He Qianwen, Feng Ying, Wang Yanggan
Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
Heart Fail Rev. 2015 May;20(3):349-62. doi: 10.1007/s10741-015-9474-y.
Transient outward K(+) current (Ito) plays a crucial role in shaping the early phase of repolarization and setting the plateau voltage level of action potential. As a result, it extensively affects membrane current flow in the plateau window. A great body of evidence illustrates a transmural gradient of I to within ventricular wall with much higher density in epicardial than endocardial myocytes, which is important for the physiological ventricular repolarization. In heart failure (HF), this gradient is diminished due to a greater reduction of I to in epicardial myocytes. This attenuates the transmural gradient of early repolarization, facilitating conduction of abnormal impulses originated in the epicardium. In addition, I to reduction prolongs action potential duration and increases intercellular Ca(2+), thus affecting Ca(2+) handling and the excitation-contraction coupling. Furthermore, increased intercellular Ca(2+) could activate CaMKII and calcineurin whose role in cardiac hypertrophy and HF development has been well established. Based on the impact of I to reduction on electrical activity, signal conduction, calcium handling and cardiac function, restoration of I to is likely a potential therapeutic strategy for HF. In this review, we summarize the physiological and pathological role of cardiac I to channel and the potential impact of I to restoration on HF therapy with an emphasis of recent novel findings.
瞬时外向钾电流（Ito）在形成复极化早期阶段和设定动作电位的平台期电压水平方面起着关键作用。因此，它广泛影响平台期窗口内的膜电流流动。大量证据表明，心室壁内Ito存在跨壁梯度，心外膜心肌细胞中的密度远高于心内膜心肌细胞，这对生理性心室复极化很重要。在心力衰竭（HF）中，由于心外膜心肌细胞中Ito的更大程度降低，这种梯度减小。这减弱了早期复极化的跨壁梯度，促进了起源于心外膜的异常冲动的传导。此外，Ito降低会延长动作电位持续时间并增加细胞间Ca2+，从而影响Ca2+处理和兴奋-收缩偶联。此外，细胞间Ca2+增加可激活CaMKII和钙调神经磷酸酶，它们在心脏肥大和HF发展中的作用已得到充分证实。基于Ito降低对电活动、信号传导、钙处理和心脏功能的影响，恢复Ito可能是HF潜在的治疗策略。在本综述中，我们总结了心脏Ito通道的生理和病理作用以及Ito恢复对HF治疗的潜在影响，并重点介绍了最近的新发现。
