Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices.

Aims: No curative treatment is available for RASopathy-associated childhood-onset hypertrophic cardiomyopathy (RAS-CM). Preclinical data and individual reports suggest a beneficial effect of small molecules targeting the RAS-mitogen-activated protein (MAP) kinase (MAPK) pathway in severely affected RAS-CM patients. The aim of this study was to evaluate the biophysical effects of trametinib, rapamycin and dasatinib on cultivated myocardial tissue slices of a paediatric RAS-CM patient using biomimetic cultivation chambers (BMCCs) and to correlate the findings with clinical data.

Clinical interpretation of KCNH2 variants using a robust PS3/BS3 functional patch-clamp assay.

Long QT syndrome (LQTS), caused by the dysfunction of cardiac ion channels, increases the risk of sudden death in otherwise healthy young people. For many variants in LQTS genes, there is insufficient evidence to make a definitive genetic diagnosis. We have established a robust functional patch-clamp assay to facilitate classification of missense variants in KCNH2, one of the key LQTS genes.

Mid-term results following pulmonary artery patch augmentation in congenital heart disease.

Background: Treatment of pulmonary artery (PA) stenosis in congenital heart disease is associated with adverse outcomes. The aim of this retrospective cohort study was to compare outcomes after surgical patch augmentation of PA stenosis in patients with biventricular congenital heart disease using different patch materials.

Methods: We identified all patients from our institutional congenital heart disease database who underwent patch augmentation for PA stenosis on the main pulmonary artery (MPA) or PA branches between 2012 and 2018.

Bioactive adrenomedullin (bio-ADM) is associated with endothelial dysfunction in infants and children with complex congenital heart disease undergoing open-heart surgery on cardiopulmonary bypass.

Objectives: Children with congenital heart disease (CHD) undergoing cardiac surgery on cardiopulmonary bypass (CPB) are at risk for systemic inflammation leading to endothelial dysfunction associated with increased morbidity. Bioactive adrenomedullin (bio-ADM) is a peptide regulating vascular tone and endothelial permeability. The aim of this study was to evaluate the dynamics of plasma bio-ADM in this patient cohort and its role in capillary leak.

Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease.

The epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that are essential to myocardial growth and repair. Here we generate self-organizing human pluripotent stem cell-derived epicardioids that display retinoic acid-dependent morphological, molecular and functional patterning of the epicardium and myocardium typical of the left ventricular wall. By combining lineage tracing, single-cell transcriptomics and chromatin accessibility profiling, we describe the specification and differentiation process of different cell lineages in epicardioids and draw comparisons to human fetal development at the transcriptional and morphological levels.

EGFR and MMP-9 are associated with neointimal hyperplasia in systemic-to-pulmonary shunts in children with complex cyanotic heart disease.

Systemic-to-pulmonary shunt malfunction contributes to morbidity in children with complex congenital heart disease after palliative procedure. Neointimal hyperplasia might play a role in the pathogenesis increasing risk for shunt obstruction. The aim was to evaluate the role of epidermal growth factor receptor (EGFR) and matrix-metalloproteinase 9 (MMP-9) in the formation of neointimal within shunts.

New prospectives on treatment opportunities in RASopathies.

The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations.

Neointimal hyperplasia in systemic-to-pulmonary shunts of children with complex cyanotic congenital heart disease.

Objectives: Neointimal hyperplasia might affect systemic-to-pulmonary shunt failure in infants with complex cyanotic congenital heart disease. The aim of this study was to elucidate histopathologic changes in polytetrafluoroethylene shunts and to determine whether increased neointimal formation is associated with early interventions comprising balloon dilatation, stent implantation and shunt revision. Furthermore, we intended to identify clinical factors associated with increased neointimal proliferation.

Peak Oxygen Uptake on Cardiopulmonary Exercise Test Is a Predictor for Severe Arrhythmic Events during Three-Year Follow-Up in Patients with Complex Congenital Heart Disease.

Patients with congenital heart disease (CHD) are at increased risk for severe arrhythmia and sudden cardiac death (SCD). Although implantable cardioverter defibrillators (ICD) effectively prevent SCD, risk stratification for primary prophylaxis in patients with CHD remains challenging. Patients with complex CHD undergoing CPET were included in this single-center study.

It Is Not Carved in Stone-The Need for a Genetic Reevaluation of Variants in Pediatric Cardiomyopathies.

(1) Background: In cardiomyopathies, identification of genetic variants is important for the correct diagnosis and impacts family cascade screening. A classification system was published by the American College of Medical Genetics and Genomics (ACMG) in 2015 to standardize variants' classification. The aim of the study was to determine the rate of reclassification of previously identified variants in patients with childhood-onset cardiomyopathies.

Cardiovascular Function and Exercise Capacity in Childhood Cancer Survivors.

Introduction: Childhood cancer survivors (CCS) might be at high risk of additional chronic diseases due to cardiotoxic side effects. The aim of this study was to analyze long-term side effects of cancer therapy on vascular structure/function, cardiac biomarkers and on physical activity.

Methods: In total, 68 asymptomatic patients aged 16-30 years with childhood cancer (diagnosed 10.

Molecular signaling pathways in right ventricular impairment of adult patients after tetralogy of Fallot repair.

Background: Right ventricular impairment (RVI) secondary to altered hemodynamics contributes to morbidity and mortality in adult patients after tetralogy of Fallot (TOF) repair. The goal of this study was to describe signaling pathways contributing to right ventricular (RV) remodeling by analyzing over lifetime alterations of RV gene expression in affected patients.

Methods: RV tissue was collected at the time of cardiac surgery in 13 patients with a diagnosis of TOF.

Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome.

Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated.

Management of growth failure and other endocrine aspects in patients with Noonan syndrome across Europe: A sub-analysis of a European clinical practice survey.

Aim: To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe.

Materials And Methods: A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey.

Compound Mutation in Cardiac Sarcomere Proteins Is Associated with Increased Risk for Major Arrhythmic Events in Pediatric Onset Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with adverse left ventricular (LV) remodeling causing dysfunction and malignant arrhythmias. Severely affected patients present with disease onset during childhood and sudden cardiac death risk (SCD) stratification is of the highest importance in this cohort. This study aimed to investigate genotype-phenotype association regarding clinical outcome and disease progression in pediatric onset HCM.

European Medical Education Initiative on Noonan syndrome: A clinical practice survey assessing the diagnosis and clinical management of individuals with Noonan syndrome across Europe.

Introduction: Noonan syndrome (NS) is a rare genetic disorder caused by mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Patients with NS exhibit certain characteristic features, including cardiac defects, short stature, distinctive facial appearance, skeletal abnormalities, cognitive deficits, and predisposition to certain cancers. Here, a clinical practice survey was developed to learn more about differences in the diagnosis and management of this disease across Europe.

Management of cardiac aspects in children with Noonan syndrome - results from a European clinical practice survey among paediatric cardiologists.

Background: The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe.

Methods: A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed.