tbuckley/cabot-search huggingface dataset:
Abstract 13987: RBX1-CRLs Are Essential for Perinatal Heart Development by Regulating Hippo-YAP Signaling
Authors: Josue Zambrano-Carrasco, Wenjuan Wang, Juan Ayala, John Sibley, Jessica Carruth, Kai Jiao, YI SUN, Jie Li, Huabo Su
Journal: Circulation (2023)

Defects in cardiac development can lead to congenital heart diseases (CHD) or predispose the heart to cardiomyopathies in adult life. The molecular mechanisms that regulate this process remain elusive. Cullin-RING E3 ligases (CRLs) are multi-subunit complexes that are critical to maintain protein homeostasis by targeting a variety of protein substrates for proteasomal degradation. In the CRLs, RBX1 serves as the catalytic subunit that promotes the transfer of ubiquitin to the target protein. Previous animal studies uncovered a crucial role for RBX1 in development. However, its importance in the developing heart has not been explored. Here, we report for the first time the indispensable role of RBX1 in perinatal cardiac development. We created mice with cardiac-specific deletion of RBX1 driven by αMHC Cre . Compared with littermate control mice, RBX1-deficient mouse embryos exhibited no gross morphological abnormalities at E12.5 and E14.5, displayed peripheral edema at E16.5 indicative of heart failure, and eventually died around E18.5. Histological analysis revealed myocardial hypoplasia and a substantially thinner compact layer in E16.5 mutant hearts. This event was preceded by a remarkable decrease in cardiomyocyte proliferation and diminished nuclear localization of YAP, a powerful regulator of cardiomyocyte proliferation, at E14.5. In cultured cardiomyocytes, depletion of RBX1 inhibited proliferation and induced profound transcriptomic changes like the upregulation of cardiomyopathy-related genes. Mechanistically, RBX1 deficiency destabilized multiple CRLs and resulted in the accumulation of Hippo kinases and adaptor proteins such as SAV1, LATS1/2, and MOB1 leading to the inactivation of YAP by phosphorylation. We further demonstrated that RBX1 degrades the Hippo adaptors SAV1 and MOB1. Collectively, we propose that the fine-tuned, RBX1-mediated removal of Hippo components serves as a critical checkpoint to activate YAP signaling ensuring cardiac ventricular chamber development and morphogenesis.
Abstract 13725: Intravascular Ultrasound-Guided versus Angiography-Guided Percutaneous Coronary Intervention for ST Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis
Authors: Jasmeet K Kalsi, John Suffredini, Stephanie Koh, Umair Khalid, Ali E Denktas, mahboob alam, Waleed T Kayani, Xiaoming Jia
Journal: Circulation (2023)

Introduction: Intravascular ultrasound (IVUS) provides intra-procedural guidance in optimizing percutaneous coronary interventions (PCI) and has been shown to improve clinical outcomes in stent implantation. However, current data on the benefit of IVUS during PCI in STEMI patients is mixed. Research Question: Whether IVUS is associated with improved outcomes during PCI in STEMI patients is unclear. Aim: We performed a systematic review and meta-analysis assessing the utility of IVUS during PCI in the setting of STEMI. Methods: We performed a systematic search on PubMed and Embase for studies comparing IVUS versus angiography guided PCI in STEMI. Mantel-Haenszel random effects model was used to calculate risk ratios (RR) with 95% confidence intervals (CI) for outcomes of major cardiovascular adverse events (MACE), death, myocardial infarction (MI), target vessel revascularization (TVR) and stent thrombosis (ST). Analysis was performed using Review Manager version 5.4.1. Results: A total of 7 studies including 78,612 individuals presenting with STEMI were included for the meta-analysis. Follow-up ranged from 11 to 60 months. We found a significant association between IVUS-guided PCI with lower risk for MACE (RR 0.82, 95% CI 0.76-0.90) compared with angiography-guided PCI. We also found significant association between IVUS-guided PCI with lower risk for death, MI, and TVR but not ST (Figure 1). Conclusion: In our meta-analysis, IVUS-guided compared with angiography-guided PCI was associated with improved clinical outcomes in STEMI patients.
Abstract 14000: Elevated Galectin-3 Levels Are Associated With Higher Mortality in Patients With Atrial Fibrillation
Authors: Michael A Vavuranakis, Lilas Dagher, Yunyun Chen, Yi-An Ko, Arshed A Quyyumi
Journal: Circulation (2023)

Introduction: Atrial fibrillation (Afib) is associated with structural and electrical atrial remodeling. Galectin-3 (Gal-3) is a mediator of atrial fibrosis and higher levels have been associated with new onset Afib. Whether Gal-3 levels are prognostic in Afib remains unknown. Research Question: Investigate whether higher Gal-3 levels are associated with higher mortality in Afib. Methods: Patients with a history of Afib, enrolled in the Emory Cardiovascular Biobank of patients undergoing coronary angiography for suspected or confirmed CAD were included. Primary outcomes were all-cause and cardiovascular (CV) mortality. Kaplan-Meier and Cox regression analyses were used to compare survival between different Gal-3 levels. Results: We included 767 patients (mean age 68 years, 69.8% males) who were followed for a mean of 4.4 years. There were 234 (30%) all cause and 149 (19%) CV deaths. Third and fourth quartiles of Gal-3, were associated with higher hazard, when compared to the first quartile, with hazard ratios (HR) of 2.1 (1.4, 3.3) (Q3) and 3.5 (2.3, 5.3) (Q4) for all-cause mortality and 2.8 (1.5, 5.2) (Q3) and 4.9 (2.7, 8.7) (Q4) for cardiovascular mortality respectively. A one unit increase in Gal-3 was associated with HR of 1.4% and 1.8% for all-cause and CV mortality respectively, after adjusting for age, NT-proBNP, hypertension, stroke, MI, PVD, absence of coronary artery disease on left heart catheterization, history of HF and anti-coagulation therapy. Conclusions: Higher levels of Gal-3 are associated with higher incidence of all-cause and cardiovascular mortality in patients with Afib. Gal-3 can be used to identify high risk patients with Afib.
Abstract 14019: Comparing the Effect Profile of CETP in Individuals of East Asian and European Ancestries
Authors: Diana Dunca, Sandesh Choapde, Maria Gordillo-Marañón, Aaron Hingorani, Karoline Kuchenbaecker, Chris Finan, Amand Floriaan Schmidt
Journal: Circulation (2023)

Introduction: Cholesteryl ester transfer protein (CETP) is a lipid drug target under development for CHD in both European and East Asian populations.Previous drug target Mendelian randomization (MR) studies conducted in East Asians failed to show a CHD effect, which has been interpreted as lack of effectiveness of CETP inhibition for CHD prevention in this population. Hypothesis: In this study, we inferred the effect of CETP inhibition in individuals of European and East Asian ancestries using drug target Mendelian randomization. Methods: We leveraged genetic associations of CETP variants with major blood lipid fractions for individuals of European (n=1,320,016) and East Asian (n=146,492) ancestries. Colocalization was employed to identify potential cross-ancestry signals of CETP variants for plasma concentrations of LDL-C or HDL-C. Drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition. Differences between ancestries were evaluated using interaction tests, applying a multiplicity corrected alpha of 1.9х10 -3 based on the 26 considered traits. Results: There was strong support (posterior probability=1.00) of a shared causal CETP variant affecting HDL-C in both populations, which was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP was associated with lower LDL-C, Lp[a], systolic blood pressure and pulse pressure in both groups, but the effects were more pronounced in European individuals (interaction p-values &lt; 1.9х10-3). Lower CETP was protective against CHD, angina, intracerebral haemorrhage and heart failure in both ancestries, for example for CHD in East Asians (OR 0.89, 95%CI 0.84;0.94) compared to Europeans (OR 0.95, 95%CI 0.92;0.99, interaction p-value=0.05). Conclusions: In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.
Abstract 14007: Decreased Perceived Social Support and Heart Rate Variability Are Associated With Hopelessness in Patients With Ischemic Heart Disease
Authors: Madison Goodyke, Ulf G Bronas, Tracy Baynard, Nathan Tintle, Holli A Devon, Eileen G Collins, Susan L Dunn
Journal: Circulation (2023)

Introduction: Hopelessness is present in up to 52% of patients with ischemic heart disease (IHD) and associated with a 3.4 times increased risk of death and adverse outcomes. Decreased perceived social support (PSS) has been associated with hopelessness in patients with IHD reporting moderate-severe hopelessness but has not been examined in a well-powered sample with varying levels of hopelessness. Increased PSS is associated with increased high frequency (HF) heart rate variability (HRV) in adults following a stressful event, but the relationship between HRV and hopelessness has not been examined in patients with IHD. Hypothesis: The purpose of this research was to test the hypotheses that 1) lower PSS would be associated with higher hopelessness, and 2) lower HF HRV would be associated with higher hopelessness. Methods: Utilizing a cross-sectional design, 178 participants were enrolled while hospitalized for an IHD event at one large hospital in the Midwestern United States. Data collection occurred two weeks after hospital discharge using the State-Trait Hopelessness Scale, ENRICHD Social Support Inventory, Patient Health Questionnaire-9, a demographic form, and a short-term HRV measurement at rest. Linear models were used to assess association between variables in unadjusted models and models adjusted for demographic and medical history. Results: Majority of participants were male (67%), married (67%), non-Hispanic white (92%), and underwent coronary artery bypass surgery (61%). There was a moderate inverse correlation between PSS and state ( r = -0.31, p &lt; 0.001) and trait ( r = -0.28, p &lt; 0.001) hopelessness in unadjusted models. The relationships remained significant in adjusted models and did not differ between groups comparing sex, type of IHD event, and marital status. There was a moderate inverse correlation between HF HRV and state hopelessness ( r = -0.24, p = 0.023). Results remained significant in adjusted models and did not differ between groups comparing sex, type of IHD event, and beta-blocker prescription. Conclusions: There were significant inverse associations between PSS and hopelessness and HF HRV and hopelessness. Persons with low PSS and/or HF HRV may be at greater risk for experiencing hopelessness following an IHD event.
Abstract 12939: Friend or Foe: Increased Access to Care via Patient Portals
Authors: Jeffrey B Moorhead, Kwonho Jeong, Kaleab Abebe, Christina Harrington, Jared W Magnani, Amber E Johnson
Journal: Circulation (2023)

Background: Patient portals are secure online websites that grant patients access to their medical record. Portal use is associated with improved chronic disease management. Whether the use of patient portals is associated with cardiac outcomes is less well known and deserves further study. We examined the association of patient portal use with cardiac events among a large cohort of patients with CVD. We expected to find differences in portal use by sociodemographic info. We hypothesized that portal use would be negatively associated with cardiac events. Methods: De-identified data for adult patients meeting inclusion criteria were obtained between January 2018 and October 2021. The association of portal use with demographic factors was assessed using t-test and/or chi squared. Our primary outcomes were emergency department (ED) visit or all-cause readmission. We used a Cox model adjusting for demographic and clinical covariates at an alpha of 0.05. Results: The Table summarizes our findings. There was a significant difference in portal use by sex, race, ethnicity, English proficiency, and marital status. The Figure shows the adjusted findings that portal use was associated with higher hazards of ED visits and all-cause readmission at one year. Conclusions: Our data demonstrate that sociodemographic factors are associated with online patient portal use at a single institution. Contrary to our hypothesis, we found that portal use portends increased ED visits and hospitalization (lower event-free survival). These data suggest that patient portal access and closer clinician scrutiny may lead to increased health services utilization.
Abstract 12885: Pathological Perk/Atf4 Activation in Abdominal Aortic Aneurysm Formation
Authors: Hongyu Zhang, Kevin D Mangum, Amrita Joshi, Brennan Callow, Xianying Xing, Lam C Tsoi, Mary O'Riordan, Johann Gudjonsson, Katherine A Gallagher, Frank M Davis
Journal: Circulation (2023)

Introduction: Abdominal aortic aneurysms (AAA) are characterized by vascular smooth muscle cell (VSMC) apoptosis leading to pathological aortic remodeling. Activation of the endoplasmic reticulum (ER) stress response has been linked to VSMC dysfunction but the driving factors behind ER stress activation and its role on AAA development remains poorly defined. The epigenetic enzyme, MLL1, plays a critical role in establishing cellular phenotype and regulating gene expression. We examine the MLL-mediated epigenetic regulation of the ER stress response in VSMCs during AAA development and establish the ER stress pathways as a novel target in the treatment AAAs. Methods: Single-cell sequencing was conducted on human AAA and control tissue samples. For our murine model, C57BL/6 mice were injected with an AAV encoding a PCSK9 gain-of-function mutation and then fed a saturated fat-enriched diet and infused with AngII (1 μg/kg/min) with or without 4-PBA (20mg/kg/day). The elastase induced AAA model was used as a secondary murine model. AAA maximum diameters were quantified and VSCMs were isolated. Eif2a, Atf4 , and Chop gene expression was examined. Apoptosis was quantified by Annexin V staining. Results: Using single-cell RNA sequencing of human aortic tissue, we identified EIF2A, ATF4 , and CHOP were profoundly upregulated in aneurysmal VSMCs as well as two murine AAA models. Mechanistically, TNFα signaling in VSMCs leads to activation of MLL1 which trimethylates histone 3 lysine 4 (H3K4me3) at NF-κB binding sites on the EIF2A and ATF4 gene promoters thereby upregulating the ER stress response and driving VSMC apoptosis. In vivo pharmacological inhibition of the eIF2A/ATF4 ER stress response via 4-PBA injection inhibited AAA formation in both the AngII-induced and elastase-induced AAA model resulting with in significant reduction in VSMC apoptosis, elastin fragmentation, and inflammatory cytokine infiltration. Conclusions: Taken together, our results identify MLL1-mediated activation of the eIF2A/ATF4 ER stress response as a critical regulator of VSMC apoptosis in AAA formation and suggest inhibition of ER stress response as a mechanistic target for the management of AAAs.
Abstract 12697: Identifying Patients at Low Risk for Cancer Therapy Related Cardiac Dysfunction in Patients Treated With Trastuzumab for HER 2+ Breast Cancer
Authors: Abdelrahman Ali, Efstratios Koutroumpakis, Juhee Song, Nicolas L Palaskas, Anita Deswal
Journal: Circulation (2023)

Introduction: Frequent monitoring every 3 months for Cancer Therapy-Related Cardiac Dysfunction (CTRCD) is recommended in patients who receive trastuzumab (tras) for cancer therapy. Aims: We examined the frequency and predictors of asymptomatic and symptomatic CTCRD in a contemporary cohort of patients with breast cancer treated with tras with or without anthracyclines (AC). Methods: Breast cancer patients who received tras with/without AC and had at least one baseline and one follow-up echocardiogram (echo) performed at our tertiary cancer center (2013-2022) were included. CTCRD was defined as left ventricular ejection fraction (LVEF) decline (Simpson’s bi-plane quantitative assessment) of at least 10% to &lt; 50%. Risk factors for CTCRD were examined using univariable and multivariable Fine-Gray models. Results: The cohort included 502 patients with mean ± SD age 52.1±13.2 years, mean baseline LVEF 61.2±4.1%, and a median follow-up of 52.6 months. Patients had a mean of 5.5 ± 2.7 echocardiograms; 25 patients (5%) had CTCRD as defined above during follow-up, 3.4% (95% CI, 1.8-5.9) in the Tras only and 8.7% (95% CI, 4.7-14.5) in Tras + AC group. Only 8 patients (1.6%) developed new clinical HF at any time during follow-up, 6 of whom were associated with a concomitant decline in LVEF. Increasing age (HR, 95% CI, 1.03 1.01-1.06), baseline LVEF &lt;55% (HR 7.3, 2.9-18.2), history of HF (HR 6.2, 1.5-25.2) and AC therapy (HR 4.5, 1.8-11.4) were independently associated with CTCRD. On follow-up, 1.1% of Tras-only vs 2.7% of Tras + AC group had a persistently decreased LVEF. In a low-risk group without any of the risk factors for CTCRD, only 1 % of patients had CTCRD without clinical HF. Conclusions: The incidence of asymptomatic and symptomatic CTCRD was low in patients receiving tras only. Patients without any risk factors receiving tras only could be considered for less frequent monitoring of asymptomatic CTCRD.
Abstract 12695: An Atrial Fibrillation Treatment Pathway in the Emergency Department Reduces 30-day Cost of Care
Authors: Rafat Mahmood, Kevin Biese, Sally C Stearns, Tiffany Armbruster, Lindsey Rosman, Anthony J Mazzella, Anil Gehi
Journal: Circulation (2023)

Introduction: The annual cost of care for Atrial Fibrillation (AF) is estimated at $6.65 billion, with nearly 75% attributed to costs of hospitalizations. An AF treatment pathway with expedited follow-up to an AF-specialized clinic has been shown to reduce unnecessary admissions for AF and improve AF quality of care metrics. Goal: Evaluate differences in 30-day cost of care and discharge rate for adults presenting with AF to the emergency department (ED) before and after implementation of an AF treatment pathway. Methods: An AF treatment pathway with expedited follow-up to AF-specialized clinic was implemented at seven hospitals in North Carolina between 2017 to 2020. 30-day cost of care was calculated for patients presenting to ED with primary or secondary diagnosis of AF from 2016 to 2020 (N=12,543) by summing inflation-adjusted charges for initial hospital encounter, outpatient follow-up visits, and repeat hospital encounters for AF within 30 days. An adjusted quintile regression analysis and poisson regression, both with covariables of age, sex, race, CHA2DS2-VASc score and hospital site, were used to compare median 30 day cost of care and rates of ED discharge respectively. Results: Following implementation of the AF treatment pathway, the unadjusted median 30-day cost of care (Pre: $11,351, Post: $8,206), median initial hospital charge (Pre: $10,825, Post: $7,760), median repeat hospital encounter charge for those with repeat presentations within 30 days (Pre: $12,532, Post: $9,470) were all significantly lower (p&lt;0.001). The adjusted median 30-day cost of care was lower (-$1532; 95% CI: $ -2001, $ -1064) and the predicted probability of discharge was greater (Pre: 61.7%, 95% CI: 60.2%, 63,2%; Post: 71.6%, 95% CI: 70.7%, 72.6%) following implementation of AF treatment pathway. Conclusions: Implementation of an AF treatment pathway in the ED is associated with an increase in ED discharge rate and decrease in 30 day costs of care.
Abstract 13674: AIBP-Mediated Cholesterol Efflux Controls Lymphangiogenesis
Authors: Jun-dae KIM, Surbhi Chaudhary, Longhou Fang
Journal: Circulation (2023)

Background: Lymphangiogenesis give rise to lymphatic vessels that are essential for maintenance of tissue fluid homeostasis. Lymphatic vessel formation requires lymphatic endothelial cell (LEC) specification from the venous ECs and subsequent LEC proliferation and migration, all of which are regulated by the VEGFC/VEGFR3 signaling. Cholesterol is essential for cell functions and organ development yet the molecular mechanism by which it controls lymphangiogenesis is unknown. Hypothesis: In this study, we hypothesize the role of apoA-I binding protein (AIBP)-regulated cholesterol metabolism in lymphangiogenesis. Aim: We aim to dissect the role of AIBP mediated cholesterol efflux on caveolin-1 (CAV-1) disruption and its effect on VEGFC/VEGFR3 signaling and lymphangiogenesis. Methods: We utilized the mouse embryonic stem cell differentiation model to assess the role of AIBP-CAV-1-VEGFR3 axis in LEC fate determination. We used AIBP and CAV-1 knockout (KO) to assess the role of this signaling circuit in developmental lymphangiogenesis using zebrafish and in adult lymphangiogenesis using the mouse corneal lymphangiogenesis model. We used CAV-1 KO neonatal mice to study tail lymphangiogenesis. Results: We found that AIBP dictates lymphatic vessel formation by accelerating cholesterol efflux. Loss of Aibp2, the zebrafish paralog of human AIBP, impairs lymphangiogenesis. Recombinant AIBP protein induces mouse embryonic stem cell differentiation to LECs. Mechanistically, CAV-1 suppresses VEGFR3 activation, but cholesterol efflux by AIBP disrupts lipid rafts/caveolae and reduces CAV-1 bioavailability, which abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation in human LECs. Loss of CAV-1 increases LEC progenitor specification in zebrafish, and rescues lymphangiogenesis in Aibp2-deficient animals. CAV-1 KO neonatal mice significantly augmented tail lymphangiogenesis. Further, AIBP expression is reduced in the epidermis of human lymphedema. Conclusion: Our study elucidates a novel role of AIBP-mediated cholesterol efflux in lymphatic vessel formation and provides new therapeutic targets for the treatment of lymphatic dysfunctions.