scholarly journals Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Jeanne L Theis ◽  
Georg Vogler ◽  
Maria A Missinato ◽  
Xing Li ◽  
Tanja Nielsen ◽  
...  
Keyword(s):  
Hypoplastic Left Heart Syndrome ◽  
Heart Development ◽  
Heart Diseases ◽  
Heart Defects ◽  
Patient Specific ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Healthy Human ◽  
Altered Expression ◽  
Left Heart Syndrome

Congenital heart diseases (CHDs), including hypoplastic left heart syndrome (HLHS), are genetically complex and poorly understood. Here, a multidisciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole-genome and iPSC RNA sequencing of a HLHS family-trio. Filtering for rare variants and altered expression in proband iPSCs prioritized 10 candidates. siRNA/RNAi-mediated knockdown in healthy human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. Consistent with hypoplastic heart defects, compared to parents the proband’s iPSC-CMs exhibited reduced proliferation. Interestingly, rare, predicted-damaging LRP2 variants were enriched in a HLHS cohort; however, understanding their contribution to HLHS requires further investigation. Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps toward deciphering oligogenic underpinnings of CHDs, including hypoplastic left hearts.

scholarly journals Effect of left atrial ligation-driven altered inflow hemodynamics on embryonic heart development: clues for prenatal progression of hypoplastic left heart syndrome

2021 ◽  
Author(s):  
Huseyin Enes Salman ◽  
Maha Alser ◽  
Akshay Shekhar ◽  
Russell A. Gould ◽  
Fatiha M. Benslimane ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Hypoplastic Left Heart Syndrome ◽  
Heart Development ◽  
Left Atrial ◽  
Heart Defects ◽  
Systemic Circulation ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
The Right ◽  
Left Heart Syndrome

AbstractCongenital heart defects (CHDs) are abnormalities in the heart structure present at birth. One important condition is hypoplastic left heart syndrome (HLHS) where severely underdeveloped left ventricle (LV) cannot support systemic circulation. HLHS usually initiates as localized tissue malformations with no underlying genetic cause, suggesting that disturbed hemodynamics contribute to the embryonic development of these defects. Left atrial ligation (LAL) is a surgical procedure on embryonic chick resulting in a phenotype resembling clinical HLHS. In this study, we investigated disturbed hemodynamics and deteriorated cardiac growth following LAL to investigate possible mechanobiological mechanisms for the embryonic development of HLHS. We integrated techniques such as echocardiography, micro-CT and computational fluid dynamics (CFD) for these analyses. Specifically, LAL procedure causes an immediate flow disturbance over atrioventricular (AV) cushions. At later stages after the heart septation, it causes hemodynamic disturbances in LV. As a consequence of the LAL procedure, the left-AV canal and LV volume decrease in size, and in the opposite way, the right-AV canal and right ventricle volume increase. According to our CFD analysis, LAL results in an immediate decrease in the left AV canal WSS levels for 3.5-day (HH21) pre-septated hearts. For 7-day post-septated hearts (HH30), LAL leads to further reduction in WSS levels in the left AV canal, and relatively increased WSS levels in the right AV canal. This study demonstrates the critical importance of the disturbed hemodynamics during the heart valve and ventricle development.

Abstract 12937: Single-cell Transcriptomic Analysis Reveals Developmentally Impaired Endocardial Population in Hypoplastic Left Heart Syndrome

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yifei Miao ◽  
Lei Tian ◽  
Marcy Martin ◽  
Sharon Paige ◽  
Francisco X Galdos ◽  
...  
Keyword(s):  
Single Cell ◽  
Hypoplastic Left Heart Syndrome ◽  
Heart Development ◽  
Heart Diseases ◽  
Critical Role ◽  
Abnormal Development ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Mesenchymal Transition ◽  
Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is one of the most challenging forms of congenital heart diseases. Previous studies were mainly focused on intrinsic defects in myocardium. However, this does not sufficiently explain the abnormal development of the cardiac valve, septum, and vasculature, known to originate from the endocardium. Here, using single-cell transcriptomic profiling, induced pluripotent stem cells (iPSC) derived endocardial cells (iEECs), human fetal heart tissue with underdeveloped left ventricle, as well as a Xenopus model, we identified a developmentally impaired endocardial population in HLHS. The intrinsic endocardial deficits contributed to abnormal endothelial to mesenchymal transition, NOTCH signaling, and extracellular matrix organization, all of which are key factors in valve formation. Consequently, in an endocardium-myocardium co-culture system, we found that endocardial abnormalities conferred reduced proliferation and maturation of iPSC derived cardiomyocyte (iPSC-CMs) judged by Ki67 staining, contractility, sarcomere organization, and related gene expressions through a disrupted fibronectin (FN1)-integrin interaction. Several recently described HLHS de novo mutations such as ETS1 and CHD7 showed reduced binding to FN1 promoter and enhancer in HLHS vs. control iEECs based on ChIP-qPCR analysis. Additionally, we found that suppression of the ETS1 in Xenopus caused reduced endocardial FN1 expression and impaired heart development. Supplementation of FN1 or ETS1 over-expression in HLHS iEECs could rescue dysfunctions in both endocardium and myocardium in HLHS. Our studies reveal a critical role of endocardial abnormality in causing HLHS, and provide a rationale for improving endocardial function in future regenerative strategies. Schematic illustration of the endocardial and myocardial defects in HLHS.

Hypoplastic Left Heart Syndrome: Natural History in a Geographically Defined Population

PEDIATRICS ◽  
1990 ◽  
Vol 85 (6) ◽  
pp. 977-983
Author(s):  
Cynthia D. Morris ◽  
Jacquelyn Outcalt ◽  
Victor D. Menashe
Keyword(s):  
Natural History ◽  
Hypoplastic Left Heart Syndrome ◽  
Congenital Heart ◽  
Heart Defects ◽  
Norwood Procedure ◽  
Secular Change ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
History Of ◽  
Left Heart Syndrome

Advances in surgical treatment of hypoplastic left heart syndrome with the Norwood procedure and cardiac transplantation have made essential the understanding of the natural history of hypoplastic left heart syndrome. In a geographically defined population, we ascertained the prevalence of hypoplastic left heart syndrome in children born in Oregon from 1971 through 1986. Clinical and anatomic data were extracted from the charts of the 98 affected children and the survival rate was calculated. Hypoplastic left heart syndrome occurred in 0.162 per 1000 live births in Oregon during this period. No syndrome complex was prevalent and 84% were free of other congenital malformations. However, there was an increased occurrence of congenital heart defects in first-degree relatives of probands with hypoplastic left heart syndrome. Of the affected children 15 ± 4% died on the first day of life, 70 ± 5% died within the first week, and 91 ± 3% died within 30 days. No secular change in survival occurred during the study. Palliation with the Norwood procedure was performed in 20 children. Although survival was significantly improved with this surgery (P = .01), the effect was observed principally through 30 days of life and only one of these children remains alive. Hypoplastic left heart syndrome is a lethal congenital heart defect in children and poses management and ethical dilemmas.

The genetics of hypoplastic left heart syndrome

1999 ◽  
Vol 9 (6) ◽  
pp. 627-632 ◽  
Author(s):  
Paul D. Grossfeld
Keyword(s):  
Hypoplastic Left Heart Syndrome ◽  
Heart Defects ◽  
Left Ventricular ◽  
Left Ventricular Cavity ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Term Survival ◽  
Surgical Options ◽  
Systemic Ventricle ◽  
Left Heart Syndrome

Hypoplastic left heart syndrome is one of the most therapeutically challenging congenital cardiac defects. It accounts for as many as 1.5% of all congenital heart defects, but is responsible for up to one quarter of deaths in neonates with heart disease.1The management of hypoplastic left heart syndrome is controversial. Two surgical options exist:2,3the Norwood procedure, is a three stage repair in which the morphologically right ventricle is converted to function as the systemic ventricle. Alternatively, orthotopic transplantation can be performed. Although both surgical options have had improved outcomes, the prognosis for long-term survival is guarded, with a five year survival for either approach reported to be in the region of 50–60%. In this review, I explore the evidence for a genetic etiology for the “classic” hypoplastic left heart syndrome, defined as mitral and/or aortic atresia with hypoplasia of the left ventricular cavity and the other left-sided structures.

Health-related quality of life for children and adolescents in school age with hypoplastic left heart syndrome: a single-centre study

2020 ◽  
Vol 30 (4) ◽  
pp. 539-548
Author(s):  
Raphael D. Oberhuber ◽  
Sonja Huemer ◽  
Rudolf Mair ◽  
Eva Sames-Dolzer ◽  
Michaela Kreuzer ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Hypoplastic Left Heart Syndrome ◽  
Heart Diseases ◽  
Left Heart ◽  
Health Related Quality ◽  
Hypoplastic Left Heart ◽  
Related Quality ◽  
Health Related ◽  
Left Heart Syndrome

AbstractData from neurological and radiological research show an abnormal neurological development in patients treated for hypoplastic left heart syndrome. Thus, the aim of this study was to survey the quality of life scores in comparison with healthy children and children with other heart diseases (mild, moderate, and severe heart defects, heart defects in total). Children with hypoplastic left heart syndrome (aged 6.3–16.9 years) under compulsory education requirements, who were treated at the Children’s Heart Center Linz between 1997 and 2009 (n = 74), were surveyed. Totally, 41 children and 44 parents were examined prospectively by psychologists according to Pediatric Quality of Life Inventory, a health-related quality of life measurement. The results of the self-assessments of health-related quality of life on a scale of 1–100 showed a wide range, from a minimum of 5.00 (social functioning) to a maximum of 100 (physical health-related summary scores, emotional functioning, school functioning), with a total score of 98.44. The parents’ assessments (proxy) were quite similar, showing a range from 10 (social functioning) up to 100. Adolescent hypoplastic left heart syndrome patients rated themselves on the same level as healthy youths and youths with different heart diseases. The results show that patients with hypoplastic left heart syndrome aged 6–16 years can be successfully supported and assisted in their psychosocial development even if they show low varying physical and psychosocial parameters. The finding that adolescent hypoplastic left heart syndrome patients estimated themselves similar to healthy individuals suggests that they learnt to cope with a severe heart defect.

scholarly journals Umbilical Neutrophil Gelatinase-Associated Lipocalin Level as an Early Predictor of Acute Kidney Injury in Neonates with Hypoplastic Left Heart Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Piotr Surmiak ◽  
Małgorzata Baumert ◽  
Małgorzata Fiala ◽  
Zofia Walencka ◽  
Andrzej Więcek
Keyword(s):  
Acute Kidney Injury ◽  
Hypoplastic Left Heart Syndrome ◽  
Heart Defects ◽  
Kidney Injury ◽  
High Sensitivity ◽  
Left Heart ◽  
Acid Base Balance ◽  
Hypoplastic Left Heart ◽  
Umbilical Blood ◽  
Left Heart Syndrome

Acute kidney injury (AKI) is a primarily described complication after unbalanced systemic perfusion in neonates with congenital heart defects, including hypoplastic left heart syndrome (HLHS). The aim of the study was to compare the umbilical NGAL concentrations between neonates born with HLHS and healthy infants, as well as to analyze whether the determination of NGAL level could predict AKI in neonates with prenatally diagnosed HLHS. Twenty-one neonates with prenatally diagnosed HLHS were enrolled as study group and 30 healthy neonates served as controls. Perinatal characteristics and postnatal parameters were extracted from the hospital neonatal database. In umbilical cord blood, we determined plasma NGAL concentrations, acid base balance, and lactate and creatinine levels. In neonates with HLHS, complications (respiratory insufficiency, circulatory failure, NEC, IVH, and AKI) were recorded until the day of cardiosurgery. We observed in neonates with HLHS higher umbilical NGAL levels compared to controls. Among 8 neonates with HLHS and diagnosed AKI stage 1, we observed elevated NGAL levels in comparison to those newborns without AKI. Umbilical NGAL could predict, with high sensitivity and specificity, AKI development in study neonates. We suggest that the umbilical blood NGAL concentration may be an early marker to predict AKI in neonates with HLHS.

scholarly journals Single-Cell RNA-Seq Reveals Endocardial Defect in Hypoplastic Left Heart Syndrome

2019 ◽  
Author(s):  
Yifei Miao ◽  
Lei Tian ◽  
Marcy Martin ◽  
Sharon L. Paige ◽  
Francisco X. Galdos ◽  
...  
Keyword(s):  
Single Cell ◽  
Hypoplastic Left Heart Syndrome ◽  
De Novo ◽  
Heart Diseases ◽  
Heart Tissue ◽  
Abnormal Development ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Mesenchymal Transition ◽  
Left Heart Syndrome

SummaryHypoplastic left heart syndrome (HLHS) is one of the most challenging forms of congenital heart diseases. Previous studies were mainly focused on intrinsic defects in myocardium. However, this does not sufficiently explain the abnormal development of the cardiac valve, septum, and vasculature, known to originate from the endocardium. Here, using single-cell RNA profiling, induced pluripotent stem cells, and human fetal heart tissue with an underdeveloped left ventricle, we identified a developmentally impaired endocardial population in HLHS. The intrinsic endocardial deficits contributed to abnormal endothelial to mesenchymal transition, NOTCH signaling, and extracellular matrix organization, all of which are key factors in valve formation. Consequently, endocardial abnormalities conferred reduced proliferation and maturation of cardiomyocytes through a disrupted fibronectin-integrin interaction. Several recently described HLHS de novo mutations were associated with abnormal endocardial gene and FN1 regulation and expression. Our studies provide a rationale for considering endocardial function in future regenerative strategies for HLHS.

scholarly journals Early outcomes and computational fluid dynamic analyses of chimney reconstruction in the Norwood procedure

2019 ◽  
Vol 29 (2) ◽  
pp. 252-259 ◽  
Author(s):  
Satoshi Asada ◽  
Masaaki Yamagishi ◽  
Keiichi Itatani ◽  
Yoshinobu Maeda ◽  
Satoshi Taniguchi ◽  
...  
Keyword(s):  
Aortic Arch ◽  
Hypoplastic Left Heart Syndrome ◽  
Fluid Dynamic ◽  
Norwood Procedure ◽  
Patient Specific ◽  
Shear Stresses ◽  
Left Heart ◽  
Hypoplastic Left Heart ◽  
Flow Profiles ◽  
Left Heart Syndrome

Abstract OBJECTIVES The ideal configuration of a reconstructed aortic arch in the Norwood procedure for hypoplastic left heart syndrome is still a matter of debate. Chimney reconstruction was developed to avoid postoperative complications and turbulent flow in the aortic arch. This study sought to clarify early outcomes of the procedure and verify its haemodynamic advantages using computational fluid dynamics (CFD). METHODS Fourteen consecutive patients with hypoplastic left heart syndrome or a variant who underwent chimney reconstruction in the Norwood procedure between January 2013 and March 2018 were enrolled. Median age and body weight at the time of operation were 2.5 months and 4.1 kg, respectively. Thirteen patients (93.9%) had been palliated with previous bilateral pulmonary artery (PA) banding. In addition, patient-specific CFD models of neoarches based on postoperative computed tomograms from 6 patients were created and the flow profiles analysed. RESULTS Survival rates at 1, 3 and 5 years were 76.6%, 67.3% and 67.3%, respectively. No patient developed left PA compression by neoaorta, neoaortic dilation or neoaortic insufficiency. Only 2 patients (14.3%) required surgical intervention for recoarctation. Fontan completion was performed on 5 patients. On CFD analysis, all reconstructed aortic arches showed low energy loss (9.16–14.4 mW/m2) and low wall shear stresses. CONCLUSIONS Chimney reconstruction was a feasible technique when homografts were not readily available. CFD analyses underscored the fact that this technique produced excellent flow profiles. Larger studies should be conducted to clarify long-term outcomes.

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