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AIMS: A combination of variable expression, age-related penetrance, and unpredictable arrhythmic events complicates management of relatives of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We aimed to (i) determine predictors of ARVD/C diagnosis and (ii) optimize arrhythmic risk stratification among first-degree relatives of ARVD/C patients. METHODS AND RESULTS: Detailed phenotypic and outcome data of 274 first-degree relatives (46% male; 36.5 ± 18.9 years) of 138 ARVD/C probands were obtained. Ninety-six (35%) relatives were diagnosed with ARVD/C according to 2010 Task Force Criteria (TFC). Siblings had a three-fold-increased risk of ARVD/C diagnosis compared with parents and children (odds ratio 3.11, P < 0.001). Multivariable logistic regression identified symptoms (P < 0.001), being a sibling (P < 0.001), the presence of a pathogenic mutation (P < 0.001), and female sex (P = 0.010) as predictors of ARVD/C diagnosis. During 6.7 ± 3.8 years of follow-up, 21 (8%) relatives experienced a sustained ventricular arrhythmia (cycle length 271 ± 48 ms). While being a sibling was a predictor of ARVD/C diagnosis, neither relatedness to the proband (P = 0.185) nor malignant family history (P = 0.347) was significantly associated with arrhythmic events. Meeting TFC independent of family history criteria had higher prognostic value for arrhythmic events than conventional 2010 TFC, which include family history [area under the receiver operating characteristic curve 0.95 (95% CI 0.93-0.97) vs. 0.85 (95% CI 0.82-0.88), P < 0.001]. CONCLUSION: One-third of first-degree relatives develop manifest ARVD/C. Siblings have highest risk of disease, even after correcting for age and sex. Fulfilment of TFC independent of family history is superior to conventional TFC for arrhythmic risk stratification of relatives.
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Displasia Arritmogênica Ventricular Direita/diagnóstico , Testes Genéticos/métodos , Adolescente , Adulto , Distribuição por Idade , Idade de Início , Idoso , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Displasia Arritmogênica Ventricular Direita/genética , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estudos Prospectivos , Medição de Risco , Adulto JovemRESUMO
INTRODUCTION: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by high incidence of ventricular arrhythmias. Overt ARVD/C is preceded by a subclinical stage with lack of detectable ECG and structural abnormalities. Activation delay is present before structural abnormalities and is a hallmark of arrhythmogenesis. Deformation imaging may unmask activation delay in the subclinical stage. METHODS: Three groups were compared: (1) mutation-positive definite ARVD/C-patients fulfilling 2010 Task Force criteria (TFC) (n = 44); (2) asymptomatic mutation carriers not fulfilling TFC and without history of ventricular arrhythmias (n = 31); and (3) controls (n = 30). All underwent ECG and echocardiographic deformation imaging. As a surrogate for local activation delay the electromechanical interval (EMI) was measured, defined as time between onset-QRS and onset of shortening. Arrhythmic outcome (PVC-count, VT) of asymptomatic mutation carriers was correlated with EMI and ECG TFC. RESULTS: In definite ARVD/C-patients, EMI was prolonged in all lateral RV segments. In asymptomatic mutation carriers, prolonged EMI was detected in the subtricuspid area in 14/31. Terminal activation duration ≥55 milliseconds (definition: supporting information) was the only ECG abnormality in this group (8/31). After a mean follow-up of 4.2 ± 3.1 years 10/31 asymptomatic mutation carriers experienced arrhythmic outcome. Prolonged subtricuspid EMI was the only parameter significantly associated with arrhythmogenesis during follow-up. CONCLUSION: In ARVD/C-patients, EMI prolongation was present throughout the RV. In asymptomatic mutation carriers, prolonged EMI in the subtricuspid area is often detected without any additional abnormalities. These preliminary results indicate that prolonged EMI is a new parameter unmasking activation delay in the subclinical stage and may contribute to risk stratification.
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Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Eletrocardiografia/métodos , Imagem Cinética por Ressonância Magnética/métodos , Adulto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto JovemRESUMO
AIMS: We sought to determine the influence of genotype on clinical course and arrhythmic outcome among arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated mutation carriers. METHODS AND RESULTS: Pathogenic mutations in desmosomal and non-desmosomal genes were identified in 577 patients (241 families) from USA and Dutch ARVD/C cohorts. Patients with sudden cardiac death (SCD)/ventricular fibrillation (VF) at presentation (n = 36) were younger (median 23 vs. 36 years; P < 0.001) than those presenting with sustained monomorphic ventricular tachycardia (VT). Among 541 subjects presenting alive, over a mean follow-up of 6 ± 7 years, 12 (2%) patients died, 162 (30%) had sustained VT/VF, 78 (14%) manifested left ventricular dysfunction (EF < 55%), 28 (5%) experienced heart failure (HF), and 10 (2%) required cardiac transplantation. Patients (n = 22; 4%) with >1 mutation had significantly earlier occurrence of sustained VT/VF (mean age 28 ± 12 years), lower VT-/VF-free survival (P = 0.037), more frequent left ventricular dysfunction (29%), HF (19%) and cardiac transplantation (9%) when compared with those with only one mutation. Desmoplakin mutation carriers experienced more than four-fold occurrence of left ventricular dysfunction (40%) and HF (13%) than PKP2 carriers. Missense mutation carriers had similar death-/transplant-free survival and VT/VF penetrance (P = 0.137) when compared with those with truncating or splice site mutations. Men are more likely to be probands (P < 0.001), symptomatic (P < 0.001) and have earlier and more severe arrhythmic expression. CONCLUSIONS: Presentation with SCD/VF occurs at a significantly younger age when compared with sustained monomorphic VT. The genotype of ARVD/C mutation carriers impacts clinical course and disease expression. Male sex negatively modifies phenotypic expression.
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Displasia Arritmogênica Ventricular Direita/genética , Desmogleínas/genética , Mutação/genética , Placofilinas/genética , Adolescente , Adulto , Idoso , Displasia Arritmogênica Ventricular Direita/mortalidade , Morte Súbita Cardíaca/etiologia , Desmogleína 2/genética , Desmogleína 3/genética , Desmoplaquinas/genética , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Adulto Jovem , gama CateninaRESUMO
INTRODUCTION: The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes. METHODS AND RESULTS: We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (<0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation. CONCLUSION: Mutation-positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C.
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Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/patologia , Ventrículos do Coração/patologia , Mutação , Taquicardia Ventricular/genética , Taquicardia Ventricular/patologia , Potenciais de Ação , Adulto , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Displasia Arritmogênica Ventricular Direita/cirurgia , Baltimore , Ablação por Cateter , Cicatriz/patologia , Cicatriz/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Predisposição Genética para Doença , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos , Fenótipo , Valor Preditivo dos Testes , Sistema de Registros , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.
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Cardiomiopatias , Células-Tronco Pluripotentes Induzidas , Humanos , Miócitos Cardíacos/metabolismo , Conexina 43/genética , Conexina 43/metabolismo , Desmoplaquinas/genética , Desmoplaquinas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , MutaçãoRESUMO
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive cardiac disease. Many patients with ACM harbor mutations in desmosomal genes, predominantly in plakophilin-2 (PKP2). Although the genetic basis of ACM is well characterized, the underlying disease-driving mechanisms remain unresolved. Explanted hearts from patients with ACM had less PKP2 compared with healthy hearts, which correlated with reduced expression of desmosomal and adherens junction (AJ) proteins. These proteins were also disorganized in areas of fibrotic remodeling. In vitro data from human-induced pluripotent stem cell-derived cardiomyocytes and microtissues carrying the heterozygous PKP2 c.2013delC pathogenic mutation also displayed impaired contractility. Knockin mice carrying the equivalent heterozygous Pkp2 c.1755delA mutation recapitulated changes in desmosomal and AJ proteins and displayed cardiac dysfunction and fibrosis with age. Global proteomics analysis of 4-month-old heterozygous Pkp2 c.1755delA hearts indicated involvement of the ubiquitin-proteasome system (UPS) in ACM pathogenesis. Inhibition of the UPS in mutant mice increased area composita proteins and improved calcium dynamics in isolated cardiomyocytes. Additional proteomics analyses identified lysine ubiquitination sites on the desmosomal proteins, which were more ubiquitinated in mutant mice. In summary, we show that a plakophilin-2 mutation can lead to decreased desmosomal and AJ protein expression through a UPS-dependent mechanism, which preceded cardiac remodeling. These findings suggest that targeting protein degradation and improving desmosomal protein stability may be a potential therapeutic strategy for the treatment of ACM.
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Cardiomiopatias , Placofilinas , Humanos , Camundongos , Animais , Lactente , Proteólise , Placofilinas/genética , Placofilinas/metabolismo , Miócitos Cardíacos/metabolismo , Mutação/genética , Cardiomiopatias/genéticaRESUMO
The lichen compound usnic acid is used for its antimicrobial activities in cosmetic products and is also a component of slimming agents. Its effect against cancer cells was first noted over 30 years ago. In this study possible mechanisms of this effect were investigated using two human cell lines, the breast cancer cell line T-47D and the pancreatic cancer cell line Capan-2. Pure (+)-usnic acid from CLADONIA ARBUSCULA and (-)-usnic acid from ALECTORIA OCHROLEUCA were shown to be equally effective inhibitors of DNA synthesis, with IC (50) 4.2 microg/mL and 4.0 microg/mL for (+) and (-)-usnic acid against T-47D, and 5.3 microg/mL and 5.0 microg/mL against Capan-2, respectively. Flow cytometric analysis confirmed the inhibited entry into the S-phase and showed reduction in cell size. Classical apoptosis, as assessed by TUNEL staining, was not observed. Necrosis, measured by LDH release, was seen only in Capan-2 after exposure for 48 hours. Staining with the mitochondrial dye JC-1 demonstrated dose-dependent loss of mitochondrial membrane potential following treatment with usnic acid in both cell lines. In conclusion, usnic acid had a marked inhibitory effect on growth and proliferation of two different human cancer cell lines and led to loss of mitochondrial membrane potential. Cell survival was little affected; late necrosis was seen in one of the cell lines. No difference was noted between the two enantiomers.
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Antineoplásicos Fitogênicos/farmacologia , Benzofuranos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Líquens/química , Neoplasias Pancreáticas/tratamento farmacológico , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Benzimidazóis , Benzofuranos/uso terapêutico , Neoplasias da Mama/patologia , Carbocianinas , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA/biossíntese , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Necrose , Neoplasias Pancreáticas/patologia , Fitoterapia , Extratos Vegetais/uso terapêuticoRESUMO
AIMS: Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. METHODS: We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. RESULTS: Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. CONCLUSIONS: Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.
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Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/metabolismo , Plectina/genética , Plectina/metabolismo , Displasia Arritmogênica Ventricular Direita/patologia , Estudos de Coortes , Frequência do Gene , Variação Genética , Heterozigoto , Humanos , Miocárdio/metabolismo , Miocárdio/patologia , População Branca/genéticaRESUMO
BACKGROUND: The clinical profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients with late presentation is unknown. OBJECTIVE: The purpose of this study was to characterize the genotype, cardiac phenotype, and long-term outcomes of ARVC/D patients with late presentation (age ≥50 years at diagnosis). METHODS: Five hundred two patients with an ARVC/D diagnosis from Johns Hopkins and Utrecht Registries were studied and long-term clinical outcomes ascertained. RESULTS: Late presentation was seen in 104 patients (21%; 38% PKP2 carriers); 3% were ≥65 years at diagnosis. Sustained ventricular tachycardia was the major (43%) mode of presentation in patients with late presentation, whereas cardiac syncope was infrequent (P <.001). Those with late presentation were significantly less likely to harbor a known pathogenic mutation (53%; P = .005), have less precordial T-wave repolarization changes (P <.001), and have lower ventricular ectopy burden (P = .026). Over median 6-year follow-up, 68 patients with late presentation (65%) experienced sustained ventricular arrhythmias, with similar arrhythmia-free survival at 5-year follow up (P = .48). Left ventricular dysfunction and heart failure were seen in 24 (32%) and 15 patients (14%), respectively, without need for cardiac transplantation. In the late presentation cohort, male sex, pathogenic mutation, right ventricular structural disease, lack of family history, and electrophysiologic study inducibility were associated with increased arrhythmic risk. CONCLUSION: One-fifth of all ARVC/D patients present after age 50 years, often with sustained ventricular tachycardia, and are less likely to have prior syncope, ECG changes, ventricular ectopy, or identifiable pathogenic mutation. In ARVC/D, late presentation does not confer a benign prognosis and is associated with high arrhythmic risk.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Predisposição Genética para Doença , Placofilinas/genética , Adolescente , Adulto , Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Eletrocardiografia , Feminino , Seguimentos , Genótipo , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fenótipo , Placofilinas/metabolismo , Prognóstico , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos , Adulto JovemRESUMO
OBJECTIVES: The primary objective of this study is risk stratification of patients with arrhythmic right ventricular cardiomyopathy (ARVC). BACKGROUND: There is a need to identify those who need an automatic implantable defibrillator (ICD) to prevent sudden death. METHODS: This is an analysis of 88 patients with ARVC from three centers who were not treated with an ICD. RESULTS: Risk factors for subsequent arrhythmic deaths were pre-enrollment sustained or nonsustained ventricular tachycardia (VT) and decreased left ventricular function. CONCLUSION: These factors serve as proposed guidelines for implantation of an ICD in patients with ARVC to prevent sudden death.
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OBJECTIVES: To characterise pregnancy course and outcomes in women with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). METHODS: From a combined Johns Hopkins/Dutch ARVD/C registry, we identified 26 women affected with ARVD/C (by 2010 Task Force Criteria) during 39 singleton pregnancies >13â weeks (1-4 per woman). Cardiac symptoms, treatment and episodes of sustained ventricular arrhythmias (VAs) and heart failure (HF) ≥ Class C were characterised. Obstetric outcomes were ascertained. Incidence of VA and HF were compared with rates in the non-pregnant state. Long-term disease course was compared with 117 childbearing-aged female patients with ARVD/C who had not experienced pregnancy with ARVD/C. RESULTS: Treatment during pregnancy (n=39) included ß blockers (n=16), antiarrhythmics (n=6), diuretics (n=3) and implantable cardioverter defibrillators (ICDs) (n=28). In five pregnancies (13%), a single VA occurred, including two ICD-terminated events. Arrhythmias occurred disproportionately in probands without VA history (p=0.045). HF, managed on an outpatient basis, developed in two pregnancies (5%) in women with pre-existing overt biventricular or isolated right ventricular disease. All infants were live-born without major obstetric complications. Caesarean sections (n=11, 28%) had obstetric indications, except one (HF). ß Blocker therapy was associated with lower birth weight (3.1±0.48â kg vs 3.7±0.57â kg; p=0.002). During follow-up children remained healthy (median 3.4â years), and mothers were without cardiac mortality or transplant. Neither VA nor HF incidence was significantly increased during pregnancy. ARVD/C course (mean 6.5±5.6â years) did not differ based on pregnancy history. CONCLUSIONS: While most pregnancies in patients with ARVD/C were tolerated well, 13% were complicated by VA and 5% by HF.
Assuntos
Displasia Arritmogênica Ventricular Direita , Nascido Vivo , Complicações Cardiovasculares na Gravidez , Adulto , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/terapia , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Displasia Arritmogênica Ventricular Direita/terapia , Baltimore/epidemiologia , Estudos de Casos e Controles , Cesárea , Desenvolvimento Infantil , Pré-Escolar , Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Humanos , Incidência , Lactente , Recém-Nascido , Países Baixos/epidemiologia , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/terapia , Sistema de Registros , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Among studies describing the phenotype of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), significant discrepancy exists regarding the extent and impact of left ventricular (LV) involvement. The capability of conventional and new quantitative echocardiographic techniques to accurately detect LV involvement in ARVD/C remains unknown. The aim of this study was to test the hypothesis that accurate detection of LV involvement on echocardiography identifies patients at additional risk for cardiac events during follow-up. METHODS: Thirty-eight patients with ARVD/C, 16 pathogenic mutation-positive relatives, and 55 healthy control subjects were prospectively enrolled. Conventional echocardiography with additional deformation imaging was performed in all subjects to detect LV involvement. In a subgroup (n = 27), cardiac magnetic resonance imaging was performed with late enhancement. All patients and relatives were prospectively followed for events (sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator intervention, sudden cardiac death, and heart transplantation). RESULTS: Conventional echocardiography detected LV involvement in 32% of patients with ARVD/C and in none of the relatives. Deformation imaging revealed LV involvement in 68% of patients with ARVD/C and 25% of relatives and was correlated closely with late enhancement on cardiac magnetic resonance imaging. During a mean follow-up period of 5.9 ± 2.3 years, 20 patients with ARVD/C (53%) experienced events, and no events occurred in the relatives. LV involvement detected by deformation imaging (hazard ratio, 4.9; 95% CI, 1.7-14.2) and right ventricular outflow tract enlargement (hazard ratio, 1.2; 95% CI, 1.1-1.3) were the only independent predictors of outcomes. CONCLUSIONS: Deformation imaging detected a high incidence of LV involvement in patients with ARVD/C and their relatives. Compared with conventional echocardiography, deformation imaging is superior in detecting minor LV involvement. LV involvement and an enlarged right ventricular outflow tract are independent prognostic markers of outcomes.
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Displasia Arritmogênica Ventricular Direita/diagnóstico por imagem , Ecocardiografia/métodos , Ventrículos do Coração/diagnóstico por imagem , Função Ventricular Esquerda/fisiologia , Adulto , Displasia Arritmogênica Ventricular Direita/patologia , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Morte Súbita Cardíaca/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Incidência , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
OBJECTIVES: The aims of this study were to determine the clinical characteristics and outcomes of pediatric-onset arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to compare these with those of adult-onset ARVD/C. BACKGROUND: Improved early detection and increased awareness of ARVD/C have led to a growing group of pediatric patients seeking management recommendations. Prior studies have mainly included adults with ARVD/C; however, clinical features and outcomes may differ in pediatric subjects. METHODS: Among 502 subjects fulfilling task force criteria for ARVD/C, we identified 75 (15%) with pediatric-onset disease (diagnosis at <18 years of age or probands presenting symptomatically at <18 years of age). Clinical characteristics and outcomes (sustained ventricular tachycardia, cardiac transplantation, and death) were compared between pediatric and adult patients. RESULTS: Pediatric patients presented at 15.3 ± 2.4 years of age. Most pediatric patients were male (55%) and ARVD/C-associated mutation carriers (80%). One-fourth of pediatric patients presented with sudden cardiac death (15%) or resuscitated sudden cardiac arrest (11%). Compared with adults, pediatric patients were disproportionately mutation carriers (p = 0.002) but not more often male (p = 0.696) or probands (p = 0.371). Pediatric patients were more likely to present with sudden cardiac death (p = 0.003), whereas adults more often presented with sustained ventricular tachycardia (p = 0.017). There were no other phenotypic differences between the groups. During 8.4 ± 7.5 years of follow-up, survival free from sustained ventricular tachycardia (p = 0.359), cardiac transplantation (p = 0.523), and death (p = 0.359) was similar between pediatric and adult patients. CONCLUSIONS: Pediatric patients with ARVD/C are typically male mutation carriers presenting in adolescence. Pediatric patients disproportionately present with sudden cardiac death. However, once diagnosed, clinical characteristics and outcomes are similar between pediatric and adult patients.
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BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic cohort of 1001 individuals. METHODS AND RESULTS: Clinical and genetic characteristics and follow-up data of ARVD/C index-patients (n=439, fulfilling of 2010 criteria in all) and family members (n=562) were assessed. Mutations were identified in 276 index-patients (63%). Index-patients presented predominantly with sustained ventricular arrhythmias (268; 61%). During a median follow-up of 7 years, 301 of the 416 index-patients presenting alive (72%) experienced sustained ventricular arrhythmias. Sudden cardiac death during follow-up occurred more frequently among index-patients without an implantable cardioverter-defibrillator (10/63, 16% versus 2/335, 0.6%). Overall, cardiac mortality and the need for cardiac transplantation were low (6% and 4%, respectively). Clinical characteristics and outcomes were similar in index-patients with and without mutations, as well as in those with familial and nonfamilial ARVD/C. ARVD/C was diagnosed in 207 family members (37%). Symptoms at first evaluation correlated with disease expression. Family members with mutations were more likely to meet Task Force Criteria for ARVD/C (40% versus 18%), experience sustained ventricular arrhythmias (11% versus 1%), and die from a cardiac cause (2% versus 0%) than family members without mutations. CONCLUSIONS: Long-term outcome was favorable in diagnosed and treated ARVD/C index-patients and family members. Outcome in index-patients was modulated by implantable cardioverter-defibrillator implantation, but not by mutation status and familial background of disease. One third of family members developed ARVD/C. Outcome in family members was determined by symptoms at first evaluation and mutations.
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Displasia Arritmogênica Ventricular Direita/diagnóstico , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/mortalidade , Morte Súbita Cardíaca , Desfibriladores Implantáveis , Desmocolinas/genética , Desmogleína 2/genética , Desmoplaquinas/genética , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Placofilinas/genética , Polimorfismo Genético , gama CateninaRESUMO
BACKGROUND: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers. METHODS AND RESULTS: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively. CONCLUSIONS: Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Proteínas de Ligação ao Cálcio/genética , Adulto , Fatores Etários , Idoso , Displasia Arritmogênica Ventricular Direita/mortalidade , Displasia Arritmogênica Ventricular Direita/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Estudos de Coortes , Eletrocardiografia , Feminino , Seguimentos , Deleção de Genes , Humanos , Falência Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários , Análise de SobrevidaRESUMO
BACKGROUND: Interpretation of genetic screening results in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) often is difficult. Pathogenicity of variants with uncertain clinical significance may be predicted by software algorithms. However, functional assessment can unambiguously demonstrate the effect of such variants. OBJECTIVE: The purpose of this study was to perform functional analysis of potential splice site variants in ARVD/C patients. METHODS: Nine variants in desmosomal (PKP2, JUP, DSG2, DSC2) genes with potential RNA splicing effect were analyzed. The variants were found in patients who fulfilled 2010 ARVD/C Task Force Criteria (n = 7) or had suspected ARVD/C (n = 2). Total RNA was isolated from fresh blood samples and subjected to reverse transcriptase polymerase chain reaction. RESULTS: An effect on splicing was predicted by software algorithms for all variants. Of the 9 variants, 5 were intronic and 4 exonic. RNA analysis showed a functional effect on mRNA splicing by exon skipping, generation of new splice sites, or activation of cryptic sites in 6 variants. All 5 intronic variants tested severely impaired splicing. Only 1 of 4 exonic potential splice site variants was shown to have a deleterious effect on splicing. The remaining 3 exonic variants had no detectable effect on splicing, and heterozygous presence in mRNA confirmed biallelic expression. CONCLUSION: Six variants of uncertain clinical significance in the PKP2, JUP, and DSG2 genes showed a deleterious effect on mRNA splicing, indicating these are ARVD/C-related pathogenic splice site mutations. These results highlight the importance of functional assessment of potential splice site variants to improve patient care and facilitate cascade screening.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Variação Genética , Mutação , Sítios de Splice de RNA , Adolescente , Adulto , Idoso , Algoritmos , Alelos , Proteínas de Ligação ao Cálcio/genética , Desmocolinas/genética , Desmogleína 2/genética , Desmoplaquinas/genética , Eletrocardiografia , Éxons , Feminino , Humanos , Íntrons , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Linhagem , Placofilinas/genética , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Software , gama CateninaRESUMO
Detailed histopathologic, immunohistochemical, and ultrastructural analysis of the heart of a 56-year-old woman with end-stage arrhythmogenic cardiomyopathy with a pathogenic plakophilin-2 mutation is described. The explanted heart revealed severe fibrofatty replacement of nearly the entire right ventricular free wall. The left ventricle was severely affected, and, most remarkable, there was massive involvement of the interventricular septum. Immunohistochemical and electron microscopic findings of intercalated disks revealed areas with a heterogeneous distribution of connexin43 and focal electron microscopic abnormalities among these regions. This case illustrates that arrhythmogenic cardiomyopathy is not limited to the right ventricle but involves the entire myocardium, including the interventricular septum.
Assuntos
Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/cirurgia , Transplante de Coração/métodos , Septo Interventricular/patologia , Displasia Arritmogênica Ventricular Direita/patologia , Biópsia por Agulha , Progressão da Doença , Eletrocardiografia/métodos , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/cirurgia , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Miocárdio/patologia , Miocárdio/ultraestrutura , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), a normal electrocardiogram (ECG) is considered reassuring. However, some patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG. OBJECTIVES: To estimate how often patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG during sinus rhythm, and to provide a clinical profile of these patients. METHODS: We included 145 patients with ARVD/C experiencing a documented sustained ventricular arrhythmia. Conventional 12-lead sinus rhythm ECGs within 6 months of the event were reviewed for diagnostic Task Force Criteria (TFC). ECGs were classified as abnormal (≥1 TFC), nonspecific (abnormal, no TFC), or normal. Cardiologic investigations within 6 months of the event were evaluated as per TFC in those with a nonspecific or normal ECG. RESULTS: The ECG was nonspecific or normal in 17 of 145 (12%) subjects. Mean age of these patients was 41.3 ± 12.4 years and 14 (82%) were men, comparable to those with an abnormal ECG. Most patients with a nonspecific or normal ECG showed ≥1 TFC on Holter monitoring (n = 9 of 10) and signal-averaged ECG (n = 4 of 5), and all had nonsustained ventricular tachycardia recorded. Among 15 patients who underwent structural evaluation, 11 (73%) showed structural TFC (9 major and 2 minor). CONCLUSIONS: Although most patients with ARVD/C experiencing arrhythmias have an abnormal ECG, a nonspecific or normal ECG does not preclude ARVD/C diagnosis. All patients with a nonspecific or normal ECG had alternative evidence of disease expression. These results alert the physician not to rely exclusively on ECG in ARVD/C, but to assess arrhythmic risk by comprehensive clinical evaluation.
Assuntos
Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Eletrocardiografia Ambulatorial , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Adulto , Estudos de Coortes , Diagnóstico Precoce , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Taquicardia Ventricular/etiologia , Adulto JovemRESUMO
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is considered a predominantly right ventricular (RV) desmosomal disease. However, left-dominant forms due to desmosomal gene mutations, including PKP2 variant c.419C>T, have been described. Recently, a nondesmosomal phospholamban (PLN) mutation (c.40_42delAGA) has been identified, causing dilated cardiomyopathy and arrhythmias. OBJECTIVE: To gain more insight into pathogenicity of the PKP2 variant c.419C>T by cosegregation analysis of the PKP2 variant c.419C>T vs the PLN mutation c.40_42delAGA. METHODS: A Dutch family (13 family members, median age 49 years, range 34-71 years) with ventricular tachycardia underwent (1) meticulous phenotypic characterization and (2) screening of 5 desmosomal genes (PKP2, DSC2, DSG2, DSP, JUP) and PLN. RESULTS: Six family members fulfilled 2010 AC Task Force Criteria. Seven had signs of left ventricular (LV) involvement (inverted T waves in leads V4-V6, LV wall motion abnormalities and late enhancement, and reduced LV ejection fraction), including 6 family members with proven AC. The PKP2 variant c.419C>T was found as a single variant in 3 family members, combined with the PLN mutation c.40_42delAGA in 3 others. PLN mutation was found in 9 family members, including the 6 with AC and all 7 with LV involvement. The PLN mutation c.40_42delAGA was found as a single mutation in 6, combined with the PKP2 variant c.419C>T in 3 others. A low-voltage electrocardiogram was seen in 4 of 9 PLN mutation-positive subjects. None of the family members with the single PKP2 variant showed any sign of RV or LV involvement. CONCLUSIONS: The PLN mutation c.40_42delAGA cosegregates with AC and with electrocardiographic and structural LV abnormalities. In this family, there was no evidence of disease-causing contribution of the PKP2 variant c.419C>T.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Predisposição Genética para Doença , Heterozigoto , Placofilinas/genética , Taquicardia Ventricular/genética , Adulto , Fatores Etários , Idoso , Displasia Arritmogênica Ventricular Direita/diagnóstico , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Desmossomos/genética , Eletrocardiografia/métodos , Feminino , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Prognóstico , Medição de Risco , Fatores SexuaisRESUMO
BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is closely associated with desmosomal mutations in a majority of patients. Arrhythmogenesis in patients with AC is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. OBJECTIVE: To assess the immunoreactive signal levels of the sodium channel protein NaV1.5, as well as connexin43 (Cx43) and plakoglobin (PKG), in myocardial specimens obtained from patients with AC. METHODS: Left and right ventricular free wall postmortem material was obtained from 5 patients with AC and 5 controls matched for age and sex. Right ventricular septal biopsies were taken from another 15 patients with AC. All patients fulfilled the 2010 revised Task Force Criteria for the diagnosis of AC. Immunohistochemical analyses were performed using antibodies against Cx43, PKG, NaV1.5, plakophilin-2, and N-cadherin. RESULTS: N-cadherin and desmoplakin immunoreactive signals and distribution were normal in patients with AC compared to controls. Plakophilin-2 signals were unaffected unless a plakophilin-2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to that in controls. Immunoreactive signal levels of PKG, Cx43, and NaV1.5 were disturbed in 74%, 70%, and 65% of the patients, respectively. CONCLUSIONS: A reduced immunoreactive signal of PKG, Cx43, and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.