Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial.

INTRODUCTION: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma. METHODS: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure. CONCLUSIONS: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

Association Between Serial B-Type Natriuretic Peptide Levels, Vasoactive Drug Weaning, and Adverse Cardiovascular Outcomes in Pediatric Heart Failure.

BACKGROUND: Children hospitalized with acute decompensated heart failure (ADHF) frequently require intravenous vasoactive (IVV) support drugs and are at risk for adverse cardiovascular (ACV) outcomes. We wished to assess whether serial changes in B-type natriuretic peptide (BNP) levels are associated with successful weaning off IVV support and/or prespecified ACV outcomes in children hospitalized with ADHF. METHODS AND RESULTS: Children hospitalized with ADHF from 2005 to 2021 at our institution were assessed for serial changes in BNP, weaning off of IVV support, and ACV outcomes. Changes in BNP level were evaluated using linear mixed-effects modeling. Bonferroni correction was used to adjust for multiple hypothesis testing. In 131 hospitalizations of children with ADHF, the median age was 4.8 years, with 74% receiving IVV support. ACV outcomes occurred in 62 children. IVV support was associated with lower admission left ventricular ejection fraction (26.7% versus 32%, P=0.002), more severe left ventricular dilation (left ventricular internal diastolic dimension Z score 5.9 versus 3.1, P=0.021) moderate or more mitral regurgitation (41.3% versus 20.6%, P=0.038), and qualitative right ventricular systolic dysfunction (in 45.4% versus 11.8%, P<0.001). Decline in BNP levels was more rapid in patients who were successfully weaned from IVV support (-0.20 versus -0.03 2log pg/mL per day, P<0.001) and in the non-ACV group (-0.17 versus -0.03 2log pg/mL per day, P<0.001). Right ventricular systolic dysfunction was an independent risk factor for ACV (odds ratio, 2.49; P=0.045). CONCLUSIONS: The declining rate of serial BNP levels was associated with weaning from IVV support and no ACV outcomes in children hospitalized with ADHF. Right ventricular systolic dysfunction was associated with ACV outcomes.

Recent and Upcoming Drug Therapies for Pediatric Heart Failure.

Pediatric heart failure (HF) is an important clinical condition with high morbidity, mortality, and costs. Due to the heterogeneity in clinical presentation and etiologies, the development of therapeutic strategies is more challenging in children than adults. Most guidelines recommending drug therapy for pediatric HF are extrapolated from studies in adults. Unfortunately, even using all available treatment, progression to cardiac transplantation is common. The development of prospective clinical trials in the pediatric population has significant obstacles, including small sample sizes, slow recruitment rates, challenging endpoints, and high costs. However, progress is being made as evidenced by the recent introduction of ivabradine and of sacubitril/valsartan. In the last 5 years, new drugs have also been developed for HF with reduced ejection fraction (HFrEF) in adults. The use of well-designed prospective clinical trials will be fundamental in the evaluation of safety and efficacy of these new drugs on the pediatric population. The aim of this article is to review the clinical presentation and management of acute and chronic pediatric heart failure, focusing on systolic dysfunction in patients with biventricular circulation and a systemic left ventricle. We discuss the drugs recently approved for children and those emerging, or in use for adults with HFrEF.