期刊
CIRCULATION RESEARCH
卷 105, 期 12, 页码 1213-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.108.183400
关键词
atrial fibrillation; heart failure; fibrosis; gap junction; connexin
资金
- Canadian Institutes of Health Research (CIHR) [MGP 6957]
- Quebec Heart and Stroke Foundation
- Fondation Leducq (European-North American Atrial Fibrillation Research Alliance, ENAFRA) [07/CVD/03]
- Mathematics of Information Technology and Complex Systems (MITACS)
- Fonds de Recherche en Sante du Quebec
- Heart and Stroke Foundation of Canada
- Heart Foundation/The Japanese Society of Electrocardiology
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. (Circ Res. 2009; 105: 1213-1222.)
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