tbuckley/cabot-search huggingface dataset:
Abstract 4142846: Endothelial Copper Uptake Transporter CTR1 Senses Disturbed Flow to Promote Atherosclerosis through Cuproptosis
Authors: Sudhahar Varadarajan, Zhen Xiao, Archita Das, Dipankar Ash, Shikha Yadav, Barun Chatterjee, Malgorzata McMenamin, Stephanie Kelley, Jianghong Rao, Jack Kaplan, Masuko Ushio-Fukai, Tohru Fukai
Journal: Circulation (2024)

Background: Endothelial cells (ECs) utilize molecular mechanosensors that are critical for sensing disturbed flow (DF) to promote atherosclerosis. Copper (Cu), an essential micronutrient, is increased in human atherosclerotic plaques, while Cu chelation inhibits atherosclerosis in mice. “Cuproptosis” is a recently recognized form of programmed cell death which is driven by Cu-dependent mitochondrial protein aggregation and mitochondrial dysfunction; however, its role in atherosclerosis remains unknown. Results: Here we show that the Cu uptake transporter CTR1, which mainly localizes in the plasma membrane and caveolae/lipid rafts (C/LR), functions as a novel mechanosensor for DF to promote cuproptosis and atherosclerosis. Using X-ray fluorescence and ICP-MS analysis, we found that Cu, but not Fe and Zn levels, were increased in DF-exposed EC layers in the aortic arch of high fat diet-induced atherosclerotic (ApoE-KO) mice (2.3-fold) and cultured human aortic ECs (1.73-fold). Notably, DF vs. laminar flow (LF) increased mitochondrial Cu (1.6-fold) in ECs and induced mitochondrial dysfunction and cell death. These responses were rescued by mitochondrial-targeted Cu-depleting nanoparticle (mitoCDN) or CTR1siRNA. Functionally, the partial carotid ligation model revealed that EC-Ctr1 KO mice (by 70%) or mitoCDN (i.v.)(by 58%) reduced DF-induced atherosclerotic lesions in ApoE-KO mice, suggesting that DF-induced mitochondrial Cu promotes atherosclerosis through CTR1. Importantly, DF induced cuproptosis-related responses (increased DLAT aggregation, reduced DLAT lipoylation (47%) and Fe-S cluster proteins vs. LF), thereby increasing proteotoxic stress and decreasing mitochondrial respiration. All of these DF-induced responses were blocked by mitoCDN or CTR1siRNA. To address how DF increased mitochondrial Cu via CTR1, we performed subcellular fractionation and colocalization analysis and found that DF promoted mitochondrial Cu transporter SLC25A3 translocation to the plasma membrane (C/LR)(10.2-fold) and its association with CTR1 (2.8-fold), which were blocked by the disruption of C/LR using methyl-beta cyclodextrin. Furthermore, CTR1siRNA prevented DF-induced SLC25A3 translocation to plasma membrane. Conclusion: Endothelial CTR1 functions as a novel DF “mechanosensor” to increase mitochondrial Cu levels via recruiting mitochondrial SLC25A3 to plasma membrane C/LR where it binds to CTR1, leading to cuproptosis, which contributes to atherosclerosis.
Abstract 4142110: Coronary Artery Calcium Scans Powered by Artificial Intelligence (AI-CAC) Predicts Atrial Fibrillation and Stroke Comparably to Cardiac Magnetic Resonance Imaging: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Morteza Naghavi, Anthony Reeves, Kyle Atlas, Chenyu Zhang, Thomas Atlas, Claudia Henschke, Sion Roy, Matthew Budoff, David Yankelevitz, Nathan Wong
Journal: Circulation (2024)

Background: Coronary artery calcium (CAC) scans contain more actionable information than the Agatston CAC score. We have previously shown in the Multi-Ethnic Study of Atherosclerosis (MESA) that AI-enabled left atrial (LA) volumetry in CAC scans (AI-CAC) enabled prediction of atrial fibrillation (AF) as early as one year. Furthermore, we have recently shown adding AI-CAC LA volumetry to CHA 2 DS 2 -VASc risk score improved stroke prediction in MESA. In this study we evaluated the performance of AI-CAC LA volumetry versus LA measured by human experts using cardiac magnetic resonance imaging (CMRI) for predicting AF and stroke, and compared them with CHARGE-AF risk score, Agatston score, and NT-proBNP. Methods: We used 15-year outcomes data from 3552 asymptomatic individuals (52.2% women, age 61.7±10.2 years) who underwent both CAC scans and CMRI in the MESA baseline examination. We have applied the AutoChamber TM (HeartLung.AI, Houston, TX) component of AI-CAC to 3552 CAC scans. CMRI LA volume was previously measured by human experts. Data on NT-proBNP, CHARGE-AF risk score and the Agatston score were obtained from MESA. Discrimination was assessed using the time-dependent area under the curve (AUC). Results: Over 15 years follow-up, 562 cases of AF and 140 cases of stroke accrued. The AUC for 15-year AF prediction by AI-CAC LA volume (0.801) was comparable to CMRI LA volume (0.797) and significantly higher than Agatston CAC Score (0.687) and NT-proBNP (0.704). Similarly, the AUC for 15-year stroke prediction for AI-CAC volumetry (0.761) was comparable to CMRI volumetry (0.751) and significantly higher than NT-proBNP (0.631) and Agatston CAC Score (0.646). AI-CAC LA volume outperformed CHARGE AF over 1-3 years for incident AF (p&lt;0.02), but not for subsequent years. AI-CAC significantly improved the continuous Net Reclassification Index (NRI) for prediction of AF and stroke when added to CHARGE-AF risk score (0.28, 0.21), NT-proBNP (0.43, 0.37), and Agatston score (0.69, 0.41) respectively (p for all&lt;0.0001). Conclusion: LA volumetry measured by the AutoChamber component of AI-CAC and CMRI LA volume measured by human experts similarly predicted incident AF and stroke over 15 years, and outperformed NT-proBNP and Agatston CAC Score. AI-CAC LA volumetry outperformed CHARGE-AF and NT-proBNP for short-term (1-3 years) AF prediction. Further studies to investigate the clinical utility of AI-CAC LA volumetry for AF and stroke prediction are warranted.
Abstract 4142806: Multi-stage digital animation education improves negative mood in patients with atrial fibrillation catheter ablation during hospitalization
Authors: Xiaoyu Shi, Lilei Yu
Journal: Circulation (2024)

Background: Digital education for outpatient atrial fibrillation (AF) patients is gradually increasing. However, research on digital education for patients with atrial fibrillation catheter ablation (AFCA) is limited. Objective: Our aim is to develop a new multi-stage education model based on digital animation and to evaluate its effect on quality of life and negative mood in AFCA patients. Methods: This randomized, controlled clinical trial included 208 AF patients who underwent catheter ablation in the Department of Cardiology at Renmin Hospital of Wuhan University between January 2022 and August 2023. Patients were randomly assigned to the digital animation intervention group (n=104) and the usual care group (n=104). The primary outcome was the difference in the Quality of Life in patients with Atrial Fibrillation (AF-Qol-18) scores at 3 months. Secondary outcomes included differences in Medication Adherence Report Scale (MARS-5) score, self-rating anxiety scale (SAS) score, and self-rating depression scale (SDS) score at 3 months. Results: The main outcome of the study is the change in quality of life at 3 months after discharge from AFCA, secondary outcomes of the study were improvements in patients' anxiety, depression, and medication adherence. In the digital animation intervention group, the AF-Qol-18 score increased from 38.02 (SD 6.52) to 47.77 (SD 5.74), the MARS-5 score increased from 17.04 (SD 3.03) to 20.13 (SD 2.12), the SAS score decreased from 52.82 (SD 8.08) to 45.39 (SD 6.13), and the SDS score decreased from 54.12 (SD 6.13) to 45.47 (SD 5.94). In the usual care group, the AF-Qol-18 score increased from 36.97 (SD 7.00) to 45.31 (SD 5.71), the MARS-5 score increased from 17.14 (SD 3.01) to 18.47 (SD 2.79), the SAS score decreased from 51.83 (SD 7.74) to 47.31 (SD 5.87), and the SDS score decreased from 52.78 (SD 5.21) to 45.37 (SD 6.18). Conclusions: This educational model effectively improves postoperative anxiety, depression, medication adherence, and quality of life in patients at 3 months post-discharge.
Abstract 4142087: Prevalence of Standard Modifiable Risk Factors in Patients with Ischemia and Nonobstructive Coronary Arteries
Authors: Spyridon Kostantinis, Gabriel Garcia Castro, Nida Latif, Ilias Nikolakopoulos, Natasha Cigarroa, Steffne Kunnirickal, Natalija Odanovic, Samit Shah
Journal: Circulation (2024)

Introduction: Ischemia with nonobstructive coronary arteries (INOCA) is an increasingly recognized clinical syndrome. Standard modifiable cardiovascular risk factors (SMuRFs; hypertension, diabetes, hypercholesterolemia, and smoking) are associated with the development of atherosclerotic coronary artery disease, but the prevalence in INOCA is not well described. Methods: From 2017 to 2024, 221 patients with INOCA underwent invasive coronary physiologic assessment including vasoreactivity testing with acetylcholine provocation, guidewire-based assessment of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and fractional flow reserve (FFR). In our present study, we sought to examine the prevalence of SMuRFs in patients with INOCA. Results: In the entire cohort, the prevalence of SMuRFs were as follows: hypertension (63.3%), diabetes (23.1%), hypercholesterolemia (70.6%), and smoking (7.2%). 33 (14.9%) had no SMuRFs and the rest (85.1%) had at least one modifiable risk factor. SMuRF-less INOCA patients were younger (53.0 ± 11.8 years vs 58.5 ± 10.4 years; p=0.017) and were more commonly female (90.1% vs 68.1%; p=0.007). CFR, IMR and FFR were similar in both groups, but patients with SMuRFs had higher left ventricular end diastolic pressure (14.3 ± 4.7 mmHg vs 11.6 ± 3.4 mmHg; p=0.001) (Figure 1). Among patients with SMuRFs and no SMuRFs, the frequency of coronary microvascular dysfunction (CMD), vasospastic angina (VA), and mixed CMD/VA were similar, but patients with 0 SMuRFs had higher rates of myocardial bridging (21.2% vs 8.5%; p=0.044) (Figure 2). Conclusion: There was a high prevalence of SMuRFs in our study sample, with the majority of patients having hypertension and hyperlipidemia. The presence of SMuRFs was associated with left ventricular diastolic dysfunction. Among INOCA phenotypes, myocardial bridging was more common in patients without SMuRFs.
Abstract 4142145: The Usefulness of Left Atrial Strain for Successful Weaning from Venoarterial Extracorporeal Membrane Oxygenator
Authors: Heayoung Shin, Darae Kim, Minjung Bak, Yang Hyun Cho, Jin-Oh Choi, JEONGHOON YANG
Journal: Circulation (2024)

Backgrounds: Echocardiographic predictors of successful weaning from venoarterial extracorporeal membrane oxygenator (VA-ECMO) have been fully elucidated although previous studies reported echocardiographic parameters of left ventricular systolic function as a weaning indicator. Therefore, we investigated whether left atrial (LA) strain was associated with successful weaning from VA-ECMO. Methods: A total of 144 patients with profound cardiogenic shock who received VA-ECMO between March 2016 and March 2024 were enrolled from a single-center prospective registry. The ECMO flow study assessed cardiac recovery before the weaning trial. The flow was decreased by around 30% of the initial flow for 15 minutes. We assessed conventional echocardiographic parameters, LA strain, and left ventricular global longitudinal strain (LV GLS) both at baseline and after flow reduction, respectively. The primary outcome was successful ECMO weaning. Results: After excluding 24 patients with poor image quality, 120 patients were finally analyzed. Among them, 70 patients (58.3%) had successful weaning from VA-ECMO. During the ECMO flow study, aortic velocity time integral (13.1±7.1cm vs 9.7±4.0cm, p=0.002), left ventricular ejection fraction (35.4±12.3% vs 25.2±10.7%, p, and mitral s’ velocity (7.5±2.7 vs 5.4±2.0 cm/sec, pechocardiographic parameters for ECMO weaning, were higher in the weaning success group compared to the weaning failure group at ECMO minimal flow. The increase of LA strain (p in the successful weaning group was significantly higher than in the failed group according to the reduction of flow contrast to left ventricular ejection fraction (p=0.264) and mitral s’ velocity (p=0.001). LA strain (AUROC=0.789, 95% CI 0.705-0.872, pat minimal flow had a predictive performance for successful ECMO weaning comparable to that of LVEF(AUROC=0.750, 95% CI 0.660-0.839, p at minimal flow. Conclusions: LA strain at minimal ECMO flow might be useful as an indicator of successful weaning from VA ECMO along with conventional echocardiographic parameters. Keyword: extracorporeal membrane oxygenator; weaning; left atrial strain
Abstract 4142841: Relationship Between Amino Acid Metabolomics in Patients with Acute Ischemic Stroke Undergoing Intervention
Authors: Udaya Tantry, Kevin Bliden, Sahib Singh, Lekshmi Narayan Raghavakurup, Anne Le, Taylor Stude, Pratik Khare, Xiwen Zhang, Paul Gurbel, William Ashley
Journal: Circulation (2024)

Background: Emerging data reveal the importance of metabolomics in identifying specific amino acids and their metabolites as markers of hypercoagulability and stroke. Hypercoagulability, measured by a global hemostasis assay, is associated with thrombotic risk in patients with acute ischemic stroke (AIS). Hypothesis: AIS Patients undergoing coronary intervention compared to healthy controls (HC) exhibit dysregulated amino acid metabolomics that is associated with coagulation. Methods: Serum samples were collected from HC and AIS patients during the intervention. Untargeted metabolomics was performed using a Thermo-Scientific Q Exactive Plus Orbitrap mass spectrometer with Vanquish Horizon Binary UPLC. Metabolomics results were normalized relative to control subjects and compared to patients with AIS. Whole blood samples were used for the TEG assay, and the results were compared between patients with AIS and HC. Hypercoagulability was defined as platelet-fibrin clot strength (P-FCS) &gt; 66.5 mm. Results: AIS patients undergoing interventional procedures (n=12) and HC (n=17) were included. Among AIS patients, 50% were black, 67% were male, and 67% were obese. AIS patients vs. controls had elevated levels of P-FCS (67±3mm vs. 62±2mm) and a higher prevalence of hypercoagulability (83% vs. 0%) (p&lt;0.05 for both). Compared to HC, patients with AIS had negative correlation with histidine (his), glutamine (Glu), arginine, lysine (Lys), asparagine (ASP), homoarginine (Harg), ornithine (orn), valine (Val), homocysteine (Hcyc), anthranilate (Ant), serotonin (Ser), tryptophan (Trp), proline (Prl), alanine (Ala), and beta-alanine (Bala). They positively correlated with kynurenine (Kyn), xanthine (Xan), and xanthosine (Xanth) (P&lt;0.05 for all, Figur ). Conclusions: This hypothesis-generating study of untargeted metabolomics revealed that patients with AIS at the time of intervention were characterized by significant hypercoagulability and dysregulation of amino acids associated with coagulation. Further studies are planned to analyze the relationship between these amino acids and AIS risk and to identify them as novel prognostic risk factors.
Abstract 4142138: Prediabetes Subphenotypes Show Different Associations with Time to Type 2 Diabetes in the Diabetes Prevention Program
Authors: Benjamin Stroebel, Meghana Gadgil, Li Zhang, Kimberly Lewis, Kayla Longoria, Elena Flowers
Journal: Circulation (2024)

Introduction: Prediabetes is a prominent risk factor for cardiovascular disease (CVD) and type 2 diabetes (T2D). The clinical phenotype of individuals with prediabetes, however, is diverse, and characterization of subphenotypes may identify differing underlying physiology and outcomes. This study aimed to examine associations among prediabetes clusters and time to T2D development. Methods: We performed k-means cluster analyses in a subset of individuals with prediabetes (n=994) from the Diabetes Prevention Program (DPP). Clusters were based on 7 clinically measurable variables (age, body mass index (BMI), waist circumference, triglycerides, HDL cholesterol (HDL-C), fasting glucose (FG), and hemoglobin A1c (HbA1c)). Differences in time to T2D between clusters, overall and by treatment arm, were assessed via Kaplan-Meier survival estimates with post-hoc tests adjusted for multiple comparisons via a Bonferroni correction. Cox proportional Hazard models adjusted for treatment, sex, and race and ethnicity were used to determine T2D hazard ratios (HR) by cluster. Results: Five distinct clusters were identified. 1: “older protected” (highest age and HDL-C, lowest BMI and triglycerides); 2: “dyslipidemia” (highest triglycerides, lowest HDL-C); 3: “insulin resistant” (highest FG and HbA1c); 4: “younger protected” (lowest age, FG and HbA1c, lower BMI and waist circumference); and 5: “larger protected (highest BMI and waist circumference, lower triglycerides). Clusters differed significantly in gender and race and ethnicity. Time to diabetes differed between clusters overall and by DPP treatment arm (fig. 1). Post-hoc tests indicated significantly lower time to T2D, both overall and in placebo, in cluster 3 vs. 1, cluster 2 vs. 4, and cluster 3 vs. 5. Time to T2D was also significantly lower in cluster 5 vs. 4 overall and in lifestyle, and in cluster 3 vs. 4 overall and in all treatment arms (corrected p&lt;0.05). Adjusted Cox models indicate that the HR (95% CI) for T2D vs. cluster 4 in cluster 1 is 1.92 (1.10, 3.36), 3.77 (1.88, 7.59) in cluster 2, 4.93 (2.96, 8.23) in cluster 3, and 2.74 (1.57, 4.81) in cluster 5. Conclusions: Clinical variables were used to identify 5 distinct subphenotypes of individuals with prediabetes, each demonstrating different rates of T2D development, with treatment-adjusted differences. This study highlights potential heterogeneity in individuals with prediabetes and potential clinically relevant clusters with increased risk of progression to T2D.
Abstract 4142848: Apabetalone Protects Against Heart Failure with Preserved Ejection Fraction by Suppressing Myocardial Inflammation
Authors: sarah costantino, Era Gorica, Shafeeq Mohammed, Marialucia Telesca, Alessia Mongelli, Valeria Masciovecchio, Melissa Herwig, Samuele Ambrosini, FRANK RUSCHITZKA, Hamdani Nazha, Francesco Paneni
Journal: Circulation (2024)

Background: Post-translational histone modifications wield significant influence over cardiac hypertrophy and dysfunction. Apabetalone (APA), a selective inhibitor of BET proteins, effectively disrupts the interactions between bromodomain-containing protein 4 (BRD4) and chromatin, exerting modulation over transcriptional programs across various organs. Aim: We aim to investigate if APA could be beneficial in cardiometabolic heart failure with preserved ejection fraction (cHFpEF). Methods: Comprehensive assessments including histology, mouse echocardiography, and treadmill exhaustion tests were performed on mice subjected to high-fat diet and L-NAME for 15 weeks to induce cHFpEF. Unbiased gene expression profiling via PCR array and proteomics were conducted on left ventricular (LV) myocardial of HFpEF mice and control ones. Cultured cardiomyocytes (CMs) treated with palmitic acid (PA) served as an in vitro model of metabolic stress. cHFpEF mice received chronic treatment with APA (150mg/kg/day) or vehicle (DMSO). To bridge these findings to human relevance, passive stiffness of skinned CMs from cHFpEF patients was evaluated before and after APA treatment. Results: HFpEF mice exhibited notable characteristics including LV hypertrophy, diastolic dysfunction, myocardial fibrosis, lung congestion, and compromised exercise tolerance. APA treatment significantly ameliorated diastolic dysfunction, as evidenced by improvements in the E/A ratio and isovolumic relaxation time (IVRT), alongside a reduction in lung congestion, and enhancement in exercise tolerance. Transcriptomic analysis of PA-treated CMs and LV specimens of cHFpEF mice revealed a profound dysregulation of genes involved in inflammation, particularly IL-6, TNF-alpha, and IL-1beta. Chromatin immunoprecipitation assays demonstrated BRD4 occupancy on the promoters of various inflammatory genes, including IL6, with APA treatment resulting in the suppression of most inflammatory genes, notably impacting IL6 expression. APA led to a decrease in circulating levels of several inflammatory chemokines. The beneficial effects of APA were elucidated through the modulation of the IL-6/CaMKII/STAT3 pathway in both cHFpEF hearts and PA-treated CMs. Notably, in skinned CMs obtained from cHFpEF patients, both APA treatment and IL6 blockade exhibited a capacity to attenuate passive stiffness. Conclusions: Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF.
Abstract 4143017: Insights for Direct-to-Patient Clinical Trial Recruitment Strategies From the Heartline Study
Authors: Mellanie Hills, Serge Korjian, Gerald Chi, Andrea Natale, Leslie Saxon, Keith Ferdinand, Kevin Kwaku, Scott Brancato, Katie Baca-Motes, Steve Steinhubl, Jeff Wessler, Nieca Goldberg, Anisha Asthana, Kate Shute, Jill Applebaum, Kathleen Doran, Janeta Nikolovski, Simrati Kaul, Dereck Wentworth, CV Damaraju, Frank DeFalco, Cammie Tavakoli, Mithun Patel, Anne Curtis, John Spertus, Charles Gibson
Journal: Circulation (2024)

Background: Decentralized clinical trials using direct-to-participant recruitment can potentially engage large, representative participant pools. Research Question: Can a decentralized clinical trial use a multichannel approach to recruit patients &gt;65 years old across the United States? Goals/Aims: To share insights on multichannel strategies for participant recruitment in the decentralized, app-based Heartline study. Methods: Heartline is a randomized trial testing the impact of a mobile app-based heart health program with the electrocardiogram (ECG) and Irregular Rhythm Notification (IRN) features on Apple Watch for early diagnosis, treatment, and outcomes of atrial fibrillation. Eligible participants were US adults aged ≥65 years with an iPhone and Medicare coverage. Multiple pathways for broad outreach were explored, including digital (eg, email, social media) and traditional channels (eg, direct mail, community outreach). Recruitment efforts were assessed and refined to reach a large eligible population. Results: A multichannel approach led to ~300,000 Heartline study app installations. In total, 34,244 participants completed enrollment (Feb 2020-Dec 2022), of whom 28,155 completed baseline demographic assessments. Participants were widely distributed geographically, with notable representation of outlying and rural areas ( Figure 1 ). Women accounted for 54% of the participants. Overall, most participants were White (93.0%), with Asian, Black, and Hispanic participants representing 2.8%, 2.7%, and 2.5%, respectively. Conclusion: The Heartline study demonstrated the ability to recruit large numbers of participants aged ≥65 years using a direct-to-participant approach. Broad outreach strategies ensured gender and geographic diversity, enrolling a higher percentage of women than typical cardiology trials, and participation from rural areas. However, underrepresentation across racial/ethnic groups persisted and strategies to increase enrollment are needed. For similar trials, a strategic multichannel approach, with strong data and analytics capabilities may be beneficial to effectively target and enroll eligible participants.