tbuckley/cabot-search huggingface dataset:
Abstract 84: Effects of Edaravone on Brain Apoptotic Gene in CA/CPR Rats
Authors: Meng H Chen, Lu Xie
Journal: Circulation (2013)

Edaravone(3-methyl-1-phenyl-2-pyrazolin-5-one), a strong novel free radical scavenger, is used in clinically as a novel neuroprotective agent for the treatment of patients with acute ischemic stroke. We assessed the hypothesis that the neuroprotective effect of edaravone corresponding with brain apoptosis could improvethe survival outcomes in a rat model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Adult male Sprague-Dawley rats were divided into saline, edaravone groupssubjected to sham group (sham surgery, n=10), saline group (CA for 5 min following CPR and intravenous ejection of saline 1.5 ml/kg, n=20), edaravone (CA for 5 min following CPR and intravenous ejection of edaravone 3 mg/kg, n=20)groups. The resuscitated animals were observed for 72 h after the restoration of spontaneous circulation. The rat survival time, survival rate was assessed and the expression of caspase-3, caspase-8, Bax and Bcl-2mRNA at 12, 24, 48 and 72 hours in hippocampus was measured by real time-PCR. Edaravone markedly enhanced the survival time and rate of rats (Kaplan-Meier analysis) after CA/CPR compared to saline group [(70.00±26.69) h, 95% CI (17.67-122.33)] vs[(23.00±3.91) h, 95% CI (15.33-30.67)] and (45% vs. 25%, χ2=4.900, P=0.027). The expression of apoptotic gene mRNA was significant upregulation (except caspase-8 and Bax in edaravone group at 72 h) in both the saline and edaravone groups (P&lt;0.05) compared to sham group. Edaravone significantly decreased the expression of caspase-3, caspase-8 and Bax mRNA (P&lt;0.05) and facilitate Bcl-2 expression (P&lt;0.05) compared to saline group (Tab1-4). This study suggests that (i)CA/CPR results in upregulation of pro-and anti-apoptosis; (ii)edaravone suppresses the up-regulation of the pro-apoptotic gene expression and facilitates the expression of anti-apoptotic gene in the hippocampus, involved in the improvement of the survival outcomes after CPR.
Abstract 9559: Serum Uric Acid and the Vulnerability of Carotid Atherosclerotic Plaque Measured by Magnetic Resonance Imaging
Authors: Hiroki Kagaya, Hirohumi Watanabe, Yuichiro Yoshikawa, Takahiro Kageyama, Shigeki Imamura, Aizan Hirai
Journal: Circulation (2013)

Carotid-wall intima-media thickness (IMT) is a surrogate marker of atherosclerosis associated with cardiovascular risk factors and with cardiovascular outcomes. MR imaging of carotid plaque has been shown to be superior to the diagnostic assessment of plaque vulnerability at high risk of rupture, and to provide information useful to the choice of treatment. Regression of plaque has been reported by intensive statin therapy (IST). The effect of IST on the characteristics of carotid plaques, especially on the instability of plaques was determined using a combination of ultrasonography and MR imaging. In the present investigation, 572 patients having max IMT over 1.5mm were included. Among them, 445 patients (234 males and 211 females, average age was 70 ± 9.9 and 70 ± 10.1, respectively ) had been treated on IST for more than 1 year before the study(IST group). On the other hand, 117 patients (49 males and 68 females) had not been treated on IST before the study(non-IST group). Serum levels of LDL-C, HDL-C, LDL-C/HDL-C and uric acid of IST group and non-IST group are 68 ± 15 vs 133 ± 29, 52 ± 13 vs 53 ± 12, 1.39 ± 0.4 vs 2.6 ± 0.5 and 5.4 ± 1.4 vs 5.1 ± 1.2, respectively. The black-blood method was used, and a horizontal cross-sectional image of plaque was taken with T1- and T2-weighted mode. Finally, the ratio of the lesion and the submandibular gland was determined. Plaques having the ratio of T1 evaluation more than 1.25 were defined as intraplaque hemorrhage (IPH), while those below 1.25 were defined as stable. Plaques having the ratio of T2 evaluation more than 1.25 were defined as lipid core (LC), while those below 1.25 were defined as stable. In IST group, 58% of the patients have stable plaque, 6% have IPH, 24% have LC and 11% have IPH+LC. On the other hand, 50% of the patients of non-IST group have stable plaque, 4% have IPH, 33% have LC and 12% have IPH+LC. In IST group, among various parameters, only serum uric acid has strong and significant correlation with the presence of LC in carotid plaque in male (p=0.0030). Odds ratio of uric acid in the presence of LC in carotid plaque is 1.530. No such correlation was observed in female patients. Thus the present investigation provides a new insight into the role of uric acid in the vulnerability of carotid atherosclerotic plaque.
Abstract 9936: Hypoxanthine is a Biomarker of Ischemia
Authors: Lynne Gehr, Todd Gehr, Lorin Bachmann, George Vetrovec
Journal: Circulation (2013)

We hypothesize that hypoxanthine (HX) is an early biomarker of ischemia. Our goal was to assess early HX values in patients presenting with acute chest pain (ACP) and late troponin elevation (n=27) compared to those with known coronary artery disease (CAD) presenting for elective CABG (n=10) and normal controls without known CAD (n=24). Methods: In a retrospective manner after IRB approval was obtained, we examined residual plasma for HX in 27 patients presenting to the emergency room with troponin samples requested by the clinician as per routine clinical practice. Patients with a non diagnostic troponin level for myocardial infarction (MI) at the time of presentation but who subsequently ruled in for MI (troponin of &gt; .39 μg/L) were included in the study. Significant differences between the groups was determined using a standard t test. Results: Initial sample results for the ACP patient group who subsequently ruled in for MI by troponin show a mean troponin of 0.07+/-0.014(SEM)μg/L and a mean HX level of 27.38 +/- 3.53 μM compared to normal controls whose mean HX was 4.03 +/- 0.32 μM (p&lt;.05). Ten patients without ACP presenting for elective CABG had a mean HX of 5.09+/- 0.67 μM. In the figure below, we demonstrate that HX is elevated in ACP patients who on subsequent sampling rule in by troponin criteria for MI. Reported HX levels in normal volunteers are approximately 3.5 μM consistent with our controls. Conclusion: HX is elevated prior to troponin elevation in patients presenting with ACP that subsequently rule in for MI by troponin criteria. These levels were elevated relative to normal control patients as well as in 10 patients with known CAD without ACP presenting for elective CABG. Therefore, HX is potentially an early maker of ischemia in the acute clinical setting.
Abstract 9685: Circulating Osteoglycin and NGAL/MMP9 Complex Concentrations are Associated With 1-year Major Adverse Cardiovascular Events After Coronary Angiography
Authors: Jin M Cheng, Martijn Akkerhuis, Rohit Oemrawsingh, Hector M Garcia-Garcia, Robert-Jan van Geuns, Olivier Meilhac, Eric Malaud, Dominique Piquer, Delphine Merle, Patrick W Serruys, Eric Boersma, Jeannette Fareh, Isabella Kardys
Journal: Circulation (2013)

Background: In previous proteomics experiments, we have found several proteins to be differentially expressed in human hemorrhagic carotid atherosclerotic plaques, which are considered as unstable, when compared to fibrotic plaques. Circulating concentrations of these proteins may predict cardiovascular outcome in patients with coronary artery disease. Methods and results: Blood samples were drawn in 768 patients who underwent coronary angiography for acute coronary syndrome or stable angina pectoris in a prospective biomarker study in a tertiary center between 2008 and 2011. We selected the 88 patients (cases) with major adverse cardiovascular events (MACE) within one year and 176 controls without MACE, matched on age, sex and number of diseased coronary vessels. MACE was defined as all-cause mortality, acute coronary syndrome, unplanned coronary revascularization and stroke. Thirteen circulating protein biomarkers that were previously found to have altered expression in hemorrhagic plaques were evaluated. Univariable conditional logistic regression analyses showed that baseline plasma neutrophil gelatinase-associated lipocalin (NGAL, p=0.038), osteoglycin (OGN, p=0.011), thrombospondin-2 (p=0.066), pro-B-type natriuretic peptide 1-108 (p=0.088), metalloproteinase inhibitor-1 (p=0.020) and NGAL/matrix metalloproteinase-9 complex (NGAL/MMP9, p=0.070) concentrations were higher in patients with MACE during follow-up. After further adjustment for established cardiovascular risk factors, OGN (OR 1.84 per SD of ln-transformed OGN unit, 95%CI 1.10-3.08, p=0.021) and NGAL/MMP9 (OR 1.76, 95%CI 1.04-2.98, p=0.034) were independently associated with MACE. Conclusions: Circulating OGN and NGAL/MMP9 complex may be promising biomarkers that are expressed in atherosclerotic plaques and that are independently associated with occurrence of MACE after coronary angiography.
Abstract 9518: Follistatin-like 1 Functions as a Cardiokine That Plays a Protective Role in Renal Injury
Authors: Satoko Hayakawa, Koji Ohashi, Rei Shibata, Yoshiyuki Kataoka, Megumi Miyabe, Yusuke Uemura, Takahiro Kambara, Takashi Enomoto, Kenneth Walsh, Toyoaki Murohara, Noriyuki Ouchi
Journal: Circulation (2013)

Objective: Heart diseases including chronic heart failure contribute to the progression of chronic kidney disease. Heart tissue produces a variety of secretory proteins, also known as cardiokines, which play roles in inter-cellular and inter-tissue communication under physiological and pathological conditions. Recently we found that follistatin-like 1 (Fstl1) acts as a stress-inducible cardiokine that exerts cardio-protective function. Here, we investigated the role of cardiac Fstl1 in renal disease in a mouse model of subtotal nephrectomy. Methods and Results: Cardiac specific Fstl1-deficient (Fstl1-KO) mice were generated by crossing cardiac myocyte-specific α-MHC-Cre transgenic mice and Fstl1 flox/flox mice. Subtotal (5/6) nephrectomy operation was performed in Fstl1-KO mice and control mice. At 2 months after operation, urinary albumin excretion was significantly increased in Fstl1-KO mice compared to control mice. A histological analysis of the remnant kidney demonstrated that Fstl1-KO mice showed a significant increase in intraglomerular cell number and glomerular size compared to control mice. Fstl1-KO mice also had a larger area of tubulointerstitial fibrosis in the remnant kidney compared to control mice, which was accompanied with increased mRNA levels of transforming growth factor-β1 and collagen type I/III. Furthermore, Fstl1-KO mice showed elevated expression levels of NADPH oxidase components and pro-inflammatory cytokines including TNF and IL-6 in the remnant kidney. Conclusions: Our findings indicate that Fstl1 functions as a cardiokine that prevents glomerular and tubulointerstitial damages through attenuation of oxidative stress and inflammatory response.
Abstract 9261: Dantrolene May Suppress Arrhythmogenesis by Inhibition of CaMKII-mediated Aberrant Ca2+ Release Within the Ryanodine Receptor in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy
Authors: Shinichi Okuda, Masakazu Fukuda, Takayoshi Kato, Shigehiko Nishimura, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
Journal: Circulation (2013)

Cardiac troponin T (cTnT) mutations cause Familial Hypertrophic Cardiomyopathy (FHC), which leads to sudden cardiac death. Ca2+ sensitivity in myofilaments was increased, however, the underlying mechanism by which the cTnT mutations lead to lethal arrhythmia and the therapeutic approach remains elusive. Here, we investigated the pathogenic role of phosphorylation-mediated aberrant Ca2+ release via the cardiac ryanodine receptor (RyR2) and the therapeutic effects of dantrolene, which was found to correct inter-domain interactions of RyR2 in failing hearts (i.e. unzipping to zipping), in transgenic mouse (TG) model with FHC-related cTnT mutation (delta160E). Methods and results: In 6thmonths of age, there was no appreciable difference in the structural or functional features of the hearts between non-TG and TG mice. In response to isoproterenol (ISO; 10 nmol/L), the Ca2+ spark frequency (SpF: s-1·100μm-1; by fluo4) was much higher in TG cardiomyocytes (ISO-TG: n=11: 7.7±0.7; p&lt;0.01) than in non-TG cardiomyocytes (n=6: 3.5±0.5). It was largely reversed by CaMKII inhibitor {ISO-TG with KN-93(1μM), n=6: 5.2±0.4; p&lt;0.05}}, but not by PKA inhibitor{ISO-TG with H-89(1μM), n=6: 7.3±0.4;n.s}}. ISO-TG (but not ISO-treated non-TG 0/14; n=14) showed spontaneous Ca2+ transient (sCaT) after 5 Hz pacing (12/18; n=13), whereas it was again attenuated by KN-93 (0/5; n=5), but not by H-89 (3/5; n=5)}. These abnormal events in ISO-TG were reproduced by adding EGTA-AM into ISO-treated non-TG, suggesting that increased Ca2+ buffering capacity, causing an increase in diastolic [Ca2+], predisposes to aberrant Ca2+ release events. Moreover, dantrolene (1μM) attenuated SpF (n=6: 5.2±0.3; p&lt;0.05 vs ISO-TG), time from peak to 70% decline of Ca2+ transient and sCaT (3/10; n=10) in ISO-treated TG cardiomyocytes. Conclusions: In FHC-linked cTnT mutated hearts, aberrant local Ca2+ release through defective RyR2 was induced by beta-adrenergic stimulation, presumably due to mutation-linked, increased Ca2+ buffering capacity, and subsequent CaMKII activation. The inhibition of CaMKII-mediated aberrant Ca2+ release by stabilizing RyR2 could be a new therapeutic approach to prevent the development of arrhythmias in FHC.
Abstract 19097: Mutant Gravin Positively Modulates Cardiac Hypertrophy Following Chronic Beta Adrenergic Stimulation
Authors: Andrea C Diaz Diaz, Cori Wijaya, Sonal Singh, Bradley K McConnell
Journal: Circulation (2013)

Gravin, an A kinase anchoring protein (AKAP), scaffolds protein kinase A (PKA) and other signaling molecules to the β2-adrenergic receptor (AR). Gravin plays a vital role in the desensitization of the β2-AR upon agonist stimulation. The objective of this study was to evaluate whether disruption of PKA/gravin interaction prevents cardiac hypertrophy induced by chronic β-AR stimulation and to correlate ventricular hemodynamics to cardiac hypertrophy. Chronic β-AR stimulation was induced in wild-type (WT) and gravin truncated (t/t) mutant mice with isoproterenol (ISO) (60mg/kg/day for 14 days). Ascorbic acid (AA) was used as control. The heart to body weight (HW/BW) ratio, an indicator of hypertrophy, showed that WT-ISO (5.71±0.28) had a significantly higher ratio as compared to WT-AA (3.86±0.082) whereas there was no significant difference between t/t-ISO (4.88±0.24) and t/t-AA (4.31±0.24) groups. Expression of atrial natriuretic factor - a marker of cardaic hypertrophic - was quantified using RT-qPCR and found to be significantly higher in WT-ISO compared to WT-AA but with no significant difference between the t/t-AA and t/t-ISO groups. Next, in vivo performance was evaluated by pressure volume measurements. dP/dt max, indicative of the left ventricular performance was significantly lower in the WT-ISO (7676±376.1) compared to the WT-AA (10175±640.9) with no significant difference between the t/t-ISO (7021±405.5) and t/t-AA (8857±778.2) groups. Ees, representing a parameter of contractility was significantly decreased in the WT-ISO (3.80±0.43) as compared to the WT-AA (7.36 ±0.96) whereas t/t-AA (8.42±1.92) and t/t-ISO (9.77±1.17) groups exhibited no significant differences. Finally the diastolic performance parameter tau was significantly elevated in WT-ISO (9.02±0.19) as compared to the WT-AA (6.76±0.36) whereas t/t-AA (7.28±0.43) and t/t-ISO (7.67±0.54) groups had similar values. Overall, mutant gravin mice (t/t) were resistant to cardiac hypertrophy and had preserved cardiac hemodynamics in response to chronic β-AR stimulation, as compared to WT mice. The data suggests that modulation of gravin and its interaction with the binding partners may play an important role in the progression of heart failure due to cardiac hypertrophy.
Abstract 251: Measuring the Association of CPR Quality Metrics and Intra-Arrest End-Tidal Carbon Dioxide
Authors: Kelsey Sheak, Douglas J Wiebe, Marion Leary, Benjmain S Abella
Journal: Circulation (2013)

Background: End-tidal carbon dioxide (ETCO 2 ) is an indicator of blood flow during low-flow states such as during CPR delivery. Given that cardiac arrest survival is sensitive to CPR quality, ETCO2 might serve to guide CPR during clinical care. ETCO 2 has been shown to be a useful indicator of CPR quality in laboratory arrest models, however, there is a lack of clinical data assessing this relationship in humans. Objectives: To determine the association between quantitative CPR performance and intra-arrest ETCO2 in a time-based analysis of clinical resuscitation events. Methods: In this single center retrospective study we collected ETCO 2 data and time-synchronized CPR quality metrics using CPR-recording defibrillators (MRx QCPR, Philips Healthcare) during cardiac arrest events between 08/2007-06/2012. For each case, mean ETCO 2 for each 30 sec segment of CPR was calculated manually by averaging the peaks of each capnographic waveform. CPR 30 sec segments were divided into tertiles based on rate and depth, and combined to form nine groups representing combinations of CPR performance. A mixed-effect regression of mean ETCO 2 with the nine CPR combinations was performed using shallow depth and slow rate as the reference category. Results: Of the 54 arrest events with both CPR quality metrics and ETCO 2 waveform data, we extracted 992 30 sec blocks that had compression pauses &lt; 5 sec. Deep compression depth coupled with a slow, medium or fast rate and a medium depth coupled with a fast rate produced statistically significant higher ETCO 2 values than the reference category (see figure). Conclusions: Greater compression rate and depth are associated with higher mean ETCO 2 during the same 30 sec period of time. This relationship suggests a physiologic response to CPR quality as detected via ETCO 2 measurement. The potential clinical use of ETCO2 to guide CPR requires further investigation.
Abstract 272: Association Between Pre-hospital Intubation, Epinephrine And Neurological Outcome Following Out-of-hospital Cardiac Arrest In Japan: Sos-kanto 2012 Study Interim Report
Authors: Yosuke Homma, Takashi Shiga, Hiraku Funakoshi, Dai Miyazaki, Yoshio Tahara, Ken Nagao, Arino Yaguchi, Naoto Morimura
Journal: Circulation (2013)

Background: Emergency medical technicians (EMT) typically perform endotracheal intubation (ETI) and administer epinephrine for out-of-hospital cardiac arrest (OHCA) patients. However, the clinical effectiveness of these procedures is still controversial, especially in regards to neurological outcomes in patients subsequently receiving intensive care after hospitalization. Study Objectives: The aim of this study was to evaluate the effectiveness of ETI and epinephrine administration in the pre-hospital setting on neurological outcomes following OHCA. Methods: This was a multicenter retrospective cohort study in Japan from January 2012 to February 2013. We used data from the Survey of Survivors after Cardiac Arrest in the Kanto Area in 2012 (SOS-KANTO 2012) database. Collected variables included age, gender, witnessed status, bystander CPR, first documented rhythm, hospital arrival time, and type of ICU care received after admission. To address selection bias, those who had early return of spontaneous circulation (ROSC) without ETI and epinephrine were excluded. Multivariate logistic regression was performed to investigate the association between EMT interventions and 1) hospitalization with ROSC, 2) 7-day survival, and 3) favorable neurological outcome, defined as 1-month cerebral performance category score of 1 or 2. Results: Of 6,019 OHCAs, 5,111 met the inclusion criteria (male, 57%; mean age, 71 years). 932 patients (18%) underwent ETI and 251 patients (4.9%) received epinephrine. 1,062 patients (20.8%) were hospitalized after ROSC. Multivariate logistic regression showed that OHCA patients who received pre-hospital epinephrine had a higher rate of hospital admission after ROSC (odds ratio [OR]=1.63, 95% confidence interval [CI] 1.35-1.97, P&lt;0.001). However, they demonstrated poorer neurological outcomes (OR=0.31, 95%CI 0.12-0.82, P=0.02). OHCA patients undergoing pre-hospital ETI did not demonstrate significantly different outcomes. Conclusion: These findings suggest that pre-hospital procedures may not be necessary for increasing favorable neurological outcomes.
Abstract 9795: Deficiency of Phospholipase A <sub>2</sub> Receptor Exacerbates Airway Inflammation and Pulmonary Vessel Remodeling After Ovalbumin Treatment Through Impaired Clearance of Secretory Phospholipase A <sub>2</sub>
Authors: Shun Tamaru, Hideto Mishina, Yosuke Watanabe, Kazuhiro Watanabe, Daisuke Fujioka, Soichiro Takahashi, Koji Suzuki, Takamitsu Nakamura, Jun-ei Obata, Kenichi Kawabata, Yasunori Yokota, Kohji Hanasaki, Kiyotaka Kugiyama
Journal: Circulation (2013)

Secretory phospholipase A 2 (sPLA 2 ) plays a critical role in the genesis of various inflammatory diseases through pro-inflammatory eicosanoids. We previously discovered a cell surface receptor for sPLA 2 (PLA 2 R) and showed that PLA 2 R as well as its ligands, sPLA 2 groups IB and X, were expressed in the lung, but the pathogenic role of PLA 2 R in the lung is unknown. This study examined the role of PLA 2 R in the pathogenesis of inflammation of the airway and pulmonary vessels using PLA 2 R knockout (KO) mice. Methods and Results: Allergic lung inflammation was induced by immuno-sensitization with ovalbumin (OVA). In immunohistochemical analysis, PLA 2 R was detected in airway smooth muscle cells in PLA 2 R wild type (WT) lung. PLA 2 R KO mice showed a significantly greater infiltration of inflammatory cells around the airways and blood vessels (1.7 fold greater than WT mice) and a greater wall thickness of blood vessels (1.3 fold greater than WT mice) after OVA-treatment. PLA 2 R KO mice had significantly higher levels of sPLA 2 -IB and -X in bronchoalveolar lavage fluid (BALF) after OVA treatment than WT mice (sPLA 2 -IB, 34.4 ± 3.2 pg/mL vs. 13.5 ± 1.8 pg/mL; sPLA 2 -X, 9.8 ± 2.4 pg/mL vs. 3.9 ± 0.9 pg/mL; respectively, p &lt; 0.05 for both). This difference was associated with greater levels of eicosanoids (LTB 4 , CysLTs and PGD 2 ), and Th2 cytokines (IL-4 and IL-5) and higher numbers of eosinophils and neutrophils in OVA-treated BALF of PLA 2 R KO mice than WT mice. When 125 I-labeled sPLA 2 -IB was endotracheally instilled into the lung, 125 I-sPLA 2 -IB was cleared much more slowly from BALF of PLA 2 R KO mice than from WT mice (instilled 125 I-sPLA 2 -IB remaining in BALF at 2 hrs; 40% vs. 10%, respectively). Degradation of instilled 125 I-sPLA 2 -IB, assessed by TCA-soluble radioactivity in BALF, was lower in PLA 2 R KO mice (70% of WT mice at 4 hr). In experiments using cultures of airway smooth muscle cells, binding, internalization and degradation of 125 I-sPLA 2 -IB were lower in PLA 2 R KO cells than WT cells, supporting the impaired clearance of sPLA 2 from lungs of PLA 2 R KO mice. Conclusions: PLA 2 R-deficiency increased sPLA 2 -IB and -X levels in the lungs due to impaired clearance from the lung, leading to exaggeration of airway inflammation and pulmonary vessel remodeling after OVA treatment in a mouse model.