Abstract 10100: Central Role of MicroRNA-21 in Atrial Fibrillation Associated with Structural Remodeling
Background: Heart failure (HF) is a major cause of atrial fibrillation (AF), with fibrosis a putative mechanistic contributor. MiR-21 promotes tissue-fibrosis by downregulating fibroblast Sprouty1, an antiproliferative protein acting via ERK1/2-hyperphosphorylation. This study assessed the role of miR-21 in the AF-substrate caused by HF, and the potential value of miR-21 knockdown as an antiarrhythmic target.
Methods and Results: HF was produced by LAD-ligation in rats (MI group). MI-rats were compared to a contemporary sham-operated control group, with thoracotomy and cardiac exposure but no coronary ligation. AF-duration was assessed by repeated AF-induction with atrial burst-pacing at terminal study. In a first series, MI was found to upregulate miR-21, enhance fibrosis and promote AF. Then, paired groups received LA intramyocardial injections with an antimiR-21 oligomer to knock down miR-21 (KD21) or a scrambled control sequence (Scr21) during MI or sham surgery. MI-rats treated with Scr21 developed progressive LA dilation, LA fibrosis and increased AF duration. miR-21 expression increased significantly 2 weeks post MI (Figure A). Sprouty-1 protein decreased by 65% (P<0.05) and ERK1/2-phosphorylation increased 220% (P<0.05). KD21 reduced miR-21 levels in 2-wk MI-rats to those of Sham-controls treated with inactive Scr21 (Figure A), and prevented AF-duration increases (Figure B) as well as atrial fibrosis (Figure C). KD21 and Scr21 had similar MI-size, LV dysfunction and atrial dilation, excluding benefit from ventricular effects or prevention of LA enlargement.
Conclusions: MI-induced HF promotes AF, while activating profibrotic miR21 signaling. Suppression of miR-21 activation with a knockdown probe prevents atrial fibrosis and AF-promotion. Our results demonstrate a role for microRNAs, specifically miR-21, in atrial structural remodeling and suggest miR-21 as a possible new anti-AF therapeutic target.
- © 2012 by American Heart Association, Inc.