tbuckley/cabot-search huggingface dataset:
Abstract 18938: Identification and Diagnosis of Culprit Lesions by Optical Coherence Tomography (OCT) in Patients With Non-ST Elevated Acute Coronary Syndromes
Authors: Alina Zainab, Shifa Younus, Laraib Jumani, Azouba Gulraiz, FNU Neelam, Saad Mehmood, Samina Raza
Journal: Circulation (2023)

Introduction and Hypothesis: Optical coherence tomography (OCT) is a reliable imaging modality for plaque characterization in patients with acute coronary syndromes (ACS). While numerous studies have provided insight into the utility of OCT in ST-elevated ACS patients, our study sought to evaluate the frequency and morphological characters of lesions in patients with non-ST elevated acute coronary syndromes (Unstable angina (UA) and Non-ST elevated myocardial infarction (NSTEMI)). Methods: This multi-center, observational study included 170 patients admitted with a working diagnosis of NST-elevated ACS from October 2021 to January 2023. OCT imaging was obtained during coronary angioplasty for lesion characterization and morphology. Frequencies were compared between UA and NSTEMI sub-groups. Results: OCT imaging in patients with non-ST elevated acute coronary syndromes showed plaque erosion in 46% (n= 78), plaque rupture in 35% (n= 60), tight stenosis in 13% (n= 22), and calcified nodules in 6% (n= 10). Sub-group comparative analysis showed a statistically significant increase in plaque erosion in NSTEMI compared to UA (p&lt;0.005), while tight stenosis was significantly more common in UA (p=0.017). Morphological analysis showed a high presence of calcified nodules and red thrombus in NSTEMI patients compared to UA patients (p&lt;0.005). Conclusions: Our study concluded that optical coherence tomography is reliable in identifying and characterizing lesions in patients with non-ST elevated ACS. NSTEMI patients have a higher occurrence of plaque erosion, plaque rupture, calcified nodules, and red thrombus than patients with unstable angina.
Abstract 17218: CES1 Deficiency is Associated With Metabolic Reprograming and Endothelial Dysfunction in Pulmonary Arterial Hypertension
Authors: Stuti Agarwal, Lyong Heo, Ananya Chakraborty, Natasha Auer, Gowri Swaminathan, Lichao Liu, James West, Karthik Suresh, Ramesh Nair, Marlene Rabinovitch, Mark Nicolls, Christophe Morisseau, Bruce D Hammock, Robert Lafyatis, Steven M Kawut, Roham Zamanian, Vinicio A Dejesus
Journal: Circulation (2023)

Introduction: PAH is associated with loss of pulmonary microvessels &amp; vascular remodeling. Metabolic reprogramming(MR) characterized by high glycolysis &amp; reduced FAO is hallmark feature of PAH linked to oxidative stress, endothelial cell(EC) dysfunction &amp; reduced angiogenesis. BMPR2 gene mutations promote MR; however, due to low penetrance, alterations in other genes are likely necessary for PAH development. We found Carboxylesterase 1 (CES1) is an ER enzyme involved in lipid metabolism &amp; cellular detoxification with a potentially important role in MR &amp; EC dysfunction in PAH. Hypothesis: Loss of CES1 leads to EC dysfunction through MR, lipotoxicity &amp; oxidative stress &amp; serves as a genetic modifier of BMPR2 in ECs Methods: Healthy/PAH ECs &amp; lung tissues were obtained from transplants and commercial sources. Healthy ECs were transfected with siRNA/plasmid to knockdown/overexpress CES1. Mitochondrial &amp; ER structure &amp; function was assessed by confocal microscopy &amp; proteomic assays. Metabolic flux in ECs was analyzed using the SeahorseXF. CES1 HET KO mice exposed to normoxia and hypoxia were studied &amp; lungs were processed for scRNA-seq. Results: CES1 mRNA/protein expression was reduced in PAH ECs &amp; lung vascular lesions. Compared to controls, siCES1 ECs have high apoptosis,reduced angiogenesis,increased ROS,mitochondrial fragmentation &amp; ER stress. Lipid staining of siCES1 PMVECs demonstrates cytoplasmic lipid droplet accumulation correlating with reduced FAO and switch to glycolysis. Restoring CES1 expression reverses MR, reduces ROS &amp; improves functional status of siCES1/PAH ECs. CES1 is a downstream target of BMPR2 under NRF2 transcriptional regulation &amp; its loss exacerbates MR &amp; dysfunction associated with BMPR2 loss that improves via CES1 restoration. Hemodynamic &amp; scRNA-seq studies show that hypoxic CES1 HETKO mice develop more severe PH &amp; demonstrate dysregulation of genes in key metabolic &amp; angiogenic pathways. Conclusions: CES1 is essential for maintenance &amp; repair of the pulmonary endothelium &amp; acts as a key modifier of BMPR2 signaling. Limitations of current therapies to reverse EC dysfunction and prevent small vessel loss warrant therapeutic interventions that can restore CES1 expression and serve as a novel treatment approach for PAH.
Abstract 12891: Outcomes After Heart Failure Hospitalization Among Patients With Myeloproliferative Neoplasms
Authors: Orly Leiva, Jose Alvarez-Cardona, Andrew Brunner, Joan How, Gabriela Hobbs
Journal: Circulation (2023)

Introduction: Myeloproliferative neoplasms (MPNs) are chronic leukemias associated with increased risk of cardiovascular (CV) events. MPNs most commonly harbor mutations in the JAK2 gene, which has been associated with adverse cardiac remodeling in mouse models of cardiomyopathy and heart failure (HF). Prior studies suggest patients with MPN are at increased risk of HF. However, in-hospital and readmission outcomes of patients with MPN admitted for HF have not been well characterized. Methods: Adult patients admitted with HF from January 2017 to December 2018 MPN were identified using the National Readmission Database. Propensity score matching (PSM) was performed to match 1 MPN for 10 non-MPN controls. Primary outcomes were in-hospital death and 90-day CV-related, HF-related and all-cause readmissions Results: Patient characteristics after PSM are described in Table 1. Patient characteristics were well-balanced between MPN and non-MPN groups after PSM. MPN patients had similar rates of in-hospital mortality but higher rates of bleeding during index hospitalization. MPN patients had increased risk of in-hospital death (OR 1.17, 95% CI 1.00 - 1.35) and 90-day CV-related (HR 1.10, 95% CI 1.02 - 1.18) and all-cause readmissions (HR 1.24, 95% CI 1.17 - 1.31) but not HF-related (HR 1.05, 95% CI 0.97 - 1.14). Conclusions: Among patients hospitalized for HF, MPN was associated with increased risk of in-hospital death, and 90-day CV-related readmissions. Further investigation is needed in order to improve outcomes in patients with MPN and HF.
Abstract 13087: TRPM7 Kinase Regulates Inflammation in Hypomagnesemia-Induced Cardiac Diastolic Dysfunction
Authors: Man Liu, Hong Liu, Gyeoung-Jin Kang, Yugene Guo, Salman Ali, Samuel C Dudley
Journal: Circulation (2023)

Introduction: Hypomagnesemia (HypoMg) is commonly observed in heart failure and associated with inflammation. We have reported that inflammation contributes to mitochondrial oxidative stress and causes cardiac diastolic dysfunction (DD) in diabetic mice and that Mg supplementation shows therapeutic benefits. Meanwhile, diet-induced HypoMg alone can lead to DD. Transient receptor potential melastatin 7 (TRPM7), a Mg transporter with a kinase domain, regulates Mg homeostasis in different types of cells. Object: We aim to assess the role of TRPM7 in HypoMg-associated inflammation and DD. Methods: Wild type (WT) C57BL/6J and transgenic kinase dead TRPM7 K1646R mice (with a global homozygous K1646R mutation in the kinase domain) were fed with a normal (2 g/kg Mg) or a HypoMg diet (15-30 mg/kg Mg) for 6 weeks. Echocardiography was performed to monitor E/e’ (an DD indicator when increased). Hearts were collected for protein levels of TRPM7, inflammatory markers IL-1β and NLRP3, and total protein oxidation. Isolated cardiac macrophages (Mϕs) were used for phenotyping by flow cytometry. Raw264.7 cells (a Mϕ cell line) and RL-14 cells (a cardiomyocyte cell line) were treated with a normal (0.81 mM Mg) or a HypoMg medium (0.04 mM Mg) for 48 h. TRPM7 protein and IL-1β collected from the culture media or from cell lysates were tested. Results: In the WT-HypoMg mouse group, E/e’, protein levels of TRPM7, IL-1β and NLRP3, and total protein oxidation were all significantly elevated, which were not observed in the TRPM7 K1646R -HypoMg group. Cardiac Mϕs phenotype showed increased recruited pro-inflammatory Mϕs and decreased resident pro-resolving Mϕs, while the former was prevented by TRPM7 K1646R . TRPM7 protein levels in Raw264.7 and RL-14 cells were also significantly increased by HypoMg treatment, as well as Mϕ-secreted IL-1β (2.7±0.6 pg/mL vs. undetectable in control, P=0.012) and IL-1β in RL-14 cell lysates (2.6±0.2-fold of control, P=0.006). Conclusions: TRPM7 kinase function is upregulated under HypoMg in both Mϕs and cardiomyocytes. It contributes to inflammatory Mϕ activation, elevated IL-1β production, increased oxidative stress, and cardiac DD, suggesting inflammation as a potential mediator of HypoMg-induced DD.
Abstract 15375: Status of Cardiovascular Health and Early Carotid Artery Changes in Contemporary Young Adults From Disadvantaged Social Backgrounds: The Future of Families and Child Wellbeing Study (FFCWS)
Authors: Donald M Lloyd-Jones, Norrina B Allen, Noreen Goldman, James H Stein, Amanda M Marma, Russell Tracy, Hongyan Ning, Lifang Hou, Yinan Zheng, Brian Joyce, Linda Van Horn, Daniel Notterman
Journal: Circulation (2023)

Background: Effects of childhood social determinants of health (SDOH) on young adult cardiovascular health (CVH) are postulated, but few studies have measured both SDOH from birth and CVH status in young adulthood. Methods: In 1998-2000, FFCWS enrolled 4898 mother-baby dyads at delivery in 20 US cities, oversampling mothers who were unmarried, including a disproportionate number of minority and low-income families. In 2021-23, offspring were invited to an in-person exam for CVH measurement and carotid artery ultrasound. Individual CVH metrics (except sleep) and overall Life’s Essential 8 (LE8) scores (range, 0-100; higher = better CVH), as well as carotid intima-media thickness (IMT), were compared between self-identified sex and race/ethnicity groups. LE8 scores were also compared with a representative sample of US young adults aged 19-25 years from NHANES. Results: Among 1211 offspring participants (ppts), mean age was 22y, 55% were female, 50.8% Black, 25.1% Hispanic, 20.5% White, and 3.6% Other; characteristics at birth and through childhood were similar between FFCWS ppts who were/were not examined. Diet, physical activity, nicotine exposure, and BMI scores were unfavorable in FFCWS ppts (Table). Overall LE8 scores did not differ significantly by sex, and ranged from 64.6 in Black ppts to 74.8 in ppts from Other racial/ethnic groups. LE8 scores did not differ between Black and Hispanic ppts, but both groups had significantly lower scores than ppts from White and Other groups (all P≤0.01). After adjustment for age, sex, and LE8 score, Black ppts had significantly greater mean-maximum and mean-mean carotid IMT. Mean LE8 scores were lower among FFCWS ppts compared with young adults from the same racial/ethnic groups in NHANES. Conclusions: In this novel cohort of young adults largely from disadvantaged social backgrounds, overall CVH status was sub-optimal, and ppts who identified as Black had the lowest CVH and highest carotid IMT measures, even at this young age.
Abstract 18863: Clinical Assessment of Volume Status in Heart Failure is Inaccurate at Detecting Hypervolemia and Anemia as Quantified by Blood Volume Measurement
Authors: Jacob Joseph, Wendy Nguyen, KAREN MURRAY, Noa Kohl, Bradley Bart, Jonathan Feldschuh
Journal: Circulation (2023)

Introduction: Blood volume status is a crucial input for care decisions, especially the use of diuretics for decongestion, in acute decompensated heart failure (ADHF). In the absence of direct measurements, total blood volume (TBV) status is typically measured via clinical assessment of external fluid overload (edema, jugular venous distension, etc.), and red blood cell volume (RBCV) is assessed via hematocrit. A recent retrospective analysis showed that direct blood volume assessment (BVA) leads to better outcomes in ADHF. Hypothesis: We hypothesize that BVA-guided ADHF care can be protocolized and integrated into clinical workflow of ADHF management. Methods: The objective of this study is to prospectively compare the efficacy of standard care treatment decisions to those in a BVA-guided fluid management protocol. ADHF patients admitted to a Veterans Affairs Medical Center were randomized to either a control (n=8) or BVA-guided (n=8) arm. TBV, plasma volume (PV) and RBCV were measured at admission and prior to discharge by BVA utilizing an I-131 labeled albumin indicator-dilution technique (Daxor BVA-100). Clinician assessments of volume status were collected for all patients prior to BVA measurement. TBV status was defined relative to patient norms as: Hypovolemic (&lt; -10%), Euvolemic (-10% to +10%), Hypervolemic (&gt; +10%). RBCV status was defined as Anemic (&lt; -10%) Not Anemic (&gt; -10%). Results: Measured volume status at admission was quite heterogeneous, with 62.5% Anemic, and with 37.5% Hypovolemic, 31.25% Euvolemic, and 31.25% Hypervolemic. Clinical assessment at admission was notably inaccurate, with only 56% accuracy (sensitivity 40%, specificity 83%) on the presence of anemia, and only 31% accuracy on the presence of hypervolemia, with 94% of patients assessed by clinicians as hypervolemic. Non-hypervolemic patients in the BVA-Guided group received less diuretic treatment than non-hypervolemic controls. Conclusions: We successfully embedded a BVA guided treatment protocol into the clinical workflow of ADHF management at a large medical center. Clinical assessment of volume status was less accurate that direct BVA. Future studies will address whether BVA guided treatment leads to better outcomes in ADHF.
Abstract 14573: Dissecting Genetic Determinants Underlying Cardioskeletal Phenotypes Induced by Myopalladin Mutation in Murine Genetic Reference Population of Hybrid BXD Strains
Authors: Buyan-Ochir Orgil, Fuyi Xu, Neely Alberson, Nathan Stecchi, Hugo Martinez, Jason N Johnson, Lu Lu, Jeffrey A Towbin, Enkhsaikhan Purevjav
Journal: Circulation (2023)

Introduction: Mutations in myopalladin ( MYPN) gene are associated with cardiomyopathies (CM) and skeletal myopathies (SM). This study is aimed to identify Mypn -induced cardioskeletal phenotypes in a murine genetic reference population (GRP) and uncover common genetic mechanisms underlying the development of CM and SM. Hypothesis: Mypn induces common molecular signaling in cardiac and skeletal muscles. Methods: Pearson correlation between cardiac function and expression of Mypn in gastrocnemius muscles was performed in 40 mouse BXD recombinant inbred strains derived from C57BL/6J and DBA/2J parental mice. A causal Mypn-Q526X mutation was introduced to BXDs by crossing with MypnWT/Q526X knock-in mice and this generated F1 hybrid mutant (BXDQ526X) and wild type (BXDWT) strains. Cardiac (morphology, function by echo) and skeletal muscle (muscle mass, strength) phenotypes and transcriptomics (RNA-seq) were assessed in 3- and 6-month-old hybrid mice (N=5). Results: Skeletal muscle expression of Mypn was significantly associated with heart rate (HR) and heart mass (HM) in BXDs, while it was negatively associated with interventricular septum (IVS) thickness, indicating BXD strains with higher skeletal muscle Mypn expression had faster HR, higher HM but thinner IVS. Varied phenotypes in ejection fraction (EF%), ventricular volume and hypertrophy were found among BXD Q526X mice; BXD51 Q526X , BXD48 Q526X and BXD69 Q526X strains had significantly higher EF%, while some mutant mice showed EF% decrease compared to their respective BXD WT littermates. Many mutant lines displayed significantly reduced skeletal muscle strength or mass. Overt SM-related signs (rear limb deformity, restricted movement, waddling) were seen in BXD78 Q526X , while we found overlapping CM/SM traits in BXD51 Q526X mice. Conclusions: In this study, common Mypn -induced molecular signaling in cardiac and skeletal muscles is identified. Introduction of the Mypn -Q526X mutation into the diverse genetic background of BXD GRP exposed CM- and SM-related phenotypes in hybrid lines. The most susceptible lines with overt and overlapping CM/SM phenotypes will be useful to identify common genes, networks and pathways involved in CM and SM using systems genetics methods.
Abstract 14068: The Lipid Droplet-Associated lncRNA <i>LIPTER</i> Preserves Cardiac Lipid Metabolism of Human Cardiomyocytes
Authors: Lei Han, Dayang Huang, Shiyong Wu, Sheng Liu, Cheng Wang, Jun Wan, Lei Yang
Journal: Circulation (2023)

Background: Lipid droplets (LDs) are cellular organelles critical for maintaining lipid homeostasis. LD accumulation is associated with cardiomyopathies and heart failure in hyperlipidemia-related metabolic disorders. Currently, the cardiomyocyte (CM) intrinsic mechanism governing LD transport remains poorly understood. Hypothesis: We hypothesize that long non-coding RNA (lncRNA) can directly participate in LD transport in human CMs. Goals: To reveal a lncRNA LIPTER -mediated lipid droplet transport system in human CMs and define its role in preserving cardiac lipid metabolism. Methods: LIPTER and MYH10 were knocked out in human iPS cells using CRISPR/Cas-9. Myh10 was conditionally knocked out in mouse CMs. A LIPTER transgenic mouse line was established to test the effects of LIPTER transgene on high fat diet-induced cardiac dysfunction. LIPTER was delivered into CMs of Lepr db/db mice using AAV-9. Results: We identified a human lncRNA, Lipid-Droplet Transporter (LIPTER), essential for LD transport in human CMs. LIPTER binds phosphatidic acid and phosphatidylinositol 4-phosphate on LD surface membranes and the MYH10 protein, connecting LDs to the MYH10-ACTIN cytoskeleton and facilitating LD transport. LIPTER and MYH10 deficiencies impair LD trafficking, mitochondrial function, and survival of human iPS cell-derived CMs. Conditional Myh10 deletion in mouse CMs leads to LD accumulation, reduced fatty acid oxidation, and compromised cardiac function. We identify NKX2.5 as the primary regulator of CM-specific LIPTER transcription. Notably, LIPTER transgenic expression mitigates cardiac lipotoxicity, preserves cardiac function, and alleviates cardiomyopathies in high fat diet-fed and Lepr db/db mice. Conclusions: We unveil a molecular connector role of LIPTER in intramyocyte LD transport, crucial for lipid metabolism of the human heart, and hold significant clinical implications for treating metabolic syndrome-associated heart diseases.
Abstract 16030: Efficacy and Safety of Catheter Directed Thrombolysis in Intermediate to High-Risk Pulmonary Embolism: A Meta-Analysis of Randomized Trials
Authors: Muhammad Aslam khan, Hammad Rahman, Syed Zamrak Khan, Bilal Khan
Journal: Circulation (2023)

Background: Systemic anticoagulation (SA) is the standard treatment for acute pulmonary embolism (PE). The role of catheter directed thrombolysis (CDT) in addition to SA in intermediate-high risk PE remains unclear. Methods: Three randomized controlled trials comparing CDT+SA versus SA alone in intermediate-high risk PE were included in the analysis using databases including Embase, PubMed and Cochrane databases (inception June 01, 2023). The primary outcome was 90-day all-cause mortality. The secondary outcomes were major bleeding, number of patients with RV/LV ratio &gt;0.9 at 3 months, and vascular access complication. The outcomes were reported as relative risk (RR) with a 95% confidence interval (CI) using random effects model. Results: The analysis comprised of 179 patients with 88 in the CDT group and 79 in the SA group. There was no significant difference in 90-day all-cause mortality (RR: 0.19, 95% CI, 0.02-1.64, p=0.30) among both the groups. Similarly there was no significant difference in major bleeding (RR: 1.20, 95% CI, 0.03-46.18 p= 0.92), RV/LV ratio &gt;0.9 at 3 months (RR: 0.70, 95% CI, 0.41-1.21p=0.2) and vascular access complications (RR: 2.51, 95% CI, 0.44-14.35 p= 0.30). Conclusions: Our study found no significant advantage of CDT+SA versus SA alone in patients with intermediate-high risk PE. Given the scarcity of randomized data, we emphasize the need for a large-scale randomized trial to investigate the long-term effects of CDT in this population.
Abstract 16450: Increased Monocyte Count and Neutrophil-to-Lymphocyte Ratio With ICI Myocarditis
Authors: Antonia Chan, Yuhsin Huang, Maja Ivanovic, Maja Ivanovic, Sarah Waliany, Ryan Batchelder, Joel Neal, Heather Wakelee, Alice Fan, Sunil Reddy, Tamiko Katsumoto, Paul Cheng, Sean M Wu, Ronald M Witteles, Han Zhu
Journal: Circulation (2023)

Introduction: Diagnosing immune checkpoint inhibitor (ICI) myocarditis remains complex in practice, often requiring advanced imaging or invasive endomyocardial biopsy. We constructed an institutional cohort of patients who received at least 1 dose of ICI and developed probable or definite ICI myocarditis. Hypothesis: We hypothesized that routine serum biomarkers, including troponin I, neutrophil-to-lymphocyte ratio (NLR), monocytes, and AST/ALT, would be elevated and peak at diagnosis. Methods: This retrospective cohort study used EHR data from patients on ICI at a single academic institution who developed probable or definite myocarditis from 7/2015 - 1/2023. Inclusion criteria and diagnosis date were defined using Bonaca criteria and/or documented clinical consensus, e.g. initiation of steroids for presumed myocarditis. Primary outcomes were levels of troponin I/high sensitivity troponin I, monocytes, NLR, and AST/ALT. LOESS regression with default smoothing parameter α = 0.75 was used to evaluate biomarker patterns 7 days pre- and post- diagnosis. Results: We included 16 cases of myocarditis. At diagnosis, most patients had at least 1 significant elevation in troponin I (100%), AST (81%), ALT (63%), or monocytes (69%) while on ICI (Figure 1). After diagnosis, absolute monocyte and lymphocyte count initially decreased before rebounding. Serum NLR rose prior to and briefly after diagnosis (Figure 2). Conclusions: Peripheral cardiac and non-cardiac biomarkers change with ICI myocarditis. Further research on routine non-cardiac biomarkers associated with myocarditis and other ICI toxicities may help prevent high-grade adverse events.