Diffuse functional and structural abnormalities in fibrosis: Potential structural basis for sustaining atrial fibrillation

Abstract

Background: Structural remodeling has been associated with increased incidence of atrial fibrillation, but how fibrotic regions allow atrial fibrillation to be sustained remains unclear.

Objective: With a novel transgenic goat model, we evaluated structural and functional differences between structurally remodeled and healthy regions of the atria.

Methods: A novel transgenic goat model with cardiac-specific overexpression of transforming growth factor β1 was used. Ex vivo cardiac magnetic resonance imaging and histology were used to evaluate differences in fibrosis, fiber disarray, and structural anisotropy. Functional analysis examined conduction speeds and direction heterogeneity. By use of underlying fiber orientation obtained with diffusion tensor imaging, conduction anisotropy was calculated.

Results: The transgenic goats had on average 21% of the left atria labeled fibrotic, determined from ex vivo cardiac magnetic resonance imaging. The histology samples within the labeled fibrotic regions showed an increase in fibrosis percentage. Fractional anisotropy, a measurement of structural anisotropy, was lower, whereas fiber direction heterogeneity, a measurement of the angle difference of the fiber from its neighbors, was greater, indicating increased fiber disarray in fibrotic regions. The fibrotic regions had slower conduction speeds and more aligned conduction directions, potentially allowing unidirectional conduction block to develop. Conduction anisotropy, measured on the underlying fiber directions, was found to be lower in the fibrotic regions.

Conclusion: Fibrotic regions had slower conduction, and propagation tended to flow more unidirectionally. The direction of propagation differs from the underlying fiber direction, leading to lower conduction anisotropy. Functional and structural abnormalities of the fibrotic tissue may allow fibrotic regions to serve as a substrate for an arrhythmia to develop and to be sustained.

Keywords: Anisotropy; Atrial fibrillation; Conduction velocity; Fiber; Fibrosis; Heterogeneity; Structural remodeling.