Safety and Efficacy of Selexipag for Pediatric Pulmonary Arterial Hypertension in Japanese Patients - An Open-Label Phase 2 Study.

Background: Selexipag, an oral prostacyclin (PGI) receptor agonist, is approved for adult patients with pulmonary arterial hypertension (PAH). This study evaluated the efficacy and safety of selexipag for Japanese pediatric patients with PAH.

Methods And Results: The study enrolled 6 patients who received selexipag twice daily at an individualized dose based on body weight; maintenance doses were determined for each patient by 12 weeks after starting administration.

Computational and Experimental Analyses for Pathogenicity Prediction of Missense Variants in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants showed no detectable cell surface expression and impairment of bone morphogenetic protein 9 (BMP9) responsiveness of SMAD-dependent transcription in luciferase assays.

Pulmonary Arteriovenous Fistulae After Fontan Operation: Incidence, Clinical Characteristics, and Impact on All-Cause Mortality.

Background: The Fontan operation is a surgical procedure used in children with univentricular hearts. Pulmonary arteriovenous fistulae (PAVF) is a major complication after a Fontan operation. However, the incidence and related clinical pathophysiology of PAVF remain unclear.

Cerebral embolism accompanied by remarkable diffusion-weighted imaging reversal in a 10 month-old infant with congenital heart disease.

•The case of infant ischemic stroke with remarkable DWI reversal.•A mismatch between core volume and visually DWI lesion predicts DWI reversal.•Chronic hypoxia and early recanalization may contribute to large DWI reversal.

Effect of Stiffened and Dilated Ascending Aorta on Aerobic Exercise Capacity in Repaired Patients With Complex Congenital Heart Disease.

Several studies have reported aortic dilation and increased stiffness of the ascending aorta in patients after repair of congenital heart disease (CHD), which may be a predominant cardiovascular risk. However, the clinical significance has not been described in detail. In this retrospective study, 175 repaired patients with complex CHD achieving biventricular circulation and age-matched 39 control subjects were reviewed (median age: 14.

Progressive stiffening and relatively slow growth of the dilated ascending aorta in long-term Fontan survivors-Serial assessment for 15 years.

Background: A stiffened, dilated ascending aorta may represent an important predictor of cardiovascular mortality, and has been reported in patients with congenital heart disease, including single ventricle. However, the serial conformational changes and determinants of reduced distensibility in ascending aorta have not been clarified.

Methods: This retrospective study investigated 115 postoperative Fontan survivors (median age at Fontan: 3.

Abnormal glucose metabolism in patients with Fontan circulation: Unique characteristics and associations with Fontan pathophysiology.

Background: Fontan patients exhibit a high prevalence of abnormal glucose metabolism (AGM). We aimed to characterize AGM and clarify its association with Fontan pathophysiology.

Methods: We prospectively evaluated AGM with plasma glucose dynamics [mg/dL; fasting glucose (FPG), and maximum glucose increase (PG-spike)] during oral glucose tolerance test and hemoglobin A1c (HbA1c) in 276 consecutive Fontan patients (aged 19 ± 7 years).

Positive pediatric exercise capacity trajectory predicts better adult Fontan physiology rationale for early establishment of exercise habits.

Objective: Exercise training is recommended for its possible favorable effects on Fontan pathophysiology. This study aimed to elucidate the impact of pediatric exercise capacity trajectory, which may mimic the effect of exercise training, on late adult Fontan pathophysiology.

Methods: Since 1990, 97 Fontan patients had consecutively undergone two serial cardiopulmonary exercise tests (CPX1 and CPX2) during childhood (ages 8 ± 2 and 14 ± 2 years) and one during adulthood (CPX3; age 23 ± 5 years).

Long-term respiratory outcomes after primary total correction for tetralogy of Fallot and absent pulmonary valve in patient with respiratory symptoms.

Objective: To review long-term respiratory outcomes for tetralogy of Fallot and absent pulmonary valve (TOF/APV) in respiratory symptomatic populations.

Methods: Of 25 consecutive patients undergoing primary total correction for TOF/APV between 1987 and 2016, Sixteen patients (64%) with a preoperative respiratory disturbance were enrolled. The median age at operation was 1.

Heart failure with preserved right ventricular ejection fraction in postoperative adults with congenital heart disease: A subtype of severe right ventricular pathophysiology.

Background: Right ventricle (RV) may determine heart failure (HF) severity in adults with congenital heart disease (ACHD). However, the association of RV properties with clinical profiles remains unclear.

Purpose: To clarify the associations of RV properties with biomarkers, exercise capacity, and unscheduled hospitalization (USH) in postoperative ACHD patients.

Left ventricular reverse remodeling with infantile dilated cardiomyopathy and pitfalls of carvedilol therapy.

Background: The left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (DCM) and the treatment with carvedilol in infants with severe heart failure remain poorly understood.

Methods: We reviewed the medical records of 5 infants around 12 months old referred to our hospital with severe heart failure due to DCM. Increased left ventricular fractional shortening (LVFS) by more than 10% and the percent of normal of left ventricular end-diastolic dimension (%LVDd) less than 120% were defined as LVRR in this study.

Low fasting plasma glucose level predicts morbidity and mortality in symptomatic adults with congenital heart disease.

Background: Adults with complex congenital heart disease (ACHD) have a high prevalence of abnormal glucose regulation (AGR: impaired glucose tolerance and diabetes mellitus). However, the impact of AGR on the prognosis remains unclear.

Purpose: Our purpose was to clarify the prognostic value of AGR in ACHD.

Comparison of prognostic variables in children and adults with Fontan circulation.

Background: Non-cardiac complications, such as hepato-renal and metabolic problems, are emerging late after the Fontan operation due to its unique hemodynamics. Consequently, associations between clinical variables and postoperative outcome may change during the prolonged postoperative course.

Methods And Results: To determine if child and adult Fontan patients differ in the impact of cardiac and non-cardiac variables on clinical outcome, we prospectively evaluated associations between hemodynamics, neurohumoral factors, exercise variables, hepato-renal function and metabolic variables and unscheduled hospitalization, including death in 167 consecutive child and 116 adult Fontan patients.

Countermeasures against physical motion in schoolchildren requiring no sedation during rest and stress myocardial perfusion imaging with technetium-99m-tetrofosmin.

For children, cardiac nuclear medicine imaging has not been widely used because of problems of physical motion, even in schoolchildren who require no sedation. In this study, rest-stress myocardial perfusion imaging (MPI) with technetium-99m-tetrofosmin (Tc-99m TF) was performed with the use of a Vac-Loc cushion, a patient immobilizer commonly used for radiotherapy, for immobilizing school-age patients. The immobilizer attenuated the gamma radiation by 6%.

Neonatal mouse testis-derived multipotent germline stem cells improve the cardiac function of acute ischemic heart mouse model.

Multipotent germline stem (mGS) cells have been established from neonatal mouse testes. We previously reported that undifferentiated mGS cells are phenotypically similar to embryonic stem cells and that fetal liver kinase 1 (Flk1)(+) mGS cells have a similar potential to differentiate into cardiomyocytes and endothelial cells compared with Flk1(+) embryonic stem cells. Here, we transplanted these Flk1(+) mGS cells into an ischemic heart failure mouse model to evaluate the improvement in cardiac function.

Generation of skeletal muscle stem/progenitor cells from murine induced pluripotent stem cells.

Induced pluripotent stem (iPS) cells, which are a type of pluripotent stem cell generated from reprogrammed somatic cells, are expected to have potential for patient-oriented disease investigation, drug screening, toxicity tests, and transplantation therapies. Here, we demonstrated that murine iPS cells have the potential to develop in vitro into skeletal muscle stem/progenitor cells, which are almost equivalent to murine embryonic stem cells. Cells with strong in vitro myogenic potential effectively were enriched by fluorescence-activated cell sorting using the anti-satellite cell antibody SM/C-2.

Generation of transplantable, functional satellite-like cells from mouse embryonic stem cells.

Satellite cells are myogenic stem cells responsible for the postnatal regeneration of skeletal muscle. Here we report the successful in vitro induction of Pax7-positive satellite-like cells from mouse embryonic stem (mES) cells. Embryoid bodies were generated from mES cells and cultured on Matrigel-coated dishes with Dulbecco's modified Eagle medium containing fetal bovine serum and horse serum.

Flk1(+) cardiac stem/progenitor cells derived from embryonic stem cells improve cardiac function in a dilated cardiomyopathy mouse model.

Objectives: Flk1(+) cells derived from embryonic stem (ES) cells are known to differentiate into mesodermal lineages such as hematopoietic and endothelial cells. Here we demonstrate that they can develop into cardiomyocytes that support functional recovery in a dilated cardiomyopathy (DCM) C57/BL6 mouse model.

Methods: Flk1(+) and Flk1(-) cells were sorted at day 4 of differentiation, and cardiomyogenesis was assessed in vitro.

Generation of cardiac and endothelial cells from neonatal mouse testis-derived multipotent germline stem cells.

Multipotent germline stem (mGS) cells have been established from neonatal mouse testes. Here, we compared mGS, embryonic stem (ES), and embryonic germ (EG) cells with regard to their ability to differentiate into mesodermal cells, namely, cardiomyocytes and endothelial cells. The in situ morphological appearances of undifferentiated mGS, ES, and EG cells were similar, and 4 days after being induced to differentiate, approximately 30%-40% of each cell type differentiated into Flk1(+) cells.