tbuckley/cabot-search huggingface dataset:
Abstract 18616: NoxA1-Dependent NADPH Oxidase Regulates VSMC Phenotype, Hypertension, and Atherosclerosis
Authors: Arihiro Sumida, Aleksandr E Vendrov, Jinling Yuan, Qi-An Sun, Nageswara R Madamanchi, Marschall S Runge
Journal: Circulation (2013)

Increased oxidative stress and inflammation are key components in the pathogenesis of atherosclerosis and hypertension. We previously reported that Nox activator 1 (NoxA1) is the functional homolog of p67phox in Nox1 NADPH oxidase activation in mouse vascular smooth muscle cells (VSMCs), and its mRNA and protein expression are induced by TNF-α, a proinflammatory cytokine. Here we investigated the physiological function of NoxA1-dependent NADPH oxidase activity in mouse VSMCs, and NoxA1 expression in human aortic SMCs (HASMCs), in response to TNF-α. Furthermore, we evaluated the role of this enzyme in angiotensin II-mediated hypertension and in atherogenesis in ApoE -/- mice. TNF-α-induced ROS generation was significantly attenuated in NoxA1 -/- VSMCs compared with the wild-type (p &lt;0.05). NoxA1 deletion also significantly decreased TNF-α-induced DNA synthesis and migration in mouse VSMCs (p &lt;0.05 in each case). In HASMCs, NoxA1 mRNA expression was 10-fold higher than that of p67phox, and NoxA1 mRNA and protein expression were markedly induced by TNF-α (p&gt;0.05 in each case). Angiotensin II infusion for 2 weeks significantly increased systolic blood pressure in wild-type mice, but this response was attenuated in NoxA1 -/- mice. Atherosclerotic lesion size was reduced by 50% in ApoE -/- /NoxA1 -/- compared with ApoE -/- in mice that were fed Western diet for three months. ROS levels in the aortic wall of ApoE -/- /NoxA1 -/- were significantly lower compared with ApoE -/- mice. In addition, ApoE -/- /NoxA1 -/- mice had less accumulation of inflammatory CD11b + macrophages, CD3 + T-lymphocytes, and c-kit + mast cells in atherosclerotic lesions. In conclusion, NoxA1-dependent NADPH oxidase regulates oxidative stress, inflammation, angiotensin II-induced hypertension, and atherogenesis in hypercholesterolemic mice, suggesting that selective targeting of NoxA1 is beneficial.
Abstract 18510: Pericardiectomy Impact on Cardiac Index in Patients With Constrictive Pericarditis
Authors: M Chadi Alraies, Teerapat Yingchonch?aroen, Alpana Senapati, Mohammad U Tariq, Allan L Klein
Journal: Circulation (2013)

Background: Advanced constrictive pericarditis (CP) has been associated with change in cardiac hemodynamics including cardiac output and cardiac index (CI). Etiology and duration of constriction can affect recovery of CI postpericardiectomy. We sought to look into the change in post-operative cardiac index (CI) among different CP etiologies using echocardiogram and right heart catheterization. Methods: We Included 301 patients from Cleveland Clinic pericardial disease database with surgically confirmed CP form 1999 to 2010. Post-operative CI was measured using Fick method immediately before and after pericardiectomy. The bootstrap-validated analysis of covariates was performed to compare the mean of post-operative CI among different CP etiologies after adjustment with baseline relevant covariates. Results: Etiology of CP was idiopathic in 136 patients (45%), viral in 24 patients (8%), prior cardiac surgery in 89 patients (30%), autoimmune in 30 patients (10%) and radiation treatment in 22 patients (7%). Mean CI was reduced and improved after pericardiectomy (2.1±0.7 L/min/m2 to 3.0±0.8 L/min/m2, p&lt;0.001). After adjustment for age, gender, NYHA, LVEF, RVSP, medial e’, lateral e’ and pre-operative CI, the post-operative CI recovered based on different etiologies (2.99±0.7, 3.07±0.16, 3.00±0.09, 3.48±0.15 and 2.76±0.17 L/min/m2 for Idiopathic, viral, prior cardiac surgery, autoimmune and post radiation respectively, p=0.019) (Figure1). Conclusion: Post-operative cardiac index recovery is related to underlying etiology. Considering CP etiology for patient selection for pericardiectomy may identify patients who will benefit from the surgery and avoid post-pericardiectomy low cardiac output syndrome that may lead to early post-operative mortality
Abstract 18326: Elevated Right Ventricular Operant Diastolic Elastance Strongly Predicts Increased Risk of Mortality Following Heart Transplantation
Authors: June-Wha Rhee, Naga L Sudini, Michael Pham, William Fearon, David Lee, Ramin E Beygui, Jose G Montoya, Joseph C Wu, Bojan Vrtovec, Sharon A Hunt, FranÇois Haddad
Journal: Circulation (2013)

Background: Hemodynamic parameters are routinely measured at 1 year after heart transplant but their prognostic implications have not been extensively studied. Previous research has suggested that post-transplant right ventricular diastolic dysfunction (RVDD) is a strong predictor of cardiac mortalities. However, these results have not been independently validated. Thus, we aim to evaluate the incidence, correlates, and prognostic implication of post-transplant RVDD defined as elevated ventricular operant diastolic elastance (Ed). Methods: All patients who underwent heart transplantation at Stanford University between 1999 and 2011 with right-heart catheterization at 1-year post-transplant were included. RV Ed was calculated as mean right atrial pressure divided by stroke volume (SV). Left ventricular (LV) Ed was calculated as mean pulmonary capillary wedge pressure divided by SV. Predefined RV Ed greater than 120 mmHg/mL and LV Ed greater than 200 mmHg/mL were considered significantly elevated. Results: In total, 216 patients were included in the study with mean age of 49±15 years. Abnormal RV Ed and LV Ed were found in 23% and 27% of the patients, respectively. RV Ed and LV Ed were strongly correlated with an r= 0.89 (P&lt;0.001). Logistic regression analysis revealed that pre-transplant ventilatory support, cyclosporine-based therapy, LVEF &lt;55% at 1 year, and cardiac allograft vasculopathy (CAV) at 1 year were strongly associated with RVDD (OR 11 (95% CI 1.6-76), 2.5 (1.2-5.6), 4.4 (2.0-9.9), and 9.6 (1.7-56) respectively). Patients with RVDD were at significantly increased risk of death with adjusted HR of 3.28 (95% CI 1.8-5.8). Other significant independent correlates include pre-transplant life support and history of rejections at 1 year. Conclusion: Post-transplant RVDD at 1 year is a strong independent predictor of outcome following heart transplantation. Further studies are warranted to see whether therapies targeted for RVDD could improve outcome.
Abstract 18378: Apical and Anterior Lead Location of Surgically Implanted Epicardial Left Ventricular Leads in Cardiac Resynchronization Therapy is Associated With Lower Survival Rate
Authors: Lu CHEN, Haixia Fu, Yong-Mei Cha, Ulrika M Birgersdotter-Green, Victor Pretorius
Journal: Circulation (2013)

Introduction: Surgically implanted epicardial left ventricular (eLV) lead is an alternative approach when transvenous LV (tLV) lead implantation in CRT patients has failed. With advancement in surgical technique and free from limitations of cardiac venous anatomy, operators have the freedom to choose the most optimal LV pacing site. Recent literatures noted differential clinical response in tLV-CRT patients with different LV lead locations. However, to the best of the authors’ knowledge, no such analysis has been published for eLV-CRT patients. Hypothesis: We hypothesize that optimal LV lead location in eLV-CRT is similar to tLV-CRT and similar clinical response is expected. Methods: After unsuccessful attempt(s) of tLV-CRT implantation, 44 (Age 63±15, 28M) patients received eLV-CRT from UCSD and Mayo Clinics between 2002 and 2013. Two-view (PA, lateral) chest radiographs were used to determine lead location by blinded independent observers. 9 patients were partially excluded from lead location analysis due to congenital cardiac anomaly or unavailable lateral chest radiograph. eLV lead locations were classified as basal, mid, or apical on the PA view; and anterior, anterolateral, lateral, posterolateral, or posterior on the lateral view. Survival data were collected from the national death and location database. Results: During an average follow up of 65 months, 15 patients have died following eLV-CRT implant. No death was attributed to acute surgical complication to eLV-CRT implantation. Kaplan-Meyer survival estimate showed anterior and apical eLV lead positions had lower survival rate as compared to non-anterior (p&lt;0.01, figure A) and non-apical location (p=0.07, figure B). Conclusion: In this two-center study, apical and anterior eLV lead locations were associated with significantly lower survival rate. The study implies apical and/or anterior locations should be avoided, if possible, during eLV-CRT implantation.
Abstract 18501: A Major Opportunity for Obstetricians and Gynecologists: Improving Awareness of Cardiovascular Disease Among Women
Authors: Allison J Brusati, Mary L Rosser
Journal: Circulation (2013)

Background: Cardiovascular disease (CVD) is the number one killer of women in the US, yet many women are still unaware of their risk of heart disease. A large ethnic gap in awareness exists: black and Hispanic women correctly identified CVD as their greatest health threat 36% and 34% of the time, respectively, compared to 56% of American women overall (Mosca 2013). We sought to determine the proportion of women who name heart disease as the leading killer of women in a diverse urban hospital in New York City. We also sought to determine which providers women see for primary care and if heart health was discussed by Ob/Gyns. Methods: A 33-question survey was administered to women (age 18 and older) at 5 Ob/Gyn clinics affiliated with a large urban academic hospital center. Results: 1013 questionnaires were completed. Of the female population analyzed, 63.3% were 18-40 years old and 35.3% were 41+ years old. Respondents were 40% Hispanic, 31% black, 20% white, 9% multi-ethnic and 30.5% have high school or less education and 42% have annual household income less $30K. Of all women sampled, only 28% were able to cite heart disease as the number one killer of women, 55% of these respondents were white and 21% were non-white (p&lt;0.01). Young women identified CVD less frequently than older women (21% v 40%) (p&lt;0.01). Respondents reported seeing an Ob/Gyn for annual visits more frequently than an Internist (66% v 48%) (p&lt;0.01). This response was consistent among all age and ethnic groups analyzed. Most women (65%) (p&lt;0.01) perceive that their Ob/Gyn does not discuss their heart health. This finding is consistent among non-white women (64%) and women 18-40 years old (66%). Conclusions: Young, non-white women are least aware of cardiovascular disease as the leading killer of women. Awareness (21%) among non-white women in this urban, ethnically diverse part of New York City is even lower than levels of awareness reported among minorities nationally. These very women are more likely to see an Ob/Gyn annually than any other physician, and yet few women report that Ob/Gyns discuss their heart health. Given the high morbidity of CVD in women, Ob/Gyns should take advantage of their enormous access to young, reproductive aged women to begin a dialogue about heart health aimed at prevention.
Abstract 18484: Impaired Skeletal Muscle Efficiency and Power After Correction for Lean Muscle Mass in Patients With Advanced Heart Failure
Authors: Christina Wu, Mark Dunlop, Hilary Armstrong, Tomoko S Kato, Daniel Foreman, Matthew N Bartels, Paul Christian Schulze
Journal: Circulation (2013)

Introduction: Patients with advanced heart failure (HF) develop metabolic abnormalities leading to skeletal muscle wasting and changes in body composition that include lean skeletal muscle and adipose tissue. Hypothesis: We hypothesized that HF subjects have decreased skeletal muscle efficiency, work performance and muscle power compared to control subjects. Methods: Whole body dual-energy X-ray absorptiometry (DEXA) scanning for determination of total body mass, fat mass, % body fat, lean body mass was performed in 9 control subjects (age 51±8 yrs, EF 63.0±4.2 %, BMI 25.7±28.2 kg/m 2 , peak VO2 30.3±7.4 mL/kg/min) and 31 HF subjects (age 59±10 yrs, EF 27.9±7.8 %, BMI 28.2±4.7 kg/m 2 , peak VO2 15.3±3.8 mL/kg/min). Muscle function was assessed by isometric and isokinetic functional testing using the Biodex System 4 Pro of all extremities. Functional parameters were corrected for lean muscle mass determined by DEXA scanning. Results: Total fat mass and percentage body fat were higher in HF subjects (fat mass: 25.5±7.8 vs 16.4±4.8 kg in controls; p=0.002; % body fat: 31±7 vs 23±7 % in controls; p=0.006) without differences in any of the parameters of lean muscle mass. After correction for lean muscle mass, HF subjects showed decreased muscle power (0.32±0.15 vs 0.45±0.13 watts/kg in controls; p=0.02) and total muscle work (2.57±1.16 vs 3.58±0.94 J/kg in controls; p=0.02) in the lower extremities. Of note, no differences between HF and control subjects were found in the upper extremities. Conclusion: HF subjects have similar lean muscle mass compared to controls. Skeletal muscle power and work performance is significantly reduced in HF subjects even when normalized for lean muscle mass. These novel findings indicate the development of an intrinsic skeletal myopathy that is impairing muscle performance and likely contributes to increased fatigue and frailty in patients with advanced HF.
Abstract 18592: A Hmg-Coa Reductase Inhibitor (Statin) Directly Activates Endothelial Erk5 and Prevents Endothelial Dysfunction and Acute Cardiac Allograft Rejection
Authors: Nhat-Tu Le, Yuichiro Takei, Yuki Izawa-Ishizawa, Kyung-Sun Heo, Hakjoo Lee, Carolyn McClain, Hannah Cushman, Alan V. Smrcka, Benjamin Miller, Kyung Ae Ko, Craig Morrell, Keigi Fujiwara, Masashi Akaike, Jun-ichi Abe
Journal: Circulation (2013)

Background: Statins inhibit HMG-CoA reductase and are principal therapeutic agents for the treatment of hypercholesteremia. However, statins also have cholesterol-independent effects such as improving endothelial cell (EC) functions, preventing cardiovascular diseases and suppressing cardiac allograft rejection. How statins exert these cholesterol-independent effects is not known. Because ERK5 exerts beneficial effects on ECs and is anti-atherogenic, it may play a role in these statin effects. Methods and Results: We screened small molecules that activate ERK5 using high throughput screening and found that several statins were strong activators of ERK5 transcriptional activity. We found pitavastatin was especially effective. It increased ERK5 transcriptional activity and the promoter activity and mRNA expression of KLF2 and eNOS in ECs. These effects were abolished by the depletion of ERK5 but not its direct upstream kinase, MEK5. We found that pitavastatin dose-dependently activated ERK5 kinase activity in an in vitro kinase assay, suggesting that ERK5 is a direct target of statins. To examine roles of statin in EC ERK5 activation in vivo, we used inducible endothelial ERK5 knock out (EC-ERK5-KO) mice. When EC ERK5 was depleted, these mice exhibited significantly increased EC inflammation (increased leukocyte rolling) and dysfunction (impaired vascular reactivity), and these conditions could not be corrected by pitavastatin. However, when the EC inflammation and dysfunction were induced in wild type (WT) mice by STZ treatment (i.e. diabetic), their conditions were reversed by pitavastatin. Interestingly, the heart from EC-ERK5-EKO mice had significantly increased mRNA levels of inflammatory genes (TNFα, MCP1, IL-1, IL-6) and decreased expression of an anti-inflammatory cytokine, IL-10. Hearts from EC-ERK5-KO and littermate WT mice were used to perform prolonged allograft survival in a full allomismatch combination model. After 5 days of transplantation, a robust increase in inflammatory gene expression was inhibited by pitavastatin in WT but not in EC-ERK5-EKO hearts. Conclusion: These data suggest a crucial role of endothelial ERK5 in the pleiotropic effects of statins on EC dysfunction and allograft rejection.
Abstract 18369: Interleukin-1 Blockade Improves Exercise Capacity in Heart Failure With Preserved Ejection Fraction (HFpEF): Results of the D-HART Study
Authors: Benjamin W Van Tassell, Ross A Arena, Claudia Oddi, Justin Canada, Nayef Abouzaki, Arehzo Jahangiri, Ryan Melchior, Raquel A Falcao, Michael C Kontos, Keyur Shah, Norbert F Voelkel, Charles A Dinarello, Antonio Abbate
Journal: Circulation (2013)

Treatment options remain limited for patients with heart failure and preserved ejection fraction (HFpEF). Reduced exercise capacity is a common finding in HFpEF. Peak oxygen consumption (peak VO2) represents a gold standard for functional capacity and is a strong independent predictor of adverse outcomes. HFpEF patients also exhibit high levels of systemic inflammation that may be associated with mechanisms of diastolic dysfunction. We enrolled 12 patients with symptomatic HFpEF (LVEF&gt;50% and evidence of abnormal LV relaxation, filling, diastolic distensibility, or diastolic stiffness) and elevated hsCRP (&gt;2 mg/L). Patients were randomized to 14 day crossover treatment with daily subcutaneous injections of IL-1 receptor antagonist (anakinra); 100 mg or matching placebo in a double blind fashion ( NCT01542502 ). The pre-specified primary endpoint was change in peak VO2. Cardiopulmonary exercise testing was performed at baseline and upon completion of each treatment course. We observed a significant improvement in peak VO2 (+1.1 vs -0.1 ml•kg-1•min-1, P=0.009) and the oxygen uptake efficiency slope (+0.23 vs +0.09, P=0.006) and a significant reduction in hsCRP (-84% vs -10%, P=0.006) upon completion of anakinra treatment versus placebo. Correlative studies also revealed significant associations between changes in peak VO2 and hsCRP (R=-0.60, P=0.002). Improvements in ventilator efficiency (VE/VCO2 slope) were limited to patients with above median values for ventilator efficiency (VE/VCO2 slope&gt;26), suggesting that maximum benefits may occur in patients with impaired baseline function. These findings support the hypothesis that systemic inflammation and exercise intolerance in HFpEF are, at least in part, IL-1-dependent and provide the rationale for larger randomized clinical trials to confirm the benefits of IL-1 blockade in patients with HFpEF.
Abstract 18427: Impact of Medication on Quantification of Plasma MicroRNAs in Patients With Cardiovascular Disease
Authors: Dorothee Kaudewitz, Regent Lee, Peter Willeit, Anna Zampetaki, Allison C Morton, Tim D Warner, Robert F Storey, Keith Channon, Manuel Mayr
Journal: Circulation (2013)

Background: MicroRNAs are small non-coding RNAs that are detectable in the blood. Circulating levels of microRNAs have been measured in various epidemiological studies, but the effects of medication are unclear. To address these uncertainties, we assessed how plasma microRNAs change in response to platelet inhibition and heparin administration. We also correlated plasma levels of microRNAs with existing markers of platelet activation. Methods and Results: 92 microRNAs were assessed in a dose-escalation study with aspirin and prasugrel in healthy volunteers (n=11). Plasma levels of platelet microRNAs, such as miR-223, miR-191 and others decreased on platelet inhibition. Findings were confirmed by individual TaqMan qPCR assays and validated in an independent cohort of patients with symptomatic carotid stenosis (n=33). In a cohort of patients on dual anti-platelet therapy 30 days post myocardial infarction (n=129), plasma levels of most platelet microRNAs were positively correlated to the VASP assay. Levels of miR-126 were also significantly associated with results from the VerifyNow P2Y12 aggregation assay. No association was observed with optical aggregometry with arachidonic acid or ADP. When platelet-poor plasma was collected at different time points from patients undergoing PCI (n=20) or diagnostic angiography with (n=7) and without (n=10) heparin administration, heparin was found to have pronounced effects on the assessment of the exogenous C. elegans spike-in control (decrease by &gt;3 cycles), which disappeared six hours after the heparin bolus. Normalisation of individual microRNAs with the average cycle threshold value of all microRNAs provided a suitable alternative to normalization with exogenous C. elegans spike-in control in this setting. Conclusions: Our studies provide evidence for a correlation of plasma microRNAs with commonly used methods in platelet testing. They also highlight that microRNA levels are sensitive to medication, in particular antiplatelet and anticoagulation therapy. This has to be taken into account when designing studies to investigate the relation of circulating microRNAs to cardiovascular disease.
Abstract 18333: Tdag51 Deficiency Protects Against Aortic Vascular Calcification by Attenuating Smooth Muscle Cell Death and Osteoblastic Trans-Differentiation
Authors: Imtisal Al-Bondokji, Alistair Ingram, Joan Krepinsky, Richard Austin
Journal: Circulation (2013)

Vascular Calcification (VC), a severe complication increasing the risk of cardiovascular (CV) mortality and morbidity in ageing, diabetic and chronic renal failure patients. VC occurs as vascular smooth muscle cells (VSMC) differentiate into osteoblast- like cells or undergoing apoptosis, resulting in arterial stiffness, elevated pulse pressure (PP) and left ventricular hypertrophy. Yet, molecular mechanisms modulating VSMC differentiation and viability are unclear. Our previous findings demonstrate that T-cell death associated gene 51 (TDAG51, pleckstrin homology-like domain family member) deficiency protects against atherosclerotic lesions. This study provides evidence that TDAG51 contributes to VC by regulating osteogenic transcription factor RUNX2 expression and VSMC survival. To study aortic calcification (AC), male C57Bl/6 wild-type (TDAG51+/+) and TDAG51 deficient (TDAG51-/-) mice were injected subcutaneously with Vitamin D3 (VD3, 50,000 IU/kg) or vehicle (0.9% Saline) for 10 days, an established model of VC. AC was assessed by plasma Pi and Ca2+ levels and aortic valve, thoracic and abdominal aorta segments stained with von Kossa. Osteogenic differentiation and TDAG51 levels were assessed by immunoblot, qRT-PCR and immunohistochemistry. TDAG51-/- mice are protected against osteogenic differentiation in aortic artery. Hallmark features of VC including elastinolysis, collagen deposition and RUNX2 expression were significantly reduced in TDAG51-/- mice compared to control. TDAG51-/- mice maintained PP levels. Microarray analysis revealed ENPP1 (inhibitor of VC) was increased 15-fold in cultured TDAG51-/- aortic smc. The results were verified by qRT-PCR and immunoblots showing elevated ENPP1 expression in TDAG51-/- in presence or absence of VD3 compared to control. Also plasma pyrophosphate remained elevated in TDAG51-/- mice in presence of VD3, indicating increased endogenous ENPP1 activity. ENPP1 transient knockdown in TDAG51-/- vsmc lead to VC, elevated RUNX2, alkaline phosphatase activity and apoptosis. Our data demonstrate TDAG51 is a novel and key promoter of VC by regulating RUNX2 and ENPP1 levels in VC. TDAG51 loss confers protection against VC, apoptosis and PP elevation thereby reducing CV injury risk.