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Relations between dietary sodium and potassium intakes and mortality from cardiovascular disease: the Japan Collaborative Cohort Study for Evaluation of Cancer Risks^1,2,3

¹ From the Department of Public Health Medicine, Graduate School of Comprehensive Human Sciences, and the Institute of Community Medicine, University of Tsukuba, Tsukuba, Japan (MU); Public Health, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan (HI); the Department of Food Sciences and Nutrition, Faculty of Human Life and Environment, Nara Women's University, Kitauoyanishi-machi, Nara, Japan (CD); the Infectious Disease Research Division, Hyogo Prefectural Institute of Public Health and Environmental Sciences, Kobe, Japan (AY); Anjo Kosei Hospital, Anjo, Japan (HT); the Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan (YW); the Department of Public Health, Aichi Medical University School of Medicine, Aichi, Japan (SK); the Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan (AK); the Department of Public Health/Health Information Dynamics, Fields of Science, Program of Health and Community Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan (TK); the Department of Epidemiology and Environmental Health, Juntendo University School of Medicine, Tokyo, Japan (YI); the Department of Community Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (NT); and the Division of Clinical Trials, National Center for Geriatrics and Gerontology, Obu, Japan (AT)

² The JACC Study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (Monbusho) (no. 61010076, 62010074, 63010074, 1010068, 2151065, 3151064, 4151063, 5151069, 6279102, 11181101, and 14207019).

³ Address reprint requests to H Iso, Public Health, Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka-fu 565-0871. E-mail: iso{at}pbhel.med.osaka-u.ac.jp.

	ABSTRACT

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Background: Limited evidence is available about the relations between sodium and potassium intakes and cardiovascular disease in the general population.

Objective: The objective was to investigate relations between sodium and potassium intakes and cardiovascular disease in Asian populations whose mean sodium intake is generally high.

Design: Between 1988 and 1990, a total of 58 730 Japanese subjects (n = 23 119 men and 35 611 women) aged 40–79 y with no history of stroke, coronary heart disease, or cancer completed a lifestyle questionnaire including food intake frequency under the Japan Collaborative Cohort Study for Evaluation of Cancer Risk sponsored by the Ministry of Education, Sports and Science.

Results: After 745 161 person-years of follow-up, we documented 986 deaths from stroke (153 subarachnoid hemorrhages, 227 intraparenchymal hemorrhages, and 510 ischemic strokes) and 424 deaths from coronary heart disease. Sodium intake was positively associated with mortality from total stroke, ischemic stroke, and total cardiovascular disease. The multivariable hazard ratio for the highest versus the lowest quintiles of sodium intake after adjustment for age, sex, and cardiovascular disease risk factors was 1.55 (95% CI: 1.21, 2.00; P for trend < 0.001) for total stroke, 2.04 (95% CI: 1.41, 2.94; P for trend < 0.001) for ischemic stroke, and 1.42 (95% CI: 1.20, 1.69; P for trend < 0.001) for total cardiovascular disease. Potassium intake was inversely associated with mortality from coronary heart disease and total cardiovascular disease. The multivariable hazard ratio for the highest versus the lowest quintiles of potassium intake was 0.65 (95% CI: 0.39, 1.06; P for trend = 0.083) for coronary heart disease and 0.73 (95% CI: 0.59, 0.92; P for trend = 0.018) for total cardiovascular disease, and these associations were more evident for women than for men.

Conclusions: A high sodium intake and a low potassium intake may increase the risk of mortality from cardiovascular disease.

	INTRODUCTION

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Several epidemiologic studies conducted in Western countries have shown that a high sodium intake was associated with an increased incidence of stroke among overweight adults (1), whereas a high potassium intake was associated with a reduced risk of stroke (2-5). A high sodium intake was also associated with an increased risk of mortality from coronary heart disease (1), whereas potassium intake was not associated with the risk of coronary heart disease (5). In Asian countries, a 7-y prospective study of Japanese showed a positive association between sodium intake and mortality from stroke (6), but the associations of sodium and potassium intakes with the risk of coronary heart disease were not reported.

Mean sodium intake has been shown to be higher in the Japanese (7) than in whites (8), probably because traditional Japanese diets are rich in soybean paste, soy sauce, and salty pickles, and the mortality rate from stroke has been shown to be higher in Japan than in many Western countries (9). According to the INTERSALT Study, 24-h urinary sodium excretion is 167–201 mmol/d in the Japanese and is 96–137 mmol/d in Americans, whereas the respective potassium excretion rates are 41–46 and 23–52 mmol/d, respectively (10). To examine the relations of sodium and potassium intakes with cardiovascular disease in the Japanese is of public health importance.

The aim of the present study was to determine the associations of dietary intakes of sodium and potassium with the mortality risk related to total stroke, stroke subtypes, coronary heart disease, and total cardiovascular disease in a large prospective study of Japanese men and women. Our a priori hypothesis was that sodium intake is positively associated, and potassium intake is inversely associated, with mortality from total stroke, each stroke subtype, coronary heart disease, and total cardiovascular disease.

	SUBJECTS AND METHODS

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Subjects
The Japan Collaborative Cohort (JACC) Study for Evaluation of Cancer Risks, sponsored by the Ministry of Education, Sports and Science, was conducted from 1988 to 1990. A total of 110 792 subjects (n = 46 465 men and 64 327 women) aged 40–79 y of age completed self-administered questionnaires about their lifestyles and medical histories related to hypertension, diabetes, stroke, myocardial infarction, and cancer. The population sample was from 45 communities across Japan, and most of the participants underwent questionnaires and municipal health screening examinations according to the Health Law for the Aged in their communities (11, 12). The sampling methods and protocols of the JACC Study were described in detail previously (11). We excluded from analysis 16 109 subjects (n = 4683 men and 11 426 women) with a medical history of stroke, coronary heart disease, or cancer. Of the remaining 94 683 subjects, 58 730 (n = 23 119 men and 35 611 women) provided valid responses to the dietary questionnaires and were enrolled in the present study.

Mortality surveillance
For mortality surveillance in each area, investigators unaware of the results of questionnaires reviewed death certificates for target populations in each surveyed area, all of which were forwarded to the public health center in the area of residency. Mortality data were sent centrally to the Ministry of Health and Welfare, and the underlying cause of death was coded according to the International Classification of Disease (ICD), 9th revision, from 1988 to 1994 or according to the 10th revision from 1995 to 2003 for the National Vital Statistics in Japan. The classifications of stroke subtypes and coronary heart disease were based on the ICD codes. The registration of death is required by the Family Registration Law and is believed to be followed across Japan. Therefore, all deaths that occurred in the cohort were ascertained by death certificates from a public health center, except for subjects who died after they had moved from their original community, in which case the subject was treated as a censored case when they moved out. Of the total of 58 730 subjects, 2487 (4.2%) moved out. The follow-up was conducted until the end of 2003, except for 5 areas (n = 7237 subjects), where follow-up was terminated at the end of 1999. The average follow-up period for the participants was 12.7 y. The present study was approved by the ethics committees of Nagoya University School of Medicine and University of Tsukuba.

Calculation of sodium and potassium intakes
Each participant was asked to record the frequency of the intake of 35 foods. The response was based on the usual food intake for the past year. Five responses were possible for each food item: "rarely," "1–2 d/mo," "1–2 d/wk," "3–4 d/wk," and "almost every day". The consumption of each food item was calculated by multiplying the frequency score of consumption of each food by 0, 0.38, 1.5, 3.5, and 7/wk, respectively. Each portion size was estimated from a validation study conducted in 85 of the baseline participants. The reproducibility and validity of this dietary questionnaire were reported elsewhere (13). The average daily intake of nutrients and total energy was calculated by multiplying the frequency of consumption of each item with its nutrient content and energy per serving and totaling the nutrient intake for all food items. The energy-adjusted nutrient intakes were calculated by the residual method. The Spearman rank correlation coefficients between the food-frequency questionnaire (FFQ) and four 3-d dietary records were 0.36 for sodium intake and 0.43 for potassium intake for 85 individuals in the validation study. The estimated mean sodium intake was 83 mmol/d from the questionnaire and 167 mmol/d from four 3-d dietary records under the validation study. The respective mean values of potassium intake were 55 and 70 mmol/d. Thus, we calculated calibrated intakes of sodium and potassium, multiplied by 2.0 and 1.3, respectively. The Spearman rank correlation coefficients between 2 FFQs conducted 1 y apart were 0.73 for sodium intake and 0.78 for potassium intake.

Statistical analysis
Statistical analysis was based on age- and sex-adjusted mortality rates of stroke and coronary heart disease during the follow-up period from 1989 to 2003. For each participant, the person-years of follow-up were calculated from the date that the baseline questionnaire was completed until the time of death, the participant moved out of the community, or the end of 2003 or 1999, whichever occurred first. Age- and sex-adjusted hazard ratios of mortality from stroke and coronary heart disease were defined as the death rate among participants according to quintiles of sodium and potassium intakes: <62, 62–80, 80–98, 98–118, and >118 mmol/d for uncalibrated sodium intake and <40, 40–48, 48–54, 54–62, and >62 mg/d for uncalibrated potassium intake.

Age- and sex-adjusted median and mean values and proportions of selected cardiovascular disease risk factors were presented according to quintiles of dietary intakes of sodium and potassium. The age- and sex-adjusted and multivariable-adjusted hazard ratios and their 95% CIs were calculated by using the Cox proportional hazard model. We conducted tests for trend across quintiles of sodium and potassium intakes by assigning median values of each quintile and testing the significance of this variable. These confounding variables for the multivariable adjustment included body mass index (BMI; in kg/m²; sex-specific quintiles), smoking status (never, ex-smoker, and current smokers of 1 to 19 or 20 cigarettes/d), alcohol intake category (never, ex-drinker, and current ethanol drinkers of 1 to 22, 23 to 45, 46 to 68, or 69 g/d), history of hypertension (yes or no), history of diabetes (yes or no), menopause (yes or no), hormone-replacement therapy (yes or no), time spent in physical activity (never, 1–2, 3–4, and 5 h/wk), walking time (never and 30, 30–60, or 60 min/d), educational status (educated until 12, 13–15, 16–18, and 19 y of age), perceived mental stress (low, median, high, or extremely high), and calcium intake (quintiles).

Another multivariable model, after further adjustment for other electrolyte intakes, was constructed to examine an independent effect of sodium or potassium intake on mortality. We tested the interaction of sodium or potassium intake with sex by using an interaction term generated by multiplying the median of each quintile of sodium or potassium intake with sex. There were no significant sex interactions between them except for the association between potassium intake and risk of mortality from coronary heart disease (P = 0.04) and total cardiovascular disease (P = 0.03). We presented the sex-specific results of these endpoints as well.

We also examined the association between sodium intake and risk of mortality from cardiovascular disease stratified by BMI, because salt sensitivity could be enhanced by overweight (14). We divided subjects into 2 groups: BMI < 25 (n = 46 888 subjects) and BMI 25 (n = 11 842 subjects) and examined the multivariable hazard ratios associated with a 100-mmol increment in uncalibrated dairy sodium intake.

Cause-specific mortality was determined by total deaths due to stroke (ICD codes 430–438, 9th revision; ICD, 10th revision, codes I60–I69), coronary heart disease (codes 410–414 and I20–I25), and total cardiovascular diseases (codes 390–459 and I01–I99). Stroke was further categorized into subarachnoid hemorrhage (codes 430 and I60), intraparenchymal hemorrhage (codes 431 and code I61), and ischemic stroke (codes 433–434 and I63 and I693). We used SAS version 8.02 software (SAS Institute Inc, Cary) for all analyses. P values < 0.05 were regarded as statistical significance.

	RESULTS

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Of the cohort followed up for an average 12.7 y, we documented 500 deaths caused by stroke (n = 47 subarachnoid hemorrhage, 118 intraparenchymal hemorrhage, 289 ischemic stroke, and 46 undetermined type of stroke) for men and 486 for women (n = 106 subarachnoid hemorrhage, 109 intraparenchymal, 221 ischemic stroke, and 50 undetermined type of stroke) and 233 deaths caused by coronary heart disease for men and 191 for women. In total, there were 986 cases of stroke and 424 cases of coronary heart diseases.

Age- and sex-adjusted selected cardiovascular disease risk factors and cation intakes according to quintiles of dietary intakes of sodium and potassium are shown in Table 1. Compared with persons in the lowest quintile of dietary sodium intake, those in the highest quintile were older, had a lower prevalence of current smokers and drinkers, and had a higher prevalence of menopause. On the other hand, persons in the highest quintile of potassium intake were older, had a lower prevalence of current smokers and drinkers, and had a higher prevalence of menopause than did persons in the lowest quintile.

Table 2

Table 3

Table 4

Table 5

	DISCUSSION

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The main findings of our large prospective study of Japanese men and women were that a high sodium intake was associated with high risks of mortality from total stroke, ischemic stroke, and total cardiovascular disease, whereas a high potassium intake was associated with a reduced risk of mortality from coronary heart disease and total cardiovascular disease after adjustment for cardiovascular disease risk factors. These associations were strengthened slightly when adjusted further for the other cation. The positive associations between sodium intake and mortality from stroke and total cardiovascular disease were independent of potassium intake and were similarly observed for nonoverweight and overweight persons. The inverse associations between potassium intake and mortality from coronary heart disease were more pronounced when sodium intake was high.

Our results were supported by the findings of previous studies. Two prospective studies of Americans (1) and Japanese (6) showed that sodium intake was associated with an increased risk of stroke incidence and mortality. A 100-mmol increment in daily sodium intake was reported to be associated with 32% higher incidence of stroke among overweight Americans (1). Japanese men with the highest tertile of daily sodium intake (306 mmol) had a 2-fold increased risk of stroke mortality compared with the lowest tertile (174 mmol) (6). In the present study, a 100-mmol increment in uncalibrated daily sodium intake was associated with 83% higher mortality from total stroke.

Several studies have shown that potassium intake is associated with a reduced risk of stroke incidence (5) and mortality (3). A 10-mmol increment in daily potassium intake was associated with 40% reduced risk of death from stroke (3). Americans had a 28% higher risk of stroke incidence in the lowest versus the highest quartiles of potassium intake (< versus 34.6 mmol/d) (5). On the other hand, the association between dietary potassium intake and risk of coronary heart disease was not significant among Americans (5). In the present study, we found an inverse association between potassium intake and mortality from coronary heart disease and total cardiovascular disease, but not from stroke.

Overweight may enhance salt-sensitivity for blood pressure (14), and a previous prospective study of Americans showed positive association between sodium intake and risk of cardiovascular disease only in overweight individuals (1). However, we found a strong positive association between sodium intake and mortality from stroke for persons with either a BMI < 25.0 or a BMI 25.0. Our findings suggests that a high sodium intake was a risk factor for cardiovascular disease not only in overweight but also in nonoverweight Japanese.

The limitations of the present study warrant discussion. First, the estimated sodium intake from the present questionnaire studywas 50% lower than that estimated from dietary records (13). However, the Spearman correlation coefficient between the sodium intakes from questionnaire and dietary records was fairly good; thus, the misclassification for the rank of sodium intake was not large. In addition, any errors concerning the misclassification were likely nondifferential and would have attenuated the associations between sodium intake and mortality from cardiovascular disease. Second, we classified stroke subtypes according to the ICD codes, which may have led to misclassification. However, in Japan, computerized tomography has been widely used in local hospitals nationally since the 1980s. This widespread use of computerized tomography made a death certificate diagnosis of stroke subtypes sufficiently accurate (15, 16). Third, we estimated sodium intakes with an FFQ, which is considered to be a weaker tool than is urinary measurement (17). However, in Japan, salty seasonings such as soy sauce, soybean paste, and salty pickles account for 74% of total sodium intake (7), which may allow us to evaluate ranks of sodium intake by FFQ.

Poor nutrition may reflect poor compliance on FFQs. Then, we examined the association between sodium and potassium intakes and the risk of mortality from cardiovascular disease excluding subjects whose energy intake was <840 kcal/d (<5% of subjects). However, the results did not change significantly.

In conclusion, our large prospective study of Japanese men and women showed that a high dietary sodium intake is associated with the risk of mortality from stroke and total cardiovascular disease and that a high dietary potassium intake is inversely associated with the risk of mortality from total cardiovascular disease. The inverse association between a high dietary potassium intake and the risk of mortality from coronary heart disease was nearly significant in the subjects as a whole and was significant in women. Our findings suggest that a reduction in sodium intake may help prevent stroke and an increase in potassium intake may help prevent coronary heart disease.

	ACKNOWLEDGMENTS

 
We sincerely express our appreciation to Kunio Aoki (Professor Emeritus, Nagoya University School of Medicine and former chairman of the JACC Study) and to Haruo Sugano (former Director of the Cancer Institute, Tokyo), who greatly contributed to the initiation of the JACC Study.

The authors' responsibilities were as follows—MU and HI: developed the study hypothesis; MU: conducted the analysis and drafted the manuscript; and HI, CD, AY, HT, YW, SK, AK, TK, YI, NT, and AT: critically revised the manuscript. None of the authors had a personal or financial conflict of interest.

	REFERENCES

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