European Heart Journal Advance Access published August 19, 2011

CLINICAL RESEARCH

European Heart Journal

doi:10.1093/eurheartj/ehr292

Serum aldosterone and its relationship to left

ventricular structure and geometry in patients
with preserved left ventricular ejection fraction
Frank Edelmann 1*, Andreas Tomaschitz 2, Rolf Wachter 1, Gotz Gelbrich 3,
Manuela Knoke1, Hans-Dirk Dungen 4, Stefan Pilz 2,5, Lutz Binder6,
Raoul Stahrenberg 1, Albrecht Schmidt 7, Winfried Marz8, and Burkert Pieske 7
Department of Cardiology and Pneumology, University of Goettingen, Robert-Koch-Strae 40, Goettingen 37075, Germany; 2Department of Endocrinology and Metabolism,
Medical University of Graz, Graz, Austria; 3Coordination Center for Clinical Trials, University of Leipzig, Leipzig, Germany; 4Department of Cardiology, Charite-Universitatsmedizin,
Berlin, Germany; 5Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands;
6
Department of Clinical Chemistry, University of Goettingen, Goettingen, Germany; 7Department of Cardiology, Medical University of Graz, Graz, Austria; and 8Synlab Centre of
Laboratory Diagnostics, Heidelberg, Germany
Received 8 February 2011; revised 28 June 2011; accepted 25 July 2011

Aims

Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular (CV) morbidity and
mortality. Previous studies relating aldosterone to left ventricular (LV) structure however revealed conflicting results.
.....................................................................................................................................................................................
Methods
We aimed to evaluate the relationship of serum aldosterone concentration (SAC) and aldosterone-to-renin ratio
(ARR) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejecand results
tion fraction (LVEF). We studied 1575 participants (54.1% female) with CV risk factors and LVEF .50%
(61.7 + 6.1%). Of the total, 94.7% of patients had no overt heart failure. All patients underwent measurement of
SAC, ARR, and comprehensive echocardiographic analysis. Overall, multivariate adjusted analysis of covariance
(ANCOVA) showed a significant increase in LV mass (P 0.001), LV mass index (P 0.001), relative wall thickness
(P 0.011), and LV posterior wall thickness (P , 0.001) with increasing SAC. This overall association of SAC and LV
remodelling was driven by a statistic significant effect exclusively in women. In multivariate logistic regression analysis
higher SAC levels were independently related to concentric LV hypertrophy [odds ratio (OR; with 95% CI) by comparing SAC levels in the third gender-specific tertile with the first tertile: 1.87; 95% CI: 1.312.68; P 0.001]. Higher
SAC levels were positively related to concentric LVH in either sex. We observed no significant associations between
the ARR and echocardiographic parameters of LV remodelling.
.....................................................................................................................................................................................
Conclusion
Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure, particularly in women. Higher SAC however was related to concentric LVH in either sex. Our findings in a large
CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway
for structural alterations of the left ventricular myocardium.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Serum aldosterone Left ventricular structure and geometry

Introduction
The adrenal hormone aldosterone regulates salt and water
homeostasis via binding to the mineralocorticoid receptor (MR)
in the kidney. Beside of the classical binding sites of aldosterone

to MR such as the renal collecting duct and the salivary glands,

MRs have been additionally localized in non-epithelial tissues, i.e.
in the myocardium. Absolute aldosterone excess in terms of
primary aldosteronism has been associated with higher risk of
arterial hypertension, kidney damage, and left ventricular (LV)

* Corresponding author. Tel: +49 551 3912100, Fax: +49 551 3913354, Email: fedelmann@med.uni-goettingen.de

These authors contributed equally to this work.

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2011. For permissions please email: journals.permissions@oup.com

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Page 2 of 10

Methods
Study characteristics
The ongoing, multi-centre observational trial DIAST-CHF on prevalence and clinical course of diastolic dysfunction (DD) and HF with
preserved ejection fraction (HFpEF) is part of the nationwide
German Competence Network Heart Failure project.11 Patients
(aged between 50 and 85 years) who revealed at least one risk
factor for DD or HFpEF (defined as history of arterial hypertension,
diabetes mellitus, sleep apnea syndrome, or atherosclerotic disease)
or a documented history of HF were prospectively included into the
DIAST-CHF study after reference to primary care physicians. Only
patients with an inability to participate or give written consent, i.e.
due to severe concomitant diseases or geographic reasons were not
included. For the present analyses, we excluded patients with systolic
dysfunction [left ventricular ejection fraction (LVEF) ,50%] or with
atrial fibrillation. Heart failure with preserved ejection fraction was
diagnosed in accordance with recent ESC guidelines and with Framingham diagnostic criteria.12,13
The majority of 1935 patients (1728) who were included in
DIAST-CHF were from Goettingen and Berlin, Germany. Serum

aldosterone concentration (SAC) was measured in 1575 patients

(78.8%) who revealed an LVEF 50% and sinus rhythm at presentation. No statistical differences were seen for age, gender distribution,
systolic and diastolic BP, LV mass, N-terminal pro B-type brain
natriuretic peptide (NT-proBNP) levels, intake of antihypertensive
medication, and the presence of chronic HF in participants with and
without SAC measurements, respectively. Out of n 1557, in n
78 (5.3%) patients HFpEF was diagnosed. Since associations reported
below were not significantly different (P . 0.05) between patients
with or without overt HFpEF, this group was not listed separately.
The study complied with the Declaration of Helsinki, the protocol
was approved by the responsible Ethics Committee and all patients
provided written informed consent.
Comprehensive echocardiographic analysis of cardiac function and
structure was performed by experienced physicians on Sonos 5500
device (Hewlett-Packard, Andover, MA, USA) according to current
guidelines of the American Society of Echocardiography. In addition,
randomly chosen echo examinations were reviewed by the echo
core laboratory at the University of Essen for quality assurance.
Dimensions were recorded by standard techniques. Interventricular
septum, LV posterior wall thickness, LV end-diastolic diameter
(LVEDD), and end-systolic diameter (LVESD) were determined by
M-mode or anatomically, as appropriate. Left ventricular end-diastolic
volume (LVEDV), left ventricular end-systolic volume (LVESV), and LV
ejection fraction (EF) were measured by the modified Simpsons
method. Left ventricular mass (g) was calculated by the Devereux
formula and also expressed as LV mass index (g/cm2).14 Relative wall
thickness was calculated by the formula LV posterior wall thickness
x 2/LVEDD.
Left ventricular hypertrophy was defined as an LV mass index
exceeding 110 g/m2 in women and 125 g/m2 in men, respectively,
and the cut-off point for abnormal relative wall thickness was 0.44.15
Concentric remodelling (CR) was defined as elevation of relative
wall thickness but normal (gender-specific) LV mass index, concentric
LV hypertrophy was defined as a gender-specific elevation of LV mass
and relative wall thickness and eccentric LV hypertrophy as a genderspecific elevation of LV mass but normal relative wall thickness.16
Diastolic dysfunction was characterized according to the ASE guidelines and graded by an algorithm [(i) normal diastolic function; (ii) mild
DD; (iii) moderate DD; and (iv) severe DD], which has been defined in
the study protocol and described previously in detail.17,18

Definition of covariates
Body mass index (BMI) was calculated as weight in kilogram divided by
height in meter squared. History of coronary heart disease (CHD),
hyperlipidaemia, current smoking status, chronic obstructive pulmonary disease, alcohol abuse, history of cancer, and sleep apnea syndrome were evaluated at presentation through a patient provided
medical history. Detailed ongoing medication [ACE-inhibitors
(ACE-I), angiotensin-II type-1 receptor blockers (ARB), beta-blockers,
calcium channel blockers, diuretics, and statins] was recorded at baseline. In addition, only 14 participants (0.9%) took MR-blockers at baseline. Diabetes mellitus was defined according to the current
recommendations of the American Diabetes Association as fasting
glucose .7.0 mmol/L or 2 h glucose .11.1 mmol/L after performing
an oral glucose tolerance test.19 Arterial hypertension was defined
according to the JNC VII report (Seventh Report of the Joint National
Committee for Prevention, Detection, Evaluation, and Treatment of
Hypertension) as systolic/diastolic BP .140/90 mmHg and/or
ongoing intake of antihypertensive medication. Systolic and diastolic
BP was measured at baseline by experienced physicians under standardized conditions. The heart rate was recorded after resting via

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hypertrophy.1 However, an increasing body of evidence points to

aldosterone as a major cardiovascular risk factor in the absence
of primary aldosteronism and independent of its primary stimulator angiotensin II.2
In the last years various experimental and clinical studies
revealed that apart from neurohormonal activation in the setting
of heart failure (HF), pre-existing tissue damage, high dietary salt
intake, increased reactive oxygen species-generation and presumably lower kidney function might be important pre-requisites for
the initiation of aldosterone-mediated deleterious effects.3
Accordingly, it has been recently shown that circulating aldosterone levels within the physiological range are strongly related to
increased risk of cardiovascular mortality, fatal stroke, and
sudden cardiac death.4 Consistent with this finding Pitt et al. and
Zannad et al.5 7 impressively demonstrated an improvement of
survival after MR-blockade in patients with severe HF but presenting with normal aldosterone levels. Further interventional studies
revealed that MR-blockade effectively attenuates LV hypertrophy
in hypertensive patients and in patients with mild to moderate
HF, respectively.8,9
Several experimental investigations in salt fed animals documented profibrotic and pro-hypertrophic effects of aldosterone independent of arterial blood pressure (BP) and circulating plasma
volume.10 In view of LV hypertrophy as a major independent risk
factor of HF, sudden cardiac death and cardiovascular mortality
studies in humans revealed conflicting results regarding the
relationship of circulating aldosterone levels to cardiac structure.
Most of these studies however were limited by small sample
size, selection bias, and inappropriate consideration of confounding
factors.
In view of the inconsistency regarding the associations between
circulating aldosterone levels and cardiac structure, we aimed to
evaluate the gender-specific relationship of serum aldosterone
and aldosterone-to-renin ratio (ARR) levels, which reflect inappropriate aldosterone secretion, to LV structure and pathological
patterns of LV geometry.

F. Edelmann et al.

Page 3 of 10

Serum aldosterone and left ventricular remodelling

electrocardiography at baseline. Estimated glomerular filtration rate

(eGFR) was calculated according to the MDRD (modification of diet
in renal disease) study formula to estimate GFR. All patients at presentation were on a normal Western (sodium) diet.

Laboratory methods

Statistical methods

Results

Clinical and anthropometric characteristics of the study participants

are reported according to levels of SAC (in tertiles) and were presented as percentages for categorical data and as medians with interquartile ranges or as means with SD for continuous data. Comparisons
between SAC groups were performed using the x2 test with P by
linear-for-linear test for categorical data and by using analysis of variance for continuous data. All continuous parameters following a
skewed distribution (PRC, ARR, high sensitive C-reactive protein,
TSH, NT-proBNP, and LV mass) were logarithmically transformed
before being used in parametric statistical procedures.
Pearson correlation analysis was used to analyse the correlations
between SAC, ARR, and echocardiographic variables of LV structure
and function overall and separately in women and men, respectively.
To better adhere to suggested sex-related relationship of SAC to LV
mass, LV mass index, relative wall thickness, LV-PW, and interventricular septum levels over a broader range of data, we also categorized
patients into gender-specific tertiles of SAC. Analysis of Covariance
(ANCOVA) followed by Bonferronis post hoc test was used to
compare mean values of LV mass, LV mass index, relative wall thickness, LV-PW, and interventricular septum across gender-specific tertiles of SAC. Each model was adjusted for relevant key elements in

At baseline, SAC (mean: 232.5 + 208.9 pmol/L) was determined in

1575 study participants (mean age: 65.5 + 8.4 years; 54.1%
women). The distribution of demographics, co-morbidities, laboratory characteristics, and echocardiographic parameters according
to levels of SAC (in tertiles) of patients at baseline is shown in
Table 1. Higher SAC levels were associated with higher diastolic
arterial BP and lower eGFR values. In addition, SAC levels were
related to higher values of interventricular septum, LV posterior
wall thickness, LV mass, LV mass index, and relative wall thickness
values. Baseline SAC levels were not associated with varying severity of DD, age, BMI, hyperlipidaemia, arterial hypertension, high
sensitive C-reactive protein levels and prevalence of abnormal geometric LV patterns.
Across the entire cohort, SAC correlated with echocardiographic parameters except for LVEF (Table 2). Overall no
associations were found between ARR and echocardiographic parameters of the LV. The correlation analysis was further stratified by
gender. In women, positive correlations were seen between SAC
and LV mass, relative wall thickness and LV posterior wall

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Serum aldosterone concentration (pmol/L; conversion factor pg/mL

2.744 pmol/L) was determined according to manufactures instructions by the Direct Aldosterone ELISA kit (Aldosterone ELISA, IBL
GmbH, Hamburg, Germany). The intra-assay and inter-assay coefficients
of variation of this assay were 4.1 10.4 and 9.49.7%, respectively.
Plasma renin concentration (PRC, mIU/mL) was measured using a fully
automated chemiluminiscent assay for the direct measurement of
renin (LIAISONw Direct Renin, DiaSorin, Saluggia, Italy). This newly
developed assay reportedly has suggested to have an improved functional sensitivity of up to ,2 mU/L (measuring range: 0.5500 mIU/mL;
referenced to WHO68/356). The analytical sensitivity and functional
sensitivity was 0.5 and , 1.96 mIU/mL, respectively. The ARR (SAC in
pmol/L/PRC in mIU/mL) was calculated as a recommended screening
method for the detection of primary aldosteronism. A recently published
evaluation of cut-off values for positive primary aldosteronism screening
based on the DiaSorin Liaison automated chemiluminiscent immunoassay for direct renin revealed a 100% sensitivity and 93% specificity
for detecting primary aldosteronism by use of an ARR cut-point
.35 pmol/L/mIU/mL in patients with circulating aldosterone levels
.300 pmol/L.20 N-terminal pro B-type brain natriuretic peptide (pg/
mL; conversion factor: pg/mL 0.118 pmol/L) was measured by an
electrochemiluminiscent assay (ECLIAw, Roche Diagnonstics GmbH,
Mannheim, Germany). High sensitive C-reactive protein (mg/L) was
measured by the new C-reactive protein high-sensitive assay on
COBAS
INTEGRAw (Roche Diagnostics GmbH, Mannheim,
Germany). LDL-cholesterol (mg/dL) was determined by a selective
direct single measurement by the LDL-C Select FS method (DiaSys Diagnostic Systems GmbH, Holzheim, Germany) and HDL-cholesterol (mg/
dL) was measured by an in vitro assay (Wako Chemical GmbH, Neuss,
Germany). Thyroid stimulating hormone (TSH, mU/mL) was determined
by an electrochemiluminiscent assay (ECLIAw, Cobas, Roche Diagnostics GmbH, Mannheim, Germany).

regard to the variable of interest [age, gender, BMI, HDL-cholesterol,

LDL-cholesterol, systolic BP, serum sodium, serum potassium, NTproBNP, detailed antihypertensive medication (ACE-I use, ARB use,
beta-blocker use, calcium-channel blocker use, diuretic use, and
MR-blocker use), statin use, eGFRMDRD, diabetes mellitus, history of
CHD, high sensitive C-reactive protein, current smoking status, TSH,
alcohol abuse, heart rate, history of cancer, history of sleep apnea syndrome, chronic obstructive pulmonary disease, and PRC].
Logistic regression analysis (with backward elimination) was performed to investigate the association of SAC for patients presenting
with pathological patterns of LV geometry (concentric LV remodelling,
concentric LV hypertrophy, and eccentric LV hypertrophy). We calculated odds ratios (OR) with 95% confidence interval (95% CI) relating
different pathological patterns of LV geometry to gender-specific tertiles of SAC (pmol/L) by comparing high SAC levels within the third
and second gender-specific tertile, respectively, with SAC levels
within the first (reference) gender-specific tertile. The analysis was
performed overall and separately in women and men, respectively.
According to the adjustment for important confounders, three different models were computed: model 1: crude; model 2: age-adjusted;
model 3: multivariate adjusted [age, gender, BMI, HDL-cholesterol,
LDL-cholesterol, systolic BP, serum sodium, serum potassium, NTproBNP, detailed antihypertensive medication (ACE-I use, ARB use,
beta-blocker use, calcium-channel blocker use, diuretic use, and
MR-blocker use), statin use, eGFRMDRD, diabetes mellitus, history of
CHD, high sensitive C-reactive protein, current smoking status, TSH,
alcohol abuse, heart rate, history of cancer, history of sleep apnea syndrome, chronic obstructive pulmonary disease, and PRC]. Additionally,
ORs (with 95% CI) for 1 SD increment in log-SAC (derived from multivariate adjusted model 3) for each abnormal LV geometric pattern
were calculated.
Finally, interaction terms were introduced into the fully adjusted
(model 3) logistic regression models to evaluate whether the nature
of the association between SAC and concentric LV hypertrophy
differs according to further parameters related to LV structure.
A P-value ,0.05 was considered statistically significant and all statistical tests were two-sided. Data were analysed using SPSS 17.0 statistical package (SPSS, Inc., Chicago, IL, USA).

Page 4 of 10

Table 1

F. Edelmann et al.

Baseline characteristics according to serum aldosterone concentration tertiles

Variable

Tertile 1
(<164.8 pmol/L)
n 5 525

Tertile 2
(164.8 224.8 pmol/L)
n 5 525

Tertile 3
(>224.8 pmol/L)
n 5 525

139.0 (116.3 152.3)

13.6 (6.4 33.8)

193.1 (179.4206.1)
16.5 (7.5 43.1)

287.9 (249.0 370.9)

19.0 (8.654.7)

P Trend

...............................................................................................................................................................................
SAC, pmol/L
PRC, mIU/mL
ARR, pmol/L/mIU/mL
Age, years
Female sex, %

9.4 (3.6 19.8)

65.9 + 8.4
67.6

0.001

11.7 (4.5 25.4)

15.9 (6.042.0)

,0.001

65.3 + 8.4
52.0

64.8 + 8.4
42.1

0.238
,0.001

Body mass index, kg/m2

28.7 + 5.0

28.8 + 4.8

28.7 + 4.6

0.880

LDL cholesterol, mg/dL

HDL cholesterol, mg/dL

124.8 + 33.6
56.6 + 16.6

127.1 + 32.1
53.2 + 17.0

125.9 + 31.5
53.2 + 15.7

0.483
0.016

39.8

39.8

36.8

0.311

Statin use, %
Current smokers, %

28.1
10.9

23.7
14.1

25.1
10.1

0.271
0.774

Alcohol abuse, %

10.5

12.5

15.8

0.693

9.1
5.1

7.0
5.7

7.4
6.5

0.303
0.355

History of cancer, %
Sleep apnea syndrome, %
Chronic obstructive pulmonary disease, %

7.2

8.2

5.3

0.224

Diabetes mellitusa, %
Arterial hypertension, %

22.7
77.1

24.8
77.3

21.9
79.2

0.770
0.413

Systolic blood pressure, mmHg

147 + 21

147 + 21

146 + 23

0.520

Diastolic blood pressure, mmHg

Heart rate, b.p.m.

82 + 12
66 + 10

84 + 12
67 + 11

84 + 12
67 + 12

0.046
0.170

History of CHD, %

15.6

14.1

15.4

0.931

36.7
16.5

37.9
14.6

39.8
15.9

0.301
0.778

...............................................................................................................................................................................

Antihypertensive treatment
ACE-inhibitors, %
ARBs, %
Beta-blockers, %

39.8

40.8

44.1

0.164

Calcium-channel blockers, %
Diuretics, %

17.7
36.2

17.1
44.4

18.8
46.7

0.648
0.001

0.2

2.7

,0.001

MR-blocker, %

...............................................................................................................................................................................
eGFR, mL/min per 1.73 m2
Serum sodium, mmol/L
Serum potassium, mmol/L
High sensitivity C-reactive protein, mg/L
Thyroid stimulating hormone, mU/mL
NT-proBNP, pg/mL

75.6 (64.588.1)
140.5 + 2.4
4.3 + 0.5
1.7 (0.8 4.1)
0.97 (0.621.47)
102.0 (57.3187.4)

74.7 (65.186.5)
140.5 + 2.4
4.3 + 0.5
1.7 (0.9 3.4)

71.4 (63.382.1)
140.3 + 2.7
4.4 + 0.7
1.6 (0.83.5)

1.01 (0.661.60)
82.4 (44.4154.7)

1.07 (0.731.54)
83.9 (43.2165.4)

0.018
0.397
0.119
0.685
0.170
0.005

...............................................................................................................................................................................

NYHA-classification, %

0.871

0
I

90.6
1.3

92.4
2.9

89.5
2.7

II

5.5

4.3

5.7

III

2.5

1.3

2.1

...............................................................................................................................................................................
Echocardiographic parameters
LV end-diastolic diameter, mm

48.2 + 5.5

49.0 + 5.6

49.0 + 5.7

0.032

LV end-systolic diameter, mm

29.9 + 5.3

30.5 + 5.4

30.4 + 5.5

0.182

LV end-diastolic volume, mL
LV end-systolic volume, mL

110.4 + 28.3
36.4 + 15.9

114.7 + 29.9
38.2 + 16.1

115.1 + 29.5
38.1 + 16.9

0.033
0.182

LV ejection fraction, %

61.6 + 6.2

61.8 + 6.2

61.5 + 6.1

Interventricular septum, mm
LV posterior wall, mm

12.0 (10.313.0)
10.9 + 1.6

12.0 (11.013.0)
11.3 + 1.7

12.0 (11.013.0)
11.4 + 1.7

,0.001
,0.001

LV mass, g

124.5 (85.5180.1)

146.8 (98.1205.4)

149.1 (101.2 217.5)

,0.001

LV mass index, g/cm2

109.4 + 24.3

116.9 + 25.9

116.7 + 26.6

,0.001

0.675

Continued

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Hyperlipidaemia, %

Page 5 of 10

Serum aldosterone and left ventricular remodelling

Table 1 Continued
Variable

Tertile 1
(<164.8 pmol/L)
n 5 525

Tertile 2
(164.8 224.8 pmol/L)
n 5 525

Tertile 3
(>224.8 pmol/L)
n 5 525

P Trend

...............................................................................................................................................................................
Relative wall thickness

0.46 + 0.1

0.47 + 0.1

0.47 + 0.1

0.046

...............................................................................................................................................................................
Patterns of LV-hypertrophy
Normal LV, %

,0.001

68.5

62.7

62.9

LV concentric remodelling, %

14.4

15.9

15.7

0.567

LV concentric hypertrophy, %
LV eccentric hypertrophy, %

4.2
12.9

4.4
16.9

5.5
15.9

0.377
0.308

None, %

20.2

18.1

23.2

Mild, %
Moderate, %

60.0
19.6

60.4
21.4

56.5
20.1

0.2

0.2

0.2

...............................................................................................................................................................................
DIAST-CHF grade of DDb

0.810

Values are given as mean with SD or as median (25th, 75th percentile) for continuous variables, and percentage for categorical data. Group differences (P for trend) were
calculated by ANOVA for continuous and x2 test for categorical variables. Tertiles are from baseline serum aldosterone concentration.
SAC, serum aldosterone concentration; PRC, plasma renin concentration; ARR, aldosterone to renin ratio; CHD, coronary heart disease; ACE, angiotensin converting enzyme;
MR blocker, mineralocorticoid receptor blocker; ARB, angiotensin-II type-1 receptor blocker; eGFR, estimated glomerular filtration according to the MDRD (modification of diet
in renal disease) formula to estimate GFR; LV, left ventricular.
a
Diabetes was classified according to the recommendations of the American Diabetes Association; bDIAST-CHF grade of DD (Grade of diastolic dysfunction).

Table 2 Correlation coefficients between serum aldosterone levels, aldostereon-to-renin ratio levels, N-terminal pro
B-type brain natriuretic peptide, and echocardiographic parameters of left ventricular function and structure
Variables

Overall (n 5 1575)

Women (n 5 849)

Men (n 5 726)

....................................

....................................

....................................

SAC

SAC

SAC

ARR

ARR

ARR

...............................................................................................................................................................................
SAC
ARR

0.236**

NT-proBNP

20.085*

LV ejection fraction
LV mass

20.035
0.133**

0.132**
20.009
20.020

0.231**
20.067
20.004
0.076*

0.040

0.063

0.092**

0.257**
20.054

20.027
20.012

20.034
0.015

0.168**
0.010
20.017

LV mass index

0.109**

0.043

0.034

0.076

Relative wall thickness

0.060*

20.027

0.075*

20.040

0.044

20.010

Interventricular septum
LV posterior wall

0.107**
0.125**

20.017
20.030

0.058
0.096**

20.071
20.033

0.050
0.038

0.067
20.018

LV end-diastolic diameter

0.061*

0.007

20.004

0.030

20.028

20.009

LV end-systolic diameter
LV end-diastolic volume

0.052*
0.060*

0.002
0.008

0.020
20.004

0.017
0.031

20.006
20.027

20.006
20.009

LV end-systolic volume

0.052*

0.003

20.021

0.019

20.006

20.006

SAC, serum aldosterone concentration; ARR, aldosterone-to-renin ratio; LV, left ventricular.
*P , 0.05; **P , 0.001.

thickness. No associations were observed between aldosterone

and echocardiographic parameters of the LV in men. No relationship was found between aldosterone and internal LV dimension in
either gender.
In an attempt to further assess the association between the SAC
and echocardiographic parameters, the overall cohort was

stratified according to gender-specific tertiles (T; each comprising

525 patients) of SAC. In fully adjusted ANCOVA, we noted a significant increase in LV mass (P 0.001), LV mass index (P
0.001), and relative wall thickness (P 0.011) values across
increasing values of SAC in the entire cohort (Figure 1). Moreover,
mean values of LV posterior wall thickness and interventricular

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Severe, %

Page 6 of 10

F. Edelmann et al.

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Figure 1 (A C) Distribution of left ventricular mass, left ventricular mass index and relative wall thickness values according to genderspecific tertiles of serum aldosterone concentration levels overall, in women and men, respectively (n 1575). Mean values for echocardiographic parameters of each ANCOVA-analysis are illustrated. ANCOVA models were adjusted for: age, gender, body mass index,
HDL-cholesterol, LDL-cholesterol, systolic blood pressure, serum sodium, serum potassium, N-terminal pro B-type brain natriuretic
peptide, detailed antihypertensive medication (ACE-inhibitor use, angiotensin II type-1 receptor blocker use, beta-blocker use, calcium-channel
blocker use, diuretic use, and mineralocorticoid receptor-blocker use), statin use, eGFRMDRD, diabetes mellitus, history of coronary heart
disease, high sensitive C-reactive protein, current smoking status, thyroid stimulating hormone, alcohol abuse, heart rate, history of cancer,
history of sleep apnea syndrome, chronic obstructive pulmonary disease, and plasma renin concentration. *P , 0.05.

Page 7 of 10

Serum aldosterone and left ventricular remodelling

Table 3 Logistic regression analysis relating plasma aldosterone levels (stratified in gender specific tertiles) to
abnormal geometric left ventricular patterns
LV
geometric
pattern

Overall

Women

Men

.................................................. .................................................. ..................................................

OR (95% CI) by
comparing SAC
gender-specific
tertile 2 with
tertile 1

OR (95% CI) by
comparing SAC
gender-specific
tertile 3 with
tertile 1

OR (95% CI) by
comparing SAC
gender-specific
tertile 2 with
tertile 1

OR (95% CI) by
comparing SAC
gender-specific
tertile 3 with
tertile 1

OR (95% CI) by
comparing SAC
gender-specific
tertile 2 with
tertile 1

OR (95% CI) by
comparing SAC
gender-specific
tertile 3 with
tertile 1

...............................................................................................................................................................................
Concentric remodelling
Model 1
Model 2

1.01 (0.771.34)
1.02 (0.771.35)

0.95 (0.72 1.26)

0.96 (0.72 1.27)

0.99 (0.68 1.45)

0.99 (0.69 1 .45)

1.05 (0.721.53)
1.04 (0.711.52)

1.04 (0.691.56)
1.05 (0.701.58)

0.84 (0.55 1.29)

0.84 (0.55 1.29)

Model 3

0.91 (0.651.24)

0.84 (0.60 1.18)

0.96 (0.59 1.56)

0.94 (0.581.52)

0.92 (0.561.51)

0.80 (0.49 1.31)

SAC per
log-SD

0.94 (0.82 1.08)

0.95 (0.781.15)

0.90 (0.72 1.13)

...............................................................................................................................................................................
Concentric hypertrophy
Model 1
Model 2

1.49 (1.102.02)
1.52 (1.122.07)

1.74 (1.28 2.35)

1.75 (1.29 2.36)

1.70 (1.12 2.58)

1.69 (1.11 2.57)

1.77 (1.17.2.67)
1.74 (1.152.63)

1.29 (0.822.01)
1.35 (0.862.11)

1.70 (1.10 2.65)

1.76 (1.13 2.75)

Model 3

1.63 (1.142.35)

1.87 (1.31 2.68)

1.56 (0.94 2.57)

1.62 (0.982.67)

1.72 (1.012.92)

2.06 (1.23 3.46)

SAC per
log-SD

1.22 (1.06 1.40)

1.22 (1.011.48)

1.22 (0.98 1.52)

...............................................................................................................................................................................
Eccentric hypertrophy
Model 1
Model 2

0.94 (0.671.32)
0.94 (0.671.32)

0.80 (0.56 1.13)

0.80 (0.56 1.13)

1.23 (0.76 2.01)

1.23 (0.76 2.01)

0.91 (0.551.52)
0.91 (0.551.52)

0.73 (0.451 16)

0.73 (0.451.16)

0.72 (0.44 1.16)

0.72 (0.45 1.16)

Model 3

1.08 (0.731.61)

0.86 (0.58 1.29)

1.53 (0.87 2.69)

0.93 (0.511.69)

0.64 (0.361.12)

0.69 (0.39 1.20)

SAC per
log-SD

0.94 (0.80 1.12)

0.89 (0.701.14)

0.94 (0.72 1.24)

Data represent odds ratios (OR) with 95% confidence interval (95% CI) relating different pathological pattern of LV geometry to gender-specific tertiles of serum aldosterone
concentration (SAC in pmol/L) by comparing high SAC levels within the second and third gender-specific tertile, respectively with SAC levels within the first (reference)
gender-specific tertile. Model 1: crude. Model 2: age-adjusted; Model 3: multivariate adjusted (according to ANCOVA models (Figure 1)).
Additionally, odds ratios (with 95% CI) for 1 SD increment in log-SAC (derived from multivariate adjusted model 3) for each abnormal LV geometric pattern are shown.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 26, 2015

ANVOCA models as stated above), patients in the highest genderspecific T of SAC were at a 1.9-fold increased risk of presenting
with a concentric LV hypertrophy (adjusted OR: 1.87, 95% CI:
1.31 2.68, P 0.001) compared with patients in the first genderspecific T of SAC. Gender-specific analysis revealed a significant
relation of higher SAC levels to increased risk of concentric LV
hypertrophy in both, women and men, respectively.
When SAC was evaluated as a continuous variable the association between SAC levels and concentric LV hypertrophy
remained highly significant (adjusted OR: 1.22, 95% CI: 1.06
1.40, per log SD increase in SAC levels, P 0.005). Furthermore,
these significant results did not materially change after exclusion of
76 (4.8%) participants, who were suggestive for primary aldosteronism (indicated by an ARR .35 pmol/L/mIU/mL and SAC
.300 pmol/L). The highest gender-specific T remained related
to a 1.7-fold increased risk of concentric LV hypertrophy compared with the first gender-specific T of SAC (P 0.012).
We found that the association between SAC and risk of concentric
LVH is modulated by gender distribution (P , 0.001), age (P ,
0.001), BMI (P 0.006), HDL-cholesterol (P 0.004), systolic BP
(P 0.006), serum sodium (P 0.006), NT-proBNP (P 0.003),

septum increased significantly from the first to the third genderspecific T of SAC (P , 0.001 for both).
Gender specific analyses revealed a significant association
between higher SAC levels and LV mass, LV mass index, relative
wall thickness and interventricular septum exclusively in women.
Left ventricular posterior wall thickness increased significantly
from the first (reference) gender-specific T of SAC to the third
T in both, men (P 0.046) and women (P 0.008), respectively.
Detailed multivariate adjusted analyses showed no significant
associations between ARR and echocardiographic parameters
(data not shown) overall and in either sex, respectively.
Left ventricular CR, concentric LV hypertrophy, and eccentric
LV hypertrophy were present in 30.5, 26.1, and 16.9% of the
study population. Table 3 shows the associations between higher
SAC levels and abnormal geometric LV patterns across the
whole cohort and stratified according to gender distribution
derived from logistic regression models. Across the whole
cohort and in gender-specific analysis, SAC levels in the highest
(third) gender-specific T were strong correlates of concentric LV
hypertrophy compared with the first (reference) T of SAC. After
multivariate adjustment (model 3; adjusted according to

Page 8 of 10
use of ACE-I (P 0.026), use of beta-blocker (P 0.013),
eGFRMDRD (P 0.001), and sleep apnea syndrome (P 0.006).
Overall, no significant association was seen for SAC and risk of
concentric LV remodelling and eccentric LV hypertrophy, respectively. Furthermore, no associations were found between ARR
levels and pathological patterns of LV geometry overall and in
either sex.

Discussion

were older, showed higher systolic/diastolic BP values and suffered

more frequently from diabetes compared with subjects from the
Framingham study. Aldosterone-related alterations of the LV structure when comparing different studies might be hampered by the
heterogeneity of study participants, i.e. differences in dietary salt
intake, investigated. Accumulating evidence mainly derived from
animal studies suggests that the combination of dietary salt
excess and high aldosterone contributes to the development of
cardiac fibrosis and hypertrophy independent of arterial BP and
ventricular loading.27 Two recent observational studies in
humans confirmed an increase in LV mass index in normo- and
hypertensive patients with both increasing urinary sodium and
aldosterone levels.28,29 Inappropriate downward adjustment of
aldosterone synthesis during high dietary salt intake, which typically
occurs in modern societies, may contribute to the development of
a relative aldosterone excess induced cardiac remodelling.30 In
addition, gender differences in LV adaption to pressure overload
might be in part due to oestrogen signalling in the myocardium
resulting in gender-specific differences of aldosterone-related variances of cardiac structure.31 Accordingly, a previous study showed
that MR-blockade reduces ischaemia-induced cardiac remodelling
and phenotypic alterations of gene expression to a greater
extent in females than in male rats.32
We observed a higher risk of concentric LV hypertrophy in both
men and women with increasing SAC levels independent of established LV-hypertrophic mediators. Previous studies however
reported inconsistent findings in this field. Muscholl et al.33 found
highest values of aldosterone in patients with LV remodelling and
eccentric LV hypertrophy. Schunkert et al.34 observed significantly
higher aldosterone levels in women with concentric or eccentric
hypertrophy compared with women with normal LV patterns.
Our investigation points to an association between aldosterone
and concentric LV hypertrophy, which is supported by the
observed reduction in the LV mass index after addition of MR
blockers in patients with concentric LV hypertrophy.35
In contrast to previous investigations, we did not find any association between higher ARR levels and both, LV structure and pathological patterns of LV geometry, respectively.36 In the Framingham
Offspring study, ARR was positively related to eccentric and concentric hypertrophy.37 This is in disagreement with our results and
it might be speculated that differences in dietary sodium intake,
prevalence of co-morbidities and aldosterone-renin determining
factors such as ongoing medication might impact aldosterone and
renin levels which results in contradicting findings.38 In particular,
a slight elevation of the PRC (or activity), which is the main determinant of the ARR is itself considered as an independent correlate
of cardiovascular outcome, due to intake of medication or the
presence of co-morbidities such as HF, might result in lower
ARR levels and presumably in less strong or absent associations
with functional and structural pattern of the LV.39 Moreover,
inconsistent cut-off values for pathological patterns of LV geometry and different laboratory methods used for aldosterone
and renin determination might damper comparability of
aldosterone-associated changes of the LV structure between
studies. However, previous investigations showed that the ARR
is one of the most important predictors of arterial BP, which is
in itself a powerful risk factor of LV hypertrophy.40 The consistent

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 26, 2015

In this large cohort of CV risk patients with preserved LVEF, we

demonstrated that higher circulating aldosterone but not ARR
levels were associated with increased levels of LV mass, LV mass
index, relative wall thickness, interventricular septum, and LV posterior wall thickness. These associations were stronger in women
and remained stable after consideration of several confounders
such as plasma renin levels, arterial hypertension, current medication, diabetes mellitus, BMI, and kidney function. In addition,
this is the first study to show in a large cohort of patients that
higher circulating aldosterone levels are independently correlated
with concentric LV hypertrophy in both men and women. This
relationship did not change materially after exclusion of those participants who were suggestive for primary aldosteronism and were
similar in patients with and without overt HF. Finally, gender distribution, age, BMI, HDL-cholesterol, systolic BP, serum sodium, NTproBNP, use of ACE-I, use of beta-blocker, eGFRMDRD, and sleep
apnea syndrome are crucial effect modifiers for SAC-related risk of
concentric LV hypertrophy.
Our findings indicate that excessive adrenal aldosterone
secretion in the setting of primary aldosteronism is not mandatory
for aldosterone-mediated alterations of the LV structure. This is in
line with previous findings of Tomaschitz et al.4,21 who documented that plasma aldosterone levels within the normal range predict
higher risk of fatal cardiovascular events and sudden cardiac death.
Thus, aldosterone-mediated alterations of the LV structure indicate an important role for mineralocorticoids in arrhythmogenesis.5 This concept is supported by significant LV hypertrophy
regression and antiarrhythmogenic effects of MR-blockers in
hypertensive and CHD patients.8,22
Most of the previous investigations regarding the associations
between higher circulating aldosterone levels and LV structure in
patients without confirmed primary aldosteronism revealed conflicting results. El-Gharbawy et al.23 noted no associations
between circulating aldosterone levels and cardiac mass in hypertensive Caucasians. Other cross-sectional studies showed a positive correlation between circulating aldosterone levels and LV
mass index.24,25 However, these investigations might have been
limited by small sample sizes and lacking of gender-specific analyses. In a large community-based investigation, Vasan et al.26 documented a significant association between plasma aldosterone levels
and LV posterior wall thickness and relative wall thickness exclusively in women. Interestingly, no association was seen for aldosterone and LV mass. In contrast to Vasan et al., we found robust
associations between echocardiographic parameters of LV structure including LV mass and LV mass index and SAC across the
whole cohort, but consistent associations were found exclusively
in women. However, the participants of the DIAST-CHF study

F. Edelmann et al.

Page 9 of 10

Serum aldosterone and left ventricular remodelling

Limitations
Findings regarding the association between circulating aldosterone
levels and echocardiographic LV structure should be treated with
caution. Since we did not measure structural parameters of the
right ventricle, no assumptions about the association of aldosterone and the right heart structure and geometry can be made.
Local extra-adrenal aldosterone synthesis, a complex cross-talk
between aldosterone and angiotensin II and the aldosteronecortisol interplay at MR-level might not be accurately reflected
by a one-time aldosterone measurement in serum or plasma. In
addition dietary salt intake has not been evaluated. Several other
factors, which have been shown to interfere with aldosterone
and renin levels, i.e. ongoing medication, might have confounded
our analysis.38 The determination of 24-h urinary aldosterone
excretion is superior to the measurement of serum/plasma aldosterone levels in estimating the integrated daily exposure to aldosterone.28 It is also important to stress that the cross-sectional
design of our analysis does not enable conclusions with regard
to causal relationships. However, the findings of our analyses in a
large sample of CV risk patients with preserved LV EF might be
extrapolated to a broader population within the related age class
and is strengthened by gender-specific analyses and the consideration of a panel of established confounders.

Conclusions
The association of unremarkable circulating aldosterone levels with
parameters of LV structure favours the notion of potential
aldosterone-mediated effects on the cardiovascular system in the
absence of primary aldosteronism. Mechanistic studies however
are warranted to elucidate both the permissive milieu and mechanisms beyond aldosterone-driven effects on the myocardium. Our
findings further support the idea that MR-blockade may delay or

prevent the occurrence of abnormal patterns in patients with preserved LV EF, which warrants further observational and interventional studies in this field.

Funding
This work was supported by grants from the German Federal Ministry
of Education and Research (German Heart Failure Network), TP 7
(FKZ 01GI0205) and the German Diabetes Foundation.
Conflict of interest: none declared.

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association between SAC and echocardiographic parameters of

LV structure even after consideration of PRC levels in the
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stimulators of aldosterone secretion such as ACTH, parathyroid
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