Resolved Myositis, Normal Creatine Kinase, and Peaking Cardiac Troponin T

A 46-year-old man was admitted to intensive care with sepsis from acute cholangitis associated with cholelithiasis. He was stabilized with antibiotics and endoscopic retrograde cholangiopancreatography with stenting. During his admission, he was found to have diffuse weakness and pain more over his proximal muscles and over his hips bilaterally. He had no skin rash, extra-myopathic clinical features, or signs of a viral prodrome. His creatine kinase (CK) was >25 000 U/L. His atorvastatin was then stopped. His rheumatoid, lupus, antineutrophilic cytoplasmic antibody (ANCA), and infectious serology were normal as were thyroid-stimulating hormone (TSH) and malignancy screening. His thigh magnetic resonance imaging revealed bilateral symmetric edema suggestive of myositis. His electromyography showed severe sensory motor polyneuropathy along with proximal myopathy with inflammatory features involving both the upper and lower extremities. Necrotizing myopathy with an inflammatory component was identified in his muscle biopsy. His myositis panel was negative for anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) and anti-signal recognition particle (anti-SRP). He was diagnosed with seronegative immune-mediated necrotizing myositis. He was treated with steroids, intravenous immunoglobulin, and azathioprine. His CK recovered (Fig. 1), along with an improvement in symptoms. Timeline of cTnT and CK changes. Due to atypical body pain accompanied by chest pain cardiac troponin T (cTnT) was ordered. The result was 1158 ng/L (CK was 13 626 U/L at this time). A follow-up cTnT measurement of 1238 ng/L was measured 10 h later. The corresponding electrocardiogram (EKG) patterns were normal at both time points, and unchanged compared to a previous EKG 5 weeks earlier. The cTnT elevations, while significantly above his baseline of approximately 300 ng/L, were attributed to end-stage renal disease (ESRD) in a patient on regular dialysis, deemed non-myocardial, and associated with skeletal muscle injury, possibly with or without non-ischemic myocardial injury. Unfortunately, during the initial admission, only EKGs and cTnT measurement were performed, and the patient did not experience any more chest pain. No further cTnT measurements or investigations were conducted at that time. Of note, his past medical history was significant for multiple comorbidities including hypertension, dyslipidemia, obstructive sleep apnea, obesity, depression, self-limited arthritis, and type II diabetes mellitus (hemoglobin A1c of 8%) complicated by polyneuropathy, retinopathy, peripheral vascular disease with bilateral amputation of the toes, ischemic heart disease status post bypass surgery, and nephropathy with ESRD requiring regular hemodialysis (4 times per week). His medications included alfacalcidol, aspirin, atorvastatin, bisoprolol, cinacalcet, insulin, pregabalin, methadone, quetiapine, and venlafaxine. His family history was positive for coronary artery disease with no known autoimmune disorders. He did not smoke cigarettes or use illicit drugs. Three weeks after his CK levels recovered, he had a brief, self-limited episode of atypical chest pain. Subsequent daily chart reviews revealed no recurrence of chest pain. Notably, hospitalization continued due to ongoing functional decline from myositis. His cTnT level was 4098 ng/L, while his cardiac troponin I (cTnI) level was only 49 ng/L (Siemens Dimension Vista assay used and the male 99th cutoff of 75 ng/L). He had a negative cardiac workup, and his repeat echocardiogram showed no acute changes, indicating a left ventricle ejection fraction of 55%, concentric left ventricular hypertrophy, and moderate diastolic dysfunction with N-terminal prohormone of brain natriuretic peptide levels elevated to 4433 ng/L and 3587 ng/L, respectively in keeping with historical measurements for this patient. Serial myocardial injury biomarker testing was conducted on the asymptomatic patient with CK levels normalizing (as shown in Fig. 1). His cTnT levels exhibited an initial increasing trend and subsequently plateaued near 4000 ng/L (Table 1 and Fig. 1). To assess the possibility of analytic error, the patient’s plasma specimens were reanalyzed with heterophile blocking treatment (Scantibodies) and after immunoglobulin depletion using a validated laboratory-developed method based on Protein A/G agarose (ThermoFisher). The cTnT fraction recovered after heterophile blocking was 4093 ng/L/4180 ng/L or (98%). cTnT recovered on the immunoglobulin-depleted serum was 1.1 (method-specific expected cTnT recovery in the absence of macro complexes: 0.9 to 1.2). Normal cutoffs for the presence of macrotroponin T were obtained by testing samples from patients with documented elevations in troponin T that were preceded by a normal high-sensitivity TnT within the previous 7 days. These findings were consistent with the absence of immunoglobulin-mediated analytical interference with cTnT (1). Temporal trends in cTnT and CK, GFR, and creatinine levels. aGFR, glomerular filtration rate. bcTnI = 49 ng/L. Temporal trends in cTnT and CK, GFR, and creatinine levels. aGFR, glomerular filtration rate. bcTnI = 49 ng/L. What causes the delayed cTnT rise in this patient with ESRD, myositis, and no active myocardial injury? What analytic interferences should be considered when faced with elevated cTnT without active myocardial injury? How do you explain the distinct cTnT expression in skeletal muscle? How does ESRD lead to delayed cTnT elevation? This patient with a history of seronegative immune-mediated necrotizing myositis, absence of an active myocardial injury by echocardiogram, high-sensitivity cTnT (Roche E601) peaking above 4000 ng/L, and high-sensitivity cTnI of 49 ng/L (Siemens Vista), while CK was within the reference interval. This combination of results suggested a noncardiac cause of troponin T elevation. Interference from heterophile antibodies and macro-troponin T were ruled out. Accordingly, the best explanation for the discordant laboratory findings is inferred to be that the resolved history of acute myositis induced skeletal expression of cardiac troponin T. This observational study does not definitively rule out competing explanations: acute myocardial infarction missed by echocardiography and cTnI testing, analytic error resulting in falsely negative cTnI measurement, or false-negative investigations for macro cTnT or heterophil interference in cTnT. However, after reviewing the available evidence, we conclude that the best explanation for the delayed peak in cTnT is an acute, relatively remote, myositis injury that induced a delayed but progressively increased expression of skeletal cTnT. It is known that patients with active chronic skeletal muscular disorders exhibit elevated levels of cTnT unrelated to cardiac disease and without an elevated cTnI. The underlying mechanism is thought to be re-expression of the Troponin T2, Cardiac Type gene in injured skeletal muscles, leading to the production of cTnT (2, 3). This phenomenon has been observed in patients with chronic myositis or a metabolic myopathy, as well as one 48-year-old patient with acute drug-induced rhabdomyolysis and cTnT increased to 471 ng/L, 7 days after admission (4). Unlike previous reports, the present case describes apparent skeletal muscle expression of cTnT several weeks after acute rhabdomyolysis, at a stage when the CK had completely normalized. This case also suggests, in the setting of ESRD, the cTnT elevation associated with skeletal muscle may be larger than expected for patients with preserved renal function. This case study is particularly novel with regard to the delayed rise in cTnT after the acute myositis episode. The explanation for the delayed and persistent rise is unknown. Specifically, ESRD is a known cause of cTnT expression (5) at baseline. The concurrence of transient acute myositis in ESRD may induce a temporary but persistent and delayed rise in skeletal muscle cTnT that is not otherwise expected in skeletal muscle with normal metabolism prior to the acute myositis episode. We think a prospective study of the time course of cTnT elevations in ESRD patients, and non-ESRD patients, with acute transient myositis will allow for clarification of whether this patient’s clinical trajectory is an anomaly or an expected outcome of the concurrence of clinical risk factors for cTnT production. Gaining insights into the patterns and mechanisms of cTnT alterations following rhabdomyolysis in patients. Acknowledging the uncertain and multifactorial nature of the mechanisms causing troponin T elevation in the setting of ESRD complicated by myositis. Recognizing potential analytic interference from heterophile antibodies and macro-troponin T. Understanding the possibility of induced skeletal muscle expression of cardiac troponin T. Ethical Approval/Consent: A written informed consent was obtained from the patient for publication of the details of their medical case. Nonstandard Abbreviations: CK, creatine kinase; cTnT, cardiac troponin T; cTnI, cardiac troponin I; ESRD, end-stage renal disease. Author Contributions: The corresponding author takes full responsibility that all authors on this publication have met the following required criteria of eligibility for authorship: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Nobody who qualifies for authorship has been omitted from the list. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

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