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Molecular Research Progress of Inherited Cardiomyopathies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 7544

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Prof. Dr. Michael T. Chin

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Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02145, USA
Interests: inherited cardiomyopathies; heart failure; cardiac hypertrophy; gene expression; genetics; molecular biology; single cell transcriptomics; spatial transcriptomics; proteomics; metabolomics
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Dear Colleagues,

The heart is one of the earliest-forming organs during development, and many genes contribute to its morphogenesis and function. Consequently, the diversity of genetic disorders that manifest with cardiomyopathic dysfunction is extensive. Functionally, defects in transcription, signaling, mitochondrial function, metabolism, cellular architecture, autophagy, chaperone function and other molecular and cellular processes have been implicated. Strategies to treat inherited disorders range from gene and enzyme replacement therapy to molecules that attenuate the consequences of primary gene dysfunction. Mechanisms of inherited cardiomyopathy gene dysfunction are sometimes relevant in acquired cardiomyopathies as well. For many inherited cardiomyopathies, however, disease-targeted therapy remains an elusive goal and ongoing unmet need. Understanding the molecular basis of inherited cardiomyopathies will provide wide-ranging insights into the mechanisms of cardiovascular disease and provide opportunities for better therapeutic targeting.

Prof. Dr. Michael T. Chin
Guest Editor

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Keywords

inherited cardiomyopathy
genetic disorder
congenital heart disease
heart failure
sudden cardiac death
cardiac hypertrophy
cardiomyopathy

Published Papers (4 papers)

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Research

12 pages, 2829 KiB

Open AccessArticle

Spatial Transcriptomic Analysis of Focal and Normal Areas of Myocyte Disarray in Human Hypertrophic Cardiomyopathy

by Jason Laird, Gayani Perera, Rebecca Batorsky, Hongjie Wang, Knarik Arkun and Michael T. Chin

Int. J. Mol. Sci. 2023, 24(16), 12625; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612625 - 10 Aug 2023

Cited by 1 | Viewed by 1949

Abstract

Hypertrophic Cardiomyopathy (HCM) is a common inherited disorder that can lead to heart failure and sudden cardiac death, characterized at the histological level by focal areas of myocyte disarray, hypertrophy and fibrosis, and only a few disease-targeted therapies exist. To identify the focal and spatially restricted alterations in the transcriptional pathways and reveal novel therapeutic targets, we performed a spatial transcriptomic analysis of the areas of focal myocyte disarray compared to areas of normal tissue using a commercially available platform (GeoMx, nanoString). We analyzed surgical myectomy tissue from four patients with HCM and the control interventricular septum tissue from two unused organ donor hearts that were free of cardiovascular disease. Histological sections were reviewed by an expert pathologist, and 72 focal areas with varying degrees of myocyte disarray (normal, mild, moderate, severe) were chosen for analysis. Areas of interest were interrogated with the Human Cancer Transcriptome Atlas designed to profile 1800 transcripts. Differential expression analysis revealed significant changes in gene expression between HCM and the control tissue, and functional enrichment analysis indicated that these genes were primarily involved in interferon production and mitochondrial energetics. Within the HCM tissue, differentially expressed genes between areas of normal and severe disarray were enriched for genes related to mitochondrial energetics and the extracellular matrix in severe disarray. An analysis of the gene expression of the ligand–receptor pair revealed that the HCM tissue exhibited downregulation of platelet-derived growth factor (PDGF), NOTCH, junctional adhesion molecule, and CD46 signaling while showing upregulation of fibronectin, CD99, cadherin, and amyloid precursor protein signaling. A deconvolution analysis utilizing the matched single nuclei RNA-sequencing (snRNA-seq) data to determine cell type composition in areas of interest revealed significant differences in fibroblast and vascular cell composition in areas of severe disarray when compared to normal areas in HCM samples. Cell composition in the normal areas of the control tissue was also divergent from the normal areas in HCM samples, which was consistent with the differential expression results. Overall, our data identify novel and potential disease-modifying targets for therapy in HCM. Full article

(This article belongs to the Special Issue Molecular Research Progress of Inherited Cardiomyopathies)

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13 pages, 4466 KiB

Open AccessArticle

Single Cell Transcriptomic Analysis in a Mouse Model of Barth Syndrome Reveals Cell-Specific Alterations in Gene Expression and Intercellular Communication

by Gayani Perera, Liam Power, Amy Larson, Christina J. Codden, Junya Awata, Rebecca Batorsky, Douglas Strathdee and Michael T. Chin

Int. J. Mol. Sci. 2023, 24(14), 11594; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411594 - 18 Jul 2023

Viewed by 1666

Abstract

Barth Syndrome, a rare X-linked disorder affecting 1:300,000 live births, results from defects in Tafazzin, an acyltransferase that remodels cardiolipin and is essential for mitochondrial respiration. Barth Syndrome patients develop cardiomyopathy, muscular hypotonia and cyclic neutropenia during childhood, rarely surviving to middle age. At present, no effective therapy exists, and downstream transcriptional effects of Tafazzin dysfunction are incompletely understood. To identify novel, cell-specific, pathological pathways that mediate heart dysfunction, we performed single-nucleus RNA-sequencing (snRNA-seq) on wild-type (WT) and Tafazzin-knockout (Taz-KO) mouse hearts. We determined differentially expressed genes (DEGs) and inferred predicted cell–cell communication networks from these data. Surprisingly, DEGs were distributed heterogeneously across the cell types, with fibroblasts, cardiomyocytes, endothelial cells, macrophages, adipocytes and pericytes exhibiting the greatest number of DEGs between genotypes. One differentially expressed gene was detected for the lymphatic endothelial and mesothelial cell types, while no significant DEGs were found in the lymphocytes. A Gene Ontology (GO) analysis of these DEGs showed cell-specific effects on biological processes such as fatty acid metabolism in adipocytes and cardiomyocytes, increased translation in cardiomyocytes, endothelial cells and fibroblasts, in addition to other cell-specific processes. Analysis of ligand–receptor pair expression, to infer intercellular communication patterns, revealed the strongest dysregulated communication involved adipocytes and cardiomyocytes. For the knockout hearts, there was a strong loss of ligand–receptor pair expression involving adipocytes, and cardiomyocyte expression of ligand–receptor pairs underwent reorganization. These findings suggest that adipocyte and cardiomyocyte mitochondria may be most sensitive to mitochondrial Tafazzin deficiency and that rescuing adipocyte mitochondrial dysfunction, in addition to cardiomyocyte mitochondrial dysfunction, may provide therapeutic benefit in Barth Syndrome patients. Full article

(This article belongs to the Special Issue Molecular Research Progress of Inherited Cardiomyopathies)

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17 pages, 4509 KiB

Open AccessArticle

Cardiomyocyte Apoptosis Is Associated with Contractile Dysfunction in Stem Cell Model of MYH7 E848G Hypertrophic Cardiomyopathy

by Alexander M. Loiben, Wei-Ming Chien, Clayton E. Friedman, Leslie S.-L. Chao, Gerhard Weber, Alex Goldstein, Nathan J. Sniadecki, Charles E. Murry and Kai-Chun Yang

Int. J. Mol. Sci. 2023, 24(5), 4909; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054909 - 03 Mar 2023

Cited by 1 | Viewed by 1880

Abstract

Missense mutations in myosin heavy chain 7 (MYH7) are a common cause of hypertrophic cardiomyopathy (HCM), but the molecular mechanisms underlying MYH7-based HCM remain unclear. In this work, we generated cardiomyocytes derived from isogenic human induced pluripotent stem cells to model the heterozygous pathogenic MYH7 missense variant, E848G, which is associated with left ventricular hypertrophy and adult-onset systolic dysfunction. MYH7^E848G/+ increased cardiomyocyte size and reduced the maximum twitch forces of engineered heart tissue, consistent with the systolic dysfunction in MYH7^E848G/+ HCM patients. Interestingly, MYH7^E848G/+ cardiomyocytes more frequently underwent apoptosis that was associated with increased p53 activity relative to controls. However, genetic ablation of TP53 did not rescue cardiomyocyte survival or restore engineered heart tissue twitch force, indicating MYH7^E848G/+ cardiomyocyte apoptosis and contractile dysfunction are p53-independent. Overall, our findings suggest that cardiomyocyte apoptosis is associated with the MYH7^E848G/+ HCM phenotype in vitro and that future efforts to target p53-independent cell death pathways may be beneficial for the treatment of HCM patients with systolic dysfunction. Full article

(This article belongs to the Special Issue Molecular Research Progress of Inherited Cardiomyopathies)

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19 pages, 8875 KiB

Open AccessArticle

Alterations in Calcium Handling Are a Common Feature in an Arrhythmogenic Cardiomyopathy Cell Model Triggered by Desmosome Genes Loss

by Marta Vallverdú-Prats, David Carreras, Guillermo J. Pérez, Oscar Campuzano, Ramon Brugada and Mireia Alcalde

Int. J. Mol. Sci. 2023, 24(3), 2109; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032109 - 20 Jan 2023

Cited by 2 | Viewed by 1576

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium. Deleterious variants in desmosomal genes are the main cause of ACM and lead to common and gene-specific molecular alterations, which are not yet fully understood. This article presents the first systematic in vitro study describing gene and protein expression alterations in desmosomes, electrical conduction-related genes, and genes involved in fibrosis and adipogenesis. Moreover, molecular and functional alterations in calcium handling were also characterized. This study was performed d with HL1 cells with homozygous knockouts of three of the most frequently mutated desmosomal genes in ACM: PKP2, DSG2, and DSC2 (generated by CRISPR/Cas9). Moreover, knockout and N-truncated clones of DSP were also included. Our results showed functional alterations in calcium handling, a slower calcium re-uptake was observed in the absence of PKP2, DSG2, and DSC2, and the DSP knockout clone showed a more rapid re-uptake. We propose that the described functional alterations of the calcium handling genes may be explained by mRNA expression levels of ANK2, CASQ2, ATP2A2, RYR2, and PLN. In conclusion, the loss of desmosomal genes provokes alterations in calcium handling, potentially contributing to the development of arrhythmogenic events in ACM. Full article

(This article belongs to the Special Issue Molecular Research Progress of Inherited Cardiomyopathies)

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