What does this research mean for the field?

Congestive heart failure-induced atrial conduction disturbances and atrial fibrillation promotion are primarily driven by fibrotic interruption of muscle bundles rather than atrial connexin alterations. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

October 30, 2009Circulation ResearchOpen Access

Changes in Connexin Expression and the Atrial Fibrillation Substrate in Congestive Heart Failure

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Why the study?

Do connexin alterations or fibrosis primarily contribute to the atrial fibrillation substrate during the development and reversal of congestive heart failure in a dog model?

Structured PICO

Do connexin alterations or fibrosis primarily contribute to the atrial fibrillation substrate during the development and reversal of congestive heart failure in a dog model?

Population

Dogs (n=50 total: 15 CHF, 16 CHF recovery, 19 sham controls)

Intervention

Congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), with or without a 4-week nonpaced recovery interval

Comparator

Nonpaced sham controls

Outcome

Atrial connexin (Cx40 and Cx43) expression/distribution, atrial conduction indexes, duration of burst pacing-induced AF (DAF), and atrial fibrous tissue contentsurrogate

In a canine model of CHF, atrial fibrillation promotion and conduction disturbances are primarily driven by structural fibrotic remodeling rather than reversible connexin alterations.

Implication

Fibrosis, not connexin changes, sustains AF after CHF recovery in dogs; hypothesis-generating for antifibrotic AF strategies in patients.

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.