Serum Troponins as Biomarkers of Drug-Induced Cardiac Toxicity

Based on the foregoing exhaustive review of the currently available evidence, the Expert Working Group on Biomarkers of Drug-Induced Cardiac Toxicity has drawn the following conclusions: 1) cTnI and cTnT are specific, sensitive, and robust biomarkers of myocardial damage that are released into the serum soon following tissue pathogenesis and reflect the extent of irreversible myocardial cell injury caused by both natural and drug-induced diseases in humans and common laboratory species. (a) The troponins are more specific and sensitive than conventionally used biomarkers of cardiac injury. (b) Robust detection assays are available and applicable to both human and common preclinical laboratory animal species. (c) The troponins present a potential bridge between nonclinical and clinical studies in that they appear to be useful biomarkers for assessing drug-induced cardiac injury in both humans and laboratory species. 2) The troponins exhibit critical diagnostic windows that must be considered in the design and interpretation of experimental results. (a) Elevated serum cTnI and cTnT report, but do not predict, active irreversible myocardial cell injury. (b) Within the context of a given pathogenic process, the magnitude of increase in serum cTnI or cTnT correlates with the extent of myocardial cell injury. (c) Elevations in serum cTnI and cTnT concentration resolve towards baseline within hours or days following cessation of the active process of cell injury. Tissue histopathology and functional deficits may persist well beyond the return of serum troponins to baseline values. 3) Any increase in serum troponin above baseline is evidence of possible cardiac damage and warrants further investigation. (a) There may exist thresholds for troponin release below which the myocardial injury is fully compensated at the organ level and there are no associated functional deficits. (b) Elevated serum cTnI or cTnT may reflect a direct effect of the drug on the myocardium or may be secondary to a drug effect on some other organ system that subsequently leads to myocardial damage. (c) cTnI and cTnT are not biomarkers of all forms of drug-induced cardiac injury. (1) Cardiac cell injury that does not result in altered cardiac muscle cell membrane permeability may not be associated with increases in serum troponins. (2) Serum troponins are not expected to increase in direct response to drug-induced dysrythmias, altered ion homeostasis, valvular disease, contractile dysfunction, etc.