A model of sinoatrial node cell regulation by the autonomic nervous system

Danilo Scepanovic, Harvard/Massachusetts Institute of Technology

Heart rate (HR) is one of the most commonly monitored physiological signals for patients in emergency rooms and intensive care wards. Usually, average HR is observed; however, a more clinically relevant quantity is the state of the autonomic nervous system (ANS) which controls the heart rate. Unfortunately, our understanding of the mechanisms by which the ANS regulates HR is limited. Several models describe the effects of neurotransmitters released by the ANS upon sinoatrial node cell function; however, they do not describe intermediate messengers and appropriate dynamics. Given the availability of anatomical and physiological data describing the geometry of neuron/cell interface and the sensitivity and function of the key molecular players (G-proteins, cAMP, phosphodiesterase, and protein kinase A), we created the most thorough mathematical model of sinoatrial node cell regulation available to date. Our model is mechanistically motivated and incorporates experimental data from numerous studies published over the course of decades. It is implemented as a system of nonlinear, coupled ordinary differential equations that can be solved by standard numerical integration methods. The results of this work are threefold: Our model 1) reproduces the known effects of the ANS on HR; 2) provides an explicit and unified framework for including new experimental data and testing the effects of possible interventions; and 3) highlights areas where further experimental work is needed in order to elucidate the molecular mechanisms. In all, we have created a window through which we can unintrusively peer into the world of cardiovascular regulation and better understand the mechanisms at play in health and disease.

Abstract Author(s): Danilo Scepanovic