Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Takuya Kiyohara Last modified date:2023.11.22

Assistant Professor / Department of Clinical Medicine / Faculty of Medical Sciences

1. Kuniyuki Nakamura, Kana Ueki, Ryu Matsuo, Takuya Kiyohara, Fumi Irie, Yoshinobu Wakisaka, Tetsuro Ago, Masahiro Kamouchi, Takanari Kitazono, Association between decreases in serum uric acid levels and unfavorable outcomes after ischemic stroke: A multicenter hospital-based observational study., PloS one, 10.1371/journal.pone.0287721, 18, 6, e0287721, 2023.06, BACKGROUND: The association between clinical outcomes in ischemic stroke patients and decreases in serum uric acid levels, which often occur during the acute phase, remains unknown. Herein, we aimed to investigate the association using a large-scale, multicenter stroke registry. METHODS: We analyzed 4,621 acute ischemic stroke patients enrolled in the Fukuoka Stroke Registry between June 2007 and September 2019 whose uric acid levels were measured at least twice during hospitalization (including on admission). The study outcomes were poor functional outcome (modified Rankin Scale score ≥3) and functional dependence (modified Rankin Scale score 3-5) at 3 months after stroke onset. Changes in uric acid levels after admission were evaluated using a decrease rate that was classified into 4 sex-specific grades ranging from G1 (no change/increase after admission) to G4 (most decreased). Multivariable logistic regression analyses were used to assess the associations between decreases in uric acid levels and the outcomes. RESULTS: The frequencies of the poor functional outcome and functional dependence were lowest in G1 and highest in G4. The odds ratios (95% confidence intervals) of G4 were significantly higher for poor functional outcome (2.66 [2.05-3.44]) and functional dependence (2.61 [2.00-3.42]) when compared with G1 after adjusting for confounding factors. We observed no heterogeneity in results for subgroups categorized according to age, sex, stroke subtype, neurological severity, chronic kidney disease, or uric acid level on admission. CONCLUSIONS: Decreases in serum uric acid levels were independently associated with unfavorable outcomes after acute ischemic stroke..
2. Masamitsu Takashima, Kuniyuki Nakamura, Takuya Kiyohara, Yoshinobu Wakisaka, Masaoki Hidaka, Hayato Takaki, Kei Yamanaka, Tomoya Shibahara, Masanori Wakisaka, Tetsuro Ago, Takanari Kitazono, Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects., Communications biology, 10.1038/s42003-022-03605-4, 5, 1, 653-653, 2022.07, Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the effects of luseogliflozin, a selective SGLT2 inhibitor, in acute ischemic stroke, using a permanent middle cerebral artery occlusion (pMCAO) model in non-diabetic mice. Pretreatment with low-dose luseogliflozin, which does not affect blood glucose levels, significantly attenuated infarct volume, blood-brain barrier disruption, and motor dysfunction after pMCAO. SGLT2 was expressed predominantly in brain pericytes and was upregulated in peri- and intra-infarct areas. Notably, luseogliflozin pretreatment reduced pericyte loss in ischemic areas. In cultured pericytes, luseogliflozin activated AMP-activated protein kinase α and increased mitochondrial transcription factor A expression and number of mitochondria, conferring resistance to oxygen-glucose deprivation. Collectively, pre-stroke inhibition of SGLT2 induces ischemic tolerance in brain pericytes independent of the glucose-lowering effect, contributing to the attenuation of ischemic brain injury..
3. Takuya Kiyohara, Yasuhiro Kumai, Tomohiro Yubi, Eiichi Ishikawa, Yoshinobu Wakisaka, Tetsuro Ago, Takanari Kitazono, Association between Early Cognitive Impairment and Short-Term Functional Outcome in Acute Ischemic Stroke., Cerebrovascular diseases (Basel, Switzerland), 10.1159/000524839, 1-7, 2022.06, BACKGROUND: Little is known about the association between poststroke cognitive impairment (PSCI) and functional outcome in the acute care phase of ischemic stroke and the influence of the clinical condition of acute stroke on this association. We examined this issue, taking into account stroke-related factors, in a hospital-based prospective study of patients with acute ischemic stroke. The same analysis was also performed after subsequent rehabilitation to investigate whether the association observed in the acute care phase persisted after that. For comparison, the same analysis was performed for pre-stroke dementia (PreSD). METHODS: We included in the study a total of 923 patients with acute ischemic stroke who were admitted to a hospital from 2012 to 2020 in Japan. Cognitive function was assessed using the Mini-Mental State Examination and Raven's Colored Progressive Matrices test at an average of 6.3 days after stroke onset. The subjects were divided into three groups with normal cognition, PSCI, and PreSD. Study outcome was a poor functional outcome, defined as a modified Rankin Scale score of ≥3 at the end of acute care (median 21 days after admission). Among total subjects, 460 were also assessed for poor functional outcome after rehabilitation (median 77 days after admission). A logistic regression model was applied in this study. RESULTS: Patients with PSCI and PreSD had higher median National Institute of Health Stroke Scale scores than those with normal cognition (median [IQR]: 3 [2-6], 4 [2-12], and 2 [1-4], respectively). The age- and sex-adjusted cumulative incidence of poor functional outcome was significantly higher in patients with PSCI and PreSD than in those with normal cognition in the acute care and rehabilitation phases. In the acute care phase, these associations remained significant after adjustment for stroke-related factors and other confounders (multivariable-adjusted odds ratio [95% CI] for PSCI vs. normal cognition: 3.28 [2.07-5.20]; for PreSD: 2.39 [1.40-4.08]). Similar results were observed in the rehabilitation phase (for PSCI: 2.48 [1.31-4.70]; for PreSD: 3.92 [1.94-7.92]). CONCLUSIONS: Our findings suggest that PSCI, as well as PreSD, is possibly associated with the development of poor functional outcome in the acute care phase of ischemic stroke, and this association continues thereafter..
4. Takuya Kiyohara, Tetsuro Ago, Can calcium channel blockers prevent ischemic stroke in nonvalvular atrial fibrillation patients?-the optimal choice of antihypertensive drug for subtype-specific stroke prevention., Hypertension research : official journal of the Japanese Society of Hypertension, 10.1038/s41440-022-00907-2, 45, 6, 1076-1078, 2022.06.
5. Kei Miyano, Shuichiro Okamoto, Akira Yamauchi, Chikage Kawai, Mizuho Kajikawa, Takuya Kiyohara, Momoe Itsumi, Masahiko Taura, Futoshi Kuribayashi, The downregulation of NADPH oxidase Nox4 during hypoxia in hemangioendothelioma cells: a possible role of p22phox on Nox4 protein stability, Free Radical Research, 10.1080/10715762.2021.2009116, 55, 9-10, 996-1004, 2021.10, NADPH oxidase (Nox) 4 produces H2O2 by forming a heterodimer with p22phox and is involved in hemangioendothelioma development through monocyte chemoattractant protein-1 (MCP-1) upregulation. Here, we show that Nox4 protein levels were maintained by p22phox in hemangioendothelioma cells and Nox4 protein stability was dependent on p22phox coexpression. Conversely, the degradation of Nox4 monomer was enhanced by p22phox knockdown. Under hypoxic conditions in hemangioendothelioma cells, p22phox was downregulated at the mRNA and protein levels. Downregulation of p22phox protein resulted in the enhanced degradation of Nox4 protein in hypoxia-treated hemangioendothelioma cells. In contrast, Nox2, a Nox isoform, was not altered at the protein level under hypoxic conditions. Nox2 exhibited a higher affinity for p22phox compared with Nox4, suggesting that when coexpressed with Nox4 in the same cells, Nox2 acts as a competitor. Nox2 knockdown restored Nox4 protein levels partially reduced by hypoxic treatment. Thus, Nox4 protein levels were attenuated in hypoxia-treated cells resulting from p22phox depletion. MCP-1 secretion was decreased concurrently with hypoxia-induced Nox4 downregulation compared with that under normoxia..
6. Takuya Kiyohara, Ryu Matsuo, Jun Hata, Kuniyuki Nakamura, Yoshinobu Wakisaka, Masahiro Kamouchi, Takanari Kitazono, Tetsuro Ago, Takao Ishitsuka, Setsuro Ibayashi, Kenji Kusuda, Kenichiro Fujii, Tetsuhiko Nagao, Yasushi Okada, Masahiro Yasaka, Ooboshi Hiroaki, Tsuyoshi Omae, Kazunori Toyoda, Hiroshi Nakane, Hiroshi Sugimori, Shuji Arakawa, Kenji Fukuda, Jiro Kitayama, Shigeru Fujimoto, Shoji Arihiro, Junya Kuroda, Yoshihisa Fukushima, Yasuhiro Kumai, Ryu Matsuo, β-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke, Stroke, 10.1161/STROKEAHA.120.031392, 52, 8, 2621-2628, 2021.08, [Figure: see text]..
7. Kei Miyano, Shuichiro Okamoto, Akira Yamauchi, Chikage Kawai, Mizuho Kajikawa, Takuya Kiyohara, Minoru Tamura, Masahiko Taura, Futoshi Kuribayashi, The NADPH oxidase NOX4 promotes the directed migration of endothelial cells by stabilizing vascular endothelial growth factor receptor 2 protein, Journal of Biological Chemistry, 10.1074/jbc.RA120.014723, 295, 33, 11877-11890, 2020.08.
8. Takuya Kiyohara, Tadataka Mizoguchi, Junya Kuroda, Yoshinobu Wakisaka, Aya Irie, Chie Kitaoka, Kiichiro Fujisaki, Udai Nakamura, Kazuhiko Tsuruya, Takanari Kitazono, Tetsuro Ago, Repeated Paradoxical Brain Infarctions in a Patient on Self-Managed Home Hemodialysis Using a Long-Term Indwelling Catheter, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2017.06.004, 26, 9, e183-e185, 2017.09, We describe the case of a 51-year-old Japanese man with an end-stage kidney disease caused by a 30-year history of type 1 diabetes mellitus. The patient had suffered repeated bilateral multiple brain infarctions within a short period of time after the initiation of a self-managed daily home hemodialysis regimen using a long-term indwelling catheter inserted into the right atrium. Despite extensive examinations, we could not find any embolic causes except for the catheter and a patent foramen ovale (PFO). The patient had experienced repeated brain infarctions under antiplatelet and anticoagulation therapies, but suffered no further brain infarctions after the removal of the catheter and the alteration of vascular access from the catheter to an arteriovenous fistula in the forearm. We speculate that the indwelling catheter-associated thrombi or air and the right-to-left shunt through the PFO may have caused the repeated paradoxical brain embolisms in this patient..
9. Takuya Kiyohara, Masahiro Kamouchi, Yasuhiro Kumai, Toshiharu Ninomiya, Jun Hata, Sohei Yoshimura, Tetsuro Ago, Yasushi Okada, Takanari Kitazono, Takao Ishitsuka, Shigeru Fujimoto, Setsuro Ibayashi, Kenji Kusuda, Shuji Arakawa, Kinya Tamaki, Seizo Sadoshima, Katsumi Irie, Kenichiro Fujii, Yasushi Okada, Masahiro Yasaka, Tetsuhiko Nagao, Hiroaki Ooboshi, Tsuyoshi Omae, Kazunori Toyoda, Hiroshi Nakane, Hiroshi Sugimori, Kenji Fukuda, Ryu Matsuo, Junya Kuroda, Yoshihisa Fukushima, ABCD3 and ABCD3-I Scores Are Superior to ABCD2 Score in the Prediction of Short- and Long-Term Risks of Stroke After Transient Ischemic Attack, Stroke, 10.1161/strokeaha.113.003077, 45, 2, 418-425, 2014.02, Background and Purpose—

Several risk scores have been developed to predict the stroke risk after transient ischemic attack (TIA). However, the validation of these scores in different cohorts is still limited. The objective of this study was to elucidate whether these scores were able to predict short-term and long-term risks of stroke in patients with TIA.


From the Fukuoka Stroke Registry, 693 patients with TIA were followed up for 3 years. Multivariable-adjusted Cox proportional hazards model was used to assess the hazard ratio of risk factors for stroke. The discriminatory ability of each risk score for incident stroke was estimated by using C-statistics and continuous net reclassification improvement.


The multivariable-adjusted Cox proportional hazards model revealed that dual TIA and carotid stenosis were both significant predictors for stroke after TIA, whereas abnormal diffusion-weighted image was not. ABCD3 (C-statistics 0.61) and ABCD3-I (C-statistics 0.66) scores improved the short-term predictive ability for stroke (at 7 days) compared with the ABCD2 score (C-statistics 0.54). Addition of intracranial arterial stenosis (at 3 years, continuous net reclassification improvement 30.5%; P

The present study demonstrates that ABCD3 and ABCD3-I scores are superior to the ABCD2 score for the prediction of subsequent stroke in patients with TIA. Addition of neuroimaging in the ABCD3 score may enable prediction of long-term stroke risk after TIA..