Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T

Abstract

Background: Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs).

Methods: We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD.

Results: Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, P_Wald<0.001); the expression correlated with pathological disease activity (R=0.59, P_t-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, P_t-statistic=0.031).

Conclusions: In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT03660969.

Keywords: muscle, skeletal; myocardial infarction; myopathies, structural, congenital; troponin.

Figure 1.

Violine plots representing the distribution of hs-cTnT/I concentrations for the 4 tested assays and across categories of cardiac disease. A single comparison using a Mann-Whitney U test was conducted between the control subjects of the APACE (Advantageous Predictors of Acute Coronary Syndromes Evaluation) cohort and the overall cohort of patients with skeletal muscle disorder. Bioequivalent and overall approved upper limits of normal (ULNs) are represented as broken lines. High-sensitivity cardiac troponin T (hs-cTnT)–Elecsys and high-sensitivity cardiac troponin I (hs-cTnI)–Architect concentrations were available in all 211 patients; hs-cTnI–Access concentrations, in 187 patients; and hs-cTnI–Vista concentrations, in 194 patients. The P values were calculating with a Wilcoxon test comparing the overall group with the control group and have been corrected for multiple testing (4 tests) with the Benjamini and Hochberg method.

Figure 2.

Interassay hs-cTnT/I mismatches using biologically equivalent ULN. For each subpanel, 2 high-sensitivity cardiac troponin T/I (hs-cTnT/I) assays are represented with their biologically equivalent assay-specific 99th percentile upper limit of normal (ULN). In each panel, the 4 quadrants represent the percentage of patients with the following constellations: green when both hs-cTnT/I assays were below the ULN, gray when both were above the ULN, and red when there was an hs-cTnT/I mismatch (with 1 of the assays above and 1 of the assays below the ULN). A, Overall cohort. B, Subgroup without cardiac disease.

Figure 3.

Different types of skeletal muscle disorders are represented on the x axis and concentrations of the biomarkers are represented on the y axis with a logarithmic scale. Boxplots represents the interquartile range (IQR), and whiskers show the ±1.5×IQR. Bioequivalent and overall approved upper limits of normal (ULNs) are represented as broken lines. A, Overall cohort. B, Cohort without cardiac disease. The P values have been corrected for multiple testing with the Benjamini and Hochberg method. AD indicates autoimmune disease; CK, creatine kinase; and hs-cTnT/I, high-sensitivity cardiac troponin T/I.

Figure 4.

Correlation between creatine kinase and hs-cTn. Correlation between CK and hs-cTn in (A) the overall cohort and (B) patients with no cardiac disease. Biomarkers have been log-transformed to approximate normal distribution. CK indicates creatine kinase; and hs-cTnT/I, high-sensitivity cardiac troponin T/I.

Figure 5.

mRNA analyses of muscle biospies. A, Differential gene expression (DGE) results from a case/control study comparing skeletal muscle biopsies from patients with (33 cases) and without (16 controls) skeletal muscle disorder (SMD). After correction for multiple testing with the Benjamini and Hochberg procedure, 847 of 17 124 protein-coding genes were upregulated and 966 were downregulated at a significance level of 𝛼 = 0.05. Three of 6 genes of the troponin gene family show a significant upregulation (TNNT2, top 96 differentially expressed gene [DEG]; TNNT3, top 881 DEG; TNNI2, top 1821 DEG). B, Detailed DGE results for 6 genes of the Troponin gene family. Fold changes (FCs) and significance levels are concordant among the slow (TNNT3 and TNNI2) and fast (TNNT1, TNNI1) skeletal muscle gene pairs but not for the cardiac gene pair (TNNT2 and TNNI3). C, Base-level expression of the troponin gene family in skeletal muscle. Cardiac genes TNNT2 and TNNI3 exhibit an expression of 6 and 6.3 transcripts per million (TPM), ranking among the top 39% and 38% expressed protein-coding genes in the DGE analysis. Fast and slow skeletal muscle genes TNNT1, TNNI1, TNNT3, and TNNI2 exhibit a mean expression of 6848, 3614, 1590, and 1418 TPM (all top 0.1%). D, Variation of TNNT2 expression in the case samples (n=28 after filtering for missingness in marker variables for disease activity) can be explained by biopsy-specific disease activity. Linear regression shows a significant positive correlation (R=0.59, P<0.001) between a disease activity score derived from 14 disease activity markers and normalized counts. The score remains significant (P=0.001) after adjustment for disease class (myopathy [n=7], myositis [n=13], other SMD [n=8]). Conversely, the case subset showed borderline significant differences between disease classes after adjustment for disease activity score in a likelihood ratio test (P=0.069). A detailed description of the score calculation is available in the Supplement Material.

Figure 6.

Correlation between normalized gene expression of the 3 cTnT genes and circulating hs-cTnT concentrations. High-sensitivity cardiac troponin T (hs-cTnT) concentrations and normalized gene expression have been log-transformed to approximate normal distribution.