Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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

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Language：Japanese   Publisher：日本肺高血圧・肺循環学会  

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Publishing type：Research paper (scientific journal)  

DOI： 10.3390/jvd3020014

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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

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Language：English   Publishing type：Research paper (scientific journal)  

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

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Language：English  

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

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：English   Publishing type：Research paper (scientific journal)  

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

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Language：English   Publishing type：Research paper (scientific journal)  

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

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.nutos.2023.03.006

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Language：Japanese   Publisher：日本肺高血圧・肺循環学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10157-023-02323-3

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Other Link： https://link.springer.com/article/10.1007/s10157-023-02323-3/fulltext.html

Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/tkm2.1347

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/tkm2.1347

Language：English   Publishing type：Research paper (scientific journal)  

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

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Language：Japanese   Publisher：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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Language：English  

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

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Publishing type：Research paper (scientific journal)   Publisher：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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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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

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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI  

DOI： 10.3390/ijms222111849

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publisher：(一社)日本心臓病学会  

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Language：English   Publishing type：Research paper (scientific journal)  

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

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

DOI： 10.1016/j.jccase.2020.11.018

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Language：Japanese   Publisher：(一社)日本東洋医学会  

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Language：Japanese   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/tkm2.1271

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Language：English   Publisher：(一社)日本循環器学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publisher：東京医科大学医学会  

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Language：English   Publisher：東京医科大学医学会  

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Other Link： 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

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DOI： 10.1111/jch.14160

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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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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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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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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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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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(一社)日本医学教育学会  

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Language：English   Publisher：(一社)日本循環器学会  

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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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Language：Japanese   Publisher：(株)日本臨床社  

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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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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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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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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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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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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DOI： 10.1016/j.conctc.2020.100542

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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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Language：Japanese   Publisher：日本成人先天性心疾患学会  

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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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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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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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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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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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DOI： 10.1038/s41598-019-42657-1

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Circulation Society  

DOI： 10.1253/circj.CJ-18-1044

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Language：English   Publisher：(一社)日本成人先天性心疾患学会  

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Language：English   Publisher：(一社)日本成人先天性心疾患学会  

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Language：English   Publisher：(一社)日本成人先天性心疾患学会  

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Language：English   Publisher：(一社)日本成人先天性心疾患学会  

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Language：English   Publisher：(一社)日本成人先天性心疾患学会  

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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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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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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

DOI： 10.1007/s10157-017-1520-8

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Physiological Society  

DOI： 10.14814/phy2.13687

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/s41598-018-24749-6

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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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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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Circulation Society  

DOI： 10.1253/circj.CJ-17-0510

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Abnormal angiogenesis plays a major role in the development of early stage diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a classical proangiogenic factor that regulates abnormal glomerular angiogenesis linked to glomerular hypertrophy in the early stage of diabetic nephropathy. Leucine-rich α-2-glycoprotein-1 (LRG1) was recently reported as a novel proangiogenic factor that is expressed in endothelial cells and promotes angiogenesis by modulating the transforming growth factor-β signaling pathway. However, the pathophysiology of LRG1 in diabetic nephropathy remains largely unknown. In the present study, we investigated intrarenal expression of the novel proangiogenic factor LRG1 in diabetic db/db mice by immunohistochemistry and a laser capture microdissection method during the development of diabetic nephropathy. We hypothesized that glomerular LRG1 expression is increased earlier than VEGF expression under conditions of pathological angiogenesis in the early stage of diabetic nephropathy. Thus, we compared glomerular expression of VEGF and LRG1 in diabetic db/db mice at 16 and 24 weeks of age. At 16 weeks, diabetic db/db mice exhibited glomerular hypertrophy with abnormal angiogenesis characterized by endothelial cell proliferation, which was concomitant with an increase in LRG1 expression of glomerular endothelial cells. However, glomerular VEGF expression was not increased at this early stage. At 24 weeks, the features of early diabetic nephropathy in db/db mice had developed further, along with further enhanced glomerular LRG1 expression. At this late stage, glomerular VEGF and fibrosis-related-gene expression was also significantly increased compared with nondiabetic db/m mice. These results suggest that LRG1 plays a pivotal role in the initial development of diabetic nephropathy by promoting abnormal angiogenesis, thereby suggesting that LRG1 is a potential preemptive therapeutic target of diabetic nephropathy.

DOI： 10.1155/2018/2817045

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DOI： 10.1016/j.atherosclerosis.2017.11.003

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DOI： 10.1016/j.jjcc.2017.04.001

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DOI： 10.1161/JAHA.117.006120

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Language：Japanese   Publisher：(NPO)日本小児循環器学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms18061268

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DOI： 10.3390/ijms18061250

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DOI： 10.14814/phy2.13316

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DOI： 10.1253/circj.CJ-16-1018

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DOI： 10.1016/j.joa.2016.07.008

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DOI： 10.3390/ijms18030676

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Language：Japanese   Publisher：(一社)日本成人先天性心疾患学会  

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Language：Japanese   Publisher：(一社)日本成人先天性心疾患学会  

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DOI： 10.1016/j.jjcc.2016.06.004

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DOI： 10.21037/jtd.2016.12.03

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DOI： 10.1016/j.ebiom.2016.10.039

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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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DOI： 10.1097/FJC.0000000000000397

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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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DOI： 10.1016/j.jjcc.2014.08.008

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Language：Japanese   Publisher：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.46.35

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DOI： 10.1253/circj.CJ-14-1255

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DOI： 10.1097/HJH.0000000000000293

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DOI： 10.1161/HYPERTENSIONAHA.114.03394

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DOI： 10.1253/circj.CJ-14-0104

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DOI： 10.1016/j.joa.2014.02.003

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1096/fj.12-222653

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DOI： 10.1016/j.bbrc.2012.09.144

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DOI： 10.1016/j.jjcc.2012.06.001

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DOI： 10.1159/000348660

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DOI： 10.1016/S0735-1097(11)60524-X

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Language：Japanese   Publisher：Japan Heart Foundation  

DOI： 10.11281/shinzo.43.505

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Other Link： http://search.jamas.or.jp/link/ui/2011188811

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DOI： 10.4020/jhrs.27.226

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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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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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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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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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DOI： 10.1161/HYPERTENSIONAHA.109.147207

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Authorship：Lead author,　Corresponding author   Language：English  

DOI： 10.1161/HYPERTENSIONAHA.109.146738

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DOI： 10.1016/j.atherosclerosis.2009.04.005

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DOI： 10.3109/10641960903407033

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DOI： 10.1016/j.bbrc.2009.07.158

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DOI： 10.1007/s10157-009-0192-4

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DOI： 10.1007/s10157-009-0209-z

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DOI： 10.1016/j.jjcc.2009.04.015

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DOI： 10.1080/10641960902822518

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DOI： 10.1097/MNM.0b013e328314b879

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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：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

DOI： 10.1159/000210572

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DOI： 10.1253/circj.72.700

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Language：Japanese   Publisher：(一社)日本不整脈心電学会  

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DOI： 10.1080/10641960802068477

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DOI： 10.1161/HYPERTENSIONAHA.107.102061

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DOI： 10.1080/10641960701813890

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DOI： 10.1161/HYPERTENSIONAHA.107.096115

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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DOI： 10.1111/j.1447-0594.2007.00382.x

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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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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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Other Link： 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

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DOI： 10.1080/10641960601096760

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DOI： 10.1253/circj.70.1462

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DOI： 10.1291/hypres.29.837

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Language：Japanese   Publisher：ライフサイエンス出版(株)  

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DOI： 10.1007/s00380-005-0881-1

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Language：Japanese   Publisher：横浜市立大学医学会  

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DOI： 10.1016/j.bbrc.2005.11.120

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Language：Japanese   Publisher：(一社)日本循環器病予防学会  

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Other Link： 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

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DOI： 10.4020/jhrs.22.48

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Language：Japanese   Publisher：(一社)日本脈管学会  

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DOI： 10.1016/j.febslet.2005.01.068

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DOI： 10.4020/jhrs.21.553

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DOI： 10.1111/j.1523-1755.2004.00635.x

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DOI： 10.1086/420793

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DOI： 10.1038/sj.mp.4001422

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DOI： 10.1007/s10038-003-0103-6

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DOI： 10.1046/j.1523-1755.2003.00302.x

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DOI： 10.1007/s10038-003-0055-x

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DOI： 10.1097/00006231-200208000-00014

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DOI： 10.1161/01.HYP.0000016177.20565.A0

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DOI： 10.1086/338454

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DOI： 10.1007/s100380200102

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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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DOI： 10.1007/s100380170100

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DOI： 10.1007/s100380170055

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DOI： 10.1074/jbc.M004421200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1097/00041444-200010030-00007

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DOI： 10.1007/s100380070019

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1161/01.HYP.34.3.430

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DOI： 10.1046/j.1523-1755.1999.00377.x

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.88.198

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Other Link： http://search.jamas.or.jp/link/ui/1999141462

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Language：Japanese   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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DOI： 10.1161/01.HYP.32.3.521

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Hypertension  

DOI： 10.1291/hypres.21.155

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DOI： 10.1152/ajpregu.1998.275.1.R1

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DOI： 10.1006/bbrc.1998.8548

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DOI： 10.1097/00004872-199816030-00005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing  

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

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Language：Japanese   Publisher：Japan Heart Foundation  

DOI： 10.11281/shinzo1969.30.Supplement4_63

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DOI： 10.1536/ihj.38.821

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DOI： 10.1074/jbc.272.27.16845

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DOI： 10.1006/bbrc.1997.6706

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DOI： 10.1016/S0895-7061(97)00053-8

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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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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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/ki.1997.213

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DOI： 10.1016/S0024-3205(97)00129-X

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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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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1161/01.CIR.91.4.951

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DOI： 10.1016/0895-7061(94)00184-D

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Language：Japanese   Publisher：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.26.69

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：横浜市立大学医学部看護学科・大学院医学研究科看護学専攻  

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Language：Japanese   Publisher：(公大)横浜市立大学医学部看護学科  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：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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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(NPO)生物試料分析科学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：Japanese  

J-GLOBAL

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：(株)医学書院  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

J-GLOBAL

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Language：English   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publisher：(NPO)日本高血圧学会  

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