tbuckley/cabot-search huggingface dataset:
Abstract 4943: Enhanced Stability of Plasminogen Activator Inhibitor-1 in Patients With Livedoid Vasculopathy
Authors: Mehmet Agirbasli, Mesut Eren, Douglas E Vaughan
Journal: Circulation (2009)

Livedoid vasculopathy (LV) is a chronic, recurrent, painful cutaneous disease with distinctive clinical features and an uncertain etiology. The skin lesions are recognizable by focal purpura, depigmentation and shallow ulcers. Thrombophilic conditions occur frequently in patients with LV. While no definitive treatment exists for LV, smoking cessation, antiplatelet therapy, immunosuppressive treatment, anabolic steroids are often included in the therapeutic ladder. Recently, a possible link between LV and impaired fibrinolysis was suggested and cutaneous LV lesions responded to tissue plasminogen activator (t-PA) infusion. Hence, inhibition of the fibrinolysis through plasminogen activator inhibitor-1 (PAI-1) activity may determine the disease course in patients with LV. In this study, we investigated PAI-1 Ag and activity levels in 8 patients with biopsy proven LV (mean age 33±18, M/F = 1, median disease duration 5 years). All patients received antiplatelet treatment with aspirin and/or dipyrimadole and 6 patients received anabolic steroids or immunosuppressive treatment. Fasting PAI-1 antigen and activity levels were measured at 9 AM in all patients. Both PAI-1 Ag levels were 44±11 (ng/ml) and PAI activity levels were 16±9 (U/ng/ml) were moderately elevated compared to age-matched controls. However, PAI-1 kinetic studies demonstrated, markedly enhanced stability of PAI-1 activities in plasma from patients with LV. Specific activity at 16 hours were significantly higher than expected activity levels (0.1±0.1 versus 0.001±0.001 u/ng/ml, p=0.028). In conclusion, enhanced stability of PAI-1 may contribute to the pathophysiology of LV, mediated via either binding with stablizing co-factors or by post-translational modification in the PAI-1 protein. Systemic or local treatment with PAI-1 inhibitors may offer potential treatment alternative in patients with LV.
Abstract 4903: Control of Hypertension in All Age Groups in a Large Multiyear Multicenter Analysis From the Department of Veterans Affairs
Authors: Ross D Fletcher, Vasilios Papademetriou, Richard Amdur, Charles Faselis, Christopher McManus, Ronald Jones
Journal: Circulation (2009)

Introduction: Benefits of blood pressure (BP) control have been well elucidated, but overall BP control remains poor. Elderly patients are considered resistant or difficult to control. Thus, we assessed the effect of organized interventions to control blood pressure in a large cohort of patients in the Department of Veteran Affairs. Methods: From January of 2000 to December 2007, we assessed BP control in 478,099 patients from 15 VA hospitals in various geographic locations around the United States. Patients were divided in 4 groups based on age: G1 &lt;55 (N = 105,119), G2 55- &lt;70 (N = 174,418), G3 70- &lt;80 (N = 129,516), G4 ≥ 80 (N = 69,046). Medical interventions to control BP included use of electronic medical records with automated reminders, medical regimen adjustments, and frequent visits to both specialty and nurse run clinics. Results : Control rates (BP ≤ 140/90) at baseline were: 49.5% in G1, 43.6% in G2, 43.5% in G3 and 44.0% in G4. After 7 years of follow up BP control improved to 69.9% in G1, 70.9% in G2, 72.3% in G3 and 71.6% in G4 (p &lt;0.0001 for all groups compared to baseline). Average blood pressure changes are shown (figure ). Patients over the age of 70 achieved the greatest systolic BP reduction. Diastolic BP decreased in all age groups over the age of 55, but remained unchanged in the younger age group. BP levels were lower during the summer time as compared to winter in all age groups. Conclusions: High rates of BP control can be achieved even among the very old. Older patients respond well to appropriate interventions. Diastolic BP decreased in all age groups over the age of 55, but remained unchanged in younger patients. Seasonal BP variation is seen independent of age.
Abstract 4904: Comparative Anti-atherogenic Effects of a Single Intravenous Injection of rAAV8 Or rAAV2 Encoding Apo A-IMilano Gene
Authors: Fung Tian, Lai Wang, Mingjie Yang, Behrooz G Sharifi, Prediman K Shah
Journal: Circulation (2009)

Background: We previously reported potent anti-atherogenic effects of gene transfer of Apo A-IMilano through transplant of retrovirally transduced bone marrow. In anticipation of potential evaluation of Apo A-IMilano gene transfer in human atherosclerosis, we evaluated the comparative anti- atherogenic efficacy of Apo A-IMilano gene transfer using intravenous injection of type-2 and type-8 recombinant adeno-associated viruses (rAAV2 and rAAV8) as vectors in Apo A-I/apo E null mice. Methods: Mice received one intravenous injection of 1.2×1012 vector genome copies of rAAV2 -Milano or rAAV2 -Control or rAAV8 -Milano or rAAV8 -Control (12 mice per group). Four weeks after injection mice were placed on high fat diet. Twenty weeks later mice were euthanized to analyze Apo A-IMilano gene expression and quantitative extent of aortic atherosclerosis after oil-red O staining. ELISA analysis of blood samples and real-time PCR analysis of target organs was used to determine the Apo A-IMilano gene expression. Blood was analyzed for cholesterol levels. Results: The circulating cholesterol levels were comparably elevated among the 4 groups. Serum Apo A-IMilano levels were significantly higher in rAAV8 -Milano injected mice compared to rAAV2 -Milano injected mice at 4 weeks (71 ± 31 ng/ml vs. 31 ± 21ng/ml) 12 weeks (92 ± 61 ng/ml vs. 30 ± 27), and at 24 weeks (45 ± 32 ng/ml vs. 7.6 ± 6 ng/ml) (P &lt;0.001 all groups). Real time PCR showed a significantly higher level of transgene expression in the heart (122 ± 36 fold), liver (32 ± 25 fold) and the brain (14 ± 0.39 fold) with rAAV8 -Milano compared to rAAV2 -Milano. Compared to rAAV8 -Control, the mean aortic lesion area was reduced by 42% by rAAV8 -Milano (7.7 ± 0.06% vs 13.4 ± 1.1 % of aorta; p = 0.001). Compared to rAAV2-Control, the mean aortic lesion area was reduced by 16% by rAAV2 -Milano (12.6 ± 0.8 vs 10.6 ± 0.8 % of aorta; p = NS). rAAV8 -Milano reduced lesion area by 27% compared to rAAV2 -Milano (p = 0.01). Conclusions: Intravenous rAAV8 -Milano results in higher in-vivo transgene expression and a significantly greater reduction in aortic atherosclerosis compared to vector control or rAAV2 -Milano.
Abstract 192: Defibrillation Strategy with Postshock Synchronized Pacing in Excitable Gaps
Authors: Liang Tang, Gyo-Seung Hwang, Shien-Fong Lin
Journal: Circulation (2006)

Introduction: It was previously demonstrated that ventricular fibrillation (VF) can be synchronized with a novel spatiotemporal excitable gap pacing (SyncP) technique using low-energy pacing pulses that causes pace termination of VF. Therefore, we hypothesize that a spatiotemporally controlled (STCD) defibrillation strategy using defibrillation shocks followed by SyncP may be effective in defibrillation efficacy improvement. Methods and Results: We explored the STCD effects in 10 isolated rabbit hearts (n=10) with optical mapping of the anterior wall in LV. Optical recording guided real-time detection and stimulation of spatiotemporal excitable gaps was performed. SyncP was shown to cause wavefront synchronization as indicated by a decreased number of phase singularity points (p&lt;0.0001) and reduced spatial dispersion of VF cycle length (p&lt;0.01). After a defibrillation shock delivery, an isoelectrical window (IW) was present and the duration of the IW was a function of the shock strength. When the reference site detected the earliest activation (early site) of the reinitiated VF during IW, a 5-mA electric stimulus was delivered from the pacing electrode to depolarize the excitable gap, creating a functional block to stop VF propagation or change the propagation timing/pattern for VF termination. The location of the early site varied, however, about 80% arose from the right side of LV anterior wall close to apex, with the arrangement of the defibrillation anode electrode in the RV and cathode against the posterior wall. For 90% of the episodes where the reference site accurately detected the early site location, the SyncP pacing electrode successfully administered pacing in the excitable gap after low-energy shock delivery. VF was demonstrated to be successfully terminated by the STCD defibrillation with low-energy shock and pacing in the excitable gaps to cause functional block for reinitiated VF propagation in heart tissues. Conclusion: We implemented the concept of post-shock synchronized pacing in excitable gaps by a real-time feedback mechanism. Further optimization of this technique may prove effective in improving the defibrillation efficacy by synchronized VF activation.
Abstract 5102: Patients Developing STEMI In-hospital Have Delayed Reperfusion and Increased 1-year Mortality Compared to STEMI Patients Presenting to the Emergency Department
Authors: Anand Haryani, Tyler Richmond, Janet M Haw, Norma Melgoza, Yaninia Purim-Shem-Tov, James E Calvin, Gary L Schaer
Journal: Circulation (2009)

BACKGROUND: Despite recent advances in ST-elevation myocardial infarction (STEMI) systems of care, there has been little focus on patients who develop STEMI in-hospital. We hypothesized that inpatients who develop STEMI receive less timely care and have worse clinical outcome compared to patients who present to the emergency department (ED) with STEMI. METHODS: One hundred and twenty-six consecutive cases of STEMI treated with primary percutaneous coronary intervention (PCI) from May 2004 to May 2009 were included in the analysis. A retrospective medical record review was utilized to identify ECG to balloon times, intraaortic balloon pump (IABP) utilization, pre-discharge left ventricular ejection fraction, and duration of hospital stay following STEMI. In-hospital, 30-day, and 1-year mortality data was collected using the National Death Registry. RESULTS: Twenty-nine inpatients and 97 ED patients diagnosed with STEMI and undergoing PCI were included in this analysis. ECG to balloon time (357±419 min vs 163±188 min, p &lt;0.001), one-year mortality (24.1% vs 5%, p &lt;0.006), and duration of hospital stay (9±12.6 d vs 4.1±4.5 d, p &lt;0.001) were significantly increased in inpatients compared to patients admitted through the ED. Inpatients trended toward increased need for IABP (28% vs. 14.4%, p =0.09) and increased 30-day mortality (13.8% vs 5%, p=0.12). There were no differences in LVEF (45% vs 50%, p=0.22) or in-hospital mortality (10% vs 5%, p=0.27) between the two cohorts. CONCLUSION: Inpatients who develop STEMI have delayed reperfusion, increased length of stay, and greater 1-year mortality compared to STEMI patients admitted through the ED. Further study is needed to determine if improved identification and more rapid PCI could improve the clinical outcome of patients who develop STEMI in-hospital.
Abstract 4946: Comparison of Prasugel With Clopidogrel on Platelet Function in Coronary Artery Disease Patients With Type 2 Diabetes Mellitus - Third Optimizing Anti-Platelet Therapy in Diabetes MellitUS (OPTIMUS-3)
Authors: Dominick J Angiolillo, Juan Badimon, Jorge F Saucedo, Andrew L Frelinger, Alan D Michelson, Joseph A Jakubowski, Baojin Zhu, Clement K Ojeh, Brian Baker, Mark B Effron
Journal: Circulation (2009)

Introduction: Type 2 diabetes mellitus (T2DM) patients (pts) have decreased response to clopidogrel (Clop) compared to non-diabetic patients. Prasugrel (Pras) has shown to be more efficacious than Clop in reducing thrombotic cardiovascular events in T2DM pts with acute coronary syndrome undergoing percutaneous coronary interventions. However, the pharmacodynamic effects of Pras compared to Clop in T2DM have not been fully explored. The OPTIMUS-3 study evaluated pharmacodynamic responses of Pras compared with Clop in coronary artery disease (CAD) pts with T2DM. Methods: A total of 35 CAD pts with T2DM on chronic aspirin were randomized to Pras 60 mg loading dose (LD)/10 mg maintenance dose (MD) or Clop 600 mg LD/150 mg MD for 1 week in a double-blind cross-over design with a 2 week washout period between study drugs. Platelet function was assessed by the VerifyNow P2Y12 (VN-P2Y 12 ) assay, light transmission aggregometry (LTA) following 5 and 20 μ M ADP, and phosphorylation of vasodilator stimulated phosphoprotein (VASP), at baseline, 1 hr, 4 hr and 24 hr post LD, and 6 – 8 days post-MD. The primary comparison of inhibition of platelet aggregation (IPA) at 4 hours after LD between 60 mg Pras and 600 mg Clop was assessed by VN-P2Y 12 . Results: Significantly greater IPA by VN-P2Y 12 at 4 hr post LD was achieved by Pras vs. Clop (89.3 % vs. 27.7%, p&lt;0.0001). Significantly greater IPA was also observed at 1 hr and 24 hr post LD and 7 days post-MD (Figure ). Similar results were obtained when platelet function was assessed by VN-P2Y 12 Reaction Units, LTA and VASP. Conclusion: In CAD pts with T2DM, Pras is associated with significantly greater inhibition of platelet function than high LD and MD regimens of Clop.
Abstract 4161: Cholesterol Levels in Different LDL Subclasses and CHD Incidence in Apparently Healthy Men and Women: The EPIC-Norfolk Prospective Population Study
Authors: Benoit J Arsenault, Isabelle Lemieux, Jean-Pierre Després, Matthijs S Boekholdt, Nicholas J Wareham, Sheila A Bingham, Kay-Tee Khaw
Journal: Circulation (2006)

Background: Measurement of cholesterol levels in small LDL particles represents a novel metabolic marker that might add to the coronary risk prediction attributed to LDL cholesterol and LDL particle size taken separately. We examined, in a nested case-control study performed in the prospective EPIC-Norfolk cohort, the association of LDL cholesterol in small LDL particles to future CHD in apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CHD over 10-year follow-up. Methods and results: Cases (n=1035) were matched to 1920 controls who remained free of CHD, by age, gender and enrollment time. Electrophoretic characteristics of LDL particles were measured using 2–16% nondenaturing polyacrylamide gradient gel electrophoresis. Cholesterol levels in small LDL particles (&lt;255 Å) were higher in cases than in controls (1.26 ± 0.87 vs. 1.07 ± 0.78 mmol/l, P&lt;0.001) Participants in the top tertile of cholesterol concentrations in small LDL particles were characterized by the highest waist circumference, by the highest triglyceride, C-reactive protein and apolipoprotein B levels and by the lowest HDL cholesterol concentrations. These participants had an unadjusted odds ratio (OR) for future CHD of 1.72 (95% CI, 1.42 to 2.09; P&lt;0.001) which remained significant after adjustment for classical risk factors such as age, smoking, diabetes, body mass index, systolic blood pressure and LDL cholesterol concentrations (OR, 1.43; 95% CI, 1.16 to 1.76; P=0.001). However, after further adjustments for triglyceride and HDL cholesterol levels, the association between cholesterol in small LDL particles and CHD was no longer significant (OR, 1.18; 95% CI, 0.95 to 1.48; NS). Conclusions: Cholesterol concentrations in different LDL subclasses show different relationships with CHD incidence in a European cohort representative of a contemporary Western population.
2006 Thomas W. Smith Memorial Lecture—From a Girl to a Mouse: A Journey in the Rhythm of the Heart
Authors: Silvia Priori
Journal: Circulation (2006)

In the past 10 years, impressive advancements have occurred in the understanding of genetic bases of cardiac arrhythmias. This field has evolved into truly “translational” science in which the flow of data from bench to bedside has promoted advancements in basic electrophysiology and in clinical arrhythmology alike. As a paradigm of the fruitful integration between basic and clinical science in this area, I will present the story of the discovery of the molecular basis of catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare arrhythmogenic disorder characterized by adrenergically induced polymorphic ventricular tachycardia and sudden death in children. After being profoundly involved in the management of a little girl who experienced cardiac arrest, we diagnosed CPVT and initiated the search for the gene of this disease. We discovered that CPVT is caused by mutations in the cardiac ryanodine receptor’s gene (RyR2), a key protein implicated in the control of intracellular calcium. In vitro functional characterization demonstrated that the mutant RYR2 releases calcium from the sarcoplasmic reticulum during diastole, thus causing life-threatening arrhythmias. We developed a knock-in mouse model of CPVT that carries the same mutation identified in our patients, and this model is now an important source of data contributing to the understanding of CPVT and helping in the assessment of novel therapeutic strategies. Thus, the little girl is now hoping that the mouse will help doctors find a better treatment for her disease.
Abstract 5041: Insulin Resistance Reduces Circulating Endothelial Progenitor Cells and Impairs Endothelial Regeneration Following Wire-induced Vascular Injury
Authors: Matthew B Kahn, Richard Cubbon, Hema Visvambharan, Nadira Yuldasheva, Mark T Kearney, Stephen Wheatcroft
Journal: Circulation (2009)

Introduction: Endothelial progenitor cells (EPCs) contribute to endothelial regeneration following damage accrued through exposure to various risk factors. Type 2 diabetes is associated with reduced EPC numbers, EPC dysfunction and delayed endothelial repair. However, it remains unknown whether insulin resistance per se has an effect on EPCs or endothelial regeneration. Methods: We assessed metabolic and endothelial function, circulating, spleen- and bone marrow-derived EPCs and endothelial regeneration following wire-injury in mice hemizygous for deletion of the insulin receptor (IR+/−) and their littermate wild type (WT) controls. Results: The metabolic phenotype of IR+/− mice was consistent with compensated insulin resistance, with hyperinsulinaemia after a glucose challenge but a normal blood glucose response to a glucose tolerance test. Endothelial function was impaired in aorta from IR+/− mice, with decreased basal nitric oxide production and blunted eNOS activity in response to insulin. Sca-1/VEGFR-2 positive EPCs, measured in peripheral blood by flow cytometry, were reduced in IR+/− mice compared to WT controls (67±6 vs 87±6 cells/100 000 events; P&lt;0.05). Culture of mononuclear cells from peripheral blood, spleen and bone marrow revealed significantly reduced numbers of circulating EPCs in IR+/− mice compared to WT controls (P&lt;0.05), however there was no difference in the number of spleen- and bone marrow-derived EPCs. Endothelial regeneration, assessed by Evan’s blue staining of femoral artery at intervals following denuding wire-injury, was significantly delayed in IR+/− mice compared to WT controls (reendothelialised area 35.8±4.8% vs 66.6±5.2% at day 5 following injury and 35.6±4.8% vs 59.8±6.6% at day 7 following injury; P&lt;0.05). Conclusions: These novel data demonstrate that mild insulin resistance reduces the number of basal circulating EPCs and delays endothelial regeneration following injury. The findings support the hypothesis that insulin resistance may promote atherosclerosis by adversely affecting the balance between endothelial damage and repair.
Abstract 5019: Circulating MicroRNAs as New Biomarkers of Myocardial Infarction in Man
Authors: Yuri d Alessandra, Paolo Devanna, Federica Limana, Stefania Straino, Franco Moro, Barbara Micheli, Anna Di Carlo, Felice Achilli, Stefano Maggiolini, Giulio Pompilio, Maurizio Colognesi Capogrossi
Journal: Circulation (2009)

Background and objective: microRNAs (miRs) are small non-coding RNAs that regulate translation of messenger RNAs (mRNA) into proteins. Recently, it has been suggested that circulating miR may represent a novel class of biomarkers in cancer and liver disease, however no data are available in cardiovascular diseases. Our objective was to examine miR plasma levels in humans and mice with acute myocardial infarction (MI). Results: We analyzed the expression of 365 human miRs in plasma from healthy donors (n=9) and patients (n=11) with acute MI and ST-segment elevation (STEMI). In STEMI patients, during the initial 1 to 7 hours after the onset of MI symptoms, miR 1, 133a, 133b and 499 plasma levels increased over 10–190-folds (p&lt;0.05) and at day 5 they were back to control values; in contrast, miR 122 and miR 375, at day 0 exhibited a 60 and 80 % decrease, respectively, and at day 30 they were still 50% lower than control (p&lt;0.05). In 4 additional MI patients miR plasma levels were measured simultaneously and in the same blood samples with total CPK and TnI, at frequent intervals after reaching the hospital. All patients were reperfused within 4 hours after admission to the hospital. Both CPK and TnI had their peak expression 6 hours after reaching the hospital; in contrast miR 1, 133a and 133b peak increase was achieved within 3h whereas miR 499 peak occurred at 12 hours. Additional studies were performed in a mouse model of MI and miR plasma levels were measured at a single time point, i.e. 3 hr after coronary artery occlusion. Experiments in sham operated control (n=4) and MI (n=9) mice showed that circulating miR 1, 133a, 133b and 499 increased 10–18 folds (p&lt; 0.01); this miR signature closely mimicked the results in humans. Conclusions: miR 1, 133a, 133b and 499 plasma levels are strongly upregulated after MI and may represent novel and sensitive biomarkers of cardiac damage. The negative regulation of miR 122 and 375 observed in humans raises the possibility that in man, during severe cardiac ischemia, miR release from cardiac cells may be due also to the modulation of active transport mechanisms and not only to cardiac necrosis.
MicroRNA-210 Controls Metabolic Adaptation During Hypoxia in Pulmonary Vascular Endothelium
Authors: Stephen Y. Chan
Journal: Circulation (2009)

Abstract #3060 Stephen Y. Chan, Massachusetts General Hosp, Brigham &amp; Women’s Hosp, Boston, MA; Ying-Yi Zhang, Brigham &amp; Women’s Hosp, and Harvard Medical Sch, Boston, MA; Craig Hemann, Jay L. Zweier, Ohio State Univ, Columbus, OH; Joseph Loscalzo, Brigham &amp; Women’s Hosp, and Harvard Medical Sch, Boston, MA Stephen Y. Chan, 2009 Finalist and Presenting Author
Abstract 5050: Wnt11 Enhances Mesenchymal Stem Cells Mediated Angiogenesis via Paracrine Signaling
Authors: Shi Zuo, Hongxia Li, Zhisong He, Yigang Wang, Muhammad Ashraf, Meifeng Xu
Journal: Circulation (2009)

Neovascularization is essential for an organ repair. It has been previously reported that MSC transfected with Wnt11 (MSC Wnt11 ) promotes ischemic heart repair through protecting native cardiomyocytes. However, the mechanism of cardioprotection of MSC Wnt11 remains unknown. Here, it is hypothesized that Wnt11 may enhance MSC mediated angiogenesis via the paracrine effects. Methods: MSCs were isolated from bone marrow of rats and transfected with Wnt11 using Clontech pMSCV retroviral expression system. MSCs transfected with GFP (MSC GFP ) were used as control. MSC (2×10 6 /50 μ l) were transplanted into the border area of ischemic rat hearts which have already underwent left anterior descending coronary artery (LAD) ligation. Four weeks post LAD ligation, regional myocardial blood flow in the ischemic and border zone was evaluated with a colored microsphere technique. The blood vessels were stained with von Willebrand factor (vWF) and counted in peri-infarct regions. Spontaneous capillary-like structure formation was monitored with Gelatin-coated Cytodex 3 microcarrier beads. The expression of growth factors was assayed by microarray and ELISA. Results: The blood flow was significantly increased and the density of blood vessel was higher in MSC Wnt11 transplanted heart than that in MSC GFP transplanted hearts (Fig. A, B ). Microcarrier beads were completely covered by MSC Wnt11 and formed a confluent monolayer and sprouts than MSC GFP (Fig. C ). Growth factors were highly expressed in MSC Wnt11 (Table and Fig. D ). Conclusions: Wnt11 promotes MSC mediated angiogenesis via up-regulating paracrine factors.