Document Detail

Altered connexin43 expression produces arrhythmia substrate in heart failure.
MedLine Citation:
PMID:  15205174     Owner:  NLM     Status:  MEDLINE    
Recently, we found that repolarization heterogeneities between subepicardial and midmyocardial cells can form a substrate for reentrant ventricular arrhythmias in failing myocardium. We hypothesized that the mechanism responsible for maintaining transmural action potential duration heterogeneities in heart failure is related to intercellular uncoupling from downregulation of cardiac gap junction protein connexin43 (Cx43). With the use of the canine model of pacing-induced heart failure, left ventricles were sectioned to expose the transmural surface (n = 5). To determine whether heterogeneous Cx43 expression influenced electrophysiological function, high-resolution transmural optical mapping of the arterially perfused canine wedge preparation was used to measure conduction velocity (theta(TM)), effective transmural space constant (lambda(TM)), and transmural gradients of action potential duration (APD). Absolute Cx43 expression in failing myocardium, quantified by confocal immunofluorescence, was uniformly reduced (by 40 +/- 3%, P < 0.01) compared with control. Relative Cx43 expression was heterogeneously distributed and lower (by 32 +/- 18%, P < 0.05) in the subepicardium compared with deeper layers. Reduced Cx43 expression in heart failure was associated with significant reductions in intercellular coupling between transmural muscle layers, as evidenced by reduced theta(TM) (by 18.9 +/- 4.9%) and lambda(TM) (by 17.2 +/- 1.4%; P < 0.01) compared with control. Heterogeneous transmural distribution of Cx43 in failing myocardium was associated with lower subepicardial theta(TM) (by 12 +/- 10%) and lambda(TM) (by 13 +/- 7%), compared with deeper transmural layers (P < 0.05). APD dispersion was greatest in failing myocardium, and the largest transmural APD gradients were consistently found in regions exhibiting lowest relative Cx43 expression. These data demonstrate that reduced Cx43 expression produces uncoupling between transmural muscle layers leading to slowed conduction and marked dispersion of repolarization between epicardial and deeper myocardial layers. Therefore, Cx43 expression patterns can potentially contribute to an arrhythmic substrate in failing myocardium.
Steven Poelzing; David S Rosenbaum
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-06-17
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  287     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2004 Oct 
Date Detail:
Created Date:  2004-09-16     Completed Date:  2004-11-09     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1762-70     Citation Subset:  IM    
MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive, Hamman 330, Cleveland, OH 44109-1998, USA.
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MeSH Terms
Action Potentials*
Connexin 43 / metabolism*
Death, Sudden, Cardiac
Electric Conductivity
Gap Junctions / physiology
Heart Failure / metabolism,  physiopathology*
Heart Ventricles / metabolism
Pacemaker, Artificial
Tachycardia, Ventricular / metabolism,  physiopathology*
Grant Support
Reg. No./Substance:
0/Connexin 43

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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