Risk stratification in acute coronary syndrome using cardiac troponin I.

The interest in risk stratification of patients with acute coronary syndrome (ACS), i.e., acute myocardial infarction (MI) and unstable angina pectoris (AP), has increased considerably within recent years because of improved knowledge of pathology, progress in immunoassays of already existing biochemical markers, introduction of new biochemical markers [especially cardiac troponin I (cTnI) and T (cTnT)], and new methods of treatments. Coronary artery disease may present clinically as stable AP or ACS. In cases of stable AP, myocardial ischemia commonly results from increases in myocardial oxygen demand that outstrip the ability of stenosed coronary arteries to increase oxygen delivery (1 ). In ACS, the accepted cause of acute MI is a plaque disruption, or fissuring, leading to coronary thrombosis with or without vasospasm, and thereby intermittent or persistent coronary occlusion. In patients with unstable AP, pathological postmortem investigations have documented that unstable AP leading to MI or cardiac death frequently is preceded by microinfarctions (2 ). This is important because patients with non-Q-wave MI tend to have smaller infarcts on presentation and rarely have total occlusion of the infarct-related vessel; it therefore is considered a relatively unstable condition associated with a lower initial mortality but a higher risk of later MI or cardiac death (3). On the basis of the above considerations, many large-scale trials divide the patients with ACS into patients with STsegment elevation and non-ST-segment elevation. If the patient presents with signs of evolving acute MI, i.e., an electrocardiogram (ECG) with unequivocal ST-segment elevation, then the patient in most cases is subjected to thrombolysis or primary percutaneous transluminal coronary angioplasty. However, evaluation of patients with non-STsegment elevation is a key issue today because new treatments are focused to a great extent on this group, i.e., low-molecular weight heparins, platelet glycoprotein IIb/IIIa antagonist, direct thrombin inhibitors, and coronary intervention in the acute as well as the subacute phase. Therefore, our diagnostic strategy of ACS is concentrated primarily on confirmation/exclusion of acute MI and the detection of minor myocardial damage (MMD) to facilitate risk stratification and treatment. To detect MMD, it is necessary to use markers sensitive to myocardial injury and specific for myocardial tissue. Measurements of creatine kinase isoenzyme MB (CKMB), especially the new immunoassays measuring CKMB mass, have improved the diagnosis of MMD as well as being of prognostic importance. However, the greatest attention has been given to the new biochemical markers, the troponins, especially because of their high cardiospecificity, high sensitivity for MMD, and their long diagnostic time-window. The troponins are components of the troponin regulatory complex located on the thin filament of the contractile apparatus of the myocyte. Three types of troponins exist: troponin C (TnC), TnI, and TnT. The high cardiac tissue specificity of TnI and TnT compared with TnC and other cardiac biochemical markers is well established. The evaluation of cTnI and cTnT was initially carried out in patients with acute MI (4–6). However, increased serum cTnT concentrations were also seen in approximately one-third of patients with unstable AP or in other chest pain patients in whom an acute MI had been ruled out (7 ). A multicenter study first suggested that increased cTnT may be a useful prognostic indicator in patients with unstable AP (8 ). Numerous prognostic studies on cTnT have corroborated this finding (7 ). However, only one commercial immunoassay is available for the measurement of cTnT. This has led to a great interest in cTnI, and in the last few years, the prognostic value of increased cTnI in patients with ACS has triggered considerable interest. However, no prognostic studies have been published with regard to the great majority of cTnI assays, and in those assays where prognostic studies have been published, only one or two of the assays have been the subject of more than one prognostic study published in a peer-reviewed journal. The study by Morrow et al. (9) in this issue of Clinical Chemistry is welcome. This study deals with three main issues: different cTnI immunoassays, decision limits/diagnostic timewindow, and risk stratification in a non-ST-segment patient population. The present study is especially important because it makes reference to a commercially available cTnI immunoassay that has been approved by the Food and Drug Administration (FDA) in the US and is waiting for a standardization of cTnI. However, a not inconsiderable number of commercial cTnI immunoassays have been approved by the FDA (16 different immunoassays from eight different companies). Add to this those not FDA approved. As noted by Morrow et al. (9 ), large differences exist in the construction of cTnI assays, e.g., anti-cTnI antibody components that target different protein epitopes; interaction between the locations of these protein regions; the action of proteolytic enzymes, causing degradation of both COOH and NH2 termini of TnI; and conformational changes resulting from the association of cTnI with TnC and TnT in binary and ternary complexes (10–12). Reported results for the same sample may vary up to 20-fold among cTnI methods (12 ), and the diversity of these assays can therefore lead to substantial confusion concerning reference ranges, analytical interferences, coefficients of variation, diagnostic time-windows, and decision values for both diagnostic and prognostic purposes. Both the AACC and the IFCC have set up subcommittees to establish cTnI standardization. In the meantime, the only way the clinician/clinical chemist can rely on a specific cTnI immunoassay is from publication in a peer-reviewed journal. In this respect, it is vital that all information on the specific cTnI immunoassay is given. Also bear in mind that if one looks at the international literature on CKMB as a cardiac marker, it often is difficult to figure out (a) just what the authors have measured—CKB, CKMB, or merely CK—catalytic activity (immunoinhibition or electrophoresis) or mass Editorial