Placental-Heart Axis: An Evolutionary Perspective.

To maintain its development, the growing fetus is directly dependent on the placenta, an organ that acts as both a modulator and mediator. As an essential component of pregnancy that is derived from both maternal and fetal tissues, the placenta facilitates the passage of all oxygen and nutrients from the expecting parent to their fetuses. Further, the placenta conveys multiple impacts of the maternal environment to the growing fetus. The timing of placental development parallels that of the fetal cardiovascular system, and placental anomalies are implicated as a potential cause of congenital heart disease. For example, congenital heart disease is more common in pregnancies complicated by maternal preeclampsia, a condition characterized by placental dysfunction. Given the placenta's intermediary links to the maternal environment and fetal health outcomes, it is an emerging focus of evolutionary medicine, which seeks to understand how interactions between humans and the environment affect our biology and give rise to disease. The present review provides an overview of the evolutionary and developmental courses of the placenta as well as their implications on infant health.

Maternal Vascular Malperfusion and Anatomic Cord Abnormalities Are Prevalent in Pregnancies With Fetal Congenital Heart Disease.

OBJECTIVE: Impairments in the maternal-fetal environment are associated with adverse postnatal outcomes among infants with congenital heart disease. Therefore, we sought to investigate placental anomalies as they related to various forms of fetal congenital heart disease (FCHD). METHODS: We reviewed the placental pathology in singleton pregnancies with and without FCHD. FCHD was divided into separate categories (transposition physiology, obstructive left, obstructive right, biventricular without obstruction, and others). Exclusion criteria included other prenatally known structural malformations and/or aneuploidy. The significance threshold was set at p < 0.05 or False Discovery rate q < 0.05 when multiple tests were performed. RESULTS: The cohort included 215 FCHD and 122 non-FCHD placentas. FCHD placentas showed increased rates of maternal vascular malperfusion (24% vs. 5%, q < 0.001) and cord anomalies (27% vs. 1%, q < 0.001). Placentas with fetal TGA demonstrated a lower rate of hypoplasia when compared with other FCHD types (1/39 vs. 51/176, Fisher's exact p = 0.015). CONCLUSION: Placental maternal vascular malperfusion is increased in FCHD. The prevalence of vascular malperfusion did not differ by FCHD type, indicating that CHD type does not predict the likelihood of placental vascular dysfunction. Further investigation of the placental-fetal heart axis in FCHD is warranted given the importance of placental health.

Predictive modeling of endocardial fibroelastosis recurrence in patients with congenital heart disease.

BACKGROUND: Endocardial fibroelastosis (EFE) is a major effector in the maldevelopment of the heart in patients with congenital heart disease. Despite successful surgical removal, EFE can redevelop, but the underlying cause of EFE recurrence remains unknown. This study aimed to identify hemodynamic predictors and genetic links to epithelial/endothelial-to-mesenchymal transition (EMT/EndMT) alterations for preoperative risk assessment. METHODS: We assessed the impact of preoperative hemodynamic parameters on EFE recurrence in a cohort of 92 patients with congenital heart disease who underwent left ventricular (LV) EFE resection between January 2010 and March 2021. Additionally, whole-exome sequencing in 18 patients was used to identify rare variants (minor allele frequency <10-5) in high-expression heart (HHE) genes related to cardiac EMT/EndMT and congenital heart disease. RESULTS: EFE recurred in 55.4% of patients, within a median of 2.2 years postsurgery. Multivariable analysis revealed specific hemodynamic parameters (mitral valve inflow and area, LV filling pressure, and aortic valve gradient and diameter) as predictors, forming a predictive model with an area under the receiver operating characteristic curve of 0.782. Furthermore, 89% of the patients exhibited damaging variants in HHE genes, with 38% linked to cardiac EMT/EndMT Gene Ontology processes and 22% associated with known congenital heart disease genes. Notably, HHE genes associated with cardiac EMT/EndMT were significantly associated with faster EFE recurrence in a multivariate analysis (hazard ratio, 3.56; 95% confidence interval, 1.24-10.17; P = .018). CONCLUSIONS: These findings established a predictive scoring system using preoperative hemodynamic parameters for EFE recurrence risk assessment. Alterations in HHE genes, particularly those linked to cardiac EMT/EndMT, exacerbate the risk of recurrence.

Elevated serum neurologic biomarker profiles after cardiac arrest in a porcine model.

Introduction: Swine exhibit cerebral cortex mitochondrial dysfunction and neuropathologic injury after hypoxic cardiac arrest treated with hemodynamic-directed CPR (HD-CPR) despite normal Cerebral Performance Category scores. We analyzed the temporal evolution of plasma protein biomarkers of brain injury and inflammatory cytokines, as well as cerebral cortical mitochondrial injury and neuropathology for five days following pediatric asphyxia-associated cardiac arrest treated with HD-CPR. Methods: One-month-old swine underwent asphyxia associated cardiac arrest, 10-20 min of HD-CPR (goal SBP 90 mmHg, coronary perfusion pressure 20 mmHg), and randomization to post-ROSC survival duration (24, 48, 72, 96, 120 h; n = 3 per group) with standardized post-resuscitation care. Plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokine levels were collected pre-injury and 1, 6, 24, 48, 72, 96, and 120 h post-ROSC. Cerebral cortical tissue was assessed for: mitochondrial respirometry, mass, and dynamic proteins; oxidative injury; and neuropathology. Results: Relative to pre-arrest baseline (9.4 pg/ml [6.7-12.6]), plasma NfL was increased at all post-ROSC time points. Each sequential NfL measurement through 48 h was greater than the previous value {1 h (12.7 pg/ml [8.4-14.6], p = 0.01), 6 h (30.9 pg/ml [17.7-44.0], p = 0.0004), 24 h (59.4 pg/ml [50.8-96.1], p = 0.0003) and 48 h (85.7 pg/ml [61.9-118.7], p = 0.046)}. Plasma GFAP, inflammatory cytokines or cerebral cortical tissue measurements were not demonstrably different between time points. Conclusions: In a swine model of pediatric cardiac arrest, plasma NfL had an upward trajectory until 48 h post-ROSC after which it remained elevated through five days, suggesting it may be a sensitive marker of neurologic injury following pediatric cardiac arrest.

A genome-wide CRISPR screen identifies BRD4 as a regulator of cardiomyocyte differentiation.

Human induced pluripotent stem cell (hiPSC) to cardiomyocyte (CM) differentiation has reshaped approaches to studying cardiac development and disease. In this study, we employed a genome-wide CRISPR screen in a hiPSC to CM differentiation system and reveal here that BRD4, a member of the bromodomain and extraterminal (BET) family, regulates CM differentiation. Chemical inhibition of BET proteins in mouse embryonic stem cell (mESC)-derived or hiPSC-derived cardiac progenitor cells (CPCs) results in decreased CM differentiation and persistence of cells expressing progenitor markers. In vivo, BRD4 deletion in second heart field (SHF) CPCs results in embryonic or early postnatal lethality, with mutants demonstrating myocardial hypoplasia and an increase in CPCs. Single-cell transcriptomics identified a subpopulation of SHF CPCs that is sensitive to BRD4 loss and associated with attenuated CM lineage-specific gene programs. These results highlight a previously unrecognized role for BRD4 in CM fate determination during development and a heterogenous requirement for BRD4 among SHF CPCs.

Results of the RVA Breathes randomized controlled trial.

OBJECTIVE: This study tested a randomized controlled trial of RVA Breathes, a community asthma program, in reducing asthma-related healthcare utilization among children living in an area with a high poverty rate. METHODS: Participants included 250 caregivers (78% African American/Black; 73.3% household income<$25,000/year) and their children with asthma (5-11 years). Inclusion criteria included an asthma-related emergency department (ED) visit, hospitalization, unscheduled doctor's visit, or systemic steroids in the past 2 years. Families were randomized to a full active intervention (asthma education with community health workers [CHWs], home remediation with home assessors, and a school nurse component; n = 118), partial active intervention (asthma education and home remediation; n = 69), or a control group (n = 63) for 9 months. Measures on healthcare utilization and asthma-related factors were collected. Follow-up assessments occurred across a 9-month period. RESULTS: Although we did not find any significant effects, there was a trend toward significance for a group by time effect with objective healthcare utilization as the outcome (F4,365 = 2.28, p = .061). The full intervention group experienced a significant decrease from baseline to 9-month follow-up compared with the other groups (p < .001). Only the full intervention group experienced a significant increase in reported asthma action plans across time (no significant group effect). CONCLUSIONS: In the context of the unprecedented COVID-19 pandemic, which led to a substantial global decrease in healthcare utilization, the study's main hypotheses were not supported. Nevertheless, findings support the benefit of community asthma programs that integrate care across multiple settings and connect families with CHWs.

Identifying novel data-driven subgroups in congenital heart disease using multi-modal measures of brain structure.

Individuals with congenital heart disease (CHD) have an increased risk of neurodevelopmental impairments. Given the hypothesized complexity linking genomics, atypical brain structure, cardiac diagnoses and their management, and neurodevelopmental outcomes, unsupervised methods may provide unique insight into neurodevelopmental variability in CHD. Using data from the Pediatric Cardiac Genomics Consortium Brain and Genes study, we identified data-driven subgroups of individuals with CHD from measures of brain structure. Using structural magnetic resonance imaging (MRI; N = 93; cortical thickness, cortical volume, and subcortical volume), we identified subgroups that differed primarily on cardiac anatomic lesion and language ability. In contrast, using diffusion MRI (N = 88; white matter connectivity strength), we identified subgroups that were characterized by differences in associations with rare genetic variants and visual-motor function. This work provides insight into the differential impacts of cardiac lesions and genomic variation on brain growth and architecture in patients with CHD, with potentially distinct effects on neurodevelopmental outcomes.

Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes.

Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (P = 1.2 × 10-8) of SOST (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (P = 8.7 × 10-8) of the SOST transcriptional activator ZNF467 (chr7). Euploid and T21 cardiac endothelial cells coexpressed SOST and ZNF467; however, T21 endothelial cells expressed 6.9-fold more SOST than euploid endothelial cells (P = 2.7 × 10-27). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of DSCAM, residing within the chr21 CHD critical region, correlated with SOST (P = 1.9 × 10-5) and ZNF467 (P = 2.9 × 10-4). Deletion of DSCAM from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.

The Evolving Role of Genetic Evaluation in the Prenatal Diagnosis and Management of Congenital Heart Disease.

Congenital heart disease (CHD) is increasingly diagnosed prenatally and the ability to screen and diagnose the genetic factors involved in CHD have greatly improved. The presence of a genetic abnormality in the setting of prenatally diagnosed CHD impacts prenatal counseling and ensures that families and providers have as much information as possible surrounding perinatal management and what to expect in the future. This review will discuss the genetic evaluation that can occur prior to birth, what different genetic testing methods are available, and what to think about in the setting of various CHD diagnoses.

Meta-regression of sulcal patterns, clinical and environmental factors on neurodevelopmental outcomes in participants with multiple CHD types.

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change ß = 0.7, false discovery rate P = 0.004; ß = 4.1, false discovery rate P = 0.03; and ß = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.

"Are we working (too) comfortably?": a focus group study to understand sedentary behaviour when working at home and identify intervention strategies.

BACKGROUND: The Covid-19 pandemic initiated an enduring shift in working patterns, with many employees now working at home (w@h). This shift has exacerbated existing high levels of occupational sedentary behaviour (SB) in office workers, which is a recognised risk to health and well-being. This study aimed to use the Capability-Opportunity-Motivation-Behaviour (COM-B) model to better understand both employees' SB, and line managers behaviour to assist employees to reduce SB when w@h, and identify how employees can best be supported to reduce SB. METHODS: Three online focus groups with employees aged 18-40 working in desk-based roles (e.g. administrative / sales / customer services) (n = 21), and three with line managers (n = 21) were conducted. The focus groups facilitated discussion regarding participants' current behaviour, what impacts it, and what could be done to reduce employee SB when w@h. The focus group data were thematically analysed guided by the COM-B framework to understand influences on behaviour, and to identify promising intervention strategies. RESULTS: Most participants recognised that w@h had elevated employee occupational SB, and line managers reported the importance of supporting employees to manage their workload, and encouraging and modelling taking breaks. There were multiple influences on both employee and line manager behaviour with capability, opportunity and motivation all perceived as influential, although not equally. For example, a major theme related to the reduced physical opportunities for employees to reduce their SB when w@h, including blurred work-life boundaries. Changes in physical opportunities also made supporting employees challenging for line managers. Additionally, the w@h environment included unique social opportunities that negatively impacted the behaviour of both groups, including an expectation to always be present online, and social norms. A range of strategies for reducing SB when w@h at both individual and organisational level were suggested. CONCLUSIONS: It was evident that SB when w@h is influenced by a range of factors, and therefore multi-component intervention strategies are likely to be most effective in reducing SB. Future intervention research is a priority to evaluate and refine strategies, and inform w@h guidance to protect both the short-term and long-term health consequences of elevated SB for those who continue to w@h.

What is the Evidence for Using Intranasal Medicine in the Prehospital Setting? A Systematic Review.

OBJECTIVES: Intranasal (IN) medications offer a safe non-invasive way to rapidly deliver drugs in situations where intravenous (IV) access and intramuscular (IM) administration is challenging or not feasible. In the prehospital setting, this can be an essential alternative in time critical situations including trauma management, seizures, and agitated patients. However, there is a paucity of evidence summarizing its efficacy in this environment. This systematic review aims to assess the current evidence supporting the use of IN medicine (midazolam, ketamine, fentanyl, morphine, glucagon, and naloxone) in the prehospital setting alone. METHODS: A systematic literature search (PROSPERO CRD42023440713) of PubMed, Web of Science, OVID Medline, "Cochrane Central Register of Controlled Trials," Cochrane reviews and Embase was performed from inception to June 2023 to identify studies where IN medications were administered to patients in the prehospital setting. All randomized controlled trials, observational cohort studies, case series, and case reports were included. Papers not written in English, review articles, abstracts, and non-published data (including letters to the editor) were excluded. The methodological quality of the included studies was interpreted using the Cochrane risk of bias tool and rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. No funding was received. RESULTS: From 4818 studies, 39 were included (seven for midazolam, five for ketamine, twelve for fentanyl, one for diamorphine, two for glucagon, and twelve for naloxone). A total of 24,097 patients were treated with IN medications across all the studies. There were five moderate quality, four low quality, and thirty very low quality studies. The potential efficacy of IN fentanyl and ketamine was demonstrated consistently throughout the studies with less clear evidence for midazolam, morphine, glucagon, and naloxone. This review was severely limited by the study quality, with most studies demonstrating "high concerns" for bias. CONCLUSIONS: Prehospital IN medication administration has wide-ranging potential, particularly for administering analgesia. There are likely to be certain populations, for example, pediatrics, that will benefit the most, although conclusions are limited by the quality of evidence currently available. We encourage additional research in this area, particularly with robust prospective double-blind RCTs.

Preliminary report of a thoracic duct-to-pulmonary vein lymphovenous anastomosis in swine: A novel technique and potential treatment for lymphatic failure.

OBJECTIVE: The thoracic duct is the largest lymphatic vessel in the body, and carries fluid and nutrients absorbed in abdominal organs to the central venous circulation. Thoracic duct obstruction can cause significant failure of the lymphatic circulation (i.e., protein-losing enteropathy, plastic bronchitis, etc.). Surgical anastomosis between the thoracic duct and central venous circulation has been used to treat thoracic duct obstruction but cannot provide lymphatic decompression in patients with superior vena cava obstruction or chronically elevated central venous pressures (e.g., right heart failure, single ventricle physiology, etc.). Therefore, this preclinical feasibility study sought to develop a novel and optimal surgical technique for creating a thoracic duct-to-pulmonary vein lymphovenous anastomosis (LVA) in swine that could remain patent and preserve unidirectional lymphatic fluid flow into the systemic venous circulation to provide therapeutic decompression of the lymphatic circulation even at high central venous pressures. METHODS: A thoracic duct-to-pulmonary vein LVA was attempted in 10 piglets (median age 80 [IQR 80-83] days; weight 22.5 [IQR 21.4-26.8] kg). After a right thoracotomy, the thoracic duct was mobilized, transected, and anastomosed to the right inferior pulmonary vein. Animals were systemically anticoagulated on post-operative day 1. Lymphangiography was used to evaluate LVA patency up to post-operative day 7. RESULTS: A thoracic duct-to-pulmonary vein LVA was successfully completed in 8/10 (80.0%) piglets, of which 6/8 (75.0%) survived to the intended study endpoint without any complication (median 6 [IQR 4-7] days). Initially, 2/10 (20.0%) LVAs were aborted intraoperatively, and 2/10 (20.0%) animals were euthanized early due to post-operative complications. However, using an optimized surgical technique, the success rate for creating a thoracic duct-to-pulmonary vein LVA in six animals was 100%, all of which survived to their intended study endpoint without any complications (median 6 [IQR 4-7] days). LVAs remained patent for up to seven days. CONCLUSION: A thoracic duct-to-pulmonary vein LVA can be completed safely and remain patent for at least one week with systemic anticoagulation, which provides an important proof-of-concept that this novel intervention could effectively offload the lymphatic circulation in patients with lymphatic failure and elevated central venous pressures.

Normoxic Management during Cardiopulmonary Bypass Does Not Reduce Cerebral Mitochondrial Dysfunction in Neonatal Swine.

Optimal oxygen management during pediatric cardiopulmonary bypass (CPB) is unknown. We previously demonstrated an increase in cortical mitochondrial reactive oxygen species and decreased mitochondrial function after CPB using hyperoxic oxygen management. This study investigates whether controlled oxygenation (normoxia) during CPB reduces cortical mitochondrial dysfunction and oxidative injury. Ten neonatal swine underwent three hours of continuous CPB at 34 °C (flow > 100 mL/kg/min) via cervical cannulation targeting a partial pressure of arterial oxygen (PaO2) goal < 150 mmHg (normoxia, n = 5) or >300 mmHg (hyperoxia, n = 5). The animals underwent continuous hemodynamic monitoring and serial arterial blood sampling. Cortical microdialysate was serially sampled to quantify the glycerol concentration (represents neuronal injury) and lactate-to-pyruvate ratio (represents bioenergetic dysfunction). The cortical tissue was analyzed via high-resolution respirometry to quantify mitochondrial oxygen consumption and reactive oxygen species generation, and cortical oxidized protein carbonyl concentrations were quantified to assess for oxidative damage. Serum PaO2 was higher in hyperoxia animals throughout CPB (p < 0.001). There were no differences in cortical glycerol concentration between groups (p > 0.2). The cortical lactate-to-pyruvate ratio was modestly elevated in hyperoxia animals (p < 0.03) but the values were not clinically significant (<30). There were no differences in cortical mitochondrial respiration (p = 0.48), protein carbonyls (p = 0.74), or reactive oxygen species generation (p = 0.93) between groups. Controlled oxygenation during CPB does not significantly affect cortical mitochondrial function or oxidative injury in the acute setting. Further evaluation of the short and long-term effects of oxygen level titration during pediatric CPB on cortical tissue and other at-risk brain regions are needed, especially in the presence of cyanosis.

Who Still Gets Ligated? Reasons for Persistence of Surgical Ligation of the Patent Ductus Arteriosus Following Availability of Transcatheter Device Occlusion for Premature Neonates.

(1) Background: To identify reasons for the persistence of surgical ligation of the patent ductus arteriosus (PDA) in premature infants after the 2019 Food and Drug Administration (FDA) approval of transcatheter device closure; (2) Methods: We performed a 10-year (2014-2023) single-institution retrospective study of premature infants (<37 weeks) and compared clinical characteristics and neonatal morbidities between neonates that underwent surgical ligation before (epoch 1) and after (epoch 2) FDA approval of transcatheter closure; (3) Results: We identified 120 premature infants that underwent surgical ligation (n = 94 before, n = 26 after FDA approval). Unfavorable PDA morphology, active infection, and recent abdominal pathology were the most common reasons for surgical ligation over device occlusion in epoch 2. There were no differences in demographics, age at closure, or outcomes between infants who received surgical ligation in the two epochs; (4) Conclusions: Despite increasing trends for transcatheter PDA closure in premature infants, surgical ligation persists due to unfavorable ductal morphology, active infection, or abdominal pathology.

Genome Sequencing is Critical for Forecasting Outcomes following Congenital Cardiac Surgery.

While genome sequencing has transformed medicine by elucidating the genetic underpinnings of both rare and common complex disorders, its utility to predict clinical outcomes remains understudied. Here, we used artificial intelligence (AI) technologies to explore the predictive value of genome sequencing in forecasting clinical outcomes following surgery for congenital heart defects (CHD). We report results for a cohort of 2,253 CHD patients from the Pediatric Cardiac Genomics Consortium with a broad range of complex heart defects, pre- and post-operative clinical variables and exome sequencing. Damaging genotypes in chromatin-modifying and cilia-related genes were associated with an elevated risk of adverse post-operative outcomes, including mortality, cardiac arrest and prolonged mechanical ventilation. The impact of damaging genotypes was further amplified in the context of specific CHD phenotypes, surgical complexity and extra-cardiac anomalies. The absence of a damaging genotype in chromatin-modifying and cilia-related genes was also informative, reducing the risk for adverse postoperative outcomes. Thus, genome sequencing enriches the ability to forecast outcomes following congenital cardiac surgery.

Accurate prediction of neurologic changes in critically ill infants using pose AI.

Infant alertness and neurologic changes can reflect life-threatening pathology but are assessed by exam, which can be intermittent and subjective. Reliable, continuous methods are needed. We hypothesized that our computer vision method to track movement, pose AI, could predict neurologic changes in the neonatal intensive care unit (NICU). We collected 4,705 hours of video linked to electroencephalograms (EEG) from 115 infants. We trained a deep learning pose algorithm that accurately predicted anatomic landmarks in three evaluation sets (ROC-AUCs 0.83-0.94), showing feasibility of applying pose AI in an ICU. We then trained classifiers on landmarks from pose AI and observed high performance for sedation (ROC-AUCs 0.87-0.91) and cerebral dysfunction (ROC-AUCs 0.76-0.91), demonstrating that an EEG diagnosis can be predicted from video data alone. Taken together, deep learning with pose AI may offer a scalable, minimally invasive method for neuro-telemetry in the NICU.