Abstract
BackgroundChemotherapy-induced cardiotoxicity is a well-recognized adverse effect of chemotherapy. Quantitative T1-mapping cardiovascular magnetic resonance (CMR) is useful for detecting subclinical myocardial changes in anthracycline-induced cardiotoxicity. The aim of the present study was to histopathologically validate the T1 and T2 mapping parameters for the evaluation of diffuse myocardial changes in rat models of cardiotoxicity.MethodsRat models of cardiotoxicity were generated by injecting rats with doxorubicin (1 mg/kg, twice a week). CMR was performed with a 9.4 T ultrahigh-field scanner using cine, pre-T1, post-T1 and T2 mapping sequences to evaluate the left ventricular ejection fraction (LVEF), native T1, T2, and extracellular volume fraction (ECV). Histopathological examinations were performed and the association of histopathological changes with CMR parameters was assessed.ResultsFive control rats and 36 doxorubicin-treated rats were included and classified into treatment periods. In the doxorubicin-treated rats, the LVEF significantly decreased after 12 weeks of treatment (control vs. 12-week treated: 73 ± 4% vs. 59 ± 9%, P = 0.01). Increased native T1 and ECV were observed after 6 weeks of treatment (control vs. 6-week treated: 1148 ± 58 ms, 14.3 ± 1% vs. 1320 ± 56 ms, 20.3 ± 3%; P = 0.005, < 0.05, respectively). T2 values also increased by six weeks of treatment (control vs. 6-week treated: 16.3 ± 2 ms vs. 10.3 ± 1 ms, P < 0.05). The main histopathological features were myocardial injury, interstitial fibrosis, inflammation, and edema. The mean vacuolar change (%), fibrosis (%), and inflammation score were significantly higher in 6-week treated rats than in the controls (P = 0.03, 0.03, 0.02, respectively). In the univariable analysis, vacuolar change showed the highest correlation with native T1 value (R = 0.60, P < 0.001), and fibrosis showed the highest correlation with ECV value (R = 0.78, P < 0.001). In the multiple linear regression analysis model, vacuolar change was a significant factor for change in native T1 (P = 0.01), and vacuolar change and fibrosis were significant factors for change in ECV (P = 0.006, P < 0.001, respectively) by adding other histopathological parameters (i.e., inflammation and edema scores)ConclusionsQuantitative T1 and T2 mapping CMR is a useful non-invasive tool reflecting subclinical histopathological changes in anthracycline-induced cardiotoxicity.
Highlights
Chemotherapy-induced cardiotoxicity is a well-recognized adverse effect of chemotherapy
In the present study, we aimed to evaluate histopathologic changes associated with anthracycline-induced cardiotoxicity in rat models more comprehensively, and validate the native T1, extracellular volume (ECV), and T2 values acquired using ultrahigh-field T1 mapping cardiovascular magnetic resonance (CMR) against histopathologic features
Physiological and functional data Compared to control rats, the doxorubicin-treated rats showed a significantly lower Hct (58.8 ± 2.0% vs. 43.3 ± 12.0%, P = 0.001), cardiac output (0.15 ± 0.01 l/ min vs. 0.12 ± 0.03 l/min, P = 0.009), and left ventricular ejection fraction (LVEF) (73 ± 4% vs. 65 ± 8%, P = 0.03), and a higher left ventricular (LV) end-systolic volume (LVESV) (0.18 ± 0.02 ml vs. 0.24 ± 0.05 ml, P = 0.05)
Summary
Chemotherapy-induced cardiotoxicity is a well-recognized adverse effect of chemotherapy. Quantita‐ tive T1-mapping cardiovascular magnetic resonance (CMR) is useful for detecting subclinical myocardial changes in anthracycline-induced cardiotoxicity. Many mechanisms of anthracycline cardiotoxicity have been suggested, but the main mechanism is thought to involve the iron-dependent generation of reactive oxygen species and subsequent widespread oxidative damage to cardiomyocyte [1]. This results in myofibrillar loss and cellular necrosis and can lead to irreversible diffuse myocardial fibrosis [2, 3], which is known to be associated with adverse cardiac events [4]. Other studies demonstrated that subclinical myocyte injury occurs at lower and intermediate cumulative doses with preserved LV systolic function [10,11,12]
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