tbuckley/cabot-search huggingface dataset:
Abstract 4204: Osteoprotegerin Levels and Risk of Future Cardiovascular Events in Apparently Healthy Men and Women: the Prospective EPIC-Norfolk Population Study 1993–2003
Authors: Anne Grete Semb, T Ueland, P Aukrust, J- A Kuivenhoven, N J Wareham, S A Bingham, N E Day, R Luben, L Gullestad, T Pedersen, J J Kastele, S M Boekholdt, K- T Khaw
Journal: Circulation (2006)

Introduction: The identification of osteoprotegerin (OPG) as a novel cardiovascular risk marker suggests an association between mediators of bone homeostasis and cardiovascular disease. OPG is a member of the tumour necrosis factor (TNF) superfamily, and functions as a soluble decoy receptor for RANKL. There is no epidemiological evidence that OPG levels predict future coronary events in healthy individuals. It was therefore our objective to study the prospective relationship between plasma levels of OPG and the risk of future CAD in such a population. Methods and Results: A nested case-control study among participants of the European prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) study, a prospective population study of 25 663 men and women between 45 and 79 years of which 988 apparently healthy individuals developed coronary artery disease (CAD) were matched by sex and age with 1812 healthy controls which did not develop CAD. Baseline OPG was higher in cases than in controls [6957 pg/ml (5778 – 8727) vs. 6602 pg/ml (5434–8242) (p&lt;0.005) median and interquartile range], and significantly higher in women than men in both cases and controls. Using OPG quartiles based on the distribution among controls, baseline OPG levels were independently correlated with fatal and non fatal coronary events and the risk increased continuously (p for linearity= 0.008 men, p=0.01 women), also when adjusted for age, smoking, diabetes, body mass index, LDL, HDL, systolic blood pressure, this strong relationship still existed. When adjusted for log (CRP) as well, the OR in the highest OPG quartile was 2.17(0.86–5.49)(95% CI)(p=0.04) for women and 2.78 (1.45–5.32)(p&lt;0.001) for men. Conclusion: Among apparently healthy men and women, an elevated level of OPG is associated with increased risk of future fatal and non fatal CAD.
Feasibility of Three Dimensional Anatomic, Dynamic and Perfusion Imaging of Myocardial Scar Using Contrast Enhanced Multi-Detector Computer Tomography to Guide Ventricular Tachycardia Ablations
Authors: Jing Tian
Journal: Circulation (2009)

Abstract #252 Jing Tian, Jean Jeudy, Mark Smith, Peng Lei, Univ of Maryland Sch of Med, Baltimore, MD; Aharon Turgeman, Aharon Abbo, Biosense Webster Inc., Tirat Carmel, Israel; Robert Peters, Magdi Saba, Stephen Shorofsky, Timm Dickfeld, Univ of Maryland Sch of Med, Baltimore, MD Jing Tian, 2009 Finalist and Presenting Author
Abstract 4919: Contradictive Estrogen Effects on BMP Signaling in Pulmonary Artery Depend on Oxygen Concentration
Authors: Hiroaki Ichimori, Shigetoyo Kogaki, Kunihiko Takahashi, Hidekazu Ishida, Jun Narita, Nobutoshi Nawa, Toshiki Uchikawa, Shu Maekawa, Sayaka Matsumoto, Yoko Okada, Keiichi Ozono
Journal: Circulation (2009)

Epidemiologic studies have shown that the female predominance in the morbidity of Idiopathic PAH (pulmonary arterial hypertension) in the world, which suggests a role of female sex hormones in the pathogenesis of PAH. Our previous study demonstrated the contradictory effects of estrogen on pulmonary arterial endothelial cells (PAEC) via BMP (Bone Morphogenetic Protein) signaling depend on cellular oxygen environment. This study is to investigate the mechanism of the contradictory effect of β -estradiol (E2) upon BMP signaling in PAEC. &lt;MATERIALS and METHODS&gt; Human and rat PAEC were cultured and the expression of BMPR2, Smad1/5/8, and Id1 were examined under 21%O 2 (normoxic; N) or 1%O 2 (hypoxic; H) condition in the presence of E2. We investigated the effect of estrogen receptor antagonist (ICI 182.780.) and searched for an evidence of binding interaction between estrogen receptor (ER) and Smad. In the presence of E2 (10 −7 M), the expression of BMPR2, phosphorylated Smad (p-Smad)1/5/8 proteins, Id1 mRNA was augmented under N and suppressed under H. We confirmed same phenomena by using Id1 promoter assay. These alterations of BMPR signal expression were inhibited by ICI182.780. An Immunoprecipitation experiment demonstrated a direct binding interaction between ER and p-Smad1/5/8 proteins only under H, whereas estrogen response activity measured by luciferase assay was increased by E2 only under N. In addition, HIF-1 α augmentation by cobalt chloride suppressed BMP signaling, whereas HIF-1 α inhibition by YC-1 augmented those expression. By inhibiting de novo synthesis by administration of cycloheximide, p-Smad1/5/8 were suppressed under N, but could not change under H. We demonstrated that the alteration of BMP signaling in PAEC under different O 2 condition was associated with HIF-1 α expression and the presence of E2. This alteration may also relate to an interaction between BMP signaling and receptor-mediated estrogen pathway under hypoxia, and to de novo synthesis under normoxia. Our observations provide the new mechanism how sex hormone affects on BMP signaling, a key signal pathway for PAH, which can offer novel therapeutic targets in the treatment of PAH.
Abstract 605: ERK5 Activation Regulates PPARalpha Activity and Subsequent Cardioprotection After Ischemia/Reperfusion
Authors: Bo Ding, Chen Yan, Weiming Liu, Tetsuro Shishido, Chang Hoon Woo, Carolyn McClain, Jun-Ichi Abe
Journal: Circulation (2006)

Background: The strong cardioprotective effect of erythropoietin (EPO) and heme oxygenase-1 (HO-1) have been reported, but the mechanism are not understood. Previously we found that activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extra-cellular signal-regulated kinase 5(ERK5). We hypothesize that ERK5 activation induced by insulin growth factor-1(IGF-1), erythropoietin(EPO) and heme oxygenase-1(HO-1) is a “key modulator” of PPARa activity and provides a cardioprotective effect after I/R. Thus the aim of this study was to explore the mechanism of the protective effect of EPO, HO-1 and IGF-1 via ERK5 activation. Method and Results: We have found that EPO, HO-1 and IGF-1 stimulate ERK5 activation in the heart, and increase PPARa activity via an ERK5 dependent manner. To prove the role of ERK5 kinase/PPARa activation in IGF-1, EPO and HO-1 mediated cardioprotection after I/R, we characterized the unique role of ERK5 in IGF-1, EPO and HO-1-mediated PPARa activation. In cardiomyocytes, IGF-1, EPO and HO-1 mediate endogenous ERK5 association with endogenous PPARa but not phosphorylation of the PPARa. Activation of ERK5 by Ad-CA-MEK5a trigged the induction of mCPT-1 and PDK4, which promote fatty acid beta-oxidation (FAO) enzyme pathway via increasing PPARa transcriptional activation. Also we found that increased apoptosis in cardiomyocytes incubated by H2O2 compared to non-treated group( 3– 4 times increase H2O2 group vs. wildtype group). However HO-1 induction, EPO and IGF-1 treatment blocked the increased apoptosis induced by H2O2 stimulation. To determine the role of ERK5 kinase in EPO-mediated cardioprotection in vivo, we used the I/R mouse model in CA-MEK5a transgenic mice. Our preliminary experiments suggest a smaller infarction size in CA-MEK5a transgenic mice hearts compared to control hearts. Conclusion: We propose a key role for PPARa and subsequent activation of FAO enzyme induced by EPO and HO-1 mediated cardioprotection. These factors are induced by ERK5 activation. These data suggest that ERK5 is a critical factor and therefore a future therapeutic target.
Abstract 187: Reduced Rapid Delayed Rectifier (I <sub>Kr</sub> ) and Inward Rectifier Current (I <sub>K1</sub> ) Contribute Action Potential Prolongation and Diastolic Depolarization in a Chronic Canine Heart Failure Model
Authors: Arun Sridhar, Yoshinori Nishijima, Anusak Kijtawornrat, Robert L Hamlin, Cynthia A Carnes
Journal: Circulation (2006)

Heart Failure (HF) produces prolongation of the action potential duration (APD). Since human HF is a chronic syndrome, we used a chronic canine HF model to study HF-induced changes in K + currents and action potentials (APs). METHODS: Right ventricular tachypacing (5–24 months) was used to induce heart failure with increases in QRS Amplitude, QRS widening, Left Ventricular (LV) Mass, and LV dimensions. LV myocytes were isolated from lateral mid-myocardial wall; perforated whole cell patch clamp was done at 36°C. RESULTS: The AP duration was significantly prolonged in the HF dogs compared to controls (Panel A). Chronic HF produced a large reduction in the transient outward K + current (I to ) (10.7±1pA/pF (Control) vs. 1.8±0.7pA/pF (HF)). Inward rectifier K + current (I K1 ) inward conductance and peak outward I K1 were significantly reduced in HF (p&lt;0.05). The rapid component of the delayed rectifier (I Kr ) was significantly reduced with chronic HF (Panel B). Chronic HF did not alter the slow component of the delayed rectifier current (I Ks, p=NS). CONCLUSIONS: In chronic canine non-ischemic cardiomyopathy, the large reductions in I K1 , I to and I Kr cause diastolic depolarization and AP prolongation. These alterations may contribute to ventricular tachyarrhythmias during chronic nonischemic HF.
Abstract 563: Fibroblast Infiltration Reduces Conduction Velocity and Leads to Reentry Multiplication in Cardiomyocyte Monolayers
Authors: Viviana Muñoz, Omer Berenfeld, José Jalife
Journal: Circulation (2006)

Background : Cardiac fibrosis acts as an electrical obstacle and is thought to cause discontinuous propagation and arrhythmias. Fibrosis results from proliferation of fibroblasts which can form gap junctions with myocytes. Methods and Results: We conducted optical mapping experiments in 35 x 35 mm hetero-cellular neonatal rat monolayers of cardiac origin to test the hypothesis that fibroblast infiltration modifies the dynamics of reentry. When one half of the monolayer had a randomly distributed myocyte/fibroblast mixture (~50/50%), and the other half had &gt;95% myocytes, slow (2.75 Hz) sustained reentry stabilized in the region with more fibroblasts. The wavefronts propagated 2:1 to the 95% myocyte region at twice the conduction velocity (CV) (27.75 vs 12.86 cm/s). In separate experiments, as the percentage of fibroblasts in the monolayers was increased, the number of wavebreaks and reentry circuits increased and the excitation pattern became progressively more complex. In 4-s movies, when the preparations contained 5% fibroblasts, phase maps revealed only 1–2 singularity points corresponding to organizing cores of sustained reentrant activity. At 30% fibroblasts, the number of wavebreaks increased to 5±2 and the activity was much more irregular and disorganized. Finally, at 70% fibroblasts, the monolayers underwent extremely complex self-sustained activity with 42±5 repeated wavebreaks forming small wavelets that remained confined to small areas and rotated around their own singularity points. All wavelets rotated at the same frequency and the more stable ones clustered at or near the center of the preparations. Conclusions: Co-culturing fibroblasts with myocytes significantly reduces CV while creating a substrate for increased stability and multiplication of reentry. These results predict that increased fibrosis in cardiac muscle would increase the complexity of wave propagation and reduce the frequency of reentry.
Abstract 4942: Identification of Insulin Receptor Substrate Family Proteins Mediating PAI-1 Production in Cardiac and Adipose Tissues From IRS-1 Null Mice
Authors: Tomoo Furumoto, Satoshi Fujii, Hiroyuki Tsutsui
Journal: Circulation (2009)

Obesity is associated with dysfunctional insulin receptor substrate (IRS)-1 pathway and compensatory hyperinsulinemia. Insulin can stimulate production of plasminogen activator inhibitor (PAI)-1, the physiologic inhibitor of fibrinolysis, in adipocytes. Because hypofibrinolysis by PAI-1 confers cardiovascular risk, the role of IRS-1-mediated signaling in PAI-1 expression was elucidated in IRS-1 knockout (KO) mice. PAI-1 mRNA was increased by 10-fold in adipose tissue from IRS-1 KO (P&lt;0.001). Abdominal adipocyes isolated from IRS-1 KO released 11-fold more PAI-1 to the conditioned media (P&lt;0.001), indicating increased PAI-1 production in IRS-1 KO. IRS-2 was barely detectable in abdominal adipose tissue of IRS-1 KO. In contrast, IRS-3 was increased by 60% in IRS-1 KO, suggesting that IRS-3-mediated pathway was compensating for the lack of IRS-1 in adipose tissue. PAI-1 mRNA was increased in IRS-1 heart and perivascular fibrosis was persistently augmented, suggesting that PAI-1 can contribute to coronary arterial remodeling. In IRS-1 KO, cardiac expressions of IRS-2 and p85, a substrate of IRS-2, were increased by 2.7- and 2.4-fold over control and active JNK1 was increased by 1.36-fold and active JNK2 was increased by 2.18-fold, suggesting the presence of compensatory IRS-2-mediated pathway. Thus, impaired IRS-1 mediated signaling can be compensated by diverse alternative pathways in IRS-1 KO. These alternative pathways may contribute to persistent PAI-1 expression and hypofibrinlysis in the setting of hyperinsulinemia in obesity.
Abstract 4925: TGF- <i>β</i> Downregulates PPARgamma Gene Expression in Pulmonary Arterial Smooth Muscle Cells (PASMCs): Novel Mechanism of Hypoxia-induced Pulmonary Vascular Remodeling
Authors: Peng Li, Kaizheng Gong, Jason Lucas, Yun Zhang, Qinglin Yang, Suzanne Oparil, Yiu-Fai Chen
Journal: Circulation (2009)

Introduction: Pharmacologic activation of PPAR γ in lung has been shown to attenuate pulmonary arterial remodeling and fibrosis associated with hypoxic pulmonary hypertension. We previously have shown that transforming growth factor (TGF)- β plays a critical role in hypoxia-induced pulmonary vascular remodeling and fibrosis. The current study tested the novel hypotheses that endogenous PPAR γ gene expression is downregulated in lung exposed to chronic hypoxia and in PASMCs treated with TGF- β . Methods: In vivo: 10 wk old male Sprague-Dawley rats were exposed to 10% O 2 for 2 wks. PPAR γ protein levels in lung were assessed using Western blot analysis. In vitro: Rat PASMCs were transfected with a plasmid including PPAR γ promoter and a luciferase reporter gene and then exposed to TGF- β 1 (1 ng/ml) for 24 hrs. PPAR γ promoter activity and mRNA levels were assessed using luciferase activity and real time qRT-PCR analyses. Results : 2-wk hypoxic exposure significantly decreased PPAR γ protein levels in lung. TGF- β 1 treatment decreased PPAR γ promoter activity and mRNA levels in PASMCs (Figure ). Conclusion : These provocative findings indicate that TGF- β inhibits expression of PPAR γ , a putative endogenous anti-fibrogenic transcription factor, in PASMCs. This observation, coupled with the finding that chronic hypoxic exposure decreases PPAR γ in lung, suggests that TGF- β -induced downregulation of PPAR γ in PASMCs represents a novel mechanism of hypoxia-induced pulmonary vascular remodeling and fibrosis. The interaction between TGF- β and PPAR γ signaling pathways at this level may play an important role in modulating the pro-fibrogenic response of lung to hypoxic exposure. This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico &amp; Tennessee).
Abstract 5206: Aortic Valve Calcification and Stenosis is Strongly Associated With Cardiac and All-cause Mortality in End-stage Renal Disease Patients
Authors: Kyuichi Furuhashi, Hideki Ishii, Yoshitaka Kumada, Toru Aoyama, Miho Tanaka, Daisuke Kamoi, Yoshihiro Kawamura, Hiroshi Takahashi, Toyoaki Murohara
Journal: Circulation (2009)

Background: Vascular or tissue calcification has been recognized as a frequent complication in patients with end-stage renal disease (ESRD). Aortic valve calcification (AVC) is especially frequent, and the presence of AVC is a strong predictor of restenosis after drug-eluting stent implantation in ESRD patients. However, its prevalence in ESRD patients and the association with adverse events remain unclear. The aim of this study was to clarify the prevalence and predictive power of AVC and aortic valve stenosis (AVS) for cardiac and all-cause mortality in ESRD patients. Methods: Consecutive 1,290 ESRD patients were screened by echocardiography within 1 month after initiating hemodialysis (HD). AVC was defined as bright echoes &gt;1mm on one or more cusps of the aortic valve. AVS was also defined as pressure gradient &gt;20mmHg. They were followed-up for 7 years. Results: AVC was seen in 627 patients (49%). Among patients with AVC, AVS was observed in 76 patients (12%). Patients were divided into 3 groups; those without AVC (n=663), with AVC alone (n=551) and with AVC and AVS (n=76). Mean follow-up period was 45±34months. Cardiac survival for 7 years was 93.0% in patients without AVC, 84.5% in patients with AVC alone and 69.5% in patients with AVC and AVS, respectively (p&lt;0.0001). Cardiovascular survival was 87.6%, 76.4% and 64.1%, respectively (p=0.0004), and all-cause survival was 74.4%, 58.1% and 39.7% (p&lt;0.0001), respectively. On Cox analysis, AVC and AVC with AVS were independently stratified as predictors of mortalities even after adjustment for gender, age, traditional risk factors, body mass index, hemoglobin, albumin, cholesterol and C-reactive protein levels (Table ). Conclusion: AVC was seen in about a half of ESRD patients even at initial phase of HD therapy, and was strongly associated with cardiac and all-cause mortality in this population.
Abstract 4885: Folic Acid Modulates eNOS Phosphorylation Status/Activity via Phosphoinositide 3-Kinase-Dependent and Independent Pathways
Authors: Sarah Taylor, Derek Lang
Journal: Circulation (2009)

While evidence suggests that folic acid can improve endothelial function through the regulation of endothelial nitric oxide synthase (eNOS), the exact mechanism(s) involved in this process remain elusive. Given that the phosphorylation status of eNOS can play a significant role in modifying its activity, the present study investigated the effect of folic acid on the phosphorylation of eNOS at important regulatory sites. Cultured porcine aortic endothelial cells (PAEC) were exposed to folic acid (0 –50 μ M for 24 hours) in the absence or presence of phosphoinositide 3-kinase (PI3K) inhibition (wortmannin 100nM or LY294002 10 μ M for 30 minutes before folic acid). The phosphorylation status of eNOS as well as total eNOS protein levels were then determined by western blotting. In other experiments similarly treated PAEC were subsequently exposed to calcimycin (10 μ M for 30 minutes) before being lysed. The cGMP content of the cell lysates was then measured by ELISA to provide an index of eNOS activity. Exposure of PAEC to folic acid promoted significant (p&lt;0.05) concentration-dependent dephosphorylation of eNOS at Ser116 and Thr495 (negative regulatory sites) and increased phosphorylation at Ser635 and Ser1177 (positive regulatory sites). In the presence of PI3K inhibition the observed folic acid-induced changes in phosphorylation at Ser116, Ser635 and Ser1177, but not Thr495 (a regulatory site well known to be independent of PI3K control), were prevented. Importantly, the expression of total eNOS protein was not affected by any of the treatments outlined above. The folic acid-induced change in eNOS phosphorylation status was accompanied by increased eNOS activity (as measured by calcimycin-induced cGMP production). Again this increase in eNOS activity was prevented by the presence of PI3K inhibition. In conclusion, these data would suggest that exposure of PAEC to folic acid modulates eNOS phosphorylation status/activity via both PI3K-dependent and independent pathways. Such changes may underlie the beneficial effect of folic acid on endothelial function described by many previous studies.
Abstract 567: Aldosterone Modulates Gap Junction Remodeling in Cultured Rat Ventricular Myocytes
Authors: Shinsuke Suzuki, Tomoko Ohkusa, Takashi Sato, Jong-Kook Lee, Kenji Yasui, Itsuo Kodama, Masunori Matsuzaki
Journal: Circulation (2006)

Background and Objectives : A variety of stresses impact the heart and the renin-angiotensin-aldosterone system (RAAS) affects cellular structure and electrophysiology. Modulation of intercellular coupling through gap junction could lead to an alteration in conduction velocity and conduction block. The aim of this study was to investigate the effects of aldosterone (Ald) on the expression of connexin (Cx)43 gap junction in neonatal rat cultured ventricular myocytes and the consequence changes of conduction properties. Methods: Culture was exposed to Ald for 24h. The expression of Cx43 was characterized by western blotting and real-time RT-PCR. Propagation of excitation was visualized by extracellular potential mapping by using a multiple electrode array system. Results: Exposure to 10 -4 M Ald resulted in a significant downregulation of Cx43 (by ~0.4-fold in protein). Treatment with 10 -8 M Ald induced a significant increase of Cx43 (by ~1.4-fold in protein and by ~1.3-fold in mRNA). Conduction velocity was increased significantly by the treatment of 10 -8 M Ald (~20% increase) with a random propagation of contraction. Ald is known to bind to two types of binding sites: mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). To clarify the effects of dose dependency of Ald on Cx43 expression, Ald was applied to cardiomyocytes pretreated with GR antagonist (mifepristone) or MR antagonist (eplerenone). Mifepristone inhibited the decrease of Cx43 of cardiomyocytes exposed to 10 -4 M Ald. The increase of Cx43 of cardiomyocytes exposed to 10 -8 M Ald was prevented by eplerenone. On the other hand, losartan did not affect the alterations in Cx43 expression caused by 10 -4 and 10 -8 Ald exposure. Conclusions: These results suggest that Ald affects gap junction remodeling in a dose dependent manner by modulating Cx43 synthesis through a different receptor and causes a concomitant change of conduction velocity. An effective prevention of RAAS activation during development of gap junction remodeling might be a new therapeutic strategy for the treatment of arrhythmias.