Serum Aldosterone Concentration, Blood pressure, and Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis

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Title

Serum Aldosterone Concentration, Blood Pressure, and Coronary Artery Calcium: The

Multi-Ethnic Study of Atherosclerosis.

Permalink

https://escholarship.org/uc/item/648289g3

Journal

Hypertension, 76(1)

Authors

Inoue, Kosuke

Goldwater, Deena

Allison, Matthew

et al.

Publication Date

2020-07-01

DOI

10.1161/HYPERTENSIONAHA.120.15006

Peer reviewed

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University of California

Serum Aldosterone Concentration, Blood pressure, and

Coronary Artery Calcium: Multi-Ethnic Study of Atherosclerosis

Kosuke Inoue, MD

, Deena Goldwater, MD, PhD

2,3

, Matthew Allison, MD, MPH

, Teresa

Seeman, PhD

1,3

, Bryan R. Kestenbaum, MD, MS

, Karol E. Watson, MD, PhD

Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA

Department of Medicine, Division of Cardiology, UCLA, Los Angeles, CA

Department of Medicine, Division of Geriatrics, UCLA, Los Angeles, CA

Department of Family Medicine and Public Health, Division of Preventive Medicine, UCSD, San

Diego, CA

Kidney Research Institute, Division of Nephrology, Department of Medicine, University of

Washington, Seattle, WA

Abstract

Aldosterone is a steroid hormone regulating fluid and electrolyte homeostasis and is known

to increase the risk of atherosclerosis. In this study, we examined the associations of serum

aldosterone concentrations with subclinical atherosclerosis and all-cause mortality. This study

included 948 adults aged 46–88 years from the Multi-Ethnic Study of Atherosclerosis (MESA)

with measurements of serum aldosterone and plasma renin activity (PRA) and not taking

antihypertensive medications. Coronary calcification was longitudinally assessed using Agatston

coronary artery calcium (CAC) score from computed tomography scans. All-cause mortality was

ascertained from the medical record. The average age (SD) was 62.3 (9.4) years, and 53% were

male. Among 700 subjects who had follow-up CAC score (median follow-up of 6.4 years), higher

aldosterone levels (per 100 pg/ml) were associated with higher CAC (relative ratio, 1.17; 95%

confidence interval [CI], 1.04–1.32), with the association being most prominent in males with

suppressed PRA (≤0.5 μg/L). Systolic or diastolic blood pressure mediated around 45% of the

total effect of aldosterone on CAC. Over a median follow-up of 12.5 years (120 deaths identified

among 948 subjects), aldosterone was associated with the increased risk of all-cause mortality

when PRA was suppressed; hazard ratio per 100 pg/ml, 1.70; 95% CI, 1.10–2.63. In this study, we

found that higher aldosterone levels were associated with the increased risk of subclinical coronary

atherosclerosis and all-cause mortality particularly when renin was suppressed. Our findings

indicate the importance of aldosterone levels (even within the reference range) with respect to the

cardiovascular system and overall health.

Corresponding author: Kosuke Inoue, MD, Department of Epidemiology, UCLA Fielding School of Public Health, 650 Charles E.

Young Dr. South, Los Angeles, CA 90095, Phone: 310-206-7458 Fax: 310-206-6039, [email protected].

Disclosures: None.

HHS Public Access

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Published in final edited form as:

Hypertension

. 2020 July ; 76(1): 113–120. doi:10.1161/HYPERTENSIONAHA.120.15006.

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Keywords

Aldosterone; Coronary artery calcium; Blood pressure; Mediation analysis; Mortality; Multi-

ethnic atherosclerosis study

Introduction

Aldosterone is a steroid hormone that contributes to the regulation of sodium reabsorption,

water retention, and blood pressure control.

Primary aldosteronism, characterized by

elevated aldosterone concentrations and suppressed renin activity, is a major cause of

secondary hypertension.

The associations of aldosterone with long-term adverse health

outcomes including cardiovascular events and mortality have been demonstrated in high-

risk populations such as patients with congestive heart failure,

3–7

acute myocardial

infarction,

7–10

and coronary artery disease.

The association between aldosterone and

atherosclerosis has also been widely shown on animal models,

12,13

but is still controversial

in humans.

11,14,15

Moreover, since aldosterone levels are usually only measured when its

excess (i.e. primary aldosteronism) is suspected, much less is known about the long-term

health outcomes of increasing aldosterone concentrations among the general population and

even less is known about the consequences of higher aldosterone levels within the reference

range.

Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and strongly

predicts atherosclerotic cardiovascular disease events.

While previous studies have

evaluated the association of aldosterone with subclinical atherosclerosis makers such as

carotid intima-media thickness (IMT) and ankle-brachial index (ABI),

its association

with CAC is incompletely explored. Given the strong association between aldosterone and

blood pressure, it is important to clarify the extent to which blood pressure mediates the

relationship between aldosterone and cardiovascular disease.

In the present study, using data from the Multi-Ethnic Study of Atherosclerosis (MESA),

we investigated the longitudinal association between serum aldosterone concentrations and

CAC. Given that plasma renin activity (PRA) could be one of the indicators of autonomous

aldosterone secretion and mineralocorticoid receptor activity,

18–20

we also investigated the

association stratified by PRA levels. Then, using causal mediation analysis, we examined the

extent to which an increase in blood pressure mediates the association between aldosterone

and CAC. Finally, we investigated the association between serum aldosterone concentrations

and all-cause mortality.

Methods

Data Sources and Study Population

The data of this study can be accessed at https://www.mesa-nhlbi.org. MESA is a

multicenter longitudinal cohort study of 6,814 community-dwelling adults aged 45–84

years free from overt CV disease at baseline from six communities (Baltimore, Maryland;

Chicago, Illinois; Forsyth County, North Carolina; Los Angeles, California; New York, New

York; and St. Paul, Minnesota).

Its main goal was to investigate risk factors related to the

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development and progression of cardiovascular disease and incident cardiovascular events.

Participants were recruited between July 2000 and August 2002 with a longitudinal follow-

up through July 2015. The Institutional Review Boards of all participating institutions

approved the study protocols and consent procedures. More detail about MESA study design

and recruitment is described elsewhere.

As part of an ancillary study investigating renal artery calcification, a random sample of

1,960 participants had aldosterone and PRA levels measured at either visit 2 (between

September 2002 and February 2004) or 3 (between March 2004 and September 2005).

18,22

Among the 1,960 participants, we excluded participants if either aldosterone or PRA was

missing (n=185), or if the CAC score was missing at the visit when aldosterone and

PRA were measured (i.e. visit 2 or 3) (n=52). We further excluded participants with

antihypertensive medications (n=775) as these medications impact aldosterone and PRA

levels. Among the final analytical cohort who had mortality follow-up data (n=948), 700

subjects (74%) had CAC score measured at either visit 4 or 5.

Aldosterone levels and renin activity

Aldosterone and PRA were measured two times using competition-based radioimmunoassay

(DiaSorin) and radioimmunoassay (DiaSorin), respectively.

PRA was defined as

nanograms of angiotensin I generated per milliliter of sample per hour (ng/mL/h = μg/L/

h).

Aldosterone-renin ratio (ARR) was calculated by dividing aldosterone by PRA. In

addition, we dichotomized participants based on PRA; i.e. suppressed renin phenotype,

PRA ≤0.5 μg/L/h; intermediate to unsuppressed renin phenotype, PRA >0.5 μg/L/h.

combined intermediate and unsuppressed phenotype to keep statistical power in our main

analysis.

Blood pressure

Blood pressure was measured 3 times with the participant in a seated position using a

Dinamap Pro 1000 automated oscillometric sphygmomanometer (Critikon, Tampa, FL). The

mean of the last 2 measurements were used in our analysis as previous studies did.

18,22

divided both the systolic and diastolic blood pressure by 10 to facilitate result interpretation

as per 10 mmHg increase in systolic or diastolic blood pressure.

Outcomes

The primary outcome was CAC score at either visit 4 (between September 2005 and June

2007) or visit 5 (between April 2010 and December 2011). Each participant underwent

two coronary artery computed tomography (CT) scans, and all CT scans were read at the

Harbor-UCLA Research and Education Institute in Torrance, California.

The Agatson

score was calculated for each scan (phantom adjusted) and the mean of the two CAC scores

was employed in the analysis.

23,24

The same approach was used to measure CAC at visit

2 and 3. The secondary outcome was all-cause mortality ascertained from the medical

record. Two physicians from the MESA study events committee independently reviewed

all the medical records for endpoint classification using prespecified criteria for all-cause

death. In this study, we did not assess cardiovascular events due to the small number of the

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outcome. A detailed description of the follow-up methods is available on the MESA website

(www.mesa-nhlbi.org).

Covariates

At each visit, participants completed self-administered questionnaires which include age,

sex (male, female), race/ethnicity (White, Chinese American, African American, Hispanic),

education status (≤11 grade, high school to college, associate’s or bachelor’s or professional

degree), health insurance (yes, no), annual income (<$30,000, $30,000 to $75,000,

>$75,000), smoking status (never, former, current), alcohol intake (yes, no), physical activity

levels (MET-min/week), and medication intake. Body mass index (BMI) was measured by

trained staff. Fasting peripheral blood samples were obtained after 12-hour overnight fasting

and at least 5 minutes of the seated posture. Specimens were immediately flash-frozen,

processed, and stored at −80 °C.

Serum and urinary sodium and potassium were measured

at visit 1 as previously described.

18,25

Estimated glomerular filtration rate (eGFR) was

calculated from serum creatinine measurements employing the Chronic Kidney Disease

Epidemiology Collaboration equation.

Statistical analyses

First, we described baseline characteristics among the total study sample, suppressed renin

phenotype group, and intermediate to unsuppressed renin phenotype group. Second, we

examined the cross-sectional association between serum aldosterone concentrations and

systolic or diastolic blood pressure (at baseline; i.e. the same visit at which aldosterone was

measured [visit 2 or 3]) using ordinary least squares (OLS) regression after we confirmed

that blood pressures were almost normally distributed. Third, we examined the association

between serum aldosterone concentrations (at visit 2 or 3) and CAC score (at visit 4 or

5) using multivariable negative binomial regression models to account for a right-skewed

distribution of CAC score. The analysis was conducted for the total population and each

renin phenotype subgroup. We first adjusted for age, sex, CAC score at visit 2 or 3, and

time from aldosterone measurement to coronary CT scan at visit 4 or 5 (Model 1). As the

main model, we further adjusted for race, education, insurance, annual income, smoking

status, alcohol use, physical activity, statin prescription, BMI, low-density lipoprotein

(LDL), serum sodium and potassium levels, urinary sodium and potassium levels, and

plasma renin activity in addition to covariates in Model 1 (Model 2: main model). Missing

covariate values were replaced using a multiple imputation algorithm that included all of the

abovementioned covariates in the model.

Then, we examined the dose-response association between serum aldosterone concentrations

and the relative ratio of CAC by fitting a restricted cubic spline model with three knots

at 10

, 50

, and 90

percentile of aldosterone concentrations.

Given the difference in

the CVD risks according to sex and age,

29,30

stratum-specific analyses were conducted to

estimate the effects of aldosterone on subclinical atherosclerosis by sex (male, female),

age (≤60 years, >60 years), and both (i.e. 2×2=4) categories. In addition, using the causal

mediation analysis,

31,32

we aimed to quantify the degree to which systolic and diastolic

blood pressure mediates the association between aldosterone and subclinical atherosclerosis.

We employed a marginal structural approach within the counterfactual framework and

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the mediated proportion was computed as the pure natural indirect effect divided by the

total effect (IE/TE).

31,32

Bias-corrected 95% confidence intervals (CIs) were estimated by

repeating the analysis on 200 bootstrapped samples.

Finally, multivariable Cox proportional hazards regression models were employed adjusting

for potential confounders to generate hazard ratios (HRs) of all-cause mortality for 100

pg/ml increase in serum aldosterone among the total population and subgroups based on

renin phenotypes. All analyses were performed using Stata, version 15 (Stata-Corp). The

study was exempted from human subjects review by the institutional review board at the

University of California, Los Angeles.

Sensitivity analyses—We conducted a series of sensitivity analyses. First, to evaluate

whether our findings can generalize to people without high aldosterone concentrations,

we restricted participants to those with aldosterone <200 pg/ml.

Second, to assess the

robustness of our findings, we additionally adjusted for fasting glucose levels and eGFR

(Model 3) as well as smoking status and alcohol use at visit 4 or 5 (Model 4) assuming

that these risk factors of atherosclerosis might not be affected by aldosterone concentrations

at baseline. We also estimated the effect of aldosterone on the absolute change in CAC

score from baseline (i.e. visit 2 or 3) to visit 4 or 5. Lastly, we analyzed the data using

logistic regression for the following two dichotomized outcomes; i) CAC>0 vs CAC=0 and

ii) CAC>300 vs CAC≤300.

Additional analyses—To further understand our findings from the context of the renin-

angiotensin-aldosterone system (RAAS), we dichotomized subjects based on both ARR and

aldosterone levels (ARR>200 pg/ml per μg/L/h and aldosterone >150 pg/ml) according to

the previous literature about primary aldosteronism.

2,33

Then, we run the negative binomial

regression models to estimate the relative ratio of CAC and Cox proportional hazard models

to estimate HR of all-cause mortality among these categories. We also analyzed the data

using the same approach by categorizing subjects into 4 groups based on PRA and serum

aldosterone concentrations (i.e. suppressed PRA & low aldosterone, suppressed PRA &

high aldosterone, unsuppressed PRA & low aldosterone, and unsuppressed PRA & high

aldosterone). In this analysis, we defined high aldosterone when they showed >150 pg/

ml.

2,33

Results

The mean ± standard deviation (SD) age of participants was 62.3 ± 9.4 years, and

53% were male. Baseline characteristics are shown in Table 1. The median [interquartile

range] aldosterone concentrations and PRA were 127.1 [90.6–173.3] pg/ml and 0.5

[0.3–0.9] μg/L/h, respectively. Among 948 participants, 218 (23%) had both aldosterone

concentrations >150 pg/ml and ARR>200 pg/ml per ng/ml/h, and 129 (14%) showed

systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg at baseline.

Individuals with suppressed renin phenotype were more likely to be older, female, African

American, and less physically active compared to intermediate or unsuppressed renin

phenotype.

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Aldosterone, Blood pressure, and subclinical atherosclerosis

Among 700 subjects with coronary CT scans, the median duration of follow-up for

CAC ascertainment was 6.4 (interquartile range, 6.1–7.6) years. After adjusting for

potential confounders, we found a positive linear relationship of serum aldosterone

concentrations (per 100 pg/ml) with systolic blood pressure (coefficient, 2.46; 95% CI,

0.81–4.12; p-value=0.004) and diastolic blood pressure (coefficient, 1.91; 95% CI, 1.06–

2.78; p-value<0.001) (Figure S1). We also found a significant association between higher

aldosterone concentrations and higher CAC score (relative ratio, 1.17; 95% CI, 1.04–1.32).

The association between aldosterone (per 100 pg/ml increase) and CAC was prominent in

subjects with suppressed renin phenotype (relative ratio, 1.41; 95% CI, 1.11–1.81; p for

interaction, 0.05) (Table 2). Moreover, we found the dose-response association between

increasing aldosterone and CAC (Figure 1).

In stratified analyses, we found a modestly larger magnitude of the association between

aldosterone and CAC score among males as compared to females with suppressed renin

phenotype (male: relative ratio, 1.67; 95% CI, 1.20–2.32; female: relative ratio, 1.21; 95%

CI, 0.68–2.12) (p for interaction = 0.002) (Table 3). The sex difference was observed

among subjects aged ≤60 years when we further stratified by age (Table S1). In mediation

analyses, we estimated that systolic or diastolic blood pressure mediated 43% or 48% of the

association between increasing aldosterone concentrations and subclinical atherosclerosis,

respectively (Figure 2).

Our findings were not qualitatively affected by restricting participants to those with serum

aldosterone concentrations <200 pg/ml (Table S2). The results were also consistent when

we additionally adjusted for covariates which can be both mediators and confounders (Table

S3) or when we used a change in CAC score as an outcome (Table S4). In the logistic

regression analysis, while we did not find the association between increasing aldosterone

and the presence of CAC (i.e. CAC >0), the association was found between increasing

aldosterone and the presence of high CAC score (i.e. CAC>300) (Table S5). This association

was also prominent among subjects with suppressed renin phenotype, but 95% CI was wide.

Aldosterone and mortality

Among 948 subjects, the median duration of follow-up for mortality ascertainment was

12.5 (interquartile range, 11.9–13.3) years, during which 120 deaths from all causes were

identified (13%). After adjusting for potential confounders, we did not find the association

between serum aldosterone concentrations and all-cause mortality (Table S6). However,

when we stratified by renin phenotype, serum aldosterone concentrations among subjects

with suppressed renin phenotype were associated with risk for all-cause mortality (HR,

1.70; 95% CI, 1.10–2.63). In contrast, we found a decreased risk of all-cause mortality in

individuals with elevated aldosterone concentrations and unsuppressed renin phenotype.

Additional analyses

We found the consistent results when we analyzed the data with categorical exposures: i.e.

subjects with high ARR and high aldosterone showed the significant association with higher

CAC and increased risk of mortality (only among PRA suppressed group for mortality)

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compared to others (Table S7), and subjects with low PRA and high aldosterone showed the

highest relative ratio of CAC and hazard ratio of all-cause mortality (Table S8).

Discussion

Using a prospective longitudinal cohort from the multiethnic population, we found the

association between higher serum aldosterone concentrations and higher levels of CAC

measured 6–7 years later. The association was most prominent in participants with

suppressed renin phenotype, particularly among males. We also found a dose-response

relationship between aldosterone and CAC, supporting a possible causal relationship

between aldosterone and subclinical atherosclerosis. Blood pressure mediated around

45% of the association. These findings highlight the potential health burden of elevated

aldosterone concentrations particularly with renin suppression phenotype and the importance

of the management targeting blood pressure control to prevent cardiovascular disease due to

aldosterone.

To the best of our knowledge, this is the first study to investigate the association of serum

aldosterone concentration with CAC scores among an ethnically diverse population without

antihypertensive medication and free of cardiovascular disease at baseline. A recent meta-

analysis revealed that patients with primary aldosteronism showed the increased risk of

stroke, coronary artery disease, atrial fibrillation, and heart failure compared to patients

with essential hypertension.

Moreover, aldosterone has been associated with subclinical

atherosclerosis makers including IMT and ABI among patients with primary aldosteronism

or essential hypertension.

17,34,35

However, little is known about the association between

aldosterone and CAC. Given the important role of CAC as a non-invasive marker of

subclinical atherosclerosis which strongly predicts the risk of cardiovascular events,

our

findings advance the current state of knowledge about the potential effect of aldosterone

on subclinical atherosclerosis. Moreover, aldosterone concentrations were associated with

the increased risk of all-cause mortality only among renin suppression phenotype. The

inconsistent results between suppressed and unsuppressed renin phenotype could be due to

the possibility that some individuals with suppressed renin phenotype might have subclinical

primary aldosteronism.

18,20

Previous studies have shown the associations of aldosterone

with mortality among individuals with prevalent CVD.

3–6,8,9

A recent study using the

Jackson Heart Study showed that aldosterone was associated with CVD and mortality

among African Americans without prevalent CVD. Our findings from the multiethnic

population free of CVD allow us to generalize the idea that high aldosterone concentrations

might increase the long-term adverse health outcomes even among individuals with low-risk

of CVD.

We found a larger association between aldosterone and subclinical atherosclerosis among

males as compared to females with renin suppression phenotype. This sex heterogeneity

remained in the younger group but not the older group when we additionally stratified by

age. These findings may be due to dynamic changes in sex hormones in females before and

after menopause, as premenopausal females are relatively protected from CVD as compared

to males of the same age while postmenopausal females are not.

In addition, a recent

study found that endothelial cell mineralocorticoid receptor deletion significantly reduced

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atherosclerotic vascular inflammation only in male mice.

Taken together, we may need to

consider the potential cardiovascular burden of aldosterone differently based on sex and age.

Although we could not perform a stratified analysis by race due to insufficient statistical

power, future research is needed to entangle the race-specific association given the reported

difference in the association between aldosterone and blood pressure by race/ethnicity.

It has been well known that aldosterone increases the risk of acute ischaemic events

both directly and indirectly (mostly mediated by hypertension),

but few epidemiological

studies have sufficiently quantified these two pathways separately. Previous research has

shown an increased risk of hypertension and cardiovascular disease in patients with

primary aldosteronism mainly due to the excessive stimulation of the mineralocorticoid

receptor.

37–42

Our findings from the mediation analysis support that the management

targeting blood pressure might be effective to prevent subclinical atherosclerosis due to

the activation of aldosterone system. Meanwhile, it is also noteworthy that not all effects

of aldosterone could be explained by elevated blood pressure. Based on the previous

biological studies, aldosterone induces vascular calcification mediated through genomic

responses (e.g., activation of osteoinductive signaling, oxidative stress, inflammation, and

vascular smooth muscle cells apoptosis) and non-genomic responses (e.g. activation of

mitogen-activated protein kinase signaling and protein kinase C signaling).

43,44

Given these

mechanisms, our findings highlight the importance of considering the potential burden of

elevated aldosterone levels on cardiovascular system not through hypertension.

Our study has several limitations. First, we have only a single measurement of aldosterone,

and therefore, it was not possible to consider any trends or changes in aldosterone levels

over follow-up. In this context, the present study does not provide information as to the

clinical effectiveness of reducing aldosterone levels among the study sample. Second, in our

mediation analysis, the exposure-mediator association is not well defined temporarily, and

therefore, we need to consider the possibility of reverse causation (i.e. blood pressure levels

might affect aldosterone concentrations). However, given the negative feedback system of

RAAS, this temporality is likely to induce bias towards the null. Third, we assumed that

there were no other unmeasured confounders and no confounding between the mediator

and outcome as affected by exposure.

Given the reported associations of aldosterone with

obesity, glucose metabolism, adipokines, and renal function,

38,45,46

such metabolic factors

can be confounders between blood pressure and subclinical atherosclerosis affected by

aldosterone. More advanced mediation analysis with multiple mediators would be helpful

to disentangle the causal pathway from aldosterone to cardiovascular disease in future

research.

Perspectives

Higher aldosterone concentrations are associated with the increased risk of subclinical

coronary atherosclerosis and all-cause mortality particularly among individuals with renin

suppression. Increase in blood pressure substantially, but not entirely, mediated the effect of

increasing aldosterone on subclinical atherosclerosis. Our findings indicate the importance

of aldosterone levels (even within the reference range) with respect to the cardiovascular

system and overall health. Future studies with a larger sample and longitudinal measures

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of aldosterone concentrations are warranted to overcome the limitations of our studies, to

replicate and validate our findings, and establish causality including sequential mediating

effects of metabolic disorders and blood pressure levels on the pathway from serum

aldosterone concentrations to long-term adverse health outcomes.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

Acknowledgement:

The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable

contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-

nhlbi.org.

Funding/Support:

KI was supported by the Summer Research Fellowship Award from the Endocrine Society, the Burroughs

Wellcome Fund Interschool Training Program in Chronic Diseases (BWF-CHIP), and a Graduate Student

Fellowship from the Department of Epidemiology at the UCLA Fielding School of Public Health. The MESA

study was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-

HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168

and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040,

UL1-TR-001079, and UL1-TR-001420 from NCATS. Study sponsors were not involved in study design, data

interpretation, writing, or the decision to submit the article for publication. The funders had no role in the design

and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or

approval of the manuscript; and decision to submit the manuscript for publication.

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Novelty and Significance

What Is New?

•

This study firstly showed that aldosterone was associated with higher CAC

among an ethnically diverse population without antihypertensive medication

and free of cardiovascular disease at baseline.

•

The association was most prominent in males with suppressed renin

phenotype.

•

Our mediation analysis revealed that elevated blood pressure mediated around

45% of this association.

What Is Relevant?

•

Our findings highlight the potential health burden of elevated aldosterone

concentrations particularly with renin suppression phenotype and the

importance of the management targeting blood pressure control to prevent

cardiovascular disease due to aldosterone.

Summary

•

Higher aldosterone levels are associated with the increased risk of subclinical

coronary atherosclerosis and all-cause mortality particularly when renin was

suppressed.

•

Future investigation regarding the potential benefit of controlling aldosterone

levels (even within the reference range) with respect to the cardiovascular

system and overall health would be warranted.

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Figure 1.

Dose-response association between serum aldosterone concentrations and CAC

Association between aldosterone and CAC using a restricted cubic spline regression model

with three knots at 10

, 50

, and 90

percentile of serum aldosterone concentrations.

Negative binomial regression model was employed adjusting for age, sex, CAC at exam 2 or

3, race, education, insurance status, income, smoking status, alcohol intake, physical activity,

statin prescription, BMI, LDL, serum sodium, serum potassium, urinary sodium, urinary

potassium, plasma renin activity, and time from aldosterone measurement to CAC follow-up.

The dashed lines represent the 95% CIs for the spline model (reference is 50 pg/ml). We

restricted the range of aldosterone to below 300 pg/ml because predictions >300pg/ml are

based on too few data points.

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Figure 2.

Direct and Indirect effects of serum aldosterone concentrations on coronary artery calcium

score via 10mmHg increase in blood pressure

CAC, coronary artery calcium score; CI, confidence interval.

Adjusted for age, sex, CAC at exam 2 or 3, race, education, insurance status, income,

smoking status, alcohol intake, physical activity, statin prescription, BMI, LDL, serum

sodium, serum potassium, urinary sodium, urinary potassium, plasma renin activity, and

time from aldosterone measurement to CAC follow-up. Relative ratio of CAC at follow-up

is calculated per 100 pg/ml increase in serum aldosterone concentrations. 200 iterations were

performed for bootstrapping to estimate 95% CI.

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Inoue et al. Page 16

Table 1.

Baseline Characteristics of Study Participants

Variables Total

Suppressed Renin Phenotype

(PRA ≤ 0.5)

Unsuppressed Renin Phenotype

(PRA > 0.5)

N of participants 948 467 481

Age 62.3 ± 9.4 64.3 ± 9.6 60.4 ± 8.8

Male, N (%) 498 (52.5) 198 (41.2) 283 (58.8)

Race/ethnicity, N (%)

White 395 (41.7) 187 (40.0) 208 (43.2)

Chinese American 151 (15.9) 74 (15.9) 77 (16.0)

African American 136 (14.4) 101 (21.6) 35 (7.3)

Hispanic 266 (28.1) 105 (22.5) 161 (33.5)

Education status, N (%)

≤11 grade 160 (16.9) 79 (16.9) 81 (16.9)

High school to college 361 (38.0) 182 (39.0) 179 (37.3)

Associate’s, bachelor’s, or professional

degree

426 (45.0) 206 (44.1) 220 (45.8)

Annual income, N (%)

<$30,000 290 (31.6) 149 (33.3) 141 (31.6)

$30,000 to $75,000 388 (42.2) 183 (40.9) 205 (42.2)

>$75,000 241 (26.2) 115 (25.7) 126 (26.2)

Health insurance, N (%) 683 (72.1) 322 (69.1) 361 (75.1)

Smoking status, N (%)

Never 483 (51.2) 249 (53.4) 234 (49.0)

Former 339 (35.9) 164 (35.2) 175 (36.6)

Current 122 (12.9) 53 (11.4) 69 (14.4)

Alcohol use, N (%) 521 (55.0) 244 (52.4) 277 (57.6)

Physical activity, MET-min/week, Median

[Interquartile range]

3885 [2040–7003] 3630 [2145–6675] 4080 [2015–7230]

BMI, kg/m

27.2 ± 4.9 27.0 ± 4.8 27.3 ± 5.0

Systolic blood pressure, mmHg 118.6 ± 18.5 122.9 ± 19.3 114.4 ± 16.8

Diastolic blood pressure, mmHg 69.4 ± 9.5 70.2 ± 9.8 68.7 ± 9.1

Serum sodium, mEq/l 147.1 ± 3.4 147.0 ± 3.4 147.1 ± 3.3

Serum potassium, mEq/l 4.3 ± 0.3 4.4 ± 0.4 4.3 ± 0.3

Fasting glucose, mg/dl 95.5 ± 26.9 93.7 ± 23.5 97.2 ± 29.8

eGFR, mL/min/1.73 m

75.3 ± 14.0 74.5 ± 13.8 76.1 ± 14.1

LDL, mg/dl 116.1 ± 29.9 115.5 ± 30.3 116.6 ± 29.4

Statin prescription 132 (13.9) 50 (10.7) 82 (17.1)

Urinary sodium, mmol/l 104.9 ± 53.9 103.6 ± 53.7 106.1 ± 54.1

Urinary potassium, mmol/l 56.2 ± 30.8 54.1 ± 31.3 58.3 ± 30.1

Aldosterone concentration, pg/ml

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Inoue et al. Page 17

Variables Total

Suppressed Renin Phenotype

(PRA ≤ 0.5)

Unsuppressed Renin Phenotype

(PRA > 0.5)

Mean ± Standard deviation 139.7 ± 70.9 118.3 ± 52.8 160.5 ± 79.6

Median [Interquartile range] 127.1 [90.6–173.3] 109.3 [80.1–147.6] 147.3 [109.0–194.9]

PRA, μg/L per h

Mean ± Standard deviation 0.7 ± 0.7 0.3 ± 0.1 1.1 ± 0.7

Median [Interquartile range] 0.5 [0.3–0.9] 0.3 [0.2–0.4] 0.9 [0.7–1.3]

ARR

Mean ± Standard deviation 518 ± 1597 874 ± 2219 173 ± 98

Median [Interquartile range] 243 [148–408] 395 [267–710] 157 [104–217]

BMI, body mass index; eGFR, estimated glomerular filtration rate; PRA, plasma renin activity; ARR, aldosterone-renin ratio (pmol/L)/(μg/L per

h); CAC, coronary artery calcium score.

Mean ± standard deviation was described for continuous variables, otherwise indicated.

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Table 2.

Association between serum aldosterone concentrations and CAC.

Estimates

Adjusted relative ratio [95% CI]

*, †, ‡

Model 1

Model 2

‖

Total

700 1.25 [1.12–1.40] 1.17 [1.04–1.32]

Renin phenotype

PRA ≤ 0.5 338 1.58 [1.30–1.93] 1.41 [1.11–1.81]

PRA > 0.5 362 1.14 [1.01–1.29] 1.14 [1.00–1.30]

P for interaction 0.001 0.05

CAC, coronary artery calcium score; CI, confidence interval.

Relative ratio of CAC at exam 4 or 5 (follow-up) is calculated per 100 pg/ml increase in serum aldosterone concentrations.

†

Negative binomial regression model was employed to estimate relative ratio accounting for a right-skewed distribution of CAC at follow-up.

‡

All models were adjusted for time from aldosterone measurement to CAC follow-up.

Adjusted for age, sex, and CAC at exam 2 or 3 (baseline).

‖

Adjusted for race, education, insurance status, income, smoking status, alcohol intake, physical activity, statin prescription, BMI, LDL, serum

sodium, serum potassium, urinary sodium, urinary potassium, and plasma renin activity in addition to covariates in Model 1.

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Inoue et al. Page 19

Table 3.

Association between serum aldosterone concentrations and CAC stratified by sex or age.

Estimates

Adjusted relative ratio [95% CI]

*, †, ‡

P for interaction

Male Female

Total

1.23 [1.04–1.45] 1.00 [0.84–1.20] 0.06

PRA ≤ 0.5

1.67 [1.20–2.32] 1.21 [0.68–2.12] 0.002

PRA > 0.5

1.10 [0.90–1.35] 1.05 [0.82–1.34] 0.77

Age ≤60 years Age >60 years

Total

1.25 [1.04–1.51] 1.19 [1.00–1.42] 0.66

PRA ≤ 0.5

0.62 [0.36–1.04] 1.67 [1.15–2.43] 0.11

PRA > 0.5

1.38 [1.10–1.74] 1.08 [0.86–1.35] 0.21

CAC, coronary artery calcium score; CI, confidence interval.

Relative ratio of CAC at follow-up is calculated per 100 pg/ml increase in serum aldosterone concentrations.

†

Negative binomial regression model was employed to estimate relative ratio accounting for a right-skewed distribution of CAC.

‡

Adjusted for age, sex, CAC at exam 2 or 3, race, education, insurance status, income, smoking status, alcohol intake, physical activity, statin

prescription, BMI, LDL, serum sodium, serum potassium, urinary sodium, urinary potassium, plasma renin activity, and time from aldosterone

measurement to CAC follow-up.

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