recently reported for US women and together help to explain the high rate of this stroke subtype in Asian countries, where intakes of these nutrients are low.

cerebrovascular accident; fats; prospective studies; proteins

Abbreviations: Abbreviation: CI, confidence interval.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A large prospective study of US women, the Nurses’ Health Study, recently showed that low intakes of saturated fat and animal protein are associated with increased risk of intraparenchymal brain hemorrhage and that the excess risk associated with a low intake of saturated fat is confined to hypertensive women (1). This finding is consistent with previous prospective observations on the relation between low serum total cholesterol levels and risk of intraparenchymal hemorrhage (29). Similarly, previous Japanese ecologic studies suggested that populations with low intakes of saturated fat and animal protein are at higher risk of intraparenchymal hemorrhage than are populations with higher intakes (10, 11), but no prospective study has been known to investigate the individual relation between diet and risk of intraparenchymal hemorrhage in Asian countries, where intakes of saturated fat and animal protein are relatively low.

We hypothesized that low intakes of saturated fat and animal protein increase the risk of intraparenchymal hemorrhage and that this relation is most pronounced in Japanese with hypertension. To test our hypothesis, we examined these relations in the present 14-year prospective study of middle-aged Japanese men and women who undertook a single 24-hour dietary recall.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Population
The surveyed population included residents of five communities who were aged 40–69 years and participated in cardiovascular risk surveys. The surveys were conducted between 1973 and 1984 in two northeast rural communities, Ikawa and Ishizawa, and in a western urban suburb, Yao; between 1973 and 1979 in a southwest rural community, Noichi; and between 1982 and 1988 in a central rural community, Kyowa. Approximately 10 percent of the participants underwent a 24-hour dietary recall at examination. Persons with a history of stroke (n = 64) were excluded, and data for 4,775 Japanese (2,269 men and 2,506 women) aged 40–69 years were used for the analyses.

Subjects were followed up to determine stroke endpoints occurring by the end of 1997. Persons who moved out of the communities during the follow-up period numbered 206 (4 percent), and 488 persons died (10 percent). These subjects were censored at the date of moving out or the date of death. The average follow-up period was 14.3 years.

Assessment of nutrient intake
An interview to administer the 24-hour dietary recall was conducted by trained dietitians, and nutrient intakes were calculated by using the fourth revision of the standard Japan Food Table (12). No data on transpolyunsaturated fat are available in the table. Nutrient intakes were adjusted for total energy intake (13).

Reproducibility of the 24-hour recall data was tested by comparing nutrient estimates, adjusted for sex-specific total energy intake, between the two studies conducted 1 year apart in 242 subsamples (n = 24 in one northeastern, n = 48 in the other northeastern, n = 25 in western, n = 38 in southwestern, and n = 107 in central communities). Spearman’s correlation coefficients for the selected macronutrients were moderately high: 0.71 (range, 0.54 to 0.77) for total energy, 0.50 (range, 0.19 to 0.61) for total fat, 0.44 (range, 0.18 to 0.46) for saturated fat, 0.48 (range, 0.20 to 0.58) for monounsaturated fat, 0.37 (range, 0.16 to 0.52) for n-3 polyunsaturated fat and 0.47 (range, 0.09 to 0.57) for n-6 polyunsaturated fat, 0.30 (range, –0.06 to 0.50) for cholesterol, 0.59 (range, 0.45 to 0.70) for total protein, 0.39 (range, 0.23 to 0.50) for animal protein, and 0.63 (range, 0.24 to 0.74) for vegetable protein.

Determination of potential confounding variables
At baseline, nonfasting blood samples were drawn from seated participants into a plain, siliconized glass tube, and the serum was separated. Serum total cholesterol levels were measured by the Liebermann-Burchard direct method using an Autoanalyzer II (Technicon, Tarrytown, New York) at the Osaka Medical Center for Cancer and Cardiovascular Diseases (14). The Osaka, Japan, laboratory has been standardized by the Lipid Standardization Program, Centers for Disease Control and Prevention, Atlanta, Georgia, and has successfully met the criteria for precision and accuracy of cholesterol measurements (15). Serum glucose was measured by the cupric-neocuproine method between 1976 and July 1986 and by the enzymatic method after July 1986. The values obtained with the cupric-neocuproine method were adjusted by using a linear regression formula: glucose value x 0.8546 – 9.7531, which was derived from comparing the two methods.

Trained observers used standard mercury sphygmomanometers to measure baseline blood pressure on the right arm of seated participants after a 5-minute rest (16). Hypertension was defined as systolic blood pressure >=140 mmHg and/or diastolic blood pressure >=90 mmHg, and/or taking antihypertensive medication. Height was measured with participants in stocking feet and weight was measured with subjects wearing light clothing. Body mass index was calculated as weight (kg) divided by the square of height (m2). An interview was conducted to ascertain number of cigarettes smoked per day, usual weekly intake of ethanol in units of go (a Japanese traditional unit of volume corresponding to 23 g of ethanol), medication use for hypertension and diabetes, and menopausal status (for women).

We did not have information on use of anticoagulant medications in these populations, including aspirin or warfarin. Although we expect that levels of use of these medications in the general population are low in persons without a history of myocardial infarction or stroke, they may be higher in persons with atrial fibrillation. There was only one person who developed intraparenchymal hemorrhage with atrial fibrillation at baseline, but this person was not taking medication.

Endpoint determination
Systematic surveillance was conducted for incident strokes that included a constellation of neurologic deficits of sudden or rapid onset, lasting 24 hours or more, or until death. The endpoint of stroke was ascertained via six sources (17): 1) national insurance claims, 2) reports by local physicians, 3) ambulance records, 4) death certificates, 5) reports by public health nurses and health volunteers, and 6) cardiovascular risk surveys. From death certificates, we selected cases that included certain underlying causes of death (International Classification of Diseases, Ninth Revision, codes 430–438).

To confirm the diagnosis, all living patients or their families (if the patients were dead) were visited to obtain histories of the incidence. Medical records and computed tomography and/or magnetic resonance imaging findings were reviewed by study physicians. On the basis of the clinical criteria, three to four study physicians determined whether incident strokes had occurred. Stroke events were further subclassified as intraparenchymal hemorrhages, subarachnoid hemorrhages, ischemic strokes (thrombotic or embolic), or strokes of undetermined type based primarily on computed tomography or magnetic resonance imaging (18).

Statistical analyses
Age- and sex-adjusted mean values and prevalences of covariates were calculated according to quartiles of saturated fat and animal protein intakes, and the differences were tested by using analysis of covariance or chi-square tests. Person-years of follow-up were calculated as the sum of individual follow-up time until the occurrence of incident stroke, death, emigration, or the end of 1998. The relative risk of stroke incidence and its 95 percent confidence interval were calculated with reference to the risk of participants in the lowest quartile of nutrient intake by using the Cox proportional hazards model.

The nutrients examined in the present study were total fat, saturated fat, monounsaturated fat, total polyunsaturated fat, n-3 and n-6 polyunsaturated fat, cholesterol, total protein, and animal and vegetable protein. We adjusted for age, sex, and community and for other potential confounding variables including sex-specific quartiles of total energy intake and body mass index, hypertension category (normal, mild hypertension: systolic blood pressure of 140–159 mmHg and diastolic blood pressure of 90–99 mmHg; moderate or severe hypertension: systolic blood pressure >=160 mmHg, diastolic blood pressure >=100 mmHg, and/or antihypertensive medication use), serum total cholesterol levels (<160, 160–179, 180–199, 200–219, >=220 mg/dl), serum glucose category (normal, impaired glucose tolerance, and diabetes), smoking status (never, former, current 1–19 and >=20 cigarettes/day), ethanol intake (never, former, and current <46, 46–68, and >=69 g/day of ethanol), and (for women) menopausal status (premenopause and postmenopause).

Impaired glucose tolerance was defined as a fasting glucose level of 6.1–6.9 mmol/liter and/or a nonfasting glucose level of >=7.8 mmol/liter, without use of medication for diabetes. Diabetes was defined as a fasting glucose level of >=7.0 mmol/liter and/or a nonfasting glucose level of >=11.1 mmol/liter and/or use of medication for diabetes. The time intervals of the baseline surveys (1973–1976, 1977–1980, 1981–1984, and 1985–1988) were also adjusted since there was a 20–30 percent increase in sex-, age-, and community-adjusted intakes of total fat, saturated fat, monounsaturated fat, polyunsaturated fat, n-3 polyunsaturated fat, n-6 polyunsaturated fat, cholesterol, total protein, and animal protein between 1973–1976 and 1985–1988.

Tests for a linear trend across the dietary categories were also conducted by using median variables of each dietary category. We conducted analyses stratified by sex, hypertension status, body mass index category (<25.0 and >=25.0 kg/m2), or serum glucose category (normal vs. impaired glucose tolerance or diabetes) to assess effect modification, and the significance of interaction was tested by using interaction terms of continuous nutrient variables and stratified variables.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
By the end of 1997, after 68,510 person-years of follow-up (14 years on average), we documented 68 incident intraparenchymal hemorrhages (85 percent were confirmed by computed tomography or magnetic resonance imaging) as well as 41 subarachnoid hemorrhages, 166 ischemic strokes, and 20 unclassified strokes. Of the 68 intraparenchymal hemorrhages, 18 percent were fatal (death occurred within a month of onset); 79 percent were confirmed by imaging or autopsy. There were only five lobar hemorrhages; none was confirmed to include amyloid angiopathy or to be secondary to arteriovenous malformation.

The age- and sex-adjusted rate (number) of intraparenchymal hemorrhage (per 1,000 person-years) varied among communities. Rates were 1.2 (n = 19) in one northeastern community, 2.4 (n = 13) in the other northeastern community, 0.5 (n = 8) in the western community, 0.7 (n = 12) in the southwestern community, and 1.0 (n = 16) in the central community (p for difference < 0.001), which correlated with the prevalence of moderate or severe hypertension (systolic blood pressure >=160 mmHg, diastolic blood pressure >=100 mmHg, or antihypertensive medication use); the prevalences in the respective communities were 31, 36, 18, 26, and 28 percent (p for difference < 0.001)). The respective mean intakes of saturated fat were 11, 10, 12, 9, and 12 g/day (p < 0.001) and of animal protein were 35, 31, 33, 36, and 32 g/day (p < 0.001). However, an inverse relation between saturated fat and animal protein intakes and risk of intraparenchymal hemorrhage was observed in all communities. Thus, in this paper the main results have been presented by adjusting communities using dummy variables.

As shown in table 1, saturated fat intake correlated positively with the proportion of men in the cohort, serum total cholesterol, and intakes of total fat, monounsaturated fat, n-3 and n-6 polyunsaturated fat, cholesterol, total protein, and animal protein and correlated inversely with age, body mass index, hypertension, ethanol intake, and vegetable protein intake. Animal protein intake correlated with serum total cholesterol levels, ethanol intake, and intakes of total fat, saturated fat, monounsaturated fat, n-3 polyunsaturated fat, cholesterol, and total protein and correlated inversely with body mass index, hypertension, and vegetable protein intake. Intakes of saturated fat and animal protein were not correlated with diabetes or smoking.


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TABLE 1. Age- and sex-adjusted baseline characteristics and risk factors for intraparenchymal hemorrhage in a cohort of 4,775 Japanese men and women aged 40–69 years who participated in a 14-year prospective study ending in 1997
 
The age-, sex-, and community-adjusted risk of total stroke was half as high in the lowest quartile of energy-adjusted total fat intake (23 g/day) as in the highest quartile (61 g/day; table 2). This inverse association was observed for saturated and monounsaturated fat but not for other types of fat. The inverse correlation for saturated fat was particularly strong and remained statistically significant even after adjustment for cardiovascular risk factors: the multivariate relative risk for the lowest quartile compared with the highest quartile was 0.30 (95 percent confidence interval (CI): 0.12, 0.71), p for trend = 0.005. When serum total cholesterol was excluded from the adjusted variables, the respective relative risk was 0.28 (95 percent CI: 0.12, 0.66), p for trend = 0.003 (not shown in table 2). We also examined the relation between saturated fat intake in each community: the multivariate relative risks associated with a one standard deviation increase in saturated fat intake (5.4 g/day) were 0.52 (95 percent CI: 0.27, 1.00) in one northeastern community, 0.42 (95 percent CI: 0.16, 1.11) in the other northeastern community, 0.12 (95 percent CI: 0.02, 0.67) in the western community, 0.89 (95 percent CI: 0.40, 1.98) in the southwestern community, and 0.86 (95 percent CI: 0.45, 1.65) in the central community.


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TABLE 2. Relative risks of intraparenchymal hemorrhage according to quartiles of dietary fat and protein intake in a 14-year prospective study (ending in 1997) of 4,775 Japanese men and women aged 40–69 years*
 
Inverse relations were observed among both hypertensives and nonhypertensives. The respective multivariate relative risks associated with a one standard deviation increase in saturated fat intake were 0.72 (95 percent CI: 0.52, 1.00) and 0.36 (95 percent CI: 0.14, 0.95), with no interaction (p for interaction = 0.26).

Intakes of total protein, animal protein, total fat, and monounsaturated fat tended to correlate inversely with risk of intraparenchymal hemorrhage, albeit statistically insignificantly. However, the multivariate relative risk associated with a one standard deviation increase in animal protein intake (17.6 g/day) was of borderline statistical significance: 0.79 (95 percent CI: 0.60, 1.02), p = 0.07. This trend was also observed among hypertensives and nonhypertensives; the respective multivariate relative risks associated with a one standard deviation increase in saturated animal protein intake were 0.80 (95 percent CI: 0.60, 1.07) and 0.70 (95 percent CI: 0.33, 1.51), with no interaction (p for interaction = 0.90).

The inverse relations of saturated fat and animal protein intakes did not vary according to body mass index category (<25.0 vs. >=25.0 kg/m2) or serum glucose category (normal vs. impaired glucose tolerance or diabetes), with no interaction (p for interaction = 0.55 and p for interaction = 0.62, respectively). The inverse relation for monounsaturated fat was modest and was not statistically significant after multivariate adjustment. Intakes of dietary cholesterol, n-3 or n-6 polyunsaturated fat, or vegetable protein did not correlate with risk. These nutrients did not correlate with risk of other stroke subtypes (data not shown in the table).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our prospective data obtained from Japanese study participants confirmed that a very low intake of saturated fat (approximately <10 g/day) is associated with increased risk of intraparenchymal hemorrhage. The results also emphasized the protective role of animal protein against this stroke subtype.

We compared the relation between saturated fat and animal protein intakes and risk of intraparenchymal hemorrhage found in the present study with that reported by the Nurses’ Health Study (1). We recalculated the multivariate relative risks in reference to the highest quartile of these nutrients, since the median intakes in the highest quartile of saturated fat and animal protein in the present study were similar to those in the lowest and second-lowest quintiles, respectively, in the Nurses’ Health Study (figure 1). Although comparability of these nutrient intakes between the studies was not examined, a large difference in the nutrient intakes of Japanese and US subjects was suggested, as shown in figure 1.



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FIGURE 1. Multivariate relative risks (RR) and 95% confidence intervals (vertical lines) of intraparenchymal hemorrhage according to saturated fat and animal protein intakes in a 14-year prospective study of 4,775 Japanese men and women aged 40–69 years, which ended in 1997 (closed circles), and in the 14-year follow-up of the Nurses’ Health Study of 85,764 US women aged 34–59 years, which ended in 1994 (open circles) (1).

 
A previous cross-cultural study showed that dietary intakes of saturated fat and animal protein were far lower in Japanese than in US subjects: average intakes of saturated fat were 16 g/day for Japanese living in Japan and 59–66 g/day for Japanese-Americans living in Honolulu, Hawaii, and California (10). Furthermore, the respective intakes of animal protein were 40 g/day and 66–71 g/day (10). In spite of the large difference in intake of these nutrients, inverse relations with risk of intraparenchymal hemorrhage were persistently observed in both Japanese and US participants.

In the present study, similar relations of saturated fat and animal protein with risk were observed between women and men, with no interaction (p = 0.31 and p = 0.79, respectively), although the confidence intervals of the relative risks were large because of a small number of cases. The multivariate relative risks for the lowest versus highest quartiles of saturated fat were 3.91 (95 percent CI: 0.81, 18.8), p for trend = 0.04 for women and 2.51 (95 percent CI: 0.85, 7.43), p for trend = 0.12 for men; the respective relative risks for animal protein were 1.91 (95 percent CI: 0.38, 9.64), p for trend = 0.38 for women and 2.04 (95 percent CI: 0.89, 4.68), p for trend = 0.15 for men.

The inverse correlation between a low intake of saturated fat and risk of intraparenchymal hemorrhage may in part be mediated by low serum cholesterol levels. In the present study, we observed a significant correlation between dietary saturated fat and serum total cholesterol levels, as expected from experimental studies (19, 20). Age- and sex-adjusted mean levels of serum total cholesterol according to quartile of saturated fat intake were 4.81 (lowest quartile), 4.82, 4.95, and 5.07 mmol/liter (highest quartile, p for difference < 0.001). Moreover, the relative risk of intraparenchymal hemorrhage associated with saturated fat intake was somewhat attenuated after further adjustment for serum total cholesterol in the multivariate analysis.

We did not find any interaction for hypertension with the relation between a low saturated fat intake and risk of intraparenchymal hemorrhage, in contrast to the Nurses’ Health Study (1). The exact reason for this discrepancy is not clear. A possible explanation is that approximately half (5 of 11) of the incident cases who did not have hypertension at baseline had high-normal blood pressure levels: systolic blood pressure of 130–139 mmHg or diastolic blood pressure of 85–89 mmHg, and it is likely that some developed hypertension during the long-term follow-up. In a prospective study of Japanese-American men, the relation between low serum cholesterol and risk of intraparenchymal hemorrhage was more evident for nonhypertensives than for hypertensives (7). Thus, the discrepancy might be due to the difference in race and distribution of blood pressure levels.

The potential mechanisms for the correlation between a low saturated fat intake or low serum total cholesterol levels and risk of intraparenchymal hemorrhage have been discussed previously (22, 23). Briefly, low serum cholesterol may lead to enhanced vulnerability of vascular smooth muscle walls in small intracerebral penetrating arterioles (diameter, 100–200 µm) of the basal ganglia, thalamus, and brain stem (21, 22). Furthermore, neonatal rat cardiomyocytes depleted of cholesterol were more prone to anoxia since cholesterol depletion increases permeability and ion fluxes across the cell membrane, which may lead to cell death (23). Previous studies reported that a diet-induced elevation in serum cholesterol levels from very low to moderate was associated with a reduction of arterionecrosis (fibrinoid necrosis or lipohyalinosis), a basic pathology of intracerebral hemorrhage characterized by necrosis of smooth muscle cells (24), and with fewer strokes (25). Reduced platelet aggregation due to a low saturated fat intake may be another mechanism (26, 27).

The present study has several limitations. First, it is possible that subjects whose intakes of saturated fat and animal protein were low were at high risk of intraparenchymal hemorrhage because of other health habits and behaviors. This likelihood was reduced by multivariate adjustment for potential confounding variables, which had only a small effect on the associations we observed. Our previous study showed that heavy ethanol drinking (>=69 g/day) was associated with increased risk of intraparenchymal hemorrhage (17). When heavy drinkers (5.3 percent of this cohort) were excluded, the results were essentially the same (number of cases = 58): the multivariate relative risk associated with a 5.4-g/day increase in saturated fat intake was 0.67 (95 percent CI: 0.48, 0.99), p = 0.03, and that associated with a 17.6-g/day increase in animal protein intake was 0.74 (95 percent CI: 0.55, 0.99), p = 0.04.

Second, we used the nutrient data estimated from a single 24-hour recall, which has intrinsically lower reliability than a food frequency questionnaire (28). The reliability of 24-hour recall was relatively as good among our Japanese subjects as among Japanese Americans (28). The correlation coefficients between some of the nutrient values examined a year apart in the present study were somewhat lower than those estimated by using repeated semiquantitative food frequency questionnaires in other studies; for example, r = 0.44 in the present study and r = 0.55 in the Nurses’ Health Study for saturated fat (29). Measurement errors in assessing nutrient intake are inevitable, but any errors are likely to be nondifferential and would have tended to attenuate associations with saturated fat and animal protein toward the null value.

The strength of the present study was our use of a population-based sample from five Japanese communities, and our findings could probably be generalized to other Japanese populations. Furthermore, we measured serum total cholesterol levels and found that the relation between a low saturated fat intake and risk of intraparenchymal hemorrhage was in part mediated by low serum total cholesterol levels.

In conclusion, we demonstrated in the present study that saturated fat intake correlated inversely with risk of intraparenchymal hemorrhage and that animal protein intake tended to correlate with the risk among middle-aged Japanese. Our results and similar findings in US women help to explain the high rate of this stroke subtype in Asian countries, where intakes of these nutrients are low.


    ACKNOWLEDGMENTS
 
This study was supported in part by a grant (10C-3) from the National Cardiovascular Center, Osaka, Japan.

The authors thank Drs. Meir Stampfer and Walter Willet for their valuable comments.


    NOTES
 
Reprint requests to Dr. Hiroyasu Iso, Department of Public Health Medicine, Institute of Community Medicine, University of Tsukuba 1-1-1, Tsukuba-shi, Ibaraki-ken, 305-8575 Japan (e-mail: fvgh5640{at}mb.infoweb.ne.jp). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Iso H, Stampfer MJ, Manson JE, et al. Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women. Circulation 2001;103:856–63.[Abstract/Free Full Text]
  2. Komachi Y, Iida M, Ozawa H, et al. Risk factors of stroke. (In Japanese). Saishin Igaku 1977;32:2264–9.
  3. Ueshima H, Iida M, Shimamoto T, et al. Multivariate analysis of risk factors for stroke: eight-year follow-up study of farming villages in Akita, Japan. Prev Med 1980;9:722–40.[ISI][Medline]
  4. Tanaka H, Ueda U, Hayashi M, et al. Risk factors for cerebral hemorrhage and cerebral infarction in a Japanese rural community. Stroke 1982;13:62–73.[Abstract]
  5. Shimamoto T, Komachi Y, Inada H, et al. Trends for coronary heart disease and stroke and their risk factors in Japan. Circulation 1989;79:503–15.[Abstract]
  6. Iso H, Jacobs DR Jr, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med 1989;320:904–10.[Abstract]
  7. Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke 1989;20:1460–5.[Abstract]
  8. Iribarren C, Jacobs DR, Sadler M, et al. Low total serum cholesterol and intracerebral hemorrhagic stroke: is the association confined to elderly men? The Kaiser Permanente Medical Care Program. Stroke 1996;27:1993–8.[Abstract/Free Full Text]
  9. Leppala JM, Virtamo J, Fogelholm R, et al. Different risk factors for different stroke subtypes. Association of blood pressure, cholesterol, and antioxidants. Stroke 1999;30:2535–40.[Abstract/Free Full Text]
  10. Kagan A, Harris BR, Winkelstein W Jr. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. J Chronic Dis 1974;27:345–64.[ISI][Medline]
  11. Takeya Y, Popper JS, Shimizu Y, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: incidence of stroke in Japan and Hawaii. Stroke 1984;15:15–23.[Abstract]
  12. The Resource Council, Science and Technology Agency. Standard tables of food composition in Japan. 4th rev. (In Japanese). Tokyo, Japan: Ministry of Finance, 1982.
  13. Willett WC, Sampson L, Browne ML, et al. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol 1988;127:188–99.[Abstract]
  14. Manual of laboratory operations, Lipid Research Clinics Program. Lipid and lipoprotein analysis. Vol 1. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Welfare, 1974. (DHEW publication no. (NIH) 75–628).
  15. Nakamura M, Morita M, Yabuuchi E, et al. The evaluation and the results of cooperative cholesterol and triglyceride standardization program by WHO-CDC. (In Japanese). Risho Byori 1982;30:325–32.
  16. Kirkendall WM, Feinlieb M, Freis ED, et al. Recommendations for human blood pressure determination by sphygmomanometers. Subcommittee of the AHA Postgraduate Education Committee. Circulation 1980;62:1146A–55A.[Medline]
  17. Iso H, Kitamura A, Shimamoto T, et al. Alcohol intake and the risk of cardiovascular disease in middle-aged Japanese men. Stroke 1995;26:767–73.[Abstract/Free Full Text]
  18. Iso H, Rexrode K, Hennekens CH, et al. Application of computer tomography-oriented criteria for stroke subtypes classification in a prospective study. Ann Epidemiol 2000;10:81–7.[CrossRef][ISI][Medline]
  19. Keys A, Parlin RW. Serum cholesterol response to changes in dietary lipids. Am J Clin Nutr 1966;19:175–81.[ISI][Medline]
  20. Hegsted DM, Ausman LM, Johnson JA, et al. Dietary fat and serum lipids: an evaluation of the experimental data. Am J Clin Nutr 1993;57:875–83.[Abstract]
  21. Ooneda G, Yoshida Y, Suzuki K, et al. Morphogenesis of plasmatic arterionecrosis as the cause of hypertensive intracerebral hemorrhage. Virchows Arch A Pathol Pathol Anat 1973;361:31–8.[Medline]
  22. Masawa N, Yoshida Y, Yamada T, et al. Morphometry of structural preservation of tunica media in aged and hypertensive human intracerebral arteries. Stroke 1994;25:122–7.[Abstract]
  23. Bastiaanse EML, van der Valk-Kokshoorn LJM, Egas-Kenniphaas JM, et al. The effect of sarcolemmal cholesterol content on the tolerance to anoxia in cardiomyocyte cultures. J Mol Cell Cardiol 1994;26:639–48.[CrossRef][ISI][Medline]
  24. Ooneda G, Yoshida Y, Suzuki K, et al. Smooth muscle cells in the development of plasmatic arterionecrosis, arteriosclerosis, and arterial contraction. Blood Vessels 1978;15:148–56.[ISI][Medline]
  25. Yamori Y, Horie R, Ohtaka M, et al. Effects of hypercholesterolaemic diet on the incidence of cerebrovascular and myocardial lesions in spontaneously hypertensive rats (SHR). Clin Exp Pharmacol Physiol 1976;(suppl 3):205–8.
  26. Renaud S, Godsey F, Dumont E, et al. Influence of long-term diet modification on platelet function and composition in Moselle farmers. Am J Clin Nutr 1986;43:136–50.[Abstract]
  27. Tandon N, Harmon JT, Rodbard D, et al. Thrombin receptors define responsiveness of cholesterol-modified platelets. J Biol Chem 1983;258:11840–5.[Abstract/Free Full Text]
  28. McGee D, Rhoads G, Hankin J, et al. Within-person variability of nutrient intake in a group of Hawaiian men of Japanese ancestry. Am J Clin Nutr 1982;36:657–63.[Abstract]
  29. Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:51–65.[Abstract]