JACC: CARDIOVASCULAR IMAGING VOL. 8, NO.

12, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-878X/$36.00

PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jcmg.2015.07.014

EDITORIAL COMMENT

In Sickness and in Health

Coronary Artery Calcium or Risk Factors*

Harvey S. Hecht, MD,y Jagat Narula, MD, PHD,y Y. Chandrashekhar, MDz

Insanity: doing the same thing over and over vulnerability; or 3) contributing to plaque formation,
again and expecting different results. progression or rupture as in the case of low-density li-
—Albert Einstein (1) poprotein cholesterol, diabetes, smoking, and other

R
factors. For all of these hypotheses, one could argue
isk stratification using historical elements
it would be better to just visualize the plaque and pla-
(age, smoking and family history), clinical
que progression itself via imaging (as with computed
examination (hypertension) or biomarkers
tomography imaging and CAC scoring) instead of
(lipids and glucose, etc.) predates the availability of
guessing its presence or fate. Indeed, the finding of
high-quality imaging and was the main vehicle for
subclinical atherosclerosis through imaging is likely
cardiovascular risk prediction. It was soon realized
to upset the current logical notion that the results of
that these markers, even in combination, were at
population-wide risk factors can be extrapolated reli-
best modest in their efficacy. Moreover, the bulk of
ably to individuals for the institution of primary
events still occurred in the large population with
prevention.
low-risk scores, suggesting the need to develop better
Although the relationship between CAC and risk
paradigms of risk prediction. Imaging has allowed us
factors has been extensively investigated in the pre-
to visualize directly and indirectly atheromatous pla-
diction of future sickness there is less information
que and can unveil the consummate biomarker. It was
about how well they relate to each other in predicting
but natural that imaging markers including the coro-
health (vascular health)? The ability to remain true in
nary artery calcium score (CAC) would be very effec-
sickness and in health is a much-cherished vow in the
tive tools for risk stratification as supported by
marital contract, but risk factor–based paradigms
multiple studies. CAC score seems to be far more
have shown less than optimal fidelity in sickness (see
facile than any other available marker for noninva-
below), and, from a report in this issue of iJACC (2),
sively predicting risk in both asymptomatic and
in health as well.
symptomatic subjects. It allows reclassification of
risk derived from conventional risk factor testing SEE PAGE 1393
(net reclassification index). The question then natu-
rally arises whether conventional risk factor based IN HEALTH
stratification schemes exert their limited predictive
ability through: 1) just identifying the likelihood of Whelton et al. (2) tried to answer whether any risk
coronary plaque burden; 2) better correlating with profile can also reliably predict healthy aging of the
plaques that had a turbulent history (e.g., calcified coronaries. They evaluated 1,850 asymptomatic
plaque) or correlating with a tendency for plaque MESA (Multi-Ethnic Study of Atherosclerosis) partic-
ipants with 0 CACs at baseline who underwent repeat
CAC at a median of almost 10 years after the initial
*Editorials published in JACC: Cardiovascular Imaging reflect the views of
scan. Absence of CAC persisted in 55% of the cohort
the authors and do not necessarily represent the views of JACC: while 45% developed a median CAC score of 25.
Cardiovascular Imaging or the American College of Cardiology. Healthy aging was defined as persistence of a 0 cal-
From the yIcahn School of Medicine at Mount Sinai, New York, New York; cium score. A baseline atherosclerotic cardiovascular
and the zUniversity of Minnesota, Minneapolis, Minnesota. Dr. Narula (ASCVD) risk score of <2.5% was associated with a
has received support from GE Healthcare and Philips Healthcare in the
greater probability of healthy aging compared with a
form of equipment to the institution. All other authors have reported
that they have no relationships relevant to the contents of this paper to score of $7.5%. Although the absence of risk factors
disclose. was associated with healthy aging, there was no
1402 Hecht et al.
Editorial Comment
association of persistent 0 CAC with the Healthy
Lifestyle variables of body mass index, physical ac-
tivity, Mediterranean diet, and never smoking; no
single traditional risk factor or combination of risk
factors improved on the crude area under the curve of
0.65 obtained from the combination of age, gender,
and ethnicity. During the decade-long follow-up,
more than one-third of high-risk subjects (age $65
years, or those with ASCVD $7.5% or $3 traditional
risk factors) remained free of coronary artery calcifi-
cation. A similar proportion of low-risk subjects
(age <55 years, ASCVD <2.5%, or those with no
traditional risk factors) developed coronary calcifica-
tion. Carotid intima media thickening and high-
sensitivity C-reactive protein also played no role in
predicting incident CAC. The findings are consistent
with the earlier report from Min et al. (3), which
evaluated 422 individuals with 0 CAC scores at base-
line with annual scanning for 5 years. In the 106 who
developed CAC >0, only age, diabetes, and smoking
were associated with incident CAC, but no risk factors
contributed to accelerated times to conversion.
Among 621 with CAC scores of >0 at baseline, only the
presence of CAC itself was associated with progres-
sion without any contribution from the presence or
absence of traditional risk factors (3). This raises the
interesting possibility that vascular health or the lack
of it correlates only modestly with the presence or
absence of a healthy or unhealthy risk factor profile.
Because no identifiable low-risk phenotype could
predict healthy arterial aging, we need to be looking
elsewhere to predict the transition of healthy to un-
healthy vasculature—imaging may fill in some of the
gap in the future.
Although the findings from Whelton et al. (2) are
interesting, they obviously should not detract from
the benefits of practicing a healthy lifestyle, because
the study was not designed to evaluate the effects of
lifestyle and behavioral components on plaque
development and progression. We should also note
that the study population was extremely low risk,
with 10-year hard event rates of 0.2% and 1.3% in the
persistent 0 CAC and incident CAC groups, respec-
tively, which renders differences in plaque evolution
in response to any intervention very unlikely. More-
over, in an analysis of the entire eligible MESA pop-
ulation of 6,229 participants, the same group
demonstrated slower CAC plaque progression and
lower mortality in those with higher healthy lifestyle
scores, albeit with a shorter scan interval and follow-
up (4). The results must not be misinterpreted as a
failure of healthy lifestyle, but must force us to think
about additional and possibly better biomarkers for
vascular risk.
JACC: CARDIOVASCULAR IMAGING, VOL. 8, NO. 12, 2015
DECEMBER 2015:1401–3
Their report exemplifies the need for a balance
between analyzing data from a population wide study
and application of the results to individuals. It is
seemingly easy to conclude from the statistical out-
comes of a cohort study that a younger age, female
gender, and lack of traditional risk factors are likely to
be associated with the persistence of healthy arterial
aging in an individual patient. This study, however,
provides some data to the contrary and thus raises
questions about clinical applicability, in view of the
heterogeneity of disease development in individual
subjects, wherein traditional risk factor-based pre-
diction might be wrong in one-third of subjects on
either side of the risk factor spectrum. Of course,
risk factors have other pathogenetic aspects beyond
just correlation with CAC (even when used as an
index of vascular health) and it would be unrea-
sonable to believe that events they predict happen
only in those with development of CAC. The study
did not measure serial changes in risk factors and
their associations with serial changes in CAC which
could present a different picture. It is also impor-
tant to remember that the ultimate goals are first to
predict and then, more importantly, to prevent
events, for which CAC determined vascular age is
an interesting intermediate step, with final proof
yet to be provided.
IN SICKNESS
The results of the current study mirror the observa-
tions made in substantially larger studies: the
inability of risk factors to robustly predict outcomes
in primary prevention and the superiority of the
demonstration of subclinical atherosclerosis to the
mere presence of risk factors. In more than one-half
million patients presenting with a first myocardial
infarction, almost 50% had #1 risk factor and only
20% had $3 risk factors (5). The net reclassification
indices of the Framingham Risk Score by CAC from 3
major prospective population based trials (MESA [6],
Heinz-Nixdorf [7], and Rotterdam [8]), ranged from
10% to 15% in the low-risk, 50% to 65% in the
intermediate-risk, and 35% in the high-risk groups,
with 19% to 25% for the entire population. In the
intermediate-risk group, risk prediction by risk fac-
tors seems worse than a flip of the coin, questioning
the robustness of population-based observation
when applied to an individual on a one-on-one
basis. In the Whelton et al. (2) study, one-third
of the entire 0 CAC population were in the ASCVD
$7.5% high-risk group and one-third of this
group failed to develop CAC, contrary to their risk
factor based prediction of high risk for events.
JACC: CARDIOVASCULAR IMAGING, VOL. 8, NO. 12, 2015
DECEMBER 2015:1401–3
If we believe, as much data show, that a CAC of
0 means very minimal risk for events, it is clear that
risk factor based prediction has much to improve
upon.
The authors correctly state that the prediction of
individuals who will or will not continue to have
healthy aging is elusive given the currently available
risk factors and further work using genetic markers
would be needed to perfect predictive values for in-
dividual application. Genetic factors may not only
allow for the identification of the unhealthy pheno-
type, but would also explain the likelihood of the
response to medical therapy and aggressive risk fac-
tor control (9). It is expected that the individual
genetic fabric would reconcile the translation of
population-based risk factor profile to disease devel-
opment or healthy aging.
REFERENCES
1. Einstein A. Available at: https://www.quora.
com/Did-Einstein-really-define-insanity-as-doing-
the-same-thing-over-and-over-again-and-expecting-
different-results. Accessed November 4, 2015.
2. Whelton SP, Silverman MG, McEvoy JW, et al.
Predictors of long-term healthy arterial aging: cor-
onary artery calcium nondevelopment in the MESA
Study. J Am Coll Cardiol Img 2015;8:1393–400.
3. Min JK, Lin FY, Gidseg DS, et al. Determinants of
coronary calcium conversion among patients with
a normal coronary calcium scan. What is the
“warranty period” for remaining normal? J Am Coll
Cardiol 2010;55:1110–7.
4. Ahmed HM, Blaha MJ, Nasir K, et al. Low-risk
lifestyle, coronary calcium, cardiovascular events,
Hecht et al. 1403
Editorial Comment
CONCLUSIONS
The goal of primary prevention is to produce a match
made, not in heaven after an unpredicted fatal event,
but on earth while the patient is still living. A multi-
tude of data consistently shows that imaging the
plaque itself (e.g., CAC) is the most powerful
biomarker for both sickness and health. It may be
time to acknowledge that the marriage of CAC to in-
dividual risk prediction, faithful in both vascular
health and future sickness, is more likely to provide
an accurate assessment of the future than risk factors.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Harvey Hecht, Icahn School of Medicine at Mount
Sinai Cardiology, 1111 Amsterdam Avenue, New York,
New York 10025. E-mail: hhecht@aol.com.
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2013;178:12–21. Coronary calcium score improves classification of
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