title: Role of suppression of the inward rectifier current in terminal action potential repolarization in the failing heart.
abstract: The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K+current (IK1) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear.
  
  
  
  The purpose of this study was to define the effect of IK1suppression on the cardiac AP and excitability in the normal and failing hearts.
  
  
  
  We used electrophysiological and pharmacological approaches to investigate IK1function in a swine tachy-pacing model of heart failure (HF).
  
  
  
  Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes (P < .001) and 26.2% in HF wedges (P = .014). The increase in TRAP was recapitulated by the potent and specific IK1inhibitor, PA-6 (pentamidine analog 6), indicating that IK1is the primary determinant of the final phase of repolarization. Moreover, we find that IK1suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction.
  
  
  
  Using an objective measure of terminal repolarization, we conclude that IK1is the major determinant of the terminal repolarization time course. Moreover, suppression of IK1prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how IK1suppression may contribute to arrhythmogenesis in the failing heart.
authors.affiliation: Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Electronic address: michael.klein@usuhs.edu.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Klein
authors.affiliation: Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Matie
authors.initials: M
authors.lastname: Shou
authors.affiliation: Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Jayna
authors.initials: J
authors.lastname: Stohlman
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Soroosh
authors.initials: S
authors.lastname: Solhjoo
authors.affiliation: Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Myles
authors.initials: M
authors.lastname: Haigney
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.affiliation: Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Goldstein
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Flagg
authors.affiliation: Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Haigney
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010419:Pentamidine / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism*; D013552:Swine
chemical_list: D015221:Potassium Channels; D010419:Pentamidine
keywords: Andersen syndrome; Arrhythmia; Diastolic variance; Effective refractory period; Inward rectifier; PA-6; Pentamidine