tbuckley/cabot-search huggingface dataset:
Abstract 9658: Concomitant Maze Procedure Reduces Adverse Clinical Events in Patients with Left Ventricular Dysfunction Undergoing Open Cardiac Surgery
Authors: Joon Bum Kim, Sung-Ho Jung, Suk Jung Choo, Cheol Hyun Chung, Jae Won Lee
Journal: Circulation (2012)

Background: Clinical benefits of concomitant maze procedure can be offset by surgical risks added by the procedure especially in patients with left ventricular (LV) dysfunction undergoing open heart surgery. Methods: Between January 1999 and March 2011, a total of 139 patients (mean age 52.7±12.3 years, 54 females) with valvular atrial fibrillation (AF) and a LV ejection fraction (EF) of 40% or less underwent open heart surgery with (n=77) or without (n=62) the concomitant maze procedure. We compared primary adverse outcomes (death; composite of death, thromboembolic events, or congestive heart failure [CHF]) during a median follow-up period of 66.9 months (inter-quartile range, 27.8-105.5 months). Results: Primary outcomes occurred in 41 patients including 36 deaths, 7 thromboembolic events and 8 hospitalizations due to CHF. After adjustment for baseline risk profiles, patients who had undergone the maze procedure were at similar risks of death (hazard ratio, 0.48; 95% confidence interval, 0.17-1.35; P =0.17) but a significantly lower risk of the composite adverse outcomes (hazard ratio, 0.34; 95% confidence interval, 0.14-0.83; P =0.017) compared with those who did not undergo the maze procedure (Figure). For 23 propensity-score matched pairs, the combination of the maze procedure resulted in decreased LV systolic ( P =0.013) and diastolic ( P =0.041) dimensions, and increased LV EF (56.2±7.9% vs. 49.9±11.9%, P =0.010) compared with cardiac surgery alone on echocardiographic assessments performed at a median of 62.8 months (inter-quartile range, 26.5-119.0 months) after surgery. At the end of follow-up, patients who had undergone the maze procedure had superior New York Heart Association functional status than those who did not ( P =0.008). Conclusion: Adding the maze procedure in patients with valvular AF and LV dysfunction reduced adverse outcomes, and improved LV systolic function and functional status as compared with cardiac surgery alone.
Abstract 9687: Aldosterone Enhances MR/NADPH Oxidase Physical Association, and Induces Cardiomyocyte Hypertrophy and Cardiac Fibroblast Proliferation via Amplification of IL-18 Signaling
Authors: Anthony J Valente, Bysani Chandrasekar
Journal: Circulation (2012)

Hyperaldosteronism is associated with inflammation, progressive myocardial hypertrophy, fibrosis and adverse remodeling. Since interleukin (IL)-18 is a hypertrophic and mitogenic inflammatory cytokine, we investigated whether Aldosterone (Aldo)-induced cardiomyocyte (CaM) hypertrophy and cardiac fibroblast (CF) proliferation and migration are IL-18 dependent. Aldo-induced hypertrophy of primary rat CaM was inhibited by the mineralocorticoid receptor (MR) antagonists spiranolactone, and eplerenone. Interestingly, knockdown of IL-18, or its neutralization with IL-18BP or polyclonal anti-rat IgG blunted Aldo’s growth effects. In CaM, Aldo induced IL-18 expression via DPI-inhibitable, Nox2- and Nox4-dependent ROS generation, and NF-κB and AP-1 activation. Knockdown of Nox2, Nox4, p65 or c-Jun inhibited IL-18 and IL-18Rα expression and CaM growth. Further, using GST pull-down assays and co-immunoprecipitation/immunoblotting, we demonstrate for the first time that MR physically associates with Nox2 and Nox4 both in vitro and in vivo under basal conditions, and Aldo enhances their interactions in vivo. In CF, Aldo stimulated DPI-inhibitable, Nox4-dependent ROS generation, IL-18, IL-18Rα, and MMP-9 induction, and IL-18-dependent migration and proliferation. In these cells, MR was found bound to Nox4. Continuous infusion of Aldo into rats resulted in myocardial hypertrophy and fibrosis, DPI-inhibitable ROS generation, MR binding to Nox2 and Nox4, and IL-18, IL-18Rα, and MMP-9 expression in the heart. Co-treatment with spironolactone blunted these effects. Notably, Aldo-induced myocardial hypertrophy and fibrosis were markedly attenuated in IL-18-null mice. These results demonstrate that Aldo amplifies IL-18 signaling in both cell types by inducing IL-18 and its receptor expression. Importantly, Aldo-induced cardiomyocyte hypertrophy and fibroblast proliferation are IL-18 dependent, and may involve the direct interaction of MR with NADPH oxidases. IL-18 is a potential therapeutic target in Aldo-induced myocardial hypertrophy, fibrosis and adverse remodeling.
Abstract 9576: A Nuclear Receptor-microRNA Circuit Links Control of Muscle Fiber Type to Energy Metabolism
Authors: Zhenji Gan, John Rumsey, Bethany C Hazen, Ling Lai, Teresa C Leone, Richard B Vega, Johan Auwerx, Eric N Olson, Anastasia Kralli, Daniel P Kelly
Journal: Circulation (2012)

Muscle fitness deteriorates in many chronic diseases including heart failure. The mechanisms involved in the coordinate control of the energy metabolic and structural programs that determine muscle fitness are unknown. Recent studies indicate that the nuclear receptors PPARβ (δ) and PPARα exert opposing actions upon muscle endurance in transgenic mice (MCK-PPAR mice). We took advantage of the divergent effects of PPARβ and PPARα in muscle to delineate the regulatory circuitry that orchestrates control of muscle fiber type and energy metabolic programs. Muscle fiber typing and transcriptional profiling revealed that type I fibers were induced in MCK-PPARβ soleus muscle but markedly suppressed in MCK-PPARα muscle. Conversely, type I fibers were significantly increased in PPARα null gastrocnemius muscle whereas shRNA-mediated “knockdown” (KD) of PPARβ in primary skeletal myotubes reduced type I gene markers. Muscle microRNA (miR) profiling revealed that levels of miR-208b and miR-499 were increased in MCK-PPARβ muscle but dramatically reduced in MCK-PPARα muscle. miR-208b and miR-499, which are embedded in the Myh7 and Myh7b genes, respectively, have been shown to activate slow myofiber gene expression. Combined inhibition of miR-208b and miR-499 abolished the enhancing effects of PPARβ on slow myofiber gene expression in MCK-PPARβ myotubes, while transgenic overexpression of miR-499 in MCK-PPARα muscle prevented the PPARα-mediated repression of the type I fiber program, and reversed the poor exercise performance phenotype of the MCK-PPARα mice. PPARβ was shown to mediate its effects on Myh7/miR-208b and Myh7b/miR-499 expression and type I fiber composition in cooperation with the nuclear receptor ERRγ. Lastly, type I fibers were reduced in muscle-specific ERRβ/γ-deficient muscle together with a profound reduction of miR-499 and miR-208b. Taken together, we have identified a nuclear receptor-miRNA circuit that allows for bi-directional, coordinate, control of muscle slow fiber proportion and energy metabolic capacity. This network shows promise as a target for novel therapeutic approaches aimed at enhancing muscle fitness in conditions that lead to muscle de-training and heart failure.
Abstract 9566: LRP1 Deficiency Promotes Smooth Muscle Cell Apoptosis in Atherosclerotic Plaques via PDGF Receptor Mediated Downregulation of Bcl-2
Authors: Marius Vantler, Li Zhou, Schwab Moritz, Mario Zierden, Evren Caglayan, Wolfram H Zimmermann, Michelle Tallquist, Joachim Herz, Stephan Rosenkranz
Journal: Circulation (2012)

Apoptosis of smooth muscle cells (SMCs) promotes instability of atherosclerotic plaques. Apoptosis is believed to be suppressed by growth factor dependent activation of PI 3-kinase (PI3K). We investigated the effect of LRP1 knockout driven elevated platelet-derived growth factor beta receptor (PDGFR) signaling on SMC apoptosis in atherosclerotic plaques. We quantified apoptotic TUNEL-positive SMCs in lesions from 12 months old LDLR-/-/smLRP1-/- double knockout mice. LDLR (low-density lipoprotein receptor) deficiency accelerates atherosclerosis in mice. LDLR-/-/smLRP1-/- increased the percentage of TUNEL-positive cells compared to LDLR-/-/smLRP1+/+ controls (3.6±0.7% vs. 0.7±0.3%,respectively, P &lt; 0.05, n = 6). Mutation of the PI3K binding site in the PDGFR in LDLR-/-/smLRP1-/--F2/F2 mice suppressed SMC apoptosis (2.4%±0.3%, P &lt; 0.05, n = 6) suggesting that the PDGFR exerts proapoptotic effects via PI3K. In vitro studies (Cell Death Detection ELISA) revealed that chronic stimulation of SMCs with PDGF-BB (96 h) led to 3.1±0.4-fold increased apoptosis (n=3, P&lt;0.05). To characterize proapoptotic PDGFR driven signaling pathways we analysed PDGFR mutants in which the binding sites for different signaling molecules were deleted. Lack of PI3K binding completely abolished the proapoptotic effect, whereas a mutant which only binds PI3K was able to induce apoptosis like the WT receptor. Further analysis of PDGFR mutants revealed that activation of PI3K led to induction of c-Myc and decreased expression of antiapoptotic Bcl-2 as assessed by RT-PCR and Westernblotting. siRNA mediated knockdown of c-Myc prevented both, Bcl-2 downregulation and PDGF induced apoptosis. Consistently, immunohistochemical analysis of atherosclerotic plaques from LDLR-/-/smLRP1-/- and LDLR-/-/smLRP1-/--F2/F2 mice revealed that PDGFR dependent activation of PI3K impairs the expression of antiapoptotic Bcl-2. In conclusion, our study identified a new PDGFR driven proapoptotic signaling pathway in SMCs. Chronically elevated PDGFR/PI3K signaling downregulates Bcl-2 via induction of c-Myc. This has direct implications in atherogenesis, as PDGF promotes cell death in atherosclerotic plaques, which can ultimately lead to plaque instability and rupture.
Abstract 9592: Left Ventricular Hypertrophy Reduction and Clinical Events. A Meta-regression Analysis of 14 Studies in 12,809 Hypertensive Patients
Authors: Gianluigi Savarese, Pierluigi Costanzo, Giuseppe Rosano, Francesca Musella, Laura Casaretti, Enrico Vassallo, Stefania Paolillo, Fabio Marsico, Pasquale Perrone-Filardi
Journal: Circulation (2012)

Objective: Left ventricular hypertrophy (LVH) is an independent risk factor for clinical events (CE), and disappearance of LVH is associated with reduction of cardiovascular risk. However, whether a continuous relationship between reduction of LVH and risk of CE exists has not been investigated. Methods: Randomized clinical trials evaluating LVH at baseline and reporting quantitative LVH changes and CE (all-cause death, myocardial infarction (MI), stroke or new onset heart failure) were included. Meta-regression analysis was performed to test the relationship between changes in LVH and incidence of the composite outcome (all-cause death, MI, stroke or new onset heart failure) and between changes of LVH and occurrence of each component of the composite outcome. Analysis of potential confounder variables was also performed. Results: Fourteen trials including 12,809 participants and reporting 2,259 events were included. Follow-up ranged from 0.50 to 5 years, with mean 1.97±1.50 years. Mean age was 62±5 years and 52% of patients were women. The composite outcome was significantly reduced by active treatments (odds ratio [OR]: 0.851, 95% confidence intervals [CI]: 0.780 to 0.929, p&lt;0.001), as well stroke (OR: 0.756, CI:0.638 to 0.895, p&lt;0.001) whereas MI (OR:1.031, CI:0.846 to 1.255, p=0.763) and new onset heart failure (OR:0.994, CI:0.798 to 1.238, p=0.955) were not significantly reduced by treatments. LVH changes did not predict the reduction of the risk of the composite outcome (t=0.69, p=0.50)(Figure) or all-cause death (t=-1.27, p=0.26), stroke (t=0.15, p=0.89), MI (t=1.20, p=0.28) and new onset heart failure (t=0.69, p=0.50). No significant influence on the association of baseline patients and studies characteristics was found. Conclusions: A significant continuous relationship between LVH changes and CE could not be demonstrated in hypertensive patients, independently on the technique or drug used. patients.
Abstract 9675: Restoration of Normal Cardiomyocyte Basal and Beta-Adrenergic Receptor (AR) Subtype Modulation of L-Type Calcium Current in Heart Failure by Chronic Beta <sub>3</sub> -AR Deficiency: Insights into the Underlying Electrophysiological Mechanism
Authors: Peng Zhou, Heng-Jie Cheng, Che Ping Cheng
Journal: Circulation (2012)

Background. We have previously shown that heart failure (HF) is associated with upregulation of the cardiac β 3 -adrenergic receptor (AR). Isoproterenol (ISO)-induced HF was prevented in β 3 -AR knockout (β 3 KO) mice. However, the cellular mechanism is unclear. The L-type calcium current (I Ca,L ) plays a fundamental role in cardiac function and is impaired in HF. No previous studies have examined the influence of β 3 KO on I Ca,L in normal or diseased states. We assessed the hypothesis that β 3 KO will prevent HF-induced abnormalities of basal and β-AR subtype-stimulated regulation on I Ca,L , thereby preserving normal myocyte function. Methods. β 3 KO and wild type (WT) mouse experimental groups received ISO (170 mg/kg sq for 2 days), and β 3 KO and WT mouse control groups received saline (7/group). After 16 weeks (W) of treatment, we compared the response of myocyte contractile function and I Ca,L to β-AR subtype stimulation by random exposure of myocytes to ISO (10 -8 M) or a selective β 1 -, β 2 -, or β 3 -agonist, Norepinephrine (NE, 10 -7 M), Zinterol (ZIN,10 -5 M) and BRL-37,344 (BRL,10 -8 M), respectively, during drug superfusion. Results. ISO-treated WT mice had HF onset at 8W and progressed to severe HF at 16W. Compared with normal myocytes (N), basal I Ca,L (HF:4.1 vs N:7.8 pA/pF) and cell contraction (dL/dt max , 76 vs 144 µm/s) decreased by more than 40% in HF myocytes. ISO-stimulated I Ca,L (14% vs 32%) was attenuated accompanied by a diminished NE-mediated increase in I Ca,L (16% vs 37%), but enhanced BRL-induced decreases in I Ca,L (17% vs 29%).The response of I Ca,L (17% vs 29%) to ZIN was relatively unaltered in HF myocytes. Importantly, in ISO/β 3 KO myocytes, the basal I Ca,L (8.1 pA/pF) and dL/dt max (154 µm/s) remained close to control levels with preserved β-stimulated positive modulation on I Ca,L . The increases in I Ca,L in response to ISO (33%), NE (35%) or ZIN (13%) were similar as that in normal WT myocytes, respectively. Conclusion. Chronic β 3 -AR deficiency prevents HF-induced abnormalities of basal and β-AR subtype-stimulated modulation on I Ca,L and leads to preservation of myocyte contractile function in a mouse model of progressive HF. These findings provide the first electrophysiological evidence that upregulation of β 3 -AR in HF is detrimental.
Abstract 9615: Longitudinal Strain as a Novel Predictor of All-cause and Cardiovascular Mortality in Asymptomatic Hemodialysis Patients with Preserved Left Ventricular Ejection Fraction
Authors: Yen-Wen Liu
Journal: Circulation (2012)

Background End-stage renal disease is notorious for high mortality. For asymptomatic hemodialysis patients with preserved left ventricular ejection fraction (LVEF), little is known regarding the prognostic predictors. Two-dimensional speckle-tracking echocardiography with myocardial deformation analysis (2D strain) is reliable to assess LV function accurately and objectively. The prospective study was conducted to investigate prognostic value of LV global peak systolic longitudinal strain (GLS) in asymptomatic hemodialysis patients with preserved LVEF. Methods Asymptomatic hemodialysis patients with LVEF≥50% underwent biochemistry blood tests, echocardiography, and 2D strain analysis. These patients were followed-up for more than 2.5 years. Results Lower albumin levels, deteriorated GLS, and higher cardiac troponin T (cTnT) levels were detected in the mortality group compared to the controls. In Cox regression model, reduced GLS (GLS≥-15%, Hazard ratio (HR): 1.26, p =0.002) and increased cTnT level (cTnT &gt;0.03 ng/ml, log cTnT HR: 14.43, p &lt;0.001) were predictors to all-cause mortality (Figure A and B). Furthermore, hemodialysis patients with reduced GLS, but not those with increased cTnT level, had higher cardiovascular mortality rate (Figure C and D). Patients with cTnT &gt;0.03 ng/ml and GLS ≥-15% had 7.8 times the risk of all-cause mortality and 6.1 times the risk of cardiovascular death compared to those with cTnT ≤0.03 ng/ml and GLS &lt;-15%. Conclusions Among asymptomatic hemodialysis patients with preserved LVEF, increased cTnT level and reduced GLS were associated with worse prognosis. Compared to cTnT, GLS is a stronger prognostic indicator in asymptomatic hemodialysis patients. The incremental prognostic value of GLS with elevated cTnT is potentially efficient and reliable.
Abstract 9613: Two-dimensional Strain (2d-strain) Analysis for the Differentiation Between Constrictive Pericarditis and Restrictive Cardiomyopathy
Authors: Thomas Butz, Lothar Faber, Cornelia Piper, Norbert Reckefuss, Gunnar Plehn, Dieter Horstkotte, Hans-Joachim Trappe
Journal: Circulation (2012)

Introduction: Two-dimensional strain (2DS) is a novel method to measure strain from standard two-dimensional echocardiographic images. The aim of our study was to characterize global and regional function abnormalities using this technique in patients (pts) with constrictive pericarditis (CP) and restrictive cardiomyopathy (RCM). Methods: We studied 90 individuals, 58 consecutive pts with heart failure of either proven pericardial (CP) or myocardial origin (RCM; biopsy proven cardiac amyloidosis), and 32 individuals as contol group. Global longitudinal strain (GLS) and regional peak systolic strain (PSS), as well as global transversal strain (GTS) was assessed by 2DS in the apical four-chamber-view using a dedicated software package (Vivid 7, GE Healthcare). Global radial strain (GRS) and global circumferential strain (GCS) was assessed in the parasternal short axis view. All pts underwent a complete echocardiographic and hemodynamic assessment. Results: Out of the 90 individuals (mean age: 57±12 years) 27 had CP, 31RCM, and 32 were controls. The thickness of the interventricular septum (IVSD) was significantly increased in pts with RCM (16±4 mm vs. 8±2 mm, resp. 9±2, p&lt;0.001). Mean GLS was -13.2±4.0% in the CP-group, -9.4±3.4% in the RCM-group (p&lt;0.001), and -20.0±3.7% in the control group. The pts with RCM showed a significant base-to-apex gradient of the longitudinal PSS in the septal and lateral segments (see table). GRS was significantly decreased in RCM in comparison to CP (13.5±8.6 % RCM, 32.2±17.4% CP, 35.4±22.1% control, p&lt;0.001). There was no significant difference of GTS and GCS between the RCM and CP groups Conclusion: 2DS-analysis of GLS, PPS and GRS proved to be useful as additional echocardiographic tool for the differentiation between pts with RCM and CP. The RCM pts showed a significant base-to-apex-gradient of the PSS in the septal and lateral segments.
Abstract 9701: A Novel Adipocytokine Chemerin Stimulates Proliferation and Hypercontractility of Vascular Smooth Muscle: Implication for Pathogenesis of Obesity-related Hypertension
Authors: Hideyuki Yamawaki, Mizuho Takai, Mayuko Oda, Muneyoshi Okada, Yukio Hara
Journal: Circulation (2012)

Chemerin is a recently identified adipose tissue-derived cytokine (adipocytokine) which plays roles in inflammatory responses of immune cells such as dendritic cells and macrophages as well as differentiation and metabolisms of adipocytes. Chemerin acts as a chemoattractant for the immune cells, while it induces differentiation of adipocytes and glucose tolerance. Blood chemerin level increases in patients with obesity, and correlates positively with several key factors of metabolic syndrome such as body mass index and triglyceride level. Since blood chemerin level also correlates positively with systolic blood pressure in the obese subjects, we hypothesized that chemerin might relate to pathogenesis of obesity-related hypertension. To test the hypothesis, we examined the effects of chemerin on proliferation and contractility of vascular smooth muscle which play key roles in the development of hypertension. In cultured rat mesenteric arterial smooth muscle cells (SMCs), chemerin (1-100 ng/ml, 24h) stimulated proliferation in a concentration-dependent manner (n=8, P&lt;0.01). Chemerin (100 ng/ml, 20 min) stimulated phosphorylation of Akt (n=8, P&lt;0.05), and an Akt inhibitor prevented the chemerin-induced SMCs proliferation (n=4). Chemerin produced oxidant radicals in SMCs, and an anti-oxidant drug, N-acetyl-L-cysteine inhibited SMCs proliferation (n=6) and Akt phosphorylation (n=4, P&lt;0.05). In rat isolated mesenteric artery, chemerin (100 ng/ml, 30 min) augmented noradenaline (1 nM-1 μM)-induced concentration-dependent contraction (n=6, P&lt;0.05). The effect was higher in endothelium-intact artery than endothelium-denuded artery (n=7), and was normalized by an endothelin type A receptor blocker, BQ123 (n=13). Chemerin had no influence on noradrenaline-stimulated endothelial nitric oxide production (n=10). The present results for the first time demonstrated that chemerin stimulates proliferation of vascular SMCs via oxidative-stress-dependent Akt activation. It is also demonstrated that chemerin mediates hypercontractility of isolated mesenteric artery likely via endothelial-derived endothelin-1. The results may represent chemerin as a new adipocytokine to understand the link between obesity and hypertension.
Abstract 9608: Intracoronary Administration of Nicorandil During Direct Coronary Stenting Complements Restoration of Regional Perfusion at Subacute Phase of Myocardial Infarction: A Demonstration With O-15 Water Pet
Authors: Wataru Takabatake, Yasuyoshi Iwado, Kaori Ishikawa, Yuka Miyauchi, Kumi Tada, Kazushi Murakami, Takahisa Noma, Koji Ohmori, Yosihiro Nisiyama, Masakazu Kohno
Journal: Circulation (2012)

Purpose: Controversies exist regarding the impact of nicorandil as the adjunctive therapy for direct coronary stenting in patients with ST elevation myocardial infarction (STEMI).Therefore, we performed O-15 water positron emission tomography (water PET) to quantify regional myocardial perfusion in patients with STEMI who received nicorandil or no adjunctive therapy during successful direct stenting. Methods: In 28 patients with STEMI (65+/-13 yrs: 22 males), direct stenting was performed within 8 hrs after the onset. Five of 28 patients who underwent successful direct stenting received intracoronary administration (i.c.) of nicorandil 4 mg immediately after the first recanalization of culprit lesion.At 3 to 4 weeks from the onset, water PET was performed in which myocardial blood flow (MBF) was measured at rest and during hyperemia and myocardial vascular esistance (MVR) was calculated. Data were obtained from both reperfused and normal control regions in each patient. Results: See Figure. In patients who did not receive nicorandil (No-Nico), MBF in reperfused area (Rep) was lower than that in normal control regions (Cont) both at rest and during hyperemia (ATP). However, in the nicorandil-treated patients, MBF in Rep was restored to the similar level of that in Cont both at rest and during ATP. MVR was elevated in Rep both at rest and during ATP in No-Nico patients; such elevation of MVR in Rep was successfully prevented in the nicorandil-treated patients. Conclusion: O-15 water-PET at subacute phase revealed that i.c.nicorandil during direct stenting successfully prevented the elevation of myocardial vascular resistance and thus, restored myocardial blood flow in reperfused areas to the similar level as that in non-infarcted regions in patients with STEMI.