Volume 25 Supplement 1 Pages S1–S180 doi:10.1017/S1047951115000529 Cardiology in the Young © 2015 Cambridge University Press 49th Annual Meeting of the Association for European Paediatric and Congenital Cardiology, AEPC with joint sessions with the Japanese Society of Pediatric Cardiology and Cardiac Surgery, Asia-Pacific Pediatric Cardiology Society, European Association for Cardio-Thoracic Surgery and Canadian Pediatric Cardiology Association, Prague, Czech Republic, 20–23 May 2015 YIA-1 lesions and significantly decreased an anti-apoptotic molecule Macitentan Reverses Early Obstructive Pulmonary survivin protein and mRNA expression in lungs and the propor- Vasculopathy in Rats: Early Intervention in Overcoming tion of survivin positive αSMA cells in occlusive lesions in the early the Survivin-mediated Resistance to Apoptosis study but not in the late study. Shinohara T. (1,4), Sawada H. (1), Otsuki S. (1), Yodoya N. (1), Conclusions: Macitentan reversed early but not late obstructive pul- Kato T. (1), Ohashi H. (1), Zhang E. (2), Saitoh S. (4), monary vascular disease in rats. This reversal was associated with the Shimpo H. (3), Maruyama K. (2), Komada Y. (1), Mitani Y. (1) suppression of survivin-related resistance to apoptosis and prolifera- Department of Pediatrics (1); Anesthesiology and Critical Care Medicine tion of αSMA cells in occlusive lesions. These findings could be (2); Thoracic and Cardiovascular Surgery (3); Mie University Graduate mechanistic basis for the efficacy of early treatment and give an insight School of Medicine, Tsu, Japan, Department of Pediatrics and into later appearance of resistance to treatment for this disorder. Neonatology, Nagoya City University Graduate School of Medical Sciences, Nogoya, Japan (4) YIA-2 Objectives: We tested the hypothesis that a novel endothelin Does reversal of flow in the fetal aortic arch in second trimester receptor antagonist macitentan reverses the early and/or late stages aortic stenosis predict hypoplastic left heart syndrome? of occlusive pulmonary vascular disease in rats. Kovacevic A. (1,2), Öhman A. (3), Tulzer G. (4), Herberg U. (5), Methods: Rats with pulmonary arterial hypertension (PAH), which Dangel J. (6), Bartrons J. (7), Carvalho J.S. (1,8), Fesslova V. (9), were produced by combined exposure to a vascular endothelial Jicinska H. (10), Sarkola T. (11), Toler A.J. (12), Mellander M. (13), growth factor receptor inhibitor Sugen 5416 and hypobaric Gardiner H.M. (1,14,15) hypoxia for 3 weeks (SuHx), were assigned to receive macitentan Department of Paediatric and Congenital Cardiology, Royal Brompton (30 mg/kg, once daily by oral gavage) or vehicle during 3–5 weeks and Harefield Hospital, NHS Foundation Trust, London, UK (1); (early study, n = 40) or during 5–8 weeks (late study, n = 38) after Department of Paediatric and Congenital Cardiology, University of Sugen injection. A baseline SuHx PAH rat group, sacrificed just Heidelberg, Heidelberg, Germany (2); Department of Women’s and before treatment initiation, was present in each study to evaluate Children’s Health, Uppsala University, Sweden (3); Department of the reversal of disease during treatment. A P-value of <0.05 was Paediatric Cardiology, Children’s Heart Centre, Linz, Austria (4); considered to be statistically significant. Department of Paediatric Cardiology, University Hospital Bonn, Results: Compared with vehicle-treated PAH rats and baseline Germany (5); Perinatal Cardiology Clinic, 2nd Department of Obstetrics SuHx PAH rats, the macitentan-treated rats significantly showed and Gynecology, Medical University of Warsaw, Poland (6); Department decreases of the proportion of occlusive lesionsin all small arteries of Paediatric Cardiology, Hospital Clinic, Sant Johan de Deu, Barcelona, (outer diameter: 15–50 μm) per lung section in the early study Spain (7); Fetal Medicine Unit, St. George’s Hospital NHS Trust, (baseline PAH rats: 33.8 ± 4.4%, vehicle-treated PAH rats: London, UK (8); Center of Fetal Cardiology, Policlinico San Donato 41.5 ± 4.1% and macitentan-treated PAH rats: 17.9 ± 2.8%), a IRCSS, Milan, Italy (9); University Hospital and Masaryk University finding consistent with the reversal of right ventricular systolic Brno, Czech Republic (10); Children’s Hospital, University of Helsinki pressure (control rats: 19.4 ± 1.4 mmHg, baseline PAH rats: and Helsinki University Central Hospital, Helsinki, Finland (11); 78.3 ± 4.9 mmHg, vehicle-treated PAH rats: 79.5 ± 6.4 mmHg Department of Data Analytics, Southern New Hampshire University, and macitentan-treated PAH rats: 50.3 ± 5.0 mmHg), indices of Manchester, New Hampshire, USA (12); Department of Paediatric right ventricular hypertrophy and medial wall thickness. Maci- Cardiology, Queen Silva Children’s Hospital, Sahlgrenska University tentan ameliorated but did not reverse the proportion of occlusive Hospital, Gothenburg, Sweden (13); Department of Reproductive lesions in the late study. Although macitentan significantly Biology, Division of Cancer, Faculty of Medicine, Imperial College decreased the proportion of Ki67 positive lesions in both studies, London at Queen Charlotte’s and Chelsea Hospital (14); The Fetal macitentan significantly increased the proportion of cleaved cas- Center, Children’s Memorial Hermann Hospital, University of Texas, pase 3 positive α smooth muscle actin (αSMA) cells in occlusive Houston, TX, USA (15) Downloaded from https://www.cambridge.org/core. IP address: 170.106.34.90, on 30 Sep 2021 at 09:21:39, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/S1047951115000529 S2 Cardiology in the Young: Volume 25 Supplement 1 Introduction: Although the treatment of intravenous immunoglo- bulin (IVIG) significantly resolves inflammation, 10-20% of Kawasaki disease (KD) patients have persistent or recurrent fever after the administration of IVIG, and IVIG-resistant patients have a particularly high risk of developing coronary artery abnormalities. The mechanisms of IVIG-resistant KD have been analyzed using the patients’ leukocyte samples. However, vascular endothelial cells (ECs), closely related to the vasculitis of KD, have not been examined in the previous reports. We propose a hypothesis that ECs are mainly involved in the etiology of IVIG-resistance. Methods: The purpose of this study is to establish new in vitro disease models of vasculitis using induced pluripotent stem cell (iPSC) tech- nology, and clarify the mechanisms of IVIG-resistance in KD. Dermal fibroblasts or T cells from 2 IVIG-resistant and 2 IVIG-responsive KD patients were reprogrammed by episomal vectors encoding Oct3/4, Sox2, Klf4, L-Myc, LIN28, and p53 shRNA. The iPSC lines were then differentiated into ECs and smooth muscle cells (SMCs) by using a previously-reported differentiation method, and the EC and SMC samples were subjected to the microarray analyses. Results: The KD patient-derived iPSCs could be differentiated into Figure 1. a-c: Kaplan Meier curves showing no significant ECs and SMCs. The gene expression profiles were compared between difference in survival and BV for case control groups (FV = Fetal iPS-derived ECs (iPS-ECs) generated from IVIG-resistant and IVIG- aortic valvuloplasty, NH = Natural history, matched for + /- one responsive KD patients, and between iPS-derived SMCs (iPS-SMCs) Z-score for MV, AoV, LV inlet Z-scores and retrograde aortic arch generated from two group patients. We found the expression of che- flow at 23 + /-3 gestational weeks at 4 years after birth). mokine X, which stimulates migration of monocytes and T-lympho- cytes through its receptors, was significantly up-regulated both in iPS- Introduction: Fetal aortic valvuloplasty (FV) has been proposed as an ECs and in iPS-SMCs from IVIG-resistant KD patients compared with effective therapy to prevent progression from aortic stenosis to hypo- those from IVIG-responsive patients. The Principle Component plastic left heart syndrome (HLHS). Reversal of aortic arch flow in Analysis (PCA) was performed, but the gene expression levels showed second trimester is thought predictive of HLHS without FV. We no significant differences between the groups. The Gene Set Enrich- hypothesized that reversed arch flow does not predict HLHS. ment Analysis (GSEA) revealed that the gene sets related to IL-6, Methods: In a retrospective multicenter and multinational study NRAS (a member of the RAS oncogene family) and breast cancer (2005-2012) 214 fetuses with aortic stenosis were enrolled into a were up-regulated in iPS-ECs from IVIG-resistant KD patients. hybrid case-control and repeated samples cohort. Liveborn surgical Conclusions: Taking into account that the concentration of IL-6 has candidates undergoing FV or without FV (natural history, NH) were been reported to be elevated in acute phase of IVIG-resistant KD, our matched for between + /- one Z-score for mitral valve (MV) and results suggest that the up-regulation of IL-6 related genes in ECs might aortic valve (AoV) diameters, left ventricular inlet length (LV) and be involved in the pathogenesis of IVIG-resistant KD. retrograde arch flow at 23 + /-3 gestational weeks, producing best match cohorts for each. Outcome measures were survival with biventricular circulation (BV) at four years. We analysed outcomes YIA-4 using Cox proportional hazards regressions and Kaplan Meier curves. Improvement of haemodynamic flow abnormalities after Results: FV was performed in 67/214, technically successful in 59 aortic valve replacement in bicuspid aortic valve disease (88.0%).