Researchers Database

miyashita hiroshi

    JichiMedicalUniversityHealthCareCenter Associate Professor
Last Updated :2021/12/04

Researcher Information

Degree

  • Doctor(Medicine)(Jichi Medical University)

URL

J-Global ID

Research Areas

  • Life sciences / Internal medicine - General / Priventive medicine
  • Life sciences / Cardiology / Cardiovasculer medicine
  • Life sciences / Clinical pharmacy / Cardiovascular physiology
  • Life sciences / Physiology / Cardiovascular physiology
  • Manufacturing technology (mechanical, electrical/electronic, chemical engineering) / Measurement engineering / Blood pressure and flow waveform analysis
  • Life sciences / Biomaterials / Hemodynamic measurements
  • Life sciences / Biomedical engineering / Hemodynamic measurements

Academic & Professional Experience

  • 2019/04 - Today  Jichi Medical UniversityHealth Care CenterDirector / Professor
  • 2000 - 2010/01  - 自治医科大学 講師
  • 1997 - 2000  Jichi Medical University
  • 1997 - 2000  Jichi Medical School, Research Assistant
  • 2000  - Jichi Medical School, Lecturer
  • 1995 - 1997  国立循環器病センター研究所 COE特別研究員 流動研究員
  • 1995 - 1997  National Cardiovascular Center Research Institute, COE research worker

Education

  •        - 1984  Jichi Medical University  医学部
  •        - 1984  Jichi Medical University  Faculty of Medicine

Association Memberships

  • JAPAN SOCIETY OF NINGEN DOCK   JAPAN SOCIETY OF HEALTH EVALUATION AND PROMOTION   日本循環制御医学会   日本臨床生理学会   日本高血圧学会   日本生理学会   日本生体医工学会   日本心臓病学会   日本循環器学会   日本内科学会   

Published Papers

  • Ken Yoshida, Kazuha Yokota, Yukinobu Kutsuwada, Kazuhiro Nakayama, Kazuhisa Watanabe, Ayumi Matsumoto, Hiroshi Miyashita, Seik-Soon Khor, Katsushi Tokunaga, Yosuke Kawai, Masao Nagasaki, Sadahiko Iwamoto
    Hepatology communications 4 (8) 1124 - 1135 2020/08 
    Nonalcoholic fatty liver disease (NAFLD) is supposed to manifest its metabolic phenotype in the liver, but it is common to have lean individuals diagnosed with NAFLD, known as lean NAFLD. We conducted a two-stage analysis to identify NAFLD-associated loci in Japanese patients. In stage I, 275 metabolically healthy normal-weight patients with NAFLD were compared with 1,411 non-NAFLD controls adjusted for age, sex, and alcohol consumption by a genome-wide association study (GWAS). In stage II, human leukocyte antigen (HLA) in chromosome 6 (chr6) (P = 6.73E-08), microRNA (MIR) MIR548F3 in chr7 (P = 4.25E-07), myosin light chain 2 (MYL2) in chr12 (P = 4.39E-07), and glycoprotein precursor (GPC)6 in chr13 (P = 5.43E-07), as suggested by the GWAS, were assessed by single nucleotide polymorphism (SNP) association analysis of whole NAFLD against non-NAFLD in 9,726 members of the general population. A minor allele of the secondary lead SNP in chr6, rs2076529, was significantly associated (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.11-1.28; P = 2.10E-06) and the lead SNP in chr7 was weakly associated (OR 1.15; 95% CI, 1.04-1.27; P = 6.19E-03) with increased NAFLD risk. Imputation-based typing of HLA showed a significant difference in the distribution of HLA-B, HLA-DR-beta chain 1 (DRB1), and HLA-DQ-beta chain 1 (DQB1) alleles in lean NAFLD GWAS. Next-generation sequence-based typing of HLA in 5,649 members of the general population replicated the significant difference of HLA-B allele distribution and the significant increase of the HLA-B*54:01 allele in whole NAFLD. Fecal metagenomic analysis of 3,420 members of the general population showed significant dissimilarity in beta-diversity analysis of rs2076529 and HLA-B*54:01 allele carriers from noncarriers. Veillonellaceae was increased but Verrucomicrobia was decreased in rs2076529 minor allele and HLA-B*54:01 allele carriers as in NAFLD. Conclusion: HLA was identified as a novel locus associated with NAFLD susceptibility, which might be affected by the alteration of gut microbiota.
  • Eguchi K, Miyashita H, Takenaka T, Tabara Y, Tomiyama H, Dohi Y, Hashimoto J, Ohkubo T, Ohta Y, Hirooka Y, Kohara K, Ito S, Kawano Y, Sunagawa K, Suzuki H, Imai Y, Kario K, Takazawa K, Yamashina A, Shimada K, ABC-J II Investigator Group
    Hypertension research : official journal of the Japanese Society of Hypertension 41 (11) 947 - 956 0916-9636 2018/11 [Refereed][Not invited]
     
    It is not established whether central blood pressure (BP) evaluated by a radial pulse wave analysis is useful to predict cardiovascular prognoses. We tested the hypothesis that central BP predicts future cardiovascular events in treated hypertensive subjects. We conducted a multicenter, observational cohort study of 3566 hypertensives being treated with antihypertensive medications at 27 institutions in Japan. We performed the radial pulse wave analyses using applanation tonometry in all subjects. The primary outcome was the incidence of any of the following: stroke, myocardial infarction (MI), sudden cardiac death, and acute aortic dissection. The mean age of the subjects was 66.0 ± 10.9 years, and 50.6% were male. The mean brachial SBP and central SBP were 138 ± 18 mm Hg and 128 ± 19 mm Hg, respectively. When the central SBP was divided into quintiles, the number of events was least in the 2nd quintile, and we set it as the reference. In the Cox regression analysis adjusting for age, sex, body mass index, creatinine, diabetes, use of β-blocker, and history of MI/stroke, the patients in the 3rd (hazard ratio (HR) 3.55, 95% confidence interval 1.29-9.78, p = 0.014), 4th (HR 4.12, 95% CI 1.53-11.10, p = 0.005), and 5th quintiles (HR 2.87, 95% CI 1.01-8.18, p = 0.048) had a significantly higher incidence of cardiovascular events compared to the 2nd quintile. The results were essentially unchanged when brachial DBP was additionally adjusted. In conclusion, in treated hypertensives, high central SBP was associated with worse cardiovascular outcomes.
  • Mitsuyo Mieda, Hiroshi Miyashita, Hiroyuki Osawa, Tomosuke Hirasawa, Nobuko Makino, Sachiko Toma, Takeshi Tomiyama, Yoshimasa Miura, Alan K. Lefor, Hironori Yamamoto
    Kaohsiung Journal of Medical Sciences 34 (5) 295 - 300 1607-551X 2018/05 [Refereed][Not invited]
     
    Transnasal endoscopy is widely used in screening for upper gastrointestinal lesions because of less associated pain. Nasal bleeding is the most severe adverse effect, but specific risk factors have not been identified. The aim of this study is to identify risk factors for nasal bleeding during transnasal endoscopy. Nasal bleeding occurred in 160/3035 (5.3%) of patients undergoing transnasal endoscopy as part of health checkups. Patient data were retrospectively evaluated including anthropometric, medical, and life-style parameters with multiple logistic regression analysis. Multiple logistic regression revealed that nasal bleeding was significantly associated with age in decades [odds ratio/10 years 0.78, 95% confidence interval (CI) 0.63–0.97, p = 0.027], female gender (2.15, 95% CI 1.48–3.12, p < 0.001), a history of previous upper gastrointestinal endoscopy (0.55, 95% CI 0.36–0.82, p = 0.004), and chronic/allergic rhinitis (0.60, 95% CI 0.36–0.98, p = 0.043). Other factors including the use of antiplatelet and/or anticoagulant drugs were not significantly associated with nasal bleeding. Female and young patients are significantly associated with an increased risk of bleeding from transnasal endoscopy, but antiplatelet and/or anticoagulant medications and a history of chronic/allergic rhinitis may not be associated.
  • Tsuneo Takenaka, Hiromichi Suzuki, Kazuo Eguchi, Hiroshi Miyashita, Kazuyuki Shimada
    Hypertension Research 41 (4) 299 - 307 1348-4214 2018/04 [Refereed][Not invited]
     
    The progression of chronic kidney disease (CKD) inverts the arterial stiffness gradient. However, central hemodynamic pressure profiles in CKD have not been fully examined. A cross-sectional study was performed to assess the relationship between the CKD stage and central hemodynamic processes. The study enrolled 2020 hypertensive patients who had undergone echocardiography and measurement of their serum creatinine levels. Radial tonometry was applied to all patients to measure central blood pressure. Patients were classified according to six CKD stages based on their estimated glomerular filtration rate. Central (PP2) and brachial pulse pressure (PP) were elevated at stages 3a and 3b, respectively. Diastolic blood pressure (DBP) was higher at stage 1 compared to the other stages. The left ventricular mass index was greater at CKD stages 3b-5 than that at stage 1. Either PP or PP2 was sensitive for detecting the presence of left ventricular hypertrophy (LVH). Age, weight, pulse rate, brachial blood pressure, and antihypertensive medication differed among the six stages. Pulse amplification (PA) adjusted for these confounders was the lowest in CKD stages 3a and 3b. The present observations support that cardiovascular risk is higher in CKD stages 3b and later. Our findings indicate that PA is inverted in CKD stages 4 and 5. The present results suggest that aortic stiffening and the subsequent elevation in PA during CKD progression relate to a reduction in the ability of PP2 to predict LVH.
  • Supichaya Boonvisut, Ken Yoshida, Kazuhiro Nakayama, Kazuhisa Watanabe, Hiroshi Miyashita, Sadahiko Iwamoto
    LIPIDS IN HEALTH AND DISEASE 16 (1) 183  1476-511X 2017/09 [Refereed][Not invited]
     
    Background: Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive fat deposits in hepatocytes without excessive alcohol intake. NAFLD is influenced by genetic factors, and the heritability has been estimated at 0.35 to 0.6 by twin studies. We explored rare variants in known NAFLD-associated genes to investigate whether these rare variants are involved in the susceptibility to NAFLD. Methods: The target genes for re-sequencing were PNPLA3, TM6SF2, and MTTP. All exons of these three genes were amplified from a discovery panel of 950 Japanese males, and the identified rare variants were further tested for genetic association in 3014 individuals from the Japanese general population and for in vitro functional evaluation. Results: Target re-sequencing analysis using next-generation sequencing identified 29 rare variants in 65 Japanese males (6.84%), 12 of which were newly identified base substitutions. A splicing mutation in TM6SF2 that resulted in deletion of 31 amino acids was identified in an NAFLD case. Among eight genotyped rare single-nucleotide polymorphisms (SNPs; minor allele frequency < 0.02), rs143392071 (Tyr220Cys, PNPLA3) significantly increased (odds ratio = 3.52, P = 0.008) and rs756998920 (Val42Ile, MTTP) significantly decreased (odds ratio = 0.03, P = 0.019) the NAFLD risk. Functional assays showed that these two SNPs disrupted protein functions and supported the genetic association. Conclusion: Collectively, 1.79% of individuals in our studied population were estimated carriers of rare variants that are potentially associated with NAFLD.
  • Kazuhiro Nakayama, Shinichi Saito, Kazuhisa Watanabe, Hiroshi Miyashita, Fuyuhiko Nishijima, Yoshie Kamo, Koji Tada, Satoshi Ishizuka, Toshimitsu Niwa, Sadahiko Iwamoto, Hidehisa Shimizu
    BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 81 (6) 1120 - 1124 0916-8451 2017 [Refereed][Not invited]
     
    The function of aryl hydrocarbon receptor repressor (AHRR) in the kidney is unclear. The present study investigated associations between AHRR Pro189Ala polymorphism and estimated glomerular filtration rates (eGFR), serum creatinine, and hemoglobin levels in 2775 Japanese adults without diabetes. In addition, we examined whether AHRR expression levels in the kidney of control and chronic kidney disease (CKD) rats were changed. Multiple linear regression analyses showed that carriers of the Ala allele had increased eGFR and lower concentrations of serum creatinine and hemoglobin (p < 0.05). Immunohistochemical analysis showed that the expression of AHRR was upregulated in the kidneys of rats with CKD. These findings suggest that AHRR plays distinct roles in kidney functions and hemoglobin values. The effects of the AHRR polymorphism might be intensified in the kidneys of patients with CKD.
  • Taishi Fukushima, Kazuo Eguchi, Akihide Ohkuchi, Hiroshi Miyashita, Kazuomi Kario
    JOURNAL OF CLINICAL HYPERTENSION 18 (4) 329 - 336 1524-6175 2016/04 [Refereed][Not invited]
     
    The authors tested the hypothesis that central hemodynamic parameters in women with hypertensive disorders of pregnancy (HDP) change between before and after delivery. A total of 137 pregnant women were studied: 72 with HDP, 42 with chronic hypertension (CH), and 23 with white-coat hypertension (WCH; control group). Aortic augmentation index adjusted by heart rate 75 beats per minute (AIx@75), central pulse pressure (PP), total peripheral resistance (TPR), and cardiac output (CO) before and after delivery were recorded. AIx@75 and central PP were higher in the HDP group than in the control group, but both parameters declined after delivery until they were similar to the controls. AIx@75 and central PP, but not TPR or CO, were significantly decreased after delivery in the HDP group, but no such effects were seen in the other groups. These findings suggest that increased wave reflection caused by the stiffened aorta could be a key factor in the pathophysiology of HDP.
  • Kazuo Eguchi, Satoshi Hoshide, Hiroshi Miyashita, Shoichiro Nagasaka, Kazuomi Kario
    ATHEROSCLEROSIS 246 338 - 343 0021-9150 2016/03 [Refereed][Not invited]
     
    Background: Radial augmentation index (rAI), a marker of aortic wave reflection, is usually lower in patients with diabetes (DM) than in non-DM subjects, even though atherosclerotic change is advanced in DM. Objective: We sought to explore why rAI in DM is lower than in non-DM. Methods: We performed radial applanation tonometry in 1787 subjects who had at least one cardiovascular risk factor. The rAI was defined as [late systolic shoulder pressure amplitude (PP2)]/[radial pulse pressure (rPP)]. The late systolic shoulder blood pressure (SBP2) and PP2 of a radial pressure wave were used as estimates of the central SBP and PP (cPP), respectively. Results: The age (65.8 +/- 9.8 vs. 65.8 +/- 12.1 yrs) and mean brachial SBP (141 +/- 16 vs. 141 +/- 17 mmHg) were similar between the DM and non-DM groups. The rAI was significantly lower in the DM group (83.3 +/- 14.1 vs. 87.3 +/- 15.7%, p < 0.001), but clinic PP (62 +/- 14 vs. 59 +/- 14 mmHg, p < 0.001) and cPP (51 +/- 15 vs. 49 +/- 15 mmHg, p = 0.019) were significantly greater in the DM group than in the non-DM group. In multivariable analyses adjusting for covariates, the significant determinants of rAI were the estimated glomerular filtration rate (eGFR) (beta = 0.17, p < 0.001) in the DM group, and the log-transformed homeostatic model assessment of insulin resistance (HOMA-IR) (beta = -0.15, p < 0.001) in the non-DM group. The same trends were also seen for central SBP and cPP. Conclusions: The lower rAI in DM associated with higher cPP compared to non-DM suggests proximal conduit-predominant arterial stiffening causing reduced reflection coefficients at systemic reflection sites. As renal function decreases, a cPP increase may overcome the increase of augmentation pressure in the DM group. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Supichaya Boonvisut, Kazuhiro Nakayama, Saho Makishima, Kazuhisa Watanabe, Hiroshi Miyashita, Munkhtulga Lkhagvasuren, Yasuo Kagawa, Sadahiko Iwamoto
    LIPIDS IN HEALTH AND DISEASE 15 8  1476-511X 2016/01 [Refereed][Not invited]
     
    Background: The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity. Methods: Samples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis. Results: rs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (+/- 3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (+/- 11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (+/- 3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289-2.196, p value 0.00013). Conclusion: This study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.
  • Kazuhiro Nakayama, Hiroshi Miyashita, Sadahiko Iwamoto
    JOURNAL OF PHYSIOLOGICAL ANTHROPOLOGY 33 38  1880-6791 2014/12 [Refereed][Not invited]
     
    Background: Non-shivering thermogenesis (NST) involves a substantial amount of energy expenditure in humans and, thus, contributes to reducing the risk for obesity. Molecular evolutionary studies have reported that SNPs in/near the uncoupling protein 3 gene (UCP3) and the regulatory associated protein of mTOR complex 1 gene (RPTOR) might influence NST and confer adaptive advantages for modern human dispersal into cold environments. In the present study, the impact of these SNPs on obesity-related traits was investigated. Methods: Study subjects consisted of 2,834 Japanese adults (percentage of female: 46%, mean age: 51.5). Associations of the UCP3-55C/T and the RPTOR-26934C/T - the 2 potential genetic variations involved in cold adaptation and thermogenic mechanisms in mammals, with quantitative obesity-related traits including body mass index (BMI), waist circumference, visceral fat area (VFA), VFA adjusted for BMI, and selected blood parameters - were tested using multiple linear regression models. Sliding windowsampling analysis was applied to depict seasonal effects of the SNPs on the obesity-related phenotypes. Results: UCP3-55C/T and the RPTOR-26934C/T did not show any association with obesity traits and blood chemical parameters in multiple linear regression models consisting of the whole subjects. Moreover, sliding window sampling-based association analyses involving seasonality also failed to find associations between these two SNPs and obesity-related traits. Conclusions: UCP3-55C/T and the RPTOR-26934C/T may only have subtle effects on the development of obesity-related traits in the present humans. These two SNPs might be irrelevant to inter-individual variations in energy metabolism and efficiency of NST.
  • Hirofumi Tomiyama, Mari Odaira, Kazutaka Kimura, Chisa Matsumoto, Kazuki Shiina, Kazuo Eguchi, Hiroshi Miyashita, Kazuyuki Shimada, Akira Yamashina
    AMERICAN JOURNAL OF HYPERTENSION 27 (12) 1479 - 1485 0895-7061 2014/12 [Refereed][Not invited]
     
    BACKGROUND The effect of age on the augmentation index (AI) differs between young adults and the elderly, and the AI reaches a plateau after the age of 60 years. We examined whether the effects of age and an elevation in blood pressure on the AI differ between young adults and the elderly, between subjects with and without high blood pressure, or between subjects with and without a high AI. METHODS The radial AI was measured in 10,190 subjects who were either healthy or had hypertension (n = 5,477 men and 4,743 women). RESULTS In both sexes, a phased increase in the radial AI with age could only be confirmed up to an age of 60 years. A phased increase in the radial AI with the systolic blood pressure (SBP) could be confirmed up to an SBP of > 170 mm Hg. Among subjects categorized within the highest age tertile, the highest SBP tertile, or the highest radial AI tertile, stepwise multivariable analyses demonstrated that SBP, but not age, was a significant independent factor influencing the radial AI. CONCLUSIONS The effect of age and blood pressure on AI differ not only between young adults and the elderly but also between those with and those without high blood pressure or between those with and those without a high AI. The effect of an elevation in blood pressure, but not aging, on the AI is significant in the elderly, in subjects with high blood pressure, or in those with a high AI.
  • Kazuhiro Nakayama, Kazuhisa Watanabe, Supichaya Boonvisut, Saho Makishima, Hiroshi Miyashita, Sadahiko Iwamoto
    AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY 307 (11) G1108 - G1114 0193-1857 2014/12 [Refereed][Not invited]
     
    Animal studies have demonstrated that glucose-dependent insulinotropic polypeptide (GIP) and GIP receptor (GIPR) contribute to the etiology of obesity. In humans, genomewide association studies have identified single nucleotide polymorphisms (SNPs) in the GIPR gene that are strongly associated with body mass index (BMI); however, it is not clear whether genetic variations in the GIP gene are involved in the development of obesity. In the current study, we assessed the impact of GIP SNPs on obesity-related traits in Japanese adults. Six tag SNPs were tested for associations with obesity-related traits in 3,013 individuals. Multiple linear regression analyses showed that rs9904288, located at the 3'-end of GIP, was significantly associated with visceral fat area (VFA). Moreover, rs1390154 and rs4794008 showed significant associations with plasma triglyceride levels and hemoglobin A(lc) levels, respectively. Among the significant SNPs, rs9904288 and rs1390154 were independently linked with SNPs in active enhancers of the duodenum mucosa, the main GIP-secreting tissue. The haplotypes of these two SNPs exhibited stronger associations with VFA. Numbers of VFA-increasing alleles of rs9904288 and BMI-increasing alleles of previously identified GIPR SNPs showed a strong additive effect on VFA, waist circumference, and BMI in the subject population. These novel results support the notion that the GIP-GIPR axis plays a role in the etiology of central obesity in humans, which is characterized by the accumulation of visceral fat.
  • Yuumi Ishizuka, Kazuhiro Nakayama, Ayumi Ogawa, Saho Makishima, Supichaya Boonvisut, Atsushi Hirao, Yusaku Iwasaki, Toshihiko Yada, Yoshiko Yanagisawa, Hiroshi Miyashita, Masafumi Takahashi, Sadahiko Iwamoto
    JOURNAL OF MOLECULAR ENDOCRINOLOGY 52 (2) 145 - 158 0952-5041 2014/04 [Refereed][Not invited]
     
    Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (P = 9.39 x 10(-7)) associated with ultrasonographically diagnosed nonalcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.
  • Shin-ichiro Katsuda, Hiroshi Miyashita, Kazuyuki Shimada, Yoshinori Miyawaki, Iwao Kojima, Yuri Shiogai, Akihiro Hazama
    HYPERTENSION RESEARCH 37 (1) 19 - 25 0916-9636 2014/01 [Refereed][Not invited]
     
    We investigated whether the subservient relationship of peripheral to central hemodynamic parameters, such as the augmentation index (AI) and the second systolic (SBP2) and pulse pressures, were preserved with the progression of atherosclerosis in the Kurosawa and Kusanagi-hypercholesterolemic (KHC) rabbit, an animal model for hypercholesterolemia and atherosclerosis. Male KHC rabbits, aged 12 and 24 months, were anesthetized with pentobarbital sodium. Two catheter-tip transducers were introduced to the central (ascending aorta) and peripheral (distal region of the right brachial artery) arteries through the left common carotid and the right radial arteries, respectively. Pressure waves were simultaneously recorded under regular atrial pacing to investigate changes in response to the intravenous infusion of angiotensin II (Ang II) (30-40 ng kg(-1) min(-1)) and sodium nitroprusside (NTP) (20-30 mu g kg(-1) min(-1)). Central systolic blood pressure (cSBP) and diastolic blood pressure (DBP), peripheral systolic blood pressure (pSBP) and DBP, and peripheral second systolic blood pressure (pSBP(2)) showed no significant difference between the 12- and 24-month-old groups before the administration of vasoactive drugs. There was no significant difference in central AI (cAI) between the two age groups before the drug infusion, even though atherosclerosis progressed with aging. Peripheral AI (pAI) changed in parallel with cAI in response to vasopressor and depressor actions due to the infusion of Ang II and NTP, respectively. We conclude that the subservience of pSBP(2) to cSBP and pAI to cAI, in addition to the regression relationship of these parameters between peripheral and central arteries, were well preserved, irrespective of the progression of atherosclerosis.
  • Kazuhiro Nakayama, Hiroshi Miyashita, Yoshiko Yanagisawa, Sadahiko Iwamoto
    PLoS ONE 8 (9) e74720  1932-6203 2013/09 [Refereed][Not invited]
     
    Uncoupling protein 1 (UCP1) and β3 adrenergic receptor (ADRB3) genes play central roles in the thermogenesis of brown adipose tissue (BAT) in adult humans. However, the importance of single-nucleotide polymorphisms (SNPs) in both genes during the development of obesity is controversial. Although active BAT in adult humans is frequently observed in the winter season, the effects of sampling season have not been taken into consideration in previous association studies. Here, we tested the associations of UCP1 -3826A/G and ADRB3 Trp64Arg with body mass index (BMI) and visceral fat area (VFA) in 3013 Japanese adults sampled during different seasons. Association between SNPs and the obesity-related traits were assessed using multiple linear regression models, including sex, age, physical activity, and genotypes. Both SNPs did not show significant associations in the models based on the entire cohort. However, in subsets comprising individuals mainly sampled from winter to spring, UCP1 showed significant associations with VFA (P = 0.0098) and VFA adjusted for BMI (P = 0.0128). Moreover, the effects of UCP1 on VFA were strongly negatively correlated with outdoor temperature (P = 0.00011), but not with night length (P = 0.039). ADRB3 did not show these associations, but an additive effect with UCP1 was observed for VFA adjusted for BMI (P = 0.0067). Subsets sampled in the hot season did not show significant associations for both SNPs. The season-specific effects of UCP1 on VFA were consistent with a previous finding that active BAT was more frequently found in winter than in summer, and supported the importance of cold stress in BAT activation and the significance of BAT in the development of obesity in adult humans. © 2013 Nakayama et al.
  • Kazuhiro Nakayama, Ayumi Ogawa, Hiroshi Miyashita, Yasuharu Tabara, Michiya Igase, Katsuhiko Kohara, Tetsuro Miki, Yasuo Kagawa, Yoshiko Yanagisawa, Mitsuhiro Katashima, Tomohiro Onda, Koichi Okada, Shogo Fukushima, Sadahiko Iwamoto
    HUMAN GENETICS 132 (2) 201 - 217 0340-6717 2013/02 [Refereed][Not invited]
     
    Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 x 10(-6) and P = 9.0 x 10(-6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA-associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians.
  • Hiroshi Miyashita, Shin-ichiro Katsuda
    2013 35TH ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY (EMBC) 2013 221 - 224 1557-170X 2013 [Refereed][Not invited]
     
    In hypertension clinics, central blood pressure (CBP) should be estimated, instead of directly measured, by the "signal processing" of a noninvasive peripheral pressure waveform. This paper deals with the data obtained in our three separate studies focusing on a major estimation method, i.e., radial artery late systolic shoulder pressure (rSBP2)-based CBP estimation. Study 1: Using a wave separation analysis of precise animal data of pressure wave transmission along the upper-limb arteries, we first demonstrate that pulse pressure amplification is largely attributable to local wave reflection alone. Study 2: A frequency component analysis of simultaneously recorded human central and radial artery pressure waveforms showed a predominance of lower (1st+2nd) harmonic components in determining the central augmentation peak amplitude. The features of a central pressure waveform, including its phase property, may contribute to the less-altered transmission of augmentation peak pressure to rSBP2. Study 3: Comparisons of noninvasive rSBP2 with direct or estimated central systolic blood pressure (cSBP) revealed broad agreement but also augmentation-dependent biases. Based on the features of the biases as well as the counterbalanced relationship between pulse pressure amplification and the transmission-induced alterations of augmentation peak amplitude observed in Study 2, we propose an improved cSBP estimate, SBPm, the simple arithmetic mean of rSBP2 and peripheral systolic blood pressure.
  • Hiroshi Miyashita
    Current Hypertension Reviews 8 (2) 80 - 90 1573-4021 2012 [Refereed][Not invited]
     
    Central aortic blood pressure (CBP) is increasingly considered a better cardiovascular prognostic marker than conventional cuff brachial blood pressure. Because CBP cannot be directly measured noninvasively, it has to be estimated from peripheral pressure pulses. To assess estimated CBP appropriately, the accuracy and features of the estimation method should be considered. The aim of this review is to provide basic knowledge and information useful for interpreting and assessing estimated CBP from a methodological point of view. Precise peripheral pressure pulse recording has been enabled by the introduction of arterial applanation tonometry, for which the radial artery may be the optimal site. An automated tonometry device utilizing a sensor array is preferable in terms of reproducibility and objectivity. Calibration of a peripheral pressure waveform has unresolved problems for any estimation method, due to imperfect brachial sphygmomanometry. However, if central and peripheral pressure calibrations are equivalent, two major methods to estimate CBP-those based on generalized pressure transfer function or radial late systolic pressure-may be comparable in their accuracy of CBP parameter estimation. © 2012 Bentham Science Publishers.
  • Hiroshi Miyashita, Akira Aizawa, Junichiro Hashimoto, Yoshitaka Hirooka, Yutaka Imai, Yuhei Kawano, Katsuhiko Kohara, Kenji Sunagawa, Hiromichi Suzuki, Yasuharu Tabara, Kenji Takazawa, Tsuneo Takenaka, Hisayo Yasuda, Kazuyuki Shimada
    AMERICAN JOURNAL OF HYPERTENSION 23 (3) 260 - 268 0895-7061 2010/03 [Refereed][Not invited]
     
    BACKGROUND Central blood pressure (CBP) has been reported to be superior to brachial blood pressure (BP) as a cardiovascular risk predictor in hypertensive patients, however, the effects of antihypertensives on CBP have not been fully examined. This cross-sectional hypothesis-generating study aimed to tentatively characterize all classes of antihypertensives in relation to CBP METHODS Calibrated tonometric radial artery pressure waveforms were recorded using an automated device in 1,727 treated hypertensive patients and 848 nonhypertensive (non-HT) participants Radial artery late systolic BP (SBP) has been reported to reflect central SBP The difference between late and peak SBPs (Delta SBP2) was assessed with linear regression model-based adjustments. Separate regression models for Delta SBP2 were constructed for both participant groups as well as specified sub-populations RESULTS Delta SBP2 was 3.3 mm Hg lower in patients treated with any single-vasodilating (VD) antihypertensive agent without significant interclass difference than with non-VD agents, and was 2 0 mmHg lower than estimated in nonhypertensive subjects Combinations of two vasodilators were 6 6 and 2.9 mm Hg lower in Delta SBP2 than nonvasodilator combinations and nonhypertensive subjects, respectively (P < 0 001 for all comparisons) Nonvasodilators and their combination showed high Delta SBP2, 1.1 and 3.7 mm Hg higher than in nonhypertensive subjects (P < 0 001 for both) Additional adjustment of the pulse rate reduced high Delta SBP2 with beta-blockers (beta BLs) CONCLUSIONS This cross-sectional observation suggests that vasodilatory antihypertensives lower CBP independently of peripheral BP levels without evident class-specific differences, whereas nonvasodilators may raise CBP
  • Yoshio Matsui, Kazuo Eguchi, Michael F. O'Rourke, Joji Ishikawa, Hiroshi Miyashita, Kazuyuki Shimada, Kazuomi Kario
    HYPERTENSION 54 (4) 716 - U62 0194-911X 2009/10 [Refereed][Not invited]
     
    The aim of this study was to compare the effects between calcium channel blockers and diuretics when used in combination with angiotensin II receptor blocker on aortic systolic blood pressure (BP) and brachial ambulatory systolic BP. We conducted a prospective, randomized, open-label, blinded end point study in 207 hypertensive patients (mean age: 68.4 years). Patients received olmesartan monotherapy for 12 weeks, followed by additional use of azelnidipine (n = 103) or hydrochlorothiazide (n = 104) for 24 weeks after randomization. The central BP by radial artery tonometry, aortic pulse wave velocity, and ambulatory BP were assessed at baseline and 24 weeks later. After adjustment for baseline covariates, the extent of the reduction in central systolic BP in the olmesartan/azelnidipine group was significantly greater than that in the olmesartan/hydrochlorothiazide group (the between-group difference was 5.2 mm Hg; 95% CI: 0.3 to 10.2 mm Hg; P = 0.039), whereas the difference in the reduction in brachial systolic BP between the groups was not significant (2.6 mm Hg; 95% CI: -2.2 to 7.5 mm Hg; P = 0.29). The aortic pulse wave velocity showed a significantly greater reduction for the olmesartan/azelnidipine combination than for the olmesartan/hydrochlorothiazide combination (0.8 m/s; 95% CI: 0.5 to 1.1 m/s; P < 0.001) after adjustment for covariates. The extent of the reduction in brachial ambulatory systolic BP was similar between the groups. These data showed that the combination of olmesartan (20.0 mg) and azelnidipine (16.0 mg) had a more beneficial effect on central systolic BP and arterial stiffness than the combination of olmesartan (20.0 mg) and hydrochlorothiazide (12.5 mg), despite the lack of a significant difference in brachial systolic BP reduction between the 2 treatments. (Hypertension. 2009; 54: 716-723.)
  • Yoshio Matsui, Joji Ishikawa, Kazuo Eguchi, Satoshi Hoshide, Hiroshi Miyashita, Kazuyuki Shimada, Kazuomi Kario
    HYPERTENSION RESEARCH 31 (4) 649 - 656 0916-9636 2008/04 [Refereed][Not invited]
     
    It has been established that a positive association exists between the augmentation index (Alx) and left ventricular mass (LVM) in hypertensives, but it remains unclear whether this association is affected by age or gender. The aim of the study was to assess the effect of age and gender on the association between carotid Alx and LVM in hypertensive patients. We performed arterial tonometry and echocardiography in 512 treated hypertensive patients who were divided into 4 groups by gender and age (older or younger than 65 years). Correlations between carotid Alx and echocardiographic indices were evaluated by univariable and multivariable models. In females, carotid Alx increased with age up to 60 years, but decreased thereafter. In univariable analyses, carotid Alx was positively correlated with the LVM index in younger females (r=0.25, p=0.04) and males (r=0.48, p<0.001), but not in the older age groups. Multivariable analyses showed that this positive correlation in younger males remained significant (beta=0.39, p<0.001) after adjusting for age, body mass index, and mean arterial pressure. In contrast, in the older subjects, carotid Alx was negatively correlated with relative wall thickness in females (beta=-0.14, p=0.034) and males (beta=-0.17, p=0.037) independent of age and mean arterial pressure. A significant association between carotid Alx and LVM index was seen only in younger males. The lack of any such association in older hypertensives can be explained by both the plateau in the values of carotid Alx, and the fact that LVM increased with age.
  • Takayuki Ito, Takashi Okada, Jun Mimuro, Hiroshi Miyashita, Ryosuke Uchibori, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume, Masafumi Takahashi, Uichi Ikeda, Yoichi Sakata, Kazuyuki Shimada, Keiya Ozawa
    HYPERTENSION 50 (3) 531 - 536 0194-911X 2007/09 [Refereed][Not invited]
     
    Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1-based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week-old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F-1 alpha increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1x10(10) genome copies per body) significantly decreased mean pulmonary arterial pressure (33.9 +/- 2.4 versus 46.1 +/- 3.0 mm Hg; P < 0.05), pulmonary vascular resistance (0.26 +/- 0.03 versus 0.41 +/- 0.03 mm Hg . mL(-1) . min(-1) . kg(-1); P < 0.05), and medial thickness of the peripheral pulmonary artery (14.6 +/- 1.5% versus 23.5 +/- 0.5%; P < 0.01) as compared with the controls. Furthermore, the PGIS-transduced rats demonstrated significantly improved survival rates as compared with the controls (100% versus 50%; P < 0.05) at 8 weeks postmonocrotaline administration. An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans.
  • Takayuki Ito, Takashi Okada, Hiroshi Miyashita, Tatsuya Nomoto, Mutsuko Nonaka-Sarukawa, Ryosuke Uchibori, Yoshikazu Maeda, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume, Masafumi Takahashi, Uichi Ikeda, Kazuyuki Shimada, Keiya Ozawa
    CIRCULATION RESEARCH 101 (7) 734 - 741 0009-7330 2007/09 [Refereed][Not invited]
     
    Pulmonary arterial hypertension (PAH) is a fatal disease associated with inflammation and pathological remodeling of the pulmonary artery (PA). Interleukin (IL)-10 is a pleiotropic antiinflammatory cytokine with vasculoprotective properties. Here, we report the preventive effects of IL-10 on monocrotaline-induced PAH. Three-week-old Wistar rats were intramuscularly injected with an adeno-associated virus serotype 1 vector expressing IL-10, followed by monocrotaline injection at 7 weeks old. IL-10 transduction significantly improved survival rates of the PAH rats 8 weeks after monocrotaline administration compared with control gene transduction (75% versus 0%, P < 0.01). IL-10 also significantly reduced mean PA pressure (22.8 +/- 1.5 versus 29.7 +/- 2.8 mm Hg, P < 0.05), a weight ratio of right ventricle to left ventricle plus septum (0.35 +/- 0.04 versus 0.42 +/- 0.05, P < 0.05), and percent medial thickness of the PA (12.9 +/- 0.3% versus 21.4 +/- 0.4%, P < 0.01) compared with controls. IL-10 significantly reduced macrophage infiltration and vascular cell proliferation in the remodeled PA in vivo. It also significantly decreased the lung levels of transforming growth factor-beta(1) and IL-6, which are indicative of PA remodeling. In addition, IL-10 increased the lung level of heme oxygenase-1, which strongly prevents PA remodeling. In vitro analysis revealed that IL-10 significantly inhibited excessive proliferation of cultured human PA smooth muscle cells treated with transforming growth factor-beta(1) or the heme oxygenase inhibitor tin protoporphyrin IX. Thus, IL-10 prevented the development of monocrotaline-induced PAH, and these results provide new insights into the molecular mechanisms of human PAH.
  • Shin-ichiro Katsuda, Hiroshi Miyashita, Kenji Takazawa, Noboru Machida, Masahiko Kusanagi, Masao Miyake, Akihiro Hazama
    PHYSIOLOGICAL MEASUREMENT 27 (12) 1361 - 1371 0967-3334 2006/12 [Refereed][Not invited]
     
    The coexistence of hypertension and hypercholesterolaemia from youth may increase the prevalence of and mortality from cardiovascular disease and stroke. We thus investigated haemodynamics of mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits aged 10-12 months old, as models of heritable hypercholesterolaemia. Pressure and flow waves were simultaneously recorded at the ascending aorta with a catheter-tip micromanometer and ultrasonic flow meter under pentobarbital anaesthesia, respectively. Systolic (119.3 +/- 6.5 and 138.4 +/- 7.4 mmHg (mean +/- SD) for control and KHC rabbit groups; p +/- 0.001), diastolic (95.7 +/- 6.1 and 109.8 +/- 5.2; p < 0.001), mean (105.8 +/- 6.5 and 122.5 +/- 4.9; p < 0.001) and pulse (23.7 +/- 2.5 and 28.6 +/- 4.0; p < 0.001) pressures as well as total peripheral vascular resistance (0.32 +/- 0.02 and 0.37 +/- 0.03 mmHg/ml/min; p < 0.001) were significantly greater in the KHC rabbit group than those in the age-matched control rabbit group, respectively, while there were no significant differences in the mean aortic flow, heart rate or stroke volume between the two rabbit groups. Aortic input impedance (p < 0.05) and reflection coefficient (p < 0.05) were significantly greater at lower frequency in the KHC rabbit group than in the control rabbit group, whereas there was no significant difference in the characteristic impedance between the two rabbit groups. Plasma angiotensin I (p < 0.01) and II ( p < 0.01) levels and serum angiotensin converting enzyme activity (p < 0.05) were significantly greater in theKHCrabbit group than in the age-matched control rabbit group. Atheromatous plaque was in the early stage and composed mainly of abundant foam cells. Neither sclerotic lesions nor stenosis were observed in main peripheral arteries. The mild hypertension in young KHC rabbits was due partly to the increased activity of the renin-angiotensin system. These findings may be thought provoking in elucidating the mechanism and developing preventive and therapeutic strategies in young patients with coexistent hypertension and hypercholesterolaemia.
  • Chihiro Suzuki, Masafumi Takahashi, Hajime Morimoto, Atsushi Izawa, Hirohiko Ise, Minoru Hongo, Yasushi Hoshikawa, Takayuki Ito, Hiroshi Miyashita, Eiji Kobayashi, Kazuyuki Shimada, Uichi Ikeda
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 349 (2) 781 - 788 0006-291X 2006/10 [Refereed][Not invited]
     
    Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent inummosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAR (c) 2006 Elsevier Inc. All rights reserved.
  • Hiroshi Miyashita
    HYPERTENSION RESEARCH 29 (7) 467 - 468 0916-9636 2006/07 [Refereed][Not invited]
  • K Nakae, K Saito, T Iino, N Yamamoto, M Wakabayashi, S Yoshikawa, S Matsushima, H Miyashita, H Sugimoto, A Kiba, J Gupta
    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 315 (3) 1136 - 1142 0022-3565 2005/12 [Refereed][Not invited]
     
    Prostacyclin, one of the cyclooxygenase metabolites, causes various biological effects, including vasodilation and antithrombogenicity, and is also involved in several pathophysiological effects, such as inflammatory pain and bladder disorders. The prostacyclin receptor (IP receptor) agonists iloprost, cicaprost, and carbacyclin have been useful for clarifying the role of the IP receptor signaling, since the endogenous ligand, prostacyclin, is very unstable. On the other hand, only a few IP receptor antagonists have been reported to date. Here, we characterized the biological activities of 2-[4-(1H-indol-4- yloxymethyl)benzyloxycarbonylamino]-3-phenyl-propionic acid (compound A) in various in vitro systems. Compound A inhibited the accumulation of the second messenger cyclic AMP in the UMR-108 rat osteosarcoma cell line and primary cultured rat dorsal root ganglion (DRG) neurons in a concentration- dependent manner up to 10 mu M, without affecting other eicosanoid receptors. Functionally, the IP receptor plays an important role in DRG neuron sensitization, which is measured by release of the neurotransmitter substance P. Although the effects of iloprost or Lys-bradykinin, an inflammatory peptide, alone on substance P release were limited, stimulation of the neurons with both these ligands induced substantial amounts of substance P release. This synergistic effect was suppressed by compound A. Collectively, these results suggest that compound A is a highly selective IP receptor antagonist that inhibits iloprost- induced sensitization of sensory neurons. Furthermore, these findings suggest that IP receptor antagonist administration may be effective for abnormal neural activities of unmyelinated sensory afferents. Compound A should prove useful for further investigations of the IP receptor in various biological processes.
  • Miyashita H, Shimada K
    Nihon rinsho. Japanese journal of clinical medicine 6 63 (6) 959 - 968 0047-1852 2005/06 [Refereed][Not invited]
  • S Katsuda, N Machida, M Hasegawa, H Miyashita, M Kusanagi, H Tsubone, A Hazama
    PHYSIOLOGICAL MEASUREMENT 25 (2) 505 - 522 0967-3334 2004/04 [Refereed][Not invited]
     
    The rheological properties of the arterial wall have intimate connections with the fine structure of the wall. Alteration in fine structure due to cardiovascular disease, such as atherosclerosis, could affect the rheological characteristics of the wall. The present study was designed to investigate changes in the static rheological properties of the aorta in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits aged 10-12, 22-24 and 34-36 months in relation to histological alteration of the wall due to progression of atherosclerosis with age. Circumferential wall strips were excised from the ascending, proximal descending thoracic and proximal abdominal aortas and their stress/strain relationship was recorded. Tensile force of the wall showed a slight but insignificant decrease in the KHC rabbit group aged 10-12 months compared to that in the age-matched control group in the proximal thoracic aorta and increased significantly with ageing in the KHC rabbits in these aortic regions mainly at medium and high strain ranges. Wall stress was significantly smaller in the 10-12 months old KHC rabbit group than in the age-matched control group in the proximal thoracic and proximal abdominal aortas and increased significantly with ageing in the KHC rabbit groups chiefly at medium and high strain ranges. Incremental elastic modulus determined at 50% stretching of the initial length of the wall strip was also significantly lower in the KHC rabbit group aged 10-12 months in comparison to that in the age-matched control group and increased significantly with ageing in the KHC rabbit group. The intima thickened severely with abundant foam cells in the KHC rabbits aged 10-12 months. With increasing age, collagen and elastin fibres showed signs of gradual proliferation among the foam cells. The aortic wall in KHC rabbits was viscoelastic in the relatively early stage of atherosclerosis due to abundant foam cells, and thereafter increased in stiffness gradually with fibrous proliferation and calcification. We can conclude that the static rheological properties of the atherosclerotic aortic wall changed in association with alteration in the microstructure of the wall with progression of atherosclerosis.
  • S Katsuda, H Miyashita, M Hasegawa, N Machida, M Kusanagi, M Yamasaki, H Waki, A Hazama
    AMERICAN JOURNAL OF HYPERTENSION 17 (2) 181 - 187 0895-7061 2004/02 [Refereed][Not invited]
     
    Background: Pulse wave velocity, conventionally determined between the carotid and femoral arteries, is a useful measure to estimate stiffness of the aorta. We investigated local pulse wave velocity (LPWV) in different segments in the aorta with relatively early-stage atherosclerosis in relation to the extent and severity of atherosclerotic lesions. Methods: Pressure waves were recorded in eight aortic positions using two catheters with one or two micromanometers to determine LPWV in the ascending aorta, distal end of the aortic arch, proximal, middle, and distal thoracic aortas, and proximal, middle, and distal abdominal aortas in Kurosawa and Kusanagi-hypercholesterolemic (KHC) and normal rabbits aged 10 to 12 months. Results: The LPWV in the KHC rabbit was greatest in the aortic arch, decreased almost to the normal level in the middle and distal thoracic aorta, increased in the proximal abdominal aorta, and showed almost identical change to that in the normal rabbit in the middle and distal abdominal aortic regions. There was significant difference in LPWV in the aortic arch, proximal thoracic, and proximal abdominal aortas between the two rabbit groups. The sclerotic lesion was prominent in the aortic arch, proximal thoracic aorta, and proximal abdominal aortas. The wall was severely thickened with abundant foam cells. The significant increase in LPWV would be mainly related to the increased wall thickness in these aortic regions. Conclusions: We can conclude that LPWV reflects well the distribution and severity of atherosclerotic lesion and the increased wall thickness in the local aortic region in which pulse waves were traveled. (C) 2004 American Journal of Hypertension, Ltd.
  • M Shimpo, U Ikeda, Y Maeda, M Takahashi, H Miyashita, H Mizukami, M Urabe, A Kume, T Takizawa, M Shibuya, K Ozawa, K Shimada
    CARDIOVASCULAR RESEARCH 53 (4) 993 - 1001 0008-6363 2002/03 [Refereed][Not invited]
     
    Objectives: Clinical trials on therapeutic angiogenesis using vascular endothelial growth factor (VEGF) are ongoing, however the benefits of these therapies are still controversial. To establish a more efficient gene transfer method for ischemic diseases, we investigated the therapeutic potential of adeno-associated virus (AAV)-mediated VEGF gene transfer. Methods: We produced VEGF(165)-express in AAV vectors (AAV-VEGF). HEK-293 cells were transduced with AAV-VEGF in vitro and VEGF expression and secretion were examined. We used a rat ischemic hindlimb model and AAV-VEGF was administered intramuscularly into the ischemic limb. Gene expression was evaluated by RT-PCR and ELISA. Six weeks after gene transfer, we measured the blood flow of limb vessels and the skin temperature of limbs. Histochemical examination was performed to illustrate capillary growth. Results: Western blotting and ELISA revealed VEGF protein expression and secretion from AAV-VEGF-transduced HEK-293 cells. VEGF mRNA and protein expression was consistently observed in the injected muscle at least 10 weeks after the injection, while no VEGF mRNA could be detected at remote organs. The mean blood flow in AAV-VEGF-transduced ischemic limbs was significantly higher than in AAV-LacZ-transduced limbs. Capillary density was significantly higher in AAV-VEGF-injected tissues than in AAV-LacZ-injected tissues. Conclusions: This study demonstrates that (1) AAV-mediated VEGF gene transfer into rat skeletal muscles is efficient and stable without ectopic expression, and (2) AAV-mediated VEGF gene transfer stimulates angiogenesis and thereby improves blood flow in a rat hindlimb ischemia model. These findings suggest that AAV-mediated VEGF gene transfer may be useful for treatment of ischemic diseases. (C) 2002 Elsevier Science BY All rights reserved.
  • R Yoshimura, T Sato, T Kawada, T Shishido, M Inagaki, H Miyano, T Nakahara, H Miyashita, H Takaki, T Tatewaki, Y Yanagiya, M Sugimachi, K Sunagawa
    JOURNAL OF CARDIAC FAILURE 6 (1) 66 - 72 1071-9164 2000/03 [Refereed][Not invited]
     
    Background: The renin-angiotensin system (RAS) plays a key role in the pathophysiology of chronic heart failure (CHF). In rats, we reported that CHF enhances dipsogenic responses to centrally administered angiotensin I, and central inhibition of the angiotensin-converting enzyme (ACE) prevents cardiac hypertrophy in CHF. This suggests that the brain RAS is activated in CHF. To clarify the mechanism of the central RAS activation in CHF, we examined brain ACE and the angiotensin receptor (AT) among rats with CHF. Methods and Results: We created high-output heart failure in 22 male Sprague-Dawley rats by aortocaval shunt. Four weeks after surgery, we examined ACE mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) and AT by binding autoradiography. ACE mRNA levels were not significantly increased in the subfornical organ (SFO), the hypothalamus, or in the lower brainstem of CHF rats (n = 5) compared with sham-operated rats (SHM) (n = 6). Binding densities for type 1 AT (AT(1)) in the SFO (P <.05), paraventricular hypothalamic nuclei (P <.05)1 and solitary tract nuclei (P <.05) were higher in rats with CHF (n = 5) than in SHM rats (n = 6). Thus, in rats with CHF, AT(1) expression is increased in brain regions that are closely related to water intake, vasopressin release, and hemodynamic regulation. Conclusions: The fact that AT(1) expression was regulated in important brain regions related to body fluid control in CHF rats indicates that the brain is a major site of RAS action in CHF rats and, therefore, a possible target site of ACE-inhibitors in the treatment of CHF.
  • H Miyashita, M Sugimachi, T Sato, T Kawada, T Shishido, T Nakahara, R Yoshimura, H Takaki, H Miyano, K Sunagawa
    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 278 (3) H998 - H1007 0363-6135 2000/03 [Refereed][Not invited]
     
    To clarify the pathophysiological role of dynamic arterial properties in cardiovascular diseases, we attempted to develop a new control system that imposes desired aortic impedance on in situ rat left ventricle. In 38 anesthetized open-chest rats, ascending aortic pressure and flow waveforms were continuously sampled (1,000 Hz). Desired flow waveforms were calculated from measured aortic pressure waveforms and target impedance. To minimize the difference between measured and desired aortic flow waveforms, the computer generated commands to the servo-pump, connected to a side branch of the aorta. By iterating the process, we could successfully control aortic impedance in such a way as to manipulate compliance and characteristic impedance between 60 and 160% of their respective native values. The error between desired and measured aortic flow waveforms was 70 +/- 34 mu l/s (root mean square; 4.4 +/- 1.4% of peak flow), indicating reasonable accuracy in controlling aortic impedance. This system enables us to examine the importance of dynamic arterial properties independently of other hemodynamic and neurohumoral factors in physiological and clinical settings.
  • T Kawada, G Sunagawa, H Takaki, T Shishido, H Miyano, H Miyashita, T Sato, M Sugimachi, K Sunagawa
    JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION 63 (12) 945 - 950 0047-1828 1999/12 [Refereed][Not invited]
     
    Although treadmill exercise involves a more familiar range of motions and is thus more physiological in terms of daily activity than cycle ergometer exercise, difficulties in controlling the exercise intensity have limited its utility. As heart rate (HR) has been used as a measure of exercise intensity, controlling HR should allow for the proper control of exercise intensity during treadmill exercise. Thus, a servo-controller framework was applied to regulate HR during treadmill exercise. After estimating an averaged transfer function from speed command to HR, feedback parameters were optimized via a computer simulation in order to achieve a quick and stable HR response. The performance of the servo-controller of HR was then examined in 10 healthy subjects. Standard deviations of the steady-state difference between the target and measured HRs were 2.7+/-0.9 and 5.0+/-1.4 beats/min in the stepwise and ramp target HR protocols, respectively. The rise time to reach 90% of the target HR was 93+/-20 s in the stepwise protocol. It was concluded that a treadmill implemented with a negative feedback mechanism made it possible to precisely regulate HR and thus exercise intensity.
  • Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, Yoshimura R, Miyashita H, Inagaki M, Alexander J Jr, Sunagawa K
    The American journal of physiology 1 Pt 2 277 R140 - 6 0002-9513 1999/07 [Refereed][Not invited]
  • Kawada T, Sugimachi M, Shishido T, Miyano H, Sato T, Yoshimura R, Miyashita H, Nakahara T, Alexander J Jr, Sunagawa K
    The American journal of physiology 3 Pt 2 276 R782 - 9 0002-9513 1999/03 [Refereed][Not invited]
  • H Miyano, T Shishido, T Kawada, H Miyashita, T Sato, M Sugimachi, K Sunagawa
    CRITICAL CARE MEDICINE 27 (1) 168 - 176 0090-3493 1999/01 [Refereed][Not invited]
     
    Objectives: We hypothesized that tumor necrosis factor-alpha (TNF-alpha) acutely alters left ventricular mechanoenergetics in blood-perfused hearts. To test this hypothesis, we examined the relation between left ventricular mechanics and energetics, both before and after infusion of TNF-alpha. Design: Prospective, experimental study. Setting: Research laboratory. Subjects: Nine isolated, blood-perfosed canine hearts. Interventions: Recombinant human TNF-alpha (90 mu g/min) was infused into the coronary circulation of the isolated hearts for 20 mins. Measurements and Main Results: In the isolated, cross circulated, blood perfused canine left ventricles, left ventricular contractility was assessed through measurement of end-systolic elastance (Ees). Energetics were examined in terms of the end systolic pressure volume area-myocardial oxygen consumption (MVo(2)) relation. TNF-alpha concentration in coronary venous blood was >1000 ng/mL throughout the experiments. Nevertheless, infusion of TNF-alpha barely affected contractility acutely, i.e., there was a minimal decrease during the infusion (8.1 +/- 2.8% at 10 mins, p<.01) and a minimal increase after the infusion (11.2 +/- 2.5% at 10 mins, p<.01). Neither did the TNF-alpha infusion affect the slope of the end-systolic pressure-volume area MVo(2) relation. This finding indicated that the chemomechanical conversion efficiency remained unchanged. However, TNF-alpha infusion significantly increased the oxygen cost of contractility by 40% (1.25 +/- 0.13 vs. 1.75 +/- 0.24 mt oxygen.mL/mm Hg/beat, p<.05), indicating that MVo(2) for the excitation-contraction coupling increased. Conclusions: TNF-alpha minimally alters left ventricular mechanics, but significantly changes energetics. The latter effect may result from changes in intracellular calcium handling.
  • Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, Yoshimura R, Miyashita H, Inagaki M, Alexander J Jr, Sunagawa K
    The American journal of physiology 2 Pt 2 275 H562 - 7 0002-9513 1998/08 [Refereed][Not invited]
  • Miyano H, Nakayama Y, Shishido T, Inagaki M, Kawada T, Sato T, Miyashita H, Sugimachi M, Alexander J Jr, Sunagawa K
    The American journal of physiology 2 Pt 2 275 H400 - 8 0002-9513 1998/08 [Refereed][Not invited]
  • Nakahara T, Kawada T, Sugimachi M, Miyano H, Sato T, Shishido T, Yoshimura R, Miyashita H, Sunagawa K
    The American journal of physiology 2 Pt 2 275 R541 - 7 0002-9513 1998/08 [Refereed][Not invited]
  • Sato T, Shishido T, Kawada T, Miyano H, Miyashita H, Inagaki M, Sugimachi M, Sunagawa K
    The American journal of physiology 5 Pt 2 274 H1429 - 34 0002-9513 1998/05 [Refereed][Not invited]
  • Sato T, Kawada T, Shishido T, Miyano H, Inagaki M, Miyashita H, Sugimachi M, Knuepfer MM, Sunagawa K
    The American journal of physiology 1 Pt 2 274 H358 - 65 0002-9513 1998/01 [Refereed][Not invited]
  • Kawada T, Sugimachi M, Sato T, Miyano H, Shishido T, Miyashita H, Yoshimura R, Takaki H, Alexander J Jr, Sunagawa K
    The American journal of physiology 2 Pt 2 273 H1024 - 31 0002-9513 1997/08 [Refereed][Not invited]
  • K. Shimada, H. Miyashita, A. Kawamoto, K. Matsubayashi, M. Nishinaga, S. Kimura, T. Ozawa
    Journal of Hypertension, Supplement 12 (6) S7 - S12 0952-1178 1994 [Refereed][Not invited]
     
    Pathophysiology of hypertension: Blood pressure increases with advancing age in most developed countries. The pathophysiology of elderly hypertension is characterized by changes in the structure and function of the cardiovascular system. Changes in arterial structure lead to a decrease in aortic compliance, which augments the aortic pressure component generated by the wave reflection mechanism. The age-related increase in the reflected-wave component of arterial pressure may contribute, at least in part, to the age-related rise in systolic blood pressure. Disproportionately elevated systolic blood pressure in the elderly may account for the progressive increase in left ventricular mass with advancing age. In addition to the changes in vascular and cardiac structures, the haemodynamic function of elderly hypertensives is characterized by increased peripheral resistance as well as reduced cardiac output, renal blood flow and intravascular volume. In contrast to younger hypertensives, the sympathetic and renin-angiotensin systems may not be major factors in the genesis of high peripheral resistance in this patient group. End-organ damage: The most important end-organ damage in elderly hypertensives is left ventricular hypertrophy with or without coronary heart disease, cerebrovascular disease or renal impairment. Furthermore, this end-organ damage is frequently asymptomatic (silent). The prevalence of silent cerebrovascular disease in particular is surprisingly high in this elderly population. Asymptomatic cerebrovascular disease has been shown to be associated with various cardiovascular risk factors, and depressed neurobehavioural function. Diurnal blood pressure variations appear to be related to end-organ damage. The presence of occult end-organ damage and co-existing diseases common in elderly hypertensives has important clinical implications in the management of this disorder.

Books etc

  • PWVおよび中心血圧(AI)の心不全への応用 In 小澤利男(監修), 臨床血圧脈波研究会(編): 新しい血圧測定と脈波解析マニュアル
    ()
    Medical View、東京 2008
  • 循環器の構造と機能 In 島田和幸, 宗村美江子(編): 新体系看護学全書16巻 循環器疾患. pp 3-32
    ()
    メヂカルフレンド社, 東京 2007
  • AI ―PWVとの類似点と相違点― In: 宗像正徳(編): Hands-on Book PWVを知るPWVで診る
    ()
    中山書店、東京 2006
  • Becker's muscular dystrophy associated with precocious cardiomyopathy : Report of a case In: Cardiomyopathy Update 5
    ()
    University of Tokyo Press, Tokyo 1995

Works

  • 高脂血症ウサギの脈波波形解析による大動脈粥状硬化の評価
    2002
  • Assessment of atherosclerosis in a rabbit model of hypercholesterolemia by analyses of pulse waveform
    2002
  • 末梢動脈疾患に対するVEGF遺伝子治療
    2000 -2001
  • Therapeutic potential of adeno-associated virus(AAV)-mediated VEGF gene transfer for peripheral vascular diseases
    2000 -2001

MISC

  • 末梢動脈血圧から中心動脈血圧の簡便な推定法の検討 粥状硬化が進行したKHCウサギにおける有用性
    勝田 新一郎, 宮下 洋, 清水 強  日本病態生理学会雑誌  28-  (2)  55  -55  2019/07  [Not refereed][Not invited]
  • 健診システム更新・再構築の経験に基づく健診システム機能・要件に関する考察
    宮下 洋, 志村 名佳子, 光田 清佳, 三枝 充代, 吉田 友直  総合健診  46-  (1)  198  -198  2019/01  [Not refereed][Not invited]
  • 宮下洋, 志村名佳子, 光田清佳, 三枝充代, 吉田友直, 鈴木恵理, 中澤晶子, 山本さやか  総合健診  45-  (1)  254  2018/01  [Not refereed][Not invited]
  • 宮下洋  日本臨床生理学会雑誌  47-  (4)  86  2017/10  [Not refereed][Not invited]
  • 宮下洋  総合健診  42-  (6)  660  -661  2015/11  [Not refereed][Not invited]
  • 宮下洋, 宮下洋  日本臨床生理学会雑誌  45-  (1)  33  -34  2015/02  [Not refereed][Not invited]
  • 中山一大, 宮下洋, 渡邉和寿, 巻島咲穂, SUPICHAY Boonvisut, 岩本禎彦  肥満研究  20-  (Supplement)  212  2014/10  [Not refereed][Not invited]
  • 宮下洋  日本臨床生理学会雑誌  44-  (4)  84  2014/10  [Not refereed][Not invited]
  • 勝田新一郎, 挾間章博, 宮下洋  日本病態生理学会雑誌  23-  (2)  44  2014/07  [Not refereed][Not invited]
  • 中山一大, 宮下洋, 岩本禎彦  日本生理人類学会誌  19-  (2)  63  -67  2014/05  [Not refereed][Not invited]
  • 中山一大, 大橋順, MUNKHTULGA Lkhagvasuren, 宮下洋, 岩本禎彦  日本栄養・食糧学会大会講演要旨集  68th-  187  2014/04  [Not refereed][Not invited]
  • 山科章, 苅尾七臣, 小原克彦, 佐田政隆, 菅原順, 鈴木洋通, 高沢謙二, 冨山博史, 野出孝一, 橋本潤一郎, 東幸仁, 藤代健太郎, 松尾汎, 宮田哲郎, 宗像正徳, 綿田裕孝, 伊賀瀬道也, 絵本正憲, 小形幸代, 尾山純一, 重松邦広, 杉山正悟, 野間玄督, 松本知沙, 三田智也, 宮下洋, 宮田昌明, 山田博胤, 渡部芳子, 大屋祐輔, 久木山清貴, 朔啓二郎, 砂川賢二  循環器病の診断と治療に関するガイドライン  2013-  3  -112  2014/01  [Not refereed][Not invited]
  • 中山一大, 大橋順, MUNKHUTULGA Lkhagvasuren, 香川靖雄, 宮下洋, 岩本禎彦  日本遺伝子診療学会大会プログラム・抄録集  21st-  322  2014  [Not refereed][Not invited]
  • 宮下洋, 宮下洋  脈波解析研究会講演予稿集(Web)  55th-  ENDAI3 (WEB ONLY)  2014  [Not refereed][Not invited]
  • 宮下洋, 稲葉洋子, 関口美知子, 吉澤充代, 當摩祥子, 冨山剛  総合健診  41-  (1)  163  2014/01  [Not refereed][Not invited]
  • 冨山剛, 吉澤充代, 當摩祥子, 宮下洋  総合健診  41-  (1)  176  2014/01  [Not refereed][Not invited]
  • Kazuo Eguchi, Satoshi Hoshide, Hiroshi Miyashita, Shoichiro Nagasaka, Kazuomi Kario  CIRCULATION  128-  (22)  2013/11  [Not refereed][Not invited]
  • 宮下洋  Arterial Stiffness  (19)  30  -31  2013/11  [Not refereed][Not invited]
  • 勝田新一郎, 宮下洋, 苅尾七臣, 狹間章博  日本高血圧学会総会プログラム・抄録集  36th-  335  2013/10  [Not refereed][Not invited]
  • 中山一大, 宮下洋, 柳沢佳子, 岩本禎彦  日本生理人類学会誌  18-  62  -63  2013/06  [Not refereed][Not invited]
  • 中山一大, 柳沢佳子, 岩本禎彦, 宮下洋, 田原康玄, 恩田智彦, 片嶋充弘, 岡田浩一, 福島省吾, 香川靖雄  DNA多型  21-  245  -249  2013/05  [Not refereed][Not invited]
     
    日本人3013名(男1621名、女1392名)を対象に、腹部インピーダンス法に基づく内臓脂肪測定器を利用して臍の高さの内臓脂肪面積を測定した。また、DNA試料の提供を受け、著者等が腹囲との関連を報告したTRIB2遺伝子のSNPrs1057001および他の肥満関連遺伝子多型についてTaqMan法で解析した。内臓脂肪面積は男性の方が有意に大きく、年齢と正の相関が認められた。FTO遺伝子は多くの人集団においてBMIとの関連が認められているが、日本人における内臓脂肪面積との関連は認められなかった。TRIB2遺伝子のrs1057001は、BMIで調節した内臓脂肪面積と最も強い関連を示した。TRIB2は、一般的な皮下脂肪組織とは異なる発生学的起源をもつ脂肪組織の分化・機能に関与している可能性が高い。
  • 宮下洋, 勝田新一郎, 苅尾七臣  日本臨床生理学会雑誌  43-  (1)  24  -26  2013/02  [Not refereed][Not invited]
  • 勝田新一郎, 宮下洋, 塩貝有里, 小嶋巌, 宮脇義徳, 挾間章博  日本臨床生理学会雑誌  43-  (1)  27  -29  2013/02  [Not refereed][Not invited]
  • 宮下洋, 稲葉洋子, 古内めぐみ, 中山一大, 佐藤清明, 出井充, 伊勢孝雄, 吉澤充代, 大津真弓, 岩本禎彦  総合健診  40-  (1)  163  2013/01  [Not refereed][Not invited]
  • 吉澤充代, 宮下洋, 冨山剛, 大津真弓, 中田明江, 関口美知子, 戸室由美  総合健診  40-  (1)  202  2013/01  [Not refereed][Not invited]
  • 中山一大, 宮下洋, 岩本禎彦  日本人類遺伝学会大会プログラム・抄録集  58th-  179  2013  [Not refereed][Not invited]
  • 宮下洋  Arterial Stiffness  (18)  34  -35  2012/10  [Not refereed][Not invited]
  • 鯉渕晴美, 尾本きよか, 宮下洋, 松永宏明, 谷口信行  日本乳癌検診学会誌  21-  (3)  497  2012/10  [Not refereed][Not invited]
  • 勝田新一郎, 宮下洋, 塩貝有里, 小嶋巌, 宮脇義徳, 挾間章博  日本臨床生理学会雑誌  42-  (5)  87  2012/10  [Not refereed][Not invited]
  • 宮下洋, 勝田新一郎, 苅尾七臣  日本臨床生理学会雑誌  42-  (5)  87  2012/10  [Not refereed][Not invited]
  • 塩貝有里, 小嶋巌, 河野知記, 宮下洋, 宮脇義徳  日本高血圧学会総会プログラム・抄録集  35th-  486  2012/09  [Not refereed][Not invited]
  • 勝田新一郎, 宮下洋, 島田和幸, 小嶋巌, 塩貝有里, 挾間章博  日本高血圧学会総会プログラム・抄録集  35th-  523  2012/09  [Not refereed][Not invited]
  • 岩本禎彦, 石塚裕美, 北村愉介, 巻嶋咲穂, SUPICHAYA Boonvisut, 中山一大, 宮下洋  日本人類遺伝学会大会プログラム・抄録集  57th-  151  2012  [Not refereed][Not invited]
  • 中山一大, 柳沢佳子, 恩田智彦, 片嶋充弘, 岡田浩一, 福島省吾, 宮下洋, 岩本禎彦  日本人類遺伝学会大会プログラム・抄録集  57th-  171  2012  [Not refereed][Not invited]
  • 吉澤充代, 宮下洋  総合健診  39-  (1)  192  2012/01  [Not refereed][Not invited]
  • 宮下洋  循環制御  32-  (3)  164  -171  2011/12  [Not refereed][Not invited]
  • 勝田新一郎, 宮下洋, 島田和幸, 挾間章博  日本高血圧学会総会プログラム・抄録集  34th-  424  2011/10  [Not refereed][Not invited]
  • 宮下洋, 勝田新一郎, 島田和幸  日本臨床生理学会雑誌  41-  (5)  78  2011/10  [Not refereed][Not invited]
  • 勝田新一郎, 宮下洋, 島田和幸, 挾間章博  日本臨床生理学会雑誌  41-  (5)  77  2011/10  [Not refereed][Not invited]
  • 宮下洋  医学のあゆみ  238-  (3)  256  -263  2011/07  [Not refereed][Not invited]
  • ISHIZUKA Yuumi, NAKAYAMA Kazuhiro, OGAWA Ayumi, YANAGISAWA Yoshiko, GOTOH Takaya, IWAMOTO Sadahiko, MIYASHITA Hiroshi  DNA多型 = DNA polymorphism  19-  271  -274  2011/05  [Not refereed][Not invited]
  • 中山一大, 小川歩美, 石塚裕美, 柳沢佳子, 宮下洋, 香川靖雄, 岩本禎彦  日本人類遺伝学会大会プログラム・抄録集  56th-  154  2011  [Not refereed][Not invited]
  • 岩本禎彦, 石塚裕美, 小川歩美, 木村凌矢, 森本真之助, 宮下洋, 中山一大  日本人類遺伝学会大会プログラム・抄録集  56th-  182  2011  [Not refereed][Not invited]
  • 宮下洋  総合健診  38-  (1)  180  2011/01  [Not refereed][Not invited]
  • Atsubumi Murakami, Kazuo Eguchi, Akio Kawasaki, Koji Ogata, Hiroshi Miyashita, Kazuomi Kario  CIRCULATION  122-  (21)  2010/11  [Not refereed][Not invited]
  • 宮下洋, 河野知記, 星野史博, 勝田新一郎, 島田和幸  日本臨床生理学会雑誌  40-  (5)  89  2010/10  [Not refereed][Not invited]
  • 中山一大, 小川歩美, 柳沢佳子, 後藤孝也, 宮下洋, LKHAGVASULEN Munkhtulga, 神田芳郎, 香川靖雄, 岩本禎彦  日本人類遺伝学会大会プログラム・抄録集  55th-  210  2010/10  [Not refereed][Not invited]
  • 小川歩美, 中山一大, 柳沢佳子, 後藤孝也, 山中一央, 岩本禎彦, 宮下洋  DNA多型  18-  246  -249  2010/05  [Not refereed][Not invited]
  • 宮下洋, 河野知記, 星野史博, 島田和幸  日本臨床生理学会雑誌  40-  (1)  37  -41  2010/02  [Not refereed][Not invited]
  • 宮下洋, 梶井英治  総合健診  37-  (1)  204  2010/01  [Not refereed][Not invited]
  • 宮下洋, 勝田新一郎, 島田和幸  日本高血圧学会総会プログラム・抄録集  32nd-  249  2009/10  [Not refereed][Not invited]
  • 宮下洋, 河野知記, 星野史博, 島田和幸  日本臨床生理学会雑誌  39-  (5)  90  2009/09  [Not refereed][Not invited]
  • 宮下洋  血圧  16-  (9)  767  -772  2009/09  [Not refereed][Not invited]
  • 宮下洋, 河野知記, 星野史博, 島田和幸  日本臨床生理学会雑誌  39-  (4)  235  -241  2009/08  [Not refereed][Not invited]
  • 勝田新一郎, 挾間章博, 宮下洋, 島田和幸, 山崎睦夫, 小島巌, 宮脇義徳  日本臨床生理学会雑誌  39-  (4)  233  -234  2009/08  [Not refereed][Not invited]
  • Shin-ichiro Katsuda, Hiroshi Miyashita, Kazuyuki Shimada, Akihiro Hazama, Mutsuo Yamazaki, Iwao Kojima, Yoshinori Miyawaki  JOURNAL OF PHYSIOLOGICAL SCIENCES  59-  498  -498  2009  [Not refereed][Not invited]
  • 福冨基城, 宮下洋  日本臨床生理学会雑誌  38-  (5)  71  2008/10  [Not refereed][Not invited]
  • 勝田新一郎, 宮下洋, 島田和幸, 挾間章博, 山崎睦夫, 小嶋巌, 宮脇義徳  日本臨床生理学会雑誌  38-  (5)  71  2008/10  [Not refereed][Not invited]
  • 宮下洋, 河野知記, 星野史博, 島田和幸  日本臨床生理学会雑誌  38-  (5)  71  2008/10  [Not refereed][Not invited]
  • 宮下洋, 島田和幸  綜合臨床  57-  (5)  1563  -1569  2008/05  [Not refereed][Not invited]
  • 特定健診・特定保健指導の実際:脳血管障害
    宮下洋, 島田和幸  綜合臨牀  57-  (5)  1563  -1569  2008  [Not refereed][Not invited]
  • Takayuki Ito, Takashi Okada, Jun Mimuro, Hiroshi Miyashita, Ryosuke Uchibori, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume, Masafumi Takahashi, Uichi Ikeda, Yoichi Sakata, Kazuyuki Shimada, Keiya Ozawa  HYPERTENSION  50-  (3)  531  -536  2007/09  [Not refereed][Not invited]
     
    Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1-based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week-old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F-1 alpha increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1x10(10) genome copies per body) significantly decreased mean pulmonary arterial pressure (33.9 +/- 2.4 versus 46.1 +/- 3.0 mm Hg; P < 0.05), pulmonary vascular resistance (0.26 +/- 0.03 versus 0.41 +/- 0.03 mm Hg . mL(-1) . min(-1) . kg(-1); P < 0.05), and medial thickness of the peripheral pulmonary artery (14.6 +/- 1.5% versus 23.5 +/- 0.5%; P < 0.01) as compared with the controls. Furthermore, the PGIS-transduced rats demonstrated significantly improved survival rates as compared with the controls (100% versus 50%; P < 0.05) at 8 weeks postmonocrotaline administration. An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans.
  • Takayuki Ito, Takashi Okada, Hiroshi Miyashita, Tatsuya Nomoto, Mutsuko Nonaka-Sarukawa, Ryosuke Uchibori, Yoshikazu Maeda, Masashi Urabe, Hiroaki Mizukami, Akihiro Kume, Masafumi Takahashi, Uichi Ikeda, Kazuyuki Shimada, Keiya Ozawa  CIRCULATION RESEARCH  101-  (7)  734  -741  2007/09  [Not refereed][Not invited]
     
    Pulmonary arterial hypertension (PAH) is a fatal disease associated with inflammation and pathological remodeling of the pulmonary artery (PA). Interleukin (IL)-10 is a pleiotropic antiinflammatory cytokine with vasculoprotective properties. Here, we report the preventive effects of IL-10 on monocrotaline-induced PAH. Three-week-old Wistar rats were intramuscularly injected with an adeno-associated virus serotype 1 vector expressing IL-10, followed by monocrotaline injection at 7 weeks old. IL-10 transduction significantly improved survival rates of the PAH rats 8 weeks after monocrotaline administration compared with control gene transduction (75% versus 0%, P < 0.01). IL-10 also significantly reduced mean PA pressure (22.8 +/- 1.5 versus 29.7 +/- 2.8 mm Hg, P < 0.05), a weight ratio of right ventricle to left ventricle plus septum (0.35 +/- 0.04 versus 0.42 +/- 0.05, P < 0.05), and percent medial thickness of the PA (12.9 +/- 0.3% versus 21.4 +/- 0.4%, P < 0.01) compared with controls. IL-10 significantly reduced macrophage infiltration and vascular cell proliferation in the remodeled PA in vivo. It also significantly decreased the lung levels of transforming growth factor-beta(1) and IL-6, which are indicative of PA remodeling. In addition, IL-10 increased the lung level of heme oxygenase-1, which strongly prevents PA remodeling. In vitro analysis revealed that IL-10 significantly inhibited excessive proliferation of cultured human PA smooth muscle cells treated with transforming growth factor-beta(1) or the heme oxygenase inhibitor tin protoporphyrin IX. Thus, IL-10 prevented the development of monocrotaline-induced PAH, and these results provide new insights into the molecular mechanisms of human PAH.
  • Hiroshi Miyashita, Akira Oshiumi, Satoshi Ubukata, Hideki Niwayama, Tomoki Kawano, Fumilhiro Hoshino, Kazuyuki Shimada  JOURNAL OF HYPERTENSION  24-  321  -321  2006/12  [Not refereed][Not invited]
  • Takayuki Ito, Takashi Okada, Jun Mimuro, Hiroshi Miyashita, Mutsuko Nonaka-Sarukawa, Hiroaki Mizukami, Akihiro Kume, Keiji Yamamoto, Masafumi Takahashi, Uichi Ikeda, Yoichi Sakata, Kazuyuki Shimada, Keiya Ozawa  JOURNAL OF GENE MEDICINE  8-  (12)  1463  -1464  2006/12  [Not refereed][Not invited]
  • Shin-ichiro Katsuda, Hiroshi Miyashita, Kenji Takazawa, Noboru Machida, Masahiko Kusanagi, Masao Miyake, Akihiro Hazama  PHYSIOLOGICAL MEASUREMENT  27-  (12)  1361  -1371  2006/12  [Not refereed][Not invited]
     
    The coexistence of hypertension and hypercholesterolaemia from youth may increase the prevalence of and mortality from cardiovascular disease and stroke. We thus investigated haemodynamics of mild hypertension in young Kurosawa and Kusanagi-hypercholesterolaemic (KHC) rabbits aged 10-12 months old, as models of heritable hypercholesterolaemia. Pressure and flow waves were simultaneously recorded at the ascending aorta with a catheter-tip micromanometer and ultrasonic flow meter under pentobarbital anaesthesia, respectively. Systolic (119.3 +/- 6.5 and 138.4 +/- 7.4 mmHg (mean +/- SD) for control and KHC rabbit groups; p +/- 0.001), diastolic (95.7 +/- 6.1 and 109.8 +/- 5.2; p < 0.001), mean (105.8 +/- 6.5 and 122.5 +/- 4.9; p < 0.001) and pulse (23.7 +/- 2.5 and 28.6 +/- 4.0; p < 0.001) pressures as well as total peripheral vascular resistance (0.32 +/- 0.02 and 0.37 +/- 0.03 mmHg/ml/min; p < 0.001) were significantly greater in the KHC rabbit group than those in the age-matched control rabbit group, respectively, while there were no significant differences in the mean aortic flow, heart rate or stroke volume between the two rabbit groups. Aortic input impedance (p < 0.05) and reflection coefficient (p < 0.05) were significantly greater at lower frequency in the KHC rabbit group than in the control rabbit group, whereas there was no significant difference in the characteristic impedance between the two rabbit groups. Plasma angiotensin I (p < 0.01) and II ( p < 0.01) levels and serum angiotensin converting enzyme activity (p < 0.05) were significantly greater in theKHCrabbit group than in the age-matched control rabbit group. Atheromatous plaque was in the early stage and composed mainly of abundant foam cells. Neither sclerotic lesions nor stenosis were observed in main peripheral arteries. The mild hypertension in young KHC rabbits was due partly to the increased activity of the renin-angiotensin system. These findings may be thought provoking in elucidating the mechanism and developing preventive and therapeutic strategies in young patients with coexistent hypertension and hypercholesterolaemia.
  • Takayuki Ito, Takashi Okada, Hiroshi Miyashita, Mutsuko Nonaka-Sarukawa, Keiji Yamamoto, Keiya Ozawa, Kazuyuki Shimada  CIRCULATION  114-  (18)  327  -327  2006/10  [Not refereed][Not invited]
  • Takayuki Ito, Takashi Okada, Hiroshi Miyashita, Mutsuko Nonaka-Sarukawa, Keiji Yamamoto, Keiya Ozawa, Kazuyuki Shimada  CIRCULATION  114-  (18)  82  -82  2006/10  [Not refereed][Not invited]
  • Chihiro Suzuki, Masafumi Takahashi, Hajime Morimoto, Atsushi Izawa, Hirohiko Ise, Minoru Hongo, Yasushi Hoshikawa, Takayuki Ito, Hiroshi Miyashita, Eiji Kobayashi, Kazuyuki Shimada, Uichi Ikeda  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS  349-  (2)  781  -788  2006/10  [Not refereed][Not invited]
     
    Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent inummosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAR (c) 2006 Elsevier Inc. All rights reserved.
  • Hiroshi Miyashita  Hypertension Research  29-  (7)  467  -468  2006/07  [Not refereed][Not invited]
  • H. Miyashita, A. Oshiumi, T. Yuasa, S. Ubukata, H. Niwayama, Y. Miyawaki, K. Shimada  JOURNAL OF HYPERTENSION  24-  S353  -S353  2006/06  [Not refereed][Not invited]
  • Takayuki Ito, Takashi Okada, Jun Mimuro, Hiroshi Miyashita, Mutsuko Nonaka-Sarukawa, Hiroaki Mizukami, Akihiro Kume, Masafumi Takahashi, Keiji Yamamoto, Kazuyuki Shimada, Keiya Ozawa  MOLECULAR THERAPY  13-  S333  -S333  2006/05  [Not refereed][Not invited]
  • T Ito, T Okada, H Miyashita, M Sarukawa, T Nomoto, T Yoshioka, Y Maeda, H Mizukami, T Matsushita, A Kume, K Yamamoto, M Takahashi, U Ikeda, K Shimada, K Ozawa  JOURNAL OF GENE MEDICINE  8-  (3)  381  -382  2006/03  [Not refereed][Not invited]
  • 橈骨動脈Augmentation indexの心拍数依存性
    宮下洋, 鴛海 明, 生方 聡, 庭山 秀毅, 宮脇 義徳, 島田 和幸  Arterial Stiffness  10-  24  -28  2006  [Not refereed][Not invited]
  • [講座] PWA
    宮下洋  循環制御  27-  (2)  136  -144  2006  [Not refereed][Not invited]
  • T Ito, T Okada, H Miyashita, M Sarukawa, T Nomoto, Y Maeda, M Shimpo, K Ozawa, K Yamamoto  CIRCULATION  112-  (17)  U153  -U153  2005/10  [Not refereed][Not invited]
  • J Ishikawa, K Kario, M Morinari, S Hoshide, K Eguchi, H Miyashita, K Shimada  AMERICAN JOURNAL OF HYPERTENSION  18-  (5)  34A  -34A  2005/05  [Not refereed][Not invited]
  • 高齢者高血圧━病態と診断・治療の進歩━:加齢による動脈コンプライアンスの低下
    宮下洋, 島田 和幸  日本臨牀  63-  (6)  959  -968  2005  [Not refereed][Not invited]
  • Arterial Stiffnessと心機能:Back to the Future
    宮下洋, 砂川賢二  Arterial Stiffness  7-  4  -5  2005  [Not refereed][Not invited]
  • T Ito, T Okada, M Sarukawa, T Yoshioka, Y Maeda, H Miyashita, T Nomoto, T Matsushita, H Mizukami, A Kume, K Yamamoto, K Ozawa, K Shimada  CIRCULATION  110-  (17)  11  -11  2004/10  [Not refereed][Not invited]
  • S Katsuda, N Machida, M Hasegawa, H Miyashita, M Kusanagi, H Tsubone, A Hazama  PHYSIOLOGICAL MEASUREMENT  25-  (2)  505  -522  2004/04  [Not refereed][Not invited]
     
    The rheological properties of the arterial wall have intimate connections with the fine structure of the wall. Alteration in fine structure due to cardiovascular disease, such as atherosclerosis, could affect the rheological characteristics of the wall. The present study was designed to investigate changes in the static rheological properties of the aorta in Kurosawa and Kusanagi-Hypercholesterolemic (KHC) rabbits aged 10-12, 22-24 and 34-36 months in relation to histological alteration of the wall due to progression of atherosclerosis with age. Circumferential wall strips were excised from the ascending, proximal descending thoracic and proximal abdominal aortas and their stress/strain relationship was recorded. Tensile force of the wall showed a slight but insignificant decrease in the KHC rabbit group aged 10-12 months compared to that in the age-matched control group in the proximal thoracic aorta and increased significantly with ageing in the KHC rabbits in these aortic regions mainly at medium and high strain ranges. Wall stress was significantly smaller in the 10-12 months old KHC rabbit group than in the age-matched control group in the proximal thoracic and proximal abdominal aortas and increased significantly with ageing in the KHC rabbit groups chiefly at medium and high strain ranges. Incremental elastic modulus determined at 50% stretching of the initial length of the wall strip was also significantly lower in the KHC rabbit group aged 10-12 months in comparison to that in the age-matched control group and increased significantly with ageing in the KHC rabbit group. The intima thickened severely with abundant foam cells in the KHC rabbits aged 10-12 months. With increasing age, collagen and elastin fibres showed signs of gradual proliferation among the foam cells. The aortic wall in KHC rabbits was viscoelastic in the relatively early stage of atherosclerosis due to abundant foam cells, and thereafter increased in stiffness gradually with fibrous proliferation and calcification. We can conclude that the static rheological properties of the atherosclerotic aortic wall changed in association with alteration in the microstructure of the wall with progression of atherosclerosis.
  • S Katsuda, H Miyashita, M Hasegawa, N Machida, M Kusanagi, M Yamasaki, H Waki, A Hazama  AMERICAN JOURNAL OF HYPERTENSION  17-  (2)  181  -187  2004/02  [Not refereed][Not invited]
     
    Background: Pulse wave velocity, conventionally determined between the carotid and femoral arteries, is a useful measure to estimate stiffness of the aorta. We investigated local pulse wave velocity (LPWV) in different segments in the aorta with relatively early-stage atherosclerosis in relation to the extent and severity of atherosclerotic lesions. Methods: Pressure waves were recorded in eight aortic positions using two catheters with one or two micromanometers to determine LPWV in the ascending aorta, distal end of the aortic arch, proximal, middle, and distal thoracic aortas, and proximal, middle, and distal abdominal aortas in Kurosawa and Kusanagi-hypercholesterolemic (KHC) and normal rabbits aged 10 to 12 months. Results: The LPWV in the KHC rabbit was greatest in the aortic arch, decreased almost to the normal level in the middle and distal thoracic aorta, increased in the proximal abdominal aorta, and showed almost identical change to that in the normal rabbit in the middle and distal abdominal aortic regions. There was significant difference in LPWV in the aortic arch, proximal thoracic, and proximal abdominal aortas between the two rabbit groups. The sclerotic lesion was prominent in the aortic arch, proximal thoracic aorta, and proximal abdominal aortas. The wall was severely thickened with abundant foam cells. The significant increase in LPWV would be mainly related to the increased wall thickness in these aortic regions. Conclusions: We can conclude that LPWV reflects well the distribution and severity of atherosclerotic lesion and the increased wall thickness in the local aortic region in which pulse waves were traveled. (C) 2004 American Journal of Hypertension, Ltd.
  • 血管年齢と臓器障害:加齢と動脈圧波形-Augmentation Indexについて-
    宮下洋, 杉町勝, 砂川賢二  Modern Physician  24-  (11)  1699  -1704  2004  [Not refereed][Not invited]
  • 高血圧による標的臓器障害評価ハンドブック:Augmentation Indexによる動脈硬化度の評価
    宮下洋  循環器科  56-  (3)  257  -266  2004  [Not refereed][Not invited]
  • 高血圧による動脈硬化度を評価する:血圧波形解析(Augmentation Index)
    宮下洋, 杉町勝, 砂川賢二  血圧  10-  (6)  584  -591  2004  [Not refereed][Not invited]
  • 宮下洋, 勝田新一郎, 清水強, 挾間章博, 島田和幸, 矢田俊彦  循環制御  24-  (4)  360  -370  2003  [Not refereed][Not invited]
  • M Shimpo, U Ikeda, Y Maeda, M Takahashi, H Miyashita, H Mizukami, M Urabe, A Kume, T Takizawa, M Shibuya, K Ozawa, K Shimada  CARDIOVASCULAR RESEARCH  53-  (4)  993  -1001  2002/03  [Not refereed][Not invited]
     
    Objectives: Clinical trials on therapeutic angiogenesis using vascular endothelial growth factor (VEGF) are ongoing, however the benefits of these therapies are still controversial. To establish a more efficient gene transfer method for ischemic diseases, we investigated the therapeutic potential of adeno-associated virus (AAV)-mediated VEGF gene transfer. Methods: We produced VEGF(165)-express in AAV vectors (AAV-VEGF). HEK-293 cells were transduced with AAV-VEGF in vitro and VEGF expression and secretion were examined. We used a rat ischemic hindlimb model and AAV-VEGF was administered intramuscularly into the ischemic limb. Gene expression was evaluated by RT-PCR and ELISA. Six weeks after gene transfer, we measured the blood flow of limb vessels and the skin temperature of limbs. Histochemical examination was performed to illustrate capillary growth. Results: Western blotting and ELISA revealed VEGF protein expression and secretion from AAV-VEGF-transduced HEK-293 cells. VEGF mRNA and protein expression was consistently observed in the injected muscle at least 10 weeks after the injection, while no VEGF mRNA could be detected at remote organs. The mean blood flow in AAV-VEGF-transduced ischemic limbs was significantly higher than in AAV-LacZ-transduced limbs. Capillary density was significantly higher in AAV-VEGF-injected tissues than in AAV-LacZ-injected tissues. Conclusions: This study demonstrates that (1) AAV-mediated VEGF gene transfer into rat skeletal muscles is efficient and stable without ectopic expression, and (2) AAV-mediated VEGF gene transfer stimulates angiogenesis and thereby improves blood flow in a rat hindlimb ischemia model. These findings suggest that AAV-mediated VEGF gene transfer may be useful for treatment of ischemic diseases. (C) 2002 Elsevier Science BY All rights reserved.
  • アデノ随伴ウイルス(AAV)ベクターを用いたVEGF遺伝子導入―虚血性心疾患・末梢動脈疾患に対する遺伝子治療への応用―(共著)
    心筋の構造と代謝  3: 279-285-  2001  [Not refereed][Not invited]
  • Jpn Cir J  65-  (Supplement 1-A)  349  2001  [Not refereed][Not invited]
  • R Yoshimura, T Sato, T Kawada, T Shishido, M Inagaki, H Miyano, T Nakahara, H Miyashita, H Takaki, T Tatewaki, Y Yanagiya, M Sugimachi, K Sunagawa  JOURNAL OF CARDIAC FAILURE  6-  (1)  66  -72  2000/03  [Not refereed][Not invited]
     
    Background: The renin-angiotensin system (RAS) plays a key role in the pathophysiology of chronic heart failure (CHF). In rats, we reported that CHF enhances dipsogenic responses to centrally administered angiotensin I, and central inhibition of the angiotensin-converting enzyme (ACE) prevents cardiac hypertrophy in CHF. This suggests that the brain RAS is activated in CHF. To clarify the mechanism of the central RAS activation in CHF, we examined brain ACE and the angiotensin receptor (AT) among rats with CHF. Methods and Results: We created high-output heart failure in 22 male Sprague-Dawley rats by aortocaval shunt. Four weeks after surgery, we examined ACE mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) and AT by binding autoradiography. ACE mRNA levels were not significantly increased in the subfornical organ (SFO), the hypothalamus, or in the lower brainstem of CHF rats (n = 5) compared with sham-operated rats (SHM) (n = 6). Binding densities for type 1 AT (AT(1)) in the SFO (P <.05), paraventricular hypothalamic nuclei (P <.05)1 and solitary tract nuclei (P <.05) were higher in rats with CHF (n = 5) than in SHM rats (n = 6). Thus, in rats with CHF, AT(1) expression is increased in brain regions that are closely related to water intake, vasopressin release, and hemodynamic regulation. Conclusions: The fact that AT(1) expression was regulated in important brain regions related to body fluid control in CHF rats indicates that the brain is a major site of RAS action in CHF rats and, therefore, a possible target site of ACE-inhibitors in the treatment of CHF.
  • H Miyashita, M Sugimachi, T Sato, T Kawada, T Shishido, T Nakahara, R Yoshimura, H Takaki, H Miyano, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY  278-  (3)  H998  -H1007  2000/03  [Not refereed][Not invited]
     
    To clarify the pathophysiological role of dynamic arterial properties in cardiovascular diseases, we attempted to develop a new control system that imposes desired aortic impedance on in situ rat left ventricle. In 38 anesthetized open-chest rats, ascending aortic pressure and flow waveforms were continuously sampled (1,000 Hz). Desired flow waveforms were calculated from measured aortic pressure waveforms and target impedance. To minimize the difference between measured and desired aortic flow waveforms, the computer generated commands to the servo-pump, connected to a side branch of the aorta. By iterating the process, we could successfully control aortic impedance in such a way as to manipulate compliance and characteristic impedance between 60 and 160% of their respective native values. The error between desired and measured aortic flow waveforms was 70 +/- 34 mu l/s (root mean square; 4.4 +/- 1.4% of peak flow), indicating reasonable accuracy in controlling aortic impedance. This system enables us to examine the importance of dynamic arterial properties independently of other hemodynamic and neurohumoral factors in physiological and clinical settings.
  • ランダム圧発生装置によるfluid-filled血圧計測系の周波数特性評価と波形歪みの補正.(共著)
    日本ME学会誌  38(Suppl)-  146  2000  [Not refereed][Not invited]
  • 末梢動脈波形による大動脈圧推定法の検討.
    日本ME学会誌  38-  (Suppl)  148  2000  [Not refereed][Not invited]
  • 非侵襲的大動脈圧モニターの開発に関する検討
    21-  (1)  176  -181  2000  [Not refereed][Not invited]
  • A new random pressure generator for evaluation and correction of the fluid-filled pressure measurement system using transfer function.(共著)
    JJME  38-  ((Suppl))  146  2000  [Not refereed][Not invited]
  • A method to estimate central aortic pressure using peripheral arterial waveforms.
    JJME  38-  (Suppl)  148  2000  [Not refereed][Not invited]
  • Development of a noninvasive aortic pressure monitor.
    Ther Res  21-  (1)  176  -181  2000  [Not refereed][Not invited]
  • T Kawada, G Sunagawa, H Takaki, T Shishido, H Miyano, H Miyashita, T Sato, M Sugimachi, K Sunagawa  JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION  63-  (12)  945  -950  1999/12  [Not refereed][Not invited]
     
    Although treadmill exercise involves a more familiar range of motions and is thus more physiological in terms of daily activity than cycle ergometer exercise, difficulties in controlling the exercise intensity have limited its utility. As heart rate (HR) has been used as a measure of exercise intensity, controlling HR should allow for the proper control of exercise intensity during treadmill exercise. Thus, a servo-controller framework was applied to regulate HR during treadmill exercise. After estimating an averaged transfer function from speed command to HR, feedback parameters were optimized via a computer simulation in order to achieve a quick and stable HR response. The performance of the servo-controller of HR was then examined in 10 healthy subjects. Standard deviations of the steady-state difference between the target and measured HRs were 2.7+/-0.9 and 5.0+/-1.4 beats/min in the stepwise and ramp target HR protocols, respectively. The rise time to reach 90% of the target HR was 93+/-20 s in the stepwise protocol. It was concluded that a treadmill implemented with a negative feedback mechanism made it possible to precisely regulate HR and thus exercise intensity.
  • T Nakahara, T Kawada, M Sugimachi, H Miyano, T Sato, T Shishido, R Yoshimura, H Miyashita, M Inagaki, J Alexander, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY  277-  (1)  R140  -R146  1999/07  [Not refereed][Not invited]
     
    Recently, studies in our laboratory involving the use of a Gaussian white noise technique demonstrated that the transfer function from sympathetic stimulation frequency to heart rate (HR) response showed dynamic characteristics of a second-order low-pass filter. However, determinants for the characteristics remain to be established. We examined the effect of an increase in mean sympathetic stimulation frequency and that of a blockade of the neuronal uptake mechanism on the transfer function in anesthetized rabbits. We found that increasing mean sympathetic stimulation frequency from 1 to 4 Hz significantly (P < 0.01) decreased the dynamic gain of the transfer function without affecting other parameters, such as the natural frequency, lag time, or damping coefficient; In contrast, the administration of desipramine (0.3 mg/kg iv), a neuronal uptake blocking agent, significantly (P < 0.01) decreased both the dynamic gain and the natural frequency and prolonged the lag time. These results suggest that the removal rate of norepinephrine at the neuroeffector junction, rather than the amount of available norepinephrine, plays an important role in determining the low-pass filter characteristics of the HR response to sympathetic stimulation.
  • T Kawada, M Sugimachi, T Shishido, H Miyano, T Sato, R Yoshimura, H Miyashita, T Nakahara, J Alexander, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY  276-  (3)  R782  -R789  1999/03  [Not refereed][Not invited]
     
    We earlier reported that stimulation of either one of the sympathetic and vagal nerves augments the dynamic heart rate (HR) response to concurrent stimulation of its counterpart. We explained this phenomenon by assuming a sigmoidal static relationship between nerve activity and HR. To confirm this assumption, we stimulated the sympathetic and/or vagal nerve in anesthetized rabbits using large-amplitude Gaussian white noise and determined the static and dynamic characteristics of HR regulation by a neural network analysis. The static characteristics approximated a sigmoidal relationship between the Linearly predicted and the measured HRs (response range: 212.4 +/- 46.3 beats/min, minimum HR: 96.0 +/- 28.4 beats/min, midpoint of operation: 196.7 +/- 31.3 beats/min, maximum slope: 1.65 +/- 0.51). The maximum step responses determined from the dynamic characteristics were 7.9 +/- 2.9 and -14.0 +/- 4.9 beats.min(-1).Hz(-1) for the sympathetic and the vagal system, respectively. Because of these characteristics, changes in sympathetic or vagal tone alone can alter the dynamic HR response to stimulation of the other nerve.
  • T Kawada, M Sugimachi, T Shishido, H Miyano, T Sato, R Yoshimura, H Miyashita, T Nakahara, J Alexander, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY  276-  (3)  R782  -R789  1999/03  [Not refereed][Not invited]
     
    We earlier reported that stimulation of either one of the sympathetic and vagal nerves augments the dynamic heart rate (HR) response to concurrent stimulation of its counterpart. We explained this phenomenon by assuming a sigmoidal static relationship between nerve activity and HR. To confirm this assumption, we stimulated the sympathetic and/or vagal nerve in anesthetized rabbits using large-amplitude Gaussian white noise and determined the static and dynamic characteristics of HR regulation by a neural network analysis. The static characteristics approximated a sigmoidal relationship between the Linearly predicted and the measured HRs (response range: 212.4 +/- 46.3 beats/min, minimum HR: 96.0 +/- 28.4 beats/min, midpoint of operation: 196.7 +/- 31.3 beats/min, maximum slope: 1.65 +/- 0.51). The maximum step responses determined from the dynamic characteristics were 7.9 +/- 2.9 and -14.0 +/- 4.9 beats.min(-1).Hz(-1) for the sympathetic and the vagal system, respectively. Because of these characteristics, changes in sympathetic or vagal tone alone can alter the dynamic HR response to stimulation of the other nerve.
  • 大動脈スティッフネスと駆出早期の動的な左室-動脈干渉の関係.
    65-  (suppl (]G0001[))  432  1999  [Not refereed][Not invited]
  • Relationship between aortic stiffening and dynamic ventriculoarterial interaction at early ejection.
    Jpn Cir J  65-  (suppl)  432  1999  [Not refereed][Not invited]
  • H Miyano, T Shishido, T Kawada, H Miyashita, T Sato, M Sugimachi, K Sunagawa  CRITICAL CARE MEDICINE  27-  (1)  168  -176  1999/01  [Not refereed][Not invited]
     
    Objectives: We hypothesized that tumor necrosis factor-alpha (TNF-alpha) acutely alters left ventricular mechanoenergetics in blood-perfused hearts. To test this hypothesis, we examined the relation between left ventricular mechanics and energetics, both before and after infusion of TNF-alpha. Design: Prospective, experimental study. Setting: Research laboratory. Subjects: Nine isolated, blood-perfosed canine hearts. Interventions: Recombinant human TNF-alpha (90 mu g/min) was infused into the coronary circulation of the isolated hearts for 20 mins. Measurements and Main Results: In the isolated, cross circulated, blood perfused canine left ventricles, left ventricular contractility was assessed through measurement of end-systolic elastance (Ees). Energetics were examined in terms of the end systolic pressure volume area-myocardial oxygen consumption (MVo(2)) relation. TNF-alpha concentration in coronary venous blood was >1000 ng/mL throughout the experiments. Nevertheless, infusion of TNF-alpha barely affected contractility acutely, i.e., there was a minimal decrease during the infusion (8.1 +/- 2.8% at 10 mins, p<.01) and a minimal increase after the infusion (11.2 +/- 2.5% at 10 mins, p<.01). Neither did the TNF-alpha infusion affect the slope of the end-systolic pressure-volume area MVo(2) relation. This finding indicated that the chemomechanical conversion efficiency remained unchanged. However, TNF-alpha infusion significantly increased the oxygen cost of contractility by 40% (1.25 +/- 0.13 vs. 1.75 +/- 0.24 mt oxygen.mL/mm Hg/beat, p<.05), indicating that MVo(2) for the excitation-contraction coupling increased. Conclusions: TNF-alpha minimally alters left ventricular mechanics, but significantly changes energetics. The latter effect may result from changes in intracellular calcium handling.
  • H Miyano, Y Nakayama, T Shishido, M Inagaki, T Kawada, T Sato, H Miyashita, M Sugimachi, J Alexander, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY  275-  (2)  H400  -H408  1998/08  [Not refereed][Not invited]
     
    We investigated the dynamic sympathetic regulation of left ventricular end-systolic elastance (E(es)) using an isolated canine ventricular preparation with functioning sympathetic nerves intact. We estimated the transfer function from both stellate ganglion stimulation to E(es) and ganglion stimulation to heart rate (HR) for both left and right ganglia by means of the white noise approach and transformed those transfer functions into corresponding step responses. The HR response was much larger with right sympathetic stimulation than with left sympathetic stimulation (4.3 +/- 1.4 vs. 0.7 +/- 0.6 beats min(-1).Hz(-1), P < 0.01). In contrast, the E(es) responses without pacing were not significantly different between left and right sympathetic stimulation (0.72 +/- 0.34 vs. 0.76 +/- 0.42 mmHg.ml(-1).Hz(-1)). Fixed-rate pacing significantly decreased the E(es) response to right sympathetic stimulation (0.53 +/- 0.43 mmHg.ml(-1).Hz(-1), P < 0.01), but not to left sympathetic stimulation (0.67 +/- 0.32 mmHg.ml(-1).Hz(-1), not significant). Although the mechanism by which the sympathetic nervous system regulates cardiac contractility is different depending on whether the left or right sympathetic nerves are activated, this difference does not affect the apparent response of E(es) to dynamic sympathetic stimulation.
  • T Nakahara, T Kawada, M Sugimachi, H Miyano, T Sato, T Shishido, R Yoshimura, H Miyashita, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY  275-  (2)  R541  -R547  1998/08  [Not refereed][Not invited]
     
    Recent investigations in our laboratory using a Gaussian white noise technique showed that the transfer function representing the dynamic properties of transduction from vagus nerve activity to heart rate had characteristics of a first-order low-pass filter. However, the physiological determinants of those characteristics remain to be elucidated. In this study, we stimulated the vagus nerve according to a Gaussian white noise pattern to estimate the transfer function from vagal stimulation to the heart rate response in anesthetized rabbits and examined how changes in acetylcholine kinetics affected the transfer function. We found that although increases in the mean frequency of vagal stimulation from 5 to 10 Hz did not change the characteristics of the transfer function, administration of neostigmine (30 mu g . kg(-1) . h(-1) iv), a cholinesterase inhibitor, increased the dynamic gain from 8.19 +/- 3.66 to 11.7 +/- 4.88 beats . min(-1) . Hz(-1) (P < 0.05), decreased the corner frequency from 0.12 +/- 0.05 to 0.04 +/- 0.01 Hz (P < 0.01), and increased the lag time from 0.17 +/- 0.12 to 0.27 +/- 0.08 s (P < 0.05). These results suggest that the rate of acetylcholine degradation at the neuroeffector junction, rather than the amount of available acetylcholine, plays a key role in determining the dynamic properties of transduction from vagus nerve activity to heart rate.
  • T Nakahara, T Kawada, M Sugimachi, H Miyano, T Sato, T Shishido, R Yoshimura, H Miyashita, M Inagaki, J Alexander, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY  275-  (2)  H562  -H567  1998/08  [Not refereed][Not invited]
     
    Recent investigations in our laboratory using a Gausslan white noise perturbation technique have shown that simultaneous sympathetic stimulation augmented the gain of the transfer function from vagal stimulation frequency to heart rate response. Ro-ct ever, the mechanism of that augmentation remains to be elucidated. In this study, we examined in anesthetized rabbits how three pharmacological interventions known to cause intracellular accumulation of cAMP affected the transfer function. Isoproterenol (0.3 mu g.kg(-l) . min(-1) iv) increased the dynamic gain of transfer function from 7.12 +/- 0.67 to 12.4 +/-1.21 beats.min(-1).Hz(-1). (P < 0.05) without changing the corner frequency or the lag time. Similar augmentations were observed when forskolin (5 mu g. kg(-1).min(-1) iv) or theophylline (20 mg/kg iv) was administered under conditions of P-adrenergic blockade. These results suggest that the accumulation of cAMP at postjunctional effector sites contributes, at least in part, to the sympathetic augmentation of the dynamic vagal control of heart rate.
  • T Sato, T Shishido, T Kawada, H Miyano, H Miyashita, M Inagaki, M Sugimachi, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY  274-  (5)  H1429  -H1434  1998/05  [Not refereed][Not invited]
     
    We developed a miniaturized conductance catheter for in situ rat left ventricular (LV) volumetry. After the validation study of the conductance volumetry in 11 rats, we characterized the end-systolic pressure-volume relationship (SPIVERY) in 24 sinoaortic-denervated, vagotomized and urethan-anesthetized rats. Stroke volume (SV) measured with the conductance catheter correlated closely with that measured by electromagnetic flowmetry (r > 0.95). No significant difference was found between the in situ LV end-diastolic volumes measured by conductance volumetry and postmortem morphometry; a linear regression analysis indicated that the correlation coefficient was 0.934, that the slope was not significantly different from 1, and that the intercept was not significantly different from 0. During cardiac sympathotonic conditions, the ESPVR was curvilinear. The estimated slope of ESPVR (end-systolic elastance, E-es) by quadratic curve fitting at end-systolic pressure of 100 mmHg was 2,647 +/- 846 mmHg/ml. Bilateral cervical and stellate ganglionectomy depressed contractility and made the ESPVR linear; a quadratic equation did not improve the fit. E-es was 946 +/- 55 mmHg/ml with the volume-axis (V-0) intercept of 0.076 +/- 0.007 ml. Administration of propranolol (1 mg/kg) further reduced E-es (573 +/- 61 mmHg/ml, P < 0.001) and increased V-0 slightly (0.091 +/- 0.011 ml). We conclude that the conductance catheter method is useful for the assessment of the ESPVR of the in situ rat left ventricle and that the ESPVR displays contractility-dependent curvilinearity.
  • 心拍出量の求め方
    臨床医  24-  (5)  716  -718  1998  [Not refereed][Not invited]
  • 動脈圧波形の左室後負荷としての意義-in situラット心での実験的検討-
    宮下洋, 杉町勝, 佐藤隆幸, 川田徹, 宍戸稔聡, 吉村亮一, 高木洋, 宮野博史, 砂川賢二  Ther Res  19-  (2)  341  -345  1998  [Not refereed][Not invited]
  • Effects of altered aortic input impedance on wave intensity in rats.
    The Third World Congress of Biomechanics Abstracts  68  1998  [Not refereed][Not invited]
  • Effects of altered aortic input impedance on wave internsity in rats
    Third World Congress of Biomechanics Abstracts  68  1998  [Not refereed][Not invited]
  • T Sato, T Kawada, T Shishido, H Miyano, M Inagaki, H Miyashita, M Sugimachi, MM Knuepfer, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY  274-  (1)  H358  -H365  1998/01  [Not refereed][Not invited]
     
    We developed a new method for isolating in situ baroreceptor regions of the rabbit aortic depressor nerve (ADN) and estimated the transfer function from pressure to afferent nerve activity in the frequency range of 0.01-5 Hz by a white noise technique. Complete isolation of the baroreceptor area of the right ADN was made in situ by ligation of the innominate artery and the right subclavian and common carotid arteries. We altered the pressure in the isolated baroreceptor area according to a binary quasi-white noise between 80 and 100 mmHg in 12 urethan-anesthetized rabbits. The gain increased two to three times as the frequency of pressure perturbation increased from 0.01 to 2 Hz and then decreased at higher frequencies. The phase slightly led below 0.2 Hz. The squared coherence value was >0.8 in the frequency range of 0.01-4 Hz. The step responses estimated from the transfer function were indistinguishable from those actually observed. We conclude that the baroreceptor transduction of the ADN is governed by linear dynamics under the physiological operating pressure range.
  • Implication of aortic pressure waveform as left ventricular afterload -experimental study in the in-situ rat heart-
    Therapeutic Research  19-  (2)  341  -345  1998  [Not refereed][Not invited]
  • Y Nakayama, H Miyano, T Shishido, M Inagaki, H Miyashita, K Sunagawa  CIRCULATION  96-  (8)  3540  -3540  1997/10  [Not refereed][Not invited]
  • T Sato, T Shishido, H Miyashita, R Yoshimura, K Sunagawa  CIRCULATION  96-  (8)  2904  -2904  1997/10  [Not refereed][Not invited]
  • H Miyashita, T Sato, M Sugimachi, K Sunagawa  CIRCULATION  96-  (8)  2907  -2907  1997/10  [Not refereed][Not invited]
  • T Kawada, M Sugimachi, T Sato, H Miyano, T Shishido, H Miyashita, R Yoshimura, H Takaki, J Alexander, K Sunagawa  AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY  273-  (2)  H1024  -H1031  1997/08  [Not refereed][Not invited]
     
    In the circulatory system, a change in blood pressure operates through the baroreflex to alter sympathetic efferent nerve activity, which in turn affects blood pressure. Existence of this closed feedback loop makes it difficult to identify the baroreflex open-loop transfer characteristics by means of conventional frequency domain approaches. Although several investigators have demonstrated the advantages of the time domain approach using parametric models such as the autoregressive moving average model, specification of the model structure critically affects their results. Thus we investigated the applicability of a nonparametric closed-loop identification technique to the carotid sinus baroreflex system by using an exogenous perturbation according to a binary white-noise sequence. To validate the identification method, we compared the transfer functions estimated by the closed-loop identification with those estimated by open-loop identification, The transfer functions determined by the two identification methods did not differ statistically in their fitted parameters. We conclude that exogenous perturbation to the baroreflex system enables us to estimate the open-loop baroreflex transfer characteristics under closed-loop conditions.
  • 加齢の指標としての動脈硬化
    循環器科  42-  (6)  521  -528  1997  [Not refereed][Not invited]
  • In Situ Rat Heartに任意の大動脈入力インピーダンスを負荷する制御装置の開発
    宮下洋, 杉町勝, 佐藤隆幸, 川田徹, 宍戸稔聡, 吉村亮一, 高木洋, 宮野博史, 砂川賢二  Ther Res  18-  (3)  775  -778  1997  [Not refereed][Not invited]
  • Development of the servo control system that imposes arbitrary aortic input impedance on in situ rat heart
    Therapeutic Research  18-  775  -778  1997  [Not refereed][Not invited]
  • Y. Hayashi, U. Ikeda, T. Kojo, M. Nishinaga, H. Miyashita, T. Kuroda, K. Inoue, M. Nishizawa, K. Shimada  American Heart Journal  134-  (2 I)  292  -297  1997  [Not refereed][Not invited]
     
    This study investigated the correlation between cardiac abnormalities and cytosine-thymine-guanine (CTG) trinucleotide repeat expansion in patients with myotonic dystrophy (MD). We studied 18 patients with the adult form of classical MD and 18 age-matched control subjects. In patients with MD, left ventricular systolic function at rest was not different from that in normal subjects. On the other hand, of Doppler parameters of diastolic function mitral inflow peak early velocity and atrial velocity were significantly lower, and deceleration time and isovolumic relaxation time were significantly longer in patients with MD compared with normal controls. No significant correlation was observed between these diastolic parameters and CTG repeat expansion in the patients, although the parameters showed a positive correlation with age and neurologic symptom duration. Electrocardiographic conduction abnormalities were detected in 42% of patients. These patients showed a significantly longer symptom duration, although the size of CTG repeats was not different between the patients with and without conduction abnormalities. This study demonstrated that, in patients with MD, significant alterations in ventricular diastolic function (myocardial myotonia) occur in addition to conduction abnormalities. The size of CTG expansion is not a predictor of these cardiac involvements.
  • T Shishido, M Sugimachi, H Miyano, H Miyashita, K Sunagawa  CIRCULATION  94-  (8)  3568  -3568  1996/10  [Not refereed][Not invited]
  • T Sato, T Shishido, H Miyano, R Yoshimura, H Miyashita, K Sunagawa  CIRCULATION  94-  (8)  4232  -4232  1996/10  [Not refereed][Not invited]
  • T Sato, M Sugimachi, T Shishido, T Kawada, H Miyano, R Yoshimura, H Miyashita  CIRCULATION  94-  (8)  1804  -1804  1996/10  [Not refereed][Not invited]
  • In Situ Rat Heartに任意の大動脈入力インピーダンスを負荷する制御装置の開発
    第11回生体・生理工学シンポジウム論文集  381  1996  [Not refereed][Not invited]
  • H MIYASHITA, U IKEDA, M IROKAWA, T YAGINUMA, K SHIMADA  JOURNAL OF THE AMERICAN GERIATRICS SOCIETY  43-  (9)  1069  -1070  1995/09  [Not refereed][Not invited]
  • ACE阻害薬とCa拮抗薬の比較
    1995  [Not refereed][Not invited]
  • Cardiac Practice
    1995  [Not refereed][Not invited]
  • Y HAYASHI, U IKEDA, T OGAWA, H MIYASHITA, H SEKIGUCHI, K ARAHATA, K SHIMADA  AMERICAN HEART JOURNAL  128-  (6)  1264  -1266  1994/12  [Not refereed][Not invited]
  • K SHIMADA, H MIYASHITA, A KAWAMOTO, K MATSUBAYASHI, M NISHINAGA, S KIMURA, T OZAWA  JOURNAL OF HYPERTENSION  12-  S7  -S12  1994/09  [Not refereed][Not invited]
     
    Pathophysiology of hypertension: Blood pressure increases with advancing age in most developed countries. the pathophysiology of elderly hypertension is characterized by changes in the structure and function of the cardiovascular system. Changes in arterial structure lead to a decrease in aortic compliance, which augments the aortic pressure component generated by the wave reflection mechanism. The age-related increase in the reflected-wave component of arterial pressure may contribute, at least in part, to the age-related rise in systolic blood pressure. Disproportionately elevated systolic blood pressure in the elderly may account for the progressive increase in left ventricular mass with advancing age. In addition to the changes in vascular and cardiac structures, the haemodynamic function of elderly hypertensives is characterized by increased peripheral resistance as well as reduced cardiac output, renal blood flow and intravascular volume. In contrast to younger hypertensives, the sympathetic and renin-angiotensin systems may not be major factors in the genesis of high peripheral resistance in this patient group. End-organ damage: The most important end-organ damage in elderly hypertensives is left ventricular hypertrophy with or without coronary heart disease, cerebrovascular disease or renal impairment. Furthermore, this end-organ damage is frequently asymptomatic (silent). the prevalence of silent cerebrovascular disease in particular is surprisingly high in this elderly population. Asymptomatic cerebrovascular disease has been shown to be associated with various cardiovascular risk factors, and depressed neurobehavioural function. Diurnal blood pressure variations appear to be related to end-organ damage. The presence of occult end-organ damage and co-existing diseases common in elderly hypertensives has important clinical implications in the management of this disorder.
  • Y HOJO, T KURODA, M YAMASAWA, H MIYASHITA, Y SEINO, T MITSUHASHI, H SEKIGUCHI, A SHIINA, K SHIMADA  INTERNAL MEDICINE  33-  (6)  357  -359  1994/06  [Not refereed][Not invited]
     
    A 52-year-old female with polysplenia accompanied by major cardiovascular anomalies (a ventricular septal defect, atrial septal defect, persistent left superior vena cava, absent inferior vena cava with a hemiazygos connection and visceral heterotaxia) is reported. She underwent successful surgical treatment and showed prolonged survival.
  • 筋ジストロフィーの心筋病変
    循環器NOW(南江堂)  6-  149  1994  [Not refereed][Not invited]
  • 高齢者高血圧の血行動態
    日本老年医学会雑誌  31-  (12)  916  -920  1994  [Not refereed][Not invited]
  • A Doppler index for evaluating the effect of vasodilator therapy on aortic wave reflections
    Pathophysiology  1-  324  1994  [Not refereed][Not invited]
  • K. Shimada, H. Miyashita, M. Nishinaga, T. Kuroda  Japanese Journal of Geriatrics  31-  (12)  916  -920  1994  [Not refereed][Not invited]
     
    The pathophysiology, of elderly hypertension is characterized by changes in the structure and function of the cardiovascular system. The hemodynamic status of elderly hypertensives is characterized by increased peripheral resistance as well as reduced cardiac output, renal blood flow and intravascular volume. In contrast to young hypertensives, the sympathetic and renin-angiotensin system may not be major factors in the genesis of high peripheral resistance in this patient group. Blood pressure increases with age even in the group of non-hypertensive subjects in most developed countries. Changes in arterial structure lead to a decrease in aortic compliance, which augments the aortic pressure component generated by the wave reflection mechanism. The age-related increase in the reflected-wave component of arterial pressure may contribute, significantly to the age-related rise in systolic blood pressure. In the heart, the reduced compliance is reflected by an age-related reduction in diastolic function. Thus, the changes in cardiovascular structures may play a major role in the change in the hemodynamics of elderly hypertension.
  • H MIYASHITA, U IKEDA, Y TSURUYA, H SEKIGUCHI, K SHIMADA, T YAGINUMA  HEART AND VESSELS  9-  (1)  30  -39  1994  [Not refereed][Not invited]
     
    To develop a noninvasive method for evaluating the influence of aortic wave reflection on left ventricular ejection, the carotid pulse wave and the pulsed Doppler wave in the left ventricular outflow tract were evaluated in 35 patients. Agreement between the pulsed Doppler waveform and the aortic flow velocity contour (obtained invasively) was verified by Fourier analysis. The carotid augmentation index was used to determine the magnitude of the aortic pressure wave reflection. A Doppler index named ''DRI/3'' was defined as the ratio of deceleration at the first one-third in the deceleration phase to the peak flow velocity of the pulsed Doppler. This index was validated by close correlation with the carotid augmentation index (n = 48, r = 0.70, P < 0.01). Both nitrates and nifedipine induced a significant decrease in DR1/3 (indicating an increase in left ventricular ejection flow) in relation to a reduction of the reflected pressure wave. The new noninvasive index, DR1/3, is useful in evaluating the influence of aortic wave reflection as part of the left ventricular afterload and in assessing the benefit of treatment aimed at reducing wave reflection.
  • H MIYASHITA, Y TSURUYA, H SEKIGUCHI, T YAGINUMA  CIRCULATION  88-  (4)  69  -69  1993/10  [Not refereed][Not invited]
  • H MIYASHITA, M IROKAWA, T YAGINUMA  CIRCULATION  88-  (4)  499  -499  1993/10  [Not refereed][Not invited]
  • H MIYASHITA, U IKEDA, K SHIMADA, T NATSUME, K ARAHATA  INTERNAL MEDICINE  32-  (5)  408  -411  1993/05  [Not refereed][Not invited]
     
    We encountered a case of dystrophin-verified Becker muscular dystrophy which exhibited left heart failure as an initial symptom but no subjective muscle weakness. Severe cardiac involvement has been thought to rarely occur in the early stage of this disease, however accurate diagnosis was limited until the dystrophin diagnosis became available. This case suggests that some cases of dilated cardiomyopathy might be Becker muscular dystrophy, and that dystrophin tests should be added to the conventional investigation of patients with dilated cardiomyopathy.
  • 心不全における末梢循環
    内科  71-  822  -826  1993  [Not refereed][Not invited]
  • A OGUCHI, U IKEDA, H MIYASHITA, M SHIOMI, K SHIMADA  CIRCULATION  86-  (4)  759  -759  1992/10  [Not refereed][Not invited]
  • A OGUCHI, U IKEDA, H MIYASHITA, T OHARA, Y TSURUYA, T NATSUME, T YAGINUMA, K SHIMADA  ATHEROSCLEROSIS  90-  (2-3)  101  -108  1991/10  [Not refereed][Not invited]
     
    The Watanabe Heritable Hyperlipidemic (WHHL) rabbit is a widely studied animal model for the human genetic disorder familial hypercholesterolemia, and spontaneously develops atherosclerotic disease. We studied the growth characteristics of cultured vascular smooth muscle cells (VSMC) from WHHL rabbits compared with VSMC from Japanese white rabbits. We measured cell proliferation, DNA synthesis, and c-myc proto-oncogene expression, in response to growth stimuli such as fetal bovine serum (FBS) and platelet-derived growth factor (PDGF). VSMC from Japanese white rabbits exhibited a 4-fold increase in cell numbers during a 5-day incubation period compared with those from WHHL rabbits. FBS and PDGF stimulated DNA synthesis, as measured by thymidine incorporation into VSMC, in both Japanese white rabbits and WHHL rabbits, however the response was significantly higher in the former strain. The intracellular pH value of VSMC determined using the pH-sensitive fluorescence dye 2',7'-bis-carboxyethyl-carboxyfluorescein was significantly higher in WHHL rabbits than in Japanese white rabbits. Proto-oncogene c-myc was induced by exposure of VSMC to FBS, however there was no significant difference in c-myc mRNA levels between the two strains. These results suggest that VSMC from WHHL rabbits are not genetically growth accelerated, but show decreased growth response to growth stimuli.

Research Grants & Projects

  • A multicenter cross-sectional characterization of antihypertensive agents in terms of central blood pressure estimated from radial artery tonometry (ABC-J)
    Date (from‐to) : 2006 -2012
  • 降圧治療と撓骨動脈トノメトリーにより推定した中心血圧に関する国内多施設横断研究(ABC-J)
    共同研究
    Date (from‐to) : 2006 -2011
  • 末梢血圧脈波形成機序に関する実証的研究
    Date (from‐to) : 2006 -2010
  • An animal experiment producing a proof of mechanism for peripheral artery pressure waveform formation
    Date (from‐to) : 2006 -2010
  • 大動脈反射波、Augmentation Indexに関する基礎的および臨床的検討
    Date (from‐to) : 2003 -2010
  • Basic and clinical investigation of aortic wave reflections and augmentation index
    Date (from‐to) : 2003 -2010
  • 血行動態波形情報の高度解析による糖尿病性大血管症および粥状動脈硬化の早期検出と評価
    Date (from‐to) : 2002 -2010
  • Fluid-filled血圧計測系における周波数依存波形歪みの実用的補正法の開発
    Date (from‐to) : 2000 -2010
  • Assessment of cardiovascular function in animal models of cardiovascular disease or genetically modified animals
    Date (from‐to) : 2000 -2010
  • Development of a practical method to compensate frequency characteristics of the fluid-filled manometer system
    Date (from‐to) : 2000 -2010
  • 非侵襲的大動脈圧モニターシステムの開発と実用化研究
    共同研究
    Date (from‐to) : 1999 -2010
  • Development of a practical system for noninvasive monitoring of aortic pressure
    Date (from‐to) : 1999 -2010
  • 拍動性メカニカルストレスの心血管に対する病態生理学的効果に関する研究
    Date (from‐to) : 1996 -2010
  • Application of detailed analyses of hemodynamic waveforms to early detection and evaluation of diabetic macroangiopathy and atherosclerosis of the aorta
    Date (from‐to) : 2002 -2007
  • Study on pathophysiological effects of pulsatile mechanical stress on the cardiovascular system
    Date (from‐to) : 1996 -2006


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