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DYSSYNCHRONOUS ACTIVATION IN HETEROZYGOUS CX43 GERMLINE KNOCKOUT MICE INDUCES STEADY-STATE POTASSIUM CURRENT REMODELLING AND SUSTAINED DYSSYNCHRONY
A. Kontogeorgis1, R. A. Kaba1, X. Li2, A. L. Wit3, G. E. Morley2, N. S. Peters1, D. E. Gutstein2. 1Imperial College St Mary’s NHS Trust, London, UK, 2New York University School of Medicine, New York, USA, 3Columbia University College of Physicians and Surgeons, New York, USA
Right ventricular pacing induces dyssynchronous cardiac activation, an independent predictor of worsened outcomes, in patients with reduced systolic function. Dyssynchrony is associated with gap junction remodelling, a downregulation of connexin (Cx)43 expression and regional distribution. Gap junction remodelling is strongly associated with arrhythmias. We hypothesised that dyssynchronous activation in a mouse heart expressing 50% less Cx43 (with otherwise normal function) would result in aberrant cardiac performance and electrophysiology compared with wild-type (WT) littermates.
Right ventricular epicardial pacing for 6 h at 10% above the average anaesthetised sinus rate was used. We found no significant differences in baseline echocardiographic ventricular function in the WT or Cx43+/− subgroups. Cx43+/− mice at baseline demonstrated significant septal-to-posterior wall motion delay (SPWMD) compared with WT (p<0.01). After pacing or sham-pacing SPWMD in the WT (4.3 ± 0.7 ms and 6.2 ± 0.7 ms, respectively) and in sham-paced Cx43+/− mice (7.2 ± 1.5 ms) as well as other echocardiographic indices were unchanged. However, SPWMD, worsened significantly in paced Cx43+/− hearts (17.7 ± 2.3 ms; p<0.01). Two hours after cessation of pacing, SPWMD remained significantly elevated in the Cx43+/− mice (15.1 ± 0.2 ms; p<0.01) compared with baseline.
We optically mapped isolated Cx43+/− hearts. We found no significant delay in right-to-left epicardial breakthrough patterns during sinus rhythm pre and post-pacing (0.40 ± 0.32 ms and 0.62 ± 0.25 ms, respectively). This suggests that sustained dyssynchrony in Cx43+/− hearts does not result from an alteration …