Epigenetic Regulation of Cardiac Troponin Genes in Pediatric Patients with Heart Failure Supported by Ventricular Assist Device.

Rosetta Ragusa,Manuela Cabiati,Antonio Amodeo,Serena Del Turco,Maria Giovanna Trivella,Alberto Mercatanti,Milena Rizzo,Letizia Pitto,Giuseppina Basta,Arianna Di Molfetta,Chiara Caselli,Silvia Del Ry

doi:10.3390/biomedicines9101409

Abstract

Ventricular Assist Device (VAD) therapy is considered as a part of standard care for end-stage Heart Failure (HF) children unresponsive to medical management, but the potential role of miRNAs in response to VAD therapy on molecular pathways underlying LV remodeling and cardiac function in HF is unknown. The aims of this study were to evaluate the effects of VAD on miRNA expression profile in cardiac tissue obtained from HF children, to determine the putative miRNA targets by an in-silico analysis as well as to verify the changes of predicated miRNA target in the same cardiac samples. The regulatory role of selected miRNAs on predicted targets was evaluated by a dedicated in vitro study. miRNA profile was determined in cardiac samples obtained from 13 HF children [median: 29 months; 19 LVEF%; 9 Kg] by NGS before VAD implant (pre-VAD) and at the moment of heart transplant (Post-VAD). Only hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-1246 were differentially expressed at post-VAD when compared to pre-VAD, and validated by real-time PCR. Putative targets of the selected miRNAs were involved in regulation of sarcomere genes, such as cardiac troponin (cTns) complex. The expression levels of fetal ad adult isoforms of cTns resulted significantly higher after VAD in cardiac tissue of HF pediatric patients when compared with HF adults. An in vitro study confirmed a down-regulatory effect of hsa-miR-19a-3p on cTnC expression. The effect of VAD on sarcomere organization through cTn isoform expression may be epigenetically regulated, suggesting for miRNAs a potential role as therapeutic targets to improve heart function in HF pediatric patients.

Highlights

Unlike Heart Failure (HF) in adult patients, congenital heart disease (CHD) and dilated cardiomyopathy (DCM) have been identified among principal etiologic categories that favor the development of HF and the principal reasons for heart transplant in pediatric patients [4]
At the time of heart transplant all the analyzed bio-humoral markers were unmodified by Ventricular Assist Device (VAD) support when compared to pre-VAD, except for total bilirubin plasma levels (p = 0.0161) (Table 1)
Changes in cardiac miRNA profile in HF children supported by VAD were described for the changes in cardiac miRNA profile in HF children supported by VAD were described for first time in this pilot study

Summary

Introduction

Pediatric Heart Failure (HF) is a complex condition characterized by genetic, structural and neurohormonal abnormalities, resulting in ventricular dysfunction, volume or pressure overload, impaired oxygenation of organs and tissues [1,2]. The reported incidence of pediatric HF is 0.97 to 7.4 per 100,000 and it was estimated that more than 11,000 children are hospitalized for HF each year [3]. Unlike HF in adult patients, congenital heart disease (CHD) and dilated cardiomyopathy (DCM) have been identified among principal etiologic categories that favor the development of HF and the principal reasons for heart transplant in pediatric patients [4]. A dedicated trial aimed to verify the best medical treatments for HF children has not been performed yet, and drugs used in pediatric patients are Biomedicines 2021, 9, 1409.

Objectives

Results

Conclusion