Abstract 12890: Relaxin Reverses Profibrotic and Inflammatory Atrial Remodeling in a Human Tachyarrhythmia Model

Introduction: Atrial fibrosis is a critical substrate in the initiation and maintenance of atrial fibrillation (AF). Deposition of atrial collagen has been well documented in patients with AF. The accumulation of collagens results from transcriptional activation of collagens genes in the response to bioactive peptides, cytokines and oxidative stress. The present study addresses the therapeutic potential of relaxin in human atrial tissue. Hypothesis: Relaxin reverses atrial remodeling in tachyarrhythmia. Methods: Right atrial appendages were obtained from 28 patients undergoing heart surgery for coronary artery bypass graft or mitral/aortic valve replacement. Tissue samples were sliced into 350μm and cultivated for up to 24h in the presence of relaxin in the concentration range from 10nM to 1μM (n=15). To resemble AF, the tissue slices were stimulated in the electrical field at 4 Hz (vs.0.6 Hz) up to 24h without and with the presence of 0.1 μM (n=6), or 1 μM (n=7) relaxin. Then, atrial tissue was examined at the transcriptional and protein level. Results: Relaxin diminished the transcriptional expression of molecules associated with atrial fibrosis like: collagen 3 (0.1μM: 0.83±0.06; 1μM: 0.68±0.07; p<0.01), CTGF, TGF-ß1, and TGFßR2. Moreover, relaxin reduced basal expression of inflammatory molecules like ICAM-1 and IL-8. To assess the therapeutic potential of relaxin in tachyarrhythmia, tissue slices were exposed to electrical field. Relaxin prevented the pacing-dependent increase in the expression of collagen3 (0.1μM: 1.2±0.2; 1μM: 1.0±0.2; p<0.05 vs 4Hz: 2.2±0.4) CTGF (0.1μM: 1.1±0.2; 1μM: 1.2±0.2; p<0.05 vs 4Hz: 2.2±0.3), TGF-ß1 (0.1μM: 1.1±0.2; 1μM: 0.9±0.1; p<0.05 vs 4Hz: 2.2±0.4). Similarly effects achieved relaxin on the expression of inflammatory molecules. Of note, relaxin prevented the pacing-dependent activation of NF-κB transcription factor and MAP kinases. However, relaxin did not influence the pacing-induced phosphorylation of SMAD2. Conclusions: Relaxin reverses atrial remodeling in a human tachyarrhythmia model. We demonstrated that relaxin abolishes the expression of pro-fibrotic and pro-inflammatory and prevents via NF-kB inhibition the pacing-dependent pro-fibrotic and pro-inflammatory responses.