Key result
Low-dose ARNI plus SGLT2i cuts doxorubicin-induced mortality ~81% versus vehicle in preclinical model.
Why the study?
Cancer-therapy-related cardiac dysfunction is a critical clinical issue, but there is a glaring lack of evidence regarding cardiotoxicity management and optimal dosing of ARNI combined with SGLT2i.
Does low-dose ARNI combined with SGLT2i prevent doxorubicin-induced cardiac dysfunction in a rodent model?
Does low-dose ARNI combined with SGLT2i prevent doxorubicin-induced cardiac dysfunction in a rodent model?
Low-dose ARNI combined with SGLT2i provides synergistic cardioprotection against doxorubicin-induced cardiotoxicity with minimal hypotensive adverse effects.
Hypothesis-generating in rodent doxorubicin models; leaves open translation to human cardiotoxicity prevention.
Although cancer-therapy-related cardiac dysfunction (CTRCD) is a critical issue in clinical practice, there is a glaring lack of evidence regarding cardiotoxicity management. To determine an effective and suitable dosage of treatment using angiotensin receptor-neprilysin inhibitors (ARNI) with sodium-glucose cotransporter 2 inhibitors (SGLT2i), we adopted a clinically relevant rodent model with doxorubicin, which would mimic cardiac dysfunction in CTRCD patients. After the oral administration of drugs (vehicle, SGLT2i, ARNI, Low-ARNI/SGLT2i, ARNI/SGLT2i), several physiologic parameters, including hemodynamic change, cardiac function, and histopathology, were evaluated. Bulk RNA-sequencing was performed to obtain insights into the molecular basis of a mouse heart response to Low-ARNI/SGLT2i treatment. For the first time, we report that the addition of low-dose ARNI with SGLT2i resulted in greater benefits than ARNI, SGLT2i alone or ARNI/SGLT2i combination in survival rate, cardiac function, hemodynamic change, and kidney function against doxorubicin-induced cardiotoxicity through peroxisome proliferator-activated receptor signaling pathway. Low-dose ARNI with SGLT2i combination treatment would be practically beneficial for improving cardiac functions against doxorubicin-induced heart failure with minimal adverse effects. Our findings suggest the Low-ARNI/SGLT2i combination as a feasible novel strategy in managing CTRCD patients.
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Kim et al. (2022) studied Doxorubicin-induced cardiotoxicity. Low-dose ARNI and SGLT2i combination vs. Vehicle, ARNI alone, SGLT2i alone, or standard-dose ARNI/SGLT2i was evaluated on Mortality in acute doxorubicin model (p=<0.05). Low-dose ARNI combined with SGLT2i significantly reduced mortality to 14.2% compared to 75% with vehicle in a rodent model of doxorubicin-induced cardiotoxicity.
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