Date Published: November 29, 2018
Publisher: Public Library of Science
Author(s): Jelena Kornej, Petra Büttner, Elke Hammer, Beatrice Engelmann, Borislav Dinov, Philipp Sommer, Daniela Husser, Gerhard Hindricks, Uwe Völker, Andreas Bollmann, Pablo Garcia de Frutos.
Left atrial (LA) electro-anatomical remodeling and diameter increase in atrial fibrillation (AF) indicates disease progression and is associated with poor therapeutic success. Furthermore, AF leads to a hypercoagulable state, which in turn promotes the development of a substrate for AF and disease progression in the experimental setting. The aim of this study was to identify pathways associated with LA remodeling in AF patients using untargeted proteomics approach.
Peripheral blood samples of 48 patients (62±10 years, 63% males, 59% persistent AF) undergoing AF catheter ablation were collected before ablation. 23 patients with left atrial low voltage areas (LVA), defined as <0.5 mV, and 25 patients without LVA were matched for age, gender and CHA2DS2-VASc score. Untargeted proteome analysis was performed using LC-ESI-Tandem mass spectrometry in a label free intensity based workflow. Significantly different abundant proteins were identified and used for pathway analysis and protein-protein interaction analysis. Analysis covered 280 non-redundant circulating plasma proteins. The presence of LVA correlated with 30 differentially abundant proteins of coagulation and complement cascade (q<0.05). This pilot proteomic study identified plasma protein candidates associated with electro-anatomical remodeling in AF and pointed towards an imbalance in coagulation and complement pathway, tissue remodeling and inflammation.
Atrial fibrillation (AF) is the most common sustained arrhythmia occurring in approximately 2% of the general population . It is a progressive disease as an evolution from paroxysmal to persistent AF (AF type) is frequently observed. This is related to advanced structural and electrical left atrial remodeling. Structural remodeling might be suggested by electrocardiography as increased left atrial diameter (LAD). Evidence for electro-anatomical remodeling is currently detectable only invasively during catheter ablation in up to 20–25% of AF patients  and is represented by low voltage areas (LVA), e.g. pathologically low electrical signals with amplitudes less than 0.5 mV. Previous studies suggested that LVA correspond to areas of fibrotic and electrically silent myocardium . Advanced LA remodeling is associated with worse rhythm outcomes after catheter ablation [2,4,5] and as consequence is associated with higher rates of repeated catheter ablations.
Untargeted proteomic analysis was performed in 48 AF patients matched for age, gender and CHA2DS2-VASc score). The clinical characteristics of study population are presented in Table 1. There were no differences in age, gender, AF type, BMI, renal function or CHA2DS2-VASc score. However, patients with LVA had significantly larger LAD than patients without (p = 0.01).
This study used an untargeted proteomic approach to discover high and medium abundant proteins related to left-atrial remodeling in AF patients. Significant differences in protein profiles in patients with and without LVA were detected. The pathway analysis suggests that alterations in the complement and coagulation cascade, inflammatory processes, and tissue remodeling are associated with LVA and LAD. We therefore assume that the observed alterations are more specific for LVA than for increased left diameter although both phenotypes are interrelated. This is in line with previous findings  and of great clinical importance. However, because of relatively small cohort, proteomic differences in LAD phenotype did not reach significance after FDR.
Several proteins that were discussed typically act inside cells or are bound to them. We interpret this to be indicative for shedding, secretion, endothelial damage (e.g. in consequence of increased atrial sheer stress) or cell death (e.g. fibrosis-related decline of cardiomyocytes). Although, sample processing aimed to limit cell contamination of the plasma used in this study the contamination with cell debris is unlikely, nevertheless, it cannot be excluded.
This pilot proteomic study identified plasma protein candidates associated with electro-anatomical remodeling in AF and pointed towards an involvement of coagulation and complement pathway, inflammation, and tissue remodeling. Further studies are underway to replicate and apply these findings.