Mechanisms of K2P3.1 K+ channel and action potential regulation in atrial fibrillation and heart failure - implications for personalized antiarrhythmic therapy

心房颤动(房颤)是心血管疾病发病率和死亡率的重要因素。心力衰竭(HF)的并存恶化了房颤患者的预后，并对治疗提出了特殊的挑战。尽管最近取得了进展，但日益严重的流行病需要更有效的抗心律失常策略。我们的科学方法旨在基于机制开发新的抗心律失常概念，重点放在最近发现的调节动作电位(AP)持续时间的双孔结构域K+(K2P)3.1电流。K2P3.1通道在人的心房中表达。我们揭示了K2P3.1重构在房性心律失常发生中的差异性。在慢性房颤(CAF)患者中，心房K2P3.1水平升高导致AP时程缩短，而AP时程是房颤维持折返的关键驱动因素。HF引起相反的效应：左心功能障碍与K2P3.1K+通道复极化减少而延长的房室时程有关。基于这些发现，我们认为与心力衰竭和CAF相关的患者特有的心房K2P3.1表达和动作电位重构可能是针对患者量身定制的抗心律失常治疗的靶点。为了进一步将这一假说转化为临床实践，我们建议确定决定房颤和心力衰竭患者K2P3.1不同重构的信号机制。为此，我们将研究K2P3.1在250例阵发性房颤、慢性房颤和窦性心律心脏手术患者右房组织中的表达和功能。基于小的非编码RNA调节K2P3.1表达的假设，电生理学发现将根据左心室功能分层，并与人心房组织中的microRNA表达谱相关联。在培养的心房肌细胞中，microRNA对K2P3.1电流的调节，以及microRNA过表达或抑制的功能效应将被阐明。预期结果将为将针对K2P3.1通道的患者定制的抗心律失常策略转化为临床实践提供科学依据。

Atrial fibrillation (AF) contributes significantly to cardiovascular morbidity and mortality. The coexistence of heart failure (HF) worsens prognosis of AF patients and poses a particular therapeutic challenge. Despite recent advances the growing epidemic requires more effective antiarrhythmic strategies. Our scientific approach aims at mechanism-based development of new antiarrhythmic concepts, with a focus on recently discovered two-pore-domain K+ (K2P) 3.1 currents that regulate action potential (AP) duration. K2P3.1 channels are expressed in human atria. We revealed differential K2P3.1 remodeling in atrial arrhythmogenesis. In patients with chronic AF (cAF), increased atrial K2P3.1 levels resulted in shortened AP duration (APD), a key driver of AF-maintaining reentry. HF induces opposite effects: LV dysfunction is associated with prolonged atrial APD through reduction of repolarizing K2P3.1 K+ channels. Based on these findings we propose that patient-specific atrial K2P3.1 expression and APD remodeling associated with HF and cAF may be targets for patient-tailored antiarrhythmic therapy. To further translate this hypothesis into clinical practice, we here propose to identify the signaling mechanisms that determine differential K2P3.1 remodeling in patients with AF and HF. To this end, K2P3.1 expression and function will be studied in right atrial tissue of 250 patients with paroxysmal AF, chronic AF, and sinus rhythm undergoing cardiac surgery. Based on the hypothesis that small non-coding RNAs regulate K2P3.1expression, electrophysiological findings will be stratified according to LV function and correlated with microRNA expression profiles in human atrial tissue. Regulation of K2P3.1 current by microRNAs, and functional effects of microRNA overexpression or suppression will be elucidated in cultured atrial myocytes. The expected results will provide the scientific basis for translation of patient-tailored antiarrhythmic strategies targeting K2P3.1 channels into clinical practice.