Nutrition-related determinants of blood pressure

PREVENTIVE

MEDICINE

14, 413-427 (1985)

Nutrition-Related

Determinants

of Blood Pressure’

JAAKKO TUOMILEHTO,*'* PIRJO PIETINEN,* JUKKA T. SALONEN,~. PEKKA PUSKA,* AULIKKI NISSINEN,* AND EVA WOLF* *National

Public Health Institute,

Mannerheimintie 166, SF-00280 Helsinki, Kuopio, Kuopio. Finland

and Pthe University

qf

INTRODUCTION The importance of high blood pressure as a major risk factor for cardiovascular diseases (CVD) has led to extensive research in the etiology of hypertension. Regulation of blood pressure (BP) in humans involves many different organs and physiological processes that contribute either directly to the determination of BP level or indirectly by modifying the response. A large number of nutritional factors may have an influence on normal cardiovascular physiology, and many of them may also be important in the pathophysiology of hypertension (35, 37, 39). Because of the interactions among different nutrients, the importance of the contribution of a single nutrient to BP regulation is difficult to define precisely. Moreover, it is unlikely that modification in the intake of a single such nutrient would result in a universal effect on BP in all persons of all populations. The nutrient interactions mentioned above occur not only in terms of physiological events, but also in terms of diet composition and selection and nutrient absorption, bioavailability, and ultimate elimination (35). This complexity poses serious problems for the design of studies that attempt to confirm causative links between various nutrients and BP. Unfortunately, these problems have too often been ignored or overlooked in study design and in interpretation of results. As in any other type of etiological study, a clear distinction should be made between determinants (i.e., characteristics on which the BP level depends), modifiers (i.e., subject characteristics on which measurements of the relation between BP and its determinants depend), and confounding factors (i.e., predictors of BP that differ among the compared categories of the determinant). The availability of effective antihypertensive agents and the encouraging results of several well-conducted clinical trials studying the effectiveness of lowering high BP to prevent cardiovascular complications (19, 30, 65) have accelerated a move toward active drug therapy. Recent epidemiological studies have, however, clearly shown that, although significant reductions in BP levels were achieved in the 197Os, the situation is still far from adequate (23, 62). In Finland, for instance, about 40% of the hypertensive population is not adequately controlled, according ’ Presented at the symposium, “Epidemiology and Prevention of Hypertension and Its Cardiovascular Complications,” June 16-17, 1984, Saanen-Gstaad, Switzerland. ’ To whom reprint requests should be addressed: Dr. Jaakko Tuomilehto, National Public Health Institute, Mannerheimintie 166, SF-00280 Helsinki 28, Finland.

413

009 I -7435/85 $3 .OO Copyright 0 1985 by Academic Press, Inc. All nghfs of reproduction m any form reserved.

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ET AL.

to a survey carried out in 1982 (62). New approaches with regard to public health policy and more research into the public health issues of hypertension are obviously needed. Emphasis should be placed on nonpharmacological methods of BP control. A suggestion has been made that one aim in the effort to control and prevent hypertension by dietary means should be to move the entire population BP distribution to the left (68). This would basically entail a modification of the age relation of blood pressure in the population through nutritional changes. Another, clinical type of approach involves normalization by dietary means of BPS of persons with values above a certain limit. In such cases, the nutrition-related determinants for the individual patients have to be known. Theoretically, this could be done at any age. Still another approach in the use of dietary means for hypertension control would be the prevention of the elevation of BP levels among persons who are at high risk of developing hypertension. This would require the ability to identify those modifiers, both nutritional and nonnutritional (e.g., genetic markers), before hypertension develops. Then, it could be assumed that by preventing exposure in a defined high-risk subgroup, for instance, by appropriate lifetime dietary modifications, the development of hypertension could be prevented. In the past, much of the research on the association between nutrients and BP elevation has focused on salt or sodium (46). However, many other nutrients also play a role in the etiology of hypertension. Some nutritional factors seem to be associated with BP reduction and some with elevation and have, according to different investigators, either a hypertensive or a hypotensive effect. The list of such nutritional factors is long (Table 1). Whether these nutritional factors are causally related determinants of BP is debatable. Some associations are possibly due to confounding effects, and other factors may only modify the relationship between BP and a determinant. EFFECT OF VARIOUS

NUTRITIONAL

FACTORS ON BLOOD PRESSURE

Excessive Energy Intake Numerous analyses have shown that excessive energy intake may be the single most important nutritional factor in the pathogenesis of hypertension (16). Some earlier findings suggested that the association between excessive energy intake (or obesity) and BP reflects excessive sodium intake rather than energy intake TABLE 1 NUTRITIONAL FACTORS ASSOCIATED WITH BLOOD PRESSURE

Sodium Potassium Calcium Magnesium Chloride Cadmium Selenium Lead

Saturated fats PIS ratio Linoleic acid Eicosapentanoic acid Alcohol Coffee Energy Proteins

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itself (8, 31). This hypothesis may not be true, because recent studies in obese, hypertensive persons have suggested that weight reduction itself lowers BP irrespective of the changes in sodium intake (50, 60). Manipulation of energy intake will, of course, also induce other changes in the overall nutrient intake, which may have an effect on BP. Further studies are needed to elucidate the long-term effects of weight reduction on BP in persons who maintain a lower body weight but continue to eat foods similar to those they ate before their weight reductionjust in smaller quantities. Sodium and Potassium The debate about whether current epidemiological data support the hypothesis of an association between sodium intake and BP continues (13, 14, 35, 37, 39, 42). New studies have been designed to answer this question. It is obvious that several modifying and confounding factors have not been adequately controlled in earlier studies, and study samples or sample sizes have been inadequate, leading to conflicting results. These are the main reasons for the arguments against the so-called salt hypothesis, which are often based on personal beliefs rather than on an objective interpretation of the scientific data (7, 10, 28, 40). A suggestion has been made that another macronutrient, potassium, might have a confounding effect on the relationship between sodium intake and BP (9). Although results of animal experiments (41), some clinical trials (29), and some epidemiologic studies (27) suggest that high potassium intake can prevent BP elevation or lower high BP values, our findings in Finland are not consistent with this hypothesis. The average potassium intake level in Finland is approximately 90-100 mmol per day for men and 70-80 mmole per day for women (Table 2), levels that are among the highest of the industrialized countries. However, the Finnish population is well known for its high BP levels (63). In our studies, high potassium intake has not been associated with lower population levels of BP (61). Results from well-designed clinical and epidemiological studies are clearly needed to define the possible role of potassium in the prevention and control of hypertension in different populations. TABLE POTASSIUM

EXCRETION

IN 24-hr

URINE

2

SPECIMENS (MEAN AND SEX, IN 1979 Potassium

2 SD) IN NORTH

excretion

(mmo1/24

14- 19

20-29 30-39 40-49 50-59 60-65 Total

X f

76 87 99 93 94 82

SD

BY AGE

hr)

Men Age (years)

KARELIA,

Women n

X k SD

n

58 68 78 72 77 77

24 22 20 24 26 19

42

73 t 24

362

k k 2 2 k 2

21 28 31 28 37 22

34 69 76 75 71 34

91 ”

30

359

” k k k e 2

50

64 73 80 53

416

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ET AL.

Calcium Several cross-sectional analyses have shown a positive association between BP and serum total calcium concentration or urinary calcium excretion (4, 24, 34, 38). On the other hand, a negative correlation has been reported between serum ionized calcium and BP in untreated hypertensive patients (33). A negative association also seems to exist between BP and dietary calcium intake (16, 33, 37). Several important points should be taken into consideration in interpreting the results of studies on calcium and BP. It is not known how accurate the assessment of calcium intake has been in the studies reported so far. The variation in the values of calcium in both serum and urine do not only reflect variation in dietary calcium intake, but also involve several other factors. In addition, it is possible that calcium intake may act as a marker for other nutritional or social habits that were not considered in survey data analyses. According to a recent editorial (l), there is certainly a long way to go before we are able to give dietary advice for hypertensive patients concerning calcium intake. Alcohol Several studies have reported a significant association between alcohol intake and BP levels in adults (11, 22, 25, 67). The mechanism by which alcohol raises BP is unclear. Direct effects on the heart and peripheral vasculature, increased secretion of corticosteroids, increased noradrenergic activity, and increased catecholamine secretion secondary to alcohol withdrawal symptoms have been suggested (15, 26, 67). Alcohol is not strictly a nutrient, but it is an important energy source. Regular alcohol consumption is often associated with other dietary changes that might have an independent BP-raising effect. In the 1977 crosssectional survey of the North Karelia Project, mean values of mean arterial pressure (MAP) were computed for strata of reported intake of alcohol, saturated fats, and salt (54). A covariance correction for heart rate, body mass index, age, and family history was used. In this analysis, alcohol intake and a high intake of saturated fats showed overall associations with MAP. Alcohol intake was associated with MAP more strongly among men than women (Table 3). For both genders combined, the adjusted MAP was 8.0 mm Hg higher in people who used more salt, saturated fats, and alcohol than in those who used less. Alcohol consumption may also hinder the BP-lowering effect of antihypertensive drugs. In the 1977 population survey of the North Karelia Project, diastolic BP levels were higher in treated hypertensive men and women who used alcohol than in those who did not use alcohol. Compliance with antihypertensive drug treatment was assessed in this study by using copies of prescriptions obtained from the National Social Insurance Institute, which has reimbursed the antihypertensive drug costs to patients (12). Men who reported using alcohol had higher diastolic BP levels in every compliance category compared with nondrinkers. This difference was more pronounced among those men whose compliance with drug therapy was low. As many as 88% of those men whose compliance scores could not be calculated were alcohol users (Table 4). These men had collected their drugs only once during the previous year-an obvious indication of poor compliance .

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TABLE 3 ADJUSTED MEAN ARTERIAL PRESSURE(mm Hg) IN MEN AND WOMEN WITH No REFQRTED CARDIOVASCULAR DISEASES AND No DRUG THERAPY FOR HYPERTENSION, BY REPORTED INTAKE OF ALCOHOL, FATS, AND SALT IN EASTERN FINLAND IN 1977 Men

Alcohol intake: Fat intake: Salt intake Low High ANCOVA:

Women (n = 4,280)

(n = 4,199)

Low

High

Low

High

Low

High

Low

High

Low

High

Low

High

107 107

106 107

109 109

110 111

102 101

103 104

103 103

97 100

Main effects Gender, P i 0.001 Fat intake, P = 0.009 Interactions Gender x fat intake, P = 0.001 Gender x alcohol intake x fat intake x salt intake, Covariates BMI, P < 0.001 Age, P < 0.001 Heart rate, P < 0.001 Family history of hypertension, P < 0.001

P = 0.011.

Fats Dietary fat intake and quality may also be a very important determinant of BP (12, 20,49,51, 52,57,64). In the 1977 North Karelia population survey, saturated fat intake was positively and independently associated with MAP, especially among women (54) (Table 5). Evidence for the role of fat or fatty acids in BP regulation has also been obtained from animal experiments (6, 18, 21, 58). These studies suggest that a diet high in saturated fat and low in linoleic acid raises BP in several animal species. A series of controlled intervention trials has been carried out in North Karelia to study the effects of reducing total fat intake and increasing the polyunsaturated/ saturated fat (P/S) ratio on BP (20, 21, 47-49). The designs of these trials are shown in Fig. 1. Each study included a baseline period of 2 weeks, an intervention period, and a switchback period. In all the studies, BPS were measured by an automatic Sphygmetrics SR2 instrument.. Study 1 included 30 healthy couples (59 persons ages 40 to 49 years). During the baseline and switchback periods the families were instructed to continue with their usual diet and during the intervention period to change to a low-fat diet with a high P/S ratio. Salt intake and energy consumption were kept constant (21, 45). Changes in BP observed in Study 1 are shown in Table 6. Systolic BP fell significantly (P < 0.05) during the period of low-fat diet with a high P/S ratio compared with the baseline period. At the same time, a 22% reduction in the mean level of serum cholesterol was also observed. The percentage of total energy

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TABLE 4 ADJUSTED” DIASTOLICBLOODPRESSURE IN 1977 BY GENDER, COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY,AND USE OF ALCOHOLIN NORTH KARELIA IN A COHORT OF HYPERTENSIVE PEOPLE FOLLOWED FROM 1972 TO 1977

Compliance score Adequate

Poor

mm Hg

n

mm Hg

98

Total Not available

n

mm Hg

n

mm Hg

n

95 102 100

25 97 122

95 98 97

123 81 204

Men No alcohol Alcohol Total

13 47 60

92

7

93

100 100

105

14

104

101

21

102

15 36 41

Women No alcohol Alcohol Total

94 98 96

61 143 104

97 97 97

21 12 33

97 98 97

41 26 67

ANCOVA:

Main effects Alcohol, P < 0.01 Gender, P < 0.05 Compliance, NS Covariates Baseline diastolic blood pressure, P < 0.001

n Adjusted for the diastolic blood pressure in 1972 and age.

from fat decreased from 39 to 24% during the intervention period and returned to 36% during switchback. Study 2 was carried out in different communities in North Karelia. Fifty-seven healthy couples were selected for the study. None of the participants, ages 30 to 50 years, had major health problems, but at least one of the spouses had mild hypertension which was not being treated with drugs. The aim of Study 2 was to find out whether the BP-lowering effect could be obtained in people with elevated BP. The effect of a change in dietary fat on BP was compared with that of salt reduction (49). The families were randomly allocated into three groups: Group I, a low-fat diet group; Group II, a low-salt diet group; and Group III, a reference group. In Study 2, the participants kept to their usual North Karelian diets during the baseline and the switchback period. During the intervention period the subjects in Group I changed to a diet containing 23% of total energy as fat instead of the 38% typical of their usual diet. Correspondingly, the P/S ratio of their new diet was 0.9 as opposed to the 0.2 ratio of their usual diet. Group II continued their usual diet except that salt intake was lowered from 11 to 5 g/day. Group III was a reference group and maintained their usual diet throughout the study. A highly significant decrease in BP values was seen in Group I, the group consuming a low-fat diet with a high P/S ratio, whereas the changes in the ref-

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TABLE 5 MEAN ARTERIAL PRESSURE (mm Hg) BY GENDER, INTAKE OF SATURATED FATS, AND INTAKE OF SALT, ADJUSTED FOR AGE, BMI, HEART RATE, AND FAMILY HISTORYOF HYPERTENSION

Women

Men

Salt intake Low Medium High

Low fat intake

High fat intake

Low fat intake

High fat intake

107 107 107

105 107 109

102 102 103

103 103 105

ANCOVA: Main effects Gender, P < 0.001 Fat intake, P = 0.015 Salt intake, P < 0.044 Interaction Gender x fat intake, P < 0.001

erence group were negligible (Table 6). Despite a well-documented 50% decrease in salt intake in Group II (49), no consistent change was seen in systolic BP, although diastolic pressure fell slightly during the intervention period. Another study has been recently carried out (Study 3) to compare the effects of two low-fat diets with different P/S ratios and a longer intervention period. Thirty-two families were randomly allocated to two intervention groups and were followed through a 2-week baseline, a 1Zweek intervention, and a 5-week switchback period. During the intervention period, the participants in Group I were instructed to follow a diet with a goal of 25% of energy from fat and a P/S ratio of 1.0, and the participants in Group II a diet also with 25% of energy from fat but with a P/S ratio of 0.4 to 0.5. The participants were requested not to make major changes in their lifestyle other than the diet (e.g., changes in alcohol intake or physical exercise). Again, significant reductions in serum cholesterol values were observed during the low-fat diet period, and these changes were maintained throughout the 3-month observation period. Furthermore, an essentially similar BP change was seen in both groups despite the different P/S ratios (Table 6). This result can be interpreted in two different ways. Either the relative increase in linoleic acid in the group with the lower P/S ratio was sufficient to induce the BP change or the decrease in saturated fat was responsible for the changes in both groups. Trace Elements Essential trace elements and toxic heavy metals-like cadmium, copper, iron, lead, mercury, selenium, thallium, and zinc-have sometimes been found to be associated with elevated BP (17,32,43,55). Shamberger et al. (56) have suggested that there is an inverse relationship between BP and selenium in humans. Some

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--STUDY 1

(n-59)

0.2

5 weeks swftchback

6 weeks intervention

2 weeks baseline

P/S ratio

0.2

1.2

--STUDY 2

GROUP I (n-35)

0.3

GROUP II 192 (n=34) J

I

77

I

P/S ratio

0.2

1.0

I

J

I

1 201 I

Urinary Na-excretion nno1/24h No dietary

GROUP III I (n=3G) J 2 weeks baseline

I 6 weeks intervention

change

I 5 weeks switchback

--STUDY 3

GROUPI (21 families)

0.2 1

GROUPII (22 families)

0.2

I

0.9

0.4

I 0.2

I 2 weeks baseline

12 weeks intervention

P/S ratio

0.2 I

P/S ratio I

5 weeks switchback

FIG. 1. Study designs of the three separate studies on change in dietary fat intake and P/S ratio on blood pressure in middle-aged couples in North Karelia, Finland. Study I had no reference group. Study 2 compared blood pressure changes during a low-fat diet with a high P/S ratio (Group I) and during a low-sodium diet (Group II) with the usual North Karelian diet (Group III). Study 3 compared blood pressure changes during a low-fat diet with a P/S ratio of either 0.9 (Group I) or 0.4 (Group II).

animal studies (44) support this hypothesis, but only few epidemiological studies exist. A case-control study carried out in Finland showed that serum concentration of selenium might be inversely associated with risk for coronary and cardiovascular death and non-fatal myocardial infarction in people with very low serum selenium values (53). We used the material of this study to analyze the association of serum selenium concentration and BP in 416 men and 150 women ages 35-59 years who had no history of myocardial infarction or cerebral stroke in the preceding year. The mean of the serum selenium concentration was 53.5 pg/liter (SD 14.3 pg/liter). Eleven percent of the subjects were under antihypertensive drug treatment. Serum selenium concentration correlated weakly with body mass index. Al-

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TABLE 6 BLOOD PRESSUREVALUES (MEAN ? SEM, mm Hg) OF THE LAST WEEK OF EACH PERIOD IN STUDY 1, IN THREE GROUPS OF STUDY 2, AND IN Two GROUPS OF STUDY 3

Switchback period

Baseline period

Intervention period

Study 1 Systolic Diastolic

125 f 1.8 77 2 1.1

117 % 1.9* 74 k 1.2

125 f 2.0* 80 2 l.l*

Study 2 Group I (low fat) Systolic Diastolic

138 * 3.0 89 2 1.9

130 * 2.2*** 81 * 1.0***

137 2 2.6*** 85 2 1.8***

Group II (low salt) Systolic Diastolic

139 ? 2.3 90 2 1.7

137 ? 2.7 87 2 1.8

138 k 2.7 86 2 1.9

Group III (reference) Systolic Diastolic

138 5 2.0 89 I!Z 1.5

136 f 2.0 87 f 1.5*

138 k 2.2 88 2 1.5

Study 3 Group I (P/S ratio 0.9) Systolic Diastolic

128 2 2.3 88 2 1.8

124 _’ 2.0** 82 k 1.6***

129 f 2.8** 85 2 1.8**

126 t 2.1 86 f 1.9

123 2 2.0** 82 t 1.6***

126 f 2.2** 85 f 1.3**

Group II (P/S ratio 0.4) Systolic Diastolic

Note. Statistical significance of difference to the previous period shown as *P < 0.05; **P < 0.01; ***p < 0.001.

lowing for nine variables known to be associated with BP, both diastolic BP and MAP had a significant negative regression on serum selenium concentration in multivariate regression models (Table 7). The proportion of variance in diastolic pressure and MAP attributable to serum selenium explained by the models was 5 and 3%, respectively. The mean value of the MAP adjusted for age, body mass index, serum cholesterol, coffee consumption, and alcohol intake was 118 mm Hg in men with a serum selenium concentration of 45 kg/liter or less and 115 mm Hg in men with a serum selenium concentration of more than 45 pgfliter. The respective means in women were 122 and 119. Serum selenium had a significant effect in three-way ANCOVA (P < 0.05, Table 8). These results, based on cross-sectional data from a selected group of people and on variables obtained from single measurements, should be interpreted with caution. Nevertheless, the possibility that low dietary intake of selenium raises blood pressure by reducing the activity of glutathione peroxidase, a seleniumcontaining enzyme with a role in prostaglandin metabolism (59), cannot be excluded. This putative association. between serum selenium and BP is indirectly supported by another Finnish study in elderly men among whom those with low serum selenium levels were at increased risk of cerebrovascular stroke (66).

TABLE 7

*P < 0.05. **p < 0.01. ***P
Serum selenium Body mass index Antihypertensive medication Intake of coffee Serum cholesterol Family history of hypertension Age Entire model 0.010 0.072 0.030 0.027 0.015 0.007 0.000 0.199

Increase in the multiple regression coefficient R T value -2.60** 7.08*** 4.53*** -4.32*** 3.22** 2.20* -0.25 F(10,555) = 13.82***

DBP

0.006 0.056 0.042 0.022 0.014 0.015 0.007 0.236

Increase in the multiple regression coefficient R

T value -2.09* 6.38*** 5.55*** -4.02'** 3.23** 3.27** 2.30* F(10,555) = 17.12***

MAP

PARTIAL REGRESSIONOF DIASTOLIC BUNID PRESSURE (DBP) AND MEAN ARTERIAL PRESSURE(MAP) ON SERUM SELENIIJM CONCENTRATION AND OTHER SELECTED VARIABLES

%

2

!z 2

E

2

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TABLE 8 AVERAGE ADJUSTED MEAN ARTERIAL PRESSURE (mm Hg) ACCORDING TO SERUM SELENIUM CONCENTRATION AND SMOKING IN MEN AND WOMEN WITH No ANTIHYPERTENSIVE MEDICATION

Nonsmokers

Men

Women

Serum selenium concentration

Serum selenium concentration

s45 kg/l

>45 kg/l

s4.5 pg/l

>45 pg/l

116.4

117.1 (90)

123.3 (33)

119.2

114.0 (173)

114.1 (7)

110.2

(72) 117.5

115.1

(108)

(263)

121.7 (40)

119.0 (77)

(36) Smokers Total

118.0

(65) (12)

ANCOVA: Main effects Selenium, P = 0.035 Smoking, P = 0.043 Gender, NS Interactions Gender x smoking, P = 0.044 Other interactions, NS Covariates BMI, P < 0.001 Family history of hypertension, P = 0.001 Age, P = 0.011 Serum cholesterol, P = 0.013 Intake of alcohol, P = 0.060 Note. Numbers of persons are shown in parentheses.

CONCLUSIONS

The recent Finnish studies on dietary factors and blood pressure have focused on the role of fats in the pathogenesis of hypertension. The evidence from descriptive epidemiological studies (54, 62) has been confirmed in controlled clinical trials (21, 47, 49). Excessive energy intake, however, seems to be the most important nutritional determinant of BP in both cross-sectional and longitudinal population studies (16, 37). The contribution of various other nutritional factors such as sodium, potassium, alcohol, and calcium to the BP level of a population may be important, but more research is needed to define the putative factors that are causal determinants of BP and those that have a confounding or modifying effect in such a causal relationship. Ultimately, primary prevention can be effective only if the intervention measures are directed toward changing the levels of causal determinants. The significance of essential trace elements and toxic heavy metals in hypertension is relatively small and may become important only under some extreme conditions, although it is known that our diets should include sufficient amounts

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of essential trace elements and that these may have beneficial effects on cardiovascular and renal functions. It would be too simple to suggest that modification of a single nutrient could result in a universal effect on BP. For instance, based on Finnish studies (49, 54, 62), there seems to be a possible interaction between fat and sodium intake. Our knowledge of the associations and interactions between various nutrients and BP regulation is still rather limited. This is one reason why studies on dietary factors and BP require special attention from the methodological point of view. Block (5) has recently reviewed various methods for dietary assessment in epidemiological studies. Studies attempting to test hypotheses concerning associations between nutrients and BP require that the habitual intake of a particular nutrient by individuals can be measured. One reason frequently cited for the inability to show a relationship between dietary factors and BP is the significant variability in the day-to-day intake of nutrients (2, 3, 5). This high level of intraindividual variation in the intake of most nutrients suggests that a large number of replicate measurements are necessary. This makes both the research design and the interpretation of the results from different studies on nutrition and BP complicated. There has been much unnecessary debate around the issue of nutrition and hypertension. Sound and comprehensive research rather than such public exchange of beliefs is needed now. Persons having a strong family history of hypertension and hypertensive patients are asking for advice concerning their diet from physicians, dietitians, nurses, and other health workers. Although it is not possible to give straightforward answers to all their questions, especially on the individual level, the general directions are known, and we should not confuse the patients with details of scientific debates. REFERENCES 1. Anonymous. Diet and hypertension. Editorial. Lancer 2, 671 (1984). 2. Balogh, M., Kahn, H. A., and Medalie, J. H. Random repeat 24-hour dietary recalls. Amer. J. Clin. Nub-. 24, 304-310 (1971). 3. Beaton, G. H., Milner, J., Corey, P., McGuire, V., Cousins, M., Steward, E., de Ramos, M., Hewitt, D., Grambsch, P. V., Kassim, N., and Little, J. A. Sources of variance in 24-hour dietary recall data: Implications for nutrition study design and interpretation. Amer. J. C/in. Nutr. 32, 2546 (1979). 4. Belizan, J. M., and Villar, J. The relationship between calcium intake and edema-proteinuria and hypertension-gestosis: An hypothesis. Amer. J. C/in. Nutr. 33, 2202 (1980). 5. Block, G. A review of validations of dietary assessment methods. Amer. J. Epidemiol. 115, 492505 (1982). 6. Box, B. M., and Mogenso, G. J. Nutrient interactions in hypertension. Nutr. Res. 4, 111-21 (1984). 7. Brown, J. J., Lever, A. F., Robertson, J. I. S., Semple, P. F., Bing, R. F., Heagerty, A. M., Swales, J. D., Thurston, H., Ledingham, J. G. G., Laragh, J. H., Hansson, L., Nicholls, M. G., and Espiner, A. E. Salt and hypertension. Lancet 2, 456 (1984). 8. Dahl, L. K., Heine, M., and Tassinari, L. Effects of chronic salt ingestion: Evidence that genetic factors play an important role in susceptibility to experimental hypertension. J. Exp. Med. 115, 1173-90 (1962). 9. Dahl, L. K., Leitl, G., and Heine, M. Influence of dietary potassium and sodium/potassium molar ratios on the development of salt hypertension. J. Exp. Med. 136, 318-330 (1972). 10. De Wardener, H. E. Salt and hypertension. Lancer 2, 688 (1984).

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Il. Dyer, A., Stamler, J., Paul, O., Berkson, P. O., Lepper, M. H., McKean, H., Shekelle, R. B., Lindberg, H. A., and Garside, D. Alcohol, cardiovascular risk factors, and mortality in two Chicago epidemiologic studies. Circulution 56, 1067-1074 (1977). 12. Enlund, H. Measuring patient compliance in antihypertensive therapy-some methodological aspects. .I. Clin. Hosp. Pharm. I, 43 (1982). 13. Froment, A., Milon, H., and Gravier, C. Relation entre consommation sodee et hypertension arterielle. Contribution de l’epidemiologie geographique. Re\s. Epidemiol. Sunte Publiyue 27, 437-54 (1979).

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