Trastuzumab cardiotoxicity and drug cardioprotection in healthy and cardiac dysfunction mouse models

: Pre-existing cardiovascular disease is a recognised risk factor for cardiotoxicity in HER2-targeted therapies such as trastuzumab (TRZ), but few studies have addressed the impact of TRZ and the effects of cardioprotective drugs in pre-existing cardiac issues. This study examines the impact of TRZ-induced cardiotoxicity in pre-existing cardiac conditions and the effects of captopril and bisoprolol in mouse models with varying degrees of cardiac impairment. Adult mice models with and without baseline cardiac dysfunction ̶ healthy mice (WT), transgenic mice with cardiac hyperaldosteronism (AS) and mice with cardiac dysfunction (AS+ISO) ̶ were randomised to receive placebo, TRZ alone (6 mg/kg/week for 4 weeks), or TRZ administered concomitantly with a cardioprotective therapy based on captopril (ACEi, 20 mg/kg) and bisoprolol (BB, 5 mg/kg) (TRZ+ACEi/BB). Cardiac function was assessed one week after the final injection of TRZ, followed by myocardial tissue histopathological and ultrastructural assessments, and expression of genes associated with cardiomyocyte survival and mitochondrial homeostasis. TRZ reduced systolic function by approximately 10 % in each of the 3 populations studied, causing cellular and mitochondrial damage, regardless of pre-existing cardiac issues. The most severe effects were observed in mice with prior cardiac impairment linked to increased baseline frailty. Cardioprotective therapy improved LV systolic function in all groups to a similar degree. It also reversed the cellular and mitochondrial adverse changes, as well as the altered transcriptional signature caused by TRZ. Our findings demonstrate that the combined ACEi/BB therapy may prevent cardiac TRZ-related toxicity in mouse models with and without baseline cardiac dysfunction.