Sex differences in cardiac transcriptomic response to neonatal sleep apnea.

Pediatric obstructive sleep apnea poses a significant health risk, with potential long-term consequences on cardiovascular health. This study explores the dichotomous nature of neonatal cardiac response to chronic intermittent hypoxia (CIH) between males and females, aiming to fill a critical knowledge gap in the understanding of sex-specific cardiovascular consequences of sleep apnea in early life. Neonates were exposed to CIH until p28 and underwent comprehensive in vivo physiological assessments, including whole-body plethysmography, treadmill stress-tests, and echocardiography. Results indicated that male CIH rats weighed 13.7% less than age-matched control males (p = 0.0365), while females exhibited a mild yet significant increased respiratory drive during sleep (93.94 ± 0.84 vs. 95.31 ± 0.81;p = 0.02). Transcriptomic analysis of left ventricular tissue revealed a substantial sex-based difference in the cardiac response to CIH, with males demonstrating a more pronounced alteration in gene expression compared to females (5986 vs. 3174 genes). The dysregulated miRNAs in males target metabolic genes, potentially predisposing the heart to altered metabolism and substrate utilization. Furthermore, CIH in males was associated with thinner left ventricular walls and dysregulation of genes involved in the cardiac action potential, possibly predisposing males to CIH-related arrhythmia. These findings emphasize the importance of considering sex-specific responses in understanding the cardiovascular implications of pediatric sleep apnea.

Epigenetic Regulation of Cardiac Troponin Genes in Pediatric Patients with Heart Failure Supported by Ventricular Assist Device.

Ventricular Assist Device (VAD) therapy is considered as a part of standard care for end-stage Heart Failure (HF) children unresponsive to medical management, but the potential role of miRNAs in response to VAD therapy on molecular pathways underlying LV remodeling and cardiac function in HF is unknown. The aims of this study were to evaluate the effects of VAD on miRNA expression profile in cardiac tissue obtained from HF children, to determine the putative miRNA targets by an in-silico analysis as well as to verify the changes of predicated miRNA target in the same cardiac samples. The regulatory role of selected miRNAs on predicted targets was evaluated by a dedicated in vitro study. miRNA profile was determined in cardiac samples obtained from 13 HF children [median: 29 months; 19 LVEF%; 9 Kg] by NGS before VAD implant (pre-VAD) and at the moment of heart transplant (Post-VAD). Only hsa-miR-199b-5p, hsa-miR-19a-3p, hsa-miR-1246 were differentially expressed at post-VAD when compared to pre-VAD, and validated by real-time PCR. Putative targets of the selected miRNAs were involved in regulation of sarcomere genes, such as cardiac troponin (cTns) complex. The expression levels of fetal ad adult isoforms of cTns resulted significantly higher after VAD in cardiac tissue of HF pediatric patients when compared with HF adults. An in vitro study confirmed a down-regulatory effect of hsa-miR-19a-3p on cTnC expression. The effect of VAD on sarcomere organization through cTn isoform expression may be epigenetically regulated, suggesting for miRNAs a potential role as therapeutic targets to improve heart function in HF pediatric patients.

Functional annotation of differentially expressed fetal cardiac microRNA targets: implication for microRNA-based cardiovascular therapeutics.

Gene expression pattern of a failing heart depicts remarkable similarity with developing fetal heart. Elucidating genetic as well as epigenetic mechanisms regulating the gene expression during cardiac development will improve our understanding of cardiovascular diseases. In the present study, we aimed to validate and characterize differentially expressed known microRNAs (miRNA) obtained from next generation sequencing data of two fetal cardiac developmental stages (days 4th and 14th) from chicken (G. gallus domesticus) using bioinformatic approaches. Potential mRNA targets of individual miRNA were identified and classified according to their biological, cellular, and molecular functions. Functional annotation of putative target genes was performed to predict their association with cardiovascular diseases. We identified a total of 19 differentially expressed miRNAs between 4th and 14th day sample from the data sets obtained by next generation sequencing. A total of nearly 1522 potential targets ranging from 15 to 270 for each miRNA were predicted out of which 1221 were unique, while 301 were overlapping. Gene ontology and KEGG analysis revealed that majority of these target genes regulate critical cellular and molecular processes including transcriptional regulation, protein transport, signal transduction, matrix remodeling, Ras signaling, MAPK signaling, and TGF-beta signaling pathways indicating the complex nature of microRNA-mediated gene regulation during cardiogenesis. We found a significant association between potential target genes and cardiovascular diseases validating a link between fetal cardiac miRNAs and regulation of cardiovascular disease-related genes. These important findings may lay a foundation for further understanding the regulatory mechanisms operative in gene re-programming in the failing heart.