Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38alpha is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38alpha in hearts. First, we generated mice with floxed p38alpha alleles and crossbred them with mice expressing the Cre recombinase under the control of the alpha-myosin heavy-chain promoter to obtain cardiac-specific p38alpha knockout mice. These cardiac-specific p38alpha knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38alpha plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.

DOI： 10.1128/MCB.24.24.10611-10620.2004

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

The Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle-specific Raf-1-knockout (Raf CKO) mice with Cre-loxP-mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal-regulating kinase 1 (ASK1),JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism.

DOI： 10.1172/JCI200420317

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK(-/-)) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK(-/-) hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK(-/-) had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK(-/-) compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK(-/-) cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis.

DOI： 10.1072/pnas.2136717100

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BACKGROUND/AIM: Imeglimin, a novel oral antidiabetic agent, was approved in 2021 for the treatment of type 2 diabetes mellitus (T2DM). Phase III clinical trials demonstrated its safety and efficacy in managing T2DM. However, its safety profile in patients with heart failure has not been thoroughly evaluated in real-world clinical settings. PATIENTS AND METHODS: We analyzed cases of patients with heart failure (stage B or higher) who were newly prescribed imeglimin, based on electronic medical records from June 2022 to June 2024. Baseline clinical data at the initiation of imeglimin therapy were collected, and cardiovascular events, adverse effects (e.g., lactic acidosis), and blood test results, including glycated hemoglobin A1c (HbA1c), were assessed as of July 2024. RESULTS: A total of 21 patients met the inclusion criteria. HbA1c levels significantly decreased after an average of 312.1±205.8 days of imeglimin therapy (baseline vs. on therapy: 8.2±1.0% vs. 7.5±0.7%, p=0.001). Alanine aminotransferase levels were also significantly reduced (baseline vs. on therapy: 30.9±23.8 IU/l vs. 22.0±12.3 IU/l, p=0.022). No adverse drug reactions were observed during the treatment period. Major adverse cardiovascular events occurred in three patients (14%), although a clear association with imeglimin remains uncertain. CONCLUSION: Imeglimin demonstrated safety and efficacy in T2DM in patients with coexisting heart failure.

DOI： 10.21873/invivo.13838

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The accumulation of damaged mitochondria in the heart is associated with heart failure. Mitophagy is an autophagic degradation system that specifically targets damaged mitochondria. We have reported previously that Bcl2-like protein 13 (Bcl2-L-13) mediates mitophagy and mitochondrial fission in mammalian cells. However, the in vivo function of Bcl2-L-13 remains unclear. Here, we demonstrate that Bcl2-L-13-deficient mice and knockin mice, in which the phosphorylation site (Ser272) on Bcl2-L-13 was changed to Ala, showed left ventricular dysfunction in response to pressure overload. Attenuation of mitochondrial fission and mitophagy led to impairment of ATP production in these mouse hearts. In addition, we identified AMPKα2 as the kinase responsible for the phosphorylation of Bcl2-L-13 at Ser272. These results indicate that Bcl2-L-13 and its phosphorylation play an important role in maintaining cardiac function. Furthermore, the amplitude of stress-stimulated mitophagic activity could be modulated by AMPKα2.

DOI： 10.1016/j.celrep.2024.115001

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The relationship between post-ablation excessive supraventricular ectopic activity (ESVEA), a new marker for new-onset atrial fibrillation (AF), and late AF recurrence is uncertain. We enrolled 469 patients with AF who underwent initial radiofrequency catheter ablation and 24-h Holter monitoring the day after. Early AF recurrence (n = 57; 12%) and ESVEA (n = 242; 52%) were noted. During a median follow-up of 25 months, 152 (32%) patients experienced late AF recurrence. Patients with early AF recurrence or ESVEA were significantly more likely to experience late recurrence (p = 0.02). Even without AF, ESVEA was associated with late recurrence following AF ablation.

DOI： 10.1007/s00380-024-02498-z

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An 82-year-old woman with a history of myocardial infarction presented with worsening effort angina. Coronary angiography (CAG) revealed 75% stenosis in the proximal left anterior descending artery (LAD), with intravascular ultrasound (IVUS) identifying a severe calcified nodule near a previously implanted drug-eluting stent. The lesion was treated with intravascular lithotripsy (IVL) and a drug-coated balloon (DCB), avoiding left main crossover stenting. Despite initial success, the patient experienced restenosis three months later, managed conservatively based on favorable DFR/FFR values. However, worsening symptoms led to repeat CAG, revealing 99% restenosis with calcified nodule. A second IVL was performed, followed by crossover stenting from the left main to the LAD, achieving successful stent expansion. This case underscores the potential for severe restenosis following IVL and DCB angioplasty, highlighting the limitations of IVL in reducing calcified plaque volume and the importance of close follow-up.

DOI： 10.1093/omcr/omae156

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OBJECTIVES: This study evaluated the feasibility of a model-based iterative reconstruction technique (MBIR) tuned for the myocardium on myocardial computed tomography late enhancement (CT-LE). METHODS: Twenty-eight patients who underwent myocardial CT-LE and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) within 1 year were retrospectively enrolled. Myocardial CT-LE was performed using a 320-row CT with low tube voltage (80 kVp). Myocardial CT-LE images were scanned 7 min after CT angiography (CTA) without additional contrast medium. All myocardial CT-LE images were reconstructed with hybrid iterative reconstruction (HIR), conventional MBIR (MBIR_cardiac), and new MBIR tuned for the myocardium (MBIR_myo). Qualitative (5-grade scale) scores and quantitative parameters (signal-to-noise ratio [SNR] and contrast-to-noise ratio [CNR]) were assessed as image quality. The sensitivity, specificity, and accuracy of myocardial CT-LE were evaluated at the segment level using an American Heart Association (AHA) 16-segment model, with LGE-MRI as a reference standard. These results were compared among the different CT image reconstructions. RESULTS: In 28 patients with 448 segments, 160 segments were diagnosed with positive by LGE-MRI. In the qualitative assessment of myocardial CT-LE, the mean image quality scores were 2.9 ± 1.2 for HIR, 3.0 ± 1.1 for MBIR_cardiac, and 4.0 ± 1.0 for MBIR_myo. MBIR_myo showed a significantly higher score than HIR (P < 0.001) and MBIR_cardiac (P = 0.018). In the quantitative image quality assessment of myocardial CT-LE, the median image SNR was 10.3 (9.1-11.1) for HIR, 10.8 (9.8-12.1) for MBIR_cardiac, and 16.8 (15.7-18.4) for MBIR_myo. The median image CNR was 3.7 (3.0-4.6) for HIR, 3.8 (3.2-5.1) for MBIR_cardiac, and 6.4 (5.0-7.7) for MBIR_myo. MBIR_myo significantly improved the SNR and CNR of CT-LE compared to HIR and MBIR_cardiac (P < 0.001). The sensitivity, specificity, and accuracy for the detection of myocardial CT-LE were 70%, 92%, and 84% for HIR; 71%, 92%, and 85% for MBIR_cardiac; and 84%, 92%, and 89% for MBIR_myo, respectively. MBIR_myo showed significantly higher image quality, sensitivity, and accuracy than the others (P < 0.05). CONCLUSIONS: MBIR tuned for myocardium improved image quality and diagnostic performance for myocardial CT-LE assessment.

DOI： 10.1097/RCT.0000000000001652

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BACKGROUND: There are currently no established non-invasive indices of echocardiography for elevated left atrial pressure (LAP) especially in patients with atrial fibrillation (AF). Remote dielectric sensing (ReDS) is a novel non-invasive electromagnetic energy-based technology that quantifies total lung fluid, enabling the monitoring of volume status in patients with heart failure. The utility of ReDS for estimating LAP in patients with AF remains unknown. METHODS: We prospectively investigated patients with AF in whom LAP was directly measured during catheter ablation for AF, and ReDS measurements were conducted the day before ablation. Elevated LAP was defined as LAP ≥ 15 mmHg. RESULTS: A total of 61 patients were included (median age 66 years, 38 % female). Among them, 26 patients had elevated LAP. There was a positive correlation between ReDS and LAP (r = 0.363, P = 0.004). Receiver operating characteristic curve analysis for the prediction of elevated LAP demonstrated that the best cut-off value of ReDS was 30 %, with a sensitivity of 65 %, specificity of 69 %, and an area under the curve of 0.703 (95 % confidence interval 0.568-0.837). Multivariate logistic regression analysis revealed that ReDS was an independent predictor of elevated LAP, among covariates including left ventricular ejection fraction, the ratio of early transmitral flow velocity to septal mitral annular early diastolic velocity, and left atrial volume index. CONCLUSIONS: Our results suggest ReDS could be a valuable marker of elevated LAP even in patients with AF. Further studies are needed to elucidate the effectiveness of a ReDS-guided decongestive strategy in patients with heart failure.

DOI： 10.1016/j.ijcha.2024.101459

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BACKGROUND: Aromatase inhibitors (AIs) are the standard therapeutic approach for hormone receptor-positive postmenopausal breast cancer. However, there are concerns about increased cardiovascular risk due to their antioestrogenic effects. This study aimed to investigate the potential association between duration of AI treatment and the severity of coronary artery calcification (CAC). METHODS: The study included outpatients who initiated adjuvant endocrine therapy with AIs for breast cancer from August 2010 to October 2022. CAC was quantified according to a visual ordinal scoring system. Patient characteristics were assessed based on the presence of CAC. Independent risk factors for elevated CAC scores were identified through a multivariable logistic regression model. RESULTS: Among 357 patients, 44.8% exhibited CAC. No significant difference in AI treatment duration was observed between groups (1268 d [interquartile range (IQR) 725-1743 d] vs 1104 d [IQR 685-1683.25 d]; P = 0.236). Patients with CAC were characterised by higher age (63.06 y [56.81-68.78 y] vs 74.39 y [68.98-80.03 y]; P < 0.001), lower hemoglobin levels (g/dL: 13.20L [IQR 12.60-13.70L] vs 12.60 [IQR 11.60-13.43]; P < 0.001), and reduced estimated glomerular filtration rate (mL/min/1.73 m2: 72.00 [IQR 61.80-81.50] vs 62.80 [IQR 51.27-71.90]; P < 0.001) compared with those without CAC. The prevalences of hypertension, diabetes mellitus, and dyslipidemia were significantly higher in patients with CAC. No correlation was found between the duration of AI treatment and CAC score (R = -0.02; P = 0.78). Independent risk factors for CAC included higher age, lower hemoglobin levels, and the presence of hypertension and diabetes mellitus in postoperative patients with breast cancer. CONCLUSIONS: The duration of AI treatment does not exert a significant influence on CAC in postoperative patients with breast cancer.

DOI： 10.1016/j.cjca.2024.05.012

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PURPOSE: To evaluate the feasibility of left atrial strain (LAS) assessment using cardiac computed tomography (CT) in patients with paroxysmal atrial fibrillation (PAF). METHODS: This retrospective single-center study included 98 patients with PAF who underwent cardiac CT and echocardiography before the first catheter ablation. LAS was analyzed using cardiac CT (CT-LAS) and speckle-tracking echocardiography (STE; STE-LAS). LA reservoir (LASr), conduit (LASc), and pump strain (LASp) were calculated by averaging LAS measured in 4- and 2-chamber views. The results were compared using Pearson's correlation coefficients, paired t-tests, and Bland-Altman analysis. Intraclass correlation coefficients (ICCs) were used to evaluate reproducibility. RESULTS: CT-LAS could be analyzed in all patients, while STE-LAS could be analyzed in 53 (54%) patients. LASr, LASc, and LASp showed significant correlations between CT- and STE-LAS: LASr, r = 0.68, p < 0.001; LASc, r = 0.47, p < 0.001; LASp, r = 0.67, p < 0.001. LASr, LASc, and LASp of CT- and STE-LAS were 23.7 ± 6.0% and 22.1 ± 6.7%, 11.1 ± 3.6% and 11.1 ± 4.1%, and 12.6 ± 4.6% and 11.0 ± 4.1%, respectively. LASr and LASp were significantly higher in CT-LAS than that in STE-LAS (p = 0.023 for LASr and p = 0.001 for LASp). CT-LAS showed excellent reproducibility. The intra- and interobserver ICCs were 0.96 to 0.99 and 0.89 to 0.90, respectively. CONCLUSION: CT-LAS was successfully analyzed in more patients than STE-LAS and was highly reproducible. The findings suggest that CT-LAS is feasible for patients with PAF.

DOI： 10.1007/s10554-024-03162-3

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DOI： 10.1253/circj.CJ-24-0306

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OBJECTIVES: This study aimed to investigate the utility of the RAND/UCLA appropriateness method (RAM) in validating expert consensus-based multiple-choice questions (MCQs) on electrocardiogram (ECG). METHODS: According to the RAM user's manual, nine panelists comprising various experts who routinely handle ECGs were asked to reach a consensus in three phases: a preparatory phase (round 0), an online test phase (round 1), and a face-to-face expert panel meeting (round 2). In round 0, the objectives and future timeline of the study were elucidated to the nine expert panelists with a summary of relevant literature. In round 1, 100 ECG questions prepared by two skilled cardiologists were answered, and the success rate was calculated by dividing the number of correct answers by 9. Furthermore, the questions were stratified into "Appropriate," "Discussion," or "Inappropriate" according to the median score and interquartile range (IQR) of appropriateness rating by nine panelists. In round 2, the validity of the 100 ECG questions was discussed in an expert panel meeting according to the results of round 1 and finally reassessed as "Appropriate," "Candidate," "Revision," and "Defer." RESULTS: In round 1 results, the average success rate of the nine experts was 0.89. Using the median score and IQR, 54 questions were classified as " Discussion." In the expert panel meeting in round 2, 23% of the original 100 questions was ultimately deemed inappropriate, although they had been prepared by two skilled cardiologists. Most of the 46 questions categorized as "Appropriate" using the median score and IQR in round 1 were considered "Appropriate" even after round 2 (44/46, 95.7%). CONCLUSIONS: The use of the median score and IQR allowed for a more objective determination of question validity. The RAM may help select appropriate questions, contributing to the preparation of higher-quality tests.

DOI： 10.1186/s12909-024-05446-7

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DOI： 10.1253/circj.CJ-23-0698

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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DOI： 10.1016/j.celrep.2023.113383

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BACKGROUND: Haemorrhage at the puncture site is a serious complication of percutaneous coronary intervention (PCI). CASE SUMMARY: A 73-year-old man underwent transfemoral intervention because of stable angina pectoris. After a rotational atherectomy, an everolimus-eluting stent was implanted from the left main trunk to the proximal site of the left anterior descending (LAD) artery. We also recognized that myocardial bridging was significantly induced at the middle portion of the LAD, which was not evident before the PCI. We suspected puncture-related haemorrhage and immediately performed lower limb arteriography. As a result, contrast media extravasation was observed at the branch of the right inferior epigastric artery. Finally, we performed coil embolization into the left common femoral artery, and the extravasation successfully disappeared. Four months later, he underwent coronary angiography. There were no findings of myocardial bridging. DISCUSSION: Myocardial bridging during a PCI procedure may indicate hypercontraction because of haemorrhage.

DOI： 10.1093/ehjcr/ytad439

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

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Heart failure is a leading cause of mortality in developed countries. Cell death is a key player in the development of heart failure. Calcium-independent phospholipase A2β (iPLA2β) produces lipid mediators by catalyzing lipids and induces nuclear shrinkage in caspase-independent cell death. Here, we show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death, as well as contractile dysfunction mediated through its receptor, G protein-coupled receptor 34 (GPR34). Cardiomyocyte-specific iPLA2β-deficient male mice were subjected to pressure overload. While control mice showed left ventricular systolic dysfunction with necrotic cardiomyocyte death, iPLA2β-deficient mice preserved cardiac function. Lipidomic analysis revealed a reduction of 18:0 lysophosphatidylserine in iPLA2β-deficient hearts. Knockdown of Gpr34 attenuated 18:0 lysophosphatidylserine-induced necrosis in neonatal male rat cardiomyocytes, while the ablation of Gpr34 in male mice reduced the development of pressure overload-induced cardiac remodeling. Thus, the iPLA2β-lysophosphatidylserine-GPR34-necrosis signaling axis plays a detrimental role in the heart in response to pressure overload.

DOI： 10.1038/s41467-023-40201-4

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Histologic evaluations revealed excessive accumulations of macrophages and absence of fibroblastic interstitial cells in explanted bioprosthetic valves. Comprehensive gene and protein expression analysis and histology unveiled an accumulation of fibrinogen and plasminogen, an activator of infiltrated macrophages, from degenerated valve surfaces in the interstitial spaces. These pathologies were completely reproduced in a goat model replaced with an autologous pericardium-derived aortic valve. Further preclinical animal experiments using goats demonstrated that preventing infiltration of macrophages and circulating proteins by increasing collagen density and leaflet strength is an effective treatment option.

DOI： 10.1016/j.jacbts.2023.01.003

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BACKGROUND: Although remote monitoring (RM) after pacemaker implantation is common, its cost-effectiveness has not been fully investigated. Therefore, we assessed the cost-effectiveness of RM compared with conventional follow-up (CFU) in Japanese patients with pacemakers. METHODS: A Markov model was constructed to analyze costs and quality-adjusted life years after pacemaker implantation. The target population was Japanese patients implanted with a dual-chamber pacemaker for bradycardia. Transition probabilities (e.g. atrial fibrillation, stroke, and device trouble) were obtained from literature and expert sources. Additionally, stroke risk was determined according to anticoagulation and CHADS2 scores. We used a 10-year horizon with sensitivity analyses for significant variables. RESULTS: Compared to CFU, RM was more effective; however, it was also more expensive. When the range of the Japanese willingness-to-pay threshold was considered to be \5,000,000, RM was at least cost-neutral relative to the CFU in all elderly patients with pacemakers for bradycardia. The cost-effectiveness of RM relative to CFU could be higher for patients with high CHADS2 scores, especially in patients with a CHADS2 score ≥ 3. Scenario analyses changing the interval between visits to an in-office evaluation in the CFU also demonstrated the same conclusions. In particular, when the interval between office visits was 1 year for the CFU, the RM could be more cost-effective. CONCLUSIONS: This study demonstrated that RM can be a cost-effective option for Japanese patients, especially those with high CHADS2 scores and long-term intervals between office visits.

DOI： 10.1016/j.jjcc.2023.06.003

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DOI： 10.1093/ehjdh/ztad026

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DOI： 10.1016/j.cjco.2023.02.008

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

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

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

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AIMS: Currently, virtual reality (VR) constitutes a vital aspect of digital health, necessitating an overview of study trends. We classified type A studies as those in which health care providers utilized VR devices and type B studies as those in which patients employed the devices. This study aimed to analyse the characteristics of each type of studies using natural language processing (NLP) methods. METHODS AND RESULTS: Literature related to VR in cardiovascular research was searched in PubMed between 2010 and 2022. The characteristics of studies were analysed based on their classification as type A or type B. Abstracts of the studies were used as corpus for text mining. A binary logistic regression model was trained to automatically categorize the abstracts into the two study types. Classification performance was evaluated by accuracy, precision, recall, F-1 score, and c-statistics of the receiver operator curve (ROC) analysis. In total, 171 articles met the inclusion criteria, where 120 (70.2%) were type A studies and 51 (29.8%) were type B studies. Type A studies had a higher proportion of case reports than type B studies (18.3% vs. 3.9%, P = 0.01). As for abstract classification, the binary logistic regression model yielded 88% accuracy and an area under the ROC of 0.98. The words 'training', '3d', and 'simulation' were the most powerful determinants of type A studies, while the words 'patients', 'anxiety', and 'rehabilitation' were more indicative for type B studies. CONCLUSIONS: NLP methods revealed the characteristics of the two types of VR-related research in cardiology.

DOI： 10.1093/ehjdh/ztad008

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INTRODUCTION: Coronavirus disease 2019 (COVID-19) symptoms are not fully understood in non-hospitalized individuals in Japan, and COVID-19 differentiation by symptoms alone remained challenging. Therefore, this study aimed to examine COVID-19 prediction from symptoms using real-world data in an outpatient fever clinic. METHODS: We compared the symptoms of COVID-19-positive and negative patients who visited the outpatient fever clinic at Imabari City Medical Association General Hospital and tested for COVID-19 from April 2021 to May 2022. This retrospective single-center study enrolled 2,693 consecutive patients. RESULTS: COVID-19-positive patients had a higher frequency of close contact with COVID-19-infected patients compared with COVID-19-negative patients. Moreover, patients with COVID-19 had high-grade fever at the clinic compared with patients without COVID-19. Additionally, the most common symptom in patients with COVID-19 was sore throat (67.3%), followed by cough (62.0%), which was approximately twice as common in patients without COVID-19. COVID-19 was more frequently identified in patients having a fever (≥37.5℃) with a sore throat, a cough, or both. The positive COVID-19 rate reached approximately half (45%) when three symptoms were present. CONCLUSION: These results suggested that COVID-19 prediction by combinations of simple symptoms and close contact with COVID-19-infected patients might be useful and lead to recommendations for testing of COVID-19 in symptomatic individuals.

DOI： 10.7759/cureus.36614

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DOI： 10.1161/CIRCIMAGING.122.014895

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PURPOSE: To evaluate left atrial (LA) function in patients with hypertrophic cardiomyopathy (HCM) by LA strain assessment using cardiac computed tomography (CT-derived LA strain). MATERIALS AND METHODS: This was a retrospective study of 34 patients with HCM and 31 non-HCM patients who underwent cardiac computed tomography (CT) using retrospective electrocardiogram-gated mode. CT images were reconstructed every 5% (0-95%) of the RR intervals. CT-derived LA strain (reservoir [LASr], conduit [LASc], and booster pump strain [LASp]) were semi-automatically analyzed using a dedicated workstation. We also measured the left atrial volume index (LAVI) and left ventricular longitudinal strain (LVLS) for the left atrial and ventricular functional parameters to assess the relationship with CT-derived LA strain. RESULTS: CT-derived LA strain significantly correlated with LAVI: r = - 0.69, p < 0.001 for LASr; r = - 0.70, p < 0.001 for LASp; and r = - 0.35, p = 0.004 for LASc. CT-derived LA strain also significantly correlated with LVLS: r = - 0.62, p < 0.001 for LASr; r = - 0.67, p < 0.001 for LASc; and r = - 0.42, p = 0.013 for LASp. CT-derived LA strain in patients with HCM was significantly lower than that in non-HCM patients: LASr (20.8 ± 7.6 vs. 31.7 ± 6.1%, p < 0.001); LASc (7.9 ± 3.4 vs. 14.2 ± 5.3%, p < 0.001); and LASp (12.8 ± 5.7 vs. 17.6 ± 4.3%, p < 0.001). Additionally, CT-derived LA strain showed high reproducibility; inter-observer correlation coefficients were 0.94, 0.90, and 0.89 for LASr, LASc, and LASp, respectively. CONCLUSION: CT-derived LA strain is feasible for quantitative assessment of left atrial function in patients with HCM.

DOI： 10.1007/s11604-023-01401-6

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

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RATIONALE AND OBJECTIVES: We aimed to evaluate the impact of four-dimensional noise reduction filtering using a four-dimensional similarity filter (4D-SF) on radiation dose reduction in dynamic myocardial computed tomography perfusion (CTP). MATERIALS AND METHODS: Forty-three patients who underwent dynamic myocardial CTP using 320-row computed tomography (CT) were included in the study. The original images were reconstructed using iterative reconstruction (IR). Three different CTP datasets with simulated noise, corresponding to 25%, 50%, and 75% reduction of the original dose (300 mA), were reconstructed using a combination of IR and 4D-SF. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were assessed, and CT-derived myocardial blood flow (CT-MBF) was quantified. The results were compared between the original and simulated images with radiation dose reduction. RESULTS: The median SNR (first quartile-third quartile) at the original, 25%-, 50%-, and 75%-dose reduced-simulated images with 4D-SF was 8.3 (6.5-10.2), 16.5 (11.9-21.7), 15.6 (11.0-20.1), and 12.8 (8.8-18.1) and that of CNR was 4.4 (3.2-5.8), 6.7 (4.6-10.3), 6.6 (4.3-10.1), and 5.5 (3.5-9.1), respectively. All the dose-reduced-simulated CTPs with 4D-SF had significantly higher image quality scores in SNR and CNR than the original ones (25%-, 50%-, and 75%-dose reduced vs. original images, p < 0.05, in each). The CT-MBF in 75%-dose reduced-simulated CTP was significantly lower than 25%-, 50%- dose-reduced-simulated, and original CTPs (vs. 75%-dose reduced-simulated images, p < 0.05, in each). CONCLUSION: 4D-SF has the potential to reduce the radiation dose associated with dynamic myocardial CTP imaging by half, without impairing the robustness of MBF quantification.

DOI： 10.3389/fradi.2023.1214521

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BACKGROUND: Although premature atrial contractions (PACs) just after catheter ablation (CA) for atrial fibrillation (AF) are common, their clinical significance is uncertain. This study aimed to evaluate whether the PAC burden after an initial CA for AF was associated with late recurrence. METHODS: We enrolled 346 patients with AF (median age, 65 years; 30% female; 57% with paroxysmal AF) who underwent an initial radiofrequency CA and a 24-h Holter monitoring the day after the procedure. PAC was defined as supraventricular complexes occurring ≥30% earlier than expected compared with a previous RR interval, and the number of PAC/24 h during post-procedural Holter monitoring was analyzed. RESULTS: AF recurred in 106 patients (31%) during a median follow-up of 19 months. These patients had significantly more PAC/24 h than those without (median [interquartile range], 891 [316-4,351] beats vs. 409 [162-1,303] beats; P<0.01). The number of PACs was independently associated with AF recurrence after adjustment for clinical parameters and left atrial (LA) enlargement. Receiver operating characteristic curve analysis revealed that 1,431 PAC/24 h was the optimal cut-off value for predicting AF recurrence. ???Adding the PAC/24 h to the prediction model with LA diameter appeared to correctly reclassify patients who were thought to be at high risk for AF recurrence into the low-risk group and vice versa. CONCLUSIONS: The number of PACs was an independent risk factor for AF recurrence. A 24-h Holter recording the day after an initial CA is a simple and beneficial tool for the risk stratification of AF recurrence. This article is protected by copyright. All rights reserved.

DOI： 10.1111/pace.14648

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Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a key mediator of inflammation and plays an important role in the pathogenesis of atherosclerosis. Conversely, LOX-1 deficiency has been shown to decrease inflammation and atherosclerosis, both of which have been proposed to contribute to abdominal aortic aneurysm (AAA) pathogenesis. However, the role of LOX-1 in AAA pathogenesis remains unknown. Here, we investigated the effects of Olr1 (which encodes LOX-1) deletion on angiotensin II (Ang II)-induced AAA in apolipoprotein E knockout (ApoE KO) mice to determine whether LOX-1 deficiency mitigates AAA development. To accomplish this, we used serial, non-invasive ultrasound assessment, which revealed that the incidence and expansion rate of AAA were similar regardless of Olr1 deletion. However, Olr1 deletion significantly increased severe AAAs, including ruptured AAAs resulting in death. Oil Red O staining of the harvested aortas showed that the extent of atheroma burden localized in aneurysmal lesions did not differ between LOX-1-deficient and control mice, suggesting that Olr1 deletion did not decrease atheroma burden in the aneurysmal wall. Further histopathological analysis revealed that aneurysmal lesions in LOX-1-deficient mice had fewer fibroblasts and myofibroblasts, as well as thinner adventitial collagen, although the degree of elastin fragmentation or disruption was similar between LOX-1-deficient and control mice. An in vitro study confirmed that the proliferation of adventitial fibroblasts collected from LOX-1-deficient mice was significantly attenuated despite Ang II stimulation. In conclusion, Olr1 deletion may not mitigate aneurysm development but rather increases the vulnerability of rupture by suppressing adventitial fibroblast proliferation and collagen synthesis.

DOI： 10.1038/s41440-022-01093-x

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/ehjdh/ztac052

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Pulmonary artery intimal sarcomas (PAIS) are often misdiagnosed as pulmonary embolisms (PE) as their clinical findings and imaging findings are similar. However, given the clinical outcome of both diseases is different in its prognosis, accurate and rapid diagnosis is mandatory. This is a case report of a histologically-proven PAIS which was initially treated as a PE. The color-coded iodine map using dual-energy computed tomography (dual-energy CT iodine map) well reflected the distribution of the tumor consistent with 18fluoro-2-deoxyglucose-uptake region using positron emission tomography/CT. This case demonstrates the potential of using dual-energy CT iodine map to differentiate PAIS from PE. Learning objective: Use of a dual-energy computed tomography iodine map to visualize a pulmonary artery intimal sarcoma may provide useful diagnostic information.

DOI： 10.1016/j.jccase.2022.03.011

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BACKGROUND: Diagnostic guidelines for isolated cardiac sarcoidosis (iCS) were first proposed in 2016, but there are few reports on the imaging and prognosis of iCS. This study aimed to evaluate the use of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging in predicting iCS prognosis. METHODS AND RESULTS: We retrospectively reviewed the clinical and imaging data of 306 consecutive patients with suspected CS who underwent FDG PET/CT with a dedicated preparation protocol and included 82 patients (55 with systemic sarcoidosis including cardiac involvement [sCS], 27 with iCS) in the study. We compared the FDG PET/CT findings between the two groups. We examined the relationship between the CS type and the rate of adverse cardiac events. The iCS group had a significantly lower target-to-background ratio than the sCS group (P = 0.0010). The event-free survival rate was significantly lower in the iCS group than the sCS group (log-rank test, P < 0.0001). iCS was identified as an independent prognostic factor for adverse events (hazard ratio 3.82, P = 0.0059). CONCLUSION: iCS was an independent prognostic factor for adverse cardiac events in patients with CS. The clinical diagnosis of iCS based on FDG PET/CT and new guidelines may be important.

DOI： 10.1007/s12350-022-03034-0

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

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In extracardiac Fontan, an epicardial pacemaker implantation has many limitations, especially given that it is highly invasive and a high-risk procedure due to repeat thoracotomy. Herein we illustrate a case with the possibility of transvenous pacing in extracardiac Fontan being less invasive and lower risk transvenous dual-chamber pacemaker implantation by electrophysiological assessment. <Learning objective: Transvenous pacemaker implantation via left superior vena cava may be a viable alternative to epicardial pacing with a minimally invasive procedure in patients with extracardiac Fontan.>.

DOI： 10.1016/j.jccase.2022.01.010

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DOI： 10.1253/circj.CJ-21-0880

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Language：Japanese   Publisher：(NPO)日本医工学治療学会  

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DOI： 10.1253/circj.CJ-21-1001

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DOI： 10.1253/circj.CJ-21-0946

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DOI： 10.1253/circj.CJ-22-0055

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We evaluated the feasibility of myocardial perfusion ratio to the aorta (MPR) in static computed tomography perfusion (CTP) for detecting myocardial perfusion abnormalities assessed by single-photon emission computed tomography (SPECT). Twenty-five patients with suspected coronary artery disease who underwent dynamic CTP and SPECT were retrospectively evaluated. CTP images scanned at a sub-optimal phase for detecting myocardial perfusion abnormalities were selected from dynamic CTP images and used as static CTP images in the present study. The diagnostic accuracy of MPR derived from static CTP was compared to those of visual assessment and conventional quantitative parameters such as myocardial CT attenuation (HU) and transmural perfusion ratio (TPR). The area under the curve of MPR (0.84; 95% confidence interval [CI], 0.76-0.90) was significantly higher than those of myocardial CT attenuation (0.73; 95% CI, 0.65-0.79) and TPR (0.76; 95% CI, 0.67-0.83) (p &lt; 0.05). Sensitivity and specificity were 67% (95% CI, 54-77%) and 90% (95% CI, 86-92%) for visual assessment, 51% (95% CI, 39-63%) and 86% (95% CI, 82-89%) for myocardial CT attenuation, 63% (95% CI, 51-74%) and 84% (95% CI, 80-88%) for TPR, and 78% (95% CI, 66-86%) and 84% (95% CI, 80-88%) for MPR, respectively. MPR showed higher diagnostic accuracy for detecting myocardial perfusion abnormality compared with myocardial CT attenuation and TPR.

DOI： 10.3390/jcm11071816

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BACKGROUND: Tolvaptan (TLV) is effective for acute heart failure (HF) with congestion, but its long-term administration in patients with chronic HF (CHF) remains controversial. Moreover, the cost-effectiveness of TLV for CHF treatment has not yet been investigated. Thus, we sought to validate the cost-effectiveness of TLV for CHF treatment in Japan. METHODS: A Markov model was developed to compare total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) between long-term TLV strategy and the standard strategy using furosemide for CHF. The target population included 75-year-old patients with CHF. The effectiveness of the TLV strategy for CHF treatment was determined based on a systematic review and meta-analysis. We used a 10-year horizon, with sensitivity analyses for significant variables and a scenario analysis for patients with CHF receiving high-dose furosemide (≥60 mg per day). RESULTS: In the base case analysis, the total cost of the long-term TLV strategy was higher than that of the standard strategy (\3,243,779 vs. \1,179,964). The total QALYs of the long-term TLV strategy were lower than those of the standard strategy (4.52 vs 4.59). Thus, a standard TLV prescription for CHF treatment has no clinical or economic benefit. In the scenario analysis (i.e. in patients with CHF receiving high-dose furosemide), the long-term TLV strategy was more effective (total QALYs, 5.10 vs. 4.41) but more expensive (total costs, \3,540,558 vs. \1,272,208) than the standard strategy. The ICER of the TLV strategy against the standard strategy (\3,289,579/QALY) was below the willingness-to-pay of \5,000,000, which suggests that the long-term TLV strategy is cost-effective relative to the standard strategy in patients with CHF receiving high-dose furosemide. CONCLUSIONS: Long-term TLV administration did not provide a clear benefit for all patients with CHF. However, this treatment strategy may be a cost-effective therapeutic option for patients who require high-dose furosemide.

DOI： 10.1016/j.jjcc.2021.10.026

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The left and right atria serve as buffer chambers to control the flow of venous blood for ventricular filling. If an atrium is absent, blood does not flow effectively into the ventricle, leading to venous blood retention and low cardiac output. The importance of atrial function has become increasingly recognized, because left atrial (LA) function contributes to cardiac performance, and loss of LA function is associated with heart failure. LA volume change has been used for LA function assessment in experimental and clinical studies. In conjunction with LA pressure, the LA pressure-volume relationship provides a better understanding of LA mechanics. LA strain measurement by speckle tracking echocardiography was introduced to evaluate three components of LA function as a (booster) pump, reservoir and conduit. Furthermore, increasing evidence supports the theory that LA reservoir strain has prognostic utility in various cardiac diseases. In this review, we summarize LA contribution to maintain cardiac performance by evaluating LA function with echocardiography according to our experiences and previous reports. Furthermore, we discuss LA dysfunction in challenging cardiac diseases of cardiac amyloidosis and adult congenital heart disease.

DOI： 10.3390/jcdd9030068

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BACKGROUND: This study aimed to quantitatively evaluate myocardial perfusion single-photon emission computed tomography (SPECT) using an original analysis tool in the compartment model for detecting regional significant coronary artery disease (CAD).Methods and Results:This study analyzed 41 patients (median age, 76 years) with suspected or known CAD who underwent both dynamic SPECT using 99 mTc-tetrofosmin and invasive coronary angiography. The quantitative analysis was performed using a single-tissue compartment model to evaluate the diagnostic performance of the myocardial flow reserve (MFR) for regional significant CAD, excluding infarcted territories. In the regional analysis, 114 vessels were assessed, of which 31 were diagnosed as significant coronary lesions (≥70% stenosis and/or fraction flow reserve ≤0.8). The MFR of regional significant CAD was significantly lower than that of non-significant CAD (1.11 [0.97-1.31] vs. 1.74 [1.30-2.27]; P<0.001). In the receiver operating characteristic curve analysis, the MFR displayed an area under the curve (AUC) of 0.81. While analyzing each coronary artery territory, the diagnostic performance of the MFR value in the left anterior descending (LAD) artery territory was found to be significantly higher than that found in qualitative assessment (AUC: 0.84 vs. 0.61). CONCLUSIONS: A quantitative analysis of dynamic SPECT data facilitated detecting regional CAD. For the LAD artery, the MFR displayed a higher diagnostic performance than the qualitative assessment of conventional myocardial perfusion SPECT.

DOI： 10.1253/circj.CJ-21-0966

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The slow flow phenomenon is a critical complication during percutaneous coronary intervention (PCI) that leads to poor outcomes. We aimed to evaluate the mechanisms underlying the slow flow phenomenon using intravascular ultrasound (IVUS). We retrospectively analyzed IVUS data from 62 lesions in 58 consecutive patients who experienced the slow flow phenomenon during PCI. IVUS was performed immediately after the development of the slow flow phenomenon to assess its cause. No IVUS-based evidence of mechanical obstruction was categorized as distal embolization. Distal embolization was observed in 46 lesions (74%). The slow flow phenomenon occurred in all these lesions after stent implantation. In addition to distal embolization, three different mechanisms underlying the induction of the slow flow phenomenon due to mechanical obstructions (16 lesions, 26%) were detected on IVUS, namely, medial dissection/hematoma (6 lesions), intimal flap (6 lesions), and thrombus obstruction (4 lesions). Most mechanical obstructions (13 lesions, 81%) could not be identified by angiography alone. In 15/16 lesions (94%) with mechanical obstruction, deteriorated flow improved immediately after balloon dilatation or bail-out stent implantation, although intracoronary vasodilator administration could not reestablish coronary flow. The frequency of mechanical obstruction as the cause of the slow flow phenomenon was relatively high. Given the difficulty in angiographical differentiation, IVUS-guided management of slow flow may be a useful strategy.

DOI： 10.1097/MCA.0000000000001126

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Suture-based transverse aortic constriction (TAC) in mice is one of the most frequently used experimental models for cardiac pressure overload-induced heart failure. However, the incidence of heart failure in the conventional TAC depends on the operator's skill. To optimize and simplify this method, we proposed O-ring-induced transverse aortic constriction (OTAC) in mice. C57BL/6J mice were subjected to OTAC, in which an o-ring was applied to the transverse aorta (between the brachiocephalic artery and the left common carotid artery) and tied with a triple knot. We used different inner diameters of o-rings were 0.50 and 0.45 mm. Pressure overload by OTAC promoted left ventricular (LV) hypertrophy. OTAC also increased lung weight, indicating severe pulmonary congestion. Echocardiographic findings revealed that both OTAC groups developed LV hypertrophy within one week after the procedure and gradually reduced LV fractional shortening. In addition, significant elevations in gene expression related to heart failure, LV hypertrophy, and LV fibrosis were observed in the LV of OTAC mice. We demonstrated the OTAC method, which is a simple and effective cardiac pressure overload method in mice. This method will efficiently help us understand heart failure (HF) mechanisms with reduced LV ejection fraction (HFrEF) and cardiac hypertrophy.

DOI： 10.1038/s41598-021-04096-9

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Heart failure has high morbidity and mortality in the developed countries. Autophagy is important for the quality control of proteins and organelles in the heart. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) has been identified as a potent negative regulator of autophagy and endolysosomal trafficking. The aim of this study was to investigate the in vivo role of Rubicon-mediated autophagy and endosomal trafficking in the heart. We generated cardiomyocyte-specific Rubicon-deficient mice and subjected the mice to pressure overload by means of transverse aortic constriction. Rubicon-deficient mice showed heart failure with left ventricular dilatation, systolic dysfunction and lung congestion one week after pressure overload. While autophagic activity was unchanged, the protein amount of beta-1 adrenergic receptor was decreased in the pressure-overloaded Rubicon-deficient hearts. The increases in heart rate and systolic function by beta-1 adrenergic stimulation were significantly attenuated in pressure-overloaded Rubicon-deficient hearts. In isolated rat neonatal cardiomyocytes, the downregulation of the receptor by beta-1 adrenergic agonist was accelerated by knockdown of Rubicon through the inhibition of recycling of the receptor. Taken together, Rubicon protects the heart from pressure overload. Rubicon maintains the intracellular recycling of beta-1 adrenergic receptor, which might contribute to its cardioprotective effect.

DOI： 10.1038/s41598-021-03920-6

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

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Perioperative management of pregnant women with heart failure is difficult. Management of anesthesia in pregnant women is especially difficult because all of the currently available choices present challenges. We report a patient with peripartum cardiomyopathy (PPCM) who required an emergent cesarean section and discuss the possible tactics for managing anesthesia. A 40-year-old primipara with severe cardiac and respiratory failure required an emergent cesarean section at 39+1 gestational weeks. Her left ventricular ejection fraction was between 10% and 15%, and she had orthopnea. General anesthesia was planned after inserting sheaths for percutaneous cardiopulmonary support from the femoral artery and vein. However, when the patient was asked to lie down on the operation bed, she panicked and resisted because of labor pain and dyspnea. Therefore, anesthesia was induced instead of the initial plan. Finally, we successfully managed the anesthesia and delivered the newborn. There are no alternatives to general anesthesia in patients with PPCM presenting with orthopnea. Anesthesia induction in the supine position is impossible in such patients owing to dyspnea. Anesthesia should be started with light sedation in the sitting position, and ketamine or low-dose remifentanil may be an option to maintain maternal hemodynamics and prevent neonatal asphyxia.

DOI： 10.1177/03000605211063077

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DOI： 10.1093/ehjcr/ytab439

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DOI： 10.1093/ehjcr/ytab414

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BACKGROUND: Left atrial volume index (LAVI) of >34 mL/m2 is the cutoff value for identifying an enlarged left atrium. The definition of left atrial (LA) reverse remodeling after atrial fibrillation (AF) ablation is undetermined. We hypothesized that patients with LA dilatation who achieve normal LA volume (LAVI<34 mL/m2) after AF ablation have better long-term outcomes than those who do not. Furthermore, we investigated whether patients with a normal LA volume can also achieve normal LA function with AF ablation. METHODS: We enrolled 140 AF patients with baseline LAVI of ≥34 mL/m2, without AF recurrence for 1 year after the initial AF ablation. We acquired conventional and speckle-tracking echocardiographic parameters within 24 hour and at 1 year after the procedure. To define the normal range of LA function, age- and sex-matched controls without a history of AF were also enrolled. RESULTS: After restoration of sinus rhythm, LA structural and functional parameters significantly improved, and 75 patients (54%) had normal LA volume. During a median follow-up of 44 (31-61) months, 32 patients (23%) experienced a late recurrence of AF (AF recurrence >1 year). Patients who achieved normal LA volume after AF ablation had fewer late recurrences than those who did not (P < .01). However, LA abnormalities, especially LA dysfunction, persisted in AF patients even when the LA volume was normalized compared with controls. CONCLUSION: Patients who achieved normal LA volume had better long-term outcomes of AF ablation than those who did not; however, LA abnormalities persisted even after successful ablation of AF.

DOI： 10.1002/joa3.12624

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BACKGROUND Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), are associated with pulmonary hypertension (PH) and malignant lymphomas. Although the underlying mechanisms have not been completely clarified, it has been suggested that the Janus kinase 2 (JAK2) mutation, which is frequently identified in PV, can be involved in the development and/or progression of these distinct diseases in patients with MPNs. However, no reports have described the coexistence of PH and malignant lymphoma in patients with MPNs. CASE REPORT A 79-year-old man being treated for PV for 27 years and PH for 5 years was hospitalized due to severe dyspnea at rest. His soluble interleukin-2 receptor levels gradually increased and the chest computed tomography showed remarkable progression of the lung lesions and an enlargement of the mediastinal and axillary lymph nodes. A lymph node biopsy was performed and the patient was diagnosed with diffuse large B-cell lymphoma (DLBCL). Owing to his poor condition, chemotherapy was not initiated, and he died on the 89th day of hospitalization. The pathological autopsy revealed the destruction of alveolar structures with neoplastic space-occupying lesions of DLBCL. Multifactorial features of PH associated with MPNs, including the intimal thickening of pulmonary arteries accompanied by megakaryocytes and obstructed pulmonary arteries with organized thrombi in the lung tissue specimens, were observed. We found a JAK2 mutation based on a genetic analysis of the patient's bone marrow. CONCLUSIONS We present the rare case of a patient who had PV with a JAK2 mutation, which coexisted with PH and DLBCL, and he developed severe refractory respiratory failure.

DOI： 10.12659/AJCR.932956

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BACKGROUND: Cardiac amyloidosis (CA) mimics left ventricular hypertrophy (LVH). It is treatable, but its prognosis is poor. A simple screening tool for CA would be valuable. CA is more precisely diagnosed with echocardiographic deformation parameters (e.g., relative apical sparing pattern [RASP]) than with conventional parameters. We aimed to 1) investigate incremental benefits of echocardiographic deformation parameters over established parameters for CA screening; 2) determine the resultant risk score for CA screening; and 3) externally validate the score in LVH patients. METHODS: We retrospectively studied 295 consecutive non-ischemic LVH patients who underwent detailed diagnostic tests. CA was diagnosed with biopsy or 99mTc-PYP scintigraphy. The base model comprised age (≥65 years [men], ≥70 years [women]), low voltage on the electrocardiogram, and posterior wall thickness ≥ 14 mm in reference to the literature. The incremental benefit of each binarized echocardiographic parameter over the base model was assessed using receiver operating characteristic curve analysis and comparisons of the area under the curve (AUC). RESULTS: Fifty-four (18%) patients had CA. RASP showed the most incremental benefit for CA screening over the base model. After conducting multiple logistic regression analysis for CA screening using four variables (RASP and base model components), a score was determined (range, 0-4 points). The score demonstrated adequate discrimination ability for CA (AUC = 0.86). This result was confirmed in another validation cohort (178 patients, AUC = 0.88). CONCLUSIONS: We developed a score incorporating RASP for CA screening. This score is potentially useful in the risk stratification and management of LVH patients.

DOI： 10.1186/s12947-021-00258-x

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DOI： 10.1253/circj.CJ-21-0366

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press ({OUP})  

DOI： 10.1093/ehjdh/ztab064

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Computed tomography (CT)-derived three-dimensional maximum principal strain (MP-strain) can provide incremental value to coronary CT angiography for cardiac dysfunction assessment with high diagnostic performance in patients with myocardial infarction. Global longitudinal strain (GLS) measured using two-dimensional speckle tracking echocardiography (2D-STE) is more sensitive than left ventricular ejection fraction (LVEF) for detecting early myocardial dysfunction. We aimed to compare CT-derived MP-strain with each of 2D-STE-derived strains (i.e., longitudinal, circumferential, and radial strains), and identify the major determinants of CT-derived MP-strain among 2D-STE-derived strains. We studied 51 patients who underwent cardiac CT and echocardiography. CT images were reconstructed at every 5% (0-95%) of the RR interval. A dedicated workstation was used to analyze CT-derived MP-strain on the 16-segment model. We calculated CT-derived global MP-strain with all the 16 segments on a per patient basis. Pearson's test was used to assess correlations between CT-derived MP-strain and STE-strain at global and segmental levels. The intra-class correlation coefficient for interobserver agreement for CT-derived global MP-strain was 0.98 (95% confidence interval 0.96-0.99). The low-CT-derived global MP-strain group (≤ 0.43) had more patients with LV dysfunction than the high-CT-derived global MP-strain group (> 0.43). CT-derived global MP-strain was associated with STE-GLS (r = 0.738, P < 0.001), global circumferential strain (r = 0.646, P < 0.001), and global radial strain (r = 0.432, P = 0.001). In multivariate analysis, STE-GLS had the strongest association to CT-derived global MP-strain among three directional STE-strains and LVEF by echocardiography (standardized coefficient =  - 0.527, P < 0.001). STE-GLS is a major determinant of CT-derived global MP-strain. CT-derived MP-strain may enhance the value of coronary CT angiography by adding functional information to CT-derived LVEF.

DOI： 10.1007/s00380-021-01901-3

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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DOI： 10.1093/ehjci/jeab102

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AIMS: Cardiac amyloidosis (CA) is an infiltrative myocardial disease that occasionally mimics hypertrophic cardiomyopathy (HCM). The aim of this study is to investigate the discriminatory ability of visual assessment of left atrial (LA) function between CA and HCM on echocardiography. METHODS AND RESULTS: In total, 93 patients with cardiac magnetic resonance imaging (CMR)-confirmed HCM and 34 with cardiac biopsy-confirmed CA were retrospectively assessed. LA dilatation was assessed via echocardiography in an apical four-chamber view. Visual assessment was performed to identify LA dilatation grade (preserved = 1, abnormal = 2, and restricted = 3) based on the extent of outward expansion in the LA reservoir phase. Regarding the reproducibility of visually assessing LA dilatation grade, the kappa values between intra- and inter-observer measurements were 0.82 and 0.70, respectively. Of 127 participants, 57 (45%), 42 (33%), and 28 (22%) presented with LA dilatation Grades 1, 2, and 3, respectively. All 57 patients with preserved LA dilatation (Grade 1) had HCM, and 20 of 28 patients (71%) with restricted LA dilatation (Grade 3) presented with CA. Patients with CA had a higher LA dilatation grade than those with HCM (P < 0.01). LA emptying fraction and reservoir strain were also quantitatively evaluated. The area under the curves of LA dilatation grade (0.88) and LA emptying fraction (0.88) for differentiation of these two diseases were higher than that of LA reservoir strain (0.73) (P < 0.01, respectively). During follow-up, nine patients with HCM and 16 with CA experienced cardiac event (cardiac death or hospitalization due to heart failure). In Kaplan-Meier analysis including both groups of HCM and CA, the incidence of cardiac events was higher in patients with restricted LA dilatation than in those with preserved or abnormal LA dilatation (log-rank test, P < 0.01). CONCLUSIONS: Restricted LA dilatation is an indicator for the diagnosis of CA. Further, visual assessment of abnormal LA motion may facilitate diagnosis in patients with CA and high-risk patients with HCM.

DOI： 10.1002/ehf2.13442

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DOI： 10.1253/circrep.CR-21-0052

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BACKGROUND: The progression of chronic kidney disease (CKD) depends on the extent of fibrosis in the kidneys; however, a renal biopsy is necessary to evaluate the severity of renal fibrosis. Real-time tissue elastography (RTE), which measures heartbeat-induced tissue displacement, can assess the elasticity of organs. Here, we aimed to investigate the correlation between renal elasticity and the extent of fibrosis in renal biopsy samples. METHODS: We investigated 29 consecutive patients who underwent a renal biopsy at Ehime University Hospital from February 2018 to August 2019. Renal fibrosis was categorized into three grades, mild (< 25%), moderate (25-50%), and severe (> 50%), based on the total affected area within the biopsy sample. The association between renal elasticity assessed by RTE and the grade of renal fibrosis was evaluated, and a receiver operating characteristic curve was used to distinguish the severity of renal fibrosis. RESULTS: The mean age and estimated glomerular filtration rate (eGFR) were 58.8 years and 55.2 mL/min/1.73 m2, respectively. The median urine protein-to-creatinine ratio was 1.24 g/gCr. The mean renal elasticity of mild, moderate, and severe renal fibrosis was 3.40, 3.98, and 4.77, respectively. Renal elasticity of native kidneys was significantly positively correlated with the grade of renal fibrosis (ρ = 0.529, P = 0.003). At the cutoff point of 3.81, the area under the curve, sensitivity, and specificity were 0.778, 68.4%, and 81.8%, respectively. CONCLUSION: Real-time tissue elastography is a promising, non-invasive method for assessing renal fibrosis in patients with CKD.

DOI： 10.1007/s10157-021-02063-2

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

The management of systemic artery aneurysms secondary to Kawasaki disease (KD) in adults remains a therapeutic challenge. KD guidelines recommend the use of anticoagulation therapy with warfarin in addition to antiplatelet therapy when a giant coronary aneurysm or a history of thrombosis is documented. However, long-term use of warfarin presents several concerns. This case reports acute thrombotic occlusion due to the giant arterial aneurysm in an adult KD. A surgical resection of the aneurysm was performed because of recurrent thrombotic events, despite anticoagulant therapy with warfarin. Pathological examinations revealed a layered thrombus with inflammation in the aneurysm and Factor Xa expression mainly in newly formed thrombus. This study provides an insight into the anticoagulation therapy for cardiovascular sequelae after KD. <Learning objective: This study, along with pathological evidence, illustrates that Factor Xa might contribute to thrombotic events after Kawasaki disease.>.

DOI： 10.1016/j.jccase.2020.11.005

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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

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DOI： 10.1161/CIRCHEARTFAILURE.120.007571

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In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

DOI： 10.1080/15548627.2020.1797280

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Objective Coronary plaques with low attenuation on computed tomography (CT) angiography may indicate vulnerable plaques. However, plaque CT attenuation is reported to be significantly affected by intracoronary attenuation. Recently, the diluted-contrast injection protocol was established to facilitate more uniform intracoronary attenuation than can be achieved with the generally used body-weight-adjusted protocol. We validated the relationship between low-attenuation plaque on CT and lipid-rich plaque using integrated backscatter-intravascular ultrasound (IB-IVUS) as the standard reference. Methods Plaques were divided into tertiles (T1, T2, and T3) according to the plaque CT attenuation, calculated as the average of five intra-plaque regions of interest, and compared with the plaque characteristics noted on IB-IVUS. Patients Patients who underwent both CT angiography using a diluted-contrast injection protocol and IB-IVUS were retrospectively analyzed. Results Thirty-nine plaques in 32 patients were analyzed by CT angiography and IB-IVUS. The median plaque CT attenuation (Hounsfield units) of each tertile was 30 (T1), 48 (T2), and 68 (T3). Although no significant difference was noted in conventional quantitative IVUS parameters (e.g. plaque burden), the T1 with lowest plaque CT attenuation had the highest percentage lipid area by IB-IVUS [75.1% (T1), 57.8% (T2), and 50.8% (T3), respectively, p<0.01]. Furthermore, the plaque CT attenuation had a significant negative correlation with the percentage lipid area (r=-0.59, p<0.01). Conclusion CT angiography-based plaque characterization using a diluted-contrast injection protocol may aid in the quantitative detection of lipid-rich plaque.

DOI： 10.2169/internalmedicine.6683-20

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/eurheartj/ehaa915

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Authorship：Last author   Language：English  

The Impella (Abiomed, Danvers, MA, USA) is a novel percutaneous heart pump device for left ventricular (LV) assistance; however, LV thrombus is a notable contraindication for this device. Contrast computed tomography assessment is useful for detecting LV thrombus and preventing thromboembolism in patients recommended for Impella use. <Learning objective: The Impella (Abiomed, Danvers, MA, USA) is a heart pump device which aspirates blood from a left ventricular (LV) cavity and ejects it into an ascending aorta. Therefore, LV thrombus should be explored before the Impella insertion to prevent systemic embolism. Generally, echocardiography is the first choice to detect LV thrombus. Given limited diagnostic sensitivity for detecting LV thrombus in echocardiography, contrast computed tomography might be a useful strategy for the patient targeting Impella insertion.>.

DOI： 10.1016/j.jccase.2020.07.016

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OBJECTIVES: We investigated the medical or mechanical therapy, and the present knowledge of Japanese cardiologists about aborted sudden cardiac death (ASCD) due to coronary spasm. METHODS: A questionnaire was developed regarding the number of cases of ASCD, implantable cardioverter-defibrillator (ICD), and medical therapy in ASCD patients due to coronary spasm. The questionnaire was sent to the Japanese general institutions at random in 204 cardiology hospitals. RESULTS: The completed surveys were returned from 34 hospitals, giving a response rate of 16.7%. All SCD during the 5 years was observed in 5726 patients. SCD possibly due to coronary spasm was found in 808 patients (14.0%) and ASCD due to coronary spasm was observed in 169 patients (20.9%). In 169 patients with ASCD due to coronary spasm, one or two coronary vasodilators was administered in two-thirds of patients [113 patients (66.9%)], while more than 3 coronary vasodilators were found in 56 patients (33.1%). ICD was implanted in 117 patients with ASCD due to coronary spasm among these periods including 35 cases with subcutaneous ICD. Majority of cause of ASCD was ventricular fibrillation, whereas pulseless electrical activity was observed in 18 patients and complete atrioventricular block was recognized in 7 patients. Mean coronary vasodilator number in ASCD patients with ICD was significantly lower than that in those without ICD (2.1 ± 0.9 vs. 2.6 ± 1.0, p < 0.001). Although 16 institutions thought that the spasm provocation tests under the medications had some clinical usefulness of suppressing the next fatal arrhythmias, spasm provocation tests under the medication were performed in just 4 institutions. CONCLUSIONS: In the real world, there was no fundamental strategy for patients with ASCD due to coronary spasm. Each institution has each strategy for these patients. Cardiologists should have the same strategy and the same knowledge about ASCD patients due to coronary spasm in the future.

DOI： 10.1007/s00380-020-01644-7

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

DOI： 10.15252/embr.202050949

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.15252/embr.202050949

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

DOI： 10.1016/j.ijmedinf.2020.104274

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Language：Japanese   Publisher：(公社)日本超音波医学会  

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DOI： 10.1161/CIRCIMAGING.120.010740

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OBJECTIVES: This study evaluated the characteristics of left ventricular maximum principal strain (LV-MPS) using cardiac CT in subjects with normal LV function. METHODS: Of 973 subjects who underwent retrospective electrocardiogram-gated cardiac CT using a third-generation dual-source CT without beta-blocker administration, 31 subjects with preserved LV ejection fraction ≥ 55% assessed by echocardiography without coronary artery stenosis and cardiac pathology were retrospectively identified. CT images were reconstructed every 5% (0-95%) of the RR interval. LV-MPS and the time to peak (TTP) were analyzed using the 16-segment model and compared among three levels (base, mid, and apex) and among four regions (anterior, septum, inferior, and lateral) using the Steel-Dwass test. The intra- and inter-observer reproducibilities for LV-MPS were calculated using intraclass correlation coefficients (ICCs). RESULTS: The intra- and inter-observer ICCs (95% confidence interval) for peak LV-MPS were 0.96 (0.94-0.97) and 0.94 (0.92-0.96), respectively. The global peak LV-MPS (median, inter-quantile range) was 0.59 (0.55-0.72). The regional LV-MPS significantly increased in the order of the basal (0.54, 0.49-0.59), mid-LV (0.57, 0.53-0.65), and apex (0.68, 0.60-0.84) (p < 0.05, in each), and was significantly higher in the lateral wall (0.66, 0.60-0.77), while that in the septal region (0.47, 0.44-0.54) was the lowest among the four LV regions (all p < 0.05). No significant difference in TTP was seen among the myocardial levels and regions. CONCLUSION: CT-derived LV-MPS is reproducible and quantitatively represents synchronized myocardial contraction with heterogeneous values in subjects with normal LV function. KEY POINTS: • CT-derived left ventricular maximum principal strain analysis allows highly reproducible quantitative assessments of left ventricular myocardial contraction. • In subjects with normal cardiac function, the peak value of CT-derived left ventricular maximum principal strain is the highest in the apical level and in the lateral wall and the lowest in the septum. • The regional peak left ventricular maximum principal strain shows intra-ventricular heterogeneity on a per-patient basis, but myocardial contraction is globally synchronized in subjects with normal cardiac function seen on cardiac CT.

DOI： 10.1007/s00330-020-07001-6

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DOI： 10.1016/j.jcin.2020.08.016

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

DOI： 10.1016/j.ijcha.2020.100587

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/rcr2.643

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

<title>Abstract</title>
The purpose of this study was to evaluate the feasibility of the stenosis-related quantitative perfusion ratio (QPR) for detecting hemodynamically significant coronary artery disease (CAD). Twenty-seven patients were retrospectively enrolled. All patients underwent dynamic myocardial computed tomography perfusion (CTP) and coronary computed tomography angiography (CTA) before invasive coronary angiography (ICA) measuring the fractional flow reserve (FFR). Coronary lesions with FFR ≤ 0.8 were defined as hemodynamically significant CAD. The myocardial blood flow (MBF) was calculated using dynamic CTP data, and CT-QPR was calculated as the CT-MBF relative to the reference CT-MBF. The stenosis-related CT-MBF and QPR were calculated using Voronoi diagram-based myocardial segmentation from coronary CTA data. The relationships between FFR and stenosis-related CT-MBF or QPR and the diagnostic performance of the stenosis-related CT-MBF and QPR were evaluated. Of 81 vessels, FFR was measured in 39 vessels, and 20 vessels (51%) in 15 patients were diagnosed as hemodynamically significant CAD. The stenosis-related CT-QPR showed better correlation (<italic>r</italic> = 0.70, <italic>p </italic>&lt; 0.05) than CT-MBF (<italic>r</italic> = 0.56, <italic>p</italic> &lt; 0.05). Sensitivity and specificity for detecting hemodynamically significant CAD were 95% and 58% for CT-MBF, and 95% and 90% for CT-QPR, respectively. The area under the receiver operating characteristic curve for the CT-QPR was significantly higher than that for the CT-MBF (0.94 vs. 0.79; <italic>p</italic> &lt; 0.05). The stenosis-related CT-QPR derived from dynamic myocardial CTP and coronary CTA showed a better correlation with FFR and a higher diagnostic performance for detecting hemodynamically significant CAD than the stenosis-related CT-MBF.

DOI： 10.1007/s12928-019-00627-4

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BACKGROUND: Cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) is a valuable technique for detecting myocardial disorders and fibrosis. However, we sometimes observe a linear, mid-wall high intensity signal in the basal septum in the short axis view, which often presents diagnostic difficulties in the clinical setting. The purpose of this study was to compare the linear, mid-wall high intensity in the basal septum identified by LGE with the anterior septal perforator arteries identified by coronary computed tomography angiography (CorCTA). METHODS: We retrospectively selected 148 patients who underwent both CorCTA and CMR LGE within 1 year. In the interpretation of LGE, we defined a positive linear high intensity (LHI+) as follows: ① LHI in the basal septum and ② observable for 1.5 cm or more. All other patients were defined as a negative LHI (LHI-). In LHI+ patients, we assessed the correlation between the LHI length and the septal perforator artery length on CorCTA. We also compared the length of the septal perforator artery on CorCTA between LHI+ patients and LHI- patients. RESULTS: A population of 111 patients were used for further analysis. Among these , there were 55 LHI+ patients and 56 LHI- patients. In LHI+ patients, linear regression analysis revealed that there was a good agreement between LGE LHI and septal perforator arteries by CorCTA in terms of length measurements. The measured length of the anterior septal perforator arteries was significantly shorter in LHI- patients than in LHI+ patients (10 ± 8 mm vs. 21 ± 8 mm; P < 0.05). CONCLUSIONS: The LHI observed in the basal septum on short axis LGE may reflect contrast enhancement of the anterior septal perforator arteries. It is important to interpret this septal LHI against knowledge of anatomic structure, to avoid misinterpretations of LGE and prevent misdiagnosis.

DOI： 10.1186/s12968-020-00665-5

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AIMS: Traditional criteria for heart transplantation by cardiopulmonary exercise testing (CPX) include peak oxygen uptake (VO2 ) < 14 mL/kg/min. Reaching a sufficient exercise load is challenging for patients with refractory heart failure (HF) because of their exercise intolerance. Recently, a substantial impact of right ventricular (RV) dysfunction was highlighted on urgent heart transplantation and mortality. This study aims to investigate the impact of RV contractile reserve, assessed by low-load exercise stress echocardiography (ESE), on exercise intolerance defined as peak VO2  < 14 mL/kg/min, in patients with HF. METHODS AND RESULTS: We prospectively examined 67 consecutive patients hospitalized for HF who underwent ESE and CPX under a stabilized HF condition. Although low-load ESE was defined as 25 W load exercise, an increment in RV systolic (s') velocity was regarded as the preservation of RV contractile reserve. All patients completed low-load ESE. During low-load ESE, the variation in RV s' velocity significantly correlated with peak VO2 (r = 0.787, P < 0.001). The change in RV s' velocity during low-load ESE accurately identified patients with peak VO2  < 14 mL/kg/min (area under the curve, 0.95; sensitivity, 92%; specificity, 85%). The intraclass correlation coefficient for intra-observer and inter-observer agreement for the change in RV s' velocity was 0.96 (95% confidence interval, 0.88-0.99, P < 0.001) and 0.86 (95% confidence interval, 0.64-0.95, P < 0.001), respectively. The RV-to-pulmonary circulation (PC) coupling, which was assessed by the slope of the relationship between RV s' velocity and pulmonary artery systolic pressure at rest and low-load exercise, was worse in the low-peak VO2 group (<14 mL/kg/min) than the preserved-peak VO2 group (≥14 mL/kg/min). CONCLUSIONS: The change in RV s' velocity during low-load ESE could estimate the exercise capacity in HF patients. The assessments of RV contractile reserve and RV-to-PC coupling could be clinically beneficial to distinguish high-risk HF patients.

DOI： 10.1002/ehf2.12968

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DOI： 10.1093/eurheartj/ehaa088

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BACKGROUNDS: The relative apical sparing pattern (RASP) of left ventricular (LV) longitudinal strain (LS) is frequently associated with cardiac amyloidosis (CA). However, the visual assessment of RASP is inconsistent, and the quantitative assessment of RASP is time-consuming. This study aimed to compare assessments of RASP for the identification of CA with conventional assessments and investigate their reproducibility and relevance on the assessments. METHODS: Forty patients with biopsy-proven CA were compared with 80 hypertrophied patients matched for mean LV wall thickness. We compared the discriminative abilities of three assessments of RASP to identify CA (visual, quantitative, and semiquantitative). Nine patterns of semiquantitative RASP were investigated; finally, it was defined as "reduction of LS" (≥ -10%) in ≥5 (of 6) basal segments, relative to "preserved LS" (< -15%) in at least one apical segment. RESULTS: The concordance between the two observers for visual RASP was modest (κ = 0.65). On the other hand, the consistency for semiquantitative RASP was perfect (κ = 1.00). The discriminative ability of semiquantitative RASP (area under the curve [AUC]  = 0.74) was significantly better than that of visual RASP (AUC = 0.65) and equivalent to that of binary quantitative RASP. CONCLUSION: Semiquantitative RASP assessment is reproducible and accurately discriminates CA. This simple assessment may help readily refine the risk stratification of patients with diffuse LV hypertrophy.

DOI： 10.1111/echo.14833

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

BACKGROUND: Our aim was to evaluate the ability of adenosine triphosphate (ATP)-stress myocardial computed tomography perfusion (CTP) imaging to detect myocardial ischemia in the left anterior descending artery (LAD) territory, and to compare this method with coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography (TTDE). METHODS: ATP-stress CTP and CFVR were performed in 50 patients with stable angina pectoris. Myocardial ischemia assessed from CTP imaging was defined as qualitative visual perfusion defects and reduced myocardial blood flow (MBF) based on quantitative assessment. A cut-off value of CFVR of 2.0 was used. RESULTS: The mean CFVR was 1.9 ± 0.6 in ischemic regions by CTP, whereas it was 2.9 ± 0.8 in non-ischemic regions (p < 0.001). CTP imaging could accurately predict CFVR <2.0 with 84.0% diagnostic accuracy (94.7% sensitivity, 77.4% specificity, 72.0% positive predictive value, and 96.0% negative predictive value). When receiver operating characteristic curve analysis of the MBF data was performed to detect CFVR <2.0, the area under the curve was 0.89, and the optimal MBF cut-off value was 1.43 mL/g/min. CONCLUSIONS: This study suggests that qualitative and quantitative assessment of ATP-stress CTP exhibits a good correlation with CFVR for evaluation of myocardial ischemia.

DOI： 10.1016/j.jjcc.2020.03.003

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

DOI： 10.1016/j.jjcc.2020.03.006

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

DOI： 10.1007/s10554-020-01878-6

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Other Link： http://link.springer.com/article/10.1007/s10554-020-01878-6/fulltext.html

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Incisional atrial tachycardia (AT) with multiple penetrating points on one surgical incision has not been reported yet. We present a case of incisional AT following mitral valve annuloplasty with a superior transseptal approach, in which two reconduction sites were parts of the reentrant circuit. Radiofrequency ablation at the reconduction site successfully terminated the tachycardia. A total of four penetrating points were found on the incision line, and radiofrequency ablation at these sites was completed. Detailed mapping of possible reconduction sites along the incision line should be performed to avoid further instances of AT following open heart surgery.

DOI： 10.1111/jce.14690

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

Background:
Although management of obstructive sleep apnea (OSA) has been recommended to improve outcomes of catheter ablation (CA) in patients with symptomatic atrial fibrillation (AF), the most cost-effective way of preprocedural OSA screening is undetermined. This study assessed the cost-effectiveness of OSA management before CA for symptomatic AF.
Methods and Results:
A Markov model was developed to assess the cost-effectiveness of 3 OSA detection strategies before CA: no screening; Type 3 portable monitor (PM)-guided screening; and polysomnography (PSG)-guided screening. The target population consisted of a hypothetical cohort of patients aged 65 years with symptomatic AF, with 50% prevalence of OSA. We used a 5-year horizon, with sensitivity analyses for significant variables and scenario analyses for lower and higher OSA prevalence (30% and 70%, respectively). In the base-case, both types of OSA screening were dominant (less costly and more effective) relative to no screening. Although PSG-guided management was more effective than PM-guided management, it was more costly and therefore did not show clear benefit. These findings were replicated in cohorts with lower and higher OSA risks.
Conclusions:
OSA screening before CA is cost-effective in patients with symptomatic AF, with PM screening being the most cost-effective. Physicians should consider OSA management using this simple tool in the decision making for treatment of symptomatic AF.

DOI： 10.1253/circrep.CR-20-0074

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

DOI： 10.1253/circrep.CR-20-0064

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

BACKGROUND: The molecular mechanisms underlying aortic valve calcification are poorly understood. Here, we aimed to identify the master regulators of calcification by comparison of genes in valve interstitial cells (VICs) with calcified and noncalcified aortic valves. METHODS: Calcified aortic valves were surgically excised from patients with aortic valve stenosis who required aortic valve replacements. Noncalcified and calcified sections were obtained from aortic valve leaflets. Collagenase-digested tissues were seeded into dishes, and VICs adhering to the dishes were cultured for 3 weeks, followed by comprehensive gene expression analysis. Functional analyses of identified proteins were performed by in vitro calcification assays. Tissue localization was determined by immunohistochemical staining for normal (n = 11) and stenotic valves (n = 30). RESULTS: We found 87 genes showing greater than a twofold change in calcified tissues. Among these genes, 68 were downregulated and 19 were upregulated. Cyclooxygenase-1 (COX1) messenger RNA and protein levels were upregulated in VICs from calcified tissues. The COX1 messenger RNA and protein levels in VICs were also strongly increased by stimulation with osteoblast differentiation medium. These were VIC-specific phenotypes and were not observed in other cell types. Immunohistochemical staining revealed that COX1-positive VICs were specifically localized in the calcified area of aortic valve tissues. CONCLUSIONS: The VIC-specific COX1 overexpression played a crucial role in calcification by promoting osteoblast differentiation in aortic valve tissues.

DOI： 10.1016/j.athoracsur.2019.09.085

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Background: For relief of cold symptoms, methylephedrine is considered to be safer than ephedrine, particularly when used at the predetermined dose. It is often present in various over-the-counter (OTC) drugs for cold, including paediatric cough syrups. Case summary: A 52-year-old man presented with worsening dyspnoea and anorexia for 2 weeks. He was a night shift worker and had been habitually taking large doses of methylephedrine-containing paediatric cough syrup for 20 years for sleep averting. On admission, his chest X-ray revealed pulmonary congestion and electrocardiogram showed sinus tachycardia with left-axis deviation. Echocardiography revealed diffuse hypokinesis with a reduced ejection fraction (EF) of 25%. The B-type natriuretic peptide level was elevated to 1092 ng/L. Even after treatment with low-dose dobutamine and furosemide in intensive care unit, right-heart catheterization demonstrated a 'wet and cold' profile. Coronary angiography revealed normal coronary arteries. Pathological examination by endomyocardial biopsy revealed cardiomyocyte hypertrophy with moderate interstitial and replacement fibrosis. In addition, cardiac magnetic resonance imaging revealed diffuse hypokinesis with mid-wall late gadolinium enhancement, which suggested fibrosis. Discontinuation of the cough syrup and optimal medical treatment with an angiotensin-converting enzyme inhibitor and a β blocker resulted in improvement in the heart failure symptoms to New York Class Association Class II. The EF also improved to 50% at 4 months after discharge. Discussion: Methylephedrine is considered to have adrenergic effects; it has milder side effects on the cardiovascular system than ephedrine. However, the long-lasting excessive intake of methylephedrine, even through OTC paediatric cough syrups, has the potential to cause heart failure.

DOI： 10.1093/ehjcr/ytaa095

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BACKGROUND: Coronary angioscopy (CAS) is a useful modality to assess atherosclerotic changes, but interpretation of the images requires expert knowledge. Deep convolutional neural networks (DCNN) can be used for diagnostic prediction and image synthesis. METHODS: 107 images from 47 patients, who underwent CAS in our hospital between 2014 and 2017, and 864 images, selected from 142 MEDLINE-indexed articles published between 2000 and 2019, were analysed. First, we developed a prediction model for the angioscopic findings. Next, we made a generative adversarial networks (GAN) model to simulate the CAS images. Finally, we tried to control the output images according to the angioscopic findings with conditional GAN architecture. RESULTS: For both yellow colour (YC) grade and neointimal coverage (NC) grade, we could observe strong correlations between the true grades and the predicted values (YC grade, average r=0.80±0.02, p<0.001; NC grade, average r=0.73±0.02, p<0.001). The binary classification model for the red thrombus yielded 0.71±0.03 F1-score and the area under the receiver operator characteristic curve was 0.91±0.02. The standard GAN model could generate realistic CAS images (average Inception score=3.57±0.06). GAN-based data augmentation improved the performance of the prediction models. In the conditional GAN model, there were significant correlations between given values and the expert's diagnosis in YC grade but not in NC grade. CONCLUSION: DCNN is useful in both predictive and generative modelling that can help develop the diagnostic support system for CAS.

DOI： 10.1136/openhrt-2019-001177

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

BACKGROUND: Proinflammatory cytokines play an important role in the pathogenesis of heart failure. The mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in nonimmune cells such as cardiomyocytes remains to be elucidated. METHODS: To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Interleukin-6 signaling was inhibited by administration with its receptor antibody. Overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer. RESULTS: Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared with control littermates. Four weeks after transverse aortic constriction, the Il6 mRNA level was upregulated, but not other cytokine mRNAs, including tumor necrosis factor-α, in Regnase-1-deficient hearts. Although the Il6 mRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-interleukin-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction of Il6 mRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9-mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-interleukin-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice. CONCLUSIONS: The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.

DOI： 10.1161/circulationaha.119.044582

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Language：English  

BACKGROUND: Coronary magnetic resonance angiography (CMRA) is a promising technique for assessing the coronary arteries. However, a disadvantage of CMRA is the comparatively long acquisition time. Compressed sensing (CS) can considerably reduce the scan time. The aim of this study was to verify the feasibility of CS CMRA scanning during the waiting time between contrast injection and late gadolinium enhancement (LGE) scan in a clinical protocol. METHODS: Fifty clinical patients underwent contrast-enhanced CS CMRA and conventional CMRA on a 3 T CMR scanner. After contrast injection, CS CMRA was scanned during the waiting time for LGE CMR. A conventional CMRA scan was performed after LGE CMR. We assessed acquisition times and coronary artery image quality for each segment on a 4-point scale. Visible vessel length, sharpness and diameter of right (RCA), left anterior descending (LAD), and left circumflex (LCX) coronary arteries were also quantitatively compared among the scans. RESULTS: All CS CMRA scans were successfully performed within the LGE waiting time. The median total scan time was 207 s (163, 259 s) for CS and 785 s (698, 975 s) for conventional CMRA (p < 0.001). No significant differences were observed in image quality scores, vessel length measurements, sharpness, and diameter between CS and conventional CMRA. CONCLUSIONS: We could achieve all CS CMRA scans within the LGE waiting time. Contrast-enhanced CS CMRA could considerably shorten the scan time while maintaining image quality compared with conventional CMRA.

DOI： 10.1186/s12968-020-0601-0

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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Background and Objective: Spirometry is sometimes difficult to perform in elderly patients and patients with cognitive impairment. Forced oscillometry (FOT) is a simple, noninvasive technique used for measuring respiratory impedance. The aim of this study was to develop regression equations to estimate vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in 1 s (FEV1.0) on the basis of FOT indices and to evaluate the accuracy of these equations in patients with asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Materials and Methods: We retrospectively included data on 683 consecutive patients with asthma (388), COPD (128), or ILD (167) in this study. We generated regression equations for VC, FVC, and FEV1.0 by multivariate linear regression analysis and used them to estimate the corresponding values. We determined whether the estimated data reflected spirometric indices. Results: Actual and estimated VC, FVC, and FEV1.0 values showed significant correlations (all r > 0.8 and P < 0.001) in all groups. Biases between the actual data and estimated data for VC, FVC, and FEV1.0 in the asthma group were -0.073 L, -0.069 L, and 0.017 L, respectively. The corresponding values were -0.064 L, 0.027 L, and 0.069 L, respectively, in the COPD group and -0.040 L, -0.071 L, and -0.002 L, respectively, in the ILD group. The estimated data in the present study did not completely correspond to the actual data. In addition, sensitivity for an FEV1.0/FVC ratio of <0.7 and the diagnostic accuracy for the classification of COPD grade using estimated data were low. Conclusion: These results suggest that our method is not highly accurate. Further studies are needed to generate more accurate regression equations for estimating spirometric indices based on FOT measurements.

DOI： 10.2147/COPD.S250080

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

DOI： 10.1093/ehjci/jez131

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BACKGROUND AND AIMS: Abdominal aortic aneurysm (AAA) is a common disease; however, its exact pathogenesis remains unknown, and no specific medical therapies are available. Interleukin (IL)-18 plays a crucial role in atherosclerotic plaque destabilization and is a strong predictor of cardiovascular death. Here, we investigated the role of IL-18 in AAA pathogenesis using an experimental mouse model. METHODS AND RESULTS: After infusion of angiotensin II (Ang II) for 4 weeks and β-aminopropionitrile (BAPN) for 2 weeks, 58% of C57/6J wild-type (WT) mice developed AAA associated with enhanced expression of IL-18; however, disease incidence was significantly lower in IL-18-/- mice than in WT mice (p < 0.01), although no significant difference was found in systolic blood pressure between WT mice and IL-18-/- mice in this model. Additionally, IL-18 deletion significantly attenuated Ang II/BAPN-induced macrophage infiltration, macrophage polarization into inflammatory M1 phenotype, and matrix metalloproteinase (MMP) activation in abdominal aortas, which is associated with reduced expression of osteopontin (OPN). CONCLUSIONS: These findings indicate that IL-18 plays an important role in the development of AAA by enhancing OPN expression, macrophage recruitment, and MMP activation. Moreover, IL-18 represents a previously unrecognized therapeutic target for the prevention of AAA formation.

DOI： 10.1016/j.atherosclerosis.2019.08.003

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

DOI： 10.1253/circj.cj-18-1039

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

DOI： 10.1253/circj.CJ-19-0342

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

DOI： 10.1253/circj.cj-18-1249

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

In myocardial ischemia/reperfusion injury, the innate immune and subsequent inflammatory responses play a crucial role in the extension of myocardial damage. Toll-like receptor 9 (TLR9) is a critical receptor for recognizing unmethylated CpG motifs that mitochondria contain in their DNA, and induces inflammatory responses. The aim of this study was to elucidate the role of TLR9 in myocardial ischemia/reperfusion injury. Isolated hearts from TLR9-deficient and control wild-type mice were subjected to 35 min of global ischemia, followed by 60 min of reperfusion with Langendorff apparatus. Furthermore, wild-type mouse hearts were infused with DNase I and subjected to ischemia/reperfusion. Ablation of TLR9-mediated signaling pathway attenuates myocardial ischemia/reperfusion injury and inflammatory responses, and digestion of extracellular mitochondrial DNA released from the infarct heart partially improved myocardial ischemia/reperfusion injury with no effect on inflammatory responses. TLR9 could be a therapeutic target to reduce myocardial ischemia/reperfusion injury.

DOI： 10.1016/j.bbrc.2019.05.150

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Language：Japanese   Publisher：(公財)日本心臓財団  

症例は68歳女性。4年前より手根管症候群を指摘されていた。9ヵ月前近医にて両側胸水を指摘された。心臓超音波検査では左室駆出率は保たれていたが、左室壁厚の軽度肥厚を認めた。BNP値は198pg/mLと上昇しており、拡張機能障害を主体とした心不全として利尿薬を投与され、胸水の消失を得て経過観察となった。1ヵ月前より尿蛋白陽性、低アルブミン血症の進行を認めるようになり、胸水の増大および労作時呼吸困難の増悪のため入院となった。入院時のBNP値は433pg/mLと著明に上昇しており、心臓超音波検査では左室壁厚13mmと全周性に輝度上昇と肥大を認め、左室駆出率は48%と低下していた。尿Bence Jones蛋白陽性で、心筋生検にてアミロイド沈着が確認され、ALアミロイドーシスの診断に至った。左室駆出率の保たれた心不全症例において一定の割合でアミロイドーシスが含まれていると報告されており、早期から疑う必要性があったと考えられた1例を経験した。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00679&link_issn=&doc_id=20190719190007&doc_link_id=%2Fah2sinzd%2F2019%2F005107%2F009%2F0692-0697%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fah2sinzd%2F2019%2F005107%2F009%2F0692-0697%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

Mitochondrial deoxyribonucleic acid, containing the unmethylated cytidine-phosphate-guanosine motif, stimulates Toll-like receptor 9 to induce inflammation and heart failure. A small chemical, E6446 [(6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole)], is a specific Toll-like receptor 9 inhibitor in cardiomyocytes. In this study, we showed that E6446 exerts beneficial effects for the prevention and treatment of pressure overload-induced heart failure in mice. When administered before the operation and chronically thereafter, E6446 prevented the development of left ventricular dilatation as well as cardiac dysfunction, fibrosis, and inflammation. Furthermore, when administered after the manifestation of cardiac dysfunction, E6446 slowed progression of cardiac remodeling. Thus, the inhibitor may be a novel therapeutic agent for treating patients with heart failure.

DOI： 10.1016/j.jacbts.2019.01.002

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OBJECTIVES: This study sought to investigate whether elevated liver stiffness (LS) values at discharge reflect residual liver congestion and are associated with worse outcomes in patients with heart failure (HF). BACKGROUND: Transient elastography is a newly developed, noninvasive method for assessing LS, which can be highly reflective of right-sided filling pressure associated with passive liver congestion in patients with HF. METHODS: LS values were determined for 171 hospitalized patients with HF before discharge using a Fibroscan device. RESULTS: The median LS value was 5.6 kPa (interquartile range: 4.4 to 8.1 kPa; range 2.4 to 39.7 kPa) and that of right-sided filling pressure, which was estimated based on LS, was 5.7 mm Hg (interquartile range: 4.1 to 8.2 mm Hg; range 0.1 to 18.9 mm Hg). The patients in the highest LS tertile (>6.9 kPa, corresponding to an estimated right-sided filling pressure of >7.1 mm Hg) had advanced New York Heart Association functional class, high prevalence of jugular venous distention and moderate/severe tricuspid regurgitation, large inferior vena cava (IVC) diameter, low hemoglobin and hematocrit levels, high serum direct bilirubin level, and a similar left ventricular ejection fraction compared with the lower tertiles. During follow-up periods (median: 203 days), 8 (5%) deaths and 33 (19%) hospitalizations for HF were observed. The patients in the highest LS group had a significantly higher mortality rate and HF rehospitalization (hazard ratio: 3.57; 95% confidence interval: 1.93 to 6.83; p < 0.001) compared with the other tertiles. Although LS correlated with IVC diameter and serum direct bilirubin and brain natriuretic peptide levels, LS values were predictive of worse outcomes, even after adjustment for these indices. CONCLUSIONS: These data suggest that LS is a useful index for assessing systemic volume status and predicting the severity of HF, and that the presence of liver congestion at discharge is associated with worse outcomes in patients with HF.

DOI： 10.1016/j.jcmg.2017.10.022

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

The autophagic machinery is a well-conserved degradation system in eukaryotes from yeast to mammals. Autophagy has been thought of as a nonselective degradation process in which cytoplasmic proteins and organelles are degraded by fusion with lysosome. Recent studies have revealed selective forms of autophagy, such as mitochondria-specific autophagy, termed "mitophagy". Research over the past decade has revealed that autophagy in cardiomyocytes plays a protective role, not only during hemodynamic stress but in homeostasis during aging. Hemodynamic stress and aging induce mitochondrial damage, leading to increased oxidative stress and decreased ATP production. Damaged mitochondria are generally degraded through mitophagy, which might be the main protective function of autophagy in the heart. Complete digestion of mitochondrial DNA through mitophagy is important to avoid inflammatory responses that can induce heart failure. A polyamine, spermidine, is reported to bring about an extension of lifespan and to protect the heart from age-related cardiac dysfunction, both of which are mediated through induction of autophagy. Therefore, appropriate induction of autophagy could be a novel therapeutic target for cardiovascular diseases, including heart failure. However, precise evaluation of autophagic activity in the human heart is difficult at this time, but exploitation of the novel technique of autophagy evaluation is expected for both drug discovery and clinical application.

DOI： 10.1253/circj.CJ-18-1065

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

DOI： 10.1253/circrep.CR-19-0011

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

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DOI： 10.2169/internalmedicine.2626-19

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Degradation of mitochondria by selective autophagy, termed mitophagy, contributes to the control of mitochondrial quality. Bcl2-L-13 is a mammalian homolog of Atg32, which is an essential mitophagy receptor in yeast. However, the molecular machinery involved in Bcl2-L-13-mediated mitophagy remains to be elucidated. Here, we show that the ULK1 (unc-51-like kinase) complex is required for Bcl2-L-13 to process mitophagy. Screening of a series of yeast Atg mutants revealed that a different set of ATG genes is used for Bcl2-L-13- and Atg32-mediated mitophagy in yeast. The components of the Atg1 complex essential for starvation-induced autophagy were indispensable in Bcl2-L-13-, but not Atg32-mediated, mitophagy. The ULK1 complex, a counterpart of the Atg1 complex, is necessary for Bcl2-L-13-mediated mitophagy in mammalian cells. We propose a model where, upon mitophagy induction, Bcl2-L-13 recruits the ULK1 complex to process mitophagy and the interaction of LC3B with ULK1, as well as Bcl2-L-13, is important for the mitophagy.

DOI： 10.1016/j.celrep.2018.12.050

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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：Japanese   Publisher：愛媛医学会  

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BACKGROUND: Treatment decisions in dilated cardiomyopathy (DCM) patients with severe heart failure (HF) and short clinical history are challenging because of the difficulty of determining HF stage or prognosis in the acute HF phase. We hypothesized that persistent decreased systemic or increased pulmonary arterial pressure, including in the sub-clinical phase, might affect the main pulmonary artery diameter (PAD), ascending aortic diameter (AoD), and their ratio (PAD/AoD). This study assessed AoD, PAD, and PAD/AoD by non-contrast computed tomography scans in DCM patients in the acute phase of HF and examined the association of these parameters with their clinical course. METHODS: Of 261 screened individuals, we studied 110 consecutive hospitalized patients with DCM suspected of being in advanced stage of HF and 45 age-matched controls, assessing clinical data and later events (cardiac death or left ventricular assist device implantation). RESULTS: Compared with controls, DCM patients had smaller AoD (26.6 ± 4.4 vs 30.6 ± 2.7 mm) and larger PAD (27.7 ± 3.5 vs 25.4 ± 2.8 mm) and PAD/AoD (1.05 ± 0.14 vs 0.83 ± 0.08; all p < 0.01). DCM patients with high PAD/AoD (median, > 1.05) had more frequent past HF hospitalizations, lower blood pressure, stroke volume, and ejection fraction, higher brain natriuretic peptide levels, smaller AoD, and similar PAD compared with patients with a low PAD/AoD. A higher PAD/AoD was associated with poorer outcomes even after adjusting for age, blood pressure, ejection fraction, or number of hospitalizations. CONCLUSION: Assessment of AoD and PAD may have important clinical implications in determining whether DCM patients are in an advanced stage of HF with a poorer prognosis.

DOI： 10.1016/j.healun.2018.07.006

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Publishing type：Research paper (scientific journal)  

© The Author(s) 2018. Restrictive cardiomyopathy (RCM) is a rare form of cardiomyopathy that is characterized by restrictive ventricular filling. Elevated filling pressure leads to pulmonary hypertension (PH), which often progresses to combined post- and pre-capillary PH (Cpc-PH) with increased diastolic pulmonary vascular pressure gradient (DPG) and pulmonary vascular resistance (PVR) caused by longstanding backward hemodynamic consequences of left heart disease (LHD) leading to morphological changes in the pulmonary vasculature. Patients with high PVR undergoing left ventricular assist device (LVAD) implantation are at increased risk of postoperative right-sided heart failure requiring concomitant implantation of a right ventricular assist device (RVAD). We report a case of RCM with severe Cpc-PH due to extremely elevated DPG and PVR. The patient presented recurrent syncope caused by severe PH. Right heart catheterization (RHC) revealed highly elevated DPG 30 mmHg and PVR 25.3 Wood units (WU) and subsequent significant reduction of right ventricular afterload during vasoreactivity testing with inhaled nitric oxide (NO) to DPG 5 mmHg and PVR 10.5 WU. During the administration of pulmonary vasodilators, pulmonary congestion worsened. Second RHC revealed elevated pulmonary arterial wedge pressure (PAWP) and modest decrease of pulmonary arterial pressure (PAP) 87 mmHg and PVR 9.6 WU. Therefore, an inotropic agent and systemic vasodilator were added for the treatment of left-sided heart failure. Targeting elevated filling pressures with both PAH-specific and heart failure treatment, a further decrease of right ventricular afterload with DPG of 5 mmHg and PVR of 3.8 WU was achieved. In a next step, LVAD was successfully implanted, without need for RVAD, as a bridge to transplantation. This is the first reported case of Cpc-PH that revealed the potential reversibility of extremely elevated DPG and PVR, and suggests the importance of preoperative RHC-guided optimized medical PAH-specific and heart failure treatment before LVAD implantation.

DOI： 10.1177/2045894018770131

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

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

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

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

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

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Language：English  

Subcutaneous implantable cardioverter-defibrillators (S-ICDs) are susceptible to T-wave oversensing (TWOS) caused by high rate-dependent QRS-T morphology changes. We experienced an inappropriate S-ICD shock due to TWOS, which could not be predicted by routine exercise testing. A newly available high-pass filter might be effective for avoiding this.

DOI： 10.1002/ccr3.1345

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

Protein quality control in cardiomyocytes is crucial to maintain cellular homeostasis. The accumulation of damaged organelles, such as mitochondria and misfolded proteins in the heart is associated with heart failure. During the process to identify novel mitochondria-specific autophagy (mitophagy) receptors, we found FK506-binding protein 8 (FKBP8), also known as FKBP38, shares similar structural characteristics with a yeast mitophagy receptor, autophagy-related 32 protein. However, knockdown of FKBP8 had no effect on mitophagy in HEK293 cells or H9c2 myocytes. Since the role of FKBP8 in the heart has not been fully elucidated, the aim of this study is to determine the functional role of FKBP8 in the heart. Cardiac-specific FKBP8-deficient (Fkbp8-/-) mice were generated. Fkbp8-/- mice showed no cardiac phenotypes under baseline conditions. The Fkbp8-/- and control wild type littermates (Fkbp8+/+) mice were subjected to pressure overload by means of transverse aortic constriction (TAC). Fkbp8-/- mice showed left ventricular dysfunction and chamber dilatation with lung congestion 1week after TAC. The number of apoptotic cardiomyocytes was dramatically elevated in TAC-operated Fkbp8-/- hearts, accompanied with an increase in protein levels of cleaved caspase-12 and endoplasmic reticulum (ER) stress markers. Caspase-12 inhibition resulted in the attenuation of hydrogen peroxide-induced apoptotic cell death in FKBP8 knockdown H9c2 myocytes. Immunocytological and immunoprecipitation analyses indicate that FKBP8 is localized to the ER and mitochondria in the isolated cardiomyocytes, interacting with heat shock protein 90. Furthermore, there was accumulation of misfolded protein aggregates in FKBP8 knockdown H9c2 myocytes and electron dense deposits in perinuclear region in TAC-operated Fkbp8-/- hearts. The data suggest that FKBP8 plays a protective role against hemodynamic stress in the heart mediated via inhibition of the accumulation of misfolded proteins and ER-associated apoptosis.

DOI： 10.1016/j.yjmcc.2017.11.004

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Language：Japanese   Publisher：The Japan Society of Mechanical Engineers  

DOI： 10.1299/jsmebio.2018.30.2I10

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

Background: Myocardial mass at risk (MMAR) is an important predictor of adverse cardiac events in patients with ischemic heart disease. This study aims to validate the accuracy of MMAR calculated from cardiac computed tomography (CCT) data using the Voronoi-based segmentation algorithm in comparison with actual MMAR measured on ex-vivo swine hearts prepared by injecting a dye into the coronary arteries.
Methods: Fifteen extracted swine hearts had India ink injected into one of the major coronary arteries. Subsequently, all coronary arteries. manually injected with methylcellulose-based iohexiol-370 were imaged by 16-row CT. The ventricles were cross-sectioned perpendicularly to the long axis of the left ventricle (LV). The stained area and the total LV area of individual slices were measured, and actual MMAR was calculated as the ratio of the LV volume with the disc-summation method. CT-based MMAR of each coronary artery was calculated automatically with the Voronoi-based segmentation algorithm. The results were compared using Pearson's correlation coefficient.
Results: The median value of Cr-based MMAR was 50.8% for the left anterior descending artery (LAD), 36.6% for the left circumflex artery (LCX), and 23.0% for the right coronary artery (RCA). Actual MMAR was 49.8% for LAD, 32.2% for LCX, and 25.9% for RCA. CT-based MMAR was significantly related to actual MMAR (r = 0.92, p = 0.02 for LAD; r = 0.96, p = 0.009 for LCX; r = 0.96, p = 0.009 for RCA).
Conclusion: Cr-based MMAR obtained by Voronoi-based segmentation algorithm reliably estimates actual MMAR measured on ex-vivo swine hearts. (C) 2017 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jcct.2017.04.007

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Language：Japanese   Publisher：(公社)日本臨床工学技士会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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

OBJECTIVE: Refeeding syndrome occurs when reinstating nutrition to severely malnourished patients. It can sometimes be fatal, particularly as a result of cardiac involvement such as congestive heart failure and arrhythmias. The aim of this study was to report a case of cardiogenic shock that occurred during refeeding in a patient with anorexia nervosa (AN). The cardiogenic shock was due to a previously unrecognized mechanism, namely a transient left midventricular obstruction that completely disappeared after treatment. METHODS: A 46-y-old woman with AN who had followed a carbohydrate- and a fat-deficient diet for >10 y was hospitalized for dyspnea on exertion. She had severely impaired cardiac systolic function on admission and was considered high risk for refeeding syndrome. During a stepwise increase of calories, she showed no electrolyte or mineral abnormalities characteristic of refeeding syndrome. RESULTS: After intravenous administration of a fat emulsion, the patient suffered from cardiogenic shock due to an unexpected mechanism, namely a left midventricular obstruction caused by cardiac hypercontraction, a thickened left ventricular wall, and intravascular volume depletion. With cessation of the fat emulsion and initiation of volume repletion she recovered from shock immediately and her echocardiogram returned to normal by discharge. CONCLUSIONS: This case illustrated a novel cause of cardiogenic shock during refeeding and the need for caution during the intravenous administration of a fat emulsion in patients with initial left ventricular systolic dysfunction.

DOI： 10.1016/j.nut.2016.12.017

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

BACKGROUND: Dual antiplatelet therapy (DAPT) is commonly used after transcatheter aortic valve implantation (TAVI); however, the supporting evidence is limited. To determine if aspirin alone is a better alternative to DAPT, we compared the outcomes of patients treated with DAPT or aspirin alone after TAVI.Methods and Results:We analyzed a total of 144 consecutive patients (92 females, mean age 83±6 years) who underwent implantation of a balloon-expandable transcatheter valve (SAPIEN or SAPIEN XT, Edwards Lifesciences). Patients were divided into DAPT (n=66) or aspirin-alone treatment groups (n=78). At 1 year after TAVI, the composite endpoint, which consisted of all-cause death, myocardial infarction, stroke, and major or life-threatening bleeding complications, occurred significantly less frequently (Kaplan-Meier analysis) in the aspirin-alone group (15.4%) than in the DAPT group (30.3%; P=0.031). Valve function assessed by echocardiography was similar between the 2 treatment groups with respect to effective orifice area (1.78±0.43 cm2in DAPT vs. 1.91±0.46 cm2in aspirin-alone group; P=0.13) and transvalvular pressure gradient (11.1±3.5 mmHg in DAPT vs. 10.3±4.1 mmHg in aspirin-alone group; P=0.31). CONCLUSIONS: Treatment with aspirin alone after TAVI had greater safety benefits and was associated with similar valve function as DAPT. These results suggest that treatment with aspirin alone is an acceptable regimen for TAVI patients.

DOI： 10.1253/circj.CJ-16-0903

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Language：Japanese   Publisher：(NPO)日本心臓血管外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Pulmonary arterial hypertension (PAH) is known to develop as a consequence of multiple genetic and/or non-genetic factors. A 27-year-old woman with chronic hepatitis C virus (HCV) infection developed severe PAH after interferon (IFN) therapy. Although most of the reported clinical courses of IFN-induced PAH are poor despite the discontinuation of IFN, the present patient was successfully treated with a triple combination therapy. In this report, we discuss the crosstalk among chronic HCV infection, IFN therapy, autoimmune disorders, and portal hypertension in the pathogenesis and development of PAH.

DOI： 10.2169/internalmedicine.56.7822

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

We have reported that the Toll-like receptor 9 (TLR9) signaling pathway plays an important role in the development of pressure overload-induced inflammatory responses and heart failure. However, its role in cardiac remodeling after myocardial infarction has not been elucidated. TLR9-deficient and control C57Bl/6 wild-type mice were subjected to left coronary artery ligation. The survival rate 14 days postoperation was significantly lower in TLR9-deficient mice than that in wild-type mice with evidence of cardiac rupture in all dead mice. Cardiac magnetic resonance imaging showed no difference in infarct size and left ventricular wall thickness and function between TLR9-deficient and wild-type mice. There were no differences in the number of infiltrating inflammatory cells and the levels of inflammatory cytokine mRNA in infarct hearts between TLR9-deficient and wild-type mice. The number of α-smooth muscle actin (αSMA)-positive myofibroblasts and αSMA/Ki67-double-positive proliferative myofibroblasts was increased in the infarct and border areas in infarct hearts compared with those in sham-operated hearts in wild-type mice, but not in TLR9-deficient mice. The class B CpG oligonucleotide increased the phosphorylation level of NF-κB and the number of αSMA-positive and αSMA/Ki67-double-positive cells and these increases were attenuated by BAY1-7082, an NF-κB inhibitor, in cardiac fibroblasts isolated from wild-type hearts. The CpG oligonucleotide showed no effect on NF-κB activation or the number of αSMA-positive and αSMA/Ki67-double-positive cells in cardiac fibroblasts from TLR9-deficient hearts. Although the TLR9 signaling pathway is not involved in the acute inflammatory response in infarct hearts, it ameliorates cardiac rupture possibly by promoting proliferation and differentiation of cardiac fibroblasts.

DOI： 10.1152/ajpheart.00481.2016

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

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

A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

DOI： 10.1016/j.celrep.2016.06.050

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

Mitochondria are essential organelles that supply ATP through oxidative phosphorylation to maintain cellular homeostasis. Extrinsic or intrinsic agents can impair mitochondria, and these impaired mitochondria can generate reactive oxygen species (ROS) as byproducts, inducing cellular damage and cell death. The quality control of mitochondria is essential for the maintenance of normal cellular functions, particularly in cardiomyocytes, because they are terminally differentiated. Accumulation of damaged mitochondria is characteristic of various diseases, including heart failure, neurodegenerative disease, and aging-related diseases. Mitochondria are generally degraded through autophagy, an intracellular degradation system that is conserved from yeast to mammals. Autophagy is thought to be a nonselective degradation process in which cytoplasmic proteins and organelles are engulfed by isolation membrane to form autophagosomes in eukaryotic cells. However, recent studies have described the process of selective autophagy, which targets specific proteins or organelles such as mitochondria. Mitochondria-specific autophagy is called mitophagy. Dysregulation of mitophagy is implicated in the development of chronic diseases including neurodegenerative diseases, metabolic diseases, and heart failure. In this review, we discuss recent progress in research on mitophagy receptors.

DOI： 10.1016/j.yjmcc.2016.03.010

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

AIMS: Neovascularization is closely associated with plaque progression in non-heart transplantation subjects; on the other hand, cardiac allograft vasculopathy causes unfavourable outcomes. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can provide microscopic assessment in vivo. The aim of this study was to investigate the impact of neovascularization on intimal proliferation. METHODS AND RESULTS: Both IVUS and OCT were attempted in 45 consecutive patients during annual catheterization after heart transplantation. There were 115 vessels [28 vessels were catheterized within 8 weeks of heart transplantation (baseline)]. IVUS analysis assessed vessel, luminal, and intimal (vessel-lumen) volume using Simpson's method. Qualitative parameters including microchannel were assessed by OCT. A microchannel was defined as a no-signal tubuloluminal structure with a sharply delineated border considered to represent neovascularization. Microchannel was observed more often in patient who had their heart transplant more than a year prior to the imaging, compared with shorter periods (39.1 vs. 10.7%, P = 0.023). All microchannels were seen in thickness >0.5 mm, and intimal volume index (mm(3)/mm) correlated with frequency of microchannel (r = 0.54, P = 0.04). The risks for microchannels were donor age [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.22; P = 0.007], cytomegalovirus infection (OR 16.21; 95% CI 1.79-220.09; P = 0.012), diabetes (OR 9.5; 95% CI 1.21-116.10; P = 0.032), LDL-cholesterol (OR 1.07; 95% CI 1.01-1.13; P = 0.010), and intimal volume (OR 2.47; 95% CI 1.13-6.36; P = 0.023). CONCLUSION: OCT-identified microchannels increased sharply within the first year and were correlated with intimal volume and coronary risks. This suggests that neovascularization may play an important role in the progression of cardiac allograft vasculopathy.

DOI： 10.1093/ehjci/jev110

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Gram-negative fusiform rods were detected in a blood culture obtained from a 63-year-old man who had been hospitalized for a long duration for severe heart failure. Although the organism could not be identified using a conventional method, it was finally identified as a bacterium of the Capnocytophaga ochracea group based on the results of biochemical testing, 16S rRNA sequencing and a matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis. Although neutropenic patients with poor oral hygiene are exclusively vulnerable to Capnocytophaga bacteremia, this case was unique because such predisposing conditions were not noted. A multi-centered investigation is warranted for a better understanding of this clinically rare, but potentially pathogenic organism.

DOI： 10.2169/internalmedicine.55.6593

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Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/- mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts.

DOI： 10.1371/journal.pone.0152628

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

Background: Inferior vena cava (IVC) diameter and its respiratory change, as determined using echocardiography, are commonly used to assess right atrial pressure (RAP). Despite the widespread use of the IVC approach for RAP assessment, the relations among body surface area (BSA), IVC diameter, and respirophasic change remain unclear. The aim of this study was to investigate the impact of BSA on IVC parameters for predicting elevated RAP.
Methods: Ninety consecutive patients undergoing right-heart catheterization or central venous catheter insertion were prospectively included. To investigate the impact of BSA on IVC parameters, patients were divided into higher and lower BSA groups by comparing individual BSA measurements with the median value. Optimal cutoff points of IVC parameters for detecting RAP of &gt;= 10 mm Hg were defined using receiver operating characteristic curves.
Results: The median RAP and BSA were 8 mm Hg (range, 1-25 mm Hg) and 1.61 m(2) (range, 1.23-2.22 m(2)), respectively. In all patients, the optimal cutoff point for maximal IVC diameter (IVCDmax) and IVC collapsibility for the detection of RAP &gt; 10 mm Hg were 20 mm and 49.0%, respectively. The optimal cutoff point of IVCDmax for predicting RAP of &gt;= 10 mm Hg was significantly larger in patients with higher BSAs than in those with lower BSAs (21 vs 17 mm, P =.0342). No differences in collapsibility indices were detected between the two groups. IVCDmax was larger in men (1965 vs 17 +/- 5 mm in women, P =.0347) and weakly correlated with BSA (r = 0.35, P =.0007), whereas no relation was found between IVCDmax and age. However, the partial correlation coefficient of the entire cohort demonstrated that only BSA was still associated with IVCDmax after adjusting for age and gender (partial correlation coefficient = 0.32, P =.0020).
Conclusions: Body size, measured as BSA, is important to consider when IVC diameter is used to assess RAP. The optimal cutoff point of IVCDmax was 21 mm for patients with larger BSAs and 17 mm for those with smaller BSAs. However, the cutoff point of IVC collapsibility was not influenced by the difference of BSA. (J Am Soc Echocardiogr 2015; 28: 1420-7.)

DOI： 10.1016/j.echo.2015.07.008

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BACKGROUND/OBJECTIVES: Catheter ablation of atrial fibrillation (AF) might influence the cardiac autonomic nervous system. To investigate the impact of catheter ablation on the sympathetic nervous function in AF patients with and without heart failure (HF) using cardiac iodine-123-metaiodobenzylguanidine ((123)I-mIBG) scintigraphy, and the association of this effect with AF recurrence. METHODS: Forty consecutive patients (median age, 65 (54-69) years; male, 29) with paroxysmal (n=22) and persistent (n=18) AF who were scheduled for ablation were enrolled. Twelve (30%) of these patients also exhibited either stable HF, defined as an ejection fraction <40%, or a history of symptomatic HF. (123)I-mIBG scintigraphy was performed at baseline and 3months post-ablation. The heart-to-mediastinum ratio of (123)I-mIBG uptake at 15min (H/M15min) and 240min (H/M240min), as well as the washout rate (WR) were measured. RESULTS: During an 11±4-month follow-up, AF recurrence was observed in 8 (20%) patients receiving no antiarrhythmic drugs. Patients with HF had a tendency toward a lower baseline H/M15min (1.91±0.06 vs. 2.05±0.04, p=0.07), significantly lower H/M240min (1.88±0.22 vs. 2.14±0.28, p=0.008), and higher WR (40.3±9.0 vs. 32.3±7.4, p=0.007). Post-ablation, WR decreased in patients with HF (40.2±8.5 to 29.0±8.9, p=0.02) but slightly increased in those without (32.0±7.4 to 34.6±10.3, p=0.04). WR post-ablation independently predicted AF recurrence (adjusted hazard ratio=1.14 for 1 percentage point increase in the WR, 95% coincidence interval=1.02-1.34, p=0.02). CONCLUSIONS: AF ablation restores sympathetic nervous system status via attenuation of excessive adrenergic tone in HF patients. Elevated sympathetic nervous tone 3months post-ablation was a reliable predictor of AF recurrence.

DOI： 10.1016/j.ijcard.2015.07.028

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

Epicardial adipose tissue (EAT) surrounding the left atrium has been reported to have a pro-arrhythmic influence on atrial myocardium and to play an important role in the pathophysiology of atrial fibrillation (AF). The purpose of this study was to explore whether the abundance of EAT correlates with early and late recurrences of AF after ablation.
We included 53 consecutive patients with drug-refractory AF scheduled for ablation. Early and late recurrences were defined as atrial tachyarrhythmias within and after 3 months following the ablation procedure, respectively. The total and left atrial EAT volumes were obtained by 320-detector-row multislice computed tomography.
During a follow-up period of 16 +/- 4 months, early and late recurrences occurred in 29 (55 %) and 12 (23 %) patients, respectively. The left atrial EAT volume was larger in patients with than without early recurrence (35.1 +/- 13.1 vs. 25.0 +/- 9.5 cm(3), p = 0.002); however, there was no difference in the total EAT volume between the two groups (98.5 +/- 45.7 vs. 94.5 +/- 35.2 cm(3), p = 0.72). A multivariate analysis revealed that a large left atrial EAT volume, persistent AF, and large left atrial volume were independent predictors of early recurrence. Conversely, there was no significant difference in left atrial (29.3 +/- 14.6 vs. 29.7 +/- 11.7 cm(3), p = 0.93) and total EAT (91.0 +/- 50.1 vs. 97.9 +/- 37.0 cm(3), p = 0.66) volumes between patients with and without late recurrence.
The abundance of left atrial EAT independently predicted early recurrence after AF ablation; on the contrary, it did not have an impact on late recurrence. Left atrial EAT may have a pro-arrhythmic influence, especially in the early post-ablation phase.

DOI： 10.1007/s10840-015-0031-3

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Heart failure is a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or the ejection of blood, and is a leading cause of morbidity and mortality in industrialized countries. The mechanisms underlying the development of heart failure are multiple, complex and not well understood. Cardiac mass and its homeostasis are maintained by the balance between protein synthesis and degradation, and an imbalance is likely to result in cellular dysfunction and disease. The protein degradation systems are the principle mechanisms for maintaining cellular homeostasis via protein quality control. Three major protein degradation systems have been identified, namely the calpain system, autophagy, and the ubiquitin proteasome system. Proinflammatory mediators involve the development and progression of heart failure. DNA and RNA degradation systems play a critical role in regulating inflammation and maintaining cellular homeostasis mediated by damaged DNA clearance and posttranscriptional regulation, respectively. This review discusses some recent advances in understanding the role of these degradation systems in heart failure.

DOI： 10.1016/j.yjmcc.2015.05.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Cardiac hypertrophy, which is commonly caused by hypertension, is a major risk factor for heart failure and sudden death. Endogenous ghrelin has been shown to exert a beneficial effect on cardiac dysfunction and postinfarction remodeling via modulation of the autonomic nervous system. However, ghrelin's ability to attenuate cardiac hypertrophy and its potential mechanism of action are unknown. In this study, cardiac hypertrophy was induced by transverse aortic constriction in ghrelin knockout mice and their wild-type littermates. After 12 weeks, the ghrelin knockout mice showed significantly increased cardiac hypertrophy compared with wild-type mice, as evidenced by their significantly greater heart weight/tibial length ratios (9.2±1.9 versus 7.9±0.8 mg/mm), left ventricular anterior wall thickness (1.3±0.2 versus 1.0±0.2 mm), and posterior wall thickness (1.1±0.3 versus 0.9±0.1 mm). Furthermore, compared with wild-type mice, ghrelin knockout mice showed suppression of the cholinergic anti-inflammatory pathway, as indicated by reduced parasympathetic nerve activity and higher plasma interleukin-1β and interleukin-6 levels. The administration of either nicotine or ghrelin activated the cholinergic anti-inflammatory pathway and attenuated cardiac hypertrophy in ghrelin knockout mice. In conclusion, our results show that endogenous ghrelin plays a crucial role in the progression of pressure overload-induced cardiac hypertrophy via a mechanism that involves the activation of the cholinergic anti-inflammatory pathway.

DOI： 10.1161/HYPERTENSIONAHA.114.04864

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Although Atg32 is essential for mitophagy in yeast, no mammalian homolog has been identified. Here, we demonstrate that BCL2L13 (BCL2-like 13 [apoptosis facilitator]) is a functional mammalian homolog of Atg32. First, we hypothesized that a mammalian mitophagy receptor will share certain molecular features with Atg32. Using the molecular profile of Atg32 as a search tool, we screened public databases for novel Atg32 functional homologs and identified BCL2L13. BCL2L13 induces mitochondrial fragmentation and mitophagy in HEK293 cells. In BCL2L13, the BH domains are important for fragmentation, whereas the WXXI motif, an LC3 interacting region, is needed for mitophagy. BCL2L13 induces mitochondrial fragmentation and mitophagy even in the absence of DNM1L/Drp1 and PARK2/Parkin, respectively. BCL2L13 is indispensable for mitochondrial damage-induced fragmentation and mitophagy. Furthermore, BCL2L13 induces mitophagy in Atg32-deficient yeast. Induction and/or phosphorylation of BCL2L13 may regulate its activity. Our findings thus open a new chapter in mitophagy research.

DOI： 10.1080/15548627.2015.1084459

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/CIRCRESAHA.113.302024

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Background: Diabetes mellitus (DM) is a major risk factor for cardiovascular events. The study purpose was to compare DM and non-DM (nDM) patients in terms of statin-induced change of plaque characteristics using intravascular ultrasound (IVUS) and coronary angioscopy.
Methods: Patients with coronary artery disease and hypercholesterolemia who were enrolled to the TWINS were selected and classified into two groups: DM group and nDM group. Eleven DM patients and 28 nDM patients were studied.
Results: Low-density lipoprotein cholesterol levels decreased significantly to a similar extent at weeks 28 and 80 from baseline in DM and nDM (p&lt;0.001). The mean angioscopic color grades of yellow plaques in DM and nDM were similar at baseline and significantly decreased at week 80 from baseline in both groups, however, the mean change of angioscopic color grade from baseline in DM were not significantly decreased and the mean angioscopic color was significantly higher than that in nDM (1.34 vs. 1.00, p&lt;0.05) at week 28. IVUS showed plaque volume reduction in both groups (p&lt;0.01) except at week 80 in DM group, which was not statistically significant different compared to the baseline.
Conclusion: In DM patients, plaque volume regression by atorvastatin was shown to be attenuated, and its color improvement was significantly delayed. However, the yellowness became comparable between DM and nDM groups at week 80. These results indicate that patients with DM should be treated by intensive lipid-lowering therapy with atorvastatin for at least 80 weeks to stabilize vulnerable plaque. (C) 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jjcc.2013.01.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Cardiomyocytes proliferate during fetal life but lose their ability to proliferate soon after birth and further increases in cardiac mass are achieved through an increase in cell size or hypertrophy. Mammalian target of rapamycin complex 1 (mTORC1) is critical for cell growth and proliferation. Rheb (Ras homologue enriched in brain) is one of the most important upstream regulators of mTORC1. Here, we attempted to clarify the role of Rheb in the heart using cardiac-specific Rheb-deficient mice (Rheb(-/-)). Rheb(-/-) mice died from postnatal day 8 to 10. The heart-to-body weight ratio, an index of cardiomyocyte hypertrophy, in Rheb(-/-) was lower than that in the control (Rheb(+/+)) at postnatal day 8. The cell surface area of cardiomyocytes isolated from the mouse hearts increased from postnatal days 5 to 8 in Rheb(+/+) mice but not in Rheb(-/-) mice. Ultrastructural analysis indicated that sarcomere maturation was impaired in Rheb(-/-) hearts during the neonatal period. Rheb(-/-) hearts exhibited no difference in the phosphorylation level of S6 or 4E-BP1, downstream of mTORC1 at postnatal day 3 but showed attenuation at postnatal day 5 or 8 compared with the control. Polysome analysis revealed that the mRNA translation activity decreased in Rheb(-/-) hearts at postnatal day 8. Furthermore, ablation of eukaryotic initiation factor 4E-binding protein 1 in Rheb(-/-) mice improved mRNA translation, cardiac hypertrophic growth, sarcomere maturation, and survival. Thus, Rheb-dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after early postnatal period.

DOI： 10.1074/jbc.M112.423640

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Language：English   Publishing type：Part of collection (book)   Publisher：Elsevier Inc.  

DOI： 10.1016/B978-0-12-385101-7.00003-6

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DOI： 10.1038/nature11515

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Cardiomyocytes are terminally differentiated cells and thus do not have the ability to dilute damaged proteins and organelles by cell division. Thus, proteolytic and recycling systems within the cardiomyocyte are essential to maintain cardiac function. The major proteolytic systems in the cell are: the ubiquitinproteasome system, autophagy, and calpain. The ubiquitinproteasome system degrades specific proteins by labelling them with ubiquitin. Autophagy degrades cytosolic proteins and organelles; this is generally believed to be a non-specific type of degradation. Calpain is a Ca-2-sensitive cysteine protease that degrades intracellular substrates including cytoskeletal proteins, and participates in Ca-2-mediated intracellular processes. All three systems exist in the cardiomyocyte and play pivotal roles in maintaining cardiac function. However, there is still controversy regarding the role of each protein-degradation system in the heart. Our recent reports using cardiac-specific knockout mice have revealed the cardioprotective roles of autophagy and calpain in the development of heart failure. While these proteolytic systems exhibit distinct molecular mechanisms, they work cooperatively (one process can regulate another).

DOI： 10.1093/cvr/cvs236

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Authorship：Lead author   Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Constitutive autophagy is important for the control of the quality of proteins and organelles to maintain cell function. Damaged proteins and organelles accumulate in aged organs. The level of autophagic activity decreases with aging. Autophagic activity is regulated by many factors, such as the insulin receptor-signaling pathway, the TOR pathway, Sirt1, and caloric restriction. Autophagy-related genes are known to be essential for the lifespan extension of flies, nematodes, and mice. The inhibition of autophagy decreases the lifespan, and on the other hand, the induction of autophagy can prolong the lifespan. Pharmacological intervention to extend the lifespan has demonstrated a crucial role for autophagy. Heart failure is an age-related disease, as the incidence increases with age. The autophagic activity of the heart decreases during aging. Cardiac-specific autophagy-deficient mice have shown no obvious phenotype up to 10 weeks of age. However, these mice began to die after the age of 6 months, with a significant increase in the left ventricular dimensions and a decrease in the fractional shortening of the left ventricle compared with control mice. This indicates that continuous constitutive autophagy during aging has a crucial role in maintaining cardiac structure and function.

DOI： 10.1097/FJC.0b013e31824cc31c

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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

Background: Previously the stabilization of coronary plaque with atorvastatin was demonstrated in the TWINS (evaluaTion With simultaneous angIoscopy and iNtravascular ultraSound) study. The influence of the low-density lipoprotein cholesterol (LDL-C) level on plaque stabilization was analyzed.
Methods and Results: Patients (n=29) with hypercholesterolemia and coronary artery disease (CAD) were analyzed. They received atorvastatin (10-20 mg/day) for 80 weeks and were divided into low (&lt;91 mg/dl) and high (&gt;= 91 mg/dl) LDL-C groups based on their 80-week LDL-C level. Angioscopy was performed before and after treatment. Yellow coronary plaques were classified into six grades (grades 0 to 5) and mean grade was determined for each patient. The LDL-C levels at week 28 and 80 were reduced in both low LDL-C groups (n=14, 140.3 to 77.9 and 75.9 mg/dl; P&lt;0.001 both groups) and high LDL-C groups (n=15, 151.7 to 93.0 and 99.1 mg/dl; P&lt;0.001 both groups). Significant improvement in the mean grade was shown in the low LDL-C groups (1.44 to 1.00 and 1.05; P=0.003 both groups) at week 28 and 80 vs. no significant change in high LDL-C groups (1.43 to 1.23 and 1.28; P=0.032 and P=0.169 respectively).
Conclusions: Adequate reduction of LDL-C is important for the stabilization of coronary plaques. (Circ J 2012; 76: 1197-1202)

DOI： 10.1253/circj.CJ-11-0966

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Calpains make up a family of Ca(2+)-dependent intracellular cysteine proteases that include ubiquitously expressed mu- and m-calpains. Both are heterodimers consisting of a distinct large catalytic subunit (calpain 1 for mu-calpain and calpain 2 for m-calpain) and a common regulatory subunit (calpain 4). The physiological roles of calpain remain unclear in the organs, including the heart, but it has been suggested that calpain is activated by Ca(2+) overload in diseased hearts, resulting in cardiac dysfunction. In this study, cardiac-specific calpain 4-deficient mice were generated to elucidate the role of calpain in the heart in response to hemodynamic stress. Cardiac-specific deletion of calpain 4 resulted in decreased protein levels of calpains 1 and 2 and showed no cardiac phenotypes under base-line conditions but caused left ventricle dilatation, contractile dysfunction, and heart failure with interstitial fibrosis 1 week after pressure overload. Pressure-overloaded calpain 4-deficient hearts took up a membrane-impermeant dye, Evans blue, indicating plasma membrane disruption. Membrane repair assays using a two-photon laser-scanning microscope revealed that calpain 4-deficient cardiomyocytes failed to reseal a plasma membrane that had been disrupted by laser irradiation. Thus, the data indicate that calpain protects the heart from hemodynamic stresses, such as pressure overload.

DOI： 10.1074/jbc.M111.248088

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Background: The aim of this study was to compare the effect of atorvastatin treatment on high-grade yellow coronary plaques (grade &gt;= 2, group H) vs. low-grade yellow plaques (grade &lt;= 1, group L).
Methods and Results: Twenty-nine hypercholesterolemic patients with coronary heart disease were treated with atorvastatin (10-20 mg/day) for 80 weeks and were divided into 2 groups by baseline plaque color grade. The angioscopic plaque grade and the vessel, plaque, and luminal volumes were measured by intravascular ultrasound at baseline and in weeks 28 and 80. The plaque color grade decreased significantly from baseline to weeks 28 and 80 in group H (2.27 +/- 0.48, 1.47 +/- 0.75, and 1.55 +/- 0.86, respectively), but not significantly in group L (0.90 +/- 0.31, 0.83 +/- 0.61, and 0.89 +/- 0.56, respectively). The plaque volume of group HP was greater than that of group LP (respectively 158.0 +/- 45.8 vs. 107.5 +/- 21.9 mm(3) at baseline, 144.5 +/- 41.1 vs. 97.5 +/- 24.8 mm(3) in week 28, and 128.8 +/- 31.5 vs. 87.9 +/- 31.5 mm(3) in week 80 (P&lt;0.001 by ANCOVA between groups).
Conclusions: The plaque-stabilizing effect of atorvastatin was stronger for more vulnerable plaques with a higher color grade, although regression of plaque during atorvastatin therapy was noted irrespective of plaque vulnerability. (Circ J 2011; 75: 1448-1454)

DOI： 10.1253/circj.CJ-10-1035

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Constitutive autophagy is important for control of the quality of proteins and organelles to maintain cell function. Damaged proteins and organelles accumulate in aged organs. We have previously reported that cardiac-specific gene Atg5 (autophagy-related 5)-deficient mice, in which the gene was floxed out early in embryogenesis, were born normally, and showed normal cardiac function and structure up to 10 weeks old. In the present study, to determine the longer-term consequences of Atg5-deficiency in the heart, we monitored cardiac-specific Atg5-deficient mice for an additional 12 months. First, we examined the age-associated changes of autophagy in the wild-type mouse heart. The level of autophagy, as indicated by decreased LC3-II (microtubule-associated protein 1 light chain 3-II) levels, in the hearts of 6-, 14- or 26-month-old mice was lower than that of 10-week-old mice. Next, we investigated the cardiac function and life span in cardiac-specific Atg5-deficient mice. The Atg5-deficient mice began to die after the age of six months. Atg5-deficient mice exhibited a significant increase in left ventricular dimension and decrease in fractional shortening of the left ventricle at the age of 10 months, compared to control mice, while they showed similar chamber size and contractile function at the age of three months. Ultrastructural analysis revealed a disorganized sarcomere structure and collapsed mitochondria in 3- and 10-month-old Atg5-deficient mice, with decreased mitochondrial respiratory functions. These results suggest that continuous constitutive autophagy plays a crucial role in maintaining cardiac structure and function.

DOI： 10.4161/auto.6.5.11947

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

MTK1 (MEKK4) is a mitogen-activated protein kinase kinase kinase that regulates the activity of its downstream mitogen-activated kinases, p38, and c-Jun N-terminal kinase (JNK). However, the physiological function of MTK1 in the heart remains to be determined. Here, we attempted to elucidate the function of MTK1 in the heart using in vitro and in vivo models. MTK1 was activated in the hearts of mice subjected to pressure overload-induced heart failure. Overexpression of a constitutively active mutant of MTK1 (MTK1 Delta N) induced apoptosis in isolated neonatal rat cardiomyocytes, whereas a kinase domain-deleted form of MTK1 attenuated H2O2-induced apoptosis. Specific inhibitors of p38 or JNK effectively protected cardiomyocytes from MTK1 Delta N-induced cell death. In mice, cardiac-specific overexpression of MTK1 Delta N resulted in early mortality compared with the lifespan of littermate controls. Echocardiographic analysis revealed increases in end-diastolic and end-systolic left ventricular internal dimensions and a decrease in fractional shortening in MTK1 Delta N transgenic mice. In addition, the mice showed characteristic phenotypes of heart failure such as an increase in lung weight. The number of TUNEL-positive myocytes and the level of cleaved caspase 3 protein were both increased in MTK1 Delta N transgenic mice. Thus, MTK1 plays an important role in the regulation of cell death and is also involved in the pathogenesis of heart failure. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.yjmcc.2009.10.010

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Authorship：Lead author   Language：English   Publisher：JAPANESE CIRCULATION SOC  

DOI： 10.1253/circj.CJ-09-0907

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Cardiomyocyte death plays an important role in the pathogenesis of heart failure. The nuclear factor (NF)-kappa B signaling pathway regulates cell death, however, the effect of NF-kappa B pathway on cell death can vary in different cells or stimuli. The purpose of the present study was to clarify the in vivo role of the NF-kappa B pathway in response to pressure overload. First, we subjected C57B16/J mice to pressure overload by means of transverse aortic constriction (TAC) and examined the activity of the NF-kappa B pathway in response to pressure overload. I kappa B kinase (IKK) and NF-kappa B were activated after TAC. Then, we investigated the role of the activation using cardiac-specific IKK beta-deficient mice (CKO). CKO displayed normal global cardiac structure and function compared with control littermates. We subjected CKO and control mice to pressure overload. One week after TAC, CKO showed cardiac dilation, dysfunction, and lung congestion, which are characteristics of heart failure. The number of apoptotic cells in the hearts of CKO mice increased significantly after TAC. The levels of manganese superoxide dismutase mRNA and protein expression in CKO after TAC were significantly attenuated compared with control mice. The levels of oxidative stress and c-Jun N-terminal kinase (JNK) activation in CKO after TAC were significantly greater than those in control mice. Isoproterenol-induced cell death of isolated adult CKO cardiomyocytes was inhibited by treatment with either a manganese superoxide dismutase mimetic or a JNK inhibitor. Thus, the IKK beta/NF-kappa B signaling pathway plays a protective role in cardiomyocytes because of the attenuation of oxidative stress and JNK activation in a setting of acute pressure overload. (Circ Res. 2009; 105: 70-79.)

DOI： 10.1161/CIRCRESAHA.108.193318

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

Background: The aim of this stud was to elucidate the time course of atorvastatin-induced changes in vulnerable plaque using angioscopy and intravascular ultrasound (IVUS).
Methods and Results: Fifty-seven hypercholesterolemic patients with coronary artery disease (CAD) were treated with atorvastatin (10-20 mg/day) for 80 weeks and then coronary plaques were evaluated with angioscopy and IVUS. Angioscopic images were classified into 6 grades (0-5) based on yellow color intensity. A 20-mm segment containing angioscopically-identified yellow plaque was also examined by IVUS to measure atheroma volume. The mean angioscopic grade of 58 yellow plaques significantly decreased from 1.5 (95% confidence interval [CI] 1.2 to 1.8) to 1.1 (95%CI 0.9 to 1.3, P=0.012) at week 28 and 1.2 (95%CI 0.9 to 1.4, P=0.024) at week 80. Mean volume of 30 lesions, including the 58 yellow plaques, significantly reduced -8.3% (95%CI -11.5 to -5.2) at week 28 (P&lt;0.001 for baseline vs week 28) and -17.8% (95%CI -23.9 to -11.8) at week 80 (P&lt;0.001 for baseline vs week 80).
Conclusions: In patients with CAD treated with atorvastatin, serial analysis with angioscopy demonstrated early loss of yellow color in plaques, and IVUS volumetric analysis showed subsequent plaque regression. Both changes possibly indicate reduction of plaque vulnerability in an additive manner. (Circ J 2009;73:718-725)

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Ferritin heavy chain (FHC) protein was significantly reduced in murine failing hearts following left coronary ligation or thoracic transverse aortic constriction. The mRNA expression of FHC was not significantly altered in failing hearts, compared to that in control sham-operated hearts. Prussian blue staining revealed spotty iron depositions in myocardial infarct failing hearts. Oxidative stress was enhanced in the myocardial infarct failing hearts, as evidenced by increases in 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine immunoreactivity. To clarify the functional significance of FHC downregulation in hearts, we infected rat neonatal cardiomyocytes with adenoviral vector expressing short hairpin RNA targeted to FHC (Ad-FHC-RNAi). The downregulation of FHC induced a reduction in the viability of cardiomyocytes. The relative number of iron deposition-. 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cardiomyocytes was significantly higher in Ad-FHC-RNAi-infected cardiomyocytes than in control vector-infected cardiomyocytes. Treatment of Ad-FHC-RNAi-infected cardiomyocytes with desferrioxamine, an iron chelator, significantly reduced the number of iron. 4-hydroxy-2-nonenal or 8-hydroxy-2'-deoxyguanosine-positive cells, and increased viability. In addition, treatment with N-acetyl cysteine, an antioxidant, significantly reduced the number of 4-hydroxy-2-nonenal- or 8-hydroxy-2'-deoxyguanosine-positive cells. Reduced viability in Ad-FHC-RNAi-infected cardiomyocytes was significantly improved with N-acetyl cysteine treatment. These findings indicate that excessive free iron and the resultant enhanced oxidative stress caused by downregulation of FHC lead to cardiomyocyte death. The decrease in FHC expression in failing hearts may play an important role in the pathogenesis of heart failure. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yjmcc.2008.09.714

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Autophagy is a cell survival mechanism that involves degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In addition, autophagy mediates cell death under specific circumstances. Apoptosis, a form of programmed cell death, has been well characterized, and the molecular events involved in apoptotic death are well understood. Damaged cardiomyocytes that show characteristics of autophagy have been observed during heart failure. However, it remains unclear whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for the failing cardiomyocytes. Although autophagy and apoptosis are markedly different processes, several pathways regulate both autophagic and apoptotic machinery and autophagy can cooperate with apoptosis. This review summarizes the evidence for crosstalk between autophagy and apoptosis.

DOI： 10.1161/CIRCRESAHA.108.175448

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

Objectives This study examined whether a reduction in hemoglobin-oxygen affinity improves exercise capacity in mice with heart failure.
Background Exercise intolerance is a major determinant of quality of life in patients with chronic heart failure. One of the major goals of the treatment for chronic heart failure is to improve quality of life.
Methods Four weeks after left coronary ligation, we transplanted bone marrow cells isolated from the transgenic mice expressing a hemoglobin variant with low oxygen affinity, Presbyterian, into the lethally irradiated mice with heart failure or administered a synthetic allosteric modifier of hemoglobin. The mice were then exercised on a treadmill.
Results Four weeks after the left coronary artery ligation, mice showed cardiac dysfunction and chamber dilation, which were characteristics of heart failure. The transplantation led to a reduction in hemoglobin-oxygen affinity and an increase in oxygen supply for skeletal muscle without changes in muscle properties. The transplanted mice showed improved running performance on a treadmill despite impaired cardiac contractility. Furthermore, administration of the synthetic allosteric modifier of hemoglobin showed a similar effect.
Conclusions Allosteric modification of hemoglobin represents a therapeutic option for improving exercise capacity in patients with chronic heart failure. One mechanism of improvement in exercise capacity is enhanced oxygen delivery in the skeletal muscle.

DOI： 10.1016/j.jacc.2008.06.003

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

Intracellular lipid accumulation (steatosis) and resultant lipotoxicity are key features of diabetic cardiomyopathy. Since cardiac hormone-sensitive lipase (HSL) is activated in diabetic mice, we sought to explore a pathophysiological function of cardiac HSL in the development of diabetic cardiomyopathy. Transgenic (Tg) mice with heart-specific HSL overexpression were generated, and cardiac histology, function, lipid profile, and gene expressions were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wild-type (Wt) hearts after 3 wk of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac content of acylglycerides was increased similar to 50% with diabetes in Wt mice, whereas this was blunted in Tg hearts. Cardiac lipid peroxide content was twofold lower in Tg hearts than in Wt hearts. The mRNA expressions for peroxisome proliferator-activated receptor-alpha, genes for triacylglycerol synthesis, and lipoprotein lipase were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Expression of genes associated with lipoapoptosis was decreased, whereas antioxidant protein metallothioneins were increased in diabetic Tg hearts. Diabetic Wt hearts showed interstitial fibrosis and increased collagen content. However, Tg hearts displayed no overt fibrosis, concomitant with decreased expression of collagens, transforming growth factor-beta, and matrix metalloproteinase 2. Notably, mortality during the experimental period was approximately twofold lower in diabetic Tg mice compared with Wt mice. In conclusion, since HSL overexpression inhibits cardiac steatosis and fibrosis by apparently hydrolyzing toxic lipid metabolites, cardiac HSL could be a therapeutic target for regulating diabetic cardiomyopathy.

DOI： 10.1152/ajpendo.00016.2008

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Background - Mechanical stress on the heart can lead to crucially different outcomes. Physiological stimuli such as exercise cause adaptive cardiac hypertrophy, characterized by a normal cardiac structure and normal or enhanced cardiac function. Pathological stimuli such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure. Apoptosis signal-regulating kinase 1 (ASK1) is known to be involved in pathological cardiac remodeling, but it has not been determined whether ASK1 pathways coordinate the signaling cascade leading to physiological type cardiac growth.
Methods and Results - To evaluate the role of ASK1 in the physiological form of cardiac growth, mice lacking ASK1 (ASK1(-/-)) were exercised by swimming for 4 weeks. ASK1(-/-) mice showed exaggerated growth of the heart accompanied by typical characteristics of physiological hypertrophy. Their swimming-induced activation of Akt, a key molecule in the signaling cascade of physiological hypertrophy, increased more than that seen in wild-type controls. The activation of p38, a downstream kinase of ASK1, was suppressed selectively in the swimming-exercised ASK1(-/-) mice. Furthermore, the inhibition of ASK1 or p38 activity enhanced insulin-like growth factor 1-induced protein synthesis in rat neonatal ventricular cardiomyocytes, and the treatment with a specific inhibitor of p38 resulted in enhancement of Akt activation and suppression of protein phosphatase 2A activation. The cardiac-specific p38 alpha-deficient mice developed an exacerbated form of cardiac hypertrophy in response to swimming exercise.
Conclusions - These results indicate that the ASK1/p38 signaling pathway negatively regulates physiological hypertrophy.

DOI： 10.1161/CIRCULATIONAHA.107.710434

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Objectives We examined whether the inhibition of apoptosis signal-regulating kinase 1 (ASK1) would attenuate the progression of heart failure in TO-2 hamsters with hereditary dilated cardiomyopathy.
Background Heart failure remains the leading cause of mortality and requires novel therapies targeting the biologically relevant processes within cardiomyocytes that lead to cell death. Apoptosis signal-regulating kinase 1 is a key signaling molecule for cardiomyocyte death.
Methods We generated recombinant adeno-associated virus (rAAV) expressing an N-terminal truncated form of the dominant-negative mutant of ASK1 (ASK Delta N(KR)). TO-2 hamsters were subjected to an in vivo rAAV transcoronary transfer.
Results ASK Delta N(KR) retained its dominant-negative activity in vitro. The rAAV expressing ASK Delta N(KR) treatment inhibited ASK1 activation in the hamster hearts and suppressed progression of ventricular remodeling such as chamber dilation, impairment of contractile and relaxation functions, and fibrosis. Inhibition of ASK1 reduced the number of apoptotic cells and selectively attenuated c-Jun NH2-terminal kinase activation. Although the deficiency of delta-sarcoglycan, a genetic defect in the hamster, leads to the degradation of dystrophin, the treatment significantly protected hearts from this degradation, probably by inhibiting calpain activation.
Conclusions Apoptosis signal-regulating kinase I is involved in the pathogenesis of heart failure progression, mediated through c-Jun NH2-terminal kinase-mediated apoptosis and calpain-dependent dystrophin cleavage, and may be a therapeutic target to treat patients with heart failure.

DOI： 10.1016/j.jacc.2007.03.053

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (O-2(center dot)), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that O-2(center dot) generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.

DOI： 10.1074/jbc.M602118200

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

The innate immune system senses viral infection by recognizing a variety of viral components (including double-stranded (ds) RNA) and triggers antiviral responses(1,2). The cytoplasmic helicase proteins RIG-I (retinoic-acid-inducible protein I, also known as Ddx58) and MDA5 (melanoma-differentiation-associated gene 5, also known as Ifih1 or Helicard) have been implicated in viral dsRNA recognition(3-7). In vitro studies suggest that both RIG-I and MDA5 detect RNA viruses and polyinosine-polycytidylic acid (poly(I:C)), a synthetic dsRNA analogue(3). Although a critical role for RIG-I in the recognition of several RNA viruses has been clarified(8), the functional role of MDA5 and the relationship between these dsRNA detectors in vivo are yet to be determined. Here we use mice deficient in MDA5 (MDA5(-/-)) to show that MDA5 and RIG-I recognize different types of dsRNAs: MDA5 recognizes poly(I:C), and RIG-I detects in vitro transcribed dsRNAs. RNA viruses are also differentially recognized by RIG-I and MDA5. We find that RIG-I is essential for the production of interferons in response to RNA viruses including paramyxo-viruses, influenza virus and Japanese encephalitis virus, whereas MDA5 is critical for picornavirus detection. Furthermore, RIG-I-/- and MDA5(-/-) mice are highly susceptible to infection with these respective RNA viruses compared to control mice. Together, our data show that RIG-I and MDA5 distinguish different RNA viruses and are critical for host antiviral responses.

DOI： 10.1038/nature04734

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Genetic studies of families with familial Alzheimer's disease have implicated presenilin 2 (PS2) in the pathogenesis of this disease. PS2 is ubiquitously expressed in various tissues including hearts. In this study, we examined cardiac phenotypes of PS2 knockout (PS2KO) mice to elucidate a role of PS2 in hearts. PS2KO mice developed normally with no evidence of cardiac hypertrophy and fibrosis. Invasive hemodynamic analysis revealed that cardiac contractility in PS2KO mice increased compared with that in their littermate controls. A study of isolated papillary muscle showed that peak amplitudes of Ca2+ transients and peak tension were significantly higher in PS2KO mice than those in their littermate controls. PS2KO mouse hearts exhibited no change in expression of calcium regulatory proteins. Since it has been demonstrated that PS2 in brain interacts with sorcin, which serves as a modulator of cardiac ryanodine receptor (RyR2), we tested whether PS2 also interacts with RyR2. Immmunoprecipitation analysis showed that PS2, sorcin, and RyR2 interact with each other in HEK-293 cells overexpressing these proteins or in mouse hearts. Immunohistochemistry of heart muscle indicated that PS2 colocalizes with RyR2 and sorcin at the Z-lines. Elevated Ca2+ attenuated the association of RyR2 with PS2, whereas the association of sorcin with PS2 was enhanced. The enhanced Ca2+ transients and contractility in PS2KO mice were observed at low extracellular [Ca2+] but not at high levels of [Ca2+]. Taken together, our results suggest that PS2 plays an important role in cardiac excitation-contraction coupling by interacting with RyR2.

DOI： 10.1096/fj.05-3744fje

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The molecular basis of myocardial cell death in the ischernia-reperfused heart still remains to be clarified. Apoptosis signal-regulating kinase I (ASK I) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We studied ASKl(-/-) mice to examine the role of ASKl in ischemia-reperfusion injury. In the wild-type heart, ischemia-reperfusion resulted in necrotic injury, whereas infarct size was drastically reduced in the ASKl(-/-) heart. The necrotic injury was not accompanied with any evidence of apoptosis such as an increase in TUNEL-positive cells, DNA fragmentation or the activation of caspase-3. ASKl(-/-) cardiomyocytes were more resistant to H2O2- or Ca2+-induced apoptotic and non-apoptotic cell death compared with wild-type cells. These data suggest that ASKl is involved in necrosis as well as apoptosis and that ASKl-dependent necrosis is likely to contribute to myocardial cell death in the ischemia-reperfused heart. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.05.151

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one ( edaravone) is used to treat patients with ischemic brain damage. We and others reported previously that in vitro and in vivo reactive oxygen species (ROS) act as second messengers to develop cardiac hypertrophy. In this study, we used an in vivo murine model of pressure overload-induced cardiac hypertrophy to examine the effects of edaravone on left ventricular hypertrophy. The animals were subjected to the transverse thoracic aorta constriction, and edaravone (10 mg/kg) was infused intraperitoneally twice daily. Seven days after the operation, we observed a significant increase in ROS production in hearts, which was eliminated by the treatment with edaravone. Pressure-overloaded hearts showed a significant increase in left ventricular weight/body weight ratio and the expression level of atrial natriuretic factor mRNA, which were attenuated by edaravone. It also reduced perivascular and intermuscular fibrosis and inhibited pressure overload-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream kinases of c-Jun N-terminal protein kinase and p38 mitogen-activated protein kinase. Edaravone attenuated the hypertrophic response even when the treatment was started after the onset of cardiac hypertrophic response. These findings indicate that edaravone significantly attenuates pressure overload-induced cardiac hypertrophy mediated through its antioxidative function and subsequent inhibition of ASK1 signaling pathway.

DOI： 10.1161/01.HYP.0000163461.71943.e9

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Ca2+/calmodulin-dependent protein kinase (CaMK) is an important downstream target of Ca2+ in the hypertrophic signaling pathways. We previously showed that the activation of apoptosis signal-regulating kinase 1 (ASK1) or NF-kappaB is sufficient for cardiomyocyte hypertrophy. Infection of isolated neonatal cardiomyocytes with an adenoviral vector expressing CaMKIIdelta3 (AdCaMKIIdelta3) induced the activation of ASK1, while KN93, an inhibitor of CaMKII, inhibited phenylephrine-induced ASK1 activation. Overexpression of CaMKIIdelta3 induced characteristic features of in vitro cardiomyocyte hypertrophy. Infection of cardiomyocytes with an adenoviral vector expressing a dominant negative mutant of ASK1 (AdASK(KM)) inhibited the CaMKII83-induced hypertrophic responses. Overexpression of CaMKIIdelta3 increased the kappaB-dependent promoter/luciferase activity and induced IkappaBalpha degradation. Coinfection with AdCaMKIIdelta3 and AdASK(KM), and pre-incubation with KN93 attenuated CaMKIIdelta3- and phenylephrine-induced NF-kappaB activation, respectively. Expression of a degradation resistant mutant of IkappaBalpha inhibited CaMKIIdelta3-induced hypertrophic responses. These results indicate that CaMKIIdelta3 induces cardiomyocyte hypertrophy mediated through ASK1-NF-kappaB signal transduction pathway. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.12.002

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Background-Signal transducer and activator of transcription (STAT) proteins constitute a family of transcription factors that mediate many cytokine-induced responses. STAT6 is activated by angiotensin II and in rat hypertrophied hearts and in human hearts with dilated cardiomyopathy. This suggests that STAT6 may be involved in the pathogenesis of cardiac hypertrophy and heart failure. For this study we used STAT6-deficient (STAT6(-/-)) mice to examine the in vivo role of STAT6.
Methods and Results-STAT6(-/-) hearts showed no morphological, histological, or functional defects. We examined left ventricular structural and functional remodeling 1 week after thoracic transverse aortic constriction (TAC). Western blot and immunohistochemical analyses showed increased STAT6 activity after TAC in the heart of wild-type mice. STAT6(-/-) mice showed a significant increase in end-diastolic left ventricular internal dimension accompanied by impaired contractility compared with wild-type mice but no differences in hypertrophic parameters. The number of terminal deoxynucleotidyl transferase-mediated biotin dUTP nick-end labeling-positive myocytes after TAC had increased in STAT6(-/-) compared with wild-type mice. Prolonged induction of tumor necrosis factor-alpha (TNF-alpha) mRNA was observed in STAT6(-/-) hearts, whereas TNF-alpha mRNA was only transiently induced in wild-type mice. Tristetraprolin was induced after TAC in wild-type mice but not in STAT6(-/-) mice. Tristetraprolin reporter assay with the use of isolated neonatal cardiomyocyte indicated that the promoter was significantly activated by endothelin-1 in wild-type but not in STAT6(-/-) cardiomyocytes. The lack of promoter activation by endothelin-1 in STAT6(-/-) cardiomyocytes was rescued by forced expression of STAT6.
Conclusions-STAT6 plays a protective role against hemodynamic stress in hearts.

DOI： 10.1161/01.CIR.0000146798.70980.9A

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

Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in the heart might impair cardiac function, transgenic (TG) mice were generated with cardiac-specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG epitope). The level of NF-SLN expression (the NF-SLN/PLN expression ratio) was equivalent to that which induces profound superinhibition when coexpressed with PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a for Ca2+ was decreased compared with non-TG littermate control hearts. Invasive hemodynamic and echocardiographic analyses revealed impaired cardiac contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation was reduced. In isolated papillary muscle subjected to isometric tension, peak amplitudes of Ca2+ transients and peak tensions were reduced, whereas decay times of Ca2+ transients and relaxation times of tension were increased in TG mice. Isoproterenol largely restored contractility in papillary muscle and stimulated PLN phosphorylation to wild-type levels in intact hearts. No compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through stabilization of SERCA2a-PLN interaction in the absence of PLN phosphorylation and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may prevent progression to heart failure.

DOI： 10.1073/pnas.0402596101

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

G-protein-coupled receptor agonists including endothelin-1 (ET-1) and phenylephrine (PE) induce hypertrophy in neonatal ventricular cardiomyocytes. Others and we previously reported that Rac1 signaling pathway plays an important role in this agonist-induced cardiomyocyte hypertrophy. In this study reported here, we found that a Ca2+-sensitive non-receptor tyrosine kinase, proline-rich tyrosine kinase 2 (Pyk2)/cell adhesion kinase beta (CAKbeta), is involved in ET-1- and PE-induced cardiornyocyte hypertrophy medicated through Rac1 activation. ET-1, PE or the Ca2+ inophore, ionomycin, stimulated a rapid increase in tyrosine phosphorylation of Pyk2. The tyrosine phosphorylation of Pyk2 was suppressed by the Ca2+ chelator, BAPTA. ET-1- or PE-induced increases in [H-3]-leucine incorporation and expression of atrial natriuretic factor and the enhancement of sarcomere organization. Infection of cardiomyocytes with an adenovirus expressing a mutant Pyk2 which lacked its kinase domain or its ability to bind to c-Src, eliminated ET-1- and PE-induced hypertrophic responses. Inhibition of Pyk2 activation also suppressed Rac1 activation and reactive oxygen species (ROS) production. These findings suggest that the signal transduction pathway leading to hypertrophy involves Ca2(+) induced Pyk2 activation followed by Rac1-dependent ROS production. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.yjmcc.2004.03.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The small guanine nucleotide-binding protein Rac1 has emerged as an important molecule involved in cardiac myocyte hypertrophy. Recently, we reported on apoptosis signal-regulating kinase (ASK) 1 and a transcriptional factor, nuclear factor-kappaB (NF-kappaB), as novel signaling intermediates in cardiac myocyte hypertrophy. The aim of the study presented here was to clarify the role of Rac1 in the ASK1-NF-kappaB signaling pathway. Infection of isolated neonatal cardiac myocytes with an adenovirus expressing a constitutively active form of Rac1 (RacV12) enhanced the expression of a kappaB-dependent reporter gene construct and induced the degradation of IkappaBalpha. Expression of a degradation-resistant mutant of IkappaBalpha inhibited the RacV12-induced hypertrophic responses, including increases in protein synthesis and atrial natriuretic factor production and the enhancement of sarcomeric organization. An immune complex kinase assay indicated that the expression of RacV12 activated ASK1. Expression of a dominant negative mutant of ASK1 eliminated the RacV12-induced NF-kappaB activation and the biochemical and morphological hypertrophic responses, whereas expression of a dominant negative form of Rac1 attenuated phenylephrine-induced activation of ASK1 and NF-kappaB and cardiac myocyte hypertrophy. These findings suggest that Rac1 induces cardiac myocyte hypertrophy mediated through ASK1 and NF-kappaB.

DOI： 10.1074/jbc.M213203200

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The p38 mitogen-activated protein kinase (p38) is activated in the heart during ischemia-reperfusion. However, it is not clear whether the activation of p38 is the protective response or the kinase mediates the cellular damage by ischemia-reperfusion. We examined the role of p38alpha in ischemia-reperfusion injury by studying p38alpha(+/-) mice. The p38alpha protein level in the p38alpha(+/-) heart was 50+/-8.7% compared with that in the p38alpha(+/+) heart. Upon reperfusion following ischemia for 25 min, p38alpha activity was transiently increased. The maximum level of p38 activity in p38alpha(+/-) was 60+/-10.5% compared with that in p38alpha(+/+). In the p38alpha(+/+) heart, 25 min ischemia and 2 h reperfusion resulted in necrotic injury (37.1+/-2.7% of the area at risk), whereas infarct size was drastically reduced to 7.2+/-0.7% in the P38alpha(+/-) heart. These suggested that p38alpha plays a pivotal role in the signal transduction pathway mediating myocardial cell death caused by ischemia-reperfusion. (C) 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(03)00096-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

In cardiomyocytes, calcium plays important roles as a signal in cardiac hypertrophy and contraction-relaxation cycling. Elevation of Ca2+ concentration in myoplasm is associated with the onset and progression of hypertrophy as well as the enhancement of contractility. The cardiac Ca2+ ATPase (SERCA2a) of the sarcoplasmic reticulum plays a dominant role in lowering cytoplasmic calcium levels during relaxation and is regulated by phospholamban (PLN). To examine whether the modulation of SERCA2a activity results in the attenuation of cardiac hypertrophy and enhancement of contractility, we generated transgenic mice (TG) overexpressing a high calcium affinity SERCA2a mutant (K397/400E), lacking a functional association with PLN. In the TG hearts, the apparent affinity of SERCA2a for Ca2+ significantly increased compared with their nontransgenic littermate controls. The TG showed increased contraction and relaxation, with increases in the amplitude of Ca2+ transient and rapid Ca2+ decay. Upon induction of pressure overload by transverse aortic constriction, the TG developed less cardiac hypertrophy than littermate controls did. The activation of Ca2+-sensitive protein kinase C by pressure overload was significantly attenuated in the TG hearts. Our findings indicate an association of SERCA2a activity with cardiac hypertrophy and thus a new therapeutic target for the prevention and treatment of cardiac hypertrophy.

DOI： 10.1096/fj.02-0474fje

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

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OBJECTIVES In order to identify the role of reactive oxygen species (ROS) in cardiac hypertrophy, we examined the effect of N-2-mercaptopropionyl glycine (MPG) on cardiac hypertrophy.
BACKGROUND Recent in vitro studies have suggested that ROS play an important role as a second messenger in cardiac hypertrophy. It was therefore thought to be of particular value to examine the relevance of studies using in vitro models for cardiac hypertrophy in an in vivo setting.
METHODS The transverse thoracic aorta in mice was constricted, and MPG (100 mg/kg) was infused intraperitoneally twice daily. The animals were assessed seven days after the operation for hemodynamic functions, oxidative stress and antioxidative enzyme activities.
RESULTS Banding of the transverse aorta in mice resulted in an increase in the ratio of heart weight to tibia length and the appearance of an endogenous atrial natriuretic factor messenger ribonucleic acid (mRNA) seven days postoperatively. Administration of IMPG significantly attenuated the hypertrophic responses induced by pressure overload. Cardiac hypertrophy was accompanied by increases in heme oxygenase-1 mRNA expression and lipid peroxidation, which was eliminated by the treatment with MPG. Pressure overload led to increases in antioxidant enzyme activities, such as superoxide dismutase and glutathione peroxidase, but not catalase, activity.
CONCLUSIONS Our results indicated that oxidative stress was increased in our model and that it plays an important role in the development of cardiac hypertrophy. (C) 2002 by the American College of Cardiology Foundation.

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We examined the intracellular signaling mechanism for tumor necrosis factor-alpha (TNF-alpha)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes, TNF-alpha enhanced the expression of a kappaB-dependent reporter gene construct in a dose-dependent manner, which was transiently transfected in cardiomyocytes. Electrophoretic mobility shift assay demonstrated that TNF-alpha induced nuclear factor-kappaB (NF-kappaB)-specific DNA binding. Cultured cardiomyocytes were infected with a recombinant adenoviral vector expressing a degradation-resistant mutant of IkappaBalpha (AdIkappaBalpha32/36A). The IkappaBalpha mutant suppressed NF-kappaB activation induced by TNF-alpha. In cardiomyocytes infected with AdIkappaBalpha32/36A, TNF-alpha-induced hypertrophic responses, including increases in cell size, protein synthesis and atrial natriuretic factor production and enhancement of sarcomeric organization, were remarkably attenuated compared to the cells infected with an adenovirus expressing bacterial beta-galactosidase. Using a reactive oxygen species (ROS)-sensitive fluorescent dye, 2', 7'-dichlorofluorescin, we observed an increase in fluorescent signal in cardiomyocytes over time, upon addition of TNF-alpha Preincubation of n-acetyl cysteine (NAC), an antioxidant, prior to TNF-alpha treatment, abolished TNF-alpha -induced ROS generation. NAC abolished TNF-alpha-induced NF-kappaB activation and hypertrophic responses. These findings indicated that TNF-alpha-induced cardiomyocyte hypertrophy is mediated through NF-kappaB activation via the generation of ROS. (C) 2002 Elsevier Science Ltd.

DOI： 10.1006/jmcc.2001.1505

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background-Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-kappaB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase I (ASK1), in G-protein-coupled receptor (GPCR) agonist (angiotensin 11, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes.
Methods and Results-Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-kappaB activation. Antioxidants such as N-acetyl cysteine, N-mercaptopropionyl glycine, and vitamin E attenuated the NF-kappaB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant Of IkappaBalpha led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist-induced NF-kappaB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF-kappaB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-kappaB activation.
Conclusions-These data indicate that GPCR agonist-induced cardiac hypertrophy is mediated through NF-kappaB activation via the generation of ROS. ASK1 is involved in GPCR agonist-induced NF-kappaB activation and resulting hypertrophy.

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

OBJECTIVES To test our hypothesis that the development of vulnerable plaques is not limited to the culprit lesions, but is a pan-coronary process, we directly observed all three major coronary arteries by angioscopy and evaluated the prevalence of yellow plaques in patients with myocardial infarction (MI).
BACKGROUND Although pathologic studies have suggested that the disruption of atheromatous plaque plays a major role in the development of acute MI, the prevalence of yellow plaques in the whole coronary arteries of patients with MI has not been clarified.
METHODS Thirty-two patients undergoing follow-up catheterization one month after the onset of MI were prospectively and consecutively enrolled in this study. The prevalence of yellow plaques and thrombus in the major coronary arteries was successfully evaluated in 20 patients (58 coronary arteries, 21 culprit lesions) by coronary angioscopy. The diameter stenosis (DS) of the culprit lesions and the maximal diameter stenosis (maxDS) of nonculprit segments were angiographically measured for each coronary artery.
RESULTS The DS of the culprit lesions and maxDS were 27 +/- 17% and 19 +/- 13%, respectively. Yellow plaques and thrombus were detected in 19 (90%) and 17 (81%) of 21 culprit lesions, respectively. Yellow plaques were equally prevalent in the infarct-related and non-infarct-related coronary arteries (3.7 +/- 1.6 vs. 3.4 +/- 1.8 plaques/artery). However, thrombus was only detected in the nonculprit segments of one (2%) coronary artery.
CONCLUSIONS In patients with MI, all three major coronary arteries are widely diseased and have multiple yellow though nondisrupted plaques. Acute MI may represent the pan-coronary process of vulnerable plaque development. (J Am Cell Cardiol 2001;37:1284-8) (C) 2001 by the American College of Cardiology.

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OBJECTIVES: To clarify the healing process of disrupted culprit plaques of acute myocardial infarction (MI), we serially observed the culprit plaques for 18 months after the onset of acute MI by angioscopy. BACKGROUND: Although it has been reported that disruption of the yellow plaque and subsequent thrombosis cause acute MI and that the thrombogenicity of the plaque lasts for a month, the healing process of the plaque after disruption has not been clarified. METHODS: Eighty-five patients with acute MI were prospectively and consecutively enrolled. Angioscopic studies were performed immediately and at 1, 6 and 18 months after successful reperfusion. The prevalence of yellow plaques and thrombus was examined. The color grade of the plaque was determined as 0 (white), 1 (light yellow), 2 (yellow) or 3 (bright yellow). RESULTS: Although yellow plaque was present at the culprit lesion in most patients throughout follow-up, its color grade was reduced from one to six months (1.9 ± 0.6 vs. 1.1 ± 0.7, p = 0.0003) after reperfusion, especially in the patients without hyperlipidemia (HL). The incidence of thrombus was 92.5% immediately after reperfusion, which was reduced significantly to 63.8%, 4.8% and 11.8% at 1, 6 and 18 months, respectively. The incidence of thrombus (77.8% vs. 45.0%, p = 0.03) at one month was higher in the patients with diabetes mellitus (DM). CONCLUSIONS: The healing process of yellow plaques at the culprit lesions of MI was detected by angioscopy as reductions of color grade and thrombogenicity at six months and partially at one month after the onset of acute MI. This healing process appears to deteriorate by complicating cases of DM or HL. © 2001 by the American College of Cardiology.

DOI： 10.1016/S0735-1097(01)01673-4

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Language：Japanese   Publisher：(一社)日本集中治療医学会  

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Objectives: To clarify the underlying mechanism for the high restenosis rate after the coronary angioplasty for the chronic total occlusion by using the coronary angioscope. Background: Coronary angioplasty for the chronic total occlusion is associated with higher restenosis rate than for highly stenotic lesion. However, the difference in the restenosis rate has not been discussed from the angioscopic observation. Methods and Results: The lesion morphology after coronary intervention were classified into 4 grade (Grade 0 = no intimal flap
Grade 1 = intimal flap without protrusion
Grade 2 = Intimal flap with protrusion not occlusive
Grade 3 = protruding intimal flaps with occlusion of the vessel lumen). Coronary angioscopic observation was performed in 46 patients with stable angina. Most of the lesion morphology after angioplasty in 13 patients with chronic total occlusion was grade 3. On the other hand, none of grade 3 was observed in 36 patients with severe coronary stenosis. Conclusion: The various protrusions into the lumen shown by the angioscope might be a reason for higher restenosis and reocclusion rates compared with those after the angioplasty for the severe stenotic lesion.

DOI： 10.1155/DTE.7.7

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Language：Japanese   Publisher：日本心脈管作動物質学会  

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

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＜Point＞1 オートファジーは細胞内分解機構の1つであり、細胞内構造物やオルガネラの恒常性を維持し、細胞保護的に作用する。2 オートファジーは、代償期では抑制されることにより、非代償期では促進されることにより、リモデリングに関与している。3 オートファジーおよびマイトファジーの制御機構を明らかにすることにより、心不全の新しい治療標的となる可能性がある。(著者抄録)

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Language：Japanese   Publisher：医歯薬出版(株)  

2016年大隅良典博士のノーベル医学・生理学賞受賞によって、オートファジーは大きな注目を集めている。心臓におけるオートファジーについても、古くからその存在が知られていたものの、その意義については長く不明であった。哺乳類におけるオートファジーの機能がつぎつぎと報告されるなか、心筋細胞特異的Atg5(autophagy related 5)欠損遺伝子改変マウスの作製・解析によって、恒常的条件下、血行動態ストレス下、加齢でのオートファジーの心保護機能が明らかになった。近年は、オートファジー誘導能を有する物質が心血管保護作用を発揮することが動物実験やヒトを対象とした研究においても報告されている。また、既存薬剤のスクリーニングにおいて明らかにされたオートファジー誘導能を有する薬剤にも心保護作用を有する薬剤が含まれていることが報告されており、今後オートファジー誘導に基づくあらたな治療が開発されることが期待される。(著者抄録)

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Language：Japanese   Publisher：(株)最新医学社  

種々の心疾患に伴う心臓リモデリングにかかわる現象に、心筋細胞死が挙げられる。細胞死は大きくregulated cell death(RCD)とaccidental cell death(ACD)に分類される。RCDとしては、アポトーシスやオートファジーなどさまざまな細胞死にかかわる分子機構が明らかにされてきた。また、従来はACDと考えられてきたネクローシスにも制御機構の存在が解明されてきた。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2016265174

Language：Japanese   Publisher：(株)医学書院