Sex Differences in Vagus Nerve Stimulation Effects on Rat Cardiovascular and Immune Systems

Abstract

Background: Investigations into the benefits of vagus nerve stimulation (VNS) through pre-clinical and clinical research have led to promising findings for treating several disorders. Despite proven effectiveness of VNS on conditions such as epilepsy and depression, understanding of off-target effects and contributing factors such as sex differences can be beneficial to optimize therapy design. New Methods: In this article, we assessed longitudinal effects of VNS on cardiovascular and immune systems, and studied potential sex differences using a rat model of longterm VNS. Rats were implanted with cuff electrodes around the left cervical vagus nerve for VNS, and wireless physiological monitoring devices for continuous monitoring of cardiovascular system using electrocardiogram (ECG) signals. ECG morphology and heart rate variability (HRV) features were extracted to assess cardiovascular changes resulting from VNS in short-term and long-term timescales. We also assessed VNS effects on expression of inflammatory cytokines in blood during the course of the experiment. Statistical analysis was performed to compare results between Treatment and Sham groups, and between male and female animals from Treatment and Sham groups. Results: Considerable differences between male and female rats in cardiovascular effects of VNS were observed in multiple cardiovascular features. However, the effects seemed to be transient with approximately 1-h recovery after VNS. While short-term cardiovascular effects were mainly observed in male rats, females in general showed more significant long-term effects even after VNS stopped. We did not observe notable changes or sex differences in systemic cytokine levels resulting from VNS. Comparison With Existing Methods: Compared to existing methods, our study design incorporated wireless physiological monitoring and systemic blood cytokine level analysis, along with long-term VNS experiments in unanesthetized rats to study sex differences. Conclusion: The contribution of sex differences for long-term VNS off-target effects on cardiovascular and immune systems was assessed using awake behaving rats. Although VNS did not change the concentration of inflammatory biomarkers in systemic circulation for male and female rats, we observed significant differences in cardiovascular effects of VNS characterized using ECG morphology and HRV analyses.

Evidence of sex differences in cancer‐related cardiac complications in mouse models of pancreatic and liver cancer

“…Additionally, contrary to the fact that females have higher HR than males, both in humans and mice (Prabhavathi et al, 2014 ; Yang et al, 2007 ), our study showed the opposite phenomena across control and pancreatic liver groups. This is a curious discrepancy since several studies have reported in humans and conscious rats that healthy females have higher parasympathetic activity than males, which agrees with our findings (Korotkov, 2017 ; Yaghouby et al, 2020 ).…”

Efficacy profile of noninvasive vagus nerve stimulation on cortical spreading depression susceptibility and the tissue response in a rat model

“…However, clinical VNS paradigms for migraine patients do not differ between genders. Furthermore, except for cardiac activity, no significant correlation between gender and VNS efficacy on neuronal activity or inflammation has been reported in literature [ 3 , 58 , 59 ]. Second, together with our prior work, nVNS delivered at 20-40 min before CSD susceptibility testing exhibits suppressive effect on CSD, suggesting that VNS efficacy begin at 20-40 min.…”

Vagus nerve stimulation for upper limb motor impairment after ischemic stroke

“…Fortunately, there were studies reporting the sex differences in hemodynamic and autonomic regulation of cardiovascular systems both on animal and human trials. [36,37] In terms of adverse effects of VNS, female subjects were more likely to express side effects than that of males, and this difference may originate from discrepancy in the sensitivity of certain nuclei following the cardiac branch pathway in female and male subjects. [38,39] On the difference of the curative effects of VNS, female subjects also performed less effectiveness.…”