tbuckley/cabot-search huggingface dataset:
Abstract 18631: The Histone Methyltransferase Smyd3 Modulates Growth and Differentiation of Human Cardiac Stem Cells
Authors: Narasimman Gurusamy, Junghyun Kim, Toru Hosoda, Claudia Fiorini, Fumihiro Sanada, Virginia Caballero, Domenico D'Amario, Hanqiao Zheng, Marcello Rota, Federica del Monte, David A D'Alessandro, Robert E Michler, Jan Kajstura, Piero Anversa, Roberto Bolli, Annarosa Leri
Journal: Circulation (2012)

Stemness and pluripotency of embryonic stem cells (ESCs) are largely mediated by epigenetic modifications. The objective of this study was to determine whether growth and commitment of human cardiac stem cells (hCSCs) are similarly regulated. Discarded surgical specimens were enzymatically digested and c-kit-positive hCSCs were sorted by FACS. Genome-wide analysis of histone modifications documented that adult hCSCs are characterized by a bivalent chromatin configuration similar to that of ESCs with repressive and activating marks at lysine residues of histones H3 and H4. The high levels of di- (H3K4me2) and tri-methylation (H3K4me3) at lysine 4 of histone H3 prompted us to test the possibility that the histone methyltransferase Smyd3 is involved in the epigenetic control of hCSC function. Smyd3 downregulation by siRNA decreased the levels of H3K4me2 and H3K4me3 and resulted in a marked attenuation in hCSC replication and differentiation into myocytes and vascular cells. In contrast, Smyd3 overexpression led to a 1.6-fold increase in dividing hCSCs and a 2-fold increase in hCSCs committed to the myocyte lineage. Thus, we studied whether Smyd3 regulates a group of genes controlling the growth of hCSCs and their specification to the myocyte and vascular fate: telomerase (TERT), Nkx2.5, and GATA6. Downregulation of Smyd3 decreased the activity of telomerase, and the expression of Nkx2.5 and GATA6. By immunolabeling, Smyd3 co-localized with TERT, Nkx2.5 and GATA6 in hCSC nuclei. To document the role of Smyd3 in the transcription of TERT, Nkx2.5, and GATA6, ChIP assays with antibodies against Smyd3 and H3K4me3 were performed in hCSCs. Amplification and sequencing of the precipitated DNA fragments demonstrated that Smyd3 occupied the TERT, Nkx2.5, and GATA6 promoter regions in which its consensus sites are located. Gene reporter assays with plasmids carrying the 5’ flanking regions of TERT or Nkx2.5 containing mutated Smyd3 binding sites led to a marked decrease in promoter activity of the two genes. Importantly, high levels of expression of Smyd3 were found in the regenerated myocytes derived from hCSCs injected in immunosuppressed infarcted rats. Thus, Smyd3 plays a central role in the modulation of growth and differentiation of hCSCs in vitro and in vivo.
Abstract 18847: Visualization of Inflammation and Characterization of Lesions in Viral Myocarditis Mouse Model by Combined 19F-MR Cell Tracking and 1H Cardiac MRI
Authors: Yuxiang Ye, Xavier Helluy, Martina Sauter, Thomas C Basse-Luesebrink, Thomas Kampf, Karl-Heinz Hiller, Ali Yilmaz, Udo Sechtem, Wolfgang R Bauer, Reinhard Kandolf, Karin Klingel, Peter M Jakob
Journal: Circulation (2012)

Introduction Myocarditis is a challenging disease for diagnosis and treatment. Recently, we have established a non-invasive cellular 19F-MR method to visualize inflammation of myocarditis in mice [1]. In this study, we correlated detection of inflammation by 19F-MR and tissue characterization by 1H-MR in viral myocarditis mouse model. Methods Viral myocarditis was induced by infecting ABY mice (n=5 infected+3 control) with CVB3. 19F-perfluorocarbon emulsion (PFC) (150μl) was injected i.v. 13 days post-infection to label monocytes and macrophages in blood. The labeling efficiency was examined by FACS in blood samples. 19F/1H-images were acquired at a 7T MR. 19F-MRI was superimposed on 1H-Cine to localize inflammation in myocardium. Lesions were characterized by T2WI, T2*WI and Gd-DTPA enhancement. MR findings were examined by Histology and immunohistochemistry (IHC). Results Blood FACS and confocal microscopy on IHC revealed that the 19F-MR signal in myocardium was due to internalized PFC in macrophages. 19F-MR detected macrophage infiltrating myocarditis lesions. Edema and Gd enhancement could be found in some lesions. Interestingly, most patchy 19F signal co-localized with T2* hypo-intense signal in lesions, which has been reported in various mouse strains post CVB3 infection [2]. Necrosis, T cells, fibrosis, and mineral deposition were found in lesions by histology and IHC. Conclusion 19F-MRI unambiguously detected active recruitment of macrophages to myocarditis lesions. On T2*WI signal voids in lesions were closely related to 19F signal in location and volume, which indicates its association to inflammation. Caution should be taken to apply iron oxide particles to visualizing inflammation in viral myocarditis, while the significance and mechanism of this contrast, especially its existence in human, need further investigation. 1. Ye et al ISMRM proceeding 2012. 2. Helluy et al. ISMRM proceeding 2011. This work was supported partly by BMBF 01EZ0816.
Abstract 18894: Global Left Ventricular Remodeling Characteristics are More Important than Scar Extent and Location for Prediction of Severe Mitral Regurgitation in Advanced Ischemic Cardiomyopathy
Authors: Joao L Cavalcante, Qusai Saleh, Aderonke Adeniyi, Paaladinesh Thavendiranathan, Zoran B Popovic, Randall C Starling, Milind Y Desai, Scott D Flamm, Thomas H Marwick, Deborah H Kwon
Journal: Circulation (2012)

BACKGROUND: Mitral regurgitation (MR) is particularly common in patients with ischemic cardiomyopathy (ICM) following an acute myocardial infarction where its presence is independently associated with worse mortality. In patients with advanced ICM, unfavorable LV remodeling causes geometrical changes leading to MR development. The best management of these patients remains unclear. Whether magnetic resonance imaging (MRI) with its higher spatial resolution and scar information can add further insights remains unknown. HYPOTHESIS: We hypothesized that MRI assessment of LV remodeling as well as scar extent, location and papillary muscle involvement could aid in the prediction of severe MR in patients with advanced ICM. METHODS: A total of 452 patients with LVEF ≤ 40% and ≥ 70% stenosis in ≥ 1 coronary artery, history of CABG or PCI with transthoracic echocardiogram and MRI studies within 7 days were included (median=1 day). Quantitative MR assessment was performed as per ASE guidelines. LV volumes, sphericity and LVEF were calculated from cine MRI images. LV scar was measured ∼ 10-15 minutes after gadolinium injection, using phase-sensitive inversion recovery sequence. RESULTS: The mean age was 62 ± 10 years and males represented 75%. LVEF, LV end-systolic volume index were 23 ± 0.5% and 115 ± 2 ml/m 2 respectively. MR was classified as: trivial/mild (63%), moderate (22%) or severe (15%). Multinomial logistic regression analysis revealed that LV remodeling changes were independent predictors of severe MR but not scar extent, location and/or papillary muscle involvement (Table). CONCLUSION: In ICM patients with severely dilated LV, contrary to prior studies showing the importance of regional LV remodeling and scarring, global LV remodeling appears to be more important in predicting presence of severe MR. These findings further confirm the dynamic nature of the remodeling process and highlight its importance as future target for management of these patients.
Abstract 18357: Outcomes and Quality of Anticoagulant Control in Patients Newly Diagnosed with Non-valvular Atrial Fibrillation: Insights from the Worldwide GARFIELD Registry
Authors: Lorenzo Mantovani, Iris Mueller, Jean-Pierre Bassand, David Fitzmaurice, Samuel Goldhaber, Shinya Goto, Sylvia Haas, Alexander G Turpie, Freek W Verheugt, Sophie Rushton-Smith, Ajay Kakkar, None for the GARFIELD Investigators
Journal: Circulation (2012)

Background: Prevalence of atrial fibrillation (AF) is increasing due to an aging population. Most AF patients require long-term anticoagulant treatment to prevent stroke. Consequences of insufficient or excessive anticoagulation with vitamin K antagonists (VKAs) can be serious. Time within therapeutic INR range (TTR) evaluates the efficacy and quality of INR control. It remains unclear whether better anticoagulation control (TTR &gt;60%) is associated with lower thrombotic and bleeding events in real-world clinical practice. Hypothesis: The incidence of thrombotic and bleeding events in anticoagulated AF patients treated with VKAs is increased when INR is not well controlled (TTR &lt;60%). Methods: Patients were recruited at 543 sites selected at random in accordance with nationally defined AF care settings. A total of 10,609 patients newly diagnosed with non-valvular AF and with ≥1 additional investigator-determined stroke risk factor were recruited consecutively between Dec 2009 and Oct 2011. TTR was calculated by percentage of INR recordings in target range. Results: In 6047 patients treated with VKAs, 3952 had INR recordings available at the time of this analysis. TTR was &gt;60% in 1660 (42.0%) of these patients. A total of 55,257 INR measurements were recorded. Event rates and monitoring frequency in relation to quality of INR control are shown in the Table. Mean length of follow-up was 15.2 (SD 6.9) months. Patients with INR not well controlled were more likely to have a stroke/TIA, a major bleed, an ICH and death than patients with INR well controlled. Conclusions: These observational data support the findings of randomized clinical trials, by indicating that INR control is instrumental in determining adverse event rates in patients treated with VKAs, but are not consistent with the post-hoc comparisons of novel OACs with warfarin. Table: Event rates and INR recordings in relation to TTR.
Abstract 19209: Ectonucleoside Triphosphate Diphosphohydrolase-1 (cd39) Attenuates Expression f of P-Selectin Glycoprotein Ligand-1 in Hypoxic Raw Cells via Hif-1α
Authors: Hui Liao, Amy E Baek, David J Pinsky
Journal: Circulation (2012)

CD39 is a transmembrane enzyme that phosphohydrolyzes ATP and ADP to AMP. CD39 inhibits platelet reactivity and inflammation and thus limits platelet accumulation and leukocyte transmigration to sites of inflammation or injury. P-selectin glycoprotein ligand-1 (PSGL-1) is a mucin-like glycoprotein on the surface of leukocytes which binds with high affinity to P-selectin, to promote tethering and rolling adhesion of leukocytes to activated endothelial cells and platelets. As this leads to increased leukocyte migration to sites of inflammation or injury, we hypothesized that CD39 may regulate PSGL-1 expression on leukocytes under hypoxic conditions. Murine RAW macrophages transfected with a CD39 overexpression construct (CD39Tx) or a pcDNA3.1 vector (VTx) as control were incubated in hypoxia (0.5% O2) or nomoxia. Subsequent flow cytometry showed 35% more cells expressed PSGL-1 after 6 hours of exposure to hypoxia (H) on VTx cells compared to normoxic (N) VTx control (p &lt; 0.0001). The number of cells expressing PSGL-1 was reduced by 14% in H CD39Tx cells compared with H VTx cells (p = 0.0061). Western blotting showed PSGL-1 antigen expression increased 4.9, 7.0 and 3.9 fold after 2, 6, and 16 hours of hypoxia in VTx cells, respectively, compared to N VTx controls; and PSGL-1 antigen was also attenuated 19%, 30%, and 28% respectively in H CD39Tx cells compared with H VTx cells. Quantitative real-time PCR results showed that PSGL-1 mRNA expression increased by 2.1 fold in 6 hours H VTX cells compared with N VTx cells (p &lt; 0.0001) and decreased 40% in H CD39Tx cells compared with H VTx control (p &lt; 0.0001). The PSGL-1 promoter region contains 3 HIF-1α response elements (HRE). The activity of PSGL-1 promoter increased by 1.9-fold in 6 hours H VTx cells compared with N VTx controls (p &lt; 0.0001) and decreased by 61% in H CD39Tx cells compared with H VTx controls (p &lt; 0.0001). HIF-1α protein expression was also reduced in nuclear protein samples of H CD39Tx cells compared to H VTx cells. These data identify CD39 as a critical regulator of macrophage PSGL-1 expression, acting through the HIF-1alpha pathway to squelch inflammatory cell trafficking under hypoxic/ischemic conditions.
Abstract 18761: Improved Quality of Life and Functional Capacity for Patients Receiving the HVAD <sup>®</sup> Pump
Authors: Emma J Birks, Mark S Slaughter, Steven W Boyce, Edwin C McGee, William G Cotts, Samer S Najjar, Francis D Pagani, David Hathaway, Mary V Jacoski, Kevin B Najarian, Keith D Aaronson
Journal: Circulation (2012)

Background: Patients with advanced heart failure experience significant impairment in quality of life (QoL) and functional capacity. Improved survival and longer waits for transplant following LVAD implantation means QoL and functional capacity outcomes are increasingly important. We reviewed the experience of patients receiving the HeartWare ® Ventricular Assist System (HVAD), a novel design continuous flow, centrifugal pump in the pivotal ADVANCE Bridge to Transplant (BTT) Trial and Continued Access Protocol (CAP) to explore changes in QoL and functional capacity. Methods: The QoL surveys analyzed in the combined BTT and CAP trials included the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary, and the EuroQOL-5D Visual Analog Scale (VAS). The 6 minute walk test (6MW) was used to determine functional capacity. Descriptive statistics were used to evaluate differences compared to baseline. Results: In the combined BTT and CAP study (N=332), between 44% and 55% of patients completed paired QoL measurements, at baseline (pre-implant) and 180 days post-implant. Patients unable to complete a test for any reason other than incomplete follow-up visit had imputed values of zero. Of 231 patients who were available for follow-up at 6 months (i.e., not transplanted, explanted for recovery, or dead and had reached the 6 month post-implant assessment), paired data were obtained on 184, 164 and 146 patients for the 6MW, KCCQ and VAS, respectively. Of patients completing the paired assessments, there was a statistically significant improvement of 195.9 meters in the 6 Minute Walk Test. Both the EQ-5D Visual Analog Scale and KCCQ Overall Summary also showed statistically significant improvements in their scores of 27.0 and 31.1 points, respectively. Conclusion: QoL and functional capacity was substantially improved at 6 months in bridge to transplant recipients of the HeartWare HVAD System.
Abstract 18394: Gastric Inhibitory Polypeptide is Associated with Metabolic Disorder and Cardiovascular Disease Independent of Glucose in Humans
Authors: Yasunori Takata, Jun-ichi Funada, Go Hiasa, Hideki Okayama, Haruhiko Osawa
Journal: Circulation (2012)

Background - Emerging animal studies have reported the beneficial effect of interrupting gastric inhibitory polypeptide (GIP) receptor signaling in metabolic disorders including extreme fat deposition with insulin resistance and glucose intolerance. These results propose the hypothesis that hyper GIP secretion may contribute to the development of cardiovascular disease (CVD) in humans. However, most studies have focused on incretin responses to glucose loading, and the association between endogenous GIP levels and cardiometabolic disorders has not been well defined in humans. Methods and Results - To examine the association between fasting GIP and cardiometabolic disorders or CVD independent of plasma glucose (PG) levels, we analysed 300 non-diabetic subjects. Furthermore we performed in vitro functional analysis using human macrophage cells. Simple regression analysis demonstrated that the fasting total GIP was correlated with cardiometabolic disorders such as waist to hip ratio, hyperinsulinemia, and HOMA-IR. ANCOVA and logistic analysis after adjustment for age, gender, BMI, smoking, HOMA-IR, hypertension, LDL cholesterol, HDL cholesterol, eGFR and PG, revealed that fasting GIP was increased in the subjects with CVD than non-CVD (53.7 ± 32.2 v.s. 28.2 ± 18.1, p &lt;0.01), and each tertile increase in fasting GIP was associated with the prevalence of CVD (odds ratio 3.12 per tertile, 95% CI 1.73 to 5.62; p &lt;0.01). Furthermore, molecular analysis revealed that GIP receptor was present in human monocyte/macrophage, T-lymphocyte, and human carotid atherosclerotic lesion. In vitro analysis revealed that GIP stimulation up-regulated gene expression of interleukin 6, CC chemokine receptor (CCR) 2, CCR5, and scavenger receptor type A in human THP-1 macrophages. Conclusions - These results suggest that oversecretion of GIP may contribute to cardiometabolic disorder, resulting in the development of CVD independent of PG in humans.
Abstract 183: Life-Threatening Arrhythmias in Patients Hospitalized with Acute Coronary Syndrome: Data from Latvian Registry 2008-2010
Authors: Oskars Kalejs, Aija Maca, Ilja Zakkw, Svetlana Ratobilska, Iveta Mintale, Ginta Kamzola, Milana Zabunova, Inga Narbute, Sanda Jegere, Andrejs Erglis
Journal: Circulation (2012)

Purpose. Despite the major improvements in the care of patients with acute coronary syndrome (ACS), life - threatening arrhythmia (LTA) remains a common complication of myocardial infarction (MI). We have analyzed the rate of LTA in first hours after hospitalization in patients presenting with acute coronary syndrome and receiving different treatment strategies. Materials and methods. The data from Latvian registry of ACS in years 2008-2010 were analyzed. LTA was defined: complete AV block, unsustained/ sustained ventricular tachycardia (VT), ventricular fibrillation (VF). Results. In STEMI cohort, the incidence of LTA was significantly lower in PCI group after six hours (p&lt;0.05) than in patients receiving thrombolysis. In first two hours LTA incidence was higher in PCI patients, what we can be explained with earlier reperfusion changes and electrical instability. In non-STEMI cohort, the incidence of LTA was significantly lower than in STEMI patients (p&lt;0.01), but it was higher in non-invasive group compared to invasive treatment group. LTA rate was significantly reduced in statin users (p&lt;0.05). Conclusions. Despite the more aggressive treatment strategy, incidence of LTA remains high in ACS patients. Arrhythmias are often observed earlier in patients after PCI and later after thrombolysis. Earlier PCI can decrease late complication rate and potentially improve survival in STEMI patients.
Abstract 18632: Expression and Function of the Ryanodine Receptor Subtype 3 in Cardiac Purkinje Fibers: Potential Target for Selective Treatment of Purkinje Ectopy?
Authors: Rebecca E Daniels, Lawson Miller, Simran Arora, Elizabeth Chia, Masahito Miura, John McGuire, Bruno D Stuyvers
Journal: Circulation (2012)

BACKGROUND: Focal “discharges” from the Purkinje network were shown to trigger VTs and VFs in ischemic hearts. In dog model of myocardial infarction, this Purkinje ectopy was attributed to abnormal oscillations of Ca 2+ concentration in Purkinje cells (Pcells). The cause of these oscillations is unknown mostly because important features of Ca 2+ handling of normal Pcells remain obscure. It was proposed that distinct forms of Ca 2+ channels participate to Ca 2+ release from endoplasmic reticulum (ER) in canine Pcells, wherein RyR3 was found to co-exist with IP3R and RyR2. Nevertheless, presence of this system of multiple Ca 2+ channels has not been explored in other species and the function of this system in Pcells remains unclear. Here, we examined the hypothesis that a specific region of RyR3 Ca 2+ release exists in Pcells of large size hearts and forms anatomical and functional coupling between membrane and core ER-Ca 2+ releases. METHODS: Purkinje strands were dissected from hearts of 36 Yucatan swine. Enzymatically dispersed Pcells were loaded with Fluo4. Intracellular Ca 2+ dynamics was assessed by 2D confocal imaging (92cells). Function of ER-Ca 2+ channels was investigated through effects of selective inhibitors on intracellular Ca 2+ transients (65cells). mRNA level was measured in Purkinje fibers by RT-PCR for RyR isoforms 1,2,3 and IP3R (11 animals). Protein expression was characterized by immunofluorescence (34 cells). RESULTS: Compared to myocardium, 100fold larger RyR3 mRNA level was detected in Purkinje fibers. 3D distribution of RyR3-Ab revealed a concentric RyR3 layer at the cell periphery. Spark rate-pCarelations showed that Ca 2+ sensitivity of ER-Ca 2+ release at the Pcell periphery was 2fold larger than further in the core. 3 distinct velocities were detected in the typical centripetal Ca 2+ propagation of Pcells. RyR3 inhibitor dantrolene (10µM) immediately reduced the Ca 2+ release event rate by 50% in the periphery only. CONCLUSION: RyR3 is a major component of the specific Ca 2+ signaling of Pcells of large mammalian heart, suggesting that any RyR3 alteration may cause pro-arrhythmic Ca 2+ abnormalities in ischemic heart. Purkinje-specificity of RyR3 highlights a new target for selective treatment of Purkinje-originated dysrhythmia.
Abstract 16850: The Impact of Coxsackievirus Infection on Cardiac Stem Cells and Postnatal Heart Development
Authors: Jon Sin, Jenna Tabor-Godwin, Ralph Feuer, Roberta Gottlieb
Journal: Circulation (2011)

Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in young children, but in severe cases it can progress to myocarditis or meningo-encephalitis. The long-term consequences of mild CVB infection are unknown, although CVB antibodies are encountered more frequently in patients with heart failure than in the general population, raising the possibility that this cardiotropic virus could have lasting sequelae even in subclinical infection. Previously we described a mouse model in which early postnatal exposure to doxorubicin depleted c-Kit+ cardiac stem cells (CSCs) and resulted in cardiac dysfunction in adult animals that could only be elicited by a prolonged exercise challenge or experimentally induced myocardial infarction. We and others have shown that CVB infects actively proliferating neural stem cells and induces cell death. In this study, we report that cultured CSCs isolated from neonatal mouse hearts were also susceptible to cytopathic CVB infection. To test the hypothesis that CVB infection might deplete the CSC population in the heart during self-limited infection, we inoculated neonatal BALB/c mice with recombinant CVB expressing eGFP and assessed the effects of viral infection on CSCs. We observed infected CSCs in cardiac tissue as well as a 50% reduction in the number of c-Kit+ cells in adult animals. Our observations indicate that CVB can target CSCs in the neonatal heart, infecting them and triggering their destruction. Similar to our findings in the doxorubicin late-onset heart failure model, we suggest that the loss of CSCs during subclinical CVB infection in early childhood may predispose to late-onset heart failure. Further work is needed to demonstrate the cardiovascular consequences of CSC infection and depletion after neonatal CVB infection.