Abstract 9480: Vagus Nerve Stimulation Exerts Cardioprotection Against Doxorubicin-Induced Cardiotoxicity Through Improving Cardiac Mitochondrial Function and Autonomic Tone

Introduction: Cardiac sympathovagal imbalance is a common pathologic finding in patients receiving doxorubicin (DOX), and is considered as a cardiovascular risk factor. Growing evidence demonstrates that cardiac autonomic modulation by vagus nerve stimulation (VNS) exerted cardioprotection in both myocardial ischemia/reperfusion injury and heart failure models. However, the cardioprotection of VNS in DOX-induced cardiotoxicity has never been investigated. Hypothesis: Increased cardiac parasympathetic activity by VNS attenuates the sympathovagal imbalance and mitochondrial dysfunction , thereby improving left ventricular (LV) function. Methods: Rats were divided into a sham group and a VNS group. Two weeks after cervical VNS implantation, all rats were subdivided into 3 groups: control (CON), DOX-treated group (3 mg/kg/day, ip, 6 doses) without VNS (DOX+Sham: DS), and DOX-treated group with VNS (DOX+VNS: DV). VNS was activated simultaneously with the first dose of DOX (20 Hz, 500 μs pulse width, 0.5-0.75 mA, turn ON 14 s and turn OFF 48 s (23% duty cycle), and was maintained for 30 days. At the end of the study protocol, cardiac biochemical and functional analyses were evaluated. Results: DOX treatment increased cardiac mitochondrial ROS production, mitochondrial depolarization, and mitochondrial swelling, leading to left ventricular systolic (%LVFS) and diastolic (E/A ratio) dysfunctions (Fig 1). Moreover, LF/HF ratio was increased in DOX-treated rats, indicating cardiac autonomic imbalance (Fig 1F). Interestingly, VNS could effectively protect the Dox-treated heart by alleviating all of those impaired parameters (Fig 1). Conclusions: VNS protects against DOX-induced cardiotoxicity by improving cardiac mitochondrial function and attenuating cardiac autonomic dysfunctions, leading to improved LV function. Thus, enhancing parasympathetic activity by VNS could be a novel therapeutic approach to prevent DOX-induced cardiotoxicity.