RESUMEN
Fabry disease (FD) is an X-linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti-drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45- and CD45 + CCR7-CD4 T cells (respectively p < 0.014 and p < 0.02). Percentage of CD45RA-CCR7-CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (r = 0.60; p = 0.0036) and phenotype (p < 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (r = 0.33; p = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers.
Asunto(s)
Linfocitos T CD4-Positivos , Enfermedad de Fabry , Trihexosilceramidas , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Humanos , Enfermedad de Fabry/inmunología , Masculino , Trihexosilceramidas/metabolismo , Adulto , Linfocitos T CD4-Positivos/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Persona de Mediana Edad , Adulto Joven , Adolescente , Esfingolípidos/metabolismo , Estudios de Casos y Controles , Antígenos Comunes de Leucocito , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Citometría de Flujo , Antígenos CD28 , Memoria Inmunológica , Receptores CCR7/metabolismo , GlucolípidosRESUMEN
In France, mexiletine - a class I antiarrhythmic drug - can be prescribed for the symptomatic treatment of myotonia of the skeletal muscles in adult patients with myotonic dystrophy under a compassionate use programme. Mexiletine is used according to its summary of product characteristics, which describes its use for myotonia treatment in adult patients with non-dystrophic myotonia, a different neuromuscular condition without cardiac involvement. A cardiac assessment is required prior to initiation and throughout treatment due to potential proarrhythmic effects. The presence of conduction system disease, the most common cardiac manifestation of myotonic dystrophy, mandates repeated cardiac evaluations in patients with this condition, and becomes even more important when they are given mexiletine. A group of experts, including three neurologists and five cardiologists from French neuromuscular reference centres, were involved in a task force to develop a treatment algorithm to guide mexiletine use in myotonic dystrophy. The recommendations are based on data from a literature review of the safety of mexiletine-treated patients with myotonic dystrophy, the compassionate use protocol for mexiletine and the personal clinical experience of the experts. The main conclusion of the expert group is that, although existing safety data in mexiletine-treated patients with myotonic dystrophy are reassuring, cardiac assessments should be reinforced in such patients compared with mexiletine-treated patients with non-dystrophic myotonia. This expert opinion to guide mexiletine treatment in patients with myotonic dystrophy should help to reduce the risk of severe adverse events and facilitate interactions between specialists involved in the routine care of patients with myotonic dystrophy.
Asunto(s)
Mexiletine , Distrofia Miotónica , Adulto , Humanos , Algoritmos , Antiarrítmicos/uso terapéutico , Antiarrítmicos/efectos adversos , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Arritmias Cardíacas/inducido químicamente , Toma de Decisiones Clínicas , Ensayos de Uso Compasivo , Consenso , Francia , Mexiletine/uso terapéutico , Mexiletine/efectos adversos , Distrofia Miotónica/tratamiento farmacológico , Distrofia Miotónica/diagnóstico , Distrofia Miotónica/fisiopatología , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Bloqueadores del Canal de Sodio Activado por Voltaje/efectos adversosRESUMEN
Pre-participation screening and management of congenital cardiac valvulopathy in competitive athletes can be challenging, particularly within the context of ultra-endurance disciplines. A 55-year-old female athlete without a reported history of cardiac disease exhibited clinical signs of cardiogenic pulmonary edema during a 156â¯km ultra-trail race. The echocardiographic assessment revealed the presence of a parachute mitral valve, with no evidence of mitral stenosis or regurgitation at rest, but it demonstrated severe dynamic mitral stenosis during exercise. In competitive athletes, the detection of rare valvulopathy should prompt a comprehensive cardiac evaluation aimed at assessing the potential for dynamic valvular dysfunction.
Asunto(s)
Ecocardiografía , Estenosis de la Válvula Mitral , Válvula Mitral , Humanos , Femenino , Persona de Mediana Edad , Estenosis de la Válvula Mitral/diagnóstico por imagen , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/anomalías , Edema Pulmonar/diagnóstico por imagen , AtletasRESUMEN
BACKGROUND: A risk model has been proposed to provide a patient individualized estimation of risk for major clinical events (heart failure events, ventricular arrhythmia, all-cause mortality) in patients with transposition of the great arteries and atrial switch surgery. We aimed to externally validate the model. METHODS AND RESULTS: A retrospective, multicentric, longitudinal cohort of 417 patients with transposition of the great arteries (median age, 24 years at baseline [interquartile range, 18-30]; 63% men) independent of the model development and internal validation cohort was studied. The performance of the prediction model in predicting risk at 5 years was assessed, and additional predictors of major clinical events were evaluated separately in our cohort. Twenty-five patients (5.9%) met the major clinical events end point within 5 years. Model validation showed good discrimination between high and low 5-year risk patients (Harrell C index of 0.73 [95% CI, 0.65-0.81]) but tended to overestimate this risk (calibration slope of 0.20 [95% CI, 0.03-0.36]). In our population, the strongest independent predictors of major clinical events were a history of heart failure and at least mild impairment of the subpulmonary left ventricle function. CONCLUSIONS: We reported the first external validation of a major clinical events risk model in a large cohort of adults with transposition of the great arteries. The model allows for distinguishing patients at low risk from those at intermediate to high risk. Previous episode of heart failure and subpulmonary left ventricle dysfunction appear to be key markers in the prognosis of patients. Further optimizing risk models are needed to individualize risk predictions in patients with transposition of the great arteries.