scholarly journals Update on Genes Associated with Arrhythmogenic Cardiomyopathy

2020 ◽  
Author(s):  
Marta Vallverdú-Prats ◽  
Mireia Alcalde ◽  
Georgia Sarquella-Brugada ◽  
Sergi Cesar ◽  
Elena Arbelo ◽  
...  
Keyword(s):  
Rare Variants ◽  
Correct Diagnosis ◽  
Phenotypic Expression ◽  
Genetic Alterations ◽  
Left Ventricular ◽  
Incomplete Penetrance ◽  
Arrhythmogenic Cardiomyopathy ◽  
Young Males ◽  
Genes Encoding ◽  
The Right

Arrhythmogenic cardiomyopathy is a rare genetic entity characterized by progressive fibro-fatty replacement of myocardium leading to malignant arrhythmias, syncope, and sudden cardiac death. Mostly it affects the right ventricle, but cases have also been described with biventricular and even isolated left ventricular involvement. The disease affects mainly young males and arrhythmias are usually induced by exercise. Arrhythmogenic cardiomyopathy has a genetic origin and is basically caused by deleterious alterations in genes encoding desmosomal proteins, especially plakophilin-2. To date, more than 400 rare genetic alterations have been identified in 18 genes, mainly with autosomal dominant inheritance, but some recessive forms have also been reported (Naxos disease and Carvajal syndrome). A comprehensive genetic analysis identifies a rare variant as potential cause of the disease in around 60% of patients, suggesting the existence of unknown genes as well as other genome alterations not yet discovered. Genetic interpretation classifies some of these rare variants as ambiguous, playing an uncertain role in arrhythmogenic cardiomyopathy. This makes a proper translation of genetic data into clinical practice difficult. Moreover, incomplete penetrance and variable phenotypic expression makes it difficult to arrive at the correct diagnosis. In the present chapter, we focus on recent advances in the knowledge regarding the genetic basis of arrhythmogenic cardiomyopathy.

Blow/trauma to the chest and sudden cardiac death: Commotio cordis and contusio cordis are leading causes

2018 ◽  
Vol 58 (2) ◽  
pp. 93-96 ◽  
Author(s):  
Lydia Krexi ◽  
Mary N Sheppard
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Traffic Accidents ◽  
Left Ventricular ◽  
Young Males ◽  
Contusio Cordis ◽  
Commotio Cordis ◽  
Forensic Practice ◽  
Acute Changes ◽  
The Right

Background In forensic practice, a blow to the chest can lead to sudden cardiac death (SCD). Commotio cordis and contusio cordis are leading causes. Methods From a database of 4678 patients who suffered from SCD, we found three patients with commotio cordis and two patients with contusio cordis. All the patients were examined macroscopically and microscopically and had negative toxicology screen. Results The three patients who died due to commotio cordis were young males (16, 23 and 38 years old). The circumstances of death were: a blow to the chest by a football, by a friend during a party and during an assault. The hearts were completely normal at autopsy. The two patients who had contusio cordis were older males (42 and 63 years old). Both patients died during traffic accidents. At autopsy, one had significant contusion over the left ventricle, and the second had contusion over the right ventricle. Conclusion This study indicates that a blow to the chest is very important to document in the circumstances of death, and a detailed history is vital. It raises the left ventricular intra-cavitary pressure, leading to commotio cordis with immediate death with a normal heart. Blunt chest trauma can cause direct myocardial lesions, with acute changes leading to contusio cordis.

scholarly journals An Unusual Presentation of a Myocardial Crypt in Hypertrophic Cardiomyopathy

2014 ◽  
Vol 2014 ◽  
pp. 1-3
Author(s):  
Danny A. J. P. van de Sande ◽  
Jan Hoogsteen ◽  
Luc J. H. J. Theunissen
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Interventricular Septum ◽  
Positive Family History ◽  
Phenotypic Expression ◽  
Anterior Wall ◽  
Left Ventricular ◽  
Genes Encoding ◽  
History Of ◽  
Basal Septum ◽  
Myocardial Crypts

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease with prevalence of 0.2% in the population. More than 1000 mutations in more than 10 genes encoding for proteins of the cardiac sarcomere have been identified. Cardiac magnetic resonance imaging (CMR) is used to characterize left ventricular morphology with great precision in patients with HCM and it identifies unique structural abnormalities in patients with HCM. We present a case of a 56-year-old man who had positive family history of HCM who was a carrier of the genetic MYH-7 2770 G > C, exon 23 mutation. Transthoracic echocardiography showed thickening of the interventricular septum (16 mm) and in particular the basal septum. CMR confirmed the diagnosis of HCM in the anteroseptal myocardium with a thickness of 23 mm and also revealed large and deep myocardial crypts in the anterior wall. These myocardial crypts are rarely found in the so-called genotype positive and phenotype positive patients, as in our case. Also the crypts in this case are deeper and wider than those reported in other cases. So in conclusion, this case reveals an uncommon finding of a myocardial crypt at an unusual myocardial site with the unusual morphology in a patient with genotypic and phenotypic expression of hypertrophic cardiomyopathy.

scholarly journals A paradigm shift in the concept of arrhythmogenic cardiomyopathy: expanding the clinical and genetic spectrum, new diagnostic criteria for left ventricular phenotypes

2020 ◽  
Vol 25 (10) ◽  
pp. 3863
Author(s):  
T. G. Vaikhanskaya ◽  
L. N. Sivitskaya ◽  
T. V. Kurushko ◽  
T. V. Rusak ◽  
O. D. Levdansky ◽  
...  
Keyword(s):  
Genetic Diseases ◽  
Diagnostic Algorithm ◽  
Heart Rhythm ◽  
Practical Experience ◽  
Left Ventricular ◽  
High Tech ◽  
Arrhythmogenic Cardiomyopathy ◽  
Multicenter Studies ◽  
Plakophilin 2 ◽  
The Right

Recent multicenter studies using high-tech cardiac imaging and novel translational technologies have shown that cardiac fibrofatty replacement, characteristic of arrhythmogenic cardiomyopathy (ACM), is observed in both ventricles; left ventricular (LV) involvement may be minimal, on par with the right ventricle (RV), or dominant. In 2019, the Heart Rhythm Society (HRS) proposed a new approach to the assessment of arrhythmic and genetic diseases with the inclusion of new phenotypes — left-dominant ACM and biventricular ACM. In 2020, to improve the diagnosis of left ventricular phenotypes, European experts revised ACM criteria (based on the 2010 ITF criteria), which are called the Padua criteria.The presented article highlights the clinical and genetic aspects of the new concept and the difficulties in ACM diagnosis, the practical experience of using new diagnostic algorithm. To help practitioners, step-by-step differential diagnosis and risk stratification of right and left ventricular phenotypes are presented using clinical examples (leftdominant ACM with a pathogenic variant in the LMNA gene; right-dominant ACM associated with a desmoplakin gene mutation, with predominant RV and moderate LV involvement; and an isolated RV ACM associated with a mutation in the plakophilin 2 gene).

scholarly journals Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Carlos Bueno-Beti ◽  
Angeliki Asimaki
Keyword(s):  
Cardiac Myocytes ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Incomplete Penetrance ◽  
Protein Markers ◽  
Cell Coupling ◽  
Arrhythmogenic Cardiomyopathy ◽  
Right Ventricular Free Wall ◽  
Cascade Screening ◽  
Age Related

Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD) especially in young individuals. It is estimated to affect 1:5,000 individuals in the general population, with >60% of patients bearing one or more mutations in genes coding for desmosomal proteins. Desmosomes are intercellular adhesion junctions, which in cardiac myocytes reside within the intercalated disks (IDs), the areas of mechanical and electrical cell-cell coupling. Histologically, ACM is characterized by fibrofatty replacement of cardiac myocytes predominantly in the right ventricular free wall though left ventricular and biventricular forms have also been described. The disease is characterized by age-related progression, vast phenotypic manifestation and incomplete penetrance, making proband diagnosis and risk stratification of family members particularly challenging. Key protein redistribution at the IDs may represent a specific diagnostic marker but its applicability is still limited by the need for a myocardial sample. Specific markers of ACM in surrogate tissues, such as the blood and the buccal epithelium, may represent a non-invasive, safe and inexpensive alternative for diagnosis and cascade screening. In this review, we shall cover the most relevant biomarkers so far reported and discuss their potential impact on the diagnosis, prognosis and management of ACM.

scholarly journals Heritability and Pedigree Analyses of Hypertrophic Cardiomyopathy in Rhesus Macaques (Macaca Mulatta)

2021 ◽  
Vol 8 ◽  
Author(s):  
Yu Ueda ◽  
Samantha Kovacs ◽  
Rachel Reader ◽  
Jeffrey A. Roberts ◽  
Joshua A. Stern
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Rhesus Macaques ◽  
Phenotypic Expression ◽  
Pedigree Analysis ◽  
Left Ventricular ◽  
Incomplete Penetrance ◽  
Recessive Trait ◽  
Primate Research ◽  
Pedigree Data ◽  
Mode Of Inheritance

In a colony of rhesus macaques at California National Primate Research Center (CNPRC), naturally occurring hypertrophic cardiomyopathy (HCM) classified by left ventricular hypertrophy without obvious underlying diseases has been identified during necropsy over the last two decades. A preliminary pedigree analysis suggested a strong genetic predisposition of this disease with a founder effect. However, the mode of inheritance was undetermined due to insufficient pedigree data. Since 2015, antemortem examination using echocardiographic examination as well as other cardiovascular analyses have been performed on large numbers of rhesus macaques at the colony. Based on antemortem examination, HCM was diagnosed in additional 65 rhesus macaques. Using HCM cases diagnosed based on antemortem and postmortem examinations, the heritability (h2) was estimated to determine the degree of genetic and environmental contributions to the development of HCM in rhesus macaques at the CNPRC. The calculated mean and median heritability (h2) of HCM in this colony of rhesus macaques were 0.5 and 0.51 (95% confidence interval; 0.14–0.82), respectively. This suggests genetics influence development of HCM in the colony of rhesus macaques. However, post-translational modifications and environmental factors are also likely to contribute the variability of phenotypic expression. Based on the pedigree analysis, an autosomal recessive trait was suspected, but an autosomal dominant mode of inheritance with incomplete penetrance was also possible. Further investigation with more data from siblings, offspring, and parents of HCM-affected rhesus macaques are warranted. Importantly, the findings of the present study support conducting genetic investigations such as whole genome sequencing to identify the causative variants of inherited HCM in rhesus macaques.

scholarly journals Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features

2021 ◽  
Author(s):  
Alice Ghidoni ◽  
Perry M. Elliott ◽  
Petros Syrris ◽  
Hugh Calkins ◽  
Cynthia A. James ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Features ◽  
Genetic Screening ◽  
Rare Variants ◽  
Family Members ◽  
Arrhythmogenic Cardiomyopathy ◽  
Cascade Screening ◽  
Pathogenic Variants ◽  
Fatty Replacement ◽  
The Right

Background - Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants, in the non-desmosomal cadherin 2 ( CDH2 ), a novel genetic substrate of ACM. Methods - A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2 -positive probands, and clinical evaluation was assessed. Results - Genetic screening of CDH2 led to the identification of 7 rare variants: five, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2 -positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and/or sudden cardiac death occurred in 5/9 (56%). Conclusions - In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2 -ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.

scholarly journals The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?

2020 ◽  
Vol 21 (17) ◽  
pp. 6434
Author(s):  
Maria Bueno Marinas ◽  
Rudy Celeghin ◽  
Marco Cason ◽  
Gaetano Thiene ◽  
Cristina Basso ◽  
...  
Keyword(s):  
Gene Expression Regulation ◽  
Phenotypic Variability ◽  
Incomplete Penetrance ◽  
Primary Role ◽  
Arrhythmogenic Cardiomyopathy ◽  
Small Noncoding Rnas ◽  
Early Disease Detection ◽  
Pathogenic Variants ◽  
Fatty Replacement ◽  
Genes Encoding

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease characterized by a progressive fibro-fatty replacement of the working myocardium and by life-threatening arrhythmias and risk of sudden cardiac death. Pathogenic variants are identified in nearly 50% of affected patients mostly in genes encoding for desmosomal proteins. AC incomplete penetrance and phenotypic variability advocate that other factors than genetics may modulate the disease, such as microRNAs (miRNAs). MiRNAs are small noncoding RNAs with a primary role in gene expression regulation and network of cellular processes. The implication of miRNAs in AC pathogenesis and their role as biomarkers for early disease detection or differential diagnosis has been the objective of multiple studies employing diverse designs and methodologies to detect miRNAs and measure their expression levels. Here we summarize experiments, evidence, and flaws of the different studies and hitherto knowledge of the implication of miRNAs in AC pathogenesis and diagnosis.

scholarly journals 786 A case of end-stage mitochondrial cardiomyopathy undergoing heart and kidney transplantation

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Davide Diana ◽  
Giovanni Diana ◽  
Vincenzo Polizzi ◽  
Fabio Sbaraglia ◽  
Carla Giordano ◽  
...  
Keyword(s):  
Family History ◽  
Right Ventricle ◽  
Systolic Function ◽  
Electrophysiological Study ◽  
Correct Diagnosis ◽  
Accessory Pathway ◽  
Mitochondrial Diseases ◽  
Left Ventricular ◽  
Orthotopic Heart Transplant ◽  
The Right

Abstract Male, 46 year old. Family history: brother affected by deafness and repeated episodes of stroke at a young age. Pathological history: history of competitive sporting activity in which he underwent periodic outpatient checks and reported sporadic myalgic episodes. The patient was suffering from bilateral keratoconus. For the purpose of discovering Wolf–Parkinson–White syndrome with the presence of a right antero-septal accessory pathway, he underwent an electrophysiological study (2003) negative for inducible arrhythmias. During a routine checkup, a renal biopsy was performed to search for elevated blood creatinine, which concluded with acute interstitial nephritis (2005), treated ineffectively with steroids and resulted in dialysis-dependent stage V renal failure (2020). Following light tiredness, he underwent an echocardiographic examination (2009) which revealed the presence of dilated heart disease with reduced left ventricular systolic function. He underwent a cardiac MRI which showed diffuse spots of subepicardial late enhancement as a possible post-myocarditis outcome. At subsequent clinical-echocardiographic checks, progressive biventricular dysfunction, and signs of congestive heart failure were highlighted, for which medical therapy was progressively increased and insertion of an implantable cardioverter defibrillator in primary prevention for sudden cardiac death. At the subsequent clinical re-evaluations, there was evidence of progressive bilateral hearing loss. In consideration of the clinical picture and family history, considering the syndromic nature of the polypathologies to be likely, genetic investigation was required for mitochondrial diseases. Mutations 3242 and 3271mt-RNA and 13513 mtND5, frequent in the MELAS Syndrome, were searched in peripheral venous samples and resulted as negative. In 2020 he underwent an orthotopic heart transplant sec. Shamway followed by a kidney transplant from a compatible donor. In order to perform further diagnostic investigations, the explanted heart was sent to the Pathological Anatomy laboratory of the Umberto I Hospital: macroscopic analysis showed foci of fat replacement at the level of the anterior and posterior wall of the right ventricle (Figure); under microscopy, marked myocardial hypertrophy was observed, associated with cytoplasmic vacuolization of the cardiomyocytes, fibro-adipose substitution of the right ventricle, and replacement fibrosis in minute foci in the left ventricular level. A widespread and marked reduction in the enzymatic activity of cytochrome oxidase in cardiomyocytes and mitochondrial proliferation was demonstrated using histo-enzymatic staining, by staining for succinate dehydrogenase, concluding with mitochondrial disease. Mitochondrial diseases represent a challenge not only from the prognostic–therapeutic point of view but, remarkably, also from a diagnostic one: the patient received a correct diagnosis of the pathology that afflicted him, with almost two decades of delay. The integrated and multidisciplinary approach is desirable in order to obtain an early diagnosis.

scholarly journals Ultrastructural analysis of cardiomyocytes shows that loss of left ventricular desmosomes leads to shortening of ST segment time in patients with arrhythmogenic cardiomyopathy

2020 ◽  
Author(s):  
Yuan Chang ◽  
Xiumeng Hua ◽  
Yiqing Hu ◽  
Wendao Liu ◽  
Xiao Chen ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Task Force ◽  
Pearson Correlation ◽  
Left Ventricular ◽  
Normal Donor ◽  
Arrhythmogenic Cardiomyopathy ◽  
Clinical Genetic ◽  
Transmission Electron ◽  
St Segment ◽  
The Right

Abstract Background: Arrhythmogenic cardiomyopathy (AC) is an inherited myocardial disease affecting the both ventricles. It shows large heterogeneity on its clinical, genetic, and pathological manifestations. The intercalated disc remodeling has been investigated in right ventricle (RV) of AC, however, the ultrastructural features in left ventricle (LV) and among different genotypes remain unknown.Methods: The ultrastructure characters of both ventricles from 24 AC who fulfilled the international Task Force diagnostic and 10 normal donor hearts were studied by transmission electron microscope. We applied Pearson correlation analysis to identify the relationship between D structure and electrocardiogram changes.Results: These 24 patients were divided into two subtypes based on whether they carried desmosome (D) gene mutation. We found that more D structures in LV than that in the right ventricles (RV) in the normal hearts (LV vs. RV, 10.82 ± 3.12% vs. 6.75 ± 1.11%, p=0.001), but the density (AC vs. Control, 3.77 ± 1.58 per 10 μm vs. 4.21 ± 1.76 per 10 μm, p=0.001) and proportion (AC vs. Control, 6.65 ± 2.77% vs. 10.82 ± 3.12%, p=0.001) of D was declined in LV of AC compared with that in normal hearts. The width (AC vs. Control, 21.38 ± 2.31 nm vs. 18.09 ± 0.98 nm, p=0.001) and length (AC vs. Control, 0.17 ± 0.05 μm vs. 0.14 ± 0.01 μm, p=0.002) of D was increased in RV of AC compared with that in normal hearts. Destroyed D structures were found in all AC patients, regardless of carrying a D gene mutation or not. The proportion of D in LV are positively correlated with ST segment time in AC patients. The ultrastructure of mitochondria was not different between AC and normal hearts.Conclusions: The D remodeling patterns had no correlation with the type of mutation. The D of LV mainly showed a decrease in density and proportion, but the D of RV were mainly manifested as compensatory widening and lengthening. The D loss in LV may cause ST segment shortening. From the perspective of ultrastructure, we concluded that increased output power of heart may accelerate the desmosome remodeling or disintegration.

scholarly journals Familial Arrhythmogenic Cardiomyopathy: Clinical Determinants of Phenotype Discordance and the Impact of Endurance Sports

2020 ◽  
Vol 9 (11) ◽  
pp. 3781
Author(s):  
Sarah Costa ◽  
Alessio Gasperetti ◽  
Argelia Medeiros-Domingo ◽  
Deniz Akdis ◽  
Corinna Brunckhorst ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Incomplete Penetrance ◽  
Common Denominator ◽  
Arrhythmogenic Cardiomyopathy ◽  
Variable Expression ◽  
The Impact

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.

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