Abstract 12988: MicroRNA Changes and Atrial Arrhythmogenic Remodeling in Tachycardiomyopathic Heart Failure
Background: Short interfering microRNAs (miRNAs) play important roles in cardiac remodeling. Individual miRNAs have been identified with discrete responses, but the overall miRNA-system response is poorly understood. This study assessed evolving miRNA changes in experimental heart failure (HF).
Methods: Dogs subjected to ventricular tachypacing (VTP, 240 bpm) for 12, 24 hrs, 1, 2 and 5 wks to induce HF were compared to unpaced controls (CTLs, n=5/group). MiRNA expression was first assessed by high density microarray. Twenty highly-expressed miRNAs showing the largest changes were then selected for followup real-time qPCR.
Results: MiRNA microarray analysis showed much greater change in atrial tissue vs ventricular (Figure A), in agreement with extensive fibrotic remodeling that promoted AF in atria, absent in ventricles. Atrial miRNA-21, miRNA-214 and miRNA-146a increased over time (Figure B), peaking at 2 wks (∼2.6–9.0**-fold vs. CTL). miRNA-133a, miRNA-133b and miRNA-30a decreased to steady state within 12 hrs (by∼50%*). In ventricular tissue, only miRNA-214 and miRNA-146 increased significantly at 5 wks (∼1.6–2.2*-fold vs CTL). Expression changes in miRNA-21, miRNA-30 and miRNA-133 are implicated in ECM remodeling. In silico prediction also suggested miR-214 and miR-146 targeting of ECM genes in the TIMP/MMP family. ECM gene expression (qPCR) in atrial fibroblasts isolated from CTL and VTP dogs (Figure B) roughly paralleled time courses of related miRNAs: collagen (COL)-1 and COL-3 increased to steady state at 1–2 wks (by ∼5–15-fold** vs. CTL), whereas rapid changes were seen for fibronectin (increased at 24 hrs by 6-fold** vs. CTL) and MMP2 (decreased at 12 hrs by ∼85%***).
Conclusions: Tachycardiomyopathic HF causes greater miRNA changes in atria vs ventricles. Atrial expression of miRNAs predicted to affect ECM synthesis changes with a time course that parallels related ECM genes, implicating miRNAs as key control points in AF-substrate generation.
- © 2010 by American Heart Association, Inc.