Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients.

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.Results: Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229-1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

Detection of Pediatric Pulmonary Arterial Hypertension by School Electrocardiography Mass Screening.

Rationale: To detect pulmonary arterial hypertension (PAH) at any early stage is a promising approach to optimize the outcome. Objectives: To investigate the impact of school ECG-based screening on detecting idiopathic or heritable (I/H)-PAH in the general pediatric population. Methods: This was a nationwide survey of patients with I/H-PAH newly diagnosed at 3 months to 18 years of age in Japan during 2005-2012. Measurements and Main Results: Eighty-seven eligible patients (age range, 1-16 yr) were recruited. Among 68 (78%) patients diagnosed at greater than or equal to 6 years of age (the age of the first ECG-based screening), 28 (41%) were detected by the ECG-based screening (screening group) and 40 (59%) were recognized by their symptoms (n = 37) or coincidental occasions (n = 3; nonscreening group). In the screening group, the proportion of patients in World Health Organization functional class I/II at diagnosis was higher (96% vs. 60%; P < 0.001), plasma brain natriuretic peptide level was lower (149 ± 290 vs. 398 ± 559 pg/ml; P = 0.045), and 6-minute-walk distance was longer (420 ± 109 vs. 327 ± 104 m; P < 0.001) than the nonscreening group, despite similar values in mean pulmonary artery pressure (58 ± 17 vs. 61 ± 17 mm Hg; P = 0.42) and pulmonary vascular resistance index (18 ± 8 vs. 21 ± 11 Wood units ⋅ m2; P = 0.24) between groups. The proportion of patients on intravenous epoprostenol at the final visit was lower in the screening group than the nonscreening group (14% vs. 50; P = 0.004). Conclusions: These findings suggest that the ECG-based screening detects a unique subpopulation of pediatric patients with I/H-PAH that is associated with already established pulmonary hypertension but without obvious right heart failure and warrants investigating the prognostic significance of this system.

Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events.

Importance: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). Objective: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. Design, Setting, and Participants: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. Main Outcomes and Measures: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. Results: Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE. Conclusions and Relevance: Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.

Health-care transition after Kawasaki disease in patients with coronary artery lesion.

BACKGROUND: Discussion of health-care transition (HCT) for adults with a childhood history of coronary artery lesions (CAL) after Kawasaki disease (KD) is important. A nationwide questionnaire survey was performed with support by the Japanese Society of Kawasaki Disease. The purpose of this study was to clarify the reality of HCT and loss to follow-up in patients with CAL after KD. METHODS: The survey was emailed to 48 members of the Japanese Society of Kawasaki Disease from May to July 2014. RESULTS: Forty surveys were collected, giving a response rate of 83.3%. Sixty-five percent of the respondents belonged to a university hospital. Approximately 90% of the respondents dealt with patients who needed HCT, and 55% had patients who completed HCT. Approximately 70% of the respondents considered that pediatricians should continue sharing HCT information with cardiologists. More than 95% of the respondents had a favorable or average impression of HCT care provided by cardiologists. The percentage of respondents who had loss to follow up for HCT was >40%. CONCLUSION: Adult cardiologists began managing patients with CAL after KD in more than half of the institutes in this study. Pediatricians should construct a support program for better management of these patients and for cooperation with cardiologists to prevent loss to follow up.

Clinical Impact of Main Pulmonary Artery Dilatation on Outcome in Pediatric Idiopathic and Heritable Pulmonary Arterial Hypertension.

BACKGROUND: Few studies have investigated the clinical impact of pulmonary artery (PA) dilatation on outcomes in pediatric pulmonary arterial hypertension (PAH).Methods and Results:This study investigated the clinical outcomes of idiopathic or heritable PAH in 66 children aged <18 years at diagnosis. Main PA/thorax (MPA/T) ratio was measured on chest radiography in PAH patients. Patients were divided into 2 groups based on MPA/T ratio, and compared with a control group of 166 age- and gender-matched healthy children. Group A had higher MPA/T ratio than normal, and group B had normal MPA/T ratio. Composite outcomes included cardiac death, lung transplantation, and hospitalization due to heart failure. Group A consisted of 27 patients and group B, 39 patients. At diagnosis, group A had significantly higher brain natriuretic peptide (BNP), cardiothoracic ratio, PA pressure, and pulmonary vascular resistance index compared with group B. The number of patients with New York Heart Association (NYHA) functional class III and IV was significantly higher in group A than in group B. Cumulative event-free survival rate was significantly lower in group A. CONCLUSIONS: MPA dilatation correlated with BNP, NYHA functional class, and hemodynamics with regard to disease severity, and may be a potential prognostic factor in pediatric idiopathic and heritable PAH.

Infliximab for the Treatment of Refractory Kawasaki Disease: A Nationwide Survey in Japan.

OBJECTIVE: To assess the safety and efficacy of infliximab (IFX) for the treatment of patients with Kawasaki disease (KD). STUDY DESIGN: This was a nationwide survey of 274 Japanese institutions exploring how IFX was used to treat patients with KD. The patients' sex, age, treatment course, pre- and post-IFX therapy blood test results, coronary artery lesions (CALs), and adverse events (AEs) were evaluated. RESULTS: We analyzed 434 patients with KD who received IFX between March 2005 and November 2014. The median age at onset was 33 months (range 1-138), and 66 patients (15.2%) were under 1 year old. In all cases, IFX was administered as additional treatment. The median days of illness at the initiation of IFX was 9 days. In 275 patients (63.4%), IFX was administered as third-line treatment, and in 106 patients (24.4%), IFX was administered as fourth-line treatment. Single dose IFX 5 mg/kg was administered to 412 patients (94.9%). After IFX, 363 patients (83.6%) became afebrile within 2 days, and the white blood cell count, percentage of neutrophils, and serum C-reactive protein levels significantly decreased (P < .001), although 119 patients (27.4%) received additional treatment. Before IFX, 132 patients (30.4%) had already developed CALs. In patients without CALs before IFX, 31 patients (10.3%) newly developed CAL after IFX, whereas 32 patients (24.2%) with CAL before IFX showed increased CAL severity. Eighty AEs were observed in 69 patients (15.9%); however, serious AEs were few and reversible. CONCLUSIONS: IFX might be an effective and tolerable treatment for refractory KD.

Live-attenuated vaccines in a cryopyrin-associated periodic syndrome patient receiving canakinumab treatment during infancy.

We successfully immunized the neonatal-onset multisystem inflammatory disease (NOMID) patient with live-attenuated vaccines for measles, rubella, varicella, and mumps and achieved sufficient antibody titer under canakinumab therapy without complications.

A genome-wide association analysis identifies PDE1A|DNAJC10 locus on chromosome 2 associated with idiopathic pulmonary arterial hypertension in a Japanese population.

Pulmonary arterial hypertension (PAH) is a lethal disease that often affects the young. Although Bone Morphogenetic Protein Receptor Type 2 gene (BMPR2) mutations are related with idiopathic and heritable PAH, the low penetrance and variable expressivity in PAH suggest the existence of other genetic and/or environmental factors. In this study, we aimed to identify novel genetic factors associated with PAH, irrespective of BMPR2 mutation. We performed genome-wide association study (GWAS) in a Japanese population comprising 44 individuals with idiopathic and heritable PAH, and 2,993 controls. Seven loci identified in the genome-wide study were submitted to the validation study, and a novel susceptibility locus, PDE1A|DNAJC10, was identified that maps to 2q32.1 (rs71427857, P = 7.9 × 10-9, odds ratio in the validation study = 5.18; 95% CI 1.86 - 14.42). We also found the augmentation of PDE1A protein in distal remodeled pulmonary artery walls in idiopathic PAH patients. Given that phosphodiesterase 5 inhibitors are effective for the treatment of idiopathic and heritable PAH, our findings suggest that PDE1A could be a novel therapeutic target of PAH.

FCN1 (M-ficolin), which directly associates with immunoglobulin G1, is a molecular target of intravenous immunoglobulin therapy for Kawasaki disease.

Kawasaki disease (KD), an acute systemic vasculitis of early childhood, is of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is an effective treatment, but its molecular target remains elusive. DNA microarray analysis of peripheral blood mononuclear cells (PBMCs) revealed that at least 21 genes are drastically down-regulated after IVIG treatment in most KD patients. qRT-PCR analysis confirmed that the mRNA levels of five of these genes were considerably reduced in almost all KD patients after IVIG treatment. Western blot (Wb) of PBMC extracts revealed that levels of FCN1 (M-ficolin), a protein of the complement system that defends against infectious agents, were reduced after IVIG treatment in many KD patients. In another set of KD patients, Wb confirmed that levels of both FCN1 were greatly reduced after IVIG therapy. Wb revealed that the collagen-like domain of FCN1 directly bound to IgG1 in vitro through a portion of the CH1 and CH3 domains, and synthetic peptides corresponding to these domains of IgG1 efficiently inhibited these associations. These results suggest that FCN1 is a molecular target of intravenous IVIG in KD patients. We propose that these peptides and a humanized monoclonal antibody against FCN1 could be useful in combination therapy with IVIG.

Nationwide Survey of Patients With Giant Coronary Aneurysm Secondary to Kawasaki Disease 1999-2010 in Japan.

BACKGROUND: Giant coronary aneurysm is the most severe sequela in Kawasaki disease, occurring in approximately 0.2% of patients in Japan. Regression is rare, while myocardial infarction (MI) and sudden death are relatively common. Herein, we reviewed patients with giant coronary aneurysm in a 10-year period.Methods and Results:A nationwide questionnaire survey was conducted based on a national epidemiological database from 1999 to 2010. We identified 355 giant coronary aneurysm patients, of whom 209 were analyzed. The 5- and 10-year total cardiac event-free rates were 0.72 and 0.68, respectively. Twelve patients died, and MI was observed in 32 patients (18.1%). Five and 6 deaths were due to coronary rupture and MI, respectively. All ruptures occurred within 1 month of onset, while most MI occurred within 18 months. There was no death beyond 2 years. Aneurysm size was significantly related to the occurrence of MI in both the right and left coronary arteries. At the time of writing, 55% of patients had no exercise limitations. And including patients who cannot perform strenuous exercises, 81% of patients were leading ordinary lives. CONCLUSIONS: Severe cardiac events are likely to occur within 2 years from onset of Kawasaki disease, while no deaths occurred beyond this time. Hence, careful monitoring is needed especially for the first 2 years. Most patients with giant coronary aneurysms can lead ordinary lives with appropriate management.

Low risk of treatment resistance in Down syndrome with Kawasaki disease.

BACKGROUND: A Japanese nationwide survey has reported that Down syndrome (DS) is a less-frequently occurring comorbidity in Kawasaki disease (KD). Although altered immune responses are frequently observed in DS, no studies have focused on the treatment response and risk for coronary artery abnormalities (CAA) in DS patients with KD. The aim of this study was therefore to evaluate the clinical manifestations, treatment response and prevalence of CAA in DS with KD. METHODS: We retrospectively reviewed the medical records of DS patients with KD from 2005 through 2012. The survey questionnaires were sent to facilities nationwide, and clinical data regarding KD in DS were collected. A control group consisted of non-DS patients with KD who were managed at Toho University. RESULTS: Of the 94 233 children diagnosed with acute KD from 2005 to 2012, 16 children with acute KD also had DS (0.017%). The DS-KD patients were significantly older than the non-DS patients (median, 8 years vs 1 year, P < 0.05, respectively). Half of the DS patients had incomplete KD. Although 50% of the DS children were at high risk of immunoglobulin resistance, all children responded to initial treatment and none had CAA. CONCLUSIONS: All DS-KD patients responded to initial i.v. immunoglobulin (IVIG) or aspirin despite having a high risk of IVIG resistance, and none of the DS patients had CAA. This suggests that the risk of treatment resistance and development of CAA may be not higher in DS patients with acute KD.

Effect of treatment with epoprostenol and endothelin receptor antagonists on the development of thyrotoxicosis in patients with pulmonary arterial hypertension.

Thyroid disease is known to be associated with pulmonary arterial hypertension (PAH). We investigated the prevalence of thyroid disease in patients with idiopathic PAH (IPAH) or heritable PAH (HPAH), and the factors affecting the pathogenesis of thyroid disease. We retrospectively evaluated 59 patients with IPAH or HPAH who had been diagnosed with PAH before the age of 20 years. Thyrotoxicosis was detected in 12 of the 59 patients (6 patients with Graves' disease, 3 with hashitoxicosis, and 3 with silent thyroiditis) after the start of PAH treatment. The proportion of patients who received epoprostenol in the thyrotoxicosis group was significantly higher than that in the euthyroid group (12/12 vs. 27/47, p=0.015). In the 39 patients treated with epoprostenol, the proportion of patients who received combination therapy with epoprostenol and an endothelin receptor antagonist (ERA) in the thyrotoxicosis group was significantly lower than that in the euthyroid group (5/12 vs. 23/27, p=0.016). Logistic regression analysis revealed that thyrotoxicosis development was significantly associated with administration of epoprostenol (odds ratio [OR] 8.22, 95% confidence interval [CI] 1.26-53.74, p=0.028) and non-administration of ERA (OR 5.33, 95% CI 1.29-22.06, p=0.021). The prevalence of thyrotoxicosis was high in patients with IPAH or HPAH. The onset of thyrotoxicosis might be promoted by epoprostenol and inhibited by ERA.

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association.

BACKGROUND: Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries. METHODS AND RESULTS: To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and long-term outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up. CONCLUSIONS: These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.

Implication of overexpression of dishevelled-associated activator of morphogenesis 1 (Daam-1) for the pathogenesis of human Idiopathic Pulmonary Arterial Hypertension (IPAH).

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis. Evidence from our recent study suggests that IPAH pathogenesis is related to upregulation of the Wnt/planar cell polarity (Wnt/PCP) pathway. We used microscopic observation and immunohistochemical techniques to identify expression patterns of cascading proteins-namely Wnt-11, dishevelled-2 (Dvl-2), and dishevelled-associated activator of morphogenesis 1 (Daam-1)-in pulmonary arteries. METHODS: We analyzed sections of formalin-fixed and paraffin-embedded autopsied lung tissues obtained from 9 IPAH cases, 7 associated pulmonary arterial hypertension cases, and 16 age-matched controls without pulmonary arterial abnormalities. Results of microscopic observation were analyzed in relation to the cellular components and size of pulmonary arteries. RESULTS: Varying rates of positive reactivity to Dvl-2 and Daam-1 were confirmed in all cellular components of pulmonary arteries, namely, endothelial cells, myofibroblasts, and medial smooth muscle cells. In contrast, none of these components was reactive to Wnt-11. No specific expression patterns were observed for endothelial cells or myofibroblasts under any experimental conditions. However, marked expression of Dvl-2 and Daam-1 was confirmed in smooth muscle cells. In addition, Dvl-2 was depleted while Daam-1 expression was elevated in IPAH, in contrast with specimens from associated pulmonary arterial hypertension cases and controls. CONCLUSIONS: High Daam-1 expression may upregulate the Wnt/PCP pathway and cause IPAH.

Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension.

OBJECTIVES: To evaluate the clinical utility of pulmonary artery capacitance index (PACi) in the assessment of disease severity and prognostic value in children with idiopathic and heritable pulmonary arterial hypertension (PAH). STUDY DESIGN: PACi is defined as the ratio of stroke volume index over pulmonary pulse pressure. A retrospective study was performed to compare PACi, brain natriuretic peptide (BNP), 6-minute walk distance, New York Heart association (NYHA) functional class, and adverse outcomes (hospitalization due to heart failure, lung transplantation, and cardiac mortality) in 72 Japanese children (10 ± 3.6 years) with idiopathic and heritable PAH. RESULTS: PACi had significant correlations with pulmonary vascular resistance index (r =-0.73, P < .0001), BNP levels (r = -0.40, P = .0008), and 6-minute walk distance (r = 0.57, P < .05). Statistically significant differences in PACi were observed between NYHA functional class II vs combined III and IV (median; 1.1 vs 0.6 mL/mm Hg/m2, respectively, P < .05). There were 25 of 72 (35%) children who had an adverse event including initiation of hospitalization due to heart failure, lung transplantation, and death. Cumulative event-free survival rate was significantly lower when PACi was <0.85 mL/mm Hg/m2 (log-rank test, P < .0001). CONCLUSIONS: PACi correlated with BNP and NYHA functional class and may serve as a strong prognostic marker in children with idiopathic and heritable PAH.

Clinical Features of Acute and Fulminant Myocarditis in Children　- 2nd Nationwide Survey by Japanese Society of Pediatric Cardiology and Cardiac Surgery.

BACKGROUND: The 1st nationwide survey by the Japanese Society of Pediatric Cardiology and Cardiac Surgery of acute or fulminant myocarditis (AMC/FMC) in children revealed that the survival rate of FMC was only 51.6%. The 2nd nationwide survey was performed to evaluate the recent outcomes of pediatric myocarditis.Methods and Results:Questionnaires regarding patients aged ≤18 years with AMC/FMC during the period from January 2006 to December 2011 were mailed. A total of 221 cases (age 6.5±5.3 years, 116 boys and 105 girls) were reported. There were 145 (65.6%) and 74 cases (33.5%) of AMC/FMC, respectively; the type of myocarditis was not reported in the remaining 2 cases (0.9%). Viruses were identified in 56 cases (25.3%), including coxsackie B in 9 and influenza A in 8. Histopathology by either endomyocardial biopsy or autopsy was obtained in 38 cases (19.2%). Intravenous immunoglobulin was effective in 49 (34.3%) of 143 cases. Steroid therapy was effective in 20 (32.8%) of 61 cases. Mechanical circulatory support was given in 54 cases (24.4%) and 94.2% of them were patients with FMC. The survival rates for the whole study population, acute myocarditis, and FMC were 75.6%, 91.0%, and 48.6%, respectively. CONCLUSIONS: The survival rate of children with myocarditis was almost identical to that of 10 years ago. (Circ J 2016; 80: 2362-2368).

Sildenafil reduces pulmonary vascular resistance in single ventricular physiology.

BACKGROUND: High pulmonary vascular resistance (PVR) may be a risk factor for early and late mortality in both Glen shunt and Fontan operation patients. Furthermore, PVR may increase long after the Fontan operation. Whether pulmonary vasodilators such as phosphodiesterase 5 inhibitors can decrease PVR in patients with single ventricular physiology remains undetermined. METHODS AND RESULTS: This was a prospective, multicenter study. Patients with single ventricular physiology who have a PVR index higher than 2.5 Wood units·ãŽ¡ (WU) were enrolled. Cardiac catheterization was performed before and after administration of sildenafil in all patients. After the Fontan operation, a six minute walk test (6MWT) was also performed. A total of 42 patients were enrolled. PVR was significantly decreased in each stage of single ventricular physiology after sildenafil administration: from 4.3±1.5WU to 2.1±0.6WU (p<0.01) in patients before a Glenn shunt, from 3.2±0.5WU to 1.6±0.6WU (p<0.001) in patients after a Glenn shunt, and from 3.9±1.7WU to 2.3±0.8WU (p<0.001) in patients after Fontan. In patients after Fontan, the 6MWT increased from 416±74m to 485±72m (p<0.01), and NYHA functional class improved significantly (p<0.05) after sildenafil administration. No major side effects were observed in any patients. CONCLUSIONS: Sildenafil reduced PVR in patients with single ventricle physiology. Sildenafil increased exercise capacity and improved NYHA functional class in patients after a Fontan operation. This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated PVR with single ventricle physiology. Long-term clinical significance warrants further study.

A New Z Score Curve of the Coronary Arterial Internal Diameter Using the Lambda-Mu-Sigma Method in a Pediatric Population.

BACKGROUND: Several coronary artery Z score models have been developed. However, a Z score model derived by the lambda-mu-sigma (LMS) method has not been established. METHODS: Echocardiographic measurements of the proximal right coronary artery, left main coronary artery, proximal left anterior descending coronary artery, and proximal left circumflex artery were prospectively collected in 3,851 healthy children ≤18 years of age and divided into developmental and validation data sets. In the developmental data set, smooth curves were fitted for each coronary artery using linear, logarithmic, square-root, and LMS methods for both sexes. The relative goodness of fit of these models was compared using the Bayesian information criterion. The best-fitting model was tested for reproducibility using the validation data set. The goodness of fit of the selected model was visually compared with that of the previously reported regression models using a Q-Q plot. RESULTS: Because the internal diameter of each coronary artery was not similar between sexes, sex-specific Z score models were developed. The LMS model with body surface area as the independent variable showed the best goodness of fit; therefore, the internal diameter of each coronary artery was transformed into a sex-specific Z score on the basis of body surface area using the LMS method. In the validation data set, a Q-Q plot of each model indicated that the distribution of Z scores in the LMS models was closer to the normal distribution compared with previously reported regression models. Finally, the final models for each coronary artery in both sexes were developed using the developmental and validation data sets. A Microsoft Excel-based Z score calculator was also created, which is freely available online (http://raise.umin.jp/zsp/calculator/). CONCLUSIONS: Novel LMS models with which to estimate the sex-specific Z score of each internal coronary artery diameter were generated and validated using a large pediatric population.

Endogenous IL-17 as a factor determining the severity of Clostridium difficile infection in mice.

Clostridium difficile infection (CDI) is a toxin-mediated intestinal disease. Toxin A, toxin B and binary toxin are believed to be responsible for the pathogenesis of CDI, which is characterized by massive infiltration of neutrophils at the infected intestinal mucosa. IL-17 is one of the cytokines that play critical roles in several inflammatory and immunological diseases through various actions, including promoting neutrophil recruitment. The aim of this study was to examine the role of this cytokine in CDI by employing IL-17 A and F double knockout (IL-17 KO) mice for the CDI model. We demonstrated that IL-17 KO mice were more resistant to CDI than WT mice using several factors, such as diarrhoea score, weight change and survival rate. Although the bacterial numbers of C. difficile in faeces were not different, the inflammatory mediator levels at the large intestine on day 3 post-infection were attenuated in IL-17 KO mice. Finally, we showed that infiltration of neutrophils, but not macrophages, in the large intestine was significantly decreased in IL-17 KO mice compared to WT mice. In conclusion, the data demonstrate that endogenous IL-17 may be a factor determining the severity of CDI in mice. Although the mechanism is totally unknown, IL-17-mediated inflammatory responses, such as cytokine/chemokine production and neutrophil accumulation, may be plausible targets for future investigations.

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS: Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P<0.0001). 6MWD increased from 427±128 to 494±116 m (P<0.0001). WHO functional class improved in 13 patients (46.4%) and was maintained in 15 patients (53.6%), and NT-pro-BNP was reduced by 18% (P<0.0001). The favorable treatment effect on PVR was apparent regardless of concomitant therapy for PAH. CONCLUSIONS: Macitentan was efficacious and well tolerated and improved the hemodynamic parameters, exercise capacity, symptoms, and clinical biomarkers in Japanese PAH patients. Macitentan can be a valuable therapeutic option for Japanese patients with PAH. ( TRIAL REGISTRATION: JAPIC Clinical Trials Information [JapicCTI-121986].) (Circ J 2016; 80: 1478-1483).