tbuckley/cabot-search huggingface dataset:
Abstract 4141762: Multi-omics analysis of host transcriptomics and gut microbiota reveals altered tumor necrosis factor alpha signaling in older adults with heart failure
Authors: Jie Chen, Zequan Wang, Huan Kuang, Jennifer Dungan, Tingting Liu, Paula McCauley, Ming-Hui Chen, Angela Starkweather, Xiaomei Cong
Journal: Circulation (2024)

Introduction: Chronic heart failure (HF) is linked to elevated serum TNF-α levels and affects multiple signaling pathways in non-cardiomyocytes, such as immune cells, intestinal epithelial cells, lymphatic endothelial cells, vascular cells, and their interactions. The combined dysbiosis of host transcriptomics and gut microbiota concerning altered TNF-α signaling in older adults with HF remains unknown. Methods: We recruited 10 older adults with heart failure (HF) (6 females) and 16 healthy controls (HCs) (10 females) from the Northeastern U.S. Non-fasting peripheral blood and stool samples were collected. Serum TNF-α was assayed using Enzyme-linked Immunosorbent Assay (ELISA) kits. Differentially expressed genes (DEGs) between HF and HCs were investigated using the R package "DESeq2" after aligning the raw blood RNA sequence data to the reference database and undergoing quality control. The QIAGEN Ingenuity Pathway Analysis (IPA) was used to analyze the canonical pathways associated with the DEGs. The 16S rRNA V4 gene regions of stool samples were sequenced and processed using the Mothur 1.42.3 pipeline. The Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict the metagenomic functions of different gut microbiota compositions. Results: The mean ages of the HF and HC subjects were 73.50 (SD = 8.33) and 63.19 (SD = 7.75), respectively. HF subjects had significantly higher serum TNF-α levels than HCs (p &lt; 0.05). Among the DEGs, HF subjects had 18 downregulated genes (e.g., AK5 , FAM167A , RGCC , and SARDH ) and 3 upregulated genes ( SMPD3 , TMIGD3 , and FRRS1 ) compared with HCs. TNF signaling (p &lt; 0.01) was one of the significantly different canonical pathways in the DEGs between HF and HCs. HF subjects had significantly enriched Mogibacterium and diminished Sutterella than HCs (p &lt; 0.05) and lower P53 signaling pathway activity than HCs (p &lt; 0.05) among the predicted functions in stool samples. Conclusions: By analyzing serum TNF-α, whole transcriptomics, and gut microbiota, we identified higher serum TNF-α, differentially expressed genes (DEGs) and their canonical pathways, and distinct compositions and predicted functions of gut microbiota in older adults with HF compared to healthy controls. These findings suggest that TNF-α signaling may be a potential target for developing precise HF interventions and highlight the need for further large-scale multi-omics analysis in understanding and treating HF.
Abstract 4141822: Factor VIII replacement therapy in patients with hemophilia undergoing pulsed-field or radiofrequency catheter ablation for atrial fibrillation
Authors: Sanghamitra Mohanty, Paolo Compagnucci, PremGeeta Torlapati, Domenico Della Rocca, Vincenzo Mirco La Fazia, Carola Gianni, Bryan MacDonald, ANGEL QUINTERO MAYEDO, G Gallinghouse, John Burkhardt, Rodney Horton, Amin Al-Ahmad, Luigi Di biase, Michela Casella, Antonio Dello Russo, Andrea Natale
Journal: Circulation (2024)

Background: Typically, hemophilia patients receive up to 6 weeks of intravenous Factor VIII replacement therapy while undergoing radiofrequency ablation (RFA) for atrial fibrillation (AF). Objective: We report the management of Factor-VIII replacement therapy in a series of hemophilia patients receiving either pulsed-field (PFA) or RFA. Methods: Consecutive hemophilia patients undergoing AF ablation were included in this series. All patients received pulmonary vein isolation (PVI) plus isolation of left atrial posterior wall using either RFA or PFA. Results: This series included 8 male patients of which 3 (37.5%) received PFA and 5 underwent RFA for drug-refractory AF. Mean CHA 2 DS 2 -VASc score were 2.67±1.15 and 2.80 ±1.48 (p=0.899) and the HAS-BLED score were 3.33± 1.53 and 2.80±1.10 (p=0.582) in the PFA and the RFA cohorts respectively. Details of pre- and post-procedural Factor VIII replacement therapy is provided in Table 1. After the procedure, patients undergoing PFA received significantly less Factor VII replacement therapy compared to those receiving RFA (PFA: 78,866.67 ± 1,761.63 vs. RF: 152,260.00 ± 29,704.51 IU, P-value: &lt;0.001). The duration of the replacement therapy was also significantly lower in the PFA patients compared to the RFA cohort (6.65±0.229 vs 31±3.316 days, p&lt;0.001). No peri-procedural bleeding or thromboembolic events were reported at 1-year follow-up. Conclusion: In hemophilia patients undergoing PFA for AF, factor-VIII replacement therapy and oral anticoagulants could be discontinued after one week of the procedure with no bleeding or thromboembolic complications at follow-up, whereas the duration of therapy was significantly longer following RFA.
Abstract 4141811: Determining the Accuracy of Sleep and Activity Patterns in Patients Undergoing Long-Term Ambulatory ECG Monitoring
Authors: Richard Bogan, Elaine Yu, Vincent Mysliwiec, Mitchell Miller, Ardit Kacorri, Yuriko Tamura, Anthony Battisti, Vladimir Fokin, Evangelos Hytopoulos, Andrew Gilbert, Charlotte Bame, Mintu Turakhia
Journal: Circulation (2024)

Background: Ambulatory ECG (AECG) enables heart rhythm monitoring during daily activities, with a focus on arrythmia detection. Detection and quantification of sleep and activity patterns during monitoring may provide insights into lifestyle and aid in contextualizing arrhythmia events. Aims: We developed an AI algorithm to classify sleep, activity, and inactivity periods using a novel AECG patch with embedded accelerometry. We assessed algorithm performance and compared it to FDA-cleared actigraphy and consumer devices, which have shown 93-99% sensitivity (SE) and 39-54% specificity (SP) in classifying sleep vs. polysomnography (PSG). Methods: We conducted a prospective study of 81 participants at 3 sites who wore the Zio ® monitor AECG patch (iRhythm Technologies, San Francisco, CA) and Actigraph wGT3X (Pensacola, FL) simultaneously for 14 days. Sleep disordered breathing was excluded. Participants underwent a 6-minute walk test at the beginning of wear and in-clinic overnight PSG sleep testing at 7±3 days. Data were split into training (n=40) and validation (n=41) sets. Feature and model selection utilized five-fold cross-validation on the training set, focusing on total activity and body angle. The final machine model was trained on selected features using the entire training set. In validation, SE and SP for sleep were assessed based on 1-minute epochs vs. PSG and also vs. a 24-hour reference (combined PSG and actigraphy-wake labeling). SE and SP for activity were assessed vs. actigraphy over 8 minutes sampled per subject (4min walk test, 4min PSG wake periods). Results: The study population was diverse (age 43±14 years, 57% female, 64% White, 25% Black, 20% Hispanic). In the validation set, average sleep and wake times were 5.9 and 1.2 hours, respectively, during PSG. SE and SP were 88.8% and 54.0%, respectively, in sleep detection vs. PSG, or 88.8% SE and 95.6% SP vs. the 24-hour reference (Table 1). SE and SP for activity detection were 97.0% and 100%, respectively. Conclusion: Assessment of sleep and activity during AECG is feasible, with performance comparable to FDA-cleared actigraphy. This feature offers insights into patient wellness patterns, highlighting its potential for personalized healthcare monitoring.
Abstract 4141823: Deletion of Endothelial Neuropilin-1 Improves Cardiac Diastolic Function in Heart Failure with Preserved Ejection Fraction
Authors: Yu Huo, Sarah Chau, Enfeng Wang, Ahmed Fayyaz, Debabrata Mukhopadhyay, Margaret Redfield, Ying Wang
Journal: Circulation (2024)

Heart failure with preserved ejection fraction (HFpEF), characterized by cardiac diastolic dysfunction, leads to premature mortality with limited effective treatments. A recent study in HFpEF patients suggested neuropilin 1 (NRP1), an endothelial cell (EC) originated prognostic marker, might contribute to the pathogenesis of HFpEF. However, the functional role of NRP1 in the pathogenesis of HFpEF remains unclear. Purpose: To determine the functional role of NRP1 in the pathogenesis of HFpEF. Hypothesis: NRP-1 contributes to the pathogenesis of HFpEF, potentially mediated through chronic inflammation. Methods: HFpEF was induced by hypertensive and metabolic stresses in control (n=14) and tamoxifen-induced, endothelial cell-specific NRP1 knockout (NRP1 iEC-KO ) mice (n=13). We assessed cardiac diastolic function via echocardiography and pressure-volume loop through invasive catheters. To determine the inflammation level, we tested leukocyte adhesion, inflammatory marker vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1) mRNA level in control and NRP1 shRNA knockdown (NRP1 KD) human umbilical vein endothelial cells (HUVECs) with a stimulation of TNF-α. Student t-test (two tailed) was used and the criterion level of significance was set at p&lt;0.05. Results: We found a significantly improved diastolic function in NRP1 iEC-KO mice, evidenced by a significantly reduced end diastolic pressure in NRP1 iEC-KO mice (8±2mmHg; n=7) compared to the controls (17±2mmHg; n=9; p=0.01) after HFpEF induction. E/A ratio was also significantly lower in NRP1 iEC-KO mice (2.0±0.2; n=10) compared to controls (2.7±0.3; n=12; p=0.04). Moreover, the isovolumic relaxation time was also significantly reduced in NRP1 iEC-KO mice (18±0.8ms; n=13) compared to controls (20±0.8ms; n=14; p=0.03). In addition, In HUVECs, NRP1 KD significantly reduced inflammatory marker VCAM-1 mRNA expression (95±16; n=5) compared to controls (293±36; n=5; p&lt;0.01) upon TNF-α treatment. Similarly, NRP1 KD significantly reduced ICAM-1 mRNA expression (44±14; n=5) compared to controls (83±9; n=5; p=0.03) upon TNF-α treatment. Furthermore, leukocyte adhesion was significantly lower in the NRP1 KD group (57.0 ±8.6 cells/field) compared to the control group (90.8 ±9.1 cells/field; p=0.04). Conclusion: Endothelial NRP1 contributes to cardiac diastolic dysfunction and the pathogenesis of HFpEF, potentially mediated through the activation of chronic low-grade inflammation.
Abstract 4141774: Plasma omega-3 fatty acids/omega-6 fatty acids and arterial stiffness in middle aged healthy Japanese cohort
Authors: Chisa Matsumoto, Hirofumi Tomiyama, Hiroki Nakano, Takamichi Takahashi, Junya Kani, Kazuki Shiina, Akira Yamashina, Kazuhiro Satomi
Journal: Circulation (2024)

Background: Numerous studies evaluating the effects of consumption of omega-3 fatty acids (ω3FAs) and omega-6 fatty acids (ω6FAs) on the prevention of cardiovascular disease (CVD) have yielded inconsistent results. In addition, the association between ω3FAs/ω6FAs and CVD has been suggested to vary with the daily intake levels of fatty acids among individuals. On the other hand, the longitudinal associations between plasma ω3FAs/ω6FAs and arterial stiffness, which is a predictor of CVD, have not been well elucidated. Hypothesis: We hypothesized that plasma ω3FAs are associated with the suppression of age-related increases in arterial stiffness, whereas plasma ω6FAs are associated with an increase in arterial stiffness. Aims: The objective of this study is to fill the existing research gap by investigating the longitudinal association between plasma ω3FAs/ω6FAs and arterial stiffness in a Japanese people, known for their higher intake of marine products. Methods: This prospective observational study included 2520 healthy Japanese participants (mean age:43.1±8.7y, men:83.1%) who underwent repeated annual health check-ups from 2008 to 2013. Participants with a history of CVD or treatment for CVD risk factors were excluded. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV), and plasma ω3FAs [docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)]/ω6FAs [arachidonic acid (AA), dihomo-gamma-linolenic acid (DGLA)] were evaluated by gas chromatography. The longitudinal association between plasma ω3FAs/ω6FAs and baPWV was evaluated by a linear mixed model adjusted for conventional CVD risk factors. Results: During a median follow-up of 5 years (IQR 4-5 years), 11034 baPWV measurements were performed. The linear mix model adjusted for conventional CVD risk factors revealed that both higher plasma AA and DGLA levels were significantly associated with an increase in baPWV (1SD increase in AA; β=12±3, 1SD increase in DGLA; β=14±3, both P&lt;0.001). However, neither plasma EPA nor DHA levels were longitudinally associated with the baPWV. Conclusion: Plasma ω3FAs were not longitudinally associated with arterial stiffness. In contrast, higher plasma ω6FAs levels were longitudinally associated with increased arterial stiffness. Our results suggest that the potential CVD-preventive effects of ω3FAs may not involve the suppression of arterial stiffness. Conversely, the increased CVD risk associated with ω6FAs may be attributed to increased arterial stiffness.
Abstract 4141782: Maladaptive alterations in the biomechanics of the post-myocardial scar as a consequence of CD8 <sup>+</sup> T-cell transfer
Authors: Shaoni Dasgupta, Maya Learmonth, Alexa Corker, Miguel Troncoso, Philip Broughton, Catalin Baicu, Amy Bradshaw, Michael Zile, Kristine Deleon-Pennell
Journal: Circulation (2024)

CD8 + T-cells are adverse regulators post myocardial infarction (MI), leading to increased mortality and impaired cardiac function. We hypothesize that CD8 + T-cells impair cardiac function by altering scar composition. MI was induced by ligating the left anterior descending coronary artery in C57BL6/J (WT; 3-7 months of age, n≥2/sex) and CD8a tm1mak mice (CD8 -/- ; 3-7 months of age, n≥2/sex/treatment). CD8 -/- mice were injected with either vehicle or naïve splenic CD8 + T-cells (2x10 6 cells/injection) via tail vein, 4 hours post-MI. Infarct tissue was collected post-MI Day 7 and underwent biomechanical, histological, and biochemical analyses. Effects of granzyme (Gzm) A, B, and K on collagen cleavage were tested using a fluorogenic collagen cleavage assay to examine possible mechanisms of scar alteration. Mice lacking CD8 + T-cells had improved ejection fraction and decreased dilation (p&lt;0.05 for both) compared to WT mice at post-MI Day 7. This protective effect was lost in CD8 -/- mice that received splenic CD8 + T-cells (p=0.09 vs WT). Biomechanical testing revealed CD8 -/- mice had a 2-fold increase in regional scar stiffness compared to WT mice (p&lt;0.05). Re-supplementation with splenic CD8 + T-cells decreased scar tissue stiffness compared to vehicle treated mice (p&lt;0.05) mimicking biomechanics of WT mice. Picrosirius red staining showed no significant differences in total collagen levels (p=0.51) across all groups. However, further investigation using collagen hybridization peptide staining showed increased collagen cleavage in WT mice in comparison to CD8 -/- mice (p&lt;0.05) as demonstrated by overall fluorescence intensity. Evaluation of percent area of CHP staining showed WT mice had increased cleavage distribution within the infarct compared to vehicle-treated CD8 -/- mice (p&lt;0.05). This effect was lost with CD8 + T-cell supplementation (p=0.13 vs WT). Ex-vivo cleavage assay demonstrated GzmA and K cleaved collagen in a concentration (0-50 AU) and temporal-dependent manner (0-24 hrs). Both GzmA and K demonstrated a 10-fold greater capacity in collagen cleavage compared to GzmB at 25 AU, implicating distinctly separate roles for the different granzymes during post-MI scar formation and maturation. In conclusion, our data demonstrates that CD8 + T-cells regulate cardiac fibrosis in part through the release of granzymes, leading to impairments of biomechanical capability of the left ventricle and increased LV dilation.
Abstract 4141761: Safety and Efficacy of Radial Versus Femoral Access for Rotational Atherectomy: An Updated Systematic Review And Meta-Analysis
Authors: Muhammad Ahmed, Muzna Murtaza, Muhammad Muzammil, Syeda Zuha Sami, Ariba Nazir, Muhammad Ahmed, Muhammad Sohaib Asghar
Journal: Circulation (2024)

Background: Rotational atherectomy has been performed using both radial and femoral access over the years, but there is a lack of consensus on the safety and efficacy of these access sites. Aim: To assess the safety and efficacy of radial access and femoral access. Methods: MEDLINE, Scopus, and Cochrane Library were searched until May 2024 for studies comparing radial approach with femoral approach in patients undergoing rotational atherectomy. The primary outcome was major vascular site bleeding. Secondary outcomes included short-term mortality, long-term mortality, myocardial infarction, major adverse cardiovascular events (MACE), acute stent thrombosis, procedural success, procedural time, hospital stay and radiation exposure. Effect estimates were synthesized using a random-effects model and expressed as risk ratios (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, with corresponding 95% confidence intervals (CIs). Results: 13 studies including 13,581 patients with mean age of 60.76 years in the radial group and 66.86 years in the femoral group, who had undergone rotational atherectomy, were included in the analysis. For the outcome of major vascular site bleeding, there was significantly lower risk (RR: 0.25; 95% CI [0.15, 0.43]; p&lt;0.00001) in the radial group as compared to the femoral group. From the secondary outcomes, MACE was found to be significantly lower (RR:0.80; 95% CI [0.68, 0.93]; p=0.004) in radial arm as compared to femoral arm. Radial group was also significantly associated with shorter procedural time (MD: -8.30 CI: 95% [-12.03, -4.56], p&lt;0.00001) and hospital stay (MD: -2.30; 95% CI [-4.29, -0.30], p=0.02) as compared to femoral group. Whereas all the other secondary outcomes were found to be insignificant. Conclusion: Rotational atherectomy using the radial approach significantly shows a lower rate of major vascular site bleeding and MACE and is also associated with shorter procedural time and hospital stay.
Abstract 4141821: Genotype and Family History as Risk Markers of Sudden Cardiac Death in Hypertrophic Cardiomyopathy
Authors: Ali Sakhnini, Mahdi Montazeri, Cindy Chow, Josh Silver, Sudipta Saha, Raymond Chan, Michael Gollob, Steve Fan, Ethan Rowin, Martin maron, Harry Rakowski, Arnon Adler
Journal: Circulation (2024)

Introduction: The role of genotype in sudden cardiac death (SCD) risk stratification in hypertrophic cardiomyopathy (HCM) patients is unclear. Whether family history of SCD (FHxSCD) is independently associated with SCD after correction for genotype has never been investigated. Methods: This observational cohort study included HCM patients who had genetic testing at Toronto General Hospital or Tufts Medical Center. FHxSCD was defined as unexplained SCD before the age of 40 or due to HCM in a first-degree family member. SARC+ was defined as the identification of a (likely) pathogenic variant in a sarcomeric gene. The combined SCD outcome included SCD, resuscitated cardiac arrest (rCA), or appropriate ICD therapy. Results: The study included 3258 patients [2142 (65.7%) male, 896 (27.5%) SARC+]. Over a median follow-up of 5 years (IQR 1.9–9.6), 114 (3.5%) experienced a SCD outcome (10 SCD, 27 rCA, and 77 ICD therapies). Both FHxSCD and SARC+ were independently associated with SCD, with hazard ratios of 1.97 [1.26-3.10, P = 0.003] and 1.73 [1.15-2.59, P = 0.008], respectively (Fig. 1). Among patients with FHxSCD but no other risk markers, the cumulative proportion of SCD was 7.8% and 9.8% at 5 and 10 years in SARC+ patients, but only 2.6% and 4.6% in SARC- patients (Fig. 2). Adding genotype to the HCM SCD risk calculator resulted in a net reclassification index of 0.162 (0.046–0.285). Compared with the original model and using a 6%/5-year cutoff, the new model identified 8 more patients with events as high-risk but also an additional 4 patients without events. Conclusion: In our cohort, both FHxSCD and genotype were independently associated with SCD outcomes. In patients with FHxSCD as the sole risk marker, the risk of SCD is significant (&gt;6%/5 years) in SARC+ patients but not in SARC- patients. Adding genotype to the HCM SCD risk calculator improves its ability to discriminate between patients at high and low risk.
Abstract 4141778: Cell Signaling, Metabolic, and Inflammatory RNA Transcriptomic Pathways are Upregulated Among Patients with Coronary Microvascular Dysfunction and Ischemia with Non-Obstructive Coronary Arteries
Authors: Barbara Jerome, Florencia Schlamp, Anais Hausvater, Amanda Joa, Claudia Serrano, Ayman Farid, Judith Hochman, Tessa Barrett, Harmony Reynolds, Jeffrey Berger, Nathaniel Smilowitz
Journal: Circulation (2024)

Background: Coronary microvascular dysfunction (CMD) is a cause of ischemia with non-obstructive coronary arteries (INOCA), but mechanisms underlying CMD are not well understood. We previously reported a proinflammatory whole blood transcriptional signature among INOCA patients with versus without CMD. Here we sought to broadly identify pathways beyond inflammation with potential relevance to CMD mechanisms. Methods: We prospectively enrolled females with ischemic symptoms or myocardial ischemia on stress testing who underwent invasive coronary angiography with &lt;50% stenosis in all major epicardial vessels. CMD was defined as coronary flow reserve (CFR) &lt;2.5 measured invasively by bolus thermodilution. Whole blood RNA was collected at the time of coronary angiography and sequenced. Differential transcript expression analyses adjusted for age were performed using DESeq2 with CFR as binary and continuous variables. Ingenuity Pathway Analysis (IPA) was performed to identify differentially expressed canonical pathways with nominal p-values &lt;0.05 and a z-score ≥|2|. Results: Seven of 28 women with INOCA (mean age 60 ± 8.4 years, 82% white, 32% Hispanic/Latino ethnicity) had CMD. When CFR (median 3.2 [IQR 2.5-4.2]) was analyzed as a continuous variable, 55 pathways were differentially expressed: 6 related to cell adhesion and migration signaling (e.g., integrin signaling) and 13 metabolic processes (e.g., PI3K/AKT signaling). All cell adhesion and migration pathways ( Figure, Panel A) and 11/13 metabolic pathways (Panel B) were upregulated with lower CFR. As previously reported, 18/19 pathways related to inflammation were upregulated (Panel C). The remaining 17 pathways were related to the immune response to specific pathogens, the cell cycle and tumorigenesis, and signaling in the gastrointestinal, nervous, and endocrine systems. Conclusion: Pathways related to cell signaling, metabolism, and inflammation were primarily upregulated among women with INOCA and CMD versus those without CMD. Further research is needed to explore transcriptional profiles implicated in the pathogenesis of CMD in INOCA.