JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 17, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2014.07.982
EDITORIAL COMMENT
Sex Steroid as a New Oracle to Predict Cardiovascular Risk* Nadia R. Sutton, MD, MPH, David J. Pinsky, MD
E
verything we once thought we knew about the
and varying adjustments for factors known to affect
therapeutic use of estrogen for the prevention
DHEA-S levels, such as age (decreases DHEA-S) and
of cardiovascular disease (CVD) in women is
smoking (positively correlated with DHEA-S). DHEA-S
wrong (1). Everything we once knew about the role
levels have also been found to vary between pop-
of sex in CVD is still right; men are affected a decade
ulations; for example, men in California had higher
earlier than women. We are still enamored with the
levels than Japanese men, and DHEA-S levels
idea that sex steroids, particularly androgens, have,
were elevated in British women relative to Japanese
if not a causal role in CVD development, at least an as-
women (9,10).
sociation. We simply cannot get the notion out of our heads that androgens (or relative lack of estrogen)
SEE PAGE 1801
drive endothelial dysfunction and atherogenesis,
In this issue of the Journal, Tivesten et al. (11) revisit
and potentially, even plaque fracture. In this light,
the question of whether DHEA and DHEA-S predict
new studies that assess the risk associated with low
major coronary heart disease (CHD) events in elderly
levels of a particularly abundant sex steroid (dehy-
men. The primary endpoints were major CHD events
droepiandrosterone [DHEA] and its sulfated congener
(hospitalization for acute myocardial infarction, un-
[DHEA-S], which can serve as the precursor substrate
stable angina, revascularization, or death from CHD)
for either testosterone or estradiol) are of particular
and cerebrovascular disease (CBD) events (hospitali-
interest.
zation for stroke or transient ischemic attack, or death
Previous studies have examined the relationship
from stroke) as determined by the use of the Swedish
between DHEA and DHEA-S and cardiovascular out-
Causes of Death Register. This database is a particu-
comes; these studies yielded conflicting results (2–6).
larly robust registry because only 3 of 2,416 study
Prospective population-based studies on DHEA-S and
subjects were lost to follow-up. The study included
mortality in women have consistently shown no as-
2,416 men (ages 69 to 81 years). After a median follow-
sociation between DHEA-S and all-cause and CVD
up of 5.2 years, 302 participants had a CHD event, and
mortality (6). Prospective population-based studies in
225 had a CBD event. An inverse association was
men have either shown no relationship between
observed between age-adjusted DHEA and DHEA-S
DHEA-S and outcomes, or have shown that lower
levels and CHD events, with hazard ratios of 0.82
DHEA-S levels are associated with higher all-cause or
(95% confidence interval: 0.73 to 0.93) for DHEA and
CVD mortality (4,5,7,8). These apparent discrepancies
0.86 (95% confidence interval: 0.77 to 0.97) for DHEA-
have been attributed to differences in the populations
S. No significant association was found between
studied, the age and comorbidities of participants,
DHEA/-S and CBD events. The relationship between DHEA/-S and CHD events remained significant after adjustment for traditional cardiovascular risk factors,
*Editorials published in the Journal of the American College of Cardiology
including smoking, hypertension, diabetes, body
reflect the views of the authors and do not necessarily represent the
mass index (BMI), and renal function, as well as for
views of JACC or the American College of Cardiology.
high-sensitivity C-reactive protein (hsCRP) levels and
From the Division of Cardiovascular Medicine, Samuel and Jean Frankel
the apolipoprotein B/A1 ratio. Within the composite
Cardiovascular Center, University of Michigan, Ann Arbor, Michigan. This work was supported by the Ruth Professorship to Dr. Pinsky and The
endpoint, deaths from CHD and hospitalization for
Taubman Medical Research Institute. Both authors have reported that they
unstable angina were inversely associated with DHEA
have no relationships relevant to the contents of this paper to disclose.
and DHEA-S, although hospitalization for myocardial
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Sutton and Pinsky
JACC VOL. 64, NO. 17, 2014 OCTOBER 28, 2014:1811–3
Sex Steroid to Predict CV Risk
infarction and hospitalization for revascularization
younger than 75 years of age, there was no difference in
individually did not reach significance. In these anal-
these specific endpoints in those who were older than
yses, DHEA/-S levels were adjusted for age and the
75 years of age (12). Because of the similar populations
time of day for sample collection, but not for other
studied, albeit with slightly different endpoints, a
cardiovascular risk factors.
question is raised of whether the association between
Several strengths of this study deserve mention.
DHEA and DHEA-S and CHD events persists in men
This was the largest prospective trial that evaluated
older than 75 years of age. This would have im-
the relationship between DHEA and DHEA-S levels
plications for the applicability of DHEA as a biomarker
and CHD and CBD events to date. It detected a sig-
for CHD events in this age group, given the high in-
nificant association between lower DHEA/-S levels
cidence of CHD in men older than 75 years of age. There
and CHD events after a 5-year follow-up. This associ-
are other methodological issues that diminish confi-
ation appeared to be maintained even after account-
dence in the data, such as the self-reporting of base-
ing for the recognized confounders of DHEA and
line demographic characteristics. Another cautionary
DHEA-S levels of age and diurnal variation, and after
note in interpreting the study (11) stems from some
adjusting for other CVD risk factors, including smok-
of the subset analyses, such as adjustment for the
ing, hypertension, diabetes, BMI, renal function,
sites under study, and the somewhat arbitrary exclu-
hsCRP, and the apolipoprotein B/A1 ratio. Because
sion of the first 2.6 years of follow-up.
renal function has not traditionally been adjusted for
Although many biomarkers of future coronary
in previous publications that describe the relationship
events have been studied, we have yet to identify a
between DHEA/-S and cardiovascular outcomes, it is
molecule that precisely predicts future events (12–18).
noteworthy that in this study, the association between
Despite advances in primary and secondary preven-
DHEA/-S and CHD outcomes persisted even after
tion of CHD events, there is still a high incidence of
accounting for this important variable. Furthermore,
death due to CHD, including sudden cardiac death in
this study measured both DHEA and DHEA-S, and
individuals who do not have traditional coronary dis-
showed a more pronounced negative relationship
ease risk factors (19). There is room for improvement in
between mortality and DHEA than that with DHEA-S.
our collective ability to identify those at high risk for
This suggests that DHEA could be a more important
future events. Furthermore, some biomarkers have
predictor of outcomes, despite low plasma DHEA
stronger associations with outcomes than others. An
concentrations relative to DHEA-S. This has signifi-
ideal solution might be the use of weighted patterns
cant implications, because most previous negative
of biomarkers, which would take into consideration
studies examined only DHEA-S levels. If this finding is
typical
borne out in subsequent studies, then consideration
personalized biochemical fingerprint to more exactly
should be given to re-examination of banked samples
define an individual’s risk of future events. DHEA may
from populations (such as women and younger men)
represent a new arrow in the quiver of biomarkers.
in whom no differences in the effect of DHEA-S on
In such a new paradigm, biomarker patterns could
cardiovascular outcomes were previously seen.
biochemical
interactions
and
provide
a
suggest intensification of medical therapy for those at
In general, drawbacks to any DHEA study are related
the highest risk. The findings reported here should,
to DHEA’s diurnal pattern and generally low plasma
at the least, spur further interest in understanding
concentration. Certainty, regarding the results of the
DHEA as a biomarker of CVD risk.
findings in the study by Tivesten et al. (11), they are diminished when one considers a previous study by
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
this same group that used a largely overlapping cohort
David J. Pinsky, The University of Michigan Medical
of elderly Swedish men (12). This earlier study showed
Center, Division of Cardiovascular Medicine, 1500 East
that although DHEA and DHEA-S predicted all-cause
Medical Center Drive, Ann Arbor, Michigan, 48109.
and cardiovascular mortality in those who were
E-mail:
[email protected].
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Sex Steroid to Predict CV Risk
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KEY WORDS biological markers, coronary disease, dehydroepiandrosterone, male, prospective studies, risk factors
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