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

Aims Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodelling 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 pro-arrhythmic contributions of individual AF-induced alterations. Methods and results 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 signalling 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, signalling 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. Conclusions Our analysis reveals potential mechanisms by which the stress-associated adaptive changes turn into maladaptive pro-arrhythmic 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. [GRAPHICS] A novel integrative human atrial electrophysiology and signalling model reveals synergistic PKA and CaMKII interactions promoting delayed after depolarizations and triggered action potentials in both atrial myocytes and tissues. CaMKII, Ca2+/CaM-dependent protein kinase II; Cx, connexin; I-K1, inward rectifier K+ current; I-Na, fast Na+ current; I-CaL, L-type Ca2+ current; NCX, Na+/Ca2+ exchanger; NKA, Na+/K+ ATPase; PLB, phospholamban; PLM, phospholemman; RyR, ryanodine receptor 2; SERCA, sarco/endoplasmic reticulum Ca2+ ATPase; beta AR, beta adrenergic receptor; PKA, protein kinase A.