Breaking down structural remodelling in atrial fibrillation: Towards targeting the arrhythmogenic substrate

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and exerts a growing pressure on healthcare systems. This asks for therapies that target the underlying atrial substrate. Substrate targeted therapies require ample understanding of AF pathophysiology, but despite comprehensive research in the AF field, much remains unknown.
This thesis delineates a framework for atrial structural remodeling in human atrial fibrillation (AF), charting mRNA and miRNA expression changes and morphological changes associated with prevalent or incident AF. Using transcriptome sequencing, we were able to map the complete mRNA expression signature of AF. We discovered epithelial to mesenchymal transition (EMT), endothelial cell proliferation and differentiation, and extracellular matrix (ECM) remodeling among the most significantly upregulated processes in prevalent AF. Alterations in ECM remodeling encompassed not only increased collagen deposits, but also increased expression of glycoprotein and proteoglycan genes and increased interstitial glycosaminoglycan deposits. These transcriptomic changes in AF were largely regulated by miRNAs.
The PREDICT-AF trial associated EMT and ECM remodeling also with incident AF long after cardiothoracic surgery. PREDICT-AF demonstrated that signs of structural remodeling pre-exist before the emerge of AF, and, importantly, are detectable before the first onset of AF in humans.
Altogether, mRNA sequencing, miRNA sequencing and the PREDICT-AF study consistently and independently identified EMT and non-collagen ECM alterations as dominant and early features of the structural remodeling underlying AF.