tbuckley/cabot-search huggingface dataset:
Abstract 18866: HDL Subclass Heterogeneity Relates to Differences in Risk of Incident Coronary Heart Disease
Authors: Akintunde O Akinkuolie, Nina Paynter, Latha Padmanabhan, Samia Mora
Journal: Circulation (2013)

Background: Raising the cholesterol fraction of HDL particles is targeted as a cardiovascular disease reduction strategy. However, HDL particles are highly heterogeneous in composition and structure, which may relate to differences in their anti-atherogenic potential. We prospectively evaluated the association of HDL subclasses, as defined by a recently proposed nomenclature aimed to harmonize cross-comparison across different HDL subfractionation techniques, with the risk of incident coronary heart disease (CHD) in initially healthy women. Methods: Baseline HDL subclass concentrations were measured and categorized into 5 groups (very large, large, medium, small, and very small) by nuclear magnetic resonance spectroscopy in 27 177 participants of the Women’s Health Study (median follow-up 17 years). First report of incident CHD (myocardial infarction, coronary revascularization, and CHD death) was ascertained (n=1 056 cases). Results: Multivariable Cox regression HRs (95%CIs) adjusted for age, ethnicity, blood pressure, smoking, postmenopausal status, hormone therapy, and treatment assignment showed inverse associations with incident CHD for quartile 4 vs 1 concentrations of very large 0.50 (0.42-0.61), large 0.53 (0.44-0.62), and medium 0.69 (0.58-0.82) HDL subclasses (all p-trend&lt;0.0001, Table). Conversely, small and very small HDL subclasses were associated with an increased risk: HRs 1.24 (1.03-1.48, p-trend=0.04) and 1.74 (1.45-2.08, p-trend&lt;0.0001), respectively. After additionally adjusting for potential mediating factors (BMI, diabetes, and lipid/lipoprotein concentrations), only the large HDL subclass remained statistically significantly associated with CHD (p-trend=0.0004, Table). Conclusion: In this prospective study of 27,177 initially healthy women followed for 17 years, associations with risk of incident CHD differed by HDL particle subclass, which may be relevant for the development of HDL-modulating therapies.
Abstract 18855: Global Longitudinal Strain is Reduced in Congenital Aortic Stenosis and Associated With Focal Myocardial Fibrosis
Authors: Susan M Dusenbery, Fatima I Lunze, Michael Jerosch-Herold, Tal Geva, Jane W Newburger, Steven D Colan, Andrew J Powell
Journal: Circulation (2013)

Background: In congenital aortic stenosis (AS), therapy to relieve obstruction is directed toward preserving myocardial function and structure, but the optimal timing remains controversial. Myocardial strain measurements of regional systolic function may be more sensitive than conventional measures, such as ejection fraction (EF), and thus serve to refine the indications for intervention. We hypothesized that congenital AS pts with normal EF have impaired LV strain associated with myocardial fibrosis. Methods: Inclusion criteria for cases were congenital AS with a peak Doppler gradient ≥20 mm Hg at any time, age&lt;30 yo, extracellular volume fraction (ECV) and late gadolinium enhancement (LGE) assessed by cardiac MR (CMR), LV EF &gt;54%, and a concurrent echocardiogram. Strain measures were compared to normal controls of similar age (n=15, median age 15). Speckle tracking echocardiographic strain was used to measure peak global longitudinal, circumferential, and radial strain. The ECV, a measure of diffuse fibrosis, was calculated with a Look-Locker technique. LGE was used to assess focal fibrosis, and classified as present or absent. Results: Twenty-nine pts met inclusion criteria with a median age of 16 yrs (1.7-25), peak AS gradient of 48 mm Hg (0-90), aortic regurgitation fraction by CMR of 25% (0-60), LV EF 65% (55-79), and mean ECV 0.27 (0.22-0.38). Global longitudinal strain was significantly lower in AS patients than controls (-17.0 ± 3.0% vs. -20.9 ± 2.4%, p&lt;0.001). Global circumferential strain (-26.7 ± 5.6% vs. -25.9 ± 3.6%, p=0.72) and global radial strain (29.6 ± 7.7% vs. 34.2 ± 8.8%, p=0.063) were not significantly different. Reduced global longitudinal strain was associated with LGE (p=0.036) but not ECV (p=0.14) Global longitudinal strain was not associated with peak echo AS gradient prior to CMR, LV mass/volume ratio, or a history of any aortic valve intervention. Conclusions: In this cohort of children and young adults with congenital AS and preserved EF, global longitudinal strain was lower than in controls and associated with focal fibrosis but not diffuse fibrosis. Further studies are warranted to determine whether strain measurements should be used to determine the timing for intervention in AS to better preserve myocardial structure.
Abstract 13716: Pharmacokinetics of Pravastatin in Pediatric Dyslipidemia Patients: Clinical Impact of Genetic Variation on Statin Disposition
Authors: Jonathan Wagner, Susan Abdel-Rahman, Leon van Haandel, Geetha Raghuveer, Ralph Kauffman, J. Steven Leeder
Journal: Circulation (2015)

Background: In adults, genetic variation of the drug transporter, organic anion transporting polypeptide (OATP1B1) encoded by the gene SLCO1B1, decreases hepatic uptake of statins. This leads to increased circulating statin concentrations in plasma, thereby placing patients at higher risk for adverse events and decreased efficacy. Expression of OATP transporters in mice changes during development, raising the question of whether in humans the genotype-phenotype relationship observed in adults is relevant in the developing child. Methods: Participants (8-21 years) with at least one allelic variant of SLCO1B1 c.521 T&gt;C (521TC; n=8) and wild type controls (521TT; n=5) were enrolled in a single oral dose pharmacokinetics (PK) study. Pravastatin and isomers were quantified by liquid chromatography tandem mass spectrometry. A model-independent PK approach was used to define the peak plasma concentration (Cmax), area under the curve (AUC) during the sample period and AUC to infinity. Results: 521TC subjects had a nearly 3-fold increase in Cmax (177.62 vs. 56.53 ng/ml; p=0.001) and AUC (389.81 vs. 139.57 ng/ml*h; p=0.004) compared to 521TT controls (Fig. 1). Formation of the 3-alpha-iso-pravastatin acid and lactone isomers in the acidic environment of the stomach prior to absorption was variable in both groups. There was a linear relationship between pravastatin acid AUC and the ratio of pravastatin acid to total analyte (pravastatin acid, 3-alpha-iso-pravastatin, and corresponding lactones) AUC amongst genetic variants (R=0.8961) that does not appear to be present in the control. Conclusion: The impact of the SLCO1B1 c.521 gene variant on pravastatin PK in adults was replicated in our pediatric cohort. However, other physicochemical factors appear to contribute to variability in the dose-exposure relationship. This data must be replicated in a larger cohort, and the pharmacodynamic consequences assessed, before implementing OATP1B1 driven dosing guidelines.
Abstract 18816: Predicting an Accurate Intensity Threshold on LGE-MRI for Identification of Left Atrial Fibrosis
Authors: Irfan M Khurram, Vadim Zipunnikov, Jane Dewire, Roy Beinart, David D Spragg, Joseph E Marine, Ronald D Berger, Henry R Halperin, Hugh Calkins, Stefan L Zimmerman, Saman Nazarian
Journal: Circulation (2013)

Background: Late gadolinium enhanced (LGE) MRI identifies left atrial (LA) fibrosis in atrial fibrillation (AF). However, routine measurement of image intensity in “arbitrary units” limits inter-patient and longitudinal comparisons. This study is designed to identify the scar threshold identification on LGE-MRI to improve the uniformity and validity of results. Methods: High-resolution navigator-gated LGE-MRI (1.5 Tesla) was performed in 75 patients (31% female, age 62 ± 8 years) prior to the first (60%), second (24%), or third (16%) ablation for AF. Epicardial and endocardial contours were manually drawn around LA myocardium. The image intensity ratio (IIR) was defined as LA myocardial signal intensity for each of 20 sectors on contiguous axial planes divided by the mean LA blood pool image intensity. Intra-cardiac point-by-point sampled electro-anatomical map (EAM) points were registered and superimposed upon the image. Log transformed bipolar voltage was plotted against IIR and the threshold values corresponding to 0.5mV and 0.1mV were identified. Results: A total of 8153 EAM points and corresponding image sectors were analyzed. In a generalized estimating equations model accounting for within patient clustering, and adjusting for age, LA volume, mass, BMI, gender, CHADSVasc score, AF type, prior ablation, and the delay time between contrast and image acquisition, each unit increase in local IIR was associated with 91.3% decrease in bipolar LA voltage (P&lt;0.001). The IIR was strongly associated with bipolar voltage on EAM in patients with minimal and extensive LA fibrosis (figure top). IIR thresholds of 0.97 and 1.62 corresponding to 0.5 mV (fig-bottom left) and 0.1 mV (fig- bottom right), respectively, were obtained and showed convergence of the 95% CI and a stable threshold with increasing patients. Conclusion: Normalization of LGE-MRI intensity by the mean blood pool intensity results in a stable threshold to identify diffuse fibrosis or dense scar.
Abstract 13828: Fibroblast Growth Factor-23 Induces Cellular Senescence in Human Mesenchymal Stem Cells From Skeletal Muscle Independently of Klotho Pathway
Authors: Chisato Sato, Yoshitaka Iso, Takuya Mizukami, Masahiro Sasai, Ichiro Sekiya, Akira Miyazaki, Hiroshi Suzuki
Journal: Circulation (2015)

Introduction: Mesenchymal stem cells (MSCs) in skeletal muscle represent a distinct cell population from satellite cells (StCs), and the functional impairment have shown to be associated with ectopic fat formation in muscle tissues. Muscle wasting and/or degeneration are prevalent in heart failure and chronic kidney disease. However, it remains unknown whether such disease condition influences the MSC function and fate. Thus, aim of this study was to investigate effects of fibroblast growth factor (FGF)-23 and angiotensin (ANG)-II, neurohumoral factors related to pathophysiology of cardio-renal syndrome (CRS), on the MSCs in culture system. Methods and Results: MSCs were isolated from human skeletal muscle and cultured with appropriate growth medium. Gene expression analysis demonstrated the enhanced expression of FGF receptors and ANG-II type 1 receptor in the MSCs as compared with the human StCs. Klotho gene was not detected in the two progenitors. The cultured MSCs and StCs were treated with FGF-23 (10ng/ml) and ANG-II (100 nM) for 48 hours. Cell proliferation assay revealed significant decreased cell number in the MSCs treated with FGF-23 but not ANG-II than in the controls (58 % of the controls, p&lt; 0.05). The neurohumoral factors did not affect the cell counts of the StCs. The FGF-23 treated MSCs exhibited the senescent phenotype, as judged by senescence-associated β-galactosidase assay (%senescent cells: 46.5± 11.7 % in the FGF-23 vs. 35.8± 5.8% in the controls, p&lt; 0.05), cell morphology, and increased expression of p53 and p21 in western blot analysis. FGF-23 also augmented intracellular oxidative stress in the MSCs. The mechanisms responsible for the accumulation of reactive oxygen species (ROS) were attributable to increased NADPH oxidase and decreased MnSOD expression in the cells. In histological study, p53-positive senescent MSCs were detected in adipose infiltration area of degenerated gastrocunemius muscle tissues from a CRS patient. Conclusions: Results of this study indicate that FGF-23 induces premature senescence in human MSCs from skeletal muscle via promoting ROS/p53/p21 pathway in klotho-independent action. Interaction of the MSCs with FGF-23 may play a key role in muscle wasting in patients with CRS.
Abstract 18738: Pulmonary Artery Systolic Pressures Increase With Aging: A Longitudinal, Population Based Study
Authors: Suparna M Chandra, Margaret M Redfield, Barry L Karon, Richard J Rodeheffer, Garvan C Kane
Journal: Circulation (2013)

Background: A community based, cross-sectional echo survey demonstrated that pulmonary artery systolic pressure (PASP) increases with age and that PASP is associated with systemic arterial stiffness, Doppler estimated left ventricular (LV) filling pressures and lung function. Longitudinal assessment of PASP is needed to confirm cross-sectional observations. Objectives: To assess the whether PASP changes over time in longitudinally studied subjects and determine whether changes in PASP are associated with changes in systemic vascular stiffness, LV filling pressures or lung function. Methods: A random sample (n=2042) of the Olmsted County, MN population over age 40 underwent echo, record review and spirometry between 1997-2000 (Exam 1). A subset (n=1402) underwent repeat studies four years later (2001-2004; Exam 2). The current analysis includes the 723 subjects with paired PASP measurements. Changes ([[Unable to Display Character: ▵]]) in PASP, systemic arterial stiffness (pulse pressure; PP), LV filling pressure (E/e’) and lung function (% age/sex expected forced expiratory volume, %FEV1) were assessed. Results: At Exam 1, the median (interquartile range) age was 62 (69-70) years (62% female). Median time between exams was 48 (47-49) months. PASP increased from 26.1 (24.4-30.0) mmHg at Exam 1 to 28.0 (24.4-32.0) mmHg at Exam 2 (p&lt;0.0001 by paired t test) for an average (SD) [[Unable to Display Character: ▵]] of 1.2 ± 5.5 mmHg. Adjusting for age and PASP at Exam 1, [[Unable to Display Character: ▵]]PASP was associated with [[Unable to Display Character: ▵]] age with an increase (parameter estimate (pe) ± standard error (se)) of 1.4±0.7 mmHg per year increase in age (p=0.046). [[Unable to Display Character: ▵]]PASP was not associated with sex and there was no age-sex interaction. Adjusting for age and PASP at Exam 1, [[Unable to Display Character: ▵]] age and Exam 1 values for PP, E/e or %FEV1 as appropriate, [[Unable to Display Character: ▵]]PASP was associated with [[Unable to Display Character: ▵]] PP (pe±se = 0.03±0.01 mmHg; p=0.01) [[Unable to Display Character: ▵]]E/e’ (pe±se = 0.21±0.06 mmHg, p=0.001) and [[Unable to Display Character: ▵]]%FEV1 (-0.09±0.02 mmHg, p&lt;0.0001) suggesting that increases in PASP were related to increases in vascular stiffening, increases in LV filling pressures and declining lung function. Conclusions: In this longitudinal, population based study we find that PASP increases with aging and that increases in PASP over time are related to increases in systemic vascular stiffness and LV filling pressures and decreases in lung function.
Abstract 18740: Cardiac Magnetic Resonance Evaluation of Coronary Anatomy and Myocardial Viability After Arterial Switch Operation
Authors: Dilachew Adebo, Kevin Whitehead, Mark Fogel, Matthew Harris
Journal: Circulation (2013)

Background: Arterial Switch Operation (ASO) is the treatment of choice for anatomic correction of transposition of the great arteries (TGA). One of the major concerns after ASO is the evaluation of the translocated coronary arteries. There are limited studies evaluating the role of cardiac magnetic resonance (CMR) in the follow up of patients after ASO. The purpose of this study is to evaluate the extensive use of CMR for delineating coronary artery anatomy and myocardial viability after ASO. METHODS: Retrospective review of 69 consecutive CMR Whole Heart T2 Prep coronary angiography studies of patients who underwent ASO for TGA. The subjects had CMR from July 2005 to December 2012. Results of inversion recovery viability imaging were also reviewed. RESULTS: The median age at the time of CMR was 15 years with range of 1 year to 24 years); 44 male and 25 female subjects. The coronary origins and proximal coronary arteries were well demonstrated by CMR in 97% (67/69) of the cases Among these, 70% (47/67) of the cases had typical coronary pattern for TGA after ASO while 30% (20/67) had an atypical pattern. Circumflex coronary artery arising from right coronary artery was seen in 60% (12/20) and single coronary artery originating from right or left facing sinus was identified in 40% (8/20) of the subjects with atypical coronary pattern. One patient had evidence of left circumflex coronary artery occlusion with inferior and lateral myocardial fibrosis on late gadolinium enhancement imaging. In this patient, the right coronary artery originates from right facing sinus and the left coronary artery originates from left facing sinus. The two patients with unsatisfactory image quality had dental brace artifact affecting image quality. Conclusions: CMR coronary angiography and myocardial viability can reliably delineate coronary anatomy and identify myocardial fibrosis after ASO for TGA. Keywords: Arterial switch operation; Cardiovascular magnetic resonance imaging; Transposition of great arteries
Abstract 18753: Mechanisms of Left Ventricular Reverse Remodeling: Insights From a Novel Murine Model of Hypertensive Ischemic Cardiomyopathy
Authors: Carla J Weinheimer, Sara Evans, Yun Liang, Philip M Barger, Douglas L Mann, Attila Kovacs
Journal: Circulation (2013)

Background: All approved therapies for heart failure (HF) lead to reverse LV remodeling (LVRR). The lack of genetically tractable animal models of LVRR has prevented further understanding of the biology of LVRR. Here we present a murine model of HF that mimics hypertensive ischemic cardiomyopathy, which undergoes LVRR with hemodynamic unloading. Methods: Wild type mice were subjected to Sham (n=6), or transverse aortic constriction (TAC) with LAD ligation (MI), leading to progressive LV remodeling (n=12). Hemodynamic unloading was accomplished by debanding (DB) the aorta 2 wks post MI/TAC (n=6), whereas the band remained intact in the HF group (n=6). Both DB and HF groups were followed for 4 more weeks. 2D echo speckle tracking was performed at 1 &amp; 14 days post-MI/TAC, and at 4 wks post-DB. Hearts were analyzed by LV morphometry, histology and transcriptional profiling. Results: 2-D echo at 1 and 14 days post-MI/TAC showed progressive LV dilatation (1d=34ul, 14d=62ul; p&lt;0.01). LVRR occurred 4 wks post-DB, with near normalization of LV volumes (p=NS vs sham). In contrast, LV volumes increased ~ 3-fold (p&lt;0.01 vs sham) in the HF group. LV ejection fraction (LVEF) continued to decrease over 4 weeks in HF hearts (36% vs 31%, p&lt;0.05), whereas LVEF increased in post-DB hearts (33% vs 42%, p&lt;0.01). LV weights were significantly (p &lt; 0.05) smaller in the DB group (85±13g) compared to the HF group (133±16g) at 4 weeks. Myocyte size decreased significantly (p&lt;0.05) in DB hearts (409±41μ 2 ) compared to HF hearts (446±41μ 2 ), whereas interstitial fibrosis was not different (p &gt; 0.05). Transcriptional profiling showed that, relative to HF hearts, LVRR in post DB hearts was accompanied by significant (p &lt; 0.05) decreases in extracellular matrix gene expression, and significant increases in α-myosin heavy chain, calcium channels and adenylate cyclase gene expression. Conclusion: We developed a genetically tractable mouse model of hypertensive ischemic cardiomyopathy that undergoes LVRR following unloading. LVRR is accompanied by favorable changes in LV structure and function, myocyte size, as well as changes in contractile protein and calcium handling genes. Genetic manipulation of this model will permit a clearer understanding of the molecular mechanisms responsible for LVRR.
Abstract 12913: Serotonin Regulates Qt-interval: Acceleration of Cardiac Repolarization by Enhanced Kv4.3 Membrane Trafficking
Authors: Shanyu Cui, Boyoung Joung
Journal: Circulation (2016)

Background: Elevated maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant of normal fetal development. However, what roles the elevated serotonin plays in the electrophysiology of the mother’s heart has not been studied. In the present study, we therefore assessed the relationship between QTc duration and serotonin and studied underlying mechanisms. Methods and results: During pregnancy, 5-HT and tryptophan hydroxylase 1, a rate-limiting enzyme of serotonin synthesis, were markedly increased in hearts and serum. We measured QT intervals and ventricular potassium outward currents in wild-type (WT) and 5-HT3a receptor knock-out ( Htr3a -/- ) mice at non-pregnant (NP) and late-pregnant (LP) state. The 5-HT as well as m-CPBG, an Htr3 agonist, increased I peak and I to,f densities with the shortening of QTc duration in WT NP, but not in WT LP and Htr3a -/- mice. Additionally an Htr3a antagonist, ondansetron (5 μM) decreased I peak and I to,f only in WT LP, but not in WT NP mice. In contrast, I peak and I to,f densities were unchanged upon 5-HT and m-CPBG application in left ventricular myocytes freshly-isolated from the Htr3a -/- -LP mice. Kv4.3 protein and Htr3a is co-localization in the membrane and t-tubule of cardiomyocytes. Co-immunoprecipitation showed that Kv4.3 protein directly interacts with 5-HT3a receptor. Moreover, the binding between 5-HT3a receptor and Kv4.3 was facilitated by 5-HT. This increase was mediated by 5-HT3a receptor dependent promotion of Kv4.3 channel trafficking to the cell membrane. However, these findings were not observed in WT LP mice. The heat-shock protein-90 (Hsp90) inhibitor geldanamycin abolished 5-HT-induced increase of I peak and I to,f densities. Finally, we evaluated and found that serotonin could shorten QTc interval by increasing potassium outward currents in rat and rabbit. Conclusion: Elevated 5-HT levels were associated shorter QTc intervals by acceleration of I peak and I to,f densities in mouse, rat and rabbit. 5-HT acts on Kv4.3 channels via enhanced 5-HT3a-receptor-medicated Hsp90 interaction, augments membrane trafficking and thereby increases repolarizing current. These results provide mechanistic insights into hormonal control of ventricular repolarization.
Abstract 18761: Non-Muscle Myosin Light Chain Kinase Mediates Vascular Endothelial Growth Factor Induced Vascular Hyperpermeability via Specificity Protein 1 During Asthmatic Inflammation
Authors: Yuka Shimizu, Xiaoguang Sun, Tong Zhou, Ting Wang, Joe G Garcia
Journal: Circulation (2013)

INTRODUCTION: Increased vascular permeability and accumulation of alveolar fluid are cardinal features of lung inflammation and asthma. Two targets for these responses are vascular endothelial growth factor (VEGF) and the non-muscle isoform of myosin light chain kinase (nmMLCK), a key regulator of vascular barrier function via actin-myosin mediated cell contraction. Both VEGF and nmMLCK mRNA and protein expression are upregulated in asthmatic patients. Supported by preliminary in vitro studies that demonstrate increased VEGF-induced nmMLCK expression, we propose a linkage between these two asthma targets and hypothesize that nmMLCK mediates VEGF induced vascular hyperpermeability in asthmatic inflammation. Methods &amp; Results: mRNA quantified by qPCR showed increases in nmMLCK mRNA in lung biopsies from human asthmatic patients and ovalbumin (OVA, 0.4 mg/kg) challenged murine asthma model. OVA-challenged mice overexpressing nmMLCK in the endothelium (nmMLCKec/ec) exhibit increased airway pressure time index (APTI) and BAL protein levels compared to WT, whereas OVA-challenged nmMLCK-/- mice demonstrated significant attenuation of increases in APTI and BAL protein levels. Human pulmonary artery endothelial cells (HPAEC) treated with recombinant hVEGF (100ng/ml) increased nmMLCK mRNA and protein expression. In silico analysis of nmMYLK 5’ UTR 2.4 kb region and in vitro luciferase promoter assay in HPAEC revealed transcription factor binding sites of downstream effectors of VEGF signaling, with -400bp upstream of TSS being the critical region, which included the binding sites for the transcription factor, Sp1. Consistent with this, reduced Sp1 expression by siRNA attenuated VEGF-induced decrease in transendothelial electrical resistance (TER) as measured by electrical cell-substrate impedance sensing system. CONCLUSIONS: Our data demonstrate that nmMLCK induced by VEGF is mediated through Sp1 in lung EC. nmMLCK is a novel asthmatic target and represents a potential candidate for therapeutic modulation of asthmatic inflammation.