Electrotonic Coupling Effect on Pharmacological Cardiotoxicity Assessment in Atrial Tissue

Matteo costi1, Isabella Della torre1, Jose M Ferrero2, Jose F Rodriguez Matas1
1Politecnico di Milano, 2Ci2B, Universitat Politecnica de Valencia


In the last decade, considerable efforts have been dedicated to change the cardiac proarrhythmia safety paradigm. In literature, several studies who shed light to the electrophysiological mechanisms, that stands behind the pharmacological cardiotoxicity, have been carried out by considering just isolated cells; the scope of this work is that of including in the analysis the electrotonic coupling, enabling the cells to mutually interact, aiming to assess how the risk of inducing potentially fatal arrhythmias could be affected. To include variability in the model, atrial populations obtained from Courtemanche model have been generated by means of population of model technique, defining stable cardiac action potentials. They have been properly clusterized according to the most relevant atrial anatomical regions; among all the action potentials, a final population of 2989 left atrium action potentials has been randomly chosen to assess the pharmacological effect of 10 different drugs which have been identified as Pro-arrhytmic drugs, safe drugs and borderline drugs. The simulations have been firstly on isolated cells and later on tissue preparations to consider the electrotonic coupling. A parallelepiped with fibers along the longitudinal direction was considered as the tissue model. Both cases have been conducted at a frequency of 1.25 Hz comprising 500 stimuli with a Basic Cycle Length of 800 ms. The assessment of torsadogenic risk has been quantified by a TdP risk score based on the presence of repolarization abnormalities i.e., presence     of early after depolarization or excessive APD prolongation, or alternans for isolated cells model and tissue model. Results show that the electrotonic coupling related to the atrial tissue (The right panel) demonstrates that it decreases the torsadogenic risk.