tbuckley/cabot-search huggingface dataset:
Abstract 18877: Novel Mouse Model for Testing NADPH Oxidase (Nox2) Role in Insulin Resistance Mediated Endothelial Dysfunction
Authors: Piruthivi Sukumar, Hema Viswambharan, Helen Imrie, Richard M Cubbon, Nadira Yuldasheva, Matthew Gage, Stacey Galloway, Anna Skromna, Parkavi Kandavelu, Jessica Smith, Victoria K Gatenby, David J Beech, Stephen B Wheatcroft, Keith M Channon, Ajay M Shah, Mark T Kearney
Journal: Circulation (2012)

Introduction: Insulin resistance (IR) plays a pivotal role in type 2 diabetes, obesity and hypercholesterolemia. Reactive oxygen species (ROS) play a key role in IR related endothelial dysfunction. We have reported that, superoxide (SO), an important ROS is produced at higher levels in IR and established that NADPH oxidase (Nox) is the primary source of SO in IR endothelium. Here we report our study to ascertain the role of Nox2 in IR. Methods: A unique murine model of endothelium specific IR, Endothelial Specific Mutated Insulin Receptor Over-expression (ESMIRO) and mice with universal deletion of Nox2 gene (Nox2 y/- ) were used here. Nox2 y/- mice was crossed with ESMIRO to generate double transgenics (ESMIRO/Nox2 y/- ). Endothelial function was analysed by measuring 1. aortic ring relaxation. 2. superoxide production. Expression of Nox and ROS related genes were examined by PCR and Western blotting. Results: Realtime PCR and Western blot of organs and pulmonary endothelial cells (PEC) confirmed the total loss of Nox2 in ESMIRO/Nox2 y/- . Growth rate and organ weights were unaltered in ESMIRO/Nox2 y/- . However, there was a trend towards reduced BP in double transgenics (119±1 mmHg in ESMIRO Vs 114±2 mmHg in ESMIRO/Nox2 y/- ; p=0.06). Metabolic characteristics including ITT and GTT showed no difference between two lines. Blood insulin levels before and after glucose injection were similar. Basal superoxide in PEC of ESMIRO/Nox2 y/- were 240±11% (p=0.02) reduced when compared to ESMIRO. Nitric oxide (NO) mediated vascular relaxation was improved in double transgenic animals (100±4% in response to 1000 nM Ach in ESMIRO/Nox2 y/- Vs 77±6% in ESMIRO). There was no change in endothelial independent relaxation (109±5% in response to 1000 nM SNP in ESMIRO/Nox2 y/- Vs 104±6% in ESMIRO). Realtime PCR showed that the important ROS scavenger superoxide dismutase 1 (SOD1) expression was increased above 300% in ESMIRO lungs compared to ESMIRO/Nox2 y/- . Other Nox and ROS related genes (Nox4, p22, p47, p67, SOD2, SOD3, eNOS &amp; catalase) expression were unchanged. Conclusions: These results show that Nox2 NADPH oxidase is a key source of the excess superoxide seen in a model of endothelium specific insulin resistance. Targeting Nox2 may be a useful therapeutic strategy in IR conditions.
Abstract 18876: Increased Tricuspid Regurgitation after Cardiac Resynchronization Therapy Device Implantation is Associated with Reduced Likelihood of Left Ventricular Reverse Remodeling
Authors: John H Shin, Mark D Metzl, James C Hansen, Sorin Lazar, Kevin Tsai, Jonathan D Rich, Roberto M Lang, John F Beshai, Hemal M Nayak, Martin C Burke, Joshua D Moss
Journal: Circulation (2012)

Background: Increased tricuspid regurgitation (TR) is a potential consequence of pacemaker and defibrillator lead insertion. We examined the association between increased TR following cardiac resynchronization therapy (CRT) device implantation and left ventricular (LV) reverse remodeling. Methods: Patients who underwent de-novo CRT-D device implantation at our institution from 2003 to 2011 with available baseline and follow-up echocardiograms were included in this retrospective analysis. Pre- and post-operative echocardiograms were evaluated for change in degree of TR and evidence of LV reverse remodeling. TR was graded as absent (0), minimal (0.5), mild (1), mild-moderate (1.5), moderate (2), moderate-severe (2.5), or severe (3), and the numeric change in TR grade pre- and post-CRT implantation was determined. LV reverse remodeling was defined as an absolute improvement in LV ejection fraction (EF) ≥5%, a relative reduction in LV end diastolic dimension ≥10%, or improvement in mitral regurgitation ≥1 full grade. Results: A total of 101 patients were included. Median time to post-operative echocardiogram was 8.5 months, with an interquartile range of 4.7-15.1 months. Seventeen patients (17%) developed ≥1 full grade increase in TR post CRT-D. Only four of the 17 (24%) with ≥1 full grade increase in TR had evidence of LV reverse remodeling, compared with 46 of 84 (55%) with &lt;1 full grade increase (p = 0.031). In multivariate analysis, increase in TR post-device implant by ≥ 1 grade, baseline EF ≥ 35%, absence of baseline left bundle branch block, and male gender were independently associated with reduced likelihood of LV reverse remodeling. Conclusions: In patients undergoing de-novo CRT-D implantation for standard indications, increased TR of ≥ 1 full grade after device implantation is independently associated with a reduced likelihood of LV reverse remodeling. Prospective studies are needed to determine if lead-related TR adversely impacts response to CRT.
Abstract 280: Reversal of Acute Coagulopathy Using Small-Volume 7.5% NaCl with Adenocaine and Mg <sup>2+</sup> Resuscitation in a Rat Model of Severe Hemorrhagic Shock
Authors: Hayley L Letson, Natalie M Pecheniuk, Lebo P Mhango, Geoffrey P Dobson
Journal: Circulation (2011)

Acute traumatic coagulopathy occurs early in hemorrhagic trauma and is a major contributor to further bleeding, inflammation and mortality. Previously we showed that a small intravenous (IV) bolus of 7.5% NaCl with Adenocaine (adenosine and lidocaine) and Mg2+ could resuscitate mean arterial blood pressure (MAP) to within a permissive hypotensive range. Our aim was to examine the effect of the same fluid on activated partial thromboplastin times (aPTT) and prothrombin times (PT) following 60 min of resuscitation. Methods: Male fed Sprague-Dawley rats (444 ± 10g, n=64) were anesthetized, non-heparinized and randomly assigned to one of eight groups: 1) Baseline blood, 2) 20 min bleed, 3) 60 min shock, 4) Untreated resuscitation, 5) 7.5% NaCl, 6) 7.5% NaCl Adenocaine, 7) 7.5% NaCl Mg2+ and 8) 7.5% NaCl, Adenocaine Mg2+. Hemorrhagic shock was induced by phlebotomy until MAP was 35-40 mmHg and continued for 20 min (~40% blood loss). Animals were left in shock for 60 min at 34°C. 0.3 ml IV bolus was injected over 2 sec. Arterial blood pressures, MAP, heart rate and rectal temperature were monitored. Arterial blood was collected in 3.2% Na-citrate tubes, centrifuged and the plasma was snap-frozen (-196°C) and stored at -80°C. aPTT and PT were measured on an Amelung KC4A microcoagulometer. Results: Baseline aPTT and PT values were 17 ± 0.5 sec and 28 ± 0.8 sec, and increased significantly to 63 ± 21 and 107 ± 33 sec after blood withdrawal (20 min), and over 10 times baseline after 60 min shock. The large increases during shock were not due to hypothermia. Sixty minutes after 0.3 ml bolus resuscitation, the hypocoagulopathy worsened in all groups with the exception of 7.5% NaCl Adenocaine and Mg2+ with aPTT of 24 ± 1.7 sec and PT of 33 ± 1 sec. A partial restoration occurred with 7.5% NaCl Mg2+ (aPTT of 150 ± 43 and PT of 182 ± 47 sec) but was not significantly different from 7.5% NaCl alone. Conclusion: aPTT and PT clotting times significantly increased during bleeding and shock prior to resuscitation. The hypocoagulopathy increased with 7.5% NaCl and was nearly completely reversed with 7.5% NaCl Adenocaine and Mg2+. We speculate that the mechanism(s) of reversal may shed light on understanding acute traumatic coagulopathy in out-of-hospital and far forward military settings.
Abstract 69: A Tale of Two Cities: The Role of Neighborhood Socioeconomic Status in Spatial Clustering of Bystander CPR in Austin and Houston
Authors: Comilla Sasson, Bryan McNally, Paul Hinchey, Louis Gonzales, David Persse, Elisabeth D Root
Journal: Circulation (2011)

Objective: To determine 1) the location of bystander CPR clusters and 2) the effect of neighborhood-level risk factors on clusters. Methods: Secondary analysis of the Austin/Travis County and Houston/Harris County Cardiac Arrest Registry to Enhance Survival (CARES) dataset. Population: Consecutive arrests from October 1, 2006 to December 31, 2009 (Austin) and from January 1, 2007 to December 31, 2009 (Houston). Data Analysis: Spatial scan statistic (SaTScan v9.1) was used to test spatial clusters of bystander CPR stratified by private and public arrest location. A Bernoulli model was used to determine significant clustering of the case (all OHCA with a non-EMS bystander initiated CPR) location distribution as compared to the controls (all other OHCA events) location distribution. “High” clusters indicated areas where the number of bystander CPR events were greater than expected while “low” clusters indicated areas where the number of bystander CPR events were lower than expected. Results: Two “high” private and two public (one “low” and one “high”) clusters were identified in Austin. Two “high” private clusters had approximately 1.8-2.6 times more bystander CPR cases than expected, while the “high” public cluster, located in the same area as the private “high” cluster, had 2.0 times more bystander CPR cases than expected. The “low” public cluster was in the Austin city center and contained nearly 80% fewer than expected. Three private (two “high” and one “low) and one “high” public clusters, were identified in Houston. Two “high” private clusters in the south had nearly 4.4 times more than expected, while the “low” private cluster included only 34 cases, 57% fewer than expected. The “high” public cluster was, just west of city center, included 14 cases, 2.5 times more than expected. However, when adjusted for neighborhood median household income, all clusters disappeared in Austin, though only the public arrest cluster disappeared in Houston. Conclusion: Our findings suggest that high and low clusters of bystander CPR can be partially explained by median household income. Further research will be required to better understand why such vast disparities in the provision of bystander CPR exist.
Abstract 19002: LRP6 Mutation (LRP6 <sub>R611C</sub> ) Leads to PDGF Dependent Vascular Smooth Muscle Cell Hyperproliferation and Atherosclerosis
Authors: Roshni Srivastava, Arya Mani
Journal: Circulation (2012)

A loss of function mutation in the Wnt co-receptor Low Density Lipoprotein Receptor Related Protein 6, (LRP6 R611C ) causes early atherosclerosis and metabolic syndrome in humans. We have generated LRP6 R611C mice with homologous recombination. LRP6 R611C mice demonstrate enhanced vascular smooth muscle cell (VSMC) proliferation, and exaggerated neointima formation upon carotid injury mice and on LDLR knockout background develop accelerated atherosclerosis compared to their respective controls. The aorta of LRP6 R611C mice exhibits a highly proliferative media marked by an increases in PDGFRβ and ELK1 expression along with decreased myocardin expression. These findings correlate with reduced α-SMA and increased vimentin in the aortic media, indicating proliferative phenotype of VSMCs. Furthermore, in LRP6 R611C mice the aortic adventitia is loaded with PDGFRβ positive cells along with abundance of Sca1 positive progenitor cells in the aortic intimal and adventitial layers. Ex vivo, cultured LRP6 R611C VSMCs exhibit increased expression of PDGF-BB and its transcriptional regulator SP1. These findings suggest that LRP6 R611C promotes maintenance of progenitor cell in the aorta and enhances VSMC proliferation through activated PDGF signaling. Interestingly, the levels of PDGF-BB were also significantly increased in the macrophages as well as plasma of the LRP6 R611C mice. LRP6 R611C macrophages exhibited increased uptake of ox-LDL and augmented expression of vimentin, a regulator of intracellular LDL transport . Thus, LRP6 R611C mutation indicates a single gene defect in Wnt pathway leading to a major aberration in PDGF dependent signaling thereby predisposing to atherosclerosis.
Abstract 18387: Interleukin 23-signaling Affects Infarct Healing and Promotes Wound Stabilisation in an Experimental Model of Myocardial Infarction by Controling the Function of Cardiac Fibroblasts
Authors: Konstantinos Savvatis, Kathleen Pappritz, Moritz Becher, Dirk Westermann, Heinz-Peter Schultheiss, Carsten Tschöpe
Journal: Circulation (2012)

Introduction: Interleukin-23 coordinates together with other cytokines the adaptive immune response and its presence is important for the action of neutrophils, Th17 and regulatory T cells. We sought to determine the role of IL-23 in experimental myocardial infarction. Methods: Myocardial infarction was induced by ligation of the left anterior descending artery in C57Bl6j and IL-23-knockout mice. Left ventricular function was examined by conductance catheter, expression of proinflammatory and antiinflammatory cytokines by PCR and inflammatory cells in the myocardium by immunohistochemistry after 4 and 30 days. Mortality was examined 30 days after myocardial infarction. Differentiation and phenotype of cardiac fibroblasts was assessed under basal conditions and after stimulation with interferon-γ (IFNγ). Results: Endystolic and enddiastolic LV-volumes were higher in the IL-23-knockout mice 4 days after myocardial infarction (30%, p=0.05 and 35%, p=0.02 respectively). Expression of IL-1β was upregulated by 50% (p=0.006) and IFN-γ by 100% (p=0.05) in the infarction zone in the IL-23-knockout mice. Migration of neutrophils and macrophages in the infarcted area was higher in the IL23-knockout mice (by 43%, p=0.04 and 41%, p=0.03 respectively). IL-23-knockout mice showed a lower 30-days survival rate due to increased ventricular rupture (63% vs. 24%, p=0.036). Expression of α-smooth muscle actin (α-SMA, 2fold increase, p&lt;0.05), collagen I (2.1fold increase, p&lt;0.05) and III (1.9fold increase, p&lt;0.01) as markers of fibrosis and activation of myofibroblasts were significantly higher in the infarction area in the wild type mice 30 days after infarction. Cardiac fibroblasts isolated from the infarcted and non-infarcted zones showed a 50% lower expression of αSMA, 30% lower collagen I and 20% lower collagen III (p&lt;0.05) in the IL23KO-mice. Stimulation of cardiac fibroblasts with IFNγ led to a downregulation of αSMA and collagen I and upregulation of the proinflammatory chemokines CCL2 and CXCL10. Conclusions: IL23 controls the expression of IFNγ in the heart after myocardial infarction and induces the differentiation of cardiac fibroblasts into myofibroblasts promoting healing and wound stabilization.
Abstract 18950: Invasive Electrophysiology Study has Higher Sensitivity and Specificity for Sudden Cardiac Death in Patients with Congenital Heart Disease than those with Structurally Normal Hearts
Authors: Jyoti K Patel, William Bonney, Victoria L Vetter, V. Ramesh Iyer
Journal: Circulation (2012)

Introduction: The use of electrophysiology study (EPS) in pediatric and congenital heart disease (CHD) patients to identify at risk subjects for sudden cardiac death (SCD) and implantable cardiac defibrillator (ICD) is often debated. Objectives: We assessed the hypothesis that EPS was more predictive for SCD or appropriate ICD discharge in patients with CHD compared to those with structurally normal hearts. Methods: A 15 year retrospective database review was performed for subjects undergoing EPS risk stratification for SCD. Positive EPS was defined as inducible sustained ventricular tachycardia or fibrillation by programmed stimulation. Data included demographics, EPS indications, outcome of EPS, ICD complications, and follow up SCD or ICD discharge. The primary endpoint was SCD or appropriate ICD discharge. Results: The study included169 subjects with mean age of 19.1 ± 7.8 years, mean follow up after EPS of 5.8 ± 4.3 years. Of these, 50 subjects (30%) had positive EPS, with ICDs subsequently placed in 28 (56%). There were 119 subjects (70%) with negative EPS, and ICDs were placed in 9 (7%). There were 85 subjects (50%) with CHD. There were no SCDs in either group. During follow-up, 10 of 37 subjects (24%) with ICDs had appropriate discharges (6 with CHD and 4 without CHD). Device related complications including recalls were seen in 21 of 37 patients (57%). The ICD shock rate, sensitivity and specificity of EPS are shown in the Table. Sub group analysis of right heart obstruction CHD lesions (n=44) showed similar results between these patients and all CHD patients (Table). Conclusions: The use of diagnostic EPS has a higher sensitivity and specificity for appropriate ICD discharge in pediatric patients with CHD compared to those with structurally normal hearts.
Abstract 19134: Higher Red Blood Cell Distribution Width Predicts Cardiovascular Events in Patients with Heart Failure with Normal Left Ventricular Ejection Fraction
Authors: Eiichi Akiyama, Seigo Sugiyama, Masaski Konishi, Toshimitsu Nozaki, Keisuke Ohba, Junichi Matsubara, Hitoshi Sumida, Koichi Kaikita, Kazuo Kimura, Satoshi Umemura, Hisao Ogawa
Journal: Circulation (2012)

Background Red blood cell distribution width (RDW) is a quantitative measure of the variability in size of the circulating erythrocytes, and is associated with increased risk of adverse cardiovascular (CV) outcomes in patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF). We investigated whether the RDW levels could predict future CV events in patients with HF with normal LVEF (HFNEF). Methods We measured plasma levels of B-type natriuretic peptide (BNP) and RDW sampled from peripheral vein following an overnight fast in 319 patients with symptomatic HF (New York Heart Association (NYHA)-II: n=244, -III, IV; n=75, age 71±10, LVEF 63±6%, BNP 121 [33-302] pg/ml]). HFNEF patients were followed until occurring CV events (CV death, non-fatal myocardial infarction and ischemic stroke, unstable angina pectoris, hospitalization for HF, or coronary revascularization). Results RDW levels were higher in patients with moderate to severe symptoms (NYHA III or IV) compared to mild symptoms (NYHA II) (14.1±1.4 vs. 13.4±1.0%, P&lt;0.001). RDW positively correlated with BNP (r=0.42, P&lt;0.001), and C-reactive protein (r=0.28, P&lt;0.001), whereas RDW inversely correlated with hemoglobin levels (r=-0.30, P&lt;0.001), LVEF (r=-0.22, P&lt;0.001), and estimated glomerular filtration rate (r=-0.21, P&lt;0.001). During a mean follow-up of 20 months, 59 patients developed CV events. RDW levels was significantly higher in patients with CV events than those without events (13.9±1.5 vs. 13.5±1.1%, P=0.03). Kaplan-Meier analysis demonstrated a significantly higher probability of CV events in the higher RDW group (n=34) than in the lower RDW group (n=285) by the cut-off value as 15.0 (log rank test P&lt;0.001). Multivariate Cox hazard analysis identified higher RDW [hazard ratio (HR) 2.00, 95% confidence interval (CI) 1.04-3.88, P=0.04], higher NYHA class (NYHA III or IV, HR 2.69, 95% CI 1.53-4.75, P=0.001), and higher BNP levels (a cut-off value 100pg/ml, HR 2.25, 95% CI 1.16-4.37, P=0.02), but not hemoglobin levels, as independent predictors of the future CV events. Conclusions Levels of RDW correlated with HF severity, LVEF, anemia, inflammation, and renal function, and higher RDW predicted the future CV events in patients with HFNEF.
Abstract 19114: Ultrasound-Targeted Delivery of microRNA-126 for Therapeutic Angiogenesis
Authors: Michael A Kuliszewski, Christine Liao, Dmitriy Rudenko, Paul J Lee, Vanessa Shen, Howard Leong-Poi
Journal: Circulation (2012)

Introduction: MicroRNA-126 (miR-126) is an endothelial-specific microRNA that regulates angiogenesis by blocking endogenous inhibitors of vascular endothelial growth factor (VEGF), Sprouty-related protein (SPRED1) and phosphoinositol-3 kinase (PI3K). We hypothesized that ultrasound-mediated delivery of miR-126 would result in improved angiogenesis in the setting of chronic ischemia. Methods: Naked mature miR-126 was synthesized for transfection of rat specific miR-126 (22bp). Unilateral hindlimb ischemia was created by left femoral artery ligation in F-344 rats (n=45). At day 14 post-ligation, microvascular blood flow (MBF) in the distal hindlimb muscles were assessed by contrast-enhanced ultrasound (CEU). Ultrasound-mediated gene delivery (UMGD) of miR-126 (1x109 cationic microbubbles + 2 μ g of miR-126) (n=12) or scrambled miR (miR-SCR) (n=12) was performed, with control animals (n=11) receiving no treatment. An additional group (n=10) received UMGD of miR-126 (2 ug) three times every 48hours (day14, day 16 and day18). CEU perfusion was re-assessed at day 28, and transfection was assessed by real time PCR. Results: At day 14, prior to miR-126 delivery, normalized MBF for the ischemic muscle was similarly reduced in all treatment groups (55-60% of normal). At day 28, MBF remained unchanged in control and miR-SCR treated groups (0.61±0.08 vs 0.62±0.09, and 0.59±0.06 vs 0.63±0.07, respectively. In miR-126 treated animals, MBF improved (0.59±0.07 vs 0.78±0.06, p &lt; 0.001 versus control and miR-SCM). After triple delivery of miR-126, further improvement in perfusion was noted (0.58±0.04 vs 0.88±0.03, p &lt; 0.001 versus control and miR-SCM, and p &lt;0.01 versus single miR-126). Real time PCR showed a 14.3±3.4 fold increase over control at 3h post transfection of miR-126 that persisted to day 3 post-UMGD, and normalized by day7 (n=3 per time point). Conclusions: UMGD of miR-126 results in improved perfusion in the setting of chronic hindlimb ischemia. Multi-gene delivery of miR-126 showed an incremental angiogenic response as compared to single gene delivery.
Abstract 18679: Stand Alone Cox-Maze Procedure for Patients with Non Paroxysmal Atrial Fibrillation- A Single Center Experience
Authors: Niv Ad, Linda Henry, Sharon Hunt, Ted Freihling, Marc Wish, Sari Holmes
Journal: Circulation (2012)

Background: Catheter ablation for atrial fibrillation (AF) performed percutaneousely or using minimally invasive (MI) off bypass surgical techniques is shown to be limited in patients with non-paroxysmal AF (non PAF). The Cox-Maze procedure (CM) on bypass is effective in non-PAF patients, but concerns about associated morbidity were raised. The study purpose assesses the safety and efficacy of a stand alone on pump CM procedure in patients with non-PAF. Methods: Since 2005, 690 patients had surgical ablation at our institution: 175 (25%) referred for stand alone CM procedure; 138 (20%) undergoing a stand alone procedure for non-PAF . All patients are followed prospectively thru our AF registry. Rhythm verified by EKG and 24-hour holter using the Heart Rhythm Society definition of failure. Health-related quality of life (HRQL, SF-12) and AF symptoms assessed preoperatively/12 months post procedure. Results: Mean age of: 56.9±8.7 years; 60% had at least 1 prior cardioversion and 42% had a catheter ablation; other descriptives and major perioperative morbidities table. The return to sinus rhythm at 6, 12 and 24 months and off antiarrythmic drugs respectively are: 93%/83%; 93%/85%; 90%/79%. In a multivariate analysis, duration of AF predicted rhythm 12 months after surgery, with 20% greater odds of AF at 12 months for each year increase in duration (OR=1.20, CI: 1.03-1.40) after adjustment for other risk factors. By 2 years, only 20% of patients remained on Coumadin with only1 embolic stroke in 44±26 patient months. HRQL significantly improved (p&lt;0.001) and symptoms significantly decreased (p=0.003) by 12 months. By Kaplan-Meier analysis - 97.6% cumulative survival (CI: 95-100%) at 2 years. Conclusion: On pump stand alone CM procedure can be performed with comparable morbidity to catheter ablation. Long term success in non-PAF patients with large left atria is promising. Our experience suggests development of educational strategies to overcome an initial learning curve.