Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Volume 76, Issue 8
Displaying 1-42 of 42 articles from this issue
Message From the Editor-in-Chief
Cardiology Societies in the Asian/Pacific Region
  • – The National Heart Association of Malaysia and the Japanese Circulation Society –
    Alan Yean Yip Fong, Wan Azman Wan Ahmad, Azhari Rosman, Kui-Hian Sim
    2012 Volume 76 Issue 8 Pages 1807-1810
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: July 12, 2012
    JOURNAL FREE ACCESS
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Reviews
  • – Basic Discovery to Drug Development –
    Daniel I. Simon
    2012 Volume 76 Issue 8 Pages 1811-1818
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: June 30, 2012
    JOURNAL FREE ACCESS
    The invited special lecture at the 76th Annual Scientific Meeting of the Japanese Circulation Society focused on the central role of inflammation in vascular injury and repair. Early studies pioneered the concept that mechanical injury, such as balloon angioplasty and endovascular stent deployment, elicits an inflammatory response from the vessel wall. This hypothesis was developed and substantiated at a time when the prevailing dogma viewed restenosis following angioplasty as a primarily proliferative smooth muscle cell disease. Antibody targeting of Mac-1 reduced leukocyte accumulation and limited neointimal formation following balloon injury or stent implantation. Genetic absence of Mac-1 resulted in diminished leukocyte accumulation and neointimal thickening after carotid artery injury in mice. In the course of those studies, our laboratory made fundamental discoveries regarding the mechanism of leukocyte recruitment at sites of vascular injury and identified platelet glycoprotein (GP) Ibα, a component of the GPIb-IX-V complex, as the previously unknown platelet counter-receptor for Mac-1. Follow-on studies have focused extensively on the structure, function, and signaling of the leukocyte integrin Mac-1. The binding site for GPIbα in Mac-1 has been mapped and subsequently showed that leukocyte engagement of platelet GPIbα via Mac-1 is critical not only for the biological response to vascular injury, but also for thrombosis, vasculitis, glomerulonephritis, and multiple sclerosis, thereby advancing the hypothesis that virtually all inflammation is platelet-dependent. Furthermore, ligand engagement of Mac-1 initiates a novel gene program that promotes inflammation by activating NFκB and downregulating the expression of the forkhead transcription factor Foxp1 that controls monocyte differentiation. Small molecule inhibitors of Mac-1 function have been pursued, including targeting of Mac-1-GPIbα binding or the downstream tyrosine kinase spleen tyrosine kinase. Drs Teruo Inoue, Koichi Node, Tatsuya Fukotomi, Masashi Sakuma, Toshifumi Morooka, and Kohsuke Nakajima, valued Japanese collaborators and post-doctoral fellows, have contributed enormously to these discoveries.  (Circ J 2012; 76: 1811–1818)
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  • Eiki Takimoto
    2012 Volume 76 Issue 8 Pages 1819-1825
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: June 29, 2012
    JOURNAL FREE ACCESS
    Cyclic GMP (cGMP) and its effector kinase PKG regulate diverse cellular functions. In cardiac myocytes, cGMP is produced by soluble and particulate guanylyl cyclases (GCs), the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5′-GMP by cGMP-phosphodiesterases (PDEs). cGMP-PKG modulates cardiac contractility, hypertrophy and remodeling, and exerts cardioprotection. Although early research efforts have mostly focused on cGMP synthetic pathways, recent studies have revealed that cGMP degradation controlled by PDEs plays a critical role in the physiological action of cGMP. Among several cGMP-PDEs, cGMP-specific PDE5 has been intensively investigated. Studies in experimental animal models and humans consistently demonstrate benefits from PDE5 inhibitors in various cardiac pathologies. Several clinical trials are ongoing or planned to test the efficacy of PDE5 inhibitors in human heart disease, including a large multicenter clinical trial (RELAX) led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction. This review underscores the current understanding of cGMP-PKG signal regulation and its pathophysiological role in the heart, focusing on cardiac myocytes.  (Circ J 2012; 76: 1819–1825)
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Editorials
Original Articles
Arrhythmia/Electrophysiology
  • Takeshi Yamashita, Yukihiro Koretsune, Masahiro Yasaka, Hiroshi Inoue, ...
    2012 Volume 76 Issue 8 Pages 1840-1847
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 18, 2012
    JOURNAL FREE ACCESS
    Background: Edoxaban is a once-daily (QD) oral, direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to evaluate the safety of edoxaban in Japanese patients with NVAF. Methods and Results: A total of 536 NVAF patients (CHADS2 ≥1) were randomized to receive double-blinded edoxaban 30, 45, or 60mg QD or open-label warfarin (international normalized ratio [INR] 2.0-3.0 for age <70 years; 1.6-2.6 for age ≥70 years) for 12 weeks. The primary endpoint was the incidence of all bleeding events (major, clinically relevant non-major, and minor bleeds). Patients underwent CT and/or MRI to assess asymptomatic intracranial hemorrhage (ICH). Secondary endpoints included thromboembolic events and pharmacodynamic indices. The mean incidence of all bleeding events for edoxaban 30, 45, and 60mg, and warfarin was 18.5%, 22.4%, 27.7%, and 20.0%, respectively. There were no statistically significant differences among the edoxaban groups and no significant differences from the warfarin group. There were no asymptomatic ICH events in any group. One episode of cerebral infarction was observed in the edoxaban 45-mg group. Subgroup analysis suggested low body weight (≤60kg) was associated with higher bleeding risk. Conclusions: Edoxaban 30, 45, and 60mg QD in patients with NVAF was associated with a numerical increase in all bleeding across the dose range, but this was not statistically significant, nor was any dose compared with warfarin.  (Circ J 2012; 76: 1840–1847)
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Cardiovascular Intervention
  • Hiroyuki Naruse, Junnichi Ishii, Tousei Hashimoto, Tomoko Kawai, Kousu ...
    2012 Volume 76 Issue 8 Pages 1848-1855
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: April 26, 2012
    JOURNAL FREE ACCESS
    Background: The incidence, risk factors, and outcome of contrast-induced acute kidney injury (CI-AKI) in 730 patients with acute coronary syndrome (ACS) undergoing emergency percutaneous coronary intervention (PCI), whose contrast volume was below maximum allowable contrast dose (MACD) was prospectively investigated. Methods and Results: MACD was defined as (5ml×body weight [kg]/baseline creatinine [mg/dl]). CI-AKI was defined as a greater than 25% increase in creatinine from the baseline or an absolute increase of ≥0.5mg/dl within 48h after the procedure. CI-AKI occurred in 212 (29%) patients. Patients with CI-AKI had a higher risk for in-hospital mortality (9.4% vs. 1.5%, P<0.001) and a longer stay in the coronary care unit (median, 4.0 vs. 3.0 days, P<0.001) compared with those without CI-AKI. In a multivariate logistic analysis including 20 clinical variables, elevated glucose levels as variables categorized into quartiles were independently (P<0.001) associated with the development of CI-AKI. In addition, this relationship was seen in both the subgroup of patients with known diabetes and that of those without known diabetes. Conclusions: CI-AKI might occur commonly and could be be associated with a more complicated clinical course in ACS patients undergoing emergency PCI whose contrast volume does not exceed MACD. Elevated pre-procedural glucose might be a powerful and independent risk factor for the development of CI-AKI in this population.  (Circ J 2012; 76: 1848–1855)
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  • – The OUCH Study (Outcome of Cypher Stent in Hemodialysis Patients) –
    Yuji Ikari, Kengo Tanabe, Yutaka Koyama, Ken Kozuma, Koichi Sano, Taka ...
    2012 Volume 76 Issue 8 Pages 1856-1863
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 11, 2012
    JOURNAL FREE ACCESS
    Supplementary material
    Background: Pivotal studies on drug-eluting stents have excluded hemodialysis (HD) patients. No quantitative coronary angiography (QCA) analysis has been reported. Methods and Results: The OUtcome of Cypher stent in Hemodialysis patients (OUCH) Study is a prospective non-randomized single-arm registry designed to assess the results of sirolimus-eluting stents in HD patients, with follow-up QCA in an independent core laboratory. The primary endpoint was the occurrence of target-vessel failure (TVF) defined as cardiac death, myocardial infarction (MI), and target-vessel revascularization (TVR) at 1 year. A total of 117 patients were enrolled. The TVF rate was 24.9% (2.6% cardiac death, 1.4% MI, 23.9% TVR), and stent thrombosis was documented in 1 patient (0.9%). Coronary calcification was a predictor of TVF. Late lumen loss (LLL) averaged 0.69±0.93mm. The histogram of LLL showed that a total of 76% of lesions were distributed the same normally as that in normal renal function (average LLL 0.20±0.29mm), but 24% of lesions were outliers (average LLL 2.07±0.62mm). Conclusions: This report describes different clinical and QCA results in HD patients as higher TVF rate, different predictive factors, and different histogram of LLL compared with normal renal function. The different histogram of LLL was the existence of many outliers with the same average and the same deviation, suggesting the loss of sirolimus had an effect on a significant number of HD patients.  (Circ J 2012; 76: 1856–1863)
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  • Minoru Hasokawa, Masakazu Shinohara, Hiroshi Tsugawa, Takeshi Bamba, E ...
    2012 Volume 76 Issue 8 Pages 1864-1873
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 16, 2012
    JOURNAL FREE ACCESS
    Background: Despite the establishment of guidelines for the secondary prevention of coronary artery diseases, many patients still develop restenosis after stent implantation. Therefore, novel and noninvasive serum biomarkers that can identify restenosis-prone conditions are necessary to improve the follow-up and treatment of patients with coronary artery disease. Of late, considerable attention is being focused on metabolomics, which is the comprehensive analysis of low-molecular-weight metabolites. This study investigated the use of serum metabolomics in the identification of biomarkers of restenosis. Methods and Results: Gas chromatography/mass spectrometry was used to obtain the serum metabolomic profiles of male patients hospitalized for follow-up coronary angiography 6 months after stent implantation; 23 patients presented with major restenotic lesions (≥75% obstruction), 47 with minor restenotic lesions (≤50% obstruction), and 16 with de novo atherosclerotic lesions. Of 83 serum metabolites analyzed, molecules - isobutylamine, sarcosine, homoserine, ribulose, taurine, glutamine, glucose, and tryptophan - in the major restenosis group were significantly different from those in the minor restenosis group. Differences in correlation among these metabolites imply possible alternations in the activated metabolic pathways. Conclusions: This study provides the first line of evidence for the use of serum metabolic profiling in the identification of specific biomarkers of stent restenosis.  (Circ J 2012; 76: 1864–1873)
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  • Dennis Zavalloni, Patrizia Presbitero, Corrado Lodigiani, Ruggiero Man ...
    2012 Volume 76 Issue 8 Pages 1874-1879
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 26, 2012
    JOURNAL FREE ACCESS
    Background: Stent thrombosis (ST) is a multi-factorial process involving different mechanisms. The impact of inherited coagulation disorders in the genesis of ST has never been assessed. The aim of the present study was to evaluate the prevalence of G1691A Factor V Leiden mutation, G20210A Factor II (prothrombin) mutation and C677T homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism in patients with ST. Methods and Results: The prevalence of the aforementioned gene variations was assessed in 127 patients: 50 admitted for ST and 77 previously treated with percutaneous coronary intervention not developing ST. A control cohort of 529 healthy volunteers was sampled from the same geographical area. Patients with ST were carriers of at least 1 gene variation in 28% of cases. The prevalence of G1691A Factor V Leiden mutation (odds ratio [OR]=0.64; 95% confidence interval [CI]: 0.04-10.5), G20210A Factor II mutation (OR=0.63; 95% CI: 0.12-3.28) and C677T MTHFR homozygous polymorphism (OR=1.13; 95% CI: 0.47-2.72) did not differ significantly among patients with or without ST. The logistic regression model did not show a significant association between gene variations and ST (OR=0.61; 95% CI: 0.24-1.60; P=0.32). Conclusions: A specific association between studied gene variations and ST has not been detected. The relatively high prevalence of at least 1 gene anomaly in such a rare subset of patients, and its consequences in term of secondary prevention therapy, suggests that screening for thrombophilia might be justifiable in cases of ST.  (Circ J 2012; 76: 1874–1879)
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  • – Assessment of Neointimal Distribution on Optical Coherence Tomography –
    Hiromasa Otake, Junya Shite, Toshiro Shinke, Naoki Miyoshi, Amane Kozu ...
    2012 Volume 76 Issue 8 Pages 1880-1888
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 19, 2012
    JOURNAL FREE ACCESS
    Background: The Taxus Express™ paclitaxel-eluting stent (Express-PES) and Taxus Liberté™ PES (Liberté-PES) have identical drugs, drug doses, and polymers, but different stent platforms. The Liberté-PES platform has thinner struts, specifically designed for more uniform drug elution. Methods and Results: Fifty-four patients who underwent 6-month follow-up optical coherence tomography (OCT) after Express-PES (n=27) or Liberté-PES (n=27) implantation were enrolled. Longitudinal and circumferential uniformity of neointimal distribution was evaluated in 3-D by computing mean neointimal thickness (NIT) within 360 equally spaced radial sectors for every 1-mm cross-section. After stenting, intravascular ultrasound showed that Liberté-PES had a significantly smaller maximum angle between adjacent struts, with a tendency toward a lower incidence of % length of the segment with maximum angle >90° than Express-PES. Liberté-PES had a significantly thinner mean NIT than the Express-PES with comparable frequency of uncovered struts. Longitudinal and circumferential absolute variation of NIT expressed by standard deviation of NIT from each sector was significantly smaller for Liberté-PES than for Express-PES. Liberté-PES had a tendency toward a decreased incidence of thrombus and peri-strut low-intensity areas (findings suggestive of delayed arterial healing), compared to Express-PES. Conclusions: Stent design and thickness appeared to affect neointima suppression of PES. The stent platform of the Liberté-PES may offer greater and more homogeneous reduction of neointimal proliferation spatially across the full length of the PES.  (Circ J 2012; 76: 1880–1888)
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Cardiac Rehabilitation
  • Neiko Ozasa, Takeshi Morimoto, Bingyuan Bao, Tetsuo Shioi, Takeshi Kim ...
    2012 Volume 76 Issue 8 Pages 1889-1894
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 16, 2012
    JOURNAL FREE ACCESS
    Background: Conventional exercise training (ET) for elderly patients with heart failure (HF) includes low-intensity stretching and gait training. The effects of 2 types of low-intensity ET - machine-assisted cycling and conventional ET - on exercise capacity and endothelial function of elderly patients with HF was investigated in the present study. Methods and Results: Twenty-seven elderly patients with HF (mean age: 79.5 years) were randomly assigned to either a machine-assisted cycling group or a conventional ET group. At baseline and after 2 weeks of ET, all patients were tested for 6-minute walk distance (6MWD) and digital reactive hyperemia-peripheral arterial tonometry (RH-PAT). After 2 weeks of ET, a significant increase in 6MWD was observed in both groups with no significant difference between the groups. RH-PAT index significantly increased in patients aged ≤80 (1.55±0.33 to 1.93±0.62, P=0.035) and a trend toward increase in RH-PAT index in the machine-assisted cycling group was observed (1.59±0.52 to 1.93±0.63, P=0.053), although no change was observed in the conventional ET group. In the multivariate model, patients’ age and machine-assisted cycling were associated with the increases in RH-PAT index (P<0.05). Conclusions: Machine-assisted cycling appeared to be as effective as conventional ET on exercise capacity in elderly patients with HF. Additionally, machine-assisted cycling has the potential to improve endothelial function in these patients.  (Circ J 2012; 76: 1889–1894)
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Cardiovascular Surgery
  • Teruhiko Imamura, Koichiro Kinugawa, Taro Shiga, Miyoko Endo, Naoko Ka ...
    2012 Volume 76 Issue 8 Pages 1895-1903
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 23, 2012
    JOURNAL FREE ACCESS
    Supplementary material
    Background: As we have previously reported, the preoperative profile defined by INTERMACS is a good predictor for the prognosis after left ventricular assist device (LVAD) implantation, but is largely dependent on the physician’s decision. Several other risk stratification systems including objective parameters (eg, Leitz-Miller, Columbia, Seattle Heart Failure Model, APACHE II) have been proposed to estimate patient’s mortality after LVAD implantation. Methods and Results: According to the preoperative data from 59 patients who received LVAD (10 implantable, 49 extracorporeal) since 2002 through 2010, we performed a logistic analysis and constructed a new scoring system (ie, the TODAI VAD score (TVAD score), assigning 8 points to serum albumin <3.2mg/dl (odds ratio [OR] 8.475), 7 points to serum total bilirubin >4.8mg/dl (OR 7.300), 6 points to left ventricular end-diastolic diameter <55mm (OR 5.917), 5 points to central venous pressure >11mmHg (OR 5.128)). The receiver-operating characteristic analysis showed that the area under the curve of our new scoring system (0.864) was significantly larger than any of the abovementioned 5 scoring methods (all P<0.05). With the TVAD score, low (0-8 points), intermediate (9-17 points), and high (18-26 points) risk strata had significantly different 1-year survival rates of 95%, 54%, and 14%, respectively (all P<0.001). Conclusions: The TVAD score can predict the prognosis after LVAD implantation much better than the previously known methods.  (Circ J 2012; 76: 1895–1903)
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Epidemiology
  • – The Korean Genome and Epidemiology Study –
    Nam-Kyoo Lim, Sung-Hee Park, Sun-Ja Choi, Kwang-Soo Lee, Hyun-Young Pa ...
    2012 Volume 76 Issue 8 Pages 1904-1910
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: April 28, 2012
    JOURNAL FREE ACCESS
    Background: The aim of this study was to develop a risk score to predict the 4-year risk of diabetes in a middle-aged Korean cohort. Methods and Results: Participants without diabetes (6,342 participants, aged 40-69 years) were included and biennial follow ups were conducted. A logistic regression analysis was used to construct the models. The basic model was based on simple information such as age, parental or sibling history of diabetes, smoking status, body mass index, and hypertension, while clinical model 1 was constructed by adding biochemical tests such as fasting plasma glucose, high-density lipoprotein-cholesterol and triglycerides to the basic model; clinical model 2 further added glycated hemoglobin (HbA1c) to clinical model 1. The model accuracy was assessed using area under a receiver operating characteristic (AROC) curve and the Hosmer-Lemeshow statistics. Both net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated to determine the contribution of HbA1c. Two clinical models improved model discrimination (AROC=0.75 and 0.77) when compared with the basic model (AROC=0.65). The addition of HbA1c to clinical model 1 increased AROC by only 0.02 despite its high impact on the prediction of diabetes (odds ratio=2.66). However, the NRI and IDI were significantly improved with the addition of HbA1c. Therefore, a risk score system was developed to estimate the 4-year risk of diabetes based on clinical model 2. Conclusions: A risk score derived from simple biochemical examinations including HbA1c can help identify those at a high risk of diabetes in a middle-aged Korean cohort.  (Circ J 2012; 76: 1904–1910)
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Heart Failure
  • – Results of the MIRACLE-ICD Outcome Measured in Japanese Indication (MOMIJI) Study –
    Shin-ichi Momomura, Hiroyuki Tsutsui, Yoshitaka Sugawara, Makoto Ito, ...
    2012 Volume 76 Issue 8 Pages 1911-1919
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 30, 2012
    JOURNAL FREE ACCESS
    Background: Cardiac resynchronization therapy (CRT) is effective in reducing morbidity and mortality in systolic heart failure patients with cardiac dyssynchrony as demonstrated in studies with primarily Western populations. Although CRT devices with a defibrillator (CRT-D) became available in Japan since 2006, their efficacy remains uncertain in Japanese patients. In this prospective, multicenter study, the efficacy of CRT-D therapy in an all-Japanese population was compared with the study conducted in the US, Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE-ICD). Methods and Results: Ninety-three patients were evaluated according to the subject selection criteria of the MIRACLE-ICD study, and 80 patients were enrolled. Results at baseline and 6-month post-CRT-D implantation were compared in terms of composite clinical response (CCR) and other secondary endpoints. Quality of life (QOL) was assessed with a validated Japanese version of the Minnesota Living with Heart Failure questionnaire. CCR was improved in 55 patients (68.8%), unchanged in 14 (17.5%), and worsened in 11 patients (13.7%) (MIRACLE-ICD general phase: 62.0%, 13.4% and 24.6%, respectively). Non-inferiority was verified by 1-sided test with 10% equivalence margin. QOL score improved significantly (50.0±26.2 vs. 23.6±20.2, P<0.01). Conclusions: The MOMIJI study demonstrated that CRT-D effectiveness as assessed with CCR was non-inferior to the trials conducted outside Japan, thus suggesting that the benefits of CRT-D are similar between Japanese and non-Japanese patients.  (Circ J 2012; 76: 1911–1919)
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  • – A Report From the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) –
    Sanae Hamaguchi, Shintaro Kinugawa, Miyuki Tsuchihashi-Makaya, Daisuke ...
    2012 Volume 76 Issue 8 Pages 1920-1927
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 26, 2012
    JOURNAL FREE ACCESS
    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 [CI] 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)
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Hypertension and Circulatory Control
  • – A Worksite Cohort Study –
    Mari Odaira, Hirofumi Tomiyama, Chisa Matsumoto, Masanobu Yoshida, Kaz ...
    2012 Volume 76 Issue 8 Pages 1928-1933
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: April 27, 2012
    JOURNAL FREE ACCESS
    Background: It has not been fully clarified as to which marker related to arterial stiffness or central hemodynamics might be most closely associated with the blood natriuretic peptide levels. The present cross-sectional study was conducted to examine the strength of the relationships of the arterial stiffness and central hemodynamic indices with the serum N-terminal fragment B-type natriuretic peptide (NT-pro BNP) levels. Methods and Results: In a total of 2,657 male employees of a company (46±9 years old), the first and second peaks of the radial systolic pressure waveform (SBP1 and SBP2, respectively), the radial augmentation index (rAI), the PP2 (SBP2 minus the diastolic blood pressure), the brachial-ankle pulse wave velocity (baPWV), and the serum NT-pro BNP levels were measured. Even after adjustments for confounding variables, the SBP1, SBP2, PP2, rAI and baPWV showed a significant positive association with the serum NT-pro BNP levels. A stepwise multivariate linear regression analysis demonstrated that among these variables, only PP2 contributed significantly to the serum NT-pro BNP levels (β=0.176, partial R-square=0.017, P<0.001). Conclusions: In middle-aged Japanese men, among the parameters related to arterial stiffness and central hemodynamics, PP2 showed the closest relationship with the serum NT-pro BNP levels. Therefore, elevation of the serum NT-pro BNP levels appears to reflect, at least in part, the pathophysiological abnormalities related to increased central pulse pressure.  (Circ J 2012; 76: 1928–1933)
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  • Takuya Kishi, Kenji Sunagawa
    2012 Volume 76 Issue 8 Pages 1934-1941
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 11, 2012
    JOURNAL FREE ACCESS
    Background: A previous study has demonstrated that orally administered atorvastatin reduces sympathetic nervous system (SNS) activation via an anti-oxidant in the rostral ventrolateral medulla (RVLM) of hypertensive rats, whereas amlodipine did not. Furthermore, several previous reports have suggested that atorvastatin or amlodipine improves cognitive dysfunction during hypertension. The aim of the present study was to determine whether a combination of atorvastatin and amlodipine causes sympathoinhibition via reduction of oxidative stress in the RVLM and improves cognitive dysfunction of hypertensive rats. Methods and Results: Stroke-prone spontaneously hypertensive rats (SHRSPs), as a hypertensive model with sympathoexcitation, were divided into 4 groups; a combination of atorvastatin and amlodipine-treated (COM), atorvastatin-treated (ATR), amlodipine-treated (AML), hydralazine-treated (HYD), and vehicle-treated SHRSPs (VEH). After treatment for 28 days, the mean blood pressure did not change in ATR rats, and was reduced to the similar levels in COM, AML, and HYD rats. However, SNS activation and oxidative stress in the RVLM were significantly lower only in COM than in ATR, AML, HYD, and VEH rats. Cognitive performance and manganese-superoxide dismutase activity in the hippocampus were significantly higher, and oxidative stress in the hippocampus was significantly lower in COM than in VEH, AML, and HYD rats to a greater extent than in ATR rats. Conclusions: A combination of atorvastatin and amlodipine causes sympathoinhibition via an anti-oxidant in the RVLM and improves cognitive dysfunction via an anti-oxidant in the hippocampus in hypertensive rats, independent of the blood pressure-lowering effect.  (Circ J 2012; 76: 1934–1941)
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Imaging
  • Satoshi Hida, Taishiro Chikamori, Hirokazu Tanaka, Yuko Igarashi, Chie ...
    2012 Volume 76 Issue 8 Pages 1942-1952
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 29, 2012
    JOURNAL FREE ACCESS
    Background: Although stress-induced left ventricular (LV) wall motion abnormality is a well-known marker for extensive coronary artery disease (CAD), no study has yet analyzed whether phase analysis of exercise-induced LV mechanical dyssynchrony may have enhanced diagnostic value over conventional perfusion analysis in the detection of multivessel CAD. Methods and Results: A total of 278 patients with suspected or confirmed CAD underwent both exercise stress 99mTc-sestamibi gated single-photon emission computed tomography and coronary angiography. LV mechanical dyssynchrony was evaluated using the SyncTool to obtain the phase SD and histogram bandwidth. In the detection of 128 patients with multivessel CAD, a summed stress score (SSS) of ≥9 showed a sensitivity of 84% and a specificity of 53%, while an increase in phase SD of ≥4.4° and a bandwidth of ≥14° after exercise had sensitivities of 74% and 68%, and specificities of 84% and 91%, respectively. On multivariate analysis the combination of post-stress increases in phase SD, histogram bandwidth, transient ischemic dilation (TID) ratio and SSS best identified multivessel CAD (sensitivity 77%, specificity 88%, χ2=181.8), compared with TID ratio and SSS only (sensitivity 70%, specificity 76%, χ2=68.9). Conclusions: The addition of phase analysis to evaluate exercise-induced LV mechanical dyssynchrony on conventional perfusion analysis enabled better identification of patients with multivessel CAD.  (Circ J 2012; 76: 1942–1952)
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Ischemic Heart Disease
  • Manuel Alfonso Baños-González, Eduardo Anglés-Can ...
    2012 Volume 76 Issue 8 Pages 1953-1957
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: April 18, 2012
    JOURNAL FREE ACCESS
    Supplementary material
    Background: Lipoprotein (Lp(a)) and homocysteine (Hcy) are independent risk factors for coronary artery disease (CAD). Hcy promotes the release of free apo(a) from Lp(a). The high fibrin affinity of free apo(a) inhibits plasminogen binding and plasmin generation. Hyperhomocysteinemia can result from a less active variant of methylene tetrahydrofolate reductase (variant C677T). Because the C677T genotype is estimated to be present in 32.2% of the Mexican population, we took advantage of this prevalence to determine the possible potentiating effect between high plasma Lp(a) and Hcy for increasing the risk of CAD in male patients. Methods and Results: First, 222 male patients admitted for coronary angiography were recruited and classified as CAD+ or CAD-. Anthropometric measurements, traditional risk factors, and plasma total Hcy (tHcy) and Lp(a) levels were recorded in both groups. We performed a conditional logistic regression model adjusted for conventional risk factors of CAD and it became clear that Lp(a) ≥30mg/dl was a risk factor for CAD (odds ratio [OR] 5.06, 95% confidence interval [CI] 1.88-13.51, P=0.001), whereas Hcy was not related to CAD (OR 0.44, 95% CI 0.63-2.90, P=0.44). However, when both factors were considered together in an interaction model, high tHcy and high Lp(a) plasma concentrations showed a potentiated effect (OR 10.52, 95% CI 2.18-50.71, P=0.003). Conclusions: The combination of high Lp(a) and Hcy levels synergistically increases the likelihood of developing CAD in male patients.  (Circ J 2012; 76: 1953–1957)
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  • Koki Nakanishi, Shota Fukuda, Kenei Shimada, Chinami Miyazaki, Kenichi ...
    2012 Volume 76 Issue 8 Pages 1958-1964
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: April 28, 2012
    JOURNAL FREE ACCESS
    Background: In the absence of obstructive coronary narrowing, impaired coronary flow reserve (CFR) represents coronary microvascular dysfunction. Transthoracic Doppler echocardiography (TTDE) allows non-invasive measurement of CFR in the left anterior descending (LAD) artery. This study aimed to assess the prognostic value of TTDE-derived CFR (as a marker of microvascular function) in predicting long-term cardiovascular events, acute coronary syndrome (ACS) events, and the development of heart failure (HF). Methods and Results: This study consisted of 272 patients with coronary artery disease not involving obstructive narrowing (≥50%) in the LAD. Patients underwent TTDE examination for CFR measurement in the LAD. During the follow-up period of 4.0±1.9 years, 32 patients (12%) had cardiovascular events. Cox proportional hazard analysis identified lower CFR as an independent risk factor of cardiovascular events (P<0.001), ACS events (P=0.008), and HF development (P=0.003). A CFR less than 2.4 was the best cut-off value for predicting all events (area under the curve=0.82). CFR excellently predicted the development of HF (area under the curve=0.95), but not ACS events (area under the curve=0.67). Conclusions: This TTDE study demonstrated that CFR was a significant and independent determinant of long-term cardiovascular events, ACS events and HF in patients with coronary artery disease. A CFR greater than 2.0 was not suitable to predict a favorable long-term outcome, even in the absence of obstructive coronary narrowing.  (Circ J 2012; 76: 1958–1964)
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  • Yasuhiro Nagayoshi, Hiroaki Kawano, Sunao Kojima, Hirofumi Soejima, Ko ...
    2012 Volume 76 Issue 8 Pages 1965-1971
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 16, 2012
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    Background: The number of patients undergoing non-cardiac surgery has been increasing. Thus, the reduction of cardiac events is important during the perioperative period. The prevalence of Japanese patients with coronary vasospasm is higher as compared with Western countries. The present study reported the role of coronary vasospasm in the perioperative period in a Japanese university hospital. Methods and Results: A total of 77,745 consecutive patients who underwent non-cardiac surgery in Kumamoto University Hospital between April 2003 and March 2010 were retrospectively examined. Forty-two cases in which patients underwent coronary catheterization due to cardiovascular events in the perioperative period were reviewed, and data were collected on the type of surgery, urgency of surgery, cardiac risk factors, previous history and the cardiology consultation. The Revised Cardiac Risk Index (RCRI) was also calculated. A total of 18 patients were diagnosed as having definite vasospastic angina. In the definite vasospastic angina group, 9 patients had cardiovascular events intraoperatively. Six patients were in the group undergoing high-risk surgery. The RCRI score in the definite vasospastic angina group was 0.5±0.6 (mean±SEM), and only 2 patients had a preoperative consultation with a cardiologist. Conclusions: Coronary vasospasm is not often encountered, but it can be a cause of cardiac trouble in the perioperative period. It should be taken into consideration at the time of planning of operation in Japanese patients even if they apparently have low cardiac risk.  (Circ J 2012; 76: 1965–1971)
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  • Yasuhiro Uchida, Satoshi Ichimiya, Hideki Ishii, Masaaki Kanashiro, Ju ...
    2012 Volume 76 Issue 8 Pages 1972-1979
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 23, 2012
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    Background: Microvascular impairment is associated with a poor prognosis even after successful percutaneous coronary intervention (PCI) in acute myocardial infarction. The aim of the present study was to examine the impact of metabolic syndrome (MetS) on various aspects of microvascular function and clinical outcomes. Methods and Results: In 216 consecutive patients with ST-segment elevation myocardial infarction (STEMI) after successful primary PCI, data were collected and analyzed on epicardial coronary flow, ST-segment resolution (STR) on electrocardiography, maximum serum creatine kinase levels, and the incidence of major adverse cardiac events (MACE). The prevalence of MetS was 40.7% (88 patients). Corrected Thrombolysis In Myocardial Infarction frame count was significantly higher in the MetS group than in the non-MetS group (28.1±9.4 vs. 24.7±7.9, P=0.04). STR ≥50% was observed in 51.1% and 69.5%, respectively (P=0.01). Patients with MetS also had higher maximum creatine kinase levels (3,470±2,320IU/L vs. 2,664±1,850IU/L, P=0.01). On logistic regression analysis after adjustment for confounders, MetS was an independent negative predictor of complete STR (odds ratio, 0.49; 95% confidence interval [CI]: 0.25-0.95, P=0.03). On Cox multivariate analysis, MetS was an independent predictor for MACE (hazard ratio, 4.85; 95% CI: 1.28-18.3, P=0.02). Conclusions: MetS may damage microcirculation after direct PCI in patients with STEMI and lead to poor prognosis.  (Circ J 2012; 76: 1972–1979)
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  • Mikio Fukushima, Shin-ichiro Miura, Ryoko Mitsutake, Takao Fukushima, ...
    2012 Volume 76 Issue 8 Pages 1980-1986
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 16, 2012
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    Background: Little is known about the interrelationship between the lipid profile, cholesterol metabolism, and coronary risk factors in patients with hemodialysis (HD) in the presence or absence of coronary artery disease (CAD). Methods and Results: Ninety-five patients with HD were selected (HD group). Fifty-eight age-, gender-, and body mass index (BMI)-matched patients who had at least 1 cardiovascular risk factor were selected as a non-HD group. Total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and the ratio of LDL-C to HDL-C (L/H) in the HD group were significantly lower than those in the non-HD group. All markers of cholesterol absorption (campesterol/TC, sitosterol/TC, and cholestanol/TC) and the ratio of campesterol to lathosterol in the HD group were significantly higher. In addition, in the HD group, L/H was negatively correlated with lathosterol/TC, campesterol/TC, sitosterol/TC, and cholestanol/TC. Finally, CAD was significantly associated with lathosterol/TC (P=0.028), which was positively associated with BMI in the HD group, whereas CAD was significantly associated only with hypertension (P=0.020) in the non-HD group. Conclusions: HD patients showed lower cholesterol concentrations than non-HD patients, and, as compensation, their cholesterol absorption might be accelerated. However, higher cholesterol synthesis, which was correlated with higher BMI, might be an independent predictor for the presence of CAD in HD patients.  (Circ J 2012; 76: 1980–1986)
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Molecular Cardiology
  • Xiaofei Lv, Yuan Zhang, Shaoqi Rao, Jian Qiu, Min Wang, Xiaoqin Luo, X ...
    2012 Volume 76 Issue 8 Pages 1987-1992
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 12, 2012
    JOURNAL FREE ACCESS
    Supplementary material
    Background: The aim of the present study was to explore risk variants for coronary artery disease (CAD) and to evaluate their joint effects (quantified by genetic risk score; GRS) on the discrimination of CAD in a Chinese Han sample. Methods and Results: An association analysis of 91 single nucleotide polymorphisms (SNPs) with CAD risk was undertaken in 1,007 CAD patients and 889 healthy controls. Two GRSs, counted GRS (cGRS) and weighted GRS (wGRS), were calculated using the significant SNPs, and their discriminant power for CAD was assessed using receiver-operating characteristic (ROC) curve analysis. Eight SNPs (rs11206510, rs10118757, rs2383206, rs501120, rs2075292, rs174547, rs173539, and rs255052) were nominally significantly associated with CAD (P<0.05), and 5 of them were newly reported. The GRSs derived from the 8 SNPs improved the discrimination of CAD compared to that using 4 conventional risk factors (P=0.002 for cGRS and P=0.009 for wGRS). After 10-fold cross-validation 100 times, the average areas under the curve were 0.668 (95% confidence interval [CI]: 0.667-0.669), 0.686 (95% CI: 0.685-0.687) and 0.690 (95% CI: 0.689-0.691) for models with conventional risk factors only, conventional risk factors plus cGRS, and conventional risk factors plus wGRS, respectively. Conclusions: A multigenic GRS, generated by combining multiple gene variants, can improve discrimination of CAD, thereby confirming the joint effects of these gene variants on CAD in this Chinese Han population.  (Circ J 2012; 76: 1987–1992)
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  • Cai-Mei Zhang, Ling Gao, Yan-Jun Zheng, Huang-Tian Yang
    2012 Volume 76 Issue 8 Pages 1993-2002
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 15, 2012
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    Supplementary material
    Background: Berbamine, a natural compound from Barberry, was reported to protect myocardium from ischemia/reperfusion (I/R) injury, but the underlying mechanisms are largely unknown. Methods and Results: Berbamine pretreatment from 10 to 100nmol/L concentration-dependently improved post-ischemic myocardial function. Similar protection was confirmed in isolated cardiomyocytes characterized by the attenuation of I/R-induced intracellular free Ca2+ concentration ([Ca2+]i) overloading and the depression of cell shortening and Ca2+ transients, which were partially mimicked but not augmented by calpain inhibitor calpeptin and abolished by mitochondrial ATP-sensitive potassium (mitoKATP) channel inhibitor 5-hydroxydecanoate (5-HD) and phosphoinositide 3-kinase (PI3K) inhibitor wortmannin. Consistently, I/R-induced increase of calpain activity and decrease of sarcoplasmic reticulum Ca2+ ATPase (SERCA2) activity; and protein expression of SERCA2a, desmin, calpastatin and Akt was significantly attenuated by berbamine. In addition, I/R-decreased Akt protein was reversed by calpeptin. Moreover, berbamine further increased I/R-enhanced phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β). These protections were abolished by wortmannin. Furthermore, berbamine significantly attenuated I/R-induced lactate dehydrogenase release, infarct size and contractile dysfunction, and such cardioprotective actions were abolished by wortmannin and 5-HD or mimicked by glycogen synthase kinase-3β (GSK3β) inhibitor SB216763 but without additive effect. Conclusions: These findings suggest that berbamine confers cardioprotection against I/R injury by attenuating [Ca2+]i overloading and preventing calpain activation through the activation of the PI3K-Akt-GSK3β pathway and, subsequently, opening of the mitoKATP channel.  (Circ J 2012; 76: 1993–2002)
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  • Akiyoshi Ogimoto, Hideki Okayama, Takayuki Nagai, Jun Suzuki, Katsuji ...
    2012 Volume 76 Issue 8 Pages 2003-2008
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 12, 2012
    JOURNAL FREE ACCESS
    Background: Sustained cardiac adrenergic stimulation has been implicated in the progression of cardiovascular events in patients with dilated cardiomyopathy (DCM). Our group hypothesized that a combination of polymorphisms that result in increased synaptic norepinephrine release and enhanced receptor function would predispose patients with DCM to cardiovascular events. The effect of polymorphisms in adrenergic receptor-related genes on cardiovascular event-free survival in patients with idiopathic DCM was evaluated. Methods and Results: Genotyping at 3 loci (ADRB1 Ser49Gly and Arg389Gly, and NET T-182C) was performed in 83 patients with DCM. Patients were followed prospectively to the endpoint of cardiovascular events (mean follow-up, 45 months). Cardiovascular events were defined as cardiac death and emergent hospitalization as a result of congestive heart failure, arrhythmia, and cerebrovascular events. Analyses were conducted based on the number of predicted risk genotypes a patient carried. The ADRB1 Ser49 allele carrier, ADRB1 Arg389 allele carrier, and NET-182CC genotype were defined as the predicted risk genotypes. Cardiovascular event-free survival was compared based on the number of predicted risk genotypes. Cardiovascular event-free survival was significantly better in patients with fewer than 3 predicted risk genotypes than in those with 3 predicted risk genotypes. Conclusions: Genotyping at these 3 loci might be a useful approach for identification of patients with DCM at risk for cardiovascular events.  (Circ J 2012; 76: 2003–2008)
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Pediatric Cardiology and Adult Congenital Heart Disease
  • Satoru Iwashima, Takamichi Ishikawa
    2012 Volume 76 Issue 8 Pages 2009-2014
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 11, 2012
    JOURNAL FREE ACCESS
    Background: The ophthalmic artery Doppler waveform (OADW) is thought to correlate with severity of systemic atherosclerosis. The goal of the present study was to evaluate risk of cardiovascular disease (CVD) in newborns small for gestational age (SGA) and appropriate for gestational age (AGA). Methods and Results: A total of 15 SGA and 26 AGA newborns were enrolled in the study. OADW was compared between SGA and AGA groups. The median Doppler maximums of both eyes in the SGA group were significantly smaller than in the AGA group (maximum average velocity (max A) 6.4cm/s vs. 8.3cm/s, P=0.028; maximum end diastolic velocity (max D) 2.2cm/s vs. 3.4cm/s, P=0.003). The maximums of both eyes for the maximum resistivity index (max RI) and maximum pulsatility index (max PI) in the SGA group were significantly greater than in the AGA group (RI, 0.88 vs. 0.82, P=0.005; PI, 2.23 vs. 1.72, P=0.002). When a multiple linear regression analysis of the SGA group with a stepwise procedure was applied to positive variables from 2-sided comparisons, significant correlations were noted for max A and max PI (max A: R2=0.495, β=0.541, P=0.034; max PI: β=-3.318, P=0.012). Conclusions: OADW in SGA newborns may be related to future risk of CVD, which is undetectable in infancy, and can provide information to estimate future cardiovascular health.  (Circ J 2012; 76: 2009–2014)
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Vascular Biology and Vascular Medicine
  • Zongsong Wu, Yuyan Xiong, Thusitha Gajanayake, Xiu-Fen Ming, Zhihong Y ...
    2012 Volume 76 Issue 8 Pages 2015-2022
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: April 27, 2012
    JOURNAL FREE ACCESS
    Supplementary material
    Background: Hexosamine biosynthetic pathway (HBP) is implicated in increased plasminogen activator inhibitor-1 (PAI-1), and endothelial nitric oxide synthase (eNOS) dysfunction in diabetes. Glucosamine (GlcN) that directly activates HBP is a dietary supplement and is clinically used to treat osteoarthritis despite uncertain efficacy and adverse cardiovascular effects observed in animal models. p38 mitogen-activated protein kinase (p38mapk) has been shown to be involved in HBP-mediated biological processes. The aim of the present study was to investigate the role of p38mapk in GlcN-induced endothelial PAI-1 expression and eNOS dysfunction. Methods and Results: In cultured human endothelial cells, GlcN time- and concentration-dependently increased PAI-1 protein level that was further enhanced by tumor necrosis factor (TNF)-α, which was accompanied by a transient synergistic activation of p38mapk. The stimulation of PAI-1 by GlcN alone or by GlcN and TNF-α in combination was inhibited by the specific inhibitor of p38mapk, but not that of JNK or ERK1/2. Moreover, in isolated mouse aortas, GlcN caused eNOS uncoupling resulting in enhanced superoxide and decreased NO production, as well as impaired endothelium-dependent relaxations, which were also fully prevented by the p38mapk inhibitor. Conclusions: HBP activated by GlcN increases PAI-1 expression and eNOS uncoupling depending on p38mapk, which not only explains hyperglycemic vascular complications, but also may bring into question the clinical use of GlcN. The present results, support currently ongoing clinical application of p38mapk inhibitor in patients with cardiovascular disease.  (Circ J 2012; 76: 2015–2022)
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  • Kotaro Nochioka, Shin-ichi Tanaka, Masanobu Miura, Do.e Zhulanqiqige, ...
    2012 Volume 76 Issue 8 Pages 2023-2030
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: April 28, 2012
    JOURNAL FREE ACCESS
    Background: Ezetimibe is an inhibitor of cholesterol absorption in the intestine. We examined whether ezetimibe improves endothelial function, and if so, what mechanisms are involved. Methods and Results: Nineteen healthy subjects (male/female 14/5; mean age, 31±3 [SD] years-old) were randomized to receive ezetimibe (10mg/day) or pravastatin (10mg/day) for 4 weeks in a cross-over manner with a 4-week washout interval. Lipid profiles, flow-mediated dilatation (FMD) and Rho-kinase activity of circulating leukocytes (the extent of phosphorylation of myosin binding subunit, a Rho-kinase substrate) were examined. We also evaluated remnant-like particle cholesterol (RLP-C) known as an up-regulator of Rho-kinase and cholesterol absorption status by measuring cholestanol and campesterol/lathosterol ratio (CLR) (both absorption markers). Although ezetimibe and pravastatin equally reduced low-density lipoprotein cholesterol (E: -25% vs. P: -21%), the CLR was reduced by ezetimibe but was rather increased by pravastatin (E: -41% vs. P: +37%; P<0.01). Reduction in RLP-C by ezetimibe was greater compared with pravastatin (E: -33% vs. P: -14%; P<0.05). Importantly, ezetimibe significantly improved FMD (26%, P<0.05) and reduced Rho-kinase activity (-21%, P<0.05), whereas pravastatin had no such effects. A significant correlation was noted between the reduction in cholestanol and the improvement in FMD (P<0.05). Conclusions: These results indicate that ezetimibe improves endothelial function and inhibits Rho-kinase activity associated with the inhibition of cholesterol absorption, suggesting novel anti-atherogenic effects of the agent in humans.  (Circ J 2012; 76: 2023–2030)
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  • Kaori Higuchi, Yoshikazu Nakaoka, Wataru Shioyama, Yoh Arita, Takahiro ...
    2012 Volume 76 Issue 8 Pages 2031-2040
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 19, 2012
    JOURNAL FREE ACCESS
    Supplementary material
    Background: Docking protein Grb2-associated binder 1 (Gab1) has critical roles in signal transduction of various growth factors, cytokines, and numerous other molecules. Our previous reports show that Gab1 is essential for postnatal angiogenesis through the analysis of endothelium-specific Gab1 knockout (Gab1ECKO) mice. However, the role of Gab1 in atherosclerosis remains unknown. The aim of the present study was to elucidate the role of endothelial Gab1 in vascular inflammation and atherosclerosis. Methods and Results: We intercrossed Gab1ECKO mice with apolipoprotein E (ApoE) knockout (ApoEKO) mice. Six-month-old male ApoEKO/Gab1ECKO and littermate control (ApoEKO) mice were treated with angiotensin II (AngII) via an osmotic infusion mini-pump. After AngII treatment, ApoEKO/Gab1ECKO mice showed significantly enhanced atherosclerosis and aneurysm formation compared with control mice. The production of proinflammatory cytokines in the aorta was significantly enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Furthermore, the expression levels of Krüppel-like factor (KLF) 2 (KLF2) and KLF4, key transcription factors for endothelial homeostasis, were significantly reduced in the aortic endothelium of ApoEKO/Gab1ECKO mice compared with those of control mice. Consistently, both vascular cell adhesion molecule-1 expression and macrophage infiltration on the aortic walls were enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Conclusions: Collectively, endothelial Gab1 deletion accelerates AngII-dependent vascular inflammation and atherosclerosis on ApoE-null background presumably in association with downregulation of KLF2 and KLF4.  (Circ J 2012; 76: 2031–2040)
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  • Sun-Seog Kweon, Young-Hoon Lee, Min-Ho Shin, Jin-Su Choi, Jung-Ae Rhee ...
    2012 Volume 76 Issue 8 Pages 2041-2047
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 29, 2012
    JOURNAL FREE ACCESS
    Background: While prior epidemiological studies have examined the association between cigarette smoking and carotid atherosclerosis, few studies have evaluated the association of both cumulative smoking exposure and the duration of smoking cessation with carotid artery structure. Methods and Results: The study population consisted of 2,503 community-dwelling Korean males aged 50 years and older. Common carotid artery intima-media thickness (CCA-IMT), carotid plaque, and the internal diameter of the common carotid artery (CCA-diameter) were determined by high-resolution B-mode ultrasonography. Data on the characteristics of the subjects, including smoking status, pack-years of smoking, and years since quitting smoking, were collected using a standardized questionnaire. The current smokers had significantly greater CCA-IMT and CCA-diameter and a significantly higher risk of carotid plaque than did the subjects who had never smoked (P=0.009, <0.001, and 0.036, respectively). Dose-response relationships between pack-years and CCA-IMT and CCA-diameter were found among the current smokers (P=0.001 and <0.001, respectively); however, no significant association between pack-years and the carotid artery parameters was observed among the former smokers. For the former smokers, CCA-IMT and CCA-diameter tended to decrease with increasing years since quitting smoking (P=0.009 and 0.012, respectively), whereas no significant association with carotid plaque was found. Conclusions: Cumulative smoking exposure in current smokers and the duration of smoking cessation in former smokers are significant risk factors for carotid atherosclerosis.  (Circ J 2012; 76: 2041–2047)
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Images in Cardiovascular Medicine
  • – Epicardial Atrial Tachycardia Mimicking Typical Atrial Flutter –
    Boris Schmidt, Verena Urban, Stefano Bordignon, KR Julian Chun
    2012 Volume 76 Issue 8 Pages 2048-2050
    Published: 2012
    Released on J-STAGE: July 25, 2012
    Advance online publication: May 12, 2012
    JOURNAL FREE ACCESS
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