Challenges of pediatric pharmacotherapy: A narrative review of pharmacokinetics, pharmacodynamics, and pharmacogenetics.

PURPOSE: Personalized pharmacotherapy, including for the pediatric population, provides optimal treatment and has emerged as a major trend owing to advanced drug therapeutics and diversified drug selection. However, it is essential to understand the growth and developmental characteristics of this population to provide appropriate drug therapy. In recent years, clinical pharmacogenetics has accumulated knowledge in pediatric pharmacotherapy, and guidelines from professional organizations, such as the Clinical Pharmacogenetics Implementation Consortium, can be consulted to determine the efficacy of specific drugs and the risk of adverse effects. However, the existence of a large knowledge gap hinders the use of these findings in clinical practice. METHODS: We provide a narrative review of the knowledge gaps in pharmacokinetics (PK) and pharmacodynamics (PD) in the pediatric population, focusing on the differences from the perspective of growth and developmental characteristics. In addition, we explored PK/PD in relation to pediatric clinical pharmacogenetics. RESULTS: The lack of direct and indirect biomarkers for more accurate assessment of the effects of drug administration limits the current knowledge of PD. In addition, incorporating pharmacogenetic insights as pivotal covariates is indispensable in this comprehensive synthesis for precision therapy; therefore, we have provided recommendations regarding the current status and challenges of personalized pediatric pharmacotherapy. The integration of clinical pharmacogenetics with the health care system and institution of educational programs for health care providers is necessary for its safe and effective implementation. A comprehensive understanding of the physiological and genetic complexities of the pediatric population will facilitate the development of effective and personalized pharmacotherapeutic strategies.

Basic life support for non-traumatic out-of-hospital cardiac arrests during school-supervised sports activities in children: A nationwide observational study in Japan.

Objective: To investigate the prognostic impact of bystander-initiated cardiopulmonary resuscitation (CPR) and public-access automated external defibrillator (AED) use on non-traumatic out-of-hospital cardiac arrest (OHCA) occurring during school-supervised sports activities in children. Methods: From a nationwide database of pediatric OHCAs occurring under school supervision in Japan, data between April 2008 and December 2020 were obtained. We analyzed non-traumatic OHCAs that occurred during school-supervised sports activities among schoolchildren from elementary, junior high, high, and technical colleges. A multivariable logistic regression model was used to evaluate the effect of basic life support (BLS) on 1-month survival with favorable neurological outcomes after OHCA. Results: In total, 318 OHCA cases were analyzed. The 1-month survival with favorable neurological outcomes was 64.8% (164/253) in cases receiving both bystander-CPR and AED application, 40.7% (11/27) in cases receiving CPR only, 38.5% (5/13) in patients receiving AED application only, and 28.0% (7/25) in cases receiving no bystander intervention. Compared with cases receiving no BLS, cases receiving both CPR and AED had a significantly higher proportion of 1-month survival with favorable neurological outcomes (adjusted odds ratio [AOR]: 3.97, 95% confidence interval [CI]: 1.32-11.90, p = 0.014). However, compared to cases receiving no BLS, there was no significant difference in the outcome in the cases receiving CPR only (AOR: 1.35, 95% CI: 0.34-5.29, p = 0.671) and the cases receiving AED application only (AOR: 1.26, 95% CI: 0.25-6.38, p = 0.778). Conclusion: The combination of CPR and AED as BLS performed by bystanders for non-traumatic OHCA during school-supervised sports activities improved the outcomes.

Analysis of Coronary Arterial Aneurysm Regression in Patients With Kawasaki Disease by Aneurysm Severity: Factors Associated With Regression.

Background Coronary arterial aneurysms (CAAs) associated with Kawasaki disease (KD) significantly affect prognosis. However, the clinical course of CAAs and factors associated with CAA regression have not been well analyzed. Methods and Results The cohort of the Z-Score 2nd Project Stage study, a multicenter, retrospective, cohort study involving 44 institutions in Japan including 1006 patients with KD, was examined. CAAs were classified by the z score of their internal diameter in the acute phase: small (z<5), medium (5≤z<10), and large (z≥10). The lower limit of small CAA was based on the Japanese Ministry of Health, Labour and Welfare criteria. In the right coronary artery, the CAA regression rates 10 years after diagnosis were 95.5% for small, 83.2% for medium, and 36.3% for large. In the proximal left anterior descending artery, the regression rates 10 years after diagnosis were 95.3% for small, 80.1% for medium, and 28.8% for large. Cox regression analysis showed that diagnosis under the age of 1 year and onset of KD in 2010 to 2012 for the right coronary artery and the left anterior descending artery, and female for the right coronary artery were significantly associated with a high regression rate, whereas large CAAs for the right coronary artery and the left anterior descending artery were significantly associated with a low regression rate. Conclusions The current study, the largest Japanese study of its kind, found that small aneurysm, recent onset, and diagnosis under the age of 1 year predict regression, and that even giant aneurysms could regress. These data may contribute to long-term management of coronary aneurysms. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000010606.

Effect of procedural volume on the outcomes of congenital heart surgery in Japan.

OBJECTIVES: The present study developed a new risk model for congenital heart surgery in Japan and determined the relationship between hospital procedural volume and mortality using the developed model. METHODS: We analyzed 47,164 operations performed between 2013 and 2018 registered in the Japan Cardiovascular Surgery Database-Congenital and created a new risk model to predict the 90-day/in-hospital mortality using the Japanese congenital heart surgery mortality categories and patient characteristics. The observed/expected ratios of mortality were compared among 4 groups based on annual hospital procedural volume (group A [5539 procedures performed in 90 hospitals]: ≤50, group B [9322 procedures in 24 hospitals]: 51-100, group C [13,331 procedures in 21 hospitals]: 101-150, group D [18,972 procedures in 15 hospitals]: ≥151). RESULTS: The overall mortality rate was 2.64%. The new risk model using the surgical mortality category, age-weight categories, urgency, and preoperative mechanical ventilation and inotropic use achieved a c-index of 0.81. The observed/expected ratios based on the new risk model were 1.37 (95% confidence interval, 1.18-1.58), 1.21 (1.08-1.33), 1.04 (0.94-1.14), and 0.78 (0.71-0.86) in groups A, B, C, and D, respectively. In the per-procedure analysis, the observed/expected ratios of the Rastelli, coarctation complex repair, and arterial switch procedures in group A were all more than 3.0. CONCLUSIONS: The risk-adjusted mortality rate for low-volume hospitals was high for not only high-risk but also medium-risk procedures. Although the overall mortality rate for congenital heart surgeries is low in Japan, the observed volume-mortality relationship suggests potential for improvement in surgical outcomes.

Sudden Death in Patients with a History of Kawasaki Disease under School Supervision.

We investigated the incidence of sudden death in students with a history of Kawasaki disease (KD) while under school supervision. Reports of sudden death in students with a history of KD during 1990-1999 and 2000-2009 were retrieved from the mutual aid system data. The student's grade, sex, circumstances at the time of sudden death, final diagnosis, recommended restrictions on school activities, and intensity of physical activity at the time of sudden death were investigated. There were 11 cases from 1990 to 1999 and 3 from 2000 to 2009; KD was complicated with coronary artery aneurysm (CAA) in nine and one cases, respectively. The incidence of sudden death decreased by approximately 50% for KD history and 80% for KD with CAA between the two decades; however, the difference was not statistically significant. Of the 14 cases, 12 occurred during moderate-to-strenuous exercise; the restriction on exercise for students with KD complicated with CAA was not followed in at least five cases during 1990-1999, while three cases during 2000-2009 occurred without recommended restriction. Cases of sudden cardiac death decreased during 2000-2009, compared with those during 1990-1999. Special attention is required for students with a history of KD, particularly when complicated with CAA.

Epidemiology of sudden cardiac death and sudden cardiac arrest with resultant disability during high school organized sport in Japan.

OBJECTIVES: To examine the incidence and survival rates of sudden cardiac arrest that were documented during school organized sports in Japan. DESIGN: Retrospective cohort study. METHODS: Insurance claim data of cardiac events (sudden cardiac death and sudden cardiac arrest with resultant disabilities) that occurred during Japanese high school organized sports between 2009 and 2018 were retrieved. Participation data from All Japan High School Athletic Federation and Japan High School Baseball Federation were used for incidence rate calculations. Incidence rate ratios with 95 % confidence interval were calculated to compare the risk by sports and sex. The survival rate was calculated with the proportion of resuscitated cases to total number of cardiac events in this dataset. RESULTS: A total of 55 cardiac events (25 survivors and 30 deceased) were identified in the dataset. The majority affected male student-athletes (92.7 %). The frequency and incidence rate of cardiac events were highest in male baseball (n = 16 [29.1 %], incidence rate: 0.91 per 100,000 athlete-years). Incidence rate ratio revealed that male basketball (2.19, 95 % confidence interval: 1.04-4.60), male baseball (2.31, 95 % confidence interval: 1.32-4.03), and first-year male baseball (4.11, 95 % confidence interval: 2.10-8.07) had significantly higher risk of cardiac events, compared to the overall incidence rate (0.38 per 100,000 athlete-years). The survival rates were 37.5 % in the first half (2009-2013) and 56.5 % in the latter half (2014-2018) of the study period. CONCLUSIONS: The risk of cardiac events was highest in male, baseball, first-year student-athletes. Rapid AED application by bystanders should be advocated to enhance better survival.

Dissemination of Chest Compression-Only Cardiopulmonary Resuscitation by Bystanders for Out-of-Hospital Cardiac Arrest in Students: A Nationwide Investigation in Japan.

We aimed to investigate how the types of bystander-initiated cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) among students have changed recently. We also determined the association between two types of bystander-CPRs (i.e., chest compression-only CPR [CCCPR] and conventional CPR with rescue breathing [CCRB]) and survival after OHCA. From a nationwide registry of pediatric OHCAs occurring in school settings in Japan, the data of 253 non-traumatic OHCA patients (elementary, junior high, and high school/technical college students) receiving bystander-CPR between April 2008 and December 2017 were analyzed. Multivariable logistic regression analysis was conducted to assess the impact of different types of bystander-CPR on 30-day survival with favorable neurological outcomes. The proportion of patients receiving CCCPR increased from 25.0% during 2008-2009 to 55.3% during 2016-2017 (p for trend < 0.001). Overall, 53.2% (50/94) of patients receiving CCCPR and 46.5% (74/159) of those receiving CCRB survived for 30 days with favorable neurological outcomes. Multivariable analysis showed no significant difference in outcomes between the two groups (adjusted odds ratio: 1.23, 95% confidence interval: 0.67-2.28). In this setting, CCCPR is a common type of bystander-CPR for OHCA in students, and the effectiveness of CCCPR and CCRB on survival outcomes seems comparable.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

Characteristics of Kawasaki Disease Patients during the COVID-19 Pandemic in Japan: A Single-Center, Observational Study.

BACKGROUND: Under the Coronavirus disease 2019 (COVID-19) pandemic, manifestations in children with Kawasaki disease (KD) are different between the Western and the Eastern countries. Particularly, there has not been a report comparing a series of KD in Japan, where KD was originally discovered and has a large number of registered cases. METHODS: We compared patients with KD under the period of the COVID-19 pandemic in Japan with the report from Italy during its reported period by a retrospective, cohort, observational study in a Japanese single center. RESULTS: Thirty-two patients with typical KD were treated during the study period, while the Italian study reported 10 patients with the signs of KD. Concerning the proof of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, none (0%) of our KD cases showed a positive result and one and no patients developed the macrophage activation syndrome (MAS) and Kawasaki disease shock syndrome (KDSS), respectively; however, eight (80%) patients in the Italian series were confirmed with SARS-CoV-2 infection. MAS and KDSS developed in six and five patients, respectively. CONCLUSIONS: Cases reported as COVID-19 pandemic-related KD in Italy showed significantly different clinical characteristics from the typical KD symptoms known in Japan. Although they show KD-like manifestations, we cannot conclude that SARS-CoV-2 has the same etiology of our 'classic' KD at the present stage.

Epidemiology of sports-related fatalities during organized school sports in Japanese high schools between 2009 and 2018.

Limited literature has investigated epidemiology of sports-related fatalities during high school organizes sports in Japan. Therefore, the purposes of this study are to determine the frequency and incidence rate of sports-related fatalities in Japanese high schools by cause and sports, and to examine the type of on-site first responder. Insurance claim data of sports-related fatalities in Japanese high schools reported to Japan Sports Council Injury and Accident Mutual Aid Benefit System between 2009 and 2018 were retrieved as the primary data source. All fatalities were classified into direct or indirect type by the reported etiology and further categorized into cardiac-related, head and neck injury, exertional heat stroke (EHS), or other. Frequency and incidence rate were calculated by cause of death and sports, and incidence rates were expressed per 100,000 athlete-years (AY) with 95% confidence interval (CI). Information regarding first responder to the incident was also retrieved and examined by frequency. A total of 63 sports-related fatalities were analyzed. The overall incidence rate was 0.45 (95%CI = 0.25-0.65) per 100,000AY. The incidence rates of direct and indirect fatalities declined from 0.36 and 0.50 per 100,000AY to 0.28 and 0.00 per 100,000AY, respectively. The leading cause of deaths was cardiac-related (n = 30/63, 47.6%), followed by head and neck injury (n = 15/63, 23.8%) and EHS (n = 14/63, 22.2%). The number of fatalities was highest in male baseball (n = 12/63, 19.0%) and the incidence rate was highest in male judo (4.79 per 100,000 AY, 95%CI: 0.68-8.15). Coach was the most frequently reported first responder onsite (n = 52/63, 82.5%). Medically trained personnel were involved in onsite care in two cases (3.2%). In conclusion, the occurrence of sports-related fatalities has declined over time from 2009 to 2018. To deliver appropriate medical care onsite for better survival, employment of medically trained personnel should be promoted in high school sports setting in Japan.

Decreased Stroke Volume and Venous Return in School Children with Postural Tachycardia Syndrome.

In postural tachycardia syndrome (POTS), a subtype of orthostatic intolerance, the changes in hemodynamics due to postural changes are poorly understood. We speculated that inappropriate venous return, which may occur in the upright position in patients with school-aged POTS, could be detected by echocardiography. Our prospective study was conducted with 100 POTS patients (45 boys and 55 girls), aged 13.1 ± 1.5 years and 52 age- and sex-matched healthy subjects (control). Echocardiography was performed in the supine and sitting positions. Cardiac parameters [stroke volume index, cardiac index, heart rate, and the maximum inferior vena cava diameter (max IVC)] were evaluated in addition to pulse pressure. Unlike the control subjects, POTS patients demonstrated decreased stroke volume index (P = 0.02) and max IVC (P < 0.01) irrespective of posture. The rates of max IVC change did not differ between control and POTS groups. The enrolled POTS patients were divided into two subgroups [dilatation (n = 57) and contraction (n = 43)] based on whether the change rate of max IVC was less than zero or not. The contraction group showed a significantly higher heart rate than the dilatation group with respect to posture (P = 0.03), indicating the poor response of peripheral vessels in the lower limbs only in the contraction group. In conclusion, echocardiographic assessment detected decreased stroke volume and venous return in POTS. The changes in max IVC in response to postural changes may indicate an underlying pathophysiology in POTS.

Soluble factors released by dedifferentiated fat cells reduce the functional activity of iPS cell-derived cardiomyocytes.

Interactions between tissues such as epicardial adipose (EAT), and myocardial tissues is important in the pathogenesis of heart failure. Changes in adipose tissues in obesity or diabetes impair preadipocyte differentiation. Furthermore, proinflammatory cytokine secretion is higher in preadipocytes than in mature adipocytes in diabetes and obesity. However, how undifferentiated cells committed to the adipose lineage directly influence cardiomyocytes is not yet understood. We used human-derived dedifferentiated fat (DFAT) cells as models of undifferentiated cells committed to an adipose lineage. Here, we evaluated the effects of soluble factor interactions in indirect cocultures of DFAT cells and induced pluripotent stem cell-derived cardiomyocytes. Our RNA sequencing findings showed that these interactions were predominantly inflammatory responses. Furthermore, proinflammatory cytokines secreted by DFAT cells reduced myocardial functions such as contraction frequency and catecholamine sensitivity, and simultaneously increased apoptosis, decreased antioxidative stress tolerance, and reduced oxygen consumption rates in cardiomyocytes. These adverse effects might be attributable to monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligands 1 (CXCL1), and 12, granulocyte colony-stimulating factor, interleukins 6 and 8, macrophage migration inhibitory factor (MIF), and plasminogen activator inhibitor 1-A among the proinflammatory mediators secreted by DFAT cells. Our results could be useful for understanding the pathogenesis of EAT-related heart failure in terms of the involvement of undifferentiated cells committed to the adipose lineage. Furthermore, we suggest the importance of focusing on surrounding adipose tissues as a strategy with which to maximize the survival and function of transplanted stem cell-derived cardiomyocytes.

A Case of Kawasaki Disease Complicated With Cerebral Salt-Wasting Syndrome.

We report the case of a 3-years-old boy who developed severe hyponatremia and unconsciousness during an episode of Kawasaki disease (KD). He was diagnosed with cerebral salt-wasting syndrome (CSWS), which has not previously been reported as a complication of KD. He was diagnosed with KD with fever and four clinical signs and received intravenous immunoglobulin (IVIG) on the day after onset. Hyponatremia had been observed, and it worsened after IVIG. At first, syndrome of inappropriate antidiuretic hormone secretion (SIADH) was suspected, but his hyponatremia did not improve by restriction of water intake. The patient's consciousness level decreased along with the worsening hyponatremia. Electroencephalography revealed abnormal electrical discharge concordant with acute encephalopathy. Laboratory data showed hypouricemia with high fractional excretion of uric acid (FEUA), in addition to a negative balance of both Na and water. We diagnosed KD complicated with CSWS. The patient improved promptly with appropriate Na supplementation and water correction.

Incidence, characteristics, and outcomes of pediatric out-of-hospital cardiac arrest in nursery schools and kindergartens in Japan.

BACKGROUND: A better understanding of the epidemiology of pediatric out-of-hospital cardiac arrest (OHCA) occurring in nursery schools and kindergartens is indispensable to establish an evidence-based strategy for prevention and improved outcomes. This study aimed to describe the incidence, characteristics, and outcomes of pediatric OHCAs that occurred in certified nursery schools and kindergartens. METHODS: Stop and Prevent cardIac aRrest, Injury, and Trauma in Schools (SPIRITS) is a study to construct and analyze a nationwide registry of pediatric OHCAs occurring in school settings in Japan. Using data from the SPIRITS registry, we assessed the incidence, characteristics, and outcomes of pediatric OHCAs that occurred in certified nursery schools/kindergartens between April 2008 and December 2016. RESULTS: During the study period, 37 OHCA patients (31 in certified nursery schools and 6 in kindergartens) were confirmed. The overall incidence rate was 0.13 per 100,000 children per year. Among 37 patients, 57% (21/37) had an OHCA while napping and 35% (13/37) experienced OHCA that was witnessed by bystanders. Although public-access automated external defibrillator pads were applied by bystanders in 24% (9/37) of cases, only 1 patient actually received defibrillation. Overall, the proportion of 1-month survival with favorable neurological outcomes after OHCA was 19% (7/37). Among those with OHCA of non-medical origins, 60% (3/5) of patients experienced arrest caused by suffocation, 60% (3/5) by drowning, and 100% (1/1) by head injury. In contrast, no patient had 1-month favorable neurological outcomes among those with OHCA of medical origins such as presumed cardiac origin (0/17), sudden infant death syndrome (0/6), acute viral myocarditis (0/1), respiratory disease (0/1), and ventricular fibrillation (0/1). CONCLUSIONS: In this population, the majority of pediatric OHCAs occurring in certified nursery schools/kindergartens had non-ventricular fibrillation rhythm, and their outcomes after OHCA of medical origin were poor.

Normal reference values for left atrial strains and strain rates in school children assessed using two-dimensional speckle-tracking echocardiography.

Left atrium (LA) function is a known predictive marker of heart failure in adults. Few reports of LA function analyses using LA strain (ɛ) and strain rate (SR) measurements in children exist. Thus, this study aimed to determine normal reference values for LA ɛ and SR in healthy school children and to investigate methods of interpreting LA function data based on maturational changes using two-dimensional speckle-tracking echocardiography (2DSTE). We recruited 112 healthy school children (median age 12.0 years; range 6-16 years). LA ɛ and SR were investigated using 2DSTE multi-vendor analysis software (TomTec Imaging Systems, Germany) and compared to Doppler parameters and LA volumes measured by the conventional method. The onset of the P wave was selected as the reference point for the LA ɛ analysis. Normal ranges of LA ɛ [reservoir (ɛRS), conduit (ɛCD), or contractile (ɛCT)] and positive SR (SRPOS), early negative SR (SREN), and late negative SR (SRLN) were obtained using Z-score models via the lambda-mu-sigma method. According to the Z-score curves, all ɛ showed slight falling or continuous flat lines against age, body surface area (BSA), or heart rate (HR); however, ɛ CT showed modestly positive associations with HR. As for SR, the Z-score curves showed falling lines against age and BSA. In contrast, Z-score curves for SREN and SRLN showed rising lines against HR. SREN was independent of E/e' and was negatively correlated with LA volume indexed against BSA. This study demonstrated the normal reference values for LA ɛ and SR using 2DSTE in school children. The present results recommended that LA ɛ should be evaluated together with changes in LA SR for accurate assessment, considering maturational changes including age, BSA, and HR in school children.

A significance of school screening electrocardiogram in the patients with ventricular noncompaction.

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.

Emergence and Characterization of Acute Coronary Syndrome in Adults After Confirmed or Missed History of Kawasaki Disease in Japan: A Japanese Nationwide Survey.

Background: Acute coronary syndrome (ACS), which is emerging in adults long after confirmed (followed-up or lost-to-follow), or missed Kawasaki disease (KD), is poorly characterized. Methods and Results: A Japanese retrospective nationwide hospital-based questionnaire survey of ACS during 2000-09 was conducted to characterize such patients. Among a total of 67 patients (median age 35, male 76%) recruited, low conventional coronary risks (≤1/6) was noted in 75%, a diagnosis of ST-elevation and myocardial infarction or cardiac arrest in 66%, medication before ACS in 22% (warfarin in 4%), and no prior history of acute myocardial infarction in 94%. One-month mortality was 19%. KD diagnosis was made in 32 during acute illness (Group A), in which 17 were lost to follow, and retrospectively in the other 35 from coronary imaging at ACS (Group B). Group A developed ACS at lower coronary risks (≤2/5 in 87 vs. 65% in group B, p = 0.043) at a younger age (26.5 vs. 40 yo, p < 0.001). In group A, followed-up patients developed ACS under medication before ACS (87 vs. 0% in lost-to-follow patients, p < 0.001) for giant aneurysm in culprit lesions (69 vs. 29%, p = 0.030). One-month mortality was comparable between groups A and B, and between patients followed-up and lost-to-follow in group A. The culprit lesion in group A was characterized by the association of an aneurysm ≥6 mm in acute KD (100%), lack of significant stenosis (61%) or giant aneurysm (50%) in the long-term (median interval 16 y), and the presence of intravascular ultrasound-derived calcification at ACS (86%). Conclusions: The present retrospective nationwide questionnaire survey demonstrated nationwide emergence of initial ACS in young adults at low coronary risks, who are followed-up or lost-to-follow after confirmed KD and initial coronary aneurysms ≥6 mm.