tbuckley/cabot-search huggingface dataset:
Abstract 4143876: Endothelial Cell Gene Expression Profiling Demonstrates Inflammatory Activation In Young Adults Who Use Electronic Cigarettes Alone And In Combination With Combustible Cigarettes
Authors: Ross Okazaki, Yuxiang Zhou, Syed Husain Rizvi, Erika Minetti, Robert Weisbrod, Rachel Keith, Naomi Hamburg
Journal: Circulation (2024)

Background: Traditional combustible cigarette (combustible) use induces endothelial dysfunction accelerating cardiovascular disease progression. Young adults frequently use electronic cigarettes (e-cig) that is linked to impaired endothelial cell (EC) function. We aimed to use EC gene expression analysis to explore altered pathways across patterns of tobacco product use. Methods: Healthy adults aged 18-45 who regularly use e-cig (sole or dual), combustible, and non-use controls were with forearm vein EC biopsy and magnetic bead purification. EC total RNA was isolated and profiled on a NextSeq sequencer. Samples with transcript integrity number (TIN) &lt; 10 were removed, genes were filtered with edgeR::filterByExpr, and analyzed with DESeq2. Differentially expressed genes (DEGs) comparing each use group to the non-use group were defined as log 2 fold change &gt;1 and FDR p&lt;0.01. Pathway analysis was done via Gene Ontology database and analyzed using over-representation analysis with log 2 fold change &gt;1 and p&lt;0.05 and selected based on experimental observation. Results: 64 adults were recruited with a mean age 26±7 years and 34% female. After exclusion of samples not meeting TIN-quality standards, 44 samples were available for analysis sole e-cig (N=13), dual use (N=7), combustible (N=10), non-use (N=14). Each use group revealed multiple DEG compared to non-use (Figure): sole e-cig (50 DEG), dual use (18 DEG), combustible (65 DEG) with 28 DEG shared between sole e-cig use and combustible use suggesting similar patterns of altered EC phenotype. Upregulation of 4 genes 1L1B, PTPRO RYR2, and CLEC4D was shared across all three use groups suggestive of inflammatory activation. Pathway analysis in e-cig alone use group showed multiple pathways related to inflammation and immunity enhanced compared to non-use. Conclusions: Young adults who use e-cig along display evidence of enhanced inflammatory gene expression in isolated EC suggestive of vascular inflammatory activation. Patterns of altered gene expression with e-cig use demonstrated both shared and distinct components compared to combustible cigarette use. Further work is needed to determine the components in e-cig that contribute to altered EC phenotype.
Abstract 4143988: Activation of TRPA1 with allyl isothiocyanate prevents age-related cardiac diastolic dysfunction
Authors: Chunqi Qian, Zachary Fernandez, Donna Wang, Shuangtao Ma
Journal: Circulation (2024)

While its role in aging processes in mammals is largely unknown, activation of transient receptor potential ankyrin 1 (TRPA1), a sensor for noxious cold and oxidative stress , has been shown to decelerate aging and promote longevity in invertebrate animal models. Our previous study demonstrated that knockout of the Trpa1 gene accelerated age-related cardiac fibrosis and dysfunction in mice. The present study aimed to investigate whether activation of TRPA1 with its selective agonist allyl isothiocyanate (AITC) prevents age-related cardiac remodeling and dysfunction. Male and female 78-week-old aging C57BL/6J mice were randomized to receive either control diet or diet containing AITC (15 mg/Kg) for 26 weeks, and 12-week-old C57BL/6J mice were used as young controls. Transthoracic echocardiography was performed at the end of the experiment and showed that 104-week-old male and female aged mice that received control diet for 26 weeks developed restrictive-like diastolic dysfunction with significantly increased E/A ratio (2.41±0.84 vs. 1.22±0.03, P &lt;0.01) and isovolumetric relaxation time (IVRT, 15.17±1.31ms vs. 10.32±1.81ms, P &lt;0.01) compared to 12-week-old young mice. Remarkably, aged mice on AITC diet showed significantly improved diastolic function with decreased E/A ratio (1.60±0.24 vs. 2.41±0.84, P &lt;0.01) and IVRT (11.75±2.09ms vs. 15.17±1.31ms, P &lt;0.05) compared to aged mice on control diet. In contrast, the left ventricular end-diastolic and end-systolic wall thickness, internal diameter, and volume as well as left ventricular ejection fraction (young mice: 66.30±4.47% vs. aged mice on control diet: 59.49±11.27% vs. aged mice on AITC diet: 65.19±8.32%, P &gt;0.05) were not significantly different among the three groups. Pathologic analyses demonstrated that aged mice on control diet developed increased cardiac collagen I, collagen III, and transthyretin deposition compared to young mice, which were significantly improved in aged mice on AITC diet. Taken together, these results show that aged mice developed restrictive-like cardiomyopathy with remarkable diastolic but not systolic dysfunction, and that chronic activation of TRPA1 with oral AITC prevented age-related cardiac fibrosis, transthyretin deposition, and diastolic dysfunction. These results indicate that TRPA1 may serve as a therapeutic target for age-related heart failure with preserved ejection fraction.
Abstract 4143957: Assessing blood-nerve barrier permeability to nanoparticles over the course of experimental autoimmune neuritis
Authors: Chanpreet Kaur, Maleen Cabe, Kelly Langert
Journal: Circulation (2024)

The acute inflammatory demyelinating polyneuropathy (AIDP) subtype of Guillain–Barré syndrome (GBS) is a debilitating autoimmune peripheral neuropathy. Treatment options are limited to nonspecific immunomodulation and are often ineffective. Systemic or local delivery of several candidate therapeutics have been demonstrated to attenuate the severity of experimental autoimmune neuritis (EAN), an established rat model of AIDP. However, advancement of these findings has been limited due to high doses or impractical routes of administration that are not clinically translatable. While the blood nerve barrier (BNB) normally restricts access of circulating molecules to the endoneurium, during the acute inflammation associated with some peripheral neuropathies, including AIDP, the BNB exhibits increased vascular permeability and enables immune cell infiltration. These pathological changes contribute to disease, but they may also offer a unique opportunity to access the otherwise restricted peripheral nerve microenvironment for therapeutic delivery. In other fields, it is established that circulating particles with favorable size and morphology will passively accumulate in sites with fenestrated vasculature through an enhanced permeation and retention process. In this work, we tested the hypothesis that nanoparticles (NPs) with surfaces modified for prolonged circulation will accumulate in affected nerves in rats with EAN through a similar process. We assessed BNB permeability to intravenously administered small molecules (Evan’s Blue Dye) and spectrally defined NPs (58 and 134 nm polystyrene) over the length of the nerve and the course of EAN. NPs were obtained as commercially available, carboxylated Fluospheres to which we covalently attached poly(ethylene) glycol (PEG) amine using carbodiimide coupling. We also quantified immune cells present in nerve cross sections and compared our findings to naïve rats to determine the correlation between immune cell infiltration, BNB permeability, and NP accumulation. Results demonstrate increased BNB permeability to small molecules at disease onset and permeability to NPs up to 138 nm in size during the intermediate to peak stages of the disease. NP permeability coincides with CD68+ macrophage infiltration.
Abstract 4143806: Long-Term Risks of Cardiovascular Disease in the U.S. Population Based on the American Heart Association PREVENT Equations
Authors: Kamil Faridi, Devesh Malik, Mohammed Essa, Huanhuan Yang, Erica Spatz, Harlan Krumholz, Yuan Lu
Journal: Circulation (2024)

Background: The American Heart Association Predicting Risk of Cardiovascular Disease Events (PREVENT) equations were recently developed to estimate risk of cardiovascular disease (CVD). Long-term risks of cardiovascular disease based on the PREVENT equations in the U.S. population are unknown. Methods: Using data on adults aged 30-79 years from the National Health and Nutrition Examination Survey between 2011 and 2020, we determined long-term risks of total CVD (atherosclerotic cardiovascular disease or heart failure) based on the PREVENT equations. Age-standardized and survey-weighted risk prevalence was determined with further stratification by age group, sex, race and ethnicity. Results: The study population included 14,256 participants representing 160.6 million U.S. adults (mean [SD] age 51.9 [11.2] years, 49.2% women, 66.4% non-Hispanic white, 9.8% non-Hispanic black, 5.7% non-Hispanic Asian and 14.8% Hispanic). Among adults aged 30-79 years, 9.6% had existing CVD and 20.2% were CVD-free but had intermediate or high (≥7.5%) 10-year risk of CVD. The prevalence of CVD-free US adults with low or borderline (&lt;7.5%), intermediate (7.5-19.9%) and high (≥20%) estimated 10-year CVD risk was 65.6%, 18.8%, and 4.3% for men and 74.7%, 14.3% and 2.8% for women, respectively. Among adults 45 years and older, men and Black or Hispanic adults were more likely to be at intermediate or high 10-year CVD risk ( Table ). Among adults 65-79 years, 28.9% had existing CVD and 64.3% were CVD-free but had intermediate or high 10-year risk. Among CVD-free adults 30-59 years, the median 30-year risk of CVD was 17.8% for men and 12.6% for women, respectively. Among all U.S. adults 30-59 years of age, 65.4% were CVD-free with an intermediate or high 30-year risk of CVD and 6.1% had existing CVD. Conclusions: Three in ten U.S. adults aged 30-79 years has an intermediate or high 10-year risk of CVD events, including more than 90% of adults over age 65. Nearly three in four middle-aged adults have an intermediate or high 30-year risk. Men, Black and Hispanic adults were generally higher risk. These findings emphasize the need for more intensive public health efforts to prevent cardiovascular disease in the U.S.
Abstract 4143848: Trends in Ischemic Cardiomyopathy related mortality among older adults in US population: A CDC WONDER database analysis from 1999 to 2020
Authors: Huzaifa Ansari, Muhammad Ammar Samad, Eman Mahboob, Laveeza Fatima, Shurjeel Qazi, Adeel Ahmad, Asad Rahman, Hritvik Jain, Mushood Ahmed, Raheel Ahmed, M Chadi Alraies, mahboob alam
Journal: Circulation (2024)

Introduction: Ischemic cardiomyopathy (IC) is a significant contributor to cardiovascular mortality, especially among older adults in the United States. Understanding mortality trends related to IC can help identify at-risk populations and make informed targeted healthcare strategies. This study investigates IC-related mortality trends and disparities among older adults aged ≥75 years in the US population. Methods: The CDC Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) was used to analyze the National Vital Statistics System data from 1999 to 2020. Deaths with IC as the primary cause of mortality were identified, and results were presented as age-adjusted mortality rates (AAMR) per 100,000 population. Joinpoint regression was used to assess changes in trends and annual percentage change (APC). Results: A total of 186,136 deaths occurred in patients with IC from 1999 to 2020 (AAMR = 42.9, 95% CI: 42.7 - 43.2). Males had higher mortality rates (AAMR = 67.8) compared to females (AAMR = 27.7). Non-Hispanic Whites (NHW) had the highest AAMR (45.2, 95% CI: 45-45.4), followed by Hispanics (29.8, 95% CI: 29.1-30.5), non-Hispanic Blacks (NHB) (29.6, 95% CI: 29-30.1), non-Hispanic American Indian/Alaska Native (NH-AIAN) (29.1, 95% CI: 26.8-31.3). Non-Hispanic Asian/Pacific Islanders (NH-API) had the lowest AAMR (16.9, 95% CI: 16.2-17.6). Regionally, the South had the highest mortality rates (47.8, 95% CI: 47.5-48.2), followed by the Midwest (47.4, 95% CI: 46.9-47.8), the West (36.7, 95% CI: 36.3-37.1), and the Northeast (36.3, 95% CI: 35.9-36.7). Mortality rates were higher in rural areas (44.1, 95% CI: 43.5-44.7) compared to urban areas (36.5, 95% CI: 36.1-36.8). Overall, the AAMR increased from 51.3 in 1999 to 51.9 in 2005, followed by a decline to 31.5 in 2020 (APC: -2.0, 95% CI: -2.2, -1.7). Noteworthy declines in AAMR were observed in both men (APC: -2.0) and women (APC: -2.9) throughout the study (Figure, Panel A). Moreover, significant downward trends were evident in NH-AIAN (APC: -3.5), NHB (APC: -1.2), NHW (APC: -2.7 since 2004), Hispanics (APC: -5.5 since 2016), and NH-API (APC: -2.4) racial groups (Figure, Panel B). Conclusion: Our study reveals disparities in IC-related mortality, highlighting males, NHW, and the residents in the South and Midwest as well as those living in rural areas are at increased risk. Targeted interventions and resource allocation are essential to improve outcomes for vulnerable populations.
Abstract 4143822: Trial emulation comparing percutaneous left atrial appendage occlusion to direct oral anticoagulants in Medicare beneficiaries
Authors: Tianze Jiao, Mohammed Ruzieh, Fanxing Du, Michael Blotner, Andrew Foy
Journal: Circulation (2024)

Background: Percutaneous left atrial appendage occlusion (pLAAO) is widely used procedure as an alternative to oral anticoagulants in patients with atrial fibrillation at increased risk of bleeding or prior bleeding events. The efficacy and safety of pLAAO in real-world Medicare patients remain uncertain. Objectives: To compare to pLAAO to DOACs in Medicare beneficiaries with atrial fibrillation. Methods: We used a 15% sample of Medicare claims data (2015-2019) to identify patients who received pLAAO and compared them to patients who received DOACs using trial emulation design. Relying on propensity score matching, we mimicked randomization and assigned patients to receive pLAAO or DOACs in a 1:3 ratio. Confounders in the propensity score model was selected by domain knowledge and machine learning approach (i.e., high dimensional propensity score). Patients were followed for up to 4 years. The primary efficacy outcome was a composite outcome of stroke, TIA or systemic thromboembolism leading to hospital admission. The primary safety outcome was any bleeding leading to hospital admission. We used a Cox proportional hazards regression model to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes between both treatment groups. Results: We identified 3,647 and 10,941, patients who underwent pLAAO and received DOACs, respectively. The primary composite endpoint was similar between pLAAO and DOACs (0.72%/ year vs 0.72%/ year, HR: 0.98, 95% CI: 0.72 – 1.34), figure 1A. The use of pLAAO was associated with significantly more bleeding (7.48%/ year vs 4.98%/ year, HR: 1.38, 95% CI: 1.24 – 1.54), figure 1B. Consistent with the clinical trials, all-cause mortality was not significantly different between both groups, (9.04%/ year with pLAAO vs 10.00%/ year with DOACs, HR: 0.98, 95% CI: 0.90 – 1.07). Conclusion: We successfully emulated the target trial using Medicare claims data. In Medicare beneficiaries with atrial fibrillation, pLAAO use compared to DOACs did not reduce the risk of stroke, TIA or systemic thromboembolism and was associated with more bleeding. The increase in bleeding events in the pLAAO arm is likely due to high upstream anticoagulant use after the procedure.
Abstract 4143880: Functional characterization of GWAS findings highlights the protective role of REST against atherosclerosis
Authors: Maria Viskadourou, Paula Reventun, Sharjeel Chaudhry, Nunzio Alcharani, Pablo Toledano Sanz, Carlos Villapudua Gastelum, Gabriel Lopez-Cecetaite, Abigail Fennell, Roujin An, William Osburn, Andrew McCallion, Alexis Battle, Charles Lowenstein, Marios Arvanitis
Journal: Circulation (2024)

Introduction: Genome-wide association studies (GWAS) have identified multiple novel loci that contribute to CAD pathogenesis, but the mechanisms of these associations remain largely unknown. Research Question: This study aims to functionally characterize the association between the chromosomal GWAS locus for 4q12 and CAD. Methods: We combined computational methods with in vitro assays and mouse models to study REST. Results: A meta-analysis of expression quantitative trait locus (eQTL) data and multi-trait colocalization across atherosclerosis-relevant cell types revealed that the CAD-associated 4q12 locus regulates the expression of REST, a transcriptional repressor, in human aortic endothelial cells (HAEC). This analysis identified two enhancer variants as candidate causal variants for the GWAS association. CRISPR interference confirmed that the rs6853156 variant regulates REST expression in inducible human endothelial cells. Pathway analysis in HAEC after REST silencing indicated that epithelial-to-mesenchymal transition was the most upregulated pathway. Endothelial-to-mesenchymal transition (endMT) was validated in HAEC after REST silencing, as evidenced by rt-qPCR, western blot, and immunofluorescence. Consistently, REST silencing increased endothelial permeability and migration in vitro. CUT&amp;Tag sequencing, jointly analyzed with RNA-sequencing, highlighted L1CAM and its interactors as the most significant gene-set directly affected by REST in the endothelium. L1CAM, a known endMT activator, was expressed in HAEC only upon REST silencing and direct binding of REST to its promoter was confirmed. Simultaneous silencing of L1CAM and REST in HAEC inhibited the upregulation of mesenchymal genes and the enhanced migration induced by REST silencing. Pcsk9-overexpressing mice with an endothelial-specific knockout of Rest exhibited increased atherosclerotic plaque formation in their aortas, with increased macrophage and lipid deposition within the plaque after 16 weeks of high-fat diet exposure compared to littermate controls. Conclusion: In summary, our data reveal the novel role of REST in atherosclerosis as a repressor that functions to constitutively inhibit endMT and protect against atherosclerosis.
Abstract 4143819: The Cardiotoxic Effect of Androgen Deprivation Therapy on the Genome of Men Diagnosed with Prostate Cancer
Authors: McKay Mullen, Avirup Guha, Neal Weintraub, Priyanshu Nain, Abigayle Simon, Omar Elsayed, Harikrishnan Hyma Kunhiraman, Ryan Harris
Journal: Circulation (2024)

Background: Prostate cancer (PC) is the second leading cause of cancer-associated mortality among men. In addition, cardiovascular disease (CVD) is the most common cause of death in men with prostate cancer who survive chemotherapy. Conventional chemotherapy is often paired with androgen deprivation therapy (ADT) to prevent metastasis. Although ADT has increased cancer survival rates, the presence of CVD has increased substantially. From an epidemiological perspective, genetic diversity is related to disease predisposition; however, the causal factors remain unknown. Thus, this study sought to (1) evaluate the cardiotoxic effect of ADT using drug screening on differentiated cardiac stem cells, and (2) determine whether affected genes identified in the cell experiment were present in samples collected from men with PC before and following ADT. Methods: First, induced pluripotent stem cells (iPSCs) from 4 men were differentiated into endothelial cells and cardiotoxicity screening was conducted by comparing the gene response of ADT treated and untreated cells using RNA seq and gene ontology. Next, 19 men with PC were enrolled for the human experiment, and blood samples were collected at baseline, and 4 and 12 weeks following ADT. O-link proteomics was performed at all time points to determine overlap between biomarkers associated with increased CVD risk during ADT identified in the cell experiment. Results: The iPSC RNA seq data identified 301 genes that were significantly altered by ADT. Specifically, in the ADT treated cell lines, there was overexpression ( p &lt;0.001) among members of the cyclin-dependent kinase (CDK) and transforming growth factor (TGF) families when compared to the untreated cells. In the human samples, there was an increase in the normalized plasma expression of CDK1 (0.428±0.9 to 1.036±1.0; p =0.133) and TGFBR2 (0.789±0.6 to 1.128±0.6; p =0.058) from baseline to 12 weeks, respectively. Discussion: CDK and TGF, genes known to play a role in CVD, were upregulated following ADT in both cell and human experiments. Different CDKs have been linked to various aspects of heart disease. Similarly, TGFβ isoforms are known to be upregulated and activated in myocardial diseases, playing an important role in regulating the heart phenotype and function. Therapies to reduce CDK and TGF isoforms represent a novel approach to decrease the CVD risk associated with ADT in men with prostate cancer; however, future studies are certainly warranted.
Abstract 4143847: CRISPR screening identifies critical factors regulating DNA damage response in human cardiomyocytes under oxidative stress
Authors: Masayuki Kubota, Masamichi Ito, Seitaro Nomura, Norihiko Takeda, Issei Komuro
Journal: Circulation (2024)

Introduction: Our previous studies have shown that sustained activation of the DNA damage response (DDR) in cardiomyocytes leads to p53/p21 activation and cardiac dysfunction. Although the DDR generally involves molecules in DNA replication and repair pathways, the non-proliferative nature of cardiomyocytes suggests a cardio-specific DDR mechanism. However, our understanding of DDR in cardiomyocytes remains limited. Here, we aim to use CRISPR interference (CRISPRi) knockdown screens to identify genes critically involved in DDR regulation in human cardiomyocytes. We hypothesize that identifying these gene clusters may allow us to develop methods to prevent cardiac dysfunction by suppressing DDR in cardiomyocytes. Methods and Results: We established a human iPS cell line stably expressing dCas9-KRAB, which allows CRISPRi-mediated gene knockdown, and differentiated the cells into cardiomyocytes. The resulting human iPS cell-derived cardiomyocytes (hiPSCMs) showed the achievement of approximately 80% knockdown efficiency after gRNA transfection. We stimulated the hiPSCMs with H 2 O 2 and quantitatively evaluated the expression levels of the DDR markers γH2AX and p21 by immunostaining using the Operetta ® high content imaging system. The DDR markers showed a significant concentration-dependent increase in response to H 2 O 2 administration. For arrayed CRISPRi screening, we constructed a gRNA library targeting 437 DDR-related genes. Using this library, we knocked down each DDR-related gene in hiPSCMs followed by H 2 O 2 stimulation. We quantified the expression levels of DDR markers by calculating the fluorescence intensity ratios relative to control after gene knockdown, and standardized them to calculate Z scores for all 437 genes. The screening successfully revealed the differential impact of each gene knockdown on γH2AX and p21 expression. We identified 71 genes that significantly affected their expression (Z-score &lt; -1 or &gt; 1). Mapping these genes to DDR pathways highlighted the differential impact of gene knockdown within the same pathway, and stratified their importance in cardiomyocytes. Conclusions: Arrayed CRISPR screening using hiPSCMs revealed differential functional significance of DDR-related genes in cardiomyocytes, identifying 71 genes of particularly significant importance. These findings provide a critical understanding of the cardio-specific DDR pathway and important clues for establishing an appropriate method to suppress DDR in the failing heart.