tbuckley/cabot-search huggingface dataset:
Abstract 18583: Posttranslational Modification of Sirt6 Activity by Reactive Nitrogen Species
Authors: Shuqun Hu, Hua Liu, Yonju Ha, Hossein Ameril, Massoud Motamedi, Wenbo Zhang
Journal: Circulation (2013)

The mammalian sirtuin 6 (SIRT6) is a site-specific histone deacetylase that regulates chromatin structure and fundamental biological processes. It inhibits endothelial cell senescence and inflammation, prevents development of cardiac hypertrophy and heart failure, modulates glucose metabolism and represses tumor growth. The basic molecular mechanisms underlying regulation of Sirt6 enzymatic function remains unknown. Here we hypothesized that Sirt6 function can be regulated via posttranslational modification, focusing on the role of peroxynitrite. Peroxynitrite is one of the major reactive nitrogen species formed by excessive nitric oxide and superoxide generated during cardiovascular diseases. It induces nitration of protein tyrosine residue and alters the structure and function of protein.We found that incubation of purified recombinant Sirt6 protein with various doses (0.5, 1.0, 2.0, 5.0 mM ) of 3-morpholinosydnonimine (SIN-I, a peroxynitrite donor which generates NO and superoxide donor simultaneously) for 30 min at room temperature resulted in increase in Sirt6 tyrosine nitration by 6.6, 8.4, 11.1 and 14.3 fold, respectively. Correlated with the increase in Sirt6 nitration, the intrinsic catalytic activity of Sirt6 was reduced by 43.4%, 47.2%, 53.5% and 70.1% as determined with a Sirt6 deacetylase fluorometric assay kit. Nitration of endogenous Sirt6 were also observed in human umbilical vein endothelial cells and human retinal microvascular cells treated with SIN-1 (5 mM). To further test whether Sirt6 nitration occurs under pathological conditions, we monitored Sirt6 nitration using a model of endotoxin-induced retinal vascular inflammation. Measurement of 3-nitrotyrosine in immunoprecipitated Sirt6 showed that Sirt6 nitration was significantly increased in mice of inflammation. There are four tyrosine residues in Sirt6 which are conserved among human, mouse and rat. Analysis of protein nitration sites by mass spectrometry revealed that tyrosine 257 in Sirt6 was nitrated after SIN-1 treatment. These results demonstrate a novel regulatory mechanism of Sirt6 activity through reactive nitrogen species-mediated nitration under oxidative and nitrative stress.
Abstract 18254: Pathogenic Role of STIM2 and Orai2 in Pulmonary Arterial Hypertension
Authors: Ruby A Fernandez, Jun Wan, Qiang Guo, Jason X Yuan
Journal: Circulation (2013)

Pulmonary hypertension (PH) is a fatal disease attributed to increased pulmonary vascular resistance (PVR). Elevated PVR is partially due to sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling. Pulmonary arterial smooth muscle cells (PASMC) in their natural state are plastic and exist in two different phenotypes; a differentiated, contractile phenotype and a dedifferentiated, more proliferative phenotype. An increase in cytosolic free Ca 2+ concentration ([Ca 2+ ] cyt ) is a major stimulus for PASMC proliferation, contributing to pulmonary vascular remodeling. This study characterizes the phenotypic switch observed when freshly dissociated PASMC are cultured from normal male rats or in PASMC isolated from experimental PH rats. Western blot analysis showed freshly isolated pulmonary arteries (PA) express contractile markers that were decreased in cultured PASMC, demonstrating a switch to a proliferative phenotype. Cultured PASMC showed an increase in expression of store-operated and receptor-operated Ca 2+ channels Orai2, STIM2, and TRPC6 compared to freshly dissociated PASMC. Additionally, an increase in store-operated Ca 2+ entry (SOCE) and a decrease in voltage dependent Ca 2+ influx in cultured PASMC was observed when compared to freshly dissociated PASMC, suggesting SOCE plays a greater role in proliferating PASMC. Consistently, isometric force studies showed greater contraction induced by voltage-dependent Ca 2+ channel (VDCC) activation than SOCE induced contraction in freshly isolated pulmonary artery rings. Furthermore, Orai2, STIM2, and TRPC6 were upregulated in proliferative PASMC compared to quiescent PASMC. Knockdown of Orai2 was able to attenuate SOCE in proliferative PASMC demonstrating Orai2 is necessary for SOCE. These data suggest upregulation of STIM2 promotes the phenotypical transition of PASMC from a contractile to a proliferative phenotype by inhibiting VDCC and activating SOC, and that increased expression of Orai2 and TRPC6 channels mediate the increased [Ca 2+ ] cyt seen in proliferating cells. Understanding the molecular mechanisms which regulate [Ca 2+ ] cyt and PASMC proliferation is critical for the development of novel therapies for PH.
Abstract 9801: Patient- and Vessel-based SYNTAX Scores by Coronary Computed Tomographic Angiography: A Direct Comparison to Invasive Coronary Angiography
Authors: Aryeh Shalev, Ryo Nakazato, Rine Nakanishi, Reza Arsanjani, Yuka Otaki, Hyung Bok Park, Damini Dey, Heidi Gransar, Troy LaBounty, Victor Cheng, Sean W Hayes, Louise E Thomson, John D Friedman, Daniel S Berman, James K Min
Journal: Circulation (2012)

Introduction: The SYNTAX score is commonly used to assess the complexity of coronary artery disease (CAD) by invasive coronary angiography (ICA), and to classify patients at risk for major adverse cardiovascular events following percutaneous coronary intervention. To date, whether the SYNTAX score can be reliably determined from noninvasive coronary CT angiography (CCTA) has not been fully explored. Hypothesis: To determine the correlation between global and vessel-specific SYNTAX scores derived from CCTA and ICA. Methods: We evaluated 94 consecutive patients (mean age - 66 years, 66% male gender) with and without known CAD, who underwent CCTA and subsequent ICA within 5 days, due to obstructive (&gt;50% stenosis) single-, double-, or triple-vessel CAD. Patients with prior coronary bypass surgery were excluded. Per-patient and per-vessel SYNTAX scores were calculated from CCTA and ICA in blinded fashion by independent and experienced readers. CCTA SYNTAX scores incorporated identical variables as ICA SYNTAX scores. Paired student’s t-test and Spearman’s rank test were employed to determine the relation between CCTA and ICA scores, as well as Bland Altman analysis for agreement. Results: On a per-patient basis, obstructive 1-vessel disease (VD), 2-VD and 3-VD was found in 41 (44%), 37 (39%) and 16 (17%) patients, respectively. Left main (LM), left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA) obstructive disease was identified in 7 (7%), 69 (73%), 43 (46%) and 47 (50%) patients, respectively. Mean per-patient CCTA and ICA SYNTAX scores were similar (11.2 vs. 11.7, respectively, p=0.07) with excellent correlation and agreement (table). Similar results were observed for per-vessel measures (table). Conclusion: Per-patient and per-vessel SYNTAX scores derived from CCTA demonstrate high correlation and agreement to ICA SYNTAX scores. Evaluation of CCTA SYNTAX scores for prediction of pre-ICA risk for MACE now appears warranted.
Abstract 18396: Peroxisome Proliferator-Activated Receptor Gamma- Deficiency in Endothelial Cells Leads to Impaired Angiogenesis
Authors: Sanna Vattulainen, Minna M Koskenvuo, Caiyun Grace Li, Molong Li, Vinicio de Jesus Perez, Cristina Alvira, Hirofumi Sawada, Juha W Koskenvuo, Marlene Rabinovitch, Tero-Pekka Alastalo
Journal: Circulation (2013)

Rationale: TIE2 promoter mediated loss-of peroxisome proliferator-activated receptor gamma (PPARγ) in mice (TIE2CrePPARγflox/flox) (KO) leads to endothelial cell (EC) dysfunction, pulmonary arterial hypertension and osteopetrosis through loss-of osteoclasts. Although some of the functions and mechanisms of PPARγ-mediated regulation of vascular homeostasis have been revealed, the exact role of PPARγ in angiogenesis is obscure. Methods: The role of PPARγ in angiogenesis was evaluated in vivo in KO and wild type (WT) mice by matrigel plug assays. As the level of endothelial progenitor cells (EPC) (CD34+/VEGFR2+/CD45-) especially in circulation can reflect angiogenic capacity, their levels were assessed in peripheral blood, spleen and bone marrow (BM) in both mouse models by flow cytometry. BM transplantations were used to switch EPC phenotypes. Magnetic beads were used to isolate mouse pulmonary ECs (PEC) for functional studies. In human ECs (HMVEC) PPARγ-deficiency was studied using siRNA strategy. Results: In vivo angiogenesis assay showed a significant attenuation of angiogenic capacity in KO mice when compared to WT. In contrast to WT, KO mice implanted with matrigel plugs showed no significant angiogenic response to BMP2. Interestingly, KO mice had significantly (&gt;50%) reduced EPC levels in spleen and circulation when compared to WT but their levels in bone marrow (BM) were 3-fold in KO mice suggesting a mobilization defect from the BM. WT BM transplantation rescued the mobilization defect in KO mice and normalized the EPC levels but did not rescue the angiogenesis defect. In vitro studies with mature PECs isolated from KO mice showed a 40% decrease in tube-formation and migration after VEGF and BMP2 stimulation when compared to WT cells. In line with this, PPARy-deficient HMVECs showed a similar angiogenic defect in vitro (P&lt;0.001, N=9). Conclusion: PPARγ plays an important role in sustaining angiogenic potential in mature ECs both in mice and humans. Osteoclasts are essential for mobilization of EPCs from the BM.
Abstract 18413: Systolic Circumferential Strain Derived From Feature-Tracking Cardiovascular Magnetic Resonance Predicts Survival After Cardiac Resynchronization Therapy
Authors: Robin J Taylor, Fraz umar, Lai S Lin, Amar Ahmed, Rick P Steeds, Francisco Leyva
Journal: Circulation (2013)

Objective: The clinical outcome of cardiac resynchronization therapy (CRT) is variable. Feature-tracking cardiovascular magnetic resonance (FT-CMR) allows quantification of myocardial strain using a routine CMR scan. We hypothesized that pre-implant peak systolic circumferential strain (Ecc) predicts survival after CRT. Methods: In this prospective study, 98 patients (age: 66 ± 12 yrs, LVEF: 24 ±11%, QRS: 145 ± 30ms) had pre-implant assessment of peak systolic Ecc from the mid cavity LV short-axis slice. This measure, which involved 1.2 ± 0.3 min of post-processing, was assessed in relation to all cause mortality. Results: The mean peak systolic Ecc was 7.5 ± 5.0% amongst the entire cohort. 30 patients died over a follow-up of 3.9 ± 2.4 yrs (mean ± SD). Above an optimum cut-off of 10%, Ecc, predicted survival after CRT (Chi-squared: 5.37, log-rank p = 0.01; area under the receiver-operator characteristic curve: 0.67, 95% CI 0.58 - 0.79, p = 0.003). Conclusion: The rapid assessment of pre-implant peak systolic Ecc derived from FT-CMR predicts survival after CRT.
Abstract 9773: Phage Display of <i>D</i> esigned <i>A</i> nkyrin <i>R</i> epeat <i>P</i> roteins (DARPins) against the I Domain Of Mac-1 Results in Novel Diagnostic and Therapeutic Agents Specifically Acting on Activated Monocytes
Authors: Philipp Diehl, Nicole Bassler, Daniel Steiner, Alba Fricke, Karlheinz Peter
Journal: Circulation (2012)

Introduction: D esigned A nkyrin R epeat P roteins (DARPins) are a novel class of highly stable binding proteins (≈10-20kDa) and represent a valuable source for specific binders with picomolar affinities. The I domain is the activation-dependent binding site of the leukocyte integrin Mac-1 that is a central mediator of inflammation. Hypothesis: We assessed whether phage selection against the I domain results in DARPins that specifically bind to activated leukocytes without affecting non-activated ones. Methods: Selection was performed on purified mouse I domain using a DARPin phage library with a high diversity (10 10 ). Results: After 3 panning rounds, specific phages were selected and DARPins expressed with a high yield (≈ 200 mg/L). PMA activation revealed that DARPins bind stronger to activated than to non-activated mouse monocytes (Fig.1). Static and dynamic adhesion assays proved that selected DARPins inhibit binding of Mac-1 to its ligands (Fig.2). Using a peritonitis model, DARPins inhibited leukocyte migration into inflammatory areas, thereby indicating strong therapeutic, anti-inflammatory effects ( control vs DARPin: 940 vs. 230 cells, p&lt;0.02 ). DARPins showed strong crossreactivity to activated human Mac-1. Conclusion: Selected DARPins specifically bind to activated Mac-1 and can be used for direct monitoring of monocyte activation both in mice and humans. Thereby, based on the novel DARPin format we established a potential anti-monocyte drug that exerts strong anti-inflammatory effects in in vivo . Cross-reactivity with human Mac-1 promises translation into a broad spectrum of inflammation driven diseases.
Abstract 97: The Overlap in Frequency Spans of Ventricular Fibrillation and Chest Compression in Cardiac Arrest Patients
Authors: Reza Firoozabadi, Eric Helfenbein, Saeed Babaeizadeh
Journal: Circulation (2012)

Background In treating sudden cardiac arrest (SCA) patients, automatic external defibrillators automatically analyze the ECG rhythm to determine if defibrillation is necessary. Currently, this analysis must be done during hands-off period because the electrical artifact induced by chest compression (CC) makes the analysis unreliable. It is desired to analyze the ECG rhythm during CPR to minimize the hands-off period, and hence, improve CPR success. Simple filtering of CC artifact would work only if there is no significant overlap between frequency spans of CC and ventricular fibrillation (VF); otherwise, it would distort the ECG. Objective To investigate the overlap between CC and VF frequency spans. Methods ECG recordings from 170 SCA adult patients with VF rhythm were used. These cases were a subset of a larger database collected for a clinical study in 6 ambulances in 3 European regions using Laerdal HeartStart 4000 defibrillators. The defibrillator had an extra chest pad with an accelerometer and a pressure sensor to record the CC signal. The VF and CC frequency spans were calculated by frequency-domain analysis of the signals. Results The figure below demonstrates the frequency spans of VF and CC in patients with VF rhythm going under CPR. The plots are normalized and also include the higher harmonics. A significant overlap is observed at the range of 80 to 140 compressions-per-minute. Conclusion The significant overlap in frequency spans of VF and CC makes it challenging to filter the CC artifact without removing parts of VF information and hence distorting the ECG signal. Therefore, techniques for analyzing ECG during CPR should be smarter than merely filtering the CC artifact.
Abstract 18282: Association Between Cardiac Computed Tomography Perfusion Imaging and Electronatomic Mapping to Evaluate Left Atrial Fibrosis in Patients With Atrial Fibrillation
Authors: Zhiyu Ling, John McManigle, Irfan Khurram, Stefan Zimmerman, Joseph Marine, David Spragg, Hiroshi Ashikaga, Hugh Calkins, Saman Nazarian
Journal: Circulation (2013)

Background: Prior studies have shown that contrast enhanced multislice computed tomography (ceMSCT) can visualize ventricular scar. The purpose of this manuscript is to assess the ability of ceMDCT to detect left atrial (LA) fibrosis in patients undergoing repeat ablation for atrial fibrillation (AF). Methods and Results: We enrolled 10 patients prior to repeat ablation. All patients underwent pre-procedural ceMSCT of the LA followed by voltage mapping of the LA during the ablation procedure. The ceMSCT images were processed off-line using Seg3D software (University of Utah, Salt Lake City, USA). Epicardial and endocardial contours were manually drawn around LA myocardium on multi-planar axial images. Electroanatomic mapping points were retrospectively registered to the corresponding ceMSCT images. LA Scar identified by an image intensity range between 0-30 Hounsfeld units (HU) on ceMSCT correlated qualitatively with scar identified by low-voltage (bipolar voltage &lt;0.1 mV). Qualitative agreement in the posterior wall and the left pulmonary vein antrum was excellent. In a linear regression model of a subset of 4 patients, the local CT image intensity was associated with local bipolar voltage (+0.1 mV +/- 0.06 / 100 HU,P=0.019) Conclutions: We demonstrate that ceMSCT can provide valuable information about LA myocardial fibrosis with excellent electro-anatomic concordance. Electroanatomic voltage map of a redo PVI patient showing LA fibrosis in red corresponding to Low voltage (&lt;0.1 mV). Figure 1-B. Contrast enhanced multislice computed tomography imaging derived scar map of the same patient showing the same projection of the left atrium. Image intensity of LA between 0 to 30 is shown in red and blood pool of left atrium is shown in light blue.
Abstract 9794: Load Dependency of Right Ventricular Performance is a Major Factor to be Considered in Decision Making Prior to Ventricular Assist Device Implantation
Authors: Michael Dandel, Evgenij Potapov, Thomas Krabatsch, Alexander Stepanenko, Alexandra Löw, Juliane Vierecke, Christoph Knosalla, Roland Hetzer
Journal: Circulation (2012)

Background Left ventricular assist devices (LVADs) provide better quality of life than biventricular devices (BVADs), but it is a challenge to evaluate right ventricular (RV) function and to predict its time-course after LV support. Severe RV failure after LVAD implantation appeared related to pre-operative RV geometry and tricuspid regurgitation (TR) which are highly load sensitive parameters. We assessed the impact of load dependency on RV performance before and after LVAD implantation aiming to improve pre-operative decision making. Methods We evaluated our patients who received a LVAD after 1/2006. RV anatomic and functional parameters collected prospectively before LVAD implantation and invasively collected data on pulmonary hemodynamics were tested for relationship with post-implant RV function and patient outcome. Echocardiography including tissue Doppler and 2D strain imaging was used to evaluate RV size, geometry and function. Results After LVAD implantation 45 (9.5%) of 475 evaluated patients showed worsening of RV function which necessitated a mechanical support also for the RV. Whereas RVEF was similar in patients with and without stable post-operative RV function there were significant differences in pre-operative long/short axis (L/S) ratio, tricuspid annulus peak systolic velocity (TAPSm) peak global strain rate (RVSSr),RV/right atrial pressure gradient (ΔP-RV/RA) and pulmonary arterial pressure (PAP) between the two patient groups (p &lt; 0.05). The highest predictive values (up to 93.5%) for RV failure after LVAD insertion were found for pre-operative L/S ≥ 0.6, TAPSm &lt; 8cm/s, and peak RVSSr &lt; 0.7/s in patients with maximum ΔP-RV/RA &lt; 35mmHg. L/S, TAPSm and RVSSr also showed high predictive values for RV failure in patients with preoperative TR &gt; grade II and PAP &lt; 50mmHg. L/S &lt; 0.6, TAPSm ≥ 8cm/s, and peak RVSSr ≥ 0.7/s in patients with maximum ΔP-RV/RA ≥ 35mmHg showed high predictive values (≥ 92%) for postoperative freedom from RV failure. Conclusion RV geometry and velocity of contraction before LVAD implantation are highly predictive for postoperative RV function if preoperative PAP and TR are also considered. RV L/S ratio, TAPSm and RVSSr, in connection with maximum ΔP-RV/RA, can improve decision making before VAD implantation.
Abstract 18554: The Association of Diagnostic Criteria for Myocardial Infarction and Peri-Operative Cardiac Risk Factors in Vascular Surgery Patients
Authors: Christina L Cove, Naomi Hamburg, Robert Eberhardt, Denis Rybin, Jeffrey Kalish, Mohammad Eslami, Alik Farber, James McPhee
Journal: Circulation (2013)

Background: The inclusion of cardiac biomarkers and ST-T changes on electrocardiography in the diagnostic criteria for myocardial infarction (MI) has increased the apparent incidence of infarction in the general population. The impact of re-defining MI on the incidence and risk of peri-operative MI is unclear. We evaluate the association between diagnostic criteria changes and incidence of and risk factors for peri-operative MI in vascular surgery patients. Methods: Patients who underwent non-emergent vascular surgery between 2005 and 2011 were identified from the American College of Surgeons’ National Surgical Quality Improvement Program (NSQUIP) multi-center database. In 2005, MI was defined by new Q-waves on electrocardiography. In 2009, the definition included variable electrocardiographic evidence (ST elevation, new left bundle branch block, or new q-waves) or an elevation of cardiac troponin greater than 3 times the upper level of normal. Baseline characteristics were identified, and yearly incidence of MI was determined. Multivariable regression was used to determine risk factors associated with MI according to the old and new definitions. Results: Of 70,811 patients who underwent vascular surgery between 2005 and 2011, 40,017 (57%) were ≥ 70 years old, and 46,206 (65%) were male. High-risk vascular surgery (open abdominal aortic aneurysm repair or aorto-bifemoral bypass) was performed in 7,359 (10%) patients. Peri-operative MI more than tripled from the 2005-2008 to 2009-2011 time periods (1.5% vs. 0.4%; p&lt;0.001). In multivariable analyses, significant risk factors for MI also changed from the earlier to later model (See Table). Conclusions: Re-defining MI increased the apparent incidence of and number of independent risk factors for peri-operative MI. The diagnostic criteria for MI utilized in prior cardiac risk prediction models should be considered when determining risk in patients undergoing non-emergent vascular surgery.