Epicardial adipose tissue CD4+ T cells as novel drivers in the development of atrial fibrillation

Abstract

Abstract Background Epicardial adipose tissue (EAT) is now a well-established independent risk factor for all forms of atrial fibrillation (AF). However, the cellular profile and immune mediators within EAT remain poorly defined. Purpose This study sought to define the immunological signature of EAT critical to its role in the development of both persistent AF and de novo post-operative AF (POAF). Methods Adult patients undergoing elective cardiac surgery with no prior AF history and those with pre-existing AF were recruited to undergo EAT sampling alongside subcutaneous adipose tissue (SAT) and pre-operative blood (adipose tissue and systemic controls respectively) sampling. The blood and tissue samples were immediately taken to the laboratory for immune cell isolation, flow cytometry and quantitative polymerase chain reaction (qPCR) analysis. Results A total of 71 patients were recruited including 9 patients with a prior history of AF. Of the 62 a priori sinus rhythm (SR) patients, 42 remained in SR post-operatively and 20 developed de novo POAF. No differences in absolute numbers of immune cells in the blood, EAT or SAT were detected on flow cytometry analysis between the three groups of patients. However, there was a significant increase (p<0.01) in EAT-resident CD4+ memory T cell populations in pre-existing AF patients and a trend towards significance (p=0.09) in POAF patients. qPCR analysis of immune mediator expression in EAT demonstrated pre-existing AF patients uniquely showed a significant reduction (p<0.005) in the pro-fibrotic mediator transforming growth factor-β (TGF-β) compared to the pre-existing AF patients (graph 1). Conclusions and implications Resident CD4+ memory T cell populations are locally and exclusively elevated in the EAT of pre-existing AF and POAF patients. This would suggest primed antigen-specific CD4+ T cells are present prior to the development of AF in patients who go on to develop de novo POAF. The reduced TGF-β levels observed in the EAT of AF patients indicates the EAT immune mediator profile differs to the underlying myocardial tissue, where increased TGF-β levels have previously been described in the persistent AF cohort. Therapies targeting this EAT-resident CD4+ T cell population would provide a novel approach to the management of the inflammatory components of AF genesis. Graph 1 Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Barts Charity, Abbott