title: Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels.
abstract: 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 Ca(2+) 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 (INa) were measured by tissue immunofluorescence and whole-cell patch clamp 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%-66% ± 15%) in aged atria (P < .05) and decreased collagen I and III and TGF-β1 mRNA (P < .05). Voltage-clamp experiments demonstrated that relaxin treatment (100 nM for 2 days) increased atrial INa by 46% ± 4% (n = 12-13/group, P < .02).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Pittsburgh School of Medicine, Heart and Vascular Institute, Pittsburgh, Pennsylvania.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Henry
authors.affiliation: University of Pittsburgh School of Medicine, Heart and Vascular Institute, Pittsburgh, Pennsylvania.
authors.forename: Beth
authors.initials: B
authors.lastname: Gabris
authors.affiliation: University of Pittsburgh School of Medicine, Heart and Vascular Institute, Pittsburgh, Pennsylvania.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.affiliation: University of Pittsburgh Department of Bioengineering, and the McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania.
authors.forename: Brian
authors.initials: B
authors.lastname: Martin
authors.affiliation: University of Pittsburgh School of Medicine, Heart and Vascular Institute, Pittsburgh, Pennsylvania.
authors.forename: Marianna
authors.initials: M
authors.lastname: Giannini
authors.affiliation: University of Pittsburgh Department of Bioengineering, and the McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania.
authors.forename: Ashish
authors.initials: A
authors.lastname: Parikh
authors.affiliation: University of Pittsburgh School of Medicine, Heart and Vascular Institute, Pittsburgh, Pennsylvania.
authors.forename: Divyang
authors.initials: D
authors.lastname: Patel
authors.affiliation: University of Pittsburgh Department of Bioengineering, and the McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jamie
authors.initials: J
authors.lastname: Haney
authors.affiliation: University of Pittsburgh School of Medicine, Heart and Vascular Institute, Pittsburgh, Pennsylvania.
authors.forename: David S
authors.initials: DS
authors.lastname: Schwartzman
authors.affiliation: University of Pittsburgh Department of Bioengineering, and the McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania.
authors.forename: Sanjeev G
authors.initials: SG
authors.lastname: Shroff
authors.affiliation: University of Pittsburgh School of Medicine, Heart and Vascular Institute, Pittsburgh, Pennsylvania,; University of Pittsburgh Department of Bioengineering, and the McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania. Electronic address: gsalama@pitt.edu.
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology / Q000503:physiopathology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D012065:Relaxin / Q000494:pharmacology*; D015222:Sodium Channels / Q000096:biosynthesis* / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D015222:Sodium Channels; D012065:Relaxin
keywords: Aging; Atrial fibrillation; Fibrosis; Relaxin; Sodium channel