Editor's Note: Based on Jaffe AS et al. Diseased Skeletal Muscle: A Noncardiac Source of Increased Circulating Concentrations of Cardiac Troponin T. J Am Coll Cardiol: Sep 28; [Epub ahead of print].

Background

The specificity of cTnT, and to a lesser extent cTnI, was questioned with earlier generation assays when increased levels were found in patients with skeletal muscle diseases and renal insufficiency.^{(1, 2)} Further studies demonstrated that the capture antibody for the earlier cTnT assay detected not only cTnT, but some fetal skeletal muscle TnT isoforms that were expressed in skeletal muscle in response to injury.^(1-3) These re-expressed fetal isoforms were studied, and a newer assays was developed that would not detect these re-expressed skeletal muscle cTnT isoforms.^(4-7) However, even with newer cTnT assay,s elevation of cTnT has been shown in patients with inflammatory skeletal myopathies without apparent cardiac disease.⁽⁸⁾

Results

Patients with known myopathies from the Neuromuscular Clinic at the Mayo Clinic were screened. If cTnT was found to be elevated (fourth-generation assay using the Elecys E170 analyzer), then cTnI was also measured. Only patients with an elevation in cTnT and normal cTnI values were included in the hopes of excluding patients with structural heart disease. There were 16 such patients identified and 4 of these had skeletal muscle biopsies taken for Western blot analysis using the capture and detection antibodies from the fourth-generation and high-sensitivity cTnT assays. All 4 patients who underwent biopsies had a myopathy as suggested by clinical history, CK elevations (583-3,500 IU/L), myopathic electromyographic findings, and histologic changes. All 3 antibodies used in the fourth-generation and high sensitivity assays were immunoreactive with all myopathic skeletal muscle samples and in cardiac tissue by Western blot analysis.There was no immunoreactivity noted in normal skeletal muscle control samples.

Commentary

These 4 cases demonstrate that there proteins expressed in diseased skeletal that are detected by antibodies in the fourth generation and high sensitivity cTnT assays. Although sub-clinical cardiac pathology leading to cTnT elevation cannot be totally excluded on the basis of the study, as the authors point out, this is unlikely. These patients had no apparent heart disease and had normal cTnI levels. These findings are consistent with other studies that describe an elevation of cTnT with normal cTnI in patients with myopathies.^{(8, 9)} This provocative study, however, leads to more questions than answers. What is the prevalence of cTnT elevation in patients with skeletal muscle disease? Are there certain skeletal muscle diseases that more commonly have an elevation in cTnT? Will elevation of cTnT in this setting confound the diagnosis of acute coronary syndrome in a significant number of patients that present to Emergency Departments? Further studies are needed to address these issues.

What are the practical implications of these findings for the clinician? Although the majority of cTnT seem to be related primary cardiac pathology such as acute coronary syndrome from plaque rupture or other indirect stress on the heart (pulmonary embolism, congestive heart failure, sepsis, etc.), the specificity of the present formulated cTnT assays for cardiac injury is less than 100%. This finding must be considered when evaluating patients for acute coronary syndrome with skeletal muscle disease. Two clues may be helpful in the regards. The 4 patients reported in this study had small elevations (0.1-0.4 µg/L) and did not have dynamic changes over time. As we do with other patients with minor cTn elevation of unclear etiology, serial cTn measurements and selective further testing such as stress testing or imaging studies in these patients will be required to include or exclude acute coronary syndrome.

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References

1. Anderson PA, et al. Molecular basis of human cardiac troponin T isoforms expressed in the developing, adult, and failing heart. Circ Res. 1995:76;681-6.
2. Bodor GS, et al. Cardiac troponin T composition in normal and regenerating human skeletal muscle. Clin Chem. 1997:43;476-84.
3. Katus HA, et al. Development and in vitro characterization of a new immunoassay of cardiac troponin T. Clin Chem. 1992:38;386-93.
4. Muller-Bardorff M, et al. Improved troponin T ELISA specific for cardiac troponin T isoform: assay development and analytical and clinical validation. Clin Chem. 1997:43;458-66.
5. Haller C et al. Cardiac troponin T in patients with end-stage renal disease: absence of expression in truncal skeletal muscle. Clin Chem. 1998:44;930-8.
6. Ricchiuti V, Apple FS. RNA expression of cardiac troponin T isoforms in diseased human skeletal muscle. Clin Chem. 1999:45;2129-35.
7. Ricchiuti V, et al. Cardiac troponin T isoforms expressed in renal diseased skeletal muscle will not cause false-positive results by the second generation cardiac troponin T assay by Boehringer Mannheim. Clin Chem. 1998:44;1919-24.
8. Cox FM, et al. The heart in sporadic inclusion body myositis: a study in 51 patients. J Neurol. 2010:257;447-51.
9. Aggarwal R, et al. Serum cardiac troponin T, but not troponin I, is elevated in idiopathic inflammatory myopathies. J Rheumatol. 2009:36;2711-4.

Keywords: Acute Coronary Syndrome, Biopsy, Emergency Service, Hospital, Heart Failure, Immunoassay, Enzyme-Linked Immunosorbent Assay, Kidney Failure, Chronic, Muscle, Skeletal, Muscular Diseases, Myositis, Myositis, Inclusion Body, Prevalence, RNA, Renal Insufficiency, Protein Isoforms, Troponin I, Troponin T

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