An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity.
Backen, Alison C
Radford, John A
Linton, Kim M
Tugwood, Jonathan D
AffiliationClinical & 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.
MetadataShow full item record
AbstractMany 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.
CitationAn integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. 2014, 140 (1):3-15 Toxicol Sci
- Novel approach to early detection of doxorubicin cardiotoxicity by gadolinium-enhanced cardiovascular magnetic resonance imaging in an experimental model.
- Authors: Lightfoot JC, D'Agostino RB Jr, Hamilton CA, Jordan J, Torti FM, Kock ND, Jordan J, Workman S, Hundley WG
- Issue date: 2010 Sep
- Dietary omega-3 supplementation exacerbates left ventricular dysfunction in an ovine model of anthracycline-induced cardiotoxicity.
- Authors: Carbone A, Psaltis PJ, Nelson AJ, Metcalf R, Richardson JD, Weightman M, Thomas A, Finnie JW, Young GD, Worthley SG
- Issue date: 2012 Jun
- Experimental determination of diagnostic window of cardiac troponins in the development of chronic anthracycline cardiotoxicity and estimation of its predictive value.
- Authors: Adamcova M, Lencova-Popelova O, Jirkovsky E, Mazurova Y, Palicka V, Simko F, Gersl V, Sterba M
- Issue date: 2015 Dec 15
- In vitro and in vivo examination of cardiac troponins as biochemical markers of drug-induced cardiotoxicity.
- Authors: Adamcová M, Simůnek T, Kaiserová H, Popelová O, Sterba M, Potácová A, Vávrová J, Maláková J, Gersl V
- Issue date: 2007 Jul 31
- Limited cardiotoxicity after extensive thoracic surgery and intraoperative hyperthermic intrathoracic chemotherapy with doxorubicin and cisplatin.
- Authors: de Bree E, van Ruth S, Schotborgh CE, Baas P, Zoetmulder FA
- Issue date: 2007 Oct