Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy

Lahtinen, Annukka M.; Lehtonen, Eero; Marjamaa, Annukka; Kaartinen, Maija; Heliö, Tiina; Porthan, Kimmo; Oikarinen, Lasse; Toivonen, Lauri; Swan, Heikki; Jula, Antti; Peltonen, Leena; Palotie, Aarno; Salomaa, Veikko; Kontula, Kimmo

doi:10.1016/j.hrthm.2011.03.015

Cited by 49 publications

(38 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The estimated prevalence of ARVC in the general population has been ranging from 1 in 1000 to 1 in 5000. 29 -31 Nevertheless, mutations that may predispose to ARVC are more prevalent in the population, and it has been estimated that up to 1 of 200 Finns carries such a mutation, 32 suggesting a low penetrance of this mutation. Based on the results of the present study, however, no exact estimations of the prevalence of ARVC phenotype in the Finnish population can be made, because no further diagnostic procedures besides the 12-lead ECG were performed to diagnose the disease.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Prognostic Significance of T-Wave Inversions in Right Precordial Leads of a 12-Lead Electrocardiogram in the Middle-Aged Subjects

A¹,

Anttonen²,

Tikkanen³

et al. 2012

Circulation

View full text Add to dashboard Cite

Background-T-wave inversion in right precordial leads V 1 to V 3 is a relatively common finding in a 12-lead ECG of children and adolescents and is infrequently found also in healthy adults. However, this ECG pattern can also be the first presentation of arrhythmogenic right ventricular cardiomyopathy. The prevalence and prognostic significance of T-wave inversions in the middle-aged general population are not well known. Methods and Results-We evaluated 12-lead ECGs of 10 899 Finnish middle-aged subjects (52% men, mean age 44Ϯ8.5 years) recorded between 1966 and 1972 for the presence of inverted T waves and followed the subjects for 30Ϯ11 years.Primary end points were all-cause mortality, cardiac mortality, and arrhythmic death. T-wave inversions in right precordial leads V 1 to V 3 were present in 54 (0.5%) of the subjects. In addition, 76 (0.7%) of the subjects had inverted T waves present only in leads other than V 1 to V 3 . Right precordial T-wave inversions did not predict increased mortality (not significant for all end points). However, inverted T waves in leads other than V 1 to V 3 were associated with an increased risk of cardiac and arrhythmic death (PϽ0.001 for both). Conclusions-T-wave inversions in right precordial leads are relatively rare in the general population, and are not associated with adverse outcome. Increased mortality risk associated with inverted T waves in other leads may reflect the presence of an underlying structural heart disease. (Circulation. 2012;125:2572-2577.)

show abstract

Section: Discussionmentioning

confidence: 99%

Prevalence and Prognostic Significance of T-Wave Inversions in Right Precordial Leads of a 12-Lead Electrocardiogram in the Middle-Aged Subjects

A¹,

Anttonen²,

Tikkanen³

et al. 2012

Circulation

View full text Add to dashboard Cite

show abstract

“…25 Recent studies on the presence of desmosomal gene variants in the general population demonstrated that although nonmissense desmosomal gene variants are high-probability, ARVCcausing mutations, the pathogenetic potential of rare missense mutations should be interpreted with greater caution and in the context of race and ethnicity, mutation location, and sequence conservation. 26,40 In vitro functional analysis or animal studies would have been required to conclusively proof the causative nature of missense variants. However, it is important to stress that these limitations are exactly the same as present in all previous genotype-phenotype studies in ARVC.…”

Section: Study Limitationsmentioning

confidence: 99%

Compound and Digenic Heterozygosity Predicts Lifetime Arrhythmic Outcome and Sudden Cardiac Death in Desmosomal Gene–Related Arrhythmogenic Right Ventricular Cardiomyopathy

Rigato

Bauce

Rampazzo

et al. 2013

Circ Cardiovasc Genet

221

137

View full text Add to dashboard Cite

Background-Mutations in genes encoding for desmosomal proteins are the most common cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). We assessed the value of genotype for prediction of lifetime major arrhythmic events and sudden cardiac death (SCD) in desmosomal gene-related ARVC. Methods and Results-The overall study population included 134 desmosomal gene mutation carriers (68 men; median age 36 years ) from 44 consecutive ARVC families undergoing comprehensive genetic screening. The probability of experiencing a first major arrhythmic event or SCD during a lifetime was determined by using date of birth as start point for the time-to-event analysis, and was stratified by sex, desmosomal genes, mutation types, and genotype complexity (single versus multiple mutations). One hundred thirteen patients (84%) carried a single desmosomal gene mutation in desmoplakin (n=44; 39%), plakophilin-2 (n=38; 34%), desmoglein-2 (n=30; 26%), and desmocollin-2 (n=1; 1%), whereas 21 patients (16%) had a complex genotype with compound heterozygosity in 7 and digenic heterozygosity in 14. Over a median observation period of 39 (22-52) years, 22 patients (16%) from 20 different families had arrhythmic events, such as SCD (n=1), aborted SCD because of ventricular fibrillation (n=6), sustained ventricular tachycardia (n=14), and appropriate defibrillator intervention (n=1). Multiple desmosomal gene mutations and male sex were independent predictors of lifetime arrhythmic events with a hazard ratio of 3.71 (95% confidence interval, 1.54-8.92; P=0.003) and 2.76 (95% confidence interval, 1.19-6.41; P=0.02), respectively. Conclusions-Compound/digenic heterozygosity was identified in 16% of ARVC-causing desmosomal gene mutation carriers and was a powerful risk factor for lifetime major arrhythmic events and SCD. These results support the use of comprehensive genetic screening of desmosomal genes for arrhythmic risk stratification in ARVC.(Circ Cardiovasc Genet. 2013;6:533-542.)

show abstract

“…It has been reported that plakoglobin redistribution is one of the candidates that play a crucial role in the final common pathway of ARVC pathogenesis, [9][10][11] and previous studies have reported the usefulness of immunostaining for plakoglobin in the diagnosis of ARVC by endomyocardial biopsy. 6,8,12) However, the diagnostic values for ARVC differ among these studies (sensitivity, 76-91%; specificity, 57-84%), as myocardial specimens obtained by biopsy were compared with various controls, including those from hearts with ventricular arrhythmia, dilated cardiomyopathy (DCM), other cardiac diseases, and even hearts without heart disease.…”

Section: Discussionmentioning

confidence: 99%

Relationships Between Clinical Characteristics and Decreased Plakoglobin and Connexin 43 Expressions in Myocardial Biopsies From Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

et al. 2015

View full text Add to dashboard Cite

SummaryReduced expressions of plakoglobin and connexin 43 have been reported in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, the relationships between these expression abnormalities and the clinical features of ARVC remain unknown.The expressions of plakoglobin and connexin 43 in myocardial biopsy specimens from 10 patients with confirmed ARVC, and 13 control patients without ARVC (non-ARVC; hypertrophic cardiomyopathy, n = 7; dilated cardiomyopathy, n = 6), were examined by immunostaining to evaluate the relationships between these expressions and the clinical characteristics of ARVC. The ratios of plakoglobin/N-cadherin and of plakoglobin/connexin 43 expressions were significantly lower in the ARVC group than in the control group. Significantly more patients had decreased plakoglobin expression in the ARVC group than in the control group (9/10 versus 7/13; P = 0.0376). Sustained ventricular tachycardia occurred more frequently in patients with ARVC and with decreased expressions of both plakoglobin and connexin 43 than in those with decreased expression of plakoglobin alone (5/5 versus 1/4, P = 0.048).Decreased expressions of both connexin 43 and plakoglobin in the myocardium might be associated with the development of arrhythmia in ARVC. (Int Heart J 2015; 56: 626-631) Key words: Arrhythmia, Intercalated disc, Pathology A rrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder of the heart muscle that predominantly affects the right ventricle and is associated with ventricular tachycardia, syncope, sudden death, and the characteristic pathological feature of cardiac myocytes being replaced with adipocytes and fibrosis. 1) Implantation of an implantable cardioverter-defibrillator is one of the treatments of sustained ventricular arrhythmia for prevention of sudden cardiac death in ARVC patients.2) However, there is no specific biomarker or predictor of arrhythmic events in ARVC, while a number of biomarkers reflective of myocardial stress and damage have been developed, 3) and P wave analysis has been reported to be useful for predicting new onset of atrial fibrillation. 4) One of the reasons for a lack of specific biomarkers was because the precise mechanisms of ARVC had not been determined.Cardiac myocytes have three different types of intercellular junctions at the cardiac intercalated disc (adherens junctions, desmosomes, and gap junctions), and the identified gene mutations of ARVC include the intracellular junction proteins, plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. 5)It has recently been demonstrated that the expression of plakoglobin, a component of both the adherens junctions and desmosomes, was decreased in uninvolved myocardium of ARVC with normal expression of N-cadherin by immunostaining.6) Moreover, the previous study showed that immunoreactive signals for connexin 43, a gap junction component, as well as plakoglobin, were also disturbed in around 70% of patients with ARVC. 7)However, no report has ...

show abstract

Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy

Cited by 49 publications

References 36 publications

Prevalence and Prognostic Significance of T-Wave Inversions in Right Precordial Leads of a 12-Lead Electrocardiogram in the Middle-Aged Subjects

Prevalence and Prognostic Significance of T-Wave Inversions in Right Precordial Leads of a 12-Lead Electrocardiogram in the Middle-Aged Subjects

Compound and Digenic Heterozygosity Predicts Lifetime Arrhythmic Outcome and Sudden Cardiac Death in Desmosomal Gene–Related Arrhythmogenic Right Ventricular Cardiomyopathy

Relationships Between Clinical Characteristics and Decreased Plakoglobin and Connexin 43 Expressions in Myocardial Biopsies From Patients With Arrhythmogenic Right Ventricular Cardiomyopathy

Contact Info

Product

Resources

About