Abstract 11039: Adverse Remodelling of the Cardiac Conduction System (CCS) in Heart Failure Could be the Result of Up and Down Regulation of MicroRNAs
In heart failure (HF) there is remodelling of ion channels, Ca-handling, gap junctions, fibrosis, inflammation and apoptosis genes in the CCS. This impairs pacemaker reserve and causes heart and bundle branch block. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression. We have tested the hypothesis that they are responsible for the remodelling by using mice in which HF was produced by transverse aortic constriction. After 6-7 weeks there was a ~139% increase in heart/body weight ratio, a decrease of ~50% in FS, and increases of 85% in left ventricular mass and ~58% and 22% in LVIDs and LVIDd (P<0.05). In the conscious HF mouse there was a 6% decrease in heart rate and a 20% prolongation of the QRS interval (P<0.05). In the anaesthetised HF mouse (under 2% isoflurane) there were increases of 9% in the PR interval and 17% in the QRS interval (P<0.05). These data show dysfunction of the CCS, which is consistent with changes in the sinoatrial node (SAN; one part of CCS), where measurement of mRNA by qPCR showed e.g. significant downregulation of HCN4 (responsible for pacemaker funny current) and Tbx18 (transcription factor), and upregulation in Col1a1 (collagen, type 1, alpha 1) and Mef2c (transcription factor). Expression of 368 miRs in the SAN was measured by microarray analysis and compared to that in the left (LA) and right (RA) atrium. In control healthy mice 31 miRs showed significant differences in expression between SAN and LA (24 more abundant in SAN and 7 in LA) and 15 miRs showed differences in expression between SAN and RA (11 more abundant in SAN and 4 in RA). In HF, there were 17 changes in miRs in the SAN. For example, miR-582-5p (using Ingenuity IPA software, predicted to affect SUR1, PMCA1 and RYR2) was upregulated 8-fold in the SAN. miR-501-3p (predicted to affect Cx43) was upregulated 4-fold in the SAN. miR-146b (predicted to affect Tbx18) was upregulated by 190% in the SAN. miR-21 (affects Nkx2-5, Mef2c and Col1a1) was upregulated by 149% in the SAN. miR-34a was upregulated by 130% in the SAN. The altered miRs are predicted to target ion channel, Ca-handling, gap junction, fibrosis, inflammation and apoptosis genes. In conclusion, we have found up and down regulation of miRs in the CCS in HF and this could be responsible for the adverse remodelling of the system.
- © 2013 by American Heart Association, Inc.