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Model Systems and Candidate Genes for Inherited Cardiomyopathies

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 6667

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Special Issue Editors

Dr. Natascia Tiso

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Guest Editor

Developmental Genetics Laboratory, Department of Biology, University of Padova, via Ugo Bassi 58/B, I-35131 Padova, Italy
Interests: zebrafish; heart disease; mitochondrial disease; endocrine disease; melanoma; neural development; pancreatic development and cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Maria Bueno Marinas

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Co-Guest Editor

Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Cardiovascular Pathology, Cardiology and Biostatistics Units, 35121 Padua, Italy
Interests: cardiovascular genetics; microRNAs; cell culture; gene expression; biomarkers

Dr. Rudy Celeghin

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Co-Guest Editor

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Via A. Gabelli 61, I-35131 Padova, Italy
Interests: cardiovascular genetics; DNA sequencing; protein modelling; bioinformatics; gene editing

Dr. Marco Cason

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Co-Guest Editor

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Via A. Gabelli 61, I-35131 Padova, Italy
Interests: genetics; cardiomyopathies; heart disease; RNA expression analysis; immunohistochemistry

Special Issue Information

Dear Colleagues,

Inherited cardiomyopathies are a group of heart diseases considered to be a major cause of morbidity and mortality. Over the past two decades, the genetic basis of these disorders has become increasingly clear. Currently, several genes are associated with cardiomyopathies, such as arrhythmogenic cardiomyopathy (AC), hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), Brugada syndrome (BrS), long QT syndrome (LQT), etc. Nevertheless, the incomplete inheritance of these diseases among families and missing genetic links in almost half of cases suggest that other genes as well as genetic modifiers could be involved. Furthermore, the specific pathological mechanisms of these disorders are still under investigation, supporting the importance of animal models, such as mouse and zebrafish, to elucidate pathological signalling pathways. In this way, this Special Issue aims to highlight new candidate genes associated with inherited cardiomyopathies and the use of animal models to discover new pathological mechanisms responsible for these diseases.

Dr. Natascia Tiso
Dr. Maria Bueno Marinas
Dr. Rudy Celeghin
Dr. Marco Cason
Guest Editors

Manuscript Submission Information

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Keywords

cardiovascular genetics
cardiomyopathy
animal model
RNA expression
microRNA

Published Papers (4 papers)

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Research

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20 pages, 5814 KiB

Open AccessArticle

Human ApoE2 Endows Stronger Contractility in Rat Cardiomyocytes Enhancing Heart Function

by Yang Wu, Fujie Zhao, Venkata N. Sure, Abdulgafar Ibrahim, Changjiang Yu, Sean M. Carr and Ping Song

Cells 2023, 12(3), 347; https://doi.org/10.3390/cells12030347 - 17 Jan 2023

Viewed by 1545

Abstract

(1) Background: Apolipoprotein E (ApoE) is a critical plasma apolipoprotein for lipid transport and nonlipid-related functions. Humans possess three isoforms of ApoE (2, 3, and 4). ApoE2, which exhibits beneficial effects on cardiac health, has not been adequately studied. (2) Methods: We investigated the cardiac phenotypes of the humanized ApoE knock-in (hApoE KI) rats and compared to wild-type (WT) and ApoE knock-out (ApoE KO) rats using echocardiography, ultrasound, blood pressure measurements, histology strategies, cell culture, Seahorse XF, cardiomyocyte contractility and intracellular Ca²⁺ tests, and Western blotting; (3) Results: hApoE2 rats exhibited enhanced heart contractile function without signs of detrimental remodeling. Isolated adult hApoE2 cardiomyocytes had faster and stronger sarcomere contractility because of more mitochondrial energy generation and stimulation-induced fast and elevated intracellular Ca²⁺ transient. The abundant energy is a result of elevated mitochondrial function via fatty acid β-oxidation. The fast and elevated Ca²⁺ transient is associated with decreased sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA2) and increased expression of cardiac ryanodine receptor 2 (RyR2) conducting a potent Ca²⁺ release from SR.; (4) Conclusions: Our studies validated the association of polymorphic ApoEs with cardiac health in the rat model, and revealed the possible mechanisms of the protective effect of ApoE2 against heart diseases. Full article

(This article belongs to the Special Issue Model Systems and Candidate Genes for Inherited Cardiomyopathies)

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18 pages, 5235 KiB

Open AccessArticle

Humanized Dsp ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes

by Tyler L. Stevens, Heather R. Manring, Michael J. Wallace, Aaron Argall, Trevor Dew, Peter Papaioannou, Steve Antwi-Boasiako, Xianyao Xu, Stuart G. Campbell, Fadi G. Akar, Maegen A. Borzok, Thomas J. Hund, Peter J. Mohler, Sara N. Koenig and Mona El Refaey

Cells 2022, 11(19), 3049; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11193049 - 29 Sep 2022

Cited by 7 | Viewed by 1937

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibro-fatty infiltration with an increased propensity for ventricular arrhythmias and sudden death. Genetic variants in desmosomal genes are associated with ACM. Incomplete penetrance is a common feature in ACM families, complicating the understanding of how external stressors contribute towards disease development. To analyze the dual role of genetics and external stressors on ACM progression, we developed one of the first mouse models of ACM that recapitulates a human variant by introducing the murine equivalent of the human R451G variant into endogenous desmoplakin (Dsp^R451G/+). Mice homozygous for this variant displayed embryonic lethality. While Dsp^R451G/+ mice were viable with reduced expression of DSP, no presentable arrhythmogenic or structural phenotypes were identified at baseline. However, increased afterload resulted in reduced cardiac performance, increased chamber dilation, and accelerated progression to heart failure. In addition, following catecholaminergic challenge, Dsp^R451G/+ mice displayed frequent and prolonged arrhythmic events. Finally, aberrant localization of connexin-43 was noted in the Dsp^R451G/+ mice at baseline, becoming more apparent following cardiac stress via pressure overload. In summary, cardiovascular stress is a key trigger for unmasking both electrical and structural phenotypes in one of the first humanized ACM mouse models. Full article

(This article belongs to the Special Issue Model Systems and Candidate Genes for Inherited Cardiomyopathies)

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Review

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25 pages, 3585 KiB

Open AccessReview

Advances in the Generation of Constructed Cardiac Tissue Derived from Induced Pluripotent Stem Cells for Disease Modeling and Therapeutic Discovery

by Truman J. Roland and Kunhua Song

Cells 2024, 13(3), 250; https://0-doi-org.brum.beds.ac.uk/10.3390/cells13030250 - 29 Jan 2024

Cited by 1 | Viewed by 1413

Abstract

The human heart lacks significant regenerative capacity; thus, the solution to heart failure (HF) remains organ donation, requiring surgery and immunosuppression. The demand for constructed cardiac tissues (CCTs) to model and treat disease continues to grow. Recent advances in induced pluripotent stem cell (iPSC) manipulation, CRISPR gene editing, and 3D tissue culture have enabled a boom in iPSC-derived CCTs (iPSC-CCTs) with diverse cell types and architecture. Compared with 2D-cultured cells, iPSC-CCTs better recapitulate heart biology, demonstrating the potential to advance organ modeling, drug discovery, and regenerative medicine, though iPSC-CCTs could benefit from better methods to faithfully mimic heart physiology and electrophysiology. Here, we summarize advances in iPSC-CCTs and future developments in the vascularization, immunization, and maturation of iPSC-CCTs for study and therapy. Full article

(This article belongs to the Special Issue Model Systems and Candidate Genes for Inherited Cardiomyopathies)

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14 pages, 4412 KiB

Open AccessReview

Desmosomes in Cell Fate Determination: From Cardiogenesis to Cardiomyopathy

by Hoda Moazzen, Mistura Dolapo Bolaji and Rudolf E. Leube

Cells 2023, 12(17), 2122; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12172122 - 22 Aug 2023

Cited by 1 | Viewed by 1204

Abstract

Desmosomes play a vital role in providing structural integrity to tissues that experience significant mechanical tension, including the heart. Deficiencies in desmosomal proteins lead to the development of arrhythmogenic cardiomyopathy (AC). The limited availability of preventative measures in clinical settings underscores the pressing need to gain a comprehensive understanding of desmosomal proteins not only in cardiomyocytes but also in non-myocyte residents of the heart, as they actively contribute to the progression of cardiomyopathy. This review focuses specifically on the impact of desmosome deficiency on epi- and endocardial cells. We highlight the intricate cross-talk between desmosomal proteins mutations and signaling pathways involved in the regulation of epicardial cell fate transition. We further emphasize that the consequences of desmosome deficiency differ between the embryonic and adult heart leading to enhanced erythropoiesis during heart development and enhanced fibrogenesis in the mature heart. We suggest that triggering epi-/endocardial cells and fibroblasts that are in different “states” involve the same pathways but lead to different pathological outcomes. Understanding the details of the different responses must be considered when developing interventions and therapeutic strategies. Full article

(This article belongs to the Special Issue Model Systems and Candidate Genes for Inherited Cardiomyopathies)

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