Blood cardiac troponin in toxic myocardial injury: archetype of a translational safety biomarker

Abstract

A translational safety biomarker for toxic myocardial injury is needed in drug discovery and development. This need reflects the increasing recognition of occurrence of cardiotoxicities, prior lack of preclinical blood biomarkers for toxic cardiac injury, introduction of troponin as a biomarker, and regulatory and industry drivers. Cardiac troponin is considered the gold-standard biomarker in humans for cardiac injury due to ischemic injury and drug toxicity. It has been demonstrated to correlate highly with histopathological extent of injury, degree of impairment of cardiac function, and prognosis. Numerous studies have now clearly demonstrated that both cardiac troponin T and cardiac troponin I are sensitive and specific biomarkers of cardiac injury in laboratory animals. Their use is highly recommended for incorporation into preclinical drug-safety studies, especially whenever there is any history of cardiac effect in prior studies with a compound of the same or similar chemical or pharmacological class. The main caveats with respect to cross-species use of specific cardiac troponin assays are the need for species-specific validation, definition of cut-offs based on relevant assessments of imprecision and reference ranges or concurrent controls, and knowledge of the species-dependent kinetics of release into, and clearance from, the blood. Future development of high-sensitivity assays should determine whether minimal increases below a threshold concentration of troponin might reflect reversible myocardial effects.

Keywords::

• cardiac injury
• cardiac muscle
• cardiac troponin I
• cardiac troponin T
• cardiotoxicity
• laboratory animals
• skeletal muscle
• translational safety biomarker
• troponin isoforms