American Journal of Preventive Cardiology 14 (2023) 100494

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American Journal of Preventive Cardiology

journal homepage: www.journals.elsevier.com/american-journal-of-preventive-cardiology

Original Research

The role of aldosterone and ideal cardiovascular health in incident

cardiovascular disease: The Jackson heart study
Bjorn Kluwe a, 1, Neal Pohlman a, 1, Veena Kesireddy b, Songzhu Zhao c, Yubo Tan c, David Kline d,
Guy Brock c, James B. Odei d, Valery S. Effoe e, Justin B. Echouffo Tcheugui f, Rita R. Kalyani g,
Mario Sims h, Herman A. Taylor f, Morgana Mongraw-Chaffin i, Ehimare Akhabue j, Joshua
J. Joseph a, *
a
Division of Endocrinology, Diabetes and Metabolism, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
b
Division of Endocrinology, University Of Texas Medical Branch at Galveston, Galveston, Texas, United States
c
Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States
d
Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
e
Division of Biostatistics, The Ohio State University College of Public Health, Columbus, Ohio, United States
f
Division of Cardiology, Morehouse School of Medicine, Atlanta, Georgia, United States
g
Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
h
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States
i
Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States
j
Division of Cardiovascular Diseases and Hypertension, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, United States

G R A P H I C A B S T R A C T

Visual abstract (A): the percent mediation by aldosterone of the association of ideal cardiovascular health with incident cardiovascular disease,visual abstract (B): the
percent mediation by blood pressure and glucose of the association of aldosterone with incident cardiovascular disease

* Corresponding author at: 579 McCampbell Hall, 1581 Dodd Drive, Columbus, Ohio 43210
E-mail address: joseph.117@osu.edu (J.J. Joseph).
1
These two authors contributed equally to the manuscript.

https://doi.org/10.1016/j.ajpc.2023.100494
Received 16 September 2022; Received in revised form 31 March 2023; Accepted 1 April 2023
Available online 3 April 2023
2666-6677/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
B. Kluwe et al. American Journal of Preventive Cardiology 14 (2023) 100494

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Higher levels of ideal cardiovascular health (ICH) are associated with lower levels of aldosterone and
Aldosterone incidence of cardiovascular disease (CVD). However, the degree to which aldosterone mediates the association
Ideal cardiovascular health between ICH and CVD incidence has not been explored. Thus, we investigated the mediational role of aldoste­
Cardiovascular disease
rone in the association of 5 components of ICH (cholesterol, body mass index (BMI), physical activity, diet and
smoking) with incident CVD and the mediational role of blood pressure (BP) and glucose in the association of
aldosterone with incident CVD in a cohort of African Americans (AA).
Methods: The Jackson Heart Study is a prospective cohort of AAs adults with data on CVD outcomes. Aldosterone,
ICH metrics and baseline characteristics were collected at exam 1 (2000–2004). ICH score was developed by
summing 5 ICH metrics (smoking, dietary intake, physical activity, BMI, and total cholesterol) and grouped into
two categories (0–2 and ≥3 metrics). Incident CVD was defined as stroke, coronary heart disease, or heart failure.
Cox proportional hazard regression models were used to model the association of categorical ICH score with
incident CVD. The R Package Mediation was utilized to examine: 1) The mediational role of aldosterone in the
association of ICH with incident CVD and 2) The mediational role of blood pressure and glucose in the associ­
ation of aldosterone with incident CVD.
Results: Among 3,274 individuals (mean age: 54±12.4 years, 65% female), there were 368 cases of incident CVD
over a median of 12.7 years. The risk of incident CVD was 46% lower (HR: 0.54; 95%CI 0.36, 0.80) in those with
≥3 ICH metrics at baseline compared to 0–2. Aldosterone mediated 5.4% (p = 0.006) of the effect of ICH on
incident CVD. A 1-unit increase in log-aldosterone was associated with a 38% higher risk of incident CVD (HR
1.38, 95%CI: 1.19, 1.61) with BP and glucose mediating 25.6% (p<0.001) and 4.8% (p = 0.048), respectively.
Conclusion: Aldosterone partially mediates the association of ICH with incident CVD and both blood pressure and
glucose partially mediate the association of aldosterone with incident CVD, emphasizing the potential impor­
tance of aldosterone and ICH in risk of CVD among AAs.

1. Introduction association of 5 components of ICH (cholesterol, body mass index,

Cardiovascular disease (CVD) is the leading cause of death in the
United States [1,2] and disproportionately impacts African Americans
(AA). Compared to non-Hispanic whites (NHW), AAs tend to be younger
at the time of CVD diagnosis and have lower long-term survival [3,4]. In
order to combat the disease burden associated with CVD, the American
Heart Association developed a set of seven cardiovascular health metrics
(smoking, weight, physical activity, diet, blood pressure [BP], total
cholesterol, and glycemia), to define ideal cardiovascular health (ICH)
and observe changes in the cardiovascular health of Americans [5].
Higher attainment of ICH metrics is associated with lower rates of
CVD [6–8]. While the association between increased attainment of ICH
and reduced CVD is likely multifactorial, one possible contributing
factor is aldosterone. Aldosterone is a steroid hormone produced by the
zona glomerulosa of the adrenal cortex and is a key regulator of blood
pressure and electrolyte balance. We have previously reported that
higher aldosterone is associated with increased incidence of CVD and
all-cause mortality in AAs [9,10]. Furthermore, aldosterone has been
shown to contribute to higher BP and blood glucose [9]. Additionally,
aldosterone is influenced by ICH status, as higher ICH attainment is
associated with lower levels of aldosterone among AAs [11]. Specif­
ically, increased adiposity has been associated with increased aldoste­
rone production directly through adipocytes [12–14]. Adipokines,
proteins produced by adipose tissue with systemic metabolic effects,
such as leptin and adiponectin also influence aldosterone [15,16].
Higher availability of cholesterol promotes the production of aldoste­
rone [17–20]. Other behavioral aspects of ICH, including smoking and
exercise, have had mixed associations with aldosterone. Smoking was
associated with increased aldosterone in some studies [21,22], while not
in large cohort studies [23]. Exercise has been shown to decrease
aldosterone levels, although that relationship may not hold in AAs
[24–26]. Finally, the association between consumption of an ideal diet
with aldosterone in AAs is unclear.
Cumulatively, aldosterone appears to be influenced by ICH attain­
ment, and there is a well-established association between aldosterone
and CVD, but the degree to which aldosterone may mediate the rela­
tionship between ICH attainment and CVD incidence has yet to be
elucidated. In a cohort of AA adults participating in the Jackson Heart
Study (JHS), we investigated the role of aldosterone as a mediator in the
physical activity, diet and smoking) with incident CVD. We also exam­
ined blood pressure and glucose as mediators in the association of
aldosterone with incident CVD (Fig. 1).
2. Method
2.1. Study population
The JHS is a prospective community-based cohort study of the
development and progression of CVD in 5306 AA adults aged 21–94
years at baseline within the tri-county area (Hinds, Madison, and Ran­
kin) of the Jackson, Mississippi metropolitan area. The baseline exam­
ination was performed between 2000 and 2004. The design of the study
has been described elsewhere [27]. The study was approved by the
institutional review boards of the University of Mississippi Medical
Center, Jackson State University, and Tougaloo College. All participants
provided written informed consent. For this analysis, participants were
excluded if they had a history of CVD [coronary heart disease, stroke,
and/or heart failure] (n = 572), missing data for exposures (n = 973),
missing data on incident CVD status (n = 467), aldosterone (n = 5), and
baseline covariates (n = 15) [Supplemental Figure S1]. After these ex­
clusions, 3274 participants were included in the analysis. Included
participants were younger, more educated, less likely to smoke, more
physically active, had lower blood pressures as well as lower glucose and
higher cholesterol levels compared to all excluded participants,
including those with known CVD at baseline (Supplemental Table S1).
After excluding participants with known CVD at baseline (n = 572) from
the included vs. excluded table (Supplemental Table S2), the included
(n = 3274) vs. excluded (n = 1460) samples were sociodemographically
and biologically similar. Among the few variables that were statistically
different the differences were not likely to be clinically significant. For
instance, systolic blood pressure was 126.5 and 127.7 mmHg in the
included vs. excluded sample (p = 0.017), respectively.
2.2. Exposures
The primary exposure was ICH assessed using five of the seven
dichotomous ICH metrics (1=ideal, 0=intermediate/poor) which
included cigarette smoking status, diet, physical activity (PA), body

2
B. Kluwe et al.
mass index (BMI), and total cholesterol. Blood pressure (BP) and glucose
metrics were excluded from the primary mediation analysis as they are
downstream of aldosterone in the conceptual model [28–30].
2.3. Total cholesterol
Total cholesterol was measured by the cholesterol oxidase method
(Roche COBAS Fara analyzer; Roche Diagnostics), as previously
described [5]. Ideal total cholesterol was defined as an untreated total
cholesterol <200 mg/dL; intermediate total cholesterol defined by a
level of 200 to 239 mg/dL or if treated with anti-hyperlipidemic medi­
cations to goal (<200 mg/dL); and poor was defined by a level of ≥240
mg/dL.
2.4. Body mass index
BMI was calculated by dividing weight (kilograms) by the square of
height (meters). BMI <25 kg/m2 was considered ideal; 25 to 29.9 kg/m2
was intermediate; and ≥30 kg/m2 was poor [5].
2.5. Physical activity
Physical Activity was assessed using an interviewer-administered PA
questionnaire at baseline, modified from the Baeke PA survey [31]. This
instrument was identical to the one used during the Kaiser Physical
Activity survey, which showed good validity and reliability in a multi­
ethnic sample [32]. Exercise was reported by the average amount of
time per week spent, and metabolic equivalent levels were defined for
each activity. Moderate activity was defined as 3 to 6 metabolic equiv­
alents and vigorous activity as >6 metabolic equivalents. Ideal PA was
defined as ≥150 min of moderate-intensity activity or ≥75 min of
vigorous activity or ≥150 min of combined moderate-intensity and
vigorous activity per week; intermediate PA was defined as 1 to 149 min
of moderate-intensity activity or 1 to 74 min of vigorous activity or 1 to
149 min of combined moderate-intensity and vigorous activity per
week; poor PA was defined as no amount of activity (0 min per week)
[5].
3
American Journal of Preventive Cardiology 14 (2023) 100494
2.6. Smoking
Cigarette smoking was self-reported, and participants were asked
about the quantity and duration of smoking. Participants who had never
smoked or who quit smoking more than 12 months preceding the clinic
visit were considered ideal; Former smokers who quit smoking within 12
months of the clinic visit were considered intermediate; and current
smokers were considered poor [5].
2.7. Diet
In the JHS, dietary intake was assessed using the Delta Nutrition
Intervention Research Initiative food frequency questionnaire with 158
items [33,34]. The questionnaire had some slight differences compared
with the AHA categorization regarding units of servings, requiring
modification of the metrics, as has been done previously [5,35,36]. The
dietary components used to compute the AHA score, based on a
2000-kcal diet, were: fruits and vegetables of 4.5 cups/d or more, two
3.5-oz servings or more per week of non-fried fish, fiber-rich whole
grains of three 1-oz-equivalent servings/d or more, sodium less than
1500 mg/d, and sugar sweetened beverages of 450 kcal/week or less (36
oz). Ideal diet was defined by a diet including 4 to 5 components; in­
termediate diet, 2 to 3 components; and poor diet, 0 to 1 component [5].
2.8. Ideal cardiovascular health (ICH)
Each baseline metric was evaluated separately using poor, interme­
diate, and ideal categories [37]. Based on preclinical and clinical studies
we hypothesized that BMI, dietary intake, smoking, physical activity
and total cholesterol are upstream of aldosterone and impact levels of
serum aldosterone, whereas BP and glucose are downstream of aldo­
sterone [11,28,29,38]. We thus excluded BP and glucose from the score
categorization, and included the remaining 5 components in the ICH
score. Categorical scores were calculated by summing the number of
ideal levels of ICH metrics each participant attained at baseline and
categorizing participants into 0–2 ICH versus ≥3 ICH metrics, similar to
prior analyses [39–41]. Sensitivity analyses were performed with par­
ticipants categorized 0–1, 2 and ≥3 ICH metrics.
Fig. 1. Conceptual Diagram
Panel A: The role of aldosterone as a mediator
in the association of 5 components of ICH
(cholesterol, body mass index, physical activity,
diet and smoking) with Incident CVD was
assessed. Panel B: Blood pressure and glucose
were examined as mediators in the association
of aldosterone with incident cardiovascular
disease. The figure was created with BioRender.
com.
ICH = Ideal Cardiovascular Health.
B. Kluwe et al.
2.9. Mediator
2.9.1. Aldosterone
Fasting blood samples were drawn in the supine position and pro­
cessed using a standardized protocol. Plasma and serum were prepared
from samples by sedimentation in a refrigerated centrifuge within two
hours of blood collection, stored at − 70 ◦ C and sent to central labora­
tories (University of Minnesota) [42,43]. Serum aldosterone was
measured by radioimmunoassay (Siemens) and the intra-assay co­
efficients of variation were 8.7% and 6.2% for low and high concen­
trations, respectively.
2.10. Outcome
2.10.1. Incident cardiovascular disease
The primary outcome was incident CVD which was defined as cor­
onary heart disease [CHD], stroke, and/or Heart Failure [HF] events.
Methods for ascertaining cardiovascular events and deaths in the JHS
cohort have been described previously [44]. Briefly, CVD events were
ascertained through a combination of active and passive surveillance.
Annual follow-up included interviews with participants and next of kin
to ascertain health events, such as cardiac events, and hospitalizations or
death through questionnaires completed by physicians and medical
examiners or coroners and reviewed by the medical record abstraction
unit to generate diagnostic information. These diagnoses were reviewed
and adjudicated by trained medical personnel. Cardiovascular illness
hospitalizations were identified and adjudicated as described previously
[44]. Hospitalization data were obtained from the hospital discharge
index from all catchment area hospitals and annual follow-up data. Data
from non-catchment area hospitals were obtained after patient consent.
Death certificates from state vital statistic offices were surveyed for
potential CVD events. The self-reported data from annual follow-up
were reconciled with the hospital discharge index data. The primary
diagnoses based on International Classification of Diseases-9th Revi­
sion-Clinical Modification codes were reviewed and adjudicated by
trained medical personnel. We tracked the occurrence of CHD and stroke
between 2000 and 2016, and HF hospitalizations between 2005 and
2016.
2.11. Statistical analysis
2.11.1. Baseline characteristics
Baseline characteristics of participants were summarized in ICH 0–2
vs. ≥ 3 categories using Student’s t-test for normally distributed
continuous variables, Mann-Whitney U test for non-normally distributed
continuous variables, and Chi-square test for categorical variables.
Aldosterone was non-normally distributed and was thus log
transformed.
2.11.2. Survival analysis
Time to CVD was calculated from the date of first visit until date of
CVD or censored at loss to follow-up. Kaplan-Meier curves were gener­
ated to compare time (years) to CVD between 0 and 2 ICH and ≥ 3 ICH
categories. Cox proportional hazard regression models were used to
model the association of ICH metrics or aldosterone with incident CVD,
adjusted for: age, sex, education, occupation, alcohol use and estimated
glomerular filtration rate (eGFR).
2.11.3. Mediation analysis
To examine the role of aldosterone as a potential mediator in the
pathway between ICH metrics and incident CVD and all-cause mortality,
mediation analyses were performed using the “mediation” R package
[45]. First, a linear regression model was used to assess the
cross-sectional association between the exposure (ICH) and mediator
(aldosterone) which was used as the first argument of the mediate
function (model.m, class=”lm”). Next, accelerated failure time models
4
American Journal of Preventive Cardiology 14 (2023) 100494
with a Weibull distribution were used instead of Cox proportional haz­
ard models for the survival analyses to obtain estimated mean effects for
incident CVD. This model was used as the second argument of the
mediate function (model.y, class=”survreg”). The hazard ratios from
this model approximate those from the Cox proportional hazard re­
gressions as described previously [45].
The R package “mediation” uses continuous or dichotomous treat­
ment effects for the treat argument; thus, ICH metrics were categorized
as 0–2 and ≥ 3 ICH score category. Finally, statistical significance of
Average Causal Mediated Effects, Average Direct Effects, and Proportion
Mediated were assessed by quasi-Bayesian approximation with 1000
Monte Carlo draws. Importantly, because blood glucose and BP are
thought to be directly affected by aldosterone levels, both were excluded
from the mediation analysis [28,29,46]. The proportion of ≥ 3 ICH
category participants calculated without BP and glucose (14%)
approximated that in the original set with ≥ 4 out of 7 ICH metrics
(17%). To examine potential mediational effects of glucose and BP, we
performed additional mediational analysis using dichotomous metrics
treating glucose and BP (ideal vs. non-ideal) as mediators in the pathway
between aldosterone and CVD. Aldosterone was log-transformed for
analysis. To confirm the robustness of the findings, sensitivity analyses
were performed with ICH categorized 0–1 (referent group), 2 and ≥3
ICH metrics and evaluating for effect modification by sex. Statistical
significance was defined as two-sided p < 0.05. Analyses were per­
formed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA) and R version
3.4.3 (R Foundation for Statistical Computing, Vienna, Austria) with
mediation package.
3. Results
3.1. Baseline characteristics
The characteristics of the study population are presented in Table 1.
Of the 3274 participants (65% female), 460 attained three or more ICH
metrics (ideal). Participants in the ≥3 ICH category were younger with
higher levels of education, worked in managerial or professional roles,
and consumed alcohol. Additionally, participants with ≥3 ICH were less
likely to smoke and had lower BMIs, systolic blood pressures, total
cholesterol, fasting glucose, HbA1c, along with higher levels of physical
activity and diet (all p < 0.05). Median aldosterone was lower with
higher ICH attainment (p = 0.03). A 3-level categorization of ICH met­
rics ≥3 or 2 vs. 0–1 (Supplemental Table S3), revealed similar findings
as the 2-level categorization ≥3 vs. 0–2.
3.2. The association of ≥3 vs. 0–2 ich metrics with incident
cardiovascular disease and mediation by aldosterone
Participants attaining ≥3 vs. 0–2 ICH metrics had a 46% lower risk of
incident CVD (Table 2: Hazard Ratio [HR] 0.54, 95%CI: 0.36, 0.80, p =
0.0024) after adjusting for CVD risk factors. Fig. 2 shows the Kaplan-
Meier curve for ≥3 vs. 0–2 ICH metrics, demonstrating higher CVD-
free survival in the ≥3 group (log-rank p<0.0001). Aldosterone medi­
ated 5.4% (p = 0.006) of the association between higher ICH and
reduced incident CVD. In sensitivity analyses using a 3-level categori­
zation of ICH metrics ≥3 or 2 vs. 0–1, Kaplan-Meier curves demon­
strated higher CVD-free survival across groups (log-rank p<0.0001)
(Supplemental Figure S2). In Supplemental Table S4, participants with 2
ICH metrics had a 27% lower risk of CVD compared to participants with
0–1 ICH metrics (p = 0.005), aldosterone mediated 7.00% of the effect
(p<0.001). Participants with ≥3 ICH metrics had a 44% lower risk of
CVD compared to participants with 0–1 ICH metrics (p<0.001), aldo­
sterone mediated 7.12% of the effect (p<0.001). Additionally, differ­
ences in the association of ≥3 vs. 0–2 ICH metrics were examined by sex
(Supplemental Table S5). There was a greater magnitude of association
of ≥3 vs. 0–2 ICH metrics with incident CVD in women (HR 0.36, 95%
CI: 0.18–0.70) compared to men (HR 0.74, 95%CI: 0.44, 1.23) (p for
B. Kluwe et al. American Journal of Preventive Cardiology 14 (2023) 100494

interaction=0.09). The percentage of the association mediated by Table 1

aldosterone was 1.9% (p = 0.05) in women and 12% (p = 0.14) in men, Baseline characteristics comparing 0–2 and ≥3 Ideal Cardiovascular Health
but there was no statistical difference in the percentage of the associa­ (ICH) Metrics.
tion mediated by aldosterone in men and women (p = 0.92). Mean (SD)/N(%) All Participants n 0–2 ICH Metrics ≥3 ICH Metrics
= 3274 n = 2814 N = 460
3.3. The association of log-aldosterone with incident cvd and mediation Age 54 (12.4) 54.6 (12.1) 50 (13.3)
by blood pressure and glucose Sex
Men 1144 (34.9%) 953 (33.9%) 191 (41.5%)
Women 2130 (65.1%) 1861 (66.1%) 269 (58.5%)
A 1-unit increase in log-aldosterone was associated with a 38%
Education
higher risk of incident CVD (HR 1.38, 95%CI: 1.19, 1.61). BP and Less than high school 488 (14.9%) 455 (16.2%) 33 (7.2%)
glucose mediated 25.6% (p<0.001) and 4.8% (p = 0.048) of the asso­ ≥ High school 2786 (85.1%) 2359 (83.8%) 427 (92.8%)
ciation between aldosterone and incident CVD, respectively. graduate
Occupation
Management/ 1284 (39.2%) 1048 (37.2%) 236 (51.3%)
4. Discussion Professional
Other 1990 (60.8%) 1766 (62.8%) 224 (48.7%)
In this novel investigation of the mediational role of aldosterone in Alcohol use
the association of ICH with incident CVD in a prospective cohort of AA Yes 1514 (46.2%) 1258 (44.7%) 256 (55.7%)
No 1760 (53.8%) 1556 (55.3%) 204 (44.3%)
community dwelling adults, aldosterone mediated 5.4% of the 46%
Current Smoker
lower incident CVD risk for participants attaining ≥3 vs. 0–2 ICH met­ Yes 341 (10.4%) 336 (11.9%) 5 (1.1%)
rics. The findings suggest that aldosterone may be an important No 2928 (89.4%) 2474 (87.9%) 454 (98.7%)
component of the lower CVD incidence observed with higher attainment Missing 5 (0.2%) 4 (0.1%) 1 (0.2%)
BMI, kg/m2 31.7 (7.1) 32.3 (6.9) 28.2 (6.8)
of ICH metrics. The finding of a 46% reduction in the incidence of CVD
Physical Activity
among individuals with more than three ICH metrics presented here is Poor 1514 (46.2%) 1449 (51.5%) 65 (14.1%)
consistent with prior studies in multi-ethnic cohorts [8,47–50]. Intermediate 1091 (33.3%) 1025 (36.4%) 66 (14.3%)
Log-aldosterone was associated with a 38% higher risk of incident CVD Ideal 669 (20.4%) 340 (12.1%) 329 (71.5%)
in a secondary analysis with BP and glucose mediating 26% and 4.8% of Blood Pressure
Poor 613 (18.7%) 542 (19.3%) 71 (15.4%)
the association of log-aldosterone with incident CVD, respectively. Our
Intermediate 1933 (59%) 1716 (61%) 217 (47.2%)
findings suggest that aldosterone may play an important mechanistic Ideal 728 (22.2%) 556 (19.8%) 172 (37.4%)
role in the relationship between higher ICH attainment and lower risk of Cholesterol
incident CVD. Such findings may be of great importance given low Poor 491 (15%) 480 (17.1%) 11 (2.4%)
population attainment of ICH metrics [6,50], and demonstrate further Intermediate 1297 (39.6%) 1271 (45.2%) 26 (5.7%)
Ideal 1486 (45.4%) 1063 (37.8%) 423 (92%)
exploration of the role of aldosterone in the relationship between ICH Glucose
and incident CVD is merited. Poor 471 (14.4%) 444 (15.8%) 27 (5.9%)
The magnitude of mediation by aldosterone is comparable to that of Intermediate 1291 (39.4%) 1175 (41.8%) 116 (25.2%)
a prior study that assessed the association between ICH and incident Ideal 1512 (46.2%) 1195 (42.5%) 317 (68.9%)
Body Mass Index
coronary heart disease (CHD). Gaye et al. investigated these associations
Poor 1754 (53.6%) 1606 (57.1%) 148 (32.2%)
and disaggregated the mediating roles of high-sensitivity C-reactive Intermediate 1083 (33.1%) 982 (34.9%) 101 (22%)
protein (hsCRP), interleukin-6 (IL-6), and fibrinogen in 9312 European Ideal 437 (13.3%) 226 (8%) 211 (45.9%)
men (France and Northern Ireland). In this nested-case control designed Smoking
study, hsCRP, IL-6, and fibrinogen mediated 9.6%, 4.9%, and 3.6% of Poor 341 (10.4%) 336 (11.9%) 5 (1.1%)
Intermediate 38 (1.2%) 34 (1.2%) 4 (0.9%)
the association between all seven ICH metrics and incident CHD [51]. Ideal 2895 (88.4%) 2444 (86.9%) 451 (98%)
However, differences in methodological design should be considered Diet
when comparing the current study and that by Gaye et al. First, our Poor 1885 (57.6%) 1649 (58.6%) 236 (51.3%)
outcome was a combined measure of CVD (CHD, stroke, and HF) versus Intermediate 1360 (41.5%) 1153 (41%) 207 (45%)
Ideal 29 (0.9%) 12 (0.4%) 17 (3.7%)
CHD only. Second, we excluded glucose and blood pressure, and thus,
Blood Pressure,
our ICH predictor was a combined measure of five metrics, not all seven. mmHg
Finally, our studies use different modeling approaches to assess CVD Systolic Blood 126.5 (16.1) 127 (16) 123.1 (16.3)
risk. Additionally, it is important to note that the similarity between Pressure
these biomarkers and aldosterone would be expected given the interplay Diastolic Blood 76 (8.3) 76.1 (8.3) 75.7 (8.5)
Pressure
between aldosterone and general inflammation [52,53]. Aldosterone (ng/dl)† 4.3 [2.6, 7.1] 4.4 [2.6, 7.3] 4 [2.5, 6.4]
The five components of ICH included in the ICH score (BMI, total eGFRǂ 96 (19.7) 95.5 (19.8) 99 (19.3)
cholesterol, physical activity, diet, and smoking) individually impact Total Cholesterol, 200.9 (38.8) 205 (39.1) 176.1 (25.5)
aldosterone levels and are also independent risk factors for CVD. BMI is mg/dL
Fasting Plasma 98.8 (31.2) 100 (32.5) 91.2 (19.6)
widely utilized as a metric for evaluating adiposity, and is associated
Glucose, mg/dL
with higher levels of aldosterone [11]. Excess adiposity and accompa­ Hemoglobin A1c (%)ˆ 5.9 (1.2) 5.9 (1.2) 5.5 (0.9)
nying inflammation are associated with increased adipocyte differenti­ Baseline Diabetes
ation and aldosterone synthesis directly from adipocytes [12–14]. Yes 603 (18.4%) 558 (19.8%) 45 (9.8%)
Further, higher BMI is associated with higher leptin and lower adipo­ No 2671 (81.6%) 2256 (80.2%) 415 (90.2%)
Stroke
nectin. Leptin promotes aldosterone production through CYP11B2 while yes 122 (3.7%) 118 (4.2%) 4 (0.9%)
adiponectin reduces aldosterone synthesis [15,16]. The relationship no 3152 (96.3%) 2696 (95.8%) 456 (99.1%)
between excess adiposity and aldosterone demonstrates a potential Heart Failure
causal pathway for how aldosterone may mediate the relationship be­ yes 203 (6.2%) 186 (6.6%) 17 (3.7%)
no 3071 (93.8%) 2628 (93.4%) 443 (96.3%)
tween ICH and CVD incidence.
Coronary Heart
The interplay between other ICH metrics such as cholesterol, exer­ Disease
cise, smoking, and diet with aldosterone are less well established. As a Yes 144 (4.4%) 135 (4.8%) 9 (2%)
substrate required for aldosterone synthesis, increased cholesterol is tied No 3130 (95.6%) 2679 (95.2%) 451 (98%)

5
B. Kluwe et al.
P-value obtained using one-way ANOVA for continuous variables and Chi-
square test for categorical variables.
SD = standard deviation; N = number.
All p-values <0.05, except DBP (p = 0.3401).
†
Median (IQR) and Wilcoxon rank sum test was used for aldosterone.
ǂ
EGFR CKD-EPI = Estimated glomerular filtration rate was calculated based
on the Chronic Kidney Disease Epidemiology Collaboration equation.
^
Twenty individuals were missing A1c in the 0–2 group and 3 in the ≥3 group.
Table 2
The association of ideal cardiovascular health metrics excluding blood pressure
and glucose with incident cardiovascular disease and mediation by aldosterone.
Adjusted hazard ratios (95% p-
CI) value
Ideal cardiovascular health metrics ≥3 0.54 (0.36, 0.80) 0.0024
vs. 0–2
Percentage mediated (%) p-
value
Aldosterone as mediator 5.4 (1.60, 15.00) 0.006
CI = confidence interval.
Model adjusted for: age, sex, education, occupation, alcohol use and estimated
glomerular filtration rate (eGFR).
Interpretation: Attaining ≥3 Ideal cardiovascular health metrics compared to
0–2 at baseline was associated with a 46% lower risk of CVD. 5.4% of the as­
sociation was mediated by aldosterone.
to increased aldosterone through potential mechanisms including VLDL,
HDL2, and increased aldosterone substrates [17–20]. Additionally, the
interaction between cholesterol and aldosterone is supported by the
finding that statin pharmacotherapy use decreases aldosterone [54].
Interestingly, aerobic exercise may decrease aldosterone, although there
is some evidence that aerobic exercise may not reduce aldosterone in
AAs [24–26]. The effect of smoking on aldosterone is not clear which
may be a result of heterogeneity of past study designs. Some studies
demonstrate a baseline elevation in aldosterone among smokers [21],
others show an increase in aldosterone after smoking [22], and still
others detail no significant difference in aldosterone between smokers
and non-smokers [23]. The relationship between ideal AHA diet (fruits
and vegetables, sugar sweetened beverages, fish, fiber, sodium intake
and whole grains) has been evaluated previously in the JHS but was not
clear [11]. Further investigation into the multifaceted relationships
between ICH metrics and aldosterone may provide further evidence for
Fig. 2. Kaplan-Meier Curve for the Association of ≥3 vs. 0–2 Ideal Cardiovascular Health Metrics with Incident Cardiovascular Disease
Participants with ≥3 vs. 0–2 ideal cardiovascular health metrics had higher cardiovascular disease-free survival (Logrank p<0.001).
6
American Journal of Preventive Cardiology 14 (2023) 100494
the behavioral changes that might be prioritized in a clinical setting to
lower aldosterone and prevent CVD. The role of aldosterone in the
pathogenesis of CVD has largely been attributed to alterations in blood
pressure and glucose regulation [10]. The findings presented in this
study are consistent with the extant data.
The findings reveal that sex may modify the association of ICH with
incident CVD and mediation by aldosterone. The association of ICH with
incident CVD was of greater magnitude in women compared to men,
consistent with a prior study in the JHS and a large meta-analysis [47,
55]. Spahillari et al., did not assess modification of the association of LS7
with incident heart failure in the JHS, but they did show that the higher
levels of LS7 were associated with lower left ventricular mass index (p
for interaction=0.03), concentric modeling (p for interaction=0.09) and
peak global strain (p for interaction=0.06) in women compared to men
[40]. In terms of ICH and aldosterone, cross-sectionally higher ICH is
associated with lower aldosterone in women compared to men [11]. In
the present analysis, the percentage of the association mediated by
aldosterone was numerically less in women, but not statistically
different from men. Thus, future analyses in larger cohorts to explore
potential sex differences in the mediational role of aldosterone in the
association of ICH with incident CVD are necessary.
4.1. Strengths and limitations
The strengths of this analysis include a large well-characterized AA
cohort with longitudinal data that include aldosterone, ICH metrics, and
adjudicated CVD events. Despite these strengths our study has multiple
limitations. The JHS is localized in the southeastern USA, therefore
findings may not be generalizable to all AAs and other racial/ethnic
groups. Second, aldosterone was only assessed at one point in time and
thus, we were unable to explore the mediational role of changes in
aldosterone over time. Third, only participants without a history of CVD
were included in the final analytical sample and thus results may not be
generalizable for individuals with known CVD. Fourth, when exclusion
comparisons were based on the entire JHS cohort including exclusions
for having a history of CVD, missing CVD status, and missing data on ICH
metrics, included participants were younger, more educated, less likely
to smoke, more physically active, had lower blood pressures as well as
lower glucose and higher cholesterol levels compared to excluded par­
ticipants (Supplemental Table S1). When participants with prevalent
CVD at baseline were not included in the inclusion vs. exclusion tables
B. Kluwe et al.
Table 3
The mediational role of aldosterone in the association of ≥3 vs 0–2 ideal car­
diovascular health metrics with incident cardiovascular disease.
Hazard ratios (95% CI) p-value
Log-aldosterone 1.38 (1.19, 1.61) <0.001
Blood Pressure and Glucose as mediators Percentage mediated (%) p-value
Blood pressure 25.6 (10.9, 49) <0.001
Glucose 4.75 (0.14, 13) 0.048
CI = confidence interval.
Model adjusted for: age, sex, education, occupation, alcohol use and estimated
glomerular filtration rate (eGFR).
A 1-unit increase in log-aldosterone was associated with a 38% higher risk of
CVD. Blood Pressure and glucose mediated 25.6% and 4.8%, respectively.
the included and excluded sample were similar with small differences
that were not likely to be biologically significant. Even with these con­
siderations, we cannot exclude bias due to the exclusions of the in­
dividuals missing ICH metrics and CVD status. Fifth, participants with
peripheral arterial disease (PAD) only may have been under detected as
events related to PAD were not recorded by the JHS. Finally, incident
CHD and stroke were ascertained between 2000 and 2016, and HF
hospitalizations were ascertained between 2005 and 2016, thus there
may have been some participants who had HF hospitalizations that were
not captured from 2000 to 2004 and this could be a source of bias in our
findings. Given these limitations some caution is warranted in the
interpretation of our study results.
5. Conclusion
Aldosterone partially mediates the association between ICH and
incident CVD in AAs, while blood pressure and glucose partially mediate
the association of aldosterone with incident CVD. The magnitude of
mediation by aldosterone is comparable to that of hsCRP, IL-6, and
fibrinogen which are established causal factors in the development of
CVD. Improving ICH through lifestyle modifications may lower CVD
incidence and further research to explore the role of the RAAS system
including potential methods to augment the response through RAAS
modulating pharmacotherapy may be warranted.
Roles
All authors contributed meaningfully to the production of the
manuscript from conceptualization, implementation, and production of
the initial manuscript as well as editing. Table 3
CRediT authorship contribution statement
Bjorn Kluwe: Conceptualization, Methodology, Writing – original
draft, Writing – review & editing, Visualization. Neal Pohlman:
Conceptualization, Writing – original draft, Visualization. Veena
Kesireddy: Conceptualization, Methodology, Writing – review & edit­
ing, Visualization. Songzhu Zhao: Conceptualization, Methodology,
Software, Validation, Formal analysis, Investigation, Data curation,
Writing – review & editing, Visualization. Yubo Tan: Conceptualization,
Methodology, Software, Validation, Formal analysis, Investigation, Data
curation, Writing – review & editing, Visualization. David Kline:
Conceptualization, Methodology, Data curation, Writing – review &
editing, Supervision, Project administration. Guy Brock: Conceptuali­
zation, Methodology, Data curation, Writing – review & editing, Su­
pervision, Project administration. James B. Odei: Conceptualization,
Methodology, Data curation, Writing – review & editing, Supervision,
Project administration. Valery S. Effoe: Conceptualization, Methodol­
ogy, Writing – review & editing, Visualization. Justin B. Echouffo
Tcheugui: Conceptualization, Methodology, Writing – review & editing,
Visualization. Rita R. Kalyani: Conceptualization, Methodology,
Writing – review & editing, Visualization. Mario Sims:
7
American Journal of Preventive Cardiology 14 (2023) 100494
Conceptualization, Methodology, Writing – review & editing, Visuali­
zation. Herman A. Taylor: Conceptualization, Methodology, Writing –
review & editing, Visualization. Morgana Mongraw-Chaffin: Concep­
tualization, Methodology, Writing – review & editing, Visualization.
Ehimare Akhabue: Conceptualization, Methodology, Writing – review
& editing, Visualization. Joshua J. Joseph: Conceptualization, Meth­
odology, Investigation, Resources, Writing – original draft, Writing –
review & editing, Supervision, Project administration, Funding
acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The JHS is supported and conducted in collaboration with Jackson
State University (HHSN268201800013I), Tougaloo College
(HHSN268201800014I), the Mississippi State Department of Health
(HHSN268201800015I/HHSN26800001) and the University of Mis­
sissippi Medical Center (HHSN268201800010I, HHSN268201800011I
and HHSN268201800012I) contracts from the National Heart, Lung,
and Blood Institute (NHLBI) and the National Institute for Minority
Health and Health Disparities (NIMHD). Preparation of this manuscript
was supported by The Robert Wood Johnson Foundation (Harold Amos
Medical Faculty Development Program ID# 76236) and the National
Institute of Diabetes and Digestive and Kidney Diseases (K23DK117041,
JJJ) of the National Institutes of Health. This publication was supported,
in part, by the National Center for Advancing Translational Sciences of
the National Institutes of Health under Grant Number UL1TR002733.
The views expressed in this manuscript are those of the authors and do
not necessarily represent the views of the National Heart, Lung, and
Blood Institute; the National Institutes of Health; or the U.S. Department
of Health and Human Services. The authors also wish to thank the staff
and participants of the JHS.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.ajpc.2023.100494.
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