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


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.
Burstein
Brett
B
Department of Medicine and Physiology/Institute of Biomedical Engineering, Research Center Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
Comtois
Philippe
P
Michael
Georghia
G
Nishida
Kunihiro
K
Villeneuve
Louis
L
Yeh
Yung-Hsin
YH
Nattel
Stanley
S
D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016275:Atrial Function; D002304:Cardiac Pacing, Artificial; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D022062:Electrophysiologic Techniques, Cardiac; D005355:Fibrosis; D006333:Heart Failure / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D012032:Refractory Period, Electrophysiological; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D000097003:Gap Junction alpha-5 Protein
D018031:Connexin 43; D017630:Connexins; D012333:RNA, Messenger; D000097003:Gap Junction alpha-5 Protein