tbuckley/cabot-search huggingface dataset:
Cellular and Molecular Mechanisms of Diabetes-Accelerated Atherosclerosis
Authors: Karin Bornfeldt
Journal: Circulation (2013)

I will be very honored to present the 2013 Russell Ross Memorial Lecture in Vascular Biology. I will discuss our current understanding of the cellular and molecular mechanisms whereby diabetes accelerates atherosclerosis, based on data primarily from mouse models. Diabetes accelerates the formation of atherosclerotic lesions in hyperglycemic mouse models in which plasma lipid levels are unaltered by diabetes. Diabetes-accelerated lesion formation is driven, at least in part, by the altered function and properties of myeloid cells; cells that contribute to an increased inflammatory vascular state. Based on our recent studies, the enzyme acyl-CoA synthetase 1 (ACSL1), which converts long-chain fatty acids into their acyl-CoA derivatives, has emerged as causal to the enhanced lesion initiation associated with diabetes. ACSL1 is expressed at higher levels in monocytes/macrophages from diabetic mice and humans, as compared to controls, and is induced by inflammatory mediators in these cells. Interestingly, the protective effect of myeloid ACSL1-deficiency is obvious in diabetic mice, but not in non-diabetic mice, indicating that ACSL1-deficiency targets a pathway that is selectively activated by diabetes. Diabetes also accelerates progression of atherosclerotic lesions to advanced plaques characterized by hemorrhage. This effect is dependent on diabetes-induced dyslipidemia. Important questions for future research are whether ACSL1 and other factors identified in mouse models play equally important roles in diabetes-accelerated atherosclerosis and cardiovascular disease in humans.
Abstract 9457: Determining Three-Dimensional Catheter Location Using Single-Plane Fluoroscopy Only
Authors: Jasbir Sra, Barry Belanger, Mark Palma, David Krum
Journal: Circulation (2013)

Introduction: Catheter ablation of cardiac arrhythmias requires accurate navigation of a catheter in the heart. Biplane fluoroscopy is expensive and significantly increases radiation exposure. Single-plane fluoroscopy, although available in all interventional laboratories, does not provide three-dimensional (3D) catheter visualization. Thus, in a typical X-ray image seen during ablation, it is only possible to view the x-y axes; the actual depth of the cardiac catheter is not discernible. Hypothesis: We tested whether a set of digital image processing techniques and mathematical algorithms (APN Algorithm) could accurately construct 3D spatial orientation of an ablation catheter from single-plane fluoroscopy. Methods: Algorithms were designed to automatically determine 3D position and orientation of a radio-opaque mapping and ablation catheter using single-plane fluoroscopy only. Design consisted of: 1) capturing a stream of digital images from a single-plane fluoroscope; 2) detecting the image of the catheter in a subset of fluoroscopic images; and 3) applying pixel-level geometric calculations to the catheter image. The algorithms further included identifying the edges of the catheter at a subpixel level and determining the x-y-z location of the catheter. The 3D location of the catheter tip using single-plane images alone was then compared with 3D location as determined by two current gold standards: a 3D magnetic navigation system (CARTO, Biosense Webster Inc., Diamond Bar, CA), and biplane images taken in back projection technique (Ground Truth). Results: In a hexagonal phantom model (see figure), APN Algorithm revealed catheter location within 0.99 mm of Ground Truth. Conclusion: It is possible to determine the exact location of ablation catheters in three dimensions from single-plane fluoroscopic images without the need for biplane fluoroscopy. This approach could be extended to create 3D maps for catheter navigation and ablation.
Abstract 9368: Long QT Syndrome and Therapy for Attention Deficit/Hyperactivity Disorder
Authors: Claire Zhang, Arthur J Moss, Scott McNitt, Wojciech Zareba, Elizabeth S Kaufman
Journal: Circulation (2013)

Objective: This study was designed to investigate the clinical course of patients with long QT syndrome (LQTS) who are treated for attention deficit/hyperactivity disorder (ADHD) with medications. Background: Current literature on the effect of ADHD treatment on the clinical outcome of LQTS patients is limited. We hypothesized that LQTS patients on ADHD pharmacotherapy, which has known adrenergic side effects, would be at increased risk for cardiac events. Methods: Patients in this study were from the Rochester-based LQTS Registry. LQTS patients being treated with stimulant or non-stimulant ADHD medications (n=48) were compared to a 2:1 age-, gender-, and QTc-duration matched LQTS control group not exposed to ADHD medications (n=96). Kaplan-Meier and Cox proportional hazards regression analyses were used to evaluate risk of cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) in LQTS patients treated with ADHD medications compared to those who were not. Results: During a mean follow-up of 7.9 ±5.4 years of follow-up after initiation of ADHD medication at a mean age 10.7 ±7.3 years, there was a 62% cumulative probability of cardiac events in the ADHD treatment group compared to 28% in the matched LQTS control group (p&lt;0.001 [Figure]). Time-dependent use of stimulant and non-stimulant ADHD medication was associated with an increased risk for cardiac events dominated by syncope (HR=3.07; 95% CI 1.09-8.64; p=0.03) in the multivariate Cox model adjusted for time-dependent β-blocker use and prior cardiac events. Subgroup gender analyses showed that time-dependent ADHD medication was associated with an increased risk in male LQTS patients (HR=6.80, p=0.04). Conclusion: LQTS patients treated with ADHD medications have an increased risk for cardiac events during follow-up, and this risk is augmented in males.
Abstract 9878: Small Aortic Roots - Clinical Characteristics and Implications for Assessment of Aortic Stenosis in Asymptomatic Patients With Preserved Ejection Fraction
Authors: Edda Bahlmann, Dana Cramariuc, Jan Minners, Simon Ray, Christa Gohlke-Baerwolf, Christoph A Nienaber, Nikolaus Jander, John B Chambers, Karl-Heinz Kuck, Eva Gerdts
Journal: Circulation (2013)

Background: The aim was to characterize asymptomatic aortic stenosis (AS) patients with small aortic roots and the implications for assessment of AS severity. Methods: We analysed data from 1563 patients with asymptomatic AS enrolled in the Simvastatin Ezetimibe in Aortic Stenosis study. Severe AS was defined by aortic valve area (AVA) as &lt;1.0cm 2 , by AVA indexed for body surface area (AVAI) as &lt;0.6cm 2 /m 2 and by energy loss index (ELI) as &lt;0.6cm 2 /m 2 . Inconsistently graded severe AS was defined as the combination of AVA or ELI &lt;1.0 cm 2 and mean aortic gradient ≤40mmHg. Results: A small aortic root (lowest tertile of aortic sinotubular junction diameter, &lt;2.60cm) was present in 32.6% of patients. This group included more women (67.8% vs. 25.0%) and patients with hypertension and patients had smaller body surface area, height and left ventricular (LV) dimensions and higher age and pulse pressure/stroke volume index (PP/SVi) compared to the rest of the study population (all p&lt;0.001). AS severity measured by peak jet velocity or mean gradient did not differ between groups. The prevalence of inconsistently graded severe AS was more common in patients with small aortic roots when using AVA (38.3 vs. 23.5%, p&lt;0.001), but not when using ELI (23.8 vs. 24.0%, p=0.920). In multivariate logistic regression, having small aortic root was associated with a higher prevalence of inconsistently graded severe AS using AVA, independent of female gender, higher PP/SVi and lower height and smaller LV dimensions and wall thickness (Table). Conclusion: In asymptomatic AS the use of ELI for grading of AS rather than AVA lowered the prevalence of inconsistently graded severe AS among patients with small aortic roots. However inconsistently graded severe AS remained common using the currently recommended cut-off values for grading of AS. Table. Covariates of small aortic root in multivariate analysis.
Abstract 19073: Geographic Classification Scheme for High-Risk Neighborhoods for Cardiovascular Disease in Texas
Authors: Kyle Walker, Sean M Crotty
Journal: Circulation (2013)

There is substantial evidence that neighborhood characteristics have a significant impact on residents’ health outcomes. Our intent in this study was to create a classification system based on differences between high-risk neighborhoods for cardiovascular health in Texas. To accomplish this goal, we drew a total sample of 13 million cases of cardiovascular disease treatment from the 2006 Texas Hospital Inpatient Discharge Public Use Data File. These cases were then geo-coded to Zip Code Tabulation Areas (ZCTA’s) and age-adjusted hospitalization rates were calculated for each ZCTA. The top quartile of all ZCTA’s were retained for a factor and k-means cluster analysis, which used ten carefully selected socio-economic variables, to differentiate between high risk neighborhoods for cardiovascular disease. Based on this analysis, we identified four types of high-risk neighborhoods in the state. These include largely white areas in rural Texas; inner-city African-American neighborhoods; heavily Hispanic neighborhoods in large cities and the Rio Grande Valley; and diverse, working-class suburbs. . These clusters demonstrate the complexity of neighborhood effects on cardiovascular disease, as well as the linkages between race and poverty, and hospital admissions. In conclusion, in order for the American Heart Association to reach its goal of reducing cardiovascular disease and death by 20 percent by 2020, outreach and policy must be crafted to reach particular groups, and be delivered in ways that reach those particular types of neighborhoods. The classification system presented in this paper provides a framework for just such a project.
Abstract 9686: Novel GATA4 Binding Proteins, RbAp48/46 Regulate Post-Translational Modification During Hypertrophic Responses in Cardiomyocytes
Authors: Yoichi Sunagawa, Yasufumi Katanasaka, Hidetoshi Suzuki, Hiromichi Wada, Akira Shimatsu, Masatoshi Fujita, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2013)

Introduction: A zinc finger protein GATA4 associates with not only ERK1/2 but also an intrinsic histone acetyltransferase p300 and regulates myocardial transcriptional activities in response to hypertrophic stimuli. We recently reported that Retinoblastoma protein (Rb)-associated protein 48 and 46 (RbAp48/46) are novel components of the p300/GATA4 complex and form a repressor complex with HDACs in cardiomyocytes. However, precise functional regulation by RbAp48/46 during hypertrophic responses is still unknown. Hypothesis: We assessed the hypothesis that RbAp48/46 suppressed cardiac hypertrophic responses by regulating post-translational modification of GATA4 in cardiomyocytes. Methods and Results: Overexpression of RbAp48/46 inhibited phenylephrine (PE)-induced acetylation of GATA4, activation of atrial natriuretic factors (ANF) and endotheline-1 (ET-1) promoters, and increase in cell size in cultured cardiomyocytes. Conversely, knockdown of RbAp48/46 by shRNA augmented such responses. In the absence of HDAC1/2, RbAp48/46 failed to suppress cardiac hypertrophy. GST pull down assay revealed that RbAp48/46 interacted with a portion near the S105 phosphorylation site within N-terminal domain of GATA4. Immunoprecipitation and Western Blot demonstrated that a constituted active form of MEK1 induced S105 phosphorylation of GATA4, the dissociation between RbAp48/46 and GATA4, the increase in p300-dependant acetylation of GATA4, and p300/GATA4-dependant synergistic activations of ANF and ET-1 promoters. Such inductions did not occur in phosphorylation-mutated GATA4. Stimulation of cardiomyocytes with PE increased S105 phosphorylation of GATA4 and the dissociation of GATA4 from RbAp48/46 and HDAC1/2, and decreased recruitments of RbAp48/46 onto GATA element of the ANF promoter. These changes are suppressed by PD98059, a MEK1 inhibitor. Conclusion: These findings demonstrate that RbAp48 and RbAp46 form repressor complex with GATA4 as well as HDAC1/2, release p300 from GATA4, and inhibit hypertrophic responses in cardiomyocytes. The phosphorylation of GATA4 may be a trigger of the disassociation between RbAp/HDAC complex and GATA4, and of subsequent formation of p300/GATA4 complex and hypertrophic gene activation.
Abstract 9405: Lower Achieved Systolic Pressure (=130 mm Hg) is Associated With a Decreased Risk of New Atrial Fibrillation in Hypertensive Patients With Electrocardiographic Left Ventricular Hypertrophy: The LIFE Study
Authors: Peter M Okin, Darcy A Hille, Anne Cecilie K Larstorp, Kristian Wachtell, Sverre E Kjeldsen, Björn Dahlöf, Richard B Devereux
Journal: Circulation (2013)

Background: There is a well-established association between hypertension and atrial fibrillation (AF), with recent studies demonstrating that even upper normal systolic blood pressures (SBP) are long-term predictors of incident AF. These findings suggest that more aggressive control of BP may reduce the risk of new AF. However, whether more aggressive reduction of SBP is associated with a lower incidence of AF remains unclear. Methods: Risk of new-onset AF was examined in relation to last in-treatment SBP prior to AF diagnosis or last in-study measurement in the absence of new AF in 8831 hypertensive patients with ECG LVH with no history of AF, in sinus rhythm on their baseline ECG, randomly assigned to losartan- or atenolol-based treatment. Patients with in-treatment SBP ≤130 mm Hg (lowest quintile at last measurement) and SBP between 131 and 141, were compared with patients with in-treatment SBP ≥142 (median SBP at last measurement). Results: During 4.6±1.1 years follow-up, new-onset AF was diagnosed in 701 patients (7.9%). In univariate analyses, compared with in-treatment SBP ≥142, in-treatment SBP ≤130 entered as a time-varying covariate was associated with a 46% lower risk (95% CI 31-58%) and in-treatment SBP between 131 and 141 with the same 46% lower risk (95% CI 35-55%) of developing AF. After adjusting for randomized treatment, age, sex, race, diabetes, history of ischemic heart disease, MI or heart failure, prior antihypertensive therapy, baseline serum glucose, creatinine, HDL and total cholesterol entered as standard covariates, and for incident MI, heart failure and in-treatment Cornell product LVH, heart rate, diastolic BP and HDL treated as time-varying covariates, achievement of a SBP ≤130 remained associated with a 40% lower risk (95% CI 18-55%) and in-treatment SBP of 131 to 141 with a 24% lower risk (95% CI 7-38%) of new AF. Conclusions: Achieved SBP ≤130 is associated with a lower risk of developing new-onset AF in hypertensive patients with ECG LVH, independent of other known and possible risk factors for AF. Further study will be needed to determine whether targeting hypertensive patients without AF to lower SBP goals can reduce the burden of new AF in this high-risk population.
Abstract 9547: AMPKa2 Deletion Promotes Vascular Smooth Muscle Cell Migration via Skp2 Upregulation and E-cadherin Downregulation
Authors: Ping Song, Yanhong Zhou, Kathleen A Coughlan, Xiaoyan Dai, Yue Wu, Hairong Xu, Qilong Wang, Huaiping Zhu, Wencheng Zhang, Benoit Viollet, Ming-Hui Zou
Journal: Circulation (2013)

The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical events in the progression of several vasculopathologies. Adenosine monophosphate-activated protein kinase (AMPK) has been shown to play a pivotal role in cellular proliferation and migration. However, the exact role of AMPK in VSMCs migration and its underlying molecular mechanisms remain elusive. We cultured mouse VSMCs isolated from wild-type (WT) C57BL/6J mice and either AMPKα2 or AMPKα1 homozygous-deficient (AMPKα2 -/- , AMPKα1 -/- ) mice to investigate the molecular mechanisms of VSMCs migration. Deletion of AMPKα2, but not AMPKα1, led to increased phosphorylation of IκB kinase α (IκKα) and its downstream target nuclear factor κB2 (NFκB2)/p100 at serine 866/870. This resulted in pp100-S866/870 association with E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP), which contributed to NFκB2/p52 induction from the proteolytic processing of the p100 precursor. Interestingly, acetylation of histone H3 at lysine 56 (AcH3-K56) resulted in association with histone deacetylase 3 (HDAC3) which was significantly enhanced in AMPKα2 -/- VSMCs compared with either WT or AMPKα1 -/- VSMCs. Moreover, the augmented association of p52/AcH3-K56 with the promoter of ubiquitin E3 ligase S-phase kinase-associated protein 2 (Skp2) was shown in AMPKa2 -/- VSMCs by ChIP assay. Furthermore, AMPKα2 deletion caused E-cadherin downregulation, which is mediated by Skp2 and the ubiquitin-proteasome system. Skp2 siRNA abolished the increased migration of AMPKα2 -/- VSMCs via E-cadherin upregulation. Finally, neointima formation after ligation of carotid artery was increased in AMPKα2 -/- , but not AMPKα1 -/- , mice and was associated with increased AcH3-K56 as well as reduction of both HDAC3 and E-cadherin. This compelling evidence indicates that deletion of AMPKα2, rather than AMPKα1, mediates VSMCs migration and the resultant neointimal formation after vascular injury. These events appear to occur via the NFκB2/Skp2/E-cadherin pathway.
Abstract 19061: Kca3.1 Regulates Monocytosis and Monocyte Adherence in Atherosclerosis
Authors: Vincent Lemaitre, Douglas Redelman, Hiroto Miura
Journal: Circulation (2013)

Introduction: Atherosclerosis is associated with a monocytosis of an inflammatory subset (Ly-6Chi in mice), which is preferentially recruited to lesions and gives rise to pro-atherosclerotic macrophages (MΦ). We have shown that the intermediate-conductance Ca2+-activated K+ channel KCa3.1 is predominantly expressed in blood Ly-6Chi monocytes (MONO) and lesion MΦ, and KCa3.1 blockade or knockout reduces the development of atherosclerosis in mice. To further study the function of KCa3.1 in atherogenesis, we investigated its role in monocytosis and in MONO adherence to the endothelium in vivo. Methods and Results: Flow cytometric analyses of peripheral blood and bone marrow from Apoe-/- and Apoe-/- KCa3.1-/- mice showed that KCa3.1 deficiency decreased circulating MONO (8.8±1.5% of leukocytes, p&lt;0.05 vs. 15.4±2.1%; n=7-8) and Ly6Chi MONO (4.2±0.7% of leukocytes, p&lt;0.05 vs. 9.8±1.5%, n=7-8), with unchanged Ly6Clo MONO (4.6±1.3% of leukocytes, p=ns vs. 5.6±0.7%) and polymorphonuclar (11.7±1.4% of cells, p=ns vs. 12.5±1.2%; n=7-8). Apoe-/- KCa3.1-/- mice had reduced hematopoietic stem and multipotential progenitor cells (HSPCs) (2.4±0.5% of lineage negative cells, p&lt;0.05 vs. 3.0±0.5%, n=7). In vivo confocal endomicroscopic analysis of leukocyte adherence was performed in anesthetized mice 4 hours after topical application of 0.5 μg TNF-α and 0.125 μg IL-1β onto the right external carotid artery where an imaging probe (Cellvizio®, field of view=8x105 μm2) was placed. Blood and circulating leukocytes were stained by intravenous injection of 200 μg FITC-dextran and 0.02% acrydine orange, respectively. KCa3.1 deficiency markedly inhibited leukocyte rolling (4±2 vs. 52±15 cells/min, contact time: 1.6±0.5 vs. 2.7±0.2 sec, distance: 78±11 vs. 165±5 μm, and velocity: 145±24 vs. 119±5 μm/sec) and adhesion (0.5±0.3 vs. 2.0±0.6 cells/min, p&lt;0.05 for all data, n=6). Immunohistochemistry of lesions showed that Apoe-/- KCa3.1-/- mice had less CD68-positive MONO/MΦ compared to Apoe-/- mice (616±101, p&lt;0.05 vs. 937±90 cells/mm2, n=8-9). Conclusion: KCa3.1 modulates monocytosis and plays a major role in MONO adherence to the endothelium in vivo. Thus KCa3.1 constitutes a promising therapeutic target for the prevention of atherosclerosis.
Abstract 9810: Relationship Between Time of Day and Periprocedural Myocardial Infarction After Elective Angioplasty
Authors: Stephane Fournier, Serban Puricel, Beata Morawiec, Eric Eeckhout, Fabio Mangiacapra, Catalina Trana, Maxime Tapponnier, Juan Fernando Iglesias, Vincent Michiels, Jean-Christophe Stauffer, Ahmed Beggah, Pierre Monney, Stephanie Gobet, Pierre Vogt, Stephane Cook, Olivier Muller
Journal: Circulation (2013)

Introduction: Recent studies have suggested an influence of circadian rhythms on myocardial infarction size and mortality among patients with ST-elevation myocardial infarction. The aim of the study is to investigate whether periprocedural myocardial infarction (PMI) is influenced by the time of day in elective patients undergoing percutaneous coronary intervention (PCI). Hypothesis: The time of day influences the occurrence of type 4A myocardial infarction in elective patients undergoing PCI. Methods: All consecutive patients undergoing elective PCI between 2007 and 2011 at our institutions with known post-interventional troponin were retrospectively included.Patients (n=1,021) were divided into 2 groups according to the starting time of the PCI: the morning group (n=651) between 07:00 and 11:59, and the afternoon group (n=370) between 12:00 and 18:59. Baseline and procedural characteristics as well as clinical outcome defined as the occurrence of PMI were compared between groups. In order to limit selection bias, all analyses were equally performed in 308 pairs using propensity score matching. Results: In the overall population, the rate of PMI was statistically lower in the morning group compared to the afternoon group (20% vs. 30%, p&lt;0.001). This difference remained statistically significant after PS-matching (21% vs. 29%, p=0.03). Multivariate analysis shows that being treated in the afternoon independently increases the risk for PMI with an odds ratio of 2.0 (95%CI: 1.1-3.4; p=0.02). Conclusions: This observational propensity score-matched study suggests that the timing of an elective PCI influences the rate of periprocedural myocardial infarction.