Regional Differences in Kawasaki Disease Incidence Reduction Before and After the Onset of the Coronavirus Disease 2019 Pandemic.

OBJECTIVE: To assess regional differences in reduction of the incidence of Kawasaki disease during the mitigation period for the coronavirus disease 2019 pandemic, with a hypothesis that more sparsely populated regions have fewer opportunities for human-to-human contact, resulting in a greater reduction in the incidence of Kawasaki disease. STUDY DESIGN: A retrospective ecological study was conducted using data from patients hospitalized for Kawasaki disease as well as infectious diseases surveillance reports in Shiga Prefecture, Japan, during 2015-2020. We defined the periods before and after the onset of pandemic as January 2015-March 2020 and as April 2020-December 2020, respectively. We compared the reductions in the incidence of Kawasaki disease among 6 administrative regions in the prefecture according to the density of the populations. RESULTS: A total of 1290 patients with Kawasaki disease were identified. The incidence of Kawasaki disease (per 100 000 person-years) was significantly reduced after the coronavirus disease 2019 pandemic onset (period before pandemic onset, 105.6 [95% CI 99.8-111.8]; period after pandemic onset, 68.6 [95% CI 56.7-83.0]). During the period after pandemic onset, the incidence of Kawasaki disease was significantly reduced in May, compared with the corresponding period in previous years. The number of patients aged 2-4 years was significantly reduced after the pandemic onset. Notably, greater reductions in the incidence of Kawasaki disease were found in regions with lower population densities. CONCLUSIONS: Assuming that there were fewer opportunities for human-to-human contact in more sparsely populated regions during the pandemic mitigation period, our findings support the hypothesis that human-to-human contact may be associated with development of Kawasaki disease.

Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial.

OBJECTIVES: To determine the safety, pharmacokinetics, and immunomodulatory effects of 2-6 weeks of anakinra therapy in patients with acute Kawasaki disease with a coronary artery aneurysm (CAA). STUDY DESIGN: We performed a Phase I/IIa dose-escalation study of anakinra (2-11 mg/kg/day) in 22 patients with acute Kawasaki disease with CAA. We measured interleukin (IL)-1RA concentrations after the first dose and trough levels up to study week 6. Markers of inflammation and coronary artery z-scores were assessed pretreatment and at 48 hours, 2 weeks, and 6 weeks after initiation of therapy. RESULTS: Up to 6 weeks of anakinra (up to 11 mg/kg/day) was safe and well tolerated by the 22 participants (median age, 1.1 years), with no serious adverse events attributable to the study drug. All participants were treated with intravenous immunoglobulin (IVIG), and 20 also received infliximab (10 mg/kg) before initiation of anakinra. Serum levels of IL-6, IL-8, and tumor necrosis factor α decreased similarly in patients with Kawasaki disease treated with IVIG, infliximab, and anakinra compared with age- and sex-matched patients with Kawasaki disease treated only with IVIG and infliximab. Anakinra clearance increased with illness day at diagnosis. Simulations demonstrated that more frequent intravenous (IV) dosing may result in more sustained concentrations without significantly increasing the peak concentration compared with subcutaneous (SC) dosing. CONCLUSIONS: Both IV and SC anakinra are safe in infants and children with acute Kawasaki disease and CAA. IV dosing every 8-12 hours during the acute hospitalization of patients with Kawasaki disease may result in a sustained concentration while avoiding frequent SC injections. The efficacy of a short course of IV therapy during hospitalization should be studied. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT02179853.

Atypical fetal junctional ectopic tachycardia: a case report and literature review.

BACKGROUND: Junctional ectopic tachycardia (JET) is caused by ectopic rhythms, originating in the atrioventricular node, typically with heart rate between 200 and 250 bpm. Herein, we present a case of fetal JET with normal fetal heart rate and a review of nine cases. CASE PRESENTATION: A 32-year-old, gravida 2, para 1, woman in whom fetal JET could not be diagnosed prenatally because the fetal heart rate was within the normal range. The fetus was diagnosed with premature restriction of the foramen ovale, and a cesarean section was performed, owing to the right heart overload that was characterized by fetal ascites and abnormal fetal Doppler velocity. Postnatally, the female neonate was diagnosed with JET on a 12-lead electrocardiogram, which revealed a neonatal heart rate of 158 bpm with narrow QRS and atrioventricular dissociation. After failure to respond to amiodarone therapy, she was treated with flecainide, which controlled the JET rate from 120 to 150 bpm. Fetal tachycardia with ventriculo-atrial (VA) dissociation or 1:1 VA conduction with a shorter VA interval than that of atrioventricular reentrant tachycardia confirmed the diagnosis of fetal JET. CONCLUSIONS: JET should be suspected even in the absence of tachycardia in patients with ductus venosus and pulmonary vein retrograde flow or tricuspid and mitral regurgitation without a cardiac anomaly, as tachycardia might sometimes be intermittent in cases of JET.

Postnatal developmental changes in the sensitivity of L-type Ca2+ channel to inhibition by verapamil in a mouse heart model.

BackgroundIn the clinical setting, verapamil is contraindicated in neonates and infants, because of the perceived risk of hypotension or bradyarrhythmia. However, it remains unclear whether there is an age-dependent difference in the sensitivity of cardiac L-type Ca2+ channel current (ICa,L) to inhibition by verapamil.MethodsVentricular myocytes were enzymatically dissociated from the hearts of six different age groups (0, 7, 14, 21, 28 days, and 10-15 weeks) of mice, using a similar Langendorff-perfusion method. Whole-cell patch-clamp technique was applied to examine the sensitivity of ICa,L to inhibition, by three classes of structurally different L-type Ca2+ channel antagonists.ResultsVerapamil, nifedipine, and diltiazem concentration-dependently blocked the ventricular ICa,L in all six age groups. However, although nifedipine and diltiazem blocked ventricular ICa,L with a similar potency in all age groups, verapamil more potently blocked ventricular ICa,L in day 0, day 7, day 14, and day 21 mice, than in day 28, and 10-15-week mice.ConclusionIn a mouse heart model, ventricular ICa,L before the weaning age (~21 days of age) exhibited a higher sensitivity to inhibition by verapamil than that after the weaning age, which may explain one possible mechanism associated with the development of verapamil-induced hypotension in human neonates and infants.

Characteristics and Fate of Systemic Artery Aneurysm after Kawasaki Disease.

OBJECTIVE: To determine the long-term outcome of systemic artery aneurysms (SAAs) after Kawasaki disease (KD). STUDY DESIGN: We investigated the characteristics and the fate of SAAs in 20 patients using medical records and angiograms. The age of onset of KD ranged from 1 month to 20 months. The interval from the onset of KD to the latest angiogram ranged from 16 months to 24 years. The regression rate of peripheral artery aneurysm and the frequency of stenotic lesions were analyzed by the Kaplan-Meier method in 11 patients who had undergone initial angiography within 4 months. RESULTS: The mean duration of fever was 24 ± 12 days. All 20 patients had at least 1 symmetric pair of aneurysms in bilateral peripheral arteries, and 16 patients had multiple SAAs. The distributions of SAAs was as follows: brachial artery, 30; common iliac artery, 20; internal iliac artery, 21; abdominal aortic aneurysm, 7; and others, 29. The frequencies of regression of SAA and of the occurrence of stenotic lesions at 20 years after the onset of KD were 51% and 25%, respectively (n = 42). The diameter of all SAAs in the acute phase leading to stenotic lesions in the late period was >10 mm. CONCLUSION: SAAs occurred symmetrically and were multiple in younger infants and those with severe acute vasculitis. The fate of SAAs resembles that of coronary artery aneurysms, and depends on the diameter during the acute phase. Larger SAAs can lead to stenotic lesions in the late period.

Efficacy and safety of percutaneous transluminal balloon dilation to prevent progression of banding site stenosis after bilateral pulmonary artery banding.

OBJECTIVES: To investigate the efficacy and safety of percutaneous transluminal balloon dilation (PTBD) for the treatment of bilateral pulmonary artery banding (bil-PAB) site stenosis. BACKGROUND: Although bil-PAB is an alternative initial treatment for high-risk neonates with hypoplastic left heart syndrome (HLHS) or critical aortic stenosis (cAS), those patients often suffer from desaturation because of progressive stenosis of the bil-PAB sites during the interstage period. METHODS: We retrospectively evaluated the efficacy and safety of 11 consecutive PTBD procedures performed between 2006 and 2012 to treat bil-PAB site stenosis in four high-risk infants (three females) with HLHS or cAS. RESULTS: PTBD was repeated twice in two patients and three times in one patient over intervals. The mean balloon diameter (BD) and BD-to-band circumference (BC) ratio were 3.1 ± 0.5 mm and 0.31 ± 0.06, respectively. After the procedures, the mean minimum lumen diameter was dilated significantly from 1.1 ± 0.1 mm to 1.7 ± 0.3 mm (P < 0.01), and the mean peripheral oxygen saturation increased significantly from 75 ± 8% to 85 ± 4% (P < 0.01). All patients reached the next stage operation involving the Norwood & bidirectional Glenn or Ross procedure, after growth. No complications such as band rupture occurred. CONCLUSIONS: For progressive stenosis of bil-PAB sites, PTBD using a balloon size that did not exceed the BC (BD around 30% of the BC) was an effective and safe procedure.

Relationship between electrocardiographic signs and shunt volume in atrial septal defect.

BACKGROUND: The aim of this study was to determine whether electrocardiographic signs correlate with hemodynamics and the magnitude of the intracardiac shunt in children with ostium secundum atrial septal defects (ASD). METHODS: A total of 100 ASD patients (median age, 6 years 4 months; 54 girls) underwent cardiac catheterization between August 1980 and April 2010. We retrospectively investigated the relationship between electrocardiographic signs and the pulmonary/systemic blood flow ratio (Qp/Qs) in these patients. We also compared 63 postoperative electrocardiograms with those recorded before surgery. RESULTS: The mean Qp/Qs ratio of the 100 patients was 2.46 ± 0.81 (range, 1.1-5.0). The Qp/Qs ratio in patients with and without right bundle branch block (RBBB) was 2.57 ± 0.82 (n = 73) and 2.15 ± 0.72 (n = 27), respectively (P = 0.016). The Qp/Qs ratio in patients with and without isolated negative T-wave was 2.85 ± 0.87 (n = 38) and 2.22 ± 0.68 (n = 62), respectively (P = 0.0003). None of the patients with low Qp/Qs ratio (Qp/Qs ratio ≤ 1.5) had both RBBB and isolated negative T-wave. The prevalence of these two signs decreased from 73.0% (n = 46) and 36.5% (n = 23) to 15.9% (n = 10) and 15.9% (n = 10) after surgical repair, respectively. CONCLUSIONS: RBBB and isolated negative T-wave in the precordial leads are well correlated with high Qp/Qs ratio in ASD patients.

Initial intravenous immunoglobulin therapy without aspirin for acute Kawasaki disease: a retrospective cohort study with a Bayesian inference.

OBJECTIVE: To clarify the necessity of acetylsalicylic acid (ASA) administration combined with intravenous immunoglobulin (IVIG) therapy in the treatment of acute Kawasaki disease. DESIGN: Retrospective cohort study. SETTING: Multicentre. PARTICIPANTS: This study included 735 patients with Kawasaki disease aged ≤10 years and hospitalised between 4 and 10 days of illness in eight Japanese hospitals from January 2016 to December 2020. EXPOSURES: High-dose (HD) ASA was administered with initial IVIG to 333 patients in 6 hospitals (HD group). ASA was not administered routinely to 402 patients in the other two hospitals, and low-dose ASA was only administered when patients developed coronary artery lesions or pericardial effusion (non-HD group). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the presence of coronary artery lesions, defined as a coronary artery diameter >+2.5 SD of body surface area within 1 month of onset. The secondary outcome was responsiveness to the initial IVIG therapy. Adjusted risk ratios for the outcomes were calculated using modified Poisson regression models. Bayesian analysis was conducted to estimate the posterior probability of the treatment effect of HD ASA under several prior distributions. RESULTS: The incidence of coronary artery lesions was not significantly higher in the HD group than in the non-HD group (12/333 (3.6%) vs 15/402 (4.0%)). The proportion of non-responders to initial IVIG was similar between the two groups (HD group: 78/333 (23%); non-HD group: 83/402 (22%)). In the Bayesian analysis, considering a difference of ≤2% to be of no clinical importance, there was only a 9.3% chance of reduced risk of coronary artery lesions in the HD group compared with the non-HD group even with a strongly enthusiastic prior for HD treatment. CONCLUSIONS: Compared with HD ASA treatment, treatment without ASA in the acute phase of Kawasaki disease was not associated with increased complications from Kawasaki disease.

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.].

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.

Postnatal developmental decline in IK1 in mouse ventricular myocytes isolated by the Langendorff perfusion method: comparison with the chunk method.

Expression and function of cardiac ion channels exhibit postnatal developmental changes, which, however, has not yet been proven in ventricular myocytes isolated using similar techniques. In this study, ventricular myocytes were enzymatically dissociated from mouse heart at different postnatal ages (including postnatal day 0) by similar techniques using Langendorff perfusion. Whole-cell patch-clamp experiments were performed to record action potentials, I (K1), I (Kr), I (Kur), I (ss), and I (Ca,L), in ventricular myocytes freshly isolated from postnatal days 0, 7, and 14 and adult mice. Viable ventricular myocytes of day-0 mouse heart exhibited spindle-shaped appearance having cell length of approximately 50 µm, which gradually developed to a rod-shaped one having clear cross striation with cell length of approximately 120 µm (adult). The action potential duration markedly shortened, while the resting membrane potential depolarized to a small but significant extent during postnatal development. I (K1) density was maximal in postnatal day-0 ventricular myocytes and gradually decreased during development, which was accompanied by postnatal depolarization of resting membrane potential. However, I (K1) density was markedly decreased by approximately 80% in postnatal day-0 ventricular myocytes, when isolated by the chunk method. Quantitative real-time polymerase chain reaction (PCR) and western blot analyses demonstrated higher Kir2.3 expression but lower expression levels of Kir2.1 and Kir2.2 in day-0 mouse ventricles, compared with those of day-14 and adult mouse ventricles. Whereas I (Kr) exhibited marked decrease during postnatal development, I (Kur), I (ss), and I (Ca,L) exhibited postnatal developmental increase. The present cell isolation method using the Langendorff perfusion thus found that, in mouse ventricles, I (K1) exhibited postnatal developmental decrease, associated with depolarization of resting potential.

Biomarkers of inflammation and fibrosis in young adults with history of Kawasaki disease.

BACKGROUND: Myocardial histology from autopsies of young adults with giant coronary artery aneurysms following Kawasaki disease (KD) shows bridging fibrosis beyond the territories supplied by the aneurysmal arteries. The etiology of this fibrosis is unknown, but persistent, low-level myocardial inflammation and microcirculatory ischemia are both possible contributing factors. To investigate the possibility of subclinical myocardial inflammation or fibrosis, we measured validated biomarkers in young adults with a remote history of KD. METHODS: We measured plasma calprotectin, galectin-3 (Gal-3), growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and serum procollagen type 1C-terminal propeptide (P1CP) in 91 otherwise healthy young adults with a remote history of KD and in 88 age-similar, healthy controls. KD subjects were stratified by coronary artery aneurysm (CAA) status and history of remote myocardial infarction (MI). RESULTS: After correction for multiple testing, calprotectin, Gal-3, and GDF-15 levels were significantly higher in subjects with persistent CAA (n = 26) compared with KD subjects with remodeled CAA (n = 20, p = 0.005, 0.001, 0.0036, respectively). In a multivariable regression model with CA status as the main predictor and adjusting for sex, MI history, and interval from KD onset, CA status was a significant predictor (Persistent CAA vs KD Normal CA) of calprotectin, Gal-3, GDF-15 and sST2 levels (p = 0.004, <0.001, 0.007, and 0.049, respectively). CONCLUSIONS: These results suggest that ongoing inflammation and fibrosis may be occurring in individuals with persistent CAA. Longitudinal follow-up is needed to clarify the clinical significance of these elevated biomarker levels in this patient population that requires life-long monitoring.

Biomarkers of Inflammation and Fibrosis in Kawasaki Disease Patients Years After Initial Presentation With Low Ejection Fraction.

Background Coronary artery aneurysms and myocarditis are well-recognized complications of Kawasaki disease (KD) but no systematic evaluation of the consequences of myocarditis has been performed in the subset presenting with low ejection fraction (EF). We postulated that more severe myocardial inflammation as evidenced by low EF during the acute phase could lead to late myocardial fibrosis. Methods and Results We measured the carboxyterminal propeptide of procollagen type I (PIPC), soluble suppressor of tumorigenicity 2, galectin-3 (Gal-3), growth-differentiation factor-15, and calprotectin by ELISA in late convalescent blood samples from 16 KD patients who had an EF ≤55% on their initial echocardiogram. Results were compared with samples from sex- and age-matched KD patients with initial EF >60%. In the univariate analysis, the median Gal-3 and PIPC levels in the low EF group were significantly higher than those in the normal EF group (Gal-3: low EF 6.216 versus normal EF 4.976 mg/dL P=0.038, PIPC: low EF 427.4 versus normal EF 265.2 mg/dL, P=0.01). In a multivariable analysis, there were significant differences for Gal-3 and PIPC levels between the low and normal EF groups, adjusting for age, sex, and worst z score. Conclusions Convalescent KD patients with a history of low EF during the acute illness had significantly elevated levels of Gal-3 and PIPC when compared with matched-control KD patients with normal EF. These findings raise concern for myocardial fibrosis as a potential late sequela of the more severe myocarditis experienced by a subset of KD patients during the acute phase.

Circulating Markers of Inflammation Persist in Children and Adults With Giant Aneurysms After Kawasaki Disease.

BACKGROUND: The sequelae of Kawasaki disease (KD) vary widely with the greatest risk for future cardiovascular events among those who develop giant coronary artery aneurysms (CAA). We sought to define the molecular signature associated with different outcomes in pediatric and adult KD patients. METHODS: Molecular profiling was conducted using mass spectrometry-based shotgun proteomics, transcriptomics, and glycomics methods on 8 pediatric KD patients at the acute, subacute, and convalescent time points. Shotgun proteomics was performed on 9 KD adults with giant CAA and matched healthy controls. Plasma calprotectin was measured by ELISA in 28 pediatric KD patients 1 year post-KD, 70 adult KD patients, and 86 healthy adult volunteers. RESULTS: A characteristic molecular profile was seen in pediatric patients during the acute disease, which resolved at the subacute and convalescent periods in patients with no coronary artery sequelae but persisted in 2 patients who developed giant CAA. We, therefore, investigated persistence of inflammation in KD adults with giant CAA by shotgun proteomics that revealed a signature of active inflammation, immune regulation, and cell trafficking. Correlating results obtained using shotgun proteomics in the pediatric and adult KD cohorts identified elevated calprotectin levels in the plasma of patients with CAA. Investigation of expanded pediatric and adult KD cohorts revealed elevated levels of calprotectin in pediatric patients with giant CAA 1 year post-KD and in adult KD patients who developed giant CAA in childhood. CONCLUSIONS: Complex patterns of biomarkers of inflammation and cell trafficking can persist long after the acute phase of KD in patients with giant CAA. Elevated levels of plasma calprotectin months to decades after acute KD and infiltration of cells expressing S100A8 and A9 in vascular tissues suggest ongoing, subclinical inflammation. Calprotectin may serve as a biomarker to inform the management of KD patients following the acute illness.

The histological findings in transposition of the great artery with severe persistent pulmonary hypertension of the newborn.

The combination of persistent pulmonary hypertension of the newborn (PPHN) and transposition of the great arteries (TGA) has serious impacts on treatment and prognosis, often with adverse outcomes. We report the case of a male full-term newborn with TGA with intact ventricular septum and severe PPHN who died 2 h after birth; further, we examined his vascular histology. On autopsy, lung histology showed mild fibrous hypertrophy in the intima and moderate medial hypertrophy of the minimal pulmonary artery. Hypoplasia of the pulmonary artery was not detected. Pulmonary congestion was detected and pneumatization was poor. Debris was present in the alveoli. Hemosiderin deposition was detected, suggesting prenatal hemostasis or hemorrhage. Severe PPHN may have occurred because of pulmonary arterial spasm accompanying pulmonary congestion which had been in the fetal stage. A wide range of lesions can be present in the pulmonary vascular bed in TGA. The pathologies of pulmonary vascular tissues with TGA and PPHN are not uniform. .

Isolation and characterization of annexin 2 pseudogene in Rattus norvegicus.

Annexin 2 is a calcium-regulated, phospholipid-binding protein present in endothelial cells, macrophages and some tumor cells. Annexin 2 is a substrate for a variety of protein kinases, and plays roles in the regulation of endocytosis, exocytosis and thrombolysis. We have determined the nucleotide sequence of a rat genomic DNA fragment that hybridized to a rat annexin 2 DNA complementary to RNA (cDNA) probe. Sequence analysis revealed that it was an intronless rat annexin 2, consisting of a start-to-stop-codon-length copy of the processed transcript. This pseudogene contained 33 point mutations and two deletion sites in the coding region as compared with the cDNA, and thus displayed typical features of a retroposon. Transitions were more frequent than transversions, and the most frequent type of mutation was G to A transition. We isolated a phage clone that contained a functional rat annexin 2 genomic fragment including coding exons 3 and 4. Polymerase chain reaction and subsequent sequence analysis revealed an intron of approximately 4 kbp at the same site as in humans and mice. Whereas the annexin 2 gene or its cDNA homologues have been detected in various species from Xenopus to humans, its pseudogene has been reported only in humans. In the present study, we demonstrated the presence of an annexin 2 pseudogene in rats.