tbuckley/cabot-search huggingface dataset:
Abstract 172: Cumulative SAPS II Score Fails to Predict Mortality in Out-of-Hospital Cardiac Arrest
Authors: Justin D Salciccioli, Andre Dejam, Tyler Giberson, Tara Melillo, Michael N Cocchi, Michael W Donnino
Journal: Circulation (2011)

Introduction: Severity of illness scores can predict outcomes in critically ill patients. However, the calibration of existing scoring systems in post-cardiac arrest patients is poorly established. Objective: To determine if the Simplified Acute Physiology Score (SAPS II) will predict mortality in out-of-hospital cardiac arrest (OHCA). Methods: An observational study of adult cardiac arrest at an urban tertiary care hospital during the period from 12/2007 to 12/2010. Data were collected prospectively and recorded in the Utstein style. Inclusion criteria: 1. Adult (&gt;18 years); 2. OHCA; 3. Return of spontaneous circulation. Traumatic cardiac arrests were excluded. Patient demographics, co-morbid conditions, vital signs and laboratory data and in-hospital mortality were recorded. SAPS II scores were calculated. We used simple descriptive statistics to describe the study population and logistic regression to predict mortality with SAPS II as the predictor variable. Forward stepwise logistic regression selection was used to identify individual SAPS II variables that contribute to the sensitivity of the score. Discrimination was assessed using area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Results: 115 patients were analyzed. The median age was 68 years (IQR: 55 - 79) and 28% were female. Median SAPS II score was 67 (IQR: 53 - 77) and 61% of patients died. Cumulative SAPS II score was a poor predictor of mortality (p = 0.19, OR: 1.012, 95% CI: 0.99 - 1.03) and demonstrated poor discrimination (AUC: 0.61). Stepwise selection identified the following individual SAPS II variables to predict mortality: HC03 (p = 0.006, OR: 1.46, 95%CI: 1.12 - 1.90), GCS (p = 0.03, OR: 1.12, 95%CI: 1.01 - 1.23), and age (p = 0.02, OR: 1.12, 95%CI: 1.02 - 1.23); together these are strong predictors of mortality: p = 0.02, AUC: 0.75. Conclusion: Cumulative SAPS II scoring fails to predict mortality in OHCA. The risk-score assigned to age, GCS and HC03 independently predict mortality and combined are good mortality predictors. These findings suggest that an alternative severity of illness score should be used in post-cardiac arrest patients. Future studies should determine optimal risk-scores of SAPS II variables in a larger cohort of OHCA.
Abstract 17405: MicroRNA-205 Knockdown Induces Preadipocyte Cell Proliferation and Adipogenesis in Visceral Adipose of Obese Mice
Authors: Nikhil C Adi, Jennipher N Adi, Paul Kurlansky, Arthur Agatston, Keith A Webster
Journal: Circulation (2011)

Introduction: Central obesity involves deposition of fat around the trunk and in visceral adipose (VA) tissue. It is more common in men and carries a higher risk of CVD, dyslipidemia and T2D. In obese individuals, the increase in adiposity results from increases in the number and size of adipocytes, while the degree of hypertrophy relative to hyperplasia influences the level of body fat and the metabolic consequences of obesity. Hypothesis: miR-205 expression is increased in differentiated adipocytes and its inhibition leads to visceral adiposity. Methods: NONcNZO10 (NZ10) mice with polygenic susceptibility to T2D or SWR controls were fed Control (CD) or South Beach (SD; high protein/unsaturated fat) diets for 25 weeks. After 12 hr. fasting the mice were sacrificed and VA was collected. Total RNA was isolated and subjected to Sanger 14 multi-species miRNA microarray. Mouse 3T3-L1 preadipocytes were cultured in either preadipocyte maintenance medium or DM2 adipogenic differentiation medium. Preadipocytes were transfected with both pre and anti-miR-205 precursor and inhibitor molecules using OPTI-MEM and NeoFx transfection agent. Results: Visceral adiposity was not induced in the control SWR fed either diet or NZ10 mice fed south beach diet as can be assessed by their body weights and percent fat levels (p&lt;0.01). NZ10mice fed CD were hyperglycemic with impaired glucose tolerance test and hyperinsulinemic; gene expression analysis showed significant induction of key adipogenic genes; PPAR gamma and FABP4 in the VA of these mice. Microarray and real time PCR data revealed 10-fold down regulation of miR-205 in the VA of NZ10 mice fed CD vs SD or SWR mice fed either diet. miR-205 inhibition using anti-miR-205 inhibitor molecules in 3T3-L1 cells significantly increased cell proliferation as assessed by BrdU assay (p&lt;0.001). Oil Red O staining of differentiating adipocytes with miR-205 knocked down showed increased staining for lipids (p&lt;0.001). Also real time PCR analysis revealed increased mR-205 expression in differentiated adipocytes over preadipocytes (p&lt;0.001). Conclusions: miR 205 inhibition increases preadipocyte cell proliferation and adipogenesis in the visceral adipose of obese mice.
Abstract 17329: Myocardial-Specific Overexpression of a Dominant-Negative Mutant of NADPH Oxidase Subunit p67 <sup>phox</sup> Attenuates Pressure-Overload-Induced Cardiac Hypertrophy in Adult Transgenic Mice
Authors: Qiong Zhao, Xianyao Xu, Guiqing Zhao, Chongxu Zhang, Jing Deng, John W Christman, Lei Xiao
Journal: Circulation (2011)

We had reported a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67 phox that inhibits NOX activity. In order to test the role of NOX in pressure-overload-induced cardiac hypertrophy in young adult mice, age and body weight (BW)-matched male homozygous Tg and wild type (WT) C57BL/6 mice (10-12 weeks) were subjected to transverse aortic constriction (TAC) or sham operation. Four-week post TAC, 2-D echocardiography (echo) was performed to determine the following cardiac parameters: left ventricular myocardial area (LVMA); LV wall thickness at end diastole; LV internal dimension at end diastole (IDd), LV end-diastolic volume (EDV), LV ejection fraction (EF), LV mass &amp; aortic pressure gradient. Mice were divided into 4 groups (15-24 mice/group) including WT-sham, WT-TAC, Tg-sham &amp; Tg-TAC. The LVEDV, LVIDd &amp; BW were similar among all groups. The LVEF (mean 48-53%) was not statistically different among all groups. The aortic pressure gradient was between 30-60 mmHg in TAC mice and was statistically similar between the Tg and WT groups (45.3 ±1.7 vs. 50.4 ± 2.1 mmHg, p =0.1). Tg-sham showed no significant difference in LVMA, LV mass &amp; wall thickness vs. WT-sham (Table 1). The WT-TAC mice showed significant increase in LVMA, LV mass &amp; wall thickness indicating LV hypertrophy. The Tg-TAC mice also showed mild increase in the above parameters with the LV wall thickness statistically different from Tg-sham. However, these increases in Tg-TAC mice were significantly ( p &lt;0.05) smaller than those in WT-TAC mice, suggesting TAC-induced LV hypertrophy was attenuated in Tg mice. Our echo finding was also confirmed by our results of heart weight/BW ratio, ANF mRNA expression, and histological study of the LV myocardium. In summary, our results showed that selective inhibition of myocardial NOX subunit p67 phox attenuated chronic pressure-overload-Induced cardiac hypertrophy in young adult mice.
Abstract 171: Cardiac Arrest Outcomes Data Evaluation---CODE Registry: Brazilian Registry of In-Hospital Cardiopulmonary Resuscitation
Authors: Helio P Guimarães, Álvaro Avezum, Mariana T Carballo, Ligia N Laranjeira, José R Mendes, Helder J Reis, José A Manetta, Fernanda Gazoni, Otavio Berwanger, Alexandre B Cavalcanti, Renato D Lopes
Journal: Circulation (2011)

INTRODUCTION: In spite of the advances and worldwide standardization for cardiopulmonary resuscitation (CPR), knowledge on the effectiveness of in-hospital CPR is not yet sufficient in Brazil. Methods: This cross-sectional study included, prospectively, 763 patients who presented in-hospital cardiac arrest (CA) from 2007 to 2010, in 17 hospitals. CPR was performed in 575 patients. RESULTS: Asystole was the CA modality most frequently found (40.7%), followed by pulseless electrical activity (39,3%). Immediate survival (recovery of spontaneous circulation - ROSC up to 24 h) was 48,8%, survival until hospital discharge was 13%, 4.3% in 6 m and 3.8% in 12 months. Independent predictors associated with higher immediate survival were: ventricular fibrillation (VF) or ventricular tachycardia (VT) without pulse as the initial rhythm of CA (RR 1.31; IC 95% 1.10 to 1.55; p = 0.002); presence of victim consciousness signs when the emergency staff arrived (RR 1.37; IC95% 1.16 to 1.61; p &lt; 0.001); use of epinephrine (RR 1.61; IC 95% 1.32 to 1.98; p &lt; 0.001); hypoglycemia as cause of CA (RR 1.68; IC 95% 1.11 to 2.55; p = 0.014). Independent predictors associated with lower immediate survival were: hypotension as cause of CA (RR 0.74; IC 95% 0.61 to 0.90; p = 0.003); sedentary lifestyle (RR 0.76; IC 95% 0.66 to 0.88; p &lt; 0.001) and duration of the CPR. Independent predictors associated with hospital discharge survival were: the emergency team trained in ACLS and/or BLS (HR 3.07; IC 95% 1.39 to 6.78; p = 0.006), sinus rhythm after ROSC (HR 1.44; IC 95% 1.26 to 1.75; p = 0.002). Independent predictors of higher 6-month survival rate were: use of epinephrine, sinus rhythm after ROSC and previous MI. Independent predictors of 12-month survival were not identified. CONCLUSION: As independent predictors for immediate survival we identified: VF or VT without pulse as the initial rhythm, presence of signs of awareness of the victim, use of epinephrine, hypoglycemia as cause of PCR. As independent predictors associated survival until discharged: training in ACLS/BLS and the sinus rhythm after ROSC. These findings suggest a national resuscitation profile, providing relevant information, potentially representative of the in-hospital CPR in Brazil.
Abstract 17200: Cystatin C Adds Prognostic Value Over Conventional Predictors of Cardiovascular Disease Outcomes: Results from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Trial
Authors: Malcolm West, David R Sullivan, Jillian Patterson, Anthony C Keech, Paul Nestel, Paul P Glasziou, Adrienne Kirby, Tanja Zeller, David Colquhoun, Stefan Blankenberg, John Simes, Andrew Tonkin
Journal: Circulation (2011)

Background Blood levels of the polypeptide, cystatin C, have been reported to be associated with increased cardiovascular mortality. However, cystatin C levels reflect renal dysfunction, and whether there is an association with cardiovascular outcomes independent of serum creatinine or eGFR is uncertain. This was examined in the LIPID study, a double-blind, randomised, placebo-controlled trial of pravastatin in patients with prior CHD. Of 9014 patients, 7863 had a baseline blood sample of sufficient volume for measurement of biomarker levels. Methods and Results Cystatin C levels were typically higher with higher levels of other risk factors. There was no difference in the median cystatin C level between pravastatin (median (IQR) 0.8 (0.7-0.9)) and placebo (0.8 (0.7-0.9)) groups ( P =0.38) at baseline. The risk of different CVD events was considered in multivariate time-to-event models adjusting for pravastatin treatment, conventional risk factors and other novel biomarkers. Baseline cystatin C was an independent predictor of a range of CVD events. The risk of a CHD event was 66% higher in the highest than the lowest quartile of cystatin C (Q4: &gt;0.93 mg/dL) than the lowest (Q1: ≤0.72) (HR 1.66, 95% CI 1.37-2.00). The risk of a nonhemorrhagic stroke was 85% higher in Q4. The relative effects of pravastatin were similar across all quartiles of cystatin C with higher absolute reduction in Q4. While eGFR was a significant predictor (all P &lt;0.008) of all outcomes except for stroke ( P =0.08) in a model with conventional risk factors, it was not a significant risk factor for any outcome when cystatin C was included in the model. Conclusion Cystatin C is an important predictor of future cardiovascular outcomes in patients with previous CHD events independent of eGFR.
Abstract 17364: Abnormal Repolarizations in Electrocardiogram Correlate with Abnormal Diastolic Mechanics in Patients with Hypertrophic Cardiomyopathy
Authors: Xiaoping Lin, Hsin-Yueh Liang, Aurelio Pinheiro, Lea Dimaano, Lars Sorensen, Larisa Tereshchenko, Theodore Abraham, Roselle Abraham
Journal: Circulation (2011)

Introduction: HCM is often characterized by marked repolarization abnormalities. However the significance of repolarization changes in these patients has not been investigated. Aim: We investigated the prevalence and significance of ECG repolarization patterns on sensitive measures of systolic and diastolic function in a cohort of 110 patients (mean age 52± 17 yrs, male 65%, Caucasian 73%) with HCM. Method: We performed echocardiography and ECG evaluation in 110 HCM patients. ECG repolarization parameters including strain pattern, early repolarization pattern, ST elevation, ST depression and T wave inversion were measured. Conventional and longitudinal tissue Doppler- derived tissue velocity and strain were analyzed off-line. Result: The mean left ventricular mass index was 141± 48 g/m, 2 LVEF was 69± 10% and left ventricular outflow tract gradient was 27±29 mmHg. ECG analysis revealed mean QTc of 451± 34 ms; 45/110 had strain pattern, 17/110 had early repolarization pattern and 14/110 had deeply inverted T waves. Patients with strain pattern on ECG, demonstrated decreased early diastolic velocity (lateral: -3.7± 2.2 vs. -4.6± 2.3 cm/s, p= 0.044, anterior: -2.6± 1.5 vs. -3.4± 1.4 cm/s, p= 0.04 and inferior:-2.7± 1.4 vs. -3.9± 1.6 cm/s, p= 0.005 regions), and late diastolic velocity (lateral:-1.2+- 0.76 vs -2.3+- 1.6, p= 0.001, anterior: -1.6+- 0.7, -2.7+- 1.3, p= 0.0006 and inferior: -2.7+- 1.8 vs -4.1 +- 1.7, p= 0.0003) in the corresponding regional myocardium, when compared to HCM patients without strain pattern. Patients who exhibited deeply inverted T waves on ECG exhibited decrease in late diastolic strain rate in the corresponding regional myocardium (lateral: 0.44± 0.32 vs. 0.84±0.48 s -1 , p= 0.001 and anterior: 0.56±0.19 vs. 1.0± 0.56 s -1 , p= 0.005), when compared to HCM patients without this finding. In contrast, early diastolic strain rate was increased in the corresponding regional myocardium (lateral: 1.75± 0.6 vs. 1.1± 0.62 s -1 , p= 0.015 and anterior: 1.17± 0.3 vs. 0.87± 0.5 s -1 , p= 0.01) in patients with evidence of early repolarization on ECG, when compared to patients without this feature. Conclusion: Strain pattern and deeply inverted T waves are markers for abnormal diastolic mechanics in patients with hypertrophic cardiomyopathy.
Abstract 17031: Epigenetic Modifications at <i>VEGFR1</i> Locus in Response to Angiogenic Signal
Authors: Debasree Dutta, Soumen Paul
Journal: Circulation (2011)

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR1/VEGFR2) are primary regulators of angiogenesis. Among them, VEGFR1 has a dual role of either stimulating or suppressing angiogenesis. So, it is highly important to understand the molecular mechanism underlying its regulation. Earlier we found that angiogenic signal-ETS1-HIF2α regulatory axis is involved in the activation of Vegfr1 chromatin domain in endothelial cells. However, the dynamic nucleoprotein structure that assembles at the Vegfr1 chromatin locus is poorly understood. Here, we report that dynamic alteration in Vegfr1 transcription is associated with epigenetic marks that facilitate or repress transcriptional activation. The rapid induction of Vegfr1 transcription in response to angiogenic signal FGF2/EGF in yolk sac endothelial cells (YSECs) is associated with rapid increase in acetylated histone H3 at lysine 9 (H3acK9), 56 (H3acK56) and 27 (H3acK27), levels at the Vegfr1 chromatin domain. A time course analysis revealed that these acetylation levels are gradually reduced with time and is correlated with transcriptional repression of Vegfr1 . The increase in acetylation is associated with the induction in expression of histone acetyl transferase, Creb Binding Protein (CBP) in YSECs. Knockdown of CBP by RNA interference inhibited FGF2/EGF induced VEGFR1 expression with loss in histone acetylation marks. Level of repressive modification of histone H3 methylated at lysine27 (H3me3K27) at the Vegfr1 locus correlated with transcriptional repression of Vegfr1 . Member of the polycomb group family might regulate the transcriptional repression of Vegfr1 in endothelial cells as well as during differentiation of embryonic stem cells towards endothelial progenitors. This approach will provide important insights about molecular mechanisms of gene regulation in angiogenic signal-activated vs. repressed endothelial cells and will lead to therapeutic modalities for controlling angiogenesis.
Abstract 16941: The Role of the PERK-Mediated Unfolded Protein Response Pathway in the Regulation of Cardiac Sodium Channel During Human Heart Failure
Authors: Ge Gao, An Xie, Euy-Myoung Jeong, Lianzhi Gu, Samuel C Dudley
Journal: Circulation (2011)

Background: The unfolded protein response (UPR) is a series of interrelated signaling pathways that occur when the endoplasmic reticulum (ER) experiences excess secretory load, accumulates misfolded proteins, or is subject to other pathological conditions. UPR acts to attenuating general protein synthesis, induces the expression of ER chaperone proteins, and enhances the degradation of misfolded proteins. In published work, we have shown that heart failure (HF) increases alternative splicing of the SCN5A gene (encoding cardiac Na + channel), generating mRNA variants E28C and E28D encoding truncated, nonfunctional Na + channel. The presence of these variants causes a dominant negative downregulation of the wild-type SCN5A mRNA and Na + current to a sufficient extent to be arrhythmogenic. We tested whether PERK-mediated UPR contributed to the dominant negative effect on Na + current when truncated Na + channel mRNA variants are present in HF. Methods: The correlation of expression changes among PERK, major chaperon proteins (calnexin, CHOP) and SCN5A were analyzed by both qPCR and Western Blot in human HF tissue samples and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Hypoxia and Ang II were used as inducers of abnormal splicing since they have been shown to mediate some of the pathological consequences of HF. hESC-CMs were divided into six experimental groups: normoxic, 1% O 2 hypoxia-treated, 100 nmol/L Ang II-treated, E28C overexpressed, E28D overexpressed, and empty vector control. E28C and E28D constructs were transduced to overexpress the truncated proteins. Results: The expressions of major UPR components (PERK, calnexin, CHOP) were increased in HF tissues, and cardiac Na + channels were downregulated. In hESC-CMs, induction of SCN5A variants E28C and E28D with Ang II or hypoxia as well as expression of exogenous variants could induce major UPR components (PERK, calnexin, CHOP). Finally, downregulation of PERK prevented the loss of full-length SCN5A mRNA abundance with these stimuli. Conclusions: SCN5A variants could induce the expression of major UPR components and could induce PERK-mediated Na + channel downregulation. The results indicate that the UPR contributes to Na + channel regulation during human HF.
Abstract 16976: Respiratory Muscle Trainings Started in Acute Period of Complicated Myocardial Infarction in Patients with Pulmonary Hypertension
Authors: Elena Kolesnikova, Grigory Arutyunov, Anna Rylova, Natalia Rylova
Journal: Circulation (2011)

Background: Positive effects of physical exercises as a part of comprehensive rehabilitation after acute myocardial infarction (MI) are well known. Patients with MI and concomitant heart failure (HF) with pulmonary hypertension (PH) often can't take part in physical trainings. Purpose: To study the effect of respiratory muscles trainings (RMT) in patients with acute MI and concomitant HF and PH. Methods: 87 MI patients 68,1±4,3 years old were randomized to either an exercise training group (EG) or to a control group (CG). Patients were on their 3-5 day of MI and had NYHA III-IV class . The EG participated in a RMT with gradual increase of inspire and expire resistance. RMT were started at the hospital on the 3-5 day after MI and were continued for 12 months at home by patients themselves. Trainings were held for 20-30 minutes 1-2 times every day. Results: In 1 year the distance of 6 minute walk test increased significantly in EG (262,2±9,22 m in EG vs 277,1±9,1 m in CG at baseline, p&gt;0,05; in 1 year 285±8,7m vs 275,3±9,28 m p&lt;0,01). Peak VO2 also increased significantly in EG (3,95±1,71 ml/kg/min in EG vs 3,96±1,72 ml/kg/min in CG at baseline, p&gt;0,05; in 1 year 6,84±1,55 vs 4,61±1,16 ml/kg/min, p&lt;0,01). RMT helped to stabilize mean pulmonary pressure (56,1±10,3 mm Hg in TG vs 56,8±7,7 mm Hg in CG at baseline, p&gt;0,05 and 54,4±7,7 mm Hg in TG vs 79,7±9,2mm Hg in CG in 12 months,p&lt;0,01). There was a statistically significant increase in the maximal inspiratory mouth pressure in most of patients, from 4,23 kPa ± 1,12 vs 4,19 kPa ± 1,11,p&gt;0,05 at baseline to 5,6 kPa ± 0,8 vs 4,1 kPa ± 1,1; p &lt; 0,01 in 12 months). Health related quality of life measured by SF-36 increased in both groups, but results in physical functioning, bodily pain, vitality, role emotional scales were significantly higher in EG patients. In a year there was 3 lethal outcomes in EG vs 8 inCG. EG patients had significantly less hospitalizations because of HF progression (7,8% in EG vs 14,6% in CG) and pneumonias (2,1% vs 15,3%). Conclusion: RMT in patients with MI and HF with PH can be started at their acute period. It improves physical capacity, stabilize pulmonary pressure, increase health-related quality of life and decrease number of hospitalizations during first year after MI.
Abstract 16944: Ablation of the LV Endocardial Surface Reveals Origin of Ventricular Arrhythmias in a Murine CPVT Model
Authors: Michela Faggioni, Raghav Venkataraman, Franz Baudenbacher, Bjorn C Knollmann
Journal: Circulation (2011)

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disorder caused by spontaneous Ca releases from the sarcoplasmic reticulum. Cellular studies suggest that both purkinje cells and ventricular myocytes from CPVT mouse models can trigger spontaneous beats, but the precise origin of CPVT within the heart is still unknown. Methods: ECG and optical maps from isolated Casq2KO hearts were recorded at baseline and after LV endocardial ablation using Lugol's solution. The ablation was considered successful when the left ventricle breakthrough activation disappeared and the ECG showed a QRS morphology consistent with a complete left bundle branch block. The extent of the LV endocardial ablation was evaluated with TTC staining. Ventricular tachyarrhythmias were triggered with a bolus of isoproterenol after reducing the intrinsic sinus rate with carbachol. The origin of ventricular beats (VBs) was classified into 6 anatomical regions: right ventricular outflow track (RVOT), mid/lateral RV (RVM), RV apex (RVA), left ventricular base (LVB), mid/lateral LV (LVM), LV apex (LVA). Results: A total of 4334 VBs were analyzed from 16 hearts. In control conditions, 66% of VBs arose from the RV (19% RVOT, 33% RVM, 14% RVA) and 34% from the LV (11% LVB, 11% LVM, 12% LVA). LV endocardial ablation almost completely abolished VBs originating from the LV, but did not significantly change the number of RV beats (Figure). TTC staining demonstrated that ablation was restricted to &lt;20% of LV wall thickness. Conclusions: The endocardial surface plays a central role in the initiation of arrhythmias in CPVT, suggesting that Purkinje fibers are the most likely culprit for the ectopic events and they should be considered as a target for both pharmacological and gene therapy.