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Frontiers in Cardiovascular Medicine 2023The present study aimed to describe the phenotypic features and genetic spectrum of arrhythmogenic cardiomyopathy (ACM) presented in childhood and test the validity of...
INTRODUCTION
The present study aimed to describe the phenotypic features and genetic spectrum of arrhythmogenic cardiomyopathy (ACM) presented in childhood and test the validity of different diagnostic approaches using Task Force Criteria 2010 (TFC) and recently proposed Padua criteria.
PATIENTS AND METHODS
Thirteen patients (mean age at diagnosis 13.6 ± 3.7 years) were enrolled using "definite" or "borderline" diagnostic criteria of ACM according to the TFC 2010 and the Padua criteria in patients <18 years old. Clinical data, including family history, 12-lead electrocardiogram (ECG), signal-averaged ECG, 24-h Holter monitoring, imaging techniques, genetic testing, and other relevant information, were collected.
RESULTS
All patients were classified into three variants: ACM of right ventricle (ACM-RV; = 6, 46.1%), biventricular ACM (ACM-BV; = 3, 23.1%), and ACM of left ventricle (ACM-LV; = 4, 30.8%). The most common symptoms at presentations were syncope ( = 6; 46.1%) and palpitations ( = 5; 38.5%). All patients had more than 500 premature ventricular contractions per day. Ventricular tachycardia was reported in 10 patients (76.9%), and right ventricular dilatation was registered in 8 patients (61.5%). An implantable cardiac defibrillator was implanted in 61.5% of cases, and three patients with biventricular involvement underwent heart transplantation. Desmosomal mutations were identified in 8 children (53.8%), including four patients with variants, two with variants, one with variant, and one with . Four patients carried compound heterozygous variants in desmosomal genes associated with left ventricular involvement.
CONCLUSION
Arrhythmias and structural heart disease, such as chamber dilatation, should raise suspicion of different ACM phenotypes. Diagnosis of ACM might be difficult in pediatric patients, especially for ACM-LV and ACM-BV forms. Our study confirmed that using "Padua criteria" in combination with genetic testing improves the diagnostic accuracy of ACM in children.
PubMed: 37781308
DOI: 10.3389/fcvm.2023.1216976 -
Scientific Reports Sep 2023Primary cardiac mesenchymal stromal cells (C-MSCs) can promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM) by...
Primary cardiac mesenchymal stromal cells (C-MSCs) can promote the aberrant remodeling of cardiac tissue that characterizes arrhythmogenic cardiomyopathy (ACM) by differentiating into adipocytes and myofibroblasts. These cells' limitations, including restricted access to primary material and its manipulation have been overcome by the advancement of human induced pluripotent stem cells (hiPSCs), and their ability to differentiate towards the cardiac stromal population. C-MSCs derived from hiPSCs make it possible to work with virtually unlimited numbers of cells that are genetically identical to the cells of origin. We performed in vitro experiments on primary stromal cells (Primary) and hiPSC-derived stromal cells (hiPSC-D) to compare them as tools to model ACM. Both Primary and hiPSC-D cells expressed mesenchymal surface markers and possessed typical MSC differentiation potentials. hiPSC-D expressed desmosomal genes and proteins and shared a similar transcriptomic profile with Primary cells. Furthermore, ACM hiPSC-D exhibited higher propensity to accumulate lipid droplets and collagen compared to healthy control cells, similar to their primary counterparts. Therefore, both Primary and hiPSC-D cardiac stromal cells obtained from ACM patients can be used to model aspects of the disease. The choice of the most suitable model will depend on experimental needs and on the availability of human source samples.
Topics: Humans; Induced Pluripotent Stem Cells; Pluripotent Stem Cells; Stromal Cells; Mesenchymal Stem Cells; Cardiomyopathies
PubMed: 37758786
DOI: 10.1038/s41598-023-43308-2 -
Journal of Medical Case Reports Sep 2023Autoimmune bullous disorders develop due to autoantibodies targeting intercellular adhesion proteins of hemidesmosomes and desmosomes and may be triggered by viral...
BACKGROUND
Autoimmune bullous disorders develop due to autoantibodies targeting intercellular adhesion proteins of hemidesmosomes and desmosomes and may be triggered by viral infections and vaccines. Recent reports suggest that the coronavirus disease 2019 vaccination may trigger flares or exacerbations of preexisting autoimmune diseases, including new onset autoimmune bullous disorders. There are less data on whether vaccination against severe acute respiratory syndrome coronavirus 2 may also exacerbate preexisting autoimmune bullous disorders.
CASE PRESENTATION
Here we present three cases, two white males (ages 69 years and 88 years) with bullous pemphigoid and one white 50-year-old female with pemphigus foliaceus, wherein all individuals developed minor, tractable flares of their preexisting autoimmune bullous disorders after receiving the coronavirus disease 2019 vaccination, which were readily treatable with topical or low-dose systemic corticosteroids.
CONCLUSIONS
Dermatologists managing patients with autoimmune bullous disorders should be cognizant of the uncommon potential for flares of the disorder following vaccination for severe acute respiratory syndrome coronavirus 2. Flares of bullous pemphigoid and pemphigus foliaceus following vaccination for severe acute respiratory syndrome coronavirus 2 in these cases were mild and tractable.
Topics: Female; Male; Humans; Middle Aged; Pemphigus; Pemphigoid, Bullous; SARS-CoV-2; COVID-19; Autoimmune Diseases; Vaccination
PubMed: 37749657
DOI: 10.1186/s13256-023-04146-y -
Stem Cell Reviews and Reports Nov 2023Arrhythmogenic cardiomyopathy (ACM) is a hereditary myocardial disease characterized by the replacement of the ventricular myocardium with fibrous fatty deposits. ACM is... (Review)
Review
Arrhythmogenic cardiomyopathy (ACM) is a hereditary myocardial disease characterized by the replacement of the ventricular myocardium with fibrous fatty deposits. ACM is usually inherited in an autosomal dominant pattern with variable penetrance and expressivity, which is mainly related to ventricular tachyarrhythmia and sudden cardiac death (SCD). Importantly, significant progress has been made in determining the genetic background of ACM due to the development of new techniques for genetic analysis. The exact molecular pathomechanism of ACM, however, is not completely clear and the genotype-phenotype correlations have not been fully elucidated, which are useful to predict the prognosis and treatment of ACM patients. Different gene-targeted and transgenic animal models, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) models, and heterologous expression systems have been developed. Here, this review aims to summarize preclinical ACM models and platforms promoting our understanding of the pathogenesis of ACM and assess their value in elucidating the ACM genotype-phenotype relationship.
Topics: Animals; Humans; Heart Ventricles; Induced Pluripotent Stem Cells; Myocardium; Myocytes, Cardiac
PubMed: 37731079
DOI: 10.1007/s12015-023-10615-0 -
The Journal of Investigative Dermatology Feb 2024Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to...
Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients' phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.
Topics: Animals; Humans; Mice; Desmoplakins; Desmosomes; Hair; Hair Diseases; Keratoderma, Palmoplantar; Skin; Skin Abnormalities
PubMed: 37716648
DOI: 10.1016/j.jid.2023.02.044 -
Biomedicine & Pharmacotherapy =... Nov 2023Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition... (Review)
Review
Mutant desmoglein 2 (DSG2) is the second most common pathogenic gene in arrhythmogenic cardiomyopathy (ACM), accounting for approximately 10% of ACM cases. In addition to common clinical and pathological features, ACM caused by mutant DSG2 has specific characteristics, manifesting as left ventricle involvement and a high risk of heart failure. Pathological studies have shown extensive cardiomyocyte necrosis, infiltration of immune cells, and fibrofatty replacement in both ventricles, as well as abnormal desmosome structures in the hearts of humans and mice with mutant DSG2-related ACM. Although desmosome dysfunction is a common pathway in the pathogenesis of mutant DSG2-related ACM, the mechanisms underlying this dysfunction vary among mutations. Desmosome dysfunction induces cardiomyocyte injury, plakoglobin dislocation, and gap junction dysfunction, all of which contribute to the initiation and progression of ACM. Additionally, dysregulated inflammation, overactivation of transforming growth factor-beta-1 signaling and endoplasmic reticulum stress, and cardiac metabolic dysfunction contribute to the pathogenesis of ACM caused by mutant DSG2. These features demonstrate that patients with mutant DSG2-related ACM should be managed individually and precisely based on the genotype and phenotype. Further studies are needed to investigate the underlying mechanisms and to identify novel therapies to reverse or attenuate the progression of ACM caused by mutant DSG2.
PubMed: 37696084
DOI: 10.1016/j.biopha.2023.115448 -
Genes & Diseases Mar 2024Vitamin A (VA) plays an essential role in modulating both the gut microbiota and gut barrier function. Short-chain fatty acids (SCFAs), as metabolites of the gut...
Vitamin A (VA) plays an essential role in modulating both the gut microbiota and gut barrier function. Short-chain fatty acids (SCFAs), as metabolites of the gut microbiota, protect the physiological intestinal barrier; however, they are compromised when VA is deficient. Thus, there is an urgent need to understand how and which SCFAs modulate colonic epithelial barrier integrity in VA deficiency (VAD). Herein, compared with normal VA rats (VAN), at the beginning of pregnancy, we confirmed that the colonic desmosome junction was impaired in the VAD group, and the amounts of acetate, propionate, and butyrate declined because of the decreased abundance of SCFA-producing bacteria (, , and ). The differentially expressed genes correlated with the gut barrier and the histone deacetylase complex between the VAD and VAN groups were enriched by RNA sequencing. In the VAD group, the expression levels of colonic CEA cell adhesion molecule 1 (CEACAM1) were down-regulated, and the levels of histone deacetylase 1 (HDAC1) and HDAC3 were up-regulated. Intriguingly, the above changes in the VAD groups were rescued by VA supplementation in the early postnatal period. Further study indicated that in Caco-2 cells, butyrate treatment significantly repressed the enrichment of HDAC3 on the promoter of the gene to induce its expression. Our findings support that butyrate intervention can alleviate the impairment of colonic barrier function caused by VAD, and timely postnatal VA intervention may reverse the damage caused by VAD on gut barrier integrity during pregnancy.
PubMed: 37692511
DOI: 10.1016/j.gendis.2023.03.032 -
Cells Aug 2023Desmosomes play a vital role in providing structural integrity to tissues that experience significant mechanical tension, including the heart. Deficiencies in desmosomal... (Review)
Review
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.
Topics: Adult; Humans; Desmosomes; Cardiomyopathies; Cell Differentiation; Epirubicin; Myocytes, Cardiac
PubMed: 37681854
DOI: 10.3390/cells12172122 -
Molecular Genetics and Metabolism... Dec 2023ACM is a rare hereditary heart disease characterized by a progressive fibro-fatty replacement of the myocardium that can affect either the right or the left ventricle or...
ACM is a rare hereditary heart disease characterized by a progressive fibro-fatty replacement of the myocardium that can affect either the right or the left ventricle or both. It is mainly caused by variants in the desmosome genes with autosomal dominant transmission and incomplete penetrance. The disease shows a wide spectrum of clinical manifestations, including ventricular arrhythmias, HF and myocarditis. The latter is considered a 'hot phase' in the natural history of the disease and must therefore be distinguished from the isolated AM, which is frequently due to viral infections. Our case report is an example of how an AM, as the first manifestation of the disease, helped to reach a diagnosis of ACM through the genetic analysis. In fact, the multi-parametric investigation, which also included CMR and EMB, revealed controversial aspects that led us to perform the genetic test. The latter revealed a heterozygous pathogenic variant in the that was considered definitive proof of ACM.
PubMed: 37662494
DOI: 10.1016/j.ymgmr.2023.101000 -
ESC Heart Failure Oct 2023The case of a 49-year-old man with acute onset of heart failure is presented. The initial work-up showed a dilated cardiomyopathy with severely reduced left ventricular...
The case of a 49-year-old man with acute onset of heart failure is presented. The initial work-up showed a dilated cardiomyopathy with severely reduced left ventricular ejection fraction. In the differential diagnostic process, hypertensive, ischaemic, and valvular aetiologies were discarded. Subsequently, a cardiac magnetic resonance revealed global hypokinesis and inferior and anterior subepicardial fibrosis. Once differential diagnoses of subepicardial fibrosis (myocarditis, sarcoidosis, and Chagas disease) were discarded, a genetic panel was performed, resulting in a heterozygous mutation of desmoplakin (DSP) gene c.6697_6698del. A left-dominant DSP arrhythmogenic cardiomyopathy mutation was diagnosed. Structural myocardial abnormalities and ventricular arrhythmias characterize arrhythmogenic cardiomyopathy. Up to 50% of cases are associated with mutations in DSP genes (JUP, DSP, and PKP2). DSP is the fundamental component of the desmosome structure and provides structural support through intercellular adhesion. Therefore, when frequent differential diagnoses are discarded, genetic studies for dilated cardiomyopathy and DSP mutation should be considered.
PubMed: 37632291
DOI: 10.1002/ehf2.14504