tbuckley/cabot-search huggingface dataset:
Abstract 4136700: Sodium-Potassium Pump: Newly O-GlcNAc Protein Offering Potential Benefits in Hemorrhagic Shock situation
Authors: Amandine Vergnaud, Thomas Dupas, Virginie Aillerie, Antoine Persello, Angelique Erraud, Aurore Girardeau, Barbara Oliveira Mendes, Jerome Montnach, Michel De Waard, Betrand Rozec, Benjamin Lauzier
Journal: Circulation (2024)

Hemorrhagic shock(HS) results from significant blood loss, leading to insufficient oxygen delivery, which causes metabolic changes and multi-organ dysfunction.The HS-related acute kidney injury developed by the patient are mainly due to alteration in Na/K ATPase.In previous O-GlcNAcylomic studies, we identified the Na/K ATPase as potentially O-GlcNAcylated.O-GlcNAcylation, a post-translational modification, plays a role in various cellular processes, such as cell survival and stress response.O-GlcNAcylation may have beneficial effect in shock situations. The objective of this study is to ascertain whether Na/K ATPase is O-GlcNAcylated and to elucidate its potential role during HS. Hemorrhagic shock was induced by an exsanguination of rats.They were then randomly treated or not with an O-GlcNAcase inhibitor, the NButGT(10mg/kg), to increase O-GlcNAc level.Blood pressure and heart rate were monitored throughout the experiment.Blood samples were collected for complete blood analysis, including biochemistry and gas measurements. kidneys were immediately frozen for histological and biochemical studies.To study the O-GlcNAcylation of Na/K ATPase an immunoprecipitation and Wheat Germ Agglutinin(WGA) based lectin affinity gel electrophoresis were used. HEK cells were treated with or without NButGT(100µM,6 hours) and/or ouabain(Na/K ATPase inhibitor) and a colorimetric kit was assessed to study O-GlcNAcylation impact on Na/K ATPase activity. O-GlcNAc levels increased by 2 folds in heart and kidney due to the NButGT treatment(p&lt;0.05).Mean arterial pressure(MAP,p&lt;0.01) and bicarbonate(p&lt;0.01) are restored in treated group as kalemia(Sham:4.2 ± 0.1;HS:4.7±0.1;NButGT:4.3 ±0.1;mmol/L;p&lt;0.05) and natremia(Sham:141.5±0.4;HS:139.8±0.5;NButGT:141.9 ±0.4; mmol/L;p&lt;0.01).The study of the O-GlcNAcylation of the Na/K ATPase validated its O-GlcNAcylation.Histological analysis of the kidney showed that HS decreased Na/K ATPase expression, but treatment restored it(Sham:15.1±1.1;HS:10.3±0.6;NButGT:13.78±1.1;%area;p&lt;0.05). An acute increase in O-GlcNAc levels through NButGT enhances Na/K ATPase activity. Increased O-GlcNAcylation during hemorrhagic shock restored MAP and reduced indicators of metabolic acidosis.Treatment with NButGT restored natremia and kalemia.This effect is linked to an increase in the expression and activity of Na/K ATPase.Our study is the first to confirm that Na/K ATPase is regulated by O-GlcNAcylation, particularly in terms of its localization and stability.
Abstract 4136516: Intraventricular pseudoaneurysm: A diagnosis with high mortality that demands a good eye
Authors: Wisam Beauti, Nicholas Biondi, Pooneh Nabavizadeh, michael hong, Janki Hitchins, Maanas Pisati, Anissiia Dovtchinova-Crowly
Journal: Circulation (2024)

Traumatic left ventricular (LV) pseudoaneurysms (PSA) are rare, life-threatening complications of blunt chest trauma and the management is heavily reliant on early identification and diagnosis. A healthy 55-year-old female presented after blunt chest trauma from a car accident. Bedside echocardiogram revealed a mid-septal LV discontinuity with myocardial outpouching. Lab work was significant for high sensitivity troponin of 22,000 ng/L which peaked at 24,000 in 5 hours. ECG revealed normal sinus rhythm with a QRS duration of 102ms. No ventricular ectopy was detected. Transthoracic echocardiograph (TTE) using echo contrast agent and computed tomography (CT) scan confirmed the intraventricular pseudoaneurysm (Fig 1-A&amp;B). A transesophageal echocardiogram (TEE) showed an intact PSA at 3.7 x 2.5 cm LV PSA with a 5mm neck extending from the mid septum superiorly into the right ventricle (RV) with no Doppler evidence of rupture or shunt (Fig 2). With cardiology and cardiac surgery shared decision making, conservative therapy was elected in the setting of polytrauma and hemodynamic stability. Serial TTEs showed stable size and appearance of the PSA during her month long hospitalization. Cardiac magnetic resonance imaging (cMRI) 7 months later showed significant improvement in the PSA size to 0.3 cm 2 and extensive myocardial remodeling (Fig 1-C). LV septal PSA is rare following blunt chest trauma, and it confers a considerable risk of rupture with the highest risk occurring within 3 months of formation. Untreated PSA presents with risks including thromboembolism, infection, and arrhythmia. Multimodal cardiac imaging is paramount for diagnosis and surveillance. There are no guidelines for serial monitoring in hemodynamically stable patients and an individualized approach should be taken. In this patient TTE, TEE, and CT imaging modalities were utilized. Our patient progressed without complication following conservative management with shrinking and scarring of the aneurysm characterized by the cMRI.
Abstract 4136036: Five-year Outcomes of Heart-Kidney Transplant Recipients Bridged with Durable Mechanical Circulatory Support: Less AMR Better Survival?
Authors: Yosef Manla, Jignesh Patel, Michelle Kittleson, Andriana Nikolova, David Chang, Evan Kransdorf, Lily Stern, Lawrence Czer, Mason Lee, Jon Kobashigawa
Journal: Circulation (2024)

Introduction: Despite the increased risk of sensitization in patients receiving pre-transplant durable mechanical circulatory support (D-MCS), it has been suggested that removing D-MCS at the time of transplant may lead to a drop in HLA-antibody levels. Whether this may reduce rejection rates and improve long-term outcomes in patients undergoing heart-kidney transplantation (HKTx) has not been widely investigated. Therefore, we aim to investigate the impact of pre-transplant D-MCS on 5-year clinical outcomes of patients undergoing HKTx. Methods: We included 98 patients undergoing HKTx between 2010 and 2018 at a single center. Recipient pre-transplant characteristics and clinical outcomes were compared between patients receiving D-MCS (n=24) versus non-D-MCS patients (n=74). The D-MCS cohort included those who received total artificial heart (n=13), left ventricular assist device (n=8), and biventricular assist devices (n=3). Endpoints included 1- and 5-year survival, 1-year-freedom from acute cellular rejection (defined as grade 2R or 3R), 1-year-freedom from antibody-mediated rejection (AMR, defined as pathologic AMR of grade ≥1), 5-year freedom from cardiac allograft vasculopathy (CAV, stenosis ≥30% by angiography), 5-year freedom from non-fatal major adverse cardiac events (NF-MACE including myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), and 5-year freedom from left ventricular dysfunction (LVEF ≤40). Results: At 1 year, freedom for AMR was numerically higher in the D-MCS group (100 vs. 90.2%, P=0.12). Additionally, the 5-year post-transplant survival rate was higher in the D-MCS group (95.8% vs. 80.8%), but it did not reach statistical significance (P=0.091). Comparable outcomes were noted for other outcomes, including 5-year freedom from CAV, NF-MACE, or LVD (Table 1 ). Conclusion: The current study hints at better 5-year survival in HTKx recipients receiving pre-transplant D-MCS, which could be attributed to lower rates of AMR in this population. Future larger studies are warranted to further validate these findings.
Abstract 4135754: Prediction of Incident Atrial Fibrillation Using Handheld Single-Lead Electrocardiograms from the VITAL-AF Trial
Authors: Shaan Khurshid, Samuel Friedman, Mostafa Al-Alusi, Shinwan Kany, Christopher Anderson, Jennifer Ho, David McManus, Jeffrey Ashburner, Steven Lubitz, Steven Atlas, Mahnaz Maddah, Daniel Singer, Patrick Ellinor
Journal: Circulation (2024)

Background: Deep learning of 12-lead electrocardiograms (ECGs) can estimate future atrial fibrillation (AF) risk. Whether these models can be applied to single-lead ECGs (1L ECGs) from wearable or handheld devices is unknown. Aim: To apply a previously published deep learning model to estimate 2-year incident AF risk using handheld 1L ECGs obtained prospectively in a large AF screening trial. Methods: In the VITAL-AF trial (NCT03515057), over 16,000 primary care patients aged ≥65 years underwent AF screening with handheld 1L ECG. We applied our published deep learning model (ECG-AI) derived using single leads of over 450,000 standard 12-lead ECGs external to the VITAL-AF study (1L ECG-AI). We compared the performance of 1L ECG-AI to the validated CHARGE-AF clinical risk score and calculated net reclassification indices. Results: Among 15,694 individuals enrolled in VITAL-AF and without prevalent AF (age 74±7 years, 9,104 [58%] women), 1L ECG-AI discriminated 2-year incident AF (area under receiver operating characteristic curve [AUROC] 0.666 [95% CI 0.603-0.721]). With addition of age and sex (1L ECG-AI AS), 2-year AF discrimination (0.695 [0.637-0.742]) was comparable to the 11-component CHARGE-AF clinical risk score (0.679 [0.625-0.729]). Two-year AF incidence was markedly higher with 1L ECG-AI AS in the top 5% (8.0% [5.7-10.2]) vs bottom 5% (0.89% [0.23-0.55]). At a threshold of ≥3% estimated 2-year AF risk, AF incidence was progressively higher among patients at high risk according to neither model (1.5% [1.2-1.8]), one model (1L ECG-AI: 3.3% [2.3-4.2]; CHARGE-AF 3.4% [2.2-4.6]), and both models (5.8% [5.0-6.5]), implying that clinical risk and ECG-AI signals are complementary ( Figure ). Compared to screening all individuals at the guideline-based threshold of ≥65 years, 1L ECG-AI AS resulted in favorable net reclassification improvement (0.27 [0.22-0.32]). Conclusion: An ECG-AI algorithm developed using single leads of a 12-lead ECG combined with age and sex can discriminate AF risk using real-world handheld 1L ECGs with comparable performance to the CHARGE-AF score. 1L ECG-AI signals complement clinical risk factors. ECG-AI applied to 1L ECG may increase the reach and efficiency of AF screening.
Abstract 4136788: Lipoprotein(a) Levels and the Risk of Ventricular Arrhythmia: Insights from a Comprehensive Retrospective Cohort Study
Authors: Maryam Sani, Tarek Harb, Thorsten Leucker, Jonathan Chrispin
Journal: Circulation (2024)

Background: Sustained ventricular arrhythmias (VAs) are associated with an elevated risk of sudden cardiac death (SCD). Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which in turn associated with increased risk of VAs. However, whether Lp(a) is linked with VAs independent of ASCVD remains unknown. Objective: To examine the association of Lp(a) with VAs in a population-based, retrospective cohort study utilizing data from the TriNetX Research Network. Methods: We conducted a retrospective analysis of the data from 89 healthcare organizations within the TriNetX Research Network. Patients over 18 years old with available serum Lp(a) measurement were included. Participants were divided into two cohorts based on their Lp(a) levels: cohort 1 (Lp(a) ≤75 nmol/L), and cohort 2 (Lp(a) ≥76 nmol/L). Follow-up time to VA occurrence was calculated from the time of Lp(a) level measurement within each cohort. The composite endpoint was the incidence of VAs to include ventricular tachycardia, ventricular fibrillation, ventricular flutter, or cardiac arrest due to underlying cardiac conditions. We compared the two cohorts using Kaplan-Meier survival analysis along with cox proportional hazard regression analysis after propensity score matching. Results: 50,752 patients were included in cohort 1 and 24,474 in cohort 2. After propensity score matching, both cohorts had 23,668 patients. In cohort 1, 307 patients experienced VAs, compared to 303 in cohort 2 (Table 1). The mean age was 53.3 ± 15.7 years, with 53.35% of participants being female, 10.75% being Black, and 69.89% being White. The Kaplan-Meier survival analysis showed a higher survival probability at the end of the study period for the Lp(a) ≤75 compared to the Lp(a) ≥76 cohort (95.11% vs 85.35%, p=0.002). The hazard ratio (HR) for VA was 0.768 (95% CI: 0.652-0.904, p = 0.002), indicating that lower Lp(a) levels are associated with reduced VA risk. Conclusion: This study shows that increased Lp(a) levels are independently associated with a higher incidence of VA. Future research should focus on the mechanisms underlying the relationship between Lp(a) levels and VA, and whether Lp(a) reduction can reduce the risk of VA and other cardiovascular outcomes.
Abstract 4135531: The Ubiquitin-Specific Protease 30 Inhibitor, MTX652, Attenuates Cardiac Dysfunction And Remodelling In a Murine Model Of Transverse Aortic Constriction
Authors: Rebecca Dunmore, Zoe Haines, Rachel Williams, Louise Jones, Tracey Okell, Sarah Almond, Charlotte Knights, Pau Aceves, Laura Parton, Suhail Nurbhai, Paul Thompson
Journal: Circulation (2024)

Introduction: Mitochondrial abnormalities are a characteristic of heart failure leading to energy deprivation and disease worsening. The mitochondrial deubiquitinating enzyme USP30, removes ubiquitin and represses PINK1/PARKIN-mediated mitophagy leading to accumulation of dysfunctional mitochondria. In this study we investigated the role of MTX652, a clinical stage USP30 inhibitor, in a mouse model of cardiac hypertrophy using transverse aortic constriction (TAC). Hypothesis: Inhibition of USP30 will promote mitophagy resulting in clearance of dysfunctional mitochondria and improved cellular health leading to cardioprotective effects. Aims: To determine if MTX652 can protect from TAC induced cardiac hypertrophy and remodelling. Methods: Male C57BL/6 mice, 8 weeks old, were subjected to sham surgeries or TAC using a 26G needle to induce cardiac pressure overload. MTX652 (1.5 or 5 mg/kg, n =12-13) or vehicle ( n =11) was administered orally, twice daily, starting 2 days post-surgery. Captopril (30 mg/kg/d, n =13) was also included as a positive control. After 4 weeks, echocardiography assessed left ventricle (LV) function and morphology. Cell based assays assessed MTX652 target engagement and TOM20 ubiquitination in vitro. Results: LV hypertrophy and wall thickening was observed in TAC animals. Treatment with MTX652 decreased systolic LV volume (1.5 mg/kg p&lt;0.05 and 5 mg/kg p&lt;0.01) and diameter (1.5 mg/kg p&lt;0.01 and 5 mg/kg p&lt;0.05,) demonstrating comparable effects to Captopril. A reduction in anterior wall thickness in diastole was also observed with MTX652 (5 mg/kg, p&lt;0.01). Cardiac dysfunction was also evident in TAC animals with MTX652 showing improvements in both ejection fraction (1.5 mg/kg and 5 mg/kg, p&lt;0.0001) and fractional shortening (1.5 mg/kg and 5 mg/kg, p&lt;0.0001). Cellular target engagement for MTX652 was confirmed in HeLa-YFP-Parkin cells with an EC 50 of 2.7 nM ( n =2). Furthermore, the USP30 substrate TOM20 was ubiquitinated following MTX652 treatment in vitro (EC 50 =6.1 nM, n =4) providing evidence of mitophagy activation, a finding also confirmed in mouse heart tissue (MTX652, 5mg/kg). Conclusions: The USP30 inhibitor, MTX652 significantly protected mice from TAC induced cardiac hypertrophy and LV dysfunction. Furthermore, MTX652 potentiates ubiquitylation of TOM20 as a mechanism to promote mitophagy. These data suggest our clinical stage molecule could provide a novel therapeutic approach for the treatment of cardiac hypertrophy and heart failure.
Abstract 4136701: A combined approach of cardiac magnetic resonance and CardioMEMS to assess right ventricular dysfunction during exercise in HFpEF-PH
Authors: Youri Bekhuis, Stefan Janssens, Walter Droogne, Thomas Rosseel, Leticia Barrios, Jan Verwerft, Philippe Timmermans, Sander Trenson, Tom Dresselaers, Jan Bogaert, Andre La Gerche, Guido Claessen
Journal: Circulation (2024)

Background: Right ventricular dysfunction (RVD) is common in patients with heart failure with preserved ejection fraction (HFpEF) and is associated with shortened life expectancy. Early identification of these at-risk patients could facilitate the initiation of future treatments. Evaluating the RV during exercise has proven to enhance the diagnostic accuracy in revealing RVD that is not detectable at rest. The CardioMEMS device has emerged as a non-invasive tool to remotely monitor pulmonary artery pressures (PAP) and enable early identification of clinical worsening. Research Questions: Using a hybrid approach of combined real-time CMR-derived volume measurements with CardioMEMS-derived PAP measurements, we aimed to identify RVD during exercise which is not detectible at rest in a population of patients with HFpEF and pulmonary hypertension (PH). Methods: In this prospective cohort study, we used a hybrid approach of two consecutive exercise tests in HFpEF patients ( Figure 1 ). First, PAP were measured using the CardioMEMS signal on a supine bike at rest, and 25%, 50%, and 75% of peak power output determined previously on an upright cycle ergometer. Subsequently, volumes were derived by CMR at rest and during exercise at 25% and 50% of peak power output. The RV end-systolic pressure-volume relationship (RVESPVR), a surrogate of RV contractility, was calculated as mean PAP divided by RV end-systolic volume. RV contractile reserve, as a marker of RVD during exercise, was calculated as the ratio of peak exercise to resting RVESPVR, with values &lt; 2.0 indicating impairment. Results: Fourteen patients with HFpEF-PH were included (age 76.6±6.9 years, 57% women). Eleven (79%) had impaired RV contractile reserve during exercise ( Table 1 ). Although not significant, RVESPVR at rest tended to be better in the group with RVD during exercise (0.47±0.17 vs 0.27±0.03; P=0.070). Peak VO 2 was significantly reduced in patients with RVD during exercise (13.1±2.0 vs. 18.6±6.4%; P&lt;0.021). Conclusion: A new hybrid approach combining cardiac MRI and CardioMEMS is feasible during exercise in HFpEF patients and identifies RVD in approximately eighty percent of patients with HFpEF and elevated mPAP at inclusion. Evaluation of RV contractility at rest showed a discordant trend, pointing out the need to test the RV during exercise. Further research is needed to determine if this approach can predict progression of RVD over time and serve as a risk stratification tool for these patients.
Abstract 4136605: Effect Of A Bone Morphogenetic Protein Receptor Type 2 Mutation On The Cardiomyocyte Response To Pressure Overload
Authors: Aida Llucia-Valldeperas, Jessie Van Wezenbeek, rowan Smal, Fjodor Bekedam, Anton Vonk Noordegraaf, Harm Bogaard, Frances De Man
Journal: Circulation (2024)

Introduction: A mutation in the Bone Morphogenetic Protein Receptor Type 2 ( BMPR2 ) gene is in 70% of hereditary pulmonary arterial hypertension (hPAH) patients the causative mutation of the disease. Previous work demonstrated that right ventricular function is more impaired in hPAH patients with a BMPR2 mutation. However, the underlying mechanism remains elusive. Moreover, natriuretic peptides, such as N-terminal Brain Natriuretic Peptides (NTproBNP) and Mid Regional proAtrial Natriuretic Peptides (MRproANP), are secreted from cardiomyocytes upon stretch as adaptation to increased pressure overload. We hypothesize that the BMPR2 mutation impairs the response to increased pressure overload. For this purpose, we make use of ventricular induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of hPAH patients carrying a BMPR2 mutation and their isogenic controls in which the mutation was corrected. Aim: To study the effect of a BMPR2 mutation on the response to pressure overload in vitro . Methods: iPSCs from 2 hPAH patients and its isogenic controls were used. iPSCs were differentiated into ventricular iPSC-CMs and stretched 10% equiaxially for 24h at 1Hz on the Flexcell FX-6000 system. Natriuretic peptides gene expressions were quantified via RT-PCR. NTproBNP and MRproANP release were measured on cell supernatants throughout specific immunoassays. Normality of the data was checked, and statistics were performed accordingly. Results: No differences were observed on natriuretic peptides gene expression on static and stretched iPSC-CMs. There is a clear correlation between NTproBNP and MRproANP release (R 2 =0.83, p&lt;0.0001, Figure 1A). Interestingly, hPAH iPSC-CMs showed higher baseline values for NTproBNP release compared to isogenic iPSC-CMs (p&lt;0.01, Figure 1B). Furthermore, stretching resulted in increased NTproBNP and MRproANP secretion in both hPAH and isogenic iPSC-CMs (Figure 1B-C). Conclusions: Secretion of NTproBNP and MRproANP was closely correlated in iPSC-CMs. iPSC-CMs of hPAH patients with a BMPR2 mutation showed higher baseline values of NTproBNP. Increased secretion of NTproBNP and MRproANP upon mechanical stimulation was similar between hPAH and isogenic iPSC-CMs. Experiments in atrial iPSC-CMs are currently ongoing to test potential differences in natriuretic peptide secretion between ventricular and atrial cardiomyocytes as the right atrium is also under stretch in PAH.
Abstract 4135444: Sex Disparities in Enrollment of Cardiovascular Trials: A Meta-Analysis of ClinicalTrials.gov Listings
Authors: Gerald Chi, Jane Lee, Charles Gibson
Journal: Circulation (2024)

Background: Despite increasing recognition of sex differences in the burden of cardiovascular (CV) diseases, women have historically been underrepresented in clinical trials. Aims: The study aimed to systematically quantify the extent of sex disparity in the enrollment of CV trials and explore the annual enrollment trends of women in CV trials. Methods: The analysis included studies that: (1) were registered in ClinicalTrials.gov up to February 2024; (2) were randomized trials involving ≥1 intervention; (3) investigated ≥1 CV condition, as determined by Medical Subject Heading descriptors. The exclusion criteria were: (1) studies without available enrollment information; (2) studies exclusively enrolling men or women; and (3) studies with ≤100 participants. We computed enrollment disparity difference (EDD), defined as the difference between the proportion of women in trial participants and the proportion of women with CV diseases in the general population, based on the Global Burden of Disease estimates matched by country/geographic region and enrollment period. Random-effects meta-analysis was performed to summarize the overall enrollment disparity. Subgroup analysis by trial characteristics was conducted. Meta-regression was used to assess the association of enrollment disparity with the start year of the trials. Results: A total of 1,687 CV trials were identified from 484,781 studies. Among 2,198,317 trial participants for whom sex was reported, 819,570 (37.3%) were women. EDD in CV trials was -0.105 (95% CI, -0.113 to -0.097), indicating that women were under-enrolled by 10.5% (Figure 1). Except for valvular heart disease trials, disparities were evident across other CV disease trials, with the most remarkable under-enrollment of women in peripheral artery disease trials (-0.302 [95% CI, -0.324 to -0.279]). Disparities were more prominent in trials with larger sample sizes, longer study durations, device or procedural interventions, and data monitoring committee oversight (p&lt;0.001 for subgroup differences; Figure 2). There was a significant yet modest improvement in the representation of women over time (increase of 0.0028 [95% CI, 0.0011 to 0.0045] in EDD per start year of trials; p=0.001; Figure 3). Conclusion: Women remain substantially underrepresented in CV trials, particularly in peripheral artery disease trials. The findings underscore the imperative for interventions to mitigate sex inequity in the enrollment of CV trials.