Mechanistic Insights Into the Reduced Pacemaking Rate of the Rabbit Sinoatrial Node During Postnatal Development: A Simulation Study.

Azzah M Alghamdi,Dominic G Whittaker,Jules C Hancox,Craig P Testrow,Henggui Zhang,Mark R Boyett

doi:10.3389/fphys.2020.547577

Abstract

Marked age- and development- related differences have been observed in morphology and characteristics of action potentials (AP) of neonatal and adult sinoatrial node (SAN) cells. These may be attributable to a different set of ion channel interactions between the different ages. However, the underlying mechanism(s) have yet to be elucidated. The objective of this study was to determine the mechanisms underlying different spontaneous APs and heart rate between neonatal and adult SAN cells of the rabbit heart by biophysical modeling approaches. A mathematical model of neonatal rabbit SAN cells was developed by modifying the current densities and/or kinetics of ion channels and transporters in an adult cell model based on available experimental data obtained from neonatal SAN cells. The single cell models were then incorporated into a multi-cellular, two-dimensional model of the intact SAN-atrium to investigate the functional impact of altered ion channels during maturation on pacemaking electrical activities and their conduction at the tissue level. Effects of the neurotransmitter acetylcholine on the pacemaking activities in neonatal cells were also investigated and compared to those in the adult. Our results showed: (1) the differences in ion channel properties between neonatal and adult SAN cells are able to account for differences in their APs and the heart rate, providing mechanistic insight into understanding the reduced pacemaking rate of the rabbit sinoatrial node during postnatal development; (2) in the 2D model of the intact SAN-atria, it was shown that cellular changes during postnatal development impaired pacemaking activity through increasing the activation time and reducing the conduction velocity across the SAN; (3) the neonatal SAN model, with its faster beating rates, showed a greater sensitivity to parasympathetic modulation in response to acetylcholine than did the adult model. These results provide novel insights into the understanding of the cellular mechanisms underlying the differences in the cardiac pacemaking activities of the neonatal and adult SAN.

Highlights

In many species maturation leads to a decrease in the heart rate (HR) (Larson et al, 2013)
A framework for investigating the underlying mechanism of fast heart rhythm in the neonate rabbit SA node cells arising from ion channel remodeling was developed by updating: (1) the electrophysiologically detailed central and peripheral sinoatrial node (SAN) cell models developed by Zhang et al (2000) at the single cell level; (2) a 2D anatomical model of the intact SAN-atrium tissue developed by Butters et al (2010; Bai et al, 2017), which incorporated tissue geometry for SAN and the right atrium (RA), including the crista terminalis (CT) (Dobrzynski et al, 2005)
Similar age-induced remodeling of SAN If during development was observed in changes of HCN expression in other species, including rats (Huang et al, 2016), mice (Larson et al, 2013), and canines (Protas et al, 2010). These results indicate that the change in If with age may be an important contributor to the declined SAN function and the decreased HR

Summary

Introduction

In many species maturation leads to a decrease in the heart rate (HR) (Larson et al, 2013). Spontaneous APs of sinoatrial nodal pacemaker cells are produced by ion channels and ion transporters, as well as by the intracellular Ca2+ dynamics in SAN myocytes (Dobrzynski et al, 2007). It has been shown that significant developmental changes in the expression and function of ion channels and other cellular elements may be responsible for a postnatal alteration in the spontaneous activity of the transmembrane potential in single cells isolated from rabbit SAN (Yang et al, 2006; Dobrzynski et al, 2007). As compared with neonatal SAN cells, spontaneous APs in adult SAN cells show a reduction in spontaneous beating rate, increases in action potential duration (APD) and the intrinsic cycle length (CL), and an increasingly negative maximal diastolic potential (MDP) (Roberts et al, 2012; Larson et al, 2013)

Objectives

Methods

Results

Discussion

Conclusion