Computational analysis of the human sinus node action potential: model development and effects of mutations

Abstract

The sinoatrial node (SAN) is the normal pacemaker of the mammalian heart. Over several decades, a large amount of data on the ionic mechanisms underlying the spontaneous electrical activity of SAN pacemaker cells has been obtained, mostly in experiments on single cells isolated from rabbit SAN. This wealth of data has allowed the development of mathematical models of the electrical activity of rabbit SAN pacemaker cells. The present study aimed to construct a comprehensive model of the electrical activity of a human SAN pacemaker cell using recently obtained electrophysiological data from human SAN pacemaker cells. We based our model on the recent Severi-DiFrancesco model of a rabbit SAN pacemaker cell. The action potential and calcium transient of the resulting model are close to the experimentally recorded values. The model has a much smaller 'funny current' (I ) than do rabbit cells, although its modulatory role is highly similar. Changes in pacing rate upon the implementation of mutations associated with sinus node dysfunction agree with the clinical observations. This agreement holds for both loss-of-function and gain-of-function mutations in the HCN4, SCN5A and KCNQ1 genes, underlying ion channelopathies in I , fast sodium current and slow delayed rectifier potassium current, respectively. We conclude that our human SAN cell model can be a useful tool in the design of experiments and the development of drugs that aim to modulate heart rate.

Mechanism of Sinus Bradycardia in Carriers of the 1795insD Mutation in the SCN5A Gene

“…The default Fabbri et al model [5] has a beating rate of 74 bpm. This rate was lowered to 49 bpm (vagal tone) through the simulated administration of 20 nM acetylcholine (ACh).…”

“…Effects of the heterozygous 1795insD mutation in SCN5A were implemented in the CellML code [16] of the Fabbri et al human SAN cell model [5] by scaling the fully-activated conductance of I Na , shifting the voltage dependence of I Na activation and inactivation, and introducing a percentage of non-inactivating I Na channels, based on the data from literature described in the Introduction. These modifications were applied to half of the intrinsic I Na , thus representing the heterozygous nature of the mutation.…”

“…I Na has also been observed in human sinoatrial node cells [4]. Accordingly, it was included in the comprehensive computational model of a single human sinoatrial node (SAN) cell that was recently developed by Fabbri et al [5].…”

“…We studied the mechanisms of the 1795insD mutationinduced bradycardia at the cellular level with the use of the comprehensive computational model of a single human SAN cell of Fabbri et al [5].…”

Bradycardic Effects of Mutations in the HCN4 Gene at Different Levels of Autonomic Tone in Humans

“…In the present study, we attempted to assess the effects of the aforementioned HCN4 mutations on human SAN pacemaker activity by incorporating the experimentally identified changes in expression and kinetics of HCN4 [14]. This model allows different levels of autonomic tone through the simulated administration of acetylcholine (ACh; vagal tone) or isoprenaline (Iso; β-adrenergic tone).…”