Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease

Abstract

Context Right heart disease (RHD), characterized by right ventricular (RV) and atrial (RA) hypertrophy, and cardiomyocytes’ (CM) dysfunctions have been described to be associated with the incidence of atrial fibrillation (AF). RHD and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. Hypotheses RHD generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility. Methods Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275g) to provoke an RHD. Twenty-one days (D21) post-surgery, all rats underwent echocardiography and electrophysiological studies (EPS). Optical mapping was performed in situ, on Langendorff-perfused hearts. The contractility of freshly isolated CM was evaluated and recorded during 1 Hz pacing in vitro. Histological analyses were performed on formalin-fixed RA to assess myocardial fibrosis, Connexin-43 (Cx43) levels, and CM morphology. RA levels of selected genes and proteins were obtained by qPCR and Western-blot respectively. Results PAB induced severe RHD identified by RV and RA hypertrophy. PAB rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated, and hypercontractile. RA CM from PAB animals showed significant augmentation of mRNA and protein levels of proinflammatory interleukin (IL)-6 and IL1β. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and junctophilin-2 (JPH2) were decreased in RA CM from PAB compared to sham rats. Conclusions RHD-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF.