Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Midoriko Higashi Last modified date:2021.12.09

Associate Professor / Department of Clinical Medicine / Faculty of Medical Sciences

1. Ryoko Owaki-Nakano, Midoriko Higashi, Kohei Iwashita, Kenji Shigematsu, Emiko Toyama, Ken Yamaura, Anesthetic management of multiple acyl-coenzyme A dehydrogenase deficiency in a series of surgeries under general anesthesia: a case report, JA Clinical Reports, 10.1186/s40981-021-00459-3, 7, 1, 2021.12, Abstract
Glutaric acidemia is a type of multiple acyl-coenzyme A dehydrogenase deficiency, an inborn error in fatty acid metabolism. In patients with glutaric acidemia, during the perioperative period, prolonged fasting, stress, and pain have been identified as risk factors for the induction of metabolic derangement. This report describes the surgical and anesthetic management of a patient with glutaric acidemia.

Case presentation
A 56-year-old male patient with glutaric acidemia type 2 underwent a series of surgeries. During the initial off-pump coronary artery bypass surgery, the patient developed renal failure due to rhabdomyolysis upon receiving glucose at 2 mg/kg/min. However, in the second laparoscopic cholecystectomy, rhabdomyolysis was avoided by administering glucose at 4 mg/kg/min.

To avoid catabolism in patients with glutaric acidemia, appropriate glucose administration is important, depending on the surgical risk.

2. GO KUSUMOTO, Midoriko Higashi, Kenji Shigematsu, Ken Yamaura, Third-Generation Hydroxyethyl Starch Causes Dose-Dependent Coagulopathy in Patients Undergoing Off-Pump Coronary Artery Bypass with Continuation of Preoperative Aspirin, The Heart Surgery Forum, 10.1532/hsf.4061, 24, 5, E949-E854, 2021.09, Background: We aimed to evaluate the effect of third-generation hydroxyethyl starch (6% HES 130/0.4) on hemostasis and perioperative blood loss in patients undergoing off-pump coronary artery bypass (OPCAB) with continuation of preoperative aspirin.
Methods: Forty-nine consecutive patients, who underwent OPCAB at a single institution between November 1, 2014 and March 31, 2016, were included. Coagulation tests, including thromboelastometry and clinical data of all patients, retrospectively were collected from anesthesia and medical records.
Results: The total amount of intraoperative crystalloid and HES was 2057.5 ± 771.6 mL (N = 32) and 1090.6 ± 645.0 mL (N = 32), respectively. In the coagulation pathway, the change ratio of fibrinogen concentration, prothrombin time, and fibrinogen thromboelastometry-maximum clot firmness (FIBTEM-MCF) significantly correlated with HES (P < 0.001, P = 0.00131, and P < 0.001, respectively), but not with crystalloid. In the coagulation pathway concerning interaction with platelets, the change ratio of platelet count, extrinsic thromboelastometry-clotting formation time (EXTEM-CFT), and EXTEM-MCF significantly were correlated with HES (P < 0.001, P < 0.001, and P < 0.001, respectively), but not with crystalloid. At chest closure, the hematocrit decreased in a dose-dependent manner with HES (P < 0.001), but not with crystalloid administration. There was an association between the change ratio of hematocrit and EXTEM-MCF (P = 0.00122). However, intra-postoperative blood loss was not correlated with HES 130/0.4 or crystalloid administration.
Conclusion: We found that 6% HES 130/0.4 prolonged coagulation testing in a dose-dependent manner due to hemodilution but did not increase blood loss in patients undergoing OPCAB with continuation of preoperative aspirin..
3. Brachial plexus block improved refractory pain due to intraoperative position-related nerve injury: a case report.
4. Midoriko Higashi, Kenji Shigematsu, Kenji Tominaga, Kazuya Murayama, Daisuke Seo, Toshikazu Tsuda, Gen Maruta, Kohei Iwashita, Ken Yamaura, Preoperative elevated E/e’ (≥ 15) with preserved ejection fraction is associated with the development of postoperative heart failure in intermediate-risk non-cardiac surgical patients, Journal of Anesthesia, 10.1007/s00540-019-02728-z, 34, 2, 250-256, 2020.04, Purpose: Left ventricular diastolic dysfunction is an independent risk factor for adverse cardiovascular morbidities and mortalities in cardiovascular and high-risk surgical patients. However, there were only a few investigations among intermediate-risk surgical patients. This study aimed to investigate postoperative heart failure (HF) in intermediate-risk surgical patients who had preoperative diastolic dysfunction with preserved ejection fraction (EF). Methods: Consecutive patients underwent intermediate-risk surgery between January 2016 and December 2018 were retrospectively evaluated. Patients with preserved EF were divided into three groups using one of the parameters of diastolic function: the ratio of early diastolic filling velocity to the peak diastolic velocity of mitral medial annulus (E/e’) ≥ 15, E/e’ between 8 and 15, and E/e’ < 8. Postoperative HF was defined as clinical symptoms and radiological evidence and low SpO2 less than 93%. The primary outcome was the incidence of postoperative HF and its relation to preoperative E/e’. Chi-squared test, unpaired t test with Welch’s correction, and multivariate logistic regression were used for analysis. Results: In total, 965 patients were included in the final analysis. Postoperative HF developed in 36/965 (3.7%) patients with preserved EF. The incidence of postoperative HF was stratified according to the E/e’, and the rates of HF occurrence in patients with E/e’ < 8, 8–15, and ≥ 15 were 1.8%, 2.7%, and 15%, respectively (P < 0.01). Conclusion: Preoperative elevated E/e’ (≥ 15) was associated with the development of postoperative HF in intermediate-risk surgical patients with preserved EF..
5. M. Higashi, K. Shigematsu, E. Nakamori, S. Sakurai, K. Yamaura, Efficacy of programmed intermittent bolus epidural analgesia in thoracic surgery: a randomized controlled trial, BMC Anesthesiology, 10.1186/s12871-019-0780-0, 19, 1, 2019.06.
6. A case of postoperative shock due to aortic stenosis mimicking pulmonary thromboembolism.
7. Ryosuke Mimata, Midoriko Higashi, Madoka Yasui, Takanao Hirai, Ken Yamaura, Spinal epidural hematoma following epidural catheter removal in a patient with postoperative urgent coronary intervention and intra-aortic balloon pumping (IABP) A case report, American Journal of Case Reports, 10.12659/AJCR.917716, 20, 1356-1359, 2019.01, Objective: Rare disease Background: It is still challenging to remove an epidural catheter in a postoperative patient receiving urgent antiplatelet and anticoagulation therapy for acute coronary syndrome. Case Report: While under general anesthesia combined with thoracic epidural anesthesia, a 72-year-old male patient underwent right radical nephrectomy for renal cell carcinoma. On postoperative day 1 (POD1), the patient experienced bradycardia and a decrease in blood pressure, and he was diagnosed acute myocardial infarction. Intraaortic balloon pumping (IABP) was induced for cardiogenic shock, and urgent thrombus aspiration and coronary balloon angioplasty were performed. On POD3, the surgeon removed the epidural catheter under both antiplatelet and anticoagulation therapy. At that time, the platelet count was 45×109/L and the activated partial thromboplastin time (APTT) was 72.2 seconds. Four hours after the epidural catheter was removed, the patient complained of bilateral fatigue in legs and developed a loss of sensation. Six hours after the epidural catheter was removed, he developed motor paralysis and became completely paralyzed in both limbs after 9 hours. At 19 hours after the epidural catheter was removed, emergency magnetic resonance imaging detected a spinal epidural hematoma at the level of Th9-11 with compression of the spinal cord. Emergency laminectomy was performed to decompress and remove the spinal epidural hematoma at 18 hours after the onset of sensorimotor symptoms. After surgery and rehabilitation, these symptoms had only slightly improved. Conclusions: In patients with urgent antithrombotic therapy for urgent percutaneous coronary intervention (PCI) with an IABP for acute coronary syndrome, the epidural catheter should not be removed until the IABP and heparin are discontinued, and platelet counts have recovered..
8. Akira Gohara, Sumi Okamatsu-Kifuji, Shinjiro Shono, Midoriko Higashi, Ken Yamaura, Ventricular tachycardia without preceding electrocardiogram change after hypertonic mannitol administration: a case report, JA Clinical Reports, 10.1186/s40981-018-0191-0, 4, 54, 54, 2018.07.
9. Meta-analyses on measurement precision of non-invasive hemodynamic monitoring technologuies in adults
An ideal non-invasive monitoring system should provide accurate and reproducible measurements of clinically relevant variables that enables clinicians to guide therapy accordingly. The monitor should be rapid, easy to use, readily available at the bedside, operator-independent, cost-effective and should have a minimal risk and side effect profile for patients. An example is the introduction of pulse oximetry, which has become established for non-invasive monitoring of oxygenation worldwide. A corresponding non-invasive monitoring of hemodynamics and perfusion could optimize the anesthesiological treatment to the needs in individual cases. In recent years several non-invasive technologies to monitor hemodynamics in the perioperative setting have been introduced: suprasternal Doppler ultrasound, modified windkessel function, pulse wave transit time, radial artery tonometry, thoracic bioimpedance, endotracheal bioimpedance, bioreactance, and partial CO2 rebreathing have been tested for monitoring cardiac output or stroke volume. The photoelectric finger blood volume clamp technique and respiratory variation of the plethysmography curve have been assessed for monitoring fluid responsiveness. In this manuscript meta-analyses of non-invasive monitoring technologies were performed when non-invasive monitoring technology and reference technology were comparable. The primary evaluation criterion for all studies screened was a Bland-Altman analysis. Experimental and pediatric studies were excluded, as were all studies without a non-invasive monitoring technique or studies without evaluation of cardiac output/stroke volume or fluid responsiveness. Most studies found an acceptable bias with wide limits of agreement. Thus, most non-invasive hemodynamic monitoring technologies cannot be considered to be equivalent to the respective reference method. Studies testing the impact of non-invasive hemodynamic monitoring technologies as a trend evaluation on outcome, as well as studies evaluating alternatives to the finger for capturing the raw signals for hemodynamic assessment, and, finally, studies evaluating technologies based on a flow time measurement are current topics of clinical research..
10. T. Shimauchi, K. Yamaura, M. Higashi, K. Abe, T. Yoshizumi, S. Hoka, Fibrinolysis in Living Donor Liver Transplantation Recipients Evaluated Using Thromboelastometry
Impact on Mortality, Transplantation Proceedings, 10.1016/j.transproceed.2017.09.025, 49, 9, 2117-2121, 2017.11, Background Inadequate hemostasis during living donor liver transplantation (LDLT) is mainly due to coagulopathy but may also include fibrinolysis. The purpose of this study was to determine the incidence of fibrinolysis and assess its relevance to mortality in LDLT. Methods The incidence and prognosis of fibrinolysis were retrospectively studied in 76 patients who underwent LDLT between April 2010 and February 2013. Fibrinolysis was evaluated and defined by maximum lysis (ML) >15% within a 60-minute run time using thromboelastometry (ROTEM). Results Fibrinolysis was observed in 19 of the 76 (25%) patients before the anhepatic (pre-anhepatic) phase and was developed in 24 (32%) patients during and after the anhepatic (post-anhepatic) phase. In these 43 patients who had fibrinolysis, spontaneous recovery occurred in 29 patients (73%) within 3 hours after reperfusion of the liver graft. Recovery with tranexamic acid was noted in 2 patients with fibrinolysis in the post-anhepatic phase. Thrombosis in the portal vein and liver artery was noted in 14 patients, and the incidence was significantly greater in patients with post-anhepatic fibrinolysis than in those with pre-anhepatic fibrinolysis (P =.0017). Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities (P =.0003 and.0026, respectively). Conclusions Fibrinolysis existed and developed in a large percentage of patients during LDLT. Thrombosis in the portal vein and hepatic artery was more common in patients with fibrinolysis in the post-anhepatic phase. Fibrinolysis that developed in the pre-anhepatic phase was associated with increased 30-day and 6-month mortalities..
11. Hyponatremia as a Cause of Postoperative Headache after Epidural Anesthesia.
12. Midoriko Higashi, Ken Yamaura, Yukie Matsubara, Takuya Fukudome, Sumio Hoka, In-line pressure within a HOTLINEA (R) Fluid Warmer, under various flow conditions, JOURNAL OF CLINICAL MONITORING AND COMPUTING, 10.1007/s10877-014-9605-3, 29, 2, 301-305, 2015.04, Roller pump infusion devices are widely used for rapid infusion, and may be combined with separate warming devices. There may be instances however, where the pressures generated by the roller pump may not be compatible with the warming device. We assessed a commonly used roller pump in combination with a HOTLINEA (R) Fluid Warmer, and found that it could generate pressures exceeding the HOTLINEA (R) manufacturers specifications. This was of concern because the HOTLINEA (R) manufacturer guideline states that not for use with pressure devices generating over 300 mmHg. Pressure greater than 300 mmHg may compromise the integrity of the HOTLINEA (R) Fluid Warming Set. The aim of this study was to compare in-line pressure within a HOTLINEA (R) Fluid Warmer at different infusion rates of a roller pump using various sizes of intravenous cannulae. The rapid infusion system comprised a 500 mL-normal saline bag, roller pump type infusion device, HOTLINEA (R) Fluid Warmer (blood and fluid warmer system), and six different sizes of intravenous cannulae. In-line pressure was measured proximal to the HOTLINEA (R) (pre-warmer) and proximal to the cannula (post-warmer), at flow rate of 50-160 mL/min. The in-line pressures increased significantly with increasing flow rate. The pre-warmer pressures exceeded 300 mmHg when the flow rate was a parts per thousand yen120 mL/min with 20-gauge, 48 mm length cannula, 130 with 20-gauge, 25 mm cannula, and 160 mL/min with 18-gauge, 48 mm cannula. However, they were < 300 mmHg at any flow rates with 18-gauge, 30 mm cannula and 16-gauge cannulae. The post-warmer pressures exceeded 300 mmHg at the flow rate of 140 mL/min with 20-gauge, 48 mm cannula, and 160 mL/min with 20-gauge, 25 mm cannula, while they were < 300 mmHg at any flow rates with 18 and 16-gauge cannulae. The in-line pressure within a HOTLINEA (R) could exceed 300 mmHg, depending on the flow rate and size and length of cannula. It is important to pay attention to the size and length of cannulae and flow rate to keep the maximum in-line pressure < 300 mmHg when a roller pump type infusion device is used..
13. Ken Yamaura, Noriko Nanishi, Midoriko Higashi, Sumio Hoka, Effects of thermoregulatory vasoconstriction on pulse hemoglobin measurements using a co-oximeter in patients undergoing surgery, Journal of Clinical Anesthesia, 10.1016/j.jclinane.2014.04.012, 26, 8, 643-647, 2014.12, Study Objective: To validate intraoperative pulse hemoglobin (SpHb) measurements in anesthetized patients with large forearm temperature - fingertip temperature gradients. Design: prospective and observational study. Setting: Operating room of a university hospital. Patients: 28 patients undergoing surgery during general anesthesia, requiring arterial blood withdrawal. Interventions: Radial arterial blood pressure, forearm and fingertip skin surface temperatures, and SpHb were monitored. Measurements: Paired SpHb and arterial hemoglobin (Hb) measurements at different skin-surface temperature gradients. Main Results: A total of 175 paired SpHb and arterial Hb measurements were analyzed. The mean SpHb to arterial Hb differences in each group were 0.33 ± 1.41 g/dL in the < 1°C group of the forearm temperature - fingertip temperature gradient, -0.31 ± 1.24 g/dL in the 1 - 2°C group, - 0.59 ± 1.11 g/dL in the 2 - 3°C group, and - 0.53 ± 0.87 g/dL in the > 3°C group (P < 0.05). The percentage of nonmeasurable SpHb due to low perfusion state was 0% (0 of 115 paired measurements) in the < 1°C group, 6.7% (2 of 30 pairs) in the 1 - 2°C group, 16.7% (3 of 18 pairs) in the 2 - 3°C group, and 66.7% (8 of 12 pairs) in the > 3°C group. Conclusion: SpHb measured at fingertip was significantly affected by the perfusion state, with lower perfusion associated with lower SpHb. Thermoregulatory vasoconstriction affects measurement of SpHb..
14. Tetsuya Kai, Midoriko Higashi, Kouichi Sasano, Arterial line syringes are rarely responsible for infection, 日本手術医学会誌, 35, 4, 325-329, 2014.11.
15. Maiko Tanaka, Ken Yamaura, Midoriko Higashi, Sumio Hoka, Leakage of sevoflurane from vaporizer detected by air monitoring system
A case report, Journal of Clinical Monitoring and Computing, 10.1007/s10877-013-9479-9, 27, 6, 629-631, 2013.12, Leakage of inhalational anesthetic gases is an important issue not only to staff health but awareness during general anesthesia. After inhalation of sevoflurane commenced, the audible and visible alarm of our custom-made air monitoring system was activated. The system measured 2-4 ppm of sevoflurane. A thorough search failed to identify the source of the leak. After changing inhalational anesthesia to intravenous anesthesia, the concentration of sevoflurane decreased immediately to zero. The filling level on the vaporizer decreased faster than usual. A thorough check of the vaporizer after surgery identified a worn down seal in the filling device of the vaporizer..
16. M. Higashi, K. Yamaura, Mizuko Ikeda, Tsukasa Shimauchi, H. Saiki, Sumio Hoka, Diastolic dysfunction of the left ventricle is associated with pulmonary edema after renal transplantation, Acta Anaesthesiologica Scandinavica, 10.1111/aas.12168, 57, 9, 1154-1160, 2013.10, Background Post-operative pulmonary complications are associated with high mortality and graft loss in renal transplantation recipients. Left ventricular diastolic dysfunction is not uncommon in patients with chronic renal failure, including those with preserved left ventricular systolic function. The purpose of this study was to determine the relationship between left ventricular diastolic dysfunction and incidence of post-operative pulmonary edema in renal transplantation recipients with preserved left ventricular systolic function. Methods Pre-operative left ventricular function and incidence of pulmonary edema were retrospectively studied in 209 patients who underwent living-donor renal transplantation between January 2010 and October 2012. Left ventricular systolic and diastolic functions were evaluated by ejection fraction and E/E' ratio, retrospectively, using transthoracic echocardiography. Pulmonary edema was defined by evidence of pulmonary congestion on the chest X-ray together with PaO2/FiO2 ratio < 300 mmHg. Results Eleven out of 190 (5.8%) renal transplantation patients with preserved left ventricular systolic function developed post-operative pulmonary edema. Patients with pulmonary edema had a significantly higher geometric mean (95% confidence interval) of E/E' ratio than those without pulmonary edema [17.8 (14.1-22.5) vs. 11.1 (10.6-11.7), P = 0.001]. Conclusion Pre-operative left ventricular diastolic dysfunction correlated with the development of post-operative pulmonary edema in renal transplantation recipients. Meticulous intraoperative volume therapy is important to avoid post-operative pulmonary edema in such patients..
17. Nanishi N, Yamaura K, Matsushita K, Akiyoshi K, Karashima Y, Higashi M, Hoka S, Endovascular abdominal aortic aneurysm repair under general anesthesia does not decrease perioperative myocardial ischemic events compared with open repair, Open Journal of Anesthesiology, 10.4236/ojanes.2013.32021, 3, 84-89, 2013.03.
18. Anesthetic management of a parturient with congenital afibrinogenemia undergoing cesarean section
A 29-year-old parturient with congenital afibrinogenemia was scheduled to receive cesarean section at 38 weeks 2 days of gestation. Due to the bleeding tendency by her abnormality of fibrinogen and afibrinogenemia, general anesthesia was chosen. In addition to routine administration of fibrinogen, perioperative supplementation of fibrinogen with the meticulous evaluation of the coagulation and fibrinolysis status using rotation thromboelastometry (ROTEM&
reg) enabled the patient to deliver a healthy baby without any hematological complications. The ROTEM® was a useful device to check coagulopathy and fibrinolysis in this patient..
19. Fiberoptic intubation using two tracheal tubes for a child with goldenhar syndrome
Goldenhar syndrome is associated with difficult airway due to the characteristic craniofacial anomalies such as hypoplasia of the mandible and molar bones. We present our method of fiberoptic intubation using two tracheal tubes for a girl with Goldenhar syndrome undergoing cochlear implant surgery. She had received general anesthesia for dental treatment one year before, but the treatment had been cancelled because of the failure of tracheal intubation. We induced anesthesia for her with inhalation of sevoflurane and nitrous oxide. After obtaining a stable anesthetic level, we inserted two tracheal tubes from the right and left nostrils, one for a tracheal tube and the other for a nasopharyngeal airway. During the procedure, the fiberscope was advanced through the tracheal tube with a slit connector, and her ventilation was assisted through the nasopharyngeal airway with her mouth closed by a tape to avoid a leak of ventilating gas. Using this two-tube method, we successfully intubated the trachea of a patient Goldenhar syndrome..
20. T Akata, T Kanna, J Yoshino, M Higashi, K Fukui, S Takahashi, Reliability of fingertip skin-surface temperature and its related thermal measures as indices of peripheral perfusion in the clinical setting of the operating theatre, ANAESTHESIA AND INTENSIVE CARE, 32, 4, 519-529, 2004.08, During the perioperative period, evaluation of digital blood flow would be useful in early detection of decreased circulating volume, thermoregulatory responses or anaphylactoid reactions, and assessment of the effects of vasoactive agents. This study was designed to assess the reliability of fingertip temperature, core-fingertip temperature gradients and fingertip-forean-n temperature gradients as indices of fingertip blood flow in the clinical setting of the operating theatre.
In 22 adult patients undergoing abdominal surgery with general anaesthesia, fingertip skin-surface temperature, forearm skin-surface temperature, and nasopharyngeal temperature were measured every five minutes during the surgery.
Fingertip skin-surface blood flow was simultaneously estimated using laser Doppler flowmetry. These measurements were made in the same upper limb with an IVcatheter (+IVgroup, n =11) or without an IVcatheter (-IV group, n=11). Fingertip blood flow, transformed to a logarithmic scale, significantly correlated with any of the three thermal measures in both the groups. Their rank order as an index of fingertip blood flow in the -IV group was forearm-fingertip temperature gradient (r=-0.86) > fingertip temperature (r=0.83) > nasopharyngeal-fingertip temperature gradient (r=-0.82), while that in the +IV group was nasopharyngeal-fingertip temperature gradient (r=-0.77) > fingertip temperature (r=0.71) > forearm-fingertip temperature gradient (r=-0.66). The relation of fingertip blood flow to each thermal measure in the -IV group was stronger (P<0.05) than that in the +IVgroup. In the clinical setting of the operating theatre, using the upper limb without IV catheters, fingertip skin-surface temperature, nasopharyngeal-fingertip temperature gradients, and forearm-fingertip temperature gradients are almost equally reliable measures of fingertip skin-surface bloodflow..
21. J Hiroki, H Shimokawa, M Higashi, K Morikawa, T Kandabashi, N Kawamura, T Kubota, T Ichiki, M Amano, K Kaibuchi, A Takeshita, Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 10.1016/j.yjmcc.2004.05.008, 37, 2, 537-546, 2004.08, Recent studies have demonstrated that upregulated Rho-kinase plays an important role in the pathogenesis of arteriosclerosis and vasospasm in both animals and humans. However, little is known about the molecular mechanism(s) involved in the Rho-kinase upregulation. Since inflammatory mechanisms have been implicated in the pathogenesis of arteriosclerosis and vasospasm, we examined whether inflammatory stimuli upregulate Rho-kinase in vitro and in vivo. In cultured human coronary vascular smooth muscle cells (hcVSMC), inflammatory stimuli, such as angiotensin II and interleukin-1beta, increased Rho-kinase expression (at both mRNA and protein levels) and function (as evaluated by the extent of the phosphorylation of the ERM (the ezrin/radixin/moesin) family, substrates of Rho-kinase) in a time-and concentration-dependent manner. The expression of Rho-kinase was inhibited by blockades of protein kinase C (PKC) (by either GF109253 or prolonged treatment with phorbol myristate acetate for 24 h) and an adenovirus-mediated gene transfer of dominant-active Ikappa-B, suggesting an involvement of PKC and NF-kappaB in the intracellular signal transduction pathway for the Rho-kinase expression. Furthermore, coronary vascular lesion formation (characterized by medial thickening and perivascular fibrosis) induced by a long-term administration of angiotensin II was markedly suppressed in NF-kappaB(-/-) mice with reduced expression and activity of Rho-kinase in vivo. These results indicate that the expression and function of Rho-kinase are upregulated by inflammatory stimuli (e.g. angiotensin II and IL-1beta) in hcVSMC with an involvement of PKC and NF-kappaB both in vitro and in vivo. (C) 2004 Elsevier Ltd. All rights reserved..
22. T Hattori, H Shimokawa, M Higashi, J Hiroki, Y Mukai, H Tsutsui, K Kaibuchi, A Takeshita, Long-term inhibition of rho-kinase suppresses left ventricular remodeling after myocardial infarction in mice, CIRCULATION, 10.1161/01.CIR.0000127939.16111.58, 109, 18, 2234-2239, 2004.05, Background-Rho-kinase has been implicated as an important regulator of inflammatory responses mediated by cytokines and chemokines. Because proinflammatory cytokines play a critical role in left ventricular (LV) remodeling after myocardial infarction (MI), we examined whether long-term blockade of Rho-kinase suppresses LV remodeling in a mouse model of MI in vivo.
Methods and Results-Mice underwent ligation of the left coronary artery and were treated with a Rho-kinase inhibitor, fasudil (100 mg . kg(-1) . d(-1) in tap water), for 4 weeks, starting 1 day after the surgery. At 4 weeks, LV infarct size was histologically comparable between the 2 groups. LV cavity dilatation and dysfunction evaluated by echocardiography were significantly suppressed in the fasudil group (P<0.05, n=15 to 28). The beneficial effects of fasudil were accompanied by suppression of cardiomyocyte hypertrophy and interstitial fibrosis (both P<0.01, n=6). The expression of inflammatory cytokines, including transforming growth factor (TGF)-beta(2), TGF-beta(3), and macrophage migration inhibitory factor, was upregulated in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (both P<0.05, n=10 to 11). Rho-kinase activity as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, was significantly increased in the noninfarcted LV in the control group and was significantly suppressed in the fasudil group (P<0.05, n=5).
Conclusions-These results indicate that Rho-kinase is substantially involved in the pathogenesis of LV remodeling after MI associated with upregulation of proinflammatory cytokines, suggesting a therapeutic importance of the molecule for the prevention of post-MI heart failure..
23. T Hattori, H Shimokawa, M Higashi, J Hiroki, Y Mukai, K Kaibuchi, A Takeshita, Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice, CIRCULATION RESEARCH, 10.1161/01.RES.0000107196.21335.2B, 94, 1, 46-52, 2004.01, Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-kinase inhibitor and a dominant-negative Rho-kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P < 0.01, n = 9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-kinase (P < 0.05, n = 4). Among the proinflammatory cytokines examined, those of macrophage migration inhibitory factor, interferon-gamma, and transforming growth factor-beta1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group (P < 0.01, n = 5). Vascular inflammation in the allografts, as evidenced by accumulation of inflammatory cells (macrophages and T cells), was also significantly inhibited in the fasudil group (P < 0.05, n = 5 to 10). These results indicate that long-term treatment with fasudil suppresses CAV in mice, suggesting that Rho-kinase is an important therapeutic target for the prevention of CAV..
24. M Higashi, H Shimokawa, T Hattori, J Hiroki, Y Mukai, K Morikawa, T Ichiki, S Takahashi, A Takeshita, Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo - Effect on endothelial NAD(P)H oxidase system, CIRCULATION RESEARCH, 10.1161/01.RES.0000096650.91688.28, 93, 8, 767-775, 2003.10, Intracellular signaling pathway mediated by small GTPase Rho and its effector Rho-kinase plays an important role in regulation of vascular smooth muscle contraction and other cellular functions. We have recently demonstrated that Rho-kinase is substantially involved in angiotensin II-induced gene expressions and various cellular responses in vitro. However, it remains to be examined whether Rho-kinase is involved in the angiotensin II-induced cardiovascular hypertrophy in vivo and, if so, what mechanisms are involved. Long-term infusion of angiotensin II for 4 weeks caused hypertrophic changes of vascular smooth muscle and cardiomyocytes in rats. Both changes were significantly suppressed by concomitant oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor, hydroxyfasudil, after oral administration. Angiotensin II caused a perivascular accumulation of macrophages and Rho-kinase activation, both of which were also significantly suppressed by fasudil. Vascular NAD(P)H oxidase expression (nox1, nox4, gp91phox, and p22phox) and endothelial production of superoxide anions were markedly increased by angiotensin II, both of which were also significantly suppressed by fasudil. Thus, fasudil ameliorated the impaired endothelium-dependent relaxations caused by angiotensin II without affecting vasodilator function of vascular smooth muscle. These results provide evidence that Rho-kinase is substantially involved in the angiotensin II-induced cardiovascular hypertrophy in rats in vivo. The suppression of endothelial NAD( P) H oxidase upregulation and resultant superoxide production and the amelioration of endothelial vasodilator function may be involved in this process..
25. 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, 1445-1450, 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..
26. K. Yamaura, M. Higashi, K. Akiyoshi, Y. Itonaga, H. Inoue, S. Takahashi, Pulmonary lipiodol embolism during transcatheter arterial chemoembolization for hepatoblastoma under general anaesthesia, European Journal of Anaesthesiology, 10.1046/j.1365-2346.2000.00759.x, 17, 11, 704-708, 2000.11, We present a case of pulmonary embolism that occurred during the injection of lipiodol during transcatheter arterial chemoembolization under general anaesthesia. A 7-year-old child suffering from a large hepatoblastoma was admitted for arterial chemoembolization and carcinostatic administration. Pulmonary embolism due to lipiodol during arterial chemoembolization was evident by a sudden fall in oxyhaemoglobin saturation from 100 to 90%. This was associated with a spread of lipiodol into both lungs, particularly the middle lung zones and detected by chest fluoroscopy. Arterial blood gases returned to normal values 1 day later but pulmonary infiltration persisted for 7 days before final clearance. Pulmonary embolism caused by lipiodol during arterial chemoembolization is infrequent, but such a complication could prove fatal. Understanding the risk of pulmonary embolism in patients receiving lipiodol, during and after arterial chemoembolization, and late onset pulmonary injury is important and a close follow-up for several days after arterial chemoembolization is advisable..