Evaluating registry-based trial economics: Results from the STRESS clinical trial.

Background: Registry-based trials have the potential to reduce randomized clinical trial (RCT) costs. However, observed cost differences also may be achieved through pragmatic trial designs. A systematic comparison of trial costs across different designs has not been previously performed.

Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial.

Background: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown.

Methods: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes.

Endocardial-Myocardial Interactions During Early Cardiac Differentiation and Trabeculation.

Throughout the continuum of heart formation, myocardial growth and differentiation occurs in concert with the development of a specialized population of endothelial cells lining the cardiac lumen, the endocardium. Once the endocardial cells are specified, they are in close juxtaposition to the cardiomyocytes, which facilitates communication between the two cell types that has been proven to be critical for both early cardiac development and later myocardial function. Endocardial cues orchestrate cardiomyocyte proliferation, survival, and organization.

Maternal Hyperglycemia Induces Changes in Gene Expression and Morphology in Mouse Placentas.

Background: Pregestational diabetes complicates one million pregnancies in the United States and is associated with placental dysfunction. Placental dysfunction can manifest as stillbirth, spontaneous abortions, fetal growth restriction, and preeclampsia in the mother. However, the underlying mechanisms of placental dysfunction are not well understood.

Imprinted Gene Expression and Function of the Dopa Decarboxylase Gene in the Developing Heart.

Dopa decarboxylase (DDC) synthesizes serotonin in the developing mouse heart where it is encoded by , a tissue-specific paternally expressed imprinted gene. shares an imprinting control region (ICR) with the imprinted, maternally expressed (outside of the central nervous system) gene on mouse chromosome 11, but little else is known about the tissue-specific imprinted expression of . Fluorescent immunostaining localizes DDC to the developing myocardium in the pre-natal mouse heart, in a region susceptible to abnormal development and implicated in congenital heart defects in human.

Overcoming underpowering: Trial simulations and a global rank end point to optimize clinical trials in children with heart disease.

Background: Randomized controlled trials (RCTs) in children with heart disease are challenging and therefore infrequently performed. We sought to improve feasibility of perioperative RCTs for this patient cohort using data from a large, multicenter clinical registry. We evaluated potential enrollment and end point frequencies for various inclusion cohorts and developed a novel global rank trial end point.

Loss of flow responsive Tie1 results in Impaired Aortic valve remodeling.

The mechanisms regulating endothelial cell response to hemodynamic forces required for heart valve development, especially valve remodeling, remain elusive. Tie1, an endothelial specific receptor tyrosine kinase, is up-regulated by oscillating shear stress and is required for lymphatic valve development. In this study, we demonstrate that valvular endothelial Tie1 is differentially expressed in a dynamic pattern predicted by disturbed flow during valve remodeling.

Tie2 regulates endocardial sprouting and myocardial trabeculation.

The ang1-Tie2 pathway is required for normal vascular development, but its molecular effectors are not well-defined during cardiac ontogeny. Here we show that endocardial specific attenuation of Tie2 results in mid-gestation lethality due to heart defects associated with a hyperplastic but simplified trabecular meshwork (fewer but thicker trabeculae). Reduced proliferation and production of endocardial cells (ECs) following endocardial loss of Tie2 results in decreased endocardial sprouting required for trabecular assembly and extension.

Myocardial differentiation is dependent upon endocardial signaling during early cardiogenesis .

The endocardium interacts with the myocardium to promote proliferation and morphogenesis during the later stages of heart development. However, the role of the endocardium in early cardiac ontogeny remains under-explored. Given the shared origin, subsequent juxtaposition, and essential cell-cell interactions of endocardial and myocardial cells throughout heart development, we hypothesized that paracrine signaling from the endocardium to the myocardium is crucial for initiating early differentiation of myocardial cells.

Black Maternal Mortality-The Elephant in the Room.

Maternal mortality is on the rise in the United States and it disproportionately affects black women. The reasons for this staggering discrepancy hinge on three central issues: First, black women are more likely to have pre-existing cardiovascular morbidity that increase the risk of maternal mortality. Second, black women are more likely to experience adverse pregnancy outcomes which puts them at risk for developing long-term cardiovascular disease.

Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis.

The endothelial tyrosine kinase receptor Tie1 remains poorly characterized, largely owing to its orphan receptor status. Global Tie1 inactivation causes late embryonic lethality, thereby reflecting its importance during development. Tie1 also plays pivotal roles during pathologies such as atherosclerosis and tumorigenesis.

Advances in MALDI imaging mass spectrometry of proteins in cardiac tissue, including the heart valve.

Significant progress has been made for tissue imaging of proteins using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI IMS). These advancements now facilitate mapping of a wide range of proteins, peptides, and post-translational modifications in a wide variety of tissues; however, the use of MALDI IMS to detect proteins from cardiac tissue is limited. This review discusses the most recent advances in protein imaging and demonstrates application to cardiac tissue, including the heart valve.

Alterations in sarcomere function modify the hyperplastic to hypertrophic transition phase of mammalian cardiomyocyte development.

It remains unclear how perturbations in cardiomyocyte sarcomere function alter postnatal heart development. We utilized murine models that allowed manipulation of cardiac myosin-binding protein C (MYBPC3) expression at critical stages of cardiac ontogeny to study the response of the postnatal heart to disrupted sarcomere function. We discovered that the hyperplastic to hypertrophic transition phase of mammalian heart development was altered in mice lacking MYBPC3 and this was the critical period for subsequent development of cardiomyopathy.

Transcriptional Profiling of Cultured, Embryonic Epicardial Cells Identifies Novel Genes and Signaling Pathways Regulated by TGFβR3 In Vitro.

The epicardium plays an important role in coronary vessel formation and Tgfbr3-/- mice exhibit failed coronary vessel development associated with decreased epicardial cell invasion. Immortalized Tgfbr3-/- epicardial cells display the same defects. Tgfbr3+/+ and Tgfbr3-/- cells incubated for 72 hours with VEH or ligands known to promote invasion via TGFβR3 (TGFβ1, TGFβ2, BMP2), for 72 hours were harvested for RNA-seq analysis.

Making a heart: advances in understanding the mechanisms of cardiac development.

Purpose Of Review: The study of cardiac development is critical to inform management strategies for congenital and acquired heart disease. This review serves to highlight some of the advances in this field over the past year.

Recent Findings: Three main areas of study are included that have been particularly innovative and progressive.

Feasibility of a Team Approach to Complex Congenital Heart Defect Neurodevelopmental Follow-Up: Early Experience of a Combined Cardiology/Neonatal Intensive Care Unit Follow-Up Program.

Infants with complex congenital heart disease are at high risk for poor neurodevelopmental outcomes. However, implementation of dedicated congenital heart disease follow-up programs presents important infrastructure, personnel, and resource challenges. We present the development, implementation, and retrospective review of 1- and 2-year outcomes of a Complex Congenital Heart Defect Neurodevelopmental Follow-Up program.

Postnatal lethality and abnormal development of foregut and spleen in Ndrg4 mutant mice.

NDRG4 is a member of the NDRG family (N-myc downstream-regulated gene), which is highly expressed in brain and heart. Previous studies showed that Ndrg1-deficient mice exhibited a progressive demyelinating disorder of peripheral nerves and Ndrg4-deficient mice had spatial learning deficits and vulnerabilities to cerebral ischemia. Here, we report generation of Ndrg4 mutant alleles that exhibit several development defects different from those previously reported.

The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.

Tie1 is a mechanistically poorly characterized endothelial cell (EC)-specific orphan receptor. Yet, Tie1 deletion is embryonic lethal and Tie1 has been implicated in critical vascular pathologies, including atherosclerosis and tumor angiogenesis. Here, we show that Tie1 does not function independently but exerts context-dependent effects on the related receptor Tie2.

Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction.

Objective: Calcific aortic valve disease (CAVD) is a significant cardiovascular disorder, and controversy exists as to whether it is primarily a dystrophic or osteogenic process in vivo. In this study, we sought to clarify the mechanism of CAVD by assessing a genetic mutation, Notch1 heterozygosity, which leads to CAVD with 100% penetrance in humans.

Approach And Results: Murine immortalized Notch1(+/-) aortic valve interstitial cells (AVICs) were isolated and expanded in vitro.

Myocardial contraction and hyaluronic acid mechanotransduction in epithelial-to-mesenchymal transformation of endocardial cells.

Epithelial-to-mesenchymal transition (EMT) of endocardial cells is a critical initial step in the formation of heart valves. The collagen gel in vitro model has provided significant information on the role of growth factors regulating EMT but has not permitted investigation of mechanical factors. Therefore we sought to develop a system to probe the effects of mechanical inputs on endocardial EMT by incorporating hyaluronic acid (HA), the primary component of endocardial cushions in developing heart valves, into the gel assay.

Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition.

Directional cell movement is universally required for tissue morphogenesis. Although it is known that cell/matrix interactions are essential for directional movement in heart development, the mechanisms governing these interactions require elucidation. Here we demonstrate that a novel protein/protein interaction between blood vessel epicardial substance (Bves) and N-myc downstream regulated gene 4 (NDRG4) is critical for regulation of epicardial cell directional movement, as disruption of this interaction randomizes migratory patterns.