Computational prediction of drug response in short QT syndrome type 1 based on measurements of compound effect in stem cell-derived cardiomyocytes

Abstract

Short QT (SQT) syndrome is a genetic cardiac disorder characterized by an abbreviated QT interval of the patient’s electrocardiogram. The syndrome is associated with increased risk of arrhythmia and sudden cardiac death and can arise from a number of ion channel mutations. Cardiomyocytes derived from induced pluripotent stem cells generated from SQT patients (SQT hiPSC-CMs) provide promising platforms for testing pharmacological treatments directly in human cardiac cells exhibiting mutations specific for the syndrome. However, a difficulty is posed by the relative immaturity of hiPSC-CMs, with the possibility that drug effects observed in SQT hiPSC-CMs could be very different from the corresponding drug effect in vivo. In this paper, we apply a multistep computational procedure for translating measured drug effects from these cells to human QT response. This process first detects drug effects on individual ion channels based on measurements of SQT hiPSC-CMs and then uses these results to estimate the drug effects on ventricular action potentials and QT intervals of adult SQT patients. We find that the procedure is able to identify IC50 values in line with measured values for the four drugs quinidine, ivabradine, ajmaline and mexiletine. In addition, the predicted effect of quinidine on the adult QT interval is in good agreement with measured effects of quinidine for adult patients. Consequently, the computational procedure appears to be a useful tool for helping predicting adult drug responses from pure in vitro measurements of patient derived cell lines.

Effects of Antiarrhythmic Drugs on hERG Gating in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes From a Patient With Short QT Syndrome Type 1

“…Studies reported that ajmaline inhibits various currents, including I Na , I Ca-L , I to , I Kr , I K1 and I KATP (Supplementary Table 1) (Miller et al, 2017;Bébarová et al, 2005a;Khodorov and Zaborovskaya, 1983;Bébarová et al, 2005b;Kiesecker et al, 2004). The inhibition of I to , I Kr , I K1 and I KATP can prolong APD and hence APDprolongation induced by ajmaline was observed in both wild-type cells and an SQT-model (Table 1) (Bébarová et al, 2005b;Jaeger et al, 2021). This led us to assume that it may inhibit the hERG channel current in SQTS1-hiPSC-CMs.…”

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

“…The minimization is now started using the best solution for n drugs as an initial guess, and for the one additional drug, we set the initial dose to be zero. The optimal solution of this n + 1 dimensional problem is solved using the continuation method of [ 12 , 32 ]. This is repeated for the K − n remaining drugs, and the best solution is stored as the optimal drug for the case of combining n + 1 drugs.…”

“…The specific action potential model used in our computations is an updated version of the base model initially published in [ 32 ]. More specifically, we use the updated base model formulation described [ 12 ]. In that model, the I Kr current is fitted to data from measurements of wild type I Kr currents and I Kr currents for the SQT1 mutation N588K from [ 34 ].…”

“…In that model, the I Kr current is fitted to data from measurements of wild type I Kr currents and I Kr currents for the SQT1 mutation N588K from [ 34 ]. In particular, the voltage dependence of the steady state value of the inactivation gate, x Kr2 , of the I Kr current is shifted towards more positive potentials: In Fig 5 of [ 12 ] the I Kr model is compared to measurements from [ 34 ]. Furthermore, the hiPSC-CM version of the model has been fitted to data of wild type and SQT1 hiPSC-CMs from [ 28 ], and the adult human ventricular CM version of the model has been validated using adult human ECG measurements from [ 35 ] (see [ 12 ]).…”

“…Mutations affecting genes encoding one or more of the ion channels can significantly change the action potential (AP), see, e.g., [ 1 – 3 ], and some of these alterations can initiate dangerous arrhythmias [ 4 – 6 ]. The changes in the AP are often manifested in ECG recordings as prolonged or shortened QT-intervals, referred to as long-QT (LQT) or short-QT (SQT), respectively, see, e.g., [ 7 – 12 ]. In well diagnosed cases, treatment is available either in terms of anti-arrhythmic drugs [ 6 , 13 , 14 ] or in terms of an implantable cardioverter-defibrillator (ICD) [ 6 , 10 , 15 ], but at present both options have disadvantages: Many approved anti-arrhythmic drugs have serious side-effects and ICDs may fire inappropriatley and are difficult to apply for some patients [ 10 , 14 , 15 ].…”