Browsing by Subject "Heart Defects, Congenital"
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Item Atrial septal defect and associated anomalies(1962-03-02) Bashour, Fouad A.Item Cell Migration and Survival Pathways in Cardiac Development and Disease(2005-12-20) Saxena, Ankur; Srivastava, DeepakMammalian cardiac development is a complex process, rendering it susceptible to errors. As a result, congenital heart defects are the most common type of birth defect. Furthermore, heart disease in adults is the leading cause of mortality in the developed world. Given these statistics, gaining an understanding of cardiac development and disease is of paramount importance. Here, data are presented suggesting that the signaling molecules SDF-1, ephrin-B1, and ephrin-B2 play important roles in proper valve formation and maturation during cardiogenesis. Furthermore, another signaling molecule, thymosin ᴬ is implicated in promoting cell survival, potentially through an ILK-Akt pathway, as well as angiogenesis in the treatment of mice post-myocardial infarction. Finally, SDF-1 not only plays a role in cardiac development but, in a manner strikingly similar to the actions of thymosin ᴬ also appears to have therapeutic benefit post-myocardial infarction through the ILK-Akt pathway, reduced cell death, and increased angiogenesis. Together, these data and other information presented herein suggest new roles for signaling molecules in both cardiogenesis and cardiac therapy.Item Congenital Heart Defect-Associated Enhancers Shape Human Cardiomyocyte Lineage Commitment(August 2023) Armendariz, Daniel Alejandro; Xu, Jian; Hon, Gary C.; Johnson, Jane E.; Munshi, Nikhil; Wu, JunAdvancements in whole genome sequencing have identified thousands of disease-associated variants which land within enhancer boundaries. As enhancers play critical roles in orchestrating gene networks throughout development, variants which disrupt enhancer function have been shown to contribute to developmental defects. However studying enhancer variants within a developmental context has been limited by a few key challenges. First, thousands of enhancer variants have been identified which could be causal for disease. Thus, a high-throughput approach is necessary to feasibly interrogate these elements. Second, enhancers function in a cell-type specific and spatiotemporal manner to regulate target gene expression. Perturbation of these enhancers thus requires an in vitro model that can phenocopy the lineage and context in which they are active. Addressing these points, I first identify 25 putative cardiac enhancers harboring variants identified in patients with congenital heart defects (CHD). Using a CRISPRi repression system, I perturb these putative enhancers in human embryonic stem cells (hESC) followed by differentiation towards cardiomyocytes (CM). This allows for the study of enhancer activity throughout the specification of the vital muscle cells of the cardiac system. I then perform single-cell RNA sequencing to identify diverse CM cell populations and assess the impact of enhancer perturbations on lineage specification. My analysis revealed 16 enhancers of known cardiac genes which, when perturbed, result in deficient CM differentiation. Genetic knockouts of two enhancers near TBX5 phenocopied the single-cell data and revealed enrichment of early CM populations resulting from depletion of later stages. My thesis provides a framework for single-cell enhancer screens within a developmental context and provides support for the biological relevance of the approach. I expect that the throughput of this methodology and the ease at which it can be adapted towards diverse developmental systems will provide an invaluable tool for future studies.Item Congenital heart disease as it is encountered in the adult patient(1977-09-15) Willerson, James T.Item Congenital heart disease in adults: (excluding interventricular septal defects)(1962-12-20) Chapman, Carleton B.Item Effect of Chromosomal Copy Number Variations on Congenital Birth Defects and Human Development Disorders(2009-06-17) Santos, Lane Johanna Jaeckle; Zinn, Andrew R.Congenital birth defects are the leading cause of death in the first year of life and the majority of severe congenital anomalies are the result of changes in chromosomal number or structure. The genetic basis of several different congenital malformations including heart defects and urogenital/anorectal defects were explored. A critical region for hypospadias, penoscrotal transposistion and imperforate anus commonly seen in chromosome 13q deletion syndrome was refined, implicating loss of EFNB2 as a possible cause of their formation. Array comparative genomic hybridization was used to show that a significant number of children with congenital heart defects harbor cryptic chromosomal copy number variants, and patients presenting with additional neurological anomalies such as developmental delay highly increase the likelihood of discovering such copy number variants. A novel microdeletion syndrome was discovered using array comparative genomic hybridization that deletes 260 kb on chromosome Xq24 and includes the mitochondrial adenine nucleotide translocase, ANT2. This is the first described mitochondrial disorder characterized by both mitochondrial dysfunction and congenital heart defects and implicates mitochondrial dysfunction as the basis for certain congenital birth defects.Item Genetic syndromes causing congenital heart disease: a commonly unrecognized group of disorders(1977-12-15) Goldstein, Joseph L.Item [News](1979-11-06) Rutherford, SusanItem [News](1989-02-01) Harrell, AnnItem Peritoneal Drainage after Surgical Intervention for Congenital Heart Disease(2015-01-26) Ritchie, Christine; Renkes, Rachel; Burkhalter, Lorrie; Pak, S. W.; Bliss, D. P.PURPOSE: Patients who undergo surgical intervention for congenital heart disease frequently develop abdominal ascites and elevated intraabdominal pressures. In this study, we review a single institution's experience with peritoneal drainage (PD) catheters in patients who have undergone surgical intervention for congenital heart disease. METHODS: We retrospectively reviewed medical records of all patients in whom PD catheters were placed after cardiac surgery for congenital heart disease over 5 years. RESULTS: Sixty-six patients received PD catheters after cardiac surgery. Twenty-seven (40.9%) were male. The mean age was 2.5 years (Range: 5 days - 23.3 years). Mean duration of therapy was 42.5 days (Range: 1-401 days). Thirty-seven (56.1%) patients received PD catheters within 30 days (Mean 11.2 days). Thirty-three (50%) patients survived. There were no differences in sex, age, duration of therapy, drain output, vasopressor requirement, or creatinine between survivors and nonsurvivors. CONCLUSION: While peritoneal drainage catheters may facilitate end organ perfusion and venous return, it is unclear whether they confer a survival advantage. In the setting of PD catheter placement, factors other than patient sex, age, and drain effectiveness, likely play a larger role in patient outcomes.Item [Southwestern News](2003-07-06) Siem, Staishy BostickItem Transcriptional and Translational Regulation of Heart Development in Mammals(2008-09-18) Ransom, Joshua Fuller; Srivastava, DeepakThe heart is the first organ to form in the embryo to support the growing need for oxygen and nutrients. To form correctly, this vital organ requires a high degree of regulation. Thus far, almost every known form of regulation that the mammalian cell has evolved is utilized in the proper development of the heart. Because the heart is so highly regulated, there are many steps at which a wrong turn can be made, leading to congenital cardiovascular malformations, which occur in one percent of all births and are the leading non-infectious cause of death in the first year of life. The majority of genes known to be involved in cardiogenesis in mammals are grouped at nodes which control many simultaneous aspects of differentiation, morphology, and heart size. This thesis work will discuss three separate lines of inquiry into cardiogenic nodes in mammalian heart development. The first deals with post-translational regulation of the Myocardin-dependent transcriptional node. The second story delves into the role of the Notch signaling pathway in human disease and how Notch regulates Myocardin and its downstream target gene, microRNA-1. The final account looks into regulation of protein translation through microRNAs in the heart with emphasis on microRNA-1-2.Item Transcriptional Regulation of Cardiac Ventricular Development(2004-05-04) Pierce, Stephanie Angelo; Srivastava, DeepakCongenital heart disease is the leading non-infectious cause of death in children. Disruption of cardiac gene expression during development can result in congenital heart defects. Numerous transcription factors regulate specific temporo-spatial events during cardiac differentiation and morphogenesis, however the mechanisms that regulate such events are largely unknown. Using a novel modified subtractive hybridization method to identify early cardiac-specific genes, we found Bop, a histone deacetylase-dependent transcriptional repressor. Bop was expressed specifically in the myocardium of the heart and somites during development. Targeted deletion of Bop in mouse resulted in hypoplasia of the right ventricle and expansion of the extracellular matrix between the myocardium and endocardium of the embryonic heart, suggesting a persistence of immature ventricular cardiomyocytes. Expression of dHAND, the evolutionarily conserved bHLH factor necessary for proper right ventricle development, was downregulated in the heart of the Bop-null embryo. In an effort to understand the mechanism by which Bop functions in cardiac differentiation and morphogenesis, the yeast two-hybrid assay was used to identify factors that interact with m-Bop in the embryonic heart. The DNA-binding factor, skNAC, and the inhibitor of mitosis, TRB3, were identified. TRB3 enhanced repression of SV40-driven luciferase activity by m-Bop. Disruption of this interaction resulted in the inability of TRB3 to enhance m-Bop's repressive activity, suggesting a novel function for TRB3 as a corepressor of m-Bop in the developing heart. skNAC was expressed in the myocardium of the heart and somites, strikingly similar to the expression pattern of Bop. While early in vitro attempts to study m-Bop and skNAC failed, in vivo efforts to study a genetic interaction are ongoing.Item [UT News](1986-01-14) Harrell, AnnItem [UT News](1985-12-01) Lyon, PamelaItem [UT Southwestern Medical Center News](2006-07-20) Morales, Katherine