Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene expression through deacetylation of histone proteins. We hypothesized that class I HDACs in complex with neuron-restrictive silencer factor (NRSF) determine atrial K⁺ channel expression. AF was characterized by reduced atrial HDAC2 mRNA levels and upregulation of NRSF in humans and in a pig model, with regional differences between right and left atrium. In vitro studies revealed inverse regulation of Hdac2 and Nrsf in HL-1 atrial myocytes. A direct association of HDAC2 with active regulatory elements of cardiac K⁺ channels was revealed by chromatin immunoprecipitation. Specific knock-down of Hdac2 and Nrsf induced alterations of K⁺ channel expression. Hdac2 knock-down resulted in prolongation of action potential duration (APD) in neonatal rat cardiomyocytes, whereas inactivation of Nrsf induced APD shortening. Potential AF-related triggers were recapitulated by experimental tachypacing and mechanical stretch, respectively, and exerted differential effects on the expression of class I HDACs and K⁺ channels in cardiomyocytes. In conclusion, HDAC2 and NRSF contribute to AF-associated remodeling of APD and K⁺ channel expression in cardiomyocytes via direct interaction with regulatory chromatin regions. Specific modulation of these factors may provide a starting point for the development of more individualized treatment options for atrial fibrillation.

心房颤动 (AF) 与电重构有关，导致细胞电生理功能障碍和心律失常持续存在。新出现的证据表明表观遗传机制在调节离子通道表达中起关键作用。组蛋白去乙酰化酶 (HDAC) 通过组蛋白的去乙酰化来控制基因表达。我们假设 I 类 HDAC 与神经元限制性消音因子 (NRSF) 复合决定心房 K ⁺通道表达。在人和猪模型中，房颤的特征是心房HDAC2 mRNA 水平降低和NRSF上调，左右心房之间存在区域差异。体外研究揭示了Hdac2和Nrsf的反向调节在 HL-1 心房肌细胞中。染色质免疫沉淀揭示了 HDAC2 与心脏 K ⁺通道的活性调节元件的直接关联。Hdac2和Nrsf的特异性敲低诱导了 K ⁺通道表达的改变。Hdac2敲低导致新生大鼠心肌细胞的动作电位持续时间 (APD) 延长，而Nrsf的失活诱导 APD 缩短。潜在的 AF 相关触发因素分别通过实验性心动过速和机械拉伸来概括，并对 I 类 HDAC 和 K ^{+的表达产生不同的影响}心肌细胞中的通道。总之，HDAC2 和 NRSF 通过与调节染色质区域的直接相互作用，有助于 AF 相关的 APD 重塑和心肌细胞中 K ⁺通道的表达。对这些因素的特定调节可能为开发更个性化的房颤治疗方案提供了一个起点。