Myocardial infarction redefined: role of cardiac troponin testing.

As we move into the new Millennium, “the times they are a changin” regarding the diagnostic criteria used to rule in and rule out acute myocardial infarction (AMI) (1 ). The purpose of this editorial is to comment on the new cardiology guidelines for the redefinition of AMI and unstable angina, as well as to compare them with previously published laboratory medicine recommendations. Some of the new recommendations made by clinical groups may appear to be in conflict with those published previously by laboratory medicine groups; thus, we document the chronology and evolution of all guidelines on the use of cardiac markers. Consensus documents recently published by the European Society of Cardiology (ESC), the American College of Cardiology (ACC), and the American Heart Association (AHA) make specific recommendations on the use of biomarkers for the detection of myocardial infarction (MI) (2–5). The redefined criteria used to classify acute coronary syndrome (ACS) patients presenting with ischemic symptoms as acute, evolving, or recent MI are heavily predicated on an increased serum/plasma cardiac troponin (I or T) concentration (2–4). Furthermore, in the new ACC/AHA guidelines for management of patients with unstable angina and non-ST-segment elevation MI (NSTEMI), an increased cardiac troponin value establishes the diagnosis of NSTEMI, whereas a normal cardiac troponin value establishes the diagnosis of unstable angina in ACS patients with ischemic discomfort (5 ). The new guidelines emphasize the following clinical issues. First, increases of cardiac troponins are indicative of myocardial injury but are not synonymous with MI or an ischemic mechanism of injury. If an ischemic mechanism of injury is unlikely, other etiologies of myocardial injury should be pursued. Second, increases in cardiac troponin likely reflect irreversible rather than reversible injury, although there is continuing debate on this issue. Third, the degree of the increase of cardiac troponin in ischemia-induced injury patients is related to the patient’s prognosis. Fourth, patients who undergo interventional procedures, such as percutaneous transluminal coronary angioplasty (PTCA) or heart surgery, are likely to have increased cardiac troponin as a consequence of the procedure. In heart surgery patients, no biomarker is currently capable of distinguishing injury caused by a MI from the procedure-induced injury itself. However, increases of cardiac troponin after coronary angioplasty or stent placement is indicative of ischemic cell death and should be labeled as a MI. The guidelines also emphasize the following laboratory (analytical) issues. First, the diversity of the various cardiac troponin assays, especially for cardiac troponin I (cTnI), has led to substantial confusion among both clinicians and laboratorians. Standardization issues will likely assist in resolving some of these concerns. Acceptance of individual troponin assays should be based on the peerreviewed literature. Second, clinical studies in the peerreviewed literature should provide information pertaining to an assay’s imprecision (CV), reference intervals, potential analytical interferences, and acceptable specimen types. An upper reference limit, defined as the 99th percentile with an acceptable imprecision of #10%, has been proposed. This places a large responsibility on the manufacturers of all cardiac troponin assays to optimize the low end of their assays. Although it is presently recognized that relatively few, if any, companies can meet this recommendation, it was the intent of the cardiology community to challenge the troponin assay manufacturing industry to meet this critical issue because diagnostic and therapeutic decisions will be based on lower cardiac troponin cutpoints. Although the use of plasma (heparin) instead of serum had initially been advocated as a means of decreasing the overall turnaround time for reporting a result, recent studies have shown that several cardiac troponin assays may give variable and substantially lower concentrations for heparinized plasma vs serum (6, 7). Therefore, each assay needs to be validated for both serum and plasma. Third, cardiac troponin concentrations should be measured on serial blood samples collected at least 6–9 h after onset of symptoms, before a patient is ruled in or ruled out for MI. Fourth, if cardiac troponin assays are not available, the best alternative is creatine kinase MB (CK-MB) mass. Rapidly appearing biomarkers, such as myoglobin or CK-MB isoforms, are recommended for patients in need of an early triage, but they do not confirm the diagnosis of MI. We completely support the new cardiology guidelines and support the evidencebased literature that demonstrates cardiac troponin as the definitive marker to be utilized for detection of the MI, risk stratification, and to assist clinicians in optimizing therapy. From a clinical perspective, there is clear evidence that any amount of detectable cardiac troponin release is associated with risk of adverse clinical events. For cardiac troponin T (cTnT), the FRISC II study demonstrated that risk stratification was achieved with use of a cutoff concentration at the 99th percentile (8.5% incidence of death or AMI at 12 months for cTnT ,0.01 mg/L vs 18.0% for cTnT $0.01 mg/L; P ,0.001) (8 ). Similar results have been demonstrated for cTnI, where use of the 97.5th percentile cutoff of 0.1 mg/L produced significant odds ratios of 2.2 (confidence interval, 1.3–3.6), 2.8 (1.5–5.1), and 3.0 (1.5–5.7) with the Immuno 1 (Bayer), ACS:180 (Bayer), and Dimension RxL (Dade Behring) analyzers, respectively (9 ). For each assay, the values at the 97.5th vs 99th percentiles are similar. Although preliminary trials show risk stratification benefits at the low end of cardiac troponin assays, as noted above, the majority of manufacturers cannot meet the 10% imprecision (CV) recommendations at the 99th percentile. It is our opinion, therefore, that in the context of clinical medicine, a predetermined higher concentration that meets the goal of 10% imprecision be used for each assay as a medical diagnostic guide Editorial