Highly comparative time series analysis (HCTSA) is a novel approach involving massive feature extraction using publicly available code from many disciplines. The Prematurity-Related Ventilatory Control (Pre-Vent) observational multicenter prospective study collected bedside monitor data from > 700 extremely preterm infants to identify physiologic features that predict respiratory outcomes. We calculated a subset of 33 HCTSA features on > 7M 10-minute windows of oxygen saturation (SPO2) and heart rate (HR) from the Pre-Vent cohort to quantify predictive performance. This subset included representatives previously identified using unsupervised clustering on > 3500 HCTSA algorithms. Performance of each feature was measured by individual area under the receiver operating curve (AUC) at various days of life and binary respiratory outcomes. These were compared to optimal PreVent physiologic predictor IH90 DPE, the duration per event of intermittent hypoxemia events with threshold of 90%. The top HCTSA features were from a cluster of algorithms associated with the autocorrelation of SPO2 time series and identified low frequency patterns of desaturation as high risk. These features had comparable performance to and were highly correlated with IH90_DPE but perhaps measure the physiologic status of an infant in a more robust way that warrants further investigation. The top HR HCTSA features were symbolic transformation measures that had previously been identified as strong predictors of neonatal mortality. HR metrics were only important predictors at early days of life which was likely due to the larger proportion of infants whose outcome was death by any cause. A simple HCTSA model using 3 top features outperformed IH90_DPE at day of life 7 (.778 versus .729) but was essentially equivalent at day of life 28 (.849 versus .850). These results validated the utility of a representative HCTSA approach but also provides additional evidence supporting IH90_DPE as an optimal predictor of respiratory outcomes.
Abstract Pulmonary hypertension (PH) increases the mortality of preterm infants with bronchopulmonary dysplasia (BPD). There are no curative therapies for this disease. Lung endothelial carnitine palmitoyltransferase 1a (Cpt1a), the rate‐limiting enzyme of the carnitine shuttle system, is reduced in a rodent model of BPD. It is unknown whether endothelial Cpt1a reduction causes pulmonary vascular (PV) remodeling. The latter can be the result of endothelial‐mesenchymal transition (EndoMT). Here, endothelial cell (EC)‐specific Cpt1a KO and WT mice (<12 h old) are exposed to hyperoxia (70% O 2 ) for 14 days and allow them to recover in normoxia until postnatal day 28. Hyperoxia causes PH, which is aggravated in EC‐specific Cpt1a KO mice. Upregulating endothelial Cpt1a expression inhibits hyperoxia‐induced PV remodeling. Hyperoxia causes lung EndoMT, detected by immunofluorescence, scRNA‐sequencing, and EC lineage tracing, which is further increased in EC‐specific Cpt1a KO mice. Blocking EndoMT inhibits hyperoxia‐induced PV remodeling. Male mice under the same high oxygen conditions develop a higher degree of PH than females, which is associated with reduced endothelial Cpt1a expression. Conclusively, neonatal hyperoxia causes PH by decreasing endothelial Cpt1a expression and upregulating EndoMT. This provides a valuable strategy for developing targeted therapies by upregulating endothelial Cpt1a levels or inhibiting EndoMT to treat BPD‐associated PH.
Heme oxygenase-1 is induced by many cellular stressors and catalyzes the breakdown of heme to generate carbon monoxide and bilirubin, which confer cytoprotection. The role of HO-1 likely extends beyond the simple production of antioxidants, for example HO-1 activity has also been implicated in metabolism, but this function remains unclear. Here we used an HO-1 knockout lung cell line to further define the contribution of HO-1 to cellular metabolism. We found that knockout cells exhibit reduced growth and mitochondrial respiration, measured by oxygen consumption rate. Specifically, we found that HO-1 contributed to electron transport chain activity and utilization of certain mitochondrial fuels. Loss of HO-1 had no effect on intracellular non-heme iron concentration or on proteins whose levels and activities depend on available iron. We show that HO-1 supports essential functions of mitochondria, which highlights the protective effects of HO-1 in diverse pathologies and tissue types. Our results suggest that regulation of heme may be an equally significant role of HO-1.
