From New England Journal of Medicine:
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Cardiac Troponins in Acute Coronary Syndromes
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Acute coronary syndromes have a common pathophysiologic mechanism. A coronary atherosclerotic plaque ruptures and a mural or occlusive thrombus forms, impairing or interrupting the perfusion of myocardial tissue. (1) Consequently, the clinical spectrum in patients arriving at the hospital with ischemic chest pain at rest ranges from unstable angina, due to the partial occlusion of a coronary vessel, to acute myocardial infarction, due to complete occlusion. In the absence of specific electrocardiographic changes, such as the development of new Q waves, only serial measurements of serum levels of cardiac enzymes, usually creatine kinase and its myocardial MB isoenzyme, can differentiate unstable angina from myocardial infarction.
In recent years immunoassays have been developed to measure serum levels of cardiac troponin T and cardiac troponin I. (2,3,4,5) Together with troponin C, these proteins regulate the calcium-dependent interactions between myosin and actin, which result in cardiac contraction and relaxation. Whereas the identical troponin C is expressed by cells in both cardiac and skeletal muscle, the amino acid sequences of troponin I and T in cardiac muscle differ from the sequences in skeletal muscle. This difference has allowed monoclonal antibodies against cardiac troponin I and T to be developed that have very low cross-reactivity with the corresponding isoforms in skeletal muscle. In several recent studies of relatively small numbers of patients with acute coronary syndromes, cardiac troponin I and T levels measured with these new assays have been shown to be very sensitive and specific markers of myocardial-cell injury. (6,7,8) In this issue of the Journal, two large studies of such patients are reported that assess the prognostic value of a single measurement of cardiac troponins in serum at the time of hospital admission. (9,10)
In a prospective analysis, Ohman et al. (9) studied 855 patients from the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIa) trial who presented within 12 hours of the onset of acute myocardial ischemia. Cardiac troponin T and creatine kinase MB levels (measured by a mass assay) were quantified on admission. The investigators found that elevated troponin T levels (above 0.1 ng per milliliter) were associated with significantly higher mortality within 30 days, both in the total study population (11.8 percent vs. 3.9 percent) and in all electrocardiographic subgroups examined, including patients with ST-segment depression, ST-segment elevation, T-wave inversion, and electrocardiographic features that confounded the detection of ischemia (such as bundle-branch block and paced rhythms). In a multivariate analysis, the troponin T level remained significantly predictive of 30-day mortality even after the analysis was adjusted for the electrocardiographic category and the creatine kinase MB level.
In a retrospective study using blood samples obtained on admission from patients participating in the Thrombolysis in Myocardial Ischemia Phase IIIB (TIMI IIIB) study, Antman et al. had similar findings. (10) They measured serum levels of cardiac troponin I in 1404 patients with unstable angina and non-Q-wave myocardial infarction. Cardiac troponin I levels of 0.4 ng per milliliter or above were associated with a significantly higher mortality within 42 days than were lower levels (3.7 percent vs. 1.0 percent). Moreover, significant increases in mortality were found with increasing levels of troponin I even after adjustment for base-line variables that were independently predictive of death, such as an age of 65 years or older and ST-segment depression on admission.
A quantitative relation between cardiac troponin T levels and long-term clinical outcome was also found in another large study in patients with unstable angina or non-Q-wave infarction, the Fragmin during Instability in Coronary Artery Disease (FRISC) trial. (11) In that study of the effect of low-molecular-weight heparin in patients with acute coronary syndromes, the risk of death or myocardial infarction during five months of follow-up also increased significantly with increasing levels of troponin T measured within the first 24 hours.
These three large studies confirm the results of smaller studies (6,7,8) and convincingly demonstrate the value of cardiac troponin levels for early stratification of risk in patients with acute coronary syndromes. It is very likely that routinely measuring cardiac troponins in serum when patients with acute coronary syndromes are admitted to the hospital will provide a more sensitive and specific identification of those at increased risk for cardiac events, including death. Whether more cost-effective strategies of treatment and, eventually, better long-term outcomes will result remains to be proved. In this regard, it is surprising that Antman et al. did not find significant differences in the number of diseased coronary vessels or the incidence of coronary thrombi on angiography between patients who had increased levels of troponin I and those who did not. (10) However, in the TIMI IIIB study only a minority of patients underwent coronary angiography in the first few hours after their symptoms began. (12)
To assess more fully the potential of cardiac troponin measurements for identifying patients who may benefit from aggressive treatment that includes early revascularization (as compared with those at low risk for subsequent events, who can be treated more conservatively and discharged early), prospective studies using early angiography or intracoronary ultrasonography are needed. In the meantime, the FRISC study has already suggested that measuring cardiac troponin may have therapeutic value in patients with acute coronary syndromes. In that study, a subgroup of 644 patients with increased levels of cardiac troponin T on admission was identified in whom long-term treatment with low-molecular-weight heparin was associated with an impressive 48 percent reduction in 42-day mortality, as compared with a group of 327 patients without troponin T elevations in whom this treatment had no benefit. (13) It is possible that elevated cardiac troponin levels may be associated with unstable coronary plaques, a hypothesis that needs to be evaluated prospectively in studies correlating the morphologic features of plaque with cardiac troponin levels in patients with acute coronary syndromes.
Besides the uncertainty about cost effectiveness, there are many other unresolved questions about cardiac troponins: the value of serial measurements of these markers for determining whether reperfusion therapy has succeeded or failed and for quantifying myocardial-cell necrosis in patients with ST-segment elevations; the reliability of measurements of troponins performed at the bedside; the usefulness of troponin measurements in patients with renal impairment or concurrent disorders of skeletal muscle; and the relative diagnostic sensitivity and specificity of the various cardiac troponins. Only the inclusion of well-designed prospective substudies of these markers in large-scale trials in patients with acute coronary syndromes will answer these important questions.
Frans Van de Werf, M.D., Ph.D.
University Hospital Gasthuisberg
B-3000 Leuven, Belgium |
