The ideal environment for the development of postcardiac surgery atrial fibrillation: evidence for endothelial activation and poor cell-cell interaction
Authors: Lopez-Galvez R , Rivera-Caravaca J M , Mandaglio-Collados D , Martinez C M , Carpes M , Lahoz A , Hernandez-Romero D , Orenes-Pinero E , Lopez-Garcia C , Roldan V , Arribas J M , Canovas S , Lip G Y H , Marin F 
Published: October 2022

Abstract

Introduction
The development of post-operative atrial fibrillation (POAF) after cardiac surgeryis associated with pre-existing endothelial activation and systemic inflammation due to adhesion and transmigration of leukocytes into the interstitium. The electrical remodelling associated with AF causes changes in connexins, resulting in ineffective electrical coupling between cells and thus ineffective cell-cell communication.There is also an association between the inflammatory state, and the presence of cardiac fibrosis, oxidative stress and myocyte apoptosis.

Purpose
Our aim was to investigate the pathophysiologicaland regulatory mechanisms of AF through endothelial activation and inflammatory status, as well as cell-cell interactions (connexins) in relation to POAF amongst a cohort of patients undergoing cardiac surgery.

Methods
We studied prospective patients who underwent CABG (52.9%) or cardiac valve (47.1%) surgery without previous documented AF. Patients with permanent AF who underwent CABG or cardiac valve surgery were also included as positive controls. Plasma samples were collected at baseline and 24 hours after surgery, to assess the impact of surgery. To detect endothelial activation, vascular cell adhesion protein-1 (VCAM-1 (CD106)) was evaluated by ELISA assay in plasma samples. Expression of connexin 40 and 43 were measured by inmunohistochemistry in atrial tissue samples.

Results
We included 117 patients (75.2% males, median age 67 [IQR 59.5–73.0] years), of whom17 (14.5%) patients had permanent AF; 27 (23.1%) developed POAF and 73 (62.4%) had no AF detected.
We found higher baseline VCAM-1 levels versus 24-hour samples overall (p=0.001). When comparing groups, baseline VCAM-1 levels were higher in patients with permanent AF compared to non-AF (p=0.035); and in permanent AF compared to POAF (p=0.049). VCAM-1 levels at 24h followed the same trends between permanent AF and non-AF (p=0.001), and permanent AF versus POAF (p=0.013) (Table 1). VCAM-1 levels over the third tertile (i.e.&gt;49.77 ng/ml) increased the risk of AF almost 3-fold (OR 2.85, 95% CI 1.06–7.70; p=0.039). There was a significant decrease in the expression of connexion 40 in patients with AF (ie. patients with permanent AF or POAF) compared to non-AF patients (1.00 [0.50–2.31] vs. 2.48 [1.94–3.00], p=0.044), while connexin 43 was non-significantly different (1.07 [0.41–1.75] vs. 2.00 [0.63–2.25], p=0.289) (Table 2).

Conclusions
VCAM-1 levels were upregulated in patients with permanent AF and POAF compared to patients without AF, and remained higher even after surgery, thus demonstrating a relevantendothelial activation. The pro-inflammatory state presented in these patients with AF, along with decreased connexin 40 expression impacting cell-to-cell conduction, suggests a potential combination for atrial remodelling and incident AF.

Funding Acknowledgement
Type of funding sources: None.