title: Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts.
abstract: BACKGROUND
  Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy.
  
  
  OBJECTIVE
  To evaluate the efficacy of the antifibrotic hormone relaxin (RLX) in suppressing AF in spontaneously hypertensive rats (SHR).
  
  
  RESULTS
  Normotensive Wistar-Kyoto (WKY) and SHR were treated for 2 weeks with vehicle (WKY+V and SHR+V) or RLX (0.4 mg/kg per day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations, intracellular Ca²⁺ transients, and restitution kinetics, and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV; P<0.01 versus WKY), steeper CV restitution kinetics, greater collagen deposition, higher levels of transcripts for transforming growth factor-β, metalloproteinase-2, metalloproteinase-9, collagen I/III, and reduced connexin 43 phosphorylation (P<0.05 versus WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5) and SHR+V (n=4/4), but not in WKY (n=0/5) and SHR+RLX (n=1/8; P<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV restitution kinetics, reduced action potential duration at 90% recovery to baseline, increased CV (P<0.01), and reversed atrial hypertrophy (P<0.05). Independent of antifibrotic actions, RLX (0.1 µmol/L) increased Na⁺ current density, INa (≈2-fold in 48 hours) in human cardiomyocytes derived from inducible pluripotent stem cells (n=18/18; P<0.01).
  
  
  CONCLUSIONS
  RLX treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and by increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis and hypertrophy and by modulating cardiac ionic currents.
authors.affiliation: Department of Bioengineering, Medicine, University of Pittsburgh Medical Center Heart and Vascular Institute, and Developmental Biology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Parikh
authors.forename: Divyang
authors.initials: D
authors.lastname: Patel
authors.forename: Charles F
authors.initials: CF
authors.lastname: McTiernan
authors.forename: Wenyu
authors.initials: W
authors.lastname: Xiang
authors.forename: Jamie
authors.initials: J
authors.lastname: Haney
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Bo
authors.initials: B
authors.lastname: Lin
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Kaplan
authors.forename: Glenna C L
authors.initials: GC
authors.lastname: Bett
authors.forename: Randall L
authors.initials: RL
authors.lastname: Rasmusson
authors.forename: Sanjeev G
authors.initials: SG
authors.lastname: Shroff
authors.forename: David
authors.initials: D
authors.lastname: Schwartzman
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000503:physiopathology; D005355:Fibrosis / Q000503:physiopathology / Q000517:prevention & control; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006984:Hypertrophy / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012065:Relaxin / Q000502:physiology* / Q000627:therapeutic use*
chemical_list: D011994:Recombinant Proteins; D012065:Relaxin
keywords: INa upregulation; atrial fibrillation; fibrosis; hypertrophy; optical mapping, action potential; relaxin; spontaneously hypertensive rats