Integrative human atrial modeling unravels interactive PKA and CaMKII signaling as key determinant of atrial arrhythmogenesis

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 Ca 2+ -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 Ca 2+ -handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signaling pathways (i.e., protein kinase A, PKA, and Ca 2+/ 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-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis. Our analysis positions CaMKII as a key nodal master switch of the adaptive changes and the maladaptive proarrhythmic triggers at the cellular and tissue levels and establishes CaMKII inhibition as potential anti-AF strategy. 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. Significance statement Despite significant advancement in our understanding of pathological mechanisms and alterations underlying atrial fibrillation (AF), a highly prevalent clinical arrhythmia causing substantial health and socioeconomic burden, development of effective pharmacological therapeutics for AF remains an urgent unmet clinical need. We built a systems framework integrating key processes and their regulatory upstream signaling pathways that are involved in atrial electrophysiology and modified by AF. By simulating populations of single atrial cardiomyocyte models and heterogeneous tissues, our analysis demonstrated synergistic interactions between upstream signaling pathways that promote atrial arrhythmogenesis across spatial scales, added new insight into complex atrial arrhythmia mechanisms, and revealed adaptive and maladaptive alterations caused by AF, thus providing a powerful new tool for identifying innovative therapeutic approaches against AF.