Left ventricular non-compaction

Ramakumar, Venkatakrishnan; Sharma, Vibhav; Mishra, Sundeep

doi:10.1093/eurheartj/ehab099

Cited by 2 publications

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“…35,36 In addition, LVNC is associated with hypertrabeculation of the myocardium of the left ventricle (LV), and occasionally the right ventricle (RV). [1][2][3][4][5] Therefore, to assess the compact and trabecular layers of CHD4 M195I/M195I embryos, we conducted immunofluorescence with Endomucin (red) and TMY (tropomyosin; green) antibodies to delineate chamber endocardium and myocardium, respectively (Figure 1I; Figure S9). In WT and CHD4 M195I/+ hearts, the trabeculae were folded and oriented parallel to the free wall of the RV (white arrows, Figure 1I 2 and 1I 5 ).…”

Section: Chd4 M195i/m195i and Ventricular Noncompactionmentioning

confidence: 99%

“…Left ventricular noncompaction mainly affects the LV, but isolated right ventricular or biventricular noncompaction has also been reported. 1–5 Left ventricular noncompaction can be asymptomatic, but patients with LVNC are at high risk of developing heart failure and sudden death. 6 Genetic screening of individual patients with LVNC has identified mutations in genes encoding transcription factors, sarcomere, nuclear membrane, RNA-binding proteins, and ion channel proteins 7–10 ; however, a significant portion of LVNC cases are of unknown etiology.…”

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Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1

Shi

Scialdone

Emerson

et al. 2023

Circulation Research

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Background: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. Methods: We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4 M202I , with congenital heart defects. We engineered a humanized mouse model of CHD4 M202I (mouse CHD4 M195I ). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4 M195I -mediated ventricular wall defects. Results: CHD4 M195I/M195I mice developed biventricular hypertrabeculation and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4 M195I hearts, and the excessive trabeculation was associated with accumulation of ECM (extracellular matrix) proteins and a reduction of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1), an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4 M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4 M195I protein showed augmented affinity to endocardial BRG1 (SWI/SNF–related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4). This enhanced affinity resulted in the failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. Conclusions: Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4 M195I can be attenuated by the administration of ADAMTS1.

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Section: Chd4 M195i/m195i and Ventricular Noncompactionmentioning

confidence: 99%

mentioning

confidence: 99%

Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1

Shi

Scialdone

Emerson

et al. 2023

Circulation Research

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A Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1-mediated Trabeculation Cessation

Shi

Scialdone

Emerson

et al. 2022

Preprint

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BACKGROUND: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. METHODS: We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo chromodomain helicase DNA-binding protein 4 (CHD4) proband, CHD4M202I, with congenital heart defects. We engineered a patient-specific model of CHD4M202I (mouse CHD4M195I). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4M195I-mediated ventricular wall defects. RESULTS: CHD4M195I/M195I mice developed biventricular hypertrabeculaion and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4M195I hearts, and the excessive trabeculation was associated with accumulation of extracellular matrix (ECM) proteins and a reduction of ADAMTS1, an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4M195I protein showed augmented affinity to endocardial BRG1. This enhanced affinity resulted in failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. CONCLUSIONS: Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4M195I can be attenuated by the administration of ADAMTS1.

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Left ventricular non-compaction

Cited by 2 publications

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Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1

Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1

A Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1-mediated Trabeculation Cessation

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