Closed-loop vagus nerve stimulation for heart rate control evaluated in the Langendorff-perfused rabbit heart

Abstract

Persistent sinus tachycardia substantially increases the risk of cardiac death. Vagus nerve stimulation (VNS) is known to reduce the heart rate, and hence may be a non-pharmacological alternative for the management of persistent sinus tachycardia. To precisely regulate the heart rate using VNS, closed-loop control strategies are needed. Therefore, in this work, we developed two closed-loop VNS strategies using an in-silico model of the cardiovascular system. Both strategies employ a proportional-integral controller that operates on the current amplitude. While one control strategy continuously delivers stimulation pulses to the vagus nerve, the other applies bursts of stimuli in synchronization with the cardiac cycle. Both were evaluated in Langendorff-perfused rabbit hearts (n = 6) with intact vagal innervation. The controller performance was quantified by rise time (Tr), steady-state error (SSE), and percentual overshoot amplitude (%OS). In the ex-vivo setting, the cardiac-synchronized variant resulted in Tr = 10.7 ± 4.5 s, SSE = 12.7 ± 9.9 bpm and %OS = 5.1 ± 3.6% while continuous stimulation led to Tr = 10.2 ± 5.6 s, SSE = 10 ± 6.7 bpm and %OS = 3.2 ± 1.9%. Overall, both strategies produced a satisfying and reproducible performance, highlighting their potential use in persistent sinus tachycardia.

A novel ex-vivo isolated rabbit heart preparation to explore the cardiac effects of cervical and cardiac vagus nerve stimulation

“…Out of the remaining 19 hearts, we could provoke stimulation responses in 16 hearts, of which 8 hearts were used to establish the setup and instrumentation. This work completes a previous work by our group, demonstrating the approach of closed-loop VNS in this isolated-heart setup 31 .…”

“…Therefore, ex-vivo stimulation was performed as an intraneuronal stimulation approach using a bipolar array of needle electrodes mimicking the stimulation with two TIME contacts, which serves the purpose to reduce off-target stimulation and increase the cardiac selectivity. For the ex-vivo stimulation of the VN, the stimulation site was moved closer to the heart and stimulated the VN just proximal to the superior cardiac branch using needle electrodes, which is also described in Berthoud et al 48 and Haberbusch et al 49 . The fact that this intraneural approach is more invasive compared to the approach of cervical VNS using cuff electrodes, however, limits this kind of study to acute investigations.…”

“…In sum, this study highlights the challenges and advantages of an ex-vivo experimental setup and provides a novel approach towards advanced experimental setups for cardiac neuromodulation under defined experimental conditions. It further helps to gain a deeper understanding of specific questions with respect to effects of VNS on electrophysiology and cardiac physiology 31,41 .…”

“…Vagus nerve dissection ex-vivo. Vagus nerve dissection for ex-vivo experiments was performed as described previously 30,31 . Briefly, a median skin incision was made from the mandibles to the sternum and further extended to the sternal xiphoid.…”

“…were increased from the initial values in order to evoke greater cardiac effects. Further details on the stimulation strategies can be found in Haberbusch et al 31,34 . www.nature.com/scientificreports/ Data processing and analysis.…”