EDITORIAL COMMENT
Will SCUBE1 Solve the Ischemia Marker Deficit?*
W. Franklin Peacock, MD, FACEP*
Cleveland Clinic, Department of Emergency Medicine, Cleveland, Ohio.
* Reprint requests and correspondence: Dr. W. Franklin Peacock, Cleveland Clinic, Department of Emergency Medicine, 9500 Euclid Avenue, E-19, Cleveland, Ohio 44195. (Email: PEACOCW{at}ccf.org).
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.
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 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 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 patient's 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 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 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.
 |
Footnotes
|
|---|
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.
* 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. 
|
References
|
|---|
1. Dai D-F, Thajeb P, Tu C-F, et al. Plasma concentration of SCUBE1, a novel platelet protein, is elevated in patients with acute coronary syndrome and ischemic stroke J Am Coll Cardiol 2008;51:2173-2180.[Abstract/Free Full Text]2. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update Circulation 2007;115:e69-e171.[Free Full Text] 3. Wu CM, McLaughlin K, Lorenzetti DL, et al. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis Arch Intern Med 2007;167:2417-2422.[Abstract/Free Full Text] 4. Pope JH, Aufderheide TP, Ruthazer R, et al. Missed diagnoses of acute cardiac ischemia in the emergency department N Engl J Med 2000;342:1163-1170.[Abstract/Free Full Text] 5. Peacock WF, Emerman CL, McErlean ES, et al. Prediction of short and long term outcomes by troponin-T in low risk patients evaluated for acute coronary syndromes Ann Emerg Med 2000;35:213-220.[CrossRef][Web of Science][Medline] 6. Kugelmass AD, Anderson AL, Brown PP, et al. Does having a chest pain center impact the treatment and survival of acute myocardial infarction patients? Circulation 2004;110(Suppl):III409(abstr). 7. Mitchell AM, Garvey JL, Chandra A, et al. Prospective multicenter study of quantitative pretest probability assessment to exclude acute coronary syndrome for patients evaluated in emergency department chest pain units Ann Emerg Med 2006;47:438-447.[Web of Science] 8. Reilly BM, Evans AT, Schaider JJ, et al. Triage of patients with chest pain in the emergency department: a comparative study of physicians' decisions Am J Med 2002;112:95-103.[CrossRef][Web of Science][Medline]
Related Article
-
Plasma Concentration of SCUBE1, a Novel Platelet Protein, Is Elevated in Patients With Acute Coronary Syndrome and Ischemic Stroke
- Dao-Fu Dai, Peterus Thajeb, Cheng-Fen Tu, Fu-Tien Chiang, Chien-Hsiun Chen, Ruey-Bing Yang, and Jin-Jer Chen
J. Am. Coll. Cardiol. 2008 51: 2173-2180.
[Abstract]
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
T. Reichlin, W. Hochholzer, S. Bassetti, S. Steuer, C. Stelzig, S. Hartwiger, S. Biedert, N. Schaub, C. Buerge, M. Potocki, et al.
Early Diagnosis of Myocardial Infarction with Sensitive Cardiac Troponin Assays
N. Engl. J. Med.,
August 27, 2009;
361(9):
858 - 867.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Reichlin, W. Hochholzer, C. Stelzig, K. Laule, H. Freidank, N. G. Morgenthaler, A. Bergmann, M. Potocki, M. Noveanu, T. Breidthardt, et al.
Incremental value of copeptin for rapid rule out of acute myocardial infarction.
J. Am. Coll. Cardiol.,
June 30, 2009;
54(1):
60 - 68.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. DeMaria, O. Ben-Yehuda, J. J. Bax, G. K. Feld, B. H. Greenberg, W. Y.W. Lew, J. A.C. Lima, A. S. Maisel, S. M. Narayan, D. J. Sahn, et al.
Highlights of the Year in JACC 2008.
J. Am. Coll. Cardiol.,
January 27, 2009;
53(4):
373 - 398.
[Full Text]
[PDF]
|
|
|
|
Top
References