Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Heart Rhythm. 2017 Aug;14(8):1217-1223. doi: 10.1016/j.hrthm.2017.04.001. Epub 2017 Apr 8.
The failing heart exhibits an increased arrhythmia susceptibility that is often attributed to action potential (AP) prolongation due to significant ion channel remodeling. The inwardly rectifying K current (I) has been reported to be reduced, but its contribution to shaping the AP waveform and cell excitability in the failing heart remains unclear.
The purpose of this study was to define the effect of I suppression on the cardiac AP and excitability in the normal and failing hearts.
We used electrophysiological and pharmacological approaches to investigate I function in a swine tachy-pacing model of heart failure (HF).
Terminal repolarization of the AP (TRAP; the time constant of the exponential fit to terminal repolarization) was markedly prolonged in both myocytes and arterially perfused wedges from animals with HF. TRAP was increased by 54.1% in HF myocytes (P < .001) and 26.2% in HF wedges (P = .014). The increase in TRAP was recapitulated by the potent and specific I inhibitor, PA-6 (pentamidine analog 6), indicating that I is the primary determinant of the final phase of repolarization. Moreover, we find that I suppression reduced the ratio of effective refractory period to AP duration at 90% of repolarization, permitting re-excitation before full repolarization, reduction of AP upstroke velocity, and likely promotion of slow conduction.
Using an objective measure of terminal repolarization, we conclude that I is the major determinant of the terminal repolarization time course. Moreover, suppression of I prolongs repolarization and reduces postrepolarization refractoriness without marked effects on the overall AP duration. Collectively, these findings demonstrate how I suppression may contribute to arrhythmogenesis in the failing heart.
衰竭的心脏表现出增加的心律失常易感性，这通常归因于由于显著的离子通道重构导致的动作电位（AP）延长。已经报道内向整流钾电流（I）减少，但它对塑造衰竭心脏中的 AP 波形和细胞兴奋性的贡献仍不清楚。
本研究的目的是定义 I 抑制对正常和衰竭心脏中的心脏 AP 和兴奋性的影响。
我们使用电生理和药理学方法来研究心力衰竭（HF）猪心动过速起搏模型中的 I 功能。
AP 的终末复极（TRAP；指数拟合到终末复极的时间常数）在 HF 动物的心肌细胞和动脉灌注楔形物中均明显延长。HF 心肌细胞中的 TRAP 增加了 54.1%（P <.001），HF 楔形物中的 TRAP 增加了 26.2%（P =.014）。强效和特异性 I 抑制剂 PA-6（戊脒类似物 6）复现了 TRAP 的增加，表明 I 是复极终末相的主要决定因素。此外，我们发现 I 抑制降低了复极 90%时有效不应期与 AP 持续时间的比值，从而允许在完全复极之前再次兴奋，AP 上升速度降低，并且可能促进缓慢传导。
使用终末复极的客观测量，我们得出结论，I 是终末复极时间过程的主要决定因素。此外，I 抑制延长复极并降低复极后不应期，而对整体 AP 持续时间没有明显影响。总的来说，这些发现表明 I 抑制如何导致衰竭心脏中的心律失常发生。
