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Determinants of heterogeneity, excitation and conduction in the sinoatrial node: a model study.

ABSTRACT: The sinoatrial node (SAN) is a complex structure that exhibits anatomical and functional heterogeneity which may depend on: 1) The existence of distinct cell populations, 2) electrotonic influences of the surrounding atrium, 3) the presence of a high density of fibroblasts, and 4) atrial cells intermingled within the SAN. Our goal was to utilize a computer model to predict critical determinants and modulators of excitation and conduction in the SAN. We built a theoretical "non-uniform" model composed of distinct central and peripheral SAN cells and a "uniform" model containing only central cells connected to the atrium. We tested the effects of coupling strength between SAN cells in the models, as well as the effects of fibroblasts and interspersed atrial cells. Although we could simulate single cell experimental data supporting the "multiple cell type" hypothesis, 2D "non-uniform" models did not simulate expected tissue behavior, such as central pacemaking. When we considered the atrial effects alone in a simple homogeneous "uniform" model, central pacemaking initiation and impulse propagation in simulations were consistent with experiments. Introduction of fibroblasts in our simulated tissue resulted in various effects depending on the density, distribution, and fibroblast-myocyte coupling strength. Incorporation of atrial cells in our simulated SAN tissue had little effect on SAN electrophysiology. Our tissue model simulations suggest atrial electrotonic effects as plausible to account for SAN heterogeneity, sequence, and rate of propagation. Fibroblasts can act as obstacles, current sinks or shunts to conduction in the SAN depending on their orientation, density, and coupling.

SUBMITTER: Oren RV

PROVIDER: S-EPMC3009599 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Determinants of heterogeneity, excitation and conduction in the sinoatrial node: a model study.

Oren Ronit V RV Clancy Colleen E CE

PLoS computational biology 20101223 12

The sinoatrial node (SAN) is a complex structure that exhibits anatomical and functional heterogeneity which may depend on: 1) The existence of distinct cell populations, 2) electrotonic influences of the surrounding atrium, 3) the presence of a high density of fibroblasts, and 4) atrial cells intermingled within the SAN. Our goal was to utilize a computer model to predict critical determinants and modulators of excitation and conduction in the SAN. We built a theoretical "non-uniform" model com ...[more]

PMID: 21203483

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Project description:Background: Cardiac pacemaking remains an unsolved matter from many perspectives. Extensive experimental and computational studies have been performed to describe the sinoatrial physiology across different scales, from the molecular to clinical levels. Nevertheless, the mechanism by which a heartbeat is generated inside the sinoatrial node and propagated to the working myocardium is not fully understood at present. This work aims to provide quantitative information about this fascinating phenomenon, especially regarding the contributions of cellular heterogeneity and fibroblasts to sinoatrial node automaticity and atrial driving. Methods: We developed a bidimensional computational model of the human right atrial tissue, including the sinoatrial node. State-of-the-art knowledge of the anatomical and physiological aspects was adopted during the design of the baseline tissue model. The novelty of this study is the consideration of cellular heterogeneity and fibroblasts inside the sinoatrial node for investigating the manner by which they tune the robustness of stimulus formation and conduction under different conditions (baseline, ionic current blocks, autonomic modulation, and external high-frequency pacing). Results: The simulations show that both heterogeneity and fibroblasts significantly increase the safety factor for conduction by more than 10% in almost all the conditions tested and shorten the sinus node recovery time after overdrive suppression by up to 60%. In the human model, especially under challenging conditions, the fibroblasts help the heterogeneous myocytes to synchronise their rate (e.g. -82% in σCL under 25 nM of acetylcholine administration) and capture the atrium (with 25% L-type calcium current block). However, the anatomical and gap junctional coupling aspects remain the most important model parameters that allow effective atrial excitations. Conclusion: Despite the limitations to the proposed model, this work suggests a quantitative explanation to the astonishing overall heterogeneity shown by the sinoatrial node.

Project description:Each heartbeat is initiated by specialized pacemaker cells operating within the sinoatrial node (SAN). While individual cells within SAN tissue exhibit substantial heterogeneity of their electrophysiological parameters and Ca cycling, the role of this heterogeneity for cardiac pacemaker function remains mainly unknown. Here we investigated the problem numerically in a 25 × 25 square grid of connected coupled-clock Maltsev-Lakatta cell models. The tissue models were populated by cells with different degree of heterogeneity of the two key model parameters, maximum L-type Ca current conductance (g CaL ) and sarcoplasmic reticulum Ca pumping rate (P up ). Our simulations showed that in the areas of P up -g CaL parametric space at the edge of the system stability, where action potential (AP) firing is absent or dysrhythmic in SAN tissue models populated with identical cells, rhythmic AP firing can be rescued by populating the tissues with heterogeneous cells. This robust SAN function is synergistic with respect to heterogeneity in g CaL and P up and can be further strengthened by clustering of cells with similar properties. The effect of cell heterogeneity is not due to a simple summation of activity of intrinsically firing cells naturally present in heterogeneous SAN; rather AP firing cells locally and critically interact with non-firing/dormant cells. When firing cells prevail, they recruit many dormant cells to fire, strongly enhancing overall SAN function; and vice versa, prevailing dormant cells suppress AP firing in cells with intrinsic automaticity and halt SAN function. The transitions between firing and non-firing states of the system are sharp, resembling phase transitions in statistical physics. Furthermore, robust function of heterogeneous SAN tissue requires weak cell coupling, a known property of the central area of SAN where cardiac impulse emerges; stronger cell coupling reduces AP firing rate and ultimately halts SAN automaticity at the edge of stability.

Dataset Information

Determinants of heterogeneity, excitation and conduction in the sinoatrial node: a model study.

Publications

Determinants of heterogeneity, excitation and conduction in the sinoatrial node: a model study.

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