Patrick Lugenbiel1, Fabian Wenz1, Katharina Govorov1, Pascal Syren1, Hugo A Katus2, Dierk Thomas3. 1. Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany; HCR (Heidelberg Center for Heart Rhythm Disorders), Germany. 2. 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. 3. 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. Electronic address: dierk.thomas@med.uni-heidelberg.de.
Abstract
AIMS: 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. MATERIALS AND METHODS: 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. KEY FINDINGS: 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-β1, Smad2/3, and CTGF. SIGNIFICANCE: The transformation of atrial fibroblasts into myofibroblasts through activation of TGF-β1 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.
AIMS: 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. MATERIALS AND METHODS: 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. KEY FINDINGS: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-β1, Smad2/3, and CTGF. SIGNIFICANCE: The transformation of atrial fibroblasts into myofibroblasts through activation of TGF-β1 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.
Authors: Felicitas Rapp; Palma Simoniello; Julia Wiedemann; Karola Bahrami; Valeria Grünebaum; Svetlana Ktitareva; Marco Durante; P Lugenbiel; D Thomas; H Immo Lehmann; Douglas L Packer; Christian Graeff; Claudia Fournier Journal: Sci Rep Date: 2019-03-21 Impact factor: 4.379
Authors: Carlotta Citerni; Jeppe Kirchhoff; Lisbeth Høier Olsen; Stefan Michael Sattler; Fabio Gentilini; Monica Forni; Augusta Zannoni; Morten Grunnet; Nils Edvardsson; Bo Hjorth Bentzen; Jonas Goldin Diness Journal: Front Vet Sci Date: 2020-04-09