Cardiac troponin and β-type myosin heavy chain concentrations in patients with polymyositis or dermatomyositis

Abstract

Cardiac troponin T (cTnT), cardiac troponin I (cTnI), myosin heavy chains (MHC), myoglobin, creatine kinase (CK), and creatine kinase isoenzyme MB (CKMB), were measured in blood samples from 39 polymyositis (PM) or dermatomyositis (DM) patients without clinical evidence for cardiac involvement to evaluate their clinical usefulness in this patient population. MHC, myoglobin, and CKMB were frequently elevated and correlated with each other and with disease severity. Undetectable cTnI in all but one patient indicated that MHC was released from skeletal muscle, thereby providing the first laboratory evidence of frequent slow-twitch muscle fibre-necrosis in patients with PM or DM. CKMB was elevated in 51%, cTnT in 41%, and cTnI in only 2.5% of patients. cTnI did not correlate with other markers or with disease severity scores. The close correlations found between cTnT and skeletal muscle damage markers and the relationship between cTnT with disease severity without clinical evidence for myocardial damage suggest a release of cTnT from skeletal muscle. The relationship of cTnT with disease severity indicates a possible role of the marker for risk stratification. However, the prognostic values of cardiac troponins and other muscle damage markers in PM/DM patients remain to be compared in prospective outcome trials.

Introduction

The polymyositis (PM) and dermatomyositis (DM) complex encompasses a heterogeneous group of acquired muscle diseases called inflammatory myopathies. Muscle weakness and inflammatory infiltrates within the skeletal muscles are the principal clinical and histological findings. The incidence of PM, DM, and inclusion-body myositis is approximately 1 in 100,000 [1]. Clinical evidence of cardiac involvement in PM/DM patients has been reported in approximately 50% of cases [2]. Because of the ongoing destruction and regenerating processes in these chronic muscular diseases, serum enzyme activities of so-called cardiac enzymes, such as creatine kinase isoenzyme MB (CKMB) and lactate dehydrogenase 1 (LDH-1), are increased due to release from skeletal muscle [3], [4]. Creatine kinase (CK) consists of three isoenzymes, designated MM, MB, and BB. Skeletal muscle contains essentially CK-MM, but CK-MB can be also present [5]. During chronic regeneration of skeletal muscle the expression of the CK-B subunit is upregulated, which leads to an increased release of both, CK-BB and CK-MB, from skeletal muscle into the bloodstream [6]. In these disorders, abnormal serum CKMB cannot be used for diagnosing myocardial damage [7]. Determinations of the cardiac isoforms of troponin T (cTnT) and troponin I (cTnI) in serum are claimed to have the highest specificities of the available markers of myocardial damage [8], [9], [10], [11]. Because recent reports on cTnT increase in patients with PM or DM without evidence of ischaemic myocardial damage and increased cTnT concentrations in the absence of elevated cTnI concentrations in patients with chronic myopathies, questions have been raised as to the specificity of cTnT for cardiac damage in these disorders [12], [13]. Troponin T and troponin I both exist in three different isoforms with an unique structure, one for slow-twitch skeletal muscle, one for fast-twitch skeletal muscle and one for cardiac muscle [14], [15]. The three isoforms are encoded by three different genes. cTnI has an extra 31 amino acid residues at the N-terminus and its amino acid sequence shows about 40% dissimilarity from both other isoforms [15]. cTnT differs only by 6–11 amino acid residues from its skeletal muscle isoforms. Only 10–30% of the amino acid sequence show low homology [14]. Therefore, it is more difficult to produce cardiac-specific anti cTnT antibodies. However, both cTnI assays and the second generation cTnT assay show no cross-reactivity with skeletal troponins [8], [9], [10].

cTnI is never expressed in skeletal muscle, neither during fetal development nor in adult skeletal muscle in response to any pathological stimuli [16], [17]. cTnT is expressed in small amounts in skeletal muscle during fetal development. Most importantly, cTnT is not found in adult skeletal muscle [18]. cTnT has been found by immunofluorescence staining in regenerating or denervated rat skeletal muscle, probably due to reversion to a fetal-like pattern of expression of TnT isoforms [19]. Whether adult human skeletal muscle in response to any pathological stimuli re-expresses the cTnT isoform, and whether such a response is of clinical relevance remain to be further elucidated [20].

Myoglobin is an oxygen binding protein of striated muscles that is rapidly released after muscle damage. Myoglobin facilitates oxygen diffusion in striated muscle fibres. It is found most abundantly in striated muscles (heart and skeletal muscle), where it accounts for 5% to 10% of all cytoplasmatic proteins. It is located close to the sarcolemma, to the contractile apparatus, and to intracellular membranous or fibrillar structures. In skeletal muscle, myoglobin is found mainly in the slow-twitch “red” fibres. It is an established early marker of acute muscle damage [21].

Myosin is a hexameric structurally bound contractile protein containing four light and two heavy chains. MHC can be cleaved into its subfragments by enzymes. The rod portion can be further degraded to form light meromyosin and subfragment 2 [22]. An increase in plasma MHC concentration is an indicator of membrane leakage and degradation of the contractile apparatus [23]. Cardiac β-type MHC is coexpressed in slow-twitch skeletal muscle fibres.

The present study was carried out to evaluate new and established markers of cardiac and skeletal muscle damage in patients with PM or DM, i.e. cardiac troponins, myosin heavy chains, myoglobin, CK, and CKMB.