Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells

Bai, Jieyun; Gladding, Patrick; Stiles, Martin K.; Fedorov, Vadim V.; Zhao, Jichao

doi:10.1038/s41598-018-33958-y

Cited by 27 publications

(58 citation statements)

References 71 publications

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“…At the single cell level, a recent human atrial cellular kinetics model (CRN-TPA) (S1 Fig) developed by our group was further adapted to simulate control and Pitx2 deficiency-induced AF conditions [24]. Cellular heterogeneity between LA and RA was modeled by taking into account differences in mRNA level for Pitx2 and in I Kr current density (S1 Table).…”

Section: Human Atrial Cell Modelmentioning

confidence: 99%

“…Electrical remodelling due to Pitx2 insufficiency accounts for ectopic depolarizations [21,24] and abbreviated APs [14], contributing to AF, but the ionic mechanisms underlying these changes in AP characteristics remain unclear. In the present study, we incorporated variations in experimental data into four computer models (Pitx2-1, Pitx2-2, Pitx2-3 and Pitx2-4).…”

Section: Ionic Basis Of Pitx2 Insufficiency-induced Ap Phenotypementioning

confidence: 99%

“…However, the precise AF pathophysiology under reduced Pitx2 remains unclear. Population-based studies have assessed the influence of common SNPs related to AF on the response to antiarrhythmic drug (AAD) therapies and showed that carriers of the variant allele at rs10033646 on chromosome 4q25 (Pitx2) responded favourably to the class I AAD (flecainide) [22][23][24][25][26]. The possible reasons behind this remain elusive.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we aimed to utilize virtual human atrial models to investigate the functional role of Pitx2-induced remodeling in atrial arrhythmogenesis and to examine the mechanism underlying the efficacy of flecainide for patients with Pitx2-induced AF. To achieve this, we adopted the previously modified and validated Courtemanche-Ramirez-Nattel model (CRN-TPA) for the human atrial cell by incorporating formulations of intracellular calcium dynamics from the ten Tusscher-Panfilov model to reproduce triggered activity [24,27]. We then modified the model to produce four distinct models of Pitx2-induced electrical remodeling based on grouping existing literature.…”

Section: Introductionmentioning

confidence: 99%

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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: Human Atrial Cell Modelmentioning

confidence: 99%

Section: Ionic Basis Of Pitx2 Insufficiency-induced Ap Phenotypementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…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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Modeling and simulation of cardiac electric activity in a human cardiac tissue with multiple ischemic zones

2019

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Ionic and cellular mechanisms underlying TBX5/PITX2 insufficiency-induced atrial fibrillation: Insights from mathematical models of human atrial cells

Cited by 27 publications

References 71 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

Modeling and simulation of cardiac electric activity in a human cardiac tissue with multiple ischemic zones

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