Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Circ Arrhythm Electrophysiol. 2013 Jun;6(3):546-54. doi: 10.1161/CIRCEP.113.000400. Epub 2013 May 6.
Slowed Na⁺ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na⁺ channel gating in CRT remains unexplored.
Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followed by 3 weeks of biventricular pacing at the same rate (CRT). INa and INa-L were measured in left ventricular myocytes from nonfailing, DHF, and CRT dogs. DHF shifted voltage-dependence of INa availability by -3 mV compared with nonfailing, enhanced intermediate inactivation, and slowed recovery from inactivation. CRT reversed the DHF-induced voltage shift of availability, partially reversed enhanced intermediate inactivation but did not affect DHF-induced slowed recovery. DHF markedly increased INa-L compared with nonfailing. CRT dramatically reduced DHF-induced enhanced INa-L, abbreviated the APD, and suppressed early afterdepolarizations. CRT was associated with a global reduction in phosphorylated Ca²⁺/Calmodulin protein kinase II, which has distinct effects on inactivation of cardiac Na⁺ channels. In a canine AP model, alterations of INa-L are sufficient to reproduce the effects on APD observed in DHF and CRT myocytes.
CRT improves DHF-induced alterations of Na⁺ channel function, especially suppression of INa-L, thus, abbreviating the APD and reducing the frequency of early afterdepolarizations. Changes in the levels of phosphorylated Ca²⁺/Calmodulin protein kinase II suggest a molecular pathway for regulation of INa by biventricular pacing of the failing heart.
钠电流（INa）衰减减慢和晚期 INa（INa-L）增强会延长动作电位时程（APD），并导致早期后除极。心脏再同步治疗（CRT）可缩短 APD，与不同步性心力衰竭（DHF）相比；然而，改变的钠通道门控在 CRT 中的作用仍未得到探索。
成年犬接受左束支消融和右心房起搏（200 次/分）6 周（DHF）或 3 周，然后以相同的速率进行双心室起搏 3 周。从非衰竭、DHF 和 CRT 犬的左心室心肌细胞中测量 INa 和 INa-L。与非衰竭相比，DHF 使 INa 可用性的电压依赖性向负 3 mV 移位，增强了中间失活，并减慢了失活的恢复。CRT 逆转了 DHF 引起的可用性电压移位，部分逆转了增强的中间失活，但不影响 DHF 引起的失活恢复减慢。DHF 与非衰竭相比明显增加了 INa-L。CRT 显著降低了 DHF 引起的增强的 INa-L，缩短了 APD，并抑制了早期后除极。CRT 与磷酸化钙调蛋白蛋白激酶 II 的整体减少有关，该蛋白激酶 II 对心脏钠通道的失活具有独特的影响。在犬的 AP 模型中，INa-L 的改变足以重现 DHF 和 CRT 心肌细胞中观察到的对 APD 的影响。
CRT 改善了 DHF 引起的钠通道功能改变，特别是抑制 INa-L，从而缩短 APD 并减少早期后除极的频率。磷酸化钙调蛋白蛋白激酶 II 水平的变化表明了调节衰竭心脏双心室起搏时 INa 的分子途径。
