Faculty Profiles - KATO, Taichi

An electrocardiographic score to predict pulmonary hypertension in children with atrial septal defect. Reviewed International coauthorship Open Access

Murni IK, Kato T, Wirawan MT, Arafuri N, Hermawan K, Hartopo AB, Anggrahini DW, Nugroho S, Noormanto N, Emoto N, Dinarti LK

BMC pediatrics Vol. 23 ( 1 ) page： 288 2023.6

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：BMC Pediatrics

Background: In limited resource settings, identification of factors that predict the occurrence of pulmonary hypertension(PH) in children with atrial septal defect(ASD) is important to decide which patients should be prioritized for defect closure to prevent complication. Echocardiography and cardiac catheterization are not widely available in such settings. No scoring system has been proposed to predict PH among children with ASD. We aimed to develop a PH prediction score using electrocardiography parameters for children with ASD in Indonesia. Methods: A cross-sectional study reviewing medical record including ECG record was conducted among all children with newly diagnosed isolated ASD admitted to Dr Sardjito Hospital in Yogyakarta, Indonesia during 2016–2018. Diagnosis of ASD and PH was confirmed through echocardiography and/or cardiac catheterization. Spiegelhalter Knill-Jones approach was used to develop PH prediction score. Accuracy of prediction score was performed using a receiver operating characteristic (ROC) curve. Results: Of 144 children, 50(34.7%) had PH. Predictors of pulmonary hypertension were QRS axis ≥120°, P wave ≥ 3 mm at lead II, R without S at V1, Q wave at V1, right bundle branch block (RBBB), R wave at V1, V2 or aVR > normal limit and S wave at V6 or lead I > normal limit. ROC curve from prediction scores yielded an area under the curve (AUC) 0.908(95% CI 0.85–0.96). Using the cut-off value 3.5, this PH prediction score had sensitivity of 76%(61.8–86.9), specificity 96.8%(91.0-99.3), positive predictive value 92.7%(80.5–97.5), negative predictive value 88.4%(82.2–92.6), and positive likelihood ratio 23.8(7.7–73.3). Conclusions: A presence of PH in children with ASD can be predicted by the simple electrocardiographic score including QRS axis ≥120°, P wave ≥3 mm at lead II, R without S at V1, Q wave at V1, RBBB, R wave at V1, V2 or aVR > normal limit and S wave at V6 or lead I > normal limit. A total score ≥ 3.5 shows a moderate sensitivity and high specificity to predict PH among children with ASD.

DOI： 10.1186/s12887-023-04102-1

Open Access

Familial cardiac septal defect due to a novel nine-base deletion in TBX20. Reviewed International journal

Hidenori Yamamoto, Hidehito Inagaki, Satoshi Hayano, Hiroki Kurahashi, Taichi Kato

Pediatrics international : official journal of the Japan Pediatric Society Vol. 64 ( 1 ) page： e14995 2022.1

Conception by assisted reproductive technology in infants with critical congenital heart disease in Japan Reviewed Open Access

Yoshihito Morimoto, Kiyotaka Go, Hidenori Yamamoto, Yoshie Fukasawa, Michikazu Nakai, Eiji Morihana, Kazushi Yasuda, Hiroshi Nishikawa, Naoki Ohashi, Yoshiyuki Takahashi, Taichi Kato

REPRODUCTIVE BIOMEDICINE ONLINE Vol. 44 ( 1 ) page： 163 - 170 2022.1

Authorship：Corresponding author Language：English Publishing type：Doctoral thesis Publisher：ELSEVIER SCI LTD

Research question: What is the proportion of infants born as a result of assisted reproductive technology ART across different types of neonatal critical congenital heart disease (CCHD) in a Japanese population? Design: A retrospective analysis of 418 consecutive infants with CCHD that required catheter treatment or surgery within the first 28 days of life or ductal-dependent lesions, in two paediatric centres in Japan, between January 2014 and December 2019. The proportion of ART in infants with each type of CCHD was evaluated. The proportion of ART in infants with univentricular heart defect (UVH) compared with those with biventricular heart defect (BVH) was evaluated. Results: The study group included 229 boys and 189 girls, with a gestational age of 38 +/- 2 weeks. Overall, 61 infants (14.6%) were conceived by fertility treatment with 46 (11.0%) conceived by ART. Univentricular heart defect and BVH were identified in 111 infants (26.6%) and 307 infants (73.4%), respectively. The proportion of infants conceived by ART was significantly higher in UVH (16.2%) than in BVH (9.1%) (OR 2.28, 95% CI 1.11 to 4.68, P = 0.025), regardless of maternal age and maternal history of miscarriage. Conclusions: The proportion of ART in infants with CCHD, especially UVH, was high. These findings could form the basis of a rationale for carrying out fetal echocardiography in fetuses conceived by ART.

DOI： 10.1016/j.rbmo.2021.10.005

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

Yoshinaga Masao, Horigome Hitoshi, Ayusawa Mamoru, Yasuda Kazushi, Kogaki Shigetoyo, Doi Shozaburo, Tateno Sigeru, Ohta Kunio, Hokosaki Tatsunori, Nishihara Eiki, Iwamoto Mari, Sumitomo Naokata, Ushinohama Hiroya, Izumida Naomi, Tauchi Nobuo, Kato Yoshiaki, Kato Taichi, Chisaka Toshiyuki, Higaki Takashi, Yoneyama Tatsuya, Abe Katsumi, Nozaki Yoshihiro, Komori Akiko, Kawai Satoru, Ninomiya Yumiko, Tanaka Yuji, Nuruki Norihito, Sonoda Masahiro, Ueno Kentaro, Hazeki Daisuke, Nomura Yuichi, Sato Seiichi, Hirono Keiichi, Hosokawa Susumu, Takechi Fumie, Ishikawa Yuichi, Hata Tadayoshi, Ichida Fukiko, Ohno Seiko, Makita Naomasa, Horie Minoru, Matsushima Shouji, Tsutsui Hiroyuki, Ogata Hiromitsu, Takahashi Hideto, Nagashima Masami

Circulation Journal Vol. 86 ( 1 ) page： 118 - 127 2021.12

Language：English Publisher：The Japanese Circulation Society

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.

DOI： 10.1253/circj.CJ-21-0376

Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor. Reviewed International journal

Shinsuke Kataoka, Nozomu Kawashima, Yusuke Okuno, Hideki Muramatsu, Shunsuke Miwata, Kotaro Narita, Motoharu Hamada, Norihiro Murakami, Rieko Taniguchi, Daisuke Ichikawa, Hironobu Kitazawa, Kyogo Suzuki, Eri Nishikawa, Atsushi Narita, Nobuhiro Nishio, Hidenori Yamamoto, Yoshie Fukasawa, Taichi Kato, Hiroyuki Yamamoto, Jun Natsume, Seiji Kojima, Ichizo Nishino, Takeshi Taketani, Hidenori Ohnishi, Yoshiyuki Takahashi

The Journal of allergy and clinical immunology Vol. 148 ( 2 ) page： 639 - 644 2021.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Type I interferonopathies are a recently established subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA-sensing pathways. OBJECTIVE: This study aimed to unveil the molecular pathogenesis of a patient with novel type I interferonopathy, for which no known genetic mutations have been identified. METHODS: We performed the whole-exome sequencing of a 1-month-old boy with novel type I interferonopathy. We also investigated proteasome activities using patient-derived B lymphoblastoid cell lines (LCLs) and normal LCLs transduced with the mutant gene. RESULTS: Whole-exome sequencing identified a de novo proteasome 20S subunit beta 9 (PSMB9) p.G156D mutation in the patient who developed fever, a chilblain-like skin rash, myositis, and severe pulmonary hypertension due to the hyperactivation of IFN-α. Patient-derived LCLs revealed reduced proteasome activities, and exogenous transduction of mutant PSMB9 p.G156D into normal LCLs significantly suppressed proteasome activities, and the endogenous PSMB9 protein was lost along with the reduction of other immunoproteasome subunits, PSMB8 and PSMB10 proteins. He responded to the administration of a Janus kinase inhibitor, tofacitinib, and he was successfully withdrawn from venoarterial extracorporeal membranous oxygenation. At age 7 months, he received an unrelated cord blood transplantation. At 2 years posttransplantation, he no longer required tofacitinib and experienced no disease recurrence. CONCLUSIONS: We present the case of a patient with a novel type I interferonopathy caused by a de novo PSMB9 p.G156D mutation that suppressed the wild-type PSMB9 protein expression. Janus kinase inhibitor and stem cell transplantation could be curative therapies in patients with severe interferonopathies.

DOI： 10.1016/j.jaci.2021.03.010

Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect. Reviewed International journal

Hidenori Yamamoto, Satoshi Hayano, Yusuke Okuno, Atsuto Onoda, Kohji Kato, Noriko Nagai, Yoshie Fukasawa, Shinji Saitoh, Yoshiyuki Takahashi, Taichi Kato

International journal of cardiology Vol. 326 page： 81 - 87 2021.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: A gain-of-function mutation in germline ABL1 causes a syndrome including congenital heart defects. However, the molecular mechanisms of this syndrome remain unknown. In this study, we found a novel ABL1 mutation in a Japanese family with ventricular septal defect, finger contracture, skin abnormalities and failure to thrive, and the molecular mechanisms of these phenotypes were investigated. METHODS AND RESULTS: Whole-exome sequencing on several family members revealed a novel mutation (c.1522A > C, p.I508L) in the tyrosine kinase domain of ABL1, and complete co-segregation with clinical presentations was confirmed in all members. Wild-type and mutant ABL1 were transfected into human embryonic kidney 293 cells for functional analysis. Western blotting confirmed that tyrosine phosphorylation in STAT5, a substrate of ABL1, was enhanced, and the novel mutation was proved to be a gain-of-function mutation. Since this novel mutation in ABL1 enhances tyrosine kinase activity, phosphorylated proteome analysis was used to elucidate the molecular pathology. The proteome analysis showed that phosphorylation in proteins such as UFD1, AXIN1, ATRX, which may be involved in the phenotypes, was enhanced in the mutant group. CONCLUSIONS: The onset of congenital heart defects associated with this syndrome appears to involve a mechanism caused by UFD1 common to 22q.11.2 deletion syndrome. On the other hand, AXIN1 and ATRX may be important in elucidating the mechanisms of other phenotypes, such as finger contracture and failure to thrive. Verification of these hypotheses would lead to further understanding of the pathophysiology and the development of treatment methods.

DOI： 10.1016/j.ijcard.2020.10.032

Revision of diagnostic guidelines for Kawasaki disease (6th revised edition). Reviewed International journal

Tohru Kobayashi, Mamoru Ayusawa, Hiroyuki Suzuki, Jun Abe, Shuichi Ito, Taichi Kato, Masahiro Kamada, Junko Shiono, Kenji Suda, Keiji Tsuchiya, Tsuneyuki Nakamura, Yoshikazu Nakamura, Yuichi Nomura, Hiromichi Hamada, Ryuji Fukazawa, Kenji Furuno, Hiroyuki Matsuura, Tomoyo Matsubara, Masaru Miura, Kei Takahashi

Pediatrics international : official journal of the Japan Pediatric Society Vol. 62 ( 10 ) page： 1135 - 1138 2020.10

Mesenchymal stem/stromal cells stably transduced with an inhibitor of CC chemokine ligand 2 ameliorate bronchopulmonary dysplasia and pulmonary hypertension. Reviewed International journal

Toshihiko Suzuki, Yoshiaki Sato, Hidenori Yamamoto, Taichi Kato, Yuma Kitase, Kazuto Ueda, Haruka Mimatsu, Yuichiro Sugiyama, Atsuto Onoda, Shigeki Saito, Yoshiyuki Takahashi, Takayuki Nakayama, Masahiro Hayakawa

Cytotherapy Vol. 22 ( 4 ) page： 180 - 192 2020.4

Language：English Publishing type：Research paper (scientific journal)

Perinatal bronchopulmonary dysplasia (BPD) is defined as lung injury in preterm infants caused by various factors, resulting in serious respiratory dysfunction and high mortality. The administration of mesenchymal stem/stromal cells (MSCs) to treat/prevent BPD has proven to have certain therapeutic effects. However, MSCs can only weakly regulate macrophage function, which is strongly involved in the development of BPD. 7ND-MSCs are MSCs transfected with 7ND, a truncated version of CC chemokine ligand 2 (CCL2) that promotes macrophage activation, using a lentiviral vector. In the present study, we show in a BPD rat model that 7ND-MSC administration, but not MSCs alone, ameliorated the impaired alveolarization evaluated by volume density and surface area in the lung tissue, as well as pulmonary artery remodeling and pulmonary hypertension induced by BPD. In addition, 7ND-MSCs, but not MSCs alone, reduced M1 macrophages and the messenger RNA expressions of interleukin-6 and CCL2 in the lung tissue. Thus, the present study showed the treatment effect of 7ND-MSCs in a BPD rat model, which was more effective than that of MSCs alone.

DOI： 10.1016/j.jcyt.2020.01.009

A non-selective endothelin receptor antagonist bosentan modulates kinetics of bone marrow-derived cells in ameliorating pulmonary hypertension in mice Reviewed International journal Open Access

Kato Taichi, Mitani Yoshihide, Masuya Masahiro, Maruyama Junko, Sawada Hirofumi, Ohashi Hiroyuki, Ikeyama Yukiko, Otsuki Shoichiro, Yodoya Noriko, Shinohara Tsutomu, Miyata Eri, Zhang Erquan, Katayama Naoyuki, Shimpo Hideto, Maruyama Kazuo, Komada Yoshihiro, Hirayama Masahiro

PULMONARY CIRCULATION Vol. 10 ( 2 ) page： 2045894020919355 - 2045894020919355 2020.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

The aim of this study was to investigate whether a dual endothelin receptor antagonist bosentan modulates the kinetics of bone marrow-derived stem cells in inhibiting the development of pulmonary hypertension. Bone marrow chimeric mice, transplanted with enhanced green fluorescent protein (eGFP)-positive bone marrow mononuclear cells, were exposed to hypobaric hypoxia or kept in the ambient air, and were daily treated with bosentan sodium salt or saline for 21 days. After the treatment period, right ventricular pressure was measured and pulmonary vascular morphometry was conducted. Incorporation of bone marrow-derived cells was analyzed by immunohistochemistry. Gene expression and protein level in the lung tissue were evaluated by quantitative real-time PCR and western blotting, respectively. The results showed that, in hypoxic mice, right ventricular pressure and the percentage of muscularized vessel were increased and pulmonary vascular density was decreased, each of which was reversed by bosentan. Bone marrow-derived endothelial cells and macrophages in lungs were increased by hypoxia. Bosentan promoted bone marrow-derived endothelial cell incorporation but inhibited macrophage infiltration into lungs. Quantitative real-time PCR analysis revealed that interleukin 6, stromal cell-derived factor-1, and monocyte chemoattractant protein-1 were upregulated by hypoxia, in which interleukin 6 and monocyte chemoattractant protein-1 were downregulated and stromal cell-derived factor-1 was upregulated by bosentan. Protein level of endothelial nitric oxide synthase (eNOS) in the whole lung was significantly upregulated by hypoxia, which was further upregulated by bosentan. Bosentan modulated kinetics of bone marrow-derived ECs and macrophages and related gene expression in lungs in ameliorating pulmonary hypertension in mice. Altered kinetics of bone marrow-derived stem cells may be a novel mechanism of the endothelin receptor blockade in vivo and confer a new understanding of the therapeutic basis for pulmonary hypertension.

DOI： 10.1177/2045894020919355

The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension. Reviewed International coauthorship International journal

Morikawa M, Mitani Y, Holmborn K, Kato T, Koinuma D, Maruyama J, Vasilaki E, Sawada H, Kobayashi M, Ozawa T, Morishita Y, Bessho Y, Maeda S, Ledin J, Aburatani H, Kageyama R, Maruyama K, Heldin CH, Miyazono K

Science signaling Vol. 12 ( 607 ) page： eaay4430 - eaay4430 2019.11

Language：English Publishing type：Research paper (scientific journal) Publisher：American Association for the Advancement of Science (AAAS)

Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) is implicated in vascular diseases such as pulmonary arterial hypertension (PAH). Here, we showed that the transcription factor ATOH8 was a direct target of SMAD1/5 and was induced in a manner dependent on BMP but independent of Notch, another critical signaling pathway in ECs. In zebrafish and mice, inactivation of <italic>Atoh8</italic> did not cause an arteriovenous malformation–like phenotype, which may arise because of dysregulated Notch signaling. In contrast, <italic>Atoh8-</italic>deficient mice exhibited a phenotype mimicking PAH, which included increased pulmonary arterial pressure and right ventricular hypertrophy. Moreover, <italic>ATOH8</italic> expression was decreased in PAH patient lungs. We showed that in cells, ATOH8 interacted with hypoxia-inducible factor 2α (HIF-2α) and decreased its abundance, leading to reduced induction of HIF-2α target genes in response to hypoxia. Together, these findings suggest that the BMP receptor type II/ALK-1/SMAD/ATOH8 axis may attenuate hypoxic responses in ECs in the pulmonary circulation and may help prevent the development of PAH.

DOI： 10.1126/scisignal.aay4430

Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease

Frequent intragenic microdeletions of elastin in familial supravalvul araortic stenosis (vol 274, pg 290, 2019) Reviewed International journal

Hayano Satoshi, Okuno Yusuke, Tsutsumi Makiko, Inagaki Hidehito, Fukasawa Yoshie, Kurahashi Hiroki, Kojima Seiji, Takahashi Yoshiyuki, Kato Taichi

INTERNATIONAL JOURNAL OF CARDIOLOGY Vol. 292 page： 283 - 283 2019.10

Thiha K., Mashimo Y., Suzuki H., Hamada H., Hata A., Hara T., Tanaka T., Ito K., Onouchi Y., Masuda H., Kobayashi T., Jibiki T., Yamazaki T., Ohkuma Y., Fujiwara M., Kobayashi T., Takeuchi H., Ouchi K., Mizuno Y., Fuse S., Fukazawa N., Saji T., Takatsuki S., Nishimura K., Hamada H., Fukazawa R., Nishumura H., Aso K., Matsubara T., Mizuno T., Iwashima S., Ayusawa M., Ikeda K., Kosuda T., Hashimoto K., Hirasawa K., Miura M., Somura J., Toba E., Hirono K., Nomura Y., Arakawa H., Ogata S., Kajino H., Kawamura S., Aoyagi H., Suzuki H., Ichinose K., Shimozono A., Kato Y., Higashikawa M., Kawamura Y., Misawa M., Nagai N., Kato T., Nagata D., Okamoto A., Suzuki H., Kishiro M., Shiono J., Higashi K., Yokoyama N., Ebata R., Onouchi Y.

Journal of Human Genetics Vol. 64 ( 6 ) page： 511 - 519 2019.6

Publisher：Journal of Human Genetics

ORAI1 encodes a calcium channel essential in the store-operated calcium entry mechanism. A previous genetic association study identified a rare in-frame insertion variant of ORAI1 conferring Kawasaki disease (KD). To deepen our understanding of the involvement of rare variants of ORAI1 in KD pathogenesis, we investigated 3812 patients with KD and 2644 healthy individuals for variations in the protein-coding region of ORAI1. By re-sequencing the study participants’ DNA, 27 variants with minor allele frequencies (MAFs) < 0.01 that had not been examined in the previous study were identified. Although no significant association with KD was observed either in single-variant analyses or in a collapsing method analysis of the 27 variants, stratification by MAFs, variant types, and predicted deleteriousness revealed that six rare, deleterious, missense variants (MAF < 0.001, CADD C-score ≥ 20) were exclusively present in KD patients, including three refractory cases (OR = ∞, P = 0.046). The six missense variants include p.Gly98Asp, which has been demonstrated to result in gain of function leading to constitutive Ca2+ entry. Conversely, five types of frameshift variants, all identified near the N terminus and assumed to disrupt ORAI1 function, showed an opposite trend of association (OR = 0.35, P = 0.24). These findings support our hypothesis that genetic variations causing the upregulation of the Ca2+/NFAT pathway confer susceptibility to KD. Our findings also provide insights into the usefulness of stratifying the variants based on their MAFs and on the direction of the effects on protein function when conducting association studies using the gene-based collapsing method.

DOI： 10.1038/s10038-019-0588-2