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Letters |
1
Refs. (3)(4) in our references.
2
Cardiological Sciences, Analytical Unit, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
3
Department of Chemical Pathology, St. George’s Hospital, Blackshaw Road, London SW17 0QT, UK
a Author for correspondence. Fax 44-208-767-9687; e-mail frederic{at}sghms.ac.uk
To the Editor:
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.
Footnotes
1 Refs. (3) (4), in our
references. 
References
4
Department of Pathology, and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9
5
Division of Biochemistry, Department of Pathology, and Laboratory Medicine, Ottawa Hospital–General Campus, Ottawa, Ontario, Canada K1H 8L6
6
Division of Biochemistry, Department of Pathology, and Laboratory Medicine, Ottawa Hospital–Civic Campus, Ottawa, Ontario, Canada K1Y 4E9
7
Department of Biochemistry,, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5
a Address correspondence to this author at: Division of Biochemistry, Department of Laboratory Medicine, Ottawa Hospital–Civic Campus, 1053 Carling Ave., Ottawa, Ontario, Canada K1Y 4E9. Fax 613-761-5361; e-mail jdonnelly{at}civich.ottawa.on.ca
To the Editor:
We appreciate the interest that Fredericks et al. have shown in
our letter (1). As mentioned previously, our patient was a
53-year-old man with metastatic alveolar rhabdomyosarcoma who had
increased cardiac markers detected after he developed atypical chest
pain while being managed for deep venous thrombosis and inguinal lymph
node metastases. In our letter, we erroneously stated that the
patient’s AxSYM cTnI values were normal when in fact we should have
stated that cTnI values were below the cutoff value for acute
myocardial infarction (AMI; 
2.0 µg/L). In addition to being below
the cutoff for AMI, our patient’s cardiac troponin I (cTnI) values
were within the 95th percentile of cTnI for non-AMI patients (2.4
µg/L), as described by Apple et al. (2).
It is unfortunate that Fredericks et al. have either disregarded or misunderstood our previous discussion regarding cTnT expression and chronic renal failure (1). Ricchiuti et al. (3) have clearly demonstrated cTnT isoform expression in skeletal muscle from patients with chronic renal disease. Fredericks et al. cannot dismiss this expression of skeletal muscle cTnT isoforms. Although this cTnT isoform expression does not produce false-positive results in the second-generation Boehringer Mannheim cardiac troponin T (cTnT) assay (3), the discovery that skeletal muscle may re-express cTnT isoforms under certain conditions is significant. The study by McLaurin et al. (4) also confirmed cTnT expression in skeletal muscle from hemodialysis patients by use of Western blots and JS-2 antibodies. We erroneously stated that they had used M7 and M11.7 antibodies for their immunologic detection of cTnT.
Skeletal muscle cTnT expression is not restricted to patients with chronic renal disease; it has also been described in the skeletal muscle of patients with Duchenne muscular dystrophy (5). It is clear that Fredericks et al. fail to understand the significance of skeletal muscle cTnT re-expression with respect to our patient. If "diseased" skeletal muscle can re-express an immature, fetal phenotype, as manifested by cTnT re-expression (3), it is very reasonable, and in fact logical, to expect that neoplasms with features of skeletal muscle differentiation may also express cTnT isoforms. In addition, anaplastic tumors are genetically unstable, and because of lack of differentiation, they may elaborate proteins that are not usually expressed by their benign tissue counterparts.
With respect to possible doxorubicin cardiac toxicity, our patient had no clinical evidence of cardiomyopathy. Our patient received a total doxorubicin dose of 180 mg/m2. Histologic evidence of myocardial toxicity has been identified in endomyocardial biopsies of patients who have been treated with total doxorubicin doses as small as 250 mg/m2 (6). The risk of doxorubicin-induced cardiomyopathy is dose dependent (7)(8), with cardiomyopathy developing in 30% of patients once total doxorubicin doses of 550 mg/m2 have been attained (8). It is unlikely that our patient would have ever developed a doxorubicin-induced cardiomyopathy, considering his relatively small total dose of doxorubicin.
In addition to overt cardiomyopathy, it has been suggested that patients treated with doxorubicin may also develop subclinical cardiac toxicity, as evidenced by increased serum troponins, cTnT and cTnI, and cardiac uptake of radiolabeled anti-myosin antibodies (7)(9)(11). Lipshultz et al. (9) studied 15 children with acute lymphoblastic leukemia who underwent doxorubicin chemotherapy and demonstrated increases in cTnT post anthracycline chemotherapy. None of these patients showed significant increases in creatine kinase (CK), CK-MB, or myoglobin. Anthracycline-treated patients of Missov et al. (11) had postanthracycline cTnI increases attributed to subclinical myocyte toxicity, also with no significant increases in CK-MB or myoglobin. Despite the suggestion by Fredericks et al., our patient’s sustained increased CK concentrations and his grossly disproportionate increase in CK-MB are inconsistent with both doxorubicin-induced cardiac toxicity and acute cardiac ischemia. A CK concentration of 1364 U/L, a CK-MB mass of 1047 µg/L, a remarkable CK-MB index of 77, and a cTnT concentration of 2.49 µg/L, post tumor radiotherapy, cannot be explained by toxic doxorubicin therapeutic effects, especially considering that these markers were measured 5 months after the patient’s last chemotherapy cycle. In addition, our patient had a CK-BB of 25 U/L before his radiotherapy. Ongoing tumor necrosis, especially post radiotherapy, and increased tumor mitotic activity with high neoplastic cell turnover more likely explain these increased values. An association between our patient’s biochemical results and doxorubicin-induced cardiotoxicity seems inconceivable. In our experience, disproportionate increases in CK-MB in relation to total CK, along with the detection of substantial quantities of CK-BB, cannot be explained by a cardiac source.
References
The following articles in journals at HighWire Press have cited this article:
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  S. Agewall Increases of Creatine Kinase MB and Cardiac Troponin T in Serum of a Patient with Uterine Leiomyosarcoma Clin. Chem., December 1, 2000; 46(12): 2016 - 2017. [Full Text] [PDF]
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