RESUMO
BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.
RESUMO
BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.
Assuntos
Displasia Arritmogênica Ventricular Direita , Desfibriladores Implantáveis , Humanos , Desfibriladores Implantáveis/efeitos adversos , Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/terapia , Estudos Retrospectivos , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/terapia , Arritmias Cardíacas/etiologia , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Morte Súbita Cardíaca/etiologia , Fatores de Risco , América do Norte/epidemiologia , Europa (Continente)/epidemiologiaRESUMO
BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.
Assuntos
Desfibriladores Implantáveis , Taquicardia Ventricular , Feminino , Humanos , Adolescente , Masculino , Flecainida/efeitos adversos , Incidência , Estudos Cross-Over , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/tratamento farmacológico , Taquicardia Ventricular/epidemiologia , Antagonistas Adrenérgicos beta/efeitos adversos , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controleRESUMO
AIMS: Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. METHODS AND RESULTS: We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6-3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79-0.87) and calibration slope of 0.97. CONCLUSION: The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)-positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.
Assuntos
Arritmias Cardíacas , Desfibriladores Implantáveis , Feminino , Humanos , Masculino , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/terapia , Proteínas de Ligação ao Cálcio/genética , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Reprodutibilidade dos Testes , Fatores de Risco , Adulto , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: The MYH7 c.5135Gâ¯> A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect. METHODS: We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort. RESULTS: In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8-74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients. CONCLUSION: MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women <â¯30 years.
RESUMO
AIMS: To evaluate safety of leadless pacemaker implantation through the internal jugular vein in a larger cohort with longer follow-up. Moreover, feasibility of non-apical pacing as well as relation between pacing site and QRS duration were assessed. METHODS: Eighty Two consecutive patients, who received a leadless pacemaker though the internal jugular vein, were included. Electrical parameters were measured at regular follow-up and any complications were registered. Paced QRS interval was compared for three pacing sites, RVOT, RV mid septum, and RV apical septum. RESULTS: In all patients, the leadless pacemaker was implanted successfully. In 69 patients, the device was implanted in a non-apical position. In 71% of cases, the device could be deployed at first attempt. The median fluoroscopy time was 4.4 min (range 0.9-51) The paced QRS interval was significantly narrower for non-apical pacing sites compared to apical pacing si 156 vs. 179 ms. p = .04, respectively. During mean follow-up of 16 months (range 0-43 months), electrical parameters remained stable. Two complications occurred, which could be resolved during the implant procedure. There were no access site related complications. CONCLUSION: The jugular approach for leadless pacemaker implantation is feasible and may avoid vascular complications. It facilitates non-apical positioning of leadless pacemakers leading to a narrower paced QRS interval. The jugular approach allows for immediate post procedural ambulation.
Assuntos
Marca-Passo Artificial , Humanos , Desenho de Equipamento , Veias Jugulares , Estimulação Cardíaca Artificial , Resultado do TratamentoRESUMO
BACKGROUND: Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a multimodality prediction model. OBJECTIVE: This study aimed to investigate whether an explainable deep learning-based approach allows risk prediction with only electrocardiogram (ECG) data. METHODS: A total of 679 PLN p.(Arg14del) carriers without MVA at baseline were identified. A deep learning-based variational auto-encoder, trained on 1.1 million ECGs, was used to convert the 12-lead baseline ECG into its FactorECG, a compressed version of the ECG that summarizes it into 32 explainable factors. Prediction models were developed by Cox regression. RESULTS: The deep learning-based ECG-only approach was able to predict MVA with a C statistic of 0.79 (95% CI, 0.76-0.83), comparable to the current prediction model (C statistic, 0.83 [95% CI, 0.79-0.88]; P = .054) and outperforming a model based on conventional ECG parameters (low-voltage ECG and negative T waves; C statistic, 0.65 [95% CI, 0.58-0.73]; P < .001). Clinical simulations showed that a 2-step approach, with ECG-only screening followed by a full workup, resulted in 60% less additional diagnostics while outperforming the multimodal prediction model in all patients. A visualization tool was created to provide interactive visualizations (https://pln.ecgx.ai). CONCLUSION: Our deep learning-based algorithm based on ECG data only accurately predicts the occurrence of MVA in PLN p.(Arg14del) carriers, enabling more efficient stratification of patients who need additional diagnostic testing and follow-up.
Assuntos
Algoritmos , Proteínas de Ligação ao Cálcio , Aprendizado Profundo , Eletrocardiografia , Humanos , Eletrocardiografia/métodos , Masculino , Feminino , Medição de Risco/métodos , Pessoa de Meia-Idade , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Cardiomiopatias/etiologia , Adulto , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/etiologia , Estudos RetrospectivosRESUMO
Background: Patients with likely pathogenic/pathogenic desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives: The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+). Methods: DSP-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics. Results: Among 252 DSP-TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank P = 0.0239). History of nonsustained VT (aHR 2.097; P = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age (P = 0.723) nor male sex (P = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]). Conclusions: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-TFC+ patients with nonsustained VT should be considered as high-risk.
RESUMO
BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. METHODS AND RESULTS: One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). CONCLUSIONS: Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.
Assuntos
Displasia Arritmogênica Ventricular Direita , Morte Súbita Cardíaca/epidemiologia , Desmossomos/patologia , Família , Adolescente , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/mortalidade , Displasia Arritmogênica Ventricular Direita/patologia , Doenças Assintomáticas/mortalidade , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco , Taquicardia Ventricular/genética , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/patologia , Fibrilação Ventricular/genética , Fibrilação Ventricular/mortalidade , Fibrilação Ventricular/patologia , Adulto JovemRESUMO
OBJECTIVES: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by fibrofatty replacement of cardiomyocytes. In around 50% of index patients, a genetic predisposition is demonstrated. The purpose of this study was to examine a plakophilin-2 (PKP2) splice site mutation, c.2489+4A>C, identified in 4 separately ascertained Dutch ARVD/C families. METHODS: Genealogical studies and comprehensive screening of 5 desmosomal genes were undertaken. Reverse transcriptase PCR (RT-PCR) and subsequent sequencing was performed. RESULTS: An A-to-C change (c.2489+4A>C) near the splice donor site of intervening sequence 12 of PKP2 was found in all 4 families. Based on pedigree data and haplotype sharing, a common ancestor should be situated more than 7 generations ago. RT-PCR demonstrated the presence of aberrant messenger RNA. Clinical manifestations ranged from severe disease to nonpenetrance in elderly mutation carriers. CONCLUSIONS: This founder mutation in PKP2 is predicted to lead to the presence of a dysfunctional PKP2 protein, whereas most truncating mutations are expected to lead to loss of protein. Mutation carriers displayed a wide range of disease severity, suggesting that PKP2 mutations alone are not sufficient to cause disease, which results in the variable expression and incomplete penetrance characteristic of ARVD/C mutations.
Assuntos
Displasia Arritmogênica Ventricular Direita/genética , Mutação/genética , Placofilinas/genética , Adolescente , Adulto , Idoso , Éxons/genética , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Sítios de Splice de RNA/genética , Adulto JovemRESUMO
Introduction: Pulsed field ablation (PFA) was recently introduced for the treatment of symptomatic atrial fibrillation (AF) with the claim of selectively ablating the myocardium while sparing surrounding tissues. We present our initial experience with a PFA catheter for pulmonary vein isolation (PVI) and describe procedural findings and peri-procedural safety of the first 100 patients. Materials and methods: We investigated 100 patients treated for symptomatic AF using the FARAWAVE PFA catheter (Farapulse, Menlo Park, CA, USA) between July 2021 and March 2022. Procedure workflow and electrophysiological findings at the time of ablation, peri-procedural complications, and operator learning curves are described. Results: The mean age of patients was 62.9 ± 9.4 years, 62% were male subjects and 80% had paroxysmal AF. The median CHA2DS2-VASc score was 1.5 (IQR: 1.0-2.0) and the mean left atrial volume index was 35.7 ± 9.6 ml/m2. In 88 (88%) patients, PVI alone was performed and in 12 (12%) patients additional ablation of the posterior wall was performed. 3D-electroanatomic mapping was performed in 18 (18%) patients. Procedures without mapping lasted for 52.3 ± 16.6 min. The mean number of applications per pulmonary vein (PV) was 8.1 ± 0.6. In all patients (100%), all PVs were confirmed to be isolated. The learning curves of the two operators who performed > 20 procedures showed a negligible variation of performance over time and practice did not significantly predict procedure time [Operator 1 (senior): R 2 = 0.034, p = 0.35; Operator 2 (junior): R 2 = 0.004, p = 0.73]. There was no difference between the procedure times between senior and junior operators (Operator 1: 46.9 ± 9.7 min vs. Operator 2: 45.9 ± 9.9 min; p = 0.73). The only complications observed were two cases of bleeding at the site of percutaneous access. Conclusion: Our initial experience shows that use of the PFA catheter for pulmonary vein isolation (PVI) is safe, fast, and easy to learn.
RESUMO
BACKGROUND: In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. METHODS AND RESULTS: Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. CONCLUSIONS: The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00024505.
Assuntos
Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/terapia , Ecocardiografia , Eletrocardiografia Ambulatorial , Imageamento por Ressonância Magnética , Biópsia , Morte Súbita Cardíaca , Humanos , Guias de Prática Clínica como Assunto , Padrões de Referência , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: In 1994, an International Task Force proposed criteria for the clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) that facilitated recognition and interpretation of the frequently nonspecific clinical features of ARVC/D. This enabled confirmatory clinical diagnosis in index cases through exclusion of phenocopies and provided a standard on which clinical research and genetic studies could be based. Structural, histological, electrocardiographic, arrhythmic, and familial features of the disease were incorporated into the criteria, subdivided into major and minor categories according to the specificity of their association with ARVC/D. At that time, clinical experience with ARVC/D was dominated by symptomatic index cases and sudden cardiac death victims-the overt or severe end of the disease spectrum. Consequently, the 1994 criteria were highly specific but lacked sensitivity for early and familial disease. METHODS AND RESULTS: Revision of the diagnostic criteria provides guidance on the role of emerging diagnostic modalities and advances in the genetics of ARVC/D. The criteria have been modified to incorporate new knowledge and technology to improve diagnostic sensitivity, but with the important requisite of maintaining diagnostic specificity. The approach of classifying structural, histological, electrocardiographic, arrhythmic, and genetic features of the disease as major and minor criteria has been maintained. In this modification of the Task Force criteria, quantitative criteria are proposed and abnormalities are defined on the basis of comparison with normal subject data. CONCLUSIONS: The present modifications of the Task Force Criteria represent a working framework to improve the diagnosis and management of this condition. Clinical Trial Registration clinicaltrials.gov Identifier: NCT00024505.
Assuntos
Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/genética , Displasia Arritmogênica Ventricular Direita/terapia , Biópsia , Eletrocardiografia , Genótipo , Humanos , Angiografia por Ressonância Magnética/normas , Miocárdio/patologia , Fenótipo , Guias de Prática Clínica como Assunto , Sensibilidade e EspecificidadeRESUMO
Intercalated discs are the membrane sites where individual cardiomyocytes are connected to each other. Adherens-, desmosomal-, and gap junctions are situated in the intercalated disc and ensure mechanical coupling between cells and enable propagation of electrical impulses throughout the heart. A number of cardiac disorders, for example arrhythmogenic right ventricular dysplasia/cardiomyopathy, have been described in which an impaired mechanical coupling leads to electrical dysfunction, with occurrence of fatal arrhythmias. In this article the interaction between electrical and mechanical coupling is explored by reviewing studies performed in patients, animals, and in vitro. In these studies the effect of changes in protein composition of a mechanical junction on the electrical junction, and vice versa were investigated. It is shown that impaired electrical coupling does not change mechanical coupling. However, impaired mechanical coupling largely affects electrical coupling.
Assuntos
Comunicação Celular/fisiologia , Junções Intercelulares/fisiologia , Animais , Fenômenos Biomecânicos , Desmossomos/metabolismo , Desmossomos/fisiologia , Junções Comunicantes/metabolismo , Junções Comunicantes/fisiologia , Humanos , Junções Intercelulares/metabolismo , Modelos Biológicos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologiaRESUMO
INTRODUCTION: Desmosomal changes, electrical uncoupling, and surviving myocardial bundles embedded in fibrofatty tissue are hallmarks of activation delay in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Currently, generally accepted task force criteria (TFC) are used for clinical diagnosis. We propose additional criteria based on activation delay and ventricular tachycardia (VT) to improve identification of affected individuals. METHODS AND RESULTS: Activation delay and VT-related 12-lead electrocardiographic (ECG) criteria were studied, while off drugs, in 42 patients with proven ARVD/C according to TFC, and 27 controls with idiopathic VT from the RV outflow tract. Two of three measured TFC could only be identified in a small minority of ARVD/C patients. Additional ECG criteria proposed in this study included (a) prolonged terminal activation duration, an indicator of activation delay; (b) VT with LBBB morphology and superior axis; and (c) multiple different VT morphologies. These criteria were met in 30 (71%), 28 (67%), and 37 (88%) ARVD/C patients, respectively, and in one control patient (P < 0.001). Electrophysiologic studies contributed importantly to yield different VT morphologies. Pathogenic plakophilin-2 mutations were identified in 25 (60%) of ARVD/C patients and in none of the controls. In ARVD/C patients, parameters measured were not significantly different between mutation carriers and noncarriers, except for negative T waves in V1-3, occurring more frequently in patients with mutation. CONCLUSIONS: The proposed additional criteria are specific for ARVD/C and more sensitive than the current TFC. Therefore, adding the newly proposed criteria to current TFC could improve ARVD/C diagnosis, independent of DNA analysis.
Assuntos
Displasia Arritmogênica Ventricular Direita/complicações , Displasia Arritmogênica Ventricular Direita/diagnóstico , Eletrocardiografia/métodos , Taquicardia Ventricular/complicações , Taquicardia Ventricular/diagnóstico , Adulto , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
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
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently associated with desmosomal mutations. However, nondesmosomal mutations may be involved. The aim of this study was to assess the contribution of a phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised 2010 task force criteria (TFC). In 142 Dutch patients (106 men, mean age 51 ± 13 years) with proven ARVD/C (fulfillment of 2010 TFC for diagnosis), 5 known desmosomal genes (PKP2, DSP, DSC2, DSG2, and JUP) and the nondesmosomal PLN gene were screened. After genetic analysis, phenotypic characteristics of desmosomal versus PLN mutation carriers were compared. In 59 of 142 patients with ARVD/C (42%), no desmosomal mutation was found. In 19 of 142 patients (13%), the PLN founder mutation c.40_42delAGA (p.Arg14del) was identified. PLN mutation carriers more often had low-voltage electrocardiograms (p = 0.004), inverted T waves in leads V4 to V6 (p <0.001), and additional structural (p = 0.007) or functional (p = 0.017) left ventricular impairment, whereas desmosomal mutation carriers had more solitary right ventricular abnormalities. The revised TFC included 21 of 142 patients with proven ARVD/C who did not meet the 1994 TFC, including 7 PLN mutation carriers. In conclusion, there is a substantial contribution of PLN mutation to ARVD/C diagnosis by the 2010 TFC. In 32% of patients (19 of 59) with genetically unexplained proven ARVD/C, this nondesmosomal mutation was found. PLN mutation carriers have ARVD/C characteristics, including important right ventricular involvement, and additionally more often low-voltage electrocardiograms, inverted T waves in the left precordial leads, and left ventricular involvement.