Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Kouta Funakoshi Last modified date:2023.11.19

Assistant Professor / Center for Clinical and Translational Research(CCTR) / Kyushu University Hospital


Papers
1. Marie Amitani, Haruka Amitani, Tetsuhiro Owaki, Takako Monuki, Satomi Adachi, Suguru Kawazu, Takamasa Fukumoto, Hajime Suzuki, Takuya Yoshimura, Kimiko Mizuma, Yuko Nishida, Hiroko Watanabe, Masayuki Hirose, Kouta Funakoshi, Keiko Ota, Kenta Murotani, Akihiro Asakawa, The Effect of Mindfulness Yoga in Children With School Refusal: A Study Protocol for an Exploratory, Cluster-Randomized, Open, Standard Care-Controlled, Multicenter Clinical Trial., Frontiers in public health, 10.3389/fpubh.2022.881303, 10, 881303-881303, 2022.07, BACKGROUND: School refusal occurs in about 1-2% of young people. Anxiety and depression are considered to be the most common emotional difficulties for children who do not attend school. However, at present, no definitive treatment has been established for school refusal, although interventions such as cognitive behavioral therapy have been used. This paper reports a protocol for a cluster-randomized controlled trial of a mindfulness yoga intervention for children with school refusal. METHODS: This study is a multicenter, exploratory, open cluster-randomized controlled trial. This study will recruit children aged 10-15 years with school refusal. After a 2-week baseline, participants for each cluster will be randomly assigned to one of two groups: with or without mindfulness yoga for 4 weeks. Mindfulness yoga will be created for schoolchildren for this protocol and distributed to the participants on DVD. The primary outcome is anxiety among children with school refusal using the Spence Children's Anxiety Scale-Children. DISCUSSION: For this study, we developed a mindfulness yoga program and protocol, and examine whether mindfulness yoga can improve anxiety in children with school refusal. Our mindfulness yoga program was developed based on the opinions of children of the same age, and is a program that children can continue to do every day without getting bored. In this way, we believe that we can contribute to the smooth implementation of support to reduce the anxiety of children with school refusal, and to the reduction of the number of children who refuse to go to school..
2. Mosaburo Kainuma, Shinji Ouma, Shinobu Kawakatsu, Osamu Iritani, Ken-Ichiro Yamashita, Tomoyuki Ohara, Shigeki Hirano, Shiro Suda, Tadanori Hamano, Sotaro Hieda, Masaaki Yasui, Aoi Yoshiiwa, Seiji Shiota, Masaya Hironishi, Kenji Wada-Isoe, Daiki Sasabayashi, Sho Yamasaki, Masayuki Murata, Kouta Funakoshi, Kouji Hayashi, Norimichi Shirafuji, Hirohito Sasaki, Yoshinori Kajimoto, Yukiko Mori, Michio Suzuki, Hidefumi Ito, Kenjiro Ono, Yoshio Tsuboi, An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease., Frontiers in pharmacology, 10.3389/fphar.2022.991982, 13, 991982-991982, 2022.10, Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018..
3. Kisho Ohtani, Kensuke Egashira, Kaku Nakano, Gang Zhao, Kouta Funakoshi, Yoshiko Ihara, Satoshi Kimura, Ryuji Tominaga, Ryuichi Morishita, Kenji Sunagawa, Stent-based local delivery of nuclear factor-kappaB decoy attenuates in-stent restenosis in hypercholesterolemic rabbits., Circulation, 114, 25, 2773-9, 2006.12, BACKGROUND: Nuclear factor-kappaB (NF-kappaB) plays a critical role in the vascular response to injury. However, the role of NF-kappaB in the mechanism of in-stent restenosis remains unclear. We therefore tested the hypothesis that blockade of NF-kappaB by stent-based delivery of a cis-element "decoy" of NF-kappaB reduces in-stent neointimal formation. METHODS AND RESULTS: Stents were coated with a polymer containing or not containing NF-kappaB decoy, which represented a fast-release formulation (
4. Kisho Ohtani, Kensuke Egashira, Yoshiko Ihara, Kaku Nakano, Kouta Funakoshi, Gang Zhao, Masataka Sata, Kenji Sunagawa, Angiotensin II type 1 receptor blockade attenuates in-stent restenosis by inhibiting inflammation and progenitor cells., Hypertension (Dallas, Tex. : 1979), 48, 4, 664-70, 2006.10, The precise mechanism by which angiotensin II type 1 receptor blocker reduces in-stent restenosis in clinical trials is unclear. We, therefore, investigated the mechanism of in-stent neointima formation. Male cynomolgus monkeys and rabbits were fed a high-cholesterol diet and were allocated to untreated control and type 1 receptor blocker groups. Five days after grouping, multilink stents were implanted in the iliac artery. The type 1 receptor blocker reduced the development of in-stent neointima formation by approximately 30% in rabbits and monkeys. To investigate potential mechanisms, we examined the expression of renin-angiotensin system markers, all of which increased in monocytes and smooth muscle-like cells in the neointima and media within 7 days. The type 1 receptor blocker attenuated increased oxidative stress, the enhanced expression of markers of the rennin-angiotensin system and monocyte chemoattractant protein-1, and macrophage infiltration. The effects of type 1 receptor blocker on the differentiation of peripheral blood mononuclear cells into vascular progenitor cells were also examined. Treatment with type 1 receptor blocker suppressed the enhanced differentiation to smooth muscle progenitor cells induced by stenting. The type 1 receptor blocker attenuated in-stent neointima formation by inhibiting redox-sensitive inflammatory changes and by reducing recruitment of the progenitor cells. These potential actions of type 1 receptor blocker on inflammation and progenitor cells constitute a novel mechanism of suppression of in-stent restenosis by type 1 receptor blocker..
5. Kensuke Egashira, Kaku Nakano, Kisho Ohtani, Kouta Funakoshi, Gang Zhao, Yoshiko Ihara, Jun-Ichiro Koga, Satoshi Kimura, Ryuji Tominaga, Kenji Sunagawa, Local delivery of anti-monocyte chemoattractant protein-1 by gene-eluting stents attenuates in-stent stenosis in rabbits and monkeys., Arteriosclerosis, thrombosis, and vascular biology, 27, 12, 2563-8, 2007.12, OBJECTIVE: We have previously shown that the intramuscular transfer of the anti-monocyte chemoattractant protein-1 (MCP-1) gene (called 7ND) is able to prevent experimental restenosis. The aim of this study was to determine the in vivo efficacy and safety of local delivery of 7ND gene via the gene-eluting stent in reducing in-stent neointima formation in rabbits and in cynomolgus monkeys. METHODS AND RESULTS: We here found that in vitro, 7ND effectively inhibited the chemotaxis of mononuclear leukocytes and also inhibited the proliferation/migration of vascular smooth muscle cells. We then coated stents with a biocompatible polymer containing a plasmid bearing the 7ND gene, and deployed these stents in the iliac arteries of rabbits and monkeys. 7ND gene-eluting stents attenuated stent-associated monocyte infiltration and neointima formation after one month in rabbits, and showed long-term inhibitory effects on neointima formation when assessments were carried out at 1, 3, and 6 months in monkeys. CONCLUSIONS: Strategy of inhibiting the action of MCP-1 with a 7ND gene-eluting stent reduced in-stent neointima formation with no evidence of adverse effects in rabbits and monkeys. The 7ND gene-eluting stent could be a promising therapy for treatment of restenosis in humans..
6. Kaku Nakano, Kensuke Egashira, Seigo Masuda, Kouta Funakoshi, Gang Zhao, Satoshi Kimura, Tetsuya Matoba, Katsuo Sueishi, Yasuhisa Endo, Yoshiaki Kawashima, Kaori Hara, Hiroyuki Tsujimoto, Ryuji Tominaga, Kenji Sunagawa, Formulation of nanoparticle-eluting stents by a cationic electrodeposition coating technology: efficient nano-drug delivery via bioabsorbable polymeric nanoparticle-eluting stents in porcine coronary arteries., JACC. Cardiovascular interventions, 10.1016/j.jcin.2008.08.023, 2, 4, 277-83, 2009.04, OBJECTIVES: The objective of this study was to formulate a nanoparticle (NP)-eluting drug delivery stent system by a cationic electrodeposition coating technology. BACKGROUND: Nanoparticle-mediated drug delivery systems (DDS) are poised to transform the development of innovative therapeutic devices. Therefore, we hypothesized that a bioabsorbable polymeric NP-eluting stent provides an efficient DDS that shows better and more prolonged delivery compared with dip-coating stent. METHODS: We prepared cationic NP encapsulated with a fluorescence marker (FITC) by emulsion solvent diffusion method, succeeded to formulate an NP-eluting stent with a novel cation electrodeposition coating technology, and compared the in vitro and in vivo characteristics of the FITC-loaded NP-eluting stent with dip-coated FITC-eluting stent and bare metal stent. RESULTS: The NP was taken up stably and efficiently by cultured vascular smooth muscle cells in vitro. In a porcine coronary artery model in vivo, substantial FITC fluorescence was observed in neointimal and medial layers of the stented segments that had received the FITC-NP-eluting stent until 4 weeks. In contrast, no substantial FITC fluorescence was observed in the segments from the polymer-based FITC-eluting stent or from bare metal stent. The magnitudes of stent-induced injury, inflammation, endothelial recovery, and neointima formation were comparable between bare metal stent and NP-eluting stent groups. CONCLUSIONS: Therefore, this NP-eluting stent is an efficient NP-mediated DDS that holds as an innovative platform for the delivery of less invasive nano-devices targeting cardiovascular disease..
7. Kouta Funakoshi, Kazuya Hosokawa, Atsushi Tanaka, Takafumi Sakamoto, Ken Onitsuka, Kazuo Sakamoto, Tomoyuki Tobushi, Takeo Fujino, Keita Saku, Yoshinori Murayama, Tomomi Ide, Kenji Sunagawa, Baroreflex failure may play a major role in the pathogenesis of heart failure with preserved ejection fraction, FASEB JOURNAL, 25, 2011.04.
8. Kouta Funakoshi, Kazuya Hosokawa, Atsushi Tanaka, Takafumi Sakamoto, Ken Onitsuka, Kazuo Sakamoto, Tomoyuki Tobushi, Takeo Fujino, Keita Saku, Yoshinori Murayama, Tomomi Ide, Kenji Sunagawa, Baroreflex Failure Induces Striking Volume Intolerance In A Rat Model With Normal Left Ventricular Function, CIRCULATION, 124, 21, 2011.11.
9. Kazuya Hosokawa, Kouta Funakoshi, Atsushi Tanaka, Takafumi Sakamoto, Ken Onitsuka, Kazuo Sakamoto, Tomoyuki Tobushi, Takeo Fujino, Tomomi Ide, Kenji Sunagawa, Artificial Baroreflex System Restores Volume Buffering Function in the Baroreflex Failure Irrespective of Left Ventricular Systolic Function, FASEB JOURNAL, 25, 2011.04.
10. Kazuya Hosokawa, Kouta Funakoshi, Takafumi Sakamoto, Ken Onitsuka, Kazuo Sakamoto, Tomoyuki Tobushi, Fujino Takeo, Keita Saku, Yoshinori Murayama, Tomomi Ide, Kenji Sunagawa, Artificial Baroreceptor Fully Antagonizes Baroreflex Failure Induced Volume Intolerance, CIRCULATION, 124, 21, 2011.11.
11. Hideharu Tomita, Toshiaki Kadokami, Hidetoshi Momii, Natsumi Kawamura, Masayoshi Yoshida, Tetsuji Inou, Yutaka Fukuizumi, Makoto Usui, Kouta Funakoshi, Satoshi Yamada, Tohru Aomori, Koujiro Yamamoto, Tsukasa Uno, Shin-Ichi Ando, Patient factors against stable control of warfarin therapy for Japanese non-valvular atrial fibrillation patients., Thrombosis research, 10.1016/j.thromres.2013.09.003, 132, 5, 537-42, 2013.11, INTRODUCTION: Effectiveness and safety of warfarin therapy for non-valvular atrial fibrillation (NVAF) patients are strongly associated with its stability presented such as time in therapeutic range (TTR) of PT-INR. However, the factors that affect TTR have not been fully elucidated in Japan where majority of patients are controlled within the range of 1.6-2.6 of PT-INR irrespective of the age. METHODS: We retrospectively analyzed 163 NVAF patients taking warfarin to determine the factors that affect TTR including metabolic enzymes polymorphisms after TTR calculation with both the standard PT-INR range and the actual control range of 1.6-2.6. RESULTS: Overall TTR calculated using Japanese Guideline was 69.7 ± 25.1% (
12. Kouta Funakoshi, Kazuya Hosokawa, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Striking volume intolerance is induced by mimicking arterial baroreflex failure in normal left ventricular function., Journal of cardiac failure, 10.1016/j.cardfail.2013.11.007, 20, 1, 53-9, 2014.01, BACKGROUND: Patients with heart failure and preserved ejection fraction (HFpEF) are supersensitive to volume overload, and a striking increase in left atrial pressure (LAP) often occurs transiently and is rapidly resolved by intravascular volume reduction. The arterial baroreflex is a powerful regulator of intravascular stressed blood volume. We examined whether arterial baroreflex failure (FAIL) mimicked by constant carotid sinus pressure (CSP) causes a striking increase in LAP and systemic arterial pressure (AP) by volume loading in rats with normal left ventricular (LV) function. METHODS AND RESULTS: In anesthetized Sprague-Dawley rats, we isolated bilateral carotid sinuses and controlled CSP by a servo-controlled piston pump. We mimicked the normal arterial baroreflex by matching CSP to instantaneous AP and FAIL by maintaining CSP at a constant value regardless of AP. We infused dextran stepwise (infused volume [Vi]) until LAP reached 15 mm Hg and obtained the LAP-Vi relationship. We estimated the critical Vi as the Vi at which LAP reached 20 mm Hg. In FAIL, critical Vi decreased markedly from 19.4 ± 1.6 mL/kg to 15.6 ± 1.6 mL/kg (P
13. Hidetaka Kaku, Tomomi Ide, Kouta Funakoshi, Takeo Fujino, Shouji Matsushima, Kisho Ohtani, Taiki Higo, Hiroyuki Tsutsui, The Impact of Hospital Practice Factors on Early Outcomes in Patients Hospitalized for Heart Failure in Japan, CIRCULATION, 138, 2018.11, 0.
14. George Umemoto, Hideo Toyoshima, Yuji Yamaguchi, Naoko Aoyagi, Chikara Yoshimura, Kouta Funakoshi, Therapeutic Efficacy of Twin-Block and Fixed Oral Appliances in Patients with Obstructive Sleep Apnea Syndrome., Journal of prosthodontics : official journal of the American College of Prosthodontists, 10.1111/jopr.12619, 28, 2, e830-e836, 2019.02, PURPOSE: To compare the efficacy of twin-block (i.e., allows mouth opening) and fixed (i.e., maintains mouth closure) mandibular advancement splints (MASs) for the treatment of obstructive sleep apnea-hypopnea syndrome (OSA). MATERIALS AND METHODS: From 2011 to 2013, 23 patients with OSA in the twin-block group, and from 2013 to 2015, 29 patients in the fixed MAS group were included. All patients underwent polysomnography before and after 3 months of treatment. The two sets of polysomnographic and cephalometric variables were compared. RESULTS: A significant difference (p
15. Kisho Ohtani, Takeo Fujino, Tomomi Ide, Kouta Funakoshi, Ichirou Sakamoto, Ken-Ichi Hiasa, Taiki Higo, Kenjiro Kamezaki, Koichi Akashi, Hiroyuki Tsutsui, Recovery from left ventricular dysfunction was associated with the early introduction of heart failure medical treatment in cancer patients with anthracycline-induced cardiotoxicity., Clinical research in cardiology : official journal of the German Cardiac Society, 10.1007/s00392-018-1386-0, 108, 6, 600-611, 2019.06, BACKGROUND: Left ventricular (LV) dysfunction due to anthracycline-induced cardiotoxicity (AIC) has been believed to be irreversible. However, this has not been confirmed and standard medical treatment for heart failure (HF) including renin-angiotensin inhibitors and β-blockers may lead to its recovery. METHODS AND RESULTS: We thus retrospectively studied 350 cancer patients receiving anthracycline-based chemotherapy from 2001 to 2015 in our institution. Fifty-two patients (14.9%) developed AIC with a decrease in LV ejection fraction (LVEF) of 24.1% at a median time of 6 months [interquartile range (IQR) 4-22 months] after anthracycline therapy. By multivariate analysis, AIC was independently associated with cardiac comorbidities including ischemic heart disease, valvular heart disease, arrhythmia, and cardiomyopathy [odds ratio (OR) 6.00; 95% confidence interval (CI) 2.27-15.84, P = 0.00044), lower baseline LVEF (OR per 1% 1.09; 95% CI 1.04-1.14, P = 0.00034). During the median follow-up of 3.2 years, LV systolic dysfunction recovered among 33 patients (67.3%) with a median time of 4 months (IQR 2-6 months), which was independently associated with the introduction of standard medical treatment for HF (OR 9.39; 95% CI 2.27-52.9, P = 0.0014) by multivariate analysis. CONCLUSION: Early initiation of standard medical treatment for HF may lead to LV functional recovery in AIC..
16. Mosaburo Kainuma, Kouta Funakoshi, Shinji Ouma, Ken-Ichiro Yamashita, Tomoyuki Ohara, Aoi Yoshiiwa, Masayuki Murata, Yoshio Tsuboi, The efficacy and safety of hachimijiogan for mild Alzheimer disease in an exploratory, open standard treatment controlled, randomized allocation, multicenter trial: A study protocol., Medicine, 10.1097/MD.0000000000022370, 99, 38, e22370, 2020.09, BACKGROUND: Dementia among the Japanese aged 65 years or over population is estimated to approach about 700 million cases by 2025, and a corresponding rapid increase in Alzheimer disease (AD) can also be expected. The ballooning number of dementia patients, including AD, is creating major medical and social challenges. At present, only 3 drugs are recognized for the treatment of mild AD, and these are only used to alleviate symptoms. Although new therapies are needed to treat mild AD, insufficient development of disease-modifying drugs is being done. METHODS/DESIGN: The aim of this exploratory, open standard, treatment-controlled, randomized allocation, multicenter trial is to determine the efficacy of the traditional Japanese Kampo medicine hachimijiogan (HJG) on the cognitive dysfunction of mild AD.Eighty-six patients with AD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 and as mild AD according to the Mini Mental State Examination (MMSE ≥21) will be included. All will already have been taking the same dose of Donepezil, Galantamine, or Rivastigmine for more than 3 months. The patients will be randomly assigned to receive additional treatment with HJG or to continue mild AD treatment without additional HJG. The primary endpoint is the change from baseline of the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version (ADAS-Jcog). ADAS-Jcog is a useful index for detecting change over time that investigates memory and visuospatial cognition injury from the early stage. The secondary endpoints are the changes from baseline of the Instrumental Activity of Daily Life, Apathy scale, and Nueropsychiatric Inventory scores. In this protocol, we will examine the Geriatric depression scale and do Metabolome analysis as exploratory endpoints. The recruitment period will be from August 2019 to July 2021. DISCUSSION: This is the first trial of Kampo medicine designed to examine the efficacy of HJG for the cognitive dysfunction of patients with mild AD. TRIAL REGISTRATION: This trial was registered on the Japan Registry of Clinical trials on 2 August 2, 2019 (jRCTs 071190018)..
17. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, Sex Differences on Time-dependent Changes in Brain-type Natriuretic Peptide Among Patients With Hypertrophic Cardiomyopathy, CIRCULATION, 10.1161/circ.142.suppl_3.14550, 142, 2020.11, 0.
18. Tomoyuki Tobushi, Kazuyuki Matsushita, Kouta Funakoshi, Kazuhiro Sakai, Manabu Akamatsu, Yasuko Yoshioka, Takeshi Tohyama, Masayuki Hirose, Ryo Nakamura, Toshiaki Kadokami, Shin-Ichi Ando, Local temperature control improves the accuracy of cardiac output estimation using lung-to-finger circulation time after breath holding., Physiological reports, 10.14814/phy2.14632, 8, 21, e14632, 2020.11, As timely measurement of the cardiac index (CI) is one of the key elements in heart failure management, a noninvasive, simple, and inexpensive method of estimating CI is keenly needed. We attempted to develop a new device that can estimate CI from the data of lung-to-finger circulation time (LFCT) obtained after a brief breath hold in the awake state. First, we attempted to estimate CI from the LFCT value by utilizing the correlation between 1/LFCT and CI estimated with MRI. Although we could obtain LFCT from 45 of 53 patients with cardiovascular diseases, we could not find the anticipated relation between 1/LFCT and CI. However, we realized that when we adopted only LFCT from patients with a finger temperature of ≥31°C, we could obtain a consistent and clear correlation with CI (correlation coefficient, r = .81). Thus, we next measured LFCT before and after warming the forearm. We found that LFCT decreased after the local temperature increased (from 27.5 ± 13.6 to 18.4 ± 5.3 s, p 
19. Hidetaka Kaku, Kouta Funakoshi, Tomomi Ide, Takeo Fujino, Shouji Matsushima, Kisho Ohtani, Taiki Higo, Michikazu Nakai, Yoko Sumita, Kunihiro Nishimura, Yoshihiro Miyamoto, Toshihisa Anzai, Hiroyuki Tsutsui, Impact of Hospital Practice Factors on Mortality in Patients Hospitalized for Heart Failure in Japan - An Analysis of a Large Number of Health Records From a Nationwide Claims-Based Database, the JROAD-DPC., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-19-0759, 84, 5, 742-753, 2020.04, BACKGROUND: An inverse relationship exists between hospital case volume and mortality in patients with heart failure (HF). However, hospital performance factors associated with mortality in HF patients have not been examined. We aimed to identify these using exploratory factor analysis and assess the relationship between these factors and 7-day, 30-day, and in-hospital mortality among HF patients in Japan.Methods and Results:We analyzed the records of 198,861 patients admitted to 683 certified hospitals of the Japanese Circulation Society between 2012 and 2014. Records were obtained from the nationwide database of the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). Using exploratory factor analysis, 90 hospital survey items were grouped into 5 factors, according to their collinearity: "Interventional cardiology", "Cardiovascular surgery", "Pediatric cardiology", "Electrophysiology" and "Cardiac rehabilitation". Multivariable logistic regression analysis was performed to determine the association between these factors and mortality. The 30-day mortality was 8.0%. Multivariable logistic regression analysis showed the "Pediatric cardiology" (odds ratio (OR) 0.677, 95% confidence interval [CI]: 0.628-0.729, P
20. Elizabeth A Hill, Hiroyuki Sawatari, Mari K Nishizaka, Donna M Fairley, Akiko Chishaki, Kouta Funakoshi, Renata L Riha, Shin-Ichi Ando, A Cross-Sectional Comparison of the Prevalence of Obstructive Sleep Apnea Symptoms in Adults With Down Syndrome in Scotland and Japan., American journal on intellectual and developmental disabilities, 10.1352/1944-7558-125.4.260, 125, 4, 260-273, 2020.07, Small studies in Western populations report a high prevalence of obstructive sleep apnea (OSA) in adults with Down syndrome. To date, ethnic differences have not been explored. A questionnaire sent to 2,752 adults with Down syndrome aged ≥16 years in Scotland and Japan (789 valid responses) estimated OSA prevalence based on reported symptoms. Symptoms were common in both countries, with snoring (p = 0.001) and arousals (p = 0.04) more prevalent in Japan. Estimated OSA prevalence in adults with Down syndrome was similar in the two countries, and raised in comparison with the general adult population (19.6% in Scotland and 14.3% in Japan; p = 0.08), though BMI was a confounder. Identification and treatment of OSA is recommended in adults with Down syndrome, regardless of ethnicity..
21. Kazuhiro Shirozu, Keiko Nobukuni, Kouta Funakoshi, Taizo Nakamura, Makoto Sumie, Midoriko Higashi, Ken Yamaura, The effect of remimazolam on postoperative memory retention and delayed regeneration in breast surgery patients: Rationale and design of an exploratory, randomized, open, propofol-controlled, single-center clinical trial: A study protocol., Medicine, 10.1097/MD.0000000000027808, 100, 48, e27808, 2021.12, BACKGROUND: Remimazolam, a benzodiazepine ultra-short-acting sedative, has been used in general anesthesia since August 2020. It is used in awake surgeries that require awakening the patient in the middle of the surgery because of its rapid awakening effect as well as antagonistic interactions. If remimazolam has associated anterograde amnesia similar to benzodiazepines, it will have a positive effect on preventing psychological trauma. However, to our knowledge, the effect of remimazolam on anterograde amnesia has not been previously examined. METHODS/DESIGN: The aim of this exploratory, open, propofol-controlled, single-center, randomized clinical trial is to examine the effect of remimazolam on postoperative memory retention and delayed regeneration. Seventy patients undergoing breast surgery will be included in the study. The patients will be randomly assigned to receive propofol or remimazolam as sedatives during surgery. The primary endpoint is the number of posters patients remember 24 hours after surgery (among 4 posters shown after awakening from anesthesia) as an assessment of anterograde amnesia. Secondary endpoints are retrograde amnesia, dose of analgesic given from the time the patient returns to the ward until 24 hours after surgery, immediate postoperative pain numerical rating scale scores, and pain numerical rating scale scores 24 hours after leaving the operating room. Recruitment will take place between October 2021 and March 2022 to achieve the target sample size. DISCUSSION: To our knowledge, this is the first trial designed to examine the effects of remimazolam on postoperative memory retention and delayed regeneration in patients undergoing breast surgery. TRIAL REGISTRATION: This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center on September 28, 2021 (UMIN-CTR: UMIN000045593)..
22. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, The Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers Is Associated with the Recovered Ejection Fraction in Patients with Dilated Cardiomyopathy., International heart journal, 10.1536/ihj.20-671, 62, 4, 801-810, 2021.07, Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) have been shown to prevent left ventricular remodeling and improve outcomes of patients with heart failure (HF). This study aimed to investigate whether the use of ACEi/ARB could be associated with HF with recovered ejection fraction (HFrecEF) in patients with dilated cardiomyopathy (DCM).We collected individual patient data regarding demographics, echocardiogram, and treatment in DCM between 2003 and 2014 from the clinical personal record, a national database of the Japanese Ministry of Health, Labour and Welfare. Patients with left ventricular ejection fraction (LVEF)
23. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, Sex Differences in Time-Dependent Changes in B-Type Natriuretic Peptide in Hypertrophic Cardiomyopathy., Circulation reports, 10.1253/circrep.CR-21-0110, 3, 10, 594-603, 2021.10, Background: Female sex is reported to be associated with poor prognosis in hypertrophic cardiomyopathy (HCM). The plasma B-type natriuretic peptide (BNP) concentration is a prognostic predictor in HCM. However, the effect of sex on BNP concentrations remains unclear among HCM patients. Methods and Results: Patient records in the Clinical Personal Records of HCM national database of the Japanese Ministry of Health, Labour and Welfare from 2009 to 2014 were analyzed. Of 3,570 HCM patients, 611 in whom BNP concentrations were assessed at both baseline and the 2-year follow-up were included in this analysis. The mean age was 60.4 years and 254 (41.6%) patients were female. Median (interquartile range) BNP concentrations were higher in females than males at both baseline (320.3 [159.0-583.1] vs. 182.8 [86.1-363.9] pg/mL; P
24. Takeshi Tohyama, Tomomi Ide, Masataka Ikeda, Hidetaka Kaku, Nobuyuki Enzan, Shouji Matsushima, Kouta Funakoshi, Junji Kishimoto, Koji Todaka, Hiroyuki Tsutsui, Machine learning-based model for predicting 1 year mortality of hospitalized patients with heart failure., ESC heart failure, 10.1002/ehf2.13556, 8, 5, 4077-4085, 2021.10, AIMS: Individual risk stratification is a fundamental strategy in managing patients with heart failure (HF). Artificial intelligence, particularly machine learning (ML), can develop superior models for predicting the prognosis of HF patients, and administrative claim data (ACD) are suitable for ML analysis because ACD is a structured database. The objective of this study was to analyse ACD using an ML algorithm, predict the 1 year mortality of patients with HF, and finally develop an easy-to-use prediction model with high accuracy using the top predictors identified by the ML algorithm. METHODS AND RESULTS: Machine learning-based prognostic prediction models were developed from the ACD on 10 175 HF patients from the Japanese Registry of Acute Decompensated Heart Failure with 17% mortality during 1 year follow-up. The top predictors for prognosis in HF were identified by the permutation feature importance technique, and an easy-to-use prediction model was developed based on these predictors. The c-statistics and Brier scores of the developed ML-based models were compared with those of conventional risk models: Seattle Heart Failure Model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). A voting classifier algorithm (ACD-VC) achieved the highest c-statistics among the six ML algorithms. The permutation feature importance technique enabled identification of the top predictors such as Barthel index, age, body mass index, duration of hospitalization, last hospitalization, renal disease, and non-loop diuretics use (feature importance values were 0.054, 0.025, 0.010, 0.005, 0.005, 0.004, and 0.004, respectively). Upon combination of some of the predictors that can be assessed from a brief interview, the Simple Model by ARTificial intelligence for HF risk stratification (SMART-HF) was established as an easy-to-use prediction model. Compared with the conventional models, SMART-HF achieved a higher c-statistic {ACD-VC: 0.777 [95% confidence interval (CI) 0.751-0.803], SMART-HF: 0.765 [95% CI 0.739-0.791], SHFM: 0.713 [95% CI 0.684-0.742], MAGGIC: 0.726 [95% CI 0.698-0.753]} and better Brier scores (ACD-VC: 0.121, SMART-HF: 0.124, SHFM: 0.139, MAGGIC: 0.130). CONCLUSIONS: The ML model based on ACD predicted the 1 year mortality of HF patients with high accuracy, and SMART-HF along with the ML model achieved superior performance to that of the conventional risk models. The SMART-HF model has the clear merit of easy operability even by non-healthcare providers with a user-friendly online interface (https://hfriskcalculator.herokuapp.com/). Risk models developed using SMART-HF may provide a novel modality for risk stratification of patients with HF..
25. Tomoyuki Tobushi, Takatoshi Kasai, Masayuki Hirose, Kazuhiro Sakai, Manabu Akamatsu, Chizuru Ohsawa, Yasuko Yoshioka, Shoko Suda, Nanako Shiroshita, Ryo Nakamura, Toshiaki Kadokami, Takeshi Tohyama, Kouta Funakoshi, Kazuya Hosokawa, Shin-Ichi Ando, Lung-to-finger circulation time can be measured stably with high reproducibility by simple breath holding method in cardiac patients., Scientific reports, 10.1038/s41598-021-95192-3, 11, 1, 15913-15913, 2021.08, Lung to finger circulation time (LFCT) has been used to estimate cardiac function. We developed a new LFCT measurement device using a laser sensor at fingertip. We measured LFCT by measuring time from re-breathing after 20 s of breath hold to the nadir of the difference of transmitted red light and infrared light, which corresponds to percutaneous oxygen saturation. Fifty patients with heart failure were enrolled. The intrasubject stability of the measurement was assessed by the intraclass correlation coefficient (ICC). The ICC calculated from 44 cases was 0.85 (95% confidence interval: 0.77-0.91), which means to have "Excellent reliability." By measuring twice, at least one clear LFCT value was obtained in 89.1% of patients and the overall measurability was 95.7%. We conducted all LFCT measurements safely. High ICCs were obtained even after dividing patients according to age, cardiac index (CI); 0.85 and 0.84 (≥ 75 or 
26. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, Inpatient Cardiac Rehabilitation After Hospitalization for Acute Decompensated Heart Failure is Associated With Reduced Cardiovascular Events, CIRCULATION, 144, 2021.11, 0.
27. Keisuke Shinohara, Shota Ikeda, Nobuyuki Enzan, Shouji Matsushima, Takeshi Tohyama, Kouta Funakoshi, Junji Kishimoto, Hiroshi Itoh, Issei Komuro, Hiroyuki Tsutsui, Efficacy of intensive lipid-lowering therapy with statins stratified by blood pressure levels in patients with type 2 diabetes mellitus and retinopathy: Insight from the EMPATHY study., Hypertension research : official journal of the Japanese Society of Hypertension, 10.1038/s41440-021-00734-x, 44, 12, 1606-1616, 2021.12, Intensive lipid-lowering therapy is recommended in individuals exhibiting type 2 diabetes mellitus (T2DM) with microvascular complications (as high-risk patients), even without known cardiovascular disease (CVD). However, evidence is insufficient to stratify the patients who would benefit from intensive therapy among them. Hypertension is a major risk factor, and uncontrolled blood pressure (BP) is associated with increased CVD risk. We evaluated the efficacy of intensive vs. standard statin therapy for primary CVD prevention among T2DM patients with retinopathy stratified by BP levels. We used the dataset from the EMPATHY study, which compared intensive statin therapy targeting low-density lipoprotein cholesterol (LDL-C) levels of
28. Shota Ikeda, Keisuke Shinohara, Nobuyuki Enzan, Shouji Matsushima, Takeshi Tohyama, Kouta Funakoshi, Junji Kishimoto, Hiroshi Itoh, Issei Komuro, Hiroyuki Tsutsui, Effectiveness of statin intensive therapy in type 2 diabetes mellitus with high visit-to-visit blood pressure variability., Journal of hypertension, 10.1097/HJH.0000000000002823, 39, 7, 1435-1443, 2021.07, BACKGROUND: Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability. METHODS: The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C)
29. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, Clinical Characteristics and Contemporary Management of Patients With Cardiomyopathies in Japan - Report From a National Registry of Clinical Personal Records., Circulation reports, 10.1253/circrep.CR-21-0001, 3, 3, 142-152, 2021.02, Background: The clinical features of patients with cardiomyopathy, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or restrictive cardiomyopathy (RCM), have not been recently elucidated in Japan. Methods and Results: We collected individual patient data regarding demographics, echocardiogram, and treatment in DCM from 2003 to 2014 and in HCM and RCM from 2009 to 2014 from the national registry of clinical personal records organized by the Japanese Ministry of Health, Labour and Welfare. In all, 44,136 patients were included in this registry: 40,537 with DCM, 3,553 with HCM, and 46 with RCM. The median age at diagnosis was older for DCM and HCM than RCM (54 and 55 vs. 42 years, respectively). Male patients accounted for 74.6%, 58.7%, and 60.9% of the DCM, HCM, and RCM groups, respectively. NYHA functional Class III-IV was found in 26.9%, 11.3%, and 58.1% of patients in the DCM, HCM, and RCM groups, respectively. In the DCM group, the rates of β-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescription were 69% and 76%, respectively. In regional subgroup analysis, the median age at diagnosis of DCM and HCM was younger in the Kanto region. A family history of HCM was less frequent in the Hokkaido/Tohoku region. Conclusions: The national registry of clinical personal records of cardiomyopathy could provide important information regarding the demographics, clinical characteristics, and management of cardiomyopathy throughout Japan..
30. Tomomi Ide, Hidetaka Kaku, Shouji Matsushima, Takeshi Tohyama, Nobuyuki Enzan, Kouta Funakoshi, Yoko Sumita, Michikazu Nakai, Kunihiro Nishimura, Yoshihiro Miyamoto, Miyuki Tsuchihashi-Makaya, Masaru Hatano, Issei Komuro, Hiroyuki Tsutsui, Clinical Characteristics and Outcomes of Hospitalized Patients With Heart Failure From the Large-Scale Japanese Registry Of Acute Decompensated Heart Failure (JROADHF)., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-20-0947, 85, 9, 1438-1450, 2021.08, BACKGROUND: With aging population, the prevalence and incidence of heart failure (HF) have been increasing worldwide. However, the characteristics and outcomes of patients with HF in an era of aging are not well established in Japan.Methods and Results:The Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), a retrospective, multicenter, nationwide registry, was designed to study the clinical characteristics and outcomes of patients hospitalized with HF throughout Japan in 2013. One hundred and twenty-eight hospitals were selected by cluster random sampling and 13,238 hospitalized patients with HF were identified by medical record review. Demographics, medical history, severity, treatment, and in-hospital and long-term outcome data were collected from the Diagnostic Procedure Combination and medical charts. Data were analyzed using univariate and multivariate logistic regression or Cox regression analysis. The mean age of registered patients was 78.0±12.5 years and 52.8% were male. Elderly patients (age >75 years) accounted for 68.9%, and HF with preserved ejection fraction (HFpEF) accounted for 45.1%. Median length of hospital stay was 18 days and in-hospital mortality was 7.7%. The median follow-up period was 4.3 years, and the incidence rates for cardiovascular death and rehospitalization for HF were 7.1 and 21.1 per 100 person-years, respectively. CONCLUSIONS: A contemporary nationwide registry demonstrated that hospitalized HF patients were very elderly, HFpEF was common, and their prognosis was still poor in Japan..
31. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, Beta-Blocker Use Is Associated With Prevention of Left Ventricular Remodeling in Recovered Dilated Cardiomyopathy., Journal of the American Heart Association, 10.1161/JAHA.120.019240, 10, 12, e019240, 2021.06, Background Withdrawal of optimal medical therapy has been reported to relapse cardiac dysfunction in patients with dilated cardiomyopathy (DCM) whose cardiac function had improved. However, it is unknown whether beta-blockers can prevent deterioration of cardiac function in those patients. We examined the effect of beta-blockers on left ventricular ejection fraction (LVEF) in recovered DCM. Methods and Results We analyzed the clinical personal record of DCM, a national database of the Japanese Ministry of Health, Labor and Welfare, between 2003 and 2014. Recovered DCM was defined as a previously documented LVEF 10% at 2 years of follow-up. Of 5370 eligible patients, 4104 received beta-blockers. Propensity score matching yielded 1087 pairs. Mean age was 61.9 years, and 1619 (74.5%) were men. Mean LVEF was 49.3±8.2%, and median B-type natriuretic peptide was 46.6 (interquartile range, 18.0-118.1) pg/mL. The primary outcome was observed less frequently in the beta-blocker group than in the no-beta-blocker group (19.6% versus 24.0%; odds ratio [OR], 0.77; 95% CI, 0.63-0.95; P=0.013). Subgroup analysis demonstrated that female patients (women: OR, 0.54; 95% CI, 0.36-0.81; men: OR, 0.88; 95% CI, 0.69-1.12; P for interaction=0.040) were benefited by beta-blockers. Conclusions Beta-blocker use could prevent deterioration of left ventricular systolic function in patients with recovered DCM..
32. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, The use of angiotensin II receptor blocker is associated with greater recovery of cardiac function than angiotensin-converting enzyme inhibitor in dilated cardiomyopathy., ESC heart failure, 10.1002/ehf2.13790, 9, 2, 1175-1185, 2022.04, AIMS: Angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) have been shown to be associated with recovery of cardiac function in patients with dilated cardiomyopathy (DCM). The aim of this study was to assess comparative effectiveness of ACEis vs. ARBs on recovery of left ventricular ejection fraction (LVEF) among patients with DCM. METHODS AND RESULTS: We analysed the clinical personal records of DCM, a national database of the Japanese Ministry of Health, Labour and Welfare, from 2003 to 2014. Patients with LVEF 
33. Shota Ikeda, Keisuke Shinohara, Nobuyuki Enzan, Shouji Matsushima, Takeshi Tohyama, Kouta Funakoshi, Junji Kishimoto, Hiroshi Itoh, Issei Komuro, Hiroyuki Tsutsui, Serial measurement of B-type natriuretic peptide and future cardiovascular events in patients with type 2 diabetes mellitus without known cardiovascular disease., International journal of cardiology, 10.1016/j.ijcard.2022.03.049, 356, 98-104, 2022.06, BACKGROUND: In patients with type 2 diabetes mellitus (T2DM) without known cardiovascular disease, the association between B-type natriuretic peptide (BNP) and cardiovascular events except for heart failure has not been elucidated. We aimed to investigate this association in high-risk T2DM patients. METHODS: We analyzed the association between BNP and cardiovascular events, including coronary, cerebral, renal, and vascular events or cardiovascular death based on the single and serial measurement of BNP in T2DM patients with retinopathy and hyperlipidemia without known cardiovascular disease enrolled in the EMPATHY study. RESULTS: Data from 4966 patients were analyzed for baseline BNP analysis. The median BNP value was 15.0 pg/mL. When analyzed in quartiles of baseline BNP (interquartile range 7.5-29.2 pg/mL), Q2, Q3, and Q4 were associated with cardiovascular events compared with Q1 (hazard ratio [HR]: Q2, 1.91 [P = 0.003]; Q3, 1.63 [P = 0.031]; Q4, 3.20 [P 
34. Kazuhiro Shirozu, Keiko Nobukuni, Jun Maki, Kanako Nagamatsu, Ryudo Tanaka, Kaiki Oya, Kouta Funakoshi, Midoriko Higashi, Ken Yamaura, Redistributional Hypothermia Prevention by Prewarming with Forced-Air: Exploratory, Open, Randomized, Clinical Trial of Efficacy., Therapeutic hypothermia and temperature management, 10.1089/ther.2022.0009, 2022.08, Avoiding redistributional hypothermia that decreases core temperature by 0.5-1.5°C within the 1st hour of surgery is difficult. The efficacy of prewarming using a forced-air warming (FAW) device with a lower-body blanket on redistribution hypothermia during epidural procedures have not been investigated. After ethics approval, 113 patients undergoing laparoscopic surgery under general anesthesia combined with epidural anesthesia were enrolled. Intervention (prewarming) group patients who were warmed from operating room entry, including during epidural anesthesia, was compared with the control group that was warmed from just before surgery started. In total, 104 patients (52, control; 52, prewarming) were analyzed. In the prewarming group, compared to the control group, the core temperature 20 minutes after anesthesia induction (36.9 ± 0.4 vs. 37.1 ± 0.4°C, p 
35. Nobuyuki Enzan, Ken Ichi Hiasa, Kenzo Ichimura, Masaaki Nishihara, Takeshi Iyonaga, Yuji Shono, Takeshi Tohyama, Kouta Funakoshi, Takanari Kitazono, Hiroyuki Tsutsui, Delayed administration of epinephrine is associated with worse neurological outcomes in patients with out-of-hospital cardiac arrest and initial pulseless electrical activity: insight from the nationwide multicentre observational JAAM-OHCA (Japan Association for Acute Medicine) registry., European heart journal. Acute cardiovascular care, 10.1093/ehjacc/zuac026, 11, 5, 389-396, 2022.06, AIMS: The delayed administration of epinephrine has been proven to worsen the neurological outcomes of patients with out-of-hospital cardiac arrest (OHCA) and shockable rhythm or asystole. We aimed to investigate whether the delayed administration of epinephrine might also worsen the neurological outcomes of patients with witnessed OHCA and initial pulseless electrical activity (PEA). METHODS AND RESULTS: The JAAM-OHCA Registry is a multicentre registry including OHCA patients between 2014 and 2017. Patients with emergency medical services (EMS)-treated OHCA and initial PEA rhythm were included. The primary exposure was the time from the EMS call to the administration of epinephrine. The secondary exposure was the time to epinephrine dichotomized as early (≤15 min) or delayed (>15 min). The primary outcome was the achievement of a favourable neurological outcome, defined as Cerebral Performance Categories Scale 1-2 at 30 days after OHCA. Out of 34 754 patients with OHCA, 3050 patients were included in the present study. After adjusting for potential confounders, the delayed administration of the epinephrine was associated with a lower likelihood of achieving a favourable neurological outcome [adjusted odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93-0.99; P = 0.016]. The percentage of patients who achieved a favourable neurological outcome in the delayed epinephrine group was lower than that in the early epinephrine group (1.3% vs. 4.7%; adjusted OR 0.33; 95% CI 0.15-0.72; P = 0.005). A restricted cubic spline analysis demonstrated that delayed epinephrine administration could decrease the likelihood of achieving a favourable neurological outcome; this was significant within the first 10 min. CONCLUSIONS: The delayed administration of epinephrine was associated with worse neurological outcomes in patients with witnessed OHCA patients with initial PEA..
36. Atsushi Nonami, Ryu Matsuo, Kouta Funakoshi, Tomohiro Nakayama, Shigenori Goto, Tadafumi Iino, Shigeo Takaishi, Shinichi Mizuno, Koichi Akashi, Masatoshi Eto, Prospective study of adoptive activated αβT lymphocyte immunotherapy for refractory cancers: development and validation of a response scoring system., Cytotherapy, 10.1016/j.jcyt.2022.09.007, 25, 1, 76-81, 2023.01, BACKGROUND AIMS: This prospective clinical study aimed to determine the efficacy and prognostic factors of adoptive activated αβT lymphocyte immunotherapy for various refractory cancers. The primary endpoint was overall survival (OS), and the secondary endpoint was radiological response. METHODS: The authors treated 96 patients. Activated αβT lymphocytes were infused every 2 weeks for a total of six times. Prognostic factors were identified by analyzing clinical and laboratory data obtained before therapy. RESULTS: Median survival time (MST) was 150 days (95% confidence interval, 105-191), and approximately 20% of patients achieved disease control (complete response + partial response + stable disease). According to the multivariate Cox proportional hazards model with Akaike information criterion-best subset selection, sex, concurrent therapy, neutrophil/lymphocyte ratio, albumin, lactate dehydrogenase, CD4:CD8 ratio and T helper (Th)1:Th2 ratio were strong prognostic factors. Using parameter estimates of the Cox analysis, the authors developed a response scoring system. The authors then determined the threshold of the response score between responders and non-responders. This threshold was able to significantly differentiate OS of responders from that of non-responders. MST of responders was longer than that of non-responders (317.5 days versus 74 days). The validity of this response scoring system was then confirmed by internal validation. CONCLUSIONS: Adoptive activated αβT lymphocyte immunotherapy has clinical efficacy in certain patients. The authors' scoring system is the first prognostic model reported for this therapy, and it is useful for selecting patients who might obtain a better prognosis through this modality..
37. Kazuya Hosokawa, Kohtaro Abe, Kouta Funakoshi, Yuichi Tamura, Naoki Nakashima, Koji Todaka, Yu Taniguchi, Takumi Inami, Shiro Adachi, Ichizo Tsujino, Jun Yamashita, Shun Minatsuki, Nobutaka Ikeda, Hiroto Shimokawahara, Takashi Kawakami, Takeshi Ogo, Masaru Hatano, Hitoshi Ogino, Yoshihiro Fukumoto, Nobuhiro Tanabe, Hiromi Matsubara, Keiichi Fukuda, Koichiro Tatsumi, Hiroyuki Tsutsui, Long-term outcome of chronic thromboembolic pulmonary hypertension using direct oral anticoagulants and warfarin: a Japanese prospective cohort study., Journal of thrombosis and haemostasis : JTH, 10.1016/j.jtha.2023.03.036, 2023.04, BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) requires lifelong anticoagulation. Long-term outcomes of CTEPH under current anticoagulants are unclear. OBJECTIVES: The CTEPH AC registry is a prospective, nationwide cohort study comparing the safety and effectiveness of direct oral anticoagulants (DOACs) and warfarin for CTEPH. PATIENTS/METHODS: Patients with CTEPH, both tre atment-naïve and on treatment, were eligible for the registry. Inclusion criteria were patients aged ≥20 years and those who were diagnosed with CTEPH according to standard guidelines. Exclusion criteria were not specified. The primary efficacy outcome was a composite morbidity, and mortality outcome comprised all-cause death, rescue reperfusion therapy, initiation of parenteral pulmonary vasodilators, and worsened 6-minute walk distance and WHO functional class. The safety outcome was clinically relevant bleeding, including major bleeding. RESULTS: Nine hundred twenty-seven patients on oral anticoagulants at baseline were analyzed: 481 (52%) used DOACs and 446 (48%) used warfarin. The 1-, 2-, and 3-year rates of composite morbidity and mortality outcome were comparable between the DOAC and warfarin groups (2.6%, 3.1%, and 4.2% vs 3.0%, 4.8%, and 5.9%, respectively; P = .52). The 1-, 2-, and 3-year rates of clinically relevant bleeding were significantly lower in DOACs than in the warfarin group (0.8%, 2.4%, and 2.4% vs 2.5%, 4.8%, and 6.4%, respectively; P = 0.036). Multivariable Cox proportional-hazards regression models revealed lower risk of clinically relevant bleeding in the DOAC group than the warfarin group (hazard ratio: 0.35; 95% CI: 0.13-0.91; P = .032). CONCLUSION: This registry demonstrated that under current standard of care, morbidity and mortality events were effectively prevented regardless of anticoagulants, while the clinically relevant bleeding rate was lower when using DOACs compared with warfarin..
38. Mai Seki, Toshiaki Nakano, Shigeru Tanaka, Yuta Matsukuma, Kouta Funakoshi, Toshiaki Ohkuma, Takanari Kitazono, Design and methods of an open-label, randomized controlled trial to evaluate the effect of pemafibrate on proteinuria in CKD patients (PROFIT-CKD)., Clinical and experimental nephrology, 10.1007/s10157-023-02322-4, 27, 4, 358-364, 2023.04, BACKGROUND: Hypertriglyceridemia is increasingly considered a residual risk of cardiovascular disease in patients with chronic kidney disease (CKD). Pemafibrate-a novel selective peroxisome proliferator-activated receptor alpha modulator and a new treatment for hypertriglyceridemia in CKD patients-is reported to have fewer side effects in CKD patients than other fibrates. Appropriate control of hypertriglyceridemia can be expected to improve renal prognosis. However, data on the renal protective effect of pemafibrate are limited. This study aims to evaluate the effectiveness of pemafibrate on urinary protein excretion in CKD patients. METHODS: The Pemafibrate, open-label, Randomized cOntrolled study to evaluate the renal protective eFfect In hyperTriglyceridemia patients with Chronic Kidney Disease (PROFIT-CKD) study is an investigator-initiated, multi-center, open-label, parallel-group, randomized controlled trial. Participants are outpatients with hypertriglyceridemia aged 20 years and over, who have received the care of a nephrologist or a diabetologist for more than 3 months. Inclusion criteria include the following: proteinuria (urine protein/creatinine ratio of ≥ 0.15 g/gCr) within three months before allocation, and hypertriglyceridemia (triglycerides ≥ 150 mg/dL and 
39. Takeshi Tohyama, Tomomi Ide, Masataka Ikeda, Takuya Nagata, Koshiro Tagawa, Masayuki Hirose, Kouta Funakoshi, Kazuo Sakamoto, Junji Kishimoto, Koji Todaka, Naoki Nakashima, Hiroyuki Tsutsui, Deep Learning of ECG for the Prediction of Postoperative Atrial Fibrillation., Circulation. Arrhythmia and electrophysiology, 10.1161/CIRCEP.122.011579, 16, 2, e011579, 2023.02.
40. Shota Ikeda, Keisuke Shinohara, Nobuyuki Enzan, Shouji Matsushima, Takeshi Tohyama, Kouta Funakoshi, Junji Kishimoto, Hiroshi Itoh, Issei Komuro, Hiroyuki Tsutsui, A higher resting heart rate is associated with cardiovascular event risk in patients with type 2 diabetes mellitus without known cardiovascular disease., Hypertension research : official journal of the Japanese Society of Hypertension, 10.1038/s41440-023-01178-1, 46, 5, 1090-1099, 2023.05, A higher resting heart rate (RHR) is associated with an increased risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The aim of this study was to investigate the association between RHR and cardiovascular events in T2DM patients with diabetic retinopathy and without known cardiovascular disease. We analyzed the association between RHR and cardiovascular events, including coronary, cerebral, renal and vascular events or cardiovascular death in T2DM patients with retinopathy and hyperlipidemia without prior cardiovascular events who were enrolled in the EMPATHY study. Data from 4746 patients were analyzed. The median RHR was 76 bpm. Patients were divided into four groups based on their baseline RHR ( 
41. Nobuyuki Enzan, Shouji Matsushima, Tomomi Ide, Hidetaka Kaku, Takeshi Tohyama, Kouta Funakoshi, Taiki Higo, Hiroyuki Tsutsui, Sex Differences in Time-Dependent Changes in B-Type Natriuretic Peptide in Hypertrophic Cardiomyopathy, Circ Resp, https://doi.org/10.1253/circrep.CR-21-0110, 3, 10, 594-603, 2021.09.
42. Ide T, Kaku H, Matsushima S, Tohyama T, Enzan N, Funakoshi K, Sumita Y, Nakai M, Nishimura K, Miyamoto Y, Tsuchihashi-Makaya M, Hatano M, Komuro I, Tsutsui H, Clinical Characteristics and Outcomes of Hospitalized Patients With Heart Failure From the Large-Scale Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), CIRCULATION JOURNAL, 10.1253/circj.CJ-20-0947, 85, 9, 1438-+, 2021.09.
43. Tohyama T, Ide T, Ikeda M, Kaku H, Enzan N, Matsushima S, Funakoshi K, Kishimoto J, Todaka K, Tsutsui H, Machine learning-based model for predicting 1 year mortality of hospitalized patients with heart failure, ESC HEART FAILURE, 10.1002/ehf2.13556, 8, 5, 4077-4085, 2021.10.
44. Shirozu K, Nobukuni K, Funakoshi K, Nakamura T, Sumie M, Higashi M, Yamaura K, The effect of remimazolam on postoperative memory retention and delayed regeneration in breast surgery patients Rationale and design of an exploratory, randomized, open, propofol-controlled, single-center clinical trial: A study protocol, Medicine (Baltimore), 10.1097/MD.0000000000027808, 100, 48, 2021.12.
45. Kouta Funakoshi, Kazuya Hosokawa, Takuya Kishi, Tomomi Ide, Kenji Sunagawa, Striking Volume Intolerance Is Induced by Mimicking Arterial Baroreflex Failure in Normal Left Ventricular Function, JOURNAL OF CARDIAC FAILURE, 10.1016/j.cardfail.2013.11.007, 20, 1, 53-59, 2014.01, Background: Patients with heart failure and preserved ejection fraction (HFpEF) are supersensitive to volume overload, and a striking increase in left atrial pressure (LAP) often occurs transiently and is rapidly resolved by intravascular volume reduction. The arterial baroreflex is a powerful regulator of intravascular stressed blood volume. We examined whether arterial baroreflex failure (FAIL) mimicked by constant carotid sinus pressure (CSP) causes a striking increase in LAP and systemic arterial pressure (AP) by volume loading in rats with normal left ventricular (LV) function.

Methods and results: In anesthetized Sprague-Dawley rats, we isolated bilateral carotid sinuses and controlled CSP by a servo-controlled piston pump. We mimicked the normal arterial baroreflex by matching CSP to instantaneous AP and FAIL by maintaining CSP at a constant value regardless of AP. We infused dextran stepwise (infused volume [Vi]) until LAP reached 15 mm Hg and obtained the LAP-Vi relationship. We estimated the critical Vi as the Vi at which LAP reached 20 mm Hg. In FAIL, critical Vi decreased markedly from 19.4 ± 1.6 mL/kg to 15.6 ± 1.6 mL/kg (P
Conclusions: Arterial baroreflex failure induces striking volume intolerance in the absence of LV dysfunction and may play an important role in the pathogenesis of acute heart failure, especially in states of HFpEF..