(648d) Closed-Loop Modeling of Central and Intrinsic Cardiac Nervous System Circuits Underlying Cardiovascular Control

The baroreflex is a multi-input, multi-output physiological control system that regulates short-term blood pressure by modulating motor (efferent) and sensory (afferent) vagal nerve activity between the brainstem and the heart. The primary objective of the baroreflex is to maintain near-constant blood pressure while balancing multiple demands for blood flow to different organs, including coping with disturbances such as those caused by respiration or exercise. The baroreflex is regulated by the opposing effects of vagal and sympathetic activity, which decrease and increase heart rate and blood pressure, respectively. Efferent vagal outflow stems from the nucleus ambiguus, responsible primarily for fast, beat-to-beat regulation of heart rate and rhythm, and the dorsal motor nucleus of the vagus, responsible primarily for slow regulation of ventricular contractility. The vagus sends inputs to the heart’s “little brain”, the intrinsic cardiac nervous system (ICN), which receives motor inputs from the vagus to mediate central control of heart function and contributes to cardiovascular control through an inner feedback loop at the heart.

Existing computational models of the baroreflex do not explicitly incorporate the ICN. We have recently developed a computational model of closed-loop cardiovascular control by integrating a network representation of the ICN within central control reflex circuits using detailed anatomical and functional data. The model also includes respiratory sinus arrhythmia (RSA), the natural synchronous variation in heart rate with respiration, which is an indicator of good heart health when present. We show that tuning the ICN parameters based on heart rate, ventricular elastance, and ICN activity was sufficient to produce a model that represents the experimentally observed linear relationship between the lung tidal volume and the RSA amplitude. This result indicates that the ICN contributes to RSA by maintaining the variations in parasympathetic activity with respiration, providing new insight into the functional role of ICN beyond serving as a local relay for central reflex control. Furthermore, we simulated multiple scenarios of vagus nerve stimulation (VNS), an emerging bioelectronic treatment for heart failure. Our model was able to capture the hemodynamic changes in response to VNS. We found that a lower relative activation of vagal efferents (motor) compared to vagal afferents (sensory) was necessary to produce heart rate changes consistent with the experimental results. Thus, our results support the notion that VNS activates vagal efferents and afferents differentially, likely in varying proportions depending on the parameters of stimulation.

Based on our previous results, which suggested preferential afferent and efferent activation, we extend our model analysis to explore the differential activation of the fast and slow lanes of vagal efferent outflow. To probe how fast and slow lane activity contribute to cardiovascular dynamics, we simulate several experimental data sets involving selective fast or slow lane stimulation or inhibition. Our model is capable of simulating the heart rate response over a large range of vagal stimulation frequencies and under conditions of background sympathetic stimulation with few modifications to the original model when regulatory brainstem structures are intact. When we simulate scenarios with inhibition of the fast and slow lanes, we make adaptive model changes to the neuronal control system that we hypothesize reflect the in vivo adaptations. Our closed-loop cardiovascular control model is primed for evaluating bioelectronic interventions to treat heart failure and renormalize cardiovascular physiology.