Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure.
Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure.
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DOI：
10.1161/circep.113.000400
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发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
Tomaselli GF
中科院分区：
文献类型：
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作者：
Aiba T;Barth AS;Hesketh GG;Hashambhoy YL;Chakir K;Tunin RS;Greenstein JL;Winslow RL;Kass DA;Tomaselli GF
Na+电流（INa）衰减减慢和晚期INa（INa-L）增强可延长动作电位时程（APD）并导致早期后除极（埃兹）。与不同步性心力衰竭（DHF）相比，心脏复律治疗（CRT）缩短了APD，然而，改变的Na+通道门控在CRT中的作用尚未探索。成年犬行左束支分支消融和右心房起搏（200 bpm）6周（DHF）或3周后以相同频率双心室起搏3周（CRT）。在来自非衰竭（NF）、DHF和CRT狗的左心室肌细胞中测量INa和INa-L。与NF相比，DHF使INa可用性的电压依赖性偏移了−3 mV，增强了中间失活并减缓了失活的恢复。CRT逆转DHF诱导的电压漂移的可用性，部分逆转增强的中间失活，但不影响DHF诱导的缓慢恢复。与NF相比，DHF显著增加INa-L。CRT可显著降低DHF引起的INa-L升高，缩短APD，抑制埃兹。CRT与磷酸化CaMKII的整体减少相关，磷酸化CaMKII对心脏Na+通道的失活具有明显的影响。在犬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APD效应。CRT可改善DHF引起的Na+通道功能改变，尤其是抑制INa-L，从而使APD延长，埃兹频率降低。磷酸化CaMKII水平的变化提示通过双心室起搏衰竭心脏调节INa的分子途径。
Slowed Na+ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations (EADs). Cardiac resynchronization therapy (CRT) shortens APD compared to 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 bpm) 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 non-failing (NF), DHF and CRT dogs. DHF shifted voltage dependence of INa availability by −3 mV compared to NF, 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 to NF. CRT dramatically reduced DHF-induced enhanced INa-L, abbreviated the APD and suppressed EADs. CRT was associated with a global reduction in phosphorylated CaMKII, 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 EADs. Changes in the levels of phosphorylated CaMKII suggest a molecular pathway for regulation of INa by biventricular pacing of the failing heart.