Differential cardiotoxic electrocardiographic response to doxorubicin treatment in conscious versus anesthetized mice

Introduction: Doxorubicin (DOX), an anticancer drug used in chemotherapy, causes significant cardiotoxicity. This study aimed to investigate the effects of DOX on mouse cardiac electrophysiology, in conscious versus anesthetized state. Methods: Male and female C57BL/6 mice were injected with saline, 20 or 30 mg/kg DOX. ECGs were recorded 5 days post-injection in conscious and isoflurane anesthetized states. ECGs were analyzed using a custom MATLAB software to determine P, PR, QRS, QTc, and RR intervals as well as heart rate variability (HRV). Results: ECGs from the same mouse demonstrated P wave and QTc shortening as well as PR and RR interval prolongation in anesthetized versus conscious saline-treated mice. ECG response to DOX was also modulated by anesthesia. DOX treatment induced significant ECG modulation in female mice alone. While DOX20 treatment caused decrease in P and QRS durations, DOX30 treatment-induced QTc and RR interval prolongation in anesthetized but not in conscious female mice. These data suggest significant sex differences and anesthesia-induced differences in ECG response to DOX. HRV measured in time and frequency domains, a metric of arrhythmia susceptibility, was increased in DOX20-treated mice compared to saline. Conclusions: This study for the first time identifies that the ECG response to DOX is modulated by anesthesia. Furthermore, this response demonstrated stark sex differences. These findings could have significant implications in clinical diagnosis of DOX cardiotoxicity.