tbuckley/cabot-search huggingface dataset:
Abstract 18798: Gata4 and Gata6 Are Necessary for Neonatal but Not Adult Cardiac Function Under Normal Physiological Conditions
Authors: Terence W Prendiville, Aibin He, Pingzhu Zhou, Alexander Von Gise, Qing Ma, William T Pu
Journal: Circulation (2013)

Objective: Fetal inactivation of the cardiac transcription factors Gata4 and Gata6 has been shown to cause postnatal heart dysfunction. However, the postnatal requirement for these transcription factors has not been defined. Methods: Using systemic delivery of recombinant adeno-associated virus 9 expressing Cre from the cardiac specific TNNT2 promoter (1.2E x 12VG/gram body weight; n=6), we inactivated floxed Gata4 and Gata6 alleles in neonatal or adult hearts. Left ventricular performance was followed serially using M-mode echocardiography and two-dimensional speckle tracking-derived myocardial tissue deformation (Visualsonics Vevo 2100) under light isofluorane anesthesia. The intervention group was compared to a control AAV-TNNT2 encoding luciferase. Findings: In the neonatal heart (P1-P5), effective knock-down of Gata4 and Gata6 (n=6 mice) was confirmed by Western blot and quantitative reverse-transcription PCR of myocardial tissue: We observed a 4.9-fold reduction in Gata4 expression; (95% C.I. +/-1.2) and a 6-fold reduction in Gata6 expression (95% C.I. +/- 1.2). Over the course of 5 days, left ventricular ejection fraction decreased significantly from a mean of 81% to 39% +/- 3% SEM (p&lt;0.0001). Strain analysis confirmed a global reduction in myocardial performance after knock-down. The expression of heart failure markers, m-ANF and MYH7, were markedly up-regulated at 17-fold and 24-fold, respectively. In the adult heart (postnatal weeks 6-9, n=6), despite a technically successful systemic delivery of rAAV9, no noted left ventricular dysfunction was apparent on subsequent serial follow-up by m-mode echocardiography. Similarly, myocardial performance, as measured by strain &amp; strain rate analysis in the longitudinal, circumferential and radial planes, remained equal in the intervention group to that of the control group. Conclusions: AAV9-TNNT2-Cre is an effective means of achieving temporally controlled inactivation of floxed alleles in the postnatal heart. Gata4 and Gata6 are required to maintain normal left ventricular systolic function during neonatal life, but are no longer required in adulthood under normal physiological conditions.
Abstract 14128: Predictors of Long-Term Mortality for Survivors of Out-Of-Hospital Cardiac Arrest
Authors: Mony Shuvy, Laurie J Morrison, Damon Scales, Harindra C Wijeysundera, Feng Qiu, Paul Dorian, Richard P Verbeek, Jason Buick, Jack V Tu, Maria Koh, Dennis T Ko
Journal: Circulation (2015)

Background: Although outcomes of out-of-hospital cardiac arrest (OHCA) patients have improved substantially over time, little is known regarding factors that may influence their longer term prognosis. The main objective of this study was to examine independent predictors of long-term mortality for OHCA survivors. Methods: A population-based study was conducted using the Toronto Rescu Epistry database with linkage to administrative data in Ontario, Canada. OHCA patients who survived to hospital discharge in the Great Toronto Area from 2005 to 2010 were included. Multivariable hierarchical regression models were constructed to determine the independent association of factors predicting 1-year and 3-years mortality. Results: Among the 13,755 OHCA patients who were eligible for study inclusion, 704 patients were alive at discharge and were included in this analysis. Their mean age was 60 years old, 27% were women, 35% had diabetes, and 9.4% had previous myocardial infarction. Mortality rates were 11.5% at one year and 19.6% at three years. Older age, cerebrovascular disease (OR = 2.74), renal disease (OR = 4.12) were significantly associated with higher mortality at one year (Table). In contrast, patients who had shockable initial rhythm (OR = 0.31), those who received coronary revascularization (OR = 0.41), or implantable cardioverter defibrillator (OR = 0.19) were associated with substantially lower risk of mortality. Factors associated with 3-year mortality were mostly similar as compared to one year, except for cancer which was highly significant for 3-year mortality (OR = 6). These models had high discrimination ability with area under the ROC of 0.89 for 1-year model and 0.88 for 3-year model. Conclusions: Non-cardiac comorbidities are the main drivers of adverse mortality for long term survivors of OHCA. Invasive cardiac procedures such as coronary revascularizations and ICD implantations are associated with significantly improved outcomes.
Abstract 18986: Collateral Flow In the Canine Heart Derived From Coronary Wedge Pressure Overestimates Actual Collateral Flow Measured by Fluorescent Microspheres
Authors: Jeroen P van den Wijngaard, Pepijn van Horssen, Imo E Hoefer, Jan J Piek, Jos A Spaan, Maria Siebes
Journal: Circulation (2013)

Purpose: In severe coronary artery disease, coronary collateral flow may prevent distal ischemia. Clinically the ratio between coronary wedge pressure and aortic pressure is used as index of collateral flow. The aim of this study was to validate this method by selective microsphere injections in the LAD during obstruction of LCX flow. Methods: The study was conducted in ten mongrel dogs and was performed in accordance with the Principles of laboratory animal care (NIH) as well as local IACUC. Under anesthesia a thoracotomy was performed and a guide wire equipped with both a pressure and a Doppler velocity sensor was introduced in the LCX. Fluorescent microspheres were injected into the LAD with partial and full occlusions of the LCX. Collateral flow derived from pressure was expressed as the fractional flow reserve, FFRcoll_p calculated according to its definition as; FFRcoll_p = FFRmyo - FFRcor where FFRmyo is the assumed true myocardial FFR. FFRcor_p is zero by definition during full occlusion and unity in the absence of any stenosis resistance. At full occlusion FFRcoll_p equals the ratio between distal wedge pressure, Pw, and aortic pressure Pa. At partial occlusion FFRcoll_p can be calculated from distal pressure, Pd, and Pa by means of the linear FFR model. With microspheres, FFRcoll_m is measured as the ratio between microsphere density in the LCX and that in the LAD perfusion territory but corrected for the estimated contribution of septal 28%, and right, 21%, coronary contribution to LCX collateral flow as derived from literature data. Results: Both, FFRcoll_p and FFRcoll_m were inversely related to the ratio between LCX flow velocity by the maximal hyperemic coronary flow velocity in the LCX. FFRcoll_p overestimated FFR_m at all occlusion degrees by a factor of 3 in average. At full occlusion this difference was significant according to Wilcoxon paired test with P&lt;0.0005. Conclusions: These results show that during severe occlusion pressure-derived measurement of collateral flow overestimates collateral flow as determined from microsphere distributions. Pressure based assessment of collateral flow may thus yield an incorrect estimate of collateral flow.
Abstract 13674: Feedback Regulation of Cholesterol Metabolism by Lexis, a Lipid-responsive Non-coding RNA
Authors: Tamer Sallam, Marius Jones, Thomas Gilliland, Zhang Li, Xiaohui Wu, Ascia Eskin, Jaspreet Sandhu, David Casero, Thomas Vallim, Hong Cynthia, Peter Tontonoz
Journal: Circulation (2015)

The LXR and SREBP transcription factors are key regulators of cellular and systemic cholesterol homeostasis in animals. The molecular mechanisms that integrate these pathways are incompletely understood. Here we show that ligand activation of LXR in liver not only promotes cholesterol efflux, but also simultaneously inhibits the cholesterol biosynthesis pathway. We further identify the long non-coding RNA LeXis as an unexpected mediator of this effect. LeXis is the most robustly induced transcript in mouse liver in response to western diet feeding or pharmacologic LXR activation. Tissue-specific overexpression of LeXis inhibits liver cholesterol biosynthesis and lowers plasma cholesterol levels. Reciprocally, knockdown of LeXis increases hepatic cholesterol content and raises plasma cholesterol levels. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms by which LXRs orchestrate systemic sterol homeostasis.
Abstract 18987: Warning Symptoms Precede Sudden Cardiac Death in Majority of Men
Authors: Eloi Marijon, Kyndaron Reinier, Audrey Evanado, Carmen Teodorescu, Kumar Narayanan, Adriana Huertas Vazquez, Harpriya Chugh, Katherine Jerger, Ronald Mariani, Eric Stecker, Karen Gunson, Jonathan Jui, Sumeet Chugh
Journal: Circulation (2013)

Introduction: Despite significant enhancements in resuscitation methodology, survival after sudden cardiac arrest (SCA) remains low. Improved knowledge of warning signs and symptoms may assist the process of early intervention for SCA. Hypothesis: We hypothesize that a sub-group of men who suffer SCA have warning symptoms prior to SCA. Methods: In a large, ongoing, prospective, population-based study in a Northwestern US metro region (population approx. 1 million; 2002-2012), we systematically evaluated the frequency, characteristics and temporal trends of all symptomatology in the 4 weeks prior to SCA among middle aged male cases (35-65 years). We performed a detailed and comprehensive assessment of the accounts of family members/relatives, witnesses, emergency medicine personnel, as well as medical records during this time period. Results: Of the 825 SCA cases, 258 (31%) did not have sufficient information to ascertain the presence of symptoms. Of the 567 cases with appropriate assessment [mean age 52±12 yr, initial shockable rhythm 59%, presence of witness 40%, bystander CPR 27%, presence of coronary artery disease (CAD) 84%], 300 (53%) patients presented with symptoms. These were principally chest pain in 167 patients (56%), dyspnea in 38 (13%), and dizziness/syncope/palpitations in 11 (4%). Episodes of chest pain were categorized as typical angina in 111 (67%) and suspicion of angina in 56 (33%). In an additional 29 cases (10%), typical flu symptoms were noted during the 4 weeks period. Overall, most symptoms (79%) occurred more than 1 hr before the SCD event (up to 4 weeks), whereas symptoms immediately preceding (&lt;1 hour) were less frequent (21%). Symptoms were especially frequent with associated CAD compared to non CAD-related SCA (56% vs. 32%, P=0.0005). Among patients with previously known CAD 55% had symptoms before SCA. Conclusions: In this community-based study, a higher than expected proportion of middle-aged men had warning symptoms prior to SCA. These findings may be explained by longer duration of evaluation, and have implications for SCA surveillance and prevention.
Abstract 18968: Bromocriptine-QR: A Potential Novel Strategy for Cardiovascular Risk Reduction in Type 2 Diabetes
Authors: Bindu Chamarthi, Michael Ezrokhi, Anthony H Cincotta
Journal: Circulation (2013)

Type 2 diabetes (T2D) is associated with a substantially increased risk of cardiovascular disease (CVD). Of the available therapies for T2D, none have been conclusively shown to reduce CVD risk. Metformin has long been considered the only agent with some evidence, albeit limited, of a potential CVD benefit. Bromocriptine-QR (BQR), a quick release sympatholytic dopamine agonist, is a newer FDA-approved therapy for T2D. Based on preclinical and clinical study findings, it is postulated that BQR restores the normal circadian peak in central dopaminergic tone diminished in insulin resistant states, which in turn reduces hyperactive sympathetic tone and improves central fuel sensing thereby reducing postprandial hepatic glucose and lipid output as well as reduces vascular resistance, oxidative stress, and inflammation. In a one-year randomized trial of BQR vs. placebo added to standard therapy (diet and/or ≤ 2 diabetes medications including sulfonylureas, TZD, metformin, or insulin) in 3070 T2D subjects (average duration of T2D: 7.9 years), including individuals with pre-existing CVD, BQR therapy resulted in a 40% hazard rate reduction (HRR) in major CVD events, pre-specified as a composite of time to first myocardial infarction, stroke, coronary revascularization, hospitalization for angina or congestive heart failure. In the present study, this CVD effect of BQR was evaluated in a subset of this original study population on metformin +/- another anti-diabetes therapy at baseline (N = 1791). The composite CVD end point occurred in 16/1208 BQR-treated (1.3%) and 18/583 placebo-treated (3.1%) subjects resulting in a 53% CVD HRR (ITT group, Cox regression analysis; HR 0.47, 95% CI 0.24, 0.92, P = 0.028) adjusted by age (HR 1.08, 95% C.I. 1.04, 1.12, P = 0.0003) and pre-existing CVD (HR 2.27, 95% C.I. 1.02, 5.07, P = 0.041). Kaplan-Meier Curves of the cumulative incidence rate yielded a CVD HRR of 58% (HR 0.42, 95% C.I. 0.21, 0.85, Log-Rank = 0.017). These findings reaffirm prior observations of CVD risk reduction with BQR therapy and further demonstrate the potential for a marked additive effect of BQR above any derived from metformin, suggesting a potential novel strategy for CVD risk reduction in T2D.
Abstract 18994: Shear-Dependent Membrane Scrambling and Microvesiculation and an Important Role for Rac1
Authors: Michael K Delaney, Junling Liu, Yi Zheng, Xiaoping Du
Journal: Circulation (2013)

Surface exposure of phosphatidylserine (PS) and the release of membrane microvesicles (microparticles) are critically important for blood platelets and leukocytes to promote coagulation and inflammation during vascular injury. The caspase-dependent apoptotic signaling pathway and high intracellular calcium-dependent mechanisms have been implicated in the induction of these events under static conditions. However, it is known that when stimulated with physiological agonists under static conditions only a small percentage of platelets actually respond in a procoagulant manner. Thus, these mechanisms do not fully explain the potent procoagulant response of platelets to physiological stimuli. Here we demonstrate a novel shear stress-dependent mechanism of PS exposure and microvesiculation in platelets stimulated by physiological agonists. We show that exposing agonist-stimulated mouse and human platelets to increasing levels of shear led to greatly increased levels of surfaced exposed PS, shedding of membrane microvesicles, and in particular an increased sensitivity of platelets to display procoagulant activity at low concentrations of physiological agonists. Thus, shear stress is critical for inducing the surface exposure of PS and the shedding of PS-exposed microvesicles in platelets. Moreover, using the Rac1 inhibitor NSC23766 and platelet-specific Rac1 -/- platelets we identified Rac1, a member of the Rho family small GTPases, as being a critical mediator of the platelet procoagulant response to shear. We also show that Rac1 regulates this shear-induced response independent of the known apoptosis signaling pathway, as Rac1 -/- platelets showed no difference in the caspase-dependent pathway of PS exposure induced by ABT737. Importantly, the role of Rac1 in mediating shear-dependent PS exposure and microvesicle release appears to be independent of its known role in stimulating platelet secretion, and represents a common pathway of PS exposure and microvesicle release induced via several different agonists. This novel PS exposure and microvesculation mechanism is important for the function of platelets to promote coagulation.
Abstract 13024: <i>Cardiopulmonary Best Abstract Award</i> : A Disintegrin and Metalloproteinase With Thrombospondin Motifs 8 Downregulates AMP-activated Protein Kinase and Promotes Matrix Metalloproteinases Activation and Pulmonary Hypertension
Authors: Junichi Omura, Kimio Satoh, Nobuhiro Kikuchi, Taijyu Satoh, Ryo Kurosawa, Masamichi Nogi, Shinichiro Sunamura, Tomohiro Ohtsuki, Katsuya Kozu, Kazuhiko Numano, Koichiro Sugimura, Shunsuke Tatebe, Tatsuo Aoki, Kota Suzuki, Nobuhiro Yaoita, Hiroaki Shimokawa
Journal: Circulation (2016)

Background: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries (PA) and excessive proliferation of PA smooth muscle cells (PASMCs). ADAMTS8, a member of the disintegrin and metalloproteinase, is a secreted extracellular enzyme that is specifically expressed in lung tissue. Methods and Results: To explore a novel therapeutic target of PAH, we performed microarray analysis of PASMCs from patients with PAH (PAH-PASMCs) and found a significant up-regulation of ADAMTS8 in PAH-PASMCs compared with controls (&gt;5-fold, P&lt;0.01). Protein levels of ADAMTS8 were significantly increased in PAH-PASMCs compared with controls (&gt;1.3-fold, P&lt;0.05, n=5 each). Indeed, immunoreactivity of ADAMTS8 was enhanced in the thickened medial layer of PA in PAH patients (n=2-3). Additionally, hypoxia increased protein level of ADAMTS8 in mouse lung homogenates compared with controls (P&lt;0.05, n=6-10 each). Human recombinant ADAMTS8 (hrADAMTS8, 25 ng/mL) suppressed AMP-activated protein kinase (AMPK) signaling, activated matrix metalloproteinases (MMPs), and promoted PASMC proliferation (all P&lt;0.05). In contrast, ADAMTS8 siRNA reduced PASMC proliferation (P&lt;0.05). PASMC-specific ADAMTS8 -/- mice exposed to hypoxia (10% O 2 , 4 weeks) showed significantly reduced RV systolic pressure (33.5±0.3 vs. 38.9±0.4 mmHg), RV hypertrophy (0.26±0.06 vs. 0.33±0.09), and PA remodeling compared with controls (all P&lt;0.05, n=9 each). In situ zymography with DQ gelatin showed reduced MMP activities in PA in ADAMTS8 -/- compared with controls (P&lt;0.05). Primary cultured PASMCs from ADAMTS8 -/- mice showed AMPK activation, reduced migration and proliferation compared with controls (P&lt;0.05, n=6 each). Importantly, hrADAMTS8 treatment suppressed VEGFA-induced AMPK activation and VEGF receptor-2 phosphorylation in PA endothelial cells (P&lt;0.05, n=6 each). Consistently, PAEC-specific AMPK -/- mice exposed to hypoxia showed significantly increased RV systolic pressure (39.3±1.0 vs. 33.1±0.9 mmHg), RV hypertrophy, and PA remodeling compared with controls (all P&lt;0.05). Conclusions: ADAMTS8 downregulates AMPK in PA endothelial cells and induces MMP activation and PASMCs proliferation, thus promoting the development of PH.
Abstract 18804: A Saline Containing Charge-Stabilized Nanostructures Inhibits Apoptosis of Cardiomyocytes Subjected to Ischemia/Reperfusion Injury
Authors: Andreas Kalmes, Monica Anderson-Haley, Supurna Ghosh, Richard Watson
Journal: Circulation (2013)

Background: Inflammation and apoptosis contribute to ischemia/reperfusion (I/R) injury after acute myocardial infarction (AMI). RNS60 is an isotonic saline solution containing charged-stabilized nanostructures introduced by Taylor-Couette Poiseuille flow in the presence of an elevated oxygen concentration. RNS60 has shown anti-inflammatory and cytoprotective effects across models of pulmonary and neuro-inflammation and significantly reduced infarct size in a pig model of AMI. Objective: To investigate whether RNS60 reduces tissue damage after AMI by effects on cardiomyocyte apoptosis. Methods: Groups of male pigs (25-35 kg) were subjected to myocardial ischemia for 60 minutes and treated with RNS60 or normal saline (NS) by single intracoronary injection (0.1 mL/kg) at time of reperfusion and by continuous intravenous infusion (1.0 mL/kg/hour) for 4 days. Apoptosis in the peri-infarct region was quantified by counting the number of caspase 3-positive cells. The expression of proteins of the reperfusion injury salvage kinase pathway was measured by Western blot. Results: Ischemia for 60 minutes followed by reperfusion for 4 days caused infarcts measuring 44% 6% of the area at risk in NS-treated animals (n=14). RNS60 treatment reduced the infarct size by 32 % (n=13, P &lt;0.001). The number of caspase 3-positive cells in the peri-infarct region was significantly reduced in the RNS60-group ( P &lt;0.05). At 4 days after reperfusion, the expression of phospho-Akt, Bcl-2, Bcl-xl, and phospho-GSK3 was not different between the groups. Interestingly, however, RNS60 treatment significantly reduced the expression of HSP90 ( P &lt;0.01), which has recently been linked to a reduction of I/R injury by post-conditioning in pig hearts. Conclusion: Treatment with RNS60, a physically modified saline devoid of an active pharmaceutical ingredient, reduces I/R injury in a pig model of AMI, at least in part through inhibition of apoptosis and modulation of the stress protein response in cardiomyocytes. These findings suggest the possibility to develop a new class of therapeutics to limit cardiac damage after coronary revascularization procedures in AMI patients.
Abstract 13618: Effects of Type 1 Interferon on Blood-derived Smooth Muscle Progenitor Cells Differentiation and Arterial Wall
Authors: Yanpeng Diao, Rajesh Mohandas, Pui Lee, Zhiyu Liu, Larysa Sautina, Wei Mu, Li Shiyu, Xuerong Wen, Byron Croker, Mark Segal
Journal: Circulation (2015)

Introduction: System lupus erythematosus (SLE) patients have premature atherosclerosis not explained by traditional risk factors and half have elevated Type-I Interferon (IFN-I) levels. Hypothesis: We hypothesized that IFN-I would induce premature atherosclerosis by affecting the differentiation of circulating smooth muscle progenitor cells (SMPC) and promoting atherosclerosis within the vasculature. Methods: SMPC isolated from wild-type (WT) and IFN receptor knock-out (IFNR-KO) animals were cultured in medium ± IFN-I and ± TGF-β. In vivo, we analyzed the effect of muscle electroporation of IFN-I cDNA on the number of SMPC and sections of the abdominal aorta bifurcation. Results: After 2 weeks culture, IFN-I containing media led to an increase in the number of SMPC isolated from WT animals but no change when the SMPC were isolated from IFNR-KO mice. When the cultured cells were sorted, there was little monocytes/macrophage (CD14, CD36 and F4/80) marker expression while the expression of CD34 increased 50% (Figure), approximately. Real-time PCR revealed that the mRNA of calponin, SM-α-actin and SM22 increased 0.33, 4.5 and 75.1 times, respectively, while SM-myosin heavy chain was unchanged after treatment with IFN-I. Our in vivo results demonstrate a marked increase in pre-atherosclerotic like lesions and significant endothelium damage in WT mice expressing IFN-I for 3 months. However, there was no significant difference in arterial media thickness and cell density between IFN-I treated mice and control. Within these lesions, we observed “immature SMC,” cells that expressed CD34, SM-α-actin, but no SM myosin heavy chain (Figure). Conclusions: Our findings suggest that IFN-I enhances SMPC number, and maintains them in an “immature” state while TGF-β might skew SMPC along a non-SMC pathway. These results suggest a role of IFN-I in atherosclerosis by affecting SMPC maturation and have implications for the pathogenesis of atherosclerosis in lupus patients.