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1.
Exp Neurol ; 347: 113898, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34662542

RESUMO

A noninvasive monitor for concurrent evaluation of placental and fetal sagittal sinus sO 2 for both antepartum surveillance at the late 2nd and 3rd trimesters and intrapartum monitoring would be a great advantage over current methods. A PA fetal brain and placental monitor has potential value to rapidly identify the fetus at risk for developing hypoxia and ischemia of a sufficient degree that brain injury or death may develop, which may be prevented by intervention with delivery and other follow-up treatments.


Assuntos
Encéfalo/diagnóstico por imagem , Monitorização Fetal/métodos , Feto/diagnóstico por imagem , Técnicas Fotoacústicas/métodos , Placenta/diagnóstico por imagem , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Circulação Cerebrovascular/fisiologia , Feminino , Hipóxia Fetal/diagnóstico por imagem , Hipóxia Fetal/fisiopatologia , Feto/fisiologia , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/fisiopatologia , Placenta/irrigação sanguínea , Placenta/fisiologia , Gravidez
2.
Exp Neurol ; 347: 113917, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34748755

RESUMO

Perinatal brain injury is a multifactorial process. In utero placental physiology plays a major role in neuroprotection and the normal development of the fetal central nervous system. Advances in placental pathology have clarified several specific mechanisms of injury and the histologic lesions most strongly associated with them. This review provides an updated summary of the relevant placental anatomy and physiology, the specific placental pathways leading to brain injury, the revised Amsterdam classification system for placental pathology, and the known associations of specific placental lesions with subtypes of adverse neurologic outcomes.


Assuntos
Lesões Encefálicas/patologia , Feto/patologia , Placenta/patologia , Lesões Encefálicas/metabolismo , Corioamnionite/metabolismo , Corioamnionite/patologia , Feminino , Hipóxia Fetal/metabolismo , Hipóxia Fetal/patologia , Feto/metabolismo , Humanos , Placenta/metabolismo , Gravidez
3.
BMC Pregnancy Childbirth ; 21(1): 788, 2021 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-34809600

RESUMO

BACKGROUND: Umbilical artery thrombosis is a rare complication of pregnancy strongly associated with poor fetal and perinatal outcomes, such as intrauterine asphyxia, fetal growth restriction, and stillbirth. Its pathogenesis remains unclear, and there is the added challenge of selecting an appropriate delivery time to achieve excellent neonatal outcomes. METHODS: Our Hospital is a critical maternal rescue center with approximately 7000 births annually. We present a series of 8 cases of umbilical artery thrombosis diagnosed at the hospital between Apr 1, 2018, and Jan 31, 2020. We identified the cases through a keyword search of the maternity and pathology information management systems. RESULTS: Three patients were diagnosed with a transabdominal ultrasound scan and hypoxia on fetal heart monitoring. All three patients had emergency cesarean section delivery. Four patients were observed closely for 5 to 13 weeks from initial detection by an ultrasound scan to delivery. Only one patient was diagnosed after vaginal delivery by Hematoxylin-eosin staining of umbilical cord sections. Seven patients had deliveries by cesarean section, and one patient had a vaginal delivery. All infants were born alive. CONCLUSIONS: Umbilical artery thrombosis is a challenging and rare condition that can occur at different gestational ages, especially when diagnosed in the third trimester and accompanied by fetal growth restriction. Consequently, these patients require close monitoring of umbilical blood flow and fetal growth and intervention at the appropriate time to achieve an optimal outcome.


Assuntos
Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Trombose/diagnóstico por imagem , Artérias Umbilicais/diagnóstico por imagem , Adulto , Cesárea/estatística & dados numéricos , Feminino , Retardo do Crescimento Fetal/etiologia , Hipóxia Fetal , Monitorização Fetal , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Ultrassonografia Pré-Natal
4.
Medicina (Kaunas) ; 57(10)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34684073

RESUMO

Background and Objectives: Intrauterine growth restriction (IUGR) is the term used to describe a fetus whose estimated weight is less than the 10th percentile of its age growth curve. IUGR is the second most common cause of perinatal death. In many cases there is a deficiency in the standardization of optimal management, prenatal follow-up and timing of delivery. Doppler examination is the most sensitive test that can assess the condition of the fetus and indicate fetal intrauterine hypoxia. Numerous studies of the fetal intrauterine state focus on the umbilical artery and the fetal cerebral blood vessels, while the peripheral arteries have so far received insufficient attention. Materials and Methods: We present a case of an IUGR fetus monitored with a non-stress test (NST) and a Doppler examination of the fetal arteries (tibial, umbilical, middle cerebral and uterine) and the ductus venosus. In this case the first early sign of fetal hypoxia was revealed by blood flow changes in the tibial artery. Results: We hypothesize that peripheral vascular changes (in the tibial artery) may more accurately reflect the onset of deterioration in the condition of the IUGR fetus, such that peripheral blood flow monitoring ought to be employed along with other techniques already in use. Conclusion: This paper describes the clinical presentation of an early detection of late IUGR hypoxia and claims that blood flow changes in the tibial artery signal the worsening of the fetus's condition.


Assuntos
Retardo do Crescimento Fetal , Hipóxia Fetal , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Hipóxia Fetal/diagnóstico por imagem , Feto/diagnóstico por imagem , Humanos , Gravidez , Gravidez de Alto Risco , Artérias da Tíbia , Ultrassonografia Doppler , Ultrassonografia Pré-Natal
5.
Sci Rep ; 11(1): 16799, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408219

RESUMO

Foetal hypoxia-ischaemia is a key trigger of meconium aspiration syndrome (MAS). However, many neonates develop MAS without evidence of hypoxia-ischaemia, suggesting the presence of covert but important risk variables. We evaluated the association of MAS with clinical variables, placental histopathologic findings, and inflammatory biomarkers at birth. Of 1336 symptomatic and asymptomatic term singleton neonates with meconium-stained amniotic fluid, 88 neonates (6.6%) developed MAS. Univariate analysis showed that MAS development was associated with low 1- and 5-min Apgar scores, low cord blood pH, funisitis, higher α1-acid glycoprotein levels, and higher haptoglobin levels (all p < 0.001 except for p = 0.001 for haptoglobin). Associations of MAS with caesarean delivery (p = 0.004), premature rupture of the membranes (p = 0.006), chorioamnionitis (p = 0.007), and higher C-reactive protein levels (p = 0.008) were lost when adjusted for multiple comparisons. The final multivariate model to explain MAS development comprised lower cord blood pH (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.47-0.73; p < 0.001), funisitis (OR 2.45; 95% Cl 1.41-4.26; p = 0.002), and higher α1-acid glycoprotein levels (OR 1.02; 95% Cl 1.01-1.03; p = 0.001). Our data from a large cohort of neonates suggested that intrauterine inflammation is one of the key independent variables of MAS development, together with foetal hypoxia-ischaemia.


Assuntos
Hipóxia Fetal/fisiopatologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Inflamação/fisiopatologia , Síndrome de Aspiração de Mecônio/fisiopatologia , Proteína C-Reativa/genética , Corioamnionite/genética , Corioamnionite/fisiopatologia , Feminino , Hipóxia Fetal/complicações , Hipóxia Fetal/genética , Humanos , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/genética , Recém-Nascido , Inflamação/complicações , Masculino , Síndrome de Aspiração de Mecônio/complicações , Síndrome de Aspiração de Mecônio/genética , Placenta/metabolismo , Placenta/fisiopatologia , Gravidez , Respiração Artificial , Fatores de Risco
8.
BMC Vet Res ; 17(1): 182, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33933084

RESUMO

BACKGROUND: Mechanisms of fetal death following maternal PRRSV2 infection remain uncharacterized, although hypoxia from umbilical cord lesions and/or placental detachment due to apoptosis are hypothesized. We performed two experiments examining hypoxia and apoptosis in PRRSV-infected and non-infected, third-trimester fetuses to elucidate possible associations with fetal death. Fetuses were selected based on four phenotypic infection groups: fetuses from non-challenged control gilts (CTRL); low viral load fetuses (LVL; Exp 1) or uninfected fetuses (UNINF; Exp 2) from inoculated gilts; viable high viral load fetuses (HVL-VIA); and HVL meconium-stained fetuses (HVL-MEC). RESULTS: In experiment 1, paraffin embedded fetal tissues collected 21 days post maternal infection (DPI) were examined for DNA fragmentation associated with apoptosis. Positively stained foci were larger and more numerous (P < 0.05) in heart, liver, and thymus of HVL-VIA and HVL-MEC compared to CTRL and LVL fetuses. In experiment 2, group differences in gene expression within the hypoxia (HIF1a, IDO1, VEGFa, LDHA, NOS2, NOX1) and apoptosis (CASP3, CASP7, CASP8, CASP9, RIPK1, RIPK3) pathways were assessed by RT-qPCR in fetal tissues collected at 12 DPI. High viral load fetuses showed differential expression relative to the CTRL and UNINF (P < 0.05 for all). Brain tissue from HVL-VIA and HVL-MEC fetuses presented increased expression of CASP7, CASP8, RIPK3, HIF1a and IDO1. Fetal heart showed increased expression of CASP8, HIF1a, IDO and NOX1 and a decrease in NOS2 expression in infected groups. CASP7, CASP9, RIPK1 and RIPK3 were only increased in the heart of HVL-VIA while VEGFa was only increased for HVL-MEC fetuses. Thymus from HVL-MEC had decreased expression of CASP9 and there was increased IDO1 in all infected fetuses. CONCLUSIONS: There is strong evidence of apoptosis occurring in the heart, liver and thymus of highly viral load fetuses at 21 DPI. Furthermore, there was clear upregulation of apoptotic genes in the heart of high viral load infected fetuses and less prominent upregulation in the brain of PRRSV-infected fetuses, whereas thymus appears to be spared at 12 DPI. There was no strong evidence of hypoxia at 12 DPI in brain and thymus but some indication of hypoxia occurring in fetal heart.


Assuntos
Apoptose , Hipóxia Fetal/veterinária , Síndrome Respiratória e Reprodutiva Suína/patologia , Complicações Infecciosas na Gravidez/veterinária , Animais , Encéfalo/metabolismo , Feminino , Feto/virologia , Expressão Gênica , Miocárdio/metabolismo , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína , Gravidez , Complicações Infecciosas na Gravidez/virologia , Sus scrofa , Suínos , Timo/metabolismo , Carga Viral/veterinária
10.
S Afr Med J ; 111(3b): 280-288, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33944711

RESUMO

The science surrounding cerebral palsy indicates  that it is a complex medical condition with multiple contributing variables and factors, and causal pathways are often extremely difficult to delineate. The pathophysiological processes are often juxtaposed on antenatal factors, genetics, toxins, fetal priming, failure of neuroscientific autoregulatory mechanisms, abnormal biochemistry and abnormal metabolic pathways. Placing this primed compromised compensated brain through the stresses of an intrapartum process could be the final straw in the pathway  to brain injury and later CP.  It is thus simplistic to base causation of cerebral palsy on only an intrapartum perspective with radiological 'confirmation', as is often the practice in medicolegal cases in South African courts. The present modalities (MRI and CTG when available) that retrospectively attempt to determine causation in courts are inadequate when used in isolation. Unless a holistic scientific review of the case including all contributing clinical factors (antepartum, intrapartum and neonatal), fetal heart rate monitoring, neonatal MRI if possible (and preferred) or late MRI, and histology (placental histology if performed) are taken into account, success for plaintiff or defendant currently in a court of law will depend on eloquent legal argument rather than true scientific causality. The 10 criteria set out in this document to implicate acute intrapartum hypoxia in hypoxic ischaemic encephalopathy/neonatal encephalopathy serve as a guideline in the medicolegal setting.


Assuntos
Paralisia Cerebral/etiologia , Hipóxia Fetal/complicações , Hipóxia Fetal/diagnóstico , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/diagnóstico , Cardiotocografia , Feminino , Humanos , Recém-Nascido , Responsabilidade Legal , Imageamento por Ressonância Magnética , Gravidez , Diagnóstico Pré-Natal , África do Sul
11.
Minerva Obstet Gynecol ; 73(4): 453-461, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33949824

RESUMO

Late-onset fetal growth restriction (FGR) accounts for approximately 70-80% of all cases of FGR secondary to uteroplacental insufficiency. It is associated with an increased incidence of adverse antepartum and perinatal events, which in most instances result from hypoxic insults either present at the onset of labor or supervening during labor as a result of uterine contractions. Labor represents a stressful event for the fetoplacental unit being uterine contractions associated with an up-to 60% reduction of the uteroplacental perfusion. Intrapartum fetal heart rate monitoring by means of cardiotocography (CTG) currently represents the mainstay for the identification of fetal hypoxia during labor and is recommended for the fetal surveillance during labor in the case of FGR or other conditions associated with an increased risk of intrapartum hypoxia. In this review we discuss the potential implications of an impaired placental function on the intrapartum adaptation to the hypoxic stress and the role of the CTG and alternative techniques for the intrapartum monitoring of the fetal wellbeing in the context of FGR secondary to uteroplacental insufficiency.


Assuntos
Retardo do Crescimento Fetal , Trabalho de Parto , Cardiotocografia , Feminino , Hipóxia Fetal , Humanos , Placenta , Gravidez
12.
J Physiol ; 599(12): 3221-3236, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33977538

RESUMO

KEY POINTS: Brief episodes of severe fetal hypoxia can arise in late gestation as a result of interruption of normal umbilical blood flow Systemic parameters and blood chemistry indicate complete recovery within 1-2 hours, although the long-term effects on fetal brain functions are unknown Fetal sheep were subjected to umbilical cord occlusion (UCO) for 10 min at 131 days of gestation, and then monitored intensively until onset of labour or delivery (<145 days of gestation) Normal patterns of fetal behaviour, including breathing movements, episodes of high and low voltage electorcortical activity, eye movements and postural (neck) muscle activity, were disrupted for 3-10 days after the UCO Preterm labour and delivery occurred in a significant number of the pregnancies after UCO compared to the control (sham-UCO) cohort. ABSTRACT: Complications arising from antepartum events such as impaired umbilical blood flow can cause significant fetal hypoxia. These complications can be unpredictable, as well as difficult to detect, and thus we lack a detailed understanding of the (patho)physiological changes that occur between the antenatal in utero event and birth. In the present study, we assessed the consequences of brief (∼10 min) umbilical cord occlusion (UCO) in fetal sheep at ∼0.88 gestation on fetal plasma cortisol concentrations and fetal behaviour [electrocortical (EcoG), electo-oculargram (EOG), nuchal muscle electromyography (EMG) and breathing activities] in the days following UCO. UCO caused a rapid onset of fetal hypoxaemia, hypercapnia, and acidosis; however, by 6 h, all blood parameters and cardiovascular status were normalized and not different from the control (Sham-UCO) cohort. Subsequently, the incidence of fetal breathing movements decreased compared to the control group, and abnormal behavioural patterns developed over the days following UCO and leading up to the onset of labour, which included increased high voltage and sub-low voltage ECoG and EOG activities, as well as decreased nuchal EMG activity. Fetuses subjected to UCO went into labour 7.9 ± 3.6 days post-UCO (139.5 ± 3.2 days of gestation) compared to the control group fetuses at 13.6 ± 3.3 days post-sham UCO (144 ± 2.2 days of gestation; P < 0.05), despite comparable increases in fetal plasma cortisol and a similar body weight at birth. Thus, a single transient episode of complete UCO late in gestation in fetal sheep can result in prolonged effects on fetal brain activity and premature labour, suggesting persisting effects on fetal cerebral metabolism.


Assuntos
Trabalho de Parto , Cordão Umbilical , Animais , Feminino , Hipóxia Fetal , Feto , Hipóxia , Gravidez , Ovinos
13.
Neurochem Res ; 46(8): 2046-2055, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34003417

RESUMO

Mild intrauterine hypoperfusion (MIUH) can induce placental dysfunction and lead to long-term changes during the process of brain development. A better understanding of the mechanism of MIUH will help in the development of new neuroprotective strategies for the placental chamber. To better understand the mechanism of the effect of MIUH on the neural development of offspring, we constructed a model of MIUH in pregnant rats. The proliferation, apoptosis, and autophagy of hippocampal neurons in fetal rats were studied via flow cytometry, immunofluorescence staining, JC-1 staining, western blotting, and real-time polymerase chain reaction at different time points (6, 24, 48, and 72 h). The results showed that MIUH significantly inhibited the proliferation of hippocampal neurons and promoted their apoptosis and autophagy. Simultaneously, MIUH could promote PTEN expression and affect the PTEN signaling pathway. bpV, an inhibitor of PTEN, could restore the inhibition of hippocampal nerve cell growth caused by MIUH. MIUH may inhibit neuronal proliferation and promote neuronal apoptosis and autophagy by regulating the PTEN signaling pathway.


Assuntos
Proliferação de Células/fisiologia , Hipóxia Fetal/fisiopatologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Neurônios/metabolismo , Circulação Placentária/fisiologia , Transdução de Sinais/fisiologia , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Constrição Patológica , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Feto , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Hipocampo/patologia , Neurônios/patologia , Ovário/irrigação sanguínea , Ovário/patologia , PTEN Fosfo-Hidrolase/metabolismo , Gravidez , Ratos Sprague-Dawley , Artéria Uterina/patologia
14.
Am J Obstet Gynecol ; 225(5): 544.e1-544.e9, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-33887239

RESUMO

BACKGROUND: Nifedipine is a widely used drug in pregnancies complicated by maternal hypertensive disorders that can be associated with placental insufficiency and fetal hypoxemia. The evidence regarding fetal myocardial responses to nifedipine in hypoxemia is limited. OBJECTIVE: We hypothesized that nifedipine would not impair fetal sheep cardiac function under hypoxemic environment. In particular, we investigated the effects of nifedipine on fetal ventricular functional parameters and cardiac output. STUDY DESIGN: A total of 21 chronically instrumented fetal sheep at 122 to 134 gestational days (term, 145 days) were included in this study. Fetal cardiac function was evaluated by measuring global longitudinal strain, indices describing ventricular systolic and diastolic function, and cardiac outputs using two-dimensional speckle tracking and tissue and spectral pulsed-wave Doppler echocardiography. Fetal carotid artery blood pressure and blood gas values were invasively monitored. After baseline data collection, fetal hypoxemia was induced by maternal hyperoxygenation. After hypoxemia phase data collection, 9 fetuses received nifedipine infusion, and 12 fetuses received saline infusion. Data were collected 30 and 120 minutes after the infusion was started. After 120 minutes of data collection, maternal and fetal oxygenation were normalized, and normoxemia phase data were collected, while infusion was continued. RESULTS: Hypoxemia decreased fetal carotid artery mean arterial pressure from 40 (8) mm Hg to 35 (8) mm Hg (P<.007), and left ventricular global longitudinal strain showed less deformation than at baseline (P=.001). Under hypoxemia, nifedipine caused a reduction in right ventricular global longitudinal strain (P<.05), a decrease in right ventricular isovolumic relaxation velocity and its deceleration (P<.01) indicating diastolic dysfunction, and a drop in right ventricular cardiac output (P<.05). Nifedipine did not alter fetal left ventricular functional parameters or cardiac output. When normoxemia was restored, fetal right ventricular functional parameters and cardiac output returned to baseline level. CONCLUSION: In hypoxemic fetus, nifedipine impaired right ventricular function and reduced its cardiac output. The detrimental effects of nifedipine on fetal right ventricular function were abolished, when normoxemia was restored. Our findings suggest that in a hypoxemic environment nifedipine triggers detrimental effects on fetal right ventricular function.


Assuntos
Bloqueadores dos Canais de Cálcio/efeitos adversos , Débito Cardíaco/efeitos dos fármacos , Hipóxia Fetal/complicações , Nifedipino/efeitos adversos , Disfunção Ventricular Direita/induzido quimicamente , Animais , Pressão Arterial/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Diástole/efeitos dos fármacos , Ecocardiografia Doppler de Pulso , Monitorização Fetal , Modelos Animais , Ovinos
15.
FASEB J ; 35(5): e21477, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33891326

RESUMO

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.


Assuntos
Ácido Ascórbico/uso terapêutico , Atrofia/tratamento farmacológico , Hipóxia Fetal/complicações , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Animais , Animais Recém-Nascidos , Antioxidantes/uso terapêutico , Atrofia/etiologia , Atrofia/metabolismo , Atrofia/patologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/tratamento farmacológico , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/etiologia , Complicações na Gravidez/metabolismo , Complicações na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar
16.
FASEB J ; 35(5): e21446, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33788974

RESUMO

Mitochondria-derived oxidative stress during fetal development increases cardiovascular risk in adult offspring of pregnancies complicated by chronic fetal hypoxia. We investigated the efficacy of the mitochondria-targeted antioxidant MitoQ in preventing cardiovascular dysfunction in adult rat offspring exposed to gestational hypoxia, integrating functional experiments in vivo, with those at the isolated organ and molecular levels. Rats were randomized to normoxic or hypoxic (13%-14% O2 ) pregnancy ± MitoQ (500 µM day-1 ) in the maternal drinking water. At 4 months of age, one cohort of male offspring was chronically instrumented with vascular catheters and flow probes to test in vivo cardiovascular function. In a second cohort, the heart was isolated and mounted onto a Langendorff preparation. To establish mechanisms linking gestational hypoxia with cardiovascular dysfunction and protection by MitoQ, we quantified the expression of antioxidant system, ß-adrenergic signaling, and calcium handling genes in the fetus and adult, in frozen tissues from a third cohort. Maternal MitoQ in hypoxic pregnancy protected offspring against increased α1 -adrenergic reactivity of the cardiovascular system, enhanced reactive hyperemia in peripheral vascular beds, and sympathetic dominance, hypercontractility and diastolic dysfunction in the heart. Inhibition of Nfe2l2-mediated oxidative stress in the fetal heart and preservation of calcium regulatory responses in the hearts of fetal and adult offspring link molecular mechanisms to the protective actions of MitoQ treatment of hypoxic pregnancy. Therefore, these data show the efficacy of MitoQ in buffering mitochondrial stress through NADPH-induced oxidative damage and the prevention of programmed cardiovascular disease in adult offspring of hypoxic pregnancy.


Assuntos
Antioxidantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , Hipóxia Fetal/complicações , Mitocôndrias/metabolismo , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Feminino , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar
17.
Am J Physiol Heart Circ Physiol ; 320(5): H1873-H1886, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33739154

RESUMO

Compared with acyanotic congenital heart disease (CHD), cyanotic CHD has an increased risk of lifelong mortality and morbidity. These adverse outcomes may be attributed to delayed cardiomyocyte maturation, since the transition from a hypoxic fetal milieu to oxygen-rich postnatal environment is disrupted. We established a rodent model to replicate hypoxic myocardial conditions spanning perinatal development, and tested the hypothesis that chronic hypoxia impairs cardiac development. Pregnant mice were housed in hypoxia beginning at embryonic day 16. Pups stayed in hypoxia until postnatal day (P)8 when cardiac development is nearly complete. Global gene expression was quantified at P8 and at P30, after recovering in normoxia. Phenotypic testing included electrocardiogram, echocardiogram, and ex vivo electrophysiology study. Hypoxic P8 animals were 47% smaller than controls with preserved heart size. Gene expression was grossly altered by hypoxia at P8 (1,427 genes affected), but normalized after recovery (P30). Electrocardiograms revealed bradycardia and slowed conduction velocity in hypoxic animals at P8, with noticeable resolution after recovery (P30). Notable differences that persisted after recovery (P30) included a 65% prolongation in ventricular effective refractory period, sinus node dysfunction, 23% reduction in ejection fraction, and 16% reduction in fractional shortening in animals exposed to hypoxia. We investigated the impact of chronic hypoxia on the developing heart. Perinatal hypoxia was associated with changes in gene expression and cardiac function. Persistent changes to the electrophysiological substrate and contractile function warrant further investigation and may contribute to adverse outcomes observed in the cyanotic CHD population.NEW & NOTEWORTHY We utilized a new mouse model of chronic perinatal hypoxia to simulate the hypoxic myocardial conditions present in cyanotic congenital heart disease. Hypoxia caused numerous abnormalities in cardiomyocyte gene expression, the electrophysiologic substrate of the heart, and contractile function. Taken together, alterations observed in the neonatal period suggest delayed cardiac development immediately following hypoxia.


Assuntos
Cianose/etiologia , Coração Fetal/crescimento & desenvolvimento , Cardiopatias Congênitas/etiologia , Hipóxia/complicações , Fatores Etários , Animais , Animais Recém-Nascidos , Doença Crônica , Cianose/genética , Cianose/metabolismo , Cianose/fisiopatologia , Modelos Animais de Doenças , Feminino , Coração Fetal/metabolismo , Hipóxia Fetal/complicações , Hipóxia Fetal/genética , Hipóxia Fetal/metabolismo , Hipóxia Fetal/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento , Idade Gestacional , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/fisiopatologia , Frequência Cardíaca , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Camundongos , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Organogênese , Gravidez , Efeitos Tardios da Exposição Pré-Natal
18.
J Med Case Rep ; 15(1): 87, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602315

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19), the global pandemic that has spread throughout the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the limited scientific evidence on the manifestations and potential impact of this virus on pregnancy, we decided to report this case. CASE PRESENTATION: The patient was a 38 year-old Iranian woman with a triplet pregnancy and a history of primary infertility, as well as hypothyroidism and gestational diabetes. She was hospitalized at 29 weeks and 2 days gestational age due to elevated liver enzymes, and finally, based on a probable diagnosis of gestational cholestasis, she was treated with ursodeoxycholic acid. On the first day of hospitalization, sonography was performed, which showed that biophysical scores and amniotic fluid were normal in all three fetuses, with normal Doppler findings in two fetuses and increased umbilical artery resistance (pulsatility index [PI] > 95%) in one fetus. On day 4 of hospitalization, she developed fever, cough and myalgia, and her COVID-19 test was positive. Despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses leading to the rapid development of absent umbilical artery end-diastolic flow. Finally, 6 days later, the patient underwent cesarean section due to rapid exacerbation of placental insufficiency and declining biophysical score in two of the fetuses. Nasopharyngeal swab COVID-19 tests were negative for the first and third babies and positive for the second baby. The first and third babies died 3 and 13 days after birth, respectively, due to collapsed white lung and sepsis. The second baby was discharged in good general condition. The mother was discharged 3 days after cesarean section. She had no fever at the time of discharge and was also in good general condition. CONCLUSIONS: This was a complicated triplet pregnancy, in which, after maternal infection with COVID-19, despite mild maternal symptoms, exacerbated placental insufficiency occurred in two of the fetuses, and the third fetus had a positive COVID-19 test after birth. Therefore, in cases of pregnancy with COVID-19 infection, in addition to managing the mother, it seems that physicians would be wise to also give special attention to the possibility of acute placental insufficiency and subsequent fetal hypoxia, and also the probability of vertical transmission.


Assuntos
COVID-19/fisiopatologia , Hipóxia Fetal/fisiopatologia , Insuficiência Placentária/fisiopatologia , Complicações Infecciosas na Gravidez/fisiopatologia , Gravidez de Trigêmeos , Adulto , COVID-19/complicações , Cesárea , Colestase Intra-Hepática , Diabetes Gestacional , Feminino , Hipóxia Fetal/etiologia , Hemorragia , Hospitalização , Humanos , Hipotireoidismo/complicações , Recém-Nascido , Recém-Nascido Prematuro , Transmissão Vertical de Doenças Infecciosas , Irã (Geográfico) , Pneumopatias , Masculino , Artéria Cerebral Média/diagnóstico por imagem , Sepse Neonatal , Insuficiência Placentária/diagnóstico por imagem , Insuficiência Placentária/etiologia , Gravidez , Complicações na Gravidez , Terceiro Trimestre da Gravidez , Fluxo Pulsátil , SARS-CoV-2 , Índice de Gravidade de Doença , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Artérias Umbilicais/diagnóstico por imagem , Resistência Vascular
19.
Am J Physiol Lung Cell Mol Physiol ; 320(5): L770-L784, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33624555

RESUMO

Gestational long-term hypoxia increases the risk of myriad diseases in infants including persistent pulmonary hypertension. Similar to humans, fetal lamb lung development is susceptible to long-term intrauterine hypoxia, with structural and functional changes associated with the development of pulmonary hypertension including pulmonary arterial medial wall thickening and dysregulation of arterial reactivity, which culminates in decreased right ventricular output. To further explore the mechanisms associated with hypoxia-induced aberrations in the fetal sheep lung, we examined the premise that metabolomic changes and functional phenotypic transformations occur due to intrauterine, long-term hypoxia. To address this, we performed electron microscopy, Western immunoblotting, calcium imaging, and metabolomic analyses on pulmonary arteries isolated from near-term fetal lambs that had been exposed to low- or high-altitude (3,801 m) hypoxia for the latter 110+ days of gestation. Our results demonstrate that the sarcoplasmic reticulum was swollen with high luminal width and distances to the plasma membrane in the hypoxic group. Hypoxic animals were presented with higher endoplasmic reticulum stress and suppressed calcium storage. Metabolically, hypoxia was associated with lower levels of multiple omega-3 polyunsaturated fatty acids and derived lipid mediators (e.g., eicosapentaenoic acid, docosahexaenoic acid, α-linolenic acid, 5-hydroxyeicosapentaenoic acid (5-HEPE), 12-HEPE, 15-HEPE, prostaglandin E3, and 19(20)-epoxy docosapentaenoic acid) and higher levels of some omega-6 metabolites (P < 0.02) including 15-keto prostaglandin E2 and linoleoylglycerol. Collectively, the results reveal broad evidence for long-term hypoxia-induced metabolic reprogramming and phenotypic transformations in the pulmonary arteries of fetal sheep, conditions that likely contribute to the development of persistent pulmonary hypertension.


Assuntos
Reprogramação Celular , Hipóxia Fetal/fisiopatologia , Feto/fisiopatologia , Hipóxia/fisiopatologia , Metaboloma , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Artéria Pulmonar/fisiopatologia , Altitude , Animais , Cálcio , Feminino , Idade Gestacional , Gravidez , Ovinos
20.
Am J Physiol Heart Circ Physiol ; 320(3): H980-H990, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416457

RESUMO

Perinatal hypoxia induces permanent structural and functional changes in the lung and its pulmonary circulation that are associated with the development of pulmonary hypertension (PH) in later life. The mechanistic target of the rapamycin (mTOR) pathway is vital for fetal lung development and is implicated in hypoxia-associated PH, yet its involvement in the developmental programming of PH remains unclear. Pregnant C57/BL6 dams were placed in hyperbaric (760 mmHg) or hypobaric chambers during gestation (505 mmHg, day 15 through postnatal day 4) or from weaning through adulthood (420 mmHg, postnatal day 21 through 8 wk). Pulmonary hemodynamics and right ventricular systolic pressure (RVSP) were measured at 8 wk. mTOR pathway proteins were assessed in fetal (day 18.5) and adult lung (8 wk). Perinatal hypoxia induced PH during adulthood, even in the absence of a sustained secondary hypoxic exposure, as indicated by reduced pulmonary artery acceleration time (PAAT) and peak flow velocity through the pulmonary valve, as well as greater RVSP, right ventricular (RV) wall thickness, and RV/left ventricular (LV) weight. Such effects were independent of increased blood viscosity. In fetal lung homogenates, hypoxia reduced the expression of critical downstream mTOR targets, most prominently total and phosphorylated translation repressor protein (4EBP1), as well as vascular endothelial growth factor, a central regulator of angiogenesis in the fetal lung. In contrast, adult offspring of hypoxic dams tended to have elevated p4EBP1 compared with controls. Our data suggest that inhibition of mTORC1 activity in the fetal lung as a result of gestational hypoxia may interrupt pulmonary vascular development and thereby contribute to the developmental programming of PH.NEW & NOTEWORTHY We describe the first study to evaluate a role for the mTOR pathway in the developmental programming of pulmonary hypertension. Our findings suggest that gestational hypoxia impairs mTORC1 activation in the fetal lung and may impede pulmonary vascular development, setting the stage for pulmonary vascular disease in later life.


Assuntos
Hipóxia Fetal/complicações , Hipertensão Pulmonar/etiologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Neovascularização Fisiológica , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Feminino , Hipóxia Fetal/metabolismo , Hipóxia Fetal/fisiopatologia , Idade Gestacional , Hemodinâmica , Oxigenação Hiperbárica , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/fisiopatologia , Camundongos Endogâmicos C57BL , Fosforilação , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Circulação Pulmonar , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Função Ventricular Direita , Pressão Ventricular
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