Dataset Information

Balance between sodium and calcium currents underlying chronic atrial fibrillation termination: An in silico intersubject variability study.

ABSTRACT:

Background

Atrial remodeling as a result of long-standing persistent atrial fibrillation (AF) induces substrate modifications that lead to different perpetuation mechanisms than in paroxysmal AF and a reduction in the efficacy of antiarrhythmic treatments.

Objective

The purpose of this study was to identify the ionic current modifications that could destabilize reentries during chronic AF and serve to personalize antiarrhythmic strategies.

Methods

A population of 173 mathematical models of remodeled human atrial tissue with realistic intersubject variability was developed based on action potential recordings of 149 patients diagnosed with AF. The relationship of each ionic current with AF maintenance and the dynamics of functional reentries (rotor meandering, dominant frequency) were evaluated by means of 3-dimensional simulations.

Results

Self-sustained reentries were maintained in 126 (73%) of the simulations. AF perpetuation was associated with higher expressions of I_Na and I_CaL (P <.01), with no significant differences in the remaining currents. I_CaL blockade promoted AF extinction in 30% of these 126 models. The mechanism of AF termination was related with collisions between rotors because of an increase in rotor meandering (1.71 ± 2.01cm²) and presented an increased efficacy in models with a depressed I_Na (P <.01).

Conclusion

Mathematical simulations based on a population of models representing intersubject variability allow the identification of ionic mechanisms underlying rotor dynamics and the definition of new personalized pharmacologic strategies. Our results suggest that the underlying mechanism of the diverging success of I_CaL block as an antiarrhythmic strategy is dependent on the basal availability of sodium and calcium ion channel conductivities.

SUBMITTER: Liberos A

PROVIDER: S-EPMC5221730 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Balance between sodium and calcium currents underlying chronic atrial fibrillation termination: An in silico intersubject variability study.

Liberos Alejandro A Bueno-Orovio Alfonso A Rodrigo Miguel M Ravens Ursula U Hernandez-Romero Ismael I Fernandez-Aviles Francisco F Guillem Maria S MS Rodriguez Blanca B Climent Andreu M AM

Heart rhythm 20160826 12

<h4>Background</h4>Atrial remodeling as a result of long-standing persistent atrial fibrillation (AF) induces substrate modifications that lead to different perpetuation mechanisms than in paroxysmal AF and a reduction in the efficacy of antiarrhythmic treatments.<h4>Objective</h4>The purpose of this study was to identify the ionic current modifications that could destabilize reentries during chronic AF and serve to personalize antiarrhythmic strategies.<h4>Methods</h4>A population of 173 mathem ...[more]

PMID: 27569443

Similar Datasets

Project description:BackgroundAtrial fibrillation (AF) often arises from structural abnormalities in the left atria (LA). Annotation of the noncoding genome in human LA is limited, as are effects on gene expression and chromatin architecture. Many AF-associated genetic variants reside in noncoding regions; this knowledge gap impairs efforts to understand the molecular mechanisms of AF and cardiac conduction phenotypes.MethodsWe generated a model of the LA noncoding genome by profiling 7 histone post-translational modifications (active: H3K4me3, H3K4me2, H3K4me1, H3K27ac, H3K36me3; repressive: H3K27me3, H3K9me3), CTCF binding, and gene expression in samples from 5 individuals without structural heart disease or AF. We used MACS2 to identify peak regions (P<0.01), applied a Markov model to classify regulatory elements, and annotated this model with matched gene expression data. We intersected chromatin states with expression quantitative trait locus, DNA methylation, and HiC chromatin interaction data from LA and left ventricle. Finally, we integrated genome-wide association data for AF and electrocardiographic traits to link disease-related variants to genes.ResultsOur model identified 21 epigenetic states, encompassing regulatory motifs, such as promoters, enhancers, and repressed regions. Genes were regulated by proximal chromatin states; repressive states were associated with a significant reduction in gene expression (P<2×10-16). Chromatin states were differentially methylated, promoters were less methylated than repressed regions (P<2×10-16). We identified over 15 000 LA-specific enhancers, defined by homeobox family motifs, and annotated several cardiovascular disease susceptibility loci. Intersecting AF and PR genome-wide association studies loci with long-range chromatin conformation data identified a gene interaction network dominated by NKX2-5, TBX3, ZFHX3, and SYNPO2L.ConclusionsProfiling the noncoding genome provides new insights into the gene expression and chromatin regulation in human LA tissue. These findings enabled identification of a gene network underlying AF; our experimental and analytic approach can be extended to identify molecular mechanisms for other cardiac diseases and traits.

Dataset Information

Balance between sodium and calcium currents underlying chronic atrial fibrillation termination: An in silico intersubject variability study.

Background

Objective

Methods

Results

Conclusion

Publications

Balance between sodium and calcium currents underlying chronic atrial fibrillation termination: An in silico intersubject variability study.

Similar Datasets

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