Calcium homeostatic feedback control predicts atrial fibrillation initiation, remodeling, and progression

Abstract

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. We hypothesize that calcium homeostatic feedback regulating ion channel expression is a critical mechanistic component of this pathological process. 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. Simulations predict that single cells respond to fast pacing by maintaining intracellular calcium concentrations through dynamic ion channel expression and electrical phenotype changes. In two-dimensional (2D) homogeneous tissue, spontaneous spiral waves stabilize into permanent re-entry. In 2D 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. Thus, the model joins multiple lines of inquiry (i.e., long-term calcium regulation, ion channel co-expression 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.