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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