Saljic Arnela, Friederike Fenner Merle, Winters Joris, Flethøj Mette, Eggert Eggertsen Caroline, Carstensen Helena, Dalgas Nissen Sarah, Melis Hesselkilde Eva, van Hunnik Arne, Schotten Ulrich, Sørensen Ulrik, Jespersen Thomas, Verheule Sander, Buhl Rikke
Laboratory of Cardiac Physiology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Agrovej 8, DK-2630 Taastrup, Denmark.
Int J Cardiol Heart Vasc. 2021 Jul 20;35:100842. doi: 10.1016/j.ijcha.2021.100842. eCollection 2021 Aug.
Fibroblasts maintain the extracellular matrix homeostasis and may couple to cardiomyocytes through gap junctions and thereby increase the susceptibility to slow conduction and cardiac arrhythmias, such as atrial fibrillation (AF). In this study, we used an equine model of persistent AF to characterize structural changes and the role of fibroblasts in the development of an arrhythmogenic substrate for AF.
Eleven horses were subjected to atrial tachypacing until self-sustained AF developed and were kept in AF for six weeks. Horses in sinus rhythm (SR) served as control. In terminal open-chest experiments conduction velocity (CV) was measured. Tissue was harvested and stained from selected sites. Automated image analysis was performed to assess fibrosis, fibroblasts, capillaries and various cardiomyocyte characteristics.
Horses in SR showed a rate-dependent slowing of CV, while in horses with persistent AF this rate-dependency was completely abolished (CV•basic cycle length relation ). Overall and interstitial amounts of fibrosis were unchanged, but an increased fibroblast count was found in left atrial appendage, Bachmann's bundle, intraatrial septum and pulmonary veins ( for all) in horses with persistent AF. The percentage of α-SMA expressing fibroblasts remained the same between the groups.
Persistent AF resulted in fibroblast accumulation in several regions, particularly in the left atrial appendage. The increased number of fibroblasts could be a mediator of altered electrophysiology during AF. Targeting the fibroblast proliferation and differentiation could potentially serve as a novel therapeutic target slowing down the structural remodeling associated with AF.
成纤维细胞维持细胞外基质的稳态，并可能通过缝隙连接与心肌细胞耦联，从而增加对缓慢传导和心律失常（如心房颤动（AF））的易感性。在本研究中，我们使用持续性房颤的马模型来表征结构变化以及成纤维细胞在房颤致心律失常基质形成中的作用。
11匹马接受心房超速起搏，直至出现自限性房颤，并维持房颤状态6周。窦性心律（SR）的马作为对照。在终末期开胸实验中测量传导速度（CV）。从选定部位采集组织并进行染色。进行自动图像分析以评估纤维化、成纤维细胞、毛细血管和各种心肌细胞特征。
SR组的马CV呈频率依赖性减慢，而持续性房颤组的马这种频率依赖性完全消失（CV•基本周期长度关系）。总体纤维化和间质纤维化量未改变，但持续性房颤组马的左心耳、巴赫曼束、房间隔和肺静脉（所有部位）的成纤维细胞计数增加。两组间α - SMA表达成纤维细胞的百分比保持不变。
持续性房颤导致成纤维细胞在几个区域积聚，特别是在左心耳。成纤维细胞数量增加可能是房颤期间电生理改变的介导因素。靶向成纤维细胞的增殖和分化可能成为减缓与房颤相关的结构重塑的新治疗靶点。
