No abstract

http://www.clinicaltrials.gov: NCT00266188; Results.

Mutations in RBM20 encoding the RNA-binding motif protein 20 (RBM20) are associated with an early onset and clinically severe forms of cardiomyopathies. Transcriptome analyses revealed RBM20 as an important regulator of cardiac alternative splicing. RBM20 mutations are especially localized in exons 9 and 11 including the highly conserved arginine and serine-rich domain (RS domain). Here, we investigated in several cardiomyopathy patients, the previously described RBM20-mutation p.Pro638Leu localized within the RS domain. In addition, we identified in a patient the novel mutation p.Val914Ala localized in the (glutamaterich) Glu-rich domain of RBM20 encoded by exon 11. Its impact on the disease was investigated with a novel TTN-and RYR2-splicing assay based on the patients' cardiac messenger RNA. Furthermore, we showed in cell culture and in human cardiac tissue that mutant RBM20-p.Pro638Leu is not localized in the nuclei but causes an abnormal cytoplasmic localization of the protein. In contrast the splicing deficient RBM20-p.Val914Ala has no influence on the intracellular localization. These results indicate that disease-associated variants in RBM20 lead to aberrant splicing through different pathomechanisms dependent on the localization of the mutation. This might have an impact on the future development of therapeutic strategies for the treatment of RBM20-induced cardiomyopathies.

Pulmonary hypertension (PH) is a condition of multiple aetiologies with underestimated prevalence and incidence. Indeed, despite access to modern therapies, pulmonary hypertensive vascular disease (PHVD) remains a progressive, usually life-limiting condition, severely impacting on the patients' well-being. We herein provide practical, expert consensus recommendations on the initial diagnostic work-up, clinical management and follow-up of children and adolescents with PH/PHVD, including a diagnostic algorithm. The major topics and methods that need to be tailored and put into context of the individual patient include PH classification, clinical signs and symptoms, basic diagnostic and advanced imaging measures (ECG, chest X-ray, transthoracic echocardiography, cardiac magnetic resonance, chest CT angiography, cardiac catheterisation, ventilationperfusion lung scan, abdominal ultrasound), lung function tests, 6 min walk and cardiopulmonary exercise testing, sleep study ( polysomnography), laboratory/ immunological tests, considerations for elective surgery/ general anaesthesia, physical education and exercise, flying on commercial airplanes, vaccinations, care of central intravenous lines and palliative care. Due to the complexity of PH/PHVD, the clinical care has to be multidisciplinary and coordinated by a dedicated specialist paediatric PH centre, not only to decrease mortality but to allow children with PH/PHVD to reach a reasonable quality of life.

Background-The impact of gender and age on cardiac function by cardiac magnetic resonance (CMR) in repaired tetralogy of Fallot (TOF) is unknown, which limits the value of currently discussed volumetric thresholds and the accuracy of individual follow-up. Methods and Results-In a nationwide, prospective, 14-center study, 407 consecutive patients with repaired TOF (age, 17.9Ϯ8.3 years; range, 8 -59 years; 226 male patients) underwent standardized CMR ventricular volumetry and flow quantification (pulmonary artery/ascending aorta). There were no sex differences for age at TOF repair, type of repair, number of prior repair palliations or reinterventions after repair, pulmonary regurgitation fraction, and maximal gradient across the right ventricular outflow tract. Biventricular volumes and mass (indexed to body surface area), available in 380 of 407 patients, respectively, were higher in male patients (PϽ0.003), but biventricular ejection fraction was higher in female patients (PϽ0.012). As opposed to reported data of healthy populations, sex-specific reference percentiles computed for an age range of 8 to 40 years (lambda-mu-sigma method) demonstrated (1) an increase of end-diastolic and end-systolic left ventricular volumes, particularly in female patients; (2) an increase of end-systolic right ventricular volumes in both sexes; and (3) a decrease of biventricular ejection fraction in male patients, whereas in female patients, only right ventricular ejection fraction decreased. Conclusions-Significant gender differences of biventricular volumes, function, and mass by CMR exist late after repair of TOF, suggesting that age and gender cannot be ignored when discussing thresholds. Gender-specific percentiles may present a more relevant framework of reference for an individual patient at a given age and suggest a gradual decline of biventricular systolic function over time.