Calcium Homeostatic Feedback Control Predicts Atrial Fibrillation Initiation, Remodeling, and Progression.

Abstract

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.