Exemestane chronic exposure induces cardiotoxicity by disrupting calcium homeostasis and endothelin pathway: Evidence from biochemical, radiological and histopathological analyses.

Exemestane (EMT) is a third-generation steroidal aromatase inhibitor extensively used in hormone receptor (HR)-positive breast cancer therapy and has been known to exert cardiovascular effects during prolonged treatment. The current study was planned to investigate the dose-dependent cardiotoxic effects of EMT. Thirty-two Sprague Dawley rats were randomly divided into four groups i.e., control group, EMT (5 mg/kg), EMT (15 mg/kg) and EMT (25 mg/kg) groups. Gene expression analysis showed downregulated expression of ATP2A2 (SERCA2a), CACNA1C, NOS3 (eNOS) and KLF2 coupled with marked upregulation in the expression of RYR2, PLN, CAMK2D, VEGFA, EDN1 and ICAM1, suggesting impaired calcium handling and endothelial dysfunction. The antioxidant enzymes (CAT, SOD, GPx, GST, GSR, HO-1 and GSH) were decreased significantly while the concentrations of ROS and MDA were increased in dose-dependent manner after EMT intoxication. Cardiac function assessment by echocardiography showed that EMT caused dose-dependent cardiac dysfunction as evidenced by reduced heart rate, wall thickness and cardiac chamber volumes of the ventricles thereby suggesting progressive ventricular remodeling, myocardial hypertrophy, and chamber enlargement particularly at 25 mg/kg EMT administration. Furthermore, EMT intoxication caused elevation in the levels of CK-MB, CPK, troponins, LDH, BNP, NT-proBNP and CRP. Significant upregulation observed in the levels of NF-κB, TNF-α, IL-1β, IL-6 and COX-2 after EMT administration. Moreover, EMT exposure promoted the levels of Bax, Caspase-3 and Caspase-9 while suppressing the levels of Bcl-2. Histopathological analysis demonstrated progressive myocardial degeneration, edema, inflammatory infiltration and peripheral necrosis. Overall, chronic EMT exposure leads to severe, dose-dependent cardiotoxicity, characterized by calcium dysregulation, oxidative stress, inflammatory responses, endothelial dysfunction and apoptosis, and thus warrants cardiac monitoring during prolonged EMT therapy.