Atrial Fibrillation Initiated by Early Afterdepolarization-Mediated Triggered Activity during Acute Oxidative Stress: Efficacy of Late Sodium Current Blockade
Abstract:Background
The mechanism of Atrial Fibrillation (AF) that emerges spontaneously during acute oxidative stress is poorly defined and its drug therapy remains suboptimal. We hypothesized that oxidative activation of Ca-calmodulin dependent protein kinase (CaMKII) promotes Early Afterdepolarization-(EAD)-mediated triggered AF in aged fibrotic atria that is sensitive to late Na current (INa-L) blockade.
Method and Results
High-resolution voltage optical mapping of the Left and Right Atrial (LA & RA) epicardial s… Show more
“…Initiation and maintenance of atrial rhythm disturbances is known to be modulated by enhanced production of free radicals that are generated, e.g., during a sterile inflammatory response ( Coppini et al, 2019 ; Varró et al, 2020 ). This finding may be related to the pattern of results revealed by our computations in two ways: (i) It is known that Na + /K + pump activity is reduced significantly by this type of “redox challenge” ( Figtree et al, 2012 ) and to free radical production and in particular enhanced generation of hydrogen peroxide can increase the slowly inactivating or late component of the Na + current ( Ward et al, 2006 ; Pezhouman et al, 2018 ). Both of these effects would be expected to destabilize the resting potential, and may be proarrhythmic through their ability to reduce the net outward current in diastole.…”
Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K+, Na+, Ca2+, and/or Mg2+ can significantly alter physiological responses in the heart, blood vessels, and intrinsic (intracardiac) autonomic nervous system. We have used mathematical models of the human atrial action potential (AP) to explore the electrophysiological mechanisms that underlie changes in resting potential (Vr) and the AP following decreases in plasma K+, [K+]o, that were selected to mimic clinical hypokalemia. Such changes may be associated with arrhythmias and are commonly encountered in patients (i) in therapy for hypertension and heart failure; (ii) undergoing renal dialysis; (iii) with any disease with acid-base imbalance; or (iv) post-operatively. Our study emphasizes clinically-relevant hypokalemic conditions, corresponding to [K+]o reductions of approximately 1.5 mM from the normal value of 4 to 4.5 mM. We show how the resulting electrophysiological responses in human atrial myocytes progress within two distinct time frames:(i) Immediately after [K+]o is reduced, the K+-sensing mechanism of the background inward rectifier current (IK1) responds. Specifically, its highly non-linear current-voltage relationship changes significantly as judged by the voltage dependence of its region of outward current. This rapidly alters, and sometimes even depolarizes, Vr and can also markedly prolong the final repolarization phase of the AP, thus modulating excitability and refractoriness.(ii) A second much slower electrophysiological response (developing 5–10 minutes after [K+]o is reduced) results from alterations in the intracellular electrolyte balance. A progressive shift in intracellular [Na+]i causes a change in the outward electrogenic current generated by the Na+/K+ pump, thereby modifying Vr and AP repolarization and changing the human atrial electrophysiological substrate.In this study, these two effects were investigated quantitatively, using seven published models of the human atrial AP. This highlighted the important role of IK1 rectification when analyzing both the mechanisms by which [K+]o regulates Vr and how the AP waveform may contribute to “trigger” mechanisms within the proarrhythmic substrate. Our simulations complement and extend previous studies aimed at understanding key factors by which decreases in [K+]o can produce effects that are known to promote atrial arrhythmias in human hearts.
“…Initiation and maintenance of atrial rhythm disturbances is known to be modulated by enhanced production of free radicals that are generated, e.g., during a sterile inflammatory response ( Coppini et al, 2019 ; Varró et al, 2020 ). This finding may be related to the pattern of results revealed by our computations in two ways: (i) It is known that Na + /K + pump activity is reduced significantly by this type of “redox challenge” ( Figtree et al, 2012 ) and to free radical production and in particular enhanced generation of hydrogen peroxide can increase the slowly inactivating or late component of the Na + current ( Ward et al, 2006 ; Pezhouman et al, 2018 ). Both of these effects would be expected to destabilize the resting potential, and may be proarrhythmic through their ability to reduce the net outward current in diastole.…”
Although plasma electrolyte levels are quickly and precisely regulated in the mammalian cardiovascular system, even small transient changes in K+, Na+, Ca2+, and/or Mg2+ can significantly alter physiological responses in the heart, blood vessels, and intrinsic (intracardiac) autonomic nervous system. We have used mathematical models of the human atrial action potential (AP) to explore the electrophysiological mechanisms that underlie changes in resting potential (Vr) and the AP following decreases in plasma K+, [K+]o, that were selected to mimic clinical hypokalemia. Such changes may be associated with arrhythmias and are commonly encountered in patients (i) in therapy for hypertension and heart failure; (ii) undergoing renal dialysis; (iii) with any disease with acid-base imbalance; or (iv) post-operatively. Our study emphasizes clinically-relevant hypokalemic conditions, corresponding to [K+]o reductions of approximately 1.5 mM from the normal value of 4 to 4.5 mM. We show how the resulting electrophysiological responses in human atrial myocytes progress within two distinct time frames:(i) Immediately after [K+]o is reduced, the K+-sensing mechanism of the background inward rectifier current (IK1) responds. Specifically, its highly non-linear current-voltage relationship changes significantly as judged by the voltage dependence of its region of outward current. This rapidly alters, and sometimes even depolarizes, Vr and can also markedly prolong the final repolarization phase of the AP, thus modulating excitability and refractoriness.(ii) A second much slower electrophysiological response (developing 5–10 minutes after [K+]o is reduced) results from alterations in the intracellular electrolyte balance. A progressive shift in intracellular [Na+]i causes a change in the outward electrogenic current generated by the Na+/K+ pump, thereby modifying Vr and AP repolarization and changing the human atrial electrophysiological substrate.In this study, these two effects were investigated quantitatively, using seven published models of the human atrial AP. This highlighted the important role of IK1 rectification when analyzing both the mechanisms by which [K+]o regulates Vr and how the AP waveform may contribute to “trigger” mechanisms within the proarrhythmic substrate. Our simulations complement and extend previous studies aimed at understanding key factors by which decreases in [K+]o can produce effects that are known to promote atrial arrhythmias in human hearts.
“…Mice with long-QT syndrome 3 show excessive atrial APD-prolongation and EADs [63]. Similarly, acute Calcium-calmodulin dependent protein kinase II (CaMKII) activation initiates AF through EAD-mediated triggered activity in old rats, which can be suppressed by inhibition of I Na,late [64]. Figure 1Summary of mechanisms underlying the initiation and maintenance of atrial fibrillation.…”
Section: Pathophysiology Of Atrial Fibrillationmentioning
Atrial fibrillation (AF) is a very common cardiac arrhythmia with an estimated prevalence of 33.5 million patients globally. It is associated with an increased risk of death, stroke and peripheral embolism. Although genetic studies have identified a growing number of genes associated with AF, the definitive impact of these genetic findings is yet to be established. Several mechanisms, including electrical, structural and neural remodelling of atrial tissue, have been proposed to contribute to the development of AF. Despite over a century of exploration, the molecular and cellular mechanisms underlying AF have not been fully established. Current antiarrhythmic drugs are associated with a significant rate of adverse events and management of AF using ablation is not optimal, especially in cases of persistent AF. This review discusses recent advances in our understanding and management of AF, including new concepts of epidemiology, genetics and pathophysiological mechanisms. We review the current status of antiarrhythmic drug therapy for AF, new potential agents, as well as mechanism-based AF ablation.
This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
“…The cells were incubated in the 25 µl volume for 8-12 h to facilitate cell attachment. Once spontaneous contractions were observed, cells were stained with voltage-sensitive dye, Di-8-ANEPPS (Invitrogen, D3167, 40 µM) and washed with normal Tyrode solution three times (Pezhouman et al, 2014;Pezhouman et al, 2015;Pezhouman et al, 2018;Pezhouman et al, 2021). Optical AP recording were made using MiCAM-Ultima CMOS camera at 500 frames per second (fps).…”
Background: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) can be used as a source for cell delivery to remuscularize the heart after myocardial infarction. Despite their therapeutic potential, the emergence of ventricular arrhythmias has limited their application. We previously developed a double reporter hESC line to isolate first heart field (FHF: TBX5+NKX2-5+) and second heart field (SHF: TBX5-NKX2-5+) CMs. Herein, we explore the role of TBX5 and its effects on underlying gene regulatory networks driving phenotypical and functional differences between these two populations.Methods: We used a combination of tools and techniques for rapid and unsupervised profiling of FHF and SHF populations at the transcriptional, translational, and functional level including single cell RNA (scRNA) and bulk RNA sequencing, atomic force and quantitative phase microscopy, respirometry, and electrophysiology.Results: Gene ontology analysis revealed three biological processes attributed to TBX5 expression: sarcomeric structure, oxidative phosphorylation, and calcium ion handling. Interestingly, migratory pathways were enriched in SHF population. SHF-like CMs display less sarcomeric organization compared to FHF-like CMs, despite prolonged in vitro culture. Atomic force and quantitative phase microscopy showed increased cellular stiffness and decreased mass distribution over time in FHF compared to SHF populations, respectively. Electrophysiological studies showed longer plateau in action potentials recorded from FHF-like CMs, consistent with their increased expression of calcium handling genes. Interestingly, both populations showed nearly identical respiratory profiles with the only significant functional difference being higher ATP generation-linked oxygen consumption rate in FHF-like CMs. Our findings suggest that FHF-like CMs display more mature features given their enhanced sarcomeric alignment, calcium handling, and decreased migratory characteristics. Finally, pseudotime analyses revealed a closer association of the FHF population to human fetal CMs along the developmental trajectory.Conclusion: Our studies reveal that distinguishing FHF and SHF populations based on TBX5 expression leads to a significant impact on their downstream functional properties. FHF CMs display more mature characteristics such as enhanced sarcomeric organization and improved calcium handling, with closer positioning along the differentiation trajectory to human fetal hearts. These data suggest that the FHF CMs may be a more suitable candidate for cardiac regeneration.
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