tbuckley/cabot-search huggingface dataset:
Abstract 5108: Variation in Pial Collaterals in 15 Mouse Strains is a Major Determinant of Infarct Volume After Middle Cerebral Artery Occlusion (MCAO)
Authors: Hua Zhang, Sehoon Keum, Douglas Marchuk, Robert Sealock, James Faber
Journal: Circulation (2009)

The importance of vascular, non-vascular and genetic factors in the wide variability in severity of infarct volume (IV) is unclear. We have reported previously that density and diameter of native collaterals in tissues vary widely with genetic background. The purpose of this study was to determine the contribution of genetic variation in collaterals to variation in IV in a cohort of genetic reference strains. IV was determined 1 day after MCAO. In a second set of mice, the vasculature was dilated, fixed and cast 6 days after MCAO. The number and diameter of pial collaterals were determined for the unligated left and ligated right hemispheres, as were territories of the MCA, ACA and PCA trees. Variations among strains in IV, native collateral number and diameter, and MCA, ACA and PCA territories were, respectively: 30-fold, 56-fold, and 3-fold, and 42%, 56% and 61%. IV and collateral dimensions did not correlate with brain size or PCA territory, but IV correlated highly with collateral number and diameter ((p&lt;0.0001), and less so with MCA (p&lt;0.05) and ACA territory (p&lt;0.01). Arrangement of these parameters (excepting IV) into an expression of collateral conductance strongly predicted IV (p&lt;0.0001). Prediction was improved by factoring in collateral length and hematocrit. There was no correlation between MCA territory and collateral number or diameter, suggesting genetic determinants of tree territory do not specify collateral dimensions. However, collateral dimensions were highly inter-correlated, suggesting they could arise from common genetic variants. Increase in collateral diameter on the ligated side (remodeling) varied by more than 2-fold and correlated with collateral diameter (p&lt;0.0001) and number (p&lt;0.01). Genome-wide haplotype and C57BL/6 × BALB/cBy F2 mapping are underway to identify potential loci harboring variants important in collateral formation. These data suggest that conductance of the pial collateral circulation is the primary determinant of stroke severity, and that polymorphisms in genes specifying formation of the native collateral circulation and its remodeling in ischemia are important determinants of stroke risk and stroke variance. These findings may generalize to heart, limb and other tissues.
Abstract 5138: Secretoneurin Therapy Improves Cardiac Function in a Model of Myocardial Infarction in-vivo and Induces Angiogenesis and VEGF Expression in Cardiac Cells in-vitro
Authors: Wilfried Schgoer, Karin Albrecht, Markus Theurl, Arno Beer, Ivan Tancevski, Danijela Vasiljevic, Jakob Voelckl, Nikolaos Bonaros, Alfred Kocher, Dominik Wiedemann, Florian Aumayr, Gregor Oeberseder, Christina Steger, Peter Schratzberger, Josef Patsch, Rudolf Kirchmair
Journal: Circulation (2009)

Introduction The angiogenic neuropeptide Secretoneurin (SN) is upregulated by hypoxia in several tissues like neurones and skeletal muscle cells and SN gene therapy restores tissue integrity, function and perfusion in the mouse hind-limb ischemia model by induction of angiogenesis, arteriogenesis and vasculogenesis. We therefore hypothesized that this cytokine might also affect function of cardiac cells and exert beneficial effects in a rat model of myocardial infarction (MI). Results To investigate the effect of SN in vitro , a matrigel assay using human coronary artery endothelial cells (HCAEC) in the absence or presence of different concentrations of SN was performed. SN dose dependently induced angiogenesis in vitro with a maximum effect at 1ng/ml (rel. capillary tube formation 2.06+/−0.15; n=4; p&lt;0.001 vs. Ctr.). A specific SN antibody abolished the observed effect (rel. cap. tube form. 1.05+/−0.14; n=4; p&lt;0.01 vs. SN). Western Blot analysis of HCAEC extracts revealed stimulation of ERK1/2 by SN 10ng/ml indicating activation of this signal transduction pathway. PCR analysis of hypoxic human cardiac myocytes showed no effect on the expression of SN (in contrast to skeletal myocytes) but stimulation of this cell line with SN 100ng/ml lead to an upregulation of VEGF mRNA after 12 hours. In an acute MI model in rats, SN gene therapy was performed by injecting 500ug plasmid intramyocardially 10 min after LAD ligation. GFP plasmid was used as control. Left ventricular function was evaluated post-operatively and on day 14 and 28 after LAD ligation by echocardiography (ejection fraction, EF) and fractional area change (FAC) was measured using magnetic resonance imaging. On day 28 SN treated rats showed a significant better outcome with improved EF (75% for SN vs. 44% for Ctr, n=5; p&lt;0.05) and improved FAC (0.59 for SN and 0.46 for Ctr, n=5; p&lt;0.05). Conclusion In vitro data for SN on cardiac cells suggest induction of angiogenesis and upregulation of VEGF. In vivo , SN gene therapy significantly improved left ventricular function in the rat MI model. Future studies will have to clarify if beneficial effects of SN in vivo are mediated by VEGF. These findings suggest that SN gene therapy might be a promising new therapeutic agent to improve ischemic cardiac dysfunction.
Abstract 4867: Circulating Chemical and Cellular Injury/Repair Responses Are Linked to the Extent of Heart Injury in Human Myocardial Infarction
Authors: Ross McGeoch, Anne McGarrity, Alexander R Payne, Stuart Watkins, Tracey Steedman, Andrew P Davie, Mitchell M Lindsay, Stephen D Robb, Eric Rheaume, Jean-Claude Tardif, Keith G Oldroyd, Colin Berry
Journal: Circulation (2009)

Introduction: Circulating injury and repair pathways in human myocardial infarction (MI) are incompletely understood. We investigated rheological and regenerative pathways acutely and in the longer term post-MI. Methods: Blood constituents implicated in myocardial injury (e.g. red cell volume distribution width, hemoglobin) and repair (circulating CD34 + progenitor cells, serum vascular endothelial growth factor (VEGF), serum thymosin β 4 and AcSDKP excreted in urine) were quantified in patients 2 days and 3 months after ST elevation MI (STEMI). Coronary collateral flow was measured invasively during emergency percutaneous coronary intervention. Cardiac function and remodeling were quantified by gadolinium contrast enhanced MRI at 1.5T at these time-points. Results: Thirty-five consecutive STEMI patients (mean±SD age 58±10 years; 3(9%) women) were included. Mean (SD) thymosin β 4 concentration was lower at day 2 compared to at 3 months post-MI (3.0±1.6 vs. 7.0±2.9 μ g/L; P&lt;0.0001). Two days post-MI, AcSDKP correlated negatively with white cell count (R=−0.54; P=0.024) and VEGF (R=−0.57; P=0.038). After adjustment for white cell count, AcSDKP two days post-MI negatively predicted left ventricular (LV) ejection fraction (R 2 =0.43; P=0.024) and positively predicted LV end-systolic volume index (R 2 =0.56; P=0.011) at 3 months. At follow-up, CD34 + count negatively predicted myocardial infarct mass (R 2 =0.29; P=0.015) and LV end-systolic volume index (R 2 =0.20; P=0.02). Delta CD34 + negatively predicted infarct mass (R 2 =0.13; P=0.049) at 3 months. Mean red cell volume at day 2 negatively predicted LV end-systolic volume index (R 2 =0.24; P=0.038) and infarct size (R 2 =0.13; P=0.045) at 3 months. In multivariable analyses, VEGF at day 2 predicted LV end-diastolic volume index at follow-up (coefficient of variation (95% CI) −0.021 (−0.038, −0.035); P=0.021). Coronary collateral supply was negatively predicted by hemoglobin (−0.04 (−0.06, −0.11); P=0.006) and positively predicted by red cell volume distribution width (0.06 (0.02, 0.10); P=0.004) and platelet count (0.001 (0.0001, 0.002); P=0.001) at day 2. Conclusions: Circulating injury/repair responses predict coronary collateral recruitment and cardiac function and remodeling post-MI.
Abstract 5251: H <sub>2</sub> O <sub>2</sub> -induced Protein Kinase G Dimerization and Vasodilation in Human Coronary Arteriole
Authors: David Zhang, Suelhem Mendoza, Natalya Zinkevich, Lena Borbouse, David Gutterman
Journal: Circulation (2009)

Flow-induced dilation of human coronary arterioles (HCA) is mediated by a unique mechanism involving the release of H 2 O 2 from the mitochondria of endothelial cells and subsequent smooth muscle relaxation via K + -channel-dependent membrane hyperpolarization. The precise mechanisms by which H 2 O 2 induces smooth muscle hyperpolarization remain largely undefined. An important mechanism of action of H 2 O 2 involves the oxidation of key cysteine residues in its target proteins, including protein kinase G 1-alpha (PKG-1 α ). Here we hypothesize that H 2 O 2 dilates HCA through direct oxidation and activation of PKG-1 α leading to the subsequent opening of large-conductance Ca 2+ -activated K + channels (BK Ca ) in smooth muscle cells. In isolated HCA, H 2 O 2 (10 −6 −3×10 −4 M) induced dose-dependent dilations in both endothelium-intact and -denuded vessels (relaxations at 10 −4 M of 83.5±3.7% and 85.1±8.4%, respectively; n=4 – 6). The relaxations were largely abolished by iberiotoxin, a BK Ca blocker (3.4±2.1% and 19.0±10.2% in intact and denuded vessels, respectively). The PKG inhibitor Rp-8-Br-cGMP also markedly inhibited H 2 O 2 -induced dilations (4.5±6.0%; n=6), whereas the guanylyl cyclase inhibitor ODQ has no significant effects (75.6±8.4%; n=3). The expression of PKG-1 α and BK Ca channels in HCA smooth muscles were confirmed by immunohistochemistry and Western blot analysis. In cultured human coronary arterial smooth muscle cells, H 2 O 2 induced dose-dependent dimerization of PKG-1 α , which was subsequently reduced to the monomer forms by the reducing agent β -mecaptomethanol. We also examined flow-mediated dilation in HCA pretreated with iberiotoxin or Rp-8-Br-cGMP. Both agents markedly inhibited relaxation responses as compared to control (maximal relaxations of 36.0±3.8% vs. 69.2±6.8% in controls, and 30.1±4.8% vs. 57.8±3.0% in controls, respectively; n=4 –5). It is concluded that the activation of PKG-1 α via H 2 O 2 -induced protein dimerization and subsequent opening of BK Ca channels serves as a novel mechanism of flow-induced H 2 O 2 -mediated relaxations in HCA. This signaling pathway may have implications for the pathogenesis and therapy of coronary disease.
Abstract 4918: Cytochrome P450 4F2 Transgenic Mice Increase 20-hete and Blood Pressure by Oxidative Stress
Authors: Xiaoliang Liu, Jingjing Wu, Hong Liu, Yanyan Zhao
Journal: Circulation (2009)

Cytochrome P450 4F2 (CYP4F2) is a primary enzyme that converts arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a vasoconstrictive and natriuretic metabolite that regulates human blood pressure. We recently established a CYP4F2 transgenic mouse model using mouse kidney androgen-regulated protein (KAP) promoter, which demonstrated increased 20-HETE production and elevated blood pressure. The present study aims to elucidate the relationship between oxidative stress and 20-HETE in the development of hypertension. The level of oxidative stress was evaluated by measuring malondialdehyde (MDA), a marker of lipid peroxidation, and superoxide dismutase (SOD), a major antioxidative parameter. Plasma MDA was significantly higher in transgenic mice than in wild-type controls ( P &lt;0.05), which was consistent with the level of 20-HETE. Plasma SOD activity was decreased in transgenic mice compared with wild-type controls ( P &lt;0.05). Kidney homogenate also showed increased MDA and decreased SOD activity. In addition, treatment of 5 α -dihydrotestosterone (DHT) strongly induced the synthesis of 20-HETE, and hence enhanced the MDA production and impaired the SOD activity. These results indicate that 20-HETE overproduction in CYP4F2 transgenic mice suffered higher level of oxidative stress. Oxidative stress may possibly be involved in the pathogenesis of 20-HETE-mediated hypertension.
2006 Robert Levy Memorial Lecture—Physical Activity in the Prevention and Treatment of Cardiovascular Disease
Authors: Steven Blair
Journal: Circulation (2006)

Much of the evidence linking a sedentary way of life to cardiovascular disease (CVD) has been derived from relatively healthy populations, but there are data on the effects of physical activity in individuals with health problems or with risk factors for chronic disease. Clinicians, and often the general public, frequently consider the primary value of physical activity as the contribution it makes to control of these other risk factors. This approach underestimates the value of physical activity in the prevention and treatment of CVD. There is a steep inverse gradient of CVD and all-cause mortality across categories of cardiorespiratory fitness and physical activity in all subgroups—women and men who are middle-aged or older, obese or normal weight, or healthy or unhealthy. The overall death rates vary by these subgroups (older individuals obviously have higher death rates than younger persons), but the pattern of association of fitness or activity to mortality is comparable for the various population subgroups. In fact, fit individuals with another risk factor often have lower death rates than unfit individuals without the risk factor. Regular physical activity and moderate to high levels of cardiorespiratory fitness provide protection against CVD and all-cause mortality, and these items should be given increased attention by physicians and other healthcare professionals. These findings are supported by both observational studies and randomized trials.
Abstract 4760: Effect of Cyclosporine on Left Ventricle Remodeling After Reperfused Myocardial Infarction
Authors: Nathan Mewton, Pierre Croisille, Gerald Gahide, Gilles Rioufol, Eric Bonnefoy, Thien Tri Cung, Catherine Sportouch, Denis Angoulvant, Christophe Piot, Didier Revel, Michel Ovize
Journal: Circulation (2009)

Introduction: In a human study, administration of cyclosporine A at the time of acute myocardial infarction (AMI) reperfusion was associated with a smaller infarct size. However, experimental data suggest that cyclosporine A has a detrimental effect on left ventricular remodeling. This study examined the effect of cyclosporine A used at the time of reperfusion, on LV remodeling and function by cardiac magnetic resonance (CMR) in the early days and several months after AMI. Material and Methods: 28 patients of the original cyclosporine A study had an acute (day 5) and a follow-up (6 months) CMR study. Cine imaging was used to determine LV volumes, mass, ejection fraction and myocardial wall thickness in infarcted and remote non-infarcted myocardium, and late gadolinium imaging was used to determine infarct size. Results: There was a persistent reduction of the absolute infarct size at 6 months in the cyclosporine A group compared with the control group of patients (29±15 grams VS 38±14 grams; P=0.04). There was a significant reduction of LV end-systolic volume (and a trend for LV end-diastolic volume; P=0.07) in the cyclosporine A group, compared with the control group, both at day 5 and at 6 months after infarction. There was no significant difference between the two groups in either global LV mass or regional wall thickness of the remote non-infarcted myocardium at day 5 or at 6 months. Attenuation of LV dilatation and improvement of LV ejection fraction by cyclosporine A at 6 months were correlated with infarct size reduction. Conclusion: Cyclosporine A used at the moment of AMI reperfusion persistently reduces infarct size and does not have a detrimental effect on LV remodeling.
Abstract 5219: Reduced Number of CD34+ Circulating Progenitor Cells Predict Long-term Cardiovascular Outcome in Chronic Kidney Disease Patients With Hemodialysis
Authors: Miho Tanaka, Hideki Ishii, Toru Aoyama, Daisuke Kamoi, Yoshihiro Kawamura, Yoshitaka Kumada, Hiroshi Takahashi, Syuichi Maruyama, Seiichi matsuo, Toyoaki Murohara
Journal: Circulation (2009)

Background: Patients with chronic kidney disease(CKD) on hemodialysis (HD) are the highest risk population for cardiovascular (CV) disease, and endothelial dysfunction is regarded as an important cause of CV risk in this population. Circulating endothelial progenitor cells (EPCs) are believed to be involved in maintenance of endothelial integrity, and are close proximity to CD34+ circulating progenitor cells (CPCs). We prospectively examined whether reduced number of CD34+ CPCs would predict long-term CV outcome in HD patients. Methods: The number of CD34+ CPCs was determined with the use of flow-cytometry in blood sample before dialysis session in 216 outer HD patients. To avoid the influence of body fluid overload, the ratio of CD34+ CPCs to peripheral mononuclear cells (CD34+/PMNCs) were calculated. The patients were divided into tertiles according to CD34+/PMNCs levels; tertile 1 (T1): &lt;0.012, T2: 0.013–0.022 and T3: &gt;0.023 (n=72 each), and were prospectively followed for 4 years. Results: During 42±10months, 67 CV events and 35 deaths (21 CV deaths) occurred. Four-year event-free survival were 54%, 68% and 82% for CV events (p=0.0013), 78%, 92% and 98% for CV death (p=0.0009) and 73%, 84% and 93% for all-cause death (p=0.0058) in T1, T2 and T3, respectively. On Cox multivariate analysis, reduced CD34+CPCs levels were independent predictor for CV events (HR 2.40, 95%CI 1.25–4.62, p=0.028 for T1 vs. T3), for CV death (HR 5.46, 95%CI 1.18–25.26, p=0.029 for T1 vs. T3) and for all-cause death (HR 3.72, 95%CI 1.37–10.09, p=0.030 for T1 vs. T3), respectively. Conclusion: These data suggest that reduced number of CD34+ CPCs predicts long-term CVoutcome in CKD patients with HD.
Abstract 4898: Genetic Polymorphism on Type 2 Receptor of Angiotensin II Affects Systemic Inflammatory Process in Hypertensive Individuals
Authors: Dimitris Tousoulis, Nikolaos Koumallos, Charalambos Antoniades, Antigoni Miliou, Alexis Antonopoulos, Dimitris Mentzikof, Kyriakoula Marinou, Constantinos Bakogiannis, Pavlos Stougiannos, Eftihia Kallikazarou, Costas Tsioufis, Christodoulos Stefanadis
Journal: Circulation (2009)

Introduction: Evidence suggests that there is a balance between angiotensin II effects on proatherogenic constitutive type 1, and antiatherogenic inducible type 2 (AT2R) receptors. The AT2R gene is located on chromosome X, and the biological effect of a newly described polymorphism (A1675G) in this gene is unclear. Aim: We examined the impact of A1675G polymorphism on AT2R, on the risk for coronary atherosclerosis, and its effect on the expression of proatherogenic inflammatory molecules. Methods: The study population consisted of 437 males: 155 with coronary artery disease (111 with hypertension) and 282 healthy age-matched controls (121 with hypertension). The presence of A1675G polymorphism on AT2R gene (located in chromosome X) was determined by PCR. Serum levels of C-reactive protein, fibrinogen, interleukin-6 (IL-6) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured in all the participants. Results: The frequency of the A allele was similar among healthy individuals (41.8% 118/282) and CAD patients (47.7%, 74/155, p = NS). However the presence of the A allele was more frequent in hypertensives with CAD (55%, 59/107) than in hypertensives without CAD (35.8%, 43/120, p &lt;0.01). Importantly, the A allele was associated with increased risk for CAD among hypertensive individuals (OR: 2.201[95%CI: 1.291–3.752], p = 0.004), an effect which was not seen among normotensive subjects (p = NS). Importantly, the presence of the A allele was also associated with significantly higher levels of CRP (mean[25th–95th percentile]: A:3.52[1.98 – 6.08] vs G:1.18[0.66 –1.71] mg/dL, p = 0.0001), fibrinogen (A:407[347–513] vs G:369[320 – 416] mg/dl, p = 0.001), IL-6 (A:1.55[3.63–5.40] vs G:0.99[0.51–2.46] pg/ml, p = 0.002), and sVCAM-1 (A:702[648 –925] vs G:621[476 –799] ng/ml, p = 0.03). Conclusions: Genetic polymorphism A1675G on AT2R affects systemic inflammatory mechanisms, since the presence of the A allele is associated with higher levels of CRP, fibrinogen, IL-6 and sVCAM-1. In addition, the A allele is associated with elevated cardiovascular risk among hypertensive individuals.
Abstract 5078: Sustained Acting Atrial Natriuretic Peptide: A Novel Natriuretic Peptide With Potent Blood Pressure Lowering and Renal Enhancing Properties in a Canine Model of Acute Angiotensin Induced Hypertension
Authors: Paul McKie, Alessandro Cataliotti, Guido Boerrigter, Horng Chen, Fernando Martin, John Burnett
Journal: Circulation (2009)

Background Sustained Acting Atrial Natriuretic Peptide (SA-ANP) is a 40 AA peptide consisting of native ANP (1–28) with a 12 AA C-terminus extension which we synthesized based upon a familial ANP gene frameshift mutation. SA-ANP possesses markedly greater and more sustained mean arterial pressure (MAP) lowering, diuretic/natriuretic, angiotensin-aldosterone suppressing, and cGMP activating properties compared to ANP in normal dogs consistent with a super agonist of the ANP receptor (NPR-A) ( JACC in press ). Here we evaluated SA-ANP in a model of acute hypertension with the hypothesis that SA-ANP would have potent MAP lowering and renal enhancing properties. Methods Integrated physiological studies were performed in a canine model of ANG induced hypertension (20 ng/kg/min continuous infusion) before, during, and up to 3 hours following a 45 minute infusion of SA-ANP (30 pmol/kg/min) (n=6) or vehicle (n=6). Results MAP is shown in Figure 1 . SVR significantly decreased and despite a significant reduction in MAP both renal blood flow (RBF) and GFR were significantly increased following SA-ANP infusion. There were significant reductions in proximal and distal tubule sodium reabsorption resulting in a significant increase (&gt;50 fold) in diuresis and natriuresis with SA-ANP. These renal actions were associated with significant increases in plasma and urine cGMP and a significant inhibition of aldosterone activation. Discussion We report for the first time in an acute model of hypertension that SA-ANP reduced MAP while enhancing RBF, GFR, and sodium/water excretion and thus may serve as a potential therapeutic agent in the treatment of hypertension in the setting of volume overload.