Non-invasive transcutaneous vagal nerve stimulation improves myocardial performance in doxorubicin-induced cardiotoxicity.

Abstract

AIMS\nThe clinical use of antitumor agent doxorubicin (DOX) is hampered by its dose-dependent cardiotoxicity. Development of highly efficient and safe adjuvant intervention for preventing DOX-induced adverse cardiac events is urgently needed. We aimed to investigate whether transcutaneous vagal nerve stimulation (tVNS) plays a cardio-protective role in DOX-induced cardiotoxicity.\n\n\nMETHODS AND RESULTS\nHealthy male adult Sprague Dawley rats were used in the experiment and were randomly divided into four groups including control, DOX, tVNS and DOX+tVNS groups. A cumulative dose of 15\u2009mg/kg DOX was intraperitoneally injected into rats to generate cardiotoxicity. Non-invasive tVNS was conducted for 6 weeks (30\u2009min/day). After six-week intervention, the indices from the echocardiography revealed that tVNS significantly improved left ventricular function compared to the DOX group. The increased malondialdehyde (MDA) and Interleukin-1β (IL-1β), and decreased superoxide dismutase (SOD) were observed in the DOX group, while tVNS significantly prevented these changes. From cardiac histopathological analysis, the DOX+tVNS group showed a mild myocardial damage, and decreases in cardiac fibrosis and myocardial apoptosis compared to the DOX group. Heart rate variability (HRV) analysis showed that tVNS significantly inhibited DOX-induced sympathetic hyperactivity compared to the DOX group. Additionally, the results of RNA-sequencing analysis showed that there were 245 differentially expressed genes in the DOX group compared to the control group, among which 39 genes were downregulated by tVNS and most of these genes were involved in immune system. Moreover, tVNS significantly downregulated the relative mRNA expressions of chemokine-related genes and macrophages recruitment compared to the DOX group.\n\n\nCONCLUSION\nThese results suggest that tVNS prevented DOX-induced cardiotoxicity by rebalancing autonomic tone, ameliorating cardiac dysfunction and remodeling. Notably, crosstalk between autonomic neuromodulation and innate immune cells macrophages mediated by chemokines might be involved in the underlying mechanisms.\n\n\nA TRANSLATIONAL PERSPECTIVE\nNon-invasive tVNS has been identified an effective neuromodulation strategy exerting beneficial effects on rebalancing autonomic tone and cardiac pathological conditions. The present study provided direct evidence for a beneficial role of tVNS in preventing DOX-induced autonomic dysfunction and cardiotoxicity in vivo. Additionally, recent studies revealed the importance of sympathetic nerve fibers involving in tumorigenesis and the benefits of higher vagal tone for tumor prognosis either in animal or human trials. Together, tVNS may not only become a novel, nonpharmacological adjuvant therapy for preventing doxorubicin-induced cardiotoxicity, but also may be beneficial for prognosis of cancer patients during chemotherapy. In our future study, we would investigate the effect of tVNS on both combined chemotherapy-induced cardiotoxicity and the antitumor efficacy of DOX in tumor models.