ABSTRACT
Objective: Prolonged mechanical ventilation in children undergoing cardiac surgery is related to the decrease in cardiac output. The pressure recording analytical method (PRAM) is a minimally invasive system for continuous hemodynamic monitoring. To evaluate the postoperative prognosis, our study explored the predictive value of hemodynamic management for the duration of mechanical ventilation (DMV). Methods: This retrospective study included 60 infants who underwent cardiac surgery. Cardiac index (CI), the maximal slope of systolic upstroke (dp/dtmax), and cardiac cycle efficiency (CCE) derived from PRAM were documented in each patient 0, 4, 8, and 12 h (T0, T1, T2, T3, and T4, respectively) after their admission to the intensive care unit (ICU). A linear mixed model was used to deal with the hemodynamic data. Correlation analysis, receiver operating characteristic (ROC), and a XGBoost machine learning model were used to find the key factors for prediction. Results: Linear mixed model revealed time and group effect in CI and dp/dtmax. Prolonged DMV also have negative correlations with age, weight, CI at and dp/dtmax at T2. dp/dtmax outweighing CI was the strongest predictor (AUC of ROC: 0.978 vs. 0.811, p < 0.01). The machine learning model suggested that dp/dtmax at T2 ≤ 1.049 or < 1.049 in combination with CI at T0 ≤ 2.0 or >2.0 can predict whether prolonged DMV (AUC of ROC = 0.856). Conclusion: Cardiac dysfunction is associated with a prolonged DMV with hemodynamic evidence. CI measured by PRAM immediately after ICU admission and dp/dtmax 8h later are two key factors in predicting prolonged DMV.
ABSTRACT
BACKGROUND: Congenital heart disease (CHD) is resulted from the interaction of genetic aberration and environmental factors. Imprinted genes, which are regulated by epigenetic modifications, are essential for the normal embryonic development. However, the role of imprinted genes in the etiology of CHD remains unclear. METHODS: After the samples were treated with bisulfate salt, imprinted genes methylation were measured by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. T test and One-way ANOVA were performed to evaluate the differences among groups. Odds ratios (ORs) were performed to evaluate the incidence risk of CHD in relation to methylation levels. RESULTS: We investigated the alterations of imprinted gene germline differential methylation regions (gDMRs) methylation in patients with CHD. Eighteen imprinted genes that are known to affect early embryonic development were selected and the methylation modification genes were detected by massarray in 27 CHD children and 28 healthy children. Altered gDMR methylation level of 8 imprinted genes was found, including 2 imprinted genes with hypermethylation of GRB10 and MEST and 6 genes with hypomethylation of PEG10, NAP1L5, INPP5F, PLAGL1, NESP and MEG3. Stratified analysis showed that the methylation degree of imprinted genes was different in different types of CHD. Risk analysis showed that 6 imprinted genes, except MEST and NAP1L5, within a specific methylation level range were the risk factors for CHD CONCLUSION: Altered methylation of imprinted genes is associated with CHD and varies in different types of CHD. Further experiments are warranted to identify the methylation characteristics of imprinted genes in different types of CHD and clarify the etiologies of imprinted genes in CHD.
Subject(s)
Heart Defects, Congenital , Child , DNA Methylation , Epigenesis, Genetic , Female , Humans , Male , Pilot Projects , PregnancyABSTRACT
Congenital heart disease (CHD) with extracardiac malformations (EM) is the most common multiple malformation, resulting from the interaction between genetic abnormalities and environmental factors. Most studies have attributed the causes of CHD with EM to chromosomal abnormalities. However, multi-system dysplasia is usually caused by both genetic mutations and epigenetic dysregulation. The epigenetic mechanisms underlying the pathogenesis of CHD with EM remain unclear. In this study, we investigated the mechanisms of imprinting alterations, including those of the Small nuclear ribonucleoprotein polypeptide N (SNRPN), PLAG1 like zinc finger 1 (ZAC1) and inositol polyphosphate-5-phosphatase F (INPP5F) genes, in the pathogenesis of CHD with EM. The methylation levels of SNRPN, ZAC1, and INPP5F genes were analysed by the MassARRAY platform in 24 children with CHD with EM and 20 healthy controls. The expression levels of these genes were detected by real-time polymerase chain reaction (PCR). The correlation between methylation regulation and gene expression was confirmed using 5-azacytidine (5-Aza) treated cells. The methylation levels of SNRPN and ZAC1 genes were significantly increased in CHD with EM, while that of INPP5F was decreased. The methylation alterations of these genes were negatively correlated with expression. Risk analysis showed that abnormal hypermethylation of SNRPN and ZAC1 resulted in 5.545 and 7.438 times higher risks of CHD with EM, respectively, and the abnormal hypomethylation of INPP5F was 8.38 times higher than that of the control group. We concluded that abnormally high methylation levels of SNRPN and ZAC1 and decreased levels of INPP5F imply an increased risk of CHD with EM by altering their gene functions. This study provides evidence of imprinted regulation in the pathogenesis of multiple malformations.
