ArticleJournal of molecular and cellular cardiology2013
β-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets.
Article in Journal of molecular and cellular cardiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 70 citations in OpenAlex.
- Dynamic visualization of physiological CaMKII activity using sensitive FRET biosensors.bioRxiv : the preprint server for biology · 2026Article
- Beat-to-beat variability of ventricular repolarization reveals sex-specific instability and proarrhythmic risk.The Journal of physiology · 2026Article
- Role of dynamical instability in QT interval variability and early afterdepolarization propensity.Biophysical journal · 2025Article
- Modeling autoregulation of cardiac excitation-Ca-contraction and arrhythmogenic activities in response to mechanical load changes.iScience · 2025Article
- Tilt-induced changes in f-wave characteristics during atrial fibrillation: an experimental and computational investigation.Frontiers in physiology · 2025Article
- Computational Modeling of Cardiac Electrophysiology.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy.JCI insight · 2023Article
- 25 years of basic and translational science in EP Europace: novel insights into arrhythmia mechanisms and therapeutic strategies.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 · 2023Review
- Sudden cardiac death in the adolescent population: a narrative review.The Egyptian journal of internal medicine · 2023Review
- Article
- Modeling Calcium Cycling in the Heart: Progress, Pitfalls, and Challenges.Biomolecules · 2022Review
- Subcellular Propagation of Cardiomyocyte β-Adrenergic Activation of Calcium Uptake Involves Internal β-Receptors and AKAP7.Function (Oxford, England) · 2022Article
- Autonomic modulation of ventricular electrical activity: recent developments and clinical implications.Clinical autonomic research : official journal of the Clinical Autonomic Research Society · 2021Review
- Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications.Science advances · 2021Article
- Prediction of arrhythmia susceptibility through mathematical modeling and machine learning.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Emerging evidence for a mechanistic link between low-frequency oscillation of ventricular repolarization measured from the electrocardiogram T-wave vector and arrhythmia.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 · 2021Review
- Air Pollution and Cardiac Arrhythmias: From Epidemiological and Clinical Evidences to Cellular Electrophysiological Mechanisms.Frontiers in cardiovascular medicine · 2021Review
- Inhibition of cardiac potassium currents by oxidation-activated protein kinase A contributes to early afterdepolarizations in the heart.American journal of physiology. Heart and circulatory physiology · 2020Article
- Quantitative analysis of variability in an integrated model of human ventricular electrophysiology and β-adrenergic signaling.Journal of molecular and cellular cardiology · 2020Article
- Balance Between Rapid Delayed Rectifier KCirculation. Arrhythmia and electrophysiology · 2020Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Sympathetic stimulation regulates cardiac excitation-contraction coupling in hearts but can also trigger ventricular arrhythmias caused by early afterdepolarizations (EADs) in pathological conditions. Isoproterenol (ISO) stimulation can transiently cause EADs which could result from differential kinetics of L-type Ca current (ICaL) vs. delayed rectifier potassium current (IKs) effects, but multiple PKA targets complicate mechanistic analysis. Utilizing a biophysically detailed model integrating Ca and β-adrenergic signaling, we investigate how different phosphorylation kinetics and targets influence β-adrenergic-induced transient EADs. We found that: 1) The faster time course of ICaL vs. IKs increases recapitulates experimentally observed ISO-induced transient EADs (which are due to ICaL reactivation). These EADs disappear at steady state ISO and do not occur during more gradual ISO application. 2) This ICaL vs. IKs kinetic mismatch with ISO can also induce transient EADs due to spontaneous sarcoplasmic reticulum (SR) Ca release and Na/Ca exchange current. The increased ICaL, SR Ca uptake and action potential duration (APD) raise SR Ca to cause spontaneous SR Ca release, but eventual IKs activation and APD shortening abolish these EADs. 3) Phospholemman (PLM) phosphorylation decreases both types of EADs by increasing outward Na/K-ATPase current (INaK) for ICaL-mediated EADs, and reducing intracellular Na and Ca loading for SR Ca-release-mediated EADs. Slowing PLM phosphorylation kinetics abolishes this protective effect. 4) Blocking phospholamban (PLB) phosphorylation has little effect on ICaL-mediated transient EADs, but abolishes SR Ca-release-mediated transient EADs by limiting SR Ca loading. 5) RyR phosphorylation has little effect on either transient EAD type. Our study emphasizes the importance of understanding non-steady state kinetics of several systems in mediating β-adrenergic-induced EADs and arrhythmias.
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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.