Lugenbiel Patrick, Wenz Fabian, Govorov Katharina, Syren Pascal, Katus Hugo A, Thomas Dierk
Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), Germany.
Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), Germany; DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany.
Life Sci. 2017 Jul 15;181:1-8. doi: 10.1016/j.lfs.2017.05.025. Epub 2017 May 22.
Atrial fibrillation (AF) is associated with fibrosis that slows electrical conduction and causes perpetuation of the arrhythmia. The molecular characterization of AF pathophysiology may provide novel therapeutic options. This study was designed to elucidate profibrotic signaling and myofibroblast activation in a porcine model of atrial tachypacing-induced AF and reduced left ventricular function.
Ten domestic pigs were randomized to sinus rhythm (SR) or AF groups. Prior to AF induction and on day 14 the animals underwent echocardiographic examinations. Profibrotic pathways were analyzed in right atrial tissue obtained from AF animals compared to SR controls using histology, immunofluorescence microscopy, Western blot, and real-time PCR.
AF was associated with atrial dilation, increased atrial fibrosis, and enhanced expression of collagens I and V in right atrial tissue after 14days follow-up. The fraction of α-smooth muscle actin (SMA)-producing activated myofibroblasts was elevated in AF, whereas the abundance of vimentin-expressing inactive fibroblasts was not affected. Profibrotic signaling involved upregulation of TGF-β, Smad2/3, and CTGF.
The transformation of atrial fibroblasts into myofibroblasts through activation of TGF-β and CTGF emerged as potential cellular trigger of fibrogenesis. Prevention of fibroblast-to-myofibroblast switching may serve as target for remodeling-based antiarrhythmic AF therapy.
心房颤动（AF）与纤维化相关，纤维化会减慢电传导并导致心律失常持续存在。AF病理生理学的分子特征可能提供新的治疗选择。本研究旨在阐明心房超速起搏诱导的AF和左心室功能降低的猪模型中的促纤维化信号传导和成肌纤维细胞激活。
将10头家猪随机分为窦性心律（SR）组或AF组。在诱导AF之前和第14天，对动物进行超声心动图检查。使用组织学、免疫荧光显微镜、蛋白质印迹和实时PCR分析从AF动物获得的右心房组织与SR对照组相比的促纤维化途径。
随访14天后，AF与右心房组织中的心房扩张、心房纤维化增加以及I型和V型胶原蛋白表达增强相关。在AF中，产生α平滑肌肌动蛋白（SMA）的活化成肌纤维细胞比例升高，而表达波形蛋白的非活化成纤维细胞数量未受影响。促纤维化信号传导涉及TGF-β、Smad2/3和结缔组织生长因子（CTGF）的上调。
通过激活TGF-β和CTGF将心房成纤维细胞转化为成肌纤维细胞成为纤维化潜在的细胞触发因素。防止成纤维细胞向肌成纤维细胞的转变可能作为基于重塑的抗心律失常AF治疗的靶点。
