Essential hypertension is assumed to be a hereditary

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ORIGINAL CONTRIBUTIONS A Gender Difference in the Association Between Salt Sensitivity and Family History of Hypertension Shunichi Kojima, Kazuo Murakami Genjiro Yamura, Tom Sanai, Kaoru Yoshida,

1 ORIGINAL CONTRIBUTIONS A Gender Difference in the Association Between Salt Sensitivity and Family History of Hypertension Shunichi Kojima, Kazuo Murakami Genjiro Yamura, Tom Sanai, Kaoru Yoshida, Masahito Imanishi, Hitoshi Abe, Minoru Kawamura, Yuhei Kawano, Terunao Ashida, Hiroki Yoshimi, Morio Kuramochi, Teruo Omae, and Keiichi Ito We examined 174 subjects (82 men and 92 women) with essential hypertension to determine whether gender played an important role in the association of blood pressure (BP) familial disposition, and hypertension. To evaluate the salt sensitivity of BP, we measured changes in blood pressure after restricting salt intake from about 15 g/day to less than 3 g/day. The familial disposition to hypertension was categorized into four groups according to the presence or absence of hypertension in the father, mother, and siblings. If none, one, two, or three family members had hypertension, they were assigned the FH(-), FH(+), FH<++), and FH(+++) groups, respectively. Only in women did the FH( ) group show a significantly smaller blood pressure reduction than that of the other groups. The mean Essential hypertension is assumed to be a hereditary disease, based on the familial studies that have shown a correlation of blood pressure (BP) measurements among family members, 1-4 and on the development of spontaneously hypertensive rats Received May 13, Accepted September 19, From the Division of Hypertension and Renal Diseases, Department of Medicine, National Cardiovascular Center Hospital, Osaka, Japan (SK, KM, GT, TS, KY, MI, HA, MK, YK, ΤΑ, HY, MK, TO), and the Department of Medicine, Youkaichi National Hospital, Youkaichi, Japan (KI). This research was supported by a research grant for cardiovascular diseases (2C-3) from the Ministry of Health and Welfare of Japan. Address correspondence and reprint requests to Shunichi Kojima MD, Division of Hypertension and Renal Diseases, Department of Medicine, National Cardiovascular Center Hospital, Fujishirodai , Suita, Osaka 565, Japan. BP reduction in the four groups was 4.1 ± 1.9, 8.5 ± 1.1,10.1 ± 1.5, and 11.2 ± 2.8 mm Hg (mean ± SEM), respectively. This difference in BP reduction was not observed in men. Multiple regression analysis, using percent changes in mean BP as the dependent variable and other factors as independent variables, also showed a significant partial correlation coefficient for familial disposition to hypertension only in women. Thus, the relationship between salt sensitivity and familial disposition to hypertension differed according to gender. This difference may provide an important insight into the hereditary nature of hypertension. Am J Hypertens 1992;5:1-7 KEY WORDS: Essential hypertension, salt sensitivity, sodium, sexual differences, heredity of hypertension. in several laboratories However, the precise pathogenesis of essential hypertension remains elusive, and we do not know what factors responsible for essential hypertension are heritable. Dahl et al 5 have developed a salt-sensitive rat through inbreeding, which becomes hypertensive only when salt-loaded. Several clinical studies have reported a familial resemblance in terms of BP salt sensitivity or an association between salt sensitivity and a family history of hypertension. Furthermore, in the Intersalt study, 16 the association between sodium intake and BP tended to be more marked in women than in men. These findings led us to examine the gender difference in the association between BP salt sensitivity and family history of hypertension. Previous studies 13 " 15 have been conducted in outpatient clinics,

2 in which it is impossible to provide diets containing a constant amount of salt and to accurately collect urine. The salt sensitivity of BP originally was evaluated by giving hospitalized patients high and low salt diets of 1 week's duration. 17 Since at least 3 to 5 days are necessary to attain an equilibrium between salt intake and urinary sodium excretion, 18 the present study involved only patients who were given high and low salt diets of 1 week's duration. The results snowed a gender difference in the association between BP salt sensitivity and familial disposition to hypertension. A significant association between the variables was observed only in women. SUBJECTS AND METHODS TABLE 1. The subjects consisted of 174 essential hypertensive patients admitted to the National Cardiovascular Center Hospital of Japan from 1977 to 1990 who had an examination for BP salt sensitivity. Of these patients, 82 were men, aged 22 to 70 years (mean ± SD, 49.0 ± 9.9 years), and 92 were women, aged 21 to 69 years (54.2 ± 9.7 years). The blood pressure of all patients was at hypertensive levels in the outpatient clinic: systolic blood pressure (SBP) was greater than 160 mm Hg and/or diastolic blood pressure (DBP) was greater than 95 mm Hg. Following admission, however, the BP normalized (SBP < 140 mm Hg and DBP < 90 mm Hg) in 44 patients. In all patients, secondary causes of hypertension and heart, liver, and kidney diseases were excluded by history and physical and laboratory examinations, and, when necessary, by radiological examinations. Antihypertensive drugs were discontinued at least 10 days after admission and BP salt sensitivity was evaluated. After subjects were given a high salt diet containing about 15 g/day for 1 week, the salt intake was restricted to less than 3 g/day the following week. The subjects rested for 10 min. Blood pressure was then measured with the subjects in the supine position. Trained nurses used a sphygmomanometer at 6 AM, 10 AM, 2 PM, and 6 PM daily. The blood pressures of the last 3 days of each 1-week period were averaged and used for evaluation of salt sensitivity. Urine was collected during the last 3 days of each period and was measured for determination of daily urinary sodium excretion, which was used to estimate sodium intake. We also measured urinary creatinine excretion in the same urine samples to determine creatinine clearance. Salt sensitivity was expressed as the change in BP when salt intake was altered from a high to a low salt diet. Mean BP was the sum of the DBP plus one-third of the pulse pressure. A blood sample was taken on the last day of each period of the high and low salt diets for measurement of plasma renin activity (PRA), plasma aldosterone concentration (PAC) and serum creatinine level. We measured sodium, potassium, and creatinine levels in urine and serum samples with autoanalyzers, and measured PRA and PAC by radioimmunoassay using commercial kits (Dinabot Co., Tokyo, Japan). The family history of hypertension was obtained COMPARISON OF AGE AND URINARY ELECTROLYTE EXCRETION AMONG FOUR GROUPS WITH DIFFERENT FAMILY HISTORIES OF HYPERTENSION Family History of Hypertension FH (-) FH (+) FH (++) FH (+++) Number Age (years) 56 ± 2 55 ± 2 51 ± 2 55 ± 3 50 ± 2 48 ± 2 50 ± 1 48 ± 3 Urinary sodium excretion (meq/day) 200 ± ± ± ± ± ± ± ± ± 4 28 ± 2 33 ± 3 26 ± 3 32 ± 3 33 ± 3 33 ± 4 32 ± 3 Changes in urinary sodium excretion (meq/day) 174 ± ± ± ± ± ± ± ± 15 Urinary potassium excretion (meq/day) 39 ± 3 42 ± 1 41 ± 2 39 ± 2 50 ± 2 46 ± 2 46 ± 2 51 ± 4 36 ± 3 40 ± 2 41 ± 3 37 ± 3 47 ± 2 46 ± 2 40 ± 3 43 ± 2

3 TABLE 2. PLASMA RENIN ACTIVITY, PLASMA ALDOSTERONE CONCENTRATION, AND CREATININE CLEARANCE IN THE FOUR GROUPS Family History of Hypertension FH (-) FH (+) FH (++) FH (+++) PRA (ng/ml/h) PAC (ng/dl) Creatinine clearance (ml/min) 0.7 ± ± ± ± ± ± ± ± ±5 112 ±6 67 ±4 95 ±4 PRA = plasma renin activity; PAC = plasma aldosterone concentration. from hospital charts of the subject and was categorized by the presence or absence of hypertension in the father, mother, and siblings. If none, one, two, or three members of the family had hypertension, the family history of hypertension was designated as FH( ), FH(+), FH(++), and FH(+++), respectively. Statistical analyses were performed within each gender, using the analysis of variance to test differences among the various parameters of these four groups with differences in family history of hypertension. We used Dunnett's t test to compare the difference between two groups. Taking percent changes in BP as the dependent variable and age, BP, PRA, PAC, and creatinine clearance as independent variables, we performed multiple regression analysis. When Ρ <.05, the difference was regarded as statistically significant. Data are shown as means ± SEM. RESULTS 0.4 ± ± ± ± ± ± ± ± ±3 98 ±4 68 ±3 87 ±4 0.6 ± ± : 6.4: :0.8 : ± ± ± ± ±6 103 ±5 70 ±5 95 ±5 0.8 ± ± ± ± ± ± ± ± ±6 100 ±5 78 ±6 81 ±7 The clinical parameters in the four groups are shown in Tables 1 and 2. Although the women in these groups tended to be older than the men, there were no significant differences within each gender in the clinical parameters. Table 3 shows the average values in BP for subjects given high and low salt diets. The levels of BP tended to increase with a greater familial disposition to hypertension only in men. Although BP levels significantly decreased after salt restriction in almost all groups with different familial dispositions to hypertension except DBP in the FH( ) group in both genders and the FH(+++) group in men (Table 3), the reduction in mean BP as a whole was significantly (P <.05) greater in women (8.4 ± 0.8 mm Hg) than in men (6.0 ± 0.8 mm Hg). Although they were statistically insignificant, SBP and DBP tended to decrease less in men than in women. In women, the reduction of SBP in the FH( ) group was significantly (P <.05) less than that in the FH(++) group, and the reduction of DBP and mean BP in the FH( ) group was significantly less than that in all other groups. On the other hand, we did not observe a difference in BP changes among the male groups. These results were not altered if the changes in BP were analyzed by use of percent changes compared with BP while the subject was given a high salt diet (Table 4). We also examined the BP salt sensitivity to determine the relationship with other variables. We performed multiple regression analysis taking the percent reduction in BP as the dependent variable and several parameters as independent variables. The independent variables included family history of hypertension, age, BP with high salt intake, PRA, PAC, and creatinine clearance while the subject was given both high and low salt intakes. Since one or more variables were deficient in 12 of 92 cases in women and in 13 of 82 cases in men, the multiple regression analysis was performed in 80 and 69 cases, respectively. As shown in Tables 5 and 6 family history of hypertension, as well as the BP of subjects given a high salt diet and the PRA of subjects given a low salt diet, exhibited a significant partial correlation coeffi-

4 TABLE 3. BLOOD PRESSURES IN THE FOUR GROUPS WITH DIFFERENT FAMILIAL DISPOSITION TO HYPERTENSION. Family History of Hypertension FH (-) FH (+) FH (++) FH (+++) SBP (mm Hg) 153 ±5 158 ±3 153 ±3 156 ±6 143 ± 3t 143 ± 3J 136 ± 3φ 141 ±5% DBP (mm Hg) 90 ±2 93 ±2 93 ±2 93 ±3 89 ±2 88±2t 86±2}: 84±2t MBP (mm Hg) 111 ±3 115 ±2 113 ±2 114 ±3 107 ±3* 106 ± 2% 103 ± 2% 103 ± 3φ en SPB (mm Hg) 146 ±3 153 ±3 153 ±5 159 ±5 136 ±2% 140 ± 3J 139 ± 4t 147 ±4 DBP (mm Hg) 90 ±2 94 ±2 96 ±3 98 ±4 88 ±2 91 ±2* 92±2f 96 ±3 MBP (mm Hg) 109 ±2 114 ±2 115 ±3 118±4 104 ± ±2% 108 ± 3J 113 ±3* SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure. * Ρ <.05, t Ρ <.01, % Ρ <.001 (ν high salt). cient in women, while only BP with high salt intake exhibited a significant partial correlation in men. DISCUSSION There have been many reports regarding the relationship between salt sensitivity and factors such as severity of hypertension, 19,20 race, 20,21 age, gender, 16 PRA, 19,22,23 and sympathetic nerve activity. 24 Salt sensitivity was reported to increase with severity of hypertension, older age, and inappropriately high plasma catecholamine and low PRA. Moreover, salt sensitivity was greater in black compared with white subjects, and an analysis of the Intersalt study showed that the association between sodium intake and BP tended to be more marked in women than in men. 16 There have been several reports regarding the heredity of salt sensitivity in human subjects. 12 " 15 Dahl et al 5 have developed a salt sensitive rat which manifests hypertension only when give a high salt diet. It is also known that normotensive and hypertensive black subjects are more salt sensitive than white subjects. 20,21 Moreover, Luft et al 12 examined the effect of genetic variance on sodium homoestatis and its regulatory determinants in a study of 37 pairs of monozygotic twins and 18 pairs of dizygotic twins under conditions of volume expansion and contraction. They found that sodium excretion in response to provocative maneuvers was influenced by genetic variance. Skrabal et al 13 also examined the effect of 2 weeks of salt restriction on normotensive subjects and found that BP decreased only in subjects with a family history of hypertension. Further, Miller et al 14 showed a significant correlation in the change in BP with sodium restriction only in the mother-offspring relationship, but not in the father-offspring relationhip. This difference between mother- and father-offspring correlations in BP change with salt restriction might be analogous to our result which showed a gender difference in the association between BP salt sensitivity and family history of hypertension. The family history concerning siblings might be unreliable because the siblings may live in the areas far from the subjects when they become adults. However, an analysis of the data according to the history of parents alone revealed that gender was important. Only in women was a significantly greater salt sensitivity observed in patients with a familial history of hypertension, compared with patients without a familial hypertensive history. Moreover, there was a significant partial correlation coefficient between salt sensitivity and a familial disposition to hypertension only in women. Although this significant correlation between salt sensitivity and familial disposition agrees with the findings of previous works, our study is the first to imply a gender difference in the association between these two variables. In contrast to these reports, Watt et al 15 provided evidence against the hypothesis that people with a family history of hypertension are more susceptible in their BP response to dietary sodium. They examined 35 subjects

5 TABLE 4. CHANGES IN BLOOD PRESSURE BY SALT RESTRICTION IN FOUR GROUPS WITH DIFFERENT FAMILIAL DISPOSITIONS TO HYPERTENSION Family History of Hypertension FH(-) FH(+) FH(++) FH(+++) Changes in blood pressure (mm Hg) SBP 10.1 ± ± 1.7* 16.7 ± ± ± ± ± ±3.3 DBP 1.1 ± ± ± 1.6* 9.0 ± 1.4f 2.1 ± ± ± ± 1.7 MBP 4.1 ± ± 1.1* 10.1 ±1.5* 11.2±2.8t 4.5 ± ± ± ±1.9 Percent changes in blood pressure SBP 6.2 ± ± ± 1.3* 9.8 ± ± ± ± ±2.1 DBP 0.7 ± ± 1.1* 6.7 ± 1.7* 9.5± ± ± ± ±1.7 MBP 3.4 ± ± 0.9* 8.7± 1.3* 9.7± ± ± ± ± 1.6 SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure. * Ρ <.05, t Ρ < 0.1 (ν FH( ) group). with both parents in the top third of their age-specific BP distribution and 31 subjects with both parents in the bottom third of their BP distributions. The sodium intake of the subjects was restricted for 8 weeks while they took part in a double blind, randomized crossover trial of sodium supplementation and placebo. A comparison of two periods of 4 weeks at different sodium intakes showed no differences in BP response between the two groups. However, the normotensive subjects were originally salt resistant, which made the difference in salt sensitivity between groups less apparent. Furthermore in the study of Watt et al the difference in urinary sodium excretion between high and low salt intakes was only 70 mmol/day, too small to evaluate the salt sensi- TABLE 5 MULTIPLE REGRESSION ANALYSIS OF BLOOD PRESSURE SALT SENSITIVITY RELATING TO NINE VARIABLES IN WOMEN Standard Partial Correlation Coefficient SBP DBP MBP Variable (percent change) (percent change) (percent change) Family History of Hypertension f 0.263t Age Blood pressure with high salt diet 0.256* 0.362^ 0.251* PRA t f PAC Creatinine clearance SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure, PRA plasma renin activity, PCA = plasma aldosterone concentration. *?<.05,-\?<.01,t?<.001.

TABLE 6 MULTIPLE REGRESSION ANALYSIS OF BLOOD PRESSURE SALT SENSITIVITY RELATING TO NINE VARIABLES IN MEN Standard Partial Correlation Coefficient SBP DBP MBP Variable (percent change) (percent

6 TABLE 6 MULTIPLE REGRESSION ANALYSIS OF BLOOD PRESSURE SALT SENSITIVITY RELATING TO NINE VARIABLES IN MEN Standard Partial Correlation Coefficient SBP DBP MBP Variable (percent change) (percent change) (percent change) Family History of Hypertension Age Blood pressure with high salt diet 0.500* 0.529* 0.532* PRA PAC Creatinine clearance SBP = systolic blood pressure, DBP = diastolic blood pressure, MBP = mean blood pressure, PRA = plasma renin activity, PCA = plasma aldosterone concentration. * Ρ <.001). tivity. In the original study by Kawasaki et al, 17 who defined BP salt sensitivity in essential hypertensive patients, the difference in sodium intake between a high and low salt diet was 200 mmol/day, approximately the same as in our study. Moreover, with the exception of the study of Skrabal et al, 13 previous study protocols 12,14,15 were undertaken in outpatient clinics, where it is impossible to provide diets containing a constant amount of salt and to accurately collect urine. Furthermore, BP appears to be more labile in outpatient clinic patients than in hospitalized patients, which leads to larger variations in BP. The present study involved many hospitalized patients with essential hypertension. Thus, the errors in BP measurement and urinary sodium excretion were minimized. Although previous studies of the relation between salt sensitivity and family history of hypertension were concerned mainly with normotensive subjects, our study showed that a family history of hypertension is related to BP salt sensitivity in hypertensive patients as well. These findings suggest that in a number of patients, especially in women, essential hypertension develops in relation to salt sensitivity. If salt sensitivity is unaltered through the development of hypertension, the positive relationship between salt sensitivity and family history of hypertension supports the view that salt sensitivity is not entirely acquired as a consequence of hypertension. Although we do not know why the association between salt sensitivity and familial disposition of hypertension differed according to gender, this may provide an important insight in the hereditary mode of hypertension. Our study also suggests that hypertensive women with a family history of hypertension are more salt sensitive; therefore, their hypertension may be more responsive to diuretics. REFERENCES 1. Miall WE, Heneage P, Khosala T, et al: Factors influencing the degree of resemblance in arterial pressure of close relatives. Clin Sci 1967;33: Johnson BC, Epstein FH, Kjelsberg MO: Distributions and familial studies of blood pressure and serum cholesterol levels in a total community Techmseh, Michigan. J Chronic Dis 1965;18: Havlik RJ, Garrison RJ, Feinleib M, et al: Blood pressure aggregation in families. Am J Epidemiol 1979;110: Williams RR, Hunt SC, Hasstedt SJ, et al: Definition of genetic factors in hypertension: a search for major genes, polygenes, and homogeneous subtypes. J Cardiovas Pharmacol 1988;12(suppl 3):S7-S Dahl LK, Heine M, Tassinari L: Effects of chronic excess salt in ingestion. Evidence that genetic factors play an important role in susceptibility to experimental hypertension. J Exp Med 1962;115: Okamoto K, Aoki K: Development of a strain of spontaneously hypertensive rats. Jpn Circ J 1963;27: Bianchi G, Baer PG, Fox U, et al: Changes in renin, water balance, and sodium balance during development of high blood pressure in genetically hypertensive rats. Circ Res 1975;36-37(suppl I): Yamori Y: Importance of genetic factors in hypertensive cerebrovascular lesions: an evidence obtained by successive selective breeding of stroke-prone and resistant SHR. Jpn Circ J 1974;38: Smirk FH, Hall WH. Inherited hypertension in rats. Nature 1958;182: Ben-Ishay D, Saliternick R, Welner A: Separation of two

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7 strains of rats with inbred dissimilar sensitivity to Docasalt hypertension. Experimentia 1972;28: Dupont J, Dupont JC, Fromont A, et al: Selection of three strains with spontaneously different levels of blood pressure. Biomedicine 1973;19: Luft FC, Miller JZ, Weinberger MH, et al: Influence of genetic variance on sodium sensitivity of blood pressure. Klin Wochenschr 1987;65: Skrabal F, Helholz H, Neummayr M, et al: Salt sensitivity in humans is linked to enhanced sympathetic responsiveness and to enhanced proximal tubular reabsorption. Hypertension 1984;6: Miller JZ, Weinberger MH, Christian JC, Daugherty SA: Familial resemblance in the blood pressure response to sodium restriction. Am J Epidemiol 1987;126: ' Watt GCM, Foy CJW, Hart JT, et al: Dietary sodium and arterial blood pressure: evidence against genetic susceptibility. Br Med J 1985;291: Elliott P, Dyer A, Stamler R: INTERS ALT study: results for 24 hour sodium and potassium, by age and sex. J Hum Hypertens 1989;3: Kawasaki T, Delea CS, Bartter FC, Smith H: The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med 1978;64: Resneck Η J, Stein JH: Sodium metabolism, in Maxwell MH, Kleeman CR, Narins RG (eds): Clinical Disorders of Fluid and Electrolyte Metabolism, 4th ed. New York, McGraw-Hill, Inc., 1987, pp Parfrey PS, Markandu ND, Roulston JE, et al: Relation between arterial pressure, dietary sodium intake, and renin system in essential hypertension. Br Med J 1981;283: Sullivan JM, Prewitt RL, Ratts TE: Sodium sensitivity in normotensive and borderline hypertensive humans. Am J Med Sci 1988;295: Luft FC, Weinberger MH, Grim CE, et al: Sodium sensitivity in normotensive human subjects. Ann Intern Med 1983;98: Longworth DL, Drayer JIM, Weber MA, Laragh JH: Divergent blood pressure responses during short-term sodium restriction in hypertension. Clin Pharmacol Ther 1980;27: Miller JZ, Weinberger MH, Daugherty SA, et al: Heterogeneity of blood pressure response to dietary sodium restriction in normotensive adults. J Chronic Dis 1987;40: Fujita T, Henry WL, Bartter FC, et al: Factors influencing blood pressure in salt-sensitive patients with hypertension. Am J Med 1980;69:

A hypertensive father, but not hypertensive mother, determines blood pressure in normotensive male offspring through body mass index

Journal of Human Hypertension (1998) 12, 441 445 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE A hypertensive father, but not hypertensive