Transcriptomic Signatures of End-Stage Human Dilated Cardiomyopathy Hearts with and without Left Ventricular Assist Device Support.

Mihir Parikh,Gavin Y Oudit,Konrad S Famulski,Daniel Kim,Saumya Shah,Philip F Halloran,Ratnadeep Basu,John C Mullen

doi:10.3390/ijms23042050

Mihir Parikh, Gavin Y Oudit + Show 6 more

Open Access

https://doi.org/10.3390/ijms23042050

Copy DOI

Abstract

Left ventricular assist device (LVAD) use in patients with dilated cardiomyopathy (DCM) can lead to a differential response in the LV and right ventricle (RV), and RV failure remains the most common complication post-LVAD insertion. We assessed transcriptomic signatures in end-stage DCM, and evaluated changes in gene expression (mRNA) and regulation (microRNA/miRNA) following LVAD. LV and RV free-wall tissues were collected from end-stage DCM hearts with (n = 8) and without LVAD (n = 8). Non-failing control tissues were collected from donated hearts (n = 6). Gene expression (for mRNAs/miRNAs) was determined using microarrays. Our results demonstrate that immune response, oxygen homeostasis, and cellular physiological processes were the most enriched pathways among differentially expressed genes in both ventricles of end-stage DCM hearts. LV genes involved in circadian rhythm, muscle contraction, cellular hypertrophy, and extracellular matrix (ECM) remodelling were differentially expressed. In the RV, genes related to the apelin signalling pathway were affected. Following LVAD use, immune response genes improved in both ventricles; oxygen homeostasis and ECM remodelling genes improved in the LV and, four miRNAs normalized. We conclude that LVAD reduced the expression and induced additional transcriptomic changes of various mRNAs and miRNAs as an integral component of the reverse ventricular remodelling in a chamber-specific manner.

Highlights

Dilated cardiomyopathy (DCM) is a common manifestation of end-stage heart disease, characterized by left ventricle (LV) dilation, systolic dysfunction, and heart failure (HF) [1,2]
We showed that hypoxia-inducible factor 1 (HIF-1) was down-regulated in both LV and right ventricle (RV) of end-stage dilated cardiomyopathy (DCM) hearts suggesting that disturbance of oxygen homeostasis may play a role in the pathogenesis of end-stage DCM
Findings from our study suggest that changes in gene expression after Left ventricular assist device (LVAD) implementation is partly attributable to miRNA regulation, and LVAD use has a more pronounced effect on miRNA normalization in the RV compared to the LV

Summary

Introduction

Dilated cardiomyopathy (DCM) is a common manifestation of end-stage heart disease, characterized by left ventricle (LV) dilation, systolic dysfunction, and heart failure (HF) [1,2]. DCM is currently the leading cause of cardiac transplantation in adults. The improved survival of patients with HF, coupled with the overall rise in the prevalence of heart diseases, has led to an increase in the number of patients with advanced HF [3,4]. This creates a supply–demand imbalance for cardiac transplantation, with the number of recipients far exceeding the number of available donor hearts.

Methods

Results

Discussion

Conclusion