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Structural heterogeneity of the rat pulmonary vein myocardium: consequences on intracellular calcium dynamics and arrhythmogenic potential.

ABSTRACT: Mechanisms underlying ectopic activity in the pulmonary vein (PV) which triggers paroxysmal atrial fibrillation are unknown. Although several studies have suggested that calcium signalling might be involved in these arrhythmias, little is known about calcium cycling in PV cardiomyocytes (CM). We found that individual PV CM showed a wide range of transverse tubular incidence and organization, going from their virtual absence, as described in atrial CM, to well transversally organised tubular systems, like in ventricular CM. These different types of CM were found in groups scattered throughout the tissue. The variability of the tubular system was associated with cell to cell heterogeneity of calcium channel (Cav1.2) localisation and, thereby, of Cav1.2-Ryanodine receptor coupling. This was responsible for multiple forms of PV CM calcium transient. Spontaneous calcium sparks and waves were not only more abundant in PV CM than in LA CM but also associated with a higher depolarising current. In conclusion, compared with either the atrium or the ventricle, PV myocardium presents marked structural and functional heterogeneity.

SUBMITTER: Pasqualin C

PROVIDER: S-EPMC5818479 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Structural heterogeneity of the rat pulmonary vein myocardium: consequences on intracellular calcium dynamics and arrhythmogenic potential.

Pasqualin C C Yu A A Malécot C O CO Gannier F F Cognard C C Godin-Ribuot D D Morand J J Bredeloux P P Maupoil V V

Scientific reports 20180219 1

Mechanisms underlying ectopic activity in the pulmonary vein (PV) which triggers paroxysmal atrial fibrillation are unknown. Although several studies have suggested that calcium signalling might be involved in these arrhythmias, little is known about calcium cycling in PV cardiomyocytes (CM). We found that individual PV CM showed a wide range of transverse tubular incidence and organization, going from their virtual absence, as described in atrial CM, to well transversally organised tubular syst ...[more]

PMID: 29459735

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Project description:Deterministic models of biochemical processes at the subcellular level might become inadequate when a cascade of chemical reactions is induced by a few molecules. Inherent randomness of such phenomena calls for the use of stochastic simulations. However, being computationally intensive, such simulations become infeasible for large and complex reaction networks. To improve their computational efficiency in handling these networks, we present a hybrid approach, in which slow reactions and fluxes are handled through exact stochastic simulation and their fast counterparts are treated partially deterministically through chemical Langevin equation. The classification of reactions as fast or slow is accompanied by the assumption that in the time-scale of fast reactions, slow reactions do not occur and hence do not affect the probability of the state. Our new approach also handles reactions with complex rate expressions such as Michaelis-Menten kinetics. Fluxes which cannot be modeled explicitly through reactions, such as flux of Ca(2+) from endoplasmic reticulum to the cytosol through inositol 1,4,5-trisphosphate receptor channels, are handled deterministically. The proposed hybrid algorithm is used to model the regulation of the dynamics of cytosolic calcium ions in mouse macrophage RAW 264.7 cells. At relatively large number of molecules, the response characteristics obtained with the stochastic and deterministic simulations coincide, which validates our approach in the limit of large numbers. At low doses, the response characteristics of some key chemical species, such as levels of cytosolic calcium, predicted with stochastic simulations, differ quantitatively from their deterministic counterparts. These observations are ubiquitous throughout dose response, sensitivity, and gene-knockdown response analyses. While the relative differences between the peak-heights of the cytosolic [Ca(2+)] time-courses obtained from stochastic (mean of 16 realizations) and deterministic simulations are merely 1%-4% for most perturbations, it is specially sensitive to levels of G(βγ) (relative difference as large as 90% at very low G(βγ)).

Dataset Information

Structural heterogeneity of the rat pulmonary vein myocardium: consequences on intracellular calcium dynamics and arrhythmogenic potential.

Publications

Structural heterogeneity of the rat pulmonary vein myocardium: consequences on intracellular calcium dynamics and arrhythmogenic potential.

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