Key Words: atrial fibrillation Ⅲ heart failure Ⅲ fibrosis Ⅲ gap junction Ⅲ connexin C ongestive heart failure (CHF) predisposes to atrial fibrillation (AF), although the underlying mechanisms remain incompletely understood. 1 Ventricular tachypacing produces a clinically relevant animal model of CHF. 2 The atria of dogs with ventricular tachypacing-induced CHF are characterized by structural remodeling, conduction abnormalities and the ability to sustain AF. 3 Myocardial electric continuity is assured by gap junctions, cell-to-cell connections that maintain low-resistance intercellular coupling via specialized hemichannel subunit proteins called connexins. Connexin (Cx)43 and Cx40 are the principle atrial gap junctional subunits 4 ; abnormalities in their expression and localization are commonly observed in patients and experimental animals with AF. 5 Phosphorylation of Cx43 can regulate channel assembly, 6 degradation, 7 and conductance. 8 In the ventricles, CHF produces hypophosphorylation of Cx43 and redistribution to lateral cell membranes, associated with proarrhythmic conduction slowing. 9,10 Little is known, however, about connexin changes during CHF-related atrial remodeling and their role in AF maintenance. The present study was designed to assess the changes in atrial connexin expression caused by tachypacing-induced CHF in the dog.In initial experiments, we noted significant changes in connexin phosphorylation and sought to understand their role in AF. We previously noted that the cessation of ventricular tachypacing, which is followed by the reversal of CHF, dissociates atrial size and function changes from structural remodeling and AF sustainability. 11,12 Both structural (particularly tissue fibrosis) and connexin remodeling could contribute to CHF-associated AF. We therefore exploited CHF reversal to assess the reversibility of atrial connexin alterations and evaluate their contribution to CHF-related conduction disturbances and AF maintenance. MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Animal ModelAnimal-handling procedures followed National Institutes of Health guidelines. Animals were prepared and studied as described previously. 11,12 Forty-nine mongrel dogs (18 to 34 kg) were instrumented with a right ventricular tachypacemaker. Dogs were assigned to 3 groups: (1) pacemaker inactive sham controls (CTL group, nϭ19); (2) 2-week ventricular tachypacing at 240 bpm to induce CHF (CHF group, nϭ15); (3) 2-week ventricular tachypacing followed by 4-week recovery (REC group, nϭ16). Atrial effective refractory period (ERP) was measured with 10 basic (S1) stimuli. ERP was measured at multiple basic cycle lengths (BCLs) in the left atrial (LA) appendage of all dogs and at 7 additional sites (BCL, 300 ms) in 5 dogs per group. AF was induced by burst pacing and mean AF duration estimated based on 10 inductions. AF Ն30 minutes was considered sustained and was cardioverted. Five plastic arrays containing a total of 240 bipolar elect...

Key points• Cardiac repolarization, through which heart-cells return to their resting state after having fired, is a delicate process, susceptible to disruption by common drugs and clinical conditions. • Animal models, particularly the dog, are often used to study repolarization properties and responses to drugs, with the assumption that such findings are relevant to humans. However, little is known about the applicability of findings in animals to man.• Here, we studied the contribution of various ion-currents to cardiac repolarization in canine and human ventricle.• Humans showed much greater repolarization-impairing effects of drugs blocking the rapid delayed-rectifier current I Kr than dogs, because of lower repolarization-reserve contributions from two other important repolarizing currents (the inward-rectifier I K1 and slow delayed-rectifier I Ks ).• Our findings clarify differences in cardiac repolarization-processes among species, highlighting the importance of caution when extrapolating results from animal models to man.Abstract The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used. Selective I Kr block (50-100 nmol l −1 dofetilide) lengthened AP duration at 90% of repolarization (APD 90 ) >3-fold more in human than dog, suggesting smaller repolarization reserve in humans. Selective I K1 block (10 μmol l −1 BaCl 2 ) and I Ks block (1 μmol l −1 HMR-1556) increased APD 90 more in canine than human right ventricular papillary muscle. Ion current measurements in isolated cardiomyocytes showed that I K1 and I Ks densities were 3-and 4.5-fold larger in dogs than humans, respectively. I Kr density and kinetics were similar in human versus dog. I Ca and I to were respectively ∼30% larger and ∼29% smaller in human, and Na + -Ca 2+ exchange current was comparable. Cardiac mRNA levels for the main I K1 ion channel subunit Kir2.1 and the I Ks accessory subunit minK were significantly lower, but mRNA expression of ERG and KvLQT1 (I Kr and I Ks α-subunits) were not significantly different, in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein expression in human versus canine cardiomyocytes. I K1 and I Ks inhibition increased the APD-prolonging effect of I Kr block more in dog (by 56% and 49%, respectively) than human (34 and 16%), indicating that both currents contribute to increased repolarization reserve in the dog. A mathematical model incorporating observed human-canine ion current differences confirmed the role of I K1 and I Ks in repolarization reserve differences. Thus, humans show greater repolarization-delaying effects of I Kr block than dogs, because of lower repolarization reserve contributions from I K1 and I Ks , emphasizing species-specific determinants of repolarization and the limitations of animal models fo...