An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity.
Authors
Cove-Smith, LauraWoodhouse, N
Hargreaves, A
Kirk, J
Smith, S
Price, S
Galvin, M
Betts, C
Brocklehurst, S
Backen, Alison C
Radford, John A
Linton, Kim M
Roberts, R
Schmitt, M
Dive, Caroline
Tugwood, Jonathan D
Hockings, P
Mellor, H
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.Issue Date
2014-07
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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.Citation
An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. 2014, 140 (1):3-15 Toxicol SciJournal
Toxicological SciencesDOI
10.1093/toxsci/kfu057PubMed ID
24675088Type
ArticleLanguage
enISSN
1096-0929ae974a485f413a2113503eed53cd6c53
10.1093/toxsci/kfu057
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