RELAXIN, A POTENTIAL THERAPY FOR ATRIAL FIBRILLATION
Guy Salama, Ph.D., University of Pittsburgh, Pittsburgh, PA, USA
Relaxin, a hormone of reproduction and has been identified as an insulin-like peptide with pleiotropic actions throughout the body including important cardiovascular actions. We recently demonstrated that Relaxin suppresses atrial fibrillation (AF) in spontaneously hypertensive rat (SHR) hearts by remodeling the extracellular matrix, modulating cardiac ion channels and reducing cell hypertrophy. Here, we test the potential therapeutic effects of Relaxin in a geriatric model of AF based on old rats (F-344, 24-months). Rats were implanted with osmotic mini-pumps (Alzet) to deliver Relaxin for 2-weeks (0.4 mg/kg/day) or to deliver the vehicle as controls. Heart rate, blood pressure and serum relaxin were measured at the onset and at the end of the 2-weeks treatment. Hearts were perfused in a Langendorff apparatus to optically map action potentials and Ca2+ transients, conduction velocity (CV), restitution kinetics, programmed stimulation (10-S1-S1 impulses at 300 ms CL, decreasing S1-S2 intervals) was applied to assess AF susceptibility, then atrial tissues were prepared for analysis by immuno-cytochemistry and RT-PCR. In control hearts, sustained AF was readily elicited (n=7/8) whereas AF was suppressed in relaxin treated rats (n=0/8). Relaxin increased CV by ~2-fold, reversed fibrosis and cellular hypertrophy. Consistent with these cardiac effects, collagen (I&III) deposition was reduced as well as transcripts of fibrosis (TGF-beta, collagen I and III, metalloproteinase 1 and 9) and upregulated voltage-gated Na+ channels Nav1.5 protein by 1.8 fold compared to untreated old-rats. In whole cell voltage-clamp experiments, atrial myocytes incubated with 100 nM relaxin for 24-48 hours had a 2-fold increase in current density compared to myocytes incubated with vehicle. These results may explain the clinical trial results of greater survival (37%) of patients with acute heart failure whom received relaxin (2-days,i.v.) and suggest that Relaxin may be a transformative therapy for AF.