| Tetsuya Matoba | Last modified date：2023.12.06 |
Lecturer /
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences /
Angiocardiology /
Kyushu University Hospital
Papers
| 1. | Shunsuke Katsuki, Tetsuya Matoba, Yusuke Akiyama, Hiroshi Yoshida, Kazuhiko Kotani, Hisako Fujii, Mariko Harada-Shiba, Yutaka Ishibashi, Tatsuro Ishida, Yasushi Ishigaki, Daijiro Kabata, Yasuki Kihara, Satoshi Kurisu, Daisaku Masuda, Kota Matsuki, Takeshi Matsumura, Kenta Mori, Tomoko Nakagami, Masamitsu Nakazato, Satsuki Taniuchi, Hiroaki Ueno, Shizuya Yamashita, Hisako Yoshida, Hiroyuki Tsutsui, Tetsuo Shoji, Association of Serum Levels of Cholesterol Absorption and Synthesis Markers with the Presence of Cardiovascular Disease: The CACHE Study CVD Analysis., Journal of atherosclerosis and thrombosis, 10.5551/jat.64119, 2023.04, AIM: Serum levels of cholesterol absorption and synthesis markers have been associated with cardiovascular risk in the United States and European countries. In this study, we examined the relevance of these biomarkers and the presence of cardiovascular disease (CVD) in Japanese individuals. METHODS: The CACHE consortium, comprising of 13 research groups in Japan possessing data on campesterol, an absorption marker, and lathosterol, a synthesis marker measured by gas chromatography, compiled the clinical data using the REDCap system. RESULTS: Among the 2,944 individuals in the CACHE population, those with missing campesterol or lathosterol data were excluded. This cross-sectional study was able to analyze data from 2,895 individuals, including 339 coronary artery disease (CAD) patients, 108 cerebrovascular disease (CeVD) patients, and 88 peripheral artery disease (PAD) patients. The median age was 57 years, 43% were female, and the median low-density lipoprotein cholesterol and triglyceride levels were 118 mg/dL and 98 mg/dL, respectively. We assessed the associations of campesterol, lathosterol, and the ratio of campesterol to lathosterol (Campe/Latho ratio) with the odds of CVD using multivariable-adjusted nonlinear regression models. The prevalence of CVD, especially CAD, showed positive, inverse, and positive associations with campesterol, lathosterol, and the Campe/Latho ratio, respectively. These associations remained significant even after excluding individuals using statins and/or ezetimibe. The associations of the cholesterol biomarkers with PAD were determined weaker than those with CAD. Contrarily, no significant association was noted between cholesterol metabolism biomarkers and CeVD. CONCLUSION: This study showed that both high cholesterol absorption and low cholesterol synthesis biomarker levels were associated with high odds of CVD, especially CAD.. |
| 2. | Seiji Hokimoto, Koichi Kaikita, Satoshi Yasuda, Kenichi Tsujita, Masaharu Ishihara, Tetsuya Matoba, Yasushi Matsuzawa, Yoshiaki Mitsutake, Yoshihide Mitani, Toyoaki Murohara, Takashi Noda, Koichi Node, Teruo Noguchi, Hiroshi Suzuki, Jun Takahashi, Yasuhiko Tanabe, Atsushi Tanaka, Nobuhiro Tanaka, Hiroki Teragawa, Takanori Yasu, Michihiro Yoshimura, Yasuhide Asaumi, Shigeo Godo, Hiroki Ikenaga, Takahiro Imanaka, Kohei Ishibashi, Masanobu Ishii, Takayuki Ishihara, Yunosuke Matsuura, Hiroyuki Miura, Yasuhiro Nakano, Takayuki Ogawa, Takashi Shiroto, Hirofumi Soejima, Ryu Takagi, Akihito Tanaka, Atsushi Tanaka, Akira Taruya, Etsuko Tsuda, Kohei Wakabayashi, Kensuke Yokoi, Toru Minamino, Yoshihisa Nakagawa, Shozo Sueda, Hiroaki Shimokawa, Hisao Ogawa, JCS/CVIT/JCC 2023 Guideline Focused Update on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-22-0779, 87, 6, 879-936, 2023.03. |
| 3. | Kota Matsuki, Mariko Harada-Shiba, Mika Hori, Masatsune Ogura, Yusuke Akiyama, Hisako Fujii, Yutaka Ishibashi, Tatsuro Ishida, Yasushi Ishigaki, Daijiro Kabata, Yasuki Kihara, Kazuhiko Kotani, Satoshi Kurisu, Daisaku Masuda, Tetsuya Matoba, Takeshi Matsumura, Kenta Mori, Tomoko Nakagami, Masamitsu Nakazato, Satsuki Taniuchi, Hiroaki Ueno, Shizuya Yamashita, Hiroshi Yoshida, Hisako Yoshida, Tetsuo Shoji, Association between Familial Hypercholesterolemia and Serum Levels of Cholesterol Synthesis and Absorption Markers: The CACHE Study FH Analysis., Journal of atherosclerosis and thrombosis, 10.5551/jat.63899, 2023.01, AIM: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Familial hypercholesterolemia (FH) is a well-known inherited disorder presenting elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels and premature coronary disease. In this study, we aim to examine the differences in terms of serum markers of cholesterol metabolism between FH and non-FH individuals and to examine their associations with serum lipid levels. METHODS: In this study, we utilized data on serum markers of cholesterol metabolism, namely, lathosterol (Latho, synthesis marker), campesterol (Campe, absorption marker), and sitosterol (Sito, absorption marker) measured by gas chromatography of the CACHE consortium, which comprised of 13 research groups in Japan. Clinical data were compiled using REDCap system. Among the 2944 individuals in the CACHE population, we selected individuals without lipid-lowering medications and hemodialysis patients for this CACHE study FH analysis. Multivariable adjustment was performed to assess the associations. RESULTS: In this study, we analyzed data from 51 FH patients and 1924 non-FH individuals. After adjustment for possible confounders, the FH group was shown to have significantly higher Campe and Sito concentrations and insignificantly higher Latho concentrations than the non-FH group. These marker concentrations showed nonlinear associations with TC in the FH group. Campe/Latho and Sito/Latho ratios were significantly higher in the FH group than in the non-FH group. CONCLUSION: FH group had significantly elevated serum Campe and Sito concentrations and insignificantly elevated Latho concentrations; thus, intestinal cholesterol absorption relative to hepatic cholesterol synthesis was suggested to be elevated in patients with FH. Serum Latho, Campe, and Sito concentrations showed nonlinear associations with TC in the FH group.. |
| 4. | Daisuke Yoshida, Toru Hashimoto, Masato Katsuki, Akihito Ishikita, Yusuke Ishikawa, Takeo Fujino, Keisuke Shinohara, Shouji Matsushima, Shintaro Kinugawa, Yasuhiro Nakano, Shunsuke Katsuki, Tetsuya Matoba, Shunji Hayashidani, Hiroyuki Tsutsui, Histologic Diagnosis of Coronary Amyloidosis Using Percutaneous Transluminal Directional Atherectomy., CJC open, 10.1016/j.cjco.2022.11.009, 5, 1, 99-102, 2023.01. |
| 5. | Yasuhiro Nakano, Mitsutaka Yamamoto, Tetsuya Matoba, Shunsuke Katsuki, Soichi Nakashiro, Susumu Takase, Yusuke Akiyama, Takuya Nagata, Yasushi Mukai, Shujiro Inoue, Keiji Oi, Taiki Higo, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, Makoto Usui, Kenji Sadamatsu, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Hiroyuki Tsutsui, Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial, JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, 10.5551/jat.63507, 2022.12, Aim: Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial.Methods: The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S+E). We enrolled 79 patients (S group, 39 patients; S+E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6-8 months of follow-up.Results: After the treatment period, the S+E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9 +/- 3.7 vs. 67.7 +/- 3.8 mg/dL, p=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (0-epoxycholesterol, 40-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S +E group. IVUS analyses revealed greater plaque regression in the S+E group than in the S group (-6.14% vs. -1.18% for each group, p=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression.Conclusions: Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.. |
| 6. | Masanobu Ishii, Koichi Kaikita, Satoshi Yasuda, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Kenichi Tsujita, Rivaroxaban Monotherapy in Atrial Fibrillation and Stable Coronary Artery Disease Across Body Mass Index Categories., JACC. Asia, 10.1016/j.jacasi.2022.08.004, 2, 7, 882-893, 2022.12, BACKGROUND: The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial showed both noninferiority for efficacy and superiority for safety endpoints of rivaroxaban monotherapy compared with those of rivaroxaban plus antiplatelet therapy (combination therapy) in patients with atrial fibrillation and stable coronary artery disease. OBJECTIVES: This study sought to evaluate outcomes of rivaroxaban monotherapy in those patients across body mass index (BMI) categories. METHODS: Patients were categorized into 4 groups: underweight (BMI |
| 7. | Yasuhiro Nakano, Mitsutaka Yamamoto, Tetsuya Matoba, Shunsuke Katsuki, Soichi Nakashiro, Susumu Takase, Yusuke Akiyama, Takuya Nagata, Yasushi Mukai, Shujiro Inoue, Keiji Oi, Taiki Higo, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, Makoto Usui, Kenji Sadamatsu, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Hiroyuki Tsutsui, Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial., Journal of atherosclerosis and thrombosis, 10.5551/jat.63507, 2022.12, AIM: Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial. METHODS: The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S＋E). We enrolled 79 patients (S group, 39 patients; S＋E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6-8 months of follow-up. RESULTS: After the treatment period, the S＋E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9±3.7 vs. 67.7±3.8 mg/dL, p=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (β-epoxycholesterol, 4β-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S ＋E group. IVUS analyses revealed greater plaque regression in the S＋E group than in the S group (-6.14% vs. -1.18% for each group, p=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression. CONCLUSIONS: Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.. |
| 8. | Mitsuru Ishii, Masaharu Akao, Satoshi Yasuda, Koichi Kaikita, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Rivaroxaban Monotherapy in Patients With Atrial Fibrillation and Coronary Stenting at Multiple Vessels or the Left Main Trunk: The AFIRE Trial Subanalysis., Journal of the American Heart Association, 10.1161/JAHA.122.027107, 11, 21, e027107, 2022.11. |
| 9. | Muneo Yamaguchi, Shintaro Nakao, Iori Wada, Tetsuya Matoba, Mitsuru Arima, Yoshihiro Kaizu, Mariko Shirane, Keijiro Ishikawa, Takahito Nakama, Yusuke Murakami, Masaharu Mizuochi, Wataru Shiraishi, Ryo Yamasaki, Toshio Hisatomi, Tatsuro Ishibashi, Masabumi Shibuya, Alan W Stitt, Koh-Hei Sonoda, Identifying Hyperreflective Foci in Diabetic Retinopathy via VEGF-induced Local Self-Renewal of CX3CR1+ Vitreous Resident Macrophages., Diabetes, 10.2337/db21-0247, 71, 12, 2685-2701, 2022.10, Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P |
| 10. | Kazuo Sakamoto, Tetsuya Matoba, Michikazu Nakai, Yoshio Tahara, Takahiro Nakashima, Hayato Hosoda, Yoshihiro Miyamoto, Kunihiro Nishimura, Yoko Sumita, Tsukasa Yagi, Kenzo Ichimura, Naohiro Yonemoto, Eizo Tachibana, Ken Nagao, Takanori Ikeda, Naoki Sato, Hiroyuki Tsutsui, Clinical picture of the duration of venoarterial extracorporeal membrane oxygenation: analysis from JROAD-DPC., Heart and vessels, 10.1007/s00380-022-02158-0, 38, 2, 228-235, 2022.09, Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been widely used for critically ill patients all over the world; however, comprehensive survey regarding the relationship between VA-ECMO duration and prognosis is limited. We conducted a survey of VA-ECMO patients in the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC), which was a health insurance claim database study among cardiovascular centers associated with the Japan Circulation Society, between April 2012 and March 2016. Out of 13,542 VA-ECMO patients, we analyzed 5766 cardiovascular patients treated with VA-ECMO. 68% patients used VA-ECMO only for 1 day and 93% had VA-ECMO terminated within 1 week. In multivariate analysis, the hazard ratio of 1-day support was significantly high at 1.72 (95% confidence intervals; 95% CI 1.53-1.95) (p |
| 11. | Takeshi Matsumura, Yasushi Ishigaki, Tomoko Nakagami, Yusuke Akiyama, Yutaka Ishibashi, Tatsuro Ishida, Hisako Fujii, Mariko Harada-Shiba, Daijiro Kabata, Yasuki Kihara, Kazuhiko Kotani, Satoshi Kurisu, Daisaku Masuda, Tetsuya Matoba, Kota Matsuki, Kenta Mori, Masamitsu Nakazato, Satsuki Taniuchi, Hiroaki Ueno, Shizuya Yamashita, Hiroshi Yoshida, Hisako Yoshida, Tetsuo Shoji, Relationship between Diabetes Mellitus and Serum Lathosterol and Campesterol Levels: The CACHE Study DM Analysis., Journal of atherosclerosis and thrombosis, 10.5551/jat.63725, 30, 7, 735-753, 2022.09, AIM: Risk of cardiovascular disease is increased in patients with diabetes mellitus (DM). Cholesterol metabolism (hepatic synthesis and intestinal absorption) is known to be associated with cardiovascular risk. Next, we examined the association of DM with cholesterol absorption/synthesis. METHODS: The CACHE Consortium, which is comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured by gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were used for several analyses including this study. RESULTS: This study analyzed data from eligible 2182 individuals including 830 patients with DM; 42.2% were female, median age was 59 years, and median HbA1c of patients with DM was 7.0%. There was no difference in Latho between DM and non-DM individuals. Campe and Campe/Latho ratio were significantly lower in DM individuals than in non-DM individuals. When the associations of glycemic control markers with these markers were analyzed with multivariable-adjusted regression model using restricted cubic splines, Campe and Campe/Latho ratio showed inverse associations with glucose levels and HbA1c. However, Latho showed an inverted U-shaped association with plasma glucose, whereas Latho showed a U-shaped association with HbA1c. These associations remained even after excluding statin and/or ezetimibe users. CONCLUSION: We demonstrated that DM and hyperglycemia were independent factors for lower cholesterol absorption marker levels regardless of statin/ezetimibe use.. |
| 12. | Hiroyuki Arashi, Junichi Yamaguchi, Nobuhisa Hagiwara, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Rivaroxaban Underdose for Atrial Fibrillation with Stable Coronary Disease: The AFIRE Trial Findings., Thrombosis and haemostasis, 10.1055/s-0042-1744543, 122, 9, 1584-1593, 2022.09, BACKGROUND: Rivaroxaban monotherapy was noninferior to combination therapy (rivaroxaban plus antiplatelet therapy) in efficacy but superior in safety in the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial. Among 2,215 patients with atrial fibrillation (AF) and stable coronary artery disease (CAD), 1,378 had baseline creatinine clearance (CrCl) ≥50 mL/min and received 10 (underdose) or 15 mg/d (standard-dose) rivaroxaban. We aimed to assess the effects of rivaroxaban underdose on clinical outcomes. METHODS: We assessed efficacy endpoint (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, and death from any cause) and major bleeding in the subgroup of patients with preserved renal function in the AFIRE trial. RESULTS: Age ≥75 years, female sex, lower CrCl, heart failure, and percutaneous coronary intervention history were associated with the underdose prescription. The underdose group had a similar incidence of the efficacy endpoint (3.62 vs. 3.51% per patient-year; p = 0.871) and significantly lower incidence of major bleeding (0.82 vs. 2.17% per patient-year; p = 0.022) than the standard-dose group. In patients receiving monotherapy, the incidences of efficacy endpoint and major bleeding were similar between the groups, whereas in those receiving combination therapy, the incidence of major bleeding was significantly lower in the underdose group than that in the standard-dose group. CONCLUSION: In patients with AF, stable CAD, and preserved renal function, rivaroxaban underdose was associated with similar rates of thrombotic events but a lower incidence of hemorrhagic events than the standard dose. CLINICAL TRIAL REGISTRATION: AFIRE UMIN Clinical Trials Registry (https://www.umin.ac.jp/ctr/), number UMIN000016612, and ClinicalTrials.gov, number NCT02642419.. |
| 13. | Ryo Naito, Katsumi Miyauchi, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Rivaroxaban Monotherapy vs Combination Therapy With Antiplatelets on Total Thrombotic and Bleeding Events in Atrial Fibrillation With Stable Coronary Artery Disease: A Post Hoc Secondary Analysis of the AFIRE Trial., JAMA cardiology, 10.1001/jamacardio.2022.1561, 7, 8, 787-794, 2022.08, Importance: Appropriate regimens of antithrombotic therapy for patients with atrial fibrillation (AF) and coronary artery disease (CAD) have not yet been established. Objective: To compare the total number of thrombotic and/or bleeding events between rivaroxaban monotherapy and combined rivaroxaban and antiplatelet therapy in such patients. Design, Setting, and Participants: This was a post hoc secondary analysis of the Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease (AFIRE) open-label, randomized clinical trial. This multicenter analysis was conducted from February 23, 2015, to July 31, 2018. Patients with AF and stable CAD who had undergone percutaneous coronary intervention or coronary artery bypass grafting 1 or more years earlier or who had angiographically confirmed CAD not requiring revascularization were enrolled. Data were analyzed from September 1, 2020, to March 26, 2021. Interventions: Rivaroxaban monotherapy or combined rivaroxaban and antiplatelet therapy. Main Outcomes and Measures: The total incidence of thrombotic, bleeding, and fatal events was compared between the groups. Cox regression analyses were used to estimate the risk of subsequent events in the 2 groups, with the status of thrombotic or bleeding events that had occurred by the time of death used as a time-dependent variable. Results: A total of 2215 patients (mean [SD] age, 74 [8.2] years; 1751 men [79.1%]) were included in the modified intention-to-treat analysis. The total event rates for the rivaroxaban monotherapy group (1107 [50.0%]) and the combination-therapy group (1108 [50.0%]) were 12.2% (135 of 1107) and 19.2% (213 of 1108), respectively, during a median follow-up of 24.1 (IQR, 17.3-31.5) months. The mortality rate was 3.7% (41 of 1107) in the monotherapy group and 6.6% (73 of 1108) in the combination-therapy group. Rivaroxaban monotherapy was associated with a lower risk of total events compared with combination therapy (hazard ratio, 0.62; 95% CI, 0.48-0.80; P |
| 14. | Sunao Kojima, Takeshi Yamamoto, Migaku Kikuchi, Hiroyuki Hanada, Toshiaki Mano, Takahiro Nakashima, Katsutaka Hashiba, Akihito Tanaka, Junichi Yamaguchi, Kunihiro Matsuo, Naoki Nakayama, Osamu Nomura, Tetsuya Matoba, Yoshio Tahara, Hiroshi Nonogi, Supplemental Oxygen and Acute Myocardial Infarction ― A Systematic Review and Meta-Analysis ―, Circulation Reports, 10.1253/circrep.cr-22-0031, 4, 8, 335-344, 2022.08. |
| 15. | Katsutaka Hashiba, Takahiro Nakashima, Migaku Kikuchi, Sunao Kojima, Hiroyuki Hanada, Toshiaki Mano, Takeshi Yamamoto, Akihito Tanaka, Junichi Yamaguchi, Kunihiro Matsuo, Naoki Nakayama, Osamu Nomura, Tetsuya Matoba, Yoshio Tahara, Hiroshi Nonogi, Prehospital Activation of the Catheterization Laboratory Among Patients With Suspected ST-Elevation Myocardial Infarction Outside of a Hospital ― Systematic Review and Meta-Analysis ―, Circulation Reports, 10.1253/circrep.cr-22-0034, 2022.07. |
| 16. | Akihito Tanaka, Kunihiro Matsuo, Migaku Kikuchi, Sunao Kojima, Hiroyuki Hanada, Toshiaki Mano, Takahiro Nakashima, Katsutaka Hashiba, Takeshi Yamamoto, Junichi Yamaguchi, Naoki Nakayama, Osamu Nomura, Tetsuya Matoba, Yoshio Tahara, Hiroshi Nonogi, Systematic Review and Meta-Analysis of Diagnostic Accuracy to Identify ST-Segment Elevation Myocardial Infarction on Interpretations of Prehospital Electrocardiograms., Circulation reports, 10.1253/circrep.CR-22-0002, 4, 7, 289-297, 2022.07, Background: The aim of this study was to assess and discuss the diagnostic accuracy of prehospital ECG interpretation through systematic review and meta-analyses. Methods and Results: Relevant literature published up to July 2020 was identified using PubMed. All human studies of prehospital adult patients suspected of ST-segment elevation myocardial infarction in which prehospital electrocardiogram (ECG) interpretation by paramedics or computers was evaluated and reporting all 4 (true-positive, false-positive, false-negative, and true-negative) values were included. Meta-analyses were conducted separately for the diagnostic accuracy of prehospital ECG interpretation by paramedics (Clinical Question [CQ] 1) and computers (CQ2). After screening, 4 studies for CQ1 and 6 studies for CQ2 were finally included in the meta-analysis. Regarding CQ1, the pooled sensitivity and specificity were 95.5% (95% confidence interval [CI] 82.5-99.0%) and 95.8% (95% CI 82.3-99.1%), respectively. Regarding CQ2, the pooled sensitivity and specificity were 85.4% (95% CI 74.1-92.3%) and 95.4% (95% CI 87.3-98.4%), respectively. Conclusions: This meta-analysis suggests that the diagnostic accuracy of paramedic prehospital ECG interpretations is favorable, with high pooled sensitivity and specificity, with an acceptable estimated number of false positives and false negatives. Computer-assisted ECG interpretation showed high pooled specificity with an acceptable estimated number of false positives, whereas the pooled sensitivity was relatively low.. |
| 17. | Takahiro Nakashima, Katsutaka Hashiba, Migaku Kikuchi, Junichi Yamaguchi, Sunao Kojima, Hiroyuki Hanada, Toshiaki Mano, Takeshi Yamamoto, Akihito Tanaka, Kunihiro Matsuo, Naoki Nakayama, Osamu Nomura, Tetsuya Matoba, Yoshio Tahara, Hiroshi Nonogi, Impact of Prehospital 12-Lead Electrocardiography and Destination Hospital Notification on Mortality in Patients With Chest Pain - A Systematic Review., Circulation reports, 10.1253/circrep.CR-22-0003, 4, 5, 187-193, 2022.05, Background: To achieve early reperfusion therapy for ST-elevation myocardial infarction (STEMI), proper and prompt patient transportation and activation of the catheterization laboratory are required. We investigated the efficacy of prehospital 12-lead electrocardiogram (ECG) acquisition and destination hospital notification in patients with STEMI. Methods and Results: This is a systematic review of observational studies. We searched the PubMed database from inception to March 2020. Two reviewers independently performed literature selection. The critical outcome was short-term mortality. The important outcome was door-to-balloon (D2B) time. We used the GRADE approach to assess the certainty of the evidence. For the critical outcome, 14 studies with 29,365 patients were included in the meta-analysis. Short-term mortality was significantly lower in the group with prehospital 12-lead ECG acquisition and destination hospital notification than in the control group (odds ratio 0.72; 95% confidence interval [CI] 0.61-0.85; P |
| 18. | Osamu Nomura, Katsutaka Hashiba, Migaku Kikuchi, Sunao Kojima, Hiroyuki Hanada, Toshiaki Mano, Takeshi Yamamoto, Takahiro Nakashima, Akihito Tanaka, Naoki Nakayama, Junichi Yamaguchi, Kunihiro Matsuo, Tetsuya Matoba, Yoshio Tahara, Hiroshi Nonogi, Performance of the 0-Hour/1-Hour Algorithm for Diagnosing Myocardial Infarction in Patients With Chest Pain in the Emergency Department ― A Systematic Review and Meta-Analysis ―, Circulation Reports, 10.1253/circrep.cr-22-0001, 2022.04. |
| 19. | Tetsuo Shoji, Yusuke Akiyama, Hisako Fujii, Mariko Harada-Shiba, Yutaka Ishibashi, Tatsuro Ishida, Yasushi Ishigaki, Daijiro Kabata, Yasuki Kihara, Kazuhiko Kotani, Satoshi Kurisu, Daisaku Masuda, Tetsuya Matoba, Kota Matsuki, Takeshi Matsumura, Kenta Mori, Tomoko Nakagami, Masamitsu Nakazato, Satsuki Taniuchi, Hiroaki Ueno, Shizuya Yamashita, Hisako Yoshida, Hiroshi Yoshida, Association of Kidney Function with Serum Levels of Cholesterol Absorption and Synthesis Markers: The CACHE Study CKD Analysis., Journal of atherosclerosis and thrombosis, 10.5551/jat.63311, 29, 12, 1835-1848, 2022.03, AIM: Serum levels of cholesterol absorption and synthesis markers are known to be associated with cardiovascular risk. Individuals with reduced kidney function or chronic kidney disease (CKD) are at an increased risk for cardiovascular disease. Hence, we examined the relationship between estimated glomerular filtration rate (eGFR) and serum markers of cholesterol absorption and synthesis. METHODS: The CACHE (Cholesterol Absorption and Cholesterol synthesis in High-risk patiEnts) Consortium, comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured via gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were utilized for five analyses including this CKD analysis. RESULTS: This study analyzed data from 2200 individuals including 522 hemodialysis patients; 42.3% were female, the median age was 58 years, and the median eGFR was 68.9 mL/min/1.73 m2. Latho, Campe, and Campe/Latho ratio were significantly different when compared across CKD stages. When the associations of eGFR with these markers were assessed with multivariable nonlinear regression models, Latho, Campe, and Campe/Latho ratio showed positive, inverse, and inverse associations with eGFR. These associations were significantly modified by sex, the presence/absence of diabetes mellitus, and the presence/absence of statin use. CONCLUSION: We showed that individuals with lower eGFR have lower cholesterol synthesis marker levels and higher cholesterol absorption marker levels in this large sample.. |
| 20. | Junichi Yamaguchi, Tetsuya Matoba, Migaku Kikuchi, Yuichiro Minami, Sunao Kojima, Hiroyuki Hanada, Toshiaki Mano, Takahiro Nakashima, Katsutaka Hashiba, Takeshi Yamamoto, Akihito Tanaka, Kunihiro Matsuo, Naoki Nakayama, Osamu Nomura, Yoshio Tahara, Hiroshi Nonogi, Effects of Door-In to Door-Out Time on Mortality Among ST-Segment Elevation Myocardial Infarction Patients Transferred for Primary Percutaneous Coronary Intervention - Systematic Review and Meta-Analysis., Circulation reports, 10.1253/circrep.CR-21-0160, 4, 3, 109-115, 2022.03, Background: Primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is now widely accepted. Recent guidelines have focused on total ischemic time, because shorter total ischemic time is associated with a more favorable prognosis. The door-in to door-out (DIDO) time, defined as time from arrival at a non-PCI-capable hospital to leaving for a PCI-capable hospital, may affect STEMI patient prognosis. However, a relevant meta-analysis is lacking. Methods and Results: We searched PubMed for clinical studies comparing short-term (30-day and in-hospital) mortality rates of STEMI patients undergoing primary PCI with DIDO times of ≤30 vs. >30 min. Two investigators independently screened the search results and extracted the data. Random effects estimators with weights calculated by the inverse variance method were used to determine pooled risk ratios. The search retrieved 1,260 studies; of these, 2 retrospective cohort studies (15,596 patients) were analyzed. In the DIDO time ≤30 and >30 min groups, the primary endpoint (i.e., in-hospital or 30-day mortality) occurred for 51 of 1,794 (2.8%) and 831 of 13,802 (6.0%) patients, respectively. The incidence of the primary endpoint was significantly lower in the DIDO time ≤30 min group (odds ratio 0.45; 95% confidence interval 0.34-0.60). Conclusions: Our findings suggest that a DIDO time ≤30 min is associated with a lower short-term mortality rate. However, further larger systematic reviews and meta-analyses are needed to validate our findings.. |
| 21. | Kunihiko Matsui, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Hisao Ogawa, The impact of kidney function in patients on antithrombotic therapy: a post hoc subgroup analysis focusing on recurrent bleeding events from the AFIRE trial., BMC medicine, 10.1186/s12916-022-02268-6, 20, 1, 69-69, 2022.02, BACKGROUND: The success of antithrombotic therapies is assessed based on thrombotic and bleeding events. Simultaneously assessing both kinds of events might be challenging, and recurrent bleeding events are often ignored. We tried to confirm the effects of kidney function on outcome events in patients undergoing antithrombotic therapy. METHODS: As a post hoc subgroup analysis of the Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial, a randomized clinical trial with a median follow-up of 36 months, patients were divided into high and low estimated glomerular filtration rate (eGFR) groups with a cutoff value of 50 mL/min. The cumulative incidence of bleeding and crude incidence of recurrent bleeding per 100 patient-years were calculated. We used the Cox regression model with multiple failure time data for recurrent bleeding events. RESULTS: Among 2092 patients, 1386 (66.3%) showed high eGFR. The cumulative bleeding events per 100 patients at 1 year were 5.4 and 6.2 in the high and low eGFR groups, respectively. The difference continued to increase over time. The hazard ratio for time to the first bleeding event in the high eGFR group was 0.875 (95% confidence interval 0.701-1.090, p = .234) and that for the first composite event was 0.723 (95% confidence interval 0.603-0.867, p |
| 22. | Hidehira Fukaya, Junya Ako, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Tetsuya Matoba, Masato Nakamra, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Aspirin versus P2Y12 inhibitors with anticoagulation therapy for atrial fibrillation., Heart (British Cardiac Society), 10.1136/heartjnl-2021-319321, 107, 21, 1731-1738, 2021.11, OBJECTIVE: Patients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y12 inhibitors and aspirin in patients also receiving anticoagulant therapy. METHODS: We evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician's discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y12 inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria. RESULTS: A total of 1075 patients were included (P2Y12 inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456). CONCLUSIONS: There were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y12 inhibitors or aspirin in the chronic phase. TRIAL REGISTRATION NUMBER: UMIN000016612; NCT02642419.. |
| 23. | Tetsuya Matoba, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Rivaroxaban Monotherapy in Patients With Atrial Fibrillation After Coronary Stenting: Insights From the AFIRE Trial., JACC. Cardiovascular interventions, 10.1016/j.jcin.2021.07.045, 14, 21, 2330-2340, 2021.11, OBJECTIVES: The aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting. BACKGROUND: Of 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment. METHODS: The benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment. RESULTS: Efficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097). CONCLUSIONS: In patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612, NCT02642419).. |
| 24. | Yasushi Matsuzawa, Kazuo Kimura, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Antithrombotic Therapy for Atrial Fibrillation and Coronary Artery Disease in Patients With Prior Atherothrombotic Disease: A Post Hoc Analysis of the AFIRE Trial, Journal of the American Heart Association, 10.1161/JAHA.121.020907, 10, 21, e020907, 2021.10, Background Among patients with atrial fibrillation and stable coronary artery disease, those with histories of atherothrombotic disease are at high-risk for future ischemic events. This study investigated the efficacy and safety of rivaroxaban monotherapy in patients with atrial fibrillation, coronary artery disease, and histories of atherothrombotic disease. Methods and Results This was a post hoc subanalysis of the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial. Patients with non-valvular atrial fibrillation and coronary artery disease were recruited and randomized to receive the rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. For the purpose of this sub-study, participants were divided into 2 subgroups, including the atherothrombosis group (those with histories of myocardial infarction, stroke, and/or peripheral artery disease; n=1052, 47.5%) and non-atherothrombosis group (n=1163, 52.5%). The efficacy end point included cardiovascular events or all-cause death, while the safety end point was major bleeding. Net adverse events consisted of all-cause death, myocardial infarction, stroke, or major bleeding. In the atherothrombosis group, rivaroxaban monotherapy was significantly associated with a lower risk of net adverse events when compared with combination therapy (hazard ratio [HR], 0.50; 95% CI, 0.34-0.74; P |
| 25. | Yoshiyuki Yazaki, Masato Nakamura, Raisuke Iijima, Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Clinical Outcomes of Rivaroxaban Monotherapy in Heart Failure Patients With Atrial Fibrillation and Stable Coronary Disease: Insights From the AFIRE Trial, Circulation, 10.1161/CIRCULATIONAHA.121.055374, 144, 17, 1449-1451, 2021.10. |
| 26. | Koichi Kaikita, Satoshi Yasuda, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Bleeding and Subsequent Cardiovascular Events and Death in Atrial Fibrillation With Stable Coronary Artery Disease: Insights From the AFIRE Trial, Circulation: Cardiovascular Interventions, 10.1161/CIRCINTERVENTIONS.120.010476, 14, 11, CIRCINTERVENTIONS120010476, 2021.09, BACKGROUND: Early bleeding after percutaneous coronary intervention is associated with increased risk of death and myocardial infarction; however, the association between bleeding and subsequent major adverse cardiac and cerebrovascular events (MACCE) remains unclear in patients with atrial fibrillation and stable coronary artery disease. We thus aimed to investigate this association. METHODS: The AFIRE trial (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) was a multicenter, open-label trial conducted in Japan. This post hoc analysis included 2215 patients with atrial fibrillation and stable coronary artery disease treated with rivaroxaban or rivaroxaban plus an antiplatelet agent. MACCE was defined as a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. The association of bleeding with subsequent MACCE risk was investigated using time-adjusted Cox multivariate analysis after adjusting for baseline characteristics and time from bleeding. Bleeding events were classified according to the International Society on Thrombosis and Haemostasis criteria. RESULTS: Among the 2215 patients, 386 (17.4%) had bleeding during follow-up, of whom 63 (16.3%) also experienced MACCE; MACCE incidence was higher in patients with bleeding than in those without (8.38% versus 4.20% per patient-year; hazard ratio, 2.01 [95% CI, 1.49-2.70]; P |
| 27. | Tomohiro Minakawa, Tetsuya Matoba, Fumiyoshi Ishidate, Takahiro K Fujiwara, Sho Takehana, Yasuhiko Tabata, Jun K Yamashita, Extracellular vesicles synchronize cellular phenotypes of differentiating cells., Journal of extracellular vesicles, 10.1002/jev2.12147, 10, 11, e12147, 2021.09, During embryonic development, cells differentiate in a coordinated manner, aligning their fate decisions and differentiation stages with those of surrounding cells. However, little is known about the mechanisms that regulate this synchrony. Here we show that cells in close proximity synchronize their differentiation stages and cellular phenotypes with each other via extracellular vesicle (EV)-mediated cellular communication. We previously established a mouse embryonic stem cell (ESC) line harbouring an inducible constitutively active protein kinase A (CA-PKA) gene and found that the ESCs rapidly differentiated into mesoderm after PKA activation. In the present study, we performed a co-culture of Control-ESCs and PKA-ESCs, finding that both ESC types rapidly differentiated in synchrony even when PKA was activated only in PKA-ESCs, a phenomenon we named 'Phenotypic Synchrony of Cells (PSyC)'. We further demonstrated PSyC was mediated by EVs containing miR-132. PKA-ESC-derived EVs and miR-132-containing artificial nano-vesicles similarly enhanced mesoderm and cardiomyocyte differentiation in ESCs and ex vivo embryos, respectively. PSyC is a new form of cell-cell communication mediated by the EV regulation of neighbouring cells and could be broadly involved in tissue development and homeostasis.. |
| 28. | Tetsuya Matoba, Hiroyuki Tsutsui, Pursuit of Optimal Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-21-0645, 85, 10, 1849-1850, 2021.09. |
| 29. | Masaharu Akao, Satoshi Yasuda, Koichi Kaikita, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Rivaroxaban monotherapy versus combination therapy according to patient risk of stroke and bleeding in atrial fibrillation and stable coronary disease: AFIRE trial subanalysis., American heart journal, 10.1016/j.ahj.2021.02.021, 236, 59-68, 2021.06, BACKGROUND: In the AFIRE trial, rivaroxaban monotherapy was noninferior to combination therapy with rivaroxaban and an antiplatelet agent for thromboembolic events or death, and superior for major bleeding in patients with atrial fibrillation (AF) and stable coronary artery disease. Little is known about impacts of stroke and bleeding risks on the efficacy and safety of rivaroxaban monotherapy. METHODS: In this subanalysis of the AFIRE trial, we assessed the risk of stroke and bleeding by the CHADS2, CHA2DS2-VASc, and HAS-BLED scores. The primary efficacy end point was the composite of stroke, systemic embolism, myocardial infarction (MI), unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding defined by the International Society on Thrombosis and Haemostasis. RESULTS: Rivaroxaban monotherapy significantly reduced the primary efficacy and safety end points with no evidence of differential effects by stroke risk (CHADS2, p for interaction = 0.727 for efficacy, 0.395 for safety; CHA2DS2-VASc, p for interaction = 0.740 for efficacy, 0.265 for safety) or bleeding risk (HAS-BLED, p for interaction = 0.581 for efficacy, 0.225 for safety). There was also no evidence of statistical heterogeneity across patient risk categories for other end points; stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, MI, MI or unstable angina, death from any cause, any bleeding, or net adverse clinical events. CONCLUSIONS: The advantages of rivaroxaban monotherapy compared with those of combination therapy with respect to all prespecified end points, including thromboembolism, bleeding, and mortality were similar across patients with AF and stable coronary artery disease, irrespective of their risk for stroke and bleeding. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry number, UMIN000016612, and ClinicalTrials.gov number, NCT02642419.. |
| 30. | Gentaro Ikeda, Tetsuya Matoba, Ayako Ishikita, Kazuhiro Nagaoka, Kaku Nakano, Jun‐ichiro Koga, Hiroyuki Tsutsui, Kensuke Egashira, Nanoparticle‐Mediated Simultaneous Targeting of Mitochondrial Injury and Inflammation Attenuates Myocardial Ischemia‐Reperfusion Injury, Journal of the American Heart Association, 10.1161/JAHA.120.019521, 10, 12, e019521, 2021.06, Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia-reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle-mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C-C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30-45 minutes) after reperfusion, whereas C-C chemokine receptor 2 contributes to IR injury at later time point (45-60 minutes) after reperfusion. Double deficiency of CypD and C-C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C-C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly-6Chigh monocytes after myocardial IR injury. In CypD-knockout mice, administration of interleukin-1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly-lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte-mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle-mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.. |
| 31. | Tetsuya Matoba, Kazuo Sakamoto, Michikazu Nakai, Kenzo Ichimura, Masahiro Mohri, Yasuyuki Tsujita, Masao Yamasaki, Yasushi Ueki, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Satoru Suwa, Hirohide Matsuura, Hayato Hosoda, Takahiro Nakashima, Yoshio Tahara, Yoko Sumita, Kunihiro Nishimura, Yoshihiro Miyamoto, Naohiro Yonemoto, Tsukasa Yagi, Eizo Tachibana, Ken Nagao, Takanori Ikeda, Naoki Sato, Hiroyuki Tsutsui, Institutional Characteristics and Prognosis of Acute Myocardial Infarction With Cardiogenic Shock in Japan - Analysis From the JROAD/JROAD-DPC Database., Circulation journal : official journal of the Japanese Circulation Society, 10.1253/circj.CJ-20-0655, 85, 10, 1797-1805, 2021.03, BACKGROUND: The high mortality of acute myocardial infarction (AMI) with cardiogenic shock (i.e., Killip class IV AMI) remains a challenge in emergency cardiovascular care. This study aimed to examine institutional factors, including the number of JCS board-certified members, that are independently associated with the prognosis of Killip class IV AMI patients.Methods and Results:In the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (years 2012-2016), the 30-day mortality of Killip class IV AMI patients (n=21,823) was 42.3%. Multivariate analysis identified age, female sex, admission by ambulance, deep coma, and cardiac arrest as patient factors that were independently associated with higher 30-day mortality, and the numbers of JCS board-certified members and of intra-aortic balloon pumping (IABP) cases per year as institutional factors that were independently associated with lower mortality in Killip class IV patients, although IABP was associated with higher mortality in Killip classes I-III patients. Among hospitals with the highest quartile (≥9 JCS board-certified members), the 30-day mortality of Killip class IV patients was 37.4%. CONCLUSIONS: A higher numbers of JCS board-certified members was associated with better survival of Killip class IV AMI patients. This finding may provide a clue to optimizing local emergency medical services for better management of AMI patients in Japan.. |
| 32. | Yusuke Akiyama, Tetsuya Matoba, Shunsuke Katsuki, Susumu Takase, Soichi Nakashiro, Yasuhiro Nakano, Kensuke Noma, Hiroyuki Tsutsui, Comparison of Endothelial Dysfunction in Coronary Arteries with Bare Metal and 2nd-Generation Drug-Eluting Stents., Journal of atherosclerosis and thrombosis, 10.5551/jat.61366, 2021.02, AIMS: Previous studies suggested that implantation with a 1st-generation DES was associated with coronary endothelial dysfunction, which was associated with Rho-kinase activation. Second-generation drug-eluting stents (DESs) may preserve coronary endothelial function in stented coronary arteries; however, because of methodological limitations, further study is needed to clarify the association between 2nd-generation DESs and coronary endothelial dysfunction. METHODS: We retrospectively analysed the CuVIC trial database, where we identified 112 patients who underwent coronary stenting in the left coronary arteries with either a bare metal stent (BMS, n=53) or 2nd-generation DES (n=59). We compared vasomotions of target vessels with stents and non-target vessels without stents. Furthermore, we measured the Rho-kinase activation detected in mononucleocytes from aortic and coronary sinus blood. RESULTS: ACh-induced vasoconstrictive responses of target vessels were not enhanced with a 2nd-generation DES (45±21% vs. 44±20%, P=0.56, paired t-test), but significantly enhanced in the coronary arteries with a BMS (50±18% vs. 42±20%, P=0.002). Rho-kinase activation did not differ between patients with a BMS and 2nd-generation DES. In the target vessels with a BMS, large late lumen loss and acute coronary syndrome (ACS) at the index percutaneous coronary intervention (PCI) were associated with ACh-induced enhanced coronary vasoconstrictive responses. CONCLUSIONS: Evaluation of ACh-induced vasomotion of target vessels comparing with non-target vessels revealed that 2nd-generation DESs were not associated with coronary endothelial dysfunction in target vessels, nor activation of Rho-kinase in the coronary sinus blood 6-8 months after stenting.. |
| 33. | Tetsuya Matoba, Influenza and Pneumococcal Vaccination in Coronary Artery Disease., Journal of atherosclerosis and thrombosis, 10.5551/jat.ED160, 2021.02. |
| 34. | Shunsuke Katsuki, Jun-Ichiro Koga, Tetsuya Matoba, Ryuta Umezu, Soichi Nakashiro, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apoe－/－ Mice., Journal of atherosclerosis and thrombosis, 10.5551/jat.54379, 29, 1, 111-125, 2021.01, AIM: Abdominal aortic aneurysm (AAA) is a lethal and multifactorial disease. To prevent a rupture and dissection of enlarged AAA, prophylactic surgery and stenting are currently available. There are, however, no medical therapies preventing these complications of AAA. Statin is one of the candidates, but its efficacy on AAA formation/progression remains controversial. We have previously demonstrated that nanoparticles (NPs) incorporating pitavastatin (Pitava-NPs)-clinical trials using these nanoparticles have been already conducted-suppressed progression of atherosclerosis in apolipoprotein E-deficient (Apoe－/－) mice. Therefore, we have tested a hypothesis that monocytes/macrophages-targeting delivery of pitavastatin prevents the progression of AAA. METHODS: Angiotensin II was intraperitoneally injected by osmotic mini-pumps to induce AAA formation in Apoe－/－ mice. NPs consisting of poly(lactic-co-glycolic acid) were used for in vivo delivery of pitavastatin to monocytes/macrophages. RESULTS: Intravenously administered Pitava-NPs (containing 0.012 mg/kg/week pitavastatin) inhibited AAA formation accompanied with reduction of macrophage accumulation and monocyte chemoattractant protein-1 (MCP-1) expression. Ex vivo molecular imaging revealed that Pitava-NPs not only reduced macrophage accumulation but also attenuated matrix metalloproteinase activity in the abdominal aorta, which was underpinned by attenuated elastin degradation. CONCLUSION: These results suggest that Pitava-NPs inhibit AAA formation associated with reduced macrophage accumulation and MCP-1 expression. This clinically feasible nanomedicine could be an innovative therapeutic strategy that prevents devastating complications of AAA.. |
| 35. | Arihide Okahara, Jun-Ichiro Koga, Tetsuya Matoba, Masaki Fujiwara, Masaki Tokutome, Gentaro Ikeda, Kaku Nakano, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Hiroyuki Tsutsui, Kensuke Egashira, Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia-reperfusion injury., Scientific reports, 10.1038/s41598-020-71326-x, 10, 1, 14435-14435, 2020.09, Ischemia-reperfusion injury impairs the efficacy of reperfusion therapy after ischemic stroke. Cyclophilin D (CypD)-mediated openings of mitochondrial permeability transition pore (mPTP) and subsequent monocyte-mediated inflammation are considered as major mechanisms of reperfusion injury. However, no medical therapies are currently available. Therefore, we have tested a hypothesis that simultaneous targeting of mPTP and inflammation confers substantial neuroprotection after cerebral ischemia-reperfusion. To address this point, we prepared CypD knockout mice, C-C chemokine receptor 2 (CCR2) knockout mice and CypD/CCR2 double knockout mice. These mice were subjected to 60 min transient cerebral ischemia by occluding middle cerebral arteries. Neurological deficits evaluated 3 days after reperfusion were significantly attenuated in CypD/CCR2 double knockout mice as compared to wild-type mice and other single knockout mice. Then, we have prepared polymeric nanoparticles containing cyclosporine A (CsA-NPs) and pitavastatin (Pitava-NPs), targeting mPTP opening and inflammation, respectively. Simultaneous administration of CsA-NP and Pitava-NP at the time of reperfusion also decreased infarct size and attenuated neurological deficits as compared to control nanoparticles and single administration of CsA-NPs or Pitava-NPs. These results indicate that simultaneous targeting of the mPTP opening and monocyte-mediated inflammation could be a novel strategy for better neurological outcomes in patients with ischemic stroke.. |
| 36. | Masaharu Nakayama, Kazuya Takehana, Takahide Kohro, Tetsuya Matoba, Hiroyuki Tsutsui, Ryozo Nagai, Standard Export Data Format for Extension Storage of Standardized Structured Medical Information Exchange., Circulation reports, 10.1253/circrep.CR-20-0077, 2, 10, 587-616, 2020.09, Background: In the era of big data, the utilization and analysis of large amounts of clinical data are imperative. The standardized structured medical information exchange version 2 (SS-MIX2) is a standard data storage format used in Japan to share clinical data from various vendor-derived hospital information systems. This storage format is divided into 2 categories: standardized and extension storage. Although the standardized storage includes clinical data such as basic patient data, prescriptions, and laboratory results, all other data are stored in the extension storage, because their formats are not standardized. Methods and Results: In 2015, the Japanese Circulation Society developed the standard export data format (SEAMAT) for electrocardiography (ECG), ultrasound cardiography (UCG), and catheterization (CATH) data for the SS-MIX2 extension storage. Using physical examination and catheter report systems in accordance with the SEAMAT, specific cardiological data such as ECG, UCG, and CATH can be transferred to the SS-MIX2 extension storage, resulting in efficient secondary use of these data for research purposes. Conclusions: SEAMAT can aid in the effective establishment of a nationwide clinical database, and reduce tedious manual data input by clinicians and clinical research coordinators. Moreover, a program that enables the conversion of comma-separated data from information systems into SEAMAT can provide a useful and economical tool for transferring huge clinical data to the SS-MIX2.. |
| 37. | Ryuta Umezu, Jun-Ichiro Koga, Tetsuya Matoba, Shunsuke Katsuki, Lixiang Wang, Nao Hasuzawa, Masatoshi Nomura, Hiroyuki Tsutsui, Kensuke Egashira, Macrophage (Drp1) Dynamin-Related Protein 1 Accelerates Intimal Thickening After Vascular Injury., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.120.314383, 40, 7, e214-e226, 2020.07, [URL], OBJECTIVE: Mitochondria consistently change their morphology in a process regulated by proteins, including Drp1 (dynamin-related protein 1), a protein promoting mitochondrial fission. Drp1 is involved in the mechanisms underlying various cardiovascular diseases, such as myocardial ischemia/reperfusion injury, heart failure, and pulmonary arterial hypertension. However, its role in macrophages, which promote various vascular diseases, is poorly understood. We therefore tested our hypothesis that macrophage Drp1 promotes vascular remodeling after injury. METHOD AND RESULTS: To explore the selective role of macrophage Drp1, we created macrophage-selective Drp1-deficient mice and performed femoral arterial wire injury. In these mice, intimal thickening and negative remodeling were attenuated at 4 weeks after injury when compared with control mice. Deletion of macrophage Drp1 also attenuated the macrophage accumulation and cell proliferation in the injured arteries. Gain- and loss-of-function experiments using cultured macrophages indicated that Drp1 induces the expression of molecules associated with inflammatory macrophages. Morphologically, mitochondrial fission was induced in inflammatory macrophages, whereas mitochondrial fusion was induced in less inflammatory/reparative macrophages. Pharmacological inhibition or knockdown of Drp1 decreased the mitochondrial reactive oxygen species and chemotactic activity in cultured macrophages. Co-culture experiments of macrophages with vascular smooth muscle cells indicated that deletion of macrophage Drp1 suppresses growth and migration of vascular smooth muscle cells induced by macrophage-derived soluble factors. CONCLUSIONS: Macrophage Drp1 accelerates intimal thickening after vascular injury by promoting macrophage-mediated inflammation. Macrophage Drp1 may be a potential therapeutic target of vascular diseases.. |
| 38. | Satoshi Yasuda, Koichi Kaikita, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Hisao Ogawa, Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease., The New England journal of medicine, 10.1056/NEJMoa1904143, 381, 12, 1103-1113, 2019.09, BACKGROUND: There are limited data from randomized trials evaluating the use of antithrombotic therapy in patients with atrial fibrillation and stable coronary artery disease. METHODS: In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring revascularization to receive monotherapy with rivaroxaban (a non-vitamin K antagonist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority. RESULTS: The trial was stopped early because of increased mortality in the combination-therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient-year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P |
| 39. | Kazuo Sakamoto, Tetsuya Matoba, Masahiro Mohri, Yasushi Ueki, Yasuyuki Tsujita, Masao Yamasaki, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Satoru Suwa, Hirohide Matsuura, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, Clinical characteristics and prognostic factors in acute coronary syndrome patients complicated with cardiogenic shock in Japan: analysis from the Japanese Circulation Society Cardiovascular Shock Registry., Heart and vessels, 10.1007/s00380-019-01354-9, 34, 8, 1241-1249, 2019.08, Cardiogenic shock frequently leads to death even with intensive treatment. Although the leading cause of cardiogenic shock is acute coronary syndrome (ACS), the clinical characteristics and the prognosis of ACS with cardiogenic shock in the present era still remain to be elucidated. We analyzed clinical characteristics and predictors of 30-day mortality in ACS with cardiogenic shock in Japan. The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multicenter, cohort study. Between May 2012 and June 2014, 495 ACS patients with cardiogenic shock were analyzed. The primary endpoint was 30-day all-cause mortality. The median [interquartile range; IQR] age was 71.0 [63.0, 80.0] years. The median [IQR] value of systolic blood pressure (SBP) and heart rate were 75.0 [50.0, 86.5] mm Hg and 65.0 [38.0, 98.0] bpm, respectively. Multivariable analysis showed an odds ratio (OR) of 4.76 (confidence intervals; CI 1.97-11.5, p |
| 40. | Masaki Fujiwara, Tetsuya Matoba, Jun-Ichiro Koga, Arihide Okahara, Daiki Funamoto, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Nanoparticle incorporating Toll-like receptor 4 inhibitor attenuates myocardial ischaemia-reperfusion injury by inhibiting monocyte-mediated inflammation in mice., Cardiovascular research, 10.1093/cvr/cvz066, 115, 7, 1244-1255, 2019.06, AIMS: Myocardial ischaemia-reperfusion (IR) injury hampers the therapeutic effect of revascularization in patients with acute myocardial infarction (AMI). Innate immunity for damage-associated protein patterns promotes the process of IR injury; however, the blockade of Toll-like receptor 4 (TLR4) in myocardial IR injury has not been translated into clinical practice. Therefore, we aimed to examine whether the nanoparticle-mediated administration of TAK-242, a chemical inhibitor of TLR4, attenuates myocardial IR injury in a clinically feasible protocol in a mouse model. METHODS AND RESULTS: We have prepared poly-(lactic-co-glycolic acid) nanoparticles containing TAK-242 (TAK-242-NP). TAK-242-NP significantly enhanced the drug delivery to monocytes/macrophages in the spleen, blood, and the heart in mice. Intravenous administration of TAK-242-NP (containing 1.0 or 3.0 mg/kg TAK-242) at the time of reperfusion decreased the infarct size, but the TAK-242 solution did not even when administered at a dosage of 10.0 mg/kg. TAK-242-NP inhibited the recruitment of Ly-6Chigh monocytes to the heart, which was accompanied by decreased circulating HMGB1, and NF-κB activation and cytokine expressions in the heart. TAK-242-NP did not decrease the infarct size further in TLR4-deficient mice, confirming the TLR4-specific mechanism in the effects of TAK-242-NP. Furthermore, TAK-242-NP did not decrease the infarct size further in CCR2-deficient mice, suggesting that monocyte/macrophage-mediated inflammation is the primary therapeutic target of TAK-242-NP. CONCLUSION: The nanoparticle-mediated delivery of TAK-242-NP represent a novel and clinical feasible strategy in patients undergone coronary revascularization for AMI by regulating TLR4-dependent monocytes/macrophages-mediated inflammation.. |
| 41. | Yasushi Ueki, Masahiro Mohri, Tetsuya Matoba, Toshiaki Kadokami, Satoru Suwa, Tsukasa Yagi, Hiroshi Takahashi, Nobuhiro Tanaka, Yohei Hokama, Rei Fukuhara, Ken Onitsuka, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, Prognostic value of neurological status on hospital arrival for short-term outcome in patients with cardiovascular shock - Sub-analysis of the Japanese circulation society cardiovascular shock registry ―, Circulation Journal, 10.1253/circj.CJ-18-1323, 83, 6, 1247-1253, 2019.05, © 2019, Japanese Circulation Society. All rights reserved. Background: Consciousness disturbance is one of the major clinical signs associated with shock state, but its prognostic value has not been previously evaluated in cardiovascular shock patients. We aimed to evaluate the prognostic value of neurological status for 30-day mortality in cardiovascular shock patients without out-of-hospital cardiac arrest (OHCA). Methods and Results: Patients with out-of-hospital onset cardiovascular shock were recruited from the Japanese Circulation Society Shock Registry. Neurological status upon hospital arrival was evaluated using the Japan Coma Scale (JCS). Patients were divided into 4 groups according to the JCS: alert, JCS 0; awake, JCS 1–3 (not fully alert but awake without any stimuli); arousable, JCS 10–30 (arousable with stimulation); and coma JCS 100–300 (unarousable). The primary endpoint was 30-day all-cause death. In total, 700 cardiovascular shock patients without OHCA were assessed. The coma group was associated with a higher incidence of 30-day all-cause death compared with other groups (alert, 15.3%; awake, 24.4%; arousable, 36.8%; coma, 48.5%, P |
| 42. | Tetsuya Matoba, Takahide Kohro, Hideo Fujita, Masaharu Nakayama, Arihiro Kiyosue, Yoshihiro Miyamoto, Kunihiro Nishimura, Hideki Hashimoto, Yasuaki Antoku, Naoki Nakashima, Kazuhiko Ohe, Hisao Ogawa, Hiroyuki Tsutsui, Ryozo Nagai, Architecture of the Japan Ischemic Heart Disease Multimodal Prospective Data Acquisition for Precision Treatment (J-IMPACT) System., International heart journal, 10.1536/ihj.18-113, 60, 2, 264-270, 2019.03, The utilization of electronic medical records and multimodal medical data is an ideal approach to build a real-time and precision registry type study with a smaller effort and cost, which may fill a gap between evidence-based medicine and the real-world clinical practice. The Japan Ischemic heart disease Multimodal Prospective data Acquisition for preCision Treatment (J-IMPACT) project aimed to build an clinical data registry system that electronically collects not only medical records, but also multimodal data, including coronary angiography and percutaneous coronary intervention (PCI) report, in standardized data formats for clinical studies.The J-IMPACT system comprises the standardized structured medical information exchange (SS-MIX), coronary angiography and intervention reporting system (CAIRS), and multi-purpose clinical data repository system (MCDRS) interconnected within the institutional network. In order to prove the concept, we acquired multimodal medical data of 6 consecutive cases that underwent PCI through the J-IMPACT system in a single center. Data items regarding patient background, laboratory data, prescriptions, and PCI/cardiac catheterization report were correctly acquired through the J-IMPACT system, and the accuracy of the multimodal data of the 4 categories was 100% in all 6 cases.The application of J-IMPACT system to clinical studies not only fills the gaps between randomized clinical trials and real-world medicine, but may also provide real-time big data that reinforces precision treatment for each patient.. |
| 43. | Masaki Tokutome, Tetsuya Matoba, Yasuhiro Nakano, Arihide Okahara, Masaki Fujiwara, Jun-Ichiro Koga, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Peroxisome proliferator-activated receptor-gamma targeting nanomedicine promotes cardiac healing after acute myocardial infarction by skewing monocyte/macrophage polarization in preclinical animal models., Cardiovascular research, 10.1093/cvr/cvy200, 115, 2, 419-431, 2019.02, Aims: Monocyte-mediated inflammation is a major mechanism underlying myocardial ischaemia-reperfusion (IR) injury and the healing process after acute myocardial infarction (AMI). However, no definitive anti-inflammatory therapies have been developed for clinical use. Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, has unique anti-inflammatory effects on monocytes/macrophages. Here, we tested the hypothesis that nanoparticle (NP)-mediated targeting of pioglitazone to monocytes/macrophages ameliorates IR injury and cardiac remodelling in preclinical animal models. Methods and results: We formulated poly (lactic acid/glycolic acid) NPs containing pioglitazone (pioglitazone-NPs). In a mouse IR model, these NPs were delivered predominantly to circulating monocytes and macrophages in the IR heart. Intravenous treatment with pioglitazone-NPs at the time of reperfusion attenuated IR injury. This effect was abrogated by pre-treatment with the PPARγ antagonist GW9662. In contrast, treatment with a pioglitazone solution had no therapeutic effects on IR injury. Pioglitazone-NPs inhibited Ly6Chigh inflammatory monocyte recruitment as well as inflammatory gene expression in the IR hearts. In a mouse myocardial infarction model, intravenous treatment with pioglitazone-NPs for three consecutive days, starting 6 h after left anterior descending artery ligation, attenuated cardiac remodelling by reducing macrophage recruitment and polarizing macrophages towards the pro-healing M2 phenotype. Furthermore, pioglitazone-NPs significantly decreased mortality after MI. Finally, in a conscious porcine model of myocardial IR, pioglitazone-NPs induced cardioprotection from reperfused infarction, thus providing pre-clinical proof of concept. Conclusion: NP-mediated targeting of pioglitazone to inflammatory monocytes protected the heart from IR injury and cardiac remodelling by antagonizing monocyte/macrophage-mediated acute inflammation and promoting cardiac healing after AMI.. |
| 44. | Yasushi Ueki, Masahiro Mohri, Tetsuya Matoba, Toshiaki Kadokami, Satoru Suwa, Tsukasa Yagi, Hiroshi Takahashi, Nobuhiro Tanaka, Yohei Hokama, Rei Fukuhara, Ken Onitsuka, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, Prognostic value of neurological status on hospital arrival for short-term outcome in patients with cardiovascular shock - Sub-analysis of the Japanese circulation society cardiovascular shock registry ―, Circulation Journal, 10.1253/circj.CJ-18-1323, 83, 6, 1247-1253, 2019.01, Background: Consciousness disturbance is one of the major clinical signs associated with shock state, but its prognostic value has not been previously evaluated in cardiovascular shock patients. We aimed to evaluate the prognostic value of neurological status for 30-day mortality in cardiovascular shock patients without out-of-hospital cardiac arrest (OHCA). Methods and Results: Patients with out-of-hospital onset cardiovascular shock were recruited from the Japanese Circulation Society Shock Registry. Neurological status upon hospital arrival was evaluated using the Japan Coma Scale (JCS). Patients were divided into 4 groups according to the JCS: alert, JCS 0; awake, JCS 1–3 (not fully alert but awake without any stimuli); arousable, JCS 10–30 (arousable with stimulation); and coma JCS 100–300 (unarousable). The primary endpoint was 30-day all-cause death. In total, 700 cardiovascular shock patients without OHCA were assessed. The coma group was associated with a higher incidence of 30-day all-cause death compared with other groups (alert, 15.3%; awake, 24.4%; arousable, 36.8%; coma, 48.5%, P |
| 45. | Ichimura K, Matoba T, Koga JI, Nakano K, Funamoto D, Tsutsui H, Egashira K, Nanoparticle-Mediated Targeting of Pitavastatin to Small Pulmonary Arteries and Leukocytes by Intravenous Administration Attenuates the Progression of Monocrotaline-Induced Established Pulmonary Arterial Hypertension in Rats., International heart journal, 10.1536/ihj.17-683, 59, 6, 1432-1444, 2018.10, Statins are known to improve pulmonary arterial hypertension (PAH) by their anti-inflammatory and anti-proliferative effects in animal models. However, recent clinical studies have reported that clinically approved statin doses failed to improve clinical outcomes in patients with PAH. We therefore hypothesized that nanoparticle (NP) -mediated targeting of pitavastatin could attenuate the progression of established PAH.We induced PAH by subcutaneously injecting monocrotaline (MCT) in Sprague-Dawley rats. On day 14 after the MCT injection, animals that displayed established PAH on echocardiography were included. On day 17, they were randomly assigned to the following 5 groups: daily intravenous administration of (1) vehicle, (2) fluorescein-isothiocyanate-NP, (3) pitavastatin, (4) pitavastatin-NP, or (5) oral sildenafil. Intravenous NP was selectively delivered to small pulmonary arteries and circulating CD11b-positive leukocytes. On day 21, pitavastatin-NP attenuated the progression of PAH at lower doses than pitavastatin alone. This was associated with the inhibition of monocyte-mediated inflammation, proliferation, and remodeling of the pulmonary arteries. Interestingly, sildenafil attenuated the development of PAH, but had no effects on inflammation or remodeling of the pulmonary arteries. In separate experiments, only treatment with pitavastatin-NP reduced the mortality rate at day 35.NP-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes attenuated the progression of established MCT-induced PAH and improved survival. Therapeutically, pitavastatin-NP was associated with anti-inflammatory and anti-proliferative effects on small pulmonary arteries, which was completely distinct from the vasodilatory effect of sildenafil. Pitavastatin-NP can be a novel therapeutic modality for PAH.. |
| 46. | Kaku Nakano, Tetsuya Matoba, Jun-Ichiro Koga, Yushi Kashihara, Masato Fukae, Ichiro Ieiri, Masanari Shiramoto, Shin Irie, Junji Kishimoto, Koji Todaka, Kensuke Egashira, Safety, Tolerability, and Pharmacokinetics of NK-104-NP., International heart journal, 10.1536/ihj.17-555, 59, 5, 1015-1025, 2018.09, Pulmonary hypertension (PH) is a disease with poor prognosis, caused by the obstruction/stenosis of small pulmonary arteries. Statin is known to have vasodilating and anti-inflammatory property and is considered to be a candidate of therapeutic agents for the treatment of PH, but its efficacy has not been verified in clinical trials. We have formulated pitavastatin incorporating nanoparticles composed of poly (lactic-co-glycolic acid) (NK-104-NP) to improve drug delivery to the pulmonary arteries and evaluated their safety and pharmacokinetics in healthy volunteers. To accomplish this purpose, phase I clinical trials were conducted. In the single intravenous administration regimen, 40 healthy subjects were enrolled and PK (pharmacokinetic) parameters in 4 groups (1, 2, 4, and 8 mg as pitavastatin calcium) were as follows: 1.00 hour after the administration, the plasma concentration of pitavastatin reached Cmax (the maximum drug concentration) in all groups. Cmax, AUC0-t (area under the curve from time 0 to the last measurable concentration) and AUC0-∞ (area under the curve from time 0 extrapolated to infinite time) were increased in a dose-dependent manner. Population pharmacokinetic analysis based on these results indicated no accumulation of pitavastatin after repeated administration of NK-104-NP for 7 days. In this 7-day administration trial, the mean Cmax and AUC0-∞ of pitavastatin were not significantly different between days 1 and 7, suggesting that pitavastatin is unlikely to accumulate after repeated administration. In these trials, three adverse events (AEs) were reported, but they were resolved without any complications and judged to have no causal relationships with NK-104-NP. These results indicate that the innovative nanotechnology-based medicine NK-104-NP exhibited dose-dependent pharmacokinetics and was well tolerated with no significant AEs in healthy volunteers.. |
| 47. | Satoshi Yasuda, Koichi Kaikita, Hisao Ogawa, Masaharu Akao, Junya Ako, Tetsuya Matoba, Masato Nakamura, Katsumi Miyauchi, Nobuhisa Hagiwara, Kazuo Kimura, Atsushi Hirayama, Kunihiko Matsui, Atrial fibrillation and ischemic events with rivaroxaban in patients with stable coronary artery disease (AFIRE): Protocol for a multicenter, prospective, randomized, open-label, parallel group study., International journal of cardiology, 10.1016/j.ijcard.2018.04.131, 265, 108-112, 2018.08, BACKGROUND: In atrial fibrillation (AF) patients with coronary artery disease (CAD), anticoagulants are commonly used in combination with antiplatelet drugs. However, dual therapy can increase the risk of bleeding, and the potential therapeutic benefits must be weighed against this. Therefore, it is recommended that dual therapy is only used for a limited time, and that monotherapy with anticoagulants should start from 1 year after percutaneous coronary intervention (PCI). However, there is a lack of evidence on the use of monotherapy, in particular with direct oral anticoagulants, in this group of patients. METHODS: The AFIRE Study is a multicenter, prospective, randomized, open-label, parallel group study conducted in patients aged ≥20 years with non-valvular AF (NVAF) and CAD. Patients who have undergone PCI or coronary artery bypass graft at least 1 year prior to enrollment, or those without significant coronary lesions requiring PCI (≥50% stenosis), will be included. Approximately 2200 participants will be randomized to receive either rivaroxaban monotherapy or rivaroxaban plus an antiplatelet drug (aspirin, clopidogrel, or prasugrel). The primary efficacy endpoints are the composite of cardiovascular events (stroke, non-central nervous system embolism, myocardial infarction, and unstable angina pectoris requiring revascularizations) and all-cause mortality. The primary safety endpoint is major bleeding as defined by the International Society on Thrombosis and Haemostasis criteria. CONCLUSIONS: This study will be the first to assess the efficacy and safety of rivaroxaban monotherapy in NVAF patients with stable CAD.. |
| 48. | Katsuya Honda, Tetsuya Matoba, Yoshibumi Antoku, Jun-Ichiro Koga, Ikuyo Ichi, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.117.310244, 38, 4, 757-771, 2018.04, [URL], OBJECTIVE: Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion. APPROACH AND RESULTS: Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits. CONCLUSIONS: We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols.. |
| 49. | 的場 哲哉, 坂本 和生, 立花 栄三, 米本 直裕, 長尾 建, 心原性ショックを伴う急性心筋梗塞の予後に施設特徴が及ぼす影響 JROAD/JROAD-DPCの分析(The impact of institutional characteristics on the prognosis of acute myocardial infarction with cardiogenic shock: Analysis from the JROAD/JROAD-DPC), J-ReSS, 11, 31-31, 2018.04. |
| 50. | Tetsuya Matoba, Jun-ichiro Koga, Kaku Nakano, Kensuke Egashira, Hiroyuki Tsutsui, Nanoparticle-mediated drug delivery system for atherosclerotic cardiovascular disease, JOURNAL OF CARDIOLOGY, 10.1016/j.jjcc.2017.03.005, 70, 3-4, 206-211, 2017.09, Administration of drugs and other therapeutic agents has been the central strategy of contemporary medicine for cardiovascular disease. The use of drug delivery systems (DDS) includes micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and crystalline metals. Nano-DDS modify in vivo drug kinetics, depending on (patho)physiological mechanisms such as retard excretion, vascular permeability, and incorporation by mononuclear phagocyte systems, which constitute the 'passive-targeting' property of nano-DDS. These properties of nano-DDS are applicable to inflammatory diseases including atherosclerosis. Atherosclerotic plaque destabilization and rupture account for the majority of acute myocardial infarction, for which inflammatory monocytes and macrophages play critical roles. In our experience, polymeric nanoparticles have been delivered to inflammatory monocytes and macrophages in an atherosclerotic mouse model. Nano-DDS loaded with pioglitazone reduced Ly6C(high) inflammatory monocytes and increased Ly6C(low) non-inflammatory monocytes in the peripheral blood, and induced M2 macrophage-associated genes in the aorta. Pioglitazone-nanoparticles finally stabilized atherosclerotic plaques assessed by a decrease in the number of buried fibrous caps in the plaque. Application of nano-DDS is a unique and promising approach to prevent life-threatening cardiovascular events including acute myocardial infarction by regulating inflammation in the cardiovascular system. (C) 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.. |
| 51. | Yajing Mao, Jun-Ichiro Koga, Masaki Tokutome, Tetsuya Matoba, Gentaro Ikeda, Kaku Nakano, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Left Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting Monocyte-Mediated Inflammation., International heart journal, 10.1536/ihj.16-457, 58, 4, 615-623, 2017.08, Left ventricular (LV) remodeling after myocardial infarction (MI) causes heart failure. Although medical therapies including angiotensin converting enzyme inhibitors show inhibitory effects on post-infarct LV remodeling, the prognosis of patients with post-infarct heart failure is still poor. Accumulating evidence suggests that an inflammatory response is implicated in the process of post-infarct LV remodeling. Therefore, we hypothesized that anti-inflammatory therapy by nanoparticle-mediated monocyte/macrophage-targeting delivery of pitavastatin may protect the heart from post-infarct LV remodeling.Male C57BL/6 mice were subjected to permanent coronary ligation and pitavastatin-incorporating nanoparticles (Pitavastatin-NPs) were intravenously injected for 3 to 5 consecutive days. Pitavastatin-NPs were delivered to CD11b+ monocytes/macrophages, but not to cardiomyocytes. Treatment with Pitavastatin-NPs after establishment of MI attenuated post-infarct LV remodeling accompanied by a reduction of monocytes/macrophages in the heart, whereas pitavastatin solution treatment did not. Pitavastatin-NPs inhibited mobilization of monocytes from the spleen after MI. In mice after splenectomy, Pitavastatin-NPs still decreased the number of monocytes/macrophages in the infarcted heart and inhibited post-infarct LV remodeling.Nanoparticle-mediated delivery of pitavastatin to monocytes/macrophages may be a novel therapeutic strategy to protect the heart from post-infarct LV remodeling. Inhibition of monocyte mobilization from the bone marrow is one of the major mechanisms by which Pitavastatin-NPs attenuated post-infarct LV remodeling.. |
| 52. | Susumu Takase, Tetsuya Matoba, Response by takase and matoba to letter regarding article, "ezetimibe in combination with statins ameliorates endothelial dysfunction in coronary arteries after stenting The cuvic trial (effect of cholesterol absorption inhibitor usage on target vessel dysfunction after coronary stenting), a multicenter randomized controlled trial", Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.117.309301, 37, 5, e54, 2017.05. |
| 53. | Taketo Sonoda, Manabu Ogita, Tetsuya Matoba, Masahiro Mohri, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Yasushi Ueki, Hirohide Matsuura, Satoru Suwa, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, ASSOCIATION BETWEEN PRESENTATION TIME AND SHORT-TERM MORTALITY IN PATIENTS WITH CARDIOGENIC SHOCK COMPLICATING ACUTE CORONARY SYNDROME: FROM JCS SHOCK REGISTRY, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 69, 11, 295-295, 2017.03. |
| 54. | Ken Onitsuka, Masahiro Mohri, Yasushi Ueki, Satoru Suwa, Hiroshi Takahashi, Yohei Hokama, Nobuhiro Tanaka, Toshiaki Kadokami, Tetsuya Matoba, Rei Fukuhara, Tsukasa Yagi, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, CLINICAL CHARACTERISTICS AND IN-HOSPITAL MORTALITY OF VERY ELDERLY PATIENTS WITH CARDIOVASCULAR SHOCK IN JAPAN: THE RESULTS FROM JAPANESE CIRCULATION SOCIETY SHOCK REGISTRY, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 69, 11, 293-293, 2017.03. |
| 55. | Susumu Takase, Tetsuya Matoba, Soichi Nakashiro, Yasushi Mukai, Shujiro Inoue, Keiji Oi, Taiki Higo, Shunsuke Katsuki, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, Mitsutaka Yamamoto, Makoto Usui, Kenji Sadamatsu, Shinji Satoh, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Kensuke Egashira, Kenji Sunagawa, Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.116.308388, 37, 2, 350-358, 2017.02, OBJECTIVES: We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. APPROACH AND RESULTS: We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P |
| 56. | Koshin Horimoto, Kotaro Abe, kisho ohtani, Yusuke Takahara, Kazuya Hosokawa, Keiji Oi, Yasushi Mukai, Takashi Kubo, Tetsuya Matoba, Hiroyuki Tsutsui, Optical Frequency Domain Imaging of Covered Stent-Graft for Pulmonary Artery Pseudoaneurysm After Balloon Pulmonary Angioplasty, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2016.08.022, 9, 21, 2255-2256, 2016.11. |
| 57. | Kenzo Ichimura, Tetsuya Matoba, Kaku Nakano, Masaki Tokutome, Katsuya Honda, Jun-ichiro Koga, Kensuke Egashira, A Translational Study of a New Therapeutic Approach for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Porcine Model, PLOS ONE, 10.1371/journal.pone.0162425, 11, 9, 2016.09, Background There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemiareperfusion (IR) injury. We recently reported that bioabsorbable poly(lactic acid/glycolic acid) (PLGA) nanoparticle-mediated treatment with pitavastatin (pitavastatin-NP) exerts a cardioprotective effect in a rat IR injury model by activating the PI3K-Akt pathway and inhibiting inflammation. To obtain preclinical proof-of-concept evidence, in this study, we examined the effect of pitavastatin-NP on myocardial IR injury in conscious and anesthetized pig models. Methods and Results Eighty-four Bama mini-pigs were surgically implanted with a pneumatic cuff occluder at the left circumflex coronary artery (LCx) and telemetry transmitters to continuously monitor electrocardiogram as well as to monitor arterial blood pressure and heart rate. The LCx was occluded for 60 minutes, followed by 24 hours of reperfusion under conscious conditions. Intravenous administration of pitavastatin-NP containing >= 8 mg/body of pitavastatin 5 minutes before reperfusion significantly reduced infarct size; by contrast, pitavastatin alone (8 mg/body) showed no therapeutic effects. Pitavastatin-NP produced anti-apoptotic effects on cultured cardiomyocytes in vitro. Cardiac magnetic resonance imaging performed 4 weeks after IR injury revealed that pitavastatin-NP reduced the extent of left ventricle remodeling. Importantly, pitavastatin-NP exerted no significant effects on blood pressure, heart rate, or serum biochemistry. Exploratory examinations in anesthetized pigs showed pharmacokinetic analysis and the effects of pitavastatin-NP on no-reflow phenomenon. Conclusions NP-mediated delivery of pitavastatin to IR-injured myocardium exerts cardioprotective effects on IR injury without apparent adverse side effects in a preclinical conscious pig model. Thus, pitavastatin-NP represents a novel therapeutic modality for IR injury in acute myocardial infarction.. |
| 58. | Ayako Ishikita, Tetsuya Matoba, Gentaro Ikeda, Jun-Ichiro Koga, Yajing Mao, Kaku Nakano, Osamu Takeuchi, Junichi Sadoshima, Kensuke Egashira, Nanoparticle-Mediated Delivery of Mitochondrial Division Inhibitor 1 to the Myocardium Protects the Heart From Ischemia-Reperfusion Injury Through Inhibition of Mitochondria Outer Membrane Permeabilization: A New Therapeutic Modality for Acute Myocardial Infarction., Journal of the American Heart Association, 10.1161/JAHA.116.003872, 5, 7, 2016.07, [URL], BACKGROUND: Mitochondria-mediated cell death plays a critical role in myocardial ischemia-reperfusion (IR) injury. We hypothesized that nanoparticle-mediated drug delivery of mitochondrial division inhibitor 1 (Mdivi1) protects hearts from IR injury through inhibition of mitochondria outer membrane permeabilization (MOMP), which causes mitochondrial-mediated cell death. METHODS AND RESULTS: We formulated poly (lactic-co-glycolic acid) nanoparticles containing Mdivi1 (Mdivi1-NP). We recently demonstrated that these nanoparticles could be successfully delivered to the cytosol and mitochondria of cardiomyocytes under H2O2-induced oxidative stress that mimicked IR injury. Pretreatment with Mdivi1-NP ameliorated H2O2-induced cell death in rat neonatal cardiomyocytes more potently than Mdivi1 alone, as indicated by a lower estimated half-maximal effective concentration and greater maximal effect on cell survival. Mdivi1-NP treatment of Langendorff-perfused mouse hearts through the coronary arteries at the time of reperfusion reduced infarct size after IR injury more effectively than Mdivi1 alone. Mdivi1-NP treatment also inhibited Drp1-mediated Bax translocation to the mitochondria and subsequent cytochrome c leakage into the cytosol, namely, MOMP, in mouse IR hearts. MOMP inhibition was also observed in cyclophilin D knockout (CypD-KO) mice, which lack the mitochondrial permeability transition pore (MPTP) opening. Intravenous Mdivi1-NP treatment in vivo at the time of reperfusion reduced IR injury in wild-type and CypD-KO mice, but not Bax-KO mice. CONCLUSIONS: Mdivi1-NP treatment reduced IR injury through inhibition of MOMP, even in the absence of a CypD/MPTP opening. Thus, nanoparticle-mediated drug delivery of Mdivi1 may be a novel treatment strategy for IR injury.. |
| 59. | Yasuhiro Nakano, Tetsuya Matoba, Masaki Tokutome, Daiki Funamoto, Shunsuke Katsuki, Gentaro Ikeda, Kazuhiro Nagaoka, Ayako Ishikita, Kaku Nakano, Jun-Ichiro Koga, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Delivery of Irbesartan Induces Cardioprotection from Myocardial Ischemia-Reperfusion Injury by Antagonizing Monocyte-Mediated Inflammation., Scientific reports, 10.1038/srep29601, 6, 29601-29601, 2016.07, [URL], Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction (AMI), in which the recruitment of inflammatory monocytes plays a causative role. Here we develop bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles incorporating irbesartan, an angiotensin II type 1 receptor blocker with a peroxisome proliferator-activated receptor (PPAR)γ agonistic effect (irbesartan-NP). In a mouse model of IR injury, intravenous PLGA nanoparticles distribute to the IR myocardium and monocytes in the blood and in the IR heart. Single intravenous treatment at the time of reperfusion with irbesartan-NP (3.0 mg kg(-1) irbesartan), but not with control nanoparticles or irbesartan solution (3.0 mg kg(-1)), inhibits the recruitment of inflammatory monocytes to the IR heart, and reduces the infarct size via PPARγ-dependent anti-inflammatory mechanisms, and ameliorates left ventricular remodeling 21 days after IR. Irbesartan-NP is a novel approach to treat myocardial IR injury in patients with AMI.. |
| 60. | Michinobu Nagao, Yuzo Yamasaki, Takeshi Kamitani, Satoshi Kawanami, Koji Sagiyama, Torahiko Yamanouchi, Yamato Shimomiya, Tetsuya Matoba, Yasushi Mukai, Keita Odashiro, Shingo Baba, Yasuhiro Maruoka, Yoshiyuki Kitamura, Akihiro Nishie, Hiroshi Honda, Quantification of coronary flow using dynamic angiography with 320-detector row CT and motion coherence image processing: Detection of ischemia for intermediate coronary stenosis., European journal of radiology, 10.1016/j.ejrad.2016.02.027, 85, 5, 996-1003, 2016.05, OBJECTIVES: Anatomical coronary stenosis is not always indicative of functional stenosis, particularly for intermediate coronary lesions. The purpose of this study is to propose a new method for quantifying coronary flow using dynamic CT angiography for the whole heart (heart-DCT) and investigate its ability for detecting ischemia from intermediate coronary stenosis. METHODS: Participants comprised 36 patients with coronary artery disease who underwent heart-DCT using 320-detector CT with tube voltage of 80kV and myocardial perfusion scintigraphy (MPS). Heart-DCT was continuously performed at mid-diastole throughout 15-25 cardiac cycles with prospective ECG-gating after bolus injection of contrast media (12-24ml). Dynamic datasets were computed into 90-100 data sets by motion coherence image processing (MCIP). Next, time-density curves (TDCs) for coronary arteries with a diameter >3mm were automatically calculated for all phases using MCIP. On the basis of the maximum slope method, coronary flow index (CFI) was defined as the ratio of the maximum upslope of coronary artery attenuation to the upslope of ascending aorta attenuation on the TDC, and was used to quantify coronary flow. CFIs for the proximal and distal sites of coronary arteries with mild-to-moderate stenosis were calculated. Coronary territories were categorized as non-ischemic or ischemic by MPS. Receiver-operating-characteristic (ROC) analysis was performed to determine the optimal cutoff for CFI to detect ischemia. RESULTS: Distal CFI was significantly lower for ischemia (0.26±0.08) than for non-ischemia (0.50±0.17, p |
| 61. | Tetsuya Matoba, Knowing the Risks of the Vessels From the Vessels, CIRCULATION JOURNAL, 10.1253/circj.CJ-16-0164, 80, 4, 825-826, 2016.04. |
| 62. | Satoshi Akagi, Kazufumi Nakamura, Hiromi Matsubara, Megumi Kondo, Daiji Miura, Tetsuya Matoba, Kensuke Egashira, Hiroshi Ito, Intratracheal Administration of Prostacyclin Analogue-incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension., Journal of cardiovascular pharmacology, 10.1097/FJC.0000000000000352, 67, 4, 290-8, 2016.04, Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.. |
| 63. | Yasushi Ueki, Masahiro Mohri, Tetsuya Matoba, Yasuyuki Tsujita, Masao Yamasaki, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, Characteristics and Predictors of Mortality in Patients With Cardiovascular Shock in Japan - Results From the Japanese Circulation Society Cardiovascular Shock Registry -, CIRCULATION JOURNAL, 10.1253/circj.CJ-16-0125, 80, 4, 852-859, 2016.04, Background: There are little data about cardiovascular shock caused by various diseases. We evaluated the characteristics and predictors of 30-day mortality in patients with cardiovascular shock in Japan.Methods and Results: The Japanese Circulation Society Cardiovascular Shock registry was a prospective, observational, multicenter, cohort study. Between May 2012 and June 2014, 979 patients with cardiovascular shock were analyzed. The primary endpoint was 30-day all-cause mortality. The mean systolic blood pressure on hospital arrival was 78+/-18 mmHg. The main causes of shock were acute coronary syndrome (51.0%), non-ischemic arrhythmia (16.4%), and aortic disease (14.9%). The 30-day all-cause mortality was 34.3%. After adjustment for independent predictors of 30-day mortality, the odds ratios for systolic blood pressure (per 10-mmHg decrease), consciousness disturbance, congestive heart failure, out-of-hospital cardiac arrest, estimated glomerular filtration rate (per 10-ml/min/1.73 m(2) decrease), and causes of shock (non-ischemic arrhythmia, aortic disease, and myocarditis) were 1.15 (95% confidence interval [CI], 1.08-1.22), 2.62 (95% CI, 1.80-3.82), 2.58 (95% CI, 1.67-3.99), 1.62 (95% CI, 1.05-2.51), 1.20 (95% CI, 1.10-1.30), and 0.48 (95% CI, 0.30-0.77), 3.98 (95% CI, 2.32-6.81), and 3.25 (95% CI, 1.20-8.84), respectively.Conclusions: The 30-day mortality for cardiovascular shock was still high at 34%. Primary predictors of mortality were cardiorenal function on hospital arrival and shock etiology.. |
| 64. | Hideki Ebina, Matoba Tetsuya, Mohri Masahiro, Tanaka Nobuhiro, Hokama Yohei, Fukutomi Motoki, Hashiba Katsutaka, Fukuhara Rei, Ueki Yasushi, Suwa Satoru, Matsuura Hirohide, Tachibana Eizo, Yonemoto Naohiro, Nagao Ken, IMPACT OF ONSET TO BALLOON TIME AND SHORT-TERM MORTALITY IN PATIENTS WITH CARDIOGENIC SHOCK COMPLICATING ACUTE CORONARY SYNDROME TREATED WITH PRIMARY PERCUTANEOUS CORONARY INTERVENTION FROM JCS SHOCK REGISTRY, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 10.1016/S0735-1097(16)30638-6, 67, 13, 637-637, 2016.04. |
| 65. | Soichi Nakashiro, Tetsuya Matoba, Ryuta Umezu, Jun-Ichiro Koga, Masaki Tokutome, Shunsuke Katsuki, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE-/- Mice., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.115.307057, 36, 3, 491-500, 2016.03, OBJECTIVE: Inflammatory monocytes/macrophages produce various proteinases, including matrix metalloproteinases, and degradation of the extracellular matrix by these activated proteinases weakens the mechanical strength of atherosclerotic plaques, which results in a rupture of the plaque. Peroxisome proliferator-activated receptor-γ induces a polarity shift of monocytes/macrophages toward less inflammatory phenotypes and has the potential to prevent atherosclerotic plaque ruptures. Therefore, we hypothesized that nanoparticle-mediated targeted delivery of the peroxisome proliferator-activated receptor-γ agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model. APPROACH AND RESULTS: We prepared bioabsorbable poly(lactic-co-glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic-co-glycolic-acid) nanoparticles incorporated with fluorescein isothiocyanate were found in circulating monocytes and aortic macrophages by flow cytometric analysis. Weekly intravenous administration of pioglitazone-NPs (7 mg/kg per week) for 4 weeks decreased buried fibrous caps, a surrogate marker of plaque rupture, in the brachiocephalic arteries of ApoE(-/-) mice fed a high-fat diet and infused with angiotensin II. In contrast, administration of control-NPs or an equivalent dose of oral pioglitazone treatment produced no effects. Pioglitazone-NPs inhibited the activity of matrix metalloproteinases and cathepsins in the brachiocephalic arteries. Pioglitazone-NPs regulated inflammatory cytokine expression and also suppressed the expression of extracellular matrix metalloproteinase inducer in bone marrow-derived macrophages. CONCLUSIONS: Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic ApoE(-/-) mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.. |
| 66. | Gentaro Ikeda, Tetsuya Matoba, Yasuhiro Nakano, Kazuhiro Nagaoka, Ayako Ishikita, Kaku Nakano, Daiki Funamoto, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Targeting of Cyclosporine A Enhances Cardioprotection Against Ischemia-Reperfusion Injury Through Inhibition of Mitochondrial Permeability Transition Pore Opening., Scientific reports, 10.1038/srep20467, 6, 20467-20467, 2016.02, Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effects of early reperfusion therapy for acute myocardial infarction (MI), in which mitochondrial permeability transition pore (mPTP) opening plays a critical role. Our aim was to determine whether poly-lactic/glycolic acid (PLGA) nanoparticle-mediated mitochondrial targeting of a molecule that inhibits mPTP opening, cyclosporine A (CsA), enhances CsA-induced cardioprotection. In an in vivo murine IR model, intravenously injected PLGA nanoparticles were located at the IR myocardium mitochondria. Treatment with nanoparticles incorporated with CsA (CsA-NP) at the onset of reperfusion enhanced cardioprotection against IR injury by CsA alone (as indicated by the reduced MI size at a lower CsA concentration) through the inhibition of mPTP opening. Left ventricular remodeling was ameliorated 28 days after IR, but the treatment did not affect inflammatory monocyte recruitment to the IR heart. In cultured rat cardiomyocytes in vitro, mitochondrial PLGA nanoparticle-targeting was observed after the addition of hydrogen peroxide, which represents oxidative stress during IR, and was prevented by CsA. CsA-NP can be developed as an effective mPTP opening inhibitor and may protect organs from IR injury.. |
| 67. | Jun Ichiro Koga, Tetsuya Matoba, Kensuke Egashira, Anti-inflammatory nanoparticle for prevention of atherosclerotic vascular diseases, Journal of atherosclerosis and thrombosis, 10.5551/jat.35113, 23, 7, 757-765, 2016.01, Recent technical innovation has enabled chemical modifications of small materials and various kinds of nanoparticles have been created. In clinical settings, nanoparticle-mediated drug delivery systems have been used in the field of cancer care to deliver therapeutic agents specifically to cancer tissues and to enhance the efficacy of drugs by gradually releasing their contents. In addition, nanotechnology has enabled the visualization of various molecular processes by targeting proteinases or inflammation. Nanoparticles that consist of poly (lactic-co-glycolic) acid (PLGA) deliver therapeutic agents to monocytes/macrophages and function as anti-inflammatory nanoparticles in combination with statins, angiotensin receptor antagonists, or agonists of peroxisome proliferator-activated receptor-γ (PPARγ). PLGA nanoparticle-mediated delivery of pitavastatin has been shown to prevent inflammation and ameliorated features associated with plaque ruptures in hyperlipidemic mice. PLGA nanoparticles were also delivered to tissues with increased vascular permeability and nanoparticles incorporating pitavastatin, injected intramuscularly, were retained in ischemic tissues and induced therapeutic arteriogenesis. This resulted in attenuation of hind limb ischemia. Ex vivo treatment of vein grafts with imatinib nanoparticles before graft implantation has been demonstrated to inhibit lesion development. These results suggest that nanoparticle-mediated drug delivery system can be a promising strategy as a next generation therapy for atherosclerotic vascular diseases.. |
| 68. | Kazuo Sakamoto, Tetsuya Matoba, Masahiro Mohri, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Yasushi Ueki, Satoru Suwa, Hirohide Matsuura, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, Prognostic Impact of Coronary Revascularization in Acute Coronary Syndrome Patients With Cardiogenic Shock, CIRCULATION, 132, 2015.11. |
| 69. | Kazuhiro Nagaoka, Tetsuya Matoba, Yajing Mao, Yasuhiro Nakano, Gentaro Ikeda, Shizuka Egusa, Masaki Tokutome, Ryoji Nagahama, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, A New Therapeutic Modality for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin Induces Cardioprotection from Ischemia-Reperfusion Injury via Activation of PI3K/Akt Pathway and Anti-Inflammation in a Rat Model, PLOS ONE, 10.1371/journal.pone.0132451, 10, 7, 2015.07, Aim There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticle-mediated targeting of pitavastatin protects the heart from IR injury. Methods and Results In a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11b-positive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3 beta, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium. Conclusions Nanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.. |
| 70. | Satoshi Akagi, Kazufumi Nakamura, Daiji Miura, Yukihiro Saito, Hiromi Matsubara, Aiko Ogawa, Tetsuya Matoba, Kensuke Egashira, Hiroshi Ito, Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension., International heart journal, 10.1536/ihj.14-338, 56, 3, 354-9, 2015.05, Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs.. |
| 71. | Satoshi Akagi, Kazufumi Nakamura, Daiji Miura, Yukihiro Saito, Hiromi Matsubara, Aiko Ogawa, Tetsuya Matoba, Kensuke Egashira, Hiroshi Ito, Delivery of Imatinib-Incorporated Nanoparticles into Lungs Suppresses the Development of Monocrotaline-Induced Ulmonary Arterial Hypertension, International Heart Journal, 10.1536/ihj.14-338, 56, 3, 354-359, 2015.04, Platelet–derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by 3H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PASMCs.. |
| 72. | Shunsuke Katsuki, Tetsuya Matoba, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes, CIRCULATION, 10.1161/CIRCULATIONAHA.113.002870, 129, 8, 896-906, 2014.02, Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture. We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2(+/+)Ly-6C(high) inflammatory macrophages, but not CCR2(-/-) leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G(-)CD11b(+) monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture. The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model.. |
| 73. | Ken Nagao, Hiroshi Nonogi, Naohiro Yonemoto, Singo Furuya, Sigemasa Tani, Naoya Matumoto, Morimasa Talcayama, Shinichi Shirai, Takeshi Kimura, Choukou Genka, Eizo Tachibana, Hiromi Seo, Hideharu Tanaka, Hiromi Seo, Hiroyuki Yokoyama, Kazuo Kimura, Keijiro Saku, Kunio Oota, Mamoru Hase, Migaku Kikuchi, Naoki Shimizu, Satoshi Takeda, Shigeru Kanesaka, Sunao Kojima, Takanori Ikeda, Taku Iwami, Tetsuya Matoba, Toshiaki Mano, Tetsuhisa Kitamura, Yoshihiko Seino, Yoshio Tahara, Chest-Compression-Only Bystander Cardiopulmonary Resuscitation in the 30:2 Compression-to-Ventilation Ratio Era - Nationwide Observational Study -, CIRCULATION JOURNAL, 10.1253/circj.CJ-13-0457, 77, 11, 2742-2750, 2013.11, Background: The compression-to-ventilation ratio for basic cardiopulmonary resuscitation (CPR) was changed from 15:2 to 30:2, but there are few human studies comparing chest-compression-only CPR with standard CPR.Methods and Results: From the All-Japan Utstein Registry in the 30:2 CPR era, 173,565 adult cardiac arrests witnessed by bystanders were included. On arrival at the scene, emergency medical services responders assessed the status of dispatcher-assisted CPR instruction and bystander CPR technique (chest compression with or without rescue breathing). The primary endpoint was favorable neurological outcome 30 days after cardiac arrest. The prevalence of dispatcher-assisted CPR instruction increased year by year, contributing to an overall increase of chest-compression-only bystander CPR from 20.6% to 35.0%. Among 78,150 patients receiving bystander CPR, favorable neurological outcome did not differ between dispatcher-assisted and -unassisted CPR (adjusted odds ratio [OR], 1.00; 95% confidence interval [CI]: 0.94-1.08). Chest-compression-only CPR resulted in better favorable neurological outcome than standard CPR in the whole cohort (adjusted OR, 1.09; 95% CI: 1.00-1.18) and in the subgroup with cardiac etiology (adjusted OR, 1.12; 95% CI: 1.02-1.22). The addition of rescue breathing provided no neurological benefit in the non-cardiac etiology subgroup.Conclusions: In the 30:2 CPR era, dispatcher-assisted CPR instruction contributed to an increase of chest-compression-only bystander CPR, supporting the use of chest-compression-only CPR for bystander-witnessed out-of-hospital cardiac arrest in all adults.. |
| 74. | Tetsuya Matoba, Kensuke Egashira, Mouse models of plaque rupture, CURRENT OPINION IN LIPIDOLOGY, 10.1097/MOL.0b013e3283646e4d, 24, 5, 419-425, 2013.10. |
| 75. | Noriaki Tsukie, Kaku Nakano, Tetsuya Matoba, Seigo Masuda, Eiko Iwata, Miho Miyagawa, Gang Zhao, Wei Meng, Junji Kishimoto, Kenji Sunagawa, Kensuke Egashira, Pitavastatin-incorporated nanoparticle-eluting stents attenuate in-stent stenosis without delayed endothelial healing effects in a porcine coronary artery model, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.13862, 20, 1, 32-45, 2013.02, Aim: The use of currently marketed drug-eluting stents presents safety concerns including increased late thrombosis, which is thought to result mainly from delayed endothelial healing effects (impaired re-endothelialization resulting in abnormal inflammation and fibrin deposition). We recently developed a bioabsorbable polymeric nanoparticle (NP)-eluting stent using a novel cationic electrodeposition technology. Statins are known to inhibit the proliferation of vascular smooth muscle cells (VSMC) and to promote vascular healing. We therefore hypothesized that statin-incorporated NPeluting stents would attenuate in-stent stenosis without delayed endothelial healing effects. Methods: Among six marketed statins, pitavastatin (Pitava) was found to have the most potent effects on VSMC proliferation and endothelial regeneration in vitro. We thus formulated a Pitava-NP-eluting stent (20 μg Pitava per stent). Results: In a pig coronary artery model, Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as polymer-coated sirolimus-eluting stents (SES). At SES sites, delayed endothelial healing effects were noted, whereas no such effects were observed in Pitava-NP-eluting stent sites. Conclusion: Pitava-NP-eluting stents attenuated in-stent stenosis as effectively as SES without the delayed endothelial healing effects of SES in a porcine coronary artery model. This nanotechnology platform could be developed into a safer and more effective device in the future.. |
| 76. | Noriaki Tsukie, Kaku Nakano, Tetsuya Matoba, Seigo Masuda, Eiko Iwata, Miho Miyagawa, Gang Zhao, Wei Meng, Junji Kishimoto, Kenji Sunagawa, Kensuke Egashira, Pitavastatin-incorporated nanoparticle-eluting stents attenuate in-stent stenosis without delayed endothelial healing effects in a porcine coronary artery model., J Atheroscler Thromb, 20, 1, 32-45, 2013.01. |
| 77. | Kei Sato, Kaku Nakano, Shunsuke Katsuki, Tetsuya Matoba, Kyoichi Osada, Tatsuya Sawamura, Kenji Sunagawa, Kensuke Egashira, Dietary cholesterol oxidation products accelerate plaque destabilization and rupture associated with monocyte infiltration/activation via the MCP-1-CCR2 pathway in mouse brachiocephalic arteries Therapeutic effects of ezetimibe, Journal of atherosclerosis and thrombosis, 10.5551/jat.13391, 19, 11, 986-998, 2012.12, Aim: No prior studies have investigated the effects of dietary cholesterol oxidation products (oxysterols) on atherosclerotic plaque destabilization and rupture. We used an atherosclerotic mouse model with histological features similar to those seen in ruptured human plaques to test the hypothesis that (1) dietary oxysterols accelerate plaque destabilization and rupture and (2) a NPC1L1 inhibitor, ezetimibe, has therapeutic effects on these processes. Methods and Results: Advanced atherosclerotic plaques were examined in innominate arteries of ApoE-/- mice that were fed either a regular high-fat diet (HFD) or HFD containing oxysterols (oxysterol-HFD; 6.8% of added cholesterol was oxidized) and infused with angiotensin II. Compared with HFD, oxysterol-HFD did not affect plasma lipid levels but did accelerate plaque destabilization and rupture, which was associated with increased monocyte infiltration/activation, monocyte chemoattractant protein-1 (MCP-1) expression, and matrix metalloproteinase (MMP) activity. Dietary oxysterol-induced plaque destabilization and rupture were blunted in ApoE-/-CCR2-/- mice. Oral treatment with ezetimibe, significantly decreased plasma lipid levels and prevented the acceleration of plaque destabilization and rupture induced by dietary oxysterol. These data indicate a primary role for monocyte-mediated inflammation via the MCP-1-CCR2 pathway and the resultant increase in MMP activity in plaque destabilization and rupture induced by dietary oxysterols in ApoE-/- mice. These data also provide a mechanism by which dietary oxysterols are connected with the pathogenesis of plaque destabilization and rupture. Conclusions: These data suggest that inhibition of the absorption of oxysterols by ezetimibe may be useful for the treatment of high-risk patients with high oxysterol intake.. |
| 78. | Naohiro Yonemoto, Hiroyuki Yokoyama, Tetsuya Matoba, Ken Nagao, Takeshi Kimura, Nonogi Hiroshi, Impact with Child and Adolescence on Time of the Chain of Survival in Out-of Hospital Cardiac Arrest from All-Japan Utstein Registry Data, CIRCULATION, 126, 21, 2012.11. |
| 79. | Ryoji Nagahama, Tetsuya Matoba, Kaku Nakano, Kim-Mitsuyama, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pioglitazone Enhances Therapeutic Neovascularization in a Murine Model of Hindlimb Ischemia, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 10.1161/ATVBAHA.112.253823, 32, 10, 2427-+, 2012.10. |
| 80. | Masao Takemoto, Yasushi Mukai, Shuujirou Inoue, Tetsuya Matoba, Mari Nishizaka, Tomomi Ide, Akiko Chishaki, Kenji Sunagawa, Usefulness of non-contact mapping for radiofrequency catheter ablation of inappropriate sinus tachycardia New procedural strategy and long-term clinical outcome, Internal Medicine, 10.2169/internalmedicine.51.5882, 51, 4, 357-362, 2012.02, Objectives The present study evaluated the clinical benefits of a new therapeutic method of radiofrequency catheter ablation (RFCA) using an EnSite system for inappropriate sinus tachycardia (IST). Materials and Methods Six patients with debilitating IST underwent RFCA using EnSite. Using the betaadrenergic blocker and agonist, the heart rate was controlled between 70 to 150 bpm before and after the RFCA. The areas of the breakout sites (BOSs) were clearly distinguished between those from the normal Pwave zones during rates of less than 100 bpm and those from more upper rate sites during rates of more than 100 bpm using the EnSite system, in accordance with the appearance of tall P-waves (tall P-wave zone) in the IST patients. This was selected as the target for ablation. Results After the RFCA, the BOSs observed during heart rates of more than 100 bpm moved completely from the tall P-wave zone to the normal P-wave zone in the IST patients. The total number of heart beats and average heart beat on the 24-h Holter monitoring decreased statistically from that before the RFCA to that after, and no adverse heart rate responses was observed after the RFCA. Before the RFCA, the brain natriuretic peptide was elevated, New York Heart Association functional class was worse, and there was an impaired exercise tolerance observed with exercise electrocardiogram testing. The RFCA for the IST significantly improved those parameters. Conclusion This new therapeutic method for IST using EnSite is effective and produces clinical benefits.. |
| 81. | Tetsuya Matoba, Kensuke Egashira, Anti-inflammatory gene therapy for cardiovascular disease., Curr Gene Ther, 11, 6, 442-446, 2011.12, [URL], Inflammation in the vascular wall is an essential hallmark during the development of atherosclerosis, for which major leukocytes infiltrated in the lesions are monocytes/macrophages. Therefore, monocyte chemoattractant protein-1 (MCP-1) and its primary receptor CC chemokine receptor 2 (CCR2) are feasible molecular targets for gene therapy to inhibit monocyte/macrophage-mediated inflammation in atherogenesis. A mutant MCP-1 that lacks N-terminal 7 amino acids (7ND) has been shown to heterodimerize with native MCP-1, bind to CCR2 and block MCP-1-mediated monocyte chemotaxis by a dominant-negative manner. Gene therapy using intramuscular transfection with plasmid DNA encoding 7ND showed inhibitory effects on atherosclerosis in hypercholesterolemic mice, and neointima formation after vascular injury in animal models. Bare metal stents for coronary intervention were coated with multiple thin layers of biocompatible polymer with 7ND plasmid. The 7ND gene-eluting stent inhibited macrophage infiltration surrounding stent struts and in-stent neointima formation in rabbit femoral arteries and cynomolgus monkey iliac arteries. Finally, the authors describe new application of 7ND plasmid encapsulated in polymer nanoparticle (NP) that functions as gene delivery system with unique in vivo kinetics. NP-mediated 7ND gene delivery inhibited MCP-1-induced chemotaxis of mouse peritoneal macrophage ex vivo, which may be applicable for the treatment of atherosclerotic cardiovascular disease. In conclusion, anti-inflammatory gene therapy targeting MCP-1/CCR2 signal, with a novel NP-mediated gene delivery system, is a potent therapeutic strategy for the treatment of cardiovascular diseases.. |
| 82. | Seigo Masuda, Kaku Nakano, Kouta Funakoshi, Gang Zhao, Wei Meng, Satoshi Kimura, Tetsuya Matoba, Miho Miyagawa, Eiko Iwata, Kenji Sunagawa, Kensuke Egashira, Imatinib mesylate-incorporated nanoparticle-eluting stent attenuates in-stent neointimal formation in porcine coronary arteries, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.8730, 18, 12, 1043-1053, 2011.12, Aim: The use of currently marketed drug-eluting stents (DES) presents safety concerns, including an increased risk for late thrombosis in the range of 0.6% per year in patients, including acute coronary syndrome, which is thought to result from delayed endothelial healing effects. A new DES system targeting vascular smooth muscle cells without adverse effects on endothelial cells is therefore needed. Platelet-derived growth factor (PDGF) plays a central role in the pathogenesis of restenosis; therefore, we hypothesized that imatinib mesylate (PDGF receptor tyrosine kinase inhibitor) encapsulated bioabsorbable polymeric nanoparticle (NP)-eluting stent attenuates in-stent neointima formation. Methods: Effects of imatinib-incorporated NP-eluting stent on neointima formation and endothelial healing were examined in a pig coronary artery stent model. Effects of imatinib-NP were also examined in cultured cells. Results: In a cultured cell study, imatinib-NP attenuated the proliferation of vascular smooth muscle cells associated with inhibition of the target molecule (phosphorylation of PDGF receptor-β), but showed no effect on endothelial proliferation. In a pig coronary artery stent model, imatinib-NPeluting stent markedly attenuated in-stent neointima formation and stenosis by approximately 50% as assessed by angiographic, histopathological, and intravascular ultrasound imaging analyses. Imatinib- NP-eluting stent also attenuated MAP kinase activity, but did not affect inflammation and re-endothelialization. Conclusion: These data suggest that suppression of neointima formation by a imatinib-NP-eluting stent holds promise as a molecular-targeting NP delivery system for preventing in-stent restenosis.. |
| 83. | Soichi Nakashiro, Tetsuya Matoba, Naohiro Yonemoto, Hiroshi Nonogi, Hiromi Seo, Hiroyuki Yokoyama, Ken Nagao, Takeshi Kimura, Time-Dependent Benefit of Biphasic Defibrillators in Patients with Witnessed Out-of-Hospital Cardiac Arrest from VF/Pulseless VT, CIRCULATION, 124, 21, 2011.11. |
| 84. | Ling Chen, Kaku Nakano, Satoshi Kimura, Tetsuya Matoba, Eiko Iwata, Miho Miyagawa, Hiroyuki Tsujimoto, Kazuhiro Nagaoka, Junji Kishimoto, Kenji Sunagawa, and Kensuke Egashira, Nanoparticle-mediated delivery of pitavastatin into lungs ameliorates the development and induces regression of monocrotaline-induced pulmonary artery hypertension., Hypertension, 10.1161/HYPERTENSIONAHA.110.157032, 57, 2, 343-350, 2011.06, [URL]. |
| 85. | Tetsuya Matoba, Hiroshi Nonogi, Hiromi Seo, Hiroyuki Yokoyama, Naohiro Yonemoto, Ken Nagao, Takeshi Kimura, Effect of 'Early Defibrillation' on the Survival of Patients With Witnessed Cardiac Arrest From Ventricular Fibrillation in the Guideline 2005 Era in Japan, CIRCULATION, 122, 21, 2010.11. |
| 86. | Shinichiro Oda, Ryoji Nagahama, Kaku Nakano, Tetsuya Matoba, Mitsuki Kubo, Kenji Sunagawa, Ryuji Tominaga, Kensuke Egashira, Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia., Journal of vascular surgery, 10.1016/j.jvs.2010.03.020, 52, 2, 412-20, 2010.08, [URL], OBJECTIVES: We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals. METHODS: Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle. RESULTS: Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects. CONCLUSIONS: The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients.. |
| 87. | , [URL]. |
| 88. | Masao Takemoto, Yoshisato Shibata, Ken Ichi Eshima, Yasushi Mukai, Shujiro Inoue, Yoji Sagara, Tetsuya Matoba, Hideo Tada, Kenji Sunagawa, Rotational atherectomy for calcified coronary stenosis in elderly patients with severe left ventricular dysfunction: Three case reports, Japanese Journal of Interventional Cardiology, 24, 141-147, 2009.08, Rotational atherectomy (ROTA) is an effective modality of percutaneous coronary intervention (PCI) for calcified coronary stenoses. However, the manufacture dose not recommend the use of ROTA in patients with severe left ventricular (LV) dysfunction, especially with a LV ejection fraction of less than 30%. We experienced 3 elderly patients with severe LV dysfunction and an EF of less than 25%, who underwent ROTA for coronary calcified stenoses without any complications while taking appropriate measures before and during the PCI, and ultimately obtained excellent clinical courses.. |
| 89. | Kimio Satoh, Patrizia Nigro, Tetsuya Matoba, Michael R O'Dell, Zhaoqiang Cui, Xi Shi, Amy Mohan, Chen Yan, Jun-ichi Abe, Karl A Illig, Bradford C Berk, Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms., Nature medicine, 10.1038/nm.1958, 15, 6, 649-56, 2009.06, [URL], Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII-induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.. |
| 90. | Mitsuki Kubo, Kensuke Egashira, Takahiro Inoue, Jun-ichiro Koga, Shinichiro Oda, Ling Chen, Kaku Nakano, Tetsuya Matoba, Yoshiaki Kawashima, Kaori Hara, Hiroyuki Tsujimoto, Katsuo Sueishi, Ryuji Tominaga, Kenji Sunagawa, Therapeutic neovascularization by nanotechnology-mediated cell-selective delivery of pitavastatin into the vascular endothelium., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.108.182584, 29, 6, 796-801, 2009.06, [URL], OBJECTIVE: Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization. METHODS AND RESULTS: In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice. CONCLUSIONS: NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.. |
| 91. | Hiasa, Ken-ichi Takemoto, Masao Matsukawa, Ryuichi Matoba, Tetsuya Kuga, Takeshi Sunagawa, Kenji, Chest pain without significant coronary stenosis after implantation of sirolimus-eluting stents, Intern Med, 48, 4, 213-7, 2009.04, [URL]. |
| 92. | Kaku Nakano, Kensuke Egashira, Seigo Masuda, Kouta Funakoshi, Gang Zhao, Satoshi Kimura, Tetsuya Matoba, Katsuo Sueishi, Yasuhisa Endo, Yoshiaki Kawashima, Kaori Hara, Hiroyuki Tsujimoto, Ryuji Tominaga, Kenji Sunagawa, Formulation of nanoparticle-eluting stents by a cationic electrodeposition coating technology: efficient nano-drug delivery via bioabsorbable polymeric nanoparticle-eluting stents in porcine coronary arteries., JACC. Cardiovascular interventions, 10.1016/j.jcin.2008.08.023, 2, 4, 277-83, 2009.04, [URL], OBJECTIVES: The objective of this study was to formulate a nanoparticle (NP)-eluting drug delivery stent system by a cationic electrodeposition coating technology. BACKGROUND: Nanoparticle-mediated drug delivery systems (DDS) are poised to transform the development of innovative therapeutic devices. Therefore, we hypothesized that a bioabsorbable polymeric NP-eluting stent provides an efficient DDS that shows better and more prolonged delivery compared with dip-coating stent. METHODS: We prepared cationic NP encapsulated with a fluorescence marker (FITC) by emulsion solvent diffusion method, succeeded to formulate an NP-eluting stent with a novel cation electrodeposition coating technology, and compared the in vitro and in vivo characteristics of the FITC-loaded NP-eluting stent with dip-coated FITC-eluting stent and bare metal stent. RESULTS: The NP was taken up stably and efficiently by cultured vascular smooth muscle cells in vitro. In a porcine coronary artery model in vivo, substantial FITC fluorescence was observed in neointimal and medial layers of the stented segments that had received the FITC-NP-eluting stent until 4 weeks. In contrast, no substantial FITC fluorescence was observed in the segments from the polymer-based FITC-eluting stent or from bare metal stent. The magnitudes of stent-induced injury, inflammation, endothelial recovery, and neointima formation were comparable between bare metal stent and NP-eluting stent groups. CONCLUSIONS: Therefore, this NP-eluting stent is an efficient NP-mediated DDS that holds as an innovative platform for the delivery of less invasive nano-devices targeting cardiovascular disease.. |
| 93. | Jun-ichiro Koga, Tetsuya Matoba, Kensuke Egashira, Mitsuki Kubo, Miho Miyagawa, Eiko Iwata, Katsuo Sueishi, Masabumi Shibuya, Kenji Sunagawa, Soluble Flt-1 gene transfer ameliorates neointima formation after wire injury in flt-1 tyrosine kinase-deficient mice., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.109.183772, 29, 4, 458-64, 2009.04, [URL], OBJECTIVE: We have demonstrated that vascular endothelial growth factor (VEGF) expression is upregulated in injured vascular wall, and blockade of VEGF inhibited monocyte infiltration and neointima formation in several animal models. In the present study, we aimed to clarify relative role of two VEGF receptors, flt-1 versus flk-1/KDR, in neointima formation after injury using flt-1 tyrosine kinase-deficient (Flt-1 TK(-/-)) mice and soluble Flt-1(sFlt-1) gene transfer. METHODS AND RESULTS: Neointima formation was comparable between wild-type and Flt-1 TK(-/-) mice 28 days after intraluminal wire injury in femoral arteries. By contrast, neointima formation was significantly suppressed by sFlt-1 gene transfer into Flt-1 TK(-/-) mice that blocks VEGF action on flk-1 (intima/media ratio: 2.8+/-0.4 versus 1.4+/-0.4, P |
| 94. | Hiasa Ken-Ichi, Masao Takemoto, Ryuichi Matsukawa, Tetsuya Matoba, Takeshi Kuga, Kenji Sunagawa, Chest pain without significant coronary stenosis after implantation of sirolimus-eluting stents, Internal Medicine, 10.2169/internalmedicine.48.1581, 48, 4, 213-217, 2009.03, We encountered a case of exercise-induced chest pain after the implantation of sirolimus-eluting stents (SESs). She had no history of previous chest pain, and an exercise stress test just after the implantation of the SESs was negative without any symptoms. However, six months after the implantation of the SESs, she began to experience frequent episodes of severe chest pain on effort in spite of there being no significant coronary stenosis. Interestingly, severe coronary vasoconstriction was induced by an intracoronary administration of acetylcholine, and exercise stress testing revealed positive findings with chest pain and ST-T segment depression on ECG. An intensive treatment with two types of calcium channel blockers could readily and completely abolish the exercise-induced chest pain and ST-T segment depression on the ECG. In view of these findings, we presumed that coronary microvessel dysfunction and/or exercise-induced coronary vasoconstriction leading to myocardial ischemia had appeared 6 months after the implantation of the SESs. Although the pathogenesis of this phenomenon could not be completely elucidated, the anatomical and functional abnormalities of the coronary arteries associated with the implantation of the SESs may have been one of the most important mechanisms.. |
| 95. | Jun-ichiro Koga, Kensuke Egashira, Tetsuya Matoba, Mitsuki Kubo, Yoshiko Ihara, Masaru Iwai, Masatsugu Horiuchi, Kenji Sunagawa, Essential role of angiotensin II type 1a receptors in the host vascular wall, but not the bone marrow, in the pathogenesis of angiotensin II-induced atherosclerosis., Hypertension research : official journal of the Japanese Society of Hypertension, 10.1291/hypres.31.1791, 31, 9, 1791-800, 2008.09, The angiotensin II (Ang II) type 1a (AT1a) receptor is expressed on multiple cell types in atherosclerotic lesions, including bone marrow-derived cells and vascular wall cells, and mediates inflammatory and proliferative responses. Indeed, Ang II infusion accelerates atherogenesis in hyperlipidemic mice by recruiting monocytes and by activating vascular wall cells. Here, we investigated the relative roles of AT1a receptors in the bone marrow vs. the vascular wall in Ang II-induced atherogenesis. Apolipoprotein E-knockout (ApoE(-/-)) mice with or without bone marrow AT1a receptor were generated by experimental bone marrow transplantation using AT1a(+/+) or AT1a(-/-) recipients. In these mice, 28-d Ang II infusion induced significant atherosclerosis in the aorta, and the severity of plaque formation was not affected by the absence of bone marrow AT1a receptor. We then generated AT1a(-/-)ApoE(-/-) mice with or without bone marrow AT1a receptor. Ang II-induced plaque formation was blunted irrespective of the presence of bone marrow AT1a receptor. Host AT1a receptor deficiency was found to suppress Ang II-induced reactive oxygen species production. In addition, AT1a receptor deficiency also impaired monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in the arterial wall 7 d after Ang II initiation. These molecules normally initiate later macrophage-mediated inflammation in the vascular wall. By contrast, AT1a receptor deficiency in the bone marrow did not affect MCP-1-induced monocyte chemotaxis in vitro. In conclusion, AT1a receptors in the host vascular wall, but not in the bone marrow, are essential in Ang II-induced atherogenesis.. |
| 96. | Kimio Satoh, Tetsuya Matoba, Jun Suzuki, Michael R. O'Dell, Patrizia Nigro, Zhaoqiang Cui, Amy Mohan, Shi Pan, Lingli Li, Zheng Gen Jin, Chen Yan, Jun Ichi Abe, Bradford C. Berk, Cyclophilin a mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation, Circulation, 10.1161/CIRCULATIONAHA.107.756106, 117, 24, 3088-3098, 2008.06, Background - Oxidative stress, generated by excessive reactive oxygen species, promotes cardiovascular disease. Cyclophilin A (CyPA) is a 20-kDa chaperone protein secreted from vascular smooth muscle cells (VSMCs) in response to reactive oxygen species that stimulates VSMC proliferation and inflammatory cell migration in vitro; however, the role CyPA plays in vascular function in vivo remains unknown. Methods and Results - We tested the hypothesis that CyPA contributes to vascular remodeling by analyzing the response to complete carotid ligation in CyPA knockout mice, wild-type mice, and mice that overexpress CyPA in VSMC (VSMC-Tg). After carotid ligation, CyPA expression in vessels of wild-type mice increased dramatically and was significantly greater in VSMC-Tg mice. Reactive oxygen species-induced secretion of CyPA from mouse VSMCs correlated significantly with intracellular CyPA expression. Intimal and medial hyperplasia correlated significantly with CyPA expression after 2 weeks of carotid ligation, with marked decreases in CyPA knockout mice and increases in VSMC-Tg mice. Inflammatory cell migration into the intima was significantly reduced in CyPA knockout mice and increased in VSMC-Tg mice. Additionally, VSMC proliferation assessed by Ki67 + cells was significantly less in CyPA knockout mice and was increased in VSMC-Tg mice. The importance of CyPA for intimal and medial thickening was shown by strong correlations between CyPA expression and the number of both inflammatory cells and proliferating VSMCs in vivo and in vitro. Conclusions - In response to low flow, CyPA plays a crucial role in VSMC migration and proliferation, as well as inflammatory cell accumulation, thereby regulating flow-mediated vascular remodeling and intima formation.. |
| 97. | Jun Suzuki, Zheng Gen Jin, David F. Meoli, Tetsuya Matoba, Bradford C. Berk, Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells, Circulation research, 10.1161/01.RES.0000216405.85080.a6, 98, 6, 811-817, 2006.03, Reactive oxygen species (ROS) contribute to the pathogenesis of atherosclerosis in part by promoting vascular smooth muscle cell (VSMC) growth. Previously we demonstrated that cyclophilin A (CyPA) is a secreted oxidative stress-induced factor (SOXF) that promotes inflammation, VSMC growth, and endothelial cell apoptosis. However, the mechanisms that regulate CyPA secretion are unknown. In this study, we hypothesized that ROS-induced CyPA secretion from VSMC requires a highly regulated process of vesicle transport, docking, and fusion at the plasma membrane. Conditioned medium and plasma membrane sheets were prepared by exposing VSMC to 1 μmol/L LY83583, which generates intracellular superoxide. A vesicular transport mechanism was confirmed by colocalization at the plasma membrane with vesicle-associated membrane protein (VAMP). CyPA transport to the plasma membrane and secretion were significantly increased by LY83583. Reduction of VAMP-2 expression by small interfering RNA inhibited LY83583-induced CyPA secretion. Pretreatment with 3 μmol/L cytochalasin D, an actin depolymerizing agent, abrogated CyPA secretion. Infection with dominant-negative RhoA and Cdc42 adenovirus inhibited CyPA secretion by 72% and 63%, respectively, whereas dominant-negative Rac1 had a small effect (11%). Pretreatment with the Rho kinase inhibitor Y27632 (3 to 30 μmol/L) and myosin II inhibitor blebbistatin (1 to 10 μmol/L) inhibited CyPA secretion in a dose-dependent manner. Simvastatin (3 to 30 μmol/L) also dose-dependently inhibited LY83583-induced CyPA secretion likely via decreased isoprenylation of small GTPases. Our findings define a novel VSMC vesicular secretory pathway for CyPA that involves actin remodeling and myosin II activation via RhoA-, Cdc42-, and Rho kinase-dependent signaling events.. |
| 98. | Yoshihiro Fukumoto, Akira Ito, Toyokazu Uwatoku, Tetsuya Matoba, Takuya Kishi, Haruki Tanaka, Akira Takeshita, Kenji Sunagawa, Hiroaki Shimokawa, Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease, Coronary Artery Disease, 10.1097/00019501-200602000-00011, 17, 1, 63-70, 2006.02, OBJECTIVE: Prognosis of severe coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting remains poor. We have recently demonstrated that shock wave therapy effectively induces neovascularization and improves myocardial ischemia in a porcine model in vivo. METHODS: With permission from the Ethical Committee of our Institute, we treated nine patients with end-stage coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting (55-82 years old, five men and four women) with our cardiac shock wave therapy (200 shots/spot at 0.09 mJ/mm2 for 20-40 spots, 3 times a week/series). We followed-up the patients at 1, 3, 6, and 12 months after the therapy to examine the amelioration of myocardial ischemia. When needed, shock wave therapy was performed up to three series at 0, and 1, 3 or 6 months. RESULTS: The cardiac shock wave therapy improved symptoms (Canadian Cardiovascular Society functional class score, from 2.7±0.2 to 1.8±0.2, P |
| 99. | Keiko Morikawa, Tetsuya Matoba, Hiroshi Kubota, Makoto Hatanaka, Takako Fujiki, Shosuke Takahashi, Akira Takeshita, Hiroaki Shimokawa, Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice, Journal of Cardiovascular Pharmacology, 10.1097/01.fjc.0000159657.93922.cb, 45, 5, 485-490, 2005.05, The endothelium synthesizes and releases several vasodilator substances, including vasodilator prostaglandins, NO, and EDHF. NO-mediated relaxations are reduced by various risk factors, such as diabetes mellitus and hypercholesterolemia. However, it remains to be elucidated whether EDHF-mediated relaxations also are reduced by those factors and their combination. In this study, we addressed this point in mice. We used small mesenteric arteries from control, diabetic (streptozotocin-induced), apolipoprotein-E-deficient (ApoE -/- ), and diabetic ApoE -/- mice. In control mice, endothelium-dependent relaxations to acetylcholine were largely mediated by EDHF. This EDHF-mediated component was slightly reduced in diabetic mice, preserved in ApoE -/- mice, and markedly reduced in diabetic ApoE -/- mice with an increase in NO-mediated component and a negative contribution of indomethacin-sensitive endothelium-derived contracting factor (EDCF). Endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of calcium-activated K channels, were attenuated in ApoE -/- and diabetic ApoE -/- mice. Endothelium-dependent hyperpolarizations were significantly reduced in diabetic mice, preserved in ApoE -/- mice, and again markedly reduced in diabetic ApoE -/- mice. These results indicate that hypercholesterolemia alone minimally affects the EDHF-mediated relaxations, and diabetes mellitus significantly attenuated the responses, whereas their combination markedly attenuates the responses with a compensatory involvement of NO and a negative contribution of EDCF.. |
| 100. | Takako Fujiki, Hiroaki Shimokawa, Keiko Morikawa, Hiroshi Kubota, Makoto Hatanaka, M. A.Hassan Talukder, Tetsuya Matoba, Akira Takeshita, Kenji Sunagawa, Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin-converting enzyme inhibitor on endothelium-derived hyperpolarizing factor-mediated responses in mice, Arteriosclerosis, thrombosis, and vascular biology, 10.1161/01.ATV.0000158498.19027.75, 25, 4, 766-771, 2005.04, Background - We have recently identified that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans, for which endothelial nitric oxide synthase (eNOS) is an important source. Angiotensin-converting enzyme (ACE) inhibitors are known to enhance EDHF-mediated responses. In this study, we examined whether endothelium-derived H 2 O 2 accounts for the enhancing effect of an ACE inhibitor on EDHF-mediated responses and, if so, what mechanism is involved. Methods and Results - Control and eNOS -/- mice were maintained with or without temocapril (10 mg/kg per day orally) for 4 weeks, and isometric tensions and membrane potentials of mesenteric arteries were recorded. In control mice, temocapril treatment significantly enhanced EDHF-mediated relaxations and hyperpolarizations to acetylcholine (n=8 each). Catalase, a specific scavenger of H 2 O 2 , abolished the beneficial effects of temocapril, although it did not affect endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of K Ca channels (n=6 each). Western blot analysis demonstrated that the temocapril treatment significantly upregulated the expression of eNOS. By contrast, this enhancing effect of temocapril was absent in eNOS -/- mice (n=6). Conclusions - These results indicate that endothelium-derived H 2 O 2 accounts for the enhancing effect of temocapril on EDHF-mediated responses caused in part by eNOS upregulation, further supporting our H 2 O 2 theory.. |
| 101. | Yoshihiro Fukumoto, Tetsuya Matoba, A. Ito, H. Tanaka, Takuya Kishi, Shunji Hayashidani, Kotaro Abe, A. Takeshita, H. Shimokawa, Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension, Heart, 10.1136/hrt.2003.029470, 91, 3, 391-392, 2005.03. |
| 102. | Keiko Morikawa, Takako Fujiki, Tetsuya Matoba, Hiroshi Kubota, Makoto Hatanaka, Shosuke Takahashi, Hiroaki Shimokawa, Important role of superoxide dismutase in EDHF-mediated responses of human mesenteric arteries, Journal of Cardiovascular Pharmacology, 10.1097/00005344-200411000-00006, 44, 5, 552-556, 2004.11, The endothelium synthesizes and releases several vasodilator substances, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have identified hydrogen peroxide (H 2 O 2 ) as an EDHF in mouse and human mesenteric arteries and porcine coronary microvessels. We also have recently demonstrated that Cu,Zn-SOD plays an important role in EDHF synthesis in mouse mesenteric arteries. However, it remains to be determined whether SOD also plays an important role in EDHF-mediated responses of human arteries. In this study, we addressed this point in human mesenteric arteries. We used small mesenteric arteries of patients who underwent gastrectomy operations. Isometric tensions and membrane potentials were recorded in the presence of indomethacin and N ω -nitro-L-arginine to inhibit the synthesis of prostacyclin and NO, respectively. Pretreatment with Tiron, a cell-permeable SOD-mimetic, significantly enhanced the EDHF-mediated relaxations and hyperpolarizations to bradykinin, and this effect was abolished by catalase, indicating that this enhancing effect was achieved by H 2 O 2 . By contrast, Tiron did not affect endothelium-independent relaxations, indicating that the enhancing effect of Tiron is not caused by the enhancement of vascular smooth muscle responses. These results indicate that SOD plays an important role in EDHF-mediated relaxations and hyperpolarizations of human mesenteric arteries.. |
| 103. | Kousuke Inokuchi, Akira Ito, Yoshihiro Fukumoto, Tetsuya Matoba, Akira Shiose, Takahiro Nishida, Munetaka Masuda, Shigeki Morita, Hiroaki Shimokawa, Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery., Journal of cardiovascular pharmacology, 10.1097/01.fjc.0000134775.76636.3f, 44, 3, 275-7, 2004.09, We have recently demonstrated that fasudil, a Rho-kinase inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the inhibitory effect of fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosorbide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.. |
| 104. | Keiko Morikawa, Hiroaki Shimokawa, Tetsuya Matoba, Hiroshi Kubota, Takaaki Akaike, M A Hassan Talukder, Makoto Hatanaka, Takako Fujiki, Hiroshi Maeda, Shosuke Takahashi, Akira Takeshita, Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization., The Journal of clinical investigation, 10.1172/JCI200319351, 112, 12, 1871-9, 2003.12, The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, NO, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived H2O2 is an EDHF in mesenteric arteries of mice and humans and in porcine coronary microvessels. However, the mechanism for the endothelial production of H2O2 as an EDHF remains to be elucidated. In this study, we tested our hypothesis that Cu,Zn-superoxide dismutase (Cu,Zn-SOD) plays a pivotal role in endothelium-dependent hyperpolarization, using control and Cu,Zn-SOD-/- mice. In mesenteric arteries, EDHF-mediated relaxations and hyperpolarizations were significantly reduced in Cu,Zn-SOD-/- mice with no inhibitory effect of catalase, while endothelium-independent relaxations and hyperpolarizations were preserved. Endothelial H2O2 production also was significantly reduced in Cu,Zn-SOD-/- mice. In Langendorff isolated heart, bradykinin-induced increase in coronary flow was significantly reduced in Cu,Zn-SOD-/- mice, again with no inhibitory effect of catalase. The exogenous SOD mimetic tempol significantly improved EDHF-mediated relaxations and hyperpolarizations and coronary flow response in Cu,Zn-SOD-/- mice. These results prove the novel concept that endothelial Cu,Zn-SOD plays an important role as an "EDHF synthase" in mice, in addition to its classical role to scavenge superoxide anions.. |
| 105. | Yasushi Mukai, Hiroaki Shimokawa, Tetsuya Matoba, Junko Hiroki, Ikuko Kunihiro, Takako Fujiki, Akira Takeshita, Acute vasodilator effects of HMG-CoA reductase inhibitors Involvement of PI3-kinase/Akt pathway and Kv channels, Journal of Cardiovascular Pharmacology, 10.1097/00005344-200307000-00018, 42, 1, 118-124, 2003.07, 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) have several non-lipid-lowering actions; however, characteristics of their acute vasodilator effects remain to be elucidated. In this study, acute vasodilator effects of statins were examined in isolated rat blood vessels. After incubation with cerivastatin (1 μM) for 2 hours, acetylcholine-induced endothelium-dependent relaxations were enhanced in the rat aorta. This effect was abolished by a nitric oxide synthase (NOS) inhibitor, L-NNA, and by a PI3 kinase inhibitor, LY294002. Western blot analysis showed that the extent of phosphorylation of Akt, an active form of Akt, was increased by cerivastatin while it was reduced by LY294002, suggesting an involvement of PI3 kinase/Akt-dependent activation of endothelial NOS. At higher concentrations (1-300 μM), both cerivastatin and fluvastatin, but not pravastatin, directly relaxed the blood vessels, regardless of the presence or absence of the endothelium. These relaxations were abolished by KCI and were significantly inhibited by an inhibitor of Kv channel, 4-aminopyridine. These results indicate that multiple mechanisms are involved in the acute vasodilator effects of statins, including augmentation of nitric oxide-mediated endothelium-dependent relaxations through the PI3 kinase/Akt pathway and endothelium-independent relaxations via Kv channel-mediated smooth muscle hyperpolarizations. These acute vasodilator effects of statins may account, at least in part, for their beneficial effects on cardiovascular diseases associated with impaired organ blood flow.. |
| 106. | Tetsuya Matoba, Hiroaki Shimokawa, Keiko Morikawa, Hiroshi Kubota, Ikuko Kunihiro, Lemmy Urakami-Harasawa, Yasushi Mukai, Yoji Hirakawa, Takaaki Akaike, Akira Takeshita, Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/01.ATV.0000078601.79536.6C, 23, 7, 1224-30, 2003.07, OBJECTIVE: Endothelium-derived hyperpolarizing factor (EDHF) plays an important role in modulating vascular tone, especially in microvessels, although its nature has yet to be elucidated. This study was designed to examine whether hydrogen peroxide (H2O2) is an EDHF in porcine coronary microvessels with use of an electron spin resonance (ESR) method to directly detect H2O2 production from the endothelium. METHODS AND RESULTS: Isometric tension and membrane-potential recordings demonstrated that bradykinin and substance P caused EDHF-mediated relaxations and hyperpolarizations of porcine coronary microvessels in the presence of indomethacin and Nomega-nitro-L-arginine. The contribution of H2O2 to the EDHF-mediated responses was demonstrated by the inhibitory effect of catalase and by the relaxing and hyperpolarizing effects of exogenous H2O2. Endothelial production of H2O2 was quantified in bradykinin- or substance P-stimulated intact blood vessels by ESR spectroscopy. Tiron, a superoxide scavenger that facilitates H2O2 formation, enhanced bradykinin-induced production of H2O2, as well as the EDHF-mediated relaxations and hyperpolarizations. By contrast, cytochrome P-450 inhibitors (sulfaphenazole or 17-octadecynoic acid) or a gap junction inhibitor (18alpha-glycyrrhetinic acid) failed to inhibit the EDHF-mediated relaxations. Involvement of endothelium-derived K+ was not evident in experiments with ouabain plus Ba2+ or exogenous K+. CONCLUSIONS: These results provide ESR evidence that H2O2 is an EDHF in porcine coronary microvessels.. |
| 107. | Yasushi Mukai, Hiroaki Shimokawa, Midoriko Higashi, Keiko Morikawa, Tetsuya Matoba, Junko Hiroki, Ikuko Kunihiro, Hassan M A Talukder, Akira Takeshita, Inhibition of renin-angiotensin system ameliorates endothelial dysfunction associated with aging in rats., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/01.ATV.0000029121.63691.CE, 22, 9, 1445-50, 2002.09, OBJECTIVE: Endothelial vasodilator functions are progressively impaired with aging, which may account in part for the increased incidence of cardiovascular events in elderly people. We examined what treatment could ameliorate the endothelial dysfunction associated with aging in rats. METHODS AND RESULTS: Aged (12-month-old) Wistar-Kyoto rats were treated with vehicle, temocapril, CS-866 (an angiotensin II type 1 receptor antagonist), cerivastatin, or hydralazine for 2 weeks. Endothelium-dependent relaxations (EDRs) of aortas from aged rats were markedly impaired compared with EDRs of aortas from young (3-month-old) rats. Indomethacin, NS-398 (a cyclooxygenase [COX]-2 inhibitor), and SQ-29548 (a thromboxane A2/prostaglandin H2 receptor antagonist) acutely restored EDRs in aged rats, suggesting an involvement of COX-2-derived vasoconstricting eicosanoids. Tiron, a superoxide scavenger, also partially improved EDRs, suggesting an involvement of superoxide. EDRs were significantly ameliorated in aged rats after long-term treatment with temocapril or CS-866 but not after treatment with cerivastatin or hydralazine. Indomethacin induced no further improvement of EDRs after treatment with temocapril or CS-866. COX-2 protein expression and superoxide production were increased in the aortas of aged rats and were also attenuated by treatment with temocapril or CS-866. CONCLUSIONS: These results demonstrate that long-term inhibition of the renin-angiotensin system ameliorates endothelial dysfunction associated with aging through the inhibition of the synthesis of COX-2-derived vasoconstricting factors and superoxide anions.. |
| 108. | Tadashi Kandabashi, Hiroaki Shimokawa, Yasushi Mukai, Tetsuya Matoba, Ikuko Kunihiro, Keiko Morikawa, Masaaki Ito, Shosuke Takahashi, Kozo Kaibuchi, Akira Takeshita, Involvement of Rho-kinase in agonists-induced contractions of arteriosclerotic human arteries, Arteriosclerosis, thrombosis, and vascular biology, 10.1161/hq0202.104274, 22, 2, 243-248, 2002.02, Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart diseases. We have recently demonstrated that Rho-kinase plays a key role in the spasm in our porcine model. However, it remains to be elucidated whether Rho-kinase-mediated pathway also contributes to vasoconstriction of human arteries. From 15 patients who underwent coronary artery bypass operation, segments of isolated left internal thoracic arteries were obtained, and the endothelium was gently removed. Serotonin and histamine caused contractions, which were markedly inhibited by a specific Rho-kinase inhibitor, hydroxyfasudil. Western blot analysis showed that, during the serotonin-induced contractions, the extent of phosphorylation of myosin-binding subunit of myosin phosphatase (MBS, one of the major substrates of Rho-kinase) was significantly increased in the specimens. Hydroxyfasudil again significantly suppressed the serotonin-induced increase in MBS phosphorylation. There was a significant positive correlation between the extent of MBS phosphorylation and that of the serotonin-induced contractions and between hydroxyfasudil-sensitive components of the contractions and the extent of arteriosclerosis. These results indicate that Rho-kinase plays an important role in vascular smooth muscle contractions of arteriosclerotic human arteries, suggesting that Rho-kinase could be regarded as an important target for the treatment of arteriosclerotic vascular diseases in humans.. |
| 109. | Tetsuya Matoba, Hiroaki Shimokawa, Hiroshi Kubota, Keiko Morikawa, Takako Fujiki, Ikuko Kunihiro, Yasushi Mukai, Yoji Hirakawa, Akira Takeshita, Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries, Biochemical and Biophysical Research Communications, 10.1006/bbrc.2001.6278, 290, 3, 909-913, 2002.01, The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an EDHF in mice. The present study was designed to examine whether this is also the case in humans. Bradykinin elicited endothelium-dependent relaxations and hyperpolarizations in the presence of indomethacin and Nω-nitro-L-arginine, which thus were attributed to EDHF, in human mesenteric arteries. The EDHF-mediated relaxations were significantly inhibited by catalase, an enzyme that specifically decomposes H 2 O 2 , whereas catalase did not affect endothelium-independent hyperpolarizations to levcromakalim. Exogenous H 2 O 2 elicited relaxations and hyperpolarizations in endothelium-stripped arteries. Gap junction inhibitor 18α-glycyrrhetinic acid partially inhibited, whereas inhibitors of cytochrome P450 did not affect the EDHF-mediated relaxations. These results indicate that H 2 O 2 is also a primary EDHF in human mesenteric arteries with some contribution of gap junctions.. |
| 110. | Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension.. |
| 111. | T Matoba, H Shimokawa, M Nakashima, Y Hirakawa, Y Mukai, K Hirano, H Kanaide, A Takeshita, Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice, JOURNAL OF CLINICAL INVESTIGATION, 106, 12, 1521-1530, 2000.12, The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several endothelium-derived relaxing factors, such as prostacyclin, nitric oxide (NO), and the previously unidentified endothelium-derived hyperpolarizing factor (EDHF). In this study, we examined our hypothesis that hydrogen peroxide (H2O2) derived from endothelial NO synthase (eNOS) is an EDHF. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine (ACh) were markedly attenuated in small mesenteric arteries from eNOS knockout (eNOS-KO) mice. In the eNOS-KO mice, vasodilating and hyperpolarizing responses of vascular smooth muscle per se were fairly well preserved, as was the increase in intracellular calcium in endothelial cells in response to ACh, Antihypertensive treatment with hydralazine failed to improve the EDHF-mediated relaxation. Catalase, which dismutates H2O2 to form water and oxygen, inhibited EDHF-mediated relaxation and hyperpolarization, but it did not affect endothelium-independent relaxation following treatment with the K+ channel opener levcromakalim. Exogenous H2O2 elicited similar relaxation and hyperpolarization in endothelium-stripped arteries. Finally, laser confocal microscopic examination with peroxide-sensitive fluorescence dye demonstrated that: the endothelium produced H2O2 upon stimulation by ACh acid that the H2O2 production was markedly reduced in eNOS-KO mice. These results indicate that H2O2 is an EDHF in mouse small mesenteric arteries and that eNOS is a major source of the reactive oxygen species.. |
| 112. | MAH Talukder, H Shimokawa, T Fujiki, K Morikawa, H Kubota, T Matoba, A Takeshita, Involvement of neuronal NO synthase in NO-cGMP-mediated pathway in the maintenance of bradykinin-induced coronary flow in endothelial NO synthase knockout mice, FASEB JOURNAL, 17, 4, A504-A504, 2003.03. |
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