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門田 真  カドタ シン

教員組織学術研究院(医学系)電話番号
教育組織先鋭領域融合研究群 バイオメディカル研究所 バイオテクノロジー・生体医工学部門FAX番号
職名講師メールアドレス
住所〒390-8621 長野県松本市旭3-1-1ホームページURL

プロフィール

兼担研究科・学部
医学部 医学科 再生医科学
研究分野
細胞生物学
循環器内科学
キーワード:バイオペースメーカー , 心筋再生 , 再生医療
所属学会
所属学会
日本再生医療学会
日本心臓病学会
日本内科学会
日本循環器学会
学歴
出身大学院
2013 , 京都大学 , 医学研究科

出身学校・専攻等(大学院を除く)
2003 , 京都大学 , 医学部 , 医学科

取得学位
博士(医学) , 京都大学(日本)
研究職歴等
研究職歴
2017- , 信州大学 医学部再生医科学教室 助教
2016-2017 , 信州大学 循環器内科
2013-2016 , ワシントン大学 病理 博士研究員
2010-2013 , 日本学術振興会 特別研究員(DC1)
2004-2009 , 市立岸和田市民病院 循環器科
2003-2004 , 京都大学医学部付属病院 内科研修医

研究活動業績

研究業績(著書・
発表論文等)
論文
Efficacy of exon-skipping therapy for DMD cardiomyopathy with mutations in actin binding domain 1.
Molecular therapy. Nucleic acids,34:102060-102060 2023(Dec. 12)
Author:Naoko Shiba; Xiao Yang; Mitsuto Sato; Shin Kadota; Yota Suzuki; Masahiro Agata; Kohei Nagamine; Masaki Izumi; Yusuke Honda; Tomoya Koganehira; Hideki Kobayashi; Hajime Ichimura; Shinichiro Chuma; Junichi Nakai; Shugo Tohyama; Keiichi Fukuda; Daigo Miyazaki; Akinori Nakamura; Yuji Shiba
Abstract:Exon-skipping therapy is a promising treatment strategy for Duchenne muscular dystrophy (DMD), which is caused by loss-of-function mutations in the DMD gene encoding dystrophin, leading to progressive cardiomyopathy. In-frame deletion of exons 3-9 (Δ3-9), manifesting a very mild clinical phenotype, is a potential targeted reading frame for exon-skipping by targeting actin-binding domain 1 (ABD1); however, the efficacy of this approach for DMD cardiomyopathy remains uncertain. In this study, we compared three isogenic human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) expressing Δ3-9, frameshifting Δ3-7, or intact DMD. RNA sequencing revealed a resemblance in the expression patterns of mechano-transduction-related genes between Δ3-9 and wild-type samples. Furthermore, we observed similar electrophysiological properties between Δ3-9 and wild-type hiPSC-CMs; Δ3-7 hiPSC-CMs showed electrophysiological alterations with accelerated CaMKII activation. Consistently, Δ3-9 hiPSC-CMs expressed substantial internally truncated dystrophin protein, resulting in maintaining F-actin binding and desmin retention. Antisense oligonucleotides targeting exon 8 efficiently induced skipping exons 8-9 to restore functional dystrophin and electrophysiological parameters in Δ3-7 hiPSC-CMs, bringing the cell characteristics closer to those of Δ3-9 hiPSC-CMs. Collectively, exon-skipping targeting ABD1 to convert the reading frame to Δ3-9 may become a promising therapy for DMD cardiomyopathy.


Mature human induced pluripotent stem cell-derived cardiomyocytes promote angiogenesis through alpha-B crystallin.
Stem cell research & therapy,14(1):240-240 2023(Sep. 07)
Author:Yuki Tanaka; Shin Kadota; Jian Zhao; Hideki Kobayashi; Satomi Okano; Masaki Izumi; Yusuke Honda; Hajime Ichimura; Naoko Shiba; Takeshi Uemura; Yuko Wada; Shinichiro Chuma; Tsutomu Nakada; Shugo Tohyama; Keiichi Fukuda; Mitsuhiko Yamada; Tatsuichiro Seto; Koichiro Kuwahara; Yuji Shiba
Abstract:BACKGROUND: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to treat heart diseases; however, the optimal maturity of hiPSC-CMs for effective regenerative medicine remains unclear. We aimed to investigate the benefits of long-term cultured mature hiPSC-CMs in injured rat hearts. METHODS: Cardiomyocytes were differentiated from hiPSCs via monolayer culturing, and the cells were harvested on day 28 or 56 (D28-CMs or D56-CMs, respectively) after differentiation. We transplanted D28-CMs or D56-CMs into the hearts of rat myocardial infarction models and examined cell retention and engraftment via in vivo bioluminescence imaging and histological analysis. We performed transcriptomic sequencing analysis to elucidate the genetic profiles before and after hiPSC-CM transplantation. RESULTS: Upregulated expression of mature sarcomere genes in vitro was observed in D56-CMs compared with D28-CMs. In vivo bioluminescence imaging studies revealed increased bioluminescence intensity of D56-CMs at 8 and 12 weeks post-transplantation. Histological and immunohistochemical analyses showed that D56-CMs promoted engraftment and maturation in the graft area at 12 weeks post-transplantation. Notably, D56-CMs consistently promoted microvessel formation in the graft area from 1 to 12 weeks post-transplantation. Transcriptomic sequencing analysis revealed that compared with the engrafted D28-CMs, the engrafted D56-CMs enriched genes related to blood vessel regulation at 12 weeks post-transplantation. As shown by transcriptomic and western blot analyses, the expression of a small heat shock protein, alpha-B crystallin (CRYAB), was significantly upregulated in D56-CMs compared with D28-CMs. Endothelial cell migration was inhibited by small interfering RNA-mediated knockdown of CRYAB when co-cultured with D56-CMs in vitro. Furthermore, CRYAB overexpression enhanced angiogenesis in the D28-CM grafts at 4 weeks post-transplantation. CONCLUSIONS: Long-term cultured mature hiPSC-CMs promoted engraftment, maturation and angiogenesis post-transplantation in infarcted rat hearts. CRYAB, which was highly expressed in D56-CMs, was identified as an angiogenic factor from mature hiPSC-CMs. This study revealed the benefits of long-term culture, which may enhance the therapeutic potential of hiPSC-CMs.


Gene editing to prevent ventricular arrhythmias associated with cardiomyocyte cell therapy.
Cell stem cell,30(4):396-414 2023(Apr. 06)
Author:Silvia Marchiano; Kenta Nakamura; Hans Reinecke; Lauren Neidig; Michael Lai; Shin Kadota; Filippo Perbellini; Xiulan Yang; Jordan M Klaiman; Leslie P Blakely; Elaheh Karbassi; Paul A Fields; Aidan M Fenix; Kevin M Beussman; Anu Jayabalu; Faith A Kalucki; Akiko Futakuchi-Tsuchida; Gerhard J Weber; Sarah Dupras; Hiroshi Tsuchida; Lil Pabon; Lili Wang; Björn C Knollmann; Steven Kattman; R Scott Thies; Nathan Sniadecki; W Robb MacLellan; Alessandro Bertero; Charles E Murry
Abstract:Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) offer a promising cell-based therapy for myocardial infarction. However, the presence of transitory ventricular arrhythmias, termed engraftment arrhythmias (EAs), hampers clinical applications. We hypothesized that EA results from pacemaker-like activity of hPSC-CMs associated with their developmental immaturity. We characterized ion channel expression patterns during maturation of transplanted hPSC-CMs and used pharmacology and genome editing to identify those responsible for automaticity in vitro. Multiple engineered cell lines were then transplanted in vivo into uninjured porcine hearts. Abolishing depolarization-associated genes HCN4, CACNA1H, and SLC8A1, along with overexpressing hyperpolarization-associated KCNJ2, creates hPSC-CMs that lack automaticity but contract when externally stimulated. When transplanted in vivo, these cells engrafted and coupled electromechanically with host cardiomyocytes without causing sustained EAs. This study supports the hypothesis that the immature electrophysiological prolife of hPSC-CMs mechanistically underlies EA. Thus, targeting automaticity should improve the safety profile of hPSC-CMs for cardiac remuscularization.


Intracoronary transplantation of pluripotent stem cell-derived cardiomyocytes: Inefficient procedure for cardiac regeneration.
Journal of molecular and cellular cardiology,174:77-87 2022(Nov. 18)
Author:Hideki Kobayashi; Shugo Tohyama; Hideaki Kanazawa; Hajime Ichimura; Shuji Chino; Yuki Tanaka; Yota Suzuki; Jian Zhao; Naoko Shiba; Shin Kadota; Kazumasa Narita; Takafumi Naito; Tatsuichiro Seto; Koichiro Kuwahara; Yuji Shiba; Keiichi Fukuda
Abstract:Advances in stem cell biology have facilitated cardiac regeneration, and many animal studies and several initial clinical trials have been conducted using human pluripotent stem cell-derived cardiomyocytes (PSC-CMs). Most preclinical and clinical studies have typically transplanted PSC-CMs via the following two distinct approaches: direct intramyocardial injection or epicardial delivery of engineered heart tissue. Both approaches present common disadvantages, including a mandatory thoracotomy and poor engraftment. Furthermore, a standard transplantation approach has yet to be established. In this study, we tested the feasibility of performing intracoronary administration of PSC-CMs based on a commonly used method of transplanting somatic stem cells. Six male cynomolgus monkeys underwent intracoronary administration of dispersed human PSC-CMs or PSC-CM aggregates, which are called cardiac spheroids, with multiple cell dosages. The recipient animals were sacrificed at 4 weeks post-transplantation for histological analysis. Intracoronary administration of dispersed human PSC-CMs in the cynomolgus monkeys did not lead to coronary embolism or graft survival. Although the transplanted cardiac spheroids became partially engrafted, they also induced scar formation due to cardiac ischemic injury. Cardiac engraftment and scar formation were reasonably consistent with the spheroid size or cell dosage. These findings indicate that intracoronary transplantation of PSC-CMs is an inefficient therapeutic approach.


Chemical Genetics Reveals a Role of Squalene Synthase in TGFβ Signaling and Cardiomyogenesis.
Angewandte Chemie (International ed. in English) 2021(Aug. 10)
Author:Yasushi Takemoto; Shin Kadota; Itsunari Minami; Shinya Otsuka; Satoshi Okuda; Masahiro Abo; Louvy Lynn Punzalan; Yan Shen; Yuji Shiba; Motonari Uesugi
Abstract:KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY-I. By disrupting the interaction of SQS with cardiac ER-membrane protein TMEM43, KY02111 impairs TGFβ signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFβ signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFβ/SMAD signaling.


β-Arrestin–Biased AT1 Agonist TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect Without Increasing Heart Rate
JACC: Basic to Translational Science,5(11):1057-1069 2020(Nov. 11)
Author:Toshihide Kashihara; Hiroyuki Kawagishi; Tsutomu Nakada; Takuro Numaga-Tomita; Shin Kadota; Elena E. Wolf; Cheng-Kun Du; Yuji Shiba; Sachio Morimoto; Mitsuhiko Yamada
Abstract:The treatment of pediatric heart failure is a long-standing unmet medical need. Angiotensin II supports mammalian perinatal circulation by activating cardiac L-type Ca2+ channels through angiotensin type 1 receptor (AT1R) and β-arrestin. TRV027, a β-arrestin-biased AT1R agonist, that has been reported to be safe but not effective for adult patients with heart failure, activates the AT1R/β-arrestin pathway. We found that TRV027 evokes a long-acting positive inotropic effect specifically on immature cardiac myocytes through the AT1R/β-arrestin/L-type Ca2+ channel pathway with minimum effect on heart rate, oxygen consumption, reactive oxygen species production, and aldosterone secretion. Thus, TRV027 could be utilized as a valuable drug specific for pediatric heart failure.


Heart regeneration using pluripotent stem cells.
Journal of cardiology,76(5):459-463 2020(Nov.)
Author:Shin Kadota; Yuki Tanaka; Yuji Shiba
Abstract:Pluripotent stem cells (PSCs), which include embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively), have great potential in regenerative medicine for heart diseases due to their virtually unlimited cardiogenic capacity. Many preclinical studies have described the functional benefits after transplantation of PSC-derived cardiomyocytes (PSC-CMs). However, transient ventricular arrhythmias were detected after injection into non-human primates and swine ischemic hearts; as engrafted PSC-CMs form an electrical coupling between host and graft, the immature characteristics of PSC-CMs may serve as an ectopic pacemaker. We are entering a critical time in the development of novel therapies using PSC-CMs, with the recent first clinical trial using human iPSC-CMs (hiPSC-CMs) being launched in Japan. In this review, we summarize the updated knowledge, perspectives, and limitations of PSC-CMs for heart regeneration.


Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo.
Scientific reports,10(1):11883-11883 2020(Jul. 17)
Author:Hajime Ichimura; Shin Kadota; Toshihide Kashihara; Mitsuhiko Yamada; Kuniaki Ito; Hideki Kobayashi; Yuki Tanaka; Naoko Shiba; Shinichiro Chuma; Shugo Tohyama; Tatsuichiro Seto; Kenji Okada; Koichiro Kuwahara; Yuji Shiba
Abstract:Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect "heart regeneration", replacing injured cardiac scar tissue with concomitant electrical integration. However, electrically coupled graft cardiomyocytes were found to innately induce transient post-transplant ventricular tachycardia in recent large animal model transplantation studies. We hypothesised that these phenomena were derived from alterations in the grafted cardiomyocyte characteristics. In vitro experiments showed that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) contain nodal-like cardiomyocytes that spontaneously contract faster than working-type cardiomyocytes. When transplanted into athymic rat hearts, proliferative capacity was lower for nodal-like than working-type cardiomyocytes with grafted cardiomyocytes eventually comprising only relatively matured ventricular cardiomyocytes. RNA-sequencing of engrafted hESC-CMs confirmed the increased expression of matured ventricular cardiomyocyte-related genes, and simultaneous decreased expression of nodal cardiomyocyte-related genes. Temporal engraftment of electrical excitable nodal-like cardiomyocytes may thus explain the transient incidence of post-transplant ventricular tachycardia, although further large animal model studies will be required to control post-transplant arrhythmia.


ラット心筋内におけるヒトES細胞由来心筋細胞の経時的変化
日本心臓血管外科学会学術総会抄録集,50回:O10-2 2020(Mar.)
Author:市村 創; 門田 真; 茅野 周治; 御子柴 透; 小松 正樹; 田中 晴城; 山本 高照; 大橋 伸朗; 福家 愛; 和田 有子; 柏原 俊英; 山田 充彦; 柴 祐司; 瀬戸 達一郎


Pluripotent Stem Cell-Derived Cardiomyocyte Transplantation for Heart Disease Treatment.
Current cardiology reports,21(8):73 2019(Jun.)
Author:Kadota S; Shiba Y


Long-Term Culture In Vitro Enhanced Maturation and Engraftment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in vivo
CIRCULATION,138 2018(Nov.)
Author:Shin Kadota; Yuki Tanaka; Yuji Shiba
Abstract:0


Cardiac Sodium Channel Disease Modeling Using Patient-Derived Induced Pluripotent Stem Cells
CIRCULATION JOURNAL,81(12):1764-1765 2017(Dec.)
Author:Shin Kadota; Naoko Shiba; Yuji Shiba


Impact of extracellular matrix on engraftment and maturation of pluripotent stem cell-derived cardiomyocytes in a rat myocardial infarct model
SCIENTIFIC REPORTS,7(1):8630 2017(Aug.)
Author:Tatsuki Ogasawara; Satomi Okano; Hajime Ichimura; Shin Kadota; Yuki Tanaka; Itsunari Minami; Motonari Uesugi; Yuko Wada; Naoto Saito; Kenji Okada; Koichiro Kuwahara; Yuji Shiba
Abstract:Pluripotent stem cell-derived cardiomyocytes show great promise in regenerating the heart after myocardial infarction; however, several uncertainties exist that must be addressed before clinical trials. One practical issue is graft survival following transplantation. Although a pro-survival cocktail with Matrigel has been shown to enhance graft survival, the use of Matrigel may not be clinically feasible. The purpose of this study was to test whether a hyaluronan-based hydrogel, HyStem, could be a substitute for Matrigel. Human induced pluripotent stem cell-derived cardiomyocytes diluted with HyStem alone, HyStem plus pro-survival factors, or a pro-survival cocktail with Matrigel (PSC/MG), were transplanted into a rat model of acute myocardial infarction. Histological analysis at 4 weeks post transplantation revealed that, among the three groups, recipients of PSC/MG showed the largest graft size. Additionally, the grafted cardiomyocytes in the recipients of PSC/MG had a more matured phenotype compared to those in the other two groups. These findings suggest that further studies will be required to enhance not only graft size, but also the maturation of grafted cardiomyocytes.


In Vivo Maturation of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Neonatal and Adult Rat Hearts.
Stem cell reports,8(2):278-289 2017(Feb.)
Author:Kadota S; Pabon L; Reinecke H; Murry CE
Abstract:We hypothesized that the neonatal rat heart would bring transplanted human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) to maturity as it grows to adult size. In neonatal rat heart, engrafted hiPSC derivatives developed partially matured myofibrils after 3 months, with increasing cell size and sarcomere length. There was no difference between grafts from hiPSC-CMs or hiPSC-derived cardiac progenitors (hiPSC-CPs) at 3 months, nor was maturation influenced by infarction. Interestingly, the infarcted adult heart induced greater human cardiomyocyte hypertrophy and induction of cardiac troponin I expression than the neonatal heart. Although human cardiomyocytes at all time points were significantly smaller than the host rat cardiomyocytes, transplanted neonatal rat cardiomyocytes reached adult size and structure by 3 months. Thus, the adult rat heart induces faster maturation than the neonatal heart, and human cardiomyocytes mature more slowly than rat cardiomyocytes. The slower maturation of human cardiomyocytes could be related to environmental mismatch or cell-autonomous factors.


Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure
EUROPEAN JOURNAL OF HEART FAILURE,17(8):772-781 2015(Aug.)
Author:Shin Kadota; John Carey; Hans Reinecke; James Leggett; Sam Teichman; Michael A. Laflamme; Charles E. Murry; Michael Regnier; Gregory G. Mahairas
Abstract:AimsHeart failure remains a leading cause of morbidity, hospitalizations, and deaths. We previously showed that overexpression of the enzyme ribonucleotide reductase (RNR) in cardiomyocytes increased levels of the myosin activator, 2-deoxy-ATP, catalysed enhanced contraction, and improved cardiac performance in rodent hearts. Here we used a swine model of myocardial infarction (MI) to test preliminarily a novel gene therapy for heart failure based on delivery of the human RNR enzyme complex under the control of a cardiac-specific promoter via an adeno-associated virus serotype 6 vectordesignated as BB-R12. Methods and resultsWe induced heart failure following MI in Yucatan minipigs by balloon occlusion of the left anterior descending artery. Two weeks, later, pigs received BB-R12 at one of three doses via antegrade coronary infusion. At 2 months post-treatment, LVEF and systolic LV dimension (measured by echocardiography) improved significantly in the high-dose group, despite further deterioration in the saline controls. Haemodynamic parameters including LV end-diastolic pressure, +dP/dt, and -dP/dt all trended towards improvement in the high-dose group. We observed no difference in the histopathological appearance of hearts or other organs from treated animals vs. controls, nor did we encounter any safety or tolerability concerns following BB-R12 delivery. ConclusionThese pilot results suggest cardiac-specific gene therapy using BB-R12 may reverse cardiac dysfunction by myosin activation in a large-animal heart failure model with no observed safety concerns. Thus further research into the therapeutic potential of BB-R12 for patients with chronic heart failure appears warranted.


Development of a reentrant arrhythmia model in human pluripotent stem cell-derived cardiac cell sheets
European Heart Journal,34(15):1147-1156 2013(Apr. 14)
Author:Shin Kadota; Itsunari Minami; Nobuhiro Morone; John E. Heuser; Konstantin Agladze; Norio Nakatsuji
Abstract:AimsDevelopment of a human cell-derived reentrant arrhythmia model is needed for studying the mechanisms of disease and accurate drug response.Methods and resultsWe differentiated human pluripotent stem cells (hPSCs) into cardiomyocytes, and then re-plated them into cell sheets that proved capable of forming electrically coupled assemblies. We monitored the function of these re-plated sheets optically with the Ca2+ sensitive dye Fluo-4, and found that they generated characteristic waves of activity whose velocity and patterns of propagation depended upon the concentration of sodium channel blockers lidocaine and tetrodotoxin, and also the time after re-plating, as well as the applied stimulation frequency. Importantly, reentrant spiral-wave propagation could be generated in these sheets by applying high-frequency stimulation, particularly when cell-density in the sheets was relatively low. This was because cardiac troponin T-positive cells were more non-homogeneously distributed at low cell densities. Especially in such sheets, we could terminate spiral waves by administering the anti-arrhythmic drugs nifekalant, E-4031, sotalol, and quinidine. We also found that in these sheets, nifekalant showed a clear dose-dependent increase in the size of the unexcitable 'cores' of these induced spiral waves, an important parallel with the treatment for ventricular tachycardia in the clinical situation, which was not shown properly in cardiac-cell sheets derived from dissociated rodent hearts.ConclusionsWe have succeeded in creating from hPSCs a valuable type of cardiomyocyte sheet that is capable of generating reentrant arrhythmias, and thus is demonstrably useful for screening and testing all sorts of drugs with anti-arrhythmic potential. © 2013 The Author.


A Small Molecule that Promotes Cardiac Differentiation of Human Pluripotent Stem Cells under Defined, Cytokine- and Xeno-free Conditions
CELL REPORTS,2(5):1448-1460 2012(Nov.)
Author:Itsunari Minami; Kohei Yamada; Tomomi G. Otsuji; Takuya Yamamoto; Yan Shen; Shinya Otsuka; Shin Kadota; Nobuhiro Morone; Maneesha Barve; Yasuyuki Asai; Tatyana Tenkova-Heuser; John E. Heuser; Motonari Uesugi; Kazuhiro Aiba; Norio Nakatsuji
Abstract:Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, are potentially useful in regenerative therapies for heart disease. For medical applications, clinical-grade cardiac cells must be produced from hPSCs in a defined, cost-effective manner. Cell-based screening led to the discovery of KY02111, a small molecule that promotes differentiation of hPSCs to cardiomyocytes. Although the direct target of KY02111 remains unknown, results of the present study suggest that KY02111 promotes differentiation by inhibiting WNT signaling in hPSCs but in a manner that is distinct from that of previously studied WNT inhibitors. Combined use of KY02111 and WNT signaling modulators produced robust cardiac differentiation of hPSCs in a xeno-free, defined medium, devoid of serum and any kind of recombinant cytokines and hormones, such as BMP4, Activin A, or insulin. The methodology has potential as a means for the practical production of human cardiomyocytes for regeneration therapies.


Curvature-dependent excitation propagation in cultured cardiac tissue
JETP Letters,94(11):824-830 2012(Feb.)
Author:S. Kadota; M. W. Kay; N. Magome; K. Agladze
Abstract:The geometry of excitation wave front may play an important role on the propagation block and spiral wave formation. The wave front which is bent over the critical value due to interaction with the obstacles may partially cease to propagate and appearing wave breaks evolve into rotating waves or reentry. This scenario may explain how reentry spontaneously originates in a heart. We studied highly curved excitation wave fronts in the cardiac tissue culture and found that in the conditions of normal, non-inhibited excitability the curvature effects do not play essential role in the propagation. Neither narrow isthmuses nor sharp corners of the obstacles, being classical objects for production of extremely curved wave front, affect non-inhibited wave propagation. The curvature-related phenomena of the propagation block and wave detachment from the obstacle boundary were observed only after partial suppression of the sodium channels with Lidocaine. Computer simulations confirmed the experimental observations. The explanation of the observed phenomena refers to the fact that the heart tissue is made of finite size cells so that curvature radii smaller than the cardiomyocyte size loses sense, and in non-inhibited tissue the single cell is capable to transmit excitation to its neighbors. © 2011 Pleiades Publishing, Ltd.


[Embryonic stem cell research].
Nihon rinsho. Japanese journal of clinical medicine,69(12):2109-2113 2011(Dec.)
Author:Kadota S; Aiba K; Nakatsuji N


The association between post-load low insulin level and high mortality rates in patients with no previous diagnosis of diabetes mellitus
INTERNATIONAL JOURNAL OF CARDIOLOGY,148(1):59-63 2011(Apr.)
Author:Shin Kadota; Mitsuo Matsuda; Masayasu Izuhara; Osamu Baba; Hirokazu Mitsuoka; Keisuke Shioji; Takashi Uegaito
Abstract:Background: Hyperinsulinemia and insulin resistance have been proposed as having a causal role in pathogenesis of atherosclerosis; however, the relationship between post-load insulin levels and long-termsurvival is not clear. We investigated whether post-load insulin response is a predictor of outcome in patients without previously recognized diabetes. Methods: Data from 933 Japanese patients who underwent both a 75 g oral glucose tolerance test and coronary angiography with suspected coronary artery disease were analyzed. The determinant factors in association with all-cause death or cardiovascular events, including reinfarction, heart failure or angina requiring re-hospitalization, and coronary revascularization were examined by multivariate Cox regression analysis. Results: The numbers of patients with normal glucose tolerance, impaired glucose regulation and diabetes were 326, 408 and 199, respectively. During the follow-up period (median 1113 days), death occurred in 37 patients including 13 cardiac causes. There were no significant differences in mortality or cardiovascular event incidence between glucose tolerance status. Kaplan-Meier curves indicated that the lower-response group of 2-hour insulin levels (< 75.3 mU/L; median) was associated with higher mortality rates (Log-rank P=0.006). Multivariate Cox regression analysis revealed that 2-hour insulin level was an independent predictor of all-cause death (P=0.026) after adjustment for age, gender, number of stenosed vessels, ejection fraction, metabolic factors, and treatments. Conclusions: Post-load low insulin response is seen as a predictor of mortality rates for patients with no previous diagnosis of diabetes mellitus. (C) 2009 Elsevier Ireland Ltd. All rights reserved.


A case of marked ST depression and myocardial injury as a result of disulfiram-ethanol reaction
Journal of Cardiology Cases,1(3):e137-e140 2010(Jun.)
Author:Keisuke Shioji; Masayasu Izuhara; Shin Kadota; Osamu Baba; Hirokazu Mitsuoka; Takashi Uegaito; Mitsuo Matsuda
Abstract:We report a case of a 50-year-old man with intractable hypotension, which led to ischemic electrocardiogram (ECG) changes and myocardial injury due to relative myocardial ischemia as a result of a disulfiram-ethanol reaction. This is the first report that assessed cardiac function during hypotension and ischemic ECG changes by emergency coronary angiography, left ventriculography, and right heart catheterization. This case indicates that disulfiram potentially has fatal side effects due to a disulfiram-ethanol reaction. © 2009 Japanese College of Cardiology.


A case of right atrial angiosarcoma: The utility of PET and CT fusion imaging in detecting a malignant cardiac tumor
Journal of Cardiology Cases,1(2):e84-e87 2010(Apr.)
Author:Shin Kadota; Mitsuo Matsuda; Nao Umei; Masayasu Izuhara; Osamu Baba; Hirokazu Mitsuoka; Keisuke Shioji; Takashi Uegaito; Takuma Satsu; Masahiko Onoe; Eiji Kadota
Abstract:A 49-year-old woman was admitted to the hospital because of cardiac tamponade. The hemorrhagic pericardial effusion was cytologically negative for malignant cells. Cardiac magnetic resonance imaging showed two masses in the anterior and lateral right atrium however, positron emission tomography (PET) image using 18F-fluorodeoxyglucose revealed strong uptake in the anterior right atrium, without other tumors or metastasis. Intraoperatively, the lateral mass was confirmed as a thrombus, whereas the anterior mass was removed surgically and was diagnosed as an angiosarcoma with histopathological examination. However, she was re-admitted to the hospital 1 month after the operation because of cerebral hemorrhage, suspicious of distant metastasis. PET is useful for the detection of cardiac angiosarcoma. © 2009 Japanese College of Cardiology.


Determinant factors of plasma B-type natriuretic peptide levels in patients with persistent nonvalvular atrial fibrillation and preserved left ventricular systolic function
JOURNAL OF CARDIOLOGY,54(3):402-408 2009(Dec.)
Author:Osamu Baba; Masayasu Izuhara; Shin Kadota; Hirokazu Mitsuoka; Keisuke Shioji; Takashi Uegaito; Satoru Mutsuo; Mitsuo Matsuda
Abstract:Background and objective: Plasma B-type natriuretic peptide (BNP) levels are determined by several factors. The presence of atrial. fibrillation (AF) is one of these factors. Meanwhile, plasma BNP levels are well correlated with left ventricular (LV) fitting pressure in patients with sinus rhythm. Furthermore, LV filling pressure can be estimated by the ratio of early diastolic transmitral velocity to early diastolic mitral annular velocity (E/e' ratio) in patients with sinus rhythm or with AF However, it is still unclear if elevated plasma BNP levels reflect increases in LV filling pressure in patients with AF, especially with preserved LV systolic function. This study was designed to examine which factors determine plasma BNP levels in patients with persistent nonvalvular AF and preserved W systolic function. Methods and results: We examined 195 clinically stable outpatients with persistent nonvalvular AF and preserved W systolic function. They underwent comprehensive 2-dimensional and Doppler echocardiography, plasma BNP and creatinine levels, clinical history, and heart rate were determined. Then we statistically analyzed the correlation between plasma BNP levels and several variables including E/e' ratio. On univariate analyses, plasma BNP levels were significantly correlated with age, LV diastolic diameter (LVDd), E/e' ratio, and mitral E wave deceleration time. In addition, plasma BNP levels were significantly higher in mates and in patients with a history of congestive heart failure and those who had been administered a beta-blocker. On multiple linear regression analyses, E/e' ratio, age, LVDd, and administration of beta-blocker were independent determinant factors of plasma BNP levels. Conclusions: Plasma BNP levels in patients with persistent AF and preserved LV systolic function are affected by E/e' ratio, age, LVDd, and administration of beta-blockers. (C) 2009 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.


Relationship of Cardio-Ankle Vascular Index (CAVI) to Carotid and Coronary Arteriosclerosis
CIRCULATION JOURNAL,72(11):1762-1767 2008(Nov.)
Author:Masayasu Izuhara; Keisuke Shioji; Shin Kadota; Osamu Baba; Yuzo Takeuchi; Takashi Uegaito; Satoru Mutsuo; Mitsuo Matsuda
Abstract:Background The cardio-ankle vascular index (CAVI) has been recently reported as a new index of aortic stiffness, which is less influenced by blood pressure than pulse wave velocity (PWV). The present study investigated the relationship between the levels of CAVI and carotid and coronary arteriosclerosis. Methods and Results The 443 consecutive patients who underwent CAVI, carotid sonography, and coronary angiography in hospital were examined. Intima-media thickness (IMT) and carotid plaque were evaluated by Ultrasonography. The severity of coronary artery disease (CAD) was evaluated by coronary angiography and the subjects were divided into 4 groups (0, no significant organic stenosis: 1, 1-vessel disease: 2, 2-vessel disease: 3, 3-vessel disease). Univariate analyses showed that both CAVI and brachial-ankle PWV (baPWV) were associated with IMT and the presence of carotid plaque. Multiple stepwise regression analyses revealed that CAVI (p=0.0427), but not baPWV, was associated with the IMT. Both CAVI (p < 0.0001) and baPWV (p=0.0140) were significantly associated with the severity of CAD. Multiple logistic analyses revealed that CAVI (p=0.0342), but not baPWV (p=0.8027), was associated with the presence of multivessel disease. Conclusion High CAVI implies progression of carotid and coronary arteriosclerosis. CAVI may be more closely linked with arteriosclerosis than baPWV. (Circ J 2008; 72: 1762- 1767)


The importance of serial cardiac troponin measurement for evaluating the response to immunosuppressive therapy for myocarditis
JOURNAL OF CARDIOLOGY,52(2):154-158 2008(Oct.)
Author:Shin Kadota; Yuzo Takeuchi; Masayasu Izuhara; Osamu Baba; Keisuke Shioji; Takashi Uegaito; Eiji Kadota; Mitsuo Matsuda
Abstract:A 71-year-old woman was admitted to our department because of acute myocarditis. She was ameliorated with conventional heart failure treatment, however she developed left ventricular dilatation and cardiac troponin T (cTnT) was elevated again to >1.0 ng/ml 6 month after the first admission. She was readmitted because of recurrent decompensated heart failure in spite of conventional treatment. Right ventricular endomyocardial biopsy revealed active myocarditis. Immunosuppressive therapy with prednisolone and azathioprine improved her symptoms and left ventricular function accompanied by a striking decrease of cTnT levels. The decreased cTnT level indicated an effective response to immunosuppression early after the beginning of treatment. These findings suggested that it is possible to evaluate the response to immunosuppressive therapy by serial measurement of cardiac troponin. (C) 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.


Long-term effects of early statin therapy for patients with acute myocardial infarction treated with stent implantation
JOURNAL OF CARDIOLOGY,51(3):171-178 2008(Jun.)
Author:Shin Kadota; Mitsuo Matsuda; Masayasu Izuhara; Osamu Baba; Soji Moriwaki; Keisuke Shioji; Yuzo Takeuchi; Takashi Uegaito
Abstract:Objectives: Statins are widely administered to patients with acute myocardial infarction (AMI), but knowledge of the effects of early statin therapy on the long-term mortality of AMI patients after stent implantation is still limited, especially for beyond low-density lipoprotein cholesterol (LDL-C) lowering effects. Methods: Our 378 consecutive AMI patients who were discharged alive from the hospital with successful stent implantation between 1997 and 2005 were included. We retrospectively evaluated the effects of statin therapy on major adverse cardiovascular events (MACE), including all-cause death, reinfarction, coronary artery bypass grafting, heart failure requiring rehospitalization, and target lesion revascularization. Results: Statins were given to 271 patients according to the physician to achieve a LDL-C level of less than 100 mg/dL. The achieved LDL-C levels in the statin group were 100.7, 95.1, 96.7, and 102.8 mg/dL at discharge, 6 months, 1 year, and 3 years, respectively, whereas those in the non-statin group were 103.2, 107.3, 102.8, and 103.0 mg/dL. These levels were not significantly different between the groups during 3 years. Based on Kaplan-Meier estimates, statin therapy was associated with a reduction of long-term mortality (log-rank test P=0.007). Multivariate Cox regression analysis revealed that statin therapy (P=0.015, hazard ratio: 0.10; 95% confidence interval: 0.01-0.64) was a significant predictor of favorable prognosis. Multivariate analysis revealed that statin treatment had a beneficial effect against MACE over 3 years (P=0.008). Conclusions: Early statin therapy was beneficial for long-term mortality of AMI patients treated with stenting. (c) 2008 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.


Cardiac tamponade due to a ruptured solitary mediastinal varix: A case report
HEART SURGERY FORUM,10(3):E199-E201 2007(Jun.)
Author:Toshio Kaneda; Masahiko Onoe; Soji Moriwaki; Shin Kadota; Osamu Baba; Mitsuo Matsuda; Eiji Kadota; Toshihiko Saga
Abstract:Mediastinal varix is rare. Some reports have noted that the mediastinal vein can become varicose in cases of portal hypertension or obstruction of the vena cava. However, solitary mediastinal varices without portal hypertension or obstruction of the vena cava are very rare. Mediastinal varicose veins have been problematic as pseudotumors, as no symptoms have been described in the literature. We encountered a case of cardiac tamponade due to a ruptured solitary mediastinal varicose vein. To the best of our knowledge, this is the first report of sustained symptomatic mediastinal varicose vein.


Intestinal decontamination using povidone-iodine compromises small bowel storage quality
TRANSPLANTATION,75(9):1460-1462 2003(May)
Author:DW Olson; S Kadota; A Cornish; KL Madsen; J Zeng; LD Jewell; DL Bigam; TA Churchill
Abstract:Background. Povidone-iodine (PI) (Betadine, Purdue Fredrick Co., Norwalk, CT) is used during pancreas transplantation to provide duodenal decontamination without any intestinal complications. Methods. This study assessed the combined effect of a luminal pretreatment with PI followed by a proven amino acid (AA)-rich preservation solution on small bowel (SB) storage quality. Rat SB was procured using intra-arterial University of Wisconsin solution followed by luminal administration with combinations of AA +/- PI pretreatment as follows: group 1, 20 m-L AA solution; group 2, 20 mL PI and 20 mL AA solution; group 3, 100 mL AA solution; and group 4, 20 mL PI and 100 mL AA solution. Cellular energetics, permeability, and histology were analyzed throughout 10-hr cold storage. Results. After 10 hr, adenosine triphosphate levels remained 2.9 to 3.2 mumol/g protein lower in the PI-treated groups than in groups 1 and 3. Functional parameters were also negatively affected by PI treatment. Mannitol permeability was 203 and 66 nmol/cm(2) per hr in groups 2 and 4 versus 46 and 44 nmol/cm(2) per hr in groups 1 and 3. Median grades of histologic injury (Park's) at 10 hr were 3, 5.5, 4, and 5 for groups I through 4, respectively. Luminal flushing with PI or AA solution resulted in an equivalent clearance greater than 95% of enteric bacteria present. Conclusion. Short-duration luminal PI exposure potentiates SB injury and provides no improved intestinal decontamination.


MISC
【不整脈治療の最新デバイステクノロジーとリードマネジメント】ペースメーカ バイオペースメーカ
循環器ジャーナル,68(3):422-427 2020(Jul.)
Author:門田 真; 柴 祐司
Abstract:<文献概要>Point ・遺伝子治療や細胞治療によるペースメーカ開発を目指した研究がある.・自動能をもつように局所的に遺伝子を発現させる,もしくは細胞を移植する.・将来的には機械式ペースメーカに代わる可能性がある.


ヒト多能性幹細胞由来心筋細胞を用いたバイオペースメーカーの開発
福田記念医療技術振興財団情報,(31):89-92 2018(Dec.)
Author:門田 真


iPS細胞を用いた新しい心不全治療法開発
心臓,49(12):1203-1207 2017
Author:門田 真; 柴 祐司


多能性幹細胞を用いた心筋再生治療
信州医学雑誌 = The Shinshu medical journal,65(3):143-152 2017
Author:門田 真; 柴 祐司


BB-R12, a Novel Gene Therapy for Heart Failure
CIRCULATION,130 2014(Nov.)
Author:Sam L. Teichman; Shin Kadota; Michael Regnier; Charles E. Murry; Michael Laflamme; Gregory G. Mahairas


PJ-168 Post-load Reduced Insulin Level is Associated with High Mortality Rates in Patients with No Previous Diagnosis of Diabetes Mellitus(PJ029,Diabetes 2 (H),Poster Session (Japanese),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)
Circulation journal : official journal of the Japanese Circulation Society,73:588-588 2009(Mar. 01)
Author:Kadota Shin; Matsuda Mitsuo; Izuhara Masayasu; Baba Osamu; Mitsuoka Hirokazu; Shioji Keisuke; Uegaito Takashi


PE-253 Assessment of the Relation between Plasma B-type Natriuretic Peptide (BNP) Concentrations and Serum Amino-terminal proBNP (Nt-proBNP) Concentrations(PE043,Heart Failure (Biomarker) 1 (M),Poster Session (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)
Circulation journal : official journal of the Japanese Circulation Society,73:462-463 2009(Mar. 01)
Author:Baba Osamu; Matsuda Mitsuo; Uegaito Takashi; Shioji Keisuke; Mitsuoka Hirokazu; Kadota Shin; Izuhara Masayasu


PE-087 The Influence of Hyperglycemia on Admission and Post-load Insulin Response for Patients with Acute Coronary Syndrome without Treated Diabetes Mellitus(PE015,ACS/AMI (Clinical/Pathophysiology) 1 (IHD),Poster Session (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)
Circulation journal : official journal of the Japanese Circulation Society,73:420-420 2009(Mar. 01)
Author:Kadota Shin; Matsuda Mitsuo; Izuhara Masayasu; Baba Osamu; Mitsuoka Hirokazu; Shioji Keisuke; Uegaito Takashi


Postload Reduced Insulin Level Is Associated With High Mortality Rates in Patients With no Previous Diagnosis of Diabetes Mellitus
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY,53(10):A347-A347 2009(Mar.)
Author:Shin Kadota; Mitsuo Matsuda; Masayasu Izuhara; Osamu Baba; Hirokazu Mitsuoka; Keisuke Shioji; Takashi Uegaito


PJ-845 Post-load hyperinsulinemia is a significant determinant factor in association with multivessel coronary artery disease in patients with impaired glucose tolerance(Diabetes / Obesity / Metabolic syndrome(16)(H),Poster Session(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)
Circulation journal : official journal of the Japanese Circulation Society,72:724-724 2008(Mar. 01)
Author:Matsuda Mitsuo; Izuhara Masayasu; Kadota Shin; Baba Osamu; Shioji Keisuke; Takeuchi Yuzo; Uegaito Takashi; Mutsuo Satoru


PJ-426 The Cardio-Ankle Vascular Index (CAVI), the Novel Aortic Stiffness Parameter, is Related with the Carotid Artery Sclerosis(Cerebrovascular circulation/Stroke(02)(H),Poster Session(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)
Circulation journal : official journal of the Japanese Circulation Society,72:619-619 2008(Mar. 01)
Author:Shioji Keisuke; Izuhara Masayasu; Kadota Shin; Baba Osamu; Takeuchi Yuzo; Uegaito Takashi; Mutsuo Satoru; Matsuda Mitsuo


OE-258 Long-term Effect of Statin Therapy for Patients with Acute Myocardial Infarction Treated with Stent Implantation(Acute myocardial infarction, clinical (diagnosis/treatment)-1, The 71st Annual Scientific Meeting of the Japanese Circulation Society)
Circulation journal : official journal of the Japanese Circulation Society,71:215-215 2007(Mar. 01)
Author:Kadota Shin; Izuhara Masayasu; Baba Osamu; Moriwaki Soji; Shioji Keisuke; Takeuchi Yuzo; Uegaito Takashi; Matsuda Mitsuo


Ischemic duodenitis
Endoscopy,37(1):91 2005(Jan.)
Author:H. Seno; S. Mikami; K. Komatsu; S. Kadota; S. Yazumi; T. Chiba

研究費
科学研究費補助金(研究代表者)
2021 - 2023 , ペースメーカー細胞を用いた自動能維持機構の解明と治療法開発 , 基盤研究(C)
2019 - 2020 , 多能性幹細胞由来心筋細胞による傷害心筋修復機構の解明 , 若手研究
2017 - 2018 , ヒト多能性幹細胞由来心筋細胞の成熟化メカニズムの解明 , 研究活動スタート支援