tbuckley/cabot-search huggingface dataset:
Abstract 16623: Wnt Signaling Inhibits T-Type Calcium Channels in Cardiomyocytes
Authors: Kaya Florczak
Journal: Circulation (2018)

Introduction: The Wnt/β-catenin pathway plays a critical role in embryonic heart development but is mostly inactive in adult hearts. Recent studies have shown that the pathway is re-activated in many heart diseases including myocardial infarction, cardiac hypertrophy and heart failure. Previous work from our laboratory demonstrated that activation of the Wnt/β-catenin pathway reduces the voltage-gated Na + current (I Na ) in neonatal rat ventricular myocytes (NRVMs). In this study, we examined the effects of Wnt signalling on T-type calcium channels (Ca v 3.1), which play a key role in the pacemaker function of the sinoatrial node (SAN). Methods: NRVMs were treated with Wnt3a protein or CHIR-99021, which activates the Wnt/β-catenin pathway by GSK-3β inhibition. PCR array assays, RT-qPCR, and western blot were used to examine changes in mRNA and protein levels of ion channels. To investigate the impact of ion channel alterations on SAN function, a protocol was developed to isolate SAN tissue from mouse hearts and maintain it ex vivo during ECG recording and drug perfusion. Results: PCR array assays showed a 72% reduction in mRNA of Cacna1g (encoding Ca v 3.1) by treatment with Wnt3a protein (130.4±13.2 in control cells vs. 37.4±2.4 in Wnt3a-treated cells, n=4, p&lt;0.05). RT-qPCR and western blot analyses showed a dose-dependent reduction (p&lt;0.05, n=4) in Cacna1g mRNA and Ca v 3.1 protein levels in NRVMs treated with CHIR-99021. Patch-clamp recording also revealed recued T-type calcium current in NRVMs treated with CHIR. Ex vivo perfusion of mouse SANs with a small molecule inhibitor of I Na , flecainide, led to slowed conduction velocity and sinus-exit block in a dose-dependent manner (p&lt;0.05, n=5). Conclusion: The Wnt/β-catenin pathway regulates the expression of both T-type Ca 2+ channels and voltage-gated Na + channels, which are important for impulse generation and conduction in the SAN. Thus, the Wnt pathway may play a role in sinoatrial node dysfunction.
Abstract 16626: Optical Coherence Tomography Guided Percutaneous Coronary Intervention is Not Associated With Decline in Kidney Function
Authors: Teruyoshi Nemoto, Yoshiyasu Minami, Toshimitsu Sato, Yusuke Muramatsu, Ryota Kakizaki, Takuya Hashimoto, Kazuhiro Fujiyoshi, Jun Oikawa, Kentaro Meguro, Takao Shimohama, Taiki Tojo, Junya Ako
Journal: Circulation (2018)

Introduction: Optical coherence tomography (OCT) guided percutaneous coronary intervention (PCI) may increase the contrast volume. However, the impact of OCT-guided PCI on the incidence of decline in kidney function (DKF) in real-world clinical practice had not been fully evaluated. Methods: Among a total of 1,003 consecutive patients who underwent PCI in our institute, we identified 201 propensity score matched pairs adjusted by baseline factors for DKF with either OCT-guided or intravascular ultrasound (IVUS)-guided PCI. The incidence of DKF was compared between the two groups. Patients on hemodialysis were excluded from the analysis. DKF was defined as an increase in serum creatinine level ≥0.5 mg/dl or the relative increase with ≥25% from the baseline value within 48 hours or one month after the PCI. Results: The baseline clinical characteristics including the prevalence of chronic kidney disease (CKD) (52 vs. 49%, P=0.62) were comparable between the groups. There was no significant difference in contrast volume between the OCT group and the IVUS group (148 vs. 142 ml, P=0.29) though it was significantly greater in the OCT group in cases of acute coronary syndrome (ACS) (175 vs. 156 ml, P=0.026). The incidence of DKF was comparable between the two groups at both 48 hours (0.5% vs. 2%, P=0.37) and one month (4% vs. 8%, P=0.14) after the PCI. Multivariate analysis demonstrated that diabetes (odds ratio [OR] 2.74, 95% confidential interval [CI] 1.18-6.37, P=0.02), ACS (OR 4.13, 95% CI 1.71-9.96, P&lt;0.01) and age (≥70 years old; OR 4.55, 95% CI 1.65-12.6, P&lt;0.01) were the predictors for DKF at either 48 hours or one month. Conclusions: OCT-guided PCI did not increase the incidence of DKF as compared with IVUS-guided PCI in real-world clinical practice.
Abstract 16661: Circulating microRNAs as Prognostic Biomarkers in Single Ventricle Heart Disease
Authors: Stephanie J Nakano, Megan SooHoo, Anis Karimpour-Fard, Armin Korst, Kristine Pauly, Christina M Phelps, Alix Michael, Ann Mackey, Shelley D Miyamoto, Carmen C Sucharov
Journal: Circulation (2018)

Introduction: Despite significant improvements in surgical technique and post-surgical management, mortality remains high for infants with single ventricle congenital heart disease (SV) and the ability to risk-stratify infants with SV is limited. microRNAs (miRs) are short regulatory RNAs that modulate gene expression and miRs in the circulation are increasingly recognized as valuable biomarkers in a broad range of diseases. Hypothesis: Circulating miR profiles prior to surgical palliation may correlate with SV survival at one year and assist with risk-stratification in this population. Methods: Serum samples from subjects with SV (of right ventricular morphology) were obtained at the following time points: Pre-Norwood (n=71), Pre-Glenn (n=46) and Pre-Fontan (n=25). Outcomes were classified as alive versus death or heart transplant listing by one year of age. Serum was subject to three freeze/heat cycles to maximize miR release, then miRs were reverse transcribed using a pool of primers specific for each miR. Real-time PCR was performed in 384-well plates containing sequence-specific primers and TaqMan probes in the ABI7900HT. Results: Random forest analysis of Pre-Norwood samples demonstrates downregulation of miRs-194, -15b and -193b in patients who died or required heart transplant listing (n=22) compared to those who were alive (n=49). Hierarchical clustering based on these 3 specific miRs is demonstrated in Figure 1 (blue = alive, red = death/transplant). miRs-483-5p, -140-3p and -30b are differentially expressed between the Pre-Norwood, Pre-Glenn, and Pre-Fontan groups and are associated with each surgical stage. Conclusions: Circulating miRs demonstrate promise as prognostic biomarkers of 1-year outcome in the Pre-Norwood SV population. Circulating miR profiles are also distinct at each surgical stage. Notably, the identified miRs are known to regulate gene expression in other forms of heart disease and warrant further investigation.
Abstract 11987: Bariatric Surgery Reduces the Incidence of Heart Failure in Patients With Obesity
Authors: Luke Kostanjsek, Maddalena Ardissino, Osama Moussa, Peter Collins, Sanjay Purkayastha
Journal: Circulation (2021)

Introduction: Obesity, and the related metabolic syndrome, is one of the largest public health challenges facing medical systems across the globe. A growing body of evidence supports using bariatric surgery in patients with obesity for weight loss and prevention of cardiovascular disease. However, relatively little research has considered whether bariatric surgery reduces the risk of heart failure. This propensity-score matched UK-wide retrospective study aims to answer that question. Hypothesis: We hypothesised that bariatric surgery would reduce the incidence of heart failure in patients with obesity, as compared to non-surgical management. Methods: Using the Clinical Practice Research Datalink, a study cohort containing 3,052 patients who had received bariatric surgery were matched by propensity score to 3,052 controls. The primary endpoint was development of any heart failure. The secondary endpoints were all-cause mortality, development of heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) specifically, and hospitalisations due to heart failure. These endpoints were assessed using a Cox proportional hazards model. Results: The mean follow-up duration was 7.50 years. Patients who received bariatric surgery had a significantly lower incidence of new heart failure (hazard ratio 0.45, 95% confidence interval 0.28-0.73, p=0.0011) and all-cause mortality (hazard ratio 0.56, 95% confidence interval 0.38-0.83, p=0.0036). There was no significant difference in the rates of HFrEF or HFpEF individually, though these analyses were notably underpowered. Conclusions: In conclusion, this UK retrospective study provides evidence of lower rates of heart failure and all-cause mortality in patients who have bariatric surgery when compared to propensity-score matched controls. Future efforts to understand the mechanism behind this reduction and explore the lifetime benefits in high risk cohorts are paramount.
Abstract 16725: A Novel Role for MAGI1 in Disturbed Flow-Induced Endoplasmic Reticulum Stress in Endothelial Cells
Authors: Jesus Paez-Mayorga, Yin Wang, Sivareddy Kotla, Junichi Abe, Nhat-Tu Le
Journal: Circulation (2018)

Introduction: Atherosclerotic plaque predominantly develops in areas where endothelial cells (ECs) are exposed to disturbed flow (d-flow). Endoplasmic reticulum (ER) stress, characterized by the activation of ER transmembrane sensor ATF6 and transcription factor XBP-1, has been implicated in d-flow-induced atherogenesis. At d-flow regions, expression of both total and spliced XBP-1 and activation of ATF6 are increased, resulting in EC apoptosis. Additionally, over-expression of XBP-1 accelerates atherosclerotic formation. A recent genome-wide association study revealed a strong correlation between membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein that associates with the tight and adherens junctions, and chronic inflammatory diseases. Hypothesis: We hypothesize that MAGI1 is crucial in d-flow-induced EC inflammation, apoptosis, and atherogenesis via regulating ER stress signaling. Methods and Results: Microarray analysis revealed that MAGI1 depletion inhibits ER-stress related genes, including XBP-1. qRT-PCR results confirmed that MAGI1 depletion abolished d-flow-mediated expression of spliced and full-length XBP-1 which correlated with reduced d-flow-induced apoptosis. To examine the mechanism by which MAGI1 regulates ER stress signaling, we found that MAGI1 is associated with ATF6, and that MAGI1-ATF6 complex formation is increased by inflammatory stimuli including d-flow and thrombin. Because the cleaved form of ATF6 can translocate from ER and Golgi to the nucleus, where it binds to ER-stress response elements and upregulates XBP-1 expression, we asked if MAGI1 facilitates ATF6 nuclear translocation. We found that thrombin-mediated ATF6 nuclear translation is significantly inhibited by MAGI1 depletion. Conclusions: Our results indicate that d-flow elicits the formation and translocation of a MAGI1-ATF6 complex from the cytosol to the nucleus that leads to ER stress via XBP1 induction and EC apoptosis. Our study suggests a novel role for endothelial MAGI1 as a link between d-flow and ER stress, both of which are fundamental constituents of atherogenesis.
Abstract 16819: Circulating Growth Factors and Cardiac Remodeling in the Community: The Framingham Heart Study
Authors: Cecilia Castro-Diehl, Rebecca J Song, Vanessa Xanthakis, Douglas B Sawyer, Susan Cheng, Ramachandran S Vasan
Journal: Circulation (2018)

Cardiac and vascular growth factors may influence myocardial and vascular remodeling through their pro- and anti-angiogenic effects. We hypothesized that higher circulating concentrations of growth factors will be associated with cardiac remodeling patterns consistent with their known biological effects. We related circulating concentrations of vascular endothelial growth factor (VEGF), VEGF-1, angiopoietin 2 (Ang2), Hepatocyte GF (HGF), insulin-like GF (IGF)-1, IGF binding protein (IGFBP)-3, growth differentiation factor-15 (GDF-15), to echocardiographic (echo) indices of cardiac remodeling in 3151 Framingham Study participants (mean age 40 years, 55% women). We evaluated the following echo measures (dependent variables): left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), global longitudinal strain (GLS), left atrial ejection fraction (LAEF), and aortic root diameter (AoR) using generalized linear models to account for relatedness. We also related circulating NTProBNP and Troponin (TnI) to echo measures (as positive controls). In multivariable-adjusted analyses blood GDF-15 levels were associated with higher values of LVMi. TnI concentrations were negatively associated with LVEF. IGF-1 and Ang2 concentrations were positively and negatively associated with GLS, respectively. Lower IGFBP-3 concentrations and higher NT-ProBNP concentrations were associated with lower LAEF. Higher VEGF-1, Ang2 and NT-Pro-BNP levels were associated with smaller AoR (Figure). In our large community-based cross-sectional study, we observed patterns of associations between several circulating vascular growth factors and cardiac remodeling indices that are consistent with the known biological effects of these pro- and anti-angiogenic factors on the myocardium and conduit arteries. Additional findings are warranted to replicate our findings and assess their prognostic significance
Abstract 16829: Pericardium Improves Cardiac Scaffold Mechanics and Cell Retention
Authors: Yutao T Xi, Po T Feng-Lee, Camila T Hochman-Mendez, Anita T Chandler, Karis R Tang-Quan, Luiz C Sampaio, Doris A Taylor
Journal: Circulation (2018)

Background: Building a transplantable bioartificial heart from a decellularized extracellular matrix (dECM) scaffold is a promising option to solve the donor organ shortage. Yet, strategies are needed for cell retention, survival and function in recellularized dECM hearts. The objective of this work was to determine if the preservation of the pericardium during decellularization provides benefit to the resulting dECM mechanically and functionally when recellularized. Methods: Hearts ± pericardium (8.0 ± 1.3 g) from New Zealand White rabbits (2.9 ± 0.6 kg) were perfusion decellularized via Langendorff under constant pressure (60 mmHg). Perfusion solutions were: hypertonic NaCl (500mM), hypotonic NaCl (20mM), 1% sodium dodecyl sulfate (SDS), peracetic acid (0.01%) in 1% SDS, and PBS. After decellularization, dECM hearts (n=7 with pericardium, n=9 without pericardium) were sectioned into 2 mm thick rings. Force-elongation curves, DNA, SDS, glycosaminoglycan (GAG) content, and matrix fiber density were measured. Vasculature of dECM whole hearts (n=14) was recellularized by anterograde infusion of human endothelial cells (hECs, 86.09 ± 18.26 million) through the coronary vasculature (2 ml/min at 1.5 million cells/ml). Results: Hearts decellularized with pericardium contained more DNA (427± 26, n=6, vs. 217 ± 46 ng/mg, n=7, p&lt;0.05) than those without, but remnant DNA content was less than 10% of cadaveric. The GAG content was comparable in hearts with or without pericardium. Matrix fiber densities were higher in hearts with pericardium (64.47% ± 1.55%, vs. 54.28% ± 2.45%, p&lt;0.01, n=3). Force-elongation tests showed that rings of left ventricle with pericardium had better flexibility with a slope of 1.56% ± 0.65% mm/gram vs. 0.91% ± 0.28% mm/gram (p&lt;0.01, n=3 hearts per group). In recellularized hearts, more hECs were retained (83.82% vs. 70.04%, p&lt;0.05, n=7) in hearts with pericardium. Conclusion: Retaining the native pericardium preserves the mechanical flexibility and matrix fiber densities of dECM scaffold, which promotes cell retention during recellularization.
Abstract 16718: Electronic Cigarette Aerosols Alter Cardiac Expression of Genes Key to Electrical and Structural Remodeling in Mice
Authors: Alex P Carll, Kyle Fulghum, Daniel J Conklin, Aruni Bhatnagar, Sanjay Srivastava
Journal: Circulation (2018)

Background: Electronic cigarette (e-cig) use has mounted. Some health authorities have even proclaimed e-cigs are profoundly safer than conventional cigarettes. However, e-cigs generate several potentially cardiotoxic constituents by heating their solvent vehicles propylene glycol (PG) and vegetable glycerin (VG) into aerosols to deliver nicotine and flavors. Objectives: To investigate the effects of chronic E-cig exposures, with or without nicotine, on cardiac gene expression compared to mainstream cigarette smoke (MCS). Methods: Healthy C57BL/6J male mice were exposed chronically (12 weeks, 3 hours/day) to e-cig aerosols from an equal-ratio mixture of PG and VG (PG:VG) with nicotine (36 mg/mL) or without nicotine, or to MCS, and compared to filtered air control group (Air). Hearts (n=8/group) were assayed by quantitative PCR for expression of genes associated with electrical and structural remodeling. Results: PG:VG exposure increased gene expression for a gap junction protein (connexin 43, 1.8-fold), voltage-gated potassium and sodium channels (K v 4.3, 2.5-fold; Na v 1.5, 1.6-fold), calcium sequestration protein (sarco/endoplasmic reticulum calcium ATP-ase, 1.4-fold), cytokines (TGFβ1, 1.8-fold; TNF-α, 3.8-fold), and collagen III (3.8-fold) relative to Air (all P &lt; 0.05). Nicotine did not enhance PG:VG’s effects on gene expression relative to PG:VG-alone (all P &gt; 0.05), and cigarette smoke did not significantly affect any of the transcripts assayed (all P &gt; 0.05 vs. Air). Conclusions: E-cigs may induce cardiac electrical and structural remodeling via their primary vehicle ingredients and irrespective of nicotine or flavors. Such effects could precipitate fatal arrhythmia, stroke, and/or heart failure. Electronic nicotine delivery systems may pose cardiac risks distinct from conventional cigarettes.
Abstract 16688: CZT Equilibrium Radionuclide Angiography (ERNA) Detects Improvements in Right Ventricle Size and Function for Pulmonary Arterial Hypertension Participants Intensifying Therapy
Authors: Allison Light, Daniel Lachant, Maria Mackin, Ronald Schwartz, R. James White
Journal: Circulation (2018)

Introduction: Pulmonary Arterial Hypertension (PAH) is associated with pruning and vasconstriction of the pulmonary arteries, resulting in right ventricular (RV) failure and death. RV size and function are among the most powerful prognostic predictors for disease outcomes and can change in response to therapy. However, obtaining quantitative RV information remains challenging with echocardiography, while cardiac MRI remains expensive, claustrophobic, and relatively less accessible. Hypothesis: CZT ERNA is a simple and readily available cardiac imaging technique that will measure changes in RV size and function for PAH participants intensifying therapy (RVEF, RVEDV, RVESV). Methods: D-SPECT (Spectrum Dynamics) CZT-ERNA was performed on 24 participants using low dose (approximately 10 mCi Tc-99m TCO4 - ; ~2.5 mSv), 10 minute imaging protocol: 12 were imaged just prior to starting or intensifying therapy and again 6 months later (Active), and 12 age- and sex-matched controls on stable therapy were imaged twice within a 3 week period. Additionally, 6 minute walk distance, laboratories (including NTproBNP) and WHO functional class were assessed at the time of each scan. All scans were processed using Cedars Sinai QBS automatic software; we did manual re-processing when chamber separation was poor or extra-cardiac activity was substantial (n=22/40 scans). Results: All 24 participants completed two scans; four (2 Active, 2 control) were excluded from paired analysis due to low intensity images on one scan (of a pair), and one Active participant was excluded due to clinical worsening requiring hospitalization. There were no adverse events related to imaging. RVEF (45% ± 3.5 vs 55% ± 4.2; p=0.008) and RV stroke volume (89mL ± 10.3 vs 108mL ± 12.3; p=0.03) improved in the active group but were stable in the control group (RVEF= 58% ± 3.7 vs 56% ± 5.0; RVSV=108mL ± 12.9 vs 116mL ± 16.6). A participant with particularly striking improvement is illustrated below. Scan times were 10 minutes with total testing time between 60-90 min. Conclusions: CZT-ERNA is quick, easy and seems effective for obtaining quantitative measures of the RV in PAH.
Abstract 16771: Patient Selection for Therapies to Prevent Major Adverse Limb Events
Authors: Marc P Bonaca, Robert P Giugliano, Patrice Nault, Bejamin M Scirica, Terje R Pedersen, Deepak L Bhatt, Anthony C Keech, Robert F Storey, P. Gabriel Steg, Marc Cohen, Erica M Goodrich, Sabina A Murphy, Marc S Sabatine, David A Morrow
Journal: Circulation (2018)

Introduction: Recently medical therapies have shown benefit in reducing major adverse limb events (MALE) including acute limb ischemia (ALI), urgent revascularization for ischemia, and ischemic amputation in patients with atherosclerotic vascular disease. Defining predictors of MALE may facilitate patient selection for application of novel therapies. Hypothesis: Clinical characteristics can be used to develop a risk score that will predict MALE Methods: Clinical characteristics independently predictive of ALI were identified among 3,985 patients with PAD randomized to placebo in TRA 2°P-TIMI 50 and were used to develop a risk score (c-statistic 0.82). This score was prospectively validated in 7,053 and 13,723 placebo patients from the PEGASUS-TIMI 54 and FOURIER trials respectively. Risk in each trial was evaluated stratified by the investigational treatment (vorapaxar, ticagrelor, or evolocumab). Results: In the broad PAD placebo population of TRA 2°P-TIMI 50, seven independent predictors of ALI with relative risks ranging from 1.69 to ~10 fold were identified including claudication, prior peripheral revascularization or amputation, ankle brachial index ≤ 0.5, heart failure, low body weight, elevated CRP and ASA monotherapy and assigned a point score.There was a gradient of MALE risk in placebo treated patients from 0.1% to 19.7% with increasing score (p&lt;0.0001; Figure, Top). When validated in PEGASUS-TIMI 54 and FOURIER, discrimination remained high (c-statistic of 0.81 in both datasets). A risk of 4 generally correlated to an annualized risk of MALE of ~ 1% (1.1% TRA2P-TIMI 50, 0.93% PEGASUS-TIMI 54, 1.2% FOURIER). A score &lt;4 identified patients at low risk of MALE, whereas those with a score ≥ 4 had greater baseline risk and benefit of randomized therapy (Figure, Bottom). Conclusions: A simple risk score can identify patients at greater risk of MALE who derive greater absolute reductions with effective therapies.