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Journal of the American College of Cardiology

2008 by the American College of Cardiology Foundation


Published by Elsevier Inc.

EDITORIAL COMMENT

Will SCUBE1 Solve the


Ischemia Marker Deficit?*
W. Franklin Peacock, MD, FACEP
Cleveland, Ohio

In this issue of the Journal, Dai et al. (1) report their


findings regarding plasma SCUBE1. This marker, a protein
associated with platelet-endothelial interactions, may be
indicative of platelet activation occurring during acute
ischemic events. The significance of detecting this interaction is its potential as a nonspecific indicator of acute
ischemia. Dai et al. (1) report that SCUBE1 is elevated in
both acute coronary syndromes (ACS) and acute ischemic
stroke (AIS), while being undetectable in healthy control
subjects and chronic coronary artery disease. SCUBE1
concentrations were also related to stroke severity, and
correlated with sCD40L, thus providing support that it
reflects platelet activation indicative of acute thrombosis.
See page 2173

This, therefore, begs the question what is the value in


detecting platelet activation? The answer lies in our understanding that thrombosis plays a principal role in ACS/AIS
pathogenesis. In fact, beyond diagnosis, many of our most
effective therapies (aspirin, P2Y12 inhibition, 2b3a antagonists, and so on) rely on interrupting pathways of platelet
activation. Thus, in the proper clinical setting, detecting
thrombosis may help solve one of the challenges in evaluating patients presenting to the hospital with symptoms
consistent with a thrombotic event: our inability to detect
ischemia that prefaces infarction. While current tools detect
myocardial necrosis reasonably well (e.g., troponin), they are
blind for ischemia without necrosis, and no good serum test
for cerebral ischemia exists. SCUBE1 is also promising by
its signal that it may overcome the weakness of many risk
stratification tools (e.g., C-reactive protein): the inability to

*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Cleveland Clinic, Department of Emergency Medicine, Cleveland, Ohio.
Dr. Peacock is on the Scientific Advisory Board of Abbott, Beckman-Coulter,
Biosite, Inovise, Inverness, Ortho Clinical Diagnostics, and The Medicines Co. He
has received research grants from Abbott, Biosite, Brahms, CHF Solutions,
Heartscape, Inovise, Inverness, PDL, and The Medicines Co. He has been on the
Speakers Bureau for Abbott, Biosite, Ortho Clinical Diagnostics, PDL, and Scios
and he also has ownership interest in Vital Sensors.

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Vol. 51, No. 22, 2008


ISSN 0735-1097/08/$34.00
doi:10.1016/j.jacc.2008.02.060

differentiate long-term risk that does not need emergency


intervention, from an acute event requiring immediate
life-saving therapy.
What is the potential role for SCUBE1? With the
exception of the occasional individual with dynamic electrocardiogram (ECG) changes, our approach for chest pain
is to use highly specific grossly insensitive testing to determine who has newly dead myocardium. By this strategy,
identifying who will benefit from an intervention requires
cell death to have already happened. And for AIS, we can
rule in events with imaging, but no rapid blood test
accurately excludes brain ischemia. The ability to identify a
patient at risk for cell death, before it actually occurs, would
represent an important advance for patients presenting with
suspected ACS or AIS.
An accurate ischemia marker represents one of the large
unmet needs in contemporary medicine. Beyond selected
ACS markers, our existing risk stratification tools are blunt
in the acute care environment. Our strategies are driven
almost entirely by ruling in disease. Nowhere in the early
evaluation of ACS or AIS can we definitively exclude
ischemia. By focusing on cell death, rather than the process
of cell injury, we lose the ability to prevent necrosis. While
there is great value in treating patients who have suffered
cellular death, it is the vascular equivalent of closing the
barn door after the horse is gone.
If validated, an accurate ischemia marker will change
medicine. This is no exaggeration. Cardiovascular disease
(ACS and AIS) is the big one; 79 million U.S. adults (1 of
every 3) suffer from it, and a cardiovascular disease death
occurs every 2.8 s (2). Who needs an ischemia marker? That
would be the overcrowded U.S. emergency departments
where patients with suspected ischemia present. It is predicted that in 2008 there will be 11.2 million emergency
department visits for chest pain. While the numbers for
stroke mimics are less clear, they too are certainly in the
millions. This is a problem. Our diagnostic tools are limited
and the risks are high. Patients discharged in the throes of
impending ACS suffer disproportionate morbidity and mortality, and missed myocardial infarction represents the
highest malpractice award for emergency physicians. On the
cerebral side, patients with transient ischemic attack suffer a
3.5% and 8.0% risk of stroke in the following 2 and 30 days,
respectively, with their inappropriate discharge representing
an opportunity lost (3).
While some presentations are clearly low risk, some result
in acute mortality, and separating these groups is difficult. In
patients presenting with suspected myocardial ischemia,
12-lead ECG-diagnosed ST-segment elevation myocardial
infarction identifies the highest-risk cohort, but occurs in only
3% of all chest pain patients (4). Unfortunately, for both
ACS/AIS the majority of presentations fall into the gray zone
where unclear risk drives a number of testing strategies.
As recently as 10 years ago, emergency physicians made
admission and discharge decisions based solely on clinical

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Peacock
Editorial Comment

grounds. But inaccuracy caused errors, some with adverse


outcomes, and emergency physicians collectively lowered
their admission threshold. The addition of rapid turnaround
troponin assays helps to identify high-risk patients, but a
critical sensitivity deficit still exists. Acute coronary syndromes cannot be excluded with troponin. In one emergency department study of low-risk emergency department
patients (5), troponin had a specificity and sensitivity of
99.2% and 9.5%, respectively, for predicting acute adverse
events. While troponin confirms a diagnosis and identifies
interventional need (e.g., percutaneous coronary intervention), it does not exclude the presence of disease, which is
critically needed in the emergency department. On the
stroke side, with no marker whatsoever, we rely on advanced
imaging (e.g., computed tomography/magnetic resonance
imaging angiographic and perfusion studies) with both time
and interpretation challenges that make it difficult to rapidly
exclude cerebral events. A marker that excluded thrombosis
would allow the physician to focus on other reasons for the
patients presentation. While an event marker (e.g., necrosis) is helpful, in the clinical value hierarchy, this is not
optimal. Better yet would be a marker indicating an adverse
event is about to occur. Best would be a marker that reliably
excluded ischemia.
To address the inability to exclude ACS, chest pain
centers (CPCs) have been developed, and the Society of
Chest Pain was formed to insure appropriate quality processes. They allow serial markers and provocative testing to
be performed without in-patient hospitalization. And they
work. In one before-and-after study of 4,477 patients,
Kugelmass et al. (6) reported CPC use decreased mortality
and increased discharges by a whopping 37% and 36%,
respectively. This process rarely concludes with a discharged
patient suffering a short-term adverse event. But this advantage only occurs at great cost in time and resources.
Single-visit charges can exceed $4,500, and CPC use has
skyrocketed, with ever lower-risk patients being admitted
for evaluation. Some centers now report 98% of all CPC
evaluations are negative (7,8). The math is obvious; we have
overcome the sensitivity deficit of necrosis markers by
providing extensive work up for nearly all emergency department patients with chest pain. And recently a similar
trend began occurring with suspected stroke, where patients
are admitted to observation units for more and more
extensive evaluations. Although time consuming and expensive, these strategies provide the most accurate diagnoses in
a medical climate driven to a miss rate approaching zero.
Are there any real serum ischemia markers currently
available? Both ischemia modified albumin and myeloperoxidase have Food and Drug Administration approval for
use as risk stratification tools in ACS, but they suffer from
limited clinical use. Although ischemia modified albumin
has a more extensive database, neither marker has been
evaluated in an all comer prospective trial where the results
of clinical decision making based on these analytes are
reported. Risk stratification of suspected ACS/AIS can be a

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JACC Vol. 51, No. 22, 2008


June 3, 2008:21813

dicey game. Any new marker must at least meet the 95%
sensitivity standard obtainable by current clinical practice.
Where does SCUBE1 fit in? The report in this issue of
the Journal is a significant clinical investigation for this
marker. It appears promising. Its biology seems consistent
with the genesis of ischemia. Its elevation in both AIS and
ACS provide consistency of mechanism, a relationship to
severity of illness is suggested, and its lack of elevation in
non-ACS diseased control subjects suggests that it may
have some degree of sensitivity.
But as to the question of can we use SCUBE1 today,
the answer is a short no, and much work remains before
we can determine if that deserves to change. A number of
important questions must first be answered:
1. This was a tube and bottle study; a commonly used
method to improve the pathophysiological understanding of an analyte with potential value. While the results
are promising, this methodology provides minimal understanding of the clinical consequences if patient care
was based solely on SCUBE1 results.
2. Per the protocol, the 40 patients in the ACS group
could be enrolled up to 120 h after onset. Since patients
may present earlier than 120 h, this is a major limitation,
and changes the conclusion to in patients presenting up
to 5 days after symptom onset, SCUBE1 may identify
ACS.
3. Understanding the early kinetics of SCUBE1 is critical.
In the acute care setting, if SCUBE1 is a late riser, it is
a dead horse. A late-rising marker will not have adequate sensitivity to exclude ischemia at presentation, and
a nonspecific answer 3 days later will have limited
applicability.
4. The effects of confounders on SCUBE1 must be much
more detailed. What is the impact of body mass index,
renal dysfunction, and age? Does a hematoma elevate
SCUBE1, what is the effect of trauma, and what
happens with an intramuscular injection? Furthermore,
since we do not know the rate of daily or hourly
SCUBE1 changes in large populations (is it elevated
every time you brush your teeth?), much more understanding is needed before clinical use can be considered.
5. Pre-test odds of disease drive predictive values. When
highly selected populations are used to evaluate test
performance, as in this study, the results can be remarkably different when they are used in an all-comers
suspected ischemia population. Many conditions causing platelet activation are likely to result in elevated
SCUBE1. We need to know how SCUBE1 works in
real life patients before we can use this marker.
We clearly need a sensitive ischemia marker. This study
does not tell us if SCUBE1 can insure the absence of
ischemia anywhere in the patient. Nor can it tell us if
SCUBE1 will allow enough early safe discharges of the
suspected ACS/AIS patient in the acute care population to

Peacock
Editorial Comment

JACC Vol. 51, No. 22, 2008


June 3, 2008:21813

justify its expense and the probability that some rate of false
positives will drive increased negative evaluations.
These limitations do not detract from the potential of
SCUBE1. We already have a signal that it will not be
elevated in every single patient, as the 40 normal subjects
and 83 nonacute diseased control subjects in this study had
undetectable levels. Furthermore, the mechanism of
SCUBE1 suggests that it may rise even before necrosis. If
this holds true as additional research is performed, it will be
a very important marker. Will an early intervention based on
initial SCUBE1 levels prevent a subsequent troponin rise?
Can SCUBE1 be mated with other new emerging technologies? Will a normal SCUBE1 and a normal 80-lead ECG
move us to immediate discharge? Only more study will tell.
Reprint requests and correspondence: Dr. W. Franklin Peacock,
Cleveland Clinic, Department of Emergency Medicine, 9500
Euclid Avenue, E-19, Cleveland, Ohio 44195. E-mail:
PEACOCW@ccf.org.

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