tbuckley/cabot-search huggingface dataset:
Abstract 10888: Impact of Sodium Bicarbonate on Survival in Patients With Prolonged Out-of-Hospital Cardiac Arrest; SOS-KANTO study 2002 &amp; 2012
Authors: Koichiro Shinozaki, Tomoko Ogasawara, Shigeto Oda, Atsushi Sakurai, Yoshio Tahara, Naohiro Yohemoto, Ken Nagao, Arino Yaguchi, Naoto Morimura
Journal: Circulation (2015)

Introduction: The impact of sodium bicarbonate (SB) usage on survival outcomes in patients who have prolonged cardiac arrest (CA) remains unclear. A change in the overall use of SB has occurred over the last decade due to changes in ILCOR recommendations. This natural experiment in the SB use provides an opportunity to explore the association of SB and possible benefits in survival from CA. Objective: To evaluate the association between SB use and outcomes of CA patients; and to describe temporal patterns of SB use and factors related to SB usage Methods: In 2002-03 and 2012-13, we identified 9,592 and 16,452 patients, respectively, from two cohorts in Japan. All adult OHCA patients were included. Patients who gained return of spontaneous circulation in pre-hospital settings were excluded as prolonged CA was selected. The primary and secondary outcomes were successful hospital admission and 1 month survival. Factors associated with SB usage were assessed by multivariable logistic regression analysis. Results: Overall SB usage decreased from 17.3% (n=6,652) in 2002, to 9.7% (n=10,970) in 2012. Patients who received SB had significantly higher rates of admission compared with non-SB patients during both time periods (33.8% vs. 15.4% in 2002, and 39.3% vs. 17.2% in 2012, respectively, p&lt;.001) and significantly higher 1m-survival (4.8% vs. 2.1%, and 4.1% vs. 1.9%, p&lt;.001). Logistic regression demonstrated that SB use was significantly associated with admission (adjusted odds ratio, 2.74 [95%CI 2.29-3.27], p&lt;0.001 in 2002, and 2.68 [2.27-3.18], p&lt;0.001 in 2012) and 1m-survival (2.07 [1.42-3.01], p&lt;0.001, and 1.55 [1.05-2.29], p=0.03) adjusting for possible confounders. Intubation and defibrillation within the ER were most associated with SB usage in both cohorts, while blood pH, potassium levels, and cause of poisoning were not associated with SB use in either cohort. Conclusions: SB usage was associated with increased survival rates in patients with OHCA transported to the ED in CA. Factors related to current CPR guidelines, that suggest more prolonged ED efforts such as intubation and defibrillation are associated with SB use. Surprisingly blood pH showed no association with SB use. Additional studies on the optimal role for SB during CA seem warranted.
Abstract 18109: β-Arrestins Regulate Collagen Synthesis in Human Cardiac Fibroblasts via GPCR-Dependent and Independent Signaling
Authors: Jinju Li, Jennifer L. Philip, Tiju Theccanat, Shahab Akhter
Journal: Circulation (2013)

End-stage heart failure (HF) is characterized by high levels of circulating catecholamines to increase cardiac output and uncoupling of cardiac β-adrenergic receptors (β-ARs). β-arrestins are scaffold signaling molecules that also play a key role in G protein-coupled receptor (GPCR) desensitization, but also have other G protein independent functions including activation of MAPK signaling. This study investigates a potential novel role of β-arrestins in regulating cardiac fibroblasts (CF) biology and myocardial fibrosis which can lead to HF. Both isoforms of β-arrestins expressed in the heart, β-arrestin1 and 2 are upregulated in failing CF versus normal controls. This is a primary mechanism for impaired β-AR signaling as basal and β-agonist-stimulated cAMP production is much lower in the failing CF and there is loss of the β-agonist-mediated inhibition of collagen synthesis in the failing cells. siRNA-mediated knockdown of β-arrestins in failing CF led to decreased α-SMA and fibronectin expression indicative of a reversal from the activated myofibroblast phenotype to the normal quiescent state. β-arrestin knockdown also restored CF β-AR signaling as measured by β-agonist-stimulated cAMP production as well as β-agonist-stimulated inhibition of collagen synthesis. Overexpression of either β-arrestin1 or 2 in normal control CF uncoupled β-AR signaling and blunted the inhibition of collagen synthesis by β-agonist stimulation. To investigate potential non-GPCR effects of β-arrestins in CF, cells were treated with TGF-β. Knockdown of β-arrestin1 or 2 in failing CF significantly inhibited TGF-β-stimulated collagen synthesis and expression of collagen I and III were decreased under both basal conditions and with TGF-β. Pre-treatment of these CF with the pharmacological ERK inhibitor, UO126, abolished Smad phosphorylation in the setting of β-arrestin overexpression and inhibited TGF-β-stimulated collagen synthesis. Both of these isoforms of β-arrestin play a significant role in CF transformation and regulating collagen synthesis via GPCR-dependent and independent signaling pathways. Targeted inhibition of β-arrestins in CF may represent a novel therapeutic strategy to prevent pathological myocardial fibrosis and progression to HF.
Abstract 18114: Continuous Flow LVAD Technology Has Influenced Wait Times and Impacted Donor Allocation in Cardiac Transplantation
Authors: Sharven Taghavi, Senthil N Jayarajan, Eugene Komaroff, Abeel Mangi
Journal: Circulation (2013)

Introduction: Bridge to transplantation (BTT) patients with continuous flow Left Ventricular Assist Devices (cfLVAD) are assigned UNOS Status 1A or 1B priority while awaiting heart transplantation (OHT). The influence of cfLVAD on waitlist times and organ allocation was investigated. Hypothesis: We hypothesized that cfLVAD patients on the waitlist live longer, allowing them to wait for more favorable donors. Methods: The UNOS database was examined from 2005-2012 for all OHTs. The pulsatile flow (pLVAD) era (2005-2008) was compared to the cfLVAD era (2009-2012). The majority of LVADs placed during these 2 eras were corroborated to be pLVAD and cfLVAD respectively. These 2 cohorts were compared to patients that did not receive LVAD. Results: Of 16,476 total OHT, 3,270 (19.8%) were BTT. From 2005-2008, 1,389 (16.3%) of OHT were BTT, while from 2009-2012, 1,881 (23.7%) were BTT, marking broader acceptance of device technology (p&lt;0.001). The cfLVAD recipients were older, more often diabetic, and had higher serum creatinine (table). The cfLVAD cohort spent 44.0 days as status 1A while pLVAD patients spent 9.8 days and non-LVAD patients spent 16.4 days as status 1A (p&lt;0.001). The cfLVAD group spent 117.4 numbers of days as status 1B, while the pLVAD cohort spent 104.8 days and non-LVAD group spent 121.7 days in status 1B (p&lt;0.001). One-year waitlist survival was highest in the cfLVAD era (77.5%), as compared to the pLVAD (54.1%) and non-LVAD cohorts (53.6%) (p&lt;0.001). The cfLVAD cohort received older, more male donors that had higher BMI. Ischemic time was lowest in the cfLVAD group. One year post-transplant survival was highest in non-LVAD (91.4%) as compared to cfLVAD (91.0%) and pLVAD patients (87.2%) (p&lt;0.001). Conclusion: Despite being older and less favorable recipients, cfLVAD patients spend more time as status 1A and have higher waitlist survival. This may allow cfLVAD patients to receive preferred donor hearts, which may explain their higher post-transplant survival.
Abstract 18006: Nuclear Calcineurin is a Sensor for Detecting Ca2+ Release From the Nuclear Envelope via InsP3R
Authors: Martin Czolbe, Melanie Muehlfelder, Peter Nordbeck, Silvana Olivares, Lea Seidlmayer, Tatjana Williams, Oliver Ritter
Journal: Circulation (2013)

Background: Recent evidence demonstrates that not only NFAT, but also calcineurin (CN) is translocated to the nucleus upon hypertrophic stimulation. It was also shown that calpain-mediated degradation caused a constitutive active CN. We hypothesised 1) that nuclear CN is an intranuclear Ca2+ sensor, 2) that the nucleus in cardiac myocytes is a Ca2+ microdomain largely independent of cytosolic Ca2+ alterations and that 3) inhibition of nuclear translocation of CN is a therapeutic strategy to prevent hypertrophy. Methods: Employing a transgene mouse model with conditional calpastatin overexpression (resulting in calpain inhibition), different adenoviral CN mutants and confocal microscopy in isolated adult cardiac myocytes we investigated CN translocation and nuclear Ca2+ transients. Assessment of cardiac function in transgenic animals was performed by MRI. Results: We could demonstrate that chronic Ang II stimulation of mice caused calpain-mediated degradation of CN resulting in a constitutive active CN with nuclear translocation. The constitutive active CN in the nucleus escaped degradation by the UPS and sustained an ongoing hypertrophic response, even after removal of Ang II. Transgenic inhibition of calpain by calpastatin overexpression prevented proteolysis of CN and allowed for relocation of CN from the nucleus back to the cytosol and regression of hypertrophy after removal of Ang II. Inhibition of the interaction between CN and the transport protein importin ß1 by an inhibitory peptide prevented nuclear translocation of activated CN. The synthetic peptide prevented myocardial hypertrophy in vivo. We were able to demonstrate that Ang II increases nuclear Ca2+ transients via nuclear InsP3 receptors. We also showed that Ca2+ levels are constantly elevated during diastole (up to 0.2 μM) in Ang II stimulated cardiac myocytes and that CN is able to act as nuclear Ca2+ sensor detecting this local Ca2+ release from the nuclear envelope via InsP3R. Nuclear CN mutants that are defective for Ca2+ activation failed to activate NFAT dependent transcription. Conclusion: These results provide an explanation how Ca2+ and CN can regulate transcription in cardiac myocytes in response to neurohumoral signals apart from Ca2+ changes in contraction regulation.
Abstract 17989: C-Myc Regulates Substrate Oxidation Patterns During Early Pressure-Overload Hypertrophy
Authors: Dolena Ledee, Lincoln Smith, Masaki Kajimoto, Margaret Bruce, Nancy Isern, Chun Xu, Michael Portman, Aaron Olson
Journal: Circulation (2013)

Background: Cardiac hypertrophy alters substrate metabolism towards an increased reliance on glucose utilization. Inactivation of the transcription factor c-Myc (Myc) in the adult myocardium attenuated hypertrophic growth and decreased expression of glycolytic genes in response to aortic constriction. Accordingly, we hypothesize that Myc is an important regulator of substrate utilization for the citric acid cycle during pressure overload hypertrophy. Methods: We subjected FVB mice with cardiac specific, inducible Myc inactivation (MycKO) and non-transgenic littermates (Myc-intact) to transverse aortic constriction (n=7/group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13 C labeled mixed fatty acids, lactate, ketones and unlabeled glucose and insulin. Results: Cardiac function was similar between the groups although dP/dT, -dP/dt and developed pressure trended towards improvement in the MycKO mice. MycKO had reduced fractional contribution of fatty acids to the citric acid cycle versus Myc-intact (28%±3 vs 37%±2, p&lt;0.05) along with ketones (19%±1 vs 25%±1, p&lt;0.05). Unlabeled, presumably glucose, contribution increased in MycKO (33%±4 vs 19%±2, p&lt;0.05). While MVO2 was similar between the groups, fatty acid and ketone oxidative flux was decreased in MycKO. Conclusion: Myc regulates substrate oxidation preferences during pressure overload cardiac hypertrophy. Further, our data indicates that the change in substrate utilization pattern during hypertrophy is not necessary to maintain cardiac function during this hemodynamic stress.
Abstract 18129: Sex-Based Comparison of Angina Severity, Extent of Inducible Ischemia, and Burden of Angiographic Coronary Disease: A Post Hoc Analysis of the COURAGE Trial
Authors: Subroto Acharjee, Mandeep S Sidhu, Pamela M Hartigan, Koon K Teo, David J Maron, Stephen P Sedlis, G.B. John Mancini, Bernard R Chaitman, John A Spertus, William S Weintraub, William E Boden
Journal: Circulation (2013)

Background: While sex-based differences in anginal symptoms are well-described, it is unclear whether similar differences exist in the extent of inducible ischemia and angiographic findings between men and women with stable ischemic heart disease. We examined the interrelationship of angina severity, objective measures of ischemia (by myocardial perfusion imaging [MPI]), and the burden of angiographic coronary artery disease (CAD) in both men and women participants in the COURAGE trial. Methods: At baseline, 2,279 patients underwent coronary angiography and were divided into subgroups based on the number of diseased vessels and a myocardial jeopardy score to assess the extent/magnitude of inducible ischemia. Men and women were further stratified by Canadian Cardiology Society (CCS) angina class and were compared across measures of ischemia and anatomy. The 625 patients who underwent baseline stress MPI were also stratified by both angina severity and extent of angiographic CAD. Odds ratios for angina were calculated and compared by sex, after adjusting for potential confounders. Results: In the unadjusted analysis, as compared with men, women had a similar overall prevalence of angina (86.4% vs. 87.8%, p = 0.47) and mean percent ischemic myocardium (7.9% vs. 7.7%, P = 0.84), but a lower prevalence of 3-vessel CAD (14.5% vs. 24.5%, P= 0.001) and mean jeopardy score (2.3% vs. 2.5%, P = 0.08), despite exhibiting a greater proportion of CCS II-III angina (64.5% vs. 56.5%, P = 0.006); see Figure 1. After multivariable adjustment, the significantly higher prevalence of CCS Class II-III angina in women persisted. Conclusion: For any given severity of angiographic CAD or extent of myocardial ischemia, women had more moderate-severe (CCS Class II-III) angina than did men. However, this difference was more pronounced in subgroups of patients with more extensive angiographic CAD or severe ischemia by MPI, which likely reflects a greater atherosclerotic burden.
Abstract 18127: Gene Expression Changes Associated With β-Blocker Reverse Remodeling in the Failing Human Heart Constitute a β1-Adrenergic Receptor Gene Regulatory Network
Authors: L. E Epperson, David P Kao, Wayne Minobe, Edward M Gilbert, Brian D Lowes, Michael R Bristow
Journal: Circulation (2013)

Background: When β-blocking agents produce reverse remodeling on nonischemic dilated cardiomyopathies (NDCMs) they effect a partial reversal of heart-failure associated changes in expression of constituents of the classic fetal-adult contractile protein (CP)/natriuretic peptide (NP)/SR Ca2+ ATPase (SERCA2a) gene "program". We have also reported that the DCM abnormalities in CPs, SERCA2a and NPs are associated with evidence of hypothyroidism at the thyroid hormone receptor (THR)-α level. Methods and results: We treated 47 NDCM patients (mean baseline LVEFs 24+9%, RVEFs 27+9%) with β-blockers (metoprolol CR/XL, metoprolol + doxazosin, or carvedilol in a randomized allocation) for 18 months. A total of 37 patients had reverse remodeling responses. mRNA expression from RV septal biopsies at baseline, 3 and 12 months of treatment was assessed by quantitative PCR for 50 prespecified genes, as well as using microarrays that included sequences for 21,700 human genes (Affymetrix HGU133 plus 2.0). The 50 prespecified genes were selected for having fetal or adult expression characteristics, being THR or β1 adrenergic receptor (AR) responsive, or for encoding Gq-coupled, metabolic or cytokine proteins. Using last-observation-carried-forward and non-parametric statistical analysis, 21 genes changed expression in the 37 patients who had reverse remodeling responses compared to the 10 patients who did not. All 21 reverse remodeling-associated genes have been previously described as being regulated by β1-AR signaling. Seventeen (81%) of the 21 changed mRNAs had a previously described fetal-adult pattern, and 72% were THR responsive. Of the changed β1-AR responsive genes, 13/21 were also statistically significant by microarray analysis, with all 21 mRNAs changing in the same direction on the microarray as in the qPCR results. Conclusion: Myocardial gene expression changes associated with β-blocker reverse remodeling of human NDCMs are most consistent with a β1 adrenergic receptor gene regulatory network. The transcription factors and/or miRs involved in this network remain to be identified.
Abstract 18067: Phosphodiesterase 4B Controls a Subsarcolemmal Pool of Cyclic AMP
Authors: Delphine Mika, Wito Richter, Marco Conti
Journal: Circulation (2013)

Rationale: Sympathetic regulation of the heart is mediated via β1- and β2-adrenergic receptors (βARs). Both receptors signal through cAMP, but produce distinct or even opposing effects on cardiac function. Localized or compartmentalized cAMP is thought to be the basis for these differential effects. Cyclic nucleotide phosphodiesterases (PDEs), the enzymes that degrade and inactivate cAMP, may contribute to compartmentalization and βAR signaling specificity. Objective: To elucidate the role of the cardiac PDE4B in βAR signaling. Methods and Results: Cyclic AMP accumulation was measured with FRET-based cAMP sensors in cytosolic and sarcolemmal compartments of cardiomyocytes from Wild Type and PDE4BKO mice. Ablation of PDE4B alters the cAMP transient induced by βAR stimulation at the sarcolemma but not in the cytosol. The effect of PDE4B ablation is further restricted to β1AR-induced cAMP transients, whereas β2AR or E prostanoid receptor (EPR) responses are not affected. In PDE4BKO cells, PKA-phosphorylation of proteins in the sarcolemmal compartment, including the vasodilator-stimulated phosphoprotein, the L-type Ca2+ channel (LTCC), the ryanodine receptor (RyR2) is increased. Conversely, phosphorylations of proteins distant from the cell membrane, including phospholamban or contractile proteins are not affected. β1AR but not β2AR ligation causes PKA-dependent activation of PDE4B. PKA inhibition produces a significant increase in subsarcolemmal cAMP in Wild Type cardiomyocytes, but has only a limited effect in PDE4BKO myocytes, confirming that this feedback regulation of PDE4B shapes the cAMP transient at the sarcolemma. Consistent with the augmented phosphorylation of LTCC and RyR2, contraction rate in PDE4BKO myocytes in response to βAR stimulation is increased compared to Wild Type. Conclusions: PDE4B mediates a critical PKA-dependent feedback mechanism that controls β1AR-, but not β2AR- or EPR-induced cAMP signals. This regulation functions in a restricted subsarcolemmal compartment containing LTCC and RYR2.
Abstract 18133: Between- and Within-Person Changes in Weight and Cardiorespiratory Fitness and the Effect on Blood Pressure and Lipids in Men and Women From the Cooper Center Longitudinal Study
Authors: Carrie E Finley, David S Leonard, Carolyn E Barlow, William L Haskell
Journal: Circulation (2013)

Introduction: Cardiovascular disease (CVD) is the leading cause of death in the U.S. Controlling risk factors such as hypertension and dyslipidemia by maintaining a healthy weight and achieving an adequate level of cardiorespiratory fitness (CRF) could result in improvements in cardiovascular health. The Cooper Center Longitudinal Study is the most extensive resource available for evaluating the simultaneous effects of changes in weight and CRF on CVD risk factors. Objective: The purpose of this study was to evaluate the within-person relationships between body weight, CRF, and CVD risk factors, while controlling for the corresponding between-person relationships. We hypothesized that increases in weight and decreases in CRF over a ten-year time period would result in detrimental effects on blood pressure and lipids, and vice-versa. Methods: The study sample consisted of 4,439 men and 651 women who had at least 5 preventive medical examinations during any ten year period from 1977 to 2006. The examination included a maximal exercise test, anthropometric and clinical measures, and a medical history questionnaire. Linear mixed-effects regression was used to model the cardiovascular risk factors over time, providing estimates of between- and within-person effects. Results: Aging alone did not significantly predict changes in CVD risk factors in women or men after adjustment for covariates including CRF and weight, with the exception of total and LDL cholesterol in men. Increases in body weight were associated with increases in systolic and diastolic blood pressure, total cholesterol, LDL, and triglycerides and decreases in HDL in women and men. The largest effect of weight gain for women and men was seen in triglycerides, with a 2.29 mg/dL and 3.57 mg/dL increase per pound of weight gained per year, respectively ( P &lt; 0.001). Increases in CRF were associated with improvements in diastolic blood pressure [-0.39 mmHg (women); -0.10 mmHg (men)] and HDL [0.35 mg/dL (women); 0.63 mg/dL (men)] over time and in triglycerides (-2.26 mg/dL) in men only ( P &lt; 0.05 for all). Conclusion: Changes in body weight over a ten year period predicted changes in all CVD risk factors examined in women and men; whereas changes in CRF predicted changes in diastolic blood pressure and HDL.
Abstract 18123: An Integrated Resuscitation Service, Combining a Specialist Pre-Hospital Physician Response Unit With Delivery to a Dedicated High-Volume Cardiac Arrest Centre, Optimises Survival Following Cardiac Arrest
Authors: Mohammed M Akhtar, Ceri Hunter-Dunn, Anne Weaver, Paul Rees
Journal: Circulation (2013)

Background: Despite advances in resuscitation medicine, survival rates to discharge following out-of-hospital cardiac arrest (OHCA) remain poor. Recent data support early critical care interventions including therapeutic hypothermia (TH) and immediate percutaneous coronary intervention (PCI). In London, a package of high quality physician-led critical care intervention on scene, with the capacity to transfer these patients direct to a PCI centre, is available through the deployment of London’s Air Ambulance specialist Physician Response Unit (PRU). Methods: Prospective data was gathered on OHCA treated by the PRU, which were transferred to a single PCI centre. Data included patient demographics, clinical characteristics, interventions and outcome. Results: Between April 2011 and April 2013, data was obtained on 20 patients, with a mean age of 59. Clinical characteristics - presenting rhythm: VF 65%, asystole 15%, PEA 15%, VT 5%. Return of spontaneous circulation (ROSC) was achieved at scene in 75%. PRU interventions: Advanced airway management 90%, rapid sequence induction 50%, early TH 45%, mechanical CPR (mCPR) during transfer 15%. Overall survival to ICU was 50%, with overall survival to discharge 45%. Of those patients who underwent emergency angiography, 71% survived to ICU, with 64% surviving to discharge. Of patients presenting in VF, 62% survived to discharge. Interestingly, 66% of patients who received TH survived to discharge, compared with 45% where TH was not used. All patients who underwent successful PCI survived to discharge with good neurological outcomes. 9 patients had a confirmed single vessel culprit lesion treated by PCI, one patient had complex mutlivessel disease complicated by cardiogenic shock and underwent mutivessel PCI, and 2 patients had an undiagnosed underlying cardiomyopathy. Conclusions: In selected cases, outcomes following OHCA can be optimized by integrating a PRU cardiac arrest service, enabling direct triage of patients to a cardiac arrest centre, with early application of neuroprotective strategies, mCPR, circulatory support and interventional cardiology techniques.