Simulation Study of the Arrhythmogenic Effects of two Missense Mutations in Human Atrial Fibrillation

Rebecca Belletti1, Laura Martinez-Mateu2, Lucía Romero3, Javier Saiz4
1Universitat Politècnica de València, 2Departamento de Teoría de la Señal y las Comunicaciones y Sistemas Telemáticos y Computación, Universidad Rey Juan Carlos, 31Centro de Investigación e Innovación en Bioingeniería (Ci2B), Universitat Politècnica de València,, 4Centro de Investigación e Innovación en Bioingeniería (Ci2B), Universitat Politècnica de València


Aim: Atrial fibrillation (AF) is a cardiac arrhythmia associated with genetic mutations affecting ion channels playing a role in the action potential (AP) repolarization phase of human atrial cells. This computational study aimed to assess the arrhythmogenicity of two missense mutations, T895M and T436M, both affecting the α-subunit of IKr protein structures. The effects of the mutations were studied in single cell and tissue strand simulations to understand the mechanisms favouring AF initiation and progression, providing insights for future patient-specific targeted therapies.

Methods: Courtemanche model for human atrial cells was modified to introduce changes in the potassium channel dynamics, according to mutant experimental data. Single cell simulations were performed to study mutated APs and current traces properties in control conditions. The wild-type (WT) and mutant cell models were incorporated into 2D tissue models along with electrical and structural remodelling to reproduce paroxysmal (pAF) and permanent (peAF) conditions, both in right (RA) and left (LA) atrium. AP duration (APD) restitution (APDr) curves were computed and the temporal vulnerability of atrial tissue to re-entry was studied.

Results: Under control conditions and pAF conditions in RA, the APs shortened of about 18%/7%, due to 70%/19% increase in IKr peaks for T895M and T436M, respectively. APDr curves revealed rate-dependent behaviour, showing flattening in presence of T895M, with a 20%/42% decrease of maximum slope respect to WT in RA/LA, but not in presence of T436M. In LA pAF and RA/LA peAF conditions, APDr curves flattened. Under LA pAF conditions, the mutation T895M produced a 20%/23% decrease of maximum slope in RA/LA, while T436M hadn’t effect. In contrast, under peAF, neither of the mutations induced significant changes in APDr curve slopes.

Conclusions: The strong APD shortening and resistance to high frequency pacing suggest that both mutations may favour arrhythmogenic mechanisms, mainly in control and pAF conditions.