Trastuzumab reduced systolic function by approximately 10% in mouse models regardless of baseline cardiac function, which was prevented by combined captopril and bisoprolol therapy.
RCT
randomised
Does combined captopril and bisoprolol therapy prevent trastuzumab-induced cardiotoxicity in mouse models with and without baseline cardiac dysfunction?
Combined captopril and bisoprolol therapy mitigates trastuzumab-induced myocardial damage and preserves systolic function in mouse models regardless of pre-existing cardiac impairment.
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. Trastuzumab exacerbates cardiac dysfunction in mice with pre-existing cardiac impairment, while ACE inhibitors and beta-blockers mitigate myocardial damage and preserve mitochondrial homeostasis. • TRZ causes cardiac impairment in mouse models with and without baseline cardiac dysfunction • TRZ treatment causes damage to both cardiomyocytes and mitochondria. • A cardioprotective ACEi/BB therapy is effective in the prevention of TRZ-induced cardiotoxicity .
L’Abbate et al. (Thu,) conducted a rct in Trastuzumab-induced cardiotoxicity. Trastuzumab with or without captopril and bisoprolol vs. Placebo was evaluated on Cardiac function, myocardial tissue histopathological and ultrastructural assessments, and gene expression. Trastuzumab reduced systolic function by approximately 10% in mouse models regardless of baseline cardiac function, which was prevented by combined captopril and bisoprolol therapy.
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