Impact of aldosterone on left ventricular structure and function in young normotensive and mildly hypertensive subjects

Impact of Aldosterone on Left Ventricular Structure and Function in Young Normotensive and Mildly Hypertensive Subjects Markus P. Schlaich,

MD,

Hans P. Schobel, MD, Karl Hilgers, Roland E. Schmieder, MD

MD,

and

Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality. Experimental data revealed that elevated circulating aldosterone is associated with increased collagen accumulation resulting in myocardial fibrosis. To analyze whether aldosterone is also associated with cardiac structural and functional changes in humans, we examined the effects of aldosterone on LV structure and function before and after suppression of aldosterone by increasing oral salt intake. The study group comprised 26 normotensive male white healthy control subjects (age 26 ⴞ 3 years) and 31 male white subjects (age 25 ⴞ 3 years) with mild essential hypertension (World Health Organization stages I to II). Two-dimensional– guided M-mode echocardiography and 24-hour ambulatory blood pressure (BP) monitoring was performed in each subject. Simultaneously, we measured 24-hour urinary sodium excretion, 24-hour urinary aldosterone, and serum aldosterone concentration at baseline and after increasing oral salt intake to suppress aldosterone secretion. In all subjects LV mass correlated with body mass index (r ⴝ 0.42, p <0.001) and both 24-hour ambulatory systolic (r ⴝ 0.28, p <0.05) and diastolic (r ⴝ 0.25, p <0.05) BP. Changes in urinary sodium excretion correlated inversely with changes in serum aldosterone concentration (r ⴝ ⴚ0.28; p <0.05). Urinary aldosterone concentration after salt loading decreased in normotensive (10.98

vs 7.44 ␮g/24 hours; p <0.02) but not in hypertensive (9.34 vs 10.51 ␮g/24 hours; p ⴝ NS) subjects. Serum and urinary aldosterone levels at baseline were not related to LV structure or function. In contrast, after increasing oral salt intake, urinary aldosterone concentration was related to LV mass (r ⴝ 0.43; p <0.01) and impaired midwall fractional fiber shortening (r ⴝ ⴚ0.33; p <0.02) in all subjects, independent of 24-hour ambulatory BP. Subgroup analysis revealed that this was significant only in hypertensive (r ⴝ 0.46; p <0.01 and r ⴝ ⴚ0.44; p <0.02, respectively) but not in normotensive (r ⴝ 0.28 and ⴚ0.16; p ⴝ NS for both, respectively) subjects. Consistently, the greater serum aldosterone remained after increasing oral salt intake, the greater was LV mass (r ⴝ 0.35; p <0.01). The latter was found in hypertensive subjects (r ⴝ 0.44; p <0.02), independent of 24-hour ambulatory BP, but not in normotensive subjects (r ⴝ 0.025; p ⴝ NS). Inadequate suppression of aldosterone in response to an increase in oral salt intake is related to LV structural and functional changes in hypertensive subjects. Thus, our results support experimental data indicating that aldosterone affects LV structure and function in humans and that this effect is BP independent. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:1199 –1206)

eft ventricular (LV) hypertrophy increases cardiovascular morbidity and mortality. Various facL tors such as elevated preload and afterload have been

angiotensin-aldosterone cascade have also been identified to be important determinants.12,13 In experimental models the central role of aldosterone in collagen synthesis by myocardial fibroblasts and the subsequent accumulation of interstitial and perivascular collagen have been demonstrated. Arterial hypertension together with elevated circulating aldosterone levels are associated with excessive collagen accumulation resulting in myocardial fibrosis.14,15 Myocyte hypertrophy has been found to be most closely related to ventricular loading, whereas circulating angiotensin II and aldosterone have been associated with the regulation of collagen accumulation within the right and left ventricles in rats.16 Progressive interstitial and perivascular fibrosis seems to account for abnormal myocardial stiffness and may ultimately lead to ventricular dysfunction.14,15 We conducted this study to assess whether changes in aldosterone concentration after salt loading are related to myocardial structural

1,2

described to determine LV hypertrophy.3 However, discrepancies between the level of arterial pressure and the degree of LV hypertrophy have been repeatedly shown in hypertensive subjects.4 – 6 This indicates that LV structural adaptation is additionally determined by nonhemodynamic factors such as age,7 sex,8 race,9 and obesity.10 Activity of the sympathetic nervous system,11 high dietary salt intake, and the reninFrom the Department of Medicine IV/Nephrology, University of Erlangen-Nu¨rnberg, Nu¨rnberg, Germany. This study was supported by Grant DFG/Schm 638/8 –2 from the Deutsche Forschungsgesellschaft, Bonn, Germany. Manuscript received July 28, 1999; revised manuscript received and accepted December 7, 1999. Address for reprints: Roland E. Schmieder, MD, Medizinische Klinik IV/Nephrology, Universita¨t Erlangen-Nu¨rnberg, Breslauer Strasse 201, D-90471 Nu¨rnberg, Germany. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 May 15, 2000

0002-9149/00/$–see front matter PII S0002-9149(00)00728-1

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and functional changes in human essential hypertension.

METHODS A total of 60 white male students from the University of Erlangen-Nu¨rnberg agreed to participate in a scientific study and gave written consent. Subjects screened for normal or mildly elevated blood pressure (BP) at the University campus were asked to refer to our outpatient clinic of the Department of Medicine, University of Erlangen-Nu¨rnberg, and BP readings were taken according to the World Health Organization (WHO) recommendations. To ensure correct BP readings, a standard sphygmanometer was used and the cuff size was adjusted according to the participant’s arm circumference. Measurements were obtained with the subject seated after 5 minutes of rest in standardized fashion by specifically trained personnel. A total of 57 subjects with normal or mildly elevated BP fulfilled all study criteria for statistical analysis. Up to 60 participants were consecutively enrolled if they fulfilled all inclusion criteria, such as male gender, age range 20 to 40 years, and absence of any renal, hepatic, or cardiovascular disease (with the exception of mildly elevated BP), as well as any history of previous cardiovascular medication and any other current or previous medication. According to the recommendations of the WHO,17 participants were classified as hypertensive (n ⫽ 31) if the mean of 4 casual BP measurements obtained in our outpatient clinic was ⱖ140 mm Hg systolic or ⱖ90 mm Hg diastolic on at least 2 different occasions (at least 4 weeks apart). Normotensive subjects had a systolic BP ⬍140 mm Hg and a diastolic BP ⬍90 mm Hg (n ⫽ 26). Secondary forms of hypertension had to be ruled out by thorough clinical workup. In particular, a 12-lead electrocardiogram at rest, fundoscopic evaluation, standard and duplex sonography of the kidneys, intraarterial digital subtraction angiography of renal arteries (if indicated), and routine laboratory tests were performed. Detailed evaluation of hormones and endocrine metabolites was conducted if necessary. No participant followed any specific dietary guidelines before the first hemodynamic and endocrine measurements. The study protocol was approved by the Clinical Investigation Ethics Committee of the University of Erlangen-Nu¨rnberg. Ambulatory 24-hour BP monitoring was performed simultaneously with the 24-hour urinary collection. Echocardiographic and endocrine investigations were done directly after 24-hour urinary collection for sodium excretion. Ambulatory 24-hour BP was measured with an automatic portable device (Spacelabs no. 90207, Redmond, Washington) simultaneously. Measurement intervals were every 15 minutes during daytime and every 30 minutes during nighttime. Time periods (daytime, nighttime) were individually adjusted to the awake/sleep reports of each participant, as previously outlined.18 To assess dietary salt intake, 24-hour urinary sodium excretion, which represents a rough but valuable estimate of daily sodium intake,13,19 was measured first on regular 1200 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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diet (representing the usual oral salt intake in the Bavarian area) and second after increasing salt intake by 6 g/day via administration of oral tablets. Samples with a volume of ⬍600 ml/24 hours and those containing less than the expected creatinine/kg body weight were excluded (n ⫽ 3) to ensure complete collection of urine.20,21 Two-dimensional– guided Mmode echocardiography was performed once at baseline using an ultrasonoscope (Picker-Hitachi CS 192, Tokyo, Japan) with a 2.5-MHz probe. Echocardiograms were recorded at rest in the third or fourth intercostal space lateral to the left sternal border, with the participant lying in a supine or partial left-sided position, and were read independently by 2 physicians according to the recommendations of the American Society of Echocardiography.22 Parameters of LV structure included end-diastolic septal and posterior wall thicknesses, as well as LV end-diastolic diameter. Relative wall thickness, taken as a parameter for concentric LV hypertrophy, was calculated as 2 ⫻ posterior wall thickness divided by end-diastolic diameter. LV mass was calculated according to the recommendations of the American Society of Echocardiography,22 but then corrected following the suggestions of Devereux et al.23 Duplicate blood samples for the determination of plasma renin activity, plasma angiotensin II concentration, and serum aldosterone were collected (for details see reference 24) in the supine position for 1 hour along with resting BP. In brief, immunoreactive angiotensin II was measured by radioimmunoassay with antiserum (provided with permission of Prof. D. Ganten, Max Delbru¨ck Zentrum, Berlin, Germany) and labeled angiotensin II (NEX 105, DuPont, Mechelen, Belgium). Cross-reactivity for this method is 100% for angiotensin II and III and 1.2% for angiotensin I, respectively.24 All determinations of immunoreactive angiotensin II were made in duplicate and the mean value is given. Plasma renin activity was measured with angiotensin I radioimmunoassay (antibody K 18 provided with permission of Prof. Hackenthal, Heidelberg, Germany). Serum and 24-hour urinary aldosterone concentration were measured by a commercially available radioimmunoassay kit (Aldosterone Maia 12254, Serono Diagnostics, Freiburg, Germany). Measurements were obtained in duplicate, and the mean value is given. The coefficient of variance was ⬍10% for serum as well as urinary aldosterone concentrations. After baseline measurements as described above, dietary salt intake was increased by the administration of salt tablets (6 g/day) in addition to the usual diet. This intervention was performed to assess the response of the renin-angiotensin-aldosterone system to increasing salt intake. Physiologically, high sodium intake leads to a suppression of the renin-angiotensinaldosterone system. A steady state between salt intake and sodium excretion is reached after 7 days, with a corresponding suppression of the renin-angiotensinaldosterone system.19 After 7 days on increased salt intake, 24-hour urinary sodium excretion and aldosterone concentration were measured again. Resting BP (mean of 10 automatic measurements over a period of MAY 15, 2000

TABLE I Characteristics of Study Group All Subjects (n ⫽ 57)

Characteristics Age (yrs) Body surface area (m2) Body mass index (kg/m2) Casual systolic BP (mm Hg) Casual diastolic BP (mm Hg) Ambulatory systolic BP (mm Hg) Ambulatory diastolic BP (mm Hg) Relative wall thickness (mm) LV mass (g) LV mass/height (g/cm) Posterior wall thickness (mm) Septal wall thickness (mm) Diastolic diameter (mm) Midwall fractional fiber shortening (%) Plasma renin activity (ngAI/ml/h) Angiotensin II (pg/ml) Serum aldosterone (pg/ml) Urinary aldosterone (␮g/24 h) Urinary sodium excretion (mmol/24 h) Serum potassium (mmol/L)

26 2.0 23.7 135 85 127 75 0.39 242 1.33 9.9 10.5 50.7 16.8 1.48 7.94 148 10.1 181 3.99

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

3 0.12 2.2 16 14 9 8 0.07 45 0.25 1.3 1.5 3.92 2.25 0.73 4.25 28.7 4.3 75.1 0.34

Normotensives (n ⫽ 26) 26 1.97 23.2 123 76 121 71 0.36 222 1.22 9.1 9.8 51.1 17.8 1.54 7.19 152 10.9 163 3.92

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

Hypertensives (n ⫽ 31)

p Values N vs H

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

NS NS 0.086 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.002 ⬍0.002 ⬍0.001 ⬍0.001 NS ⬍0.002 NS NS NS NS NS NS

3 0.12 1.86 13 12 7 5 0.04 38 0.21 0.8 1.1 3.57 2.21 0.79 3.70 22.1 4.8 67.1 0.41

25 2.03 24.2 146 92 132 78 0.42 259 1.42 10.6 11.1 50.3 15.9 1.45 8.56 145 9.3 196 4.04

3 0.13 2.39 10 11 8 8 0.07 44 0.24 1.3 1.6 4.20 1.96 0.73 4.63 33.4 3.7 79.4 0.25

TABLE II Response to Increase in Salt Intake All Subjects (n ⫽ 57) Baseline Resting systolic BP (mm Hg) Changes (mm Hg) Resting diastolic BP (mm Hg) Changes (mm Hg) Sodium excretion (mmol/24 h) Plasma renin activity (ngAI/ml/h) Angiotensin II (pg/ml) Urinary aldosterone (␮g/24 h) Serum aldosterone (pg/ml)

Response

127 ⫾ 13 142 ⫾ 17* ⫹15 ⫾ 13 76 ⫾ 8 76 ⫾ 8 ⫹0.8 ⫾ 1.4 181 ⫾ 75 265 ⫾ 82* 1.48 ⫾ 0.73 1.24 ⫾ 0.57 7.94 ⫾ 4.25 7.44 ⫾ 4.11 10.12 ⫾ 4.33 8.92 ⫾ 5.21† 148 ⫾ 28 98 ⫾ 38*

Normotensive Subjects (n ⫽ 26) Baseline

Response

118 ⫾ 9 129 ⫾ 12* ⫹11 ⫾ 12 70 ⫾ 6 72 ⫾ 6 ⫹1.2 ⫾ 7.0 163 ⫾ 67 250 ⫾ 85* 1.54 ⫾ 0.79 1.14 ⫾ 0.69 7.19 ⫾ 3.72 6.66 ⫾ 2.85 10.98 ⫾ 4.85 7.44 ⫾ 3.73† 151 ⫾ 22 94 ⫾ 30*

Hypertensive Subjects (n ⫽ 31) Baseline

Response

135 ⫾ 10 153 ⫾ 12* ⫹18 ⫾ 11 80 ⫾ 6 80 ⫾ 7 ⫺0.35 ⫾ 6.9 196 ⫾ 79 280 ⫾ 79* 1.44 ⫾ 0.72 1.28 ⫾ 0.52 8.56 ⫾ 4.63 8.07 ⫾ 4.88 9.34 ⫾ 3.62 10.51 ⫾ 7.92 144 ⫾ 33 112 ⫾ 38*

*p ⬍0.001 (baseline vs response); †p ⬍0.05 (baseline vs response).

10 minutes) (Dinamap, Criticon, Tampa, Florida), plasma renin activity, angiotensin II, and serum aldosterone concentrations were measured on day 8 after 1 hour of rest in the supine position as described above; these concentrations were already obtained at baseline. All statistical analyses were performed using the SPSS program (SPSS Inc., Chicago, Illinois).25 Linear correlation analysis (Pearson), partial correlation analysis, and stepwise multiple regression analysis were applied to identify determinants of LV structure. Analysis of variance was done when indicated. The analysis was carried out according to a prefixed scheme for the total population as well as for the 2 subgroups that were divided and worked up according to WHO recommendations.17 All values are expressed as mean ⫾ 1 SD. Two-tailed p values are given throughout the text.

RESULTS

Determinants of left ventricular structure: Fifty-seven young, white, male participants were included in the study. According to the study entry criteria, no par-

ticipant was on any medication. Clinical characteristics of the entire study group and the 2 subgroups are listed in Table I. Both body mass index (r ⫽ 0.42, p ⬍0.001) and 24-hour ambulatory BP (systolic: r ⫽ 0.28, p ⬍0.05; diastolic: r ⫽ 0.25, p ⬍0.05) correlated with LV mass. Similarly, posterior and septal wall thickness correlated with body mass index (r ⫽ 0.31, p ⬍0.01; r ⫽ 0.44; p ⬍0.001, respectively) and ambulatory BP (systolic: r ⫽ 0.47 [p ⬍0.001]; r ⫽ 0.49 [p ⬍0.001]; diastolic: r ⫽ 0.39 [p ⬍0.005]; r ⫽ 0.45 [p ⬍0.001], respectively). Relative wall thickness correlated with ambulatory BP (systolic: r ⫽ 0.47, p ⬍0.001; diastolic: r ⫽ 0.37, p ⬍0.01). No BP-independent correlation was found between 24-hour urinary sodium excretion and echocardiographically determined structural parameters of the left ventricle at baseline. Plasma renin activity, plasma angiotensin II, serum, and urinary aldosterone concentrations at baseline were not associated with echocardiographic LV parameters. Because subjects were young and male, age and gender were not analyzed as potential determinants of LV structure.

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FIGURE 1. A, relation of urinary aldosterone concentration after salt intake to LV mass in mildly hypertensive subjects. B, relation of urinary aldosterone concentration after salt intake to LV mass in normotensive subjects. ● ⴝ normotensive subjects; Œ ⴝ hypertensive subjects.

Response to increased salt intake: After increasing salt intake, systolic BP and sodium excretion increased significantly in all subjects compared with baseline measurement (Table II). Systolic BP increased by 15 ⫾ 13 mm Hg (p ⬍0.001), but diastolic BP did not change. Changes in systolic BP differed between the normotensive and hypertensive groups (p 1202 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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⬍0.01) (Table II). Serum potassium levels were similar between both groups before and after salt loading and did not correlate with LV mass or aldosterone concentrations. Changes in angiotensin II concentration were not significantly different between the groups. As expected, changes in urinary sodium excretion were negatively correlated with changes in MAY 15, 2000

FIGURE 2. A, relation of changes in serum aldosterone concentration after salt intake to LV mass in mildly hypertensive subjects. B, relation of changes in serum aldosterone concentration after salt intake to LV mass in normotensive subjects. ● ⴝ normotensive subjects; Œ ⴝ hypertensive subjects.

aldosterone concentration (r ⫽ ⫺0.28; p ⬍0.05) in all subjects. Urinary aldosterone concentration after salt loading decreased in normotensive (p ⬍0.02) but not in hypertensive (p ⫽ NS) subjects. Serum aldosterone levels decreased in normotensive and hypertensive subjects (p ⬍0.001), but changes in serum aldosterone

after salt loading tended to be less in hypertensive than in normotensive subjects (p ⫽ 0.06). Most striking, in contrast to the findings at baseline, urinary aldosterone concentration after increasing salt intake was related to LV mass for all subjects (r ⫽ 0.45; p ⬍0.01), independently of ambulatory BP

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FIGURE 3. A, relation of urinary aldosterone concentration after salt intake to midwall fractional fiber shortening in mildly hypertensive subjects. B, relation of urinary aldosterone concentration after salt intake to midwall fractional fiber shortening in normotensive subjects. ● ⴝ normotensive subjects; Œ ⴝ hypertensive subjects.

(partial r ⫽ 0.43; p ⬍0.01). Separate analysis revealed that this was significant only in hypertensive (r ⫽ 0.46; p ⬍0.01) but not in normotensive (r ⫽ 0.28; p ⫽ NS) subjects (Figures 1a and 1b). The lower the decrease in serum aldosterone concentration after increasing salt intake, the greater the LV mass (r ⫽ 0.35; 1204 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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p ⬍0.01), independent of BP (partial r ⫽ 0.31; p ⬍0.05). Again, this was significant only in hypertensive (r ⫽ 0.44; p ⬍0.02) but not in normotensive (r ⫽ ⫺0.025; p ⫽ NS) subjects (Figures 2a and 2b). Urinary aldosterone concentration correlated with midwall fractional fiber shortening (r ⫽ ⫺0.31; p ⬍0.02), MAY 15, 2000

independent of ambulatory BP (partial r ⫽ ⫺0.33; p ⬍0.02). This was significant only in hypertensive (r ⫽ ⫺0.44; p ⬍0.02) but not in normotensive (r ⫽ ⫺0.16; p ⫽ NS) subjects (Figure 3).

DISCUSSION In the present study we examined the association between aldosterone concentration and LV structure and function in young, male, healthy white subjects with normal or mildly elevated BP. Because LV mass in normotensive young adults is related to the risk of developing subsequent hypertension, early myocardial structural changes are important in evaluating a patients’s risk profile for cardiovascular events. Our results indicate that inadequate suppression of aldosterone is related to LV mass and function independent of BP, because changes in aldosterone concentration after increasing salt intake correlated with LV mass and midwall fractional fiber shortening (in contrast to the findings at baseline) independent of 24hour ambulatory BP. To suppress aldosterone concentration, the salt intake of all patients was increased by an average of 6 g/day in addition to their usual diet. Dietary salt intake was in the typical range for the Bavarian area in Germany at baseline as estimated by urinary sodium excretion. In our outpatient setting, compliance to the increase in daily salt intake was assessed by 24-hour urinary sodium excretion. Three subjects had to be excluded owing to noncompliance. Although not as accurate as the assessment by a dietician,13 24-hour urinary sodium excretion has been shown to represent a valuable estimate of daily salt intake and may dilute, but not produce, false relations.4 As a consequence, correlation coefficients in our study may be expected to be lower than in reality. As reported in previous studies,10 we were able to confirm the impact of body mass index and ambulatory BP on LV structure. Twenty-four-hour urinary sodium excretion did not correlate with echocardiographically determined LV structure in the present study. Of note, only a few subjects in our study population had an elevated LV mass. In a separate analysis of our study cohort (as reported elsewhere26), we found a correlation between diastolic filling parameters and 24-hour urinary sodium excretion. The higher the urinary sodium excretion, the more marked the late-to-early diastolic filling ratio as evaluated by Doppler sonography.26 It is well known that diastolic filling abnormalities reflect the first stage of hypertensive heart disease. Thus, a BPindependent effect of dietary salt intake on the left ventricle has been observed in our study cohort as well. The importance of nonhemodynamic factors in cardiac hypertrophy in humans has been shown by Duprez and colleagues.27 In moderate essential hypertension, the investigators found that LV mass correlated with serum aldosterone levels independent of BP. An increased interventricular septum, posterior wall thickness, and a higher LV mass index was observed in patients with excess aldosterone due to aldosteroneproducing adenomas when compared with patients

with essential hypertension.28 This finding supports experimental data suggesting that aldosterone affects LV structure independently of other factors. In animal models the most prominent features of structural changes in the myocardium include myocyte hypertrophy, excessive accumulation of collagen in the heart, and pathologic changes in coronary blood vessels.29 From their observations the investigators conclude that myocyte hypertrophy is primarily a response to chronic pressure or volume overload, whereas myocardial fibrosis depends on activation of circulating and tissue renin-angiotensin-aldosterone systems. In our study cohort consisting of subjects with normal or mildly elevated BP, aldosterone concentration at baseline was not associated with LV structural changes. Furthermore, aldosterone concentration did not differ between the normotensive and mildly hypertensive groups. In our subjects, the level of aldosterone and the early and mild stage of hypertension may account for this discrepancy. However, this changed when the renin-angiotensin-aldosterone system was challenged by an increase in salt intake. Although in normotensive subjects a physiologic decrease in aldosterone concentration after high oral salt intake was noticed, this was not the case for hypertensive subjects. The lower the decrease in aldosterone concentration (i.e., the higher aldosterone concentration remained), the greater the LV mass and the more impaired the LV systolic function. Furthermore, aldosterone concentration after high oral salt intake correlated with LV mass, independent of other factors. Clearly, such a relation does not necessarily imply a cause-effect relation. However, with experimental and previous findings in humans, these data suggest that in mildly hypertensive subjects, an inadequate suppression of aldosterone after high salt intake is associated with LV structural and functional changes independent of 24-hour ambulatory BP. In a recent study with uninephrectomized rats30 given a 1% sodium chloride drinking solution, aldosterone was shown to raise BP and to cause marked interstitial and perivascular fibrosis. These effects were not seen in rats on a low salt diet, suggesting a crucial importance of high salt intake in this model of mineralocorticoid excess. A dysregulation in response to increased salt intake resulting in inadequately high aldosterone concentration, as seen in our subjects, could be the pathophysiologic link between high salt intake and cardiac fibrosis. In our Western hemisphere with a high oral salt intake, this dysregulation of aldosterone may contribute to the cardiovascular risk in hypertensive subjects with LV hypertrophy. Since in most human studies salt intake and the corresponding response of the renin-angiotensin-aldosterone system has not been measured, this hypothesis needs to be addressed in further prospective studies. 1. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic

implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561–1566.

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