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

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.

microRNAs as biomarkers of risk of major adverse cardiovascular events in atrial fibrillation

“…In this context, the main cause of stroke in the general population has been described to be the embolization of the thrombus typically formed in the left atrial appendage in the context of AF ( 60 ). The relationship between AF, EVs, miRNAs, and the risk of stroke has recently been tested by Zietzer et al ( 61 ). These authors characterized cell-derived EVs (endothelial cells, platelets, and erythrocytes) isolated from the left atrial appendage of patients with permanent AF, non-permanent AF, and no history of AF.…”

“…non-permanent AF. Based on in vitro experiments, these authors suggested that, in a state of platelet activation, platelet-derived EVs loaded with miR-223 transfer this miRNA to endothelial cells, thereby reducing endothelial healing ( 61 ), a key process to control thrombosis ( 62 ). These data therefore suggest for the first time a role for EVs loaded with miRNAs as a thrombogenic mechanism in AF.…”

Extracellular Vesicles in Atrial Fibrillation—State of the Art

“…Zietzer et al proved that patients suffering from AF had higher levels of large EVs derived from platelets in the left atrial appendage than patients with no AF. Moreover, patients with permanent AF presented higher levels of these EVs when compared with non-permanent AF patients [ 61 ]. All studies discussed in this subsection with additional data are summarized in Table 4 .…”

A microfluidic model to study the effects of arrhythmic flows on endothelial cells

“…Atrial fibrilation (AF) is the most common type of cardiac arrhythmias, which is characterised by irregular rhythm and can result in a reduction of cardiac output and may lead to thrombus formation and consequently to potentially fatal strokes. 1 Risk factors of AF include heart failure, obesity, diabetes, hypertension, and aging. Development of AF has been correlated with increased arterial stiffness and is more prevalent in aging adults.…”