研究者詳細 - 小山　雅之

論文 - 小山　雅之

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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.

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