scholarly journals Pathogenesis, Diagnosis and Risk Stratification in Arrhythmogenic Cardiomyopathy

2021 ◽  
Vol 11 (4) ◽  
pp. 263-289
Author(s):  
Maria Teresa Florio ◽  
Filomena Boccia ◽  
Erica Vetrano ◽  
Marco Borrelli ◽  
Thomas Gossios ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Molecular Mechanisms ◽  
Arrhythmogenic Cardiomyopathy ◽  
Icd Implantation ◽  
Electrical Instability ◽  
Genes Encoding ◽  
Nosological Entity ◽  
Clinical Tools ◽  
The Right

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease associated with sudden cardiac death (SCD). It is most frequently caused by mutations in genes encoding desmosomal proteins. However, there is growing evidence that ACM is not exclusively a desmosome disease but rather appears to be a disease of the connexoma. Fibroadipose replacement of the right ventricle (RV) had long been the hallmark of ACM, although biventricular involvement or predominant involvement of the left ventricle (LD-ACM) is increasingly found, raising the challenge of differential diagnosis with arrhythmogenic dilated cardiomyopathy (a-DCM). A-DCM, ACM, and LD-ACM are increasingly acknowledged as a single nosological entity, the hallmark of which is electrical instability. Our aim was to analyze the complex molecular mechanisms underlying arrhythmogenic cardiomyopathies, outlining the role of inflammation and autoimmunity in disease pathophysiology. Secondly, we present the clinical tools used in the clinical diagnosis of ACM. Focusing on the challenge of defining the risk of sudden death in this clinical setting, we present available risk stratification strategies. Lastly, we summarize the role of genetics and imaging in risk stratification, guiding through the appropriate patient selection for ICD implantation.

Molecular signatures of Emery–Dreifuss muscular dystrophy

2008 ◽  
Vol 36 (6) ◽  
pp. 1354-1358 ◽  
Author(s):  
Matthew A. Wheeler ◽  
Juliet A. Ellis
Keyword(s):  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Signalling Pathways ◽  
Lamin A ◽  
Degenerative Diseases ◽  
Hypertrophic Growth ◽  
Genes Encoding

Mutations in genes encoding the nuclear envelope proteins emerin and lamin A/C lead to a range of tissue-specific degenerative diseases. These include dilated cardiomyopathy, limb-girdle muscular dystrophy and X-linked and autosomal dominant EDMD (Emery–Dreifuss muscular dystrophy). The molecular mechanisms underlying these disorders are poorly understood; however, recent work using animal models has identified a number of signalling pathways that are altered in response to the deletion of either emerin or lamin A/C or expression of Lmna mutants found in patients with laminopathies. A distinguishing feature of patients with EDMD is the association of a dilated cardiomyopathy with conduction defects. In the present article, we describe several of the pathways altered in response to an EDMD phenotype, which are known to be key mediators of hypertrophic growth, and focus on a possible role of an emerin–β-catenin interaction in the pathogenesis of this disease.

scholarly journals Arrhythmogenic Cardiomyopathy

2019 ◽  
Vol 87 (11-12) ◽  
pp. 599-618
Author(s):  
Blaž Podgoršek ◽  
Gregor Poglajen ◽  
Andraž Cerar ◽  
Matjaž Šinkovec ◽  
Bojan Vrtovec
Keyword(s):  
Task Force ◽  
Current Knowledge ◽  
Diagnostic Yield ◽  
Treatment Strategies ◽  
Arrhythmogenic Cardiomyopathy ◽  
Icd Implantation ◽  
Fatty Replacement ◽  
Current Task ◽  
Advanced Stages ◽  
The Right

Arrhythmogenic cardiomyopathy (AC) is a genetic disease of the myocardium characterized by fibro-fatty replacement of the apoptotic myocardium. It primarily affects the right ventricle, however in advanced stages of the disease the left ventricle can also be significantly affected. AC is a challenging diagnosis, especially in the early stages of the disease, and should be considered in all patients presenting with palpitations, syncope or sudden cardiac death when other, more common causes of these symptoms/signs are excluded. In patients with suspected AC, evaluation according to the current Task Force Criteria should be applied to achieve optimal diagnostic yield. The main therapeutic concern in AC patients is the prevention of SCD, and thus all patients with established diagnosis have to be evaluated for potential ICD implantation, which is indicated in the majority of symptomatic patients. In this narrative review we aim to outline current knowledge on the pathophysiology, diagnosis and treatment strategies of AC.

scholarly journals Low QRS voltage and atrial fibrillation precluding implantation of a subcutaneous implantable cardioverterdefibrillator in a patient with arrhythmogenic cardiomyopathy

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Peter C. Kahr ◽  
Jan Steffel ◽  
Alexander Breitenstein ◽  
Thomas Wolber ◽  
Laurent M. Haegeli ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ventricular Arrhythmias ◽  
Vascular System ◽  
Persistent Atrial Fibrillation ◽  
Hereditary Disease ◽  
Fatty Tissue ◽  
Arrhythmogenic Cardiomyopathy ◽  
Foreign Material ◽  
Icd Implantation ◽  
The Right

Arrhythmogenic cardiomyopathy (AC) is a rare mostly hereditary disease, in which fibro-fatty tissue replaces cardiomyocytes. Typically, the first alterations of the disease can be encountered in the epicardium of the right ventricle in adolescent patients. From there, the disease usually progresses over time. Besides the development of heart failure, the clinical significance of the disease is determined by the predisposition to potentially lethal ventricular arrhythmias. Hence, a majority of patients with AC require an implantable cardioverter-defibrillator (ICD) to be protected from sudden cardiac death. A recently developed alternative to transvenous systems are subcutaneous ICDs (S-ICD), associated with a lower risk of device-related complications such as endocarditis since no foreign material is implanted within the heart and vascular system. In this report, we describe and discuss our experience with the implantation of a S-ICD in a patient with AC, who had low QRS voltage and persistent atrial fibrillation precluding successful S-ICD implantation, as well as the challenges encountered during subsequent transvenous lead implantation.

scholarly journals Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease

2020 ◽  
Vol 21 (17) ◽  
pp. 6320
Author(s):  
Shanshan Gao ◽  
Deepa Puthenvedu ◽  
Raffaella Lombardi ◽  
Suet Nee Chen
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Genetic ◽  
Autoimmune Response ◽  
Arrhythmogenic Cardiomyopathy ◽  
Cellular Mechanisms ◽  
Paracrine Factors ◽  
Epicardial Cells ◽  
Genes Encoding ◽  
Advanced Stages ◽  
Canonical Wnt

Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field.

Gene structure of urea transporters

2003 ◽  
Vol 284 (1) ◽  
pp. F3-F10 ◽  
Author(s):  
Serena M. Bagnasco
Keyword(s):  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Renal Physiology ◽  
The Past ◽  
New Information ◽  
Lower Vertebrates ◽  
Genes Encoding ◽  
Concentrate Urine

Urea plays various roles in the biology of diverse organisms. The past decade has produced new information on the molecular structure of several urea transporters in various species. Availability of DNA probes has revealed that the presence of urea transporters is not confined to the mammalian kidney but is also evident in testis and brain, raising new questions about the possible physiological role of urea in these organs. Cloning of the genes encoding the two closely related mammalian urea transporters UT-A and UT-B has helped in identifying molecular mechanisms affecting expression of urea transporters in the kidney, such as transcriptional control for UT-A abundance. On the basis of analysis of genomic sequences of individuals lacking the UT-B transporter, mutations have been found that explain deficits in their capacity to concentrate urine. More urea transporters are being characterized in marine organisms and lower vertebrates, and studying the role and regulation of urea transport from an evolutionary perspective can certainly enrich our understanding of renal physiology.

scholarly journals Sex difference in the mouse BAT transcriptome reveals a role of progesterone

2020 ◽  
Author(s):  
Kasiphak Kaikaew ◽  
Aldo Grefhorst ◽  
Jacobie Steenbergen ◽  
Sigrid M.a. Swagemakers ◽  
Anke McLuskey ◽  
...  
Keyword(s):  
Differential Expression ◽  
Molecular Mechanisms ◽  
Gonadal Hormones ◽  
Cell Contact ◽  
Differential Expression Pattern ◽  
Brown Adipose ◽  
Transcriptional Pattern ◽  
Genes Encoding

Brown adipose tissue (BAT) is a metabolically active organ that exhibits sex-differential features, i.e., being generally more abundant and active in females than in males. Although sex steroids, particularly estrogens, have been shown to regulate BAT thermogenic function, the underlying molecular mechanisms contributing to sexual dimorphism in basal BAT activity have not been elucidated. Therefore, we assessed the transcriptome of interscapular BAT of male and female C57BL/6J mice by RNA sequencing and identified 295 genes showing ≥2-fold differential expression (adjusted P<0.05). In silico functional annotation clustering suggested an enrichment of genes encoding proteins involved in cell-cell contact, interaction, and adhesion. Ovariectomy reduced the expression of these genes in female BAT towards a male pattern whereas orchiectomy had marginal effects on the transcriptional pattern, indicating a prominent role of female gonadal hormones in this sex-differential expression pattern. Progesterone was identified as a possible upstream regulator of the sex-differentially expressed genes. Studying direct effects of progesterone in vitro in primary adipocytes showed that progesterone significantly altered the transcription of several of the identified genes, possibly via the glucocorticoid receptor. In conclusion, this study reveals a sexually dimorphic transcription profile in murine BAT at general housing conditions and demonstrates a role for progesterone in the regulation of the interscapular BAT transcriptome.

scholarly journals MIR822 modulates monosporic female gametogenesis through an ARGONAUTE9-dependent pathway in Arabidopsis thaliana

2021 ◽  
Author(s):  
ANDREA TOVAR AGUILAR ◽  
Daniel GRIMANELLI ◽  
Gerardo Acosta Garcia ◽  
Jean Philippe Vielle Calzada ◽  
Jesus Agustin Badillo-Corona ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Flowering Plants ◽  
Loss Of Function ◽  
Genes Encoding ◽  
Functional Megaspore ◽  
Dependent Pathway ◽  
Female Gametogenesis

In the ovule of flowering plants, the establishment of the haploid generation occurs when a somatic cell differentiates into a Megaspore Mother Cell (MMC) and initiates meiosis. As most flowering plants, Arabidopsis thaliana undergoes a monosporic type of gametogenesis; three meiotically derived cells degenerate without further division, and a single one, the functional megaspore (FM), divides mitotically to form the female gametophyte. In Arabidopsis, the ARGONAUTE4 clade proteins are involved in the control of megasporogenesis. In particular, mutations in ARGONAUTE9 (AGO9) lead to the ectopic differentiation of gametic precursors that can give rise female gametophytes. However, the genetic basis and molecular mechanisms that control monosporic gametogenesis remain largely unknown. Here, we show that Arabidopsis plants carrying loss-of-function mutations in the AGO9-interacting miR822a give rise to extranumerary surviving megaspores that acquire a FM identity and divide without giving rise to differentiated female gametophytes. The overexpression of three miR822a target genes encoding Cysteine/Histidine-Rich C1 domain proteins (DC1) phenocopy mir822a plants. The miR822a targets are overexpressed in ago9 mutant ovules, confirming that miR822a acts through an AGO9-dependent pathway to negatively regulate DC1 domain proteins. Our results identify a new role of miRNAs in the most prevalent form of female gametogenesis in flowering plants

scholarly journals Insights Into Genetics and Pathophysiology of Arrhythmogenic Cardiomyopathy

2021 ◽  
Author(s):  
Brenda Gerull ◽  
Andreas Brodehl
Keyword(s):  
Ventricular Arrhythmias ◽  
Disease Onset ◽  
Therapeutic Approaches ◽  
Arrhythmogenic Cardiomyopathy ◽  
Preclinical Research ◽  
Cellular Junctions ◽  
Genes Encoding ◽  
Life Threatening ◽  
Apparently Healthy

Abstract Purpose of Review Arrhythmogenic cardiomyopathy (ACM) is a genetic disease characterized by life-threatening ventricular arrhythmias and sudden cardiac death (SCD) in apparently healthy young adults. Mutations in genes encoding for cellular junctions can be found in about half of the patients. However, disease onset and severity, risk of arrhythmias, and outcome are highly variable and drug-targeted treatment is currently unavailable. Recent Findings This review focuses on advances in clinical risk stratification, genetic etiology, and pathophysiological concepts. The desmosome is the central part of the disease, but other intercalated disc and associated structural proteins not only broaden the genetic spectrum but also provide novel molecular and cellular insights into the pathogenesis of ACM. Signaling pathways and the role of inflammation will be discussed and targets for novel therapeutic approaches outlined. Summary Genetic discoveries and experimental-driven preclinical research contributed significantly to the understanding of ACM towards mutation- and pathway-specific personalized medicine.

scholarly journals Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes

2016 ◽  
Vol 5 (2) ◽  
pp. 90 ◽  
Author(s):  
Deniz Akdis ◽  
Corinna Brunckhorst ◽  
Firat Duru ◽  
Ardan M Saguner ◽  
◽  
...  
Keyword(s):  
Heart Failure ◽  
Molecular Mechanisms ◽  
Task Force ◽  
Sudden Cardiac Arrest ◽  
Clinical Manifestations ◽  
Right Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Implantable Cardioverter Defibrillators ◽  
Arrhythmogenic Cardiomyopathy ◽  
Genes Encoding

This overview gives an update on the molecular mechanisms, clinical manifestations, diagnosis and therapy of arrhythmogenic cardiomyopathy (ACM). ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. Three subtypes have been proposed: the classical right-dominant subtype generally referred to as ARVC/D, biventricular forms with early biventricular involvement and left-dominant subtypes with predominant LV involvement. Typical symptoms include palpitations, arrhythmic (pre)syncope and sudden cardiac arrest due to ventricular arrhythmias, which typically occur in athletes. At later stages, heart failure may occur. Diagnosis is established with the 2010 Task Force Criteria (TFC). Modern imaging tools are crucial for ACM diagnosis, including both echocardiography and cardiac magnetic resonance imaging for detecting functional and structural alternations. Of note, structural findings often become visible after electrical alterations, such as premature ventricular beats, ventricular fibrillation (VF) and ventricular tachycardia (VT). 12-lead ECG is important to assess for depolarisation and repolarisation abnormalities, including T-wave inversions as the most common ECG abnormality. Family history and the detection of causative mutations, mostly affecting the desmosome, have been incorporated in the TFC, and stress the importance of cascade family screening. Differential diagnoses include idiopathic right ventricular outflow tract (RVOT) VT, sarcoidosis, congenital heart disease, myocarditis, dilated cardiomyopathy, athlete’s heart, Brugada syndrome and RV infarction. Therapeutic strategies include restriction from endurance and competitive sports, β-blockers, antiarrhythmic drugs, heart failure medication, implantable cardioverter-defibrillators and endocardial/epicardial catheter ablation.

Role of metabolomics in identifying cardiac hypertrophy: an overview of the past 20 years of development and future perspective

2021 ◽  
Vol 23 ◽  
Author(s):  
Sachendra Pratap Singh ◽  
Rishi Sethi ◽  
Shailendra Kumar Saxena ◽  
Ashish Gupta
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Enzymatic Reaction ◽  
Work Load ◽  
Left Ventricular ◽  
Future Perspective ◽  
Resonance Spectroscopy ◽  
Comprehensive Information ◽  
The Right

Abstract Cardiac hypertrophy (CH) is an augmentation of either the right ventricular or the left ventricular mass in order to compensate for the increase of work load on the heart. Metabolic abnormalities lead to histological changes of cardiac myocytes and turn into CH. The molecular mechanisms that lead to initiate CH have been of widespread concern, hence the development of the new field of research, metabolomics: one ‘omics’ approach that can reveal comprehensive information of the paradigm shift of metabolic pathways network in contrast to individual enzymatic reaction-based metabolites, have attempted and until now only 19 studies have been conducted using experimental animal and human specimens. Nuclear magnetic resonance spectroscopy and mass spectrometry-based metabolomics studies have found that CH is a metabolic disease and is mainly linked to the harmonic imbalance of glycolysis, citric acid cycle, amino acids and lipid metabolism. The current review will summarise the main outcomes of the above mentioned 19 studies that have expanded our understanding of the molecular mechanisms that may lead to CH and eventually to heart failure.

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