tbuckley/cabot-search huggingface dataset:
Abstract 185: Additional Benefit of Cyclosporine-Assisted Adipose-Derived Mesenchymal Stem Cell Therapy for Against Acute Kidney Ischemia-Reperfusion Injury
Authors: Tzu -Hsien Tsai, Sarah Chua, Jiunn-Jye Sheu, Hon-Kan Yip
Journal: Circulation (2013)

Objectives: This study tested the hypothesis that cyclsporine (CsA)-supported adipose-derived mesenchymal stem cell (ADMSC) therapy offered superior attenuation of acute ischemia-reperfusion (IR) kidney injury than either therapy alone. Methods: Adult SD-rats (n=40) were equally divided into group 1 (sham controls), group 2 (IR injury), group 3 [IR + CsA (20 mg/kg at 1 and 24 hr after procedure)], group 4 [ADMSC (1.2x106) at 1, 6 and 24 h after procedure], and group 5 (IR + CsA-ADMSC). Results: By 72 h after IR procedure, creatinine level and the ratio of urine protein to creatinine were highest in group 2 and lowest in group 1, significantly higher in groups 3 and 4 than in group 5, but they showed no differences between groups 3 and 4 (all p&lt;0.0001). The inflammatory biomarkers at mRNA (MMP-9, RANTES, TNF-α), protein (TNF-α, NF-κB, ICAM-1, PDGF), and cellular (CD68+) levels of IR kidney showed an identical pattern to creatinine level in all groups (all p&lt;0.0001). The protein expressions of oxidative stress (oxidized protein), ROS (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP) and DNA damage markers (γH2AX+, PNCA+ cells) exhibited a similar pattern to inflammatory mediators (all p&lt;0.0001) amongst all groups (all p&lt;0.0001). Anti-oxidant biomarkers at cellular (GPx, GR, HO-1) and protein (NQO-1, HO-1, eNOS) levels, and endothelial progenitor cell markers (CXCR4+, SDF-1α+) were lowest in groups 1 and 2, higher in groups 3 and 4 and highest in group 5 (all p&lt;0.0001). Conclusions: Combination therapy using cyclosporine-plus-ADMSCs offers improved protection against acute IR kidney injury. Key words: cyclosporine, adipose-derived mesenchymal stem cell, acute kidney ischemia-reperfusion injury, combination therapy, inflammation, oxidative stress, apoptosis
Abstract 9770: Overcoming Persistent Hypertension in Primary Care: Potential Impact of a Proven Strategy of Intensive Blood Pressure Management Within a National Patient Cohort
Authors: Simon Stewart, Melinda J Carrington, Carla H Swemmer, Nicol P Kurstjens, Garry L Jennings
Journal: Circulation (2012)

BACKGROUND: The Valsartan Intensified Primary carE Reduction of Blood Pressure (VIPER-BP) Study involved &gt; 2000 hypertensive patients with persistently elevated BP managed by &gt; 250 family physicians. It demonstrated that a computer-assisted algorithm to apply intensive pharmacological therapy substantially improved BP levels relative to usual care. METHODS: From a national cohort study of 733 family physicians and 532,050 patients during 2005-2010, we identified a sub-set of patients being treated for hypertension but with a BP persistently &gt;140/90mmHg who would theoretically benefit from more structured and intensive management. The potential impact of the VIPER-BP intervention, on a sex and BP-specific basis was therefore applied from trial data. RESULTS: Of 51,721 hypertensive individuals with follow-up visits in the national cohort, 24,710 (48%) remained hypertensive after one year. Of these, 7,235 men (66 ± 13 years, BP 155 ± 13/86 ± 11 mmHg) and 7,844 women (71 ± 13 years, BP 156 ± 14/84 ± 12 mmHg) being treated for hypertension were identified. The “pre and post” histograms show the modeled impact of the VIPER-BP intervention on systolic BP. In men post-intervention BP was projected to have fallen to 139 ± 6 / 80 ± 9 mmHg and in women to 141 ± 7 / 77 ± 9mmHg. Overall, this strategy would likely achieve additional BP control (&lt;140/90mmHg) in 3,930 (54%) of men (top) and 4,476 (57%) of women. CONCLUSIONS: These data confirm the “real-world” potential for structured and intensive BP management to achieve markedly better BP control in primary care in those with persistent hypertension despite initial pharmacological treatment.
Abstract 9897: Frequency of Non-Systems Delays in STEMI Patients Undergoing Primary PCI and Implications for Door-to-Balloon Time Reporting. A Report from The ACTION Registry®-GWTG™ and AHA
Authors: David A Cotoni, Matthew T Roe, Shuang Li, George W Vetrovec, Michael C Kontos
Journal: Circulation (2012)

Introduction: Door to balloon (D2B) time ≤90 minutes (min), and percentage of primary PCI patients (pts) with a D2B ≤90 min are used as performance metrics by many organizations. Pts can be excluded from this measure if they have a non-systems related delay. However, how frequently exclusions occur, and how it affects the reporting of D2B times at the hospital level is unknown. Methods: The percentage of pts having non-systems delays (cardiac arrest, intubation, difficult vascular access, etc) for primary PCI at the hospital level was calculated using data from the ACTION Registry®-GWTG™. Pts were excluded if the first ECG was not diagnostic, or were transferred to or from another hospital. Hospitals having &lt; 36 primary PCIs during the study period were also excluded. Hospitals were categorized into three groups based on tertiles of percentage of excluded pts. The percentage of hospitals with a D2B ≤90 min in ≥90% of pts were calculated by first including and then excluding pts that had non-systems delays. Results: From 1/1/07-3/31/11, 43,909 pts from 294 hospitals were included. The percentage of exclusions recorded differed substantially among hospitals, ranging from 0-68% of pts (median 9.2% [IQR 5.6%, 13.5%] with low tertile ≤7.1%, intermediate tertile 7.1% to 11.2% and high tertile ≥11.2%. Reasons for exclusion included vascular access difficulty (7.8%) cardiac arrest/intubation (38%) and PCI procedural difficulties (20%). There were no significant differences in hospital annual total MI, STEMI, or primary PCI volumes, or hospital bed size among the three groups. Including pts with non-systems delays significantly increased D2B times and decreased the proportion of pts achieving D2B ≤90 min as well as percentage of hospitals having ≥90% of STEMI pts with D2B ≤90 min (TABLE). Discussion: The proportion of pts excluded from D2B reporting varies substantially among hospitals. This has an important impact on reported performance measures.
Abstract 9760: Plasma Levels of Nitric Oxide Metabolites Are Markedly Reduced In Normotensive Individuals With Electrocardiographically Determined Left Ventricular Hypertrophy
Authors: Fumihiko Kamezaki, Masato Tsutsui, Tetsuo Adachi, Masao Takahashi, Shinjo Sonoda, Masaaki Takeuchi, Yutaka Otsuji
Journal: Circulation (2012)

Objective: It has recently been revealed that normotensive subjects with electrocardiographically determined left ventricular hypertrophy (ECG-LVH) are at risk of multiple cardiovascular diseases, but the underlying mechanism remains to be elucidated. To address this point, we examined the hypothesis that normotensive individuals with ECG-LVH show reduced plasma levels of metabolites of nitric oxide (NO), a critical regulator of cardiovascular function. Methods: A total of 579 Japanese male workers (40-65 years of age) were studied. Since hypertension (blood pressure ≥140/90 mmHg) or medications could influence plasma NOx (NO metabolites, nitrite and nitrate), workers with such factors were excluded from the study. ECG-LVH was assessed by the Sokolow-Lyon voltage criteria and the Cornell voltage-duration product. The subjects were categorized by quartiles of plasma NOx level, and a multivariate logistic regression analysis was conducted relating ECG-LVH to NOx quartiles after adjustment for potential confounders. Results: The mean levels of plasma NOx were markedly lower in individuals with ECG-LVH (n=73, 28.9±19.2 μ mol/l) than in those without (n=506, 42.5±31.2 μ mol/l) ( P &lt;0.0001). The multivariate-adjusted odd ratio for the presence of ECG-LVH compared with the forth quartile of NOx (≥51.9 μ mol/l) was 1.38 (95% CI 0.55-3.59) for the third (NOx 33.1-51.8 μ mol/l), 1.83 (0.76-4.64) for the second (NOx 21.3-33.0 μ mol/l) and 4.93 (2.31-11.47) for the first quartile (NOx ≤21.2 μ mol/l). Similar result was obtained when subjects were stratified by waist circumference. The mean levels of plasma extracellular superoxide dismutase (EC-SOD), a major antioxidant in the cardiovascular system, were comparable in individuals with and without ECG-LVH. On the other hand, plasma EC-SOD levels were significantly decreased with lower quartiles of NOx ( P &lt;0.01). Conclusion: This study demonstrated for the first time that plasma NOx levels are markedly reduced in normotensive individuals with ECG-LVH. These results indicate that disrupted NO production through the involvement of down-regulation of the antioxidant enzyme may explain, at least in part, the potential mechanism for increased cardiovascular risk in normotensive individuals with ECG-LVH.
Abstract 9819: The Significance of Early Recovery of the ST Segment Depression in the Recovery Period
Authors: Rudy Chow, Sammy Chan, Kenneth Gin, Min Gao, Matthew T Bennett
Journal: Circulation (2012)

Background Persistence of ST segment depression in recovery signifies a strongly positive ETT, predictive of more ischemia and underlying CAD. It is unclear if early recovery of the ST segment portends a similar prognosis. We sought to determine if persistence of horizontal / down-sloping ST depression into recovery correlates with CAD burden based on myocardial perfusion imaging (MPI). Methods Retrospective analysis of men and women referred for exercise MPI testing was performed. Normal groups were defined as negative ETT (&lt;1mm of ST depression). Those with positive ECG tests were further stratified based on the ST segment at 1 min in recovery. Persistence group was those with &gt;1mm while the Early Recovery group &lt;1mm. Measured MPI variables were summed stress scores (SSS) and high-risk MPI findings. Analysis of variance was used to compare SSS among groups. To assess whether SSS of Early Recovery is no worse than the Normal group, a one-sided 95% confidence limit was calculated for the difference between groups. A non-inferiority margin of -1 was considered clinically acceptable. Results 538 men and 315 women were analyzed. Mean SSS of the Persistence group (7.90 ± 7.69) was significantly different from Early Recovery (4.67 ± 6.18, p&lt;0.001) and Normal (4.78 ± 5.92, p&lt;0.001). Early Recovery was non-inferior to Normals based on SSS (mean difference 0.12, lower 95% CL=-0.66 &gt;-1, p&lt;0.001). Proportion in Early Recovery was similar to Normal but different from Persistence group based on SSS severity (figure). Conclusion Persistence group manifested significantly higher SSS and greater proportion of moderate to high-risk MPI findings when compared to Early Recovery and Normal groups. Furthermore, there was no significant difference in MPI findings between Normal and Early Recovery groups. Early recovery of the ST segment during recovery may represent an underappreciated false positive finding. The results question the accuracy of the ACC/AHA definition of a positive study.
Abstract 18612: Normal c-Myb Activity is Critical for Both Vessel-Resident and Bone Marrow-Derived Cell Responses to Arterial Remodeling Following Injury
Authors: Eric A Shikatani, Abdul Momen, Cedric C Li, Mansoor Husain
Journal: Circulation (2013)

Background: The c-myb proto-oncogene regulates the proliferation of adult vascular smooth muscle cells (VSMCs) and the differentiation of VSMCs from a specific embryonic stem cell-derived hematogenic progenitor cell population. It remains unknown if c-myb has a critical role in the proliferation or potential (trans)differentiation of bone marrow (BM)-derived vs. vessel resident cells in intimal hyperplasia following wire denudation carotid artery injury (CI). We used a mouse harboring a non-lethal point mutation in c-myb resulting in a hypomorphic (h) allele of c-myb with defective c-Myb activity. Previously, we showed that hypomorphic (h/h) mice on a C57BL6 background have decreased neointimal hyperplasia versus wild-type (wt) mice following CI. While BM transplantation (BMT) of h/h BM into wt recipients (h/h→wt) inhibited neointimal hyperplasia compared to injured wt→h/h mice, the role of c-myb in vessel resident cells remained unclear. Also, as many strain-specific differences exist in BM-derived cells, h/h mice were backcrossed 10 generations into a FVB/N background to study injury response. Methods and results: Reciprocal BMTs were performed in 5 wk old mice, which were allowed to reconstitute for 7 wks before CI. Injured arteries from wt→wt mice had greater intima formation than h/h→wt mice (19,222±2,622 vs. 8,080±1337 μm2; p&lt;0.0001; N= 7/group), with no differences observed in uninjured BMT controls. However, reconstitution of h/h mice with WT BM had no effect on neointimal proliferation compared to h/h→h/h mice (14,519±486 vs. 13,437±1,175 μm2; p=NS; N= 7/group). To examine cell integration and (trans)differentiation of BM-derived cells, we generated h/h and wt mice with eGFP expression. When subjected to CI, eGFPxh/h mice show decreased neointimal hyperplasia consistent with non-eGFPxh/h mice. Wire injured 10-12wk old FVB/N h/h mice had reduced intima area (30,251±2,306 μm2 vs. 57,059±9,336 μm2; p=0.11) and I/M ratio (0.53±.010 vs 1.19±0.12; p=0.049) versus FVB/N wt mice (N=3/group). Conclusions: Effects of defective c-myb activity do not appear to be strain specific. Our data suggest that c-myb has a critical role in regulating neointimal hyperplasia in both vessel resident and BM-derived cell populations.
Abstract 9748: <i>In Vivo</i> Cardiac Cellular Reprogramming Efficacy is Enhanced by Angiogenic Preconditioning of the Infarcted Myocardium
Authors: Megumi Mathison, Robert Gersch, Ahmed Nasser, Mallory Korman, Mitchell Fourman, Neil Hackett, Li Qian, Deepak Srivastava, Kenneth Shroyer, Yupo Ma, Ron Crystal, Todd Rosengart
Journal: Circulation (2012)

A new in situ cellular reprogramming strategy demonstrated to convert fibroblasts into cardiomyocytes may represent an ideal cardiac regenerative therapy, obviating challenges inherent in stem cell implantation. We hypothesized that this strategy would be enhanced by angiogenic pretreatment of myocardial scar targeted by this treatment. Methods: The efficacy of lentivirus-mediated delivery of Gata4, Mef 2c and Tbx5 to transdifferentiate rat fibroblasts into induced cardiomyocytes (iCMs; Ieda et. al ., Cell . 2010; 142: 375-386) was validated by i n vitro FACS and immunofluorescence studies. Adult male Fischer 344 rats (n=12/group) then underwent coronary ligation and intramyocardial administration of AdVEGF-All6A+, an adenovirus encoding all three major isoforms of VEGF, or AdNull, an empty expression cassette vector. Three wks later, 6 animals/group received lentiviruses each encoding Gata4, Mef 2c or Tbx5 (GMT), or encoding only GFP. Echocardiograms were performed prior to and 3d after coronary ligation, at the time of GMT or GFP administration (baseline), and 2 and 4 wks later. Results: In vitro studies demonstrated rat fibroblast conversion into iCMs based on cellular morphology and expression of markers including cardiac troponin T. Echo analyses in the myocardial infarction model above demonstrated significant improvement from baseline for cardiac ejection fraction (EF) 2 and 4 wks after GMT vs GFP administration (EF% change 4 wks after treatment: 12% ± 9% vs -7% ± 10%, p&lt;0.01). Eight GFP-treated but no GMT animals demonstrated decreased EF during this interval (p&lt;0.01). Moreover, improvement in EF was 4 times greater in GMT/VEGF vs GMT/AdNull animals (17% ± 7 % vs 4% ± 3%, p&lt;0.01). No significant change in EF was detected in animals treated with AdVEGF-All6A+ without GMT. Conclusion: Angiogenic pretreatment of myocardial scar significantly enhances the efficacy of cellular reprogramming after myocardial infarction.
Abstract 9891: Usefulness of Transthoracic Echocardiography with Strain Analysis in Initial Assessment of Acute Chest Pain in Emergency Department
Authors: Mirae Lee, Sung-A Chang, Gwan-Hyeop Sohn, Sung-Ji Park, Jin-Oh Choi, Sang-Cheol Lee, Jae K Oh, Seung Woo Park
Journal: Circulation (2012)

Background: Conventional transthoracic echocardiography (TTE) is currently not recommended as an initial test to diagnose coronary artery disease (CAD) due to its insensitivity. Left ventricular (LV) strain was reported to be more sensitive than regional wall motion abnormality (RWMA). The aim of this study was to evaluate the usefulness of TTE including LV strain analysis in initial assessment of acute chest pain in emergency department (ED). Methods: Patients visiting ED with acute chest pain were included. Patients with ST elevation myocardial infarct (MI), hemodynamic instability, known CAD or cardiomyopathy, high probability of non-cardiac chest pain, and poor echocardiographic window were excluded. All the patients were initially assessed by an ED physician for pretest probability of CAD. TTE was performed including LV strain image and global and regional LV longitudinal stain (S GL and S RL ) was analyzed online. S RL abnormality was defined as decreased S RL in at least 2 adjacent segments. Diagnosis of CAD (based on coronary angiography or CT angiography) and cardiac events (cardiac death, revascularization, MI, or recurrent ED visit due to chest pain) were reviewed at 1 month after ED visit. Results: Overall 104 patients were analyzed. CAD was diagnosed in 24% (n=25) and cardiac event was detected in 25% (n=26) of patients.Diagnostic accuracy for CAD was higher when using S RL with cut-off value of -13% (sensitivity of 89%, specificity of 77%, NPV = 92%, PPV = 70%) than when using RWMA (sensitivity of 62%, specificity of 88%, NPV = 80%, PPV = 76%). S RL showed better diagnostic performance for CAD than S GL , and pretest probability (Figure). Predictive value of S RL for cardiac events was also highest in those of S GL , RWMA, and pretest probability (Figure). Conclusion: LV strain echocardiography can diagnose the CAD and predict future events with high accuracy. TTE including strain analysis can be used as an initial diagnostic tool in evaluation of acute chest pain in ED.
Abstract 18536: Performance of Framingham Risk Function With Coronary Artery Calcium in Predicting Major Coronary Events in an Asian Cohort
Authors: Oyere K Onuma, Eun Ju Chun, Karol Pencina, Joseph M Massaro, Christopher J O’Donnell, Udo Hoffmann
Journal: Circulation (2013)

Background: In non-White populations, the original Framingham risk functions (FRF) overestimates coronary heart disease (CHD) risk and requires recalibration. We tested whether the inclusion of coronary artery calcium (CAC) can improve the performance of the FRF in CHD prediction in an asymptomatic Asian cohort. Methods: We determined risk factors, CAC burden and CV outcomes in a sample of 4502 asymptomatic South Koreans (from the registry-based ESCORT Study) and in 3141 asymptomatic Caucasian participants from the Framingham Heart Study (FHS). Primary endpoint was a composite of cardiovascular death, myocardial infarction, and unstable angina with revascularization. We assessed both the discriminatory value of the original FRF before and after the addition of CAC using area under the receiver operator characteristic (AUC) and the calibration/predictive ability using the D’Agostino-Nam Chi squared test for survival data, where a chi-square statistic &gt; 20 indicates poor calibration. Results: There were 95 hard CHD events (45 ESCORT, 50 FHS) over a 55 month (ESCORT) and 60 month (FHS) follow-up period. For the FRF, the AUROC was 0.82, and the D’Agostino-Nam chi-squared statistic was 22.59 (p = 0.007) for predicting MACE in the ESCORT cohort. After the addition of CAC, the AUC improved to 0.85 and the D’Agostino-Nam chi-squared statistic improved to 16.14 (p = 0.064). The Caucasian-derived FRF model had poor predictive ability/calibration and consistently overestimated event rates in the Asian ESCORT cohort over all risk categories. For instance, in the 10th decile of risk, the predicted event rate using the FRF was 6% compared to an actual rate of 3.5% in the ESCORT cohort (Figure 1a) Conclusion: Addition of CAC to the classic Framingham risk functions significantly improves its performance in terms of discrimination and calibration in the prediction of major adverse CHD events in an Asian (South Korean) population.
Abstract 18556: S100A1 Released From Ischemic Cardiomyocytes Signals Myocardial Damage and Functions as Cardiac Alarmin
Authors: David Rohde, Christoph Schön, Melanie Boerries, James N Tsoporis, Thomas G Parker, Karsten Peppel, Hugo A Katus, Patrick Most
Journal: Circulation (2013)

Rationale: S100 proteins released from necrotic cells function as danger signals, referred to as alarmins, which play an active role in tissue inflammation and repair via recognition of molecular pattern receptors such as Toll-like receptors (TLRs). Objective: To investigate whether S100A1, the S100 isoform with the highest abundance in cardiomyocytes, acts as an alarmin in response to ischemic myocardial injury. Methods and Results: Patients with acute ST-elevation myocardial infarction (MI) revealed a significant increase in circulating S100A1 protein serum levels assessed by enzyme-linked immunosorbent assay. Experimental MI in C57Bl/6 mice induced comparable S100A1 release, and immunofluorescence uncovered S100A1 internalization in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes in vivo . Further in vitro analyses using genetic, biochemical and imaging techniques demonstrated exclusive and rapid endocytosis of S100A1 by CFs, followed by endosomal TLR4-dependent transient activation of mitogen- and stress-activated protein kinases (MAPK/SAPK) and nuclear factor kappaB component p65. CFs exposed to S100A1 assumed an anti-fibrotic and immunomodulatory phenotype exemplified by decreased collagen and smooth muscle actin and enhanced intercellular adhesion molecule 1 and interleukin 10 mRNA and protein levels downstream of MAPK/SAPK and p65. In C57Bl/6 mice, intramyocardial S100A1 injection recapitulated the specific transcriptional changes in vivo . Subsequently, antibody-mediated neutralization of MI-released S100A1 enlarged infarct size and enhanced pro-fibrotic marker expression. Conclusion: Our study identifies cardiomyocyte damage-released S100A1 as cardiac alarmin and uncovers the molecular mechanisms conveying anti-fibrotic and immunomodulatory actions. The beneficial impact of the S100A1-mediated TLR4-dependent cardiac fibroblast phenotype conversion warrants continued investigation of its role in myocardial infarct healing.