Arrhythmogenicity quantification of two genetic defects affecting IKr channel in AF patients

[EN] Atrial fibrillation (AF) is the most common cardiac arrhythmia characterized by disorganized electrical activations of the upper chambers of the heart, leading to uncoordinated contraction and compromising the pumping action of the organ. AF risk factors include cardiovascular pathologies, endocrine disorders, advanced age, obesity, smoking and heritability. Genetic mutations affecting gene encoding for ion channel protein structures are in fact considered as cause of fibrillatory events in individuals who do not present any other co-morbidities. In this work, two genetic mutations found in literature and affecting the alpha-subunit of the rapid delayed rectifier potassium channel are modelled, by reparametrizing the IKr current formulation and by fitting it to mutant experimental data. The modified potassium current was then incorporated into the Courtemanche-Ramirez-Nattel (CRN) model and single cell simulations have been performed to study the mutations¿ effects on action potential and current traces, as well as, restitution properties, in right and left atrium. Both mutations produced a shortening of the action potential duration at 90% of repolarization (APD90), a higher current peak and lower APD values in the restitution curves. T895M yielded also to a reduction in the maximum slope of restitution curve. Tissue patch simulations revealed that T895M and T436M provide a substrate to initiate and maintain re-entries during the 5 seconds of simulation. Rotor¿s meandering in T895M appears more stable with a less extended area and more regular pattern than in T436M. Investigation on 3D atria and torso models will be necessary to provide further insights in understanding the mechanisms behind these genetic mutations.I am grateful to the teams at GaTech, who helped me in the realization of this work. This project has been funded by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie gran agreement No.766082 and by Generalitat Valenciana, Prometeo programme 2020/043.Belletti, R.; Martínez Mateu, L.; Romero Pérez, L.; Cherry, E.; Fenton, FH.; Saiz Rodríguez, FJ. (2020). Arrhythmogenicity quantification of two genetic defects affecting IKr channel in AF patients. Sociedad Española de Ingeniería Biomédica. 141-144. http://hdl.handle.net/10251/17826814114