tbuckley/cabot-search huggingface dataset:
Abstract 4139873: Isolated Tricuspid Replacement versus Repair among Medicare Beneficiaries
Authors: Tomonari Shimoda, Hiroki Ueyama, Yoshihisa Miyamoto, Atsuyuki Watanabe, Hiroshi Gotanda, Sammy Elmariah, Yujiro Yokoyama, Shinichi Fukuhara, Tsuyoshi Kaneko, Toshiki Kuno, Yusuke Tsugawa
Journal: Circulation (2024)

Background: Evidence is limited regarding mid-term outcomes following isolated tricuspid operations for tricuspid regurgitation at the population level. Objective: This study aimed to compare the mid-term outcomes following isolated tricuspid valve replacement versus repair using contemporary data. Methods: We analyzed the national data on Medicare beneficiaries aged ≥65 who underwent isolated tricuspid valve replacement or repair between January 2016 and December 2020. The primary outcome was mid-term (up to 3 years) all-cause mortality. The secondary outcomes included mid-term major adverse cardiovascular events (MACE) and heart failure hospitalizations, as well as in-hospital permanent pacemaker implantation rates. MACE comprised all-cause mortality, heart failure hospitalization, stroke, and tricuspid reoperations. A propensity score-matching analysis was conducted to compare the two groups. Results: A total of 1,693 patients were included (replacement= 655 patients, repair= 1,038 patients). In the matched cohort (597 patients in each group), the overall mortality and MACE were 40% and 47% at 3 years, respectively. Tricuspid valve replacement was associated with similar all-cause mortality in comparison to repair (adjusted hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.95-1.39; P=0.15). Similarly, the rates of MACE and heart failure hospitalizations were similar (adjusted HR, 1.10; 95% CI, 0.93-1.32, P=0.27; subdistribution HR, 1.07, 95% CI, 0.75-1.54, P=0.69, respectively) between these two procedures. Patients undergoing replacement required permanent pacemaker implantations more frequently (25.4% vs. 12.4%; P&lt;0.001). Conclusions: Isolated surgical tricuspid valve replacement was associated with similar clinical outcomes compared to repair, except for permanent pacemaker implantation rates. The overall high mid-term mortality and morbidity with either treatment highlight the need for better options and further research to optimize the indication and timing of intervention.
Abstract 4140287: Comparison of Coronary Artery Calcium and Measures of Renal Dysfunction in Reclassifying Cardiovascular Risk Among Individuals with Diabetes
Authors: Sina Kianoush, Rachelle Bishay, Keishi Ichikawa, Srikanth Krishnan, Travis Benzing, Jairo Aldana, Ahmed Ghanem, Hossein Hamidi, Marziyeh Bagheri, Mina Deljavanghodrati, April Kinninger, Shaista Malik, Nathan Wong, Matthew Budoff
Journal: Circulation (2024)

Background: The risk of cardiovascular disease (CVD) varies among patients with diabetes. Evidence is insufficient for comparing coronary artery calcium (CAC) and measures of renal dysfunction in reclassifying CVD risk among these patients. Hypothesis: This study assesses whether CAC enhances discrimination and net reclassification improvement (NRI) compared to measures of renal dysfunction in persons with diabetes. Methods: We used Cox proportional hazard models to compare the performance of CAC and measures of renal dysfunction in predicting CVD in the Multi-Ethnic Study of Atherosclerosis (MESA). Models adjusted for age, sex, race, ever smoking, body mass index, systolic blood pressure, total cholesterol, high-density cholesterol, triglycerides, A1c, fasting blood sugar, hypertension medication use, and insulin use. Measures of renal dysfunction included estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR), assessed individually or as composite variables (eGFR &lt;60 mL/min/1.73 m 2 or UACR &gt;30 mg/g). Improvements in c-statistics and the 10-year area under the curve (AUC) were calculated. Results: A total of 839 participants, with a mean age of 64.5 ± 9 years, 396 female (47.2%), 155 White (18.4%), 321 Black (38%), 260 Hispanic (31%), and 103 Chinese (12%), were included. Of the total, 528 (63%) had CAC &gt;0, 139 (17%) had eGFR &lt;60 mL/min/1.73 m 2 , and 232 (28%) had UACR &gt;30 mg/g. Patients were followed up for a mean of 13.4 years. CAC, eGFR, and UACR were associated with an increased risk of CVD in all predefined models. CVD risk increased incrementally with the increase in CAC category (Table). The addition of CAC significantly increased AUC in Model 1 with baseline variables (0.680 vs. 0.726, p=0.002), Model 2 with individual measures of renal dysfunction (0.702 vs. 0.745 p=0.003), and Model 3 with composite measures of renal dysfunction (0.706 vs. 0.746, p=0.004). Conclusion: CAC reclassifies CVD risk beyond measures of renal dysfunction and may be used to identify higher-risk patients among those with diabetes.
Abstract 4140511: Synergistic insulinotropic and lipolytic actions of GLP-1 and a novel miniaturized designer GC-A peptide activator in Beta cells and adipocytes: Potential therapeutic insights for cardiometabolic disease
Authors: Ye Zheng, Shuchong Pan, Dante Moroni, Horng Chen, Jeson Sangaralingham, John Burnett
Journal: Circulation (2024)

BACKGROUND: Atrial natriuretic peptide (ANP) and glucagon-like peptide-1 (GLP-1) are endogenous hormones known for roles in cardiovascular regulation and metabolic homeostasis. ANP mediates its actions via the GC-A receptor, while GLP-1 via the GLP-1 receptor (GLP-1R). Both peptides may stimulate insulin secretion from pancreatic beta cells and augment lipid metabolism in adipocytes, yet potential synergistic effects remain unexplored. To optimize ANP activation of GC-A, we developed a novel 15 amino acid miniaturized GC-A activating peptide CRRL555. CRRL555 possesses greater GC-A binding and activating properties than ANP. AIMS: We investigated the metabolic properties of CRRL555/GC-A and its interaction with GLP-1/GLP-1R in vitro. METHODS: Rat pancreatic beta cells (INS-1) were stimulated with high glucose (20mM) and treated with GLP-1 or CRRL555 (10 -10 -10 -6 M) and together for 1 hr. Supernatant was collected and insulin was measured by ELISA. Human visceral adipocytes were differentiated for 10 days and then treated with GLP-1 or CRRL555 (10 -10 -10 -6 M) or together for 6 hrs. Supernatant was collected and glycerol and free fatty acid (NEFA), indicators of lipolysis, were measured. RESULTS: CRRL555 (p&lt;0.05) and GLP-1 (p&lt;0.05), dose dependently, stimulated insulin secretion in INS-1 cells in the presence of high glucose. Importantly, CRRL555 combined with GLP-1, resulted in a greater enhancement (p&lt;0.05) of insulin secretion compared to either peptide alone. While high dose CRRL555 and GLP-1 (10 -6 M) stimulated lipolysis in visceral adipocytes with increases in glycerol and NEFA, only CRRL555 at low dose (10 -10 M), and not low dose GLP-1 (10 -10 M), stimulated glycerol and NEFA production (p&lt;0.05). When low dose GLP-1 (10 -10 M) was added to low dose CRRL555(10 -10 M), lipolysis was like CRRL555 alone. CONCLUSION: We report a novel synergy in insulin release from beta cells with combined stimulation of the potent and miniaturized GC-A designer peptide CRRL555 with GLP-1. CRRL555 possesses greater lipolytic properties compared to GLP-1 in visceral adipocytes at low doses advancing novel metabolic actions of CRRL555 alone or combined with GLP-1R activation. These in vitro studies of dual receptor activation of GC-A and GLP-1R highlight the therapeutic potential of combining CRRL555 with GLP-1-based therapies for the treatment of cardiometabolic diseases, thus supporting studies of dual GC-A/GLP-1R activation in experimental cardiometabolic disease states.
Abstract 4140245: Electronic Clinical Decision Support Tool Increases Oral Anticoagulant Prescription in the Emergency Department: Initial Findings From a Multi-Phase, Multi-Center Stepped-Wedge Cluster Randomized Trial
Authors: Sombuddha Bhadra, Bradley Hopkins, Miriam Elman, Thuan Nguyen, Erin Kinney, Joy Kim, Mariam Anwar, Kaye Ann Obando, Diana Prychyna, Nikolai Schnittke, Matthew Neth, Benjamin Sun, Bory Kea
Journal: Circulation (2024)

INTRODUCTION: Atrial fibrillation (AF), often diagnosed in the Emergency Department (ED), increases the risk of stroke by 64% but can be mitigated by guideline-directed oral anticoagulant (OAC) treatment. RESEARCH QUESTION: Does clinician education of an AF clinical decision support (CDS) tool increase OAC prescription rates for patients with new-onset AF or paroxysmal AF (pAF)? GOALS: To increase guideline recommended care practice of OAC prescribing for appropriate candidates in the ED. Methods: This multi-center, multi-phase, stepped-wedge cluster-randomized clinical trial includes a retrospective phase (Phase 0) and implementation of an external browser link to the CDS in the EHR (Phase 1) which included patient-specific stroke and bleeding risk stratification scores with recommendation for OAC based on professional society guidelines, along with targeted provider education on how to use the resource. Data was collected from ED visits of patients aged &gt; 18 with a primary AF/pAF diagnosis from Jan 1, 2020–May 25, 2024. The three sites, one academic and two community hospitals, implemented Phase 1 in January ‘22, April ‘22, and April ‘23. Eligibility for OAC treatment was based on clinical judgment weighing the benefit of stroke prevention against the risk of bleeding. A logistic GEE model assessed the intervention's impact on OAC prescribing and treated ED providers as a random effect to account for clustering. The model included the CDS intervention and covariates for site, cardiology consultation, guideline citation, and patient factors such as sex, race, ethnicity, and age. Results: Of 4397 patients analyzed, 655 met inclusion criteria, among which 296 (45.19%, median age 68) were prescribed OAC, 175 in Phase 0, and 121 in Phase 1. The odds ratio estimates and their corresponding 95% confidence intervals are as follows: CDS intervention 1.75 [1.20, 2.54], sex female vs male 2.31 [1.57, 3.38], age 0.27 [0.12, 0.61], site 0.55 [0.29, 1.04] and 0.45 [0.25, 0.83] for each community site vs academic, cardiology consultation 4.56 [2.80, 7.42], and guideline citation 2.23 [1.44, 3.43]. Race and ethnicity did not show significant associations. CONCLUSION(S): We demonstrated that clinician education and limited CDS tool integration into the EHR are linked to an almost two-fold increase in OAC prescribing for suitable AF/pAF patients. Future studies should evaluate the influence of further CDS integration on OAC prescribing, long-term adherence, patient outcomes.
Abstract 4139632: Narciclasine Reverses Vascular Aging and Atherosclerosis by Suppressing SPP1-mediated Inflammation Signals
Authors: Zhiyi Fang, Linghuan Wang, Yan Fang, Renzheng Chen, Weiwei Zhang, Hui Li, Sijia Chen, Xiaoying Shen, Yingjie Zhang, Ruihua Cao, Feng Cao
Journal: Circulation (2024)

Objective: The senescence of smooth muscle is one of the significant risk factors in atherosclerosis progression in which the vascular inflammation plays an important role on dysfunction. This study is designed to explore the novel vascular aging inflammation biomarkers and screen the potential molecular interventional targets through bioinformatic analysis. Methods&amp;Results: The transcriptional analysis on GSE16487 database from 15 human vascular tissue samples, 8 from less than 60 yro (young group) and 7 from older than 75 yro (Aged group). The comparison between two groups contained 252 (114 upregulated and 138 downregulated) DEGs with minimum 1.5-fold change. As shown in FigA-B, 114 upregulated genes were mainly involved in 5 biological processes and 5 signaling pathways using GO and KEGG functional enrichment analysis. PPI network results indicated that 9 genes had interactions at medium confidence (score＞0.415), which are mainly included the GO and KEGG inflammation-related terms leukocyte cell-cell adhesion, Cytokine-cytokine receptor interaction, TGF-beta signaling pathway and regulation of T cell activation (Fig C). Furthermore, the association between 9 genes and vascular aging was validated in an independent cohort (GSE117715, GSE116277, GSE130727) and senescent VSMCs induced by 250 μM oleic acid (OA). ssGSEA analysis results revealed a higher abundance of Tem and Th2 cells within aged vascular tissues, indicating that the local inflammation activated the immune system and immune cell recruitment (p&lt;0.05) (Fig D). To further screen novel therapeutics, all DEGs expression data were uploaded to CMap database. The results showed that narciclasine, known as RhoA activator, may alleviate inflammation-related vascular aging by regulating SPP1-mediated cytokines release(Fig E-G). In vitro experiments demonstrated that narciclasine alleviated senescence of VSMCs(p&lt;0.05). In vivo experiments revealed that narciclasine treatment reduced aortic plaque area and diminished lipid core size within atherosclerotic plaques in ApoE -/- mice fed a high-fat diet(p&lt;0.05). Conclusion: The 9 inflammatory biomarkers were screened and validated in senescent VSMCs. The compound narciclasine can regulate SPP1-mediated cytokines release to suppress inflammation signals and alleviate vascular aging. This research explores potential inflammation-related biomarkers and interventional targets for alleviating vascular aging.
Abstract 4140422: Molecular and Functional Characterization of DENND3 as a Novel Regulator of Ion Channel Trafficking
Authors: Shan Gao, Dan Ye, Raquel Neves, Changsung Kim, David Tester, Wei Zhou, John Giudicessi, Michael Ackerman
Journal: Circulation (2024)

Background: We identified a novel, ultra-rare missense variant (p.R534S) in DENND3 as a potential disease-susceptibility variant in a multi-generational pedigree of familial idiopathic ventricular fibrillation (IVF). DENND3 is a guanine nucleotide exchange factor and activator for small GTPase Rab proteins involved in endosome and ion channel membrane trafficking. However, the role of DENND3 in the heart and its potential involvement in cardiac arrhythmias are unknown. Objective: To functionally characterize DENND3-p.R534S and determine its impact on channel trafficking. Methods: Heterologous co-expression studies in TSA201 cells were performed with DENND3-WT or DENND3-p.R534S and ion channels: KCNQ1 (Kv7.1, IKs), KCNH2 (Kv11.1, IKr), SCN5A (Nav1.5, INa), or CACNA1C (Cav1.2, ICa) as well as Rab proteins (Rab4, Rab5, Rab6, Rab7, Rab11, Rab12). Patient-specific DENND3-p.R534S iPSC-derived cardiomyocytes (iPSC-CMs) and isogenic controls (IC) were created. Localization and expression of ion channel and Rab proteins was assessed using immunofluorescence (IF) by super resolution AiryScan microscopy. GTPase-Glo assays measured Rab protein activity. Electrophysiology studies using patch-clamp and FluoVolt were performed on iPSC-CM models. Results: IF imaging showed significant increases in membrane expression of KCNQ1 (11714±157to 21929±378, p&lt;0.05), KCNH2 (11378±160 to 31965±544, p&lt;0.05), , SCN5A (10339±8 to 11225±23, p&lt;0.05), and CACNA1C (11879±83 to 13749±138, p&lt;0.05) in DENND3-p.R534S compared to DENND3-WT expressing TSA201 cells. Rab5 distribution was altered significantly by the DENND3-p.R534S variant, with increased dispersion away from the nucleus (0.23±0.01 vs. 0.17±0.01, p&lt;0.05) and increased proximity to the plasma membrane (0.16±0.02 vs. 0.23±0.01, p&lt;0.05). Additionally, Rab5 activity was enhanced significantly (57% increase) by p.R534S versus WT (p&lt;0.05). iPSC-CMs revealed similar increases in channel membrane accumulation and irregular arrhythmic activity including frequent action potential duration alternans and afterdepolarizations in 78% of p.R534S iPSC-CMs versus none in IC cells (p&lt;0.05). Conclusion: DENND3 is a novel ion channel trafficking protein in the heart. The DENND3-p.R534S variant disrupts cardiac ion channel trafficking. These findings highlight DENND3’s role in cardiac ion channel distribution, cellular function, and potential association with arrhythmogenic risk.
Abstract 4140406: Common Misdiagnoses During the Workup of Inherited Channelopathies
Authors: Sahej Bains, Raquel Neves, Johan Bos, John Giudicessi, Michael Ackerman
Journal: Circulation (2024)

Background: Cardiac channelopathies are a heterogenous group of genetic heart diseases (GHDs) that affect cardiac ion channel function. The most prevalent among these are long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) which predispose patients to potentially life threatening ventricular arrhythmias. Accurate and timely diagnosis is important for the management and risk stratification of the index case and identification of potentially at-risk relatives. Unfortunately, despite rising awareness of these GHDs, critical warning signs are overlooked. Objective: To describe the phenotypes of patients who present with a delayed or missed diagnosis of LQTS or CPVT. Methods: EMR data was reviewed for all patients evaluated and treated at Mayo Clinic between 2000-2023 who arrived with a mis- or delayed diagnosis of LQTS or CPVT. Data was abstracted for patient demographics, clinical characteristics, family history of SCD, and cardiac and genetic test results. Results: Overall, 47/2119 (2%) patients [33 (70%) female, mean age at correct diagnosis 26±18 years] diagnosed with LQTS (30; 2% of LQTS cohort) or CPVT (17; 7% of CPVT cohort) arrived with an outside misdiagnosis (37, 79%) or underdiagnosis (10, 21%). The most common misdiagnosis was epilepsy (20; 43%) or vasovagal syncope (14; 30%) and 3 CPVT patients (6%) were misdiagnosed with LQTS. Of the 10 underdiagnosed patients, 4 (40%) had QT prolongation, 4 (40%) family history of SCD, 3 (30%) bilateral deafness, and 1 (10%) fetal bradycardia and syndactyly. Overall, 40/47 (85%) were symptomatic (syncope: 29 [73%], seizures: 21 [53%], SCA: 10 [25%]) prior to diagnosis. Of note, 34/40 (85%) had symptoms with exertion, 5 (13%) at rest, and trigger was unknown in 1 (2%). Of the 7 asymptomatic patients (15%), 4 (57%) had QT prolongation and 4 (57%) had family history of SCD. In total, 20/47 patients (43%) had positive family history of SCD under 45 years of age. Overall, patients experienced a median delay in diagnosis of 8 years during which a median of 4 events (range: 1-150) occurred. As a result, an additional 29 family members of these patients received a delay in their diagnosis. Conclusions: Recognizing the signs and symptoms of patients with GHDs is important to reduce the ongoing burden of misdiagnosis or delayed diagnosis in LQTS and CPVT. The most important factors for suspicion of an inherited channelopathy are symptoms during exertion and family history of SCD.
Abstract 4140037: The association of housing unaffordability with medication adherence and health outcomes among non-elderly adult Medicaid beneficiaries with atherosclerotic cardiovascular disease
Authors: Sameed Ahmed Khatana, Lin Yang, Lauren Eberly, Ashwin Nathan, Fatima Qaisrani, Eric Roberts, Vincent Reina, Peter Groeneveld
Journal: Circulation (2024)

Background: The burden of housing costs is at an all-time high in the United States. Individuals with lower socioeconomic status experience worse health outcomes and are also disproportionately impacted by housing costs. Whether housing unaffordability is independently associated with medication adherence or health outcomes in individuals with cardiovascular (CV) disease is not well studied. Methods: All 19- to 64-year-old Medicaid beneficiaries in the United States with atherosclerotic CV disease (ASCVD) – coronary artery disease, peripheral arterial disease, and cerebrovascular disease/stroke – in 2018 were identified using Medicaid administrative claims data. The study population was limited to people continuously enrolled in 2019 and excluded Medicare-Medicaid dual enrolled beneficiaries. Medication adherence to Statin therapy and the number of all-cause and CV emergency department (ED) visits and hospitalizations were assessed in 2019. ZIP code level housing cost burden was measured as the proportion of all residents who spent more than 30% of their income on housing costs and was obtained from the 2015-2019 American Community Survey. Negative binomial generalized estimating equation (GEE) models were fit to account for the hierarchical nature of the data and were adjusted for individual demographic and clinical variables and area-level measures of socioeconomic status and social vulnerability. Results: A total of 443,984 beneficiaries with ASCVD living in 24,349 ZIP codes were identified. The mean ZIP-code level proportion of residents with unaffordable housing was 33.5% (SD=6.3%). In the multivariable GEE models, a 1 percentage point increase in the proportion of residents with unaffordable housing was associated with 0.05% (95% CI 0.01% to 0.1%) lower adherence to Statin therapy. It was also associated with a 0.6% (95% CI 0.3% to 0.8%) increase in the number of CV ED visits and a 0.3% (95% CI 0.04% to 0.5%) increase in CV hospitalizations. Housing unaffordability was also associated with a significant increase in all-cause ED visits [0.4% (95% CI 0.2% to 0.5%)]. Conclusion: Among non-elderly adult Medicaid beneficiaries with ASCVD, residence in a ZIP code with higher levels of housing unaffordability was independently associated with lower medication adherence to Statin therapy and a higher number of CV ED visits and hospitalizations. Whether improving housing affordability among this population can improve CV health outcomes needs to be studied further.
Abstract 4139688: Empagliflozin versus Placebo in Patients with Cardiovascular Disease and Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Authors: Adarsh Raja, Muhammad Ahmed, Muhammad Sohaib Asghar, Hafsah Alim Ur Rahman, Sandesh Raja
Journal: Circulation (2024)

Background: Historically, patients with type 2 diabetes mellitus (T2DM) and concurrent cardiovascular disease (CVD) have been managed through multifactorial interventions, including lifestyle modifications. Recently, empagliflozin, a potent sodium-glucose cotransporter 2 inhibitor (SGLT2i), has emerged as a novel antidiabetic agent demonstrating significant improvements in cardiovascular outcomes. Aim: To conduct a meta-analysis comparing empagliflozin with placebo in patients with T2DM and concomitant CVD. Methods: We performed a thorough literature search of PubMed, EMBASE, and the Cochrane Library up to May 2024 to identify studies comparing empagliflozin with placebo in patients with T2DM and concomitant CVD. Effect estimates were pooled using a random-effects model and reported as risk ratios (RR) for dichotomous outcomes and standard mean difference (SMD) or mean differences (MD) for continuous outcomes, each accompanied by 95% confidence intervals (CIs). Due to varying units of measurement for HbA1c that were not interconvertible, SMD was employed. Conversely, MD was used for the analysis of other continuous outcomes. Results: 16 studies fulfilled the inclusion criteria. Empagliflozin significantly reduced HbA1c (SMD: -1.33 [-2.28, -0.38]; p=0.006; Figure ) and cardiac mortality (RR= 0.62 [0.50, 0.78]; p&lt;0.0001), in comparison to placebo. Empagliflozin was also associated with a significantly greater reduction in systolic blood pressure (MD: -5.22 [-7.97, -2.47]; p=0.0002) and diastolic blood pressure (MD: -3.31 [-5.76, -0.85]; p= 0.008). However, empagliflozin was associated with a significantly greater risk of genital infections (RR=3.66 [2.69, 5.00]; p&lt;0.00001). Conclusion: In individuals diagnosed with T2DM and CVD, the use of empagliflozin could lead to improved clinical results.