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.

Functional and Structural Assessment of the Effect of Human Umbilical Cord Blood Mesenchymal Stem Cells in Doxorubicin‐Induced Cardiotoxicity

“…The present study showed decreased of physical activity; decline in general health, significantly lower body weight, and significant ascites in DOXadministered groups (II, III) at the end of the 3rd week. This is consistent with previous reports [Merlet et al, 2013;Cove-Smith et al, 2014;Ammar et al, 2015].…”

Experimental determination of diagnostic window of cardiac troponins in the development of chronic anthracycline cardiotoxicity and estimation of its predictive value

“…The slight cTn rise observed in both groups might be at least partially explained by a cardiac burden induced by anesthesia, repeated blood sampling and animal manipulations, together with the excellent sensitivity of modern cardiac troponin immunoassays employed in this study. The lack of ANT-induced elevation of cTnT after the first dose is in an agreement with Cove-Smith et al [32] who reported that only electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose of doxorubicin, while Table 3 Correlation of area under curve (AUC) of cardiac troponins in 1st, 5th and 8th weeks and AUC 5-10 (calculated from the 5th till the 10th week) with left ventricular systolic function (LV fractional shortening and dP/dt max ). significant increases in serological cTnI (measured using a human ultrasensitive troponin I assay kit, Siemens, Camberley, UK) emerged later.…”

Update on cardiotoxicity of anti‐cancer treatments

“…provided the most comprehensive characterization to the time course of events underlying chemotherapy‐related cardiomyopathy: while subcellular degeneration occurs after a single dose and progressive cardiomyocyte degeneration begins after two doses, extensive replacement fibrosis may develop during the off‐dosing period (functional indices assessed by cardiac MRI decline progressively and reach statistical significance after two doses), culminating in ‘clinical’ LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I have been shown to appear after eight doses, importantly preceding LVEF decline to <50% . Another aspect that may be evaluated is increased signal intensity on T1 and T2 weighted images and signal prolongation (in msec) on T1 and T2 maps due to myocyte loss and interstitial oedema.…”