Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T

Abstract

Background: Cardiac troponin T (cTnT) and cTnI are considered cardiac-specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a non-cardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMD). Methods: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in four hospitals in two countries. After cardiac work-up, patients were adjudicated into three predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed using high-sensitivity cTnT (hs-cTnT-Elecsys) and three hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista), and compared to controls without SMD presenting with adjudicated non-cardiac chest pain to the emergency department (n=3508, mean age 55y, 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared to biopsies obtained in controls without SMD. Results: Among 211 patients (mean age 57y, 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) mild and 59 (28%) severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no versus mild versus severe cardiac disease for all assays (all p<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus controls (median 16ng/L (IQR 7-32.5) versus 5ng/L (IQR 3-9), p<0.001) while hs-cTnI concentrations were mostly similar (hs-cTnI-Architect 2.5ng/L (IQR 1.2-6.2) versus 2.9ng/L (IQR 1.8-5.0), hs-cTnI-Access 3.3ng/L (IQR 2.4-6.1) versus 2.7ng/L (IQR 1.6-5.0) and hs-cTnI-Vista 7.4ng/L (IQR 5.2-13.4) versus 7.5ng/L (IQR 6-10)). hs-cTnT-Elecsys concentrations were above the upper-limit of normal (ULN) in 55% of patients with SMD vs 13% of controls (p<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from non-inflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI); versus controls (n=16, pWald <0.001), the expression correlated with pathological disease activity (R=0.59, pt-statistic <0.001) and circulating hs-cTnT concentrations (R=0.26, pt-statistic =0.031). Conclusions: In patients with active chronic SMD, elevations in cTnT concentrations are common and not due to cardiac disease in the majority. This was not observed for cTnI, and may in part be explained by re-expression of cTnT in skeletal muscle.

Response by du Fay de Lavallaz et al to Letter Regarding Article, “Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T”

“…We thank Giannitsis and colleagues for their interest in our work. 1 We entirely agree with their thoughtful comments highlighting several of the still incompletely understood aspects related to possible differences between cardiac troponin (cTn) T and cTnI, including chronic active skeletal muscle disease as a noncardiac contributor to the systemic high-sensitivity cTnT signal.…”

Copeptin as a Diagnostic and Prognostic Biomarker in Cardiovascular Diseases

“…When a sufficient number of myocytes die due to necrosis or apoptosis, cTn can be detected in the blood ( 57 ). Two specific cardiac isoforms of troponin are cTnI and cTnT which are almost exclusively in the heart ( 58 ), but cTnT is found to express in skeletal muscles to a minor extent, which means some elevations of cTnT might be due to skeletal muscle abnormality ( 59 ). In patients with AMI, cTnI and cTnT start to appear in the circulation early after the AMI onset.…”

Macrotroponin Complex as a Cause for Cardiac Troponin Increase after COVID-19 Vaccination and Infection

“…Multiple causes for assay interference have been identified, such as heterophilic antibodies, rheumatoid factor, macrotroponin complex, and human antianimal antibodies in response to monoclonal antibodies used in production of therapeutic agents or vaccination ( 7 ). In addition, increases in hs-cTnT concentrations can be associated with reexpression of cTn in skeletal muscle in the absence of cardiac involvement ( 8 ). Clinicians should be aware of the possibility of immunoassay interference, particularly if there is discordance between cTn concentrations and the clinical presentation or other investigation results.…”