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: pathogenesis, pro-arrhythmic remodelling, and novel approaches for risk stratification and therapy

2020 ◽  
Vol 116 (9) ◽  
pp. 1571-1584 ◽  
Author(s):  
Stephanie M van der Voorn ◽  
Anneline S J M te Riele ◽  
Cristina Basso ◽  
Hugh Calkins ◽  
Carol Ann Remme ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Disease Course ◽  
Arrhythmogenic Cardiomyopathy ◽  
Intercalated Disc ◽  
Disease Mechanisms ◽  
Life Threatening ◽  
Fibrofatty Tissue ◽  
New Biomarkers ◽  
Novel Therapeutic Strategies ◽  
Apparently Healthy

Abstract Arrhythmogenic cardiomyopathy (ACM) is a life-threatening cardiac disease caused by mutations in genes predominantly encoding for desmosomal proteins that lead to alterations in the molecular composition of the intercalated disc. ACM is characterized by progressive replacement of cardiomyocytes by fibrofatty tissue, ventricular dilatation, cardiac dysfunction, and heart failure but mostly dominated by the occurrence of life-threatening arrhythmias and sudden cardiac death (SCD). As SCD appears mostly in apparently healthy young individuals, there is a demand for better risk stratification of suspected ACM mutation carriers. Moreover, disease severity, progression, and outcome are highly variable in patients with ACM. In this review, we discuss the aetiology of ACM with a focus on pro-arrhythmic disease mechanisms in the early concealed phase of the disease. We summarize potential new biomarkers which might be useful for risk stratification and prediction of disease course. Finally, we explore novel therapeutic strategies to prevent arrhythmias and SCD in the early stages of ACM.

1175Structural progression increases the risk of ventricular arrhythmias in patients with arrhythmogenic cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Chivulescu ◽  
Ø.H Lie ◽  
H Skulstad ◽  
B A Popescu ◽  
R O Jurcut ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ventricular Arrhythmias ◽  
Arrhythmogenic Cardiomyopathy ◽  
Cardioverter Defibrillator ◽  
Structural Progression ◽  
Life Threatening ◽  
Arrhythmic Event ◽  
History Of ◽  
Structural Disease

Abstract Background Arrhythmogenic cardiomyopathy (AC) is an inheritable cardiomyopathy with incomplete penetrance, variable phenotype severity and poorly described disease progression. It is characterized by high risk of life-threatening ventricular arrhythmias and sudden cardiac death in young individuals. Risk stratification and selection of patients presenting without history of life-threatening arrhythmic events for cardioverter-defibrillator implantation in primary prevention remains challenging. Purpose We aimed to assess the impact of disease progression on arrhythmic outcomes in AC patients. Methods We included consecutive AC probands and mutation-positive family members with at least one complete follow-up evaluation. Echocardiographic and electrical parameters were defined according to the 2010 Revised Task Force criteria at inclusion and at last follow-up. Structural progression was defined as development of new echocardiographic diagnostic criteria. Electrical progression was defined as the development of new diagnostic depolarization, repolarization and/or premature ventricular complex count criteria during follow-up. Non-sustained ventricular tachycardia or ventricular tachycardia occurring during follow-up defined incident ventricular arrhythmic events. Results We included a total of 144 patients (48% female, 47% probands, 40±16 years old). At inclusion, 54 patients (37%) had a history of arrhythmic events, 30 patients (21%) had overt structural disease and 114 (79%) had no or minor structural disease. During 7.0 (IQR: 4.5 to 9.4) years of follow-up, 49 patients (43%) with no or minor structural disease at inclusion developed new structural criteria being defined as progressors. Among 80 participants with no or minor structural disease and no arrhythmic history at inclusion, a first arrhythmic event occurred in 14 (17%). The incidence of arrhythmic events was higher in progressors (11/27, 41%) than in non-progressors (3/53, 6%) (p<0.001) (Figure). Structural progression was associated with higher risk of first arrhythmic events during follow-up when adjusted for sex, age at inclusion and follow-up duration, independent of electrical progression (7.6, 95% CI [1.5, 37.2], P=0.01). Incident arrhythmic events distribution Conclusion Almost half of patients without overt structural cardiac disease at genetic diagnosis develop new structural criteria during 7 years follow-up and 17% experienced their first ventricular arrhythmic event. Structural progression was independently associated with ventricular arrhythmic events during follow-up. These findings highlight the increased risk of arrhythmias when structural abnormalities are detected. Their finding may initiate the evaluation for primary prevention cardioverter-defibrillator implantation.

scholarly journals Autophagy Intertwines with Different Diseases—Recent Strategies for Therapeutic Approaches

Diseases ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 15 ◽  
Author(s):  
Janani Ramesh ◽  
Larance Ronsard ◽  
Anthony Gao ◽  
Bhuvarahamurthy Venugopal
Keyword(s):  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Open Reading Frames ◽  
Signaling Cascades ◽  
Progression Rate ◽  
Therapeutic Approaches ◽  
Genes Encoding ◽  
Novel Therapeutic Strategies ◽  
Reading Frames

Autophagy is a regular and substantial “clear-out process” that occurs within the cell and that gets rid of debris that accumulates in membrane-enclosed vacuoles by using enzyme-rich lysosomes, which are filled with acids that degrade the contents of the vacuoles. This machinery is well-connected with many prevalent diseases, including cancer, HIV, and Parkinson’s disease. Considering that autophagy is well-known for its significant connections with a number of well-known fatal diseases, a thorough knowledge of the current findings in the field is essential in developing therapies to control the progression rate of diseases. Thus, this review summarizes the critical events comprising autophagy in the cellular system and the significance of its key molecules in manifesting this pathway in various diseases for down- or upregulation. We collectively reviewed the role of autophagy in various diseases, mainly neurodegenerative diseases, cancer, inflammatory diseases, and renal disorders. Here, some collective reports on autophagy showed that this process might serve as a dual performer: either protector or contributor to certain diseases. The aim of this review is to help researchers to understand the role of autophagy-regulating genes encoding functional open reading frames (ORFs) and its connection with diseases, which will eventually drive better understanding of both the progression and suppression of different diseases at various stages. This review also focuses on certain novel therapeutic strategies which have been published in the recent years based on targeting autophagy key proteins and its interconnecting signaling cascades.

scholarly journals Epidermolysis Bullosa-Associated Squamous Cell Carcinoma: From Pathogenesis to Therapeutic Perspectives

2019 ◽  
Vol 20 (22) ◽  
pp. 5707 ◽  
Author(s):  
Angelo Giuseppe Condorelli ◽  
Elena Dellambra ◽  
Elena Logli ◽  
Giovanna Zambruno ◽  
Daniele Castiglia
Keyword(s):  
Squamous Cell ◽  
Epidermolysis Bullosa ◽  
Genetic Determinants ◽  
Therapeutic Approaches ◽  
Molecular Events ◽  
Genes Encoding ◽  
Skin Fragility ◽  
Serious Disease ◽  
Almost All

Epidermolysis bullosa (EB) is a heterogeneous group of inherited skin disorders determined by mutations in genes encoding for structural components of the cutaneous basement membrane zone. Disease hallmarks are skin fragility and unremitting blistering. The most disabling EB (sub)types show defective wound healing, fibrosis and inflammation at lesional skin. These features expose patients to serious disease complications, including the development of cutaneous squamous cell carcinomas (SCCs). Almost all subjects affected with the severe recessive dystrophic EB (RDEB) subtype suffer from early and extremely aggressive SCCs (RDEB-SCC), which represent the first cause of death in these patients. The genetic determinants of RDEB-SCC do not exhaustively explain its unique behavior as compared to low-risk, ultraviolet-induced SCCs in the general population. On the other hand, a growing body of evidence points to the key role of tumor microenvironment in initiation, progression and spreading of RDEB-SCC, as well as of other, less-investigated, EB-related SCCs (EB-SCCs). Here, we discuss the recent advances in understanding the complex series of molecular events (i.e., fibrotic, inflammatory, and immune processes) contributing to SCC development in EB patients, cross-compare tumor features in the different EB subtypes and report the most promising therapeutic approaches to counteract or delay EB-SCCs.

scholarly journals The role of antioxidant system genes in the formation of coronary heart disease clinical phenotypes

2013 ◽  
Vol 94 (2) ◽  
pp. 228-234
Author(s):  
A A Podolskaya ◽  
A S Galyavich ◽  
E V Maikova ◽  
O A Kravtsova ◽  
F K Alimova
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Antioxidant System ◽  
Genetic Defect ◽  
Disease Onset ◽  
Phenotypic Expression ◽  
Current Data ◽  
Pathogenic Factors ◽  
Genes Encoding

Genetic predisposition alongside with environmental factors play a major role in the pathogenesis of coronary heart disease, causing the deregulation of various biochemical processes leading to the disease onset. Antioxidant system deregulation, marked mainly by lipid peroxidation products and a number of enzymes, is known to be one of the risk factors for coronary heart disease. A genetic defect might lead to a change in enzyme activity and inhibition of antioxidant protection. However, the pathogenic factors and antioxidant system deregulation mechanisms in different clinical courses of coronary heart disease are not studied enough as phenotypic expression of genetic polymorphism is largely dependent on the gene pool and the living conditions of a particular population, explaining the controversial data on the association of polymorphisms candidate genes with the risk of coronary heart disease. Currently, the role of genes encoding antioxidant system enzymes in predisposition to coronary heart disease development is not sufficiently studied, and research results are contradictory. The review summarizes the current data on the antioxidant system genes (superoxide dismutase enzymes, glutathione peroxidase and catalase) genetic polymorphisms association with the risk of coronary heart disease (as an acute myocardial infarction, angina рectoris).

scholarly journals Novel Therapeutic Approaches to Familial HLH (Emapalumab in FHL)

2020 ◽  
Vol 11 ◽  
Author(s):  
Pietro Merli ◽  
Mattia Algeri ◽  
Stefania Gaspari ◽  
Franco Locatelli
Keyword(s):  
Progressive Disease ◽  
Interferon Γ ◽  
Line Treatment ◽  
Therapeutic Approaches ◽  
Front Line ◽  
Hematopoietic Stem ◽  
Fda Approval ◽  
Neutralizing Monoclonal Antibody ◽  
Life Threatening

Primary Hemophagocytic lymphohistiocytosis (pHLH) is a rare, life-threatening, hyperinflammatory disorder, characterized by uncontrolled activation of the immune system. Mutations affecting several genes coding for proteins involved in the cytotoxicity machinery of both natural killer (NK) and T cells have been found to be responsible for the development of pHLH. So far, front-line treatment, established on the results of large international trials, is based on the use of glucocorticoids, etoposide ± cyclosporine, followed by allogeneic hematopoietic stem cell transplantation (HSCT), the sole curative treatment for the genetic forms of the disease. However, despite major efforts to improve the outcome of pHLH, many patients still experience unfavorable outcomes, as well as severe toxicities; moreover, treatment-refractory or relapsing disease is a major challenge for pediatricians/hematologists. In this article, we review the epidemiology, etiology and pathophysiology of pHLH, with a particular focus on different cytokines at the origin of the disease. The central role of interferon-γ (IFNγ) in the development and maintenance of hyperinflammation is analyzed. The value of emapalumab, a novel IFNγ-neutralizing monoclonal antibody is discussed. Available data support the use of emapalumab for treatment of pHLH patients with refractory, recurrent or progressive disease, or intolerance to conventional therapy, recently, leading to FDA approval of the drug for these indications. Additional data are needed to define the role of emapalumab in front-line treatment or in combination with other drugs.

Role of Delayed Rectifier Potassium Channels in Cardiac Repolarization and Arrhythmias

Physiology ◽  
1997 ◽  
Vol 12 (4) ◽  
pp. 152-157 ◽  
Author(s):  
MC Sanguinetti ◽  
MT Keating
Keyword(s):  
Potassium Channels ◽  
Action Potentials ◽  
Ventricular Arrhythmias ◽  
Gene Mutations ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Cardiac Action ◽  
Life Threatening ◽  
Slow Onset

Cardiac action potentials are long because the magnitude of some potassium currents is reduced at depolarized potentials. The slow onset of repolarization is initiated by the opening of delayed rectifier potassium channels. A decrease in function of these channels resulting from gene mutations or pharmacological block increases risk of life-threatening ventricular arrhythmias.

scholarly journals Role of Exercise as a Modulating Factor in Arrhythmogenic Cardiomyopathy

2021 ◽  
Vol 23 (6) ◽  
Author(s):  
Alessandro Zorzi ◽  
Alberto Cipriani ◽  
Riccardo Bariani ◽  
Kalliopi Pilichou ◽  
Domenico Corrado ◽  
...  
Keyword(s):  
Physical Activity ◽  
Gene Mutation ◽  
Ventricular Arrhythmias ◽  
Muscle Disease ◽  
Moderate Intensity ◽  
Moderate Physical Activity ◽  
Fatty Tissue ◽  
Arrhythmogenic Cardiomyopathy ◽  
Mutation Carriers

Abstract Purpose of Review The review addresses the role of exercise in triggering ventricular arrhythmias and promoting disease progression in arrhythmogenic cardiomyopathy (AC) patients and gene-mutation carriers, the differential diagnosis between AC and athlete’s heart and current recommendations on exercise activity in AC. Recent Findings AC is an inherited heart muscle disease caused by genetically defective cell-to-cell adhesion structures (mainly desmosomes). The pathophysiological hallmark of the disease is progressive myocyte loss and replacement by fibro-fatty tissue, which creates the substrates for ventricular arrhythmias. Animal and human studies demonstrated that intense exercise, but not moderate physical activity, may increase disease penetrance, worsen the phenotype, and favor life-threatening ventricular arrhythmias. It has been proposed that in some individuals prolonged endurance sports activity may in itself cause AC (so-called exercise-induced AC). Summary The studies agree that intense physical activity should be avoided in patients with AC and healthy gene-mutation carriers. However, low-to-moderate intensity exercise does not appear detrimental and these patients should not be entirely deprived from the many health benefits of physical activity.

scholarly journals Edaravone May Prevent Ferroptosis in ALS

2020 ◽  
Vol 21 (8) ◽  
pp. 776-780 ◽  
Author(s):  
Snežana Spasić ◽  
Aleksandra Nikolić-Kokić ◽  
Srđan Miletić ◽  
Zorana Oreščanin-Dušić ◽  
Mihajlo B. Spasić ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Disease Onset ◽  
Cell Types ◽  
Therapeutic Approaches ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Multiple Cell ◽  
New Treatment ◽  
Lateral Sclerosis

Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.

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