Influence of dietary sodium on the renin–angiotensin–aldosterone system and prevalence of left ventricular hypertrophy by EKG criteria

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We investigated the interplay of dietary sodium and renin–angiotensin–aldosterone system (RAAS) activity with the prevalence of left ventricular hypertrophy (LVH) in essential hypertension. Electrocardiograms (EKG) were reviewed for the presence of LVH in 160 hypertensive patients. We then compared the rate of LVH to levels of plasma renin activity (PRA) and serum aldosterone under high and low sodium diet conditions. On high sodium diet, serum aldosterone was significantly higher (7.7±0.93 vs 5.7±0.35 ng/dl, P=0.02) in participants with LVH. With low sodium diet and upright posture, PRA was significantly lower in subjects with LVH vs those without (5.6±1.1 vs 7.6±0.56 ng/ml/h, P=0.026). Aldosterone levels on low sodium diet were not different between those with and those without LVH. PRA was then dichotomized at the lowest quartile under low sodium/upright posture conditions to define a ‘low renin’ group. In a multivariate logistic regression containing renin status (low renin vs normal/high renin), aldosterone on a high sodium diet, age, body mass index, gender, race, duration of hypertension, systolic and diastolic blood pressure and salt-sensitivity only low-renin status on a low sodium diet (P=0.019) and serum aldosterone on a high sodium diet (P=0.04) were significant predictors of LVH. Thus, reduced modulation of renin activity in response to sodium restriction and an increased aldosterone on a high sodium diet appear to identify characteristics of hypertensive patients predisposed to abnormal cardiac remodelling.


Left ventricular hypertrophy (LVH) represents abnormal cardiac remodelling and is a well-established independent risk factor for premature cardiovascular morbidity and mortality.1, 2, 3, 4 Although sustained hypertension predicts the presence of LVH, blood pressure itself correlates only modestly with left ventricular mass.5, 6, 7 This suggests that blood pressure-independent mechanisms may contribute to the pathophysiology. Alterations in renin–angiotensin–aldosterone system (RAAS) activity8, 9 and dietary sodium intake10, 11, 12 have both been linked to the development of LVH.

Classical understanding of the RAAS involvement in hypertension describes volume-dependent and -independent mechanisms where lower renin activity reflects volume-dependent hypertension and higher renin activity, volume-independent hypertension. There is evidence on the one hand that higher renin is associated with increased risk of LVH.13, 14, 15, 16 Seemingly contradictory evidence exists for sodium-sensitive (volume dependent) hypertension being associated with LVH.10, 11, 12 Reconciling these findings might reside in recognizing the inverse relationship between modulation of RAAS activity and dietary sodium intake.

We sought to determine factors that were associated with LVH by investigating plasma renin activity (PRA) and serum aldosterone levels measured during three controlled sodium intake conditions (high sodium diet, low sodium diet and low sodium with upright posture) in hypertensive patients.

Materials and methods

Electrocardiogram (EKG) and subject information from 160 unrelated patients were obtained from the HyperPath consortium (Boston, MA (n=58), Paris, France (n=50), Salt Lake City, UT (n=52)). This project represents a multicentre effort to create homogeneous intermediate phenotypes within the essential hypertensive population to enable more effective genetic associations. The characteristics of this population have been described elsewhere.17, 18 As part of this study, approval was obtained from each institution's Human Research Committee and informed witnessed consent obtained from each subject prior to enrollment.

Patients with mild to moderate hypertension were enrolled, as defined by a history of hypertension with a diastolic blood pressure (DBP)100 mmHg on no medications, DBP90 mmHg on one antihypertensive agent, or the use of two or more antihypertensive medications at the time of screening visit. Patients with diabetes or known active cardiac or cerebrovascular disease were excluded. EKGs were obtained at the time of screening for entry into the study protocol. All patients receiving a converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB) or aldosterone antagonist were washed out for 3 months prior to study because of their known effects on modulation of RAAS function in some hypertensive patients. Those on beta blockade therapy were withdrawn for 3–4 weeks. If needed, patients were placed on either a dihydropyridine calcium channel blocker or diuretic or both to control blood pressure during washouts. All medications were discontinued 2–4 weeks prior to study. Participants were then randomized to high (200 mEq/day) or low (10 mEq/day) sodium diet for 7 days and crossed over to the opposite diet for an additional 7 days (Figure 1). High sodium diet consisted of the individual's usual diet supplemented with 2–3 packets of broth at lunch and dinner or some participants were provided a high sodium diet prepared by each centre's General Clinical Research Center (GCRC). The metabolic kitchen of the GCRC prepared all low sodium diet meals, drinks and snacks. External sodium balance in each phase of the study was determined by a 24-h urine collection for creatinine and sodium at the end of each week. ‘High sodium balance’ required a 24-h urinary sodium excretion >180 mmol/day and ‘low sodium balance’ <30 mmol/day.

Figure 1

Protocol outline. ACEI=angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; HS=high sodium diet; LS=low sodium diet; PRA=plasma renin activity; Aldo=serum aldosterone concentration.

At the end of each diet period, subjects were admitted to the GCRC for 1 night and 1 day during which metabolic studies were performed to assess activity of the RAAS. Blood pressure used in the analysis was obtained while supine in the morning following 10 h of overnight rest using the average of three readings from an indirect recording sphygmomanometer. Salt-sensitivity was defined as a difference in mean blood pressure between high and low sodium diets that was 10 mmHg. Baseline supine PRA and aldosterone levels were assessed on each diet in the morning after admission. Additionally, at the end of the low sodium diet period, PRA and aldosterone levels were measured after subjects assumed and maintained upright posture for 90 min. Results of these PRA levels were used to classify subjects as having low renin (LR) or normal/high renin hypertension based on previous results from our laboratory identifying a bimodal distribution of PRA, dichotomized at the lowest quartile, obtained under similar conditions (LR=PRA<2.4 ng/ml/h; normal/high renin=PRA2.4 ng/ml/h).19, 20

Primary hyperaldosteronism was excluded based on measurements of urinary aldosterone excretion rates and the ratio of serum aldosterone concentration to PRA while in high salt balance, according to standard diagnostic criteria.21

Laboratory analyses

Blood samples were collected on ice and centrifuged for 20 min. Samples were stored at −20°C without preservatives until assayed. PRA, serum aldosterone concentration, sodium, potassium and creatinine were measured as previously described.18, 22

EKG analysis

EKGs obtained at screening were analysed for the presence of LVH by a single operator (JSW), masked to the subject's biochemical profile. Two standardized methods for EKG assessment were employed. For each subject, the values of three QRS complexes were averaged from the EKG. To meet criteria for LVH, the sum of the S wave in V1 and the R wave in V5 or V635 mm and/or R wave in aVL11 mm (Sokolow–Lyon), and/or for men: S in V3 plus R in aVL>28 mm, and for women: S in V3+R in aVL>20 mm (Cornell).23 LVH was considered as present if criteria were met by either method.

Statistical analysis

All data are presented as mean values±s.e.m. and percentages. Homogeneity testing was performed to assess possible differences across the three study sites before proceeding with pooled analysis. Independent sample t test, Fisher's exact test and nonparametric testing (Mann–Whitney test) were used to detect statistical differences between groups. Multivariate logistic regression was employed to determine the effect of various predictors and interaction terms on the odds of LVH. P-value for entry into the model was set at 0.10 and P-value for exit from the model at 0.101. The final model was selected based on concordance of forward, backward and conditional modelling. The level for significance for all tests conducted was set at α=0.05. Data analyses were performed using Statistical Package for Social Sciences (SPSS, Inc., Chicago, IL, USA) version 11.



The overall prevalence of LVH by either Cornell and/or Sokolow–Lyon EKG criteria was 18% (29/160). On univariate analysis, comparing characteristics of participants with LVH to those without, participants with LVH were more likely to have higher systolic (SBP). There was no significant difference in age, race, gender, duration of hypertension, body mass index (BMI) or salt-sensitivity among those with and without LVH (Table 1).

Table 1 Demographic and baseline haemodynamic profile according to LVH status

Plasma renin activity

On the high sodium diet, PRA was not significantly different between those with LVH vs those without (LVH: 0.81±0.16 vs no LVH: 0.63±0.05 ng/ml/h, P=0.57). However, while on the low sodium diet, patients with LVH had lower PRA levels compared to those without LVH both in the supine position (LVH: 1.97±0.32 vs no LVH: 2.45±0.15 ng/ml/h, P=0.055), and with upright posture (LVH: 5.60±1.1 vs no LVH: 7.55±0.55 ng/ml/h, P=0.026) (Figure 2). The change in PRA in response to upright posture was also significantly lower in subjects with LVH (LVH: 4.79±1.1 vs no LVH: 6.92±0.56 ng/ml/h, P=0.011). In concordance with these findings, patients with LVH were more likely to be classified as LR (31.7 vs 13.5%, P=0.009).

Figure 2

Plasma renin activity and prevalence of LVH based on dietary sodium intake and posture (error bars represent±s.e.m.). PRA=plasma renin activity; LVH=left ventricular hypertrophy. *P=0.055 PRA LVH(+) vs PRA LVH(−); P=0.026 PRA LVH(+) vs PRA LVH(−).

Serum aldosterone concentration

Aldosterone levels were significantly higher in subjects with LVH while on a high sodium diet (LVH: 7.7 vs no LVH: 5.7 ng/dl, P=0.022), but were not different on low sodium diet or following upright posture. Other biochemical parameters were similar between subjects with and without LVH (Table 2).

Table 2 Biochemical indices by dietary/posture profile (mean±s.e.m.)

Logistic regression

After adjusting for possible predictors of LVH (renin status (LR vs normal/high renin), aldosterone on high sodium diet, BMI, SBP, DBP, age, race, gender, salt-sensitivity and duration of hypertension) with multivariate logistic regression, only the LR phenotype, determined during low sodium balance and aldosterone concentration on a high sodium diet remained significant predictors for LVH (LR OR, 2.97; 95% CI, 1.29–6.94; aldosterone OR, 1.11; 95% CI, 1.01–1.22). In order to estimate the effect of the nonsignificant predictors, all variables (BMI, SBP, DBP, race, age, gender, salt-sensitivity, duration of hypertension) were then forced into the final model (Table 3).

Table 3 Multivariate logistic regression predicting odds of LVH


In this cross-sectional study of patients with mild to moderate essential hypertension, we documented that 18% had LVH by EKG criteria. This is similar to the prevalence reported by others.24, 25, 26, 27 We then addressed whether differences in factors associated with LVH existed in those with LVH vs those without, with particular attention to components of the RAAS. In individuals with LVH, the most striking observation was a lower PRA level under low sodium conditions and higher aldosterone levels on a high sodium conditions. Furthermore, LR defined under low sodium conditions and upright posture, and high sodium aldosterone levels were associated with LVH even after controlling for several possible confounding factors. Importantly, these findings did not place the LVH group entirely within the LR hypertensive subgroup, as only 32% of the LVH patients met our criteria of having LR. These findings taken together strongly suggest that sodium status at the time of PRA and aldosterone profiling substantially influences the interpretation of risk for LVH in patients with mild/moderate hypertension.

The present study first identified patients with LVH and then assessed PRA and aldosterone levels. Previous reports usually used the opposite approach. Koga et al28 described 108 subjects with untreated essential hypertension in whom Sokolow–Lyon criteria for LVH correlated positively with PRA. However, these patients were studied in the ambulatory setting without standardization of dietary sodium intake, and had moderate to severe hypertension. Malmqvist et al29 investigated the relationship between PRA and LVH by echocardiography in a large case–control study and reported elevated PRA in hypertensive subjects with LVH but, again, no attempt was made to control dietary sodium at the time of study nor were subjects with secondary aldosteronism excluded. Rowlands et al30 were unable to reveal an association between PRA and left ventricular mass in hypertensive patients. However, du Cailar et al31 reported that in 333 treatment-naive hypertensive patients, lower PRA was associated with echocardiographic evidence of eccentric LVH. Our findings underscore the importance of adequately controlling sodium intake when linking PRA with LVH. Indeed as others have reported, we observed slightly, albeit insignificantly, higher PRA in our LVH patients on a high sodium diet only to uncover their inability to modulate PRA in response to sodium restriction and upright posture.

What might be the possible mechanisms for development of LVH and how does it relate to a lower PRA on low sodium diet in these patients? One possible clue is provided in the present data set, namely, elevated aldosterone levels on a high sodium diet. Mineralocorticoid excess, such as occurs with primary hyperaldosteronism (PA), is a low renin state in which cardiac hypertrophy is a prominent finding.32 When matched for several factors (blood pressure, duration of hypertension, age, gender, BMI, race), subjects with PA have more cardiac hypertrophy developing at an earlier age than subjects with essential hypertension.33 Although primary hyperaldosteronism was excluded in this cohort, it is possible that subjects with lower renin hypertension, as defined in this study, are part of a continuum of mineralocorticoid excess relative to the level of sodium intake. Therefore, these subjects are vulnerable to the same BP-independent adverse effects of relative aldosterone excess on the cardiomyocyte as in subjects with PA. Importantly, this relative excess of aldosterone in LVH-positive subjects was not present with sodium restriction but only in the condition more commonly found in the free-living setting—a high salt intake—where LVH-positive subjects had aldosterone levels 35% higher than LVH-negative subjects.

Limitations of this study include our inability to address causality due to the observational nature of the study design and the relatively small study population. We sought to limit possible confounder influences in the hormonal evaluations by observing strict entry criteria including prolonged medication wash-out, assurance of adequate sodium balance with 7 days of controlled diet followed by 24-h urine assessment of sodium and potassium excretion, and overnight supine status in a General Clinical Research Center. Additionally, we further attempted to remove confounding by considering known predictors of LVH in our logistic regression model. The intent of these investigations was to be hypothesis generating in nature, to provoke future studies.

EKG as a tool for determining the presence of LVH may have variable specificity and sensitivity depending on the criteria used. However, clearly there is value in EKG assessment of LVH as a meaningful research tool as evidenced in the recently published LIFE trial34 and others35 demonstrating the high degree of concordance with echocardiography.36

In summary, lower PRA on a low sodium diet and higher aldosterone on a high sodium diet predict the presence of LVH in subjects with mild and moderate essential hypertension. These findings suggest that an underlying defect in the modulation of the RAAS in response to changes in sodium intake is associated with abnormal cardiac remodelling and identifies a more vulnerable subset of hypertensive subjects.


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This research was supported by the following grants: National Institutes of Health Grants HL47651, HL59424, DK63214, Specialized Center of Research in Hypertension from the National Heart, Lung and Blood Institute (HL55000), National Center for Research Resources (General Clinical Research Centers) in Boston (M01 RR 02635) and Salt Lake City (M01 RR 00064). Dr J Williams was in part supported by an NIH training grant (T32 HL 0760917). We gratefully acknowledge the assistance of the dietary, nursing, administrative and laboratory staffs of the three clinical research centres.

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Williams, J., Williams, G., Jeunemaitre, X. et al. Influence of dietary sodium on the renin–angiotensin–aldosterone system and prevalence of left ventricular hypertrophy by EKG criteria. J Hum Hypertens 19, 133–138 (2005) doi:10.1038/sj.jhh.1001784

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  • renin
  • left ventricular hypertrophy
  • aldosterone
  • dietary sodium
  • blood pressure

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