RATIONALE: 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). METHODS AND 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.
RATIONALE: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensivepatients 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 hypertensiverats (SHR). METHODS AND 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: Valentin Fuster; Lars E Rydén; David S Cannom; Harry J Crijns; Anne B Curtis; Kenneth A Ellenbogen; Jonathan L Halperin; Jean-Yves Le Heuzey; G Neal Kay; James E Lowe; S Bertil Olsson; Eric N Prystowsky; Juan Luis Tamargo; Samuel Wann; Sidney C Smith; Alice K Jacobs; Cynthia D Adams; Jeffery L Anderson; Elliott M Antman; Jonathan L Halperin; Sharon Ann Hunt; Rick Nishimura; Joseph P Ornato; Richard L Page; Barbara Riegel; Silvia G Priori; Jean-Jacques Blanc; Andrzej Budaj; A John Camm; Veronica Dean; Jaap W Deckers; Catherine Despres; Kenneth Dickstein; John Lekakis; Keith McGregor; Marco Metra; Joao Morais; Ady Osterspey; Juan Luis Tamargo; José Luis Zamorano Journal: Circulation Date: 2006-08-15 Impact factor: 29.690
Authors: Edna D Lekgabe; Helen Kiriazis; Chongxin Zhao; Qi Xu; Xiao Lei Moore; Yidan Su; Ross A D Bathgate; Xiao-Jun Du; Chrishan S Samuel Journal: Hypertension Date: 2005-06-20 Impact factor: 10.190
Authors: Ken W Lee; Thomas H Everett; Dulkon Rahmutula; Jose M Guerra; Emily Wilson; Chunhua Ding; Jeffrey E Olgin Journal: Circulation Date: 2006-10-09 Impact factor: 29.690
Authors: Gordon W Moe; Gabriel Laurent; Liia Doumanovskaia; Andrea Konig; Xudong Hu; Paul Dorian Journal: J Card Fail Date: 2008-08-22 Impact factor: 5.712
Authors: Brian L Henry; Beth Gabris; Qiao Li; Brian Martin; Marianna Giannini; Ashish Parikh; Divyang Patel; Jamie Haney; David S Schwartzman; Sanjeev G Shroff; Guy Salama Journal: Heart Rhythm Date: 2015-12-19 Impact factor: 6.343
Authors: Michelle L Halls; Ross A D Bathgate; Steve W Sutton; Thomas B Dschietzig; Roger J Summers Journal: Pharmacol Rev Date: 2015 Impact factor: 25.468
Authors: Yangyang Bao; B Cicero Willis; Chad R Frasier; Luis F Lopez-Santiago; Xianming Lin; Roberto Ramos-Mondragón; David S Auerbach; Chunling Chen; Zhenxun Wang; Justus Anumonwo; Héctor H Valdivia; Mario Delmar; José Jalife; Lori L Isom Journal: Circ Arrhythm Electrophysiol Date: 2016-12
Authors: A Aragón-Herrera; S Feijóo-Bandín; D Rodríguez-Penas; E Roselló-Lletí; M Portolés; M Rivera; M Bigazzi; D Bani; O Gualillo; J R González-Juanatey; F Lago Journal: Endocrine Date: 2018-02-06 Impact factor: 3.633