Enhanced Sarcoplasmic Reticulum Ca2+ Leak and Increased Na+-Ca2+ Exchanger Function Underlie Delayed Afterdepolarizations in Patients With Chronic Atrial Fibrillation
Niels Voigt,Na Li,Qiongling Wang,Wei Wang,Andrew W. Trafford,Issam Abu-Taha,Qiang Sun,Thomas Wieland,Ursula Ravens,Stanley Nattel,Xander H.T. Wehrens,Dobromir Dobrev +11 more
598
TL;DR: Enhanced SR Ca2+ leak through CaMKII-hyperphosphorylated RyR2, in combination with larger INCX for a given SR Ca 2+ release and increased diastolic [Ca2+]i-voltage coupling gain, causes AF-promoting atrial delayed afterdepolarizations/triggered activity in cAF patients.
read more
Abstract: Background—Delayed afterdepolarizations (DADs) carried by Na+-Ca2+-exchange current (INCX) in response to sarcoplasmic reticulum (SR) Ca2+ leak can promote atrial fibrillation (AF). The mechanisms leading to delayed afterdepolarizations in AF patients have not been defined. Methods and Results—Protein levels (Western blot), membrane currents and action potentials (patch clamp), and [Ca2+]i (Fluo-3) were measured in right atrial samples from 76 sinus rhythm (control) and 72 chronic AF (cAF) patients. Diastolic [Ca2+]i and SR Ca2+ content (integrated INCX during caffeine-induced Ca2+ transient) were unchanged, whereas diastolic SR Ca2+ leak, estimated by blocking ryanodine receptors (RyR2) with tetracaine, was ≈50% higher in cAF versus control. Single-channel recordings from atrial RyR2 reconstituted into lipid bilayers revealed enhanced open probability in cAF samples, providing a molecular basis for increased SR Ca2+ leak. Calmodulin expression (60%), Ca2+/calmodulin-dependent protein kinase-II (CaMKII) a...
read more
Chat with Paper
AI Agents for this Paper
Find similar papers on Google Scholar, PubMed and Arxiv
Write a critical review of this paper
Analyze citations of this paper to find unaddressed research gaps
Citations
Afterdepolarizations and abnormal calcium handling in atrial myocytes with modulated SERCA uptake: a sensitivity analysis of calcium handling channels
TL;DR: For the first time, a modelling study reconciles different mechanisms of abnormal depolarizations in the setting of ‘lone’ AF, reduced TBX5, diabetes and heart failure, and may lead to more targeted treatment for these patients.
11
Changes in the atrial transcriptome and atrial fibrillation: susceptibility, persistence, causes, and consequences.
TL;DR: An interesting and elegant analysis of the atrial transcriptome (the global pattern of mRNA expression) in clinical AF is presented, showing differences in genes related to gene/protein synthesis, contraction/cytoskeleton, immune/inflammatory response, metabolism, fibrosis, and ion channels.
11
Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update.
TL;DR: Recent advances in the current understanding of NDPK functions are described and how they have an impact on local regulation of G-protein signaling.
11
Effect of antiarrhythmic drugs on small conductance calcium - activated potassium channels.
TL;DR: A large number of AADs were tested on the human K Ca2.2 and KCa2.3 channels to assess their effect on a new target, the small conductance calcium‐activated K+ channels, and the calculated IC50 values were very high compared to the effective free therapeutic plasma concentration of the drugs when used for AF treatment.
11
References
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
TL;DR: A new family of highly fluorescent indicators has been synthesized for biochemical studies of the physiological role of cytosolic free Ca2+ using an 8-coordinate tetracarboxylate chelating site with stilbene chromophores that offer up to 30-fold brighter fluorescence.
22.7K
Cardiac excitation–contraction coupling
TL;DR: Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important and spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
4.8K
Atrial remodeling and atrial fibrillation: mechanisms and implications.
TL;DR: The types of atrial remodeling, their underlying pathophysiology, the molecular basis of their occurrence, and finally, their potential therapeutic significance are reviewed.
1.1K
Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness.
TL;DR: Data is presented to support a novel paradigm in which changes in NaCaX and IK1, and residual &bgr;-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF.
802
FKBP12.6 Deficiency and Defective Calcium Release Channel (Ryanodine Receptor) Function Linked to Exercise-Induced Sudden Cardiac Death
Xander H.T. Wehrens,Stephan E. Lehnart,Fannie Huang,John A. Vest,Steven Reiken,Peter J. Mohler,Jie Sun,Silvia Guatimosim,Long-Sheng Song,Nora Rosemblit,Jeanine D'Armiento,Carlo Napolitano,Mirella Memmi,Silvia G. Priori,W. J. Lederer,Andrew R. Marks +15 more
TL;DR: It is shown that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca(2+) release and cardiac contractility, suggesting that "leaky"RyR2 channels can trigger fatal cardiac arrhythmias.
740