Large extracellular vesicles in the left atrial appendage in patients with atrial fibrillation\u2014the missing link?

Andreas Zietzer,Baravan Al-Kassou,Philip Roger Goody,Eva Steffen,Georg Nickenig,Verena Rolfes,Felix Jansen,Jan Wilko Schrickel,Nikos Werner,Bernardo S Franklin,Paul Jamme,Mohammed Rabiul Hosen,Marko Bulic,Alexander Sedaghat,Sebastian Zimmer,Vedat Tiyerili

doi:10.1007/s00392-021-01873-4

Abstract

Atrial fibrillation (AF) is the most frequent arrhythmic disease in humans, which leads to thrombus formation in the left atrial appendage and stroke through peripheral embolization. Depending on their origin, large extracellular vesicles (lEVs) can exert pro-coagulant functions. In the present study, we investigated how different types of AF influence the levels of large EV subtypes in three distinct atrial localizations. Blood samples were collected from the right and left atrium and the left atrial appendage of 58 patients. 49% of the patients had permanent AF, 34% had non-permanent AF, and 17% had no history of AF. Flow cytometric analysis of the origin of the lEVs showed that the proportion of platelet-derived lEVs in the left atrial appendage was significantly higher in permanent AF patients compared to non-permanent AF. When we grouped patients according to their current heart rhythm, we also detected significantly higher levels of platelet-derived lEVs in the left atrial appendage (LAA) in patients with atrial fibrillation. In vitro studies revealed, that platelet activation with lipopolysaccharide (LPS) leads to higher levels of miR-222-3p and miR-223-3p in platelet-derived lEVs. Treatment with lEVs from LPS- or thrombin-activated platelets reduces the migration of endothelial cells in vitro. These results suggest that permanent atrial fibrillation is associated with increased levels of platelet-derived lEVs in the LAA, which are potentially involved in LAA thrombus formation.

Highlights

Atrial fibrillation (AF) is the most frequent arrhythmic cardiac disease in humans and a significant health burden across the world [1, 2]
We show for the first time, that the type of atrial fibrillation present in a patient has an effect on the distribution of large extracellular vesicles (lEVs) subtypes in the left atrial appendage
We found that extracellular vesicles (EVs) from activated platelets exhibit significantly higher levels of miR-222-3p and miR-223-3p and reduce the migratory potential of the endothelial EV-recipient cells

Summary

Introduction

Atrial fibrillation (AF) is the most frequent arrhythmic cardiac disease in humans and a significant health burden across the world [1, 2]. While genetic susceptibility plays a certain role in the development of AF [4, 5], it is primarily the remodeling of the atrial tissue that is both the cause and consequence of further arrhythmic episodes [6]. This inflicts a vicious circle of disease progression which starts with few, usually self-limiting, arrhythmic episodes (paroxysmal AF) but almost inevitably leads to permanent AF, if no treatment is administered [7]. Along with stasis of the blood in the LAA, impaired endothelial function has been shown to

Methods

Results

Conclusion