Modeling and Analysis of Closed-Loop Control of the Cardiovascular System.

The baroreceptor reflex is a multi-input, multi-output physiological control system that regulates short-term blood pressure by modulating parasympathetic and sympathetic nerve activity between the brainstem and the heart. The opposing effects of parasympathetic and sympathetic nerve activity work in conjunction to maintain cardiovascular homeostasis, with imbalances in activity associated with cardiovascular disease. Recently, attention has focused on the role of the intrinsic cardiac nervous system (ICN) in local control of nervous regulation of the heart and its role in balancing parasympathetic and sympathetic nerve activity. However, it is unknown how the ICN network structure contributes to integrative control of the heart. We formulated multiple alternative network options based on the anatomical, molecular and physiological evidence. We extended a quantitative closed-loop computational model of the baroreceptor reflex by incorporating a high-fidelity representation of the ICN to evaluate the impact of altered ICN network structures on overall cardiovascular control. The present computational model consists of (1) a system of ordinary differential equations to represent blood flow in the cardiovascular system, and (2) transfer function representations of sensory neurons, central nervous system neuronal groups, and ICN neuronal groups, connected in a closed-loop control circuit. We use this model to investigate, via simulation, the role of the intrinsic cardiac nervous system in integrating and modulating parasympathetic and sympathetic nerve activity in healthy and diseased states. Our results show that the local circuit neurons may modulate the ICN network response to distinct vagal inputs towards the integrative control of local cardiac function.