tbuckley/cabot-search huggingface dataset:
Abstract 5126: Platelet Specific Factor XIII Gene Expression and Embolic Propensity in Atrial Fibrillation
Authors: Izabela Gosk-Bierska, Yanhong Wu, Thomas G McLeod, Dylan Miller, Jozef Mruk, Robert D McBane, Waldemar E Wysokinski
Journal: Circulation (2009)

Background and Aim: Cardioembolic stroke from non-valvular atrial fibrillation (NVAF) begins with the development of left atrial appendage thrombus (LAAT). Although nearly 15% of patients with NVAF have LAAT by transesophageal echocardiography, the annual stroke rate is 5% on average. The overall aim of this project is to identify variables associated with embolic propensity of LAAT. Materials and Methods: LAAT specimens were obtained during cardiac surgery (MAZE procedure; n=26). Embolized thrombi (n=51) were obtained during surgical embolectomy from lower (n=36) and upper extremities (n=11) and mesenteric arteries (n=4). Platelet-rich regions within sectioned thrombi were sampled by punch biopsy from which total RNA was extracted and analyzed for expression of 5 platelet specific genes: A1 domain of factor XIII, (F13A1); integrin α 2b β 3 (ITGA2B); glycoprotein IX (GP9), platelet factor 4 (PF4), glycoprotein Ib (GP1BB). Gene expression was quantified using TaqMan MGB-probe based quantitative real-time polymerase chain reaction normalized to β 2 macroglobulin using cDNAs reverse transcribed from total RNA. Results: Factor XIII gene expression (Figure ) was significantly lower in embolic (mean fold change 0.08) compared to left atrial thrombi in situ (mean fold change 0.28; p=0.03). Expression of other genes did not show significant change by embolic status. Conclusions: Variable Factor XIII gene expression in thrombi generated during NVAF may in part explain the propensity to embolization. Whereas Factor XIII stabilizes thrombi by crosslinking fibrin without influencing atrial attachment, this data suggests that embolization occurs through fragmentation.
Abstract 606: Myocardial Protection by Glycogen Synthase Kinase-3β Inhibition during Resuscitation from Cardiac Arrest
Authors: Jeejabai Radhakrishnan, Iyad M Ayoub, Sufen Wang, Julieta D Kolarova, Domenico M Taglieri, Raúl J Gazmuri
Journal: Circulation (2006)

Background: GSK-3β functions as a “master switch” that is negatively regulated by various cardioprotective mechanisms. GSK-3β is upregulated by tyrosine 216 phosphorylation (P-Y216) and downregulated by serine 9 phosphorylation (P-S9). We investigated whether modulation of GSK-3β phosphorylation occurs during cardiac resuscitation and whether pharmacological GSK-3β inhibition improves post-resuscitation (PR) myocardial function. Methods: Three groups of two rats each were randomized to 8 mins of untreated VF followed by 8 mins of closed-chest resuscitation and defibrillation or to sham intervention. Rats subjected to VF received a 0.6 mg/kg bolus of the GSK-3β inhibitor SB216763 (SB21) or 0.9% NaCl before chest compression. Hearts were harvested at 10 mins PR. Results: Western blots with corresponding densitometries indexed to total GSK-3β are shown in Figure . P-S9 increased in control rats ( p = 0.052 vs sham) and further increased in SB21-treated rats ( p = 0.024 vs sham). SB21 lessened PR myocardial dysfunction yielding significantly higher mean aortic pressure (109 ± 7 vs 79 ± 2 mmHg; p &lt; 0.05) with numerically higher +dP/dt max (5.1 ± 7 vs 3.5 ± 0.2 mmHg/sec x 10 3 ), cardiac index (108 ± 59 vs 76 ± 28 ml/min/kg) and left ventricular stroke work index (0.58 ± 0.24 vs 0.32 ± 0.11 mmHg x ml/kg). Conclusions: Increased P-S9 independent of P-Y216 suggests activation of endogenous protective pathways that may downregulate GSK-3β activity. Pharmacological inhibition of GSK-3β further increased serine 9 phosphorylation state and lessened post-resuscitation myocardial dysfunction. Thus, GSK-3β may represent an important target for myocardial protection during resuscitation.
Abstract 4893: Selective Aldosterone Blocker Enhances Protective Effects of Calcium Channel Blocker (CCB) Against Salt-sensitive Hypertension-induced Cardiovascular Injury, Independently of Blood Pressure
Authors: Taishi Nakamura, Keiichiro Kataoka, Masaya Fukuda, Hisato Nako, Kensuke Toyama, Hisao Ogawa, Shokei Kim-Mitsuyama
Journal: Circulation (2009)

Purpose : The effects of aldosterone blocker against hypertension (HTN)-induced cardiovascular injury are still unclear. We compared the protective effects of eplerenone (EPL), an aldosterone blocker and amlodipine (AML), a CCB on salt-sensitive HTN-induced cardiovascular injury, and examined these combined effects on cardiovascular protection. Methods : Dahl salt-sensitive rats fed on 8% NaCl containing diet were divided into vehicle, EPL (100mg/kg), AML (10mg/kg), and EPL combined with AML. Results : EPL monotherapy, without affecting blood pressure (BP) and plasma renin activity, significantly suppressed HTN-induced cardiac macrophage infiltration and interstitial fibrosis, coronary arterial remodeling, and improved HTN-induced vascular endothelial dysfunction, to a similar extent to strongly BP lowering AML. Beneficial effects of the combination therapy against HTN-induced cardiac inflammation, fibrosis, and vascular endothelial dysfunction were greater than AML monotherapy despite no lowering BP. Moreover, combination of EPL and AML markedly improved HTN-induced cardiac diastolic dysfunction compared with vehicle. These additive amelioration by the combination against hypertensive cardiac injury compared with AML monotherapy were associated with more attenuation of cardiac MCP-1, IL-6 and TGF- β 1 expressions, and more reduction of cardiac superoxide partially derived from NADPH oxidase. Furthermore, improvement of vascular endothelial dysfunction by the combination compared with AML monotherapy was attributed to not only more reduction of vascular NADPH oxidase-mediated superoxide but also more increase of NO by vascular endothelial NO synthase phosphorylation. It is interesting that the amelioration of endothelial fucntion by EPL was associated with the attenuation of HTN-induced vascular apoptosis signal-regulating kinase 1 (ASK1) activation. Actually, we found that vascular ASK1 deficiency markedly reduced vascular superoxide, and improved vascular endothelial dysfunction caused by aldosterone/salt-induced HTN in ASK1 deficient mice. Conclusions : Without lowering BP, aldosterone blocker enhanced protective effects of CCB against salt sensitive HTN-induced cardiovascular injury.
2006 Laennec Clinician/Educator Lecture—The Contemporary Management of Patients Admitted to Hospital With Acute Decompensated Heart Failure
Authors: Gary Francis
Journal: Circulation (2006)

René Laénnäc was an adolescent at the time of the French Revolution and went on to a career of lasting importance in the history of medicine. Among his many accomplishments was the invention of the stethoscope, but as with many new ideas, there was much early skepticism. Eventually it became widely accepted. In today’s world of high-tech medicine, some would opine that the usefulness of the stethoscope is again declining. Of the many cardiological conditions that we treat on a day-to-day basis, heart failure is one where the stethoscope is still quite useful. Heart failure remains a clinical diagnosis, requiring that the physician actually extract a history and examine the patient at the bedside. However, the treatment of acute decompensated heart failure has changed dramatically over the years, even though advances in treatment have been hampered to some extent by the lack of randomized clinical trials. Management of these patients can be extremely difficult, particularly when complicated by resistance to loop diuretics, refractory edema, hyponatremia, and oliguria. Strategies to date have primarily depended on previous observational studies and include the use of diuretics, vasodilators, inotropic agents for selected patients, ultrafiltration, and occasionally dialysis. Although there are both European and US guidelines for the treatment of acute heart failure, we are in need of further randomized controlled trials to guide us through the maze of therapeutic options. Future considerations should include an understanding of how the syndrome develops and how it can be prevented in its early stages.
Abstract 5114: Leptin Promotes Mobilization of Flk1-positive Vascular Progenitor Cells From the Bone Marrow and Enhances Neovascularization After Peripheral Ischemia
Authors: Marco R Schroeter, Susanne Stein, Nana-Maria Heida, Maren Leifheit, Gerd Hasenfuss, Stavros Konstantinides, Katrin Schaefer
Journal: Circulation (2009)

Experimental evidence suggests that bone marrow-derived progenitor cells participate in the formation of new blood vessels and endothelial repair. We have previously shown that leptin enhances the recruitment and incorporation of human, culture-expanded endothelial progenitor cells (EPC) into neointimal lesions after vascular injury and promotes re-endothelialization. The aim of the present study was to examine the potential of circulating leptin to promote ischemia-induced neovascularization in vivo, and to determine the contribution of bone marrow-derived (endothelial) progenitor cells to this process. In wild-type mice, daily intraperitoneal injection of leptin over five days promoted neovascularization after hindlimb ischemia, as determined by the quantification of CD31-immunopositive capillary endothelial cells (P&lt;0.01 vs. control). In vitro studies demonstrated that systemic administration of leptin increased the number of cultured, spleen-derived acLDL+, lectin+ EPC (P&lt;0.01 vs. vehicle), and enhanced their potential to integrate into endothelial cell networks (P&lt;0.001) or to adhere to endothelial cell sprouts (P&lt;0.001). Analysis of mice after sublethal irradiation and transplantation of GFP-positive bone marrow revealed that bone marrow-derived cells are recruited to ischemic muscles and incorporate into CD31-positive capillaries. Although flow cytometry analysis revealed that leptin did not alter the number of sca1+, c-kit+ cells within the bone marrow or peripheral blood, leptin increased the number of circulating sca1+ or GFP+, Flk1+ cells, in contrast to vehicle or GCSF (P&lt;0.05 for both). PCR analysis confirmed mRNA expression of the leptin receptor in bone marrow cells. Ongoing studies focussing on potential mechanisms mediating the effects of leptin on bone marrow cells indicate increased protein kinase B phosphorylation and MMP9 expression in response to leptin. Taken together, our studies suggest that the proangiogenic effects of leptin may involve the interaction with leptin receptor-positive cells within the bone marrow resulting in enhanced mobilization of Flk1+ vascular progenitors and neovascularization in response to ischemia.
Abstract 5199: Oral Administration of an Active Form Vitamin D <sub>3</sub> Decreases Atherosclerosis in Mice via Modulating Immune Cell Phenotypes and Functions
Authors: Masafumi Takeda, Tomoya Yamashita, Masakazu Shinohara, Naoto Sasaki, Kenji Nakajima, Tomoyuki Kita, Ken-ichi Hirata
Journal: Circulation (2009)

Background and Objectives: Recent several clinical studies demonstrated the low level of plasma vitamin D 3 would be a risk of cardiovascular events. An active form vitamin D 3 not only regulates bone metabolisms but also has an immunosuppressive and anti-inflammatory actions which target dendritic cells (DCs) and T lymphocytes. Vitamin D 3 has been reported to inhibit the maturation of DCs and to induce regulatory T cells (Tregs) in experimental autoimmune disease models. We hypothesized an active form vitamin D 3 (calcitriol), could prevent atherosclerosis through changing immune responses. Method and Results : Six-week-apolipoprotein E knockout mice on a standard diet were orally administered 200 ng calcitriol dissolved in carboxymethyl cellulose (n=12) or carboxymethyl cellulose alone (n=15; control) twice a week for 12 weeks and atherosclerosis was assessed at 18 weeks old. Calcitriol administration decreased atherosclerotic lesion 39.1 % at aortic sinus compared to control group (mean plaque area: 0.18±0.05×10 6 vs. 0.27±0.07×10 6 μ m 2 , p&lt;0.01) without lowering cholesterol. The drug was also shown to reduce the infiltration of inflammatory cells to the atherosclerotic lesions by immunohistochemistry. To evaluate the induction of Tregs and immature state of DCs (iDC) in small intestine and other organs, we examined the ratio of Tregs and iDC by flow cytometry in mesenteric lymph nodes (MLNs) and spleens. Calcitriol markedly increased CD4 + CD25 + FoxP3 + Tregs in MLNs by 17.1% and spleens by 23.4% (p&lt;0.01), and further reduced the mature state (CD11c + CD80 + CD86 + ) DCs in MLNs by 10.6% (p=0.02) compared to control. RT-PCR demonstrated mRNA expressions of CD80 and interferon-gamma were markedly decreased in MLNs and spleens in calcitriol-treated group, respectively. Conclusion : An active form vitamin D 3 could prevent the development of atherosclerosis via changing the function or differentiation of DCs and T lymphocytes. At least, we demonstrated calcitriol increased the number of Tregs and reduced the mature state DCs in the present study, though further studies are required to examine the role of iDC and Tregs in this process. This treatment could be a potential immunotherapy for preventing atherosclerosis and must contribute to the clinics.
Abstract 5127: Left Atrial Ejection Fraction (LAEF) is a Novel Marker of Left Atrial Appendage Dysfunction in Acute Stroke Patients
Authors: Satoshi Nishiyama, Tetsu Watanabe, Shintaro Sasaki, Harutoshi Tamura, Hiroki Takahashi, Takanori Arimoto, Tetsuro Shishido, Takehiko Miyashita, Takuya Miyamoto, Joji Nitobe, Isao Kubota
Journal: Circulation (2009)

Background Recently, it was reported that left atrial ejection fraction (LAEF) may be as a marker of left atrial dysfunction. However, the feasibility of LAEF remains to be determined. We investigated whether LAEF is a marker of left atrial appendage (LAA) dysfunction which causes cardiogenic embolism in stroke patients. Methods We performed trans-thoracic echocardiography (TTE) and trans-esophageal echocardiography (TEE) in 53 consecutive stroke patients (cardiogenic embolism, male/female=14/9, 70±12y; stroke of other sources, male/female =21/9, 66±16y). LAEF was calculated by the biplane area-length method from apical 4- and 2-chamber views at end systolic and diastolic phase. We compared LAEF to LAA peak emptying flow velocity which is an established marker of LAA dysfunction. Results LAEF was significantly lower in patients with cardiogenic embolism than in those without it (LAEF, 30.4±11.0 vs. 45.4±14.7, P&lt;0.01). Left atrial dimensions, time and the ratio of the early diastolic trans-mitral inflow velocity (E wave), left atrial volume index (LAVI) and LAEF were significantly correlated with LAA emptying flow velocity. However, only LAEF was significantly correlated with LAA emptying flow velocity in patients with atrial fibrillation (R=0.566, p&lt;0.05). Furthermore, the multivariate logistic regression analysis revealed that only LAEF was an independent predictor of LAA dysfunction in TTE parameters (odds ratio 3.96; 95% confidence interval 1.02–15.27; P&lt;0.05). Conclusions LAEF may be a reliable non-invasive maker of LAA dysfunction and predict cardiogenic embolism in stroke patients.
Abstract 608: Valsartan Reverses Post-Translational Modifications of ATP Synthase D-Chain During Prolonged Post-Ischemic Reperfusion
Authors: Bodh I Jugdutt, Grzegorz Sawicki
Journal: Circulation (2006)

We hypothesized that reperfused myocardial infarction (RMI) induces post-translational modifications (PTMs) of the metabolic enzyme mitochondrial ATP synthase D-chain (ATP/D) which are reversed by the angiotensin II type 1 receptor (AT 1 R) blocker valsartan. We applied a pharmaco-proteomics approach to detect regional differences in PTMs of ATP/D in ischemic (IZ) and non-ischemic (NIZ) zones of hearts subjected to in vivo RMI (90 min left anterior descending coronary occlusion; 120 min reperfusion) in dogs randomized to placebo or valsartan. We measured hemodynamics and left ventricular (LV) function (2D-Echocardiogram/ Doppler) and identified/analyzed ATP/D using 2D electrophoresis, PD Quest, and in-gel trypsin digestion of protein spots (Fig. A ) followed by mass spectrometry, and FindMod tool for finding potential PTMs. Compared to sham, RMI induced ischemic injury and systolic and diastolic dysfunction in the placebo group and these were attenuated by valsartan. Compared to the NIZ, RMI increased ATP/D in the IZ (nearly 2-fold) and this was normalized by valsartan (Fig. B ). Importantly, RMI increased hydroxylation of ATP/D, S-nitrosylation of cysteine-100, nitration of tyrosine-80 and -225, and hydroxylation of lysine-182 followed by its myristoylation (Fig. C ). Valsartan reduced ATP/D hydroxylation, abolished the PTMs including lysine myristoylation in the IZ, and additionally triggered phosphorylation of serine-76 in both the IZ and NIZ. Valsartan-induced cardioprotection is associated with reversal of PTMs of ATP/D during RMI. This new pleiotropic effect of AT 1 R blockade suggests that PTMs may represent a novel therapeutic target after RMI.
Abstract 5226: Endothelial Nox4 NADPH Oxidase Enhances Vasodilatation via Hydrogen Peroxide-induced Hyperpolarization and Reduces Blood Pressure
Authors: Minshu Wang, Robin Ray, Colin Murdoch, Min Zhang, Simon Walker, Alison Brewer, Ajay Shah
Journal: Circulation (2009)

Introduction NADPH oxidases (Noxs) are reactive oxygen species-generating enzymes implicated in cardiovascular disease. Nox4 is the most abundantly expressed isoform in endothelial cells but its function is unclear. We investigated the role of endothelial Nox4 on vascular function in vivo . Methods and Results We generated transgenic mice with endothelium-specific overexpression of Nox4 (Nox4TG) and studied the effects on endothelial function (aortic rings ex vivo) and blood pressure (BP, telemetry). Nox4 protein levels were 2-fold higher in Nox4TG aorta compared to wild-type littermates (WT), with no changes in expression of other Nox isoforms. Nox4TG had enhanced relaxation to acetylcholine (ACh) than WT (−log EC50 7.76±0.07 vs. 7.20±0.05; n=12; p&lt;0.001) but similar relaxation to sodium nitroprusside. The ACh response in Nox4TG and WT was identical in the presence of catalase (1500U/ml) but remained greater in Nox4TG in the presence of inhibitors of nitric oxide synthesis (L-NMMA, 100 μ M; −log EC50 7.44±0.22 vs. 6.93±0.22; n=6; p&lt;0.01), soluble guanylate cyclase (ODQ, 5 μ M; −log EC50 6.92±0.21 vs. 6.78±0.30; n=6; p&lt;0.001) or protein kinase G (KT5823, 2 μ M; −log EC50 7.77±0.11 vs. 7.27±0.12; n=6; p&lt;0.001). However, the difference between Nox4TG and WT was abolished in the presence of high extracellular potassium (30mM). Nox4TG also had significantly lower BP than WT (mean BP 102.5±1.8 vs. 109.5±2.0mmHg; n=10; P&lt;0.05), which was abolished after chronic treatment with N-acetylcysteine or an SOD/catalase mimetic, EUK-8. Plasma nitrite/nitrate levels and aortic levels of phosphorylated VASP were identical and acute iv treatment with L-NMMA (10mg/kg) increased BP to a similar extent in Nox4TG and WT. The hypertensive response to chronic 14-day angiotensin II infusion (1.1mg/kg/d) was lower in Nox4TG compared to WT (mean BP 116.7±4.7 vs. 129.4±3.5mmHg; n=10; P&lt;0.05). Conclusions Nox4TG had significantly enhanced ACh-induced vasodilatation compared to WT as a result of H 2 O 2 -induced hyperpolarization. Nox4TG also had a lower BP, which was not attributable to altered nitric oxide bioactivity but was normalized by chronic antioxidant treatment. These results suggest that endothelial Nox4 has potentially beneficial effects on vascular tone and BP.
Dichloroacetate Reverses the Impaired Cardiac Function and the Electrical Remodeling in Right Ventricular Hypertrophy by Inhibiting Pyruvate Dehydrogenase Kinase
Authors: Lin Piao
Journal: Circulation (2009)

Abstract #2362 Lin Piao, Yong-Hu Fang, Univ of Chicago, Chicago, IL; Virgilio J Cadete, Univ of Alberta, Edmonton, AB, Canada; Christian Wietholt, Dalia Urboniene, Peter T Toth, Glenn Marsboom, Hannah Zhang, Idith Haber, Jalees Rehman, Univ of Chicago, Chicago, IL; Gary D Lopaschuk, Univ of Alberta, Edmonton, AB, Canada; Stephen L Archer, Univ of Chicago, Chicago, IL Lin Piao, 2009 Finalist and Presenting Author
Abstract 5152: Normotensive and Hypertensive Obese Patients Show the Presence of Structural and Functional Alterations in Subcutaneous Small Resistance Arteries
Authors: Carolina De Ciuceis, Enzo Porteri, Damiano Rizzoni, Claudia Corbellini, Elisa La Boria, Gianluca E Boari, Annamaria Pilu, Maurizio Castellano, Mittempergher Francesco, Ernesto Di Betta, Bruno Salerni, Rossella Tosini, Claudia Agabiti Rosei, Enrico Agabiti Rosei
Journal: Circulation (2009)

Structural alterations of subcutaneous small resistance arteries of hypertensive patients, as indicated by an increased media to lumen (M/L) ratio, are frequently present in hypertensive and or/diabetic patients, and may represent the earliest alterations that may be observed. In addition, M/L of small arteries have a strong prognostic significance. However, no data are available about the structure and endothelial function of small resistance arteries of obese patients. Therefore, we have investigated 16 patients with severe obesity. Six of them were normotensive, and 10 hypertensive. We compared results obtained with those observed in 12 normotensive lean controls and in 12 hypertensive lean patients. Systolic and diastolic blood pressure were evaluated by a standard sphygmomanometric approach, using appropriate cuff for obese patients. All patients underwent a biopsy of subcutaneous fat before or during surgical intervention of gastric banding or intestinal derivation. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, according to Mulvany-Halpern technique, and M/L, media thickness, media cross-sectional area were measured. A concentration-response curve to acetylcholine (10 –9 –10 –5 Mol/l) was performed, in order to evaluate endothelial function. The results are summarized in the Table . Obese patients, independently from the presence of hypertension, diabetes and dyslipidemia, show the presence of an increased M/L and of an increased media cross-sectional area. Preliminary data suggest the presence of endothelial dysfunction, as indicated by a reduced endothelium-dependent vasodilatation, especially in hypertensive obese patients. In conclusion, our data suggest that the presence of obesity is associated to structural alterations of subcutaneous small resistance arteries, mainly characterized by hypertrophic remodeling. Table