tbuckley/cabot-search huggingface dataset:
Abstract 316: Therapeutic Hypothermia for Comatose Survivors After Out-of-Hospital Nonshockable Cardiac Arrest
Authors: Taketomo Soga, Ken Nagao, Hiroshi Nonogi, Hiroyuki Yokoyama, Naohiro Yonemoto, Kei Nishikawa, Harumi Hirose, Tukasa Yagi, Asuka Kasai
Journal: Circulation (2012)

Background Clinical evidence strongly supports therapeutic hypothermia for unconscious adult patients with return of spontaneous circulation (ROSC) after out-of-hospital shockable cardiac arrest (VF or pulseless VT), but there are insufficient data that therapeutic hypothermia had neurological benefit for those after non-shockable cardiac arrest (PEA or asystole). Methods We conducted a multicenter registry of therapeutic hypothermia (J-PULSE-HYPO study) for unconscious adult patients with ROSC after out-of-hospital cardiac arrest due to cardiac etiology from 14 institutions. At the same periods, All-Japan Utstein Registry, a prospective, nationwide, population-based registry of out-of-hospital cardiac arrest was established by the Fire and Disaster Management Agency. From the data of the two registries, we extracted the eligible patients with ROSC after bystander-witnessed non-shockable cardiac arrest; the intervention group consisting of patients who treated with post-ROSC cooling (32-34°C for 12-72 hours), and the control group consisting of patients who met the inclusion criteria of the J-PULSE-HYPO study and matched with the baseline characteristics of the intervention group. The primary endpoint was a 30-day favorable neurological outcome after cardiac arrest. Results Between 2005 and 2009, 65 of the 452 comatose adult patients treated with post-ROSC cooling were eligible as the intervention group. In the intervention group, the time interval from collapse to ROSC ranged from 5 to 50 minutes, with a mean (± SD) of 27.2 ±11.1 minutes, a median of 27 minutes, and 25th and 75th percentile values of 19.75 and 33.25 minutes, respectively. Of the 4,037 patients with ROSC after bystander-witnessed non-shockable cardiac arrest due to cardiac etiology, 634 were matched as control group. Frequency of a 30-day favorable neurological outcome was a significantly higher in the intervention group than in the control group (37% vs.18%, p=0.0004). The adjusted odds ratio for favorable neurological outcome after the intervention group was 2.9 (95% CI, 1.5 to 5.6). Conclusions Therapeutic hypothermia improved neurological outcome for unconscious adult patients with ROSC after out-of-hospital non-shockable cardiac arrest.&gt;
Abstract 330: Fluid Resuscitation Guided by Sublingual PCO2 During Hemorrhagic Shock in Swine
Authors: Jiefeng Xu, Linhao Ma, Xiaoye Lu, Xiaobo Wu, Shijie Sun, Wanchun Tang
Journal: Circulation (2012)

Introduction: Aggressive fluid resuscitation during hemorrhagic shock to restore normal levels of aortic pressure often results in volume overload. We investigated whether fluid resuscitation guided by sublingual PCO 2 (PslCO 2 ) would minimize volume overload without compromising the outcomes of hemorrhagic shock. Hypothesis: Fluid resuscitation guided by PslCO 2 reduces the volume of fluid resuscitation without compromising the outcomes of hemorrhagic shock when compared with the fluid resuscitation guided by blood pressure (BP). Methods: Ten male domestic pigs weighing between 34-37 kg were utilized. Forty-five percent of estimated blood volume (EBV) was removed over an interval of 1 hour. The animals were then randomized to receive fluid resuscitation based on either PslCO 2 or BP. In the PslCO 2 guided group, resuscitation was initiated when PslCO 2 exceeded 70 mm Hg and stopped when it decreased to 50 mm Hg. In the BP guided group, resuscitation was initiated when mean aortic pressure decreased to 60 mm Hg and stopped when it increased to 90 mm Hg. Ringer’s lactate solution (RLS) of 30 ml/kg was infused and followed with the shed blood if needed. All animals were observed for 72 hours. Results: In the PslCO 2 guided group, fluid resuscitation was required in only 2 animals with a significantly low volume of RLS without the need of blood infusion. However, in the BP guided group, all animals required a significantly larger volume of fluid including both RLS and blood. There were no differences in the 72 hours of survival and neurological alertness score between groups (Table). Conclusion: During hemorrhagic shock, fluid resuscitation guided by PslCO 2 significantly reduced the amount of resuscitation fluid without compromising the outcomes of hemorrhagic shock.
Abstract 326: Direct Ventricular Compression Improves Mechanical Synchrony of the Acutely Failing Heart
Authors: Benjamin A Schmitt, Nicholas J Garvin, Subbaraju Budharaju, David B Reynolds, Rebecca J Darner, Lawrence J Prochaska, Mark P Anstadt
Journal: Circulation (2012)

Introduction: Mechanical dyssynchrony during acute cardiac failure contributes to ventricular dysfunction. Direct Mechanical Ventricular Actuation (DMVA) provides non-blood-contacting augmentation of systolic and diastolic ventricular function. The purpose of this study was to determine if DMVA can improve mechanical synchrony in the acutely failing heart. Methods: New Zealand white rabbits (n = 10) were anesthetized, underwent sternotomy, and instrumented for arterial pressures and aortic flow. A 10 MHz transvascular ultrasound probe acquired two-chambered, long-axis transesophageal ventricular images. Heart failure (50% of baseline cardiac output) was modeled using a titrated Esmolol drip. Phenylephrine maintained mean arterial pressure between 60 -70 mm Hg as needed. LV images were analyzed using Siemens speckle tracking software. The LV was divided into six regions which were analyzed for peak strain rate and time to peak strain rate. Average peak systolic and diastolic strain rates were used to assess global myocardial function. Synchrony was determined by analyzing the standard deviation of regional time differences between peak systolic strain rates (dyssynchrony index). Results: Systolic and diastolic global strain rates were significantly reduced during failure and significantly augmented to near normal during DMVA support. Following a similar relationship, DMVA significantly improved mechanical synchrony during acute heart failure. Recovery strain rates and synchrony were significantly improved vs. failure but did not return to baseline values. Conclusion: DMVA effectively augments myocardial function in the acutely failing heart. The improvements in pump function are associated with normalization of mechanical synchrony. DMVA’s ability to restore mechanical synchrony during resuscitative ventricular support has favorable implications on cardiac recovery.
Abstract 323: G-Protein Coupled Estrogen Receptor 1 Activation Protects the Heart Against Ischemia/Reperfusion Injury by Inhibiting the mPTP Opening via PKC/ERK/GSK-3? Pathway
Authors: Bopassa Chrisostome, Rong Lu, Harpreet Singh, Bjorn Olde, Andree Krust, Fredrik Leeb-Lundberg, Ligia Toro, Enrico Stefani
Journal: Circulation (2012)

Estrogen effect can be mediated by three receptors: Classical estrogen receptors: alpha (ERα) and beta (ERβ), and recently identified G protein-coupled estrogen receptor1 (GPER1). We investigated the role of ERα, ERβ and GPER1 in mediating rapid estrogen-induced cardioprotection in male mice hearts subjected to ischemia/reperfusion using wild type (WT) and gene specific knockout animals. Isolated hearts from wild type (WT: C57BL/6NCrL), ERα -/- , ERβ -/- and GPER1 -/- were perfused using Langendorff apparatus with Krebs Henseleit buffer (control) or with the addition of estrogen (40 nM). Hearts were subjected to 18 min global ischemia followed by 60 min reperfusion. Cardiac function was recorded during the entire experiment and myocardial infarct size measured by TTC staining at the end of the reperfusion. Mitochondria calcium retention capacity (CRC) required to induce the mitochondrial permeability transition pore (mPTP) opening was assessed after 10 min reperfusion. Protein levels were measured by Western Blot in whole heart lysates after 5 min treatment just before ischemia, and after 10 min reperfusion. LY294002, U0126 and Chelerythrin-Cl were used as inhibitor of PI-3K/Akt, MAPK/ERK and PKC translocation, respectively. In WT, ERα -/- and ERβ -/- , estrogen treatment significantly improved cardiac functional recovery, reduced infarct size and improved mitochondrial CRC. However, estrogen effects were completely absent in GPER1 -/- . Estrogen treatment during 5 min before ischemia induced up-regulation of Akt, GSK-3β, and ERK 1/2 phosphorylation in WT mouse as compared with control but not in GPER1 -/- . However, after 10 min reperfusion estrogen effect was still oserved on GSK-3β, but not on Akt and ERK 1/2 . Chelerythrin-Cl, and U126, inhibitors of MEK and PKC translocation, respectively abolished estrogen-induced cardioprotection while LY294002, a PI-3K inhibitor, did not prevent estrogen-induced cardioprotection in observed in WT. P&lt;0.05 and n=4-7. Rapid activation of GPER1 induces cardioprotection effect against ischemia/reperfusion injury. Estrogen effects through GPER1 are mediated by phosphorylation of GSK-3β and ERK 1/2 , PKC translocation, and inhibition of the mPTP opening.
Abstract 18980: Cardioprotective Role of NO Derived from Sodium Nitrite in Attenuating Severity of Chronic Ischemia-Induced Heart Failure
Authors: Shashi Bhushan, Kazuhisa Kondo, Maxim A Zlatopolsky, James J Greer, John W Calvert, David J Lefer
Journal: Circulation (2012)

Background: Nitric oxide (NO) bioavailability is reduced in the setting of congestive heart failure. Nitrite (NO 2 ) is a critically important NO intermediate that is readily metabolized to NO during ischemic conditions. We have previously demonstrated that NO 2 - ameliorates acute myocardial ischemia/reperfusion (MI/R). However, no evidence exists as to whether increasing NO bioavailability through NO 2 - therapy attenuates chronic heart failure following acute myocardial infarction. Methods: Male C57/BL6J Mice (n=13-15 per group) at 12-14 weeks of age underwent 60 min. of myocardial ischemia (MI) induced by transient LCA occlusion followed by 4 weeks of reperfusion. Sodium nitrite (NaNO 2 ) or saline vehicle (VEH) was administered at a dose of 165 µg/kg (intracardiac injection) at reperfusion and then daily for 4 weeks in the drinking water (50 mg/L or 100 mg/L). Two-dimensional echocardiography was performed at baseline and 4 weeks post MI to assess left ventricular (LV) dimensions and ejection fraction (EF). Myocardial and blood NO metabolite levels were measured using HPLC and chemiluminescence methods. Results: Both circulating and cardiac NaNO 2 levels were increased in mice treated with oral NaNO 2 . Furthermore, NaNO 2 (100 mg/L) significantly preserved LVEF (47 ± 4% vs. 32 ± 4%, p &lt; 0.01) and improved left ventricular LV dimensions (LVEDD/LVESD; 4.0/3.1 mm vs. 4.5/3.9 mm, p&lt;0.05) at 4 weeks when compared to VEH. Conclusions : These data demonstrate that sodium nitrite therapy significantly improves LV function during heart failure following acute myocardial infarction. Studies are currently underway to define the cellular and molecular mechanisms by which NO derived from NaNO 2 protects the myocardium in the setting of heart failure.
Abstract 19823: Whole-Exome Sequencing in an Extended Family with Myocardial Infarction Identified a Potential Functional Mutation in PDE5A
Authors: Ingrid Brænne, Anja Medack, Klaus Stark, Sarah Field, Salih Tuna, Panos Deloukas, Nilesh J Samani, Christian Hengstenberg, Heribert Schunkert, Jeanette Erdmann
Journal: Circulation (2012)

Objective: Despite the enormous success of genome-wide association studies (GWAS), only a small fraction of the expected heritability for CAD and MI is explained so far. One drawback of GWAS is the lack of power to detect rare yet functionally important variants. Rare variants may however cluster in families. Aim: Studying extended MI-families by means of whole-exome sequencing (WES) may give new insights in the pathophysiology of CAD. Methods: We analyzed a German MI family with 9 affected and 46 unaffected individuals. We sequenced three distantly related affected family members using the Agilent SureSelect 38 Mb Kit. Variants were validated by Sanger re-sequencing. Results and Discussion: The three sequenced individuals shared 22,048 variants. Filtering for SNPs with a frequency &gt;1% in dbSNP left 2,845 variants. Of these, 988 variants are conserved (46 Way) and again 772 were located outside of regions of segmental duplication. 23 potentially function-altering variants were left after filtering based on an avsift score &gt;0.05 and ,,HIGH“ effect predicted by Annovar and SNPEFF respectively. To further reduce the number of variants, we focused on those not in dbSNP. This approach left two variants of which only one was successfully validated by Sanger re-sequencing. The variant is a new single nucleotide substitution (A&gt;T) that causes a stop-codon (g.120548312T&gt;A) in the first exon of one of the three known PDE5A transcripts. In addition, the variant lies in a strong regulatory region and may hence also influence transcription. We genotyped all family members available for genetic analysis and found that the variant co-segregates with the disease. Previous independent linkage studies show that the variant lies in a linkage region (LOD=2.63; p=0.0003) which supports the hypothesis that the identified variant is truly disease-causing. To determine whether the variant is found in unrelated individuals we genotyped 2,012 cases and 2,808 controls. Of the cases 0.1% carry the variant, of the controls only 0.03% . Conclusion: We have in this study identified a new potentially MI-causing variant in the PDE5A gene using WES. Upcoming functional analyses will help us to unravel the disturbed mechanisms and provide us with new insights in the pathogenesis underlying CAD.
Abstract 334: Noninvasive Carbon Dioxide Monitoring During Acute Lung Injury Due to Smoke Inhalation and Burns
Authors: Slava M Belenkiy, Katherine M Ivey, Andriy I Batchinsky, Thomas Langer, Vittoria Vecchi, Jose Salinas, Leopoldo C Cancio
Journal: Circulation (2012)

Introduction: We evaluated the accuracy of transcutaneous CO 2 (tPCO 2 ) and end-tidal CO 2 (ETCO 2 ) monitors in a porcine model of Acute Lung Injury (ALI) due to smoke inhalation and burns. Methods: Anesthetized pigs (n=6) received smoke inhalation injury and 40% total body surface area (TBSA) full-thickness flame burns. They were then transferred to an animal ICU. A SenTec system was used for tPCO 2 measurements, and an Oridion Capnostream for ETCO 2 . PaCO 2 was analyzed with an i-STAT blood analyzer. These measurements were recorded every 6 hrs and as needed. Data are means ±SD, and were analyzed (Bland-Altman and linear regression) both pre- and post-ALI, as well as during hemodynamically stable and unstable (unstable = mean arterial pressure (MAP) &lt; 60 mmHg or receiving i.v.norepinephrine). Results: See Table. All animals developed ALI (PaO 2 /FiO 2 &lt;300) at 23.5±15.1 hrs. Mean survival time was 46.3 ± 26.3 hrs. Conclusions: In a porcine model of ALI and under hemodynamically stable conditions, tPCO 2 was an acceptable surrogate for PaCO 2 and was more accurate than ETCO 2 . Overall, tPCO 2 monitoring is a consistent noninvasive substitute for PaCO 2 . Its shortcomings include a slower response time to PaCO 2 changes than ETCO 2 .
Abstract 204: Incidence Rate of Shockable Cardiac Arrest Varies Considerably Among Facilities
Authors: Hiroshi Kaneko, Tetsuo Hatanaka, Aki Nagase, Tetsuya Sakamoto, Seishiro Marukawa
Journal: Circulation (2012)

Introduction: Despite wide proliferation of AEDs in public facilities in Japan, only ∼1% of patients with out-of-hospital cardiac arrest receive defibrillation attempts using on-site AEDs. In the decision-making process as to what specific facilities may merit the placement of on-site AEDs, each facility needs to estimate a site-specific incidence rate of cardiac arrest. We hypothesized that the incidence of cardiac arrest per person-year differs significantly across types of facilities. Methods: Locations of cardiac arrest from 2003 through 2010 were abstracted from the database of the Fire Department of Nagoya City (population of 2.2 million; ∼2,000 cardiac arrests annually). The locations of cardiac arrests were tallied and grouped into 36 facility categories consistent with the Fire Service Act, and the number of cardiac arrests within each category was determined. Data on the number of visitors/workers/residents for each category were obtained from governmental databases and annual financial reports. The incidence rate was calculated as the number of cardiac arrest per 1 billion person-years. Results: In 18 facility categories, the database for cardiac arrest and the database for numbers of visitors/workers/residents coincided in the categorization rules. For each of the categories, the incidence rate of cardiac arrest with initial shockable rhythm was calculated (the top 7 categories are shown in the table). Conclusions: The incidence rate of shockable cardiac arrest varies considerably among facilities. Such variation in the incidence rate may reflect divergence among facilities in terms of characteristics of visitors/workers/residents, average duration of stay, intensity of physical or emotional activities, etc. These incidence rates, combined with the expected numbers of visitors/workers/residents, may be used to estimate anticipated numbers of shockable cardiac arrests per facility and the need for placing on-site AEDs.
Abstract 19619: A Novel Role of the Valosin-Containing Protein (VCP) In Cardiac Protection via Regulation of Mitochondrial Protein Nitrosylation
Authors: Eman R Rashed, Huacheng Dai, Hongyu Qiu
Journal: Circulation (2012)

Introduction: We have previously shown that over expression of the valosin-containing protein (VCP) in a cardiac specific transgenic (TG) mouse conferred a cardiac protection against ischemia as well as a dose dependent induction of inducible isoform of nitric oxide synthase (iNOS). However, the link between iNOS and the VCP-conferred cardiac protection remains unclear. Hypothesis: Our hypothesis is that VCP elicits cardiac protection by the induction of inducible isoform of nitric oxide synthase (iNOS), leading to the nitrosylation of mitochondrial proteins, resulting in the stimulation of mitochondrial respiration. Methods and Results . Biotin switch was used to identify S-nitrosylated proteins in the VCP TG mouse heart, which a majority of them were found to be mitochondrial proteins involved in the regulation of mitochondrial metabolism and respiration, including succinate semialdehyde dehydrogenase, mitochondrial heat shock protein 60, cytochrome c1. One of the most upregulated nitrosylated proteins was Malic enzyme 3 (Me3), an enzyme which catalyzes the oxidative decarboxylation of malate to pyruvate, was significantly increased by 2.5 fold (p&lt;0.01) in TG mouse compared to WT, although the total protein level was unchanged. Reciprocally, we found a significant decrease by 50% of S-nitrosylated complex I subunit, (NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 9 (NDUFA9)), in VCP TG heart compared to WT (p&lt;0.05). Since S-nitrosylation serves to inhibit Complex I activity, this reduction indicates a reversal of this inhibition by VCP. Basal cardiac mitochondrial respiration was measured using a Clark type oxygen electrode on VCP TG mice (n = 5) and wild-type (WT) mice (n = 6). Mitochondrial State 3 respiration was significantly (p &lt; 0.01) elevated in the VCP TG (72 ±2 nmol O2/min/mg prot) mice compared to WT (45.9 ±6 nmol O2/min/mg prot) with no difference in State 4 or State 2, indicating that VCP over expression enhances the capacity for ATP production without a change in basal levels of respiration. Conclusion: In conclusion, our data reveals a critical and novel role of VCP in mediating cardioprotection through the stimulation of mitochondrial function by inducing nitrosylation of mitochondrial proteins via increased expression of iNOS.
Abstract 19115: Cardiac MR Evaluation of Diffuse Myocardial Fibrosis in Children and Young Adults with Congenital Aortic Stenosis
Authors: Susan M Dusenbery, Michael Jerosch-Herold, Tal Geva, Jane W Newburger, Andrew J Powell
Journal: Circulation (2012)

Background: Diffuse myocardial fibrosis (DF) in adults with aortic stenosis (AS) is associated with heart failure, arrhythmias, and mortality; however, little is known about its role in younger patients with congenital AS. Study aims were to apply for the first time a recently validated cardiac magnetic resonance (CMR) extracellular volume fraction (Vec) measurement technique to quantify DF in children and young adults with AS and to explore associations between DF and indices of diastolic function. Methods: All pts who had a CMR with myocardial T1 measurement, were &lt;30 yrs, and had congenital AS with a peak Doppler gradient ≥20 mm Hg at any time prior to the CMR were included. The Vec, a measure of DF, was calculated in the mid-LV by measuring T1 values for blood pool and myocardium before and after gadolinium with a modified Look-Locker technique, and adjusting for hematocrit. Vec results were compared to published values in healthy volunteers (n=14). Results: Thirty-five pts met inclusion criteria with a median age of 15 yrs (1.7-27), peak AS gradient of 36 mm Hg (0-90), and aortic regurgitation (AR) fraction by CMR of 25% (0-48). Vec was significantly greater in AS pts than volunteers (0.29 ± 0.06 (range, 0.22-0.48) vs. 0.25 ± 0.02 (range, 0.22-0.28), p&lt;0.001) with 13 pts (37%) having an increased Vec (&gt;0.28). Factors associated with higher Vec included any AS intervention (p=0.031), late gadolinium enhancement (p=0.028), and younger age at CMR (r=-0.37, p=0.031). Vec was not significantly associated with AS gradient, AR fraction, indexed LV mass, mass/volume ratio, or ejection fraction at the time of CMR, or a history of cardiac surgery. Increased Vec was significantly correlated with echo indices of diastolic dysfunction: E’ (r=-0.55, p=0.002), E/E’ (r=0.62, p&lt;0.001), and indexed LA volume (r=0.56, p=0.001). In the 24 pts with contemporaneous cath data, Vec did not correlate with LV end-diastolic pressure (r=0.09, p=0.72). Conclusions: In this cohort of children and young adults with congenital AS, an elevated Vec indicating DF was present in approximately one-third. Increased Vec was associated with aortic valve interventions, late gadolinium enhancement, and echo indices of diastolic dysfunction. For congenital AS, therapies to reverse DF may be warranted.