tbuckley/cabot-search huggingface dataset:
Abstract 4134792: SIRTUIN5 Modulates Na <sup>+</sup> /Ca <sup>2+</sup> Handling Via Oxidative Stress Dependent Manner In Mouse Heart
Authors: Hannah Choi, Biyi Chen, Long-Sheng Song, David Lombard, Jin-Young Yoon, Barry London
Journal: Circulation (2024)

Background: The cardiac Na + channel Na V 1.5 (encoded by SCN5A ) governs cardiac inward Na + current (I Na ) and the fast upstroke and plateau phases of the cardiac action potential. Mutations in Na V 1.5 can cause acquired or inherited arrhythmias and conduction diseases, including ~20% of cases of Brugada Syndrome (BrS). Changes in I Na can impact Ca 2+ handling and cardiac excitation-contraction coupling. We have previously shown that SIRT1-mediated deacetylation of Na V 1.5 increased I Na . Recently, potential mutations (including P114T) in SIRT5, another NAD + -dependent deACYLase in the Sirtuin family localized to mitochondria, were identified in small families with BrS. Hypothesis: Sirt5 dysfunction evokes arrhythmias via Na + and Ca 2+ mishandling in an oxidative stress-dependent manner in mouse hearts. Aims: To explore the potential role of SIRT5 in BrS using heterologous expression systems and homozygous P114T-Sirt5 knock-in (P114T-KI) mice. Methods: Protein expression and physical interactions were detected by immunoprecipitation and immunoblot. The effects of SIRT5 on Na + current was measured using patch clamp in HEK cells and mouse cardiac myocytes. Confocal microscopy was used to measure reactive oxygen species (ROS) and for Ca 2+ imaging. Results: Both WT and P114T-SIRT5 co-immunoprecipitate with Na V 1.5, but WT increased peak I Na in HEK cells while P114T did not (Fig A,B). Live-cell staining using DCFDA or mitoSOX showed that P114T-KI hearts had increased basal ROS and were more sensitive to oxidative stress induced by H 2 O 2 than WT littermates. P114T-KI hearts had increased Na + /Ca 2+ exchange protein 1 (NCX1) expression, and Langendorff-perfused hearts displayed abnormal Ca 2+ handling and arrhythmias (Fig C). Notably, treatment with the mitochondrial ROS scavenger mitotempo mitigated the aberrant Ca 2+ handling and arrhythmias. Conclusion: These findings suggest that the P114T-SIRT5 causes abnormal Na + and Ca 2+ handling and arrhythmias in a ROS-dependent manner, highlighting potential mechanisms underlying BrS. This finding may pave the way for the use of SIRT5 or its activators as novel anti-arrhythmic therapies in the future.
Abstract 4134900: Cellular Crosstalk in Endocardial Fibroelastosis: NRG Signaling Dysregulation Contributes to Fibrosis and Myocardial Dysfunction in Hypoplastic Left Heart Complex
Authors: Daniel Diaz-Gil, Sarah Morton, Kemar Brown, Eric Wei, Kerstin Saraci, Magnus von Piechowski, Sitaram Emani, Pedro Del Nido, Jonathan Seidman, Christine Seidman, Ingeborg Friehs
Journal: Circulation (2024)

Background: Endocardial fibroelastosis (EFE) is marked by a thickened fibro-elastic layer derived by endothelial-to-mesenchymal transition (EndMT), leading to restrictive myocardial function and poor cardiac growth, complicating biventricular repair in hypoplastic left heart complex (HLHC) patients. Neuregulin (NRG) signaling, crucial in EndMT and myocardial development, is implicated in various cardiomyopathies and heart failure, and its dysregulation may drive EFE pathogenesis. Hypothesis: NRG signaling dysregulation influences the cellular and molecular mechanisms of EFE. Methods: Single nucleus RNA sequencing (snRNA-seq) was conducted on human left ventricular (LV) tissue resected from 7 EFE patients (0.4-15 years) and 4 non-congenital heart disease (CHD) postmortem human controls (0.02-16 years). Differential gene expression was analyzed using the Wilcoxon Rank Sum test. We used CellChat, a computational tool for analyzing intercellular communication networks, to identify signaling changes via quantitative contrasts and joint manifold learning. Results: We identified 11 cell types in 64,963 nuclei. In EFE samples compared to non-CHD samples, NRG1-expressing fibroblasts increased from 3.4% to 21.2% (P&lt;0.0001), and NRG2-expressing cardiomyocytes from 11.9% to 45.9% (P&lt;0.001). CellChat analysis revealed a denser NRG signaling network in EFE, with enhanced interactions among cardiomyocytes, endocardial cells, fibroblasts, mast cells, and smooth muscle cells (Fig. 1A-B). Cardiomyocytes emerged as significant senders of NRG signaling in EFE, while endocardial cells, though still key senders, showed reduced influence. Fibroblasts became strong mediators, receivers, and influencers, smooth muscle cells emerged as prominent receivers, and mast cells gained roles as mediators and influencers (Fig. 1 C-D). These changes indicate a complex NRG signaling network in EFE, highlighting altered cellular interactions driving disease progression. Conclusion: Dysregulated NRG signaling in EFE contributes to pathological cellular crosstalk, fibrosis, and myocardial dysfunction, potentially hindering successful biventricular repair in HLHC patients. Targeting NRG pathways could represent a novel therapeutic approach. These findings offer promising implications for affected patients, potentially improving outcomes. Future research should explore additional molecular pathways involved in EFE and assess the therapeutic efficacy of targeting NRG signaling.
Abstract 4134863: Major Cardiovascular Events Following Non-Cardiovascular Surgeries in Minority Patients Compared to White Patients
Authors: Jatin Goyal, Erij Elkamel, Sebastian Alarcon, Grettel Castro, Pura Rodriguez de la Vega, Rupa Seetharamaiah, Ruben Ricardo, Georgeta Vaidean
Journal: Circulation (2024)

Introduction: Racial disparities are pervasive in cardiovascular outcomes. Although disparities following cardiovascular surgery have been extensively studied, fewer current, nationwide reports exist for postoperative outcomes in non-cardiovascular surgery. Research Aim: To investigate the incidence of 30-day post-operative major adverse cardiac, cerebral and thrombotic events (MACCTE) following non-cardiovascular surgeries in non-White patients as compared to White patients. Methods: This retrospective cohort study used the 2018-2022 National Surgical Quality Improvement Program database. Patients aged 18 or older who underwent non-cardiovascular surgeries (general, gynecology, neurosurgery, orthopedics, otolaryngology, plastics, thoracic, urology, obstetrics, and interventional radiology) were included. Race/ethnicity was categorized as non-Hispanic White (Whites), Hispanic, non-Hispanic Asian (Asians), non-Hispanic Black or African American (Blacks), and non-Hispanic Others. MACCTE was defined as a composite of death, MI, cardiac arrest, stroke, PE, or DVT. Five multivariable logistic regression models were used to hierarchically adjust for age, gender, ASA class, surgical subspecialty, operation time, transfer status, and all other comorbidities. Results: Among the 3,775,920 patients: 70.9% were Whites, 11.8% Hispanics, 4.1% Asians, 11.6% Blacks, 1.5% of Other race, 58.9% female, and 46.7% had an ASA classification of 3 or greater. The MACCTE incidence was 1.95% overall and 2.01% in Whites, 1.27% Hispanics, 1.48% Asians, 2.11% Blacks, and 1.69% Others. Compared to Whites, Blacks had higher incidences of cardiac arrest (0.40% vs. 0.23%), stroke (0.17% vs. 0.15%), PE (0.47% vs. 0.34%), and DVT (0.55% vs. 0.48%), and Asians (0.18% vs 0.15%) and Others (0.21% vs. 0.15%) had a higher incidence of stroke (p&lt;0.001). With Whites as reference, the crude odds ratios, OR (95% CI) were 0.63 (0.61-0.65) in Hispanics, 0.73 (0.70-0.76) Asians, 1.05 (1.03-1.07) Blacks, and 0.84 (0.78-0.89) Others. The fully adjusted model odds ratios, OR (95% CI) were 0.88 (0.82-0.95) Hispanics, 0.89 (0.80-1.00) Asians, 1.11 (1.04-1.18) Blacks, and 0.80 (0.69-0.94) Others. Conclusion: Black patients experienced a higher MACCTE risk compared to Whites, even after adjustment for age, sex, ASA class, type of surgical procedure, and other comorbidities. These findings emphasize the importance of implementing comprehensive measures to prevent excess risk and promote equitable surgical care.
Abstract 4134945: Biomechanical Impact of Crossing Neochords In Mitral Valve Repair Using Ex Vivo Mitral Valve Prolapse Models
Authors: Yuanjia Zhu, Chris Huynh, Catherine Wu, Matthew Park, Stefan Elde, Shin Yajima, Joon Bum Kim, Y Joseph Woo
Journal: Circulation (2024)

Background: Neochord repair is a common technique to mitigate mitral regurgitation (MR). Certain techniques, such as the loop technique, purposefully anchor all neochords to one papillary muscle head, generating crossed configurations. The objective was to evaluate the impact of crossing neochord on mitral valve (MV) biomechanics using ex vivo mitral valve prolapse (MVP) models. Methods: Twenty-four healthy porcine MVs were explanted. The valves were randomly assigned to generate A2 or P2 MVP models by transecting A2 or P2 primary and secondary native chords. For each model, the valves were further randomly assigned to neochord repair by crossing the medial-lateral plane or the anterior-posterior plane. Fiber Bragg grating force sensors were mounted to measure chordal forces. Data were collected using an ex vivo heart simulator for baseline, MVP, and neochord repair in the native and the crossed configuration. Statistical analysis was performed using repeated measures analysis of variance with post-hoc correction. Results: In the P2 MVP model, AP crossed configuration was effective in reducing MR (p=.003) compared with the native configuration (p=.004), but the medial-laterally (ML) crossed configuration was not effective in reducing MR (p=.07) compared with the native configuration (p=.05). In the A2 MVP model, anterior-posteriorly crossed configuration was associated with increased average neochordal force compared with the native configuration (0.16±0.06N vs. 0.09±0.07N, p=.05). The ML crossed configuration was also associated with increased average neochordal force compared with the native configuration (0.05±0.03N vs.0.03±0.03N, p=.03). Peak native secondary chordal forces were increased in the ML crossed configuration compared with the native configuration (0.76±0.45N vs. 0.61±0.38N, p=.05). No differences between the crossed and native configurations were observed in the P2 MVP model. Conclusions: Differences exist in P2 MVP model hemodynamics and A2 MVP model chordal forces when neochords were crossed compared with the native configurations. These findings may provide important biomechanics insight regarding neochord implantation techniques and repair durability.
Abstract 4134837: Checkpoint Kinase 1 Attenuates Myocardial Ischemia-Reperfusion Injury Through Maintaining SIRT1-Dependent Mitochondrial Homeostasis
Authors: tongtong yang, liu-hua Zhou, tiankai shan, Hao Wang, Liansheng Wang
Journal: Circulation (2024)

Background: Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation and cardiac repair post myocardial infarction, however, its role on mitochondrial function in I/R injury remains unknown. Research Questions: The purpose of this study is to explore the potential effects and mechanisms of CHK1 on mitochondrial homeostasis during myocardial I/R injury. Methods: To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/knock-in mouse models were generated. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism of CHK1. The interaction between CHK1 and SIRT1 was explored using truncated plasmids. Results: CHK1 was downregulated in myocardium post I/R and neonatal mouse cardiomyocytes (NMCMs) post oxygen-glucose deprivation/re-oxygenation (OGD/R). In vivo , CHK1 overexpression protected against myocardial I/R injury, while heterogenous CHK1 knockout exacerbated cardiomyopathy. In vitro , CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266-390 domain of CHK1 interacted with the 160-583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown partially attenuated the protective role of CHK1 in I/R injury. Conclusions: Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.
Abstract 4134619: A Novel Missense Mutation in TNNT2 Gene in a Lebanese Pedigree With Ebstein Anomaly And Wolf-Parkinson-White Syndrome: A Case Report
Authors: Montaser Atasi, Razan Dankar, Salim Barakat, Jad Wehbi, Marwan Refaat
Journal: Circulation (2024)

Background: Ebstein anomaly (EA) is a rare congenital heart defect occurring in 1.2 to 5 in 100,000 live births, characterized by a downward displacement of the tricuspid valve, thin-walled right ventricle, and tricuspid valve regurgitation. It can present variably from asymptomatic cases to severe symptoms like arrhythmias and right-sided heart failure. EA is often associated with other anomalies such as interatrial communication and mitral valve prolapse. The condition can lead to accessory atrioventricular pathways, frequently resulting in Wolff-Parkinson-White syndrome (WPW), which involves abnormal heart electrical activity and increases the risk of sudden cardiac death. While the genetic basis of EA is not fully understood, it appears to involve multiple genes like FLNA and NKX2-5, MYH6, MYH7 suggesting a complex polygenic inheritance pattern. TNNT2 is known to be associated with Cardiomyopathy but has not been previously associated with EA and WPW. Case: In this report, we present findings from a lebanese family with EA, comprising 2 affected individuals. Whole exome sequencing in the affected individuals identified a pathogenic variant in the TNNT2 gene at coding strain position 260 (a missense mutation: C to T), resulting in the substitution of Proline with Leucine at position 87 in affected individuals (Figure 1). No variants were detected in any other candidate gene examined. Individuals I:1 and II:2 were found to be normal, with no EA findings on echocardiography. Methods: Whole exome sequencing in the patients involved collecting blood samples after obtaining consent. These samples were sent to Centogene lab, where genomic DNA is enzymatically fragmented. The regions of interest are then enriched using DNA capture probes, facilitating detailed genetic analysis. Results: The whole exome sequencing identified a heterozygous missense mutation in both the father and his daughter. This nonsynonymous variant is located on chromosome 1 (GRCh37) in the TNNT2 gene region. The specific variant, NM_001276345.1:c.260C&gt;T p.(Pro87Leu), was found in both individuals. Conclusion: In conclusion, the genetic basis of EA is rather complex and remains poorly understood. It is established that mutations in the TNNT2 gene are linked to several cardiomyopathies, none of them overlap with the described phenotype of our patients. In this report, we therefore confirm the potential role of TNNT2 gene mutation in the genetic basis of familial EA with WPW.
Abstract 4134926: Association of Eicosanoid Metabolites with Body Mass Index
Authors: Mandana Chitsazan, Juhi Parekh, Emily Lau, Mona Alotaibi, Bing Yu, Norrina Allen, Matthew Allison, Mohit Jain, Susan Cheng, Jennifer Ho
Journal: Circulation (2024)

Introduction: The specific molecular pathways from obesity to inflammation to cardiovascular disease remain unclear. Eicosanoids are a unique class of bioactive lipids that govern the upstream initiation of pro- and anti-inflammatory activity. Objective: We leveraged a novel lipidomic platform to quantify &gt; 800 eicosanoid metabolites and examined their association with body mass index (BMI). Methods: We studied Multi-Ethnic Study of Atherosclerosis (MESA) participants with available samples for eicosanoid analysis. Eicosanoids and related metabolites were assessed using a directed, non-targeted mass spectrometry-based platform. We examined the cross-sectional association of eicosanoid metabolites with BMI using multivariable linear regression models. Analyses were considered significant at FDR q-value &lt;0.01. Results: A total of 5101 individuals (age 63 ± 10 years; 53% women, 60% non-Whites) were included. The mean BMI was 28.3 ± 5.1 kg/m2. Of 811 eicosanoids analyzed, 255 showed a significant association with BMI (see Figure for putative metabolite identities; FDR q-value &lt;0.01 for all). Derivatives of docosahexaenoic acid (DHA; 19,20 DiHDPA, β = - 0.206, standard error [SE] = 0.013) and eicosatetraenoic acid (11(S) HEPE, β = - 0.180, SE = 0.014) were associated with lower BMI. Linoleic acid derivatives (12,13 diHOME, an exercise-induced lipokine) had a similar association. Conversely, derivatives of linoleic acid (13-oxoODE, β = 0.241, SE = 0.01) and arachidonic acid (11-HETE, β = 0.236, SE = 0.017) were associated with higher BMI. Other derivatives of linoleic acid (15 (S) HETrE) and prostaglandin (11b PGF2α) were also associated with higher BMI. Conclusions: We found that specific eicosanoid metabolites, including DHA and linoleic acid derivatives with known anti-inflammatory, atheroprotective, and beneficial metabolic effects (e.g., 19,20 DiHDPA; 12,13 diHOME), were associated with lower BMI. By contrast, specific arachidonic acid and prostaglandin derivatives with known pro-inflammatory and adverse CV effects (e.g. oxylipin 11-HETE; PGF2α; 13-oxoODE) were associated with higher BMI. These findings further the understanding of specific inflammatory pathways underlying the development of obesity-related CVD.
Abstract 4134630: Focal Delivery of Antiplatelet Therapy to Prevent Post-Stent Bleeding in High-Risk Patients
Authors: Soheb Anwar Mohammed, Muhammad Wahab Amjad, Jared Romeo, Kathryn Harris, Ellen Gawalt, John Pacella
Journal: Circulation (2024)

Background: Over 3 million percutaneous coronary interventions (PCI) are performed yearly to treat coronary artery stenosis. Stent thrombosis is a catastrophic complication associated with high morbidity and mortality, and its prevention requires the use of prolonged dual antiplatelet therapy (DAPT), which increases bleeding risk. Within the first 30 days after PCI, the mortality of DAPT-associated major bleeding is on par with recurrent myocardial infarction. Research question: No stent system that provides focal antiplatelet activity to prevent stent thrombosis exists, eliminating the need for systemic DAPT and subsequent bleeding risk. Aim: To address this unmet need, we have developed such a stent, termed “the ticagrelor coated stent” (TCS). Methods: Self-assembled monolayers (SAMs) of 12-aminododecylphosphonic acid (ADPA) were formed on cobalt-chromium stents. The amine tail group of ADPA was used to link the ticagrelor molecule through a Mitsunobu reaction and confirmed via infrared spectroscopy. Coating uniformity was validated via atomic force microscopy. In an ex-vivo porcine arterio-venous fistula model, the ticagrelor-coated stents (TCS) were placed in alternating series adjacent to uncoated bare metal stents (BMS). Similarly, TCS and everolimus-eluting stents were placed in the porcine left circumflex arteries for acute (7 days) and chronic (35 days) studies. Results: ( Figure 1 ): Grossly, no thrombus was seen on the TCS compared to the BMS. Platelet and micro-thrombi adherence were significantly reduced on TCS. Notably, inflammation, measured by neutrophil and monocyte adherence, was also reduced by approximately 10-fold on the TCS vs the BMS. Angiography, optical coherence tomography (OCT), and histopathology results show the TCS widely patent without systemic DAPT. Conclusion: These findings show that TCS prevents stent thrombosis through focal anti-platelet action and may reduce the bleeding risk associated with prolonged use of systemic DAPT. Long-term safety and efficacy studies are underway.
Abstract 4134460: Application of Principal Component Analysis to Heterogenous Fontan Registry Data to Identify Independent Contributing Factors to Decline
Authors: Margaret Ferrari, Michal Schafer, Kendall Hunter, Michael Di Maria
Journal: Circulation (2024)

Introduction: Single ventricle heart disease is a severe and life-threatening illness, and improvements in clinical outcomes of those with Fontan circulation have not yet yielded acceptable survival over the past two decades. Patients are at risk of developing a diverse variety of Fontan-associated comorbidities that may ultimately require heart transplant. Goal: Our study goal was to determine if principal component analysis (PCA), which determines unique directions of data variance, applied to data collected from a pediatric Fontan cohort can predict functional decline (N=140). Methods: Heterogeneous data broadly consisting of measures of cardiac and vascular function, exercise (VO 2max ), lymphatic biomarkers, and blood biomarkers were collected over 9 years at a single site as part of a prospectively applied clinical care pathway; in that time, 16 events occurred that are considered here in a composite adverse outcome measure. After standardization and PCA, principal components (PCs) representing &gt;5% of total variance were thematically labeled based on their constituents and tested for association with the composite outcome. Results: Our main findings suggest that the 6 th PC (PC6), representing 7.1% percent of the total variance in the set, is greatly influenced by albumin, alkaline phosphatase, total protein, BUN and BNP max and is a superior measure of proportional hazard compared to EF; it displayed the greatest accuracy for classifying Fontan patients as determined by AUC. In bivariate hazard analysis, we found that models combining systolic function (EF or PC5) and blood biomarkers (PC6) were most predictive, with the former having the greatest AIC, and the latter having the highest c-statistic. Conclusion: Our findings support the hypothesis that a broad, prospectively collected, multiorgan system model analyzed by way of unsupervised machine learning methods will improve prognosis of adverse outcomes in a Fontan cohort.