title: Cellular mechanism of premature ventricular contraction-induced cardiomyopathy.
abstract: BACKGROUND
  Frequent premature ventricular contractions (PVCs) are associated with increased risk of sudden cardiac death and can cause secondary cardiomyopathy.
  
  
  OBJECTIVE
  We sought to determine the mechanism(s) responsible for prolonged refractory period and left ventricular (LV) dysfunction demonstrated in our canine model of PVC-induced cardiomyopathy.
  
  
  METHODS
  Single myocytes were isolated from LV free wall of PVC and control canines and used for patch-clamp recording, intracellular Ca(2+) measurements, and immunocytochemistry/confocal microscopy. LV tissues adjacent to the area of myocyte isolation were used for the immunoblot quantification of protein expression.
  
  
  RESULTS
  In the PVC group, LV ejection fraction decreased from 57.6% ± 1.5% to 30.4% ± 3.1% after ≥4 months of ventricular bigeminy. Compared to control myocytes, PVC myocytes had decreased densities of both outward (transient outward current [Ito] and inward rectifier current [IK1]) and inward (L-type Ca current [ICaL]) currents, but no consistent changes in rapid or slow delayed rectifier currents. The reduction in Ito, IK1, and ICaL was accompanied by decreased protein levels of their channel subunits. The extent of reduction in Ito, IK1, and ICaL varied among PVC myocytes, creating marked heterogeneity in action potential configurations and durations. PVC myocytes showed impaired Ca-induced Ca release from the sarcoplasmic reticulum (SR), without increase in SR Ca leak or decrease in SR Ca store. This was accompanied by a decrease in dyad scaffolding protein, junctophilin-2, and loss of Cav1.2 registry with Ca-releasing channels (ryanodine receptor 2).
  
  
  CONCLUSIONS
  PVCs increase dispersion of action potential configuration/duration, a risk factor for sudden cardiac death, because of the heterogeneous reduction in Ito, IK1, and ICaL. The excitation-contraction coupling is impaired because of the decrease in ICaL and Cav1.2 misalignment with respect to ryanodine receptor 2.
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Eltit
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University; McGuire VA Medical Center.
authors.forename: Karoly
authors.initials: K
authors.lastname: Kaszala
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University; McGuire VA Medical Center.
authors.forename: Alex
authors.initials: A
authors.lastname: Tan
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University. Electronic address: gtseng@vcu.edu.
authors.forename: Gea-Ny
authors.initials: GN
authors.lastname: Tseng
authors.affiliation: Department of Physiology and Biophysics, Virginia Commonwealth University; McGuire VA Medical Center; Pauley Heart Center of Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Huizar
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004285:Dogs; D015151:Immunoblotting; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D032342:Muscle Cells / Q000166:cytology*; D018408:Patch-Clamp Techniques; D018879:Ventricular Premature Complexes / Q000150:complications* / Q000503:physiopathology*
keywords: Cardiomyopathy; Electrical remodeling; Excitation-contraction coupling; Premature ventricular contraction