ArticleHeart rhythm2011
Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: a computational analysis.
Article in Heart rhythm, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers, 1 of them a synthesis that pooled it.
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Who cites it
73 citing papers in PubMed, 1 synthesis or guideline pooled it, 106 citations in OpenAlex.
- Co-expression of calcium and hERG potassium channels reduces the incidence of proarrhythmic events.Cardiovascular research · 2021Pooled it
- Population Modeling Approach for Human Cardiac Arrhythmia Risk Prediction.Circulation. Arrhythmia and electrophysiology · 2026Article
- In silico analysis of ventricular action potential with a current-voltage-time representation: Thresholds, membrane resistance, repolarization reserve.Physiological reports · 2024Article
- STAT4 Mediates IL-6 Trans-Signaling Arrhythmias in High Fat Diet Guinea Pig Heart.International journal of molecular sciences · 2024Article
- Diversity of cells and signals in the cardiovascular system.The Journal of physiology · 2023Article
- Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Review
- Coupling and heterogeneity modulate pacemaking capability in healthy and diseased two-dimensional sinoatrial node tissue models.PLoS computational biology · 2022Article
- Prediction of arrhythmia susceptibility through mathematical modeling and machine learning.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Delayed KCNQ1/KCNE1 assembly on the cell surface helps IThe Journal of physiology · 2021Article
- In Silico Assessment of Class I Antiarrhythmic Drug Effects onInternational journal of molecular sciences · 2021Article
- Mechanisms of Premature Ventricular Complexes Caused by QT Prolongation.Biophysical journal · 2021Article
- In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment.Progress in biophysics and molecular biology · 2021Article
- Review
- Populations of in silico myocytes and tissues reveal synergy of multiatrial-predominant KBritish journal of pharmacology · 2020Article
- Overcoming Compensatory Mechanisms toward Chronic Drug Administration to Ensure Long-Term, Sustainable Beneficial Effects.Molecular therapy. Methods & clinical development · 2020Review
- Use of Patient Health Records to Quantify Drug-Related Pro-arrhythmic Risk.Cell reports. Medicine · 2020Article
- Mechanoelectrical feedback in pulmonary vein arrhythmogenesis: Clinical challenges and therapeutic opportunities.Journal of arrhythmia · 2020Article
- Quantitative analysis of variability in an integrated model of human ventricular electrophysiology and β-adrenergic signaling.Journal of molecular and cellular cardiology · 2020Article
- General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy.Clinical pharmacology and therapeutics · 2020Article
- A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources.The Journal of physiology · 2019Article
13 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
background"Repolarization reserve" is frequently invoked to explain why potentially proarrhythmic drugs cause, across a population, a range of changes to cardiac action potentials (APs). However, the mechanisms underlying this interindividual variability are not understood quantitatively.
objectiveThe purpose of this study was to perform a novel analysis of mathematical models of ventricular myocytes to quantify repolarization reserve and gain insight into the factors responsible for variability in the response to proarrhythmic drugs. METHODS/
resultsIn several models of human or canine ventricular myocytes, variability was simulated by randomizing model parameters and running repeated simulations. With each randomly generated set of parameters, APs before and after simulated 75% block of the rapid delayed rectifier current (I(Kr)) were calculated. Multivariable regression was performed to determine how much each model parameter attenuated or exacerbated the AP prolongation caused by the I(Kr)-blocking drug. Simulations with a human ventricular myocyte model suggest that drug response is influenced most strongly by (1) the density of I(Kr), (2) the density of slow delayed rectifier current I(Ks), (3) the voltage dependence of I(Kr) inactivation, (4) the density of L-type Ca2+ current, and (5) the kinetics of I(Ks) activation. The analysis also identified mechanisms underlying nonintuitive behavior, such as ionic currents that prolong baseline APs but decrease drug-induced AP prolongation. Finally, the simulations provided quantitative insight into conditions that aggravate the drug response, such as silent ion channel mutations and heart failure.
conclusionThese modeling results provide the first thorough quantification of repolarization reserve and improve our understanding of interindividual variability in adverse drug reactions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.