tbuckley/cabot-search huggingface dataset:
Abstract 19553: Statin Therapy is Associated with Improvement of Osteoporosis, Adipose Tissue and Coronary Atherosclerosis
Authors: Naser Ahmadi, Fereshteh Hajsadeghi, Vahid Nabavi, Sulkha Ramayya, Michael Fahmy, Ajay Bhandari, John Sanchez, Andrew Choi, Ramin Ebrahimi, Matthew Budoff
Journal: Circulation (2012)

Background: There is a significant associations of osteoporosis with atherosclerosis. This study evaluates the effect of statin therapy on osteoporosis, coronary artery distensibility(CDI), vulnerable plaque composition and epicardial adipose tissue in subjects with intermediate risk for coronary artery disease. Method: Two hundred and forty subjects underwent computed tomography angiography (age: 61±9 years, 60% male). CDI in left anterior descending artery (LAD) was defined as: [(Early-diastole - mid-diastole lumen cross section area(CSA))/(lumen CSA in mid-diastole x central pulse pressure) x1000]. Vulnerable plaque composite score(VPS) was measured using semi-quantified plaque volume (none, localized, intermediate, or diffuse) and severity of diseased coronaries (normal, mild, moderate, or severe) in non-calcified and mixed plaques based on AHA 15-segment model. Trabecular-BMD(mg/cc) of four consecutive thoracic-vertebrae below the left-main coronary artery slice-level was assessed. EAT, adipose tissue inside pericardial sac, was measured from slice level 15 mm above to the bottom of the heart. Results: Osteoporosis was significant correlated with impaired CDI, VPS and EAT(p&lt;0.05). Statin therapy was associated with increase in CDI and BMD (p&lt;0.05). Similarly, statin therapy was associated with decrease in VPS of vulnerable plaque as well as EAT (p&lt;0.05) (Table). Significant association between decrease in VPS of vulnerable plaque, and increase in BMD in response to statin therapy was observed, in which statin therapy was associated with 46% decrease in risk of osteoporosis and VPS (relative risk: 0.54, 95%CI:0.41-0.95, p=0.01)). Conclusion: There a significant and independent association between decrease in EAT, VPS of vulnerable plaques, coronary vascular function improvement, and increase in BMD in response to statin therapy. This highlights the dual beneficial cardio- and osteoporosis-protective effects of statin therapy.
Abstract 19524: The Cardioprotective Phenotype in Mammalian Hibernators is Associated with Attenuation of Reperfusion-Induced Nuclear Factor-Kappa B Regulated Myocardial Inflammation
Authors: Mihai V Podgoreanu, Qing Ma, Zhiquan Zhang, James Bain, Christopher B Newgard, Matthias Riess, Brian M Barnes
Journal: Circulation (2012)

Using an experimental model of surgical deep hypothermic circulatory arrest (DHCA), we hypothesized that hibernating arctic ground squirrels (AGS) display reduced myocardial injury following I/R compared to a non-hibernator (rat) through reduced NF-kB signaling and myocardial inflammation. We further explored the role of myocardial accumulation of ceramides, known regulators of NF-kB inflammatory signaling, in the hibernator cardioprotective phenotype. Methods: Euthermic AGS aroused from torpor and rats underwent DHCA (45min, with 3 or 24h reperfusion) or sham. We compared between species/time points by two-way ANOVA: 1) biochemical severity of myocardial injury (plasma HFABP, TnI, ELISA); 2) myocardial apoptosis (activated caspase-3, immunostaining; TUNEL); 3) myocardial NF-kB activation (transcription factor binding assay; nuclear translocation) 4) myocardial cytokine expression and leukocyte extravasation; 5) myocardial PPARa activity (ELISA); 6) myocardial levels of 12 ceramides (MS) Results: Compared to rats, AGS displayed robust ischemic tolerance following DHCA (Fig A). This was accompanied by reduced NF-kB DNA binding activity and nuclear translocation (Fig B), as well as decreased expression of downstream inflammatory cytokines. Significant post-I/R accumulation of 4 species of sphingoid base ceramides and 1 monohexosyl ceramide was found in rat vs AGS. Preservation of myocardial PPARa activity occurred in AGS, but was significantly downregulated in the rat (Fig B). Conclusion: We found an association between the hibernator cardioprotective phenotype and differences in myocardial activation of NF-kB inflammatory signaling. Mechanistically, this was associated with a) accumulation of several species of ceramides in rat vs AGS hearts, previously implicated in triggering mitochondrial dysfunction and apoptosis following I/R; and b) preservation of PPARa activity in AGS, with known dual metabolic anti-inflammatory effects.
Abstract 19544: Rate and Magnitude of Atrial Remodeling in Permanent Atrial Fibrillation
Authors: Christina Luong, Michael Y Tsang, John Jue, Kenneth G Gin, Parvathy Nair, Pui-Kee Lee, Marion E Barnes, Min Gao, Teresa S Tsang
Journal: Circulation (2012)

Background: Atrial fibrillation (AF) is associated with progressive enlargement of atrial size. Yet, the rate of change in left atrial (LA) and right atrial (RA) size is poorly defined. Methods: This cohort study included 51 patients with a history of permanent AF who had serial transthoracic echocardiograms performed between 2005 and 2010 at Vancouver General Hospital in British Columbia, a large university-based tertiary care hospital. Each had at least 3 transthoracic studies completed and had adequate views for assessment of LA and RA volume. Echocardiographic measurements were performed offline by one person using standardized methodology. Apical 4-chamber LA and RA volume by Simpson’s method was used for assessment of atrial size. Linear mixed effects modeling was used in analyzing changes over time. Results: Of the 51 subjects who underwent 183 studies in total, 28 were men (55%). The mean age at study entry was 72±10 yrs (47-85 yrs). The mean follow-up time was 3.2±2.9 years. The findings for the first 3 consecutive studies for these patients are shown in the attached table. There was a significant increase in LA and RA volume; the increases were 2.98 mL/m2 per year (95% CI 1.23-4.73, P&lt;0.0001) and 1.25 mL/m2 per year (95% CI 1.01-1.61, P&lt;0.0001) respectively. In parsimonious models adjusting for age, sex, and length of follow-up, left ventricular ejection fraction of less than 50% at first study was associated with a significantly more rapid increase in LA volume over time (P&lt;0.001). Conclusion: Both LA and RA volume increased over time in patients with permanent AF. The absolute magnitude of increase appeared greater, and the rate of change faster, for LA than RA volume. Further studies are needed to determine the factors that mediate these changes and their reversibility.
Abstract 19558: An Increase in Visceral Adipose Tissue Attenuation After a One-Year Lifestyle Intervention in Men with Features of the Metabolic Syndrome is Related to Improvements in Lipid Profile Independent of the Reduction in Visceral Adiposity
Authors: Julie-Anne Nazare, Jessica Smith, Anne-Laure Borel, Isabelle Lemieux, Natalie Alméras, Jean Bergeron, Angelo Tremblay, Paul Poirier, Jean-Pierre Després
Journal: Circulation (2012)

Background: On the basis of its specific attenuation range (expressed in Hounsfields units, HU), visceral adipose tissue (VAT) can be identified and quantified by computed tomography (CT). In addition, cross-sectional studies have suggested that mean VAT attenuation in HU could reflect variation in VAT density. Objectives: The present study examined: 1) the effect of a one year lifestyle modification program on VAT attenuation in a sample of abdominally obese subjects with features of the metabolic syndrome, 2) whether changes in VAT attenuation were independently associated with improvements in the cardiometabolic risk (CMR) profile, beyond the reduction in VAT area. Methods: From the 144 subjects initially recruited, 109 men with features of the metabolic syndrome (age: 48±9 y, waist circumference: 108±9 cm, triglycerides: 2.46±0.92 mmol/L) who had an abdominal CT scan at the L4-L5 level at both baseline and after one year of lifestyle intervention were included in the present analyses. VAT area and VAT attenuation were assessed as well as a comprehensive CMR profile. Results: After one year of the lifestyle intervention, VAT attenuation significantly increased (+5.6 ± 3.9 HU, p&lt;0.0001). One-year changes in VAT attenuation were significantly correlated with changes in VAT area (r=-0.62, p&lt;0.0001), triglycerides (r=-0.40, p&lt;0.0001), HDL cholesterol (r=0.35, p=0.0002), apolipoprotein B (r=-0.42, p&lt;0.0001) and HOMA-IR (r=-0.24, p=0.01). Multiple regression analyses including changes in both VAT attenuation and VAT area showed that only VAT attenuation was an independent correlate of changes in triglycerides, HDL cholesterol and apolipoprotein B, whereas VAT area alone explained the variance in changes in HOMA-IR. Conclusion: The increase in VAT attenuation after one year of lifestyle intervention is independently associated with improvements in lipid profile, beyond the reduction in visceral adiposity.
Abstract 19574: Overexpression of Active Katp Channels in Adult Mouse Hearts Leads to Conduction Block and Heart Failure
Authors: Haixia Zhang, Keita Uchida, Qiusha Guo, Feng Chen, Colin G Nichols
Journal: Circulation (2012)

ATP-sensitive potassium (KATP) channels are hetero-octamers of four inward rectified potassium channel subunits (Kir6.1 or Kir6.2) with four sulfonylurea receptor subunits (SUR1 or SUR2). Cardiac sarcolemmal KATP channels are normally closed by high intracellular ATP concentration and will activate under severe pathological conditions where intracellular ATP depletes. Double transgenic mice overexpressing both ATP-insensitive Kir6.2 [K185Q, ΔN30] and SUR1 have shown arrhythmia and premature death. The premature death prevented further investigation of the underlying mechanism. In the present study, the tamoxifen (Tx)-inducible Cre-ER system was introduced to control timing of Kir6.2 [K185Q, ΔN30] expression. Transgenic mice carrying αMHC-Cre-SUR1 were cross-bred with mice carrying myh6-Cre-ER and Rosa26-Kir6.2 [K185Q, ΔN30] (a loxP-flanked DNA STOP sequence was inserted before Kir6.2 transgene). Adult triple transgenic (TTG) as well as littermate double transgenic (DTG), single transgenic (STG), and wild type (WT) mice were injected with Tx and conscious ECG recordings were monitored daily. Prior to Tx induction, SUR1 overexpressing mice have a prolonged PR interval. Within one week after Tx induction, TTG mice show further PR prolongation progressing to 2° AV block and occasionally AV dissociation. TTG mice also displayed severe bradycardia and morphological changes in the ST segment, which were not observed in littermate DTG, STG or WT mice. Two weeks after Tx induction, TTG mice developed larger hearts (wet heart weight: tibia length of 8.9 vs. 7.7 mg/mm in SUR1 expressing mice, p&lt;0.05) and over half of the TTG mice developed edema throughout the body. TTG mice also showed higher mortality following induction (10 of 23 TTG deaths vs. 1 of 35 in littermates). H &amp; E staining of heart slices revealed larger intercellular volume in TTG but not in littermates. These results suggest that overexpression of both active KATP subunits in adult hearts leads to conduction block, possible alterations in repolarization patterns, heart failure, and higher mortality. This model reiterates and further defines the severe pathology of overactive myocardial KATP channels and now provides the necessary system in which to dissect the mechanistic basis.
Abstract 8783: Methylation of <i>FOXP3</i> In Regulatory T Cells is Related to the Severity of Coronary Atherosclerosis
Authors: Lei Jia, Jizheng Wang, Xiaojian Wang, Jingzhou Chen, Channa Zhang, Rutai Hui
Journal: Circulation (2011)

Objective: Regulatory T (Treg) cells play a protective role in experimental atherosclerosis. However, the role of Treg in the development of human coronary artery disease (CAD) is inconsistent. Demethylation in the DNA that encodes transcription factor forkhead box P3 ( FOXP3 ) is a prerequisite for the stable maintenance of suppressive properties in Tregs, which is also identified as the most specific marker for human Tregs. We aim to evaluate Treg levels in CAD patients by a novel method based on Treg-specific DNA demethylation within FOXP3 gene. Methods and Results: We included patients with acute myocardial infarction (AMI) and unstable angina (UA), and control subjects with normal coronary artery on angiography (NCA) in our study. Peripheral blood mononuclear cells were collected to determine Treg levels by both flow cytometry and PCR based DNA methylation analysis. We found that Treg levels that were quantified by the demethylation rate of Treg-specific demethylated region in FOXP3 gene, but not by flow cytometry, were univocally decreased in UA and AMI patients (NCA 4.22% ± 1.92%; UA 3.29% ± 1.45%; AMI 2.86% ± 1.26%). This decline was inversely related to the severity of CAD ( r =−0.308, P &lt;0.05). After adjustment for traditional risk factors, the association was still significant ( β =−0.336, P &lt;0.05). Furthermore, we detected the expression of DNA methyltransferases in CD4 + CD25 + Tregs sorted from included subjects. A significant increase of DNA methyltransferase3b was observed in CAD patients compared with normal controls. Treatment of CD4 + CD25 + Tregs with ox-LDL induced a 41% increase in the methylation of FOXP3 , accompanied with a more than 3-fold reduction of FOXP3 mRNA expression and increases in the expressions of DNA methyltransferase 3a and 3b. Moreover, the effect of ox-LDL on FOXP3 can be reversed by methyltransferase inhibitor (-)-epigallocatechin-3-gallate. Conclusion: Our data demonstrate that Treg cells are decreased in CAD patients and its reduction are associated with the severity of atherosclerosis. Ox-LDL decreases the expression of FOXP3 by DNA methylation. Thus, we confirm the important role of Treg cells in human CAD and suggest potential epigenetic regulation in the progression of atherosclerosis.
Abstract 19538: Integrin-Linked Kinase Regulates Cardiomyocyte Calcium Signaling through Protein-Protein Interaction with Sarcoplasmic Reticulum Calcium ATPase
Authors: Mark Li, Alexandra Traister, Shabana Aafaqi, Mingliang Lu, Jiahua Jiang, Gil Gross, Greg Hannigan, Jason Maynes, John Coles
Journal: Circulation (2012)

The transduction of mechanical load into dynamic changes in cardiac contractility is an incompletely understood process. ILK is a Ser/Thr kinase sarcomeric Z-disk protein with known mechanoreceptor function and cardioprotective properties. We hypothesized that ILK modulates calcium signaling in the cardiomyocyte to orchestrate both mechanoreceptor function and cytoprotection. ILK immunoprecipitates (IP) from transgenic mice with cardiac overexpression of ILK showed dose-dependent co-IP of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) confirmed by mass spectroscopy. Transduction of wild type ILK upregulated SERCA2a expression, and increased the phosphorylation (Thr17) of phospholamban, in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). ILK knockdown by siRNA decreased SERCA2a expression. The upregulation of SERCA2a was not prevented by the ILK kinase small molecule inhibitor QLT0267 suggesting a scaffolding rather than catalytic effect of ILK. The beat rate response to the SERCA2a inhibitor thapsigargin (TG) in iPSC-CMs was determined by long-term measurements of electrical impedance using the xCELLigence RTCA Cardio System (Roche). ILK transduction resulted in a faster baseline beat rate compared to untreated and vector control cells (p &lt; 0.01). TG significantly decreased beat rate with incomplete recovery after 30 hours (p &lt; 0.01). TG also reduced beat rate in ILK-transduced cells; however, the recovery to pre-TG baseline was accelerated by the ILK transfection (time to recover 10 hr; p=0.017), consistent with increased ILK-mediated SERCA2a activity. Cardiomyocyte calcium transients were measured in human iPSC-CMs using confocal microscopy and analyzed using Origin 8.6. ILK-transduced iPSC-CMs showed a significantly reduced time constant Tau (p&lt;0.01) and increased beat rate (p=0.01) compared to GFP-reporter control, consistent with SERCA2a-dependent increased rate of SR-mediated calcium uptake. We conclude that ILK regulates the expression and activity of SERCA2a in the cardiomyocyte. The demonstrated ILK-SERCA2a interaction provides an elegant mechanism for transduction of mechano- and stress- reception into dynamic, calcium-mediated changes in cardiomyocyte contractility.
Abstract 194: ST Changes on Continuous Telemetry Monitoring Before In-Hospital Cardiac Arrests
Authors: Duc H Do, Justin Hayase, Sunghan Kim, Xiao Hu, Noel G Boyle
Journal: Circulation (2012)

Introduction: In-hospital cardiac arrests (CA) remain a significant problem in the United States, affecting up to 750,000 patients annually. No more than 30% survive to discharge - this has improved little in the past 25 years, and is unlikely to improve further without major changes in treatment or better identification of at risk patients. Hence, there is significant interest in predicting impending CA to allow for intervention and possibly improve survival. In this retrospective study, we examine the characteristics of ST changes prior to CA to evaluate their utility in predicting CA. Methods: We evaluated all “Code Blue” events at UCLA Ronald Reagan Medical Center, a 520 bed tertiary care hospital, from April 2010 to April 2012. Inclusion criteria were: age ≥ 18, actual cardiac arrest, continuous telemetry data available for at least 3 hours immediately prior to CA. Up to 24 hours of telemetry data prior to CA was obtained and analyzed for each case. The arrhythmic mode and likely underlying cause, and presence/absence/duration of ST changes prior to CA were assessed for each case. Results: Of 65 cases meeting inclusion criteria, 19(29%) had progressive ST changes leading up to CA. The most likely cause was respiratory failure in 5(26%), multiorgan failure in 7(37%), acute cardiac failure (pulmonary embolism or myocardial infarction) in 5(26%), metabolic acidosis in 1(5%), and hemorrhagic shock in 1(5%). The arrhythmic mode of CA was pulseless electrical activity in 14(73%), bradycardic in 4(21%) and torsade de pointes in 1(5%). ST changes were detectable on telemetry monitoring in 6(32%) more than 60 minutes prior to CA, in an additional 6(32%) between 10 and 60 minutes prior to CA, and only in the last 10 minutes in a further 6(32%). Conclusions: ST changes leading up to CA occurred in one third of cases in this small series, mainly in PEA and bradycardic arrests. These were associated with multiple underlying medical conditions that may lead to cardiac hypoperfusion such as multiorgan failure on pressors, severe hypoxia, pulmonary embolism and myocardial infarction. In about two thirds of the cases in which ST changes were detectable, they were evident more than 10 minutes prior to onset of arrest, which may allow sufficient time for rapid intervention to prevent CA.
Abstract 19564: Role of Insulin Resistance and Excess Free Fatty Acids in Determining Endothelial Function in the Metabolic Syndrome
Authors: Todd S Perlstein, J. S Buck, Samoneh Kadivar, Joshua A Beckman
Journal: Circulation (2012)

Introduction: It is hypothesized that insulin resistance and endothelial dysfunction are reciprocally linked, though clinical data are limited. In particular, impaired endothelial insulin signaling is thought to result in endothelial dysfunction. Excess circulating free fatty acids (FFAs) are hypothesized to impair insulin signaling and result in both insulin resistance and the associated endothelial dysfunction. Aims: We examined the relationship between insulin resistance and endothelial function in the metabolic syndrome, a clinical state of insulin resistance. We also tested whether lowering of FFAs would improve endothelial function in persons with the metabolic syndrome. Methods: A total of 70 adults, 39 with the metabolic syndrome and 31 healthy controls, were studied. Subjects underwent euglycemic hyperinsulinemic clamp to measure insulin resistance (‘M’, mg/kg/min) and insulin-stimulated, endothelium-dependent vasodilation (%), as well as ultrasound-measured brachial artery flow-mediated dilation (FMD, %) to measure endothelial function. Thirty-five subjects, 18 with the metabolic syndrome and 17 controls, completed a double-blinded, placebo controlled crossover trial to examine the effects of 7 days of FFA lowering with acipimox on endothelial function and insulin resistance. Results: FFA levels were higher in the metabolic syndrome (p &lt; 0.01). Persons with the metabolic syndrome were insulin resistant compared with control subjects (M 5.1 (1.4) mg/kg/min vs. 9.7 (3.9) mg/kg/min, p &lt; 0.001), but FMD (10.9 (6.4) % vs. 10.7 (5.0)%, p = 0.92) and insulin stimulated vasodilation (36.9 (32.4) % vs. 86.6 (140) %, p = 0.31) were not different between groups. Acipimox therapy improved insulin resistance approximately 20% (p &lt; 0.05) but did not alter FMD (p = 0.67) or insulin-stimulated dilation (p = 0.26). Interpretation: These data demonstrate preserved endothelial function in persons with the metabolic syndrome despite severe systemic insulin resistance, and no effect of FFA lowering therapy on endothelial function despite improvement insulin sensitivity. Insulin resistance and elevated FFA levels may not be sufficient to cause endothelial dysfunction in humans.
Abstract 19552: Exercise-Induced Changes in Mechanotransduction Improve Myocardial Function in a Porcine Model of Chronic Occlusion
Authors: Mariappan Muthuchamy, Sanjukta Chakraborty, Xin Wu, Vandana Sarin, Cristine L Heaps
Journal: Circulation (2012)

Introduction: Exercise training has been shown to improve cardiac dysfunction both in patients and animal models of coronary artery disease; however, the underlying cellular and molecular mechanisms have not been completely understood. Transmembrane integrins that connect the extracellular matrix (ECM) and intracellular cytoskeleton are important for mechanotransduction in cardiomyocytes. Hypothesis: The binding probability and adhesion force between integrins-ECM, and their subsequent signaling that is cell stiffness will be increased in the myocytes from exercise-trained animals when compared to the sedentary group. Methods: Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of adult female Yucatan pigs. Twenty-two weeks postoperatively, myocardium was isolated from non-occluded and collateral-dependent regions of sedentary and exercise trained (treadmill run; 5 days/wk for 14 wks) pigs. We used atomic force microscopy for measuring cell stiffness and adhesion force between integrin and fibronectin (FN) in pig cardiomyocytes. In addition, integrins and FN expression were determined. Results: While exercise-trained pigs showed an increase in β1 integrin expression, β3 integrin expression was detected at an increased level in the sedentary myocardium. An increase in the amount of total FN and its fragments were found in the myocardium from collateral-dependent regions of exercise-trained and sedentary pigs when compared to the non-occluded myocardium regions. The peak bond rupture force of FN-integrin (46.4±0.3 pN vs 34.8±0.2 pN), the probability of adhesion (72% vs 54%) and cell stiffness (67.9±4.7 kPa vs 29.0±1.8 kPa) were significantly increased (p&lt;0.05; n=10) in myocytes from exercise-trained pigs when compared to sedentary hearts, which were prevented by function blocking α5 and αv integrin antibodies, respectively. Conclusion: Our data demonstrate that the differences seen in adhesion force, probability and stiffness between the sedentary and exercise-trained myocytes are due to interactions of FN to different integrins, e.g., αvβ3 in sedentary and α5β1 in exercise-trained cells, suggesting potential importance of mechanotransduction pathway for therapeutic development.