Mechanisms Underlying the Emergence of Post-acidosis Arrhythmia at the Tissue Level: A Theoretical Study

Bai, Jieyun; Yin, Renli; Wang, Kuanquan; Zhang, Henggui

doi:10.3389/fphys.2017.00195

Cited by 19 publications

(17 citation statements)

References 72 publications

(128 reference statements)

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“…Therefore, the CRN model was modified and validated to generate our basal model (CRN-TPA) developed by our group [24]. In this study, the modified Grandi model and the CRN-TPA model were chosen as they are able to reproduce human AP morphology, triggered activity ( S8 Fig and S2 Table), APD rate dependence and excitation dynamics for studying re-entrant arrhythmias in human atrial tissue [24,47,48]. There are several limitations special to this study here.…”

Section: Limitationsmentioning

confidence: 99%

In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2

Bai

Gladding

et al. 2020

PLoS Comput Biol

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that pairedlike homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca 2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na + channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.

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Section: Limitationsmentioning

confidence: 99%

In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2

Bai

Gladding

et al. 2020

PLoS Comput Biol

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“…In addition, the concentration-dependent effects of drugs were also investigated at the low, middle, and high concentrations (Supplementary Table 2). The IC 50 and nH values describing the effects of drugs on ionic currents were listed in the Supplementary Tables 3-6.…”

Section: Modelling Effects Of Drugs On Sndmentioning

confidence: 99%

“…was developed to simulate electrical waves under the AF-induced SND condition in the presence of drugs. In the 1D cable model, the mathematical model of the human atrial myocyte developed in our previous study [47][48][49][50][51][52] was used, and AF was simulated by introducing electrical remodelling based on experimental data [53][54][55][56][57][58][59][60][61][62] (listed in the Supplementary Table 8). The membrane potential is described by:…”

Section: Multicellular 1d Simulations a 1d San-atrial Model Which Cmentioning

confidence: 99%

In silico study of the effects of anti-arrhythmic drug treatment on sinoatrial node function for patients with atrial fibrillation

Bai

Zhang

2020

Sci Rep

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Sinus node dysfunction (SND) is often associated with atrial fibrillation (AF). Amiodarone is the most frequently used agent for maintaining sinus rhythm in patients with AF, but it impairs the sinoatrial node (SAN) function in one-third of AF patients. This study aims to gain mechanistic insights into the effects of the antiarrhythmic agents in the setting of AF-induced SND. We have adapted a human SAN model to characterize the SND conditions by incorporating experimental data on AF-induced electrical remodelling, and then integrated actions of drugs into the modified model to assess their efficacy. Reductions in pacing rate upon the implementation of AF-induced electrical remodelling associated with SND agreed with the clinical observations. And the simulated results showed the reduced funny current (I f) in these remodelled targets mainly contributed to the heart rate reduction. Computational drug treatment simulations predicted a further reduction in heart rate during amiodarone administration, indicating that the reduction was the result of actions of amiodarone on I Na , I Kur , I CaL , I CaT , I f and beta-adrenergic receptors. However, the heart rate was increased in the presence of disopyramide. We concluded that disopyramide may be a desirable choice in reversing the AF-induced SND phenotype. Sinus node dysfunction (SND) is associated with abnormal sinoatrial node (SAN) impulse formation resulting in sinus bradycardia. As the elderly population continues to increase, SND is becoming an increasingly common medical condition in patients with atrial fibrillation (AF) 1. AF and SND often coexist and interact in clinical practice, but the causal link between these two arrhythmias remains unclear 2,3. AF itself may alter the function of the normal SAN or promote pre-existing SND. AF is believed to shut down the normal function of the SAN by long-term overdrive suppression of its activity 4. AF-induced SND was evidenced by slowed intrinsic heart rate, which was gradually reversed after the termination of AF 5-7. The intrinsic heart rate was jointly regulated by the voltage (cyclic activation and deactivation of membrane ion channels) and calcium clocks (rhythmic spontaneous sarcoplasmic reticulum calcium release) 8. In the pacing-induced canine model of AF, changes in membrane ion channels and calcium handling proteins imply the impact of the voltage and calcium clocks. Alterations in hyperpolarization-activated cyclic nucleotide-gated channels HCN4, slow delayed-rectifier α-subunit KvLQT1, L-type/T-type calcium current subunit Cav1.2/Cav3.1 6 and calcium handling proteins 9 were observed in SAN cells, suggesting that AF may lead to SAN remodeling and thereby SND. It was shown in large-scale clinical studies that amiodarone is the most effective drug for maintaining sinus rhythm in patients with AF 10-13. However, amiodarone impairs SAN function in one-third of AF patients 14. Touboul et al. showed that amiodarone has no effects on sinus cycle length (CL) in pacing-induced AF patients 15 , whereas Hoffmann et ...

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“…Local synchronization of afterdepolarizations cells was suggested the mechanism underlying the formation of PVCs. Of course, our previous study has demonstrated that afterdepolarizations induced by SR calcium overload are synchronized to overcome the source-sink mismatch and produce PVCs in cardiac tissues (Bai et al, 2017 ). These studies support the notion that R858H-induced afterdepolarizations in MCELL cells are implicated in the induction of electrical-wave turbulence.…”

Section: Discussionmentioning

confidence: 99%

“…In 2013, the calcium-induced-calcium release flux ( I rel ) was modeled as the combination of both SR calcium release and SR calcium leak by Lascano et al ( 2013 ). The same modifications were employed in our previous studies (Bai et al, 2016b , 2017 ; Liu et al, 2016 ; formulations are listed in Supplementary Material).…”

Section: Methodsmentioning

confidence: 99%

Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation

et al. 2017

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Functional analysis of the L-type calcium channel has shown that the CACNA1C R858H mutation associated with severe QT interval prolongation may lead to ventricular fibrillation (VF). This study investigated multiple potential mechanisms by which the CACNA1C R858H mutation facilitates and perpetuates VF. The Ten Tusscher-Panfilov (TP06) human ventricular cell models incorporating the experimental data on the kinetic properties of L-type calcium channels were integrated into one-dimensional (1D) fiber, 2D sheet, and 3D ventricular models to investigate the pro-arrhythmic effects of CACNA1C mutations by quantifying changes in intracellular calcium handling, action potential profiles, action potential duration restitution (APDR) curves, dispersion of repolarization (DOR), QT interval and spiral wave dynamics. R858H “mutant” L-type calcium current (ICaL) augmented sarcoplasmic reticulum calcium content, leading to the development of afterdepolarizations at the single cell level and focal activities at the tissue level. It also produced inhomogeneous APD prolongation, causing QT prolongation and repolarization dispersion amplification, rendering R858H “mutant” tissue more vulnerable to the induction of reentry compared with other conditions. In conclusion, altered ICaL due to the CACNA1C R858H mutation increases arrhythmia risk due to afterdepolarizations and increased tissue vulnerability to unidirectional conduction block. However, the observed reentry is not due to afterdepolarizations (not present in our model), but rather to a novel blocking mechanism.

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Mechanisms Underlying the Emergence of Post-acidosis Arrhythmia at the Tissue Level: A Theoretical Study

Cited by 19 publications

References 72 publications

In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2

In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2

In silico study of the effects of anti-arrhythmic drug treatment on sinoatrial node function for patients with atrial fibrillation

Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation

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