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Abstract 280: Pigment Epithelium-Derived Factor (PEDF) Inhibits Neointima Formation by Suppressing NADPH Oxidase-Mediated Reactive Oxygen Species Generation
- Kazuo NAKAMURA
Circulation Volume 114, Issue suppl_1831 October 2006

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We have previously found that pigment epithelium-derived factor (PEDF), a glycoprotein with neuronal differentiating activity, inhibited tumor necrosis factor-a- or angiotensin II-induced endothelial cell activation through its anti-oxidative properties, thus suggesting that PEDF may play a protective role against endothelial injury. However, the effects of PEDF on restenosis, a frequent complication of coronary angioplasty, remain to be elucidated. The pathophysiological feature of restenosis is characterized by increased superoxide formation and accumulation of smooth muscle cells (SMCs) within the intimal area via overexpression of platelet-derived growth factor (PDGF), it is conceivable that PEDF inhibits this process via suppression of reactive oxygen species (ROS) generation. Accordingly, we investigated here whether and how an overexpression of PEDF could prevent neointima formation in balloon-injured rat carotid arteries. Fourteen days after balloon injury, intima/media (I/M) ratio was increased by about 40-folds of that of non-injured artery. Adenoviral vector encoding human PEDF (Ad-PEDF) decreased the I/M ratio by 80%. Expression levels of two membrane components of NADPH oxidase, p22phox and gp91phox and superoxide generation in the neointima were also significantly blocked by Ad-PEDF. Further, Ad-PEDF not only reduced expression levels of G1 cyclins, cyclin D and E, but also stimulated p27, a cyclin-dependent kinase inhibitor that causes G1 arrest, thus decreasing the number of proliferating cell nuclear antigen-positive SMCs in the neointima. In vitro, 10 nM PEDF was found to inhibit PDGF-B-induced SMC proliferation and migration by blocking ROS generation via suppression of NADPH oxidase activity. PEDF down-regulated cyclin D and up-regulated p27 levels in PDGF-BB-exposed SMC as well. These results demonstrate that PEDF could prevent the neointima formation by suppressing the proliferation and migration of SMCs via inhibition of NADPH oxidase-mediated ROS generation. Our present study suggests that PEDF may be a novel therapeutic target for the treatment of restenosis after balloon angioplasty.
Methionine enkephalinergic neuronal activity in cerebral nuclei of spontaneously hypertensive rats.
- K Nakamura and
- T Hayashi
Hypertension Volume 4, Issue 51 September 1982

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The role of methionine enkephalin (ME) neurons in the development of genetic hypertension in SHR is the subject of this study. Methionine enkephalin-like immunoreactivity (MELI) and ME receptor binding (MERB) levels were assayed quantitatively by microdensitometry of fluorescence micrographs and autoradiographs of 85 cerebral nuclei and areas of both young and adult spontaneously hypertensive rats (SHR). Normotensive Wistar Kyoto rats (WKY) were used as controls. In young SHR, both MELI and MERB levels were markedly higher in the n. dorsalis nervi vagi, n. amygdaloideus medialis, and group of stria terminal nuclei than in those of young WKY, while both levels were lower in the n. reticularis lateralis, n. corporis mamillaris lateralis, and n. arcuatus. MELI levels in the tractus spinalis nervi trigemini and MERB in the n. tractus spinalis nervi trigemini and median eminence were also lower in young SHR, whereas MERB in the n. amygdaloideus centralis was higher. Alteration in these nuclei was no longer detectable in adult SHR. Whereas in adult SHR, both MELI and MERB levels in the n. reticularis medialis were higher than those of adult WKY, and MELI in the n. accumbens septi and MERB in the n. caudatus were also higher, while MELI in the area lateralis hypothalami was lower than that in adult WKY. The findings indicate that activation of ME neurons in the n. dorsalis nervi vagi and limbic area and also a decrease in ME neuronal activity in the area spinalis nervi trigemini, n. reticularis lateralis, and n. arcuatus may be casually related to the development of hypertension and hyperreactivity in SHR.
Abstract 14136: Effectiveness of Adaptive Servo-Ventillation for the Prevention of Atrial fibrillation Recurrence after Radiofrequency Catheter Ablation
- Keijiro Nakamura,
- Koji Kumagai,
- Takehito Sasaki,
- Naofumi Tsukada,
- Yohsuke Nakatani,
- Mamoru Hayano,
- Suguru Nishiuchi,
- Kohki Nakamura,
- Kenichi Kaseno,
- Shigeto Naito and
- Shigeru Ohshima
Circulation Volume 126, Issue suppl_2120 November 2012

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Bachground: Early recurrence of atrial fibrillation (AF) after successful pulmonary vein electrical isolation (PVI) is indicated as a predictor of late recurrence, the prevention of early recurrence by aggressive intervention improves AF outcome. A novel respiration device called adaptive servo-ventilation (ASV) has been developed for central sleep apnea, ASV therapy improves heart failure and cardiac function. The aim of the present study was to investigate the efficacy of ASV therapy during a short period for preventing AF recurrence after catheter ablation.Methods: This study consisted of consecutive 112 AF patients (mean age: 64.3±8.1, 87 male, paroxysmal: n=42, persistent: n=37, long-standing: n=33). All patients underwent an overnight full polysomnography and circumferential PVI guided by CARTO system. 56 patients were randomly received ASV therapy (ASV group) with agreement by informed consent at overnight during 3 days after ablation procedure, 4 rejected patients with poor compliance after first introductory night were excluded from this study. Other 56 patient were analyzed as control (non ASV group). Plasma B-type natriuretic peptide (BNP) and serum C reactive protein (CRP) were evaluated before and on 2 days after ablation.Results: Baseline characteristics did not differ significantly between two groups. Plasma BNP after ablation was significantly lower in ASV group than non ASV group (p<0.01), and Plasma BNP significantly decreased in ASV group (p<0.05). Serum CRP after ablation was increased in non ASV group (p<0.05). Early AF recurrence during 30 days after ablation significantly was lower in ASV group than in non ASV group (ASV goup= 24%, non ASV group=41%, p<0.05). During a follow-up of 14.3 ± 5.7 months, AF free rate in persistent AF patients ( including long-standing persistent AF) was lower in ASV group than in non ASV group (p<0.05 by the log-rank test). Multivariate analysis showed that AF recurrence in persistent AF was associated with was associated with BNP after ablation and E/e’ (p<0.01,p<0.05, respectively).Conclusion: ASV therapy during a short period after AF ablation improved plasma BNP, and may be effective for AF recurrence, especially in patients with persistent AF.
Sequential changes of cerebrospinal fluid sodium during the development of hypertension in Dahl rats.
- K Nakamura and
- A W Cowley
Hypertension Volume 13, Issue 31 March 1989

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The role of sodium retention and consequent changes in cerebrospinal fluid sodium concentration in the genesis of hypertension in Dahl rats was evaluated. Dahl salt-sensitive (DS, n = 7), Dahl salt-resistant (DR, n = 7), and Sprague-Dawley (n = 6) rats were housed in metabolic cages and instrumented with a stainless steel cannula in the cisterna magna and a femoral arterial catheter. A blood sample was drawn daily (200 microliters), and cerebrospinal fluid was collected by continuous 24-hour withdrawal (200 microliters/day). Daily sodium, potassium, and water balances were also determined. Rats were studied sequentially on 0.4%, 4%, and 8% sodium diets (7 days per sodium level). Mean arterial pressure increased with 4% NaCl from 107 to 120 mm Hg (p less than 0.05) over 24 hours in DS rats and remained at about that level until the NaCl was increased to 8%, which resulted in a gradual rise of mean arterial pressure over the next 7 days to 135 mm Hg. Cerebrospinal fluid sodium was unchanged in DR and Sprague-Dawley rats fed 4% or 8% sodium, but in DS rats rose from 152.3 to 155.2 +/- 0.6 meq/l on the third day at 4% sodium and remained elevated over the next 2 weeks of study. Blood sodium was unchanged throughout the study in all groups. On the first day only of the 4% and 8% sodium diets, both DS and DR rats exhibited a similar net retention of sodium, which was greater than the Sprague-Dawley rats (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Nocturnal Blood Pressure Dip in Stroke Survivors : A Pilot Study
- Kensei Nakamura,
- Jiro Oita and
- Takenori Yamaguchi
Stroke Volume 26, Issue 81 August 1995

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Background and Purpose The influence of a nocturnal blood pressure dip on stroke recurrence has not yet been clarified. In this pilot study, we attempted to establish a correlation of the nocturnal blood pressure dip with stroke recurrence and development of new silent ischemic lesions in patients with chronic ischemic cerebrovascular disease.Methods We monitored circadian blood pressure patterns by use of a portable blood pressure monitoring device in 81 patients with chronic ischemic cerebrovascular disease and divided them into two subgroups according to levels of diurnal and nocturnal blood pressure (nocturnal blood pressure dippers and nondippers). The subgroups were prospectively followed up and compared for stroke recurrence and new silent ischemic lesions on magnetic resonance imaging.Results The average follow-up period was 27.2±11.3 months (mean±SD). Seventy-six patients completed the study; 43 (36 men and 7 women, aged 63.0±6.3 years) were being treated with antihypertensive agents and 33 (25 men and 8 women, aged 64.7±9.2 years) were not receiving treatment. In the treated group, recurrence was more frequent among the nocturnal dippers (5 of 18 patients, 12.5% per patient-year) than among the nondippers (1 of 25 patients, 1.5% per patient- year) (P<.05). All subjects who developed a recurrent attack during sleep had had a nocturnal blood pressure dip pattern before the attack. Furthermore, the increase in symptomatic (recurrence) and/or asymptomatic (silent) brain lesions was more frequent in the nocturnal dippers than in the nondippers (9 of 14 versus 2 of 18, P<.01). In the nontreated group, no clear difference was found between the two subgroups.Conclusions This study indicated that the nocturnal blood pressure dip in patients treated with antihypertensive agents may accelerate the increase in ischemic brain lesions.
Abstract 13499: A 34-year-old Man With Debilitating Polyneuropathy, Pericardial Effusion and Monoclonal Gammopathy Presents With Right Heart Failure
- Kenta Nakamura,
- Mary H Zhang and
- Jordan T Shin
Circulation Volume 130, Issue suppl_225 November 2014

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A 34-year-old man with debilitating polyneuropathy and monoclonal gammopathy presents with progressive lower extremity edema, pericardial effusion and dyspnea. Pulmonary edema, elevated jugular venous pressure and peripheral edema suggested right heart failure, and dyspnea responded initially to diuresis. Echocardiography revealed occult pericardal effusion, right heart dysfunction and estimated right ventricular systolic pressure of 54 mmHg. The differential diagnosis included pulmonary hypertension secondary to chronic pulmonary or left heart processes, pericardial constriction, restrictive myopathy or a syndromic condition capturing his neurologic and hematologic findings. Chest CT and VQ-scan were negative for acute and chronic pulmonary thromboembolic disease, respectively. Cardiac magnetic resonance imaging was most consistent with amyloidosis. Pericardial enhancement was normal, arguing against constriction. Amyloidosis was thought to be unlikely given preserved left ventricular size and function, increase in both serum free κ and λ light chains, and was ultimately excluded by fat pad biopsy. The paraneoplastic disease Crow-Fukase or POEMS syndrome, classically described as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes explained the patient’s constellation of signs and symptoms. Pulmonary hypertension subsequent to cor pulmonale is common and reversible with treatment of the underlying gammopathy. Diagnosis of the POEMS syndrome was confirmed by the presence of sclerotic bone lesions and markedly elevated vascular endothelial growth factor (VEGF) level of 1028 pg/mL (ref. range 31-86 pg/mL). VEGF is highly induced in the POEMS syndrome and correlates closely with disease activity. VEGF-mediated microangiopathy, neovascularization, and vasopermeability likely underlie multiple clinical sequelae of extravascular volume overload such as pericardial effusion and peripheral edema. The patient responded to sildenafil for pulmonary arterial hypertension and immunomodulatory therapy for the monoclonal gammopathy. At six months of treatment, the patient has recovered substantial strength, heart failure has not reoccurred and repeat VEGF level reduced to 383 pg/mL.
Detection of mitral ring abscess by two-dimensional echocardiography.
- K Nakamura,
- S Suzuki,
- G Satomi,
- H Hayashi and
- K Hirosawa
Circulation Volume 65, Issue 41 April 1982

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M-mode and two-dimensional echocardiographic features of mitral ring abscess are described. A round, dense echo mass between the posterior mitral leaflet and left ventricular posterior wall was demonstrated in long- and short-axis views of the left ventricle. The diagnosis of mitral ring abscess was confirmed at surgery. The superiority of two-dimensional echocardiography over M-mode echocardiography for evaluating patients with mitral ring abscess is also discussed.
Pressor response to small elevations of cerebroventricular pressure in conscious rats.
- K Nakamura,
- J W Osborn and
- A W Cowley
Hypertension Volume 10, Issue 61 December 1987

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Acute relationships between cerebrospinal fluid hydrostatic pressure and arterial pressure were quantified in conscious rats. The rats were catheterized with a left femoral artery catheter, and a double set of catheters was implanted into the third cerebral ventricle. In three groups of rats, artificial cerebrospinal fluid with various sodium concentrations (142, 152, and 162 mM) was infused into the third ventricle for 3 hours at 1.0 microliter/min. Mean arterial pressure (MAP) and third ventricular pressure were monitored simultaneously, and both increased progressively over the 3-hour infusion period; the rate of rise was significantly greater with infusion of the hypertonic solution. There were no significant differences between the rat groups infused with low, normal, or high artificial cerebrospinal fluid sodium in either the slope or the intercept of the regression equation relating cerebrospinal fluid pressure and MAP: a 1 cm H2O rise of cerebrospinal fluid pressure was always associated with nearly a 1 mm Hg rise in MAP. In other rats, changes in both cerebrospinal fluid pressure and MAP were shown to be highly dependent on the rate of ventricular infusion. We conclude that elevations of systemic arterial pressure are associated with only small elevations of cerebrospinal fluid pressure and that physiological changes of cerebrospinal sodium (+/- 10 mM) influence arterial pressure by altering intravascular hydrostatic pressure rather than sodium or osmosensitive receptors in the cerebral ventricles.
cGMP-Dependent Relaxation of Smooth Muscle Is Coupled With the Change in the Phosphorylation of Myosin Phosphatase
- Kensei Nakamura,
- Yasuhiko Koga,
- Hiroyasu Sakai,
- Kazuaki Homma and
- Mitsuo Ikebe
Circulation Research Volume 101, Issue 728 September 2007

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Nitric oxide/cGMP pathway induces vasodilatation, yet the underlying mechanism is obscure. In the present study, we studied the mechanism of cGMP-induced relaxation of the smooth muscle contractile apparatus using permeabilized rabbit femoral arterial smooth muscle. 8-Br-cGMP–induced relaxation was accompanied with a decrease in myosin light chain (MLC) phosphorylation. MLC phosphatase (MLCP) activity, once decreased by agonist-stimulation, recovered to the resting level on addition of 8-Br-cGMP. Because MLCP activity is regulated by the phosphorylation of a MLCP-specific inhibitor, CPI17 at Thr38 and MBS (myosin binding subunit of MLCP) at Thr696, we examined the effect of 8-Br-cGMP on the phosphorylation of these MLCP modulators. Whereas CPI17 phosphorylation was unchanged after addition of 8-Br-cGMP, MBS phosphorylation at Thr696 was significantly decreased by 8-Br-cGMP. We found that 8-Br-cGMP markedly increased MBS phosphorylation at Ser695 in the fiber pretreated with phenylephrine. MBS phosphorylation of Thr696 phosphorylated MBS at Ser695 partially resumed MLCP activity inhibited by Thr696 phosphorylation. Whereas Ser695 phosphorylation was markedly increased, the extent of diphosphorylated MBS at Ser695 and Thr696 in fibers was unchanged after cGMP-stimulation. We found that MBS phosphatase activity in arteries for both diphosphorylated MBS and monophosphorylated MBS at Thr696 significantly increased by 8-Br-cGMP, whereas MBS kinase activity was unchanged. These results suggest that the phosphorylation at Ser640 induced by cGMP shifted the equilibrium of the Thr641 phosphorylation toward dephosphorylation, thus increasing MLCP activity. This results in the decrease in MLC phosphorylation and smooth muscle relaxation.
Abstract WMP27: Cerebral Blood Velocity Changes During Dobutamine Administration for Experimental Subarachnoid Hemorrhage in Mice
- Kazuhiro Nakamura,
- Tatsushi Mutoh,
- Kazumasu Sasaki,
- Yasuyuki Taki and
- Tatsuya Ishikawa
Stroke Volume 48, Issue suppl_11 February 2017

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Introduction: Hyperdynamic therapy with dobutamine (DOB) administration on patients with subarachnoid hemorrhage (SAH) is a useful strategy for treating cerebral vasospasm and neurological deterioration. Even some reports have suggested that DOB administration caused the cerebral blood flow (CBF) augmentation by increasing cardiac output, microcirculatory behavior in brain remains unclear.Hypothesis: Red blood cell (RBC) velocity should be increased under DOB administration. To investigate the cortical microcirculation, two-photon laser scanning microscopy with successive line-scans was used for red blood cell (RBC) velocity estimation.Methods: SAH was induced in ten male wild-type C57BL/6 mice (23 - 25g) using endovascular perforation technique. Five days after SAH, a cranial window was prepared for optical access to the cortical vasculature. Then we observed two-photon microscopy with intravenously injected rhodamine-dextran. The RBC velocity was visualized as dark objects against the fluorescent plasma background. The velocity was estimated from dark objects angle in successive line-scans analyzed by Radon function based algorithm. DOB was administrated intravenously at the dose of 6 and 12 μg/kg/min.Results: RBC velocity was increased in 8 mice after the DOB administration and 2 mice were reduced. The RBC velocity in increased mice of baseline , 6 , and 12 μg/kg/min was 1.29±0.40, 1.70±0.74 and 1.37±0.53 mm/sec, respectively. In the reduced mice, the RBC velocity was dropped almost half value of baseline at the DOB administration.Conclusions: DOB administration was increased RBC velocity in cortical microcirculation. It indicates DOB hyperdynamic therapy on patients with SAH is effective in the viewpoint of cortical microcirculatory control.
Abstract 10638: Uninterrupted vs. Interrupted Periprocedural Direct Oral Anticoagulants for Catheter Ablation of Atrial Fibrillation: A Prospective Randomized Study on Post-Ablation Thromboembolic and Hemorrhagic Events
- Kohki Nakamura,
- Takehito Sasaki,
- Yutaka Take,
- Nobusada Funabashi and
- Shigeto Naito
Circulation Volume 138, Issue Suppl_16 November 2018

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Introduction: This prospective, randomized, single-center study aimed to directly compare the safety and efficacy of uninterrupted and interrupted periprocedural anticoagulation protocols with direct oral anticoagulants (DOACs) in patients undergoing catheter ablation of non-valvular atrial fibrillation (NVAF).Methods: We randomly assigned 846 NVAF patients receiving DOACs prior to ablation to uninterruption (n = 422) or interruption (n = 424) of the DOACs on the day of the procedure. The primary endpoint was a composite of symptomatic thromboembolisms and major bleeding events within 30 days after the ablation. Secondary endpoints included symptomatic and silent thromboembolisms and major and minor bleeding events.Results: The primary endpoint occurred in 0.7% of the uninterrupted DOAC group (1 transient ischemic attack [TIA] and 2 major bleeding events) and 1.2% of the interrupted DOAC group (1 TIA and 4 major bleeding events) (Figure). A Kaplan-Meier analysis showed that the cumulative event rates of a primary endpoint until 30 days after the procedure were comparable between the two groups (P = 0.480) The incidence of major and minor bleeding was also comparable between the two groups (Figure). Silent cerebral ischemic lesions (SCILs) were observed in 138 (20.9%) of the 661 patients undergoing post-ablation magnetic resonance (MR) imaging. The uninterrupted and interrupted DOAC groups revealed a similar incidence of SCILs (Figure) and percentage of SCILs with disappearance on follow-up MR imaging (77.8% vs. 82.1%, P = 0.428).Conclusions: Both the uninterrupted and interrupted DOAC protocols revealed a low risk of symptomatic thromboembolisms and major bleeding events and similar incidence of SCILs and minor bleeding events, and may be feasible for periprocedural anticoagulation in NVAF patients undergoing catheter ablation.
Abstract 12242: Post-Ablation Cerebral Thromboembolisms in Balloon-Based Ablation of Atrial Fibrillation With Periprocedural Direct Oral Anticoagulants: A Comparison Between Cryoballoon and Hotballoon Ablation
- Kohki Nakamura,
- Takehito Sasaki,
- Yutaka Take,
- Nobusada Funabashi and
- Shigeto Naito
Circulation Volume 138, Issue Suppl_16 November 2018

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Introduction: This prospective observational study aimed to investigate the incidence of symptomatic and silent cerebral thromboembolisms after balloon-based ablation of paroxysmal atrial fibrillation (PAF) in patients receiving periprocedural oral anticoagulation with direct oral anticoagulants (DOACs), and compare that between cryoballoon ablation (CBA) and HotBalloon ablation (HBA).Methods: We enrolled 106 consecutive patients (65 ± 10 years; 86 males) undergoing balloon-based pulmonary vein isolation (PVI) of PAF and brain magnetic resonance (MR) imaging on the next day after the ablation procedure (CBA, n = 54; HBA, n = 52). The DOACs were uninterrupted in 47 patients (CBA, n = 21; HBA, n = 26) throughout the periprocedural period, and interrupted in 59 patients (CBA, n = 33; HBA, n = 26) on the day of the procedure. Intravenous heparin was infused to maintain an activated clotting time (ACT) of 300 - 400 seconds during the procedure.Results: No symptomatic thromboembolisms occurred in this series. Silent cerebral ischemic lesions (SCILs) were detected on MR imaging in 20 patients (18.9%), and the incidence of SCILs did not significantly differ between the CBA and HBA groups (24.1% vs. 13.5%; P = 0.163). The CBA group included fewer patients requiring touch-up ablation than the HBA group (18.9% vs. 36.5%; P = 0.043), while the age, CHA2DS2-VASc score, left atrial size, total procedure time, intraprocedural ACT value, and percentage of periprocedural DOAC continuation did not significantly differ between the two groups. According to the multivariable logistic regression analysis, an older age was an independent positive predictor of SCILs after the balloon-based PVI (odds ratio 1.089; 95% confidence interval, 1.014 - 1.169; P = 0.019), but neither the balloon catheter type (CB or HB) nor periprocedural continuation or discontinuation of the DOACs were significant predictors. The incidence of major and minor bleeding complications was comparable between the CBA and HBA groups (1.9% vs. 0%, P = 0.509; 9.3% vs. 5.8%, P = 0.379).Conclusions: Both the CBA and HBA of PAF revealed a similar incidence of post-ablation cerebral thromboembolisms. Elderly patients may be at a risk of SCILs after a balloon-based PVI with periprocedural DOAC treatment.
Progressive Onset of Extracardiac and Myocardial Symptoms: Right Heart Failure and Cor Pulmonale in a Young Man With Debilitating Polyneuropathy and Monoclonal Gammopathy
- Kenta Nakamura,
- Mary Z. Bechis,
- Andrew J. Yee and
- David M. Dudzinski
Circulation Volume 132, Issue 17 July 2015

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Abstract 14169: Crucial Role of RAGE in Inappropriate Increase of Smooth Muscle Cells From Patients With Pulmonary Arterial Hypertension
- Kazufumi Nakamura,
- Satoshi Akagi,
- Toshihiro Sarashina,
- Masakiyo Sakaguchi,
- Hiromi Matsubara and
- Hiroshi Ito
Circulation Volume 134, Issue suppl_111 November 2016

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Background: Receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of inflammatory, degenerative and hyperproliferative diseases. RAGE is also implicated in etiology of pulmonary arterial hypertension (PAH) and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in PAH.Methods and Results: PASMCs were obtained from 12 patients with PAH (including 2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining (Figure) revealed that RAGE and S100A9, a ligand of RAGE, were overexpressed in PAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE and S100A8, a ligand of RAGE, in PAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by ³H-thymidine incorporation. This result shows overgrowth characterized by continued growth under non-growth stimulated conditions in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under non-growth stimulated conditions in PASMCs obtained from idiopathic PAH (IPAH) and hereditary PAH (HPAH) patients (P<0.0001). AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH- and HPAH-PASMCs (P<0.0001).Conclusions: RAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.
Abstract 19432: Neuronal Isoform of Nitric Oxide Synthase is Upregulated in Cardiac Intrinsic, and Extrinsic Sympathetic Afferent and Efferent Ganglia Following Myocardial Infarction
- Keijiro Nakamura,
- Olujimi A Ajijola,
- Tadanobu Irie,
- Kentaro Yamakawa,
- Jeffrey Ardell and
- Kalyanam Shivkumar
Circulation Volume 132, Issue suppl_310 November 2015

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Objective: The impact of myocardial infarction (MI) on neuronal nitric oxide synthase (nNOS), an important mediator of cardiac neurotransmission is not well understood.Methods: Yorkshire pigs (n=10) underwent anterior MI by LAD occlusion. After 6-8 weeks, bilateral stellate ganglia (SG), T1 dorsal root ganglia (DRG), right atrial (RAGP) and ventral inter-ventricular ganglionated plexi (VIVGP)were extracted, formalin-fixed, paraffin-embedded, and sectioned. Immno-staining for nNOS was performed on representative slides through the middle of the ganglia, and for calcitonin-gene related peptide (CGRP), a marker of sensory afferent neurons. The percentage of immunoreactive (IR) neurons was quantified.Results: An average of 63.1±40.7, 169.7±55.5, and 448.1±204.5 neurons were counted in the GPs, DRG, and SG respectively. There was no significant difference in the number of neurons counted in controls vs MIs. In the GPs, nNOS was differentially altered by MI, with significant upregulation in VIVGP but not RAGP of MI (13.8±2.8% vs 46.6±5.3%, p<0.001; and 12.1±3.6% vs 12.5±2.9%, p=NS, respectively) compared to control animals. In the DRG, IR of both CGRP and nNOS was increased (36.3±6.2% vs 65.3±4.8%, p<0,001 for nNOS; and 64.1±6.2% vs 85.2±5.6%, p<0.001 for CGRP), with increased co-expression of both CGRP and nNOS in approximately 20% of DRG neurons. In the SG, the number of neurons demonstrating strong IR for nNOS was approximately 0.4% in control animals. After MI, this increased 8-fold to 3.12% (P<0.01).Conclusions: nNOS expression is upregulated differentially following MI in the GPs, with increased expression in the ventricular GP innervating the region of MI, but not in the RAGP. Both cardiac sympathetic afferent (DRG) neurons, and efferent (SG) neurons increase expression of nNOS following MI. The impact of nNOS in these different sites warrants further investigation.
Abstract 12450: Biological Pacemaker Created by HCN4-Overexpressing Human iPS Cell-Derived Cardiomyocytes
- Kazufumi Nakamura,
- Yukihiro Saito,
- Masashi Yoshida,
- Kaoru Akazawa,
- Nobuhiro Nishii,
- Toru Miyoshi and
- Hiroshi Ito
Circulation Volume 138, Issue Suppl_16 November 2018

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Background: Establishment of a biological pacemaker is expected to solve the persisting problems of a mechanical pacemaker including short battery life. Enhancement of the funny current (I_f) flowing through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and attenuation of the inward rectifier K⁺ current (I_K1) are essential for generation of a biological pacemaker. Therefore, we generated HCN4-overexpressing human induced pluripotent stem cells (hiPSC), and we induced cardiomyocytes that originally show poor I_K1currents.Methods and Results: We generated HCN4-overexpressing hiPSC-derived cardiomyocytes (hiPSC-CMs). The human Hcn4 gene was inserted into the AASV1 locus, a safe harbor locus for inserting transgenes, by TALENs. HCN4-overexpressing hiPSC-CMs expressed an approximately 20-times higher level of the Hcn4 gene than did non-overexpressing hiPSC-CMs. HCN4-overexpressing hiPSC-CMs showed significantly larger I_f than did non-overexpressing hiPSC-CMs. Expression level of the Kcnj2 gene encoding Kir2.1, which is essential for generation of I_K1 currents, in hiPSC-CMs was lower than that in an adult ventricle. HCN4-overexpressing hiPSC-CMs showed significantly more rapid beating than did non-HCN4-overexpressing hiPSC-CMs (Figure). The beating rate of HCN4-overexpressing hiPSC-CMs responded to ivabradine, an I_f inhibitor, and to isoproterenol, a beta-adrenergic receptor agonist.Conclusions: We established HCN4-overexpresssing hiPSC-CMs that show downregulation of the KCNJ2 gene and rapid spontaneous beating and responses to an I_f inhibitor and beta-adrenergic receptor agonist. The results indicated that these cells could be applied to a biological pacemaker.
Inhibitory Effects of Antioxidants on Neonatal Rat Cardiac Myocyte Hypertrophy Induced by Tumor Necrosis Factor-α and Angiotensin II
- Kazufumi Nakamura,
- Kazuo Fushimi,
- Hirosuke Kouchi,
- Koichiro Mihara,
- Masahiro Miyazaki,
- Tohru Ohe and
- Masayoshi Namba
Circulation Volume 98, Issue 825 August 1998

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Background—Tumor necrosis factor-α (TNF-α) and angiotensin II (Ang II) modulate heart failure in part by provoking the hypertrophic response. Signal transduction pathways of those factors are implicated in reactive oxygen intermediates (ROIs). Therefore, we hypothesized that TNF-α and Ang II might cause myocyte hypertrophy via the generation of ROIs.Methods and Results—To test the hypothesis, we tested whether TNF-α and Ang II could induce the generation of ROIs and whether antioxidants such as butylated hydroxyanisole (BHA), vitamin E, and catalase might inhibit the hypertrophy in cultured neonatal rat cardiac myocytes. ROIs were measured by the ROI-specific probe 2′,7′-dichlorofluorescin diacetate in cultured cardiac myocytes. We demonstrated that TNF-α and Ang II induced the generation of ROIs in a dose-dependent manner. TNF-α (10 ng/mL) and Ang II (100 nmol/L) enlarged cardiac myocytes and increased [³H]leucine uptake, and BHA (10 μmol/L) significantly inhibited both effects. Other antioxidants, such as vitamin E (1 μg/mL) and catalase (100 U/mL), also inhibited the enlargement of cardiac myocytes induced by TNF-α.Conclusions—These results indicate that TNF-α and Ang II cause hypertrophy in part via the generation of ROIs in cardiac myocytes.
Abstract 10826: Lineage Specific Integrin Alpha V Augmentation Promotes Tgf-β Induced Integrin-FAK-Akt^thr308 Signaling Pathway
- Ken Nakamura,
- Nobu Yokoyama,
- Albert J Pedroza,
- Alex R Dalal,
- Tetsuro Uchida and
- Michael P Fischbein
Circulation Volume 144, Issue Suppl_116 November 2021

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Introduction: Marfan syndrome (MFS) patients classically develop focal aortic root aneurysms. Aortic root smooth muscle cells (SMCs) develop predominately from second heart field (SHF), whereas ascending aorta/arch SMCs originate from cardiac neural crest (CNC). We previously demonstrated induced pluripotent stem cell (iPSC)-derived SHF SMCs overexpress integrin αV (ITGAV). Therefore, we hypothesize that ITGAV promotes SHF SMC proliferation, contributing to thoracic aortic root aneurysm development.Methods: iPSCs from MFS patients (n=2) and healthy control (n=1) were differentiated into SHF and CNC SMCs. ITGAV-pFAK-pAkt^Thr308 levels were detected with western blot and ELISA at baseline and following recombinant TGF-β (2ng/ml) and/or an ITGAV antagonist (GLPG0187, 10nM) for 24 hours. Cell proliferation was measured with quantitative BrdU assay.Results: Baseline ITGAV-pFAK-pAkt^Thr308 activation were significantly elevated in MFS SHF lines (n=5 experimental replicates) compared to MFS CNC (n=5) or control SHF (n=4, p<0.05). Addition of recombinant TGF-β to SMC differentiation media further enhanced pFAK-pAkt^Thr308 levels in MFS SHF. Treatment with GLPG0187 reduced pFAK-pAkt^Thr308 in MFS SHF and CNC, confirming ITGAV-mediated signaling promotes pathologic FAK- Akt^Thr308 activation. SMCs from MFS SHF (n=6) had increased proliferation compared to other SMCs (p<0.01 vs MFS CNC and control SHF) which was reversed to the same level as control SHF (p=0.132) with GLPG0187 treatment.Conclusions: The integrin-FAK-Akt^Thr308 signaling pathway is activated in iPSC SMCs from MFS patients specifically from the SHF lineage, which is further exacerbated by TGF-β. Mechanistically, this pathway promotes SMC proliferation in vitro. ITGAV blockade via GLPG0187 may be a promising therapeutic approach for MFS aneurysmal growth.
Clinical and echocardiographic features of pulmonary valve endocarditis.
- K Nakamura,
- G Satomi,
- T Sakai,
- M Ando,
- A Hashimoto,
- H Koyanagi,
- K Hirosawa and
- A Takao
Circulation Volume 67, Issue 11 January 1983

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We studied the clinical and echocardiographic features of eight patients with infective pulmonary valve endocarditis. In two patients, the vegetation was limited to the pulmonary valve; in the six other patients, infective lesions were also present on the mitral or aortic valves. None of the patients were addicted to narcotics. Seven of the eight patients had underlying congenital heart disease. In six patients the organism responsible for the infective endocarditis was Streptococcus viridans. Two-dimensional echocardiography performed using a wide-angle sector scanner was more useful than M-mode echocardiography for evaluating patients with pulmonary valve endocarditis.
Abstract 12918: Comparison between Standard and Reduced Doses of Direct Oral Anticoagulants for Periprocedural Anticoagulation in Truly Low Thromboembolic Risk Patients Undergoing Catheter Ablation of Atrial Fibrillation
- Kohki Nakamura,
- Shigeto Naito,
- Kentaro Minami,
- Takehito Sasaki,
- Koji Kumagai,
- Nobusada Funabashi,
- Yoshio Kobayashi and
- Shigeru Oshima
Circulation Volume 134, Issue suppl_111 November 2016

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Introduction: Direct oral anticoagulants (DOACs) are generally administered in truly low thromboembolic risk patients undergoing atrial fibrillation (AF) ablation. All DOACs have two dose settings, but reduced doses are commonly used in patients for whom a DOAC dose reduction is not necessary according to the dose reduction criteria in the real world.Purpose: This study aimed to evaluate the safety and efficacy of periprocedural DOACs in AF patients with a CHA₂DS₂-VASc score of 0 (male) or 1 (female), and compare that between standard and reduced DOAC doses.Methods: We retrospectively enrolled 1013 consecutive patients receiving periprocedural DOACs, and 232 patients (median, 54 years) with a CHA₂DS₂-VASc score of 0 (190 males) or 1 (42 females) were analyzed (dabigatran, n=36; rivaroxaban, n=121; apixaban, n=59; edoxaban, n=16). Standard and reduced doses were administered in 149 and 83 patients, respectively, but essentially a dose reduction was not necessary in 95.2% of the reduced dose patients. All DOACs were discontinued on the day of the procedure and no pre-ablation heparin bridging was performed.Results: The standard and reduced dose patients required a similar heparin dosage (median, 13630 vs. 13330 units, P=0.671), and the mean and maximum activated clotting times were 303 and 329 seconds with the standard doses, and 310 and 333 seconds with the reduced doses, respectively (P=0.012 and 0.076). No symptomatic thromboembolisms occurred. The incidence of major and minor bleeding and silent cerebral ischemic lesions on magnetic resonance imaging was 0.7%, 5.4%, and 10.0% with the standard doses and 0%, 1.2%, and 12.5% with the reduced doses, respectively (P=0.642, 0.107, and 0.558). The standard and reduced doses revealed a similar bleeding risk (2 with minor bleeding vs. 0; P=0.305) during the post-ablation oral anticoagulation (median, 106 days vs. 92 days; P=0.627).Conclusions: Standard and reduced DOAC doses for periprocedural anticoagulation revealed a similar thromboembolic and hemorrhagic risk in CHA₂DS₂-VASc low-risk patients undergoing AF ablation. A reduced dose use, if not according to the dose reduction criteria, may not contribute to either a reduction in bleeding or an increase in thromboembolisms associated with AF ablation.

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