An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity

Laura Cove-Smith; Neil Woodhouse; Adam Hargreaves; Jason Kirk; Susan Smith; Sally A. Price; Melanie Galvin; Catherine J Betts; Simon Brocklehurst; Alison Backen; John Radford; Kim Linton; Ruth Roberts; Matthias Schmitt; Caroline Dive; Jonathan D Tugwood; Paul D. Hockings; Howard R.  Mellor

doi:10.1093/toxsci/kfu057

An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity

Laura Cove-Smith, Neil Woodhouse, Adam Hargreaves, Jason Kirk, Susan Smith, Sally A. Price, Melanie Galvin, Catherine J Betts, Simon Brocklehurst, Alison Backen, John Radford, Kim Linton, Ruth Roberts, Matthias Schmitt, Caroline Dive, Jonathan D Tugwood, Paul D. Hockings, Howard R. Mellor

Biosciences

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28 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3-15
Number of pages	13
Journal	Toxicological Sciences
Volume	140
Issue number	1
Early online date	27 Mar 2014
DOIs	https://doi.org/10.1093/toxsci/kfu057
Publication status	Published - 1 Jul 2014

Keywords

doxorubicin
cardiotoxicity
chemotherapy
cardiac MRI
anthracycline
ejection fraction

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Cove-Smith, L., Woodhouse, N., Hargreaves, A., Kirk, J., Smith, S., Price, S. A., Galvin, M., Betts, C. J., Brocklehurst, S., Backen, A., Radford, J., Linton, K., Roberts, R., Schmitt, M., Dive, C., Tugwood, J. D., Hockings, P. D., & Mellor, H. R. (2014). An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity. Toxicological Sciences, 140(1), 3-15. Advance online publication. https://doi.org/10.1093/toxsci/kfu057

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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.",

keywords = "doxorubicin, cardiotoxicity, chemotherapy, cardiac MRI, anthracycline, ejection fraction",

author = "Laura Cove-Smith and Neil Woodhouse and Adam Hargreaves and Jason Kirk and Susan Smith and Price, {Sally A.} and Melanie Galvin and Betts, {Catherine J} and Simon Brocklehurst and Alison Backen and John Radford and Kim Linton and Ruth Roberts and Matthias Schmitt and Caroline Dive and Tugwood, {Jonathan D} and Hockings, {Paul D.} and Mellor, {Howard R.}",

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Cove-Smith, L, Woodhouse, N, Hargreaves, A, Kirk, J, Smith, S, Price, SA, Galvin, M, Betts, CJ, Brocklehurst, S, Backen, A, Radford, J, Linton, K, Roberts, R, Schmitt, M, Dive, C, Tugwood, JD, Hockings, PD & Mellor, HR 2014, 'An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity', Toxicological Sciences, vol. 140, no. 1, pp. 3-15. https://doi.org/10.1093/toxsci/kfu057

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T1 - An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity

AU - Cove-Smith, Laura

AU - Woodhouse, Neil

AU - Hargreaves, Adam

AU - Kirk, Jason

AU - Smith, Susan

AU - Price, Sally A.

AU - Galvin, Melanie

AU - Betts, Catherine J

AU - Brocklehurst, Simon

AU - Backen, Alison

AU - Radford, John

AU - Linton, Kim

AU - Roberts, Ruth

AU - Schmitt, Matthias

AU - Dive, Caroline

AU - Tugwood, Jonathan D

AU - Hockings, Paul D.

AU - Mellor, Howard R.

PY - 2014/7/1

Y1 - 2014/7/1

N2 - 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.

AB - 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.

KW - doxorubicin

KW - cardiotoxicity

KW - chemotherapy

KW - cardiac MRI

KW - anthracycline

KW - ejection fraction

U2 - 10.1093/toxsci/kfu057

DO - 10.1093/toxsci/kfu057

M3 - Article

SN - 1096-6080

VL - 140

SP - 3

EP - 15

JO - Toxicological Sciences

JF - Toxicological Sciences

IS - 1

ER -

An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity

Abstract

Keywords

UN SDGs

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