title: An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity.
abstract: Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers.
authors.affiliation: Clinical & Experimental Pharmacology, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Cove-Smith
authors.affiliation: Personalised Healthcare & Biomarkers, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Neil
authors.initials: N
authors.lastname: Woodhouse
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Hargreaves
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Kirk
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Smith
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Price
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Galvin
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Betts
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Brocklehurst
authors.affiliation: Clinical & Experimental Pharmacology, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Backen
authors.affiliation: University of Manchester, Institute of Cancer Sciences, Oxford Road, Manchester M13 9PT, UK Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: John
authors.initials: J
authors.lastname: Radford
authors.affiliation: University of Manchester, Institute of Cancer Sciences, Oxford Road, Manchester M13 9PT, UK Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Kim
authors.initials: K
authors.lastname: Linton
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Roberts
authors.affiliation: North West Regional Heart Centre, University Hospital of South Manchester, Wythenshawe, Manchester M23 9LT, UK.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Clinical & Experimental Pharmacology, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
authors.affiliation: Clinical & Experimental Pharmacology, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Tugwood
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK MedTech West, Chalmers University of Technology, 41296 Gothenburg, Sweden.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Hockings
authors.affiliation: Drug Safety & Metabolism, Innovative Medicines, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK howard_mellor@vrtx.com.
authors.forename: Howard R
authors.initials: HR
authors.lastname: Mellor
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced / Q000473:pathology*; D066126:Cardiotoxicity; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D005355:Fibrosis; D006334:Heart Function Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D009206:Myocardium / Q000648:ultrastructure*; D017208:Rats, Wistar; D019210:Troponin I / Q000097:blood*
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D019210:Troponin I; D004317:Doxorubicin
keywords: anthracycline; cardiac MRI; cardiotoxicity; chemotherapy; doxorubicin; ejection fraction