Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Shintaro Kinugawa Last modified date:2021.11.01

Associate Professor / Research Institute of Angiocardiology / Faculty of Medical Sciences


Papers
1. Arata Fukushima, Shintaro Kinugawa, Shingo Takada, Shouji Matsushima, Mochamad Ali Sobirin, Taisuke Ono, Masashige Takahashi, Tadashi Suga, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Tomoyasu Kadoguchi, Takashi Yokota, Koichi Okita, Hiroyuki Tsutsui, (Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 10.1152/ajpendo.00449.2013, 307, 6, E503-E514, 2014.09, We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P) H oxidase-dependent oxidative stress. (Pro) renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P) RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham + HRP, 0.1 mg.kg(-1).day(-1), n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI + HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P) RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 +/- 2 vs. 44 +/- 3%, P < 0.05), and was greater in MI + HRP (38 +/- 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI + HRP. Superoxide production and NAD(P) H oxidase activities were increased in MI, which was inhibited in MI + HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P) H oxidase-induced superoxide production in the skeletal muscle. The (P) RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF..
2. S Kinugawa, H Huang, ZP Wang, PM Kaminski, MS Wolin, TH Hintze, A defect of neuronal nitric oxide synthase increases xanthine oxidase-derived superoxide anion and attenuates the control of myocardial oxygen consumption by nitric oxide derived from endothelial nitric oxide synthase, CIRCULATION RESEARCH, 10.1161/01.RES.0000155331.09458.A7, 96, 3, 355-362, 2005.02, Endothelial nitric oxide synthase (eNOS) plays an important role in the control of myocardial oxygen consumption (MVO2) by nitric oxide (NO). A NOS isoform is present in cardiac mitochondria and it is derived from neuronal NOS (nNOS). However, the role of nNOS in the control of MVO2 remains unknown. MVO2 in left ventricular tissues from nNOS(-/-) mice was measured in vitro. Stimulation of NO production by bradykinin or carbachol induced a significant reduction in MVO2 in wild-type (WT) mice. In contrast to WT, bradykinin- or carbachol-induced reduction in MVO2 was attenuated in nNOS(-/-). S-methyl-L-thiocitrulline, a potent isoform selective inhibitor of nNOS, had no effect on bradykinin- induced reduction in MVO2 in WT. Bradykinin-induced reduction in MVO2 in eNOS(-/-) mice, in which nNOS still exists, was also attenuated. The attenuated bradykinin- induced reduction in MVO2 in nNOS(-/-) was restored by preincubation with Tiron, ascorbic acid, Tempol, oxypurinol, or SB203850, an inhibitor of p38 kinase, but not apocynin. There was an increase in lucigenin-detectable superoxide anion (O-2(-)) in cardiac tissues from nNOS(-/-) compared with WT. Tempol, oxypurinol, or SB203850 decreased O-2(-) in all groups to levels that were not different from each other. There was an increase in phosphorylated p38 kinase normalized by total p38 kinase protein level in nNOS(-/-) compared with WT mice. These results indicate that a defect of nNOS increases O-2(-) through the activation of xanthine oxidase, which is mediated by the activation of p38 kinase, and attenuates the control of MVO2 by NO derived from eNOS..
3. A mitochondrial delivery system using liposome-based nanocarriers that target myoblast cells..
4. Mikito Nishikawa, Naoki Ishimori, Shingo Takada, Akimichi Saito, Tomoyasu Kadoguchi, Takaaki Furihata, Arata Fukushima, Shouji Matsushima, Takashi Yokota, Shintaro Kinugawa, Hiroyuki Tsutsui, AST-120 ameliorates lowered exercise capacity and mitochondrial biogenesis in the skeletal muscle from mice with chronic kidney disease via reducing oxidative stress, NEPHROLOGY DIALYSIS TRANSPLANTATION, 10.1093/ndt/gfv103, 30, 6, 934-942, 2015.06, Background. Exercise capacity and quality of life are markedly impaired in chronic kidney disease (CKD). Increased plasma uremic toxins such as indoxyl sulfate (IS), which induce oxidative stress, may be involved in this process. An oral adsorbent, AST-120, can reduce circulating IS, however, its effects on skeletal muscle and exercise capacity have not been investigated in CKD.
Methods. Subtotal-nephrectomy or sham operation was performed in 8-week-old C57BL/6J mice. They were divided into two groups with or without 8% (w/w) of AST-120 in standard diet for 20 weeks. Sham, Sham + AST-120, CKD and CKD + AST-120 (n = 12, each group) were studied. We also conducted a C2C12 cell culture study to determine the direct effects of IS on oxidative stress.
Results. Plasma IS levels were significantly increased in CKD compared with Sham (1.05 +/- 0.11 versus 0.21 +/- 0.03 mg/dL, P < 0.05), which was significantly ameliorated in CKD + AST120 (0.41 +/- 0.06 mg/dL). The running distance to exhaustion determined by treadmill tests was significantly reduced in CKD compared with Sham (267 +/- 17 versus 427 +/- 36 m, P < 0.05), and this reduction was also significantly ameliorated in CKD + AST-120 (407 +/- 38 m) without altering skeletal muscle weight. Citrate synthase activity and mitochondrial biogenesis gene were downregulated, and superoxide production was significantly increased in the skeletal muscle from CKD, and these changes were normalized in CKD + AST-120. Incubation of C2C12 cells with IS significantly increased NAD(P) H oxidase activity.
Conclusions. The administration of AST-120 improved exercise capacity and mitochondrial biogenesis of skeletal muscle via reducing oxidative stress. AST-120 may be a novel therapeutic agent against exercise intolerance in CKD..
5. Mochamad Ali Sobirin, Shintaro Kinugawa, Masashige Takahashi, Arata Fukushima, Tsuneaki Homma, Taisuke Ono, Kagami Hirabayashi, Tadashi Suga, Putri Azalia, Shingo Takada, Masaru Taniguchi, Toshinori Nakayama, Naoki Ishimori, Kazuya Iwabuchi, Hiroyuki Tsutsui, Activation of Natural Killer T Cells Ameliorates Postinfarct Cardiac Remodeling and Failure in Mice, CIRCULATION RESEARCH, 10.1161/CIRCRESAHA.112.270132, 111, 8, 1037-+, 2012.09, Rationale: Chronic inflammation in the myocardium is involved in the development of left ventricular (LV) remodeling and failure after myocardial infarction (MI). Invariant natural killer T (iNKT) cells have been shown to produce inflammatory cytokines and orchestrate tissue inflammation. However, no previous studies have determined the pathophysiological role of iNKT cells in post-MI LV remodeling.
Objective: The purpose of this study was to examine whether the activation of iNKT cells might affect the development of LV remodeling and failure.
Methods and Results: After creation of MI, mice received the injection of either alpha-galactosylceramide (alpha GC; n=27), the activator of iNKT cells, or phosphate-buffered saline (n=31) 1 and 4 days after surgery, and were followed during 28 days. Survival rate was significantly higher in MI+alpha GC than MI+PBS (59% versus 32%, P<0.05). LV cavity dilatation and dysfunction were significantly attenuated in MI+alpha GC, despite comparable infarct size, accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis. The infiltration of iNKT cells were increased during early phase in noninfarcted LV from MI and alpha GC further enhanced them. It also enhanced LV interleukin (IL)-10 gene expression at 7 days, which persisted until 28 days. AntienIL-10 receptor antibody abrogated these protective effects of alpha GC on MI remodeling. The administration of alpha GC into iNKT cell-deficient J alpha 18(-/-) mice had no such effects, suggesting that alpha GC was a specific activator of iNKT cells.
Conclusions: iNKT cells play a protective role against post-MI LV remodeling and failure through the enhanced expression of cardioprotective cytokines such as IL-10. (Circ Res. 2012;111:1037-1047.).
6. Yoshikuni Obata, Naoki Ishimori, Akimichi Saito, Shintaro Kinugawa, Takashi Yokota, Shingo Takada, Ippei Nakano, Naoya Kakutani, Katsuma Yamanashi, Toshihisa Anzai, Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice., European journal of preventive cardiology, 10.1177/2047487319901208, 27, 19, 2047487319901208-2047487319901208, 2020.03.
7. Homma T, Kinugawa S, Takahashi M, Sobirin MA, Saito A, Fukushima A, Suga T, Takada S, Kadoguchi T, Masaki Y, Furihata T, Taniguchi M, Nakayama T, Ishimori N, Iwabuchi K, Tsutsui H, Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice., Journal of molecular and cellular cardiology, 10.1016/j.yjmcc.2013.06.004, 62, 179-188, 2013.09.
8. Satoh S, Kinugawa S, Tsutsui H, Takeshita A, Adrenoceptor-mediated regulation of myofibrillar Ca2+ sensitivity through the GTP-binding protein-related mechanisms: tension recording in beta-escin-skinned single rat cardiac cells with preserved receptor functions, Pflugers Arch-Eur J Physiol, 437, 5, 702-709, 1999.05.
9. Suematsu N, Satoh S, Kinugawa S, Tsutsui H, Hayashidani S, Nakamura R, Egashira K, Makino N, Takeshita A, Alpha1-Adrenoceptor-Gq-RhoA signaling is upregulated to increase myofibrillar Ca2+ sensitivity in failing hearts, Am J Physiol Heart Circ Physiol, 281, 2, 637-646, 2001.06.
10. Ide T, Tsutsui H, Kinugawa S, Utsumi H, Takeshita A, Amiodarone protects cardiac myocytes against oxidative injury by its free radical scavenging action, Circulation, 100, 7, 690-692, 1999.03.
11. Sanae Hamaguchi, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Takashi Yokota, Akira Takeshita, Hisashi Yokoshiki, Hiroyuki Tsutsui, Anemia is an Independent Predictor of Long-Term Adverse Outcomes in Patients Hospitalized With Heart Failure in Japan - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), CIRCULATION JOURNAL, 10.1253/circj.CJ-09-0184, 73, 10, 1901-1908, 2009.10, Background: Anemia is common in patients with heart failure (HF) and is associated with worse outcomes. However, the effects of anemia are unknown in an unselected group of HF patients encountered in routine clinical practice in Japan. The impact of anemia on long-term outcomes including mortality and rehospitalization among patients hospitalized with HF was thus assessed.
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed. Study cohorts (n=1,960) were classified into 4 groups by discharge hemoglobin quartiles: <10.1 g/dl (n=482), 10.1-11.9 g/dl (n=479), 12.0-13.6 g/dl (n=487), and >= 13.7 g/dl (n=512). Of the total cohort of HF patients, 57% had anemia, defined by using the World Health Organization definition. Patients with lower hemoglobin quartiles had higher rates of all-cause death, cardiac death, and rehospitalization due to worsening HF. After multivariable adjustment, the risk for all-cause death, cardiac death, and rehospitalization significantly increased with low hemoglobin concentrations.
Conclusions: Anemia was quite common especially in patients with HF encountered in routine clinical practice in Japan, and lower hemoglobin was independently associated with long-term adverse outcomes in these patients. (Circ J 2009; 73: 1901 - 1908).
12. Shintaro Kinugawa, Angiotensin II and skeletal muscle abnormalities, EXPERIMENTAL PHYSIOLOGY, 10.1113/EP086216, 102, 6, 614-615, 2017.06.
13. Tomoyasu Kadoguchi, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Takaaki Furihata, Tsuneaki Homma, Yoshihiro Masaki, Wataru Mizushima, Mikito Nishikawa, Masashige Takahashi, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle, EXPERIMENTAL PHYSIOLOGY, 10.1113/expphysiol.2014.084095, 100, 3, 312-322, 2015.03, New findings
What is the central question of this study? Does angiotensinII directly induce skeletal muscle abnormalities?
What is the main finding and its importance? AngiotensinII induces skeletal muscle abnormalities and reduced exercise capacity. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest early, while muscle atrophy is seen later. Thus, angiotensinII may play an important role in the skeletal muscle abnormalities observed in a wide variety of diseases.
Skeletal muscle abnormalities, such as mitochondrial dysfunction, a decreased percentage of oxidative fibres and atrophy, are the main cause of reduced exercise capacity observed in ageing and various diseases, including heart failure. The renin-angiotensin system, particularly angiotensinII (AngII), is activated in the skeletal muscle in these conditions. Here, we examined whether AngII could directly induce these skeletal muscle abnormalities and investigated their time course. AngiotensinII (1000ngkg(-1)min(-1)) or vehicle was administered to male C57BL/6J mice (10-12weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4weeks. AngiotensinII significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with AngII. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with AngII at 1 and 4weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complexI and complexIII activities were significantly decreased in the skeletal muscle from mice treated AngII at 1 and 4weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that typeI fibres were decreased and typeIIb fibres increased in mice treated with AngII at 1week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with AngII at 4weeks. Thus, AngII could directly induce the abnormalities in skeletal muscle function and structure..
14. Shingo Takada, Shintaro Kinugawa, Kagami Hirabayashi, Tadashi Suga, Takashi Yokota, Masashige Takahashi, Arata Fukushima, Tsuneaki Homma, Taisuke Ono, Mochamad A. Sobirin, Yoshihiro Masaki, Wataru Mizushima, Tomoyasu Kadoguchi, Koichi Okita, Hiroyuki Tsutsui, Angiotensin II receptor blocker improves the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice, JOURNAL OF APPLIED PHYSIOLOGY, 10.1152/japplphysiol.00053.2012, 114, 7, 844-857, 2013.04, Angiotensin II receptor blocker improves the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice. J Appl Physiol 114: 844-857, 2013. First published January 17, 2013; doi:10.1152/japplphysiol.00053.2012.-NAD(P)H oxidase-induced oxidative stress is at least in part involved with lowered exercise capacity and impaired mitochondrial function in high-fat diet (HFD)-induced diabetic mice. NAD(P)H oxidase can be activated by activation of the renin-angiotensin system. We investigated whether ANG II receptor blocker can improve exercise capacity in diabetic mice. C57BL/6J mice were fed a normal diet (ND) or HFD, and each group of mice was divided into two groups: treatment with or without olmesartan (OLM; 3 mg.kg(-1).day(-1) in the drinking water). The following groups of mice were studied: ND, ND+OLM, HFD, and HFD+OLM (n = 10 for each group). After 8 wk, HFD significantly increased body weight, plasma glucose, and insulin compared with ND, and OLM did not affect these parameters in either group. Exercise capacity, as determined by treadmill tests, was significantly reduced in HFD, and this reduction was ameliorated in HFD+OLM. ADP-dependent mitochondrial respiration was significantly decreased, and NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence were significantly increased in skeletal muscle from HFD, which were attenuated by OLM. There were no such effects by OLM in ND. We concluded that OLM ameliorated the decrease in exercise capacity in diabetic mice via improvement in mitochondrial function and attenuation of oxidative stress in skeletal muscle. These data may have a clinical impact on exercise capacity in the medical treatment of diabetes mellitus..
15. Hiroyuki Tsutsui, Shouji Matsushima, Shintaro Kinugawa, Tomomi Ide, Naoki Inoue, Yukihiro Ohta, Takashi Yokota, Sanae Hamaguchi, Kenji Sunagawa, Angiotensin II type 1 receptor blocker attenuates myocardial remodeling and preserves diastolic function in diabetic heart, HYPERTENSION RESEARCH, 10.1291/hypres.30.439, 30, 5, 439-449, 2007.05, Blockade of the renin-angiotensin system reduces cardiovascular morbidity and mortality in diabetic patients. Angiotensin II (Ang II) plays an important role in the structural and functional abnormalities of the diabetic heart. We investigated whether or not Ang II type 1 receptor blocker (ARB) could attenuate left ventricular (LV) remodeling in male mice with diabetes mellitus (DM) induced by the injection of streptozotocin (200 mg/kg, i.p.). Diabetic mice were treated with candesartan (1 mg/kg/day; DM+Candesartan, n=7) or vehicle (DM+Vehicle, n=7) for 8 weeks. Heart rate and aortic blood pressure were comparable between the groups. Normal systolic function was preserved in diabetic mice. In contrast, diastolic function was impaired in DM+Vehicle and was improved in DM+Candesartan, as assessed by the deceleration time of the peak velocity of transmitral diastolic flow (40.3 +/- 0.3 vs. 37.3 +/- 0.5 ms, p<0.01) and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 10.6 +/- 0.7 vs. 8.7 +/- 0.6 ms, p<0.05) without significant changes in heart rate and aortic blood pressure. Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis and apoptosis in association with the expression of connective tissue growth factor (CTGF) and myocardial oxidative stress. Moreover, candesartan directly inhibited Ang II-mediated induction of CTGF in cultured cardiac fibroblasts. ARB might be beneficial to prevent cardiac abnormalities in DM..
16. Hidenori Matsusaka, Shintaro Kinugawa, Tomomi Ide, Shouji Matsushima, Tetsuya Shiomi, Toru Kubota, Kenji Sunagawa, Hiroyuki Tsutsui, Angiotensin II type 1 receptor blocker attenuates exacerbated left ventricular remodeling and failure in diabetes-associated myocardial infarction, JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 10.1097/01.fjc.0000245405.41317.60, 48, 3, 95-102, 2006.09, Diabetes mellitus adversely affects the outcomes in patients with myocardial infarction (MI), due in part to the exacerbation of left ventricular (LV) remodeling. Although angiotensin 11 type I receptor blocker (ARB) has been demonstrated to be effective in the treatment of heart failure, information about the potential benefits of ARB on advanced LV failure associated with diabetes is lacking. To induce diabetes, male mice were injected intraperitoneally with streptozotocin (200 mg/kg). At 2 weeks, anterior MI was created by ligating the left coronary artery. These animals received treatment with olmesartan (0.1 mg/kg/day; n = 50) or vehicle (n 51) for 4 weeks. Diabetes worsened the survival and exaggerated echocardiographic LV dilatation and dysfunction in MI. Treatment of diabetic MI mice with olmesartan significantly improved the survival rate (42% versus 27%, P < 0.05) without affecting blood glucose, arterial blood pressure, or infarct size. It also attenuated LV dysfunction in diabetic MI. Likewise, olmesartan attenuated myocyte hypertrophy, interstitial fibrosis, and the number of apoptotic cells in the noninfarcted LV from diabetic MI. Post-MI LV remodeling and failure in diabetes were ameliorated by ARB, providing further evidence that angiotensin 11 plays a pivotal role in the exacerbated heart failure after diabetic MI..
17. Naoki Inoue, Shintaro Kinugawa, Tadashi Suga, Takashi Yokota, Kagami Hirabayashi, Satoshi Kuroda, Koichi Okita, Hiroyuki Tsutsui, Angiotensin II-induced reduction in exercise capacity is associated with increased oxidative stress in skeletal muscle, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.00534.2011, 302, 5, H1202-H1210, 2012.03, Inoue N, Kinugawa S, Suga T, Yokota T, Hirabayashi K, Kuroda S, Okita K, Tsutsui H. Angiotensin II-induced reduction in exercise capacity is associated with increased oxidative stress in skeletal muscle. Am J Physiol Heart Circ Physiol 302: H1202-H1210, 2012. First published December 30, 2011; doi:10.1152/ajpheart.00534.2011.-Angiotensin II (ANG II)-induced oxidative stress has been known to be involved in the pathogenesis of cardiovascular diseases. We have reported that the oxidative stress in skeletal muscle can limit exercise capacity in mice (16). We thus hypothesized that ANG II could impair the skeletal muscle energy metabolism and limit exercise capacity via enhancing oxidative stress. ANG II (50 ng.kg(-1).min(-1)) or vehicle was infused into male C57BL/6J mice for 7 days via subcutaneously implanted osmotic minipumps. ANG II did not alter body weight, skeletal muscle weight, blood pressure, cardiac structure, or function. Mice were treadmill tested, and expired gases were analyzed. The work to exhaustion (vertical distance x body weight) and peak oxygen uptake were significantly decreased in ANG II compared with vehicle. In mitochondria isolated from skeletal muscle, ADP-dependent respiration was comparable between ANG II and vehicle, but ADP-independent respiration was significantly increased in ANG II. Furthermore, complex I and III activities were decreased in ANG II. NAD(P)H oxidase activity and superoxide production by lucigenin chemiluminescence were significantly increased in skeletal muscle from ANG II mice. Treatment of ANG II mice with apocynin (10 mmol/l in drinking water), an inhibitor of NAD(P)H oxidase activation, completely inhibited NAD(P)H oxidase activity and improved exercise capacity, mitochondrial respiration, and complex activities in skeletal muscle. ANG II-induced oxidative stress can impair mitochondrial respiration in skeletal muscle and limit exercise capacity..
18. Naoya Kakutani, Shingo Takada, Hideo Nambu, Satoshi Maekawa, Hikaru Hagiwara, Katsuma Yamanashi, Yoshikuni Obata, Ippei Nakano, Yoshizuki Fumoto, Soichiro Hata, Takaaki Furihata, Arata Fukushima, Takashi Yokota, Shintaro Kinugawa, Angiotensin-converting enzyme inhibitor prevents skeletal muscle fibrosis in diabetic mice., Experimental physiology, 10.1113/EP089375, 106, 8, 1785-1793, 2021.08, NEW FINDINGS: What is the central question of this study? We questioned whether an angiotensin-converting enzyme (ACE) inhibitor prevents skeletal muscle fibrosis in diabetic mice. What is the main finding and its importance? Administration of ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after induction of diabetes by streptozotocin. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. ABSTRACT: Fibrosis is characterized by the excessive production and accumulation of extracellular matrix components, including collagen. Although the extracellular matrix is an essential component of skeletal muscle, fibrosis can have negative effects on muscle function. Skeletal muscle fibrosis was shown to be increased in spontaneously hypertensive rats and to be prevented by an angiotensin-converting enzyme (ACE) inhibitor, an antihypertensive drug, in dystrophic mice or a mouse model of myocardial infarction. In this study, we therefore analysed whether (1) there is increased skeletal muscle fibrosis in streptozotocin (STZ)-induced diabetic mice, and (2) a preventive effect on skeletal muscle fibrosis by administration of an ACE inhibitor. Skeletal muscle fibrosis was significantly increased in STZ-induced diabetic mice compared with control mice from 2 to 14 days post-STZ. The ACE inhibitor prevented both skeletal muscle fibrosis and the reduction in muscle function in STZ-treated mice. Our study demonstrated that administration of an ACE inhibitor prevents the increase in skeletal muscle fibrosis during the early phase after onset of diabetes. Our findings might provide a new therapeutic target for skeletal muscle abnormalities in diabetes. Future studies are required to clarify whether skeletal muscle fibrosis is also linked directly to physical activity..
19. Teruhiko Imamura, Koichiro Kinugawa, Tomohito Ohtani, Yasushi Sakata, Taiki Higo, Shintaro Kinugawa, Hiroyuki Tsutsui, Kenji Sunagawa, Issei Komuro, Assessment of Quality of Life During Long-Term Treatment of Tolvaptan in Refractory Heart Failure Design and Rationale of the AQUA-TLV Study, INTERNATIONAL HEART JOURNAL, 10.1536/ihj.13-326, 55, 3, 264-267, 2014.05, The vasopressin type 2 receptor antagonist tolvaptan (TLV) has recently become available to treat congestion in in-hospital patients with heart failure (HF). However, there is no evidence confirming the long-term efficacy of TLV. The Assessment of QUAlity of life during long-term treatment of TLV in refractory heart failure (AQUA-TLV) study is a multicenter, open-labeled, randomized, controlled clinical trial that will enroll 100 patients from 18 hospitals in Japan. Patients with HF assigned to New York Heart Association class III or IV, who had a previous history of hospitalization due to congestive HF during the past 1 year and ongoing symptomatic congestion with baseline urine osmolality > 350 mOsm/L regardless of being prescribed daily furosemide >= 60 mg are randomized to the conventional diuretics group (50 patients) and TLV add-on group (50 patients), and their quality of life will be assessed using the Minnesota Living with Heart Failure Questionnaire after 6 months of treatment. This study is the first multicenter prospective randomized study in Japan to evaluate the long-term clinical effectiveness of TLV compared with conventional treatment in patients with congestive HF..
20. Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Hisashi Yokoshiki, Sanae Hamaguchi, Takashi Yokota, Daisuke Goto, Kazutomo Goto, Akira Takeshita, Hiroyuki Tsutsui, Beta-Blocker Use at Discharge in Patients Hospitalized for Heart Failure Is Associated With Improved Survival, CIRCULATION JOURNAL, 10.1253/circj.CJ-09-0993, 74, 7, 1364-1371, 2010.07, Background: Previous studies demonstrated that beta-blocker use at the time of hospital discharge significantly increased postdischarge treatment rates, associated with an early (60- to 90-day) survival benefit in patients with heart failure (HF). However, it is unknown whether this therapeutic approach can also improve the long-term survival. We thus examined the long-term effects of beta-blocker use at discharge on outcomes in patients hospitalized for HF and left ventricular systolic dysfunction (LVSD) (ejection fraction <40%).
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) enrolled HF patients hospitalized with worsening symptoms and they were followed during an average of 2.2 years. A total of 947 patients had LVSD, among whom 624 (66%) were eligible to receive a beta-blocker at discharge. After adjustment for covariate and propensity score, discharge use of beta-blocker, when compared to no beta-blocker use, was associated with a significant reduced risk of all-cause mortality (hazard ratio (HR) 0.564, 95% confidence interval (CI) 0.358-0.889, P=0.014) and cardiac mortality (HR 0.489, 95%CI 0.279-0.859, P=0.013) after hospital discharge.
Conclusions: Beta-blocker use at the time of discharge was associated with a long-term survival benefit in a diverse cohort of patients hospitalized with HF. (Circ J 2010; 74: 1364-1371).
21. Shingo Takada, Koichi Okita, Tadashi Suga, Masashi Omokawa, Noriteru Morita, Masahiro Horiuchi, Tomoyasu Kadoguchi, Masashige Takahashi, Kagami Hirabayashi, Takashi Yokota, Shintaro Kinugawa, Hiroyuki Tsutsui, Blood Flow Restriction Exercise in Sprinters and Endurance Runners, MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, 10.1249/MSS.0b013e31822f39b3, 44, 3, 413-419, 2012.03, TAKADA, S., K. OKITA, T. SUGA, M. OMOKAWA, N. MORITA, M. HORIUCHI, T. KADOGUCHI, M. TAKAHASHI, K. HIRABAYASHI, T. YOKOTA, S. KINUGAWA, and H. TSUTSUI. Blood Flow Restriction Exercise in Sprinters and Endurance Runners. Med. Sci. Sports Exerc., Vol. 44, No. 3, pp. 413-419, 2012. Purpose: We demonstrated that blood flow restriction (BFR) remarkably enhances muscular metabolic stress in resistance exercise, although there is a wide range of individual differences in the responses. It is possible that these differences could be due to training status and muscular physiological characteristics. We investigated intramuscular metabolic responses during low-intensity resistance exercise with BFR between two different types of track athletes. Methods: Twelve age-matched male track athletes (sprinter group, n = 6; endurance runner group, n = 6) were recruited and performed unilateral plantarflexion (30 repetitions per minute). The exercise protocols were as follows: low-intensity exercise at 20% of one-repetition maximum (1RM) (L), high-intensity exercise at 65% 1RM without BFR (1.3 times of systolic blood pressure), L with BFR for 2 min (L-BFR), and prolonged exercise time in L-BFR for 3 min (prolonged BFR). Metabolic stress, defined as phosphocreatine and intramuscular pH decrease, and muscle fiber recruitment were evaluated using 31 P magnetic resonance spectroscopy. Results: Endurance runners showed higher peak oxygen uptake and lower muscle strength than sprinters. Phosphocreatine decreases in endurance runners during exercise with BFR protocols were significantly greater than those in sprinters (P < 0.05), although those occurring during L were significantly lower than those in sprinters (P < 0.05). The changes in intramuscular pH and the incidence of fast-twitch fiber recruitment did not show a statistical difference between the two groups. Phosphocreatine decreases in L-BFR were significantly correlated with peak oxygen uptake (P < 0.05). Conclusions: The effects of low-intensity resistance exercise with BFR are greater in endurance runners according to higher aerobic capacity..
22. Sanae Hamaguchi, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Daisuke Goto, Takashi Yokota, Kazutomo Goto, Satoshi Yamada, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui, Body Mass Index Is an Independent Predictor of Long-Term Outcomes in Patients Hospitalized With Heart Failure in Japan - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), CIRCULATION JOURNAL, 10.1253/circj.CJ-10-0599, 74, 12, 2605-2611, 2010.12, Background: Obesity is a risk factor for cardiovascular disease (CVD) and is also associated with an increased risk of death in subjects without CVD. However, in heart failure (HF), elevated body mass index (BMI) has been shown to be associated with better prognosis, but it is unknown whether this is the case in unselected HF patients encountered in routine clinical practice in Japan.
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed for 2.1 years. Study cohort (n=2,488) was classified into 3 groups according to baseline BMI <20.3 kg/m(2) (n=829), 20 3-23.49 kg/m(2) (n=832), and 23.5 kg/m(2) (n=827). The mean BMI was 22.3+/-4.1 kg/m(2). Patients with higher BMI had lower rates of all-cause death, cardiac death, and rehospitalization because of worsening HF After multivariable adjustment, the risk for all-cause death and cardiac death significantly increased with decreased BMI levels compared with patients with BMI 5 kg/m(2). However, BMI levels were not associated with rehospitalization for worsening HF.
Conclusions: Lower BMI was independently associated with increased long-term all-cause, as well as cardiac, mortality in patients with HF encountered in routine clinical practice in Japan. (Circ J 2010; 74: 2605-2611).
23. Junichi Matsumoto, Shingo Takada, Takaaki Furihata, Hideo Nambu, Naoya Kakutani, Satoshi Maekawa, Wataru Mizushima, Ippei Nakano, Arata Fukushima, Takashi Yokota, Shinya Tanaka, Haruka Handa, Hisataka Sabe, Shintaro Kinugawa, Brain-Derived Neurotrophic Factor Improves Impaired Fatty Acid Oxidation Via the Activation of Adenosine Monophosphate-Activated Protein Kinase-ɑ - Proliferator-Activated Receptor-r Coactivator-1ɑ Signaling in Skeletal Muscle of Mice With Heart Failure., Circulation. Heart failure, 10.1161/CIRCHEARTFAILURE.119.005890, 14, 1, e005890, 2021.01, BACKGROUND: We recently reported that treatment with rhBDNF (recombinant human brain-derived neurotrophic factor) improved the reduced exercise capacity of mice with heart failure (HF) after myocardial infarction (MI). Since BDNF is reported to enhance fatty acid oxidation, we herein conducted an in vivo investigation to determine whether the improvement in exercise capacity is due to the enhancement of the fatty acid oxidation of skeletal muscle via the AMPKα-PGC1α (adenosine monophosphate-activated protein kinase-ɑ-proliferator-activated receptor-r coactivator-1ɑ) axis. METHODS: MI and sham operations were conducted in C57BL/6J mice. Two weeks postsurgery, we randomly divided the MI mice into groups treated with rhBDNF or vehicle for 2 weeks. AMPKα-PGC1α signaling and mitochondrial content in the skeletal muscle of the mice were evaluated by Western blotting and transmission electron microscopy. Fatty acid β-oxidation was examined by high-resolution respirometry using permeabilized muscle fiber. BDNF-knockout mice were treated with 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside, an activator of AMPK. RESULTS: The rhBDNF treatment significantly increased the expressions of phosphorylated AMPKα and PGC1α protein and the intermyofibrillar mitochondrial density in the MI mice. The lowered skeletal muscle mitochondrial fatty acid oxidation was significantly improved in the rhBDNF-treated MI mice. The reduced exercise capacity and mitochondrial dysfunction of the BDNF-knockout mice were improved by 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside. CONCLUSIONS: Beneficial effects of BDNF on the exercise capacity of mice with HF are mediated through an enhancement of fatty acid oxidation via the activation of AMPKα-PGC1α in skeletal muscle. BDNF may become a therapeutic option to improve exercise capacity as an alternative or adjunct to exercise training..
24. Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure..
25. Katsuma Yamanashi, Shintaro Kinugawa, Arata Fukushima, Naoya Kakutani, Shingo Takada, Yoshikuni Obata, Ippei Nakano, Takashi Yokota, Yasuyuki Kitaura, Yoshiharu Shimomura, Toshihisa Anzai, Branched-chain amino acid supplementation ameliorates angiotensin II-induced skeletal muscle atrophy., Life sciences, 10.1016/j.lfs.2020.117593, 117593-117593, 2020.03, AIMS: Sarcopenia is characterized by muscle mass and strength loss and reduced physical activity. Branched-chain amino acids (BCAAs) were recently described as an activator of protein synthesis via mammalian target of rapamycin (mTOR) signaling for muscle atrophy. In cardiovascular diseases, excessive activation of the renin-angiotensin system may induce an imbalance of protein synthesis and degradation, and this plays a crucial role in muscle atrophy. We investigated the effects of BCAAs on angiotensin II (Ang II)-induced muscle atrophy in mice. MATERIALS AND METHODS: We administered Ang II (1000 ng/kg/min) or vehicle to 10-12-week-old male C57BL/6J mice via subcutaneous osmotic minipumps for 4 weeks with or without BCAA supplementation (3% BCAA in tap water). KEY FINDINGS: The skeletal muscle weight/tibial length and cross-sectional area were smaller in the Ang II mice than the vehicle mice; these changes were induced by an imbalance of protein synthesis and degradation signaling such as Akt/mTOR and MuRF-1/Atrogin-1. Compared to the Ang II mice, the mTOR signaling was significantly activated and Ang II-induced muscle atrophy was ameliorated in the Ang II + BCAA mice, and this attenuated the reduction of exercise capacity. Notably, the decrease of muscle weight/tibial length in the fast-twitch dominant muscles (e.g., the extensor digitorum longus) was significantly ameliorated compared to that in the slow-twitch dominant muscles (e.g., soleus). Histologically, the effect of BCAA was larger in fast-twitch than slow-twitch fibers, which may be related to the difference in BCAA catabolism. SIGNIFICANCE: BCAA supplementation could contribute to the prevention of skeletal muscle atrophy induced by Ang II..
26. Miyuki Tsuchihashi-Makaya, Sanae Hamaguchi, Shintaro Kinugawa, Takashi Yokota, Daisuke Goto, Hisashi Yokoshiki, Norihiro Kato, Akira Takeshita, Hiroyuki Tsutsui, Characteristics and Outcomes of Hospitalized Patients With Heart Failure and Reduced vs Preserved Ejection Fraction - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), CIRCULATION JOURNAL, 10.1253/circj.CJ-09-0254, 73, 10, 1893-1900, 2009.10, Background: Heart failure (HF) with preserved ejection fraction (EF) is common. We compared the characteristics. treatments, and outcomes in HF patients with reduced vs preserved EF by using the national registry database in Japan.
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) is a prospective observational study in a broad sample of patients hospitalized with worsening HF. The study enrolled 2,675 patients from 164 hospitals with an average of 2.4 years of follow-up. Patients with preserved EF (EF >= 50% by echocardiography: n=429) were more likely to be older, female, have hypertension and atrial fibrillation, and less likely to have ischemic etiology compared with those with reduced EF (EF <40%; n=985). Unadjusted risk of in-hospital mortality (6.5% vs 3.9%; P=0.03) and post-discharge mortality (22.7% vs 17.8%; P=0.058) was slightly higher in patients with preserved EF, which, however, were not different after multivariable adjustment. Patients with preserved EF had similar rehospitalization rates (36.2% vs 33.4%; P=0.515) compared with patients with reduced EF.
Conclusions: HF patients with preserved EF had a similar mortality risk and equally high rates of rehospitalization as those with reduced EF. Effective management strategies are critically needed to be established for this type of HF. (Circ J 2009; 73: 1893 - 1900).
27. Hiroyuki Tsutsui, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Daisuke Goto, Akira Takeshita, Characteristics and outcomes of patients with heart failure in general practices and hospitals - Japanese cardiac registry of heart failure in general practice (JCARE-GENERAL), CIRCULATION JOURNAL, 10.1253/circj.71.449, 71, 4, 449-454, 2007.04, Background The characteristics and outcomes of patients discharged from hospitals with a diagnosis of heart failure (HF) have been described by a number of previous epidemiological studies. However, very little information is available on this issue in general practice in Japan.
Methods and Results The Japanese Cardiac Registry of Heart Failure in General Practice (JCARE-GENERAL) is designed to study the characteristics, treatment and outcomes prospectively in a broad sample of outpatients with HF who were managed by cardiologists in hospital (Hospital-HF) and primary care physicians in general practice (GP-HF). Out of 2,685 patients. with HF, 1,280 patients were Hospital-HF and 1,405 GP-HF. Compared to the Hospital-HF patients, GP-HF patients were more likely to be elderly and female, and they had a higher prevalence of hypertensive heart disease as a cause of HF. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and beta-blockers were more prescribed to Hospital-HF than GP-HF patients. At the follow-up of 1.2 year, after adjustment, the mortality was comparable between the Hospital-HF and GP-HF groups, whereas HF-related admission was higher in the Hospital-HF group than in in the GP-HF group.
Conclusions Based on the JCARE-GENERAL, the characteristics, treatment and outcomes of GP-HF patients differed from those of Hospital -HFpatients in Japan..
28. Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Daisuke Goto, Satoshi Yamada, Hisashi Yokoshiki, Hiroyuki Tsutsui, Characteristics, management, and outcomes for patients during hospitalization due to worsening heart failure-A report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), JOURNAL OF CARDIOLOGY, 10.1016/j.jjcc.2013.03.009, 62, 1-2, 95-101, 2013.07, Background: The characteristics, in-hospital management, and outcomes of patients hospitalized with worsening heart failure (HF) have been described by large-scale registries performed mainly in the USA and Europe. However, little information is available in Japan. We thus clarified the characteristics and clinical status as well as in-hospital management and outcomes among patients hospitalized with worsening HF in Japan and compared them with those reported in previous studies.
Methods: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in patients hospitalized with worsening HF. From the total cohort of JCARE-CARD, 1677 patients were randomly selected and their detailed data during acute phase were collected as another registry database in the present study. The characteristics, in-hospital management, and outcomes were analyzed.
Results: The mean age was 70.7 years and 59.4% were male. Etiology was ischemic in 34.0% and mean left ventricular ejection fraction was 42.5%. Carperitide was highly used as in-hospital management in Japan (33.5%) compared to the use of nesiritide in the USA (8-11%). The use of angiotensin-converting enzyme inhibitors was lower and angiotensin II receptor blockers (ARB) were more commonly used in this study compared to other studies in the USA and Europe. In-hospital crude mortality rate was comparable among studies (4-8%), however, length of stay was longer in Japan (15-20 versus 4-9 days).
Conclusions: The characteristics, clinical status, and laboratory data on admission in patients hospitalized with worsening HF were similar between the present study and previous Japanese and western studies. Management was also similar except for higher use of carperitide and ARB. The most striking difference between Japanese registries and those from the USA and Europe was the longer length of stay. (C) 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved..
29. Sanae Hamaguchi, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Takashi Yokota, Tomomi Ide, Akira Takeshita, Hiroyuki Tsutsui, Chronic Kidney Disease as an Independent Risk for Long-Term Adverse Outcomes in Patients Hospitalized With Heart Failure in Japan - Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) -, CIRCULATION JOURNAL, 10.1253/circj.CJ-09-0062, 73, 8, 1442-1447, 2009.08, Background: Previous studies have demonstrated that renal dysfunction is common in patients with heart failure (HF), but it is not known whether chronic kidney disease (CKD) is associated with increased risks of long-term adverse outcomes in unselected HF patients encountered in current routine clinical practice in Japan. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied a broad sample of patients hospitalized with worsening HF and their outcomes with an average of 2.4 years of follow-up. The study cohort (n=2,013) were classified into 3 groups by estimated glomerular filtration rate (eGFR): >= 60 (n=579), 30-59 (n=1,025), and <30 ml.min(-1) . 1.73 m(-2) or patients with dialysis (n=409); 1,372 patients (70.3%) had an eGFR <60 ml.min(-1) . 1.73 m(-2) and 62 patients were treated with dialysis. The multivariable adjusted risk for all-cause death or rehospitalization increased with reduced eGFR; an adjusted hazard ratio (HR) 1.520 (95% confidence interval (Cl) 1.186-1.949) for eGFR 30-59 ml.min(-1) . 1.73 m(-2) (P=0.001) and HR 2.566 (95%CI 1.885-3.492) for eGFR <30 ml.min(-1) . 1.73 m(-2) or patients with dialysis (P<0.001). Conclusions: CKD is common in HF and was independently associated with long-term adverse outcomes in a broad cohort of Japanese patients. (Circ J 2009; 73: 1442-1447).
30. Sanae Hamaguchi, Shintaro Kinugawa, Shouji Matsushima, Arata Fukushima, Takashi Yokota, Mamoru Sakakibara, Hisashi Yokoshiki, Miyuki Tsuchihashi-Makaya, Hiroyuki Tsutsui, Clinical characteristics and CHADS(2) score in patients with heart failure and atrial fibrillation: Insights from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2014.06.068, 176, 1, 239-242, 2014.09.
31. Daisuke Goto, Shintaro Kinugawa, Sanae Hamaguchi, Mamoru Sakakibara, Miyuki Tsuchihashi-Makaya, Takashi Yokota, Satoshi Yamada, Hisashi Yokoshiki, Hiroyuki Tsutsui, Clinical characteristics and outcomes of dilated phase of hypertrophic cardiomyopathy: Report from the registry data in Japan, JOURNAL OF CARDIOLOGY, 10.1016/j.jjcc.2012.08.010, 61, 1-2, 65-70, 2013.01, Background: A subset of patients with hypertrophic cardiomyopathy (HCM) has been reported to progress into dilated-HCM (D-HCM), characterized by left ventricular (LV) systolic dysfunction and cavity dilatation, resembling idiopathic dilated cardiomyopathy (DCM). We compared the characteristics, treatments, and outcomes in patients with heart failure (HF) due to D-HCM vs. DCM by using national registry data in Japan.
Methods and results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) is a prospective observational study of patients hospitalized due to worsening HF with an average of 2.2 years of follow-up. Patients with D-HCM (n=41) were more likely to be male, have prior stroke, atrial fibrillation, and sustained ventricular tachycardia or ventricular fibrillation compared with DCM (n=486). Echocardiography demonstrated that D-HCM patients had smaller LV end-systolic diameter, higher ejection fraction, and greater wall thickness. Treatments for HF including angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blocker, and spironolactone were similar between groups except for higher use of amiodarone, warfarin, and implantable cardioverter-defibrillator for D-HCM. Mortality was significantly higher in patients with D-HCM (29.7% vs. 14.4%; p<0.05). Sudden death tended to be higher also in D-HCM (8.1% vs. 2.6%; p=0.06), which, however, did not reach statistical significance.
Conclusions: HF patients with D-HCM had higher mortality risk than those with DCM. Effective management strategies are critically needed to be established for D-HCM. (C) 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved..
32. Hiroyuki Tsutsui, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Clinical characteristics and outcomes of heart failure with preserved ejection fraction: Lessons from epidemiological studies, JOURNAL OF CARDIOLOGY, 10.1016/j.jjcc.2009.09.003, 55, 1, 13-22, 2010.01, Recent epidemiological studies have demonstrated that nearly half of all patients with heart failure (HF) have preserved Left ventricular ejection fraction (HFPEF). Compared to those with reduced EF, patients with HFPEF are older, more likely to be women, less likely to have coronary artery disease, and more likely to have hypertension and atrial. fibrillation. Patients with HFPEF receive different pharmacological as well as nonpharmacological treatments from those with reduced EF Morbidity and mortality in patients with HFPEF are largely similar to those with reduced EF Although much information has recently been obtained about the clinical characteristics, medications, and outcomes of HFPEF by Large-scale clinical and epidemiological studies, effective management strategies need to be established for this type of HF. (C) 2009 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved..
33. Hiroyuki Tsutsui, Miyuki Tsuchihashi-Makaya, Shintaro Kinugawa, Daisuke Goto, Akira Takeshita, Clinical characteristics and outcome of hospitalized patients with heart failure in Japan - Rationale and design of Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), CIRCULATION JOURNAL, 10.1253/circj.70.1617, 70, 12, 1617-1623, 2006.12, Background Heart failure (HF), defined as a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood, is a leading cause of mortality and hospitalization for adults older than 65 years in the industrialized countries. The characteristics and outcome of patients with HF have been described by several epidemiological studies and large scale clinical trials, performed mainly in the United States and Europe. Very little information is available on this issue in Japan.
Methods and Results The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) is designed to prospectively study the characteristics, treatment, and outcomes of a broad sample of patients hospitalized with HF at teaching hospitals throughout Japan between January 2004 to June 2005 and the outcomes, including death and hospital readmission, will be followed through 2006 (mean follow-up at least 1 year). Participating cardiologists identify patients admitted for worsening of HF symptoms. Demographics, medical history, severity, treatment, and outcome data are collected and entered into a database via secure web browser technology. As of June 2005, baseline data for 2,676 patients with HF have been registered from 164 participating hospitals.
Conclusions The JCARE-CARD will provide important insights into the management of patients with HF in routine clinical practice in Japan, thus providing the framework for improved management strategies for these patients..
34. Ishikawa K, Fukushima A, Yokota T, Takada S, Furihata T, Kakutani N, Yamanashi K, Obata Y, Nakano I, Abe T, Kinugawa S, Anzai T, Clinical impacts and associated factors of delayed ambulation in patients with acute heart failure, Circ Rep, 1, 4, 179-186, 2019.04.
35. Tadashi Suga, Shintaro Kinugawa, Shingo Takada, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Masashige Takahashi, Mochamad A. Sobirin, Taisuke Ono, Kagami Hirabayashi, Takashi Yokota, Shinya Tanaka, Koichi Okita, Hiroyuki Tsutsui, Combination of Exercise Training and Diet Restriction Normalizes Limited Exercise Capacity and Impaired Skeletal Muscle Function in Diet-Induced Diabetic Mice, ENDOCRINOLOGY, 10.1210/en.2013-1382, 155, 1, 68-80, 2014.01, Exercise training (EX) and diet restriction (DR) are essential for effective management of obesity and insulin resistance in diabetes mellitus. However, whether these interventions ameliorate the limited exercise capacity and impaired skeletal muscle function in diabetes patients remains unexplored. Therefore, we investigated the effects of EX and/or DR on exercise capacity and skeletal muscle function in diet-induced diabetic mice. Male C57BL/6J mice that were fed a high-fat diet (HFD) for 8 weeks were randomly assigned for an additional 4 weeks to 4 groups: control, EX, DR, and EX+DR. A lean group fed with a normal diet was also studied. Obesity and insulin resistance induced by a HFD were significantly but partially improved by EX or DR and completely reversed by EX+DR. Although exercise capacity decreased significantly with HFD compared with normal diet, it partially improved with EX and DR and completely reversed with EX+DR. In parallel, the impaired mitochondrial functionandenhanced oxidative stress in the skeletal muscle caused by the HFD were normalized only by EX+DR. Although obesity and insulin resistance were completely reversed by DR with an insulin-sensitizing drug or a long-term intervention, the exercise capacity and skeletal muscle function could not be normalized. Therefore, improvement in impaired skeletal muscle function, rather than obesity and insulin resistance, may be an important therapeutic target for normalization of the limited exercise capacity in diabetes. In conclusion, a comprehensive lifestyle therapy of exercise and diet normalizes the limited exercise capacity and impaired muscle function in diabetes mellitus..
36. S Kinugawa, H Post, PM Kaminski, XP Zhang, XB Xu, H Huang, FA Recchia, M Ochoa, MS Wolin, G Kaley, TH Hintze, Coronary microvascular endothelial stunning after acute pressure overload in the conscious dog is caused by oxidant processes - The role of angiotensin II type 1 receptor and NAD(P)H oxidase, CIRCULATION, 10.1161/01.CIR.0000096488.78151.97, 108, 23, 2934-2940, 2003.12, Background-Few studies have examined the effect of acute pressure overload on endothelial function in the coronary microcirculation.
Methods and Results-In instrumented conscious dogs with heart rate held constant, veratrine caused a cholinergic nitric oxide ( NO)-dependent increase in coronary blood flow by 23+/-3 mL/min (Bezold-Jarisch reflex). Ten minutes after release of constriction of the ascending aorta to increase left ventricular (LV) systolic pressure to 214+/-5 mm Hg for 30 minutes, the veratrine-induced increase in coronary blood flow (7+/-1 mL/min) was reduced by 66% and remained depressed for 2 hours (ie, endothelial stunning [ES]). Nitrite production from isolated coronary microvessels during ES was not different from normal. Ascorbic acid (AA), losartan, or apocynin prevented ES. Myocardial oxygen consumption (M(V) over dot o(2)) of LV tissue was measured in vitro in response to bradykinin with preincubation of angiotensin II for 30 minutes. Bradykinin (10(-4) mol/L)-induced reduction in M(V) over dot o(2) was reversed in a concentration-dependent manner by angiotensin II (38+/-1% versus 19+/-2% at 10(-8) mol/L) and restored by coincubation of AA (37+/-2%), tempol (33+/-2%), losartan (34+/-2%), or apocynin (36+/-1%). Exogenous NO-induced reduction in M(V) over dot o(2) was not altered by angiotensin II. Angiotensin II increased lucigenin-detectable superoxide anion in LV tissue in a manner that was inhibited by bradykinin, AA, tempol, losartan, or apocynin.
Conclusions-Endothelial stunning is caused by oxidant processes inhibited by ascorbate, and the activation of NAD(P)H oxidase by increased angiotensin II plays an important role in this process..
37. Taisuke Ono, Shingo Takada, Shintaro Kinugawa, Hiroyuki Tsutsui, Curcumin ameliorates skeletal muscle atrophy in type 1 diabetic mice by inhibiting protein ubiquitination, EXPERIMENTAL PHYSIOLOGY, 10.1113/EP085049, 100, 9, 1052-1063, 2015.09, New Findings
What is the central question of this study? We sought to examine whether curcumin could ameliorate skeletal muscle atrophy in diabetic mice by inhibiting protein ubiquitination, inflammatory cytokines and oxidative stress.
What is the main finding and its importance? We found that curcumin ameliorated skeletal muscle atrophy in streptozotocin-induced diabetic mice by inhibiting protein ubiquitination without affecting protein synthesis. This favourable effect of curcumin was possibly due to the inhibition of inflammatory cytokines and oxidative stress. Curcumin may be beneficial for the treatment of muscle atrophy in type1 diabetes mellitus.
Skeletal muscle atrophy develops in patients with diabetes mellitus (DM), especially in type1 DM, which is associated with chronic inflammation. Curcumin, the active ingredient of turmeric, has various biological actions, including anti-inflammatory and antioxidant properties. We hypothesized that curcumin could ameliorate skeletal muscle atrophy in mice with streptozotocin-induced type1 DM. C57BL/6J mice were injected with streptozotocin (200mgkg(-1) i.p.; DM group) or vehicle (control group). Each group of mice was randomly subdivided into two groups of 10 mice each and fed a diet with or without curcumin (1500mgkg(-1)day(-1)) for 2weeks. There were significant decreases in body weight, skeletal muscle weight and cellular cross-sectional area of the skeletal muscle in DM mice compared with control mice, and these changes were significantly attenuated in DM+Curcumin mice without affecting plasma glucose and insulin concentrations. Ubiquitination of protein was increased in skeletal muscle from DM mice and decreased in DM+Curcumin mice. Gene expressions of muscle-specific ubiquitin E3 ligase atrogin-1/MAFbx and MuRF1 were increased in DM and inhibited in DM+Curcumin mice. Moreover, nuclear factor-B activation, concentrations of the inflammatory cytokines tumour necrosis factor- and interleukin-1 and oxidative stress were increased in the skeletal muscle from DM mice and inhibited in DM+Curcumin mice. Curcumin ameliorated skeletal muscle atrophy in DM mice by inhibiting protein ubiquitination, inflammatory cytokines and oxidative stress. Curcumin may be beneficial for the treatment of muscle atrophy in type1 DM..
38. Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takashi Yokota, Shouji Matsushima, Takahiro Abe, Tadashi Suga, Shingo Takada, Tomoyasu Kadoguchi, Ryoichi Katsuyama, Koji Oba, Koichi Okita, Hiroyuki Tsutsui, Decreased serum brain-derived neurotrophic factor levels are correlated with exercise intolerance in patients with heart failure., International journal of cardiology, 10.1016/j.ijcard.2013.08.073, 168, 5, e142-4-4, 2013.10.
39. Kadoguchi T, Takada S, Yokota T, Furihata T, Matsumoto J, Tsuda M, Mizushima W, Fukushima A, Okita K, Kinugawa S, Deletion of NAD(P)H Oxidase 2 Prevents Angiotensin II-Induced Skeletal Muscle Atrophy, Biomed Res Int, 10.1155/2018/3194917, 2018, 3194917-3194917, 2018.01.
40. Miyauchi H, Hashimoto C, Ikeda Y, Li M, Nakano Y, Kozawa J, Sai E, Nagasawa Y, Kinugawa S, Kawaguchi K, Shimada K, Ide T, Amano T, Higashi M, Inaba T, Nakamura H, Kobayashi K, Hirano K, Diagnostic criteria and severity score for triglyceraide deposit cardiomyovasculopathy, Ann Nucl Cardiol, 4, 1, 94-100, 2018.01.
41. Shingo Takada, Yoshihiro Masaki, Shintaro Kinugawa, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Masashige Takahashi, Shinichi Harashima, Shouji Matsushima, Takashi Yokota, Shinya Tanaka, Koichi Okita, Hiroyuki Tsutsui, Dipeptidyl peptidase-4 inhibitor improved exercise capacity and mitochondrial biogenesis in mice with heart failure via activation of glucagon-like peptide-1 receptor signalling, CARDIOVASCULAR RESEARCH, 10.1093/cvr/cvw182, 111, 4, 338-347, 2016.09, Aims Exercise capacity is reduced in heart failure (HF) patients, due mostly to skeletal muscle abnormalities including impaired energy metabolism, mitochondrial dysfunction, fibre type transition, and atrophy. Glucagon-like peptide-1 (GLP-1) has been shown to improve exercise capacity in HF patients. We investigated the effects of the administration of a dipeptidyl peptidase (DPP)-4 inhibitor on the exercise capacity and skeletal muscle abnormalities in an HF mouse model after myocardial infarction (MI).
Methods and resultsMI was created in male C57BL/6J mice by ligating the left coronary artery, and a sham operation was performed in other mice. The mice were then divided into two groups according to the treatment with or without a DPP-4 inhibitor, MK-0626 [1 mg/kg body weight (BW)/day] provided in the diet. Four weeks later, the exercise capacity evaluated by treadmill test was revealed to be limited in the MI mice, and it was ameliorated in the MI + MK-0626 group without affecting the infarct size or cardiac function. The citrate synthase activity, mitochondrial oxidative phosphorylation capacity, supercomplex formation, and their quantity were reduced in the skeletal muscle from the MI mice, and these decreases were normalized in the MI + MK-0626 group, in association with the improvement of mitochondrial biogenesis. Immunohistochemical staining also revealed that a shift toward the fast-twitch fibre type in the MI mice was also reversed by MK-0626. Favourable effects of MK-0626 were significantly inhibited by treatment of GLP-1 antagonist, Exendin-(9-39) (150 pmol/kg BW/min, subcutaneous osmotic pumps) in MI + MK-0626 mice. Similarly, exercise capacity and mitochondrial function were significantly improved by treatment of GLP-1 agonist, Exendin-4 (1 nmol/kg/BW/h, subcutaneous osmotic pumps).
ConclusionsaEuro integral A DPP-4 inhibitor may be a novel therapeutic agent against the exercise intolerance seen in HF patients by improving the mitochondrial biogenesis in their skeletal muscle..
42. Ide T, Tsutsui H, Kinugawa S, Suematsu N, Hayashidani S, Ichikawa K, Utsumi H, Machida Y, Egashira K, Takeshita A, Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium, Circ Res, 86, 2, 152-157, 2000.01.
43. Arata Fukushima, Shintaro Kinugawa, Shingo Takada, Junichi Matsumoto, Takaaki Furihata, Wataru Mizushima, Masaya Tsuda, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice, EUROPEAN JOURNAL OF PHARMACOLOGY, 10.1016/j.ejphar.2016.03.022, 779, 147-156, 2016.05, Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham operation (Sham, n=10), sham-operation and aliskiren (Sham +Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI +Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14 + 5% vs. 36 + 2%), and was ameliorated in MI +Aliskiren (34 + 5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI +Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI +Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress. (C) 2016 Elsevier B.V. All rights reserved..
44. Miyuki Tsuchihashi-Makaya, Tomoo Furumoto, Shintaro Kinugawa, Sanae Hamaguchi, Kazutomo Goto, Daisuke Goto, Satoshi Yamada, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui, Discharge use of angiotensin receptor blockers provides comparable effects with angiotensin-converting enzyme inhibitors on outcomes in patients hospitalized for heart failure, HYPERTENSION RESEARCH, 10.1038/hr.2009.199, 33, 3, 197-202, 2010.03, Large-scale, placebo-controlled, randomized clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduce mortality and hospitalization in patients with heart failure (HF) caused by left ventricular systolic dysfunction (LVSD). However, it is unknown whether ACE inhibitors and ARBs have similar effects on the long-term outcomes in HF patients encountered in routine clinical practice. The Japanese Cardiac Registry of Heart Failure in Cardiology enrolled HF patients hospitalized with worsening symptoms and they were followed during an average of 2.2 years. The outcome data were compared in patients with LVSD by echocardiography (ejection fraction, EF <40%) according to the predischarge use of ACE inhibitors (n=356) or ARBs (n=372). The clinical characteristics were similar between patients with ACE inhibitor and ARB use, except for higher prevalence of hypertensive etiology and diabetes mellitus. There was no significant difference between ACE inhibitor and ARB use in all-cause death (adjusted hazard ratio 0.958, 95% confidence interval 0.601-1.527, P=0.858) and rehospitalization (adjusted hazard ratio 0.964, 95% confidence interval 0.683-1.362, P=0.836). The effects of ACE inhibitor and ARB use on the outcomes were generally consistent across all clinically relevant subgroups examined, including age, sex, etiology, EF, hypertension, diabetes mellitus, and beta-blocker use. Discharge use of ARBs provided comparable effects with ACE inhibitors on outcomes in patients hospitalized for HF. These findings provide further support for guideline recommendations that ARBs can be used in patients with HF and LVSD as an alternative of ACE inhibitors. Hypertension Research (2010) 33, 197-202; doi:10.1038/hr.2009.199; published online 4 December 2009.
45. Tadashi Suga, Koichi Okita, Noriteru Morita, Takashi Yokota, Kagami Hirabayashi, Masahiro Horiuchi, Shingo Takada, Masashi Omokawa, Shintaro Kinugawa, Hiroyuki Tsutsui, Dose effect on intramuscular metabolic stress during low-intensity resistance exercise with blood flow restriction, JOURNAL OF APPLIED PHYSIOLOGY, 10.1152/japplphysiol.00504.2009, 108, 6, 1563-1567, 2010.06, Suga T, Okita K, Morita N, Yokota T, Hirabayashi K, Horiuchi M, Takada S, Omokawa M, Kinugawa S, Tsutsui H. Dose effect on intramuscular metabolic stress during low-intensity resistance exercise with blood flow restriction. J Appl Physiol 108: 1563-1567, 2010. First published April 1, 2010; doi:10.1152/japplphysiol.00504.2009.-Our previous study reported that metabolic stress in skeletal muscle achieved by combining moderate blood flow restriction (BFR) with low-intensity resistance exercise at 20% of one repetition maximum (1 RM) could not reach the level achieved by high-intensity resistance exercise. Since the previous protocol is typical of current regimens of this type, we sought in this study to optimize the exercise protocol for low-intensity resistance exercise with BFR by examining the dose effects of exercise intensity and pressure. Twelve healthy subjects participated in this study. They were asked to perform unilateral plantar flexion for 2 min (30 repetitions/min) under six different conditions: two resistance exercises (20% 1 RM and 65% 1 RM) without BFR, and four BFR protocols. The four BFR protocols included three different exercise intensities (20, 30, and 40% 1 RM) with moderate pressure (MP) using 130% of systolic blood pressure (147 +/- 17 mmHg, mean +/- SD) and 20% 1 RM with high pressure at 200 mmHg. Intramuscular metabolites and pH were obtained by P-31-magnetic resonance spectroscopy. Significant dose effects on intramuscular metabolites and pH were observed for exercise intensity (P < 0.001) but not for BFR pressure. The BFR protocol combining 30% 1 RM with MP had similar results as the high-intensity load at 65% 1 RM. Intramuscular metabolic stress during BFR exercise might be susceptible to increasing exercise intensity. To replace high-intensity resistance exercise, the BFR protocol might require an intensity of >= 30% 1 RM..
46. Tadashi Suga, Koichi Okita, Shingo Takada, Masashi Omokawa, Tomoyasu Kadoguchi, Takashi Yokota, Kagami Hirabayashi, Masashige Takahashi, Noriteru Morita, Masahiro Horiuchi, Shintaro Kinugawa, Hiroyuki Tsutsui, Effect of multiple set on intramuscular metabolic stress during low-intensity resistance exercise with blood flow restriction, EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY, 10.1007/s00421-012-2377-x, 112, 11, 3915-3920, 2012.11, Our previous study reported that intramuscular metabolic stress during low-intensity resistance exercise was significantly enhanced by combining blood flow restriction (BFR); however, they did not reach the levels achieved during high-intensity resistance exercise. That study was performed using a single set of exercise; however, usual resistance exercise consists of multiple sets with rest intervals. Therefore, we investigated the intramuscular metabolic stress during multiple-set BFR exercises, and compared the results with those during multiple-set high-intensity resistance exercise. Twelve healthy young subjects performed 3 sets of 1-min unilateral plantar flexion (30 repetitions) with 1-min intervals under 4 different conditions: low intensity (L, 20 % 1 RM) and high intensity (H, 65 % 1 RM) without BFR, and L with intermittent BFR (IBFR, only during exercise) and with continuous BFR (CBFR, during rest intervals as well as exercise). Intramuscular metabolic stress, defined as intramuscular metabolites and pH, and muscle fiber recruitment were evaluated by P-31-magnetic resonance spectroscopy. The changes of intramuscular metabolites and pH during IBFR were significantly greater than those in L but significantly lower than those in H. By contrast, those changes in CBFR were similar to those in H. Moreover, the fast-twitch fiber recruitment, evaluating by a splitting Pi peak, showed a similar level to H. In conclusion, the multiple sets of low-intensity resistance exercise with continuous BFR could achieve with the same metabolic stress as multiple sets of high-intensity resistance exercise..
47. Tsutsui H, Ide T, Hayashidani S, Kinugawa S, Suematsu N, Utsumi H, Takeshita A, Effects of ACE inhibition on left ventricular failure and oxidative stress in Dahl salt-sensitive rats, J Cardiovasc Pharmacol, 37, 6, 725-733, 2001.06.
48. Horiuchi M, Okita K, Takada S, Omokawa M, Suga T, Morita N, Hirabayashi K, Yokota T, Kinguawa S, Tsutsui H, Effects of oral single-dose administration of sarpogrelate hydrochloride on saturation o2 of calf muscle during plantar flexion exercise, Adv Exp Med Biol, 662, 531-536, 2010.10.
49. Sanae Hamaguchi, Hisashi Yokoshiki, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Takashi Yokota, Akira Takeshita, Hiroyuki Tsutsui, Effects of Atrial Fibrillation on Long-Term Outcomes in Patients Hospitalized for Heart Failure in Japan - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), CIRCULATION JOURNAL, 10.1253/circj.CJ-09-0316, 73, 11, 2084-2090, 2009.11, Background: Atrial fibrillation (AF) is a common arrhythmia in patients with heart failure (HF), but its prognostic importance is controversial. The effect of AF on long-term outcomes, including mortality and rehospitilization, among unselected HF patients hospitalized with HF in routine clinical practice in Japan was assessed in the present study.
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatment strategies of a broad sample of patients hospitalized with worsening HF and the outcomes were followed with an average of 2.4 years of follow-tip The Study cohort (n=2,659) was according to the presence (n=937; 35.2%) or absence (n=1,71.2, 64.8%) of AF at baseline. After multivariable adjustment, patients with and without AF had a comparable risk for all-cause death (adjusted hazard ratio (HR) 0.931, 95% confidence interval (CI) 0.690-1.259. P=0.643), cardiac death (adjusted HR 0.949, 95%CI 0.655-1.377. P=0.784). rehospitalization because of the worsening HF (adjusted HR 1.028, 95%CI 0.816-1.295. P=0.816), and all-cause death or rehospitalization (adjusted HR 1.039, 95%CI 0.842-1.281, P=0.721).
Conclusions: Among patients hospitalized for HF in Japan, AF was common. but was not all independent risk for long-term adverse outcomes, including death or rehospitalization. in routine clinical practice. (Circ J 2009: 73: 2084-2090).
50. Elucidation of the Strongest Predictors of Cardiovascular Events in Patients with Heart Failure..
51. Nambu H, Takada S, Fukushima A, Matsumoto J, Kakutani N, Maekawa S, Shirakawa R, Nakano I, Furihata T, Katayama T, Yamanashi K, Obata Y, Saito A, Yokota T, Kinugawa S, Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure., European journal of pharmacology, 10.1016/j.ejphar.2019.172810, 866, 172810-172810, 2020.01.
52. Igarashi-Saito K, Tsutsui H, Takahashi M, Kinugawa S, Egashira K, Takeshita A, Endocardial versus epicardial differences of sarcoplasmic reticulum Ca2+-ATPase gene expression in the canine failing myocardium, Basic Res Cardiol, 94, 4, 267-273, 1999.04.
53. Nakano I, Hori H, Fukushima A, Yokota T, Kinugawa S, Takada S, Yamanashi K, Obata Y, Kitaura Y, Kakutani N, Abe T, Anzai T, Enhanced Echo Intensity of Skeletal Muscle Is Associated With Exercise Intolerance in Patients With Heart Failure., Journal of cardiac failure, 10.1016/j.cardfail.2019.09.001, 26, 8, 685-693, 2019.09.
54. Koichi Okita, Shintaro Kinugawa, Hiroyuki Tsutsui, Exercise Intolerance in Chronic Heart Failure - Skeletal Muscle Dysfunction and Potential Therapies, CIRCULATION JOURNAL, 10.1253/circj.CJ-12-1235, 77, 2, 293-300, 2013.02, Chronic heart failure (CHF) is characterized as a clinical disorder displaying exercise intolerance; patients typically complain of early muscular fatigue. Previously, it was thought to be simply a failure of perfusion to the exercising musculature and consequent early onset of intramuscular acidosis in CHF. However, improved hemodynamics by cardiotonic agents did not lead to an increase. in exercise tolerance. Later studies have shown that intrinsic skeletal muscle abnormalities exist in patients with CHF and could induce the early anaerobic metabolism that limits exercise tolerance. We review the clinical importance of skeletal muscle abnormalities in patients with CHF. Considering the significance of peripheral muscle abnormalities and their development might help physicians and researchers better understand the mechanisms of well-established exercise training and pharmacological therapies that have been shown to improve the prognosis for CHF, and thus develop potential novel therapies. (Circ J 2013; 77: 293-300).
55. Mayumi Yamato, Takeshi Shiba, Masayoshi Yoshida, Tomomi Ide, Naoko Seri, Wataru Kudou, Shintaro Kinugawa, Hiroyuki Tsutsui, Fatty acids increase the circulating levels of oxidative stress factors in mice with diet-induced obesity via redox changes of albumin, FEBS JOURNAL, 10.1111/j.1742-4658.2007.05914.x, 274, 15, 3855-3863, 2007.08, Plasma concentrations of free fatty acids are increased in metabolic syndrome, and the increased fatty acids may cause cellular damage via the induction of oxidative stress. The present study was designed to determine whether the increase in fatty acids can modify the free sulfhydryl group in position 34 of albumin (Cys34) and enhance the redox-cycling activity of the copper-albumin complex in high-fat diet-induced obese mice. The mice were fed with commercial normal diet or high-fat diet. and water ad libitum for 3 months. The high-fat diet-fed mice developed obesity, hyperlipemia, and hyperglycemia. The plasma fatty acid/albumin ratio also significantly increased in high-fat diet-fed mice. The increased fatty acid/albumin ratio was associated with conformational changes in albumin and the oxidation of sulfhydryl groups. Moreover, an ascorbic acid radical, an index of redox-cycling activity of the copper-albumin complex, was detected only in the plasma from obese mice, whereas the plasma concentrations of ascorbic acid were not altered. Plasma thiobarbituric acid reactive substances were significantly increased in the high-fat diet group. These results indicate that the increased plasma fatty acids in the high-fat diet group resulted in the activated redox cycling of the copper albumin complex and excessive lipid peroxidation..
56. S Hayashidani, H Tsutsui, T Shiomi, N Suematsu, S Kinugawa, T Ide, J Wen, A Takeshita, Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction, CIRCULATION, 10.1161/hc0702.104164, 105, 7, 868-873, 2002.02, Background-Short-term administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to attenuate ischemia-reperfusion injury. However, the effect, of long-term administration of statins on left ventricular (LV) remodeling and failure after myocardial infarction remain unknown.
Methods and Results-Mice were subjected to coronary artery ligation and were treated for 4 weeks with vehicle or fluvastatin (10 mg/kg per day PO). Fluvastatin increased survival (61% versus 86%; P<0.05) without affecting the infarct size (52+/-2% versus 49+/-3%; P=NS). Fluvastatin not only attenuated LV dilatation but also decreased LV end-diastolic pressure and lung weight. Furthermore, it reduced cardiac myocyte hypertrophy and interstitial fibrosis of the noninfarcted LV and also improved LV ejection performance. LV matrix metalloproteinase (MMP)-2 and MMP-13 were increased in myocardial infarction, which was attenuated in fluvastatin-treated mice.
Conclusions-Fluvastatin increased survival in a murine model of postinfarct heart failure, which was associated with the amelioration of LV structural remodeling and contractile failure. Moreover, these effects were associated with the attenuation of increased MMP activity. Thus, long-term treatment with fluvastatin might be beneficial also in patients with heart failure and might improve their long-term survival..
57. Matsushima S, Kuroda J, Zhai P, Liu T, Ikeda S, Nagarajan N, Oka S, Yokota T, Kinugawa S, Hsu CP, Li H, Tsutsui H, Sadoshima J, Fyn is a physiological regulator of Nox4 in the heart, J Clin Invest, 126, 9, 3403-3416, 2016.09.
58. Kadoguchi T, Horiuchi M, Kinugawa S, Okita K, Heterogeneity in the vasodilatory function of individual extremities, Vascular, doi: 10.1177/1708538119868411, 2019.08.
59. Mayumi Yamato, Takeshi Shiba, Tomomi Ide, Naoko Seri, Wataru Kudo, Makoto Ando, Ken-ichi Yamada, Shintaro Kinugawa, Hiroyuki Tsutsui, High-fat diet-induced obesity and insulin resistance were ameliorated via enhanced fecal bile acid excretion in tumor necrosis factor-alpha receptor knockout mice, MOLECULAR AND CELLULAR BIOCHEMISTRY, 10.1007/s11010-011-1010-3, 359, 1-2, 161-167, 2012.01, Tumor necrosis factor-alpha (TNF-alpha) is one of the main mediators of inflammatory response activated by fatty acids in obesity, and this signaling through TNF-alpha receptor (TNFR) is responsible for obesity-associated insulin resistance. Recently, TNF-alpha has shown to affect lipid metabolism including the regulation of lipase activity and bile acid synthesis. However, there is scanty in vivo evidence for the involvement of TNF-alpha in this process, and the mechanistic role of TNFR remains unclear. In this study, TNFR2 knockout mice (R2KO) and wild-type (WT) mice were fed commercial normal diet (ND) or high-fat diet (HFD) for 8 weeks. In R2KO/HFD mice, the increase in body weight and the accumulation of fat were significantly ameliorated compared with WT/HFD mice in association with the decrease in plasma total cholesterol (137.7 +/- A 3.1 vs. 98.6 +/- A 3.1 mg/dL, P < 0.005), glucose (221.9 +/- A 14.7 vs. 167.3 +/- A 8.1 mg/dL, P < 0.01), and insulin (5.1 +/- A 0.3 vs. 3.4 +/- A 0.3 ng/mL, P < 0.05). Fecal excretion of lipid contents was significantly increased in R2KO mice. In R2KO/HFD mice, the decrease in hepatic cholesterol-7a-hydroxylase activity, the rate-limiting enzyme in bile acid synthesis, was inhibited (1.7 +/- A 0.2 vs. 8.1 +/- A 1.0 pmol/min/mg protein, P < 0.01). These results suggested that HFD-induced obesity with metabolic derangements could be ameliorated in mice lacking TNF-alpha receptor 2 via increasing fecal bile acid and lipid content excretion. Therefore, TNF-alpha signaling through TNFR2 is essentially involved in the bile acid synthesis and excretion of lipids, resulting in its beneficial effects..
60. Miyuki Tsuchihashi-Makaya, Hisashi Matsuo, Shigeo Kakinoki, Shigeru Takechi, Shintaro Kinugawa, Hiroyuki Tsutsui, Home-Based Disease Management Program to Improve Psychological Status in Patients With Heart Failure in Japan, CIRCULATION JOURNAL, 10.1253/circj.CJ-13-0115, 77, 4, 926-933, 2013.04, Background: A disease management program can reduce mortality and rehospitalization of patients with heart failure (HF), but little is known about whether it can improve psychological status. The purpose of this study was to determine the effects of home-based disease management on the psychological status of patients with HF.
Methods and Results: We randomly assigned patients hospitalized for HF to undergo either home-based disease management (n=79) or usual care (n=82). The mean age of the study patients was 76 years, 30% were female, and 93% were in NYHA class I or II. Home-based disease management was delivered by nurses via home visit and telephone follow-up to monitor symptoms and body weight and to educate patients. The primary endpoint was psychological status, including depression and anxiety assessed by the Hospital Anxiety and Depression Scale during follow-up of 1 year. Secondary endpoints included quality of life, all-cause death and hospitalization for HF. The intervention group had significantly lower depression (P=0.043) and anxiety (P=0.029) scores than the usual-care group. There were no significant differences in all-cause death [hazard ratio (HR) 1.02, 95% confidence interval (Cl) 0.37-2.61, P=0.967]. However, hospitalization for HF was significantly lower in the intervention group than in the usual-care group (HR 0.52, 95% Cl 0.27-0.96, P=0.037).
Conclusions: Home-based disease management improved psychological status and also reduced rehospitalization for HF in patients with HF. (Circ J 2013; 77: 926-933).
61. Nobuhiro Suematsu, Caroline Ojaimi, Shintaro Kinugawa, Zipping Wang, Xiaobin Xu, Akos Koller, Fabio A. Recchia, Thomas H. Hintze, Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric oxide bioavailability through oxidative stress, CIRCULATION, 10.1161/CIRCULATIONHA.106.652693, 115, 2, 255-262, 2007.01, Background - Hyperhomocysteinemia ( HHcy) has been considered a vascular disease associated with increased levels of oxidative stress that results in scavenging of NO. However, little is known of the impact of HHcy on cardiac function and especially myocardial metabolism.
Methods and Results - L-Homocysteine was intravenously infused into conscious dogs, and the dogs were fed methionine to increase plasma homocysteine to 10 mu mol/L for acute and 24 mu mol/L for chronic HHcy. There was no significant change in hemodynamics with HHcy. Veratrine-induced, NO-dependent, coronary vasodilation ( Bezold-Jarisch reflex) was reduced by 32% but was restored by simultaneous intravenous infusion of ascorbic acid or apocynin. Acute and chronic HHcy significantly increased uptake of glucose and lactate and decreased uptake of free fatty acid by the heart. HHcy significantly decreased bradykinin- or carbachol- induced reduction of myocardial oxygen consumption in vitro, and this effect was completely restored by coincubation with ascorbic acid, Tempol, or apocynin. Western blot analysis indicated an increase in Nox2 ( 82%) and a reduction in endothelial nitric oxide synthase ( 39%), phospho-endothelial nitric oxide synthase ( 39%), and superoxide dismutase-1 ( 45%). Microarray analysis of gene expression in heart tissue from chronic HHcy indicated a switch in cardiac phenotype to enzymes that metabolize glucose.
Conclusions - HHcy directly modulates substrate use by the heart independent of changes in hemodynamics or ventricular function by reducing NO bioavailability through the generation of superoxide. The progression of cardiac or coronary heart disease associated with HHcy should be evaluated in light of the impact of alterations in the regulation of cardiac metabolism and substrate use..
62. Sanae Hamaguchi, Tomoo Furumoto, Miyuki Tsuchihashi-Makaya, Kazutomo Goto, Daisuke Goto, Takashi Yokota, Shintaro Kinugawa, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui, Hyperuricemia predicts adverse outcomes in patients with heart failure, INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2010.05.002, 151, 2, 143-147, 2011.09, Background: Hyperuricemia is associated with worse outcomes of patients with chronic heart failure (HF). However, it is unknown in an unselected HF patients encountered in routine clinical practice. We thus assessed the impact of hyperuricemia on long-term outcomes including mortality and rehospitalization among patients hospitalized with worsening HF.
Methods: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of hospitalized HF patients and the outcomes were followed for 2.1 years after discharge. Study cohorts (n=1869) were divided into 2 groups according to serum uric acid (UA) at discharge; >= 7.4 mg/dL (n=908) and <7.4 mg/dL (n=961).
Results: Of the total cohort of HF patients, 56% had hyperuricemia defined as UA >= 7.0 mg/dl. Patients with UA >= 7.4 mg/dL had higher rates of all-cause death, cardiac death, rehospitalization, and all-cause death or rehospitalization due to worsening HF. After multivariable adjustment, higher UA levels were a significant and independent predictor for all-cause death (adjusted hazard ratio [HR] 1.413, 95% confidence interval [CI] 1.094-1.824, P=0.008) and cardiac death (adjusted HR 1.399, 95% CI 1.020-1.920, P=0.037).
Conclusions: Hyperuricemia was common in patients with HF encountered in clinical practice and higher UA was independently associated with long-term adverse outcomes in these patients. (C) 2010 Elsevier Ireland Ltd. All rights reserved..
63. Hyponatremia as a surrogate marker for optimal diuretic selection in acute heart failure..
64. Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Shouji Matsushima, Mamoru Sakakibara, Naoki Ishimori, Daisuke Goto, Hiroyuki Tsutsui, Hyponatremia is an independent predictor of adverse clinical outcomes in hospitalized patients due to worsening heart failure, JOURNAL OF CARDIOLOGY, 10.1016/j.jjcc.2013.07.012, 63, 3-4, 182-188, 2014.03, Background and purpose: Hyponatremia is common and is associated with poor in-hospital outcomes in patients hospitalized with heart failure (HF). However, it is unknown whether hyponatremia is associated with long-term adverse outcomes. The purpose of this study was to clarify the characteristics, clinical status on admission, and management during hospitalization according to the serum sodium concentration on admission, and determine whether hyponatremia was associated with in-hospital as well as long-term outcomes in 1677 patients hospitalized with worsening HF on index hospitalization registered in the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD).
Methods and subjects: We studied the characteristics and in-hospital treatment in 1659 patients hospitalized with worsening HF by using the JCARE-CARD database. Patients were divided into 2 groups according to serum sodium concentration on admission < 135 mEq/mL (n= 176; 10.6%) or >= 135 mEq/mL (n = 1483; 89.4%).
Results: The mean age was 70.7 years and 59.2% were male. Etiology was ischemic in 33.9% and mean left ventricular ejection fraction was 42.4%. After adjustment for covariates, hyponatremia was independently associated with in-hospital death [adjusted odds ratio (OR) 2.453, 95% confidence interval (CI) 1.265-4.755, p = 0.008]. It was significantly associated also with adverse long-term (mean 2.1 +/- 0.8 years) outcomes including all-cause death (OR 1.952, 95% CI 1.433-2.657), cardiac death (OR 2.053, 95% CI 1.413-2.983), and rehospitalization due to worsening HF (OR 1.488,95% CI 1.134-1.953).
Conclusions: Hyponatremia was independently associated with not only in-hospital but also long-term adverse outcomes in patients hospitalized with worsening HF. (C) 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved..
65. Kakutani N, Fukushima A, Yokota T, Katayama T, Nambu H, Shirakawa R, Maekawa S, Abe T, Takada S, Furihata T, Ono K, Okita K, Kinugawa S, Anzai T, Impact of High Respiratory Exchange Ratio During Submaximal Exercise on Adverse Clinical Outcome in Heart Failure, Circ J, 2018.08.
66. Nakajima T, Yokota T, Shingu Y, Yamada A, Iba Y, Ujihira K, Wakasa S, Ooka T, Takada S, Shirakawa R, Katayama T, Furihata T, Fukushima A, Matsuoka R, Nishihara H, Dela F, Nakanishi K, Matsui Y, Kinugawa S, Impaired mitochondrial oxidative phosphorylation capacity in epicardial adipose tissue is associated with decreased concentration of adiponectin and severity of coronary atherosclerosis., Scientific reports, 10.1038/s41598-019-40419-7, 9, 1, 3535-3535, 2019.03.
67. Shouji Matsushima, Shintaro Kinugawa, Takashi Yokota, Naoki Inoue, Yukihiro Ohta, Sanae Hamaguchi, Hiroyuki Tsutsui, Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.01332.2008, 297, 1, H409-H416, 2009.07, Matsushima S, Kinugawa S, Yokota T, Inoue N, Ohta Y, Hamaguchi S, Tsutsui H. Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes. Am J Physiol Heart Circ Physiol 297: H409-H416, 2009. First published May 22, 2009; doi: 10.1152/ajpheart.01332.2008.-Type 2 diabetes adversely affects the outcomes in patients with myocardial infarction (MI), which is associated with the development of left ventricular (LV) failure. NAD(P)H oxidase-derived superoxide (O(2)(-)) production is increased in type 2 diabetes. However, its pathophysiological significance in advanced post-MI LV failure associated with type 2 diabetes remains unestablished. We thus hypothesized that an inhibitor of NAD(P)H oxidase activation, apocynin, could attenuate the exacerbated LV failure after MI in high-fat diet (HFD)-induced obese mice with type 2 diabetes. Male C57BL/6J mice were fed on either HFD or normal diet (ND) for 8 wk. At 4 wk of feeding, MI was created in mice by ligating the left coronary artery. HFD-fed MI mice were treated with either 10 mmol/l apocynin or vehicle. HFD + MI had significantly greater LV end-diastolic diameter (LVEDD; 5.7 +/- 0.1 vs. 5.3 +/- 0.2 mm), end-diastolic pressure (12 +/- 2 vs. 8 +/- 1 mmHg), and lung weight/tibial length (10.1 +/- 0.3 vs. 8.7 +/- 0.7 mg/mm) than ND + MI, which was accompanied by an increased interstitial fibrosis of non-infarcted LV. Treatment of HFD (MI with apocynin significantly decreased LVEDD (5.4 +/- 0.1 mm), LV end-diastolic pressure (9.7 +/- 0.8 mmHg), lung weight/tibial length (9.0 +/- 0.3 mg/mm), and concomitantly interstitial fibrosis of noninfarcted LV to the ND + MI level without affecting body weight, glucose metabolism, and infarct size. NAD(P)H oxidase activity and O(2)(-) (production were increased in noninfarcted LV tissues from HFD + MI, both of which were attenuated by apocynin to the ND + MI level. Type 2 diabetes was associated with the exacerbation of LV failure after MI via increasing NAD(P)H oxidase-derived O(2)(-), which may be a novel important therapeutic target in advanced heart failure with diabetes..
68. Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takahiro Abe, Tadashi Suga, Shingo Takada, Tomoyasu Kadoguchi, Koichi Okita, Shouji Matsushima, Hiroyuki Tsutsui, Increased plasma soluble (pro)renin receptor levels are correlated with renal dysfunction in patients with heart failure, INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2013.04.176, 168, 4, 4313-4314, 2013.10.
69. Hideo Nambu, Shingo Takada, Satoshi Maekawa, Junichi Matsumoto, Naoya Kakutani, Takaaki Furihata, Ryosuke Shirakawa, Takashi Katayama, Takayuki Nakajima, Katsuma Yamanashi, Yoshikuni Obata, Ippei Nakano, Masaya Tsuda, Akimichi Saito, Arata Fukushima, Takashi Yokota, Junko Nio-Kobayashi, Hironobu Yasui, Kei Higashikawa, Yuji Kuge, Toshihisa Anzai, Hisataka Sabe, Shintaro Kinugawa, Inhibition of xanthine oxidase in the acute phase of myocardial infarction prevents skeletal muscle abnormalities and exercise intolerance., Cardiovascular research, 10.1093/cvr/cvaa127, 117, 3, 805-819, 2020.05, AIMS: Exercise intolerance in patients with heart failure (HF) is partly attributed to skeletal muscle abnormalities. We have shown that reactive oxygen species (ROS) play a crucial role in skeletal muscle abnormalities, but the pathogenic mechanism remains unclear. Xanthine oxidase (XO) is reported to be an important mediator of ROS overproduction in ischemic tissue. Here we tested the hypothesis that skeletal muscle abnormalities in HF are initially caused by XO-derived ROS and are prevented by the inhibition of their production. METHODS AND RESULTS: Myocardial infarction (MI) was induced in male C57BL/6J mice, which eventually led to HF, and a sham operation was performed in control mice. The time course of XO-derived ROS production in mouse skeletal muscle post-MI was first analyzed. XO-derived ROS production was significantly increased in MI mice from days 1 to 3 postsurgery (acute phase), whereas it did not differ between the MI and sham groups from 7 to 28 days (chronic phase). Second, mice were divided into three groups: sham+vehicle (Sham+Veh), MI+vehicle (MI+Veh), and MI+febuxostat (an XO inhibitor, 5 mg/kg body weight/day; MI+Feb). Febuxostat or vehicle was administered at 1 hr and 24 hr before surgery, and once-daily on days 1-7 postsurgery. On day 28 postsurgery, exercise capacity and mitochondrial respiration in skeletal muscle fibers were significantly decreased in MI+Veh compared with Sham+Veh mice. An increase in damaged mitochondria in MI+Veh compared with Sham+Veh mice was also observed. The wet weight and cross-sectional area of slow muscle fibers (higher XO-derived ROS) was reduced via the downregulation of protein synthesis-associated mTOR-p70S6K signaling in MI+Veh compared with Sham+Veh mice. These impairments were ameliorated in MI+Feb mice, in association with a reduction of XO-derived ROS production, without affecting cardiac function. CONCLUSIONS: XO inhibition during the acute phase post-MI can prevent skeletal muscle abnormalities and exercise intolerance in mice with HF. A TRANSLATIONAL PERSPECTIVE: We clearly demonstrated that febuxostat, an inhibitor of xanthine oxidase (XO), prevents exercise intolerance and skeletal muscle abnormalities (mitochondrial dysfunction and atrophy) via the suppression of XO-derived reactive oxygen species increase during hypoxia (e.g., myocardial infarction [MI]) in skeletal muscle during the early phase of heart failure (HF) model mouse. Our results shed light on the pathogenic mechanism of skeletal muscle abnormalities in HF after MI. The use of XO inhibitors requires consideration of the time course of XO activity. Our results indicate that the timing of administration is very important to achieve maximum beneficial effects when using XO inhibitors..
70. Tadashi Suga, Koichi Okita, Noriteru Morita, Takashi Yokota, Kagami Hirabayashi, Masahiro Horiuchi, Shingo Takada, Tomohiro Takahashi, Masashi Omokawa, Shintaro Kinugawa, Hiroyuki Tsutsui, Intramuscular metabolism during low-intensity resistance exercise with blood flow restriction, JOURNAL OF APPLIED PHYSIOLOGY, 10.1152/japplphysiol.90368.2008, 106, 4, 1119-1124, 2009.04, Suga T, Okita K, Morita N, Yokota T, Hirabayashi K, Horiuchi M, Takada S, Takahashi T, Omokawa M, Kinugawa S, Tsutsui H. Intramuscular metabolism during low-intensity resistance exercise with blood flow restriction. J Appl Physiol 106: 1119-1124, 2009. First published February 12, 2009; doi:10.1152/japplphysiol.90368.2008.-Although recent studies have reported that low-intensity resistance training with blood flow restriction could stress the muscle effectively and provide rapid muscle hypertrophy and strength gain equivalent to those of high-intensity resistance training, the exact mechanism and its generality have not yet been clarified. We investigated the intramuscular metabolism during low-intensity resistance exercise with blood flow restriction and compared it with that of high-intensity and low-intensity resistance exercises without blood flow restriction using P-31-magnetic resonance spectroscopy. Twenty-six healthy subjects (22 +/- 4 yr) participated and performed unilateral plantar flexion (30 repetitions/min) for 2 min. Protocols were as follows: low-intensity exercise (L) using a load of 20% of one-repetition maximum (1 RM), L with blood flow restriction (LR), and high-intensity exercise using 65% 1 RM (H). Intramuscular phosphocreatine (PCr) and diprotonated phosphate (H2PO4-) levels and intramuscular pH at rest and during exercise were obtained. We found that the PCr depletion, the H2PO4- increase, and the intramuscular pH decrease during LR were significantly greater than those in L (P < 0.001); however, those in LR were significantly lower than those in H (P < 0.001). The recruitment of fast-twitch fiber evaluated by inorganic phosphate splitting occurred in only 31% of the subjects in LR, compared with 70% in H. In conclusion, the metabolic stress in skeletal muscle during low-intensity resistance exercise was significantly increased by applying blood flow restriction, but did not generally reach that during high-intensity resistance exercise. This new method of resistance training needs to be examined for optimization of the protocol to reach equivalence with high-intensity resistance training..
71. Kagami Hirabayashi, Shintaro Kinugawa, Takashi Yokota, Shingo Takada, Arata Fukushima, Tadashi Suga, Masashige Takahashi, Taisuke Ono, Noriteru Morita, Masashi Omokawa, Kuniaki Harada, Noriko Oyama-Manabe, Hiroaki Shirato, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Intramyocellular lipid is increased in the skeletal muscle of patients with dilated cardiomyopathy with lowered exercise capacity, INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2014.07.113, 176, 3, 1110-1112, 2014.10.
72. Tsutsui H, Isobe M, Ito H, Okumura K, Ono M, Kitakaze M, Kinugawa K, Kihara Y, Goto Y, Komuro I, Saiki Y, Saito Y, Sakata Y, Sato N, Sawa Y, Shiose A, Shimizu W, Shimokawa H, Seino Y, Node K, Higo T, Hirayama A, Makaya M, Masuyama T, Murohara T, Momomura SI, Yano M, Yamazaki K, Yamamoto K, Yoshikawa T, Yoshimura M, Akiyama M, Anzai T, Ishihara S, Inomata T, Imamura T, Iwasaki YK, Ohtani T, Onishi K, Kasai T, Kato M, Kawai M, Kinugasa Y, Kinugawa S, Kuratani T, Kobayashi S, Tanaka A, Toda K, Noda T, Nochioka K, Hatano M, Hidaka T, Fujino T, Makita S, Yamaguchi O, Ikeda U, Kimura T, Kohsaka S, Kosuge M, Yamagishi M, Yamashina A, Japanese Circulation Society, the Japanese Heart Failure Society Joint, Working Group, JCS 2017/JHFS 2017 Guideline on Diagnosis and Treatment of Acute and Chronic Heart Failure - Digest Version., Circulation Journal, 10.1253/circj.CJ-19-0342, 83, 10, 2084-2184, 2019.09.
73. Hiroaki Kitaoka, Hiroyuki Tsutsui, Toru Kubo, Tomomi Ide, Taishiro Chikamori, Keiichi Fukuda, Noboru Fujino, Taiki Higo, Mitsuaki Isobe, Chizuko Kamiya, Seiya Kato, Yasuki Kihara, Koichiro Kinugawa, Shintaro Kinugawa, Shigetoyo Kogaki, Issei Komuro, Nobuhisa Hagiwara, Minoru Ono, Yuichiro Maekawa, Shigeru Makita, Yoshiro Matsui, Shouji Matsushima, Yasushi Sakata, Yoshiki Sawa, Wataru Shimizu, Kunihiko Teraoka, Miyuki Tsuchihashi-Makaya, Hatsue Ishibashi-Ueda, Masafumi Watanabe, Michihiro Yoshimura, Arata Fukusima, Satoshi Hida, Shungo Hikoso, Teruhiko Imamura, Hiroko Ishida, Makoto Kawai, Toshiro Kitagawa, Takashi Kohno, Satoshi Kurisu, Yoji Nagata, Makiko Nakamura, Hiroyuki Morita, Hitoshi Takano, Tsuyoshi Shiga, Yasuyoshi Takei, Shinsuke Yuasa, Teppei Yamamoto, Tetsu Watanabe, Takashi Akasaka, Yoshinori Doi, Takeshi Kimura, Masafumi Kitakaze, Masami Kosuge, Morimasa Takayama, Hitonobu Tomoike, JCS/JHFS 2018 Guideline on the Diagnosis and Treatment of Cardiomyopathies., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-20-0910, 85, 9, 1590-1689, 2021.08.
74. Hiroyuki Tsutsui, Tomomi Ide, Hiroshi Ito, Yasuki Kihara, Koichiro Kinugawa, Shintaro Kinugawa, Miyuki Makaya, Toyoaki Murohara, Koichi Node, Yoshihiko Saito, Yasushi Sakata, Wataru Shimizu, Kazuhiro Yamamoto, Yasuko Bando, Yu-Ki Iwasaki, Yoshiharu Kinugasa, Isamu Mizote, Hitoshi Nakagawa, Shogo Oishi, Akiko Okada, Atsushi Tanaka, Takashi Akasaka, Minoru Ono, Takeshi Kimura, Shun Kosaka, Masami Kosuge, Shin-Ichi Momomura, JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-21-0431, 2021.09.
75. Hiroyuki Tsutsui, Tomomi Ide, Hiroshi Ito, Yasuki Kihara, Koichiro Kinugawa, Shintaro Kinugawa, Miyuki Makaya, Toyoaki Murohara, Koichi Node, Yoshihiko Saito, Yasushi Sakata, Wataru Shimizu, Kazuhiro Yamamoto, Yasuko Bando, Yu-Ki Iwasaki, Yoshiharu Kinugasa, Isamu Mizote, Hitoshi Nakagawa, Shogo Oishi, Akiko Okada, Atsushi Tanaka, Takashi Akasaka, Minoru Ono, Takeshi Kimura, Shun Kosaka, Masami Kosuge, Shin-Ichi Momomura, JCS/JHFS 2021 Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure., Journal of cardiac failure, 10.1016/j.cardfail.2021.04.023, 2021.09.
76. S Kinugawa, ZP Wang, PM Kaminski, MS Wolin, JG Edwards, G Kaley, TH Hintze, Limited exercise capacity in heterozygous manganese superoxide dismutase gene-knockout mice - Roles of superoxide anion and nitric oxide, CIRCULATION, 10.1161/01.CIR.0000159261.11520.63, 111, 12, 1480-1486, 2005.03, Background - We have reported that there is a limitation of exercise capacity in mice with defects in the expression of endothelial nitric oxide ( NO) synthase, which is associated with a greater increase in whole-body oxygen consumption ((V) over dot O-2). We hypothesized that in states in which superoxide anion (O-2(-)) is increased, especially in the mitochondria, whole-body (V) over dot O-2 will be increased because of the inactivation of NO, and consequently, exercise capacity will be reduced.
Methods and Results - Heterozygous manganese superoxide anion dismutase ( SOD2) gene - knockout mice ( SOD2(+/-)), in which SOD2 activity is reduced by 30% to 80%, and wild-type control mice (SOD2(+/+)) were treadmill-tested to measure indices defining exercise capacity. Tempol was given to each mouse for 7 days by an intraperitoneal injection to scavenge O-2(-) before a second treadmill testing. (V) over dot O-2 and carbon dioxide production ((V) over dot CO2) at rest were increased in SOD2(+/-). The work ( vertical distance run x body weight) to exhaustion was decreased in SOD2(+/-). When the maximum (V) over dot O-2 and (V) over dot CO2 were corrected to per work unit, they were increased in SOD2(+/-). Tempol normalized basal (V) over dot O-2 and (V) over dot CO2 and improved the work to exhaustion and corrected (V) over dot O-2 and (V) over dot CO2 in SOD2(+/-). (V) over dot O-2 of skeletal muscle was measured in vitro. Bradykinin-induced reduction in (V) over dot O-2 in vitro was attenuated in SOD2(+/-), and was acutely restored by Tempol. There was a decrease in SOD2 protein level and a concomitant increase in lucigenin-detectable O-2(-) production in skeletal muscle from SOD2(+/-).
Conclusions - These results suggest that exercise capacity is reduced in conditions in which superoxide anion is increased, and this is associated with a greater increase in whole-body oxygen consumption in SOD2(+/-) compared with SOD2(+/+)..
77. Maekawa S, Takada S, Nambu H, Furihata T, Kakutani N, Setoyama D, Ueyanagi Y, Kang D, Sabe H, Kinugawa S, Linoleic acid improves assembly of the CII subunit and CIII2/CIV complex of the mitochondrial oxidative phosphorylation system in heart failure., Cell communication and signaling : CCS, 10.1186/s12964-019-0445-0, 17, 1, 128-128, 2019.10.
78. Imamura T, Kinugawa S, Muramatsu T, Shiga T, Ogimoto A, Anzai T, Hagiwara N, Tsutsui H, Komuro I, Kinugawa K, Long-term treatment of tolvaptan in refractory heart failure, Circ Rep, 1, 10, 431-437, 2019.10.
79. Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Daisuke Goto, Satoshi Yamada, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui, Loop Diuretic Use at Discharge Is Associated With Adverse Outcomes in Hospitalized Patients With Heart Failure - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), CIRCULATION JOURNAL, 10.1253/circj.CJ-11-1196, 76, 8, 1920-1927, 2012.08, Background: Loop diuretics are commonly used in patients with heart failure (HF) to remove retained fluid and improve symptoms. However, they may potentially worsen outcomes in HF. It remains unknown whether the use of loop diuretics is associated with adverse HF outcomes in routine clinical practice. We thus determined the effects of loop diuretic use at discharge on long-term mortality and rehospitalization among patients hospitalized with HF.
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatments of a broad sample of patients hospitalized with worsening HF and followed for 2.1 years. Among a total of 2,549 HF patients, loop diuretics were used by 2,015 patients (79%), but not 534 patients (21%). The mean age was 70.7 years and 60% were male. Etiology was ischemic in 32% and mean left ventricular ejection fraction was 42%. After adjustment for covariates, discharge use of loop diuretics was associated with significant adverse risks of cardiac death (adjusted hazard ratio [HR] 2.348, 95% confidence interval [Cl] 1.246-4.423, P=0.008) and rehospitalization (adjusted HR 1.427, 95% CI 1.040-1.959, P=0.027).
Conclusions: Among patients hospitalized with worsening HF, loop diuretic use at discharge was associated with long-term adverse outcomes, which suggests that routine chronic use of loop diuretics may be harmful for patients with HF. (Circ J 2012; 76: 1920-1927).
80. Ippei Nakano, Masaya Tsuda, Shintaro Kinugawa, Arata Fukushima, Naoya Kakutani, Shingo Takada, Takashi Yokota, Loop diuretic use is associated with skeletal muscle wasting in patients with heart failure., Journal of cardiology, 10.1016/j.jjcc.2020.01.003, 76, 1, 109-114, 2020.01, BACKGROUND: Loop diuretics are widely used for the management of fluid retention in patients with heart failure (HF). Sarcopenia, defined as decreased skeletal muscle mass, is frequently present in patients with HF and is associated with poor prognosis. The effects of loop diuretics on skeletal muscle in HF patients have not been fully elucidated. Here, we investigated the impact of loop diuretics on the skeletal muscle mass in patients with HF. METHODS: We conducted a subanalysis of a cross-sectional study from 10 hospitals evaluating 155 patients with HF (age 67 ± 13 yrs, 69% men). RESULTS: We compared the HF patients who were treated with loop diuretics (n = 120) with the patients who were not (n = 35). The thigh and arm circumferences were significantly small in the group treated with loop diuretics compared to those not so treated (39.9 ± 4.8 vs. 43.5 ± 6.9 cm, p < 0.001 and 26.7 ± 3.5 vs. 28.9 ± 6.2 cm, p < 0.001, respectively). In a univariate analysis, higher age, lower body mass index, lower hemoglobin, and loop diuretic use were significantly associated with smaller thigh circumference. In a multivariable analysis, the use of loop diuretics was independently associated with smaller thigh circumference (β = -0.51, 95% confidence interval -0.98 to -0.046, p = 0.032). CONCLUSION: Loop diuretics are associated with decreased thigh and arm circumferences in patients with HF, independent of the severity of HF. Our findings revealed for the first time the adverse effects of loop diuretics on skeletal muscle wasting. These findings will have a significant impact in clinical practice regarding the frequent use of loop diuretics in HF patients..
81. Masashige Takahashi, Shintaro Kinugawa, Shingo Takada, Kagami Hirabayashi, Takashi Yokota, Shouji Matsushima, Akimichi Saito, Koichi Okita, Hiroyuki Tsutsui, Low-intensity exercise under ischemic conditions enhances metabolic stress in patients with heart failure, INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2015.08.022, 201, 142-144, 2015.12.
82. Shingo Takada, Koichi Okita, Tadashi Suga, Masashi Omokawa, Tomoyasu Kadoguchi, Takashi Sato, Masashige Takahashi, Takashi Yokota, Kagami Hirabayashi, Noriteru Morita, Masahiro Horiuchi, Shintaro Kinugawa, Hiroyuki Tsutsui, Low-intensity exercise can increase muscle mass and strength proportionally to enhanced metabolic stress under ischemic conditions, JOURNAL OF APPLIED PHYSIOLOGY, 10.1152/japplphysiol.00149.2012, 113, 2, 199-205, 2012.07, Takada S, Okita K, Suga T, Omokawa M, Kadoguchi T, Sato T, Takahashi M, Yokota T, Hirabayashi K, Morita N, Horiuchi M, Kinugawa S, Tsutsui H. Low-intensity exercise can increase muscle mass and strength proportionally to enhanced metabolic stress under ischemic conditions. J Appl Physiol 113: 199-205, 2012. First published May 24, 2012; doi: 10.1152/japplphysiol.00149.2012.Skeletal muscle bulk and strength are becoming important therapeutic targets in medicine. To increase muscle mass, however, intensive, long-term mechanical stress must be applied to the muscles, and such stress is often accompanied by orthopedic and cardiovascular problems. We examined the effects of circulatory occlusion in resistance training combined with a very low-intensity mechanical load on enhancing muscular metabolic stress and thereby increasing muscle bulk. Muscular metabolic stress, as indicated by the increases in inorganic phosphate (Pi) and a decrease in intramuscular pH, was evaluated by P-31-magnetic resonance spectroscopy during unilateral plantar-flexion at 20% of the one-repetition maximum (1-RM) with circulatory occlusion for 2 min in 14 healthy, male untrained participants (22 yr) at baseline. Participants performed two sets of the same exercise with a 30-s rest between sets, 2 times/day, 3 days/wk, for 4 wk. The muscle cross-sectional area (MCA) of the plantar-flexors and the 1-RM were measured at baseline and after 2 and 4 wk of training. MCA and 1-RM were significantly increased after 2 and 4 wk (P < 0.05, respectively). The increase in MCA at 2 wk was significantly (P < 0.05) correlated with the changes in Pi (r = 0.876) and intramuscular pH (r = 0.601). Furthermore, the increases in MCA at 4 wk and 1-RM at 2 wk were also correlated with the metabolic stress. Thus enhanced metabolic stress in exercising muscle is a key mechanism for favorable effects by resistance training. Low-intensity resistance exercise provides successful outcomes when performed with circulatory occlusion, even with a short training period..
83. Takashi Yokota, Shintaro Kinugawa, Koichi Okita, Kagami Hirabayashi, Tadashi Suga, Masaaki Hattori, Yoshinao Nakagawa, Noriko Oyama-Manabe, Hiroki Shirato, Hiroyuki Tsutsui, Lower aerobic capacity was associated with abnormal intramuscular energetics in patients with metabolic syndrome, HYPERTENSION RESEARCH, 10.1038/hr.2011.78, 34, 9, 1029-1034, 2011.09, Lower aerobic capacity is a strong and independent predictor of cardiovascular morbidity and mortality in patients with metabolic syndrome (MetS). However, the mechanisms are not fully elucidated. We tested the hypothesis that skeletal muscle dysfunction could contribute to the lower aerobic capacity in MetS patients. The incremental exercise tests with cycle ergometer were performed in 12 male patients with MetS with no habitual exercise and 11 age-, sex-and activity-matched control subjects to assess the aerobic capacity. We performed (31)phosphorus-magnetic resonance spectroscopy (MRS) to assess the high-energy phosphate metabolism in skeletal muscle during aerobic exercise. Proton-MRS was also performed to measure intramyocellular lipid (IMCL) content. Peak oxygen uptake (peak VO(2); 34.1 +/- 6.2 vs. 41.4 +/- 8.4 ml kg(-1) min(-1), P < 0.05) and anaerobic threshold (AT; 18.0 +/- 2.4 vs. 23.1 +/- 3.7 ml kg(-1) min(-1), P < 0.01) adjusted by lean body mass were lower in MetS patients than control subjects. Phosphocreatine (PCr) loss during exercise was 1.5-fold greater in MetS, suggesting reduced intramuscular oxidative capacity. PCr loss was inversely correlated with peak VO(2) (r = -0.64) and AT (r = -0.60), respectively. IMCL content was threefold higher in MetS and was inversely correlated with peak VO(2) (r = -0.47) and AT (r = -0.52), respectively. Moreover, there was a positive correlation between IMCL content and PCr loss (r = 0.64). These results suggested that lean-body aerobic capacity in MetS patients was lower compared with activity-matched healthy subjects, which might be due to the reduced intramuscular fatty acid oxidative metabolism. Hypertension Research (2011) 34, 1029-1034; doi: 10.1038/hr.2011.78; published online 14 July 2011.
84. Malnutrition in Heart Failure: Important But Undervalued Issue..
85. Ide T, Tsutsui H, Kinugawa S, Ustumi H, Kang D, Hattori N, Uchida K, Arimura K, Egashira K, Takeshita A, Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium, Circ Res, 85, 4, 357-363, 1999.01.
86. Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Mitochondrial oxidative stress and dysfunction in myocardial remodelling, CARDIOVASCULAR RESEARCH, 10.1093/cvr/cvn280, 81, 3, 449-456, 2009.02, Recent experimental and clinical studies have suggested that oxidative stress is enhanced in myocardial remodelling and failure. The production of oxygen radicals is increased in the failing heart, whereas normal antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and can be a therapeutic target against oxidant-induced damage in the failing myocardium. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive myocardial remodelling and failure. Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of the genes for peroxiredoxin-3 (Prx-3), a mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM), could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in mitochondrial function was also prevented. Therefore, the activation of Prx-3 or TFAM gene expression could ameliorate the pathophysiological processes seen in mitochondrial dysfunction and myocardial remodelling. Inhibition of oxidative stress and mtDNA damage could be novel and effective treatment strategies for heart failure..
87. Hiroyuki Tsutsui, Tomomi Ide, Shintaro Kinugawa, Mitochondrial oxidative stress, DNA damage, and heart failure, ANTIOXIDANTS & REDOX SIGNALING, 10.1089/ars.2006.8.1737, 8, 9-10, 1737-1744, 2006.09, Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart, whereas antioxidant enzyme activities are preserved as normal. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target of oxidant-induced damage. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, mitochondrial oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number and preserve it at a normal level in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities was also prevented. Therefore, the activation of TFAM expression could ameliorate the pathophysiologic processes seen in myocardial failure. Inhibition of mitochondrial oxidative stress and mtDNA damage could be novel and potentially very effective treatment strategies for heart failure..
88. Mitochondrial reactive oxygen species generation in blood cells is associated with disease severity and exercise intolerance in heart failure patients..
89. Maekawa S, Takada S, Furihata T, Fukushima A, Yokota T, Kinugawa S, Mitochondrial respiration of complex II is not lower than that of complex I in mouse skeletal muscle., Biochemistry and biophysics reports, 10.1016/j.bbrep.2019.100717, 21, 100717-100717, 2020.03.
90. Sanae Hamaguchi, Shintaro Kinugawa, Mochamad Ali Sobirin, Daisuke Goto, Miyuki Tsuchihashi-Makaya, Satoshi Yamada, Hisashi Yokoshiki, Hiroyuki Tsutsui, Mode of Death in Patients With Heart Failure and Reduced vs. Preserved Ejection Fraction - Report From the Registry of Hospitalized Heart Failure Patients, CIRCULATION JOURNAL, 10.1253/circj.CJ-11-1355, 76, 7, 1662-1669, 2012.07, Background: The mode of death has not been investigated in the registry data of patients with heart failure and reduced ejection fraction (HFREF) vs. preserved ejection fraction (HFPEF). The aim of the present study was therefore to carry out this comparison.
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatments in a broad sample of 2,675 patients hospitalized with worsening HF, and followed them for an average of 2.1 years. This study included 323 patients in whom information on both the mode of death and left ventricular EF on echocardiography could be obtained. The mode of death was cardiovascular (CV) in 63% (including 17% sudden, 36% HF, 3% myocardial infarction, and 3% stroke), non-CV in 23%, and unknown in 14%. The prevalence of CV death including sudden death was high in patients with HFREF compared to HFPEF (68% vs. 58%, P=0.020). HF death, the most common mode of death, was similar between groups (37% vs. 35%, P=0.694). In contrast, non-CV mortality was significantly higher in HFPEF than those with HFREF (28% vs. 18%, P=0.021).
Conclusions: In 60-70% of deaths the mode was CV, and HF death was the most common mode of death in either HFREF or HFPEF. The prevalence of sudden death was lower, and that of non-CV death higher, in HFPEF compared with HFREF. (Circ J 2012; 76: 1662-1669).
91. Ishibashi Y, Urabe Y, Tsutsui H, Kinugawa S, Sugimachi M, Takahashi M, Yamamoto S, Tagawa H, Sunagawa K, Takeshita A, Negative inotropic effect of basic fibroblast growth factor on adult rat cardiac myocytes, Circulation, 96, 8, 2501-2504, 1997.02.
92. Shouji Matsushima, Shintaro Kinugawa, Tomomi Ide, Hidenori Matsusaka, Naoki Inoue, Yukihiro Ohta, Takashi Yokota, Kenji Sunagawa, Hiroyuki Tsutsui, Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.00427.2006, 291, 5, H2237-H2245, 2006.11, Oxidative stress plays an important role in the structural and functional abnormalities of diabetic heart. Glutathione peroxidase (GSHPx) is a critical antioxidant enzyme that removes H2O2 in both the cytosol and mitochondia. We hypothesized that the overexpression of GSHPx gene could attenuate left ventricular (LV) remodeling in diabetes mellitus (DM). We induced DM by injection of streptozotocin (160 mg/kg ip) in male GSHPx transgenic mice (TG + DM) and nontransgenic wildtype littermates (WT + DM). GSHPx activity was higher in the hearts of TG mice compared with WT mice, with no significant changes in other antioxidant enzymes. LV thiobarbituric acid-reactive substances measured in TG + DM at 8 wk were significantly lower than those in WT + DM (58 +/- 3 vs. 71 +/- 5 nmol/g, P < 0.05). Heart rate and aortic blood pressure were comparable between groups. Systolic function was preserved normal in WT + DM and TG + DM mice. In contrast, diastolic function was impaired in WT DM and was improved in TG + DM as assessed by the deceleration time of peak velocity of transmitral diastolic flow and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 13.5 +/- 1.2 vs. 8.9 +/- 0.7 ms, P < 0.01). The TG + DM values were comparable with those of WT + Control (tau; 7.8 +/- 0.2 ms). Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis, and apoptosis. Overexpression of GSHPx gene ameliorated LV remodeling and diastolic dysfunction in DM. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac abnormalities in DM..
93. Masaaki Hokari, Satoshi Kuroda, Shintaro Kinugawa, Tomomi Ide, Hiroyuki Tsutsui, Yoshinobu Iwasaki, Overexpression of mitochondrial transcription factor A (TFAM) ameliorates delayed neuronal death due to transient forebrain ischemia in mice, NEUROPATHOLOGY, 10.1111/j.1440-1789.2009.01086.x, 30, 4, 401-407, 2010.08, Mitochondrial transcription factor A (TFAM) is an important regulator to maintain mitochondrial DNA copy number. However, no studies have denoted its roles in cerebral ischemia. Therefore, this study was aimed to assess whether the forced overexpression of TFAM ameliorates delayed neuronal death following transient forebrain ischemia. We have established human TFAM-transgenic (Tg) mice. Wild type (WT) and TFAM-Tg mice were subjected to 20-min bilateral common carotid artery occlusion (BCCAO). Immunostaining against cytochrome c was performed to estimate its release from mitochondria at 24 h after 20-min BCCAO. Histological analysis was performed to evaluate the effect of TFAM overexpression on delayed neuronal death at 72 h after 20-min BCCAO. The number of cytochrome c-positive neurons in the hippocampal CA1 sector was significantly smaller in TFAM-Tg mice than in WT mice (P = 0.005). The percentage of viable neurons in the hippocampal CA1 sector was significantly higher in TFAM-Tg mice than in WT mice (P < 0.001), and the number of TUNEL-positive neurons was significantly smaller in TFAM-Tg mice than in WT mice (P < 0.001). Our data strongly suggest that TFAM overexpression can reduce mitochondrial permeability transition and ameliorate delayed neuronal death in the hippocampus after transient forebrain ischemia..
94. S Matsushima, T Ide, M Yamato, H Matsusaka, F Hattori, M Ikeuchi, T Kubota, K Sunagawa, Y Hasegawa, T Kurihara, S Oikawa, S Kinugawa, H Tsutsui, Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice, CIRCULATION, 10.1161/CIRCULATIONAHA.105.582239, 113, 14, 1779-1786, 2006.04, Background-Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process.
Methods and Results-We created MI in 12- to 16-week-old, male Prx-3-transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid-reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean +/- SEM, 1.5 +/- 0.2 vs 2.2 +/- 0.2 nmol/mg protein; n=8 each, P<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56 +/- 1% vs 55 +/- 1%; n=6 each, P=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice.
Conclusions-Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure..
95. Caroline Ojaimi, Shintaro Kinugawa, Fabio A. Recchia, Thomas H. Hintze, Oxidant-NO dependent gene regulation in dogs with type I diabetes: impact on cardiac function and metabolism, CARDIOVASCULAR DIABETOLOGY, 10.1186/1475-2840-9-43, 9, 43, 2010.08, Background: The mechanisms responsible for the cardiovascular mortality in type I diabetes (DM) have not been defined completely. We have shown in conscious dogs with DM that: 1) baseline coronary blood flow (CBF) was significantly decreased, 2) endothelium-dependent (ACh) coronary vasodilation was impaired, and 3) reflex cholinergic NO-dependent coronary vasodilation was selectively depressed. The most likely mechanism responsible for the depressed reflex cholinergic NO-dependent coronary vasodilation was the decreased bioactivity of NO from the vascular endothelium. The goal of this study was to investigate changes in cardiac gene expression in a canine model of alloxan-induced type 1 diabetes.
Methods: Mongrel dogs were chronically instrumented and the dogs were divided into two groups: one normal and the other diabetic. In the diabetic group, the dogs were injected with alloxan monohydrate (40-60 mg/kg iv) over 1 min. The global changes in cardiac gene expression in dogs with alloxan-induced diabetes were studied using Affymetrix Canine Array. Cardiac RNA was extracted from the control and DM (n = 4).
Results: The array data revealed that 797 genes were differentially expressed (P < 0.01; fold change of at least +/- 2). 150 genes were expressed at significantly greater levels in diabetic dogs and 647 were significantly reduced. There was no change in eNOS mRNA. There was up regulation of some components of the NADPH oxidase subunits (gp91 by 2.2 fold, P < 0.03), and down-regulation of SOD1 (3 fold, P < 0.001) and decrease (4 - 40 fold) in a large number of genes encoding mitochondrial enzymes. In addition, there was down-regulation of Ca(2+) cycling genes (ryanodine receptor; SERCA2 Calcium ATPase), structural proteins (actin alpha). Of particular interests are genes involved in glutathione metabolism (glutathione peroxidase 1, glutathione reductase and glutathione S-transferase), which were markedly down regulated.
Conclusion: our findings suggest that type I diabetes might have a direct effect on the heart by impairing NO bioavailability through oxidative stress and perhaps lipid peroxidases..
96. Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Oxidative stress and heart failure, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.00554.2011, 301, 6, H2181-H2190, 2011.12, Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol 301: H2181-H2190, 2011. First published September 23, 2011; doi:10.1152/ajpheart.00554.2011.-Oxidative stress, defined as an excess production of reactive oxygen species (ROS) relative to antioxidant defense, has been shown to play an important role in the pathophysiology of cardiac remodeling and heart failure (HF). It induces subtle changes in intracellular pathways, redox signaling, at lower levels, but causes cellular dysfunction and damage at higher levels. ROS are derived from several intracellular sources, including mitochondria, NAD(P) H oxidase, xanthine oxidase, and uncoupled nitric oxide synthase. The production of ROS is increased within the mitochondria from failing hearts, whereas normal antioxidant enzyme activities are preserved. Chronic increases in ROS production in the mitochondria lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage as well as functional decline, further ROS generation, and cellular injury. ROS directly impair contractile function by modifying proteins central to excitation-contraction coupling. Moreover, ROS activate a broad variety of hypertrophy signaling kinases and transcription factors and mediate apoptosis. They also stimulate cardiac fibroblast proliferation and activate the matrix metalloproteinases, leading to the extracellular matrix remodeling. These cellular events are involved in the development and progression of maladaptive myocardial remodeling and failure. Oxidative stress is also involved in the skeletal muscle dysfunction, which may be associated with exercise intolerance and insulin resistance in HF. Therefore, oxidative stress is involved in the pathophysiology of HF in the heart as well as in the skeletal muscle. A better understanding of these mechanisms may enable the development of novel and effective therapeutic strategies against HF..
97. Yukihiro Ohta, Shintaro Kinugawa, Shouji Matsushima, Taisuke Ono, Mochamad A. Sobirin, Naoki Inoue, Takashi Yokota, Kagami Hirabayashi, Hiroyuki Tsutsui, Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.01185.2009, 300, 5, H1637-H1644, 2011.05, Ohta Y, Kinugawa S, Matsushima S, Ono T, Sobirin MA, Inoue N, Yokota T, Hirabayashi K, Tsutsui H. Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure. Am J Physiol Heart Circ Physiol 300: H1637-H1644, 2011. First published February 18, 2011; doi:10.1152/ajpheart.01185.2009.-Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) (30). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase..
98. Hiroyuki Tsutsui, Shintaro Kinugawa, Shouji Matsushima, Takashi Yokota, Oxidative stress in cardiac and skeletal muscle dysfunction associated with diabetes mellitus, JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION, 10.3164/jcbn.11-012FR, 48, 1, 68-71, 2011.01, Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease. It also causes skeletal muscle dysfunction, which is responsible for reduced exercise capacity commonly seen in heart failure. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac and skeletal muscle dysfunction in heart failure and diabetes mellitus. Based on the findings in animal models, this review discusses the role of oxidative stress that may be involved in the development and progression of cardiac and skeletal dysfunction associated with diabetes..
99. Takashi Yokota, Shintaro Kinugawa, Kagami Hirabayashi, Shouji Matsushima, Naoki Inoue, Yukihiro Ohta, Sanae Hamaguchi, Mochamad A. Sobirin, Taisuke Ono, Tadashi Suga, Satoshi Kuroda, Shinya Tanaka, Fumio Terasaki, Koichi Okita, Hiroyuki Tsutsui, Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.00267.2009, 297, 3, H1069-H1077, 2009.09, Yokota T, Kinugawa S, Hirabayashi K, Matsushima S, Inoue N, Ohta Y, Hamaguchi S, Sobirin MA, Ono T, Suga T, Kuroda S, Tanaka S, Terasaki F, Okita K, Tsutsui H. Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 297: H1069-H1077, 2009. First published July 17, 2009; doi: 10.1152/ajpheart.00267.2009.-Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake ((V) over dotO(2))). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak (V) over dotO(2). Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes..
100. Shingo Takada, Kagami Hirabayashi, Shintaro Kinugawa, Takashi Yokota, Shouji Matsushima, Tadashi Suga, Tomoyasu Kadoguchi, Arata Fukushima, Tsuneaki Homma, Wataru Mizushima, Yoshihiro Masaki, Takaaki Furihata, Ryoichi Katsuyama, Koichi Okita, Hiroyuki Tsutsui, Pioglitazone ameliorates the lowered exercise capacity and impaired mitochondrial function of the skeletal muscle in type 2 diabetic mice, EUROPEAN JOURNAL OF PHARMACOLOGY, 10.1016/j.ejphar.2014.06.008, 740, 690-696, 2014.10, We have reported that exercise capacity is reduced in high fat diet (HFD)-induced diabetic mice, and that this reduction is associated with impaired mitochondrial function in skeletal muscle (SKM). However, it remains to be clarified whether the treatment of diabetes ameliorates the reduced exercise capacity. Therefore, we examined whether an insulin sensitizing drug, pioglitazone, could improve exercise capacity in HFD mice. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated with or without pioglitazone (3 mg/kg/day) to yield the following 4 groups: ND+vehicle, ND+pioglitazone, FLED I vehicle, and HFD+pioglitazone (n=10 each). After 8 weeks, body weight, plasma glucose, and insulin in the HFD+vehicle were significantly increased compared to the ND I vehicle group. Pioglitazone normalized the insulin levels in RED fed mice, but did not affect the body weight or plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in the HFD+vehicle, and this reduction was almost completely ameliorated in HFD+pioglitazone mice. ADP dependent mitochondrial respiration, complex l and Ill activities, and citrate synthase activity were significantly decreased in the SKM of the HFD+vehicle animals, and these decreases were also attenuated by pioglitazone. NAD(P)H oxidase activity was significantly increased in the HFD+vehicle compared with the ND+vehicle, and this increase was ameliorated in HFD+pioglitazone mice. Pioglitazone improved the exercise capacity in diabetic mice, which was due to the improvement in mitochondria! function and attenuation of oxidative stress in the SKM. Our data suggest that pioglitazone may be useful as an agent for the treatment of diabetes mellitus. (C) 2014 Elsevier B.V. All rights reserved..
101. Takashi Yokota, Shintaro Kinugawa, Kagami Hirabayashi, Tadashi Suga, Shingo Takada, Masashi Omokawa, Tomoyasu Kadoguchi, Masashige Takahashi, Arata Fukushima, Shouji Matsushima, Mayumi Yamato, Koichi Okita, Hiroyuki Tsutsui, Pioglitazone improves whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome, JOURNAL OF DIABETES INVESTIGATION, 10.1111/jdi.12606, 8, 4, 535-541, 2017.07, Aims/Introduction: Low aerobic capacity is a strong and independent predictor of all-cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole-body aerobic capacity and skeletal muscle energy metabolism in MetS patients.
Materials and Methods: A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole-body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high-energy phosphates in the calf muscle during plantar-flexion exercise were measured using (1)proton-and (31)phosphorus magnetic resonance spectroscopy, respectively.
Results: Pioglitazone significantly increased peak oxygen uptake (25.1 +/- 4.9 mL/kg/min pretreatment vs 27.2 +/- 3.9 mL/kg/min post-treatment, P < 0.05) and anaerobic threshold (12.7 +/- 1.9 mL/kg/min pretreatment vs 13.6 +/- 1.6 mL/kg/min post-treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high-energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment.
Conclusions: Pioglitazone significantly improved the MetS patients' whole-body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole-body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle..
102. Tsutsui H, Kinugawa S, Ide T, Hayashidani S, Suematsu N, Satoh S, Nakamura R, Egashira K, Takeshita A, Positive inotropic effects of calcium sensitizers on normal and failing cardiac myocytes, J Cardiovasc Pharmacol, 37, 1, 16-24, 2001.01.
103. 9. Kinugawa S, Tsutsui H, Ide T, Nakamura R, Arimura K, Egashira K, Takeshita A, Positive inotropic effect of insulin-like growth factor-1 on normal and failing cardiac myocytes, Cardiovasc Res, 43, 1, 157-164, 1999.01.
104. Sanae Hamaguchi, Shintaro Kinugawa, Daisuke Goto, Miyuki Tsuchihashi-Makaya, Takashi Yokota, Satoshi Yamada, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui, Predictors of Long-Term Adverse Outcomes in Elderly Patients Over 80 Years Hospitalized With Heart Failure - A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), CIRCULATION JOURNAL, 10.1253/circj.CJ-11-0267, 75, 10, 2403-2410, 2011.10, Background: Aging is associated with adverse outcomes in patients with cardiac diseases. Whether elderly patients hospitalized with heart failure (HF) had increased risks for mortality and rehospitalization compared with younger patients during the long-term follow-up was examined. The predictors of these adverse outcomes were also identified.
Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of 2,675 patients hospitalized with worsening HF and the outcomes were followed up. The majority of elderly patients were female, had lower body mass index (BMI), a higher rate of ischemic, valvular, and hypertensive heart disease as etiologies of HF, a lower estimated glomerular filtration rate (eGFR), lower hemoglobin, and higher left ventricular ejection fraction values. Even after adjustment for covariates, the elderly patients were associated with higher risks of adverse outcomes. The predictors for all-cause death were: lower eGFR, lower BMI, male sex, sustained ventricular tachycardia or fibrillation (VT/VF), and the use of diuretics at discharge.
Conclusions: Among patients hospitalized with HF, elderly patients had a worse prognosis than younger patients. Lower eGFR, lower BMI, male sex, sustained VT/VF, and diuretic use were independent predictors for all-cause death in these patients with higher risk. (Circ J 2011; 75: 2403-2410).
105. Yutaka Miura, Yoshihiro Fukumoto, Nobuyuki Shiba, Toshiro Miura, Kazunori Shimada, Yoshitaka Iwama, Atsutoshi Takagi, Hidenori Matsusaka, Takaki Tsutsumi, Akira Yamada, Shintaro Kinugawa, Masanori Asakura, Shuichi Okamatsu, Hiroyuki Tsutsui, Hiroyuki Daida, Masunori Matsuzaki, Hitonobu Tomoike, Hiroaki Shimokawa, Prevalence and Clinical Implication of Metabolic Syndrome in Chronic Heart Failure - Report From MetS-CHF Study, CIRCULATION JOURNAL, 10.1253/circj.CJ-10-0677, 74, 12, 2612-2621, 2010.12, Background: Metabolic syndrome (MetS) is a pathological condition with a clustering of metabolic components and is a well-known risk and prognostic factor for ischemic heart disease (IHD). However, the prevalence and clinical significance of MetS remain to be fully elucidated in chronic heart failure (CHF), an important clinical syndrome caused by various cardiac abnormalities.
Methods and Results: The present nationwide, large-scale clinical study enrolled 3,603 patients with stage C/D CHF from 6 institutes in Japan First, the prevalence of MetS in CHF patients was demonstrated to be 45% in males and 19% in females, which is more than double compared with the general population in Japan. The CHF patients with MetS were characterized by younger age, higher prevalence of current smoking and drinking, IHD, and hypertensive heart disease, whereas the prevalence of HF with preserved ejection fraction and MetS was higher in elderly female patients. Next, the contribution of the metabolic components (waist circumference, hypertension, glucose intolerance/diabetes mellitus and dyslipidemia) was found to be comparable between the ischemic and the non-ischemic CHF patients.
Conclusions: The prevalence of MetS in CHF patients is more than double compared with the general population in Japan and suggest that the metabolic components may have a substantial effect on the development of both ischemic and non-ischemic CHF. (Circ J 2010,74 2612-2621).
106. Kakutani N, Fukushima A, Kinugawa S, Yokota T, Oikawa T, Nishikawa M, Nakamura R, Tsukada T, Mori S, Yoshida I, Anzai T, Progressive mobilization program for patients with acute heart failure reduces the hospital stay and improves clinical outcomes, Circ Rep, 1, 3, 123-130, 2019.03.
107. Tsuda M, Fukushima A, Matsumoto J, Takada S, Kakutani N, Nambu H, Yamanashi K, Furihata T, Yokota T, Okita K, Kinugawa S, Anzai T, Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure, J Cachexia Sarcopenia Muscle, 2018.08.
108. Yokota T, Fukushima A, Kinugawa S, Okumura T, Murohara T, Tsutsui H, Randomized trial of effect of urate-lowering agent febuxostat in chronic heart failure patients with hyperuricemia (LEAF-CHF): study design, Int Heart J, 59, 5, 976-982, 2018.05.
109. Rapidly Progressive Heart Failure in a Female Carrier of Becker Muscular Dystrophy with No Skeletal Muscle Symptoms.
© 2019 Japanese Society of Internal Medicine. All rights reserved. Becker muscular dystrophy (BMD) carriers are at risk to developing cardiac dysfunction. The prevalence of female BMD carriers remains underestimated, and the disease progression varies. We herein report the case of a young female BMD carrier who developed dilated cardiomyopathy (DCM) and heart failure without any skeletal muscle signs. Her cardiac dysfunction progressed over a mere two months, resulting in the need for left ventricular assist device implantation. Her case demonstrates that progressive cardiomyopathy can be the only clinical manifestation in some BMD carriers, suggesting the need for a more aggressive implementation of genetic testing in female DCM patients..
110. Arata Fukushima, Shintaro Kinugawa, Renin-Angiotensin-Aldosterone System and Natriuretic Peptides as Possible Targets of Waon Therapy in Heart Failure, CIRCULATION JOURNAL, 10.1253/circj.CJ-17-0286, 81, 5, 635-636, 2017.05.
111. Naoki Ishimori, Shintaro Kinugawa, Satoshi Yamada, Hisashi Yokoshiki, Hirofumi Mitsuyama, Hiroyuki Tsutsui, Report of the American Heart Association (AHA) Scientific Sessions 2013, Dallas, CIRCULATION JOURNAL, 10.1253/circj.CJ-13-1466, 78, 1, 51-56, 2014.01, The American Heart Association (AHA) Scientific Sessions were held in Dallas on November 16-20, 2013. The meeting is one of the most leading conferences of cardiology in the world, with over 18,000 professional attendees from more than 105 countries. There were 315 invited sessions and 443 abstract sessions, comprising more than 5,000 presentations. The sessions were expanded to 26 program tracks, which included and integrated basic, translational, clinical, and population science. In the series of late-breaking sessions, updates of results from 20 clinical trials were disclosed. Japanese scientists submitted the second most abstracts to the Scientific Sessions in 2013. We appreciate the significant contribution to the sessions by Japanese cardiologists as well as the Japanese Circulation Society..
112. Okita K, Takada S, Suga T, Kadoguchi T, Taniura T, Morita N, Yokota T, Kinugawa S, Tsutsui H, Resistance exercise with blood flow restriction in women, Proceeding of Asian Federation of Sports Medicine, 73-75, 2013.12.
113. Okita K, Takada S, Morita N, Takahashi M, Hirabayashi K, Yokota T, Kinugawa S, Resistance training with interval blood flow restriction effectively enhances intramuscular metabolic stress with less ischemic duration and discomfort, Appl Physiol Nutr Metab, 10.1139/apnm-2018-0321, 2018 Dec 19, 7, 759-764, 2018.12.
114. Kinugawa S, Tsutsui H, Satoh S, Takahashi M, Ide T, Igarashi-Saito K, Arimura K, Egashira K, Takeshita A, Role of Ca2+ availability to myofilaments and their sensitivity to Ca2+ in myocytes contractile dysfunction in heart failure, Cardiovasc Res, 44, 2, 398-406, 1999.02.
115. K Igarashi-Saito, H Tsutsui, S Yamamoto, M Takahashi, S Kinugawa, H Tagawa, M Usui, M Yamamoto, K Egashira, A Takeshita, Role of SR Ca2+-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 275, 1, H31-H40, 1998.07, Sarcoplasmic reticulum (SR) Ca2+-ATPase gene expression is reduced in the failing myocardium. However, the functional relevance of these changes to myocardial contractility is not yet established. We assessed myocardial contractile function by analyzing sarcomere motion of isolated myocytes and also quantified SR Ca2+ regulatory protein gene expression by Northern blot analysis in the same hearts obtained from 10 dogs with pacing-induced heart failure (HF; 240 beats/min, 4 wk) and 7 control dogs. Sarcomere-shortening velocity was depressed in HF myocytes, accompanied by the prolongation of intracellular Ca2+ concentration ([Ca2+](i)) transient measured by indo 1 fluorescence ratio. SR Ca2+-ATPase mRNA levels (normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA) were significantly depressed in HF, and calsequestrin mRNA was increased. For control and HF dogs, sarcomere-shortening velocity correlated positively with Ca2+-ATPase mRNA levels (r = 0.73, n = 17, P < 0.01) but not with calsequestrin mRNA. Ca2+-ATPase mRNA levels were correlated with Ca-45(2+) uptake rate by SR, which was also reduced in HF. Moreover, the inhibition of SR Ca2+-ATPase with thapsigargin or cyclopiazonic acid reproduced in normal myocytes the abnormalities observed in HF myocytes, such as depressed contractility and the prolonged [Ca2+](i) transient duration. A downregulation of Ca2+-ATPase gene expression and a resultant decrease in Ca2+ uptake by SR may be responsible for the contractile dysfunction and the alterations of[Ca2+](i) transient in HF..
116. Takahashi M, Tsutsui H, Kinugawa S, Igarashi-Saito K, Yamamoto S, Yamamoto M, Tagawa H, Imanaka-Yoshida K, Egashira K, Takeshita A, Role of microtubles in the contractile dysfunction of myocytes from tachycardia-induced dilated cardiomyopathy, J Mol Cell Cardiol, 30, 5, 1047-1057, 1998.05.
117. Takashi Fujita, Noboru Fujino, Ryuichiro Anan, Chuwa Tei, Toru Kubo, Yoshinori Doi, Shintaro Kinugawa, Hiroyuki Tsutsui, Shigeki Kobayashi, Masafumi Yano, Masanori Asakura, Masafumi Kitakaze, Issei Komuro, Tetsuo Konno, Kenshi Hayashi, Masa-aki Kawashiri, Hidekazu Ino, Masakazu Yamagishi, Sarcomere Gene Mutations Are Associated With Increased Cardiovascular Events in Left Ventricular Hypertrophy, JACC-HEART FAILURE, 10.1016/j.jchf.2013.08.007, 1, 6, 459-466, 2013.12, Objectives This study investigated the occurrence of cardiovascular events in patients with hypertensive heart disease (HHD) or hypertrophic cardiomyopathy (HCM) with or without sarcomere gene mutations.
Background Although HHD and HCM are associated with left ventricular hypertrophy (LVH), few data exist regarding the difference in prognosis between them.
Methods We enrolled 256 patients with LVH (>13 mm) screened for sarcomere gene mutations. We divided them into 3 groups: the first had HHD without sarcomere gene mutations (group H), the second had sarcomere gene mutations (group G), and the third had neither sarcomere gene mutations nor HHD (group NG). We compared the occurrence of sudden cardiac death, ventricular tachycardia/fibrillation, admission for heart failure, and atrial fibrillation for 1 year.
Results Group G (n = 78, 36 men; mean age, 53.4 years) experienced more total cardiovascular events than group H (n = 45, 32 men; mean age, 67.4 years) (p = 0.042) after adjustments for age and sex, although there was no significant difference in total cardiovascular events between groups H and NG (n = 98, 66 men; mean age, 62.0 years). With Kaplan-Meier analysis, group G exhibited a significantly higher incidence of admission for heart failure (p = 0.017) and atrial fibrillation (p = 0.045) than group H in those 50 years of age and older. Additionally, there was a significant difference in total cardiovascular events between groups G and NG (p = 0.021).
Conclusions These results demonstrate that HCM with sarcomere gene mutations can be associated with increased cardiovascular events compared with HHD or HCM without sarcomere gene mutations. (1 Am Coll Cardiol HF 2013;1:459-66) (C) 2013 by the American College of Cardiology Foundation.
118. Ippei Nakano, Shintaro Kinugawa, Hiroaki Hori, Arata Fukushima, Takashi Yokota, Shingo Takada, Naoya Kakutani, Yoshikuni Obata, Katsuma Yamanashi, Toshihisa Anzai, Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure., International heart journal, 10.1536/ihj.19-400, 61, 1, 96-102, 2020.01, Heart failure (HF) is associated with aberrant skeletal muscle impairments, which are closely linked to the severity of HF. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However, little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60, 63 ± 13 years) and age-matched controls (n = 29, 61 ± 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 ± 0.9 versus 28.6 ± 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength (β-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients..
119. Arata Fukushima, Shintaro Kinugawa, Tsuneaki Homma, Yoshihiro Masaki, Takaaki Furihata, Takashi Yokota, Shouji Matsushima, Shingo Takada, Tomoyasu Kadoguchi, Koji Oba, Koichi Okita, Hiroyuki Tsutsui, Serum brain-derived neurotropic factor level predicts adverse clinical outcomes in patients with heart failure., Journal of cardiac failure, 10.1016/j.cardfail.2015.01.003, 21, 4, 300-6, 2015.04, BACKGROUND: Brain-derived neurotropic factor (BDNF) is involved in cardiovascular diseases as well as skeletal muscle energy metabolism and depression. We investigated whether serum BDNF level was associated with prognosis in patients with heart failure (HF). METHODS AND RESULTS: We measured the serum BDNF level in 58 patients with HF (59.2 ± 13.7 years old, New York Heart Association functional class I-III) at baseline, and adverse events, including all cardiac deaths and HF rehospitalizations, were recorded during the median follow-up of 20.3 months. In a univariate analysis, serum BDNF levels were significantly associated with peak oxygen capacity (β = 0.547; P = .003), anaerobic threshold (β = 0.929; P = .004), and log minute ventilation/carbon dioxide production slope (β = -10.15; P = .005), but not Patient Health Questionnaire scores (β = -0.099; P = .586). A multivariate analysis demonstrated that serum BDNF level was an independent prognostic factor of adverse events (hazard ratio 0.41, 95% confidence interval 0.20-0.84; P = .003). The receiver operating characteristic curve demonstrated that low levels of BDNF (<17.4 ng/mL) were associated with higher rates of adverse events compared with high levels of BDNF (≥17.4 ng/mL; log rank test: P < .001). CONCLUSIONS: Decreased serum BDNF levels were significantly associated with adverse outcomes in HF patients, suggesting that these levels can be a useful prognostic biomarker..
120. Takaaki Furihata, Shintaro Kinugawa, Arata Fukushima, Shingo Takada, Tsuneaki Homma, Yoshihiro Masaki, Takahiro Abe, Takashi Yokota, Koji Oba, Koichi Okita, Hiroyuki Tsutsui, Serum myostatin levels are independently associated with skeletal muscle wasting in patients with heart failure., International journal of cardiology, 10.1016/j.ijcard.2016.06.231, 220, 483-7, 2016.10, BACKGROUND: It has been reported that skeletal muscle mass and strength are decreased in patients with heart failure (HF), and HF is associated with both reduced exercise capacity and adverse clinical outcomes. Myostatin has been known as a negative regulator of muscle growth, follistatin as the myostatin antagonist, maintaining tissue homeostasis. We thus determined serum myostatin levels in HF patients and whether they are associated with skeletal muscle wasting. METHODS AND RESULTS: Forty one consecutive HF patients (58±15years old, New York Heart Association class I-III) and 30 age-matched healthy subjects as controls (53±8years old) were studied. Serum myostatin levels were significantly lower in HF patients than controls (18.7±7.4 vs. 23.6±5.2ng/mL, P<0.001). Circumference of the thickest part of the right thigh was significantly small (468±72 vs. 559±37mm, P=0.001) and lower extremity muscular strength was lower in patients with HF (129±55 vs. 219±52N×m, P<0.001). Fourteen HF patients (34%) had muscle wasting. By univariate analysis, higher age, higher serum follistatin, and lower serum myostatin were significantly associated with the presence of muscle wasting. By multivariate analysis, serum myostatin levels were independently associated with muscle wasting (OR=0.77, 95% CI [0.58, 0.93], P=0.02). CONCLUSION: Serum myostatin levels were significantly decreased in HF patients and associated with lower extremity muscle wasting, suggesting that myostatin may be an important factor for maintaining skeletal muscle mass and strength in HF..
121. Shingo Takada, Shintaro Kinugawa, Shouji Matsushima, Daisuke Takemoto, Takaaki Furihata, Wataru Mizushima, Arata Fukushima, Takashi Yokota, Yoshiko Ono, Hiroshi Shibata, Koichi Okita, Hiroyuki Tsutsui, Sesamin prevents decline in exercise capacity and impairment of skeletal muscle mitochondrial function in mice with high-fat diet-induced diabetes, EXPERIMENTAL PHYSIOLOGY, 10.1113/EP085251, 100, 11, 1319-1330, 2015.11, New Findings What is the central question of this study? Our aim was to examine whether sesamin can prevent a decline in exercise capacity in high-fat diet-induced diabetic mice. Our hypothesis was that maintenance of mitochondrial function and attenuation of oxidative stress in the skeletal muscle would contribute to this result. What is the main finding and its importance? The new findings are that sesamin prevents the diabetes-induced decrease in exercise capacity and impairment of mitochondrial function through the inhibition of NAD(P)H oxidase-dependent oxidative stress in the skeletal muscle. Sesamin may be useful as a novel agent for the treatment of diabetes mellitus.
AbstractWe previously reported that exercise capacity and skeletal muscle mitochondrial function in diabetic mice were impaired, in association with the activation of NAD(P)H oxidase. It has been reported that sesamin inhibits NAD(P)H oxidase-induced superoxide production. Therefore, we examined whether the antioxidant sesamin could prevent a decline in exercise capacity in mice with high-fat diet (HFD)-induced diabetes. C57BL/6J mice were fed a normal diet (ND) or HFD, then treated or not with sesamin (0.2%) to yield the following four groups: ND, ND+Sesamin, HFD and HFD+Sesamin (n=10 each). After 8 weeks, body weight, fat weight, blood glucose, insulin, triglyceride, total cholesterol and fatty acid were significantly increased in HFD compared with ND mice. Sesamin prevented the increases in blood insulin and lipid levels in HFD-fed mice, but did not affect the plasma glucose. Exercise capacity determined by treadmill tests was significantly reduced in HFD mice, but almost completely recovered in HFD+Sesamin mice. Citrate synthase activity was significantly decreased in the skeletal muscle of HFD mice, and these decreases were also inhibited by sesamin. Superoxide anion and NAD(P)H oxidase activity were significantly increased in HFD mice compared with the ND mice and were ameliorated by sesamin. Sesamin prevented the decline in exercise capacity in HFD-induced diabetic mice via maintenance of mitochondrial function, fat oxidation and attenuation of oxidative stress in the skeletal muscle. Our data suggest that sesamin may be useful as a novel agent for the treatment of diabetes mellitus..
122. Miyuki Tsuchihashi-Makaya, Sanae Hamaguchi, Shintaro Kinugawa, Kazutomo Goto, Daisuke Goto, Tomoo Furumoto, Satoshi Yamada, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui, Sex differences with respect to clinical characteristics, treatment, and long-term outcomes in patients with heart failure, INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2011.03.042, 150, 3, 338-339, 2011.08.
123. Shintaro Kinugawa, Shingo Takada, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui, Skeletal Muscle Abnormalities in Heart Failure, INTERNATIONAL HEART JOURNAL, 10.1536/ihj.15-108, 56, 5, 475-484, 2015.09, Exercise capacity is lowered in patients with heart failure, which limits their daily activities and also reduces their quality of life. Furthermore, lowered exercise capacity has been well demonstrated to be closely related to the severity and prognosis of heart failure. Skeletal muscle abnormalities including abnormal energy metabolism, transition of my-fibers from type I to type II, mitochondrial dysfunction, reduction in muscular strength, and muscle atrophy have been shown to play a central role in lowered exercise capacity. The skeletal muscle abnormalities can be classified into the following main types: 1) low endurance due to mitochondrial dysfunction; and 2) low muscle mass and muscle strength due to imbalance of protein synthesis and degradation. The molecular mechanisms of these skeletal muscle abnormalities have been studied mainly using animal models. The current review including our recent study will focus upon the skeletal muscle abnormalities in heart failure..
124. Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Kazutomo Goto, Daisuke Goto, Takashi Yokota, Satoshi Yamada, Hisashi Yokoshiki, Akira Takeshita, Hiroyuki Tsutsui, Spironolactone use at discharge was associated with improved survival in hospitalized patients with systolic heart failure, AMERICAN HEART JOURNAL, 10.1016/j.ahj.2010.08.036, 160, 6, 1156-1162, 2010.12, Background The RALES trial demonstrated that spironolactone improved the prognosis of patients with heart failure (HF). However, it is unknown whether the discharge use of spironolactone is associated with better long-term outcomes among hospitalized systolic HF patients in routine clinical practice. We examined the effects of spironolactone use at discharge on mortality and rehospitalization by comparing with outcomes in patients who did not receive spironolactone.
Methods The JCARE-CARD studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed with an average of 2.2 years of follow-up.
Results A total of 946 patients had HF with reduced left ventricular ejection fraction (LVEF) (<40%), among whom spironolactone was prescribed at discharge in 435 patients (46%), but not in 511 patients (54%). The mean age was 66.3 years and 72.2% were male. Etiology was ischemic in 39.7% and mean LVEF was 27.1%. After adjustment for covariates, discharge use of spironolactone was associated with a significant reduction in all-cause death (adjusted hazard ratio 0.612, P = .020) and cardiac death (adjusted hazard ratio 0.524, P = .013).
Conclusions Among patients with HF hospitalized for systolic dysfunction, spironolactone use at the time of discharge was associated with long-term survival benefit. These findings provide further support for the idea that spironolactone may be useful in patients hospitalized with HF and reduced LVEF. (Am Heart J 2010;160:1156-62.).
125. Izawa H, Yoshida T, Ikegami T, Izawa KP, Ito Y, Okamura H, Osada N, Kinugawa S, Kubozono T, Kono Y, Kobayashi K, Nishigaki K, Higo T, Hirashiki A, Miyazawa Y, Morio Y, Yanase M, Yamada S, Ikeda H, Momomura SI, Kihara Y, Yamamoto K, Goto Y, Makita S; Japanese Association of Cardiac Rehabilitation Standard Cardiac Rehabilitation Program Planning Committee, Standard cardiac rehabilitation program for heart failure, Circ J, 83, 12, 2394-2398, 2019.12.
126. Omote Kazunori, Sakakibara Mamoru, Nanbu Hideo, Maekawa Satoshi, Asakawa Naoya, Noguchi Keiji, Tokuda Yusuke, Kamiya Kiwamu, Kinugawa Shintaro, Tsutsui Hiroyuki, Successful Evaluation for Reversibility of Pulmonary Hypertension Using Inhaled Nitric Oxide Determining Candidate for Heart Transplantation, JOURNAL OF CARDIAC FAILURE, 10.1016/j.cardfail.2016.07.402, 22, 9, S228-S229, 2016.09.
127. Takashi Yokota, Shintaro Kinugawa, Mayumi Yamato, Kagami Hirabayashi, Tadashi Suga, Shingo Takada, Kuniaki Harada, Noriteru Morita, Noriko Oyama-Manabe, Yasuka Kikuchi, Koichi Okita, Hiroyuki Tsutsui, Systemic Oxidative Stress Is Associated With Lower Aerobic Capacity and Impaired Skeletal Muscle Energy Metabolism in Patients With Metabolic Syndrome, DIABETES CARE, 10.2337/dc12-1161, 36, 5, 1341-1346, 2013.05, OBJECTIVE-Systemic oxidative stress is associated with insulin resistance and obesity. We tested the hypothesis that systemic oxidative stress is linked to lower aerobic capacity and skeletal muscle dysfunction in metabolic syndrome (MetS).
RESEARCH DESIGN AND METHODS-The incremental exercise testing with cycle ergometer was performed in 14 male patients with MetS and 13 age-, sex-, and activity-matched healthy subjects. Systemic lipid peroxidation was assessed by serum thiobarbituric acid reactive substances (TBARS), and systemic antioxidant defense capacity was assessed by serum total thiols and enzymatic activity of superoxide dismutase (SOD). To assess skeletal muscle energy metabolism, we measured high-energy phosphates in the calf muscle during plantar flexion exercise and intramyocellular lipid (IMCL) in the resting leg muscle, using P-31- and (1)proton-magnetic resonance spectroscopy, respectively.
RESULTS-Serum TBARS were elevated (12.4 +/- 7.1 vs. 3.7 +/- 1.1 mu mol/L; P < 0.01), and serum total thiols and SOD activity were decreased (290.8 +/- 51.2 vs. 398.7 +/- 105.2 mu mol/L, P < 0.01; and 22.2 +/- 8.4 vs. 31.5 +/- 8.5 units/L, P < 0.05, respectively) in patients with MetS compared with healthy subjects. Peak VO2 and anaerobic threshold normalized to body weight were significantly lower in MetS patients by 25 and 31%, respectively, and inversely correlated with serum TBARS (r = -0.49 and r = -0.50, respectively). Moreover, muscle phosphocreatine loss during exercise was 1.4-fold greater in patients with MetS (P < 0.05), and IMCL content was 2.9-fold higher in patients with MetS (P < 0.01), indicating impaired skeletal muscle energy metabolism, and these indices positively correlated with serum TBARS (r = 0.45 and r = 0.63, respectively).
CONCLUSIONS-Systemic oxidative stress was associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in patients with MetS..
128. H Matsusaka, T Ide, S Matsushima, M Ikeuchi, T Kubota, K Sunagawa, S Kinugawa, H Tsutsui, Targeted deletion of p53 prevents cardiac rapture after myocardial infarction in mice, CARDIOVASCULAR RESEARCH, 10.1016/j.cardiores.2006.02.001, 70, 3, 457-465, 2006.06, Objective: Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts.
Methods: Anterior MI was created in male heterozygous p53-deficient (p53(+/-); n=28) mice and sibling wild-type (P53(+/-); n = 29) mice by ligating the left coronary artery.
Results: By day 7, p53(+/-) mice had significantly better survival rate than p53(+/+) mice (89% vs. 69%, P < 0.05). Notably, p53(+/-) mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 +/- 2% vs. 59 +/- 2%, P=NS), heart rate (488 +/- 15 vs. 489 +/- 17 bpm, P=NS), or mean arterial blood pressure (80 +/- 2 vs. 78 +/- 3 mm Hg, P=NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53(+/-) and p53(+/+) mice with MI. However, the p53(+/-) mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53(+/-) mice than in p53(+/+) mice (423 +/- 86 vs. 1330 +/- 275/10(5) cells, P < 0.01).
Conclusions: p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved..
129. H Matsusaka, T Ide, S Matsushima, M Ikeuchi, T Kubota, K Sunagawa, S Kinugawa, H Tsutsui, Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload, HYPERTENSION, 10.1161/01.HYP.0000208840.30778.00, 47, 4, 711-717, 2006.04, Matrix metalloproteinases ( MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload ( PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction ( TAC) in male MMP 2 knockout ( KO) mice ( n = 10) and sibling wild-type ( WT) mice ( n = 9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4- fold increased in WT + TAC, and this increase was not observed in KO + TAC, with no significant alterations in other MMPs ( MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs ( 1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular ( LV) weight and LV end-diastolic pressure ( EDP) with preserved systolic function. KO + TAC mice exerted significantly lower LV weight/body weight ( 4.2 +/- 0.2 versus 5.0 +/- 0.2 mg/ g; P < 0.01), lung weight/body weight ( 4.9 +/- 0.2 versus 6.2 +/- 0.4 mg/ g; P < 0.01), and LV end-diastolic pressure ( 4 +/- 1 versus 10 +/- 2 mm Hg; P < 0.05) than WT + TAC mice despite comparable aortic pressure. KO + TAC mice had less myocyte hypertrophy ( cross-sectional area; 322 +/- 14 versus 392 +/- 14 mu m(2); P < 0.01) and interstitial fibrosis ( collagen volume fraction; 3.3 +/- 0.5 versus 8.2 +/- 1.0%; P < 0.01) than WT + TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease..
130. Masashige Takahashi, Shintaro Kinugawa, Shingo Takada, Naoya Kakutani, Takaaki Furihata, Mochamad Ali Sobirin, Arata Fukushima, Yoshikuni Obata, Akimichi Saito, Naoki Ishimori, Kazuya Iwabuchi, Hiroyuki Tsutsui, The disruption of invariant natural killer T cells exacerbates cardiac hypertrophy and failure caused by pressure overload in mice., Experimental physiology, 10.1113/EP087652, 105, 3, 489-501, 2020.03, NEW FINDINGS: What is the central question of this study? We questioned whether the disruption of invariant natural killer T (iNKT) cells exacerbates left ventricular (LV) remodelling and heart failure after transverse aortic constriction in mice. What are the main findings and their importance? Pressure overload induced by transverse aortic constriction increased the infiltration of iNKT cells in mouse hearts. The disruption of iNKT cells exacerbated LV remodelling and hastened the transition from hypertrophy to heart failure, in association with the activation of mitogen-activated protein kinase signalling. Activation of iNKT cells modulated the immunological balance in this process and played a protective role against LV remodelling and failure. ABSTRACT: Chronic inflammation is involved in the development of cardiac remodelling and heart failure (HF). Invariant natural killer T (iNKT) cells, a subset of T lymphocytes, have been shown to produce various cytokines and orchestrate tissue inflammation. The pathophysiological role of iNKT cells in HF caused by pressure overload has not been studied. In the present study, we investigated whether the disruption of iNKT cells affected this process in mice. Transverse aortic constriction (TAC) and a sham operation were performed in male C57BL/6J wild-type (WT) and iNKT cell-deficient Jα18 knockout (KO) mice. The infiltration of iNKT cells was increased after TAC. The disruption of iNKT cells exacerbated left ventricular (LV) remodelling and hastened the transition to HF after TAC. Histological examinations also revealed that the disruption of iNKT cells induced greater myocyte hypertrophy and a greater increase in interstitial fibrosis after TAC. The expressions of interleukin-10 and tumour necrosis factor-α mRNA and their ratio in the LV after TAC were decreased in the KO compared with WT mice, which might indicate that the disruption of iNKT cells leads to an imbalance between T-helper type 1 and type 2 cytokines. The phosphorylation of extracellular signal-regulated kinase was significantly increased in the KO mice. The disruption of iNKT cells exacerbated the development of cardiac remodelling and HF after TAC. The activation of iNKT cells might play a protective role against HF caused by pressure overload. Targeting the activation of iNKT cells might thus be a promising candidate as a new therapeutic strategy for HF..
131. Takaaki Furihata, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Masashige Takahashi, Tsuneaki Homma, Yoshihiro Masaki, Masaya Tsuda, Junichi Matsumoto, Wataru Mizushima, Shouji Matsushima, Takashi Yokota, Hiroyuki Tsutsui, The experimental model of transition from compensated cardiac hypertrophy to failure created by transverse aortic constriction in mice., International journal of cardiology. Heart & vasculature, 10.1016/j.ijcha.2016.03.007, 11, 24-28, 2016.06, BACKGROUND: Transverse aortic constriction (TAC) operation is used as an experimental model of left ventricular (LV) hypertrophy and LV failure in mice. The severity of LV remodeling or failure may depend on the degree of TAC, but is variable among operated animals. Therefore, we tried to identify the optimal diameter of TAC to create this model with ease and high reproducibility. METHODS AND RESULTS: To produce TAC in C57BL/6J mice (7-9 weeks, body weight 19-26 g, n = 109), a 7-0 nylon suture ligature was tightly tied around the transverse aorta against needles with 3 different diameters (mm); 0.40, 0.385 and 0.375. LV wall thickness, end-diastolic dimension, fractional shortening were measured by echocardiography. At 4 weeks after TAC, no mouse with the 0.400 mm gauge progressed in LV failure. The 0.385 mm pin gauge mouse kept a more survival rate compared with the 0.375 mm (59% vs 48%), representing same efficient in LV failure. With the 0.385 mm pin gauge, hearts of mice remained LV hypertrophy at 1 week after TAC, followed by LV failure at 4 weeks. CONCLUSION: TAC with the diameter of 0.385 mm can effectively induce the transition from LV hypertrophy to failure in mice with relatively preserved survival..
132. The impact of creating mathematical formula to predict cardiovascular events in patients with heart failure..
133. Wataru Mizushima, Hidehisa Takahashi, Masashi Watanabe, Shintaro Kinugawa, Shouji Matsushima, Shingo Takada, Takashi Yokota, Takaaki Furihata, Junichi Matsumoto, Masaya Tsuda, Ikuru Chiba, Shun Nagashima, Shigeru Yanagi, Masaki Matsumoto, Keiichi I. Nakayama, Hiroyuki Tsutsui, Shigetsugu Hatakeyama, The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 10.1016/j.yjmcc.2016.09.013, 100, 43-53, 2016.11, A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction. Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure. Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure. (C) 2016 Elsevier Ltd. All rights reserved..
134. Hiroyuki Sawatari, Mari K. Nishizaka, Mami Miyazono, Shin-ichi Ando, Shujiro Inoue, Masao Takemoto, Takafumi Sakamoto, Daisuke Goto, Tomoo Furumoto, Shintaro Kinugawa, Nobuko Hashiguchi, Anita Rahmawati, Hiroaki Chishaki, Tomoko Ohkusa, Chie Magota, Hiroyuki Tsutsui, Akiko Chishaki, Three nights leg thermal therapy could improve sleep quality in patients with chronic heart failure, Heart and Vessels, 10.1007/s00380-017-1047-7, 33, 2, 155-162, 2018.02, Sleep quality is often impaired in patients with chronic heart failure (HF), which may worsen their quality of life and even prognosis. Leg thermal therapy (LTT), topical leg warming, has been shown to improve endothelial function, oxidative stress, and cardiac function in patients with HF. However, its short-term influence to sleep quality has not been evaluated in HF patients. Eighteen of 23 patients with stable HF received LTT (15 min of warming at 45 °C and 30 min of insulation) at bedtime for 3 consecutive nights and 5 patients served as control. Subjective sleep quality was evaluated by St. Mary’s Hospital Sleep Questionnaire, Oguri–Shirakawa–Azumi Sleep Inventory, and Epworth sleepiness scale, and also objectively evaluated by polysomnography. LTT significantly improved subjective sleep quality indicated by depth of sleep (p <
 0.01), sleep duration (p <
 0.05), number of awaking (p <
 0.01), nap duration (p <
 0.01), sleep quality (p <
 0.05), and sleep satisfaction (p <
 0.05). It was also objectively affirmed by a slight but significant decrease of sleep stage N1 (p <
 0.01), and increase in sleep stage N2 (p <
 0.05). No significant changes occurred in the controls. Hence, the short-term LTT could improve subjective and objective sleep quality in patients with HF. LTT can be a complimentary therapy to improve sleep quality in these patients..
135. Hiroyuki Tsutsui, Shin-ichi Momomura, Tohru Masuyama, Yoshihiko Saito, Issei Komuro, Toyoaki Murohara, Shintaro Kinugawa, Koji Oba, Norihiro Sato, Yoshio Yasumura, Shinya Hiramitsu, Yukihito Satou, Takayuki Inomata, Katsuya Onishi, Yasushi Sakata, Kyoichi Mizuno, Kenji Sunagawa, Hisao Ogawa, Mitsuaki Isobe, Hiroyuki Daida, Masahiko Kurabayashi, Shintaro Kinugawa, Tetsuro Kohya, Yuji Ogawa, Naofumi Itoh, Shigeo Kakinoki, Kenji Aoki, Akihito Tsuchida, Hiroshi Ito, Osamu Yamaguchi, Yutaka Eki, Shigeru Toyoda, Akihiko Nakano, Norimichi Koitabashi, Toshihiro Muramatsu, Hideo Nakahara, Hiroyuki Tanaka, Akira Yamashina, Kiyoshi Takasu, Yasuhiro Maejima, Yukihiko Momiyama, Iwao Nakamura, Keisuke Kida, Takashi Naruke, Hideshi Takenobu, Tohru Minamino, Masahiko Nakamura, Masatoshi Ikeda, Kazuhiro Ashida, Shigekiyo Takahashi, Shinya Minatoguchi, Satoru Suwa, Hiroshi Satoh, Hideo Izawa, Hidekatsu Fukuta, Naoya Tsuboi, Hiroyasu Uzui, Atsuyuki Wada, Takeshi Kimura, Ken Takenaka, Takao Kato, Masaaki Okutsu, Tomohito Ohtani, Shinji Hasegawa, Toshihisa Anzai, Kenshi Fujii, Ichiro Shiojima, Yoshinori Yasaka, Tohru Masuyama, Ken-ichi Hirata, Yoshihiko Saito, Takashi Akasaka, Hiroshi Ito, Yasuki Kihara, Ritsu Tamura, Hiroki Teragawa, Kotaro Yasuda, Koichiro Okuhara, Eiji Karashima, Masataka Sata, Akira Ota, Takahisa Noma, Jun Suzuki, Kouki Watanabe, Hiroaki Kitaoka, Ryuichi Matsukawa, Takeshi Yoshihiro, Nobuhide Tanaka, Kiyoshi Ozumi, Masaru Takahashi, Koji Maemura, Nobuhiko Atsuchi, Tolerability, Efficacy, and Safety of Bisoprolol vs. Carvedilol in Japanese Patients With Heart Failure and Reduced Ejection Fraction - The CIBIS-J Trial -, CIRCULATION JOURNAL, 10.1253/circj.CJ-18-1199, 83, 6, 1269-+, 2019.06, Background: The comparative tolerability, efficacy, and safety of bisoprolol and carvedilol have not been established in Japanese patients with heart failure and reduced ejection fraction (HFrEF).Methods and Results: The CIBIS-J trial is a multicenter, open-label, non-inferiority randomized controlled trial of bisoprolol vs. carvedilol in 217 patients with HFrEF (EF <= 40%). The primary endpoint was tolerability, defined as reaching and maintaining the maximum maintenance dose (bisoprolol 5 mg/day or carvedilol 20 mg/day) during 48 weeks of treatment. The primary endpoint was achieved in 41.4% of patients in bisoprolol (n=111) and 42.5% in carvedilol (n=106) groups. The non-inferiority of tolerability of bisoprolol compared with carvedilol was not supported, however, neither beta-blocker was superior with regard to tolerability. Heart rate (HR) decreased in both groups and its decrease from baseline was significantly greater in the bisoprolol group (20.3 vs. 15.4 beats/min at 24 week, P<0.05). Plasma B-type natriuretic peptide (BNP) levels decreased in both groups and the decrease was significantly greater in the carvedilol group (12.4 vs. 39.0 % at 24 weeks, P<0.05).Conclusions: There were no significant differences between bisoprolol and carvedilol in the tolerability of target doses in Japanese HFrEF patients. The clinical efficacy and safety were also similar despite the greater reduction in HR by bisoprolol and plasma BNP by carvedilol..
136. C Ojaimi, W Li, S Kinugawa, H Post, A Csiszar, P Pacher, G Kaley, TH Hintze, Transcriptional basis for exercise limitation in male eNOS-knockout mice with age: heart failure and the fetal phenotype, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.00170.2005, 289, 4, H1399-H1407, 2005.10, Endothelium-derived nitric oxide (NO) is pivotal in regulating mitochondrial O-2 consumption ((V)over dotO(2)) and glucose uptake in mice. The aim of this study was to investigate the mechanism of age- and genotype-related exercise limitation in male endothelial NO synthase (eNOS)-knockout (KO, n=16) and wild-type (WT, n=19) mice. Treadmill testing was performed at 12, 14, 16, 18, and 21 mo of age. (V)over dotO(2), CO2 production, respiratory exchange ratio, and maximal running distance were determined during treadmill running. There were good linear correlations for increase of speed with increase of (V)over dotO(2). The difference between KO and WT mice was not significant at 12 mo but was significant at 18 mo. Linear regression showed that KO mice consumed more O-2 at the same absolute and relative workloads, suggesting that (V)over dotO(2) was not inhibited by NO in KO mice. KO mice performed 30-50% less work than WT mice at each age (work=vertical distance x weight). In contrast to WT mice, the work performed by KO mice significantly decreased from 17 +/- 1.4 m.kg at 12 mo to 9.4 +/- 1.7 m.kg at 21 mo. Running distance was significantly decreased from 334 +/- 27 m at 12 mo to 178 +/- 38 m at 21 mo, and maximal (V)over dotO(2), CO2 production, and respiratory exchange ratio per work unit were significantly higher in KO than in WT mice. Gene arrays showed evidence of a fetal phenotype in KO mice at 21 mo. In conclusion, age- and genotype-related exercise limitations in maximal work performed and maximal running distance in male eNOS-KO mice indicated that fetal phenotype and age were related to onset of heart failure..
137. Kinugawa S, Tsutsui H, Hayashidani S, Ide T, Suematsu N, Satoh S, Utsumi H, Takeshita A, Treatment with dimethylthiourea prevents left ventricular remodeling and failure after experimental myocardial infarction in mice: role of oxidative stress, Circ Res, 87, 5, 392-398, 2000.02.
138. Li M, Hirano K, Ikeda Y, Higashi M, Hashimoto C, Zhang B, Kozawa J, Sugimura K, Miyauchi H, Suzuki A, Hara Y, Takagi A, Ikeda Y, Kobayashi K, Futsukaichi Y, Zaima N, Yamaguchi S, Shrestha R, Nakamura H, Kawaguchi K, Sai E, Hui SP, Nakano Y, Sawamura A, Inaba T, Sakata Y, Yasui Y, Nagasawa Y, Kinugawa S, Shimada K, Yamada S, Hao H, Nakatani D, Ide T, Amano T, Naito H, Nagasaka H, Kobayashi K, on behlf of the Japan TGCV study group, Triglyceride deposit cardiomyovasculopathy: a rare cardiovascular disorder, Orphanet J Rare Dis, 14, 1, 134, 2019.01.
139. Takahiro Abe, Takashi Yokota, Arata Fukushima, Naoya Kakutani, Takashi Katayama, Ryosuke Shirakawa, Satoshi Maekawa, Hideo Nambu, Yoshikuni Obata, Katsuma Yamanashi, Ippei Nakano, Shingo Takada, Isao Yokota, Koichi Okita, Shintaro Kinugawa, Toshihisa Anzai, Type 2 diabetes is an independent predictor of lowered peak aerobic capacity in heart failure patients with non-reduced or reduced left ventricular ejection fraction., Cardiovascular diabetology, 10.1186/s12933-020-01114-4, 19, 1, 142-142, 2020.09, BACKGROUND: Although type 2 diabetes mellitus (T2DM) is one of the most frequent comorbidities in patients with chronic heart failure (CHF), the effects of T2DM on the exercise capacity of CHF patients are fully unknown. Here, we tested the hypothesis that the coexistence of T2DM lowers CHF patients' peak aerobic capacity. METHODS: We retrospectively analyzed the cases of 275 Japanese CHF patients with non-reduced ejection fraction (left ventricular ejection fraction [LVEF] ≥ 40%) or reduced EF (LVEF < 40%) who underwent cardiopulmonary exercise testing. We divided them into diabetic and nondiabetic groups in each CHF cohort. RESULTS: The mean peak oxygen uptake (VO2) value was 16.87 mL/kg/min in the non-reduced LVEF cohort and 15.52 mL/kg/min in the reduced LVEF cohort. The peak VO2 was lower in the diabetics versus the nondiabetics in the non-reduced LVEF cohort with the mean difference (95% confidence interval [95% CI]) of - 0.93 (- 1.82 to - 0.04) mL/kg/min and in the reduced LVEF cohort with the mean difference of - 1.05 (- 1.96 to - 0.15) mL/kg/min, after adjustment for age-squared, gender, anemia, renal function, LVEF, and log B-type natriuretic peptide (BNP). The adjusted VO2 at anaerobic threshold (AT), a submaximal aerobic capacity, was also decreased in the diabetic patients with both non-reduced and reduced LVEFs. Intriguingly, the diabetic patients had a lower adjusted peak O2 pulse than the nondiabetic patients in the reduced LVEF cohort, but not in the non-reduced LVEF cohort. A multivariate analysis showed that the presence of T2DM was an independent predictor of lowered peak VO2 in CHF patients with non-reduced LVEF and those with reduced LVEF. CONCLUSIONS: T2DM was associated with lowered peak VO2 in CHF patients with non-reduced or reduced LVEF. The presence of T2DM has a negative impact on CHF patients' exercise capacity, and the degree of impact is partly dependent on their LV systolic function..
140. Shouji Matsushima, Junya Kuroda, Peiyong Zhai, Tong Liu, Shohei Ikeda, Narayani Nagarajan, Shin-ichi Oka, Takashi Yokota, Shintaro Kinugawa, Chiao-Po Hsu, Hong Li, Hiroyuki Tsutsui, Junichi Sadoshima, Tyrosine kinase FYN negatively regulates NOX4 in cardiac remodeling, JOURNAL OF CLINICAL INVESTIGATION, 10.1172/JCI85624, 126, 9, 3403-3416, 2016.09, NADPH oxidases (Noxes) produce ROS that regulate cell growth and death. NOX4 expression in cardiomyocytes (CMs) plays an important role in cardiac remodeling and injury, but the posttranslational mechanisms that modulate this enzyme are poorly understood. Here, we determined that FYN, a Src family tyrosine kinase, interacts with the C-terminal domain of NOX4. FYN and NOX4 colocalized in perinuclear mitochondria, ER, and nuclear fractions in CMs, and FYN expression negatively regulated NOX4-induced O-2(-) production and apoptosis in CMs. Mechanistically, we found that direct phosphorylation of tyrosine 566 on NOX4 was critical for this FYN-mediated negative regulation. Transverse aortic constriction activated FYN in the left ventricle (LV), and FYN-deficient mice displayed exacerbated cardiac hypertrophy and dysfunction and increased ROS production and apoptosis. Deletion of Nox4 rescued the exaggerated LV remodeling in FYN-deficient mice. Furthermore, FYN expression was markedly decreased in failing human hearts, corroborating its role as a regulator of cardiac cell death and ROS production. In conclusion, FYN is activated by oxidative stress and serves as a negative feedback regulator of NOX4 in CMs during cardiac remodeling..
141. Eriko Kawamura, Minako Maruyama, Jiro Abe, Akira Sudo, Atsuhito Takeda, Shingo Takada, Takashi Yokota, Shintaro Kinugawa, Hideyoshi Harashima, Yuma Yamada, Validation of Gene Therapy for Mutant Mitochondria by Delivering Mitochondrial RNA Using a MITO-Porter., Molecular therapy. Nucleic acids, 10.1016/j.omtn.2020.04.004, 20, 687-698, 2020.04, Here, we report on validating a mitochondrial gene therapy by delivering nucleic acids to mitochondria of diseased cells by a MITO-Porter, a liposome-based carrier for mitochondrial delivery. We used cells derived from a patient with a mitochondrial disease with a G625A heteroplasmic mutation in the tRNAPhe of the mitochondrial DNA (mtDNA). It has been reported that some mitochondrial gene diseases are caused by heteroplasmic mutations, in which both mutated and wild-type (WT) genes are present, and the accumulation of pathological mutations leads to serious, intractable, multi-organ diseases. Therefore, the decrease of the mutated gene rate is considered to be a useful gene therapy strategy. To accomplish this, wild-type mitochondrial pre-tRNAPhe (pre-WT-tRNAPhe), prepared by in vitro transcription, was encapsulated in the MITO-Porter. The pre-WT-tRNAPhe encapsulated in the MITO-Porter was transfected into diseased mitochondrial cells, and the resulting mutant levels were examined by an amplification refractory mutation system (ARMS)-quantitative PCR. The mutation rate of tRNAPhe was decreased, and this therapeutic effect was sustained even on the 8th day after transfection. Furthermore, mitochondrial respiratory activity of the disease cells was increased after the transfection of therapeutic pre-WT-tRNAPhe. These results support the conclusion that the mitochondrial delivery of therapeutic nucleic acids represents a viable strategy for mitochondrial gene therapy..
142. Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Daisuke Goto, Hiroyuki Tsutsui, Weekend versus weekday hospital admission and outcomes during hospitalization for patients due to worsening heart failure: a report from Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD), HEART AND VESSELS, 10.1007/s00380-013-0359-5, 29, 3, 328-335, 2014.05, The day of the week of admission may influence the length of stay and in-hospital death. However, the association between the admission day of the week and in-hospital outcomes has been inconsistent in heart failure (HF) patients among studies reported from Western countries. We thus analyzed this association in HF patients encountered in routine clinical practice in Japan. We studied the characteristics and in-hospital treatment in 1620 patients hospitalized with worsening HF by using the database of the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Patients were divided into two groups according to weekday (n = 1355; 83.6 %) or weekend admission (n = 265; 16.4 %). The mean age was 70.7 years and 59.4 % were male. Etiology was ischemic in 34.0 %, and mean left ventricular ejection fraction was 42.5 %. Patients admitted on the weekend were significantly older and had more comorbidities, and more severe symptoms and signs of HF on admission. Length of stay was comparable between weekend and weekday admission (35.2 +/- 47.0 days vs 33.6 +/- 32.0 days, P = 0.591). Crude in-hospital mortality did not differ between patients admitted on the weekend and weekdays (7.5 % vs 5.2 %, P = 0.136). Even after adjustment for covariates in multivariable modeling with patients admitted on weekday as the reference, in-hospital death was comparable between patients admitted on the weekend and weekdays (adjusted odds ratio 1.125, 95 % confidence interval 0.631-2.004, P = 0.691). Among patients hospitalized for worsening HF, admission day of the week did not affect in-hospital death and length of stay..
143. [Ca channel blocker and heart failure]..
144. [Multidisciplinary management for heart failure --prevention, diagnosis and updated treatment]..
145. [Inotropic drug]..
146. [Myocardial ischemia and metabolic disorder]..
147. [Diabetic heart disease]..
148. [Molecular mechanisms of chronic heart failure]..
149. [Recovery from circulatory support with long term left ventricular assist device in a 29-year-old woman with fulminant giant cell myocarditis]..
150. [Oxidative stress and heart failure]..
151. S Kinugawa, JH Zhang, E Messina, E Walsh, H Huang, PM Kaminski, MS Wolin, TH Hintze, gp91(phox)-containing NAD(P)H oxidase mediates attenuation of nitric oxide-dependent control of myocardial oxygen consumption by ANG II, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 10.1152/ajpheart.00076.2005, 289, 2, H862-H867, 2005.08, We have previously reported that ANG II stimulation increased superoxide anion (O-2(-)) through the activation of NAD(P)H oxidase and inhibited nitric oxide (NO)-dependent control of myocardial oxygen consumption (M(V) over dot(O2)) by scavenging NO. Our objective was to investigate the role of NAD(P)H oxidase, especially the gp91(phox) subunit, in the NO-dependent control of M(V) over dot(O2). M(V) over dot(O2) in mice with defects in the expression of gp91(phox) [gp91(phox)(-/-)] was measured with a Clark-type oxygen electrode. Baseline M(V) over dot(O2) was not significantly different between wild-type (WT) and gp91(phox)(-/-) mice. Stimulation of NO production by bradykinin (BK) induced significant decreases in M(V) over dot(O2) in WT mice. BK-induced reduction in M(V) over dot(O2) was enhanced in gp91(phox)(-/-) mice. BK-induced reduction in M(V) over dot(O2) in WT mice was attenuated by 10(-8) mol/l ANG II, which was restored by coincubation with Tiron or apocynin. In contrast to WT mice, BK-induced reduction in M(V) over dot(O2) in gp91(phox)(-/-) mice was not altered by ANG II. There was a decrease in lucigenin (5 x 10(-6) mol/l)-detectable O-2(-) in gp91(phox)(-/-) mice compared with WT mice. ANG II resulted in significant increases in O-2(-) production in WT mice, which was inhibited by coincubation with Tiron or apocynin. However, ANG II had no effect on O-2(-) production in gp91(phox)(-/-) mice. Histological examination showed that the development of abscesses and/or the invasion of inflammatory cells occurred in lungs and livers but not in hearts and kidneys from gp91(phox)(-/-) mice. These results indicate that the gp91(phox) subunit of NAD(P)H oxidase mediates O-2(-) production through the activation of NAD(P)H oxidase and attenuation of NO-dependent control of M(V) over dot(O2) by ANG II..