tbuckley/cabot-search huggingface dataset:
Abstract 13926: Air Pollution and Pulse Wave Velocity in Patients With Hypertension
Authors: Sadeer Al-Kindi, Robert D Brook, Mirela A Dobre, Mahboob Rahman, Jackson T Wright, Sanjay Rajagopalan
Journal: Circulation (2021)

Introduction: Ambient air pollution has been linked with increased cardiovascular risk, yet the mechanisms of this are incompletely understood. We sought to investigate the linkage between ambient particulate matter (PM 2.5 ) and pulse wave velocity (PWV), a marker of arterial stiffness, in the systolic blood pressure intervention trial (SPRINT). Methods: A subset of SPRINT participants underwent PWV measurements at baseline, and annually through 3 years using the Sphygmocor CPV® system and were linked with ambient PM 2.5 using participant address at study entry. Spearman’s correlations and linear regression analyses were performed to investigate the relationship between PM 2.5 , baseline PWV, and change in PWV through year 3. Results: A total of 517 participants were included (259 to standard BP, and 258 to intensive BP). Mean PM 2.5 was 9.5±1.8 μg/m 3 and mean baseline PWV was 10.7±2.7 m/s. Over 3 years, PWV increased by a mean of 0.27 m/sec from baseline (P&lt;0.001). There was no correlation between PM 2.5 and PWV at baseline (rho=0.01, P=0.84) or year 1 (rho=0.04, P=0.38). PM 2.5 , however, significantly correlated change in PWV between baseline and year 2 (rho=0.23, P&lt;0.001), and between baseline and year 3 [ΔPWV 0-3 ] (rho=0.26, P&lt;0.001). The association between PM 2.5 and ΔPWV 0-3 was similar in the intensive (rho=0.29, P&lt;0.001) and standard BP arms (rho=0.25, P&lt;0.001). After adjusting for age, sex, race, study randomization, Framingham risk score, smoking, prevalent cardiovascular disease, and eGFR, PM 2.5 remained associated with ΔPWV 0-3 (β 0.37 per 1 μg/m 3 of PM 2.5 , standard error 0.06, P&lt;0.001). Among participants living under the national air quality of 12 μg/m 3 , there was no change in PWV over 3 years (ΔPWV 0-3 0.13 m/s, P=0.26) while participants living above the NAAQS threshold experience significantly increased PWV over 3 years (ΔPWV 0-3 1.3 m/s, P&lt;0.001), P=0.001 between PM 2.5 &lt;12 vs ≥12 μg/m 3 . Conclusions: SPRINT participants who live in areas with higher ambient air pollution (PM 2.5 ) levels experienced larger increase in PWV over 3 years, without a significant impact of intensive BP lowering strategy. Arterial stiffness should be investigated as a mediator of air pollution-related cardiovascular risk.
Multiplexed rapid technologies for sexually transmitted infections: a systematic review
Authors: Angela Karellis, Faheel Naeem, Suma Nair, Sneha D Mallya, Jean-Pierre Routy, Jacqueline Gahagan, Cédric P Yansouni, John Kim, Nitika Pant Pai
Journal: The Lancet Microbe (2021)

Multiplexed technologies for sexually transmitted infections offer a convenient diagnostics option to screen, confirm, and treat multiple pathogens simultaneously. Due to scarce published real-world diagnostic performance data, we did a systematic review. Two reviewers searched major databases for data published between Jan 1, 2009, and April 20, 2020, and abstracted and analysed sensitivity and specificity data from 24 studies, which assessed 17 multiplex rapid nucleic acid amplification test platforms and seven multiplex immunochromatographic devices. Overall, these studies evaluated 19 sexually transmitted infections in 26 126 individuals. High sensitivity and specificity were shown for rapid nucleic acid amplification platform tests and immunochromatographic devices, with performance varying by pathogen, device, seropositivity, and subpopulation screened. As most devices yielded more than 95% sensitivity and specificity, immunochromatographic tests and rapid nucleic acid amplification test platforms can be advised for screening and confirmatory use. These highly accurate devices are appropriate for integrated, rapid screening initiatives for sexually transmitted infections to screen and treat many of these infections simultaneously, for antimicrobial stewardship, and for disease elimination programmes.
Abstract 11214: Ibrutinib Decreases Mitochondrial Oxidative Phosphorylation and Metabolic Gene Expression in Atrial-Like Engineered Heart Tissue
Authors: Julie H Rennison, Beth Lovano, Laurie Castel, Cheryl R Lin, Feixong Cheng, Rohit Moudgil, Jonathan D Smith, John Barnard, Mina K Chung, David R Van Wagoner
Journal: Circulation (2021)

Introduction: Ibrutinib is a Bruton kinase inhibitor which treats many hematological malignancies, but also precipitates atrial fibrillation (AF). The precise mechanism(s) remain to be elucidated. Hypothesis: We hypothesized ibrutinib treatment would decrease mitochondrial function and metabolic gene expression in human inducible pluripotent stem cell-derived atrial cardiomyocytes grown as atrial-like engineered heart tissues (aEHTs). Methods: aEHTs were treated with vehicle or 1 μM ibrutinib daily, for 72 hours. Oxidative phosphorylation was assessed (n=5/group) using an Oroboros Oxygraph. Gene expression was evaluated by RNAseq (n=3/group). Results: Oxidative phosphorylation in the presence of complex I and complex II substrates, and maximal oxidative capacity, was decreased in ibrutinib-treated aEHTs compared to vehicle (Panel A). Subunit expression of complex I (NDUFA6, NDUFA9, NDUFS1, NDUFS2, NDUFS4, ND3, ND4, ND5, ND4L), complex II (SDHA, SDHB, SDHD), complex III (UQCR10, UQCRB, UQCRC1, UQCRC2, UQCRFS1), and complex IV (CO2, COX10, COX7A2, CYCS) was decreased. Ingenuity Pathway Analysis of genes differentially expressed identified TCA Cycle and Glycolysis I (Panel B), pathways that provide reducing equivalents to the electron transport chain, as pathways that were decreased by ibrutinib. These changes were accompanied by decreased AMPK Signaling, including key metabolic regulators (PRKAA2, PRKAB2, PRKAG2, SIRT1, and PPARGC1A), and Calcium Signaling. Tumor protein (TP53), nuclear protein 1 (NUPR1), and erb-B2 receptor tyrosine kinase (ERBB2) were identified as top upstream regulators. Conclusions: Ibrutinib treatment decreased oxidative phosphorylation and gene expression of electron transport chain subunits and key modulators of atrial metabolism. Together, these data identify metabolic pathways that are altered by ibrutinib in aEHTs and metabolic regulators that could be targeted for AF therapeutic intervention.
Abstract 10188: Sotatercept Phase 3 Program Design and Rationale: A Novel Treatment for Pulmonary Arterial Hypertension
Authors: Ioana R Preston, David Badesch, H A Ghofrani, Simon Gibbs, Mardi Gomberg-maitland, Marius Hoeper, Vallerie McLaughlin, Rogerio Souza, Aaron B Waxman, Barry Miller, Jonathan Lu, John Butler, Marc Humbert
Journal: Circulation (2021)

Introduction: PAH is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Sotatercept acts as a reverse remodeling agent proposed to rebalance anti- and pro-proliferative signaling based on pre-clinical models of PAH. Clinical efficacy and safety of sotatercept are being studied in the Phase 2 PULSAR and SPECTRA studies. Sotatercept will be further investigated in a Phase 3 clinical program comprised of 4 studies to establish efficacy, safety, and its potential value on top of background therapy across the spectrum of PAH. Methods: Sotatercept will be administered at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously every 21 days. All participants will be on background PAH therapy. The efficacy/safety of sotatercept in patients with WHO FC II/III will be assessed in STELLAR (NCT04576988), a double-blind, placebo-controlled, randomized study. The primary endpoint is change in 6MWD from baseline to week 24. A secondary endpoint is multicomponent improvement (MCI), defined as meeting all the following at week 24 vs baseline: ≥30m increase in 6MWD, decrease in NT-proBNP ≥30% or maintenance/achievement of &lt;300 ng/L, and WHO FC improvement or maintenance of WHO FC II. The effects of sotatercept on PAH patients diagnosed within 6 months of screening, with WHO FC II/III, and at intermediate- and high-risk will be studied in HYPERION (NCT04811092), a randomized, double-blind, placebo-controlled study with a primary endpoint of time to clinical worsening. Sotatercept will also be assessed in PAH patients with WHO FC III/IV at high-risk in ZENITH (NCT04896008), a double-blind, placebo-controlled, randomized study evaluating time to first confirmed morbidity or mortality event. Participants transitioning from parent PAH sotatercept clinical studies will further be evaluated for long term safety/tolerability in SOTERIA (NCT04796337), a long-term follow up study. Results: HYPERION, ZENITH and SOTERIA are active, and STELLAR is recruiting, with a target enrollment of 284 participants. Conclusion: The robust Phase 3 clinical program has the potential to further characterize the efficacy and safety of sotatercept across a broad spectrum of patients with PAH and provide a novel treatment option.
Abstract 14286: Crosstalk Between Methylglyoxal and Acetylation Modifications on Actin, Myosin, and Myosin Light Chain Proteins Affects Sarcomere Functionality
Authors: Christine E Delligatti, Maria Papadaki, Thomas Martin, Jonathan A Kirk
Journal: Circulation (2021)

Diabetes affects ten percent of Americans. Risk of developing heart failure in these patients is doubled, independent of coronary artery disease and hypertension. However, the mechanistic connection between these two diseases is poorly understood. We have shown one connection is likely due to methylglyoxal (MGO), a highly reactive glycolysis product that can irreversibly modify lysine and arginine residues, a process called glycation. Moreover, we found MGO glycation of the myofilament decreased both calcium sensitivity and maximum calcium activated force (Fmax). Here, we hypothesized that MGO may also negatively impact function by competing for lysine residues that would otherwise be targets for acetylation, which has been shown to be beneficial to cardiac function. Using non-failing human left ventricular (LV) myocardial tissue that had been exposed to acute treatment of MGO (500 μM) or vehicle and subsequently treated with a high dose of acetic anhydride in acetonitrile (300μM) overnight, we found that compared to the vehicle treated samples, MGO inhibited overall acetylation, suggesting that these two PTMs do compete for a subset of lysine residues in the heart. Next, we compared mass spectrometry data sets from diabetic humans, MGO treated mouse myocytes, and acetylated myocytes to identify the specific overlapping residues that acetylation and glycation compete for. This analysis identified multiple sites of crosstalk on actin, myosin, and myosin light chains - proteins essential for normal contractile function. Our preliminary data support a contractile consequence to this crosstalk. Incubation of mouse LV isolated skinned myocytes with acetic anhydride in acetonitrile (300μM, overnight) increased both calcium sensitivity and Fmax. However, exposure to MGO first (500μM) blocked these beneficial functions acetylation (300μM, overnight) in mouse myocytes. Together, we believe these data demonstrate that glycation and acetylation do compete for residues in the myofilament, and that glycation is capable of blocking the beneficial functional effects of protein acetylation. If these results are confirmed and extended in vivo, they could have important consequences in diabetes and in the utility of using HDAC inhibitors clinically.
Abstract 10858: Comparison of Clinical Effect of Living Alone Between Urban Area and Rural Area in Patient with Acute Coronary Syndrome
Authors: Mitsuhiro Takeuchi, Tomotaka Dohi, Tatsuya Fukase, ryota nishio, Norihito Takahashi, Hirohisa Endo, Hideki Wada, Shinichiro Doi, Tsuboi Shuta, Yoshiteru Kato, Manabu Ogita, Iwao Okai, Hiroshi Iwata, Shinya Okazaki, Kikuo Isoda, Satoru SUWA, Katsumi MIYAUCHI, Tohru Minamino
Journal: Circulation (2021)

Background and Objective: Living alone is reported as an independent risk factor for worse clinical outcomes after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Manifestations of psychological stress in patients living alone is reported to be associated with subsequent cardiovascular events. The impact of living alone on the psychological factors of patients may be differ depending on their living environment. However, comparison of the effects of living alone in different living environment on the prognosis of patients with ACS has not been reported. Purpose: The aim of the study was to compare the effect of living alone on clinical outcomes in patients with ACS between urban and rural area. Methods: Data from a multi-center, observational study of consecutive ACS patients who underwent emergency PCI between January 2012 and December 2016 were analyzed. The clinical endpoint was major adverse cardiovascular events (MACE) which defined as composite of cardiovascular death, ACS, and stroke. Results: In this study, 1349 patients were enrolled and divided into two population according to their living environment; urban area (n=417), and rural area (n=932). 87 patients (20.9 %) in urban area, and 169 patients (18.1 %) in rural were living alone. There were no significant differences in baseline characteristics between the living alone and the living together group in both urban and rural area. During a median follow-up period of 2.1 years, Kaplan-Meier curves showed the living alone group had higher risk of MACE than the living together group in urban area (log-rank, p=0.01). On the other hands, no significant differences were shown in the incidences of MACE between two groups in rural area (p=0.86). After adjustment for other covariates, the living alone was significantly associated with MACE (hazard ratio [HR], 2.83; 95 % confidential interval [CI], 1.16-6.91; p=0.02) compared with the living together in urban area. However, in rural area, the living alone group was not significantly associated with MACE (HR, 1.02; 95 % CI, 0.66-1.57; p=0.92) compared with the living together group. Conclusion: Living alone was significantly associated with worse clinical outcomes after emergency PCI of ACS in urban area but not in rural area.
Abstract 12414: 3D Fusion of MRI Mechanical Activation, Cardioinsight Electrical Activation, and Fluoroscopic Lead Location for CRT
Authors: Kenneth C Bilchick, Pim Oomen, Mohamad Abdi, Randoph Setser, Frederick Epstein, Jeffrey Holmes
Journal: Circulation (2021)

Introduction: 3D image integration can help achieve personalized medicine for patients undergoing device therapy for heart failure, such as cardiac resynchronization therapy (CRT). Hypothesis: Electrical mapping data and mechanical activation from cardiac magnetic resonance (CMR) integrated with live fluoroscopic data will provide complementary information to optimize CRT procedures. Methods: Ten patients underwent cardiac CT and electrical mapping with the CardioInsight 252-electrode vest (Medtronic) during CRT implantation using a 3D-capable fluoroscopy system (Artis zeego, Siemens) and a 3D image integration software prototype (Guide-CRT, Siemens). A myocardial mechanical activation map based on strain from CMR Displacement Encoding with Stimulated Echoes (DENSE) and an electrical activation map from CardioInsight were fused with fluoroscopic images using Guide-CRT. Results: In a representative patient with LBBB and QRS duration 140 ms, integrated 3D maps of electrical and mechanical activation with the fluoroscopic lead location are shown for right/left anterior oblique (RAO/LAO) and anterior-posterior (AP) views (Figure). While the area of late mechanical activation is centered at about 3 o’clock on the mitral annulus, a slightly more anterolateral and smaller focus of late electrical activation is noted on the CardioInsight maps (Figure). Furthermore, more basal activation data is possible with the electrical maps, as strain imaging typically starts below the mitral valve. While a middle LV electrode (LV2-4) was chosen for CRT pacing based on the CMR map, the more proximal and anterolateral LV electrode could have been chosen based on the electrical map. Conclusions: Multimodality mapping and 3D fusion of mechanical activation, electrical activation, and lead position provide important information regarding electromechanical coupling and the choice of the optimal pacing location.
Abstract 12203: Sotatercept Analog RAP-011 is More Effective Than Sildenafil in Improving Pulmonary Hypertension and Reducing Right Ventricular Hypertrophy in a ZSF1 Rat Model of Heart Failure With Preserved Ejection Fraction
Authors: Sachindra R Joshi, Jun Liu, Patrick Andre, Ravi Kumar, Gang Li
Journal: Circulation (2021)

Introduction: Pulmonary hypertension (PH) due to heart failure with preserved ejection fraction (PH-HFpEF) is the most prevalent form of WHO Group 2 PH but lacks effective treatment options. We previously found that sequestration of activins and growth differentiation factors with the sotatercept analog RAP-011, an activin receptor type IIA-Fc fusion protein, reverses pathological remodeling of pulmonary arteries and the right ventricle (RV) in experimental models of pulmonary arterial hypertension (PAH, Group 1 PH). This strategy of selective multi-ligand neutralization offers a promising new approach for treating patients with PAH and is under active clinical evaluation (PULSAR, SPECTRA, and STELLAR). Here, we compared the cardiopulmonary effects of therapeutic treatment with RAP-011 to those of sildenafil in a rat model of PH-HFpEF. Methods: PH was induced in adult male obese ZSF1 rats by a single subcutaneous injection of SU5416 (100 mg/kg). To model the timeline of diagnosis and treatment for Group 2 PH patients, we initiated treatment with RAP-011 and sildenafil 8 weeks post SU5416 administration—at which point RV dysfunction is prominent—and continued treatment for 8 weeks. RV systolic pressure (RVSP), pulmonary artery acceleration time (PAAT), RV hypertrophy, and tricuspid annular plane systolic excursion (TAPSE) were evaluated by right heart catheterization and echocardiography following the 8-week treatment regimen. Results: Obese ZSF1 rats treated with SU5416 displayed significantly increased RVSP (P &lt; 0.0001) and decreased PAAT (P &lt; 0.0001). RAP-011 treatment fully reversed changes in RVSP (P &lt; 0.0001) and PAAT (P &lt; 0.0001), whereas sildenafil treatment improved RVSP by 19% (P &lt; 0.05) and PAAT by 36% (P &lt; 0.001). Treatment with RAP-011, but not sildenafil, normalized RV hypertrophy (P &lt; 0.0001) and increased TAPSE (P &lt; 0.0001). Conclusions: Therapeutic treatment with the sotatercept analog RAP-011 exerted beneficial cardiopulmonary effects in a ZSF1 rat model of PH-HFpEF that were significantly greater than those produced by sildenafil, fully normalizing PH and RV hypertrophy and improving RV function. These findings support evaluation of sotatercept in patients with PH-HFpEF (Group 2 PH).
QOLP-06. THE CHALLENGE OF FACING A NEW MALIGNANT GLIOMA DIAGNOSIS: PATIENT EXPERIENCES LEARNING ABOUT THEIR ILLNESS AND COMMUNICATING WITH THEIR PROVIDERS IN THE NEURO-ONCOLOGY CLINIC
Authors: Michelle Mesa, Emilia Kaslow-Zieve, Lara Traeger, Jennifer Temel, Deborah Forst
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Patients with newly diagnosed malignant gliomas (MG) face the sudden and unexpected news that they have a terminal neurological illness. However, little is known about these patients’ experiences learning about their illness and communicating with their oncology providers. METHODS We conducted semi-structured interviews with patients with MG who had recently completed chemoradiation, to explore patient-clinician communication and evaluate how patients process information about their diagnosis. We excluded patients with marked cognitive dysfunction, with eligible patients required to have a Mini-Mental Status Exam score of 24/30 or greater. We terminated enrollment once we reached thematic saturation, after a total of 9 patient interviews. We thematically analyzed qualitative data to describe patterns common to the patients’ experiences. RESULTS Most patients were male (6/9, 66.7%), with median age of 55 years (range 26-72) and had a diagnosis of glioblastoma (6/9, 66.7%). The majority of patients described a positive experience communicating with their providers, noting that information was delivered clearly, and visits were not rushed. Despite this, patients found it difficult to absorb and process the large volume of new information, particularly in the setting of their shock and dismay about the diagnosis and their ongoing neurological deficits. Emergent themes included concerns about the impact of the disease on their loved ones, struggles in coping with uncertainty, and worries about preserving their quality of life and functioning. Additionally, patients described their efforts to balance their knowledge about their poor prognosis with their desire to maintain hope, with many patients expressing a goal to “beat the odds” or exceed expectations with respect to their survival. CONCLUSION Although patients with newly diagnosed MG describe effective communication with their providers, they face many challenges coping with their terminal diagnosis. Supportive interventions aimed at this population are needed.
Abstract 13021: Post-Myocardial Infarction Differences in Cardiac Histopathologic Phenotypes Across Clinical Categories
Authors: Meghna Gaddam, Sarah Kim, Ashwin Sunderraj, Arjun Sinha, Don Lloyd-jones, Edward B Thorp, Jon W Lomasney, Matthew J Feinstein
Journal: Circulation (2021)

Introduction: Defining tissue-level phenotypic factors occurring in people with different clinical profiles may yield insights into pathogenesis of post-MI cardiac dysfunction. Methods: Two trained adjudicators analyzed reports from autopsies performed on patients with clinical diagnoses of MI who underwent autopsy at a large urban medical center between 10/31/2002 and 4/1/2021 (N=275). Standardized criteria were used to extra whether patients had the following histopathological criteria: 1) cardiomegaly; 2) coronary or large artery atherosclerosis; 3) severe coronary atherosclerosis; histopathologic features of 4) remote and/or 5) acute MI; 6) and myocardial fibrosis; and/or 7) myocardial inflammation. Interobserver agreement for histopathologic phenotypes was 0.929. Chi-squared and ANOVA were used to determine differences in histopathologic phenotypes by demographic and clinical variables. A Bonferroni-corrected p-value of 0.001 was used to determine statistical significance. Results: Among patients with clinical diagnoses of MI who underwent autopsy (N=275), not all had evidence of MI observed on histopathology; 185 (67%) had histopathologic evidence of remote MI, 86 (31%) had histopathologic evidence of acute MI (including 50 who had evidence of both acute and remote MI), and 55 (20%) had no histopathologic evidence of prior MI (Table). Patients with MI diagnoses who had chronic inflammatory diseases were significantly more likely than those without chronic inflammatory diseases to have myocardial tissue inflammation at autopsy (78% vs. 23%; p=0.0008). Patients with LVEF &gt;=50% were substantially less likely than those with LVEF &lt;40% and 40 to &lt;50% to have histopathologic evidence of remote MI (51%, 69%, and 87% in each group, respectively; p=0.0002). Conclusion: Chronic inflammatory disease status and LVEF strata were associated with different myocardial tissue-level phenotypes at autopsy among patients with clinical diagnoses of MI.