JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 64, NO. 7, 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.2014.06.1148
EDITORIAL COMMENT
The Fermi Paradox and
Coronary Artery Disease*
Ilan Gottlieb, MD, PHD,y Ronaldo Souza Leão Lima, MD, PHDz
“Where is everybody?”
W
nonobstructive ones (4–7). The apparent paradox here
—Enrico Fermi (1)
hile working at Los Alamos National
Laboratory in the 1950s, physicist Enrico
Fermi noticed that our galaxy contains
billions of stars younger than the Sun and that some
of these stars probably have planets similar to Earth
that may also develop intelligent life. Given enough
time, these civilizations should be able to develop
interstellar travel and in tens of millions of years
(a blink of an eye in the time span of a universe),
they should be able to colonize the entire galaxy,
including Earth, of course. The lack of convincing
evidence of extraterrestrial life here on Earth or in
the remaining 80 billion galaxies, led Fermi to ask
the famous question: “Where is everybody?”
Fermi
was
confronted
with
a
paradox
that
involved probability, scale, and evidence. Coronary
artery disease (CAD) presents a similar challenge. The
pathophysiological importance of nonobstructive CAD
is well known, as two-thirds of acute coronary syndromes (ACS) originate from plaques with less than
50% stenosis and five-sixths from plaques with less
than 70% stenosis (2). This alone might explain why
approximately one-half of acute myocardial infarctions occur as the first presentation of CAD in previously asymptomatic patients (3). Nevertheless, there is
overwhelming evidence from both functional and
anatomic studies that luminal obstruction is a major
determinant of cardiovascular prognosis because
more obstructive lesions tend to rupture more than
is easily unraveled by recognizing that nonobstructive
CAD is much more prevalent than obstructive CAD, so
that even though the latter has higher individual risk,
the former overpowers by the collective risk (2).
Still,
an
important
question
remains
to
be
answered. Why has the revascularization of obstructive lesions proven beneficial in the acute setting (8)
but proven so difficult in chronic CAD (9,10)? The
pathophysiological rationale that embodies the key
for this answer is the fact that rapidly progressing
symptoms—chest pain at rest or positive cardiac
enzymes—are markers of an unstable plaque that has
rapidly enlarged due to an acute event, such as
intraplaque hemorrhage or rupture of the fibrous cap
(11). Revascularization of these unstable plaques
successfully interrupts the acute cascade, and the
patient fares better on average than those administered medical treatment alone, mainly because the
past is being predicted by selecting a plaque that has
already destabilized. On the other hand, in chronic
atherosclerosis, future risk of plaque rupture needs to
be predicted, and predicting the future is no easy
feat, especially with atherosclerosis.
SEE PAGE 684
In this issue of the Journal, Puchner et al. (12) present results from a substudy of the multicenter
ROMICAT II (Rule Out Myocardial Infarction/Ischemia
Using Computer-Assisted Tomography II) trial that
tested the use of computed tomography angiography
(CTA) in the evaluation of patients with chest pain in
the emergency department. The researchers should be
congratulated for their well-presented work, but
*Editorials published in the Journal of the American College of Cardiology
mostly because they add an important piece to the
reflect the views of the authors and do not necessarily represent the
complex CAD puzzle. They reported that certain “high-
views of JACC or the American College of Cardiology.
risk” anatomic findings by CTA are associated with ACS
From the yCardiovascular Imaging Department, National Institute of
(a composite of myocardial infarction and unstable
Cardiology, Rio de Janeiro, Brazil; and the zSchool of Medicine, Department of Cardiology, Federal University of Rio de Janeiro, Rio de Janeiro,
angina) and significantly added diagnostic capability
Brazil. Both authors have reported that they have no relationships rele-
of coronary CTA for ACS over stenosis assessment
vant to the contents of this paper to disclose.
alone. These high-risk features were positive plaque
Gottlieb and Lima
694
JACC VOL. 64, NO. 7, 2014
AUGUST 19, 2014:693–5
The Fermi Paradox
of other large multicenter studies (16,17) and allowed
Sensitivity
100%
97%
94%
92%
for CTA to be successfully implemented to rule out ACS
Specificity
among patients with normal cardiac enzyme levels
95%
and nonischemic electrocardiograms at admission in
many emergency departments worldwide. Despite the
75%
ability to discharge patients earlier, total hospital costs
73%
in the ROMICAT-II trial were similar between the CTA
and usual care groups, probably due to slightly higher
60%
(with borderline statistical significance) invasive
50%
coronary angiography and revascularization utiliza43%
tion rates (15), which underlie the importance of better
patient selection for revascularization.
32%
In this ROMICAT-II substudy, one-third of all
25%
patients had at least 1 high-risk plaque feature,
whereas only 10% had obstructive ($50%) CAD.
Furthermore, although 95% of patients with ACS had at
0%
Positive Remodeling
Low Attenuation
Napkin Ring Sign
Spotty Calcification
least 1 high-risk plaque feature, 30% of the patients
without ACS still had this finding, which proves to be
much more sensitive than specific. This bias toward
F I G U R E 1 Point Accuracy Values for Acute Coronary Syndrome
sensitivity in spite of specificity was driven by a high
These point accuracy values for acute coronary syndrome, which are divided by each
prevalence of spotty calcification. Findings such as
individual plaque feature, are derived from the ROMICAT-II (Rule Out Myocardial
napkin-ring sign, low attenuation plaques, and posi-
Infarction/Ischemia Using Computer-Assisted Tomography II) substudy.
tive remodeling had much higher specificity values for
ACS diagnosis, as shown in Figure 1, derived from their
remodeling (10% increase in adventitial diameter),
work. It should be noted, however, that revasculari-
low attenuation within a plaque (indicative of lipid-
zation of all patients with high-risk plaque features
rich content), spotty calcification, and the “napkin-
would likely result in overutilization of resources,
ring” sign (a ring-like peripheral higher attenuation
with much potential for harm, and we would need
of the noncalcified portion of the coronary plaque),
randomized trials before any such conclusions could
all plaque characteristics that have been previously
be inferred.
reported
to
be
independently
associated
with
Importantly, the finding of markers of bad prog-
worse prognosis (13,14). The study’s main finding was
nosis does not make them therapeutic targets. The
that, even after adjustment for clinical variables and
CAD paradox involves the higher probability of an
the presence of coronary luminal obstruction, the
obstructive plaque to rupture, but the scale of non-
presence of at least 1 high-risk feature was associated
obstructive CAD and other factors besides luminal
with an overwhelming 8.9 times increase in the odds of
narrowing hinder the finding of convincing evi-
ACS. However, the 95% CI ranged from 1.8 to 43.3.
dence that revascularization of obstructive lesions is
The main findings from the ROMICAT-II original
trial (15) were that patients could be safely discharged
much faster from the emergency department using
beneficial in chronic CAD.
Probability, scale, and evidence. So, where is
everybody?
CTA rather than usual care (e.g., 8.6 h to discharge
50% of the CTA population compared with 26.7 h in
REPRINT REQUESTS AND CORRESPONDENCE : Dr.
the usual care group [mean of 7.6 h less], with 47%
Ilan Gottlieb, Cardiovascular Imaging Department,
of the CTA patients being discharged directly from the
National
emergency department compared with only 12% in the
Azevedo, 36, Apt 502, Rio de Janeiro, RJ 22471-220
usual care group). These findings were similar to those
Brazil. E-mail: [email protected].
Institute
of
Cardiology,
Rua
Carvalho
REFERENCES
1. Fermi paradox. Available at: http://www.seti.
org/seti-institute/project/details/fermi-paradox.
Accessed July 2, 2014.
3. Murabito JM, Evans JC, Larson MG, Levy D.
Prognosis after the onset of coronary heart
disease. An investigation of differences in
outcome between the sexes according to initial
4. Patel MR, Dehmer GJ, Hirshfeld JW, et al.
ACCF/SCAI/STS/AATS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization: a
report of the American College of Cardiology
2. Falk E, Shah PK, Fuster V. Coronary plaque
disruption. Circulation 1995;92:657–71.
coronary disease presentation. Circulation 1993;
88:2548–55.
Foundation Appropriateness Criteria Task Force,
Society for Cardiovascular Angiography and
Gottlieb and Lima
JACC VOL. 64, NO. 7, 2014
AUGUST 19, 2014:693–5
Interventions, Society of Thoracic Surgeons,
American Association for Thoracic Surgery, American Heart Association, and the American Society
of Nuclear Cardiology: endorsed by the American
Society of Echocardiography, the Heart Failure
Society of America, and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol
2009;53:530–53.
5. Chow BJW, Small G, Yam Y, et al. The
incremental prognostic value of cardiac CT in
CAD using CONFIRM (Coronary Computed Tomography Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry). Circ
Cardiovasc Imaging 2011;4:463–72.
6. Min JK, Dunning A, Lin FY, et al. Age- and
sex-related differences in all-cause mortality
risk based on coronary computed tomography
angiography findings: results from the international multicenter CONFIRM (Coronary
CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry)
of 23,854 patients without known coronary
artery disease. J Am Coll Cardiol 2011;58:
849–60.
7. Villines TC, Hulten EA, Shaw LJ, et al. Prevalence and severity of coronary artery disease and
adverse events among symptomatic patients with
coronary artery calcification scores of zero undergoing coronary computed tomography angiography: results from the CONFIRM (Coronary CT
The Fermi Paradox
Angiography Evaluation for Clinical Outcomes: an
International Multicenter). Registry. J Am Coll
Cardiol 2011;58:2533–40.
8. Fox KAA, Clayton TC, Damman P, et al. Longterm outcome of a routine versus selective
invasive strategy in patients with non–ST-segment
elevation acute coronary syndrome: a metaanalysis of individual patient data. J Am Coll
predicts acute coronary syndromes independent
of significant stenosis in acute chest pain: results
from the ROMICAT-II trial. J Am Coll Cardiol 2014;
64:684–92.
13. Motoyama S, Kondo T, Sarai M, et al. Multislice
computed tomographic characteristics of coronary
lesions in acute coronary syndromes. J Am Coll
Cardiol 2007;50:319–26.
Cardiol 2010;55:2435–45.
9. Stergiopoulos K, Brown DL. Initial coronary
stent implantation with medical therapy vs
medical therapy alone for stable coronary artery
disease. Arch Intern Med 2012;172:312–9.
10. Stergiopoulos K, Boden WE, Hartigan P,
et al. Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: a
collaborative meta-analysis of contemporary
randomized clinical trials. JAMA Intern Med
2014;174:232–40.
11. Stary HC, Chandler AB, Dinsmore RE, et al.
A definition of advanced types of atherosclerotic lesions and a histological classification of
atherosclerosis. A report from the Committee on
Vascular Lesions of the Council on Arteriosclerosis,
American Heart Association. Arterioscler Thromb
Vasc Biol 1995;15:1512–31.
12. Puchner SB, Liu T, Mayrhofer T, et al. Highrisk plaque detected on coronary CT angiography
14. Motoyama S, Sarai M, Narula J, Ozaki Y.
Coronary CT angiography and high-risk plaque
morphology. Cardiovasc Interv Ther 2013;28:1–8.
15. Hoffmann U, Truong QA, Schoenfeld DA, et al.
Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med 2012;367:
299–308.
16. Goldstein JA, Chinnaiyan KM, Abidov A, et al.
The CT-STAT (Coronary Computed Tomographic
Angiography for Systematic Triage of Acute Chest
Pain Patients to Treatment) trial. J Am Coll Cardiol
2011;58:1414–22.
17. Litt HI, Gatsonis C, Snyder B, et al. CT
angiography for safe discharge of patients with
possible acute coronary syndromes. N Engl J Med
2012;366:1393–403.
KEY WORDS chest pain, computed
tomography angiography, coronary artery disease,
emergency department, plaque morphology
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