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BACKGROUND: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers. METHODS: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy. RESULTS: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required. CONCLUSIONS: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Cardiomiopatía Hipertrófica/tratamiento farmacológico , Mutación , Sarcómeros/genética , Valsartán/uso terapéutico , Adolescente , Adulto , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Brasil , Canadá , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Niño , Dinamarca , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Recuperación de la Función , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Valsartán/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: Cardiomyopathies are a rare cause of pediatric heart disease, but they are one of the leading causes of heart failure admissions, sudden death, and need for heart transplant in childhood. Reports from the Pediatric Cardiomyopathy Registry (PCMR) have shown that almost 40% of children presenting with symptomatic cardiomyopathy either die or undergo heart transplant within 2 years of presentation. Little is known regarding circulating biomarkers as predictors of outcome in pediatric cardiomyopathy. STUDY DESIGN: The Cardiac Biomarkers in Pediatric Cardiomyopathy (PCM Biomarkers) study is a multi-center prospective study conducted by the PCMR investigators to identify serum biomarkers for predicting outcome in children with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Patients less than 21 years of age with either DCM or HCM were eligible. Those with DCM were enrolled into cohorts based on time from cardiomyopathy diagnosis: categorized as new onset or chronic. Clinical endpoints included sudden death and progressive heart failure. RESULTS: There were 288 children diagnosed at a mean age of 7.2±6.3 years who enrolled in the PCM Biomarkers Study at a median time from diagnosis to enrollment of 1.9 years. There were 80 children enrolled in the new onset DCM cohort, defined as diagnosis at or 12 months prior to enrollment. The median age at diagnosis for the new onset DCM was 1.7 years and median time from diagnosis to enrollment was 0.1 years. There were 141 children enrolled with either chronic DCM or chronic HCM, defined as children ≥2 years from diagnosis to enrollment. Among children with chronic cardiomyopathy, median age at diagnosis was 3.4 years and median time from diagnosis to enrollment was 4.8 years. CONCLUSION: The PCM Biomarkers study is evaluating the predictive value of serum biomarkers to aid in the prognosis and management of children with DCM and HCM. The results will provide valuable information where data are lacking in children. CLINICAL TRIAL REGISTRATION NCT01873976: https://clinicaltrials.gov/ct2/show/NCT01873976?term=PCM+Biomarker&rank=1.
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OBJECTIVE: To evaluate the use of imatinib mesylate with or without bevacizumab targeting neoproliferative myofibroblast-like cells with tyrosine kinase receptor expression, as adjuncts to modern interventional therapies for the treatment of multivessel intraluminal pulmonary vein stenosis (PVS). We describe the 48- and 72-week outcomes among patients receiving imatinib mesylate with or without bevacizumab for multivessel intraluminal PVS. STUDY DESIGN: This single-arm, prospective, open-label US Food and Drug Administration approved trial enrolled patients with ≥2 affected pulmonary veins after surgical or catheter-based relief of obstruction between March 2009 and December 2014. Drug therapy was discontinued at 48 weeks, or after 24 weeks of stabilization, whichever occurred later. RESULTS: Among 48 enrolled patients, 5 had isolated PVS, 26 congenital heart disease, 5 lung disease, and 12 both. After the 72-week follow-up, 16 patients had stabilized, 27 had recurred locally without stabilization, and 5 had progressed. Stabilization was associated with the absence of lung disease (P = .03), a higher percentage of eligible drug doses received (P = .03), and was not associated with age, diagnosis, disease laterality, or number of veins involved. Survival to 72 weeks was 77% (37 of 48). Adverse events were common (n = 1489 total), but only 16 were definitely related to drug treatment, none of which were serious. CONCLUSION: Survival to 72 weeks was 77% in a referral population with multivessel intraluminal PVS undergoing multimodal treatment, including antiproliferative tyrosine kinase blockade. Toxicity specific to tyrosine kinase blockade was minimal.
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Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Estenosis de Vena Pulmonar/tratamiento farmacológico , Niño , Preescolar , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Masculino , Estudios Prospectivos , Estenosis de Vena Pulmonar/mortalidad , Resultado del TratamientoRESUMEN
OBJECTIVES: To measure the health-related quality of life (HRQOL) and functional status of children with cardiomyopathy and to determine whether they are correlated with sociodemographics, cardiac status, and clinical outcomes. STUDY DESIGN: Parents of children in the Pediatric Cardiomyopathy Registry completed the Child Health Questionnaire (CHQ; age ≥ 5 years) and Functional Status II (Revised) (age ≤ 18 years) instruments. Linear and Cox regressions were used to examine hypothesized associations with HRQOL. RESULTS: The 355 children evaluated at ≥ 5 years (median 8.6 years) had lower functioning (CHQ Physical and Psychosocial Summary Scores 41.7 ± 14.4 and 47.8 ± 10.7) than that of healthy historical controls. The most extreme CHQ domain score, Parental Impact-Emotional, was one SD below normal. Younger age at diagnosis and smaller left ventricular end-diastolic dimension z score were associated independently with better physical functioning in children with dilated cardiomyopathy. Greater income/education correlated with better psychosocial functioning in children with hypertrophic and mixed/other types of cardiomyopathy. In the age ≥ 5 year cohort, lower scores on both instruments predicted earlier death/transplant and listing for transplant in children with dilated and mixed/other types of cardiomyopathy (P < .001). Across all ages (n = 565), the Functional Status II (Revised) total score was 87.1 ± 16.4, and a lower score was associated with earlier death/transplant for all cardiomyopathies. CONCLUSIONS: HRQOL and functional status in children with cardiomyopathy is on average impaired relative to healthy children. These impairments are associated with older age at diagnosis, lower socioeconomic status, left ventricular size, and increased risk for death and transplant. Identification of families at risk for functional impairment allows for provision of specialized services early in the course of disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00005391.
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Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Hipertrófica/epidemiología , Calidad de Vida , Adolescente , Factores de Edad , Cardiomiopatía Dilatada/cirugía , Cardiomiopatía Hipertrófica/cirugía , Niño , Escolaridad , Femenino , Trasplante de Corazón/estadística & datos numéricos , Humanos , Renta , Masculino , Análisis Multivariante , Sistema de Registros , Estados Unidos/epidemiologíaAsunto(s)
Humanos , Masculino , Femenino , Cardiopatías Congénitas/diagnóstico , Ecocardiografía/métodos , Ecocardiografía/normas , Pediatría/métodos , Pediatría/normas , Arterias/fisiología , /métodos , Guías como Asunto/normas , Técnicas y Procedimientos Diagnósticos/normas , Válvulas Cardíacas/fisiología , Venas Pulmonares/fisiología , Ventrículos Cardíacos , Volumen Sistólico/fisiologíaRESUMEN
OBJECTIVE: To evaluate the prevalence of coronary artery dilation in children with sickle cell disease (SCD). STUDY DESIGN: This is a retrospective analysis performed in patients, between 10 and 19 years old, with SCD who underwent a routine transthoracic echocardiographic evaluation over a 20-month period. The left main, left anterior descending, and proximal right coronary artery diameters, as well as clinical and laboratory variables and other echocardiographic results were collected. Echocardiographic measurements were converted to z scores by using information from a large control population of normal children. Coronary artery ectasia (CAE) was defined as a coronary artery diameter z score ≥ 2. The patients with CAE were compared with those without CAE by using univariate and multivariate analyses. RESULTS: Seventeen of 96 patients with SCD (17.7%) had CAE. There were no differences in sex, age, height, weight, body surface area, or genotype between those with and those without CAE. Patients with CAE had larger left ventricular end-diastolic dimension, shortening fraction, septal thickness, posterior wall thickness, mass, mass-to-volume ratio, and white blood cell count. Multivariate analysis revealed that the mass-to-volume ratio and elevated white blood cell count were associated with CAE. CONCLUSION: CAE is common in SCD and is associated with left ventricular hypertrophy and inflammation.
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Anemia de Células Falciformes/complicaciones , Vasos Coronarios/patología , Adolescente , Niño , Diástole , Dilatación Patológica/diagnóstico por imagen , Ecocardiografía , Femenino , Tabiques Cardíacos/patología , Humanos , Hipertrofia Ventricular Izquierda/patología , Inflamación/patología , Recuento de Leucocitos , Masculino , Análisis Multivariante , Estudios Retrospectivos , Volumen Sistólico , Adulto JovenRESUMEN
OBJECTIVES: To assess the performance of 3 risk scores from Japan that were developed to predict, in children with Kawasaki disease, resistance to intravenous immunoglobulin (IVIG) treatment. STUDY DESIGN: We used data from a randomized trial of pulsed steroids for primary treatment of Kawasaki disease to assess operating characteristics of the 3 risk scores, and we examined whether steroid therapy lowers the risk of coronary artery abnormalities in patients prospectively classified as IVIG resistant. RESULTS: For comparability with published cohorts, we analyzed the data of 99 patients who were not treated with steroids (16% IVIG-retreated) and identified male sex, lower albumin level, and higher aspartate aminotransferase level as independent risk factors for IVIG resistance. The Kobayashi score was similar in IVIG-resistant and -responsive patients, yielding a sensitivity of 33% and specificity of 87%. There was no interaction of high-risk versus low-risk status by treatment received (steroid versus placebo) with any of the 3 risk score algorithms. CONCLUSION: Risk-scoring systems from Japan have good specificity but low sensitivity for predicting IVIG resistance in a North American cohort. Primary steroid therapy did not improve coronary outcomes in patients prospectively classified as being at high-risk for IVIG resistance.
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Resistencia a Medicamentos , Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Síndrome Mucocutáneo Linfonodular/diagnóstico , Preescolar , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Lactante , Infusiones Intravenosas , Masculino , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Pronóstico , Curva ROC , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. METHODS: Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. FINDINGS: 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99). INTERPRETATION: Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. FUNDING: US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.
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Antibióticos Antineoplásicos/efectos adversos , Cardiomiopatías/prevención & control , Fármacos Cardiovasculares/uso terapéutico , Doxorrubicina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Razoxano/uso terapéutico , Sobrevivientes , Adolescente , Biomarcadores/sangre , Canadá , Cardiomiopatías/sangre , Cardiomiopatías/inducido químicamente , Cardiomiopatías/diagnóstico por imagen , Cardiomiopatías/fisiopatología , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Contracción Miocárdica/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Estudios Prospectivos , Puerto Rico , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Troponina T/sangre , Ultrasonografía , Estados Unidos , Función Ventricular Izquierda/efectos de los fármacos , Adulto JovenRESUMEN
OBJECTIVES: To test prospectively the reproducibility and feasibility of endothelial pulse amplitude testing (Endo-PAT), a novel Food and Drug Administration-approved technology, in healthy adolescents. STUDY DESIGN: We performed Endo-PAT testing on 2 different days separated by no more than 7 days in 30 healthy fasting adolescents, ages 13 to 19 years, to assess reproducibility and feasibility. The reported level of discomfort, as measured on a pain scale of 1 to 5, was documented. RESULTS: The mean difference in paired Endo-PAT indices was 0.12 (95% CI, -0.09-0.33; P = .24; intraclass correlation coefficient, 0.78), and the within-subject variation of Endo-PAT index was 0.16. The Endo-PAT index on test days 1 and 2 were 1.91 +/- 0.57 and 1.78 +/- 0.51 (mean plus or minus SD), respectively. All attempted studies (100%) were completed (95% CI, 88%-100%), and all completed studies (100%) could be analyzed (95% CI, 88%-100%). The median pain score was 1 on both days. CONCLUSION: In healthy adolescents, Endo-PAT is feasible and has excellent reproducibility. This technology may provide an easy and reliable means of assessing endothelial function in the pediatric population.
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Endotelio Vascular/fisiología , Pulso Arterial , Adolescente , Aterosclerosis/diagnóstico , Presión Sanguínea , Arteria Braquial , Endotelio Vascular/fisiopatología , Estudios de Factibilidad , Femenino , Dedos/irrigación sanguínea , Humanos , Hiperemia , Masculino , Dimensión del Dolor , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: We explored the association between neuroblastoma and congenital cardiovascular malformations (CCM), previously described in case reports. STUDY DESIGN: Echocardiogram and chart reviews of a series of 158 patients with neuroblastoma and a control group of 192 children with leukemia were performed. The proportion of patients with CCM in each group was compared. RESULTS: Fourteen of the 70 (20%) patients with neuroblastoma and echocardiography had CCM, compared with 7 of the 192 (3.6%) patients with leukemia with echocardiograms (P=.0001). If all of the patients with neuroblastoma without echocardiograms (n=88) are considered to have normal cardiac anatomy, this difference remains significant (14 of 158 patients with neuroblastoma have CCM detected [8.9%] versus 7 of 192 patients with leukemia [3.6%]; P=.045). Neural crest-derived CCM were more common in patients with neuroblastoma, detected in 5 of 70 patients with neuroblastoma versus 2 of 192 patients with leukemia (P=.016). Congenital cardiovascular malformations in patients with neuroblastoma were associated with a cancer diagnosis at age less than 1 year and a lower neuroblastoma stage, but there was no association with tumor MYCN amplification. CONCLUSIONS: Neuroblastoma and CCM may be associated. We recommend echocardiography for CCM screening in patients with newly diagnosed neuroblastoma.
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Cardiopatías Congénitas/complicaciones , Neuroblastoma/complicaciones , Adolescente , Distribución por Edad , Estudios de Casos y Controles , Niño , Preescolar , Ecocardiografía , Femenino , Cardiopatías Congénitas/epidemiología , Humanos , Lactante , Recién Nacido , Neuroblastoma/epidemiología , Neuroblastoma/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Embarazo , Prevalencia , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: To describe the 5-year cumulative incidence of cardiac dysfunction in human immunodeficiency virus (HIV)-infected children. STUDY DESIGN: We used a prospective cohort design, enrolling children at 10 hospitals. Group I included 205 vertically HIV-infected children enrolled at a median age of 1.9 years. Group II consisted of 600 HIV-exposed children enrolled prenatally or as neonates, of whom 93 were ultimately HIV-infected. The main outcome measures were echocardiographic indexes of left ventricular dysfunction. RESULTS: In group I, the 5-year cumulative incidence of left ventricular fractional shortening =25% was 28.0%. The 5-year incidence of left ventricular end-diastolic dilatation was 21.7%, and heart failure and/or the use of cardiac medications 28.8%. The mortality rate 1 year after the diagnosis of heart failure was 52.5% [95% CI, 30.5-74.5]. Within group II, the 5-year cumulative incidence of decreased fractional shortening was 10.7% in the HIV-infected compared with 3.1% in the HIV-uninfected children (P =.01). Left ventricular dilation, heart failure, and/or the use of cardiac medications were more common in infected compared with uninfected children. CONCLUSIONS: During 5 years of follow-up, cardiac dysfunction occurred in 18% to 39% of HIV-infected children and was associated with an increased risk of death. We recommend that HIV-infected children undergo routine echocardiographic surveillance for cardiac abnormalities.