title: Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.
abstract: BACKGROUND
  Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy.
  
  
  RESULTS
  We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage nonischemic cardiomyopathy (heart failure, n=10) and nonfailing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. Heart failure produced heterogeneous prolongation of action potential duration resulting in the decrease of transmural action potential duration dispersion (64 ± 12 ms versus 129 ± 15 ms in NF, P<0.005). In the failing hearts, transmural activation was significantly slowed from the endocardium (39 ± 3 cm/s versus 49 ± 2 cm/s in NF, P=0.008) to the epicardium (28 ± 3 cm/s versus 40 ± 2 cm/s in NF, P=0.008). Conduction slowing was likely due to connexin 43 (Cx43) downregulation, decreased colocalization of Cx43 with N-cadherin (40 ± 2% versus 52 ± 5% in NF, P=0.02), and an altered distribution of phosphorylated Cx43 isoforms by the upregulation of the dephosphorylated Cx43 in both the subendocardium and subepicardium layers. Failing hearts further demonstrated spatially discordant conduction velocity alternans which resulted in nonuniform propagation discontinuities and wave breaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in heart failure 16.4 ± 7.7 versus 9.9 ± 1.4% in NF, P=0.02).
  
  
  CONCLUSIONS
  Conduction disorder resulting from the anisotropic downregulation of Cx43 expression, the reduction of Cx43 phosphorylation, and increased fibrosis is likely to be a critical component of arrhythmogenic substrate in patients with nonischemic cardiomyopathy.
authors.affiliation: Department of Biomedical Engineering, Washington University in St. Louis, MO 63130, USA.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Glukhov
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Fedorov
authors.forename: Paul W
authors.initials: PW
authors.lastname: Kalish
authors.forename: Vinod K
authors.initials: VK
authors.lastname: Ravikumar
authors.forename: Qing
authors.initials: Q
authors.lastname: Lou
authors.forename: Deborah
authors.initials: D
authors.lastname: Janks
authors.forename: Richard B
authors.initials: RB
authors.lastname: Schuessler
authors.forename: Nader
authors.initials: N
authors.lastname: Moazami
authors.forename: Igor R
authors.initials: IR
authors.lastname: Efimov
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D009202:Cardiomyopathies / Q000503:physiopathology*; D018031:Connexin 43 / Q000032:analysis / Q000378:metabolism; D004285:Dogs; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D006801:Humans; D010766:Phosphorylation
chemical_list: D018031:Connexin 43