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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.
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INTRODUCTION: Pulmonary vein isolation (PVI) is an important treatment for atrial fibrillation (AF). However, many patients need more than one procedure to maintain long-term sinus rhythm. Even after two PVIs some may suffer from AF recurrences. We aimed to identify characteristics of patients who fail after two PVI procedures. METHODS AND RESULTS: We included 557 consecutive patients undergoing a first PVI procedure with a second-generation 28 mm cryoballoon. Follow-up procedures were performed using radiofrequency ablation targeting reconnected PVs only. Recurrent AF was defined as any episode of AF lasting >30 s on ECG or 24 hour Holter monitoring performed at 3, 6 and 12 months post procedure. Mean age was 59.1±10.2 years, 383 (68.8%) were male, 448 (80.4%) had paroxysmal AF and the most common underlying condition was hypertension (36.6%). A total of 140/557 (25.1%) patients underwent redo procedure with PVI only. Of these patients 45 (32.4%) had recurrence of AF. These patients were comparable regarding age and sex to those in sinus rhythm after one or two procedures. Multivariate logistic regression showed that non-paroxysmal AF (OR 1.08 (95% CI 1.01 to 1.15), estimated glomerular filtration rate (OR 0.96, 95% CI 0.94 to 0.99), bundle branch block (OR 4.17, 95% CI 1.38 to 12.58), heart failure (OR 4.17, 95% CI 1.38 to 12.58) and Left Atrium Volume Index (OR 1.04, 95% CI 1.01 to 1.08) were associated with AF recurrence after two PVIs. The area under the curve for the identified risk factors was 0.74. CONCLUSIONS: Using a PVI-only approach, recurrence of AF after two AF ablation procedures is associated with more advanced underlying disease and persistent types of AF.
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Fibrilación Atrial/epidemiología , Ablación por Catéter , Electrocardiografía Ambulatoria/métodos , Venas Pulmonares/cirugía , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/cirugía , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Recurrencia , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Danon disease is a rare X-linked multisystemic disorder that has primarily been described in male patients. CASE SUMMARY: We present three female patients with Danon disease with a predominantly cardiac phenotype in whom disease onset and expression was very different from that of male patients. Case 1 was first admitted for acute heart failure and then readmitted a few months later for cardiac shock, necessitating mechanical support, and heart transplantation. Case 2 had complex arrhythmias for which many antiarrhythmic drugs were tried with only limited success. Her disease accelerated after her first pregnancy, and she showed reduced left ventricular function and dilated cardiomyopathy. Case 3 was referred for near syncope and ablated for an accessory pathway; she had extensive left ventricular hypertrophy. In all three cases, a final diagnosis of Danon disease was only made after genetic testing that identified a causal variant in the lysosome-associated membrane protein 2 gene. DISCUSSION: Danon disease in female patients is a challenging diagnosis that may not be identified until genetic testing has been performed.
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BACKGROUND: Cryoballoon isolation is considered a safe and effective treatment for atrial fibrillation (AF). However, recurrence of AF after first cryoballoon ablation occurs in ~30% of patients. Pre-procedurally identifying patients at risk of AF recurrence could be beneficial. HYPOTHESIS: Our aim was to determine how pulmonary vein (PV) anatomy influences the recurrence of AF using the second-generation cryoballoon in patients with paroxysmal AF. METHODS: We included 88 consecutive patients with paroxysmal AF undergoing PVI procedure with a second-generation 28-mm cryoballoon. All patients were evaluated at 3, 6 and 12 months using a 12-lead ECG and 24-hour Holter monitoring. PV anatomy was assessed by creating three-dimensional models using computed tomography (CT) segmentations of the left atrium. RESULTS: Fifty-one patients (61%) had left PVs with a shared carina, 35 patients (42%) had a shared right carina. Nine patients (11%) were classified having a right middle PV. In total 17 (20.2%) of patients had a left common PV. At 12 months, 14 patients (17%) had experienced AF recurrence. Neither PV ovality, variant anatomy, the presence of shared carina nor a common left PV was a predictor for AF recurrence. CONCLUSIONS: No specific characteristics of PV dimensions nor morphology were associated with AF recurrence after cryoballoon ablation in patients with paroxysmal AF.
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Fibrilación Atrial/cirugía , Criocirugía/métodos , Sistema de Conducción Cardíaco/fisiopatología , Imagenología Tridimensional , Tomografía Computarizada Multidetector/métodos , Venas Pulmonares/diagnóstico por imagen , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/fisiopatología , Electrocardiografía Ambulatoria , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Venas Pulmonares/cirugía , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an uncommon inherited arrhythmia disorder characterized by adrenergically evoked ventricular arrhythmias. Mutations in the cardiac calcium release channel/ryanodine receptor gene (RYR2) are identified in the majority of patients with CPVT. RyR2 is also the major RyR isoform expressed in the brain. OBJECTIVE: The purpose of this study was to estimate the prevalence of intellectual disability (ID) and other neurodevelopmental disorders (NDDs) in RYR2-associated CPVT (CPVT1) and to study the characteristics of these patients. METHODS: We reviewed the medical records of all CPVT1 patients from 12 international centers and analyzed the characteristics of all CPVT1 patients with concomitant NDDs. We functionally characterized the mutations to assess their response to caffeine activation. We did not correct for potential confounders. RESULTS: Among 421 CPVT1 patients, we identified 34 patients with ID (8%; 95% confidence interval 6%-11%). Median age at diagnosis was 9.3 years (interquartile range 7.0-14.5). Parents for 24 of 34 patients were available for genetic testing, and 13 of 24 (54%) had a de novo mutation. Severity of ID ranged from mild to severe and was accompanied by other NDDs in 9 patients (26%). Functionally, the ID-associated mutations showed a markedly enhanced response of RyR2 to activation by caffeine. Seventeen patients (50%) also had supraventricular arrhythmias. During median follow-up of 8.4 years (interquartile range 1.8-12.4), 15 patients (45%) experienced an arrhythmic event despite adequate therapy. CONCLUSION: Our study indicates that ID is more prevalent among CPVT1 patients (8%) than in the general population (1%-3%). This subgroup of CPVT1 patients reveals a malignant cardiac phenotype with marked supraventricular and ventricular arrhythmias.
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Encéfalo/diagnóstico por imagen , Miocardio/patología , Trastornos del Neurodesarrollo/etiología , Canal Liberador de Calcio Receptor de Rianodina/genética , Taquicardia Ventricular/complicaciones , Adolescente , Niño , Análisis Mutacional de ADN , Femenino , Estudios de Seguimiento , Pruebas Genéticas , Humanos , Imagen por Resonancia Cinemagnética , Masculino , Mutación , Países Bajos/epidemiología , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/epidemiología , Fenotipo , Prevalencia , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Tomografía Computarizada por Rayos X , Reino Unido/epidemiología , Estados Unidos/epidemiologíaRESUMEN
Aims: Obesity is an increasing health problem and is an important risk factor for the development of atrial fibrillation (AF). We investigated the association of body mass index (BMI) on the safety and long-term efficacy of pulmonary vein isolation (PVI) for drug-refractory AF. Methods: 414 consecutive patients who underwent transcatheter PVI for AF between 2003 and 2013 were included. Successful PVI was defined as absence of atrial arrhythmia on Holter monitoring or ECG, without and with antiarrhythmic drugs during follow-up. Obesity was defined as BMI≥30 kg/m². Results: Mean age was 56±10 years, 316 (76%) were male, 311 (75%) had paroxysmal AF and 111 (27%) were obese. After a mean follow-up of 46±32 months (1590 patient-years), freedom from atrial arrhythmia and antiarrhythmic drugs was significantly lower in patients with obesity compared with non-obese patients (30% vs 46%, respectively, P=0.005, log-rank 0.016). With antiarrhythmic drugs, freedom from atrial arrhythmia was 56% vs 68% (P=0.036). No differences in minor and major adverse events were observed between patients with obesity and non-obese patients (major 6% vs 3%, P=0.105, and minor 5% vs 5%, P=0.512). Sensitivity analyses demonstrated that BMI (as continuous variable) was associated with PVI outcome (HR 1.08, 95% CI 1.02 to 1.14, P=0.012). Conclusion: Obesity is associated with reduced efficacy of PVI for drug-refractory AF. No relation between obesity and adverse events was found.
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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 Ventricular Derecha Arritmogénica/diagnóstico , Adulto , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/mortalidad , Muerte Súbita Cardíaca , Desfibriladores Implantables , Desmocolinas/genética , Desmogleína 2/genética , Desmoplaquinas/genética , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Placofilinas/genética , Polimorfismo Genético , gamma CateninaRESUMEN
AIMS: Pulmonary vein isolation (PVI) can be considered for treatment of symptomatic atrial fibrillation (AF). Nowadays, in addition to transcatheter ablation, thoracoscopic surgical PVI is available. The aim of this study is to compare clinical outcome of surgical with transcatheter PVI as first invasive treatment strategy of AF. METHODS AND RESULTS: From June 2009 to November 2011, 33 patients underwent minimally invasive surgical PVI, and were matched (1:2 fashion) retrospectively according to age, sex, and AF type, with 66 patients who underwent transcatheter PVI. Success was defined as freedom from atrial arrhythmias on 24 h Holter monitoring without use of anti-arrhythmic drugs (AADs) at 1 year. Mean age was 52 ± 10 years, 82% were male. Paroxysmal AF was present in 76 patients (77%), persistent AF in 23 (23%) patients. None underwent prior ablations, and failed on 1.2 ± 0.6 AADs. At 12 months, complete freedom from atrial arrhythmias without AADs in the surgical PVI group was 88% compared with 41% in the transcatheter PVI group (P < 0.001). Freedom from atrial arrhythmias with AADs was 91 vs. 62%, in the surgical vs. transcatheter PVI group, respectively (P = 0.002). Complications occurred in seven (21%) surgical PVI patients, and three (5%) transcatheter PVI patients (P = 0.015). CONCLUSION: In present matched study comparing a surgical with transcatheter PVI treatment strategy in symptomatic AF patients failed on AADs, but without prior ablations, a surgical PVI strategy was more effective to prevent recurrence of atrial arrhythmias, than a transcatheter PVI treatment strategy. However, complications were more frequent with surgical PVI.
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Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Sistema de Conducción Cardíaco/cirugía , Venas Pulmonares/cirugía , Toracoscopía/métodos , Fibrilación Atrial/diagnóstico , Femenino , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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.
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Displasia Ventricular Derecha Arritmogénica/genética , Proteínas de Unión al Calcio/genética , ADN/genética , Desmosomas/genética , Pruebas Genéticas/métodos , Ventrículos Cardíacos/fisiopatología , Mutación , Comités Consultivos , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/metabolismo , Proteínas de Unión al Calcio/metabolismo , Análisis Mutacional de ADN , Electrocardiografía , Femenino , Predisposición Genética a la Enfermedad , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Linaje , UltrasonografíaRESUMEN
AIMS: To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM). METHODS AND RESULTS: We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del- DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 %) R14del+ ARVC samples, but in only one of nine (11 %) R14del+ DCM samples (P = 0.03). CONCLUSIONS: The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.
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Displasia Ventricular Derecha Arritmogénica/genética , Proteínas de Unión al Calcio/genética , Cardiomiopatía Dilatada/genética , Adulto , Muerte Súbita Cardíaca , Femenino , Humanos , Masculino , Mutación , Fenotipo , Estudios Retrospectivos , Estadística como AsuntoRESUMEN
OBJECTIVES: The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result. BACKGROUND: ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test. METHODS: Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database. RESULTS: The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2. CONCLUSIONS: This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation.
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Displasia Ventricular Derecha Arritmogénica/epidemiología , Displasia Ventricular Derecha Arritmogénica/genética , Predisposición Genética a la Enfermedad , Adulto , Estudios de Casos y Controles , Análisis Mutacional de ADN , Pruebas Genéticas , Humanos , Persona de Mediana Edad , PrevalenciaRESUMEN
OBJECTIVE: Amiodarone is frequently associated with thyroid dysfunction. Identifying predictors for amiodarone-associated thyroid dysfunction and assessing treatment outcome may aid clinicians in daily practice. METHODS: We included 303 consecutive patients with amiodarone therapy for cardiac arrhythmias (260 with atrial fibrillation and 43 with ventricular arrhythmias). Thyroid function tests were performed every 6 months. RESULTS: Mean age was 63 ± 12 years and 66% was male. After median follow-up of 3·3 (0·1-24) years, 23 (8%) patients developed amiodarone-associated thyrotoxicosis (incidence rate 1·9 per 100 person years) and 18 (6%) hypothyroidism (incidence rate 1·1 per 100 person years). The only predictor for amiodarone-associated thyrotoxicosis was age <62 years [HR = 2·4 (95% CI 1·0-5·7), P = 0·05]. Predictors for amiodarone-associated hypothyroidism were thyroid stimulating hormone >1·4 mU/l at baseline [HR = 5·1 (95% CI 1·1-22·4), P = 0·03], left ventricular ejection fraction <45% [HR = 3·8 (95% CI 1·1-13·3), P = 0·04] and diabetes mellitus at baseline [HR = 3·3 (95% CI 1·1-10·3), P = 0·04]. Gender was not a predictor for amiodarone-associated thyroid dysfunction. Five out of 12 (42%) patients with thyrotoxicosis exhibited spontaneous normalization of thyroid function on continuation of amiodarone therapy. Mean time to normalization in the total group was 6·2 ± 3·3 months, with no difference between continuing or discontinuing amiodarone (6·6 ± 3·8 vs 5·8 ± 2·8 months, P = 0·5). CONCLUSIONS: During median follow-up of 3·3 years, the incidence of amiodarone-associated thyrotoxicosis was higher compared to hypothyroidism. Only general predictors for amiodarone-associated thyroid dysfunction were observed. Discontinuation of amiodarone did not influence treatment outcome.
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Amiodarona/efectos adversos , Arritmias Cardíacas/tratamiento farmacológico , Hipotiroidismo/fisiopatología , Tirotoxicosis/fisiopatología , Adulto , Factores de Edad , Anciano , Amiodarona/uso terapéutico , Antiarrítmicos/efectos adversos , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/fisiopatología , Bases de Datos Factuales/estadística & datos numéricos , Diabetes Mellitus/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Hipotiroidismo/inducido químicamente , Hipotiroidismo/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Pruebas de Función de la Tiroides , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiopatología , Tirotoxicosis/inducido químicamente , Tirotoxicosis/metabolismo , Tirotropina/metabolismo , Resultado del TratamientoRESUMEN
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.
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Displasia Ventricular Derecha Arritmogénica , Muerte Súbita Cardíaca/epidemiología , Desmosomas/patología , Familia , Adolescente , Adulto , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/mortalidad , Displasia Ventricular Derecha Arritmogénica/patología , Enfermedades Asintomáticas/mortalidad , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Fenotipo , Valor Predictivo de las Pruebas , Factores de Riesgo , Taquicardia Ventricular/genética , Taquicardia Ventricular/mortalidad , Taquicardia Ventricular/patología , Fibrilación Ventricular/genética , Fibrilación Ventricular/mortalidad , Fibrilación Ventricular/patología , Adulto JovenRESUMEN
AIMS: The aim of this study was to investigate the prognostic value of natriuretic peptides and atrial fibrillation (AF) on response to cardiac resynchronization therapy (CRT) and mortality. METHODS AND RESULTS: This study included 338 consecutive CRT patients. Response to CRT was defined as a reduction in left ventricular end-systolic volume of ≥15% in the absence of death at 6-month follow-up. During follow-up (27 ± 19 months), 139 patients (41%) had AF, being new onset in 40 patients (21%). Forty-two patients (12%) had permanent AF. Response to CRT was observed in 168 of 302 patients (56%): 60 of 123 patients (43%) with AF vs. 108 of 179 patients (60%) without AF (P = 0.047). Low baseline atrial natriuretic peptide (ANP) [odds ratio for log(2) ANP 0.49, 95% confidence interval (CI) 0.35-0.68, P < 0.001] and large left ventricular end-systolic volume (odds ratio for every 50 mL 1.40, 95% CI 1.09-1.79, P = 0.009) were independent predictors of response. Neither the presence of AF nor the increase in AF burden independently predicted response. Ninety patients (27%) died; 50 patients (36%) with AF vs. 40 patients (20%) without AF (log rank P = 0.029). Important predictors of all-cause mortality were new-onset AF (hazard ratio 8.11, 95% CI 3.31-19.85, P < 0.001), permanent AF (hazard ratio 3.19, 95% CI 1.61-6.30, P = 0.001), and baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) (hazard ratio for log(2) NT-proBNP 0.77, 95% CI 0.66-0.90, P = 0.001). CONCLUSION: In patients treated with CRT, lower ANP and larger left ventricular end-systolic volume were independent predictors of response. New-onset AF, permanent AF, and NT-proBNP were independently associated with increased all-cause mortality.
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Fibrilación Atrial/epidemiología , Factor Natriurético Atrial/sangre , Terapia de Resincronización Cardíaca , Insuficiencia Cardíaca/mortalidad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anciano , Femenino , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , UltrasonografíaRESUMEN
BACKGROUND: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Diagnostic Task Force Criteria (TFC) proposed in 1994 are highly specific but lack sensitivity. A new international task force modified criteria to improve diagnostic yield. A comparison of diagnosis by 1994 TFC versus newly proposed criteria in 3 patient groups was conducted. METHODS AND RESULTS: In new TFC, scoring by major and minor criteria is maintained. Structural abnormalities are quantified and TFC highly specific for ARVD/C upgraded to major. Furthermore, new criteria are added: terminal activation duration of QRS > or = 55 ms, ventricular tachycardia with left bundle-branch block morphology and superior axis, and genetic criteria. Three groups were studied: (1) 105 patients with proven ARVD/C according to 1994 TFC, (2) 89 of their family members, and (3) 39 patients with probable ARVD/C (ie, 3 points by 1994 TFC). All were screened for pathogenic mutations in desmosomal genes. Three ARVD/C patients did not meet the new sharpened criteria on structural abnormalities and thereby did not fulfill new TFC. In 62 of 105 patients with proven ARVD/C, mutations were found: 58 in the gene encoding Plakophilin2 (PKP2), 3 in Desmoglein2, 3 in Desmocollin2, and 1 in Desmoplakin. Three patients had bigenic involvement. Ten additional relatives (11%) fulfilled new TFC: 9 (90%) were female, and all carried PKP2 mutations. No relatives lost diagnosis by application of new TFC. Of patients with probable ARVD/C, 25 (64%) fulfilled new TFC: 8 (40%) women and 14 (56%) carrying pathogenic mutations. CONCLUSIONS: In this first study applying new TFC to patients suspected of ARVD/C, 64% of probable ARVD/C patients and 11% of family members were additionally diagnosed. ECG criteria and pathogenic mutations especially contributed to new diagnosis. Newly proposed TFC have a major impact in increasing diagnostic yield of ARVD/C.
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Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/genética , Técnicas de Diagnóstico Cardiovascular/estadística & datos numéricos , Técnicas de Diagnóstico Cardiovascular/normas , Adulto , Cineangiografía/normas , Cineangiografía/estadística & datos numéricos , Estudios de Cohortes , Desmocolinas/genética , Desmogleína 2/genética , Electrocardiografía Ambulatoria/normas , Electrocardiografía Ambulatoria/estadística & datos numéricos , Prueba de Esfuerzo/normas , Prueba de Esfuerzo/estadística & datos numéricos , Salud de la Familia , Humanos , Imagen por Resonancia Magnética/normas , Imagen por Resonancia Magnética/estadística & datos numéricos , Persona de Mediana Edad , Mutación , Placofilinas/genética , Sensibilidad y Especificidad , Adulto JovenRESUMEN
BACKGROUND: This study aimed to evaluate the prevalence and type of mutations in the major desmosomal genes, Plakophilin-2 (PKP2), Desmoglein-2 (DSG2), and Desmocollin-2 (DSC2), in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We also aimed to distinguish relevant clinical and ECG parameters. METHODS AND RESULTS: Clinical evaluation was performed according to the Task Force Criteria (TFC). We analyzed the genes in (a) 57 patients who fulfilled the ARVD/C TFC (TFC+), (b) 28 patients with probable ARVD/C (1 major and 1 minor, or 3 minor criteria), and (c) 31 patients with 2 minor or 1 major criteria. In the TFC+ ARVD/C group, 23 patients (40%) had PKP2 mutations, 4 (7%) had DSG2 mutations, and 1 patient (2%) carried a mutation in DSC2, whereas 1 patient (2%) had a mutation in both DSG2 and DSC2. Among the DSG2 and DSC2 mutation-positive TFC+ ARVD/C probands, 2 carried compound heterozygous mutations and 1 had digenic mutations. In probable ARVD/C patients and those with 2 minor or 1 major criteria for ARVD/C, mutations were less frequent and they were all heterozygous. Negative T waves in the precordial leads were observed more (P<0.002) among mutation carriers than noncarriers and in particular in PKP2 mutation carriers. CONCLUSIONS: Mutations in DSG2 and DSC2 are together less prevalent (10%) than PKP2 mutations (40%) in Dutch TFC+ ARVD/C patients. Interestingly, biallelic or digenic DSC2 and/or DSG2 mutations are frequently identified in TFC+ ARVD/C patients, suggesting that a single mutation is less likely to cause a full-blown ARVD/C phenotype. Negative T waves on ECG were prevalent among mutation carriers (P<0.002).
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/genética , Desmocolinas/genética , Desmogleína 2/genética , Mutación , Adolescente , Adulto , Displasia Ventricular Derecha Arritmogénica/metabolismo , Estudios de Cohortes , Desmocolinas/metabolismo , Desmogleína 2/metabolismo , Desmosomas/genética , Desmosomas/metabolismo , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Linaje , Placofilinas/genética , Placofilinas/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Desmin-related myopathy is a clinically heterogenous group of disorders encompassing myopathies, cardiomyopathies, conduction disease, and combinations of these disorders. Mutations in the gene encoding desmin (DES), a major intermediate filament protein, can underlie this phenotype. OBJECTIVE: The purpose of this study was to investigate the clinical and pathologic characteristics of 27 patients from five families with an identical mutation in the head domain region (p.S13F) of desmin. METHODS/RESULTS: All 27 carriers or obligate carriers of a p.S13F DES founder mutation demonstrated a fully penetrant yet variable phenotype. All patients demonstrated cardiac involvement characterized by high-grade AV block at young ages and important right ventricular (RV) involvement. RV predominance was demonstrated by the presence of right bundle branch block in 10 patients (sometimes as a first manifestation) and by RV heart failure in 6 patients, including 2 patients who fulfilled the diagnostic criteria for arrhythmogenic RV cardiomyopathy. Because of this clinical overlap with desmosome cardiomyopathies, we also studied the organization of the intercalated disks, particularly the distribution of desmosomal proteins. Normal amounts of the major desmosomal proteins were found, but the intercalated disks were more convoluted and elongated and had a zigzag appearance. CONCLUSION: In this largest series to date of individuals with a single head domain DES mutation, patients show a variable yet predominantly cardiologic phenotype characterized by conduction disease at an early age and RV involvement including right bundle branch block and/or RV tachycardias and arrhythmogenic RV cardiomyopathy phenocopies. A localized effect of desmin on the structure of the cardiac intercalated disks might contribute to disease pathogenesis.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/genética , Desmina/genética , Linaje , Fenotipo , Adolescente , Adulto , Displasia Ventricular Derecha Arritmogénica/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Índice de Severidad de la EnfermedadRESUMEN
AIMS: Transvenous pulmonary vein isolation (PVI) is the cornerstone of non-pharmacological rhythm control therapy in symptomatic atrial fibrillation (AF). Success and complications rates are, however, still not optimal. New techniques and energy sources are therefore being developed. METHODS AND RESULTS: Fifteen patients with lone AF refractory for antiarrhythmic drugs (AADs) underwent PVI by minimal invasive epicardial off-pump monolateral right-sided video-assisted thoracic surgery (VATS) using the UltraCinch with high-intensity focused ultrasound (HIFU). Primary endpoint was successful ablation defined as absence of AF or atrial flutter/tachycardia after 6 months assessed by complaints, 12 lead electrocardiogram, and 96 h Holter monitoring. Secondary endpoints were ablation success at the end of follow-up irrespective of AADs use or re-ablation and complications related to the procedure. Mean age was 47 +/- 10 years and 14 (93%) were male. Eleven (73%) had paroxysmal, and 4 (27%) patients had persistent AF. Median AF history was 5 (1-12) years. At 6 months, six (40%) patients had sinus rhythm after one epicardial PVI (four on AADs). After 1.3 +/- 0.6 years, four (27%) patients had sinus rhythm after one epicardial PVI (two on AADs) and in six (40%) patients endocardial radiofrequency re-ablation was performed, which was successful in three patients (20%). Two patients (13%) were planned for re-ablation. Three others (20%) refused re-ablation. Two major complications occurred (one late tamponade and one bleeding during surgery, necessitating sternotomy). CONCLUSION: Epicardial PVI using monolateral right-sided VATS with the UltraCinch delivering HIFU is feasible, but is associated with substantial complications. Furthermore, the success rate was low. More research is therefore warranted to assess optimal ablation techniques and energy sources to perform PVI.
Asunto(s)
Fibrilación Atrial/cirugía , Sistema de Conducción Cardíaco/cirugía , Ultrasonido Enfocado de Alta Intensidad de Ablación/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Pericardio/cirugía , Venas Pulmonares/cirugía , Terapia Combinada , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: Desmosomal changes, electric uncoupling, and surviving myocardial bundles in fibrofatty tissue characterize arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Resultant activation delay is pivotal for reentry and thereby ventricular tachycardia (VT). Current task force criteria (TFC) for diagnosis have limited sensitivity. The aim of this study was to assess the diagnostic value of additional criteria on activation delay and VT to improve identification of affected individuals. METHODS AND RESULTS: ECG criteria were studied, while off drugs, in 50 index patients with proven ARVD/C according to TFC (TFC > or = 4 points) and 33 patients with probable ARVD/C (TFC 3 points, or TFC3), being 21 index patients and 12 family members of proven ARVD/C patients. Newly proposed additional criteria are (1) prolonged terminal activation duration in V(1)-V(3), an indicator of activation delay, (2) VT with left bundle-branch block morphology and superior axis, and (3) multiple VT morphologies. All index patients were screened for mutations in ARVD/C-related genes encoding desmosomal proteins. Altogether, 23 of 33 (70%) TFC3 patients fulfilled ARVD/C diagnosis when newly proposed criteria were applied additionally to current TFC. VT with left bundle-branch block morphology and superior axis or multiple VT morphologies were recorded in 12 and 9 of 33 TFC3 patients, respectively, all being index patients. When applying prolonged terminal activation duration additionally to TFC on depolarization/conduction abnormalities, 14 (42%) TFC3 patients fulfilled ARVD/C diagnosis. Results were not significantly different between mutation carriers and noncarriers. CONCLUSIONS: Adding the newly proposed criteria to current TFC for ARVD/C will improve identification of affected individuals importantly, independent of outcome of DNA analyses.