tbuckley/cabot-search huggingface dataset:
Abstract 9477: Retinoblastoma Protein-associated Protein 48 and 46 Form Repressor Complex With p300/GATA4 And Inhibit Hypertrophic Responses in Cardiomyocytes
Authors: Yoichi Sunagawa, Yasufumi Katanasaka, Yuichi Watanabe, Hidetoshi Suzuki, Naruto Hajika, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2012)

Introduction: A zinc finger protein GATA4 associates with an intrinsic histone acetyltransferase p300 and regulates myocardial transcriptional activities in response to hypertrophic stimuli. Retinoblastoma protein (Rb)-associated protein 48 and 46 (RbAp48, RbAp46) form a repressor complex with HDACs and are implicated in chromatin remodeling and transcriptional repression. We showed that RbAp48 and 46 are novel component of the p300/GATA4 complex. However, precise functional relationships among p300, GATA4 and RbAp48/46 and their roles in hypertrophic responses remain unknown. Hypothesis: We have assessed the hypothesis that RbAp48/46 regulate hypertrophic responses in cardiomyocytes by modulating functions of the p300/GATA4 complex. Methods and Results: Immunoprecipitation followed by Western blotting in HEK293T cells demonstrated that overexpression of RbAp48/46 inhibited p300-induced GATA4 acetylation and the association between p300 and GATA4. Conversely, knockdown of RbAp48/46 by siRNA reversed these changes. RbAp48/46 inhibited not only p300-induced DNA binding activity of GATA4 onto the atrial natriuretic factor (ANF) and endotheline-1 (ET-1) promoters, but also p300/GATA4-induced ANF and ET-1 promoters activities. In cardiomyocytes, overexpression of RbAp48/46 significantly inhibited phenylephrine (PE)-induced GATA4 acetylation, activation of ANF and ET-1 promoters, and myocardial cell hypertrophy. On the other hand, knockdown of both RbAp48 and 46 by shRNA reversed these changes. PE decreased the binding between GATA4 and RbAp48/46, and the recruitment of RbAp48/46 onto the GATA element of the ANF promoter. Although RbAp48/46 were co-localized with GATA4 in the nucleus of cardiomyocytes at the basal state, PE stimulus induced the export of RbAp48/46 to cytoplasm. LMB, a inhibitor of chromosomal region maintenance 1 (CRM1), inhibited nuclear export of RbAp48/46. Conclusion: These findings demonstrate that RbAp48/46 interact with GATA4, disasociate GATA4 from p300, and inhibit its acetylation as well as hypertrophic responses in cardiomyocytes. The nuclear export of RbAp48/46 by hypertrophic stimuli may trigger hypertrophy-responsive transcription by releasing these inhibitions.
Abstract 9710: Contractile Reserve Assessed by Three-Dimensional Global Circumferential Strain as a Predictor of Cardiovascular Events in Patients with Idiopathic Dilated Cardiomyopathy
Authors: Kensuke Matsumoto, Hidekazu Tanaka, Kazuhiro Tatsumi, Takuma Sawa, Yasuhide Mochizuki, Yoshiki Motoji, Junichi Imanishi, Tatsuya Miyoshi, Mana Hiraishi, Akihiro Kaneko, Takayuki Tsuji, Keiko Ryo, Yuko Fukuda, Hiroya Kawai, Ken-ichi Hirata
Journal: Circulation (2012)

Background: Two-dimensional global circumferential strain (GCS) from mid-left ventricular (LV) short-axis view has been reported as a powerful predictor of cardiac events and appeared to be a better parameter than ejection fraction in heart failure (HF) patients. However, this technique is limited to two-dimensional tomographic imaging planes, which may oversimplify the complexities of left ventricular function. On the other hand, novel three-dimensional (3-D) speckle-tracking system can quantify 3 different strains simultaneously from all 16 LV segments. Accordingly, our objective was to investigate the ability of GCS with dobutamine stress using 3-D speckle-tracking to predict cardiac events in HF patients with idiopathic dilated cardiomyopathy (DCM). Methods: We prospectively recruited 54 consecutive DCM patients with ejection fraction of 34±8%. We measured GCS, global radial, and longitudinal strains using 3-D speckle-tracking echocardiography at baseline and during dobutamine infusion (20µg/kg/min). Event-free survival was pre-specified as primary end points of death from worsening HF, hospitalization for deteriorating HF, and was tracked over 12.3 months. Results: The primary endpoint occurred in 7 (17%) of patients. Of individual measures, the increase in 3-D GCS with dobutamine stress (ΔGCS) ≤2.71% was the best predictor of cardiac events with sensitivity of 90%, specificity of 81%, and the area under the curve of 0.927 (p&lt;0.001). In multivariate Cox proportional hazard model, ΔGCS was the strongest predictor of cardiac events (hazard ratio: 0.375, 95% confidential interval: 0.202-0.695, p=0.002). Furthermore, patients with ΔGCS&gt;2.71% had a significantly better prognosis than those with ΔGCS≤2.71% (Log rank p&lt;0.001). Conclusion: 3-D GCS with dobutamine stress would have potential to predict cardiac events in HF patients with DCM. These observations may have clinical implications for management of such patients.
Abstract 9660: The Impact of Anatomical Variation of the Brachial Artery for measuring Flow-mediated Vasodilation in Healthy Subjects and Patients with Cardiovascular Diseases
Authors: Yuichi Fujii, Yukihito Higashi, Takayuki Hidaka, Junko Soga, Naomi Idei, Noritaka Fujimura, Tatsuya Maruhashi, Shinsuke Mikami, Hiroki Teragawa, Yasuki Kihara
Journal: Circulation (2012)

Background: Measurement of flow-mediated vasodilation (FMD) is widely used for assessment of endothelial function. The purpose of this study was to evaluate the effect of anatomical variation of the brachial artery on FMD in healthy subjects and patients with cardiovascular diseases (CVD). Methods and results: There was no significant difference in the ratio of existence of a double brachial artery between healthy subjects (6.1%, 13/213) and patients with CVD (6.5%, 11/169). In healthy subjects, FMD was larger in a single brachial artery than in large and small vessels of a double brachial artery (7.2±3.4% vs. 4.7±3.3% and 4.5±2.5%, P&lt;0.01, respectively), while FMD was similar in large and small vessels of a double brachial artery. In patients with CVD, there were no significant differences in FMD among a single brachial artery, large vessel of a double brachial artery and small vessel of a double brachial artery (3.3±1.4%, 3.1±2.3% and 3.6±2.1%). FMD in a single brachial artery was smaller in patients with CVD than in healthy subjects (P&lt;0.01). There were no significant differences in FMD in the large vessel of a double brachial artery between the two groups or in the small vessel of a double brachial artery between the two groups. Nitroglycerine-induced vasodilation was similar in all arteries in healthy subjects and patients with CVD. These findings suggest that when measuring FMD, we should take care about the existence of a double brachial artery, especially a double brachial artery in healthy subjects. FMD measured in a double brachial artery may be underestimated in healthy subjects.
Abstract 9437: Impact of Positive Airway Pressure Therapy in Elderly Patients with Cardiovascular Disease and Sleep-disordered Breathing
Authors: Yosuke Nishihata, Yoshifumi Takata, Kota Kato, Tasuku Yamaguchi, Kazuki Shiina, Yasuhiro Usui, Akira Yamashina
Journal: Circulation (2012)

Introduction: Many studies have identified an association between sleep-disordered breathing (SDB) and cardiovascular disease (CVD). Recent studies have showed that SDB is an independent predictor of poor prognosis and continuous positive airway pressure (PAP) therapy contributes to reduce the risk. However, whether SDB is a risk factor for CVD in elderly patients and whether PAP therapy improves long-term cardiovascular outcomes are unknown. Hypothesis: We assessed the hypothesis that PAP therapy improved long-term cardiovascular outcomes in elderly patients with CVD and moderate to severe SDB. Methods: We studied 1693 patients who underwent polysomnography between November 2004 and July 2011, and enrolled 131 elderly patients (age ≥65 years old) with SDB (apnea-hypopnea index ≥15 per hour), who had been admitted to hospital due to CVD before polysomnography. They were divided into two groups; a PAP-treated group (n=64; treated with continuous positive airway pressure or adaptive servo ventilation) and an untreated SDB group (n=67; untreated with PAP devices). The frequency of death and hospitalization due to cardiovascular events (acute coronary syndrome, heart failure, stroke, fatal arrhythmias, and aortic dissection) between the groups was analyzed using multivariate analysis. Results: The mean follow-up period was 31.8 ± 23.4 months and 34 patients (26.0%) died or were re-admitted to hospital due to cardiovascular events. Kaplan-Meier survival curves indicated that event-free survival was significantly higher in the PAP-treated group than in the untreated SDB group (Figure). Multivariate analysis showed that the risk for death and re-admission due to cardiovascular events was significantly higher in the untreated SDB group than in the PAP-treated group (hazard ratio, 3.21; 95% confidence interval, 1.05 to 10.9; p &lt;0.05). Conclusions: PAP therapy improves cardiovascular outcomes in elderly patients with CVD and moderate to severe SDB.
Abstract 9431: Heart Failure Induces Significant Changes in the Nuclear Pore Complex of Human Cardiomyocytes
Authors: Miguel Rivera, Estefania Tarazon, Esther Rosello, Micaela Molina, Antonio Salvador, Ignacio Sanchez Lazaro, Luis Martinez Dolz, Luis Almenar, Anastasio Montero, Jose Ramon Gonzalez Juanatey, Francisca Lago, Inmaculada Azorin, Manuel Portoles
Journal: Circulation (2012)

Introduction: We have recently reported alterations in different transporters that orchestrate the nucleocytoplasmic transport, such as increased importin and exportin levels in patients diagnosed with heart failure (HF). We hypothesized whether we could also find alterations in the nuclear pore complex (NPC) structure, the gateway connecting the nucleoplasm and cytoplasm. Therefore, we quantified several representative proteins that compose the different parts of NPCs, named nucleoporins (Nup), in this syndrome. Methods: A total of 90 human heart samples from ischemic (ICM, n=45) and dilated (DCM, n=36) patients undergoing heart transplant and control donors (CNT, n=9), were analyzed (nuclear-cytoplasmic fractionation) by Western-blotting. Subcellular distribution of proteins was analyzed by immunocytochemistry, fluorescence and electron microscopy. Results: When we compared nucleoporin protein levels according to etiology, ICM showed significant higher levels of linker Nup93 (42%, p&lt;0.0001), FG Nup153 (139%, p&lt;0.01) and transmembrane ring Nup NDC1 (65%, p&lt;0.0001) than those of the CNT group. Furthermore, DCM also showed significant differences for Nup93 (88%, p&lt;0.0001), Nup153 (157%, p&lt;0.01) and NCD1 (41%, p&lt;0.0001). However, the nucleoporins Nup155, Nup160 and translocated promoter region (TPR) did not show significant differences. Furthermore, subcellular distribution of nucleoporins was not altered in pathological hearts, although we observed an increase in the fluorescence intensity in ICM and DCM samples of those Nup with high protein levels. Conclusions: This study shows alterations in specific proteins that compose NPC, overall those that are directly exposed to cargo undergoing transport (Nup93 and Nup153) and those that surround the core (NDC1), in hearts from patients with ICM and DCM. These changes could be accompanied by modifications in the functional dynamics through NPC and therefore our findings may be the basis for a new approach to HF management.
Abstract 9303: C-Reactive Protein Trends and Associations with Total Mortality in United States Adults between 1999-2010
Authors: Kwok Leung Ong, Matthew A Allison, Bernard MY Cheung, Ben J Wu, Philip J Barter, Kerry-Anne Rye
Journal: Circulation (2012)

Introduction: C-reactive protein (CRP) is a well-known biomarker of systemic inflammation. Elevation of CRP levels is predictive of incident cardiovascular disease morbidity and mortality. We investigated the trends in prevalence of elevated CRP levels (x003E;3.0 mg/L), as well as mean CRP levels, in a general population of United States adults and then determine the associations with mortality. Methods: Data from the 27,214 subjects aged ≥20 years in the National Health and Nutrition Examination Survey (NHANES) 1999-2010 were analyzed. Among them, 12,259 subjects from NHANES 1999-2004 had mortality data followed up through December 31, 2006. Results: After adjusting for age, sex, race/ethnicity, body mass index, and medications for lowering blood pressure, glucose and lipids, the prevalence of elevated CRP decreased significantly from 36.7% in 1999-2002 to 32.0% in 2007-2010, corresponding to a decrease in mean CRP levels from 1.92 to 1.66 mg/L (both P &lt;0.001). The trend remained significant after additional adjustment for several traditional cardiovascular risk factors and use of medications, including statins, angiotensin-converting enzyme inhibitors, metformin, aspirin and clopidogrel. However, the decreasing trends were attenuated after additional adjustment for total bilirubin ( P =0.076 and 0.024), which increased from 0.62 to 0.73 mg/dL over 12 years ( P &lt;0.001). Of note, higher CRP levels were modestly associated with a higher risk of total mortality (adjusted hazard ratio: 1.07 [95%CI, 1.03-1.12] per 10 mg/L increase, P =0.001), and this association tended to be stronger in subjects with higher total bilirubin levels ( P for interaction&lt;0.001). Conclusion: The decreasing trend of CRP levels is encouraging and may be related to the increase in total bilirubin levels. Such trends may be explained in part by the increasing use of some medications such as statins that can increase bilirubin levels and decrease CRP levels. Moreover, the prediction of total mortality by CRP levels seems to be stronger in subjects with higher total bilirubin levels.
Abstract 9448: Soluble Fibrin Monomer-Fibrinogen Complex Levels during Oral Anticoagulant Therapy Does Not Predict Subsequent Thromboembolic Events in Patients with Atrial Fibrillation
Authors: Tsuneaki Sadanaga, Hideo Mitamura
Journal: Circulation (2012)

Introduction: Atrial fibrillation (AF) is associated with hemostatic abnormality even during oral anticoagulant therapy. We previously reported that elevated D-dimer level predicted thromboembolic events in AF patients during oral anticoagulant therapy. Likewise, we assessed the hypothesis that soluble fibrin monomer-fibrinogen complex (SF) could be used for the prediction of thromboembolic events because it was considered to be a specific molecular marker for the detection of thrombin generation. Subject and method: This study is a post hoc analysis of the previously reported cohort. Protocol 1 included 24 patients with permanent AF (77±10 y/o) in whom SF was measured before and after anticoagulant therapy with warfarin. Protocol 2 included 74 AF patients (75±10 y/o) undergoing treatments with warfarin. SF was measured during warfarin therapy and the patients were prospectively followed. The end point were thromboembolic events. Results: Protocol1) Anticoagulation with warfarin significantly reduced SF levels (median, interquartile range) from 4.0 (0.0 - 8.8) to 0.0 (0.0 - 2.2) μ g/ml (left). However, SF levels were still elevated (≥3μ g/ml) in 3 (13%) patients. Protocol 2) INR levels at the time of enrollment were 2.0 ± 0.6. No relationship between SF levels and INR levels were observed (p=0.57). SF levels were ≥ 3 µg/ml in 13 (18%) patients. During an average follow-up time of 683±222 days, 8 (10.8%) thromboembolic events occurred. There were 7 thromboembolic events observed among patients with baseline SF levels &lt; 3μ g/ml as compared with one event in those with baseline SF levels ≥3μ g/ml. Kaplan-Meier thromboembolic event free curve showed that elevated SF did not predictsubsequent thromboembolic events (right). Conclusion: Warfarin significantly decreased SF levels; however, elevated level of SF during anticoagulant therapy failed to predict thromboembolic events in AF patients.
Abstract 9357: Combined Antihypertensive Regimen, Sexual Function, Oxidative Stress and Hypertension: A Randomized Controlled Trial
Authors: JING YU, Longquan Yang, Ruixin Ma, Feng Zhao, Xin Lin, Peijun Liu, Feng Bai
Journal: Circulation (2012)

Combinations of a calcium channel blocker with either an angiotensin II receptor blocker or a beta-blocker are recommended as effective therapies for hypertension. However, it remains unclear whether these two of combinations have similar effects on sexual function in men with hypertension. This prospective, randomized, parallel open label study ( ClinicalTrials.org. NCT01238705 ) compared the effects of a felodipine-irbesartan combination with those of a felodipine-metoprolol combination on the sexual function and on markers of oxidative stress in men with mild to moderate hypertension. Two-hundred and eighteen participants aged 25 to 60 years were randomly assigned to receive a once daily treatment of either felodipine combined with irbesartan or felodipine combined with metoprolol for 48 weeks. Sexual functioning was evaluated using the International Index of Erectile Function (IIEF) questionnaire at baseline and after 48-weeks of therapy. Levels of serum testosterone, sex hormone binding globulin (SHBG), 8-Hydroxy-2’-deoxyguanosine (8-OHdG), 4-hydroxynonenal (HNE) and malondialdehyde (MDA) were measured. There were no statistical differences of prevalence of erectile dysfunction (ED) between pre- and post-treatment in two groups (P&gt;0.05), also did the levels of serum testosterone, SHBG and HNE. On the other hand, in felodipine-irbesartan group, scores of erectile functions (EF) and sexual desire (SD) were improved. The concentrations of serum 8-OHdG and MDA raised up after treatment (133.47±32.31 versus 130.70±31.25 ng/L, 6.82±1.17 versus 6.59±1.14 nmol/ml). The results suggested that felodipine-irbesartan may be more benefic to EF of hypertensive male patients than felodipine-metoprolol. This effect was possibly relevant to irbesartan, which could prevent oxidative stress. However, further investigations are needed.
Abstract 9141: Distance, Treatment Strategy, and Mode of Transfer for Primary PCI in Patients Presenting to a Hospital Without PCI Capability: A Report from ACTION Registry®-GWTG™ and The AHA Mission: Lifeline Program
Authors: Benjamin D Nicholson, Harinder S Dhindsa, Matthew T Roe, Anita Y Chen, James G Jollis, Michael C Kontos
Journal: Circulation (2012)

Background: Many STEMI patients (pts) present to non-PCI hospitals, requiring interhospital transfer for primary PCI. The impact of distance and mode of transport to the PCI center on the ability to meet guideline recommended reperfusion times is not clear. Methods: Data from the ACTION Registry®-GWTG™ were used to determine reperfusion strategy (fibrinolytics, primary PCI), total time to reperfusion (Total D2B; difference between non-PCI hospital presenting time and PCI time) and transfer mode (ground, air) for pts having interhospital transfer for primary PCI. Distance between the pt’s home zip code and the PCI hospital zip code were used to estimate travel distance. Results: From 7/1/08-3/3/11, 13,974 STEMI pts were transferred to 323 PCI hospitals. The median distance from the pt’s home to the primary PCI hospital was 26 miles (IQR 13,40) (ground 20 mi; air 37 mi; p&lt;.001). Pts transported by air had a similar median age (59 yrs), but were more likely to have heart failure (8.0% vs 6.4%; p&lt;.01) and shock (8.9% vs 6.8%; p&lt;0.001). The Total D2B time for the 11,722 pts transferred for primary PCI was 115 min (IQR 93,147), with air time significantly longer [median 123 min vs 110 min; p &lt;0.001]. A total of 5,577 (56%) pts had a Total D2B ≤120 min, with only 2,215 (22%) ≤90 min. Total D2B time ≤120 min was more likely in ground pts (60% vs 47%; p &lt;.001). At distances 25 mi, air transport predominated (TABLE). Fibrinolytic therapy administration increased as distance increased. Conclusions: Interhospital transfer for primary PCI is associated with prolonged reperfusion times, despite increased use of air transport for longer distance transfers. These delays should prompt increased consideration of fibrinolytic therapy use prior to transfer by some hospitals. Conversely, the relatively short distance most pts live from a primary PCI hospital should prompt greater emphasis on EMS hospital bypass protocols.
Abstract 9292: Impact of Nicorandil on Infarct Myocardium in Comparison With Nitrate: Assessed by Cardiac Magnetic Resonance Imaging
Authors: Kiyoyasu Yamada, Satoshi Isobe, Kazuhiko Yokouchi, Hirokazu Iwata
Journal: Circulation (2012)

Objectives The complementary intravenous administration of nicorandil, a hybrid compound of ATP-sensitive potassium channel opener and nitric donor, to percutaneous coronary intervention (PCI) reportedly has a protective effect on the infarct myocardium, leading to improve clinical outcome in patients with acute myocardial infarction (AMI). We compared the infarct and edema size in AMI patients intravenously treated by nicorandil with those by nitrate, using cardiac magnetic resonance (CMR) imaging. Methods The double-blinded trial was conducted in 52 AMI patients who successfully underwent emergency PCI. The patients were assigned to receive nicorandil or nitrate just before reperfusion at random. For the assessment of infarct and edema areas, short-axis T2w and delayed enhancement (DE) CMR images were acquired 6.1 ± 2.4 days after the onset of AMI. Results The edema size on T2w CMR was significantly larger than the infarct size on DE CMR (p &lt; 0.05). A significant correlation was observed between the peak creatine kinase (CK) levels and infarct size on DE CMR (r = 0.62, p &lt; 0.05) as well as the edema size on T2w CMR (r = 0.7, p &lt; 0.05) in patients treated by nicorandil. A similar correlation was seen between the peak CK levels and infarct size on DE CMR (r = 0.84, p &lt; 0.05) as well as the edema size on T2w CMR (r = 0.84, p &lt; 0.05) in patients treated by nitrate. The maximum serum CK level was significantly lower in patients treated by nicorandil than those by nitrate (2132 ± 1689 IU. vs 2785 ± 2121 IU. ; p &lt; 0.05). Both the edema size on T2w CMR and the infarct size on DE CMR were significantly smaller in patients treated by nicorandil than those by nitrate (edema size; 17.7 ± 9.9 % vs 21.9 ± 13.7 % ; infarct size; 10.3 ± 6.0 % vs 12.7 ± 6.9 % ; p &lt; 0.05, respectively). Conclusion Using CMR imaging, we demonstrate that the complementary intravenous administration of nicorandil to PCI provides more favorable effects in reducing myocardial damage compared with nitrate.