From the Cardiovascular Division, Department of Medicine (E.K.J., S.J.S., W.W., E.J.D., Y.Z., E.M.K., K.A.Y., J.M.N.) and Department of Developmental Biology (J.M.N.), Washington University School of Medicine, St. Louis, MO.
Circ Arrhythm Electrophysiol. 2018 Jan;11(1):e005914. doi: 10.1161/CIRCEP.117.005914.
Myocardial, transient, outward currents, , have been shown to play pivotal roles in action potential (AP) repolarization and remodeling in animal models. The properties and contribution of to left ventricular (LV) repolarization in the human heart, however, are poorly defined.
Whole-cell, voltage-clamp recordings, acquired at physiological (35°C to 37°C) temperatures, from myocytes isolated from the LV of nonfailing human hearts identified 2 distinct transient currents, () and (), with significantly (<0.0001) different rates of recovery from inactivation and pharmacological sensitives: recovers in ≈10 ms, 100× faster than , and is selectively blocked by the Kv4 channel toxin, SNX-482. Current-clamp experiments revealed regional differences in AP waveforms, notably a phase 1 notch in LV subepicardial myocytes. Dynamic clamp-mediated addition/removal of modeled human ventricular , resulted in hyperpolarization or depolarization, respectively, of the notch potential, whereas slowing the rate of inactivation resulted in AP collapse. AP-clamp experiments demonstrated that changes in notch potentials modified the time course and amplitudes of voltage-gated Ca currents, . In failing LV subepicardial myocytes, was reduced and was increased, notch and plateau potentials were depolarized (<0.0001) and AP durations were prolonged (<0.001).
and are differentially expressed in nonfailing human LV, contributing to regional heterogeneities in AP waveforms. regulates notch and plateau potentials and modulates the time course and amplitude of . Slowing inactivation results in dramatic AP shortening. Remodeling of in failing human LV subepicardial myocytes attenuates transmural differences in AP waveforms.
心肌、瞬间、外向电流，在动物模型中已被证明在动作电位（AP）复极和重构中起关键作用。然而，在人类心脏中，对 LV 复极的贡献和特性尚未得到明确界定。
从非衰竭人心肌的 LV 分离的心肌细胞，在生理温度（35°C 至 37°C）下进行全细胞电压钳记录，鉴定出 2 种不同的瞬时电流，（）和（），其失活恢复率和药物敏感性有显著差异（<0.0001）： 恢复约 10 ms，比 快 100 倍，并且被 Kv4 通道毒素 SNX-482 选择性阻断。电流钳实验揭示了 AP 波形的区域性差异，特别是在 LV 心外膜下心肌细胞中存在 1 期切迹。通过动态箝位介导添加/去除建模的人类心室，导致切迹电位分别超极化或去极化，而减缓 失活的速度则导致 AP 崩溃。AP 箝位实验表明，切迹电位的变化改变了电压门控 Ca 电流的时间进程和幅度。在衰竭的 LV 心外膜下心肌细胞中，减少，增加，切迹和平台电位去极化（<0.0001），AP 持续时间延长（<0.001）。
和 在非衰竭人心肌 LV 中差异表达，导致 AP 波形的区域性异质性。调节切迹和平台电位，并调节时间进程和幅度。减缓失活的速度会导致 AP 显著缩短。衰竭人心肌 LV 心外膜下心肌细胞中电流的重构会减弱 AP 波形的跨壁差异。
