Electrotonic Coupling Effect on Pharmacological Cardiotoxicity Assessment in Atrial Tissue

In the last decade, considerable efforts have been dedicated to changing the cardiac proarrhythmia safety paradigm. Novel electrophysiological models are developed to accurately describe the pharmacological response, aiming at assessing pharmacological cardiotoxicity in silico. This opens the potentiality of using mathematical models at the early stages of the manufacturing of new pharmacological compounds for an initial and effective cardiotoxic screening. The Courtemanche model has been leveraged to create a population of stable action potential models which later on have been clustered according to the most relevant anatomical atrial regions. Thus, pharmacological cardiotoxicity assessment has been performed going to simulate the electrophysiological behaviour under the pharmacological effect; firstly, ten drugs have been investigated on a model of isolated cells and then the same drugs have been employed in a model of atrial tissue introducing the electrotonic coupling. In this way, by making use of a metric, the aritmic risk score (ARS Risk Score), the pro-arrhythmicity of the chosen drugs has been assessed. Results show that the electrotonic coupling lowers the Aritmic Risk Score of all the drugs investigated, opening a new scenario of the pharmacological cardiotoxicity assessment.