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Circulation. 1996;94:1304-1309

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(Circulation. 1996;94:1304-1309.)
© 1996 American Heart Association, Inc.

Articles

Angiotensin II Related to Sodium Excretion Modulates Left Ventricular Structure in Human Essential Hypertension

Roland E. Schmieder, MD; Matthias R.W. Langenfeld, MD; Anja Friedrich, RN; Hans P. Schobel, MD; Christoph D. Gatzka, MD; Horst Weihprecht, MD

the Department of Medicine IV/Nephrology, University of Erlangen-Nurnberg, Germany.


*    Abstract
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 *Abstract
down arrowIntroduction
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Background Urinary sodium excretion and angiotensin II (Ang II), which are linked in a physiological feedback mechanism, have both been described to be blood pressure-independent determinants of left ventricular hypertrophy in essential hypertension. We conducted a study to investigate the interaction of sodium excretion with Ang II and its potential impact on myocardial hypertrophy.

Methods and Results Sixty-eight patients (46 men and 22 women; mean age, 52±10 years) with untreated World Health Organization stage I to II essential hypertension were examined in a cross-sectional study. Left ventricular structure and function (two-dimensionally guided M-mode echocardiography), dietary sodium intake (as estimated by 24-hour urinary sodium excretion), and noninvasive ambulatory blood pressure over 24 hours (Spacelab 90207) were determined in parallel with plasma renin activity and plasma Ang II and serum aldosterone concentrations (radioimmunoassay). Twenty-four-hour urinary sodium excretion emerged as a strong correlate of relative wall thickness independent of 24-hour ambulatory blood pressure (partial r=.49, P<.001). Ang II concentrations were weakly correlated with septal wall thickness (r=.27, P<.05) and left ventricular mass (r=.25, P<.05). Patients with high Ang II concentrations in relation to sodium excretion had a greater left ventricular mass (318±77 versus 257±54 g, P<.02), posterior wall thickness (11.8±1.9 versus 10.5±0.8 mm, P<.02), and septal wall thickness (13.6±1.8 versus 11.9±1.3 mm, P<.01) than those with "relatively low" Ang II levels in relation to sodium excretion.

Conclusions Impaired suppression of the renin-Ang II system appeared to act as a stimulus for myocardial hypertrophy in hypertensive patients.


Key Words: angiotensin • sodium • ventricles • hypertrophy • hypertension


*    Introduction
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 *Introduction
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Hypertrophy of the left ventricle has an unfavorable prognosis for the hypertensive patient. Cardiovascular morbidity and mortality are increased considerably, as is death from all causes.1 2 3 The finding of a hypertrophied left ventricle in normotensive persons indicates a higher risk for the development of arterial hypertension.4 5 6

LVH is the result of many pathogenetic factors. Both elevated preload and afterload represent important determinants of LV structure.7 In addition to the hemodynamic component, other factors influencing cardiac structure in essential hypertension include age,8 sex,9 10 race,11 12 obesity,13 14 and the sympathetic nervous system.15 High dietary salt intake has been linked to LVH in patients with essential hypertension.16 17 18 19 Evidence exists that the RAAS is involved in the process of myocardial hypertrophy. In particular, Ang II has been documented to induce hypertrophy of myocardiocytes in experimental studies20 21 22 23 24 and also to be positively correlated with the degree of LVH in patients with essential hypertension.25 ACE inhibition was found to be the most effective factor in reducing LVH in the treatment of hypertension in comparison with the effects of ß-blockers, calcium blockers, and diuretics.26 27 This stresses the significance of the RAAS in the development of hypertensive LVH.

Sodium excretion and activity of the RAAS are physiologically linked in a negative feedback mechanism. Hence, it appears controversial that both high rates of sodium excretion and high Ang II concentrations are linked with myocardial hypertrophy. Alternatively, sodium and Ang II might have additive actions on the myocardial cells. Sodium homeostasis may influence cardiac growth through changes in the ionic composition of cardiac cells, acting directly by cellular growth factors and Ang II by stimulation of Ang I receptors.21 24 In the present study, we analyzed the impact of dietary salt intake, Ang II concentrations, and the possible influence of the interaction between Ang II and sodium excretion on echocardiographic LV structure and function in essential hypertension.


*    Methods
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 up arrowIntroduction
 *Methods
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Study Cohort
Characteristics of the study population are shown in Table 1Down. The study group comprised 68 white patients (46 men and 22 women) of various ages who were referred to our hypertension unit for evaluation and treatment of high BP and were consecutively enrolled in the study if they fulfilled all of the inclusion criteria. Their mean age was 52±10 years, and average body mass index was 27.8±4.0 kg/m2. All participants received a diagnosis of elevated arterial BP if at least three of four casual BP readings assessed with a standard sphygmomanometer on two different occasions (at least 2 weeks apart) with the patient at rest were >=160 mm Hg systolic or >=95 mm Hg diastolic. The cuff size of the sphygmomanometer was adjusted according to the patient's arm circumference, and the BP was measured with the patient seated after 5 minutes of rest. All patients had either not received any cardiovascular medication or had treatment discontinued at least 4 weeks before the study began and casual BP measurements were taken. None of the participants followed any specific dietary guidelines before hemodynamic evaluation and measurement of sodium excretion. Each participant underwent a complete routine clinical workup. Hypertensive patients were enrolled only if secondary hypertension had been ruled out as well as World Health Organization stage III hypertensive disease. Therefore, exclusion criteria were advanced hypertensive fundoscopic changes, myocardial infarction or other evidence of coronary artery disease, congestive heart failure (New York Heart Association classes II through IV), previous cerebrovascular event, and hepatic or renal insufficiency. In particular, 12-lead electrocardiography at rest and with exercise was performed, as well as fundoscopic evaluation, sonography of the kidneys, examination of renal plasma flow and glomerular filtration rate, and routine laboratory tests. Detailed evaluation of hormones and endocrine metabolites was conducted if indicated. The study protocol was approved by our Clinical Investigation Committee, and informed consent describing the purpose and protocol of the study was obtained from each participant.


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  		Table 1. Characteristics of the Hypertensive Patients Examined

Measurements
According to the study protocol, the 24-hour urine collection took place in parallel with ambulatory BP monitoring, and the echocardiographic and endocrine investigations were done either directly before or after evaluation of 24-hour BP and sodium excretion. Two-dimensional M-mode echocardiography was performed with an ultrasonoscope (Picker-Hitachi CS 192) 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 patient recumbent in the supine or half left-sided position and were read independently by two physicians.

Parameters of LV structure included septal wall thickness, posterior wall thickness, and LV end-diastolic diameter. Midwall fractional fiber shortening was measured as a parameter of global systolic function.28 Relative wall thickness, taken as a parameter for concentric LVH (the "classic" pattern of LVH in arterial hypertension), was calculated as two times posterior wall thickness divided by end-diastolic diameter. LVM was calculated according to the American Society of Echocardiography recommendations29 but then was corrected according to the suggestions of Devereux and associates.30

Twenty-four-hour BP measurements were taken with an automatic portable device (Spacelab 90207). Measurement intervals were every 15 minutes during the day (defined from 6 AM to 10 PM) and every 30 minutes during the night. Dietary salt intake was assessed while patients were on an ad libitum diet by measurement of sodium excretion in urine collected over 24 hours, which represents a rough but valuable estimate of daily sodium intake.31 To ensure complete collection of urine, all samples with a volume of <600 mL/24 h and those containing less than the expected level of creatinine per kilogram of body weight were excluded (n=6).32 33

Blood samples for the determination of plasma renin activity, plasma Ang II concentration, and serum aldosterone concentration were collected from patients who were in the supine position after 1 hour of complete rest. For plasma Ang II measurement, blood was collected into prechilled 10-mL syringes prepared with 125 mmol EDTA and 26 mmol phenanthrolin (Merck) to inhibit ACE. The samples were centrifuged for 10 minutes at 4°C immediately after collection, and plasma was stored rapidly after centrifugation at -21°C and analyzed within 3 months. Plasma samples (1 mL) were extracted with Bond Elut PH cartridges (PK 100, ICT-ASS-Chem), and bound angiotensin was eluted with 0.5 mL methanol. Subsequently, plasma extracts were evaporated in a SpeedVac (SVC 100, Savant Instruments) for 1 hour under reduced pressure.

Immediately after purification of the samples, immunoreactive Ang II was measured by radioimmunoassay with antiserum (kindly provided by Prof Ganten, Max Delbruck Zentrum, Berlin)34 and labeled Ang II (NEX 105, Du Pont). Cross-reactivity of this method is 100% for Ang II and III and 1.2% for Ang I, respectively. The quantification of radioactivity was performed with a 12-channel gamma counter (LBK). Measurements made by this method are accurate within a range from 1.9 to 32 pg Ang II/mL. All determinations of immunoreactive Ang II were made in duplicate, and the mean values are given. The coefficient of variation was <5%.

Blood samples used for determination of plasma renin activity and levels of serum aldosterone were also collected into prechilled syringes and centrifuged for 10 minutes at 4°C. Plasma was quickly frozen and stored at -21°C until it was analyzed (within 3 months). Plasma renin activity was measured by Ang I radioimmunoassay. Serum aldosterone concentration was measured by a commercially available radioimmunoassay kit (Aldosterone Maia 12254, Serono Diagnostics). Measurements were performed in duplicate; the mean values are given. The coefficient of variation was <10%.

Statistics
All statistical analysis was carried out by use of the SPSS program.35 Linear correlation analysis (Pearson), partial correlation analysis, and stepwise multiple regression analysis were applied to identify determinants of LV structure. ANOVA and ANCOVA with Bonferroni correction were applied to investigate differences between tertiles. All values, unless stated otherwise, are expressed as mean±SD. Two-sided probability values are given throughout the text.

To analyze the relationship of Ang II levels and sodium excretion and their influence on LV structure, we divided our patients into three groups with "relatively low," "relatively medium," and "relatively high" concentrations of Ang II in relation to their corresponding rates of sodium excretion. As illustrated in Fig 1Down, it cannot be decided whether this is a linear or curvilinear relationship. Thus, a linear analysis as well as curvilinear analysis (logarithmic transformation of Ang II concentrations thereby assuming an exponential curve) was computed. For each value of 24-hour sodium excretion (x), the expected corresponding Ang II concentration (y) was calculated according to the regression equation in Fig 1Down: for raw values, y=12.8-0.027x (r=-.37, P<.006), and for logarithmic values, ln y=2.64-0.0042x (r=-.45; P<.001). Subsequently, the expected concentration of Ang II was subtracted from the concentration that actually had been measured and was given as a percentage of the expected concentration (corresponding to the measured urinary sodium excretion).



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  		Figure 1. Relationship between 24-hour urinary sodium excretion and Ang II concentration (raw values) in our study cohort (for details, see "Methods").

These relative Ang II levels were used to categorize our patients: those with relatively low (lower tertile), those with relatively medium (middle tertile), and those with relatively high (upper tertile) Ang II levels.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
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Population Characteristics
Casual systolic BP averaged 163±20 mm Hg, and diastolic BP averaged 105±11 mm Hg. Twenty-four-hour BP measurements recorded lower values, but the averages were still in the hypertensive range: 149±20 mm Hg for systolic and 94±8 mm Hg for diastolic BP. Average posterior wall thickness was 11.1±1.6 mm, and average relative wall thickness was 0.46±0.09. Average LVM in our population was 285±70 g. In 41 patients, LVH was present, defined as LVM index >=134 g/m2 for men and >=110 g/m2 for women.36 Ambulatory systolic BP correlated with relative wall thickness (r=.30, P<.05), as did diastolic ambulatory BP (r=.31, P<.05).

Sodium Excretion and LVH
Relative wall thickness, serving as an indicator for concentric LVH, correlated with urinary sodium excretion over 24 hours (r=.49, P<.001): The higher the 24-hour sodium excretion, the more marked the concentric LVH (see Fig 2Down). Similarly, the higher the 24-hour urinary sodium excretion, the greater the posterior wall thickness (r=.44, P<.001). In contrast, 24-hour sodium excretion was not significantly associated with end-diastolic diameter of the left ventricle in the examined hypertensive cohort with mild to moderate essential hypertension. Hence, it is not surprising that LVMs calculated from diastolic diameter and septal and posterior wall thicknesses were not significantly related to sodium excretion.



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  		Figure 2. Relationship between 24-hour urinary sodium excretion and relative wall thickness.

When the correlation of urinary sodium excretion and relative wall thickness was controlled for other confounding factors of myocardial hypertrophy, such as age, body mass index, or systolic and diastolic ambulatory BP, 24-hour urinary sodium excretion still correlated significantly with relative wall thickness (partial r=.43, P<.001). Stepwise multiple regression analysis confirmed that 24-hour sodium excretion was the strongest predictor of relative wall thickness, and this finding was independent of other clinical parameters including ambulatory BP (R2=.21, ß=.47, P<.001). Regardless of whether BP averages over the 24-hour period or averages of the all-day or all-night measurements were entered into the partial correlation and multiple regression analysis, we always found a BP-independent association between 24-hour sodium excretion and relative wall thickness (all P<.001).

Ang II and LVH
Within the RAAS, only Ang II was correlated with plasma renin activity (r=.55, P<.001). Serum aldosterone was not significantly linked to either plasma renin activity or Ang II concentrations.

Plasma Ang II concentrations correlated weakly with septal wall thickness (r=.27, P<.05) and LVM (r=.25, P<.05) but not with other LV structural parameters. Plasma renin activity and serum aldosterone concentrations were unrelated to LV structure. Ang II concentrations were unrelated to midwall fractional fiber shortening in our study cohort.

Ang II Related to 24-Hour Urinary Sodium Excretion and LVH
In our population, Ang II concentrations and logarithmic Ang II values were correlated with 24-hour urinary sodium excretion (partial correlation coefficients, r=-.37 and r=-.45, P<.01, respectively). On the basis of this relationship between sodium excretion and Ang II, all patients were categorized into three groups: Ang II levels that were relatively low, relatively medium, or relatively high with respect to their corresponding levels of urinary sodium excretion (see "Methods"). Characteristics were similar among the three groups (Table 2Down). Only Ang II concentrations were different in the tertiles, as expected. Hence, to analyze the difference between the tertiles, we used ANCOVA using Ang II concentrations as a cofactor whose statistical influence was thereby eliminated.


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  		Table 2. Clinical and Echocardiographic Characteristics of Patients With Relatively `Low,'`Medium,' and `High' Ang II Levels (Curvilinear Analysis)

When the relationship between the logarithmic value of Ang II concentrations was used (curvilinear analysis), we found that the relationship between Ang II and sodium excretion was linked to septal wall thickness, posterior wall thickness, and LVM. Patients with a relatively high level of Ang II had the greatest posterior (P<.02) and septal (P<.01) wall thicknesses and tended to have the greatest relative wall thickness (P<.10). Consistently, patients with relatively high Ang II levels had a greater LVM (318±77 g) than those with relatively low Ang II levels (257±54 g, P<.02; Fig 3Down). In contrast, LV end-diastolic diameter was not statistically different among the three groups (Table 2Up).



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  		Figure 3. LVM in patients with "relatively low," "relatively medium," and "relatively high" levels of Ang II in relation to urinary sodium excretion.

On the basis of a linear relationship between sodium excretion and Ang II concentrations, similar results were found: Patients with a relatively high Ang II level had a greater posterior (10.3±0.9 versus 11.3±1.6 mm, P<.05) and septal (11.9±1.4 versus 13.5±1.9, P<.05) wall thickness as well as LVM (240±11 versus 333±70 g, P<.02) than patients with a relatively low Ang II level.

Consistently, a subgroup analysis of men only (n=46) showed a greater septal wall thickness (12.3±1.6 versus 13.8±1.6 mm, P<.05) and LVM (262±59 versus 331±74 g, P<.05) in those with relatively high Ang II levels than in patients with low Ang II concentrations (Table 3Down). In women, the tertiles became too small to allow any conclusions (Table 3Down).


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  		Table 3. Degree of LVH in Groups With `Low,' `Medium,' and `High' Ang II Levels

When analyzing global systolic function in the total study cohort, we found that midwall fractional fiber shortening was different among the three groups divided according to the curvilinear relationship between sodium excretion and Ang II concentrations. Patients with an inappropriately high Ang II concentration had a lower midwall fractional fiber shortening than those with relatively low (P<.05) and relatively medium Ang II levels (Table 2Up).


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Many previous studies have shown that dietary salt intake modulates LV structure in arterial hypertension, regardless of whether dietary salt intake is measured directly18 or, less precisely, via measures of 24-hour urinary sodium excretion.16 17 We were able to reconfirm this effect. In the present study, 24-hour urinary sodium excretion was the strongest predictor of relative wall thickness, an indicator for concentric LVH, independent of the level of BP. Previous studies have used casual BP measurements to eliminate the possibility that sodium excretion exerts its effect on the myocardium via an increase in BP. In contrast to all previous studies, we used ambulatory BP monitoring to determine the afterload imposed on the left ventricle, since this method is more closely correlated with the degree of LVH than casual BP readings.37 38 We found that a high level of 24-hour urinary sodium excretion was associated with increased relative wall thickness independent of the level of average daytime and/or nighttime BP.

Our most striking result is that Ang II concentrations in relation to sodium excretion were linked to the degree of myocardial hypertrophy. So far, there is evidence that Ang II induces myocardial hypertrophy in animal models20 21 22 23 24 and is correlated with LV structural parameters in humans. In a previous study conducted with a heterogeneous population of white and black, male and female hypertensive patients, we found a correlation between absolute Ang II concentrations and relative wall thickness.25 In the present study, with a more homogeneous group of white middle-aged patients with mild to moderate essential hypertension, we could reproduce our earlier results, although the relation was somewhat weak. Our data suggest that both urinary sodium excretion and Ang II modulate LV structure.21 24 28

The present finding that Ang II in relation to sodium excretion modulates cardiac structure suggests that dysregulation of the RAAS is related to myocardial hypertrophy. In some of our hypertensive patients, Ang II appears to be insufficiently downregulated, as indicated by relatively high Ang II concentrations. In a previous study, some patients with essential hypertension were found to have attenuated downregulation of Ang II concentrations in response to high dietary salt intake, which then led to a relatively high level of Ang II.39 Our study suggests that a similar finding of a relatively high level of Ang II represents a pathogenetic link between high salt intake and myocardial hypertrophy.

Brunner et al40 and Alderman et al,41 in accordance with earlier results, reported that the renin sodium profile determined subsequent cardiovascular events, ie, a relatively high plasma renin activity was associated with a higher risk of myocardial infarction. More recently, Levy et al42 found that low urinary sodium excretion, high plasma renin activity, and electrocardiographic LVH were associated with greater risk of myocardial infarction among treated hypertensive men. Interestingly, within each group (tertile) with low, medium, or high plasma renin activity, a low urinary sodium excretion was associated with a higher rate of myocardial infarction. This would indicate that a dysregulation of the renin-sodium relation (low urinary sodium excretion related to the corresponding plasma renin activity or, conversely, high plasma renin activity related to the corresponding sodium excretion) is a risk factor for myocardial infarction independent of electrocardiographically determined LVH in patients with essential hypertension. Electrocardiography, however specific it may be in identifying LVH, is of minor sensitivity in this respect. Echocardiography, in contrast, reveals >90% of existing cardiac hypertrophy,30 which itself represents a severe cardiovascular risk factor.1 2 3 On the basis of the results of our study, we raise the hypothesis that the population in Alderman's study with high renin levels could have had a dysregulation of the RAAS identical to what we observed in our patients with relatively high Ang II levels. This might have led to (electrocardiographically undetected) echocardiographic LVH that was ultimately responsible for the higher incidence of cardiac events in this group.

Parallel to the results of previous studies,43 44 we found that midwall LV fiber shortening was lowest in the group with relatively high Ang II levels. Previous studies have used plasma renin activity for classification and found that the high-renin group was associated with a mildly depressed systolic LV performance.43 Whether Ang II is related to the lower systolic function directly or via aldosterone, known to impact the collagen content of the myocardium, remains to be determined in subsequent studies.

In summary, we conclude that dysregulation of the RAAS is a pathogenetic factor that influences the development of LVH in hypertensive patients, in particular persons with a high dietary salt intake. Our data suggest that a relatively high level of Ang II in relation to sodium intake might be one pathogenetic link that mediates the effect of sodium intake on LV structure.


*    Selected Abbreviations and Acronyms
 
Ang = angiotensin
BP = blood pressure
LV = left ventricular
LVH = LV hypertrophy
LVM = LV mass
RAAS = renin-angiotensin-aldosterone system


*    Acknowledgments
 
This study was supported by a grant from the Deutsche Forschungsgesellschaft.


*    Footnotes
 
Reprint requests to Prof Dr Roland E. Schmieder, Medizinische Klinik IV/Nephrologie, Universitat Erlangen-Nurnberg, Breslauer Str 201, D-90471 Nurnberg, Germany.

Received October 19, 1995; revision received March 21, 1996; accepted March 26, 1996.


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 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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