The utility of serum biomarkers to detect myocardial alterations induced by Imatinib in rats

Abstract

Background: Imatinib (Imb) is a tyrosine kinase inhibitor with cardiotoxic activity (decreases in left ventricular function and congestive heart failure) in patients. Currently, clinical diagnosis of Imb cardiotoxicity relies primarily on evaluation of left ventricular function, Imb also induces cardiac lesions in rats.

Aims: This study, in rats, sought to determine whether monitoring biochemical markers would be a sensitive means to detect Imb-induced changes in cardiomyocyte morphology.

Materials and methods: Groups of male Sprague-Dawley rats were dosed orally with 50, 100, 200 mg kg(-1) Imb or water daily for 28 days. Tissues and blood samples were collected 24 h after the last dosing. Cardiac biomarkers such as cardiac troponin I (cTnI), cardiac troponin T (cTnT), and fatty acid binding protein 3 (FABP3) were monitored by the Erenna, Elecsys, and Meso Scale immunoassay systems.

Results: Imb caused microscopic myocardial lesions (myofibrillar loss, cytoplasmic vacuolization, and necrosis) at all doses as determined by unbiased histopathology analysis. The severity of the alterations was dose-related with mean lesion scores (based on a scale of 0-3) of 1.2 (50 mg kg(-1)), 2.1 (100 mg kg(-1)) and 2.9 (200 mg kg(-1)). However, the increases in cTnI, cTnT, and FABP3 levels were noted primarily in high-dose Imb treated animals.

Discussion and conclusion: The occurrence of myocardial alterations in animals without consistent changes in cardiac troponin and FABP3 concentrations raises questions regarding the utility of these biomarkers as early indicators of Imb-induced cardiotoxicity. Due to limited numbers of animals the reasons for this discrepancy could not be determined.

Keywords: Cardiac biomarkers; Imatinib cardiotoxicity; rats.

Figure 1

(A–D) Light micrographs showing cardiac alterations in left ventricle from male Sprague–Dawley rats treated orally with water (A, B) or Imatinib (Imb) at doses of 200 mg kg⁻¹ (C, D) for 28 days. (A) The cardiac myofibrils from water-treated rats showed regular arrangement of thick and thin myofilaments. (B) Spontaneous background cardiac myocyte necrosis with mixed mononuclear cell infiltration in a water-treated control rat. (C) Focal myofibrillar loss and formation of varied-sized cytoplasmic vacuoles in the myocardium of a rat treated with 200 mg kg⁻¹ Imb. (D) Focus of intact and fragmented necrotic cardiomyocytes in association with cytoplasmic vacuoles in the myocardium from a rat treated with 200 mg kg⁻¹ Imb. Glycol methacrylate-embedded, alkaline toluidine blue-stained, 1-μm thick plastic sections. Original magnification 630×.