Abstract 2338: Cardiac Resynchronization Therapy Improves Altered Na channel Gating in Canine Model of Dyssynchronous Heart Failure
Slowed Na current (INa) decay and enhanced late INa (INa-L) prolongs the action potential (AP) and contributes to the high incidence of early after depolarizations (EADs). We have recently reported cardiac resynchronization therapy (CRT) improves dyssynchronous heart failure (DHF)-induced molecular and ion channel remodeling, but the effect of CRT on DHF-induced alterations in Na channel gating is unexplored.
Methods and Results: Adult dogs underwent left-bundle branch ablation and RA pacing (200bpm) for either 6 weeks (DHF) or 3 weeks followed by 3 weeks of resynchronization by bi-V pacing at the same pacing rate (CRT). INa and INa-L were measured in LV myocytes isolated from the non-failing (NF), DHF and CRT dogs using standard patch clamp. DHF shifted voltage dependence of Na channel availability by −4 mV compared to NF, enhanced intermediate inactivation and slowed recovery from inactivation. CRT completely reversed DHF-induced voltage shift of availability and partially reversed enhanced intermediate inactivation and slowed recovery from inactivation. DHF slowed INa decay and markedly increased INa-L compared to NF both in [Na+]o=10 and 140mM bath solution. Moreover, inhibition of INa-L by ranolazine normalized DHF-induced prolongation of APD and increase in EADs. CRT dramatically reduced DHF-induced greater INa-L and abbreviated APD as well as suppressed EADs. Alteration of INa-L in a canine mathematical AP model mimicking DHF and CRT also reproduced the experimental effects of DHF and CRT on the APD.
Conclusion: CRT improves DHF-induced alterations of Na channel function, especially suppression of INa-L, thus abbreviating the APD and reducing the frequency of EADs.