Masafumi Watanabe

The University of Tokyo, Tōkyō, Japan

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Publications (35)121.81 Total impact

  • Amyloid 11/2014; DOI:10.3109/13506129.2014.987865 · 2.51 Impact Factor
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    ABSTRACT: Purpose The physiological role of vasomotion, rhythmic oscillations in vascular tone or diameter, and its underlying mechanisms are unknown. We investigated the characteristics of brachial artery vasomotion in patients with ischemic heart disease (IHD). Methods We performed a retrospective study of 37 patients with IHD. Endothelial function was assessed using flow-mediated dilation (FMD), and power spectral analysis of brachial artery diameter oscillations during FMD was performed. Frequency-domain components were calculated by integrating the power spectrums in three frequency bands (in ms2) using the MemCalc (GMS, Tokyo, Japan): very-low frequency (VLF), 0.003–0.04 Hz; low frequency (LF), 0.04–0.15 Hz; and high frequency (HF), 0.15–0.4 Hz. Total spectral power (TP) was calculated as the sum of all frequency bands, and each spectral component was normalized against TP. Results Data revealed that HF/TP closely correlated with FMD (r = −0.33, p = 0.04), whereas VLF/TP and LF/TP did not. We also explored the relationship between elevated C-reactive protein (CRP) levels and vasomotion. HF/TP was significantly increased in subjects with high CRP levels (CRP;>0.08 mg/dL) compared with subjects with low CRP levels (0.052±0.026 versus 0.035±0.022, p<0.05). The HF/TP value closely correlated with CRP (r = 0.24, p = 0.04), whereas the value of FMD did not (r = 0.023, p = 0.84). In addition, elevated CRP levels significantly increased the value of HF/TP after adjustment for FMD and blood pressure (β = 0.33, p<0.05). Conclusion The HF component of brachial artery diameter oscillation during FMD measurement correlated well with FMD and increased in the presence of elevated CRP levels in subjects with IHD.
    PLoS ONE 10/2014; 9(10):e110013. DOI:10.1371/journal.pone.0110013 · 3.53 Impact Factor
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    ABSTRACT: Background In-stent restenosis (ISR) is still a recognized clinical problem in the era of drug-eluting stent (DES). Some previous studies have suggested that circulating eosinophils play an important role in both restenosis and thrombosis after DES implantation. However, the contribution of eosinophils to the pathogenesis of ISR has not yet been concisely clarified. Case Report We present the case of an 83-year-old male Japanese patient with ISR exacerbated by drug-induced severe eosinophilia. He had previous histories of coronary stent implantations by DES and was referred to our hospital because of erythema with severe eosinophilia (maximum was 6500/μl [48% of total white blood cell count]). Around the same time, the patient developed ISR, for which a stent was deployed 2 years earlier. Arterial wall injury due to the increase in circulating eosinophils was verified in several findings, such as the increase of D-dimer and brain natriuretic peptide. In addition, the histology of the resected tissue from erythema demonstrated that the nuclei of endothelial cells were swollen where eosinophils and lymphocytes heavily infiltrated into the extravascular space, suggesting the presence of vascular injury. This injury due to the increase in circulating eosinophils may have a marked impact on the pathologic process of ISR in DES implantation. Conclusions Just a few anecdotal reports are available of ISR occurring in the setting of hypereosinophilia. The clarification of the mechanism in this patient provides a new effective therapeutic strategy against ISR in the setting of DES implantation.
    09/2014; 15:397-400. DOI:10.12659/AJCR.891106
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    ABSTRACT: The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.
    Journal of Clinical Hypertension 07/2014; 16(8). DOI:10.1111/jch.12366 · 2.96 Impact Factor
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    ABSTRACT: Aortic stenosis (AS) is the most common valvular disease and aortic valve replacement (AVR) is one of its most effective interventions. AS affects not only the left ventricle, but also vascular function beyond the stenotic valve, which can lead to various types of vascular dysfunction. However, research evaluating the effect of AS on aortic vascular function is limited. In this study, we investigated clinical meaning to evaluate endothelial function in subjects with AS. From April 2011 to April 2012, 20 consecutive adult patients with degenerative AS (mean age, 74.7 ± 7.4 years; range 50-83 years) who underwent AVR at our institution were included in the study. We measured flow-mediated dilation (FMD) to evaluate the effect of AS on endothelial function. The difference between brachial artery diameter (BAD) before (4.0 ± 0.7 mm) and after AVR (3.9 ± 0.6 mm) was not significant (p = 0.043), but FMD significantly improved after AVR (from 3.1 ± 1.8 to 6.0 ± 2.7 %, p < 0.0001). We also analyzed FMD × BAD index, endogenous vasodilatory capability independent of BAD, resulting that it also significantly increased after AVR (12.3 ± 7.0-22.5 ± 9.3, p < 0.0001). We divided patients into two groups by pre- to post-AVR change in FMD (ΔFMD); large-ΔFMD group [ΔFMD >3.0 % (median value)] and small-ΔFMD group (ΔFMD <3.0 %). There were no significant changes in age, blood pressure, heart rate, B-type natriuretic peptide, or echocardiographic parameters in either group. In contrast, BAD was significantly larger in the small ΔFMD group (4.3 ± 0.7 mm) than in the large ΔFMD group (3.7 ± 0.7 mm) (p = 0.030). In addition, cardio-thoracic ratio was significantly greater in the small ΔFMD group (58.4 ± 7.1 %) than in the large ΔFMD group (53.7 ± 4.6 %) (p = 0.048). Receiver operating characteristic curve analysis of BAD to differentiate large and small ΔFMD demonstrated an area under the curve of 0.750 (p = 0.059) and that optimal cutoff for BAD was 4.28 mm (70 % sensitivity, 80 % specificity). AVR in subjects with AS is associated with a significant improvement in FMD in the brachial artery. Measurement of the BAD may be helpful in distinguishing whether the impairment of FMD in AS derives from a stenotic valve or vascular remodeling.
    Heart and Vessels 02/2014; DOI:10.1007/s00380-014-0475-x · 2.11 Impact Factor
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    ABSTRACT: Background: Right atrial pressure (RAP) is commonly estimated using inferior vena cava (IVC) diameter and its respirophasic variations. Although a guideline has been provided for estimation of RAP due to variation in IVC dimensions based on studies in Western subjects, echocardiographic values in Asian subjects are unknown. Methods and Results: We studied 369 patients who underwent IVC ultrasound within 24h of right heart catheterization (RHC). The maximum and minimum IVC diameter during a respiratory cycle and the percent collapse after a sniff test were measured. These IVC parameters were compared with mean RAP measured on RHC. Receiver operating characteristic curves were generated for each IVC parameter to determine the optimal cut-off to detect RAP >10mmHg. The IVC maximum diameter cut-off for detecting RAP >10mmHg was 19mm (sensitivity, 75%; specificity, 78%) and the percent collapse cut-off was 30% (sensitivity, 75%; specificity, 83%). Both cut-offs were smaller than those previously reported in patients from Western countries. When the cut-off values from the existing guideline were applied to the present cohort, the sensitivity and specificity for normal RAP (0-5mmHg) were 38.6% and 74.2%, respectively, and 60.0% and 92.0% for elevated RAP (>10mmHg). Conclusions: The optimal IVC maximum diameter and percent collapse cut-offs to detect elevated RAP were smaller in Asian subjects than in a previously reported Western cohort.
    Circulation Journal 01/2014; 78(4). DOI:10.1253/circj.CJ-13-1234 · 3.69 Impact Factor
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    ABSTRACT: We conducted a retrospective study of 60 patients with ischemic heart disease (31 with diabetes and 29 without diabetes) to investigate the impact of diabetes on diurnal body temperature patterns. We found that the increase of axillary body temperature in the evening was reduced in the presence of diabetes, which was associated with autonomic neuropathy.
    Clinical Autonomic Research 01/2014; 24(2). DOI:10.1007/s10286-013-0223-9 · 1.86 Impact Factor
  • Eisuke Amiya, Masafumi Watanabe, Issei Komuro
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    ABSTRACT: Endothelial dysfunction and autonomic nervous system dysfunction are both risk factors for atherosclerosis. There is evidence demonstrating that there is a close interrelationship between these two systems. In hypertension, endothelial dysfunction affects the pathologic process through autonomic nervous pathways, and the pathophysiological process of autonomic neuropathy in diabetes mellitus is closely related with vascular function. However, detailed mechanisms of this interrelationship have not been clearly explained. In this review, we summarize findings concerning the interrelationship between vascular function and the autonomic nervous system from both experimental and clinical studies. The clarification of this interrelationship may provide more comprehensive risk stratification and a new effective therapeutic strategy against atherosclerosis.
    Annals of Vascular Diseases 01/2014; 7(2):109-19. DOI:10.3400/avd.ra.14-00048
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    ABSTRACT: Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 ± 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = -0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = -0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 ± 1.8 versus 15.2 ± 3.0 mm/m(2), p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.
    Heart and Vessels 07/2013; 29(4). DOI:10.1007/s00380-013-0393-3 · 2.11 Impact Factor
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    ABSTRACT: Melatonin is well known to have a beneficial effect on the cardiovascular system, but it remains to be elucidated whether melatonin has a therapeutic effect on the vascular damage induced by the potential vasoactive substance angiotensin II (Ang II). In this study, the effects of melatonin on Ang II-induced vascular endothelial damage were investigated. In cultured vascular endothelial cells, Ang II stimulation increased ROS generation and inhibited eNOS phosphorylation (Ser1177), both of which were clearly restored by pretreatment with melatonin. The translocation of p47(phox) subunit of NADPH oxidase from the cytosol to plasma membrane was promoted in Ang II-treated vascular endothelial cells, which was canceled by melatonin pretreatment. In Ang II-infused rats, increased ROS generation in the aortic wall and impaired endothelial function of the aortic ring were observed, which were rescued by coadministration of melatonin. In vasculature, melatonin receptor agonist ramelteon had the antioxidative effect in the same manner as melatonin by itself. These findings suggest that melatonin directly ameliorates Ang II-induced vascular endothelial damage partly via its antioxidative properties, providing with us the potential rationale for clinical application of melatonin to the prevention from cardiovascular diseases.
    Journal of Pineal Research 06/2013; DOI:10.1111/jpi.12071 · 7.81 Impact Factor
  • International journal of cardiology 05/2013; 168(1). DOI:10.1016/j.ijcard.2013.05.076 · 6.18 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor-A (VEGF-A) is one of the major angiogenic factors, and its actions are primarily mediated through its two membrane receptors, VEGFR-1 and VEGFR-2. A soluble form of VEGFR-1 (sVEGFR-1) sequesters the free form of VEGF-A, and acts as a potent anti-angiogenic factor. While sVEGFR-1 is synthesized as a splice variant of VEGF-R1 gene, the interactions between VEGF-A and sVEGFR-1 remain largely unknown. Here, we show that VEGF-A upregulates sVEGF-R1 expression in human vascular endothelial cells but leaves full-length VEGF-R1 expression unchanged, and that this induction was dependent on the VEGFR-2-protein kinase C-MEK signaling pathway. The VEGF-A-induced sVEGFR-1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis. performed.
    FEBS letters 05/2013; 587(14). DOI:10.1016/j.febslet.2013.05.038 · 3.34 Impact Factor
  • International journal of cardiology 05/2013; 168(3). DOI:10.1016/j.ijcard.2013.04.046 · 6.18 Impact Factor
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    ABSTRACT: Vascular endothelial function is impaired in hypercholesterolemia partly because of injury by modified LDL. In addition to modified LDL, free cholesterol (FC) is thought to play an important role in the development of endothelial dysfunction, although the precise mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms of endothelial dysfunction induced by an FC-rich environment. Loading cultured human aortic endothelial cells with FC induced the formation of vesicular structures composed of FC-rich membranes. Raft proteins such as phospho-caveolin-1 (Tyr14) and small GTPase Rac were accumulated towards FC-rich membranes around vesicular structures. In the presence of these vesicles, angiotensin II-induced production of reactive oxygen species (ROS) was considerably enhanced. This ROS shifted endothelial NOS (eNOS) toward vesicle membranes and vesicles with a FC-rich domain trafficked toward perinuclear late endosomes/lysosomes, which resulted in the deterioration of eNOS Ser 1177 phosphorylation and NO production. Angiotensin II-induced ROS decreased the bioavailability of eNOS under the FC-enriched condition.
    Journal of Biological Chemistry 04/2013; DOI:10.1074/jbc.M112.448522 · 4.60 Impact Factor
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    ABSTRACT: OBJECTIVE: To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc). METHODS: Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia. RESULTS: Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = -0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05). CONCLUSION: The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.
    Modern Rheumatology 03/2013; DOI:10.1007/s10165-013-0867-2 · 2.21 Impact Factor
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    ABSTRACT: Background: Differences in regulating factors and the clinical implications of body temperature variability (BTV) between subjects with and without diabetes have not been clarified to date. Methods and Results: In 66 subjects with ischemic heart disease (33 with diabetes and 33 without diabetes), BTV, the difference between the highest and lowest temperature measurements, and body temperature standard deviation (BT SD) were measured from axillary body temperature (ABT) records of 3 consecutive days and followed for 16.4±8.4 months. In subjects without diabetes BTV and BT SD were closely associated with endothelial function as evaluated on flow-mediated dilation (BTV, R=0.33, P=0.026; BT SD, R=0.41, P=0.029), whereas there was a poor association in subjects with diabetes. In the absence of an interrelationship between vascular function and thermoregulation, the contribution of inflammation to BTV was increased in subjects with diabetes (BTV, 0.59±0.21°C for C-reactive protein [CRP] <0.08mg/dl vs. 0.79±0.28°C for CRP >0.08mg/dl, P=0.014). Event-free survival analysis showed that in subjects with diabetes higher BT SD was associated with shorter event-free survival (log-rank P=0.012), but this relationship was not found in subjects without diabetes. Conclusions: In subjects with diabetes, the interrelationship between thermoregulation and vascular function was disrupted and the effect of inflammation on thermoregulation was enhanced, so that BTV had a sufficient predictive value for cardiovascular events in diabetic subjects.
    Circulation Journal 03/2013; 77(7). DOI:10.1253/circj.CJ-12-1591 · 3.69 Impact Factor
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    ABSTRACT: Amniotic fluid embolism (AFE) is a rare but devastating complication of pregnancy. Acute circulatory failure and obstetric disseminated intravascular coagulopathy are often associated with AFE and lead to poor prognosis of this syndrome. Although many reports of AFE and its cardiopulmonary complications exist, their etiology remains unknown. Classically, it was believed that the fatal cardiopulmonary complication in AFE is due to acute and severe pulmonary hypertension caused by critical obstruction of the pulmonary vessels by embolized amniotic fluid. However, recent hypotheses are suggesting that anaphylactic reaction or a cytokine effect induced by amniotic fluid is the main pathophysiological mechanism. We report a case in which cardiac magnetic resonance imaging was performed at the chronic stage of AFE. Late gadolinium enhancement (LGE) was detected at the mid-wall of the left ventricle with no evidence of pulmonary hypertension. This finding suggests that the pathophysiological mechanism of severe cardiac complications in AFE may include direct left ventricular myocardial injury through an immune reaction or cytokine release, rather than pulmonary embolism.
    International Heart Journal 01/2013; 54(2):119-22. DOI:10.1536/ihj.54.119 · 1.13 Impact Factor
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    ABSTRACT: Background: Endothelial dysfunction and autonomic nervous system imbalance are both risk markers of atherosclerotic vascular damage. The relationship between these 2 factors, however, has not been clarified concisely. Methods and Results: Flow-mediated dilation (FMD) was measured in 47 patients with ischemic heart disease (IHD; mean age, 68.1±7.1 years) using an ultrasound semi-automatic measuring system (UNEXEF18G), and autonomic nervous system activity was evaluated by simultaneous measurements of heart rate variability. FMD was significantly correlated with standard deviation of normal-to-normal beats (r=0.33, P=0.022) and the power ratio of low-frequency power to high-frequency power (LF/HF; r=-0.38, P=0.0087). Furthermore, multiple regression analysis indicated that LF/HF was the most important predictor of the magnitude of FMD. This interaction was severely blunted by β-blockers and the presence of diabetes. Moreover, standardized FMD according to autonomic nervous system activity was a better predictor of future cardiovascular events than FMD. Subjects with cardiovascular events had a significantly smaller corrected FMD (event (+), 3.62±0.41; event (-), 5.10±2.35; P=0.001), and the higher corrected FMD was associated with longer event-free survival. Conclusions: Autonomic nervous system activity is an important regulatory factor of FMD in subjects with IHD. Assessment of this interaction can help provide more accurate risk stratification of subjects with IHD.
    Circulation Journal 12/2012; 77(4). DOI:10.1253/circj.CJ-12-1043 · 3.69 Impact Factor
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    ABSTRACT: Modulator recognition factor-2 (Mrf2/AT-rich interaction domain (Arid)5b) has been revealed to be involved in pathogenesis of atherosclerosis and adipogenesis. Single-nucleotide polymorphisms (SNPs) in the MRF2/ARID5B gene are associated with coronary artery disease (CAD) and has been proposed as a candidate gene for type 2 diabetes (T2D). The study was aimed to determine whether any of the four MRF2/ARID5B SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) associated with susceptibility to CAD are also associated with T2D, and to determine whether SNP genotype influences the levels of adiponectin and other clinical factors. Association of MRF2/ARID5B SNPs was investigated in 500 diabetic patients from the Department of Metabolic Diseases at the University of Tokyo and 243 hospital-based nondiabetic individuals from the Institute for Adult Disease Asahi Life Foundation Hospital and 500 community-based nondiabetic individuals from the Hiroshima Atomic Bomb Casualty Council Health Management Center. Associations of haplotypes of these SNP with levels of adiponectin and other clinical factors were evaluated when the data was available. We found rs2893880C, rs10740055A, rs7087507A and rs10761600T were increasingly associated with T2D in terms of allele/genotype frequencies of each SNP and their haplotype combinations. Individuals with haplotype CAAT indicated an 1.86 times higher prevalence of diabetes compared with individuals with GCGA (OR 1.86 (95% confidence interval (CI) 1.43-2.41)). Furthermore, CAAT significantly associated with adiponectin levels and other clinical factors. In conclusion, polymorphisms on the MRF2/ARID5B gene were associated with susceptibility to T2D as well as adiponectin and other clinical factors, which was in a completely concordant way with their associations with CAD.Journal of Human Genetics advance online publication, 13 September 2012; doi:10.1038/jhg.2012.101.
    Journal of Human Genetics 09/2012; 57(11). DOI:10.1038/jhg.2012.101 · 2.53 Impact Factor
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    Journal of the American College of Cardiology 03/2012; DOI:10.1016/S0735-1097(12)61036-5 · 15.34 Impact Factor

Publication Stats

376 Citations
121.81 Total Impact Points


  • 2006–2013
    • The University of Tokyo
      • • Department of Cardiovascular Medicine
      • • Division of Internal Medicine
      Tōkyō, Japan
  • 2004
    • Duke University
      Durham, North Carolina, United States
  • 2003
    • Brigham and Women's Hospital
      • Center for Brain Mind Medicine
      Boston, MA, United States
  • 2002
    • University of Chicago
      Chicago, Illinois, United States
  • 2001–2002
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States