The ECG has long been the standard for the detection of ischemia. This capitalizes on the fact that ischemic myocardium repolarizes differently than normal myocardium, seen as changes in the ST-complex. Ischemic myocardium also does not contract normally because energy production and utilization are altered. Thus, the effects of ischemia can be observed by examining myocardial function through a number of imaging modalities. Finally, ischemia interferes with a myriad of biochemical processes and metabolic pathways, providing additional opportunities for detection.
ACS is a dynamic syndrome, and ischemic ECG changes are temporal in nature. This variability results in significant loss of sensitivity because any changes that do occur during ischemia may be transient (21). The role for serial ECGs in maximizing sensitivity for ischemia is intuitive but does not entirely overcome this limitation. For instance, there are areas of the heart that are difficult to "see" with the ECG, particularly in the left circumflex distribution. Small areas of ischemia may be missed altogether. Enhancing the ECG with additional inputs, including continuous ST-segment monitoring or enhanced lead configurations (22-24), decreases but does not completely obviate these limitations. Again, it must be remembered that the ECG sensitivity is limited because ischemic changes are evanescent. These temporal aspects remain a significant hindrance to the usefulness of the ECG in detecting ACS. The addition of immediate exercise treadmill testing has been used to improve sensitivity. Amsterdam et al. (25) reported on their experience with 1000 low-risk patients with nontraumatic chest pain who underwent symptom-limited exercise testing in the ED. Thirteen percent had a positive test, 23% were nondiagnostic, and the remaining 64% were discharged home (25).
When the ECG is nondiagnostic, myocardial perfusion imaging (MPI) can assist in risk stratification. The effectiveness of MPI is reflected in recent American College of Cardiology/American Heart Association/American Society for Nuclear Cardiology guidelines that assign this a class IA recommendation for the assessment of risk in patients with possible ACS when the ECG is nondiagnostic (26). The guideline stipulates that it is most appropriate for patients who have "possible" ACS following an initial triage based on the symptoms, ECG, and history. In this situation, rest MPI appears to be able to segregate patients at high risk who should be admitted from those at low risk who can be discharged home. Virtually every study incorporating technetium-based MPI in chest pain evaluation protocols has demonstrated a sensitivity of 90-100%, and a negative predictive value >99% for excluding ACS and the occurrence of short-term cardiac events (27-31). This high negative predictive value permits lower-risk patients with a negative test to be discharged safely from the ED within a couple of hours.
MPI is effective for detecting ACS, both with and without MI, with a sensitivity for the diagnosis of AMI similar to that for serial measurement of cardiac troponin. Notably, the sensitivity of the initial determination of troponin is limited to about 30%, whereas MPI is able to identify most patients with AMI rapidly. In addition, the sensitivity for predicting cardiac end points other than MI is significantly higher for MPI than for any other modality (27). "Perfusion imaging" is, to some extent, a misnomer for the technetium-based imaging agents because they fundamentally detect ischemia. Even in the presence of adequate perfusion, residual ischemia may appear as an abnormality. These agents can also be gated to the ECG to construct functional displays where regional wall motion can be assessed. The matched defects of perfusion and wall motion is a strong indicator that ischemia has occurred.
The surface 12-lead ECG, along with perfusion and functional imaging, provides proof of principle that ischemia can be detected early in the course of ACS. Furthermore, the absence of ischemia using this approach indicates low risk and allows safe discharge, while the rapid detection of ischemia provides an opportunity for early intervention that can improve outcomes, especially if necrosis has not yet occurred (32). Nevertheless, dependence on the ECG and symptoms alone is insufficiently sensitive, and strategies that include perfusion and functional imaging require a substantial investment in technology and expertise that has hindered their widespread application.
This major limitation could be overcome if ischemia could be reliably detected biochemically. A simple assay with high sensitivity and specificity for cardiac ischemia and a kinetic profile useful for an acute event marker would greatly simplify and improve the safety of the chest pain evaluation process. Biochemical tests tend to be relatively inexpensive and practical to perform, thus allowing widespread application. They can generally be performed with rapid turnaround, providing support for clinical decision making. Understanding the pathophysiology of ACS, the biochemical changes that occur, and the attendant clinical imperatives has fostered a concerted effort aimed at identifying biochemical markers of ischemia that can be widely applied toward the evaluation of patients with possible ACS.
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