Response to “Increased Creatine Kinase MB and Cardiac Troponin T with Normal Cardiac Troponin I in Metastatic Alveolar Rhabdomyosarcoma”

We wish to comment on the case reported recently by Isotalo et al. (1). Two different cardiac troponin I (cTnI) assays were used: the AxSYM (Abbott) and the Opus Plus (Dade Behring). The title of the letter claimed that the cTnI value was normal. This is not consistent with the data presented. The AxSYM values for cTnI of 1.2 (day 1), 0.8 (day 2), and 1.1 μg/L (2 weeks) are not normal. The limit of detection for the AxSYM is 0.3 μg/L, with a quoted upper reference limit of 0.4 μg/L and an acute myocardial infarction cutoff of 2.0 μg/L (2). The patient’s values fall within the range for detectable and prognostically significant myocardial damage. The main conclusion that Isotalo et al. (1) make is that the increased cardiac troponin T (cTnT) and creatine kinase MB (CK-MB) concentrations are the result of release from a non-cardiac source related to abnormal expression of these proteins. They did not perform experiments to detect evidence of abnormal cTnT or CK-MB expression in the tumor biopsy. Therefore, we fully agree with the authors that their conclusions were “speculative”. However, we disagree with their discussion. The authors clearly state that the patient had no biochemical evidence of renal failure. However, they go on to describe, in detail, the findings of three conflicting studies that discuss the issue of skeletal muscle expression of cTnT in uremic patients. The reference to these studies in this case presentation implies that the authors are making an association with the issues of cTnT in patients with renal failure. We believe this to be a tenuous link between their limited study and the subject of skeletal muscle expression of cTnT in renal failure. In addition, we feel that they have either misread or misinterpreted two of the references dealing with this subject that they quote (3)(4). The authors state that “Isoforms of cTnT have been identified in diseased skeletal muscle of chronic renal failure patients by Western blots and highly specific M7 and M11.7 monoclonal antibodies for cTnT (11), (12). These monoclonal antibodies are the same ones that are used in the [Boehringer Mannheim] second-generation cTnT immunoassay”. We disagree with this representation of the findings of the report by Ricchiuti et al. (3). In this report, positive immunoreactive bands were found with M11.7 in <45% of the samples measured, and <4.5% were found with M7. The bands did not correspond to the adult cTnT isoform. The authors specifically state that the intact adult cardiac isoform is not detected in skeletal muscle by the antibodies in the Roche assay. The study by McLaurin et al. (4) demonstrated immunoreactive bands in four of five muscle samples from renal failure patients. However, the cTnT antibody in this study was JS-2 from Lakeland Biochemical, which is no longer available, and not the M7 or the M11.7 antibody, as stated by Isotalo et al. (1). The finding of Isotalo et al. has no relationship with cTnT expression in renal failure, and the specific citation of the Roche/Boehringer Mannheim antibodies M7 and M11.7 is inaccurate. Isotalo et al. (1) also state that Haller et al. (5) were “unable to demonstrate cTnT mRNA expression in skeletal muscle… ”. This study clearly demonstrated, with control data, the absence of cTnT mRNA and cTnT protein, using two different experimental formats: Western blot and immunohistochemistry. It should also be stated that the study by Haller et al. (5) was in contrast to the two other references (3)(4). The case presented by Isotalo et al. (1) was potentially interesting but incomplete. If tissue analysis of the tumor had been performed at the protein or molecular level, this would have contributed greatly to the subject of expression of cTnT in non-cardiac tissue. We also would like to offer a possible explanation as to the causes of these high circulating concentrations of all three markers of myocardial damage. The patient received three cycles of doxorubicin, but the authors did not state the dosages (1). For nearly three decades, reports have appeared that describe the fatal cardiotoxic effects of this drug (6)(7)(8). Results from human subjects (9) and animal models of doxorubicin-induced myopathies (10)(11) have shown that these myopathies are directly related to serum concentrations of cTnT. It has even been suggested that monitoring of serum cTnT may be used to assess the severity of doxorubicin-related myocyte damage as an alternative to invasive procedures such as endomyocardial biopsy. The claim by Isotalo et al. (1) that the cTnI concentrations were not increased in this patient suggests that cTnI is not a sensitive enough marker to detect drug-induced cardiac damage, whereas CK-MB and cTnT may be.