Abstract
Introduction: The genesis of atrial fibrillation (AF) and success of AF ablation therapy have been strongly linked with atrial fibrosis. Increasing evidence suggests that patient-specific distributions of fibrosis may determine the locations of electrical drivers (rotors) sustaining AF, but the underlying mechanisms are incompletely understood. This study aims to elucidate a missing mechanistic link between patient-specific fibrosis distributions and AF drivers.Methods: 3D atrial models integrated human atrial geometry, rule-based fiber orientation, region-specific electrophysiology, and AF-induced ionic remodeling. A novel detailed model for an atrial fibroblast was developed, and effects of myocyte-fibroblast (M-F) coupling were explored at single-cell, 1D tissue and 3D atria levels. Left atrial LGE MRI datasets from 3 chronic AF patients were segmented to provide the patient-specific distributions of fibrosis. The data was non-linearly registered and mapped to the 3D atria model. Six distinctive fibrosis levels (0–healthy tissue, 5–dense fibrosis) were identified based on LGE MRI intensity and modeled as progressively increasing M-F coupling and decreasing atrial tissue coupling. Uniform 3D atrial model with diffuse (level 2) fibrosis was considered for comparison.Results: In single cells and tissue, the largest effect of atrial M-F coupling was on the myocyte resting membrane potential, leading to partial inactivation of sodium current and reduction of conduction velocity (CV). In the 3D atria, further to the M-F coupling, effects of fibrosis on tissue coupling greatly reduce atrial CV. AF was initiated by fast pacing in each 3D model with either uniform or patient-specific fibrosis. High variation in fibrosis distributions between the models resulted in varying complexity of AF, with several drivers emerging. In the diffuse fibrosis models, waves randomly meandered through the atria, whereas in each the patient-specific models, rotors stabilized in fibrotic regions. The rotors propagated slowly around the border zones of patchy fibrosis (levels 3–4), failing to spread into inner areas of dense fibrosis.Conclusion: Rotors stabilize in the border zones of patchy fibrosis in 3D atria, where slow conduction enable the development of circuits within relatively small regions. Our results can provide a mechanistic explanation for the clinical efficacy of ablation around fibrotic regions.
Highlights
The genesis of atrial fibrillation (AF) and success of Atrial fibrillation (AF) ablation therapy have been strongly linked with atrial fibrosis
After fitting the ionic currents to experimental data, the resting membrane potential (RMP) in the resulting model for a single atrial fibroblast was −42.5 mV, which was in excellent agreement with the respective experimental value of −42.8 mV recorded from atrial fibroblasts (Wu et al, 2014)
This value is more positive than the RMP of −48 mV in MacCannell et al (2007) ventricular fibroblast model, both are within the experimental data range (Table 1)
Summary
The genesis of atrial fibrillation (AF) and success of AF ablation therapy have been strongly linked with atrial fibrosis. Precise driver locations in a patient are generally unknown, and the longterm success rates of empirical ablation procedures (such as the pulmonary vein isolation) are low, with the disease recurring in 30–50% of patients (Schotten et al, 2011; Calkins et al, 2012). Both the genesis of AF and success of ablation therapy have been strongly linked with atrial fibrosis (Marrouche et al, 2014; Gal and Marrouche, 2015; Kottkamp et al, 2015). Such border heterogeneities can be presented as large collagen deposits within the functional myocardium, which can slow down or block the propagation of electrical excitation waves, creating conditions for the generation and sustenance of re-entrant drivers (rotors)
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