tbuckley/cabot-search huggingface dataset:
Abstract 18845: PPARalpha/Sirt1 Complex is Involved in the Deterioration of Fatty Acid Metabolism During the Pathological Development of Heart Failure
Authors: Shinichi Oka, Peiyong Zhai, Takanobu Yamamoto, Junichi Sadoshima
Journal: Circulation (2012)

The major substrate shifts from fatty acid to glucose during the pathological development of heart failure, which may promote left ventricular (LV) dysfunction through energetic shortage. PPARα transcribes fatty acid oxidation (FAO) genes through the PPAR response element /direct repeat 1 (DR1), which is composed of two units of AGGTCA-like sequences that directionally align, separated by a single spacer. In addition to activating transcription through DR1, PPARα, in complex with Sirt1, suppresses transcription through an isolated single hexad element which is not configured into a DR1. Since many PPREs have imperfect DR1s in which one AGGTCA sequence is conserved but the other is not, we hypothesized that the PPARα/Sirt1 complex suppresses a subset of PPAR target genes harboring the imperfect DR1 under pressure overload (PO) conditions. Both PPARα and Sirt1 are upregulated in the heart during PO, and PO-induced cardiac systolic dysfunctions are attenuated in PPARα+/- (LV ejection fraction (EF) (%), WT 51, PPARα+/- 68*, p&lt;0.05 vs WT), and Sirt1+/- (LV EF (%), WT 40, Sirt1+/- 62*, p&lt;0.05 vs WT) mice. PO-induced downregulation of a subset of PPAR target genes harboring imperfect DR1s, such as Cpt2 and Mcad, was partly normalized in PPARα+/- (relative mRNA vs Wild type (WT) sham, Cpt2: WT TAC 0.7, PPARα+/- sham 1.1, PPARα+/- TAC 1.05*, Mcad: WT TAC 0.49, PPARα+/- sham 1.1, PPARα+/- TAC 0.77* p&lt;0.05 vs WT TAC) and Sirt1+/- (relative mRNA vs WT sham, Cpt2: WT TAC 0.37, Sirt1+/- sham 1.1, Sirt1+/- TAC 0.78*, Mcad: WT TAC 0.49, Sirt1+/- sham 1.2, Sirt1+/- TAC 0.73* p&lt;0.05 vs WT TAC) mice. Forced expression of PPARα resulted in increased occupancies of PPARα and Sirt1 on the proximal regions of the imperfect DR1s of the Cpt2 and Mcad promoters in the heart, indicating that PPARα recruits Sirt1 to the imperfect DR1. FAO activity was impaired by PO, but was partly normalized in PPARα+/- mice (relative FAO activity vs WT sham, WT TAC 0.50, PPARα+/- Sham 0.88, PPARα+/- TAC 0.89*, * p&lt;0.05 vs WT TAC). PPARα and Sirt1 cooperatively suppressed reporter gene activity driven by the imperfect DR1 in the Mcad promoter. These results suggest that PPARα and Sirt1 play a role in the impaired FAO in the failing heart though transcriptional suppression of imperfect DR1s.
Abstract 16855: Comparison of Non-ST Segment Myocardial Infarction One-Year Outcomes at Academic vs Non-Academic Hospitals
Authors: Sumeet Subherwal, Matthew T Roe, Dajuanicia Holmes, Laine Thomas, Karen P Alexander, Tracy Y Wang, Eric D Peterson
Journal: Circulation (2011)

Background: Prior studies have found academic hospitals provide more consistent evidence-based therapies and do more intervention in non-ST segment myocardial infarction (NSTEMI) patients than at nonacademic centers; whether these difference in care process translate into differences in short- or long-term outcome is unclear. Methods: We compared 12,381 NSTEMI patients age &gt;65 years treated at 107 academic hospitals with 30,954 NSTEMI patients treated at 341 non-academic hospitals from Feb 2003-Dec 2006 in CRUSADE Registry. Clinical data were then linked to Medicare longitudinal claims data. Short-term (30 days) and 1-year mortality among academic vs not centers was compared were after adjusting for clinical characteristics using a validated risk model (C-index 0.75). Results: Patients treated at academic centers had slightly more cardiac risk factors. Academic centers used more early invasive strategy (49% vs 43%), in-hospital PCI (36% vs 30%), and CABG (10% vs 8%) than nonacademic centers, and were more likely to use evidence based discharge therapies (ASA 95% vs 93%; beta blocker 93% vs 91%; statin 81% v 74%; ACI or ARB 69% vs 67%). The 30-day mortality was 9.8% overall (8.9% academic vs 10.2% nonacademic); 1-year mortality was 24.6% (23.3% academic vs 25.1% nonacademic.). Academic centers had superior 30-day and 1-year risk adjusted outcomes than nonacademic centers (Table). Conclusion: Patients with NSTEMI treated at academic centers received more aggressive evidence based treatments and interventions that were associated with improved short and long-term outcomes.
Abstract 213: Changing Hand Position During Manual Chest Compressions in Cardiac Arrest Affects the Hemodynamic Response: A Clinical Pilot Study
Authors: Eric Qvigstad, Øystein Tømte, Kjetil Sunde, Tore Skålhegg, Øyvard Sørensen, Jo Kramer-Johansen, Theresa Mariero Olasveengen
Journal: Circulation (2011)

Introduction: Optimal hand position during manual chest compressions (MCC) in cardiac arrest is unknown, but current Guidelines recommend a hand position on the lower half of the sternum. Recent imaging studies suggest that significant inter-individual anatomical differences exist, which might cause altered hemodynamic responses during standard MCC. In this prospective pilot study we wanted to assess the feasibility of utilizing capnography to optimize MCC and identify the optimal hand position in out-of-hospital cardiac arrest (OCHA). Materials and methods: Patients treated by the physician-manned ambulance for non-traumatic OCHA between February and May 2011 were included. Continuous EtCO 2 was measured by sidestream capnography (Lifepak 12, Physio Control, WA, USA). The three minute intervention period was initiated after endotracheal intubation. In the first minute chest compression rate and depth was optimized with hand-position at the recommended point (P0). A two-minute test phase followed; 50 compressions performed at three different sternal positions two cm below P0; P1 midline, P2 two cm to the left, P3 two cm to the right. The hand-position with the highest EtCO 2 value was used during the remaining resuscitation effort. EtCO 2 values are given as means (range), and presented in kPa (1 kPa = 7.5 mmHg). Results: Variations in EtCO 2 values could be documented in 15 OHCA patients. Average EtCO 2 values for 11 patients with cardiac etiology were 4.5 (1.9, 8.3), 5.3 (2.3, 9.6), 5.1 (2.4, 10.3), and 5.1 (2.5, 9.1) for P0 - P3, respectively, and for four non-cardiac etiology patients 4.8 (0.8, 9.7), 5.3 (0.8, 10.7), 5.8 (0.7, 10.3), and 5.1 (0.4, 8.4) for P0 - P3, respectively. The optimal EtCO 2 value was found in P0 in three patients, and in alternative hand positions in 12 patients, with the following distribution; P1: five patients, P2: five patients, P3: one patient, and in one patient P1, P2 and P3 was equally good. Conclusions: Monitoring and optimizing CPR performance and interventions using capnography was feasible. We could demonstrate inter-individual differences affecting hemodynamics, and there were no indications that one specific hand position could be expected to give optimal cardiac output in all patients.
Abstract 19129: Clinically Important Human Leukocyte Antibody Production is Uncommon in a Large Series of Pediatric Patients Supported with the Berlin Heart EXCOR Ventricular Assist Device
Authors: Matthew J O'Connor, Terry O Harville, Bobbie Rhodes, Sherry E Pye, Kenneth R Knecht, Michiaki Imamura, Elizabeth A Frazier, W R Morrow
Journal: Circulation (2012)

Background: Ventricular assist device (VAD) support is associated with human leukocyte (HLA) antibody production. This process, known as sensitization, has not been evaluated in pediatric patients supported with the Berlin Heart EXCOR VAD. Furthermore, the impact of sensitization in the era of single antigen assays for the detection of HLA antibodies is unclear. Methods: The records of all patients supported with a Berlin Heart EXCOR VAD at our institution from 4/2005-8/2011 were reviewed. Class I and II HLA antibodies were identified by fluorescence methods pre-/post-VAD, with antibody titer reported as median fluorescence intensity (MFI). MFIs were summed to derive a total MFI for each patient post-VAD. To determine changes in HLA antibodies pre-/post-VAD, MFIs pre-VAD were compared with those ≥14 days post-VAD, but prior to transplant, using Wilcoxon matched-pairs sign-rank test. Sensitization was present if MFI for any antibody was &gt; 1000 (threshold for a positive flow cytometric crossmatch). Results: The Berlin Heart EXCOR VAD was used in 36 patients; 20 met inclusion criteria and 13 had complete MFI data. Median duration of support was 56 (21 - 131) days; all survived to transplant. For the entire group, changes in total MFI for class I and class II HLA antibodies were not significant over the course of VAD therapy. For class I antibodies, 6/13 (46%) were sensitized pre-VAD, and 7/13 (54%) were so for class II antibodies; sensitization was maintained for the same antibodies in 4/6 for class I antibodies and 5/7 for class II antibodies. De novo sensitization, including new antibodies in presensitized patients, occurred in 9/13 (69%) for class I antibodies and 4/13 (31%) for class II antibodies. Only one patient, however, had a positive flow cytometric crossmatch at transplant to one class II HLA antibody that developed on VAD. No patient was denied an acceptable donor heart on the basis of elevated HLA antibodies. Conclusions: Using single antigen techniques, HLA sensitization is seen in approximately 50% of pediatric patients prior to initiating support with the Berlin Heart EXCOR VAD; nearly 70% developed de novo class I HLA antibodies on VAD. The clinical impact of such antibodies, however, appears to be limited in this population.
Abstract 187: U/T Wave Amplitude Ratio as an Indicator of Ventricular Arrhythmia Risk After Myocardial Infarction
Authors: Bei Wang, Petri Korhonen, Heikki Väänänen, Lauri Toivonen
Journal: Circulation (2012)

Objectives: This prospective study examined if abnormal repolarization presenting as increased U/T wave amplitude ratio predicts ventricular arrhythmias in patients with a recent myocardial infarction (MI) and moderate cardiac dysfunction. Methods and results: The study group (n = 126, 24 female) comprised patients with a recent MI and left ventricular ejection fraction (LVEF) &lt; 50%. Mean age was 60 years and LVEF 40%. A 120-channel body surface potential mapping (BSPM) registration was performed at hospital discharge. After signal-averaging of 250-300 beats, T- and U waves were identified and their amplitudes computed with a custom made software. QRS duration was computed for comparison. The study endpoints were arrhythmic events (sudden cardiac death, sustained ventricular tachycardia or ventricular fibrillation), cardiac mortality, and all-cause mortality. During a mean follow-up of 51 months 22 patients (17.3%) died with 13 (10.3%) suffering cardiac death. Twelve patients (9.5%) had an arrhythmic event. Patients with arrhythmic event had significantly higher U/T maximum amplitude ratios (the ratio between the highest U and T waves in BSPM) compared to those without (0.222 ± 0.129 vs. 0.129 ± 0.085, p = 0.012). U/T maximum amplitude ratio was a significant predictor of arrhythmic events (log-rank 9.3, p = 0.002) and in multivariate analysis it showed predictive power independently of clinical variables including age, sex, LVEF, bundle branch block, and diabetes with the hazard ratio (HR) of 5.84. QRS duration also showed prediction with the HR of 1.04. A combination of the parameters further improved prediction with an area under the ROC curve of 0.80 ± 0.07 (p &lt; 0.001). U/T maximum amplitude ratio did not predict cardiac or all-cause mortality. Conclusion: U/T wave amplitude ratio is a marker of ventricular arrhythmia propensity after MI. A combination of parameters describing repolarization and depolarization abnormalities further improves ventricular arrhythmia risk assessment.
Abstract 17152: Prophylactic Left Cardiac Sympathetic Denervation for Patients with Long QT Syndrome and Beta Blocker Intolerance
Authors: Katy M Harris, Christopher Moir, Michael J Ackerman
Journal: Circulation (2011)

Introduction: Long QT Syndrome (LQTS) is a potentially lethal, but highly treatable cardiac channelopathy. Current treatment options include pharmacotherapy (mostly beta blockers), device therapy (mostly implantable cardioverter defibrillators (ICDs)), and/or left cardiac sympathetic denervation (LCSD) with the majority of patients requiring only beta blocker therapy. However, beta blockers are not without side effects and beta blocker intolerance can have a profoundly negative effect on a patient's quality of life. Heretofore, a prophylactic ICD has been utilized for the patient with LQTS who can not tolerate high dose beta blocker therapy. Here we examined the role of a prophylactic LCSD rather than an ICD for the LQTS patient with beta blocker intolerance. Methods: In this IRB-approved study, we retrospectively reviewed the electronic medical record for 58 patients (28 male (48%), mean age at diagnosis 9.6 ± 9 years (yrs), mean baseline QTc 524 ± 73 ms, 93% genotype positive) with LQTS who underwent LCSD at our institution from November 2005 through May 2011 (mean age at LCSD 14.0 ± 9.8 yrs). Results: Out of 58, 19 patients (33%; 15 female (79%) had LCSD as primary prevention because of beta blocker intolerance and were older at LQTS diagnosis (15.1 ± 8 vs 7.0 ± 9 yrs;.p=0.001), older at LCSD (20.5 ± 8 vs 10.9 ± 9 yrs; p&lt;0.001), and had a shorter baseline QTc (493 ± 32 vs 539 ± 82 ms; p = 0.004) compared to the other 38 patients. Post-LCSD, 5/19 (26 %) had QTc-shortening of &gt;30ms. With an average follow-up of 1.3 ± 0.8 yrs, none of these patients have experienced a post-LCSD cardiac event even though 7/19 (37%) had at least 1 LQTS-associated cardiac event. Qualitatively, there has been a dramatic improvement in quality of life following LCSD with subsequent decrease in beta blocker dose in 13 or discontinuation of beta blockers altogether in 5. Conclusions: Prophylactic LCSD may provide a beta blocker-reducing or even sparing strategy without increasing risk in carefully selected patients. However, LCSD should not be viewed as curative or an ICD-alternative for high-risk patients. Among appropriately selected patients who are failing to tolerate beta blocker therapy, LCSD may be an acceptable, quality of life improving alternative to an ICD and its associated comorbidities.
Abstract 256: Therapeutic Hypothermia Decreases Arrhythmia Substrates by Attenuating Repolarization Current <i>I</i> <sub>K,ATP</sub> During Myocardial Ischemia
Authors: Joseph S Piktel, David S Rosenbaum, Lance D Wilson
Journal: Circulation (2011)

Background: While hypothermia is arrhythmogenic, the effect of therapeutic hypothermia (TH) performed after cardiac arrest on susceptibility to arrhythmias is not well understood. Clinically, patients do not have an increase in arrhythmias, and it is possible that TH may be cardioprotective. The repolarization current I K,ATP is activated only during ischemia where it heterogeneously shortens action potentials increasing dispersion of repolarization (DOR). Since I K,ATP is attenuated at cooler temperatures, we hypothesized that the antiarrhythmic effect of TH during ischemia may be mediated by attenuation of I K,ATP activation. To test this hypothesis, a model of no flow global ischemia in the canine wedge preparation was created to study the effects of ischemia on all cell types spanning the transmural wall. Methods: Optical action potentials were recorded transmurally with high spatial (1 mm), temporal (.5 ms) and voltage (.5mv) resolution. To block I K,ATP, glibenclamide (10 µmol) was used at both 36 o C (normal temperature, NT+ I K,ATP block, n=3) and 32 o C (TH+ I K,ATP block, n=3) during 15 min of no flow global ischemia. I K,ATP blockade was compared to prior controls (NT=7, TH=6). Action potential duration (APD) for epicardial, mid-myocardial, and epicardial cells, DOR, and conduction velocity (CV) were measured for all conditions. Results: There was no difference in DOR between the 4 groups prior to ischemia. NT+ I K,ATP block attenuated ischemia-induced increase in DOR compared to NT controls (22±4 ms to 25±5 ms vs. 30±5 to 57±5 ms, p=.002). NT+ I K,ATP block also attenuated ischemia-induced conduction slowing (44±2 to 30±3 cm/s vs 34±5 to 18±3 cm/s, p=.03). Addition of I K,ATP block to TH did not further attenuate the DOR or CV vs. TH alone (p&gt;0.05). Ischemia-induced epicardial conduction bock was attenuated by I K,ATP blockade, (0/3 I K,ATP block vs. 6/7 NT) Epicardial block was attenuated in both TH groups. Conclusions: I K,ATP blockade attenuates ischemia-induced DOR, conduction slowing, and epicardial conduction block, reproducing the effect of TH. This suggests that hypothermia-induced attenuation of I K,ATP may play a role in the mechanism of attenuation of ischemia-induced arrhythmias observed in TH.
Abstract 18420: Regional Variations in Processes of Care and Vascular Morbidity in Diabetic Adults in the United States
Authors: Puja B Parikh, Fabio Lima, Raymond Goldsteen, David L Brown
Journal: Circulation (2012)

Background : It is unclear whether geographic variation in processes of care and vascular morbidity exists among diabetics in the U.S. We sought to determine the extent of regional variations in processes of care and their association with vascular disease in a cohort of diabetic adults in the U.S. Methods and Results: The 2007 Centers for Disease Control Behavioral Risk Factor Surveillance Survey was utilized to identify a cohort of diabetic patients. Participant residence was classified based on four U.S. regions: (1) Northeast, (2) Midwest, (3) South, and (4) West. Demographic data, clinical history, processes of care (regular medical checkup, foot exam, eye exam, diabetic education, aspirin use, and antihypertensive use) and vascular morbidity for diabetics of each region were compared. Presence of vascular morbidity was based upon patient report of myocardial infarction, stroke, retinopathy, nonhealing foot sores or bilateral foot amputations. Among the 42,072 diabetics, 43.9% were from the South, while 18.7%, 18.7%, and 18.6% were from the Midwest, Northeast, and South respectively. Diabetics of each region differed significantly with respect to demographic characteristics, prior medical history, and processes of care. Vascular morbidity also differed among the regions such that the West had significantly lower rates of myocardial infarction, while the South had higher rates of stroke and diabetic retinopathy. On multivariate analysis, geographic region was found to be independently associated with processes of care. However, geographic region was not found to be independently predictive of vascular morbidity. Independent variables associated with vascular morbidity included older age (OR, 1.01; 95%CI, 1.01-1.02), male gender (OR, 1.55; 95%CI, 1.43-1.67), employment status, level of education, lower annual income, financial barriers to health care (OR, 1.48; 95%CI, 1.31-1.66), active smoking status (OR, 1.12; 95%CI, 1.03-1.23), hypertension (OR, 1.26; 95%CI, 1.16-1.37) and hypercholesterolemia (OR, 1.23; 95%CI, 1.14-1.34). Conclusion : Despite significant regional differences in process of care, no regional variations in vascular morbidity were observed in diabetic adults.
Abstract 19262: Hexokinase-2-Mediated Protection Against Cell Death is Dependent Upon Voltage-Dependent Anion Channels 2&amp;3
Authors: Kyle S McCommis, Christopher P Baines
Journal: Circulation (2012)

It is well known that tumor cells, which by definition do not die easily, have high rates of glycolysis. Hexokinase (HK), the first enzyme in glycolysis, is often overexpressed in these tumor cells, and is thought to be driving these high glycolytic rates. As HK is localized partly to the outer mitochondrial membrane (OMM), it has been proposed that HK may also be playing a role in these tumor cells’ resistance to death. Cardiomyocytes and murine embryonic fibroblasts (MEFs) express both HK1 and HK2 isoforms, both of which are capable of localizing to the OMM mainly through interaction with Voltage-Dependent Anion Channels (VDACs). Therefore, the purpose of this study was to assess whether overexpression of HK1 or HK2 could protect cultured cardiomyocytes or MEFs against H 2 O 2 -induced cell death. Additionally, HK2-mediated protection was also investigated in MEFs with genetic deletion of VDAC1 or VDAC3, or WT MEFs treated with a VDAC2 siRNA to significantly reduce VDAC2 protein levels. HK1 or HK2 protein expression and enzymatic activity was increased 2-3 fold by infection of cells with HK1 or HK2-encoding adenovirus. Control cells were infected with adenovirus encoding Β-Galactosidase. Cell death was induced by 50 μM H 2 O 2 in cultured neonatal rat cardiomyocytes (NRCM), or by 500 μM H 2 O 2 in MEFs. Overexpression of HK1 or HK2 reduced H 2 O 2 -induced death by ∼50% in both NRCMs and WT MEFs. Interestingly, overexpression of HK2 also protects MEFs devoid of VDAC1 by ∼50%. However, in MEFs with reduced VDAC2 expression or MEFs with deletion of VDAC3, HK2-mediated protection against H 2 O 2 -induced death is completely lost. Thus, it appears that the minor VDAC isoforms 2 &amp; 3 are essential, while the main VDAC1 isoform is dispensable for HK2-mediated protection against cell death.
Abstract 18789: Pharmacologically Induced Hypothermia with Cannabinoid Receptor Agonist WIN55,212-2 vs Mild Therapeutic Hypothermia in a Rat Model of Cardiac Arrest with Extracorporeal Life Support
Authors: Alessio Rungatscher, Daniele Linardi, Alice Giacomazzi, Maddalena Tessari, Tiziano Menon, Seth Hallstroem, Alessandro Mazzucco, Giuseppe Faggian
Journal: Circulation (2012)

BACKGROUND: To compare the hemodynamic, cardioprotective and metabolic effects of cannabinoid receptor agonist WIN55,212-2 with mild therapeutic hypothermia and normothermic control on post-resuscitation myocardial function in a rat model of extracorporeal life support (ECLS). METHODS AND RESULTS: Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted for 60 min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32°C) and WIN55,212 intravenous infusion (1 mg/kg/h). Cooling to 32°C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS. WIN55,212-2 administration produced pharmacologic hypothermia (32-34°C) and led to a significantly better recovery of the slope of the LV end-systolic pressure volume relationship (Ees) and Preload recruitable stroke work (PRSW) than hypothermia and normothermia: as percent of baseline 87+12 vs 54+9 vs 39+11 and 88+11 vs 59+10 vs 33+8 respectively (p&lt;.01). LV stiffness expressed by end-diastolic pressure volume relationship (EDPVR) was significantly lower after WIN55,212-2 administration (p&lt;.05). LV relaxation described by Tau was preserved after WIN55,212-2 treatment but not after hypothermia or normothermia (p&lt;.01). WIN55,212-2 and not hypothermia significantly increased phosphorylation of the kinase ERK1 and 2 (2.8+0.4 and 2.5+0.3 vs 0.5+0.2 and 0.4+0.1 -fold of baseline levels) (p&lt;.01). Both WIN55,212-2 and hypothermia but not normothermia increased phosphorylation of Akt. This resulted in a reduced cardiomyocyte apoptotic index (TUNEL, p&lt;.01). WIN55,212-2 but not hypothermia nor normothermia preserved high energy phosphates content and energy charge and reduced lactate plasma concentration. CONCLUSIONS: Pharmacologically induced hypothermia with WIN55,212-2 was more effective than mild therapeutic hypothermia in recovering myocardial function after ECLS and in improving myocardial protection through activation of the pro-survival kinases Akt and ERK1/2.