Investigation of potential sex-based differences in trastuzumab-induced chronic cardiotoxicity in a rat model

Although trastuzumab (TZB) significantly increases survival in patients with human epidermal growth factor receptor 2 (HER2/ErbB2)-positive breast and gastrointestinal cancers, its use may be limited by chronic cardiotoxicity. Several tryptophan (Trp) metabolites are associated with oxidative stress, inflammation, and metabolic disturbances in heart failure (HF). Here, we aimed to characterize changes in left ventricular (LV) concentrations of selected Trp metabolites in a rat model of TZB-induced chronic cardiotoxicity.

Male and female Wistar-Hannover rats (300-400 g) were divided into 2-2 groups: i) physiological saline-treated (6 × 1 mL/kg, i.p.) control, and ii) TZB-treated (2 mg/kg, then 5 × 1 mg/kg, i.p.) groups. At weeks 12 and 19, echocardiography was performed. At week 20, blood and LV samples were collected. Then, histology, RT-qPCR, and UHPLC-MS/MS analyses of genes and metabolites related to nitro-oxidative stress, inflammation, glucose and fatty acid metabolism, and Trp metabolism were performed.

Diastolic dysfunction began in both TZB-treated groups by week 12. At the endpoint, both TZB-treated groups showed echocardiographic, histologic, and molecular signs of chronic cardiotoxicity, accompanied by LV overexpression of genes associated with inflammation and nitro-oxidative stress, repression of glucose transporter 4, glycerol-3-phosphate dehydrogenase, and carnitine palmitoyltransferase. However, only female TZB-treated rats showed increased LV levels of Trp, 3-hydroxykynurenine, quinolinic acid, and nicotinamide adenine dinucleotide (NAD⁺). In contrast, TZB-treated males presented lower LV levels of kynurenine and xanthurenic acid.

Comparable TZB-induced chronic cardiotoxicity developed in both sexes. However, LV Trp metabolite concentrations showed sex-divergent alterations, the significance of which should be clarified in further mechanistic studies.