Number 43, 2009
Biomarkers: past, present and future

The biological basis of troponin in heart disease: possible uses for troponin fragmentology

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Vlad C. Vasile, Allan S. Jaffe
Department of Internal Medicine, Division of Cardiovascular Diseases and
Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Medical School, Rochester, Minnesota, USA
Correspondence: Dr Allan S. Jaffe, Mayo Clinic, 200 First St SW, Division of Cardiovascular Diseases, Gonda 5, Rochester, Minnesota 55905, USA.
Tel: +1 507 284 3680; fax: +1 507 266 0228; e-mail: Jaffe.Allan@mayo.edu

Introduction
Detection of myocardial injury relies on the highly sensitive and specific determination of cardiac troponin (cTn). Thus increased cTn is essential for the diagnosis of acute myocardial infarction (AMI) [1]. However, there may be other specific applications for cTn fragments, and increases in cTn concentrations are observed in conditions other than AMI.
The troponin complex consists of three subunits: troponin C (cTnC), troponin I (cTnI) and troponin T (cTnT); it interacts with components of the thin tropomyosin and actin filament to ensure correct contraction coupling [2]. Several isoforms of cTns C, I, and T assist in this task [3].
Troponin C (TnC) lacks cardiac specificity. In contrast, it is believed that all isoforms of cTnI are expressed exclusively in cardiomyocytes, thus its detection in the blood is synonymous with myocardial injury. The cTnI isoforms are characterized by a 32 amino acid posttranslational tail at the N-terminus [4]. The junction between this sequence and the stable central part of the molecule is the target for monoclonal antibodies that recognize cTnI [5]. Expression of troponin T or I is controlled by three genes [6]. By alternative splicing, several isoforms of cTnT are generated, with sequence variability regions located at the C- or the N-terminus, or both [6,7].

Conditions other than AMI in which cTn concentrations are increased

Physical exercise
Transient increases in cTnT occur after severe physical exercise, early during exertion [8]. Initially, it was believed that these increases resolved in 24 h, but recent data from sensitive assays do not support this [9]. It is difficult to distinguish whether cTn is released by reversible or irreversible injury. Similarly, whether there are reparative processes is unclear. Either way, different fragments might be elaborated in this situation.

Chronic renal failure
Concentrations of cTnT are often abnormal in patients with chronic renal failure [10]. The etiology of these increases is obscure, but probably includes any of: endothelial dysfunction, acute cardiac stretch, intra-dialysis hypotension and hypertension, left ventricular hypertrophy, and coronary artery disease, occult or overt. Some authors report small cTn fragments [11] but others dispute that [12].

Myocardial stunning
Myocardial stunning is a reversible myocardial dysfunction seen after ischemia. It also can be induced by arrhythmias or open heart surgery [13]. A specific degradation product occurs in this circumstance from the loss of 17 residues at the C-terminus of cTnI [14]. Transgenic animals overexpressing this truncated form, cTnI_1–193, exhibit myocardial dysfunction with properties similar to those of myocyte stunning. A comparable fragment was found after bypass surgery [15]. In in-vitro experiments, transfection of truncated cTnI_1–193 produces a diastolic impairment in healthy human cardiomyocytes [16]. This suggests that the degradation of cTnI contributes to diastolic dysfunction in vivo. If these cTn fragments were causative, they could be monitored to identify which patients with impaired function might improve.

Transient left ventricular apical ballooning syndrome
This syndrome can mimic AMI clinically [17]. It is characterized by more extensive ventricular dysfunction than would be expected from the modest increases observed in cTn values, which are good surrogates for infarct size [18,19]. Phosphorylated or truncated cTn may be the basis for this dysfunction.

Reperfusion in acute myocardial infarction
Reperfusion in AMI can be induced by thrombolytic therapy or percutaneous coronary angioplasty. It may increase the extent of cardiac injury [20]. Under hypoxia, modifications of cTn may be specifically associated with this “ischemia-reperfusion” process [21]. Patients with larger myocardial infarctions display greater amounts of degraded cTn fragments. It is possible that the proteases involved in clot dissolution or those implicated in induction of inflammation in response to injury could degrade cTns. The biochemical environment of the myocardium might be different than that of blood, leading to different cTn changes. Detectable changes might be useful in distinguishing more from less robust recanalization.

Acute myocarditis
Acute myocarditis can present similarly to AMI [22]. Increases in cTnI occur in mouse models of autoimmune myocarditis [23] and in patients with heart failure secondary to chronic myocarditis. Presumably, inflammation leads to myocardial injury. It may be that fragments produced secondary to inflammation are different from those triggered by ischemia. Recognition of dissimilarities might permit differentiation of distinct disease states in clinical practice. Moreover, cTn may play a part in inflammation itself [24].

Basic molecular biology on which fragmentology is based
The regulation of contraction physiology is complex and includes abundant phosphorylation and dephosphorylation steps within troponin and actin-tropomyosin. cTnI is phosphorylated at specific serine/threonine residues by protein kinase A (PKA) [25]. The extent of phosphorylation of cTnI and cTnT depends on these kinases and phosphatases, but also on their spatial conformation, which confers accessibility to phosphorylation sites. Posttranslational phosphorylation of cTnI/cTnT by processes that block or reveal specific sites may also change the status of cTn. Physiologic degradation occurs at the N-terminus; residues 27, 28 or 31 seem to possess key significance.
During ischemia, protein kinase C (PKC) and p21-activated kinase induce cTn phosphorylation [26]. Proteolysis occurs initially at the C-terminus, at amino acid 192, followed by additional cleavages. Truncation of cTnI at amino acid residue 192 is associated with human disease [13,14]. The alteration of cTnT/cTnI by proteolysis, phosphorylation, or both, generates an assortment of fragments (Table I).

Table I. Modified forms of cTnI.

Conclusion
The complex biology of cTns should allow for the development of novel assays able to discriminate various fragments that may be elaborated selectively within distinct pathological processes. These fragments resulting from metabolism or phosphorylation have the potential for both diagnostic and therapeutic importance.

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