Hiroshi Akazawa

The University of Tokyo, Edo, Tōkyō, Japan

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Publications (107)567.54 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Engineering of three-dimensional (3D) cardiac tissues using decellularized extracellular matrix could be a new technique to create an "organ-like" structure of the heart. To engineer artificial hearts functionally comparable to native hearts, however, much remain to be solved including stable excitation-propagation. To elucidate the points, we examined conduction properties of engineered tissues. We repopulated the decellularized hearts with neonatal rat cardiac cells and then, we observed excitation-propagation of spontaneous beatings using high resolution cameras. We also conducted immunofluorescence staining to examine morphological aspects. Live tissue imaging revealed that GFP-labeled-isolated cardiac cells were migrated into interstitial spaces through extravasation from coronary arteries. Engineered hearts repopulated with Ca(2+)-indicating protein (GCaMP2)-expressing cardiac cells were subjected to optical imaging experiments. Although the engineered hearts generally showed well-organized stable excitation-propagation, the hearts also demonstrated arrhythmogenic propensity such as disorganized propagation. Immunofluorescence study revealed randomly-mixed alignment of cardiomyocytes, endothelial cells and smooth muscle cells. The recellularized hearts also showed disarray of cardiomyocytes and markedly decreased expression of connexin43. In conclusion, we successfully demonstrated that the recellularized hearts showed dynamic excitation-propagation as a "whole organ". Our strategy could provide prerequisite information to construct a 3D-engineered heart, functionally comparable to the native heart.
    Biomaterials 06/2014; · 8.31 Impact Factor
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    ABSTRACT: Enzymatic proteolysis by calpains, Ca(2+)-dependent intracellular cysteine proteases, has been implicated in pathological processes such as cellular degeneration or death. Here, we investigated the role of calpain activation in the hearts subjected to myocardial infarction. We produced myocardial infarction in Cast(-/-) mice deficient for calpastatin, the specific endogenous inhibitory protein for calpains, and Cast(+/+) mice. The activity of cardiac calpains in Cast(+/+) mice was not elevated within 1 day, but showed a gradual elevation after 7 days following myocardial infarction, which was further pronounced in Cast(-/-) mice. Although the prevalence of cardiomyocyte death was indistinguishable between Cast(-/-) and Cast(+/+) mice, Cast(-/-) mice exhibited profound contractile dysfunction and chamber dilatation and showed a significant reduction in survival rate after myocardial infarction, as compared with Cast(+/+) mice. Notably, immunofluorescence revealed that, at 28 days after myocardial infarction, calpains were activated in cardiomyocytes exclusively at the border zone, and that Cast(-/-) mice showed higher intensity and broader extent of calpain activation at the border zone than Cast(+/+) mice. In the border zone of Cast(-/-) mice, pronounced activation of calpains was associated with a decrease in N-cadherin expression and up-regulation of molecular markers for cardiac hypertrophy and fibrosis. In cultured rat neonatal cardiomyocytes, activation of calpains by treatment with ionomycin induced cleavage of N-cadherin, and decreased expression levels of β-catenin and connexin 43, which was attenuated by calpain inhibitor. These results thus demonstrate that activation of calpains disassembles cell-cell adhesion at intercalated discs by degrading N-cadherin, and thereby promotes left ventricular remodeling after myocardial infarction.
    The Journal of biological chemistry. 06/2014;
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    ABSTRACT: Periodontitis is known to be a risk factor for abdominal aortic aneurysm (AAA). However, the influence of periodontitis on AAA in Japanese patients has not yet been elucidated. The aim of this clinical investigation was to assess the relationship between periodontal bacterial burden in AAA patients.We studied 12 AAA patients and 24 age- and sex-matched non-AAA cardiovascular patients. We examined periodontitis and the presence of the periodontal pathogens Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia in oral samples using polymerase chain reaction assays.We found that the AAA patients had deeper pocket depth compared to the non-AAA patients (3.53 ± 0.38 mm versus 2.67 ± 0.17 mm, P < 0.05). However, the populations of periodontal bacteria were comparable between the two groups. Periodontitis may have a greater effect on aneurysm progression compared to other cardiovascular diseases.
    International Heart Journal 05/2014; · 1.23 Impact Factor
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    ABSTRACT: Although there is a link between periodontitis and cardiovascular disease (CVD), the influence of periodontitis on CVD is unclear. The aim of this study was to assess the relationship between periodontal bacterial burden and CVD. We studied 142 patients with tachyarrhythmia (TA) and 25 patients with abdominal aortic aneurysm (AAA). We examined periodontitis and the presence of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans and Prevotella intermedia in the patients' saliva and subgingival plaque using PCR. We also measured serum antibody titers against the pathogens using ELISA. We found that the patients with AAA had fewer remaining teeth (14.6 ± 2.0 vs. 20.9 ± 0.7, P < 0.05) and deeper pocket depth (3.01 ± 0.26 vs. 2.52 ± 0.05 mm, P < 0.05) compared to the TA patients. The existence of each periodontal bacterium in their saliva or subgingival plaque and serum antibody titers was comparable between the two groups. Periodontitis may have a larger affect on aneurysm progression compared to arrhythmia.
    Heart and Vessels 04/2014; · 2.13 Impact Factor
  • Hiroshi Akazawa, Issei Komuro
    Cardiovascular research 03/2014; · 5.81 Impact Factor
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    ABSTRACT: Cardiac hypertrophy is an adaptive response to physiological and pathological overload. In response to the overload, individual cardiac myocytes become mechanically stretched and activate intracellular hypertrophic signaling pathways to re-use embryonic transcription factors and to increase the synthesis of various proteins, such as structural and contractile proteins. These hypertrophic responses increase oxygen demand and promote myocardial angiogenesis to dissolve the hypoxic situation and to maintain cardiac contractile function; thus, these responses suggest crosstalk between cardiac myocytes and microvasculature. However, sustained pathological overload induces maladaptation and cardiac remodeling, resulting in heart failure. In recent years, specific understanding has increased with regard to the molecular processes and cell-cell interactions that coordinate myocardial growth and angiogenesis. In this review, we summarize recent advances in understanding the regulatory mechanisms of coordinated myocardial growth and angiogenesis in the pathophysiology of cardiac hypertrophy and heart failure.
    Circulation Research 01/2014; 114(3):565-571. · 11.86 Impact Factor
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    ABSTRACT: Increasing evidence suggests a critical role for mitochondrial aldehyde dehydrogenase 2 (ALDH2) in protection against cardiac injuries; however, the downstream cytosolic actions of this enzyme are largely undefined.
    Journal of the American Heart Association. 01/2014; 3(5).
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    ABSTRACT: Although periodontitis is a risk factor for cardiovascular disease (CVD), the influence of periodontitis on Marfan syndrome (MFS) with CVD is unclear. The aim of this study was to assess the relationship between periodontal bacterial burden and MSF with CVD. The subjects were patients with MFS with CVD (n = 47); age and gender matched non-MFS CVD patients (n = 48) were employed as controls. Full-mouth clinical measurements, including number of teeth, probing of pocket depth (PD), bleeding on probing (BOP) and community periodontal index (CPI) were recorded. We also evaluated the existence of three periodontal pathogens, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia using polymerase chain reaction assays. Serum antibody titers against the pathogens were also measured. We revealed that MFS with CVD patients had periodontitis more frequently than the age and gender matched non-MFS CVD control subjects. MFS with CVD patients had significantly severer periodontitis, fewer remaining teeth and deeper PD compared to the non-MFS CVD controls. Furthermore, the serum antibody titer level against Prevotella intermedia was significantly lower in MFS plus CVD patients compared to the non-MFS CVD patients. Periodontitis may influence the pathophysiology of cardiovascular complications in MFS patients. A specific periodontal pathogen might be a crucial therapeutic target to prevent CVD development.
    PLoS ONE 01/2014; 9(4):e95521. · 3.53 Impact Factor
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    ABSTRACT: Recent epidemiological studies suggest that periodontitis is a major risk factor for renal failure and cerebral infarction. The aim of this study was to evaluate the association among periodontitis, renal failure, and cerebral infarction, focusing on microbiological and immunological features. Twenty-one patients treated with hemodialysis (HD) were enrolled in this study. They were 8 with diabetic nephropathy and 13 with non-diabetic nephropathy. Blood examination, periodontal examination, brain magnetic resonance image (MRI), and dental radiography were performed on all patients. Subgingival plaque, saliva, and blood samples were analyzed for the periodontal pathogens, Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), Porphyromonas gingivalis (P. gingivalis), and Prevotella intermedia (P. intermedia) using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). We found that the patients with diabetic nephropathy had more A. actinomycetemcomitans compared with non-diabetic nephropathy (P = 0.038) in dental plaque. Furthermore, the patients with diabetic nephropathy showed a significantly higher incidence of cerebral infarction compared with those with non-diabetic nephropathy (P = 0.029). Clinical oral and radiographic scores tended to be higher among patients in the diabetic nephropathy group than in the non-diabetic nephropathy group. Periodontal pathogens, particularly A. actinomycetemcomitans, may play a role, at least a part, in the development of cerebral infarction in Japanese HD patients with diabetic nephropathy.
    BMC Infectious Diseases 11/2013; 13(1):557. · 3.03 Impact Factor
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    ABSTRACT: Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the extracellular matrix protein fibrillin-1. While it is known that patients with MFS are at high risk of dental disorders and cardiovascular diseases, little information has been provided to date. To clarify the prevalence of periodontitis in patients with MFS, their oral condition and cardiovascular complications were evaluated. The subjects were patients with MFS (n = 40) who attended the University of Tokyo hospital; age- and gender-matched healthy individuals (n = 14) constituted a control group. Cardiovascular complications and full-mouth clinical measurements, including number of teeth, probing of pocket depth (PD), bleeding on probing (BOP), and community periodontal index (CPI) were recorded. MFS patients had more frequent cardiovascular complications (95 %) compared with the controls (0 %). MFS patients had periodontitis (CPI 3 and 4) more frequently (87.5 %) than the age- and gender-matched control subjects (35.7 %). Furthermore, MFS patients had significantly more severe periodontitis (CPI 2.90 ± 0.12 vs 1.64 ± 0.32) and fewer remaining teeth (26.7 ± 0.4 vs 28.4 ± 0.4) compared with the controls. However, PD and BOP were comparable between MFS patients and the control group. A high incidence of periodontitis and cardiovascular complications was observed in Japanese MFS patients.
    Heart and Vessels 11/2013; · 2.13 Impact Factor
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    ABSTRACT: Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.Hypertension Research advance online publication, 30 May 2013; doi:10.1038/hr.2013.52.
    Hypertension Research 05/2013; · 2.79 Impact Factor
  • Yoko Sakamoto, Hiroshi Akazawa, Issei Komuro
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    ABSTRACT: Calpains are Ca(2 +) -dependent cysteine proteases. Fifteen gene products of calpains are expressed in mammals. Among them, Calpain 1 and Calpain 2 are ubiquitously expressed and have been investigated extensively. Under the physiological conditions, calpain activity is strictly regulated by endogenous inhibitory protein, Calpastatin. Calpains are activated in the various cardiovascular diseases and implicated in their pathogenesis by degrading numerous target proteins. Here we briefly summarize the physiological and pathological role of calpains in the cardiovascular diseases.
    Clinical calcium 04/2013; 23(4):519-25.
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    ABSTRACT: The octapeptide angiotensin II (Ang II) plays a homeostatic role in the regulation of blood pressure and water and electrolyte balance, and also contributes to the progression of cardiovascular remodeling. Ang II activates Ang II type 1 (AT1) receptor and type 2 (AT2) receptor, both of which belong to the seven-transmembrane, G protein-coupled receptor family. Most of the actions of Ang II such as promotion of cellular prolifaration, hypertrophy, and fibrosis are mediated by AT1 receptor. However, in some pathological situations, AT2 receptor shows an increase in tissue expression and functions to antagonize the actions induced by AT1 receptor. Recent studies have advanced our understanding of the molecular mechanisms underlying receptor activation and signal transduction of AT1 and AT2 receptor in the cardiovascular system.
    Current pharmaceutical design 11/2012; · 4.41 Impact Factor
  • Hiroshi Akazawa, Issei Komuro
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    ABSTRACT: Pharmacological inhibitions of the renin-angiotensin-aldosterone system (RAAS) are crowned with one of the greatest success in the current field of cardiovascular medicine. In addition to the systemic effects including elevation of blood pressure and retention of sodium and water, sustained and excessive RAAS activation has direct and deleterious effects on a wide variety of tissues. Recent studies have deciphered the regulatory mechanisms underlying tissue RAAS activation at cellular and molecular levels, and suggested pathogenic roles of RAAS activation in hitherto unanticipated disorders such as muscular dystrophy, osteoporosis, cancer, and aging itself. Novel drugs targeting RAAS are under research and development in search for further efficacy, specificity, and even multifunctionality. This review will discuss the current progress and future perspective of RAAS research.
    Nippon rinsho. Japanese journal of clinical medicine 09/2012; 70(9):1471-6.
  • Hiroshi Akazawa, Issei Komuro
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    ABSTRACT: A growing body of evidence indicates that activation of angiotensin II (Ang II) type 1 (AT1) receptor, a seven -transmembrane G protein -coupled receptor, is critically involved in the development of various cardiovascular diseases. Inherently, AT1 receptor is structurally unstable, and shows spontaneous constitutive activity in an Ang II-independent manner. The constitutive activity of AT1 receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when AT1 receptor is up-regulated in the heart. Furthermore, mechanical stress can activate AT1 receptor by inducing conformational switch without the involvement of Ang II, and induce cardiac hypertrophy in vivo. These agonist-independent activities of AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonism of AT1 receptor blockers provides therapeutic benefits in the prevention of cardiac remodeling, and thus has potential impact on long-term outcomes in patients with cardiovascular diseases.
    Nippon rinsho. Japanese journal of clinical medicine 09/2012; 70(9):1492-8.
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    ABSTRACT: Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.
    Cell 06/2012; 149(6):1298-313. · 31.96 Impact Factor
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    ABSTRACT: A growing body of evidence has suggested that the use of angiotensin II (Ang II) type 1 (AT(1)) receptor blockers (ARBs) leads to a significant decrease in mortality and morbidity in patients with congestive heart failure. The AT(1) receptor is a seven-transmembrane G protein-coupled receptor, and is involved in regulating the physiological and pathological process of the cardiovascular system. Systemically and locally generated Ang II has agonistic action on AT(1) receptor. However, recent in vitro studies have demonstrated that AT(1) receptor is structurally flexible and instable, and has significant and varying levels of spontaneous activity in an Ang II-independent manner. Furthermore, mechanical stress activates AT(1) receptor by inducing conformational switch without the involvement of Ang II. Experimental studies have demonstrated that Ang II-independent activation of AT(1) receptor is profoundly relevant to the pathogenesis of cardiac remodeling in vivo, and that these agonist-independent activities of AT(1) receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonist activity emerges as an important pharmacological parameter that contributes to cardioprotective effects of ARBs through inhibiting both Ang II-dependent and -independent activation of AT(1) receptor.
    Cardiovascular Drugs and Therapy 04/2012; · 2.67 Impact Factor
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    ABSTRACT: The angiotensin II (Ang II) type 1 (AT(1)) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT(1) receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II-independent AT(1) receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT(1) receptor under the control of α-myosin heavy chain promoter in angiotensinogen-knockout background (AT(1)Tg-AgtKO mice). In AT(1)Tg-AgtKO hearts, redistributions of the Gα(q11) subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT(1) receptor is constitutively activated independent of Ang II. As a consequence, AT(1)Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT(1)Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT(1) receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT(1) receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT(1) receptor is upregulated in the heart.
    Hypertension 03/2012; 59(3):627-33. · 6.87 Impact Factor
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    ABSTRACT: Ryanodine receptor type 2 (RyR-2) mediates Ca(2+) release from sarcoplasmic reticulum and contributes to myocardial contractile function. However, the role of RyR-2 in the development of cardiac hypertrophy is not completely understood. Here, mice with or without reduction of RyR-2 gene (RyR-2(+/-) and wild-type, respectively) were analyzed. At baseline, there was no difference in morphology of cardiomyocyte and heart and cardiac contractility between RyR-2(+/-) and wild-type mice, although Ca(2+) release from sarcoplasmic reticulum was impaired in isolated RyR-2(+/-) cardiomyocytes. During a 3-week period of pressure overload, which was induced by constriction of transverse aorta, isolated RyR-2(+/-) cardiomyocytes displayed more reduction of Ca(2+) transient amplitude, rate of an increase in intracellular Ca(2+) concentration during systole, and percentile of fractional shortening, and hearts of RyR-2(+/-) mice displayed less compensated hypertrophy, fibrosis, and contractility; more apoptosis with less autophagy of cardiomyocytes; and similar decrease of angiogenesis as compared with wild-type ones. Moreover, constriction of transverse aorta-induced increases in the activation of calcineurin, extracellular signal-regulated protein kinases, and protein kinase B/Akt but not that of Ca(2+)/calmodulin-dependent protein kinase II, and its downstream targets in the heart of wild-type mice were abolished in the RyR-2(+/-) one, suggesting that RyR-2 is a regulator of calcineurin, extracellular signal-regulated protein kinases, and Akt but not of calmodulin-dependent protein kinase II activation during pressure overload. Taken together, our data indicate that RyR-2 contributes to the development of cardiac hypertrophy and adaptation of cardiac function during pressure overload through regulation of the sarcoplasmic reticulum Ca(2+) release; activation of calcineurin, extracellular signal-regulated protein kinases, and Akt; and cardiomyocyte survival.
    Hypertension 12/2011; 58(6):1099-110. · 6.87 Impact Factor
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    ABSTRACT: Macrophages are integrated into adipose tissues and interact with adipocytes in obese subjects, thereby exacerbating adipose insulin resistance. This study aimed to elucidate the molecular mechanism underlying the insulin-sensitizing effect of the angiotensin II receptor blocker (ARB) valsartan, as demonstrated in clinical studies. Insulin signaling, i.e., insulin receptor substrate-1 and Akt phosphorylations, in 3T3-L1 adipocytes was impaired markedly by treatment with tumor necrosis factor-α (TNFα) or in the culture medium of lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages, and valsartan had no effects on these impairments. However, in contrast, when cocultured with RAW 264.7 cells using a transwell system, the LPS-induced insulin signaling impairment in 3T3-L1 adipocytes showed almost complete normalization with coaddition of valsartan. Furthermore, valsartan strongly suppressed LPS-induced productions of cytokines such as interleukin (IL)-1β, IL-6, and TNFα with nuclear factor-κB activation and c-Jun NH(2)-terminal kinase phosphorylation in RAW 264.7 and primary murine macrophages. Very interestingly, this effect of valsartan was also observed in THP-1 cells treated with angiotensin II type 1 (AT1) siRNA or a peroxisome proliferator-activated receptor-γ (PPARγ) antagonist as well as macrophages from AT1a receptor-knockout mice. We conclude that valsartan suppresses the inflammatory response of macrophages, albeit not via PPARγ or the AT1a receptor. This suppression appears to secondarily improve adipose insulin resistance.
    AJP Endocrinology and Metabolism 11/2011; 302(3):E286-96. · 4.51 Impact Factor

Publication Stats

3k Citations
567.54 Total Impact Points

Institutions

  • 2004–2014
    • The University of Tokyo
      • Faculty & Graduate School of Medicine
      Edo, Tōkyō, Japan
    • University Hospital Medical Information Network
      Edo, Tōkyō, Japan
  • 2010–2013
    • Osaka City University
      • Department of Cardiovascular Medicine
      Ōsaka, Ōsaka, Japan
  • 2011
    • Tokyo Women's Medical University
      • Department of Cardiology
      Tokyo, Tokyo-to, Japan
  • 2007–2009
    • Chiba University
      • Graduate School of Medicine
      Chiba-shi, Chiba-ken, Japan
    • Seirei Yokohama Hospital
      Yokohama, Kanagawa, Japan
  • 2005
    • Gunma Children's Medical Center
      Shibukawa, Gunma Prefecture, Japan
  • 2003
    • Kanazawa Medical University
      • Department of Cardiology
      Kanazawa-shi, Ishikawa-ken, Japan
  • 2000
    • Japanese Foundation for Cancer Research
      Edo, Tōkyō, Japan