LAUSR

Objective: Today, the diverse acute cardiac effects of vagus nerve stimulation (VNS) are still not fully understood. Therefore, we propose a numerical model that can predict the acute cardiac responses to VNS and explain the underlying mechanisms on different levels. Methods: We integrated a model of vagal nerve fiber recruitment and acetylcholine (ACh) kinetics at vagal nerve terminals into a cardiovascular system model. A sensitivity analysis was performed to identify the most important parameters of vagal cardiac pathways. These parameters were tuned, and the model was validated based on published data of experiments in anesthetized sheep. Results: The four most important parameters are related to vagus nerve anatomy (electrode-fiber distances, fiber diameters) and ACh kinetics in the vagal neuroeffector junction (rate of ACh release and -hydrolysis) which together explain >53% of the observed variability in acute cardiac responses to VNS. The mean electrode-fiber distance and nerve fiber diameters obtained from tuning are 1.3 ± 0.09 mm, and 4.9 ± 0.25 μm; the ACh release and -hydrolysis rate constants are 0.023 s-1 and 0.77 s-1, respectively. With this parameterization, the model could accurately predict published data on the acute cardiac effects of VNS. Conclusions: The model can explain the cardiac responses to VNS on multiple levels. The results highlight the importance of four parameters tied to ACh dynamics and vagus nerve anatomy for predicting the cardiac effects of VNS. Significance: The model represents a substantial improvement in terms of comprehensibility of the underlying mechanisms of the acute cardiac responses to VNS.