| Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy. | |
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MedLine Citation:
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PMID: 15345654 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias. Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain. HF was produced in dogs by rapid RV-pacing for 3 to 4 weeks. High-resolution optical action potentials were recorded from epicardial and endocardial surfaces of arterially perfused canine wedge preparations isolated from LV and RV of normal and failing dogs. Cellular and molecular determinants of conduction were investigated using patch-clamp recordings, Western blot analysis, and immunocytochemistry. HF was associated with marked prolongation (by 33%) of the QRS duration of the volume conducted electrocardiogram and significant (>20%) slowing of epicardial and endocardial conduction velocities (CV) in both LV and RV. Cx43 expression was reduced by >40% in epicardial and endocardial layers of the LV, but was unchanged in the RV of failing hearts. Despite greater epicardial than endocardial Cx43 expression, epicardial CV was consistently slower (P<0.01). Immunocytochemical analysis revealed predominant colocalization of Cx43 with N-cadherin in normal versus failing samples, because Cx43 was redistributed from the intercalated disk to lateral cell borders in failing tissue. Moreover, a significant (P<0.05) increase in hypophosphorylated Cx43 was detected in the LV and RV of failing hearts. Action potential upstroke velocities in isolated ventricular myocytes from normal and failing hearts were not different (P=0.8, not significant), and Masson trichrome staining revealed no significant change in fibrosis content in HF. Nonischemic dilated cardiomyopathy is associated with significant slowing of CV that was not directly related to reduced Cx43 expression. Changes in phosphorylation and localization of Cx43 may contribute to gap-junction dysfunction, CV slowing, and arrhythmias in HF. |
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Authors:
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Fadi G Akar; David D Spragg; Richard S Tunin; David A Kass; Gordon F Tomaselli |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. Date: 2004-09-02 |
Journal Detail:
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Title: Circulation research Volume: 95 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2004 Oct |
Date Detail:
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Created Date: 2004-10-01 Completed Date: 2005-04-25 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 717-25 Citation Subset: IM |
Affiliation:
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Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md 21205, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Action Potentials Animals Arrhythmias, Cardiac / physiopathology* Blotting, Western Cadherins / analysis, physiology Cardiac Pacing, Artificial / adverse effects Cardiomyopathy, Dilated / etiology, physiopathology* Cell Size Connexin 43 / analysis, chemistry, physiology Dogs Fibrosis Gap Junctions / physiology Heart Conduction System / physiopathology* Microscopy, Confocal Microscopy, Fluorescence Myocardium / pathology Myocytes, Cardiac / pathology Neural Conduction Patch-Clamp Techniques Phosphorylation Protein Processing, Post-Translational Subcellular Fractions / chemistry |
| Grant Support | |
ID/Acronym/Agency:
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L30 HL078264-01/HL/NHLBI NIH HHS; P50 HL 52307/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cadherins; 0/Connexin 43 |
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