RESUMEN
AIMS: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
Asunto(s)
Cardiomiopatía Dilatada , Insuficiencia Cardíaca Sistólica , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas Reguladoras de la Apoptosis , Cardiomiopatía Dilatada/genética , Cromosomas , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Insuficiencia Cardíaca Sistólica/genética , Humanos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.
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Cardiomiopatía Hipertrófica/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas con Dominio LIM/genética , Proteínas Musculares/genética , Adolescente , Adulto , Anciano , Animales , Cardiomiopatía Hipertrófica/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Niño , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas con Dominio LIM/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Proteínas Musculares/metabolismo , Mutación , Miocitos Cardíacos/metabolismo , Linaje , Adulto JovenRESUMEN
BACKGROUND: Fibrofatty degeneration of myocardium in ARVC is associated with wall motion abnormalities. The aim of this study was to examine whether Cardiovascular Magnetic Resonance (CMR) based strain analysis using feature tracking (FT) can serve as a quantifiable measure to confirm global and regional ventricular dysfunction in ARVC patients and support the early detection of ARVC. METHODS: We enrolled 20 patients with ARVC, 30 with borderline ARVC and 22 subjects with a positive family history but no clinical signs of a manifest ARVC. 10 healthy volunteers (HV) served as controls. 15 ARVC patients received genotyping for Plakophilin-2 mutation (PKP-2), of which 7 were found to be positive. Cine MR datasets of all subjects were assessed for myocardial strain using FT (TomTec Diogenes Software). Global strain and strain rate in radial, circumferential and longitudinal mode were assessed for the right and left ventricle. In addition strain analysis at a segmental level was performed for the right ventricular free wall. RESULTS: RV global longitudinal strain rates in ARVC (-0.68 ± 0.36 sec⻹) and borderline ARVC (-0.85 ± 0.36 sec⻹) were significantly reduced in comparison with HV (-1.38 ± 0.52 sec⻹, p ≤ 0.05). Furthermore, in ARVC patients RV global circumferential strain and strain rates at the basal level were significantly reduced compared with HV (strain: -5.1 ± 2.7 vs. -9.2 ± 3.6%; strain rate: -0.31 ± 0.13 sec(-1) vs. -0.61 ± 0.21 sec⻹). Even for patients with ARVC or borderline ARVC and normal RV ejection fraction (n=30) global longitudinal strain rate proved to be significantly reduced compared with HV (-0.9 ± 0.3 vs. -1.4 ± 0.5 sec(-1); p < 0.005). In ARVC patients with PKP-2 mutation there was a clear trend towards a more pronounced impairment in RV global longitudinal strain rate. On ROC analysis RV global longitudinal strain rate and circumferential strain rate at the basal level proved to be the best discriminators between ARVC patients and HV (AUC: 0.9 and 0.92, respectively). CONCLUSION: CMR based strain analysis using FT is an objective and useful measure for quantification of wall motion abnormalities in ARVC. It allows differentiation between manifest or borderline ARVC and HV, even if ejection fraction is still normal.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/diagnóstico , Interpretación de Imagen Asistida por Computador/métodos , Imagen por Resonancia Cinemagnética/métodos , Contracción Miocárdica , Volumen Sistólico , Función Ventricular Izquierda , Función Ventricular Derecha , Adolescente , Adulto , Anciano , Área Bajo la Curva , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Fenómenos Biomecánicos , Diagnóstico Precoz , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Estrés Mecánico , Adulto JovenRESUMEN
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death especially in times of increased sympathetic tone, for example, during sports, which have been confirmed by nuclear imaging studies. However, the underlying biochemical pathways remain to be delineated. Therefore, we investigated the expression levels of proteins of the signaling cascade in patients with ARVC. METHODS: During diagnostic work-up, right ventricular endomyocardial biopsies (EMBs) were sampled from 15 consecutive male ARVC patients (52 ± 14 years). Tissue levels of key proteins of the signaling cascade were analyzed. Results were compared to those obtained from EMBs of 10 patients with idiopathic right ventricular outflow-tract tachycardia (RVOT; 41 ± 14 years) and of five control subjects without identifiable structural heart disease (42 ± 13 years; P = ns). RESULTS: Among the proteins analyzed, only tissue levels of norepinephrine (NE; P < 0.04) and cyclic adenosine-3´,5´-monophospate (cAMP; P < 0.01) were significantly lower in ARVC when compared to RVOT patients. When compared to controls, mean cAMP levels were lower in patients with ARVC but did not reach statistical significance. No differences in cAMP were observed between RVOT and controls. CONCLUSIONS: The current findings confirm and expand the concept of adrenergic dysfunction in ARVC: the reduction of NE in ARVC could lead to an impaired stimulation of ß-adrenoceptor subsequent signaling pathways with potential implication for cardiac fibrosis and arrhythmogenesis.
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Displasia Ventricular Derecha Arritmogénica/complicaciones , Displasia Ventricular Derecha Arritmogénica/metabolismo , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Enfermedades del Sistema Nervioso Autónomo/metabolismo , AMP Cíclico/metabolismo , Ventrículos Cardíacos/metabolismo , Norepinefrina/metabolismo , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transducción de SeñalRESUMEN
Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the lategadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.
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Displasia Ventricular Derecha Arritmogénica , Cardiomiopatías , Humanos , Cicatriz , Consenso , Medios de Contraste , Gadolinio , Cardiomiopatías/diagnóstico por imagen , Arritmias Cardíacas/diagnósticoRESUMEN
AIMS: Clinical and electrocardiographic (ECG) presentation of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and idiopathic right ventricular outflow-tract tachycardia (RVOT) may be similar. The aim of the study was to assess the validity and utility of T-wave integral measurement as an ECG discriminator of patients with ARVC and RVOT using a body surface mapping (BSM). METHODS AND RESULTS: A 120-channel BSM with quantitative signal analysis of the T-wave integral was performed in 10 patients with ARVC. Results were compared with those obtained from 13 patients with RVOT and a control group of 12 healthy subjects (controls). Age, body mass index, and QRS-axis on surface ECG were not significantly different between the groups. Arrhythmogenic right ventricular cardiomyopathy patients showed a significantly negative T-wave integral in the right lower anterior region of the torso when compared with RVOT (P < 0.001). There was no statistically significant difference between RVOT patients and controls. At a cut-off level of -0.3 mV ms, sensitivity and specificity were 83% [area under curve (AUC) 0.85 ± 0.04 for the comparison of ARVC and RVOT]. These differences were pronounced in ARVC patients with a plakophlin-2 mutation (P < 0.001). CONCLUSION: Quantitative analysis of the BSM T-wave integral in distinct anatomical regions discriminates ARVC patients from RVOT patients and controls and may serve as an additional diagnostic tool.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/diagnóstico , Mapeo del Potencial de Superficie Corporal , Taquicardia Ventricular/diagnóstico , Adulto , Anciano , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/fisiopatología , Estudios de Casos y Controles , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Predisposición Genética a la Enfermedad , Frecuencia Cardíaca , Humanos , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Placofilinas/genética , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Taquicardia Ventricular/fisiopatologíaRESUMEN
Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06 × 10â»6, ORâ = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21 × 10â»5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⻳, ORâ= 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⻳, ORâ = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10â»4, ORâ = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⻹³, OR= 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.
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Cardiomiopatía Dilatada/genética , Predisposición Genética a la Enfermedad , Proteínas de Choque Térmico HSP27/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Desequilibrio de Ligamiento , Modelos Logísticos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. In 32 of 120 unrelated individuals with ARVC, we identified heterozygous mutations in PKP2, which encodes plakophilin-2, an essential armadillo-repeat protein of the cardiac desmosome. In two kindreds with ARVC, disease was incompletely penetrant in most carriers of PKP2 mutations.
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Displasia Ventricular Derecha Arritmogénica/genética , Mutación , Proteínas/genética , Adolescente , Desmosomas , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , PlacofilinasRESUMEN
PURPOSE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a nonischaemic cardiomyopathy and leading cause of sudden death in the young. It has been shown that microvascular dysfunction reflected by an impaired myocardial blood flow (MBF) response to stress is present in patients with other forms of nonischaemic cardiomyopathy, e.g. dilated cardiomyopathy, and that the reduced MBF may be related to a poor prognosis. Therefore, we quantified MBF, coronary flow reserve and coronary vascular resistance in patients with nonfailing ARVC using H(2)(15)O and PET. METHODS: In ten male patients with ARVC (mean age 49 ± 14 years), MBF was quantified at rest and during adenosine-induced hyperaemia using H(2)(15)O PET. Results were compared with those obtained in 20 age-matched healthy male control subjects (mean age 46 ± 14 years). RESULTS: Resting MBF was not significantly different between patients with ARVC and controls (MBF(rest) 1.19 ± 0.29 vs. 1.12 ± 0.20 ml/min/ml). However, hyperaemic MBF was significantly lower in patients with ARVC than in controls (2.60 ± 0.96 vs. 3.68 ± 0.84 ml/min/ml; p = 0.005). Consequently, patients with ARVC had a significantly lower coronary flow reserve than control subjects (2.41 ± 1.34 vs. 3.39 ± 0.93; p = 0.030). In addition, hyperaemic coronary vascular resistance was increased in patients with ARVC (36.79 ± 12.91 vs. 26.31 ± 6.49 mmHg × ml(-1) × min × ml; p = 0.007), but was found to be unchanged at rest. CONCLUSION: In this small well-characterized cohort of patients with nonfailing ARVC, we found a significantly reduced hyperaemic MBF and increased coronary vascular resistance. Further studies are necessary to corroborate this potential new functional aspect of the pathophysiological mechanisms underlying ARVC.
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Displasia Ventricular Derecha Arritmogénica/fisiopatología , Microvasos/fisiopatología , Adulto , Anciano , Displasia Ventricular Derecha Arritmogénica/diagnóstico por imagen , Estudios de Casos y Controles , Circulación Coronaria , Vasos Coronarios/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Resistencia VascularRESUMEN
AIMS: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. METHODS AND RESULTS: One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P < 5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. CONCLUSION: This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.
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Proteínas Adaptadoras Transductoras de Señales/genética , Cardiomiopatía Dilatada/genética , Cromosomas Humanos Par 10/genética , Cromosomas Humanos Par 1/genética , Sitios Genéticos/genética , Insuficiencia Cardíaca/genética , Adulto , Proteínas Reguladoras de la Apoptosis , Canales de Cloruro/genética , Femenino , Estudio de Asociación del Genoma Completo , Proteínas de Choque Térmico HSP27/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: The role of implantable cardioverter-defibrillator (ICD) in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior ventricular fibrillation (VF) or sustained ventricular tachycardia is an unsolved issue. METHODS AND RESULTS: We studied 106 consecutive patients (62 men and 44 women; age, 35.6±18 years) with arrhythmogenic right ventricular cardiomyopathy/dysplasia who received an ICD based on 1 or more arrhythmic risk factors such as syncope, nonsustained ventricular tachycardia, familial sudden death, and inducibility at programmed ventricular stimulation. During follow-up of 58±35 months, 25 patients (24%) had appropriate ICD interventions and 17 (16%) had shocks for life-threatening VF or ventricular flutter. At 48 months, the actual survival rate was 100% compared with the VF/ventricular flutter-free survival rate of 77% (log-rank P=0.01). Syncope significantly predicted any appropriate ICD interventions (hazard ratio, 2.94; 95% confidence interval, 1.83 to 4.67; P=0.013) and shocks for VF/ventricular flutter (hazard ratio, 3.16; 95% confidence interval, 1.39 to 5.63; P=0.005). The positive predictive value of programmed ventricular stimulation was 35% for any appropriate ICD intervention and 20% for shocks for VF/ventricular flutter, with a negative predictive value of 70% and 74%. None of the 27 asymptomatic patients with isolated familial sudden death had appropriate ICD therapy. Twenty patients (19%) had inappropriate ICD interventions, and 18 (17%) had device-related complications. CONCLUSIONS: One fourth of patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia and no prior sustained ventricular tachycardia or VF had appropriate ICD interventions. Syncope was an important predictor of life-saving ICD intervention and is an indication for ICD. Prophylactic ICD may not be indicated in asymptomatic patients because of their low arrhythmic risk regardless of familial sudden death and programmed ventricular stimulation findings. Programmed ventricular stimulation had a low predictive accuracy for ICD therapy.
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Displasia Ventricular Derecha Arritmogénica/fisiopatología , Displasia Ventricular Derecha Arritmogénica/terapia , Desfibriladores Implantables , Taquicardia Ventricular/fisiopatología , Fibrilación Ventricular/fisiopatología , Adolescente , Adulto , Displasia Ventricular Derecha Arritmogénica/mortalidad , Técnicas Electrofisiológicas Cardíacas , Femenino , Estudios de Seguimiento , Humanos , Cooperación Internacional , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenAsunto(s)
Comités Consultivos , Algoritmos , Displasia Ventricular Derecha Arritmogénica/terapia , Agencias Internacionales , Antagonistas Adrenérgicos beta/uso terapéutico , Antiarrítmicos/uso terapéutico , Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/epidemiología , Ablación por Catéter , Desfibriladores Implantables , Electrocardiografía , Trasplante de Corazón , Humanos , Factores de RiesgoRESUMEN
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.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/terapia , Ecocardiografía , Electrocardiografía Ambulatoria , Imagen por Resonancia Magnética , Biopsia , Muerte Súbita Cardíaca , Humanos , Guías de Práctica Clínica como Asunto , Estándares de Referencia , Sensibilidad y EspecificidadRESUMEN
PURPOSE: Increased sympathetic activation is a key modifier for arrhythmogenesis in patients with long QT syndrome (LQTS), a congenital channelopathy. Therefore, we investigated cardiac sympathetic function using 123I-metaiodobenzylguanidine (MIBG) single photon emission computed tomography (SPECT) in a cohort of symptomatic LQTS patients and correlated these findings with the underlying genotype. METHODS: [123I]MIBG SPECT was performed in 28 LQTS patients. Among these, 18 patients (64%) had a previous syncope and 10 patients (36%) survived sudden cardiac arrest. Patients were characterized in terms of genetic subtypes and QTc interval on surface ECGs. SPECT images were analysed for regional [123I]MIBG uptake in a 33-segment bullseye scheme and compared to those obtained from 10 age-matched healthy control subjects (43±12 years). RESULTS: An abnormal 123I-MIBG scan was found in 17 of 28 LQTS patients (61%) with a tracer reduction mainly located in the anteroseptal segments of the left ventricle. This finding was independent of the genetic LQTS subtype. In addition, no differences were found between LQTS patients with a QTc>500 ms vs <500 ms or those suffering from syncope vs VF (p>0.05). CONCLUSION: A distinct regional pattern of impaired cardiac sympathetic function was identified in the majority of symptomatic LQTS patients. This innervation defect was independent of the underlying genotype and clinical disease expression.
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Corazón/inervación , Síndrome de QT Prolongado/fisiopatología , Sistema Nervioso Simpático/fisiopatología , 3-Yodobencilguanidina , Adulto , Anciano , Estudios de Cohortes , Electrocardiografía , Femenino , Genotipo , Corazón/fisiopatología , Humanos , Síndrome de QT Prolongado/diagnóstico por imagen , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/patología , Masculino , Persona de Mediana Edad , Neuronas/diagnóstico por imagen , Neuronas/patología , Sistema Nervioso Simpático/diagnóstico por imagen , Sistema Nervioso Simpático/patología , Tomografía Computarizada de Emisión de Fotón Único , Adulto JovenRESUMEN
BACKGROUND: In patients with Brugada syndrome (BrS), life-threatening ventricular tachyarrhythmias predominantly occur during vagal stimulation at rest or during sleep. Previous imaging studies displayed an impaired autonomic function in BrS patients. However, it remains unclear whether these alterations primarily stem from a reduction of synaptic release of norepinephrine (NE) or an enhanced presynaptic reuptake. Both conditions could lead to reduced NE concentrations in the synaptic cleft. Therefore, we analyzed key components of the sympathoadrenergic signaling pathways in patients with BrS. METHODS AND RESULTS: Endomyocardial biopsies were obtained from eight BrS patients (seven male; age 49 ± 15 years) and five controls (three male; age 43 ± 13 years; P = ns). The concentrations of NE, epinephrine (Epi), NE transport (NET) carrier protein, cyclic adenosine 5'monophosphate (cyclic adenosine monophosphate [cAMP]), inhibitory G-proteins (G(i1,2) α), troponin-I (TNI), and phosphorylated TNI were analyzed. Levels of NET, G(i1,2) α, TNI, Epi, and phosphorylated TNI were comparable between the groups. Compared to controls, patients with BrS showed reduced cAMP and NE concentrations. CONCLUSIONS: The current findings expand the concept of adrenergic dysfunction in BrS: the reduction of NE in BrS could lead to an impaired stimulation of ß-adrenoceptors resulting in a reduction of cAMP and alterations of the subsequent signaling pathway with potential implication for arrhythmogenesis.
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Sistema Nervioso Autónomo/fisiopatología , Síndrome de Brugada/fisiopatología , Transducción de Señal/fisiología , Adulto , Biopsia , AMP Cíclico/análisis , Epinefrina/análisis , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/análisis , Corazón/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Miocardio/química , Miocardio/metabolismo , Norepinefrina/análisis , Troponina/análisisAsunto(s)
Displasia Ventricular Derecha Arritmogénica/terapia , Antagonistas Adrenérgicos beta/uso terapéutico , Antiarrítmicos/uso terapéutico , Ablación por Catéter/métodos , Consenso , Desfibriladores Implantables , Técnicas Electrofisiológicas Cardíacas/métodos , Fibrinolíticos/uso terapéutico , Insuficiencia Cardíaca/etiología , Trasplante de Corazón/métodos , Humanos , Cuidados a Largo Plazo , Guías de Práctica Clínica como Asunto , Medición de Riesgo/métodos , Conducta de Reducción del RiesgoRESUMEN
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.
Asunto(s)
Displasia Ventricular Derecha Arritmogénica/diagnóstico , Displasia Ventricular Derecha Arritmogénica/genética , Displasia Ventricular Derecha Arritmogénica/terapia , Biopsia , Electrocardiografía , Genotipo , Humanos , Angiografía por Resonancia Magnética/normas , Miocardio/patología , Fenotipo , Guías de Práctica Clínica como Asunto , Sensibilidad y EspecificidadRESUMEN
Arrhythmogenic cardiomyopathy (AC) is a rare heart muscle disease with a genetic background and autosomal dominant mode of transmission. The clinical manifestation is characterized by ventricular arrhythmias (VA), heart failure (HF) and the risk of sudden cardiac death (SCD). Pregnancy in young female patients with AC represents a challenging condition for the life and family planning of young affected women. In addition to genetic mechanisms that influence the complex pathophysiology of AC, experimental and clinical data have confirmed the pathogenetic role of strenuous exercise and competitive sports in the early onset and rapid progression of AC symptoms and complications. Pregnancy and exercise share a number of physiological aspects of adaptation. In AC, both result in ventricular volume overload and myocardial stretch. Therefore, pregnancy has been postulated as a potential risk factor for HF, VA, SCD, and pregnancy-related obstetric complications in patients with AC. However, the available evidence on pregnancy in AC does not confirm this hypothesis. In most women with AC, pregnancies are well tolerated, uneventful, and follow a benign course. Pregnancy-related symptoms (VA, syncope, HF) and mortality, as well as obstetric complications, are uncommon in AC patients and range in the order of background populations and cohorts with AC and no pregnancy. The number of completed pregnancies is not associated with an acceleration of AC pathology or an increased risk of VA or HF during pregnancy and follow-up. Accordingly, there is no medical indication to advise against pregnancy in patients with AC. Preconditions include stability of rhythm and hemodynamics at baseline, as well as clinical follow-ups and the availability of multidisciplinary expert consultation during pregnancy and postpartum. Genetic counseling is recommended prior to pregnancy for all couples and their families affected by AC.