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.
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ABSTRACT |
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cerebrovascular accident; fats; prospective studies; proteins
Abbreviations: Abbreviation: CI, confidence interval.
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INTRODUCTION |
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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.
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MATERIALS AND METHODS |
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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). Spearmans 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 430438).
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 140159 mmHg and diastolic blood pressure of 9099 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, 160179, 180199, 200219,
220 mg/dl), serum glucose category (normal, impaired glucose tolerance, and diabetes), smoking status (never, former, current 119 and
20 cigarettes/day), ethanol intake (never, former, and current <46, 4668, 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 6.16.9 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 (19731976, 19771980, 19811984, and 19851988) were also adjusted since there was a 2030 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 19731976 and 19851988.
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.
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RESULTS |
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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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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).
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DISCUSSION |
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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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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 130139 mmHg or diastolic blood pressure of 8589 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, 100200 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.
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ACKNOWLEDGMENTS |
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The authors thank Drs. Meir Stampfer and Walter Willet for their valuable comments.
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NOTES |
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REFERENCES |
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