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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
- Source :
- PLoS Computational Biology, Vol 17, Iss 2, p e1008089 (2021), PLoS Computational Biology
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
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.<br />Author summary A number of cardiac disorders originate from genetic mutations affecting the function of ion channels populating the membrane of cardiomyocytes. One example is short QT syndrome, associated with increased risk of arrhythmias and sudden cardiac death. Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) provide a promising platform for testing potential pharmacological treatments for such disorders, as human cardiomyocytes exhibiting specific mutations can be generated and exposed to drugs in vitro. However, the electrophysiological properties of hiPSC-CMs differ significantly from those of adult native cardiomyocytes. Therefore, drug effects observed for hiPSC-CMs could possibly be very different from corresponding drug effects for adult cells in vivo. In this study, we apply a computational framework for translating drug effects observed for hiPSC-CMs derived from a short QT patient to drug effects for adult short QT cardiomyocytes. For one of the considered drugs, the effect on adult QT intervals has been measured and these measurements turn out to be in good agreement with the response estimated by the computational procedure. Thus, the computational framework shows promise for being a useful tool for predicting adult drug responses from measurements of hiPSC-CMs, allowing earlier identification of compounds to accurately treat cardiac diseases.
- Subjects :
- 0301 basic medicine
ERG1 Potassium Channel
Physiology
Drug Evaluation, Preclinical
Action Potentials
030204 cardiovascular system & hematology
Biochemistry
Ion Channels
Electrophysiological Properties
Sudden cardiac death
Translational Research, Biomedical
Electrocardiography
0302 clinical medicine
Heart Rate
Medicine and Health Sciences
Ivabradine
Myocytes, Cardiac
Biology (General)
Ajmaline
Ecology
Physics
Models, Cardiovascular
Quinidine
Electrophysiology
Bioassays and Physiological Analysis
Computational Theory and Mathematics
Modeling and Simulation
Physical Sciences
Cardiology
Stem cell
Anti-Arrhythmia Agents
Algorithms
medicine.drug
Research Article
Optimization
Adult
Heart Defects, Congenital
medicine.medical_specialty
QH301-705.5
Induced Pluripotent Stem Cells
Biophysics
Neurophysiology
Mexiletine
In Vitro Techniques
Research and Analysis Methods
QT interval
Membrane Potential
Cell Line
03 medical and health sciences
Cellular and Molecular Neuroscience
In vivo
Heart Conduction System
Internal medicine
Genetics
medicine
Humans
Molecular Biology
Ecology, Evolution, Behavior and Systematics
business.industry
Electrophysiological Techniques
Biology and Life Sciences
Proteins
Computational Biology
Short QT syndrome
Arrhythmias, Cardiac
medicine.disease
030104 developmental biology
Mutation
Cardiac Electrophysiology
business
Biomarkers
Mathematics
Neuroscience
Subjects
Details
- Language :
- English
- ISSN :
- 15537358
- Volume :
- 17
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- PLoS Computational Biology
- Accession number :
- edsair.doi.dedup.....b95331630ffe2f53231b106bd27059e7