Ability of the Right Ventricle to Serve as a Systemic Ventricle in Response to the Volume Overload at the Neonatal Stage

SIMPLE SUMMARY: The right ventricle (RV) of children with hypoplastic left heart syndrome (HLHS), in which volume overload (VO) is inevitable, pumps blood into the systemic circulation. Understanding the molecular differences and their different responses to VO between the RV and left ventricle (LV) at the neonatal and highly plastic stages may improve the long-term management of children with HLHS. Using our newly developed neonatal ventricular VO model, we demonstrated that one of the major differences between a normal neonatal RV and LV is related to the insulin and thyroid hormone signaling pathways. In response to VO, the RV favored an arrhythmogenic right ventricular cardiomyopathy (ARVC) phenotypic change and the LV favored a reduction in microRNAs in cancer. Considering that a major cause of death in children with HLHS is arrhythmia, which is the hallmark of ARVC, the current study suggests that inhibiting ARVC may improve RV function. In addition, the current study also suggests that insulin, thyroid hormone, and cancer-associated microRNAs may be potential therapeutic targets that should be explored by basic science studies to improve the function of the RV to match that of the LV. ABSTRACT: Background: In children with hypoplastic left heart syndrome (HLHS), volume overload (VO) is inevitable, and the right ventricle (RV) pumps blood into the systemic circulation. Understanding the molecular differences and their different responses to VO between the RV and left ventricle (LV) at the neonatal and highly plastic stages may improve the long-term management of children with HLHS. Methods and Results: A neonatal rat ventricular VO model was established by the creation of a fistula between the inferior vena cava and the abdominal aorta on postnatal day 1 (P1) and confirmed by echocardiographic and histopathological analyses. Transcriptomic analysis demonstrated that some of the major differences between a normal neonatal RV and LV were associated with the thyroid hormone and insulin signaling pathways. Under the influence of VO, the levels of insulin receptors and thyroid hormone receptors were significantly increased in the LV but decreased in the RV. The transcriptomic analysis also demonstrated that under the influence of VO, the top two common enriched pathways between the RV and LV were the insulin and thyroid hormone signaling pathways, whereas the RV-specific enriched pathways were primarily associated with lipid metabolism and arrhythmogenic right ventricular cardiomyopathy (ARVC); further, the LV-specific enriched pathways were primarily associated with nucleic acid metabolism and microRNAs in cancer. Conclusions: Insulin and thyroid hormones may play critical roles in the differences between a neonatal RV and LV as well as their common responses to VO. Regarding the isolated responses to VO, the RV favors an ARVC change and the LV favors a reduction in microRNAs in cancer. The current study suggests that insulin, thyroid hormone, and cancer-associated microRNAs are potential therapeutic targets that should be explored by basic science studies to improve the function of the RV to match that of the LV.