Troponin Autoantibodies: From Assay Interferent to Mediator of Cardiotoxicity

Twenty years ago in Clinical Chemistry , cardiac troponin I (cTnI)3 autoantibodies to the stable portion of cTnI near the carboxyterminal end of the molecule were first identified as an etiology for false-negative cTnI results (1). Since then, there has been a continuing evolution of our understanding of cardiac troponin autoantibodies as both assay interferents as well as mediators of cardiac pathogenesis. Of particular clinical significance, there is an emerging link between cTnI autoantibodies and cardiotoxicity perhaps related to immune-checkpoint inhibition \[i.e., anti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and anti–programmed cell death protein 1 cancer immunotherapy (PD-1)\] (2, 3). Cardiac troponins are the biomarkers of choice for the assessment of myocardial injury, including myocardial infarction. Clinical assays for cardiac troponins are sandwich immunoassays directed to stable portions of cardiac cTnI and cTnT. As with all such assays, antibody interference can occur. This issue of Clinical Chemistry contains an article in which the authors have evaluated the impact of such antibodies for the various cardiac troponin fragments and complexes in a series of carefully done studies (4). By gel filtration, cTnI autoantibodies were demonstrated to bind to cTnI when cTnI was associated with troponins T and C (the I–T–C ternary complex). However, they did not bind to either free cTnI or when cTnI was associated with C (the I–C binary complex). The authors thus suggest that the negative interference by troponin autoantibodies in cTnI immunoassays is a result of interference with circulating complexes of I-T-C. Importantly, they suggest that a similar effect can be seen with cTnT assays as well as with cTnI assays, given that the I-T-C complex is commonly detected with the cTnT assay as well. Based on the specificity of cTnI autoantibodies for the I-T-C ternary complex, the authors propose a model where, …