scholarly journals A Computational Study of the Effects of Tachycardia-Induced Remodeling on Calcium Wave Propagation in Rabbit Atrial Myocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Márcia R. Vagos ◽  
Hermenegild Arevalo ◽  
Jordi Heijman ◽  
Ulrich Schotten ◽  
Joakim Sundnes
Keyword(s):  
Wave Propagation ◽  
Computational Study ◽  
Experimental Studies ◽  
Wave Pattern ◽  
Calcium Handling ◽  
Calcium Wave ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Rapid Pacing ◽  
The Individual

In atrial cardiomyocytes without a well-developed T-tubule system, calcium diffuses from the periphery toward the center creating a centripetal wave pattern. During atrial fibrillation, rapid activation of atrial myocytes induces complex remodeling in diffusion properties that result in failure of calcium to propagate in a fully regenerative manner toward the center; a phenomenon termed “calcium silencing.” This has been observed in rabbit atrial myocytes after exposure to prolonged rapid pacing. Although experimental studies have pointed to possible mechanisms underlying calcium silencing, their individual effects and relative importance remain largely unknown. In this study we used computational modeling of the rabbit atrial cardiomyocyte to query the individual and combined effects of the proposed mechanisms leading to calcium silencing and abnormal calcium wave propagation. We employed a population of models obtained from a newly developed model of the rabbit atrial myocyte with spatial representation of intracellular calcium handling. We selected parameters in the model that represent experimentally observed cellular remodeling which have been implicated in calcium silencing, and scaled their values in the population to match experimental observations. In particular, we changed the maximum conductances of ICaL, INCX, and INaK, RyR open probability, RyR density, Serca2a density, and calcium buffering strength. We incorporated remodeling in a population of 16 models by independently varying parameters that reproduce experimentally observed cellular remodeling, and quantified the resulting alterations in calcium dynamics and wave propagation patterns. The results show a strong effect of ICaL in driving calcium silencing, with INCX, INaK, and RyR density also resulting in calcium silencing in some models. Calcium alternans was observed in some models where INCX and Serca2a density had been changed. Simultaneously incorporating changes in all remodeled parameters resulted in calcium silencing in all models, indicating the predominant role of decreasing ICaL in the population phenotype.

scholarly journals Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study

2008 ◽  
Vol 295 (2) ◽  
pp. H598-H609 ◽  
Author(s):  
T. Tao ◽  
S. C. O'Neill ◽  
M. E. Diaz ◽  
Y. T. Li ◽  
D. A. Eisner ◽  
...  
Keyword(s):  
Ryanodine Receptors ◽  
Experimental Studies ◽  
Release Mechanism ◽  
Cardiac Cell ◽  
Open Probability ◽  
Propagating Waves ◽  
Random Block ◽  
Intracellular Ca ◽  
Uptake Sites ◽  
Rapid Pacing

Mechanical alternans in cardiac muscle is associated with intracellular Ca2+ alternans. Mechanisms underlying intracellular Ca2+ alternans are unclear. In previous experimental studies, we produced alternans of systolic Ca2+ under voltage clamp, either by partially inhibiting the Ca2+ release mechanism, or by applying small depolarizing pulses. In each case, alternans relied on propagating waves of Ca2+ release. The aim of this study is to investigate by computer modeling how alternans of systolic Ca2+ is produced. A mathematical model of a cardiac cell with 75 coupled elements is developed, with each element contains L-type Ca2+ current, a subspace into which Ca release takes place, a cytoplasmic space, sarcoplasmic reticulum (SR) release channels [ryanodine receptor (RyR)], and uptake sites (SERCA). Interelement coupling is via Ca2+ diffusion between neighboring subspaces via cytoplasmic spaces and network SR spaces. Small depolarizing pulses were simulated by step changes of cell membrane potential (20 mV) with random block of L-type channels. Partial inhibition of the release mechanism is mimicked by applying a reduction of RyR open probability in response to full stimulation by L-type channels. In both cases, systolic alternans follow, consistent with our experimental observations, being generated by propagating waves of Ca2+ release and sustained through alternation of SR Ca2+ content. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca2+ alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing.

Larger late sodium current density as well as greater sensitivities to ATX II and ranolazine in rabbit left atrial than left ventricular myocytes

2014 ◽  
Vol 306 (3) ◽  
pp. H455-H461 ◽  
Author(s):  
Antao Luo ◽  
Jihua Ma ◽  
Yejia Song ◽  
Chunping Qian ◽  
Ying Wu ◽  
...  
Keyword(s):  
Left Atrial ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Left Ventricular ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Late Sodium Current ◽  
Ventricular Cells ◽  
Open Time ◽  
Hill Slope

An increase of cardiac late sodium current ( INa.L) is arrhythmogenic in atrial and ventricular tissues, but the densities of INa.L and thus the potential relative contributions of this current to sodium ion (Na+) influx and arrhythmogenesis in atria and ventricles are unclear. In this study, whole-cell and cell-attached patch-clamp techniques were used to measure INa.L in rabbit left atrial and ventricular myocytes under identical conditions. The density of INa.L was 67% greater in left atrial (0.50 ± 0.09 pA/pF, n = 20) than in left ventricular cells (0.30 ± 0.07 pA/pF, n = 27, P < 0.01) when elicited by step pulses from −120 to −20 mV at a rate of 0.2 Hz. Similar results were obtained using step pulses from −90 to −20 mV. Anemone toxin II (ATX II) increased INa.L with an EC50 value of 14 ± 2 nM and a Hill slope of 1.4 ± 0.1 ( n = 9) in atrial myocytes and with an EC50 of 21 ± 5 nM and a Hill slope of 1.2 ± 0.1 ( n = 12) in ventricular myocytes. Na+ channel open probability (but not mean open time) was greater in atrial than in ventricular cells in the absence and presence of ATX II. The INa.L inhibitor ranolazine (3, 6, and 9 μM) reduced INa.L more in atrial than ventricular myocytes in the presence of 40 nM ATX II. In summary, rabbit left atrial myocytes have a greater density of INa.L and higher sensitivities to ATX II and ranolazine than rabbit left ventricular myocytes.

Excitable calcium wave propagation in the presence of localized stores

2000 ◽  
Vol 62 (6) ◽  
pp. 8420-8426 ◽  
Author(s):  
C. S. Pencea ◽  
H. G. E. Hentschel
Keyword(s):  
Wave Propagation ◽  
Calcium Wave

scholarly journals Sarcoplasmic reticulum and L-type Ca2+channel activity regulate the beat-to-beat stability of calcium handling in human atrial myocytes

2011 ◽  
Vol 589 (13) ◽  
pp. 3247-3262 ◽  
Author(s):  
Anna Llach ◽  
Cristina E. Molina ◽  
Jacqueline Fernandes ◽  
Josep Padró ◽  
Juan Cinca ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Calcium Handling ◽  
Channel Activity ◽  
Atrial Myocytes ◽  
Human Atrial Myocytes

scholarly journals Ca2+/calmodulin-dependent kinase II-dependent regulation of atrial myocyte late Na+ current, Ca2+ cycling, and excitability: a mathematical modeling study

2017 ◽  
Vol 313 (6) ◽  
pp. H1227-H1239 ◽  
Author(s):  
Birce Onal ◽  
Daniel Gratz ◽  
Thomas J. Hund
Keyword(s):  
Protein Kinase ◽  
Computational Model ◽  
Ryanodine Receptor ◽  
The United States ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Dependent Protein Kinase ◽  
Protein Kinase Ii ◽  
Dependent Protein ◽  
Atrial Myocyte

Atrial fibrillation (AF) affects more than three million people per year in the United States and is associated with high morbidity and mortality. Both electrical and structural remodeling contribute to AF, but the molecular pathways underlying AF pathogenesis are not well understood. Recently, a role for Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the regulation of persistent “late” Na+ current ( INa,L) has been identified. Although INa,L inhibition is emerging as a potential antiarrhythmic strategy in patients with AF, little is known about the mechanism linking INa,L to atrial arrhythmogenesis. A computational approach was used to test the hypothesis that increased CaMKII-activated INa,L in atrial myocytes disrupts Ca2+ homeostasis, promoting arrhythmogenic afterdepolarizations. Dynamic CaMKII activity and regulation of multiple downstream targets [ INa,L, L-type Ca2+ current, phospholamban, and the ryanodine receptor sarcoplasmic reticulum Ca2+-release channel (RyR2)] were incorporated into an existing well-validated computational model of the human atrial action potential. Model simulations showed that constitutive CaMKII-dependent phosphorylation of Nav1.5 and the subsequent increase in INa,L effectively disrupt intracellular atrial myocyte ion homeostasis and CaMKII signaling. Specifically, increased INa,L promotes intracellular Ca2+ overload via forward-mode Na+/Ca2+ exchange activity, which greatly increases RyR2 open probability beyond that observed for CaMKII-dependent phosphorylation of RyR2 alone. Increased INa,L promotes atrial myocyte repolarization defects (afterdepolarizations and alternans) in the setting of acute β-adrenergic stimulation. We anticipate that our modeling efforts will help identify new mechanisms for atrial NaV1.5 regulation with direct relevance for human AF. NEW & NOTEWORTHY Here, we present a novel computational model to study the effects of late Na+ current ( INa,L) in human atrial myocytes. Simulations predict that INa,L promotes intracellular accumulation of Ca2+, with subsequent dysregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling and ryanodine receptor 2-mediated Ca2+ release. Although INa,L plays a small role in regulating atrial myocyte excitability at baseline, CaMKII-dependent enhancement of the current promoted arrhythmogenic dynamics. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/camkii-dependent-regulation-of-atrial-late-sodium-current-and-excitability/ .

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