Key result
Computational models predict spiral wave activity drives substrate remodeling and creates niches supporting fast re-entry.
Why the study?
Although AF is known to be a progressive disorder driven by chaotic electrical activity, the mechanisms underlying this progression are not yet well defined.
A novel computational modeling framework demonstrates that calcium homeostatic feedback and spiral wave activity drive the long-term progression and substrate remodeling in atrial fibrillation.
No immediate clinical implications for atrial fibrillation; leaves open validation of computational remodeling predictions in humans.
BACKGROUND: Atrial fibrillation (AF) is a progressive disorder, with arrhythmia episodes becoming increasingly longer and ultimately permanent. The chaotic electrical activity by itself is well known to drive progression, a process classically summarized as "AF begets AF." However, the mechanisms underlying this progression are not yet well defined. OBJECTIVES: We hypothesize that calcium homeostatic feedback regulating ion channel expression is a critical mechanistic component of this pathological process. METHODS: We propose a modeling framework that tracks both short-term beat-to-beat electrical and calcium activity and long-term tissue substrate remodeling as a single coupled dynamical system. Importantly, the full AF progression from healthy to pathological remodeled tissue is reproduced, in contrast with prior studies that consider "snapshots" of various AF stages. RESULTS: Simulations predict that single cells respond to fast pacing by maintaining intracellular calcium concentrations through dynamic ion channel expression and electrical phenotype changes. In 2-dimensional homogeneous tissue, spontaneous spiral waves stabilize into permanent re-entry. In 2-dimensional heterogeneous tissue, we observe the initiation of re-entrant activity in response to fast pacing, followed by increasingly longer intermittent, and then permanent, arrhythmic activity. Simulations predict critical properties of re-entrant wave locations, leading to a novel hypothesis: spiral wave activity itself drives underlying substrate remodeling and the emergence of remodeled tissue "niches" that support the stabilization of fast re-entrant activity. CONCLUSIONS: Thus, the model joins multiple lines of inquiry (ie, long-term calcium regulation, ion channel coexpression and remodeling, and tissue-scale arrhythmia spatiotemporal organization) into a single coherent framework, and for the first time, captures the dynamics of the long-term natural history of AF.
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Moise et al. (2025) studied Atrial fibrillation. Computational modeling framework was evaluated on Atrial fibrillation initiation, remodeling, and progression. A computational modeling framework predicts that spiral wave activity drives underlying substrate remodeling and the emergence of remodeled tissue niches supporting fast re-entrant activity.
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