Pregestational Diabetes Mellitus and Congenital Heart Defects

Correa, Adolfo

doi:10.1161/circulationaha.116.022960

Cited by 9 publications

(24 citation statements)

References 32 publications

(33 reference statements)

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“…This increasingly prevalent disease carries a high prenatal disease and mortality risk. Numerous retrospective case studies have reported a clear correlation between maternal DM during pregnancy and an increase in the risk of CHDs (Correa, 2016; Geurtsen et al., 2019; Øyen et al., 2016). In addition, in vivo studies in mice have investigated the symptoms and potential mechanisms in which pregestational diabetes affects fetal development.…”

Section: Commentarymentioning

confidence: 99%

“…Significant efforts have been devoted to understanding the molecular pathology of PGD-CHD using animal models (Buchanan & Kitzmiller, 1994;Correa, 2016), leading to the identification of increased ROS production, abnormal lipid metabolism, and mitochondrial stress, among other contributing factors (Engineer et al, 2018;Lehtoranta et al, 2013Lehtoranta et al, , 2017Ornoy et al, 2015;Piddington, Joyce, Dhanasekaran, & Baker, 1996). The molecular links and the overall contribution of these abnormalities to the different phenotypes observed in PGD-CHD, however, remain elusive.…”

Section: Introductionmentioning

confidence: 99%

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Modeling the Effects of Maternal Diabetes on the Developing Human Heart Using Pluripotent Stem Cell–Derived Heart Organoids

et al. 2022

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Congenital heart defects (CHD) constitute the most common type of birth defect in humans. Maternal diabetes during the first trimester of pregnancy (pregestational diabetes, or PGD) is one of the most prominent factors contributing to CHD, and is present in a significant population of female patients with diabetes in reproductive age. PGD is challenging to manage clinically due to the extreme sensitivity of the developing embryo to glucose oscillations, and constitutes a critical health problem for the mother and the fetus. The prevalence of PGD-induced CHD is increasing due to the ongoing diabetes epidemic. While studies using animal models and cells in culture have demonstrated that PGD alters critical cellular and developmental processes, the mechanisms remain obscure, and it is unclear to what extent these models recapitulate PGD-induced CHD in humans. Clinical practice precludes direct studies in developing human embryos, further highlighting the need for physiologically relevant models. To bypass many of these technical and ethical limitations, we describe here a human pluripotent stem cell (hPSC)-based method to generate developmentally relevant self-organizing human heart organoids. By using glucose and insulin to mimic the diabetic environment that the embryo faces in PGD, this system allows modeling critical features of PGD in a human system with relevant physiology, structure, and cell types. The protocol starts with the generation of hPSC-derived embryoid bodies in a 96-well plate, followed by a small molecule-based three-step Wnt activation/inhibition/activation strategy. Organoids are then differentiated under healthy (normal insulin and glucose) and diabetic conditions (high insulin and glucose) over time, allowing for the study of the effects of pregestational diabetes on the developing human heart. We also provide an immunofluorescence protocol for comparing, characterizing, and analyzing the differences between the healthy and diabetic organoids, and comment on additional steps for preparing the organoids for analysis by other techniques after differentiation.

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Section: Commentarymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling the Effects of Maternal Diabetes on the Developing Human Heart Using Pluripotent Stem Cell–Derived Heart Organoids

et al. 2022

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“…Diabetes mellitus (DM) is characterized by high levels of blood glucose. During pregnancy, DM is correlated with an elevated risk for congenital heart disease (CHDs), e.g., atrial or ventricular septal defects, Tetralogy of Fallot and transposition of the great arteries, in the offspring of humans and animals [1][2][3]. The potential teratogenic effect of high glucose on heart morphogenesis has been documented in previous research [4]; however, the mechanism remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Effects of miR-155 on High Glucose Induced-Cardiac Developmental Defects of Zebrafish Embryos

et al. 2020

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Background: Gestational diabetes mellitus (GDM) is known to have a teratogenic effect on heart development. However, the underlying mechanisms are still unclear. Former studies determined that miR-155 is elevated in GDM patients. Besides, miR-155 is a key molecule for development. In the present study, we explored the potential role of miR-155 in heart development and the effect of miR-155 on high glucose-induced cardiac developmental defects.Methods: Zebra sh embryos were exposed to 2% D-Glucose in a uctuating manner. Activators or inhibitors of miR-155, Ets1, and Igf1 were injected into one-cell stage embryos. The expression levels of miR-155, Ets1 and cardiac speci c genes were evaluated by real-time PCR. The regulation of Igf1 by Ets1 was examined using luciferase assays. The levels of reactive oxygen species (ROS) were analyzed by DCFH-DA. Proteins involved in Igf1 pathway were detected by western blot analysis. Maternal serum miR-155 was determined using ELISA. Fetal cardiac structural and functional characteristics in diabetic or healthy pregnancies were performed by echocardiography.Results: miR-155 levels are increased in serum from GDM patients and are correlated with fetal cardiac structural changes. High glucose exposure in zebra sh embryos altered the morphology of the heart, impaired the heart function, and increased the expression of miR-155 as well as cardiac speci c genes.Upregulation of miR-155 activated Igf1-Akt-Gsk3β pathway by targeting Ets1 and increased the production of ROS and may thereby exert teratogenic effect on cardiac development. In addition, knockdown of miR-155 blocked Igf1 survival pathway and induced apoptosis and may thus induced zebra sh cardiac developmental defects.Conclusion: miR-155 is a key molecule for heart development and is involved in high glucose-induced cardiac malformation, and it might be a novel biomarker as well as a potential drug target of high glucose-induced cardiac defects. BackgroundDiabetes mellitus (DM) is characterized by high levels of blood glucose. During pregnancy, DM is correlated with an elevated risk for congenital heart disease (CHDs), e.g., atrial or ventricular septal defects, Tetralogy of Fallot and transposition of the great arteries, in the offspring of humans and animals [1][2][3]. The potential teratogenic effect of high glucose on heart morphogenesis has been documented in previous research [4]; however, the mechanism remains unclear. miR-155 is a well-known multifunctional microRNA that participates in diverse physiology and pathology processes including in ammation, metabolism, and tumor genesis [5,6]. Recently, several studies reported that miR-155 also functions as a key molecular in development. For example, Burocchi et al [7] determined that miR-155 directly targets Ets proto-oncogene 1 (Ets1) to modulate human T cells development. Interestingly, previous studies identi ed that both miR-155 and Ets1 are also expressed in cardiomyocytes [8,9]. Besides, it has been demonstrated that Ets1 plays a vital role in myocardial

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“…Congenital heart defects (CHDs), which affect 40,000 births per year in the United States, 1 represent the most prevalent congenital defects. 1 2 3 4 5 6 7 8 In addition, they are a major cause of noninfectious death in infants 7 and convey an increase in healthcare costs, 9 so their prenatal diagnosis through fetal echocardiography is essential. 4 6 …”

Section: Introductionmentioning

confidence: 99%

“… 2 10 It threatens normal fetal cardiac development at several levels, which explains the wide spectrum of associated CHDs, from small structural and/or functional defects to major heart disease, with potential long-term sequelae. 7 9 10 11 12 Some studies point to a three times higher risk of CHD in the offspring of women with PGD compared with the offspring of nondiabetic women. 4 7 8 Similarly, there is a higher prevalence for each CHD phenotype in this population.…”

Section: Introductionmentioning

confidence: 99%

Pregestational Diabetes and Congenital Heart Defects

Maduro

Castro

Moleiro

et al. 2022

Rev Bras Ginecol Obstet

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Studies have consistently shown a significant increase in the risk of congenital heart defects in the offspring of diabetic mothers compared with those of nondiabetic pregnancies. Evidence points that all types of pregestational diabetes have the capacity of generating cardiac malformations in a more accentuated manner than in gestational diabetes, and there seems to be an increased risk for all congenital heart defects phenotypes in the presence of maternal diabetes. Currently, the application of some therapies is under study in an attempt to reduce the risks inherent to diabetic pregnancies; however, it has not yet been possible to fully prove their effectiveness. The present review aims to better understand the mechanisms that govern the association between pregestational diabetes and congenital heart defects and how maternal diabetes interferes with fetal cardiac development, as there is still a long way to go in the investigation of this complex process.

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Pregestational Diabetes Mellitus and Congenital Heart Defects

Cited by 9 publications

References 32 publications

Modeling the Effects of Maternal Diabetes on the Developing Human Heart Using Pluripotent Stem Cell–Derived Heart Organoids

Modeling the Effects of Maternal Diabetes on the Developing Human Heart Using Pluripotent Stem Cell–Derived Heart Organoids

Effects of miR-155 on High Glucose Induced-Cardiac Developmental Defects of Zebrafish Embryos

Pregestational Diabetes and Congenital Heart Defects

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