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

Abstract

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 ...

In Silico Assessment of Class I Antiarrhythmic Drug Effects on Pitx2-Induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

“…In our previous studies [ 37 , 89 ], the actions of the class I AADs disopyramide, quinidine, and propafenone on human atrial electrophysiology were simulated in the setting of hERG-linked short QT syndrome [ 37 ]. The effects of these class I AADs on ion currents were modelled by changing maximum current conductances with a simple pore blocking scheme based on IC 50 and nH [ 31 ]. Maximum current conductances associated with these drugs included G Na , G CaL , G to , G Ks , G Kr , G Kur , and G K1 .…”

“…Gene expression analyses highlighted that Pitx2 regulated genes of ion channels and gap junctions [ 11 , 12 , 17 , 22 , 23 , 25 , 26 ] in a dose-dependent manner. Based on these experimental data on changes in the expression of ion channels and gap junctions, we constructed multi-scale models of human atrial electrophysiology to investigate mechanisms by which Pitx2 -induced remodelling promotes AF in our previous studies [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. However, the effective management of AF remains a challenge, and is incompletely understood in the context of Pitx2-induced AF.…”

“…Although the efficacy of disopyramide, quinidine, and propafenone on human atrial patho-electrophysiology associated with human Ether-à-go-go-Related Gene(hERG) -linked short QT syndrome has been investigated using a multi-scale computational model [ 37 ], mechanisms by which short QT mutations promote AF may be different from that underlying Pitx2 -induced AF [ 27 , 28 , 29 , 30 , 31 , 32 , 36 ]. Additionally, both clinical [ 34 ] and theoretical [ 36 ] studies of pharmacotherapy for Pitx2 -induced AF often ignored inter-subject variability in atrial electrophysiology properties.…”

In Silico Assessment of Class I Antiarrhythmic Drugs Effects on Pitx2-induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

“…Gene expression analyses highlighted that Pitx2 regulated genes of ion channels [11,12,17,22,23,25,26] in a dose-dependent manner. Based on these experimental data on changes in expression of ion channels, we constructed multi-scale models of human atrial electrophysiology to investigate mechanisms by which Pitx2-induced remodelling promotes AF in our previous studies [27][28][29][30][31][32][33]. However, effective management of AF remains a challenge, and is incompletely understood in the context of Pitx2-induced AF.…”

“…Although the efficacy of disopyramide, quinidine, and propafenone on human atrial pathoelectrophysiology associated with hERG-linked short QT syndrome has been investigated using a multi-scale computational model [37], mechanisms by which short QT mutations promote AF may be different from that underlying Pitx2-induced AF [27][28][29][30][31][32]36]. Also, both clinical [34] and theoretical [36] studies of pharmacotherapy for Pitx2-induced AF often ignored inter-subject variability in atrial electrophysiology properties.…”