tbuckley/cabot-search huggingface dataset:
Abstract 4859: Genetic Polymorphism T45G on Adiponectin Gene Affects Cardiovascular Risk by Regulating Adiponectin Levels in Arterial Hypertension
Authors: Alexis S Antonopoulos, Dimitris Tousoulis, Charalambos Antoniades, Antigoni Miliou, Nikolaos Koumallos, George Hatzis, Michalis Demosthenous, Constantinos Bakogiannis, Elli Stefanadi, Costas Tsioufis, Nikolaos Papageorgiou, Gerasimos Siasos, Ioannis Ntarladimas, Christodoulos Stefanadis
Journal: Circulation (2009)

Background: Evidence suggests that adiponectin, an adipokine facilitating insulin action, has antiatherogenic effects, while it is inversely associated with obesity and the development of arterial hypertension. We examined the impact of T45G polymorphism on adiponectin gene, on the risk for coronary artery disease (CAD) and the expression of adipokines in heathy individuals and patients with CAD. We also examined its possible impact on the development of arterial hypertension. Methods: We studied 214 pts with CAD and 147 healthy controls. Genetic polymorphism T45G was determined by PCR, while circulating adiponectin, resistin and leptin were determined by ELISA, under stable clinical conditions. Results: The genotype distribution was different between CAD patients (GG: 5(2.3%) GT: 65(30.4%), TT:144(67.3%)) and controls (GG:2(1.4%), GT: 31(21.1%), TT:114(77.6%), p&lt;0.05). The risk for CAD was OR[95%CI]:0.595[0.368 – 0.964], p=0.03 for 45TT vs 45GT+GG. Importantly, The 45TT homozygotes had lower risk of arterial hypertension (OR[95%CI]:0.439[0.270 – 0.713], p=0.001). The 45TT genotype was associated with higher adiponectin levels (13.1±1.14pg/ml) compared to 45GT+GG (8.30±2.17pg/ml, p&lt;0.05) among healthy individuals, but not in CAD patients (13.67±0.97 vs 15.20±1.6pg/ml respectively, p=NS). Circulating resistin and leptin were not different between genotypes in the control group (6.88±0.40 and 13.6±0.85 in TT vs 6.16±0.65 pg/ml and 14.04±2.23 pg/ml in GT+GG, p=NS for both). In the CAD group, leptin levels were also similar between 45TT (15.2±1.8pg/ml) and 45GT+GG (14.1±3.2pg/ml, p=NS). Similarly, the 45TT genotype had similar resistin (5.9±0.3pg/ml) compared to 45GT+GG (7.69±0.81pg/ml, p=NS), in the CAD group. Conclusions: The 45TT genotype of adiponectin gene is associated with lower risk of arterial hypertension and decreased cardiovascular risk. This genotype has a striking effect on adiponectin expression in healthy individuals, but not in CAD patients. Therefore, homozygosity for the 45T allele decreases the risk for CAD by increasing circulating levels of adiponectin in healthy individuals, while its functional effect is masked after the establishment of coronary atherosclerosis.
Abstract 4188: Tumor Necrosis Factor-Alpha Regulates Adipose Tissue Macrophage Recruitment and CCR2 Expression
Authors: Peter Bodary, Scott Denstaedt, Kevin Wickenheiser, Yuechun Shen, Sarah Sharp, Minna Ohman, Daniel Eitzman
Journal: Circulation (2006)

Factors regulating adipose tissue macrophage recruitment are largely unknown. Since tnf-alpha may promote diabetes in obesity, we hypothesized that tnf-alpha may be an important mediator of both adipose tissue macrophage infiltration and CCR2 expression. To determine the role of tnf-alpha on adipose tissue macrophage infiltration we bred tnf-alpha deficient mice onto the leptin receptor deficient background and compared obese mice with and without tnf-alpha. Immunohistochemical analysis demonstrated significantly greater percentage of Mac-3 positive cells in the epididymal fat tissue of the obese tnf-alpha wild-type versus the obese tnf-alpha deficient mice (db/db tnf wt: 12.7 + 1.2 %; db/db tnf deficient: 6.5 + 1.0%; p=0.0026; n=3 per group). RT-PCR from adipose tissue revealed a three-fold elevation in CCR2 expression in the obese tnf-alpha wild-type mice compared to the obese tnf-alpha deficient mice. To determine whether CCR2 elevation in the adipose tissue was mediated by adipocyte tnf-alpha or macrophage tnf-alpha, we performed bone marrow transplantation from tnf-alpha deficient and wild-type mice to wild-type recipients. Fifteen weeks following transplantation we examined the expression of adipose derived cytokines via RT-PCR. Importantly, tnf-alpha was found to be reduced greater than 50% (n=5 per group; p=0.007) in the mice receiving tnf-alpha deficient bone marrow demonstrating an important contribution of macrophage tnf-alpha towards adipose tissue tnf-alpha. Furthermore, CCR2 expression was also significantly decreased in mice receiving tnf-alpha deficient marrow (tnf-alpha wt: 4.6 + 0.6; tnf deficient: 2.1 + 0.8; p=0.013; n=5 per group) providing evidence that macrophage derived tnf-alpha can mediate a significant change in CCR2 expression. These findings indicate a critical role for tnf-alpha towards adipose tissue inflammation.
Abstract 4165: Impact of the National Cholesterol Education Program Third Adult Treatment Panel Lipid-Lowering Recommendations on the Management of Patients With Non-ST-Segment Elevation Acute Coronary Syndromes
Authors: John L Petersen, Matthew T Roe, Jyotsna Mulgund, Michael A Blazing, JoAnne M Foody, Sidney C Smith, Robert M Califf, Charles V Pollack, Robert A Harrington, E M Ohman, W B Gibler, Ralph G Brindis, Eric D Peterson
Journal: Circulation (2006)

Background : The National Cholesterol Education Program Third Adult Treatment Panel (NCEP ATP III) recently added an optional secondary prevention low-density lipoprotein (LDL) cholesterol goal (&lt;70 mg/dL) for high-risk patients, such as those with acute coronary syndromes (ACS). The effect of the optional goal on the need for treatment in patients (pts) presenting with non-ST-segment elevation (NSTE) ACS is unclear. Methods : We evaluated pts with NSTE ACS (positive cardiac markers and/or ischemic ECG changes) included in the CRUSADE initiative between January 2001 and July 2004 with a LDL cholesterol drawn before or during hospitalization. This population was stratified by prehospitalization use of lipid-lowering therapy and divided into LDL cholesterol categories of &lt;70, ≥70 to &lt;100, ≥100 to 130, and ≥130 mg/dL. Results : Of 129,054 total pts in CRUSADE, 71,814 (55.7%) had a LDL cholesterol available (Figure ). Of those with an LDL cholesterol, 23,728 (33.0%) received lipid-lowering therapy prior to hospitalization, including 22,046 (30.7%) on statin therapy. Of the 71,814 pts, 34,258 (47.8%) were at the NCEP-ATP III recommended treatment goal of &lt;100 mg/dL, and 12,463 (17.4%) were at the optional aggressive treatment goal of &lt;70 mg/dL on presentation with NSTE ACS. Conclusions : The majority of pts presenting with NSTE ACS are not on lipid-lowering therapy prior to admission, most are not at the NCEP ATP III recommended LDL goal, and a minority are at the optional LDL goal for high-risk patients.
Abstract 4176: No Protection Against New Cardiac Events of a High Omega-3 Index in Patients Presenting with an Acute Coronary Syndrome
Authors: Hildegunn Aarsetoey, Volker Pönitz, Heidi Grundt, William S Harris, Dennis W Nilsen
Journal: Circulation (2006)

Objectives: Previous studies evaluating the association between n-3 fatty acids (FAs) and coronary heart disease suggest that their main effect might be a reduction in the risk of fatal myocardial infarction (MI) and sudden death. This protective effect seems to be related to a direct stabilizing effect of n-3 FAs on the myocardium itself. Red blood cell EPA + DHA (expressed as percent of total FAs; the Omega-3 Index) has recently been found to be a good surrogate for the cardiac content of omega-3 FAs and may serve as an independent risk factor for cardiac events. We examined the long-time prognostic value of the Omega-3 Index in a coastal population surviving an acute coronary syndrome (ACS). Methods: The Omega-3 Index was measured at admission in 466 patients hospitalized with ACS. During a follow-up time of two years, recurrent MI (defined as a TnT &gt; 0.05 with a typical MI presentation) and all-cause mortality was registered. Odds ratios (OR) for new events were computed across quartiles of the Omega-3 Index; Q1 &lt; 5.24 %, Q2 [5.24- 6.385 %], Q3 [6.385–7.89 %] and Q4 ≥ 7.89%. Results: Follow-up event-rates are given in Table 1 . Comparing Q4 to Q1 the univariate analysis gives an OR of 1.03 (p = 0.787) for re-MI, 0.90 (p= 0.328) for all-cause mortality and 0.95 (p= 0.556) for the combined endpoint of re-MI and/or death after two years of follow-up. Conclusion: A high Omega-3 Index had no protective effect against new cardiac events and/ or death in this cohort of Norwegian ACS patients. This might be related to the very high intake of fish in this costal population, with the level of n-3 FAs exceeding a threshold limit beyond which no further protection can be demonstrated. Table 1
Abstract 5055: CC Chemokine Receptor 5 Signaling Suppresses Inflammation and Attenuates Adverse Remodeling Following Myocardial Infarction by Recruiting Regulatory T Cells
Authors: Marcin Dobaczewski, Ying Xia, Nikolaos G Frangogiannis
Journal: Circulation (2009)

Myocardial infarction triggers an inflammatory reaction that is critically involved in the pathogenesis of cardiac remodeling. Optimal cardiac repair is dependent on regulatory mechanisms that suppress inflammation preventing excessive matrix degradation. Chemokines are rapidly induced in the healing infarct mediating recruitment of leukocyte subsets with distinct properties. CCR5, the receptor for the CC chemokines MIP-1 α , MIP-1 β and RANTES plays an important role in immunoinflammatory responses. We hypothesized that CCR5 signaling may regulate the inflammatory response following myocardial infarction playing a role in the development of cardiac remodeling. CCR5 and its ligands MIP-1 α and MIP-1 β were markedly induced in reperfused mouse infarcts. Flow cytometry demonstrated that 38.3%+3.75 of the mononuclear cells infiltrating the infarcted myocardium after 24h of reperfusion expressed CCR5. CCR5 −/− mice and WT animals showed comparable macrophage and neutrophil infiltration in the infarct; however, CCR5 absence was associated with marked upregulation of pro-inflammatory cytokine (IL-1 β , TNF- α and IL-6) and chemokine (MIP-2, MIP-1 α , - β and IP-10) mRNA expression in the infarcted myocardium. CCR5+ mononuclear cells isolated from WT infarcts had anti-inflammatory properties exhibiting higher expression of the inhibitory cytokine IL-10 than CCR5- cells. In addition, mononuclear cells isolated from CCR5 −/− infarcts had reduced IL-10 expression. Enhanced inflammation in the absence of CCR5 was associated with impaired recruitment of foxp3+ regulatory T cells (Tregs), a CD4+ lymphocyte subpopulation with suppressive properties (Tregs as a percentage of T cells: WT 13.1%+ 1.1 vs. KO 7.2%+ 1.1; p&lt;0.05). In WT mice the CCR5+ subset of Tregs exhibited enhanced expression of IL-10 reflecting potent anti-inflammatory activity. Enhanced inflammation in CCR5 −/− infarcts was associated with increased MMP and decreased TIMP expression, resulting in accentuated cardiac dilation (LVEDV: WT 52.99+2.43 mm3 vs. KO 65.13+4.53 mm3; p=0.02) without affecting the size of the infarct. CCR5-mediated recruitment of Tregs may restrain post-infarction inflammation preventing excessive matrix degradation and attenuating adverse remodeling.
Abstract 5275: STAT3-dependent Acute RANTES Production in Vascular Smooth Muscle Cells Modulates Inflammation Following Arterial Injury
Authors: Jason C Kovacic, Rohit Gupta, Angela C Lee, Mingchao Ma, Fang Fang, Claire N Tolbert, Avram D Walts, Leilani E Beltran, Hong San, Guibin Chen, Manfred Boehm
Journal: Circulation (2009)

Inflammation is a key component of arterial injury, with vascular smooth muscle cell (VSMC) proliferation and neointimal formation the final outcome of this process. However, the acute events that establish the blueprint for this vascular inflammatory response are incompletely understood. To address this deficiency we examined events immediately after femoral artery wire injury in mice and identified a marked acute recruitment of macrophages and T cells, with vessel-associated CD3 + T cells increasing ~20-fold within 1 day of injury. Correspondingly RANTES, a T cell and macrophage chemo-attractant, was upregulated in vessels &gt; 20-fold within 6 h of injury. RANTES production was modulated by p21 Cip1 ; at 6 h local RANTES was 45-fold higher in p21 −/− than wild type (WT) mice, and acute T cell infiltration was &gt; 2-fold greater in p21 −/− than WT mice at 1 day post injury. Immune-staining and reciprocal bone marrow (BM) transplantation between WT and RANTES −/− mice identified medial VSMCs as the principal source of acute RANTES production. Unique to VSMCs, RANTES production was initiated by TNF α , but not IL-6 or gp130 (an IL-6 signal transducer). RANTES transcription was dependent on downstream binding of a complex formed between NF- κ B (p65 subunit) and STAT3 to NF- κ B binding sites in the RANTES promoter, with shRNA knockdown of either STAT3 or p65 in VSMCs markedly abrogating RANTES production. p21 Cip1 potentially modulated RANTES levels by both restraining STAT3 transcription and co-association with p65. In vivo , acute activation of NF- κ B and STAT3 in medial VSMCs was identified, with RANTES levels 6 h after injury in TNFα −/− mice significantly reduced compared to WT controls. One day after injury, RANTES −/− mice reconstituted with WT BM displayed a marked reduction in T cell and macrophage infiltration compared to identically reconstituted WT mice. Finally, we generated mice with smooth muscle cell-specific conditional STAT3-knockout ( STAT3 fl/fl ;SM22α-Cre ) and confirmed the STAT3-dependence of acute RANTES production by VSMCs. We conclude that early inflammatory cell recruitment following arterial injury is regulated by acute local RANTES production by medial VSMCs, which is in turn stimulated by TNF α and modulated by downstream NF- κ B-STAT3 signaling.
Abstract 5021: Copeptin Improves Early Diagnosis of Acute Myocardial Infarction
Authors: Till Keller, Stergios Tzikas, Tanja Zeller, Ewa Czyz, Lars Lillpopp, Alexander Roth, Christoph Sinning, Philipp S Wild, Edith Lubos, Dirk Peetz, Jan Kunde, Oliver Hartmann, Andreas Bergmann, Felix Post, Karl J Lackner, Sabine Genth-Zotz, Viviane Nicaud, Laurence Tiret, Thomas Münzel, Stefan Blankenberg
Journal: Circulation (2009)

Introduction: Early diagnosisof myocardial infarction in chest pain patients is crucial to identify patients at risk and to maintain a fast treatment initiation. Background: Aim of the current investigation is to test whether determination of copeptin, an indirect marker for arginin-vasopressin, adds diagnostic information to conventional troponin in early evaluation of patients with suspected myocardial infarction. Methods: Between 06/2006 and 03/2008 patients with suspected acute coronary syndrome were enrolled consecutively. Copeptin, troponin T, myoglobin and creatine kinase-MB were determined at admission and after 3 and 6 hours. Results: Of 1293 (66.1% male) enrolled patients 244 (18.9%) had the discharge diagnosis of acute myocardial infarction, 211 (16.3%) presented with unstable angina and in 838 (64.8%) patients an acute coronary syndrome could be excluded. Combined measurement of copeptin and troponin T at admission improved the c-statistic from 0.85 for troponin T alone to 0.94 in the overall population and from 0.77 to 0.91 in patients presenting within 3 hours after chest pain onset. In this group the combination provided an excellent negative predictive value of 91.1%. Conclusions: In triage of chest pain patients determination of copeptin in addition to conventional troponin T improves diagnostic performance, especially early after chest pain onset. Combined determination of troponin T and copeptin provides an excellent negative predictive value virtually independent of chest pain onset time and therefore allows an early and safe rule-out of myocardial infarction.
Abstract 575: Both Phosphorylation and Dephosphorylation of Ryanodine Receptor Enhance Sarcoplasmic Reticulum Calcium Leak in Canine Ventricular Myocytes
Authors: Dmitry Terentyev, Radmila Terentyeva, Sandor Gyorke
Journal: Circulation (2006)

In recent years, there has been an increase of emphasis on the possibility that alterations in phosphorylation of the cardiac ryanodine receptor (RyR2) may contribute to the defective intracellular Ca release in heart failure (HF). However, the specific mechanisms proposed by different laboratories remain controversial. We studied the effects of exogenous and endogenous kinases and phosphatases on sarcoplasmic reticulum (SR) Ca release by measuring [Ca] changes in the cytosolic and SR luminal ([Ca]SR) compartments, using the Ca indicators rhod-2 and fluo-5N, respectively, in permeabilized canine ventricular myocytes. Application of PP1 (10 u/ml) led to an acute increase in the frequency of spontaneous Ca release events (Ca sparks) followed by a decline in intra-SR [Ca] consistent with the possibility that activation of RyR2s contributes to unloading of the SR by releasing Ca. Indeed, PP1 caused a marked acceleration of the RyR2-mediated SR Ca leak directly measured as time-dependent decline of [Ca]SR in the presence of the inhibitor of the SR CaATPase (SERCA2), thapsigargin. Application of cAMP (20 uM) and PKA (10 u/ml) resulted in a significant increase in Ca spark frequency that was paralleled by an increase in [Ca]SR. Direct measurements of the RyR2-mediated leak in the presence of thapsigargin revealed a small but significant acceleration in the leak following cAMP or PKA application, implying that the potentiation of sparks in the absence of thapsigargin may involve direct effects upon RyR2s in addition to effects mediated by SERCA2-dependent increase in [Ca]SR. As determined by a phosphospecific antibody, RyR2 phosphorylation on Ser-2809 was increased by cAMP and reduced by PP1. Collectively, these results suggest that under baseline phosphorylation conditions, both phosphorylation and dephosphorylation stimulate RyR2 activity resulting in an increased SR Ca leak. Considering the multimeric nature of the RyR2 and the presence of multiple sets of phophorylation sites, these results can be rationalized by suggesting that the effects of kinases and phosphotases on RyR2 function are mediated by different degrees of RyR2 phosphorylation at a certain set of sites (e.g. Ser-2809) or by phosphorylation/dephosphorylation of different sets of sites.
Abstract 592: Erythropoietin Attenuates the Development of Experimental Autoimmune Myocarditis
Authors: Masafumi Takahashi, Sho-ichi Hirose, Ryo Ogawa, Hajime Morimoto, Atsushi Izawa, Hirohiko Ise, Hirohiko Ise, Hirohiko Ise, Minoru Hongo, Uichi Ikeda
Journal: Circulation (2006)

Background: Myocarditis is a major cause of dilated cardiomyopathy (DCM) and end-stage heart failure; however, no effective treatment has been established. Recent evidence indicates that autoimmunity plays an important role in the development of myocarditis and DCM. Since erythropoietin (EPO) has been shown to not only have cardioprotective effects but also attenuate autoimmune diseases, we investigated whether EPO attenuates the development of a rat experimental autoimmune myocarditis (EAM) model. Methods and Results: Male Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. Rats were received human recombinant EPO (EPO group: 6000 IU/kg, 3 days/week, day 0 to 20, n = 14) or saline (control group, n = 15) subcutaneously, and evaluated on day 21. In EPO group, the myocarditis-affected area and heart/body weight ratio was significantly attenuated compared with those in control group (area: 7.7 ± 2.5 vs. 27.4 ± 4.3%, p&lt;0.001; ratio: 3.79 ± 0.8 vs. 4.81 ± 1.4, p&lt;0.05). Echocardiogram and blood pressure (BP) study demonstrated significant improvement of left ventricular contraction and systolic BP in EPO group (%FS: 45.1 ± 1.8 vs. 38.5 ± 2.8%, p&lt; 0.05; BP: 113.4 ± 4.7 vs. 97.8 ± 2.4 mmHg, p&lt;0.001). Immunohistochemistry showed that EPO treatment decreased the infiltration of macrophages (ED1: 30.2 ± 10.7 vs. 122.9 ± 3.3/HPF, p&lt;0.01) and T cells (OX-38: 10.6 ± 2.7 vs. 41.6 ± 2.9/HPF, p&lt;0.01), and %degranulation of mast cells (27.5 ± 7.5 vs. 62.5 ± 7.5%, p&lt;0.05). Real-time RT-PCR analysis revealed that EPO treatment decreased the expression of inflammatory cytokines, such as IFN-γ (p&lt;0.01), MCP-1 (p&lt;0.01), and osteopontin (p&lt;0.01), but not TNF-α and IL-10, in the myocardium. We further tested the effect of EPO on cardiac myosin-induced lymphocyte proliferation and cytokine expression in the splenocytes isolated from EAM rats in vitro. Treatment with cardiac myosin significantly stimulated proliferation and the expression of IFN-γ and TNF-α; however, EPO failed to inhibit them. Conclusions: These findings suggest that EPO attenuated inflammatory cell infiltration and cytokine expression, and improved cardiac function in EAM; thus, EPO has a therapeutic potential for the treatment of myocarditis.
Abstract 5016: Circulating MicroRNA: A Novel Potential Biomarker for Early Detection of Acute Myocardial Infarction
Authors: Guo-Kun Wang, Jia-Qi Zhu, Jun-Tao Zhang, Qing Li, Yue Li, Yong-Wen Qin, Qing Jing
Journal: Circulation (2009)

Background: MicroRNA (miRNA), a class of 19~25-nucletide noncoding RNA, is present in the plasma or serum of humans and other animals, and has been increasingly reported to be the potential biomarkers for several diseases including cancers and liver injury. The objective of this study is to determine the potential of cardiac-specific miRNAs to serve as early-detectable biomarkers in the plasma for acute myocardial infarction (AMI). Methods and Results: With miRNA microarray analysis, we observed the expression profile of miRNAs from the plasma of 5 healthy people. In the plasma, several miRNAs including miR-451 and miR-16 were presented with relative high levels, and the muscle-specific miRNAs, miR-1 and miR-133a were detected with low abundance. However, miR-499 and miR-208, specifically expressed in heart, were undetectable in the plasma. The above results with 6 miRNAs were additionally confirmed by real-time PCR analysis. Interestingly, the levels of miR-1, miR-133a, miR-499, and miR-208, but not miR-451 and miR-16 were significantly increased in the plasma from the rats with coronary artery ligation for 3 hours, compared to those from sham-operated controls (n=6 in both groups). Among them, the elevation of miR-208 was most remarkable. The level of miR-208 in plasma was then examined at various time points (0, 1, 3, 6, 12, 24 hours after coronary artery occlusion). Real-time PCR analysis showed that the amount of miR-208 in plasma became detectable at as early as 1 hour, peaked at 3~6 hours, and declined after 12 hours. Next, the levels of these 6 miRNAs in plasma from 18 patients with AMI, 12 patients with non-AMI CHD and 15 patients with non-CHD were evaluated. The levels of miR-1, miR-133a, miR-499 and miR-208 were substantially higher in AMI group than those in the two other groups. Additionally, the plasma levels of these 4 miRNAs from 5 of 18 AMI patients were decreased during the follow-up investigation. Conclusions: Our results that the levels of miR-1, miR-133a, miR-499 and miR-208 increase in plasma from both AMI rats and patients reveal for the first time that they may serve as potential biomarkers for AMI diagnosis. Importantly, miR-208, increased rapidly at the early stage of AMI, may improve the accuracy in early diagnosis of myocardial damage.