Asta Literature Retrieval: Pathophysiology and clinical mechanisms of arrhythmogenic right ventricular cardiomyopathy. Core disease mechanisms,...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Special issue Heidelberg Heart II: Abstracts of oral and poster presentations

• Authors: W. Franke
• Year: 2012
• Venue: Cell and Tissue Research
• URL: https://www.semanticscholar.org/paper/969e98278c5ef7588af320ca0f980b09522c21e7
• DOI: 10.1007/s00441-012-1412-x
• PMCID: 3349853
• Citations: 1
• Summary: Interference with the architectural roles of desmosome molecules has been assumed to make an important contribution to tissue responses that lead to disease pathogenesis, functions that transcend their well-established roles in adhesion and IF-anchorage are emerging.
• Evidence snippets:
• Snippet 1 (score: 0.691) > A 16 -Disease mechanisms in arrhythmogenic cardiomyopathy: immunohistochemistry and beyond Jeffrey E. Saffitz Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA jsaffitz@bidmc.harvard.edu Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial disorder characterized by an especially high incidence of ventricular arrhythmias and sudden death. The identification of desmosomal gene mutations in ∼50 % of patients has led to the idea that ARVC is a disease of abnormal cell-cell adhesion. However, recent insights gained largely from studies of the human disease suggest a greater degree of complexity. These insights include observations that: (1) plakoglobin (γ-catenin) is consistently redistributed from desmosomes to intracellular/nuclear sites in all forms of ARVC regardless of the underlying mutation, (2) ARVC patients have elevated circulating cytokine levels and myocardial production of cytokines, and (3) disease flares often follow strenuous exercise in ARVC patients. Objective: to define the genetic and mechanistic basis of arrhythmogenic cardiomyopathy. Background: arrhythmogenic cardiomyopathy, previously known as arrhythmogenic right ventricular dysplasia (ARVD) or arrhythmogenic right ventricular cardiomyopathy (ARVC), is characterized by myocardial fibrofatty replacement, ventricular dysfunction, and arrhythmias associated with sudden death. Autosomal dominant inheritance is most common, and reduced penetrance is the rule of thumb, but the underlying basis of low penetrance is poorly understood. The causative genes identified to date are generally associated with desmosome function, the "final common pathway" of this disease. We previously described compound and digenic heterozygosity as a feature of this disorder which plays a role in the development of the clinical phenotype and the severity of disease.

[2] Prediction of Ventricular Arrhythmias in Patients at Risk of Sudden Cardiac Death

• Authors: K. Haugaa, J. Amlie, T. Edvardsen
• Year: 2011
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/366318c37e6eff3d2740558b56fc30d650950fd1
• DOI: 10.5772/20670
• Summary: In this report, a novel echocardiographic method will be presented in order to evaluate the cardiac contractility pattern in patients at increased risk of life-threatening arrhythmias.
• Evidence snippets:
• Snippet 1 (score: 0.652) > Arrhythmogenic right ventricular cardiomyopathy is an inheritable, chronic and progressive cardiomyopathy and is one of the leading causes of sudden unexpected cardiac death in previously healthy young individuals (Sen-Chowdhry, 2010a; Thiene, 1988). Prevalence has been estimated to be at least 1 in 1000 (Sen-Chowdhry, 2010a). Recent molecular genetic reports have revealed arrhythmogenic right ventricular cardiomyopathy as mainly a desmosomal disease (Xu, 2010). Mutations in one of the 5 desmosomal or 3 extra desmosomal genes so far identified, lead to progressive loss of myocytes, followed by fibro-fatty replacement. Penetrance is age and gender dependent and the progressive clinical picture is highly variable (Dalal, 2006). Four clinical stages have been documented: An early concealed phase, overt electrical disorder, isolated right heart failure (Fig 4a), and biventricular pump failure (Fig 4b) (Basso, 1996;Sen-Chowdhry, 2007;Sen-Chowdhry, 2010a). Importantly, life-threatening arrhythmias can occur with only discrete or even absent myocardial structural changes (Senwww.intechopen.com Chowdhry, 2010b). Risk stratification of ventricular arrhythmias and sudden cardiac death is therefore challenging. Mechanisms of arrhythmias in early stages of arrhythmogenic right ventricular cardiomyopathy are probably due to dysfunction of desmosomal proteins and disturbed cell to cell coupling (Saffitz, 2009). In later stages of arrhythmogenic right ventricular cardiomyopathy when structural abnormalities in the myocardium have developed, reentrant ventricular arrhythmias can occur in tissue with fibro fatty replacement. Therefore, electrical conduction delay with consequent electrical dispersion has been suggested as an important mechanism of ventricular arrhythmias (Amlie, 1997;Turrini, 2001). In a recent study we investigated if arrhythmogenic right ventricular cardiomyopathy patients had cardiac contraction heterogeneity assessed as mechanical dispersion and

[3] Update on Genes Associated with Arrhythmogenic Cardiomyopathy

• Authors: M. Vallverdú-Prats, M. Alcalde, G. Sarquella-Brugada, S. César, E. Arbelo et al.
• Year: 2020
• Venue: Cardiomyopathy - Disease of the Heart Muscle [Working Title]
• URL: https://www.semanticscholar.org/paper/1ffe68704d6dcbf0977f3587844705d96df69259
• DOI: 10.5772/INTECHOPEN.95332
• Citations: 1
• Summary: Recent advances in the knowledge regarding the genetic basis of arrhythmogenic cardiomyopathy are focused on, suggesting the existence of unknown genes as well as other genome alterations not yet discovered.
• Evidence snippets:
• Snippet 1 (score: 0.623) > Arrhythmogenic cardiomyopathy is an inherited rare cardiac disease characterized by progressive replacement of myocardium by fibrofatty tissue, leading to ventricular arrhythmias and sudden cardiac death. Structural abnormalities mainly occur in the right ventricle, but it is well recognized that also sole left ventricular involvement and even biventricular substitution is common, particularly in advanced stages of the disease. Several molecular mechanisms are involved in the phenotype of ACM such as myocardial inflammation and signaling pathways that cause fibrosis and adipogenesis. Today, most of these mechanisms are not completely understood. Task Force Criteria for the diagnosis of arrhythmogenic cardiomyopathy include several clinical tests and also genetic data. Despite progressive improvement in diagnosis, it is difficult to obtain conclusive risk stratification in families suffering from arrhythmogenic cardiomyopathy. Hundreds of rare alterations are reported in mainly genes encoding desmosomal proteins, but there are also other causal genes with several functions within the cardiac tissue. A comprehensive genetic analysis may identify the potential genetic cause of the disease in nearly 60% of cases. Genetic testing is especially useful in families with at least one affected member that carries a potential deleterious alteration because it allows early identification and adoption of therapeutic measures among relatives at risk of malignant arrhythmias. Currently, one of main challenges is the genetic interpretation and clinical translation of amount of genetic data generated by new genetic technologies. > Update on Genes Associated with Arrhythmogenic Cardiomyopathy DOI: http://dx.doi.org/10.5772/intechopen.95332

[4] Focus on arrhythmogenic right ventricular cardiomyopathy

• Authors: G. Sinagra, C. Cappelletto, A. de Luca, S. Romani, A. Paldino et al.
• Year: 2020
• Venue: European Heart Journal Supplements : Journal of the European Society of Cardiology
• URL: https://www.semanticscholar.org/paper/e4392c990ad29851d1c76e19a03845d6db0c611a
• DOI: 10.1093/eurheartj/suaa152
• PMID: 33239987
• PMCID: 7673615
• Citations: 7
• Summary: The main goal in the management of patients is the prevention of sudden cardiac death, where implantable cardioverter-defibrillator is the only effective therapeutic strategy.
• Evidence snippets:
• Snippet 1 (score: 0.615) > Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a primary heart muscle disease, characterized by progressive epi-endocardial replacement of cardiomyocytes with fibro-adipose tissue. Clinically, ARVC is characterized by ventricular arrhythmias, heart failure (HF), and sudden cardiac death (SCD). 1 The first descriptions of the disease were reported in the '70 s of the last century but only in 1995 ARVC become part of the WHO/IFSC (World Health Organization/International Society and Federation of Cardiology) Classification of Cardiomyopathies. > Originally the disease was known as 'Arrhythmogenic Dysplasia of the Right Ventricle' and was considered as a developmental defect of the right ventricle (RV) myocardium. > Since then, significant progress has been made in knowledge of pathogenetic mechanisms, natural history and clinical management of the disease. > Arrhythmogenic right ventricular cardiomyopathy is caused by a genetic defects, mainly affecting cell junction proteins (desmosomes). Structural alterations may be absent or mild in the initial stages of the disease, confined to a limited regions of the RV, the so called 'triangle of dysplasia'. With the progression of the disease also the left ventricle (LV) may be involved. > ][3][4][5][6] Growing evidences of genotypic overlap between ARVC and 'arrhythmic' Dilated Cardiomyopathy (caused by mutations of desmosomal genes, filamin or lamin) led to the definition of 'Arrhythmogenic Cardiomyopathy' (AC). 3,5,6 rrhythmogenic cardiomyopathy includes a heterogeneous spectrum of phenotypes, ranging from isolated involvement of the RV to exclusive involvement of the LV, sharing a common genetic basis and clinically characterized by electrical instability, that could lead to atrial or ventricular tachyarrhythmias and bradyarrhythmias.

[5] Arrhythmogenic Cardiomyopathy: Genetic Pathology, Inflammatory Syndrome, or both?

• Authors: Héctor O. Rodríguez
• Year: 2017
• Venue: EMJ Cardiology
• URL: https://www.semanticscholar.org/paper/a13b5f1adff7a0f90200a5d30040b7263a5f2f9b
• DOI: 10.33590/emjcardiol/10314768
• Summary: Findings taken from other sudden death-causing cardiomyopathies allow us to propose proinflammatory cytokines, such as tumour necrosis factor and interleukins 17 and 2, as possible serological markers of sudden death and/or ventricular dysfunction in order to conduct further research and identify diagnosis/prognosis markers for ACM.
• Evidence snippets:
• Snippet 1 (score: 0.596) > Arrhythmogenic cardiomyopathy (ACM), previously called arrhythmogenic right ventricular cardiomyopathy or arrhythmogenic right ventricular dysplasia, was classically defined as a fibro-fatty substitution of ventricular myocardium. Recent advances have given a more complete view of its pathophysiology, including genetic and electrophysiological criteria to classify the disease. Therefore, we can consider ACM as a ventricular arrhythmogenic syndrome with a structural substrate associated to intercalated disc protein mutations. The possible role of ionic disturbances in lethal arrhythmias make it challenging to specify a precise definition and adopt a rational approach to prevention and therapeutics and this should be acknowledged. > Initially, ACM was reported mainly in the right ventricle, 1 but may also implicate the left ventricle, as well as both ventricles simultaneously. ACM principally affects young men and can cause sudden death by ventricular arrhythmias, 2 especially in athletes, which is not always associated to structural changes in ventricular walls. As a result of these variables, we can classify ACM into ionic and non-ionic-associated origin by the presence or absence of structural ventricular changes. In this review, we explore the possible role of inflammation as a concomitant cause in ACM, a mechanism poorly explored in the literature and one that possibly should be included in further classifications. > ACM was first described early in the 1980s. Initially, it was reported as hypokinetic cardiomyopathy associated with non-ischaemic tachycardia. 1 Progressively, ACM was described as being in association with lethal arrhythmias, 3 functional myocardial involvement, 4 and biventricular affectation. 5,6 0][11][12][13] In the next sections, we briefly describe the most recent advances in the comprehension of the pathophysiology of ACM.

[6] Molecular Mechanisms of Inherited Arrhythmias

• Authors: C. Wolf, C. Berul
• Year: 2008
• Venue: Current Genomics
• URL: https://www.semanticscholar.org/paper/8dc574fc997d6e863ac851b4a75d122de6d9aa61
• DOI: 10.2174/138920208784340768
• PMID: 19440513
• PMCID: 2679644
• Citations: 26
• Influential citations: 3
• Summary: The molecular basis of inherited arrhythmias in structurally normal and altered hearts is summarized, which helps explain the molecular and functional mechanisms of long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and other electrical myopathies.
• Evidence snippets:
• Snippet 1 (score: 0.592) > Inherited arrhythmias can be life threatening, and are major cause of mortality and morbidity in developed nations. Identification of molecular pathways that increase susceptibility to arrhythmia is necessary to prevent disease occurrence, to improve current therapies and to target new drug development. In recent years, the discovery of pathogenic mutations in inherited arrhythmia syndromes has provided novel insights for the understanding and treatment of diseases predisposing to sudden cardiac death. In patients with the long QT syndromes (LQTS), genotype-phenotype relation studies [1] and genetic testing have influenced patient risk stratification [2] and refined treatment strategies [3]. > Arrhythmia mechanisms include abnormal automaticity, triggered activity, and re-entrant excitation. Each of these mechanisms can occur in any type of myocardial disease or in inherited cardiac arrhythmias. The current article focuses on molecular mechanisms of arrhythmias in the structurally abnormal and normal heart. Hypertrophic and dilated cardiomyopathies, as well as arrhythmogenic right ventricular dysplasia/cardiomyopathy are common substrates of inherited arrhythmias in the structurally abnormal heart. Genetic diseases causing arrhythmias in the structural normal heart, also called electrical myopathies, include the long QT syndromes, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and non-defined familiar idiopathic ventricular fibrillation. Most, but not all of these disorders are caused by mutations in genes encoding cardiac ion-channel proteins. Among family members carrying an identical mutation in a single gene, remarkable phenotypic variability and expressivity may be observed, suggesting both environmental [4] and genetic modifiers [5].

[7] Arrhythmogenic cardiomyopathy: diagnosis, genetic background, and risk management

• Authors: J. Groeneweg, J. Groeneweg, J. Heijden, J. Heijden, D. Dooijes et al.
• Year: 2014
• Venue: Netherlands Heart Journal
• URL: https://www.semanticscholar.org/paper/7b6e9177653c6930262a978a3f44f7c979cfcce8
• DOI: 10.1007/s12471-014-0563-7
• PMID: 24817548
• PMCID: 4099433
• Citations: 28
• Influential citations: 3
• Summary: Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation, and patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.
• Evidence snippets:
• Snippet 1 (score: 0.591) > Arrhythmogenic right ventricular (RV) dysplasia/ cardiomyopathy (ARVD/C) is histopathologically characterised by progressive fibrofatty replacement of cardiomyocytes, primarily in the right ventricle [1][2][3]. However, histopathologically and functionally the left ventricle is affected in many cases and both ventricles are similarly affected by desmosomal and gap junctional protein redistribution [4,5]. Because of these observations, at present arrhythmogenic cardiomyopathy (AC) is the preferred terminology [6]. AC can be defined as a structural myocardial disease preceded by ventricular arrhythmias. Typical ARVD/C with predominant RV abnormalities can be considered a large and important subcategory of AC. Clinical diagnosis is made according to international consensus-based Task Force Criteria [7,8]. > The first series of ARVD/C patients was published in 1982 [1]. It was described as a developmental disease of the RV musculature, hence the terminology 'dysplasia'. In the past 25 years, increased insight into the development of the disease as well as the discovery of pathogenic gene mutations involved led to the current understanding that AC is a genetically determined cardiomyopathy. The molecular genetic substrate for the disease is mainly acknowledged in genes encoding desmosomal adhesion proteins in the intercalated disk [9][10][11][12][13][14]. > This review provides an overview of AC, from phenotypic and genetic features of the disease, to diagnosis, risk stratification and treatment options.

[8] Arrhythmogenic right ventricular cardiomyopathy: diverse substrate characteristics and ablation outcome.

• Authors: W. Cheng, F. Chung, Yenn‐Jiang Lin, L. Lo, S. Chang et al.
• Year: 2021
• Venue: Reviews in cardiovascular medicine
• URL: https://www.semanticscholar.org/paper/21563d7592478c853ce2ce3c54165855ba02fabf
• DOI: 10.31083/j.rcm2204136
• PMID: 34957771
• Citations: 7
• Summary: A better understanding of the pathogenesis, underlying arrhythmogenic substrates, and putative VT isthmus in ARVC contributes to a significant improvement in ablation outcomes through comprehensive endocardial and epicardial approaches.
• Evidence snippets:
• Snippet 1 (score: 0.590) > Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy caused by defective desmosomal proteins. The typical histopathological finding of ARVC is characterized by progressive fibrofatty infiltration of the right ventricle due to the dysfunction of cellular adhesion molecules, thus, developing arrhythmogenic substrates responsible for the clinical manifestation of ventricular tachycardia/fibrillation (VT/VF). Current guidelines recommend implantable cardiac defibrillator (ICD) implantation to prevent sudden cardiac death (SCD) in ARVC, especially for those experiencing VT/VF or aborted SCD, while antiarrhythmic drugs, despite their modest effectiveness and several undesirable adverse effects, are frequently used for those experiencing episodes of ICD interventions. Given the advances in mapping and ablation technologies, catheter ablation has been implemented to eliminate drug-refractory VT in ARVC. A better understanding of the pathogenesis, underlying arrhythmogenic substrates, and putative VT isthmus in ARVC contributes to a significant improvement in ablation outcomes through comprehensive endocardial and epicardial approaches. Regardless of ablation strategies, there is a diversity of arrhythmogenic substrates in ARVC, which could partly explain the nonuniform ablation outcome and long-term recurrences and reflect the role of potential factors in the modification of disease progression and triggering of arrhythmic events.

[9] Distinct Myocardial Transcriptomic Profiles of Cardiomyopathies Stratified by the Mutant Genes

• Authors: K. Sielemann, Z. Elbeck, A. Gärtner, A. Brodehl, C. Stanasiuk et al.
• Year: 2020
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/9f8ceb185d87f8def9e3c9dc016922d53a936b4a
• DOI: 10.3390/genes11121430
• PMID: 33260757
• PMCID: 7768427
• Citations: 10
• Summary: Genotype-specific differences in regulated pathways, Gene Ontology (GO) terms as well as gene groups like secreted or regulatory proteins and potential candidate drug targets revealing specific molecular pathomechanisms for the four subtypes of genetic cardiomyopathies are identified.
• Evidence snippets:
• Snippet 1 (score: 0.589) > TTNtv are associated with incomplete penetrance and late onset heart failure, whereas patients with i.e., pathogenic RBM20 or LMNA mutations are affected by comparably early cardiomyopathies with incomplete penetrance [3]. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is most frequently associated with defects in the desmosome [10]. The right ventricle is mainly affected, but with ongoing disease, the left ventricle is significantly affected as well [12]. Left ventricular forms of arrhythmogenic cardiomyopathy (ACM), which is a broader description of ARVC, are almost missing in the 2010 update diagnostic criteria, which are therefore not entirely specific for the disease [13,14]. However, due to advances in the clinical, pathological and genetic architecture of ARVC [14], left ventricular involvement and left-dominant or biventricular subtypes are now increasingly recognized. Further, genotype-phenotype correlation studies have recently identified clinical forms of ARVC associated with early dominant left ventricular involvement, which may parallel or even exceed the severity of right ventricular involvement [13,15,16]. The introduction of the term ACM was therefore recently proposed by the Heart Rhythm Society/European Heart Rhythm Association (HRS/EHRA) [17] to embrace the different pathologies of the disease [14]. However, there is still a lack of diagnostic and prognostic data and of the genetic basis and pathogenesis of ACM [18]. In our study, we therefore included ACM cases and compared this cardiomyopathy to other forms based on their genotypes. Mutations in the desmosomal genes cause ARVC but other genes like e.g., FLNC [19] can be affected as well [3]. However, the most frequent affected gene is PKP2 (11-51%) [5] encoding the desmosomal plaque protein plakophilin 2. This protein mediates the molecular connection of the desmosomal cadherins with the cytolinker protein desmoplakin.

[10] Blockade of the Adenosine 2A Receptor Mitigates the Cardiomyopathy Induced by Loss of Plakophilin-2 Expression

• Authors: M. Cerrone, C. J. V. van Opbergen, K. Malkani, N. Irrera, Mingliang Zhang et al.
• Year: 2018
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/8535f5196dd6979a590543055872e433646d94c1
• DOI: 10.3389/fphys.2018.01750
• PMID: 30568602
• PMCID: 6290386
• Citations: 11
• Summary: Paracrine adenosine 2A receptor activation contributes to the progression of fibrosis and impaired cardiac function in animals deficient in PKP2.
• Evidence snippets:
• Snippet 1 (score: 0.583) > Arrhythmogenic right ventricular cardiomyopathy (ARVC, indicated also as "arrhythmogenic cardiomyopathy, ACM" or "arrhythmogenic right ventricular dysplasia, ARVD") is an inherited disease characterized by fibrofatty infiltration of right ventricular (RV) predominance, ventricular arrhythmias and high propensity for sudden death in the young (Basso et al., 2009). Cardiac arrest is often associated with exercise, and it is the first disease manifestation in a high proportion of probands. (Basso et al., 2009;Groeneweg et al., 2015) Most often the disease begins with a subclinical, concealed stage, followed by overt stages of RV predominance (though LV is often involved) then biventricular dilated cardiomyopathy and failure. (Basso et al., 2009;Groeneweg et al., 2015) The disease can progress to end-stage heart failure and in the absence of a heart transplant, death. At present, no medical treatment exists to prevent or delay the progression of the disease. > Familial ARVC is most commonly consequent to mutations in the gene coding for Plakophilin-2 (PKP2; Groeneweg et al., 2015), a protein classically defined as a component of the desmosome, though also known to participate in other cellular functions. The relation between PKP2 on one hand, and the structural disease that results from its absence or altered sequence, on the other, remains a matter of investigation. Previous studies on the molecular mechanisms leading to fibro-adiposis in ARVC have proposed that activation of the Hippo and Wnt pathways are the causative mechanisms of the structural disease (Garcia-Gras et al., 2006;Chen et al., 2014). Recently, Dubash et al. (2016) demonstrated an additional route whereby loss of PKP2 expression causes an increase in the expression of TGF-beta1, and activation of the p38-MAPK-dependent pro-fibrotic program.

[11] The Challenges of Diagnosis and Treatment of Arrhythmogenic Cardiomyopathy: Are We there yet?

• Authors: A. Spadotto, D. Morabito, A. Carecci, G. Massaro, G. Statuto et al.
• Year: 2022
• Venue: Reviews in Cardiovascular Medicine
• URL: https://www.semanticscholar.org/paper/c49b90d8007f1358bc50f48696245a86fda4560b
• DOI: 10.31083/j.rcm2308283
• PMID: 39076647
• PMCID: 11266951
• Citations: 6
• Summary: Background: we sought to review the evolution in the diagnosis and treatment of Arrhythmogenic Cardiomyopathy (ACM), a clinically multifaceted entity beyond the observation of ventricular arrhythmias, and the outcome of therapies aiming at sudden death prevention in a single center experience. Methods: retrospective analysis of the data of consecutive patients with an implanted cardioverter-defibrillator (ICD) and a confirmed diagnosis of ACM according to the proposed Padua Criteria, who were...
• Evidence snippets:
• Snippet 1 (score: 0.578) > This review on Arrhythmogenic Cardiomyopathy (ACM) focuses on its diagnostic challenges, on the debated role of risk-stratification of sudden cardiac death, and reports the outcome of ICD treatment for sudden death prevention in all cardiac phenotypes. ACM is a general term that encompasses a group of diseases different amongst themselves depending on type of pathologic involvement of the heart, aetiology, and genetics. While it is rationale to assign a specific nosographic classification to entities having a homogeneous genetic background (mutations of the same gene/group of genes) resulting in a common clinical phenotype (Figs. 1,2), it is much more clinically challenging to classify a disease whose phenotypic appearance is the outcome of several unlinked genetic diseases with different pathogenic mechanisms. Even more difficult is disease classification when different mutations of the same gene are disease-causative in the same organ with differ-ent phenotypes (hypertrophic vs arrhythmogenic disease). Debate as to whether a genomic-based classification of diseases or a clinical phenotype-based one is more appropriate is ongoing. We focus on ACM phenotype expressed as right ventricular, biventricular, and left ventricular involvement of the heart caused by progressive replacement of the myocardium by fibrotic or fibro-fatty tissue, which acts as an arrhythmogenic substrate predisposing to lifethreatening ventricular arrhythmias and heart failure due to systolic ventricular dysfunction, caused by inherited genetic abnormalities. The earliest clinical manifestations of these diseases are ventricular arrhythmias, typically occurring between the third and the fourth decade, though they represent a relevant cause of sudden death in adolescents, especially in the physically active and in high-level athletes [1]. Sudden cardiac death (SCD) can be the first manifestation in a minority of patients, thereby heightening medical attention in the event ventricular arrhythmias are detected in otherwise healthy and young individuals.

[12] Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families

• Authors: E. Marchionni, Sonia Lomuscio, A. Latini, M. Murdocca, F. Romeo et al.
• Year: 2025
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/afff57f85745a4204acf47c04f8d5948b7866657
• DOI: 10.3390/genes16040419
• PMID: 40282378
• PMCID: 12027432
• Summary: The clinical onset of ACM can be Sudden Cardiac Death, and hence, it is recommended to perform a segregation test on first-degree relatives of pathogenic variant carriers, even if they are asymptomatic, with the purpose of promptly detecting those at risk.
• Evidence snippets:
• Snippet 1 (score: 0.573) > Arrhythmogenic Cardiomyopathy (ACM, MIM 609040) is a genetic disease characterized by incomplete penetrance and a wide variable expressivity. In most cases, it is caused by pathogenic variants in genes encoding for desmosomal proteins, which are involved in cardiomyocyte adhesion [1]. Among the desmosomal genes, Plakophilin-2 (PKP2, MIM 602861) is the most frequently associated with ACM [2]. Reduced expression of desmosomal proteins has been shown to induce cardiac dysfunction [3]. This is attributable to a progressive weakening of cell-to-cell junctions leading to fibrotic remodeling areas, due to a decrease in mechanical traction tolerance [4]. > The consequential cardiomyocyte apoptosis results in an uneven slowing of signal propagation, which implies the development of arrhythmias in affected patients. This explains why ACM is associated with a high risk of Sudden Cardiac Death (SCD), especially when PKP2 mutation carriers have not undergone appropriate cardiological follow-up [5]. > Clinical diagnosis of ACM is based on evaluating signs and symptoms, imaging, histological characterization, and electrocardiographic features. It is also important to obtain medical information about patients' pedigrees, as approximately 30% to 50% of those affected have a positive family history [6]. > According to the 2010 Revised Task Force Criteria for the Diagnosis of Arrhythmogenic Cardiomyopathy (formerly known as Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia), all the clinical features detected through the cardiological assessment can be sorted into six different categories, each consisting of major and minor criteria: > Morphofunctional Alterations (right ventricular (RV) dilatation or wall motion bnormalities); 2. > Myocardium Histology (fibro-adipose replacement); 3. > Repolarization Abnormalities (inverted T waves in right precordial leads); 4. > Depolarization/Conduction Abnormalities (ε waves in the right precordial leads, prolonged QRS duration); 5.

[13] The genetic background of arrhythmogenic right ventricular cardiomyopathy

• Authors: S. Ohno
• Year: 2016
• Venue: Journal of Arrhythmia
• URL: https://www.semanticscholar.org/paper/913fda12a4950f207552feb583a7d267a58e34a5
• DOI: 10.1016/j.joa.2016.01.006
• PMID: 27761164
• PMCID: 5063271
• Citations: 76
• Influential citations: 8
• Summary: The clinical issues of ARVC from the genetic background are discussed and many studies have reported clinical manifestations of, prognosis for, and appropriate therapies for AR VC from the perspective of gene mutations.
• Evidence snippets:
• Snippet 1 (score: 0.564) > Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by degeneration of the right ventricle and ventricular tachycardia originating from the right ventricle. Additionally, the disease is an inherited cardiomyopathy that mainly follows the autosomal dominant pattern. More than 10 genes have been reported as causative genes for ARVC, and more than half of ARVC patients carry mutations in desmosome related genes. The desmosome is one of the structures involved in cell adhesion and its disruption leads to various diseases, including a skin disease called pemphigus. Among desmosome genes, mutations in PKP2 are most frequently identified in ARVC patients. Although the genotype–phenotype correlations remain to be fully studied, many studies have reported clinical manifestations of, prognosis for, and appropriate therapies for ARVC from the perspective of gene mutations. A collective review of these reports would enhance the understanding of ARVC pathogenesis and clinical manifestation. This review discusses the clinical issues of ARVC from the genetic background.

[14] Using Zebrafish Animal Model to Study the Genetic Underpinning and Mechanism of Arrhythmogenic Cardiomyopathy

• Authors: Yujuan Niu, Yuanchao Sun, Yuting Liu, Ke Du, Xiaolei Xu et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/1ea7360cab3224c8bbe08bf376ceb2f4c216ca49
• DOI: 10.3390/ijms24044106
• PMID: 36835518
• PMCID: 9966228
• Citations: 5
• Summary: Arrhythmogenic cardiomyopathy (ACM) is largely an autosomal dominant genetic disorder manifesting fibrofatty infiltration and ventricular arrhythmia with predominantly right ventricular involvement. ACM is one of the major conditions associated with an increased risk of sudden cardiac death, most notably in young individuals and athletes. ACM has strong genetic determinants, and genetic variants in more than 25 genes have been identified to be associated with ACM, accounting for approximately...
• Evidence snippets:
• Snippet 1 (score: 0.562) > Arrhythmogenic cardiomyopathy (ACM) is an updated term for the heart muscle disorder originally known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), manifesting as malignant ventricular arrhythmias and fibrofatty infiltration in the myocardium of both ventricles, with right ventricular involvement being more common. Depending on the patient cohorts studied, the prevalence of ACM is estimated to be 1 case per 2000 to 5000 individuals in the general population [1]. While recognized as a rare form of cardiac disease, ACM with sustained ventricular arrhythmia represents a major risk condition, causing a significant proportion of sudden cardiac deaths, especially in young individuals and athletes [2,3]. > In the 2000s, through pedigree linkage analysis, homozygous truncating mutations in the junction plakoglobin (JUP) and desmoplakin (DSP) genes were identified in parallel to cause ACM that overlaps with cardio-cutaneous syndromes, representing the first two genetic studies to recognize ACM as an inheritable type of cardiomyopathy [4,5]. Since then, over the past almost two decades, mostly through the combined approaches of familial genetic linkage and candidate gene sequencing, numerous pathogenic variants in more than 25 genes have been identified to cause ACM, accounting for up to 60% of ACM cases [6][7][8][9]. These findings underscore the strong genetic determinant of ACM. However, the genotype-phenotype relationship in ACM patients remains complex; even for ACM cases harboring the same identified gene mutations, disease onset and disease severity can manifest with highly variable expressivity, likely due to the contributions of other comorbidities combined with different genetic background and environmental factors [10,11]. In addition, for patients with known genetic causes, the molecular mechanisms underlying their ACM disease progression remain poorly understood. Currently, clinical management of ACM patients mainly focuses on the general control of heart failure and the prevention of arrhythmic sudden cardiac death (SCD) [12].

[15] Contemporary genetic testing in inherited cardiac disease: tools, ethical issues, and clinical applications

• Authors: F. Girolami, G. Frisso, M. Benelli, L. Crotti, M. Iascone et al.
• Year: 2017
• Venue: Journal of Cardiovascular Medicine (Hagerstown, Md.)
• URL: https://www.semanticscholar.org/paper/1685069e7fbb47642dbd475d1b5cca90133ea1c6
• DOI: 10.2459/JCM.0000000000000589
• PMID: 29176389
• PMCID: 5732648
• Citations: 50
• Influential citations: 1
• Summary: This document reflects the multidisciplinary, ‘real-world’ experience required when implementing genetic testing in cardiomyopathies and arrhythmic syndromes, along the recommendations of various guidelines.
• Evidence snippets:
• Snippet 1 (score: 0.562) > Inherited cardiac diseases comprise a wide and heterogeneous spectrum of diseases of the heart, including the cardiomyopathies and the arrhythmic diseases in structurally normal hearts, that is, channelopathies. 1 With a combined estimated prevalence of 3% in the general population, 1 these conditions represent a relevant epidemiological entity worldwide, and are a major cause of cardiac morbidity and mortality in the young. The extraordinary progress achieved in molecular genetics over the last three decades has unveiled the complex molecular basis of many familial cardiac conditions, paving the way for routine use of gene testing in clinical practice. According to the European Society of Cardiology classification, cardiomyopathies are divided into dilated cardiomyopathy (DCM), hypertrophic (HCM), arrhythmogenic right ventricular (ARVC), restrictive and unclassified, although in practice there may be extensive overlap between these phenotypes. 2 The hypokinetic nondilated cardiomyopathy has been recently added to the prior major phenotypes. 3 The American Heart Association advanced a gene-based classification 4 so that HCM was viewed as a disease of the sarcomere 5 and ARVC as a disease of intercellular junctions, caused by mutations in genes encoding desmosomal proteins. 6,7 The genetics of familial DCM is far more heterogeneous: currently, DCM mutations have been described in genes encoding cytoskeletal, sarcomeric, desmosomal, nucleoskeletal, mitochondrial, and calcium handling proteins. 8 Additionally, sarcomere mutations have been identified in association with more complex disorders of cardiac structure and function, including restrictive physiology and left ventricular noncompaction. 4 In the same manner, ARVC e DCM phenotypes can be a different expression of variants in the same genes (Lamin A, Filamin C, and desmosomal genes). 7 Channelopathies, generally caused by mutations in proteins constituting or regulating cardiac ion channels, include the long-Q waves and T waves (QT) syndrome (LQTS), the short-QT syndrome (SQTS), Brugada syndrome (BrS), and

[16] Experimental models of spontaneous ventricular arrhythmias and of sudden cardiac death.

• Authors: M. Štengl
• Year: 2010
• Venue: Physiological research
• URL: https://www.semanticscholar.org/paper/2d6baf492e82162573b5c2be03a82a8d95b314fd
• DOI: 10.33549/PHYSIOLRES.932001
• PMID: 20626217
• Citations: 23
• Summary: In this review, a number of experimental animal models with high incidence of sudden cardiac death were developed and are intensively studied to get new insights into theudden cardiac death mechanisms.
• Evidence snippets:
• Snippet 1 (score: 0.560) > Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac disease associated with substantial cardiovascular morbidity and sudden death in young people (Thiene et al. 1988). Causative mutations were identified in genes encoding desmosomal proteins (Basso et al. 2009). A spontaneous, genetically transmitted model of arrhythmogenic right ventricular cardiomyopathy, closely resembling the human disease, was described in boxer dogs (Basso et al. 2004). Clinical events included sudden death, ventricular arrhythmias of suspected right ventricular origin, syncope and heart failure. Severe right ventricular myocyte loss with replacement by fatty or fibrofatty tissue was present. The cardiomyopathy in the model was shown to be associated with a substantial loss of gap junction plaques as well as with remodeling of other intercalated disc structures (Oxford et al. 2007). Calstabin2 deficiency associated with a significantly increased open probability of single sarcoplasmic reticulum release channels was also identified and suggested as a potential mechanism for calcium leak-induced ventricular arrhythmias in these dogs (Oyama et al. 2008).

[17] Extracellular vesicles in cardiomyopathies: A narrative review

• Authors: A. Rizzuto, A. Faggiano, C. Macchi, S. Carugo, C. Perrino et al.
• Year: 2023
• Venue: Heliyon
• URL: https://www.semanticscholar.org/paper/d9f9d3f5e11a4f42af7d1ead3cff3c874fff64a4
• DOI: 10.1016/j.heliyon.2023.e23765
• PMID: 38192847
• PMCID: 10772622
• Citations: 5
• Influential citations: 1
• Summary: The aims of this narrative review are to elucidate the potential role of EVs in the paracrine cell-to-cell communication among cardiac tissue compartments, in aiding the diagnosis of the diverse subtypes of cardiomyopathies in a minimally invasive manner, and to address whether certain molecular and phenotypical characteristics of EVs may correlate with cardiomyopathy disease phenotype and severity.
• Evidence snippets:
• Snippet 1 (score: 0.559) > Cardiomyopathies refer to myocardial disorders affecting the heart muscle, in which structural and functional abnormalities are observed, in the absence of diseases such as coronary artery disease, hypertension, valvular disease, or congenital heart disease that could account for the observed abnormalities. According to the 2023 European Society of Cardiology (ESC) guidelines for the management of cardiomyopathies, morphological traits (ventricular hypertrophy: left and/or right; ventricular dilation: left and/or right; non-ischemic ventricular scar) and functional characteristics (global and/or regional ventricular systolic and/or diastolic dysfunction) are clinically employed to categorize five distinct cardiomyopathy phenotypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). Furthermore, the guidelines also specify the existence of syndromic and metabolic cardiomyopathies, including Anderson-Fabry disease, RASopathies, Friedreich ataxia, and Glycogen storage disorders [4]. > Whilst this phenotypic description is essential in paving the diagnostic and therapeutic pathway, the exact evolving nature of cardiomyopathies, along with their underlying aetiological complexities, are yet to be fully elucidated [5]. Within this context, biomarkers represent putative tools for identifying high-risk patients in a prompt manner, unveiling potential risk associations with disease progression and outcomes, and may also provide insights on unexplored molecular mechanisms at the basis of the pathophysiology of these disorders. > Thus, the aim of the present narrative review is to summarize the current knowledge on EVs in the setting of cardiomyopathies and to elucidate whether certain molecular and phenotypical characteristics of EVs (e.g., miRNA content) may correlate with cardiomyopathy phenotypes and severity.

[18] Familial Arrhythmogenic Cardiomyopathy: Clinical Determinants of Phenotype Discordance and the Impact of Endurance Sports

• Authors: S. Costa, A. Gasperetti, A. Medeiros-Domingo, D. Akdis, C. Brunckhorst et al.
• Year: 2020
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/cfa322e3e3e111e155b2634afedc42ee1aa5c0bc
• DOI: 10.3390/jcm9113781
• PMID: 33238575
• PMCID: 7700696
• Citations: 11
• Summary: Different phenotypic expression profiles of ACM are analyzed in the context of the same familial genetic mutation by studying nine adult cases from four different families with four different familial variants from the Swiss Arrhythmogenic Right Ventricular Cardiomyopathy Registry.
• Evidence snippets:
• Snippet 1 (score: 0.558) > Arrhythmogenic cardiomyopathy (ACM) is primarily a familial disease with autosomal dominant inheritance. Incomplete penetrance and variable expression are common, resulting in diverse clinical manifestations. Although recent studies on genotype–phenotype relationships have improved our understanding of the molecular mechanisms leading to the expression of the full-blown disease, the underlying genetic substrate and the clinical course of asymptomatic or oligo-symptomatic mutation carriers are still poorly understood. We aimed to analyze different phenotypic expression profiles of ACM in the context of the same familial genetic mutation by studying nine adult cases from four different families with four different familial variants (two plakophilin-2 and two desmoglein-2) from the Swiss Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Registry. The affected individuals with the same genetic variants presented with highly variable phenotypes ranging from no disease or a classical, right-sided disease, to ACM with biventricular presentation. Moreover, some patients developed early-onset, electrically unstable disease whereas others with the same genetic variants presented with late-onset electrically stable disease. Despite differences in age, gender, underlying genotype, and other clinical characteristics, physical exercise has been observed as the common denominator in provoking an arrhythmic phenotype in these families.

[19] Altered Electrical, Biomolecular, and Immunologic Phenotypes in a Novel Patient-Derived Stem Cell Model of Desmoglein-2 Mutant ARVC

• Authors: Robert N Hawthorne, A. Blazeski, Justin Lowenthal, Suraj Kannan, R. Teuben et al.
• Year: 2021
• Venue: Journal of Clinical Medicine
• URL: https://www.semanticscholar.org/paper/6da345fa7e27ceec663bb0cbe8949a5e52f4f9a7
• DOI: 10.3390/jcm10143061
• PMID: 34300226
• PMCID: 8306340
• Citations: 36
• Influential citations: 1
• Summary: A novel human induced pluripotent stem cell-derived cardiomyocyte model of ARVC from a patient with a c.2358delA variant in desmoglein-2 (DSG2) found DSG2Mut hiPSC-CMs could underlie early mechanisms of disease manifestation in ARVC patients.
• Evidence snippets:
• Snippet 1 (score: 0.555) > Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited, progressive arrhythmogenic cardiomyopathy (ACM) characterized by cardiomyocyte death and fibrofatty scarring in the ventricular myocardium. Clinically, patients with ARVC develop ventricular arrhythmias which often present more frequently as the disease progresses. > ARVC is estimated to account for more than 10% of all cardiovascular deaths in patients younger than 65 years old and is a leading cause of sudden cardiac death (SCD) in young athletes [1][2][3]. ARVC prevalence is approximately 1:1000-1:5000, and patients are typically diagnosed in young adulthood; diagnosis before puberty is extremely rare [4][5][6]. > While the pathophysiology underlying ARVC is still poorly understood, there has been general scientific consensus that the common final pathway of the disease involves the disruption of the cardiac desmosome, a cellular structure present at the intercalated disc that is critical for intercellular mechanical and electrical coupling between cardiomyocytes [7,8]. Pathogenic variants in any of the five cardiac desmosomal genes -plakoglobin (JUP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmoplakin (DSP) and desmocollin-2 (DSC2)-account for more than 60% of inherited ARVC and have a combined estimated prevalence of approximately 1.2 per 1000 in the general population [9]. Among these, PKP2 and DSG2 are the first and second most common variants, respectively [6,10]. > Determining the pathogenic mechanisms underlying ARVC has proven difficult. The study of human tissue is challenging, as ARVC is frequently diagnosed in later stages of disease (e.g., myocardial scarring) when retrieval of a myocardial biopsy presents significant risk of cardiac perforation.

[20] Misdiagnosed myocarditis in arrhythmogenic cardiomyopathy induced by a homozygous variant of DSG2: a case report

• Authors: Xuwei Liu, Y. Zhang, Wen‐Jing Li, Qian Zhang, Lei Zhou et al.
• Year: 2023
• Venue: Frontiers in Cardiovascular Medicine
• URL: https://www.semanticscholar.org/paper/1236e1d0916ff4dccfecafe269c149a1847b4987
• DOI: 10.3389/fcvm.2023.1150657
• PMID: 37288269
• PMCID: 10242036
• Citations: 5
• Summary: A rare pediatric case initially presenting as myocarditis that transitioned into ACM during follow-up is reported, expanding the clinical feature spectrum of DSG2-associated ACM at an early age.
• Evidence snippets:
• Snippet 1 (score: 0.553) > Misdiagnosed myocarditis in arrhythmogenic cardiomyopathy induced by a homozygous variant of DSG2: a case report 1. Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC, OMIM:#610476) is an inherited heart muscle disease characterized by the loss of the ventricular myocardium and fibrofatty replacement, which predisposes patients to fatal ventricular arrhythmias and sudden cardiac death (SCD) (1,2). A genetic etiology has been identified for most inherited cardiovascular diseases, especially cardiomyopathies, with the rapid development of sequencing techniques. Regarding the molecular mechanism, ARVC has been identified as being related to pathogenetic variants in desmosomes and adherens junctions, which are critical for establishing cell-cell junctions and maintaining intercellular communication (3,4). Thus, the disease group ACM should be considered to define the broader spectrum of the phenotypic expressions of the disease (4). From a molecular perspective, multiple genes encoding desmosomal proteins, such as plakophilin-2 (PKP2), desmoplakin (DSP), DSG2, desmocollin (DSC2), and plakoglobin (JUP), account for 50% of patients with ACM in different cohorts (5,6). However, there are other genetic (non-desmosomal) and non-genetic causes of the disease. The non-desmosomal genes include DES, LMNA, SCN5A, PLN, TMEM43, and TGFB3, which are not involved in the molecular formation of desmosomes and participate in several types of ARVC origins (2). The inclusion of sarcomere-, ion transporter-, and cytokine-related genes would increase the percentage of patients positive for molecular characterization. However, the incomplete dominance and variable expressiveness of certain variants suggest that environmental factors play an important role. Initially, ARVC was considered to mainly cause right ventricular lesions and impair the function of the right ventricle.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.