Maternal Sirolimus Therapy for Fetal Cardiac Rhabdomyomas.
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ABSTRACT:
SUBMITTER: Barnes BT
PROVIDER: S-EPMC6201692 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
Publications
Maternal Sirolimus Therapy for Fetal Cardiac Rhabdomyomas.
Barnes Benjamin T BT Procaccini David D Crino Jude J Blakemore Karin K Sekar Priya P Sagaser Katelynn G KG Jelin Angie C AC Gaur Lasya L
The New England journal of medicine 20180501 19
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Project description:Ligand-independent, constitutive activation of Hedgehog signalling in mice expressing a mutant, activated SmoM2 allele results in the development of multifocal, highly differentiated tumours that express myogenic markers (including desmin, actin, MyoD and myogenin). The histopathology of these tumours, commonly classified as rhabdomyosarcomas, more closely resembles human fetal rhabdomyoma (FRM), a benign tumour that can be difficult to distinguish from highly differentiated rhabdomyosarcomas. We evaluated the spectrum of Hedgehog (HH) pathway gene mutations in a cohort of human FRM tumours by targeted Illumina sequencing and fluorescence in situ hybridization testing for PTCH1. Our studies identified functionally relevant aberrations at the PTCH1 locus in three of five FRM tumours surveyed, including a PTCH1 frameshift mutation in one tumour and homozygous deletions of PTCH1 in two tumours. These data suggest that activated Hedgehog signalling contributes to the biology of human FRM.
| S-EPMC3875333 | biostudies-literature
Project description:Graphical abstract Highlights • Cardiac rhabdomyomas are commonly associated with TSC.• They are often the first presentation of TSC, diagnosed prenatally or in neonates.• Fetal or neonatal echocardiography is useful for their early detection.• Familial TSC may be seen even in cases with phenotypically normal parents.• Rhabdomyomas in both dizygotic twins, suggesting familial TSC, is very rare.
| S-EPMC10102993 | biostudies-literature
Project description:BackgroundCardiac rhabdomyoma (RHM) is considered one of the most frequent benign heart tumors in children. However, encounters with cardiac RHM in clinical practice remain rare. Clinical information is primarily available in the form of single case reports or smaller studies with a shortage of large-scale reviews encompassing a substantial number of cases.ResultsIn order to congregate existing and future information on cardiac RHM we established a web-based cardiac RHM online registry using an online survey tool. In addition we integrated previously published data from individual case reports and case series. The evaluation of this paper is intended to provide a brief overview of the cohort that we have been able to include so far. Our findings mainly confirm the previous knowledge on cardiac RHM. At the same time, our cohort shows a clear heterogeneity in the treatment methods with regard to rhabdomyomas requiring therapy and revealed a bias between literature data and our registry data with regard to symptoms and need for therapy.ConclusionIn the view of the heterogeneity of treatment methods, a systematic overview of cardiac RHM is all the more important, especially as specific drug treatment options now exist. The registry should not just provide a comprehensive and informative overview of causes, time course, symptoms and therapeutic options of cardiac RHM but also facilitate information sharing among clinicians and researchers and serve as a basis for future clinical and pharmacological studies.
| S-EPMC11780848 | biostudies-literature
Project description:The human fetal heart develops arrhythmias and conduction disturbances in response to ischemia, inflammation, electrolyte disturbances, altered load states, structural defects, inherited genetic conditions, and many other causes. Yet sinus rhythm is present without altered rate or rhythm in some of the most serious electrophysiological diseases, which makes detection of diseases of the fetal conduction system challenging in the absence of magnetocardiographic or electrocardiographic recording techniques. Life-threatening changes in QRS or QT intervals can be completely unrecognized if heart rate is the only feature to be altered. For many fetal arrhythmias, echocardiography alone can assess important clinical parameters for diagnosis. Appropriate treatment of the fetus requires awareness of arrhythmia characteristics, mechanisms, and potential associations. Criteria to define fetal bradycardia specific to gestational age are now available and may allow detection of ion channelopathies, which are associated with fetal and neonatal bradycardia. Ectopic beats, once thought to be entirely benign, are now recognized to have important pathologic associations. Fetal tachyarrhythmias can now be defined precisely for mechanism-specific therapy and for subsequent monitoring of response. This article reviews the current and future diagnostic techniques and pharmacologic treatments for fetal arrhythmia.
| S-EPMC2995324 | biostudies-literature
Project description:Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that the IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p<0.05) in male IUGR. Expression of cardiac fibrotic markers TGFβ, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p<0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and females (p<0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4α, and NFκB p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk.
| S-EPMC5548301 | biostudies-literature
Project description:RationaleFetal cells enter the maternal circulation during pregnancy and may persist in maternal tissue for decades as microchimeras.ObjectiveBased on clinical observations of peripartum cardiomyopathy patients and the high rate of recovery they experience from heart failure, our objective was to determine whether fetal cells can migrate to the maternal heart and differentiate to cardiac cells.Methods and resultsWe report that fetal cells selectively home to injured maternal hearts and undergo differentiation into diverse cardiac lineages. Using enhanced green fluorescent protein (eGFP)-tagged fetuses, we demonstrate engraftment of multipotent fetal cells in injury zones of maternal hearts. In vivo, eGFP+ fetal cells form endothelial cells, smooth muscle cells, and cardiomyocytes. In vitro, fetal cells isolated from maternal hearts recapitulate these differentiation pathways, additionally forming vascular tubes and beating cardiomyocytes in a fusion-independent manner; ≈40% of fetal cells in the maternal heart express Caudal-related homeobox2 (Cdx2), previously associated with trophoblast stem cells, thought to solely form placenta.ConclusionsFetal maternal stem cell transfer appears to be a critical mechanism in the maternal response to cardiac injury. Furthermore, we have identified Cdx2 cells as a novel cell type for potential use in cardiovascular regenerative therapy.
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Project description:Congenital heart disease (CHD) is the most common type of birth defect and is both a significant pediatric and adult health problem, in light of a growing population of survivors. The etiology of CHD has been considered to be multifactorial with genetic and environmental factors playing important roles. The combination of advances in cardiac developmental biology, which have resulted in the elucidation of molecular pathways regulating normal cardiac morphogenesis, and genome sequencing technology have allowed the discovery of numerous genetic contributors of CHD ranging from chromosomal abnormalities to single gene variants. Conversely, mechanistic details of the contribution of environmental factors to CHD remain unknown. Maternal diabetes mellitus (matDM) is a well-established and increasingly prevalent environmental risk factor for CHD, but the underlying etiologic mechanisms by which pregestational matDM increases the vulnerability of embryos to cardiac malformations remains largely elusive. Here, we will briefly discuss the multifactorial etiology of CHD with a focus on the epidemiologic link between matDM and CHD. We will describe the animal models used to study the underlying mechanisms between matDM and CHD and review the numerous cellular and molecular pathways affected by maternal hyperglycemia in the developing heart. Last, we discuss how this increased understanding may open the door for the development of novel prevention strategies to reduce the incidence of CHD in this high-risk population.
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Project description:Fetal hyperthyroidism can occur secondary to maternal autoimmune hyperthyroidism. The thyroid-stimulating hormone receptor antibody (TRAb) transferred from the mother to the fetus stimulates the fetal thyroid and causes fetal thyrotoxicosis. Fetuses with this condition are difficult to detect, especially after maternal Graves disease therapy. Here, we present two cases of fetal hyperthyroidism with maternal hypothyroidism and review the assessment and intrauterine therapy for fetal hyperthyroidism. Both women were referred at 22+ and 23+ weeks of gestation with abnormal ultrasound findings, including fetal heart enlargement, pericardial effusion, and fetal tachycardia. Both women had a history of Graves disease while in a state of hypothyroidism with a high titer of TRAb. A sonographic examination showed a diffusely enlarged fetal thyroid with abundant blood flow. Invasive prenatal testing revealed no significant chromosomal aberration. Low fetal serum TSH and high TRAb levels were detected in the cord blood. Fetal hyperthyroidism was considered, and maternal oral methimazole (MMI) was administered as intrauterine therapy, with the slowing of fetal tachycardia, a reduction in fetal heart enlargement, and thyroid hyperemia. During therapy, maternal thyroid function was monitored, and the dosage of maternal levothyroxine was adjusted accordingly. Both women delivered spontaneously at 36+ weeks of gestation, and neonatal hyperthyroidism was confirmed in both newborns. After methimazole and propranolol drug treatment with levothyroxine for 8 and 12 months, both babies became euthyroid with normal growth and development.
| S-EPMC10795960 | biostudies-literature
Project description:Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that the IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p<0.05) in male IUGR. Expression of cardiac fibrotic markers TGFß, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p<0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and females (p<0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4a, and NF?B p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk.
2018-04-30 | MTBLS426 | MetaboLights