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

Immunomodulatory drugs (IMiDs) are key drugs for treating multiple myeloma and myelodysplastic syndrome with chromosome 5q deletion. IMiDs exert their pleiotropic effects through the interaction between cell-specific substrates and cereblon, a substrate receptor of the E3 ubiquitin ligase complex. Thus, identification of cell-specific substrates is important for understanding the effects of IMiDs. IMiDs increase the risk of thromboembolism, which sometimes results in fatal clinical outcomes. In this study, we sought to clarify the molecular mechanisms underlying IMiDs-induced thrombosis. We investigated cereblon substrates in human megakaryocytes using liquid chromatography-mass spectrometry and found that thrombospondin-1 (THBS-1), which is an inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), functions as an endogenous substrate in human megakaryocytes. IMiDs inhibited the proteasomal degradation of THBS-1 by impairing the recruitment of cereblon to THBS-1, leading to aberrant accumulation of THBS-1. We observed a significant increase in THBS-1 in peripheral blood mononuclear cells (PBMNCs) as well as larger von Willebrand factor (vWF) multimers in the plasma of patients with myeloma, who were treated with IMiDs. These results collectively suggest that THBS-1 represents an endogenous substrate of cereblon. This pairing is disrupted by IMiDs, and the aberrant accumulation of THBS-1 plays an important role in the pathogenesis of IMiDs-induced thromboembolism.

DOI： 10.1182/bloodadvances.2023010080

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

2016～2020年に日本の14自治体で行われたLIFE研究のデータベースを用いて、血管内皮増殖因子シグナル伝達経路(VSP)阻害薬治療を行った癌患者3460例を特定し、臨床成績に対する高血圧の影響を評価した。VSP阻害薬投与後に高血圧を発症した569例(16.4%)を新規発症高血圧群、ベースラインに高血圧を有していた1790例(51.7%)を既存高血圧群、高血圧を認めなかった1101例(31.8%)を非高血圧群に分類した。主要評価項目は、治療無効までの期間(TTF)とした。TTF中央値は、新規発症高血圧群301日、既存高血圧群170日、非高血圧群146日であった。調整Cox比例ハザードモデルにおいて、新規発症高血圧と既存高血圧は非高血圧に比べてTTFを有意に延長し(ハザード比はそれぞれ0.58、0.85)、新規発症高血圧は既存高血圧に比べてTTFを有意に延長した(ハザード比0.68)。VSP阻害薬は、新規発症高血圧および既存の高血圧を有する進行癌患者の死亡率を改善する可能性が示唆された。

Language：Japanese   Publisher：The Japanese Society of Toxicology  

<p>The number of cancer patients worldwide is increasing every year. On the other hand, there are still many unknowns regarding the development of cardiovascular disease in cancer patients. Osimertinib is used for treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer and significantly improves the prognosis. However, heart failure is observed in 1-5% of patients during treatment and QT prolongation in 10%, with a lethal course in some cases, but the mechanism of cardiotoxicity caused by osimertinib has not been elucidated.</p><p>In this study, we focused on the mitochondria of human iPS-derived cardiomyocytes (hiPSC-CMs) to analyze the cardiotoxicity mechanism of osimertinib. Exposure of hiPSC-CMs to anticancer drugs (osimertinib, doxorubicin, and trastuzumab) induced mitochondrial hyperfission and suppressed respiratory capacity. Our laboratory has previously found that sulfur metabolism plays an important role in maintaining mitochondrial quality in cardiomyocytes. When sulfur molecular donors (Na₂S, Na₂S₂, and Na₂S₃) were added, Na₂S most strongly inhibited osimertinib-induced mitochondrial dysfunction. Intracellular imaging using a sulfur molecular detection probe showed that osimertinib reduced intracellular H₂S concentrations, which were restored by Na₂S exposure.</p><p>These results indicate that osimertinib reduces intracellular H₂S levels concurrently with mitochondrial dysfunction in myocardium. Our results also indicate that maintenance of intracellular H₂S levels may contribute to the mitigation of osimertinib cardiotoxicity.</p>

DOI： 10.14869/toxpt.51.1.0_p-139

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DOI： 10.1016/j.annonc.2023.09.209

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Language：English   Publisher：European Heart Journal - Case Reports  

Background Cystic myxomas are quite rare. Moreover, few reports have evaluated the causes that constituted them. Case summary A 73-year-old Asian man presented for pre-operative examination of osteoarthritis, and transthoracic echocardiography (TTE) revealed an incidental intracardiac mass. Therefore, he was referred to our department for further evaluation. He had no specific symptoms or family history related to tumours and heart failure. The TTE showed a 32 × 24 mm spherical mass adherent to the left atrial septum. The upper part of the mass was cystic in formation and hypoechoic inside and resembled a light bulb. Transoesophageal echocardiography showed the feeding arteries flowing from the bottom into the cystic part. In addition, two jet strips drained from the cystic part in the direction of the mitral valve. Coronary angiography revealed the feeding arteries, which consisted mainly of the right coronary artery conus branch and the left circumflex branch, and the blood flowed into the saccular area from the feeding arteries and excreted towards the mitral valve. Surgical resection was performed due to the mobility, and the histopathology confirmed a cystic myxoma. Discussion We described the unique anatomical formation of a cystic myxoma, which consisted of an exquisite balance between the tumour feeding arteries and the draining outlet vessels.

DOI： 10.1093/ehjcr/ytad331

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Language：English   Publisher：European Heart Journal - Case Reports  

DOI： 10.1093/ehjcr/ytad025

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

BACKGROUND: Cancer treatment with vascular endothelial growth factor signalling pathway (VSP) inhibitors frequently causes hypertension. Although previous reports suggested that the antihypertensive drug renin-angiotensin system inhibitor (RASI) may have a positive synergistic effect with VSP inhibitors, the actual impact on clinical outcomes is unknown. OBJECTIVES: The study aims to clarify whether RASIs exhibit clinical benefits for patients with cancer with hypertension. METHOD: From the Longevity Improvement and Fair Evidence Study database, comprising Japanese claims data between 2016 and 2020, we reviewed 2380 patients treated with VSP inhibitors who received antihypertensive treatment during cancer therapy. The patients were classified into two groups: with-RASI (n=883) and without-RASI (n=1497). In addition, 1803 of these patients treated for hypertension with RASI-only (n=707) or calcium channel blocker-only (n=1096) were also reviewed. The time-to-treatment failure (TTF), the interval from initiation of chemotherapy to its discontinuation, was applied as the primary endpoint. RESULTS: The median TTFs were 167 (60-382) days in the with-RASI group and 161 (63-377) days in the without-RASI group (p=0.587). All models, including Cox proportional hazard models and multiple propensity score models, did not reveal the superiority of with-RASI treatment. In the propensity score matching model, the HR for treatment with-RASI compared with that for without-RASI was 0.96 (95% CI 0.86 to 1.06, p=0.386). In addition, the TTFs of RASI-only were not superior to calcium channel blocker-only (p=0.584). CONCLUSIONS: RASIs for hypertension do not benefit clinical outcomes during cancer therapy with VSP inhibitors. In addition, RASIs and calcium channel blockers have comparable clinical efficacy as first-line antihypertensive.

DOI： 10.1136/openhrt-2022-002135

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

<p><b><i>Background:</i></b> Hypertension is a frequent adverse event caused by vascular endothelial growth factor signaling pathway (VSP) inhibitors. However, the impact of hypertension on clinical outcomes during VSP inhibitor therapy remains controversial.</p><p><b><i>Methods and Results:</i></b> We reviewed 3,460 cancer patients treated with VSP inhibitors from the LIFE Study database, comprising Japanese claims data between 2016 and 2020. Patients were stratified into 3 groups based on the timing of hypertension onset: (1) new-onset hypertension (n=569; hypertension developing after VSP inhibitor administration); (2) pre-existing hypertension (n=1,790); and (3) no hypertension (n=1,101). Time to treatment failure (TTF) was used as the primary endpoint as a surrogate for clinical outcomes. The median (interquartile range) TTF in the new-onset and pre-existing hypertension groups was 301 (133–567) and 170 (72–358) days, respectively, compared with 146 (70–309) days in the non-hypertensive group (P<0.001 among all groups). In an adjusted Cox proportional hazard model, new-onset (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.50–0.68; P<0.001) and pre-existing (HR 0.85; 95% CI 0.73–0.98; P=0.026) hypertension were independent factors for prolonged TTF. The TTF of new-onset hypertension was longer than that of pre-existing hypertension (HR 0.68; 95% CI 0.62–0.76; P<0.001).</p><p><b><i>Conclusions:</i></b> This study highlighted that new-onset hypertension induced by VSP inhibitors was an independent factor for favorable clinical outcomes. Pre-existing hypertension before VSP inhibitor initiation was also a significant factor.</p>

DOI： 10.1253/circj.CJ-22-0628

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Language：English   Publisher：Brain Research Bulletin  

Decreased plasma levels of plasmalogens in neurodegenerative diseases have been watched with interest. We previously reported the decreases of erythrocyte ethanolamine plasmalogen (PlsPE) of blood not only in Alzheimer's disease (AD) and Parkinson's disease (PD), but also in coronary artery disease (CAD). In the present study, by using the same high-performance liquid chromatography (HPLC) method, we investigated the pattern of changes in the phospholipid composition of erythrocyte membrane in AD, PD and CAD compared with healthy individuals. The common patten of changes among them was as follows: The decrease of erythrocyte PlsPE was accompanied by a decrease of phosphatidylcholine although phosphatidylethanolamine remained unchanged. The decreases of PlsPE and phosphatidylcholine were replaced by an increase of sphingomyelin (SM) in the total phospholipids. The dissociated change between PlsPE and phosphatidylethanolamine (PE) may be caused by the differences in molecular structure or in location in the cell membrane. Such special changes provide another piece of biochemical evidence that these different diseases are caused by identical pathological mechanism, suggesting potential biomarkers for these chronic diseases due to aging.

DOI： 10.1016/j.brainresbull.2022.08.009

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Publisher：メディカルレビュー社  

DOI： 10.18885/hv.0000001037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.9234-21

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese journal of clinical oncology  

BACKGROUND: The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. METHODS: We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. RESULTS: In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n = 40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P = 0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. CONCLUSIONS: IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism.

DOI： 10.1093/jjco/hyac103

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Language：English   Publisher：Oxford University Press  

癌関連血栓症を有する進行消化器癌患者に対する抗凝固療法の患者選択を改善するため、出血の発生率や危険因子を後方視的に検討した。2014～2018年に化学療法を受けた進行消化器癌患者194例(年齢31～84歳)を対象とした。消化器癌の内訳は胃癌74例、大腸癌120例であった。194例のうち、静脈血栓塞栓症と診断された患者は40例(20.6%)、肺血栓塞栓症を併発した患者は10例(5.2%)であった。出血は29名(15%)に認められた。出血部位は、原発巣17例、転移巣9例、出血性胃潰瘍3例であり、静脈血栓塞栓症群40例のうち10例(25%)に出血が認められた。多変量解析により、International Medical Prevention Registry on Venous Thromboembolism(IMPROVE)出血スコア7以上と大出血は有意に相関していた(P=0.01)。出血リスクの低い患者では大出血は3例のみであった。以上より、IMPROVE出血スコアは静脈血栓塞栓症を有する消化器癌患者における出血リスクを予測する可能性があった。

Language：English   Publisher：Modern Rheumatology Case Reports  

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

DOI： 10.1093/mrcr/rxac009

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Language：English   Publisher：Oxford University Press  

症例は25歳女性で、咳嗽および労作時呼吸困難を主訴に来院した。7年前に全身性エリテマトーデス(SLE)と診断され、プレドニゾロン(PSL)5mgを服用していた。SLEの再燃を疑い、入院となった。抗核抗体は2560倍、抗dsDNA抗体は11.3IU/mL、抗Sm抗体96.2U/mLであった。右心カテーテル検査で平均肺動脈圧は56mmHg、心係数は1.25L/min/m2、肺血管抵抗は27.1 Wood単位であった。SLEに伴う肺動脈高血圧症と診断した。心不全の重症度はNYHA心機能分類でIV度、SLEの重症度はSLEDAIスコアで14点であった。ステロイドパルス療法を施行し、経口PSLおよびシクロホスファミド静注療法を開始した。肺高血圧症に対してマシテンタンとタダラフィルを投与したが、効果は限定的であった。エポプロステノール静注を開始したところ、2ヵ月後にSLEDAIスコアは2点に改善した。エポプロステノール在宅持続静注療法を勧めたが患者が拒否したため、経口セレキシパグおよびイロプロスト吸引投与に切り替えた。10ヵ月後の再診で症状の再燃はなかった。

Language：English   Publisher：Frontiers in Cardiovascular Medicine  

A 31-year-old woman was referred to our hospital for evaluation of a cardiac mass in the right atrium. Cardiac magnetic resonance imaging indicated a cystic mass filled with fluid accumulation in the right atrium. The mass was identified as a cardiac cyst and was surgically removed. Pathological examination revealed an extremely rare bronchogenic cyst. Bronchogenic cysts are benign congenital abnormalities of primitive foregut origins that form in the mediastinum during embryonic development. There is unusual clinical dilemmas surrounding the treatment plan for cardiac surgery or biopsy of cardiac masses, especially in patients with rare cardiac cysts. The anatomical location of the cyst can be related to various clinical symptoms and complications. In cases of indeterminate cardiac cysts, direct cyst removal without prior biopsy is of utmost importance.

DOI： 10.3389/fcvm.2022.915876

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

OBJECTIVE: Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients. METHODS: The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT. RESULTS: Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9-35) days. Patients were followed up for 347 (132-1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m2) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type. CONCLUSIONS: Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies.

DOI： 10.1136/openhrt-2022-002007

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DOI： 10.1093/mrcr/rxac009.

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

Adaptive pacing algorithmを用いた心臓再同期療法(adaptive CRT)の治療効果を両心室ペーシング法によるCRT(BiV-CRT)と比較した。QRS幅が120ms以上の患者17例にadaptive CRTを施行し、START試験にてBiV-CRTを行った17例と傾向スコアマッチング解析を行った。その結果、CRT後に全例の左室容積が有意に減少し、左室収縮末期容積の減少率に有意な群間差はなかった。CRT後のQRS幅の短縮は、adaptive CRT群の方が有意に大きく、QRS幅がやや長い120～149msの患者において差が顕著であった。QRS幅がやや長い患者では、左室収縮末期容積の減少率、左室容積が減少した患者の割合もadaptive CRT群の方が有意に大きかった。QRS幅がやや長い患者にadaptive CRTを行うことでCRT無効例が減少する可能性がある。

Language：English   Publisher：Frontiers in Cardiovascular Medicine  

Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy. Case Summary: A 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion. Conclusion: Interleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.

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DOI： 10.1016/j.jjcc.2021.11.004.

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

Language：English   Publisher：Journal of Cardiology  

Background: Mechanical and electrical restoration by cardiac resynchronization therapy (CRT) with adaptive pacing algorithm (aCRT) in heart failure patients with a moderately wide (120–149 ms) QRS has not been fully evaluated. The purpose of this study was to investigate the therapeutic effect of aCRT compared with conventional biventricular CRT (BiV-CRT) regardless of QRS morphology. Methods: Seventeen consecutive patients with a QRS ≥120 ms, regardless of morphology, underwent CRT device implantation with an aCRT pacing algorithm. Propensity score matched analysis was performed to evaluate the impact of aCRT on the improvement in mechanical and electrical parameters after CRT device implantation using historical controls (HC) from the clinical registry of BiV-CRT (START trial). Results: Left ventricular (LV) volume significantly decreased after CRT in all patients in both the aCRT and HC groups. The difference in relative reduction of LV end-systolic volume (LVESV) was not significantly different between the 2 arms. QRS shortening after CRT was significantly greater in the aCRT group than in the BiV-CRT group, and the difference was prominent in patients with a moderately wide QRS (120–149 ms). In patients with a moderately wide QRS, the relative reduction in LVESV [39 (29–47)% vs. 2 (−6–20)%, p = 0.04] and proportion of LV volume responders (90% vs. 38%, p = 0.04) were significantly greater in the aCRT group than in the HC group. The proportion of volume responders was not significantly different in patients with a wide QRS (≥150 ms). Conclusions: The aCRT algorithm improved electrical and mechanical parameters in patients with a moderately wide QRS, regardless of QRS morphology.

DOI： 10.1016/j.jjcc.2021.11.004

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DOI： 10.2169/internalmedicine.9234-21.

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

Background: Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established. Case summary: A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed. Discussion: IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.

DOI： 10.1093/ehjcr/ytab002

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

Tyrosine kinase inhibitors (TKI) work against various types of cancer by inhibiting angiogenic signaling. Little is understood about the incidence, characteristics, and risk factors associated with thromboembolism induced by TKI in routine clinical practice. We retrospectively analyzed data derived from 29 patients with thyroid cancer or soft tissue sarcoma (STS) treated with lenvatinib (n=10) and pazopanib (n=19). Eight (arterial n=4; venous n=4) thromboembolic events developed in 6 (20&#37;) patients. Thromboembolisms occurred during a mean of 149 (range, 42-847) days from starting TKI. The primary disease progressed in all patients with thromboembolism. The overall survival durations of patients with and without improved thromboembolism were 572 [95&#37; confidence interval (CI), 225- 918] and 176 (95&#37; CI, 84-394) days, respectively, which did not significantly differ (P=0.33). Patients with and without improved thromboembolism survived after onset for 122 (95&#37; CI, 71-173) versus 27 (95&#37; CI, 21-42) days (P=0.049), which significantly differed. Univariate analysis and variate selection for multivariate analysis selected a history of thromboembolism as the most powerful risk factor for new thromboembolism. In summary, the frequency of thromboembolism in clinical practice was higher than that in previous clinical trials. Furthermore, a history of thromboembolism was a risk factor for the development of new thromboembolism in patients treated with TKI. Thromboembolism developed particularly as the primary disease progressed. Our findings require validation in a large-scale study.

DOI： 10.1097/IJ9.0000000000000089

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

Acute decompensated heart failure (ADHF) requires immediate treatments because it impairs perfusion to systemic organs and their function. Half of all patients with ADHF are diagnosed with heart failure with reduced left ventricular ejection fraction (HFrEF). The initial goal of management for ADHF is to stabilize hemodynamic status. Pulmonary edema is treated with vasodilators or diuretics. Inhibitors of the renin-angiotensin-aldosterone system and β-blockers should be started and/or increased to meet the maximum dose, ideally the target dose, that the patient can tolerate as a treatment of HFrEF. Patients with severe circulatory failure need inotropic drugs or mechanical circulatory support.

DOI： 10.1016/j.hfc.2019.12.007

Language：English  

Several cancer treatments cause cardiotoxicity that can lead to heart failure, coronary artery disease, arrhythmia, and pericardial disease. In this review, representative cases of heart failure following cardiotoxicity caused by trastuzumab, anthracycline, and hematopoietic stem cell transplantation are described with case notes. Additionally, other important points regarding cardiotoxicity related to heart failure are reported. During and after potentially cardiotoxic therapy, periodic cardiac examinations are recommended to detect any cardiovascular disorders; these are ameliorated if appropriately diagnosed at an earlier stage. It is important for cardiologists and oncologists to understand the pathophysiology of representative cardiovascular disease cases following cancer treatment.

DOI： 10.1016/j.hfc.2019.11.002

Language：English  

Acute decompensated heart failure (ADHF) requires immediate treatments because it impairs perfusion to systemic organs and their function. Half of all patients with ADHF are diagnosed with heart failure with reduced left ventricular ejection fraction (HFrEF). The initial goal of management for ADHF is to stabilize hemodynamic status. Pulmonary edema is treated with vasodilators or diuretics. Inhibitors of the renin-angiotensin-aldosterone system and β-blockers should be started and/or increased to meet the maximum dose, ideally the target dose, that the patient can tolerate as a treatment of HFrEF. Patients with severe circulatory failure need inotropic drugs or mechanical circulatory support.

DOI： 10.1016/j.hfc.2019.12.007

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

Several cancer treatments cause cardiotoxicity that can lead to heart failure, coronary artery disease, arrhythmia, and pericardial disease. In this review, representative cases of heart failure following cardiotoxicity caused by trastuzumab, anthracycline, and hematopoietic stem cell transplantation are described with case notes. Additionally, other important points regarding cardiotoxicity related to heart failure are reported. During and after potentially cardiotoxic therapy, periodic cardiac examinations are recommended to detect any cardiovascular disorders; these are ameliorated if appropriately diagnosed at an earlier stage. It is important for cardiologists and oncologists to understand the pathophysiology of representative cardiovascular disease cases following cancer treatment.

DOI： 10.1016/j.hfc.2019.11.002

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

Erythrocytes are the most abundant cells and acting as carrier, deliverer and sensor of oxygen. Therefore, human erythrocyte behavior is a fundamental health indicator. Lifespan of circulating erythrocytes is about 120 days, and hence erythrocyte population shows distribution of aging. The physicochemical property of hemoglobin (Hb) influences the density and the deformability of erythrocytes. Senescent erythrocytes are dense, shrunk, less deformable and finally removed from circulation by several mechanisms such as phagocytosis and eryptosis. Earlier removal leads to the short lifespan of less deformable erythrocytes. Herein, anemic and cardiometabolic diseases are presented in order to consider the relationship between the agedependent erythrocyte density and deformability. The main cause of impaired deformability in sickle cell disease is the presence of dense cells characterized by cellular dehydration and polymerization of sickle Hb, that in hereditary hemolytic diseases is cellular geometry, and that in iron deficiency anemia is an increased susceptibility of lighter erythrocytes to the oxidative stress. Diabetic erythrocytes show seemingly normal density and reduced deformability under the enhanced oxidative stress. This article addresses that distribution profiles of both erythrocyte density and deformability are important for better understanding of the encapsulated Hb interacting membrane of erythrocytes showing individual aging.

DOI： 10.17106/jbr.34.61

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

BACKGROUND: Disturbed microcirculation is related to diabetic complications, and erythrocyte deformability is a critical factor regulating microcirculation. OBJECTIVES: To know the relationship between the impaired deformability and density profile in diabetic erythrocytes. METHODS: We recruited patients with type 2 diabetes (n = 15, diabetic group) and age- and sex-matched non-diabetic subjects (n = 15, control group). Erythrocyte density (ED) profile was obtained by the phthalate ester separation technique. ED distribution was fitted by sigmoidal curve, yielding specific gravity of phthalate ester allowing passage of half erythrocytes population (ED50) and slope factor. Erythrocyte deformability was estimated by our specific filtration technique. RESULTS: Diabetic group showed significantly (p < 0.001) higher HbA1c and fasting blood glucose concentration. Erythrocyte deformability in diabetic group was impaired as compared with that in control group (p < 0.001) and proportional to HbA1c (p = 0.009). However, ED50 and the slope factor in diabetic group did not differ from respective parameters in control group. CONCLUSIONS: This study demonstrated that erythrocyte deformability was impaired in diabetic patients even under treatment. HbA1c up to 7.5&#37; is concluded not to alter the erythrocyte density but to impair the deformability, which might be a warning to clinicians for prevention of diabetic complications.

DOI： 10.3233/CH-200873

Language：English  

0

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

Fluorouracil (5-FU), a commonly used anticancer agent, has potent cardiotoxicity that is mediated by vascular endothelial injury and vasospasm. Here, we report a patient demonstrating atrial fibrillation (AF), which was most likely induced by vasospasm mediated by 5-FU. A 69-year-old man presented with dysphagia and was diagnosed with advanced esophageal cancer. Frequent paroxysms of atrial fibrillation (AF) were observed during combination chemotherapy including 5-FU. AF was refractory to disopyramide, but was sensitive to antianginal agents (nicorandil and nitroglycerin transdermal patch). Coronary angiography performed within the chemotherapeutic period demonstrated moderate stenosis in the right coronary artery (RCA). Severe spasm at the proximal portion of the atrial branch in RCA was induced by provocation test using acetylcholine. Our case indicated that 5-FU predisposed vasospasm in RCA and the subsequent atrial ischemia may lead to AF. <Learning objective: Fluorouracil (5-FU), a commonly used anticancer agent, induces cardiac ischemic events and sometimes leads to the paroxysms of atrial fibrillation (AF). Coronary-dilating agents should be considered for the treatment of AF which occurs after the administration of 5-FU and is refractory to antiarrhythmic agents.>

DOI： 10.1016/j.jccase.2019.08.005

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

Fluorouracil (5-FU), a commonly used anticancer agent, has potent cardiotoxicity that is mediated by vascular endothelial injury and vasospasm. Here, we report a patient demonstrating atrial fibrillation (AF), which was most likely induced by vasospasm mediated by 5-FU. A 69-year-old man presented with dysphagia and was diagnosed with advanced esophageal cancer. Frequent paroxysms of atrial fibrillation (AF) were observed during combination chemotherapy including 5-FU. AF was refractory to disopyramide, but was sensitive to antianginal agents (nicorandil and nitroglycerin transdermal patch). Coronary angiography performed within the chemotherapeutic period demonstrated moderate stenosis in the right coronary artery (RCA). Severe spasm at the proximal portion of the atrial branch in RCA was induced by provocation test using acetylcholine. Our case indicated that 5-FU predisposed vasospasm in RCA and the subsequent atrial ischemia may lead to AF. <Learning objective: Fluorouracil (5-FU), a commonly used anticancer agent, induces cardiac ischemic events and sometimes leads to the paroxysms of atrial fibrillation (AF). Coronary-dilating agents should be considered for the treatment of AF which occurs after the administration of 5-FU and is refractory to antiarrhythmic agents.>.

DOI： 10.1016/j.jccase.2019.08.005

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

BACKGROUND: Venous thromboembolism (VTE) is highly associated with advanced gastric cancer (AGC) and is sometimes lethal. Predictors of VTE have not been identified, and the efficacy and safety of direct oral anticoagulants (DOACs) for AGC-associated VTE remain to be clarified. METHODS: A total of 188 AGC patients who started chemotherapy during the period from January 2014 to December 2017 in our institutions were retrospectively examined for the incidence of VTE, risk factors for VTE, and the efficacy and safety of DOAC-based anticoagulant therapy for VTE. RESULTS: Thirty-four patients (18&#37;) were diagnosed with VTE at the start or during the course of chemotherapy (VTE group). More VTE group patients had a history of abdominal surgery and had moderate-severe ascites (32&#37; versus 17&#37;, 32&#37; versus 14&#37;, respectively) than non-VTE group patients (NVTE group). The mean serum albumin concentrations in the VTE group were significantly lower than NVTE group (3.38 mg/dL vs 3.65 mg/dL, respectively). Multivariate analysis showed that hypoalbuminemia was significantly correlated with VTE (P = 0.012). In the VTE group, 29 patients (85&#37;) received anticoagulant therapy, including 24 patients treated with DOACs. No lethal VTE was observed in any patients. Thirteen patients (45&#37;) terminated DOACs because of anemia or bleeding events, of whom eleven developed major bleeding. Median overall survivals of the VTE and NVTE groups were 9.63 months and 11.5 months, respectively (P = 0.262). CONCLUSION: Hypoalbuminemia appears to be a risk factor for AGC-associated VTE. DOACs are effective to AGC-associated VTE, but careful observation of bleeding events is required.

DOI： 10.1007/s10120-019-00930-2

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

A 58-year-old woman complained of general fatigue and was diagnosed with sick sinus syndrome (SSS) by ambulatory electrocardiogram, which demonstrated sinus arrest at midnight and paroxysmal atrial fibrillation (AF) at nighttime. Since her plasma cholinesterase (ChE) activity had been persistently zero, she was diagnosed with ChE deficiency. She refused permanent pacemaker implantation, and treatment with positive chronotropic drugs is ongoing. A novel association of ChE deficiency with SSS is theoretically possible rather than coincident, considering that ChE plays a key role in cholinergic influences on the sinus node leading to sinus bradyarrhythmia and on the atria, causing vagally mediated AF.

DOI： 10.2169/internalmedicine.1229-18

Language：English  

Atrial fibrillation (AF) is a common arrhythmia and gastroesophageal reflux disease (GERD) is popular in Japan. The two common diseases share several predisposing factors such as lifestyle and senescence, and inflammation and oxidative stress play an important role in their development and progression. Incidental cases of AF treated successfully by proton pump inhibitor (PPI) applied for coexisting GERD have been sporadically reported. An increasing evidence indicates that GERD induces the initiation and the perpetuation of AF. This is caused by the autonomic nerve influence, mechanical compression, and propagation of local inflammation due to proximity of left atrium (LA) and lower esophagus. Meanwhile, AF also develops GERD by mechanical and inflammatory actions of LA characterized by remodeling and inflammation. The robust association of AF with GERD is not limited to their natural interaction, i.e., pharmacological or nonpharmacological treatment of AF is reported to aggravate GERD. Many cardiac drugs (anticoagulants, calcium antagonists, and nitrates) induce esophageal mucosal damage and lower esophageal sphincter relaxation promoting acid reflux. These drugs are frequently prescribed in patients with AF for stroke prevention, rate control, and for coexisting coronary heart disease. Catheter ablation also yields both GERD and esophageal thermal injury, which is a precursor lesion of atrioesophageal fistula. The notion that AF and GERD are mutually interdependent is widely and empirically recognized. However, mechanistic link of the two common diseases and objective evaluation of PPI as an adjunctive AF treatment warrant future large-scale prospective trials.

DOI： 10.1002/joa3.12125

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

Background: Venous thromboembolism (VTE) is highly associated with advanced gastric cancer (AGC) and is sometimes lethal. Predictors of VTE have not been identified, and the efficacy and safety of direct oral anticoagulants (DOACs) for AGC-associated VTE remain to be clarified. Methods: A total of 188 AGC patients who started chemotherapy during the period from January 2014 to December 2017 in our institutions were retrospectively examined for the incidence of VTE, risk factors for VTE, and the efficacy and safety of DOAC-based anticoagulant therapy for VTE. Results: Thirty-four patients (18%) were diagnosed with VTE at the start or during the course of chemotherapy (VTE group). More VTE group patients had a history of abdominal surgery and had moderate–severe ascites (32% versus 17%, 32% versus 14%, respectively) than non-VTE group patients (NVTE group). The mean serum albumin concentrations in the VTE group were significantly lower than NVTE group (3.38 mg/dL vs 3.65 mg/dL, respectively). Multivariate analysis showed that hypoalbuminemia was significantly correlated with VTE (P = 0.012). In the VTE group, 29 patients (85%) received anticoagulant therapy, including 24 patients treated with DOACs. No lethal VTE was observed in any patients. Thirteen patients (45%) terminated DOACs because of anemia or bleeding events, of whom eleven developed major bleeding. Median overall survivals of the VTE and NVTE groups were 9.63 months and 11.5 months, respectively (P = 0.262). Conclusion: Hypoalbuminemia appears to be a risk factor for AGC-associated VTE. DOACs are effective to AGC-associated VTE, but careful observation of bleeding events is required.

DOI： 10.1007/s10120-019-00930-2

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

A 58-year-old woman complained of general fatigue and was diagnosed with sick sinus syndrome (SSS) by ambulatory electrocardiogram, which demonstrated sinus arrest at midnight and paroxysmal atrial fibrillation (AF) at nighttime. Since her plasma cholinesterase (ChE) activity had been persistently zero, she was diagnosed with ChE deficiency. She refused permanent pacemaker implantation, and treatment with positive chronotropic drugs is ongoing. A novel association of ChE deficiency with SSS is theoretically possible rather than coincident, considering that ChE plays a key role in cholinergic influences on the sinus node leading to sinus bradyarrhythmia and on the atria, causing vagally mediated AF.

DOI： 10.2169/internalmedicine.1229-18

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

Atrial fibrillation (AF) is a common arrhythmia and gastroesophageal reflux disease (GERD) is popular in Japan. The two common diseases share several predisposing factors such as lifestyle and senescence, and inflammation and oxidative stress play an important role in their development and progression. Incidental cases of AF treated successfully by proton pump inhibitor (PPI) applied for coexisting GERD have been sporadically reported. An increasing evidence indicates that GERD induces the initiation and the perpetuation of AF. This is caused by the autonomic nerve influence, mechanical compression, and propagation of local inflammation due to proximity of left atrium (LA) and lower esophagus. Meanwhile, AF also develops GERD by mechanical and inflammatory actions of LA characterized by remodeling and inflammation. The robust association of AF with GERD is not limited to their natural interaction, i.e., pharmacological or nonpharmacological treatment of AF is reported to aggravate GERD. Many cardiac drugs (anticoagulants, calcium antagonists, and nitrates) induce esophageal mucosal damage and lower esophageal sphincter relaxation promoting acid reflux. These drugs are frequently prescribed in patients with AF for stroke prevention, rate control, and for coexisting coronary heart disease. Catheter ablation also yields both GERD and esophageal thermal injury, which is a precursor lesion of atrioesophageal fistula. The notion that AF and GERD are mutually interdependent is widely and empirically recognized. However, mechanistic link of the two common diseases and objective evaluation of PPI as an adjunctive AF treatment warrant future large-scale prospective trials.

DOI： 10.1002/joa3.12125

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

A 53-year-old woman reported burning pain, muscle weakness, and dysesthesia of the left arm 2 months after permanent pacemaker insertion in the ipsilateral side for the treatment of sick sinus syndrome. Complex regional pain syndrome (CRPS) induced by pacemaker implantation was diagnosed. In 2017, her pulse generator became exhausted and was exchanged carefully to avoid exacerbation of CRPS, under the application of local anesthesia and premedication. Six months later, the patient's grip strength in her left hand remained lower relative to that in her right hand. Although rare, the presence of CRPS following device implantation should be remembered.

DOI： 10.1016/j.joa.2017.08.005

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

RATIONALE: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. PATIENT CONCERNS: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. DIAGNOSIS: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. INTERVENTIONS: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. OUTCOMES: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. LESSONS: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.

DOI： 10.1097/MD.0000000000008987

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

A 53-year-old woman reported burning pain, muscle weakness, and dysesthesia of the left arm 2 months after permanent pacemaker insertion in the ipsilateral side for the treatment of sick sinus syndrome. Complex regional pain syndrome (CRPS) induced by pacemaker implantation was diagnosed. In 2017, her pulse generator became exhausted and was exchanged carefully to avoid exacerbation of CRPS, under the application of local anesthesia and premedication. Six months later, the patient's grip strength in her left hand remained lower relative to that in her right hand. Although rare, the presence of CRPS following device implantation should be remembered.

DOI： 10.1016/j.joa.2017.08.005

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

Rationale: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. Patient concerns: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. Diagnosis: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. Interventions: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. Outcomes: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. Lessons: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.

DOI： 10.1097/MD.0000000000008987

Language：English  

0

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

Acetylcholine is widely used for a diagnostic provocation test of coronary spasm in patients with vasospastic angina. Acetylcholine usually induces coronary vasodilatation mediated by muscarinic receptor activation, but sometimes it evokes vasoconstriction of coronary arteries where the endothelium is damaged. Early repolarization syndrome is characterized by a J wave observed at the end of the QRS complex in a surface electrocardiogram. The J wave is attributed to the transmural voltage gradient at the early repolarization phase across the ventricular wall, which stems mainly from prominent transient outward current in the epicardium, but not in the endocardium. Transient high-dose application of acetylcholine into the epicardial coronary arteries provides a unique opportunity to augment net outward current, selectively, in the ventricular epicardium and unmask the J wave, irrespective of the cardiac ischemia based on coronary spasm. Acetylcholine augments cardiac membrane potassium conductance by enhancing acetylcholine-activated potassium current directly and by activating adenosine triphosphate-sensitive potassium current, in addition to the reduced sodium and calcium currents in the setting of severe ischemia due to vasospasm. However, the role of acetylcholine as an arrhythmogenic probe of the J wave induction in patients with suspected early repolarization syndrome warrants future prospective study.

DOI： 10.1016/j.joa.2016.12.005

Language：English  

Acetylcholine is widely used for a diagnostic provocation test of coronary spasm in patients with vasospastic angina. Acetylcholine usually induces coronary vasodilatation mediated by muscarinic receptor activation, but sometimes it evokes vasoconstriction of coronary arteries where the endothelium is damaged. Early repolarization syndrome is characterized by a J wave observed at the end of the QRS complex in a surface electrocardiogram. The J wave is attributed to the transmural voltage gradient at the early repolarization phase across the ventricular wall, which stems mainly from prominent transient outward current in the epicardium, but not in the endocardium. Transient high-dose application of acetylcholine into the epicardial coronary arteries provides a unique opportunity to augment net outward current, selectively, in the ventricular epicardium and unmask the J wave, irrespective of the cardiac ischemia based on coronary spasm. Acetylcholine augments cardiac membrane potassium conductance by enhancing acetylcholine-activated potassium current directly and by activating adenosine triphosphate-sensitive potassium current, in addition to the reduced sodium and calcium currents in the setting of severe ischemia due to vasospasm. However, the role of acetylcholine as an arrhythmogenic probe of the J wave induction in patients with suspected early repolarization syndrome warrants future prospective study.

DOI： 10.1016/j.joa.2016.12.005

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

DOI： 10.1016/j.hrcr.2017.06.006

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

DOI： 10.1016/j.hrcr.2017.06.006

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

A 51-year-old man with a resuscitation episode was referred to our hospital. Coronary angiography revealed a focal spasm overlapped with organic stenosis where a bare metal stent was implanted. Acetylcholine (ACh) provocation test did not induce chest pain. It revealed no discernible ST-T changes but unmasked a J wave at the end of the QRS complex, which was associated with short-coupled repetitive premature ventricular beats. A J wave reportedly appears immediately before the onset of ventricular fibrillation caused by vasospastic angina. However, a J wave observed newly after a coronary spasm provocation test using ACh without ST-T changes is informative when considering the mechanisms of the J wave.

DOI： 10.1016/j.joa.2016.09.001

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

A 51-year-old man with a resuscitation episode was referred to our hospital. Coronary angiography revealed a focal spasm overlapped with organic stenosis where a bare metal stent was implanted. Acetylcholine (ACh) provocation test did not induce chest pain. It revealed no discernible ST-T changes but unmasked a J wave at the end of the QRS complex, which was associated with short-coupled repetitive premature ventricular beats. A J wave reportedly appears immediately before the onset of ventricular fibrillation caused by vasospastic angina. However, a J wave observed newly after a coronary spasm provocation test using ACh without ST-T changes is informative when considering the mechanisms of the J wave.

DOI： 10.1016/j.joa.2016.09.001

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

Erythrocyte deformability plays a key role in pulmonary microcirculation, which raised the hypothesis that erythrocyte deformability is impaired in pulmonary thromboembolism (PTE) and subsequent chronic thromboembolic pulmonary hypertension (CTEPH). We encountered a case of PTE followed by CTEPH and investigated erythrocyte deformability by our specified filtration technique to test this hypothesis. Erythrocyte deformability was normal before but was impaired after the onset of PTE. It was restored partially in the stage of CTEPH. This case taught us that erythrocyte deformability is impaired and that this impairment relates to the hemodynamics of pulmonary microcirculation and pathophysiology of PTE and CTEPH.

DOI： 10.17106/jbr.31.57

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

Erythrocyte deformability plays a key role in pulmonary microcirculation, which raised the hypothesis that erythrocyte deformability is impaired in pulmonary thromboembolism (PTE) and subsequent chronic thromboembolic pulmonary hypertension (CTEPH). We encountered a case of PTE followed by CTEPH and investigated erythrocyte deformability by our specified filtration technique to test this hypothesis. Erythrocyte deformability was normal before but was impaired after the onset of PTE. It was restored partially in the stage of CTEPH. This case taught us that erythrocyte deformability is impaired and that this impairment relates to the hemodynamics of pulmonary microcirculation and pathophysiology of PTE and CTEPH.

DOI： 10.17106/jbr.31.57

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

AIM: Although warfarin remains important despite the widespread use of nonvitamin K antagonist oral anticoagulants (NOACs), to date, the reality of warfarin use in the "NOACs era" is unclear. This multicenter observational study aimed to clarify the key factors contributing to warfarin treatment stability. METHODS: The practical use of warfarin, stability of warfarin therapy, and factors contributing to this stability were investigated in community-based hospitals through a real-world study. Clinical data were retrospectively extracted from the medical records of warfarin-treated Japanese patients (age, 71.3±5.5 years) with atrial fibrillation (AF), prosthetic heart valve, or other concerns requiring anticoagulation. Treatment stability was considered as time in therapeutic range of international normalized ratio of prothrombin time (TTR: &#37;). The factors contributing to TTR were investigated, including CHADS2 score components. RESULTS: Mean CHADS2 score was highest (1.38±0.88, p＜0.001), and most CHADS2 score components in addition to hepatorenal dysfunction were factors contributing to the low TTR in patients with AF (n=176). The similarity was found in overall patients who were prescribed warfarin (n= 518). TTR decreased according to the CHADS2 score component accumulation. Gender, dose and prescription interval of warfarin, and co-administration of antiplatelet agents did not correlate with the low TTR. CONCLUSIONS: This retrospective study demonstrated that the CHADS2 score component accumulation and hepatorenal dysfunction are factors significantly contributing to the low TTR, which is indicative of poor warfarin treatment stability, in patients such as those with AF.

DOI： 10.5551/jat.35121

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

Aim: Although warfarin remains important despite the widespread use of nonvitamin K antagonist oral anticoagulants (NOACs), to date, the reality of warfarin use in the “NOACs era” is unclear. This multicenter observational study aimed to clarify the key factors contributing to warfarin treatment stability. Methods: The practical use of warfarin, stability of warfarin therapy, and factors contributing to this stability were investigated in community-based hospitals through a real-world study. Clinical data were retrospectively extracted from the medical records of warfarin-treated Japanese patients (age, 71.3±5.5 years) with atrial fibrillation (AF), prosthetic heart valve, or other concerns requiring anticoagulation. Treatment stability was considered as time in therapeutic range of international normalized ratio of prothrombin time (TTR: %). The factors contributing to TTR were investigated, including CHADS₂ score components. Results: Mean CHADS₂ score was highest (1.38±0.88, p＜0.001), and most CHADS₂ score components in addition to hepatorenal dysfunction were factors contributing to the low TTR in patients with AF (n =176). The similarity was found in overall patients who were prescribed warfarin (n = 518). TTR decreased according to the CHADS₂ score component accumulation. Gender, dose and prescription interval of warfarin, and co-administration of antiplatelet agents did not correlate with the low TTR. Conclusions: This retrospective study demonstrated that the CHADS₂ score component accumulation and hepatorenal dysfunction are factors significantly contributing to the low TTR, which is indicative of poor warfarin treatment stability, in patients such as those with AF.

DOI： 10.5551/jat.35121

Language：English  

Language：English  

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

Objective: This study aims to demonstrate the protective effect on mortality among participants of a health education program, Brain-Oriented Obesity Control System (BOOCS). Methods: A quasi-experimentally designed, 15-year (1993 to 2007) follow-up study was conducted with a total of 13,835 male and 7791 female Japanese workers. They were divided into three groups: participants in the program (1565 males and 742 females), nonparticipant comparative obese controls (1230 males and 605 females), and nonparticipant reference subjects (11,012 males and 6426 females). Hazard ratios were calculated with survival curves drawn to evaluate the mortality effects by the program participation. Results: The male participants showed significantly lower mortality risk for all causes of death at hazard ratio = 0.54 (95% confidence interval: 0.31 to 0.94) with significantly different survival curves (P = 0.014 by log-rank test) than obese controls. Conclusions: The results support a protective effect on mortality by participating in BOOCS program.

DOI： 10.1097/JOM.0000000000000399

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

OBJECTIVE: This study aims to demonstrate the protective effect on mortality among participants of a health education program, Brain-Oriented Obesity Control System (BOOCS). METHODS: A quasi-experimentally designed, 15-year (1993 to 2007) follow-up study was conducted with a total of 13,835 male and 7791 female Japanese workers. They were divided into three groups: participants in the program (1565 males and 742 females), nonparticipant comparative obese controls (1230 males and 605 females), and nonparticipant reference subjects (11,012 males and 6426 females). Hazard ratios were calculated with survival curves drawn to evaluate the mortality effects by the program participation. RESULTS: The male participants showed significantly lower mortality risk for all causes of death at hazard ratio = 0.54 (95&#37; confidence interval: 0.31 to 0.94) with significantly different survival curves (P = 0.014 by log-rank test) than obese controls. CONCLUSIONS: The results support a protective effect on mortality by participating in BOOCS program.

DOI： 10.1097/JOM.0000000000000399

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

DOI： 10.1253/circj.CJ-15-0963

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

This study aimed to evaluate short- and mid-term outcomes of percutaneous transluminal renal artery angioplasty (PTRA) in patients with symptomatic renal artery stenosis caused by renal artery fibromuscular dysplasia (RAFMD). Retrospective analysis of 22 patients with RAFMD who were performed PTRA between 2006 and 2012. These patients underwent PTRA due to poorly controlled hypertension. Pre- and post-PTRA blood pressure (BP) measurements and renal function were evaluated. Freedom from events (restenosis, repeat intervention, renal failure, and recurrent hypertension) was investigated using life table analysis. Twenty-two patients (54.5 % women, mean age 39.2 years) with 24 renal arteries underwent PTRA. The technical success rate was 100 %. The mean systolic BP decreased from 155.9 ± 14.7 to 138.3 ± 9.41 mmHg (P = 0.00004), and the mean diastolic BP decreased from 99.0 ± 11.5 to 88.0 ± 7.19 mmHg (P = 0.0043). Rates of freedom from recurrent or worsening hypertension, defined by >140 mmHg systolic BP and >90 mmHg diastolic BP, were 89.4, 89.4, 81.3, and 71.1 % at 1, 2, 3, and 4 years, respectively. Restenosis-free rates were 90.0, 83.6, 73.4, and 61.9 %, respectively. No patient underwent repeat intervention and renal failure. PTRA is a durable modality for treating RAFMD with favorable short- and mid-term clinical outcomes.

DOI： 10.1007/s12928-014-0253-9

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

This study aimed to evaluate short- and mid-term outcomes of percutaneous transluminal renal artery angioplasty (PTRA) in patients with symptomatic renal artery stenosis caused by renal artery fibromuscular dysplasia (RAFMD). Retrospective analysis of 22 patients with RAFMD who were performed PTRA between 2006 and 2012. These patients underwent PTRA due to poorly controlled hypertension. Pre- and post-PTRA blood pressure (BP) measurements and renal function were evaluated. Freedom from events (restenosis, repeat intervention, renal failure, and recurrent hypertension) was investigated using life table analysis. Twenty-two patients (54.5&#37; women, mean age 39.2 years) with 24 renal arteries underwent PTRA. The technical success rate was 100&#37;. The mean systolic BP decreased from 155.9 ± 14.7 to 138.3 ± 9.41 mmHg (P = 0.00004), and the mean diastolic BP decreased from 99.0 ± 11.5 to 88.0 ± 7.19 mmHg (P = 0.0043). Rates of freedom from recurrent or worsening hypertension, defined by >140 mmHg systolic BP and >90 mmHg diastolic BP, were 89.4, 89.4, 81.3, and 71.1&#37; at 1, 2, 3, and 4 years, respectively. Restenosis-free rates were 90.0, 83.6, 73.4, and 61.9&#37;, respectively. No patient underwent repeat intervention and renal failure. PTRA is a durable modality for treating RAFMD with favorable short- and mid-term clinical outcomes.

DOI： 10.1007/s12928-014-0253-9

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

A 73-year-old woman with breast cancer and metastasis under chemotherapy suffered from fever, pleural effusion and pericardial effusion. Despite the administration of treatment with cefozopran and prednisolone, the patient's fever relapsed. An electrocardiogram identified a new complete atrioventricular block and an echocardiogram revealed vegetation with an unusual pseudotumoral mass in the right atrium. Blood cultures grew Listeria monocytogenes. The patient was eventually diagnosed with right-sided infective endocarditis, which improved following the six-week administration of ampicillin and gentamicin. Homemade yoghurt was suspected to be the cause of infection in this case. Listeria endocarditis is rare; however, physicians should pay more attention to preventing this fatal disease in immunocompromised patients.

DOI： 10.2169/internalmedicine.53.1925

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

Although coronary risk factors promote the formation of atherosclerotic plaque containing activated platelets and inflammatory leukocytes, and play a pivotal role in the development of coronary artery diseases (CAD), the hemorheological effects of these risk factors on circulating intact erythrocytes, a major component of whole blood cells, are poorly understood. Therefore, this study aimed to quantify erythrocyte deformability in patients with coronary risk factors, and enrolled 320 consecutive cardiac outpatients including 33 patients with nonvalvular atrial fibrillation (AF). Patients,with acute coronary syndrome or valvular AF,were excluded. Demographic variables obtained by medical records were correlated with erythrocyte deformability investigated by our highly sensitive and reproducible filtration technique. Among demographic variables, triglyceride (p = 0.004), HbA1c (p = 0.014) and body weight (p = 0.020) showed significant inverse correlation to the erythrocyte deformability. This deformability was not associated with types of CAD (old myocardial infarction vs. stable angina) or modality of treatment (percutaneous intervention vs. coronary artery bypass grafting). Unexpectedly, stepwise multiple regression analysis demonstrated that nonvalvular AF was the most significant contributor to the impaired erythrocyte deformability (p = 0.002). Hypertension and dyslipidemia are more prevalent in the AF patients (p < 0.001), and the erythrocyte deformability was found to be impaired synergistically and significantly (p < 0.001) during the stepwise accumulation of the coronary risk factors in addition to AF. In conclusion coronary risk factors synergistically impair the erythrocyte deformability, which may play an important role in critically stenotic coronary arteries. Since the impairment of intact erythrocyte deformability is mostly associated with nonvalvular AF, this common arrhythmia may reflect the coronary risk accumulation.

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

Although coronary risk factors promote the formation of atherosclerotic plaque containing activated platelets and inflammatory leukocytes, and play a pivotal role in the development of coronary artery diseases (CAD), the hemorheological effects of these risk factors on circulating intact erythrocytes, a major component of whole blood cells, are poorly understood. Therefore, this study aimed to quantify erythrocyte deformability in patients with coronary risk factors, and enrolled 320 consecutive cardiac outpatients including 33 patients with nonvalvular atrial fibrillation (AF). Patients,with acute coronary syndrome or valvular AF,were excluded. Demographic variables obtained by medical records were correlated with erythrocyte deformability investigated by our highly sensitive and reproducible filtration technique. Among demographic variables, triglyceride (p = 0.004), HbA1c (p = 0.014) and body weight (p = 0.020) showed significant inverse correlation to the erythrocyte deformability. This deformability was not associated with types of CAD (old myocardial infarction vs. stable angina) or modality of treatment (percutaneous intervention vs. coronary artery bypass grafting). Unexpectedly, stepwise multiple regression analysis demonstrated that nonvalvular AF was the most significant contributor to the impaired erythrocyte deformability (p = 0.002). Hypertension and dyslipidemia are more prevalent in the AF patients (p < 0.001), and the erythrocyte deformability was found to be impaired synergistically and significantly (p < 0.001) during the stepwise accumulation of the coronary risk factors in addition to AF. In conclusion coronary risk factors synergistically impair the erythrocyte deformability, which may play an important role in critically stenotic coronary arteries. Since the impairment of intact erythrocyte deformability is mostly associated with nonvalvular AF, this common arrhythmia may reflect the coronary risk accumulation.

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

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

A reduced ratio of plasma eicosapentaenoic acid-arachidonic acid (EPA-AA) is a newly recognized atherosclerotic risk factor. This ratio has not been fully investigated in peripheral artery disease (PAD). Seventy Japanese patients with atherosclerotic risk factors were enrolled and divided into 2 groups, those with PAD (group A: n = 38) and those without PAD (group B: n = 32). The EPA-AA ratio (P =.001) and ankle-brachial index (ABI: P <.001) in group A were significantly lower than those in group B. Univariate and multivariate analyses demonstrated that EPA-AA, ABI, and prescription of clopidogrel had significant correlation with PAD. Given the appropriate cutoff values, EPA-AA (odds ratio [OR] = 11.7, 95% confidence interval [CI] = 3.0-45.8; P <.001) and ABI (OR = 44.0, 95% CI = 5.4-358.5; P <.001) are factors independently associated with PAD. In conclusion, this study demonstrated that reduced plasma EPA/AA may underlie PAD at least in Japanese.

DOI： 10.1177/0003319712437031

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

A reduced ratio of plasma eicosapentaenoic acid-arachidonic acid (EPA-AA) is a newly recognized atherosclerotic risk factor. This ratio has not been fully investigated in peripheral artery disease (PAD). Seventy Japanese patients with atherosclerotic risk factors were enrolled and divided into 2 groups, those with PAD (group A: n = 38) and those without PAD (group B: n = 32). The EPA-AA ratio (P = .001) and ankle-brachial index (ABI: P < .001) in group A were significantly lower than those in group B. Univariate and multivariate analyses demonstrated that EPA-AA, ABI, and prescription of clopidogrel had significant correlation with PAD. Given the appropriate cutoff values, EPA-AA (odds ratio [OR] = 11.7, 95&#37; confidence interval [CI] = 3.0-45.8; P < .001) and ABI (OR = 44.0, 95&#37; CI = 5.4-358.5; P < .001) are factors independently associated with PAD. In conclusion, this study demonstrated that reduced plasma EPA/AA may underlie PAD at least in Japanese.

DOI： 10.1177/0003319712437031

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

Peripheral mycotic aneurysm is a rare complication of infective endocarditis. We herein report the case of a 61-year-old man with a mycotic aneurysm in the left brachial artery, that appeared during treatment with antibiotics against infective endocarditis caused by Streptococcus sanguinis. After confirming the collateral blood flow on arteriography, we resected the aneurysm and performed valvuloplasty, annuloplasty and coronary artery bypass grafting. The patient has been in good condition without complications, such as motor dysfunction or neuropathy.

DOI： 10.2169/internalmedicine.52.0747

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

BACKGROUND: Definite identification of the cell types and the mechanism relevant to cardiomyogenesis is essential for effective cardiac regenerative medicine. We aimed to identify the cell populations that can generate cardiomyocytes and to clarify whether generation of donor-marker(+) cardiomyocytes requires cell fusion between BM-derived cells and recipient cardiomyocytes. METHODOLOGY/PRINCIPAL FINDINGS: Purified BM stem/progenitor cells from green fluorescence protein (GFP) mice were transplanted into C57BL/6 mice or cyan fluorescence protein (CFP)-transgenic mice. Purified human hematopoietic stem cells (HSCs) from cord blood were transplanted into immune-compromised NOD/SCID/IL2rγ(null) mice. GFP(+) cells in the cardiac tissue were analyzed for the antigenecity of a cardiomyocyte by confocal microscopy following immunofluorescence staining. GFP(+) donor-derived cells, GFP(+)CFP(+) fused cells, and CFP(+) recipient-derived cells were distinguished by linear unmixing analysis. Hearts of xenogeneic recipients were evaluated for the expression of human cardiomyocyte genes by real-time quantitative polymerase chain reaction. In C57BL/6 recipients, Lin(-/low)CD45(+) hematopoietic cells generated greater number of GFP(+) cardiomyocytes than Lin(-/low)CD45(-) mesenchymal cells (37.0+/-23.9 vs 0.00+/-0.00 GFP(+) cardiomyocytes per a recipient, P = 0.0095). The number of transplanted purified HSCs (Lin(-/low)Sca-1(+) or Lin(-)Sca-1(+)c-Kit(+) or CD34(-)Lin(-)Sca-1(+)c-Kit(+)) showed correlation to the number of GFP(+) cardiomyocytes (P<0.05 in each cell fraction), and the incidence of GFP(+) cardiomyocytes per injected cell dose was greatest in CD34(-)Lin(-)Sca-1(+)c-Kit(+) recipients. Of the hematopoietic progenitors, total myeloid progenitors generated greater number of GFP(+) cardiomyocytes than common lymphoid progenitors (12.8+/-10.7 vs 0.67+/-1.00 GFP(+) cardiomyocytes per a recipient, P = 0.0021). In CFP recipients, all GFP(+) cardiomyocytes examined coexpressed CFP. Human troponin C and myosin heavy chain 6 transcripts were detected in the cardiac tissue of some of the xenogeneic recipients. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HSCs resulted in the generation of cardiomyocytes via myeloid intermediates by fusion-dependent mechanism. The use of myeloid derivatives as donor cells could potentially allow more effective cell-based therapy for cardiac repair.

DOI： 10.1371/journal.pone.0062506

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

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

DOI： 10.1136/heartasia-2012-010105

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

Comprehensive research to quantify the deformability of erythrocytes in diabetic animals and humans has been lacking. The objective of this study was to compare the impairment of erythrocyte deformability in diabetic rats and patients by use of the same rheologic method. Deformability was investigated in streptozotocin-induced diabetic rats and diabetic patients, by using the highly sensitive and quantitative nickel-mesh-filtration technique. Erythrocyte filterability (whole-cell deformability) was defined as flow rate of hematocrit-adjusted erythrocyte suspension relative to that of saline (%). Hematological and biochemical data for diabetic rats did not differ from those for age-matched control rats except for hyperglycemia and malnutrition. Erythrocyte filterability for diabetic rats was significantly lower than that for control rats (69. 4 ± 10. 1%, n = 8, compared with 83. 1 ± 4. 2%, n = 8; p < 0. 001). Likewise, erythrocyte filterability for diabetic patients was significantly impaired compared with that for controls (87. 6 ± 3. 4%, n = 174, compared with 88. 6 ± 2. 1%, n = 51; p = 0. 046). Stepwise multiple regression analysis revealed that this impairment was mostly attributable to associated obesity (BMI, p = 0. 029) and glycemic stress (HbA1c(JDS), p = 0. 046). We therefore conclude that erythrocyte filterability is commonly impaired in diabetic rats and in humans. Moreover, metabolic risk accumulation further impairs erythrocyte filterability, resulting in derangement of the microcirculation.

DOI： 10.1007/s12573-011-0032-5

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

Comprehensive research to quantify the deformability of erythrocytes in diabetic animals and humans has been lacking. The objective of this study was to compare the impairment of erythrocyte deformability in diabetic rats and patients by use of the same rheologic method. Deformability was investigated in streptozotocin-induced diabetic rats and diabetic patients, by using the highly sensitive and quantitative nickel-mesh-filtration technique. Erythrocyte filterability (whole-cell deformability) was defined as flow rate of hematocrit-adjusted erythrocyte suspension relative to that of saline (&#37;). Hematological and biochemical data for diabetic rats did not differ from those for age-matched control rats except for hyperglycemia and malnutrition. Erythrocyte filterability for diabetic rats was significantly lower than that for control rats (69. 4 ± 10. 1&#37;, n = 8, compared with 83. 1 ± 4. 2&#37;, n = 8; p < 0. 001). Likewise, erythrocyte filterability for diabetic patients was significantly impaired compared with that for controls (87. 6 ± 3. 4&#37;, n = 174, compared with 88. 6 ± 2. 1&#37;, n = 51; p = 0. 046). Stepwise multiple regression analysis revealed that this impairment was mostly attributable to associated obesity (BMI, p = 0. 029) and glycemic stress (HbA1c(JDS), p = 0. 046). We therefore conclude that erythrocyte filterability is commonly impaired in diabetic rats and in humans. Moreover, metabolic risk accumulation further impairs erythrocyte filterability, resulting in derangement of the microcirculation. © 2011 Japanese Society of Biorheology.

DOI： 10.1007/s12573-011-0032-5

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

Background: Although gastroesophageal reflux disease (GERD) causes noncardiac chest pain mimicking angina peetons, systemic studies surveying the effects of common cardiac drugs on symptomatic GERD are rare. Methods: To investigate the drug- related GER.1), this multicenter trial enrolled 201 consecutive cardiac outpatients (69.7 ±10.5 y) after obtaining written infomied consent. They were assessed using the Frequency Scale for Symptoms of GERD (F-scale) to screen for GERD with a cut-off value of 8.0. Clinical background was obtained from medical records. Gastric medicine was empirically administered at the discretion of the attending physician. F-scale score and incidence of GERI) were analyzed individually in relation to background and prescription. Results: The avenge F-scale score did not correlate with gender, age or underlying diseases. F-scale score was elevated significantly (p - 0.006) by administration of calcium channel blockers to the patients treated with gastric medicine, suggesting that calcium channel blockers exacerbate the possibly preexisting GERD. Incidence of GERD within 2 months after starting warfarin tended to be greater than that at other durations (p = 0.087). Patients showing a high score (≥ 8.0) suggestive of GERD showed a correlation with the combined administration of calcium channel blockers (OR 3.19; 95% CI of 1.01 - 10.11; p = 0.049) and warfarin (OR = 3.05; 95% CI of 1.00- 9.27; p = 0.049) in the best logistic model. Conclusion: Although larger cohort is required, this survey demonstrates that the combination of calcium channel blockers and warfarin is an independent risk factor for GERD.

DOI： 10.5414/CP201558

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

Background: Although gastroesophageal reflux disease (GERD) causes noncardiac chest pain mimicking angina peetons, systemic studies surveying the effects of common cardiac drugs on symptomatic GERD are rare. Methods: To investigate the drug- related GER.1), this multicenter trial enrolled 201 consecutive cardiac outpatients (69.7 ±10.5 y) after obtaining written infomied consent. They were assessed using the Frequency Scale for Symptoms of GERD (F-scale) to screen for GERD with a cut-off value of 8.0. Clinical background was obtained from medical records. Gastric medicine was empirically administered at the discretion of the attending physician. F-scale score and incidence of GERI) were analyzed individually in relation to background and prescription. Results: The avenge F-scale score did not correlate with gender, age or underlying diseases. F-scale score was elevated significantly (p - 0.006) by administration of calcium channel blockers to the patients treated with gastric medicine, suggesting that calcium channel blockers exacerbate the possibly preexisting GERD. Incidence of GERD within 2 months after starting warfarin tended to be greater than that at other durations (p = 0.087). Patients showing a high score (≥ 8.0) suggestive of GERD showed a correlation with the combined administration of calcium channel blockers (OR 3.19; 95&#37; CI of 1.01 - 10.11; p = 0.049) and warfarin (OR = 3.05; 95&#37; CI of 1.00- 9.27; p = 0.049) in the best logistic model. Conclusion: Although larger cohort is required, this survey demonstrates that the combination of calcium channel blockers and warfarin is an independent risk factor for GERD. ©2011 Dustri-Verlag Dr. K Feistle.

DOI： 10.5414/CP201558

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

OBJECTIVES: The relationship between atrial fibrillation (AF) and gastroesophageal reflux disease (GERD) remains controversial, and investigations into this relationship have been based on small series. This multicenter survey evaluated the relationship between these diseases. METHODS: The study enrolled 188 consecutive subjects (110 males and 78 females, mean age 60.4 ± 0.9 years) treated as outpatients. Patients were classified by the frequency scale for symptoms of GERD (F-scale) after obtaining informed consent for screening for GERD. Scores on this questionnaire were correlated to baseline characteristics obtained from medical records. The cutoff value for a diagnosis of GERD was set at 8.0 points. RESULTS: Total scores on the F-scale were significantly greater in female subjects (p = 0.004) and in patients with AF (p = 0.019) compared to the other subjects. Univariate and multivariate analysis of the prevalence of GERD demonstrated that GERD was not related to gender, hypertension, dyslipidemia or coronary artery disease and that AF alone showed a significant (p < 0.001) correlation with GERD. CONCLUSIONS: This multicenter questionnaire survey demonstrated that among traditional cardiovascular risk factors, AF was an independent risk factor for GERD. A large cohort study to assess the potential relationship between GERD and AF is warranted.

DOI： 10.1159/000331497

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A 55-year-old housewife was diagnosed as polymyositis due to leg weakness, when she was 33-year-old. Polymyositis was associated with cardiomegaly and nonsustained VT. Myocarditis secondary to polymyositis was confirmed. She complained palpitation, when she was 51-year-old. Paroxysmal AF was documented. AF was eliminated by the first catheter ablation (i.e., pulmonary vein isolation). She complained exertional dyspnea due to impaired LV function caused by persistent AT last year. Secondary RF ablation was performed and AT was successfully ablated by blockline formation in the damaged right atrial anterior wall under the 3D mapping. Thereafter, frequent PVCs were recorded by Holter monitoring this year. PVCs were refractory to antiarrhythmics. Therefore, third RF ablation was conducted under the CARTO mapping. Polymorphic PVCs were originated from LV posterolateral and right ventricular inferior walls. These foci of PVCs were coincided well with the areas showing contractile abnormalities. PVCs were ablated successfully under the pace-mapping. After the third RF ablation, PVCs were remarkably decreased and LV function was gradually restored. She is well being at present under the administration of sotalol. This case is didactic in that myocarditis secondary to polymyositis demonstrates various kinds of drug-refractory tachyarrhythmias (i.e., AF, AT and VT) and RF catheter ablation is recommended in such a case. © 2011, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.27.PJ3_064

Language：Japanese  

近年携帯型のイベントレコーダーが普及しつつあるが、ホルター心電計と比較した費用対効果分析はほとんどなされていない。そこで今回不整脈の精査目的に受診した症例を対象に、ホルター心電計に対する医療用イベントレコーダーの費用対効果分析を行った。費用は各々の保険点数から算出し、効果は治療対象となる不整脈が診断された患者数とした。2007～09年までに来院した連続107名の不整脈が疑われる症例に、ホルター心電計(48名)かイベントレコーダー(44名)のいずれかを割り付けた。残り15名はホルター心電計を割り付けたものの治療対象となる不整脈が診断されなかったためイベントレコーダーを貸与した。症例によっては不整脈の診断に至るまで複数回の検査を行ったが、全対象者でホルター心電図とイベントレコーダーの検査回数に有意差はなかった。またそれらの平均コストはイベントレコーダーがホルター心電図検査より低く(p<0.001)、患者一人当たりの不整脈診断に要した総費用も同様であった。一方不整脈の検出率はホルター心電計が39.6&#37;、イベントレコーダーが56.8&#37;で有意差はなかった(p=0.39)。以上より今回使用したイベントレコーダーはホルター心電図検査に比較して明らかに費用対効果に優れ、動悸などの症状が強い割に不整脈発作の頻度が少ない症例に対してより医療経済的であると考えられた。(著者抄録)

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

Delay of QT interval adaptation to sudden heart rate change causes hysteresis in dynamic QT-RR relationship. We analyzed QT-RR plotting during and after exercise in a patient with genetically identified type 2 long QT syndrome before and after starting oral propranolol. Blunted QT shortening by exercise and augmented postexercise QT prolongation resulted in an open-loop, clockwise QT-RR hysteresis immediately before the onset of torsades de pointes before propranolol. However, this hysteresis was eliminated by propranolol. QT-RR analysis provided insight into the mechanisms of the onset of torsades de pointes at least in this case of type 2 long QT syndrome.

DOI： 10.1016/j.jelectrocard.2009.12.005

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

Delay of QT interval adaptation to sudden heart rate change causes hysteresis in dynamic QT-RR relationship. We analyzed QT-RR plotting during and after exercise in a patient with genetically identified type 2 long QT syndrome before and after starting oral propranolol. Blunted QT shortening by exercise and augmented postexercise QT prolongation resulted in an open-loop, clockwise QT-RR hysteresis immediately before the onset of torsades de pointes before propranolol. However, this hysteresis was eliminated by propranolol. QT-RR analysis provided insight into the mechanisms of the onset of torsades de pointes at least in this case of type 2 long QT syndrome. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.jelectrocard.2009.12.005

Language：English  

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

The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34+CD38- fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34+CD38+CD19+, CD34+CD38-CD19+ and CD34+CD38-CD19- bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/SCID/IL2rγnull mice. We found that both CD34+CD38+CD19+ and CD34+CD38-CD19+ cells initiate B-ALL in primary recipients, whereas the recipients of CD34+CD38-CD10-CD19- cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34+CD38+CD19+ cells and those transplanted with CD34+CD38-CD19+ cells. In each of the three cases studied, transplantation of CD34+CD38+CD19+ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34+CD38+CD19+ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/ IL2rγnull recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.

DOI： 10.1038/leu.2008.83

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

The presence of rare malignant stem cells supplying a hierarchy of malignant cells has recently been reported. In human acute myelogenous leukemia (AML), the leukemia stem cells (LSCs) have been phenotypically restricted within the CD34+CD38- fraction. To understand the origin of malignant cells in primary human B-precursor acute lymphocytic leukemia (B-ALL), we established a novel in vivo xenotransplantation model. Purified CD34+CD38+CD19+, CD34+CD38-CD19+ and CD34+CD38-CD19- bone marrow (BM) or peripheral blood (PB) cells from three pediatric B-ALL patients were intravenously injected into sublethally irradiated newborn NOD/SCID/IL2rγ^null mice. We found that both CD34+CD38+CD19+ and CD34+CD38-CD19+ cells initiate B-ALL in primary recipients, whereas the recipients of CD34+CD38-CD10-CD19- cells showed normal human hematopoietic repopulation. The extent of leukemic infiltration into the spleen, liver and kidney was similar between the recipients transplanted with CD34+CD38+CD19+ cells and those transplanted with CD34+CD38-CD19+ cells. In each of the three cases studied, transplantation of CD34+CD38+CD19+ cells resulted in the development of B-ALL in secondary recipients, demonstrating self-renewal capacity. The identification of CD34+CD38+CD19+ self-renewing B-ALL cells proposes a hierarchy of leukemia-initiating cells (LICs) distinct from that of AML. Recapitulation of patient B-ALL in NOD/SCID/ IL2rγ^null recipients provides a powerful tool for directly studying leukemogenesis and for developing therapeutic strategies.

DOI： 10.1038/leu.2008.83

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

Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2rγ^null mice carrying a complete null mutation of the cytokine γc upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.

DOI： 10.1038/nbt1350

Language：English  

Language：English  

DOI： 10.1182/blood.V110.11.780.780

Language：English  

DOI： 10.1182/blood.V110.11.2797.2797

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

Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.

DOI： 10.1038/nbt1350

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

DOI： 10.1038/sj.bmt.1705764

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

Aims: To characterise bone marrow derived cells in the sclera under normal and inflammatory conditions, we examined their differentiation after transplantation from two different sources, bone marrow and haematopoietic stem cells (HSC). Methods: Bone marrow and HSC from green fluorescent protein (GFP) transgenic mice were transplanted into irradiated wild-type mice. At 1 month after transplantation, mice were sacrificed and their sclera examined by histology, immunohistochemistry (CD11b, CD11c, CD45), and transmission and scanning electron microscopy. To investigate bone marrow derived cell recruitment under inflammatory conditions, experimental autoimmune uveitis (EAU) was induced in transplanted mice. Results: GFP positive cells were distributed in the entire sclera and comprised 22.4 (2.8)% (bone marrow) and 28.4 (10.9)% (HSC) of the total cells in the limbal zone and 18.1 (6.7)% (bone marrow) and 26.3 (3.4)% (HSC) in the peripapillary zone. Immunohistochemistry showed that GFP (+) CD11c (+), GFP (+) CD11b (+) cells migrated in the sclera after bone marrow and HSC transplantation. Transmission and scanning electron microscopy revealed antigen presenting cells among the scleral fibroblasts. In EAU mice, vast infiltration of GFP (+) cells developed into the sclera. Conclusion: We have provided direct and novel evidence for the migration of bone marrow and HSC cells into the sclera differentiating into macrophages and dendritic cells. Vast infiltration of bone marrow and HSC cells was found to be part of the inflammatory process in EAU.

DOI： 10.1136/bjo.2006.102046

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

AIMS: To characterise bone marrow derived cells in the sclera under normal and inflammatory conditions, we examined their differentiation after transplantation from two different sources, bone marrow and haematopoietic stem cells (HSC). METHODS: Bone marrow and HSC from green fluorescent protein (GFP) transgenic mice were transplanted into irradiated wild-type mice. At 1 month after transplantation, mice were sacrificed and their sclera examined by histology, immunohistochemistry (CD11b, CD11c, CD45), and transmission and scanning electron microscopy. To investigate bone marrow derived cell recruitment under inflammatory conditions, experimental autoimmune uveitis (EAU) was induced in transplanted mice. RESULTS: GFP positive cells were distributed in the entire sclera and comprised 22.4 (2.8)&#37; (bone marrow) and 28.4 (10.9)&#37; (HSC) of the total cells in the limbal zone and 18.1 (6.7)&#37; (bone marrow) and 26.3 (3.4)&#37; (HSC) in the peripapillary zone. Immunohistochemistry showed that GFP (+) CD11c (+), GFP (+) CD11b (+) cells migrated in the sclera after bone marrow and HSC transplantation. Transmission and scanning electron microscopy revealed antigen presenting cells among the scleral fibroblasts. In EAU mice, vast infiltration of GFP (+) cells developed into the sclera. CONCLUSION: We have provided direct and novel evidence for the migration of bone marrow and HSC cells into the sclera differentiating into macrophages and dendritic cells. Vast infiltration of bone marrow and HSC cells was found to be part of the inflammatory process in EAU.

DOI： 10.1136/bjo.2006.102046

Language：English  

DOI： 10.1182/blood.V108.11.3184.3184

Language：English  

DOI： 10.1182/blood.V108.11.279.279

Language：English  

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

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

To obtain insights into the cardiomyogenic potential of hematopoietic tissue, we intravenously (i.v.) injected purified hematopoietic stem/progenitor cells into newborn recipients that may fully potentiate the developmental plasticity of stem cells. Transplantation of mouse bone marrow (BM) lineage antigen-negative (Lin-) cells resulted in the generation of the cells that displayed cardiomyocyte-specific antigenic profiles and contractile function when transplanted into syngeneic newborn recipients. To clarify the mechanism underlying the cardiomyogenic potential, green fluorescent protein (GFP)-labeled BM Lin-ScaI+ hematopoietic progenitors were transplanted into neonatal mice constitutively expressing cyan fluorescence protein (CFP). Lambda image acquisition and linear unmixing analysis using confocal microscopy successfully separated GFP and CFP, and revealed that donor GFP+ cardiomyocytes coexpressed host-derived CFP. We further reconstituted human hemopoietic- and immune systems in mice by injecting human cord blood (CB)-derived Lin-CD34+CD38- hematopoietic stem cells (HSCs) into neonatal T cell(-)B cell(-)NK cell- immune-deficient NOD/SCID/IL2rgamma(null) mice. Fluoroescence in situ hybridization analysis of recipient cardiac tissues demonstrated that human and murine chromosomes were colocalized in the same cardiomyocytes, indicating that cell fusion occurred between human hematopoietic progeny and mouse cardiomyocytes. These syngeneic- and xenogeneic neonatal transplantations provide compelling evidence that hematopoietic stem/progenitor cells contribute to the postnatal generation of cardiomyocytes through cell fusion, not through transdifferentiation.

DOI： 10.1096/fj.05-4863fje

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

To obtain insights into the cardiomyogenic potential of hematopoietic tissue, we intravenously (i.v.) injected purified hematopoietic stem/progenitor cells into newborn recipients that may fully potentiate the developmental plasticity of stem cells. Transplantation of mouse bone marrow (BM) lineage antigen-negative (Lin^-) cells resulted in the generation of the cells that displayed cardiomyocyte-specific antigenic profiles and contractile function when transplanted into syngeneic newborn recipients. To clarify the mechanism underlying the cardiomyogenic potential, green fluorescent protein (GFP)-labeled BM Lin^-ScaI⁺ hematopoietic progenitors were transplanted into neonatal mice constitutively expressing cyan fluorescence protein (CFP). Lambda image acquisition and linear unmixing analysis using confocal microscopy successfully separated GFP and CFP, and revealed that donor GFP⁺ cardiomyocytes coexpressed host-derived CFP. We further reconstituted human hemopoietic- and immune systems in mice by injecting human cord blood (CB)-derived Lin^-CD34⁺CD38^- hematopoietic stem cells (HSCs) into neonatal T cell^-B cell ^-NK cell^- immune-deficient NOD/SCID/IL2rγ ^null mice. Fluoroescence in situ hybridization analysis of recipient cardiac tissues demonstrated that human and murine chromosomes were colocalized in the same cardiomyocytes, indicating that cell fusion occurred between human hematopoietic progeny and mouse cardiomyocytes. These syngeneic- and xenogeneic neonatal transplantations provide compelling evidence that hematopoietic stem/progenitor cells contribute to the postnatal generation of cardiomyocytes through cell fusion, not through transdifferentiation.

DOI： 10.1096/fj.05-4863fje

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

PURPOSE. Bone marrow (BM)- derived stem cells are thought to possess extensive differentiation capacity. The present study was conducted to investigate the characteristics and distribution of these cells in the normal mouse cornea. METHODS. BM cells and BM-derived hematopoietic stem/progenitor cells (HSCs) from enhanced GFP (eGFP) transgenic mice (lin^-, Sca-1⁺) were intravenously transplanted into irradiated wild-type C57BL/6 mice. At 4 to 6 months after transplantation, the mice were killed, and their whole corneas examined by histologic and immunohistochemical methods (CD11c, CD11b, and CD45). RESULTS. At 2 weeks after BM cell transplantation, GFP⁺ cells gradually migrated into the cornea from the limbal area. At 2 to 6 months, they were distributed over the entire cornea. In cross sections of whole cornea, GFP⁺ cells comprised 27.3% ± 11.1% (BM) and 24.0% ± 8.01% (HSC) of total cells in the peripheral corneal stroma. In the center of the corneal stroma, GFP⁺ cells were 7.58% ± 2.63% (BM) and 8.06% ± 1.76% (HSC) of total cells. Immunohistochemistry showed that GFP⁺ CD11c⁺, CD11b ⁺, CD11c^-, and CD11b^- cells occupied the entire corneal stroma. CONCLUSIONS. The present study provides direct evidence of the distribution of BM-derived cells in the mouse cornea. Immunohistochemical study showed that some of these cells are BM-derived antigen-presenting cells such as dendritic cells and macrophages. Some elements of BM-derived cells may continue to exist in the corneal stroma.

DOI： 10.1167/iovs.04-1154

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

PURPOSE: Bone marrow (BM)-derived stem cells are thought to possess extensive differentiation capacity. The present study was conducted to investigate the characteristics and distribution of these cells in the normal mouse cornea. METHODS: BM cells and BM-derived hematopoietic stem/progenitor cells (HSCs) from enhanced GFP (eGFP) transgenic mice (lin(-), Sca-1(+)) were intravenously transplanted into irradiated wild-type C57BL/6 mice. At 4 to 6 months after transplantation, the mice were killed, and their whole corneas examined by histologic and immunohistochemical methods (CD11c, CD11b, and CD45). RESULTS: At 2 weeks after BM cell transplantation, GFP(+) cells gradually migrated into the cornea from the limbal area. At 2 to 6 months, they were distributed over the entire cornea. In cross sections of whole cornea, GFP(+) cells comprised 27.3&#37; +/- 11.1&#37; (BM) and 24.0&#37; +/- 8.01&#37; (HSC) of total cells in the peripheral corneal stroma. In the center of the corneal stroma, GFP(+) cells were 7.58&#37; +/- 2.63&#37; (BM) and 8.06&#37; +/- 1.76&#37; (HSC) of total cells. Immunohistochemistry showed that GFP(+) CD11c(+), CD11b(+), CD11c(-), and CD11b(-) cells occupied the entire corneal stroma. CONCLUSIONS: The present study provides direct evidence of the distribution of BM-derived cells in the mouse cornea. Immunohistochemical study showed that some of these cells are BM-derived antigen-presenting cells such as dendritic cells and macrophages. Some elements of BM-derived cells may continue to exist in the corneal stroma.

DOI： 10.1167/iovs.04-1154

Event date： 2020.6

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Event date： 2016.5

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<p>PDFファイルをご覧ください。</p>

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The effects of lactic acid bacteria-fermented soymilk extract on patients with colonic polyps: a randomized, double-blind, placebo-controlled pilot trial

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Report of Three Cases with Complications which Required Psychosomatic Approaches during Device Therapies for Arrhythmias
We present herein three cases with complications which required psychosomatic approaches during device therapies for arrhythmias. The first case is a 55-year-old female patient with sick sinus syndrome, who underwent permanent pacemaker implantation. She complained of dysphagia, dysphonia, and severe left arm pain and paralysis, and was diagnosed as having reflex sympathetic dystrophy. She lost her job and became depressed. Some sessions with physical and occupational therapists helped her recover from the depression. The second case is a 62-year-old female patient who was implanted with an implantable cardioverter-defibrillator (ICD). ICD was infected. However, local infection was controlled by intensive chemotherapy without reoperation. Her reactive depression was improved by peer-support from ICD support group. The third case is a 48-year-old female patient with hereditary long QT syndrome. She repeatedly complained of left arm phantom swelling after implantation with ICD. She was diagnosed as having transient hypochondriasis upon psychiatric consultation. Her psychiatric condition improved after explaining the result of thoracic computed tomography (CT), which was performed in the presence of a cardiac device representative (CDR). Although CT was not an ideal resolution of her hypochondriasis, this promoted her own awareness of the psychosomatic linkage. These three cases were didactic for cardiac device complications, which often require multidisciplinary psychosomatic approaches.

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Clinical morphological and rheological investigation of erythrocytes in patients undergoing prosthetic heart valve replacement

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Influence of proton pump inhibitors on anticoagulation by warfarin: Comparison of rabeprazole and lansoprazole

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A Case of Brugada Syndrome Associated with Inferolateral Early Repolarization Presenting Idiopathic Ventricular Fibrillation
The relationship between Brugada syndrome and early repolarization syndrome remains controversial. Here, we report a case of a 34-year-old male who had visited the hospital due to nocturnal atrial fibrillation (AF). Sinus rhythm was restored after the administration of pilsicainide at the first episode of AF, but AF was converted to ventricular fibrillation (VF) after the same treatment during the second episode. Immediately prior to the onset of VF, ST elevation in inferior leads and J waves in lateral leads were observed. No organic heart diseases were suspected. Diagnosis of Brugada syndrome associated with inferolateral early repolarization was made based on the positive pilsicainide infusion test (1 mg/kg). VF was not detected after the implantation of implantable cardioverter-defibrillator and coadministration of cilostazol (200 mg) and bepridil (100 mg). This case provides additional information on the complicated relationship between Brugada syndrome and early repolarization syndrome.

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A case of morbid obesity associated with various lethal complications
Obesity is becoming a global epidemic problem in both children and adults of industrialized countries because of alterations of life style including high-calorie food intake and lack of aerobic exercise. Here, we present a case of Judo wrestler with morbid obesity associated with various lethal complications such as juvenile hypertension, renal dysfunction, deep vein thrombophlebitis, pulmonary infarction, polycythemia and bronchial bleeding. All of these obesity-associated complications were treated intensively under hospitalization. This case is now under careful follow-up in outpatient clinic. In this article, we address the importance of weight reduction after retiring the vigorous sport such as Judo by calorie restriction and habitual aerobic exercise.

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J-GLOBAL

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Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy. Case Summary: A 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion. Conclusion: Interleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.

DOI： 10.3389/fcvm.2022.848091

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＜文献概要＞Point ・診断的意義のあるcoved型心電図は,QRS終末部からhigh-take offを示し,上に凸もしくは直線的にST部分が上昇し,陰性T波へ移行する.・Brugada phenocopyを示す疾患について知り,Corrado indexなどの指標を用いることが鑑別に有用である.

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Psychosomatic Medicine in Arrhythmia
<p>Although a psychosomatic approach to the patients with arrhythmia is important, this importance is not so widely recognized. The sensation of palpitation is most frequently encountered in cardiac patients but is not necessarily coincided with the occurrence of arrhythmia. Persons sensitive to body sensations or with many daily irritants are prone to feel palpitation. Anxious or depressive mood is associated with the symptom, therapeutic response and prognosis in patients with atrial fibrillation. Implantable cardioverter defibrillator (ICD) does not necessarily improve the quality of life in patients with ventricular arrhythmias. Moreover, patients with anxiety or depression are abnormally sensitive to the real and phantom shock delivered by ICD, indicating that multidisciplinary mental support to such patients is important.</p>

DOI： 10.15064/jjpm.60.5_405

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DOI： 10.11272/jssabst.45.0_S162_2

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DOI： 10.11272/jssabst.45.0_S195_1

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Case Report : Radiofrequency Catheter Ablations of Left Ventricular Arrhythmias Originating from Posteromedial Followed by Anterolateral Papillary Muscles
A 61-year-old male presented fatigue, and ambulatory monitoring demonstrated frequent isolated premature ventricular beats (PVBs) with superior axis and right-bundle-branch-block (RBBB) configuration. Echocardiogram showed diffuse hypokinetic left ventricular (LV) wall motion and subnormal LV ejection fraction (LVEF). In electrophysiological study (EPS), pace map was optimal at the posteromedial papillary muscle (PM). Low-frequency mid-diastolic Purkinje potential (P1) preceded surface QRS complex of PVBs by 20 msec, and high-frequency Purkinje potential (P2) was observed immediately before QRS complex of sinus beats and PVBs. After successful radiofrequency ablation for PVBs arising from posteromedial PM, LVEF restored. However, one and half year later, PVBs showing inferior axis and RBBB appeared and LVEF declined. EPS and ablation were performed again and PVBs originating from anterolateral PM were eliminated. Considering that LV arrhythmia arising from PMs is refractory to ablation due to anatomical and technical reasons, careful follow-up is required.

DOI： 10.15017/1931474

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Plasma and Erythrocyte Membrane Plasmalogen Diminished in Severe Atherosclerotic Patients Undergoing Endovascular Therapy

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Cardioembolic Stroke from the Viewpoint of Hemorheology and the Development of Oral Anticoagulation
<p>Blood coagulation cascade consists of intrinsic, extrinsic and final common pathways forming fibrin network. Thrombus is divided into fibrin thrombus and platelet thrombus. The former is formed by low shear condition and treated by anticoagulants. The latter is formed by platelets activated by high shear stress in the stenotic arteries. The concept of Virchow's triad such as blood stasis, hypercoagulability and vascular injury is still available in considering clinical thrombogenesis. Atrial fibrillation becomes prevalent in older generation, and its major complication is cardioembolic stroke. This type of stroke is caused mainly by left atrial thrombus. Therefore, this stroke should be prevented by oral anticoagulants including vitamin K-dependent anticoagulant (warfarin) or direct oral anticoagulant (DOAC). Warfarin suppresses several steps of coagulation cascade, whereas DOAC inhibits thrombin (dabigatran) or factor Xa (ribaroxaban, apixaban, and edoxaban) directly and specifically. These agents of DOAC are characterized by short half-lives, more predictable pharmacodynamics and pharmacokinetics, less interaction with other drugs, and less frequent adverse effects of intracranial bleeding in comparison with conventional warfarin. Since critical step of final common pathway in coagulation cascade is inhibited directly by DOAC, these agents may impair the fibrin polymerization and mechanical clot stabilization. Although efficacy and safety of DOAC are recognized clinically, hemorheological effects of DOAC on thrombus formation, structure and property under the hydrodynamic blood flowing warrant future study.</p>

DOI： 10.11262/jpnbr.31.1_2

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Is J wave a Delayed Depolarization or an Early Repolarization?:Perspective from E-journals in J-STAGE
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DOI： 10.5105/jse.37.111

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Cardioembolic Stroke from the Viewpoint of Hemorheology and the Development of Oral Anticoagulation

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症例は67歳、男性。持続性心室頻拍(VT)。急性下壁心筋梗塞(右冠動脈#2、左回旋枝#13)発症4ヵ月後に持続性VTが出現した。VTは左脚ブロック(LBBB)型・上方軸で、頻拍周期は400msecであった。心室プログラム刺激では臨床的VTは誘発不能で、右脚ブロック(RBBB)型・上方軸の非持続性多型性VT(NSPVT)(最長21連)のみが再現性をもって誘発された。3次元マップでは右室自由壁基部と左室後中隔(LVPS)に、わずかに低電位領域を認めた。右室後中隔(RVPS)において遅延電位(LP)が記録され、ペースマップは臨床的VTに一致した。LVPSからは孤立性LP(ILP)が記録され、ペースマップで刺激出力を減少させるとQRS波形が中隔型(V1でQS型)からRBBB型に変化した。RBBB型QRSの際の心内電位は中隔型QRSと比較して、刺激(S)-RV間隔が延長し、心筋電位が直接捕捉されなくなっていたが、S-ILP間隔は不変であった。LVPSおよびRVPSへの高周波通電後には、NSPVTを含むすべてのVTが誘発されなくなった。本症例のVT回路は後中隔心筋層内に存在し、右室にexitを有する単形性VTと左室中隔Purkinje網にexitを有するPVTと推察された。【総括】右室・下壁心筋梗塞後VTにおいて両心室側にexitを有する後中隔心筋層内VT回路がペースマップとその際のLP・ILP変化によって推察された。(著者抄録)

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50歳代男。うっ血性心不全で入院し、諸精査で拡張型心筋症と診断された。房室ブロックと心房細動が認められ、ペースメーカー移植術を受けた。意識消失発作をきたし、無脈性心室頻拍(VT)を認めたため、心肺蘇生を行った。その後、アミオダロンの服用を開始した。2度のカテーテルアブレーション(CA)と両室ペーシング機能付植込み型除細動器移植術が行われた。次第に非持続性VTや心室性期外収縮が増加し、心室ペーシング率の低下で心不全の増悪傾向が認められた。アミオダロンの持続静注を継続し、次第にVTは漸減したが、経過中2度の甲状腺機能亢進が認められた。アミオダロンの内服中止とプレドニゾロンの投与で、甲状腺機能亢進は次第に改善した。引き続いて甲状腺機能低下を認めたため、レボチロキシンナトリウムを投与し、アミオダロン内服も再開した。アミオダロンとCAによる治療を組み合わせて、難治性VTの統制を行うことができた。

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特発性心室細動は,正常な構造を有する心臓に,失神や心臓突然死をきたす疾患である.典型的には,ストレスや活動とは関連なく,連結期の短い心室期外収縮に引き続いて認められる心室細動や多形性心室頻拍発生時に臨床的なイベントが生じる.特発性心室細動をQT延長症候群やカテコラミン感受性多形性心室頻拍等の通常考えられている遺伝性心室細動と区別した場合,Brugada症候群と早期再分極(J波)症候群が特発性心室細動に含まれる代表的な疾患群である.両者には共通する特徴があり,電気生理学的背景が類似している可能性も指摘されているが,厳密な疾患区分はいまだ確立していない.また,J波を有する症例でのリスク層別化の方法は確立しておらず,これらは今後の課題といえる.心室細動歴を有する患者に対して植込み型除細動器が絶対的適応であるが,心室性不整脈の予防的治療にはならず,実際には薬剤やカテーテルアブレーションを組み合わせて治療を行う.(著者抄録)

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A multicenter study to assess upper digestive tract symptoms caused by dabigatran etexilate administered to the patients with non-valvular atrial fibrillation

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DOI： 10.4009/jsdt.44.289

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A Case of Endovascular Revascularization for Chronic Mesenteric Ischemia (CMI)

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＜POINT 1＞静脈還流量と心拍出量の関係にはフランク・スターリング(Frank-Starling)の法則がある。＜POINT 2＞心不全では代償機構として静脈還流を増加しようと水・ナトリウム貯留が起こる。＜POINT 3＞静脈還流の駆動力には、静脈還流圧較差、筋ポンプ、呼吸ポンプ、伴走動脈の拍動などがある。＜POINT 4＞静脈は血液貯蔵器であり運動時、出血時はとくに内臓血管から血液が動員される。(著者抄録)

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Comparison of precordial ECG recorded by event-recorder with those by standard 12-lead systems

DOI： 10.5105/jse.28.225

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PJ-849 Comparison of precordial manual recordings by event-recorder with standard precordial ECG as a reference(ECG / Body surface potential mapping / Holter(07)(A),Poster Session(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

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PJ-025 Further echocardiographic assessment of pulmomary vein flow velocity in focal atrial fibrillation: Longitudinal study(Arrhythmia, diagnosis/Pathophysiology/EPS(12)(A),Poster Session(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

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DOI： 10.1038/sj.bmt.1705764

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臨床医学基本実習「検査実習」講義