tbuckley/cabot-search huggingface dataset:
Abstract 4145109: Disturbed Flow (d-flow)-induced Endothelial Senescence-Associated Stemness (SAS): Unveiling the Impact of CD38 and LATS1/2 Depletion on Atherothrombosis Development
Authors: Sivareddy Kotla, Kyung Ae Ko, Jonghae Lee, Abigail Osborn, Weiqing Chen, Venkata Subrahman K Samanthapudi, Rajneesh Pathania, Gilbert Mejia, Oanh Hoang, Keila Carolina Ostos Mendoza, Karla Natalia Mariscal Reyes, Khanh Chau, Jared K Burks, Keri Schadler, Guangyu Wang, Eduardo Chini, James Martin, NHAT TU LE, Junichi Abe
Journal: Circulation (2024)

Background: Atherosclerotic plaques, especially high-risk ones, form in blood vessel regions exposed to d-flow. EC dysfunction induced by d-flow likely contributes to plaque development. In contrast, regions with laminar flow (l-flow) are less susceptible to plaque formation. Although the Hippo pathway is implicated in mechano-transduction, the exact role and molecular mechanisms of LATS1/2 in response to d-flow remain incompletely understood. Methods: We employed endothelial cell (EC)-specific Lats1 and Lats2 knockout mice within a partial left carotid ligation (PLCL) model to simulate disturbed flow conditions. We characterized plaques using imaging mass cytometry (IMC) and sequential immunofluorescence via COMET TM . Results: We investigated the effects of d-flow on YAP activity and LATS1/2 expression. While both l-flow and d-flow activate YAP activity, only d-flow leads to decreased LATS1/2 expression. We induced Lats1/2 deletion in tamoxifen-inducible Lats1 -/- /Lats2 -/- EKO mice. Within 14 days, all mice (27/27) died due to severe systemic edema and increased vascular permeability. In Lats1 +/- /Lats2 -/- EKO mice (LATS1/2-EKO), we observed atherothrombotic lesions characterized by increased EC proliferation and a senescence-associated secretory phenotype (SASP) in vivo . Mechanistically, d-flow reduces LATS1/2 expression, leading to increased CD38 expression. CD38 triggers not only SASP, but also senescence-associated stemness (SAS) via NAD + depletion, dependent on Lamin A but independent of YAP. We also explored the relationship between CD38 and Ki67 in plaques in vivo. We calculated the logarithm of the Ki67:CD38 expression ratio at the single-cell level using IMC/COMET data. Based on the trimodal density distribution of this parameter, we found that in one group, CD38 and Ki67 were linearly co-expressed, and the percentage of LATS1/2-depleted cells in this group exceeded that of wild type (WT) cells, suggesting that CD38’s pro-proliferative effects dominate under LATS1/2 depletion conditions, despite its role in inducing senescence. Lastly, inhibiting CD38 mitigated d EC SAS/SASP, and atherothrombosis under LATS1/2 depletion conditions. Conclusions: Reduced LATS1/2-mediated CD38 expression in response to d-flow leads to an EC response marked by increased SASP/SAS, ultimately contributing to atherothrombosis. While this phenomenon is common in human advanced coronary atherosclerosis, it is not observed in commonly used mouse models of atherosclerosis.
Abstract 4144974: Pulsed ElectRic FiEld versus Cryoballoon to Treat Paroxysmal Atrial Fibrillation (PERFECT-PAF) Randomized Trial: a Periprocedural Clinical and Cost Analysis
Authors: Gian Battista Chierchia, Domenico Della Rocca, Giampaolo Vetta, Michele Magnocavallo, Andrzej Glowniak, Carla Fernandez Barcelo, Vedran Velagic, Juliane Hafermann, Ubong Silas, Luigi Pannone, lorenzo marcon, Alexandre Almorad, Adam Tarkowski, Charles Audiat, Pietro Rossi, Steffen Uffenorde, KAZUTAKA NAKASONE, Gezim Bala, Aleksander Konopka, Ingrid Overeinder, Ioannis Doundoulakis, Saverio Iacopino, Dimitrios Tsiachris, Antonio Sorgente, Andrea Marangoni, Erwin Stroker, Juan Sieira, Andrea Sarkozy, STEFANO BIANCHI, Carlo de Asmundis
Journal: Circulation (2024)

Background: Pulsed ElectRic FiEld versus Cryoballoon to Treat Paroxysmal Atrial Fibrillation (PERFECT-PAF) is an investigator initiated, multicentre, randomized trial on pulmonary vein isolation (PVI) using either a pentaspline pulsed field ablation (PFA) or cryoballoon (CRYO) catheter. Hypothesis: It is of utmost importance to assess both the clinical and economic value of novel ablation technologies to ensure access to therapies that are effective and economically sustainable. Aim: To compare periprocedural safety and costs of PVI via PFA versus CRYO. Methods: Paroxysmal AF patients 18-75 years old were randomly assigned to PFA or CRYO at 6 European Centres. Data regarding clinical management during index hospitalisation, procedural details, and resources used were collected. The primary safety endpoint included procedure- and technology-related adverse events within 7 days post-ablation (e.g., pericardial effusion, persistent (&gt;30 days) or transient (periprocedural) phrenic nerve (PN) injury, vascular complications). Results: A total of 269 paroxysmal AF patients were randomly assigned to undergo PFA (n=134) or CRYO (n=135). Baseline characteristics were similar. Room time (mean ± SD) was 77.1±13.9 min for PFA vs. 97.0±20.4 min for CRYO (+19.9 min, p&lt;0.001). Procedural time was 52.5±11.8 min for PFA and 69.3±18.0 min for CRYO (+16.8 min, p&lt;0.001). Overall periprocedural adverse events were significantly more frequent with CRYO than PFA (+7.4%; p=0.0053). Major adverse events were documented in 1 (0.7%) and 4 (3.0%) patients for PFA and CRYO, respectively (p=0.3703). CRYO-related PN injury, either persistent (n=2; 1.5%) or transient (n=4; 3.0%), was the main determinant of this difference and hindered effective isolation of the right PVs in 3 (2.2%) CRYO cases. The adverse event rate at 7 days was also higher with CRYO than PFA (+5.2%; p=0.036). The total costs per patient within 30 days were 13.7% lower in the PFA group. Conclusion: In paroxysmal AF patients, PFA overcame safety limitations of CRYO with optimal effectiveness, fewer adverse events, and shorter procedural times. Long-term follow-up data will be collected and analysed to further investigate the potential clinical and economic impact of PFA versus CRYO.
Abstract 4144944: Critical Insights for a High-Risk Population: Low Life’s Essential 8 Scores among Post-Operative Coronary Artery Bypass and Percutaneous Coronary Intervention Patients; All of Us Research Program
Authors: Austin Chang, Daniel Won, James Walker, Harrshavasan Congivaram, Ruoqi Li, Anagha Prasanna, Laura Davidson, chris mehta, Donald Lloyd-Jones, S. Christopher Malaisrie
Journal: Circulation (2024)

Background: The American Heart Association’s (AHA) Life’s Essential 8 (LE8) concept serves as a quantitative framework for assessing cardiovascular health (CVH). Post-operative coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI) patients are at high-risk for subsequent cardiovascular events (CVE). However, LE8 scores for post-procedural CABG or PCI patients remain unknown. Methods: Isolated post-operative CABG (n=208) or PCI (n=739) non-institutionalized patients from the National Institutes of Health’s (NIH) All of Us (AoU) Research Program (2017-2022) were included. LE8 scores (range 0-100, higher = better CVH; excluding diet metric) were calculated using methods recommended by the AHA. Physical activity and sleep metrics were derived from patients' Fitbit data, while all other metrics were sourced from electronic health records (EHR). Results: Overall LE8 scores for post-operative CABG (57.9 [95% CI: 56.6-59.2]) and PCI patients (55.3 [54.4-56.1]) were significantly lower than that of the general population (65.9 [65.1-66.7] (p&lt;0.001). Significantly lower LE8 metrics were observed in post-op CABG and PCI patients compared to the general population for the following factors: nicotine exposure (-4.1 vs. -8.3, respectively), sleep health (-19.5 vs. -23.6), body mass index (-9.4 vs. -10.8), blood glucose (-36.5 vs. -35.0), and blood pressure (-13.5 vs. -16.5). Physical activity scores were low for post-op CABG patients (56.6 [52.3-60.8]), PCI patients (54.7 [52.3-57.1]), and the general population (51.6 [53.5-59.7]) (Figure 1A, 1B). Conclusion: Our study indicates that post-op CABG and PCI patients, who are at significantly increased risk for subsequent CVE, exhibit critically low overall CVH as measured by AHA’s LE8 metrics. These findings highlight the urgent need for targeted interventions, with nicotine exposure, physical activity, BMI, blood glucose, and blood pressure identified as key areas for improvement. Since LE8 metrics include behavioral and physiologic metrics associated with CVD risk, further research should focus on effective strategies to address these deficits in post-operative PCI and CABG patients.
Abstract 4145196: The role of extracellular vesicle-mediated interorgan crosstalk in obesity and risk of arrhythmias
Authors: Worawan Limpitikul, Ling Xiao, Emeli Chatterjee, Quanhu Sheng, Saumya Das
Journal: Circulation (2024)

Background: The worldwide prevalence of obesity has increased in the past decades. Obesity is known to be epidemiologically associated with an increased risk of sudden cardiac death (SCD). However, the mechanisms underlying this phenomenon are not completely understood. We hypothesize that the crosstalk between metabolic organs, such as adipose tissue, and cardiac tissues may contribute to cardiac electrical and structural remodeling that ultimately increases the propensity for SCD; and that extracellular vesicles (EVs), lipid membrane-delimited particles containing diverse cargo (protein, nucleic acids, and metabolites), are as potential key mediators of these interorgan communications. Method: Plasma samples were obtained from 5 lean and 6 obese patients without a history of arrhythmias or heart failure (patients were matched by age, sex, and comorbidities). Small EVs (sEVs) were extracted from patients’ plasma and characterized. These sEVs were used to treat human induced pluripotent stem cell-derived ventricular cardiomyocytes (iPSC-vCMs). Action potentials of sEV-treated iPSC-vCMs were measured via optical mapping. Lastly, plasma extracellular small RNAs were extracted and sequenced. Results: IPSC-vCMs treated with sEVs derived from obese patients have significantly prolonged action potential duration (APD) at 1-Hz pacing, compared to those treated with EVs from lean counterparts (Figure 1, 589±8 ms vs. 540±11 ms, p &lt; 0.001, n = 2 differentiations) without significant difference in spontaneous contraction rate between the two groups. Preliminary differential gene expression analysis of obese vs. lean plasma extracellular small RNAs demonstrates enrichment in critical signaling pathways, including those involved in calcium homeostasis, reactive oxygen species, fibrosis, and mitochondrial energetics. Conclusion: An increased APD in iPSC-vCMs treated with plasma-derived EVs from obese patients correlates with QT interval prolongation, a known risk factor for SCD which is epidemiologically observed in obese populations. Further in-depth analysis to pinpoint targetable EV cargo may shed light on novel mechanisms responsible for obesity-related SCD and potential preventive strategies for SCD in this patient population.
Abstract 4144988: Association of Neutrophil-Lymphocyte Ratio with All-Cause Mortality and Cardiovascular Mortality in Patients Receiving Peritoneal Dialysis: A Systematic Review and Meta-Analysis
Authors: Denise Mourad, Nanush Damarlapally, Roopeessh Vempati, Srivatsa Surya Vasudevan, Prathibha Banda, Harshavardhan Polamarasetty, Afrasayab Khan, Gaurav Mathur, Rupak Desai
Journal: Circulation (2024)

Background: The neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory marker predicting cardiovascular mortality (CVM) and all-cause mortality (ACM) among the general population. We aim to investigate this association in patients who underwent peritoneal dialysis (PD). Methods: We systematically reviewed articles from PubMed, Google Scholar, and Scopus until May 2024 on the association of ACM and CVM in patients with NLR following PD. We used a fixed effects model, 95% confidence intervals (CI), and I 2 statistics to pool unadjusted and adjusted hazard ratios (HR) and measure heterogeneity. Leave-one-out sensitivity analysis was employed to study how each study alters the overall effect of the studies. Multivariate meta-regression was utilized to identify influencing confounding factors. Quality assessment of the studies was done through the Joanna Briggs Institute (JBI) tool. For all results, a P value &lt; 0.05 was considered significant. Results: Out of 160 articles screened, seven studies spanning from 2011 to 2023 with 4,350 patients, a mean age of 49.9 ± 15, and a median follow-up of four years were included in our meta-analysis. We found that higher NLR (&gt;2.88) was significantly associated with ACM (aHR: 1.09, 95% CI: 1.05–1.12, p&lt;0.0001) (Fig. 1a) and CVM (aHR: 1.08, 95% CI: 1.03–1.13, p=0.002) (Fig.1b) in patients following PD. Sensitivity analysis showed no variations, indicating that no single study influenced the overall results. JBI tool scores revealed low bias among the studies. Multivariate meta-regression revealed a significant relationship between age and ACM outcomes (Coefficient: 0.14, 95% CI: 0.001–0.2905, p=0.04) (Fig.1d). Conclusion: Our meta-analysis identifies a significant association between higher NLR (&gt;2.88) and outcomes such as ACM and CVM. This association can help prevent deaths in the older population and encourage proper utilization of the elderly resources. Additionally, age was a significant potential confounder for ACM in patients who are receiving PD. Thus, caution should be taken when predicting mortality in the elderly population.
Abstract 4145133: Impact of Neutrophil-to-Lymphocyte Ratio on clinical outcomes in patients with and without Diabetes undergoing Percutaneous Coronary Intervention
Authors: Francesca Di Muro, Samantha Sartori, Birgit Vogel, Benjamin Bay, ANGELO OLIVA, Kenneth Smith, Mauro Gitto, Prakash Krishnan, Joseph Sweeny, Pedro Moreno, Pier Pasquale Leone, Parasuram Krishnamoorthy, Annapoorna Kini, George Dangas, Samin Sharma, Roxana Mehran
Journal: Circulation (2024)

Background: The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation associated with adverse cardiovascular outcomes. Its prognostic role in patients with diabetes mellitus (DM) undergoing percutaneous coronary intervention (PCI) is unknown. Aims: To investigate the prognostic impact of NLR in patients with and without DM undergoing PCI. Methods: We retrospectively evaluated consecutive patients undergoing PCI at a large tertiary center between 2012 and 2022. Quartiles of NLR were derived in the overall population, and patients were stratified according to the presence of DM. Within each group, we estimated the risk of adverse events with a multivariable Cox regression model using the lowest NLR quartile as a reference. The primary endpoint was major adverse cardiovascular events (MACE), a composite of all-cause death, myocardial infarction (MI), or stroke. Secondary endpoints were MACE individual components, target vessel revascularization (TVR), bleeding and acute kidney injury (AKI). Results: A total of 7,287 patients were included (47.7% with DM). DM patients had more comorbidities and higher baseline hs-CRP levels. Overall, patients with elevated NLR exhibited multi-vessel disease with moderate to severe calcification, thus requiring more complex PCI. At 1 year, among DM patients, the 4 th quartile had a higher crude risk of MACE compared to the 1 st quartile, albeit attenuated after adjustment (p=0.059). This difference was mainly driven by MI rates occurring in 6.0% vs 3.8% respectively (adjHR 1.70, 95% CI 1.01-2.87; P=0.045). Non-DM patients in the highest NLR quartile had increased rates of MACE (adjHR 2.12, 95% CI 1.29-3.49; P=0.003) primarily due to all-cause mortality (adjHR 3.04, 95% CI 1.49-6.20; P=0.002) after adjustment. Regarding secondary endpoints, elevated NLR correlated with higher incidence of (i) bleeding and AKI in both groups and (ii) TVR only in non-DM patients (Figure 1). Conclusions: Our results suggest that patients undergoing PCI with a higher NLR experience worse clinical outcomes regardless of DM status. This was due to more MI in DM group and higher all-cause mortality in non-DM group. Higher NLR was also associated with an increased risk of bleeding and AKI.
Abstract 4145182: Decadal Shifts in Metabolic Risk Factors Associated Ischemic Heart Disease Mortality Trends: Insights from Global Burden of Disease Study 1990-2021
Authors: Bilawal Nadeem, Muhammad Subhan Saeed, Ziad Qadadeh, Saeed Abughazaleh, Amel Fatima, Dariush Jahandideh
Journal: Circulation (2024)

Background: Ischemic heart disease (IHD) continues to be a major contributor to global mortality. Metabolic risk factors are known to be the leading drivers of IHD burden. Our study aims to explain the trends in Metabolic Risk Factors (MRF) associated IHD mortality by utilizing Global Burden of Disease Study data spanning over three decades from 1990 to 2021. Method: MRF associated IHD mortality rates in the United States from 1990 to 2021 were sourced from the Global Burden of Diseases 2021 database. Monte Carlo permutation analysis utilizing JointPoint Regression Software (version 4.9.0.1, NCI) was employed to estimate the time trends, using annual percentage change (APC) and average annual percentage change (AAPC) metrics. Initially, these trends were assessed for the overall population. Analysis was then stratified by gender, evaluating age-adjusted rates separately for males and females. Further stratification involved, assessing age-specific trends within two distinct age groups: younger adults (20-54 years) and older adults (&gt;55 years). Results: A statistically significant decline in overall mortality was noted, with a moderate decline occurring during the decade 1990 to 2001 (APC= -2.2, p&lt;0.000001), the most substantial decrease during the decade 2001 to 2010 (APC = -4.91, p &lt; 0.000001), and the least decline from 2010 to 2021 (APC = -1.64, p &lt; 0.000001). There was no statistically significant difference in mortality trends between males and females (AAPC difference= -0.14, p = 0.1177). Age-specific analysis revealed a significantly greater decline in mortality among older adults (AAPC = -2.80, p &lt; 0.000001) compared to younger adults (AAPC = -1.32, p &lt; 0.000001). Conclusion: Significant decline in metabolic risk factors associated IHD mortality from 1990 to 2021 could be attributed to improved medical interventions and public health strategies, particularly during the decade of 2001 to 2010. The subsequent slower decline from 2010 to 2021 suggests potential limitations in the reach or efficacy of these interventions over time. These findings underscore the need for continued focus on age-specific interventions and public health strategies to further reduce metabolic risk factors associated IHD mortality.
Abstract 4144964: Low-Dose IL-2 Lowers Arterial Inflammation and Trends Towards Lower MACE in patients with ACS: The results of the IVORY trial and IVORY FINALE study
Authors: Rouchelle Sriranjan Rothwell, Tian Zhao, Stephen Hoole, Simon Bond, Jason Tarkin, Annette hubsch, Joanna Helmy, Elaine Bumanlag-Amis, Navazh Jalaludeen, Heike Templin, Jacob Brubert, Unni Krishnan, James O'Brien, James Rudd, Joseph Cheriyan, Ziad Mallat
Journal: Circulation (2024)

Major adverse cardiovascular (CV) events (MACE) occur in a substantioal percentage of individuals following acute coronary syndromes (ACS), primarily driven by residual vascular inflammation. Anti-inflammatory drugs have improved CV outcomes but their use is limited by significant side-effects. Low-dose interleukin 2 (IL2) increases regulatory T (Treg) cells, which are powerful endogenous regulators of the immune response, and could provide a new, targeted anti-inflammatory strategy in high-risk ACS patients. In IVORY, we hypothesised that treatment with low-dose IL2 would reduce arterial inflammation measured by 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT), compared to placebo. In IVORY FINALE we hypothesised that low dose IL2 could reduce MACE compared to placebo at follow up (up to 5 years.) IVORY was a double-blind, placebo-controlled, Phase IIb trial randomising ACS patients with high-sensitivity CRP levels ≧ 2mg/L to receive either 1.5×10 6 IU IL2 or placebo (1:1). Dosing consisted of a daily induction (5 days) and a weekly maintenance phase (7 weeks). 18 F-FDG-PET/CT imaging of the ascending aorta and carotid arteries was performed before and after treatment. The primary outcome was the difference in the mean maximum target-to-background ratio (TBRmax) in the index vessel on follow-up imaging between the groups. 60 patients (IL2:placebo, n=31:29) completed the trial. Arterial inflammation in the index vessel was lower at the end of treatment in the IL2 group than in placebo (TBRmax = -0.171[-7.7%], 95% CI -0.308 to -0.034, p=0.015)[Fig1]. In more inflamed areas with a mean TBRmax ≧ 2 (active slices), the difference between the groups was greater (-0.185 [-8.3%], P=0.009, 95% CI -0.323 to -0.0478). Overall, the additive treatment effect of low-dose IL2 was greater at higher baseline inflammation [Fig 2]. Low-dose IL2 significantly increased circulating Tregs compared to placebo (p&lt;0.001) [Fig 3]. There was no difference between the groups for changes in effector T cells. It was well-tolerated in ACS. At a median follow-up of 2.5 years, a trend towards lower MACE in the IL2 group (number of events [n]=0), compared to placebo (n= 7; 2 deaths, 2 non-fatal MIs, 3 unplanned revascularisations) was seen. In summary, in high-risk ACS, immunomodulation with low-dose IL2 produces a safe and significant reduction in arterial inflammation, compared to placebo. Larger trials are needed to confirm its impact on CV outcomes.