tbuckley/cabot-search huggingface dataset:
Abstract 4137693: CC-Chemokine Receptor 2 Inhibition Prevents Monocyte/Macrophages Recruitment in Abdominal Aortic Aneurysms
Authors: Santiago Elizondo Benedetto, Mohamed Zaghloul, Batool Arif, Andrea Bredemeyer, Kory Lavine, Robert Gropler, Yongjian Liu, Mohamed Zayed
Journal: Circulation (2024)

Intro: Abdominal aortic aneurysm (AAA) is a prevalent condition in the elderly, with a significant risk of mortality if it ruptures. Despite this, there is currently no effective medical therapy to prevent AAA growth and rupture. The monocyte chemoattractant protein (MCP-1) / C-C chemokine receptor type 2 (CCR2) axis appears to play a role in AAA development. We demonstrated the potential of CCR2 as a theranostic marker for predicting AAA rupture, along with the effectiveness of a CCR2 inhibitor (RS-504393) in mitigating rupture. We further hypothesized that CCR2 inhibition can impact monocytes/macrophages trafficking in aortic tissue. Mehtods: Sprague-Dawley rats (N=54) underwent intraluminal aortic exposure to porcine pancreatic elastase (PPE) to induce aneurysmal degeneration. To stimulate AAA rupture, rats also recieved β-aminopropionitrile (BAPN). After 3 days of PPE exposure, a group of rats with AAA were administered a CCR2 inhibitor (CCR2i) either daily until the end of the study (CCR2i Full), or discontinued at day 5 (CCR2i Short), while the remaining rats proceeded without intervention (Fig1A). Ultrasound (12MHz) was performed at 7&amp;14 days to assess diameter, while another cohort of animals were euthanized at 6 days, prior to rupture, for single-cell RNA sequencing analysis. The relative content of inflammatory cells within the aortic tissue was analyzed. Results: Both CCR2i Short and CCR2i Full treated, exhibited a significant reduction in AAA diameter at day 7 and 14 compared to controls (p&lt;0.05; Fig1B&amp;C). Notably, rats treated with CCR2i Full did not experience any AAA ruptures, while controls had a 56% risk of rupture. In contrast, CCR2i Short delayed the occurrence of ruptures without reducing the rupture rate (p&lt;0.01; Fig1D). Single-cell RNA seq analysis of aortic tissue revealed that CCR2 inhibition led to a decrease in the number of recruited monocytes/macrophages. Cell recruitment was also relative to the duration of CCR2i treatment (Fig1E-G). Conclusions: Our study findings highlight the impact of CCR2-targeting in reducing AAA growth and the risk of rupture. Interestingly, length of CCR2i was a crucial variable for AAA rupture prevention. Furthermore, treatment length impacted the relative recruitment of monocytes/macrophages to AAA tissue, highlighting the role these cells in AAA disease pathology. Future analysis of CCR2+ inflammatory cell subgroups may help elucidate how CCR2 mechanistically modulates AAA progression and rupture risk.
Abstract 4137311: Inhibition of IL-33 by tozorakimab in patients with diabetic kidney disease: Cardiovascular insights from FRONTIER-1
Authors: Viknesh Selvarajah, Kaisa Maki-Petaja, Stefano Bartesaghi, Elena Surkova, Andrea Vavere, Deepa Arya, Dennis Brooks, Daniel Grice, Yan Zhu, Roberto Pecoits-Filho, Hiddo Lambers Heerspink, Alexis Hofherr
Journal: Circulation (2024)

Introduction: Interleukin-33 (IL-33) is a potent mediator of injury-induced local inflammation. Soluble ST2 (sST2), a decoy receptor of IL-33, is a prognostic serum biomarker for heart failure (HF). Here, we evaluated the impact of tozorakimab, an IL-33-neutralizing monoclonal antibody, on sST2-related secondary cardiac endpoints. Methods: FRONTIER-1 was a 24-week phase 2B study (NCT04170543) in patients with diabetic kidney disease (DKD). Key cardiac exclusion criteria were: 1) NYHA Class 3/4; 2) Left ventricular ejection fraction (LVEF) &lt; 40%; 3) B-type natriuretic peptide (BNP) &gt; 200 pg/mL. Local echocardiography (LVEF) was performed at Screening and Week 24. For exploratory analysis, echocardiography recordings were evaluated by a core laboratory. Throughout the study, BNP and sST2 were assessed and adverse events (AE) recorded. Safety and tolerability were evaluated for all dosed participants (Safety Analysis Population, SAP). Results: 573 participants were included in the SAP (139 = placebo / 434 = tozorakimab). Baseline characteristics were balanced across treatment groups. Tozorakimab was generally well tolerated and the incidences of AE, serious AE (SAEs), discontinuations, and death were similar to placebo. In the placebo group, cardiac disorder AE were reported in 6.5%, and SAE in 2.2%. Decline in LVEF of &gt; 10% was seen in 5 participants (4.3%). None developed BNP &gt; 200 pg/mL or clinical signs of HF. 1 participant (0.7%) presented with clinical symptoms of HF (SAE) without significant changes in LVEF or BNP. On tozorakimab, cardiac disorder AE/SAE were less frequent (3.7%/1.8%). Decline in LVEF of &gt; 10% was observed in 31 participants (8.3%), with 3 showing BNP elevation to 200–308 pg/mL. Two of these participants (0.5%) developed clinical signs of HF with LVEF 55%/30% and BNP &lt; 200 pg/mL. No further AE related to HF were reported for tozorakimab. Central analysis of LVEF revealed a substantial variability of site-based measurements indicating LVEF reductions &gt; 10 % in 2 (3.7%) participants on placebo and 6 (2.9%) on tozorakimab. Furthermore, central exploratory analysis demonstrated a slight increase in LVEF from baseline (1.62%, 95% CI: 0.22, 3.03) and a reduction in average E/e' (-0.47, 95% CI: -0.93, -0.01) for tozorakimab, but not placebo. Trends in BNP and sST2 over time were comparable. Conclusion: This study suggests a favorable cardiac safety profile for tozorakimab in patients with DKD. IL-33 inhibition did not elevate serum sST2 significantly.
Abstract 4137449: Diagnostic Yield and Testing Characteristics of an Invasive Coronary Function Testing Program
Authors: Fouad Bitar, Roukoz Abou-Karam, Fangzhou Cheng, Shoshana Gady, Rahul Sakhuja, Farouc Jaffer, Akl Fahed
Journal: Circulation (2024)

Background: Angina, ischemia, or myocardial infarction in the absence of obstructive coronary artery disease (ANOCA, INOCA, or MINOCA) is common and underdiagnosed. Invasive coronary function testing (CFT) for microvascular disease through coronary thermodilution and for coronary vasospasm through coronary reactivity testing can provide definitive diagnoses and improve patient quality of life. Here, we describe a single site experience launching a CFT program and present the diagnostic yield and test characteristics of the first 66 patients. Methods: The first 66 patients who underwent invasive CFT at Mass General Hospital after the launch of the program in 2022 were included. Invasive CFT data and clinical characteristics before and after were entered into a registry. We used descriptive statistics to summarize patient characteristics, diagnostic yield and change in management with invasive CFT. We describe the dose-response and safety of incremental doses of acetylcholine. Results: Among 66 patients (mean age 61.73±11.02 years, 56% female), 17 patients underwent testing at the time of an index angiogram and 49 were scheduled after knowledge of coronary anatomy. Reasons for invasive coronary function testing were post-revascularization angina (n=30, 45.5%), ANOCA (n=21, 31.8%), INOCA (n=9, 13.6%), MINOCA (n=4, 6.1%), and heart transplant patients (n=2, 3%). 24 (36.3%) patients underwent coronary thermodilution only, 6 (9.1%) coronary reactivity testing only , and 36 (54.5%) both. CFT resulted in a definitive diagnosis in 45 (68.1%) of participants – 37.9% with coronary vasospasm only, 13.6% with microvascular dysfunction only, and 16.7% with both. There were 21 (31.8%) patients who remained negative after invasive CFT. Invasive CFT led to a change in management in 46 (70%) patients. For example, nitrate, calcium channel blocker and beta blocker prescriptions were modified in 47%, 50%, and 52.3% of patients, respectively. Among 42 patients who underwent coronary reactivity testing by provocation with intracoronary acetylcholine doses of 20, 100, and 200 mcg, there was a dose-response to angina (18.5%, 70.2%, and 95.2%), ischemic ECG changes (11.1%, 75.7%, and 95.2%), and vessel spasm of greater than 90% (3.7%, 27%, and 57.1%). There was only one safety event(PTCA to re-establish flow after spasm). Conclusions: We demonstrate the safe implementation of an invasive coronary function testing program with very high diagnostic yield and impact on management.
Abstract 4137350: Temporal Trends and Effect of Superior Vena Cava Isolation Plus Pulmonary Vein Isolation for Paroxysmal Atrial Fibrillation Ablation: A Systematic Meta-Analysis with Trial Sequential Analysis
Authors: Wenchi Guan, Jun Liu, Xiaofeng Li, Keping Chen, yan yao
Journal: Circulation (2024)

Objectives: To assess the efficacy and safety of Superior Vena Cava Isolation (SVCI) plus Pulmonary Vein Isolation (PVI) compared to PVI alone in patients with drug-refractory paroxysmal atrial fibrillation (PAF). Methods: We utilized PubMed, EMBASE, Cochrane Library (CENTRAL) and Web of Science to identify the published randomized controlled trials (RCTs) involving patients undergoing SVCI+PVI ablation compared to PVI alone therapy. The search, conducted until February 17, 2024, used the terms "Superior Vena Cava," "Pulmonary Vein," "Radiofrequency Ablation," and "Atrial Fibrillation." Two reviewers screened records, extracted outcomes, and evaluated risk bias. The analysis employed Revman 5.4 and Trial Sequential Analysis (TSA 0.9.5.10 Beta). Results: The results included 4 RCTs involving 532 patients. Recurrence of atrial fibrillation significantly reduced in the SVCI+PVI group compared to the PVI alone group (RR 0.42, 95% CI 0.26–0.69, P = 0.0005; I 2 = 16%, P heterogeneity = 0.04) during a mean 12-month follow-up. Trial Sequential Analysis (TSA) supported these findings. Procedural complications did not show significant differences (RR 1.72, 95% CI 0.52–5.75, P = 0.38; I 2 = 0%, P heterogeneity = 0.56). Conclusion: In conclusion, the meta-analysis of RCTs suggests that SVCI in addition to PVI is superior to PVI alone for PAF, with no increase in procedural complications. TSA demonstrated consistent results with an adequate sample size, indicating no need for further RCTs on this matter.
Abstract 4137414: Uncovering MLKL as a Novel Regulator of Endothelial Cells in the Splenic Niche to Repress Hematopoiesis During Atherosclerosis
Authors: Adil Rasheed, Sabrina Robichaud, Taylor Dennison, My-Anh Nguyen, Michele Geoffrion, Jordan Reed, Hailey Wyatt, Yacine Marouf, Adir Baxi, Richard Lee, Hilal Kazan, Mete Civelek, qwerty uiop, Mireille Ouimet, Katey Rayner
Journal: Circulation (2024)

Background: Atherosclerosis occurs as lipid and immune cell rich plaques deposit within the arterial wall of the heart. These immune cells are produced from hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) and spleen, a process known as hematopoiesis that is dictated by their microenvironment, including endothelial cells (ECs). Objective: While others have shown adverse remodeling of BM ECs during atherogenesis, whether splenic ECs show a similar dysfunction leading to exacerbated hematopoiesis has not been described. Methods: We analyzed RNA sequencing data from chow fed C57Bl/6 mice and high cholesterol diet (HCD) fed Apoe -/- mouse BM and splenic ECs obtained from published studies, as well as our own. In vivo studies were performed in mice on an atherogenic background ( Apoe -/-&amp; Ldlr -/-) fed a HCD for 4 to 16 weeks. Knockdown of the mixed lineage kinase domain-like protein ( Mlkl KD) was achieved by weekly administration of antisense oligonucleotides (ASOs) or scrambled control (50mg/kg sc.). In vitro studies were performed in primary mouse splenic ECs transfected with siRNA. Results: Pathway analysis revealed remarkable tissue-specific responses to an atherogenic milieu, including dysregulation of Lipid Metabolism, Endocytosis and Cell Death pathways in splenic ECs. Interestingly, we previously showed that the mixed lineage kinase domain-like protein (MLKL) regulates the endocytic trafficking of lipids and cell death in macrophages. Indeed using Mlkl KD Apoe -/- mice, transplantation of Mlkl -/- BM into Ldlr -/- mice or EC-specific Mlkl -/- Apoe -/- mice, we show that loss of MLKL drives myelopoiesis and plaque development through regulation of splenic ECs. Both in vivo and in vitro , silencing Mlkl in splenic but not BM ECs potently increased lipid content and disrupted endocytosis by an accumulation of the multivesicular body marker CHMP4B, which mirror the dysregulated pathways we identified above. Furthermore, co-culture with Mlkl KD splenic ECs increased HSPC activation (pStat5) and myeloid colony formation, an effect that was lost when ECs were pre-treated with the upstream endocytosis inhibitor Dynasore. Conclusions: In conclusion, we establish a novel role for MLKL in regulating the balance of HSPCs, specifically through preservation of splenic, but not BM, ECs that repress hematopoiesis, highlighting the importance of splenic lipid metabolism and endocytosis and its impact on atherogenesis.
Abstract 4137457: Cross-sectional Investigation of Proteomic Signatures of Blood Pressure Traits.
Authors: Mohit Aggarwal, Tianxiao Huan, Paul Courchesne, Roby Joehanes, Josee Dupuis, George O'Connor, Daniel Levy
Journal: Circulation (2024)

Background: Hypertension is a major risk factor for cardiovascular disease affecting one third of the adult population worldwide. Over 90% cases of hypertension are without a distinct etiology. Identification of protein biomarkers of hypertension may provide insight into disease pathophysiology and highlight novel therapeutic targets. Methods: We conducted association analyses between 2922 plasma proteins (exposure) and blood pressure (BP) traits (outcome) in 45,926 UK Biobank participants (aged 57 ± 8 years; 54% women). We employed linear mixed models to study protein associations with systolic and diastolic BP and logistic mixed models to test abundance of proteins in hypertensive vs. normal individuals. The associations were adjusted for age, sex, body mass index, estimated glomerular filtration rate, smoking and alcohol drinking status, and batch effects. Hypertension was defined as systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) or current use of anti-hypertensive medication. Sensitivity analysis excluded individuals taking BP medication (n=10,229). Functional enrichment analysis was performed to elucidate biological functions and tissue specificity of significant protein signatures ( P &lt; 0.00017). We further performed Mendelian randomization (MR) to infer causal relations of protein biomarkers and BP. Results: We identified 1469 proteins associated with systolic BP and 1638 with diastolic BP. The corresponding numbers were 1410 and 1566 after excluding treated individuals. Plasma levels of 1215 proteins (1105 upregulated, 110 downregulated) differed in individuals with hypertension (N=24,724) compared to normal (N= 21,202). Most of these proteins were specific to liver, adipose tissue, renal cortex and coronary artery. Protein signatures of hypertension showed enrichment in pathways involved in inflammatory response, cholesterol homeostasis, complement and coagulation cascades, and hemostasis. Putatively causal associations were observed for 141 proteins with SBP and 142 with DBP. Discussion: This study elucidates protein signatures associated with BP and hypertension. Systemic inflammation and cholesterol homeostasis play important roles in the pathophysiology of hypertension.
Abstract 4137337: Targeting Macrophage NCOR1 to Alleviate Inflammation in Heart Failure with Preserved Ejection Fraction
Authors: Era Gorica, Shafeeq Mohammed, Alessandro Mengozzi, Frank Ruschitzka, Nazha Hamdani, sarah costantino, Francesco Paneni
Journal: Circulation (2024)

Background: Inflammatory response is a key player in heart failure with preserved ejection fraction, however the underlying mechanisms remain unclear. Recent evidence indicates that macrophage inflammation driven by the transcriptional coregulatory protein NCOR1 could play a pivotal role in disease states. Hypothesis: NCOR1 orchestrates macrophage inflammation and cardiac dysfunction in HFpEF. Methods: HFpEF was induced in mice using a validated model combining high-fat diet and L-NAME for 15 weeks. Cardiac function was assessed using high-resolution ultrasound imaging and LV samples were used to study macrophage polarization and inflammation by FACS. We generated myeloid-specific NCOR1-KO mice to investigate the in vivo effects of macrophage NCOR1 depletion on HFpEF. In vitro experiments included RAW 264.7 cells polarization and the assessment of macrophage phenotype switching in the presence or the absence of NCOR1. To study the crosstalk of macrophages with the surrounding cardiac cells, cardiomyocytes (H9c2) and endothelial cells (HAECS) were exposed to conditioned media from cultured RAW. Results: The expression of macrophage markers in human LV specimens showed an increase in pro-inflammatory macrophages (M1) and a decrease in regulatory macrophages (M2) as compared to age-matched control mice. HFpEF mice showed increased expression of vascular adhesion molecules (ICAM1, ICAM2, E-selectin) and a significant recruitment of M1 macrophages as proved by qPCR, WB, and flow cytometry analysis. Of interest, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) – and lung congestion were significantly reduced in mice with macrophage NCOR1 deletion as compared to WT littermates, while exercise tolerance was significantly improved. These findings were associated with a reduction of myocardial inflammation (TNF-a, IL6, IL-1b) in Ncor1-KO mice. In vitro assays showed that stimulation of macrophages with PA induced M1 type switch and increased NCOR1, TNF-a, IL-6, and IL-1b levels, whereas NCOR1 depletion prevented detrimental changes of macrophage conditional medium (Fig.1). Conclusion: Targeting macrophage NCOR1 could represent a promising approach to blunt myocardial inflammation in HFpEF.
Abstract 4137695: Bundle Branch Block(BBB) is Independently Associated With Adverse Cardiovascular Outcomes in Patients With Heart Failure With Preserved Ejectionfraction(HFPEF): A Propensity Score Matched Analysis
Authors: April Slee, Sanjeev Saksena
Journal: Circulation (2024)

Background: Ventricular dyssynchrony due to BBB can cause adverse cardiovascular(CV) outcomes in HF with reduced EF and is known to occur in HFpEF but its independent impact on is unclear. Objective: To determine if BBB is an independent risk factor for adverse HF outcomes in HFpEF and the impact of atrial fibrillation (AF).. Methods: We studied the impact of BBB in HFpEF utilizing propensity score(PS) matched cohorts without and with BBB from the TOPCAT Americas trial to account for confounding by other co-morbidities. Outcomes analyzed included the TOPCAT primary outcome, CV death&amp;hospitalization (CVH), sudden death, pump failure death (PFD), HF hospitalizations(H), and progression of HF. The impact of concomitant AF ( defined as any AF or AF on ECG) on these outcomes with and without BBB was analyzed. Results: 329 pts with HFpEF&amp;BBB were PS matched for 24 demographic&amp;disease state variables, BNP strata and AF status with a cohort of 329 pts with HFpEF without BBB. BBB was associated with increased risk of the TOPCAT primary outcome (Hazard ratio{HR} 1.44, 95% confidence intervals {CI} 1.10-1.89, p=0.008), increased risk of HF hospitalizations by 41%(HR 1.41 95% CI 1.04-1.91 p=0.0248) but not CVH (HR 1.18, 95% CI 0.93-1.49, p=..169), but not sudden death (HR 1.40, 95% CI 0.70-2.82, p=0.342) or CV death (HR 1.26, 95% CI 0.84-1.89, p=0.257). Risk of pump failure death (PFD) with BBB was significantly higher in HFpEF subjects without a history of AF (Figure left panel .Kaplan Meier Log rank p=0.0478, HR: 4.22, 95% CI: 0.89 to 19.87, p=0.0689) but not in AF (p=0.138). PFD risk was markedly higher in AF subjects without BBB ( Figure right, Kaplan Meier Log rank p=.0012, HR:7.99, 95% CI:1.80 to 35.41,p = 0.0063) than those with BBB (p=0.91) Conclusion: Ventricular dysynchrony induced by BBB independently worsens HFH risk in HFpEF. Its adverse impact on PFD iis seen in the absence of AF. Increase in PFD risk with AF in HFpEF subjects is most prominent in those with normal intraventricular conduction. Mechanical dyssynchrony induced by BBB may have a role in HFpEF subgroups with preserved atrioventricular filling, leading to these adverse HF outcomes
Abstract 4137717: Atrial Fibrillation in Valvular Heart Disease: Assessing the Impact of Genetics in the UK Biobank
Authors: Luca Cristin, Janet Tang, Lionel Tastet, Gregory Marcus, Francesca Delling
Journal: Circulation (2024)

Background: Atrial fibrillation (AF) in valvular heart disease (VHD) is typically linked to pressure or volume overload resulting in atrial remodeling. However, the independent contribution of genetics to AF in VHD beyond abnormal hemodynamics and other risk factors remains unclear. Objective: To study the role of a previously developed Polygenic Risk Score (PRS) for AF in predicting AF across different VHDs in the UK Biobank cohort. Methods: We analyzed UK Biobank data between 2000 and 2022. ICD codes were used to define incident AF and VHD status, including mitral valve (MV) disease [prolapse (MVP), regurgitation (MR) and stenosis (MS)] and aortic (AV) disease [stenosis (AS) and regurgitation (AR)]. Prior AF was excluded. Participants were divided into quintiles based on the PRS: the top quintile was defined as high genetic AF risk, second through fourth as intermediate genetic risk, and bottom quintile as low genetic risk. Results: Among 452841 participants with available PRS, 2238 had at least one VHD (385 MVP, 1058 MR, 81 MS, 421 AR, and 509 AS). AF incidence was 9.9%, 13.6%, and 19% in the low, intermediate and high genetic risk groups respectively, compared to 1.4%, 2.8%, and 5.7% in the general population (all p&lt;0.05) - Figure 1A . Cox regression models adjusted for cardiovascular risk factors showed different genetic effects on AF across VHD types. Censoring patients at death, including valve intervention as a time-dependent variable, and excluding AF within 30 days post-intervention, PRS independently predicted AF in MV disease (hazard ratio [HR] 1.7, p=0.03 for the intermediate risk/mid PRS; HR 2.3, p=0.002 for the high risk PRS), particularly in those with MVP (HR 3.1, p=0.03 for the high PRS). However, in those with AV disease, PRS was not significantly associated with AF (p=0.93 and p=0.07) - Figure 1B. Conclusion: In patients with VHD, AF PRS is significantly associated with an increased risk of developing AF. However, the genetic impact varies across different VHD. In AV disease, there is a minimal genetic contribution, and the elevated AF risk may be predominantly due to pressure or volume overload. In contrast, in MV disease, particularly in MVP, there is a substantial genetic influence on AF risk.