tbuckley/cabot-search huggingface dataset:
Abstract 207: Comparison of Noninvasive pHm and Blood pH in a Swine Model of Resuscitation of Uncontrolled Hemorrhage
Authors: Babs Soller, Charles Smith, Fengmei Zou, Jill Sondeen
Journal: Circulation (2013)

Near infrared spectroscopy can be used noninvasively and continuously to assess deep muscle pH (pHm) as an indicator of acidosis and adequacy of resuscitation. Since pHm is a new parameter, it was compared to blood measurements of arterial and venous pH (pHa, pHv) during shock in swine to provide data to aid in interpretation during clinical use. Methods: Anesthetized 40 kg female swine (n=26) underwent hemorrhage until 24 mL/kg of blood was removed (Shock); followed by transection of the spleen causing uncontrolled hemorrhage throughout the remainder of the protocol. After 15min, 15.25mg/kg of resuscitation fluid (hextend, fresh frozen plasma or platelets) was given over 30min. Arterial and venous blood gases were measured at baseline, shock, end resuscitation and end of the study. Spectra were collected continuously from the posterior thigh muscle using a prototype CareGuide 1100 Oximeter. pHm was calculated from the spectra using the equation contained in the CareGuide 3100 product. Differences between survivors and non-survivors were assessed with two-way repeated measured ANOVA followed by a Tukey test. RESULTS: Thirteen of the 26 swine did not survive for the full 5 hrs. pHv and pHm discriminated survivors and non-survivors at the end of resuscitation (p &lt; 0.05) with lower pH for the non-survivors. pHa did not discriminate between survivors and non-survivors at any time point. Conclusions: Noninvasive pHm is a surrogate for peripheral venous pH during swine hemorrhage and resuscitation.
Abstract 19146: Disruption of TRAF2-TAK1-IKKB Signaling Triggers Mitochondrial Perturbations and Necrotic Cell Death in Doxorubicin Cardiotoxicity
Authors: Lorrie A. Kirshenbaum, Rimpy Dhingra, Victoria Margulets
Journal: Circulation (2013)

The anthracycline doxorubicin (dox) is a highly effective anti-tumour agent, however, its use is limited by its severe cardiotoxic effects that manifests as heart failure. The decline in cardiac performance induced by doxorubicin remains poorly defined. A critical survival role for the canonical IKKβ -NF-κB signaling pathway has been demonstrated in ventricular myocytes. In this report, we demonstrate that, dox impairs IKKβ- NF-κB signaling in ventricular myocytes accompanied by mitochondrial perturbations including mPTP, loss of membrane potential and ROS production. IKKβ- NF-κB signaling involves TRAF 2 mediated ligation of K63 ubiquitin chains to RIP1 (Receptor Interacting Protein 1) which serves as scaffold for recruitment of ubiquitylated Tak1 complex and phosphorylation-dependent activation of IKKβ -NF-kB signaling. Interestingly, ventricular myocytes treated with dox demonstrated reduction in expression levels of TRAF2 and TAK1. This was accompanied by a decline in K63- ubiquitylation chains and concomitant increase in K-48 polyubiquitination of RIP1, impaired NF-kB activation and necrotic cell death. Interestingly, inhibiting the kinase activity of RIP1 with Necrostatin-1, (Nec1) suppressed necrotic cell injury induced by dox but not NF-kB activation. Concordant with these findings was a marked increase in necrotic cell death in cardiac myocytes defective for IKKB signaling or MEF cells deficient for p65 treated with dox. Notably, mitochondrial perturbations, including PT-pore opening , ROS production, calcium uptake, LDH, Tn(T) and HMGB-1 release and necrotic cell injury induced by dox were completely abrogated by restoring IKKB-NF-kB signaling in cardiac myocytes or Nec-1. Herein, we provide novel evidence that K-48 ubiquitylation of RIP1 by doxorubicin provides a functional switch that signals necrotic cell death in cells defective for IKKβ-NF-kB signaling. Hence, interventions that modulate IKKB- NF-kB activation may prove beneficial in mitigating the cardiotoxic effects of dox.
Abstract 19101: Is Stop-Flow Necessary for Efficacious Intracoronary Cell Delivery? Comparison With Nonocclusive Intracoronary Infusion in a Porcine Model
Authors: Eleni Tseliou, James Dawkins, Hideaki Kanazawa, Michelle Kreke, Supurna Chowdhury, Konstantinos Malliaras, Ryan Middleton, Rachel Smith, Linda Marbán, Raj Makkar, Eduardo Marbán
Journal: Circulation (2013)

Background: Since the first intracoronary delivery of cells to the heart in 2001, the stop-flow technique has been used by default. A balloon angioplasty catheter is inflated in the target vessel and cells infused via the luminal port. However, the need for balloon occlusion has never been demonstrated. Objective: We sought to compare the safety and efficacy of intracoronary delivery of allogeneic cardiosphere derived cells (CDCs) under stop-flow versus nonocclusive intracoronary delivery in a porcine model of myocardial infarction (MI). Methods: MI was created by 2.5 hr occlusion of the mid-LAD in adult female Yucatan minipigs. Three weeks later, 12.5M CDCs were intracoronarily infused in the LAD under stop-flow (in 3 3-min occlusions with 3 min rest intervals) or nonocclusive conditions (continuous-flow infusion over 10 min; n=5 in each group). During the course of the study, animals underwent contrast enhanced magnetic resonance imaging at baseline (just before infusion) and 4 weeks post infusion. Left ventricular ejection fraction, scar mass and viable mass were evaluated at both time points. Results: No adverse events (arrhythmias, death) were observed during or soon after cell infusion in any of the animals infused. Coronary blood flow evaluated by TIMI grade was TIMI 3 in all animals following completion of infusion. TnI and CK-MB values were within normal range 1 day post-infusion in all animals. One month post-infusion, allogeneic CDCs reduced scar mass in both groups (continuous flow p=0.015 vs. baseline; stop-flow p=0.044). The effects on ejection fraction (p=0.08) and viable mass (p=0.88) were equivalent in the two groups. Conclusions: Nonocclusive continuous-flow delivery is equally efficient to stop-flow method as a means of cell delivery to the infarcted myocardium, at least for this particular cell type. The need for stop-flow delivery, while traditional, is therefore questionable.
Abstract 19141: Natural History of Tricuspid Annulus and Right Atrial Remodeling in Permanent Atrial Fibrillation
Authors: Christina Luong, Michael Tsang, Kenneth Gin, John Jue, Parvathy Nair, PK Lee, Teresa S Tsang
Journal: Circulation (2013)

Background: The natural history of tricuspid annulus and right atrial (RA) remodeling in patients with permanent atrial fibrillation (AF) has not been assessed. We aimed to determine the rate of change in tricuspid annulus diameter and RA volume in patients with permanent AF. Methods: This cohort study included 160 patients with a history of permanent AF who had at least 2 transthoracic echocardiograms performed between 2005 and 2010 at Vancouver General Hospital in British Columbia. Patients with structural valve disease at onset, congenital heart disease, and patients with more than mild-moderate tricuspid or mitral regurgitation were excluded from analyses. The tricuspid annulus diameter, defined as the distance between the points of attachment of the anterior and septal tricuspid leaflets from the apical 4-chamber view, was measured during end-systole and end-diastole. Maximal RA size was measured in terms of RA volume using single plane Simspon’s method from 4 chamber view. Linear mixed effects modelling was used in analyzing the changes in measurements over time. Results: Of the 160 subjects included in this analysis, 100 were men (62.5%). The mean age at study entry was 74±10 yrs. The median number of echocardiographic studies performed was 3 (range 2 - 6). All 160 patients showed progressive increase in tricuspid annulus diameter over time. There was a significant increase in tricuspid annulus diameter at end-systole and end-diastole over a mean follow up time of 3.2 ± 2.8 years. Respectively, the increase was 0.68 mm/ year, 95% CI 0.232 -1.02, P=0.0027) and end-diastole 0.63 mm/year, 95% CI 0.182-0.93, P=0.0015). Mean RA volume increased from a mean of 39 mL/m2 to 81 mL/m2 for the cohort, or 13 mL/m2 per year, which was significantly greater than the increase in left atrial volume (10 mL/m2 per year, P&lt;0.001). Conclusions: Permanent AF was associated with significant increase in tricuspid annulus diameter and RA volume over time. The rate of changes appeared greater on the right side than on the left. How these differential changes relate to the frequent findings of right heart failure in these patients warrant further investigations.
Abstract 19107: Trends in Atrial Fibrillation Hospitalization and Cost of Care in the United States From 1998-2010
Authors: Sadip Pant, Abhishek Deshmukh, Kathan Mehta, Sameer Raina, Apurva O Badheka, Nileshkumar Patel, Shilp Arora, Neeraj Shah, Tushar Tuliani, Jawahar L Mehta, Hakan Paydak
Journal: Circulation (2013)

Introduction: The aim of our study was to investigate time trend in atrial fibrillation (AF) related hospitalization and the cost of hospitalization over the last decade in the United States and make projections for 2020. Methods: The Nationwide Inpatient Sample database was used to estimate the annual number and prevalence of hospitalizations with AF from 1998-2010. Identification of AF-related hospitalizations was based on the designation of the International Classification of Diseases (9th Edition) Clinical Modification (ICD-9-CM) diagnosis code 427.31 (AF) as the principal discharge diagnosis. Results: There were total 4,676,758 AF related hospitalizations from 1998-2010 in the US. The relative percentage increase in hospitalizations from 1998 to 2010 was 46%. We used exponential model to identify the trend (R2=0.88). Assuming a similar trend in AF hospitalization over next decade, 541,000 hospitalizations can be expected in 2020 (28% relative increment from 2010). The cost of hospitalization follows a linear trend (R2=0.98) and is expected to rise by 55% in 2020 as compared to cost of care in 2010. Conclusions: These data indicate that AF related hospitalizations and the cost of care has increase tremendously over the last decade and is likely to pose a large public health burden in the future.
Abstract 19135: Shh-hippo Signaling Pathway Controls Cardiomyocyte Proliferation
Authors: Bhairab N Singh
Journal: Circulation (2013)

In contrast to newts and zebrafish, the mammalian heart has limited regenerative potential. Defining the molecular cues controlling cardiac regeneration/cellular proliferation would help construct a blueprint to enhance our understanding of cardiac regeneration in mammals. Here, we demonstrate the essential requirement of sonic hedgehog (Shh) signaling during newt heart regeneration and neonatal cardiomyocyte proliferation. In response to ventricular resection, Shh and its downstream effectors including Ptch1 and Smoothened (Smo) are robustly expressed in the injured region. We find that Shh signaling is required for the proliferation of both epicardial as well as myocardial cell types during the regenerative process. Our data indicate that newt cardiomyocytes undergo dedifferentiation in response to resection injury allowing proliferation, regeneration and restoration of cardiac function. Furthermore, pharmacogical inhibition of Shh signaling results in complete ablation of regeneration and subsequent scar formation. Similar to the newt heart, the activation of Shh signals in cultured neonatal cardiomyocytes (MVCMs) promotes cardiomyocyte proliferation, whereas inhibition results in markedly reduced proliferation. Molecular analyses indicate that activation of Shh signaling increases TAZ (a transcriptional co-activator of Hippo signaling) expression, while inhibition results in its reduction. Interestingly, the intracellular localization of TAZ is not altered upon modulation of Shh signaling. These data suggest that the effect of Shh signals on proliferation is mediated through the TAZ-hippo signaling pathway. Our findings demonstrate that the Shh-Hippo signaling pathways function as a key regulator of cardiomyocyte proliferation and potential targets for cardiac regenerative therapies.
Abstract 19109: Hypoxia-Induced Reprogramming of Exosomal MicroRNAs From Human CD34+ Progenitor Cells Promotes Its Angiogenic Activity and Ischemic Tissue Repair
Authors: Susmita Sahoo, Rajesh Gupta, Sol Misener, David Kim, Douglas E Vaughan, Douglas W Losordo
Journal: Circulation (2013)

Introduction: In early clinical trials, human CD34+ stem cells have been shown to improve exercise tolerance in pts with myocardial ischemia and reduce amputation rates in pts with critical limb ischemia. Recently, we have demonstrated that adult human CD34+ stem cells secrete microRNA containing membrane bound nanovesicles called exosomes (Exo) that mimic the angiogenic and therapeutic activity of the cells. We hypothesized that the regenerative efficacy of the cell-free Exo derived from human CD34+ cells can be improved by hypoxic pre-conditioning, modulating its pro-angiogenic miRNA content. Methods and Results: Exo from human peripheral blood-derived CD34+ cells cultured under hypoxia (H-Exo) were significantly more proliferative, anti-apoptotic and angiogenic in vitro, as compared to Exo from cells under normoxia (N-Exo). Treatment with H-Exo significantly improved perfusion (ratio: 0.93±0.05 v 0.77±0.02), increased capillary density (1.6±0.2 v 1.1±0.1/HPF) and prevented ischemic limb amputation (0% v 37.5%) as compared to N-Exo (p&lt;0.05; n=7-8), in a mouse model of hind limb ischemia. H-Exo were not significantly different in size, quantity of Exo secreted per cell, or, in the expression of major proteins as compared to N-Exo, measured using DLS and 2-D differential gel electrophoresis (DIGE) and mass spectrometry analyses. Interestingly, H-Exo had significantly higher expression of several pro-angiogenic miRNAs. Trafficking studies using confocal microscopy and flow cytometry revealed that fluorescent-labeled CD34 Exo were selectively internalized by endothelial cells in the ischemic tissue and directly transfer pro-angiogenic miRNA content, inducing cell cycle changes and cell division in the recipient endothelial cells. Currently, we are investigating the role of transcription factors in hypoxia-induced miRNA expression. Conclusion: Hypoxia modulates the miRNA content of adult human CD34+ progenitor cell-derived exosomes improving their angiogenic and therapeutic potency. Use of hypoxia to enhance microRNA composition of CD34+ exosomes could have important clinical implications for therapeutic angiogenesis, especially in diabetic and cardiovascular patients with compromised stem cell population.
Abstract 19147: Time From First Medical Contact to Aspirin in ST Elevation Myocardial Infarction: An International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC) Study
Authors: Raffaele Bugiardini, Edina Cenko, Maria Dorobantu, Sashko Kedev, Zorana Vasiljevic, Knezevic Bozidarka, Dabor Milicic, Beatrice Ricci, Marta Majstorovic Stakic, Olivia Manfrini
Journal: Circulation (2013)

BACKGROUND: A significant number of patients who suffer from STEMI do not reach a hospital within the recommended timeframe in the South Eastern European countries. Unequal dispersion of PCI-capable facilities throughout this area results in transport distances that can exceed 100 miles, while response times vary greatly dependent upon volunteer ambulance services. METHODS: The aim of the International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS-TC / NCT01218776 ) registry was to assess whether initial antiplatelet/ anticoagulant treatment at the point of prehospital first medical contact impacts in-hospital outcomes. To assess the value of this strategy were compared: prehospital versus in-hospital first medical contact; those arriving at the hospital by ambulance versus those whose initial hospital care was an ambulatory/community center. RESULTS: Of the 2295 patients enrolled in the study, 392 received fibrinolysis, 753 primary PCI, 86 facilitated PCI, and 1064 standard medical therapy having overcome the golden hours for reperfusion therapy. Compared with the in-hospital group, patients who underwent facilitated PCI (7%, n=34) experienced 9.6 % reduction in cardiovascular mortality (odd ratio [OR] 0.096 coefficient interval [C.I] 0.012-0.69 P=0.004). Arrival by an ambulatory/community center incurred a substantial delay from first medical contact to reperfusion (fibrinolysis 76 min [63 min to 105 min] and PCI 35 min [224 min to 612 min]) compared with arrival by ambulance (fibrinolysis 47 min [32 min to 68 min] and PCI 108 min [85 min to 150 min]). CONCLUSIONS: These findings support prehospital antiplatelet/ anticoagulant treatment followed by reperfusion therapy in patients presenting early with STEMI, who do not have access to hospital care within the recommended time-frame of 60 minutes from first medical contact. Those activating the prehospital medical response system without receiving prehospital ambulance assignment experienced the longest delay from first medical contact to reperfusion, indicating a lost opportunity to enhance ST elevation myocardial infarction patient outcomes.
Abstract 14772: Routine Coronary Angiography Prior to Pulmonary Thromboendarterectomy in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Noel S Lee, Kirk U Knowlton, Anna M McDivit, Daniel G Blanchard, Victor Pretorius, Michael M Madani, Peter F Fedullo, Kim M Kerr, Nick H Kim, David S Poch, William R Auger, Lori B Daniels
Journal: Circulation (2015)

Introduction: At UC San Diego Health System, routine coronary angiography has been performed in men &gt;40 years and women &gt;45 years (or earlier in those with significant cardiovascular risk factors) prior to pulmonary thromboendarterectomy (PTE) for chronic thromboembolic pulmonary hypertension (CTEPH). However, the prevalence of significant coronary artery disease (CAD) in this population has not been evaluated, and the optimal screening strategy has not been systematically established. Hypothesis: We hypothesized that the current approach of routine age-based coronary angiography in screening candidates for PTE may be better optimized based on cardiac risk factors. Methods: The study included 349 consecutive patients (51.3% male) with CTEPH undergoing preoperative coronary angiography for PTE between January 1, 2007 and November 7, 2014. Charts were reviewed for baseline demographic and medical information. Major cardiac risk factors included: diabetes, hypertension, hyperlipidemia, obesity (BMI ≥25 kg/m2), tobacco use, and family history of CAD. Coronary angiography reports and PTE operative reports were reviewed for significant CAD (≥50% obstruction) and revascularization. Results: Significant CAD was found in 43 (12.3%) of the 349 patients who underwent routine preoperative coronary angiography. The subset with significant CAD included 14 (8.2%) of 170 women and 29 (16.2%) of 179 men. Significant CAD was present in only 5.6% of patients ≤50 years of age, compared to 14.6% of patients &gt;50 years of age. The absence of major cardiac risk factors was a key indicator in excluding significant CAD in patients ≤50 years: no patient ≤50 years without risk factors for CAD was found to have significant coronary artery obstruction. Furthermore, in patients ≤50 years, significant CAD was found only among those with ≥3 major risk factors. Conclusions: In patients ≤50 years with CTEPH, the prevalence of significant CAD was low, and omitting preoperative coronary angiography in this subset of men and women may be reasonable when no cardiac risk factors are present. Routine preoperative coronary angiography is reasonable in individuals &gt;50 years, as well as those ≤50 years with significant risk factors or clinical suspicion of CAD.
Abstract 19099: Epicarial Progenitors Contribute to Neonatal Mammalian Heart Regeneration
Authors: Wataru Kimura, Shalini A Muralidhar, Hesham O Sadek
Journal: Circulation (2013)

Heart failure is a costly and deadly disease affecting over 5 million Americans. At the core of the pathophysiology of heart failure is the inability of the adult mammalian heart to regenerate following injury. In sharp contrast to the adult mammalian heart, we recently showed that the neonatal mammalian heart is capable of complete regeneration, including re-vascularization of the myocardium, following resection of the ventricular apex or myocardial infarction (MI). However, this remarkable regenerative capacity is lost by 7 days post natally. The regenerative response of the neonatal mouse heart is mediated mostly by proliferation of pre-existing cardiomyocytes, which is in line with the mechanism of zebrafish heart regeneration. We also have shown that neonatal heart injury is associated with epicardial activation, which is also a hallmark of zebrafish heart regeneration. However, the lineage contribution of epicardial cells during neonatal mouse heart regeneration remains to be determined. We performed genetic lineage tracing data using Capsulin (Cap)MerCreMer knock-in mouse crossed with Rosa26/tdTomato reporter mouse, in which epicardial cells are specifically and irreversibly labeled by tamoxifen pulse at postnatal day 0, revealed the contribution of neonatal epicardium to multiple lineages of the heart, including the majority of interstitial fibroblasts, vascular endothelial and smooth muscle cells both during normal post natal growth and after injury.. Considering that embryonic epicardial cells contribute to fibroblasts, vascular endothelial/smooth muscle cells and in contrast adult epicardium only contribute to interstitial fibroblasts and very rarely to vascular smooth muscle cells after the injury, it appears that lineage contribution of epicardial cells is highly correlated with the capacity for neovascularization following cardiac injury. These findings uncover a novel and important role of Capsulin positive epicardium derived cells in vasculogenesis during neonatal heart development and regeneration, and opens the door for future studies to better understand the dynamics of Capsulin expression and function in the post-natal mammalian heart.