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1
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Huang S, Li N, Yan D. Delayed treatment with endostatin displays a protective role against pulmonary hypertension by targeting VEGF pathway. Minerva Med 2025; 116:13-21. [PMID: 33913657 DOI: 10.23736/s0026-4806.21.07145-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Endostatin (ES) is an endogenous angiogenesis inhibitor. It is confirmed that ES has antitumor effects and plays a crucial part in regulating vascular smooth cells' proliferation. However, ES's effect on pulmonary hypertension (PH) is unclear. The aim of this study was to determine the effect of ES on PH's pathogenesis. METHODS PH was induced by pneumonectomy plus monocrotaline (MCT) injection, as indicated with significantly increased pulmonary arterial pressure and vascular wall thickness. RESULTS Immunohistochemical analysis showed that under physiological conditions, ES localized in endothelial cells (ECs) and spread to the muscular vascular layers in PH rats. ES was transfected into the lungs of rats intratracheally 2 weeks after MCT injection. Consequently, ES not only reduced elevated VEGF's expression but also reversed pulmonary artery remodeling. Eventually, ES improved elevated right ventricular (RV) mean pressure and RV hypertrophy. CONCLUSIONS The administration of ES may be a new treatment for PH and PA remodeling, associating with the downregulation of VEGF production.
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Affiliation(s)
- Shuai Huang
- Department of Cardiology, Yuncheng People Hospital, Heze, China
| | - Nannan Li
- Emergency Department, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Dong Yan
- Department of Bone and Joint Surgery, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China -
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2
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Dennery PA, Yao H. Emerging role of cellular senescence in normal lung development and perinatal lung injury. CHINESE MEDICAL JOURNAL PULMONARY AND CRITICAL CARE MEDICINE 2024; 2:10-16. [PMID: 38567372 PMCID: PMC10987039 DOI: 10.1016/j.pccm.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Cellular senescence is a status of irreversible growth arrest, which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external factors. Senescent cells are typically enlarged and flattened, and characterized by numerous molecular features. The latter consists of increased surfaceome, increased residual lysosomal activity at pH 6.0 (manifested by increased activity of senescence-associated beta-galactosidase [SA-β-gal]), senescence-associated mitochondrial dysfunction, cytoplasmic chromatin fragment, nuclear lamin b1 exclusion, telomere-associated foci, and the senescence-associated secretory phenotype. These features vary depending on the stressor leading to senescence and the type of senescence. Cellular senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related diseases. Interestingly, senescence can also both promote and inhibit wound healing processes. We recently report that senescence as a programmed process contributes to normal lung development. Lung senescence is also observed in Down Syndrome, as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this disease. Furthermore, this senescence results in neonatal lung injury. In this review, we briefly discuss the molecular features of senescence. We then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving senescence. Finally, we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.
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Affiliation(s)
- Phyllis A. Dennery
- Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA
- Department of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
| | - Hongwei Yao
- Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA
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3
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Danhaive O, Galambos C, Lakshminrusimha S, Abman SH. Pulmonary Hypertension in Developmental Lung Diseases. Clin Perinatol 2024; 51:217-235. [PMID: 38325943 DOI: 10.1016/j.clp.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Diverse genetic developmental lung diseases can present in the neonatal period with hypoxemic respiratory failure, often associated with with pulmonary hypertension. Intractable hypoxemia and lack of sustained response to medical management should increase the suspicion of a developmental lung disorder. Genetic diagnosis and lung biopsy are helpful in establishing the diagnosis. Early diagnosis can result in optimizing management and redirecting care if needed. This article reviews normal lung development, various developmental lung disorders that can result from genetic abnormalities at each stage of lung development, their clinical presentation, management, prognosis, and differential diagnoses.
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Affiliation(s)
- Olivier Danhaive
- Division of Neonatology, Saint-Luc University Hospital, UCLouvain, Avenue Hippocrate 10, B-1200 Brussels, Belgium; Department of Pediatrics, University of California San Francisco, 530 Parnassus Avenue, San Francisco, CA 94143, USA.
| | - Csaba Galambos
- Department of Pathology and Laboratory Medicine, University of Colorado Anschutz School of Medicine, 13001 East 17th Place, Aurora, CO 80045, USA
| | - Satyan Lakshminrusimha
- Department of Pediatrics, University of California, UC Davis Children's Hospital, 2516 Stockton Boulevard, Sacramento CA 95817, USA
| | - Steven H Abman
- Department of Pediatrics, The Pediatric Heart Lung Center, University of Colorado Anschutz Medical Campus, Mail Stop B395, 13123 East 16th Avenue, Aurora, CO 80045, USA
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4
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Sullivan RT, Raj JU, Austin ED. Recent Advances in Pediatric Pulmonary Hypertension: Implications for Diagnosis and Treatment. Clin Ther 2023; 45:901-912. [PMID: 37517916 DOI: 10.1016/j.clinthera.2023.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 07/03/2023] [Accepted: 07/06/2023] [Indexed: 08/01/2023]
Abstract
PURPOSE Pediatric pulmonary hypertension (PH) is a condition characterized by elevated pulmonary arterial pressure, which has the potential to be life-limiting. The etiology of pediatric PH varies. When compared with adult cohorts, the etiology is often multifactorial, with contributions from prenatal, genetic, and developmental factors. This review aims to provide an up-to-date overview of the causes and classification of pediatric PH, describe current therapeutics in pediatric PH, and discuss upcoming and necessary research in pediatric PH. METHODS PubMed was searched for articles relating to pediatric pulmonary hypertension, with a particular focus on articles published within the past 10 years. Literature was reviewed for pertinent areas related to this topic. FINDINGS The evaluation and approach to pediatric PH are unique when compared with that of adults, in large part because of the different, often multifactorial, causes of the disease in children. Collaborative registry studies have found that the most common disease causes include developmental lung disease and subsets of pulmonary arterial hypertension, which includes genetic variants and PH associated with congenital heart disease. Treatment with PH-targeted therapies in pediatrics is often guided by extrapolation of adult data, small clinical studies in pediatrics, and/or expert consensus opinion. We review diagnostic considerations and treatment in some of the more common pediatric subpopulations of patients with PH, including developmental lung diseases, congenital heart disease, and trisomy 21. IMPLICATIONS The care of pediatric patients with PH requires consideration of unique pediatric-specific factors. With significant variability in disease etiology, ongoing efforts are needed to optimize treatment strategies based on disease phenotype and guide evidence-based practices.
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Affiliation(s)
- Rachel T Sullivan
- Department of Pediatrics, Division of Cardiology, Vanderbilt University Medical Center, Monroe Carrell Jr Children's Hospital, Nashville, Tennessee.
| | - J Usha Raj
- Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois
| | - Eric D Austin
- Department of Pediatrics, Division of Pulmonary Medicine, Vanderbilt University Medical Center, Monroe Carrell Jr Children's Hospital, Nashville, Tennessee
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5
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Ishida S, Nakanishi H, Kosaka Y, Yamaguchi A, Ooka M. Evaluation of newborns with Down syndrome with weight less than 1500 g in the neonatal intensive care unit: A Japanese multicentre study. J Paediatr Child Health 2023; 59:912-918. [PMID: 37114469 DOI: 10.1111/jpc.16418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 02/05/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023]
Abstract
AIM This study aimed to clarify the characteristics and their mortality-related factors in very low birthweight infants with Down syndrome (DS) in Japan. METHODS This retrospective case-control study enrolled newborns with DS weighing <1500 g admitted to neonatal intensive care unit (NICU) of the perinatal centre registered with the Neonatal Research Network of Japan (NRNJ) database from 2008 to 2019. The clinical characteristics and their mortality-related factors were compared among the Dead group (newborns with DS who died in the NICU), the Survival group (newborns with DS who were alive from the NICU) and the Control group (newborns without congenital or chromosomal condition). RESULTS A total of 53 656 newborns weighing <1500 g were registered in the NRNJ database for 12 years. Of these, 310 (0.6%) were diagnosed with DS: 62 newborns in the Dead group, 248 in the Survival group and 49 786 in the Control group without chromosomal condition. Logistic analysis revealed that there was a significant difference in the mortality-related factors in congenital anomalies, pulmonary haemorrhage and persistent pulmonary hypertension of the newborn; the adjusted odds ratios were 8.6, 121 and 9.5, respectively. Newborns with DS weighing <1000 g showed the earliest death in the NICU on the Kaplan-Meier survival curve (P < 0.01). CONCLUSION The mortality rate for newborns with DS weighing <1500 g was 20% (5% in the Control group). The mortality-related factors were complications of congenital anomalies, pulmonary haemorrhage and persistent pulmonary hypertension of the newborn.
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Affiliation(s)
- Shuji Ishida
- Department of Pediatrics of Kitasato University Hospital, Sagamihara-shi, Kanagawa, Japan
| | - Hidehiko Nakanishi
- Division of Neonatal Intensive Care Medicine, Research and Development Center for New Medical Frontiers of Kitasato University Hospital, Sagamihara-shi, Kanagawa, Japan
| | - Yukako Kosaka
- Department of Pediatrics of Kitasato University Hospital, Sagamihara-shi, Kanagawa, Japan
| | - Ayano Yamaguchi
- Department of Pediatrics of Kitasato University Hospital, Sagamihara-shi, Kanagawa, Japan
| | - Mari Ooka
- Department of Pediatrics of Kitasato University Hospital, Sagamihara-shi, Kanagawa, Japan
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6
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Bhattacharya S, Cherry C, Deutsch G, Glass IA, Mariani TJ, Alam DA, Danopoulos S. A Trisomy 21 Lung Cell Atlas. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.30.534839. [PMID: 37066313 PMCID: PMC10103948 DOI: 10.1101/2023.03.30.534839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Trisomy 21 (T21), resulting in Down Syndrome (DS), is the most prevalent chromosomal abnormality worldwide. While pulmonary disease is a major cause of morbidity and mortality in DS, the ontogeny of pulmonary complications remains poorly understood. We recently demonstrated that T21 lung anomalies, including airway branching and vascular lymphatic abnormalities, are initiated in utero. Here, we aimed to describe molecular changes at the single cell level in prenatal T21 lungs. Our results demonstrate differences in the proportion of cell populations and detail changes in gene expression at the time of initiation of histopathological abnormalities. Notably, we identify shifts in the distribution of alveolar epithelial progenitors, widespread induction of key extracellular matrix molecules in mesenchymal cells and hyper-activation of IFN signaling in endothelial cells. This single cell atlas of T21 lungs greatly expands our understanding of antecedents to pulmonary complications and should facilitate efforts to mitigate respiratory disease in DS.
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7
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Pulmonary Hypertension in Children with Down Syndrome: Results from the Pediatric Pulmonary Hypertension Network Registry. J Pediatr 2023; 252:131-140.e3. [PMID: 36027975 DOI: 10.1016/j.jpeds.2022.08.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 08/11/2022] [Accepted: 08/18/2022] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension in a large, multicenter pediatric pulmonary hypertension registry. STUDY DESIGN We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with Down syndrome and children without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome. RESULTS Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. The median age at diagnosis of pulmonary hypertension in patients with Down syndrome was 0.49 year (IQR, 0.21-1.77 years), similar to that in patients without Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with Down syndrome and those without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%; repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). Pulmonary hypertension resolved in 43% after 3 years, associated with a diagnosis of pulmonary hypertension at age <6 months (54% vs 29%; P = .002) and a pretricuspid shunt (65% vs 38%; P = .02). Five-year transplantation-free survival was 88% (95% CI, 80%-97%). Tracheostomy (hazard ratio [HR], 3.29; 95% CI, 1.61-6.69) and reflux medication use (HR, 2.08; 95% CI, 1.11-3.90) were independently associated with a composite outcome of severe pulmonary hypertension. CONCLUSIONS Despite high rates of cardiac and respiratory comorbidities that influence the severity of pulmonary hypertension, children with Down syndrome-associated pulmonary hypertension generally have a survival rate similar to that of children with non-Down syndrome-associated pulmonary hypertension. Resolution of pulmonary hypertension is common but reduced in children with complicated respiratory comorbidities.
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8
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Moon JE, Lawrence JB. Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling. Cell Rep 2022; 40:111174. [PMID: 35947952 PMCID: PMC9505374 DOI: 10.1016/j.celrep.2022.111174] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 12/24/2021] [Accepted: 07/18/2022] [Indexed: 11/28/2022] Open
Abstract
Despite the prevalence of Down syndrome (DS), little is known regarding the specific cell pathologies that underlie this multi-system disorder. To understand which cell types and pathways are more directly affected by trisomy 21 (T21), we used an inducible-XIST system to silence one chromosome 21 in vitro. T21 caused the dysregulation of Notch signaling in iPSCs, potentially affecting cell-type programming. Further analyses identified dysregulation of pathways important for two cell types: neurogenesis and angiogenesis. Angiogenesis is essential to many bodily systems, yet is understudied in DS; therefore, we focused next on whether T21 affects endothelial cells. An in vitro assay for microvasculature formation revealed a cellular pathology involving delayed tube formation in response to angiogenic signals. Parallel transcriptomic analysis of endothelia further showed deficits in angiogenesis regulators. Results indicate a direct cell-autonomous impact of T21 on endothelial function, highlighting the importance of angiogenesis, with wide-reaching implications for development and disease progression. Moon and Lawrence examine the immediate effects of trisomy 21 silencing and find angiogenesis and neurogenesis pathways, including Notch signaling, affected as early as pluripotency. In endothelial cells, functional analyses show that trisomy delays the angiogenic response for microvessel formation and transcriptomics show a parallel impact on angiogenic regulators and signal-response and cytoskeleton processes.
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Affiliation(s)
- Jennifer E Moon
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Jeanne B Lawrence
- Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01655, USA.
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9
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Smith A, Bussmann N, Breatnach C, Levy P, Molloy E, Miletin J, Curley A, McCallion N, Franklin Mrcpch O, El-Khuffash A. Serial Assessment of Cardiac Function and Pulmonary Hemodynamics in Infants with Down Syndrome. J Am Soc Echocardiogr 2022; 35:1176-1183.e5. [PMID: 35868547 DOI: 10.1016/j.echo.2022.07.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 07/13/2022] [Accepted: 07/13/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND There is a dearth of longitudinal data describing the evolution of cardiopulmonary haemodynamics in infants with Down Syndrome (DS) beyond infancy. We hypothesized that babies with DS, independent of the presence of congenital heart disease (CHD), demonstrate biventricular systolic and diastolic impairment and sustained elevation of pulmonary pressures compared to controls over the first two years of age. METHODS This was a prospective observational cohort study of 70 infants with DS (48 with CHD and 22 without CHD) and 60 controls carried out in three tertiary neonatal intensive care units in Dublin, Ireland. Infants with DS with and without CHD and non-DS controls underwent serial echocardiograms at birth, 6 months, 1 year and 2 years of age to assess biventricular systolic and diastolic function using deformation analysis. Pulmonary vascular resistance (PVR) was assessed using pulmonary artery acceleration time (PAAT) and left ventricular (LV) eccentricity index. RESULTS Infants with DS exhibited smaller LV (Birth: 27±4 vs. 31±2 mm, p<0.01; 2 years: 43±5 vs. 48±4 mm, p<0.01) and RV (Birth: 28±3 vs. 31±2 mm, p<0.01; 2 years: 40±4 vs. 44±3 mm, p<0.01) lengths and lower LV (Birth: -19±3 vs. -22±2 %, p<0.01; 2 years: -24±2 vs. -26±2 %, p<0.01) and RV (Birth: -19±4 vs. -22±3 %, p<0.01; 2 years: -29±6 vs. -33±4 %, p<0.01) systolic strain over the two year period. PAAT was lower in the DS group throughout the study period (Birth: 44±10 vs. 62±14 ms, p<0.01; 2 years 71±12 vs. 83±11 ms, p<0.01). No differences were observed between DS infants with and without CHD (all p >0.05). CONCLUSIONS Infants with DS exhibit impaired maturational changes in myocardial function and PVR. Such novel findings provide valuable insights into the pathophysiology affecting cardiorespiratory morbidity in this population.
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Affiliation(s)
- Aisling Smith
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - Neidin Bussmann
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - Colm Breatnach
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - Philip Levy
- Boston Children's Hospital Department of Pediatrics, Boston, Massachusetts, USA; Department of Paediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Eleanor Molloy
- Department of Neonatology, Coombe Women and Infants University Hospital, Dublin, Ireland; Department of Paediatrics and Child Health, Trinity College Dublin, Dublin, Ireland
| | - Jan Miletin
- Department of Neonatology, Coombe Women and Infants University Hospital, Dublin, Ireland
| | - Anna Curley
- Department of Neonatology, The National Maternity Hospital, Dublin, Dublin, Ireland
| | - Naomi McCallion
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland; Department of Paediatrics, The Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Orla Franklin Mrcpch
- Department of Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland
| | - Afif El-Khuffash
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland; Department of Paediatrics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
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10
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Hines CB, Simmons SA. Down Syndrome: A Review of Key Perioperative Implications. AORN J 2022; 116:4-20. [PMID: 35758744 DOI: 10.1002/aorn.13712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/22/2021] [Accepted: 12/12/2021] [Indexed: 11/11/2022]
Abstract
Down syndrome (DS) is the most common chromosomal abnormality in humans that is compatible with life. This syndrome occurs when there is an extra copy of the 21st chromosome. Down syndrome is associated with numerous comorbidities that can pose challenges for the perioperative nurse caring for a patient with DS undergoing surgery. These challenges can affect the patient assessment, communication with the patient, and patient safety (eg, preventing complications). As the life expectancy of people with DS has increased, so too have the chances that perioperative nurses will care for a patient with this disorder. This article reviews the pathophysiology of DS, discusses common comorbidities that may directly affect perioperative care, and reviews an exemplar case study that demonstrates how personnel with knowledge of DS can positively influence surgical team decision making for these patients in the perioperative setting.
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11
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Jastania EI, Alqarni MS, Abukhodair AW, Bukhari ZM, Bukhari RA, Khatrawi S, Alsomali N, Waggass R. Risk Factors of Persistent Pulmonary Hypertension in Neonate in A Tertiary Care Referral Center. Cureus 2022; 14:e22416. [PMID: 35371731 PMCID: PMC8942133 DOI: 10.7759/cureus.22416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2022] [Indexed: 11/05/2022] Open
Abstract
Background: Persistent pulmonary hypertension of the newborn (PPHN) is a condition in which pulmonary vascular resistance fails to decrease after birth. PPHN leads to hypoxemia due to right-to-left shunting of the blood through the fetal circulation. This study aimed to determine the association between PPHN and prematurity in neonates admitted to the neonatal intensive care unit (NICU). Materials and methods: This study is a single-center, retrospective, and cross-sectional study. Patients diagnosed with PPHN had been selected by using a non-probability consecutive sampling technique from 2016 to 2020 at King Abdulaziz Medical City in Jeddah, Saudi Arabia. Patients with PPHN who did not admit to NICU were excluded. Results: Fifty-six patients had met the inclusion and exclusion criteria. Twenty-six neonates were born prematurely before 37 weeks of gestation, and 30 were born at 37 weeks or more. Among the study population, respiratory complications were seen in 30 patients with a rate of 53.6%. The most common complications were respiratory failure, persistent pulmonary hypertension, and cardiopulmonary arrest. Conclusion: Mortality was documented in 26 patients, with the complicated group having a rate of 73.3% compared to the uncomplicated group 15.4%. The most common complications seen in our patients were respiratory failure, persistent pulmonary hypertension, and cardiopulmonary arrest.
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12
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Griffiths M, Yang J, Vaidya D, Nies M, Brandal S, Ivy DD, Hickey F, Wolter-Warmerdam K, Austin ED, Mullen M, Pauciulo MW, Lutz KA, Rosenzweig EB, Hirsch R, Yung D, Nichols WC, Everett AD. Biomarkers of Pulmonary Hypertension Are Altered in Children with Down Syndrome and Pulmonary Hypertension. J Pediatr 2022; 241:68-76.e3. [PMID: 34687693 PMCID: PMC9092284 DOI: 10.1016/j.jpeds.2021.10.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 10/05/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE To evaluate the performance of pulmonary hypertension (PH) biomarkers in children with Down syndrome, an independent risk factor for PH, in whom biomarker performance may differ compared with other populations. STUDY DESIGN Serum endostatin, interleukin (IL)-1 receptor 1 (ST2), galectin-3, N-terminal pro hormone B-natriuretic peptide (NT-proBNP), IL-6, and hepatoma-derived growth factor (HDGF) were measured in subjects with Down syndrome and PH (n = 29), subjects with Down syndrome and resolved PH (n = 13), subjects with Down syndrome without PH (n = 49), and subjects without Down syndrome with World Symposium on Pulmonary Hypertension group I pulmonary arterial hypertension (no Down syndrome PH group; n = 173). Each biomarker was assessed to discriminate PH in Down syndrome. A classification tree was created to distinguish PH from resolved PH and no PH in children with Down syndrome. RESULTS Endostatin, galectin-3, HDGF, and ST2 were elevated in subjects with Down syndrome regardless of PH status. Not all markers differed between subjects with Down syndrome and PH and subjects with Down syndrome and resolved PH. NT-proBNP and IL-6 levels were similar in the Down syndrome with PH group and the no Down syndrome PH group. A classification tree identified NT-proBNP and galectin-3 as the best markers for sequentially distinguishing PH, resolved PH, and no PH in subjects with Down syndrome. CONCLUSIONS Proteomic markers are used to improve the diagnosis and prognosis of PH but, as demonstrated here, can be altered in genetically unique populations such as individuals with Down syndrome. This further suggests that clinical biomarkers should be evaluated in unique groups with the development of population-specific nomograms.
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Affiliation(s)
- Megan Griffiths
- Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD; Department of Internal Medicine, Johns Hopkins University, Baltimore, MD
| | - Jun Yang
- Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD
| | - Dhananjay Vaidya
- Division of Pediatric Cardiology, Children's Hospital Colorado, Aurora, CO
| | - Melanie Nies
- Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD
| | - Stephanie Brandal
- Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD
| | - D Dunbar Ivy
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Francis Hickey
- Sie Center for Down Syndrome, Children's Hospital Colorado, Aurora, CO
| | - Kristine Wolter-Warmerdam
- Division of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN
| | - Eric D Austin
- Department of Cardiology, Boston Children's Hospital, Boston, MA
| | - Mary Mullen
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Michael W Pauciulo
- Division of Pediatric Cardiology; Department of Pediatrics, Columbia University, New York, NY
| | - Katie A Lutz
- Division of Pediatric Cardiology; Department of Pediatrics, Columbia University, New York, NY
| | - Erika B Rosenzweig
- Department of Internal Medicine, Johns Hopkins University, Baltimore, MD
| | - Russel Hirsch
- Division of Pediatric Cardiology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Delphine Yung
- Division of Pediatric Cardiology, Department of Pediatrics, University of Washington, Seattle, WA
| | - William C Nichols
- Division of Pediatric Cardiology; Department of Pediatrics, Columbia University, New York, NY
| | - Allen D Everett
- Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD.
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13
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Abstract
Persons with Down syndrome (DS) have an increased reported incidence of pulmonary hypertension (PH). A majority of those with PH have associations with congenital heart disease (CHD) or persistent pulmonary hypertension of the newborn (PPHN); however, there are likely multifactorial contributions that include respiratory comorbidities. PH appears to be most commonly identified early in life, although respiratory challenges may contribute to a later diagnosis or even a recurrence of previously resolved PH in this population. Currently there are few large-scale, prospective, lifetime cohort studies detailing the impact PH has on the population with DS. This review will attempt to summarize the epidemiology and characteristics of PH in this population. This article will additionally review current known and probable risk factors for developing PH, review pathophysiologic mechanisms of disease in the population with DS, and evaluate current screening and management recommendations while suggesting areas for additional or ongoing clinical, translational, and basic science research.
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Affiliation(s)
- Douglas S Bush
- Department of Pediatrics, Division of Pulmonology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1202B, New York, NY, 10029, USA.
| | - D Dunbar Ivy
- Department of Pediatrics, Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA
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14
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Muneuchi J, Ezaki H, Sugitani Y, Watanabe M. Comprehensive assessments of pulmonary circulation in children with pulmonary hypertension associated with congenital heart disease. Front Pediatr 2022; 10:1011631. [PMID: 36313863 PMCID: PMC9614099 DOI: 10.3389/fped.2022.1011631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Pulmonary hypertension associated with congenital heart disease (CHD-PH) encompasses different conditions confounded by the left-to-right shunt, left heart obstruction, ventricular dysfunction, hypoxia due to airway obstruction, dysplasia/hypoplasia of the pulmonary vasculature, pulmonary vascular obstructive disease, and genetic variations of vasoactive mediators. Pulmonary input impedance consists of the pulmonary vascular resistance (Rp) and capacitance (Cp). Rp is calculated as the transpulmonary pressure divided by the pulmonary cardiac output, whereas Cp is calculated as the pulmonary stroke volume divided by the pulmonary arterial pulse pressure. The plots of Rp and Cp demonstrate a unique hyperbolic relationship, namely, the resistor-capacitor coupling curve, which represents the pulmonary vascular condition. The product of Rp and Cp is the exponential pressure decay, which refers to the time constant. Alterations in Cp are more considerable in CHD patients at an early stage of developing pulmonary hypertension or with excessive pulmonary blood flow due to a left-to-right shunt. The importance of Cp has gained attention because recent reports have shown that low Cp potentially reflects poor prognosis in patients with CHD-PH and idiopathic pulmonary hypertension. It is also known that Cp levels decrease in specific populations, such as preterm infants and trisomy 21. Therefore, both Rp and Cp should be individually evaluated in the management of children with CHD-PH who have different disease conditions.
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Affiliation(s)
- Jun Muneuchi
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization
| | - Hiroki Ezaki
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization
| | - Yuichiro Sugitani
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization
| | - Mamie Watanabe
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization
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15
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Taksande A, Pujari D, Jameel PZ, Taksande B, Meshram R. Prevalence of pulmonary hypertension among children with Down syndrome: A systematic review and meta-analysis. World J Clin Pediatr 2021; 10:177-191. [PMID: 34868894 PMCID: PMC8603643 DOI: 10.5409/wjcp.v10.i6.177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/13/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pulmonary hypertension (PH) has serious short- and long-term consequences. PH is gaining increasing importance in high risk groups such as Down syndrome (DS) as it influences their overall survival and prognosis. Hence, there is a dire need to collate the prevalence rates of PH in order to undertake definitive measures for early diagnosis and management. AIM To determine the prevalence of PH in children with DS. METHODS The authors individually conducted a search of electronic databases manually (Cochrane library, PubMed, EMBASE, Scopus, Web of Science). Data extraction and quality control were independently performed by two reviewers and a third reviewer resolved any conflicts of opinion. The words used in the literature search were "pulmonary hypertension" and "pulmonary arterial hypertension"; "Down syndrome" and "trisomy 21" and "prevalence". The data were analyzed by Comprehensive Meta-Analysis Software Version 2. Risk of bias assessment and STROBE checklist were used for quality assessment. RESULTS Of 1578 articles identified, 17 were selected for final analysis. The pooled prevalence of PH in these studies was 25.5%. Subgroup analysis was carried out for age, gender, region, year of publication, risk of bias and etiology of PH. CONCLUSION This review highlights the increasing prevalence of PH in children with DS. It is crucial for pediatricians to be aware of this morbid disease and channel their efforts towards earlier diagnosis and successful management. Community-based studies with a larger sample size of children with DS should be carried out to better characterize the epidemiology and underlying etiology of PH in DS.
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Affiliation(s)
- Amar Taksande
- Department of Pediatrics, Jawaharlal Nehru Medical College, Wardha 442004, Maharashtra, India
| | - Divya Pujari
- Department of Pediatrics, Jawaharlal Nehru Medical College, Wardha 442004, Maharashtra, India
| | - Patel Zeeshan Jameel
- Department of Pediatrics, Jawaharlal Nehru Medical College, Wardha 442004, Maharashtra, India
| | - Bharati Taksande
- Department of Medicine, Mahatma Gandhi Institute of Medical Sciences, Wardha 442102, Maharashtra, India
| | - Revat Meshram
- Department of Pediatrics, Jawaharlal Nehru Medical College, Wardha 442004, Maharashtra, India
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16
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Hatai E, Muneuchi J, Sugitani Y, Doi H, Furuta T, Ezaki H, Kobayashi M, Sato R, Watanabe M. Pulmonary vascular resistance and compliance in individuals with trisomy 18. Am J Med Genet A 2021; 188:534-539. [PMID: 34729911 DOI: 10.1002/ajmg.a.62550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/14/2021] [Accepted: 10/16/2021] [Indexed: 11/10/2022]
Abstract
Individuals with trisomy 18 (T18) usually have congenital heart disease, often with pulmonary hypertension, which is associated with poor outcomes. This study aimed to explore the characteristics of pulmonary circulation including pulmonary vascular resistance (Rp) and compliance (Cp) among them. We retrospectively reviewed cardiac catheterization data in subjects with T18, trisomy 21 (T21), and without chromosomal anomaly (control group) who were referred due to heart failure associated with ventricular septal defect between 2000 and 2020. Pulmonary hemodynamic parameters including Rp and Cp were compared between these groups. We studied 20 subjects with T18, 88 subjects with T21, and 240 control subjects. There was no significant difference in age (T18: 4.6 [3.0-6. 9] vs. T21: 2.8 [1.9-4.0] vs. control: 2.9 [1.6-3.2] months, p = 0.06) and mean pulmonary arterial pressure (T18: 41 [33-49] vs. T21: 35 [30-41] vs. control: 36 [28-43] mmHg, p = 0.121) between the groups. The pulmonary to systemic blood flow ratio (Qp/Qs) (p = 0.983), Rp (p = 0.449), and Cp (p = 0.195) did not differ between T18 and control groups. However, Qp/Qs and Cp in T18 group were significantly greater than that in T21 group (T18: Qp/Qs: 3.4 [2.3-5.2] vs. T: 21 2.3 [1.7-3.7], p = 0.001. Cp: 3.5 [2.3-5.5] vs. 2.3 [1.6-3.1] mmHg/mL/m2 , p = 0.007), while Rp was identical between the groups (T18: 2.0 [1.6-3.3] vs. T21: 2.3 [1.7-3.7], p = 0.386). The pulmonary circulation in T18 subjects differed from that observed in T21 subjects, and identical to that observed in control subjects. Pulmonary hypertension is expected to be normalized after reasonable corrective surgery in T18 patients with congenital heart disease.
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Affiliation(s)
- Eriko Hatai
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Jun Muneuchi
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Yuichiro Sugitani
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Hirohito Doi
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Takashi Furuta
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Hiroki Ezaki
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Masaru Kobayashi
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Rie Sato
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
| | - Mamie Watanabe
- Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Fukuoka, Japan
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17
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Danopoulos S, Deutsch GH, Dumortier C, Mariani TJ, Al Alam D. Lung disease manifestations in Down syndrome. Am J Physiol Lung Cell Mol Physiol 2021; 321:L892-L899. [PMID: 34469245 PMCID: PMC8616621 DOI: 10.1152/ajplung.00434.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 08/25/2021] [Accepted: 08/25/2021] [Indexed: 11/22/2022] Open
Abstract
Down syndrome (DS) is one of the most prevalent chromosomal abnormalities worldwide, affecting 1 in 700 live births. Although multiple organ systems are affected by the chromosomal defects, respiratory failure and lung disease are the leading causes of morbidity and mortality observed in DS. Manifestations of DS in the respiratory system encompass the entire lung starting from the nasopharynx to the trachea/upper airways to the lower airways and alveolar spaces, as well as vascular and lymphatic defects. Most of our knowledge on respiratory illness in persons with DS arises from pediatric studies; however, many of these disorders present early in infancy, supporting developmental mechanisms. In this review, we will focus on the different lung phenotypes in DS, as well as the genetic and molecular pathways that may be contributing to these complications during development.
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Affiliation(s)
- Soula Danopoulos
- Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California
| | - Gail H Deutsch
- Seattle Children's Research Institute, Seattle, Washington
| | - Claire Dumortier
- Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California
| | - Thomas J Mariani
- Pediatric Molecular and Personalized Medicine Program, University of Rochester, Rochester, New York
| | - Denise Al Alam
- Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, California
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18
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Daly CM, Griffiths M, Simpson CE, Yang J, Damico RL, Vaidya RD, Williams M, Brandal S, Jone PN, Polsen C, Ivy DD, Austin ED, Nichols WC, Pauciulo MW, Lutz K, Nies MK, Rosenzweig EB, Hirsch R, Yung D, Everett AD. Angiostatic Peptide, Endostatin, Predicts Severity in Pediatric Congenital Heart Disease-Associated Pulmonary Hypertension. J Am Heart Assoc 2021; 10:e021409. [PMID: 34622662 PMCID: PMC8751905 DOI: 10.1161/jaha.120.021409] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Background Endostatin, an angiogenic inhibitor, is associated with worse pulmonary arterial hypertension (PAH) outcomes in adults and poor lung growth in children. This study sought to assess whether endostatin is associated with disease severity and outcomes in pediatric PAH. Methods and Results Serum endostatin was measured in cross-sectional (N=160) and longitudinal cohorts (N=64) of pediatric subjects with PAH, healthy pediatric controls and pediatric controls with congenital heart disease (CHD) (N=54, N=15), and adults with CHD associated PAH (APAH-CHD, N=185). Outcomes, assessed by regression and Kaplan-Meier analysis, included hemodynamics, change in endostatin over time, and transplant-free survival. Endostatin secretion was evaluated in pulmonary artery endothelial and smooth muscle cells. Endostatin was higher in those with PAH compared with healthy controls and controls with CHD and was highest in those with APAH-CHD. In APAH-CHD, endostatin was associated with a shorter 6-minute walk distance and increased mean right atrial pressure. Over time, endostatin was associated with higher pulmonary artery pressure and pulmonary vascular resistance index, right ventricular dilation, and dysfunction. Endostatin decreased with improved hemodynamics over time. Endostatin was associated with worse transplant-free survival. Addition of endostatin to an NT-proBNP (N-terminal pro-B-type natriuretic peptide) based survival analysis improved risk stratification, reclassifying subjects with adverse outcomes. Endostatin was secreted primarily by pulmonary artery endothelial cells. Conclusions Endostatin is associated with disease severity, disease improvement, and worse survival in APAH-CHD. Endostatin with NT-proBNP improves risk stratification, better predicting adverse outcomes. The association of elevated endostatin with shunt lesions suggests that endostatin could be driven by both pulmonary artery flow and pressure. Endostatin could be studied as a noninvasive prognostic marker, particularly in APAH-CHD.
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Affiliation(s)
| | - Megan Griffiths
- Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD
| | - Catherine E Simpson
- Division of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD
| | - Jun Yang
- Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD
| | - Rachel L Damico
- Division of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD
| | | | - Monica Williams
- Department of Anesthesia and Critical Care Medicine Johns Hopkins University Baltimore MD
| | - Stephanie Brandal
- Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD
| | - Pei-Ni Jone
- Department of Pediatric Cardiology Children's Hospital ColoradoUniversity of Colorado Aurora CO
| | - Cassandra Polsen
- Department of Pediatric Cardiology Children's Hospital ColoradoUniversity of Colorado Aurora CO
| | - D Dunbar Ivy
- Department of Pediatric Cardiology Children's Hospital ColoradoUniversity of Colorado Aurora CO
| | - Eric D Austin
- Division of Allergy, Immunology, and Pulmonary Medicine Department of Pediatrics Vanderbilt University Medical Center Nashville TN
| | - William C Nichols
- Division of Human Genetics Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH
| | - Michael W Pauciulo
- Division of Human Genetics Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH
| | - Katie Lutz
- Division of Human Genetics Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH
| | - Melanie K Nies
- Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD
| | - Erika B Rosenzweig
- Division of Pediatric Cardiology Department of Pediatrics Columbia University New York City NY
| | - Russel Hirsch
- Division of Pediatric Cardiology Department of Pediatrics University of Cincinnati College of Medicine Cincinnati OH
| | - Delphine Yung
- Division of Pediatric Cardiology Department of Pediatrics University of Washington Seattle WA
| | - Allen D Everett
- Division of Pediatric Cardiology Department of Pediatrics Johns Hopkins University Baltimore MD
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19
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Novel Approaches to an Integrated Route for Trisomy 21 Evaluation. Biomolecules 2021; 11:biom11091328. [PMID: 34572541 PMCID: PMC8465311 DOI: 10.3390/biom11091328] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/16/2021] [Accepted: 09/06/2021] [Indexed: 12/31/2022] Open
Abstract
Trisomy 21 (T21) is one of the most commonly occurring genetic disorders, caused by the partial or complete triplication of chromosome 21. Despite the significant progress in the diagnostic tools applied for prenatal screening, commonly used methods are still imprecise and involve invasive diagnostic procedures that are related to a maternal risk of miscarriage. In this case, novel prenatal biomarkers are still being evaluated using highly specialized techniques, which could increase the diagnostic usefulness of biochemical prenatal screening for T21. From the other hand, the T21′s pathogenesis, caused by the improper division of genetic material, disrupting many metabolic pathways, could be further evaluated with the use of omics methods, which could result in bringing relevant insights for the evaluation of potential medical targets. Accordingly, a literature search was undertaken to collect novel information about prenatal screening for Down syndrome with the use of advanced technology, with a particular emphasis on the evaluation of novel screening biomarkers and the discovery of potential medical targets. These meta-analyses are focused on novel approaches designed with the use of omics techniques, representing the most rapidly developing and promising field in research today. Considering the limitations and progress of these methods, the use of omics techniques in evaluating T21 pathogenesis could bring beneficial results in prenatal screening, simultaneously uncovering novel potential medical targets.
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20
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Danopoulos S, Bhattacharya S, Deutsch G, Nih LR, Slaunwhite C, Mariani TJ, Al Alam D. Prenatal histological, cellular, and molecular anomalies in trisomy 21 lung. J Pathol 2021; 255:41-51. [PMID: 34050678 PMCID: PMC9109699 DOI: 10.1002/path.5735] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/12/2021] [Accepted: 05/25/2021] [Indexed: 11/10/2022]
Abstract
Down syndrome (DS), also known as trisomy 21 (T21), is the most common human chromosomal anomaly. Although DS can affect many organ systems, lung and heart disease are the leading causes of death. An abundance of existing data suggests that lung abnormalities originate postnatally in DS. However, a single report of branching insufficiency in DS has inferred a potential prenatal origin. The histology of T21 fetal lungs (n = 15) was assessed by an experienced pathologist. Spatial differences in cellular phenotypes were examined using immunohistochemistry (IHC). Comprehensive gene expression in prenatal T21 lungs (n = 19), and age-matched controls (n = 19), was performed using high-throughput RNA sequencing (RNAseq) and validated by RT-qPCR. Histopathological abnormalities were observed in approximately half of T21 prenatal lung samples analyzed, which included dilated terminal airways/acinar tubules, dilated lymphatics, and arterial wall thickening. IHC for Ki67 revealed significant reductions in epithelial and mesenchymal cell proliferation, predominantly in tissues displaying pathology. IHC demonstrated that airway smooth muscle was reduced and discontinuous in the proximal airway in conjunction with reduced SOX2. RNAseq identified 118 genes significantly dysregulated (FDR < 0.05) in T21 lung when unadjusted and 316 genes when adjusted for age. Ontology analysis showed that IFN pathway genes were appreciably upregulated, whereas complement and coagulation cascades and extracellular matrix pathway genes were downregulated. RT-qPCR confirmed the changes in genes associated with these pathways in prenatal T21 lungs. Our data demonstrate that specific histological, cellular, and molecular abnormalities occur prenatally in different compartments of human T21 lung, which could be representative of premature stage progression. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Soula Danopoulos
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Soumyaroop Bhattacharya
- Pediatric Molecular and Personalized Medicine Program and Division of Neonatology, University of Rochester, Rochester, NY, USA
| | - Gail Deutsch
- Seattle Children’s Research Institute, Seattle, WA, USA
| | - Lina R Nih
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Chris Slaunwhite
- Pediatric Molecular and Personalized Medicine Program and Division of Neonatology, University of Rochester, Rochester, NY, USA
| | - Thomas J Mariani
- Pediatric Molecular and Personalized Medicine Program and Division of Neonatology, University of Rochester, Rochester, NY, USA
| | - Denise Al Alam
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
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21
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Voges I, Nyktari E. Late presentation of shunt lesions in Down syndrome patients: the importance of multidisciplinary assessment and lifelong follow-up. Eur Heart J Case Rep 2021; 5:ytab238. [PMID: 34377920 PMCID: PMC8340798 DOI: 10.1093/ehjcr/ytab238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/25/2021] [Accepted: 05/27/2021] [Indexed: 11/14/2022]
Affiliation(s)
- Inga Voges
- Department of Congenital Heart Disease and Paediatric Cardiology, University Hospital Schleswig-Holstein, Arnold-Heller-Str. 3, 24105 Kiel, Germany
| | - Evangelia Nyktari
- Cardiovascular MRI Unit, BIOATRIKI SA (Biomedicine Group of Companies), Athens, Greece
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22
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Bajolle F, Malekzadeh-Milani S, Lévy M, Bonnet D. Multifactorial origin of pulmonary hypertension in a child with congenital heart disease, Down syndrome, and BMPR-2 mutation. Pulm Circ 2021; 11:20458940211027433. [PMID: 34285797 PMCID: PMC8264736 DOI: 10.1177/20458940211027433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Accepted: 06/05/2021] [Indexed: 11/25/2022] Open
Abstract
A late preterm infant had pulmonary hypertension caused by a variety of mechanisms leading to complex management. This child had complete atrioventricular septal defect associated with mild left ventricular hypoplasia and Down syndrome diagnosed prenatally. The mother had been treated by antiretroviral HIV treatment during pregnancy. Aortic coarctation was diagnosed and rapidly repaired. After surgery, he required noninvasive ventilation for persisting elevated PCO2. Pulmonary CT scan showed normal bronchial tree, lung parenchymal abnormalities with mosaic aspect and hyperlucent zones, and indirect signs of lung hypoplasia with peripheral microbubbles. During follow-up, severe pulmonary hypertension was diagnosed on echocardiography without recoarctation, significant intracardiac shunting or diastolic dysfunction. The patient died after four months unable to be weaned from noninvasive ventilation. Post mortem lung biopsy showed abnormally muscularized arterioles with intimal fibrosis and pulmonary immaturity. Gentetic screening identified a BMPR-2 mutation. This patient illustrates the multifactorial origin of pulmonary hypertension in the neonatal period. The respective contribution of left-to-right shunt, post-capillary obstruction, and abnormally elevated pulmonary vascular resistances led to perform right heart catheterization to exclude excessive shunting and restrictive physiology of the left heart. Subjects with Down syndrome are also highly susceptible to decreased lung vascular and alveolar growth, which may increase the risk for pulmonary hypertension and lung hypoplasia. This case highlights two issues. The first one is that right heart catheterization should be discussed in neonates with unexplained pulmonary hypertension and the second is to extend indications of genetic testing for pulmonary hypertension genes in neonates who have unusual course of neonatal pulmonary hypertension, particularly in the setting of associated congenital heart disease (CHD).
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Affiliation(s)
- Fanny Bajolle
- M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - S Malekzadeh-Milani
- M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - M Lévy
- M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - D Bonnet
- M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France.,Université de Paris, Paris, France
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23
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Hypoxemia in infants with trisomy 21 in the neonatal intensive care unit. J Perinatol 2021; 41:1448-1453. [PMID: 34035452 PMCID: PMC8576738 DOI: 10.1038/s41372-021-01105-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/26/2021] [Accepted: 05/10/2021] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Newborns with trisomy 21 (T21) often require NICU hospitalization. Oxygen desaturations are frequently observed in these infants, even in the absence of congenital heart defects (CHD). We hypothesized that NICU patients with T21 have more hypoxemia than those without T21. DESIGN All infants with T21 without significant CHD discharged home from the NICU between 2009 and 2018 were included (n = 23). Controls were matched 20:1 for gestational age and length of stay. We compared daily severe hypoxemia events (SpO2 < 80% for ≥10 s) for the whole NICU stay and the pre-discharge week. RESULTS Infants with T21 showed significantly more daily hypoxemia events during their entire NICU stay (median 10 versus 7, p = 0.0064), and more so in their final week (13 versus 7, p = 0.0008). CONCLUSION NICU patients with T21 without CHD experience more severe hypoxemia events than controls, particularly in the week before discharge. Whether this hypoxemia predicts or contributes to adverse outcomes is unknown.
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24
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Abstract
PURPOSE OF REVIEW Pulmonary arterial hypertension (PAH) causes high morbidity and mortality in children. In this review, we discuss advances in diagnosis and treatment of this disorder. RECENT FINDINGS Proceedings published from the 2018 World Symposium updated the definition of pulmonary hypertension to include all adults and children with mean pulmonary artery pressure more than 20 mmHg. Targeted PAH therapy is increasingly used off-label, but in 2017, bosentan became the first Food and Drug Administration-targeted PAH therapy approved for use in children. SUMMARY In recent years, advanced imaging and clinical monitoring have allowed improved risk stratification of pulmonary hypertension patients. New therapies, approved in adults and used off-label in pediatric patients, have led to improved outcomes for affected children.
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25
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Bush D, Galambos C, Dunbar Ivy D. Pulmonary hypertension in children with Down syndrome. Pediatr Pulmonol 2021; 56:621-629. [PMID: 32049444 DOI: 10.1002/ppul.24687] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 01/23/2020] [Indexed: 12/26/2022]
Abstract
Individuals with Down syndrome (DS) have an increased risk of developing pulmonary hypertension (PH). In this review, we explore the epidemiology and clinical characteristics of PH in the population with DS and examine genetic, molecular and clinical contributions to the condition. The presence of an additional copy of chromosome 21 (trisomy 21) increases the risk of developing PH in children with DS through many mechanisms, including increased hemodynamic stress in those with congenital heart disease, hypoxemia through impaired ventilation to perfusion matching secondary to developmental lung abnormalities, pulmonary hypoplasia from pulmonary vascular endothelial dysfunction, and an increase in pulmonary vascular resistance often related to pulmonary comorbidities. We review recent studies looking at novel biomarkers that may help diagnose, predict or monitor PH in the population with DS and examine current cardiopulmonary guidelines for monitoring children with DS. Finally, we review therapeutic interventions specific to PH in individuals with DS. Contemporary work has identified exciting mechanistic pathways including the upregulation of antiangiogenic factors and interferon activity, which may lead to additional biomarkers or therapeutic opportunities. Throughout the manuscript, we identify gaps in our knowledge of the condition as it relates to the population with DS and offer suggestions for future clinical, translational, and basic science research.
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Affiliation(s)
- Douglas Bush
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Csaba Galambos
- Department of Pathology and Laboratory Medicine, University of Colorado School of Medicine, Aurora, Colorado
| | - David Dunbar Ivy
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado
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26
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De Toma I, Dierssen M. Network analysis of Down syndrome and SARS-CoV-2 identifies risk and protective factors for COVID-19. Sci Rep 2021; 11:1930. [PMID: 33479353 PMCID: PMC7820501 DOI: 10.1038/s41598-021-81451-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 01/06/2021] [Indexed: 12/12/2022] Open
Abstract
SARS-CoV-2 infection has spread uncontrollably worldwide while it remains unknown how vulnerable populations, such as Down syndrome (DS) individuals are affected by the COVID-19 pandemic. Individuals with DS have more risk of infections with respiratory complications and present signs of auto-inflammation. They also present with multiple comorbidities that are associated with poorer COVID-19 prognosis in the general population. All this might place DS individuals at higher risk of SARS-CoV-2 infection or poorer clinical outcomes. In order to get insight into the interplay between DS genes and SARS-cov2 infection and pathogenesis we identified the genes associated with the molecular pathways involved in COVID-19 and the host proteins interacting with viral proteins from SARS-CoV-2. We then analyzed the overlaps of these genes with HSA21 genes, HSA21 interactors and other genes consistently differentially expressed in DS (using public transcriptomic datasets) and created a DS-SARS-CoV-2 network. We detected COVID-19 protective and risk factors among HSA21 genes and interactors and/or DS deregulated genes that might affect the susceptibility of individuals with DS both at the infection stage and in the progression to acute respiratory distress syndrome. Our analysis suggests that at the infection stage DS individuals might be more susceptible to infection due to triplication of TMPRSS2, that primes the viral S protein for entry in the host cells. However, as the anti-viral interferon I signaling is also upregulated in DS, this might increase the initial anti-viral response, inhibiting viral genome release, viral replication and viral assembly. In the second pro-inflammatory immunopathogenic phase of the infection, the prognosis for DS patients might worsen due to upregulation of inflammatory genes that might favor the typical cytokine storm of COVID-19. We also detected strong downregulation of the NLRP3 gene, critical for maintenance of homeostasis against pathogenic infections, possibly leading to bacterial infection complications.
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Affiliation(s)
- Ilario De Toma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
| | - Mara Dierssen
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
- Universitat Pompeu Fabra (UPF), Barcelona, Spain.
- Biomedical Research Networking Center On Rare Diseases (CIBERER), Institute of Health Carlos III, Madrid, Spain.
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27
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Tahara M, Sanada K, Morita R, Hawaka H, Urayama K, Sugino M, Masaki N, Yamaki S. Insufficient development of vessels and alveoli in lungs of infants with trisomy 18-Features of pulmonary histopathological findings from lung biopsy. Am J Med Genet A 2021; 185:1059-1066. [PMID: 33394558 DOI: 10.1002/ajmg.a.62060] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 11/11/2022]
Abstract
The aim of this study was to evaluate the features of pulmonary histopathological changes in cases of trisomy 18 complicated with congenital heart disease and pulmonary arterial hypertension. Twenty-eight patients with trisomy 18 underwent open lung biopsy at the time of primary operation in our hospital between 2008 and 2019. We compared these histopathological findings with those from previously described groups without trisomy 18. Mean age at primary cardiac surgery was 37 days (range, 9-69 days). According to the Heath-Edwards (HE) classification, 1, 8, 12, and 5 patients were graded as 0, 1, 2, and 3, respectively, whereas 2 patients were not classifiable due to medial defects in the small pulmonary arteries (MD). Four (14.3%) and 13 (46.4%) patients presented with MD and hypoplasia of the small pulmonary arteries (HS). Fifteen (53.6%) and 21 (75.0%) patients presented with alveolar hypoplasia (AH) and alveolar wall thickening (AT). MD, HS, and AH in trisomy 18 were present frequently, differing significantly from previous reports. These findings might be associated with congenital inadequate development of vessels and alveoli in the lung, contributing to a high risk of PAH in trisomy 18.
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Affiliation(s)
- Masahiro Tahara
- Department of Pediatrics, Tsuchiya General Hospital, Hiroshima, Japan
| | - Kazuya Sanada
- Department of Pediatrics, Tsuchiya General Hospital, Hiroshima, Japan
| | - Risa Morita
- Department of Pediatrics, Tsuchiya General Hospital, Hiroshima, Japan
| | - Hideyuki Hawaka
- Department of Pediatrics, Tsuchiya General Hospital, Hiroshima, Japan
| | - Kotarou Urayama
- Department of Pediatrics, Tsuchiya General Hospital, Hiroshima, Japan
| | - Mitsunobu Sugino
- Department of Pediatrics, Tsuchiya General Hospital, Hiroshima, Japan
| | - Naoki Masaki
- Japanese Research Institute of Pulmonary Vasculature, Sendai, Japan.,Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shigeo Yamaki
- Japanese Research Institute of Pulmonary Vasculature, Sendai, Japan
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28
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Virumbrales-Muñoz M, Chen J, Ayuso J, Lee M, Abel EJ, Beebe DJ. Organotypic primary blood vessel models of clear cell renal cell carcinoma for single-patient clinical trials. LAB ON A CHIP 2020; 20:4420-4432. [PMID: 33103699 PMCID: PMC8743028 DOI: 10.1039/d0lc00252f] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Clear cell renal cell carcinoma (ccRCC) is a common genitourinary cancer associated with the development of abnormal tumor angiogenesis. Although multiple anti-angiogenic therapies have been developed, responses to individual treatment are highly variable between patients. Thus, the use of one-patient clinical trials has been suggested as an alternative to standard trials. We used a microfluidic device to generate organotypic primary patient-specific blood vessel models using normal (NEnC) and tumor-associated primary CD31+ selected cells (TEnC). Our model was able to recapitulate differences in angiogenic sprouting and vessel permeability that characterize normal and tumor-associated vessels. We analyzed the expression profile of vessel models to define vascular normalization in a patient-specific manner. Using this data, we identified actionable targets to normalize TEnC vessel function to a more NEnC-like phenotype. Finally, we tested two of these drugs in our patient-specific models to determine the efficiency in restoring vessel function showing the potential of the model for single-patient clinical trials.
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Affiliation(s)
- María Virumbrales-Muñoz
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, 1111 Highland Avenue, Madison, Wisconsin 53705, USA.
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29
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Smith AM, Levy PT, Franklin O, Molloy E, El-Khuffash A. Pulmonary hypertension and myocardial function in infants and children with Down syndrome. Arch Dis Child 2020; 105:1031-1034. [PMID: 32160992 DOI: 10.1136/archdischild-2019-318178] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 02/12/2020] [Accepted: 02/17/2020] [Indexed: 12/15/2022]
Abstract
Down Syndrome (DS) is the most common chromosomal abnormality of live born babies. Individuals with DS are at increased risk of cardiopulmonary morbidities in the early neonatal period, infancy and childhood that manifest with elevated pulmonary arterial pressures and altered myocardial performance. Pulmonary hypertension (PH) during the early neonatal period remains under-recognised in this population. PH may occur with or without a congenital heart defect in children with DS and is more common than in the general population. Early detection and continued screening of PH throughout infancy and childhood for these at-risk children is crucial for prompt intervention and potential prevention of long-term sequelae on cardiac function. This review summarises the main physiological concepts behind the mechanisms of PH in children with DS and provides a summary of the current available literature on PH and its impact on myocardial performance.
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Affiliation(s)
| | - Philip T Levy
- Paediatrics, Boston Childrens Hospital, Boston, Massachusetts, USA.,Harvard Medical School, Boston, Massachusetts, USA
| | - Orla Franklin
- Paediatric Cardiology, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
| | - Eleanor Molloy
- Paediatrics and Child Health, Trinity College Dublin, Dublin, Ireland.,Neonatology, Coombe Women and Infants University Hospital, Dublin, Ireland
| | - Afif El-Khuffash
- Neonatology, Rotunda Hospital, Dublin, Ireland.,School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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30
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Welch CL, Chung WK. Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension. Genes (Basel) 2020; 11:E1213. [PMID: 33081265 PMCID: PMC7603012 DOI: 10.3390/genes11101213] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/02/2020] [Accepted: 10/13/2020] [Indexed: 12/14/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene-environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.
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Affiliation(s)
- Carrie L Welch
- Department of Pediatrics, Irving Medical Center, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA
| | - Wendy K Chung
- Department of Pediatrics, Irving Medical Center, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA
- Department of Medicine, Irving Medical Center, Columbia University, 622 W 168th St, New York, NY 10032, USA
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31
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Haarman MG, Kerstjens-Frederikse WS, Vissia-Kazemier TR, Breeman KTN, Timens W, Vos YJ, Roofthooft MTR, Hillege HL, Berger RMF. The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension. J Pediatr 2020; 225:65-73.e5. [PMID: 32502478 DOI: 10.1016/j.jpeds.2020.05.051] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/27/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. RESULTS Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. CONCLUSIONS Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.
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Affiliation(s)
- Meindina G Haarman
- Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands.
| | | | - Theresia R Vissia-Kazemier
- Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands
| | - Karel T N Breeman
- Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands
| | - Wim Timens
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | - Yvonne J Vos
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Marc T R Roofthooft
- Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands
| | - Hans L Hillege
- Department of Epidemiology, University Medical Center Groningen, Groningen, the Netherlands; Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Rolf M F Berger
- Center for Congenital Heart Diseases, Department of Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands
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32
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Ruoss JL, Rios DR, Levy PT. Updates on Management for Acute and Chronic Phenotypes of Neonatal Pulmonary Hypertension. Clin Perinatol 2020; 47:593-615. [PMID: 32713453 DOI: 10.1016/j.clp.2020.05.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Neonatal pulmonary hypertension is a heterogeneous disease in term and preterm neonates. It is characterized by persistent increase of pulmonary artery pressures after birth (acute) or an increase in pulmonary artery pressures after approximately 4 weeks of age (chronic); both phenotypes result in exposure of the right ventricle to sustained high afterload. In-depth clinical assessment plus echocardiographic measures evaluating pulmonary blood flow, pulmonary vascular resistance, pulmonary capillary wedge pressure, and myocardial contractility are needed to determine the cause and provide individualized targeted therapies. This article summarizes the causes, risk factors, hemodynamic assessment, and management of neonatal pulmonary hypertension.
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Affiliation(s)
- Jessica Lauren Ruoss
- Division of Neonatology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA
| | - Danielle R Rios
- Division of Neonatology, Department of Pediatrics, University of Iowa, Iowa City, IA, USA
| | - Philip T Levy
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
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33
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Albinni S, Marx M, Lang IM. Focused Update on Pulmonary Hypertension in Children-Selected Topics of Interest for the Adult Cardiologist. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:E420. [PMID: 32825190 PMCID: PMC7559541 DOI: 10.3390/medicina56090420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/13/2020] [Accepted: 08/16/2020] [Indexed: 11/16/2022]
Abstract
Pulmonary hypertensive vascular disease (PHVD), and pulmonary hypertension (PH), which is a broader term, are severe conditions associated with high morbidity and mortality at all ages. Treatment guidelines in childhood are widely adopted from adult data and experience, though big differences may exist regarding aetiology, concomitant conditions and presentation. Over the past few years, paediatric aspects have been incorporated into the common guidelines, which currently address both children and adults with pulmonary hypertension (PH). There are multiple facets of PH in the context of cardiac conditions in childhood. Apart from Eisenmenger syndrome (ES), the broad spectrum of congenital heart disease (CHD) comprises PH in failing Fontan physiology, as well as segmental PH. In this review we provide current data and novel aspects on the pathophysiological background and individual management concepts of these conditions. Moreover, we focus on paediatric left heart failure with PH and its challenging issues, including end stage treatment options, such as mechanical support and paediatric transplantation. PH in the context of rare congenital disorders, such as Scimitar Syndrome and sickle cell disease is discussed. Based on current data, we provide an overview on multiple underlying mechanisms of PH involved in these conditions, and different management strategies in children and adulthood. In addition, we summarize the paediatric aspects and the pros and cons of the recently updated definitions of PH. This review provides deeper insights into some challenging conditions of paediatric PH in order to improve current knowledge and care for children and young adults.
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Affiliation(s)
- Sulaima Albinni
- Paediatric Heart Centre Vienna, Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Wien, Austria;
| | - Manfred Marx
- Paediatric Heart Centre Vienna, Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Wien, Austria;
| | - Irene M. Lang
- AKH-Vienna, Department of Cardiology, Medical University of Vienna, 1090 Wien, Austria;
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34
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Song S, Babicheva A, Zhao T, Ayon RJ, Rodriguez M, Rahimi S, Balistrieri F, Harrington A, Shyy JYJ, Thistlethwaite PA, Makino A, Yuan JXJ. Notch enhances Ca 2+ entry by activating calcium-sensing receptors and inhibiting voltage-gated K + channels. Am J Physiol Cell Physiol 2020; 318:C954-C968. [PMID: 32186932 PMCID: PMC7294324 DOI: 10.1152/ajpcell.00487.2019] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 03/12/2020] [Accepted: 03/12/2020] [Indexed: 12/27/2022]
Abstract
The increase in cytosolic Ca2+ concentration ([Ca2+]cyt) and upregulation of calcium-sensing receptor (CaSR) and stromal interaction molecule 2 (STIM2) along with inhibition of voltage-gated K+ (KV) channels in pulmonary arterial smooth muscle cells (PASMC) have been implicated in the development of pulmonary arterial hypertension; however, the precise upstream mechanisms remain elusive. Activation of CaSR, a G protein-coupled receptor (GPCR), results in Ca2+ release from the endoplasmic/sarcoplasmic reticulum (ER/SR) and Ca2+ influx through receptor-operated and store-operated Ca2+ channels (SOC). Upon Ca2+ depletion from the SR, STIM forms clusters to mediate store-operated Ca2+ entry. Activity of KV channels, like KCNA5/KV1.5 and KCNA2/KV1.2, contributes to regulating membrane potential, and inhibition of KV channels results in membrane depolarization that increases [Ca2+]cyt by opening voltage-dependent Ca2+ channels. In this study, we show that activation of Notch by its ligand Jag-1 promotes the clustering of STIM2, and clustered STIM2 subsequently enhances the CaSR-induced Ca2+ influx through SOC channels. Extracellular Ca2+-mediated activation of CaSR increases [Ca2+]cyt in CASR-transfected HEK293 cells. Treatment of CASR-transfected cells with Jag-1 further enhances CaSR-mediated increase in [Ca2+]cyt. Moreover, CaSR-mediated increase in [Ca2+]cyt was significantly augmented in cells co-transfected with CASR and STIM2. CaSR activation results in STIM2 clustering in CASR/STIM2-cotransfected cells. Notch activation also induces significant clustering of STIM2. Furthermore, activation of Notch attenuates whole cell K+ currents in KCNA5- and KCNA2-transfected cells. Together, these results suggest that Notch activation enhances CaSR-mediated increases in [Ca2+]cyt by enhancing store-operated Ca2+ entry and inhibits KCNA5/KV1.5 and KCNA2/KV1.2, ultimately leading to voltage-activated Ca2+ entry.
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Affiliation(s)
| | - Aleksandra Babicheva
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Tengteng Zhao
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Ramon J Ayon
- Department of Physiology, University of Arizona, Tucson, Arizona
| | - Marisela Rodriguez
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Shamin Rahimi
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Francesca Balistrieri
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - Angela Harrington
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
| | - John Y-J Shyy
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, La Jolla, California
| | | | - Ayako Makino
- Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
| | - Jason X-J Yuan
- Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, La Jolla, California
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35
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Abstract
Background: Tessellated fundus refers to a specific change in the appearance of the internal layers of the eye in which the choroidal large vessels became visible through polygonal hypopigmented areas. Such hypopigmented areas alternate with hyperpigmented zones in a tigroid pattern. Fundus tessellation is often associated with myopia and choroidal thinning.Materials and Methods: We analyzed fundus images from 50 children with Down syndrome and 52 controls.Results: Tessellation was present in 64% of children with Down syndrome, compared with only 13.5% of controls (p < .0001). In most cases, tessellation was located peripapillary, and no difference was observed in tessellation localization between children with Down syndrome and controls (p = .60). Although more prevalent in myopic children with and without Down syndrome, tessellation was present in almost half (48%) of children with Down syndrome with hyperopia versus only 5% of controls with the same refractive status.Conclusions: Mechanical stretching of the choroid could explain the high rate of tessellation in myopes. Other factors must contribute to the higher prevalence of tessellated fundus in children with Down syndrome without myopia. We discuss potentially relevant factors and propose vascular involvement as a contributor to tessellation in our population with Down syndrome. Further studies assessing choroidal vasculature in individuals with Down syndrome are needed to confirm this theory.
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Affiliation(s)
- Lavinia Postolache
- Ophthalmology Department, Queen Fabiola University Children's Hospital, Université Libre De Bruxelles, Brussels, Belgium
| | - Casper De Jong
- Ophthalmology Department, Queen Fabiola University Children's Hospital, Université Libre De Bruxelles, Brussels, Belgium
| | - Georges Casimir
- Pediatric Department, Queen Fabiola University Children's Hospital, Université Libre De Bruxelles, Brussels, Belgium
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36
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Genetics and Other Omics in Pediatric Pulmonary Arterial Hypertension. Chest 2020; 157:1287-1295. [PMID: 32006592 DOI: 10.1016/j.chest.2020.01.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 12/09/2019] [Accepted: 01/07/2020] [Indexed: 12/15/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite therapeutic advances. Clinical management of children with PAH is particularly challenging because of increased complexity of disease etiology and clinical presentation, and the lack of data from pediatric-specific clinical trials. In children, PAH often develops in association with congenital heart disease and other developmental disorders. Emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 35% of pediatric-onset idiopathic PAH (IPAH) compared with approximately 11% of adult-onset IPAH. De novo variants are the most frequent monogenetic cause of PAH in children, likely contributing to approximately 15% of all cases. Rare deleterious variants in BMPR2 contribute to pediatric-onset IPAH and familial PAH with similar frequency as adult-onset disease but rarely explain cases of PAH associated with other diseases. Rare deleterious variants in developmental genes-including TBX4, SOX17, and other genes requiring confirmation in larger cohorts-are emerging as important contributors to pediatric-onset disease. Because each causal gene contributes to only a small number of cases, large cohorts of pediatric-onset PAH are needed to further identify the unique etiologic differences of PAH in children. We propose a genetics-first approach followed by focused phenotyping of pediatric patients grouped by genetic diagnosis to define endophenotypes that can be used to improve risk stratification and treatment.
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37
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Birjiniuk A, Glinton KE, Villafranco N, Boyer S, Laufman J, Mizerik E, Scott D, Elsea SH, Galambos C, Varghese NP, Scaglia F. Multiple mitochondrial dysfunctions syndrome 1: An unusual cause of developmental pulmonary hypertension. Am J Med Genet A 2020; 182:755-761. [PMID: 31970900 DOI: 10.1002/ajmg.a.61491] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 12/30/2019] [Accepted: 01/05/2020] [Indexed: 11/06/2022]
Abstract
Pulmonary hypertension (pHTN) is a severe, life-threatening disease, which can be idiopathic or associated with an underlying syndrome or genetic diagnosis. Here we discuss a patient who presented with severe pHTN and was later found to be compound heterozygous for pathogenic variants in the NFU1 gene causing multiple mitochondrial dysfunctions syndrome 1 (MMDS1). Review of autopsy slides from an older sibling revealed the same diagnosis along with pulmonary findings consistent with a developmental lung disorder. In particular, these postmortem, autopsy findings have not been described previously in humans with this mitochondrial syndrome and suggest a possible developmental basis for the severe pHTN seen in this disease. Given the rarity of patients reported with MMDS1, we review the current state of knowledge of this disease and our novel management strategies for pHTN and MMDS1-associated complications in this population.
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Affiliation(s)
- Alona Birjiniuk
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Kevin E Glinton
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Natalie Villafranco
- Department of Pulmonary Medicine, Texas Children's Hospital, Houston, Texas.,Department of Pediatrics, Section of Pediatric Pulmonology, Baylor College of Medicine, Houston, Texas
| | - Suzanne Boyer
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Jason Laufman
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Elizabeth Mizerik
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Daryl Scott
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Sarah H Elsea
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Csaba Galambos
- Department of Pathology and Laboratory Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.,Pediatric Heart Lung Center, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado
| | - Nidhy P Varghese
- Department of Pulmonary Medicine, Texas Children's Hospital, Houston, Texas.,Department of Pediatrics, Section of Pediatric Pulmonology, Baylor College of Medicine, Houston, Texas
| | - Fernando Scaglia
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.,BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Shatin, Hong Kong.,Texas Children's Hospital, Houston, Texas
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38
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Abman SH, Galambos C. Pediatric Pulmonary Hypertension on the World Stage: Do We Need Separate Neonatal Guidelines? ACTA ACUST UNITED AC 2019. [DOI: 10.21693/1933-088x-18.3.92] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Steven H. Abman
- Pediatric Heart Lung Center and Pulmonary Hypertension Program, Section of Pediatric Pulmonary Medicine, University of Colorado Anschutz Medical Center and Children's Hospital Colorado, Aurora, CO
| | - Csaba Galambos
- Pediatric Heart Lung Center, Department of Pathology, University of Colorado Anschutz Medical Center and Children's Hospital Colorado, Aurora, CO
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39
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Bush D, Wolter-Warmerdam K, Wagner BD, Galambos C, Ivy D, Abman SH, McMorrow D, Hickey F. EXPRESS: Angiogenic Profile Identifies Pulmonary Hypertension in Children with Down Syndrome. Pulm Circ 2019; 9:2045894019866549. [PMID: 31293212 PMCID: PMC6696852 DOI: 10.1177/2045894019866549] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 07/08/2019] [Indexed: 11/16/2022] Open
Abstract
Past studies have shown that lung angiogenic signaling may be abnormal in children with Down syndrome, but whether differences in circulating angiogenic proteins can identify pulmonary hypertension in children with Down syndrome is unknown. A prospective study of 78 children from birth to 21 years of age was conducted to evaluate clinical data, echocardiograms, and cardiac catheterizations. Four patient populations were enrolled, including children with Down syndrome who have pulmonary hypertension (Down syndrome + pulmonary hypertension, n = 12); control children without Down syndrome who have pulmonary hypertension (C + pulmonary hypertension, n = 15); children with Down syndrome without a known diagnosis of pulmonary hypertension (Down syndrome − pulmonary hypertension, n = 26); and children without Down syndrome or a known diagnosis of pulmonary hypertension (C − pulmonary hypertension, n = 25). Blood samples were collected at enrollment and concentrations for 11 proteins were evaluated. A classification tree was created to identify angiogenic peptide signals that may be associated with pulmonary hypertension in children with Down syndrome compared with controls. Findings identified elevated endostatin levels (>4.98 log10 pg/ml) were associated with Down syndrome. Platelet-derived growth factor AA levels (>2.51 log10 pg/ml) were higher in non-Down syndrome patients with pulmonary hypertension (C + pulmonary hypertension), whereas lower angiogenin (<5.428 log10 pg/ml) or lower angiogenin with elevated angiopoietin-1 levels (>3.59 log10 pg/ml) distinguished pulmonary hypertension in those with Down syndrome from the other groups. This study suggests that children with Down syndrome have high endostatin levels, but low levels of angiogenin levels in children with Down syndrome more often identified pulmonary hypertension than Down syndrome subjects without pulmonary hypertension or non-Down syndrome children. We speculate that these changes in circulating peptides support the concept of dysregulated angiogenesis in children with Down syndrome and pulmonary hypertension, which may further support potential utility as biomarkers for identifying subjects with Down syndrome at risk for pulmonary hypertension in this population.
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Affiliation(s)
- Douglas Bush
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | - Brandie D. Wagner
- Department of Biostatistics and Informatics, University of Colorado and Children’s Hospital Colorado, Aurora, USA
| | - Csaba Galambos
- Department of Pathology, University of Colorado School of Medicine, Aurora, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA
| | - D.Dunbar Ivy
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA
| | - Steven H. Abman
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA
| | - Deven McMorrow
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA
| | - Francis Hickey
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, USA
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Relationship Between Pulmonary Arterial Resistance and Compliance in Patients with Down Syndrome. Pediatr Cardiol 2019; 40:841-847. [PMID: 30830280 DOI: 10.1007/s00246-019-02080-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 02/23/2019] [Indexed: 12/20/2022]
Abstract
This study aimed to clarify the characteristics of pulmonary arterial resistance (Rp)-compliance (Cp) coupling in individuals with Down syndrome (DS), who have increased risks of pulmonary arterial hypertension (PAH). We performed cardiac catheterization before and after corrective surgery in 85 DS infants and 85 controls with congenital heart disease and PAH. We retrospectively collected hemodynamic data and compared Rp and Cp between the groups. Age at surgery was 3.5 (2.6-4.6) months. The first and second catheterizations were performed 1 month before and after corrective surgery in both groups. Preoperative Cp in DS patients was significantly lower than that in controls [2.27 (1.62-3.0) vs. 2.50 (1.86-3.31) mL/mmHg/m2, p = 0.039], although there was no significant difference in mean pulmonary arterial pressure and Rp between the groups. Analysis of covariance revealed that the slopes of the preoperative regression lines for the logarithmic transformations of Rp and Cp were identical in DS patients and controls (p = 0.299). However, the postoperative regression line was shifted downward in DS patients after corrective surgery. Postoperative home oxygen therapy (HOT) was performed in 39 patients (36 DS patients) and multivariate logistic regression analysis revealed that postoperative HOT was significantly related to low preoperative Cp (p = 0.039) and DS (p = 0.0001). Individuals with DS have the unique pulmonary vasculature characterized with low Cp that is related to postoperative HOT.
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Al-Khafaji KHA, Al-Dujaili MN, Al-Dujaili AN. Estimation of Endostatin level in pulmonary arterial hypertension patients and its relation with some parameters. CURRENT ISSUES IN PHARMACY AND MEDICAL SCIENCES 2019. [DOI: 10.1515/cipms-2018-0032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Biomarkers are attractive non-invasive tools for estimating and monitoring pulmonary arterial hypertension (PAH) disease and for predicting survival in patients with PAH; therefore, many studies encouraged the investigation of new biomarkers to facilitate the diagnosis of PAH. Endostatin (ES) is an endogenous inhibitor of angiogenesis. It is produced by proteolytic cleavage of the collagen XVIII that is present in both normal and cancerous tissue. In vitro examination shows that ES can manage endothelial cells (EC) physiology in ways that could influence angiogenesis. For example, solvent ES hinders EC movement and prompts improvements of the cytoskeleton that incorporate the loss of Actin stretch strands and central grips. This effect embraces restrictions on the α5β1integrins, Tropomyosin, and putative heparan sulfate proteoglycans. Consequences for the human EC cytoskeleton include Es-induced down-regulation of Mitogen-actuated Protein Kinase (MAPK), Focal Adhesion Kinase (FAK), the Urokinase Plasminogen Activator (uPA) System, and the RhoA GTPase. Human ES has likewise been shown in a few investigations to repress EC multiplication. Moreover, ES-instigated cell cycle capture in the G1 stage is joined by Cyclin D1 down-regulation. Of note, ES blocks the proliferation and organization of endothelial cells into new blood vessels, and in animal studies, ES also inhibits angiogenesis and the growth of both primary tumors and secondary metastasis. ES was initially identified by its capacity to inhibit tumor angiogenesis in vitro and also in vivo. It can also be found in both healthy and patient’ serum, and has been detected in peripheral circulation. ES could be an attractive, non-invasive prognostic marker for some diseases, notably PAH. Therefore, the presented work is aimed at investigating the ES level in blood serum as a biomarker for detection, diagnosis and early treatment of PAH patients. In doing so, the association is ascertained between gender, age, body mass index (BMI), waist circumferences, smoking, types of PAH (primary and secondary) and this potential biomarker is assessed in PAH patients.
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Rosenzweig EB, Abman SH, Adatia I, Beghetti M, Bonnet D, Haworth S, Ivy DD, Berger RMF. Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J 2019; 53:1801916. [PMID: 30545978 PMCID: PMC6351335 DOI: 10.1183/13993003.01916-2018] [Citation(s) in RCA: 388] [Impact Index Per Article: 64.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 10/09/2018] [Indexed: 12/16/2022]
Abstract
Paediatric pulmonary arterial hypertension (PAH) shares common features of adult disease, but is associated with several additional disorders and challenges that require unique approaches. This article discusses recent advances, ongoing challenges and distinct approaches for the care of children with PAH, as presented by the Paediatric Task Force of the 6th World Symposium on Pulmonary Hypertension. We provide updates of the current definition, epidemiology, classification, diagnostics and treatment of paediatric PAH, and identify critical knowledge gaps. Several features of paediatric PAH including the prominence of neonatal PAH, especially in pre-term infants with developmental lung diseases, and novel genetic causes of paediatric PAH are highlighted. The use of cardiac catheterisation as a diagnostic modality and haemodynamic definitions of PAH, including acute vasoreactivity, are addressed. Updates are provided on issues related to utility of the previous classification system to reflect paediatric-specific aetiologies and approaches to medical and interventional management of PAH, including the Potts shunt. Although a lack of clinical trial data for the use of PAH-targeted therapy persists, emerging data are improving the identification of appropriate targets for goal-oriented therapy in children. Such data will likely improve future clinical trial design to enhance outcomes in paediatric PAH.
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Affiliation(s)
- Erika B Rosenzweig
- Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA
| | - Steven H Abman
- University of Colorado, Children's Hospital Colorado, Denver, CO, USA
| | - Ian Adatia
- Glenwood Children's Heart Clinic, Edmonton, AB, Canada
| | - Maurice Beghetti
- Pediatric Cardiology Unit and Centre Universitaire de Cardiologie et Chirurgie Cardiaque Pédiatrique, University Hospitals of Geneva and Lausanne, Lausanne, Switzerland
| | - Damien Bonnet
- Hôpital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France
| | | | - D Dunbar Ivy
- University of Colorado, Children's Hospital Colorado, Denver, CO, USA
| | - Rolf M F Berger
- Center for Congenital Heart Diseases, Pediatric Cardiology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Schlereth SL, Karlstetter M, Hos D, Matthaei M, Cursiefen C, Heindl LM. Detection of Pro- and Antiangiogenic Factors in the Human Sclera. Curr Eye Res 2018; 44:172-184. [PMID: 30358460 DOI: 10.1080/02713683.2018.1540704] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Avascular tissues can be used to identify antilymph- or antihemangiogenic factors. The human sclera-the outer covering layer of the eye, lacks lymphatic vessels and contains only a superficial network of blood vessels and was used here to identify endogenous antiangiogenic factors. METHODS Expression levels of a panel of 96 known pro- and antiangiogenic factors were analyzed in 12 scleral or conjunctival control samples from normal human donors using real-time PCR. In vitro, scleral homogenate was cocultured with blood- and lymphatic endothelial cells (BECs and LECs) and immunohistochemistry was performed of scleral fibroblasts and BECs. RESULTS Three antiangiogenic factors were significantly upregulated in the human sclera compared to the conjunctiva, including FBLN5 (fibulin 5), SERPINF1 (serpin peptidase inhibitor, clade F, member 1 = pigment epithelium derived factor) and TIMP2 (Tissue inhibitor of metalloproteinases 2). Six proangiogenic factors were significantly downregulated in the sclera, including FLT4 (Fms-related tyrosine kinase 4=VEGF-R3), HGF (hepatocyte growth factor), KIT (CD117 / c-kit), PROX1 (prospero homeobox 1), SEMA3F (semaphorin-3F) and TGFA (transforming growth factor alpha). In vitro, scleral homogenate inhibited the growth of both BECs and LECs. Immunohistochemistry labeling of three major antiangiogenic factors from scleral tissue confirmed TIMP3 and PEDF expression both in scleral fibroblasts and in blood endothelial cells, whereas TIMP2 was not detectable. CONCLUSION Balancing anti- and proangiogenic factors actively regulates human scleral avascularity, inhibits endothelial cell growth in vitro, and thus may help maintaining the vascular privilege of the inner eye.
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Affiliation(s)
- Simona L Schlereth
- a Department of Ophthalmology , University of Cologne , Cologne , Germany
| | - Marcus Karlstetter
- a Department of Ophthalmology , University of Cologne , Cologne , Germany
| | - Deniz Hos
- a Department of Ophthalmology , University of Cologne , Cologne , Germany
| | - Mario Matthaei
- a Department of Ophthalmology , University of Cologne , Cologne , Germany
| | - Claus Cursiefen
- a Department of Ophthalmology , University of Cologne , Cologne , Germany
| | - Ludwig M Heindl
- a Department of Ophthalmology , University of Cologne , Cologne , Germany
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Hosokawa S, Vanderpool RR, Ishii T, Nishiyama M, Doi S. What Causes Pulmonary Arterial Hypertension in Down Syndrome With Congenital Heart Disease? Circ J 2018; 82:1513-1514. [PMID: 29760348 DOI: 10.1253/circj.cj-18-0471] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2024]
Affiliation(s)
- Susumu Hosokawa
- Department of Pediatrics, Tokyo Medical and Dental University
- Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine
| | - Rebecca R Vanderpool
- Division of Translational and Regenerative Medicine, The University of Arizona College of Medicine
| | - Taku Ishii
- Department of Pediatrics, Tokyo Medical and Dental University
| | | | - Shozaburo Doi
- Department of Pediatrics, Tokyo Medical and Dental University
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Alimi A, Taytard J, Abou Taam R, Houdouin V, Forgeron A, Lubrano Lavadera M, Cros P, Gibertini I, Derelle J, Deschildre A, Thumerelle C, Epaud R, Reix P, Fayon M, Roullaud S, Troussier F, Renoux MC, de Blic J, Leyronnas S, Thouvenin G, Perisson C, Ravel A, Clement A, Corvol H, Nathan N, for the French RespiRare® group. Pulmonary hemosiderosis in children with Down syndrome: a national experience. Orphanet J Rare Dis 2018; 13:60. [PMID: 29678139 PMCID: PMC5910623 DOI: 10.1186/s13023-018-0806-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 04/12/2018] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS. METHODS Patients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients' data were compared. RESULTS A total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution. CONCLUSIONS DS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease.
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Affiliation(s)
- Aurelia Alimi
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
| | - Jessica Taytard
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
| | - Rola Abou Taam
- APHP, Pediatric Pulmonology department, RespiRare, Necker Enfants Malades Hospital , 75015 Paris, France
| | - Véronique Houdouin
- APHP, Pediatric Pulmonology department, RespiRare, Faculty Paris Diderot VII, Inserm U1149, Robert Debré Hospital, Paris, France
| | - Aude Forgeron
- Pediatric department, Hospital Center, Inserm U646, 72037 Le Mans, France
| | | | - Pierrick Cros
- Pediatric Pulmonology department, University Hospital, Inserm 1078, Brest, France
| | | | | | - Antoine Deschildre
- Pediatric Pulmonology department, University Hospital, UMR CNRS 8204 - Inserm U1019, Lille, France
| | - Caroline Thumerelle
- Pediatric Pulmonology department, University Hospital, UMR CNRS 8204 - Inserm U1019, Lille, France
| | - Ralph Epaud
- Pediatric Pulmonology department, RespiRare, Créteil University Hospital, Inserm U955, Créteil, France
| | - Philippe Reix
- Pediatric Pulmonology department, University Hospital, UMR CNRS 5558, Lyon, France
| | - Michael Fayon
- Pediatric Pulmonology department, University Hospital, U1219, Bordeaux, France
| | | | - Françoise Troussier
- Pediatric Pulmonology department, University Hospital, Inserm U892, Angers, France
| | - Marie-Catherine Renoux
- Pediatric Pulmonology department, University Hospital, Inserm U1046, Montpellier, France
| | - Jacques de Blic
- APHP, Pediatric Pulmonology department, RespiRare, Necker Enfants Malades Hospital , 75015 Paris, France
| | - Sophie Leyronnas
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
| | - Guillaume Thouvenin
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
- Sorbonne Université, Inserm UMR-S938, Paris, France
| | - Caroline Perisson
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
| | | | - Annick Clement
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
- Sorbonne Université, Inserm UMR-S933, Paris, France
| | - Harriet Corvol
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
- Sorbonne Université, Inserm UMR-S938, Paris, France
| | - Nadia Nathan
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
- Sorbonne Université, Inserm UMR-S933, Paris, France
| | - for the French RespiRare® group
- Assistance Publique Hôpitaux de Paris (APHP), Pediatric Pulmonology department and Reference centre for rare lung diseases, RespiRare, Trousseau Hospital, 75012 Paris, France
- APHP, Pediatric Pulmonology department, RespiRare, Necker Enfants Malades Hospital , 75015 Paris, France
- APHP, Pediatric Pulmonology department, RespiRare, Faculty Paris Diderot VII, Inserm U1149, Robert Debré Hospital, Paris, France
- Pediatric department, Hospital Center, Inserm U646, 72037 Le Mans, France
- Pediatric Pulmonology department, University Hospital, Rouen, France
- Pediatric Pulmonology department, University Hospital, Inserm 1078, Brest, France
- Pediatric department, University Hospital, Tours, France
- Pediatric department, University Hospital, Nancy, France
- Pediatric Pulmonology department, University Hospital, UMR CNRS 8204 - Inserm U1019, Lille, France
- Pediatric Pulmonology department, RespiRare, Créteil University Hospital, Inserm U955, Créteil, France
- Pediatric Pulmonology department, University Hospital, UMR CNRS 5558, Lyon, France
- Pediatric Pulmonology department, University Hospital, U1219, Bordeaux, France
- Pediatric department, Hospital Centre, Angouleme, France
- Pediatric Pulmonology department, University Hospital, Inserm U892, Angers, France
- Pediatric Pulmonology department, University Hospital, Inserm U1046, Montpellier, France
- Sorbonne Université, Inserm UMR-S938, Paris, France
- Institut Jérôme Lejeune, Paris, France
- Sorbonne Université, Inserm UMR-S933, Paris, France
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Martin T, Smith A, Breatnach CR, Kent E, Shanahan I, Boyle M, Levy PT, Franklin O, El-Khuffash A. Infants Born with Down Syndrome: Burden of Disease in the Early Neonatal Period. J Pediatr 2018; 193:21-26. [PMID: 29174996 DOI: 10.1016/j.jpeds.2017.09.046] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 07/28/2017] [Accepted: 09/19/2017] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To evaluate the incidence of direct admission of infants with Down syndrome to the postnatal ward (well newborn nursery) vs the neonatal intensive care unit (NICU), and to describe the incidence of congenital heart disease (CHD) and pulmonary hypertension (PH). STUDY DESIGN This retrospective cohort study of Down syndrome used the maternal/infant database (2011-2016) at the Rotunda Hospital in Dublin, Ireland. Admission location, early neonatal morbidities, outcomes, and duration of stay were evaluated and regression analyses were conducted to identify risk factors associated with morbidity and mortality. RESULTS Of the 121 infants with Down syndrome, 54 (45%) were initially admitted to the postnatal ward, but 38 (70%) were later admitted to the NICU. Low oxygen saturation profile was the most common cause for the initial and subsequent admission to the NICU. Sixty-six percent of the infants (80/121) had CHD, 34% (41/121) had PH, and 6% died. Risk factors independently associated with primary NICU admission included antenatal diagnosis of Down syndrome, presence of CHD, PH, and the need for ventilation. CONCLUSIONS Infants with Down syndrome initially admitted to the postnatal ward have a high likelihood of requiring NICU admission. Overall, high rates of neonatal morbidity were noted, including rates of PH that were higher than previously reported. Proper screening of all infants with Down syndrome for CHD and PH is recommended to facilitate timely diagnoses and potentially shorten the duration of the hospital stay.
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Affiliation(s)
- Therese Martin
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - Aisling Smith
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - Colm R Breatnach
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - Etaoin Kent
- Department of Obstetrics and Gynecology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Ita Shanahan
- Department of Obstetrics and Gynecology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Michael Boyle
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland
| | - Phillip T Levy
- Department of Pediatrics, Washington University School of Medicine, St Louis, MO; Goryeb Children's Hospital, Atlantic Health System, Morristown, NJ
| | - Orla Franklin
- Department of Pediatric Cardiology, Our Lady's Children's Hospital, Dublin, Ireland
| | - Afif El-Khuffash
- Department of Neonatology, The Rotunda Hospital, Dublin, Ireland; School of Medicine (Department of Pediatrics), Royal College of Surgeons in Ireland, Dublin, Ireland.
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Zbucka-Kretowska M, Charkiewicz K, Goscik J, Wolczynski S, Laudanski P. Maternal plasma angiogenic and inflammatory factor profiling in foetal Down syndrome. PLoS One 2017; 12:e0189762. [PMID: 29244857 PMCID: PMC5731759 DOI: 10.1371/journal.pone.0189762] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Accepted: 12/03/2017] [Indexed: 12/14/2022] Open
Abstract
Objective and design Angiogenic factors are proteins that are related to certain foetal chromosomal abnormalities. The aim of this study was to determine the concentration of 60 angiogenic factors in the plasma of women with offspring possessing trisomy 21/Down syndrome (DS). Method After analysing karyotyping results, we selected 20 patients with foetuses possessing DS, and for the control group, we selected 28 healthy patients with uncomplicated pregnancies who delivered healthy newborns at term (i.e., 15–18 weeks of gestation). To assess the concentration of proteins in the blood plasma, we used a protein macroarray which enabled simultaneous determination of 60 angiogenic factors per sample. Results We observed a statistically significant increase in the concentration of these five angiogenic and inflammatory factors: TGFb1 (p = 0.039), angiostatin (p = 0.0142), I-309 (p = 0.0476), TGFb3 (p = 0.0395), and VEGF-D (p = 0.0173)—compared to concentrations in patients with healthy foetuses. Conclusion Our findings suggest that angiogenic factors may play role in DS pathogenesis.
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Affiliation(s)
- Monika Zbucka-Kretowska
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland
| | - Karol Charkiewicz
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Bialystok, Poland
| | - Joanna Goscik
- Faculty of Computer Science, Bialystok University of Technology, Bialystok, Poland
| | - Slawomir Wolczynski
- Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland
| | - Piotr Laudanski
- Department of Perinatology and Obstetrics, Medical University of Bialystok, Bialystok, Poland
- * E-mail:
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Efficacy and safety of oral sildenafil in children with Down syndrome and pulmonary hypertension. BMC Cardiovasc Disord 2017; 17:177. [PMID: 28676038 PMCID: PMC5496590 DOI: 10.1186/s12872-017-0569-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 05/15/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Despite the increased risk for pulmonary hypertension in children with Down syndrome, the response to treatment with targeted therapies for pulmonary hypertension in these patients is not well characterized. The Sildenafil in Treatment-naive children, Aged 1-17 years, with pulmonary arterial hypertension (STARTS-1) trial was a dose-ranging study of the short-term efficacy and safety of oral sildenafil in children with pulmonary arterial hypertension. We assessed the safety and efficacy of oral sildenafil in children with Down syndrome and pulmonary arterial hypertension. METHODS This was a post-hoc analysis of children with Down syndrome and pulmonary arterial hypertension enrolled in the STARTS-1 trial. Mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), and cardiac index (CI) were assessed at baseline and following 16 weeks of treatment with sildenafil. RESULTS Of 234 patients randomized and treated in the STARTS-1 trial, 48 (20.5%) had Down syndrome. Although sildenafil produced dose-related reductions in PVRI and mPAP, compared with placebo, in non-Down syndrome patients and children developmentally able to exercise, this was not satisfactorily marked in patients with Down syndrome. The dose-related reductions in PVRI, compared with placebo, occurred in all subgroups, with the exception of the Down syndrome subgroup. Sildenafil appeared to be well tolerated in the Down syndrome subpopulation and the most frequently reported AEs were similar to those reported for the entire STARTS-1 population. CONCLUSION Sildenafil treatment for 16 weeks had no effect on PVRI or mPAP in children with Down syndrome and pulmonary arterial hypertension. The results suggest that children with Down syndrome may be less responsive to sildenafil for pulmonary arterial hypertension, but the incomplete work-up for the etiology of pulmonary arterial hypertension may have introduced a potential bias. TRIAL REGISTRATION Study received, September 8, 2005 (retrospectively registered); Study start, August 2003; ClinicalTrials.gov identifier, NCT00159913 .
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Colvin KL, Yeager ME. What people with Down Syndrome can teach us about cardiopulmonary disease. Eur Respir Rev 2017; 26:26/143/160098. [DOI: 10.1183/16000617.0098-2016] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 11/13/2016] [Indexed: 12/19/2022] Open
Abstract
Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations (particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.
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50
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Thébaud B. Impaired Lung Development and Neonatal Lung Diseases: A Never-Ending (Vascular) Story. J Pediatr 2017; 180:11-13. [PMID: 27793337 DOI: 10.1016/j.jpeds.2016.10.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 10/07/2016] [Indexed: 12/31/2022]
Affiliation(s)
- Bernard Thébaud
- Department of Pediatrics Children's Hospital of Eastern Ontario and Children's Hospital of Ontario Research Institute (CHEORI); Sinclair Centre for Regenerative Medicine Ottawa Hospital Research Institute (OHRI); Department of Cellular and Molecular Biology University of Ottawa Ottawa, Ontario, Canada.
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