title: Atrial fibrillation in pigs induces left atrial endocardial transcriptional remodelling.
abstract: The leading cause of cardioembolic stroke is atrial fibrillation (AF), which predisposes to atrial thrombus formation. Although rheological alterations promote a hypercoagulable environment, as yet undefined factors contribute to thrombogenesis. The role of the endocardium has barely been explored. To approach this topic, rapid atrial pacing (RAP) was applied in four pigs to mimic AF. Left and right endocardial cells were isolated separately and their gene expression pattern was compared with that of four control pigs. The AF-characteristic rhythm disorders and endothelial nitric oxide synthase down-regulation were successfully reproduced, and validated RAP to mimic AF. A change was observed in the transcriptomic endocardial profile after RAP: the expression of 364 genes was significantly altered (p<0.01), 29 of them having passed the B>0 criteria. The left atrial endocardium [325 genes (7 genes, B>0)] was largely responsible for such alterations. Blood coagulation, blood vessel morphogenesis and inflammatory response are among the most significant altered functions, and help to explain the activation of coagulation observed after RAP: D-dimer, 0.49 (1.63) vs. 0.23 (0.24) mg/l [median (interquartile range)] in controls, p=0.02. Furthermore, three genes directly related to thrombotic processes were differentially expressed after RAP: FGL2 [fold change (FC)=0.85; p=0.007], APLP2 (FC=-0.47; p=0.005) and ADAMTS-18 (FC=-0.69; p=0.004). We demonstrate for the first time that AF induces a global expression change in the left atrial endocardium associated with an activation of blood coagulation. The nature of some of the altered functions and genes provides clues to identify new therapeutic targets.
authors: Division of Cardiovascular Sciences, Laboratory of Thrombosis and Haemostasis, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: Jorge
authors: J
authors: Cerveró
authors: Víctor
authors: V
authors: Segura
authors: Alfonso
authors: A
authors: Macías
authors: Juan José
authors: JJ
authors: Gavira
authors: Ramón
authors: R
authors: Montes
authors: José
authors: J
authors: Hermida
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D004699:Endocardium / Q000378:metabolism; D005260:Female; D006325:Heart Atria / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034421:Sus scrofa; D013927:Thrombosis / Q000209:etiology; D059467:Transcriptome
chemical_list: D012333:RNA, Messenger; D052250:Nitric Oxide Synthase Type III