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.