記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: This study aimed to systematically evaluate voice symptoms during heart failure (HF) treatments and to exploratorily extract HF-related vocal biomarkers. METHODS AND RESULTS: This single-center, prospective study longitudinally acquired 839 audio files from 59 patients with acute decompensated HF. Patients' voices were analyzed along with conventional HF indicators (New York Heart Association [NYHA] class, presence of pulmonary congestion and pleural effusion on chest X-ray, and B-type natriuretic peptide [BNP]) and GOKAN scores based on the assessment of a cardiologist. Machine-learning (ML) models to estimate HF conditions were created using a Light Gradient Boosting Machine. Voice analysis identified 27 acoustic features that correlated with conventional HF indicators and GOKAN scores. When creating ML models based on the acoustic features, there was a significant correlation between actual and ML-derived BNP levels (r=0.49; P<0.001). ML models also identified good diagnostic accuracies in determining HF conditions characterized by NYHA class ≥2, BNP ≥300 pg/mL, presence of pulmonary congestion or pleural effusion on chest X-ray, and decompensated HF (defined as NYHA class ≥2 and BNP levels ≥300 pg/mL; accuracy: 75.1%, 69.1%, 68.7%, 66.4%, and 80.4%, respectively). CONCLUSIONS: The present study successfully extracted HF-related acoustic features that correlated with conventional HF indicators. Although the data are preliminary, ML models based on acoustic features (vocal biomarkers) have the potential to infer various HF conditions, which warrant future studies.

DOI： 10.1253/circrep.CR-24-0064

PubMed

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.3390/jvd3020014

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: We retrospectively investigated the effects of the severity and classification of sleep-disordered breathing (SDB) on left ventricular (LV) function in patients with ST-segment elevation myocardial infarction (STEMI). Methods: A total of 115 patients with STEMIs underwent a sleep study using a multichannel frontopolar electroencephalography recording device (Sleep Profiler) one week after STEMI onset. We evaluated LV global longitudinal strain (LV-GLS) using two-dimensional echocardiography at one week and seven months. Patients were classified as no SDB (AHI < 5 events/h), obstructive SDB (over 50% of apnea events are obstructive), and central SDB (over 50% of apnea events are central). Due to the device's limitations in distinguishing obstructive from central hypopnea, SDB classification was based on apnea index percentages. Results: The obstructive apnea index (OAI) was significantly associated with LV-GLS at one week (r = 0.24, p = 0.027) and seven months (r = 0.21, p = 0.020). No such correlations were found for the central apnea index and SDB classification. Multivariable regression analysis showed that the OAI was independently associated with LV-GLS at one week (β = 0.24, p = 0.002) and seven months (β = 0.20, p = 0.008). Conclusions: OAI is associated with persistent LV dysfunction assessed by LV-GLS in STEMI.

DOI： 10.3390/jcm13040986

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Drug-induced pseudoaldosteronism is a typical adverse effect of Kampo formulas. Previous research described the potential risks of Kampo formula-linked pseudoaldosteronism. However, few studies assessed the risk factors using a real-world database and a data-mining approach. Using the Japanese Adverse Drug Event Report database, we extracted pseudoaldosteronism reports for 148 Kampo formulas covered by Japanese national health insurance. Adverse events were decided according to the preferred terminology of the Medical Dictionary for Regulatory Activities/Japanese version 25.1. We calculated reporting odds ratio (RORs) and identified Kampo formulas as suspected causes of pseudoaldosteronism. Moreover, we evaluated clinical factors associated with Kampo formula-induced pseudoaldosteronism via logistic regression. From April 2004 to November 2022, 6334 adverse events related to the Kampo formulas were reported. We selected 2471 reports containing complete clinical data, including 210 reports on pseudoaldosteronism. In the pseudoaldosteronism group, 69.0% of patients were female, and 85.2% were ≥70 years old. The formulas most commonly associated with pseudoaldosteronism were Shakuyakukanzoto, Yokukansan, and Ryokeijutsukanto (ROR [95% confidence interval {CI}] = 18.3 [13.0-25.9], 8.1 [5.4-12.0], and 5.5 [1.4-21.9], respectively). Logistic analysis identified female sex (odds ratio [OR] [95% CI] = 1.7 [1.2-2.6]; P = 0.006), older age (≥70, 5.0 [3.2-7.8]; P < 0.001), low body weight (<50 kg, 2.2 [1.5-3.2]; P < 0.001), diuretics usage (2.1 [1.3-4.8]; P = 0.004), hypertension (1.6 [1.1-2.4]; P = 0.014), and dementia (7.0 [4.2-11.6]; P < 0.001) as pseudoaldosteronism-related factors. Additionally, the daily Glycyrrhiza dose (OR = 2.1 [1.9-2.3]; P < 0.001) and duration of administration (>14 days, OR = 2.8 [1.7-4.5]; P < 0.001) were associated with adverse events. We did not observe an interaction between aging and hypertension. Careful follow-up is warranted during long-term Glycyrrhiza-containing Kampo formula use in patients with multiple clinical factors for pseudoaldosteronism.

DOI： 10.1371/journal.pone.0296450

PubMed

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記述言語：英語  

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in various cancers, including non-small cell lung cancer, small cell lung cancer, melanoma, classical Hodgkin lymphoma, head and neck squamous cell carcinoma, urothelial cancer, and renal cell carcinoma [...].

DOI： 10.3390/cancers15225487

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We previously reported the finding of symptom relief in a randomized controlled trial with the combined use of kakkonto and shosaikotokakikyosekko added to conventional treatment in patients with coronavirus disease 2019 (COVID-19). For further evaluation, we performed post hoc analysis focused on symptom disappearance without recurrence, to determine a clearer effect of Kampo medicine. Patients with mild and moderate COVID-19 were randomly allocated to a control group receiving symptomatic therapy or a Kampo group receiving kakkonto (2.5 g) with shosaikotokakikyosekko (2.5 g) three times daily in addition to symptomatic therapy. The data of 161 patients (Kampo group, n = 81; control group, n = 80) were analyzed post hoc for the time to symptom disappearance. Kaplan-Meier and Cox proportional hazard estimates of disappearance of symptoms showed that all and each symptom targeted in this study disappeared faster in the Kampo group than in the control group, although not statistically significant (all symptomatic cases; hazard ratio [HR] 3.73, 95% confidence interval [CI] 0.46-29.98, log-rank p = 0.1763). In a supplemental assessment using covariate adjustment and competing risk analysis, fever disappeared faster in the Kampo group than in the control group (all symptomatic cases, HR 1.62, 95% CI 0.99-2.64, p = 0.0557; unvaccinated cases, HR 1.68, 95% CI 1.00-2.83, p = 0.0498) and shortness of breath disappeared significantly faster in Kampo group than in control group (all symptomatic cases, HR 1.92, 95% CI 1.07-3.42, p = 0.0278; unvaccinated cases, HR 2.15, 95% CI 1.17-3.96, p = 0.0141). These results demonstrate the advantages of Kampo treatment for acute COVID-19.

DOI： 10.1016/j.jiac.2023.07.013

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary hypertension (PH) has recently been described as a complex clinical syndrome affecting multiple organ systems, including the heart, lungs, and skeletal muscle, each of which plays an important role in exercise capacity. However, the relationship between exercise capacity and skeletal muscle abnormalities in patients with PH has not been fully elucidated. METHODS: We retrospectively analysed the exercise capacity and measures of skeletal muscle of 107 patients with PH without left heart disease (mean age 63 ± 15 years, 32.7% males, n = 30/6/66/5 in the clinical classification Group 1/3/4/5). RESULTS: Sarcopenia, low appendicular skeletal muscle mass index, low grip strength, and slow gait speed, determined by international criteria, were found in 15 (14.0%), 16 (15.0%), 62 (57.9%), and 41 (38.3%) patients, respectively. The mean 6-min walk distance of all patients was 436 ± 134 m and was independently associated with sarcopenia (standardised β = -0.292, p < 0.001). All patients with sarcopenia showed reduced exercise capacity defined as 6-min walk distance <440 m. Multivariable logistic regression analysis showed that each of the components of sarcopenia was associated with reduced exercise capacity (adjusted odds ratio and 95% confidence interval of appendicular skeletal muscle mass index: 0.39 [0.24-0.63] per 1 kg/m2, p = 0.006, grip strength: 0.83 [0.74-0.94] per 1 kg, p = 0.003, and gait speed: 0.31 [0.18-0.51] per 0.1 m/s, p < 0.001). CONCLUSIONS: Sarcopenia and its components are associated with reduced exercise capacity in patients with PH. A multifaceted evaluation may be important in the management of reduced exercise capacity in patients with PH.

DOI： 10.1016/j.ijcard.2023.06.006

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.nutos.2023.03.006

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects.

DOI： 10.3390/ijms24097778

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Thromboangiitis obliterans (TAO) can lead to the development of critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients (<50 years) still require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has been tested and shown to have reasonable efficacy in CLTI. In this multicenter prospective clinical trial, we evaluated the safety and efficacy of BM-MNC implantation in CLTI patients with TAO.Methods and Results: We enrolled 22 CLTI patients with skin perfusion pressure (SPP) <30 mmHg. The primary endpoint of this trial is the recovery of SPP in the treated limb after a 180-day follow-up period. Secondary endpoints include the pain scale score and transcutaneous oxygen pressure (TcPO2). One patient dropped out during follow-up, leaving 21 patients (mean age 48 years, 90.5% male, Fontaine Class IV) for analysis. BM-MNC implantation caused no serious adverse events and increased SPP by 1.5-fold compared with baseline. Surprisingly, this effect was sustained over the longer term at 180 days. Secondary endpoints also supported the efficacy of this novel therapy in relieving pain and increasing TcPO2. Major amputation-free and overall survival probabilities at 3 years among all enrolled patients were high (95.5% and 89.5%, respectively). CONCLUSIONS: BM-MNC implantation showed safety and significant efficacy in CLTI patients with TAO.

DOI： 10.1253/circj.CJ-23-0046

PubMed

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s10157-023-02323-3

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その他リンク： https://link.springer.com/article/10.1007/s10157-023-02323-3/fulltext.html

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/tkm2.1347

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/tkm2.1347

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Immune checkpoint inhibitors (ICIs) are becoming widely used for novel cancer treatments. Immune-related adverse events, including cardiac toxicity, are frequently observed following immune checkpoint inhibitor (ICI) use. However, little is known regarding the association between ICIs initiation and hypertension in cancer patients. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. The risk of hypertension associated with ICI initiation in randomized controlled trials (RCTs) was evaluated. Hypertension was categorized according to the Common Terminology Criteria for Adverse Events. The odds ratios of grades I to V and grades III to V hypertension were calculated using a random-effects meta-analysis. RESULTS: Thirty-two RCTs (n=19 810 cancer patients) were included. At a median follow-up of 36 months, the median overall survival was 15 months in the ICI group. ICI initiation was not significantly associated with hypertension (grades I-V: odds ratio, 1.12 [95% CI, 0.96-1.30]; grades III-V: odds ratio, 0.95 [95% CI, 0.78-1.16]). Additionally, no significant differences in hypertension risk were evident in ICI combination therapies with various drugs, including anti-VEGF (vascular endothelial growth factor) agents. In a subgroup analysis based on clinical setting (placebo RCT versus nonplacebo RCT), there were discrepancies between the results obtained with different methodologies, with patients in the nonplacebo RCTs having higher grades I-V hypertension (I2=88.6%, P for heterogeneity=0.003). CONCLUSIONS: ICI initiation was not associated with short-term risk of hypertension in cancer patients, and the association was similar regardless of concomitant treatment with other anticancer drugs.

DOI： 10.1161/HYPERTENSIONAHA.122.19865

PubMed

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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記述言語：英語  

A 69-year-old woman was referred for upgrading implantable cardioverter defibrillator (ICD) to cardiac resynchronization therapy defibrillator (CRT-D) because of symptomatic heart failure due to dilated cardiomyopathy. Her electrocardiogram showed left bundle branch block and echocardiography showed severe left ventricular dysfunction. Venography confirmed the presence of persistent left superior vena cava (PLSVC), and occlusion of innominate vein and the coronary sinus (CS) ostium. We tried to insert the left ventricular (LV) lead through the PLSVC. Because the PLSVC was narrow, there was concern that insertion of the guiding catheter through the PLSVC might cause vascular damage. Therefore, we planned to implant the LV lead without a guiding catheter. Although the LV lead did not advance to the CS due to the acute angle, using a second wire (buddy wire system), the tip of the first wire was trapped by an inflated balloon delivered by a second wire (anchor balloon technique). This technique allowed us to reinforce the support of the other wire. The LV lead was easily advanced along with the fixed first wire and was delivered to the lateral vein of the CS. Thus, we successfully performed minimally invasive implantation of an LV lead through a PLSVC approach. <Learning objective: The double wire (buddy wire) technique and anchor balloon technique are effective options for implantation of a left ventricular lead through a persistent left superior vena cava in cardiac resynchronization therapy.>.

DOI： 10.1016/j.jccase.2021.11.009

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本東洋医学会  

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記述言語：日本語   出版者・発行元：(一社)日本東洋医学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

This network meta-analysis was performed to rank the safety and efficacy of periprocedural anticoagulant strategies in patients undergoing atrial fibrillation ablation. MEDLINE, EMBASE, CENTRAL, and Web of Science were searched to identify randomized controlled trials comparing anticoagulant regimens in patients undergoing atrial fibrillation ablation up to July 1, 2021. The primary efficacy and safety outcomes were thromboembolic and major bleeding events, respectively, and the net clinical benefit was investigated as the primary-outcome composite. Seventeen studies were included (n = 6950). The mean age ranged from 59 to 70 years; 74% of patients were men and 55% had paroxysmal atrial fibrillation. Compared with the uninterrupted vitamin-K antagonist strategy, the odds ratios for the composite of primary safety and efficacy outcomes were 0.61 (95%CI: 0.31–1.17) with uninterrupted direct oral anticoagulants, 0.63 (95%CI: 0.26–1.54) with interrupted direct oral anticoagulants, and 8.02 (95%CI: 2.35–27.45) with interrupted vitamin-K antagonists. Uninterrupted dabigatran significantly reduced the risk of the composite of primary safety and efficacy outcomes (odds ratio, 0.21; 95%CI, 0.08–0.55). Uninterrupted direct oral anticoagulants are preferred alternatives to uninterrupted vitamin-K antagonists. Interrupted direct oral anticoagulants may be feasible as alternatives. Our results support the use of uninterrupted direct oral anticoagulants as the optimal periprocedural anticoagulant strategy for patients undergoing atrial fibrillation ablation.

DOI： 10.3390/jcm11071872

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom's relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan-Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03-3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference -0.13, 95% CI -0.27-0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020].

DOI： 10.3389/fphar.2022.1008946

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The number of people with obesity is rapidly increasing worldwide. Since obesity is a critical risk factor for cardiovascular diseases and mortality, the management of obesity is an urgent issue. However, anti-obesity drugs are insufficient in current clinical settings. Bofutsushosan (BTS, Fang-Feng-Tong-Sheng-San in China) is a traditional Japanese Kampo formula for patients with obesity. Recent basic studies have indicated that BTS potentially improves the pathophysiology of obesity. However, it is still unknown whether BTS clinically reduces body mass index (BMI) in patients with obesity. METHODS: We searched electronic databases, including the Medline, EMBASE, Cochrane Library, and Japanese/Chinese/Korean databases, on June 15, 2021. We conducted a meta-analysis of randomized controlled trials to evaluate the effects of BTS on BMI, waist circumference, glycolipid metabolism, and blood pressure in participants with obesity. The primary outcome was change in BMI. RESULTS: We included seven studies and 679 participants (351 in the BTS group and 328 in the control group). In participants with obesity, BTS significantly reduced BMI relative to controls (mean difference, MD [95% confidence interval]: -0.52 kg/m2 [-0.86, -0.18], P = 0.003). There was no significant difference in waist circumference, glycolipid parameters, or blood pressure. Sensitivity analyses showed robust outcomes for the primary endpoint, although the heterogeneity was considerable. Moreover, no serious adverse events were observed in the BTS group. CONCLUSION: BTS showed a potential benefit in safely and tolerably improving BMI in participants with obesity.

DOI： 10.1371/journal.pone.0266917

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

DOI： 10.3390/ijms23010302

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

To explore the biological and immunological basis of human rheumatoid arthritis and human atherosclerosis, we planned and reported a detailed design and rationale for Orencia Atherosclerosis and Rheumatoid Arthritis Study (ORACLE Arthritis Study) using highly sensitive, high-throughput, human autoantibody measurement methods with cell-free protein synthesis technologies. Our previous study revealed that subjects with atherosclerosis had various autoantibodies in their sera, and the titers of anti-Th2 cytokine antibodies were correlated with the severity of atherosclerosis. Because rheumatoid arthritis is a representative autoimmune disease, we hypothesized that both rheumatoid arthritis and atherosclerosis are commonly developed by autoantibody-mediated autoimmune processes, leading to incessant inflammatory changes in both articular joint tissues and vessel walls. We planned a detailed examination involving carotid artery ultrasonography, measurements of adhesion molecules, such as ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) for the evaluation of atherosclerosis progression, and high-throughput, high-sensitivity, autoantibody analyses using cell-free technologies, with detailed examinations of the disease activity of rheumatoid arthritis. Analyses of correlations and associations between biological markers and degrees of carotid atherosclerosis over time under consistent conditions may enable us to understand the biological and humoral immunity background of human atherosclerosis and autoimmune diseases.

DOI： 10.3390/mps4040083

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI  

The newly established mouse cortical-bone-derived stem cells (mCBSCs) are unique stem cells compared to mouse mesenchymal stem cells (mMSCs). The mCBSC-treated hearts after myocardial infarction have been reported to have greater improvement in myocardial structure and functions. In this study, we examined the stemness features, cell surface glycan profiles, and paracrine functions of mCBSCs compared with mMSCs. The stemness analysis revealed that the self-renewing capacity of mCBSCs was greater than mMSCs
however, the differentiation capacity of mCBSCs was limited to the chondrogenic lineage among three types of cells (adipocyte, osteoblast, chondrocyte). The cell surface glycan profiles by lectin array analysis revealed that α2-6sialic acid is expressed at very low levels on the cell surface of mCBSCs compared with that on mMSCs. In contrast, the lactosamine (Galβ1-4GlcNAc) structure, poly lactosamine-or poly N-acetylglucosamine structure, and α2-3sialic acid on both N-and O-glycans were more highly expressed in mCBSCs. Moreover, we found that mCBSCs secrete a greater amount of TGF-β1 compared to mMSCs, and that the TGF-β1 contributed to the self-migration of mCBSCs and activation of fibroblasts. Together, these results suggest that unique characteristics in mCBSCs compared to mMSCs may lead to advanced utility of mCBSCs for cardiac and noncardiac repair.

DOI： 10.3390/ijms222111849

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The efficacy and bleeding complications of direct oral anticoagulant (DOAC) therapy for isolated distal deep vein thrombosis (IDDVT) associated with cancer in routine clinical practice remain unclear. Moreover, prior studies on prolonged therapy for IDDVT are limited. METHODS: This retrospective study enrolled 1641 consecutive patients with acute venous thromboembolism (VTE) who had received oral anticoagulant therapy, including warfarin or DOAC, between April 2014 and September 2018 in our institutions. In these patients, 200 patients with cancer-associated IDDVT were evaluated. RESULTS: Mean follow-up period was 780 ± 593 days. Major bleeding and VTE recurrence were observed in 22 (11.0%) and 11 (5.5%) patients, respectively. In multivariate analysis, statistically significant factors correlated with major bleeding were advanced cancer stage, high performance status, stomach cancer, and gallbladder cancer; those correlated with all-cause death were advanced cancer stage, high performance status, liver dysfunction, pancreatic cancer, and major bleeding. Cumulative events of major bleeding and recurrence between patients with prolonged DOAC therapy (≥90 days) and those with nonprolonged therapy were not significantly different. CONCLUSIONS: Preventing major bleeding is important because it is a significant risk factor for all-cause death. Major bleeding and recurrent events were comparable between prolonged and nonprolonged therapy.

DOI： 10.3390/jcm10204648

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Many studies have revealed numerous potential biomarkers for atherosclerosis, but tissue-specific biomarkers are still needed. Recent lineage-tracing studies revealed that smooth muscle cells (SMCs) contribute substantially to plaque formation, and the loss of SMCs causes plaque vulnerability. We investigated the association of SMC-specific myosin heavy chain 11 (myosin-11) with atherosclerosis. Forty-five patients with atherosclerosis and 34 control subjects were recruited into our study. In the atherosclerosis patients, 35 patients had either coronary artery disease (CAD) or peripheral artery disease (PAD), and 10 had both CAD and PAD. Coronary arteries isolated from five patients were subjected to histological study. Circulating myosin-11 levels were higher in the CAD or PAD group than in controls. The area under the receiver operating characteristic curve of myosin-11 was 0.954. Circulating myosin-11 levels in the CAD and PAD group were higher than in the CAD or PAD group, while high-sensitivity C-reactive protein concentrations did not differ between these groups. Multinomial logistic regression analyses showed a significant association of myosin-11 levels with the presence of multiple atherosclerotic regions. Myosin-11 was expressed in the medial layer of human atherosclerotic lesions where apoptosis elevated. Circulating myosin-11 levels may be useful for detecting spatial expansion of atherosclerotic regions.

DOI： 10.3390/jcm10143155

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Previous clinical studies have suggested that commensal microbiota play an important role in atherosclerotic cardiovascular disease; however, a synthetic analysis of coronary heart disease (CHD) has yet to be performed. Therefore, we aimed to investigate the specific types of commensal microbiota associated with CHD by performing a systematic review of prospective observational studies that have assessed associations between commensal microbiota and CHD. Of the 544 published articles identified in the initial search, 16 publications with data from 16 cohort studies (2210 patients) were included in the analysis. The combined data showed that Bacteroides and Prevotella were commonly identified among nine articles (n = 13) in the fecal samples of patients with CHD, while seven articles commonly identified Firmicutes. Moreover, several types of commensal microbiota were common to atherosclerotic plaque and blood or gut samples in 16 cohort studies. For example, Veillonella, Proteobacteria, and Streptococcus were identified among the plaque and fecal samples, whereas Clostridium was commonly identified among blood and fecal samples of patients with CHD. Collectively, our findings suggest that several types of commensal microbiota are associated with CHD, and their presence may correlate with disease markers of CHD.

DOI： 10.3390/jcm10143120

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier Ltd  

The vascular involvement in patients with Behcet's disease is defined as vascular Behcet's disease, which can greatly influence the prognosis. However, there are few reports on endovascular treatment (EVT) for subclavian pseudoaneurysms with long-term prognosis over 10 years. We present the case of a 42-year-old man with left subclavian artery pseudoaneurysm due to vascular Behcet's disease who was treated with EVT along with immunosuppressive therapies. Subsequently, 8 years after, the aneurysm recurred in the stent with stent fracture. Therefore, additional EVT was performed. We present the details of the patient's clinical course over 10 years after the EVT. &lt
Learning objective: Vascular Behcet's disease can greatly influence the prognosis. Therefore, understanding its treatment and management is important. There are few reports on endovascular treatment (EVT) for subclavian pseudoaneurysms with long-term prognosis over 10 years. Long-term management and recurrence monitoring are required for vascular Behcet's disease even after EVT.&gt

DOI： 10.1016/j.jccase.2020.11.018

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記述言語：日本語   出版者・発行元：(一社)日本東洋医学会  

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/tkm2.1271

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The comparative severity of patent foramen ovale (PFO)-related stroke in patients without atrial fibrillation (AF) and AF-related stroke in patients without PFO is unknown. Therefore, we compared the severity of PFO-related stroke and AF-related stroke. Twenty-six patients who underwent transesophageal echocardiography (TEE) were diagnosed with cardioembolic stroke from July 2018 to March 2020. Cases with AF detected by electrocardiograms or thrombus in the left atrium or left atrial appendage on TEE were included in the AF-related stroke group. Cases with a positive microbubble test on the Valsalva maneuver during TEE, and with no other factors that could cause stroke, were included in the PFO-related stroke group. This study was designed as a single-center, small population pilot study. The stroke severity of the two groups by the National Institute of Health Stroke Scale (NIHSS) score was compared by statistical analysis. Of the 26 cases, five PFO-related stroke patients and 21 AF-related stroke patients were analyzed. The NIHSS score was 2.2 ± 2.8 and 11.5 ± 9.2 (p-value < 0.01), the rate of hypertension was 20.0% and 85.7% (p-value = 0.01), and the HbA1c value was 5.5 ± 0.2% and 6.3 ± 1.3% (p-value = 0.02) in the PFO-related and AF-related stroke groups, respectively. Compared with AF-related stroke patients, stroke severity was low in PFO-related stroke patients.

DOI： 10.3390/jcm10020332

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In the treatment of adult congenital heart disease (ACHD), the transfer of patients from pediatric cardiologists to ACHD cardiologists is of relevance. However, little is known about the clinical courses of ACHD patients that have been referred by non-CHD-specialized doctors (n-CSDs). METHODS: This retrospective cohort study included 230 patients (average age: 37 ± 15.2 years, male: 97) who were referred to a single specialized ACHD center between April 2016 and July 2019. We compared the characteristics and clinical courses between patients referred by n-CSDs and those referred by CHD-specialized-doctors (CSDs). RESULTS: Overall, 121 (53%) patients were referred by n-CSDs. Among them, 91 (75%) patients were referred by adult cardiologists. Univariate analysis showed that the patients referred by n-CSDs were older than those referred by CSDs (41.6 ± 16.3 vs. 32.0 ± 12.0 years, p <  0.01), were more likely to have simple CHD, and less likely to have severe CHD (27.0% vs. 12.8% and 16.5% vs. 40.4%, respectively, p <  0.01). Patients referred by n-CSDs were also more likely to have a history of loss of follow-up (16.5% vs. 3.7%, p <  0.01) and to require invasive treatments after referral, including cardiac surgeries and transcatheter interventions (47.9% vs. 26.6 %, p <  0.01). Notably, unintended invasive treatments that were not designated by the referring doctors were more frequently required in patients with moderate complexity referred by n-CSDs (50.0% vs. 23.3%, p =  0.02). CONCLUSIONS: Patients with moderate CHD complexity referred by n-CSDs are more likely to require unintended invasive treatments. Referrals to specialized ACHD centers may be most beneficial for these patients.

DOI： 10.1016/j.jjcc.2020.06.018

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記述言語：英語   出版者・発行元：東京医科大学医学会  

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記述言語：英語   出版者・発行元：東京医科大学医学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00877&link_issn=&doc_id=20210924430042&doc_link_id=%2Fcr4tokyo%2F2021%2Fs07901%2F033%2F0104-0104%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcr4tokyo%2F2021%2Fs07901%2F033%2F0104-0104%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jch.14160

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adiponectin (APN) has cardioprotective properties and bisoprolol has been reported to increase myocardial APN expression and reduce myocardial damage. Administration of landiolol, which has a higher cardio-selectivity and shorter half-life than bisoprolol, during the percutaneous coronary intervention (PCI) may increase serum APN and high-molecular weight (HMW)-APN, an active form of APN, in patients with stable angina pectoris (SAP). We recruited 70 patients with SAP and randomized them to intravenous landiolol during PCI (N = 35) or control group (N = 35). The primary endpoint was serum APN and HMW-APN level 3 days after PCI. There was no difference in the primary endpoint between the landiolol and control groups (8.93 ± 5.24 vs. 10.18 ± 5.81 μg/mL, p = 0.35 and 3.36 ± 2.75 vs. 4.28 ± 3.13 μg/mL, p = 0.20) for APN and HMW-APN levels, respectively. APN and HMW-APN level were significantly decreased 1 day after PCI [-0.55 ± 0.92 μg/mL (9.87-9.32 μg/mL), p < 0.001 and -0.20 ± 0.45 μg/mL (3.89-3.69 μg/mL), p < 0.001, respectively]. Additionally, the absolute change in HMW-APN was significantly smaller in the landiolol group compared to the control group (-0.08 ± 0.27 vs. -0.31 ± 0.55 μg/mL, p = 0.031). Multiple linear regression analysis showed that use of landiolol was an independent predictor of change in HMW-APN (β = 0.276, p = 0.014). Serum APN and HMW-APN level 3 days after PCI were similar between patients treated with and without landiolol. APN and HMW-APN decreased 1 day after PCI in the SAP and landiolol mitigated decrease in HMW-APN.

DOI： 10.1007/s00380-020-01637-6

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記述言語：英語  

A 54-year-old male with a history of unrepaired ventricular septal defect (VSD) suffered from easy fatigability on exertion. A Levine grade V/VI continuous murmur was auscultated. Transthoracic echocardiogram showed a ruptured sinus of Valsalva aneurysm (SVA) and a significant left-to-right shunting from the ascending aorta to the right ventricle (RV). In addition, a 36 mmHg of pressure gradient was observed between the inflow and outflow tract in the RV, suggesting double-chambered RV (DCRV). Cardiac catheterization also revealed 33 mmHg of the pressure gradient in the mid-potion of the RV, which was coincident with DCRV. A calculated pulmonary-to-systemic flow ratio was 3.0. Therefore, the patient was offered surgical repair of the ruptured SVA and VSD, which was successfully performed. During the surgery, an anomalous muscle band, which is usually the cause of DCRV, was not found, instead, a thickened RV free-wall due to the exposure of the left-to-right shunt flow, so-named jet lesion, was found. Therefore, surgical resection of the anomalous muscle band was not required. The protruded SVA toward the RV, the jet lesion, and the increased RV stroke volume, which could induce relative stenosis, were the causes of the unusual DCRV. <Learning objective: A mechanism of an unusual double-chambered right ventricle induced by ruptured sinus of Valsalva aneurysm (SVA) is as follows. One is a morphological stenosis in the right ventricle (RV) due to a protruded SVA toward the RV. The second is a jet lesion; a thickened RV wall induced by the exposure of the shunt flow from the ascending aorta. The third is a relative stenosis due to the increased stroke volume of the RV.>.

DOI： 10.1016/j.jccase.2020.07.009

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記述言語：英語  

A 20-year-old male without any symptoms was referred for heart murmur on a medical examination. A thrill was palpable at the upper left sternal border. His cardiac murmur showed respiratory variation. The systolic murmur was louder (Levine grade IV/VI) during expiration and diminished during inspiration (Levine grade I/VI). He was thin and had a narrow thoracic cage in the anteroposterior direction due to straight back syndrome (SBS). An echocardiogram and a right ventriculogram showed changes in the diameter of the right ventricular outflow tract (RVOT) on respiration. During expiration, the RVOT was compressed and narrow, while it was expanded during inspiration. Cardiac catheterization demonstrated a 10-mmHg of pressure gradient across the RVOT during expiration but no pressure gradient during inspiration. Thus, respiratory compression to the RVOT by a narrow thoracic cage due to SBS was the cause of the cardiac murmur with respiratory alterations. Our case highlights the importance of physical examination, including an inspection of the patient's physique. <Learning objective: When examining a patient with a cardiac murmur, respiratory alterations of cardiac murmurs should be auscultated. In these cases, straight back syndrome would be one of the differential diagnoses and should be considered. During a physical examination, inspection of the patient's physique is also important.>.

DOI： 10.1016/j.jccase.2020.07.008

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記述言語：英語  

OBJECTIVES: We aimed to test our hypothesis that additional administration of traditional Japanese (Kampo) medicine, kakkonto (kakkon-to: KT) and shosaikotokakikyosekko (sho-saiko-to-ka-kikyo-sekko: SSKKS), is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated only with conventional treatment. TRIAL DESIGN: The study is designed as a multi-center, interventional, parallel-group, randomized (1:1 ratio), investigator-sponsored, two-arm study. PARTICIPANTS: Patients and inpatients will be recruited from 8 Japanese academic and non-academic hospitals. The inclusion and exclusion criteria are as follows: Inclusion criteria: 1. Diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 2. Clinical stages of mild-to-moderate COVID-19 3. Symptomatic 4. ≥ 20 years of age 5. Male or female 6. Ability to communicate in Japanese 7. Outpatients and inpatients 8. Provided informed consent Exclusion criteria: 1. Difficulty in providing informed consent due to dementia, psychosis, or psychiatric symptoms 2. Allergic to Kampo or Western medicines used in this study 3. Pregnant and lactating 4. Unable to follow up 5. Participating in another clinical trial or interventional study 6. Hypokalemic or taking oral furosemide or steroids 7. Determined unsuitable for this study by the physician INTERVENTION AND COMPARATOR: Patients in the control group will receive conventional treatment with antipyretics, painkillers, or antitussives for symptoms that occurred after they contracted the SARS-CoV-2 infection. Patients in the Kampo group will receive 2.5 g of KT (TJ-1@TSUMURA and Co.) and 2.5 g of SSKKS (TJ-109@TSUMURA and Co.) 3 times a day, orally, for 14 days in addition to the conventional treatment as mentioned above. MAIN OUTCOMES: The number of days till at least one of the symptoms (fever, cough, sputum, malaise, shortness of breath) improves in the first 14 days of treatment. To assess the cough, sputum, malaise, and shortness of breath, a numeric rating scale will be used to define improvement in terms of a 2-point decrease in the number of days from the start of treatment for at least 2 days. Fever will be defined as an improvement when the temperature is less than 37 °C. RANDOMIZATION: Patients are randomized (1:1 ratio) to each group using the minimization method, with balancing of the arms with severity of disease stage and patient age (< 65, 65 to < 75, or ≥ 75 years). Computer-generated random numbers will be used for the minimization method. BLINDING (MASKING): Open-label with no blinding NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The main research hypothesis of this study is that the combination of Kampo medicine and conventional treatment will significantly improve the patients' symptoms (fever, fatigue, cough, sputum, and shortness of breath) during the first 14 days of treatment as compared with conventional treatment alone. Concerning the analysis of the primary endpoint, the duration of time before improvement of at least one of the common cold-like symptoms (fever, malaise, cough, sputum, and shortness of breath) will be estimated using the Kaplan-Meier method, and the survival curves will be compared between groups using the log-rank test. Assuming this method of analysis and based on previous studies reporting the efficacy of Kampo medicine for COVID-19 and H1N1 influenza patients, the median survival time in the Kampo medicine group is estimated as 3 days; this time will be 1.5 times longer in the control group. Assuming a one-sided significance level of 5%, a power of 70%, and an allocation ratio of 1:1, the required sample size is calculated as 126 cases. To compensate for a loss in follow-up, we plan to include 150 cases in both groups (Kampo group = 75, control group = 75). TRIAL STATUS: Protocol version 1.2 as of August 20, 2020 Recruitment start (expected): October 1, 2020 Recruitment finish (expected): October 31, 2023 TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) jRCTs021200020 . Registered on August 25, 2020 FULL PROTOCOL: The full protocol is attached as an additional file and is accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

DOI： 10.1186/s13063-020-04746-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The incidence of ventricular arrhythmia in patients with an implanted pacemaker is not yet known. The aim of this study was to analyze non-sustained ventricular tachycardia (NSVT) episodes based on stored electrograms (EGM) and determine the occurrence rate and risk factors for NSVT in a pacemaker population.This study included 302 consecutive patients with a dual-chamber pacemaker. A total of 1024 EGMs stored in pacemakers as ventricular high-rate episodes were analyzed. The definition of NSVT was ≥ 5 consecutive ventricular beats at ≥ 150 bpm lasting < 30 seconds.In baseline, most patients (94.8%) had ≥ 60% left ventricular ejection fraction. Of 1024 EGMs, 420 (41.0%) showed appropriate NSVT episodes, as well as premature atrial contractions, atrial tachyarrhythmia, or atrial fibrillation with a rapid ventricular response, whereas other EGMs did not show an actual ventricular arrhythmia. On EGM analysis, during a mean follow-up period of 46.1 months, NSVT occurred one or more times in 82 patients (33.1%). On multivariate analysis, ≥ 50% right ventricular pacing was an independent risk factor for NSVT (odds ratios, 4.519; P < 0.001), but NSVT was not associated with increased all-cause mortality.Moreover, in the pacemaker population, ≥ 50% right ventricular pacing is an independent risk factor for NSVT; however, NSVT was not associated with increased all-cause mortality because of the preserved left ventricular function.

DOI： 10.1536/ihj.20-141

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Atherosclerosis is the leading cause of cardiovascular mortality and morbidity worldwide and is described as a complex disease involving several different cell types and their molecular products. Recent studies have revealed that atherosclerosis arises from a systemic inflammatory process, including the accumulation and activities of various immune cells. However, the immune system is a complicated network made up of many cell types, hundreds of bioactive cytokines, and millions of different antigens, making it challenging to readily define the associated mechanism of atherosclerosis. Nevertheless, we previously reported a potential persistent inflammatory process underlying atherosclerosis development, centered on a pathological humoral immune response between commensal microbes and activated subpopulations of substantial B cells in the vicinity of the arterial adventitia. Accumulating evidence has indicated the importance of gut microbiota in atherosclerosis development. Commensal microbiota are considered important regulators of immunity and metabolism and also to be possible antigenic sources for atherosclerosis development. However, the interplay between gut microbiota and metabolism with regard to the modulation of atherosclerosis-associated immune responses remains poorly understood. Here, we review the mechanisms by which the gut microbiota may influence atherogenesis, with particular focus on humoral immunity and B cells, especially the gut-immune-B2 cell axis. Graphical abstract Under high-fat and high-calorie conditions, signals driven by the intestinal microbiota via the TLR signaling pathway cause B2 cells in the spleen to become functionally active and activated B2 cells then modify responses such as antibody production (generation of active antibodies IgG and IgG3), thereby contributing to the development of atherosclerosis. On the other hand, intestinal microbiota also resulted in recruitment and ectopic activation of B2 cells via the TLR signaling pathway in perivascular adipose tissue (PVAT), and, subsequently, an increase in circulating IgG and IgG3 led to the enhanced disease development. This is a potential link between microbiota alterations and B cells in the context of atherosclerosis.

DOI： 10.1007/s00109-020-01936-5

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The efficacy and bleeding complications of direct oral anticoagulant (DOAC) therapy for cancer-associated venous thromboembolism (VTE) in routine clinical practice remain unclear. Moreover, data on long-term outcomes in patients with cancer-associated VTE who received DOAC therapy are limited.Methods and Results:This retrospective study enrolled 1,096 consecutive patients with acute VTE who received warfarin or DOAC therapy between April 2014 and May 2017. The mean follow-up period was 665±490 days. The number of cancer-associated VTE patients who received DOAC therapy was 334. Patients who could not be followed up and those prescribed off-label under-dose DOAC were excluded. Finally, 303 patients with cancer-associated VTE were evaluated. The number of cases of major bleeding and VTE recurrence was 54 (17.8%) and 26 (8.6%), respectively. In the multivariate analysis, the factors correlated with major bleeding were high cancer stage, high performance status, liver dysfunction, diabetes mellitus, and stomach cancer; those correlated with recurrent VTE were initial diagnosis of pulmonary embolism, uterine cancer, and previous cerebral infarction. Major bleeding was an independent risk factor of all-cause death. In the Kaplan-Meier analysis, those who received prolonged DOAC therapy had lower composite major bleeding and recurrent VTE risks than those who did not. CONCLUSIONS: In DOAC therapy for cancer-associated VTE, major bleeding prevention is important because it is an independent risk factor of death.

DOI： 10.1253/circj.CJ-20-0084

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記述言語：日本語   出版者・発行元：(一社)日本医学教育学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Erythropoietin-stimulating agents (ESAs) are used to treat renal anemia in patients with non-dialysis CKD, but this can lead to increases in blood pressure (BP). Objective: We investigated the effects of continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) on office/ambulatory BP in 36 patients with non-dialysis CKD and renal anemia who did not receive ESA treatment. Methods: Participants were randomly assigned to CERA or DA, and received ESA treatment for 24 weeks. ESA doses were adjusted to maintain hemoglobin (Hb) at 10-12 g/dL. Primary outcomes were office/ambulatory BP after 24 weeks of ESA treatment. Hb levels were within the target range at 24 weeks. Results: Office/ambulatory BP, renal function, and other parameters were not significantly different between groups. However, we could not exclude the possibility that differences may exist because our sample size was small. Therefore, we also performed analysis of all of the data that were compiled from the groups of per-protocol population. Although office/ambulatory BP profiles had not worsened after 24 weeks of ESA treatment, more than half of the patients required an increase in the antihypertensive agent dose. Conclusions: CERA and DA may have similar effects on BP profiles in patients with non-dialysis CKD and renal anemia. ESA treatment often requires increases in the doses of antihypertensive agents.

DOI： 10.1159/000507396

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：英語  

The patient was a 19-year-old woman who had experienced headache for 1 year. Soon after birth, ventricular septal defects were diagnosed, the size of which were small, therefore not requiring surgical repair. She also noticed hypertension, with up to 184/110 mmHg of blood pressure. Her physical examination revealed a difference in blood pressure between her upper and lower limbs (160/108 and 92/65 mmHg, respectively). A cardiac computed tomography image clearly demonstrated the narrowing of the aortic isthmus. Coarctation of the aorta (CoA) was definitively diagnosed and was the cause of the upper limb hypertension and headache. Cardiac catheterization revealed 3.8 mm of the aortic isthmus and 65 mmHg of the peak-to-peak pressure gradient across the CoA. The patient was offered endovascular therapy of the CoA. A non-covered stent implantation was successfully performed and the pressure gradient across the aortic isthmus disappeared. Her upper limb hypertension also improved. Aortic angioscopy revealed a yellow plaque on the aortic intima, located proximal to the coarctation site, which was exposed owing to high blood pressure. Our case highlights that an atherosclerotic change can develop even in young patients with hypertension. <Learning objective: An aortic angioscope can detect an early atherosclerotic change of aorta, which other imaging modalities such as computed tomography and intravascular ultrasonography cannot show. An early atherosclerosis can develop even in a young patient with hypertension; therefore, coarctation of the aorta should be diagnosed and treated appropriately as soon as possible.>.

DOI： 10.1016/j.jccase.2020.03.001

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記述言語：英語  

A 76-year-old male was admitted to our hospital for progressive bilateral pleural effusion. Because of typical echocardiographic findings such as left ventricular (LV) hypertrophy, thickness of the mitral valve, and a granular sparkling appearance of the LV wall, amyloid cardiomyopathy was suspected. Regardless of up-titration of several diuretic agents, the bilateral pleural effusion did not improve. Because the histological findings of the right ventricular septum (direct-fast-scarlet staining) obtained by biopsy that demonstrated amyloid deposits in perivascular and pericellular lesions, amyloid cardiomyopathy was diagnosed. However, cardiac catheterization revealed normal right and left atrial pressure and normal right and left ventricular end-diastolic pressure. Therefore, hemodynamic deterioration was less likely to be the cause of persistent pleural effusion. Amyloid deposits were also detected in the pleural biopsy specimen, so pleural amyloidosis was diagnosed and may have played an important role in the refractoriness of the pleural effusion. <Learning objective: Systolic and diastolic dysfunction of various degrees can occur in patients with amyloid cardiomyopathy, which is usually progressive and induces heart failure. In these patients, diuretics are key drugs for resolving fluid retention issues such as pleural effusion. In cases of refractory pleural effusion associated with amyloid cardiomyopathy despite aggressive diuretic therapy, these may be induced by pleural amyloidosis.>.

DOI： 10.1016/j.jccase.2020.01.003

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ubiquitination is a representative, reversible biological process of the post-translational modification of various proteins with multiple catalytic reaction sequences, including ubiquitin itself, in addition to E1 ubiquitin activating enzymes, E2 ubiquitin conjugating enzymes, E3 ubiquitin ligase, deubiquitinating enzymes, and proteasome degradation. The ubiquitin-proteasome system is known to play a pivotal role in various molecular life phenomena, including the cell cycle, protein quality, and cell surface expressions of ion-transporters. As such, the failure of this system can lead to cancer, neurodegenerative diseases, cardiovascular diseases, and hypertension. This review article discusses Nedd4-2/NEDD4L, an E3-ubiquitin ligase involved in salt-sensitive hypertension, drawing from detailed genetic dissection analysis and the development of genetically engineered mice model. Based on our analyses, targeting therapeutic regulations of ubiquitination in the fields of cardio-vascular medicine might be a promising strategy in future. Although the clinical applications of this strategy are limited, compared to those of kinase systems, many compounds with a high pharmacological activity were identified at the basic research level. Therefore, future development could be expected.

DOI： 10.3390/ijms21113871

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記述言語：英語  

A 75-year-old male suffered from dyspnea on exertion. In a referring hospital, cardiac catheterization demonstrated a 25% increase in oxygen saturation between the high superior vena cava (SVC) and the right atrium, suggesting a pre-tricuspid left-to-right shunt. However, neither an intracardiac shunt nor a partial anomalous pulmonary venous connection was detected. Therefore, he was referred to our hospital for further evaluation. A transesophageal echocardiogram revealed a retrograde-dominant bidirectional flow in the right upper pulmonary vein (RUPV). A contrast agent injected via the left upper limb appeared in the SVC and thereafter some contrast entered into the RUPV. A three-dimensional reconstructed computed tomography showed a side-to-side communication between the RUPV and the SVC. A cavopulmonary window was definitively diagnosed, in which the RUPV not only drained into the left atrium but also connected to the SVC side-to-side. <Learning objective: In a suspected case of a pre-tricuspid left-to-right shunt without atrial septal defect and anomalous pulmonary venous connection, a cavopulmonary window would be another differential diagnosis. This rare cardiac anomaly should be taken into consideration in diagnosing a pre-tricuspid left-to-right shunt. Identifying the direction of pulmonary venous flow can be an opportunity to find it.>.

DOI： 10.1016/j.jccase.2020.01.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Doxorubicin (DOX)-induced heart failure has a poor prognosis, and effective treatments have not been established. Because DOX shows cumulative cardiotoxicity, we hypothesized that minimal cardiac remodelling occurred at the initial stage in activating cardiac fibroblasts. Our aim was to investigate the initial pathophysiology of DOX-exposed cardiac fibroblasts and propose prophylaxis. METHODS AND RESULTS: An animal study was performed using a lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulative dose. Histological analysis was performed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay, picrosirius red staining, and immunohistochemical staining. The mechanism was analysed in vitro with a low dose of DOX, which did not induce cell apoptosis. Microarray analysis was performed. Differentially expressed genes were confirmed by enrichment analysis. Mitochondrial damage was assessed by mitochondrial membrane potential. The production of inflammatory cytokines and fibrosis markers was assessed by western blot, quantitative polymerase chain reaction, and ELISA. A phosphokinase antibody array was performed to detect related signalling pathways. Low-dose DOX did not induced cell death, and fibrosis was localized to the perivascular area in mice. Microarray analysis suggested that DOX induced genes associated with the innate immune system and inflammatory reactions, resulting in cardiac remodelling. DOX induced mitochondrial damage and increased the expression of interleukin-1. DOX also promoted the expression of fibrotic markers, such as alpha smooth muscle actin and galectin-3. These responses were induced through stress-activated protein kinase/c-Jun NH2-terminal kinase signalling. A peroxisome proliferator-activated receptor (PPARγ) agonist attenuated the expression of fibrotic markers through suppressing stress-activated protein kinase/c-Jun NH2-terminal kinase. Furthermore, this molecule also suppressed DOX-induced early fibrotic responses in vivo. CONCLUSIONS: Low-dose DOX provoked reactive fibrosis through sterile inflammation evoked by the damaged mitochondria.

DOI： 10.1002/ehf2.12616

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Critical limb ischemia (CLI) is a potentially life-threatening condition that involves severely reduced blood flow to the peripheral arteries due to arteriosclerosis obliterans (ASO) of the limbs or a similar condition. CLI patients must undergo revascularization to avoid amputation of the lower limbs and improve their survival prognosis. However, the outcomes of conventional surgical revascularization or endovascular therapy are inadequate; therefore, establishing further effective treatment methods is an urgent task. We perform therapeutic angiogenesis using autologous bone marrow-derived mononuclear cells in clinical practice and demonstrated its safety and efficacy for CLI patients for whom conventional treatments failed or are not indicated. Exercise therapies must be devised for CLI patients who have undergone therapeutic angiogenesis to save their limbs and improve survival. Because evidence regarding the efficacy and safety of exercise therapy for CLI patients is lacking, we plan to perform a prospective trial of the efficacy and safety of optimal exercise therapy following therapeutic angiogenesis for CLI patients.The trial will enroll 30 patients between 20 and 79 years with Rutherford category 4 or 5 CLI caused by ASO who will undergo therapeutic angiogenesis. Participants will be randomly allocated to receive either optimal exercise therapy or fixed exercise therapy. Those receiving optimal exercise therapy will undergo tissue muscle oxygen saturation monitoring using near-infrared spectroscopy while performing exercises and will be prescribed optimal exercise therapy. The optimal amount of exercise will be determined on day 8, 31, 61, 91 and 181 after therapeutic angiogenesis. Ethics and dissemination: This protocol was approved by the Institutional Review Boards of Kyoto Prefectural University of Medicine. In accordance with the Helsinki Declaration, written informed consent has been obtained from all participants prior to enrollment. The results of this trial will be disseminated by publication in a peer-reviewed journal. Trial registration: This trial is registered at http://www.umin.ac.jp/ctr/index.htm (identifier: UMIN000035288).

DOI： 10.1016/j.conctc.2020.100542

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.

DOI： 10.1038/s41598-020-58214-0

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記述言語：日本語   出版者・発行元：日本成人先天性心疾患学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Both native T1 time and extracellular volume (ECV) fraction have been shown to be important measures for the detection of myocardial fibrosis. However, ECV determination requires the administration of an intravenous contrast agent, whereas native T1 mapping can be performed without a contrast agent. Methods: Here, we conducted a meta-analysis of myocardial native T1 data obtained for non-ischemic cardiomyopathy (NIC) patients and controls. A literature review included studies that applied T1 mapping using modified Look-Locker inversion recovery to measure myocardial fibrosis, and the results were validated by comparing datasets for dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) patients and healthy controls (HCs). Results: We identified 16 eligible studies. Pooled mean differences (MDs) and 95% confidence intervals (CIs) were estimated as follows. Native T1 at 1.5-T, DCM vs. HC: MD = 45.26 (95% CI: 30.92-59.59); HCM vs. HC: MD = 47.09 (95% CI: 32.42-61.76). Native T1 at 3.0-T, DCM vs. HC: MD = 82.52 (95% CI: 47.60-117.44); HCM vs. HC: MD = 115.87 (95% CI: 50.71-181.04). ECV at 1.5-T, DCM vs. HC: MD = 4.26 (95% CI: 3.06-5.46); HCM vs. HC: MD = 1.49 (95% CI: -1.45-4.43). ECV at 3.0-T, DCM vs. HC: MD = 8.40 (95% CI: 2.94-13.86); HCM vs. HC: MD = 8.02 (95% CI: 5.45-1-0.59). Conclusion: In conclusion, native T1 values were significantly different between NIC patients and controls. Native T1 mapping may be a useful noninvasive method to detect diffuse myocardial fibrosis in NIC patients.

DOI： 10.1016/j.ijcha.2019.100422

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The proximal tubule is a particularly important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. However, the mechanisms of SIRT1 regulation remain to be elucidated. We recently reported that angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP)-deficient mice displayed age-associated renal function decline and tubulointerstitial fibrosis. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, although the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, therefore, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageing-associated kidney dysfunction. Here, since ageing studies are inherently lengthy, we used an ex vivo model of the proximal tubule to determine the role of ATRAP in SIRT1 protein expression. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP. Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Thus, ATRAP likely mediates SIRT1 protein abundance in ciRPTEC.

DOI： 10.1038/s41598-019-52566-y

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Trimethylamine N-oxide (TMAO), a metabolite derived from the gut microbiota, is proatherogenic and associated with cardiovascular events. However, the change in TMAO with secondary prevention therapies for ST-segment elevation acute myocardial infarction (STEMI) remains unclear. The purpose of this study was to investigate the sequential change in TMAO levels in response to the current secondary prevention therapies in patients with STEMI and the clinical impact of TMAO levels on cardiovascular events We included 112 STEMI patients and measured plasma TMAO levels at the onset of STEMI and 10 months later (chronic phase). After the chronic-phase assessment, patients were followed up for cardiovascular events. Plasma TMAO levels significantly increased from the acute phase to the chronic phase of STEMI (median: 5.63 to 6.76 μM, P = 0.048). During a median period of 5.4 years, 17 patients experienced events. The chronic-phase TMAO level independently predicted future cardiovascular events (adjusted hazard ratio for 0.1 increase in log chronic-phase TMAO level: 1.343, 95% confidence interval 1.122-1.636, P = 0.001), but the acute-phase TMAO level did not. This study demonstrated the clinical importance of the chronic-phase TMAO levels on future cardiovascular events in patients after STEMI.

DOI： 10.1038/s41598-019-48246-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Recent pacemakers with transthoracic impedance sensors have a specific algorithm identifying sleep apnea (SA). Our aim was to evaluate the algorithm in Japanese patients. METHODS: Consecutive patients implanted with a pacemaker with sleep apnea monitoring algorithm at our hospital were enrolled prospectively. After implantation, patients underwent polysomnography (PSG). The respiratory disturbance index measured by pacemaker (RDI-PM) was extracted in the morning after PSG. RESULTS: Forty-five patients were recruited; 78% of patients underwent overnight PSG completely, and among them RDI-PM was invalid for one patient. Then the analysis was performed in 34 patients. Moderate/severe SA (apnea hypopnea index, AHI≥15events/h) and severe SA (AHI≥30events/h) by PSG were diagnosed in 65% and 41% of patients. The mean AHI-PSG and RDI-PM were 30.4±22.6 and 21.7±14.2events/h, respectively. There was a significant positive correlation between AHI-PSG and RDI-PM (r=0.543; p=0.001). The correlation was stronger in the severe SA group (r=0.664; p=0.010), in a group whose apnea index was higher than hypopnea index (r=0.822; p=0.002), and in a group whose central sleep apnea (CSA) index was higher than obstructive sleep apnea index (r=0.977; p<0.001). RDI-PM cut-off value for identifying severe SA was 22 (area under the curve, 0.682; sensitivity, 64%; specificity, 75%). CONCLUSIONS: The pacemaker-based algorithm is a useful screening tool for SA in Japanese individuals, especially in the severe SA group, apnea-dominant group, and CSA-dominant group.

DOI： 10.1016/j.jjcc.2018.10.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The underlying pathogenesis of chronic kidney disease involves an activated renin-angiotensin system and systemic inflammation which ultimately develop renal injury. Rikkunshito (RKT) has been reported to exert anti-fibrotic and anti-inflammatory effects through enhancement of ghrelin signaling pathway. In this study, we investigated the effects of RKT on renal fibrosis and inflammation in angiotensin II (Ang II)-induced renal injury model. Ang II-infused mice exhibited hypertension, cardiac hypertrophy, increases in blood urea nitrogen and serum creatinine, moderate albuminuria and renal pathological changes such as mild urinary cast, interstitial macrophage infiltration and modest interstitial fibrosis. RKT had no evident effects on the Ang II-induced renal functional insufficiency and fibrosis, but attenuated renal interstitial macrophage infiltration. In addition, RKT significantly restored the Ang II-induced alteration in the expression of renal fibrosis- and inflammation-related genes such as type 3 collagen, transforming growth factor-β, monocyte chemoattractant protein-1 and interleukin-6. Furthermore, although RKT did not affect the expression of renal ghrelin receptor, an Ang II-induced decrease in renal sirtuin 1 expression, a critical down-stream pathway of the ghrelin receptor, was restored by RKT. These findings suggest that RKT potentially has a renal anti-inflammatory effect in the development of renal injury, and this effect could be mediated by the ghrelin signaling pathway.

DOI： 10.1038/s41598-019-42657-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background We have previously shown that ATRAP (angiotensin II receptor-associated protein; Agtrap) interacts with AT1R (angiotensin II type 1 receptor) and promotes constitutive internalization of AT 1R so as to inhibit hyperactivation of its downstream signaling. In response to angiotensin II , systemic ATRAP deficiency exacerbates angiotensin II -mediated hypertension via hyperactivation of renal tubular AT 1R. Although ATRAP expression is abundant in renal proximal tubules, little is known about the actual function of renal proximal tubule ATRAP in angiotensin-mediated hypertension. Methods and Results In this study, we examined the in vivo functional role of renal proximal tubule ATRAP in angiotensin-dependent hypertension. We succeeded in generating proximal tubule-specific ATRAP knockout ( PT - KO ) mice for the first time using the Cre/loxP system with Pepck-Cre. Detailed analysis of renal ATRAP expression in PT - KO mice estimated by immunohistochemical and laser-capture microdissection analysis revealed that ATRAP mRNA expression decreased by ≈80% in proximal regions of the nephron in PT - KO mice compared with wild-type ( WT ) mice. We compared blood pressure of PT - KO and WT mice using both tail-cuff and radiotelemetric methods. Blood pressure of PT - KO mice was comparable with that of WT mice at baseline. Moreover, no significant differences were noted in pressor response to angiotensin II (600 ng/kg per min or 1000 ng/kg per minute) infusion between PT - KO and WT mice. In addition, angiotensin II -mediated cardiac hypertrophy was identical between PT - KO and WT mice. Conclusions ATRAP deficiency in proximal tubules did not exacerbate angiotensin-dependent hypertension in vivo. The results indicate that renal proximal tubule ATRAP has a minor role in angiotensin-dependent hypertension in vivo.

DOI： 10.1161/JAHA.119.012395

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

Background: Many patients with collagen disease (CD), particularly scleroderma (SSc), develop critical limb ischemia (CLI), which leads to limb amputation. However, conventional therapies, including revascularization via surgical bypass, showed poor outcomes in CLI patients with CD. Many CLI patients with SSc showed poor responses to combination therapies including intravenous iloprost, PDE-5 inhibitors, and bosentan. Therefore, new methods of improving the peripheral circulation for limb salvage are required. This study was a subanalysis of the long-term clinical outcomes after autologous bone marrow-derived mononuclear cells (BM-MNC) in CLI patients with SSc. Methods and Results: We assessed no-option CLI patients with CD who underwent BM-MNC implantation at 10 institutes
69 patients (39 with SSc-related diseases (SSc group) and 30 with other CDs (non-SSc group)), were included. The median follow-up duration was 36.5 months. The 10-year overall survival rate was 59.1% in the SSc group and 82.4% in the non-SSc group. The 10-year major amputation-free rates were 97.4% and 82.6%, respectively. The number of major or minor amputations in the SSc group trended to be less than that in the non-SSc group. Significant improvements in visual analog scale scores were observed in both groups. Conclusions: The BM-MNC implantation may be feasible in no-option CLI patients with CD. In the SSc group, limb salvage rate tended to be higher than in the non-SSc group.

DOI： 10.1253/circj.CJ-18-1044

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記述言語：英語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：英語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：英語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：英語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：英語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The interaction between atherosclerosis and commensal microbes through leaky gut syndrome (LGS), which is characterized by impaired intestinal permeability and the introduction of undesired pathogens into the body, has not been fully elucidated. Our aim was to investigate the potential role of a ClC-2 chloride channel activator, lubiprostone, which is reported to have beneficial effects on LGS, in the development of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. After a 15-week feeding period of a Western diet (WD), ApoE-/- mice were treated with a Western-type diet (WD) alone or WD with oral supplementation of lubiprostone for 10 weeks. This feeding protocol was followed by experimental evaluation of LGS and atherosclerotic lesions in the aorta. In mice with lubiprostone, in vivo translocation of orally administered 4-kDa FITC-dextran was significantly improved, and RNA expression of the epithelial tight junction proteins, Zo-1 and occludin, was significantly up-regulated in the ileum, compared to the WD alone group, suggesting a possible reversal of WD-induced intestinal barrier dysfunction. As a result, WD-induced exacerbation of atherosclerotic lesion formation was reduced by 69% in longitudinally opened aortas and 26% in aortic root regions. In addition, there was a significant decrease in circulating immunoglobulin level, followed by an attenuation of inflammatory responses in the perivascular adipose tissue, as evidenced by reduced expression of pro-inflammatory cytokines and chemokines. Lubiprostone attenuates atherosclerosis by ameliorating LGS-induced inflammation through the restoration of the intestinal barrier. These findings raise the possibility of targeting LGS for the treatment of atherosclerosis.

DOI： 10.1371/journal.pone.0218096

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although doxorubicin (DOX)-induced cardiomyopathy causes lethal heart failure (HF), no early detection or effective treatment methods are available. The principal mechanisms of cardiotoxicity are considered to involve oxidative stress and apoptosis of cardiomyocytes. However, the effect of DOX on cardiac fibroblasts at non-lethal concentrations remains unknown. The aim of this study was to investigate the direct effect of doxorubicin on the activation of cardiac fibroblasts independent of cell death pathways. We first found that DOX induced α-SMA expression (marker of trans-differentiation) at a low concentration range, which did not inhibit cell viability. DOX also increased MMP1, IL-6, TGF-β and collagen expression in human cardiac fibroblasts (HCFs). In addition, DOX promoted Akt and Smad phosphorylation. A Smad inhibitor prevented DOX-induced α-SMA and IL-6 protein expression. An PI3K inhibitor also prevented MMP1 mRNA expression in HCFs. These findings suggest that DOX directly induces fibrotic changes in HCFs via cell death-independent pathways. Furthermore, we confirmed that these responses are organ- and species-specific for HCFs based on experiments using different types of human and murine fibroblast cell lines. These results suggest potentially new mechanisms of DOX-induced cardiotoxicity from the viewpoint of fibrotic changes in cardiac fibroblasts.

DOI： 10.1371/journal.pone.0221940

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10157-017-1520-8

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記述言語：日本語   出版者・発行元：(NPO)日本小児循環器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Endothelial dysfunction and increased arterial stiffness gradually develop before the manifestation of catastrophic cardiovascular events. Therefore, detection and assessment of vascular function are required to address pre-existing pathological conditions. However, the currently available diagnostic devices and methods are insufficient due to variability among investigators and the time-consuming nature of manual procedures. METHODS: Recently, novel devices were developed for the detection of both arterial stiffness and endothelial dysfunction in a single blood pressure measurement using a cuff-oscillometric technique (AVE-1500, Shisei Datum, Japan). API (arterial pressure volume index) is defined as the reciprocal of the slope of the tangent of the brachial artery pressure-volume curve, and AVI (arterial velocity pulse index) is defined as the ratio of the difference between the ejection and reflection waves. In the present study, we performed retrospective, cross-sectional analyses of subjects (n = 102; mean age = 70.5 ± 10.4 years) with detailed coronary angiographic examinations and clinical background parameters. RESULTS: After adjusting for various variables using multiple linear regression analyses, we found that API, but not AVI, was significantly correlated with coronary artery severity and complexity scores. CONCLUSIONS: We propose that API may be a new vascular index useful for monitoring and assessing the severity and complexity of atherosclerosis in subjects with coronary artery disease and for evaluating atherosclerotic diseases.

DOI： 10.1080/10641963.2018.1465072

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Physiological Society  

Mechanical stresses play important roles in the process of constructing and modifying heart structure. It has been well established that stretch force acting on cardiac fibroblasts induces fibrosis. However, the effects of compressive force, that is, hydrostatic pressure (HP), have not been well elucidated. We thus evaluated the effects of HP using a pressure-loading apparatus in human cardiac fibroblasts (HCFs) in vitro. In this study, high HP (200 mmHg) resulted in significant phosphorylation of Akt in HCFs. HP then greatly inhibited glycogen synthase kinase 3 (GSK-3)α, which acts downstream of the PI3K/Akt pathway. Similarly, HP suppressed mRNA transcription of inflammatory cytokine-6, collagen I and III, and matrix metalloproteinase 1, compared with an atmospheric pressure condition. Furthermore, HP inhibited collagen matrix production in a three-dimensional HCF culture. Taken together, high HP suppressed the differentiation of fibroblasts into the myofibroblast phenotype. HP under certain conditions suppressed cardiac fibrosis via Akt/GSK-3 signaling in HCFs. These results might help to elucidate the pathology of some types of heart disease.

DOI： 10.14814/phy2.13687

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-24749-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Enhancement of AT1 receptor-associated protein (ATRAP) in adipose tissue improves high fat diet (HFD)-induced visceral obesity and insulin resistance, and suppresses adipose oxidative stress. However, HFD loading is not a direct stimulatory factor for AT1 receptor. In the present study, we investigated the effect of chronic, low-dose angiotensin II (Ang II) stimulation on glucose and lipid metabolism in mice and functional role of ATRAP. ATRAP expression was higher in adipose tissue (5-10-fold) and skeletal muscle tissue (approximately 1.6-fold) in ATRAP transgenic (TG) mice compared with wild-type (WT) mice. After Ang II infusion, insulin sensitivity was impaired in WT mice, but this response was suppressed in TG mice. Unexpectedly, Ang II infusion did not affect the adipose tissue profile in WT or TG mice. However, in skeletal muscle tissue, Ang II stimulus caused an increase in oxidative stress and activation of p38 MAPK, resulting in a decrease in glucose transporter type 4 expression in WT mice. These responses were suppressed in TG mice. Our study suggests that Ang II-induced insulin resistance is suppressed by increased ATRAP expression in skeletal muscle tissue. Hyperactivity of AT1 receptor could be related to formation of insulin resistance related to metabolic syndrome.

DOI： 10.1038/s41598-018-21270-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Sleep-disordered breathing (SDB) is associated with cardiovascular complications. However, the effect of SDB on renal function in patients with acute coronary syndrome (ACS) treated by percutaneous coronary intervention (PCI) remains unclear. METHODS: We enrolled 154 consecutive ACS patients without heart failure. A sleep study was performed immediately after PCI. RESULTS: The mean apnea-hypopnea index (AHI) was 16.4±13.1, and 33 patients (21%) had severe SDB, defined as AHI≥25. Estimated glomerular filtration rate (eGFR) values on admission (60±12mL/min/1.73m2 vs. 67±17mL/min/1.73m2, p=0.046) and at discharge (54±15mL/min/1.73m2 vs. 63±15mL/min/1.73m2, p=0.002) were lower in patients with severe SDB than in those patients without severe SDB. Multiple linear regression analysis showed that AHIs were significantly correlated with absolute changes in eGFR values from admission to discharge (β=0.201, p=0.004). Median 24-h urinary noradrenaline excretion measured on the same day of the sleep study was higher [297 (interquartile range {IQR}: 232-472) vs. 174 (IQR: 107-318)μg/day, p=0.021] in patients with severe SDB. On multivariate logistic regression analysis, the presence of severe SDB was a significant predictor (adjusted odds ratio 3.76, 95% confidence interval 1.06-13.9, p=0.047) for eGFR of less than 45mL/min/1.73m2 at discharge. This association was independent of age, eGFR on admission, and a presentation of ST-segment elevation myocardial infarction. CONCLUSION: In patients with ACS who undergo PCI, severe SDB is associated with impaired renal function on admission and its deterioration during hospitalization. Further studies will be needed to conclude that SDB would be a therapeutic target in ACS.

DOI： 10.1016/j.jjcc.2017.07.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: The components of the renin-angiotensin system in leukocytes is involved in the pathophysiology of non-communicable diseases (NCDs), including hypertension, atherosclerosis and chronic kidney disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) is an AT1R-specific binding protein, and is able to inhibit the pathological activation of AT1R signaling in certain animal models of NCDs. The aim of the present study was to investigate the expression and regulation of ATRAP in leukocytes. METHODS: Human leukocyte ATRAP mRNA was measured with droplet digital polymerase chain reaction system, and analyzed in relation to the clinical variables. We also examined the leukocyte cytokines mRNA in bone-marrow ATRAP-deficient and wild-type chimeric mice after injection of low-dose lipopolysaccharide. RESULTS: The ATRAP mRNA was abundantly expressed in leukocytes, predominantly granulocytes and monocytes, of healthy subjects. In 86 outpatients with NCDs, leukocyte ATRAP mRNA levels correlated positively with granulocyte and monocyte counts and serum C-reactive protein levels. These positive relationships remained significant even after adjustment. Furthermore, the leukocyte ATRAP mRNA was significantly associated with the interleukin-1β, tumor necrosis factor-α and monocyte chemotactic protein-1 mRNA levels in leukocytes of NCDs patients. In addition, the leukocyte interleukin-1β mRNA level was significantly upregulated in bone marrow ATRAP-deficient chimeric mice in comparison to wild-type chimeric mice after injection of lipopolysaccharide. CONCLUSIONS: These results suggest that leukocyte ATRAP is an emerging marker capable of reflecting the systemic and leukocyte inflammatory profile, and plays a role as an anti-inflammatory factor in the pathophysiology of NCDs.

DOI： 10.1016/j.atherosclerosis.2018.01.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

Background: The Therapeutic Angiogenesis by Cell Transplantation (TACT) trial demonstrated the efficacy and safety of autologous bone marrow-derived mononuclear cells (BM-MNCs) in patients with critical limb ischemia (CLI). The present study aimed to assess the long-term clinical outcomes of therapeutic angiogenesis using autologous BM-MNC implantation under advanced medical treatment in Japan. Methods and Results: The study was retrospective, observational, and non-controlled. We assessed no-option CLI patients who had BM-MNC implantation performed in 10 institutes. Overall survival (OS), major amputation-free (MAF), and amputation-free survival (AFS) rates were primary endpoints of this study. The median follow-up duration was 31.7 months. The 10-year OS rate was 46.6% in patients with arteriosclerosis obliterans (ASO) (n=168), 90.5% in patients with thromboangiitis obliterans (TAO) (n=108), and 67.6% in patients with collagen disease-associated vasculitis (CDV) (n=69). The 10-year MAF rate was 70.1%, 87.9%, and 90.9%, respectively. The 10-year AFS rate was 37.8%, 80.9%, and 61.2%, respectively. Major adverse cardiovascular events occurred in 6.0% of patients with ASO, 1.9% of patients with TAO, and no patients with CDV. Conclusions: Therapeutic angiogenesis using autologous BM-MNC implantation may be feasible and safe in patients with no-option CLI, particularly those with CLI caused by TAO or CDV.

DOI： 10.1253/circj.CJ-17-0510

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1155/2018/2817045

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

BACKGROUND AND AIMS: Endothelial dysfunction and coronary artery calcification (CAC) may represent two distinct and separate processes in the development of coronary atherosclerosis. However, the interaction between these factors in determining the development of coronary artery disease (CAD) is uncertain. METHODS: Brachial artery flow-mediated dilatation (FMD) was measured by high-resolution ultrasound before coronary angiography, in 156 patients undergoing coronary CT angiography on suspicion of CAD (M/F 100/56, age 67 ± 11yrs). CAC score was measured with the Agatston method. RESULTS: The discriminative performance of FMD and CAC score in predicting the presence of type C lesion, multivessel disease, and high SYNTAX score (>22) was determined by ROC curve analysis. The optimal cutoff values for type C lesion were FMD ≤3.70% (AUC 0.663, p = 0.037) and log(CACscore+1)≥ 6.452 (AUC 0.735, p = 0.006). The combination of these cutoff values identified the lesion with the highest predictive accuracy of 82%. In addition, the optimal cutoff values for multivessel disease were FMD ≤5.40% (AUC 0.689, p = 0.001) and log(CACscore+1)≥ 5.914 (AUC 0.731, p = 0.001), while those for high SYNTAX score were FMD ≤4.10% (AUC 0.664, p = 0.020) and log(CACscore+1) ≥6.693 (AUC 0.817, p = 0.001). The combined measurement of each cutoff value identified multivessel disease and high SYNTAX score with predictive accuracy of 77% and 83%, respectively, which were significantly higher than each parameter alone, with the exception of the predictive accuracy of log(CACscore+1) for high SYNTAX score (p = 0.083). CONCLUSIONS: Endothelial dysfunction and CAC may provide complementary information in predicting the extent and severity of coronary artery disease.

DOI： 10.1016/j.atherosclerosis.2017.11.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

BACKGROUND: Research on the correlation of serum bilirubin level with cardiac function as well as outcomes in heart failure patients with cardiac resynchronization therapy (CRT) has not yet been reported. The aim of this study was to analyze the relationship between change in serum bilirubin level and left ventricular reverse remodeling, and also to clarify the impact of bilirubin change on clinical outcomes in CRT patients. METHODS: We evaluated 105 consecutive patients who underwent CRT. Patients who had no serum total-bilirubin data at both baseline and 3-9 months' follow-up or had died less than 3 months after CRT implantation were excluded. Accordingly, a total of 69 patients were included in the present analysis. The patients were divided into two groups: decreased bilirubin group (serum total-bilirubin level at follow-up≤that at baseline; n=48) and increased bilirubin group (serum total-bilirubin level at follow-up>that at baseline; n=21). RESULTS: Mean follow-up period was 39.3 months. In the decreased bilirubin group, mean left ventricular end-systolic diameter decreased from 54.5mm to 50.2mm (p=0.001) and mean left ventricular ejection fraction increased significantly from 29.8% to 37.0% (p=0.001). In the increased bilirubin group, there was no significant change in echocardiographic parameters from baseline to follow-up. In Kaplan-Meyer analysis, cardiac mortality combined with heart failure hospitalization in the increased bilirubin group was significantly higher than that in the decreased bilirubin group (log-rank p=0.018). Multivariate Cox regression analysis revealed that increased bilirubin was an independent predictor of cardiac mortality combined with heart failure hospitalization (OR=2.66, p=0.023). CONCLUSIONS: The change in serum bilirubin is useful for assessment of left ventricular reverse remodeling and prediction of outcomes in heart failure patients with CRT.

DOI： 10.1016/j.jjcc.2017.04.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The kidney is easily affected by aging-associated changes, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Particularly, renal tubulointerstitial fibrosis is a final common pathway in most forms of progressive renal disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP), which was originally identified as a molecule that binds to AT1R, is highly expressed in the kidney. Previously, we have shown that ATRAP suppresses hyperactivation of AT1R signaling, but does not affect physiological AT1R signaling. METHODS AND RESULTS: We hypothesized that ATRAP has a novel functional role in the physiological age-degenerative process, independent of modulation of AT1R signaling. ATRAP-knockout mice were used to study the functional involvement of ATRAP in the aging. ATRAP-knockout mice exhibit a normal age-associated appearance without any evident alterations in physiological parameters, including blood pressure and cardiovascular and metabolic phenotypes. However, in ATRAP-knockout mice compared with wild-type mice, the following takes place: (1) age-associated renal function decline and tubulointerstitial fibrosis are more enhanced; (2) renal tubular mitochondrial abnormalities and subsequent increases in the production of reactive oxygen species are more advanced; and (3) life span is 18.4% shorter (median life span, 100.4 versus 123.1 weeks). As a key mechanism, age-related pathological changes in the kidney of ATRAP-knockout mice correlated with decreased expression of the prosurvival gene, Sirtuin1. On the other hand, chronic angiotensin II infusion did not affect renal sirtuin1 expression in wild-type mice. CONCLUSIONS: These results indicate that ATRAP plays an important role in inhibiting kidney aging, possibly through sirtuin1-mediated mechanism independent of blocking AT1R signaling, and further protecting normal life span.

DOI： 10.1161/JAHA.117.006120

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記述言語：日本語   出版者・発行元：(NPO)日本小児循環器学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr). Both ion channels have also been shown to bind to Nedd4-2 via a conserved Proline-Tyrosine (PY) motif in C-terminal with subsequent ubiquitination and degradation by proteasome. Therefore, loss of Nedd4-2 C2 isoform might be involved in electrophysiological impairment under various conditions. We demonstrate here that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI). The Nedd4-2 C2 knockout (KO) mice showed bradycardia, prolonged QRS, QT intervals, and suppressed PR interval in resting condition. In addition, enhancement of T peak/T end interval was found in mice with surgical ligation of the distal left coronary artery. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that Nedd4-2 C2 KO mice show no significant structural changes from wild-type littermates under resting conditions. These results suggested that Nedd4-2 with C2 domain might play an important role in cardio-renal syndrome through post-transcriptional modification of both ENaC and cardiac ion channels, which are critical for kidney and heart functions.

DOI： 10.3390/ijms18061268

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination.

DOI： 10.3390/ijms18061250

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Plasma membrane calcium pump isoform 1 (PMCA1) is encoded by ATPase plasma membrane Ca
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transporting 1 (ATP2B1), the most likely candidate gene responsible for hypertension. Although PMCA1 is highly expressed in the kidney, little is known about regulation of its renal expression in various pathological conditions in vivo. Our study was designed to elucidate regulation of renal PMCA1 expression in mice. We employed three mouse models for kidney disease. These were the unilateral ureteral obstruction (UUO), the remnant kidney using 5/6 nephrectomy, and chronic angiotensin II administration models. Mice were assessed for systolic blood pressure and renal injury in accordance with the damage induced in the specific model. Kidney PMCA1 mRNA levels were measured in all mice. The UUO model showed renal fibrosis but no changes in blood pressure or renal PMCA1 mRNA expression. Similarly, the 5/6 nephrectomy model exhibited declined renal function without changes in blood pressure or renal PMCA1 mRNA expression. In contrast, chronic angiotensin II administration increased albuminuria and blood pressure as well as significantly increasing renal PMCA1 mRNA and protein expression. These results suggest that renal PMCA1 has a role as one of the molecules involved in angiotensin II-induced hypertension and kidney injury.

DOI： 10.14814/phy2.13316

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

BACKGROUND: The characteristics and prognosis of implanted pacemaker-identified new-onset atrial fibrillation (AF) in Japanese people has not been well evaluated.Methods and Results:A total of 395 consecutive patients with newly implanted pacemakers were retrospectively analyzed between January 2010 and December 2015 at Yokohama City University Hospital. Patients with a prior history of AF, VVI mode pacemaker, congenital heart disease, severe valvular heart disease, and cardiovascular surgery before pacemaker implantation were excluded. Among the remaining patients, 44 (21.3%) developed new AF during follow-up (mean follow-up, 1,115±651 days; range, 9-2,176 days). Patients with new-onset AF had a significantly higher CHADS2score (2.09±1.27 vs. 1.31±1.08, P<0.001) and CHA2DS2-VASc score (3.00±1.39 vs. 2.26±1.19, P<0.001) compared with those without new-onset AF. On Cox regression analysis only age at implantation was significantly correlated with new-onset AF. Interestingly, the incidence of hospitalization due to heart failure was significantly higher in the new-onset AF than in the without new-onset AF group. CONCLUSIONS: A total of 21.3% of pacemaker-implanted patients with high CHADS2and CHA2DS2-VASc scores developed new-onset AF during a mean follow-up of 3.1 years; and pacemaker-identified AF was associated with an increased risk of worsening heart failure.

DOI： 10.1253/circj.CJ-16-1018

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier B.V.  

BACKGROUND: Atrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias associated with substantially increased risks of ischemic stroke and thromboembolism. Oral anticoagulants (OACs) are the cornerstone of AF management and effectively prevent AF-related stroke. As new non-vitamin K antagonist OACs (NOACs) have become available, the landscape of stroke prevention in AF has changed. However, there are considerable gaps between daily clinical practice and current guideline-based recommendations for anticoagulant therapy in Japan. Consequently, little is known about the real-world setting and the current use of NOACs, especially by practitioners in Japan. METHODS: We conducted a prospective, observational study in 3847 patients with AF who were enrolled in clinics and hospitals located in Kanagawa Prefecture from September 2013 through March 2015. The participating centers included practitioners (small clinics), medium-sized hospitals, and university hospitals. The primary endpoints were epidemiologic characteristics, status of treatment with anticoagulants and antiplatelet agents, outcomes, and adverse events, including cerebrovascular disease, bleeding, and death. RESULTS: The mean CHADS2 score was 1.81±1.27, the mean CHADS2-Vasc score was 3.02±1.58, and the mean HAS-BLED score was 2.23±1.06, respectively. The usage rate of warfarin was 44.2% overall, and the usage rate of NOACs was 33.5%. CONCLUSIONS: The results of the study are expected to serve as the basis for providing clinical practice guidance to healthcare institutions in Japan, with the ultimate goals of better characterizing the appropriate use of OACs and providing clinical decision support to physicians to facilitate the design of appropriate therapeutic strategies and the selection of anticoagulants for the management of AF.

DOI： 10.1016/j.joa.2016.07.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activation of tissue renin-angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAPfl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAPadipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAPfl/fl mice, ATRAPadipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAPfl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAPadipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders.

DOI： 10.3390/ijms18030676

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記述言語：日本語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：日本語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：日本語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Recently, new non-invasive vascular indexes named arterial velocity pulse index (AVI) and arterial pressure volume index (API), which is evaluated by a multifunctional blood pressure monitoring device, were developed using cuff oscillometric technologies and suprasystolic cuff oscillometric wave measurement. However, although a few studies including a computational model have been performed, data on subjects with cardiovascular diseases in actual outpatient clinics remain scant. METHODS: We examined a total 252 consecutive outpatients and analyzed two vascular indexes with various clinical parameters to explore potential utilities of these two indexes in actual clinical settings. RESULTS: Although we found that two indexes were correlated with each other, the clinical implications of these indexes seemed to differ. Our analyses showed that AVI significantly correlated with augmentation index, but not with flow-mediated dilatation, and multivariate analyses suggested that enhanced AVI represents increased workload on the heart with elevated central blood pressure. In contrast, although the results of analyses performed to identify clinical parameters independently related to API were obscure and non-specific, after adjustment for multiple clinical variables, API was found to be significantly and independently associated with both Framingham Cardiovascular Risk Score and the Suita Score, suggesting that API is a useful predictor of future cardiovascular events. CONCLUSIONS: These two new vascular indexes might be useful in actual clinical settings to evaluate cardiovascular risks with various clinical backgrounds.

DOI： 10.1016/j.jjcc.2016.06.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.21037/jtd.2016.12.03

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担当区分：最終著者,　責任著者   記述言語：英語   出版者・発行元：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.ebiom.2016.10.039

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The relation between B2 cells and commensal microbes during atherosclerosis remains largely unexplored. Here we show that under hyperlipidemic conditions intestinal microbiota resulted in recruitment and ectopic activation of B2 cells in perivascular adipose tissue, followed by an increase in circulating IgG, promoting disease development. In contrast, disruption of the intestinal microbiota by a broad-spectrum antibiotic cocktail (AVNM) led to the attenuation of atherosclerosis by suppressing B2 cells, despite the persistence of serum lipid abnormalities. Furthermore, pharmacological depletion of B2 cells with an anti-B2-cell surface CD23 antibody also attenuated commensal microbe-induced atherosclerosis. Moreover, expression analysis of TLR-signaling-related genes in the activated B2 cell subsets, assessed using the Toll-Like Receptor Signaling Pathway RT2 Profiler PCR Array, confirmed activation of the B2-cell autoantibody-production axis, which was associated with an increased capacity of B2 cells to bind to intestinal microbiota. Together, our findings reveal the critical role of commensal microbe-specific activation of B2 cells in the development of atherogenesis through lipid metabolism-independent mechanisms.

DOI： 10.1016/j.ebiom.2016.10.030

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   出版者・発行元：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/FJC.0000000000000397

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Epithelial sodium channels (ENaCs) play critical roles in the maintenance of fluid and electrolyte homeostasis, and their genetic abnormalities cause one type of hereditary salt-sensitive hypertension, Liddle syndrome. As we reported previously, both human and rodent Nedd4L/Nedd4-2 showed molecular diversity, with and without a C2 domain in their N-terminal. Nedd4L/Nedd4-2 isoforms with a C2 domain are hypothesized to be related closely to ubiquitination of ENaCs. We generated Nedd4-2 C2 domain knockout mice. We demonstrate here that loss of Nedd4-2 C2 isoform causes salt-sensitive hypertension under conditions of a high dietary salt intake in vivo. The knockout mice had reduced urinary sodium excretion, osmotic pressure and increased water intake and urine volume with marked dilatation of cortical tubules while receiving a high salt diet. To the contrary, there was no difference in metabolic data between wild-type and knockout mice receiving a normal control diet. In the absence of Nedd4-2 C2 domain, a high salt intake accelerated ENaC expression. Coimmunoprecipitation studies revealed suppressed ubiquitination for ENaC with a high salt intake. Taken together, our findings demonstrate that during a high oral salt intake the Nedd4-2 C2 protein plays a pivotal role in maintaining adaptive salt handling in the kidney.

DOI： 10.1038/srep27137

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

BACKGROUND: Chronic kidney disease (CKD) alters dose-effect relationship not only of drugs eliminated by the kidney but also of some drugs metabolized by the liver and not renally excreted. It is not known whether impaired renal function alters dose-effect relationship of warfarin in Asian patients. It is also unknown whether the maintenance dose of warfarin can be predicted more accurately by incorporating renal function in Asians. METHODS: This was a cross-sectional study of patients receiving constant doses of warfarin who had PT-INR within 1.5-3.0 for 3 months or longer. RESULTS: In a total of 137 participants, the estimated creatinine clearance (eCrCl) was 62.5±25.5 [ml/min] and the warfarin dose was 3.21±1.46 [mg/day] (both mean±standard deviation). There was a significant correlation between warfarin dose and eCrCl (p<0.0001, r(2)=0.23). In a stepwise linear regression with the maintenance dose of warfarin as the dependent variable, eCrCl as well as age, body weight, intra-individual average prothrombin time/international normalized ratio (PT-INR), and genotype of VKORC1 -1639 G>A polymorphism were chosen as independent variables. The coefficient of determination (r(2)) of this formula was 0.47. A regression equation with all the same explanatory variables except for eCrCl had an r(2) of 0.41. CONCLUSIONS: The maintenance warfarin dose was positively correlated with kidney function as represented by eCrCl in Japanese patients. Incorporating eCrCl improved accuracy of predicting warfarin maintenance dose in this population.

DOI： 10.1016/j.jjcc.2014.08.008

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記述言語：日本語   出版者・発行元：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.46.35

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

BACKGROUND: The incidence of atrioventricular block (AVB) in pacemaker patients with sick sinus syndrome (SSS) is not yet known. The aim of this study was to analyze AVB episodes in SafeR mode based on stored electrograms (EGM), and determine the occurrence rate and risk factors for advanced AVB in a pacemaker population with SSS. METHODS AND RESULTS: The study included 50 consecutive patients with SSS without a history of advanced AVB who had a dual-chamber pacemaker programmed in SafeR mode. A total of 377 EGM stored in the pacemakers as AVB episodes fulfilling the second- or third-degree criterion were analyzed. Of 377 EGM, 73 EGM (19.4%) were appropriate episodes, whereas the other EGM did not show actual AVB, and showed atrial tachyarrhythmia, ventricular event in the blanking period, or premature atrial contractions with block. On EGM analysis, advanced AVB occurred in 9 patients (18%), and the occurrence rate was 11.7% per year. Moreover, on multivariate analysis β-blocker use was an independent risk factor for advanced AVB (OR, 9.10; P=0.004). CONCLUSIONS: The occurrence rate of advanced AVB in patients with SSS is much higher than previously reported, and β-blocker use is an independent risk factor for advanced AVB. SafeR is useful to detect latent AVB. Stored EGM, however, sometimes include inaccurately classified events.

DOI： 10.1253/circj.CJ-14-1255

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担当区分：筆頭著者,　責任著者   記述言語：英語  

DOI： 10.1097/HJH.0000000000000293

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Renin belongs to a family of aspartyl proteases and is the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II. Processing of renal renin has been extensively investigated in juxtaglomerular granular cells, in which prorenin and active renin are present in secretory condensed granules. Previous studies demonstrated alternative renin transcription in rat adrenal glands. Different studies reported novel intracellular forms of renin deduced from novel 5' variants derived from renin mRNA in both mice and humans. Comprehensive detailed studies in genetically engineered mice showed that both a secreted and an intracellular form of renin plays divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system; however, the presence, regulation, and functions of these renin isoforms in kidney and adrenal gland are not fully understood in mice. To investigate the characteristics of renin isoforms in mice, we performed a systematic inventory of renin transcripts of mice with and without a duplication of the renin gene alternatively from previous studies. We discovered a novel isoform of renin of the Ren2 gene, which conserved functionally important residues of the prosegment and incomplete isoforms of the Ren1C/D gene lacking a pre-pro segment. In situ hybridization assays revealed alternative renin isoforms expressed along cortical tubules. Newly generated transgenic mice with systemic overexpression of alternative renin transcript showed enhanced local angiotensin II generation without elevation of plasma renin activity and systemic insulin resistance in vivo, providing new pathophysiological insights into insulin resistance exaggerated by bona fide renin isoform.

DOI： 10.1161/HYPERTENSIONAHA.114.03394

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

BACKGROUND: Obstruction of the access vein is a well-known complication after cardiovascular implantable electronic device (CIED) implantation. In that case, well-developed collateral superficial veins are frequently observed on the skin surface around the CIED. The aim of this study was to clarify the relationship between venous obstruction and development of a superficial vein across the clavicle. METHODS AND RESULTS: A total of 107 patients scheduled for generator replacement, device upgrade, or lead extraction were enrolled. The skin surface around the device was photographed. A 20-ml bolus of contrast medium was injected into a peripheral arm vein on the side of CIED implantation, and contrast venography was performed. Venous obstruction was defined as luminal diameter narrowing >75%. Venography showed venous obstruction in 27 patients (25.2%). There were no statistically significant differences in patient characteristics between the venous obstruction and no venous obstruction group. Of 107 patients, 44 (41.1%) had a superficial vein across the clavicle on the side of CIED implantation. The sensitivity of the presence of a superficial vein across the clavicle in the diagnosis of venous obstruction was 96.3% and specificity was 77.5% (P<0.001). CONCLUSIONS: The presence of a superficial vein across the clavicle is useful for the prediction of venous obstruction in patients with CIED.

DOI： 10.1253/circj.CJ-14-0104

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier B.V.  

Background: The effect of cardiac pacing on sleep-disordered breathing is controversial. We investigated the long-term effect of cardiac pacing on sleep disordered breathing in patients with conventional indications for permanent pacemakers Methods: Subjects comprised 40 patients (29 men
mean age 69 ± 9 years, mean left ventricle ejection fraction 69 ± 8%, and body mass index 23.6 ± 3.5 kg/m2) who were diagnosed with indications for permanent pacemakers (sick sinus syndrome in 23 patients, atrioventricular block in 15, and brady atrial fibrillation in 2). All patients received polysomnographic evaluations before implantation of permanent pacemakers. After implantation of permanent pacemakers, all patients received polysomnographic evaluations during use of the pacemaker settings (AAI/DDD/VVI at 70 beats per minute). Results: The mean follow-up period was 35 ± 13 months. Before implantation, the distribution of sleep-disordered breathing was as follows: 93% had apnea hypopnea index &gt
5, 58% had apnea hypopnea index &gt
15, and 20% had apnea hypopnea index &gt
30. The mean apnea hypopnea index for all patients was 20 ± 15, for those with obstructive type apnea was 4.9 ± 5.3, and for those with central type apnea was 3.0 ± 4.5. The mean Epworth Sleepiness Score was 5.9 ± 4.0. No patient received continuous positive airway pressure therapy or any other therapy for sleep-disordered breathing during the follow up period. The mean apnea hypopnea index at 1 week after implantation of permanent pacemakers was 21 ± 14 (P=0.8) and the mean apnea hypopnea index at end of follow-up was 11 ± 7(P&gt
0.0001). Conclusion: Long term cardiac pacing significantly reduces the number of episodes of sleep apnea in patients with conventional permanent pacemaker indications. © 2014 Japanese Heart Rhythm Society.

DOI： 10.1016/j.joa.2014.02.003

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：FEDERATION AMER SOC EXP BIOL  

Atherosclerotic diseases, such as coronary artery disease and peripheral artery disease, are systemic disorders and among the leading causes of mortality and morbidity throughout the world. However, the exact pathophysiological mechanisms underlying the development of atherosclerosis remain unknown; currently, atherosclerosis is thought to involve an inflammatory process. Systemic inflammatory reactions and accumulation of immune cells in atherosclerotic lesions in situ are considered essential. We have comprehensively analyzed autoantibodies in patients with atherosclerosis by means of a newly developed high-throughput autoantibody analysis system. A wide range of autoantibodies was found in sera from patients with atherosclerosis. After we statistically analyzed the titers of each autoantibody with conventional techniques, the results underwent text-mining analyses based on natural language processing. Combinatory analysis revealed a close association between anti-interleukin (IL)-5 antibody and atherosclerosis. Titers of anti-IL-5 antibodies and serum IL-5 concentrations were also closely associated with other risk factors, such as low-density lipoprotein cholesterol, serum creatinine, fasting plasma glucose, gender, and age, suggesting that suppressed IL-5 function mediated by autoantibodies in patients with atherosclerosis plays an important role in the disease process. To validate the clinical significance of these findings, we computed the specificity and sensitivity of titers of anti-IL-5 autoantibodies for human atherosclerosis. When antibody titers of 1.49 were assumed to predict the presence of atherosclerosis, the sensitivity was 95.0% and the specificity 91.0%, with an area under the curve of 0.940. Our results provide important clues to understanding the role of autoantibody-mediated immune reactions in human atherosclerosis and suggest novel therapeutic opportunities for management of the disease.Ishigami, T., Abe, K., Aoki, I., Minegishi, S., Ryo, A., Matsunaga, S., Matsuoka, K., Takeda, H., Sawasaki, T., Umemura, S., and Endo, Y. Anti-interleukin-5 and multiple autoantibodies are associated with human atherosclerotic diseases and serum interleukin-5 levels.

DOI： 10.1096/fj.12-222653

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Interferon-beta (IFN-β) is a critical antiviral cytokine and is essential for innate and acquired immune responses to pathogens. Treatment with polyinosinic:polycytidylic acid (poly(I:C)) induces transient accumulation of IFN-β mRNA, which involves an increase and a decrease of IFN-β mRNA. This phenomenon has been extensively analyzed as a model for understanding the mechanisms of transient gene induction in response to external stimuli. Using a new RNA metabolic labeling method with ethynyluridine to directly measure de novo RNA synthesis and RNA stability, we reassessed both de novo synthesis and degradation of IFN-β mRNA. We found that transcriptional activity is maintained after the maximum accumulation of IFN-β mRNA following poly(I:C) treatment on immortalized human bronchial epithelial cells. We also observed an unexpected change in the stability of IFN-β mRNA before and after the maximum accumulation. The results indicate that this method of RNA metabolic labeling provides a general approach for the simultaneous analysis of transcriptional activity and mRNA stability coupled with transcriptional timing.

DOI： 10.1016/j.bbrc.2012.09.144

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

BACKGROUND: Renal insufficiency is recognized as a predictor of mortality and adverse outcome in heart failure (HF) patients. However, the long-term clinical outcome of cardiac resynchronization therapy (CRT) in Japanese HF patients with renal insufficiency remains uncertain. METHODS: We evaluated 67 consecutive patients who underwent CRT at our hospital. The patients were divided into two groups according to a baseline estimated glomerular filtration rate (e-GFR) cut-off value of 50ml/min, which is defined as the time at which patients should be referred to a nephrologist, by the Japanese Society of Nephrology. Follow-up echocardiographic findings and renal function were examined at 3-6 months after CRT. Then, we compared long-term clinical outcomes between the two groups, and analyzed the effect of CRT on renal function, echocardiographic parameters and cardiac survival. RESULTS: During a mean follow-up period of 30.3 months, patients with advanced renal insufficiency (e-GFR<50ml/min) had significant higher all-cause mortality (log-rank p=0.033) and higher cardiac mortality combined with HF hospitalization (log-rank p=0.017) than patients with e-GFR≥50ml/min. Multivariate analysis revealed that advanced renal insufficiency was an independent predictor of cardiac mortality combined with HF hospitalization (odds ratio=3.01, p=0.008). Subgroup analysis in the baseline advanced renal insufficiency group revealed that patients with preserved renal function by CRT (<10% reduction in e-GFR) had a higher rate of decrease of left ventricular end-systolic diameter (-14.0% vs. -0.8%, p=0.023) and lower cardiac mortality combined with HF hospitalization (log-rank p=0.029) compared with patients with deterioration of renal function (≥10% reduction in e-GFR). CONCLUSIONS: The present study suggests that advanced renal insufficiency is quite useful for the prediction of worsening clinical outcomes in HF patients treated by CRT. Preservation of renal function by CRT brings about better cardiac survival through prevention of adverse cardiac events, even in HF patients with advanced renal insufficiency.

DOI： 10.1016/j.jjcc.2012.06.001

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記述言語：英語   出版者・発行元：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Epithelial sodium channels (ENaC) are ion transporters in the aldosterone-sensitive distal nephron that play an important role in sodium reabsorption in the terminal nephron. Our study of inbred C57Bl6/J mice given a high-sodium diet showed increased ENaC expression accompanied by tubular renin activation on qRT-PCR of laser-captured tubule specimens and Western blotting of membrane proteins, despite inhibition of aldosterone. Treatment with an angiotensin-converting-enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) effectively lowered blood pressure. In addition to lowering blood pressure, ACEI and ARB inhibition downregulated ENaC and renin expression in renal tubules. These effects would act to suppress sodium reabsorption via ENaC and normalize molecular mechanisms that elevate blood pressure in response to increased salt intake.

DOI： 10.1159/000348660

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0735-1097(11)60524-X

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記述言語：日本語   出版者・発行元：Japan Heart Foundation  

症例は76歳, 女性. 1989年に洞不全症候群(II型)にてDDDペースメーカー植え込みを施行した. 2001年にペースメーカー感染を発症したため, 保存的治療を行い, 以降, 良好に経過していた. 2008年6月に電池消耗のため, ペースメーカー交換を施行した. その18日後にポケット部の皮膚に瘻孔が形成され, 膿の漏出が認められ, ペースメーカー感染の診断で入院となった. ペースメーカー本体を除去し, ポケット内デブリードマンを行った. リード線は用手法では容易には抜去できず, 可視範囲内で2本ともリードのコネクト部を切断した. 血液とポケット内の培養より緑膿菌が検出されたため, 6週間抗生物質投与を行った. しかし, 2009年3月に39℃の発熱にて入院となった. 血液培養より緑膿菌が検出され, 残存リード線の感染と診断した. 2009年3月中旬に心臓外科医および体外循環装置の待機下, 心室リード(フィン型)に対して, 右大腿静脈アプローチでリード抜去術を行った. 8Frブライトチップシースを右大腿静脈に挿入した. ピッグテイルカテーテルをリードにかけ, アンプラッツグーズネックスネアでガイドワイヤーを捕捉し, ループを作成した. リードの中の鎖骨下静脈断端に近い部位に固定し引いたところ, 同側のリード断端が遊離された. 次にその断端をスネアで捕捉し, シースとともに引いたところ, リード全体を抜去することができた. ペースメーカーリード感染に対し, 経大腿静脈アプローチにて留置後20年のペーシングリードを抜去し得た症例について報告する.

DOI： 10.11281/shinzo.43.505

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その他リンク： http://search.jamas.or.jp/link/ui/2011188811

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 60-year-old man with hypertrophic obstructive cardiomyopathy (HOCM) was implanted dual-chamber ICD for the purpose of both the left ventricular outflow tract (LVOT) gradient reduction by ventricular pacing and the primary prevention of ventricular tachyarrhythmia. Because the LVOT gradient reduction and improvement of symptoms by pacing were insufficient, however, a new pacing lead was inserted in the right ventricular apex at a different position 1.5 cm away from the site of the defibrillation lead, and the LVOT gradient greatly declined from 108 to 30 mmHg. This DDD pacing was continued over seven years. On this occasion, he was referred to our hospital because of battery depletion, and a cardiac catheterization study was performed after ICD replacement. The LVOT gradient was 10 mmHg in sinus rhythm. After administration of isoproterenol (0.02γ), the gradient was increased to 92 mmHg in sinus rhythm. DDD pacing using a newly placed ventricular pacing lead significantly decreased the gradient to 36 mmHg. This case study indicated that DDD pacing from a suitable location in the right ventricular apex caused a marked early reduction in the LVOT gradient, and at long-term follow up a further significant effect was obtained, also in sinus rhythm. © 2011, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.27.226

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng·kg(-1)·min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng·kg(-1)·min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the α-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng·kg(-1)·min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.

DOI： 10.1152/ajprenal.00738.2009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Wakui H, Tamura K, Matsuda M, Bai Y, Dejima T, Shigenaga A, Masuda S, Azuma K, Maeda A, Hirose T, Ishigami T, Toya Y, Yabana M, Minamisawa S, Umemura S. Intrarenal suppression of angiotensin II type 1 receptor binding molecule in angiotensin II-infused mice. Am J Physiol Renal Physiol 299: F991-F1003, 2010. First published August 25, 2010; doi:10.1152/ajprenal.00738.2009.-ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng . kg(-1) . min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng . kg(-1) . min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the alpha-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng . kg(-1) . min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.

DOI： 10.1152/ajprenal.00738.2009

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The intrarenal renin-angiotensin system plays a crucial role in the regulation of renal circulation and sodium reabsorption through the activation of vascular, glomerular, and tubular angiotensin II type 1 (AT1) receptor signaling. We previously cloned a molecule that specifically interacted with the murine AT1 receptor to inhibit AT1 receptor signaling, which we named ATRAP (for AT1 receptor-associated protein). Since murine ATRAP was shown to be highly expressed in the kidney, in the present study we investigated expression and distribution of human ATRAP in normal kidney and renal biopsy specimens from patients with IgA nephropathy. In the normal human kidney, both ATRAP mRNA and protein were widely and abundantly distributed along the renal tubules from Bowman's capsule to the medullary collecting ducts. In all renal tubular epithelial cells, the ATRAP protein colocalized with the AT1 receptor. In renal biopsy specimens with IgA nephropathy, a significant positive correlation between ATRAP and AT 1 receptor gene expression was observed. There was also a positive relationship between tubulointerstitial ATRAP expression and the estimated glomerular filtration rate in patients with IgA nephropathy. Furthermore, we examined the function of the tubular AT1 receptor using an immortalized cell line of mouse distal convoluted tubule cells (mDCT) and found that overexpression of ATRAP by adenoviral gene transfer suppressed the angiotensin II-mediated increases in transforming growth factor-β production in mDCT cells. These findings suggest that ATRAP might play a role in balancing the renal renin-angiotensin system synergistically with the AT 1 receptor by counterregulatory effects in IgA nephropathy and propose an antagonistic effect of tubular ATRAP on AT1 receptor signaling. Copyright © 2010 the American Physiological Society.

DOI： 10.1152/ajprenal.00667.2009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

The intrarenal renin-angiotensin system plays a crucial role in the regulation of renal circulation and sodium reabsorption through the activation of vascular, glomerular, and tubular angiotensin II type 1 (AT(1)) receptor signaling. We previously cloned a molecule that specifically interacted with the murine AT(1) receptor to inhibit AT(1) receptor signaling, which we named ATRAP (for AT(1) receptor-associated protein). Since murine ATRAP was shown to be highly expressed in the kidney, in the present study we investigated expression and distribution of human ATRAP in normal kidney and renal biopsy specimens from patients with IgA nephropathy. In the normal human kidney, both ATRAP mRNA and protein were widely and abundantly distributed along the renal tubules from Bowman's capsule to the medullary collecting ducts. In all renal tubular epithelial cells, the ATRAP protein colocalized with the AT(1) receptor. In renal biopsy specimens with IgA nephropathy, a significant positive correlation between ATRAP and AT(1) receptor gene expression was observed. There was also a positive relationship between tubulointerstitial ATRAP expression and the estimated glomerular filtration rate in patients with IgA nephropathy. Furthermore, we examined the function of the tubular AT(1) receptor using an immortalized cell line of mouse distal convoluted tubule cells (mDCT) and found that overexpression of ATRAP by adenoviral gene transfer suppressed the angiotensin II-mediated increases in transforming growth factor-β production in mDCT cells. These findings suggest that ATRAP might play a role in balancing the renal renin-angiotensin system synergistically with the AT(1) receptor by counterregulatory effects in IgA nephropathy and propose an antagonistic effect of tubular ATRAP on AT(1) receptor signaling.

DOI： 10.1152/ajprenal.00667.2009

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor-associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II-mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy by angiotensin II infusion in vivo. We first examined the effect of angiotensin II infusion on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy, concomitant with a significant decrease in cardiac ATRAP expression, but without significant change in cardiac angiotensin II type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the alpha-myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy, activation of p38 mitogen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin II treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice. These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy.

DOI： 10.1161/HYPERTENSIONAHA.109.147207

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/HYPERTENSIONAHA.109.146738

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

OBJECTIVE: Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatory short-term BP variability in hypertensive patients on hemodialysis. METHODS: Forty hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the control treatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy. RESULTS: After 6- and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchanged in the control group. Compared with the control group, losartan significantly decreased left ventricular mass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycation end products (AGE). Furthermore, multiple regression analysis showed significant correlations between changes in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMI and changes in the plasma levels of AGE. CONCLUSION: These results suggest that losartan is beneficial for the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatory short-term BP variability during nighttime.

DOI： 10.1016/j.atherosclerosis.2009.04.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

Blood pressure (BP) variability is calculated as the standard deviation of ambulatory BP. Blood pressure variability is associated with the cardiovascular morbidity; however whether it is related to target organ damage is controversial. In this study we examined a possible relationship between the BP variability and left ventricular hypertrophy (LVH), and between BP variability and brachial-ankle pulse wave velocity (baPWV). The present study was conducted on 111 consecutive Japanese hypertensive patients who were hospitalized for the educational program in our hospital under stable sodium chloride intake (6 g/day). Blood pressure measurements were at 30-minute intervals all day. In a multivariable analysis adjusted with confounding factor, LVH was associated with 24-hour systolic BP (SBP), 24 hour diastolic BP (DBP), daytime SBP, daytime DBP, nighttime SBP, and nighttime DBP. Additionally, nighttime DBP variability was related to LVH. By the same method, baPWV as a dependent variable was related to 24-hour SBP and nighttime SBP. Furthermore, nighttime SBP variability was concerned with baPWV. The LVH was associated with not only BP level but also with nighttime DBP variability. The baPWV was also related not only to BP level but also to nighttime SBP variability.

DOI： 10.3109/10641960903407033

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH(2) terminal of the protein for subsequent degradation. One of the isoforms of human Nedd4L with evolutionarily new C2 domain was reported to play a significant role for degradating cell surface ENaC with interfering with wild isoforms by us previously. We focused the current analyses on isolating the binding molecules with C2 domain using yeast two-hybrid screening to elucidate further molecular interactions between ENaC and Nedd4L. We found NPC2, also known as HE-1, bind C2 domain of human Nedd4L and express along ASDN colocalized with Nedd4L. Additionally, in experiments using a model of salt-sensitive hypertension in Dahl rats, we provided evidence suggesting that transcriptional regulation and activation of NPC2 protein depends on sodium intake. NPC2 might regulate sodium reabsorption in the terminal nephron by interacting with ENaC-Nedd4L system.

DOI： 10.1016/j.bbrc.2009.07.158

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

BACKGROUND: Recent evidence indicates that both ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) are more useful than the measurement of office blood pressure for evaluating cardiovascular risks in subjects with hypertension. The major advantage of ABPM over HBPM is the ability to measure nighttime blood pressure and ambulatory blood pressure during the day. A newly developed, programmable HBPM device (HEM-5041, Omron Healthcare, [corrected] Kyoto, Japan) can record blood pressure up to 600 [corrected] times and measure nighttime blood pressure automatically. METHODS: To validate the utility, feasibility, and safety of this device, we measured blood pressure by HBPM using HEM-5041 and by ABPM and compared the values in healthy volunteers. RESULTS: As compared with ABPM, daytime blood pressures, coefficients of variation for systolic blood pressure, diastolic blood pressure, and pulse rate, and the percentage nighttime fall in these variables were significantly lower with HBPM. However, nighttime blood pressures did not significantly differ between HBPM and ABPM. The results of a questionnaire survey indicated that the subjects were more comfortable when blood pressure was measured by HBPM than by ABPM, whereas the quality of sleep was similar. CONCLUSIONS: Our results suggest that HEM-5041 is useful for evaluating nighttime blood pressures as well as nighttime blood pressure falls, without causing clinically significant discomfort.

DOI： 10.1007/s10157-009-0192-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10157-009-0209-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

BACKGROUND: Studies of the characteristics, risk factors, prognostic factors, and outcomes of diastolic heart failure (DHF) have yielded inconsistent findings. Moreover, few epidemiological studies of DHF have been performed in Japan. METHODS AND RESULTS: We studied patients with heart failure who were admitted consecutively to Yokohama City University Hospital from 2000 through 2003. Heart failure with a left ventricular ejection fraction (LVEF) of > or = 50% was classified as DHF (n=67), and that with an LVEF of < or = 35% was classified as systolic heart failure (SHF; n=72). Relative wall thickness (RWT) (0.61 vs. 0.34, p<0.0001) and left ventricular mass index (210.3 vs. 152.1, p<0.0001) were greater in DHF than in SHF. Age (odds ratio [OR]=1.068, 95% CI=1.020-1.119; p=0.006) and RWT (OR=17.945, CI=5.883-54.745; p<0.0001) were positive risk factors for DHF. A history of myocardial infarction was a negative risk factor for DHF (OR=0.053, CI=0.008-0.342; p=0.002). Left ventricular mass index was slightly but not significantly related to DHF (OR=1.010, CI=1.000-1.019; p=0.053). Survival did not differ significantly between patients with DHF and those with SHF. Advancing age and a greater RWT were positive risk factors for DHF. CONCLUSION: LV geometry of DHF and SHF are quite different. DHF is characterized by concentric hypertrophy of the left ventricle, whereas SHF is characterized by eccentric hypertrophy. Age and RWT were positive risk factors for DHF. Survival is similar in DHF and SHF.

DOI： 10.1016/j.jjcc.2009.04.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：INFORMA HEALTHCARE  

We examined risk factors for coronary heart disease (CHD) by ambulatory blood pressure (BP) monitoring in 72 diabetic hypertensives who were hospitalized for the educational program. The patients were divided into two groups (CHD group, 19 subjects; and non-CHD group, 53 subjects) along with or without co-existing CHD. On ambulatory BP monitoring, no significant differences were found between the groups regarding BP values through the day. However, the CHD group had a significantly greater BP variability than non-CHD group. The result of logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CHD.

DOI： 10.1080/10641960902822518

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: Chronic kidney disease is a noteworthy pathophysiology as a risk factor of cardiovascular disease. We investigated the usefulness of combining glomerular filtration rate and 201thallium(201Tl) / 123iodine-β-methyliodophenyl pentadecanoic acid ( 123I-BMIPP) dual myocardial scintigraphic findings for predicting cardiac events. Methods: Seventy-five patients suspected of coronary artery disease underwent 201Tl/123I-BMIPP dual myocardial scintigraphy. Clinical and nuclear variables were included in the multivariate analysis for predicting hard events (cardiac death and nonfatal myocardial infarction) and soft events (unstable angina, heart failure, and coronary revascularization). Glomerular filtration rate was estimated by the modification of diet in renal disease formula. Kaplan-Meier analysis was performed to investigate the incremental prognostic value of glomerular filtration rate. Results: During the mean follow-up period of 425 days, eight patients had hard events and 20 patients had soft events. Multivariate analysis revealed that glomerular filtration rate and the sum of total defect score in 123I-BMIPP image were independent predictors of total cardiac events, whereas sex, diabetes, glomerular filtration rate, and the number of abnormal segments in 201Tl image were those of hard events. Kaplan-Meier analysis revealed that greater risk stratification was achieved by adding a glomerular filtration rate of lesser than 60 ml/min/1.73 m2 to the sum of the total defect score ≥ 5 in the 123I-BMIPP image. Greater risk stratification for hard events was also achieved by adding a glomerular filtration rate of lesser than 30 ml/min/1.73 m2 to the number of abnormal segments ≥ 2 in 201Tl image. Conclusion: Better risk stratification can be achieved by adding glomerular filtration rate to 201Tl/123I-BMIPP dual myocardial scintigraphic findings. © 2009 Wolters Kluwer Health | Lippincott Williams &amp; Wilkins.

DOI： 10.1097/MNM.0b013e328314b879

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: In this study, we examined whether addition of an angiotensin II type 1 receptor blocker (ARB), candesartan or valsartan, to conventional antihypertensive treatment could improve blood pressure (BP) variability in hypertensive patients on peritoneal dialysis. METHODS: 45 hypertensive patients on chronic peritoneal dialysis therapy were randomly assigned to the ARB treatment groups either by candesartan (n = 15) or valsartan (n = 15), or the control group (n = 15). At baseline and 6 months after the treatment, 24-hour ambulatory BP monitoring, echocardiography, and measurement of brachial-ankle pulse wave velocity (baPWV) were performed. RESULTS: After the 6 months of treatment, 24-hour ambulatory BP values were similarly decreased in both the control group and ARB groups. However, short-term BP variability assessed on the basis of the standard deviation of 24-hour ambulatory BP was significantly decreased in the ARB groups, but remained unchanged in the control group. Furthermore, parameters of cardiovascular remodeling assessed by natriuretic peptides, echocardiography, and baPWV were significantly improved in the ARB groups but not in the control group. CONCLUSION: ARB treatment and control antihypertensive treatment similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis. However, ARB treatment is beneficial for the suppression of pathological cardiovascular remodeling with a decrease in BP variability.

DOI： 10.1159/000210572

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Backgrounds/Aims: It has been reported that urinary oxidative stress markers are higher in diabetic patients with proteinuria. We performed the present study to elucidate the relationship between urinary excretion of oxidative stress markers, albumin excretion, and histological changes, and to confirm the potential utility of oxidative stress markers for clinical treatment. Methods: Diabetic db/db mice or nondiabetic db/m mice were administered candesartan (10 mg/kg/day) or hydralazine (50 mg/kg/day) for 18 weeks. Results: Thirty-week-old male db/db mice treated with control vehicle revealed elevated urinary excretion and immunohistological levels of 8-hydroxydeoxyguanosine in glomeruli when compared to db/m mice. Treatment with candesartan, but not hydralazine, reduced these values to levels in db/m mice. Increased mesangial expansion, urinary excretion of albumin and 8-isoprostane, and glomerular immunohistological levels of nitrotyrosine in db/db mice were also decreased markedly by candesartan but not hydralazine. Interestingly, correlations between levels of albumin and oxidative stress markers in urine were very high, even when groups undergoing long-term (44 weeks) treatment were included (correlation coefficient 0.767 with respect to 8-hydroxydeoxyguanosine, 0.888 with respect to 8-isoprostane). Conclusion: It is anticipated that urinary concentrations of oxidative stress markers will be direct barometers of glomerulus-derived oxidative stress and glomerular injury in diabetic nephropathy. Copyright (c) 2009 S. Karger AG, Basel

DOI： 10.1159/000178764

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUNDS/AIMS: It has been reported that urinary oxidative stress markers are higher in diabetic patients with proteinuria. We performed the present study to elucidate the relationship between urinary excretion of oxidative stress markers, albumin excretion, and histological changes, and to confirm the potential utility of oxidative stress markers for clinical treatment. METHODS: Diabetic db/db mice or nondiabetic db/m mice were administered candesartan (10 mg/kg/day) or hydralazine (50 mg/kg/day) for 18 weeks. RESULTS: Thirty-week-old male db/db mice treated with control vehicle revealed elevated urinary excretion and immunohistological levels of 8-hydroxydeoxyguanosine in glomeruli when compared to db/m mice. Treatment with candesartan, but not hydralazine, reduced these values to levels in db/m mice. Increased mesangial expansion, urinary excretion of albumin and 8-isoprostane, and glomerular immunohistological levels of nitrotyrosine in db/db mice were also decreased markedly by candesartan but not hydralazine. Interestingly, correlations between levels of albumin and oxidative stress markers in urine were very high, even when groups undergoing long-term (44 weeks) treatment were included (correlation coefficient 0.767 with respect to 8-hydroxydeoxyguanosine, 0.888 with respect to 8-isoprostane). CONCLUSION: It is anticipated that urinary concentrations of oxidative stress markers will be direct barometers of glomerulus-derived oxidative stress and glomerular injury in diabetic nephropathy.

DOI： 10.1159/000178764

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Aims: In this study, we examined whether addition of an angiotensin II type 1 receptor blocker (ARB), candesartan or valsartan, to conventional antihypertensive treatment could improve blood pressure (BP) variability in hypertensive patients on peritoneal dialysis. Methods: 45 hypertensive patients on chronic peritoneal dialysis therapy were randomly assigned to the ARB treatment groups either by candesartan (n = 15) or valsartan (n = 15), or the control group (n = 15). At baseline and 6 months after the treatment, 24-hour ambulatory BP monitoring, echocardiography, and measurement of brachial-ankle pulse wave velocity (baPWV) were performed. Results: After the 6 months of treatment, 24-hour ambulatory BP values were similarly decreased in both the control group and ARB groups. However, short-term BP variability assessed on the basis of the standard deviation of 24-hour ambulatory BP was significantly decreased in the ARB groups, but remained unchanged in the control group. Furthermore, parameters of cardiovascular remodeling assessed by natriuretic peptides, echocardiography, and baPWV were significantly improved in the ARB groups but not in the control group. Conclusion: ARB treatment and control antihypertensive treatment similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis. However, ARB treatment is beneficial for the suppression of pathological cardiovascular remodeling with a decrease in BP variability. Copyright (C) 2009 S. Karger AG, Basel

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOC  

Background Several preliminary studies have indicated that atrial pacing can prevent atrial tachyarrhythmias. The suggested mechanisms by which pacing may be effective include suppression of premature atrial beats.
Methods and Results The Atrial Pacing Preference(TM) (APP; Guidant, St Paul, MN, USA) algorithm allows the pacemaker to maintain a pacing rate slightly higher than the sinus rate. The preventive effects of APP on paroxysmal atrial fibrillation (AF) were studied in 51 patients (70 +/- 11 years). Nine patients did not complete the protocol. The pacemaker was programmed in random order to APP off and APP on at 3 different settings (ie, 8, 16 and 32 cycles) for 4 weeks each, using a cross-over design. Percentage atrial pacing was lower in APP off than at the other settings. Premature beat counts were greater in APP off than at the other settings. There was a significant difference in mode switch episode counts between APP off and the most effective setting (3,818 +/- 15,356 vs 596 +/- 1,719; p&lt;0.01).
Conclusions The APP algorithm is a promising method for preventing atrial tachyarrhythmia in patients with an implanted pacemaker and AF. Optimizing the setting of the APP algorithm is an important issue in the prevention of AF.

DOI： 10.1253/circj.72.700

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記述言語：日本語   出版者・発行元：(一社)日本不整脈心電学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

The purpose of this study was to examine the possible difference in the 24-hr BP profile--including short-term BP variability, assessed as the standard deviation--between diabetic and non-diabetic hypertensives. We measured 24-hr ambulatory BP in 11 diabetic hypertensives (diabetic HT) and 10 non-diabetic hypertensives (non-diabetic HT) who were hospitalized for the educational program in our hospital and were under stable salt intake. Renal function and sleep apnea were also estimated. There were no significant differences in 24-hr systolic BP (141 mmHg vs. 135 mmHg, ns), daytime systolic BP (143 mmHg vs. 138 mmHg, ns), and nighttime systolic BP (135 mmHg vs. 130 mmHg, ns) between diabetic HT and non-diabetic HT. The values of 24-hr HR (69.7 beats/min vs. 65.2 beats/min, ns) and 24-hr HR variability (9.9 beats/min vs. 10.1 beats/min, ns) were also similar between the groups. Interestingly, diabetic HT had a significantly greater 24-hr systolic and diastolic BP variability than non-diabetic HT (18.2 mmHg vs. 14.5 mmHg, p < 0.05; 11.5 mmHg vs. 9.6 mmHg, p < 0.05, respectively). The values for creatinine clearance, urinary protein excretion, and apnea-hypopnea index were similar between the groups. Bivariate linear regression analysis demonstrated that fasting blood glucose was the primary determinant of 24-hr diastolic BP variability (r = 0.661, p < 0.01). Multiple stepwise regression analysis revealed that fasting blood glucose was a significant and independent contributor to 24-hr systolic BP variability (r = 0.501, p < 0.05). Taken together, these results demonstrate that BP variability is increased in diabetic hypertensives. Furthermore, it is possible that an elevation of fasting blood glucose may contribute to the enhanced BP variability in hypertensives.

DOI： 10.1080/10641960802068477

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Net sodium balances in humans are maintained through various ion transporters expressed along the entire nephron. Among these ion transporters, epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. This is supported by analyses of inherited hypertensive disorders, showing that genes encoding ENaC and other modulatory proteins cause hereditary hypertension, such as Liddle syndrome. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH(2) terminus of the protein for subsequent degradation. Both evolutionarily conserved and evolutionarily new C2 domains of human Nedd4L, a cryptic splice variant resulting in a disrupted isoform product formed by a frame-shift mutation, were reported previously. We focused on one of the isoforms, isoform I, generated by SNP (rs4149601), and studied its expression and interactions with other isoforms by molecular biological, immunohistochemical, and electrophysiological methods. We found that isoform I may interact with other human isoforms in a dominant-negative fashion. Such interactions might abnormally increase sodium reabsorption. Taken together, our analyses suggest that the human Nedd4L gene, especially the evolutionarily new isoform I, is a candidate gene for hypertension.

DOI： 10.1161/HYPERTENSIONAHA.107.102061

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

The purpose of this study was to examine a possible difference in the 24-h blood pressure (BP) profile between hypertensives with diabetic nephropathy (DN) and those with non-diabetic glomerulopathy (non-DN). We measured 24-h ambulatory BP in 34 type 2 DN and 34 non-DN patients who were hospitalized for the educational program in our hospital. There were no significant differences in 24-h and daytime systolic BP between DN (143 vs. 136 mmHg, NS for 24-h systolic BP) and non-DN (143 vs. 138 mmHg, NS for daytime systolic BP). Although both groups disclosed blunted nocturnal decrease in BP and were classified as "non-dipper" type, DN patients had a significantly higher nighttime systolic BP than patients with non-DN (142 vs. 132 mmHg, p = 0.0217). BP and heart rate (HR) variabilities were also estimated, and patients with DN showed a reduced nighttime HR variability than those with non-DN (4.8 vs. 6.6 beats/min, p = 0.0115). DN patients had an increase in urinary protein excretion (3.0 vs. 1.4 g/day, p = 0.0095) and a decrease in serum albumin concentration (3.1 vs. 3.7 mg/dl, p < 0.0001). Furthermore, urinary protein excretion was significantly correlated with nighttime systolic BP (r = 0.480, p = 0.0031) but not with nighttime HR variability. Taken together, these results demonstrate that the circadian rhythms of BP and HR are affected by underlying diseases and suggest that an elevated nighttime BP level may contribute to the enhanced urinary protein excretion in hypertensives with DN.

DOI： 10.1080/10641960701813890

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

We have recently cloned a novel molecule that interacts with the angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP). In this study, we tested the hypothesis that ATRAP modulates angiotensin II-induced responses in vascular smooth muscle cells. The results of immunoprecipitation and bioluminescence resonance energy transfer assay demonstrated a direct interaction between ATRAP and AT1R at baseline and showed that angiotensin II enhanced the interaction of these proteins >2-fold. The results of immunofluorescence analysis also demonstrated that >65% of ATRAP constitutively colocalized with an endosome marker. Although only 36% of ATRAP colocalized with AT1R at baseline, angiotensin II enhanced the colocalization of these molecules and made 92% of ATRAP colocalize with AT1R on a quantitative fluorescence analysis. Overexpression of ATRAP by adenoviral transfer decreased the cell surface AT1R number from 4.33 to 2.13 fmol/10(6) cells at baseline and from 3.04 to 1.26 fmol/10(6) cells even after removal of angiotensin II. ATRAP also suppressed angiotensin II-mediated increases in c-fos gene transcription and transforming growth factor-beta production. Furthermore, this suppression was accompanied by inhibition of angiotensin II-induced activation of 5-bromodeoxyuridine incorporation. Finally, ATRAP knockdown by small-interference RNA activated angiotensin II-induced c-fos gene expression, which was effectively inhibited by valsartan, an AT1R-specific antagonist. These results indicate that ATRAP promotes internalization of AT1R and attenuates the angiotensin II-mediated c-fos-transforming growth factor-beta pathway and proliferative response in vascular smooth muscle cells, suggesting a novel strategy to inhibit vascular fibrosis and remodeling through a novel and specific blockade of AT1R signaling.

DOI： 10.1161/HYPERTENSIONAHA.107.096115

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

The ubiquitin ligase, NEDD4L, participates in plasma volume and blood pressure regulation by controlling cell surface expression of kidney epithelial sodium channel (ENaC). Impairment of ENaC internalization with disrupting Nedd4L binding PY motif in the C-terminal of the protein showed rare Mendelian human hypertension disorder, Liddle syndrome. Therefore, possible involvements of ENaC-Nedd4L system abnormalities were suggested in development of human hypertension. Previously, we discovered a common variant, named v13(G/A), that affects the formation of an evolutionally new C2-encoding isoform of the Nedd4L gene in humans. The aim of this study was to test a hypothesis whether this variant is involved in essential hypertension; we performed the association study in a sample of the Japanese population. We found a gender-specific genotypic and allelic association with statistical significance achieved only in males. Our data suggest that this Genetic variation may contribute to essential hypertension in Japanese male patients through the mechanism of disrupting the C2 encoding isoform in vivo. Furthermore, molecular and functional studies will be required to elucidate the mechanism by which genetic variation in NEDD4L contributes to the development of essential hypertension.

DOI： 10.1111/j.1447-0594.2007.00382.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MAK-V/Hunk is an SNF1-related serine/threonine kinase which was previously shown to be highly expressed in the mammary gland and central nervous system. In this study, we found MAK-V/Hunk is abundantly and specifically expressed in the thick ascending limbs and distal convoluted tubules (DCT) of the kidney from the embryonic stage to the adult stage. We demonstrated that dietary salt depletion significantly enhances renal MAK-V/Hunk mRNA levels compared with a normal-salt diet. To analyze the possible renal cellular function of this kinase, we employed mouse distal convoluted tubule (mDCT) cells. The results of reverse transcriptase-polymerase chain reaction and Western blot analysis revealed that MAK-V/Hunk is expressed endogenously in mDCT cells. Overexpression of MAK-V/Hunk by adenoviral gene transfer significantly inhibited the ANG II-induced stimulation of c-fos gene transcription and suppressed the ANG II-mediated increases in transforming growth factor-beta production into the medium. This phenomenon was accompanied by inhibition of ANG II-induced activation of BrdU incorporation. On the other hand, the MAK-V/Hunk knockdown by siRNA activated the ANG II-induced c-fos gene expression. In the consecutive sections stained for MAK-V/Hunk and AT(1) receptor, MAK-V/Hunk-immunopositive distal tubules expressed the AT(1) receptor. This is the first report on the intrarenal localization of MAK-V/Hunk and its cellular function in renal tubular cells.

DOI： 10.1152/ajprenal.00451.2006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MAK-V/Hunk is an SNF1-related serine/threonine kinase which was previously shown to be highly expressed in the mammary gland and central nervous system. In this study, we found MAK-V/Hunk is abundantly and specifically expressed in the thick ascending limbs and distal convoluted tubules (DCT) of the kidney from the embryonic stage to the adult stage. We demonstrated that dietary salt depletion significantly enhances renal MAK-V/Hunk mRNA levels compared with a normal-salt diet. To analyze the possible renal cellular function of this kinase, we employed mouse distal convoluted tubule (mDCT) cells. The results of reverse transcriptase-polymerase chain reaction and Western blot analysis revealed that MAK-V/Hunk is expressed endogenously in mDCT cells. Overexpression of MAK-V/Hunk by adenoviral gene transfer significantly inhibited the ANG II-induced stimulation of c-fos gene transcription and suppressed the ANG II-mediated increases in transforming growth factor-β production into the medium. This phenomenon was accompanied by inhibition of ANG II-induced activation of BrdU incorporation. On the other hand, the MAK-V/ Hunk knockdown by siRNA activated the ANG II-induced c-fos gene expression. In the consecutive sections stained for MAK-V/Hunk and AT1 receptor, MAK-V/Hunk-immunopositive distal tubules expressed the AT1 receptor. This is the first report on the intrarenal localization of MAK-V/Hunk and its cellular function in renal tubular cells. Copyright © 2007 the American Physiological Society.

DOI： 10.1152/ajprenal.00451.2006

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記述言語：日本語   出版者・発行元：(株)南山堂  

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記述言語：日本語   出版者・発行元：(一社)日本不整脈心電学会  

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記述言語：日本語   出版者・発行元：(株)南山堂  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2007&ichushi_jid=J00821&link_issn=&doc_id=20070205080034&doc_link_id=%2Faf5thrpc%2F2007%2F008902%2F034%2F0408-0412%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faf5thrpc%2F2007%2F008902%2F034%2F0408-0412%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS INC  

Evidence suggests a relationship between short-term blood pressure (BP) variability and cardiovascular target-organ damage. Although a blunted nocturnal decrease in BP and reduced heart rate variability have been shown to be associated with cardiovascular morbidity in diabetic patients, little information is available on short-term BP variability. In this study, short-term BP variability was assessed in 36 subjects with type 2 diabetes and overt nephropathy who underwent ambulatory BP monitoring, and the factors that correlated with short-term BP variability were examined. The incidence of coronary artery disease (CAD) was significantly greater in the patients with increased 24-h systolic BP variability (67% versus 11%; p < 0.0005), while that of cerebrovascular disease was not significantly affected (61% versus 50%). Multiple stepwise regression analysis revealed that serum cholesterol (cholesterol) and plasma norepinephrine (p-NE) were significant and independent contributors to nighttime systolic BP variability (partial R2 = 0.490, p < 0.001; partial R2 = 0.470, p < 0.001) and demonstrated that body mass index and p-NE were primary determinants of nighttime diastolic BP variability (partial R2 = 0.539, p < 0.0005; partial R2 = 0.304, p < 0.05). Diabetic nephropathy patients with CAD had significantly increased daytime systolic (17.8 mmHg versus 13.1 mmHg, p < 0.0005), nighttime systolic (17.4 mmHg versus 10.5 mmHg, p < 0.0001), and nighttime diastolic (10.4 mmHg versus 7.2 mmHg, p < 0.05) BP variability. Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CAD (odds ratio 3.13 [95% CI 1.02-9.61]; p < 0.05). The increase in nighttime BP variability is associated with a proportional sympathetic activation in diabetic nephropathy. Elevated short-term BP variability combined with relative sympathetic prevalence during the night might represent an important risk factor for cardiovascular events in the diabetic population.

DOI： 10.1080/10641960601096760

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE CIRCULATION SOCIETY  

BACKGROUND: Clinical data suggest that changes in intrathoracic impedance and fluid accumulation in the lung are inversely related. METHODS AND RESULTS: Daily shock impedance (S-IMP) was evaluated in 29 patients in whom a Ventak Prizm 2 was implanted (61+/-14 years old). The mean follow-up period was 45+/-18 weeks, during which 6 patients had episodes of decompensated heart failure (DHF group) and the others did not (NHF group). There was no significant difference between the DHF group and NHF group in the mean value of the S-IMP (46.4 +/-3.3 vs 45.4+/-5.4 Omega). The range of S-IMP in individual patients in the DHF group was significantly greater than that in the NHF group (13.8+/-0.38 vs 7.0+/-3.1 Omega, p<0.0001). Mean weekly change of S-IMP in individual patients in the DHF group was significantly greater than that in the NHF group (1.583+/-0.630 vs 1.092+/-0.361 Omega, p<0.0176). When the cut-off value was set at >1.242 Omega, sensitivity was 100% and specificity was 69.6% for a diagnosis of DHF. There was a significant negative correlation between the percent increases in brain natriuretic peptide (BNP) and S-IMP (correlation coefficient: -0.775 p<0.0001) in the DHF group. There was an inverse relation between BNP and S-IMP. CONCLUSIONS: Measurement of shock impedance may be useful in the management of congestive heart failure.

DOI： 10.1253/circj.70.1462

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担当区分：筆頭著者,　責任著者   記述言語：英語   出版者・発行元：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

DOI： 10.1291/hypres.29.837

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記述言語：日本語   出版者・発行元：ライフサイエンス出版(株)  

症例は78歳男性で、拡張型心筋症と診断され、心不全にて2回の入院歴があった。2回目の入院時に植え込み型除細動器移植術を施行したが、移植後に慢性心不全急性増悪にて入院を繰り返した。植え込みに用いた除細動器Guidant社製Ventak Prizm2が植え込み後に毎日自動的に行う無痛ショックインピーダンステストで得られたデータと採血検査によって得られたBNP値との間に負の相関関係が認められた。インピーダンステストのデータが心不全の管理の一指標として利用できる可能性が示唆された。

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

This study was conducted to clarify the relationship between myocardial endogenous adenosine concentration in the great cardiac vein during ischemia and reperfusion-induced ventricular fibrillation (VF) and the occurrence rate of ischemia and reperfusion-induced VF. Sixty anesthetized mongrel dogs were subjected to 10-min left anterior descending artery occlusion and reperfusion. Blood from the great cardiac vein was sampled for the determination of adenosine and catecholamine concentrations. Hemodynamic parameters (blood pressure, lift ventricular dp/dt, left ventricular end-diastolic pressure, and cardiac output) were monitored throughout the experimental period. During coronary occlusion and reperfusion, VF occurred in 25 dogs (VF group). Ventricular fibrillation did not occur in 35 other dogs (non-VF group). Adenosine concentration in the great cardiac vein before the coronary occlusion did not differ between the two groups. However, the adenosine concentration in the great cardiac vein of the non-VF group significantly increased compared with that of the VF group (2,343 vs 65 pmol/ml, P = 0.026) during coronary occlusion and reperfusion. In contrast, hemodynamic parameters did not differ between the two groups. The study results demonstrated that adenosine concentration in the great cardiac vein was higher in the non-VF group than in the VF group, suggesting that myocardial endogenous adenosine may have a role in the suppression of ischemia and reperfusion-induced VF in dogs.

DOI： 10.1007/s00380-005-0881-1

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記述言語：日本語   出版者・発行元：横浜市立大学医学会  

企業の健康診断を受けた1042名(男801名,女241名,平均51歳)を対象に,身体計測,メタボリックシンドローム関連検査,レプチン遺伝子解析を行い,肥満とレプチン遺伝子多型(Lys109Arg)の関連性を検討した.男性でBMI25以上のLysアレルを有する群では内臓脂肪/皮下脂肪比が有意に高値であった.相関解析で,内臓脂肪はBMI,LDL-コレステロール(LDL-C)と正の相関を示した.多変数解析で,内臓脂肪はBMI,性別(女性),LDL-C,Lysアレルの有無と有意な関連を示した.皮下脂肪はレプチン受容体遺伝子多型,血圧,LDL-Cとの間に関連はみられなかった.内臓脂肪は心血管リスクとレプチン受容体遺伝子多型と関連することが示唆された

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

The ubiquitin ligase NEDD4L participates in plasma volume and blood pressure regulation by controlling expression of the epithelial sodium channel (ENaC). Genetic impairment of EnaC-Nedd4L-Proteasome system caused a rare mendelian hereditary human hypertension, Liddle syndrome. This finding suggested that Nedd4L is playing an important role in pathogenesis for hypertensive disorders. This prompted us to test a possible involvement of NEDD4L for the development of sodium-sensitive hypertension in Dahl salt-sensitive (DS) rats and its normotensive littermate Dahl salt-resistant (DR) rats. First, we analyzed the transcriptional diversity of rat Nedd4L gene and observed several isoforms with and without calcium-dependent membrane binding (C2) domain at the N-terminal of the protein as we found in human and mouse before. Then, we analyzed the expression of rat NEDD4L in the kidney of both DS and DR under high and low sodium regimens. NEDD4L expression examined by quantitative PCR technique revealed lower expression of NEDD4L transcripts in DS rats under either diet compared to DR animals; additionally, NEDD4L expression was significantly increased with sodium loading. Using in situ hybridization experiments, rat NEDD4L was predominantly expressed in distal nephron in a manner dependent on both sodium regimen and genetic background. A similar histological distribution pattern was observed in human kidney. The expression of NEDD4L in distal nephron and its response to chronic sodium loading suggest that it participates in the functioning of this segment in sodium reabsorption. This response was impaired in genetically sodium-sensitive animals. These findings suggested that Nedd4L gene products were involved in the development of salt-sensitive hypertension.

DOI： 10.1016/j.bbrc.2005.11.120

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記述言語：日本語   出版者・発行元：(一社)日本循環器病予防学会  

高血圧患者38例において夜間血圧および早朝血圧とHealth-related QOL(HRQOL)の関連性,夜間血圧の関連因子について検討した.非観血的携帯型血圧計による血圧日内変動(睡眠時基底血圧)および心拍変動により自律神経機能を測定し,同時に24時間蓄尿を行った.夜間降下度は,(昼間平均SBP-夜間平均SBP)/昼間平均SBP×100(%)とし,non-dipper群(10%未満),dipper群(10%以上)の2群に分類した.若中年者の高血圧において,Non-dipper群ではHRQOLの健康状態指標がdipper群と比較して低値を示した.基底血圧の上昇は,早朝血圧の高値とHRQOLの健康状態指標の低値と関連し,HRQOLは血圧変動型に密接に関係していることが推定された

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2006&ichushi_jid=J03571&link_issn=&doc_id=20060203250016&doc_link_id=%2Fcs3cardi%2F2006%2F004101%2F001%2F0026-0031%26dl%3D2&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcs3cardi%2F2006%2F004101%2F001%2F0026-0031%26dl%3D2&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_5.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The patient was a 64-year-old man with chronic atrial fibrillation with bradycardia. Left ventricular ejection fraction was 34%. He was treated with biventricular pacing. Heart failure improved from NYHA class III to II. Sympathetic nerve activity (SNA) was recorded during 6 minutes of biventricular (BV), right ventricular apical (RVA) and left ventricular (LV) pacing. SNA was significantly lower during biventricular pacing (49.5 ± 4.0/min) compared with RVA (58.8 ± 6.9/min, p = 0.016) and LV (63.3 ± 4.3/min, p = 0.002) pacing. BV pacing improves hemodynamics and decreases SNA compared with RVA or LV pacing. © 2006, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.22.48

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記述言語：日本語   出版者・発行元：(一社)日本脈管学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Activation of angiotensin II (Ang II) type 1 receptor (AT1R) signaling is reported to play an important role in cardiac hypertrophy. We previously cloned a novel molecule interacting with the AT1R, which we named ATRAP (for Ang II type 1 receptor-associated protein). Here, we report that overexpression of ATRAP significantly decreases the number of AT1R on the surface of cardiomyocytes, and also decreases the degree of p38 mitogen-activated protein kinase phosphorylation, the activity of the c-fos promoter and protein synthesis upon Ang II treatment. These results indicate that ATRAP significantly promotes downregulation of the AT1R and further attenuates certain Ang II-mediated hypertrophic responses in cardiomyocytes.

DOI： 10.1016/j.febslet.2005.01.068

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The patient was a 78-year-old man with dilated cardiomyopathy. His cardio-thoracic ratio was 60.4% and left ventricular ejection fraction (LVEF) was 33%. He had been repeatedly admitted for congestive heart failure. He underwent implantation of an implantable cardioverter-defibrillator (ICD) for ventricular fibrillation. We compared the values of BNP and shock impedance stored by the ICD. The correlation coefficient (p-value) between BNP and shock impedance was -0.700 (p &lt
0.0005), increase of BNP and shock impedance was -0.778 (p &lt
0.0001), percent increase of BNP and shock impedance was -0.767 (p &lt
0.0005). In conclusion, there is an inverse relation between BNP and shock impedance, and measurements of shock impedance may be useful in the management of congestive heart failure. © 2005, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.21.553

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

BACKGROUND: Proximal tubule (PT) angiotensinogen (AGT) is part of a tubular renin-angiotensin system (RAS) that participates in the regulation of sodium reabsorption along the entire nephron. Physiologic maneuvers affecting AGT expression in PT also affect systemic RAS. Here, we tested the hypothesis that PT AGT is regulated by increased glomerular filtration rate (GFR). METHODS: Complete unilateral nephrectomy (UNX) in mice was used to induce a sustained increase in GFR in the remaining kidney. AGT expression was monitored by quantitative reverse transcription-polymerase chain reaction (RT-PCR). AGT protein in PT was investigated by semiquantitative histology. We also measured AGT concentration in plasma and in 24-hour urine by a specific enzyme-linked immunosorbent assay (ELISA). RESULTS: Seven weeks after nephrectomy, UNX animals exhibited a 2-fold increase in tubular AGT mRNA (P <.001) compared with sham-operated control animals. The proportion of PT sections exhibiting AGT immunostaining was significantly increased at day 3 (P <.05), and remained elevated at seven weeks (UNX = 0.63 +/- 0.09, sham = 0.38 +/- 0.02, P <.01), revealing recruitment of AGT-producing cells along the PT. AGT excretion in final urine corrected for creatinine and kidney weight was also elevated by UNX at seven weeks (UNX = 209 +/- 42 pmol/mg/g, sham = 147 +/- 29 pmol/mg/g, P <.05), with no difference in plasma AGT between UNX and control animals. CONCLUSION: These observations suggest that AGT expression in PT adapts in the long-term to changes in GFR. In the UNX model, urinary AGT excretion is also elevated as a consequence of increase in net tubular flow.

DOI： 10.1111/j.1523-1755.2004.00635.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：UNIV CHICAGO PRESS  

Several lines of evidence suggest that patterns of genetic variability in the human angiotensinogen gene (AGT) contribute to phenotypic variability in human hypertension. The A(-6) promoter variant of AGT is associated with higher plasma angiotensinogen levels and increased risk of essential hypertension. The geographic distribution of the A(-6) variant leads to the intriguing hypothesis that the G(-6) promoter variant has been selectively advantageous outside Africa. To test these hypotheses, we investigated the roles of population history and natural selection in shaping patterns of genetic diversity in AGT, by sequencing the entire AGT gene (14400 bp) in 736 chromosomes from Africa, Asia, and Europe. We found that the A(-6) variant is present at higher frequency in African populations than in non-African populations. Neutrality tests found no evidence of a departure from selective neutrality, when whole AGT sequences were compared. However, tests restricted to sites in the vicinity of the A(-6)G polymorphism found evidence of a selective sweep. Sliding-window analyses showed that evidence of the sweep is restricted to sites in tight linkage disequilibrium (LD) with the A(-6)G polymorphism. Further, haplotypes carrying the G(-6) variant showed elevated levels of LD, suggesting that they have risen recently to high frequency. Departures from neutral expectation in some but not all regions of AGT indicate that patterns of diversity in the gene cannot be accounted for solely by population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggest that natural selection has generally favored the G(-6) variant over the A(-6) variant in non-African populations. However, important localized effects may also be present.

DOI： 10.1086/420793

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

A genetic predisposition to the development of neuroleptic malignant syndrome (NMS) has been suggested by clinical studies. Although the molecular basis of NMS is unclear, a dopaminergic blockade mechanism has been considered the main cause. We therefore investigated the association between NMS and three functional polymorphisms of the dopamine D(2) receptor (DRD(2)) gene: TaqI A, -141C Ins/Del, and Ser311Cys. Subjects included 32 Japanese patients, previously diagnosed with NMS, and 132 schizophrenic patients treated with neuroleptics without occurrence of NMS. Polymerase chain reaction and restriction fragment length polymorphism analyses were performed to determine each genotype. We found significant differences in genotypic and allelic frequencies of the -141C Ins/Del polymorphism between patients with and without NMS. The -141C Del allele was significantly more frequent in the NMS group (23.4 vs 11.7%, P=0.026). Similarly, the proportion of -141C Del allele carriers was significantly higher in the NMS group (40.6 vs 20.5%, P=0.022). No significant differences between the two groups were seen for allelic and genotypic frequencies of the TaqI A and Ser311Cys polymorphisms. This result suggests that the -141C Ins/Del polymorphism is likely to predispose toward the development of NMS, probably together with other unidentified factors.

DOI： 10.1038/sj.mp.4001422

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Plasma lipid and lipoprotein in general reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH in which 69 members were affected with type IIa hyperlipoproteinemia (HLPIIa; high plasma cholesterol) and ten with type IIb hyperlipoproteinemia (HLPIIb; high plasma cholesterol as well as plasma triglyceride). Soluble epoxide hydrolase ( EPHX2, sEH) plays a role in disposition of epoxides in plasma lipoprotein particles. Intrafamilial correlation analysis of the modifier effect of Glu287Arg substitution in the EPHX2 gene was carried out among 79 LDLR mutation carriers and 81 noncarriers. In the carriers, plasma cholesterol levels were elevated among carriers of the 287Arg allele (mean +/- SD=358 +/- 72 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=302 +/- 72 mg/dl) (p=0.0087). Similarly, in the LDLR mutation carriers, the plasma triglyceride levels were elevated among carriers of the 287Arg allele (mean +/- SD=260 +/- 100 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=169 +/- 83 mg/dl) (p=0.020). No such gene-interactive effect was observed among noncarriers of the LDLR mutation. Half of the patients who presented with HLPIIb had inherited a defective LDLR allele as well as an EPHX2-287Arg allele, whereas the majority who presented with HLPIIa had a defective LDLR allele but not an EPHX2-287Arg allele. These results indicate a significant modification of the phenotype of FH with defective LDLR allele by EPHX2-287Arg variation in our studied kindred.

DOI： 10.1007/s10038-003-0103-6

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING INC  

BACKGROUND: The observation of renin expression in connecting tubule, a segment that also expresses tissue kallikrein (KLK-1), raises two questions. Are the genes expressed in the same or in different cells of connecting tubule? Does this topography support the hypothesis that KLK-1 activates prorenin or is it more likely that it affords coordinated gene regulation? METHODS: Renin and KLK-1 were examined by immunostaining and in situ hybridization. Renin activation by KLK-1 was investigated in vitro. In vivo, excretion of prorenin and active renin was compared in mice homozygous for targeted inactivation of KLK-1 (TK(-/-)) and normal littermates (TK(+/+)). RESULTS: Using in situ immunostaining for renin and in situ hybridization for KLK-1 mRNA, we found that connecting tubule cells expressing renin also expressed KLK-1. We confirmed in vitro activation of prorenin by KLK-1, but found no difference in the ratio of active renin to prorenin in urine of TK(-/-) and TK(+/+) animals. Compared to TK(+/+) controls, TK(-/-) mice exhibited significantly lower 24-hour excretion of prorenin (5.05 +/- 1.16 mg Ang I/hour vs. 9.39 +/- 1.96 mg Ang I/hour, P < 0.05) and active renin (1.98 +/- 0.25 mg Ang I/hour vs. 3.58 +/- 0.39 mg Ang I/hour, P < 0.05), with no difference in either urine volumes or plasma renin concentrations. CONCLUSION: Direct interaction between renin and KLK-1, not ruled out in vitro, is not supported in vivo. By contrast, lower excretion of active renin and prorenin in TK(-/-) compared to TK(+/+) suggest coordinated regulation of the two proteins in their participation to collecting duct function.

DOI： 10.1046/j.1523-1755.2003.00302.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG TOKYO  

Factors predisposing to the phenotypic features of higher total cholesterol (TC) have not been clearly defined. Here we report an association between a promoter SNP (-1323T>C) in G-substrate gene (GSBS) and TC levels in 368 adult individuals from an east-central area of Japan. Age and gender-adjusted levels of LDL-cholesterol, TG, TC, and HDL-cholesterol were analyzed. When we separate the subjects into two genotypic groups regarding T allele, those who bear the T allele had significantly higher plasma TC levels than the others who lack the T allele (mean; 239.6 mg/dl vs. 210.6 mg/dl; p=0.003; Mann-Whitney test). Of the 341 individuals with the T allele, approximately 80% individuals presented with hypercholesterolemia, whereas only 44% were hypercholesterolemic among the 27 individuals without the T allele (p=0.0001). These results indicate a significant elevating effect of plasma TC levels by a SNP in the putative regulatory region of the G-substrate gene in our studied population. These data suggest that genetic variation at the G-substrate gene may be one of the determinants for plasma lipoprotein levels.

DOI： 10.1007/s10038-003-0055-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

The purpose of this study was to evaluate whether or not cardiac sympathetic nerve activity, using (123)I-meta-iodobenzylguanidine ((123)I-MIBG) imaging, and cardiac natriuretic peptides (atrial and brain, ANP and BNP) were independent predictors of cardiac events, and, if so, which was the stronger predictor. Planar (123)I-MIBG images were obtained from 62 patients with heart disease. Plasma ANP and BNP levels, left ventricular ejection fraction (LVEF) by echocardiography, serum total cholesterol and triglyceride were measured. (123)I-MIBG was assessed as the heart-to-mediastinum (H/M) ratio of the delayed image and the washout rate (WoR) from the early to the delayed image. Patients were followed up for an average of 16.2 months, and 12 of 62 patients had cardiac events. Patients with events had significantly lower LVEF and H/M ratio compared with those without events. They had significantly higher WoR, ANP and BNP. By multivariate Cox proportional hazard analysis, (123)I-MIBG (H/M or WoR), ANP and BNP were independent predictors for cardiac events. Event-free survival using a Kaplan-Meier model, with a threshold value of 2.0 for H/M and 45% for WoR, showed that patients with H/M<2.0 and/or WoR>45% had a significantly poorer prognosis. These results suggest that (123)I-MIBG imaging and cardiac natriuretic peptides are useful tools for the evaluation of patients with heart disease, and that cardiac sympathetic nerve activity is a stronger predictor of cardiac events.

DOI： 10.1097/00006231-200208000-00014

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Elements of a renin-angiotensin system expressed along the entire nephron, including angiotensinogen secreted by proximal tubule and renin expressed in connecting tubule, may participate in the regulation of sodium reabsorption at multiple sites of the nephron. The response of this tubular renin-angiotensin system to stepwise changes in dietary sodium was investigated in 2 mouse strains, the sodium-sensitive inbred C57BL/6 and the sodium-resistant CD1 outbred. Plasma angiotensinogen was not affected by sodium regimen, whereas plasma renin increased 2-fold under low sodium. In both strains, the variation in urinary parameters did not parallel the changes observed in plasma. Angiotensinogen and renin excretion were significantly higher under high sodium than under low sodium. Water deprivation, by contrast, induced significant activation in the tubular expression of angiotensinogen and renin. C57BL/6 exhibited significantly higher urinary excretion of angiotensinogen than did CD1 animals under both conditions of sodium intake. The extent to which these urinary parameters reflect systemic or tubular responses to challenges of sodium homeostasis may depend on the relative contribution of sodium restriction and volume depletion.

DOI： 10.1161/01.HYP.0000016177.20565.A0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Variation in the angiotensinogen gene, AGT, has been associated with variation in plasma angiotensinogen levels. In addition, the T235M polymorphism in the AGT product is associated with an increased risk of essential hypertension in multiple populations, making AGT a good example of a quantitative-trait locus underlying susceptibility to a common disease. To better understand genetic variation in AGT, we sequenced a 14.4-kb genomic region spanning the entire AGT and identified 44 single-nucleotide polymorphisms (SNPs). Forty-two SNPs were observed both in 88 white and in 77 Japanese unselected subjects. Six major haplotypes accounted for most of the variation in this region, indicating less allelic complexity than in many other genomic regions. Although the two populations were found to share all of the major AGT haplotypes, there were substantial differences in haplotype frequencies. Pairwise linkage disequilibrium (LD), measured by the D', r(2), and d(2) statistics, demonstrated a general pattern of decline with increasing distance, but, as expected in a small genomic region, individual LD values were highly variable. LD between T235M and each of the other 39 SNPs was assessed in order to model the usefulness of LD to detect a disease-associated mutation. Among the Japanese subjects, 13 (33%) of the SNPs had r(2) values >0.1, whereas this statistic was substantially higher for the white subjects (occurring in 35/39 [90%]). LD between a hypertension-associated promoter mutation, A-6G, and 39 SNPs was also measured. Similar results were obtained, with 33% of the SNPs showing r(2)>0.1 in the Japanese subjects and 92% of the SNPs showing r(2)>0.1 in the white subjects. This difference, which occurs despite an overall similarity in LD patterns in the two populations, reflects a much higher frequency of the M235-associated haplotype in the white sample. These results have important implications for the usefulness of LD approaches in the mapping of genes underlying susceptibility to complex diseases.

DOI： 10.1086/338454

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG TOKYO  

The ubiquitin ligase NEDD4L is a candidate gene for essential hypertension on both functional and genetic grounds. By targeting the epithelial sodium channel (ENaC) for degradation, NEDD4L is a significant determinant of sodium reabsorption in the distal nephron. Genetic linkage has been reported to a region of chromosome 18q harboring the gene, with phenotypes that include a rare orthostatic hypotension disorder, essential hypertension, and postural change in systolic blood pressure. A systematic search for genetic polymorphisms by resequencing exons and intron boundaries in 48 Caucasians yielded 38 variants. Among these, variant 13 is common, with either G (70%) or A (30%) as the last nucleotide of a putative exon 1. This mutation could affect the generation of a previously unrecognized splice isoform. In subsequent experiments, (1) we confirmed the presence of this putative isoform in both kidney and adrenals; (2) we established that variant 13-A leads to the systematic use of an alternative splice site, generating a transcript encoding a nonfunctional protein; and (3) we demonstrated differences in tissue-specific expression of the novel isoform relative to its previously reported counterpart. Variant 13-A precludes the formation of a transcript encoding a full-length Ca2+-dependent lipid-binding (C2) domain with very high evolutionary conservation among NEDD4L orthologs. A similar C2 domain in the paralogous NEDD4 gene plays a significant role in the transfer of its product to the apical membrane of epithelial cells. Differential function of NEDD4L isoforms could prove significant in blood pressure regulation through an effect on ENaC-dependent sodium reabsorption.

DOI： 10.1007/s100380200102

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Prostaglandin (PG) F(2)a is known to initiate luteal cell apoptosis in the bovine corpus luteum (CL) via its specific receptor (FP) on the luteal membrane by inducing intracellular Ca(2+) mobilization and the activation of PKC. In order to identify the signaling components involved in cell apoptosis, mRNA levels and activities of antioxidative enzymes were analyzed using bovine CL at different stages of the estrous cycle. Northern blot analysis revealed that the levels of two isozymes of superoxide dismutase (SOD), the Mn and Cu/Zn types, and catalase are highly enriched in the middle estrous phase, whereas glutathione peroxidase (GPx) levels gradually decrease as the estrous cycle progresses. The incubation of bovine luteal cells with H(2)O(2) and mercaptosuccinate (MS), a specific inhibitor of GPx, resulted in an increase in chromatin DNA condensation and apoptotic DNA fragmentation. Analyses of the enzymatic activities of GPx and catalase support the RNA data, indicating that H(2)O(2) produced due to the lack of GPx is a potent inducer of luteal cell apoptosis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG TOKYO  

Adrenomedullin (ADM), a peptide characterized by persistent hypotensive activity, is thought to be involved when the control mechanism of blood pressure is deranged, because its plasma concentration is upregulated in hypertensive patients. The receptor for ADM, a molecular complex consisting of calcitonin-receptor-like receptor (CRLR) and receptor-activity-modifying protein 2 (RAMP2), is activated through a unique intracellular transport mechanism. By analyzing the nucleotide sequences of bacterial artificial chromosome (BAC) clones, we have established that the gene encoding CRLR is spread over a genomic distance of 103,145 bases; it contains 15 exons interrupted by 14 introns, including 1 that spans more than 60 kilobases. Exons 1-3 constitute the 5' noncoding region; exons 4 through 15 are coding elements, of which exons 8 to 14 encode seven transmembrane domains. Eight novel single-nucleotide polymorphisms (SNPs) and their allelic frequencies in the Japanese population were found by direct sequencing of 32 alleles; two SNPs were in the 5' flanking region, one in exon 2, and the other five around intron-exon junctions. Eight haplotypes were constructed using these alleles in our Japanese population sample. The data establish a basis for investigations to detect molecular variants in the ADM receptor that might alter control of blood pressure and confer on individuals a predisposition to essential hypertension.

DOI： 10.1007/s100380170100

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG TOKYO  

Tissue-type plasminogen activator (t-PA), a serine protease, activates the conversion of plasminogen to the fibrinolytic protein, plasmin. The t-PA gene, mapped to chromosome 8p12-p11.2, contains 14 exons. An Alu insertion/deletion (I/D) polymorphism in this gene has been associated with an increased risk for myocardial infarction. In the work reported here we sequenced 11 kilobases (kb) of genomic DNA from 50 normal Japanese volunteers (100 alleles), to include all 14 exons of the t-PA gene, flanking intronic sequences, and 6kb of the 5' sequence. These experiments identified eight novel single-nucleotide polymorphisms (SNPs), in addition to the known Alu I/D polymorphism, from which genotypic data we constructed 12 haplotypes in the tested population. Two-way comparisons of SNPs and the Alu polymorphism revealed strong linkage disequilibrium between the Alu site and SNPs at positions 20,209 (chi2 = 92.263) and 27,555 (chi2 = 47.53), and between SNPs at positions 27,849 and 28,902 chi2 = 66.331). A phylogenic tree was constructed to infer a process of genome construction that would reflect the sequence variations we observed. Our results help to explain the lack of agreement among results of various disease-association studies in which a contribution of the human t-PA gene has been suspected but not always confirmed.

DOI： 10.1007/s100380170055

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Fibronectin plays an important role in vascular remodeling. A functional interaction between mechanical stimuli and locally produced vasoactive agents is suggested to be crucial for vascular remodeling. We examined the effect of mechanical stretch on fibronectin gene expression in vascular smooth muscle cells and the role of vascular angiotensin II in the regulation of the fibronectin gene in response to stretch. Cyclic stretch induced an increase in vascular fibronectin mRNA levels that was inhibited by actinomycin D and CV11974, an angiotensin II type 1 receptor antagonist; cycloheximide and PD123319, an angiotensin II type 2 receptor antagonist, did not affect the induction. In transfection experiments, fibronectin promoter activity was stimulated by stretch and inhibited by CV11974 but not by PD123319. DNA-protein binding experiments revealed that cyclic stretch enhanced nuclear binding to the AP-1 site, which was partially supershifted by antibody to c-Jun. Site-directed mutation of the AP-1 site significantly decreased the cyclic stretch-mediated activation of fibronectin promoter. Furthermore, antisense c-jun oligonucleotides decreased the stretch-induced stimulation of the fibronectin promoter activity and the mRNA expression. These results suggest that cyclic stretch stimulates vascular fibronectin gene expression mainly via the activation of AP-1 through the angiotensin II type 1 receptor.

DOI： 10.1074/jbc.M004421200

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記述言語：英語   出版者・発行元：UNIV CHICAGO PRESS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Lippincott Williams and Wilkins  

Decreased activity of debrisoquine 4-hydroxylase (CYP2D6), which participates in hepatic metabolism of several frequently used neuroleptics and antidepressants, is inherited as an autosomal recessive trait through polymorphic CYP2D6 gene alleles. In eastern Orientals, a C --> T substitution at nucleotide 188 (Pro34Ser) is primarily responsible for decreased ability to metabolize CYP2D6 substrates. We therefore studied a possible association between neuroleptic malignant syndrome (NMS) and the C188T mutation. We examined the frequency of the C188T mutation by polymerase chain reaction and restriction fragment length polymorphism analysis in 36 Japanese patients previously diagnosed with NMS and 107 neuroleptic-treated schizophrenic patients with no NMS history. The C188T allele frequency was 0.417 in NMS patients and 0.463 in patients without NMS. No significant allele or genotype associations were observed. We cannot conclude that low CYP2D6 activity genotype causes susceptibility to NMS in Japanese patients.

DOI： 10.1097/00041444-200010030-00007

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER-VERLAG TOKYO  

Recent evidence suggests that an insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) is associated with myocardial infarction and related cardiovascular diseases. We investigated a possible association of the ACE polymorphism with essential hypertension in a total of 263 cases/controls from among the elderly (age, over 70 years) and middle-aged (age between 30 and 60 years) Japanese population. The frequency of the I/I homozygote was significantly higher in hypertensive subjects than in controls in the elderly age group (33/57 vs 16/46; P = 0.02), but no association was observed in the middle-aged group (25/75 vs 26/85; P = 0.71). Similarly, having at least one insertion allele was associated with essential hypertension in the elderly age group (83/114 vs 46/92 in controls; P = 0.001), but not in the middle-aged group (78/150 vs 94/170; P = 0.524). These data suggest that genetic variation at the ACE locus may be associated with some determinants for blood pressure in elderly persons, and imply the involvement of the ACE insertion/deletion polymorphism in the etiology of age-related essential hypertension in the Japanese population.

DOI： 10.1007/s100380070019

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Lippincott Williams and Wilkins  

Molecular variants of the angiotensinogen gene, a key component of the renin-angiotensin system, are considered genetic risk factors for primary hypertension. A relation between the angiotensinogen gene locus and hypertension has been found in whites, Japanese, and African Caribbeans but not in Chinese. The lack of a consistent association between M235T polymorphism at exon 2 and hypertension has suggested that another site in linkage disequilibrium with M235T is the causal mutation. We studied the relations among plasma angiotensinogen concentrations, blood pressure, related clinical variables, and mutations of the 5' upstream core promoter region of the human angiotensinogen gene in 274 subjects recruited from our outpatient clinic. We confirmed that plasma angiotensinogen concentration was significantly correlated with A-20C mutation and percent body fat and found that systolic and diastolic blood pressures were significantly correlated with G-6A and T+68C mutations. These results suggest that mutations near the transcription start site may be associated with increased blood pressure.

DOI： 10.1161/01.HYP.34.3.430

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background. Macrophage-type nitric oxide synthase (NOS-II) is expressed in glomerular mesangial cells in response to inflammatory cytokines. Nitric oxide (NO) has antithrombotic and cytostatic activities in glomerular diseases. Recent studies have suggested that several vasoactive substances and growth factors modulate NO production in a tissue-specific manner. The aim of this study was to examine whether angiotensin II and transforming growth factor-β (TGF-β) modulate cytokine-stimulated NO production and NOS- II gene expression in rat glomerular mesangial cells. Methods. Cultured rat mesangial cells were incubated with interleukin-1β (IL-1β) for 24 hours. The effects of angiotensin II and TGF-β on stimulated nitrite accumulation and NOS-II mRNA levels were determined. Results. Angiotensin II and TGF-β significantly decreased IL-1β-stimulated nitrite accumulation. The angiotensin type 1 receptor antagonist CV11974 prevented angiotensin II- mediated inhibition of NO production. TGF-β-neutralizing antibody reversed the effect of TGF-β without affecting angiotensin II-mediated inhibition of NO production. TGF-β markedly decreased steady-state levels of NOS-II mRNA and the half-life of the message, whereas angiotensin II did not alter these parameters. Conclusions. These results suggest that in mesangial cells, angiotensin II and TGF-β participate in the inhibitory regulation of cytokine-induced NO production. TGF-β inhibits NO production by decreasing NOS-II mRNA levels, whereas angiotensin II may regulate NO production at the levels after NOS-II gene expression. An autocrine action of TGF-β induced by angiotensin II is unlikely to contribute to angiotensin II-mediated inhibition of NO production.

DOI： 10.1046/j.1523-1755.1999.00377.x

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記述言語：日本語   出版者・発行元：The Japanese Society of Internal Medicine  

日本に3000万人以上の患者がいるといわれている高血圧症の9割以上を占める本態性高血圧症の原因は不明である.その成因の3～4割に遺伝が関与しており,複数個ある原因候補遺伝子の解析が進み,レニンーアンジオテンシン系を中心とした遺伝子異常との関連が明かとなりつつある.単一遺伝子異常原因とするまれな家族性高血圧症も次々と明らかになってきている.今後,これらの明らかとなってくる原因遺伝子変異を知ることにより,高血圧症発症の予防や治療がより個々の患者に適したものとなってくる可能性がある.

DOI： 10.2169/naika.88.198

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その他リンク： http://search.jamas.or.jp/link/ui/1999141462

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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The purpose of this study was to assess Tc-99m tetrofosmin (TF) kinetics in viable but injured myocardium in patients with acute myocardial infarction (AMI). Fourteen patients (11 males, 72+ 10 years) with AMI were studied. Ten patients undergoing successful reperfusion therapy and 4 treated medically. All patients showed viable but injured myocardium revealed as Tc-99m pyrophosphate (PYP) and thallium-201 (Tl) overlap lesions. PYP and Tl SPECT was performed 90 mins after injection of PYP 740MBq and Tl 111MBq by dual SPECT aquisition within 8 days from onset of AMI. Rest TF SPECT was performed 15 mins and 120 rains after injection of TF 740MBq at one month after the onset of AMI. Rest I-123 betamethyl branched fatty acid (BMIPP) SPECT was performed 15 mins after injection of BMIPP 111MBq at one month after the onset of AMI. All tracers activities were visually scored using a four-point grading system : 0=normal to 3=severe defect and a 17 segmental model. The lower cutoff level of PYP and Tl were 40% and 25%. Overlap lesions were defined as PYP positive and defect score of Tl was 0 to 2 in at least 2 segments. For quantitative analysis, the decay-corrected washout rate (WO) was calculated in each segment. The number of score deteriorated (tracer washout) segments and WO values were larger in overlap segments than PYP negative segments (34/69 vs 25/115, p≤0.01, 18.6±11.6 vs 10.6±13.2, p≤0.01). Ninety percents of the segments with high washout of TF showed decreased BMIPP uptake. One patient showed residual myocardium with endocardial fibrosis by the results of autopsy. Those patients with AMI after one month from the onset showed high washout, of TF and TF kinetics was modulated by intracellular calcium concentration as shown by PYP accumulation.

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記述言語：日本語   出版者・発行元：(一社)日本循環器学会  

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記述言語：日本語   出版者・発行元：(一社)日本循環器学会  

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Recently a point mutation of guanine to thymine at nucleotide position 1917 in the endothelial nitric oxide synthase (eNOS) gene has been reported to be associated with coronary artery spasm. In addition, a significant association of the 4a/b polymorphism in intron 4 of the eNOS gene with coronary artery disease has been reported. However, the implications of these polymorphisms with respect to acute myocardial infarction (AMI) remain to be established. We conducted a case-control study of 226 patients with AMI and 357 healthy gender- and age-matched control subjects. In the former group, coronary angiograms were evaluated according to angiographic criteria based on the number of diseased vessels (>/=75%) and the number of stenotic lesions (>/=50%). Homozygosity for the Glu-Asp298 polymorphism existed in 5 of 226 patients with AMI (2.2%) but not in any of the 357 control subjects (P=.0085). However, when we evaluated the coronary angiograms of 226 case patients, there was no difference in the number of diseased vessels or the number of stenotic lesions between the patients with this homozygote and those without it. By contrast, there was no evidence of a significant increase in the risk of AMI or the severity of coronary atherosclerosis among individuals with the a/a genotype of the eNOS4a/b polymorphism. Our results imply that patients who are homozygous for the Glu-Asp298 polymorphism may be genetically predisposed to AMI; however, this mutation apparently is not related to the severity of coronary atherosclerosis. Further studies are needed to confirm our results and characterize the molecular mechanisms by which eNOS is involved in susceptibility to AMI.

DOI： 10.1161/01.HYP.32.3.521

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Society of Hypertension  

We studied the localization of angiotensinogen mRNA in rat nephron segments and the differences in angiotensinogen mRNA levels between male Sprague-Dawley rats at 6 and 12 wk of age using reverse transcription and polymerase chain reaction (RT-PCR). Each nephron segment of the rat kidney was microdissected. Total RNA was prepared and used in the following RT-PCR assay. The PCR products were size-fractionated by agarose gel electrophoresis, visualized with ethidium bromide staining, and identified by Southern blot analysis. The relative amounts of products were determined by densitometry. Strong bands corresponding to angiotensinogen mRNA were detected from proximal convoluted and straight tubules, and weaker bands were found in glomeruli. The signals in all tissues in 12-wk-old rats were weaker than those in 6-wk-old rats. Since local angiotensinogen is the unique substrate of the tissue renin-angiotensin system and exerts an autocrine-paracrine influence on renal function, the changes in tubular angiotensinogen may be related to physiological and morphological changes in the rat kidney during development.

DOI： 10.1291/hypres.21.155

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

This study examined expression of renin-angiotensin system (RAS) component mRNAs in angiotensinogen gene knockout (Atg-/-) mice. Wild-type (Atg+/+) and Atg-/- mice were fed a normal-salt (0.3% NaCl) or high-salt (4% NaCl) diet for 2 weeks. Angiotensinogen, renin, angiotensin-converting enzyme (ACE), angiotensin II type la receptor (AT1A), and angiotensin II type 2 receptor (AT2) mRNA levels were measured by Northern blot analysis. In Atg+/+ mice, activities of circulating RAS and renal angiotensinogen mRNA level were decreased by salt loading, whereas levels of renal and cardiac ACE; renal, brain, and cardiac AT1A; and brain and cardiac AT2 mRNA were increased by salt loading. Although activities of circulating RAS were not detected in Atg-/- mice, salt loading increased blood pressure in Atg-/- mice. In Atg-/- mice, renal renin mRNA level was decreased by salt loading; in contrast, salt loading increased renal AT1A and cardiac AT2 mRNA levels in Atg-/- mice, and these activated levels in Atg-/- mice were higher than those in Atg+/+ mice fed the high-salt diet. Thus, expression of each component of the RAS is regulated in a tissue-specific manner that is distinct from other components of systemic and local RAS and that appears to be mediated by a mechanism other than changes in the circulating or tissue levels of angiotensin peptides.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：STOCKTON PRESS  

It has recently been found that there were very few hypertensives in the inhabitants of one Nepalese village, even though their salt consumption, per capita, was as high as citizens in many western countries. To evaluate the genetic factors involved in this phenomenon, we studied whether they had a special genotype distribution of angiotensin-converting enzyme (ACE) gene I/D polymorphism, which was recently reported to be involved in salt sensitivity. One hundred and thirty-eight subjects were evaluated in Nepal. Only nine subjects (6.5%) in this population were hypertensives (over 140/90 mm Hg) while consuming 11 g salt/day, which confirmed the previous results. The distribution of genotypes and alleles of ACE gene I/D polymorphism was similar to that in the Japanese and Chinese, who had five-times more hypertensives while consuming almost as much salt as Nepalese, but significantly different from those in Caucasians. The present study reports, for the first time, the genotype distribution of ACE gene I/D polymorphism in Nepalese subjects. Furthermore, the results suggest ACE gene polymorphism may not be involved in the 'salt-resistance' in this population.

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER PHYSIOLOGICAL SOC  

Circulating and cardiac renin-angiotensin systems (RAS) play important roles in the development of cardiac hypertrophy. Mechanical stretch of cardiac myocytes induces secretion of ANG II and evokes hypertrophic responses. Angiotensinogen is a unique substrate of the RAS. This study was performed to examine the regulation of the angiotensinogen gene in cardiac myocytes in response to ANG II and stretch. ANG II and stretch significantly increased the levels of angiotensinogen mRNA in cardiac myocytes. Actinomycin D completely inhibited ANG II- and stretch-mediated increases in angiotensinogen mRNA. Although CV-11974 abolished ANG II-mediated increases in mRNA level and promoter activity of the angiotensinogen gene, the inhibition of stretch-mediated activation by CV-11974 was significant but not complete. These results indicate that ANG II activates transcription of the angiotensinogen gene exclusively via ANG II type 1-receptor pathway and that stretch activates such transcription mainly via the same pathway in cardiac myocytes. Furthermore, factors other than ANG II may also be involved in stretch-mediated activation of the angiotensinogen gene in cardiac myocytes.

DOI： 10.1152/ajpregu.1998.275.1.R1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC  

We have recently reported that mitogen activated protein kinase (MAP kinase) is activated by the stretch of the cultured cardiac myocytes in the angiotensin II deficient state in the angiotensinogen-deficient mice (Atg-/-), suggesting that factors other than the cardiac renin-angiotensin system are involved in the stretch-induced MAP kinase activation. We examined the contribution of cytokines using RX435, an anti-gp130 antibody. Leukemia inhibitory factor, which is one of the cytokines and has the common receptor subunit gp130, activated MAP kinase and the response was completely blocked by pretreatment of the Atg-/- cardiac myocytes with RX435. RX435 pretreatment greatly reduced stretch-induced activation of MAP kinase in Atg-/- cardiac myocytes. Interestingly, the same results were obtained in the cardiac myocytes of control mice. These results suggest that cytokine-gp130 may play a role in the stretch-induced MAP kinase activation independently of Ang II in cardiac myocytes.

DOI： 10.1006/bbrc.1998.8548

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVE: Physiological roles of the renin-angiotensin system in maintaining blood pressure and sodium-water balance in angiotensinogen gene-knockout mice were evaluated with special reference to endogenous pressor substances. METHODS: Angiotensinogen-gene knockout mice and control mice were fed a 0.3 or 4% NaCl diet for 2 weeks. Systolic blood pressure and urinary excretions of electrolytes, creatinine, aldosterone, adrenaline, noradrenaline, dopamine and vasopressin were measured. RESULTS: About 60% of our angiotensinogen-gene knockout mice did not survive until weaning. These mice presented with hypotension and polyuria. Urinary excretion of aldosterone from such mice was significantly lower (not detected) than that from control mice (2.0+/-0.3 pg/mg creatinine). In contrast, urinary excretion of vasopressin from angiotensinogen-gene knockout mice (0.7+/-0.1 ng/mg creatinine) was greater than that from control mice (0.3+/-0.1 ng/mg creatinine), and those of adrenaline and of noradrenaline were similar for knockout and control mice. After salt loading (a 4% NaCl diet), angiotensinogen-gene knockout mice exhibited a significant increase in systolic blood pressure (from 68.3+/-2.9 to 95.9+/-5.9 mmHg), significant decreases in urinary excretions of adrenaline (from 65+/-8 to 40+/-7 pg/mg creatinine) and noradrenaline (from 467+/-48 to 281+/-41 pg/mg creatinine) and no change in excretion of vasopressin compared with such mice fed a 0.3% NaCl diet CONCLUSION: The present results with angiotensinogen-gene knockout mice confirm that the renin-angiotensin system plays fundamental roles in maintaining the blood pressure and sodium-water balance. Because the vasopressin and catecholaminergic systems may be altered by lack of angiotensin in angiotensinogen-gene knockout mice, these systems perhaps are not able to restore blood pressure and sodium-water depletion to normal levels in these mice.

DOI： 10.1097/00004872-199816030-00005

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It is reported that 123I-metaiodobenzylguanidine (MIBG) can be a useful tool for the evaluation of the prognosis in the patients with chronic heart failure. The purpose of this study is to investigate whether MIBG can predict the prognosis in the patients with chronic heart failure associated with impaired left ventricular function. Forty patients with chronic heart failure whose left ventricular ejection fraction (LVEF) were less than 40% by ultrasonic cardiography were studied. Planar MIBG cardiac imaging was performed. Myocardial uptake of MIBG was calculated as the heart/mediastial activity ratio (H/M) of the delayed image. Washout rate (WoR) was calculated as percent myocardial MIBG washout from 15 min to 4 hr after the radioisotope injection. The lower limit of H/M 2.0 and the upper limit of WoR 45.0% in our hospital were used as cut-off values. At the same time, ultrasonic cardiography was performed, and LVEF was calculated using Teichholz method. Plasma total cholesterol level was also measured. After MIBG imaging, they were followed for average 24.2 months. During the follow-up period, 10 out of 40 patients (25%) had severe cardiac events including 4 cardiac deaths, 4 progression of congestive heart failure (CHF), and 2 sustained ventricular tachycardia or ventricular fibrillation. These patients were named event (+) group, and the patients without cardiac events were named event (-) group. LVEF, age, and the presence of hypertension and diabetes mellitus were not different between event (-) group and event (+) group. Medication for CHF was not different between two groups. However, H/M was significantly lower in event (+) group, and WoR was significantly higher in event (+) group (p &lt; 0.05). The follow-up period was significantly shorter in event (+) group (p &lt; 0.05). Multivariate stepwise discriminant analysis revealed that H/M and WoR were independent indicator for the cardiac events (p &lt; 0.05). Cox proportional hazard analysis revealed that H/M or WoR was significant factor for the cardiac events (p &lt; 0.05). Event-free survival curves with a threshold value of 2.0 for H/M and 45% for WoR using Kaplan-Meier model showed that the patients with H/M &lt; 2.0 had significantly poor prognosis (p &lt; 0.01) and that the patients with WoR &gt; 45% had the tendency of poor prognosis (p = 0.06). In conclusion, the abnormality of the cardiac sympathetic nerves, which is low H/M and/or high WoR, can be a good predictor for the cardiac events with the patients of impaired LV function.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Two subtypes of angiotensin II (Ang II) receptors, type 1 (AT1-R) and type 2 (AT2-R), have been identified in the heart. However, little is known about the regulation of cardiac AT1-R and AT2-R by Ang II in vivo. Thus, we examined cardiac AT1-R and AT2-R in angiotensinogen-deficient (Atg-/-) mice that are hypotensive and lack circulating Ang II. Cardiac Ang II receptors (Ang II-R) were assessed by radioligand binding with 125I-[Sar1,Ile8]-Ang II in plasma membrane fractions. AT1-R and AT2-R were distinguished using their specific antagonists CV-11974 and PD123319, respectively. Total densities of Ang II-R and AT1-R density were significantly greater in the Atg-/- mice than Atg+/+ mice (31.1+/-2.8 versus 18.8+/-2.1, 28.7+/-3.0 versus 16.9+/-2.3 fmol/mg protein, P<.01, respectively), and AT2-R showed a slight but not significant increase in Atg-/- mice relative to Atg+/+ control animals. Kd values were not different between the two groups. In contrast to binding experiments, levels of Ang II type 1a receptor (AT1a-R) and AT2-R mRNA did not differ between Atg-/- and Atg+/+ mice. These results suggest that lack of Ang II may upregulate AT1-R through translational and/or posttranslational mechanisms in Atg-/- mice.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing  

1. Dahl Iwai salt-sensitive (DS) rats have been reported as becoming hypertensive with left ventricular hypertrophy (LVH) and heart failure when on a high-salt diet. Their circulating renin-angiotensin system (RAS) has been reported to be suppressed. To evaluate the role of angiotensin II (AngII) type 1 and type 2 receptors (AT1 and AT2, respectively) in LVH, we compared cardiac AT1 and AT2 receptors in 10-week-old DS rats and Dahl Iwai salt-resistant (DR) rats. 2. Seven pairs of 6-week-old male DS and DR rats were fed either a low- or high-salt diet (0.3 or 8% NaCl, respectively) for 4 weeks. Left ventricular AngII receptors were measured by radioligand binding assays using [125I]-[Sar1,Ile8]-AngII in plasma membrane fractions from these four groups. The AT1 and AT2 receptors were distinguished using their specific antagonists CV 11974 and PD 123319, respectively. 3. The high-salt diet increased blood pressure and the left ventricle:bodyweight ratio in DS rats. However, neither B(max) for AT1 and AT2 receptors nor K(d) for [125I]-Sar1,Ile8]-AngII differed between the groups. These results are different from those of other reports of pressure-overload LVH, such as spontaneously hypertensive rats or renovascular hypertension rats, in which AT1 and AT2 receptors were reported to be up-regulated.

DOI： 10.1111/j.1440-1681.1998.t01-16-.x

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記述言語：日本語   出版者・発行元：Japan Heart Foundation  

症例は43歳女性.30歳時に糖尿病と診断され,インスリン療法を受けていたが,1996年6月心不全のため入院となった.心臓超音波検査ではび慢性の左室壁運動の低下を認め,左室駆出率は33.6%であった.心臓カテーテル検査では冠状動脈に有意狭窄はなく,心筋生検では,異常ミトコンドリアの集積,無構造な沈着物の集積を認めた.ミトコンドリアDNAを検索したところ,3243の点変異が認められたため,ミトコンドリア心筋症と診断した.その後,利尿剤・ACE阻害剤投与により心不全症状軽快し,全身状態良好であったが,1997年4月27日,突然高度の洞性徐脈から心停止,呼吸停止に陥り,心肺蘇生術,緊急一時ペーシングを行った.電気生理学的検査ではprocainamide 800mg静注後に高度の洞停止を認め,洞不全症候群と診断し永久ペースメーカー植え込み術を行った.従来,ミトコンドリア異常症は高度の房室ブロックを合併することが知られているが,洞不全症候群,とりわけ心肺蘇生術を必要とするような高度な洞停止を合併する例は比較的稀であり,報告する.

DOI： 10.11281/shinzo1969.30.Supplement4_63

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

The angiotensinogen (AGT) gene M235T variant is associated with essential hypertension and elevated plasma AGT concentrations, although the underlying mechanisms are unknown. Recent studies have suggested that AGCE 1 (human AGT gene core promoter element 1) located in the 5' upstream core promoter region (position -25 to -1) of the human AGT gene has an important part in the expression of AGT mRNA by binding with transcription factor AGCF 1 (human AGT gene core promoter element binding factor 1), and a mutation at -20 from adenine to cytosine (A-20C) increases the level of expression of this transcript. We therefore examined subjects with this mutation to study the association with increased plasma AGT concentrations and with essential hypertension. One hundred eighty-eight subjects receiving no antihypertensive medication were examined with regard to the correlation between A-20C and plasma AGT concentrations, and 234 subjects were studied with respect to the association between A-20C and essential hypertension. A-20C was determined by polymerase chain reaction-restriction fragment length polymorphism analysis with EcoOR 109I. Multiple regression analysis showed a weak but significant correlation between A-20C and plasma AGT concentrations (P=.047) and essential hypertension (P=.049). The results suggest that A-20C may underlie the increase in plasma AGT concentrations and be involved in the development of essential hypertension.

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPAN HEART JOURNAL, SECOND DEPT OF INTERNAL MED  

The relationships between angiotensin-converting enzyme (ACE) gene insertion (I) / deletion (D) polymorphism and left ventricular hypertrophy induced by hypertension or idiopathic hypertrophic cardiomyopathy have been studied. However, little is known about the association between this polymorphism and left ventricular hypertrophy induced by volume overload. The relationship between left ventricular hypertrophy and the ACE gene I/D polymorphism was examined in 80 maintenance hemodialysis patients (mean age: 60.1+/-1.4 <SEM> years). Multivariate regression analysis showed that the left ventricular mass index calculated by M-mode echocardiography was associated with serum creatinine (p = 0.040), male gender (p = 0.027), antihypertensive drug treatment (p = 0.026), weight gain between hemodialysis (p = 0.018) and mean blood pressure after hemodialysis (p=0.010), but not with ACE I/D genotype (p = 0.69). These findings suggest that although hemodialysis patients seem to be under volume overload, ACE genotype may not be involved in their left ventricular hypertrophy. Hypertension and other factors related to renal failure are involved in the left ventricular hypertrophy in chronic hemodialysis patients.

DOI： 10.1536/ihj.38.821

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER HEART ASSOC  

There is now convincing evidence that various tissues express their own tissue renin-angiotensin system, which may be regulated independently of the systemic renin-angiotensin system. However, little information is available on the regulation of the tissue renin-angiotensin system. We investigated the regulation of tissue angiotensinogen gene expression with respect to the development of hypertension. We measured basal and lipopolysaccharide-stimulated plasma angiotensinogen concentrations by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 4 and 13 weeks of age. Basal plasma angiotensinogen concentration in SHR was comparable to that in WKY at 4 weeks of age and was significantly higher than that in WKY at 13 weeks of age. Lipopolysaccharide induced a significant increase in plasma angiotensinogen concentration in both WKY and SHR at 4 and 13 weeks of age. At 4 weeks of age, the basal levels of angiotensinogen mRNA in the liver, fat, adrenal, and aorta were higher in WKY than in SHR. At 13 weeks of age, the basal levels of angiotensinogen mRNA in the fat, adrenal, aorta, spleen, and kidney were higher in WKY than in SHR, while that in the liver did not differ significantly between the two strains. At 4 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, fat, adrenal, and aorta in both WKY and SHR. At 13 weeks of age, pretreatment with lipopolysaccharide increased the angiotensinogen mRNA levels in the liver, aorta, and adrenal; decreased those in the spleen; and had no effect in the kidney in both WKY and SHR. Interestingly, lipopolysaccharide increased the angiotensinogen mRNA level in fat only in SHR, with no effect in WKY, at 13 weeks of age. Lipopolysaccharide stimulated tumor necrosis factor-a mRNA expression in fat of WKY and SHR, and the increase in tumor necrosis factor-alpha mRNA level in SHR was significantly greater than that in WKY. Therefore, the increased tumor necrosis factor-alpha mRNA expression may be involved in the increased lipopolysaccharide-induced expression of angiotensinogen gene in fat of SHR at 13 weeks of age. These data suggest that the transcriptional and probably posttranscriptional regulation of angiotensinogen mRNA differs between SHR and WKY, that the regulation of angiotensinogen gene expression is tissue-specific, and that the altered expression of the angiotensinogen gene may be involved in the development of hypertension.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER HEART ASSOC  

To clarify the role of genetic factors in atherosclerotic plaque formation in the carotid artery and magnetic resonance imaging abnormalities in the brain, we investigated the association of these abnormalities with the angiotensin-converting enzyme (ACE) genotype. One hundred sixty-nine subjects (age, 59.2+/-0.8 years, mean+/-SE) admitted to our hospital for health checkups underwent brain magnetic resonance imaging to evaluate lacunar infarction. B-mode ultrasound examinations of the carotid arteries were performed to detect atherosclerotic plaque. The I/D polymorphism of the ACE gene was determined by the polymerase chain reaction method. Multivariate regression analysis was performed to assess the effects of the following variables on the presence of plaque, mean plaque thickness, and number of plaques: fibrinogen, sex, age, body mass index, mean blood pressure, glycosylated hemoglobin, LDL cholesterol, HDL cholesterol, hematocrit, and the D allele of the ACE gene. The frequency of carotid atherosclerotic plaque was significantly (P=.034) higher in subjects with the D allele than in those without this allele. However, the frequency of lacunar stroke was similar in these groups. A multivariate regression analysis showed that the presence of plaque was independently associated with the D allele (odds ratio=3.27, P=.016). However, mean plaque thickness and the number of plaques were not associated with the D allele. The D allele of the ACE gene may be involved in the presence of carotid plaque but not in the extent of this plaque or asymptomatic lacunar stroke in Japanese subjects.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

To investigate the relation between the angiotensin-converting enzyme (ACE) gene polymorphism and acute coronary syndromes with respect to environmental factors, we analyzed the association of genotype with the coronary angiographic findings of patients with acute myocardial infarction or unstable angina pectoris, and we examined the linkage of each genotype with established risk factors for coronary artery disease. We determined the ACE genotype in 152 Japanese patients with acute coronary syndromes and 399 healthy individuals. The genotype distributions were not different between the two groups (P=.74, chi2 test). In the former group, coronary angiograms were evaluated by criteria based on the number of diseased vessels, the number of stenotic lesions (> or = 50%), and the relative abnormal arterial portion (extent index). Although the number of stenotic lesions was higher in patients with the DD genotype than in those with the ID or II genotype (P=.006), there were no differences in the number of diseased vessels or the extent index. When only smokers were analyzed, the number of diseased vessels (P=.032), number of stenotic lesions (P=.003), and extent index (P=.019) were all higher in patients with the DD genotype than in those with the ID or II genotype. In contrast, these differences in the respective parameters did not exist in nonsmokers. The results indicate smoking-associated effects of the ACE genotype on the severity of coronary atherosclerosis.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The protein product of the retinoblastoma susceptibility gene, RB, is a nuclear phosphoprotein that modulates transcription of genes involved in growth control via interactions with transcription factors. Renin is a rate-limiting enzyme of the renin-angiotensin system that regulates blood pressure and water-electrolyte balance. Renin gene expression is regulated in a tissue-specific and developmentally linked manner. Similarly, the expression of RB is controlled in a differentiation-linked manner. Thus, to investigate whether RB is involved in the regulation of renin gene expression, we examined the effects of RB on transcriptional activity of the mouse renin (Ren-1C) promoter. The Ren-1C promoter contains two transcriptionally important elements; the RU-1 (-224 to -138) and RP-2 (-75 to -47) elements. RB activated the Ren-1C promoter in human embryonic kidney cells. The promoter element responsible for RB-mediated transcriptional regulation was the RP-2 element. The results of DNA-protein binding experiments showed that RB increased nuclear binding activity to the RP-2 element, and site-directed mutation which disrupted binding of nuclear factors to the RP-2 element markedly reduced RB-mediated activation of Ren-1C promoter in human embryonic kidney cells. These results indicate that the RP-2 element plays an important role in RB-mediated transcriptional regulation of Ren-1C promoter activity in human embryonic kidney cells, thereby suggesting an interesting mechanism by which RB may modulate the renin-angiotensin system.

DOI： 10.1074/jbc.272.27.16845

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

The renin-angiotensin system plays an important role in the hypertrophic responses in cardiac myocytes through the activation of signal transduction pathways and expression of oncogenes. In the present study, we examined mechanical stretch-induced activation of mitogen-activated protein kinases (MAP kinases) using cultured cardiac myocytes derived from neonatal angiotensinogen gene deficient mice (Agt-/-) and neonatal wild type mice (Agt+/+). Within 2 minutes of being added to cardiac myocytes, angiotensin II activated MAP kinases and the response was completely blocked by pretreatment of the cardiac myocytes with CV-11974, a selective antagonist of angiotensin II type 1 receptors. Interestingly, mechanical stretch resulted in significantly greater activation of MAP kinases in Agt-/- cardiac myocytes than in Agt+/+ cardiac myocytes. CV-11974 failed to suppress the stretch-induced activation of MAP kinases in Agt-/- cardiac myocytes while it inhibited the activation in Agt+/+ cardiac myocytes. BQ123, an endothelin type A receptor antagonist, had no effect on stretch-induced activation of MAP kinases in cardiac myocytes from either mouse strain. These results suggest that cardiac RAS is important for stretch-induced MAP kinase activation in Agt+/+ cardiac myocytes; however, angiotensin II is not indispensable for mechanical stretch-induced activation of MAP kinases in Agt-/- cardiac myocytes.

DOI： 10.1006/bbrc.1997.6706

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

A close relationship between obesity and hypertension has been recognized, and plasma angiotensinogen concentrations (p-AGT) have been reported to correlate with blood pressure (BP). However, little is known about AGT in obese patients with hypertension. To define the role of AGT in obese hypertension, we measured p-AGT in obese patients. The subjects were 42 obese patients diagnosed on the basis of a body mass index (BMI) of more than 25 kg/m2, and 21 sex- and age-matched nonobese patients, whose BMI was less than 25 kg/m2. The hypertensive patients had not previously received antihypertensive drugs. P-AGT (P < .05) and mean BP (P < .0001) was increased in the obese patients as compared with the nonobese patients. Positive correlations were observed between BMI and p-AGT, mean BP and p-AGT, and BMI and mean BP (all P < .05). However, after adjustment for blood pressure, p-AGT was not different between groups, and after adjustment a positive correlation remained only between BMI and mean BP. These results suggested the possible involvement of increased p-AGT in hypertension in obese patients, although this may be a secondary change to hypertension or obesity.

DOI： 10.1016/S0895-7061(97)00053-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Wistar fatty rats (WFR) show obesity and obesity-related features, including hypertension. In this study, we examined the expression of angiotensinogen mRNA in a variety of tissues at different times in WFR and control Wistar lean rats (WLR). WFR were obese and hypertensive at 16 and 24 wk. Plasma renin activity and plasma angiotensinogen concentration showed age-dependent increases in WFR but decreases in WLR. Northern blot analysis showed no significant differences in the levels of hepatic and renal angiotensinogen mRNA between WFR and WLR, and the levels of fat and adrenal angiotensinogen mRNA were lower in WFR than in WLR. On the other hand, the levels of cardiac angiotensinogen mRNA at 16 and 24 wk and those of aortic angiotensinogen mRNA at 16 wk were significantly higher in WFR than in WLR. These results show that the expression of tissue angiotensinogen mRNA is regulated differently in WFR and WLR and indicate that the development of hypertension in WFR is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as in cardiac and aortic angiotensinogen mRNA. Moreover, these results suggest the existence of obesity hypertension-linked and tissue-specific regulation of angiotensinogen gene expression.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

The standardization of clinical laboratory information systems is one of the most difficult but important subjects for clinical laboratory community and laboratorians. International Standard Organization (ISO) has the projects in this field (JTC1/SC7) which is the part of approach to the international laboratory standardization (ISO/TC 212). US NCCLS and European CEN/TC 251 are working under ISO/TC 212. In the United States, the National Academy for Clinical Biochemistry (NACB) and the American Association for Clinical Chemistry (AACC) had started recently to organize the international collaboration program on the subject. The Japan Society of Clinical Pathology (JSCP)'s Council of Laboratory Informatics had joined this program in 1995. NACB/AACC's Ad Hoc Committee which was organized in 1996 is now trying to collect the general opinions ("what and how") through their internet home page. The current status of the works on the standardization of clinical laboratory information systems in the U.S., Europe, and Japan is reviewed briefly in this article. HL7 electronic data exchange specification and clinical testing coding systems such as LOINC coding project and JSCP's coding project are also reviewed.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

Molecular evidence, using DNA fingerprint analyses, of extensive genetic heterogeneity between spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and even within some of the WKY colonies has been reported. Thus we investigated the genetic relations between Dahl S and R rats newly inbred by Dr. Iwai. Genomic DNA was isolated from the liver of four Dahl S and four Dahl R rats, digested with the restriction enzyme HinfI or AluI, and separated in 1.2% agarose gel by electrophoresis. Then, DNA fingerprinting was performed by Southern blot analysis using the human myoglobin 33.6 minisatellite probe. Bands were detected in an alkaline phosphatase reaction system. Within the same strains, there was no heterogeneity of these fingerprinting patterns. The S and R rats shared 82% of the bands in the HinfI-digested DNA and 93% of those in the AluI-digested DNA. These shared values were much greater than the reported value (54%) between SHR and WKY from Charles River Laboratories. These newly inbred Dahl S and R rats may be appropriate, although still limited, experimental animals for investigating the pathophysiology of salt-sensitive hypertension.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although several α-adrenergic receptor genes are expressed i the rat kidney, little information is available on their expression in the renal nephron segments. We investigated the distribution of α(1B)-adrenergic receptor mRNA in rat nephron segments using reverse transcription and polymerase chain reaction (RT-PCR). The nephron segments of six- to eight- week-old male Sprague-Dawley rats were microdissected. Total RNA was prepared by the acid-guanidinium-phenol-chloroform method and used in the following RT-PCR assay. The PCR products were size-fractionated with electrophoresis, visualized with ethidium bromide staining and confirmed by Southern blot analysis. Because the PCR primers spanned an intron, the amplification product of the predicted size was considered to be from α(1B)-adrenergic receptor cDNA and not from genomic DNA. The PCR products were detected in glomerulus (Glm), proximal convoluted and straight tubules (PCT, PST) and cortical and medullary thick ascending limbs of Henle (CTAL, MTAL). No signals were detected in cortical or medullary collecting ducts (CCD, MCD). Large signals were detected in the PCT, and PST&lt; while small signals were found in the Glm. CTAL and MTAL. The α(1B)-adrenergic receptor mRNA was detected for the first time in rat Glm, PCT, PST and TAL using RT-PCR, α(1B)AR mRNA seems to be expressed in the specific sites along the nephron and may play significant roles in renal functions, although the specific physiological effects of the renal α(1B)-adrenergic receptor are unknown.

DOI： 10.1038/ki.1997.213

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD  

Recent association and linkage studies suggested that angiotensinogen may play an important role in the pathogenasis of essential hypertension. However, there is little information in human concerning a relationship between plasma angiotensinogen levels and the angiotensinogen mRNA expression in the liver, which is the main production site of angiotensinogen. Therefore, the aim of this study was to examine whether hepatic angiotensinogen gene expression determines the level of circulating angiotensinogen and the activity of the renin-angiotensin system in humans. The subjects were 36 patients with chronic hepatitis. Blood was collected from each patients for estimation of plasma renin activity, plasma angiotensinogen and angiotensin II concentrations and several parameters of liver function. In addition, total RNA was isolated from liver biopsy specimens, which were then used to measure angiotensinogen mRNA with Northern blot analysis. Levels of angiotensinogen mRNA were detected easily in the liver biopsy specimens in all of the patients. Hepatic angiotensinogen mRNA levels were positively correlated with plasma angiotensinogen levels (r=0.41, P=0.013). In contrast, hepatic angiotensinogen mRNA levels did not show any significant relationship with plasma renin activity, plasma angiotensin II concentration, histological subgroup of hepatitis, histological activity index and parameters of liver function tests. The present study demonstrated, for the first time, that hepatic angiotensinogen mRNA levels correlated with plasma angiotensinogen concentration in humans.

DOI： 10.1016/S0024-3205(97)00129-X

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER VERLAG  

In this study, to investigate the mechanism of hypertension-associated induction of cardiac angiotensinogen in vivo and in vitro, we studied the regulation of angiotensinogen mRNA in the hearts of genetically hypertensive rats and in the rat cardiomyocytes. Levels of cardiac angiotensinogen mRNA were significantly increased in the hypertensive rats. Steady state mRNA levels for angiotensinogen mRNA in cardiomyocytes were increased by angiotensin II and mechanical stretch. The addition of an angiotensin II type 1 receptor antagonist (CV11974) and a transcriptional inhibitor (actinomycin D) completely blocked the induction of angiotensinogen mRNA by angiotensin II in cardiomyocytes. The addition of CV11974 significantly, but not completely, inhibited the induction of angiotensinogen mRNA by mechanical stretch. Actinomycin D completely blocked the induction of angiotensinogen mRNA by stretch in cardiomyocytes. An angiotensin II type 2 receptor antagonist (PD123319) and a protein synthesis inhibitor (cycloheximide) did not affect the induction. These results indicate that the expression of cardiac angiotensinogen mRNA is activated by the development of hypertensive cardiac hypertrophy, and that angiotensin II and mechanical stretch activates the angiotensinogen gene via the angiotensin II type 1 receptor-pathway in cardiomyocytes.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Wistar fatty rats (WFR) show obesity and obesity-related features, including hypertension. In this study, we examined the expression of angiotensinogen mRNA in a variety of tissues at different times in WFR and control Wistar lean rats (WLR). WFR were obese and hypertensive at 16 and 24 wk. Plasma renin activity and plasma angiotensinogen concentration showed age-dependent increase in WFR but decreases in WLR. Northern blot analysis showed no significant differences in the levels of hepatic and renal angiotensinogen mRNA between WFR and WLR, and the levels of fat and adrenal angiotensinogen mRNA were lower in WFR than in WLR. On the other hand, the levels of cardiac angiotensinogen mRNA at 16 and 24 wk and those of aortic angiotensinogen mRNA at 16 wk were significantly higher in WFR than in WLR. These results show that the expression of tissue angiotensinogen mRNA is regulated differently in WFR and WLR and indicate that the development of hypertension in WFR is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as in cardiac and aortic angiotensinogen mRNA. Moreover, these results suggest the existence of obesity hypertension-linked and tissue-specific regulation of angiotensinogen gene expression.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER HEART ASSOC  

Angiotensinogen is expressed in many tissues besides the liver. Recent studies have suggested that abnormalities in the regulation of angiotensinogen gene expression may be involved in the development of hypertension. However, little information is available concerning the functional significance of tissue angiotensinogen. In this study, we measured plasma angiotensinogen concentration by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although plasma angiotensinogen concentration in SHR was comparable to that in WKY at 6 weeks of age, it was increased significantly at 14 weeks of age in SHR and became higher than that in WKY. The levels of hepatic angiotensinogen mRNA were similar in SHR and WKY, and the levels of aortic, adrenal, and renal angiotensinogen mRNAs were lower in SHR than in WKY at both 6 and 14 weeks of age. Brain angiotensinogen expression in SHR was higher than in WKY at 6 weeks of age and was comparable to that in WKY at 14 weeks of age. On the other hand, cardiac and fat angiotensinogen mRNA levels were significantly increased at 14 weeks of age in SHR. These results demonstrate that the expression of tissue angiotensinogen is regulated differently in SHR and WKY and indicate that the development of hypertension is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as cardiac and adipogenic angiotensinogen mRNA in SHR.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Adenosine plays several roles in the kidney mediated by the specific receptors A1, A2, and possibly A3. We studied the localization of adenosine A1 receptor mRNA in rat nephron segments using reverse transcription and polymerase chain reaction (RT-PCR). The nephron segments of male Sprague-Dawley rats (6 to 8 weeks old) were microdissected. Total RNA was prepared by the acid-guanidinium-phenol-chloroform method and used in the following RT-PCR assay. Because the PCR primers spanned no intron, samples reacted in the absence of RT were used as controls for amplification of genomic DNA. The PCR products were size-fractionated by electrophoresis, visualized with ethidium bromide staining, and confirmed by Southern blot analysis. PCR products were detected in all of the nephron segments examined. No signals were detected in samples reacted in the absence of RT. Strong signals were detected in glomeruli, medullary collecting duct, cortical thick ascending limb, and medullary thick ascending limb, while weak signals were found in proximal convoluted and straight tubules. Previously, the presence of A1 receptors has been demonstrated in glomeruli, collecting duct, and thick ascending limb in the rat kidney by autoradiography and binding studies. In addition to these segments, we further detected A1 receptor mRNA in proximal convoluted and straight tubules. Thus, A1 receptor mRNA seems to be broadly expressed along the nephron.

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Lippincott Williams and Wilkins  

BACKGROUND: A positive association was previously reported between angiotensin-converting enzyme (ACE) gene polymorphism and several cardiovascular diseases, such as myocardial infarction, left ventricular hypertrophy, and restenosis after percutaneous transluminal coronary angioplasty. Plasma ACE activity and carotid-wall thickening measured by ultrasonography were related, and it was postulated that long-term exposure to high levels of plasma ACE could be involved in structural changes of the arterial wall. In addition, angiotensinogen gene mutation was recently reported to be associated with essential hypertension and preeclampsia. There exists a possibility that the renin-angiotensin system plays an important role in the progress of cardiovascular diseases in humans. Therefore, we examined the association between the molecular variant of the angiotensin gene and coronary atherosclerosis. METHODS AND RESULTS: This study included 82 patients who had coronary atherosclerosis and 160 control subjects; all study participants were Japanese. All patients with coronary atherosclerosis had at least one coronary artery with > 25% luminal diameter obstruction on average according to multiple coronary angiographic views. Angiotensinogen gene molecular variants were designated AA, Aa, and aa. The a allele indicated thymine-cytosine transition at nucleotide 704 in exon 2. Genomic DNA was extracted from peripheral blood leukocytes. Polymerase chain reaction was performed to amplify the concerned region of the angiotensinogen gene. After restriction enzyme digestion, it was possible to distinguish the molecular variant of the angiotensinogen gene. The frequencies of these genotypes were 7.3%, 26.8%, and 65.9% in the patients and 18.8%, 31.9%, and 49.3% in the control subjects for the AA, Aa, and aa alleles, respectively. There was an excess in the a allele among patients (P < .01). CONCLUSIONS: We found a significant association between coronary atherosclerosis and a molecular variant of the angiotensin gene. The results suggested that the molecular variant of the angiotensinogen gene could be a new risk factor for coronary atherosclerosis.

DOI： 10.1161/01.CIR.91.4.951

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE PUBL CO INC  

A polymorphism of the angiotensin I converting enzyme (ACE) gene has recently been reported and analysis of this polymorphism has indicated that it is associated with several cardiovascular diseases. However, the results are still controversial and such association has not yet been established conclusively. To determine whether the ACE gene may be responsible for essential hypertension in a Japanese population, we also compared the distribution of genotypes and the allele frequency of this polymorphism in our findings of a Japanese population with these features in other countries. Eighty-seven hypertensive patients with a family history of essential hypertension and 95 normotensive patients whose parents had no such history were enrolled in the study. Polymorphism of the ACE gene was determined by using the polymerase chain reaction. Homozygotes for this polymorphism had either a 490-bp band (II) or a 190-bp band (DD) and heterozygotes had both bands (ID). In hypertensive subjects, the numbers and frequency of the ACE genotypes were: II, 44 (0.51); ID, 26 (0.30); DD, 17 (0.19). In normotensive subjects these were: II, 35 (0.37); ID, 43 (0.45); DD, 17 (0.18). There were no significant differences between the two groups in derived allele frequencies (chi 2 = 1.41). The difference between the overall allelic frequency in Japan and that reported in several other countries was significant. We did not find any association between ACE gene polymorphism and essential hypertension in Japan. However, there were significant differences in derived allele frequencies between our findings in a Japanese population and those reported from Europe and Australia.

DOI： 10.1016/0895-7061(94)00184-D

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.26.69

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL SCIENCE INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(公大)横浜市立大学医学部看護学科  

はじめに 心筋梗塞(MI)モデルマウスの実験において、超音波検査法(エコー)は、最も重要かつ不可欠な評価の一つである。本研究の目的は、検者が看護学生の初学者の場合のエコーを用いた手技の評価について検討することである。方法 Sham群とMI群で各3匹のC57BL/6の12週齢雄マウスを用いた。研究期間は、2017年4月から12月であった。エコー評価手技については、事前に専門医よりインストラクションを受けた。そして、検者は、IVSTd、IVSTs、LVIDd、LVIDs、LVPWTd、LVPWTs、EDV、ESV、EF、FSの測定を行うためにエコーを実施した。さらに、エコー評価によりSham群とMI群の振り分けを行った。この本研究は、横浜市立大学の動物実験委員会にて承認を受けた。結果 検者はエコー評価よりSham群とMI群を振り分けることができた。MI作製の施術前後の平均体重については、Sham群で順に25.27±0.55g、24.77±1.16gとなっており、MI群では23.97±1.59g、23.67±0.90gであった。心筋梗塞は、心臓を廓清後のMasson's trichrome染色によりSham群とMI群の2群の振り分けを行った。施術前後のEFの平均値は、Sham群で73.9±1.7%、75.5±4.4%となっており、MI群では73.5±2.2%、53.2±1.2%となっていた。検者は、これらの群間の違いを検出することができた。EF以外の他の項目における計測値の信頼性や安定性に関しては、先行論文の値を参照した場合、測定値にいくつかの逸脱した値が観察された。(著者抄録)

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記述言語：日本語   出版者・発行元：(公大)横浜市立大学医学部看護学科  

はじめに 心筋梗塞(MI)モデルマウスの実験において、超音波検査法(エコー)は、最も重要かつ不可欠な評価の一つである。本研究の目的は、検者が看護学生の初学者の場合のエコーを用いた手技の評価について検討することである。方法 Sham群とMI群で各3匹のC57BL/6の12週齢雄マウスを用いた。研究期間は、2017年4月から12月であった。エコー評価手技については、事前に専門医よりインストラクションを受けた。そして、検者は、IVSTd、IVSTs、LVIDd、LVIDs、LVPWTd、LVPWTs、EDV、ESV、EF、FSの測定を行うためにエコーを実施した。さらに、エコー評価によりSham群とMI群の振り分けを行った。この本研究は、横浜市立大学の動物実験委員会にて承認を受けた。結果 検者はエコー評価よりSham群とMI群を振り分けることができた。MI作製の施術前後の平均体重については、Sham群で順に25.27±0.55g、24.77±1.16gとなっており、MI群では23.97±1.59g、23.67±0.90gであった。心筋梗塞は、心臓を廓清後のMasson&#039;s trichrome染色によりSham群とMI群の2群の振り分けを行った。施術前後のEFの平均値は、Sham群で73.9±1.7%、75.5±4.4%となっており、MI群では73.5±2.2%、53.2±1.2%となっていた。検者は、これらの群間の違いを検出することができた。EF以外の他の項目における計測値の信頼性や安定性に関しては、先行論文の値を参照した場合、測定値にいくつかの逸脱した値が観察された。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：日本成人先天性心疾患学会  

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：日本語   出版者・発行元：(NPO)生物試料分析科学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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J-GLOBAL

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記述言語：日本語  

J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：(株)医学書院  

＜ポイント＞高血圧性臓器障害のなかで最も血圧の影響を受けるのは左室肥大である.心電図検査による左室肥大の検出力は,再現性・特異度は高いが,感度が低い.心エコーは心臓の形態や機能の評価に優れており,左室肥大の検出感度も高い.高血圧症による早期〜長期の合併症に対して,心電図や心エコーは重要な役割を果たす.(著者抄録)

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

J-GLOBAL

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記述言語：英語   出版者・発行元：(NPO)日本高血圧学会