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

Aims 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). Right heart disease and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. We hypothesized that right heart disease generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility.Methods and results Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275 g) 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 levels, and CM morphology. Right atrial levels of selected genes and proteins were obtained by qPCR and Western blot, respectively. Pulmonary artery banding induced severe RHD identified by RV and RA hypertrophy. Pulmonary artery banding rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated and hypercontractile. Right atrial CM from PAB animals showed significant augmentation of mRNA and protein levels of pro-inflammatory interleukin (IL)-6 and IL1 beta. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) and junctophilin-2 were decreased in RA CM from PAB compared to sham rats.Conclusions Right heart disease-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF. Graphical abstract Conditions associated with an increased right-sided cardiac pressure-volume overload can lead to right ventricular (RV) and right atrial (RA) dilation and hypertrophy accompanied by tricuspid valve regurgitation. Chronic dilation of RV and RA chambers provokes mechanical stretch of the cardiomyocytes (CM). Stretched RA CM show signs of dysfunctional gap-junctions, including connexin-43, involved in the propagation of the electrical depolarization. Persistent RA CM stretch is an abnormal condition that may promote dysfunctional Ca2+-handling and activate the inflammatory response. It is unclear whether inflammation can also be a cause or a consequence of abnormal Ca2+-handling. However, evidence suggests that sustained CM contractile disturbance and chronic inflammation are promotors of atrial fibrosis. Right atrial fibrosis is a physical barrier provoking conduction slowing and promoting electrical re-entry circuits. Altogether, these phenomena occurring in the RA during right heart disease (RHD) constitute an arrhythmogenic substrate increasing the vulnerability to AF. Red arrows: increased (up) or decrease (down) parameter in RHD. Dashed square: Events occurring in the RA CM during RHD.