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.

Background— Sustained bradycardia is associated with long-QT syndrome in human beings and causes spontaneous torsades de pointes in rabbits with chronic atrioventricular block (CAVB), at least partly by downregulating delayed-rectifier K⁺-current to cause action potential (AP) prolongation. We addressed the importance of altered Ca²⁺ handling, studying underlying mechanisms and consequences.

Methods and Results— We measured ventricular cardiomyocyte [Ca²⁺]_i (Indo1-AM), L-type Ca²⁺-current (I_CaL) and APs (whole-cell perforated-patch), and Ca²⁺-handling protein expression (immunoblot). CAVB increased AP duration, cell shortening, systolic [Ca²⁺]_i transients, and caffeine-induced [Ca²⁺]_i release, and CAVB cells showed spontaneous early afterdepolarizations (EADs). I_CaL density was unaffected by CAVB, but inactivation was shifted to more positive voltages, increasing the activation-inactivation overlap zone for I_CaL window current. Ca²⁺-calmodulin–dependent protein kinase-II (CaMKII) autophosphorylation was enhanced in CAVB, indicating CaMKII activation. CAVB also enhanced CaMKII-dependent phospholamban-phosphorylation and accelerated [Ca²⁺]_i-transient decay, consistent with phosphorylation-induced reductions in phospholamban inhibition of sarcoplasmic reticulum (SR) Ca²⁺-ATPase as a contributor to enhanced SR Ca²⁺ loading. The CaMKII-inhibitor KN93 reversed CAVB-induced changes in caffeine-releasable [Ca²⁺]_i and I_CaL inactivation voltage and suppressed CAVB-induced EADs. Similarly, the calmodulin inhibitor W7 suppressed CAVB-induced I_CaL inactivation voltage shifts and EADs, and a specific CaMKII inhibitory peptide prevented I_CaL inactivation voltage shifts. The SR Ca²⁺-uptake inhibitor thapsigargin and the SR Ca²⁺ release inhibitor ryanodine also suppressed CAVB-induced EADs, consistent with an important role for SR Ca²⁺ loading and release in arrhythmogenesis. AP-duration changes reached a maximum after 1 week of bradypacing, but peak alterations in CaMKII and [Ca²⁺]_i required 2 weeks, paralleling the EAD time course.

Conclusions— CAVB-induced remodeling enhances [Ca²⁺]_i load and activates the Ca²⁺-calmodulin-CaMKII system, producing [Ca²⁺]_i-handling abnormalities that contribute importantly to CAVB-induced arrhythmogenic afterdepolarizations.