tbuckley/cabot-search huggingface dataset:
Abstract 11042: New-Onset Atrial Fibrillation After Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis
Authors: Tammy Ryan, Rehman Jinah, Alexander Grindal, Avinash Pandey, Maria Vadakken, Iqbal Jaffer, Jeff S Healey, Emilie P Belley-cote, William McIntyre
Journal: Circulation (2021)

Background: New-onset atrial fibrillation (NOAF) is a common complication after transcatheter aortic valve replacement (TAVR), though estimates of the precise incidence are variable. We sought to quantify the incidence of NOAF after TAVR, explore the associated outcomes and identify predictors for this complication. Methods: Using a broad strategy, we searched Medline, EMBASE and the Cochrane database from 2015-2020 for articles that reported any outcomes of TAVR. We extracted data for studies published prior to 2015 from a previous systematic review (22 studies in total). Reviewers performed screening and data extraction in duplicate. We pooled data using a random effects model with Mantel-Haenszel weighting. Results: We identified 183 studies with 296,986 total participants that reported NOAF from 2008 to 2020. The pooled incidence of NOAF after TAVR was 9.9% (95%CI 8.1-12%). NOAF after TAVR was associated with longer index hospitalization (MD 2.66 days, 95% CI 1.05-4.27), higher risk of stroke (RR 1.65, 95% CI 1.09-2.5) and 30-day mortality (RR 1.76, 95%CI 1.12-2.76). NOAF after TAVR was also associated with increased risk of major or life-threatening bleeding (RR 1.60, 95%CI 1.39-1.84) and new permanent pacemaker implantation (RR 1.12, 95%CI 1.05-1.18). Risk factors for the development of NOAF after TAVR included trans-apical access, pulmonary hypertension, chronic kidney disease, peripheral vascular disease, and severe mitral regurgitation. Conclusions: NOAF is common after TAVR and associated with a longer hospital stay, a higher risk of stroke, major bleeding, mortality and permanent pacemaker implantation. Whether this risk is modifiable requires further study.
Abstract P494: Truncated Titin Protein In Dilated Cardiomyopathy
Authors: Quentin McAfee, Christina Yingxian Chen, Matthew Caporizzo, Michael Morley, Apoorva Babu, Sunhye Jeong, Jeff Brandimarto, Kenneth Bedi, Emily Flam, Joseph Cesare, Tom Cappola, Kenneth B Margulies, Benjamin Prosser, Zoltan Arany
Journal: Circulation Research (2021)

Truncating variations in the gene coding for titin (TTNtv) have been known to cause dilated cardiomyopathy for nearly 20 years. Efforts to detect direct evidence of either haploinsufficiency or dominant negative mechanisms have thus far failed, leaving the mechanism open to controversy. By analyzing a collection of 184 post-transplant human hearts, 22 of which bear TTNtv’s, we show evidence supporting both haploinsufficient (lack of sufficient full length titin to maintain normal cardiomyocyte contractility) and dominant-negative (toxic gain of function due to truncated titin) mechanisms. Using allele specific proteomics as well as epitope specific agarose gel immunoblotting we show that TTNtv are present in human myocardium at the expected molecular weight and bear only the epitopes expected to be present in TTNtv protein. TTNtv associate with the sarcomere bearing insoluble fraction of human myocardium but are more weakly attached to the sarcomere than full length titin, consistent with their lack of thick filament and M-line attachment sites. We further show that DCM hearts bearing TTNtv have less full length titin than non-TTNtv bearing DCM hearts, by both total protein and in ratio to sarcomeric proteins, indicating TTN haploinsufficiency is also present in TTNtv hearts. This unambiguous detection of TTNtv protein in the myocardium of DCM combined with a reduction in full length titin supports a combined dominant negative and haploinsufficient mechanism of pathogenesis of TTNtv induced DCM.
Abstract 9708: Direct Normal Irradiance from Solar Radiation Negatively Correlates With Af Hospitalization in the United States
Authors: Malak Modi, Zoya Mohammad, Ruchi Bhandari, Marjan Boerma, Rakesh Gopinathannair, Brian Olshansky, Paari Dominic
Journal: Circulation (2021)

Introduction: Medical radiation has been linked to increased risk of AF but any association between solar irradiation and AF remains unexplored. Aim: To study the role of solar radiation on AF. Methods: State-wise and county-wise CDC data with AF hospitalization rates in Medicare beneficiaries from 2015 to 2017 was used. Data regarding solar irradiation and other meteorological parameters, specifically, the midpoints of direct normal irradiation (DNI), direct horizontal irradiation (DHI), global horizontal irradiation (GHI), global tilted irradiation (GTI), terrain elevation, sunny hours, clear day and air temperature were collected from publicly available sources for 49 states. Bivariate and multivariable regression were carried out with environmental factors as the independent and AF as the dependent variables. Results: AF hospitalization correlated negatively with DNI [Standardized Beta Coefficient (β) = -0.352, p = 0.013], GHI (β = -0.146, p = 0.316), GTI (β = -0.264, p = 0.067) and terrain elevation (β = -0.590, p = 0.000), whereas DHI correlated positively with AF hospitalization rate (β = 0.480, p = 0.000). Other environmental factors such as sunny hours (β = -0.296, p = 0.046) and clear days (β = -0.198, p = 0.172) negatively correlated with AF hospitalization rates, but air temperature positively correlated with AF hospitalization rates (β = 0.374, p = 0.008). Multivariable regression analysis showed that DHI and DNI independently had a positive and negative correlation, respectively, to AF hospitalization rates after adjusting for potential confounders including age, COPD, hypertension, diabetes and air quality index. A sensitivity analysis with multivariate regression, adjusting for air temperature showed that DNI had a significant negative correlation (β = -0.277, p = 0.000) and DHI had a significant positive correlation (β = 0.370, p = 0.000) with AF hospitalization rates for the counties with five largest cities of each state. Conclusions: DNI (direct radiation without diffusion) negatively correlates with AF hospitalization rate, whereas DHI (rays scattering due to clouds, particulate matter and ozone) has a positive correlation. Further research may shed light on the mechanisms behind solar radiation-induced protection from AF.
Abstract 12124: A Composite Score Summarizing Use and Dosing of Evidence-Based Medical Therapies in Heart Failure: A Nationwide Cohort Study
Authors: Niklas Johansen, Muthiah Vaduganathan, Deewa Zahir, Mona Fiuzat, Ersilia M Defilippis, James L Januzzi, Javed Butler, Christopher O'Connor, William T Abraham, Mitchell Psotka, John J McMurray, Jens-Ulrik Staehr Jensen, Morten Schou, Christian Torp-Pedersen, Lars Kober, Gunnar H Gislason, Tor Biering-Sørensen
Journal: Circulation (2021)

Introduction: As heart failure (HF) therapeutic care becomes increasingly complex, determining optimal medical therapy (OMT) can be challenging. The HF Collaboratory consortium developed a scoring system to assist with standardization of comparing OMT within and across trials. We evaluated the score in the Danish HF population. Methods: In a retrospective nationwide cohort study, we identified all Danish HF patients alive on July 1, 2018. Patients were excluded if they were diagnosed after July 1, 2017 to allow a minimum of 365 days for up-titration of medical therapy. Treatment doses were estimated by analysis of consecutive claimed prescriptions. An integer-based composite medical therapy score (range 0-10) was designed to consider use and dosing of multiple therapies prescribed to each patient ( Panel A ). Risk-adjusted association was assessed between the composite score and subsequent death. Results: In total, 26,779 patients (median age 73y; 32% women) were identified. At baseline, ACEi/ARB was used in 77%, β-blocker in 81%, MRA in 30%, ARNi in 2%, SGLT2i in 2%, and ivabradine in 2%. The median composite medical therapy score was 4 (and was consistently 4 from January 2016-July 2018). During median follow-up of 1.5 years, 3,326 deaths occurred. After accounting for demographics, comorbidities, loop diuretic use, HF diagnosis setting, and time since HF diagnosis, higher composite scores were independently associated with lower mortality (≥median vs &lt;median: aHR 0.73 [0.67-0.78]; p&lt;0.001). In restricted cubic spline analysis based on a fully adjusted Poisson regression model, a graded, inverse association between the score and death was observed; p&lt;0.001 ( Panel B ). Conclusions: Nationwide assessment of therapeutic optimization in HF using a composite medical therapy score was feasible and the score was independently associated with survival. These data suggest that most patients can achieve a score of 4 or more in current clinical care.
TAMI-08. THE CCL2-CCR2 ASTROCYTE-CANCER CELL AXIS IN TUMOR EXTRAVASATION AT THE BRAIN
Authors: Cynthia Hajal, Yoojin Shin, Leanne Li, Jean Carlos Serrano, Tyler Jacks, Roger Kamm
Journal: Neuro-Oncology (2021)

Abstract Although brain metastases are common in cancer patients, little is known about the mechanisms of extravasation across the blood-brain barrier (BBB), a key step in the metastatic cascade that regulates the entry of cancer cells into the brain parenchyma through its selective endothelial barrier. Progress in this area has been impeded by challenges in conducting high spatio-temporal resolution imaging in vivo and isolating factors and cellular interactions directly contributing to extravasation rather than cancer survival and proliferation in the brain tissue. To address these limitations, we engineered a three-dimensional in vitro BBB microvascular model with endothelial cells derived from induced pluripotent stem cells, brain pericytes, and astrocytes, into which we perfused cancer cells to recapitulate their circulation and extravasation at the BBB. With this platform, we revealed that astrocytes play a major role in promoting cancer cell transmigration via their secretion of C-C motif chemokine ligand 2 (CCL2). We found that this chemokine promoted the chemotaxis and chemokinesis of cancer cells via their C-C chemokine receptor type 2 (CCR2), with no significant changes in vascular permeability. These findings were validated in vivo, where CCR2-deficient cancer cells exhibited significantly reduced cancer cell arrest and transmigration in mouse brain capillaries. Our results attest to the translational value of our BBB-on-a-chip model and reveal that the CCL2-CCR2 astrocyte-cancer cell axis plays a fundamental role in extravasation and consequently metastasis to the brain.
CTNI-11. TUMOR-TREATING FIELDS COMBINED WITH SECOND-LINE CHEMOTHERAPY IN RECURRENT GLIOBLASTOMA: A MATCHED RETROSPECTIVE STUDY
Authors: Yonggao Mou, Yang Qun-ying, Cheng-Cheng Guo, Meiling Deng, Yin-Sheng Chen, Xiao-Jing Du, Shao-xiong Wu, Jian Wang, Sai Ke
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Tumor-treating Fields (TTFields) has been approved for patients with newly diagnosed and recurrent GBM. However, TTFields combined with second-line chemotherapy has not been well studied in china. This study aims to explore the efficacy and safety of such combination therapy for recurrent GBM. METHODS Forty-nine patients with supratentorial GBM who failed the standard Stupp treatment from April 2019 to January 2021 in our center were enrolled. Fourteen patients received combination therapy while 35 received second-line chemotherapy alone (temozolomide or CPT-11) as a control. PFS, OS, and adverse reactions were compared. RESULTS There were no significant differences between these two groups in baseline characteristics except the use of anti-angiogenesis drugs which was higher in the control group. The median duration of TTFields was 19 weeks (10.1-43.4) with a median compliance rate of 93.5% (67-97%). The control group had a higher rate of disease progression than the combination group (adjusted HR=2.49, 95% CI: 1.08-5.75, P=0.033). The 6-month PFS rate was 55.6% (95% CI: 26.6%-77.0%) in the combination group, and 29.2% (95% CI：14.9%-45.1%) in the control group (p=0.03). The median OS was 8.6 months (95% CI: 3.9-NE) and 7.1 months (95% CI:5.1-9.8), respectively (HR=1.29, P= 0.56). Skin rash beneath the tranducer arrays was a common adverse event in the combination group (42.6% mild and 14.3% moderate). This condition was easily treated with topical corticosteroids and did not require substantial treatment breaks. CONCLUSION TTFields combined with second-line chemotherapy had significantly less progression rate than chemotherapy alone for patients with recurrent GBM. In addition, the combination therapy was well tolerated.
Cox-2 expression and inflammation in Barretts Esophagus
Authors: Fazal Omar, Omar Al-Subee, Mejia Luis, Violeta Yordanova, Yi Xu, James Hatfield, Nabiha Khoury, Martin Tobi
Journal: Cancer Research (2005)

4861  Cox-2 is overexpressed in Barretts Esophagus (BE) a premalignant condition. However, it also modulates inflammation (INF), not necessarily a concomitant of premalignancy. We prospectively studied Cox-2 expression in 55 patients with BE, BE & IFN, IFN only & normal controls correlating Cox-2 with IFN & tumor markers. Methods: We stained endoscopic biopsy sections of squamous esophagus (Sq), BE, gastro-esophageal junction (GEJ) and fundus (fun) & other sites with a Cox-2 monoclonal; with a marker of the adenoma-carcinoma (Adnab-9) & the de novo pathway (p53), vasculogenic (VEGF), & inflammatory bowel disease (IBD) biomarkers (Tn and Das-1). The slides were pre-graded for INF and BE by a pathologist and intake of NSAIDs (Cox-2 inhibitors)/esophageal irritant drugs (EID) noted. Results: Patient mean age 59.3+12.9 years, 91% male. 29% took NSAID/EID, 5 had BE, 10 BEI VEGF in 44%; Tn 33% & Das-1 23%. There were correlations of intensity between Cox-2 and p53 (r=0.53;p
DDRE-16. DRUG REPURPOSING SCREEN REVEALS GLIOBLASTOMA CELL LINE SUSCEPTIBILITY TO STATINS
Authors: Dylan Harwood, Signe Michaelsen, Filip Mundt, Bjarne Kristensen
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND The standard therapy for glioblastoma patients is tumor resection followed by radiotherapy and temozolomide chemotherapy. Although glioblastoma has been extensively molecularly profiled along with other cancers, this knowledge has not yet been translated into improved survival outcomes. We used a bioinformatics approach to identify potential novel therapeutic strategies for glioblastoma. OBJECTIVES: Comprehensive online datasets which have assessed up to 1376 cancer cell lines in multiple ways were interrogated to identify potential drug candidates for glioblastoma. METHODS Datasets included were from the cancer cell line encyclopedia (mRNA expression), the Achilles project (cell viability following Crispr-Cas9 knockout) and PRISM (drug treatment). A t-test comparing cell viability of glioblastoma cell lines versus other cancers was used to identify potential drug candidates, followed by the use of multiple statistical tools to investigate potential mechanism of action and status of biomarkers. RESULTS Fluvastatin and pitavastatin produced the most significant effects in glioblastoma cell lines. The anti-cancer properties of statins have previously been attributed to the inhibition of HMG-Coa reductase. Here, we found their effects correlated with erastin, an enhancer of ferroptosis and with gene knockout of UBIAD1, which participates in non-mitochondrial ubiquinone synthesis. These effects were both found in glioblastoma cells and other cancers with a mesenchymal-like phenotype. CONCLUSION Statins appeared to be especially effective against glioblastoma lines and the effect could be linked to ferroptosis and inhibition of UBIAD1. In vitro validation of this finding is ongoing.
Abstract 11928: Perm1 Promotes Cardiomyocyte Mitochondrial Biogenesis and Protects Against Hypoxia/Reoxygenation-Induced Damage in Mice
Authors: Yoshitake Cho, Shizuko Tachibana, Kayla Lam, Yoh Arita, Shamim Khosrowjerdi, Oliver L Zhang, Alex Liang, Ruixia Li, Aleksander Andreyev, Anne N Murphy, Robert S Ross
Journal: Circulation (2021)

Introduction: Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. In contrast, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and ERR induced regulator, muscle 1) that is enriched in skeletal and cardiac muscle and transcriptionally regulated by PGC-1 (Peroxisome proliferator-activated receptor gamma coactivator 1) and ERR (Estrogen-related receptor). The role of Perm1 in the heart is poorly understood and was studied here. Hypothesis: We hypothesize that Perm1 plays a crucial role in cardiac metabolism and ischemic injury. Methods: To directly study the effect of Perm1 on cardiomyocyte oxidative metabolism, Perm1 or LacZ (control) was expressed in mouse neonatal cardiomyocytes (NCM) using an adenovirus system. We analyzed genes and proteins that play essential roles in cardiac metabolism. NCM were also subjected to hypoxia/reoxygenation (H/R). Finally, to study the mechanism underlying Perm1’s action, we investigated the effect of Perm1 on the activity of ERR and the interaction of Perm1 and PGC-1α. Results: Cardiac Perm1 expression was down-regulated in mice with heart failure and human patients with dilated cardiomyopathy. Perm1 selectively regulated PGC-1/ERR targets, such as Ckmt2 and Sirt3. Perm1 interacted with PGC-1α, enhanced activation of PGC-1 and ERRs, and increased recruitment of PGC-1α to the target gene promoters (Ckmt2 and Sirt3), possibly creating a feedforward loop of Perm1 and PGC-1α/ERRs. Perm1 also increased mitochondrial DNA copy number and augmented oxidative capacity in NCM. Moreover, we found that Perm1 reduced cellular damage induced by H/R and mitigated cell death in cardiomyocytes. Conclusions: Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes through PGC-1/ERR and protects cellular damage induced by H/R. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction caused by ischemic injury. An NIH grant, R01HL151239, supports this work (To Y. C. and R. S. R.).
Abstract 11080: A Young Woman with Incessant Left Atrial Tachycardia
Authors: Banveet K Khetarpal, Binna M Chokshi, Sadaf Fakhra, Arjun Gururaj
Journal: Circulation (2021)

Introduction: Left atrial tachycardia (AT) is uncommon and usually does not occur in the absence of congenital heart disease, or prior catheter ablation (CA). Case: A 29-year-old woman with a 2-year history of SVT refractory to metoprolol and no prior CA presented to the emergency department with palpitations. Initial ECG showed a regular, narrow complex, short RP tachycardia, at 180 bpm, insensitive to adenosine and 2 electrical cardioversions. Echocardiogram showed LVEF of 40%. The patient underwent an entirely non-fluoroscopic electrophysiology study using intracardiac echocardiography and electroanatomic mapping (EAM). AT (cycle length 300 ms) was induced by programmed atrial stimulation with isoproterenol infusion. AT was confirmed with ventriculo-atrial dissociation after pacing maneuvers and adenosine administration. Right atrial (RA) activation map revealed early atrial activation in the mid coronary sinus (CS), raising suspicion of a left atrial (LA) origin. LA was accessed via transseptal puncture. The site of earliest atrial activation was in the LA wall inferior to the left inferior pulmonary vein (LIPV) ostium and was successfully terminated with radiofrequency ablation (40 W, 5 to 10 g) (Figure) with no further inducibility. The patient's symptoms resolved after the procedure. Discussion: Left AT usually originates from PVs or the atrial wall. The EAM in this patient showed centrifugal activation consistent with a focal mechanism. Adenosine is generally not helpful in terminating AT but is useful in diagnosis. Rapid conduction across the LA to CS may have given rise to early activation in the mid CS on RA mapping. However, LA mapping revealed that atrial activation was earliest in the LA wall inferior to the LIPV. Conclusion: AT is unusual in young, healthy women. A high index of suspicion to perform transseptal puncture can lead to successful ablation of AT with LA origin. We surmise that the patient’s EF may improve with termination of the tachycardia.
Abstract 10663: Outcomes After Heart Transplantation in Patients with Cardiac Sarcoidosis
Authors: Paulino Alvarez, Rabea Asleh, Hilmi Alnsasra, Ilias P Doulamis, Polydoros Kampaktsis, Sudhir Kushwaha, Alexandros Briasoulis
Journal: Circulation (2021)

Introduction: The number of patients with sarcoidosis requiring heart transplantation (HT) is on the rise. Hypothesis: The aim of this study was to evaluate outcomes of isolated HT in patients with sarcoid cardiomyopathy. Methods: Adult HT recipients were identified in the UNOS Registry between 1990 and 2020. Patients were grouped according to diagnosis. The cumulative incidences for the all-cause mortality and rejection were compared using Fine and Gray model analysis, accounting for re-transplantation as a competing risk. Moreover, we reviewed characteristics and outcomes of all HT recipients with previous diagnosis of sarcoid cardiomyopathy from a single-center. Results: A total of 30,874 HT recipients were included in the present study (n=240 sarcoidosis, n=1,431 non-ischemic restrictive cardiomyopathy, and n=29,203 non-ischemic dilated cardiomyopathy). During a total of 196,985 patient-years, all-cause mortality at the latest follow-up was not significantly different when comparing sarcoidosis to non-ischemic dilated cardiomyopathy (adjusted subhazard ratio [aSHR] 1.4, 95% confidence intervals [CI]: 0.88-2.3, p=0.15) or restrictive cardiomyopathy (aSHR 1.12, 95% CI: 0.65-1.95, p=0.67). Accordingly, multivariable analysis suggested that 1-year mortality was not significantly different between sarcoidosis and non-ischemic dilated cardiomyopathy (aSHR 1.56, 95% CI: 0.9-2.7, p=0.12) or restrictive (aSHR 1.15, 95% CI: 0.61-2.18, p=0.66) cardiomyopathy. Additionally, no differences were observed regarding 30-day mortality after HT. Data from the single-center case review showed excellent long-term outcomes with sirolimus-based immunosuppression. Conclusions: Short- and long-term outcomes after isolated HT do not seem to be inferior in sarcoid cardiomyopathy when compared to common types of non-ischemic cardiomyopathy.
Abstract 13144: 18F-NaF Positron Emission Tomography Imaging Detects Femoral Artery Microcalcification in Patients With Type 2 Diabetes Mellitus and Macroalbuminuria. An Early Marker for Vascular Disease?
Authors: Melanie Reijrink, Judith K Sluiter, Charlotte A Te Velde-Keyzer, Martin H de Borst, Gijs D Van Praagh, Marcel Greuter, Robert A Pol, Jan-Luuk Hillebrands, Peter R Van Dijk, Klaas Hoogenberg, Douwe J Mulder, Riemer Slart
Journal: Circulation (2021)

Background: Although albuminuria is an established risk factor for progression of kidney disease and cardiovascular outcomes, its association with subclinical arterial disease is unclear. [18F]-sod...
Autograft-Absolute Lymphocyte Count Infusion Predicts Survival in Double/Triple Hit Lymphomas Post-Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation
Authors: Luis F. Porrata, David J. Inwards, Stephen M. Ansell, Ivana N. Micallef, Patrick B. Johnston, Jose Villasboas, Jonas Paludo, Svetomir N. Markovic
Journal: Blood (2021)