Metabolic maturation during postnatal right ventricular development switches to heart-contraction regulation due to volume overload

Abstract

Background: Metabolic maturation is one of the primary processes of postnatal cardiomyocyte development. How volume overload (VO), a pathological state of the right ventricle (RV) in children with congenital heart disease (CHD) and patients with heart failure, affects cardiomyocyte metabolic maturation is unclear.

Methods and results: A fistula between the abdominal aorta and inferior vena cava on postnatal day 7 (P7) was created in a mouse model to induce a young-aged RV VO. RNA sequencing revealed that the most enriched gene ontology (GO) terms of the upregulated transcriptome had been changed from metabolic maturation to heart contraction by VO. Transmission electron microscopy imaging showed that metabolic maturation marker-mitochondria were converted into the maturation style in the sham group while remaining unchanged in VO group. Calcium imaging showed that the calcium handling ability had slightly increased in the sham group but dramatically increased in the VO group, even with irregular contraction. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the top three enriched KEGG pathways for the upregulated transcriptome during normal RV development were the citrate cycle, cardiac muscle contraction, and protein processing in the endoplasmic reticulum. VO changed those to arrhythmogenic RV cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy.

Conclusions: Metabolic maturation of postnatal RV development was partly interrupted by VO, and the underlining mechanism was associated with the activation of cardiomyopathy pathways.

Keywords: Heart contraction; Metabolic maturation; RNA sequencing; Right ventricle; Volume overload.