Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, Royal Adelaide Hospital, University of Adelaide, Australia; Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.
Heart Rhythm. 2024 May;21(5):622-629. doi: 10.1016/j.hrthm.2024.01.033. Epub 2024 Jan 26.
More than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient, vagally mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs.
The purpose of this study was to investigate the effect of pharmacologic inhibition of the G-protein-gated acetylcholine-regulated potassium current (I) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events.
In 21 pigs, SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by an S1S2 atrial pacing-protocol. Pigs were randomized into 3 groups-group 1: vehicle (n = 4); group 2: XAF-1407 (I inhibitor) (n = 7); and group 3: nicotine followed by XAF-1407 (n = 10).
In group 1, INAP shortened aERP (ΔaERP -42.6 ms; P = .004) and transiently increased AF inducibility from 0% to 31%. In group 2, XAF-1407 prolonged aERP by 25.2 ms (P = .005) during normal breathing and prevented INAP-induced aERP shortening (ΔaERP -3.6 ms; P = .3) and AF inducibility. In group 3, INAP transiently shortened aERP during nicotine perfusion (ΔaERP -33.6 ms; P = .004) and increased AF inducibility up to 61%, which both were prevented by XAF-1407.
Simulated obstructive respiratory events transiently shorten aERP and increase AF inducibility, which can be prevented by the I-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether I channels represent a target for SDB-related AF in humans warrants further study.
超过 50%的心房颤动（AF）患者患有睡眠呼吸障碍（SDB）。阻塞性呼吸事件导致短暂的、迷走神经介导的心房致心律失常基质，而这种基质对大多数可用的抗心律失常药物具有抗性。
本研究旨在探讨在模拟阻塞性呼吸事件的猪模型中，使用 G 蛋白门控乙酰胆碱调节钾电流（I）抑制剂（XAF-1407）并结合尼古丁急性自主神经系统激活对其的影响。
在 21 头猪中，通过施加间歇性负压上气道压力（INAP）模拟 SDB。通过 S1S2 心房起搏方案，在 INAP 之前和期间确定 AF 可诱导性和心房有效不应期（aERP）。猪被随机分为 3 组-组 1：载体（n = 4）；组 2：XAF-1407（I 抑制剂）（n = 7）；组 3：尼古丁后 XAF-1407（n = 10）。
在组 1 中，INAP 缩短了 aERP（ΔaERP-42.6 ms；P =.004），并使 AF 可诱导性从 0%短暂增加到 31%。在组 2 中，XAF-1407 在正常呼吸时延长了 aERP 25.2 ms（P =.005），并防止了 INAP 引起的 aERP 缩短（ΔaERP-3.6 ms；P =.3）和 AF 可诱导性。在组 3 中，INAP 在尼古丁灌注期间短暂缩短了 aERP（ΔaERP-33.6 ms；P =.004），并使 AF 可诱导性增加至 61%，这些都被 XAF-1407 所预防。
模拟阻塞性呼吸事件短暂缩短 aERP 并增加 AF 可诱导性，而 I 抑制剂 XAF-1407 可以预防这些变化。XAF-1407 还可以防止在尼古丁灌注期间由阻塞性呼吸事件引起的这些致心律失常变化。I 通道是否代表与 SDB 相关的 AF 的靶点，需要进一步研究。
