tbuckley/cabot-search huggingface dataset:
Abstract 8393: IL-18 Binding Protein (IL-18BP) Inhibits β-AR Induced Cardiomyocyte Hypertrophy <i>in vitro</i> and Myocardial Hypertrophy i <i>n vivo</i>
Authors: David R Murray, Srinivas Mummidi, Anthony J Valente, Charles A Dinarello, Patrice Delafontaine, Bysani Chandrasekar
Journal: Circulation (2011)

Crosstalk between the sympathetic nervous system and proinflammatory cytokines such as interleukin-18 (IL-18) plays a key role in the pathophysiology of the hypertrophied failing heart. Importantly, IL-18 can directly promote cardiomyocyte hypertrophy. IL-18 binding protein (IL-18BP) is a natural inhibitor of IL-18, and counters its biological effects. While β-AR stimulation induces IL-18, it is not known whether it also regulates IL-18BP. Here we demonstrate that the β-AR agonist isoproterenol (ISO) upregulates IL-18BP mRNA and protein expression in adult mouse cardiomyocytes in β 2 -AR/Gi-dependent manner. We cloned mouse Il18bp 5’ cis -regulatory region, and identified several putative transcription factor-binding sites, including CREB, C/EBP, NF- k B, and Sp1. While forced expression of dnp65 or kdIKKβ, or pre-treatment with mithramycin (Sp1 inhibitor) had no significant effect, forced expression of dnCREB or C/EBPβ knockdown markedly attenuated ISO-induced Il18bp transcription. ISO induced Il18bp promoter-reporter activity, and the deletion or mutation of CREB and C/EBP motifs reduced the response. ISO induced CREB and C/EBPβ DNA-binding activity, reporter gene activation, and in vivo binding to Il18bp promoter. ISO induced CREB and C/EBPβ activation via PI3K/Akt and ERK1/2. Importantly, ISO-induced hypertrophy (increased cell surface area and protein and not DNA synthesis) was blunted in cardiomyocytes isolated from IL-18BP Tg mice, by the forced expression of IL-18BP, and IL-18 neutralizing Ab. Further, ISO treatment in vivo was associated with Akt and ERK1/2 phosphorylation, CREB and C/EBPβ activation, and IL-18BP expression. Notably, ISO-induced myocardial hypertrophy was markedly attenuated in IL-18BP Tg mice. These data provide the first evidence that ISO induces mouse IL-18BP expression in cardiomyocytes via β 2 -AR/Gi-mediated Akt and ERK1/2-dependent CREB and C/EBPβ activation. Moreover, IL-18BP inhibits ISO-induced cardiomyocyte hypertrophy both in vitro and in vivo , likely via prevention of the biologic effects of IL-18. Thus, catecholamine induced expression of IL-18BP may play a protective role in the hypertrophied failing heart, a disease state characterized by sustained β-AR activation and IL-18 signaling.
Abstract 19155: The Impact of Expeditious Management of Perioperative Myocardial Ischemia in Patients Undergoing Isolated Coronary Artery Bypass Surgery
Authors: Piroze Davierwala, Alexander Verevkin, Sergey Leontyev, Martin Misfeld, Michael A Borger, Friedrich W Mohr
Journal: Circulation (2012)

Objective: To analyze the effect of immediate treatment of perioperative myocardial ischemia due to early graft failure in patients undergoing coronary artery bypass surgery (CABG). Patients and methods: Between January 2004 and December 2010, 7489 patients underwent isolated CABG at our institution. All patients (n=427, 5.7%) who showed evidence of perioperative myocardial ischemia (PMI) underwent emergent coronary angiography. PMI was characterized by an isoenzyme ratio of creatinine phosphokinase (CK/CK-MB) &gt; 10% and/or new ST-segment changes and/or recurrent episodes of ventricular tachycardia or fibrillation and/or hemodynamic deterioration with new regional wall motion abnormalities on echocardiography. One thousand and thirteen grafts and 1131 distal anastomoses were examined angiographically. Results: One hundred and seventy-six patients had a normal postoperative coronary angiography. Two hundred and fifty-one patients had stenoses or occlusions of 372 grafts. Revision CABG (group A) or percutaneous coronary intervention (PCI) (group B) was performed in 130 (51.8%) and 31 (12.4%) patients with graft stenosis or occlusion, respectively. Conservative therapy was implemented in 92 (36.6%) patients (group C). In-hospital mortality was 8.4% and 2.9% in patients with and without PMI (p &lt; 0.001). In the former group, in-hospital mortality was 10.4% and 5.7% in patients with and without graft failure, respectively (p=0.087). There was no difference in early and long-term survival between the 3 treatment groups for graft failure (p=0.8). On the other hand, 1- and 5-year survival in patients with no PMI (93.3±0.03% and 83.6±0.05%, respectively) was significantly better than those with PMI (92.3±0.1% and 82.4±0.2%, respectively) [p&lt;0.001 log rank]. When in-hospital mortality was excluded, there was no difference (p=0.1) in long-term survival between patients with and without perioperative myocardial ischemia. Conclusions: Perioperative ischemia is associated with increased in-hospital mortality in patients undergoing isolated coronary bypass surgery. Expeditious treatment of bypass graft stenosis or occlusion results in similar long-term survival to non-ischemic patients in hospital survivors.
Abstract 18719: The Morphologic and Topographic Characters of Pulmonary Vein Function in Relation to Velocity of Propagation and Diastology in Heart Failure with Preserved Ejection Fraction: A Dedicated Computed Tomography Study
Authors: Chun-Ho Yun, Shoting Hung, Chung-Lieh Hung
Journal: Circulation (2012)

The Morphologic and Topographic Characters of Pulmonary Vein Function in Relation to Velocity of Propagation and Diastology in Heart Failure with Preserved Ejection Fraction: A Dedicated Computed Tomography Study Background Diastolic dysfunction (DD), an assumed pathophysiologic intermediate between hypertension and heart failure (HF), has traditional be evaluated by echocardiography. However, data regarding the transition from DD to diastolic HF by assessing pulmonary vein morphological and topographic descriptions utilizing high spatial resolution computed tomography (CT) had been lacking. Materials and Methods We studies totally 124 subjects with conventional echo done and 64-slice CT performed. Of all, only 119 had data analyzable for both echo and CT methods. Sequential pulmonary veins orifice diameter and area from all four veins, both max and minimal value, during consecutive 1 R-R heart cycle were analyzed equally into 6 parts. Echo-derived left atrial and ventricular volume, high-frame rate tissue Doppler imaging (TDI), velocity of propagation (VP), estimated LV filling pressure (PCWP by E/E’) and some other diastolic indices were all obtained. ResultsM Of all 119 subjects (43 non-DD, 44 DD, and 32 DHF) entered for our final study (age: 59.3 ± 11.2, 37% female), we observed a graded enlargement, both max and minimum value, for all 4 pulmonary vein orifices across these three groups (all trend p&lt;0.05). In addition, linear relationship was observed between all 4 PV orifices area and echo-derived PCWP and VP (all p&lt;0.05) value, with both left superior and inferior PV maximum area further related to serum BNP level (both p&lt;0.05). When left superior and inferior PV maximum area were superimposed on LV mass index, PCWP and LA volume, there were significant increase in the DHF prediction model X2 value using likelihood ratio test (both p&lt;0.05). Conclusion Topographic PV size estimates using computed tomography rendered detailed assessment of structural and functional characters feasible, which correlated well with diastolic dysfunction. Our data suggested that CT-based PV measure may help identify subjects at risk even in a more early stage heart failure.
Abstract 17161: Bradycardia Elicits a Secondary Cai Elevation During the Action Potential (AP) Plateau Which is Spatially Heterogeneous, Prolongs AP Durations (APD) Further, Enhances Dispersion of Repolarization (DOR) and May Explain the Arrhythmogenic Properties of Bradycardia
Authors: Jong Kim, Jan Nemec, Rita Papp, Guy Salama
Journal: Circulation (2011)

Introduction: Bradycardia is known to prolong APD and DOR and is a factor that promotes arrhythmia in long QT type 2. In numerous conditions, spontaneous Ca 2+ release from sarcoplasmic reticulum has been shown to trigger early afterdepolarizations, ectopic activity that initiate arrhythmias, but the interplay between secondary Ca 2+ elevation (SCE) and membrane excitability has not been demonstrated in bradycardia. Objectives: To correlate voltage-depolarization during the AP plateau to SCE during bradycardia. Methods: Dual optical mapping of intracellular calcium transient (CaT) and AP was performed in Langendorff perfused rabbit hearts. After AV node ablation, CaT and AP dynamics were investigated at physiological (120 beats per minute (bpm)) and slow heart rate (50 bpm). Results: Upon changing HR from 120 to 50 bpm, APD gradually increased with a time-constant of 53.8±8.9 s, consistent with clinical QT measurements. The shift from 120 to 50 bpm elicited SCE during the AP plateau that was a) regionally heterogeneous, b) associated with enhanced depolarization of the AP plateau and was reversed by pacing at 120 bpm. Regional differences of SCE at 50 bpm were significantly increased (P&lt;0.01, n=7) and were correlated with dispersion of APD (r=0.9277±0.03, n=7). SCE and APD prolongation were more pronounced at the base of right ventricles than the apex of left ventricles (P&lt;0.01, n=7) (Figure). Suppression of SCE with K201 (1 µM/L) (to stabilize RyR2) reduced APD (P&lt;0.01, n=5) and DOR (P&lt;0.02, n=5). The molecular basis of the spatial distribution of SCE is currently being correlated to the intrinsic distributions of Ca 2+ handling channels and transporters (Cav1.2α, RyR2, NCX and SERCA2a) Conclusion: These data show for the first time that bradycardia elicits SCE which contributes to AP prolongation and its spatial heterogeneity increases DOR. These changes explain why bradycardia is a critical factor to trigger Torsade de Pointes in LQT2.
Abstract 18381: Ten Years Genetic Screening in a Large Cohort of Patients with Dilated Cardiomyopathy
Authors: Peter van Tintelen, Karin Y Spaendonck-Zwarts, Ingrid A van Rijsingen, Jan D Jongbloed, Ronald H Lekanne Dit Deprez, Jan G Post, Anneke van Mil, Imke Christiaans, Arthur A Wilde, Maarten P van den Berg, Yigal M Pinto
Journal: Circulation (2012)

Introduction: Idiopathic Dilated Cardiomyopathy (DCM) is familial in up to 35% of cases. Conventional genetic analysis of DCM is hampered by genetic heterogeneity because over 40 DCM related genes have been identified, most of them accounting for only a minority of cases. We hypothesized that conventional genetic screening in DCM index-patients lead to a modest mutational yield. Therefore we evaluated the results of genetic screening in DCM patients over the last 10 years. Methods: Clinical data, family history, and results of conventional genetic analyses in 418 DCM index-patients (224 familial, 173 sporadic and 21 with neuromuscular disease) were collected. We assessed the prevalence of mutations in DCM related genes and evaluated its clinical expression. Results: Thirty-five putative pathogenic mutations were identified in 82 of 418 DCM index-patients (20%). When analyzing subgroups, mutations were found in 25% of familial DCM, 8% of sporadic DCM, and 62% of patients with DCM and neuromuscular disease. Most prevalent were a PLN founder mutation (p.R14del) in 43 index-patients and 16 different LMNA mutations in 19 index-patients. The majority of these patients showed a gene-specific phenotype. Other genes involved were: MYH7 , DES , TNNT2 , DMD , TPM1 , DMPK , SCN5A , SCGB , and TNNI3 . Only one patient was double heterozygous. After a median follow-up of 40 months (interquartile range; 13 to 90 months), combined death from any cause, cardiac transplantation, and malignant ventricular arrhythmias in mutation carriers was worse compared to DCM patients without a known genetic cause (HR 2.0, 95% CI: 1.4-3.0). This seems to be mainly due to the arrhythmogenic phenotypes of LMNA and PLN mutation carriers. Conclusions: Extensive genetic analysis in a large and well-defined DCM cohort shows that the yield of genetic analysis is high (62%) in DCM patients with neuromuscular disease, moderate (25%) in familial DCM, and low (8%) in sporadic DCM. When resources are limited, specific clinical characteristics can be used to select cases for DNA analysis. These results form a solid base to develop next generation sequencing for DCM that will provide high-throughput, rapid and affordable genetic analysis for DCM.
Abstract 18944: Decreased Postprandial Active Glucagon-Like Peptide-1 Levels Correlate with Coronary Spastic Angina
Authors: Eiichi Akiyama, Seigo Sugiyama, Masaski Konishi, Toshimitsu Nozaki, Keisuke Ohba, Junichi Matsubara, Hitoshi Sumida, Koichi Kaikita, Kazuo Kimura, Satoshi Umemura, Hisao Ogawa
Journal: Circulation (2012)

Background: Coronary endothelial dysfunction plays an important pathogenic role in coronary spastic angina (CSA). Glucagon-like peptide-1 (GLP-1), a gut-derived peptide hormone, has attracted remarkable attention from clinical practice for diabetes care. Vascular cells express a GLP-1 receptor and exogenous GLP-1 infusion improves endothelial function in human and animal models, however, impact of endogenous active GLP-1 (aGLP-1) in CSA have not been clinically examined. Aim of the present study was to investigate association between plasma levels of aGLP-1 and CSA. Methods and Results: At fasting state or during 75g-oral glucose tolerance test (OGTT), we measured plasma levels of aGLP-1 sampled from peripheral vein in 33 CSA patients without obstructive coronary artery disease (age 58±16, female 48%), and 31 gender-, comorbidity-matched patients without ischemic heart disease (non-IHD, age 65±10, female 48%). There were no significant differences in clinical characteristics between CSA patients and non-IHD patients, except for age. The rate of patients with undetectable fasting aGLP-1 (&lt;2.0 pmol/L) was similar between CSA and non-IHD patients [6 (18%) vs. 5 (16%), P=0.83]. Fasting aGLP-1 levels were similar between CSA and non-IHD patients (3.6 [2.7-4.7] vs. 3.9 [2.7-5.0] pmol/L, p=0.58). During 75g-oral glucose tolerance test (OGTT) in non-diabetic patients, the aGLP-1 levels after glucose ingestion were significantly lower in CSA patients (n=30) than non-IHD patients (n=26) (30 min; 6.7 [4.8-12.4] vs. 12.0 [8.4-18.5], p=0.03, 60 min; 5.3 [3.0-10.7] vs. 7.6 [6.2-10.1] pmol/L, p=0.04). Area under the curve of aGLP-1 during OGTT was significantly smaller in CSA patients than non-IHD patients (697 [436-1022] vs. 941 [815-1602] pmol/L*min, p=0.03). Multivariate logistic regression analysis revealed that the lower aGLP-1 levels at 30 minutes during OGTT (below median, 9.0pmol/L) were independently associated with the presence of CSA (odds ratio; 0.17, 95%-confidence interval 0.04-0.65, p=0.01). Conclusions: Plasma levels of aGLP-1 during OGTT were significantly reduced in CSA patients. Decreased postprandial levels of endogenous aGLP-1 might play a key role in pathogenesis of CSA.
Abstract 8238: Relationship Between Red Blood Cell Omega-3 Fatty Acid Index and Bleeding During Hospitalization for Acute Myocardial Infarction
Authors: Adam C Salisbury, William S Harris, Amit P Amin, Kimberly J Reid, James H O'Keefe, John A Spertus
Journal: Circulation (2011)

Background: Omega-3 fatty acids have established cardiovascular benefits, but may also inhibit platelet aggregation and increase bleeding. If this platelet inhibition is clinically meaningful, patients with the highest omega-3 indices (red blood cell eicosapentaenoic plus docosahexaenoic acid), which reflect long-term omega-3 fatty acid intake, should be at the greatest bleeding risk, particularly in the setting of acute myocardial infarction (AMI) when patients are aggressively treated with antithrombotic agents and frequently undergo invasive procedures. Methods: We studied 1523 patients from 24 US centers who had their omega-3 index assessed at the time of AMI. The rates of serious bleeding (TIMI major &amp; minor) and mild-moderate bleeding (TIMI minimal) were identified in patients with low (&lt;4%), intermediate (4-8%) and high (&gt;8%) omega-3 indices. We used separate hierarchical modified Poisson models to identify the independent association between the omega-3 index and bleeding adjusting for age, gender, creatinine, heart failure, peripheral arterial disease, cath/PCI, and use of thienopyridines, warfarin, heparin, bivalirudin and GP IIb/IIIa inhibitors. Potential interactions between omega-3 index and antithrombotic medications were tested. Results: Omega-3 indices were high in 5.2% of patients, intermediate in 68.0% and low in 26.8%. There were no differences in bleeding across omega-3 index categories. There were also no significant differences in bleeding rates between those on omega-3 supplements and patients who were not (serious bleeding: 14/251 (5.5%) using omega-3 supplements vs. 103/1258 (8.2%) of patients who were not taking omega-3 supplements [p=0.16]; mild-moderate bleeding: 17/251 (6.8%) using omega-3 supplements vs. 67/1258 (5.3%) not taking omega-3 supplements[p=0.42]). There was no multivariable adjusted association between the omega-3 index and either serious (per 2% increase: RR 1.02, 95% CI 0.88-1.18) or mild-moderate (per 2% increase: RR 1.02, 95% CI 0.85-1.22) bleeding. There were no interactions between omega-3 index and antithrombotic medications (all p&gt;0.05). Conclusions: We found no relationship between the omega-3 index and bleeding in this large, multicenter cohort of AMI patients.
Abstract 18716: Survival for Infants with Critical Congenital Heart Defects in Atlanta, Georgia, 1979-2005: Temporal Trends and Prognostic Factors
Authors: Matthew E Oster, Kyung A Lee, Margaret A Honein, Tiffany Colarusso, Mikyong Shin, Adolfo Correa
Journal: Circulation (2012)

Introduction: Pulse oximetry screening for critical congenital heart defects (CCHD) was added to the Recommended Uniform Screening Panel for newborns in 2011. However, benchmark population-based data on trends in survival and prognostic factors for infants born with CCHD in the United States are limited. Methods: We performed a retrospective cohort study of infants born with structural congenital heart defects (CHD) between 1979 and 2005 and ascertained by the Metropolitan Atlanta Congenital Defects Program. Infants with non-cardiac defects or chromosomal disorders were excluded. After determining survival through 2006 via linkage with state vital records and the National Death Index, we estimated Kaplan-Meier survival probabilities for 12 CCHD phenotypes (7 primary and 5 secondary targets of screening) by birth era and timing of diagnosis. We then used stratified Cox proportional hazards models to assess potential prognostic factors, including birth era, timing of diagnosis, maternal age, birth weight, race/ethnicity, sex, and socioeconomic status. Results: One-year survival was 75.2% for those with CCHD (n=1336) vs. 97.1% for those with other CHD (n=3530; p&lt;0.0001), with a survival to 18 years of age of 68.8% for those with CCHD vs. 95.4% for those with other CHD (p&lt;0.0001). One-year survival for infants with CCHD improved from 67.4% for the 1979-1993 birth era to 82.5% for the 1994-2005 era (p&lt;0.0001). One-year survival was 71.7% for infants with CCHD diagnosed at ≤1 day of age (n=890) vs. 82.5% for those diagnosed at &gt;1 day of age (n=405; p&lt;0.0001). There was a significantly higher risk of one-year mortality for infants with earlier birth era, earlier diagnosis, maternal age &lt;30, and low birth weight (Table). Conclusions: One-year survival for infants with CCHD has been improving over time, yet mortality remains high. These benchmark data and identified prognostic factors may aid future evaluations of the impact of pulse oximetry screening on survival from CCHD.
Abstract 19116: Efficacy of a Small Molecule HDAC Inhibitor in a Model of Diastolic Dysfunction with Preserved Ejection Fraction
Authors: Maria A Cavasin, Kim Demos-Davies, Paolo Mascagni, Charles A Dinarello, Timothy A McKinsey
Journal: Circulation (2012)

Heart failure (HF) is a major health problem and growing economic burden worldwide. Of the patients with HF, ∼50% suffer from heart failure with preserved ejection fraction (HFpEF), also known as diastolic HF. Current standards-of-care for systolic HF provide little to no benefit to patients with HFpEF. Histone deacetylase inhibitors (HDACi) have been shown to improve systolic function in a variety of rodent models of HF. However, the impact of HDACi on diastolic function remains poorly understood. This study assessed the efficacy of an HDACi in a rat model of HFpEF. Dahl salt-sensitive (DSS) rats were fed low salt (LS, 0.4% NaCl) or high salt (HS, 4.0% NaCl) diets for 10 weeks. Rats were treated either with vehicle (LS and HS groups) or the pan-HDAC inhibitor, ITF2357, at 3 and 30 mg/kg (HS groups). Serial echocardiography was performed to assess left ventricle (LV) dimensions and function. At study endpoint, pressure-volume analyses were performed to further quantify effects of HS and HDACi on hemodynamic properties. HS feeding caused hypertension, cardiac hypertrophy and diastolic dysfunction, as shown by a 30% reduction of E/A and E’/A’ from baseline (measured by flow and tissue Doppler), a 27% increase of isovolumic relaxation time (IVRT), and a significant increase in LV end-diastolic pressure (LVEDP). EF was preserved in HS fed animals. ITF2357 was well tolerated and did not cause hematological side effects. ITF2357 dose-dependently prevented diastolic dysfunction of the heart; E/A and E’/A’ decreased 14% and 5% from baseline with low and high doses of ITF2357, respectively. Efficacy of ITF2357 was also observed at the level of IVRT and LVEDP. HDAC inhibition-mediated improvement in cardiac function and hemodynamics occurred independently of effects on cardiac hypertrophy and systemic hypertension. These data suggest that HDACs play a critical role in the pathogenesis of diastolic HF and that small molecule HDAC inhibitor have potential as novel therapeutics for HFpEF