Pediatric/Adult Congenital Heart Disease -> Translational D-PO06 - Poster Session VI (ID 26) Poster

D-PO06-062 - Identification Of Novel Therapeutic Targets For Pacing Induced Cardiomyopathy In Children (ID 693)

Disclosure
 B.M. Navarre: Nothing relevant to disclose.

Abstract

Background: Chronic ventricular pacing in children can lead to pacing-induced cardiomyopathy. The pathogenesis of pacing-induced cardiomyopathy is poorly understand and therapies such as cardiac resynchronization may have limited effectiveness. Micro RNAs (miRs) are small non-coding RNAs which regulate gene expression and are emerging as key biomarkers of heart failure and may elucidate the mechanisms of pacing-induced cardiomyopathy.
Objective: To identify a circulating miR signature to understand adverse myocardial remodeling preceding pacing-induced cardiomyopathy and to identify novel therapeutic targets.
Methods: Blood was collected from children with right ventricular pacing for over 5 years with congenital complete AV block (N=7) and non-paced controls (N=6). Inclusion criteria included structurally normal hearts and normal left ventricular function. RNA was isolated from the buffy coat. miR microarrays were performed and GeneSpring GX software was used to identify differently regulated miRs (fold change >2, FDR corrected p value <0.05) and miR target pathways.
Results: There was no difference in age between patient groups (15.9±2.7 yrs vs. 14.2±2.0 yrs, p = NS). Average duration of pacing was 11.7±3.4 years, ventricular pacing occurring >85% of the time, and QRS duration was longer in paced 145±22 msec vs. control 94±11 msec (p<0.01) patients. 488 miRs were differently regulated between paced and control groups. 296 miRs were up-regulated, predicting down-regulation of pro-inflammatory and pro-fibrotic pathways (FoxO and Wnt). 192 miRs were down-regulated, predicting up-regulation of fatty acid metabolism and biosynthesis. miRs regulating TGF-&#914; (pro-fibrotic) and Hippo (anti-proliferative and pro-apoptotic) pathways were both up and down-regulated.
Conclusion: In this pilot study, we identified a unique, noninvasive miR signature in paced children with normal function suggesting increased energy demand as well as competing maladaptive and protective signaling changes involving myocyte survival, inflammation and fibrosis. Changes in circulating miRs may reflect an early signal of adverse myocardial remodeling paving the way for the development of novel therapies to preserve long-term ventricular function.
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