tbuckley/cabot-search huggingface dataset:
Abstract 5154: Isolated Nocturnal Hypertension is Associated With Pre-clinical Vascular Pathology in People of African Descent
Authors: Muzi J Maseko, Agela J Woodiwiss, Gavin R Norton
Journal: Circulation (2009)

Recent large clinical studies indicate that an inability to decrease blood pressure (BP) at night is associated with excessive cardiovascular morbidity and mortality. In a randomly selected population sample of subjects (40% hypertensive, 60% overweight and obese, and 8% diabetic), in whom 458 had high quality 24-hour ambulatory BP monitoring and target organ assessments, we determined whether isolated nocturnal hypertension was associated with renal and vascular target organ changes. Pre-clinical renal target organ changes were assessed from urinary microalbumin-to-creatinine ratios (ACR) determined from 24-hour urine samples, and pre-clinical vascular pathology was assessed from carotid-femoral pulse wave velocity (PWV) determined using applanation tonometry. software. In the study sample 7.6% of participants had isolated nocturnal hypertension. Compared to the normomotensives, the isolated nocturnal hypertensives had a higher BMI (31 versus 27). In multivariate regression analysis adjusting for multiple confounders, participants with increased 24-hour BP values had a greater PWV (p&lt;0.0001) and an increased urinary ACR (p&lt;0.0001) as compared to participants with a normal 24-hour, day and night BP. Similarly, participants with isolated nocturnal hypertension, had an increased PWV as compared to participants with a normal 24-hour, day and night BP (p&lt;0.0005). However, participants with isolated nocturnal hypertension had similar urinary ACR values as compared to participants with a normal 24-hour, day and night BP (p=0.62). There was also a strong relationship between nocturnal hypertension and both diabetes (p&lt;0.017) and waist to hip ratio (p&lt;0.038). Isolated nocturnal hypertension is associated with waist to hip ratio, diabetes and pre-clinical vascular but not renal target organ changes in a population sample of African ancestry. As pre-clinical vascular pathology, diabetes and increased waist to hip ratio are independent predictors of cardiovascular outcomes, these data suggest that outcome studies are required to determine whether isolated nocturnal hypertension is a clinical entity that requires therapeutic intervention and lifestyle changes.
Abstract 4869: Association Between Admission Neutrophil to Lymphocyte Ratio and Angiographical Findings in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes
Authors: Tatsuya Nakachi, Masami Kosuge, Kiyoshi Hibi, Toshiaki Ebina, Kengo Tsukahara, Jun Okuda, Noriaki Iwahashi, Yoshio Tahara, Satoshi Umemura, Kazuo Kimura
Journal: Circulation (2009)

Background: Recently, neutrophil to lymphocyte ratio (NLR) was found to be an independent predictor of adverse outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS); however, its underlying mechanism remains unknown. Methods: We examined the relation between NLR and coronary artery disease (CAD) progression in 290 patients with NSTE-ACS who underwent percutaneous coronary intervention, followed by planned coronary angiography 8 months later. The counts of white blood cell, neutrophils, and lymphocytes, high-sensitivity C-reactive protein (hsCRP) level, troponin T, estimated glomerular filtration rate (eGFR) and lipid profiles were measured on initial admission. Patients were divided into the 2 groups according to NLR at initial admission: G-H [NLR ≥2.53 (upper tertile), n=97] and G-L [NLR &lt;2.53 (low and middle tertiles), n=193]. Rapid progression was defined as ≥10% diameter reduction of a pre-existing stenosis ≥50%, ≥30% diameter reduction of a stenosis &lt;50% on follow-up coronary angiography. Results: There were no differences in sex, hypertension, diabetes mellitus, smoking, troponin T, lipid profiles, medications, multivessel disease, and restenosis rate between the 2 groups. G-H patients were older (67±10 vs 65±9 years, p&lt;0.05) and had less frequently hyperlipidemia (44% vs 59%, p=0.02), higher hsCRP level (0.233 vs 0.125 mg/dl, p=0.02), white blood cell count (8235±3205 vs 7004±2190/ μ l, p=0.009), and lower eGFR (65±17 vs 71±18 ml/min/1.73m 2 , p=0.02). G-H patients had more frequently culprit lesion with complex morphology (76% vs 61%, p=0.02), multiple complex lesion (57% vs 43%, p=0.007), rapid progression of non-culprit lesion (31% vs 15%, p=0.002), and adverse events (death, [re] infarction, or urgent revascularization) at 24 months (14% vs 5%, p=0.007). Multivariate analysis revealed that upper tertile of NLR (odds ratio 2.41, p=0.01) and upper tertile of hsCRP (odds ratio 2.29, p=0.01) were independently associated with rapid progression, but white blood cell count was not. Conclusions: High NLR is associated with not only plaque vulnerability but also rapid CAD progression in patients with NSTE-ACS. These findings may partly explain adverse outcomes in patients with high NLR.
Abstract 5202: Increased Aortic Stiffness in Young Subjects With Migraine
Authors: Giuseppe Schillaci, Giacomo Pucci, Ilaria Corbelli, Paola Sarchielli, Massimo R Mannarino, Matteo Pirro, Paolo Calabresi, Elmo Mannarino
Journal: Circulation (2009)

Background: Migraine is associated with an increased risk for ischemic stroke and other cardiovascular (CV) events, including angina, myocardial infarction, and CV death. However, the mechanisms which link migraine to CV disease remain uncertain. In the present case-control study, we hypothesized that aortic stiffness, a direct measure of aortic stiffness and an independent predictor of stroke and cardiovascular disease, may be increased in young migraineurs with no overt CV disease or major CV risk factors. Methods and Results: We studied 41 individuals with migraine (age 31±8 years, 82% females, blood pressure 118/73±12/9 mmHg) and 41 age- and sex-matched healthy control subjects. In all participants, carotid-to-femoral pulse wave velocity was determined by applanation tonometry (SphygmoCor). Cases and controls were free from overt CV disease, diabetes, and major CV risk factors. Subjects with migraine had a higher aortic pulse wave velocity than matched control subjects (7.4±1.2 vs 6.5±1.1 m×s −1 , p=0.001). Age, mean arterial pressure as a measure of distending pressure and the presence of migraine (all p&lt;0.05) independently predicted aortic pulse wave velocity when a consistent number of cardiovascular risk factors was simultaneously controlled for. Conclusions: Migraine is independently associated with an increased aortic stiffness. This finding, obtained in young subjects without major cardiovascular risk factors, may represent one possible mechanism underlying the increased cardiovascular risk in patients with migraine.
Abstract 5109: LKB1 in Vascular Endothelial Cells is Essential for Revascularization in a Mouse Ischemic Hind-limb Model
Authors: Koji Ohashi, Noriyuki Ouchi, Kenneth Walsh
Journal: Circulation (2009)

Recent reports have indicated that LKB1 is a regulator of AMP-activated protein kinase (AMPK) signaling in many tissues including liver, skeletal muscle and cardiac myocytes. In vascular endothelial cells, AMPK signaling is essential for cell function and angiogenic responses to tissue ischemia. Homozygous LKB1 deficiency in mice leads to embryonic lethality associated with abnormal vascular development. Here, we investigated whether heterozygous LKB1 deficiency in endothelial cells has a role in regulating revascularization to tissue ischemia in hind limb ischemic mouse model. We also explored the role of AMPK signaling downstream of LKB1 in vascular endothelial cells. Homozygous vascular endothelial cell deletion of LKB1, using the conditional loxP gene regulation system crossed with Tie2-Cre transgenic mice, led to an embryonic lethal phenotype. Thus, we produced endothelial specific reduced LKB1 model, Lkb1 flox/ + ;Tie2 Tg/ + (heterozygous-KO) mice. LKB1 expression level was decreased to half in the isolated endothelial cells from heterozygous-KO mice compared with those from Lkb1 flox/ + ;Tie2 +/+ (control) mice, but mice were normal in viability, body weight and vascular density. Revascularization of hind limb following ischemic surgery was significantly impaired in heterozygous-KO mice compared with control mice as evaluated by laser Doppler Flow method and capillary density analyses at day 14 and 28 after surgery. In cultured endothelial cells, reduction of LKB1, using both siRNA and adenovirus expressing non-functional kinase dead LKB1 protein, attenuated differentiation into network structures that was accompanied by diminished phosphorylation levels of AMPK (Thr-172) and acetyl-CoA carboxylase (ACC) (Ser-79). Conversely, LKB1 over-expression by adenovirus (Ad-LKB1) augmented differentiation into network structure with elevated phosphorylation levels of AMPK, ACC and eNOS (Ser-1177). The augmented network structure induced by Ad-LKB1 was abrogated by the co-transduction of a dominant negative mutant of AMPK. Taken together, our observations suggest that LKB1-AMPK axis in endothelial cells plays a pivotal role in the revascularization response to tissue ischemia.
Abstract 4847: COUP-TFII Inhibits Expression of Transcription Factor Hey2 in Human Arterial Endothelial Cells
Authors: Slobodanka Korten, Winfried Goettsch, Henning Morawietz
Journal: Circulation (2009)

Normal development of an organism requires formation, differentiation and stabilization of blood vessels. Furthermore, many diseases have their origin in disturbed arterial and venous function, e.g. coronary artery disease, peripheral arterial occlusive disease or deep-vein thrombosis. Arteries and veins differ not only in their physiology, but also in their structure. We identified two transcription factors specifically expressed in venous (COUP-TFII) or in arterial endothelial cells (Hey2). In this study, we analyzed a potential direct molecular interaction of these two determinants of an arterial and venous phenotype. Using lentiviral gene transfer, we overexpressed venous marker gene COUP-TFII in human primary arterial endothelial cells. Using this approach, we reached high transduction efficiency of HUAEC. We were able to show, that the overexpressed transcription factor COUP-TFII was correctly processed and transported into the nucleus. More importantly, COUP-TFII overexpression caused downregulation of arterial marker gene Hey2. These data suggested that COUP-TFII could be a direct repressor of Hey2. Using two independent methods, chromatin immunoprecipitation and electrophoretic mobility shift assay, we can show that COUP-TFII binds to the Hey2 promoter thus repressing its activity. This was confirmed by COUP-TFII supershift strongly supporting a direct interaction of COUP-TFII with the Hey2 promoter. In conclusion, using lentiviral gene transfer allowing efficient and stabile transduction of primary endothelial cells, we were able to show that the venous marker gene COUP-TFII downregulates the expression of the arterial marker gene Hey2 in primary arterial endothelial cells. Additional analysis confirmed that the transcription factor COUP-TFII directly binds to specific sites of the Hey2 promoter, thus leading to the downregulation of its expression. This is a novel molecular mechanism defining an arterial or venous phenotype in human endothelial cells.
Association of ST2 Levels With Cardiac Structure and Function and Mortality in Outpatients
Authors: Lori B. Daniels
Journal: Circulation (2009)

Abstract #2370 Lori B. Daniels, Univ of California, San Diego, La Jolla, CA; Paul Clopton, VA San Diego Healthcare System and Univ of California, San Diego, San Diego, CA; Kimberly Tran, VA San Diego Healthcare System, San Diego, CA; Alan S. Maisel, VA San Diego Healthcare System and Univ of California, San Diego, San Diego, CA Lori B. Daniels, 2009 Finalist and Presenting Author
Abstract 589: Activation of Toll-like Receptor Induces Cardiac Remodeling
Authors: Qianli Yu, Douglas F Larson
Journal: Circulation (2006)

Introduction: Diastolic heart failure, due to increased ventricular stiffness, is brought about by extracellular matrix (ECM) remodeling. We have previously shown that T-lymphocyte function directly affects cardiac fibroblast function and thereby the ECM composition and diastolic function. Oligodeoxynucleotides (ODN) that selectively stimulate the Toll-like receptor-9 (TLR9) receptor on dendritic cells (DC), induce TH1 immune response. Hypothesis: Selective stimulation of the DC TLR 9 receptor with ODN CPG1668 activates TH1 lymphocytes resulting in ECM remodeling and diastolic dysfunction. Methods: Weight matched C57BL/6J female mice were treated either with PBS (n=8) or with CPG1668 (n=8) at a dose of 50 μg/mouse/week (i.p.) for 4 weeks. After 6 weeks, left ventricular mechanics were determined with pressure-volume loop analysis, ECHO, and ventricular tissue harvested for gene expression, collagen content and crosslinking, and the collagen crosslinking enzymatic activity of lysyl oxidase (LOX). Splenic lymphocytes were harvested for the cytokine determination. Results: CPG1668 administration increased the TH1 cytokine, IFN-γ, from 429±21 to 954±21 (ng/10 6 T-cells), while TH2 cytokine, IL-4, decreased from 614±79 to 51±19 (pg/10 6 T-cells). CPG1668 significantly decreased the end-diastolic volume from 18±1 to 14±1μL (P=0.02), and cardiac output from 6.7±0.6 to 4.9±0.6 mL/min (P=0.05) with no change of ejection fraction 71±3 to 73±4 compared with controls. An increase of ventricular stiffness (β), from 0.16±0.01 to 0.23±0.01 mmHg/μL (P=0.0007), was supported by a decreased E deceleration slope of −8.8±0.6 to −4.1±0.4 (P&lt;0.0001). CPG increased total cardiac collagen two-fold (P=0.0004) and collagen crosslinking by 3-fold (P=0.0007) compared with controls. Correspondingly, CPG administration increased cardiac LOX enzymatic activity by 61% (P=0.02). Real time PCR showed that LOXL3 gene expression increased 9.1-fold (P&lt;0.0001) as well as LOX 1.7-fold (P=0.05) when comparing CPG with controls. Conclusions: This study demonstrates that stimulation of the TH1 lymphocytes via DC TLR 9 receptor induces cardiac ECM remodeling and diastolic dysfunction associated with LOX induced collagen crosslinking.
Abstract 5079: Hypertension in Soluble Guanylate Cyclase <i>α</i> <sub>1</sub> - Deficient Mice is Associated With Hyperaldosteronism
Authors: Emmanuel S Buys, Michael J Raher, Kristen M Rauwerdink, Patrick Y Sips, Peter Brouckaert, Kenneth D Bloch
Journal: Circulation (2009)

Introduction . Hypertension is an important modifiable risk factor for cardiovascular disease. Altered activity of both the renin-angiotensin system (RAS) and the nitric oxide (NO)-cGMP signaling pathway have been associated with hypertension. However, the interaction of the RAS and the NO-cGMP signaling pathway remains incompletely characterized. We previously reported that male mice deficient in the α 1 subunit of soluble guanylate cyclase (sGC α 1 −/− mice), an important NO receptor, develop hypertension. Here, we hypothesized that increased activity of the RAS underlies the hypertension associated with sGC α 1 -deficiency. Methods . Plasma renin activity and aldosterone were measured in the plasma of anesthetized (100 mg/kg ketamine, 5 mg/kg xylazine) 12–14 weeks old male wild-type (WT) and sGC α 1 −/− mice by radioimmunoassay. Na + and K + were analyzed using Spotchem blood chemistry. Blood pressure was measured invasively (Millar pressure volume catheter) in male WT and sGC α 1 −/− mice, treated with vehicle or the aldosterone receptor antagonist, Spironolactone (100 mg/kg/day, sc for 7 days). Results . PRA was higher in sGC α 1 −/− than in WT mice (0.29±0.01 vs 0.23±0.03 μ g/ml/hr, respectively, P&lt;0.05). Plasma levels of aldosterone were elevated in sGC α 1 −/− mice as compared to WT mice (0.47±0.03 vs 0.34±0.03 ng/ml, respectively, P&lt;0.05). Correlating with the hyperaldosteronism seen in sGC α 1 −/− mice, plasma K + levels were higher (5.4±0.2 vs 4.4±0.2 mEq/L, respectively, P&lt;0.05), and plasma Na + levels were lower (144±0 vs 146±1 mEq/L, respectively, P&lt;0.05) in sGC α 1 −/− mice than in WT mice. Mean arterial pressure (MAP) was the same in WT mice treated with Spironolactone or vehicle (131±5 vs 137±3 mmHg, respectively), but MAP was less in sGC α 1 −/− mice after treatment with Spironolactone than after treatment with vehicle (125±8 vs 173±14 mmHg, respectively, P&lt;0.01). Conclusions . Together, these data suggest that altered RAS activity and, more specifically, increased aldosterone signaling, contribute to the hypertension associated with sGC α 1 -deficiency. These findings highlight the importance of sGC in the regulation of the RAS and suggest that sGC may be a therapeutic target in renin-dependent hypertension.
Abstract 5169: Endovascular Injury Induces Rapid Phenotypic Changes in Perivascular Adipose Tissue
Authors: Minoru Takaoka, Ryozo Nagai, Masataka Sata
Journal: Circulation (2009)

Background: It was reported that the serum levels of circulating proinflammatory cytokines are increased in overweight people with enhanced accumulation of visceral fat. In contrast to visceral fat, little attention has been paid to the role of perivascular fat in the pathogenesis of obesity-associated diseases. Here, we investigated the effect of endovascular injury on the phenotype of perivascular fat. Methods and Results: First, endovascular injury significantly down-regulated adiponectin and up-regulated proinflammatory adipocytokines, TNF-alpha, IL-6, PAI-1 and MCP-1 within perivascular fat tissue in models of murine femoral artery wire injury and rat iliac artery balloon injury (p&lt;0.05). Second, diet-induced obesity augmented endovascular injury-induced up-regulation of proinflammatory adipocytokines within perivascular fat tissue (p&lt;0.05) and neointimal hyperplasia (p&lt;0.05) compared with standard chow diet in wild-type mice. Third, up-regulation of proinflammatory adipocytokines within perivascular fat by endovascular injury was significantly blunted in TNF-alpha deficient mice (p&lt;0.05). Neointima formation was attenuated in TNF-alpha deficient mice compared with wild-type mice (p&lt;0.05). Furthermore, perivascular delivery of TNF-alpha to the femoral artery using osmotic minipump enhanced endovascular injury-induced up-regulation of proinflammatory adipocy-tokines within perivascular fat (p&lt;0.05) and neointimal hyperplasia (p&lt;0.05) compared with contralateral PBS delivered artery in TNF-alpha deficient mice. Fourth, conditioned medium from the coculture of 3T3L1-derived adipocyte and RAW264 macrophage stimulated rat vascular smooth muscle cells proliferation relative to the control medium from 3T3L1-derived adipocyte (p&lt;0.05). Blockade of TNF-alpha in the co-culture using an anti-TNF-alpha neutralizing antibody reduced the stimulatory activity of the condition medium (p&lt;0.05). Conclusions: Our findings indicate that endovascular injury induces rapid and marked changes in perivascular adipose tissue, mainly mediated by TNF-alpha. It is suggested that the phenotypic changes in perivascular adipose tissue may have a role in the pathogenesis of neointimal hyperplasia after angioplasty.
Abstract 4897: Right Ventricular Diastolic Dysfunction in Upper-normal and Mildly Hypertensives: A Tissue Doppler Imaging Study
Authors: Maria Laura Canale, Enrica Talini, Cristina Giannini, Stefano Bendinelli, Giulia Dell’Omo, Vitantonio Di Bello, Roberto Pedrinelli
Journal: Circulation (2009)

Background: Systemic hypertension is known to affect the right ventricle in addition to its wide-ranging effects on left ventricular structure and function. Whether upper-normal increments in systemic blood pressure (BP), sampled by ABPM, exert any effect on right ventricular function is, however, unknown at this point. Methods: Left (LV) and right ventricular (RV) diastolic longitudinal function were assessed by pulsed-wave TDI sampled at mitral (early:Em MIT and late:Am MIT ) and tricuspid (Em TRIC and Am TRIC ) annular level in a group of 98 (37F/61M, age: 46 ± 14yrs) otherwise normal subjects with office BP values ranging from the optimal (&lt; 120/80 mmHg) to the mild hypertensive (140–160/90–100 mmHg) range. RV free wall (FWT) and interventricular septum thickness (IVST), LV ejection fraction (EF), TRIC annulus plane systolic excursion (TAPSE, an index of RV systolic function), LV mass index (MI, g/m 2.7 ) were evaluated by standard methods. The sample was stratified by ascending 24-hr systolic(S) BP tertiles (cutoffs:117 and 130 mmHg, I:110 ± 7/68 ± 7, II:125 ± 4/77 ± 7, III:139 ± 7/87 ± 8 mmHg) and analyzed accordingly. Results : Em TRIC decreased significantly at each increasing 24-hr SBP stratum (I:15.9 ± 2.8, II:12. ± 3.1, III:10.9 ± 3.6 cm/sec, I vs II p &lt; 0.01, II vs III p &lt; 0.01) in parallel with consensual reductions in Em MIT (I:11.1 ± 2.8, II:8.7 ± 2.9, III:8.3 ± 2.6 cm/sec, I vs II &amp; III p &lt; 0.001). RVFWT (I:3.5 ± 0.6, II:4.0 ± 1.1, III:3.6 ± 0.9 mm, NS) and LVMI (I:38.6 ± 8.3, II: 41.3 ± 6.6, III: 43.0 ± 9.1 g/m 2.7 , NS) did not change in contrast to the graded, BP-related thickeness of IVS (I: 7.9 ± 1.1, II: 9.3 ± 1.25, III: 10.3 ± 1.34 mm, I vs II: p = 0.001, II vs III: p = 0.001). Intra-individually (n = 98), Em TRIC associated with 24-hr SBP (r =−0.52, p &lt; 0.001), IVST (r = −0.63, p &lt; 0.001) and Em MIT (r = 0.41, p &lt; 0.001) but only the two latter (IVST: t = 5.5, p &lt; 0.0001; Em MIT : t = 2.8, p = 0.006) were independent predictors of Em TRIC when entered in a multiple regression model. Conclusions : Systemic BP increments still within the normal range associate with echocardiographic evidence of RV diastolic longitudinal dysfunction. Interventricular septum thickening appears to be the main determinant of that behavior, possibly as an expression on interventricular dependence.