PE-568-02 IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS FOR PACING INDUCED CARDIOMYOPATHY: A PILOT STUDY IN CHILDREN WITH CONGENITAL COMPLETE ATRIOVENTRICULAR BLOCK

Abstract

Chronic ventricular pacing in children can lead to pacing-induced cardiomyopathy (PICM). It is difficult to predict who will develop PICM, and CRT may have limited effectiveness when used too late. Micro RNAs (miRs), small non-coding RNAs which regulate gene expression, are emerging as tools to evaluate the mechanisms of heart failure and may aid in early diagnosis of PICM. To identify a circulating miR signature of adverse myocardial remodeling in paced patients preceding PICM to better follow disease progression. Clinical data and blood were collected from children with normal cardiac structure and function with RV pacing for >5 yrs for congenital complete AV block (N=9) and non-paced controls (N=13). miR microarrays were performed and differentially expressed miRs (FC>2, corrected p<0.05) and target pathways were identified using GeneSpring and mirPATH. RV paced patients and controls were age matched (15.7±2.4 vs 15.03±2.0 yrs, p=NS). Average pacing duration was 12.31±3.2 yrs, ventricular pacing occurred >95% of the time. No difference in EF was seen between groups (62±0.06% vs 65±0.03%, p=NS). 488 miRs were differently regulated between the groups. 296 miRs were upregulated, predicting downregulation of FoxO: gluconeogenesis and glycogenolysis; adherens junctions (miR-548); and protein turnover and degradation (miR-205). 192 miRs were downregulated, predicting upregulation of fatty acid metabolism (miR-195, 15), neurotransmitter and estrogen signaling (miR-126, 148). miRs regulating profibrotic TGF-Β and pro-apoptotic Hippo pathways, were both up and downregulated. We identified a unique, noninvasive miR signature in chronically paced children implicating heightened fatty acid metabolism to support increased energy demands of the paced heart, and protective estrogen signaling to promote nitric oxide metabolism and ion homeostasis. Profibrotic signaling was upregulated while cell-cell interaction was impaired. This miR pattern suggests early evidence of adverse myocardial remodeling despite normal EF on echo. Changes in circulating miRs may reflect an early signal of heart failure prior to the onset of ventricular dysfunction thus paving the way for the development of biomarkers predicting PICM.