A translational approach to detecting drug-induced cardiac injury with cardiac troponins: Consensus and recommendations from the Cardiac Troponins Biomarker Working Group of the Health and Environmental Sciences Institute Brian R. Berridge, DVM, PhD, a Syril Pettit, MS, b Dana B. Walker, DVM, PhD, c Alan S. Jaffe, MD, d Albert E. Schultze, DVM, PhD, e Eugene Herman, PhD, f William J. Reagan, DVM, PhD, g Steven E. Lipshultz, MD, h Fred S. Apple, PhD, i and Malcolm J. York, MPhil j Research Triangle Park, NC; Washington, DC; East Syracuse, NY; Rochester, and Minneapolis, MN; Indianapolis, IN; Silver Spring, MD; Groton, CT; Miami, FL; and Hertfordshire, UK Cardiac troponins (cTns) are established biomarkers of ischemic heart disease in humans. However, their value as biomarkers of cardiac injury from causes other than ischemic heart disease is now being explored, particularly in drug development. In a workshop sponsored by the Cardiac Troponin Biomarker Working Group of the Health and Environmental Sciences Institute, preclinical, clinical, and regulatory scientists discussed the application of cTns in their respective environments, issues in translating the preclinical application of cTn to clinical studies, and gaps in our understanding of cTn biology and pathobiology. Evidence indicates that cTns are sensitive and specific biomarkers of cardiac injury from varying causes in both animals and humans. Accordingly, monitoring cTns can help ensure patient safety during the clinical evaluation of new drugs. In addition, preclinical characterization of cardiac risk and cTns as biomarkers of that risk can guide relevant clinical application and interpretation. We summarize here the outcomes of the workshop which included consensus statements, recommendations for further research, and a proposal for a cross-disciplinary group of clinical, regulatory, and drug development scientists to collaborate in such research. (Am Heart J 2009;158:21-9.) Cardiac troponins (cTns) I and T are receiving increas- ing attention as biomarkers of myocardial injury beyond their traditional clinical applications in acute coronary syndrome. Accordingly, a new and growing interest is their usefulness as biomarkers of drug-induced myocardial toxicity in both preclinical and clinical drug safety testing. This interest has risen, in part, from the recognition that cardiovascular toxicity is a major contributor to adverse clinical events, marketed drug withdrawals and drug development terminations. 1-3 Interest has also risen because cTn analysis has similar use across species. Studies in laboratory animals indicate that cTns have many characteristics of ideal translational biomarkers bridging preclinical safety assessment and clinical manage- ment of drug-induced cardiac injury. 3-5 However, the application of cTn monitoring to either preclinical or clinical drug safety testing presents sig- nificant and novel challenges. Although most increases in serum concentrations of cTn in humans are thought to be associated with an adverse prognosis, corresponding data in animals are lacking. 6,7 In addition, because growing evidence suggests that increases in the serum concentra- tion of cTn may be more sensitive than histologic analysis and other objective measures of cardiac myocyte injury, the clinical importance of subtle isolated increases in the concentration of cTn in individual animals or patients without morphologic correlates may be difficult to interpret. 8-10 Finally, interpreting cTn results is compli- cated by differences among assays. The single assay for cTnT allows for greater comparability across laboratories than that possible with the multitude of commercially available cTnI assays. Variability among cTnI assays with respect to reagents, calibration standards, and perfor- mance characteristics complicates comparing data across laboratories as well as across species. 11,12 A relatively From the a GlaxoSmithKline Safety Assessment, Research Triangle Park, NC, b ILSI Health and Environmental Sciences Institute, Washington DC, c Bristol-Myers Squibb, East Syracuse, NY, d Mayo Clinic, Rochester, MN, e Pathology Department, Eli Lilly and Company, Indianapolis, IN, f FDA Center for Drug Evaluation and Research, Silver Spring, MD, g Drug Safety Evaluation, Pfizer Inc., Groton, CT, h Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, i Hennepin County Medical Center, Minneapolis, MN, and j GlaxoSmithKline Safety Assessment, Hertfordshire, UK. Submitted April 23, 2009; accepted April 23, 2009. Reprint requests: Brian R. Berridge, DVM, PhD, GlaxoSmithKline Safety Assessment, 5 Moore Dr., RD9.3005, Research Triangle Park, NC. E-mail: brian.x.berridge@gsk.com 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2009.04.020 Results of Expert Meetings