Increased expression of extracellular matrix proteins in rapid atrial pacing-induced atrial fibrillation

Background: Atrial fibrillation (AF) is characterized by structural remodeling of the extracellular matrix (ECM) in cardiac atrium. Objective: The purpose of this study was to gain further insight into atrial ECM remodeling at the molecular level and to test whether altered expression of ECM proteins was associated with the disease. Methods: Sustained AF was induced in nine adult pigs after 3-4 weeks of continuous rapid atrial pacing at a rate of 600 bpm. Histologic studies and immunohistochemical stain were performed to identify the potential pathologic substrate underlying abnormalities in atrial tissues with sustained AF. Results: In the pathologic findings, the fraction of myocardial ECM (ECM%) was measured, with a significantly greater ECM% found in the AF group compared with the sham operated group (n = 6; i.e., pigs with normal sinus rhythm [SR]). A set of 9,182 genes was screened with cDNA microarray analysis. In AF animals, expression of 121 genes increased and 24 genes decreased by ≥1.75-fold compared with SR animals. Significant up-regulation of fibronectin-1 (4.9-fold), fibrillin-1 (3.1-fold), and fibromodulin (1.9-fold) in the fibrillating atria was confirmed by quantitative real-time reverse transcriptase-polymerase chain reaction. Western blot analysis revealed significantly increased atrial fibronectin-1, fibrillin-1, and fibromodulin in the AF group compared with the SR group (1.5-, 2.7-, and 2.1-fold, respectively). Immunohistochemical staining of AF tissue displayed increased accumulation of fibronectin-1 and fibrillin-1 in the atrial interstitial space. Conclusion: Increased expression of ECM proteins in fibrillating atria supports the hypothesis that ECM metabolism contributes to the development of AF.