tbuckley/cabot-search huggingface dataset:
Abstract 4120480: HIV-Nef extracellular vesicles utilize the novel Btk-NFκB-MerTK signaling axis to impair macrophage efferocytosis and promote atherosclerosis: A multiomics study
Authors: Sarvesh Chelvanambi, Julius L Decano, Yuto Nakamura, Yoshihiro Yangihara, Amelie Jule, Constance Delwarde, Francesca Bartoli-Leonard, prabhash Jha, Adrien Lupieri, Takashi Enomoto, Joan Matamalas, Shin Mukai, Diego Pestana, Rile Ge, katelyn Perez, Taku Kasai, Shiori Kuraoka, Gabriel Silva Monteiro, Ira Tabas, Shannan Ho Sui, Abhijeet Sonawane, Sasha Singh, Elena Aikawa, Masanori Aikawa
Journal: Circulation (2024)

Background: People living with HIV (PLWH) on anti-retroviral therapy remain at risk for cardiovascular diseases, including atherosclerosis. We hypothesized that persistent viral protein (HIV-Nef) in extracellular vesicles (EVs) modulate macrophage heterogeneity to impair atheroprotective efferocytosis to accelerate cardiovascular disease. Methods and Results: Macrophage heterogeneity was characterized in human primary macrophages (50,931 cells; 4 donors) stimulated with EVs engineered to contain HIV-Nef by simultaneous scRNAseq and scATACseq. Among 16 clusters (Fig.1A), two inflammatory Nef dominant clusters were characterized using gene set enrichment analysis. Gene regulatory network analysis of scRNAseq (pySCENIC) and transcription factor footprinting analysis of sc-ATACseq (ChromVar) suggest elevated NFκB activation in these clusters. Whole cell and sub-cellular compartmentalized proteomics of nucleus, cytosol, cell surface and secreted EVs indicate changes in immune response related biological pathways. Network analysis of our multi-omics data predicts Bruton Tyrosine Kinase (Btk) signaling as a potential contributor to Nef induced macrophage dysregulation. Pathway enrichment analysis of these multiomics dataset suggest Nef influences atheroprotective efferocytosis through the Btk-NFκB signaling axis. Spectral flow cytometry, high content imaging and multiplexed qPCR showed reduction in key effector of efferocytosis, MerTK. Btk inhibition using siRNA, reversible and irreversible Btk inhibitors restored MerTK expression and rescued efferocytosis. Importantly, CRISPRa based overexpression of MerTK in human primary macrophages rescued Nef impaired efferocytosis. Injection of HIV-Nef EVs into male and female C57BL6/J mice impaired efferocytosis of peritoneal and bone marrow derived macrophages which was rescued with Btk inhibition in vivo . Critically, injection of HIV-Nef EV into male and female Ldlr -/- enhanced atherogenesis with larger aortic wall thickness and necrotic core (Fig.1B). Conclusion: Persistent Nef in EV in PLWH may modulate macrophage heterogeneity to impair efferocytosis. These findings may help develop novel atheroprotective therapies by restoring macrophage efferocytosis.
Abstract 4118341: Outcomes of Heart Failure with Preserved Ejection Fraction Patients With Concurrent Opioid Use: Insights From the National Inpatient Sample
Authors: Ahmed Younes, Ahmed Maraey, Ahmed Elzanaty
Journal: Circulation (2024)

Background: Opioid use has increased significantly in the past few decades, impacting cardiac and non-cardiac patients. As heart failure with preserved ejection fraction (HFpEF) comprises half of all heart failure cases, understanding its management and effect on outcomes is crucial. This study aims to evaluate the outcomes of chronic opioid therapy on HFpEF patients. Methods: Studying the National Inpatient Sample (2016-2020), we identified adult HFpEF patients using the appropriate ICD-10 codes -after excluding patients with end-stage renal disease (ESRD)- and compared outcomes between chronic opioid users and non-users. Multivariate logistic and linear regression analyses were performed, adjusting for multiple patient and hospital confounders. The primary outcome was all-cause in-hospital mortality while secondary outcomes included acute kidney injury/hemodialysis (AKI/HD), cardiogenic shock, cardiac arrest, mechanical ventilation, length of stay, and total charges. Results: Among 1,557,344 HFpEF patients, 21,655 (1.4%) were on opioids chronically. Inpatient mortality was not significantly different between patients who were on opioids and those who were not. (adjusted odds ratio [aOR] 1.01, 95% CI 0.85 - 1.2, p=0.89). There was a non-significant increased risk of cardiogenic shock (aOR 1.14, 95% CI 0.87 - 1.5, p=0.35) and cardiac arrest (aOR 1.05, 95% CI 0.8 - 1.36, p=0.74) in patients on chronic opioids. Chronic opioids were associated with increased risk of AKI/HD (aOR 1.12, 95% CI 1.04 - 1.2, p=0.002) and mechanical ventilation (aOR 1.29, 95% CI 1.16 - 1.43, p&lt; 0.001). Opioid use was also associated with longer hospital stay (adjusted MD [aMD] 1.07 days, 95% CI 0.75 - 1.39, p&lt;0.001) and a non-significant increase in total charges (aMD $2,593, 95% CI -$2,044 - $7,229, p=0.27). Conclusions: While chronic opioid use in hospitalized HFpEF patients did not significantly impact in-hospital mortality, it was associated with increased risk of other adverse events and longer hospital stay. Further research is needed to understand the impact of chronic opioid use on HFpEF patients.
Abstract 4120140: Catastrophic Bioprosthetic Aortic Valve Thrombosis: An Unappreciated Complication of Veno-Arterial Extracorporeal Membrane Oxygenation Support in Cardiogenic Shock
Authors: Patrick O'Hara, Lauren Truby, Montana Goral, Han Kim, Paris Malensek, Hadi Beaini, Ravi Patel, Anas Jawaid, Fizza Hussain, Christopher Heid, Peiman Lahsaei, Maryjane Farr, Sonia Garg, Faris Araj
Journal: Circulation (2024)

Description of Case: A 56-year-old male with a history of cardiac sarcoidosis with biventricular systolic heart failure (HF) and a bioprosthetic aortic valve presented with acute decompensated HF. Progressive cardiogenic shock and hemodynamic instability ensued, requiring urgent bedside placement of an intra-aortic balloon pump (IABP) which provided only marginal hemodynamic support. After extensive multidisciplinary discussion, emergent cannulation for veno-arterial ECMO (VA-ECMO) was performed at the bedside as a bridge-to-decision for advanced HF therapies. The IABP was left in place for LV venting. Within 72 hours, extensive bilateral pulmonary opacities had developed. It was later realized that true LV ejection (as evidenced by aortic pulsatility on the arterial line) was not present and had been masked by pseudo-pulsatility provided by IABP inflations and deflations. Compared to an echocardiogram done 7 days prior to VA-ECMO cannulation, the bioprosthetic leaflets were no longer opening, thrombosis of the AV had occurred, and thrombus formation along the ECMO venous drainage cannula was noted. Failure to achieve LV venting culminated in complete thrombosis of the entire LV and LA and the patient ultimately expired. Discussion: Bioprosthetic valve thrombosis is a lesser-known complication of VA-ECMO support, with most reports involving bioprosthetic valves in the mitral position. Indeed, bioprosthetic valve thrombosis occurs at a higher rate than native valve thrombosis during VA-ECMO support. However, bioprosthetic AV thrombosis is an extremely rare complication of VA-ECMO support and arguably results in a more catastrophic scenario as most traditional approaches to LV unloading are contraindicated. The optimal LV unloading strategy for these patients (IABP, Impella, surgical apical unloading, etc) is unknown. Data from large retrospective analyses have demonstrated extremely poor outcomes when prosthetic valve thrombosis occurs, and it is thus critical to prevent this complication from developing. In contrast to IABP counter-pulsation, the benefit of upfront transvalvular LV venting with an Impella device safeguards the presence of a direct LV vent in the event of bioprosthetic AV thrombosis and eliminates the false reassurance of IABP pseudo-pulsatility. Further studies are needed to better elucidate the optimal LV unloading strategy in patients with bioprosthetic valves, particularly in the aortic position.
Abstract 4120919: Cell physiology and multi-omics analysis revealed disordered embryogenesis as early as mesoderm specification in models of Holt-Oram Syndrome
Authors: Masahiro Satoh, Ryota Teramoto, Rachelle Victorio, Shinichi Goto, Wandi Zhu, Max Homilius, Aryan Kaveh, David Chiang, Kusumika Saha, Yao Zu, Ashmita KC, Manu Beerens, Calum Macrae
Journal: Circulation (2024)

Introduction: Congenital heart diseases (CHDs) are the leading cause of childhood morbidity and mortality. The dysregulation of several cardiac transcription factors (TFs) leads to CHD. The coordination of several cardiac TFs is required and essential for cardiogenesis. However, the mechanisms to acquire its cardiac cell identity remain unclear. Hypothesis: Mutant Tbx5 dysregulates embryogenesis during mesoderm specification, prior to its expression in the tissues in Holt-Oram syndrome. Methods: Using cellular physiology and multiomics analysis in both human ES cells and a zebrafish model of TBX5 germline mutation. we evaluated embryonic structure and function, prior to the onset of gastrulation in the context of both heterozygous and homozygous TBX5 mutation. Results: Zebrafish time course transcriptome profiles over gastrulation revealed that loss of Tbx5 impacted transcriptional profiles at the blastula stage. Single cell RNA sequencing (scRNA-seq) on 16243 zebrafish blastula stage cells showed loss of Tbx5 impacted transcription noise at the blastula stage prior to the expression of zygotic Tbx5 with associated effects on chromatin accessibility using omni-assay for transposase-accessible chromatin (ATAC) and evidence of aberrant Wnt signaling even at the blastula stage. Embryo-wide cell structure and function were abnormal in both Tbx5 mutant zebrafish heterozygotes or homozygotes. To validate Undifferentiated human ES cell H3K4me3 Cleavage Under Targets&amp;Release Using Nuclease (CUT&amp;RUN) also showed abnormal Wnt signaling in TBX5 homozygous mutation and TBX5 CUT&amp;RUN showed aberrant mesoderm pathway. Calcium imaging analysis demonstrated the lowest excitation frequency in TBX5 homozygous mutation prior to mesoderm specification. TBX5 homozygous human ES derived mesoderm cells exhibited low expression levels of mesoderm marker genes compared to TBX5 wild type mesoderm. Conclusion: Integrating single cell physiology and multi-omics technologies, we idneifified fundamental dysregulation of embryogenesis in mutant cardiac-restricted gene disorder prior to mesoderm specification or the zygotic expression of the mutant gene. These findings suggest that Tbx5 started to determine cell fate prior to mesoderm specification by altering chromatin accessibilities and histone modification. Tbx5 affected mesoderm differentiation by influencing Wnt signaling and cell physiology.
Abstract 4118766: Lower Winter and Higher Summer Temperatures Increase the Risk of Hospitalization With Aortic Aneurysm or Aortic Dissection
Authors: Kanhua Yin, Yaguang Wei, Joel Schwartz
Journal: Circulation (2024)

Background: Seasonal variation in aortic dissection incidence are well-documented. This study utilized a high-resolution surface temperature model and state-specific administrative medical data to investigate the relationship between long-term exposure to winter and summer temperature averages and hospitalization rates for aortic aneurysm or dissection. Methods: Using data from the 2000-2016 State Inpatient Databases (SID), 265,795 hospitalizations with a principal diagnosis of aortic aneurysm or dissection for residents of 19 U.S. states were identified via ICD-9 and 10 codes. Daily surface temperature data, extracted from Oak Ridge National Laboratory’s Daymet weather model on a 1-km grid, were aggregated to zip codes to match SID's spatial resolution. Linear regressions, adjusted for demographics, comorbidities (including hypertension, hyperlipidemia, atherosclerosis, smoking, and genetic disorders), air pollution, and neighborhood socioeconomic status, estimated absolute changes in annual hospitalization rates associated with variations in winter and summer temperature averages. Nonlinear exposure-effect relationships were assessed using penalized cubic splines with at most nine degrees of freedom. Results: Each Celsius degree decrease in winter and increase in summer was associated with 19.0 (95% CI: 17.5, 20.8, p&lt;0.001) and 10.4 (95% CI: 8.0, 12.7, p&lt;0.001) additional hospitalizations per one million person-years, respectively. These statistically significant associations were consistent across subgroups, including thoracic vs. abdominal and aneurysm vs. dissection. Further analysis revealed that cooler-than-average winter temperatures consistently correlated with increased hospitalization rates for overall aortic aneurysms or dissections and their subtypes. Conclusion: Colder winter and hotter summer temperatures significantly increase the risk of hospitalization for aortic aneurysm or dissection. This emphasizes the importance of understanding how environmental factors contribute to aortic disease.
Abstract 4114436: Feto-maternal outcomes of subsequent pregnancy among women with Peripartum Cardiomyopathy in Tanzania.
Authors: Pedro Pallangyo, Zabella Mkojera, Makrina Komba, Peter Richard Kisenge
Journal: Circulation (2024)

Background: Besides survival and recovery, women afflicted with peripartum cardiomyopathy (PPCM) harbor significant apprehension regarding the safety of future pregnancies. Current knowledge regarding the maternal and fetal outcomes in subsequent pregnancies among women with a history of PPCM is sparse. Likewise, there is insufficient medical evidence to provide guidance for women who opt to become pregnant again after experiencing PPCM. Research Questions: What is the feto-maternal prognosis of subsequent pregnancies following a history of PPCM? Aims: To describe the fetal and maternal outcomes of subsequent pregnancies following a history of PPCM. Methods: We included women from the Tanzania PPCM registry who had subsequent pregnancies after PPCM and assessed PPCM recurrence, maternal prognosis, and fetal outcomes. Results: Among the 870 survivors (286 of whom left ventricular function had returned to normal [group 1] and 584 with persistent left ventricular dysfunction [group 2]), subsequent pregnancies were observed in 121 (13.9%) women (78 in group 1 and 43 in group 2). Forty (51.3%) women in group 1 had PPCM relapse, and during a mean follow-up of 896 days, 34 (85.0%) had complete recovery, 3 (7.5%) had persistent heart failure, and 3 (7.5%) died. In group 2, four (9.3%) women had complete recovery, 32 (74.4%) had persistent heart failure, and 7 (16.3%) died. The infant mortality rate was 23.4%. Conclusions: After the initial pregnancy complicated by peripartum cardiomyopathy, subsequent pregnancies could lead to PPCM relapse and deleterious feto-maternal outcomes, including death.
Abstract 4117594: Fetal Synthetic Glucocorticoid (sGC) Exposure Results in Later Life Cardiac Dysfunction and Ventricular Remodeling in Male Baboon Offspring
Authors: Bowen Yang, Daniel Adekunbi, Chen Zhang, Hillary Huber, Feiyang Zhao, Raechel Camones, Jinqi Li, Alexander Moody, Cun Li, Laura Cox, Lu Wang, Adam Salmon, Geoffrey Clarke, Peter Nathanielsz
Journal: Circulation (2024)

The “theory of developmental origins of health and disease” posits that stress in critical developmental periods will program life-course health and may affect cardiovascular (CV) health. Mothers at risk for premature delivery receive synthetic glucocorticoids (sGC) to enhance fetal lung maturation and manage fetal respiratory distress, but sGC exposure is linked to long-term CV dysfunction in offspring. Four groups of male baboons were studied: sGC exposed in utero at middle age (sGC-MA, 13.8±0.2Y), older sGC exposed in utero (sGC-O, 17.1±0.4Y), middle age unexposed (CTR-MA, 13.5±0.6Y), and older, unexposed baboons (CTR-O, 17.4±0.4Y). Gated, breath-hold, cine cardiac magnetic resonance imaging was performed at 3 Tesla (Siemens TIM Trio) to assess left ventricular (LV) function and myocardial strain, analyzed using cvi42® software. Mitochondrial electron transport chain (ETC) complex activity was analyzed using LV tissue from sGC-O and CTR-O euthanized baboons. Protein quantification was used to measure mitochondrial function and RNA-seq assessed differential gene expression and gene ontology (GO) enrichment. Unpaired t-tests were used. Data are reported as mean ± SD. Stroke volume and ejection fraction were similar in the elderly groups (4 sGC-O, 8 CTR-O). However, higher end-systolic and end-diastolic sphericity indexes (SI) and shorter LV axis lengths indicated remodeling. Also, global longitudinal and radial strains were reduced (both p&lt;0.04) in sGC-O vs. CTR-O. Reduced LV cardiac output (p=0.005) was found in 5 sGC-MA animals vs 4 sGC-O animals, but not in 5 CTR-MA vs 8 CTR-O. In sGC-MA vs sGC-O, but not CTR-MA vs CTR-O, significant increases in SI (p=0.001), radial strain (p=0.02), and longitudinal (p=0.03) strain were found, but LV axis length (p=0.03) was reduced. LV mitochondrial analysis in 4 sGC-O vs 4 CTR-O myocardial samples revealed 33.5% less ETC activity (p=0.002) and 19.8% less complex I expression (p=0.048) in sGC. LV RNA-seq identified 63 upregulated and 20 downregulated genes in the sGC-O samples. GO pathway enrichment included changes in heart contraction, wounding responses, and leukocyte regulation pathways. These findings indicate that fetal sGC exposure developmentally programs offspring with LV remodeling and long-term cardiac and gene expression changes in male baboons, the closest available experimental nonhuman primate species to man. Future studies on females will probe sexual dimorphism in developmental programming.
Abstract 4117767: Interplay Between ST2 Gene Downregulation and Inflammatory Processes in Hypertrophic Cardiomyopathy
Authors: Huang Sun, Xiying Guo, Xingyu Cao, Haixia Diao, Yan Ang
Journal: Circulation (2024)

Introduction: Hypertrophic Cardiomyopathy (HCM) is an inherited heart disease and the pathogenesis of HCM involves genetic mutations, hemodynamic stress, and metabolic factors, with myocardial fibrosis playing a crucial role in severe clinical events. IL-33/ST2 signaling pathway known for its roles in immune response and tissue repair, participates in cardiac protection and anti-cardiac fibrosis in heart failure. The role of ST2 in HCM remains unclear, and IL-33/ST2 pathway and broader inflammatory responses may be critical in HCM. Hypothesis: ST2 gene downregulation and dysregulation of inflammatory pathways represent a novel mechanism in HCM. Methods: We re-analyzed the raw whole transcriptome sequencing data using a comprehensive bioinformatics pipeline from 9 GEO datasets. After removing low-quality samples, myocardial tissue samples from 109 HCM patients and 210 non-HCM controls were included. HTSeq-count was used to obtain the read count of each gene. Differential expression analyses were conducted using DESeq2. Spearman correlation analysis was performed for ST2 with all other protein-coding genes. Gene set enrichment analysis (GSEA) was performed to explore the biological significance of ST2 related genes. CIBERSORTx was used to estimate the immune cell composition of heart tissues. Additionally, network analyses and statistical correlations were conducted. Results: Our analysis identified significant downregulation of the ST2 gene in HCM patients compared to controls (log2FC = -5.0, p = 2.7E-147). In total, 5,180 upregulated and 741 downregulated genes were detected. Additionally, 208 genes were significantly correlated with the expression of ST2. GSEA based on the correlation coefficients revealed a significant increase in immune response, inflammation, and IFN-γ pathway activity, along with a decrease in the expression of genes related to sarcomeric function, cardiac morphogenesis, and metabolism in HCM. Notably, the significant inverse correlation between ST2 expression and regulatory T cells (r = -0.34) and a positive correlation with neutrophils (r = 0.39) suggest that ST2 may modulate immune cell populations in HCM. Pathway analysis indicated ST2's central role in networks involving inflammatory and fibrotic responses. Conclusion: The interplay between ST2 and inflammatory pathways may drive myocardial remodeling and fibrosis in HCM. This study paves a new way for investigating pathogenic mechanisms and therapeutic strategies for HCM.
Abstract 4120785: Differential Cardiovascular Impact of ω-3 Fatty Acid in Patients at High Cardiovascular Risk in Asians versus non-Asians: Sub-analysis of the STRENGTH Randomized Clinical Trial
Authors: Tom Kai Ming Wang, Stephen Nicholls, Julie St John, Kathy Wolski, Steven Nissen
Journal: Circulation (2024)

Background: Racial differences in lipid and cardiovascular risk profiles are well-established including for Asians. The STRENGTH trial found that ω-3 carboxylic acid (CA) formulation of eicosapentaenoic acid and docosahexaenoic acid did not result in significant changes in cardiovascular event rates compared with corn oil in statin-treated patients at high cardiovascular risk, however drug efficacy may vary by race. We evaluated and compared the cardiovascular treatment effect of ω-3 CA between Asians and non-Asians in this sub-analysis of the STRENGTH trial. Methods: The STRENGTH trial was a double-blinded 1:1 randomized controlled trial of 13,078 high cardiovascular risk patients enrolled during 10/30/2014-6/14/2017 at 675 centers. Efficacy of ω-3 CA for Asians (n=1,355) and non-Asians (n=11,723) and interactions between race and treatment effect were assessed. The primary endpoint is a composite of cardiovascular death, non-fatal myocardial infarction, stroke, coronary revascularization and unstable angina hospitalizations. Results: Key differences in baseline characteristics include Asians having significantly higher prevalence of men, secondary prevention, and lower total cholesterol, LDL, apoB100, and hsCRP. In Asians, ω-3 CA was associated with significantly lower primary endpoint during follow-up, with 81/698 events [Kaplan-Meier (KM) Estimate: 14.8%] in the ω-3 CA group, 103/657 events (KM Estimate: 20.4%) in the corn oil group, and hazard ratio (HR) 0.72, 95% CI 0.54-0.96, P=0.026 (Figure A). In non-Asians, there was not a significant difference in primary endpoint rates between the two groups, with 704/5841 events (KM Estimate: 15.6%) in the ω-3 CA group, 692/5882 events (KM Estimate: 15.9%) in the corn oil group, and HR 1.03 95% CI 0.93-1.14, P=0.60 (Figure B). There were significant interactions between race (Asian versus non-Asian) and treatment group for the primary endpoint (P=0.021) and non-fatal stroke (P=0.016) and remained significant after adjusting for other covariates. Conclusion: ω-3 CA was associated with significant reduction in major adverse cardiovascular events compared with corn oil in Asians but not in non-Asian patients with high cardiovascular risk. Further research is necessary to elucidate the mechanisms for potentially beneficial effects of ω-3 CA unique to Asian race.