tbuckley/cabot-search huggingface dataset:
Abstract 16065: AICD Lead Endocarditis With Large Vegetation Complicated by Septic Pulmonary Embolism
Authors: Noreen Mirza, Mohammad Nabil Rayad, Mariam Mirza, Iyad Farouji, Joaquim Correia
Journal: Circulation (2023)

Introduction: Infective endocarditis of an automatic implantable cardioverter-defibrillator (AICD) lead is a rare and serious complication. Less than 4% of AICD related endocarditis cases are caused by Enterococcus faecalis . Herein, we report a rare case of a patient with an infected AICD lead and a large vegetation caused by Enterococcus faecalis . Case Presentation: A 66-year-old male with a history of mitral valve replacement, heart failure with reduced ejection fraction status post AICD and hypertension presented with loss of appetite, subjective fevers and chills. Initial vitas were significant for tachycardia and tachypnea. Physical examination revealed lethargy and an irregular rate and rhythm. Initial labs showed an elevated WBC count, elevated C-reactive protein, elevated D-dimer, negative procalcitonin, negative High-sensitivity troponins and elevated BNP. Electrocardiogram showed atrial fibrillation. Echocardiogram showed an EF of 25-30% with a vegetation on the right ventricular lead. A CT angiogram chest was done and showed a right pulmonary artery embolism. Blood cultures were positive for Enterococcus faecalis . The patient was started on IV antibiotics, anticoagulation and he underwent open removal of the AICD along with multiple vegetations with the largest being 3.5cm. He recovered well post-operatively. Discussion: Cardiac device endocarditis is a difficult to manage condition that has been increasing in incidence over the years. Persistent infection is a problem faced when a patient has AICD endocarditis since these infections are typically resistant to many antibiotics necessitating surgical removal of the AICD. Patients that present with large vegetations larger than 2.5cm are at highest risk of complications. These complications include septic pulmonary emboli as seen in our patient, pulmonary abscess formation and pneumonia. Early diagnosis and lead extraction has been related to the highest reduction in mortality.
Abstract 18596: Sildenafil Modulates Metabolic Remodeling by Increasing Fatty Acid β-Oxidation in Single Ventricle Congenital Heart Disease
Authors: Ashley E Pietra, Mary E Turner, Erin E Sanchez, Matthew Stone, Brian L Stauffer, Carmen C Sucharov, Shelley D Miyamoto, Anastacia M Garcia
Journal: Circulation (2023)

Introduction: Sildenafil, a phosphodiesterase-5 inhibitor (PDE5i), is used to treat heart and circulatory failure (HF) in single ventricle congenital heart disease (SV). We previously demonstrated that human SVHF myocardium is characterized by increased PDE5 activity and impaired mitochondrial energetics, which are improved with PDE5i. Using an in vitro model in combination with SV myocardial tissue, we test the hypothesis that mitochondrial fatty acid β-oxidation (FAO) is improved with PDE5i therapy via activation of sirtuin-3 (Sirt3) and resulting protein deacetylation. Methods: Primary cardiomyocytes (neonatal rat ventricular myocytes, NRVMs) were treated with 2% serum from SVHF patients or non-failing (NF) controls +/-PDE5i (72 hours). To mechanistically interrogate whether PDE5i acts via Sirt3, we utilized siRNAs against Sirt3 +/-PDE5i. FAO was directly assessed via the Seahorse Bioanalyzer (Agilent). Mitochondrial protein levels and acetylation profiles were quantified via Western blot. Sirt3 activity was measured in isolated mitochondria from SVHF myocardium using a fluorescent-based enzymatic assay. Statistical analysis was performed using a Welch ANOVA with post-hoc Dunnett’s multiple comparisons test (FAO) or a paired T test (Sirt3 activity). Results: NRVMs treated with SVHF serum have impaired mitochondrial FAO and while PDE5i therapy results in improved FAO, siRNA knockdown of Sirt3 abolishes the PDE5i protective effect (A). Mitochondria isolated from SVHF myocardium are hyperacetylated, and ex vivo PDE5i treatment enhances Sirt3 deacetylase activity (B-C), and deacetylates mitochondrial proteins. Conclusions: SVHF serum treatment of cardiomyocytes is a novel in vitro platform for mechanistic investigations of SV-related pathophysiology. These data suggest PDE5i directly augments mitochondrial FAO via Sirt3-mediated protein deacetylation and provides important insight into the myocardial specific mechanisms of PDE5i.
Abstract 15024: Immunomodulatory Effects of Human Embryonic Stem Cell-Derived Epicardial Cells in Myocardial Infarct Healing
Authors: Huang-Tian Yang, Xiaoling Luo, Yun Jiang, Qiang Li, Xiu-Jian Yu, Min-Xia Ke, Peng Zhang, Ji-Liang Tan, Ling Gao
Journal: Circulation (2023)

Background: Acute myocardial infarction (AMI) causes excessive myocardium damage, including epicardium. Cell therapy by implantation of human pluripotent stem cell (hPSC)-derived cardiovascular cells has been tested in the infarcted hearts of preclinical models and clinical studies. However, whether hPSC-derived epicardial cells (hEPs) can be a therapeutic approach for infarcted hearts remains unclear. AMI induces inflammatory cascades, leading to multifaceted processes of myocardial injury and healing, whereas it is unknown whether hEPs regulate immune responses, especially macrophage plasticity at the acute phase of MI. Aims: to determine whether hEP implantation promotes myocardial infarct healing and modulates inflammatory response. Results: intramyocardial injection of hEPs at the acute phase of MI ameliorated functional worsening (p&lt;0.001 vs. MI control) and scar formation of adult male NOD-SCID mouse hearts (p&lt;0.05 vs. MI control) at day 28 post-MI, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis (p&lt;0.05 vs. MI control). Mechanistically, hEPs suppressed AMI-induced increases of type I interferon (IFN-I) response, infiltration and cytokine-release of inflammatory cells, and promoted polarization of reparative macrophages. These effects were blocked by a IFN-I receptor agonist RO8191 in mouse model of MI. Moreover, hEP abundantly secreted intelectin 1 (ITLN1), which interacted with IFN-β and mimicked the effects of hEP-condition medium in the suppression of IFN-β-stimulated responses in macrophages and promotion of reparative macrophage polarization. However, ITLN1 downregulation in the hEPs canceled beneficial effects of hEPs in anti-inflammation and anti-IFN-I response, and in cardiac repair of infarcted hearts. Conclusions: our resutls demonstrate the reparative effects of hEP implantations in the infarcted hearts and reveal hEPs as an inflammatory modulator in promoting infarct healing via paracrine factor-mediated cell-cell communications. These findings provide new knowledges for the functions and mechanisms of hEPs for cardiac repair and suggest a therapeutic option of hEPs for ischemic myocardial repair.
Abstract 15000: Renal Denervation Improves Cardiac Function and Mitigates Pathophysiological Changes in a Novel Murine Model of Heart Failure With Preserved Ejection Fraction
Authors: Li Zhuqing, Chengzhi Lu
Journal: Circulation (2023)

Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) is a multifaceted disease, intricately linked with sympathetic nervous system activation. Despite advancements, therapeutic options for HFpEF remain constrained, largely due to a dearth of fitting preclinical models. Renal denervation (RDN), an emerging intervention, holds potential in attenuating sympathetic activity and ameliorating HFpEF high-risk factors such as hypertension and insulin resistance. Aims: our study is designed to establish a multifactorial HFpEF mouse model and assess the therapeutic implications of RDN. Methods: Aged 12-month-old male C57BL/6N mice were exposed to a high-fat diet (60% calories from lard) and L-NAME (0.5 g/L in drinking water) over a 5-week period to generate a multi-hit HFpEF model. The efficacy of the model was assessed through a range of methods, encompassing echocardiography, histology, exercise exhaustion tests, serum NT-proBNP measurements, and intraperitoneal glucose tolerance tests. Upon successful model establishment, mice were randomized to receive either bilateral renal denervation or a sham operation. The subsequent impact of RDN on the aforementioned parameters was then evaluated. Results: In C57BL/6N mice, a cardiometabolic HFpEF phenotype was effectively induced through a multi-hit approach encompassing a high-fat diet, L-NAME administration, and aging. This potent combination triggered obesity and glucose intolerance, culminating in the emergence of characteristic HFpEF features such as cardiac hypertrophy, fibrosis, preserved fractional shortening with impaired deformation, atrial enlargement, lung congestion, hypertension and decreased exercise endurance. Intervention with RDN mitigated this cardiometabolic dysregulation and enhanced cardiac function, as demonstrated by reductions in cardiac hypertrophy, myocardial fibrosis, atrial weight, NT-proBNP levels, lung congestion, and improved exercise endurance. Conclusions: Our study suggests that RDN effectively mitigates cardiac function and structure in a multi-hit HFpEF mouse model, indicating its potential as a promising therapeutic strategy for HFpEF.
Abstract 12408: Response to Mavacamten by Sarcomere Gene Mutation Status in EXPLORER-HCM
Authors: Carolyn Y Ho, Pablo Garcia-Pavia, Neal K Lakdawala, Anjali T Owens, iacopo olivotto, Juan Ramon Gimeno Blanes, Luis M Rincon, David S Owens, Philippe Charron, Nuno Cardim, Amy J Sehnert, Warren Anderson, Jessica Landis, Zhaoqing Wang, Roberto Barriales-Villa
Journal: Circulation (2023)

Background: Mavacamten is a small molecule inhibitor of cardiac myosin that was developed based on insights into the molecular basis of hypertrophic cardiomyopathy (HCM). In the phase 3 EXPLORER-HCM trial (NCT03470545), patients showed consistent benefit in the primary endpoint with mavacamten treatment vs placebo while subgroup analysis of patients with pathogenic or likely pathogenic variants in a broad panel of HCM-related genes, revealed a slightly more favorable response. However, it is unknown how patients specifically with sarcomere gene variants responded. Aims: To assess the effect of HCM-specific sarcomere gene variants on response to mavacamten. Methods: Sequencing using a 60 gene panel (Invitae) was optional in EXPLORER-HCM. In this exploratory analysis, responses to mavacamten vs placebo for the primary, secondary, and exploratory endpoints were analysed. Patients were grouped based on sarcomere gene variant status (positive for pathogenic/likely pathogenic/variants of uncertain significance [SARC+], negative [SARC–]) or no sequencing). Analyses were adjusted for clinically relevant variables. Results: Of 190/251 patients sequenced, 73 were SARC+ (mavacamten, n = 33; placebo, n = 40), 117 were SARC– (mavacamten, n = 57; placebo, n = 60) and 61 had no panel sequencing (mavacamten, n = 33; placebo, n = 28). Mavacamten treatment showed a favorable response for the primary endpoint vs placebo, for SARC+ (odds ratio [OR], 4.43 [95% CI, 1.56-12.58]), and for SARC– (OR, 2.52 [95% CI, 0.99-6.42]) ( Figure ). Improvements with mavacamten vs placebo were observed in both SARC+ and SARC– subgroups for change from baseline to week 30 in post-exercise left ventricular outflow tract gradient, and peak oxygen consumption, and in New York Heart Association class. Conclusions: In this exploratory subgroup analysis, mavacamten treatment benefit was observed both in patients with and without sarcomere gene variants.
Abstract 15524: SARS-CoV-2 Spike Protein Stimulates Macropinocytosis in Murine and Human Macrophages
Authors: Wonmo Ahn, Ajay Pandey, PUSHPANKUR GHOSHAL -MMCC-, Bhupesh Singla, Abigayle B Simon, Cassandra C Derella, Ryan A Harris, Rudolf Lucas, Gabor Csanyi
Journal: Circulation (2023)

Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence of this virus has led to millions of deaths and the long-term cardiovascular and respiratory consequences of COVID-19 continue to pose a massive threat to public health. While recent studies have demonstrated that SARS-CoV-2 may enter kidney epithelial cells via angiotensin converting enzyme 2 (ACE2)-independent mechanisms by inducing receptor-independent macropinocytosis, it is currently unknown whether this process also occurs in cell types directly relevant to SARS-CoV-2-associated cardiovascular disease or pneumonia. Here, we investigated the ability of SARS-CoV-2 spike protein subunits to stimulate macropinocytosis in alveolar epithelial cells and macrophages. Flow cytometry analysis of fluid-phase marker internalization demonstrated that SARS-CoV-2 spike protein subunits S1, the receptor binding domain (RBD) of S1, and S2 stimulate macropinocytosis in both human and murine macrophages, but not in human lung epithelial cells. Pharmacological and genetic inhibition of macropinocytosis substantially decreased spike protein-induced macropinocytosis in macrophages both in vitro and in vivo . High resolution scanning electron microscopy (SEM) imaging confirmed spike protein-induced plasma membrane activities characteristic of macropinocytosis. Mechanistic studies demonstrated that inhibition of protein kinase C and phosphoinositide 3-kinase in macrophages blocks SARS-CoV-2 spike protein-induced macropinocytosis. Further, pharmacological blockade of ACE2 did not inhibit macropinocytosis in SARS-CoV-2 spike protein-treated cells. To our knowledge, these results demonstrate for the first time that SARS-CoV-2 spike protein subunits stimulate macropinocytosis in macrophages. These results may contribute to a better understanding of SARS-CoV-2 infection and its cardiovascular and respiratory complications.
Abstract 13724: Multiparameter Right Ventricular Dysfunction Predicts Worse Prognosis in Heart Failure With Preserved Ejection Fraction - Lessons From the PARAGON-HF Trial
Authors: Henri Lu, Riccardo M Inciardi, Martin Abanda, Amil M Shah, Maja Cikes, Brian Claggett, Narayana Prasad, Carolyn S Lam, Margaret M Redfield, John J McMurray, Scott Solomon, Sheila Hegde, Hicham Skali
Journal: Circulation (2023)

Introduction: Impaired tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC) and right ventricular free wall longitudinal strain (RVFWLS) have been individually associated with a worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF). However, these parameters measure different aspects of RV function and understanding their cumulative effect may provide insights into the overall impact of RV dysfunction (RVD) in HFpEF patients. Goal: Assess the association between the number of echocardiographic RVD parameters and clinical outcomes. Methods: Patients from the echocardiographic sub-study of the PARAGON-HF trial with adequate image quality (N=809, 53% women, mean age 74±8 years) were categorized based on the number of measures of RVD, which included TAPSE &lt;1.7 cm, FAC &lt;35% or RVFWLS &lt;20% (absolute value). Associations with total HF hospitalizations (HFH) and CV death, total HFH alone, first HFH or CV death, all-cause death and CV death were assessed by Groups, after accounting for confounders. Results: A total of 348 patients (43%) in Group 0 (no abnormal parameter), 355 (44%) in Group 1 (one abnormal parameter) and 106 (13%) in Group 2 (two or more abnormal parameters) were identified. After multivariable adjustment ( Table ), Group 2 was significantly associated with an increased risk of total HFH and CV death (RR 2.13, 95%CI 1.13-4.01), first HFH or CV death (RR 2.07, 95%CI 1.15-3.73), all-cause death (RR 2.61, 95%CI 1.19-5.74) and CV death (RR 3.08, 95%CI 1.14-8.31). The treatment effect of sacubitril/valsartan for total HFH and CV death was not modified by RVD Group (p-value for interaction=0.94). Conclusions: The presence of two or more RVD parameters was associated with a significantly worse prognosis, while an isolated RVD measure was not. These findings suggest that a more comprehensive approach to assessment of RV function may have better prognostic value in HFpEF.
Abstract 18363: Readmission &amp; Temporal Trends of Post LVAD Placement Complications in Patients With End-Stage Heart Failure
Authors: Sherif Eltawansy, Ndausung Udongwo, Sowmya Dandu, Hira Akhlaq, Anmol Johal, Anton Mararenko, Anas Alrefaee, Abbas Alshami, Jesus Almendral, Joseph Heaton
Journal: Circulation (2023)

Introduction: 5-10% of heart failure (HF) patients progress to advanced stages. Left ventricular assist devices (LVADs) have emerged as a favored therapy for end-stage HF as destination therapy or as a bridge to heart transplantation. However, complications and provider expertise hinder its widespread use. Third generation LVAD was introduced in 2018 to enhance usability and reduce complications. We aim to investigate the temporal trends in post-LVAD complications with the latest generation LVAD vs the previous version. Methods: We utilized the 2016-2020 Nationwide Readmission Database to identify patients ≥ 18 years of age with advanced HF implanted with an LVAD. Variables were identified using International Classification of Diseases, Tenth revision codes. We compared 2 groups based on the implant year (2016-2018 and 2019-2020). The primary outcome was 30-day readmission (30-dr), while secondary outcomes were trends in complications, mortality rate, and healthcare cost. Multivariate analyses and descriptive bivariate analyses were performed. A p-value &lt;0.05 was considered statistically significant. Results: We identified 7,975 patients (21.3% females) of which 17.1 % (n = 1,214) were readmitted within 30 days. Readmission rates were 17.7% (n = 778) for 2016-2018 and 16.2% (n = 435) for 2019-2020 (adjusted Wald test, p = 0.26). The 2019-2020 group exhibited lower rates of cardiac device complications, vasopressor usage, cardiac tamponade, and peri-procedural circulatory complications than the 2016-2018 group (adjusted Wald test, p &lt; 0.05). No significant differences in mortality or LOS were observed between the two groups (adjusted Wald test, p &gt; 0.05). Healthcare costs were higher in the 2019-2020 group (mean $276,439 vs $315,332, adjusted Wald test, p = 0.01). Conclusions: Complications following LVAD placement continue to impede broader adoption for advanced HF. Nonetheless, advancements in newer LVAD generations and improved provider expertise hold promise for increased utilization. Our study indicates a decline in complications, including cardiac tamponade and post-procedural complications, which may be attributed to newer device innovations. Further research is necessary to explore this correlation in greater depth.
Abstract 14182: Outcomes From Left Atrial Appendage Occlusion Utilizing the Watchman FLX versus Watchman 2.5: A Systematic Review and Meta-Analysis
Authors: Omar M Aldaas, Masihullah Barat, Amer M Aldaas, Frederick Han, Kurt S Hoffmayer, David E Krummen, Gordon Ho, farshad raissi, Ulrika Birgersdotter-Green, Ryan Reeves, Gregory K Feld, Jonathan C Hsu
Journal: Circulation (2023)

Introduction: Left atrial appendage occlusion with the Watchman device has been shown to be noninferior to oral anticoagulation in preventing strokes in patients with atrial fibrillation. The Watchman FLX device was designed to overcome many of the limitations of the Watchman 2.5. Hypothesis: The Watchman FLX will have better short- and long-term safety and efficacy relative to the Watchman 2.5. Methods: We performed an extensive literature search and systematic review of studies that compared the short- and/or long-term safety and efficacy of the Watchman FLX versus Watchman 2.5. Risk ratio 95% confidence intervals (CI) were measured using the Mantel-Haenszel method for dichotomous variables, where a RR&lt;1.0 favors the FLX group. Results: Seven studies with a total of 2315 patients were included, of which 24.0% (n=555) had the FLX and 76.0% (n=1760) had the 2.5 implanted. There were no statistically significant differences in procedural complications or device-related thrombosis, but significantly less peri-device leak at follow-up, as shown in Figure 1. There were no statistically significant differences in pericardial effusion/tamponade (MD 0.54; 95% CI 0.09-3.25) or device embolization (MD 0.44; 95% CI 0.05-4.14). No statistically significant differences were seen in major bleeding (MD 1.06; 95% CI 0.55-2.05), transient ischemic attack, stroke or systemic embolism (MD 0.31; 95% CI 0.08-1.20) or all-cause mortality (MD 1.65; 95% CI 0.76-3.57) at follow-up. Conclusion: Based on the results of this meta-analysis, the Watchman FLX appears to be as safe as the Watchman 2.5, but with lower rates of peri-device leak.
Abstract 18321: Identifying Predictors of Non-Home Discharge Dispositions Using Machine Learning Among Critically Ill Patients Undergoing Coronary Artery Bypass Grafting
Authors: Neel Bhattacharyya, Yanjia Zhang, Zhenwei Zhang, Md Ashfaq Ahmed, Mukesh Roy, Venkataraghavan Ramamoorthy, Muni Rubens, Anshul Saxena
Journal: Circulation (2023)

Introduction: Managing patients undergoing coronary artery bypass graft (CABG) procedures can be challenging. Research shows hospital discharges to locations other than home following CABG are associated with an increased risk of late mortality. We aimed to develop machine learning (ML) models to predict the risk of postoperative discharge dispositions other than home among these patients and assess their long-term postoperative prognosis. Methods: The Medical Information Mart for Intensive Care IV database was utilized to identify patients who underwent CABG procedures. The cases were divided into training (75%) and test (25%) sets. The AUROC, accuracy, and F1 scores were used to compare the performance of models. Several methods, such as penalized logistic regression, random forest, SVM, XGBoost, gradient boosting classifier, and lightGBM, were utilized, accounting for variables from demographics, labs, charting events, and comorbidity domains. Results: The study included 2228 eligible patients who underwent CABG procedures. The sample consisted of 23% females, 72% whites, and 43% were insured by Medicare. The median age of the sample was 69 years. Among these, 781 (35.05%) patients were discharged to locations other than home. Results show that the gradient boosting method had the highest accuracy (76.8%) with an AUROC of 80.8%. Age, BUN, male sex, PO2, hemoglobin, heart rate, mean arterial BP, chloride, platelet count, and creatinine levels were the top predictors for predicting non-home discharges. Results from the other models represented similar attributes as the top significant predictors. Conclusion: Predictors of discharge to locations other than home were identified with high accuracy, and this may aid in selective intervention to reduce the risk of death in this vulnerable patient population. ML can be used to investigate these patterns and possibly highlight particular patient subsets to enhance risk stratification and management.