tbuckley/cabot-search huggingface dataset:
Abstract 4140048: The Critical Role of Visceral Adipose Tissue in the Temporal Progression of Cardiac Remodeling Due to Pressure Overload
Authors: Alissa TARRAF, Jose-Americo Nabuco Leva Ferreira Freitas, Thais Delmont, Dogus Altintas, Costin Radu, Maria Pini, Gabor Czibik, thierry folliguet, yanyan ZHANG, Oliver Bischof, Genevieve Derumeaux
Journal: Circulation (2024)

Background: Myocardial fibrosis is a key indicator of cardiac remodeling caused by pressure overload, involving a complex interplay of mechanical, inflammatory, and neurohormonal factors. Our recent studies reveal a harmful interaction between visceral adipose tissue (VAT) and the heart during aging, where profibrotic proteins from VAT and plasma contribute to heart fibrosis. We hypothesize that transverse aortic constriction (TAC)-induced pressure overload induces VAT remodeling and VAT profibrotic secretome that aggravates cardiac fibrosis and compromises heart function. Purpose: - To determine the interaction between VAT and heart -To assess the time course of TAC-induced transcriptomic changes in presence or absence of VAT Methods: We divided wild-type male mice (5-month-old, n=10/group) into four groups: a visceral Lipectomy group and a Sham group two weeks before either a moderate TAC (26G; i.e. gradient between left ventricle and aorta of 30mmHg) or a sham surgery. We sacrificed the mice at 1- and 8-week after TAC. We performed in vivo metabolic tests, echocardiography, and invasive hemodynamics, followed by ex vivo tissue analysis. We subsequently examined cardiac transcriptomic changes in TAC versus control groups, as well as the effect of visceral lipectomy through RNA-seq followed by Partial Least Squares Regression and Over-Representation Pathway Analysis. Results: TAC-induced cardiac pressure overload initiates a pathological heart-VAT crosstalk stimulating a senescence-like profibrotic (TGFb, Spp1) and proinflammatory secretory phenotype (TNFa, IL6, PAI1) in VAT as early as 1 week after TAC. Importantly, we demonstrate that VAT lipectomy reverses TAC-induced cardiac remodeling and restores normal heart function. Transcriptomic analyses show the powerful effect of TAC on gene expression, notably profibrotic (MMP9, TGFb1, Col1a1) and prohypertrophic genes (Nppa, Nppb) increase. After 1 week, TAC had a stronger effect than lipectomy, while 8 weeks post-TAC, lipectomy could reverse all the transcriptomic changes induced by TAC with a transcriptomic profile of TAC+lipectomy similar to sham group. Conclusion: This study highlighted the exacerbation by VAT of the detrimental impact of TAC on the heart. Our findings show a dynamic crosstalk between the heart and VAT orchestrated by the secretome of the adipose tissue resulting in transcriptomic and physiological heart changes.
Abstract 4140565: Chimpanzee Induced Pluripotent Stem Cells (iPSCs)-derived Cardiomyocytes as Surrogates for Human iPSCs in Cardiomyocyte Research and Cross-Species Chimeric Embryo Development
Authors: Morteza Roodgar, Maryam Parham, Fabian Suchi, Vivek Bajpai, Hiromitsu Nakauchi, Joseph Wu, Michael Snyder
Journal: Circulation (2024)

Induced pluripotent stem cells (iPSCs) provide valuable insights into early tissue and organ development, with potential applications in cross-species comparative studies. Nonhuman primate (NHP) iPSCs, particularly those derived from chimpanzees (Pan troglodytes), which share the closest evolutionary relationship with humans, offer a unique opportunity to study cardiomyocyte comparative developmental physiology. Given the limitations of using human cells, chimpanzee iPSCs can serve as an effective surrogate in earliest stages of embryonic development. In this study, we derived and maintained chimpanzee iPSCs under novel optimized conditions. We investigated the compatibility of human and chimpanzee iPSCs and their derived cardiomyocytes by co-culturing and differentiating these cells into cardiomyocytes. Our results demonstrate that mixed colonies of human and chimpanzee iPSCs can form homologous intermix colonies and differentiate into synchronized beating cardiomyocyte layers. This high level of compatibility suggests similar differentiation pathways in both species. Utilizing chimpanzee iPSCs as surrogates for human iPSCs, we assessed their potential in forming primate cross-species chimeric preimplantation embryos. When injected into early rhesus macaque blastocysts, chimpanzee iPSCs were able to survive and proliferate near the inner cell mass. Our study not only introduces a new resource of NHP iPSCs with detailed transcriptome and proteomics characterizations but also highlights the high compatibility of chimpanzee and human iPSC-derived cardiomyocytes, evidenced by the formation of synchronized beating layers during co-culture experiments. These findings hold significant implications for advancing our understanding of cardiomyocyte development and potential therapeutic applications.
Abstract 4140419: Targeting Cardiac Fibrosis with Chimeric Antigen Receptor Neutrophils from Human Pluripotent Stem Cells
Authors: Gyuhyung Jin, Xiaoping Bao
Journal: Circulation (2024)

Cardiac fibrosis is a pathological hallmark of almost all forms of heart disease, characterized by excessive deposition of extracellular matrix (ECM) proteins by activated fibroblasts, leading to cardiomyocyte hypertrophy, arrhythmias, and heart failure. Current treatments, predominantly pharmacological, target signaling pathways involved in fibroblast activation but often come with side effects such as cardiac toxicities. There is a critical need for therapies that specifically target activated cardiac fibroblasts to mitigate these adverse effects. Recent advances have shown that chimeric antigen receptor (CAR)-T cells targeting fibroblast activation protein (FAP), expressed by activated fibroblasts, can significantly reduce fibrosis and improve cardiac function in mouse models. However, CAR-T cell therapies face challenges such as the requirement for large quantities of healthy primary immune cells, lengthy process, and the high cost of personalized treatments. To address these issues, we propose an innovative strategy using off-the-shelf CAR-neutrophils derived from human pluripotent stem cells (hPSCs). We hypothesize that hPSC-derived CAR-neutrophils engineered to target FAP will effectively reduce cardiac fibrosis and improve cardiac function post-injury due to their potent cytotoxic effects and ability to infiltrate infarct regions. To test this hypothesis, anti-FAP CAR hPSCs were generated by CRISPR/Cas9 genome editing and differentiated into neutrophils. The differentiated anti-FAP CAR hPSC-neutrophils exhibited molecular characteristics comparable to unmodified hPSC-neutrophils. We also established an in vitro cardiac fibrosis model utilizing a previously reported protocol for the generation of hPSC-derived epicardial fibroblasts. Importantly, our anti-FAP hPSC-neutrophils exhibited significant cytotoxicity against activated epicardial fibroblasts, while unmodified hPSC-neutrophils showed no/minimal killing efficiency. This study suggests a proof-of-concept therapeutic approach against cardiac fibrosis utilizing FAP-targeting CAR-neutrophils. This strategy can potentially be adapted to treat fibrosis in other organs, thereby having a broad and significant impact on the treatment of various fibrotic diseases, ultimately contributing to longer, healthier human lives.
Abstract 4140321: Assessment performance of the AHA PREVENT equations in disaggregated Asian and Hispanic Subgroups
Authors: Xiaowei Yan, Adrian Bacong, Qiwen Huang, Hannah Husby, powell jose, Latha Palaniappan, Fatima Rodriguez
Journal: Circulation (2024)

Background: New race-free Predicting Risk of Cardiovascular disease (CVD) EVENT models (PREVENT) by AHA predict 10-year total CVD, ASCVD, and heart failure (HF), respectively. Although model discrimination and calibration was generally good among Non-Hispanic White and Black, their performance among Asian and Hispanic groups, particularly in disaggregated subgroups, remain unknown. Objectives: We assessed PREVENT model performance in a diverse population with more than 10-year follow-up electronic health records (EHR) data in different race/ethnic groups and in disaggregated Asian and Hispanic subgroups. Methods: Using retrospective primary care cohort who had no baseline CVD and with at least 10-year follow-up EHR data, we estimated Harrel’s C-statistics for each PREVENT submodel and by race/ethnicity. Predicted risk based on PREVENT models verse observed corresponding CVD event risk were compared in each race/ethnicity group and Asian/Hispanic subgroups. Results: Over 191,000 primary care patients were identified and met the study criteria, with 58.5% non-Hispanic white (NHW), 3.2% non-Hispanic Black (NHB), 21.4% non-Hispanic Asian (NHA) and 10% Hispanic. Across three PREVENT sub-models, model performance in discriminating corresponding CVD event was comparable with those in the original model development and validation cohort, with best performed on NHA (C-statistics&gt;0.80) for all three models, poorest on NHB (C-statistics ranges 0.75-0.77). However, each model underestimated the risk for overall population, with most underestimated for NHB, but overestimated for NHA. Within NHA, total CVD model performed best in Asian Indian and Vietnamese (C-statistics: 0.88) and poorest on Japanese (C-statistics =0.78), ASCVD model performed best on female Vietnamese (C-statistics=0.86) and worst on female Korean (c-statistics=0.72), while HF model performed well for Asian Indian and Korean. However, total CVD model and ASCVD overestimated most for Chinese, HF overestimated most on Vietnamese (Figure 1,2,3). Within Hispanic, the models performed best in Puerto Rican. Conclusions: PREVENT models had significantly improved the discrimination performance in all race/ethnicity groups and disaggregated Asian and Hispanic subgroups. However, all three models underestimate risk for all groups except NHA. The variation emphasizes the importance in recognizing heterogeneity within population, individual risk should always be considered in using risk model in clinical practice.
Abstract 4140424: Early Insights on Mavacamten Usage in Canada: A Retrospective Cohort Study of the Patient Support Program
Authors: Kevin Chun Ong, Andrew Crean, Patrick Garceau, Andrew Moeller, Florence Brellier, Stephanie Corriveau, Michael Ward
Journal: Circulation (2024)

Introduction: Mavacamten is a first-in-class cardiac myosin inhibitor initially approved in the US for treating obstructive hypertrophic cardiomyopathy (oHCM) under the FDA-mandated Risk Evaluation Mitigation Strategy (REMS). Subsequently, mavacamten was approved in Canada with less restrictions. A patient support program (PSP) was implemented, offering a unique opportunity to generate data on mavacamten utilization in the Canadian population. Aims: The objective of the study was to obtain real-world insights into the demographic and clinical characteristics, including dosing and treatment duration of patients treated with mavacamten for oHCM in Canada. Methods: This was an observational retrospective study of 683 adult patients with symptomatic oHCM enrolled in the Canadian mavacamten PSP between January 4, 2023 to April 12, 2024. Baseline demographic and clinical data were collected for age, gender, NYHA class, vLVOT gradient, LVEF and change in mavacamten dose. Results: The baseline clinical characteristics of the 683 patients are summarized in Table 1. Patients were distributed across several provinces with a median age of 65 years and a similar distribution between the male and female populations. The majority (N=458: 67.1%) were classified as NYHA class II. Nearly all patients were initiated at 5 mg of mavacamten as per the Canadian product monograph. Most (63.7%) of patients were on β-blockers alone (Table 1). The median follow-up time was 27.4 weeks (range 1.6-70.1). Notably, at the time of data cut off, 13.2% of patients were receiving mavacamten alone compared to 10.5% at initiation. The median treatment duration was 24.6 weeks, censored at data cut-off, with a discontinuation rate of 7.9%, primarily due to adverse events (2.5%) and lack of efficacy (0.9%). Conclusions: Mavacamten has been widely adopted across Canada with low discontinuation rates indicating good tolerability. The current risk management strategies in Canada are sufficient and obviate the need for a stricter approach. These early results provide the largest dataset on mavacamten utilization in the Canadian HCM population, adding to the accruing evidence of its safe and effective use in the real world.
Abstract 4140219: Performance of a Novel Rheumatic Heart Disease Screening Protocol Led by Non-Expert Frontline Nurses in Uganda
Authors: Scott Wirth, paul warren, Doreen Nakagaayi, Jafesi Pulle, Craig Sable, Emmy Okello, David Watkins, Kristen Danforth, Andrea Beaton
Journal: Circulation (2024)

Background: Poor healthcare access results in late- or non-diagnosis of rheumatic heart disease (RHD), perpetuating the burden of RHD in low-resource settings. The ADUNU program, a partnership with the Ugandan Ministry of Health in Kitgum, Uganda, aims to improve RHD case detection through decentralized screening led by primary care nurses, who independently perform and interpret brief screening echocardiograms using handheld echocardiography. Hypothesis: We hypothesized ADUNU’s simplified screening protocol would achieve sensitivity and specificity greater than 80% on confirmatory evaluation. Aim: To determine the health system impact of deploying a novel RHD screening protocol into the public health system in Uganda through a cross-sectional study of diagnostic accuracy. Methods: Primary healthcare nurses, certified to perform echocardiographic screening using a single parasternal long axis view in 2D and color Doppler, integrated screening into their clinical and outreach workflows. Community members with positive screens (mitral regurgitation jet ≥2cm or aortic regurgitation jet ≥1cm) were referred for confirmatory echocardiograms at the District Hospital. A random subset with negative screens were recruited for confirmatory echocardiograms at the time of screening as well. Sensitivity, specificity, predictive values, likelihood ratios, accuracy, and agreement (Cohen’s kappa) were calculated between the screening protocol and the confirmatory results. Results: Between May 2023 and April 2024, 3020 community screenings (ages 5-70 years) were conducted by 19 certified nurses. Among 113 positive screens, 61 (53.9%) were confirmed to have RHD. Among 430 negative screens, 14 (3.3%) had RHD. Screening sensitivity was 82.4% (95% CI 72.2-89.4%) and specificity 89.1% (85.9-91.6%). Positive and negative predictive values were 54.5% (45.2-63.4%) and 97.0% (94.9-98.2%). Likelihood ratios were 7.55(+) and 0.19(-). Accuracy was 88.3% (85.2 – 91.4%) and kappa was 0.59 (0.49-0.68). Conclusions: ADUNU’s novel approach to RHD active case finding achieved acceptable diagnostic performance. Nurse-led RHD screening programs that are integrated into routine clinical care shows potential for use in a comprehensive public health program. Very few RHD cases were missed, and under two referrals were generated for every positive case, an acceptable false positive rate. Further economic evaluation is underway to understand the budgetary impact and cost-effectiveness of this program.
Abstract 4140021: Metabolic crisis and TRPM4 activation cause QT prolongation in TANGO2 deficiency disease
Authors: Lili Wang, Kyungsoo KIM, Prince Kannankeril, Paul Brookes, Bjorn Knollmann
Journal: Circulation (2024)

Background: TANGO2 deficiency disease (TDD), caused by a homozygous large deletion in the Tango2 gene, is associated with impaired fatty acid oxidation-triggered metabolic crises, which can include severe QT prolongation and ventricular arrhythmias. The mechanism of transient QT prolongation and arrhythmias is unknown. Here we test the hypothesis that activation of the nonselective cation channel TRPM4, regulated by intracellular ATP and Ca, contributes mechanistically to arrhythmia risk in TDD. Methods: CRISPR/Cas9 was used to generate a human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) model with a Tango 2 exon 3 to 9 deletion ( Tango2 -/- ). Mitochondrial oxygen consumption rate (OCR), intracellular ATP/ADP ratios, and action potentials (APs) were evaluated in Tango2 -/- hiPSC-CMs under metabolic conditions fueled by either 5.6 mmol/L glucose or 0.1 mmol/L palmitate. Results: Analogous to clinical TDD, Tango2 -/- hiPSC-CMs showed a significant decrease in palmitate-dependent OCR and a profound reduction in intracellular ATP production when palmitate was the sole substrate, worsened after 24-hour fasting. In contrast, when glucose was the only energy source, Tango2 -/- hiPSC-CMs demonstrated OCR and ATP production rates comparable to control. These observations suggest dysfunction in mitochondrial palmitate oxidation leading to energy deficiency in Tango2 -/- hiPSC-CMs, which subsequently result in prolongation of AP duration. Intracellular delivery of Mg-ATP normalized palmitate-induced AP prolongation in Tango2 -/- hiPSC-CMs post fasting. Additionally, although no alterations in L-type Ca current were found, L-type Ca channel inhibition with verapamil alleviated palmitate-induced AP prolongation in Tango2 -/- hiPSC-CMs post fasting by stabilizing ATP/ADP ratios and ameliorating intracellular calcium dysregulation. We found post-fasting exposure to palmitate upregulated Trpm4 gene expression in Tango2 -/- hiPSC-CMs. Targeted genetic knockdown or pharmacological blockade of TRPM4 channels normalized AP prolongation in Tango2 -/- hiPSC-CMs. Conclusion: Our findings established a mechanistic link between myocardial energy deficiency, TRPM4 activation and the development of AP prolongation in TDD, emphasizing the energetic basis of arrhythmias. Targeting TRPM4 is a promising new therapeutic strategy to prevent QT prolongation and arrhythmia in TDD.
Abstract 4140007: Potent P2Y12 inhibitors versus Clopidogrel in Cancer Patients undergoing Percutaneous Coronary Intervention
Authors: Mauro Gitto, Samantha Sartori, Birgit Vogel, Pier Pasquale Leone, Kenneth Smith, Benjamin Bay, Prakash Krishnan, Joseph Sweeny, ANGELO OLIVA, Pedro Moreno, Francesca Di Muro, Parasuram Krishnamoorthy, Annapoorna Kini, George Dangas, Roxana Mehran, Samin Sharma
Journal: Circulation (2024)

Background: Although cancer is one of the major high bleeding risk criteria, patients with cancer undergoing percutaneous coronary intervention (PCI) experience a heightened risk of both ischemic and bleeding events. Hypothesis: Potent P2Y12 inhibitors (P2Y12i; prasugrel and ticagrelor), as compared to clopidogrel, might reduce the risk of thrombotic complications in patients with cancer undergoing PCI. Aims: To evaluate the safety and efficacy of potent P2Y12 inhibitors, compared to clopidogrel, in cancer patients undergoing PCI. Methods: Consecutive cancer patients undergoing PCI at a tertiary center between 2012 and 2022 who were discharged on potent P2Y12i were compared with those on clopidogrel. Patients on chronic anticoagulant therapy were excluded. The primary composite efficacy endpoint was major adverse cardiac and cerebrovascular events (MACCE), including death, myocardial infarction or stroke, while bleeding was the key safety endpoint. Results: Of the 1,702 patients included in the study, 373 (21.9%) were treated with potent P2Y12i and 1,329 (78.1%) with clopidogrel. The prevalence of P2Y12i use was 12.3% in patients with active cancer and 23.1% in those with cancer in remission. Factors associated with potent P2Y12i use were acute coronary syndrome presentation and lesion length, while clopidogrel at discharge was associated with active cancer status, thrombocytopenia, older age and femoral access. MACCE at 1 year occurred in 3.5% of patients in the potent P2Y12i group vs. 6.8% in the clopidogrel group (p=0.038; adj. HR: 0.53, 95% CI: 0.26-1.10), while no differences in terms of bleeding were detected (5.5 vs. 7%, adj. HR: 0.92, 95% CI: 0.53 - 1.60). At subgroup analysis, the reduction in MACCE was significant in patients with remission but not active cancer (p for interaction = 0.011). Conclusions: Potent P2Y12i appear to be safe in terms of bleeding and potentially associated with greater ischemic risk reduction compared to clopidogrel among patients with cancer undergoing PCI, particularly in case of cancer in remission.
Abstract 4140255: DIAGNOSIS TO RECOVERY: PSYCHOLOGICAL DISTRESS IN PULMONARY EMBOLISM
Authors: Bhairavi Rajasekar, Karen Hurley, Scott Cameron, Leben Tefera
Journal: Circulation (2024)

Pulmonary embolism (PE) is the third leading cause of cardiovascular death. It has been shown to be accompanied by significant psychological distress. The prevalence and longitudinal trends of anxiety and depression in PE patients largely remains unknown. We conducted a prospective observational study examining 188 PE patients attending a dedicated Pulmonary Embolism Response Team (PERT) Clinic. Participants completed standardized assessments using the Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire (PHQ-9) to measure anxiety and depression, respectively, following their PE diagnosis and ensuing treatment. Our findings revealed noteworthy gender disparities in the psychological impact of PE on survivors. Among women, 41% reported anxiety and 44% reported depression. Among men, 17% reported anxiety and 20% reported depression. Women more likely to experience depression post-PE and were twice as likely than men to experience anxiety. Furthermore, regardless of gender, we observed a decrease in the prevalence of anxiety and depression over time from the date of initial diagnosis. Younger patients exhibited higher levels of anxiety and depression compared to older counterparts. Additionally, patients with recurrent PE had higher levels of anxiety and depression compared to those with a single thrombotic episode. This study represents the largest dedicated prospective study to date to examine the psychological impact of PE on patients' psyche. It underscores the significant psychological toll of PE on patients' recovery. We noted women experienced higher rates of anxiety and depression compared to men. Younger patients and those were recurrent PE were more likely to experience psychological distress. Regardless of age and sex, the prevalence of anxiety and depression decreased with time. These findings highlight the importance of tailored psychosocial support strategies to address the unique emotional needs of patients following a PE diagnosis. Disparities in anxiety and depression prevalence following PE diagnosis and treatment exist. This study highlights the importance of implementing tailored psychosocial support strategies to address the unique emotional needs of PE patients, particularly among women, younger patients, and those with recurrent PE.