Thromboinflammatory profiling in atrial cardiopathy
Authors: Claessen A , Krauel K , Pereira L C V , Martinod K , Witsch T ,   FIBRONETx
Published: October 2021

Abstract

Background
Thrombotic cardioemboli originate largely from a diseased left atrium. Disturbed blood flow in atrial cardiopathy is proposed to create a thrombogenic environment and enhance clot formation, even independently of atrial fibrillation. The formation of neutrophil extracellular traps (NETs) has been identified as a crucial mechanism in thrombotic diseases, including cardioembolic thrombus formation. Moreover, emerging evidence suggests that von Willebrand factor (VWF) plays a vital role in NET-mediated pathologies, serving as a bridge between activated endothelium, platelets, and leukocytes. VWF and NETs have also both been shown to be involved in fibrotic remodeling of the heart.

Purpose of the study
The aim of this study is to identify thrombotic markers that correlate with structural abnormalities of the heart. This may provide insight into pathomechanisms that drive detrimental left atrial remodeling as well as clues regarding thromboembolic risks that are rooted in atrial cardiopathy

Methods
Paired blood samples were collected from patients undergoing catheterization with atrial transseptal puncture. We compared blood sampled locally from the left atrium to peripheral blood samples collected prior to the catheterization procedure from the same patients, analyzing them for a wide range of thrombotic markers, including: NETs biomarkers, VWF, ADAMTS13, D-dimers, fibrinogen, as well as indicators of fibrosis like BNP and C-terminal telopeptide of type I collagen (ICTP). In parallel, echocardiographic measurements including left atrium size and ejection fraction of the left ventricle were recorded in order to perform correlation analyses with the biochemical parameters in blood.

Results
A total of 71 patients (age 64,1±14, males 46,5%) were included in the study. Myeloperoxidase (MPO)-DNA complexes and citrullinated histone H3 (H3Cit) levels were significantly elevated in samples drawn from the left atrium compared to peripheral samples, and MPO-DNA levels in the left atrium correlated with left atrial size (Figure 1). H3Cit and PAD4 levels correlated with VWF activity and antigen, in central and peripheral samples. Reduced peripheral ADAMTS13 activity levels correlated with higher values throughout all NET markers, and PAD4, which has been shown to render ADAMTS13 inactive (Figure 2). NETs and PAD4 also correlated with BNP and ICTP, providing potential novel biomarkers for fibrosis development.

Conclusion
Blood drawn from the left atrium shows significantly higher levels of specific (not all) thrombotic markers as compared to blood drawn from peripheral veins, and a relationship between NETs and dysregulation of the VWF-ADAMTS13 axis. These elevations partly correlate with structural changes of the left atrium and, therefore, may point toward a disturbed local blood flow. This may help identify patients at risk for cardioembolic events, even independently of atrial fibrillation.

Funding Acknowledgement
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Area Network - Cardio Vascular Disease (ERA-CVD)Fonds Wetenschapplijk Onderzoek Vlaanderen (FWO)