(CCSP079) ROLE OF THE INTERLEUKIN-37 IN PREVENTIN AF-ASSOCIATED INFLAMMATION AND FIBROSIS IN HEART DISEASES

Background: Atrial fibrillation (AF) is the most frequent and clinically important form of cardiac arrhythmia. Conditions such as heart failure, obesity, or pulmonary hypertension (PH) promote atrial arrhythmogenic substrates. Right-heart disease (RHD) characterized by chronic right-sided cardiac structural and functional abnormalities has also been identified as risk factor for AF. Atrial remodeling in RHD associated with AF includes structural and functional abnormalities in cardiac fibroblasts (FBs). The inflammation involving the NLRP3-IL18-IL1b-IL6 pathway in RHD affects atrial FBs and play an important role in the appearance of AF. No study has evaluated the role of interleukin-(IL)-37, an inhibitor of IL18, in the prevention of inflammation and AF in RHD, so this study aims to understand the cellular mechanisms of atrial inflammation and fibrosis.

METHODS AND RESULTS: RHD was induced in male Wistar rats (225-275g), using pulmonary artery banding (PAB) surgery, and control rats received (SHAM) surgery. After 3 weeks, PAB rats developed severe increase in pulmonary arterial pressure accompanied by hypertrophy and dilation of the right ventricle and right atrium. The FBs were freshly isolated and cultured for 48 hours under 5 specific treatment conditions: a) Normal medium, b) Pro-inflammatory supplementation with IL6, c) Anti-inflammatory supplementation with IL-37, d) Inhibition of inflammatory pathways using Tocilizumab (anti-IL6R),e) Inhibition of specific anti-inflammatory pathways using an IL18Rα antagonist (anti-IL37).

FB differentiation was assessed by immunostaining of alpha smooth muscle actin (a-SMA), and fibroblast activation protein alpha (FAP-a). The FBs were trypsinized and the expression levels of fibrosis-related molecules (trasforming growth factor beta [TGFβ], collagen [COL] 1a1, COL3a1), inflammatory markers (NLRP3 inflammasome, interleukin [IL]-6, IL-1β) and anti-inflammatory markers (IL-10) were evaluated by qPCR (genes) and western blot (proteins).

Three weeks after surgery, PAB rats developed right heart enlargement and dilation associated with inflammation and right atrial fibrosis. Compared to sham, FB from RHD rats expressed more markers of inflammation and fibrosis and this overexpression was exacerbated in the presence of IL-6, and normalized in the presence of IL-37.

Conclusion: At the level of isolated FB, treatment with IL37 seems to be an effective strategy to prevent atrial inflammation associated with RHD.