Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Fukata Mitsuhiro Last modified date:2021.08.07

Assistant Professor / Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital / Hematology, Oncology & Cardiovascular medicine / Kyushu University Hospital

1. Moriyama S, Fukata M, Tatsumoto R, Kono M., Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report., Eur Heart J Case Rep., 5, ytab002, 2021.02.
2. Arita T, Maruyama T, Yokoyama T, Hieda M, Fukata M, Fujino T, Mawatari S, Akashi K., Impaired deformability and association with density distribution of erythrocytes in patients with type 2 diabetes mellitus under treatment., Clin Hemorheol Microcirc, 76, 73-83, 2020.04.
3. Shohei Moriyama, Taku Yokoyama, Kei Irie, Mamoru Ito, Kenji Tsuchihashi, Mitsuhiro Fukata, Hitoshi Kusaba, Toru Maruyama, Koichi Akashi, Atrial fibrillation observed in a patient with esophageal cancer treated with fluorouracil, Journal of Cardiology Cases, 10.1016/j.jccase.2019.08.005, 20, 5, 183-186, 2019.11, 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. .
4. Shohei Moriyama, Mitsuhiro Fukata, Hitoshi Kusaba, Toru Maruyama, Koichi Akashi, Acute and Chronic Effects of Cancer Drugs on the Cardiovascular System, Heart Failure Clinics, 10.1016/j.hfc.2019.11.002, 16, 2, 231-241, 2020.04, 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..
5. Mitsuhiro Fukata, Acute Decompensated Heart Failure in Patients with Heart Failure with Reduced Ejection Fraction, Heart Failure Clinics, 10.1016/j.hfc.2019.12.007, 16, 2, 187-200, 2020.04, 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..
6. Toru Maruyama, Mitsuhiro Fukata, Koichi Akashi, Association of atrial fibrillation and gastroesophageal reflux disease
Natural and therapeutic linkage of the two common diseases, journal of arrhythmia, 10.1002/joa3.12125, 2018.01, 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..
7. Shioto Yasuda, Mitsuhiro Fukata, Taku Yokoyama, Takeshi Arita, Keita Odashiro, Toru Maruyama, Yoichiro Hiramoto, Koichi Akashi, Sick sinus syndrome observed in a patient with cholinesterase deficiency, Internal Medicine, 10.2169/internalmedicine.1229-18, 58, 6, 809-812, 2019.01, 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..
8. Kotoe Takayoshi, Hitoshi Kusaba, Tomomi Aikawa, Sakuya Koreishi, Kosuke Sagara, Michitaka Nakano, Masato Komoda, Mihoko Kono, Mitsuhiro Fukata, Takeshi Arita, Taito Esaki, Koichi Akashi, Eishi Baba, Hypoalbuminemia for the prediction of venous thromboembolism and treatment of direct oral anticoagulants in metastatic gastric cancer patients, Gastric Cancer, 10.1007/s10120-019-00930-2, 2019.01, 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..
9. Takahiro Nakamura, Fumihiko Ishikawa, Kohei Sonoda, Toshio Hisatomi, Hong Qiao, Jun Yamada, Mitsuhiro Fukata, Tatsuro Ishibashi, Mine Harada, Shigeru Kinoshita, Characterization and distribution of bone marrow-derived cells in mouse cornea, Investigative Ophthalmology and Visual Science, 10.1167/iovs.04-1154, 46, 2, 497-503, 2005.02, 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..
10. Fumihiko Ishikawa, Hideki Shimazu, Leonard D. Shultz, Mitsuhiro Fukata, Ryu Nakamura, Bonnie Lyons, Kazuya Shimoda, Shinji Shimoda, Takaaki Kanemaru, Kei Ichiro Nakamura, Hiroyuki Ito, Yoshikazu Kaji, Anthony C.F. Perry, Mine Harada, Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion, FASEB Journal, 10.1096/fj.05-4863fje, 20, 7, 2006, 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..
11. Toshio Hisatomi, Kohei Sonoda, Fumihiko Ishikawa, Hong Qiao, Takahiro Nakamura, Mitsuhiro Fukata, Toru Nakazawa, Kousuke Noda, Shinsuke Miyahara, Mine Harada, Shigeru Kinoshita, Ali Hafezi-Moghadam, Tatsuro Ishibashi, Joan W. Miller, Identification of resident and inflammatory bone marrow derived cells in the sclera by bone marrow and haematopoietic stem cell transplantation, British Journal of Ophthalmology, 10.1136/bjo.2006.102046, 91, 4, 520-526, 2007.04, 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..
12. Yuya Kunisaki, K. Takase, Toshihiro Miyamoto, Mitsuhiro Fukata, A. Nonami, Kenjiro Kamezaki, Y. Kaji, H. Gondo, M. Harada, K. Nagafuji, Marked improvement of cardiac function early after non-myeloablative BMT in a heavily transfused patient with severe aplastic anemia and heart failure [1], Bone Marrow Transplantation, 10.1038/sj.bmt.1705764, 40, 6, 593-595, 2007.09.
13. Fumihiko Ishikawa, Shuro Yoshida, Yoriko Saito, Atsushi Hijikata, Hiroshi Kitamura, Satoshi Tanaka, Ryu Nakamura, Toru Tanaka, Hiroko Tomiyama, Noriyuki Saito, Mitsuhiro Fukata, Toshihiro Miyamoto, Bonnie Lyons, Koichi Ohshima, Naoyuki Uchida, Shuichi Taniguchi, Osamu Ohara, Koichi Akashi, Mine Harada, Leonard D. Shultz, Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region, Nature Biotechnology, 10.1038/nbt1350, 25, 11, 1315-1321, 2007.11, 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)2rγnull 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..
14. Y. Kong, S. Yoshida, Y. Saito, T. Doi, Y. Nagatoshi, Mitsuhiro Fukata, N. Saito, S. M. Yang, C. Iwamoto, J. Okamura, K. Y. Liu, X. J. Huang, D. P. Lu, L. D. Shultz, M. Harada, F. Ishikawa, CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL, Leukemia, 10.1038/leu.2008.83, 22, 6, 1207-1213, 2008.01, 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..
15. Gen Nakaji, Masahiko Fujiwara, Mitsuhiro Fukata, Shioto Yasuda, Keita Odashiro, Toru Maruyama, Koichi Akashi, Open-loop, clockwise QT-RR hysteresis immediately before the onset of torsades de pointes in type 2 long QT syndrome, Journal of Electrocardiology, 10.1016/j.jelectrocard.2009.12.005, 43, 3, 261-263, 2010.05, 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..
16. Shioto Yasuda, Yousuke Kokawa, Hisataka Nakamura, Mitsuhiro Fukata, Keita Odashiro, Toru Maruyama, Koichi Akashi, PJ3-064 A Case of Various Supraventricular and Ventricular Tachyarrhythmias Secondary to Polymyositis, Journal of Arrhythmia, 10.4020/jhrs.27.PJ3_064, 27, 2011.01, 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..
17. G. Nakaji, M. Fujihara, Mitsuhiro Fukata, S. Yasuda, Keita Odashiro, Toru Maruyama, Koichi Akashi, Influence of common cardiac drugs on gastroesophageal reflux disease
Multicenter questionnaire survey, International Journal of Clinical Pharmacology and Therapeutics, 10.5414/CP201558, 49, 9, 555-563, 2011.09, 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..
18. Hideki Shimazu, Gen Nakaji, Mitsuhiro Fukata, Keita Odashiro, Toru Maruyama, Koichi Akashi, Relationship between atrial fibrillation and gastroesophageal reflux disease
A multicenter questionnaire survey, Cardiology, 10.1159/000331497, 119, 4, 217-223, 2011.11, 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..
19. K. Saito, Y. Kogawa, Mitsuhiro Fukata, Keita Odashiro, Toru Maruyama, Koichi Akashi, T. Fujino, Impaired deformability of erythrocytes in diabetic rat and human
Investigation by the nickel-mesh-filtration technique, Journal of Biorheology, 10.1007/s12573-011-0032-5, 25, 1-2, 18-26, 2011.12, 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..
20. Mitsuhiro Fukata, Keita Odashiro, Koichi Akashi, Coronary and peripheral artery aneurysms in a patient with hypereosinophilia, Heart Asia, 10.1136/heartasia-2012-010105, 4, 1, 54-55, 2012.
21. Masahiko Fujihara, Mitsuhiro Fukata, Keita Odashiro, Toru Maruyama, Koichi Akashi, Yoshiaki Yokoi, Reduced plasma eicosapentaenoic acid-arachidonic acid ratio in peripheral artery disease, Angiology, 10.1177/0003319712437031, 64, 2, 112-118, 2013.02, 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..
22. Mitsuhiro Fukata, Fumihiko Ishikawa, Yuho Najima, Takuji Yamauchi, Yoriko Saito, Katsuto Takenaka, Kohta Miyawaki, Hideki Shimazu, Kazuya Shimoda, Takaaki Kanemaru, Kei ichiro Nakamura, Keita Odashiro, Koji Nagafuji, Mine Harada, Koichi Akashi, Contribution of Bone Marrow-Derived Hematopoietic Stem/Progenitor Cells to the Generation of Donor-Marker+ Cardiomyocytes In Vivo, PLoS One, 10.1371/journal.pone.0062506, 8, 5, 2013.05, 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/IL2rγnull 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-/lowCD45+ hematopoietic cells generated greater number of GFP+ cardiomyocytes than Lin-/lowCD45- 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-/lowSca-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..
23. Masako Kadowaki, Mika Hashimoto, Mai Nakashima, Mitsuhiro Fukata, Keita Odashiro, Yujiro Uchida, Nobuyuki Shimono, Radial mycotic aneurysm complicated with infective endocarditis caused by Streptococcus sanguinis, Internal Medicine, 10.2169/internalmedicine.52.0747, 52, 20, 2361-2365, 2013.10, 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..
24. Keita Odashiro, Toru Maruyama, Taku Yokoyama, Hisataka Nakamura, Mitsuhiro Fukata, Shioto Yasuda, Kazuyuki Saito, Takehiko Fujino, Koichi Akashi, Impaired erythrocyte deformability in patients with coronary risk factors
Significance of nonvalvular atrial fibrillation, Journal of Atrial Fibrillation, 6, 3, 6-12, 2013.10, 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..
25. Akiko Uehara Yonekawa, Sho Iwasaka, Hisataka Nakamura, Mitsuhiro Fukata, Masako Kadowaki, Yujiro Uchida, Keita Odashiro, Shinji Shimoda, Nobuyuki Shimono, Koichi Akashi, Infective endocarditis caused by Listeria monocytogenes forming a pseudotumor, Internal Medicine, 10.2169/internalmedicine.53.1925, 53, 9, 1029-1032, 2014.01, 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..
26. Masahiko Fujihara, Mitsuhiro Fukata, Akihiro Higashimori, Hisataka Nakamura, Keita Odashiro, Yoshiaki Yokoi, Short- and mid-term results of balloon angioplasty for renal artery fibromuscular dysplasia, Cardiovascular Intervention and Therapeutics, 10.1007/s12928-014-0253-9, 29, 4, 293-299, 2014.10, 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..
27. Tsutomu Hoshuyama, Keita Odashiro, Mitsuhiro Fukata, Toru Maruyama, Kazuyuki Saito, Chikako Wakana, Michiko Fukumitsu, Takehiko Fujino, Mortality benefit of participation in BOOCS program
A follow-up study for 15 years in a Japanese Working Population, Journal of Occupational and Environmental Medicine, 10.1097/JOM.0000000000000399, 57, 3, 246-250, 2015.03, 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..
28. Toru Maruyama, Mitsuhiro Fukata, Increased coupling interval variability – Mechanistic, diagnostic and prognostic implication of premature ventricular contractions and underlying heart diseases, Circulation Journal, 10.1253/circj.CJ-15-0963, 79, 11, 2317-2319, 2015.10.
29. Keita Odashiro, Taku Yokoyama, Mitsuhiro Fukata, Takeshi Arita, Toru Maruyama, Koichi Akashi, Anticoagulation stability depends on CHADS2 score and hepatorenal function in warfarin-treated patients, including those with atrial fibrillation, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.35121, 24, 1, 68-76, 2017, 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..
30. Shunsuke Yoda, Taku Yokoyama, Mitsuhiro Fukata, Takeshi Arita, Keita Odashiro, Toru Maruyama, Koichi Akashi, Assessment of erythrocyte deformability in an obese case of chronic thromboembolic pulmonary hypertension, Journal of Biorheology, 10.17106/jbr.31.57, 31, 2, 57-60, 2017.01, 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..
31. Hiroyuki Kodama, Kazumasa Fujita, Shouhei Moriyama, Kei Irie, Hirotaka Noda, Taku Yokoyama, Mitsuhiro Fukata, Takeshi Arita, Keita Odashiro, Toru Maruyama, Koichi Akashi, Manifestation of J wave induced by acetylcholine applied for a coronary spasm provocation test in a patient with aborted sudden cardiac death, Journal of Arrhythmia, 10.1016/j.joa.2016.09.001, 33, 3, 234-236, 2017.06, 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..
32. Mitsuhiro Fukata, Takeshi Arita, Hideki Kadota, Keita Odashiro, Toru Maruyama, Koichi Akashi, Successful management of wound dehiscence after implantation of a subcutaneous implantable cardioverter-defibrillator without device removal, HeartRhythm Case Reports, 10.1016/j.hrcr.2017.06.006, 3, 9, 415-417, 2017.09.
33. Toru Maruyama, Kazumasa Fujita, Kei Irie, Shouhei Moriyama, Mitsuhiro Fukata, Intracoronary acetylcholine application as a possible probe inducing J waves in patients with early repolarization syndrome, Journal of Arrhythmia, 10.1016/j.joa.2016.12.005, 33, 5, 424-429, 2017.10, 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..
34. Kenji Tsuchihashi, Tomoyasu Yoshihiro, Tomomi Aikawa, Kenta Nio, Kotoe Takayoshi, Taku Yokoyama, Mitsuhiro Fukata, Shuji Arita, hiroshi ariyama, Yukiko Shimizu, Yuichiro Yoshida, takehiro torisu, Motohiro Esaki, Keita Odashiro, Hitoshi Kusaba, Koichi Akashi, Eishi Baba, Metastatic esophageal cancer presenting as shock by injury of vagus nerve mimicking baroreceptor reflex
A case report, Medicine; analytical reviews of general medicine, neurology, psychiatry, dermatology, and pediatries, 10.1097/MD.0000000000008987, 96, 49, 2017.12, 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..
35. Megumi Kisanuki, Kazumasa Fujita, Shohei Moriyama, Kei Irie, Chiharu Yosida, Mitsuhiro Fukata, Takeshi Arita, Taku Yokoyama, Keita Odashiro, Toru Maruyama, Koichi Akashi, Complex regional pain syndrome induced by pacemaker implantation for sick sinus syndrome, Journal of Arrhythmia, 10.1016/j.joa.2017.08.005, 33, 6, 643-645, 2017.12, 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..
36. Fukata Mitsuhiro, A Case of Takotsubo Cardiomyopathy Possibly Induced by Cilostazol Administration, Clinics in Surgery, 2016.05.
37. Mitsuhiro Fukata, Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker+ cardiomyocytes in vivo. , PLoS One, 8, e62506, 2013.05.
38. Mitsuhiro Fukata, Coronary and peripheral artery aneurysms in a patient with hypereosinophilia, Heart Asia, 4, 54-55, 2012.04.
39. Fumihiko Ishikawa, Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion., FASEB J., 20, 950-952, 2006.05.