Evaluation of Explanted CorMatrix Intracardiac Patches in Children With Congenital Heart Disease

Animal data demonstrate that intracardiac patches of decellularized porcine small intestine submucosa (CorMatrix; CorMatrix Cardiovascular, Inc, Atlanta, GA) become repopulated with native cells, suggesting the possibility of a substrate for regenerative tissue in humans. We report the only prospective series to date of explanted CorMatrix patches placed in infants with congenital heart disease

Regenerative Medicine Strategies for Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS), the most severe and common form of single ventricle congenital heart lesions, is characterized by hypoplasia of the mitral valve, left ventricle (LV), and all LV outflow structures. While advances in surgical technique and medical management have allowed survival into adulthood, HLHS patients have severe morbidities, decreased quality of life, and a shortened lifespan. The single right ventricle (RV) is especially prone to early failure because of its vulnerability to chronic pressure overload, a mode of failure distinct from ischemic cardiomyopathy encountered in acquired heart disease. As these patients enter early adulthood, an emerging epidemic of RV failure has become evident. Regenerative medicine strategies may help preserve or boost RV function in children and adults with HLHS by promoting angiogenesis and mitigating oxidative stress. Rescuing a RV in decompensated failure may also require the creation of new, functional myocardium. Although considerable hurdles remain before their clinical translation, stem cell therapy and cardiac tissue engineering possess revolutionary potential in the treatment of pediatric and adult patients with HLHS who currently have very limited long-term treatment options.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140239/1/ten.teb.2016.0136.pd

Tissue- specific angiogenic and invasive properties of human neonatal thymus and bone MSCs: Role of SLIT3- ROBO1

Although mesenchymal stem/stromal cells (MSCs) are being explored in numerous clinical trials as proangiogenic and proregenerative agents, the influence of tissue origin on the therapeutic qualities of these cells is poorly understood. Complicating the functional comparison of different types of MSCs are the confounding effects of donor age, genetic background, and health status of the donor. Leveraging a clinical setting where MSCs can be simultaneously isolated from discarded but healthy bone and thymus tissues from the same neonatal patients, thereby controlling for these confounding factors, we performed an in vitro and in vivo paired comparison of these cells. We found that both neonatal thymus (nt)MSCs and neonatal bone (nb)MSCs expressed different pericytic surface marker profiles. Further, ntMSCs were more potent in promoting angiogenesis in vitro and in vivo and they were also more motile and efficient at invading ECM in vitro. These functional differences were in part mediated by an increased ntMSC expression of SLIT3, a factor known to activate endothelial cells. Further, we discovered that SLIT3 stimulated MSC motility and fibrin gel invasion via ROBO1 in an autocrine fashion. Consistent with our findings in human MSCs, we found that SLIT3 and ROBO1 were expressed in the perivascular cells of the neonatal murine thymus gland and that global SLIT3 or ROBO1 deficiency resulted in decreased neonatal murine thymus gland vascular density. In conclusion, ntMSCs possess increased proangiogenic and invasive behaviors, which are in part mediated by the paracrine and autocrine effects of SLIT3.Comparison of mesenchymal stem/stromal cells (MSCs) from the human neonatal thymus and bone revealed that the axon guidance molecule SLIT3 is important for MSC proangiogenic effects. Not only is SLIT3 an endothelial cell stimulatory factor, but it also promotes MSC migration and invasion in an autocrine fashion via the ROBO1 receptor. Deficiency of either SLIT3 or ROBO1 can decrease the vascularization of the neonatal thymus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156475/2/sct312723_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156475/1/sct312723.pd

Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation.

BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-β signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis

Whole-Exome Sequencing Identifies Novel GATA5/6 Variants in Right-Sided Congenital Heart Defects.

One out of every hundred live births present with congenital heart abnormalities caused by the aberrant development of the embryonic cardiovascular system. The conserved zinc finger transcription factor proteins, which include GATA binding protein 5 (GATA5) and GATA binding protein (GATA6) play important roles in embryonic development and their inactivation may result in congenital heart defects (CHDs). In this study, we performed genotypic-phenotypic analyses in two families affected by right-sided CHD diagnosed by echocardiography imaging. Proband A presented with pulmonary valve stenosis, and proband B presented with complex CHD involving the right heart structures. For variant detection, we employed whole-genome single-nucleotide polymorphism (SNP) microarray and family-based whole-exome sequencing (WES) studies. Proband A is a full-term infant who was admitted to the neonatal intensive care unit (NICU) at five days of life for pulmonary valve stenosis (PVS). Genomic studies revealed a normal SNP microarray; however, quad WES analysis identified a novel heterozygous [Chr20:g.61041597C>G (p.Arg237Pro)] variant in the GATA5 gene. Further analysis confirmed that the novel variant was inherited from the mother but was absent in the father and the maternal uncle with a history of heart murmur. Proband B was born prematurely at 35 weeks gestation with a prenatally diagnosed complex CHD. A postnatal evaluation revealed right-sided heart defects including pulmonary atresia with intact ventricular septum (PA/IVS), right ventricular hypoplasia, tricuspid valve hypoplasia, hypoplastic main and bilateral branch pulmonary arteries, and possible coronary sinusoids. Cardiac catheterization yielded anatomy and hemodynamics unfavorable to repair. Hence, heart transplantation was indicated. Upon genomic testing, a normal SNP microarray was observed, while trio WES analysis identified a novel heterozygous [Chr18:c.1757C>T (p.Pro586Leu)] variant in the GATA6 gene. This variant was inherited from the father, who carries a clinical diagnosis of tetralogy of Fallot. These findings provide new insights into novel GATA5/6 variants, elaborate on the genotypic and phenotypic association, and highlight the critical role of GATA5 and GATA6 transcription factors in a wide spectrum of right-sided CHDs

Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P < 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age