tbuckley/cabot-search huggingface dataset:
Abstract 4141350: Endothelial-Mesenchymal Transition Mediated by Mechanical Stress Prompts Atrial Fibrogenesis
Authors: Chang Cui, Huiyuan Qin, YUE ZHU, YIKE ZHANG, Youmei Shen, Hailei Liu, Minglong Chen
Journal: Circulation (2024)

Background: Atrial fibrosis is crucial in developing atrial fibrillation (AF). Elevated atrial pressure may significantly mediate atrial fibrosis, yet its underlying mechanisms remain unclear. Methods: Patients with AF who underwent radiofrequency ablation were recruited. Clinical data, including high-density mapping and imaging information, was analyzed. Multivariate regression analysis was performed to identify risk factors for low-voltage areas in the atrium. The CS-CREM mouse model, an autonomic AF model, was previously developed by our research group. Millar pressure catheters were used to measure left ventricular, right ventricular, and right atrial pressures in CS-CREM mice. Single-nucleus sequencing was employed to map the single-cell transcriptomes of atrial samples in CS-CREM and wild-type mice at different disease stages. Human primary atrial endocardial endothelial cells (ACCE) and HUVEC cell lines were subjected to mechanical stretch using the Flexcell tension system, followed by in vitro validation experiments. Mg101, a calpain inhibitor, was administered to CS-CREM mice for in vivo validation experiments. Results: Elevated atrial pressure in AF patients was identified as a significant risk factor for atrial fibrosis. Atrial pressure-related indices were linearly correlated with atrial fibrosis. Compared to wild-type mice, CS-CREM heterozygous mice exhibited significantly higher atrial pressure and aggravated atrial fibrosis. Single-nucleus sequencing revealed that atrial endocardial endothelial cells in CS-CREM mice underwent endothelial-mesenchymal transition (EnMT) into fibroblasts, with mechanical stress protein Flna being a critical regulatory protein. In vitro experiments demonstrated mechanical stretch-induced EnMT in ACCE and HUVEC cell lines. Mechanical stretch-activated mechanosensitive receptors on ACCE cell membranes led to increased intracellular calcium levels and calpain activation, which cleaved Flna into Flna 90. Flna 90 facilitated the nuclear translocation of transcription factor Smad3/7 and TGF-β, promoting the expressions of EnMT genes. This EnMT process was reversible with Mg101. In vivo experiments showed that Mg101 reduced the incidence of AF and mitigated atrial fibrosis in CS-CREM mice. Conclusion: Mechanical stress induces cleaved Flna 90 from Flna in atrial endocardial endothelial cells, thus assisting transcription factors Smad3/7 and TGF-β in nuclear translocation, regulating EnMT and mediating atrial fibrosis.
Abstract 4140983: LVEF by echocardiogram does not correlate with findings on advanced cardiac imaging in cardiac sarcoidosis patients
Authors: Konner Feldhus, Briana Barkes, Lisa Maier, Jeffrey Swigris, Raphael Sung
Journal: Circulation (2024)

Background: Sarcoidosis is a systemic non-caseating granulomatous disease that can involve numerous organs, classically lung and lymph node. Patients with cardiac involvement typically have poorer outcomes, with left ventricular ejection fraction (LVEF) predicting mortality. There is little contemporary data evaluating the relationship of baseline LVEF at time of active cardiac sarcoidosis (CS) involvement or change in LVEF over time in patients with abnormal cardiac positron emission tomography (CPET) or cardiac magnetic resonance (CMR). Hypothesis: Abnormal CPET or CMR findings suggestive of CS will be associated with concurrently lower LVEF, as well as progressive decline in LVEF over long-term follow-up in those with CS. Methods: At a major sarcoidosis referral center, a retrospective analysis was performed on 1,901 biopsy-proven sarcoidosis patients and 358 probable CS patients by 2014 HRS Expert Consensus on Diagnosis. All echocardiograms, CPET, and CMR data were compiled. LVEF at time of positive and negative CMR and CPET within 6 months of each other, as well as LVEF change on long-term follow-up were analyzed by t-test and Tukey’s Studentized Range Test. Results: CPET and CMR positive findings did not correlate with lower LVEF at time of abnormal findings. Over an average of 4.98 years (range 0.25 to 11.68 years), LVEF by echocardiogram did not significantly change in patients with positive, negative, or discordant CPET/CMR imaging. Conclusions: Structural abnormalities by echocardiogram do not correlate with positive or negative CPET/CMR and are of little utility in early detection of cardiac sarcoidosis. These data suggest that combined CPET/CMR protocols increase the sensitivity of identifying early cardiac involvement of sarcoidosis. A normal echocardiogram should not be reassuring to the clinician against possible cardiac involvement of sarcoidosis.
Abstract 4141546: Acculturation Class Influences Physical Activity Among African Immigrants Living with Diabetes and/or Hypertension: A Qualitative Analysis
Authors: Onome Osokpo, Danny Bracy, Dolapo O Adeniji, Ayomide Okanlawon Bankole, Lisa Lewis, Barbara Riegel
Journal: Circulation (2024)

Background: Physical activity (PA) (e.g., walking) is critical for maintaining health, minimizing illness, and reducing mortality in adults living with diabetes and hypertension. Although acculturation may influence PA engagement, we know little about the PA of African immigrants who are more or less acculturated and factors perceived as barriers and facilitators to PA in this population. Methods: We conducted a descriptive qualitative study between March 2020 and September 2021 in the Northeastern U.S. We enrolled a purposive sample of 24 self-identified sub-Saharan African immigrant adults with symptomatic hypertension and/or diabetes. All spoke and understood English. Participants were classified as either high or low acculturated based on scores from a modified Short Acculturation Scale, reliability index (0.92), and validity index (0.65). Audio-recorded and transcribed interviews were imported to NVivo 13 and content analyzed to identify themes. Results: The sample was mean= 59 years (range 40-72). Most were Nigerian (n=16), male (n=16), married (n=17), living with family (n=21), highly educated (n=21), employed (n=16), and reported having enough to meet their needs (n=21). High acculturated participants were more (n=16). Both the high acculturated and low acculturated participants received information about PA from medical providers. Walking was the primary form of PA reported. Low acculturated participants walked with spouses/family members as is typically done back “home,” while high acculturated participants walked with friends/non-familial social connections, which is more Western. Although both groups used a treadmill or gym, only the high acculturated African immigrants had a gym membership. Family and friends facilitated PA; the high acculturated African immigrants were encouraged by friends to exercise, while the low acculturated stated that family motivated them to engage in PA. Arthritis, lack of enjoyment, mental stress, “laziness,” time, and neighborhood safety were barriers to engaging in PA. Conclusion: Interventions to promote PA should capitalize on socially relevant influences (e.g., family and friends) and address barriers to PA in immigrant populations.
Abstract 4141288: ETX-291: A GalOmic™ siRNA for the Treatment of Cardiometabolic Disease
Authors: Alexander Fischer, Natalie Pursell, Alan Whitmore
Journal: Circulation (2024)

Introduction: Cardiometabolic diseases significantly increase the risk of stroke and heart attack, leading causes of death worldwide. Due to the multifactorial nature of cardiometabolic diseases, residual cardiovascular risk remains with current monotherapies, highlighting the need for treatments with pleiotropic effects in at-risk populations. e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. HepNet™, ETX’s computational platform, identified the B4GALT1 gene as a key factor in metabolic disease. This link was supported by genetic evidence that individuals with B4GALT1 missense mutations have pronounced cardiovascular risk reduction. Together, this indicates that a GalOmic™ siRNA targeting B4GALT1 could be a potential treatment for cardiometabolic diseases. Methods: Potent siRNAs against B4GALT1 were designed in silico. siRNAs were screened in vitro in Huh7 cells, primary mouse and human hepatocytes, and in vivo in C57BL/6 mice for selection of the lead GalOmic™ siRNA, ETX-291. ApoE3*L.CETP mice on high-fat diet and fructose water were subcutaneously injected weekly with ETX-291 for 12 weeks. After 10 weeks, glucose tolerance tests were performed. Plasma fasting insulin, glucose, lipids, and fibrinogen were measured every 4 weeks and at study termination. Terminal cholesterol profiling and measurement of free fatty acids and liver mRNA expression were also performed. Results: ETX-291 displayed high potency in vitro and in vivo with long duration of action. Treatment of ApoE3*L.CETP mice with ETX-291 significantly reduced the cardiometabolic risk factors LDL and VLDL cholesterol, triglycerides, free fatty acids, and fibrinogen. ETX-291 significantly improved insulin resistance markers and normalized glucose tolerance tests. Conclusions: ETX-291, a GalOmic™ siRNA targeting B4GALT1 , positively affects multiple cardiometabolic risk factors in a humanized mouse model of metabolic disease. The pleiotropic mechanism of action beyond LDL-C lowering, combined with the validated risk reduction observed in individuals with B4GALT1 missense mutations, makes ETX-291 a promising candidate for clinical development. ETX-291 shows potential for therapeutic and preventative treatment in at-risk populations due to its favorable safety profile and prolonged duration of action.
Abstract 4141652: Duchenne Muscular Dystrophy Boys Have Diastolic Dysfunction Based on Cardiac Magnetic Resonance
Authors: Joseph Starnes, Jeffrey Weiner, Kristen GeorgeDurrett, Kimberly Crum, Christopher Henderson, Michael Campbell, Katheryn Gambetta, Kan Hor, Nazia Husain, Jennifer Li, Frank Raucci, Brian Soriano, Christopher Spurney, Larry Markham, Jonathan Soslow
Journal: Circulation (2024)

Introduction/Background: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). While cardiac magnetic resonance (CMR) is used routinely to assess fibrosis and left ventricular ejection fraction (LVEF), CMR measures of LV filling and ejection in DMD have not been reported. Hypothesis: We hypothesized that patients with DMD would have abnormal LV filling and ejection measures compared to healthy controls and that these measures would associate with mortality. Aims: We aimed to assess LV filling and ejection curves in patients with DMD compared to healthy controls and whether these measures associate with mortality. Methods: Prospectively enrolled DMD patients and healthy controls underwent CMR, including LVEF and LV filling and ejection curves. Multivariable linear regressions were used to compare filling and ejection measures between groups to adjust for baseline differences. Cox regressions were used to evaluate the relationship between diastolic function measures and mortality in the DMD cohort. Results: A total of 179 patients with DMD (mean age 14.3 years) and 96 healthy controls (mean age 14.4 years) were included. DMD patients had lower baseline LVEF, though most (112, 62%) had normal systolic function. When adjusted for age, sex, heart rate, body surface area, and left ventricular end diastolic volume (LVEDV), patients with DMD had slower peak LV filling rates (PFR) and peak LV ejection rates (PER) as well as slower time to PER (Table 1). When limited to DMD patients with normal LVEF, PER remained slower. When adjusted for heart rate, lower PER and PFR normalized to LVEDV were associated with mortality in patients with DMD (Table 2). Conclusions: Patients with DMD have different baseline CMR filling and ejection indices compared with controls, including when limited to DMD patients with normal LVEF. While filling indices associate with mortality in the short-term, longitudinal follow-up is needed to refine their prognostic role in DMD.
Abstract 4141614: Reducing the Risks of Complex Pediatric Cardiovascular Surgery using Glucagon-Like Peptide 1 Peptides
Authors: Robert Lao, Yasuyuki Kobayashi, Anamaria Stanisic, Wei Hui, Mimi Deng, Sachiko Kadowaki, M. Ahsan Siraj, Manya Lamba, Jing Li, Mark Friedberg, Mansoor Husain, Osami Honjo
Journal: Circulation (2024)

Background: Children with critical congenital heart disease (CHD) often require complex open-heart surgery with long aortic cross-clamp times (XC). Despite refinement in cardioplegia, ventricular dysfunction due to inadequate myocardial protection remains a major clinical challenge. Glucagon-like peptide-1 (GLP-1) has proven cardioprotective properties. This study characterizes the mechanisms of injury of long XC and investigates cardioprotective properties of GLP-1(28-36), a naturally occurring fragment of GLP-1. Method&amp;Results: A pediatric surgical model of cardiopulmonary bypass and long XC was developed in 4-5 wk-old Yorkshire pigs. Pigs were subjected to 90-min XC (modelling common CHD repair, e.g. Tetralogy of Fallot) or 180-min XC (modelling complex CHD repair, e.g. corrected transposition). After 90-min XC [n=8], analysis of cardiac function at baseline vs. 2-h post-bypass revealed reduced ejection fraction (55±6% vs. 28±4%; P&lt;0.001) and global longitudinal strain (-11.5±1.5% vs. -6.8±1.2%; P&lt;0.001). Levels of arterial lactate (0.6±0.1 vs. 3.9±0.8 mmol/L; P&lt;0.001), myeloperoxidase (MPO: 39±4 vs. 124±28 ng/mL; P&lt;0.001) and cardiac Troponin-I (cTnI: 0.01±0.01 vs. 4.8±0.6 ng/mL; P&lt;0.001) indicate metabolic- and oxidative-stress and cardiomyocyte injury. Markedly reduced survival after 180- vs. 90-min XC (37.5% vs. 100% survival; n=8/group, P&lt;0.05) was accompanied by more profound cardiac dysfunction, metabolic- and oxidative-stress, and cardiomyocyte injury in pigs surviving 180-min XC. Untargeted plasma metabolomics reveal XC time-dependent signatures ( Figure 1 ). Adding GLP-1(28-36) vs. control SCRAM(28-36) [30nM; n=8/group] to cardioplegia during 90-min XC caused longer time to first heart beat following XC (165±21 vs. 59±7 sec; P&lt;0.001), with markedly reduced oxidative stress (MPO: 74±19 vs. 131±30 ng/mL; P&lt;0.01) and cardiomyocyte injury (cTnI: 1.9±0.4 vs. 5.1±0.7 ng/mL; P&lt;0.001). Conclusions: In a new model of long XC designed to simulate pediatric surgical repair of common and complex CHD, we demonstrate time-dependent cardiac dysfunction correlating with metabolic- and oxidative-stress and cardiomyocyte injury. Treatment with GLP-1(28-36) reduced injury and may mediate this by inducing hibernation.
Abstract 4141285: Acute Hemodynamic Effects and Synthetic Cooling Agents in “Clear” E-cigarettes Marketed in Massachusetts After the Tobacco Product Flavoring Ban
Authors: Erika Minetti, Hanno Erythropel, Rachel Keith, Danielle Davis, Julie Zimmerman, Suchitra Krishnan-Sarin, Naomi Hamburg
Journal: Circulation (2024)

Introduction: Massachusetts (MA) enacted statewide regulation on all flavored tobacco products in June 2020. Thereafter, electronic cigarettes (e-cigarettes) labeled ‘clear’ emerged on the market. We studied the acute hemodynamic impact along with chemical analysis of ‘clear’ e-cigarettes of these novel products. Methods: In healthy young adults (age 18-45), we measured acute changes in blood pressure (BP) and heart rate (HR) following a 10-minute structured use of participants’ own e-cigarette, comparing ‘clear’ e-cigarette users with other flavored e-cigarette users and non-users. Chemical characterization and quantification of relevant flavorings and cooling agents (WS-3, WS-23) of 19 ‘clear’-labeled disposable e-cigarette liquids was carried out by gas chromatography/mass spectrometry. Results: Our data was collected between 04/2019-05/2023 and includes 22 ‘clear’ e-cig users, 115 non-‘clear’ flavored users and 73 non-users (Figure A). After the ban, participants that used ‘clear’ labeled e-cigarettes increased from 0% to 21%. Baseline BP and HR were similar across all groups. With acute use the increase in diastolic BP, mean arterial pressure, and HR was higher in ‘clear’ e-cigarettes users compared to both non-‘clear’ flavored e-cigarette users and non-users (Figure B). The greater increase in HR in ‘clear’ users remained when restricting non-‘clear’ users to Juul users (products that do not contain synthetic coolants) (8.9±7.4 vs 4.5±7.9, P=0.03). All (19/19) ‘clear’ e-liquids were found to contain synthetic cooling agents WS-23 and/or WS-3, most (18/19) contain menthol, with selected products also containing other flavorants (Figure C). Conclusion: The presence of menthol and synthetic cooling agents alongside other flavorings in newly marketed ‘clear’ e-cigs is a direct violation of the MA flavored tobacco product regulation. Acute use of ‘clear’ e-cigarette led to greater hemodynamic effects compared to other flavored e-cigarettes and Juul, raising questions about the health effects of cooling agents. Monitoring novel products and their constituents to assess their health effects is needed to protect young adults.
Abstract 4140940: Re-adjudication and Contemporary Classification of Myocardial Injury Events in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Shubham Tomar, Karita Lidani, Matthew Decker, Patrick Trainor, Craig Johnson, Susan Heckbert, Robyn McClelland, Michael Blaha, Khurram Nasir, Andrew DeFilippis
Journal: Circulation (2024)

Background: The 4th Universal Definition of Myocardial Injury (UDMI) recognizes several categories of myocardial injury, including acute myocardial infarction (MI) which is further sub-classified into five types. However, data on these different types of myocardial injury and their risk factors is limited. Methods: In the MESA study of 6814 participants, 15905 clinical events were identified over the first 14 years, 4079 of which meet MESA criteria for physician adjudication for a possible cardiovascular event. Herein, we developed a standardized data format and a REDCap tool with an interactive robust logic algorithm to re-adjudicate all 4079 cases for the presence and classification of all 9 types of myocardial injury as defined by the 4 th UDMI. Adjudication process as shown in Figure 1 . The prevalence of myocardial injury types was evaluated using descriptive statistics, and adjudicator agreement was assessed using Cohen’s kappa (κ) statistics and percent agreement. Results: Out of 4079 events, adjudication is completed on 2282, of which 15% classified into subtypes of myocardial injury. Adjudication was achieved for 91% of the events in phase 1, 7% in phase 2, 2% in phase 3. The overall agreement between two adjudicators for the presence of myocardial injury was 91% (κ: 0.67), but the agreement for the specific subtype was 53% (κ: 0.38). The most common events were Type 1 MI (N= 114), followed by Type 2 MI (N= 95), and Acute non-ischemic myocardial injury (N= 85) ( Figure 2 ). Compared to the original MESA adjudication for the presence of MI, 97% (N= 72) of probable MI and 8% (N= 174) of no MI were reclassified into five and six types of myocardial injury events respectively. Conclusion: This study highlights the complexities in identifying subtypes of myocardial injury based on current definition. This study provides a novel dataset to explore diverse correlations with these myocardial injury subtypes.
Abstract 4141601: A Multimodality Education Model Improves Healthcare Professionals' Competency in Managing Cardiovascular Risk Factors in Type 2 Diabetes: A Mixed-Methods Study
Authors: Divya Madhusudhan, Oge Okeke, Sarah Bradley, Caroline Blanco, Esteban Perla, Ruby Jennings, Kylie Picou, Patrick McWeeny, CarriAnne Crabill, Alyssa Pressley, Nuha El Sayed
Journal: Circulation (2024)

Introduction: Cardiovascular disease (CVD) is the leading cause of death among people with type 2 diabetes, significantly contributing to heart attacks, strokes, and heart failure. The complex interplay between diabetes and cardiovascular risk factors necessitates ongoing medical education to advance guideline-directed care for diabetes and CVD in clinical practice. To address this need, the American Diabetes Association and American Heart Association developed a multimodality professional education model as part of the 'Know Diabetes by Heart (KDBH) ' initiative, to provide healthcare professionals with the latest insights and evidence-based practices in diabetes management. Methods/Approach: Introduced in a phased rollout over two years (June 2022-April 2024), this model includes 9 webinars, a comprehensive certification program, and 4 interactive gamified case study series. Utilizing a pre-and-post evaluation design grounded in the Kirkpatrick evaluation framework, we assessed the effectiveness of each education modality on key indicators of competency, confidence, and participant satisfaction. Wilcoxon signed-rank test compared pre- post intervention responses. Results: The study demonstrates robust engagement in a multi-faceted education model, with 2079 webinar attendees, 1,512 certification course participants, and 1,638 gamified case study participants. A sub-analysis of webinar participants (n=651) shows a statistically significant improvement in clinical competency (p&lt;0.001, r=0.47-0.50) and confidence (p&lt;0.001, r=0.16-0.24), with 87.4% satisfaction rate. Certification course participants (n=326) exhibit notable improvements in clinical competency (p&lt;0.001, r=0.60-0.68) and confidence (p&lt;0.001, r=0.55-0.61), with a satisfaction rate of 86.1%. Gamified case studies indicate a 24.3% proficiency increase. Qualitative interviews (n=19) highlight improvement in skills such as making informed treatment decisions, refining practice management workflows, enhancing patient-provider communication, and advocating for patient needs. Conclusion: This multimodality education model effectively engages healthcare professionals through diverse learning styles and formats, leading to significant improvements in competency and confidence in managing cardiovascular risk factors in patients with type 2 diabetes. This highlights the model's value and relevance in contemporary medical education. Future analysis will illustrate the long-term impacts of this educational approach.