研究者詳細 - 神津　英至

論文 - 神津　英至

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Delayed visceral bleeding from liver injury after cardiopulmonary resuscitation

Kouzu, Hidemichi, Kokubu, Nobuaki, Nishida, Junichi, Kawamukai, Mina, Tsuchihashi, Kazufumi, Miura, Tetsuji, Shimamoto, Kazuaki, Hase, Mamoru, Meguro, Makoto, Asai, Yasufumi, Usami, Yoko, Hirokawa, Naoki

Journal of Emergency Medicine 43 ( 4 ) e245-8 2012年10月 [国際誌]

BACKGROUND: Visceral injury is a life-threatening complication of cardiopulmonary resuscitation (CPR); however, the clinical significance has been masked by the lethal outcome of out-of-hospital cardiac arrest (OHCA). OBJECTIVE: The objective is to share our experience of successful treatment of OHCA patients with serious, CPR-related visceral complications. CASE REPORTS: We report two cases of cardiac-origin OHCA with liver injury exacerbated by heparinization during mechanical circulatory support. Although both patients presented with delayed massive liver bleeding (intrahepatic or peritoneal) that compromised hemodynamic status, one patient was successfully treated by selective transcatheter arterial embolization and the other by a surgical procedure. CONCLUSION: Preventive measures such as careful CPR, as well as interventional or surgical repair after the early diagnosis of visceral injury, are required to improve the outcome in some cases of OHCA.

DOI PubMed J-GLOBAL

Role of connexin-43 in protective PI3K-AKT-GSK-3β signaling in cardiomyocytes

Ishikawa, Satoko, Kuno, Atsushi, Kuno, Atsushi, Tanno, Masaya, Miki, Takayuki, Kouzu, Hidemichi, Itoh, Takahito, Sato, Tatsuya, Sato, Tatsuya, Sunaga, Daisuke, Murase, Hiromichi, Miura, Tetsuji

American Journal of Physiology - Heart and Circulatory Physiology 302 ( 12 ) H2536-44 2012年06月 [国際誌]

Sarcolemmal connexin-43 (Cx43) and mitochondrial Cx43 play distinct roles: formation of gap junctions and production of reactive oxygen species (ROS) for redox signaling. In this study, we examined the hypothesis that Cx43 contributes to activation of a major cytoprotective signal pathway, phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3β (GSK-3β) signaling, in cardiomyocytes. A δ-opioid receptor agonist {[d-Ala(2),d-Leu(5)]enkephalin acetate (DADLE)}, endothelin-1 (ET-1), and insulin-like growth factor-1 (IGF-1) induced phosphorylation of Akt and GSK-3β in H9c2 cardiomyocytes. Reduction of Cx43 protein to 20% of the normal level by Cx43 small interfering RNA abolished phosphorylation of Akt and GSK-3β induced by DADLE or ET-1 but not that induced by IGF-1. DADLE and IGF-1 protected H9c2 cells from necrosis after treatment with H(2)O(2) or antimycin A. The protection by DADLE or ET-1, but not that by IGF-1, was lost by reduction of Cx43 protein expression. In contrast to Akt and GSK-3β, PKC-ε, ERK and p38 mitogen-activated protein kinase were phosphorylated by ET-1 in Cx43-knocked-down cells. Like diazoxide, an activator of the mitochondrial ATP-sensitive K(+) channel, DADLE and ET-1 induced significant ROS production in mitochondria, although such an effect was not observed for IGF-1. Cx43 knockdown did not attenuate the mitochondrial ROS production by DADLE or ET-1. Cx43 was coimmunoprecipitated with the β-subunit of G protein (Gβ), and knockdown of Gβ mimicked the effect of Cx43 knockdown on ET-1-induced phosphorylation of Akt and GSK-3β. These results suggest that Cx43 contributes to activation of class I(B) PI3K in PI3K-Akt-GSK-3β signaling possibly as a cofactor of Gβ in cardiomyocytes.

DOI PubMed J-GLOBAL

慢性心不全患者におけるヘモグロビンおよび腎臓機能と組合せた心臓交感神経活性の評価により改善した心臓死亡率評価

DOI Takahiro, NAKATA Tomoaki, HASHIMOTO Akiyoshi, YUDA Satoshi, WAKABAYASHI Takeru, KOUZU Hidemichi, KANEKO Naofumi, HASE Mamoru, TSUCHIHASHI Kazufumi, MIURA Tetsuji

Journal of Nuclear Medicine 53 ( 5 ) 731 - 40 2012年05月 [国際誌]

UNLABELLED: We examined prognostic interactions among cardiac autonomic function assessed by (123)I-labeled metaiodobenzylguanidine ((123)I-MIBG) activity, hemoglobin, and kidney function in chronic heart failure patients. Anemia, chronic kidney disease, and impairment of cardiac sympathetic function have been shown as determinants of prognosis in heart failure patients, but there has been little information on their synergistic correlations with cardiac mortality. METHODS: After evaluations of hemoglobin and estimated glomerular filtration rate (GFR), 468 heart failure patients with left ventricular ejection fraction less than 50% underwent cardiac (123)I-MIBG imaging before discharge and were then followed up for a mean interval of 60.5 mo with a primary endpoint of cardiac death. Cardiac (123)I-MIBG activity was quantified using heart-to-mediastinum ratio (HMR) and washout rate. RESULTS: For 89 fatal cardiac events documented (19.0%), besides New York Heart Association class, multivariate Cox analysis revealed HMR, hemoglobin, and estimated GFR as significant independent determinants, with hazard ratios of 0.215 (P = 0.0129; 95% confidence interval [CI], 0.064-0.718), 0.821 (P = 0.0062; 95% CI, 0.708-0.946), and 0.984 (P = 0.0243; 95% CI, 0.970-0.998), respectively. Receiver-operating-characteristic analysis determined the thresholds for identifying patients at increased risk for cardiac death to be 1.57 for HMR, 11.9 g/dL for hemoglobin, and 46.4 mL/min/1.73 m(2) for estimated GFR. Combining the 4 independent predictors incrementally (P < 0.05) improved prognostic powers maximally up to a global χ(2) value of 97.3 compared with sole or other combinations. CONCLUSION: Hemoglobin, kidney function, and alterations of cardiac sympathetic nerve activity are independently and synergistically associated with increased cardiac mortality in chronic heart failure patients, together with New York Heart Association functional class.

DOI PubMed J-GLOBAL

Synergistic prognostic values of cardiac sympathetic innervation with left ventricular hypertrophy and left atrial size in heart failure patients without reduced left ventricular ejection fraction: A cohort study.

Doi, Takahiro, Nakata, Tomoaki, Hashimoto, Akiyoshi, Yuda, Satoshi, Wakabayashi, Takeru, Kouzu, Hidemichi, Kaneko, Naofumi, Hase, Mamoru, Tsuchihashi, Kazufumi, Miura, Tetsuji

BMJ Open 2 ( 6 ) 2012年 [国際誌]

OBJECTIVES: This study tested whether cardiac sympathetic innervation assessed by metaiodobenzylguanidine (MIBG) activity has long-term prognostic value in combination with left ventricular hypertrophy (LVH) and left atrial size in heart failure (HF) patients without reduced left ventricular ejection fraction (LVEF). DESIGN: A single-centre prospective cohort study. SETTING/PARTICIPANTS: With primary endpoints of cardiac death and rehospitalisation due to HF progression, 178 consecutive symptomatic HF patients with 74% men, mean age of 56 years and mean LVEF of 64.5% were followed up for 80 months. The entry criteria consisted of LVEF more than 50%, completion of predischarge clinical evaluations including cardiac MIBG and echocardiographic studies and at least more than 1-year follow-up when survived. RESULTS: Thirty-four patients with cardiac evens had larger left atrial dimension (LAD), increased LV mass index, reduced MIBG activity quantified as heart-to-mediastinum ratio (HMR) than did the others. Multivariable Cox analysis showed that LAD and HMR were significant predictors (HR of 1.080 (95% CI 1.00 to 1.16, p=0.044) and 0.107 (95% CI 0.01 to 0.61, p=0.012, respectively). Thresholds of HMR (1.65) and LAD (37 mm) were closely related to identification of high-risk patients. In particular, HMR was a significant determinant of cardiac events in both patients with and without LV hypertrophy. Reduced HMR with enlarged LAD or LV hypertrophy identified patients at most increased risk; overall log-rank value, 11.5, p=0.0032 for LAD and 17.5, p=0.0002, respectively. CONCLUSIONS: In HF patients without reduced LV ejection fraction, impairment of cardiac sympathetic innervation is related to cardiac outcomes independently and synergistically with LA size and LV hypertrophy. Cardiac sympathetic innervation assessment can contribute to better risk-stratification in combination with evaluation of LA size and LV mass but is needed to be evaluated for establishing aetiology-based risk assessment in HF patients at increased risk.

DOI PubMed J-GLOBAL

Role of ER stress in ventricular contractile dysfunction in type 2 diabetes

Takada, Akifumi, Miki, Takayuki, Kuno, Atsushi, Kuno, Atsushi, Kouzu, Hidemichi, Sunaga, Daisuke, Itoh, Takahito, Tanno, Masaya, Yano, Toshiyuki, Sato, Tatsuya, Sato, Tatsuya, Ishikawa, Satoko, Miura, Tetsuji

PLoS ONE 7 ( 6 ) e39893 2012年 [国際誌]

BACKGROUND: Diabetes mellitus (DM) is associated with an increased risk of ischemic heart disease and of adverse outcomes following myocardial infarction (MI). Here we assessed the role of endoplasmic reticulum (ER) stress in ventricular dysfunction and outcomes after MI in type 2 DM (T2DM). METHODOLOGY AND PRINCIPAL FINDINGS: In hearts of OLETF, a rat model of T2DM, at 25∼30 weeks of age, GRP78 and GRP94, markers of ER stress, were increased and sarcoplasmic reticulum calcium ATPase (SERCA)2a protein was reduced by 35% compared with those in LETO, a non-diabetic control. SERCA2a mRNA levels were similar, but SERCA2a protein was more ubiquitinated in OLETF than in LETO. Left ventricular (LV) end-diastolic elastance (Eed) was higher in OLETF than in LETO (53.9±5.2 vs. 20.2±5.6 mmHg/µl), whereas LV end-systolic elastance and positive inotropic responses to β-adrenergic stimulation were similar in OLETF and LETO. 4-Phenylbutyric acid (4-PBA), an ER stress modulator, suppressed both GRP up-regulation and SERCA2a ubiquitination and normalized SERCA2a protein level and Eed in OLETF. Sodium tauroursodeoxycholic acid, a structurally different ER stress modulator, also restored SERCA2a protein level in OLETF. Though LV dysfunction was modest, mortality within 48 h after coronary occlusion was markedly higher in OLETF than in LETO (61.3% vs. 7.7%). Telemetric recording showed that rapid progression of heart failure was responsible for the high mortality rate in OLETF. ER stress modulators failed to reduce the mortality rate after MI in OLETF. CONCLUSIONS: ER stress reduces SERCA2a protein via its augmented ubiquitination and degradation, leading to LV diastolic dysfunction in T2DM. Even at a stage without systolic LV dysfunction, susceptibility to lethal heart failure after infarction is markedly increased, which cannot be explained by ER stress or change in myocardial response to sympathetic nerve activation.

DOI PubMed J-GLOBAL

Left ventricular hypertrophy causes different changes in longitudinal, radial, and circumferential mechanics in patients with hypertension: a two-dimensional speckle tracking study.

Hidemichi Kouzu, Satoshi Yuda, Atsuko Muranaka, Takahiro Doi, Hitomi Yamamoto, Shinya Shimoshige, Mamoru Hase, Akiyoshi Hashimoto, Shigeyuki Saitoh, Kazufumi Tsuchihashi, Tetsuji Miura, Naoki Watanabe, Kazuaki Shimamoto

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography 24 ( 2 ) 192 - 9 2011年02月 [国際誌]

BACKGROUND: Systolic reserve is an important compensatory mechanism against increasing afterload. Although longitudinal systolic dysfunction with preserved ejection fraction has been reported in hypertensive hearts, radial and circumferential function has not been fully examined. The aim of this study was to investigate three-directional systolic function and its relationships with left ventricular geometry in asymptomatic hypertensive patients using two-dimensional speckle-tracking imaging. METHODS: Echocardiographic evaluations were performed in 74 hypertensive patients and 55 age-matched control subjects. RESULTS: Longitudinal strain was significantly reduced in the hypertrophy groups compared with that in control subjects (concentric, -15.1 ± 4.0%; eccentric, -15.9 ± 4.4%; control, -18.9 ± 3.3%; P < .05). Conversely, radial strain was significantly higher in the normal geometry group than in control subjects (53.8 ± 19.4% vs 40.3 ± 15.1%, P < .05). However, this augmentation was attenuated in the other geometries. CONCLUSION: Hypertrophic remodeling attenuates compensatory augmentation of radial systolic function and is associated with latent longitudinal systolic dysfunction.

DOI PubMed

高血圧性肥大心筋は,心筋梗塞に対して脆弱であり,エリスロポエチン誘発性保護に対し難治性がある

YANO Toshiyuki, MIKI Takayuki, TANNO Masaya, KUNO Atsushi, ITOH Takahito, TAKADA Akifumi, SATO Tatsuya, KOUZU Hidemichi, SHIMAMOTO Kazuaki, MIURA Tetsuji

Hypertension 57 ( 1 ) 110 - 5 2011年01月 [国際誌]

The objective of this study was to examine the hypothesis that hypertensive hypertrophy is vulnerable to infarction and defective in cytoprotective mechanisms by modification of intracellular signaling and mitochondrial proteins. Myocardial infarction was induced by 20-minute coronary occlusion/reperfusion in spontaneously hypertensive stroke-prone rats (SHR-SPs) and their controls (Wistar-Kyoto rats [WKYs]). Infarct size expressed as a percentage of area-at-risk was larger by 29% in SHR-SPs than in WKYs. Pretreatment with erythropoietin (EPO) significantly limited infarct size in WKYs but not in SHR-SPs. Ca(2+) retention capacity of mitochondria, an index of the threshold for opening of the mitochondrial permeability transition pore, on reperfusion was reduced in SHR-SPs compared with that in WKYs. Suppression of reactive oxygen species by N-(2-mercaptopropionyl)-glycine increased Ca(2+) retention capacity after reperfusion and limited infarct size in SHR-SPs to levels in WKYs. EPO induced phosphorylation of Akt, extracellular signal-related kinase, and glycogen synthase kinase-3β in the myocardium in both WKYs and SHR-SPs. EPO enhanced interaction of phospho-glycogen synthase kinase-3β and adenine nucleotide translocase on reperfusion in WKYs, although such an effect of EPO was not detected in SHR-SPs. The results suggest that enhanced opening of mitochondrial permeability transition pores by reactive oxygen species and modification of the signal downstream of phospho-glycogen synthase kinase-3β in the mitochondria underlie the increased vulnerability to infarction and the lack of anti-infarct tolerance by EPO, respectively, in hypertensive hypertrophied hearts.

DOI PubMed J-GLOBAL

左房前後径が正常な患者における心エコー法容積により評価した左房拡張の予後との関連

MURANAKA Atsuko, YUDA Satoshi, ICHIMURA Maki, DOI Takahiro, YAMAMOTO Hitomi, KOUZU Hidemichi, KANEKO Naofumi, FUJII Sakiko, FUJII Noriyuki, SHIMOSHIGE Shinya, HASHIMOTO Akiyoshi, NAKATA Tomoaki, TSUCHIHASHI Kazufumi, MIURA Tetsuji, WATANABE Naoki, SHIMAMOTO Kazuaki

Journal of Echocardiography 7 ( 4 ) 63 - 63 2009年12月 [国内誌]

BACKGROUND: The purpose of this study was to clarify the clinical characteristics and prognostic implications of left atrial (LA) dilation evaluated echocardiographic volume in patients with normal LA dimension (LAD). METHODS: A total of 140 consecutive patients (81 men, mean age: 57 ± 18 years) with normal LAD (<39 mm for women and <41 mm for men) who underwent conventional echocardiography and tissue Doppler imaging were enrolled. LA volume (LAV) ≥29 ml/m(2) was defined as abnormal LAV. Hospitalization for heart failure (HF) and cardiac death were defined as cardiac events. RESULTS: Eighty-seven (62%) of the patients had LA dilation, defined as a normal LAD but an abnormal LAV. Patients with LA dilation were significantly older and had a significantly higher left ventricular (LV) mass index (LVMI) and incidences of hypertension and HF than did patients with both normal LAD and normal LAV. Logistic regression analysis revealed that increased LVMI was an independent (p < 0.01) determinant of LA dilatation. During a follow-up period of 16 ± 10 months, ten patients had cardiac events. Patients with cardiac events had a higher incidence of LA dilation than those without cardiac events (100 vs. 59%, p < 0.05). A Kaplan-Meier survival curve showed that patients with LA dilation had a significantly lower survival rate than those with both normal LAD and normal LAV (log rank 6.1, p = 0.014). CONCLUSIONS: LV hypertrophy is an independent determinant of LA dilation in patients with normal LAD. Assessment of LA morphology using LAV can contribute to risk stratification in patients with normal LAD.

DOI PubMed J-GLOBAL

Noninvasive Estimation of Pulmonary Vascular Resistance by Doppler Echocardiography in Patients With Pulmonary Arterial Hypertension

Kouzu, Hidemichi, Nakatani, Satoshi, Kyotani, Shingo, Kanzaki, Hideaki, Nakanishi, Norifumi, Kitakaze, Masafumi

American Journal of Cardiology 103 ( 6 ) 872 - 6 2009年03月 [国際誌]

Pulmonary vascular resistance (PVR) is an important hemodynamic variable in the management of patients with pulmonary hypertension. To establish a method of estimating PVR in patients with pulmonary arterial hypertension (PAH), Doppler echocardiography was performed within 24 hours of right heart catheterization in 43 patients with PAH (idiopathic PAH, n = 20; chronic thromboembolic pulmonary hypertension, n = 9; congenital heart disease, n = 9; and others). Correlations between invasive PVR and Doppler variables of pulmonary artery flow and tricuspid regurgitation were examined. Mean invasive PVR was 1,294 +/- 680 dyne s cm(-5). Linear regression analysis revealed significant correlations with invasive PVR for the time-velocity integral (TVI; r = -0.63, p = 0.009) of right ventricular outflow and peak tricuspid regurgitant pressure gradient (TRPG; r = 0.77, p <0.001). The TRPG/TVI ratio, which approximated the ratio of pulmonary artery pressure to pulmonary blood flow, showed an improved correlation coefficient of 0.82 (PVR = 187 + TRPG/TVI x 118, p <0.001). After excluding 5 patients with an intracardiac shunt, 26 of the remaining 38 patients (68%) met the hemodynamic criteria in international guidelines for the selection of lung transplantation candidates and were defined as the poor-prognosis group. A TRPG/TVI >7.6 showed 85% sensitivity and 92% specificity for identifying patients in the poor-prognosis group. In conclusion, TRPG/TVI provides a reliable estimation of PVR over a wide range in patients with PAH with various underlying causes.

DOI PubMed J-GLOBAL

Possible impairment of transcardiac utilization of adiponectin in patients with type 2 diabetes.

Masato Furuhashi, Nobuyuki Ura, Norihito Moniwa, Yasuyuki Shinshi, Hidemichi Kouzu, Masahiro Nishihara, Nobuaki Kokubu, Toru Takahashi, Ken-Ichi Sakamoto, Manabu Hayashi, Naotoshi Satoh, Takahiro Nishitani, Yasukuni Shikano, Kazuaki Shimamoto

Diabetes care 27 ( 9 ) 2217 - 21 2004年09月 [国際誌]

OBJECTIVE: Adiponectin, an adipocyte-derived protein, has been suggested to enhance insulin sensitivity and prevent atherosclerosis. Circulating adiponecin levels are reduced in states of insulin resistance such as type 2 diabetes. We examined transcardiac utilization of adiponectin in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 17 male type 2 diabetic patients and 17 male nondiabetic patients were investigated. Venous blood samples were taken to measure glucose and lipid variables. Blood samples for the measurement of adiponectin were collected simultaneously from the aortic root and coronary sinus. Angiographic semiquantitative stenosis score of coronary artery was also evaluated. RESULTS: The adiponectin levels in both the aortic root and coronary sinus in the diabetic patients were significantly lower than those in the nondiabetic patients. The adiponectin level was significantly lower in the coronary sinus than in the aortic root in the nondiabetic patients, but there was no significant difference between adiponectin levels in the aortic root and coronary sinus in the diabetic patients. The total stenosis score, as an index of severity of coronary artery stenosis, was significantly higher in the diabetic patients than in the nondiabetic patients. The stenosis score was correlated with the degree of transcardiac utilization of adiponectin from the aortic root to coronary sinus in the nondiabetic patients but not in the diabetic patients. CONCLUSIONS: Diabetic patients not only have a decreased adiponectin level in the basal state compared with nondiabetic patients but also have impaired utilization of adiponectin in the coronary artery and/or the heart, which may promote the development of atherosclerosis.

PubMed

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