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Circ Res. 2009 Dec 4;105(12):1213-22. doi: 10.1161/CIRCRESAHA.108.183400. Epub 2009 Oct 29.

Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure.

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  • 1Department of Medicine and Physiology/Institute of Biomedical Engineering, Research Center Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.

Abstract

RATIONALE:

Although connexin changes are important for the ventricular arrhythmic substrate in congestive heart failure (CHF), connexin alterations during CHF-related atrial arrhythmogenic remodeling have received limited attention.

OBJECTIVE:

To analyze connexin changes and their potential contribution to the atrial fibrillation (AF) substrate during the development and reversal of CHF.

METHODS AND RESULTS:

Three groups of dogs were studied: CHF induced by 2-week ventricular tachypacing (240 bpm, n=15); CHF dogs allowed a 4-week nonpaced recovery interval after 2-week tachypacing (n=16); and nonpaced sham controls (n=19). Left ventricular (LV) end-diastolic pressure and atrial refractory periods increased with CHF and normalized on CHF recovery. CHF caused abnormalities in atrial conduction indexes and increased the duration of burst pacing-induced AF (DAF, from 22+/-7 seconds in control to 1100+/-171 seconds, P<0.001). CHF did not significantly alter overall atrial connexin (Cx)40 and Cx43 mRNA and protein expression levels, but produced Cx43 dephosphorylation, increased Cx40/Cx43 protein expression ratio and caused Cx43 redistribution toward transverse cell-boundaries. All of the connexin-alterations reversed on CHF recovery, but CHF-induced conduction abnormalities and increased DAF (884+/-220 seconds, P<0.001 versus control) remained. The atrial fibrous tissue content increased from 3.6+/-0.7% in control to 14.7+/-1.5% and 13.3+/-2.3% in CHF and CHF recovery, respectively (both P<0.01 versus control), with transversely running zones of fibrosis physically separating longitudinally directed muscle bundles. In an ionically based action potential/tissue model, fibrosis was able to account for conduction abnormalities associated with CHF and recovery.

CONCLUSIONS:

CHF causes atrial connexin changes, but these are not essential for CHF-related conduction disturbances and AF promotion, which are rather related primarily to fibrotic interruption of muscle bundle continuity.

PMID:
19875729
[PubMed - indexed for MEDLINE]
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