tbuckley/cabot-search huggingface dataset:
Abstract 11215: Cardiac Resynchronization Therapy via Left Bundle Branch Pacing Vvrsus Optimized Biventricular Pacing with Adaptive Algorithm in Heart Failure with Left Bundle Branch Block: A Prospective, Multi-Center, Observational Study
Authors: Xueying Chen, YANGANG SU
Journal: Circulation (2021)

Objectives: The purpose of our study was to evaluate the feasibility and efficacy of cardiac resynchronization therapy (CRT) via left bundle branch pacing (LBBP-CRT) compared with optimized bi-ventricular pacing (BVP) with adaptive algorithm (BVP-aCRT) in heart failure with reduced left ventricular ejection fraction≤35% (HFrEF) and left bundle branch block (LBBB). Methods: One hundred patients with HFrEF and LBBB undergoing CRT were prospectively enrolled in a non-randomized fashion and divided into 2 groups (LBBP-CRT, n=49; BVP-aCRT, n=51) in 4 centers. Implant characteristics and echocardiographic parameters were accessed at baseline and during 6-month and 1-year follow-up. Results: The success rate for LBBP-CRT and BVP-aCRT was 98.00% and 91.07 %. Fused LBBP had the greatest reduced QRS duration compared to BVP-aCRT (102.61±9.66ms vs 126.54±11.67ms, P&lt;0.001). Higher absolute LVEF and ΔLVEF was also achieved in LBBP-CRT than BVP-aCRT at 6-month (P=0.008,P=0.020) and 1-year follow-up (P=0.021,P=0.015). There was no significant difference in response rate between two groups while higher super-response rate was observed in LBBP-CRT as compared to BVP-aCRT at 6-month(53.06% vs 36.59%, p=0.016) and 12-month(61.22% vs 39.22%, p=0.028) during follow-up. The pacing threshold was lower in LBBP-CRT at implant and during 1-year follow-up(both p&lt;0.001). Procedure-related complications and adverse clinical outcomes including heart failure hospitalization and mortality were not significantly different in 2 groups. Conclusions: The feasibility and efficacy of LBBP-CRT demonstrated better electromechanical resynchronization and higher clinical and echocardiographic response, especially higher super-response than BVP-aCRT in HFrEF with LBBB.
Abstract 11806: CT Measure of Intraparenchymal Vascular Volume in Chronic Obstructive Pulmonary Disease Patients With and Without Pulmonary Hypertension
Authors: Sneha Lakshman, Imama Ahmad, Pietro Nardelli, Ruben San Jose Estepar, Raul San Jose Estepar, George Washko, Farbod Rahaghi
Journal: Circulation (2021)

Purpose: Pulmonary hypertension, despite oxygen therapy, remains a major comorbidity of COPD. Pruning in the form of loss of small vessel fractional volume has been shown to be associated with right heart disease and poor outcomes in COPD. In this investigation we sought to investigate the relationship between this marker and the presence of precapillary pulmonary hypertension by hemodynamic measures. Methods: We conducted an automated search of patients at Brigham and Women’s Hospital with the diagnosis and PFTs consistent with COPD, CT pulmonary angiography and RHC timed within a year. Patients with other forms of lung disease, risk factors for group 1 PH, poor image quality, active lung infection or lung collapse were excluded. All data collection was approved by the IRB at Mass General Brigham (IRB #2018P000419).Using the Chest Imaging Platform ( www.chestimagingplatform.org ) we measured the total vascular volume (TBV), the small (vessels with a cross sectional area &lt;= 5 mm 2 , BV5) and large ( &gt; 5mm 2 , BVg5) for both the arteries and the veins; The small vessel fraction (BV5/TBV) a marker of pruning, and ratio of arterial to venous volumes were also calculated and analyzed using Wilcoxon Rank-sum and modeled using linear regression in R version 4.0.1 Results: Of the Total Cohort (N=44), 17 had precapillary PH (prePH), 12 had PH associated with elevated wedge pressures (pcPH) and the remaining 15 did not meet diagnostic criteria for PH. Patients with prePH had a lower arterial but not venous BV5/TBV (prePH: 0.39 vs noPH: 0.46, p = 0.04) and higher arterial to venous volume ratios for large vessels (1.95 vs 1.38 p = 0.008) compared to patients without PH. In a linear regression models, lower arterial but not venous small vessel fraction continued to be related to mean pulmonary artery pressures after adjustment for age and gender (p = 0.01). Conclusions: In this retrospective study of COPD patients with CT angiography and hemodynamic assessment, decreased small arterial vascular fraction derived from 3D reconstruction of the intraparenchymal vasculature was associated with increased mPAP and was higher in patients with precapillary PH compared to controls.
Abstract 13255: Left Ventricular Structure and Function in Patients With Chronic Kidney Disease Assessed by 3D Echocardiography
Authors: Jacob Christensen, Nino E Landler, Flemming J Olsen, Bo Feldt-Rasmussen, Ditte Hansen, Anne-Lise Kamper, Susanne L Bro, christina christoffersen, Ida Maria M Soerensen, Sasha Saurbrey Bjergfelt, Ellen Linnea L Freese Ballegaard, Eline Seidelin, Tor Biering-Sørensen
Journal: Circulation (2021)

Background: Cardiovascular disease is the leading cause of mortality amongst patients with chronic kidney disease (CKD). This is the first study using 3-dimensional echocardiography (3DE) to investigate associations between adverse changes of the left ventricle, and different stages of CKD. Methods: Participants were recruited from the Copenhagen CKD cohort study and the Herlev-Gentofte CKD cohort study. Patients were stratified according to GFR category (G1+2: eGFR≥60mL/min/1.73m 2 , G3: eGFR = 30-59mL/min/1.73m 2 , and G4+5: eGFR≤29mL/min/1.73m 2 ), and according to albuminuria (A1: UACR&lt;30 mg/g, A2: 30-300 mg/g, A3: &gt;300 mg/g). Echocardiograms were analysed for left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), and global strain measures. In adjusted analysis, eGFR groups were adjusted for confounders and albuminuria category, while albuminuria groups were adjusted for confounders and GFR category. Results: The study population consisted of 662 outpatients with CKD and 169 controls. Mean age was 57±13 years, and 61% were males. Mean LVEF and global longitudinal strain (GLS) were increasingly impaired across eGFR groups: LVEF = 60.1%, 58.4%, and 57.8% ( p =0.013), GLS = -16.1%, -14.8%, and -14.6% ( p &lt;0.0001) for G1+2, G3, and G4+5. LVMi and prevalence of LV hypertrophy increased with albuminuria severity: mean LVMi = 87.9g/m 2 , 88.1g/m 2 , and 92.1g/m 2 ( p =0.007) from A1-3. Adjusted analysis confirmed reduced LVEF in G3 compared with G1+2, and increased LVMi in A3 compared with A1. Conclusion: Increasingly impaired eGFR was associated with adverse changes in LV systolic function, while albuminuria was associated with adverse changes in LV mass assessed by 3DE. Their associations were independent of each other.
Strengthening routine polio vaccination in Afghanistan
Authors: Ayesha Ahmad, Mohammad Haqmal
Journal: BMJ (2021)

We respond to the lifting of the polio vaccination ban in Afghanistan from a humanitarian health perspective.1 The crucial importance of developing protective mechanisms against severe and harsh determinants of health amid legacies of conflict and depletion of healthcare cannot be emphasised enough. Working to provide protection from diseases such as polio is an important humanitarian and peace focused initiative to reframe …
Validation of the Pyruvate Kinase Deficiency Diary (PKDD): A Patient-Reported Outcome Measure for Pyruvate Kinase (PK) Deficiency
Authors: Shayna Egan, Erin Zagadailov, Adrian Jewett, Junlong Li, Feng Tai, Audra Boscoe, David A. Andrae
Journal: Blood (2021)
Abstract 10429: Atrial Pitx2c Overexpression Increased Atrial Arrhythmias with Altered Calcium Handling
Authors: Shunsuke Baba, Toru Akaike, Hiroki Bochimoto, Satoko Shinjo, Susumu Minamisawa
Journal: Circulation (2021)

Introduction: We have previously reported that the atrial cardiomyocyte-specific Pitx2c overexpression impaired sinus node function. It is well known that sinus node dysfunction is associated with atrial fibrillation (AF) and PITX2C increases in patients with chronic AF. Although Pitx2c overexpression in the atrium may be susceptible to atrial arrhythmias, the mechanism is not well understood. Hypothesis: Pitx2c overexpression in the atrium induces atrial arrhythmias with altered calcium handling. Methods: We generated the atrial cardiomyocyte-specific Pitx2c overexpression mice by crossing two types of mice. Then, we examined AF inducibilities, the expressions of genes related to left-right axis determination and AF, and monophasic action potential durations of B6-Tg ( CAG-LSL-Pitx2c ); SLN Cre/+ (overexpression: OE) and B6 (wild type: WT) mice. Results, Conclusions: Pitx2c was up-regulated in the right atrium (RA) of OE than WT mice. AF increased significantly following burst pacing in OE (52%, n=6) than WT (7%, n=9) mice. Furthermore, episodes of atrial arrhythmias such as premature atrial conduction and AF were increased in OE mice. TBX3 , Shox2 and Scn5a were down-regulated, and Kcne1 was up-regulated significantly in the atrium of OE than WT mice (n=8, each group). Especially in the RA of OE mice, Cacna1c and Serca2 , which were calcium regulatory genes, were significantly down-regulated. In addition, we found that monophasic action potential duration was shorter in RA of the OE mice than WT mice. In conclusion, cardiomyocyte-specific Pitx2c overexpression in RA induces atrial arrhythmias with altered calcium handling. The transcription factor Pitx2c promotes electrical remodeling similar to clinical data.
STEM-05. FUNCTIONAL MAPPING REVEALS WIDESPREAD REMODELLING AND UNRECOGNIZED PATHWAY DEPENDENCIES IN RECURRENT GLIOBLASTOMA
Authors: Chirayu R Chokshi, David Tieu, Kevin R Brown, Chitra Venugopal, Lina Liu, Laura Kuhlmann, Martin A Rossotti, Katherine Chan, Amy H Y Tong, Neil Savage, Dillon McKenna, Nikoo Aghaei, Minomi Subapanditha, Muhammad Vaseem Shaikh, Nazanin Tatari, Benjamin Brakel, Omri Nachmani, Vladimir Ignatchenko, Joseph M Salamoun, Peter Wipf, Elizabeth Sharlow, John P Provias, Jian-Qiang Lu, Naresh K Murty, John S Lazo, Thomas Kislinger, Kevin A Henry, Yu Lu, Jason Moffat, Sheila K Singh
Journal: Neuro-Oncology (2021)

Abstract Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses support parallel tumor-intrinsic mechanisms of treatment resistance which rely on acquisition of immunosuppressive capacity, including a defective mismatch repair pathway, ablation of PTEN activity, and a novel combination of de novo mutations in SWI/SNF components. We map a multilayered genetic and functional response to resist chemoradiotherapy and drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel driver of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation and a small molecule inhibitor of PTP4A2 repress axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1) and exploit a genetic dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. We conclude that functional reprogramming drives tumorigenicity and present a dependence on a PTP4A2-ROBO1 signaling axis at GBM recurrence.
Abstract 13552: Mortality Trends in the United States Due to Underlying Rheumatic Heart Disease From 1999-2018
Authors: Mohsin S Mughal, Talha Ahmad, Mohammad Madjid, Ali Ghani, Hasan Mirza, Muhammad Khakwani, Jagpreet Grewal, Khansa Ahmad, Mahboob Alam, najam wasty, Sergio Waxman
Journal: Circulation (2021)

Introduction: Rheumatic heart disease (RHD) is a preventable disease which affects almost 33 million people globally. RHD was estimated to be responsible for 305,000 deaths worldwide and 11.5 million disability-adjusted life years lost in 2015. We investigated the temporal trends of RHD related mortality in the U.S. by using nationwide data. Methods: Death certificate data were retrieved from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (WONDER) database for 1999-2018. WONDER database reports the underlying cause of death across the United States. Mortality for Rheumatic heart disease ICD-10 (I05-I09) which includes rheumatic mitral valve diseases I05; rheumatic aortic valve diseases I06; rheumatic tricuspid valve diseases I07; multiple valve diseases I08; or other rheumatic heart disease I09; as an underlying cause of death were queried from 1999-2018. This study duration was further stratified into five-year periods. Crude mortality rate and age-adjusted mortality rate per 100,000 were calculated with a 95% confidence interval in four U.S census regions. Results: Overall AAMR showed a downward trajectory and declined from 1.3 to 0.9 per 100,000 from 1999 to 2018. AAMR for Northeast (CR-1) declined by 33%; for Midwest (CR-2) declined by 23%; for South declined by 27%, and for West (CR-4) declined by 33%. Crude mortality rate, AAMR, and % deaths are shown in table 1.Temporal trends are illustrated in figure 1. Conclusions: Regional AAMRs for U.S census regions showed a downward trajectory from 1999-2018. These trends suggest the efficacy of of primary and secondary prevention of rheumatic heart disease.
DDRE-35. PRE-CLINICAL ASSESSMENT OF PPRX-1701, A NANOPARTICLE FORMULATION OF 6-BROMO-ACETOXIME, FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Mykola Zdioruk, Tomer Finkelberg, Michal Nowicki, Bin Wu, Yuji Takeda, Antonio Chiocca, Sean Lawler
Journal: Neuro-Oncology (2021)

Abstract We previously showed that derivatives of the Chinese traditional medicine indirubin promote survival in murine glioblastoma models (Williams et al. Cancer Research 2011). However, poor drug solubility hampered further development of this approach. Here we introduce PPRX-1701, a 6’-bromoindirubin acetoxime (BiA) containing drug/polymer nanoparticle formulation which can be injected intravenously at relatively high concentrations. Mechanistically, BiA is thought to act as a broadly selective serine-threonine protein kinase inhibitor, with activity against Src family kinases, GSK-3 and JAK2. Our preliminary data show that intravenous administration of PPRX-1701 is well-tolerated and can reach intracranial murine glioblastoma as assessed by luminescent reporter assays. PPRX-1701 administration leads to improved survival in the GL261 glioblastoma mouse model (median survival 30 days (control), 47 days (treated), p &amp;lt; 0.0001). Treatment with PPRX-1701 was associated with alterations in the tumor immune microenvironment, with reduced Tregs and pro-tumor macrophages, and increased CD8+ T cells. Further preliminary mechanistic studies have shown that PPRX-1701/BiA blocks the expression multiple immunosuppressive molecules in GBM downstream of interferon-g (IFNg) including PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) - a key enzyme in the tryptophan–kynurenine–aryl hydrocarbon receptor (Trp–Kyn–AhR) immunosuppressive pathway. BiA promoted more effective T-cell mediated tumor cell killing using patient derived glioblastoma ex vivo co-culture models. This data supports further development of PPRX-1701 is a candidate immunotherapeutic agent for glioblastoma treatment. Ongoing pre-clinical studies are investigating combination with other relevant therapies.
Patterns of Hematologic Function and Cytokine Release Syndrome Severity in ALL Patients Receiving CAR-T and TCR-T Therapies Using Pooled Clinical Trial Data
Authors: Vibhu Agarwal, Alexandru Socolov, Robert Buderi, Emelly Rusli, Lilia Bouzit, Aniketh Talwai, Yahav Itzkovich, Aaron Galaznik, Jacob Aptekar
Journal: Blood (2021)
Eltrombopag As Initial Monotherapy for Transfusion Dependent Patients with Low to Intermediate Risk-1 Myelodysplastic Syndrome: Single Center Experience
Authors: Yingying Shen, Hangchao Li, Jingjing Xiang, Ni Zhu, Yuzhu Li, Qi Liu, Huijie Dong, Bo Wang, Baodong Ye, Shengyun Lin, Yiping Shen, Dijiong Wu
Journal: Blood (2021)
Abstract MP202: The Effects Of Maternal Hypothyroidism On Fetal And Adult Cardiac Function
Authors: Yijia Li, Guihong Chen, Xiaoying Zhang, Ran Zhao, Steven R Houser, Xiongwen Chen
Journal: Circulation Research (2021)

Objectives: Maternal hypothyroidism (MH), a common clinical condition with a reported prevalence from 2.5% to 13%. MH could have an adverse effect on fetal cardiac development and adult heart function. However, there is a lack of systematic research for its effect on fetal and offspring’s development and cardiac function. This study aimed to determine the impact of MH on fetal and offspring’s organ structural and functional development at different gestation stages and during postnatal and puberty. Methods: MH model had been built through thyroidectomy (TX) with total thyroxine (TT4) under 1ng/dl after surgery. Pups from mice that underwent TX and Sham surgery were named THD (Deficient) and THN (Normal). Times of parturition and miscarriage from TX and Sham groups were recorded. Ultrasound was performed for fetuses and/or offspring to check the gestation, miscarriage, embryo arrest, development, malformation, and cardiac function. At different postnatal days, mice were euthanized for organ development evaluation. Result: TX mice had reduced parturition frequencies and smaller litter size but increased miscarriage frequency and malformed fetuses than the sham group. In addition, THD fetuses had smaller biparietal diameter (BPD) and abdominal circumference (AC) and significantly lower left ventricular ejection fraction (LVEF) on E14.5, but not at E18.5. Tei index, a parameter representing both systolic and diastolic cardiac function, was lower in THD fetuses than in THN fetuses at both E14.5 and E18.5. The cardiac systolic and diastolic function of female TX mice after a 9-month breeding period was also abnormal. The Postnatal T4 level was not significantly different between the two groups. On and after d21 after birth, THD mice had a higher heart weight/body weight ratio and lower LVEF still d21. Conclusion: MH impaired the development and cardiac function of the fetus and young adult. In addition, MH impaired the mother's fertility and depressed cardiac function.
Abstract 11198: Role of Different Lipid Parameters and Lipoproteins on Coronary Microvascular Dysfunction in the Young
Authors: Jindong Wan, Sen Liu, Peng Zhou, Peijian Wang
Journal: Circulation (2021)

Aim: Young with coronary microvascular dysfunction (CMD) have increased cardiovascular morbidity. Particularly, Asian patients with CMD are considerably younger than their Western peers. Blood lipids are traditionally considered risk factors for myocardial infarction (MI) of the elderly. However, little is known about CMD in the young. The purpose of our study was to test the associations between lipids and lipoprotein particles and CMD in the young. Methods: A cross-sectional study was conducted from 2014 to 2020, 1868 young participants were included. CMD was defined as angina but no obstructive coronary disease. All participants had baseline laboratory testing. Lipid parameters, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), small dense low density lipoprotein cholesterol (sd LDL-C), high-density lipoprotein (HDL), non-HDL, TC/HDL ratio, TG/HDL ratio and LDL/HDL ratio were measured. Both low- and high-density lipoprotein cholesterol (LDL-C and HDL-C) subfractions were measured using the Quantimetrix Lipoprint System. Logistic regression analysis was performed to determine associated factors for CMD. Results: Very low-, intermediate-, small dense-, and low- density lipoprotein particles were positively associated with CMD. HDL particles were inversely associated with CMD apart from small HDL. Cholesterol in large HDL was inversely associated with CMD (odds ratio [OR] = 0.75), whereas cholesterol in small HDL was not (OR = 1.08). TG within all lipoproteins, including most HDL particles, were positively associated with CMD. In multiple logistic regression analyses, non-HDL [OR = 1.56 (1.16-1.87)], sd LDL-C [OR = 1.80 (1.21-2.27)], TC [OR = 1.41 (1.25-1.93)], TC/HDL [OR = 1.26 (1.15-1.68)] were significantly associated with CMD. Conclusions: Lipids and lipoproteins showed similar associations with CMD. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with CMD. Non-HDL, sd LDL-C, TC, and TC/HDL were significantly associated with CMD than others. This result should be considered in future clinical lipid-lowering trials and a routine screening for CMD in the young.
Abstract 8860: Influence of Age on In-Hospital and One-Year Mortality in Patients with Electrical Storm
Authors: Cameron Incognito, Kristine Posadas, Jeffrey Hedley, Joshua Parker, Venu Menon, Oussama Wazni, John Rickard, Wai Hong Tang
Journal: Circulation (2021)

Introduction: Electrical storm (ES) carries poor short- and long-term prognosis although there is limited evidence regarding outcomes of ES stratified by age. Objective: Primary outcomes include all-cause in-hospital and 1-year mortality of ES based on four age groups: &lt; 55 years (1), age 55-64 (2), age 65-75 (3), and age &lt; 75 years (4). We hypothesize that older patients (Groups 3, 4) will have worse short- and long-term mortality and higher rates of in-hospital complications. Methods: Single center, retrospective study including patients admitted to the coronary intensive care unit with ES between April 2014-2020. ES was defined as ≥ 3 isolated sustained ventricular arrhythmias (VA) or ICD therapies within 24 hours. Results: Of 214 patients admitted with ES, 44 (20.6%) were Group 1, 56 (26.2%) were Group 2, 70 (32.7%) were Group 3, and 44 (20.6%) were Group 4. The overall mean age was 64 ± 13 years. There was no significant difference between age groups regarding ejection fraction (p = 0.55) or prior history of VA (p = 0.48). There was a higher incidence of prior CAD (p = 0.0057) and worse PAINESD (p &lt; 0.001) in the older groups. There was no significant difference in in-hospital complications between the four groups regarding multiorgan failure (p = 0.11), in-hospital cardiac arrest (p = 0.39), or cardiogenic shock (p = 0.27). There was no difference between the four groups in all-cause (20.5% vs. 12.5% vs. 12.9% vs. 20.5%; p = 0.51) or VA-induced in-hospital mortality (18.2% vs. 8.9% vs. 12.9% vs. 18.2%; p = 0.47). Using Group 1 as reference, only Group 4 had a significant difference in 365-day all-cause mortality (Figure 1; HR 1.94; 95% CI 1.0 - 3.8, p 0.049) but no difference in 365-day VT-free survival (Figure 2; p = 0.51). Conclusions: There is no difference in all-cause or VA-induced hospital mortality between age groups. There was a statistically significant increase in 365-day all-cause mortality between extremes of age, although there was no difference in 365-day VT-free survival.