tbuckley/cabot-search huggingface dataset:
Abstract 602: Repetitive Coronary Stenosis Induces a Third Window of Ischemic Preconditioning
Authors: You-Tang Shen, Lin Yan, Christophe Depre, Raymond K Kudej, ZhouZhou Xi, Yan Zhang, Dorothy E Vatner, Stephen F Vatner
Journal: Circulation (2006)

The mechanisms responsible for the 1 st and 2 nd window of protection following ischemic preconditioning (IPC) have been studied in detail. We tested the hypothesis that chronic myocardial ischemia (repetitive bouts of coronary stenosis, CS) may induce IPC mediated by different mechanisms. To study this, 6 episodes of 90 min chronic CS (reduction in coronary blood flow, &gt;35% from baseline), followed by reperfusion every 12 hrs were examined in conscious pigs chronically instrumented to measure left ventricular (LV) pressure and regional wall thickness. Infarct size/area at risk (IF/AAR) was assessed in all groups after 60 min of coronary artery occlusion (CAO) followed by 4 days of reperfusion. This resulted in IF/AAR of 42±5% in control pigs without IPC (n=5). Following repetitive CS, IF/AAR was markedly decreased (p&lt;0.05) (4±6%, n=4). The 2 nd window of IPC was induced in 5 pigs by two 10 min periods of CAO. 24 hrs later, the 60 min of CAO also resulted in reduced IF/AAR of 16±4%. In 6 pigs, 24 hrs after IPC without 60 min of CAO, the IPC myocardium was found to have significant, p&lt;0.05, 2– 4-fold increases in iNOS, Cox-2, phosphorylated PKC and AMPK. None of these proteins was elevated in myocardium subjected to repetitive CS. Pretreatment with an NO synthase inhibitor, L-NNA, prevented the 2 nd window of IPC as expected, since iNOS was elevated, but failed to prevent the ischemic protection following repetitive CS, where iNOS was not elevated. Following repetitive CS, genomic microarray analysis revealed upregulation of cytoprotective genes, e.g., IAP, H11 kinase, αB-crystallin, Akt 1, Bcl-2. These cytoprotective genes were also found to be upregulated in samples from patients with chronic coronary artery disease and hibernating myocardium. Thus, repetitive CS induces powerful protection against lethal myocardial ischemia, with mechanisms radically different from that observed in the 2 nd window of IPC, suggesting a novel “third window” of IPC, which could also be involved in the protection inherent to hibernating myocardium.
Abstract 4197: Statins and ACE-Inhibitors Prevent Renal Deterioration in Patients with Peripheral Arterial Disease
Authors: Harm H Feringa, Gijs Welten, Sanne Hoeks, Martin Dunkelgrun, Fahim Azizi, Yvette van Gestel, Radosav Vidakovic, Olaf Schouten, Ron van Domburg, Inge de Liefde, Stefanos Karagiannis, Don Poldermans
Journal: Circulation (2006)

Background: Renal dysfunction is an underestimated risk factor in patients with peripheral atherosclerotic disease. Aim: To assess the prevalence and prognosis of decreased estimated glomerular filtration rate (eGFR) in patients with peripheral atherosclerotic disease and to evaluate whether statins and angiotensin-convering enzyme (ACE-) inhibitors are associated with reduced renal deterioration and reduced cardiovascular event rate. Methods : In a prospective observational cohort study of 1939 consecutive patients with peripheral arterial disease, clinical characteristics, cardiac medication and serial creatinine concentrations were obtained. During follow-up, renal deterioration (&gt;25% decrease in eGFR) was determined and hard cardiac events (cardiac death or non-fatal myocardial infarction) were noted. Results: No, mild, moderate and severe renal dysfunction (eGFR of &gt;75, 60.0–74.9, 45.0–59.9, and &lt;45.0 ml/min per 1.73 m 2 , respectively), was assessed in 55%, 19%, 14% and 12% of patients. Renal deterioration occurred in 9%, 8%, 13%, and 20% of patients, respectively. Hard cardiac events during a mean follow-up of 6.4 years occurred in 20%, 27%, 30%, and 32% of patients, respectively. Statins and ACE-inhibitors were significantly associated with reduced renal deterioration (HR: 0.62, 95% CI: 0.49– 0.79, and HR: 0.55, 95% CI: 0.44– 0.70, respectively). In multivariate Cox proportional hazard regression analysis, lower baseline eGFR (per 10 mg/min/1.73 m 2 ) and higher decreases in eGFR (per 10%) were significantly associated with a higher hazard of hard cardiac events (HR: 1.16, 95% CI: 1.12–1.21 and HR: 1.07, 95% CI: 1.02–1.11, respectively). In patients with mild, moderate or severe renal dysfunction, statins and ACE-inhibitors were both associated with a reduction in hard cardiac event rate (HR: 0.60, 95% CI: 0.38–0.87 and HR: 0.65 (0.46–0.92), respectively), after adjusment for possible confounding risk factors and propensity scores. Conclusion: Abnormal eGFR and deterioration in eGFR are frequently observed in PAD and carry an adverse prognosis. Statins and ACE-inhibitors are associated with a reduction in renal deterioration and both drugs improve cardiovascular outcome in PAD patients with renal dysfunction.
Abstract 4955: Akt Cooperates with Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) in TNF-Alpha-Induced Signaling Pathways of Endothelial Dysfunction and Haemostasis
Authors: Hiroshi Ohkawara, Toshiyuki Ishibashi, Katuya Ando, Koichi Sugimoto, Hironori Uekita, Nobuo Sakamoto, Yasuchika Takeishi
Journal: Circulation (2009)

Background: Akt is a critical molecule in several signal transduction pathways involved in vascular responses. Membrane type 1-matrix metalloproteinase (MT1-MMP), a membrane-anchored MMP, functions as a signaling molecule in addition to a proteolytic enzyme. Hypothesis: Akt cooperates with MT1-MMP in tumor necrosis factor (TNF)-alpha-induced signaling pathways of vascular responses including endothelial dysfunction and haemostasis. Methods and Results: TNF-alpha (10 ng/mL) induced a transient increase in Akt phosphorylation within 15 minutes, followed by the profound decrease of Akt phosphorylation and the increase in MT1-MMP activity within 60 minutes, in cultured human aortic endothelial cells (ECs). To demonstrate the role of MT1-MMP for Akt signaling pathway in TNF-alpha-stimulated ECs, we used siRNA to knockdown MT1-MMP protein in ECs. Silencing of MT1-MMP reversed TNF-alpha-triggered transient upregulation of Akt phosohorylation within 15 minutes and the downregulation within 60 minutes, suggesting that MT1 - MMP may be a key regulator of Akt phosphortlation in TNF-alpha stimulated ECs. In the downstream events, TNF-alpha increased tissue factor (TF) expression through NF-kappa B activation and decreased thrombomoduline (TM) expression. Inhibition of Akt by Akt inhibitor X markedly enhanced TNF-alpha-induced upregulation of TF expression and downregulation of TM expression. Silencing of MT1-MMP by siRNA also reversed the changed expression of TF and TM induced by TNF-alpha. These results demonstrated that MT1-MMP-mediated Akt phosphorylation is a critical mechanism in modulation of TNF-alpha-induced signaling pathways and downstream events. Furthermore, we found that pioglitazone, PPAR gamma agonist, suppressed TNF-alpha-induced downregulation of Akt phosphorylation and reversed the upregulated TF expression and upregulated TM expression by TNF-alpha in ECs. This supports a mechanism for pleiotropic effect of pioglitazone on cardiovascular disease. Conclusions: We show new evidence that Akt is a key modifier for TNF-alpha-induced signaling pathways in cooperation with MT1-MMP for modulation of endothelial dysfunction and haemostasis.
Abstract 5092: Effects of Intensive Lipid Therapy on Atherosclerotic Plaque Burden and Time-course: A Prospective, Randomized, Double Blinded Study With Magnetic Resonance Imaging (MRI)
Authors: Li Dong, Chun Yuan, Tom S Hatsukami, Moni B Neradilek, Baocheng Chu, Hunter R Underhill, Andrew Moore, Duane A Monick, Colin D Lee, Minako Okawa, Xihai Zhao, Xue-Qiao Zhao
Journal: Circulation (2009)

Background: Intensive lipid lowering therapy has been associated with regression of atherosclerotic disease burden. However, the time-course for response to therapy has not been established. In this study, we examined the effects of intensive lipid-lowering therapy on atherosclerosis burden and its time course over 3 yrs in the carotid artery. Methods: Subjects ( N =112) with coronary or carotid artery disease, apoB &gt;= 120 mg/dl, received intensive lipid lowering therapy for 3 yrs. Subjects underwent carotid MRI scans at baseline and annually for 3 yrs. Expert reviewers, blinded to clinical information and scan time sequence, analyzed the atherosclerosis burden (percent wall volume (PWV) =100% × wall volume/[lumen volume + wall volume]). The burden change, expressed as ΔPWV, between pre- and post-therapy and the time course of changes over 3 yrs were compared. We also modeled (ΔPWV) as a function of the extent of maximum wall thickness (MaxWT) to assess association between the degree of disease in selected patients and ΔPWV. Results: 84 subjects completed 3 yr follow-up scans with acceptable image quality. After 3 yrs of therapy, PWV significantly regressed (−3.8%, p&lt;0.001). The time course over 3 yrs showed that PWV did not change significantly after the 1 st yr (−0.3 %, p=0.7), but showed significant regression during the 2nd yr (−3.6 %, p&lt;0.001). In this sample population, an additional year of therapy did not result in significant change from the reduction that occurred during the second year (+0.1 %, p=0.9). Average MaxWT at baseline was 2.27 mm (range: 1.0 to 5.6 mm). More thickened arteries showed significantly more reduction in atherosclerosis burden over 3 yrs compared to thinner arteries (p&lt;0.001 for MWT slope, fitted linear regression model for ΔPWV: mean ΔPWV =0.46 – 0.41*MWT). Conclusions: Maximal effect of intensive lipid-lowering therapy on atherosclerotic burden was observed after 2 years of therapy. This regression was mainly demonstrated in thickened arteries, but not in relatively normal (thinner) arteries. Our findings suggest that efficacy of lipid-lowering therapy on carotid plaque burden may be best evaluated in a population with pre-existing carotid atherosclerotic disease and 2 years of therapy.
Abstract 4931: RGDS-Epitope Presenting Peptide Amphiphile Nanofibers Enhance Therapeutic Potency of Cell-based Strategies in Ischemic Tissue
Authors: Joern Tongers, Matthew G Webber, Marie-Ange Renault, Jerome G Roncalli, Kentaro Jujo, Xintong Wu, Ekaterina Klyachko, Tina Thorne, Samuel I Stupp, Douglas W Losordo
Journal: Circulation (2009)

Cell-based therapies have emerged as a promising option in ischemic tissue repair. Impaired viability and retention of injected cells in the ischemic target zone and reduced biopotency of autologous cells from pts with advanced disease remain significant challenges. Advances in bionanotechnology have led to development of biomaterials that may offer solutions to overcome limitations and to enhance the efficacy of cell therapy by modulating the microenvironment. Interaction with fibronectin (FN) has been shown to effect cell survival, adhesion and motility. We developed a self-assembling peptide amphiphile (PA) nanofiber that presents the binding domain epitope of FN, Arg-Gly-Asp-Ser (RGDS). Incubation of BM-derived pro-angiogenic cells (BMPAC) with this RGDS-PA (0.2w%) reduced H 2 O 2 -induced apoptosis (0.22±0.02 TUNEL + /TUNEL − cells) compared to cells without RGDS-PA (0.60±0.07, n=5–10, P&lt;0.01). In addition, RGDS-PA increased proliferation (MTS assay; RGDS-PA 174±30% vs. 100% control, n=7–12, P&lt;0.01), adhesion to uncoated (185±95 vs. 59±25, P&lt;0.05) and vitronectin (201±84 vs. 53±26, P&lt;0.05) surfaces. Tube formation (matrigel assay) and migration (Boyden chamber), endpoints that integrate several cell functions, were enhanced and impaired respectively. Local injection of RGDS-PA combined with a sub-therapeutic dose of BMPAC (10 5 ) (R+B) vs. BMPAC alone (B) 3 days after surgical hind-limb ischemia (HLI) in 8-week-old, male FVB/N mice, improved blood flow recovery (laser Doppler, ischemic/non-ischemic limb ratio: R+B, 0.67±0.06; B, 0.55±0.04), limb salvage (score: R+B, 3.4±0.3; B 2.9±0.4; n=8 –9/group, P&lt;0.05), and motor function of the ischemic limb (score: R+B, 3.6±0.2; B, 2.9±0.2; n=8 –9/group, P&lt;0.05) at day 28. Viablity tracking with β -actin-luc + cells revealed higher bioluminescent signals, reflecting more viable cells at day 7 (R+B, 692±141%; B, 132±50%; n=7–9/group, p&lt;0.01). These findings correspond with incr CD31 + capillaries in the ischemic limb muscle at day 28 (Tx: 56±2/hpf; R+B: 91±5/hpf; B: 72±2/hpf; n=5–9/group, p&lt;0.001). Conclusion : RGDS-PA nanofibers enhance functionality of BMPAC and thereby augment potency of cell-based therapies in ischemic tissue repair. This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota &amp; Wisconsin).
2006 Sol Sherry Distinguished Lecture in Thrombosis—Crosstalk Between the Hemostatic and Inflammatory Systems
Authors: Jay Degen
Journal: Circulation (2006)

Essentially all of the major coagulation and fibrinolytic system components (including proteases, co-factors, receptors, inhibitors, and substrates) have been experimentally eliminated or functionally altered in gene-targeted mice. Detailed studies of these mutant animals have greatly improved the understanding of the role of these proteins in complex physiological and pathological processes in vivo. Hemostatic derangements were the most predictable consequence of genetically imposed alterations in key coagulation and fibrinolytic factors, but more detailed studies have illuminated another less obvious aspect of the hemostatic system—namely, that coagulation and fibrinolytic factors appear to figure prominently into a wide spectrum of biological processes in vivo that have little or nothing to do with traditional hemostasis. Studies of mice with hemostatic deficits compatible with survival to adulthood (eg, fibrinogen-, plasminogen activator–, and plasminogen-deficient mice) have revealed an important role of these factors in phenomenally diverse biological settings (eg, immune surveillance, neurodegeneration and repair, tumor metastasis, and inflammatory diseases). Regulatory crosstalk between the hemostatic and inflammatory systems has become an increasingly frequent biological theme. The precise mechanisms by which thrombin, fibrinogen, and other hemostatic factors contribute to the inflammatory response remain to be fully defined, but leukocyte receptor interactions with fibrin(ogen) and other hemostatic factors are likely to be one important means of locally regulating leukocyte function. A comprehensive understanding of the role of hemostatic factors in inflammatory processes may suggest new strategies for the treatment of a wide array of inflammatory diseases.
Abstract 4206: Invasive Treatments for Obese Patients with CAD: An Explanation for the “Obesity Paradox”? Analysis of 130,139 Hospitalizations in Get With The Guidelines
Authors: Benjamin A Steinberg, Gregg C Fonarow, Adrian F Hernandez, Wenqin Pan, Eric D Peterson, Christopher P Cannon
Journal: Circulation (2006)

BACKGROUND : Obesity is a well documented risk factor for cardiovascular disease and long-term mortality, yet a previous analysis of the Get With The Guidelines (GWTG) database revealed a paradoxically lower short-term mortality rates in patients with coronary artery disease (CAD). We hypothesized that this surprising trend may be the result of more aggressive management of such patients. METHODS : The GWTG database was analyzed for CAD hospitalizations from 1/00 to 12/05 with documented height and weight. Patients were divided into BMI (kg/m 2 ) categories: underweight (&lt; 18.5), healthy weight (18.5 − 24.9) overweight (25.0 − 29.9), and obese (≥ 30). Reperfusion therapies, as well as baseline characteristics, medications, and in-hospital mortality by BMI category were assessed. RESULTS : There were 130,139 hospitalizations from 409 US hospitals analyzed. Patients in the overweight or obese BMI categories were younger, with more obesity-related risk factors for cardiovascular disease. In-hospital mortality was 5.4% in normal weight patients and 3.1% and 2.4% in the overweight and obese categories, respectively. In unadjusted analyses, a higher percentage of obese and overweight patients received indicated, guideline-recommended therapies (see Table ). After adjusting for common confounders, overweight and obese patients were more likely to undergo cardiac catheterization (p&lt;0.01 for both, compared to normal) and PCI (p&lt;0.0001 for overweight and obese vs. normal), as well as CABG surgery (p&lt;0.0001 for both). They also had a significantly shorter length of hospitalization in the multivariate model (p&lt;0.0001). CONCLUSIONS : While obesity remains a significant risk factor for the development of CAD, increased body mass does not in of itself represent a barrier to the use of invasive therapies for CAD. It may positively influence clinicians’ use of proven and intensive treatment strategies, contributing to better short-come outcomes in these patients.
Abstract 4892: Olmesartan Potentiates the Vasorelaxation and Anti-hypertensive Effect of Angiotensin(1–7)
Authors: Robson A Santos, Silvia Q Savergnini, Roberto Q Lautner, Aline N Braga, Carlos H Castro
Journal: Circulation (2009)

It has been described that Olmesartan increases plasma angiotensin-(1–7) [Ang-(1–7)] through increase in ACE2 expression. Here we evaluated the effect of acute treatment with Olmesartan on the anti-hypertensive and vasorelaxing effects of Ang-(1–7). Vascular activity of Ang-(1–7) was evaluated in intact aorta rings of Wistar rats, pre-contracted with phenylephrine (10 −7 M). Olmesartan or Losartan were added to the bath at a concentration of 10 −7 M, 30 minutes before adding phenylephrine and performing a dose-response curve of Ang-(1–7) (10 −10 to 10 −6 M). To evaluate the acute effect of Olmesartan on the anti-hypertensive action of Ang-(1–7), experiments were performed in male SHR (14 –16 week-old). Twenty-four hours before the experiments, catheters were implanted into the abdominal aorta for arterial pressure and heart rate (HR) measurements and the femoral vein for intravenous infusions. Different doses of Ang-(1–7) (0.003, 0.03, 0.3 and 3nmol/Kg/min) or saline were infused (30 minutes each), before and after one hour administration of Olmesartan or Losartan (1mg/Kg) by gavage. Acute treatment with Olmesartan augmented the vasodilator effect of Ang-(1–7) in endothelium-intact aortic rings (E max : 28.28 ± 2.94 vs 14.94 ± 1.37% in vehicle-treated rings). The same treatment with Losartan did not change the Ang-(1–7)-induced vasorelaxation (E max : 11.08 ± 0.98). Acute infusion of Ang-(1–7) produced a dose-dependent decrease in MAP in conscious SHR. The maximum change during infusion was observed at the highest dose (3 nmol/Kg/min, Δ: −16.6 ± 3.8 mmHg). The anti-hypertensive effect of Ang-(1–7) was markedly enhanced after Olmesartan administration (maximum change: −35.4 ± 5.4 mmHg, at the dose of 3nmol/Kg/min). Losartan treatment produced only a slight increase in the Ang-(1–7) anti-hypertensive effect (Δ: −9.9 ± 6.3 mmHg). Vehicle administration did not change the anti-hypertensive effect of Ang-(1–7). At the doses used, acute administration of both AT1 blockers alone did not change blood pressure. These data show that Olmesartan but not Losartan potentiated the vasorelaxation and anti-hypertensive effects of Ang-(1–7). The absence of effect of the other AT1 blocker Losartan, suggest that this is not a class effect.
2006 George E. Brown Memorial Lecture—The CYP450 Pathway and Cardioprotection
Authors: Garrett Gross
Journal: Circulation (2006)

Ischemia-reperfusion of the heart and other organs results in the accumulation of unesterified arachidonic acid (AA) via the action of membrane-bound phospholipases, primarily phospholipase A 2 . AA can be metabolized by the classical cyclooxygenase (COX) and lipoxygenase (LOX) pathways to well-characterized metabolites and their respective cardioprotective end products such as prostacyclin (PGI 2 ) and 12-hydroxyeicosatetraenoic acid (12-HETE); however, it has only been recently recognized that another less well-characterized pathway of AA metabolism, the cytochrome P450 (CYP) pathway, may have important cardiovascular effects. Several lines of data support the possibility that certain CYP metabolites resulting from the hydroxylation of AA, such as 20-hydroxyeicosatetraenoic acid (20-HETE), are potent vasoconstrictors and may produce detrimental effects in the heart during ischemia and proinflammatory effects during reperfusion. On the other hand, a group of regioisomers resulting from the epoxidation of AA, including 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acid (EETs), have been shown to reduce ischemic and/or reperfusion injury in the heart and other organs. In this presentation, I will discuss the detrimental and beneficial actions of this novel pathway, including the potential cellular mechanisms responsible for the effects observed as a result of stimulating or inhibiting the 2 arms of this novel CYP450 pathway. The therapeutic potential of increasing EET concentrations and/or reducing 20-HETE concentrations will also be addressed.
Abstract 601: Haptoglobin Genotype Determines Myocardial Infarct Size in Diabetic Mice
Authors: Shany Blum, Roy Asaf, Julia Guetta, Rachel Miller-Lotan, Rabea Asleh, Ran Kremer, Nina S Levy, Doron Aronson, Xiaoming Fu, Renliang Zhang, Stanley L Hazen, Andrew P Levy
Journal: Circulation (2006)

Objectives. We sought to understand the importance of oxidative stress in explaining why the haptoglobin (Hp) genotype determines myocardial infarction (MI) size in diabetes mellitus (DM). Background. Two common alleles (1 and 2) exist at the Hp locus in man. The haptoglobin (Hp) 2 allele is associated with increased MI size in individuals with DM. Enhanced oxidative stress resulting in increased production of reactive oxygen species has been shown to play a critical role in the generation of myocardial ischemia-reperfusion injury (IR). Redox active labile plasma iron (LPI) and the anti-inflammatory cytokine interleukin-10 (Il-10) are known to play major roles in determining the extent of myocardial injury after myocardial IR. In vitro the Hp 2 protein is associated with increased generation of oxidatively active iron while the Hp 1 protein is associated with increased production of the antioxidant cytokine interleukin-10 (Il-10). Methods. MI was produced by myocardial ischemia-reperfusion (IR) using an occlusion of the left anterior descending artery followed by reperfusion in DM C57Bl/6 mice carrying the Hp 1 or Hp 2 allele. Myocardial oxidative stress after IR was assessed using electrospray ionization mass spectrometry. Redox active iron and Il-10 were measured in the serum after IR. Results. MI size was significantly larger in Hp 2 mice as compared to Hp 1 mice (44.3±9.3% vs. 21.0±4.0%, p=0.03) and these larger infarctions were associated with a significant increase in a panel of hydroxyl-eicosatetraenoic acids (HETEs). Redox active iron was greater in Hp 2 mice (0.45±0.11uM vs. 0.14uM±0.05uM, p=0.02) while Il-10 was greater in Hp 1 mice (4170±646 pg/ml vs. 2115±541 pg/ml, p=0.03) after IR. Administration of an antioxidant (glutathione peroxidase mimic BXT-51072) to Hp 2 mice reduced myocardial injury after IR by over 80% (44.3±9.3 % vs. 7.0±3.1%, p=0.003). but no myocardial protection was provided by the antioxidant to Hp 1 mice. Conclusions. The increased MI size in DM Hp 2 mice occurring after IR may be due to increased oxidative stress. We suggest that strategies which will be designed to decrease this oxidative stress may provide significant myocardial protection.