tbuckley/cabot-search huggingface dataset:
Abstract 17477: Role of NADPH Oxidase Subunit p67 <sup>phox</sup> in Regulation of Pressure-Overload-Induced Cardiac Hypertrophic Oxidative Stress and Antioxidant Gene Expression
Authors: Chongxu Zhang, Guiqing Zhao, Xianyao Xu, Qiong Zhao, Jing Deng, Lei Xiao
Journal: Circulation (2011)

We had reported a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67 phox that inhibits NOX activity. We showed that transverse aortic constriction (TAC)-induced cardiac hypertrophy was significantly attenuated in the Tg mice, but not in wild type (WT) mice. Since TAC had been reported to increase mouse myocardial reactive oxygen species (ROS) level, we thus tested if the myocardial ROS contributed to the above difference between WT and Tg. Age (10-12 weeks)-, body weight (BW)-matched Tg and WT C57BL/6 male mice were subjected to TAC or sham operation. Cardiac hypertrophy were confirmed 4-week post-TAC by echocardiography, heart weight/BW ratio, and fetal gene expression. Freshly isolated hearts were perfused and the left ventricle (LV) ROS level was determined using chemiluminescence method. Surprisingly, we found that the WT-TAC mouse heart showed consistently decreased ROS level (42±2% ↓, p&lt;0.01, n=4) vs. WT-sham; whereas there is no difference among the WT-sham, Tg-sham and Tg-TAC groups (n=6). This finding was different from the previous reports showing the increased ROS in WT-TAC heart. Next, we screened the LV expression profile of various antioxidant proteins. We found that the mRNA expression of SOD3 (3.0-fold↑) and thioredoxin1 (Trx1, 3.8-fold↑) was significantly increased (p&lt;0.05) in WT-TAC mice vs. WT-sham by qRT-PCR; whereas there is no difference among the WT-sham, Tg-sham and Tg-TAC groups. The increased SOD3 and Trx1 mRNA expression was confirmed by Western blotting for protein expression (3.0-fold↑). In contrast, the expression of other antioxidants including SOD1, SOD2, catalase, Trx2, Nrf2, NQO1 and glutaredoxin were not changed in WT-TAC heart. The selectively increased expression of SOD3 and Trx1 may contribute to the decreased ROS level detected in WT-TAC heart. Unlike WT-TAC, the ROS, SOD3 and Trx1 levels in Tg heart were not increased by TAC vs. sham, suggesting the critical role of p67 phox in regulation of TAC-induced myocardial ROS generation and antioxidants expression. In summary, our data show that NOX/p67 phox regulates pressure-overload-induced cardiac oxidative stress and myocardial expression of antioxidants SOD3 and Trx1.
Abstract 18870: Direct Reprogramming of Cardiac Fibroblasts to Cardiomyocyte: Insight into Mechanisms and Feasibility in Human
Authors: Imke Kirste, Tilanthi M Jayawardena, Maria Mirotsou, Victor J Dzau
Journal: Circulation (2012)

Introduction: Direct conversion of injured heart tissue to functional cardiomyocyte in situ represents an exciting approach for cardiac regeneration. We have recently shown that the combination of miRNAs 1, 133, 208 and 499 were able to reprogram mouse cardiac fibroblasts in vitro and in vivo to cardiomyocyte like cells. Here, we investigate the mechanisms involved in these processes as well as explore the feasibility of this approach in reprogramming human fibroblasts towards the cardiomyocyte fate. Methods and Results: Expression analysis miRNA transfected fibroblast demonstrated rapid induction (1-2 days) of primitive cardiac mesodermal marker Mesp2 but no change in the pluripotency markers Oct4 and Nanog suggesting that reprogramming results from a direct switch to cardiomyocyte progenitor state. Further microarray analysis using the Affymetrix GeneChip Mouse Genome 430 2.0 Array revealed that 1200 genes were differentially regulated between miRNA treated and control cardiac fibroblasts (P&lt;0.01). This list was highly enriched for transcription factors and chromatin remodeling modulators (125 genes). HDAC2, a histone deacetylase that was recently associated with reprogramming of fibroblasts to iPS cells, was the only histone deacetylase that showed significant change upon treatment with the miRNA combination (decreased nearly 95%). These results were corroborated by qRT-PCR. Clustering analysis consistently altered expression of a sub-cluster of 5 genes (with functional relevance to HDAC2, further highlighting the potential importance of HDAC in modulating the miRNA effects directly and/or indirectly. Finally, to explore the feasibility of the miRNA approach to reprogram human fibroblasts, we transiently transfected BJ cells with the microRNA combination. Our preliminary results indicate that combination microRNA treatment of human fibroblasts results in the upregulation of early cardiomyocyte markers such as Mef2. Conclusion: Our data provide insights into the mechanisms of microRNA mediated cardiac reprogramming, indicating direct conversion and the potential role of epigenetic modulation.
Abstract 19277: Neither Comorbidities nor Socioeconomic Differences Explain the Association Between Higher Altitude of Residence and Better Coronary Artery Disease Survival
Authors: Michael Sean McMurtry, Alka Patel, Adriane Lewin, Gil Kaplan, William Ghali, Merril Knudtson, Michelle M Graham
Journal: Circulation (2012)

Background: Previous studies have linked higher altitude of residence with lower mortality from coronary artery disease, but were limited by incomplete ascertainment of co-morbidities, including hypertension, dyslipidemia, diabetes, and smoking, as well as lack of adjustment for socioeconomic variables such as education status and household income. Methods: We tested whether comorbidities and socioeconomic variables alter the association between altitude of residence and both results of coronary angiography and survival of those with coronary artery disease using the APPROACH database, a prospective cohort of all subjects undergoing coronary angiography in the Province of Alberta. Co-morbidities and mortality are ascertained by periodic linkage with Alberta Health, the provincial repository of administrative health data. The population was stratified by altitude of residence into quartiles based on residence postal codes, and logistic regression was used to calculate odds ratios for high risk or left main disease at coronary angiography, with the lowest quartile the reference. A Cox proportional hazard model was used to calculate hazard ratios for mortality, with the lowest quartile the reference. Results: A total of 105,093 consecutive subjects referred for coronary angiography between 1995 and 2010 were included, spanning elevations between 210 meters to 2,164 meters. After adjustment for comorbidities and socioeconomic variables, the odds ratio for the highest quartile having high risk or left main coronary disease at angiography was 0.86 (0.82-0.90). Survival analysis was restricted to 78,349 subjects with at least one &gt;50% coronary lesion. The hazard ratio for mortality for the highest quartile was 0.88 (0.84-0.93) adjusting for all variables except coronary anatomy, and 0.95 (0.90-0.99) after adjusting for all variables. Conclusion: Higher altitude of residence was associated with lower odds of having high risk or left main coronary artery disease at coronary angiography and better survival, even after adjustment for comorbidities and socioeconomic variables.
Abstract 239: Does the Performance of Emergency Medical Dispatch (EMD) Affect Survival from Out-of-Hospital Cardiac Arrests (OHCAs)? An Analysis of the Taipei Utstein Arrest Registry
Authors: Wen-Chu Chiang, Yueh-Ping Liu, Shih-Hung Liu, Patrick Chow-In Ko, Chi-Wei Yang, Hui-Chih Wang, Bing-Chow Lee, Kuang-Hua Hsiung, Ying-Wen Hsiao, Mei-Shu Lai, Matthew Huei-Ming Ma
Journal: Circulation (2011)

Introduction Dispatch-instructed bystander cardiopulmonary resuscitation (DI-CPR) was recommended by current resuscitation guidelines. The pivotal step of DI-CPR was the accurate recognition of OHCAs by interview of caller. However, previous studies showed the compliance of dispatchers in posing priority questions to identification of OHCAs is unsatisfactory. This study aimed to estimate the incremental effect on recovery of spontaneous circulation (ROSC) of OHCAs if the dispatcher could have more OHCAs recognized through a better adhesion to dispatch protocol. Methods Emergency medical service system of Taipei City is the first one in Taiwan to implement service of prehospital advanced life support (ALS) and to develop the database of Utstein registry to track the OHCAs. We analyzed the Taipei Utstein database to evaluate the association between bystander CPR and ROSC of OHCAs stratified by EMD performance including recognition of OHCA and instruction of CPR. Because the recognition of OHCAs was not requested in registry, we used the results of dispatched tier as surrogates. The dispatcher would send an ALS team to the scene if they succeed to alert the OHCAs by call, while only a BLS team would be dispatched if they failed to. Results From 2008 to 2009, there were total 3573 adult non-traumatic OHCAs registered with attempted resuscitation. Among them, bystander CPR rate and overall ROSC rate were 15.4% and 22.2% respectively. Bystander CPR was significantly associated with better ROSC even after adjustment for other variables. The bystander CPR rate was up to 25.5% in OHCAs recognized by EMD but was only 10.0% in those who did not. The association between ROSC and the performance of dispatchers were tabulated beneath. Conclusion Bystander CPR was one of the most important factors to survival of OHCAs in Taipei. Performance of EMD had the potential to benefit the ROSC rate of OHCA patients as long as the dispatcher could recognize more OHCAs cases.
Abstract 19126: Cardiac AL Amyloidosis with or without Significantly-increased Left Ventricular Wall Thickness
Authors: Ga Yeon Lee, Jin-Oh Choi, Kihyun Kim, Seok-Jin Kim, Hye Ryoun Jang, Hee-Jin Kim, Soo-Youn Lee, Byoung-Joon Kim, Ju-Hong Min, Eun-Seok Jeon
Journal: Circulation (2012)

Background: Cardiac involvement is a major prognostic factor in AL amyloidosis. Poor survival of cardiac amyloidosis (CAm) have been reported previously. Recently, many data demonstrate methods detecting early CAm. However, data regarding the clinical meanings of early CAm without significantly-increased LV wall thickness (LVWT) are still lacking. So, we investigated clinical findings of early CAm. Methods: Total 124 patients were diagnosed as AL amyloidosis by positive Congo red stain in tissue. Among them, 46(37.1%) patients satisfied the classic definition of CAm; mean LVWT&gt;12mm without other cardiac cause. And, 19(15.3%) patients had LVWT≤12mm, but were diagnosed as CAm with cardiac biopsy or cardiac MRI. The number of patients without evidence of CAm was 51(41.1%). We compared the echocardiographic parameters as well as survival among three groups. Median follow-up duration was 14.5 months. Results: Mean LVWT was higher in the group of classic definition compared to the group of minor LVWT [14(13∼16) vs 11(9∼12)mm, p&lt;0.003]. However, LV ejection fraction, LA volume index, and e’ were not different between the group of classic definition and of minor LVWT [55.3(46.5∼62.5) vs 54(48∼61)%, p=0.908, 44.0(36.7∼55.1) vs 45.9 (37.7∼58.6)ml/m 2 , p=0.486, 0.04(0.03∼0.06) vs 0.04(0.04∼ 0.05)m/sec, p=0.796]. These parameters were better in the group of no cardiac involvement [65(61∼69)%, 23.5(18.1∼29.7)ml/m 2 , 0.08(0.06∼0.09)m/sec, all p&lt;0.003]. Overall survival rates showed similar pattern. The group of no cardiac involvement showed better prognosis compared to the other two groups (p&lt;0.003). However, between the two groups of CAm, the survival curves were not different (p=0.361). Conclusions: The parameters in echocardiography and survival rates were different according to the presence of CAm, not by the degree of LVWT. The classic definition of cardiac involvement in AL amyloidosis may need to be re-evaluated to reflect more accurate clinical findings.
Abstract 18709: Association of Reactive Oxygen Metabolites and High-sensitivity CRP with severity of angiographic Coronary Artery Disease
Authors: Yoshihiro Hirata, Eiichiro Yamamoto, Hiroaki Kusaka, Seigo Sugiyama, Hisao Ogawa
Journal: Circulation (2012)

Background: Reactive oxygen species (ROS) and inflammation play the role in the pathogenesis and the development of coronary artery disease (CAD), and high-sensitivity C-reactive protein (hs-CRP), a marker for low-grade inflammation, is one of the most studied biomarkers for the evaluation of CAD risk. In contrast, there is little biomarker of ROS, which is easy to assay and is widely accepted as marker of CAD. Hence, in this study, we compared associations of hs-CRP and derivatives of reactive oxygen metabolites (d-ROM), a newly and easier-to-assay marker of ROS, with the severity of CAD. Methods: We examined the presence of CAD by coronary angiography (coronary stenosis ≥ 50% luminal diameter narrowing) and CAD patients were divided to single-vessel disease (SVD) or multiple-vessel disease (MVD) according to the number of vessels. In consecutive CAD patients, we assessed d-ROM by simpler method for detecting hydroperoxide as a marker of ROS, and compared association between hs-CRP and severity of CAD. Results: In preliminary study, d-ROM values were significantly increased in CAD patients compared to control patients. In consecutive 261 CAD patients, d-ROM values were significantly higher in CAD patients with MVD (n=172) than CAD patients with SVD (n=89) (d-ROM: CAD+SVD; 332.2 ± 70.9 U.CARR versus CAD+MVD; 353.2 ± 70.5 U.CARR, p&lt;0.05). In receiver-operating characteristic analysis, d-ROM values was a significant determinant for the severity of CAD (area under the curve; 0.60, 95% confidence interval; 0.52-0.67, p&lt;0.01). In contrast, hs-CRP of CAD patients with MVD were not changed compared to those of CAD patients with SVD (ln[hs-CRP]: CAD+SVD; -2.79 ± 1.12 mg/dL versus CAD+MVD; -2.65 ± 1.09 mg/dL, p=0.32). By multivariate backward logistic regression analysis among various risk factors, d-ROM values, but not hs-CRP independently associated with the severity of CAD (p&lt;0.05). Conclusion: d-ROM values reflecting ROS levels significantly increased in CAD patients and significantly correlated with the severity of CAD. d-ROM assay might be a more important biomarker than hs-CRP to evaluate the severity of CAD and screen for CAD in high-risk patients. Identifying the high-risk CAD patients by d-ROM may provide clinical benefits for risk stratification.
Abstract 17554: Mice with Endothelial-Targeted Inactivation of <i>Ppap2b</i> (Lipid Phosphate Phosphatase 3) Display Enhanced Vascular Inflammation
Authors: Manikandan Panchatcharam, Sumitra Miriyala, Jessica Wheeler, Abdel K Salous, Anping Dong, Manjula Sunkara, Andrew J Morris, Diana Escalante-Alcalde, Susan S Smyth.
Journal: Circulation (2011)

Meta-analysis of data from a series of genome-wide association studies (GWAS) revealed a striking association between the PPAP2B locus and coronary artery disease. The PPAP2B gene encodes for lipid phosphate phosphatase 3 (LPP3), an integral membrane enzyme that dephosphorylates lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P) and related bioactive lipids. While emerging evidence suggests a role for both LPA and S1P in experimental models of atherosclerosis, essentially nothing is understood about the pathophysiologic role of LPP3, largely due to the fact that genetic deletion results embryonic lethality in mice. We report that constitutive inactivation of LPP3 in vascular endothelial cells accomplished by breeding mice with floxed Ppap2b to mice expressing Cre recombinase under control of the Tie1 promoter results in embryonic lethality and a similar defect in vasculogenesis as is observed in mice with global inactivation of Ppap2b , indicating that dysregulation of LPP3-dependent vascular endothelial cell function likely underlies the developmental phenotype observed in Ppap2b -null embryos. Using an estrogen inducible Cre transgene under control of the Tie1 promoter, we have inactivated Ppap2b expression in endothelial cells in adult mice and confirmed the lack of vascular endothelial LPP3 by immunologic and biochemical approaches. The absence of vascular endothelial LPP3 results in a 2.2 ± 0.5 fold increase in basal vascular permeability, as assessed by Evans blue dye extravasation in lung tissue. The permeability difference is exaggerated following an inflammatory challenge (LPS; 2 mg/kg), and LPS-induced expression of plasma inflammatory markers IL6 and KC are 3.3 ± 0.5 and 1.9 ± 0.6 fold higher in mice lacking endothelial LPP3. In addition, loss of endothelial LPP3 impairs angiogenesis in matrigel implanted in mice. These results demonstrate a fundamental role for LPP3 in maintaining the integrity of the vascular endothelium. Importantly, our findings suggest that polymorphisms associated with a reduction in LPP3 expression could promote vascular inflammation and thereby heighten risk of coronary artery disease and myocardial infarction.
Abstract 19229: DICOM-Based Regional Strain Shows Greater Variability with Base-Apex Gradient than Global Strain in a Heterogenous Population
Authors: Shafkat Anwar, Kazuaki Negishi, Allen Borowski, Patrick Gladding, Zoran Popovic, Francine Erenberg, James D Thomas
Journal: Circulation (2012)

Introduction: Two-dimensional Strain (2D S) is a powerful technique to evaluate myocardial deformation. We compared S from images in raw Polar (P) format with the same images in DICOM (D) in adult &amp; pediatric patients to test agreement. Methods: 110 patients (55/110 pediatric, 80/110 normal LV function) had echocardiograms with a General Electric (GE) Vivid 7 or E9. 4,3 &amp; 2-chamber LV apical views yielding 330 datasets were analyzed with EchoPAC (GE, v. 10.8.1) in P &amp;Velocity Vector Imaging (VVI, Siemens, v. 3.5) in D by 3 blinded readers. Regional differences in longitudinal Strain (LS) were tested with Bland Altman analysis. Results: Mean Global Longitudinal S (GLS) by EchoPAC (P) was -18.1 +/- 4.4 &amp; VVI (D) -15.3 +/- 4.1. D yielded lower absolute GS by mean of 2.8 (± SD 2.7, p &lt; 0.0001). In regional analysis, P also consistently produced higher values than D for corresponding segments. There was greater variability in RS with a consistent base to apex gradient. RS differences between P &amp; D data were lowest at the base (Difference 1, p &lt;0.00001) and highest at the apex (Difference 5.5, p &lt;0.00001), Fig. 1&amp;2. Conclusion: In this large and heterogenous population, there is region-specific variability in RS from DICOM images compared to source Polar data. These differences average out in global S analysis. Further standardization among Strain platforms is necessary to minimize differences.
Abstract 8149: A Prospective Randomized Controlled Trial of the Effects of Vitamin D Supplementation on Cardiovascular Disease Risk
Authors: Adam D Gepner, Rekha Ramamurthy, Diane C Krueger, Claudia E Korcarz, Neil Binkley, James H Stein
Journal: Circulation (2011)

Background: Low vitamin D (VitD) status is associated with increased cardiovascular disease risk. Some physicians prescribe VitD supplements for risk reduction, although little data support this intervention. Methods: This was a prospective, randomized, double-blind, placebo-controlled trial of healthy, post-menopausal women with serum 25-OH VitD concentrations &gt;10 and &lt;60 ng/ml. They were randomized to receive 2500 IU of VitD 3 or placebo daily for 4 months. Endothelial function was evaluated by ultrasound brachial artery flow-mediated dilation (FMD). Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (PWV) and aortic augmentation index (AIx) using applanation tonometry. High-sensitivity C-reactive protein (CRP) was measured by nephelometry. Changes in these parameters were compared between treatment groups using T-tests and verified by general linear models that adjusted for treatment group, VitD status, and a treatment group x VitD status interaction. Results: The 114 subjects were mean (standard deviation) 63.9 (3.0) years old with a 25-OH VitD level of 31.3 (10.6) ng/ml. Low VitD status (&lt;30 ng/ml) was present in 48% and was associated with higher body-mass index, systolic blood pressure, glucose, CRP, and lower FMD (all p&lt;0.05). After 4 months, 25-OH D levels increased by 15.7 (9.3) ng/ml in the treatment group vs. -0.2 (6.1) ng/ml on placebo (p0.10). In multivariable models, there were no significant interactions between treatment group and low VitD status for changes in FMD (p=0.65), PWV (p=0.93), AIx (p=0.97), or CRP (p=0.26). Conclusions: VitD supplementation did not improve endothelial function, vascular stiffness, or inflammation in healthy post-menopausal women. This study does not support the use of VitD supplementation to reduce cardiovascular disease risk.
Abstract 18434: Serial Quantification of Canine Post-Infarct Left Ventricular Remodeling Using a Novel Semi-Automated 3D Echo Speckle Tracking Algorithm
Authors: Ben A Lin, Diego Bellavia, Mitchel R Stacy, Mark W Maxfield, Donald P Dione, Smita Sampath, Ziheng Zhang, Donna Dione, James S Duncan, Lissa Sugeng, Albert J Sinusas
Journal: Circulation (2012)

Background: Left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by infarct expansion, progressive LV dilation, and hypertrophy of non-infarct zones. Global ventricular remodeling is associated with poor outcomes. Existing data on the temporal dynamics of post-MI remodeling are primarily based on 2D echo estimates of LV size. Accurate and convenient 3D echo measurements would allow more reliable tracking of LV size and function in both laboratory and clinical settings. Methods: MI was induced in canines (N=6) with 6-hour LAD angioplasty occlusions. Transthoracic 3D B-mode echo long-axis images were obtained at baseline, 3 days, 4 weeks, and 6 weeks post-MI using a Philips iE33 system with X7-2 transducer at 41-51 fps. End-diastolic (EDV) and end-systolic (ESV) volumes were measured using a novel semi-automated 3D echo speckle tracking algorithm (4D LV-Analysis 3; TomTec Imaging Systems; Munich, Germany). ECG-gated cardiac MR images were acquired on a 1.5 T magnet at 6 weeks post-MI. Reference MRI EDV and ESV were measured using the method-of-disks with manual contours. Results: 3D echo EDV and ESV measurements for multiple timepoints are shown in the table below. Average EDV increased from 41±14 ml at baseline to 59±12 ml at 6 weeks post-MI (p=0.02). Average ESV increased from 27±10 ml at baseline to 41±13 ml at 6 weeks post-MI (p=0.02). At 6 weeks post-MI, MRI EDV and ESV measurements were 61±6 ml and 33±7 ml, respectively, and were not significantly different from 3D echo values (p=NS for both). Conclusions: We have used a novel 3D echo speckle tracking algorithm to obtain 3D volumes in a semiautomated fashion. This approach should prove useful in the application of 3D echo in both laboratory and clinical settings. To our knowledge, this is the first report of serial LV remodeling by 3D echo in a post-MI canine model. We documented progressive increases in EDV and ESV that were consistent with reference MRI measurements at 6 weeks post-MI.