title: Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling.
abstract: OBJECTIVE
  Ventricular arrhythmias are a common cause of death in patients with heart failure (HF). Structural and electrical abnormalities in the heart provide a substrate for such arrhythmias. Canine tachypacing-induced HF models of 4-6 weeks duration are often used to study pathophysiology and therapies for HF. We hypothesized that a chronic canine model of HF would result in greater electrical and structural remodeling than a short term model, leading to a more arrhythmogenic substrate.
  
  
  METHODS
  HF was induced by ventricular tachypacing for one (short-term) or four (chronic) months to study remodeling.
  
  
  RESULTS
  Left ventricular contractility was progressively reduced, while ventricular hypertrophy and interstitial fibrosis were evident at 4 month but not 1 month of HF. Left ventricular myocyte action potentials were prolonged after 4 (p<0.05) but not 1 month of HF. Repolarization instability and early afterdepolarizations were evident only after 4 months of HF (p<0.05), coinciding with a prolonged QTc interval (p<0.05). The transient outward potassium current was reduced in both HF groups (p<0.05). The outward component of the inward rectifier potassium current was reduced only in the 4 month HF group (p<0.05). The delayed rectifier potassium currents were reduced in 4 (p<0.05) but not 1 month of HF. Reactive oxygen species were increased at both 1 and 4 months of HF (p<0.05).
  
  
  CONCLUSIONS
  Reduced Ito, outward IK1, IKs, and IKr in HF contribute to EAD formation. Chronic, but not short term canine HF, results in the altered electrophysiology and repolarization instability characteristic of end-stage human HF.
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
authors.forename: Victor P
authors.initials: VP
authors.lastname: Long
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Bonilla
authors.affiliation: College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Vargas-Pinto
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nishijima
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Sridhar
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: St. Jude Medical, Sylmar, CA, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Mowrey
authors.affiliation: Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wright
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
authors.forename: Murugesan
authors.initials: M
authors.lastname: Velayutham
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
authors.forename: Nam Y
authors.initials: NY
authors.lastname: Lee
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.
authors.forename: Sandor
authors.initials: S
authors.lastname: Györke
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA. Electronic address: carnes.4@osu.edu.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000666:Amphotericin B; D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications*; D017931:DNA Primers / Q000235:genetics; D051668:Delayed Rectifier Potassium Channels / Q000378:metabolism; D004285:Dogs; D004562:Electrocardiography; D004578:Electron Spin Resonance Spectroscopy; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D015151:Immunoblotting; D009200:Myocardial Contraction / Q000502:physiology*; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D017931:DNA Primers; D051668:Delayed Rectifier Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D017382:Reactive Oxygen Species; D000666:Amphotericin B
keywords: Electrophysiology; Fibrosis; Heart failure; Hypertrophy