tbuckley/cabot-search huggingface dataset:
Abstract 4144040: Porcine Coronary Plaque Morphology And Composition Closely Resemble Different Stages of Human Atherosclerosis
Authors: Mingqiao Li, Patrice Delafontaine, Sergiy Sukhanov
Journal: Circulation (2024)

Background: Coronary heart disease (CHD) remains the primary cause of mortality and morbidity in the USA. Although rodents are widely used to explore mechanisms, they have major biological differences with humans. Pigs develop CHD similar to humans, and pigs are the FDA-preferred species for testing anti-atherosclerotic drugs. Pigs with familial hypercholesterolemia (FH pigs) are known to develop advanced atheromas containing thin fibrous caps, and large necrotic cores. However, little is known about the porcine plaque phenotype and whether pigs develop a full range of coronary plaques similar to humans. Aims: To quantify the distribution of porcine coronary plaque types, assess plaque morphology and cellular composition to obtain insights into mechanisms of atherosclerosis in a large animal model and to facilitate development of new therapies. Methods: Right coronary and left anterior descending arteries were dissected from FH pig hearts (n=9), each artery split into 6 fragments and a total of 108 vascular fragments were used to obtain cross-sections. The sections were stained with Trichrome to quantify intima/media thickness ratio (IMT), medial and necrotic core areas. The sections were also used for immunohistochemistry with cell marker antibodies (to measure % plaque smooth muscle cells (SMC), macrophages (MF), and endothelial cells (EC)). Cell apoptosis was assessed by TUNEL assay. Results: All vascular fragments were classified into 4 groups based on IMT (from A to D). Increase in IMT significantly correlated with elevation in total vessel area (A: 3.8mm 2 to D: 7.2mm 2 ), increase in necrotic core area (B: 13.8% to D: 30.7%), elevation in plaque MF (A: 16.7% to D: 22.5%), increase in plaque cell apoptosis (A: 5.2% to D: 17.4% apoptotic cells) and with thinning of vascular media (A:1.3mm 2 to D: 0.74mm 2 ), decrease in number of plaque SMC (A: 62.5% to D:17.9%) and plaque EC (A:3.21% to D:1.48%). We assigned each porcine plaque group to the corresponding type of human plaque: A, human type III, early lesions, 28% of all coronary plaques; B, type III/IV, fibrous plaque, 43%; C, type V, fibroatheroma, 16%; D, type VI, complicated lesions, 13%. Conclusions: Like humans, pigs develop plaques that range from early lesions to advanced atheromas resembling type III-type VI lesions. These findings provide a rationale to use FH pigs to test the effect of novel anti-atherosclerotic drugs on the full range of coronary plaques mimicking human settings.
Abstract 4144199: Safety of Discontinuing Secondary Antibiotic Prophylaxis After Echocardiographic Normalization in Early Rheumatic Heart Disease, GOAL-Post Study
Authors: Joselyn Rwebembera, Jafesi Pulle, Emma Ndagire, Emmy Okello, Daniel Engelman, Anneke Grobler, Craig Sable, Andrew Steer, Andrea Beaton
Journal: Circulation (2024)

Background: The current standard for children diagnosed with rheumatic heart disease (RHD) is secondary antibiotic prophylaxis (SAP) for at least 10 years or to a minimum age of 21. However, these recommendations were developed prior to the widespread use of echocardiography and based largely on expert opinion. A recent clinical trial in Uganda found that up to 50% of children with early RHD show echocardiographic normalization by 2 years. More research is needed to understand if continued SAP is needed after echocardiographic normalization. Hypothesis: There is a low risk of RHD recurrence in individuals who have had normalization of their echocardiogram following early RHD diagnosis. Aim: To determine the 2-year safety of not providing SAP to children and adolescents with early RHD who have shown echocardiographic normalization. Methods: The GOAL trial in Uganda, 2018-2021, compared SAP with Benzathine Penicillin G (BPG) to no prophylaxis among children with early RHD. GOAL-Post is a non-randomized prospective extension study of the GOAL Trial. Children with echocardiographic normalization at the end of GOAL, regardless of treatment arm, were followed prospectively without SAP, for 2 additional years. Echocardiograms were performed at the end of follow-up, uploaded to a cloud server, and interpreted by a four-person adjudication panel. Recurrence was determined by side-by-side comparison with GOAL enrollment and completion studies. Results: Of 345 eligible participants, 330 (96%) were enrolled, mean age 16 years (SD = 2.3), 56% female, and all completed the two-year follow-up. Only one of 330 (0.3%) progressed to moderate/severe RHD after the 2 years, and an additional 26 participants (7.9%) had evidence of mild RHD, which was clinically comparable to their cardiac status at the start of the GOAL Trial. No participants had clinical signs or symptoms of RHD and no documented rheumatic fever. This means that 99% of children and adolescents who had echocardiographic normalization were safe from moderate/severe RHD and 92% were safe from any RHD, without SAP. Conclusion: These findings suggest that it may be safe to consider stopping of SAP among children who show echocardiographic normalization, providing more individualized recommendations for SAP duration, rather than the current model of long-term SAP for all. Further study is needed including a stoppage of SAP trial, to generate higher quality evidence for this approach.
Abstract 4144227: Sustained Moderate to Vigorous Physical Activity Modifies the Association Between Body Weight Changes and Survival in Stroke Patients
Authors: Sae Young Jae, Dong-Hyuk Cho, Jimi Choi, Jun Gyo Gwon
Journal: Circulation (2024)

Background: The relationship between body weight changes and survival after stroke diagnosis is complex and influenced by various factors. While higher levels of physical activity (PA) are known to improve post-stroke outcomes, it remains unclear whether PA status can impact the association between body weight changes and survival in stroke patients. This study tested the hypothesis that sustained moderate to vigorous physical activity (MVPA) modifies the association between body weight changes and all-cause and cardiovascular mortality in stroke survivors. Methods: This retrospective study followed 32,905 ischemic stroke patients registered with the National Health Insurance Service. Body mass index (BMI) and PA were measured for three years prior to and two years following stroke diagnosis. Changes in BMI were classified as BMI loss, BMI stable, and BMI gain, while changes in MVPA were classified as persistently inactive, MVPA initiation, MVPA quitting, or MVPA continuation. Outcomes included all-cause mortality (ACM) and cardiovascular mortality (CVM). Results: During a median follow-up of 6 years, we identified 4,379 cases of ACM and 1,349 cases of CVM. In adjusted models compared with the stable BMI-inactive, the hazard ratios (HRs) indicated a higher risk of ACM (HR 1.68, 95% CI 1.42-1.98) and CVM (HR 1.74, 95% CI 1.30-2.33) in the BMI loss-inactive, and a higher risk of ACM (HR 1.66, 95% CI 1.40-1.96) and CVM (HR 1.89, 95% CI 1.40-2.54) in the BMI loss-MVPA quitting. However, these risks were not observed in the BMI loss-MVPA continuation (HR 1.00, 95% CI 0.85-1.18 for ACM; HR 0.96, 95% CI 0.72-1.29 for CVM). Conversely, the BMI gain-MVPA continuation had a lower risk of ACM (HR 0.72, 95% CI 0.61-0.85) and CVM (HR 0.74, 95% CI 0.54-1.00), but this was not observed in the BMI gain-inactive (HR 0.95, 95% CI 0.79-1.15 for ACM; HR 0.89, 95% CI 0.64-1.24 for CVM), compared with the stable BMI-inactive. Conclusions: Sustained MVPA significantly modifies the association between body weight changes and survival in ischemic stroke survivors. Body weight loss combined with inactive increases the risk of death, whereas continued MVPA mitigates these risks. Body weight gain with ongoing MVPA is associated with lower mortality risks. These findings highlight the importance of sustained PA in improving survival outcomes post-stroke and suggest that PA plays a crucial role in modulating the obesity paradox in stroke patients.
Abstract 4144059: Predictors of Sudden Cardiac Arrest Presenting with Pulseless Electrical Activity
Authors: Harpriya Chugh, Kyndaron Reinier, Audrey Uy-Evanado, Arayik Sargsyan, Sumeet Chugh
Journal: Circulation (2024)

Background: The prevalence of sudden cardiac arrest (SCA) manifesting as pulseless electrical activity (PEA) has been rising, survival outcomes are poor and there are no known treatments. Little is known about the clinical profile of these individuals who present with PEA-SCA. Hypothesis: Individuals presenting with PEA-SCA have unique clinical profiles that can be determined from their lifetime clinical records and resting 12-lead ECG. Methods: From an ongoing prospective, population-based study of out-of-hospital SCA in the Northwestern US (catchment pop. ≈1 M, 2002-2020), we identified adults with PEA-SCA. Comparisons of lifetime medical records and resting 12-lead ECG closest and unrelated to the SCA event were made with a control group of which 70% had known coronary artery disease (CAD). The data archive was divided, a priori, into training and validation datasets. Prediction models were constructed using backwards stepwise logistic regression, with a p value of 0.05 to retain variables in the training dataset and applied to the validation dataset. Results: A total of 604 PEA-SCA cases (male 64%, age 72±14yr) and 1418 controls (male 68%, age 66±2yr) had medical history and ECG available. The full dataset was divided into training (67%) and validation (33%) subsets. A multivariable logistic regression model in the training dataset showed that cases were older, had higher odds of using anti-psychotic medications, and higher odds of stroke, heart failure, kidney disease, chronic obstructive pulmonary disease, seizure disorder, syncope, anemia and hyperthyroidism. ECG heart rate &gt;75 bpm, Tpeak to Tend interval ≥90 ms and delayed QRS transition zone were also associated with higher risk of PEA SCA (Table). Cases had lower odds of hypothyroidism and myocardial infarction. The model displayed very good discrimination in the training dataset (C statistic 0.86 [0.836-0.88]) and was successfully validated (C statistic 0.81 [0.77-0.84]). Conclusion: A model that combined clinical profile with ECG variables showed very good discrimination for prediction of PEA-SCA vs. controls with CAD. These findings have implications for future investigations targeted at improving prevention and management of SCA presenting with PEA.
Abstract 4144084: Enhanced External Counterpulsation as a Novel Treatment for Heart Transplant Candidates with Ischemic Heart Failure with Reduced Ejection Fraction
Authors: Asif Ali, Sami Farooqui, Emad Khalid
Journal: Circulation (2024)

Introduction: Enhanced External Counterpulsation (EECP) is a noninvasive outpatient therapy designed to improve arterial health, cardiac efficiency, and coronary collateral formation by applying sequential external pressure aligned with the patient’s cardiac cycle. It is primarily indicated for refractory angina that is not amenable to PCI or CABG with the opinion of a cardiologist. EECP can improve exercise tolerance, reduce anginal symptoms, and enhance endothelial function, offering a potential alternative for patients with ischemic HFrEF awaiting heart transplantation. Description of a Case: A 58-year-old Hispanic female with a history of severe CAD, type II DM, hyperlipidemia, and CVA. A transthoracic echocardiogram (TTE) revealed a dilated LV with an EF of 20%, left atrial enlargement, severe mitral regurgitation, moderate tricuspid regurgitation, right ventricular systolic pressure of 42 mm HG, trivial pericardial effusion, akinesis of the inferior wall, and hypokinesis of the anterior wall. Despite being a heart transplantation candidate, she declined revascularization and sought alternative treatments for angina, dyspnea, and daily activity limitations. The patient underwent EECP, consisting of 35 one-hour sessions over seven weeks. Following EECP, the patient demonstrated improvements in her Canadian Cardiovascular Society angina score (IV to I), New York Association class (IV to I), six-minute walk test performance, and EF (increased to 55%, observed from TTE). Due to these improvements, she was delisted for heart transplantation. Discussion: This case illustrates the potential of EECP as an effective noninvasive treatment for patients with symptomatic ischemic HFrEF who are awaiting heart transplantation but are ineligible or unwilling to undergo surgical interventions. Not only did EECP improve the patient's angina and functional status, but it also enhanced her cardiac function. Based on the findings of this case report, further studies should be done to expand the indications of EECP to include HF and other similar patient populations. EECP may alleviate the need for heart transplantation through its integration as a standard early intervention.
Abstract 4144122: Genetic Modulation of Cytoglobin Expression Regulates Vascular Nitric Oxide Metabolism, Vascular Tone and Blood Pressure
Authors: Elsayed Mahgoup, Sahar Khaleel, Mohamed Ewees, Mahmoud Eid, Jay Zweier
Journal: Circulation (2024)

Background: The recently identified globin Cytoglobin (Cygb), in the presence of cellular reductases, has potent nitric oxide (NO) dioxygenase (NOD) activity and serves as the major pathway of O 2 -dependent NO metabolism in vascular smooth muscle. While genetic deletion of Cygb greatly decreases vascular NO metabolism, vessel tone and blood pressure (BP), the effects of increasing or partially decreasing Cygb expression are unknown. Objective: Therefore, we investigate how upregulating or downregulating Cygb expression affects NO metabolism, vessel relaxation and BP. Methods: Wild-type (WT), Cygb -/+ (HET), Cygb -/- knockout (KO), and Cygb overexpressing (OE) mice were used to determine the effect of Cygb expression levels on NO metabolism and vascular function. Cygb levels were assayed by quantitative immunoblotting. NO diffusion across the aortic wall was measured by electrode. BP was measured by tail-cuff, and endothelial-dependent vasorelaxation by the concentration-dependent acetylecholine (Ach) response in phenylephrine-preconstricted aortic rings using a strain gauge myograph. Results: In HET mice Cygb levels were 50% of WT and in OE 500% of WT. NO diffusion flux across the aortic wall was greatly increased by the decrease/abolition of Cygb expression in HET and KO mice with 2.8 and 5.1-fold increase from WT, respectively (n= 5-7/grp, p &lt;0.01 and p &lt;0.001, respectively) (Fig. 1 A&amp;B). However, in OE mice NO flux was 2.2-fold decreased (n=5-7/grp, p =0.05). Mean BP (MBP) was 29% decreased in KO and 22% in HET (n= 21/grp, p &lt;0.01). In OE mice, MBP was 9% increased, compared to WT, p &lt;0.05 (Fig. 1 C). In aortic vessels of Cygb KO and HET, there was a marked shift to the left in the Ach relaxation-response curve, with 50% relaxation seen at 0.34 nM or 8.6 nM Ach, respectively, compared to 154 nM in WT (n= 6/grp, p &lt;0.0001). In contrast, a rightward shift was seen in Cygb OE vessels with 50% relaxation at 930 nM, p &lt;0.0001). Conclusion: Changing Cygb expression levels alters NO diffusion through the vessel wall in turn modulating vascular tone and BP. Therefore, modulation of Cygb expression could serve as a novel approach for the regulation of vascular tone in the treatment of cardiovascular disease.
Abstract 4144048: Propensity Score-Matched Analysis of GLP-1 Agonists' Impact on Clinical Cardiovascular Outcomes in Patients with Concurrent Heart Failure and Atrial Fibrillation
Authors: Toluwalase Awoyemi, Anderson Anuforo, Habib Alagbo, Isaac Ogunmola, Stephen Gbekor, Mishael Awe, Emmanuel Daniel
Journal: Circulation (2024)

Background: Heart failure (HF) and paroxysmal atrial fibrillation (AF) are major causes of morbidity and mortality, each exacerbating the other and leading to poorer outcomes. Glucagon-like peptide-1 agonists (GLP-1a), primarily used for glycemic control in type 2 diabetes, may offer cardiovascular benefits in patients with concurrent HF and paroxysmal AF. Objective: This study aims to evaluate the impact of GLP-1a on clinical outcomes in patients with concurrent HF and paroxysmal AF. Methods: This retrospective study utilized data from 51,446 HFrEF patients across 91 global healthcare organizations between January 2014 and August 2023. Propensity score matching (PSM) analysis was used to compare cardiovascular outcomes such as all-cause mortality, the need for new antiarrhythmic medication, cardioversion, AF ablation, incidence of acute myocardial infarction (AMI), and cardiac arrest, between those treated with GLP-1a and those who were not. Results: Our analysis revealed that the GLP-1a group had significantly lower odds of requiring cardioversion (3.1% vs 5.0%, OR = 0.67, 95% CI: 0.45–0.99, p=0.041), AF ablation (1.7% vs 3.7%, OR = 0.51, 95% CI: 0.27–0.98, p=0.038), new antiarrhythmic drugs (12.0% vs 13.9%, OR = 0.81, 95% CI: 0.66–0.99, p=0.036), experiencing AMI (OR: 0.70, 95% CI: 0.50–0.98, p=0.035), experiencing cardiac arrest (OR: 0.54, 95% CI: 0.37–0.80, p=0.002), and all-cause mortality (OR: 0.59, 95% CI: 0.51–0.68, p&lt;0.001) compared to the non-GLP-1a group. There were no significant differences between the groups in the need for pacemaker/ICD implantation, development of persistent or long-standing persistent AF, or the risk of ventricular fibrillation or flutter. Furthermore, Kaplan-Meier analysis showed a higher 5-year incidence-free probability of cardiac arrest (94.9% vs 90.5%), AMI (90.2% vs 87.2%, p=0.017), and a higher 5-year survival probability (62.3% vs 51.2%, p&lt;0.001) in the GLP-1a group compared to the non-GLP-1a group Conclusion: GLP-1a treatment is associated with improved clinical cardiovascular outcomes, including reduced need for new antiarrhythmic drugs, AF ablation, cardioversion, lower incidence of AMI, cardiac arrest, and all-cause mortality in patients with concurrent HF and paroxysmal AF. These findings suggest potential therapeutic benefits of GLP-1a. Additional studies are recommended to validate these findings and investigate the underlying mechanisms.
Abstract 4144255: Treatment of Human Engineered Heart Tissue with Serum from Cancer Patients with Clonal Hematopoiesis of Indeterminate Potential Cytokine Leads to Impaired Function
Authors: Harleen Kaur, Saiti Halder, Jeacy Espinoza, Nathan Chen, Jennifer VanOudenhove, Giulia Biancon, Sean Gu, Raja Chakraborty, Kanika Jain, Jinkyu Park, Yibing Qyang, Eiman Ibrahim, Stephanie Halene, John Hwa, Stuart Campbell, Alokkumar Jha, Jennifer Kwan
Journal: Circulation (2024)

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) has been shown to be an independent risk factor for heart failure and is associated with increased cardiomyopathy and mortality in cancer patients. Given that CHIP is associated with increased inflammatory cytokines, we sought to characterize the CHIP secretome in cancer patients and its impact on human engineered heart tissue (EHT) function. Methods: We used machine learning to identify top cytokine features associated with CHIP in a cardio oncology cohort of 173 patients. Serum from breast cancer patients who were age, co-morbidity and medication matched between CHIP and non CHIP were used in the experiments. We used human EHTs to assess whether CHIP serum treatment affects contractility and used RNA sequencing to identify significantly differentially expressed pathways. Cytokine profiling of serum samples was done using a Luminex platform for 71 human cytokines. Results: Machine learning identified IL-1B and CD40L as two top features of CHIP. Given DNMT3A CHIP was the most common in the cardio onc cohort, we focused on evaluating the effect of DNMT3A CHIP serum on EHT function. Compared to non CHIP serum, DNMT3A CHIP serum significantly reduced EHT contractility (p= 0.03). To evaluate whether the top cytokines identified by our machine learning model could contribute to the impairment in contractility, we co-incubated CHIP and Non-CHIP serum treated EHTs with antagonists of IL-1B or CD40L. Treatment with either IL-1B or CD40L antagonists rescued contractility defects in CHIP serum treated EHTs (p=0.015, 0.0095, respectively) but had no significant impact on non CHIP serum treated EHTs. RNA sequencing of EHTs and pathway analysis revealed differential expression of genes and pathways in CHIP-treated and Non-CHIP serum-treated EHTs as well as in IL-1B antagonist and CD40L antagonist treated EHTs. Inflammation, metabolism pathways were top pathways differentially regulated in CHIP vs non CHIP serum treated EHTs and antagonist treatment showed modulation of these pathways. Conclusion: Identification of IL-1B as a top feature of CHIP is consistent with prior work. CD40L, however, has not previously been implicated in CHIP and may be more unique to cancer patients with CHIP. We show that antagonizing this pathway was able to rescue the contractility defect in CHIP serum treated EHTs, which could be another therapeutic target in patients with CHIP. The effect of other CHIP variants are underway.
Abstract 4144032: Decadal Trends in Heart Failure Prevalence (2013-2023) Among Women of Childbearing Age with Prior Adverse Pregnancy Outcomes: Insights from a Population-Based Study
Authors: Toluwalase Awoyemi, Dania Jaamour, Anderson Anuforo, Chinenye Odo, Oluwaremilekun Tolu-Akinnawo
Journal: Circulation (2024)

Background: Heart failure (HF) represents a critical public health concern, especially among women of childbearing age, where its prevalence has been steadily increasing over recent years. Women with prior adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, gestational diabetes mellitus, or preterm birth, face an elevated risk of developing heart failure later in life. Methods: This study investigated heart failure prevalence and trends over the period 2013 to 2023, leveraging data from 64 healthcare organizations within the TriNetX global health research network within the US Collaborative Network. The cohort consisted of 979,178 females aged 15-60 who had maternal care-related encounters and were diagnosed with specific conditions indicative of adverse pregnancy outcomes. These conditions included hypertensive disorders of pregnancy, gestational diabetes mellitus, placenta previa, intrauterine growth restriction, or macrosomia. Prevalence rates were calculated annually and stratified by age and race. The analysis encompassed January 1, 2013, to December 31, 2023, with a one-day lookback period. Results: Across the decade from 2013 to 2023, there was a notable surge in heart failure prevalence, escalating from 0.39% to 1.26%, corresponding to an average annual increase of approximately 12.38%. When examining racial disparities, Asians exhibited the lowest prevalence rates, initiating at 0.236% in 2013 and ascending to 0.673% in 2023, with an average annual increase of roughly 10.1%. Of note, the Black or African American cohort manifested the highest prevalence rates in both 2013 (0.708%) and 2023 (2.35%), with an average annual increase of approximately 12.77%. Within the 45-49 years age group, prevalence surged from 1.69% to 2.57%, signifying an average annual rise of about 4.36%, highlighting the escalating burden of heart failure among middle-aged adults. Conclusions: This study illuminates a concerning surge in heart failure prevalence over the past decade, revealing alarming rises across age and racial demographics. Particularly noteworthy is the heightened impact on younger individuals and certain minority groups, notably Black or African American patients.