Angiotensin receptor-neprilysin inhibition by sacubitril/valsartan attenuates doxorubicin-induced cardiotoxicity in a pretreatment mice model by interfering with oxidative stress, inflammation, and caspase 3 apoptotic pathway

Objective: Doxorubicin (DOX) is a well-known cardiotoxic agent, whereas sacubitril/valsartan (Sac/Val) is an effective treatment option in heart failure. In this study, we aimed to evaluate the effect of Sac/Val on DOX-induced cardiotoxicity in pretreatment mice model. Methods: A total of 24 mice were equally classified into 4 groups; control group, DOX (20 mg/kg; fifth day), Sac/Val (80 mg/kg), and Sac/Val+DOX (Sac/Val was given from day one of the study before doxorubicin administration). Electrocardiography parameters, including durations of QRS, ST, QT, PP segment, and QT/PQ index were measured. Total antioxidant status (TAS), total oxidant status (TOS), tumor necrosis factor-? (TNF-?), interleukin 1? (IL-1?), IL-6, NT-proBNP concentrations, and Caspase 3 activity were evaluated. Results: At the end of the 9-day study duration, QRS, ST, QT intervals, QT/PQ index and TAS, TOS, TNF-?, IL-1?, IL-6 levels were significantly higher in the DOX group than in the control group (p<0.001). Moreover, there were significant differences only in the PP interval when comparing the Sac/Val+DOX and control groups (p<0.001). QRS, ST, QT intervals, and QT/PQ index, TAS, TOS, TNF-?, IL-1?, IL-6 levels were significantly lower in the Sac/Val+ DOX group compared with the DOX group (p<0.001). Furthermore, NT-proBNP levels were lower in the Sac/Val+DOX group compared with the DOX group along with less Caspase 3 apoptosis. Conclusion: Sac/Val seems to be cardioprotective against DOX-induced cardiotoxicity in pretreatment mice model. These findings can be attributed to the antiarrhythmic, anti-inflammatory, antioxidant, and antiapoptotic effects of Sac/Val as shown in this study. ©Copyright 2021 by Turkish Society of CardiologyWe would like to thank Nurullah Hatip for his valuable contributions

Reply to Letter to the Editor: "Can ARNI Prevent Doxorubicin-Induced Cardiotoxicity?"

We thank the authors for reading with great interest. In our study, as in previous studies, semi-quantitative histological analysis was performed.1 It was stated that the limitations of our study were that imaging methods, especially invasive methods and hemodynamic measurements, were not used. Doxorubicin (DOX)-induced cardiotoxicity can occur in acute and chronic periods. It is known in the literature that left ventricular systolic dysfunction accompanies DOX-induced ventricular-related acute arrhythmogenic events.2,3 In a recent study, it was found that natriuretic peptide levels predicted late-stage cardiotoxicity due to DOX.4 In our study, the ability of electrocardiography and natriuretic peptide data to predict both acute and chronic cardiotoxicities due to DOX has been already proven in clinical studies in the literature