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（AF）是心血管疾病发病率和死亡率的重要因素。心衰（HF）的共存恶化了房颤患者的预后，并提出了一个特殊的治疗挑战。尽管最近取得了进展，但日益增长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，重点关注最近发现的调节动作电位（AP）持续时间的双孔域K+ (K2P) 3.1电流。K2P3.1通道在人心房中表达。我们发现K2P3.1重构在心房心律失常发生中的差异。在慢性房颤（cAF）患者中，心房K2P3.1水平升高导致房颤持续时间（APD）缩短，APD是房颤维持再入的关键驱动因素。HF诱导相反的作用：左室功能障碍通过减少复极K2P3.1 K+通道与延长心房APD相关。基于这些发现，我们提出与HF和cAF相关的患者特异性心房K2P3.1表达和APD重塑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设转化为临床实践，我们在此提出确定心房颤动和心衰患者K2P3.1重塑差异的信号机制。为此，我们将对250例接受心脏手术的阵发性房颤、慢性房颤和窦性心律患者右心房组织中K2P3.1的表达和功能进行研究。基于小非编码rna调控k2p3.1表达的假设，电生理结果将根据左室功能分层，并与人心房组织中的microRNA表达谱相关。microRNA对K2P3.1电流的调控，以及microRNA过表达或抑制的功能影响将在培养心房肌细胞中得到阐明。预期结果将为针对K2P3.1通道的患者定制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.