The Left Ventricular Myocardium in Hypoplastic Left Heart Syndrome

Abstract

Hypoplastic left heart syndrome (HLHS) is a collective term applied to severe congenital cardiac malformations, characterised by a combination of abnormalities mainly affecting the left ventricle, associated valves, and ascending aorta. Although in clinical practice HLHS is usually sub-categorised based on the patency of the mitral and aortic (left-sided) valves, it is also possible to comprehensively categorise HLHS into defined sub-groups based on the left ventricular morphology. Here, we discuss the published human-based studies of the ventricular myocardium in HLHS, evaluating whether the available evidence is in keeping with this ventricular morphology concept. Specifically, we highlight results from histological studies, indicating that the appearance of cardiomyocytes can be different based on the sub-group of HLHS. In addition, we discuss the histological appearances of endocardial fibroelastosis (EFE), which is a common feature of one specific sub-group of HLHS. Lastly, we suggest investigations that should ideally be undertaken using HLHS myocardial tissues at early stages of HLHS development to identify biological pathways and aid the understanding of HLHS aetiology.

Hypoplastic Left Heart Syndrome: Signaling & Molecular Perspectives, and the Road Ahead

“…Investigating the molecular mechanisms governing the endocardial defects in HLHS, single-cell RNA (scRNA) sequencing studies with iPSC-derived endocardial cells (iECs) of HLHS hearts illustrate that anomalous ECM deposition and Endo-MT in endocardial as well as endothelial cells lead to a decrease in proliferation and maturation of cardiomyocytes, thus characterizing early stage HLHS (Figure 3) [7,49]. Reduction in blood flow, tissue hypoxia, and other environmental factors in the later stages ensure that EFE occurs because of the involvement of both epicardium and endocardium-derived fibroblasts [48,50,51]. De novo mutations of genes (TFE3, ED-NRA, ZNF292, FOXM1, ZMYND19, PCBP3, TCF12, ARID1B, NOVA1, PKD1, RBFOX2, ST5, TSC1, USP8, HERC4, KMT2D, ETS1, CHD7, CTR9, GLA, FMNL1, PHRF1, SIPA1L1, and HIRA) predominantly manifest in the endocardium, coronary, and lymphatic ECs, providing a consolidated basis for targeting the endocardium in HLHS pathogenesis [8].…”