Pediatric dilated cardiomyopathy hearts display a gene expression profile consistent with pluripotency and dedifferentiation

Abstract

Background: Our previous work has shown several myocellular differences in pediatric and adult dilated cardiomyopathy (DCM). However, a thorough characterization of the molecular pathways involved in pediatric DCM does not exist, limiting the development of age-specific therapies. To better characterize this patient population, we investigated the transcriptome profile of pediatric patients. Methods: RNA-seq from 7 DCM and 7 non-failing (NF) explanted pediatric left ventricles (LV) was performed. Changes in gene expression were confirmed by RT-PCR in 36 DCM and 21 NF pediatric hearts, and in 20 DCM and 10 NF adult hearts. The degree of myocyte hypertrophy was investigated in 4 DCM and 7 NF pediatric hearts, and in 4 DCM and 9 NF adult hearts. Neonatal ventricular myocytes (NRVMs) were treated with pluripotency-inducing factors, and changes in gene expression were determined by RT-PCR. Results: Changes in gene expression were identified in cytokine signaling, signal transduction, and transcription. Interestingly, these changes were age-dependent and are associated with dedifferentiation and pluripotency in cardiac progenitor cells. Importantly, myocytes from adult DCM hearts showed an increase in cell size that was not observed in pediatric hearts. Furthermore, treatment of NRVMs with pluripotency-inducing factors recapitulated changes in gene expression observed in the pediatric DCM heart. Conclusions: Pediatric DCM is characterized by unique changes in gene expression that suggest maintenance of an undifferentiated state. These changes are accompanied by lack of myocyte hypertrophy.