title: Evaluation of Cardiac Toxicity Biomarkers in Rats from Different Laboratories.
abstract: There is a great need for improved diagnostic and prognostic accuracy of potential cardiac toxicity in drug development. This study reports the evaluation of several commercially available biomarker kits by 3 institutions (SRI, Eli Lilly, and Pfizer) for the discrimination between myocardial degeneration/necrosis and cardiac hypertrophy as well as the assessment of the interlaboratory and interplatform variation in results. Serum concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide [NT-proANP] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), cardiac and skeletal troponins (cTnI, cTnT, and sTnI), myosin light chain 3 (Myl3), and fatty acid binding protein 3 (FABP3) were assessed in rats treated with minoxidil (MNX) and isoproterenol (ISO). MNX caused increased heart-to-body weight ratios and prominent elevations in NT-proANP and NT-proBNP concentrations detected at 24-hr postdose without elevation in troponins, Myl3, or FABP3 and with no abnormal histopathological findings. ISO caused ventricular leukocyte infiltration, myocyte fibrosis, and necrosis with increased concentrations of the natriuretic peptides, cardiac troponins, and Myl3. These results reinforce the advantages of a multimarker strategy in elucidating the underlying cause of cardiac insult and detecting myocardial tissue damage at 24-hr posttreatment. The interlaboratory and interplatform comparison analyses also showed that the data obtained from different laboratories and platforms are highly correlated and reproducible, making these biomarkers widely applicable in preclinical studies.
authors.affiliation: 1 SRI International, Menlo Park, California, USA.
authors.forename: Kyuri
authors.initials: K
authors.lastname: Kim
authors.affiliation: 1 SRI International, Menlo Park, California, USA.
authors.forename: Naseem
authors.initials: N
authors.lastname: Chini
authors.affiliation: 1 SRI International, Menlo Park, California, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Fairchild
authors.affiliation: 2 Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Engle
authors.affiliation: 3 Pfizer, Drug Safety Research and Development, Groton, Connecticut, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Reagan
authors.affiliation: 3 Pfizer, Drug Safety Research and Development, Groton, Connecticut, USA.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Summers
authors.affiliation: 1 SRI International, Menlo Park, California, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Mirsalis
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D066126:Cardiotoxicity; D055808:Drug Discovery / Q000592:standards*; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood*; D006321:Heart / Q000187:drug effects*; D007753:Laboratories / Q000592:standards*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats
chemical_list: D015415:Biomarkers
keywords: biomarker; cardiac troponins; cardiotoxicity; hypertrophy; myocardial necrosis; natriuretic peptides; rat