Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis

Abstract

Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodeling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex pathophysiological network, which renders AF resistant to existing pharmacotherapies that predominantly target transmembrane ion channels. Developing innovative therapeutic strategies requires a systems approach to disentangle quantitatively the proarrhythmic contributions of individual AF-induced alterations. Here, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signaling pathways (i.e., protein kinase A, PKA, and Ca2+/calmodulin-dependent protein kinase II, CaMKII) involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signaling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII- and PKA-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis. Our analysis reveals potential mechanisms by which the stress-associated adaptive changes turn into maladaptive proarrhythmic triggers at the cellular and tissue levels and identifies potential anti-AF targets. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches moving beyond the traditional ion channel-based strategy.

Enhanced Ca2+-Driven Arrhythmias in Female Patients with Atrial Fibrillation: Insights from Computational Modeling

“…These results are consistent with our previous study suggesting that reported LTCC reduction by AF is an adaptive mechanism of the atria to limit triggered activity, whereas enhanced RyR2 phosphorylation constitutes a maladaptation that drives the arrhythmia. 28 In this regard, our suite of sex-specific human atrial cardiomyocyte models is unique and instrumental to gain mechanistic insights into the sex-dependent differences in Ca 2+ -driven arrhythmogenesis in human atria, providing a basis to inform putative treatment strategies to correct the deranged Ca 2+ signals, especially for the female atria.…”

“…As previous studies involving animals uncovered sex-dependent differences in upstream signals including cAMP/phosphodiesterase in the ventricles, 64,65 similar differences, if confirmed in the atria, can be readily incorporated into our framework, as established in our atrial signaling model. 28 Third, our current work solely focused on isolated cardiomyocytes. Previous studies associated female atria with greater fibrosis 44,66 as compared to male atria.…”

“…Thus, the increased incidence of Ca 2+ -dependent triggers in female atria as revealed by our study may be exacerbated in tissue through mismatched source-sink relation to trigger spontaneous APs and/or subthreshold delayed afterdepolarizations. The latter could promote tissue dispersion of cell excitability due to heterogeneous availability in fast Na + current due to heterogeneous voltage and Ca 2+ -dependent signaling, 28 thereby causing functional conduction block that promotes reentry. 67 The implications for spontaneous APs and/or subthreshold delayed afterdepolarizations warrant future investigations using sex-specific tissue models of human atria.…”

“…19 Therefore, the correction of Ca 2+ -handling abnormalities has emerged as a promising anti-AF strategy. 19,23,28,29…”