研究者詳細 - 小山　雅之

論文 - 小山　雅之

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Rapid and Integrated Bacterial Evolution Analysis unveils gene mutations and clinical risk of Klebsiella pneumoniae

Kojiro Uemura, Toyotaka Sato, Soh Yamamoto, Noriko Ogasawara, Jirachaya Toyting, Kotaro Aoki, Akira Takasawa, Masayuki Koyama, Atsushi Saito, Takayuki Wada, Kaho Okada, Yurie Yoshida, Koji Kuronuma, Chie Nakajima, Yasuhiko Suzuki, Motohiro Horiuchi, Kenichi Takano, Satoshi Takahashi, Hirofumi Chiba, Shin-ichi Yokota

Nature Communications 2025年03月

Maternal age and the rising incidence of hypertensive disorders of pregnancy: A comprehensive analysis of national claims data from Japan.

Naomi Maeda, Masayuki Koyama, Shintaro Takatsuka, Keisuke Oyatani, Nobuaki Himuro, Tasuku Mariya, Yoshika Kuno, Shiro Hinotsu, Tsuyoshi Saito, Hirofumi Ohnishi

PloS one 20 ( 2 ) e0319177 2025年 [国際誌]

BACKGROUND: Hypertensive disorders of pregnancy (HDP) significantly increase the risk of developing hypertension and cardiovascular disease (CVD) later in life and are a major cause of maternal mortality. However, little is known about the nationwide, long-term, all-inclusive status of HDP. OBJECTIVE: To estimate the incidence of HDP from 2011 to 2019 in Hokkaido, Japan, with a focus on age groups. METHODS: Using National Database (NDB) insurance medical data, a retrospective analysis was conducted. Due to the absence of direct pregnancy data, birth numbers were used as a surrogate for the number of pregnant women to calculate the incidence of HDP. RESULTS: The average incidence rate of HDP over 9 years was 6.37%. The incidence rate was lowest among women aged 25-29 years, at 5.58% (95% confidence interval [CI]: 5.43-5.73), and increased with age, peaking at 10.58% (95% CI: 10.10-11.09) among women over 40 years. Notably, the incidence rate for women under 20 years of age was 6.70% (95% CI: 5.97-7.51), which was higher than that for women in their 20s. A mean annual increase of 0.25% in age-adjusted incidence was observed during this period, which was statistically significant (R² = 0.87, p < 0.01). CONCLUSION: This study reveals that the risk of developing HDP is associated with both older childbearing and younger pregnancies and follows a J-curve, suggesting that factors other than maternal aging also contribute to the increased incidence of HDP and that further research on risk factors for HDP, which is on the rise worldwide, is urgently needed.

Straightforward and immediate ultrasound-guided kidney biopsy using a guide needle technique to get adequate tissue with reduced procedural time.

Hiroaki Komatsu, Tomohisa Yamashita, Arata Osanami, Chikako Akazawa, Kota Endo, Shun Tsugawa, Ayumu Kimura, Daisuke Miyamori, Koki Abe, Satoko Takahashi, Yufu Gocho, Masayuki Koyama, Tatsuya Sato, Marenao Tanaka, Norihito Moniwa, Masato Furuhashi

Clinical and experimental nephrology 2024年08月 [国内誌]

BACKGROUND: A streamlined and effective renal biopsy technique is essential for all nephrologists, particularly those who are less experienced, such as residents. Herein, we report the efficacy of a Straightforward and Immediate ultrasound-guided kidney biopsy using a Guide Needle (SIGN) technique, which allows operators to insert a biopsy gun through a guide needle placed into the fascia of the posterior abdominal wall. METHODS: A retrospective cross-sectional study was conducted at a nephrology training institution to compare the time spent on the procedure and the number of glomeruli obtained between a group using the SIGN (n = 81) and a group using the conventional ultrasound-guided kidney biopsy technique with a needle guide device (n = 143). RESULTS: The median procedure time in the SIGN group (2 min, interquartile range [IQR]: 1-3 min) was significantly shorter than that in the conventional group (3 min, IQR: 2-4 min) (P < 0.001). Multivariable linear regression and logistic regression analyses adjusted for covariates, including operators (board-certificated nephrologists or nephrology residents), showed that the use of the SIGN technique was independently associated with a high number of glomeruli obtained and a procedure time above 2 min as the median value (odds ratio: 0.17, 95% confidence interval CI 0.09-0.34). The prevalence of complications was comparable between the two groups (P = 0.681). CONCLUSION: The SIGN technique reduces the procedure time and obtains adequate biopsy tissue regardless of the operator's experience. SIGN can be applied in nephrology training programs and used as a standard biopsy technique.

Prediction of the future number of fall-related emergency medical services calls in older individuals.

Shuji Uemura, Ryuichi Nakayama, Masayuki Koyama, Yukiko Taguchi, Naofumi Bunya, Keigo Sawamoto, Hirofumi Ohnishi, Eichi Narimatsu

International journal of emergency medicine 17 ( 1 ) 72 - 72 2024年06月 [国際誌]

BACKGROUND: Falls among older individuals contribute significantly to the rise in ambulance transport use. To recognize the importance of future countermeasures, we estimated the projected number and percentage of fall-related emergency medical service (EMS) calls. METHODS: We examined the sex, age group, and location of falls among patients aged ≥ 65 years who contacted emergency services in Sapporo City from 2013 to 2021. Annual fall-related calls per population subgroup were calculated, and trends were analyzed. Four models were used to estimate the future number of fall-related calls from the 2025-2060 projected population: (1) based on the 2022 data, estimates from the 2013-2022 data using (2) Poisson progression, (3) neural network, (4) estimates from the 2013-2019 data using neural network. The number of all EMS calls was also determined using the same method to obtain the ratio of all EMS calls. RESULTS: During 2013-2022, 70,262 fall-related calls were made for those aged ≥ 65 years. The rate was higher indoors among females and outdoor among males in most age groups and generally increased with age. After adjusting for age, the rate increased by year. Future estimates of the number of fall calls are approximately double the number in 2022 in 2040 and three times in 2060, with falls accounting for approximately 11% and 13% of all EMS calls in 2040 and 2060, respectively. CONCLUSION: The number of fall-related EMS calls among older people is expected to increase in the future, and the percentage of EMS calls will also increase; therefore, countermeasures are urgently needed.

高齢心不全患者における心臓リハビリテーションの効果と再入院の関連 National Databaseを用いた検討

阿部大介, 加藤あさひ, 園田美和, 田尾美里, 金弘子, 森真理, 小山雅之, 金岡幸嗣朗, 平田匠

日本循環器病予防学会誌 ( (一社)日本循環器病予防学会 ) 59 ( 2 ) 122 - 122 2024年04月

Sampsonの式あるいは人工知能を用いて推定したsmall dense LDLコレステロール値の精度の検証

大久保武志, 遠藤圭佑, 田中希尚, 佐藤達也, 小林亮, 田中真輝人, 秋山幸功, 保坂到, 中田圭, 小山雅之, 大西浩文, 高橋聡, 古橋眞人

糖尿病 ( (一社)日本糖尿病学会 ) 67 ( Suppl.1 ) S - 251 2024年04月

Sampsonの式あるいは人工知能を用いて推定したsmall dense LDLコレステロール値の精度の検証

大久保武志, 遠藤圭佑, 田中希尚, 佐藤達也, 小林亮, 田中真輝人, 秋山幸功, 保坂到, 中田圭, 小山雅之, 大西浩文, 高橋聡, 古橋眞人

糖尿病 ( (一社)日本糖尿病学会 ) 67 ( Suppl.1 ) S - 251 2024年04月

子ども達から子ども達へ伝えるピア健康教育の実践病気の予防プロジェクト2022

大浦麻絵, 大西浩文, 中田真由, 小山雅之, 中田圭, 長多好恵, 長谷川準子, 助友裕子, 森満

北海道公衆衛生学雑誌 ( 北海道公衆衛生学会 ) 37 ( 2 ) 137 - 141 2024年03月

本稿では札幌市内小中学校を中心として取り組んでいる「病気の予防プロジェクト」より2022年度に実施した札幌市立小学校2校での活動を紹介する.病気の予防プロジェクトは,子ども達が主体的にエビデンス(科学的根拠)に基づいた知識を学び,学びを深化させ,他者に情報発信するActive Learningプログラムである.N小学校では6年生は他校の生徒や札幌市民へ,F小学校では3年生が1,2年生を中心に全校へ向け情報発信を行った."コロナ禍において,自分達にも何かできることはないだろうか?"子ども達の素直な気持ちを活かした健康教育活動とするため,学校と学校を取り巻く地域資源の一つである大学の研究班とが連携して実施した.本活動は健康教育が目指すセルフエスティームを基盤としており,活動状況から子ども達の社会性,自己肯定感を自然な形で育むことが出来る可能性が考えられた.(著者抄録)

児童の手洗いを科学するアクションリサーチ ATPを用いた可視化の検討

大浦麻絵, 中田圭, 内藤由紀子, 大岩大祐, 小山雅之, 長多好恵, 助友裕子, 大西浩文

北海道公衆衛生学雑誌 ( 北海道公衆衛生学会 ) 37 ( 2 ) 65 - 69 2024年03月

目的:小学校教育において実践している手洗い健康教育プログラムに新たにATP(アデノシン三リン酸)検査を導入した.科学的な指標を用い,児童の手の汚れを可視化させた.汚れの可視化を導入した手洗い教育プログラムの有効性に関する資料とすることを目的とした.方法:北海道札幌市公立小学校の放課後教室でpilot studyを実施した.16人の児童に対し,IDで連結した無記名自記式アンケート調査と手洗い前後のATP検査を実施した.結果:全体における手洗い後のATP値は(中央値(四分位範囲)=4968.5(3589.0,7481.8)であり手洗い前(67738.0(56702.5,85732.5))と比べて減少していた(p<0.05).3～5年生に限定しても,手洗い後のATP値(4739.0[3249.0,7481.8])は手洗い前(67738.0[58527.3,85732.5])に比べて減少していた(p<0.05).1,2年生においては,差は認められなかった(p=0.07).活動評価:発達がより一律となる高学年の方がより深い理解や応用的な考え方が出来ることで,手洗いが上手であった可能性が考えられた.ATP検査は客観的指標として手洗い力などとして教育効果を測る新たな視点として有効であることが示唆された.(著者抄録)

COVID-19 Online Health Monitoring System to Support Municipal Health Centers.

Takumi Tanikawa, Masayuki Koyama, Ryuichi Nakayama, Tsuyoshi Mukohara, Naoki Fujimoto, Shintaro Takatsuka, Jun Fukuda, Hidehiro Ozawa

Studies in health technology and informatics 310 1554 - 1555 2024年01月 [国際誌]

An online health-monitoring system for COVID-19-infected patients who are staying in hotels and homes was developed using geographical information systems. This system provides display functions for sending health observation forms to infected residents, scoring for medical risk assessment, and centralized management. More than 1,146,000 health observation records were registered in November 2022, and the system contributed to maintaining the functionality of the municipal health center in Sapporo, Japan.

The Contributions of Knee Extension Strength and Hand Grip Strength to Factors Relevant to Physical Frailty: The Tanno-Sobetsu Study

Toshiaki Seko, Hiroshi Akasaka, Masayuki Koyama, Nobuaki Himuro, Shigeyuki Saitoh, Ogawa Shunichi, Sayo Miura, Mitsuru Mori, Hirofumi Ohnishi

Geriatrics 9 ( 1 ) 2024年01月 [国際誌]

Sarcopenia is the core factor of frailty. This study specifically focused on lower limb muscle strength and examined muscle indices that indicate the risk of frailty or pre-frailty in older adults. The study included 327 community-dwelling individuals aged ≥65 years (43.7% male) who participated in the cohort. Frailty was defined based on five symptoms: weight loss, low activity level, exhaustion, weakness and slowness. Participants were classified into frail (three or more applicable), pre-frail (one to two applicable) and non-frail groups. Muscle strength (knee extension strength, toe grip strength and hand grip strength) were assessed, and appendicular muscle mass was assessed via a bioelectrical impedance analysis. The adjusted odds ratio (OR) of muscle indices for with frailty (frail group vs. pre-frail group) or pre-frailty (pre-frail group vs. non-frail group) were calculated. The prevalence of frail and pre-frail was 7% and 40%, respectively. Adjusted for age, sex, albumin and medical history, knee extension strength was significantly associated with frailty (odds ratio 0.95, 95% CI 0.92-0.98), while hand grip strength was associated with pre-frailty (odds ratio 0.92, 95% CI 0.88-0.97) but not with other muscle indices. This study is significant for identifying knee extension strength as a factor relevant to frailty in older adults considered pre-frailty, emphasizing the importance of this specific muscle measure in predicting and managing frailty.

Science behind children's handwashing: action study of 9- to 10-years-old elementary school students in Japan.

Asae Oura, Yukiko Naito, Hiroko Yako-Suketomo, Kei Nakata, Masayuki Koyama, Hirofumi Ohnishi

Frontiers in public health 12 1425646 - 1425646 2024年 [国際誌]

BACKGROUND: Hand washing instructions for children have been implemented in school education to establish good lifestyle habits. However, repeated hand washing through education from early childhood was common for both teachers and children. If this continues, children might assume they already know how to wash their hands, stop taking handwashing instructions seriously, and become increasingly lax about washing their hands. PURPOSE: This study aimed to develop a new handwashing education method for children. METHODS: We applied the adenosine triphosphate (ATP) test to health education on hand washing in elementary schools. This study was conducted as part of a class for elementary school students in October 2023, in Hokkaido, Japan. The subjects were 157 third-grade (9-10 years old) elementary school students. After excluding absent pupils, 147 were included in the analysis. RESULTS: Both pre- and post-education, ATP values after handwashing were lower than those before handwashing. Following the education, children's handwashing behavior improved, with an increase in the number of point washed and appropriate timing of handwashing. CONCLUSION: The new handwashing education program utilizing the ATP-test succeeded in promoting handwashing behavior among many children. Visualizing handwashing using ATP values was effective in motivating children.

Validation of Estimated Small Dense Low-Density Lipoprotein Cholesterol Concentration in a Japanese General Population.

Keisuke Endo, Ryo Kobayashi, Makito Tanaka, Marenao Tanaka, Yukinori Akiyama, Tatsuya Sato, Itaru Hosaka, Kei Nakata, Masayuki Koyama, Hirofumi Ohnishi, Satoshi Takahashi, Masato Furuhashi

Journal of atherosclerosis and thrombosis 2023年12月 [国内誌]

AIM: A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. A method for estimating sdLDL-C by using Sampson's equation that includes levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides (TG) has recently been proposed. We investigated the validation and exploration of estimated sdLDL-C level. METHODS: The associations between measured and estimated sdLDL-C levels were investigated in 605 Japanese subjects (men/women: 280/325; mean age: 65±15 years) who received annual health check-ups in the Tanno Sobetsu Study, a population-based cohort. RESULTS: Estimated sdLDL-C level was highly correlated with measured sdLDL-C level in all subjects (R2 =0.701), nondiabetic subjects without any medication (n=254, R 2=0.686) and subjects with diabetes mellitus (n=128, R2=0.721). Multivariable regression analysis showed that levels of non-HDL-C, TG and γ-glutamyl transpeptidase (γGTP) were independent predictors of measured sdLDL-C level. In a stratification of the LDL window, all of the subjects with a combination of high non-HDL-C (≥ 170 mg/dL) and high TG (≥ 150 mg/dL) had high levels of measured and estimated sdLDL-C (≥ 35 mg/dL). Furthermore, machine learning-based estimation of sdLDL-C level by artificial intelligence software, Prediction One, was substantially improved by using components of Sampson's equation (R2=0.803) and by using those components with the addition of γGTP and deletion of TC (R2=0.929). CONCLUSIONS: sdLDL-C level estimated by Sampson's equation can be used instead of measured sdLDL-C level in general practice. By building multiple machine learning models of artificial intelligence, a more accurate and practical estimation of sdLDL-C level might be possible.

Reconsidering resectable oncological conditions in pancreatic tail cancer: A multicenter retrospective study on prognostic factors in pancreatic tail cancer after resection (HOPS Pt-01).

Yasutoshi Kimura, Toru Nakamura, Masafumi Imamura, Minoru Nagayama, Takeshi Murakami, Tsuyoshi Hayashi, Toru Kato, Kimitaka Tanaka, Makoto Yoshida, Kazuharu Kukita, Koji Imai, Makoto Yoshida, Yoshiharu Masaki, Masayo Motoya, Masaki Kuwatani, Masayuki Koyama, Hirofumi Ohnishi, Ichiro Takemasa

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 24 ( 1 ) 109 - 118 2023年12月 [国際誌]

BACKGROUND: Pancreatic tail cancer (Pt-PC) is generally considered resectable when metastasis is absent, but doubts persist in clinical practice due to the variability in local tumor extent. We conducted a multicenter retrospective study to comprehensively identify prognostic factors associated with Pt-PC after resection. METHODS: We enrolled 100 patients that underwent distal pancreatectomy. The optimal combination of factors influencing relapse-free survival (RFS) was determined using the maximum likelihood method (MLM) and corrected Akaike and Bayesian information criteria (AICc and BIC). Prognostic elements were then validated to predict oncological outcomes. RESULTS: Therapeutic interventions included neoadjuvant treatment in 16 patients and concomitant visceral resection (CVR) in 37 patients; 89 patients achieved R0. Median RFS and OS after surgery were 23.1 and 37.1 months, respectively. AICc/BIC were minimized in the model with ASA-PS (≥2), CA19-9 (≥112 U/mL at baseline, non-normalized postoperatively), need for CVR, 6 pathological items (tumor diameter ≥19.5 mm, histology G1, invasion of the anterior pancreatic border, splenic vein invasion, splenic artery invasion, lymph node metastasis), and completed adjuvant treatment (cAT) for RFS. Regarding the predictive value of these 11 factors, area under the curve was 0.842 for 5-year RFS. Multivariate analysis of these 11 factors showed that predictors of RFS include CVR (hazard ratio, 2.13; 95 % confidence interval, 1.08-4.19; p = 0.028) and cAT (0.38, 0.19-0.76; p = 0.006). CONCLUSIONS: The MLM identified certain Pt-PC cases warranting consideration beyond resectable during clinical management. Particular attention should be paid to conditions requiring CVR, even though immortal time bias remains unresolved with adjuvant treatment.

Independent Link Between Use of Mineralocorticoid Receptor Antagonists and Muscle Wasting in Heart Failure Patients Not Receiving Renin-Angiotensin System Inhibitors

Ryo Numazawa, Satoshi Katano, Toshiyuki Yano, Ryohei Nagaoka, Katsuhiko Ohori, Hidemichi Kouzu, Suguru Honma, Yusuke Fujisawa, Kotaro Yamano, Arata Osanami, Masayuki Koyama, Akiyoshi Hashimoto, Masato Furuhashi

Circulation Journal ( Japanese Circulation Society ) 88 ( 1 ) 10 - 19 2023年10月 [国内誌]

BACKGROUND: The renin-angiotensin system (RAS) activation is a proposed mechanism of muscle wasting (MW i.e., reduction in muscle mass). Although we reported that RAS inhibitors (RASIs) were associated with lower prevalence of MW in heart failure (HF) patients, the relationship between mineralocorticoid receptor (MR) signaling and MW has not been analyzed.Methods and Results: We analyzed data from 320 consecutive Japanese HF patients who underwent dual-energy X-ray absorptiometry scanning for assessment of appendicular skeletal muscle mass index (ASMI). In multiple linear regression analyses, plasma renin activity (PRA) was negatively correlated with ASMI in patients not receiving RASIs, indicating an untoward role of the RAS in MW. Results of analysis of covariance in which risk factors of MW served as covariates showed that use of MR antagonists (MRAs) was associated with lower ASMI and higher PRA in the non-RASIs group. The close relationship between use of MRAs and lower ASMI or higher PRA in the non-RASIs group was confirmed in analyses in which the differences in baseline characteristics between users and non-users of MRAs were minimized by using an inverse probability of treatment weighting. CONCLUSIONS: Increased PRA by MR inhibition without concurrent RAS inhibition, possibly contributing to upregulation of angiotensin II signaling, may be associated with reduction in muscle mass.

北海道の妊娠高血圧症候群の実態調査 NDBを用いた悉皆調査

前田尚美, 小山雅之, 高塚伸太朗, 親谷佳佑, 中田圭, 樋室伸顕, 大西浩文

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 ) 45回 415 - 415 2023年09月

心不全患者におけるレニン-アンジオテンシン系活性化は骨格筋量の低下と関連する

沼澤瞭, 片野唆敏, 矢野俊之, 長岡凌平, 神津英至, 大堀克彦, 藤澤佑輔, 山埜光太郎, 長南新太, 小山雅之, 橋本暁佳, 古橋眞人

日本高血圧学会総会プログラム・抄録集 ( (NPO)日本高血圧学会 ) 45回 398 - 398 2023年09月

Development and validation of osteoporosis risk assessment score, ORAS, in heart failure patients: comparison with the Osteoporosis Self-Assessment Tool for Asians (OSTA).

Ryo Numazawa, Satoshi Katano, Toshiyuki Yano, Masayuki Koyama, Ryohei Nagaoka, Yusuke Fujisawa, Kotaro Yamano, Suguru Honma, Katsuhiko Ohori, Hidemichi Kouzu, Masaki Katayose, Masato Furuhashi, Kazufumi Tsuchihashi, Akiyoshi Hashimoto

European journal of cardiovascular nursing 2023年08月 [国際誌]

AIM: Osteoporosis is prevalent and is associated with poor prognosis in heart failure (HF) patients. However, bone mineral density (BMD) measurement by a dual-energy X-ray absorptiometry (DEXA) scan is not always available in a daily clinical setting and large-scale population-based studies. METHODS: A single-center, cross-sectional observational study was conducted with 387 patients (median age: 77 years [interquartile range: 68 to 83 years]; 37% women). BMDs were measured by DEXA scans, and osteoporosis was diagnosed as ≤ -2.5 standard deviation of the BMDs in healthy young adults. Osteoporosis risk assessment score (ORAS) was developed using significant predictors from a logistic regression model for osteoporosis and was subsequently validated. RESULTS: Osteoporosis was found in 103 (27%) of the 387 HF patients. Multivariate logistic regression analyses yielded the ORAS based on sex, BMI, handgrip strength, and anti-coagulant therapy utilization. The C-index of ORAS in the developmental set (0.796, 95% confidence interval: 0.747 to 0.845) was similar to the bootstrap validation of the prediction model (0.784), and tended to be higher than that of the Osteoporosis Self-Assessment Tool for Asians (OSTA). A nomogram of ORAS, established on the basis of the final logistic regression model, demonstrated 100% sensitivity at the lowest score (35 points), with an optimal cutoff point of 127 points, yielding 85% sensitivity and 62% specificity. CONCLUSIONS: ORAS exhibits superior predictive performance to OSTA in predicting osteoporosis in HF patients, establishing itself as a valuable tool for early detection in both daily clinical practice and large-scale population-based studies.

Extension of Selection Time for the Emergency Destination of Patients with a Fever Due to the Coronavirus Disease 2019 Pandemic: A Difference-in-differences Analysis.

Ryuichi Nakayama, Shuji Uemura, Masayuki Koyama, Masahiro Hara, Naofumi Bunya, Keigo Sawamoto, Hirofumi Ohnishi, Eichi Narimatsu

Internal medicine (Tokyo, Japan) 62 ( 18 ) 2635 - 2641 2023年06月 [国内誌]

Background During the coronavirus disease 2019 (COVID-19) pandemic period, an extended total activity time (TAT) in emergency cases has been reported, especially in febrile patients. A brief selection time (ST) regarding the transport of patients to designated hospitals is vital to achieving a good outcome. However, to our knowledge, no studies have reported the impact of the COVID-19 pandemic on the ST. We therefore examined the impact of a fever on the ST for the transportation of emergency patients during the COVID-19 pandemic. Method We analyzed emergency medical services (EMS) data in Sapporo between January 2015 and December 2020. The primary outcome was the ST for the emergency destination of patients. The secondary outcomes were the number of inquiries, time from emergency call to arrival at the scene [call-to-scene time (CST)], time from arrival at the hospital to return base [arrival-to-return time (ART)], and TAT. We used a multivariable linear regression model to estimate the difference-in-differences effect. Results A total of 383,917 patients who were transported to the hospital were enrolled within the study period. The mean ST was 5.8 min in 2019 and 7.1 min in 2020. The difference-in-differences analyses showed that the mean ST increased by 2.52 min (p<0.001), the mean ART by 3.10 min (p<0.001), and the mean TAT by 7.27 min (p<0.001) for patients with a fever during the COVID-19 period. Conclusions This study showed that febrile patients had a longer ST, ART, and TAT during the 2020 COVID-19 period. Considering the COVID-19 pandemic and the threat of future pandemics, regional infection control and information-sharing should be conducted to reduce the EMS activity time.

Independent Association Between Use of Proton Pump Inhibitors and Muscle Wasting in Patients with Heart Failure: A Single-Center, Ambispective, Observational Study

Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Hidemichi Kouzu, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Masato Furuhashi

Drugs & Aging ( Springer Science and Business Media LLC ) 40 ( 8 ) 731 - 739 2023年06月 [国際誌]

BACKGROUND: Although proton pump inhibitors (PPIs) play a pivotal role in the prevention and treatment of gastric acid-related diseases and gastrointestinal adverse events caused by antiplatelet therapies, the safety of long-term use of PPIs has been questioned. OBJECTIVE: The aim of this study was to determine the effects of use of PPIs on muscle mass and bone mineral density in heart failure (HF) patients. METHODS: This was a single-center, ambispective (combined retrospective and prospective), observational study. HF patients (n = 747; 72 years of age; males, 54%) who received a dual-energy x-ray absorptiometry scan were enrolled. Muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.0 kg/m2 in males and <5.4 kg/m2 in females. Propensity scores for the use of PPIs were calculated using a multivariate logistic regression model to minimize selection bias. RESULTS: Before propensity score matching, ASMI was significantly lower in patients receiving PPIs than in patients not receiving PPIs, resulting in a higher prevalence of muscle wasting in the PPI group. Such a relationship between use of PPIs and muscle wasting remained after propensity score matching. In multivariate Cox regression analyses, use of PPIs was independently associated with presence of muscle wasting (hazard ratio 1.68, 95% confidence interval 1.05-2.69) after adjustment for established risk factors of sarcopenia. On the other hand, there were no differences in bone mineral density between the PPI group and the no-PPI group. CONCLUSION: Use of PPIs is associated with a high risk of muscle wasting in HF patients. Caution is warranted when long-term PPI treatment is performed in sarcopenic HF patients and HF patients with several risk factors for muscle wasting.

Characterization of prehospital time delay in primary percutaneous coronary intervention for acute myocardial infarction: analysis of geographical infrastructure-dependent and -independent components.

Keisuke Oyatani, Masayuki Koyama, Nobuaki Himuro, Tetsuji Miura, Hirofumi Ohnishi

International journal of health geographics 22 ( 1 ) 7 - 7 2023年03月 [国際誌]

BACKGROUND: Prehospital delay in reaching a percutaneous coronary intervention (PCI) facility is a major problem preventing early coronary reperfusion in patients with ST-elevation myocardial infarction (STEMI). The aim of this study was to identify modifiable factors that contribute to the interval from symptom onset to arrival at a PCI-capable center with a focus on geographical infrastructure-dependent and -independent factors. METHODS: We analyzed data from 603 STEMI patients who received primary PCI within 12 h of symptom onset in the Hokkaido Acute Coronary Care Survey. We defined onset-to-door time (ODT) as the interval from the onset of symptoms to arrival at the PCI facility and we defined door-to-balloon time (DBT) as the interval from arrival at the PCI facility to PCI. We analyzed the characteristics and factors of each time interval by type of transportation to PCI facilities. In addition, we used geographical information system software to calculate the minimum prehospital system time (min-PST), which represents the time required to reach a PCI facility based on geographical factors. We then subtracted min-PST from ODT to find the estimated delay-in-arrival-to-door (eDAD), which represents the time required to reach a PCI facility independent of geographical factors. We investigated the factors related to the prolongation of eDAD. RESULTS: DBT (median [IQR]: 63 [44, 90] min) was shorter than ODT (median [IQR]: 104 [56, 204] min) regardless of the type of transportation. However, ODT was more than 120 min in 44% of the patients. The min-PST (median [IQR]: 3.7 [2.2, 12.0] min) varied widely among patients, with a maximum of 156 min. Prolongation of eDAD (median [IQR]: 89.1 [49, 180] min) was associated with older age, absence of a witness, onset at night, no emergency medical services (EMS) call, and transfer via a non-PCI facility. If eDAD was zero, ODT was projected to be less than 120 min in more than 90% of the patients. CONCLUSIONS: The contribution of geographical infrastructure-dependent time in prehospital delay was substantially smaller than that of geographical infrastructure-independent time. Intervention to shorten eDAD by focusing on factors such as older age, absence of a witness, onset at night, no EMS call, and transfer via a non-PCI facility appears to be an important strategy for reducing ODT in STEMI patients. Additionally, eDAD may be useful for evaluating the quality of STEMI patient transport in areas with different geographical conditions.

Frequent coexistence of early repolarization pattern, J-point elevation, and high Sokolow-Lyon voltage in young men.

Nagomi Saito, Daigo Nagahara, Naoyuki Kamiyama, Takefumi Fujito, Masayuki Koyama, Atsushi Mochizuki, Toshiyuki Yano, Satoshi Takahashi

Journal of arrhythmia 39 ( 1 ) 61 - 70 2023年02月 [国内誌]

BACKGROUND: Earlier studies have shown male dominance of an early repolarization (ER) pattern and frequent coexistence with high Sokolow-Lyon voltage. Although possible involvement of androgen is speculated, the underlying mechanism has not been clarified yet. Previous studies were conducted in adult populations or only in children, and there has been no study in which the ER pattern was investigated in a series of individuals ranging from children before puberty to adults. METHODS: We included 600 individuals comprising six groups according to age: 10-14 years old, 15-19 years old, twenties, thirties, forties, and fifties. Each group had 50 males and 50 females. The distribution of an ER pattern and related ECG parameters were assessed by age and gender. RESULTS: In early teenagers, there was no significant gender difference in the prevalence of an ER pattern (24% in men vs. 28% in women, p = .82). The prevalence of an ER pattern increased after puberty and reached a peak in men in their twenties (42%). With further advance of age, the prevalence of an ER pattern decreased. On the other hand, the prevalence of an ER pattern in women peaked at 28% in teenagers, and it decreased through twenties (20%) to thirties (10%). Similar male dominance after puberty was observed in Sokolow-Lyon voltage and J-point elevation but not in P-wave amplitude. CONCLUSION: The prevalence of an ER pattern, Sokolow-Lyon voltage, and J-point elevation are all augmented after puberty and decrease with aging, leading to frequent coexistence of these ECG findings in young men.

Comparison OF The Treatment Persistence Among Four Direct Oral Anticoagulants In Patients With Non‐Valvular Atrial Fibrillation: A 5‐Year Retrospective Cohort Study

Tomohiro Aigami, Tomoyuki Ishigo, Ryo Takada, Toshiyuki Yano, Masayuki Koyama, Satoshi Katano, Satoshi Fujii, Masahide Fukudo

The Journal of Clinical Pharmacology ( Wiley ) 63 ( 6 ) 654 - 663 2023年01月 [国際誌]

Four direct oral anticoagulants (DOACs) are used in Japan (edoxaban, rivaroxaban, apixaban, and dabigatran); however, few studies have examined the long-term treatment persistence of these DOACs. Furthermore, the factors associated with persistence remain unclear. This single-center, retrospective cohort study enrolled participants who were newly prescribed the 4 DOACs between January 1, 2012, and April 30, 2020. We assessed the treatment persistence rate by calculating the cumulative incidence rate of prescription switch or discontinuation for 5 years from the initial prescription. The factors associated with persistence were examined using multivariate analysis. The edoxaban was used as a reference for comparison with the other DOACs. The persistence rate at 5 years was 52.9% for all DOACs, including 67.0%, 51.6%, 50.2%, and 37.0% for edoxaban, rivaroxaban, apixaban, and dabigatran, respectively. Multivariate analysis revealed that age >65 years (hazard ratio [HR], 0.62 [95%CI, 0.41-0.93]), chronic kidney disease (HR, 1.63 [95%CI, 1.11-2.39]), baseline hemoglobin (HR, 0.85 [95%CI, 0.78-0.93]), diabetes mellitus (HR, 0.51 [95%CI, 0.29-0.93]), and type of DOACs (rivaroxaban: HR, 1.81 [95%CI, 1.03-3.18]; apixaban: HR, 2.00 [95%CI, 1.15-3.48]; and dabigatran: HR, 2.84 [95%CI, 1.66-4.86]) were significantly associated with nonpersistence at 1 year. At 5 years, diabetes mellitus (HR, 0.60 [95%CI, 0.37-0.97]) and type of DOAC were significantly associated with nonpersistence (rivaroxaban: HR, 1.79 [95%CI, 1.09-2.94]; apixaban: HR, 2.04 [95%CI, 1.26-3.31]; and dabigatran: HR, 2.76 [1.73-4.42]). Long-term treatment persistence differed according to the type of DOAC, with edoxaban exhibiting the highest level of persistence. The factors associated with persistence may change over the treatment course, but larger studies are required to generalize our findings.

Case report: Transient lactate elevation by intravenous insulin infusion therapy for diabetic ketoacidosis in a patient with mitochondrial DNA 3243 A > G mutation: A glycolysis rebooting syndrome?

Wataru Ohwada, Hidemichi Kouzu, Tatsuya Sato, Kahomi Sazawa, Azumi Matsui, Nobutaka Nagano, Masayuki Koyama, Noriko Ogasawara, Akifumi Takada, Toshiyuki Yano, Masato Furuhashi

Frontiers in cardiovascular medicine 10 1144925 - 1144925 2023年 [国際誌]

Mitochondrial disease, most cases of which are caused by mitochondrial DNA (mtDNA) mutation, is present with multiple phenotypes including diabetes mellitus, sensorineural hearing loss, cardiomyopathy, muscle weakness, renal dysfunction, and encephalopathy, depending on the degree of heteroplasmy. While mitochondria play an important role in intracellular glucose and lactate metabolism in insulin-sensitive tissues such as muscles, appropriate strategies for glycemic control have not yet been established in a patient with mitochondrial disease, which is often complicated by myopathy. Here, we describe the history of a 40-year-old man with mtDNA 3243A > G who had sensorineural hearing loss, cardiomyopathy, muscle wasting, and diabetes mellitus with stage 3 chronic kidney disease. He developed mild diabetic ketoacidosis (DKA) in the process of treatment for poor glycemic control with severe latent hypoglycemia. According to the standard therapy for DKA, he was treated with continuous intravenous insulin infusion therapy, which unexpectedly resulted in an abrupt and transient elevation in blood lactate levels without exacerbation of heart failure and kidney function. Since blood lactate levels are determined by the balance between lactate production and consumption, an abrupt and transient lactate elevation following intravenous insulin injection therapy may reflect not only enhanced glycolysis in insulin-sensitive tissues with mitochondrial dysfunction but also decreased lactate consumption in the sarcopenic skeletal muscle and failing heart. Intravenous insulin infusion therapy in patients with mitochondrial disease may unmask derangements of intracellular glucose metabolism in response to insulin signaling.

THE STRAIGHTFORWARD AND IMMEDIATE KIDNEY BIOPSY USING A GUIDE NEEDLE (SIGN) REDUCES THE PUNCTURE TIME AND ENABLES ADEQUATE TISSUE TO BE OBTAINED

Masayuki Koyama

Nephrology Dialysis Transplantation 2023年

Preserved Lower Limb Muscle Mass Prevents Insulin Resistance Development in Nondiabetic Older Adults.

Toshiaki Seko, Hiroshi Akasaka, Masayuki Koyama, Nobuaki Himuro, Shigeyuki Saitoh, Tetsuji Miura, Mitsuru Mori, Hirofumi Ohnishi

Journal of the American Medical Directors Association 24 ( 3 ) 376 - 381 2022年12月 [国際誌]

OBJECTIVE: To investigate roles of sarcopenia indexes in prediction of development of insulin resistance in nondiabetic older adults. DESIGN: A 2-year follow-up cohort. SETTING AND PARTICIPANTS: The Tanno-Sobetsu study, a prospective observational cohort, included 194 community-dwelling nondiabetic older adults during 2017-2019. METHODS: Lower limb, upper limb, appendicular, and trunk muscle masses by a bioelectrical impedance analysis, grip strength, knee extension torque, and walking speed were measured in study participants aged ≥65 years (79 men and 115 women) at baseline. Muscle mass and strength were divided by the weight, and then multiplied by 100 to calculate the weight ratio (%). Insulin resistance was assessed by homeostasis model (HOMA-IR) at baseline, and the study participants whose HOMA-IR was less than 1.73 at baseline were followed for a maximum of 2 years. The study endpoint was development of insulin resistance defined as HOMA-IR ≥1.73. The adjusted hazard ratio (HR) of each sarcopenia component for development of insulin resistance was calculated. RESULTS: Lower limb muscle mass (HR 0.88, 95% CI 0.79-0.98) and appendicular muscle mass (HR 0.89, 95% CI 0.81-0.99), but not other sarcopenia components, were associated with the development of insulin resistance, independently of sex and age, HOMA-IR, and waist circumference at baseline. CONCLUSIONS AND IMPLICATIONS: The loss of lower limb muscle mass is a significant risk factor for development of insulin resistance independently of obesity in nondiabetic older adults. The lower limb muscle mass may be a novel target of interventions for the prevention of diabetes in older adults.

Walking Speed Is Better Than Hand Grip Strength as an Indicator of Early Decline in Physical Function with Age in Japanese Women Over 65: A Longitudinal Analysis of the Tanno-Sobetsu Study Using Linear Mixed-Effects Models.

Shunichi Ogawa, Nobuaki Himuro, Masayuki Koyama, Toshiaki Seko, Mitsuru Mori, Hirofumi Ohnishi

International journal of environmental research and public health 19 ( 23 ) 2022年11月 [国際誌]

The decline in physical function with age is a major contributor to the need for long-term care. Age-related changes in hand grip strength, knee extension, and walking speed have been reported in cross-sectional studies, but longitudinal data are needed. This longitudinal study measured changes in these three measures among community-dwelling adults aged 65-89 years who participated in general health examinations between 2017 and 2019. Analyses were stratified by sex. Linear mixed-effects models adjusted for confounding factors were used to examine the interaction of different patterns of change with age of the three measures. A total of 284 participants were included in the analysis. The interaction term of age × walking speed, with age × handgrip strength as the reference, was statistically significant in women and showed different patterns in walking speed and hand grip strength. In men, none of the age × physical function interaction terms were significant in any model. For early recognition of the onset of physical function decline in older adults, any of the three measures may be used in men, but walking speed may be more suitable than hand grip strength in women. These findings may be useful in devising sex-specific screening strategies.

Correction: Toe grip strength declines earlier than hand grip strength and knee extension strength in community‑dwelling older men: a cross sectional study.

Sayo Miura, Toshiaki Seko, Nobuaki Himuro, Masayuki Koyama, Shigeyuki Saitoh, Hirofumi Ohnishi

Journal of foot and ankle research 15 ( 1 ) 81 - 81 2022年11月 [国際誌]

コロナウイルス陽性者健康観察アプリ「こびまる」の自宅療養者データの分析

高塚伸太朗, 小山雅之, 中山龍一, 谷川琢海, 向原強, 藤本直樹, 福田潤, 小澤秀弘

医療情報学連合大会論文集 ( (一社)日本医療情報学会 ) 42回 542 - 544 2022年11月

情報システム開発を専門としない学生を対象としたPBLによる健康観察アプリケーションの開発と運用

向原強, 藤本直樹, 谷川琢海, 小山雅之, 高塚伸太朗, 中山龍一, 福田潤, 小澤秀弘

医療情報学連合大会論文集 ( (一社)日本医療情報学会 ) 42回 978 - 983 2022年11月

新型コロナウイルス感染症の自宅療養者に対する健康観察アプリケーションのユーザビリティ

中山龍一, 小山雅之, 高塚伸太朗, 向原強, 谷川琢海, 藤本直樹, 福田潤, 小澤秀弘, 大西浩文, 上村修二

医療情報学連合大会論文集 ( (一社)日本医療情報学会 ) 42回 539 - 541 2022年11月

官学連携により産まれたCOVID-19健康観察システム「こびまるライト」

小山雅之, 谷川琢海, 高塚伸太朗, 中山龍一, 向原強, 藤本直樹, 福田潤, 齋藤彩乃, 石川珠美, 小澤秀弘, 大西浩文

医療情報学連合大会論文集 ( (一社)日本医療情報学会 ) 42回 545 - 546 2022年11月

Python Webアプリケーションフレームワークを用いたCOVID-19健康観察管理システムの構築

谷川琢海, 中山龍一, 小山雅之, 高塚伸太朗, 向原強, 藤本直樹, 福田潤, 小澤秀弘

医療情報学連合大会論文集 ( (一社)日本医療情報学会 ) 42回 1444 - 1446 2022年11月

Toe Grip strength declines earlier than hand grip strength and knee extension strength in community-dwelling older men: a cross sectional study.

Sayo Miura, Toshiaki Seko, Nobuaki Himuro, Masayuki Koyama, Shigeyuki Saitoh, Hirofumi Ohnishi

Journal of foot and ankle research 15 ( 1 ) 79 - 79 2022年10月 [国際誌]

BACKGROUND: The aim of this study is to examine the age-related changes in the toe grip strength and its differences from hand grip strength and knee extension strength using cross-sectional data. METHODS: Of participants aged 65 years over who underwent health checkups for lifestyle-related diseases in 2018, 307 men and women met the criteria. Toe grip strength, hand grip strength, and knee extension strength were also measured as optional tests. The participants were divided into five groups categorized by every 5 years of age (Group 65-85). The data were analyzed with multiple comparisons using the linear mixed multilevel model to examine the following categories: association between age and muscle strength, differences in the pattern of change, and gender, using the 65-69 years group as a reference. RESULTS: In men, there were interaction effects between the factors of age and muscle, but in women there were not. Toe grip strength was significantly lower in Group 70, 75, 80, and 85 in men, lower in Group 85 than in 65 in women. Hand grip strength was significantly lower in Group 85 than in 65 in both men and women. There was no significant difference in knee extension strength among the age groups for both men and women. CONCLUSIONS: The decline in toe grip strength may occur earlier and in a different pattern from hand grip strength and knee extension strength in men.

Japanese female urologists' work-life balance during the COVID-19 pandemic.

Sachiyo Nishida, Hitomi Sasaki, Yoshiko Maeda, Masayuki Koyama, Katsuhito Miyazawa, Naoya Masumori

International journal of urology : official journal of the Japanese Urological Association 29 ( 12 ) 1569 - 1570 2022年09月 [国際誌]

Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy

Yugo Fujita, Toshiyuki Yano, Hiromitsu Kanamori, Daigo Nagahara, Atsuko Muranaka, Hidemichi Kouzu, Atsushi Mochizuki, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Naoyuki Kamiyama, Marenao Tanaka, Atsushi Kuno, Masaya Tanno, Tetsuji Miura

ESC Heart Failure ( Wiley ) 9 ( 5 ) 3435 - 3451 2022年07月 [国際誌]

AIMS: The role of necroptosis in dilated cardiomyopathy (DCM) remains unclear. Here, we examined whether phosphorylation of mixed lineage kinase domain-like protein (MLKL), an indispensable event for execution of necroptosis, is associated with the progression of DCM. METHODS AND RESULTS: Patients with DCM (n = 56, 56 ± 15 years of age; 68% male) were enrolled for immunohistochemical analyses of biopsies. Adverse events were defined as a composite of death or admission for heart failure or ventricular arrhythmia. Compared with the normal myocardium, increased signals of MLKL phosphorylation were detected in the nuclei, cytoplasm, and intercalated discs of cardiomyocytes in biopsy samples from DCM patients. The phosphorylated MLKL (p-MLKL) signal was increased in enlarged nuclei or nuclei with bizarre shapes in hypertrophied cardiomyocytes. Nuclear p-MLKL level was correlated negatively with septal peak myocardial velocity during early diastole (r = -0.327, P = 0.019) and was correlated positively with tricuspid regurgitation pressure gradient (r = 0.339, P = 0.023), while p-MLKL level in intercalated discs was negatively correlated with mean left ventricular wall thickness (r = -0.360, P = 0.014). During a median follow-up period of 3.5 years, 10 patients (18%) had adverse events. To examine the difference in event rates according to p-MLKL expression levels, patients were divided into two groups by using the median value of nuclear p-MLKL or intercalated disc p-MLKL. A group with high nuclear p-MLKL level (H-nucMLKL group) had a higher adverse event rate than did a group with low nuclear p-MLKL level (L-nucMLKL group) (32% vs. 4%, P = 0.012), and Kaplan-Meier survival curves showed that the adverse event-free survival rate was lower in the H-nucMLKL group than in the L-nucMLKL group (P = 0.019 by the log-rank test). Such differences were not detected between groups divided by a median value of intercalated disc p-MLKL. In δ-sarcoglycan-deficient (Sgcd-/- ) mice, a model of DCM, total p-MLKL and nuclear p-MLKL levels were higher than in wild-type mice. CONCLUSION: The results suggest that increased localization of nuclear p-MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM.

Diagnosis of prosthetic joint infection at the hip using the standard uptake value of three-phase 99mTc-hydroxymethylene diphosphonate SPECT/CT.

Naoya Yama, Satoshi Nagoya, Shintaro Sugita, Masayuki Koyama, Masamitsu Hatakenaka

Annals of nuclear medicine ( SPRINGER ) 36 ( 7 ) 634 - 642 2022年04月 [国内誌]

PURPOSE: To retrospectively investigate whether the standard uptake value (SUV) of 99mTc-bone single-photon emission computed tomography (SPECT)/CT could be useful for predicting prosthetic joint infection (PJI) at the hip. PATIENTS AND METHODS: We analyzed the cases of 37 patients with a suspected PJI at the hip who underwent 99mTc-bone SPECT/CT and surgical intervention with pathological and bacterial examinations. We divided the cases into those with and those without a causative bacterium detected in a surgical specimen, i.e., the positive bacterial culture (PBC) group (n = 17) and negative bacterial culture (NBC) group (n = 20). Cases with neutrophilic infiltration of surgical specimen comprised the positive neutrophilic infiltration (PINF) group (n = 18) and those without INF comprised the non-neutrophilic infiltration (NINF) group (n = 19). Quantitative analyses were performed using maximum SUVs and peak SUVs of blood-pool (BP) phase images (SUVmaxBP and SUVpeakBP) and late (LT)-phase images (SUVmaxLT and SUVpeakLT). RESULTS: Regarding the bacterial cultures, there were significant differences between the PBC and NBC groups in SUVmaxBP (5.26 ± 1.49 vs. 4.21 ± 1.15, respectively; p = 0.019), SUVpeakBP (4.89 ± 1.32 vs. 3.87 ± 1.06, p = 0.012), SUVmaxLT (16.10 ± 6.36 vs. 11.67 ± 4.95, p = 0.026), and SUVpeakLT (14.58 ± 5.83 vs. 10.49 ± 4.31 p = 0.036). Regarding neutrophilic infiltration, there were significant differences between the PINF and NINF groups in SUVmaxBP (5.18 ± 1.48 vs. 4.24 ± 1.19, p = 0.047) and SUVpeakBP (4.78 ± 1.32 vs. 3.92 ± 1.10, p = 0.043). CONCLUSION: An SUV analysis of 99mTc-bone SPECT/CT is a useful method to differentiate a PJI at the hip from non-infection.

Plasma Tsukushi Concentration Is Associated with High Levels of Insulin and FGF21 and Low Level of Total Cholesterol in a General Population without Medication.

Masato Furuhashi, Yukimura Higashiura, Akiko Sakai, Masayuki Koyama, Marenao Tanaka, Shigeyuki Saitoh, Kazuaki Shimamoto, Hirofumi Ohnishi

Metabolites 12 ( 3 ) 2022年03月 [国際誌]

Tsukushi (TSK) is a member of the small leucine-rich proteoglycan family that controls developmental processes and organogenesis. TSK was also identified as a new hepatokine, which is mainly expressed in the liver, and is secreted by hepatocytes, to regulate energy and glycolipid metabolism in response to nonalcoholic fatty liver disease. However, the role of plasma TSK, especially its role in the general population, has not been fully addressed. We investigated the associations between plasma TSK concentration and several metabolic markers, including fibroblast growth factor 21 (FGF21), a hepatokine, and adiponectin, an adipokine, in 253 subjects (men/women: 114/139) with no medication in the Tanno-Sobetsu Study, which employed a population-based cohort. There was no significant sex difference in plasma TSK concentration, and the level was positively correlated with the fatty liver index (FLI) (r = 0.131, p = 0.038), levels of insulin (r = 0.295, p < 0.001) and levels of FGF21 (r = 0.290, p < 0.001), and was negatively correlated with the total cholesterol level (r = -0.124, p = 0.049). There was no significant correlation between the TSK level and body mass index, waist circumference, adiponectin, high-density lipoprotein cholesterol or total bile acids. The multivariable regression analysis showed that high levels of insulin and FGF21 and a low level of total cholesterol were independent determinants of plasma TSK concentration, after adjustment for age, sex and FLI. In conclusion, plasma TSK concentration is independently associated with high levels of insulin and FGF21, a hepatokine, and a low level of total cholesterol, but not with adiposity and adiponectin, in a general population of subjects who have not taken any medications.

Serum uric acid level is associated with an increase in systolic blood pressure over time in female subjects: Linear mixed-effects model analyses.

Kazuma Mori, Masato Furuhashi, Marenao Tanaka, Yukimura Higashiura, Masayuki Koyama, Nagisa Hanawa, Hirofumi Ohnishi

Hypertension research : official journal of the Japanese Society of Hypertension 45 ( 2 ) 344 - 353 2022年02月 [国際誌]

Whether hyperuricemia is a true risk factor for elevated blood pressure (BP) is controversial, and the sex-specific effects of serum uric acid (SUA) on BP during a follow-up period remain unclear. We investigated whether the association of SUA level with systolic or diastolic BP during a 10-year period differs by sex in a Japanese general population of individuals who received annual health examinations (n = 28,990). After exclusion of subjects who had no BP or SUA data at baseline, a total of 22,994 subjects (male/female: 14,603/8391, age: 47 ± 11 years) were recruited. After adjustment for age; body mass index; BP; SUA level; use of drugs for hyperuricemia and hypertension; diagnosis of diabetes mellitus, dyslipidemia, and chronic kidney disease; family history of hypertension; habits of current smoking and alcohol consumption at baseline; the duration of the observation period; and the interaction between each covariate and the duration of the observation period indicated a significant association of SUA level with change in systolic or diastolic BP over time. There was a significant interaction between sex and SUA level for the change in systolic BP (P = 0.003) but not the change in diastolic BP (P = 0.081). The SUA level at baseline (per 1 mg/dL) was significantly associated with a change in systolic BP over time in females (estimate: 0.073 mmHg/year, P = 0.003) but not in males (estimate: 0.020 mmHg/year, P = 0.160). In conclusion, a high SUA level at baseline is significantly associated with an increase in systolic BP over time in female individuals but not in male individuals.

Loss of social role awareness, a subdomain of social frailty, is an independent predictor of future adverse events in hospitalized older patients with heart failure

Masayuki Koyama

European Heart Journal 2022年

Coexistence of sarcopenia and osteoporosis in patients with heart failure: prevalence and association with functional status

Masayuki Koyama

European Heart Journal 2022年

Circulating level of fatty acid-binding protein 4 is an independent predictor of metabolic dysfunction-associated fatty liver disease in middle-aged and elderly individuals.

Marenao Tanaka, Satoko Takahashi, Yukimura Higashiura, Akiko Sakai, Masayuki Koyama, Shigeyuki Saitoh, Kazuaki Shimamoto, Hirofumi Ohnishi, Masato Furuhashi

Journal of diabetes investigation ( WILEY ) 13 ( 5 ) 878 - 888 2021年12月 [国内誌]

AIMS/INTRODUCTION: Metabolic dysfunction-associated fatty liver disease (MAFLD), defined as hepatosteatosis with type 2 diabetes mellitus, overweight/obesity or metabolic dysregulation, has been proposed as a new feature of chronic liver disease. Fatty acid-binding protein 4 (FABP4) is expressed in adipose tissue, and secreted FABP4 is associated with the development of insulin resistance and atherosclerosis. However, the relationship between MAFLD and FABP4 has not been fully addressed. MATERIALS AND METHODS: Associations of MAFLD with metabolic markers, including FABP4, fibroblast growth factor 21 and adiponectin, were investigated in 627 individuals (men/women 292/335) in the Tanno-Sobetsu Study, a population-based cohort. RESULTS: The mean age was 65 years (range 19-98 years, median [interquartile range] 68 [56-76] years). Hepatosteatosis was determined by the fatty liver index (FLI), and FLI ≥35 for men and FLI ≥16 for women were used for detection of fatty liver, as previously reported using 14,471 Japanese individuals. FLI was positively correlated with systolic blood pressure and levels of FABP4 (r = 0.331, P < 0.001), fibroblast growth factor 21, homeostasis model assessment of insulin resistance as an insulin resistance index and uric acid, and was negatively correlated with levels of high-density lipoprotein cholesterol and adiponectin. FABP4 concentration was independently associated with FLI after adjustment of age, sex, systolic blood pressure and levels of uric acid, high-density lipoprotein cholesterol, homeostasis model assessment of insulin resistance, adiponectin and fibroblast growth factor 21 in multivariable regression analysis. Logistic regression analysis showed that FABP4 was an independent predictor of MAFLD after adjustment of age, sex, presence of diabetes mellitus, hypertension and dyslipidemia, and levels of uric acid, homeostasis model assessment of insulin resistance, adiponectin and fibroblast growth factor 21. CONCLUSIONS: FABP4 concentration is independently associated with FLI and is an independent predictor of MAFLD in middle-aged and elderly individuals.

Abrupt Onset of Cardiac Tamponade in Sarcoidosis.

Toshiyuki Yano, Shin Hisahara, Nobutaka Nagano, Takahiro Noto, Toshifumi Ogawa, Ryo Nishikawa, Masayuki Koyama, Hidemichi Kouzu, Atsuko Muranaka, Akiyoshi Hashimoto, Shun Shimohama, Tetsuji Miura

International heart journal ( INT HEART JOURNAL ASSOC ) 62 ( 5 ) 1176 - 1181 2021年09月 [国内誌]

Sarcoidosis is a systemic inflammatory disease characterized by the formation of noncaseating epithelioid granulomas. Multiple organs, including the lung, eyes, and skin, are involved in this disorder, and cardiac involvement is a major cause of morbidity and mortality in patients with this disorder. We present the case history of a 22-year-old man with neurosarcoidosis complicated by abrupt onset of cardiac tamponade. Cardiac tamponade is a rare but potentially fatal manifestation of sarcoidosis, which is treatable with glucocorticoid therapy. Including the present case, previously reported cases of sarcoidosis with cardiac tamponade are reviewed to delineate its clinical characteristics.

Barthel Index Score Predicts Mortality in Elderly Heart Failure ― A Goal of Comprehensive Cardiac Rehabilitation ―

Satoshi Katano, Toshiyuki Yano, Katsuhiko Ohori, Hidemichi Kouzu, Ryohei Nagaoka, Suguru Honma, Kanako Shimomura, Takuya Inoue, Yuhei Takamura, Tomoyuki Ishigo, Ayako Watanabe, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Akiyoshi Hashimoto, Masaki Katayose, Sumio Ishiai, Tetsuji Miura

Circulation Journal ( Japanese Circulation Society ) 86 ( 1 ) 70 - 78 2021年09月 [国内誌]

BACKGROUND: A strategy to predict mortality in elderly heart failure (HF) patients has not been established.Methods and Results:We retrospectively enrolled 413 HF patients aged ≥65 years (mean age 78 years) who had received comprehensive cardiac rehabilitation (CR) during hospitalization. Basic activities of daily life were assessed before discharge using the Barthel index (BI). Of 413 HF patients, 116 (28%) died during a median follow-up period of 1.90 years (interquartile range 1.20-3.23 years). An adjusted dose-dependent association analysis showed that the hazard ratio (HR) of mortality increased in an almost linear manner as the BI score decreased, and that a BI score of 85 corresponded to an HR of 1.0. Kaplan-Meier survival curves showed that the survival rate was lower for patients with a low BI (<85) than for those with a high BI (≥85; 65% vs. 74%, respectively; P=0.007). In multivariate Cox regression analyses, low BI was independently associated with higher mortality after adjusting for predictors, including B-type natriuretic peptide. Inclusion of the BI into the adjusted model improved the accuracy of the prediction of mortality. CONCLUSIONS: A BI score <85 at the time of discharge is associated with increased mortality independent of known prognostic markers, and achieving functional status with a BI score ≥85 by comprehensive CR during hospitalization may contribute to favorable outcomes in elderly HF patients.

Plasma amino acid profiling improves predictive accuracy of adverse events in patients with heart failure

Hidemichi Kouzu, Satoshi Katano, Toshiyuki Yano, Katsuhiko Ohori, Ryohei Nagaoka, Takuya Inoue, Yuhei Takamura, Tomoyuki Ishigo, Ayako Watanabe, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Tetsuji Miura

ESC Heart Failure ( Wiley ) 8 ( 6 ) 5045 - 5056 2021年09月 [国際誌]

AIMS: The clinical outcome of heart failure (HF) is complicated by the presence of multiple comorbidities including malnutrition and cachexia, and prediction of the outcome is still difficult in each patient. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiling improves prediction of clinical outcomes in patients with HF. METHODS AND RESULTS: We retrospectively examined 301 HF patients (70 ± 15 years old; 59% male). Blood samples for measurements of amino acid concentrations were collected in a fasting state after stabilization of HF. Plasma amino acid concentrations were measured using ultraperformance liquid chromatography. Clinical endpoint of this study was adverse event defined as all-cause death and unscheduled readmission due to worsening HF or lethal arrhythmia. During a mean follow-up period of 380 ± 214 days, 40 patients (13%) had adverse events. Results of analyses of variable importance in projection score, a measure of a variable's importance in partial least squares-discriminant analysis (PLS-DA) showed that the top five amino acids being associated with adverse events were 3-methylhistidine (3-Me-His), β-alanine, valine, hydroxyproline, and tryptophan. Multivariate Cox-proportional hazard analyses indicated that a high 3-Me-His concentration and low β-alanine and valine concentrations were independently associated with adverse events. When HF patients were divided according to the cut-off values of amino acids calculated from receiver operating characteristic curves, Kaplan-Meier survival curves showed that event-free survival rates were lower in HF patients with high 3-Me-His than in HF patients with low 3-Me-His (68% vs. 91%, P < 0.01). In a subgroup with high 3-Me-His, HF patients with low β-alanine and those with low valine had significantly lower event-free survival rates than did HF patients with high β-alanine and those with high valine, respectively. On the other hand, Kaplan-Meier curves of event-free survival rates did not differ between HF patients with and those without low β-alanine and low valine in subgroups of patients with low 3-Me-His. Inclusion of both high 3-Me-His and low β-alanine or low valine into the adjustment model including N-terminal pro-brain natriuretic peptide improved the accuracy of prediction of adverse events after discharge. 3-Me-His concentration was associated with muscle mass and nutritional status. CONCLUSIONS: Simple measurement of 3-Me-His with either β-alanine or valine improved the predictive ability for adverse events, indicating the utility of plasma amino acid profiling in risk stratification of hospitalized HF patients.

Distinct Regulation of U-ACE2 and P-ACE2 (Urinary and Plasma Angiotensin-Converting Enzyme 2) in a Japanese General Population

Masato Furuhashi, Akiko Sakai, Marenao Tanaka, Yukimura Higashiura, Kazuma Mori, Masayuki Koyama, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto

Hypertension ( Ovid Technologies (Wolters Kluwer Health) ) 78 ( 4 ) 1138 - 1149 2021年08月 [国際誌]

Severe acute respiratory syndrome coronavirus 2 in coronavirus disease 2019 invades the host through ACE (angiotensin-converting enzyme) 2 as the host cellular receptor for a viral spike protein. ACE2 converts angiotensin II to angiotensin-(1–7) and cleaved ACE2 is detectable in urine and plasma. However, regulation of U-ACE2 (urinary ACE2) and P-ACE2 (plasma ACE2) and their alterations by renin-angiotensin-aldosterone system inhibitors remain unclear. We simultaneously investigated U-ACE2 and P-ACE2 in 605 Japanese participants (male/female: 280/325, mean age: 65±15 years) in the Tanno-Sobetsu cohort study in 2017. Males had significantly lower U-ACE2 and higher P-ACE2 than did females. There was no significant correlation between U-ACE2 and P-ACE2. P-ACE2 was significantly lower in subjects treated with renin-angiotensin-aldosterone system inhibitors than in those not treated with renin-angiotensin-aldosterone system inhibitors, but there was no significant difference in U-ACE2 between the groups. Multivariable regression analyses showed that female sex, high levels of systolic blood pressure, hemoglobin A1c, and urinary albumin-to-creatinine ratio, and low uric acid level were independent predictors of high U-ACE2 level and that high levels of γ-glutamyl transpeptidase, estimated glomerular filtration rate, and uric acid were independent predictors of high P-ACE2 level. In conclusion, U-ACE2 and P-ACE2 are distinctly regulated and the use of renin-angiotensin-aldosterone system inhibitors is not an independent predictor of their levels in a Japanese general population. U-ACE2 is associated with high blood pressure, high glucose level, and microalbuminuria, and low urate level, whereas P-ACE2 is associated with liver dysfunction, high glomerular filtration rate, and high urate level.

Novel prediction equation for appendicular skeletal muscle mass estimation in patients with heart failure: Potential application in daily clinical practice.

Satoshi Katano, Toshiyuki Yano, Katsuhiko Ohori, Nobutaka Nagano, Suguru Honma, Kanako Shimomura, Tomoyuki Ishigo, Ayako Watanabe, Remi Honma, Takefumi Fujito, Masayuki Koyama, Hidemichi Kouzu, Akiyoshi Hashimoto, Masaki Katayose, Tetsuji Miura

European journal of preventive cardiology 28 ( 9 ) e18-e21 2021年08月 [国際誌]

Independent Association of Fatty Liver Index With Left Ventricular Diastolic Dysfunction in Subjects Without Medication

Masato Furuhashi, Atsuko Muranaka, Satoshi Yuda, Marenao Tanaka, Masayuki Koyama, Mina Kawamukai-Nishida, Satoko Takahashi, Yukimura Higashiura, Daisuke Miyamori, Ryo Nishikawa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

The American Journal of Cardiology ( Elsevier BV ) 158 139 - 146 2021年08月 [国際誌]

Nonalcoholic fatty liver disease has been reported to be potentially linked to cardiovascular disease. Fatty liver index (FLI) is a noninvasive and simple predictor of nonalcoholic fatty liver disease. However, little is known about the relationship between FLI and cardiac function, especially in a general population. We investigated the relationships of FLI with echocardiographic parameters in 185 subjects (men/women: 79/106) of the Tanno-Sobetsu Study, a population-based cohort, who were not being treated with any medication and who underwent echocardiography. FLI was negatively correlated with high-density lipoprotein cholesterol and peak myocardial velocity during early diastole (e'; r = -0.342, p <0.001), an index of left ventricular (LV) diastolic function, and ratio of peak mitral velocities during early and late diastole (E/A) and was positively correlated with age, systolic and diastolic blood pressures, creatinine, uric acid, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, ratio of mitral to myocardial early diastolic peak velocity (E/e'), left atrial volume index and LV mass index. No significant correlation was found between FLI and LV ejection fraction. Stepwise multivariable regression analysis showed that FLI was independently and negatively associated with e' after adjustment of age, gender, high-density lipoprotein cholesterol, homeostasis model assessment of insulin resistance, and high-sensitivity C-reactive protein. Conversely, e' was independently and negatively associated with FLI after adjustment of age, gender, systolic blood pressure, and LV ejection fraction. In conclusion, elevated FLI is independently associated with LV diastolic dysfunction in a general population without medication. FLI would be a novel marker of LV diastolic dysfunction as an early sign of myocardial injury.

Energy intake during hospital stay predicts all-cause mortality after discharge independently of nutritional status in elderly heart failure patients.

Satoshi Katano, Toshiyuki Yano, Hidemichi Kouzu, Katsuhiko Ohori, Kanako Shimomura, Suguru Honma, Ryohei Nagaoka, Takuya Inoue, Yuhei Takamura, Tomoyuki Ishigo, Ayako Watanabe, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Akiyoshi Hashimoto, Masaki Katayose, Tetsuji Miura

Clinical research in cardiology : official journal of the German Cardiac Society 110 ( 8 ) 1202 - 1220 2021年08月 [国際誌]

OBJECTIVE: Malnutrition is associated with an increased risk of mortality in heart failure (HF) patients. Here, we examined the hypothesis that assessment of energy intake in addition to nutritional status improves the stratification of mortality risk in elderly HF patients. METHODS: We retrospectively examined 419 HF patients aged ≥ 65 years (median 78 years, 49% female). Nutritional status was assessed by the Mini Nutritional Assessment Short Form (MNA-SF), and daily energy intake was calculated from intake during 3 consecutive days before discharge. RESULTS: During a median 1.52-year period (IQR 0.96-2.94 years), 110 patients (26%) died. Kaplan-Meier survival curves showed that patients with low tertile of daily energy intake had a higher mortality rate than did patients with high or middle tertile of daily energy intake. In multivariate Cox regression analyses, low daily energy intake was independently associated with higher mortality after adjustment for the model including age, sex, BNP, Charlson Comorbidity Index, history of HF hospitalization, and cachexia in addition to MNA-SF. Inclusion of both MNA-SF and energy intake into the adjustment model improved the accuracy of prediction of the mortality after discharge (continuous net reclassification improvement, 0.355, p = 0.003; integrated discrimination improvement, 0.029, p = 0.003). Results of a fully adjusted dose-dependent association analysis showed that risk of all-cause mortality was lowest among HF patients who consumed 31.5 kcal/kg/day of energy. CONCLUSIONS: Energy intake during hospital stay is an independent predictor of the mortality in elderly HF patients, and its assessment together with established predictors improves the mortality risk stratification.

Does renin-angiotensin system inhibition have impacts on muscle mass and bone mineral density in heart failure patients?

Satoshi Katano, Toshiyuki Yano, Masaki Shimizu, Katsuhiko Ohori, Hidemichi Kouzu, Masayuki Koyama, Ryohei Nagaoka, Takuya Inoue, Yuhei Takamura, Tomoyuki Ishigo, Hiroyuki Takashima, Masaki Katayose, Hirofumi Ohnishi, Tetsuji Miura

ESC heart failure 8 ( 4 ) 2617 - 2624 2021年08月 [国際誌]

AIMS: Results of experimental studies have indicated the possibility of muscle and bone mass being negatively regulated by renin-angiotensin system (RAS) activation, but that possibility has not been analysed in patients with heart failure (HF). METHODS AND RESULTS: Data for HF patients who received a dual-energy X-ray absorptiometry scan in our hospital were reviewed. Propensity scores for the use of RAS inhibitors (RASIs) were calculated using a multivariate logistic regression model to minimize selection bias. One hundred sixty pairs of patients were extracted. Plasma aldosterone concentration was significantly lower in the RASIs group than in the no-RASIs group (119 [IQR 71-185] vs. 94 [IQR 60-131] pg/mL, P = 0.003), confirming RAS inhibition in the RASIs group. Skeletal muscle mass index tended to be higher in the RASIs group than in the non-RASIs group (15.6 [IQR 14.0-17.2] vs. 15.0 [IQR 13.3-16.6] pg/mL, P = 0.065). The proportion of patients with muscle wasting, defined as appendicular skeletal muscle mass indexes of <7.00 and <5.40 kg/m2 for males and females, respectively, was significantly lower in the RASIs group than in the non-RASIs group (53% vs. 64%, P = 0.041). Multivariate logistic regression analysis showed that the no use of RASIs was associated with presence of muscle wasting independently of age, presence of diabetes, renal function, and severity of HF. Bone mineral densities and proportions of patients with osteoporosis were similar in the two groups. CONCLUSIONS: Renin-angiotensin system inhibition is associated with a lower prevalence of muscle wasting in HF patients independently of established risk factors.

Elevated Fatty Liver Index Is Independently Associated With New Onset of Hypertension During a 10-Year Period in Both Male and Female Subjects.

Yukimura Higashiura, Masato Furuhashi, Marenao Tanaka, Satoko Takahashi, Kazuma Mori, Daisuke Miyamori, Masayuki Koyama, Hirofumi Ohnishi, Norihito Moniwa, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Tetsuji Miura

Journal of the American Heart Association 10 ( 14 ) e021430 2021年07月 [国際誌]

Background Fatty liver index (FLI), a predictor of nonalcoholic fatty liver disease, has been reported to be associated with several metabolic disorders. Because of a sex difference in FLI level, we hypothesized that FLI is associated with development of hypertension to a greater extent in men or women. Methods and Results We investigated the relationship between FLI and development of hypertension during a 10-year period in a general population of subjects who received annual health examinations (n=28 990). After exclusion (44.9%) of subjects with missing data and those with hypertension at baseline, a total of 15 965 subjects (men/women: 9466/6499) were included. FLI level was significantly higher in men than in women. During the 10-year period, 2304 men (24.3%) and 745 women (11.5%) had new onset of hypertension. Multivariable Cox proportional hazard models with a restricted cubic spline showed that the hazard ratios (HRs) for development of hypertension after adjustment of age, systolic blood pressure, estimated glomerular filtration rate, habits of smoking and alcohol drinking, family history of hypertension, and diagnosis of diabetes mellitus and dyslipidemia increased gradually with increase in FLI in men and increased rapidly and then slowly with increase in FLI in women. There was a significant interaction between FLI and sex for the risk of hypertension in all of the subjects (P=0.049). The addition of FLI to traditional risk factors significantly improved the discriminatory capability. Conclusions A high level of FLI predicts the development of hypertension in both men and women, although distribution patterns of HRs were different between sexes.

Prediction of new onset of diabetes mellitus during a 10-year period by using a combination of levels of alanine aminotransferase and γ-glutamyl transferase.

Daisuke Miyamori, Marenao Tanaka, Masato Furuhashi, Hirofumi Ohnishi, Masayuki Koyama, Arata Osanami, Yukimura Higashiura, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Norihito Moniwa, Tetsuji Miura

Endocrine journal 68 ( 12 ) 1391 - 1402 2021年07月 [国内誌]

Levels of alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) have been reported to be associated with increased risk of diabetes mellitus (DM). However, whether a combination of levels of ALT and GGT predicts new onset of DM better than does ALT or GGT alone in both males and females has not fully been addressed. We investigated the relationship between the combination of ALT and GGT and DM development during a 10-year follow-up period in 13,919 subjects (male/female: 8,983/4,936; age 48 ± 10 years) who received health examinations. During the 10-year period, 617 males (6.9%) and 153 females (3.1%) had new onset of DM. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard ratios (HRs) of DM development increased with higher levels of ALT and GGT at baseline in both sexes after adjustment of confounding factors. When divided into 4 subgroups of high (H-) and low (L-) levels of ALT (male/female: 27/21 U/L) and GGT (male/female: 43/23 U/L) using cutoff values shown by receiver operating characteristic curve analyses, the adjusted HR in the H-ALT/H-GGT group was significantly higher than HR in the L-ALT/L-GGT group as the reference in males (HR [95% confidence interval]: 1.73[1.36-2.20], p < 0.001) but was not significantly higher in females (1.50 [0.97-2.33], p = 0.065). The addition of the combination of H-ALT/H-GGT to traditional risk factors with and without H-ALT or H-GGT alone significantly improved the discriminatory capability for predicting development of DM. In conclusion, the combination of H-ALT/H-GGT efficiently predicts development of DM in male individuals but not significantly in female individuals.

High level of fatty liver index predicts new onset of diabetes mellitus during a 10-year period in healthy subjects.

Yukimura Higashiura, Masato Furuhashi, Marenao Tanaka, Satoko Takahashi, Masayuki Koyama, Hirofumi Ohnishi, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Norihito Moniwa, Kazufumi Tsuchihashi, Tetsuji Miura

Scientific reports 11 ( 1 ) 12830 - 12830 2021年06月 [国際誌]

Fatty liver index (FLI), a predictor of nonalcoholic fatty liver disease, has been reported to be associated with several metabolic disorders. This study aimed to evaluate the relationship between FLI and new onset of diabetes mellitus (DM). We investigated the association of FLI with new onset of DM during a 10-year period in subjects who received annual health examinations (n = 28,990). After exclusion of subjects with DM at baseline and those with missing data, a total of 12,290 subjects (male/female: 7925/4365) who received health examinations were recruited. FLI was significantly higher in males than in females. During the 10-year period, DM was developed in 533 males (6.7%) and 128 females (2.9%). Multivariable Cox proportional hazard models with a restricted cubic spline showed that the risk of new onset of DM increased with a higher FLI at baseline in both sexes after adjustment of age, fasting plasma glucose, habits of alcohol drinking and current smoking, family history of DM and diagnosis of hypertension and dyslipidemia at baseline. When the subjects were divided into subgroups according to tertiles of FLI level at baseline (T1-T3) in the absence and presence of impaired fasting glucose (IFG), hazard ratios after adjustment of the confounders gradually increased from T1 to T3 and from the absence to presence of IFG in both male and female subjects. In conclusion, a high level of FLI predicts new onset of DM in a general population of both male and female individuals.

Independent association of plasma xanthine oxidoreductase activity with hypertension in nondiabetic subjects not using medication.

Masato Furuhashi, Yukimura Higashiura, Masayuki Koyama, Marenao Tanaka, Takayo Murase, Takashi Nakamura, Seigo Akari, Akiko Sakai, Kazuma Mori, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

Hypertension research : official journal of the Japanese Society of Hypertension 44 ( 9 ) 1213 - 1220 2021年06月 [国際誌]

Xanthine oxidoreductase (XOR), a rate-limiting and catalyzing enzyme of uric acid formation in purine metabolism, is involved in reactive oxygen species generation. Plasma XOR activity has been shown to be a novel metabolic biomarker related to obesity, liver dysfunction, hyperuricemia, dyslipidemia, and insulin resistance. However, the association between plasma XOR activity and hypertension has not been fully elucidated. We investigated the association of hypertension with plasma XOR activity in 271 nondiabetic subjects (male/female: 119/152) who had not taken any medications in the Tanno-Sobetsu Study, a population-based cohort. Males had higher plasma XOR activity than females. Plasma XOR activity was positively correlated with mean arterial pressure (r = 0.128, P = 0.036). When the subjects were divided by the presence and absence of hypertension into an HT group (male/female: 34/40) and a non-HT group (male/female: 85/112), plasma XOR activity in the HT group was significantly higher than that in the non-HT group (median: 39 vs. 28 pmol/h/mL, P = 0.028). There was no significant difference in uric acid levels between the two groups. Multivariable logistic regression analysis showed that plasma XOR activity (odds ratio: 1.091 [95% confidence interval: 1.023-1.177] per 10 pmol/h/mL, P = 0.007) was an independent determinant of the risk for hypertension after adjustment for age, sex, current smoking and alcohol consumption, estimated glomerular filtration rate, brain natriuretic peptide, and insulin resistance index. The interaction of sex with plasma XOR activity was not significant for the risk of hypertension. In conclusion, plasma XOR activity is independently associated with hypertension in nondiabetic individuals who are not taking any medications.

北海道のST上昇型急性心筋梗塞における総虚血時間と再灌流療法選択の実態

親谷佳佑, 小山雅之, 大西浩文, 三浦哲嗣

日本循環器病予防学会誌 ( (一社)日本循環器病予防学会 ) 56 ( 2 ) 173 - 173 2021年05月

Fatty liver index is independently associated with deterioration of renal function during a 10-year period in healthy subjects.

Satoko Takahashi, Marenao Tanaka, Masato Furuhashi, Norihito Moniwa, Masayuki Koyama, Yukimura Higashiura, Arata Osanami, Yufu Gocho, Hirofumi Ohnishi, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Tetsuji Miura

Scientific reports ( NATURE PORTFOLIO ) 11 ( 1 ) 8606 - 8606 2021年04月 [国際誌]

A potential link between chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) has been suggested. We investigated the relationship between fatty liver index (FLI), a noninvasive and simple predictor of NAFLD, and the development of CKD defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 or positive for urinary protein during a 10-year follow-up period in subjects who received annual health examinations (n = 28,890). After exclusion of CKD at baseline, a total of 14,163 subjects (male/female: 9077/5086) were recruited. During the 10-year period, 1458 males (16.1%) and 737 females (14.5%) had new onset of CKD. Multivariable Cox proportional hazard models with a restricted cubic spline showed that hazard ratios (HRs) of CKD development increased with a higher FLI at baseline in both males and females after adjustment of confounders. When divided by tertiles of FLI level at baseline (T1 ~ T3), the adjusted risk of CKD development in the T3 group (HR [95% confidence interval], male/female: 1.33 [1.16-1.54]/1.33 [1.08-1.63]) was significantly higher than that in both sexes in the T1 group as the reference. The addition of FLI into traditional risk factors significantly improved the discriminatory capability for predicting CKD. In conclusion, a high level of FLI predicts the development of CKD in both sexes in a general population.

Impact of atrial fibrillation on the risk of ischemic stroke in patients on hemodialysis: BOREAS-HD3 Study.

Ayumu Kimura, Marenao Tanaka, Norihito Moniwa, Arata Osanami, Koki Abe, Daisuke Miyamori, Yufu Gocho, Satoru Shibata, Makoto Terasawa, Yusuke Okazaki, Tomohisa Yamashita, Masayuki Koyama, Masato Furuhashi, Hirofumi Ohnishi, Tetsuji Miura

Clinical and experimental nephrology 25 ( 3 ) 297 - 304 2021年03月 [国内誌]

BACKGROUND: Atrial fibrillation (AF) is an established risk factor for ischemic stroke in a general population. However, its impact in patients on hemodialysis (HD), a group with a high risk for stroke, is still controversial. Here we examined this issue in a Japanese cohort. METHODS: This study was designed as a multicenter cohort study. HD patients (n = 1,067) were enrolled from 22 institutes in January 2009 and followed up for 3 years. Patients with missing data (n = 196) or kidney transplantation (n = 4) were excluded, and 867 patients contributed to the analysis of the risk of new-onset of ischemic stroke. RESULTS: At baseline, AF was observed in 123 patients (14.2%, AF group) and not in the others (n = 744: 85.8%, non-AF group). During a follow-up period of 31.3 months, the cumulative incidence rate for ischemic stroke was significantly higher in the AF group than in the non-AF group (6.5% vs. 2.9%, p < 0.05). In Cox regression analysis, AF was a significant independent risk factor for new-onset of ischemic stroke after adjustment for age, sex, prior history of ischemic stroke, use of warfarin, dialysis vintage, comorbidity of diabetic nephropathy, and interdialytic weight gain (hazard ratio 2.17-2.68). CONCLUSION: Present analyses using comprehensive adjustment for multiple confounders, including prior history of ischemic stroke, indicated that AF independently increases the risk of new-onset of ischemic stroke by more than twofold in Japanese HD patients.

循環FABP4濃度の上昇は一般集団における心血管死を予測する:12年間の前向き研究【JST・京大機械翻訳】|||

齋藤礼衣, 古橋眞人, 小山雅之, 東浦幸村, 赤坂憲, 田中希尚, 茂庭仁人, 大西浩文, 齋藤重幸, 浦信行, 島本和明, 三浦哲嗣

日本循環器学会学術集会(Web) ( (一社)日本循環器学会 ) 11 ( 1 ) 4008 - 4008 2021年02月 [国際誌]

Fatty acid-binding protein 4 (FABP4) is secreted from adipose tissue and acts as an adipokine, and an elevated circulating FABP4 level is associated with metabolic disorders and atherosclerosis. However, little is known about the causal link between circulating FABP4 level and mortality in a general population. We investigated the relationship between FABP4 concentration and mortality including cardiovascular death during a 12-year period in subjects of the Tanno-Sobetsu Study, a population-based cohort (n = 721, male/female: 302/419). FABP4 concentration at baseline was significantly higher in female subjects than in male subjects. All-cause death occurred in 123 (male/female: 74/49) subjects, and 34 (male/female: 20/14) and 42 (male/female: 26/16) subjects died of cardiovascular events and cancer, respectively. When divided into 3 groups according to tertiles of FABP4 level at baseline by sex (T1-T3), Kaplan-Meier survival curves showed that there were significant differences in rates of all-cause death and cardiovascular death, but not cancer death, among the groups. Multivariable Cox proportional hazard model analysis with a restricted cubic spline showed that hazard ratio (HR) for cardiovascular death, but not that for all-cause death, significantly increased with a higher FABP4 level at baseline after adjustment of age and sex. The risk of cardiovascular death after adjustment of age, sex, body mass index and levels of brain natriuretic peptide and high-sensitivity C-reactive protein in the 3rd tertile (T3) group (HR: 4.96, 95% confidence interval: 1.20-22.3) was significantly higher than that in the 1st tertile (T1) group as the reference. In conclusion, elevated circulating FABP4 concentration predicts cardiovascular death in a general population.

DOI PubMed J-GLOBAL

High percent body fat mass predicts lower risk of cardiac events in patients with heart failure: an explanation of the obesity paradox.

Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Hidemichi Kouzu, Suguru Honma, Kanako Shimomura, Takuya Inoue, Yuhei Takamura, Ryohei Nagaoka, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Tomoyuki Ishigo, Ayako Watanabe, Akiyoshi Hashimoto, Tetsuji Miura

BMC geriatrics 21 ( 1 ) 16 - 16 2021年01月 [国際誌]

BACKGROUND: Although high body mass index (BMI) is a risk factor of heart failure (HF), HF patients with a higher BMI had a lower mortality rate than that in HF patients with normal or lower BMI, a phenomenon that has been termed the "obesity paradox". However, the relationship between body composition, i.e., fat or muscle mass, and clinical outcome in HF remains unclear. METHODS: We retrospectively analyzed data for 198 consecutive HF patients (76 years of age; males, 49%). Patients who were admitted to our institute for diagnosis and management of HF and received a dual-energy X-ray absorptiometry scan were included regardless of left ventricular ejection fraction (LVEF) categories. Muscle wasting was defined as appendicular skeletal muscle mass index < 7.0 kg/m2 in males and < 5.4 kg/m2 in females. Increased percent body fat mass (increased FM) was defined as percent body fat > 25% in males and > 30% in females. RESULTS: The median age of the patients was 76 years (interquartile range [IQR], 67-82 years) and 49% of them were male. The median LVEF was 47% (IQR, 33-63%) and 33% of the patients had heart failure with reduced ejection fraction. Increased FM and muscle wasting were observed in 58 and 67% of the enrolled patients, respectively. During a 180-day follow-up period, 32 patients (16%) had cardiac events defined as cardiac death or readmission by worsening HF or arrhythmia. Kaplan-Meier survival curves showed that patients with increased FM had a lower cardiac event rate than did patients without increased FM (11.4% vs. 22.6%, p = 0.03). Kaplan-Meier curves of cardiac event rates did not differ between patients with and those without muscle wasting (16.5% vs. 15.4%, p = 0.93). In multivariate Cox regression analyses, increased FM was independently associated with lower cardiac event rates (hazard ratio: 0.45, 95% confidence interval: 0.22-0.93) after adjustment for age, sex, diabetes, muscle wasting, and renal function. CONCLUSIONS: High percent body fat mass is associated with lower risk of short-term cardiac events in HF patients.

Distinct determinants of muscle wasting in nonobese heart failure patients with and without type 2 diabetes mellitus.

Toshiyuki Yano, Satoshi Katano, Hidemichi Kouzu, Ryohei Nagaoka, Takuya Inoue, Yuhei Takamura, Tomoyuki Ishigo, Ayako Watanabe, Katsuhiko Ohori, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Akiyoshi Hashimoto, Tetsuji Miura

Journal of diabetes ( Wiley ) 13 ( 1 ) 7 - 18 2021年01月 [査読有り] [国際誌]

BACKGROUND: Muscle wasting, that is, reduction in muscle mass, is frequently observed in patients with chronic heart failure (CHF) and diabetes mellitus (DM). METHODS: We retrospectively examined 185 patients with CHF (median age of 71 years [interquartile range, 61-78 years]; 64% male) who received a dual-energy X-ray absorptiometry scan for assessment of appendicular skeletal muscle mass index (ASMI). RESULTS: Seventy patients with CHF (38%) had DM. Patients with DM had higher prevalences of ischemic heart disease and hypertension, lower levels of estimated glomerular filtration rate (eGFR) and ASMI, and higher levels of plasma renin activity (PRA) than did patients without DM. In simple regression analyses, ASMI was positively correlated with the Mini Nutritional Assessment Short Form (MNA-SF) score and levels of hemoglobin, eGFR, and fasting plasma insulin and was negatively correlated with levels of N-terminal pro B-type natriuretic peptide, PRA, and cortisol. In multiple linear regression analyses, age, MNA-SF score, DM, fasting plasma insulin level, and PRA were independently associated with ASMI. When multiple linear regression analyses were separately performed in a non-DM group and a DM group, MNA-SF score and fasting plasma insulin level were independent variables for ASMI in both groups. PRA was independently associated with ASMI in the DM group but not in the non-DM group, whereas cortisol concentration was independently associated with ASMI only in the non-DM group. CONCLUSIONS: In addition to malnutrition and reduction in plasma insulin, renin-angiotensin system activation may be responsible for the development of muscle wasting in CHF patients with DM.

U-shaped relationship between serum uric acid level and decline in renal function during a 10-year period in female subjects: BOREAS-CKD2.

Kazuma Mori, Masato Furuhashi, Marenao Tanaka, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Masayuki Koyama, Arata Osanami, Yukimura Higashiura, Masafumi Inyaku, Megumi Matsumoto, Norihito Moniwa, Hirofumi Ohnishi, Tetsuji Miura

Hypertension research : official journal of the Japanese Society of Hypertension 44 ( 1 ) 107 - 116 2021年01月 [査読有り] [国際誌]

While hyperuricemia is recognized as a risk factor for chronic kidney disease (CKD), the risk of CKD in subjects with a low level of serum uric acid (UA) remains controversial. Here, we examined whether the association of CKD risk with serum UA level differs depending on the sex and age of subjects in a general population. Of subjects who received annual health checkups, we enrolled 6,779 subjects (male/female: 4,454/2,325; age: 45 ± 9 years) with data from a 10-year follow-up after excluding subjects taking anti-hyperuricemic drugs and those with CKD at baseline. During the follow-up period, 11.4% of the males and 11.7% of the females developed CKD. A significant interaction of sex, but not age, with the effect of baseline UA level on CKD risk was found. A restricted cubic spline analysis showed a U-shaped association of the baseline UA level with the risk of CKD in females. Multivariable Cox proportional hazard analyses for females showed that baseline UA levels in the 5th quintile (Q5, ≥5 mg/dL; HR: 1.68) and the 1st quintile (Q1, ≤3.5 mg/dL; HR: 1.73) were independent risk factors for CKD when compared with UA levels in the 4th quintile (Q4, 4.5-4.9 mg/dL). In males, restricted cubic spline analysis indicated increased CKD risk in subjects with a higher baseline UA level but not in those with a low UA level. In conclusion, a low UA level is a significant risk factor for CKD in females, while an elevated UA level increases the risk of CKD in both sexes.

Dilemma of physician-mothers faced with an increased home burden and clinical duties in the hospital during the COVID-19 pandemic.

Sachiyo Nishida, Kanna Nagaishi, Masayo Motoya, Ayako Kumagai, Noriko Terada, Ai Kasuga, Narumi Kubota, Kotoe Iesato, Motonobu Kimizuka, Satsuki Miyajima, Masayuki Koyama, Hirofumi Ohnishi, Eichi Narimatsu, Naoya Masumori, Kazufumi Tsuchihashi, Taiji Tsukamoto, Yoshihisa Tsuji

PloS one 16 ( 6 ) e0253646 2021年 [国際誌]

PURPOSE: Since December 2019, coronavirus disease 2019 (COVID-19) has spread rapidly across the world. During the pandemic, physicians in our hospital have had to respond both to the issue of treating the patients and the increasing domestic burden associated with social disruption. The purpose of this study was to assess how much the burden on our doctors, especially female doctors, was increasing. MATERIAL AND METHODS: The Physicians' Career Support Committee in Sapporo Medical University conducted a questionnaire survey. The questionnaire inquired about a wide range of subjects with regard to working style and family life during the first and second waves of the COVID-19 pandemic, and was sent to all medical/dental physicians working in Sapporo Medical University. RESULTS: A total of 266 (42.7%) physicians in our hospital responded to our questionnaire and the data for 264 data were analyzed. The total numbers of males, females, and others, including those who did not want to specify, were 178 (67.4%), 82 (31.0%), and 4 (1.5%), respectively. Among them, 62 (23.5%) and 23 (8.7%) answered that their domestic burden was slightly or markedly increased. The increase in the domestic burden showed a significant difference between genders (p = 0.04). Even after correction for background differences using multivariate analysis, being female (p<0.001), having child dependents (p<0.001), and treating COVID-19 patients (p = 0.03) were significantly related to an increased domestic burden. Regarding family style, 58.1% of the physician-fathers were from two-income families (i.e., families with both parents in employment), and they answered that their partner mainly cared for the children. In contrast, 97.3% of physician-mothers were from two-income families, and 94.6% of the physician-mothers had to take care of children by themselves. CONCLUSION: Physician-mothers are caught in a dilemma between an increased home burden and clinical duties in the hospital, with a significantly higher ratio than physician-fathers during the pandemic. As we showed, female doctors could have not continued their careers and take responsible positions in the same way as male doctors. This is a social risk in the timing of a crisis, such as a pandemic.

Circulating PCSK7 Level is Independently Associated with Obesity, Triglycerides Level and Fatty Liver Index in a General Population without Medication

Masato Furuhashi, Yu Kataoka, Ryo Nishikawa, Masayuki Koyama, Akiko Sakai, Yukimura Higashiura, Marenao Tanaka, Shigeyuki Saitoh, Kazuaki Shimamoto, Hirofumi Ohnishi

Journal of Atherosclerosis and Thrombosis ( Japan Atherosclerosis Society ) 29 ( 9 ) 1275 - 1284 2021年 [国内誌]

AIM: Dyslipidemia and altered iron metabolism are typical features of non-alcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7), a transmembrane-anchored endonuclease, is associated with triglycerides level and processing of transferrin receptor 1. However, the significance of circulating PCSK7 has not been fully addressed, though prosegment PCSK7 is secreted from cells. We investigated the associations of plasma PCSK7 level with several parameters. METHODS: Plasma PCSK7 concentration was measured in 282 subjects (male/female: 126/156) without medication of the Tanno-Sobetsu Study, a population-based cohort study. RESULTS: There was no significant sex difference in PCSK7 level. Current smoking habit, but not alcohol drinking habit, was associated with increased PCSK7 level. PCSK7 concentration was negatively correlated with age and blood urea nitrogen and was positively correlated with body mass index (BMI) and levels of γ-glutamyl transpeptidase (γGTP), triglycerides and fatty liver index (FLI), which is calculated by BMI, waist circumference and levels of γGTP and triglycerides, as a noninvasive and simple predictor of NAFLD. There were no significant correlations of PCSK7 level with levels of iron and plasma PCSK9, a secreted PCSK family member and a regulator of low-density lipoprotein cholesterol level. Multivariable regression analyses after adjustment of age, sex and current smoking habit showed that PCSK7 concentration was independently associated with BMI (β=0.130, P=0.035), triglycerides (β=0.141, P=0.027) or FLI (β=0.139, P=0.030). CONCLUSIONS: Plasma PCSK7 concentration is independently associated with chronic liver disease including obesity and elevated triglycerides level in a general population of individuals who had not regularly taken any medications.

Clinical Risk Factors and Prognostic Impact of Osteoporosis in Patients With Chronic Heart Failure.

Satoshi Katano, Toshiyuki Yano, Takanori Tsukada, Hidemichi Kouzu, Suguru Honma, Takuya Inoue, Yuhei Takamura, Ryohei Nagaoka, Tomoyuki Ishigo, Ayako Watanabe, Katsuhiko Ohori, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Hiroyuki Takashima, Akiyoshi Hashimoto, Masaki Katayose, Tetsuji Miura

Circulation journal : official journal of the Japanese Circulation Society 84 ( 12 ) 2224 - 2234 2020年11月 [国内誌]

BACKGROUND: The clinical significance of osteoporosis in chronic heart failure (CHF) remains unclear.Methods and Results:A total of 303 CHF patients (75 years, [interquartile range (IQR) 66-82 years]; 41% female) were retrospectively examined. Bone mineral densities (BMDs) at the lumbar spine, femoral neck, and total femur were measured by using dual-energy X-ray absorptiometry (DEXA), and osteoporosis was diagnosed when the BMD at any of the 3 sites was <70% of the Young Adult Mean percentage (%YAM). The prevalence of osteoporosis in CHF patients was 40%. Patients with osteoporosis were older (79 [IQR, 74-86] vs. 72 [IQR, 62-80] years), included a large percentage of females, had slower gait speed and had a lower body mass index. Multivariate logistic regression analysis indicated that sex, BMI, gait speed, loop diuretics use and no use of direct oral anticoagulants (DOACs) were independently associated with osteoporosis. Kaplan-Meier survival curves showed that the rate of death and heart failure hospitalization was higher in patients with osteoporotic BMD at 2 or 3 sites than in patients without osteoporosis (hazard ratio 3.45, P<0.01). In multivariate Cox regression analyses, osteoporotic BMD at 2 or 3 sites was an independent predictor of adverse events after adjustment for prognostic markers. CONCLUSIONS: Loop diuretics use and no DOACs use are independently associated with osteoporosis in CHF patients. Osteoporosis is a novel predictor of worse outcome in patients with CHF.

Significance of urinary fatty acid-binding protein 4 level as a possible biomarker for the identification of minimal change disease in patents with nephrotic-range proteinuria.

Marenao Tanaka, Masato Furuhashi, Norihito Moniwa, Takuto Maeda, Hideki Takizawa, Megumi Matsumoto, Akiko Sakai, Yukimura Higashiura, Yufu Gocho, Masayuki Koyama, Yayoi Ogawa, Tetsuji Miura

BMC nephrology ( BMC ) 21 ( 1 ) 459 - 459 2020年11月 [国際誌]

BACKGROUND: Fatty acid-binding protein 4 (FABP4), but not FABP1 (liver-type FABP), is ectopically induced in injured glomerular endothelial cells, and urinary FABP4 (U-FABP4) level is associated with proteinuria and renal dysfunction in a general population. METHODS: The clinical significance of U-FABP4 was investigated in 81 patients (male/female: 43/38, age: 57 ± 17 years) who underwent kidney biopsy. RESULTS: U-FABP4 was negatively correlated with estimated glomerular filtration rate (eGFR) (r = - 0.56, P < 0.01) and was positively correlated with age, blood pressure, triglycerides, proteinuria (r = 0.58, P < 0.01), plasma FABP4 and urinary FABP1 (U-FABP1) (r = 0.52, P < 0.01). Multivariable regression analysis showed that eGFR, proteinuria and U-FABP1 were independent predictors of U-FABP4. The level of U-FABP4, but not that of proteinuria, eGFR or U-FABP1, in minimal change nephrotic syndrome (MCNS) was significantly lower than the level in membranous nephropathy (MN) and that in diabetic nephropathy. Receiver operating characteristic curve analysis indicated that U-FABP4 level ≤ 0.78 μg/gCr predicted MCNS in patients who had nephrotic-range proteinuria with a high level of accuracy. When divided by the median value of U-FABP4 at baseline in 33 of the 81 patients who could be followed up, the yearly change (post-pre) in eGFR in the low U-FABP4 group was significantly greater than that in the high U-FABP4 group (median: 11.0 vs. -5.0 mL/min/1.73m2/year). CONCLUSIONS: U-FABP4 level is independently associated with proteinuria and renal dysfunction in patients with glomerular kidney disease. A low U-FABP4 level may predict MCNS in patients with nephrotic syndrome and would be a useful biomarker for differential diagnosis of MCNS and MN, which are common causes of nephrotic syndrome.

Low urine pH predicts new onset of diabetes mellitus during a 10-year period in men: BOREAS-DM1 study.

Yukimura Higashiura, Marenao Tanaka, Masato Furuhashi, Masayuki Koyama, Hirofumi Ohnishi, Keita Numata, Takashi Hisasue, Nagisa Hanawa, Norihito Moniwa, Tetsuji Miura

Journal of diabetes investigation 11 ( 6 ) 1490 - 1497 2020年11月 [査読有り] [国内誌]

AIMS/INTRODUCTION: A low level of urine pH (U-pH) has been reported to be associated with metabolic disorders. However, the relationship between the incidence of diabetes mellitus and U-pH has not yet been fully addressed. MATERIALS AND METHODS: We investigated the relationship between U-pH and the development of diabetes mellitus during a 10-year period in a general population of individuals who received annual health examinations in 2006 (n = 28,990). After exclusion of individuals with missing data, and those with diabetes mellitus and/or chronic kidney disease at baseline, a total of 12,476 individuals (men/women: 8,027/4,449) who received health examinations at least once during the period from 2007 to 2016 were recruited. The recruited individuals were divided into four groups according to their U-pH levels: groups of U-pH ≤5.0, 5.5, 6.0 and ≥6.5. RESULTS: During a 10-year period, 521 men (6.5%) and 132 women (3.0%) had new onset of diabetes mellitus. The cumulative incidence of diabetes mellitus was 7.5% (men/women: 9.3%/4.4%) per 100 person-years. The hazard ratios (HRs) in the U-pH ≤5.0 (HR 1.93) and U-pH 5.5 groups (HR 1.46) were significantly higher than that in the U-pH ≥6.5 group as a reference for men, but not for women. After adjustment of age, obesity, fasting glucose, smoking and alcohol drinking habits, family history of diabetes mellitus, and use of drugs for hypertension and dyslipidemia, HR in the U-pH ≤5.0 group (HR 1.39) was significantly higher than that in the U-pH ≥6.5 group for men, but not for women. CONCLUSIONS: Low U-pH predicts new onset of diabetes mellitus in a general population of men.

Is Incomplete Left Atrial Posterior Wall Isolation Associated With Recurrence of Atrial Fibrillation After Radiofrequency Catheter Ablation?

Takefumi Fujito, Atsushi Mochizuki, Naoyuki Kamiyama, Masayuki Koyama, Daigo Nagahara, Tetsuji Miura

Circulation reports 2 ( 11 ) 648 - 656 2020年10月 [国内誌]

Background: Complete left atrial posterior wall isolation (LAPI) is not always achieved. We examined whether incomplete LAPI has an effect on outcomes after catheter ablation (CA). Methods and Results: This study enrolled 75 consecutive patients (mean [±SD] age 62.6±8.9 years, 74.7% male) who underwent LAPI by radiofrequency CA for persistent atrial fibrillation (AF). The median follow-up period was 541 days (interquartile range 338-840 days). Incomplete LAPI was defined as the presence of a successfully created roof or floor linear lesion. The rate of complete LAPI was 41.3% (31/75). Either a roof or floor linear lesion was created in 38 patients, whereas neither was created in 6. Multivariate Cox proportional hazards regression analysis revealed that female sex (hazard ratio [HR] 5.29; 95% confidence interval [CI] 1.81-16.8; P=0.002) and complete or incomplete LAPI (HR 0.17; 95% CI 0.03-0.79; P=0.027) were independent predictors of AF recurrence. Kaplan-Meier curves indicated that better outcome was associated with at least one rather than no successful linear lesion (86.5% vs. 50.0% at 1 year; P=0.043). There were no significant differences in outcomes between the complete LAPI and incomplete LAPI groups. Conclusions: Complete LAPI is unachievable in a significant percentage of patients with persistent AF. However, incomplete LAPI, as a result of aiming for complete LAPI, may have a benefit comparable to that of complete LAPI.

Independent link between peripheral artery disease and muscle wasting in patients with heart failure.

Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Hidemichi Kouzu, Takuya Inoue, Yuhei Takamura, Ryohei Nagaoka, Tomoyuki Ishigo, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Tetsuji Miura

ESC heart failure ( Wiley ) 7 ( 5 ) 3252 - 3256 2020年10月 [査読有り] [国際誌]

AIMS: A high prevalence of muscle wasting, that is, reduction in muscle mass, in patients with peripheral artery disease (PAD) and heart failure (HF) has been reported. However, whether the association between PAD and muscle wasting is independent of shared risk factors such as diabetes mellitus has not been examined. METHODS AND RESULTS: We retrospectively enrolled 440 HF patients (mean age, 74 years; inter-quartile range, 64-82 years; 52% male). Muscle wasting was defined as an appendicular skeletal muscle mass index (ASMI) of <7.0 kg/m2 in men and <5.4 kg/m2 in women. PAD was defined as an ankle brachial index (ABI) of <0.9 in either leg. The prevalence of PAD in HF patients was 21%. ASMI was positively correlated with ABI in HF patients. In multivariate logistic regression analysis, ASMI and muscle wasting were selected as independent explanatory factors of the presence of PAD after adjustment for age, sex, diabetes mellitus, hypertension, dyslipidaemia, estimated glomerular filtration rate, and smoking status, established risk factors of atherosclerosis. In propensity score-matched analysis, frequency of muscle wasting was higher in patients with PAD than in patients with an ABI of ≧1.1 (72.1% vs. 52.5%, P = 0.04). CONCLUSIONS: The results suggest that there is an independent link between PAD and muscle wasting in HF patients.

Hemodynamic Collapse After Influenza Vaccination: A Vaccine-Induced Fulminant Myocarditis?

Nobutaka Nagano, Toshiyuki Yano, Yugo Fujita, Masayuki Koyama, Ryo Hasegawa, Jun Nakata, Ryo Nishikawa, Naoto Murakami, Takefumi Fujito, Atsushi Mochizuki, Hidemichi Kouzu, Atsuko Muranaka, Nobuaki Kokubu, Tetsuji Miura

The Canadian journal of cardiology ( Elsevier {BV} ) 36 ( 9 ) 1554.e5-1554.e7 - 1554.e7 2020年09月 [査読有り] [国際誌]

A 14-year-old girl with cardiopulmonary arrest was referred to our hospital. She had received an injection of inactivated influenza vaccine 7 days before the referral. Her cardiac rhythm was pulseless wide QRS tachycardia, and mechanical circulatory support was immediately begun. Results of endomyocardial biopsy showed that there was massive infiltration of CD3- and CD68-positive cells and various degrees of cardiomyocyte necrosis in all of 3 endomyocardial specimens, whereas infiltration of eosinophils or giant cells was not observed. A histologic diagnosis of lymphocytic myocarditis was made. Acute myocarditis is a rare but potentially fatal complication of the influenza vaccination.

Differential regulation of hypoxanthine and xanthine by obesity in a general population.

Masato Furuhashi, Masayuki Koyama, Yukimura Higashiura, Takayo Murase, Takashi Nakamura, Megumi Matsumoto, Akiko Sakai, Hirofumi Ohnishi, Marenao Tanaka, Shigeyuki Saitoh, Norihito Moniwa, Kazuaki Shimamoto, Tetsuji Miura

Journal of diabetes investigation 11 ( 4 ) 878 - 887 2020年07月 [査読有り] [国内誌]

AIMS/INTRODUCTION: Uric acid is synthesized by oxidation of hypoxanthine and xanthine using a catalyzing enzyme, xanthine oxidoreductase (XOR), which can be a source of reactive oxygen species. Plasma XOR activity is a metabolic biomarker associated with obesity, hyperuricemia, liver dysfunction and insulin resistance. However, it has recently been reported that XOR activity in fat tissue is low in humans, unlike in rodents, and that hypoxanthine is secreted from human fat tissue. MATERIALS AND METHODS: The associations of obesity with hypoxanthine, xanthine and plasma XOR activity were investigated in 484 participants (men/women: 224/260) of the Tanno-Sobetsu Study. RESULTS: Levels of hypoxanthine, xanthine and plasma XOR activity were significantly higher in men than in women. In 59 participants with hyperuricemia, 11 (men/women: 11/0) participants were being treated with an XOR inhibitor and had a significantly higher level of xanthine, but not hypoxanthine, than that in participants without treatment. In all of the participants, hypoxanthine concentration in smokers was significantly higher than that in non-smokers. Stepwise and multivariate regression analyses showed that body mass index, smoking habit and xanthine were independent predictors of hypoxanthine after adjustment of age, sex and use of antihyperuricemic drugs. Whereas, alanine transaminase, hypoxanthine and plasma XOR activity were independent predictors for xanthine, and alanine transaminase, triglycerides and xanthine were independent predictors for plasma XOR activity. CONCLUSIONS: The concentration of hypoxanthine, but not that of xanthine, is independently associated with obesity and smoking habit, indicating differential regulation of hypoxanthine and xanthine in a general population.

Assessment of prognosis in immunoglobulin light chain amyloidosis patients with severe heart failure: a predictive value of right ventricular function.

Nobutaka Nagano, Toshiyuki Yano, Yugo Fujita, Hidemichi Kouzu, Masayuki Koyama, Hiroshi Ikeda, Kenji Yasui, Atsuko Muranaka, Ryo Nishikawa, Ryo Takahashi, Naohiro Kishiue, Satoshi Yuda, Tetsuji Miura

Heart and vessels 35 ( 4 ) 521 - 530 2020年04月 [査読有り] [国内誌]

Although the benefit of updated therapeutic regimens, including bortezomib, on the survival of immunoglobulin light chain (AL) amyloidosis patients with heart failure (HF) has been reported, predictors of mortality in the patients treated with the updated therapy remain unclear. We retrospectively enrolled AL amyloidosis patients who had severe HF at the time of diagnosis and received the updated therapy, including bortezomib (n = 19, 61 ± 6 years old, 68% male). Severe HF was defined as the presence of both NYHA functional class III or IV and BNP > 200 pg/ml or NT-pro-BNP > 900 pg/ml. One-year mortality rate during follow-up after commencement of the treatment was 37%. Left ventricular morphological parameters and indexes of left ventricular diastolic function on admission were similar in the non-survivors and survivors. However, non-survivors had higher incidences of atrial fibrillation and ventricular tachycardia, higher serum total bilirubin levels (1.34 ± 0.55 vs. 0.61 ± 0.29 mg/dl), higher right atrial volume index (RAVI 49.7 ± 29.9 vs. 27.3 ± 6.8 ml/m2), lower tricuspid annular peak velocities during systole (RVs' 8.0 ± 1.8 vs. 11.6 ± 3.7 cm/sec) and late diastole (RVa' 3.4 ± 0.9 vs. 11.4 ± 5.3 cm/sec), and larger inferior vena cava dimension (22.7 ± 6.4 vs. 16.3 ± 4.9 mm) than those in survivors. Kaplan-Meier curve analyses showed that larger RAVI and lower RVs' and RVa', but not left ventricular systolic/diastolic dysfunction, predicted higher mortality during 1-year follow-up. The present results suggest that the presence of right-sided heart abnormality on admission is associated with high 1-year mortality in AL amyloidosis patients with severe HF under the updated therapeutic regimens.

Novel prediction equation for appendicular skeletal muscle mass estimation in patients with heart failure: Potential application in daily clinical practice.

Satoshi Katano, Toshiyuki Yano, Katsuhiko Ohori, Nobutaka Nagano, Suguru Honma, Kanako Shimomura, Tomoyuki Ishigo, Ayako Watanabe, Remi Honma, Takefumi Fujito, Masayuki Koyama, Hidemichi Kouzu, Akiyoshi Hashimoto, Masaki Katayose, Tetsuji Miura

European journal of preventive cardiology 2047487320904236 - 2047487320904236 2020年02月 [査読有り] [国際誌]

Clinical determinants and prognostic impact of osteoporosis in patients with chronic heart failure

Masayuki Koyama

European Heart Journal 2020年

Lower limb muscle mass is associated with insulin resistance more than lower limb muscle strength in non-diabetic older adults.

Toshiaki Seko, Hiroshi Akasaka, Masayuki Koyama, Nobuaki Himuro, Shigeyuki Saitoh, Tetsuji Miura, Mitsuru Mori, Hirofumi Ohnishi

Geriatrics & gerontology international ( WILEY ) 19 ( 12 ) 1254 - 1259 2019年12月 [査読有り] [国内誌]

AIM: We examined the association of muscle mass and muscle strength with insulin resistance, focusing on lower limb muscles. METHODS: This was a cross-sectional study, and participants were registered in 2017 from the Tanno-Sobetsu Study, a population-based cohort study. After excluding individuals aged <64 years or with a history of diabetes mellitus, 272 non-diabetic older adults (116 men, 156 women) met the inclusion criteria. According to the homeostasis model assessment of insulin resistance, the participants were divided into two groups; that is, the insulin resistance group (homeostasis model assessment of insulin resistance ≥1.73) and non-insulin resistance group (homeostasis model assessment of insulin resistance <1.73). Muscle mass (lower limb, upper limb, appendicular and trunk) and muscle strength (grip strength and knee extension torque) were measured and divided by the weight, and then multiplied by 100 to calculate the weight ratio (%). The adjusted odds ratio (OR) of each muscle index for risk of insulin resistance was calculated separately for both men and women. RESULTS: Lower limb muscle mass (OR 0.72, 95% CI 0.55-0.92 in men; OR 0.69, 95% CI 0.51-0.96 in women, respectively) and appendicular muscle mass (OR 0.75, 95% CI 0.61-0.94 in men; OR 0.72, 95% CI 0.54-0.95 in women, respectively), but not other muscle indexes, were associated with risk of insulin resistance, after adjusting for age, body mass index, highly sensitive C-reacting protein and smoking habits. CONCLUSIONS: Lower limb muscle mass of non-diabetic older adults is independently related to insulin resistance. Geriatr Gerontol Int 2019; 19: 1254-1259.

Vanishing Cardiac Tumor: Cardiac Involvement in Methotrexate-Associated Lymphoproliferative Disorders.

Naohiro Kishiue, Toshiyuki Yano, Masayuki Koyama, Ryo Nishikawa, Nobutaka Nagano, Hidemichi Kouzu, Nobuaki Kokubu, Ryota Kawamura, Atsuko Muranaka, Shohei Kikuchi, Akihito Tsuchida, Tetsuji Miura

Circulation. Cardiovascular imaging 12 ( 11 ) e009689 2019年11月 [査読有り] [国際誌]

Risk classification of pulmonary arterial hypertension by echocardiographic combined assessment of pulmonary vascular resistance and right ventricular function.

Mina Kawamukai, Akiyoshi Hashimoto, Masayuki Koyama, Nobutaka Nagano, Junichi Nishida, Atsushi Mochizuki, Hidemichi Kouzu, Atsuko Muranaka, Nobuaki Kokubu, Daigo Nagahara, Satoshi Yuda, Kazufumi Tsuchihashi, Tetsuji Miura

Heart and vessels 34 ( 11 ) 1789 - 1800 2019年11月 [査読有り] [国内誌]

Which combination of clinical parameters improves the prediction of prognosis in patients with pulmonary arterial hypertension (PAH) remains unclear. We examined whether combined assessment of pulmonary vascular resistance and right ventricular function by echocardiography is useful for classifying risks in PAH. In 41 consecutive patients with PAH (mean age of 48.9 ± 17.3 years, 31 females), a 6-min walk test, pulmonary function test, and echocardiography were performed at baseline and during PAH-specific therapies. The study endpoint was defined as a composite of cardiovascular death and hospitalization for PAH and/or right ventricular failure. During a follow-up period of 9.2 ± 8.7 months, 18 patients reached the endpoint. Multivariate regression analysis showed that the ratio of tricuspid regurgitation pressure gradient to the time-velocity integral of the right ventricular outflow tract (TRPG/TVI) and tricuspid annular plane systolic excursion (TAPSE) during PAH-specific treatment were independent prognostic predictors of the endpoint. Using cutoff values indicated by receiver operating characteristic analysis, the patients were divided into four subsets. Multivariate analyses by Cox's proportional hazards model adjusted for age, sex and body mass index indicated that subset 4 (TRPG/TVI ≥ 3.89 and TAPSE ≤ 18.9 mm) had a significantly higher event risk than did subset 1 (TRPG/TVI < 3.89 and TAPSE > 18.9 mm): HR = 25.49, 95% CI 4.70-476.97, p < 0.0001. Combined assessment of TRPG/TVI and TAPSE during adequate PAH-specific therapies enables classification of risks for death and/or progressive right heart failure in PAH.

Annual change in plasma xanthine oxidoreductase activity is associated with changes in liver enzymes and body weight.

Masato Furuhashi, Masayuki Koyama, Megumi Matsumoto, Takayo Murase, Takashi Nakamura, Yukimura Higashiura, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

Endocrine journal 66 ( 9 ) 777 - 786 2019年09月 [査読有り] [国内誌]

Xanthine oxidoreductase (XOR), an enzyme of uric acid formation from hypoxanthine and xanthine, is recognized as a source of oxidative stress. Plasma activity of XOR has been reported to be a biomarker of metabolic disorders associated with obesity, liver dysfunction, insulin resistance, hyperuricemia and adipokines. We investigated longitudinal change in plasma XOR activity, which was determined by using mass spectrometry and liquid chromatography to detect [13C2, 15N2]-uric acid using [13C2, 15N2]-xanthine as a substrate, in 511 subjects (male/female: 244/267) of the Tanno-Sobetsu Study in the years 2016 and 2017. Plasma XOR activity in a basal state was significantly higher in men than in women, but no significant sex difference was observed in annual change in plasma XOR activity. Annual change in plasma activity of XOR was positively correlated with changes in each parameter, including body weight (r = 0.203, p < 0.001), body mass index, diastolic blood pressure, aspartate transaminase (AST) (r = 0.772, p < 0.001), alanine transaminase (r = 0.647, p < 0.001), γ-glutamyl transpeptidase, total cholesterol, triglycerides, uric acid, fasting glucose and HbA1c. Multivariate regression analysis demonstrated that change in AST and that in body weight were independent predictors of change in plasma XOR activity after adjustment of age, sex and changes in each variable with a significant correlation without multicollinearity. In conclusion, annual change in plasma XOR activity is independently associated with changes in liver enzymes and body weight in a general population. Improvement of liver function and reduction of body weight would decrease plasma XOR activity and its related oxidative stress as a therapeutic strategy.

Utility and safety of tocilizumab in Takayasu arteritis with severe heart failure and muscle wasting.

Toshiyuki Yano, Arata Osanami, Masaki Shimizu, Satoshi Katano, Nobutaka Nagano, Hidemichi Kouzu, Masayuki Koyama, Atsuko Muranaka, Ryo Harada, Hirosato Doi, Nobuyoshi Kawaharada, Tetsuji Miura

ESC heart failure ( WILEY PERIODICALS, INC ) 6 ( 4 ) 894 - 897 2019年08月 [査読有り] [国際誌]

Takayasu arteritis (TA) is a large vessel vasculitis of unknown aetiology characterized by chronic inflammatory changes of the aorta and its major branches. We report the active TA case who had severe heart failure due to acute myocardial infarction and aortic regurgitation. Bentall procedure was successfully performed, but he had severely depressed left ventricular function and muscle wasting together with vascular inflammation. The treatment with tocilizumab, an interleukin-6 receptor monoclonal antibody, in addition to prednisolone and standard heart failure therapy led to prompt remission of TA activity and improvement of left ventricular function and muscle wasting. Taken together with possible involvement of interleukin-6 in the pathogenesis of heart failure and muscle wasting, inhibition of interleukin-6 receptor signalling by tocilizumab may be a safe and reasonable approach in the treatment of active TA with heart failure and muscle wasting.

Insulin Resistance is Associated with Longitudinal Changes of Cardiac Repolarization Heterogeneity in Apparently Healthy Subjects.

Tamaki Matsumoto, Hirofumi Ohnishi, Tatsuya Sato, Takayuki Miki, Hiroshi Akasaka, Nagisa Hanawa, Masayuki Koyama, Shigeyuki Saitoh, Tetsuji Miura

Cardiology and therapy 8 ( 2 ) 239 - 251 2019年07月 [査読有り] [国際誌]

INTRODUCTION: Increased heterogeneity in ventricular repolarization is a risk factor of sudden cardiac death, but its natural history is unclear. Here we examined whether insulin resistance is associated with longitudinal change in ventricular repolarization heterogeneity in apparently healthy subjects. METHODS: The study subjects were participants in health checkups in cohort 1 and cohort 2, which were followed up for 6 years and 5 years, respectively. Subjects with diabetes, cardiovascular disease, or renal disease at baseline were excluded from the analyses. As indices of insulin resistance, the homeostasis model assessment of insulin resistance (HOMA-IR) and triglyceride to HDL-cholesterol ratio (TG/HDL-C) were used in cohort 1 and cohort 2, respectively. Heterogeneity in ventricular repolarization was assessed by heart rate-corrected Tpeak-Tend interval in V5 (cTpTe), QT interval, and QT dispersion. In regression analyses, parameters with a skewed distribution were normalized by logarithmic transformation or by Box-Cox transformation. RESULTS: In longitudinal analyses, Box-Cox-transformed cTpTe at the end of follow-up was weakly correlated with log HOMA-IR at baseline in cohort 1 (n = 153, r = - 0.207, 95% CI - 0.354 to - 0.050, p = 0.010) and with log TG/HDL-C at baseline in cohort 2 (n = 738, r = - 0.098, 95% CI - 0.169 to - 0.026, p = 0.008). Multiple regression analysis showed that indices of insulin resistance, but not glycosylated hemoglobin (HbA1c) or plasma glucose, at baseline were significant explanatory variables for cTpTe at the end of follow-up. Neither QT interval nor QT dispersion was correlated with metabolic parameters. CONCLUSION: Insulin resistance may be involved in the longitudinal increase of ventricular repolarization heterogeneity in apparently healthy subjects.

Independent links between plasma xanthine oxidoreductase activity and levels of adipokines.

Masato Furuhashi, Megumi Matsumoto, Takayo Murase, Takashi Nakamura, Yukimura Higashiura, Masayuki Koyama, Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

Journal of diabetes investigation 10 ( 4 ) 1059 - 1067 2019年07月 [査読有り] [国内誌]

AIMS/INTRODUCTION: Xanthine oxidoreductase (XOR) is a rate-limiting enzyme that catalyzes uric acid formation in the purine metabolism, is involved in an increase in reactive oxygen species. Plasma XOR activity has been shown to be associated with obesity, smoking, liver dysfunction, hyperuricemia, dyslipidemia and insulin resistance. MATERIALS AND METHODS: The association between plasma XOR activity, measured by using liquid chromatography and mass spectrometry, and levels of adipokines, including adiponectin, fatty acid-binding protein 4 (FABP4) and fibroblast growth factor 21 (FGF21), was investigated in 282 participants (male/female: 126/156) of the Tanno-Sobetsu Study who were not taking medication. RESULTS: Women had lower plasma XOR activity than did men. Smoking habit was associated with increased activity. Plasma XOR activity was positively correlated with concentrations of FABP4 (r = 0.192, P < 0.001) and FGF21 (r = 0.208, P < 0.001), homeostasis model assessment of insulin resistance as an index of insulin resistance and uric acid, and was negatively correlated with adiponectin level (r = -0.243, P = 0.001). Multivariate regression analyses showed that levels of adiponectin, FABP4 and FGF21 were independent determinants of plasma XOR activity after adjusting age, sex, uric acid and homeostasis model assessment of insulin resistance. With additional adjustment of smoking habit, the level of FABP4, but not that of adiponectin or FGF21, remained as an independent predictor of plasma XOR activity. CONCLUSIONS: Plasma XOR activity was independently associated with levels of adipokines in a general population of individuals not taking medication.

Postpartum Heart Failure Complicated With Thyroiditis: A Concealed Aggravator of Peripartum Cardiomyopathy?

Hidemichi Kouzu, Toshiyuki Yano, Nobutaka Nagano, Masayuki Koyama, Toshifumi Ogawa, Yugo Fujita, Atsuko Muranaka, Tetsuji Miura

The Canadian journal of cardiology 35 ( 6 ) 796.e1-796.e3 2019年06月 [査読有り] [国際誌]

The etiology of peripartum cardiomyopathy (PPCM) remains unestablished, but the involvement of abnormal autoimmunity has been suggested. We report a case of PPCM that was triggered by postpartum thyroiditis. Despite the presence of myocardial damage indicated by cardiac magnetic resonance imaging, the patient's cardiac function completely recovered with the addition of bromocriptine to standard therapies. We discuss the role of thyroid hormones in the development of PPCM through aggravation of a prolactin-dependent antiangiogenic effect, and we argue that more attention should be paid to postpartum thyroiditis as a novel risk factor for PPCM.

Differential Phenotypes in Perivascular Adipose Tissue Surrounding the Internal Thoracic Artery and Diseased Coronary Artery.

Ryosuke Numaguchi, Masato Furuhashi, Megumi Matsumoto, Hiroshi Sato, Yosuke Yanase, Yosuke Kuroda, Ryo Harada, Toshiro Ito, Yukimura Higashiura, Masayuki Koyama, Marenao Tanaka, Norihito Moniwa, Masanori Nakamura, Hirosato Doi, Tetsuji Miura, Nobuyoshi Kawaharada

Journal of the American Heart Association 8 ( 2 ) e011147 2019年01月 [査読有り] [国際誌]

Background Perivascular adipose tissue ( PVAT ) is causally associated with vascular function and the pathogenesis of vascular disease in association with metabolically driven chronic inflammation called metaflammation. However, the difference in PVAT surrounding the coronary artery ( CA - PVAT ) and that surrounding the internal thoracic artery (ITA-PVAT), a vessel resistant to atherosclerosis, remains unclear. Herein, we investigated whether CA - PVAT , ITA - PVAT , and subcutaneous adipose tissue ( SCAT ) have distinct phenotypes. Methods and Results Fat pads were sampled from 44 patients (men/women, 36:8; age, 67±13 years) with CA disease who underwent elective CA bypass grafting. Adipocyte size in ITA - PVAT and that in CA - PVAT were significantly smaller than that in SCAT . A greater extent of fibrosis and increased gene expression levels of fibrosis-related molecules were observed in CA - PVAT than those in SCAT and those in ITA - PVAT . CA - PVAT exhibited more pronounced metaflammation, as indicated by a significantly larger extent of CD 68-positive and CD 11c-positive M1 macrophages, a lower ratio of CD 206-positive M2 to CD 11c-positive M1 macrophages, a lower gene expression level of adiponectin, and higher gene expression levels of inflammatory cytokines and inflammasome- and endoplasmic reticulum stress-related molecules, than did ITA - PVAT and SCAT . Expression patterns of adipocyte developmental and pattern-forming genes were totally different among SCAT , ITA - PVAT, and CA - PVAT . Conclusions The phenotype of ITA - PVAT is closer to that of SCAT than that of CA - PVAT , which may result from inherent differences in adipocytes. ITA - PVAT appears to be protected from metaflammation and consecutive adipose tissue remodeling, which may contribute to the decreased atherosclerotic plaque burden in the ITA.

Low energy intake predicts readmission of elderly heart failure patients independently of nutritional status

Masayuki Koyama

European Heart Journal 2019年

Impact of body composition analysis on prediction of short-term readmission events in heart failure: muscle wasting vs. obesity

Masayuki Koyama

European Heart Journal 2019年

Activation of necroptotic pathway by downregulated caspase-8 expression is associated with progression of left ventricular remodeling in nonischemic dilated cardiomyopathy

Masayuki Koyama

European Heart Journal 2019年

Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid.

Masato Furuhashi, Kazuma Mori, Marenao Tanaka, Takuto Maeda, Megumi Matsumoto, Takayo Murase, Takashi Nakamura, Masayuki Koyama, Norihito Moniwa, Hirofumi Ohnishi, Shigeyuki Saitoh, Kazuaki Shimamoto, Tetsuji Miura

Endocrine journal 65 ( 11 ) 1083 - 1092 2018年11月 [査読有り] [国内誌]

Hypouricemia is a high-risk factor of exercise-induced acute kidney injury (EIAKI) probably through a lack of an antioxidant effect of uric acid. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the formation of uric acid from hypoxanthine and xanthine, leading to an increase in superoxide and reactive oxygen species. Activation of XOR has been proposed to promote oxidative stress-related tissue injury. We measured plasma XOR activity by a sensitive and accurate assay using a combination of liquid chromatography and triple quadrupole mass spectrometry in subjects with relatively low levels of uric acid (≤4.0 mg/dL) who were recruited from 627 subjects (male/female: 292/335) in the Tanno-Sobetsu Study, a population-based cohort. The numbers of subjects with uric acid ≤4.0 mg/dL, ≤3.0 mg/dL and ≤2.0 mg/dL were 72 (11.5%, male/female: 5/67), 13 (2.1%, all females) and 2 (0.3%, both females), respectively. Plasma XOR activities in 5 male subjects were below the median value of the 292 male subjects. In 12 (17.9%) of the 67 female subjects with uric acid ≤4.0 mg/dL, plasma XOR activities were above the upper quartile value of the 335 female subjects. Eleven of the 12 female subjects with high plasma XOR activity and a low uric acid level had liver dysfunction and/or insulin resistance. In conclusion, unexpected high plasma XOR activities were found in some female subjects with relatively low levels of uric acid. Measurement of plasma XOR activity may help to identify hypouricemic patients with a high risk for EIAKI.

Screening of primary aldosteronism by clinical features and daily laboratory tests: combination of urine pH, sex, and serum K.

Tomohisa Yamashita, Sayaka Shimizu, Masayuki Koyama, Kouhei Ohno, Tomohiro Mita, Toshiyuki Tobisawa, Akifumi Takada, Nobuhiko Togashi, Yoshito Ohnuma, Tohru Hasegawa, Akihito Tsuchida, Toshiaki Endo, Toshiaki Ando, Hideaki Yoshida, Shingo Fukuma, Shunichi Fukuhara, Norihito Moniwa, Tetsuji Miura

Journal of hypertension ( LIPPINCOTT WILLIAMS & WILKINS ) 36 ( 2 ) 326 - 334 2018年02月 [査読有り] [国際誌]

OBJECTIVE: To develop and validate a scoring system for selection of patients who should proceed to endocrinologic examinations of primary aldosteronism in newly diagnosed hypertensive patients. METHODS: A multivariate logistic regression analysis for primary aldosteronism was undertaken by use of seven possible primary aldosteronism markers, age less than 40 years, female sex, moderate-to-severe hypertension, hypokalemia, serum Na minus Cl at least 40 mmol/l, serum uric acid 237.92 μmol/l or less (4.0 mg/dl), and urine pH (U-pH) at least 7.0, in consecutive outpatients newly diagnosed with hypertension. The diagnostic criteria of primary aldosteronism were plasma aldosterone concentration-to-plasma renin activity ratio [ARR, (ng/dl)/(ng/ml per h)] at least 20 and at least one positive result in four types of challenge tests. RESULTS: Of 130 patients, 24 were diagnosed with primary aldosteronism. The area under the receiver operating characteristic curve (AUC) for a logistic model incorporating all possible primary aldosteronism markers was 0.73 [95% confidence interval (CI): 0.61-0.85]. Removing high U-pH, female sex, and hypokalemia from the full model decreased the AUC by 0.059, 0.035, and 0.011, respectively. We devised pH of urine, female sex, low serum K (PFK) score, in which one point each was assigned to high U-pH, female sex, and hypokalemia. The prevalences of primary aldosteronism in patients with 0, 1, 2, and 3 points were 11, 14, 42, and 60%, respectively. In external validation datasets (n = 106), AUC of PFK score was significantly higher than that of hypokalemia alone (0.73, 95% CI: 0.63-0.83 vs. 0.53, 95% CI: 0.44-0.63, P < 0.01). CONCLUSION: PFK score may be a better parameter than hypokalemia alone for identifying patients with a high probability of having primary aldosteronism.

Cardiac iodine-123 metaiodobenzylguanidine imaging predicts frequent hypotension during hemodialysis in patients with end-stage renal disease

Masayuki Koyama

European Heart Journal 2018年

Screening of Primary Aldosteronism by Clinical Features and Daily Laboratory Tests: Combination of Urine pH, Sex, and Serum K

Tomohisa Yamashita, Norihito Moniwa, Masayuki Koyama, Kohei Ohno, Hideaki Yoshida, Tetsuji Miura

HYPERTENSION ( LIPPINCOTT WILLIAMS & WILKINS ) 70 2017年09月

Everolimus in pregnancy: Case report and literature review.

Mie Yamamura, Takashi Kojima, Masayuki Koyama, Ataru Sazawa, Takahiro Yamada, Hisanori Minakami

The journal of obstetrics and gynaecology research ( WILEY ) 43 ( 8 ) 1350 - 1352 2017年08月 [査読有り] [国際誌]

There have been few reports on the effects of everolimus on the fetus, but none of six infants with documented everolimus exposure in utero had congenital malformations. A 32-year-old nulliparous woman on everolimus (5.0 mg/day) for renal angiomyolipoma (AML) due to tuberous sclerosis complex (TSC) was found to be pregnant at gestational week (GW) 7-5/7, at which time everolimus was withheld. To control AML in this patient, transarterial embolization was performed in the right and left kidneys at GW 21 and 24, respectively, and everolimus was reinitiated at GW 25. The patient gave birth at GW 37 to a normally formed infant weighing 3057 g, but who had cardiac tumors thought to be rhabdomyomas due to inherited TSC. Thus, although data are still limited, everolimus may be promising with respect to teratogenicity. Everolimus concentration in the maternal and umbilical cord blood at birth was 1.1 ng/mL and 1.0 ng/mL, respectively.

Lethal heart failure with anti-mitochondrial antibody: an arrhythmogenic right ventricular cardiomyopathy mimetic.

Masayuki Koyama, Toshiyuki Yano, Keisuke Kikuchi, Daigo Nagahara, Hatsue Ishibashi-Ueda, Tetsuji Miura

European heart journal ( OXFORD UNIV PRESS ) 38 ( 2 ) 123 - 123 2017年01月 [査読有り] [国際誌]

Impact of the Number of Anti-Thrombosis Agents in Hemodialysis Patients: BOREAS-HD2 Study.

Marenao Tanaka, Norihito Moniwa, Hirofumi Ohnishi, Tomohisa Yamashita, Masayuki Koyama, Yufu Gocho, Keitaro Nishizawa, Yukishige Kimura, Hirohito Sugawara, Sayaka Murakami, Yusuke Okazaki, Masato Furuhashi, Hideaki Yoshida, Tetsuji Miura

Kidney & blood pressure research ( KARGER ) 42 ( 3 ) 553 - 564 2017年 [査読有り] [国際誌]

BACKGROUND/AIMS: Relationships between the number of anti-thrombosis agents, clinical benefits and adverse events in hemodialysis (HD) patients are unclear. METHODS: All patients on HD in 22 institutes (n = 1,071) were enrolled and followed up for 3 years. After exclusion of patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204), mortality rate and ischemic and hemorrhagic events were compared between different regimens of anti-thrombosis agents. RESULTS: The use of dual or triple antiplatelet (AP) agents (HR:2.03, 95% CI:1.01-4.13, p = 0.04) and the combination of an AP agent and warfarin (WF) (HR:4.84, 95%CI 1.96-11.96, p < 0.001) were associated with an increase in hemorrhagic events compared with no use of anti-thrombosis agents. No anti-thrombosis regimen was associated with a significant change in risk of ischemic stroke. The use of dual or triple AP agents, but not WF, was associated with an increase in cardiovascular mortality (HR:2.48, 95% CI:1.24-4.76, p = 0.01). CONCLUSION: A significant increase in hemorrhagic events by the use of dual or more AP agents and by co-administration of an AP agent and WF in patients on HD should be considered in planning their anti-thrombosis regimen.

Favorable response to an endothelin receptor antagonist in mitomycin-induced pulmonary veno-occlusive disease with pulmonary capillary hemangiomatosis.

Masayuki Koyama, Toshiyuki Yano, Keisuke Kikuchi, Masashi Mizuno, Nobutaka Nagano, Akiyoshi Hashimoto, Tetsuji Miura

International journal of cardiology ( ELSEVIER IRELAND LTD ) 212 245 - 7 2016年06月 [査読有り] [国際誌]

Impact of use of angiotensin II receptor blocker on all-cause mortality in hemodialysis patients: prospective cohort study using a propensity-score analysis.

Marenao Tanaka, Tomohisa Yamashita, Masayuki Koyama, Norihito Moniwa, Kohei Ohno, Kaneto Mitsumata, Takahito Itoh, Masato Furuhashi, Hirofumi Ohnishi, Hideaki Yoshida, Kazufumi Tsuchihashi, Tetsuji Miura

Clinical and experimental nephrology ( SPRINGER ) 20 ( 3 ) 469 - 78 2016年06月 [査読有り] [国内誌]

BACKGROUND: It is controversial whether treatment with an angiotensin II receptor blocker (ARB) or a calcium channel blocker (CCB) improves prognosis of hemodialysis (HD) patients. METHODS: This study was designed as a multicenter prospective cohort study. HD patients (n = 1071) were enrolled from 22 institutes in January 2009 and followed up for 3 years. Patients with missing data, kidney transplantation or retraction of consent during the follow-up period (n = 204) were excluded, and 867 patients contributed to analysis of mortality. Propensity score (PS) for use of ARB and that for CCB was calculated using a multiple logistic regression model. RESULTS: ARB and CCB were prescribed in 45.6 and 54.7 % of patients at enrollment. During the 3-year follow-up period, all-cause mortality and cardiovascular mortality rates were 18.8 and 5.1 %, respectively. Kaplan-Meier curves showed that all-cause and cardiovascular mortality rates were lower in the ARB group than in the non-ARB group, though the mortality rates were similar in the CCB group and non-CCB group. In PS-stratified Cox regression analysis, ARB treatment was associated with 34 and 45 % reduction of all-cause death and cardiovascular death, respectively. In PS matching analysis, ARB treatment was associated with a significant reduction (46 % reduction) in the risk of all-cause death. A significant impact of CCB treatment on all-cause or cardiovascular mortality was not detected in PS analysis. CONCLUSIONS: The use of an ARB, but not a CCB, is associated with reduced all-cause and cardiovascular mortalities in patients on HD.

Cardiac tamponade leading to the diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome): a case report and review of the literature.

Toshiyuki Yano, Shutaro Ishimura, Tetsuaki Furukawa, Masayuki Koyama, Marenao Tanaka, Shinya Shimoshige, Akiyoshi Hashimoto, Tetsuji Miura

Heart and vessels ( SPRINGER ) 30 ( 6 ) 841 - 4 2015年11月 [査読有り] [国内誌]

Eosinophilic granulomatosis with polyangiitis (EGPA), which was previously called Churg-Strauss syndrome, is a necrotizing systemic vasculitis of unknown cause accompanied by prominent eosinophilia. Cardiovascular complications, including eosinophilic myocarditis, are a major cause of mortality in this disorder. Acute pericarditis with slight pericardial effusion is a typical manifestation in EGPA, though hemodynamically significant pericardial effusion has been reported in a few cases. We report a case that initially presented with isolated cardiac tamponade, which was followed by systemic manifestations of EGPA over 3 weeks. Including the present case, previous EGPA cases with cardiac tamponade are reviewed to delineate its clinical characteristics.

Everolimus-responsive dilated cardiomyopathy in tuberous sclerosis.

Masayuki Koyama, Toshiyuki Yano, Keisuke Kikuchi, Tetsuji Miura

European heart journal ( OXFORD UNIV PRESS ) 36 ( 34 ) 2338 - 2338 2015年09月 [査読有り] [国際誌]

Reduction of endoplasmic reticulum stress by 4-phenylbutyric acid prevents the development of hypoxia-induced pulmonary arterial hypertension

Masayuki Koyama, Masato Furuhashi, Shutaro Ishimura, Tomohiro Mita, Takahiro Fuseya, Yusuke Okazaki, Hideaki Yoshida, Kazufumi Tsuchihashi, Tetsuji Miura

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY ( AMER PHYSIOLOGICAL SOC ) 306 ( 9 ) H1314 - H1323 2014年05月 [査読有り] [国際誌]

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling of the pulmonary artery (PA). Recently, endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) have been disclosed in various types of diseases. Here we examined whether ER stress is involved in the pathogenesis of PAH. Four weeks of chronic normobaric hypoxia increased right ventricular (RV) systolic pressure by 63% compared with that in normoxic controls and induced RV hypertrophy and medial thickening of the PA in C57BL/6J mice. Treatment with 4-phenylbutyric acid (4-PBA), a chemical chaperone, significantly reduced RV systolic pressure by 30%, attenuated RV hypertrophy and PA muscularization, and increased total running distance in a treadmill test by 70% in hypoxic mice. The beneficial effects of 4-PBA were associated with suppressed expression of inflammatory cytokines and ER stress markers, including Grp78 and Grp94 in the activating transcription factor-6 branch, sXbp1 and Pdi in the inositol-requiring enzyme-1 branch and Atf4 in the PKR-like ER kinase branch, and reduced phosphorylation of c-Jun NH2-terminal kinase and eukaryotic translation initiation factor-2 alpha in the lung. The pattern of changes in ER stress and inflammatory markers by 4-PBA in the lung of the PAH model was reproduced in PA smooth muscle cells by chronic stimulation of platelet-derived growth factor-BB or hypoxia. Furthermore, knockdown of each UPR branch sensor activated other branches and promoted proliferation of PA smooth muscle cells. The findings indicate that activation of all branches of the UPR and accompanying inflammation play a major role in the pathogenesis of PAH, and that chemical chaperones are potentially therapeutic agents for PAH.

Circulating Levels of Fatty Acid-Binding Protein Family and Metabolic Phenotype in the General Population

Shutaro Ishimura, Masato Furuhashi, Yuki Watanabe, Kyoko Hoshina, Takahiro Fuseya, Tomohiro Mita, Yusuke Okazaki, Masayuki Koyama, Marenao Tanaka, Hiroshi Akasaka, Hirofumi Ohnishi, Hideaki Yoshida, Shigeyuki Saitoh, Tetsuji Miura

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 8 ( 11 ) e81318 2013年11月 [査読有り] [国際誌]

Objective: Fatty acid-binding proteins (FABPs) are a family of 14-15-kDa proteins, and some FABPs have been to be used as biomarkers of tissue injury by leak from cells. However, recent studies have shown that FABPs can be secreted from cells into circulation. Here we examined determinants and roles of circulating FABPs in a general population. Methods: From the database of the Tanno-Sobetsu Study, a study with a population-based cohort design, data in 2011 for 296 subjects on no medication were retrieved, and FABP1 similar to 5 in their serum samples were assayed. Results: Level of FABP4, but not the other isoforms, showed a gender difference, being higher in females than in males. Levels of all FABPs were negatively correlated with estimated glomerular filtration rate (eGFR), but a distinct pattern of correlation with other clinical parameters was observed for each FABP isoform; significant correlates were alanine aminotransferase (ALT), blood pressure (BP), and brain natriuretic peptide (BNP) for FABP1, none besides eGFR for FABP2, age, BP, and BNP for FABP3, age, waist circumference (WC), BP, BNP, lipid variables, high-sensitivity C-reactive protein (hsCRP), and HOMA-R for FABP4, and age, WC, BP, ALT, BNP, and HOMA-R for FABP5. FABP4 is the most strongly related to metabolic markers among FABPs. In a multivariate regression analysis, FABP4 level was an independent predictor of HOMAR after adjustment of age, gender, WC, BP, HDL cholesterol, and hsCRP. Conclusions: Each FABP isoform level showed a distinct pattern of correlation with clinical parameters, although levels of all FABPs were negatively determined by renal function. Circulating FABP4 appears to be a useful biomarker for detecting preclinical stage of metabolic syndrome, especially insulin resistance, in the general population.

Prognostic evaluation of patients with pulmonary hypertension by combined non-invasive assessment of pulmonary vascular resistance and right ventricular function

Masayuki Koyama

European Heart Journal 2013年

Endoplasmic Reticulum Stress in Pulmonary Artery Smooth Muscle Cells Contributes to the Development of Pulmonary Hypertension Induced by Chronic Hypoxia

Masayuki Koyama

Circulation 2013年

Elevation of Fatty Acid-Binding Protein 4 Is Predisposed by Family History of Hypertension and Contributes to Blood Pressure Elevation

Hideki Ota, Masato Furuhashi, Shutaro Ishimura, Masayuki Koyama, Yusuke Okazaki, Tomohiro Mita, Takahiro Fuseya, Tomohisa Yamashita, Marenao Tanaka, Hideaki Yoshida, Kazuaki Shimamoto, Tetsuji Miura

AMERICAN JOURNAL OF HYPERTENSION ( OXFORD UNIV PRESS ) 25 ( 10 ) 1124 - 1130 2012年10月 [査読有り] [国際誌]

BACKGROUND Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension. METHODS We first examined serum FABP4 concentrations in 18 normotensives (NT) and 30 nontreated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) based on their insulin-sensitivity index, the M value, determined by the hyperinsulinemic euglycemic clamp technique. In the second study, we determined FABP4 levels in 30 young NT men with or without a family history of hypertension (FH+ and FH-, respectively; n = 15 each). RESULTS Serum FABP4 level was significantly higher in the EHT-R than in the NT, whereas elevation of FABP4 level in the EHT-S was not statistically significant. FABP4 level was positively correlated with age, body mass index (BMI), blood pressure, and triglycerides and negatively correlated with the M value. FABP4 level was an independent predictor of mean arterial pressure after adjustment of age, gender, and adiposity. The FH+ group had a significantly lower level of M value and higher level of FABP4 than did the FH(-)group, and FABP4 concentration was an independent determinant of the M value. CONCLUSIONS FABP4 contributes to blood pressure elevation and atherogenic metabolic phenotype in hypertensives, and the elevation of FABP4 is predisposed by a family history of hypertension.

Angiotensin II receptor activation in youth triggers persistent insulin resistance and hypertension-a legacy effect?

Nobuhiko Togashi, Takuto Maeda, Hideaki Yoshida, Masayuki Koyama, Marenao Tanaka, Masato Furuhashi, Kazuaki Shimamoto, Tetsuji Miura

HYPERTENSION RESEARCH ( NATURE PUBLISHING GROUP ) 35 ( 3 ) 334 - 340 2012年03月 [査読有り] [国際誌]

Although the involvement of angiotensin II (Ang II) in insulin resistance and hypertension has been established, the temporal relationships between Ang II receptor activation and changes in insulin sensitivity and blood pressure are not clear. To better understand this issue, we infused rats with Ang II (200 ng kg(-1) min(-1)) or vehicle for 4 weeks and assessed the residual effects after the discontinuation of the infusion on blood pressure, insulin sensitivity and tissue parameters of inflammation. Four weeks after the discontinuation of the Ang II infusion, the blood pressure was higher by 12.8mmHg, and insulin sensitivity as determined by a euglycemic hyperinsulinemic glucose clamp was reduced (glucose infusion rate: 11.1+/-0.7 vs. 17.6+/-0.5mg kg(-1) min(-1)) in the Ang II-treated group compared with controls. The persistent hypertension and insulin resistance were associated with greater than two-fold increases in macrophage chemoattractant protein-1, tumor necrosis factor-alpha and thiobarbituric acid-reactive substrates in the soleus muscle. Furthermore, total and activated forms of Rac-1, a regulatory subunit of the NADPH oxidase complex, were increased by 144 +/- 14% and 277 +/- 82%, respectively, in the skeletal muscle of Ang II-treated rats. These residual effects after Ang II infusion were all attenuated by the co-administration of tempol, a free radical scavenger, or candesartan with Ang II. The effects of candesartan were not mimicked by hydralazine at an equidepressant dose. These findings suggest that Ang II receptor activation in youth triggers the upregulation of inflammatory cytokines and the production of reactive oxygen species, thereby inducing later insulin resistance and hypertension. Hypertension Research (2012) 35, 334-340; doi: 10.1038/hr.2011.206; published online 1 December 2011

Deterioration of Renal Function by Chronic Heart Failure is Associated with Congestion and Oxidative Stress in the Tubulointerstitium

Marenao Tanaka, Hideaki Yoshida, Masato Furuhashi, Nobuhiko Togashi, Masayuki Koyama, Satoshi Yamamoto, Tomohisa Yamashita, Yusuke Okazaki, Shutaro Ishimura, Hideki Ota, Tadashi Hasegawa, Tetsuji Miura

INTERNAL MEDICINE ( JAPAN SOC INTERNAL MEDICINE ) 50 ( 23 ) 2877 - 2887 2011年 [査読有り] [国内誌]

Objective We examined the hypothesis that renal congestion is responsible for the decline in renal function in patients with heart failure (HF) via tubulointerstitial inflammation. Methods First, in a longitudinal study, we retrospectively examined the relationship between cardiac functions and the decline of renal function during a period of 6.4 +/- 3.2 years in 20 patients who had a left ventricular ejection fraction of <40% and an estimated glomerular filtration ratio (eGFR) of <60 mL/min/1.73 m(2). Second, we compared the renal histology in autopsy cases of HF-induced renal dysfunction (HF-RD), cases of nephrosclerosis (NSC) and cases of neither RD nor HF (controls) in a cross-sectional study. Third, we retrospectively examined renal function in HF patients with predominantly right, but not left, ventricular dysfunction. Results eGFR decreased at 9.4 +/- 4.6%/year in the cohort of the longitudinal study. The rate of eGFR decline was correlated with blood pressure and with diameter of the inferior vena cava (IVCd) (r=0.5) measured at the initial work-up. Multivariate analysis indicated that the IVCd is an independent determinant of decline of eGFR in HF. In the cross-sectional study, fibrosis, Rac1 expression, protein nitrosylation, and number of CD68-positive cells were increased in the tubulointerstitium in both cases of HF-RD and NSC. Peritubular capillaries in HF-RD were dilated by 35% without any change in density compared with those in the controls. In right sided HF, the reduction of IVCd after treatment was associated with improvement of eGFR. Conclusion Venous congestion may contribute to HF-induced deterioration of renal function by augmenting oxidative stress-mediated inflammation in the tubulointerstitium.

Endoplasmic reticulum stress-induced chronic inflammation and cardiovascular disease

Furuhashi, M., Ishimura, S., Koyama, M.

Respiration and Circulation 59 ( 9 ) 2011年

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