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

Alan Fabbri,Matteo Fantini,Ronald Wilders,Stefano Severi

doi:10.1113/jp273259

Abstract

We constructed a comprehensive mathematical model of the spontaneous electrical activity of a human sinoatrial node (SAN) pacemaker cell, starting from the recent Severi-DiFrancesco model of rabbit SAN cells. Our model is based on electrophysiological data from isolated human SAN pacemaker cells and closely matches the action potentials and calcium transient that were recorded experimentally. Simulated ion channelopathies explain the clinically observed changes in heart rate in corresponding mutation carriers, providing an independent qualitative validation of the model. The model shows that the modulatory role of the 'funny current' (If ) in the pacing rate of human SAN pacemaker cells is highly similar to that of rabbit SAN cells, despite its considerably lower amplitude. The model may prove useful in the design of experiments and the development of heart-rate modulating drugs. 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' (If ) 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 If , 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.

Highlights

There is no need to explain the important role of the sinoatrial node (SAN) in cardiac function
The action potential (AP) generated by the model is characterized by a cycle length (CL) of 814 ms, corresponding to a beating rate of 74 beats min–1
The simulated Ca2+ transient qualitatively reproduces the single experimental trace acquired by Verkerk et al

Summary

Introduction

There is no need to explain the important role of the sinoatrial node (SAN) in cardiac function. Almost all experiments on SAN electrophysiology have been carried out on animals, rabbits These experiments have shed light on several aspects, such as characteristics of membrane currents, effects of ion channel blockers, calcium handling and beating rate modulation. This considerable amount of data has allowed the development of increasingly comprehensive and detailed action potential (AP) models (Wilders, 2007) subsequent to the first mathematical models reproducing pacemaker activity being created (McAllister et al 1975; Yanagihara et al 1980; Noble & Noble, 1984; DiFrancesco & Noble, 1985). Novel SAN AP models have been proposed, incorporating detailed calcium-handling dynamics and providing in-depth descriptions of the underlying events at the cellular level in guinea-pig, mouse and rabbit (Himeno et al 2008; Maltsev & Lakatta, 2009; Kharche et al 2011; Severi et al 2012)

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