From experiments to computational models of the fast and slow lanes of the cardiac vagus

The vagus nerve is a key mediator of cardiovascular health. Vagal outflow stems from the brainstem and reaches the heart at the intrinsic cardiac nervous system (ICN), the heart’s “little brain”. Due to the disparate, multi-scale nature of the anatomical, molecular, and physiological data on the cardiac vagus, data-derived mechanistic insights have proven elusive. Building on our recent results on spatially-tracked, single-cell transcriptomic atlases of the rat DMV and the rat and pig ICN, we developed an integrative computational modeling framework for combining these data with physiology data . These data were used to develop a computational library of neuronal electrophysiological models. The computational approach bridges the gap between abundant molecular-level gene expression and sparse cellular-level electrophysiology for studying the role of the ICN in cardiac function. Cellular-scale computational models built from these data sets represent building blocks that can be combined using anatomical and neural circuit connectivity, neuronal electrophysiology, and organ/organismal-scale physiology data to create multi-scale models that enable in silico exploration. We used a computational model-based approach that accounts for the short-term dynamics of closed-loop human cardiac control. Our model integrates disparate experimental studies on neural adaptation following myocardial infarction (MI) into a unified quantitative framework using an in silico patient cohort. The insights from the computational modelling and analyses will guide new experimental questions towards exploiting targeted vagal neuromodulatory activity to promote heart health.