Examining The Role Of Lysyl Oxidase Enzymes In Atrial Fibrillation Induced By Volume Overload

Atrial fibrillation (AF), the most prevalent cardiac arrhythmia, is linked to atrial electrical and structural remodelling. AF is associated with fibrosis; however, in models imposing atrial stretch, this occurs without changes in collagen transcription, suggesting fibrosis results from collagen stabilization by the Lysyl Oxidases (LOX) family of enzymes.

To investigate this relationship, we established a murine aortic regurgitation (AR) model, which induces atrial stretch.

AR mice exhibited increased AF susceptibility, decreased atrial refractoriness (AERP), elevated left atria (LA) fibrosis, and macrophage infiltration 2-fold compared to sham mice. LOXL2 inhibitor PXS-5382 reduced AF inducibility, shortened AF duration and attenuated fibrosis without affecting AERP. In contrast, the broader LOX inhibitor PXS-5505 prevented fibrosis without reducing AF inducibility in AR mice but exacerbated AF and fibrosis in sham mice.

These results highlight LOXL2's critical role in atrial structural remodelling and AR-induced AF, suggesting it may be a promising therapeutic target for AF.