Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels

BACKGROUND Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. OBJECTIVE To test the ability of relaxin to reverse age-dependent atrial fibrosis and suppress AF. METHODS Aged F-344 rats (24 months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2 weeks. Rat hearts were excised, perfused on a Langendorff apparatus, and stained with voltage and Cat} indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na+ current density (I-Na) were measured by tissue immunofluorescence and whole-cell patch damp technique. RESULTS In aged rats, sustained AF was readily induced with a premature pulse (n = 7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n = 1/6) (P < .01). Relaxin significantly increased atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin treatment increased Nav1.5 expression (n = 6; 36% +/- 10%) and decreased total collagen and collagen I (n = 5-6; 55%-6% +/- 15%) in aged atria (P < .05) and decreased collagen I and III and TGF-beta 1 mRNA (P < .05). Voltage-damp experiments demonstrated that relaxin treatment (100 nM for 2 days) increased atrial I-Na by 46% +/- 4% (n = 12-13/group, P < .02). CONCLUSION Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing INa. These data provide compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents.