2021
DOI: 10.1371/journal.pcbi.1008089
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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 s… Show more

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Cited by 15 publications
(29 citation statements)
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References 84 publications
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“…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.…”
Section: Discussionmentioning
confidence: 97%
“…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.…”
Section: Discussionmentioning
confidence: 97%
“…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.…”
Section: Methodsmentioning
confidence: 99%
“…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 ].…”
Section: Methodsmentioning
confidence: 99%
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