ArticleJournal of molecular and cellular cardiology2016
Atrial-selective targeting of arrhythmogenic phase-3 early afterdepolarizations in human myocytes.
Article in Journal of molecular and cellular cardiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 47 citations in OpenAlex.
- Patient-Specific Heart Rate Modulates Developmental Electrophysiology in Transcriptomic-Guided In Silico Models of Pediatric Human Atrial Cardiomyocytes.bioRxiv : the preprint server for biology · 2026Article
- Predicting Sex-Specific Antiarrhythmic Strategies for Atrial Fibrillation through a Regression-Guided Computational Modeling Pipeline.bioRxiv : the preprint server for biology · 2026Article
- KFrontiers in physiology · 2025Article
- Connecting transcriptomics with computational modeling to reveal developmental adaptations in pediatric human atrial tissue.American journal of physiology. Heart and circulatory physiology · 2024Article
- Computational Modeling of Cardiac Electrophysiology.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis.Cardiovascular research · 2023Article
- Dual effects of the small-conductance CaAmerican journal of physiology. Heart and circulatory physiology · 2023Article
- Mechanisms of spontaneous CaThe Journal of physiology · 2023Article
- Arrhythmogenesis and Prolonged Repolarization From Synthetic Opioids: Finally Sorted?Journal of the American Heart Association · 2022Article
- Cardiac potassium inward rectifier Kir2: Review of structure, regulation, pharmacology, and arrhythmogenesis.Heart rhythm · 2021Review
- Mechanisms of phase-3 early afterdepolarizations and triggered activities in ventricular myocyte models.Physiological reports · 2021Article
- Populations of in silico myocytes and tissues reveal synergy of multiatrial-predominant KBritish journal of pharmacology · 2020Article
- Genetic Loss ofCirculation. Arrhythmia and electrophysiology · 2020Article
- Review
- European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on risk assessment in cardiac arrhythmias: use the right tool for the right outcome, in the right population.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2020Article
- Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities.Journal of molecular and cellular cardiology · 2020Article
- Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes.Circulation research · 2020Article
- Biophysical Characterization of a NovelFrontiers in physiology · 2020Article
- Computational modeling: What does it tell us about atrial fibrillation therapy?International journal of cardiology · 2019Review
- Understanding AF Mechanisms Through Computational Modelling and Simulations.Arrhythmia & electrophysiology review · 2019Review
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundWe have previously shown that non-equilibrium Na(+) current (INa) reactivation drives isoproterenol-induced phase-3 early afterdepolarizations (EADs) in mouse ventricular myocytes. In these cells, EAD initiation occurs secondary to potentiated sarcoplasmic reticulum Ca(2+) release and enhanced Na(+)/Ca(2+) exchange (NCX). This can be abolished by tetrodotoxin-blockade of INa, but not ranolazine, which selectively inhibits ventricular late INa.
aimSince repolarization of human atrial myocytes is similar to mouse ventricular myocytes in that it is relatively rapid and potently modulated by Ca(2+), we investigated whether similar mechanisms can evoke EADs in human atrium. Indeed, phase-3 EADs have been shown to re-initiate atrial fibrillation (AF) during autonomic stimulation, which is a well-recognized initiator of AF.
methodsWe integrated a Markov model of INa gating in our human atrial myocyte model. To simulate experimental results, we rapidly paced this cell model at 10Hz in the presence of 0.1μM acetylcholine and 1μM isoproterenol, and assessed EAD occurrence upon return to sinus rhythm (1Hz).
resultsCellular Ca(2+) loading during fast pacing results in a transient period of hypercontractility after return to sinus rhythm. Here, fast repolarization and enhanced NCX facilitate INa reactivation via the canonical gating mode (i.e., not late INa burst mode), which drives EAD initiation. Simulating ranolazine administration reduces atrial peak INa and leads to faster repolarization, during which INa fails to reactivate and EADs are prevented.
conclusionsNon-equilibrium INa reactivation can critically contribute to arrhythmias, specifically in human atrial myocytes. Ranolazine might be beneficial in this context by blocking peak (not late) atrial INa.
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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.