Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P -5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P -2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P -3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P -2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications.

BackgroundHypoplastic left heart syndrome (HLHS) covers a spectrum of rare congenital anomalies characterised by a non-apex forming left ventricle and stenosis/atresia of the mitral and aortic valves. Despite many studies, the causes of HLHS remain unclear and there are conflicting views regarding the role of flow, valvar or myocardial abnormalities in its pathogenesis, all of which were proposed prior to the description of the second heart field. Our aim was to re-evaluate the patterns of malformation in HLHS in relation to recognised cardiac progenitor populations, with a view to providing aetiologically useful sub-groupings for genomic studies.ResultsWe examined 78 hearts previously classified as HLHS, with subtypes based on valve patency, and re-categorised them based on their objective ventricular phenotype. Three distinct subgroups could be identified: slit-like left ventricle (24%); miniaturised left ventricle (6%); and thickened left ventricle with endocardial fibroelastosis (EFE; 70%). Slit-like ventricles were always found in combination with aortic atresia and mitral atresia. Miniaturised left ventricles all had normally formed, though smaller aortic and mitral valves. The remaining group were found to have a range of aortic valve malformations associated with thickened left ventricular walls despite being described as either atresia or stenosis. The degree of myocardial thickening was not correlated to the degree of valvar stenosis. Lineage tracing in mice to investigate the progenitor populations that form the parts of the heart disrupted by HLHS showed that whereas Nkx2-5-Cre labelled myocardial and endothelial cells within the left and right ventricles, Mef2c-AHF-Cre, which labels second heart field-derived cells only, was largely restricted to the endocardium and myocardium of the right ventricle. However, like Nkx2-5-Cre, Mef2c-AHF-Cre lineage cells made a significant contribution to the aortic and mitral valves. In contrast, Wnt1-Cre made a major contribution only to the aortic valve. This suggests that discrete cardiac progenitors might be responsible for the patterns of defects observed in the distinct ventricular sub-groups.ConclusionsOnly the slit-like ventricle grouping was found to map to the current nomenclature: the combination of mitral atresia with aortic atresia. It appears that slit-like and miniature ventricles also form discrete sub-groups. Thus, reclassification of HLHS into subgroups based on ventricular phenotype, might be useful in genetic and developmental studies in investigating the aetiology of this severe malformation syndrome.

The Norwood surgical procedure restores functional systemic circulation in neonatal patients with single ventricle congenital heart defects, but this complex procedure carries a high mortality rate. In this study we address the need to provide an accurate patient specific risk prediction for one-year postoperative mortality or cardiac transplantation and prolonged length of hospital stay with the purpose of assisting clinicians and patients' families in the preoperative decision making process. Currently available risk prediction models either do not provide patient specific risk factors or only predict in-hospital mortality rates. We apply machine learning models to predict and calculate individual patient risk for mortality and prolonged length of stay using the Pediatric Heart Network Single Ventricle Reconstruction trial dataset. We applied a Markov Chain Monte-Carlo simulation method to impute missing data and then fed the selected variables to multiple machine learning models. The individual risk of mortality or cardiac transplantation calculation produced by our deep neural network model demonstrated 89 ± 4% accuracy and 0.95 ± 0.02 area under the receiver operating characteristic curve (AUROC). The C-statistics results for prediction of prolonged length of stay were 85 ± 3% accuracy and AUROC 0.94 ± 0.04. These predictive models and calculator may help to inform clinical and organizational decision making.

ObjectiveFetuses with hypoplastic left heart syndrome (HLHS) and restrictive/intact atrial septum (RAS) have high mortality, partly due to pulmonary lymphangiectasia (PL). This study aimed to characterize atrial septal morphology in fetuses with HLHS and RAS and evaluate the impact of fetal intervention on PL and outcomes.MethodWe retrospectively reviewed clinical data, fetal echocardiograms, and MRIs from all fetuses with HLHS/HLHS-variants and RAS over 20 years. RAS was defined as pulmonary venous forward-to-reverse VTI ratio ≤ 5:1.ResultsWe identified 54 fetuses (gestational age of 24.2 weeks; 21.2-28.1) with HLHS (81%) or HLHS variant (19%) and RAS. Most had a hypoplastic left atrium (LA, 80%). Four atrial septal morphology patterns were identified. PL was present among all patterns and associated with lower VTI ratio (p = 0.046). Mean VTI ratio improved in fetuses who underwent atrial septal intervention (n = 12), compared to those without (p = 0.001). Among five fetuses with pre-intervention PL and serial MRIs, three improved. Seventeen neonates were live-born with intention-to-treat; 6-months mortality was 38% with no difference by morphology pattern, PL, or fetal intervention.ConclusionMost fetuses with HLHS and RAS had hypoplastic LA. VTI ratio correlated with PL on fetal lung MRI, and most improved with fetal atrial septal intervention.