Outcomes of Dilated Cardiomyopathy in Japanese Children　- A Retrospective Cohort Study.

BACKGROUND: There has been no nationwide survey on the prognosis of pediatric dilated cardiomyopathy (DCM) in Japan. Therefore, we designed this retrospective multicenter study to investigate the long-term survival rate in pediatric patients with DCM in Japan.Methods and Results:In this multicenter retrospective observational study, data were reviewed for 106 patients aged <18 years who had been diagnosed with DCM at any 1 of 18 Japanese institutions between 1990 and 2014. The median age at diagnosis was 2.0 years and the median duration of observation was 3.3 years. Most DCM patients were diagnosed because of symptoms of heart failure. On echocardiography, the median left ventricular end-diastolic dimension z score was 5.4 and fractional shortening was 0.10. Freedom from death or transplantation rates at 1, 3, 5, 10, and 20 years after diagnosis were 76%, 66%, 64%, 58%, and 43%, respectively. Freedom from death rates at 1, 5, 10, and 20 years after diagnosis were 81%, 75%, 72%, and 53%, respectively. The incidence of heart transplantation at 1, 5, 10, and 20 years after diagnosis was 6%, 15%, 20%, and 20%, respectively, suggesting that only 15% of patients in Japan underwent heart transplantation within 5 years of diagnosis. CONCLUSIONS: In Japan, the prognosis of pediatric DCM is poor and the rate of heart transplantation is low.

[A PEDIATRIC CASE OF DIFFUSE PANBRONCHIOLITIS WHO PREDOMINANTLY SHOWED RESTRICTIVE PULMONARY DYSFUNCTION AND DRAMATICALLY RESPONDED TO MACROLIDE LOW-DOSE LONG-TERM THERAPY.]

A 12-year-old boy visited our hospital with complaints of chronic cough and dyspnea. Chest X-ray and CT revealed diffuse granular shadow in the bilateral lung fields and "Tree-in-bud appearance" in the peripheral airways, respectively. Sinusitis was present, and restrictive disorder was predominantly found in pulmonary function. The patient was diagnosed with DPB, and long-term therapy was started with low-dose clarithromycin (CAM), The patient showed a dramatic response to CAM, with improvements of both the clinical symptoms and pulmonary function within 1-2 months. According to the relevant literature, in adult patients with this disease, pulmonary dysfunction starts from an obstructive pattern; however, this is not the case in pediatric patients. It was therefore suggested that the mechanisms underlying the development of pulmonary dysfunction in cases of childhood onset differs from those with an adult onset.

[A CASE OF VOCAL CORD DYSFUNCTION, WHO USED ADRENALIN AUTOINJECTOR (EPIPEN®) FREQUENTLY AFTER BEING DIAGNOSED AS ANAPHYLAXIS].

We experienced a case of vocal cord dysfunction (VCD) in a child to whom an adrenaline autoinjector (Epipen®) had been prescribed and frequently used following a diagnosis of exercise-induced anaphylaxis. An exercise test was performed to investigate her frequent episodes of anaphylaxis-like symptoms. A few minutes after starting the test, signs of dyspnea, such as throat tightness and stridor, appeared, although hypoxia was not present and her respiratory sounds were normal. Medications were not effective for treating her respiratory symptoms. Laryngoscopy performed at the test revealed bizarre vocal cord movement, which was diagnosed as VCD. The symptoms gradually diminished after the initiation of biofeedback therapy, including pursed lips breathing and abdominal breathing. Thereafter, she did not use an adrenaline autoinjector when symptoms appeared; instead, she would perform biofeedback therapy before using the adrenaline autoinjector. Thus, VCD should be included in the differential diagnosis of patients who show anaphylactic symptoms that are resistant to preventive therapy.

Airway reversibility and inflammation in stable pre- to late-adolescent asthmatics without long-term control medications.

Objective: Pulmonary function and airway inflammation were investigated in stable pre- to late-adolescent asthmatics without long-term control medications and compared with those in currently medicated asthmatics.Methods: Subjects comprised 34 well-controlled asthmatic children (aged 8.1-18.0 years; group without medication). Flow volume curves before and after inhaling a ß2 agonist, a bronchodilator (BD), were compared and fractional exhaled nitric oxide (FENO) concentrations were measured. All patients were attack-free for at least 12 months prior to testing without the use of asthma medications for at least three months. Fifty-one age-matched stable asthmatics with medications at the time of the present study (group with current medication) underwent the same examinations.Results: The rate of children whose respiratory function after BD improved by 20% or more in both the central and peripheral airways (High responder at total airways subtype: HTA) was significantly higher in the group without medication than in that with current medication (17.6 and 2.0%, respectively; p < 0.01). Furthermore, FEV1.0% pred after BD was significantly lower for HTA than for the low responder subtype in the same group (94.8 ± 3.5 and 104.1 ± 1.5% respectively, p < 0.05). FENO concentrations in the group without medication were high, but not significantly different from those in the group with current medication.Conclusions: Stable asthmatic children without medication include a certain percentage of those with irreversible airflow limitation possibly due to airway remodeling. The control of daily asthma symptoms with long-term control medications may effectively prevent airway remodeling.

M1 macrophage is the predominant phenotype in coronary artery lesions following Kawasaki disease.

Kawasaki disease (KD) is a systemic inflammatory process that affects the medium-sized arteries, causing various cardiovascular complications. However, it is not clear if the vascular sequelae following KD can predispose to the development of atherosclerosis later in life. Our aim was to examine the macrophage phenotypes in the coronary arteries forming giant aneurysms after KD to gain insight into the pathogenesis of vascular lesions in KD. We examined histological sections of the coronary arteries from five patients with KD who underwent coronary bypass grafting procedure as treatment for giant aneurysms and subsequent stenosis. Immunohistochemical expression of M1- and M2-macrophage markers was assessed to determine the macrophage phenotype of KD to compare with that of atherosclerosis in eight adult patients. All the KD specimens showed a mild to moderate degree of intimal thickening consisting of mature fibrous tissue and distortion of elastic fibers, mimicking the histological features of atherosclerosis. The total number of CD68 positive macrophages was higher in atherosclerosis than in KD specimens. Among the CD68 positive macrophages, the proportion of M1 phenotype, detected by CD86 or SOCS3, was higher in KD than in atherosclerosis. In contrast, the proportion of M2 phenotype, detected by CD163 or MRC1, was higher in patients with atherosclerosis. Despite similar histological features, KD and atherosclerosis appear to have a different immunological etiology for progression of the chronic vascular lesions. A further study enrolling a larger number of cases is required to delineate underlying mechanisms of vascular complications in KD.

Differences in physical activity between seasons with and without snowfall among elderly individuals residing in areas that receive snowfall.

[Purpose] This study aimed to examine the influence of climatic conditions on the daily physical activities of elderly individuals by comparing the physical activity during seasons with and without snowfall. [Participants and Methods] In total, 35 participants attending the Health Promotion Program conducted by Chitose City Office participated in this study. The survey for the seasons with snowfall was conducted in February 2016, while the survey for the seasons without snowfall was conducted in September 2015. The physical activity of the participants was measured using a Kenz Lifecorder GS accelerometer. [Results] Physical activity was found to be significantly lower during seasons with snowfall than in seasons without snowfall. Multivariate analysis revealed that physical activity significantly increased with lower temperature during the seasons with snowfall, and it significantly increased with higher temperature and decreased with larger amounts of precipitation during the seasons without snowfall. [Conclusion] It was found that the climatic conditions affect the level of physical activity during seasons with and without snowfall. A lower level of physical activity was observed in areas that received snowfall than in areas that did not receive snowfall.

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.

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.

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).

Test-retest reliability of expiratory abdominal compression with a handheld dynamometer in patients with prolonged mechanical ventilation.

[Purpose] The present study aimed to examine the test-retest reliability of expiratory abdominal compression with a handheld dynamometer in patients with prolonged mechanical ventilation. [Subjects and Methods] We recruited 18 patients with prolonged mechanical ventilation. All patients had impaired consciousness. The mode of the ventilator was synchronized intermittent mandatory ventilation. The abdomen above the navel was vertically compressed using a handheld dynamometer in synchronization with expiration. Expiratory abdominal compression was performed two times. We measured the tidal volume during expiratory abdominal compression. There was an interval of 5 minutes between the first and second measurements. Intraclass correlation coefficient (ICC) and Bland-Altman analysis were performed to examine the test-retest reliability of expiratory abdominal compression with a handheld dynamometer. [Results] The test-retest reliability of expiratory abdominal compression was excellent (ICC(1, 1): 0.987). Bland-Altman analysis showed that there was no fixed bias and no proportional bias. [Conclusion] The findings of this study suggest that expiratory abdominal compression with a handheld dynamometer is reliable and useful for patients with respiratory failure and prolonged mechanical ventilation.

Parameters affecting the tidal volume during expiratory abdominal compression in patients with prolonged tracheostomy mechanical ventilation.

[Purpose] The aim of this study was to clarify physical parameters affecting the tidal volume during expiratory abdominal compression in patients with prolonged tracheostomy mechanical ventilation. [Methods] Eighteen patients with prolonged mechanical ventilation were included in this study. Expiratory abdominal compression was performed on patients lying in a supine position. The abdomen above the navel was vertically compressed in synchronization with expiration and released with inspiration. We measured the tidal volume during expiratory abdominal compression. [Results] The mean tidal volume during expiratory abdominal compression was higher than that at rest (430.6 ± 127.1 mL vs. 344.0 ± 94.3 mL). The tidal volume during expiratory abdominal compression was correlated with weight, days of ventilator support, dynamic compliance and abdominal expansion. Stepwise multiple regression analysis revealed that weight (ß = 0.499), dynamic compliance (ß = 0.387), and abdominal expansion (ß = 0.365) were factors contributing to the tidal volume during expiratory abdominal compression. [Conclusion] Expiratory abdominal compression increased the tidal volume in patients with prolonged tracheostomy mechanical ventilation. The tidal volume during expiratory abdominal compression was influenced by each of the pulmonary conditions and the physical characteristics.

Comparison of changes in tidal volume associated with expiratory rib cage compression and expiratory abdominal compression in patients on prolonged mechanical ventilation.

[Purpose] This study was designed to compare and clarify the relationship between expiratory rib cage compression and expiratory abdominal compression in patients on prolonged mechanical ventilation, with a focus on tidal volume. [Subjects and Methods] The subjects were 18 patients on prolonged mechanical ventilation, who had undergone tracheostomy. Each patient received expiratory rib cage compression and expiratory abdominal compression; the order of implementation was randomized. Subjects were positioned in a 30° lateral recumbent position, and a 2-kgf compression was applied. For expiratory rib cage compression, the rib cage was compressed unilaterally; for expiratory abdominal compression, the area directly above the navel was compressed. Tidal volume values were the actual measured values divided by body weight. [Results] Tidal volume values were as follows: at rest, 7.2 ± 1.7 mL/kg; during expiratory rib cage compression, 8.3 ± 2.1 mL/kg; during expiratory abdominal compression, 9.1 ± 2.2 mL/kg. There was a significant difference between the tidal volume during expiratory abdominal compression and that at rest. The tidal volume in expiratory rib cage compression was strongly correlated with that in expiratory abdominal compression. [Conclusion] These results indicate that expiratory abdominal compression may be an effective alternative to the manual breathing assist procedure.

Upper extremity muscle tone and response of tidal volume during manually assisted breathing for patients requiring prolonged mechanical ventilation.

[Purpose] The aim of the present study was to examine, in patients requiring prolonged mechanical ventilation, if the response of tidal volume during manually assisted breathing is dependent upon both upper extremity muscle tone and the pressure intensity of manually assisted breathing. [Subjects] We recruited 13 patients on prolonged mechanical ventilation, and assessed their upper extremity muscle tone using the modified Ashworth scale (MAS). The subjects were assigned to either the low MAS group (MAS≤2, n=7) or the high MAS group (MAS≥3, n=6). [Methods] The manually assisted breathing technique was applied at a pressure of 2 kgf and 4 kgf. A split-plot ANOVA was performed to compare the tidal volume of each pressure during manually assisted breathing between the low and the high MAS groups. [Results] Statistical analysis showed there were main effects of the upper extremity muscle tone and the pressure intensity of the manually assisted breathing technique. There was no interaction between these factors. [Conclusion] Our findings reveal that the tidal volume during the manually assisted breathing technique for patients with prolonged mechanical ventilation depends upon the patient's upper extremity muscle tone and the pressure intensity.

[Biomarker].

The most serious complication of Kawasaki disease(KD) is coronary artery lesions (CAL), which mainly occur in patients with the incomplete form of KD and intravenous gamma-globulin therapy non-responsiveness (IVIG non-responsiveness). Recently, numerous biomarkers for diagnosis of the incomplete form of KD, endothelial dysfunction, and myocardial disturbance, as well as for the prediction of CAL formation and IVIG non- responsiveness, have been reported. However, a useful single biomarker has yet to be described. Pentraxin 3 (PTX3), endothelin-1(ET-1), brain natriuretic peptide(BNP) and N-terminal pro-brain natriuretic peptide are produced and secreted from vascular and/or myocardial tissue, and are very useful for diagnosis of the incomplete form of KD, and for the prediction of IVIG non-responsiveness and CAL formation in the acute phase. Further- more, some biomarkers are helpful for evaluating chronic coronary arteritis and atheroscle- rosis in the convalescent phase of KD.

The Contributions of Knee Extension Strength and Hand Grip Strength to Factors Relevant to Physical Frailty: The Tanno-Sobetsu Study.

Sarcopenia is the core factor of frailty. This study specifically focused on lower limb muscle strength and examined muscle indices that indicate the risk of frailty or pre-frailty in older adults. The study included 327 community-dwelling individuals aged ≥65 years (43.7% male) who participated in the cohort. Frailty was defined based on five symptoms: weight loss, low activity level, exhaustion, weakness and slowness. Participants were classified into frail (three or more applicable), pre-frail (one to two applicable) and non-frail groups. Muscle strength (knee extension strength, toe grip strength and hand grip strength) were assessed, and appendicular muscle mass was assessed via a bioelectrical impedance analysis. The adjusted odds ratio (OR) of muscle indices for with frailty (frail group vs. pre-frail group) or pre-frailty (pre-frail group vs. non-frail group) were calculated. The prevalence of frail and pre-frail was 7% and 40%, respectively. Adjusted for age, sex, albumin and medical history, knee extension strength was significantly associated with frailty (odds ratio 0.95, 95% CI 0.92-0.98), while hand grip strength was associated with pre-frailty (odds ratio 0.92, 95% CI 0.88-0.97) but not with other muscle indices. This study is significant for identifying knee extension strength as a factor relevant to frailty in older adults considered pre-frailty, emphasizing the importance of this specific muscle measure in predicting and managing frailty.

Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial.

BACKGROUND: Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease. METHODS: We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940. FINDINGS: We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12-0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group. INTERPRETATION: Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted. FUNDING: Japanese Ministry of Health, Labour and Welfare.

National Japanese survey of thrombolytic therapy selection for coronary aneurysm: intracoronary thrombolysis or intravenous coronary thrombolysis in patients with Kawasaki disease.

BACKGROUND: Thrombolytic therapy for coronary aneurysm thrombosis of Kawasaki disease (KD) includes antiplatelet and anticoagulants, i.v. coronary thrombolysis (IVCT), and i.c. thrombolysis (ICT). Therapeutic methods, drugs and doses vary among medical facilities. METHODS AND RESULTS: A nationwide survey of thrombolytic therapy was conducted under the auspices of the Ministry of Health, Labour and Welfare Research Program to Intractable Diseases Research Grants. A secondary survey targeted 14 facilities conducting thrombolytic therapy during a 5 year period (2004-2009). The primary survey investigated performance of thrombolytic therapy for 23 KD patients at 14 facilities, and of these, five with acute myocardial infarction had received ICT and combined therapy. The secondary survey investigated the pre-treatment condition of aneurysm and thrombosis and actual treatment methods. ICT was effective for small thrombi (≤ 10 mm), while IVCT was effective even for giant thrombi (>10 mm). ICT was also effective for thrombi within several hours after formation. CONCLUSION: In the present nationwide survey, thrombolytic therapy was more effective in cases of a shorter duration between thrombus formation and the start of treatment. It was found that many facilities used only IVCT for thrombus alone. Medications given to KD children did not cause serious hemorrhagic complications, unlike in adults. Although doses exceeded recommended levels in many cases, the only complications were nasal bleeding and fever.

Predictors of Myocardial Ischemia in Patients with Kawasaki Disease: Insights from Patient-Specific Simulations of Coronary Hemodynamics.

Current treatments for patients with coronary aneurysms caused by Kawasaki disease (KD) are based primarily on aneurysm size. This ignores hemodynamic factors influencing myocardial ischemic risk. We performed patient-specific computational hemodynamics simulations for 15 KD patients, with parameters tuned to patients' arterial pressure and cardiac function. Ischemic risk was evaluated in 153 coronary arteries from simulated fractional flow reserve (FFR), wall shear stress, and residence time. FFR correlated weakly with aneurysm [Formula: see text]-scores (correlation coefficient, [Formula: see text]) but correlated better with the ratio of maximum-to-minimum aneurysmal lumen diameter ([Formula: see text]). FFR dropped more rapidly distal to aneurysms, and this correlated more with the lumen diameter ratio ([Formula: see text]) than [Formula: see text]-score ([Formula: see text]). Wall shear stress correlated better with the diameter ratio ([Formula: see text]), while residence time correlated more with [Formula: see text]-score ([Formula: see text]). Overall, the maximum-to-minimum diameter ratio predicted ischemic risk better than [Formula: see text]-score. Although FFR immediately distal to aneurysms was nonsignificant, its rapid rate of decrease suggests elevated risk.