Determinants and therapeutic potential of calcium handling abnormalities in atrial fibrillation: what can we learn from computer models?

Atrial fibrillation (AF) remains a major clinical problem (Nattel et al., 2021). Conceptually, AF requires a trigger, often in the form of ectopic (triggered) activity, and a vulnerable substrate for the initiation and maintenance of self-sustaining tachyarrhythmias. This vulnerable substrate is characterized by cardiac dilatation, slow heterogeneous conduction, typically due to fibrosis, connexin or ion-channel dysfunction, and areas of short repolarization. In addition, there is evidence for a central role for Ca2+-handling abnormalities in the promotion, maintenance and progression of AF (Dobrev & Wehrens, 2017). However, the complexity of cardiomyocyte Ca2+ signalling, controlled at the sub-micrometre level by myriad regulatory feedback mechanisms operating over a wide range of time scales, makes the detailed experimental dissection of proarrhythmic phenotypes and their translation to therapeutic applications challenging (Dobrev & Wehrens, 2017). Computer models provide perfect control over parameters and complete observability of all components of the system of interest. Computational modelling of cardiac electrophysiology has a long history with iterative improvement of models based on a 'ping-pong' interplay with experimental studies (Heijman et al., 2021). Modern models can reproduce a wide range of experimental data and increasingly have real-world impact. For example, randomized clinical trials comparing simulation-guided ablation to routine pulmonary vein isolation for rhythm control of AF are currently ongoing (ClinicalTrials.gov NCT04101539), and cardiomyocyte models are extensively used for cardiac safety screening in the 'Comprehensive In Vitro Proarrhythmia Assay' initiative developed by the Food and Drug Administration and pharmaceutical industry (Heijman et al., 2021). However, the models available to date usually do not incorporate precise Ca2+-handling abnormalities. In this issue of The Journal of Physiology, two back-to-back papers (Zhang, Ni et al., 2022; Zhang, Smith et al., 2022) provide a novel state-of-the-art three-dimensional human atrial cardiomyocyte model that can reproduce a wide range of Ca2+-handling features at the (sub)cellular scale. The model underscores the importance of subcellular structural remodelling of atrial cardiomyocytes for the development of proarrhythmic Ca2+-handling abnormalities, something that is challenging to study experimentally. The authors show that a reduction in the transverse-axial tubule system (TATS), a complex network of cell-membrane invaginations that facilitates the interaction between transmembrane proteins and intracellular Ca2+ sources, promotes both Ca2+ and membrane-voltage instabilities (Zhang, Ni et al., 2022). Moreover, the authors identify a key role for reduced Ca2+ extrusion via the Na+/Ca2+ exchanger when TATS density is reduced. These findings have potentially important translational implications, since pharmacological inhibition of the Na+/Ca2+ exchanger has been proposed as a potential antiarrhythmic therapy, albeit with conceptual concerns and varying degrees of success. The follow-up manuscript (Zhang, Smith et al., 2022) shows that modulating the distribution of Na+/Ca2+ exchanger, ryanodine receptors, and the sarcoplasmic reticulum Ca2+-buffer calsequestrin has varying pro- and antiarrhythmic effects, which are strongly dependent on TATS density (with intermediate levels being most sensitive to variations in the distribution of Ca2+-handling proteins). These data have practical implications for the interpretation of experimental studies on mechanisms underlying AF-associated Ca2+-handling abnormalities. In particular, the results by Zhang, Smith et al. (2022) indicate that even in the absence of changes in total expression level or phosphorylation status assessed by western blot, an altered distribution of Ca2+-handling proteins may have proarrhythmic consequences. This key finding might also explain some of the controversies related to the potential role of abnormal Ca2+ signalling for atrial arrhythmogenesis between different studies (Dobrev & Wehrens, 2017). There is a clear need for additional studies to clarify the mechanisms targeting individual Ca2+-handling proteins to specific subcellular locations as a basis for future therapeutic strategies. Although these computational models provide important insight into potential mechanisms of AF, models are only as good as the data that they are based on. Experimental data on subcellular structure and Ca2+ handling in human atrial cardiomyocytes remain limited. In addition, enzymatically dissociated human atrial cardiomyocytes, which are subjected to patch-clamp and Ca2+ imaging to study membrane potential, ion currents and Ca2+ fluxes, are typically devoid of TATS. Furthermore, cardiomyocytes are available only from certain anatomical regions (often the right-atrial appendage) and from patients undergoing cardiac surgery, who have multiple comorbidities, which potentially limits the translation to the general AF population. Thus, significant experimental challenges will need to be overcome before human-specific computational models can be developed and exploited to inform on disease mechanisms in patients (Nattel et al., 2021). Moreover, while cellular proarrhythmic mechanisms are highly relevant, cardiac arrhythmias are inherently organ-level phenomena. The clinical impact of ectopic activity-promoting Ca2+-handling abnormalities remains elusive and can at present not be directly evaluated in patients due to a lack of approved drugs specifically targeting individual Ca2+-handling abnormalities (Dobrev & Wehrens, 2017). Recent work revealed no significant difference in AF inducibility between (R)-propafenone, which inhibits the cardiac ryanodine receptor, and (S)-propafenone, which does not, in patients scheduled for AF ablation (Shoemaker et al., 2022). However, interpretation of these findings is challenging given the Na+-channel- and β-adrenoceptor-blocking effects of propafenone. Computer models, in theory, could provide a unique opportunity to systematically evaluate the translational implications of (sub)cellular Ca2+-handling abnormalities. However, the detailed cardiomyocyte models presented by Zhang et al. (Zhang, Ni et al., 2022; Zhang, Smith et al., 2022), which include stochastic gating of key ion channels and simulation of local Ca2+ concentrations at a micrometre resolution, are too computationally demanding to be integrated in organ-level simulations. However, recent work has proposed innovative approaches to phenomenologically reproduce the electrophysiological consequences of subcellular Ca2+-handling abnormalities in multiscale models (Colman, 2019), opening up new translational opportunities. In conclusion, the studies by Zhang et al. provide an important advance in the simulation of atrial cardiomyocyte Ca2+ handling. Their model underscores the importance of subcellular structural remodelling of atrial cardiomyocytes for the development of proarrhythmic Ca2+-handling abnormalities, something that is challenging to study experimentally. While the mechanistic insights from this model are at present primarily focused at the (sub)cellular level, several translational implications are evident and the model is expected to foster future studies assessing the translational and clinical importance of cardiomyocyte Ca2+-handling abnormalities in AF. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The authors' work is supported by the Netherlands Organization for Scientific Research (NWO/ZonMW Vidi 09150171910029 to J.H.), the National Institutes of Health (R01HL136389, R01HL131517, R01HL089598 and R01HL163277 to D.D.), and the European Union (large-scale integrative project MAESTRIA, No. 965286 to D.D.). Open Access funding enabled and organized by Projekt DEAL.

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