tbuckley/cabot-search huggingface dataset:
Abstract 15171: Endothelium-Derived C-Type Natriuretic Peptide Prevents the Development and Progression of Abdominal Aortic Aneurysm
Authors: Aisah A Aubdool, Amie J Moyes, Cristina Perez-Ternero, Janice C Tsui, Hong S Lu, Alan Daugherty, Adrian J Hobbs
Journal: Circulation (2023)

Background: Abdominal aortic aneurysm (AAA) is a life-threatening disease characterised by dilatation, inflammation and structural weakness of the abdominal aorta. Since the only effective existing intervention is surgery, development of pharmacological therapies is desperately needed. C-type natriuretic peptide (CNP) is a key endothelium-derived molecule that possesses vasodilator, anti-inflammatory and anti-atherogenic activity. Thus, we explored the role and therapeutic potential of CNP in AAA pathogenesis. Methods: Suprarenal aortic diameter was assessed by ultrasonography at baseline and following Angiotensin II (AngII, 1.44mg/kg/day) infusion in wild type (WT) or endothelium-restricted CNP deficient (ecCNP -/- ) mice infected with an AAV-expressing proprotein convertase subtilisin/kexin type 9 gain-of-function mutation (D377Y) or backcrossed on an apolipoprotein E deficient (ApoE -/- ) background. At 28 days, aortas were harvested for qRT-PCR, pharmacological assessment of vasorelaxant activity and histological analysis; plasma CNP concentrations were also determined. In some studies, CNP (0.2mg/kg/day) was infused to rescue any adverse phenotype. Results: ecCNP -/- exhibited an aggravated AAA phenotype compared to WT, exemplified by greater dilation, fibrosis and elastin degradation (without changes in blood pressure). Whilst plasma CNP concentrations were reduced in murine AAA, CNP mRNA abundance was elevated within aneurysmal tissue of ecCNP -/- , accompanied by increased abundance of mRNA encoding markers of inflammation ( IL-6, Adgre1, VCAM-1, CCL-2 ), extracellular matrix remodelling/calcification ( MMP-2, Notch-1, BMPR2, smoothelin ), fibrosis ( fibronectin ) and apoptosis ( Bax ) . CNP-induced relaxations were enhanced in aortic rings from aneurysmal tissue compared to control; an effect possibly underpinned by upregulation of natriuretic peptide receptor expression. Prophylactic administration of CNP protected against the severity of AngII-induced AAA. Conclusions: Endothelial CNP plays an important role in attenuating AAA formation by preserving aortic structure and function. Therapeutic strategies aimed at mimicking CNP bioactivity may prevent the clinical progression of AAA.
Abstract 13409: Maintaining a High Total Serum Magnesium Level With Intravenous Magnesium Sulfate
Authors: JooEun Kwon, brian lucas
Journal: Circulation (2023)

Introduction: Understanding how intravenous magnesium sulfate (MgSO4) administration affects total serum magnesium concentration (TsMg) is important in maintaining a target TsMg level in acute heart failure patients on loop diuretics. Hypothesis: Describe how TsMg changes after single dose of MgSO4 and estimate how often MgSO4 should be given to maintain TsMg above 2 mg/dL. Methods: We studied hospitalizations of veterans from the Veterans Health Administration (VHA) aged ≥ 65 without severe renal disease (EGFR &gt; 15 cc/min per 1.73 m2) from 2013-2017 with a primary diagnosis of acute heart failure. We constructed linear and logistic mixed-effects models with values of TsMg at level 1, nested within dose, hospitalization, and patient. Results: There were 27,474 doses of intravenous MgSO4 administered in 16,139 hospitalizations to 13,439 unique veterans across 145 hospitals in the VHA. Veterans were elderly (mean age 76), 98% male, 72% non-Hispanic white. Mean TsMg was initially high and leveled off 24-48 hours after MgSO4 administration, with an average TsMg increase of 0.2 mg/dL regardless of dose administered (Figure) . The probability of maintaining a TsMg above 2.0 mg/dL just one day after MgSO4 ranged from 49-54% (Table) . Conclusions: TsMg is often targeted above 2.0 gm/dL, especially in the setting of arrhythmias or QT-prolonging medications. As MgSO4 is frequently administered in heart failure patients on diuretics, understanding that TsMg may be misleadingly elevated for the first 48 hours after MgSO4 is important. We recommend administering MgSO4 at least once per day if the goal TsMg level is ≥ 2.0 gm/dL.
Abstract 16584: Spleen Tyrosine Kinase Inhibition Interferes With Platelet NLRP3 Inflammasome Activation in Sickle Cell Mice Leading to Reduced Platelet Aggregation
Authors: Sebastian Vogel, Sayuri Kamimura, Meghann Smith, Luis Almeida, Jeffrey Strich, Zena Quezado
Journal: Circulation (2023)

Introduction: The NOD-like receptor protein 3 (NLRP3) inflammasome is a critical inflammatory mechanism that has recently been found to be upregulated in platelets in sickle cell disease (SCD). Fostamatinib is a prodrug of the Spleen Tyrosine Kinase (Syk) inhibitor R406 that targets platelets and is approved for the treatment of immune thrombocytopenia. The effect of Syk inhibition on platelet NLRP3 inflammasome activation in SCD is unexplored. Methods: We used a SCD mouse model, the Townes strain, which expresses human sickle hemoglobin. NLRP3 inflammasome activation was assessed in isolated platelets with fluorescent labeled inhibitor of caspase-1 (FLICA) assay and immunofluorescence staining of intraplatelet NLRP3 and the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) coupled with confocal laser scanning microscopy. Platelet aggregation and ATP secretion were studied with whole blood impedance aggregometry and luminescence. Isolated platelets or blood samples were treated with the Syk inhibitor R406 and/or the NLRP3 activator nigericin where indicated. Collagen was used as platelet agonist. Results: R406 markedly decreased platelet caspase-1 activation and NLRP3:ASC speck formation found in platelets from SCD mice (RFUs: 228 ± 25.3 vs. 450.2 ± 63, mean ± SD, R406 vs. vehicle, p&lt;0.001). R406 had no effect in platelets from control mice, where only low levels of caspase-1 activity and NLRP3:ASC specks were detected in platelets. Platelet aggregation and ATP secretion were elevated in SCD mice, which was abrogated by R406 (AUC: aggregation, 39 ± 2.6 vs. 65.8 ± 4.7, mean ± SD, R406 vs. vehicle, p&lt;0.001; ATP, 7.2 ± 1.5 vs. 13.9 ± 1.6, mean ± SD, R406 vs. vehicle, p&lt;0.001). Strikingly, the NLRP3 activator nigericin reversed the inhibitory effect of R406 on platelet aggregation (44 ± 11.5% increase, p&lt;0.001) and ATP secretion (48.9 ± 22% increase, p&lt;0.01) in SCD mice, suggesting a functionally active link in platelets between Syk and NLRP3. Conclusion: Syk inhibition with R406 impairs NLRP3 inflammasome activation in platelets from SCD mice and interferes with platelet aggregation and ATP secretion in an NLRP3-dependent manner. Targeting Syk and NLRP3 in platelets might be a useful therapeutic approach in SCD.
Abstract 12869: Cardiac Intensive Care Unit Teams and Loved Ones Communicating (CICU TaLC) Intervention is Acceptable and Improves Interprofessional Clinician Communication and Teamwork in Pediatric Pre-Family Meeting Huddles
Authors: Jennifer Walter, Arzu Cetin, William Quarshie, Heather Griffis, Aaron G DeWitt, Chris Feudtner
Journal: Circulation (2023)

Introduction: Interprofessional teams often develop a care plan in pre-family meeting huddles before engaging with the family in the pediatric cardiac intensive care unit (CICU)—a process that can affect the course of the family meeting and alter team dynamics but often lacks optimal communication and teamwork. Hypothesis: An interprofessional team intervention for pre-meeting huddles in the CICU is acceptable and positively impacts teamwork. Methods: We enrolled and trained CICU clinicians in interprofessional communication skills with a focus on role clarity, then conducted a quasi-experimental pre-posttest study with clinicians participating in actual pre-family meeting huddles. Clinician acceptability was measured via survey and impact on team communication and teamwork in pre-meeting huddles was assessed using PACT novice, a TeamSTEPPS validated tool, on audio recorded and transcribed huddles. The tool evaluates the domains Team Structure , Leadership , Situation Monitoring , Mutual Support , and Communication on a five-point scale (1 = poor; 3 = average; 5 = excellent). Wilcoxon rank sum test assessed intervention impact on communication and teamwork at the meeting level comparing pre and post-intervention data. Results: 24 Clinicians enrolled in the intervention (92% retention) with 100% completion of training. All trained clinicians recommend CICU TALC to others and 96% believe it improved their participation in family meetings. In 58 huddles (28 pre and 30 post), team performance in all 5 domains were significantly (p&lt; 0.001) higher in post-intervention huddles than in pre-intervention. Median (IQR) comparisons: Team structure [pre 2.00 (1.75, 2.00) vs. post 5.00 (5.00, 5.00)], Leadership [pre 3.00 (2.00, 3.00) vs. post 5.00 (5.00, 5.00)], Situation Monitoring [pre 3.00 (2.75, 3.00) vs. post 5.00 (4.00, 5.00)], Mutual Support [pre 3.00 (2.00, 3.25) vs. post 5.00 (5.00, 5.00)], and Communication [pre 3.00 (2.00, 4.00) vs. post 5.00 (5.00, 5.00)]. Conclusion: It is acceptable to implement an interprofessional team intervention to improve team communication and teamwork in interprofessional pre-family meeting huddles. Future research should assess broader impact of the intervention on clinicians, patients, and families.
Abstract 17273: Phenotypic Clustering of Patients With Heterotaxy Syndrome Predicts Outcomes of Mortality and Transplantation
Authors: Emily M Bucholz, Tehila Sompolinsky, Rebecca S Beroukhim, Daniel A Castellanos, Elizabeth S Dewitt, Tal Geva, Sunil J Ghelani, David Hoganson, Gerald R Marx, Amy E Roberts, Sarah A Teele, David N Schidlow
Journal: Circulation (2023)

Background: Current classifications of heterotaxy syndrome (HS) (e.g. left/right isomerism, polysplenia/asplenia) do not capture the heterogeneity of cardiac anomalies observed nor provide insight on risk stratification. We aimed to improve these classifications using cluster analysis to identify anatomic phenotypes in HS patients. Methods: Using a retrospective database of all HS patients seen at Boston Children’s Hospital from 1985-2014 (n=264), we performed principal component and cluster analyses on 47 cardiac anatomic variables and compared rates of mortality/transplantation across clusters. Results: Five clusters were identified ranging in size from 19 to 91 patients. Cluster #1 had a high prevalence of right-dominant complete atrioventricular canal defects (CAVC), double-outlet right ventricle (DORV), pulmonary stenosis/atresia (PS/PA), and total anomalous pulmonary venous connection (TAPVC); Cluster #2 of left-dominant CAVC, DORV, and TAPVC; Cluster #3 of left-sided obstructive lesions and interrupted IVC; Cluster #4 of transposition of the great arteries with PS/PA; and Cluster #5 of interrupted IVC with miscellaneous cardiac anomalies (Table). Over 80% of patients in clusters 1 and 2 underwent single ventricle palliation compared with only 16% of patients in cluster 5. Transplant-free survival was lowest in clusters 1, 2, and 3 but differed by single versus biventricular repair (Figure). Conclusions: Cluster analysis of cardiac anatomic variables identified 5 phenotypes of HS including 3 higher risk and 2 lower risk phenotypes. These findings highlight the need for improved phenotyping of HS to account for the high degree of disease heterogeneity.
Abstract 15680: Serum High-Sensitivity C-reactive Protein Levels Throughout Early Adulthood and Subclinical Atherosclerosis in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Ashvita Ramesh, Hongyan Ning, Norrina B Allen, Mary J Harty, Donald M Lloyd-Jones
Journal: Circulation (2023)

Introduction: Single measures of high sensitivity C-reactive protein (hs-CRP) have been associated with atherosclerosis. However, trajectories of hs-CRP through young adulthood and their associations with mid-life coronary artery calcification (CAC) are poorly characterized. Methods: We examined longitudinal data from 4681 participants in the CARDIA study, including men and women aged 18-30 years at baseline followed for 25 years. We included participants with &gt;3 hs-CRP measurements and a CAC score measured at year 25. We also examined cardiovascular (CV) risk factor trajectories through young adulthood in parallel with hs-CRP. Multivariable logistic regression models were used to assess association between hs-CRP trajectories and CAC &gt;0 status at year 25. Results: We identified 5 discrete trajectories in hs-CRP from young adulthood to middle age according to measured hs-CRP levels and time course: low-stable (56%, n=1364), low-early rise (18%, n=432), low-late rise (7%, n=155), elevated-stable (6%, n=136), and elevated-decline (13%, n=308) (Figure 1). Compared with the low-stable group, trajectories with early, but not later elevations of hs-CRP levels had significantly higher odds of CAC score &gt; 0 at year 25. Odds ratios (OR; adjusted for age, sex, race and education) were 1.71 (95% CI, 1.11-2.64) for the elevated-stable group and 1.98 (1.49-2.65) for elevated-decline group. After adjustment for all CV risk factors, only the elevated-decline group retained significance (OR 1.46, 1.06-2.02). Trajectories of CV risk factors, especially BMI, through young adulthood were highly correlated with hs-CRP trajectories, and attenuated associations of hs-CRP with CAC. Conclusions: Trajectories with early elevations in hs-CRP in young adulthood are associated with mid-life CAC. CV risk factor trajectories correlate with hs-CRP over time, suggesting that hs-CRP trajectory may integrate data from other risk factors and provide information about CAC risk.
Abstract 14569: Chemotherapy in Pregnancy: Assessing the Safety of Adriamycin Administration in Pregnancy Complicated by Breast Cancer
Authors: Priyanshu Nain, Lakshya Seth, Ashley Bell, Priyanka Raval, Gyanendra Sharma, Garima Sharma, Monique Bethel, Avirup Guha
Journal: Circulation (2023)

Introduction: Treatment of Pregnancy Associated Breast Cancer (PABC) with radiation and endocrine therapy is challenging due to potential risks to the fetus. Surgical treatment is safe throughout pregnancy, and chemotherapy agents such as anthracyclines are safe during 2 nd and 3 rd trimesters. Case Presentation: A 39-year-old G4P3 female presented at 8 weeks gestation with a twin pregnancy and a right breast mass with bloody nipple discharge. Past medical history was significant for obesity and chronic hypertension. Biopsy of the mass confirmed weakly ER+/PR-/HER2-, node+, stage IIb PABC. After radical mastectomy and axillary lymph node dissection, 4 Adriamycin and Cyclophosphamide (AC) based adjuvant chemotherapy cycles q3 weeks were started at 12 weeks of gestation with a maternal and fetal echocardiogram, brain natriuretic peptide and troponin measurements after each cycle. A baseline echocardiogram revealed cardiomyopathy with an LVEF of 45% and a severely dilated left ventricle. She was New York Heart Association class II at baseline. Carvedilol 6.25 mg BID was started prior to beginning AC and titrated to 12.5 mg BID due to palpitations after 1 st AC cycle. She tolerated 4 AC cycles with no change in EF from baseline, no symptoms of heart failure, and a normal fetal echocardiogram. Weekly Paclitaxel was resumed to complete 12 cycles prior to radiation treatment. She delivered healthy male and female infants at 32 weeks with no complications (M: APGAR 5 and 7; F: APGAR 8 and 7). Postpartum EF decreased to 40%, necessitating titration of carvedilol to 25mg BID and the addition of Sacubitril/Valsartan 24/26 mg BID. Chest pain complaint after delivery prompted evaluation with computed tomography-based angiogram and cardiac magnetic resonance imaging (CMR), ruling out coronary artery disease. Despite this, no evidence of microvascular disease on CMR symptomatic relief was reported on long-acting nitrates. Discussion: This case demonstrates the importance of multidisciplinary patient management, particularly for those with low LVEF who are at higher risk of decompensation. Despite not knowing the etiology of PABC, she could be suffering from thrombotic microangiopathy of small coronary vessels, which explains relief from nitrates.
Abstract 16662: Factors Associated With Repeated Emergency Department Visits Among Symptomatic Patients With Heart Failure
Authors: Solim Lee, Soonbo Han
Journal: Circulation (2023)

Heart failure (HF) is a prevalent cause of emergency department (ED) visits among adults. However, there is limited understanding of the characteristics of patients with HF who frequently utilize the ED for symptom management. Aim: To describe factors associated with ED revisits among symptomatic patients with chronic HF. Methods: We identified 1,472,083 adults (age ≥ 18 years) with HF who had no history of left ventricular assist device or heart transplantation between January 2010 and March 2020 from the TriNetX Research Network, which included 47 US healthcare organizations. In this retrospective observational study, 24,070 patients presenting with dyspnea and receiving intravenous (IV) Furosemide at the ED were followed up for 1 year from the index ED visit. ED revisits related to the treatment of dyspnea with IV diuretics were tracked. Factors associated with these ED revisits were identified using multivariate Cox regression analysis. Results: A total of 3,574 ED revisits were observed from 2,559 patients (10.6% of the sample, mean age 63 years, 51% men, 39% White, 62% Non-Hispanic). The ED revisit rates were 52, 96, 125, and 148 visits per 1,000 persons within 1, 3, 6, and 12 months, respectively. The median time to the first ED revisit for symptom management with IV diuretics was 65 days (range 2-364 days). In the Cox model, younger patients (&lt; 65 years) had a higher risk of ED revisits compared to older patients (HR 1.65, 95% CI 1.50-1.82, p&lt;0.001). Men had a higher risk of ED revisits compared to women (HR 1.12, 95% CI 1.02-1.23, p=0.02). Black patients had a higher risk of ED revisits compared to other races (HR 1.36, 95% CI 1.20-1.53, p&lt;0.001). Patients with HFrEF (e.g., ICD-10 I50.2) had a higher risk of ED revisits compared to those with congestive HF (e.g., ICD-10 I50 without HF type information) (HR 1.25, 95% CI 1.12-1.40, p &lt; 0.001). Patients diagnosed with HF more than 1 year prior to the index ED visit had a higher risk of ED revisits compared to those diagnosed within 1 year (HR 1.31, 95% CI 1.19-1.44, p &lt; 0.001). Conclusions: Younger age, male gender, Black race, HFrEF classification, and longer duration of HF were associated with ED revisits among symptomatic adults with HF. To reduce repeated ED visits, targeted interventions for high-risk patients are essential.
Abstract 17501: Initial Experience With a Novel Transcatheter Aortic Valve With Open-Cell Design and Staged Delivery for Challenging Anatomies in a Developing Country
Authors: Marcos Antônio Marino, Roberto Luiz Marino, Bárbara C Marino, Walter Rabelo, Hugo A Mariano de Azevedo Frota, Evandro Vitor Andrade, Alexandre V Vasconcellos, Luis Eduardo D Couto, Jessica De Paula, Rodrigo C Bernardes, Fernando Antônio R Reis Filho, Alexandre Henrique Cobucci Santana, Bruno R Nascimento
Journal: Circulation (2023)

Introduction: Overcoming challenges of transcatheter aortic valve (TAVI) implantation, as coronary access, conduction disturbances and paravalvular leak are goals of device development. We aimed to describe the initial experience with a recently-approved self-expandable bioprosthetic valve, with supravalvular leaflets, a novel open-cell design and 2-stage deployment, in terms of efficacy and safety. Methods: Consecutive patients with aortic valve (AV) stenosis and indication for TAVI with favorable anatomy for self-expandable prostheses were prospectively enrolled in a high-volume center in Belo Horizonte, Brazil. Demographic, clinical and procedural data were collected in an online dedicated database (Coreware, RIBAC). Echocardiographic and CT-angio measurements were performed by 2 experts with proprietary software (Phillips Heart Navigator). Outcomes were prospectively collected. Results: At total, 23 patients eligible for the Acurate Neo/Neo2 TAVI were enrolled, being 15 men, mean age of 82±6 years (69 - 93). Hypertension was present in 20, diabetes in 8 and dyslipidemia in 17, and all were severely symptomatic, being 20 in functional class 3. The STS-score (morbi-mortality) was high: 19±6%. The mean AV area on echo was 0.7±0.2 cm 2 , with mean gradient of 44±15 mmHg. In CT-angio, the median calcium score was 2284, mean annular perimeter was 72±5 mm, and the height of the right and left coronary ostia were 15.2±2.6 mm and 11.9±3.2 mm (&lt;10 mm in 5 cases). All implants were transfemoral (14F) and with general anesthesia, given the high-risk profile. Pre-dilation was performed in 20 (91%) and the TAVI was deployed without repositioning in all cases, with no coronary compromise. Post-dilation was required in 13 cases, being 11 due to mild and 2 due to moderate paravalvular leak: all regressed to trivial. Vascular complications requiring surgery occurred in 1 case, and 1 (4%) patient underwent permanent pacing. All patients were discharged home, with a mean AV gradient of 9.7±3.7 mmHg. Conclusion: The initial experience in Brazil with the novel Acurate Neo/Neo2 prosthesis was promising, with high success rates in challenging anatomical scenarios, and low rates of pacemaker implantation and no occurrence of coronary obstruction or significant leak.
Abstract 15041: Single-Cell RNA Sequencing Reveals Four Distinctive Endothelial Subpopulations Through Mouse Endothelial Aging
Authors: Jung-Kyu Han, Min-Hwan Sohn, Seema Dangwal, Jeong-Sun Seo, Ronglih Liao
Journal: Circulation (2023)

Introduction: Endothelial cell (EC) dysfunction is a hallmark of vascular aging, contributing to age-related vascular diseases. Elucidating EC aging at the single cell level has significant scientific and therapeutic potential. Research Question: What is the landscape of EC aging at the single cell level? Methods: Mouse aortas were harvested from 1-, 10-, and 20 month-old mice (n=2 males and 2 females at each time point). Pooled single-cell suspensions were prepared, and PECAM1+ cells were enriched by magnetic-activated cell sorting. Results: Single cell RNA sequencing revealed 879 ECs, categorized into six subpopulations (EC 1-6). Of the three canonical EC markers ( Pecam1 , Cdh5, and Kdr ) EC1 and 2 showed higher expression of Pecam1 , whereas EC3 and 4 showed higher expression of Cdh5 and Kdr . ECs from young (1 month-old), middle-aged (10 month-old), and elderly mice (20 month-old) were enriched in EC1, EC3, and EC4, respectively. Gene regulatory network analysis identified specific regulons for each EC subcluster. EC1 displayed progenitor-like features ( Isl1 as one of the top regulons, Procr and Cd34 as highly expressed genes) with high angiogenic potential ( Twist1 as one of the top regulons, Timp2 , Mmp14 , and Mmp2 as highly expressed genes) and the longest G1 phase suggesting its quiescence. EC3 cells exhibited high proliferative status demonstrated by G2M or S phase, accompanied by upregulation of stress-responsive TF Atf3 and NF-κB family members. EC4 demonstrated pronounced Pparg regulon activity. Genes directly regulated by Pparg ( Scarb1 and Cd36 ), and genes involved in fatty acid metabolism and atherogenesis ( Tcf15 , Fabp4 , Gpihbp1 , Lpl , and Meox2) were highly expressed in EC4 and EC3. Conclusions: Our analysis identified four distinct EC subpopulations through the aging process of mouse aortic ECs: EC1, Pecam1 h progenitor-like EC; EC2, Pecam1 h common EC; EC3, Cdh5 h Kdr h inflammatory atherogenic EC; and EC4, Cdh5 h Kdr h non-inflammatory atherogenic EC.