tbuckley/cabot-search huggingface dataset:
Abstract 18584: The Hypoxic Microenvironment Alters Macrophage Lipid Metabolism and Reprograms Inflammatory Responses Through STAT3 and HIF1α Signaling
Authors: Sascha N Goonewardena, Anuli C Anyanwu, Sarah Emery, Hui Liao, David J Pinsky
Journal: Circulation (2012)

Background: Atherosclerosis is a chronic inflammatory disease mediated by numerous heterotypic interactions between cells and the microenvironment. Hypoxia in the arterial wall has been implicated in atherogenesis and is known to modulate immune responses. Macrophages, heterogeneous sentinels of the innate immune system, are involved in all phases of atherogenesis. In addition to their role in immune responses, macrophages are important orchestrators of systemic cholesterol metabolism. However, the molecular mechanisms underlying the relationship between macrophage inflammatory responses, lipid metabolism, and the hypoxic microenvironment remain poorly understood. Objective: To examine the molecular effects of hypoxia on macrophage immune responses and cholesterol metabolism. Methods and Results: Bone marrow-derived macrophages and RAW264.7 cells were stimulated with the Toll-like receptor ligand LPS (100 ng/ml for 2h) in the presence or absence of hypoxia (1% O 2 ). Activation of inflammatory and metabolic signaling pathways and transcriptional profiles were examined. Macrophages stimulated with LPS demonstrated phosphorylation of MAPK (ERK, JNK, and p38) and STAT3 and stabilization of HIF1α. In contrast, LPS stimulation of hypoxic macrophages had increased HIF1α stabilization and blunting of STAT3 phosphorylation with essentially no changes in MAPK activation, suggesting that hypoxia differentially modulates LPS signaling pathways. Additionally, LPS stimulation led to distinct transcriptional changes in macrophage inflammatory (NOS2, TNFα, CD36, mannose receptor; p&lt;0.005) and metabolic (PTGS2, ABCA1, ACAT1; p&lt;0.005) profiles. These transcriptional profiles were greatly altered by hypoxia, mirroring the changes in activation of macrophage signaling pathways. Conclusions: Hypoxia modulates macrophage inflammatory responses and their metabolic activity through differential activation of STAT3 and HIF1α and their transcriptional targets. These studies advance preliminary identification of close links between oxygen sensing and cholesterol biosynthesis, and highlight the potentially critical relationship between macrophages, metabolism, and the hypoxic microenvironment in atherogenesis.
Abstract 18601: The Role of ADMA Metabolism in the Regulation of Human Pulmonary Endothelial Cell Function
Authors: Hilda H Tsang, James Leiper, Ka Hou Lao, Gareth Barnes, John Wharton, Luke Howard, Martin Wilkins, Beata Wojciak-Stothard
Journal: Circulation (2012)

Objective: Asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, is increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA abrogates gap junctional communication required for the coordinated regulation of pulmonary endothelial permeability and angiogenesis, contributing to the disease. Methods and Results. The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells (HPAECs). ADMA inhibited protein expression and cell surface localization of connexin 43 (Cx43) in HPAECs (2-fold decrease, P&lt;0.01), resulting in impaired gap junctional communication, as shown by Fluorescence Recovery After Photobleaching (FRAP). ADMA regulated Cx43 expression and function via the nitric oxide signalling pathway, as effects could be reversed by the nitric oxide donor SNAP, and nitric oxide secondary messengers, cAMP and cGMP. Defective gap junction communication in HPAECs led to endothelial dysfunction, including increased trans-endothelial permeability (1.7-fold increase, P&lt;0.001), and impaired angiogenesis(1.7-fold decrease, P&lt;0.001). The effects of ADMA were prevented by over expressing dimethylarginine dimethylaminohydrolase I (DDAHI), an enzyme that metabolised ADMA, or treatment with the Cx43-gap junction activating drug, rotigaptide.Reduced Cx43 expression was also found in lungs of mice deficient in DDAHI. In vivo lung permeability was increased in DDAHI homozygous knockout mice (1.2-fold increase, P&lt;0.05), and was alleviated by application of rotigaptide. Endothelial colony forming cells from IPAH patients showed reduced expression of DDAHI and Cx43 (2-fold decrease, P&lt;0.05), resulting in impaired endothelial barrier function and abnormal angiogenesis. Conclusions. ADMA is critical in the regulation of gap junctional communication in pulmonary endothelium. Endothelial cells from IPAH patients show reduced ADMA metabolism resulting in defective gap junctional communication and abnormal angiogenic responses. Enhancing Cx43 function may have endothelium-protective effects in conditions associated with reduced nitric oxide signalling, such as pulmonary hypertension.
Abstract 18611: Transcatheter Aortic Valve Implantation Reduces Central Sleep Apnea in Patients with Severe Aortic Stenosis
Authors: Markus Linhart, Rebecca Fistéra, Stefan Pabst, Alexander Ghanem, Jan-Malte Sinning, Christoph Hammerstingl, Karin Springmann, Nikos Werner, Georg Nickenig, Dirk Skowasch
Journal: Circulation (2012)

Introduction While the association between congestive heart failure and central sleep apnea (CSA) is well described, the role of sleep disordered breathing (SDB) and particularly CSA in valvular heart disease is unclear. We evaluated 67 patients with high-grade aortic stenosis and high preoperative risk for the prevalence of SDB before and after transcatheter aortic valve implantation (TAVI). Methods 67 consecutive patients that were eligible for TAVI were underwent an overnight polygraphy (Embletta ® Device, Embla). Clinical, echocardiographic and invasive data were collected. SDB was defined as an apnea-hypopnea-index (AHI) &gt;5/h. In 31 patients that to date performed the 3 months follow-up, monitoring was repeated and compared to the baseline status. Results Prevalence of SDB was 61% with a clear predominance of CSA (43%, table 1). In the 3 months follow-up that was completed by 31 patients so far, significant improvement in AHI, AI central, LVEF, NYHA class and NT pro-BNP was seen (table 2). There was a highly significant inverse correlation of NT pro-BNP with LVEF (r=-0.72, p&lt;0.001) but not with severity of CSA (r=0.19, p=0.13). 18 patients died before the 3 months follow-up. Conclusion We can show a high prevalence of SDB, in particular of CSA, in this patient cohort. There is a highly significant improvement of sleep apnea in the CSA subgroup after TAVI, which is independent of left ventricular function and NT pro-BNP.
Abstract 18578: Replication of a Risk Prediction Model for Ambulatory Incident Atrial Fibrillation Using Electronic Medical Record
Authors: Babar Parvez, Anushi Shah, Raafia Muhammad, M. Benjamin Shoemaker, Amy J Graves, Susan R Heckbert, Hua Xu, Patrick T Ellinor, Emelia J Benjamin, Alvaro Alonso, Ayumi K Shintani, Dan Roden, Dawood Darbar
Journal: Circulation (2012)

Introduction: Atrial fibrillation (AF) contributes to substantial increases in morbidity, mortality and increasing healthcare expenditures. Using data from community-based cohorts, CHARGE-AF investigators developed an AF risk prediction model. We aimed to replicate the CHARGE AF risk model using the Vanderbilt electronic medical records (EMR) repository. Methods: We identified a large ambulatory cohort of Caucasians and African Americans of age ≥ 40 years without a prior history of AF, followed by assessment of incident AF over a 5-year period (December 2005 to December 2010) using prospective chart review and validated AF algorithm. Baseline clinical variables (age, ethnicity, sex, height, weight, systolic and diastolic BP, PR interval, current use of antihypertensive medications, DM, MI, CHF, current smoking, and LVH on ECG) were extracted on or within 6 months prior to December 2005. We used multiple imputation for missing values and multivariable Cox proportional hazards analysis to construct our risk prediction model. Results: Our study cohort consisted of 63,772 subjects (age 58±11 years, 47% male, 90% Caucasians) with no prior history of AF. Over a mean follow up time of 3.9±0.95 years, 3,383 (5.3%) subjects developed AF in 2.6±1.3 years. In the multivariable model, older age, Caucasian ethnicity, male sex, taller height, greater weight, history of heart failure, LVH on ECG and prolonged PR interval were all significant risk predictors of AF (similar to CHARGE-AF risk model), whereas current use of antihypertensive medication was protective of developing AF (Table). The C-index from our model, 0.768, indicated relatively good discrimination. Conclusions: From clinical factors readily accessible in a large de-identified EMR database, we replicated the CHARGE AF risk prediction model to identify individuals at risk for developing AF in an ambulatory setting. This risk model may be used to target high risk-individuals for preventive measures.
Abstract 18572: Do Obese Children Consume More Energy at Mealtime Compared to Lean Children?
Authors: Holly M Ippisch, Suzanne S Summer, Thomas R Kimball
Journal: Circulation (2012)

Overweight in childhood is known to lead to cardiac structural, functional, and vascular abnormalities making childhood obesity a major public health concern. It is often assumed that overeating at mealtime contributes to the excess weight gain, but there is limited data in pediatric populations. HYPOTHESIS: We assessed the hypothesis that obese children would consume greater kilocalories than their lean counterparts when exposed to identical food choices during a single meal, under semi-controlled conditions. METHODS: Children were provided a standardized low fat meal and allowed to eat ad lib. The meal provided significantly higher calories than what most children could comfortably eat, in order to discourage seeking additional unapproved food. The meal preparation was supervised by a dietitian and sent home with the family. The family returned the leftover food so that calorie consumption could be calculated. RESULTS: 40 young people (23 obese, 17 lean) ages 8-19 years old (average 13.5 +/- 3.6 yrs) were recruited. The average calories consumed by the obese children were significantly lower than the amount consumed by the lean children when provided similar meals (p &lt;0.01) (Figure). The obese children also consumed significantly less protein, carbohydrates, and fat (p &lt; 0.05). The study was repeated on a subsequent day with similar results. CONCLUSIONS: When provided with a low fat meal, obese children repeatedly consumed fewer calories compared to lean children. These findings may be due to a variety of factors, such as taste and research participation, but may have important implications for calorie consumption and intervention in obese children.
Abstract 18627: Cellular Encapsulation of Mesenchymal Stem Cells Enhances Cardiac Repair in a Rat Model of Myocardial Infarction
Authors: Rebecca D Levit, Natalia Landazuri, Edward A Phelps, Milton E Brown, Andres Garcia, Michael E Davis, Gigi Joseph, Robert Long, Collin J Weber, Susan A Safley, Jonathan D Suever, Alicia N Lyle, W. Robert Taylor
Journal: Circulation (2012)

Stem cell therapies for myocardial repair have shown promise in preclinical trials, but lower than expected retention and viability of transplanted cells. In an effort to improve this, we employed an alginate encapsulation strategy for human mesenchymal stem cells (hMSCs) and attached them to the heart with a biocompatible PEG hydrogel patch in a rat MI model. Encapsulation allows for diffusion of pro-angiogenic cytokines and growth factors made by the hMSCs while maintaining them at the site of implantation. Animals were treated as follows: (1) MI only, (2) MI + gel, (3) MI + gel + empty capsules, (4) MI + gel + 1x106 non-encapsulated hMSCs or (5) MI + gel + 1x106 hMSCs encapsulated in alginate. Cells were tracked using bioluminescence (BLI) and cardiac function measured by echo and CMR. Animals treated with encapsulated hMSCs in the patch had a large increase in microvascular density in the peri-infarct area (828 ± 56 vessels/mm2; n = 6; p &lt; 0.01) compared to other groups (MI: 121 ± 10, MI + gel: 153 ± 26, MI + gel + MSC: 198 ± 18, MI + gel + empty capsules: 215 ± 55; n = 6-9). Scar size at 28 days was also significantly reduced in encapsulated hMSC treated animals (7 ± 1 %; n = 6; p &lt; 0.05) compared to control hearts (MI: 12 ± 1 %, MI + gel: 14 ± 2%, MI + gel + MSC: 14 ± 1%, MI + gel + empty capsules: 12 ± 2%; n = 4-8). Longitudinal BLI showed greatest hMSC retention when the cells were encapsulated. Post MI cardiac fractional shortening and ejection fraction, as measured by echo and CMR, were improved in encapsulated hMSC treated hearts (Table 1). Alginate encapsulated hMSCs attached to the heart with a hydrogel patch resulted in a highly significant improvement in left ventricular function after acute myocardial infarction. The mechanism for this markedly enhanced effect appears to be increased cell survival and retention, resulting in improved vascularization of the peri-infarct area. Cellular encapsulation may represent a new translatable strategy applicable to many cell types for regenerative therapy for CVD.
Abstract 18311: Mechanism of Cardiovascular Benefit From Exercise in Women: Not Through Subclinical Atherosclerosis!
Authors: Laura DeFina, Nina Radford, David Leonard, Jarett Berry, Amit Khera
Journal: Circulation (2011)

Introduction: Cardiorespiratory fitness (CRF) has been shown to be inversely associated with coronary heart disease (CHD) morbidity and mortality. The cardioprotective mechanism of fitness has not been well defined. The goal of this study was to assess the relationships among subclinical coronary artery calcification as a measure of atherosclerotic burden, self reported PA and measured CRF in a single large population of generally healthy women. Methods: 6,148 women seen in a single medicine clinic between 1998 and 2007 provided self-reported measures of PA, underwent maximal treadmill exercise testing, and CAC scanning. PA was reported in MET·min per week. CRF was reported in METs derived from the maximal treadmill time. CAC was evaluated as a dichotomous variable. We used multiple logistic regression to calculate adjusted odds ratios (OR) for CAC &gt; 0, and we applied a nonparametric trend test to the relationship between PA and CRF. Results: The mean age was 50.9 years (±8.9). The overall prevalence of CAC was 18.8%. CAC was directly related to age, hypertension, diabetes, hyperlipidemia, and family history of CHD. Figure 1 shows mean CAC by quartile of CRF without adjustment for other covariates. When adjusted for age, the association between CAC and CRF remained significant (OR=0.995 [0.992,0.998] per MET, p&lt;0.001) but not when adjusted for age, hypertension, diabetes, hyperlipidemia, smoking, and family history (OR=0.998 [0.995,1.001] per MET, p=0.14). CAC was not associated with PA when adjusted for age or all covariates. In this large population, we also found a direct relationship between self-reported PA and CRF (p&lt;0.001). Conclusions: The cardiovascular benefit of self reported PA or quantitative CRF, does not appear to be mediated by the modification of absolute calcific atherosclerotic burden in women.
Abstract 18410: Predicting Long-Term Mortality Following Coronary Artery Bypass Graft Surgery
Authors: Chuntao Wu, Fabian Camacho, Edward L Hannan
Journal: Circulation (2011)

Background: Simplified bedside risk scores have been created to predict short-term mortality, e.g. in-hospital mortality, following coronary artery bypass graft (CABG) surgery. However, no such scores have been developed to predict long-term mortality. Objectives: To create a simplified risk score to predict long-term mortality following CABG surgery. Methods: The New York State's Cardiac Surgery Reporting System was used to identify the study population, which consisted of 8,413 patients who underwent isolated CABG surgery and were discharged in July through December 2000. The National Death Index was used to ascertain patients' vital status through the end of 2007. A Cox proportional hazards model was fit to predict death following CABG surgery using pre-procedural risk factors. Then points were assigned to significant predictors of death based on the values of their regression coefficients, and for each possible point total (sum of points of risk factors) the predicted risks of death at years 1, 3, 5, and 7 were calculated. Results: Kaplan-Meier analysis showed that the 7-year mortality rate was 22.6% in the study population. Significant predictors of death included age, body mass index, ejection fraction, left main coronary artery disease, cerebrovascular disease, peripheral arterial disease, congestive heart failure, chronic obstructive pulmonary disease, diabetes, and renal failure. The C statistics measuring the discrimination of the Cox proportional hazards model were 0.781, 0.773, 0.770, and 0.780 for mortality at 1, 3, 5, and 7 years of follow-up. The points assigned to these risk factors ranged from 1 to 7; and the possible point totals ranged from 0 to 24. The observed and predicted risks of death at years 1, 3, 5, and 7 across patient groups stratified by point totals were highly correlated. Conclusion: We developed a simplified risk score for predicting the risk of mortality following CABG surgery at 1, 3, 5, and 7 years. This long-term risk score can be used by providers and patients as an aid in determining the appropriate treatment for patients with coronary artery disease based on each patient's specific risk factors.
Abstract 221: The Use of Invasive Hemodynamic Monitoring in Evaluating Resuscitative End Points in Post--Cardiac Arrest Therapeutic Hypothermia (COMICA Study Group)
Authors: Anne V Grossestreuer, Sarah M Perman, Marion Leary, Michael W Donnino, Michael N Cocchi, Mary Ann Peberdy, Joseph P Ornato, John N Clore, Clifton W Callaway, Jon C Rittenberger, Benjamin S Abella, David F Gaieski
Journal: Circulation (2012)

Introduction: Patients who suffer from post-cardiac arrest syndrome (PCAS) often exhibit an inflammatory response similar to a sepsis syndrome. Invasive hemodynamic monitoring of resuscitative endpoints has been proven to impart better mortality outcomes in sepsis and has been recommended for goal-directed management of PCAS patients. Hypothesis: Centers engaged in aggressive post-cardiac arrest care will utilize invasive hemodynamic monitoring to ascertain adequacy of resuscitative endpoints including central venous pressure (CVP) and central venous oxygen saturation (ScvO 2 ). Methods: This study is a collaboration of 4 centers with aggressive PCAS and therapeutic hypothermia protocols. It is a secondary analysis from prospectively collected data of out-of-hospital cardiac arrest patients who underwent TH. The primary objective was to determine the use of invasive hemodynamic monitoring in the care of PCAS patients undergoing TH. The secondary objective was to determine if either CVP or ScvO 2 were associated with neurologic outcome measured as cerebral performance category (CPC), dichotomized into “good” (1 or 2) or “poor” (3, 4 or 5). Study variables were abstracted at baseline, 12, 24, 36 and 48 hrs. Results: A total of 111 patients were enrolled. Patients were 61 ± 16.8 yrs, 59.5% male, and had an initial rhythm of VF/VT in 50.5% of cases. At baseline, 11% (12/111) of patients had a CVP recorded and 3.6% (4/111) has ScvO 2 measured. During the middle 24 hrs, an average of 65% (72) of patients had CVP recordings and 21.6% (24) of patients had ScvO 2 recorded. ScvO 2 values were not different between patients with good versus poor neurologic outcome. Lower CVP measurement was associated with better neurologic outcome. Conclusion: ScvO 2 was infrequently utilized in this cohort of PCAS patients undergoing TH. CVP was utilized at higher rates, and lower CVP recordings were correlated with better neurologic outcome.
Abstract 18628: Aortic Arch Dissection: Does it Matter in the Current Management of Type B?
Authors: Jip Tolenaar, Thomas T Tsai, Arturo Evangelista, Patrick O'Gara, Linda Pape, Rossella Fattori, Alan C Braverman, Nimesh D Desai, Jehangir Appoo, Eduardo Bossone, Daniel G Montgomery, Eric M Isselbacher, Christoph A Nienaber, Kim A Eagle, Santi Trimarchi
Journal: Circulation (2012)

Introduction: Current guidelines report that arch involvement in aortic dissection requires open surgical repair. However, arch dissections are frequently managed with less invasive treatment when ascending aorta involvement is absent. The aim of this project is to clarify the importance of aortic arch involvement in such conditions, Methods: Patients with aortic arch dissection enrolled in IRAD from January 1, 1996 to May 1, 2012 were included in this analysis. Patient groups were defined based on the location of the entry tear and aortic extension: entry tear in the aortic arch with extension confined to the arch (group 1; n = 8), entry tear in the aortic arch with antegrade extension (group 2; n = 55) and entry tear in de descending or abdominal aorta with retrograde extension into the arch (group 3; n = 55). For this abstract, we analyzed the difference in therapies and outcome for these groups. Results: Compared with the other groups, isolated arch patients presented more frequent with syncope, an abrupt onset of pain and less frequent with posterior pain. Treatment differed among groups and most of the isolated arch patients were treated medically. One third of the Group 3 patients was managed endovascular, with excellent outcomes, with a total in-hospital mortality of 7.3% (p = .062). No differences in mortality were observed during follow-up. (p = .193) Conclusion: Aortic arch involvement in aortic dissection is diverse and our observations emphasize that open surgical repair may be not always indicated in all patients. Selective patients, based on entry tear and aortic extension, might benefit from less invasive treatment options, such as endovascular repair and medical therapy
Abstract 18597: How Accurate is the ‰Eyeball Test? A Comparison of Physicians' Subjective Assessment Versus Statistical Methods in Estimating Mortality Risk after Cardiac Surgery
Authors: Renuka Jain, Michael Kuskowski, Adabag Selcuk
Journal: Circulation (2012)

Introduction: In the era of increasing percutaneous options for ischemic and valvular heart disease, estimation of surgical risk has become a key factor in selecting optimal treatment strategies. Surgical risk has historically been estimated by physicians' subjective assessment and more recently by validated statistical risk scores. The aim of this study was to compare the performance of these two methods of risk estimation in cardiac surgery. Methods: We studied 5099 consecutive patients who underwent cardiac surgery at the Minneapolis VA Medical Center between 1993 and 2010. Perioperative mortality risk was estimated statistically by the national VA mortality risk score, and subjectively by cardiac surgeons. These surgeons were blinded to the statistical estimate. All estimates were recorded prior to surgery. Perioperative (30-day) and long-term mortality were ascertained. Results: Mean age was 65 +9 years and 75% of the pts underwent CABG only. Both methods overestimated mortality risk (Physician's estimate 5.6 + 4.4%; statistical estimate 4.3 + 5.1%; observed mortality 3.3%). Correlation between the two methods was modest (C = 0.56, P&lt;0.01). Physician estimate was higher than the statistical estimate and observed mortality in all pts except those in the highest risk category (&gt;10% mortality). Statistical estimate was significantly better than physician’s estimate in discriminating operative death vs. survival (C-index = 0.78 vs. 0.73; p=0.003) and in the long-term (C-index = 0.72 vs. 0.61; p&lt;0.001) (Figure). Conclusions: In patients undergoing cardiac surgery, statistical risk estimate is a more accurate discriminator of operative and long-term mortality than physician’s subjective assessment. However, both methods generally overestimated observed mortality.