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Journal of the American College of... Sep 2023We have followed a consistent, albeit evolving, strategy for the management of patients with pulmonary atresia or severe stenosis and major aortopulmonary collateral...
BACKGROUND
We have followed a consistent, albeit evolving, strategy for the management of patients with pulmonary atresia or severe stenosis and major aortopulmonary collateral arteries (MAPCAs) that aims to achieve complete repair with low right ventricular pressure by completely incorporating blood supply and relieving stenoses to all lung segments.
OBJECTIVES
The purpose of this study was to characterize our 20-year institutional experience managing patients with MAPCAs.
METHODS
We reviewed all patients who underwent surgery for MAPCAs and biventricular heart disease from November 2001 through December 2021.
RESULTS
During the study period, 780 unique patients underwent surgery. The number of new patients undergoing surgery annually was relatively steady during the first 15 years, then increased substantially thereafter. Surgery before referral had been performed in almost 40% of patients, more often in our recent experience than earlier. Complete repair was achieved in 704 patients (90%), 521 (67%) during the first surgery at our center, with a median right ventricular to aortic pressure ratio of 0.34 (25th, 75th percentiles: 0.28, 0.40). The cumulative incidence of mortality was 15% (95% CI: 12%-19%) at 10 years, with no difference according to era of surgery (P = 0.53). On multivariable Cox regression, Alagille syndrome (HR: 2.8; 95% CI: 1.4-5.7; P = 0.004), preoperative respiratory support (HR: 2.0; 95% CI: 1.2-3.3; P = 0.008), and palliative first surgery at our center (HR: 3.5; 95% CI: 2.3-5.4; P < 0.001) were associated with higher risk of death.
CONCLUSIONS
In a growing pulmonary artery reconstruction program, with increasing volumes and an expanding population of patients who underwent prior surgery, outcomes of patients with pulmonary atresia or stenosis and MAPCAs have continued to improve.
Topics: Humans; Aorta; Constriction, Pathologic; Heart Defects, Congenital; Pulmonary Artery; Pulmonary Atresia
PubMed: 37704311
DOI: 10.1016/j.jacc.2023.06.041 -
Hepatology Communications Sep 2023We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of...
BACKGROUND
We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity.
METHODS
We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing.
RESULTS
DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.
CONCLUSIONS
YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.
Topics: Animals; Male; Mice; Adaptor Proteins, Signal Transducing; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cholestasis; Endoderm; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Trans-Activators; Transcription Factors; YAP-Signaling Proteins; Female
PubMed: 37556373
DOI: 10.1097/HC9.0000000000000220 -
JPGN Reports Aug 2023
PubMed: 37600608
DOI: 10.1097/PG9.0000000000000338 -
Advances in Experimental Medicine and... 2024Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and...
Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.
Topics: Humans; Chromosome Aberrations; DNA Copy Number Variations; Genetic Predisposition to Disease; Heart Septal Defects, Ventricular; Mutation; Transcription Factors
PubMed: 38884729
DOI: 10.1007/978-3-031-44087-8_27 -
Hepatology (Baltimore, Md.) Nov 2023Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome...
BACKGROUND AND AIMS
Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in several mouse models generated by removing one copy of Jag1 in the germline with or without reducing the gene dosage of sex-determining region Y-box 9 in the liver.
APPROACH AND RESULTS
Using an ASO established in this study, we show that reducing Poglut1 levels in postnatal livers of ALGS mouse models with moderate to profound biliary abnormalities can significantly improve BD development and biliary tree formation. Importantly, ASO injections prevent liver damage in these models without adverse effects. Furthermore, ASO-mediated Poglut1 knockdown improves biliary tree formation in a different mouse model with no Jag1 mutations. Cell-based signaling assays indicate that reducing POGLUT1 levels or mutating POGLUT1 modification sites on JAG1 increases JAG1 protein level and JAG1-mediated signaling, suggesting a likely mechanism for the observed in vivo rescue.
CONCLUSIONS
Our preclinical studies establish ASO-mediated POGLUT1 knockdown as a potential therapeutic strategy for ALGS liver disease and possibly other diseases associated with BD paucity.
Topics: Animals; Mice; Alagille Syndrome; Bile Ducts, Intrahepatic; Calcium-Binding Proteins; Cholestasis; Gene Silencing; Glucosyltransferases; Glycosyltransferases; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Liver; Membrane Proteins; Oligonucleotides, Antisense; Phenotype; Serrate-Jagged Proteins
PubMed: 37021797
DOI: 10.1097/HEP.0000000000000380 -
Stem Cell Research Sep 2023Alagille syndrome (ALGS) is an autosomal dominant disease affecting the liver, heart and other organs with high variability. About 95% of ALGS cases are associated with...
Alagille syndrome (ALGS) is an autosomal dominant disease affecting the liver, heart and other organs with high variability. About 95% of ALGS cases are associated with pathogenic variants in JAG1, encoding the Jagged1 ligand that binds to Notch receptors. The iPSC line NCHi012-A was derived from an ALGS patient with cholestatic liver disease and mild pulmonary stenosis, who is heterozygous for a 2 bp deletion in the JAG1 coding sequence. We report here an initial characterization of NCHi012-A to evaluate its morphology, pluripotency, differentiation potential, genotype, karyotype and identity to the source patient.
Topics: Humans; Alagille Syndrome; Induced Pluripotent Stem Cells; Receptors, Notch; Heart; Jagged-1 Protein
PubMed: 37549562
DOI: 10.1016/j.scr.2023.103177 -
Gastroenterology Nursing : the Official...Alagille syndrome is a rare and complex pleiotropic multisystem disorder caused by an autosomal dominant genetic mutation of JAG1 (90%) and NOTCH2 (1%-2%) genes located...
Alagille syndrome is a rare and complex pleiotropic multisystem disorder caused by an autosomal dominant genetic mutation of JAG1 (90%) and NOTCH2 (1%-2%) genes located on the short arm of chromosome 20. This case is reported as per the CA se RE ports (CARE) guidelines (2013). A 14-year-old boy who is a known case of chronic cholestatic liver disease of neonatal onset, was diagnosed with Alagille syndrome as evident from a NOTCH 2 mutation in genetic analysis and paucity of intrahepatic bile ducts on biopsy. He presented with portal hypertension, growth failure, and persistent hyperbilirubinemia. This case highlights the gamut of multisystem dysfunctions faced by this child. He is currently on conservative management and worked up for liver transplantation. The condition is often rare and challenging due to the multisystem pathogenesis. Thus, the nursing care is also multifaceted. This case study identified relevant North American Nursing Diagnosis Association (NANDA) Classification, Nursing Interventions Classification (NIC), and Nursing Outcomes Classification (NOC) concepts to describe care of children with Alagille syndrome based on actual patient data.
Topics: Male; Child; Infant, Newborn; Humans; Adolescent; Alagille Syndrome; Standardized Nursing Terminology; Nursing Diagnosis; Patient Care
PubMed: 37581873
DOI: 10.1097/SGA.0000000000000755 -
Advances in Experimental Medicine and... 2024Tricuspid atresia (TA) is a rare congenital heart condition that presents with a complete absence of the right atrioventricular valve. Because of the rarity of familial...
Tricuspid atresia (TA) is a rare congenital heart condition that presents with a complete absence of the right atrioventricular valve. Because of the rarity of familial and/or isolated cases of TA, little is known about the potential genetic abnormalities contributing to this condition. Potential responsible chromosomal abnormalities were identified in exploratory studies and include deletions in 22q11, 4q31, 8p23, and 3p as well as trisomies 13 and 18. In parallel, potential culprit genes include the ZFPM2, HEY2, NFATC1, NKX2-5, MYH6, and KLF13 genes. The aim of this chapter is to expose the genetic components that are potentially involved in the pathogenesis of TA in humans. The large variability in phenotypes and genotypes among cases of TA suggests a genetic network that involves many components yet to be unraveled.
Topics: Humans; Chromosome Aberrations; Phenotype; Tricuspid Atresia; Univentricular Heart
PubMed: 38884756
DOI: 10.1007/978-3-031-44087-8_54 -
JPGN Reports Aug 2023Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug...
Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug for the treatment of cholestatic pruritus in children with Alagille syndrome aged 3 months and older. Clinical trials of maralixibat have reported follow-up to 4 years and reported a ≥1-pt reduction using the Itch-Reported Outcome (Observer) (ItchRO[Obs]) instrument (0-4 scale), as this decrease was previously defined as a clinically meaningful improvement in pruritus; participants in clinical trials were expected to be maintained on stable doses of antipruritic agents. We report on a patient with 3 notable features: (1) complete resolution of her pruritus; (2) durability of this response for over 7 years; and (3) ability to discontinue all other antipruritic medications.
PubMed: 37600618
DOI: 10.1097/PG9.0000000000000335 -
Pediatric Nephrology (Berlin, Germany) Oct 2023
Topics: Child; Humans; Liver Diseases; Renal Insufficiency, Chronic
PubMed: 37405491
DOI: 10.1007/s00467-023-05949-3