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The sinoatrial node (SAN), the primary pacemaker of the heart, is responsible for the initiation and robust regulation of sinus rhythm. 3D mapping studies of the ex-vivo human heart suggested that the robust regulation of sinus rhythm relies on specialized fibrotically-insulated pacemaker compartments (head, center and tail) with heterogeneous expressions of key ion channels and receptors. They also revealed up to five sinoatrial conduction pathways (SACPs), which electrically connect the SAN with neighboring right atrium (RA). To elucidate the role of these structural-molecular factors in the functional robustness of human SAN, we developed comprehensive biophysical computer models of the SAN based on 3D structural, functional and molecular mapping of ex-vivo human hearts. Our key finding is that the electrical insulation of the SAN except SACPs, the heterogeneous expression of If, INa currents and adenosine A1 receptors (A1R) across SAN pacemaker-conduction compartments are required to experimentally reproduce observed SAN activation patterns and important phenomena such as shifts of the leading pacemaker and preferential SACP. In particular, we found that the insulating border between the SAN and RA, is required for robust SAN function and protection from SAN arrest during adenosine challenge. The heterogeneity in the expression of A1R within the human SAN compartments underlies the direction of pacemaker shift and preferential SACPs in the presence of adenosine. Alterations of INa current and fibrotic remodelling in SACPs can significantly modulate SAN conduction and shift the preferential SACP/exit from SAN. Finally, we show that disease-induced fibrotic remodeling, INa suppression or increased adenosine make the human SAN vulnerable to pacing-induced exit blocks and reentrant arrhythmia. In summary, our computer model recapitulates the structural and functional features of the human SAN and can be a valuable tool for investigating mechanisms of SAN automaticity and conduction as well as SAN arrhythmia mechanisms under different pathophysiological conditions. Author summary: The human heart is driven and modulated by the sinoatrial node (SAN), our body's natural pacemaker. Recent studies using explanted human hearts discovered that to regulate heart rhythm robustly, the SAN has three pacemaker compartments–SAN head, center and tail characterized by heterogeneous expression of key ion channels and receptors. In addition, the fibrotically-insulated SAN electrically connects with the right atrium (RA) through up to five sinoatrial conduction pathways (SACPs). Due to the complexities of the human 3D structure and limited functional data on SAN conduction, the specific role of the SAN insulation/border, distinct SACPs and intranodal pacemaker molecular heterogeneity in regulating sinus rhythm in health and diseased hearts remain debatable. The goals of this study were to define the key factors influencing human SAN pacemaking function and SAN dysfunction by developing and utilizing computer models of the human SAN. This study presents the first comprehensive biophysical computer model of the human SAN complex based on direct molecular, structural and functional studies in the ex-vivo human heart. Our data show that the computer models can closely replicate pacemaking, SAN activation patterns and exit sites/earliest atrial activation through preferential SACPs, as well as physiological changes including the shift of the leading pacemaker in the presence of adenosine reported in the human heart ex-vivo. More importantly, the novel computer modeling simulation results illustrate the crucial role of the structural and electrical heterogeneity of the human SAN in pacemaking and conduction. Our human-specific SAN computer model represents a valuable tool for investigating SAN automaticity, conduction and arrhythmia mechanisms under normal and various disease conditions. [ABSTRACT FROM AUTHOR]

Micro-anatomical reentry has been identified as a potential driver of atrial fibrillation (AF). In this paper, we introduce a novel computational method which aims to identify which atrial regions are most susceptible to micro-reentry. The approach, which considers the structural basis for micro-reentry only, is based on the premise that the accumulation of electrically insulating interstitial fibrosis can be modelled by simulating percolation-like phenomena on spatial networks. Our results suggest that at high coupling, where micro-reentry is rare, the micro-reentrant substrate is highly clustered in areas where the atrial walls are thin and have convex wall morphology, likely facilitating localised treatment via ablation. However, as transverse connections between fibres are removed, mimicking the accumulation of interstitial fibrosis, the substrate becomes less spatially clustered, and the bias to forming in thin, convex regions of the atria is reduced, possibly restricting the efficacy of localised ablation. Comparing our algorithm on image-based models with and without atrial fibre structure, we find that strong longitudinal fibre coupling can suppress the micro-reentrant substrate, whereas regions with disordered fibre orientations have an enhanced risk of micro-reentry. With further development, these methods may be useful for modelling the temporal development of the fibrotic substrate on an individualised basis. [ABSTRACT FROM AUTHOR]

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 paired-like 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 Ca2+ 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. Author summary: Atrial fibrillation (AF) is an abnormal heart rhythm that can lead to stroke and death. Recent studies have uncovered that AF-associated risk variants are adjacent to the Pitx2 locus, furthermore, the have demonstrated that AF patients with these variants respond better to certain antiarrhythmic drugs (AADs). However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of AADs remain unclear. To untangle this issue, we have developed multi-scale computer models, ranging from single cell to tissue level, to mimic control and the Pitx2-knockout atria by incorporating experimental data on Pitx2-induced electrical and structural remodelling, as well as the effects of class I ADDs (flecainide). We discovered that removal of Pitx2 caused AF characterized by focal beats and re-entrant waves. It was found that these abnormalities can be attributed to triggered beats, action potential duration shortening and slow conduction arising from Pitx2-induced remodelling. Interestingly, these Pitx2-induced AF can be suppressed in the presence of class I AADs such as flecainide. Our simulations revealed that flecainide prevents triggered beats by blocking the function of ryanodine receptors and that flecainide can terminate re-entrant waves by prolonging action potential duration due to its actions on potassium channels. [ABSTRACT FROM AUTHOR]