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.

Calmodulinopathy in Japanese Children　- Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy.

BACKGROUND: Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like). CONCLUSIONS: Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.

A simple scoring model based on machine learning predicts intravenous immunoglobulin resistance in Kawasaki disease.

INTRODUCTION: In Kawasaki disease (KD), accurate prediction of intravenous immunoglobulin (IVIG) resistance is crucial to reduce a risk for developing coronary artery lesions. OBJECTIVE: To establish a simple scoring model predicting IVIG resistance in KD patients based on the machine learning model. METHODS: A retrospective cohort study of 1002 KD patients diagnosed at 12 facilities for 10 years, in which 22.7% were resistant to initial IVIG treatment. We performed machine learning with diverse models using 30 clinical variables at diagnosis in 801 and 201 cases for training and test datasets, respectively. SHAP was applied to identify the variables that influenced the prediction model. A scoring model was designed using the influential clinical variables based on the Shapley additive explanation results. RESULTS: Light gradient boosting machine model accurately predicted IVIG resistance (area under the receiver operating characteristic curve (AUC), 0.78; sensitivity, 0.50; specificity, 0.88). Next, using top three influential features (days of illness at initial therapy, serum levels of C-reactive protein, and total cholesterol), we designed a simple scoring system. In spite of its simplicity, it predicted IVIG resistance (AUC, 0.72; sensitivity, 0.49; specificity, 0.82) as accurately as machine learning models. Moreover, accuracy of our scoring system with three clinical features was almost identical to that of Gunma score with seven clinical features (AUC, 0.73; sensitivity, 0.53; specificity, 0.83), a well-known logistic regression scoring model. CONCLUSION: A simple scoring system based on the findings in machine learning seems to be a useful tool to accurately predict IVIG resistance in KD patients.

Role of microglia in blood pressure and respiratory responses to acute hypoxic exposure in rats.

Microglia modulate cardiorespiratory activities during chronic hypoxia. It has not been clarified whether microglia are involved in the cardiorespiratory responses to acute hypoxia. Here we investigated this issue by comparing cardiorespiratory responses to two levels of acute hypoxia (13% O2 for 4 min and 7% O2 for 5 min) in conscious unrestrained rats before and after systemic injection of minocycline (MINO), an inhibitor of microglia activation. MINO increased blood pressure but not lung ventilation in the control normoxic condition. Acute hypoxia stimulated cardiorespiratory responses in MINO-untreated rats. MINO failed to significantly affect the magnitude of hypoxia-induced blood pressure elevation. In contrast, MINO tended to suppress the ventilatory responses to hypoxia. We conclude that microglia differentially affect cardiorespiratory regulation depending on the level of blood oxygenation. Microglia suppressively contribute to blood pressure regulation in normoxia but help maintain ventilatory augmentation in hypoxia, which underscores the dichotomy of central regulatory pathways for both systems.

Prevention Measures for COVID-19 and Changes in Kawasaki Disease Incidence.

BACKGROUND: Kawasaki disease is suspected to be triggered by previous infection. The prevention measures for coronavirus disease 2019 (COVID-19) have reportedly reduced transmission of certain infectious diseases. Under these circumstances, the prevention measures for COVID-19 may reduce the incidence of Kawasaki disease. METHODS: We conducted a retrospective study using registration datasets of patients with Kawasaki disease who were diagnosed in all 11 inpatient pediatric facilities in Yamanashi Prefecture. The eligible cases were 595 cases that were diagnosed before the COVID-19 pandemic (from January 2015 through February 2020) and 38 cases that were diagnosed during the COVID-19 pandemic (from March through November 2020). Incidence of several infectious disease were evaluated using data from the Infectious Disease Weekly Report conducted by the National Institute of Infectious Diseases. RESULTS: Epidemics of various infectious diseases generally remained at low levels during the first 9 months (March through November 2020) of the COVID-19 pandemic. Moreover, the incidence of COVID-19 was 50-80 times lower than the incidence in European countries and the United States. The total number of 38 cases with Kawasaki disease for the 9 months during the COVID-19 pandemic was 46.3% (-3.5 standard deviations [SDs] of the average [82.0; SD, 12.7 cases] for the corresponding 9 months of the previous 5 years. None of the 38 cases was determined to be triggered by COVID-19 based on their medical histories and negative results of severe acute respiratory syndrome coronavirus 2 testing at admission. CONCLUSION: These observations provide a new epidemiological evidence for the notion that Kawasaki disease is triggered by major infectious diseases in children.

A burden of sarcomere gene variants in fetal-onset patients with left ventricular noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy, associated with high morbidity and mortality, but the role of genetics in cases of fetal-onset has not been fully evaluated. The goal of this study was to identify the genetic background in LVNC fetal-onset patients using next-generation sequencing (NGS). METHODS: Thirty-three fetal-onset Japanese probands with LVNC (20 males and 13 females) were enrolled. In the enrolled patients, 81 genes associated with cardiomyopathy were screened using next-generation sequencing (NGS) retrospectively. RESULTS: Twenty-three patients had congestive heart failure (CHF), and six patients had arrhythmias. Prominent trabeculations were mostly observed in lateral LV, posterior LV, and apex of LV in patients with LVNC. Twelve died; three patients experienced intrauterine death or termination of pregnancy. Overall, 15 variants were found among eight genes in 16 patients. Seven variants were detected in MYH7 and two in TPM1. Sarcomere gene variants accounted for 75.0%. A multivariable proportional hazards model revealed that CHF at diagnosis and a higher ratio of the noncompacted layer/compacted layer in the LV posterior wall were independent risk factors for death in LVNC fetal-onset patients (odds ratio = 4.26 × 106 and 1.36 × 108, p = 0.0075 and 0.0005, respectively). CONCLUSIONS: The present study is the first report focusing on genetic background combined with clinical features in LVNC fetal-onset patients using NGS. Sarcomere variants were most commonly identified in fetal-onset patients, and greater attention should be paid to fetal-onset patients with LVNC having prominent trabeculations in the LV because they are more likely to develop CHF.

Apparent Life-Threatening Event in an Infant with SARS-CoV-2 Infection.

The 2019 novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global outbreak of infection. In general, children with coronavirus disease-2019 have been reported to show milder respiratory symptoms than adult patients. Here, we have described a case of a SARS-CoV-2-infected infant who presented to our hospital with a severe episode of an apparent life-threatening event (ALTE). An 8-month-old, otherwise healthy female infant presented to our hospital because of a sudden cardiopulmonary arrest. Approximately 1 h before this episode, the patient showed no symptoms, except a worse humor than usual. On arrival at our hospital, the patient had severe acidosis, but there were no clear signs of inflammatory response. Chest computed tomography showed weak consolidations in the upper right lung and atelectasis in the lower left lung. No signs of congenital heart disease or cardiomyopathy were observed on echocardiography, and no significant arrhythmia was observed during the clinical course. However, SARS-CoV-2 RNA was detected by real-time reverse transcription polymerase chain reaction in tracheal aspirate and urine samples. Although the assessment of further similar cases is indispensable, this case suggests that SARS-CoV-2 infection may be an underlying factor in the pathophysiology of ALTE.

Structural and functional connectivity from the dorsomedial hypothalamus to the ventral medulla as a chronological amplifier of sympathetic outflow.

Psychological stress activates the hypothalamus, augments the sympathetic nervous output, and elevates blood pressure via excitation of the ventral medullary cardiovascular regions. However, anatomical and functional connectivity from the hypothalamus to the ventral medullary cardiovascular regions has not been fully elucidated. We investigated this issue by tract-tracing and functional imaging in rats. Retrograde tracing revealed the rostral ventrolateral medulla was innervated by neurons in the ipsilateral dorsomedial hypothalamus (DMH). Anterograde tracing showed DMH neurons projected to the ventral medullary cardiovascular regions with axon terminals in contiguity with tyrosine hydroxylase-immunoreactive neurons. By voltage-sensitive dye imaging, dynamics of ventral medullary activation evoked by electrical stimulation of the DMH were analyzed in the diencephalon-lower brainstem-spinal cord preparation of rats. Although the activation of the ventral medulla induced by single pulse stimulation of the DMH was brief, tetanic stimulation caused activation of the DMH sustained into the post-stimulus phase, resulting in delayed recovery. We suggest that prolonged excitation of the DMH, which is triggered by tetanic electrical stimulation and could also be triggered by psychological stress in a real life, induces further prolonged excitation of the medullary cardiovascular networks, and could contribute to the pathological elevation of blood pressure. The connectivity from the DMH to the medullary cardiovascular networks serves as a chronological amplifier of stress-induced sympathetic excitation. This notion will be the anatomical and pathophysiological basis to understand the mechanisms of stress-induced sustained augmentation of sympathetic activity.

Right Pulmonary Vein Atresia in a Mildly Symptomatic Boy: Comprehensive Analysis of Flow Dynamics Using Non-contrast-enhanced 4D Flow MR Imaging.

We present multimodal imaging in the rare case of isolated unilateral pulmonary vein atresia in a 6 year-old boy, including analysis of hemodynamics by magnetic resonance acquisition technique of time-resolved three-dimensional phase contrast imaging (4D flow magnetic resonance imaging). This novel imaging method enables the quantification and especially comprehensive visualization of blood flow patterns, even in complex congenital anomalies which abducted detailed assessment so far, and therefore constitutes a promising alternative to conventional vascular imaging techniques.

Plasma Exchange Downregulates Activated Monocytes and Restores Regulatory T Cells in Kawasaki Disease.

In Kawasaki disease (KD), the effect of plasma exchange (PE) on immune cells has not been fully elucidated. Therefore, we examined the changes in the number of CD14+ CD16+ activated monocytes, regulatory T (Treg ), and T-helper type 17 (Th17) cells in KD patients treated with PE. The percentage of total monocytes and subclasses of lymphocytes, including CD4+ and CD8+ T cells, and CD19+ B cells, showed no significant difference before and after PE. However, the percentage of CD14+ CD16+ monocytes in total leukocytes decreased significantly after PE (1.1% ± 1.5% vs. 2.1% ± 2.3%, P < 0.05). Furthermore, while the percentage of Th17 cells in CD4+ T cells did not change, the percentage of Treg cells in CD4+ T cells increased significantly after PE (11.1% ± 5.1% vs. 8.0% ± 4.4%, P < 0.05). Therefore, PE downregulates activated monocytes and upregulates Treg cells toward normal levels and thus attenuates inflammation in KD.

Electrical storm in an infant with short-coupled variant of torsade de pointes.

A 10-month-old infant experienced cardiac arrest caused by ventricular fibrillation (VF). His electrocardiogram (ECG) at rest was within the normal range. Amiodarone was indispensable due to its refractoriness to defibrillation. After implantable cardioverter defibrillator (ICD) implantation, ICD shock was delivered. ICD recordings documented VF and ventricular tachycardia (VT) triggered by premature ventricular contractions with an extremely short coupling interval (240 ms), which were controlled by verapamil. To the best of our knowledge, our case is the first infant with ScTdP. As the electrical storm with ScTdP occurs unpredictably, it can be a cause of sudden infant death syndrome.

Correction to: Outcomes of plasma exchange for severe dilated cardiomyopathy in children.

In original publication of the article, some of the co-author's names were not included. The correct author group is published in this article.

Infliximab regulates monocytes and regulatory T cells in Kawasaki disease.

BACKGROUND: The effect of infliximab (IFX) on immune cells has not been fully reported in Kawasaki disease (KD). To investigate the mechanism of IFX in KD, we examined changes in the abundance of CD14+ CD16+ activated monocytes, regulatory T cells (Treg ) cells, and T-helper type 17 (Th17) cells following treatment with IFX. METHODS: We collected peripheral blood from patients with i.v. immunoglobulin (IVIG)-resistant KD and analyzed absolute CD14+ CD16+ monocyte, Treg (CD4+ CD25+ FOXP3+ ) and Th17 cell (CD4+ IL-17A+ ) counts on flow cytometry. We also measured changes in serum soluble interleukin (IL)-2 receptor (IL-2R), IL-6, and tumor necrosis factor (TNF)-α on enzyme-linked immunosorbent assay. RESULTS: Treg cells and Th17 cells significantly increased after IFX treatment compared with baseline (126 ± 85 cells/µL vs 62 ± 53 cells/µL, P < 0.01; 100 ± 111 cells/µL vs 28 ± 27 cells/µL, P < 0.05, respectively). In contrast, in a subgroup of patients with CD14+ CD16+ monocytes above the normal range before IFX, the CD14+ CD16+ monocytes significantly decreased following IFX treatment (72 ± 51 cells/µL vs 242 ± 156 cells/µL, P < 0.05).. Serum TNF-α did not change, but soluble IL-2R and IL-6 decreased after IFX treatment. CONCLUSION: IFX could downregulate activated monocytes and upregulate Treg cells towards the normal range. IFX treatment thus contributes to the process of attenuating inflammation in KD.