BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro–B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (N=187) or enalapril (N=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47–0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72–1.14]; P =0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02678312.

Hur G, et al. Korean Circ J. 2018 Aug;49:e5. https://doi.org/10.4070/kcj.2018.0214

Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal-dominant vascular disorder, characterized by recurrent epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVMs) in various visceral organs. Endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1; ALK1), receptors for transforming growth factor-β (TGF-β) superfamily, have been identified as the principal HHT-causing genes. Methods: Three unrelated Korean HHT patients and their asymptomatic as well as symptomatic family members were genetically diagnosed by sequencing whole exons and their flanking regions of ENG and ACVRL1. Functionality of an aberrant translation start codon, which is created by a substitution mutation at the 5'-untranslated region (UTR) of ENG found in a HHT family, was tested by transient in vitro transfection assay. Decay of the mutant transcripts was also assessed by allele-specific expression analysis. Results: Two ENG and one ACVRL1 mutations were identified: a known ENG mutation (c.360+1G > A; p.Gly74_Tyr120del); a novel ENG mutation (c.1-127C > T); and a novel ACVRL1 mutation (c.252_253insC; p.Val85fsX168). We further validated that the 5'-UTR ENG mutation prevents translation of ENG from the biological translation initiation site of the mutant allele, and leads to degradation of the mutant transcripts. Conclusions: This is the first experimental demonstration that a 5'-UTR mutation can prevent translation of ENG among HHT patients, and further supports the previous notion that haploinsufficiency is the primary mechanism of HHT1. Our data also underscore the importance of including exons encoding 5' UTR for HHT mutation screening.

In this study, we sought predictors of mortality in children with acute myocarditis and of incomplete recovery in the survivor group. We classified our patients into three groups according to their outcomes at last follow-up: full recovery was classified as group I, incomplete recovery was classified as group II, and death was classified as group III. In total, 55 patients were enrolled in the study: 33 patients in group I, 11 patients in group II, and 11 patients in group III. The initial left ventricular fractional shortening – left ventricular fractional shortening – was significantly lower in group III (p=0.001), and the left ventricular end-diastolic dimension z score was higher in groups II and III compared with group I (p=0.000). A multivariate analysis showed that the left ventricular end-diastolic dimension z score (odds ratio (OR), 1.251; 95% confidence interval (CI), 1.004–1.559), extracorporeal membrane oxygenation (OR, 9.842; 95% CI, 1.044–92.764), and epinephrine infusion (OR, 18.552; 95% CI, 1.759–195.705) were significant predictors of mortality. The left ventricular end-diastolic dimension z score was the only factor that predicted incomplete recovery in the survivor group (OR, 1.360; 95% CI, 1.066–1.734; p=0.013). The receiver operating characteristic curve of the left ventricular end-diastolic dimension z score at admission showed a cut-off level of 3.01 for predicting mortality (95% CI, 0.714–0.948). In conclusion, a high left ventricular end-diastolic dimension z score on admission was a significant predictor of worse outcomes, both regarding mortality and incomplete recovery.