tbuckley/cabot-search huggingface dataset:
Abstract 11618: Serum and Glucocorticoid Inducible Kinase-1 (SGK-1) Activity is Upregulated in Hypertension and Promotes IL-6 Expression to Drive Aortic Macrophage Accumulation
Authors: Adam Brown, SarahRose Hall, Ying xiong, Rupak Mukherjee, Jeffrey A Jones, Jean Ruddy
Journal: Circulation (2021)

Introduction: The serum and glucocorticoid inducible kinase-1 (SGK-1) is a mechanosensitive kinase and it is hypothesized that SGK-1 activity is upregulated with elevated aortic tension to augment pro-inflammatory cytokine expression and promote macrophage accumulation to drive hypertensive remodeling. Methods: Hypertension (HTN) was induced in C57Bl/6 mice with AngiotensinII (AngII) infusion (1.46mg/kg/day x21days, n=4). Terminal procedure included blood pressure (SBP) quantification, aortic diameter (AoD) assessment, and harvest of infrarenal aorta. Abundance of SGK-1, pSGK-1, and the mature macrophage marker F4/80 was determined by immunoblot. The spontaneously hypertensive BPH/2 mice were also utilized and assessed for SBP, AoD, and target proteins (n=4). A subset of animals had systemic infusion of EMD638683, a selective SGK-1 inhibitor (2.5mg/kg/day x 21 days, n=4). Aortic VSMCs were subjected to 12% biaxial cyclic stretch for 3 and 12 hours +/- EMD638683 (10μM) with subsequent QPCR for IL-6 and MCP-1 expression. Statistical analysis included two-way ANOVA across treatment groups with significance at p&lt;0.05. Results: C57Bl/6+AngII mice and BPH/2 mice had significant elevation in SBP (p&lt;0.05) without change in AoD. The pSGK-1/SGK-1 and abundance F4/80 were increased in both models of HTN (p&lt;0.05) and decreased with systemic EMD638683 (p&lt;0.05), with no change in SBP. IL-6 expression was upregulated in VSMC that had Stretch for 3hrs (1.64 + 0.22 fold; p&lt;0.05) or 12hrs (1.99 + 0.33 fold; p&lt;0.05), and at both timepoints EMD638683 significantly inhibited IL-6 expression (p&lt;0.05 vs respective Stretch). MCP-1 expression was unchanged after 3hr Stretch, but it was significantly elevated following 12hr Stretch (2.05 + 0.38 fold; p&lt;0.05), and inhibited by EMD638683 (p&lt;0.05). This data suggests a biomechanical link between aortic VSMC mechanotransduction and cytokine production to promote macrophage accumulation, mediated in-part by SGK-1 activation. Conclusions: Mechanical stimuli can elevate SGK-1 activity and increase pro-inflammatory cytokine production to accumulate macrophages, which may lead to proteolytic aortic remodeling. Therefore, SGK-1 may represent a novel target to abrogate hypertensive aortic inflammation.
Abstract 9976: New Risk Factors for Improved Identification of Coronary Artery Disease Risk in Type 2 Diabetes by Substituting Paraoxonase 1 Activity for HDL Cholesterol in Atherogenic Ratios
Authors: Abdolkarim Mahrooz, Ahad Alizadeh, Omeh farveh Khosravi-asrami, Neda Mohmmadi, Adele Bahar, Neda Mohmmadi
Journal: Circulation (2021)

Introduction: HDL cholesterol (HDL-C) may not always represent the HDL function. This study was conducted to help predict the risk of coronary artery disease (CAD) in patients with type 2 diabetes (T2D) based on substituting paraoxonase 1 (PON1) as an important enzyme in HDL function for that of HDL-C in the atherogenic ratios LDL-C/HDL-C and log (TG/HDL-C). Methods: A total of 274 subjects undergoing diagnostic coronary angiography in this study; 92 without significant CAD and 182 with severe CAD. The hydrolysis rate of phenylacetate as a PON1 substrate was spectrophotometrically measured in kinetic mode. The area under the ROC curve (AUC) was calculated to quantify the overall discriminative capacity of the variables. Results: ROC analyses showed that LDL-C/PON1 (AUC=0.66, p=0.02) and log (TG/PON1) (AUC=0.65, p=0.019) had higher predictive powers compared with LDL-C/HDL-C (AUC=0.55, p=0.221) and log (TG/HDL-C) (AUC=0.57, p=0.121) for CAD characterization in T2D patients. Also, AUCs of LDL-C/PON1 (AUC=0.74, p=0.014) and log (TG/PON1) (AUC=0.67, p=0.057) were higher than those of LDL-C/HDL-C (AUC=0.51, p=0.469) and log (TG/HDL-C) (AUC=0.53, p=0.364) for predicting CAD in T2D patients with HbA1c ≥7%. The multiple regression analysis with adjustments for gender, age, BMI, duration of T2D, metformin and statin therapy indicated that LDL-C/PON1 [adjusted OR=1.1 (0.99,1.23), p=0.085] and log (TG/PON1) [adjusted OR=3.76 (0.94,14.89), p=0.058] were independently predictors of CAD in T2D patients. Conclusions: New cardiometabolic biomarkers using PON1 provide an incremental predictive value compared with those using HDL-C in identifying subjects at increased risk for CAD among patients with T2D and poor glycemic control. This study sought to exploit the lipoprotein-related biomarkers of CAD from a more effective perspective in T2D. Our findings may help develop clinically cost-effective and functional laboratory measurements to evaluate HDL function.
Abstract 13642: Mortality and Readmissions Following Pericardiectomy
Authors: Blair Warren, Qais Radaideh, Hussein Daoud, Pajjuru Venkat, Ryan Walters, Venkata Alla
Journal: Circulation (2021)

Introduction: Pericarditis is a relatively common cause of chest pain and is the most common pericardial syndrome in clinical practice. Pericardiectomy is the treatment of choice for patients with chronic or recurrent pericarditis refractory to medical therapy. However, perioperative morbidity and mortality rates for pericardiectomy remain high. Several factors, such as etiology, duration of disease, patient functional status, and operator/center experience, can impact outcomes. Objectives: In this study, we explore the national trends in perioperative complication rates, in-hospital mortality, readmission rates, and impact of center volumes on these endpoints in patients undergoing pericardiectomy. Methods: Using the Nationwide Readmissions Database (NRD), we identified patients who underwent isolated pericardiectomy from 2010 to 2018. Year-over-year trends in mortality and readmission rates were assessed using orthogonal polynomial contrasts, with non-linear trends evaluated as needed. Multivariable logistic regression models were constructed to identify independent predictors of mortality and readmission. All analyses accounted for NRD sampling design and were performed using the SAS v. 9.4 with a p &lt; .05 to indicate statistical significance. Results: A total of 23,230 hospitalizations for pericardiectomy were identified during the study period. Median age was 59 years and 44% were female. In-hospital mortality was 5.3%, median length of stay was 7 days, and 18% were readmitted within 30 days. While rates were relatively consistent early on, between 2015 and 2018, there was a slight increase in the hospitalizations for pericardiectomy, decrease in in-hospital mortality and an uptick in 30 day all-cause readmission rates. Advanced age, higher comorbidity index, and lower annual facility pericardiectomy volume were independent predictors of in-hospital mortality. Conclusion: Isolated pericardiectomy rates have remained largely constant with relatively small changes in in-hospital mortality and 30-day readmission rates over the last decade. Advanced age, facility pericardiectomy volume, and the Elixhauser Comorbidity Index are independent predictors of surgical mortality.
Abstract 12839: A Standardized and Regionalized System of Care Network for Cardiogenic Shock: Insights From the Inova-Shock Registry
Authors: Behnam N Tehrani, Matthew W Sherwood, Carolyn Rosner, Pramita Baghchi, Alexander G Truesdell, Hooman Bakhshi, Abdulla Damluji, mehul desai, Shashank Desai, Kelly C Epps, Michael Flanagan, Raghav Gattani, Leonard Genovese, Edward Howard, Nasrien Ibrahim, Aditya Kasarabada, Jamie Kennedy, James Lantry, Hala Moukhachen, Araba Ofosu-Somuah, Kathleen Petro, Mitchell Psotka, Xaioxiao Qion, Liam Ryan, Eric Sarin, Palak Shah, Ramesh Singh, Shashank Sinha, Alan Speir, Daniel Tang, Timothy Welch, Karl Young, Christopher Defilippi, Christopher M O'Connor, Wayne B Batchelor
Journal: Circulation (2021)

Introduction: Recent studies have demonstrated improved short-term outcomes with cardiogenic shock (CS) at centers using standardized protocols. Whether these benefits may be extended across systems of care networks is unknown. Objective: To investigate clinical characteristics &amp; short-term outcomes of CS patients initially managed at spoke hospitals &amp; transferred, &amp; those admitted directly to the hub. Methods: Observational study of 520 consecutive CS patients (1/3/2017-12/31/2019) treated in a regionalized network of 34 spoke hospitals across 600 sq miles. Presenting location, clinical characteristics, mechanical circulatory support (MCS) use &amp; outcomes were compared. Multivariate logistic regression was employed to determine factors associated with 30-day mortality. Results: Fifty five percent (n=287) initially presented to a spoke. They were more likely to have CS due to acute myocardial infarction (50.5% vs 31.8%; p &lt; 0.01) &amp; be supported initially with an IABP (32.1% 17.2%; p &lt;0.01). They were also more likely to require escalation to Impella + VA-ECMO at the hub. Hub patients had higher index lactates (2.7 vs 2.3 mg/dL; p =0.04). No differences were seen between the hub and spoke cohorts in regard to 30-day mortality (39.1% vs 36.4; p=0.60), major bleeding (19% vs 23%; p=0.23), stroke (9.4% vs 7.0%; p=0.33), &amp; 30-day readmissions (24% vs 21%; p=0.53) (Figure 1) Independent factors associated with 30-day mortality were age, diabetes, baseline lactate &gt; 2.0 mg/dL &amp; index SCAI shock stages D &amp; E. Initial presentation to a spoke was not (aOR 0.81; 95% CI 0.49-0.38; p =0.38 ) Conclusions: Despite differences in CS etiology and initial MCS use, the hub and spoke cohorts had similar 30-day mortality &amp; associated short-term outcomes. Creating a regionalized system of CS care across a multi-hospital network with dedicated protocols &amp; expedited transfer algorithms may provide similar benefits for patients initially presenting to either hub or spoke shock care centers.
Abstract 14293: Automated Arrhythmia Detection in HiPSC-Derived Cardiac Cell Sheet Models for Drug Testing and Disease Modeling
Authors: Michal Landesberg, Irit Huber, Amira Gepstein, Gil Arbel, Lior Gepstein
Journal: Circulation (2021)

Introduction: The use of human-induced pluripotent stem cells (hiPSC) derived cardiomyocytes may bring a unique value for drug testing and disease modeling applications. In this project, we developed an automatic and robust arrhythmia detection tool that enables recognition of early-after-depolarizations (EADs) and reentrant activity (spiral waves) in hiPSC-derived cardiac tissue models. Methods and Results: hiPSCs were differentiated into cardiomyocytes, seeded as large-scale hiPSC-derived cardiac cell-sheets (hiPSC-CCSs), loaded with a voltage-sensitive dye, and optically mapped. Arrhythmias were induced either spontaneously, using pacing interventions, or following drug applications. We examined two algorithms to detect spiral wave arrhythmias: optical flow (OF) and dominant frequency (DF). OF enables flow detection through spatial analysis of local velocity vectors (Fig.1 a-d). DF maps depict the frequency with the highest energy in each pixel (Fig.1 e-f). Spiral waves were readily detected by both approaches by the presence of significant diversity in both the frequencies maps (DF) and in the velocity angles (OF). Moreover, in DF maps, the core of the spiral wave (singularity point) could be identified as pixels displaying high dominant frequency as compared to values in other parts of the specimen. (Figure 1). Finally, EADs could be detected using a curve-fitting approach (Fig.1g). Figure 1: (a-d) Consecutive optical map frames (a, c) and velocity vector maps (b, d) of normal (a, b) and a spiral wave (c-d) propagations. (e-f ) DF maps of normal (e) and spiral wave (f) propagations. (g) EAD detection in red. Conclusion: Automatic algorithms were developed to enable robust detection of arrhythmic activity (EADs and spiral waves) in a hiPSC-based cardiac tissue model. This novel approach may bring a unique value to arrhythmia mechanistic studies, high throughput drug screening, and disease modeling.
Abstract 9896: Demographics and Complications According to Amyloidosis Subtypes Light Chain Amyloidosis and Hereditary Transthyretin Amyloidosis
Authors: Jennifer Ma, Sarah Ream, Tayana Rodriguez, Alejandro Sarabia-Gonzalez, Luis Alvarado, Alok Dwivedi, Debabrata Mukherjee
Journal: Circulation (2021)

Introduction: Amyloidosis is a multi-system disorder characterized by accumulation of misfolded proteins. The more common types are light chain amyloidosis (AL) and hereditary transthyretin amyloidosis (ATTR). We assess the demographics and complications of AL and ATTR subtypes for prompt recognition and treatment of this clinical entity. Methods: Our retrospective observational study analyzed the 2016 - 2018 National Inpatient Sample Databases for demographics (age, race, and gender), comorbidities (diabetes, hypertension, heart failure (HF), liver disease, pulmonary disease, coronary artery disease (CAD), and outcomes renal failure (RF), end-stage renal disease (ESRD) and mortality based on ICD-10 codes. Proportions were calculated, and unadjusted and adjusted associations of covariates according to amyloidosis subtype were determined using weight adjusted relative risk regression analyses. Results: Of the total population, 0.17% (N=34,894) had amyloidosis. 733 patients were AL+, 118 ATTR+, and 34,043 were AL-, ATTR-. ATTR was more common in blacks, in older individuals and in males and had more CAD. However, HF, renal failure, ESRD (19.4% vs 2.54%, p&lt;0.0001) and mortality (6.6% vs 5.9%, p=0.0003) was higher with AL type. Conclusions: Black individuals, older age and male gender were more often associated with ATTR subtype. Though CAD was more prevalent in ATTR, AL had more frequent and severe complications including heart failure, renal failure, ESRD and significantly higher mortality. There is a need for more effective therapies for AL type amyloidosis.
Abstract 13801: Predictive Value of Apical Sparing on Echocardiography for Cardiac Amyloidosis
Authors: James W Guo, Celeste Witting, Aakash Bavishi, Madeline Jankowski, Kameswari Maganti
Journal: Circulation (2021)

Introduction: In prior studies of patients with left ventricular thickness, the 2D speckle tracking strain echocardiography (STE) finding of relative apical sparing of longitudinal strain (RALS) was associated with a high sensitivity and specificity for diagnosing cardiac amyloidosis (CA). Use of STE is increasing, but the positive predictive value (PPV) of RALS for identifying CA among other etiologies in a large, contemporary patient population is unknown. Hypothesis: While RALS will still carry high predictive value for diagnosing CA, a significant proportion of patients will have other identifiable etiologies. Methods: We retrospectively reviewed 97 patients with RALS (defined as strain ratio ≥ 2.0) on echocardiography between June 2017 and June 2020 who had workup for CA, with cardiac MRI, 99m Technetium-pyrophosphate scan, serum/urine protein electrophoresis, and/or biopsies. These patients were then categorized into 4 groups relative to suspicion for CA (confirmed, suspicious, unlikely, ruled out). Patients without CA (unlikely/ruled out) were screened for comorbidities, including potential etiologies of RALS. Results: Of the 97 patients included, 40 (41%) were women and 39 (40%) were black. 17 (18%) had confirmed and 8 (8%) had suspicious CA while 72 (74%) had unlikely or ruled out CA. Of the confirmed cases, 10 (10%) were diagnosed with TTR amyloidosis and 7 (7%) were diagnosed with AL amyloidosis. The PPV of RALS for CA was 26% (25/97). Among the 72 patients with RALS without CA, 17 (24%) had no comorbidity, 4 (6%) had chronic kidney disease (CKD), 17 (24%) had hypertension (HTN), 16 (22%) had CKD and HTN, 2 (3%) had a malignancy treated with chemotherapy, 1 (1%) had aortic stenosis (AS), and 15 (24%) had multiple comorbidities (Figure 1). Conclusions: In a patient population with non-selective use of STE, the PPV of RALS for CA was 26%. Given the increasing use of STE, recognition of other etiologies of RALS should be noted.
Abstract 13282: Oxygen Uptake and Cardiac Output Exhibit Delayed Recovery After Maximum Incremental Ramp Exercise in Patients With Exercise Pulmonary Hypertension
Authors: Rohan R Bhat, Mark Schoenike, Anastasia M Christ, Robyn Farrell, Liana Brooks, Jennifer E Ho, Rajeev Malhotra, Greg Lewis
Journal: Circulation (2021)

Introduction: In individuals with dyspnea on exertion (DOE) and suspected exercise pulmonary hypertension (exPH), oxygen uptake (VO 2 ), cardiac output (CO), peripheral oxygen extraction (Ca-vO 2 ), and mean pulmonary artery pressure (mPAP) have been well characterized during incremental exercise but less is known about the kinetics of post-exercise recovery patterns. Hypothesis: Exercise recovery cardiac output kinetics are slowed in patients with exPH. Methods: Upright maximum incremental ramp cycle ergometry cardiopulmonary exercise testing with invasive hemodynamic monitoring and serial blood gas measurements during exercise and recovery was performed in 50 consecutive patients referred for evaluation of DOE of unclear etiology. VO 2 , arterial and venous oxygen content (Ca-vO 2 ), Fick cardiac output, and mPAP were analyzed from rest, peak exercise, and 2 minutes post-exercise. ExPH was defined in a consistent manner with recent consensus statements (ΔmPAP/ΔCO &gt;3.0 mmHg/L/min) from rest to peak exercise. Results: Among 50 patients with DOE, [62% female, Age 61.7±11.8, BMI 30.7±8.2] 2-min post-exercise VO 2 was -56±11%, CO: -22±19%, Ca-vO 2 :-42±15% compared to peak exercise values. The % fall in CO at 2min was significantly lower in the 26 patients with exPH compared to the 24 patients without exPH (Table). The average mPAP remained elevated at 2 min post-exercise (&gt;20mmHg) in exPH despite normal average resting values. Conclusions: Patients with exPH demonstrate slowed CO recovery kinetics in conjunction with persistent PAP elevation 2-min post-exercise. Persistent elevation in blood flow through the pulmonary circuit at a time conducive to non-invasive assessment of PAP (i.e. by echocardiography) may lend itself to non-invasive detection of exercise-PH in patients undergoing evaluation of dyspnea on exertion.
DDRE-31. MITOCHONDRIAL TRAFFICKING AS A TARGET FOR GBM THERAPY
Authors: Javier Lepe, Christopher Douglas, Naomi Lomeli, Kaijun Di, Bhaskar Das, Daniela Bota
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (WHO Grade IV glioma) is the most aggressive brain cancer. The current standard of care treatment includes surgery, radiation, and chemotherapy. Tumor recurrence is almost inevitable as less than 50% of patients survive more than two years. The low survival rate poses a dire need to develop an effective therapy for GBM patients. GBM cells are resistant to treatment, as they activate their DNA damage response mechanisms to overcome the effects of radiation and temozolomide (TMZ) treatments. Recurrent tumors can arise from slow cycling and self-renewing stem/tumor-initiating cells resistant to radiation and TMZ. No second-line therapy was proven to prolong survival after TMZ failure. Magmas (Mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) is a subunit of the TIM23 complex regulating precursor protein trafficking into the mitochondrial matrix. Magmas is encoded by pam16, known to be upregulated in human pituitary adenomas, prostate cancer and GBM. Previous studies have demonstrated that Magmas negatively regulates the stimulatory activity of Pam18, which in turn stimulates the ATPase activity of mitochondrial heat shock protein 70 (mtHsp70). No small molecules targeting Magmas are in clinical use. We developed a novel small molecule inhibitor (BT9) that has been specifically designed to inhibit Magmas binding to Pam18. BT9 induces apoptosis through cleavage of caspase-3, reduced mitochondrial respiration and glycolysis. Our recent findings also demonstrate that BT9 treatment reduced protein trafficking of Lon protease into the mitochondrial matrix. Pretreatment of glioma cells with BT9 sensitizes cells to radiation treatment and enhances the TMZ activity. BT9 can cross the blood-brain-barrier and improve survival in intracranial glioma PDX models. BT9 has potential therapeutic value by directly dysregulating mitochondrial function in GBM, enhancing radiation and chemotherapy response, and improving survival in a relevant animal model.
Abstract 13125: The Role of FXR1 and Cellular Senescence in Vascular Pathology
Authors: Cali Corbett, Amanda St Paul, Tani Leigh, Sheri E Kelemen, Rachel Okune Okune, Michael Autieri
Journal: Circulation (2021)

Introduction: Despite the advent of stents, intimal hyperplasia subsequent to vascular interventional procedures remains a major obstacle to success. Vascular smooth muscle cells (VSMC) play a critical role in the development and pathogenesis of intimal hyperplasia indicative of restenosis; therefore regulation of gene expression in VSMC represents a logical intervention point to attenuate this syndrome. FXR1 is a muscle-enhanced RNA binding protein and expression is increased in injured human and mouse arteries. We have shown that modulation of FXR1 levels affects abundance and stability of inflammatory transcripts in VSMC, suggesting that FXR1 is a negative regulator of inflammation. This drives our hypothesis that FXR1 is involved in mitigating vascular disease and acts as a crucial regulator of inflammatory and proliferative mRNA in VSMC. Approach/Results: Because FXR1 expression is increased in injured arteries, we have developed a novel VSMC-specific conditional knockout mouse (FXR1 VSMC/VSMC ). In a carotid artery ligation model of intimal hyperplasia, FXR1 VSMC/VSMC mice have significantly reduced neointima formation (p&lt;0.001) post-ligation compared to several controls. To determine the mechanism of these effects, we knocked down FXR1 in human VSMC by siRNA and observed decreased proliferation (p&lt;0.05) as well as an increase in beta galactosidase (p&lt;0.05) and gamma H2AX (p&lt;0.01) staining compared with controls, indicative of senescence. Senescent cells exhibit phenotypic changes called the senescence associated secretory phenotype (SASP) with characteristic gene expression leading to increased inflammation in the tissue microenvironment. RNA sequencing demonstrated a decrease in abundance of cell cycle control genes. This was validated by actinomycin D RNA stability assays, and further qPCR analysis showed an increase in abundance of SASP-related mRNA with FXR1 depletion. VSMC knockout of FXR1 via Cre adenovirus in mouse cells validated these results. Summary &amp; Conclusions: Our results are the first to suggest that in addition to destabilization of inflammatory transcripts, FXR1 may stabilize cell cycle related genes in VSMC, and absence of FXR1 leads to induction of a senescent phenotype and reduction of intimal hyperplasia.
The NPM-ALK Oncogenic Kinase Suppresses CGAS-Sting-Associated Anti-Tumor Immune Responses through STAT3 Activation in Anaplastic Large Cell Lymphoma (ALCL)
Authors: Ioanna Xagoraris, Georgia Kokaraki, Christina Plastira, Konstantina Stathopoulou, Vasiliki Leventaki, Elias Drakos, Jeffrey Medeiros, Anders Österborg, George Z. Rassidakis
Journal: Blood (2021)