The Mechanism Underlying Heart Rate and Pacemaking Activity Decline in Developing Rabbit Sino-Atrial Node

Azzah Alghamdi1, Craig P Testrow1, Dominic G Whittaker2, Henggui Zhang1
1University of Manchester, 2University of Leeds


Abstract

Diagnosis and treatment of heart disease are mainly based on the analysis of clinical and experimental data from adult myocardium. The marked age-related differences in morphology and characteristics of the action potential(AP) between neonatal and adult cardiac myocytes indicate that a different set of molecular interactions in neonatal myocytes necessitates different therapies for newborns. Computational modelling is a powerful tool to determine how interactions between components lead to systems-level behaviour, but this technique has not been used extensively to study neonatal heart cells. In this study, a mathematical model of neonatal rabbit sino-atrial node (SAN) cells was created based on available experimental data, by modifying the densities and/or formulations of ion currents in an the adult cell model. A multi-cellular two-dimensional model of intact SAN-atrium was used to address the functional impact of impaired pacemaking activities during maturation at tissue level. In addition, the effects of acetylcholine on modulating the pacemaking activities of neonatal cells were also investigated. As compared to adult SAN. Our simulation results showed: 1) the neonate rabbit SAN model reproduced a similar shape and characteristic of the AP of neonatal cells, with a higher upstroke velocity (i.e. maximal dV/dt), shorter cycle length (CL); 2) in the 2D intact model of the SAN-atria, there was an age-dependent impairment of the pacemaking activities manifested by an increased activation time but reduced conduction velocity in the postnatal SAN; 3) a positive correlation between heart rate and modulation impact of acetylcholine was observed: greater beating rates in neonate SAN were associated with a greater sensitivity to autonomic modulation than those in adults. In conclusion, the simulation results were consistent with experimental data, suggesting that the developed SAN models can be used for testing hypotheses and obtaining quantitative understanding of differences in primary pacemaker cells between neonatal and adult hearts.