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Development of mathematical atrial models at tissue, cellular and subcelular levels to study mechanisms that confer patients a high risk of atrial fibrillation

Type of activity
Competitive project
Acronym
ATRIMATH
Funding entity
AGENCIA ESTATAL DE INVESTIGACION
Funding entity code
SAF2017-88019-C3-2-R
Amount
36.300,00 €
Start date
2018-01-01
End date
2020-12-31
Keywords
Calcio, Calcium, arrhythmias, arritmias, fibrilación, fibrillation, mathematical models, modelos matemáticos, ondas, waves
Abstract
Atrial fibrillation is an important economic burden on the health care system, but the complex pathophysiology combined with its selfperpetuating
nature has so far hampered efficient treatment of this continuously growing disease. One of the main issues that remains to
be resolved is the genetic bases of AF, which remain elusive. Only rare mutations accounting for a small fraction of patients with familial
AF have been associated to changes in the function of different ion channels, as for instance the variants on 4q25 or 1q21. Therefore, a
successful identification of common genetic risk variants with a high risk of AF in this proposal could mean a break-through for risk
stratification, early detection of patients with high risk of developing AF, and for the identification of selective pharmacological targets linked
to high risk variants. The main goal is to identify the molecular and cellular electrophysiological profile of atrial myocytes from patients with
common genetic polymorphisms associated with atrial fibrillation in order to identify the variants and the underlying mechanisms that
confer a high risk for this arrhythmia on carriers of these variants.
To further explore the role of these mechanisms we shall use mathematical models of single and multicellular atrial myocyte models. The
single cell models allow investigation of the risk that a change in a single molecular mechanism imposes on myocyte function (which is
impossible to determine in isolated myocytes because all mechanisms are interconnected and cannot be separated out).
Thus, we will study the functional consequences of defects in the intracellular calcium homeostasis and changes in spatial microstructure
on atrial electrical activity and arrhythmogenesis. Among the specific goals we have are:
- Study of heterogeneity in the phosphorylation states of the ryanodine receptor (RyR2)
- Incorporate into a detailed subcellular calcium model the 3D data with the spatial distribution of RyR2 obtained experimentally
- Study the biochemistry of RyR2 phosphorylation, including the effect of cAMP, G-protein coupled receptors and phosphodiesterases and
incorporate it into a subcellular calcium model to study the effect of different spatial distributions of beta-receptors
- Improve the current subcellular calcium atrial models, introducing coupling to transmembrane voltage and the SK3 channels.
- Study the effect of the spatial localization of SK3 channels.
- Development of a new front end for the numerical simulations, so they can become a reference tool in biomedical research.
Overall, the results of this project will provide a better understanding of the mechanisms leading to atrial fibrillation and will help to devise
better means to detect and treat it.

Participants