Introduction: Current treatment for pediatric dilated cardiomyopathy (DCM) patients is extrapolated from evidence-based practices in adults with heart failure (HF); however, these therapies fail to provide the same improvement in outcomes in pediatric HF patients as they do in adult HF patients. Our work demonstrates differences in the molecular characteristics of pediatric and adult DCM patients highlighting the importance of pediatric-focused studies. Currently, there are no animal models to study this disease.
Methods: We developed a primary cell culture model to investigate pediatric DCM. Neonatal rat ventricular myocytes (NRVMs) were treated with 2% volume by volume serum of pediatric DCM patients and non-failing (NF) controls. RNA-seq (1X50 directional mRNAseq) was performed on NRVMs treated with NF (n=3) and DCM (n=3) sera for 72 hours. Aligned reads were normalized and annotated using the EdgeR pipeline. Significant changes in gene expression were calculated using a non-parametric t-test with a threshold of p<0.05. Ingenuity Pathway Analysis, Metascape, and Word Cloud were performed to investigate biological processes affected in response to dysregulated genes. Mitochondria function and autophagy were investigated in treated cells.
Results: RNA-seq analysis identified 1,715 genes dysregulated in DCM serum-treated cells. Transcriptome analysis of treated cells was compared to our recent published transcriptome dataset in pediatric DCM hearts. Pathways altered in treated cells and in DCM hearts were similar. Moreover, mitochondria function was impaired in DCM serum-treated cells and in DCM hearts, and autophagy was dysregulated in DCM serum-treated cells.
Conclusions: Our results show that serum-circulating factors can mediate pathologic changes in primary cardiomyocytes, and that these changes resemble functional changes in the pediatric DCM heart. We propose that serum-treated NRVMs are a valid model system to investigate factors involved in DCM progression.