With 8 million patients arriving with nontraumatic chest pain to emergency departments in the US each year, the clinical evaluation, triage, and management of patients with possible acute coronary syndromes (ACS) presents a substantial medical and fiscal challenge (1). Although 2–5% of patients with myocardial infarction (MI) are inadvertently discharged from the emergency department and are a leading reason for malpractice claims, more than 50% of patients hospitalized for evaluation of chest pain are discharged with diagnoses other than ACS (1). Among those patients with definite ACS, early treatment may reduce the extent of myocardial injury, and thus rapid diagnosis and initiation of therapy is a central tenet of management (2). In addition, given the increasing array of treatments for the heterogeneous population of patients admitted with definite ACS, effective risk stratification and targeting of therapy have become a focus of contemporary management of ACS (2, 3). As such, the objectives of the initial assessment are twofold:(a) to assess the probability that the patient’s symptoms are related to acute coronary ischemia; and (b) to assess the patient’s risk of recurrent cardiac events, including death and recurrent ischemia (2). In the ideal circumstance, physicians could reliably identify patients with definite ACS and begin appropriate therapy as early as possible, as well as distinguish those without acute coronary ischemia who may be candidates for early discharge without extended observation in the emergency department, chest pain unit, or inpatient wards. Unfortunately, other than in the 15% of patients with ACS who present with diagnostic ST-segment elevation, our basic clinical tools (history, physical exam, and electrocardiogram) for making the diagnosis of ACS offer limited sensitivity and specificity. Biomarkers of myocardial necrosis add importantly to these other clinical tools and are a critical component of the assessment of suspected ACS (4). In particular, cardiac troponins have emerged as powerful tools for triage, as well as for targeting the use of more aggressive (and often costly) antiplatelet, anticoagulant, and invasive therapies to those patients who are likely to benefit most (2, 3, 5). Nevertheless, despite the ability to detect quantitatively smaller degrees of myocardial necrosis, cardiac troponins exhibit a time course for release and detection in the peripheral circulation that is similar to creatine kinase-MB and necessitates measurement at least 6 h after symptom onset to exclude MI with high accuracy (5). Approximately 40–60% of patients with likely/definite ACS will present with initial troponin concentrations below the clinical decision limit for the assay (6). These patients fall into two major categories:(a) those presenting early after onset of an acute MI in whom cardiac troponin I/T or creatine kinase-MB is not yet detectable by serum/plasma testing; and (b) those presenting with acute myocardial ischemia without necrosis (ie, unstable angina). Differentiating these two groups from patients with chest pain syndrome of an etiology other than coronary ischemia is the major clinical challenge. Although multimarker strategies (7, 8), myocardial perfusion imaging (9), and carefully developed clinical pathways that integrate all of the above elements (10) improve overall diagnostic performance, they are also limited by obligatory time for observation.“Rapid rule-out MI” protocols incorporating myoglobin do not identify patients with unstable angina and are limited by diminished specificity for MI (11). Thus, a biomarker that reliably detects myocardial ischemia in the absence of necrosis or before cardiac troponins are increased would add …