Outcomes of hypertrophic cardiomyopathy in Japanese children: a retrospective cohort study.

There has been no multicenter study on the prognosis of pediatric hypertrophic cardiomyopathy (HCM) in Japan. Therefore, we conducted a retrospective multicenter observational study on the long-term survival rate in patients diagnosed with HCM under the age of 18 between 1990 and 2014. Twenty institutions participated. A total of 180 patients were identified. The median age at diagnosis was 5.8 years old and median duration of observation was 8.3 years. Although six patients (3%) deteriorated into the dilated phase of HCM, no patient received heart transplantation. Freedom from death at 1, 5, 10, and 20 years were 97%, 92%, 84%, and 80%, respectively. There were 26 deaths. Among them, 11 patients died suddenly, presumably due to arrhythmia, and 15 patients died of heart failure. The presence of heart failure symptoms and a greater cardiothoracic ratio were significant risk factors for heart failure-related death. There were no significant risk factors identified for arrhythmia-related death. In conclusion, the prognosis of pediatric HCM in Japan is good and similar to those reported in population-based studies in the United States and Australia. Significant risk factors for heart failure-related death were identified in pediatric patients with HCM in Japan.

Experimental verification of the standard model of particle physics.

The history concerning an experimental verification of the standard model of particle physics is reviewed with special emphasis on results from experiments using the highest-energy particle colliders, namely, PETRA, LEP and LHC. This article covers physics subjects from discovering the gluon and precise measurements at LEP, to discovering the Higgs boson. It also covers some searches for physics beyond the standard model, particularly supersymmetry, as well as recent developments of some particle detectors that were used in those experiments.

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.

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.

Abnormal cardiac axis as a prenatal marker of left pulmonary artery sling.

Left pulmonary artery sling (LPAS) is a rare vascular anomaly. The left pulmonary artery arises distally from the right pulmonary artery on the right side of the trachea and passes between the trachea and esophagus towards the left lung, compressing the lower trachea. LPAS is associated with congenital tracheal stenosis, which frequently requires early surgical intervention and has a poor prognosis due to severe airway obstruction after birth. Therefore, LPAS should be prenatally diagnosed to prepare for surgical intervention for tracheal stenosis. To the best of our knowledge, there are few reports on prenatal echocardiographic findings in LPAS. We report three prenatal cases of LPAS, which resulted in respiratory symptoms. We discuss fetal ultrasound findings and highlight the abnormal rotation of the fetal cardiac axis to the right as a useful sign in the prenatal screening of LPAS.

Rare combination of congenital heart disease and pulmonary alveolar proteinosis.

Here, we describe a case of total anomalous pulmonary venous return with coarctation of the aorta that was diagnosed as pulmonary alveolar proteinosis at autopsy in a male infant. Surgical repair was performed at 1 day of age, but the infant died on postoperative day 51 due to respiratory insufficiency without any evidence of pulmonary venous obstruction. He had been unexpectedly diagnosed with pulmonary alveolar proteinosis and pulmonary hypoplasia on autopsy. Congenital pulmonary alveolar proteinosis is a serious condition with a high mortality rate, which should be considered in the differential diagnosis in patients with a clinical picture of pulmonary venous obstruction, because most patients are unable to survive without proper treatment. In this report, we address specific issues that should be discussed in such cases based on our recent experience.

Fontan completion following flow adjustable bilateral pulmonary artery banding.

We have performed bilateral pulmonary artery banding operations combined with planned percutaneous balloon dilatation at banding sites for patients with hypoplastic left heart syndrome and related anomalies. Here, we report a case of Fontan completion in a patient who underwent aortic arch repair and a bidirectional Glenn procedure following flowadjustable bilateral pulmonary artery banding. The patient had a double-inlet left ventricle, a hypoplastic right ventricle, a hypoplastic aortic arch, and coarctation of the aorta. She underwent banding at 9 days of age and balloon dilatation at 2 months. The Damus-Kaye-Stansel anastomosis, aortic arch repair, and bidirectional Glenn procedure were performed at 5 months of age, and the extracardiac Fontan procedure was performed at 1.5 years.

[Prednisolone therapy for Kawasaki disease].

Prednisolone therapy for acute phase Kawasaki disease had been considered to be controversial for several decades. However, recent clinical studies revealed that prednisolone therapy might improve coronary and clinical outcomes. The present paper reviews the roles of prednisolone therapy for acute phase Kawasaki disease patients.

Corrigendum: Use of the index of pulmonary vascular disease for predicting longterm outcome of pulmonary arterial hypertension associated with congenital heart disease.

[This corrects the article DOI: 10.3389/fcvm.2023.1212882.].

Efficacy of intravenous immunoglobulin combined with prednisolone following resistance to initial intravenous immunoglobulin treatment of acute Kawasaki disease.

OBJECTIVES: To determine the most effective first-line rescue therapy for intravenous immunoglobulin (IVIG) nonresponders, using IVIG, prednisolone, or both, to prevent coronary artery abnormalities (CAAs). STUDY DESIGN: We retrospectively reviewed the clinical records of 359 consecutive patients with Kawasaki disease who failed to respond to initial IVIG. RESULTS: CAAs up to 1 month after treatment were less common in the IVIG+prednisolone group (15.9%) than in the IVIG group (28.7%, P = .005) and the prednisolone group (30.6%, P = .01). The IVIG+prednisolone group had significantly lower risks of failing to respond to first-line rescue therapy (aOR 0.16, 95% CI 0.09-0.31), CAAs up to 1 month (aOR 0.46, 95% CI 0.27-0.90), and CAAs at 1 month (aOR 0.40, 95% CI 0.18-0.91) than the IVIG group. In the prednisolone and IVIG+prednisolone groups, risk score, day of illness at first-line rescue therapy, prednisolone monotherapy, and resistance to first-line rescue therapy were independent risk factors for CAA. Sex and resistance to first-line rescue therapy were independent risk factors in the IVIG group. CONCLUSIONS: IVIG+prednisolone may be superior to IVIG or prednisolone as first-line rescue therapy in the treatment of IVIG nonresponders. To establish the efficacy of rescue therapy with IVIG+prednisolone following nonresponse to initial IVIG, a prospective randomized trial is warranted.

Use of the index of pulmonary vascular disease for predicting long-term outcome of pulmonary arterial hypertension associated with congenital heart disease.

Aims: Limited data exist on risk factors for the long-term outcome of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). We focused on the index of pulmonary vascular disease (IPVD), an assessment system for pulmonary artery pathology specimens. The IPVD classifies pulmonary vascular lesions into four categories based on severity: (1) no intimal thickening, (2) cellular thickening of the intima, (3) fibrous thickening of the intima, and (4) destruction of the tunica media, with the overall grade expressed as an additive mean of these scores. This study aimed to investigate the relationship between IPVD and the long-term outcome of CHD-PAH. Methods: This retrospective study examined lung pathology images of 764 patients with CHD-PAH aged <20 years whose lung specimens were submitted to the Japanese Research Institute of Pulmonary Vasculature for pulmonary pathological review between 2001 and 2020. Clinical information was collected retrospectively by each attending physician. The primary endpoint was cardiovascular death. Results: The 5-year, 10-year, 15-year, and 20-year cardiovascular death-free survival rates for all patients were 92.0%, 90.4%, 87.3%, and 86.1%, respectively. The group with an IPVD of ≥2.0 had significantly poorer survival than the group with an IPVD <2.0 (P = .037). The Cox proportional hazards model adjusted for the presence of congenital anomaly syndromes associated with pulmonary hypertension, and age at lung biopsy showed similar results (hazard ratio 4.46; 95% confidence interval: 1.45-13.73; P = .009). Conclusions: The IPVD scoring system is useful for predicting the long-term outcome of CHD-PAH. For patients with an IPVD of ≥2.0, treatment strategies, including choosing palliative procedures such as pulmonary artery banding to restrict pulmonary blood flow and postponement of intracardiac repair, should be more carefully considered.

Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study.

BACKGROUND: Markedly activated neutrophils or higher plasma levels of neutrophil elastase are involved in the poor response to intravenous immunoglobulin (IVIG) and the formation of coronary artery lesions (CAL) in patients with acute Kawasaki disease. We hypothesized that ulinastatin (UTI), by both direct and indirect suppression of neutrophils, would reduce the occurrence of CAL. METHODS AND RESULTS: We retrospectively analyzed the clinical records of patients with Kawasaki disease between 1998 and 2009. Three hundred sixty-nine patients were treated with a combination of UTI, aspirin, and IVIG as an initial treatment (UTI group), and 1178 were treated with a conventional initial treatment, and IVIG with aspirin (control group). The baseline characteristics did not demonstrate notable differences between the two groups. The occurrence of CAL was significantly lower in the UTI group than in the control group (3% versus 7%; crude odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25-0.86; P=0.01). The OR adjusted for sex, Gunma score (the predictive score for IVIG unresponsiveness), and dosage of initial IVIG (1 or 2 g/kg) was 0.32 (95% CI, 0.17-0.60; P<0.001). In addition, most CAL occurred in patients requiring additional rescue treatment and the proportion of those patients was significantly lower in the UTI group than in the control group (13% versus 22%; crude OR, 0.52; 95% CI, 0.38-0.73; P<0.001). The adjusted OR was 0.30 (95% CI, 0.20-0.44; P<0.001). CONCLUSIONS: UTI was associated with fewer patients requiring additional rescue treatment and reduction of CAL in this retrospective study.

A large amount of microscopic precipitates are inevitably injected during infusion therapy without an in-line filter.

Infusion route problems can have a significant impact on hemodynamics in children with severe heart failure. Here, we report the case of a 13-year-old girl with dilated cardiomyopathy. Her condition fluctuated due to frequent occlusion of the central venous catheter (CVC) route. However, a quick check revealed no apparent abnormalities in the CVC, infusion route, in-line filter or infusion pump. Scanning electron microscopy revealed that dobutamine and heparin had crystallized and that the in-line filter membrane was occluded. This case emphasizes the importance of proper infusion route management in pediatric patients with severe heart failure. Even drugs that are used daily may form microscopic crystals at several concentrations and administration rates. Without an in-line filter, microscopic particles are injected into the body, and there is no evidence that the injected crystals do not cause permanent damage.

Isolated unilateral agenesis of the pulmonary artery: surgical repair with an artificial graft.

This report describes a 3-month-old Japanese boy with a diagnosis of isolated unilateral agenesis of the proximal right pulmonary artery with severe pulmonary hypertension. One-stage reconstruction of the right pulmonary artery was performed without cardiopulmonary bypass. The hilar right pulmonary artery and the distal main pulmonary artery were joined by anastomosis to an artificial ring graft. The boy's postoperative course was uneventful, and the pressure in the pulmonary artery was within the normal range. Although mild right pulmonary artery stenosis remained, the authors' therapeutic strategy may provide a clinically important option for isolated unilateral agenesis of the pulmonary artery.

Clinical features of 35 Down syndrome patients with transient abnormal myelopoiesis at a single institution.

Transient abnormal myelopoiesis (TAM) is a unique clonal myeloproliferation characterized by immature megakaryoblasts that occurs in 5-10% of neonates with Down syndrome (DS). Although TAM regresses spontaneously in most patients, approximately 20% of TAM cases result in early death, and approximately 20% of survivors develop acute megakaryoblastic leukemia (AMKL). We retrospectively reviewed records of 35 DS patients with TAM to determine the correlation between clinical characteristics and blast percentage. Thirteen of the 35 patients were classified as low blast percentage TAM (LBP-TAM), defined as TAM with a peak peripheral blast percentage ≤ 10%. Although no patient with LBP-TAM experienced systemic edema, disseminated intravascular coagulation, or early death, eight patients had elevated direct bilirubin levels (> 2 mg/dl) and one developed AMKL. All patients with LBP-TAM had serum markers of liver fibrosis that exceeded the normal limits, and two patients underwent liver biopsy to clarify the etiology of pathological jaundice. Taken together, our results suggest that patients with LBP-TAM may be at risk of liver fibrosis and liver failure, similarly to patients with classical TAM. Although these patients generally have a good prognosis, they should be carefully monitored for potential development of liver disease and leukemia.

Visual liver assessment using Gd-EOB-DTPA-enhanced magnetic resonance imaging of patients in the early post-Fontan period.

No imaging modality can be used to evaluate Fontan-associated liver disease (FALD). We retrospectively reviewed hepatic gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) characteristics of patients within 1 year post-Fontan procedure, and we evaluated the association between hepatic imaging abnormalities and clinical parameters, including follow-up cardiac catheterization and laboratory test findings. The EOB-MR images were graded, based on the extent of the decreased enhancement, as "normal" (Grade 1), "segmental" (Grade 2), "regional" (Grade 3), and "diffuse" (Grade 4). We enrolled 37 patients (mean age, 3.5 ± 1.0 years): 9 patients had Grade 1 or 2; 14 patients, Grade 3; and 14 patients, Grade 4. EOB-MRI revealed characteristic reticular or mosaic patterns of diminished enhancement (i.e. "frog spawn" appearance). Ultrasonography did not detect diminished enhancement or "frog spawn" appearance. A trend existed toward increased grade severity in imaging with increased central venous pressure, pulmonary vascular resistance, and gamma-glutamyltransferase levels. Noninvasive EOB-MRI revealed the characteristic pattern of diminished enhancement, which was correlated with certain clinical parameters indicative of Fontan physiology and liver dysfunction. Early-stage FALD may occur soon after the Fontan procedure and is associated with increased pressure in the inferior vena cava and hepatic veins.

Risk stratification in the decision to include prednisolone with intravenous immunoglobulin in primary therapy of Kawasaki disease.

BACKGROUND: We reported previously that intravenous immunoglobulin (IVIG) plus prednisolone for initial therapy for Kawasaki disease (KD) prevented coronary artery abnormalities (CAA) more effectively than IVIG alone. However, questions remain as to whether PSL has potential benefit in all KD patients. The present study was designed to explore the possibility of stratified initial therapy including PSL in patients with and without a high predicted risk of being an IVIG nonresponder. METHODS: We retrospectively analyzed data from KD patients who received IVIG (n = 896) or IVIG + PSL (n = 110) by scoring the likely risk of being an IVIG nonresponder. We compared clinical and coronary outcomes between treatment-defined groups separately for high- and low-risk patients. RESULTS: Among low-risk patients (score 0-4), clinical and coronary outcomes were similar. Among high-risk patients (score 5 or more), incidences of treatment failure and coronary artery abnormalities until 1-month follow-up were more frequent in the IVIG than in the IVIG + PSL group. Sex- and score point-adjusted odds ratios for IVIG + PSL were 0.17 (95% confidence interval, 0.08-0.39) for treatment failure and 0.27 (95% confidence interval, 0.07-0.85) for coronary artery abnormalities A among high-risk patients. CONCLUSIONS: IVIG + PSL treatment was associated with improving clinical and coronary outcomes in patients at high risk of being IVIG nonresponders.

A large superior mesenteric artery aneurysm and ileal obstruction: a rare presentation of polyarteritis nodosa in an infant.

Polyarteritis nodosa (PAN) is a rare form of vasculitis that occurs in childhood and affects small- and medium-sized arteries. Large aneurysms due to PAN can induce fatal complications like rupturing or occlusion of the affected arteries. Here, we report a case of a 4-month-old girl with PAN complicated by a large superior mesenteric artery aneurysm and ileal obstruction. We controlled her blood pressure to prevent the artery from rupturing. A combination of prednisolone, intravenous cyclophosphamide, and plasma exchange reduced the inflammation. She developed mechanical ileus due to ileum stricture and underwent bowel resection. Histopathological examinations revealed reparative arteritis around the healed ulcer. Her postoperative course was uneventful without further dilatation of the aneurysm. This case highlights the importance of intensive immunosuppressive therapy and appropriate blood pressure control in pediatric patients with PAN complicated by large aneurysms. Mechanical ileus can develop and may require surgical management even after remission of vasculitis.

Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease.

BACKGROUND: In the present study, we developed models to predict unresponsiveness to intravenous immunoglobulin (IVIG) in Kawasaki disease (KD). METHODS AND RESULTS: We reviewed clinical records of 546 consecutive KD patients (development dataset) and 204 subsequent KD patients (validation dataset). All received IVIG for treatment of KD. IVIG nonresponders were defined by fever persisting beyond 24 hours or recrudescent fever associated with KD symptoms after an afebrile period. A 7-variable logistic model was constructed, including day of illness at initial treatment, age in months, percentage of white blood cells representing neutrophils, platelet count, and serum aspartate aminotransferase, sodium, and C-reactive protein, which generated an area under the receiver-operating-characteristics curve of 0.84 and 0.90 for the development and validation datasets, respectively. Using both datasets, the 7 variables were used to generate a simple scoring model that gave an area under the receiver-operating-characteristics curve of 0.85. For a cutoff of 0.15 or more in the logistic regression model and 4 points or more in the simple scoring model, sensitivity and specificity were 86% and 67% in the logistic model and 86% and 68% in the simple scoring model. The kappa statistic is 0.67, indicating good agreement between the logistic and simple scoring models. CONCLUSIONS: Our predictive models showed high sensitivity and specificity in identifying IVIG nonresponders among KD patients.

Liver disease is frequently observed in Down syndrome patients with transient abnormal myelopoiesis.

Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells, which resolves spontaneously. Approximately 20 % of patients with TAM die at an early age due to organ failure, including liver disease. We studied 25 DS-TAM patients retrospectively to clarify the correlation between clinical and laboratory characteristics and liver diseases. Early death (<6 months of age) occurred in four of the 25 patients (16.0 %), and two of those four patients died due to liver failure. Although physiologic jaundice improved gradually after a week, all DS patients had elevated D-Bil levels during the clinical course of TAM, except one who suffered early death. The median peak day of the WBC count, total bilirubin (T-Bil) and D-Bil levels was: day 1 (range day 0-57), day 8 (range day 1-55), and day 17 (range 1-53), respectively. Our results reveal that all patients with DS-TAM may develop liver disease irrespective of the absence or presence of symptoms and risk factors for early death. In patients of DS-TAM, careful observation of the level of D-Bil is needed by at least 1 month of age for the detection of liver disease risk.