Faculty Profiles - MORITA Hiroshi

Papers - MORITA Hiroshi

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Atrial electrophysiological and structural remodeling in high-risk patients with Brugada syndrome: assessment with electrophysiology and echocardiography. International journal

Norihisa Toh, Hiroshi Morita, Satoshi Nagase, Manabu Taniguchi, Daiji Miura, Nobuhiro Nishii, Kazufumi Nakamura, Tohru Ohe, Kengo F Kusano, Hiroshi Ito

Heart rhythm 7 ( 2 ) 218 - 24 2010

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Atrial fibrillation (AF) often occurs in Brugada syndrome (BrS), and BrS patients with spontaneous AF often experience ventricular fibrillation (VF) attacks. Atrial vulnerability providing a substrate for AF is known to be enhanced in BrS, but there are no data on atrial structural attributes. OBJECTIVE: The objective of this study was to assess atrial electrophysiological and structural characteristics in BrS and their relationships with gene mutations. METHODS: We studied 57 patients with BrS. Intra-atrial conduction time (CT) was defined as the interval from the stimulus at the high right atrium to atrial deflection at the distal portion of the coronary sinus. Left atrial volume index (LAVI) was measured by the modified Simpson method at left ventricular end-systole using echocardiography. SCN5A mutations were analyzed in all patients. RESULTS: In patients with documented VF, spontaneous AF frequently occurred and prolonged CT and increased LAVI were observed compared with those in patients without VF (all P < .05; LAVI: 22 +/- 5 vs. 32 +/- 7 ml/m(2)). Even among patients without AF, CT and LAVI were still increased in patients with VF (all P < .05; LAVI: 22 +/- 5 vs. 29 +/- 5 ml/m(2)). The presence of SCN5A mutation was associated with prolonged CT (P < .05) and increased LAVI (P < .01), but not with arrhythmic episodes. CONCLUSION: Both atrial vulnerability and structural remodeling are enhanced in high-risk patients with BrS, even in those without AF. These morphological characteristics suggest that BrS is a form of genetic myocardial disease.

DOI： 10.1016/j.hrthm.2009.10.035

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Cytokine reducing effect of azelnidipine in human peripheral blood mononuclear cells.

Ryuzea Miura, Kazufumi Nakamura, Daiji Miura, Aya Miura, Masahito Kajiya, Kenichi Hisamatsu, Satoshi Nagase, Hiroshi Morita, Kengo Fukushima Kusano, Hiromi Matsubara, Tohru Ohe, Hiroshi Ito

Biological & pharmaceutical bulletin 33 ( 7 ) 1148 - 51 2010

Language：English Publishing type：Research paper (scientific journal)

Numerous clinical trials have shown that calcium channel blocker (CCB) therapy improves the clinical outcome in patients with cardiovascular diseases. Since the progression of several types of cardiovascular diseases is closely associated with inflammation, alleviation of inflammation may be one potential mechanism of those beneficial effects of CCB therapy. We examined whether a new CCB (azelnidipine) could influence the inflammatory response of human peripheral blood mononuclear cells (PBMCs), which are recruited to inflammatory lesions and modulate inflammation. We investigated whether azelnidipine affected intracellular signaling and cytokine production by phytohemagglutinin (PHA)-stimulated human PBMCs in vitro. PBMCs were obtained from 10 healthy volunteers and stimulated with PHA. Then relative intracellular calcium ion concentration ([Ca(2+)](i)) was assessed by fluorescence microscopy, and the production of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay. Stimulation with PHA significantly raised [Ca(2+)](i) and enhanced the production of MCP-1 and TNF-alpha by human PBMCs. Azelnidipine significantly diminished the PHA-induced rise of [Ca(2+)](i), and the production of MCP-1 and TNF-alpha. These findings indicate that azelnidipine might have an anti-inflammatory influence on human PBMCs, although the mechanisms and the difference from other CCBs still remain unclear and further exploration should be required.

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Brugada syndrome: insights of ST elevation, arrhythmogenicity, and risk stratification from experimental observations. International journal

Hiroshi Morita, Douglas P Zipes, Jiashin Wu

Heart rhythm 6 ( 11 Suppl ) S34-43 2009.11

Language：English Publishing type：Research paper (scientific journal)

Brugada syndrome (BrS), caused by ion channel abnormalities, is characterized by ST segment elevation and negative T waves in the right precordial electrocardiographic (ECG) leads recorded over the right ventricular outflow tract (RVOT). BrS is sensitive to body temperature and can lead to T-wave alternans (TWA), ventricular tachycardia, and sudden death. Recent studies in an isolated canine RVOT model of BrS demonstrated that reversal of the transmural gradient of repolarization caused the ECG characteristics and that major intraepicardial and transmural dispersion of action potentials (APs) initiated phase 2 reentry, premature ventricular activations, and tachyarrhythmias. Hypothermia enhanced the heterogeneity of the AP and promoted the origination of phase 2 reentry in the epicardium of the RVOT, but the prolonged AP duration frequently blocked reentry. Hyperthermia abbreviated the AP and facilitated the maintenance of reentry and tachyarrhythmias. Bradycardia promoted alternans in the phase 2 dome of the AP within the epicardium of the RVOT, resulting in TWA. The above phenomena were localized in the epicardium of the RVOT. Blockade of the transient outward current, I(to), reduced AP heterogeneity and prevented arrhythmias in the BrS model. In addition, epicardial activation delay led to fragmented QRS, a risk marker of prognosis in BrS. Body surface mapping in patients with BrS supported these experimental findings. In conclusion, the AP heterogeneity within the epicardium of the RVOT contributes to the ECG characteristics, temperature sensitivity, TWA, and arrhythmias in BrS, and body surface mapping and fragmented QRS can be effective predictors of risk in patients with BrS.

DOI： 10.1016/j.hrthm.2009.07.018

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Imatinib Inhibits Proliferation and Migration and Induces Apoptosis in Pulmonary Artery Smooth Muscle Cells From Patients With Idiopathic Pulmonary Arterial Hypertension Reviewed

Kazufumi Nakamura, Satoshi Akagi, Hiromi Matsubara, Aiko Ogawa, Aya Miura, Daiji Miura, Nobuhiro Nishii, Satoshi Nagase, Hiroshi Morita, Yoshiki Hata, Kengo F. Kusano, Hiroshi Ito

CIRCULATION 120 ( 18 ) S1136 - S1136 2009.11

Relationship between circulating levels of monocyte chemoattractant protein-1 and systolic dysfunction in patients with hypertrophic cardiomyopathy

Jun Iwasaki, Kazufumi Nakamura, Hiromi Matsubara, Yoichi Nakamura, Nobuhiro Nishii, Kimikazu Banba, Masato Murakami, Keiko Ohta-Ogo, Hideo Kimura, Norihisa Toh, Satoshi Nagase, Takefumi Oka, Hiroshi Morita, Kengo Fukushima Kusano, Tohru Ohe

CARDIOVASCULAR PATHOLOGY 18 ( 6 ) 317 - 322 2009.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background: Progression of hypertrophic cardiomyopathy (HCM) to left ventricular dilatation and systolic dysfunction sometimes occurs. However, the mechanism of the transition from hypertrophy to dysfunction has not been elucidated. It has been reported that circulating levels of monocyte chemoattractant protein-1 (MCP-1), which is a major factor promoting the accumulation of macrophages, are increased in patients with congestive heart failure. We measured circulating levels of MCP-1 in patients with HCM and examined whether MCP-1 was expressed in the myocardium of HCM patients. We also examined whether circulating levels of MCP-1 were correlated with left ventricular dysfunction. Methods: Circulating levels of MCP-1 were measured by an enzyme immunoassay in 26 patients with HCM (60 2 years old) and 20 control subjects (57 2 years old). Cardiac function was evaluated by two-dimensional echocardiography and cardiac catheterization. Results: HCM patients had significantly elevated levels of MCP-1 (HCM: 309+/-30 vs. control: 178+/-8 pg/ml, P<001). MCPI levels in patients with systolic dysfunction were significantly higher than those in patients without systolic dysfunction (P<05) and were also significantly higher than those in patients with outflow obstruction (P<05). Immunohistochemical analysis revealed that MCP-1 was expressed in endomyocardial biopsy samples obtained from HCM patients with systolic dysfunction. Furthermore, MCP-1 levels were inversely correlated with fractional shortening (r=-.4011, P<05) and correlated with left ventricular end-diastolic pressure (r=-.579, P<01). Conclusion: These results show that MCP-1 is associated with, and might be involved in the pathogenesis of, left ventricular systolic dysfunction in patients with HCM. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.carpath.2008.12.004

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4-Hydroxy-2-nonenal induces calcium overload via the generation of reactive oxygen species in isolated rat cardiac myocytes. International journal

Kazufumi Nakamura, Daiji Miura, Kengo Fukushima Kusano, Yoshihisa Fujimoto, Wakako Sumita-Yoshikawa, Soichiro Fuke, Nobuhiro Nishii, Satoshi Nagase, Yoshiki Hata, Hiroshi Morita, Hiromi Matsubara, Tohru Ohe, Hiroshi Ito

Journal of cardiac failure 15 ( 8 ) 709 - 16 2009.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: It has been reported that that the amount of 4-hydroxy-2-nonenal (HNE), which is a major lipid peroxidation product and a cytotoxic aldehyde, is increased in the human failing myocardium. This study was designed to determine whether HNE has a pro-oxidant effect in cardiac myocytes and whether HNE causes Ca(2+) overload. METHODS AND RESULTS: Exposure to HNE for 10 minutes in the presence of ferric nitrilotriacetate induced the production of hydroxyl radical (.OH) in the rat myocardium as assessed by electron spin resonance spectroscopy, and HNE induced the generation of reactive oxygen species (ROS) in a dose-dependent manner as assessed by 2', 7'-dichlorofluorescein diacetate fluorescence. HNE increased intracellular Ca(2+) concentration ([Ca(2+)](i)) as assessed by fura-2 ratio in a dose- and time-dependent manner. After 20 minutes of HNE (400 micromol/L) exposure, hypercontracture was induced in 67% of the cells. Catalase, an antioxidative enzyme that can decompose hydrogen peroxide (H(2)O(2)), significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture. Carvedilol, a beta-blocker with potent antioxidant activity, also significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture, but propranolol had no effect on either [Ca(2+)](i) increase or hypercontracture. CONCLUSIONS: HNE induces the formation of ROS, especially H(2)O(2) and .OH, in cardiomyocytes and subsequently ROS cause intracellular Ca(2+) overload. HNE formation may play an important role as a mediator of oxidative stress in heart failure.

DOI： 10.1016/j.cardfail.2009.04.008

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心臓サルコイドーシスの新たな展開心サルコイドーシスにおける不整脈の検討

草野研吾, 伴場主一, 高谷陽一, 西井伸洋, 永瀬聡, 中村一文, 森田宏, 伊藤浩, 大江透

日本サルコイドーシス/肉芽腫性疾患学会雑誌 29 ( サプリメント号 ) 23 - 23 2009.10

Abnormal transmural repolarization process in patients with Brugada syndrome. International journal

Mutsuko Sangawa, Hiroshi Morita, Takaaki Nakatsu, Nobuhiro Nishii, Daiji Miura, Aya Miura, Takeshi Tada, Masato Murakami, Shigeki Hiramatsu, Satoshi Nagase, Kazufumi Nakamura, Takefumi Oka, Shinji Toyonaga, Keiichi Mashima, Shozo Kusachi, Kazuhide Yamamoto, Tohru Ohe, Kengo F Kusano

Heart rhythm 6 ( 8 ) 1163 - 9 2009.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Repolarization abnormality, especially during bradycardia, might be critical for initiation of ventricular fibrillation (VF) in patients with Brugada syndrome (BrS), but the contribution of the rate-dependent repolarization dynamics to the occurrence of VF is still unknown. OBJECTIVE: The aim of our study was to determine the differences in rate-dependent repolarization dynamics between BrS with and without spontaneous VF and between BrS with and without SCN5A mutation. METHODS: The subjects were 37 BrS patients with VF (VF(+) group: 10 male subjects) and without VF (VF(-) group: 27 male subjects) and 20 control subjects. Genetic analysis of SCN5A was performed in all 37 BrS patients. The relationships between QT, QTp, Tp-e, and RR intervals were obtained from Holter recordings as first linear regression lines, and the slopes of QT/RR, QTp/RR, and Tp-e/RR linear regression lines as the sensitivity of rate-dependent repolarization dynamics were compared. RESULTS: QT/RR and Tp-e/RR slopes showed loss of a rate-dependent property in the VF(+) group compared with those in the VF(-) and control groups. There was no significant difference in QTp/RR slope among the VF(+), VF(-) and control groups. The Tp-e interval had a negative correlation with the RR interval in the VF(+) group and a positive correlation with the RR interval in the VF(-) and control groups. There was no significant difference in QT/RR, QTp/RR, and Tp-e/RR slopes between BrS patients with SCN5A mutation and those without SCN5A mutation. CONCLUSIONS: Loss of rate-dependent QT dynamics may be associated with occurrence of VF in BrS.

DOI： 10.1016/j.hrthm.2009.04.037

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心腔内除細動が心機能に与える影響についての検討

杜徳尚, 西井伸洋, 森田宏, 谷口学, 永瀬聡, 中村一文, 草野研吾, 伊藤浩

日本心臓病学会誌 4 ( Suppl.I ) 226 - 226 2009.8

赤血球容積分布幅(RDW)の非虚血性心疾患患者における予後予測因子としての検討

木島康文, 草野研吾, 福家聡一郎, 西井伸洋, 永瀬聡, 幡芳樹, 中村一文, 森田宏, 伊藤浩

日本心臓病学会誌 4 ( Suppl.I ) 437 - 437 2009.8

非Brugada型特発性心室細動12例の検討

平松茂樹, 森田宏, 中川晃志, 田中正道, 村上正人, 多田毅, 西井伸洋, 永瀬聡, 幡芳樹, 草野研吾

心電図 29 ( Suppl.3 ) S - 380 2009.6

植込み型除細動器植込み術時における除細動閾値テストの心機能に与える影響についての検討

杜徳尚, 西井伸洋, 森田宏, 谷口学, 永瀬聡, 中村一文, 草野研吾

心電図 29 ( Suppl.3 ) S - 405 2009.6

植込み型除細動器を植込まれたBrugada症候群患者における適切作動、不適切作動の検討

西井伸洋, 森田宏, 中川晃司, 田中正道, 平松茂樹, 多田毅, 村上正人, 永瀬聡, 中村一文, 幡芳樹, 草野研吾

心電図 29 ( Suppl.3 ) S - 291 2009.6

Epicardial ablation eliminates ventricular arrhythmias in an experimental model of Brugada syndrome. International journal

Hiroshi Morita, Douglas P Zipes, Shiho T Morita, John C Lopshire, Jiashin Wu

Heart rhythm 6 ( 5 ) 665 - 71 2009.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Although radiofrequency catheter ablation (RFCA) has been used to treat patients with Brugada syndrome (BS), it is difficult to eliminate polymorphic ventricular tachycardias (VTs) completely. OBJECTIVE: The purpose of this study was to determine the efficacy of RFCA in eliminating recurrent VTs in an experimental model of BS. METHODS: We optically mapped electrical activity on the epicardial (n = 9) or transmural (n = 8) surface in 17 arterially perfused canine right ventricle preparations. Using pinacidil (5 microM) and pilsicainide (5 microM), we induced a model of BS that showed spontaneous VT. We then applied RFCA to the earliest activation site of premature ventricular complexes (PVCs) in the epicardium (EPI) or endocardium (ENDO) of the RV. RESULTS: After induction of BS, the transmural electrocardiogram (ECG) showed BS-type ECG in association with prominent heterogeneity of action potential duration (APDs) within the EPI (APD: maximum 272 +/- 39 ms, minimum 200 +/- 39 ms, P < .01), but not within the ENDO. PVCs originated in the EPI region having short APDs and triggered functional reentry causing VT. Multiple epicardial foci of PVCs existed in each tissue (3.7 +/- 1.9 foci/tissue). RFCA at the earliest activation site of PVCs in the EPI disconnected the short and long APD regions and eliminated all PVCs and VTs, although APD heterogeneity still existed. All successful RFCA lesions were confined to the EPI. RFCA in the ENDO failed to eliminate VT or PVCs. CONCLUSION: These experimental observations suggest that RFCA applied to the EPI may be more effective than applied to the ENDO in eliminating VT in patients with BS.

DOI： 10.1016/j.hrthm.2009.01.007

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Differential effects of cardiac sodium channel mutations on initiation of ventricular arrhythmias in patients with Brugada syndrome. International journal

Hiroshi Morita, Satoshi Nagase, Daiji Miura, Aya Miura, Shigeki Hiramatsu, Takeshi Tada, Masato Murakami, Nobuhiro Nishii, Kazufumi Nakamura, Shiho T Morita, Takefumi Oka, Kengo F Kusano, Tohru Ohe

Heart rhythm 6 ( 4 ) 487 - 92 2009.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Premature ventricular contractions (PVCs) do not occur frequently but can induce ventricular fibrillation (VF) in patients with Brugada syndrome. The effect of SCN5A mutation on the onset of ventricular arrhythmias is unknown. OBJECTIVE: The purpose of this study was to evaluate PVC morphology and onset of VF in patients with Brugada syndrome. METHODS: Morphology of PVCs was evaluated by 12-lead ECG in 32 patients with Brugada syndrome. Patients had spontaneous ventricular arrhythmia (n = 17) or sodium channel blocker-induced ventricular arrhythmia (n = 19). Patients were classified into two groups according to the existence of SCN5A mutation (22 mutation negative, 10 mutation positive). RESULTS: Patients without mutation often had PVCs of left bundle branch block (LBBB) morphology (82%), especially with inferior axis (77%). Patients with mutation had PVCs of both right bundle branch block (36%) and LBBB (64%) morphologies. Only two patients with mutation had PVCs of LBBB, inferior-axis morphology. CONCLUSION: Patients without SCN5A mutation often had PVCs of LBBB, inferior-axis morphology, suggesting a right ventricular outflow tract origin. Patients with SCN5A mutations had PVCs that originated from both the right and left ventricles.

DOI： 10.1016/j.hrthm.2009.01.031

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心内膜心筋生検において著明な脂肪浸潤を認めたBrugada症候群の1例

田中正道, 多田毅, 村上正人, 平松茂樹, 西井伸洋, 永瀬聡, 幡芳樹, 中村一文, 森田宏, 草野研吾, 由谷親夫

Circulation Journal 73 ( Suppl.II ) 970 - 970 2009.4