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Troponin

The Tns are a complex of three proteins (I, C, and T) that regulate the calcium mediated

Dr. Jaffe receives research support and is a consultant for Dade, Beckman, and Roche. He has consulted for most major diagnostic companies over the years. E-mail address: [email protected]

interaction of actin and myosin [1]. Tissue-specific isoforms of each troponin exist; however, the cardiac form of troponin C is shared by smooth muscle, so it lacks cardiac specificity [2,3]. For cardiac troponin I (cTnl), the cardiac isoform is structurally different due to the presence of a 32-amino acid posttranslational tail [4] and sequence dissimilarity with other isoforms [5]. Various monoclonal antibodies have been developed that are highly specific and have no cross-reactivity with other forms [6]. Since cTnI has not been found in any tissue outside of the heart, even in response to tissue injury, it has unique specificity for the heart [7,8].

Three different genes control the expression of cardiac troponin T. These genes and alternative mRNA splicing produce a series of isoforms with varying sequences [9]. Cardiac muscle contains four of these isoforms, but only one is characteristic of the normal adult heart, and that is the one against which antibodies have been made [10]. Some of the other cardiac troponin T (cTnT) isoforms are expressed in other tissues, including skeletal muscle in response to injury [11], and the initial assay for cTnT detected some of these and cross-reacting skeletal muscle TnT [12]. However, it has been established with immuno-histochemistry and PCR, that the antibodies used in the present iteration of the assay do not detect these forms [13,14]. Accordingly, cTnI and cTnT have high specificity for the heart.

In addition to having high specificity, these proteins have high sensitivity. Most of the tropo-nin is complexed to the contractile apparatus. A small amount (3% for cTnI and 6% for cTnT) exists which is not structurally bound [15,16]. This ''small amount'' has been termed the ''cytosolic pool,'' although its localization was not proved definitively. The relative amount of troponin in this pool is similar to that of CK-MB [15]. This pool is released acutely. Because it is of the same magnitude as CK-MB, troponin might be expected to have similar sensitively, but the sensitivity of the troponins is substantially better because a greater percentage of what is lost from the heart eventually resides in blood (ie, the so-called ''release ratio'' is higher) [17]. Subsequently, prolonged elevations of troponin occur as a result of degradation of the contractile pool in the area that has been injured. The cytosolic pool permits the early kinetics of release similar to that of CK-MB or even earlier with more sensitive assays. The persistence of elevation is due to release from the structural pool, since the half life of troponin in the circulation is short [18]. The degree of persistence varies tremendously and is somewhat longer for cTnT [19] than for some of the cTnl assays. For cTnl, the degree of persistence in part depends on which forms are measured and which epitopes the antibodies used in the assay are targeted toward. A 7- to 10-day time window during which elevations may be present, however, is a reasonable estimate. Accordingly, if the initial troponin in a patient who presents with chest pain is elevated, it may be from a prior event or from an acute event. In that situation, a rising pattern is helpful in determining if the event is acute.

The heterogeneity of assays indicated above is of particular importance. Different assays detect different forms, and various complex formations and protein modifications exist that can alter the relative sensitivity and specificity of one assay compared with another. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) group has published quality specifications for troponin assays and an analysis of the presently available assays [20,21]. Clinicians must understand which assay is being used in their center to understand how to use the data optimally [22]. As lower values are used, such as the recommended value of the 99th percentile as recommended by the ESC/ACC Committee on the Redefinition of MI [23,24], the assays invariably perform with less precision. This puts clinicians and patients at risk for false-positive and false-negative results. Accordingly, a recommendation has been made that the 99th percentile be measured with a less than 10% coefficient of variability (CV). This measurement will eliminate many false-positive and false-negative values and has been recommended until all assays can achieve detection of the 99th percentile of a normal reference population with that level of precision [21,25]. At present, only one assay meets that specification. In general, the 10% CV value is close to the 99th percentile but how close they are varies assay to assay (Table 1). Thus, clinicians must know the characteristics of the assay that they rely on. In addition, other analytic issues exist that can confound assays. Good laboratories should be able to help trouble-shoot potential problems. The most common problem is fibrin interference, which may on occasion require additional centrifugation of the sample to remove cross-reacting fibrin.

In addition, it should be appreciated that troponin elevations indicate cardiac injury but do not define the nature of the cardiac injury. In patients who present with chest pain, most tropo-nin elevations likely are related to coronary artery disease. The astute clinician must be aware, however, that elevations in troponin can occur from acute pulmonary embolism, myocarditis, and congestive heart failure to name just a few common entities that can confound the diagnosis of acute myocardial infarction [26]. Thus, the idea that an elevated troponin is synonymous with

Table 1

Concentrations corresponding to 10% CV imprecision and 99th percentile reference limit for the evaluated tro-ponin assays

Table 1

Concentrations corresponding to 10% CV imprecision and 99th percentile reference limit for the evaluated tro-ponin assays

Ratio of

10% CV

99th

10% total

concentration

percentile

CV

to 99th

limit*

concentration

percentile

Platform

(mg/L)

(mg/L)

limit

AxSYM

0.30

1.22

4.1

Centaur

0.10

0.33

3.3

Access

0.04

0.06

1.5

Vidas

0.10

0.36

3.6

Dimension

0.07

0.26

3.7

RxL

Stratus CS

0.07

0.10

1.4

Alpha Dx

0.15

ND

E170

0.01

0.04

4.0

AIA21

0.06

0.09

1.5

Abbreviations: CV, coefficient of variability; ND, not determined.

* Data obtained from manufacturer's package insert or through personal communications with manufacturers.

Data from Panteghini M, Pagani F, Yeo KT, et al. Evaluation of imprecision for cardiac troponin assays at low-range concentrations. Clin Chem 2004;50:327-32.

Abbreviations: CV, coefficient of variability; ND, not determined.

* Data obtained from manufacturer's package insert or through personal communications with manufacturers.

Data from Panteghini M, Pagani F, Yeo KT, et al. Evaluation of imprecision for cardiac troponin assays at low-range concentrations. Clin Chem 2004;50:327-32.

coronary artery disease can lead to missed diagnoses and suboptimal patient care.

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