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.
Highlights
The action potentials of cardiomyocytes are governed by the dynamics of membrane proteins located at the myocyte membrane
The main result of this study is to demonstrate that mathematical models of the ventricular myocyte action potential and calcium handling, coupled with models of how drugs interact with ion channels, can be used to find optimal drug combinations for anti-arrhythmic therapy
SQT1 mutation in hiPSC-CMs, rabbit CMs and adult human CMs In Fig 2, we show the action potentials (APs), Ca2+ transients and IKr currents generated by the wild type and SQT1 versions of the mathematical models for hiPSC-CMs, rabbit ventricular CMs and human adult CMs
Summary
The action potentials of cardiomyocytes are governed by the dynamics of membrane proteins (ion channels) located at the myocyte membrane. Mutations affecting genes encoding one or more of the ion channels can significantly change the action potential (AP), see, e.g., [1,2,3], and some of these alterations can initiate dangerous arrhythmias [4,5,6]. Mathematical models of the action potential of ventricular myocytes are well developed, see, e.g., [17,18,19,20] These models have been extensively used to reveal the effect of changes to the ion channels, see, e.g., [21,22,23], and to attempt to understand the effects of various drugs, see, e.g., [24,25,26,27]. In future projects, pending similar data for other mutations, we can repeat the same steps to find theoretically optimal drugs
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