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

Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of the viral load has passed; however, its underlying mechanisms remain unclear. In the present study, analysis of the alveolar tissue injury markers and epithelial cell death markers in patients with COVID-19 revealed that COVID-19-induced ARDS was characterized by alveolar epithelial necrosis at an early disease stage. Serum levels of HMGB-1, one of the DAMPs released from necrotic cells, were also significantly elevated in these patients. Further analysis using a mouse model mimicking COVID-19-induced ARDS showed that the alveolar epithelial cell necrosis involved two forms of programmed necrosis, namely necroptosis, and pyroptosis. Finally, the neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. Collectively, necrosis, including necroptosis and pyroptosis, is the predominant form of alveolar epithelial cell death at an early disease stage and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.

DOI： 10.1016/j.isci.2022.105748

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本臨床救急医学会  

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Language：Japanese   Publisher：(一社)日本臨床救急医学会  

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Language：Japanese   Publisher：(株)へるす出版  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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

2019年末に中国・湖北省武漢市ではじまった新型コロナウイルス感染症(COVID-19)は、そのパンデミックにより世界中で医療逼迫を引き起こした。これにより医療資源の再分配、患者層別化を目的に機械学習を用いて多くのCOVID-19患者の予後予測モデルが研究開発された。従来の統計学的手法と異なり、機械学習を用いたモデルを臨床応用するにはアプリケーションによる実装化が必要になる。その場合、当該プログラムが薬事関連の法律に該当する可能性を研究の開始段階で考慮する必要がある。2021年に医療機器プログラム(SaMD)の研究開発を推進するために、その該当性に関するガイドラインおよび相談窓口の一元化など、規制当局の体制が整備された。今後、人工知能(AI)を組み込んだSaMDの研究開発やその臨床応用がおおいに期待されている。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00060&link_issn=&doc_id=20211129010001&doc_link_id=%2Faa7ayuma%2F2021%2F027909%2F002%2F0840-0843%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2021%2F027909%2F002%2F0840-0843%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本救急医学会  

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

Cardioprotective effect of prostaglandin-E2 receptor-4 (EP4) stimulation on the ischemic heart has been demonstrated. Its effect on the heart affected by myocarditis, however, remains uncertain. In this study, we investigated therapeutic effect of EP4 stimulant using a mouse model of autoimmune myocarditis (EAM) that progresses to dilated cardiomyopathy (DCM). EP4 was present in the hearts of EAM mice. Treatment with EP4 agonist (ONO-0260164: 20 mg/kg/day) improved an impaired left ventricular (LV) contractility and reduction of blood pressure on day 21, a peak myocardial inflammation. Alternatively, DCM phenotype, characterized by LV dilation, LV systolic dysfunction, and collagen deposition, was observed on day 56, along with activation of matrix metalloproteinase (MMP)-2 critical for myocardial extracellular matrix disruption, indicating an important molecular mechanism underlying adverse ventricular remodeling after myocarditis. Continued treatment with ONO-0260164 alleviated the DCM phenotype, but this effect was counteracted by its combination with a EP4 antagonist. Moreover, ONO-0260164 inhibited in vivo proteolytic activity of MMP-2 in association with up-regulation of tissue inhibitor of metalloproteinase (TIMP)-3. EP4 stimulant may be a promising and novel therapeutic agent that rescues cardiac malfunction during myocarditis and prevents adverse ventricular remodeling after myocarditis by promoting the TIMP-3/MMP-2 axis.

DOI： 10.1038/s41598-021-99930-5

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

The COVID-19 pandemic is an unprecedented threat to humanity that has provoked global health concerns. Since the etiopathogenesis of this illness is not fully characterized, the prognostic factors enabling treatment decisions have not been well documented. Accurately predicting the progression of the disease would aid in appropriate patient categorization and thus help determine the best treatment option. Here, we have introduced a proteomic approach utilizing data-independent acquisition mass spectrometry (DIA-MS) to identify the serum proteins that are closely associated with COVID-19 prognosis. Twenty-seven proteins were differentially expressed between severely ill COVID-19 patients with an adverse or favorable prognosis. Ingenuity Pathway Analysis revealed that 15 of the 27 proteins might be regulated by cytokine signaling relevant to interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), and their differential expression was implicated in the systemic inflammatory response and in cardiovascular disorders. We further evaluated practical predictors of the clinical prognosis of severe COVID-19 patients. Subsequent ELISA assays revealed that CHI3L1 and IGFALS may serve as highly sensitive prognostic markers. Our findings can help formulate a diagnostic approach for accurately identifying COVID-19 patients with severe disease and for providing appropriate treatment based on their predicted prognosis.

DOI： 10.1038/s41598-021-98253-9

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

<title>Abstract</title>
<sec>
<title>Background</title>
Prostaglandin E2 receptor 4 (EP4) plays a crucial role in inflammatory diseases. Inflammatory cardiomyopathy often leads to refractory heart failure.


</sec>
<sec>
<title>Purpose</title>
We aimed to evaluate the role of EP4 in the development of inflammatory cardiomyopathy.


</sec>
<sec>
<title>Methods</title>
Experimental autoimmune myocarditis (EAM) was induced by immunization with cardiac myosin in balb/c mice. EP4 selective antagonist (CJ-42794, Cayman Chemical: 30 mg/kg/day), EP4 selective agonist (20 mg/kg/day), both, or vehicle alone was daily administrated after the immunization. Cardiac function and dimensions were assessed by echocardiography. Blood pressure and heart rate were assessed with tail-cuff method. Cardiac inflammation and fibrosis were immunohistologically examined. Molecular examination was performed by RT-PCR and immunoblotting.


</sec>
<sec>
<title>Results</title>
Cardiac dysfunction and dilatation were worsened on day 21 in EP4 antagonist-treated group compared with in the vehicle-treated group, accompanied by an increase in cellular infiltration area (21.7±1.9 vs. 11.0±2.7%, P=0.0367, respectively). Conversely, cardiac dysfunction and dilatation were improved in EP4 agonist-treated group compared with in the vehicle-treated group (Left ventricular fractional shortening: 69±3% vs. 40±4%, P&amp;lt;0.0001; Left ventricular systolic dimension: 0.7±0.1mm vs. 1.9±0.3mm, P=0.0007; respectively). These parameters did not show significant differences between both-treated group and the vehicle-treated group. The protective effect of EP4 stimulation in EAM was also kept on day 56. Moreover, cardiac fibrosis area as well as mRNA expressions of Type III collagen and brain natriuretic peptide in the bulk hearts was significantly reduced on day 56 in EP4 agonist-treated group compared with in the vehicle-treated group (12.3±2.4% vs. 24.7±3.0%, P=0.0278, respectively). Cardiac expression of phosphorylated smad 2/3 protein as well as TGF-β1 mRNA did not show significant differences between the 2 groups, while cardiac expression of RORgammat protein, the master regulator of Th17 immunity was increased in the EP4 antagonist-treated group.


</sec>
<sec>
<title>Conclusions</title>
EP4 activation negatively regulated the induction of cardiac autoimmunity, which alleviated cardiac dysfunction, dilatation, and fibrosis. EP4 may be a therapeutic target for preventing the development of inflammatory cardiomyopathy.


</sec>
<sec>
<title>FUNDunding Acknowledgement</title>
Type of funding sources: None.


</sec>

DOI： 10.1093/eurheartj/ehab724.0905

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BACKGROUND: Coronavirus disease 2019 (COVID-19) pneumonitis associated with severe respiratory failure is associated with high mortality. The pathogenesis of COVID-19 is associated with microembolism or microvascular endothelial injuries. Here, we report that syndecan-1 (SDC-1), a component of the endothelial glycocalyx, may be a biomarker of severity classification for COVID-19 related to endothelial injury. METHODS AND ANALYSIS: We analyzed the data of COVID-19 patients for 1 year from February 2020 at Yokohama City University Hospital and Yokohama City University Medical Center Hospital. We selected COVID-19 patients who required admission care, including intensive care, and analyzed the classification of severe and critical COVID-19 retrospectively, using various clinical data and laboratory data with SDC-1 by ELISA. RESULTS: We analyzed clinical and laboratory data with SDC-1 in five severe COVID-19 and ten critical COVID-19 patients. In the two groups, their backgrounds were almost the same. In laboratory data, the LDH, CHE, and CRP levels showed significant differences in each group (P = 0.032, P < 0.0001, and P = 0.007, respectively) with no significant differences in coagulation-related factors (platelet, PT-INR, d-dimer, ISTH score; P = 0.200, 0.277, 0.655, and 0.36, respectively). For the clinical data, the SOFA score was significantly different from admission day to day 14 of admission (p < 0.0001). The SDC-1 levels of critical COVID-19 patients were significantly higher on admission day and all-time course compared with the levels of severe COVID-19 patients (P = 0.009 and P < 0.0001, respectively). CONCLUSIONS: Temporal change of SDC-1 levels closely reflect the severity of COVID-19, therefore, SDC-1 may be a therapeutic target and a biomarker for the severity classification of Covid-19.

DOI： 10.1186/s12959-021-00308-4

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DOI： 10.1093/cid/ciaa637

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DOI： 10.1016/j.jinf.2020.08.021

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

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic rapidly increases the use of mechanical ventilation (MV). Such cases further require extracorporeal membrane oxygenation (ECMO) and have a high mortality. OBJECTIVE: We aimed to identify prognostic biomarkers pathophysiologically reflecting future deterioration of COVID-19. METHODS: Clinical, laboratory, and outcome data were collected from 102 patients with moderate to severe COVID-19. Interleukin (IL)-6 level and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA copy number in plasma were assessed with ELISA kit and quantitative PCR. RESULTS: Twelve patients died or required ECMO owing to acute respiratory distress syndrome despite the use of MV. Among various variables, a ratio of oxygen saturation to fraction of inspired oxygen (SpO2/FiO2), IL-6, and SARS-CoV-2 RNA on admission before intubation were strongly predictive of fatal outcomes after the MV use. Moreover, among these variables, combining SpO2/FiO2, IL-6, and SARS-CoV-2 RNA showed the highest accuracy (area under the curve: 0.934). In patients with low SpO2/FiO2 (< 261), fatal event-rate after the MV use at the 30-day was significantly higher in patients with high IL-6 (> 49 pg/mL) and SARS-CoV-2 RNAaemia (> 1.5 copies/μL) compared to those with high IL-6 or RNAaemia or without high IL-6 and RNAaemia (88% vs. 22% or 8%, log-rank test P = 0.0097 or P < 0.0001, respectively). CONCLUSIONS: Combining SpO2/FiO2 with high IL-6 and SARS-CoV-2 RNAaemia which reflect hyperinflammation and viral overload allows accurately and before intubation identifying COVID-19 patients at high risk for ECMO use or in-hospital death despite the use of MV.

DOI： 10.1371/journal.pone.0256022

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

DOI： 10.1093/jmcb/mjaa047

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本感染症学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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Language：Japanese   Publisher：(一社)日本救急医学会  

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

The present study aimed to identify the clinical significance of differences in detection timings of left ventricular reverse remodeling (LVRR) on heart failure (HF) prognosis in patients with idiopathic dilated cardiomyopathy (IDCM). We investigated 207 patients with IDCM who underwent pharmacotherapeutic treatment. LVRR was defined as improvements in both LV ejection fraction a parts per thousand yen10 % and indexed LV end-diastolic dimension (LVEDDi) a parts per thousand yen10 %. Patients were stratified into 3 groups by LVRR timing: patients with LVRR &lt; 24 months (Early LVRR), those with LVRR a parts per thousand yen24 months (Delayed LVRR), and those without LVRR during the entire follow-up period (No LVRR). The major endpoint was first detection of composite event including readmission for decompensated HF, major ventricular arrhythmias, or all-cause mortality. LVRR was recognized in 108 patients (52 %): Early LVRR in 83 (40 %), Delayed LVRR in 25 (12 %), and No LVRR in 99 (48 %). The survival rate for the major endpoint was significantly higher for Delayed LVRR than for No LVRR (P = 0.001); there was no significant difference between Early and Delayed LVRR. Among patients without LVRR &lt; 24 months (Delayed + No LVRR), receiver operating characteristic curve analysis showed that the area under the curve for improvement in LVEDDi during the first 6 months for predicting subsequent LVRR (Delayed LVRR) [0.822 (95 % confidence interval, 0.740-0.916; P = 0.038)] was greater than that for improvement in LVEF. In conclusion, LVRR was a favorable prognostic indicator in patients with IDCM irrespective of its detection timing. Reduced LVEDDi during the first 6 months was predictive for subsequent LVRR in the later phase.

DOI： 10.1007/s00380-015-0648-2

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

Endomyocardial biopsy (EMB) and late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) imaging performed at baseline are both used to evaluate the extent of myocardial fibrosis. However, no study has directly compared the effectiveness of these diagnostic tools in the prediction of left ventricular reverse remodeling (LVRR) and prognosis in response to therapy in patients with idiopathic dilated cardiomyopathy (IDCM). Seventy-five patients with newly diagnosed IDCM who were undergoing optimal therapy were assessed at baseline using LGE-CMR imaging and EMB; the former measured LGE area and the latter measured collagen volume fraction (CVF) as possible predictive indices of LVRR and cardiac event-free survival. Among all the baseline primary candidate factors with P &lt; 0.2 as per univariate analysis, multivariate analysis indicated that only LGE area was an independent predictor of subsequent LVRR (beta = 0.44; 95 % confidence interval (CI) 0.87-2.53; P &lt; 0.001), as indicated by decreasing left ventricular end-systolic volume index over the 1-year follow-up. Kaplan-Meier curves indicated significantly lower cardiac event-free survival rates in patients with LGE at baseline than in patients without (P &lt; 0.01). By contrast, there was no significant difference in prognosis between patients with CVF values above (severe fibrosis) and below (mild fibrosis) the median of 4.9 %. Cox proportional hazard analysis showed that LGE area was an independent predictor of subsequent cardiac events (hazard ratio 1.06; 95 % CI 1.02-1.10; P a parts per thousand currency sign 0.01). The degree of myocardial fibrosis estimated by baseline LGE-CMR imaging, but not that estimated by baseline EMB, can predict LVRR and cardiac event-free survival in response to therapy in patients with newly diagnosed IDCM.

DOI： 10.1007/s00380-013-0415-1

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

c-Cbl-associated protein (CAP), also called Sorbs1 or ponsin, has been described as an essential adapter protein in the insulin-signalling pathway. Here, we describe for the first time a unique protective role for CAP in viral myocarditis. Mortality and heart failure development were increased in CAP(-/-) mice compared to CAP(+/+) littermates after Coxsackievirus (CVB3) infection. Mechanistically, CAP protected from tissue apoptosis because of reduced CD8(+) T and natural killer cell cytotoxicity. Despite reduced cytotoxic elimination of CVB3-infected cells in CAP(+/+) hearts, however, CAP enhanced interferon regulatory factor 3 (IRF3)-dependent antiviral type I interferon production and decreased viral proliferation in vitro by binding to the cytoplasmic RIG-I-like receptor melanoma differentiation-associated protein 5 (MDA5). Taken together, these findings reveal a novel modulatory role for CAP in the heart as a key protein stabilizing antiviral type I interferon production, while protecting from excessive cytotoxic responses. Our study will help to define future strategies to develop treatments to limit detrimental responses during viral heart inflammation.

DOI： 10.1007/s00395-014-0411-3

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The appropriate indication for, management of and limitations to extracorporeal life support (ECLS) and the timing of a switch to a ventricular assist device (VAD) remain controversial issues in patients with acute myocardial infarction (AMI) complicated with cardiogenic shock or cardiopulmonary arrest. To evaluate and discuss these issues, we studied patients with AMI treated with ECLS and compared deceased and discharged patients. Thirty-eight patients with AMI who needed ECLS [35 men (92.1 %), aged 59.9 ± 13.5 years] were enrolled in this study. Of these 38 patients, 34 subsequently underwent percutaneous coronary intervention (PCI), and four subsequently received coronary artery bypass grafting (CABG). Fourteen patients (36.8 %) were discharged from the hospital. The outcome was not favorable for those patients with deteriorating low output syndrome (LOS) and the development of leg ischemia, hemolysis and multiple organ failure during ECLS. Levels of creatine kinase, creatine kinase-MB (CK-MB), lactate dehydrogenase, serum creatinine (Cr) and amylase after the patient had been put on ECLS and fluctuation of the cardiac index, blood pressure, arterial blood gas analysis and CK-MB and Cr levels during ECLS were indicators to switch from the ECLS to VAD. In the case of patients with no complication associated with ECLS, 4.6-5.6 days after initiation of ECLS was assumed to be the threshold to decide whether to switch from ECLS to VAD. Patients with AMI who suddenly developed refractory pulseless ventricular tachycardia or ventricular fibrillation without deteriorating LOS and who underwent successful PCI or CABG, and who prevented the complications associated with ECLS, showed a high probability of recovering with ECLS.

DOI： 10.1007/s10047-013-0735-z

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

Although an increased heart rate (HR) is a strong predictor of poor prognosis in cases of chronic heart failure (HF), the clinical value of HR as a predictor in acute decompensated HF (ADHF) is unclear. Seventy-eight patients with nonischemic dilated cardiomyopathy (NIDCM) with sinus rhythm who were first hospitalized for ADHF from 2002 to 2010 were retrospectively investigated after exclusion of patients with tachycardia-induced cardiomyopathy. The patients were divided into two groups stratified by HR on admission with a median value of 113 beats/min (Group H with HR a parts per thousand yen 113 beats/min; Group L with HR &lt; 113 beats/min). Despite similar backgrounds, including pharmacotherapy for HF, HR changes responding to titration of beta-blocker (BB) therapy and myocardial interstitial fibrosis, left ventricular (LV) ejection fractions improved more significantly 1 year later in Group H than in Group L (57 % +/- 11 % vs. 46 % +/- 12 %, P &lt; 0.001). Cardiac event-free survival rates were also significantly improved in Group H (P = 0.038). Multiple regression analysis revealed that only the peak HR on admission was an independent predictor of LV reverse remodeling (LVRR) 1 year later (beta = 0.396, P = 0.005). High HR on first admission for ADHF is a strong predictor of LVRR, with a better prognosis in the event of NIDCM in response to optimal pharmacotherapy, independent of pre-existing myocardial damage and subsequent HR reduction by BB therapy.

DOI： 10.1007/s00380-013-0335-0

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Experimental autoimmune myocarditis (EAM) represents a CD4+ T helper (Th) cell-mediated mouse model of inflammatory heart disease. Interferon (IFN)-γ, typically produced by Th1 cells, reduces EAM severity in myosin heavy-chain-(MyHC)-α peptide/Complete Freund adjuvant-immunized mice. Thus, developing a vaccination strategy that promotes differentiation of Th1 cells may be beneficial in EAM. FMS-like tyrosine kinase 3 ligand (Flt3L)-induced splenic CD8α+ dendritic cells (DC), which produce interleukin (IL)-12p35, were identified to selectively induce biased differentiation towards Th1. Mice vaccinated with MyHC-α-loaded Flt3L-induced splenic CD8α+ DC were protected from EAM. In contrast, when Flt3L-induced splenic CD8α+ DC were pre-stimulated and over-activated with LPS and αCD40 antibodies or loaded with unspecific OVA323-339 peptide instead of MyHC-α peptide, mice developed similar disease scores as non-vaccinated controls. Vaccination efficacy depended on IFN-γ, since CD8α+-vaccinated IFN-γR-/- mice were not protected. Importantly, splenic CD8α+ vaccination was independent of regulatory T cells. Taken together, Flt3L-induced dendritic cell-based antigen-specific vaccination limits expansion of auto-reactive Th cells and protects mice from autoimmune heart inflammation. © 2013 Elsevier Ltd.

DOI： 10.1016/j.vaccine.2013.07.084

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

Background Viral myocarditis follows a fatal course in approximate to 30% of patients. Interleukin-1 receptor-associated kinase 4 (IRAK4), a major nodal signal transducer in innate immunity, can play a pivotal role in host inflammatory response. We sought to determine how IRAK4 modulates inflammation and outcome in a mouse model of viral myocarditis.
Methods and Results Myocarditis was induced after intraperitoneal inoculation of coxsackievirus B3 into C57Bl/6 IRAK4-deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4(-/-) mice compared with their IRAK4(+/+) littermates. Disease resistance of IRAK4(-/-) mice paralleled increased amounts of protective heart-infiltrating CCR5(+) monocytes/macrophages and enhanced interferon- and interferon- production 2 days after infection. Competitive bone marrow chimera demonstrated that intact IRAK4 function inhibited heart-specific migration of bone marrow-derived CCR5(+) cells. Mechanistically, lack of IRAK4 resulted in interferon regulatory factor 5 homodimerization via reduced melanoma differentiation-associated protein 5 degradation and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral interferon- and interferon- production, as well as CCR5(+) cell recruitment, increased, whereas the overall proinflammatory response was drastically reduced in the absence of IRAK4.
Conclusions Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of interferon production and reduced mobilization of protective CCR5(+) monocytes/macrophages to the heart. The combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future.

DOI： 10.1161/CIRCULATIONAHA.113.002275

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

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

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A 30-year-old man with palpitations due to nonsustained ventricular tachycardia was referred to our hospital. His electrocardiogram revealed negative T waves in leads V1-V4 and a right bundle branch block, while his echocardiogram indicated normal left ventricular function but a markedly dilated right ventricle with impaired contraction. Provisional arrhythmogenic right ventricular cardiomyopathy (ARVC) was diagnosed on the basis of the criteria of the Task Force of the European Society of Cardiology and the International Society and Federation of Cardiology (ESC/ISFC). In addition to bilateral hilar lymph node swellings, sarcoidosis revealed through histological examination of skin eruptions, and abnormal cardiac magnetic resonance images (atypically predominant in the right ventricle) led to the suspected diagnosis of cardiac sarcoidosis (CS). After inserting an implantable cardioverter defibrillator, we employed steroid therapy for CS. After therapy, the patient's palpitations disappeared and his ventricular arrhythmia diminished. Therefore, it was established that a case of CS can mimic ARVC as a clinical phenotype, and the specificity of the diagnostic criteria of ARVC is not sufficient in itself. Moreover, the CS diagnosis guide is mainly based on left ventricular dysfunction, and hence, CS, which is atypically predominant in the right ventricle, is difficult to diagnose. Therefore, several questions regarding the diagnostic criteria of ARVC and CS should be discussed to avoid misdiagnosis of these diseases.

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

Acute myocarditis is a major inflammatory heart disease with a variety of clinical courses from the acute to chronic phases represented by unexpected circulatory deterioration during hospitalization and progression to dilated cardiomyopathy. Predicting these disease courses is important for patient management. However, biomarkers have not been fully investigated. In addition, clinical profiles including symptoms, serological data, and electrocardiographic findings in acute myocarditis often mimic more common disorders such as coronary artery disease, which have reduced the diagnostic accuracy of acute myocarditis. These issues hamper the development of safer and earlier therapeutic interventions specific for acute myocarditis. Against this background, identifying simple prognostic and diagnostic biomarkers would contribute dramatically to the improvement in outcomes. Interleukin-10 may be a strong candidate for an excellent biomarker.

DOI： 10.1007/s00059-012-3661-6

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

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

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

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

A-42-year-old man died after repetitive hospitalization with heart failure exacerbation in spite of intensive treatment such as the use of beta-blockers and cardiac resynchronization therapy. The autopsy demonstrated severe myocardial inflammation for the first time, leading to the final diagnosis as chronic myocarditis. He had complained of dyspnea and had been diagnosed as dilated cardiomyopathy (DCM) 16 years earlier through systematic evaluation including endmyocardial biopsy of the left ventricle (LV). Although the LV diastolic dimension/ejection fraction was 72 mm/23%, respectively, upon the first symptoms of the disease, such echocardiographic parameters regarding LV systolic dysfunction had not altered over the entire clinical course. On the other hand, several indicators of LV diastolic dysfunction including left atrium expansion and a restrictive pattern of transmitral flow velocity had gradually increased. This is the first case report of chronic myocarditis with progressive LV diastolic dysfunction despite unaltered LV systolic properties. It is necessary to consider the possibility of chronic myocarditis in cases of DCM which progresses into LV diastolic dysfunction.

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A 74 year-old-male patient with dilated cardiomyopathy consequently suffered from intractable hyponatremia, systemic congestion, low cardiac output syndrome (LOS) and orthostatic hypotension in spite of the intensive use of intravenous inotropic and diuretic agents after cardiac resynchronization. In particular, in the process to avoid congestion, he experienced hyponatremia and intravascular dehydration many times, and finally he fell into LOS and serious orthostatic hypotension. Because of this, we administrated Tolvaptan and reduced the amount of furosemide. Then, although daily urine volume was maintained at the same level, the BUN/Cr ratio decreased, the serum Na level improved, and systemic congestion and orthostatic hypotension dramatically disappeared. Body weight mildly increased, but pulmonary edema and pleural effusion did not occur. With the help of cardiac rehabilitation, he recovered his QOL and home ambulatory treatment became possible. Normalization of plasma osmolality seemed to produce a sufficient volume of circulating plasma by moving excess water from the intracellular and thoracic cavity into the plasma. Tolvaptan not only improved hyponatremia, but also moved the excess water into the circulating plasma. This new aquaretics seems to relieve LOS patient from intractable congestion effectively under relatively stable hemodynamics.

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A fifty-three-year-old woman with dilated cardiomyopathy caused by limb-girdle type muscular dystrophy suffered from refractory congestive heart failure (HF) and was treated with an intravenous catecholamine infusion. Assessing her long-term course indicated by echocardiographic and clinical parameters, an aneurysmal formation of the posterior left ventricular (LV) wall leading to advanced mitral valve (MV) regurgitation caused by MV tethering in addition to impaired LV contraction was found and factors of HF exacerbation. Based on the above understanding, partial left ventriculectomy using posterior wall excision and mitral annuloplasty were designated. The operation succeeded in the catecholamine secession together with intensified medical treatment for HF. This is a representative case of muscular dystrophy/cardiomyopathy in which ventriculectomy of the aneurysmal portion and mitral annuloplasty was able to reduce MV regurgitation derived from MV tethering, leading to relief of exacerbated HF.

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

Although extracorporeal membrane oxygenation (ECMO) is widely used as temporary circulation support, there are no reports of direct parameters indicating cardiac recovery to determine the timing of weaning off.
Twenty-five patients supported by ECMO due to hemodynamic deterioration were divided into 2 groups according to their outcome: weaned ECMO (W: n = 18) or not (NW: n = 7). In the W group, we examined the differences in parameters between the 2 time points, ECMO introduction, and the reduction in ECMO flow to 40% of the initial setting known as the conventional recovery point (C-point). Significant differences were observed in systolic pulmonary artery pressure, the cardiac index measured by the thermodilution method, C-reactive protein, lactate, base excess, and the end-tidal CO(2) concentration (ETCO(2)). Next, by closely examining these 6 parameters measured every 12 hours, we found that only ETCO(2) had always changed steeply, like a 'flexion point' (E-point), in all W cases, but not in NW. The E-point was defined as an initial increase in ETCO(2) of &gt;= 5 mmHg over the preceding 12 hours with a continued rise over the next 12 hours. E-points appeared as much as 95 +/- 60 hours earlier than C-points and also preceded weaning off of ECMO.
ETCO(2) can be a useful continuous parameter for predicting the adequate timing of weaning off of ECMO for circulatory failure at the bedside. (Int Heart J 2010; 51: 116-120)

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DOI： 10.1016/j.jacc.2007.11.085

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

Objectives We investigated the clinical utility of B-type natriuretic peptide (BNP) assay in stable outpatients with nonischemic dilated cardiomyopathy (NICM) after decompensated heart failure (HF).
Background Patients with NICM admitted for decompensated HF frequently experience sudden death or redecompensation after hospital discharge. The prognostic value of BNP during hospitalization has been demonstrated. However, clinical utility of BNP in stable outpatient setting has been poorly investigated.
Methods Eighty-three NICM outpatients who were clinically stable in New York Heart Association functional class 1 to 2 for 6 months after discharge for decompensated HF were enrolled, and then followed for an additional 18 months. The main end point was first readmission for decompensated HF or death. B-type natriuretic peptide levels were measured at 3-month intervals from discharge to enrollment, and echocardiographic dimensions at discharge and enrollment.
Results Mean discharge BNP level was 210 +/- 148 pg/ml. Twenty-eight patients were readmitted for decompensated HF or suddenly died at a median time of 11 months from the time of discharge. Among various variables including BNP measurements, clinical parameters and echocardiographic dimensions, a 6-month post-discharge BNP of &gt; 190 pg/ml was most closely associated with combined event in the Cox proportional hazards model (hazard ratio 2.29; 95% confidence interval 1.42 to 3.56; p = 0.0005), and had the best discriminatory power (area under the receiver operating characteristic curve 0.91, sensitivity 96%; specificity 76%).
Conclusions Even in stable low-risk outpatients with NICM at 6 months after hospital discharge for decompensated HF, BNP assessment predicts a long-term risk of redecompensation.

DOI： 10.1016/j.jacc.2007.11.085

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The impact of guideline adherence on clinical outcomes in the management of chronic heart failure (CHF) has never been evaluated in Japan.
We investigated outcomes in 92 consecutive CHF patients admitted to Kitasato University Hospital in 2004-2006 for HF exacerbation with a left ventricular ejection fraction &lt;= 40% by the use of class I drugs for pump-failure, as recommended in the Japanese Circulation Society guideline. Drugs, namely angiotensin-converting enzyme inhibitors (ACEI), beta-blockers (1313), spironolactone, diuretics, and cardiac glycosides were administered to 64.1%, 59.8%, 28.2%, 96.7%, and 68.0% of patients, respectively. Patients for whom adherence to the prescription of ACEI and BB as first-line agents was high had significantly and independently better prognostic outcomes for cardiac events (P = 0.0036) as well as subsequent improvements in clinical surrogate markers for HF status such as NYHA class and BNP. Addition of the 3 latter drugs to the prescription of ACEI and BB did not affect the superiority of ACE plus BB in improving the long-term prognosis.
We have demonstrated that adherence to treatment guidelines for CHF is a significant predictor of subsequent cardiac events in actual practice in Japan. An effective means of improving adherence to current guideline standards of care for CHF has yet to be established.

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Background: The aim of this study was to analyze the relationship between abnormal liver function tests (LFTs) coincident with heart failure (HF) exacerbation and subsequent long-term outcome in patients with chronic HF. Methods and Results: The study population consisted of 183 consecutive patients admitted for HF exacerbation with left ventricular ejection fraction ≤40%. Cox proportional hazard analysis revealed that serum total bilirubin (T-Bil) levels on admission (hazard ratio 1.896, p&lt
0.001, 95% confidence interval 1.323-2.717), but not T-Bil at discharge or other LFTs, was an independent predictor of subsequent cardiac events after hospital discharge (cardiac death or readmission for HF exacerbation) The cardiac-event-free rates significantly decreased according to increasing tertiles of T-Bil stratified by the level of 0.7 and 1.2 mg/dl (p&lt
0.001). T-Bil on admission had significant correlations with simultaneously-measured central venous pressure (CVP) (r=0.42, p&lt
0.01) and cardiac index (CI) (r=-0.50, p&lt
0.01). The patients demonstrating high CVP together with low CI showed significantly increased T-Bil compared with any other group. Conclusions: Increased T-Bil coincident with cardiac decompensation predicts a worse long-term prognosis of CHF, presumably through the potential liability to both congestion and tissue hypoperfusion simultaneously when HF deteriorates.

DOI： 10.1253/circj.72.364

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We have reported that chronic heart failure (HF) patients with increased serum bilirubin coincident with acute decompensation have a poor prognosis, indicating severe congestion and low tissue perfusion. The aim of this study was to analyze the possibility of increased bilirubin coincident with acute decompensation as a parameter which indicates the need for intravenous inotropic agents. We stratified 131 decompensated chronic HF patients with a LVEF &lt;= 40% and systolic blood pressure between 90 and 120 mmHg, based on total bilirubin levels on admission. In patients with high bilirubin (T-Bil &gt;= 1.2 mg/dL), intravenous inotropics contributed to significantly more abundant diuresis, body weight reduction, and decreases in bilirubin and serum creatinine in the first 5 in-hospital days compared to those without (group A: inotropics +; n = 24 versus group B: -; n = 38: 1726 418 versus 1458 424 mL/day: P &lt; 0.05, -3.1 + +/- 1.6 versus -2.1 2.2 kg: P &lt; 0.05, -0.74 +/- 0.51 versus -0.04 +/- 0.60 mg/dL: P &lt; 0.01, -0.29 +/- 0.89 versus -0.01 +/- 0.24 mg/dL: P &lt; 0.01), in spite of no significant difference in the doses of diuretics between the 2 groups. On the contrary, patients with low bilirubin (T-Bil &lt; 1.2 mg/dL) recovered from decompensation equally irrespective of inotropic administration (group C: inotropics +; n = 15 versus group D: -,- n = 54: 1557 329 versus 1507 406 mL/day, -2.9 +/- 1.7 versus -2.8 +/- 1.5 kg, -0.01 +/- 0.25 versus -0.08 +/- 0.23 mg/dL, 0.02 +/- 0.24 versus 0.47 +/- 0.19 mg/dL; NS, respectively). Inotropics were administered after all because of unimproved hemodynamics in 26% of group B patients, compared to 4% of group D patients (P &lt; 0.01). Increased bilirubin coincident with HF decompensation can be a useful marker indicating the need for intravenous inotropic agent administration.

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Background-The therapeutic potential of beta 2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure-induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated.
Methods and Results-Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the beta 2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-gamma mRNA levels. Propranolol, a nonselective beta-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a beta 1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin-primed lymph node cells from drug-treated rats. In vitro addition of beta 2-selective AR agonists inhibited the activation of cardiac myosin fragment-specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a beta 2-selective AR antagonist. Furthermore, treatment with 2 different beta 2-selective AR agonists starting on day 14 also ameliorated EAM on day 21.
Conclusions-beta 2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin-specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. beta 2-AR-stimulating agents may represent important immunomodulators of the cardiac myosin-induced autoimmune process and have potential as a new therapy for myocarditis.

DOI： 10.1161/CIRCULATIONAHA.105.607903

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A 75-year-old male underwent double valve replacement (DVR) for severe aortic regurgitation (AR) and secondary mitral regurgitation (MR), in the presence of marked contractile dysfunction and left ventricular dilatation. He had complete atrioventricular(AV) block during the operation, and was unable to recover from low output heart failure with right ventricular pacing. However, using left ventricular (LV) pacing, he quickly recovered and after six months, marked improvement of LV contractile function [LV ejection fraction(LVEF) 35 → 65%] and reverse remodeling(LV end systolic diameter (LVDs) 68 → 46mm) was obtained. Early valve replacement has been recommended for regurgitation before irreversible myocardial dysfunction is able to occur due to volume overload. LVEF and LV diameters have been used as useful indexes for the timing of the operation. From the point of view of these previous indexes, this case might be thought to have had irreversible myocardial damage, but tremendous reverse remodeling was shown and sufficient cardiac function equal to normal performance was obtained after DVR. This clinical course has led us to reconsider the appropriate timing of valve replacement for regurgitation.

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Background Although it is not rare to encounter patients with plasma B-type natriuretic peptide (BNP) levels unequivalent to the severity of heart failure (HF), there has been little investigation to clarify the causative background of this phenomenon.
Methods and Results Among the 1,838 outpatients whose plasma BNP was measured, persistently increased levels of BNP above 500 pg/ml was observed for more than 6 months in 14 subjects with few HF symptoms. Among these, all of 4 patients without any following cardiac events (E-/high) for 12 months showed hypertrophic nonobstructive cardiomyopathy (HNCM). When we compared the clinical parameters of these patients with those of 22 HNCM patients without any following cardiac events whose plasma BNP levels were less than 200 pg/ml. there were only 2 clinical characteristics to be distinguished: (i) plasma renin activity (PRA) and norepinephrine (NE) levels were low in spite Of Markedly increased levels of plasma BNP in E-/high HNCM; and (ii) echocardiographic investigation revealed that only global left atrial fractional shortening was significantly lower in E-/high HNCM.
Conclusions Plasma BNP levels do not always reflect the severity of HF in HNCM. It might be considered to utilize other clinical parameters such as NE and PRA to recognize HF severity in such patients.

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OBJECTIVES We assessed the significance of serum cytokine levels in patients with fulminant myocarditis.
BACKGROUND Although many investigations have demonstrated the crucial role of cytokines in the development of myocarditis, it remains uncertain whether serum levels of cytokines enable one to predict the prognosis of human myocarditis, especially concerning cardiogenic shock (CS) requiring a mechanical cardiopulmonary support system (MCSS).
METHODS We studied 22 consecutive patients with fulminant myocarditis and compared them with 15 patients with acute myocardial infarction (AMI) requiring MCSS. The patients with myocarditis were classified into three groups: eight patients with CS requiring MCSS on admission (group 1); six patients who unexpectedly lapsed into CS requiring MCSS more than two days after catecholamine had been initiated (group 2); and eight patients without MCSS (group 3). Furthermore, 14 patients with myocarditis requiring MCSS were divided into a fatal group (n = 5) and a survival group (n = 9). Biochemical markers, including serum cytokine levels and hemodynamic variables on admission, were analyzed.
RESULTS Serum levels of interleukin (IL)-10 and tumor necrosis factor-alpha, but not other cytokines, were significantly higher in myocarditis than in AMI. Only serum levels of IL-10 were significantly higher in group 1 and 2 than in group 3 (49.1 +/- 37.5/20.7 +/- 17.6 pg/ml vs. 2.4 +/- 1.1 pg/ml; p = 0.0008/0.0012). Serum IL-10 levels were also significantly higher in the fatal group than in the survival group with myocarditis (74.0 +/- 27.0 pg/ml vs. 16.4 +/- 8.8 pg/ml; p = 0.003).
CONCLUSIONS Serum IL-10 levels on admission enabled one to predict subsequent CS requiring MCSS and mortality of fulminant myocarditis patients. (C) 2004 by the American College of Cardiology Foundation.

DOI： 10.1016/j.jacc.2004.01.055

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A 34-year-old male who had suffered from refractory heart failure was relieved by adjunctive use of the angiotensin II receptor blocker(ARB). After being diagnosed as having dilated cardiomyopathy 7 years previously, the patient was treated with both an angiotensin converting enzyme inhibitor (ACEI) and with beta-blocker in the conventional way. In spite of the standardized beta-blocker therapy, the condition of his disease gradually deteriorated. Finally his cardiac state started to fall into NYHA IV, and his plasma BNP concentration could not be lowered beyond about 500 pg/ml. When the patient was in our hospital in 2002, due to repetitive and refractory attacks of orthopnea, his heart was moderately treated with intra-venous injections of furosemide and catecholamines. Though ACEI and beta-blocker combination therapy was retried as soon as possible, his condition was absolutely refractory. ARB was carefully added to his treatment as it was considered that, eventually, this would be inevitable. Immediately after this trial, his urine volume gradually increased and the intravenous injections were no longer required. After his dramatic recovery from the refractory state, he returned to his former active life. His NYHA function has been maintained at a level of class II, and his plasma BNP value has been also around 50 pg/ml. Concerning the adjunctive use of ARB in CHF patients, various contionary concerns have been focused on. However, despite several clinical trials such as the one outlined here, this drug has not yet come to be regarded as more effective than ACEI. Through this encounter, we have demonstrated a case of one good responder, showing the efficacy of adjunctive use of ARB for patients responder to the adjunctive use of ARB with chronic heart failure refractory to other treatments. We hope further cases will clarify this responder's characteristics and pharmacological reasons why ARB, used adjunctively, can be effective. If this data can be found, it will facilitate the establishment of a novel tailored adjunctive therapy for individuals refractory to other treatments.

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

A 75-year-old man recovered from an episode of acute influenza. A myocarditis with a normalized level of serum cardiac troponin T, but less than 2 weeks after recovery, he rapidly fell into cardiogenic shock and died of fulminant myocarditis. The autopsied heart showed marked inflammatory cell infiltration that mainly consisted of mononuclear cells positive for CD8, suggesting that the second bout of myocarditis was caused by viral reinfection.

DOI： 10.1253/circj.67.646

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：KLUWER ACADEMIC PUBLISHERS  

Fulminant myocarditis is a representative lethal heart disease, in which patients have only been urgently rescued with the help of mechanical cardiopulmonary supports. Nevertheless, the therapeutic outcomes of fulminant myocarditis treated with PCPS has not been elucidated. Recently, a national survey was conducted to undertake these tasks by considering the current situation of patients in Japan and to propose a therapeutic guidelines for fulminant myocarditis using PCPS. Thirty (57.7%) out of 52 patients could be rescued in the survey. Important factors concerning the prognosis were the severity and improvement grade of cardiac and renal dysfunction. Based on the data, management guidelines using PCPS to improve the survival rate of fulminant myocarditis patients were published. Of the individual prognosis of patients treated with PCPS, limiting factors have not been identified even in the present survey.

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Although a recent clinical study reported the beneficial effects of pentoxifylline (PTX), a phosphodiesterase inhibitor, on both symptoms and cardiac function in dilated cardiomyopathy (DCM), the precise mechanism of the drug has not been delineated. This study examined the efficacy of PTX in the treatment of experimental autoimmune myocarditis (EAM), as a model of the autoimmune mechanism involved in DCM. Oral PTX, or saline as control, was administered to Lewis rats at 150 mg/kg body weight per day bid daily from 5 days before immunization with cardiac myosin until death on Day 21. Histological examination of the hearts showed PTX significantly reduced the severity of EAM. rnRNA expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)4, IL-6, and IL-10 was significantly reduced in peripheral blood mononuclear cells, but expression of IL-4 and IL-6 was upregulated in heart tissue. PTX in vitro could suppress T cell proliferation and inhibit TNF-alpha and interferon-gamma production. In conclusion, the immunomodulatory effects of PTX had a significant therapeutic result in EAM. This is the first report to describe such an effect of PTX in a specific animal model for DCM.

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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DOI： 10.1016/j.yjmcc.2008.09.706

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Other Link： http://search.jamas.or.jp/link/ui/2008260562

Language：English   Publisher：Japanese Circulation Society  

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DOI： 10.1016/j.yjmcc.2007.07.025

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Other Link： http://search.jamas.or.jp/link/ui/2008092078

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Language：Japanese   Publisher：社団法人日本循環器学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Background The prognostic significance of atrial fibrillation (AF) in chronic heart failure (CHF) remains poorly understood.
Methods and Results Death and rehospitalizaion for CHF exacerbation for 427 consecutive patients hospitalized from 1996 to 2002 were retrospectively analyzed in relation to cardiac rhythm: sinus rhythm (SR; n=239) or AF (n=188). The AF group was classified according to an Intervention (n=57) or Non-Intervention (n=131) group for defibrillating AF. During the follow-up of 34 23 months, there was no significant difference of mortality or morbidity between the SR and AF groups, or between the Intervention and Non-Intervention groups, respectively. However, the Non-Intervention group consisted of 28 patients with paroxysmal AF (PAF), which spontaneously converted to SR during hospitalization, and 103 with chronic AF (CAF). The rehospitalization for CHF exacerbation was significantly higher in PAF than that in CAF and SR (p=0.00005 and 0.002, respectively). Multivariate Cox analysis demonstrated that, PAF, but not CAF, was a predictor of readmission (relative risk 2.30, p=0.004, 95% confidence interval 1.30 to 4.05).
Conclusions The present data implied that PAF coincident with cardiac decompensation could be a new predictor of prognosis for CHF. The management strategies of AF in CHF should be discussed according to the phenotype of AF.

DOI： 10.1253/circj.69.823

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Language：English   Publisher：INT HEART JOURNAL ASSOC  

A B-type natriuretic peptide (BNP)-guided strategy is being widely used as a superior management technique for heart failure (HF). However, the optimal target level of BNP to improve the prognosis of HF in clinical practice remains unclear. Several Studies have recently demonstrated that the existence of atrial fibrillation (AF) affects plasma BNP levels. We evaluated the prognostic value of BNP assay for HF management and found the optimal target level under the BNP-guided HF management according to the basal cardiac rhythms: AF or sinus rhythm (SR).
Patients hospitalized for HF exacerbation between 1996 and 2002 were stratified into SR (n = 129) and chronic AF (CAF, n = 58) groups as basal cardiac rhythms during hospitalization. Cardiac events including death and re-admission for HF exacerbation after discharge were analyzed in relation to the plasma BNP levels at predischarge. Receiver-operating characteristic (ROC) analysis demonstrated that the cut-off values for predischarge BNP, which predict cardiac events at 36 months after discharge, were 125 pg/mL in the SR group and 165 pg/mL in the CAF group. The area under the ROC curve was 0.72 and 0.82, respectively. Stratified subgroup analysis using the Kaplan-Meier method demonstrated that the risk of a cardiac event decreased in a stepwise fashion across a decreasing predischarge BNP range above these cut-off levels, while the minimum decreased risk was recognized at a BNP range below these cut-off levels in each group.
In conclusion, the optimal target levels of plasma BNP at predischarge to improve the prognosis of HF should be different and distinguishable depending oil with or without AF.

DOI： 10.1536/ihj.46.453

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：W B SAUNDERS CO LTD  

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34歳男.拡張型心筋症であった.1994年より労作時呼吸困難が出現し,アンジオテンシン変換酵素阻害薬とβ遮断薬を主体とする薬物療法を受けていた.しかし,7年前からNYHA III-IV度の心不全状態を繰り返し,管理指導にもかかわらず血漿BNP濃度は500pg/ml前後を推移し,2002年に起坐呼吸が再出現した.X線で心胸郭比64%の心拡大および肺うっ血像,両側胸水貯留を認め,心エコーで左室拡張終期径の増大とびまん性高度左室壁運動低下を認めた.アンジオテンシンII受容体拮抗薬の追加併用療法を行ったところ,尿量増加やうっ血性心不全の改善を認めた.退院時にはNYHA IIやBNPの改善を認め,社会生活を円滑に営める程度に回復した

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Language：English   Publisher：Kitasato University  

The crucial role of beta-adrenergic receptor (AR)-inhibitory (i) or stimulatory (s) G protein signal pathway in the development of chronic heart failure has been demonstrated. While, some cases dilated cardimyopathy mainly leading to chronic heart failure have an active myocarditis, of which the pathomechanism is considered to be the autoimmune process. However, the role of G protein in the myocardial inflammation remains uncertain. Thus, the immunomoduatory effect of G protein was investigated using experimental autoimmune myocarditis (EAM) produced by the immunization of cardiac myosin. We previously established cardiac-myosin-fragment CM2 specific T cell lines (MTL), which directly induced EAM. The addition of formoterol (FM), beta2-AR agonist, but denopamine (D) as a betal-AR agonist did not, suppressed the proliferation of MTL along with the production of interferon (IFN)-γ stimulated by antigen presenting cells and CM2. Intracellular c-AMP levels were augmented by the addition of FM, but by the addition of D did not. However, pertussis toxin (PTX), the Gi protein inhibitor augmented MTL proliferation in conjunction with the production of IFN-T. The daily administration of FM since 5 days before immunization ameliorated EAM at day 21 after immunization dose-dependently in conduction with a decrease in myocardial expression of IFN-γ [macroscopic scores (MS) : 2.3±0.5 for FM (22.5μg/kg/day), 1.7±0.5 for FM (225μg/kg/day) and 3.3±0.8 for control, P<0.01]. In contrast, only a single injection of PTX dose-dependently exacerbated EAM [MS : 3.3±0.2 for PTX (0.04μg/kg/day), 3.8±0.4 for FM (0.4μg/kg/day) and 2.8±0.3 for control, P<0.05]. Activation of G protein through the sympathetic nerve system is also a modulator of myocardial autoimmunity. The modulation of G protein may be also a new immunological therapeutic target for chronic heart failure.

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Language：Japanese   Publisher：社団法人日本循環器学会  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：北里大学  

CiNii Books

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

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：English   Publisher：Japanese Circulation Society  

CiNii Books

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Language：Japanese   Publisher：(有)科学評論社  

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

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Language：English   Presentation type：Oral presentation (general)  

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Presentation type：Public lecture, seminar, tutorial, course, or other speech  

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Presentation type：Oral presentation (invited, special)  

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Presentation type：Oral presentation (general)  

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Presentation type：Oral presentation (invited, special)  

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