Heart Block in the Athlete – Role of Ion Channel Remodelling as Studied Using a One-Dimensional Computational Model of the Atrioventricular Node

Abstract

In swim-trained mice, we previously observed atrioventricular (AV) node dysfunction characterised by first-degree heart block and a prolonged Wenckebach cycle length. Notably, patch clamp recordings from isolated AV node myocytes demonstrated a significant reduction of I f (by ~60%) and I Ca,L (by ~40%) in swimtrained mice as compared to sedentary control mice. The effect of the observed changes in ionic currents was investigated using a one-dimensional computational model of the AV node. This was used in conjunction with a biophysically-detailed model of the rabbit AV node action potential. On decreasing I f by ~60% and I Ca,L by ~40% to mimic the effect of athletic training, the conduction velocity of the AV node model was reduced by 25% from 9.5 to 7.1 cm/s. The reduction was solely the result of the decrease in I Ca,L. The decrease in I f (modelled in the conventional way as a time-dependent hyperpolarization-activated inward current) had no effect on the conduction velocity, despite experimental evidence that I f can affect AV node conduction. However, if the model of I f was modified to incorporate an instantaneous current, the decrease in I f also contributed to the reduction in the conduction velocity. We conclude that ionic remodelling of the AV node is a key mechanism underlying heart block in the athlete.

Pharmacological Profile of the Bradycardic Agent Ivabradine on Human Cardiac Ion Channels

“…On the other hand a slowing of AV-nodal conduction has also been observed in a murine model of inducible cardiac-specific knockout of the pacemaker channel gene Hcn4 [43] implying that HCN channels themselves may be involved in signal conduction through the AV node. This notion is supported by in-silico studies using a theoretical model of AV-nodal conduction [22,23]. Hence, both block of HCN channels and block of voltage-gated sodium channels may contribute to slowing of conduction through the AV node by ivabradine.…”

“…Hence the exploration of the molecular underpinnings of the effect of ivabradine on AV-nodal conduction may be of substantial clinical relevance [17][18][19][20][21]. Although in silico studies suggest that block of HCN channels per se may result in slowing of AV-nodal conduction [22,23], it has been suggested that this effect of ivabradine Hächl et al: Ivabradine Effects on Human Cardiac Ion Channels may result from additional block of voltage-gated Ca 2+ and/or K + channels [24]. In addition to voltage-gated Ca 2+ channels, voltage-gated Na + channels may also contribute to AV-nodal conduction (see below).…”