tbuckley/cabot-search huggingface dataset:
Abstract 18495: Lung Inflammation Impairs Hypoxic Pulmonary Vasoconstriction Through Activation of Nuclear Factor of Activated T-Cells
Authors: Dustin R Fraidenburg, Guillaume Voiriot, Nicole M Pohl, Kimberly A Smith, Jason X Yuan
Journal: Circulation (2013)

Hypoxic pulmonary vasoconstriction (HPV) is an important physiologic mechanism that directs blood flow away from poorly ventilated regions of the lung toward well-ventilated regions in order to maintain optimal ventilation (V) and perfusion (Q) matching which supports adequate gas exchange and oxygenation. Impaired HPV has been implicated in multiple disease processes that are associated with both hypoxemia and inflammation. Nuclear factor of activated T-cells (NFAT) is a calcium-dependent transcription factor with emerging evidence to suggest an important role in inflammatory as well as cardiovascular disorders. We hypothesize that lipopolysaccharide (LPS)-induced lung inflammation leads to impaired HPV as a result of NFAT activation. In the current study we have utilized the isolated perfused mouse lung (IPL) preparation to test acute hypoxic pulmonary vasoconstriction. Murine lung inflammation is induced by intratracheal instillation of LPS (1 mcg/gm body weight) and acute hypoxic pulmonary vasoconstriction is elicited by five minute challenges of 1% inspired oxygen tension. LPS-induced lung inflammation significantly impairs HPV at 24 hours compared to sham (saline) treatment. In protein isolates from whole mouse lung lysates, LPS-induced lung inflammation is associated with significant increases in both calcineurin and NFATc3 protein expression at 24 hours. Finally, pretreatment with a calcineurin inhibitor, cyclosporin A, one hour prior to LPS treatment prevents the impaired HPV seen in LPS-induced lung inflammation in a dose dependent manner at 30 and 100 mg/kg. We conclude that LPS-induced lung inflammation impairs hypoxic pulmonary vasoconstriction in mice. This effect is mediated by NFAT activation and we show that inhibition of calcineurin, leading to decreased NFAT activation, can attenuate the impaired HPV seen in murine lung inflammation. Impaired HPV results in V/Q mismatching and worsening hypoxemia, a detrimental effect in both acute and chronic cardiopulmonary disease. These results implicate NFAT as a potential novel therapeutic target in diseases characterized by hypoxemia and impaired HPV. We plan to continue this work to determine the downstream effects of NFAT activation that lead to impaired HPV.
Abstract 12477: Association of Age and Outcome After Bidirectional Cavopulmonary Anastomosis
Authors: Andrew M Koth, Claudia A Algaze, Shiying Hao, Andrew Y Shin
Journal: Circulation (2016)

Introduction: The Glenn procedure has traditionally been performed between 4-6 months of age. Several studies have investigated the benefits of performing the procedure earlier, to shorten the inter-stage period. No studies have specifically looked the unintended consequences of early Glenn procedures (&lt; 4 months) related to post-operative outcomes. Hypothesis: We hypothesized that after the Glenn procedure, younger patients would have a longer post-operative length of stay. Methods: All patients undergoing the Glenn procedure between 1/2010 and 7/2015 were included in this retrospective cohort study. Demographic data, including baseline saturations, medications, length of intubation and chest tube drainage were recorded. Mean post-operative length of stay was calculated. Standard descriptive statistics were used. A univariable analysis was conducted using the appropriate test based on data distribution. A multivariable analysis was then completed using predictors from the univariable analysis. Results: Over the study period, 50 patients were included. Patients were separated into two cohorts[≥4 months (28) and &lt;4 months (22)]. Other than height and weight, the two cohorts were indistinguishable in their pre-operative saturation, medications, catheterization hemodynamics, atrioventricular valve regurgitation and ventricular function. Length of intubation and chest tube drainage were not different between the cohorts. Younger age was associated with longer post-operative length of stay [mean 14.6 (±15) vs. 7.7(±5.1) days, p =0.03]. In a multivariable regression analysis, in addition to ventricular dysfunction ( B coefficient 8.8, p =0.05), Glenn procedures performed before 4 months were independently associated with longer length of stay ( B coefficient -6.9, p =0.03). Conclusion: We found that elective Glenn procedures performed after 4 months of age had improved outcomes compared to a younger cohort. These findings suggest that balancing timing of surgery to decrease the inter-stage period should take into consideration differences in post-operative recovery with early operations.
Abstract 13138: Antioxidant-1, a Copper Transport Protein, promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function
Authors: Sudhahar Varadarajan, Gin-Fu Chen, Archita Das, Seock-Won Youn, Bayasgalan Surenkhuu, Jaehyung Cho, John W Christman, Saran Shantikumar, Gianni D Angelini, Costanza Emanueli, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2015)

Copper (Cu), an essential micronutrient, has been implicated in inflammation and angiogenesis with unknown mechanism. Cu transport protein, antioxidant-1 (Atox1) functions not only as Cu chaperone to activate secretory Cu enzymes (including lysyl oxidase (LOX)) via Cu transporter ATP7A, but also as Cu-dependent transcription factor. However, role of Atox1 in inflammatory neovascularization has not been investigated. Here we show that Atox1 expression is markedly upregulated in patients and mice with critical limb ischemia. Together with immunohistochemistry, micro-CT analysis and sponge implant assay, Atox1 KO mice exhibit impaired ischemia induced perfusion recovery, arteriogenesis/angiogenesis and inflammatory cell infiltration (46%). Furthermore, bone marrow (BM) reconstitution and adenovirus mediated Atox1 gene transfer in Atox1 KO mice show that Atox1 in tissue resident endothelial cells (ECs), but not in BM cells, is essential for neovascularization and recruitment of inflammatory cells which release angiogenic cytokines TNFα and VEGF. Mechanistically, Atox1 depletion of mice or ECs shows inhibition of ischemia (3.4-fold) and VEGF (1.6 fold) induced extracellular matrix/secretory Cu enzyme LOX activity in Cu/ATP7A-dependent manner, resulting in impaired (42%) capillary tube formation. Moreover, Atox1 knockdown in ECs inhibits ROS production (2.5 fold) and its downstream NFκB-DNA binding, VCAM1/ICAM1 expression and monocyte adhesion in ECs activated by TNFα, in Cu-dependent and ATP7A-independent manner, which are further supported by in vivo DHE staining and Bioluminescence imaging of NFκB reporter mice. Of note, Atox1 translocates to the nucleus (90%) in response to TNFα, thereby increasing transcription of p47phox NADPH oxidase by binding to its promoter in Cu-dependent manner. p47phox re-expression rescued reduced TNFα -induced VCAM1 expression in Atox1 KO ECs. In summary, Atox1 plays an important role in inflammatory neovascularization via Cu chaperone for LOX to increase angiogenesis as well as transcription factor for p47phox to promote ROS and inflammatory responses. Thus, Atox1 is a potential therapeutic target for promoting tissue repair in ischemic cardiovascular disease.
Abstract 18519: Increased Mean Diffusivity (Brain Injury) Values in Insular, Hippocampal, Frontal, and Cerebellar Sites in Heart Failure
Authors: Mary A Woo, Rajesh Kumar, Gregg C Fonarow
Journal: Circulation (2013)

While gray matter injury appears in heart failure (HF), the presence and extent of tissue injury impacting on autonomic, cognitive, emotional, and breathing regions is unclear. Methods: We performed diffusion tensor imaging in 16 HF (age, 55.1±7.8 years; LVEF, 27.7±6.7; 12 male) and 26 control subjects (49.7±10.8 years; 17 male), and assessed whole-brain mean diffusivity (MD) changes across the brain in HF compared to controls. Groups were compared between groups using ANCOVA, with age and gender as covariates. Results: Insular (HF vs controls; left insula, 1.08±0.09 vs 0.97±0.06x10-3 mm2/s, p&lt;0.001; right insula, 1.06±0.11 vs 0.98±0.06x10-3 mm2/s, p=0.001), frontal cortices (left frontal, 0.96±0.05 vs 0.89±0.05x10-3 mm2/s, p&lt;0.001; right frontal, 0.93±0.06 vs 0.87±0.05x10-3 mm2/s, p=0.001), hippocampal (left hippocampus, 1.18±0.26 vs 1.03±0.12 x10-3 mm2/s, p=0.04; right hippocampus, 1.33±0.40 vs 1.03±0.13x10-3 mm2/s, p=0.01), and cerebellar (left cerebellar, 0.90±0.09 vs 0.81±0.05x10-3 mm2/s, p&lt;0.001; right cerebellar, 0.84±0.06 vs 0.78±0.03x10-3 mm2/s, p&lt;0.001) MD values showed significant groups differences (increased MD values in HF, indicative of tissue injury) between HF and control subjects. Whole-brain voxel-based analyses showed multiple brain regions with tissue injury, including the left and right insular lobes, frontal cortices, hippocampal, and cerebellar sites (Figure; p = 0.005) that control autonomic, cognitive, emotional, and breathing processes. CONCLUSIONS: HF subjects show injury in the insular, hippocampal, frontal cortices, and cerebellar areas, sites which control autonomic, cognitive, emotional, and breathing functions. Injury in these areas may contribute to deficient functions found in the condition.
Abstract 18511: Early Re-Implantation After Infected Device Extraction is Safe, Reduces Length of Stay and is Not Associated With a Higher Rate of Reinfection
Authors: Dina M Sparano, Kyle J Ericson, Michael T Broman, Amit K Mehrotra, Harshal Sheth, John H Shin, Martin C Burke, Joshua D Moss, Hemal M Nayak
Journal: Circulation (2013)

Introduction: Cardiac implantable electronic device (CIED) infection often necessitates complete system removal (CSR) and eventual reimplantation. Concern for reinfection and other complication can delay reimplantation. We evaluated whether early reimplantation is safer, reduces length of stay (LOS) and predisposes to a higher reinfection rate than late reimplantation in patients undergoing CSR for CIED infection. Methods: We retrospectively reviewed data in 220 patients with CIED infection requiring CSR from 1995-2013 at a single academic medical center. We compared the incidence of major complications, wound dehiscence, and reinfection in patients undergoing early (≤ 48 hours) versus delayed (&gt; 48 hours) reimplantation. A subgroup analysis in multi-drug resistant organism (MDRO) infections was performed. Results: A total of 97 patients were included. There were 43 patients reimplanted within 48 hours (88.4% men, mean age 69.0 yrs) and 54 patients reimplanted after 48 hours (77.8% men, mean age 65.1 yrs). There were more patients with initial systemic versus local infection in the delayed group (58.6% vs. 18.6%, p=0.0002). Reinfection after early reimplantation was not associated with a systemic presentation (40% vs. 50%, p=0.81). Early reimplantation did not portend a higher risk of major complications (4 vs. 1, p=0.10), wound dehiscence (1 vs. 0, p=0.26) or reinfection (5 vs.2, p=0.13). The findings were similar in early (n=18) versus delayed (n=19) reimplantation in patients with MDRO-positive infections (major complications: 2 vs.1, p=0.52, dehiscence: 0 vs.0, reinfection: 1 vs.1, p=0.97). Early reimplantation was associated with shorter hospital stay than delayed reimplantation (9.3 vs. 16.3 days, p=0.0005). Conclusions: In patients with CIED infection who have undergone CSR, including those with MDRO infections, early device reimplantation within 48 hours is safe, is not associated with a higher reinfection rate and reduces hospital LOS.
Abstract 18437: Distinct Roles of Akt Isoforms in the Development of Hypoxia Induced Pulmonary Hypertension
Authors: Haiyang Tang, Jiwang Chen, Abigail Drennan, Dustin Fraidenburg, Adriana Zimnicka, Kimberly A. Smith, Joe G.N. Garcia, Roberto F. Machado, Ayako Makino, Jason X.-J. Yuan
Journal: Circulation (2013)

Rationale: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by persistent increase in pulmonary arterial pressure associated with vascular remodeling due to excessive pulmonary vascular cell proliferation and migration. Akt/mTOR signaling is involved in regulating cell growth, proliferation, migration and apoptosis. Akt is comprised of three isoforms, Akt1, Akt2, and Akt3, with distinct but overlapping functions. The aim of this study is to examine whether the Akt/mTOR pathway is activated in pulmonary arterial smooth muscle cells (PASMC) from patients with PAH and animals with experimental pulmonary hypertension (PH), and to examine whether Akt1 or Akt2 deficient mice are protected against hypoxia-mediated PH (HPH). Methods: Lung tissues from control subjects and PAH patients as well as control mice and mice with (HPH) were used to study changes in Akt/mTOR mRNA and protein levels using real-time PCR and Western blotting, respectively. WT, Akt1-/- and Akt2-/- mice were exposed to 10% oxygen for up to five weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by RV/(LV+S) ratios were measured to evaluate pulmonary hypertensive changes. Acute hypoxia-induced pulmonary vasoconstriction response, in both WT and KO mice, was evaluated by isolated perfused / ventilated mouse lung. Results: Phosphorylation of Akt and mTOR in lung tissues from PAH patients was significantly increased in comparison to the controls. Akt/mTOR signaling was upregulated in rat and mouse lungs with hypoxia-induced pulmonary hypertension. Akt1-/- mice had significantly lower RVSP, RV/LV+S ratios, and displayed less pulmonary vascular remodeling when compared to WT mice. AKT1-/- mice also had significantly lower pulmonary arterial pressure in response to acute pulmonary vasoconstriction challenges than their WT counterparts. Conclusion: These data indicate that Akt/mTOR signaling plays an important role in the development and progression of pulmonary vascular remodeling in patients and animals with PH. This study suggests a key role for Akt1 in vascular remodeling processes and provides a novel therapeutic target for treatment of PAH.
Abstract 18517: Cardiac BIN1 Folds T-Tubule Membrane to Control Ion Flux and Limit Arrhythmia
Authors: Ting-Ting Hong, Huanghe Yang, Shan-Shan Zhang, Anamika Bhargava, Michael Grabe, Julia Gorelik, Lily Jan, Robin Shaw
Journal: Circulation (2013)

Cardiomyocyte T-tubules allow electrical stimuli to quickly reach the cell interior, triggering calcium transients and muscle contraction. Bridging Integrator 1 (BIN1), a membrane scaffolding protein associated with calcium channel trafficking to cardiac T-tubules, is down-regulated in failing hearts. Here we find that BIN1 also mediates dense folding within cardiac T-tubule invaginations. In mice, heterozygous cardiac specific Bin1 deletion does not affect cardiomyocyte morphology, but on microscopy (Figure 1) and electrophysiological studies, BIN1 knockout removes the T-tubule folds, increasing the rate of local extracellular calcium and potassium ion diffusion. Loss of folds also results in prolongation in cardiomyocyte action potential duration and spontaneous ventricular ectopy in intact animals. We find that the T-tubule folds are rescued by a particular BIN1 isoform, BIN1+13+17, which is specific for cardiac T-tubules, and non-existent in skeletal muscle. We found that BIN1+13+17 uses actin to stabilize cardiac T-tubule membrane at Z-discs, explaining how the folds can form. In conclusion, a cardiac BIN1 isoform recruits the actin cytoskeleton to fold T-tubule membrane, creating a fuzzy space that regulates ion flux and protects against arrhythmia. When BIN1 is decreased, such as in heart failure, arrhythmias can result. Figure 1: TEM images at 150,000X magnification of individual T-tubule cross sections in WT and BIN1 HT mice. Note extra membrane in the WT T-tubule. Bottom panel contains intensity profiles of the two images.
Abstract 18454: Novel Extracellular Matrix Biomarkers as Predictors of Adverse Outcome in Chronic Heart Failure
Authors: Thor Ueland, Ståle Nymo, John Kjekshus, John J Mcmurray, John Wikstrand, Dirk Block, Christian Zaugg, Pål Aukrust, Lars Gullestad
Journal: Circulation (2013)

Background: The extracellular matrix (ECM) plays an important role in left ventricular remodeling and changes in expression patterns of ECM proteins may contribute to the progression of heart failure (HF). Endostatin, biglycan and mimecan are ECM proteins that are abundantly expressed in cardiac tissue but have not been evaluated as prognostic markers in HF. We investigated if they were increased in chronic HF and if levels were associated with adverse outcome. Materials and methods: Serum endostatin, biglycan and mimecan were measured in 187 HF patients and 57 matched healthy controls. Associations with adverse outcome were assessed in 1428 patients enrolled in the in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo, which included patients with HF, aged ≥60 years, in New York Heart Association classes II to IV, who had ischemic heart disease and a reduced left ventricular ejection fraction. Outcome included the primary endpoint (cardiovascular (CV) death, nonfatal myocardial infarction, nonfatal stroke; n=408), all-cause mortality (n=422), CV mortality (n=344), coronary endpoint (n=330) and CV mortality/hospitalization for worsening of HF (n=535). Results: Serum levels of endostatin, biglycan and mimecan were all increased (31-62% p&lt;0.001) in HF patients vs. controls. In univariate analyses and multivariable analysis (adjusting for LVEF, NYHA class, age, BMI, diabetes, sex, intermittent claudication, heart rate, serum creatinine and apoA1 but not CRP and NT-proBNP), endostatin (continuous variable) was associated with all outcomes. However, the predictive value was markedly attenuated and not significant for any outcome after the addition of CRP and NT-proBNP. Biglycan was moderately but significantly associated with all outcome measures (except coronary endpoint) in univariate analysis but not after multivariable adjustment while no associations were observed for mimecan. Conclusions: Serum levels of the ECM proteins endostatin, biglycan and mimecan are all elevated in chronic HF, but add no predictive information beyond NT-proBNP for adverse outcome in older patients with advanced chronic systolic HF of ischemic aetiology.
Abstract 18654: Utility of Cardiac Stroke Score in a Prospective Study of Patients With Ischemic Stroke
Authors: Rachel-Maria Brown, Carlos Corado, Shyam Prabhakaran, Qiong Zhao, Kameswari Maganti
Journal: Circulation (2013)

Background: Ischemic stroke is a major cause of death and disability. Currently, the AHA/ASA guidelines recommend cardiovascular (CV) examination, cardiac enzyme tests, and a 12-lead ECG in all stroke patients. Combining the above parameters with echo, we developed a novel Cardiac Stroke Score (CSS). We investigated whether CSS can predict 1-month CV outcomes in a prospective cohort of ischemic stroke patients. Methods: We studied 333 patients (53.5% male; mean age 66.7 years) from an ongoing prospective stroke registry at Northwestern Memorial Hospital. The CSS was calculated based on serum troponin (&lt;5, &gt;5), ECG changes suggestive of ischemia (absent or present), wall motion abnormalities (absent or present) and ejection fraction (&gt;50%, &lt;50%), assigning a score of 0 or 1 for each of the parameters. Primary endpoints evaluated at 1 month were myocardial infarction (MI), recurrent stroke, readmission, other CV events, and cardiac death. Results: From the overall cohort, 9 patients (2.7%) had troponin &gt;5, 115 patients (35%) had ischemic changes on ECG, 49 patients (15%) had wall motion abnormalities, and 43 patients (13%) had EF &lt;50%. There appears to be a greater trend between the higher CSS and readmission, death and total CV events. Please see table 1. Conclusions: CSS appears to yield a predictive value in determining1 month CV events following an ischemic stroke. However, a larger cohort with more longitudinal follow-up is necessary to confirm our findings. Table 1: One month CV outcomes for the cohort studied. (*= p&lt;0.05)
Abstract 11780: Temporal Trends, Racial and Gender Differences in the Use of Oral Anticoagulation in Medicare Patients With Newly Diagnosed Atrial Fibrillation
Authors: Rajesh Kabra, Mary Vaughan Sarrazin
Journal: Circulation (2016)

Introduction: The novel oral anticoagulants (NOAC’s) have provided convenient anticoagulation alternatives to warfarin for stroke prevention in atrial fibrillation (AF) patients. Hypothesis: We sought to study the temporal trends and racial/gender differences in the use of anticoagulants in AF patients from 2011 to 2013 in Medicare patients with newly diagnosed AF. Methods: Medicare claims from January 2010 to December 2013 were used to identify patients ≥66 years of age with newly diagnosed AF during 2011-2013, with no documented AF or anticoagulant use in the prior year. Race was identified from the Beneficiary Summary File. Data regarding initiation of oral anticoagulation within 90 days of AF diagnosis as well as type of anticoagulant were collected. We compared oral anticoagulant use for each year by race and sex. Results: Of the 755,079 patients with newly diagnosed AF, 85% were white, 6% were black, 5% were Hispanic and 4% were other non-white race. The mean age was 79 years and 58% were females. The proportion of patients receiving anticoagulation within 90 days of AF diagnosis decreased from 45% in 2011 to 40% in 2013. Overall, blacks and Hispanics were less frequently anticoagulated compared to whites (35%, 39% and 45% respectively). Females were also less likely to receive anticoagulation compared to males (45% versus 41% respectively). The use of NOAC’s increased from 27 % of patients who received anticoagulation in 2011 to 44% in 2013. Among anticoagulated patients, blacks and Hispanics were less likely to receive NOACs compared to whites (25% and 30% Vs 36%), and females compared to males (34% vs 36%). Conclusions: In this retrospective study of Medicare patients with newly diagnosed AF, we noted an increase in the use of NOAC’s from 2011 to 2013, but a decrease in the proportion of patients receiving anticoagulation. This highlights the importance of educating health care providers regarding AF and stroke prevention. Blacks or Hispanics and females were less likely to receive any anticoagulation or anticoagulation by an NOAC, compared to whites and males respectively.