Abstract 1370: Resynchronization Therapy Restores Ion Channel Remodeling in Canine Tachypacing-induced Dyssynchronous Heart Failure
Left ventricular (LV) dyssynchrony reduces cardiac function and worsens heart failure (HF). Cardiac resynchronization therapy (CRT) is widely applied in patients with HF and dyssynchronous contraction (DHF). However, whether and what manner CRT influences electrophysiological remodeling induced by DHF is largely unknown.
Methods: Adult dogs underwent left bundle branch block and right atrial pacing (190–200 bpm) for either 6 weeks (DHF dogs: n=7) or 3 weeks followed by 3 weeks of resynchronization by bi-ventricular pacing at the same pacing rate (CRT dogs: n=7). Isolated LV lateral myocytes from normal (control), DHF and CRT dogs were studied using the whole cell patch clamp (35°C). Quantitative PCR was performed to assay mRNA expression levels of Kir2.1, Kv4.3, KChIP2, Serca2a, phospholamban (PLB), ryanodine receptor (RyR) and α1C in the LV lateral wall.
Results: While APD was significantly prolonged in DHF compared with control (759 ± 176 vs. 495 ± 120 ms at CL=1Hz) cells, CRT partially reversed the DHF-induced APD prolongation (643 ± 144 ms). DHF also led to a significant reduction in the inward rectifier K+ current (IK1) density (−18.8 ± 7.3 vs. −29.8 ± 6.9 pA/pF at −140 mV) that was partially restored by CRT (−25.3 ± 8.6 pA/pF). In contrast, the transient outward current (Ito) density was similarly reduced in both DHF and CRT compared with control (2.7 ± 3.4, 2.9 ± 2.1 vs. 10.0 ± 3.1 pA/pF at 50 mV, respectively). Most notably, the L-type Ca2+ current (ICa,L) density was significantly reduced in DHF (−2.6 ± 1.2 vs. −3.9 ± 0.5 pA/pF at 0 mV) but fully restored by CRT (−3.7 ± 1.4 pA/pF). At the mRNA level, Kir2.1 and KChIP2 were similarly reduced in DHF and CRT, and Kv4.3 was markedly reduced in CRT. There were no significant differences in Serca2a, PLB, RyR and α1C mRNA levels between the three groups.
Conclusions: CRT partially restores DHF-induced APD prolongation and IK1 down-regulation and fully restores ICa,L density. Alterations in the channel subunit mRNA levels do not explain these important electrophysiological changes, suggesting profound post-translational regulation of ion channels in both DHF and CRT. Reversal of ion channel remodeling by CRT may help suppress arrhythmias by shortening APD, stabilizing the membrane potential, and altering Ca handling.