RESUMO
With the trend towards childhood surgery in patients with Ebstein anomaly (EA), thorough imaging is crucial for patient selection. This study aimed to assess biventricular function by echocardiography and cardiac magnetic resonance (CMR) and compare EA severity classifications. Twenty-three patients (8-17 years) underwent echocardiography and CMR. Echocardiographic parameters included tricuspid annular plane systolic excursions (TAPSE), fractional area change of the functional right ventricle (fRV-FAC), fRV free wall peak systolic myocardial velocity (fRVs'), and tricuspid regurgitation (TR). End-diastolic and end-systolic volume (EDV resp. ESV), fRV- and LV ejection fraction (EF) and TR were obtained by CMR. EA severity classifications included displacement index, Celermajer index and the total-right/left-volume index. Median fRV-FAC was 38% (IQR 33-42). TAPSE and fRVs' were reduced in 39% and 75% of the patients, respectively. Echocardiographic TR was visually graded as mild, moderate, or severe in nine, six and eight patients, respectively. By CMR, median fRVEF was 49% (IQR 36-58) and TR was graded as mild, moderate, or severe in nine, twelve and two patients, respectively. In 70% of cases, fRV-EDV was higher than LV-EDV. LVEF was decreased in 17 cases (74%). There was excellent correlation between echocardiography-derived fRV-FAC and CMR-derived fRVEF (rho = 0.812, p < 0.001). While echocardiography is a versatile tool in the complex geometry of the Ebstein heart, it has limitations. CMR offers a total overview and has the advantage of reliable volume assessment of both ventricles. Comprehensive evaluation of pediatric patients with EA may therefore require a synergistic implementation of echocardiography and CMR.
Assuntos
Anomalia de Ebstein , Ecocardiografia , Imageamento por Ressonância Magnética , Adolescente , Criança , Humanos , Anomalia de Ebstein/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Reprodutibilidade dos Testes , Insuficiência da Valva Tricúspide/diagnóstico por imagem , Volume SistólicoRESUMO
A single 6-min walk test (6MWT) can be used to identify children with dilated cardiomyopathy (DCM) with a high risk of death or heart transplantation. To determine if repeated 6MWT has added value in addition to a single 6MWT in predicting death or heart transplantation in children with DCM. Prospective multicenter cohort study including ambulatory DCM patients ≥ 6 years. A 6MWT was performed 1 to 4 times per year. The distance walked was expressed as percentage of predicted (6MWD%). We compared the temporal evolution of 6MWD% in patients with and without the study endpoint (SE: all-cause death or heart transplantation), using a linear mixed effects model. In 57 patients, we obtained a median of 4 (IQR 2-6) 6MWTs per patient during a median of 3.0 years of observation (IQR 1.5-5.1). Fourteen patients reached a SE (3 deaths, 11 heart transplantations). At any time during follow-up, the average estimate of 6MWD% was significantly lower in patients with a SE compared to patients without a SE. In both patients groups, 6MWD% remained constant over time. An absolute 1% lower 6MWD% was associated with an 11% higher risk (hazard) of the SE (HR 0.90, 95% CI 0.86-0.95 p < 0.001). Children with DCM who died or underwent heart transplantation had systematically reduced 6MWD%. The performance of all patients was stable over time, so repeated measurement of 6MWT within this time frame had little added value over a single test.
Assuntos
Cardiomiopatia Dilatada/mortalidade , Teste de Caminhada , Adolescente , Criança , Feminino , Transplante de Coração/estatística & dados numéricos , Humanos , Masculino , Estudos Prospectivos , Medição de Risco , Fatores de Tempo , Teste de Caminhada/estatística & dados numéricosRESUMO
PURPOSE: We evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM. METHODS: We identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES. We used Human Phenotype Ontology (HPO)-based filtering for our data analysis. RESULTS: We reached a genetic diagnosis in 15/31 (48.4%) families. ES yielded a diagnosis in 13 probands (13/15; 86.7%), with most variants being found in genes encoding structural cardiomyocyte components. Two large deletions were identified using SNP array. If we had included the 13 excluded families, our estimated yield would have been 54%. CONCLUSION: We propose a standardized, stepwise analysis of (i) well-known cardiomyopathy genes, (ii) CNVs, (iii) all genes assigned to HPO cardiomyopathy, and (iv) if appropriate, genes assigned to other HPO terms. This diagnostic approach yields the highest increase at each subsequent step and reduces analytic effort, cost, the number of variants of unknown clinical significance, and the chance of incidental findings.
Assuntos
Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Variações do Número de Cópias de DNA/genética , Testes Genéticos/métodos , Adolescente , Cardiomiopatia Dilatada/patologia , Criança , Pré-Escolar , Exoma/genética , Feminino , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Deleção de Sequência/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: Some infants with congenital heart disease are at risk of in-hospital cardiac arrest. To better foresee cardiac arrest in infants with congenital heart disease, it might be useful to continuously assess end-organ perfusion. Near-infrared spectroscopy is a non-invasive method to continuously assess multisite regional tissue oxygen saturation. CASE PRESENTATION: We report on two infants with duct-dependent congenital heart disease who demonstrated a gradual change in cerebral and/or renal tissue oxygen saturation before cardiopulmonary resuscitation was required. In both cases, other clinical parameters such as heart rate, arterial oxygen saturation and blood pressure did not indicate that deterioration was imminent. CONCLUSIONS: These two cases demonstrate that near-infrared spectroscopy might contribute to detecting a deteriorating clinical condition and might therefore be helpful in averting cardiopulmonary collapse and need for resuscitation in infants with congenital heart disease.
Assuntos
Parada Cardíaca/prevenção & controle , Cardiopatias Congênitas/fisiopatologia , Oxigênio/metabolismo , Espectroscopia de Luz Próxima ao Infravermelho , Biomarcadores/metabolismo , Encéfalo/metabolismo , Feminino , Parada Cardíaca/diagnóstico , Parada Cardíaca/etiologia , Cardiopatias Congênitas/metabolismo , Humanos , Recém-Nascido , Rim/metabolismo , MasculinoRESUMO
OBJECTIVES: This study aimed to evaluate the predicting value of quantitative and qualitative dyssynchrony parameters as assessed by two-dimensional speckle tracking echocardiography (STE) on outcome in children with dilated cardiomyopathy (DCM). Furthermore, the reproducibility of these parameters was investigated. BACKGROUND: In previous studies in adults with heart failure, several dyssynchrony parameters have been shown to be a valuable predictor of clinical outcome. METHODS: This multicenter, prospective study included 75 children with DCM and 75 healthy age-matched controls. Using STE, quantitative (time to global peak strain and parameters describing intraventricular time differences) and qualitative dyssynchrony parameters (pattern analysis) of the apical four-chamber, three-chamber, two-chamber views, and the short axis of the left ventricle were assessed. Cox regression was used to identify risk factors for the primary endpoints of death or heart transplantation. Inter-observer and intra-observer variability were described. RESULTS: During a median of 21 months follow-up, 10 patients (13%) reached an endpoint. Although quantitative dyssynchrony measures were higher in patients as compared to controls, the inter-observer and intra-observer variability were high. Pattern analysis showed mainly reduced strain, instead of dyssynchronous patterns. CONCLUSIONS: In this study, quantitative dyssynchrony parameters were not reproducible, precluding their use in children. Qualitative pattern analysis showed predominantly reduced strain, suggesting that in children with DCM dyssynchrony may be a minor problem.
Assuntos
Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Ecocardiografia/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Coração/diagnóstico por imagem , Coração/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Lactente , Masculino , Variações Dependentes do Observador , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
Cardiopulmonary exercise testing is an important tool to predict prognosis in children and adults with heart failure. A much less sophisticated exercise test is the 6 min walk test, which has been shown an independent predictor for morbidity and mortality in adults with heart failure. Therefore, we hypothesized that the 6 min walk test could be predictive for outcome in children with dilated cardiomyopathy. We prospectively included 49 children with dilated cardiomyopathy ≥6 years who performed a 6 min walk test. Median age was 11.9 years (interquartile range [IQR] 7.4-15.1), median time after diagnosis was 3.6 years (IQR 0.6-7.4). The 6 min walk distance was transformed to a percentage of predicted, using age- and gender-specific norm values (6MWD%). For all patients, mean 6MWD% was 70 ± 21%. Median follow-up was 33 months (IQR 14-50). Ten patients reached the combined endpoint of death or heart transplantation. Using univariable Cox regression, a higher 6MWD% resulted in a lower risk of death or transplantation (hazard ratio 0.95 per percentage increase, p = 0.006). A receiver operating characteristic curve was generated to define the optimal threshold to identify patients at highest risk for an endpoint. Patients with a 6MWD% < 63% had a 2 year transplant-free survival of 73%, in contrast to a transplant-free survival of 92% in patients with a 6MWD% ≥ 63% (p = 0.003). In children with dilated cardiomyopathy, the 6 min walk test is a simple and feasible tool to identify children with a higher risk of death or heart transplantation.
Assuntos
Cardiomiopatia Dilatada/complicações , Tolerância ao Exercício , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/cirurgia , Teste de Caminhada , Adolescente , Criança , Doença Crônica , Feminino , Transplante de Coração , Humanos , Estimativa de Kaplan-Meier , Masculino , Países Baixos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Curva ROC , Fatores de RiscoRESUMO
BACKGROUND: Dilated cardiomyopathy in children causes heart failure and has a poor prognosis. Health-related quality of life in this patient group is unknown. Moreover, results may provide detailed information of parents' sense of their child's functioning. We hypothesised that health-related quality of life, as rated by parents, and the paediatric heart failure score, as assessed by physicians, have both predictive value on outcome. Methods and results In this prospective study, health-related quality of life was assessed by parent reports: the Infant Toddler Quality of Life questionnaire (0-4 years) or Child Health Questionnaire-Parent Form 50 (4-18 years) at 3-6-month intervals. We included 90 children (median age 3.8 years, interquartile range (IQR) 0.9-12.3) whose parents completed 515 questionnaires. At the same visit, physicians completed the New York University Pediatric Heart Failure Index. Compared with Dutch normative data, quality of life was severely impaired at diagnosis (0-4 years: 7/10 subscales and 4-18 years: 8/11 subscales) and ⩾1 year after diagnosis (3/10 and 6/11 subscales). Older children were more impaired (p<0.05). After a median follow-up of 3 years (IQR 2-4), 15 patients underwent transplantation. Using multivariable time-dependent Cox regression, "physical functioning" subscale and the Heart Failure Index were independently predictive of the risk of death and heart transplantation (hazard ratio 1.24 per 10% decrease of predicted, 95% confidence interval (CI) 1.06-1.47 and hazard ratio 1.38 per unit, 95% CI 1.19-1.61, respectively). CONCLUSION: Physical impairment rated by parents and heart failure severity assessed by physicians independently predicted the risk of death or heart transplantation in children with dilated cardiomyopathy.
Assuntos
Cardiomiopatia Dilatada/complicações , Nível de Saúde , Insuficiência Cardíaca/etiologia , Pais , Qualidade de Vida , Sistema de Registros , Medição de Risco/métodos , Adolescente , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/psicologia , Criança , Pré-Escolar , Estudos Transversais , Progressão da Doença , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Humanos , Incidência , Lactente , Masculino , Países Baixos/epidemiologia , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e QuestionáriosRESUMO
PURPOSE: We aimed to determine the prevalence and phenotypic spectrum of NOTCH1 mutations in left-sided congenital heart disease (LS-CHD). LS-CHD includes aortic valve stenosis, a bicuspid aortic valve, coarctation of the aorta, and hypoplastic left heart syndrome. METHODS: NOTCH1 was screened for mutations in 428 nonsyndromic probands with LS-CHD, and family histories were obtained for all. When a mutation was detected, relatives were also tested. RESULTS: In 148/428 patients (35%), LS-CHD was familial. Fourteen mutations (3%; 5 RNA splicing mutations, 8 truncating mutations, 1 whole-gene deletion) were detected, 11 in familial disease (11/148 (7%)) and 3 in sporadic disease (3/280 (1%)). Forty-nine additional mutation carriers were identified among the 14 families, of whom 12 (25%) were asymptomatic. Most of these mutation carriers had LS-CHD, but 9 (18%) had right-sided congenital heart disease (RS-CHD) or conotruncal heart disease (CTD). Thoracic aortic aneurysms (TAAs) occurred in 6 mutation carriers (probands included 6/63 (10%)). CONCLUSION: Pathogenic mutations in NOTCH1 were identified in 7% of familial LS-CHD and in 1% of sporadic LS-CHD. The penetrance is high; a cardiovascular malformation was found in 75% of NOTCH1 mutation carriers. The phenotypic spectrum includes LS-CHD, RS-CHD, CTD, and TAA. Testing NOTCH1 for an early diagnosis in LS-CHD/RS-CHD/CTD/TAA is warranted.Genet Med 18 9, 914-923.
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Cardiopatias Congênitas/genética , Insuficiência Cardíaca/genética , Síndrome do Coração Esquerdo Hipoplásico/genética , Receptor Notch1/genética , Adolescente , Adulto , Idoso , Aorta/fisiopatologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/fisiopatologia , Criança , Pré-Escolar , Feminino , Cardiopatias Congênitas/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Síndrome do Coração Esquerdo Hipoplásico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , LinhagemRESUMO
Since 2004, CHD7 mutations have been a known cause of CHARGE (Coloboma, Heart defects, Atresia of choane, Retardation of growth and development, Genital hypoplasia, Ear anomalies) syndrome, but the full clinical spectrum of CHD7 mutations is only now gradually emerging. CHD7 mutations have been identified in patients who do not fulfill the clinical criteria for CHARGE syndrome and in patients with overlapping syndromes. Variable congenital heart defects occur in the majority of patients with CHD7 mutations, with an overrepresentation of atrioventricular septal defects and conotruncal heart defects. This prompted us to study CHD7 in 46 patients with these heart defects and one other feature of CHARGE syndrome. We identified two CHD7 variants that were inherited from a healthy parent (c.3778 + 17C > T, c.7294G > A), but no pathogenic CHD7 mutations. We conclude that CHD7 mutations are not a major cause of the atrioventricular septal defects and conotruncal heart defects, not even if one extra phenotypic feature of CHARGE syndrome is present. Therefore, CHD7 analysis should not be performed routinely in this group of patients. However, we do recommend adding CHD7 to massive parallel sequencing gene panels for diagnostic work in patients with syndromic heart defects.
Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Cardiopatias Congênitas/genética , Defeitos dos Septos Cardíacos/genética , Fenótipo , Feminino , Humanos , Masculino , Mutação Puntual/genéticaAssuntos
Aorta/patologia , Desenvolvimento Fetal/fisiologia , Complicações Pós-Operatórias/patologia , Valva Pulmonar/embriologia , Transposição dos Grandes Vasos/cirurgia , Aorta/anormalidades , Estudos de Casos e Controles , Dilatação Patológica/etiologia , Feminino , Fetoscopia/efeitos adversos , Fetoscopia/métodos , Seguimentos , Humanos , Recém-Nascido , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Gravidez , Artéria Pulmonar/anormalidades , Artéria Pulmonar/patologia , Valva Pulmonar/crescimento & desenvolvimento , Valva Pulmonar/cirurgia , Estudos Retrospectivos , Transposição dos Grandes Vasos/diagnóstico , Transposição dos Grandes Vasos/fisiopatologiaRESUMO
Background The aim of this study is to describe muscle strength in pediatric patients with repaired tetralogy of Fallot compared with healthy peers and to analyze the correlation between muscle strength and peak oxygen uptake, exercise capacity (mL/min). Methods and Results A prospective, cross-sectional study was carried out in the University Medical Center Groningen between March 2016 and December 2019, which included 8 -to-19-year-old patients with repaired tetralogy of Fallot. Exclusion criteria comprised the following: Down syndrome, unstable pulmonary disease and severe scoliosis affecting pulmonary function, neuromuscular disease, and mental or physical limitations that prohibit the execution of the functional tests. Muscle strength was compared with 2 healthy pediatric cohorts from the Northern Netherlands. Handgrip strength, maximal voluntary isometric contraction, and dynamic muscle strength in correlation with peak oxygen uptake, exercise capacity (mL/min) were the main outcomes of the study. The 67 patients with repaired tetralogy of Fallot (42% female; aged 12.9 [interquartile range, 10.0-16.3] years old) were compared with healthy children. The patients showed reduced grip strength (z-score [mean±SD] -1.5±1.2, P<0.001), and total muscle strength (z-score -0.9±1.3, P<0.001). Dynamic strength (Bruininks-Oseretsky test) was significantly reduced (z-score -0.3±0.8, P=0.001), but running, speed, and agility were normal (z-score 0.1±0.7, P=0.4). Univariate correlation analyses showed strong correlations between absolute peak oxygen uptake, exercise capacity (mL/min), and muscle strength (grip strength r=0.83, total muscle strength r=0.88; P<0.001). In multivariate analyses, including correction for age and sex, total muscle strength (B 0.3; P=0.009), and forced vital capacity (B 0.5; P=0.02) correlated with peak oxygen uptake, exercise capacity (mL/min), independent of conventional cardiovascular parameters. Conclusions Children with repaired tetralogy of Fallot show reduced muscle strength, which strongly correlated with their exercise performance.
Assuntos
Tetralogia de Fallot , Humanos , Criança , Feminino , Adolescente , Adulto Jovem , Adulto , Masculino , Tetralogia de Fallot/cirurgia , Tolerância ao Exercício/fisiologia , Estudos Prospectivos , Força da Mão , Estudos Transversais , Teste de Esforço/métodos , OxigênioRESUMO
AIMS: Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV). Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a 'foetal gene programme' contributing to pathological cardiac remodelling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodelling in response to pressure overload induced by pulmonary artery banding (PAB). METHODS AND RESULTS: In this study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived haemodynamic parameters as well as molecular remodelling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control-banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV pressure-overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass, and impaired cardiac function. RNA-sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV. CONCLUSION: Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressu re overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodelling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.
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Insuficiência Cardíaca , Disfunção Ventricular Direita , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração/metabolismo , Humanos , Camundongos , RNA/metabolismo , Tamoxifeno/metabolismo , Fatores de Transcrição/metabolismo , Disfunção Ventricular Direita/genética , Disfunção Ventricular Direita/metabolismo , Função Ventricular Direita , Pressão Ventricular , Remodelação VentricularRESUMO
BACKGROUND: This study aimed to describe the current practice and results of genetic evaluation in Dutch children with dilated cardiomyopathy and to evaluate genotype-phenotype correlations that may guide prognosis. METHODS: We performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017. RESULTS: One hundred forty-four children were included. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in 7 (5%), familial in 18 (13%), inborn error of metabolism in 4 (3%), malformation syndrome in 2 (1%), and "other" in 23 (16%). Median follow-up time was 2.1 years [IQR 1.0-4.3]. Hundred-seven patients (74%) underwent genetic testing. We found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In 1 patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3-5.8, P = 0.007), while transplant-free survival was significantly lower (P = 0.006). Clinical characteristics at diagnosis did not differ between the 2 groups. CONCLUSIONS: Genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis.
Assuntos
Cardiomiopatia Dilatada , Miocardite , Humanos , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Miocardite/genética , Testes Genéticos , Estudos de Associação Genética , Medição de RiscoAssuntos
Aneurisma/complicações , Permeabilidade do Canal Arterial/complicações , Síndromes de Compressão Nervosa/etiologia , Nervo Laríngeo Recorrente/fisiopatologia , Paralisia das Pregas Vocais/etiologia , Aneurisma/congênito , Aneurisma/diagnóstico por imagem , Permeabilidade do Canal Arterial/diagnóstico por imagem , Feminino , Doença de Hashimoto , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez , Remissão Espontânea , Sons Respiratórios , Traqueotomia , UltrassonografiaRESUMO
AIM: In children with Friedreich ataxia (FRDA), ataxia is assessed using the surrogate marker the International Cooperative Ataxia Rating Scale (ICARS). We aimed to determine whether ICARS scores in children with FRDA are confounded by muscle weakness. METHOD: In 12 children with FRDA (10 males, two females; mean age 13 y 6 mo, SD 2 y 6 mo) and 12 age-matched children without FRDA (nine males; three females), we determined the association between muscle and ataxia parameters (i.e. muscle ultrasound density (MUD), muscle force, sensory evoked potentials, and ICARS scores). Children with FRDA were included on the basis of FXN gene analysis. Children in the comparison group were included on basis of uneventful pregnancy and normal cognitive and neurological development. RESULTS: In children with FRDA, muscle ultrasound density was homogeneously increased in the biceps, quadriceps, and tibialis anterior muscles (median 4SD). FRDA muscle weakness was significantly more pronounced in proximal than in distal muscles (-2SD vs -0.5SD respectively; p=0.004), with a stronger impairment of leg muscles than of arm muscles (-2SD vs -0. SD respectively; p=0.001). Comparing MUD between children with FRDA and an age-matched comparison group revealed a relatively strong increase in MUD in the proximal leg muscles in the FRDA group. Under the condition of persistently absent sensory evoked potentials, leg ICARS subscores in the FRDA group appeared to be positively associated with leg muscle force until a maximal plateau level of ICARS subscores was reached. INTERPRETATION: In children with FRDA, ataxia scales based on ICARS are confounded by muscle weakness. Longitudinal ICARS evaluations in children with FRDA do not necessarily indicate altered ataxia.
Assuntos
Ataxia de Friedreich/patologia , Ataxia de Friedreich/fisiopatologia , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Adolescente , Estudos de Casos e Controles , Criança , Avaliação da Deficiência , Potenciais Evocados/fisiologia , Feminino , Humanos , Masculino , Dinamômetro de Força Muscular , Músculo Esquelético/diagnóstico por imagem , Tempo de Reação/fisiologia , Análise de Regressão , Estudos Retrospectivos , Ultrassonografia/métodosRESUMO
AIMS: We aimed to determine whether in children with dilated cardiomyopathy repeated measurement of known risk factors for death or heart transplantation (HTx) during disease progression can identify children at the highest risk for adverse outcome. METHODS AND RESULTS: Of 137 children we included in a prospective cohort, 36 (26%) reached the study endpoint (SE: all-cause death or HTx), 15 (11%) died at a median of 0.09 years [inter-quartile range (IQR) 0.03-0.7] after diagnosis, and 21 (15%) underwent HTx at a median of 2.9 years [IQR 0.8-6.1] after diagnosis. Median follow-up was 2.1 years [IQR 0.8-4.3]. Twenty-three children recovered at a median of 0.6 years [IQR 0.5-1.4] after diagnosis, and 78 children had ongoing disease at the end of the study. Children who reached the SE could be distinguished from those who did not, based on the temporal evolution of four risk factors: stunting of length growth (-0.42 vs. -0.02 length Z-score per year, P < 0.001), less decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (-0.26 vs. -1.06 2log pg/mL/year, P < 0.01), no decrease in left ventricular internal diastolic dimension (LVIDd; 0.24 vs. -0.60 Boston Z-score per year, P < 0.01), and increase in New York University Pediatric Heart Failure Index (NYU PHFI; 0.49 vs. -1.16 per year, P < 0.001). When we compared children who reached the SE with those with ongoing disease (leaving out the children who recovered), we found similar results, although the effects were smaller. In univariate analysis, NT-proBNP, length Z-score, LVIDd Z-score, global longitudinal strain (%), NYU PHFI, and age >6 years at presentation (all P < 0.001) were predictive of adverse outcome. In multivariate analysis, NT-proBNP appeared the only independent predictor for adverse outcome, a two-fold higher NT-proBNP was associated with a 2.8 times higher risk of the SE (hazard ratio 2.78, 95% confidence interval 1.81-3.94, P < 0.001). CONCLUSIONS: The evolution over time of NT-proBNP, LVIDd, length growth, and NYU PHFI identified a subgroup of children with dilated cardiomyopathy at high risk for adverse outcome. In this sample, with a limited number of endpoints, NT-proBNP was the strongest independent predictor for adverse outcome.
Assuntos
Cardiomiopatia Dilatada , Insuficiência Cardíaca , Biomarcadores , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/epidemiologia , Criança , Insuficiência Cardíaca/epidemiologia , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Estudos Prospectivos , Fatores de RiscoRESUMO
Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently. Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants. Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures. Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes.
Assuntos
Cardiomiopatias , Cardiomiopatia Dilatada , Cardiomiopatia Hipertrófica , Tropomiosina/genética , Cardiomiopatias/genética , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/genética , Humanos , Mutação , Miócitos Cardíacos , FenótipoRESUMO
Objectives Congenital heart defects (CHD) are the most prevalent congenital anomalies. This study aims to examine the association between maternal occupational exposures to organic and mineral dust, solvents, pesticides, and metal dust and fumes and CHD in the offspring, assessing several subgroups of CHD. Methods For this case-control study, we examined 1174 cases with CHD from EUROCAT Northern Netherlands and 5602 controls without congenital anomalies from the Lifelines cohort study. Information on maternal jobs held early in pregnancy was collected via self-administered questionnaires, and job titles were linked to occupational exposures using a job exposure matrix. Results An association was found between organic dust exposure and coarctation of aorta [adjusted odds ratio (OR adj) 1.90, 95% confidence interval (CI) 1.01-3.59] and pulmonary (valve) stenosis in combination with ventricular septal defect (OR adj2.68, 95% CI 1.07-6.73). Mineral dust exposure was associated with increased risk of coarctation of aorta (OR adj2.94, 95% CI 1.21-7.13) and pulmonary valve stenosis (OR adj1.99, 95% CI 1.10-3.62). Exposure to metal dust and fumes was infrequent but was associated with CHD in general (OR adj2.40, 95% CI 1.09-5.30). Exposure to both mineral dust and metal dust and fumes was associated with septal defects (OR adj3.23, 95% CI 1.14-9.11). Any maternal occupational exposure was associated with a lower risk of aortic stenosis (OR adj0.32, 95% CI 0.11-0.94). Conclusions Women should take preventive measures or avoid exposure to mineral and organic dust as well as metal dust and fumes early in pregnancy as this could possibly affect foetal heart development.
Assuntos
Cardiopatias Congênitas/epidemiologia , Exposição Materna , Exposição Ocupacional/análise , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adolescente , Adulto , Poluentes Ocupacionais do Ar , Estudos de Casos e Controles , Poeira , Feminino , Humanos , Recém-Nascido , Masculino , Troca Materno-Fetal , Metais , Pessoa de Meia-Idade , Minerais , Países Baixos/epidemiologia , Praguicidas , Gravidez , Solventes , Adulto JovemRESUMO
BACKGROUND: Dilated cardiomyopathy (DCM) in children is an important cause of severe heart failure and carries a poor prognosis. Adults with heart failure are at increased risk of anxiety and depression and such symptoms predict adverse clinical outcomes such as mortality. In children with DCM, studies examining these associations are scarce. AIMS: We studied whether in children with DCM: (1) the level of emotional and behavioral problems was increased as compared to normative data, and (2) depressive and anxiety problems were associated with the combined risk of death or cardiac transplantation. METHODS: To assess emotional and behavioral problems in children with DCM, parents of 68 children, aged 1.5-18 years (6.9±5.7 years), completed the Child Behavior Checklist. RESULTS: Compared to normative data, more young children (1.5-5 years) with DCM had somatic complaints (24.3% vs. 8.0%; p < .001), but fewer had externalizing problems (5.4% vs. 17.0%; p = .049). Overall internalizing problems did not reach significance. Compared to normative data, more older children (6-18 years) showed internalizing problems (38.7% vs. 17.0%; p = .001), including depressive (29.0% vs. 8.0%; p < .001) and anxiety problems (19.4% vs. 8.0%; p = .023), and somatic complaints (29.0% vs. 8.0%; p < .001). Anxiety and depressive problems, corrected for heart failure severity, did not predict the risk of death or cardiac transplantation. CONCLUSION: Children of 6 years and older showed more depressive and anxiety problems than the normative population. Moreover, in both age groups, somatic problems were common. No association with outcome could be demonstrated.
Assuntos
Cardiomiopatia Dilatada/mortalidade , Cardiomiopatia Dilatada/psicologia , Comportamento Infantil/psicologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/psicologia , Transplante de Coração/psicologia , Comportamento Problema/psicologia , Adolescente , Transtornos de Ansiedade/etiologia , Cardiomiopatia Dilatada/complicações , Criança , Pré-Escolar , Feminino , Humanos , Lactente , MasculinoRESUMO
Fetal tachyarrhythmias are a life-threatening condition complicating a small proportion of normal pregnancies. Despite major advances in the (intrauterine) pharmacologic treatment of these arrhythmias over the last years major uncertainties remain. Among these are controversies in the choice of agents in relation to arrhythmia type, and timing and duration of treatment. Currently, no evidence-based approach to the management of fetal tachyarrhythmias is available. An international registry is proposed as an important step toward obtaining the necessary data to develop evidence-based management strategies.