A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes

Abstract

Mutations are known to cause perturbations in essential functional features of integral membrane proteins, including ion channels. Even restricted or point mutations can result in substantially changed properties of ion currents. The additive effect of these alterations for a specific ion channel can result in significantly changed properties of the action potential (AP). Both AP shortening and AP prolongation can result from known mutations, and the consequences can be life-threatening. Here, we present a computational method for identifying new drugs utilizing combinations of existing drugs. Based on the knowledge of theoretical effects of existing drugs on individual ion currents, our aim is to compute optimal combinations that can ‘repair’ the mutant AP waveforms so that the baseline AP-properties are restored. More specifically, we compute optimal, combined, drug concentrations such that the waveforms of the transmembrane potential and the cytosolic calcium concentration of the mutant cardiomyocytes (CMs) becomes as similar as possible to their wild type counterparts after the drug has been applied. In order to demonstrate the utility of this method, we address the question of computing an optimal drug for the short QT syndrome type 1 (SQT1). For the SQT1 mutation N588K, there are available data sets that describe the effect of various drugs on the mutated K+ channel. These published findings are the basis for our computational analysis which can identify optimal compounds in the sense that the AP of the mutant CMs resembles essential biomarkers of the wild type CMs. Using recently developed insights regarding electrophysiological properties among myocytes from different species, we compute optimal drug combinations for hiPSC-CMs, rabbit ventricular CMs and adult human ventricular CMs with the SQT1 mutation. Since the ‘composition’ of ion channels that form the AP is different for the three types of myocytes under consideration, so is the composition of the optimal drug.

Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve

“…Versions of our model have previously been used to simulate human induced pluripotent stem cell-derived CMs (hiPSC-CMs) and healthy adult human, canine, rabbit, guinea pig and zebrafish ventricular CMs 47 , 48 . In addition, this formalism has been used to study the short QT syndrome mutation N588K in ventricular CMs 40 , 49 . The base model used in this study is similar to the version used in 40 , 49 .…”

“…In addition, this formalism has been used to study the short QT syndrome mutation N588K in ventricular CMs 40 , 49 . The base model used in this study is similar to the version used in 40 , 49 . Additional membrane currents (e.g., ) have been added to more accurately represent the AP waveform and underlying dynamics of atrial myocytes.…”

Physiological accuracy in simulating refractory cardiac tissue: the volume-averaged bidomain model vs. the cell-based EMI model

“…Ongoing developments in high-performance computing make it feasible to perform meaningful simulations at such a level of detail. Due to the relative newness of the EMI model, however, there are only a handful of studies that explore its capabilities [5,4,6,7,8,9,10,11], and only one of these studies examines it in relation to the bidomain model [11]. In the present study, we compare the bidomain model to the EMI model in the context of unipolar stimulation of refractory cardiac tissue, an application relevant to the design of pacemakers and defibrillators.…”

Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach

“…Indeed, the need to explore drug combinations as an alternative for treating or preventing AF is gaining increasing relevance [ 3 ]. Several theoretical models were developed to study the effects of various drugs and their blockade of more than one ionic current in the setting of cardiac arrhythmia [ 14 , 15 , 16 ]. In detail, the combined I Na blockade with concomitant inhibition of rapid or ultrarapid delayed-rectifier K + currents ( I Kr and I Kur , respectively) enhanced anti-arrhythmic effects compared with the I Na blocker alone [ 14 ].…”