Casini Simona, Marchal Gerard A, Kawasaki Makiri, Fabrizi Benedetta, Wesselink Robin, Nariswari Fransisca A, Neefs Jolien, van den Berg Nicoline W E, Driessen Antoine H G, de Groot Joris R, Verkerk Arie O, Remme Carol Ann
Amsterdam UMC, location University of Amsterdam, Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart failure & Arrhythmias, Amsterdam, The Netherlands.
Amsterdam UMC, location University of Amsterdam, Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart failure & Arrhythmias, Amsterdam, The Netherlands.
Can J Cardiol. 2023 Mar;39(3):277-288. doi: 10.1016/j.cjca.2022.12.023. Epub 2022 Dec 28.
The cellular mechanisms underlying progression from paroxysmal to persistent atrial fibrillation (AF) are not fully understood, but alterations in (late) sodium current (I) have been proposed. Human studies investigating electrophysiological changes at the paroxysmal stage of AF are sparse, with the majority employing right atrial appendage cardiomyocytes (CMs). We here investigated action potential (AP) characteristics and (late) I remodelling in left atrial appendage CMs (LAA-CMs) from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of the "neuronal" sodium channel SCN10A/Na1.8.
Peak I, late I and AP properties were investigated through patch-clamp analysis on single LAA-CMs, whereas quantitative polymerase chain reaction was used to assess SCN5A/SCN10A expression levels in LAA tissue.
In paroxysmal and persistent AF LAA-CMs, AP duration was shorter than in SR LAA-CMs. Compared with SR, peak I and SCN5A expression were significantly decreased in paroxysmal AF, whereas they were restored to SR levels in persistent AF. Conversely, although late I was unchanged in paroxysmal AF compared with SR, it was significantly increased in persistent AF. Peak or late Na1.8-based I was not detected in persistent AF LAA-CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage.
Our findings demonstrate differences in (late) I remodeling in LAA-CMs from patients with paroxysmal vs persistent AF, indicating distinct cellular proarrhythmic mechanisms in different AF forms. These observations are of particular relevance when considering potential pharmacologic approaches targeting (late) I in AF.
阵发性房颤进展为持续性房颤的细胞机制尚未完全明确，但已有研究提出（晚期）钠电流（I）的改变与之相关。针对房颤阵发性阶段电生理变化的人体研究较少，且大多数研究采用右心耳心肌细胞（CMs）。在此，我们研究了阵发性房颤、持续性房颤患者以及窦性心律（SR）患者左心耳CMs（LAA-CMs）的动作电位（AP）特征和（晚期）I重塑，以及“神经元”钠通道SCN10A/Na1.8的潜在作用。
通过对单个LAA-CMs进行膜片钳分析来研究I峰值、晚期I和AP特性，而定量聚合酶链反应用于评估LAA组织中SCN5A/SCN10A的表达水平。
在阵发性和持续性房颤LAA-CMs中，AP持续时间短于SR LAA-CMs。与SR相比，阵发性房颤时I峰值和SCN5A表达显著降低，而在持续性房颤时恢复到SR水平。相反，虽然阵发性房颤与SR相比晚期I无变化，但在持续性房颤中显著增加。在持续性房颤LAA-CMs中未检测到基于Na1.8的I峰值或晚期I。同样，在任何阶段的左心耳中均未观察到SCN10A的表达。
我们的研究结果表明，阵发性房颤与持续性房颤患者LAA-CMs的（晚期）I重塑存在差异，提示不同房颤形式存在不同的细胞促心律失常机制。在考虑针对房颤（晚期）I的潜在药物治疗方法时，这些观察结果具有特别重要的意义。
