School of Physiology, Pharmacology & Neuroscience, Faculty of Biomedical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.
University of Bristol Veterinary School, Langford, Bristol BS40 5DU, UK.
J Mol Cell Cardiol. 2022 Nov;172:52-62. doi: 10.1016/j.yjmcc.2022.07.009. Epub 2022 Jul 29.
Loss of ventricular action potential (AP) early phase 1 repolarization may contribute to the impaired Ca release and increased risk of sudden cardiac death in heart failure. Therefore, restoring AP phase 1 by augmenting the fast transient outward K current (I) might be beneficial, but direct experimental evidence to support this proposition in failing cardiomyocytes is limited. Dynamic clamp was used to selectively modulate the contribution of I to the AP and Ca transient in both normal (guinea pig and rabbit) and in failing rabbit cardiac myocytes. Opposing native I in non-failing rabbit myocytes increased Ca release heterogeneity, late Ca sparks (LCS) frequency and AP duration. (APD). In contrast, increasing I in failing myocytes and guinea pig myocytes (the latter normally lacking I) increased Ca transient amplitude, Ca release synchrony, and shortened APD. Computer simulations also showed faster Ca transient decay (mainly due to fewer LCS), decreased inward Na/Ca exchange current and APD. When the I conductance was increased to ~0.2 nS/pF in failing cells (a value slightly greater than seen in typical human epicardial myocytes), Ca release synchrony improved and AP duration decreased slightly. Further increases in I can cause Ca release to decrease as the peak of the bell-shaped I-voltage relationship is passed and premature AP repolarization develops. These results suggest that there is an optimal range for I enhancement that may support Ca release synchrony and improve electrical stability in heart failure with the caveat that uncontrolled I enhancement should be avoided.
心室动作电位 (AP) 早期 1 期复极化的丧失可能导致心力衰竭时钙释放受损和心脏性猝死风险增加。因此，通过增强快速瞬时外向钾电流 (I) 来恢复 AP 1 期可能是有益的，但在衰竭的心肌细胞中支持这一观点的直接实验证据有限。动态箝位用于选择性调节 I 对正常（豚鼠和兔）和衰竭兔心肌细胞 AP 和 Ca 瞬变的贡献。在非衰竭兔心肌细胞中，拮抗天然 I 会增加 Ca 释放异质性、晚期 Ca 火花 (LCS) 频率和 AP 持续时间 (APD)。相比之下，在衰竭的心肌细胞和豚鼠心肌细胞中增加 I（后者通常缺乏 I）会增加 Ca 瞬变幅度、Ca 释放同步性并缩短 APD。计算机模拟还显示 Ca 瞬变衰减更快（主要是由于 LCS 减少）、内向 Na/Ca 交换电流和 APD 减少。当 I 电导在衰竭细胞中增加到约 0.2 nS/pF（略大于典型人心外膜心肌细胞中看到的值）时，Ca 释放同步性得到改善，APD 略有缩短。进一步增加 I 会导致 Ca 释放减少，因为达到 I-电压关系的钟形峰值并且过早的 AP 复极化发展。这些结果表明，存在一个最佳的 I 增强范围，它可以支持 Ca 释放同步性并改善心力衰竭中的电稳定性，但应注意避免不受控制的 I 增强。
