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J Cardiovasc Dev Dis
2022 Jul 08;97:. doi: 10.3390/jcdd9070219.
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ETS1 and HLHS: Implications for the Role of the Endocardium.
Grossfeld P
.
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We have identified the ETS1 gene as the cause of congenital heart defects, including an unprecedented high frequency of HLHS, in the chromosomal disorder Jacobsen syndrome. Studies in Ciona intestinalis demonstrated a critical role for ETS1 in heart cell fate determination and cell migration, suggesting that the impairment of one or both processes can underlie the pathogenesis of HLHS. Our studies determined that ETS1 is expressed in the cardiac neural crest and endocardium in the developing murine heart, implicating one or both lineages in the development of HLHS. Studies in Drosophila and Xenopus demonstrated a critical role for ETS1 in regulating cardiac cell fate determination, and results in Xenopus provided further evidence for the role of the endocardium in the evolution of the "hypoplastic" HLHS LV. Paradoxically, these studies suggest that the loss of ETS1 may cause a cell fate switch resulting in the loss of endocardial cells and a relative abundance of cardiac myocytes. These studies implicate an "HLHS transcriptional network" of genes conserved across species that are essential for early heart development. Finally, the evidence suggests that in a subset of HLHS patients, the HLHS LV cardiac myocytes are, intrinsically, developmentally and functionally normal, which has important implications for potential future therapies.
Figure 1. The images, all photographed by Diane E. Spicer and reproduced with her permission, show the phenotypic variants of hypoplastic left heart syndrome as seen in the clinical setting. The upper left panel (A) shows the variant with mitral stenosis and aortic atresia. The heart in the upper right-hand panel (B) has mitral and aortic stenosis. In the lower panels, to the left (C) is seen the variant with mitral atresia, and to the right (D) is the rarest variant with left ventricular hypoplasia with the small aortic and mitral valves, their size in keeping with that of the left ventricle, although the aortic valve is not seen in the four-chamber section through the heart [1].
Figure 2. Gross specimen of an explanted heart from a patient with HLHS, with mitral stenosis and aortic stenosis (A), showing a diminutive LV chamber with endocardial fibroelastosis and a thickened LV wall, and trichrome staining from the LV free wall (B), and a luminal biopsy demonstrating severe EFE (C). Images graciously provided by Dr. Denise Malicki, Department of Pathology, Rady Children’s Hospital of San Diego.
Figure 3. Ciona heart specification network. Schematic diagram depicting the transcriptional core network of genes involved in heart development in Ciona intestinalis. Mutations in at least three of these genes (ETS1, NKX2-5, and FoxF1) have been identified in patients in association with HLHS. (Kindly provided by Dr. Brad Davidson.)
Figure 4. Pointed embryos exhibit a significant increase in Svp-positive cardioblasts. Dorsal views of stage 16 wild-type (A,B) and pnt (C,D) embryos labeled for Svp-lacZ (A,C), and Svp-lacZ and Mef-2 (B,D). (A,B) In wild-type embryos, 12 Svp-negative cardioblasts arise anterior to the first Svp-positive cardioblast (broken white line); seven of these cardioblasts are visible in A and B. Posterior to this location, there is a reiterative pattern of two Svp-lacZ positive cardioblasts (yellow/orange) and four Svp-lacZ negative cardioblasts (green) per hemisegment. (C,D) In pnt embryos, cardioblast development anterior to the first Svp-positive cardioblast (broken white line) appears normal. However, many ectopic cardioblasts are found posterior to this location and the majority of these cells express Svp-lacZ at high (arrow) or moderate levels (arrowhead). The broken white line separates the anterior heart domain from the posterior seven heart segments; anterior is towards the left [5].
Figure 5. Schematic diagram model for one potential mechanism for the aortic atresia/mitral stenosis anatomic subtype of HLHS, indicating “concentric hyperplasia”, i.e., inward growth of cardiac myocytes leading to a thickened ventricular wall and diminutive chamber volume.
Figure 6. Cardiac mesoderm activation pathways in Drosophila heart development (adapted from Bryantsev and Cripps, 2009, Biochim Biophys Acta. 2009 April; 1789(4): 343–353) [19].
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