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Genetics and Mechanistic Basis of Cardiomyopathies

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (25 July 2023) | Viewed by 23770

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Special Issue Editors

Dr. Wei Guo

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Guest Editor

Department of Animal and Dairy Sciences, University of Wisconsin, Madison, WI 53706, USA
Interests: muscle structure and function; cardiomyopathies; RNA metabolism; protein trafficking
Special Issues, Collections and Topics in MDPI journals

Dr. Zachery R. Gregorich

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Cardiovascular Research Center, Department of Animal and Dairy Sciences, University of Wisconsin, Madison, WI 53706, USA
Interests: mass spectrometry; proteomics; cardiovascular disease; cardiomyopathies

Prof. Dr. Jun Ren

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1. Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
Interests: heart failure; metabolic diseases; genetic mutations

Dr. Rongxue Wu

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Guest Editor

Department of Medicine, Biological Sciences Division/ Cardiology, University of Chicago, Chicago, IL, 60637, USA
Interests: cardiac ischemia reperfusion; cardiac microvascular biology; diabetic cardiomyopathy

Special Issue Information

Dear Colleagues,

Cardiomyopathies, also known as heart muscle diseases, are a major cause of mortality and morbidity worldwide. There are two main subtypes of cardiomyopathy, namely hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), which are caused by pathogenic variants in sarcomeric or non-sarcomeric genes. Mutations in genes encoding sarcomeric proteins damage the structural and/or functional integrity of the sarcomeres and are the most common genetic cause of HCM and DCM. For example, pathogenic variants in MYH7, which encode cardiac β-myosin heavy chain, the primary component of the thick filaments of sarcomeres, impair actin-activated ATPase activity and, thus, decrease sliding velocity along actin filaments. Conversely, pathogenic variants in thin filament genes reduce the calcium sensitivity of myofibrils, leading to reduced tension and faster relaxation for a given amount of intracellular calcium. Advances in technology as well as our understanding of cardiac diseases in recent decades have led to an explosion in newly identified genetic variants linked to cardiomyopathies. Yet, the precise molecular mechanisms leading to myocardial destruction, remodeling, and impaired functional integrity of myocardium for many of these variants and, in particular, for non-sarcomere variants remain to be defined. Moreover, to move beyond simple detection and risk stratification toward treatment, knowledge of the detailed mechanisms by which pathogenic variants in both sarcomere and non-sarcomere proteins cause cardiomyopathies is desperately needed. Therefore, this Special Issue is focused on the genetic basis and molecular underpinnings of cardiomyopathies.

Dr. Wei Guo
Dr. Zachery R. Gregorich
Prof. Dr. Jun Ren
Dr. Rongxue Wu
Guest Editors

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Keywords

cardiomyopathy
sarcomere
genetic mutations
hypertrophic cardiomyopathy (HCM)
dilated cardiomyopathy (DCM)
pathogenesis
cardiac function
myocardial remodeling
cardiac contractility
pathogenic variants

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Published Papers (8 papers)

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16 pages, 4332 KiB

Open AccessArticle

Comparative Analysis of Whole Transcriptome Profiles in Septic Cardiomyopathy: Insights from CLP- and LPS-Induced Mouse Models

by Karim Ullah, Yan Li, Qiaoshan Lin, Kaichao Pan, Tu Nguyen, Solanki Aniruddhsingh, Qiaozhu Su, Willard Sharp and Rongxue Wu

Genes 2023, 14(7), 1366; https://doi.org/10.3390/genes14071366 - 28 Jun 2023

Cited by 3 | Viewed by 2426

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, with septic cardiomyopathy being a common and severe complication. Despite its significant clinical impact, the molecular mechanisms underlying sepsis-induced cardiomyopathy (SICM) remain incompletely understood. In this study, we performed a comparative analysis of whole transcriptome profiles using RNA sequencing in mouse hearts in two widely used mouse models of septic cardiomyopathy. CLP-induced sepsis was achieved by surgical cecal ligation and puncture, while LPS-induced sepsis was induced using a 5 mg/kg intraperitoneal (IP) injection of lipopolysaccharide (LPS). For consistency, we utilized sham-operated mice as the control for septic models. Our aim was to identify key genes and pathways involved in the development of septic cardiomyopathy and to evaluate the similarities and differences between the two models. Our findings demonstrated that both the CLP and lipopolysaccharide LPS methods could induce septic heart dysfunction within 24 h. We identified common transcriptional regulatory regions in the septic hearts of both models, such as Nfkb1, Sp1, and Jun. Moreover, differentially expressed genes (DEGs) in comparison to control were involved in shared pathways, including regulation of inflammatory response, regulation of reactive oxygen species metabolic process, and the JAK-STAT signaling pathway. However, each model presented distinctive whole transcriptome expression profiles and potentially diverse pathways contributing to sepsis-induced heart failure. This extensive comparison enhances our understanding of the molecular basis of septic cardiomyopathy, providing invaluable insights. Accordingly, our study also contributes to the pursuit of effective and personalized treatment strategies for SICM, highlighting the importance of considering the specific causative factors. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

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11 pages, 748 KiB

Open AccessArticle

Genetic Insights from Consanguineous Cardiomyopathy Families

by Constance Maurer, Olga Boleti, Paria Najarzadeh Torbati, Farzaneh Norouzi, Anna Nicole Rebekah Fowler, Shima Minaee, Khalid Hama Salih, Mehdi Taherpour, Hassan Birjandi, Behzad Alizadeh, Aso Faeq Salih, Moniba Bijari, Henry Houlden, Alan Michael Pittman, Reza Maroofian, Yahya H. Almashham, Ehsan Ghayoor Karimiani, Juan Pablo Kaski, Eissa Ali Faqeih, Farveh Vakilian and Yalda Jamshidi Show full author list Hide full author list

Genes 2023, 14(1), 182; https://doi.org/10.3390/genes14010182 - 10 Jan 2023

Cited by 7 | Viewed by 3471

Abstract

Inherited cardiomyopathies are a prevalent cause of heart failure and sudden cardiac death. Both hypertrophic (HCM) and dilated cardiomyopathy (DCM) are genetically heterogeneous and typically present with an autosomal dominant mode of transmission. Whole exome sequencing and autozygosity mapping was carried out in eight un-related probands from consanguineous Middle Eastern families presenting with HCM/DCM followed by bioinformatic and co-segregation analysis to predict the potential pathogenicity of candidate variants. We identified homozygous missense variants in TNNI3K, DSP, and RBCK1 linked with a dilated phenotype, in NRAP linked with a mixed phenotype of dilated/hypertrophic, and in KLHL24 linked with a mixed phenotype of dilated/hypertrophic and non-compaction features. Co-segregation analysis in family members confirmed autosomal recessive inheritance presenting in early childhood/early adulthood. Our findings add to the mutational spectrum of recessive cardiomyopathies, supporting inclusion of KLHL24, NRAP and RBCK1 as disease-causing genes. We also provide evidence for novel (recessive) modes of inheritance of a well-established gene TNNI3K and expand our knowledge of the clinical heterogeneity of cardiomyopathies. A greater understanding of the genetic causes of recessive cardiomyopathies has major implications for diagnosis and screening, particularly in underrepresented populations, such as those of the Middle East. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

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14 pages, 4298 KiB

Open AccessArticle

Oridonin Protects against Myocardial Ischemia–Reperfusion Injury by Inhibiting GSDMD-Mediated Pyroptosis

by Jiahui Lin, Xianhui Lai, Xiaoxi Fan, Bozhi Ye, Lingfeng Zhong, Yucong Zhang, Ruiyin Shao, Si Shi, Weijian Huang, Lan Su and Miaomiao Ying

Genes 2022, 13(11), 2133; https://doi.org/10.3390/genes13112133 - 17 Nov 2022

Cited by 15 | Viewed by 2240

Abstract

Pyroptosis serves a crucial function in various types of ischemia and reperfusion injuries. Oridonin, a tetracycline diterpene derived from Rabdosia rubescens, can significantly inhibit the aggregation of NLRP3-mediated inflammasome. This experiment is aimed at investigating the effect of oridonin on pyroptosis in mice cardiomyocytes. Based on the models of myocardial ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R), Evans Blue/TTC double staining, TUNEL staining, and Western blotting were applied to determine the effects of oridonin on myocardial damage, cellular activity and signaling pathways involved in pyroptosis. During I/R and H/R treatments, the extent of gasdermin D-N domains was upregulated in cardiomyocytes. Apart from that, oridonin improved cell survival in vitro and decreased the myocardial infarct size in vivo by also downregulating the activation of pyroptosis. Finally, the expression levels of ASC, NLRP3 and p-p65 were markedly upregulated in cardiomyocytes after H/R treatment, whereas oridonin suppressed the expression of these proteins. The present experiment revealed that myocardial I/R injury and pyroptosis can be alleviated and inhibited by oridonin pretreatment via NF-κB/NLRP3 signaling pathway, both in vivo and in vitro. Therefore, oridonin may serve as a potentially novel agent for the clinical treatment of myocardial ischemia-reperfusion injuries. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

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15 pages, 2644 KiB

Open AccessArticle

SR Protein Kinases Regulate the Splicing of Cardiomyopathy-Relevant Genes via Phosphorylation of the RSRSP Stretch in RBM20

by Mingming Sun, Yutong Jin, Yanghai Zhang, Zachery R Gregorich, Jun Ren, Ying Ge and Wei Guo

Genes 2022, 13(9), 1526; https://doi.org/10.3390/genes13091526 - 25 Aug 2022

Cited by 4 | Viewed by 2858

Abstract

(1) Background: RNA binding motif 20 (RBM20) regulates mRNA splicing specifically in muscle tissues. Missense mutations in the arginine/serine (RS) domain of RBM20 lead to abnormal gene splicing and have been linked to severe dilated cardiomyopathy (DCM) in human patients and animal models. Interestingly, many of the reported DCM-linked missense mutations in RBM20 are in a highly conserved RSRSP stretch within the RS domain. Recently, it was found that the two Ser residues within this stretch are constitutively phosphorylated, yet the identity of the kinase(s) responsible for phosphorylating these residues, as well as the function of RSRSP phosphorylation, remains unknown. (2) Methods: The ability of three known SR protein kinases (SRPK1, CLK1, and AKT2) to phosphorylate the RBM20 RSRSP stretch and regulate target gene splicing was evaluated by using both in vitro and in vivo approaches. (3) Results: We found that all three kinases phosphorylated S638 and S640 in the RSRSP stretch and regulated RBM20 target gene splicing. While SRPK1 and CLK1 were both capable of directly phosphorylating the RS domain in RBM20, whether AKT2-mediated control of the RS domain phosphorylation is direct or indirect could not be determined. (4) Conclusions: Our results indicate that SR protein kinases regulate the splicing of a cardiomyopathy-relevant gene by modulating phosphorylation of the RSRSP stretch in RBM20. These findings suggest that SR protein kinases may be potential targets for the treatment of RBM20 cardiomyopathy. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

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6 pages, 203 KiB

Open AccessArticle

Predisposition to Myocardial Infarction Influenced by Interleukin 13 Gene Polymorphisms: A Case-Control Study

by Seyyed Fatemeh Hosseini, Khalil Khashei Varnamkhasti, Raziyeh Naeimi, Leila Naeimi and Sirous Naeimi

Genes 2022, 13(8), 1478; https://doi.org/10.3390/genes13081478 - 19 Aug 2022

Cited by 1 | Viewed by 1795

Abstract

Background: Additional inflammatory responses and subsequent damage—arising from enhance transcriptional activity or forming the more active protein due to existence of polymorphic sites in the pro-inflammatory cytokines gene loci—give rise to myocardial infarction susceptibility. Objectives: The aim of our study was to explore whether two interleukin-13 gene polymorphisms (−1512A/C and +2044G/A) could serve as underpins genetic susceptibility of myocardial infarction. Methods: The Iranian population that belong to the Parsis ethnic group was involved in the present study. A total 250 patients with definite myocardial infarction—meeting hypertension, hypercholesterolemia, hyperglycemia, and coronary artery disease requirements—were recruited from the Shiraz urban hospitals. 250 age- and sex-matched healthy individuals without a history of cardiovascular disease and heart disease related risk factors constituted the control group. PCR-restriction fragment length polymorphism technique applied to genotyping at −1512A/C and +2044G/A loci. Hardy–Weinberg equilibrium test was performed (combined cases and controls). The differences of the genotype frequencies in cases and controls were analyzed using a chi-square test. Logistic regression analysis was performed to assess the association between the genotypes and most important risk factors for myocardial infarction. All statistical analyses were performed in SPSS Version 22.0. p-values below 0.05 were hailed as statistically significant. Results: Deviation from Hardy–Weinberg equilibrium was not significant in the −1512A/C locus. Statistically significant difference between our study groups was found in genotype frequency of the −1512A/C. This variant was found in associated with myocardial infarction risk factors. The +2044G/A polymorphism was not in Hardy–Weinberg equilibrium and no significant difference observed in the distribution of +2044G/A genotype frequency among cases and controls. However, further analysis revealed that this genotype associated with an increased susceptibility to myocardial infarction risk factors. Conclusions: The presence of interleukin-13 −1512A/C and +2044G/A gene polymorphisms underpin myocardial infarction predisposition in the ethnic Parsis of the Iranian population. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

16 pages, 3252 KiB

Open AccessArticle

Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis

by Yuanfeng Fu, Di Zhao, Yufei Zhou, Jing Lu, Le Kang, Xueli Jiang, Ran Xu, Zhiwen Ding and Yunzeng Zou

Genes 2022, 13(7), 1276; https://doi.org/10.3390/genes13071276 - 19 Jul 2022

Cited by 1 | Viewed by 4130

Abstract

Volume overload (VO) and pressure overload (PO) are two common pathophysiological conditions associated with cardiac disease. VO, in particular, often occurs in a number of diseases, and no clinically meaningful molecular marker has yet been established. We intend to find the main differential gene expression using bioinformatics analysis. GSE97363 and GSE52796 are the two gene expression array datasets related with VO and PO, respectively. The LIMMA algorithm was used to identify differentially expressed genes (DEGs) of VO and PO. The DEGs were divided into three groups and subjected to functional enrichment analysis, which comprised GO analysis, KEGG analysis, and the protein–protein interaction (PPI) network. To validate the sequencing data, cardiomyocytes from AR and TAC mouse models were used to extract RNA for qRT-PCR. The three genes with random absolute values of LogFC and indicators of heart failure (natriuretic peptide B, NPPB) were detected: carboxylesterase 1D (CES1D), whirlin (WHRN), and WNK lysine deficient protein kinase 2 (WNK2). The DEGs in VO and PO were determined to be 2761 and 1093, respectively, in this study. Following the intersection, 305 genes were obtained, 255 of which expressed the opposing regulation and 50 of which expressed the same regulation. According to the GO and pathway enrichment studies, DEGs with opposing regulation are mostly common in fatty acid degradation, propanoate metabolism, and other signaling pathways. Finally, we used Cytoscape’s three techniques to identify six hub genes by intersecting 255 with the opposite expression and constructing a PPI network. Peroxisome proliferator-activated receptor (PPARα), acyl-CoA dehydrogenase medium chain (ACADM), patatin-like phospholipase domain containing 2 (PNPLA2), isocitrate dehydrogenase 3 (IDH3), heat shock protein family D member 1 (HSPD1), and dihydrolipoamide S-acetyltransferase (DLAT) were identified as six potential genes. Furthermore, we predict that the hub genes PPARα, ACADM, and PNPLA2 regulate VO myocardial changes via fatty acid metabolism and acyl-Coa dehydrogenase activity, and that these genes could be employed as basic biomarkers for VO diagnosis and treatment. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

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38 pages, 3439 KiB

Open AccessReview

Understanding Arrhythmogenic Cardiomyopathy: Advances through the Use of Human Pluripotent Stem Cell Models

by Christianne J. Chua, Justin Morrissette-McAlmon, Leslie Tung and Kenneth R. Boheler

Genes 2023, 14(10), 1864; https://doi.org/10.3390/genes14101864 - 25 Sep 2023

Cited by 8 | Viewed by 2834

Abstract

Cardiomyopathies (CMPs) represent a significant healthcare burden and are a major cause of heart failure leading to premature death. Several CMPs are now recognized to have a strong genetic basis, including arrhythmogenic cardiomyopathy (ACM), which predisposes patients to arrhythmic episodes. Variants in one of the five genes (PKP2, JUP, DSC2, DSG2, and DSP) encoding proteins of the desmosome are known to cause a subset of ACM, which we classify as desmosome-related ACM (dACM). Phenotypically, this disease may lead to sudden cardiac death in young athletes and, during late stages, is often accompanied by myocardial fibrofatty infiltrates. While the pathogenicity of the desmosome genes has been well established through animal studies and limited supplies of primary human cells, these systems have drawbacks that limit their utility and relevance to understanding human disease. Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for modeling ACM in vitro that can overcome these challenges, as they represent a reproducible and scalable source of cardiomyocytes (CMs) that recapitulate patient phenotypes. In this review, we provide an overview of dACM, summarize findings in other model systems linking desmosome proteins with this disease, and provide an up-to-date summary of the work that has been conducted in hiPSC-cardiomyocyte (hiPSC-CM) models of dACM. In the context of the hiPSC-CM model system, we highlight novel findings that have contributed to our understanding of disease and enumerate the limitations, prospects, and directions for research to consider towards future progress. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

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20 pages, 1008 KiB

Open AccessReview

Circular RNAs: New Players in Cardiomyopathy

by Maedeh Bagheri Moghaddam, Majid Maleki, Maziar Oveisee, Mahrokh Bagheri Moghaddam, Maedeh Arabian and Mahshid Malakootian

Genes 2022, 13(9), 1537; https://doi.org/10.3390/genes13091537 - 26 Aug 2022

Cited by 4 | Viewed by 3021

Abstract

Cardiomyopathies comprise a heterogeneous group of cardiac diseases identified by myocardium disorders and diminished cardiac function. They often lead to heart failure or heart transplantation and constitute one of the principal causes of morbidity and mortality worldwide. Circular RNAs (circRNAs) are a novel type of noncoding RNAs. They are covalently closed and single-stranded and derived from the exons and introns of genes by alternative splicing. This specific structure renders them resistant to exonuclease digestion. Many recent studies have demonstrated that circRNAs are highly abundant and conserved and can play central roles in biological functions such as microRNA (miRNA) sponging, splicing, and transcription regulation. Emerging evidence indicates that circRNAs can play significant roles in cardiovascular diseases, including cardiomyopathies. In this review, we briefly describe the current understanding regarding the classification, nomenclature, characteristics, and function of circRNAs and report recent significant findings concerning the roles of circRNAs in cardiomyopathies. Furthermore, we discuss the clinical application potential of circRNAs as the therapeutic targets and diagnostic biomarkers of cardiomyopathies. Full article

(This article belongs to the Special Issue Genetics and Mechanistic Basis of Cardiomyopathies)

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