Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
Eur Heart J. 2017 Jun 7;38(22):1764-1774. doi: 10.1093/eurheartj/ehw559.
Atrial fibrillation (AF) prevalence increases with advanced stages of left ventricular (LV) dysfunction. Remote proarrhythmic effects of ventricular dysfunction on atrial electrophysiology remain incompletely understood. We hypothesized that repolarizing K2P3.1 K+ channels, previously implicated in AF pathophysiology, may contribute to shaping the atrial action potential (AP), forming a specific electrical substrate with LV dysfunction that might represent a target for personalized antiarrhythmic therapy.
A total of 175 patients exhibiting different stages of LV dysfunction were included. Ion channel expression was quantified by real-time polymerase chain reaction and Western blot. Membrane currents and APs were recorded from atrial cardiomyocytes using the patch-clamp technique. Severely reduced LV function was associated with decreased atrial K2P3.1 expression in sinus rhythm patients. In contrast, chronic (c)AF resulted in increased K2P3.1 levels, but paroxysmal (p)AF was not linked to significant K2P3.1 remodelling. LV dysfunction-related suppression of K2P3.1 currents prolonged atrial AP duration (APD) compared with patients with preserved LV function. In individuals with concomitant LV dysfunction and cAF, APD was determined by LV dysfunction-associated prolongation and by cAF-dependent shortening, respectively, consistent with changes in K2P3.1 abundance. K2P3.1 inhibition attenuated APD shortening in cAF patients irrespective of LV function, whereas in pAF subjects with severely reduced LV function, K2P3.1 blockade resulted in disproportionately high APD prolongation.
LV dysfunction is associated with reduction of atrial K2P3.1 channel expression, while cAF leads to increased K2P3.1 abundance. Differential remodelling of K2P3.1 and APD provides a basis for patient-tailored antiarrhythmic strategies.
心房颤动（AF）的患病率随着左心室（LV）功能障碍的进展而增加。心室功能障碍对心房电生理的远程致心律失常作用仍不完全了解。我们假设先前与 AF 病理生理学有关的复极化 K2P3.1 K+通道可能有助于塑造心房动作电位（AP），与 LV 功能障碍形成特定的电基质，这可能成为个性化抗心律失常治疗的靶点。
共纳入 175 例表现出不同阶段 LV 功能障碍的患者。通过实时聚合酶链反应和 Western blot 定量离子通道表达。使用膜片钳技术从心房肌细胞记录膜电流和 AP。窦性节律患者严重 LV 功能障碍与心房 K2P3.1 表达减少相关。相反，慢性（c）AF 导致 K2P3.1 水平升高，但阵发性（p）AF 与 K2P3.1 重塑无显著相关性。与 LV 功能正常的患者相比，LV 功能障碍相关的 K2P3.1 电流抑制延长了心房 AP 持续时间（APD）。在伴有 LV 功能障碍和 cAF 的个体中，APD 分别由 LV 功能障碍相关的延长和 cAF 依赖性缩短决定，这与 K2P3.1 丰度的变化一致。K2P3.1 抑制可减轻 cAF 患者的 APD 缩短，而在 LV 功能严重降低的 pAF 患者中，K2P3.1 阻断导致不成比例的 APD 延长。
LV 功能障碍与心房 K2P3.1 通道表达减少有关，而 cAF 导致 K2P3.1 丰度增加。K2P3.1 重塑和 APD 的差异为患者定制抗心律失常策略提供了基础。
