Murine ADAM15 Deficiency Is Associated With Atrial Remodelling and Atrial Arrhythmia Susceptibility

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, with significant associated morbidity and mortality. The pathophysiology underlying AF is complex, and this has limited the development of effective therapies. ADAMs (a disintegrin and metalloproteinase) are transmembrane proteinases with diverse functions involving cell-cell communication and extracellular matrix homeostasis. ADAM15 specifically has been implicated in AF pathogenesis in large-scale genetic association studies. Given the importance of atrial remodelling in AF pathogenesis, we sought to ascertain the effect of ADAM15 deficiency in murine atrial biology.

We performed extensive cardiac phenotyping in Adam15 knockout (Adam15^-/-) mice; wildtype mice were used as controls. These studies included invasive electrophysiology, echocardiography, optical mapping and biochemical assays.

ADAM15 deficiency resulted in increased AF susceptibility without overt abnormalities in cardiac structure or function by echocardiography. These findings were associated with shortened atrial action potential duration, increased atrial fibrosis, increased TGFβ signalling, as well as reduced connexin expression.

Here, we provide evidence that ADAM15 deficiency is associated with increased AF susceptibility and atrial remodelling in mice. Further work will be needed to define the molecular mechanisms underlying these findings and determine their relevance to human AF.