tbuckley/cabot-search huggingface dataset:
Abstract 4137768: Evaluation of Therapeutic Intensification for Uncontrolled Hypertension Using Different Sources of Electronic Health Records
Authors: Liang Ni, Rachelle Juan, Teresa Harrison, Jaejin An
Journal: Circulation (2024)

Background: Healthcare system level interventions to monitor therapeutic intensification for uncontrolled blood pressure (BP) may address potential therapeutic inertia, however, the best methods to evaluate therapeutic intensification using different sources of electronic health records are unknown. Question: To what extent do medication orders and pharmacy data provide comparable or distinct evaluations of therapeutic intensification? Methods: We identified adults with uncontrolled hypertension (systolic BP ≥140 or diastolic BP ≥90 mm Hg) in an outpatient encounter (index) from Kaiser Permanente Southern California in 2018. We included patients with new antihypertensive medication orders at the index encounter. We calculated therapeutic intensification score (TIS), a proportional measure of prescribed daily dose to maximum recommended daily dose of antihypertensive medications using two data sources: (1) medication orders including dose, directions for use, discontinuation order; (2) pharmacy fill data including strength, days’ supply, and quantity within 14 days after the index. Therapeutic intensification was determined by comparing the new dose at index and the previous dose [delta TIS (new dose – previous dose) &gt;0]. Differences in TIS and the percentage of concordance using two methods were compared using descriptive statistics. Results: We included 75,935 patients with medication orders at the index encounter. Using medication order data, 84% increased the dose of antihypertensive medications with a median TIS (25 th , 75 th ) of 0.25 (0.13, 0.50). Among the total, 80% (n=61,485) filled their prescriptions. Among those who filled their prescriptions, 84% and 85% increased the dose using medication order and pharmacy data, respectively, with 95% concordance between the two methods. Mean (SD) differences in dose change was -0.06 (0.55) between the two methods ( p &lt;0.001). Conclusion: A large portion of patients with uncontrolled BP failed to fill their new prescriptions, underscoring the value of utilizing medication order data to evaluate therapeutic intensification. For those who filled prescriptions, only minimal differences were observed between the evaluations using medication orders and pharmacy data.
Abstract 4137688: Inhibition of Cardiac Fibrosis and Pro-Fibrotic Collagen Hormone Endotrophin by VS-041, a Novel Drug Candidate for Heart Failure with Preserved Ejection Fraction
Authors: Artur Plonowski, Joel Berger, Benjamin Pratt, Magdalena Krupa, John Vekich, Wieslaw Bochenek, Christopher Larson, Ydalina Moreno, Federica Genovese
Journal: Circulation (2024)

Introduction: Endotrophin, a collagen type VI–derived signaling peptide, has been linked to cardiac metabolic dysregulation, inflammation, and fibrosis. Several matrix metalloproteinases (MMPs), incl. MMP2 and MMP9, have been shown to cleave collagen 6A3 and release endotrophin. Baseline plasma endotrophin levels in heart failure with preserved ejection fraction (HFpEF) patients were shown to be strongly and independently associated with increased risk of poor outcomes (death or HF-admissions). VS-041 is a novel drug candidate for HFpEF that inhibits key MMPs implicated in cardiac fibrosis and diastolic dysfunction. Previously, VS-041 demonstrated robust efficacy in the Dahl Salt Sensitive rat model of hypertension and HFpEF, improving diastolic function and dose-proportionally reducing left ventricle (LV) fibrosis. Hypothesis: Inhibition of endotrophin release by VS-041 could contribute to its anti-fibrotic mechanism and serve as a potential biomarker of MMP inhibition (target engagement) in patients. Methods and Results: The effect of VS-041 on production of endotrophin was investigated in a “Scar-in-a-Jar” model using primary human cardiac fibroblasts isolated from adult healthy ventricles. Fibroblasts were treated with 10 ng/mL platelet-derived growth factor (PDGF) AB in the presence of 0.03, 0.3, or 3 µM VS-041, or DMSO control. The concentration of endotrophin in the medium was assessed via the ELISA nordicPRO-C6 TM (Nordic Bioscience A/S). After 4 days of treatment, VS-041 at 0.3 µM and 3 µM significantly inhibited PDGF AB-stimulated production of endotrophin. Cumulative inhibitory effects of VS-041 could still be observed after 12 days of culture. The antifibrotic activity of VS-041 was also tested in a model of extensive cardiac fibrosis in 16-months old C57BL/6 mice exacerbated by angiotensin II infusion at 1 mg/kg/day for 28 days. Oral treatment with VS-041 at 75 mg/kg BID resulted in a 62% reduction (p&lt;0.01) of LV fibrosis as assessed by morphometry of Masson trichrome stained sections. VS-041 also improved the diastolic echocardiography parameters IVRT and E/a ratio. Conclusions: The production of endotrophin by fibroblasts is diminished by VS-041 and, therefore, its plasma levels could be explored as a biomarker of in vivo MMP inhibition by VS-041. Additionally, the inhibition of endotrophin release by VS-041 could be causatively linked to reduction of cardiac fibrosis and potentially translate into improved clinical outcomes in HFpEF patients.
Abstract 4137274: Optimal Timing of Pharmacoinvasive Strategy and its Impact on Clinical in Patients with ST-Elevation Myocardial Infarction: a Real-World Perspective
Authors: Andrea Stephanus, Alice Pacheco Santos, Ana Carolina Machado Rodrigues da Cunha, Ana Carolina Augusto Rocha, Amanda de Amorim Meireles, Mariana Guimaraes Souza de Oliveira, Pietra Arissa Coelho Matsunaga, Alexandre Anderson de Sousa Munhoz Soares, Ana Claudia Cavalcante Nogueira, Adriana de J B de Almeida Guimaraes, Gustavo de Almeida Alexim, Alessandra Campos-Staffico, Luiz Sergio Carvalho
Journal: Circulation (2024)

Background: Pharmacoinvasive strategy remains the cornerstone therapy for ST-elevation myocardial infarction (STEMI) where primary percutaneous coronary intervention (PCI) is unfeasible. Guidelines recommend PCI within 2 to 24 hours post-fibrinolysis. However, meta-analysis suggests that a shorter interval (&lt;4h) between fibrinolysis and PCI (lysis-PCI time) significantly reduces the 30-day risk of death and reinfarction. Real-world applicability is limited due to trial exclusions of elderly patients and those with chronic kidney disease. This study aims to evaluate the impact of lysis-PCI timing on in-hospital mortality and major adverse cardiovascular events (MACE). Hypothesis: We hypothesize that shorter lysis-PCI times (&lt;9h) increase in-hospital mortality and MACE, especially in patients over 80 years. Goals: To determine the impact of lysis-PCI timing on in-hospital mortality and MACE in STEMI patients. Methods: This retrospective cohort study of 1,043 STEMI patients in Brasília, Brazil, used multivariable categorical logistic regression models to assess the association of three lysis-PCI intervals (&lt;9h; 9-18h; &gt;18h) with in-hospital mortality and 4p-MACE (death, acute myocardial infarction, stroke, heart failure). Propensity score matching (1:1) was used to adjust for cardiovascular risk factors. Statistical significance was set at p&lt;0.05. Results: The lysis-PCI timing groups showed no significant differences in admission Killip class, GRACE score, or age. However, the &lt;9h group had higher incidences of in-hospital mortality (p=0.004), heart failure (p=0.002), cardiogenic shock (p=0.001), cardiac arrest within 24 hours (p=0.003), minor bleeding (p=0.006), and MACE (p=0.002). Multivariable categorical logistic regression revealed that each 4-h delay in lysis-PCI time reduced the risk of death (HR 0.560, 95% CI 0.381-0.771; p=0.001) and MACE (HR 0.877, 95% CI 0.811-0.948; p=0.001). These findings remained consistent after propensity score analysis (death: HR 0.721, 95% CI 0.516-0.956; p=0.034). Among patients older than 80, shorter lysis-PCI times were associated with increased mortality and MACE, even after propensity adjustment (Figure 1). Conclusion(s): Shorter lysis-PCI times (&lt;9h) are associated with higher in-hospital mortality and MACE across all age groups, with a pronounced effect in patients over 80 years. These findings underscore the need for careful consideration of lysis-PCI timing, especially in elderly populations.
Abstract 4137620: Serum Acylcarnitines Predict Longitudinal Deteriorations in Cardiac Function and Adverse Outcomes in Older Adults
Authors: JIE JUN WONG, Fei Gao, Glades Tan, Johnathan Loh, Loon Yee Teo, See Hooi Ewe, Hai Ning Wee, Kee Voon Chua, Jianhong Ching, Ru Tan, Jean Paul Kovalik, Angela Koh
Journal: Circulation (2024)

Background: Circulating acylcarnitines (ACs), biomarkers of mitochondrial β-oxidative function, are linked to cardiovascular diseases (CVD) yet the extent to which ACs relate to prospective cardiac aging remains uncertain. We investigate the longitudinal associations between ACs, cardiac function, and clinical outcomes. Methods: A population-based sample of community older adults without CVD underwent baseline serum metabolomic profiling and interval echocardiography at five years. Incident hospitalizations were prospectively tracked from 2014 to 2021. Multiple linear regression adjusted for significant clinical variables. Results: Of 202 participants (baseline 65±11.9 years, 49.3% women), we observed interval increases in risk factors (hypertension 39% vs 52.2% p&lt;0.001; dyslipidemia 39% vs 50% p=0.034; diabetes 11.7% vs 18.8% p=0.035; smoking 13.2% vs 24.7% p=0.003; waist circumference 81±10.1 vs 86±9.9cm p&lt;0.001) during follow-up (4.9±0.4 years). These changes paralleled E/e’ increases (8.9±2.6 vs 11.1±3.3 p&lt;0.001) and E/A decreases (1.09±0.4 vs 1.0±0.4 p&lt;0.001). Baseline C8:1 (β=0.182 p=0.011), C22:3 (β=0.148 p=0.047), C22:5 (β=0.210 p=0.003), C5:1 (β=-0.142 p=0.048), and C16-OH (β=-0.156 p=0.028) levels were associated with E/e’ change over time while C6 (β=0.163 adj. p=0.019), C8:1 (β=0.137 adj. p=0.047), C10:2 (β=0.153 adj. p=0.035), C14:3 (β=0.147 adj. p=0.031), and C16:1-OH/C14:1-DC (β=0.158 adj. p=0.022) were associated with E/A change. At follow-up, baseline C8:1 (β=0.178 adj. p=0.006) and C10:3 (β=0.145 adj. p=0.024) were associated with E/e’ while C4-DC/C6-OH (β=-0.004 adj. p=0.034) was associated with E/A. Baseline C22:2 predicted incident hospitalizations (HR=1.20 95%CI 1.03-1.39, adj. p=0.018). Conclusion: Circulating ACs independently predicted declining cardiac function and adverse outcomes over five years among older adults without CVD. The prognostic effect of ACs should be translated to strategies targeting mitochondrial health in cardiac aging prevention.
Abstract 4137534: Troponin Can Predict Late Gadolinium Enhancement on Cardiac MRI in COVID-19 Vaccine-Associated Myocarditis
Authors: Supriya Jain, Steven Anderson, Jeremy Steele, Hunter Wilson, Juan Carlos Muniz, Jonathan Soslow, Rebecca Beroukhim, Victoria Maksymiuk, Xander Jacquemyn, Adam Dorfman, Brian Fonseca, Sujatha Buddhe, Ravi Ashwath, Deepika Thacker, Shiraz Maskatia, Nilanjana Misra, Jennifer Su, Saira Siddiqui, Danish Vaiyani, Aswathy Vaikom House, Michael Campbell, Jared Klein, Sihong Huang, Christopher Mathis, Matthew Cornicelli, Madhu Sharma, Lakshmi Nagaraju, santosh uppu, Preeti Ramachandran, Jyoti Patel, Frank Han, Puneet Bhatla, Michael DiLorenzo, Parham Eshtehardi, Elizabeth Drugge, Lars Grosse-Wortmann
Journal: Circulation (2024)

Background/Aim: We previously reported that late gadolinium enhancement (LGE) on cardiac MRI (CMR) was as high as 82% in pediatric patients with COVID-19 vaccine-associated myocarditis (C-VAM) despite mild clinical symptoms and normal left ventricular function. As LGE can be a harbinger for future adverse events including arrhythmias, heart failure or sudden cardiac death, we sought to identify predictors for LGE in C-VAM, specifically assessing troponin as a screening marker for C-VAM patients at risk for myocardial scarring who could then be referred for a confirmatory CMR with LGE. Methods: In this longitudinal multicenter retrospective observational study across 38 U.S. member institutions of the M yocarditis A fter C OVID V accination (MACiV) study network, 333 patients with C-VAM based on CDC criteria were included from April 2021 to November 2022. Data collected included demographics, laboratory values, clinical and cardiac imaging characteristics and outcomes. Using logistic regression, troponin levels at presentation were assessed as a log transformed continuous variable and categorized into tertiles. Results: The C-VAM patients were predominantly white (67%) adolescent males (91%, 15.7± 2.8 years). There were 216/333 (65%) patients who had both a reported troponin value and had a CMR. On univariate analysis, elevated troponin increased the probability of having LGE (OR=1.29, 95% CI: 1.06, 1.58, p=0.012). Even after controlling for age, race, sex, number of vaccine doses and left ventricular ejection fraction (OR=1.32, 95% CI: 1.06, 1.65, p=0.013). Patients &gt;15 years compared to those ≤15 years of age were 2.94 (95% CI: 1.28, 6.75, p=0.011) times more likely to have LGE at presentation. Patients with troponin levels in the highest tertile compared to lowest tertile were 2.66 times (95% CI: 1.04, 6.83, p=0.042) more likely to have LGE along with a greater involvement &gt; 4 AHA myocardial segments with LGE (p=0.004) Conclusions: Higher troponin values are associated with presence of late gadolinium enhancement on cardiac MRI in patients with COVID-19 vaccine-associated myocarditis. Troponin levels at presentation may facilitate risk stratification and function as a screening tool to identify those C-VAM patients with the greatest likelihood of myocardial scarring, who may benefit from undergoing CMR for tissue characterization.
Abstract 4137665: Getting to the Heart of Stroke <sup>TM</sup> : A Novel American Heart Association Initiative Which Increases Identification of Stroke Etiology and Evidence-Based Post-Stroke Evaluation by Strengthening Cardiology and Neurology Collaboration
Authors: Edward Jauch, Ali Baird, John Witt, Alison Bailey, Dhanunjaya Lakkireddy, Alexander Schneider, Lindsay Stergar, Kevin Orndorff, Russell Harper, Kathie Thomas, Chandler Beon, Steven Manoukian
Journal: Circulation (2024)

Background: Nearly one million individuals in the U.S. experience ischemic stroke annually and one-year recurrent stroke risk may exceed 10%. American Heart Association (AHA) Get-With-The-Guidelines-Stroke® Registry (GWTG-S) data suggests that up to 40% of stroke patients are discharged with an undocumented or cryptogenic etiology which may lead to suboptimal secondary prevention. Consequently, improved cardiology and neurology collaboration and evidence-based post-stroke evaluation may help identify stroke etiology, reduce recurrent stroke risk and improve outcomes. Methods: In 2022, the AHA, in collaboration with HCA Healthcare and HCA Healthcare Foundation, designed and launched Getting to the Heart Of Stroke TM (GTTHOS) in 10 HCA Healthcare comprehensive stroke centers to improve: 1) cardiology and neurology stroke care collaboration, 2) evidence-based post-stroke diagnostic evaluation and 3) assessment of social determinants of health and barriers to care. Components included a learning collaborative model, virtual performance improvement consultations, Plan-Do-Study-Acts, multidisciplinary teams, custom and existing GWTG-S metrics and performance improvement feedback. Results: Using existing and custom GWTG-S data, GTTHOS centers increased rates of documented stroke etiology (58.06% vs. 48.63%), while decreasing cryptogenic stroke rates (31.01% vs. 34.89%) and lack of a documented stroke etiology (10.93% vs. 16.48%) (all comparisons on discharge, follow-up vs. baseline, p&lt;0.0001). In addition, the use of evidence-based post-stroke diagnostic evaluation increased in GTTHOS centers, including intracranial vascular and carotid imaging, echocardiography, short-term and extended (surface, implantable) cardiac monitoring (Table). Conclusion: In this novel AHA GTTHOS initiative in patients with stroke, which includes improved cardiology and neurology collaboration, rates of identified stroke etiology increased, while cryptogenic stroke and lack of a documented stroke etiology decreased. Furthermore, evidence-based post-stroke diagnostic evaluation, including imaging, echocardiography and short- and long-term surface and implantable cardiac monitoring, increased. These findings may contribute to improved outcomes.
Abstract 4137543: Prevalence, Genetic Correlates and Prognostic Significance of an Apical Pseudo-Infarct Late Gadolinium Enhancement Pattern in <i>LMNA</i> -Mediated Cardiac Laminopathy
Authors: Matteo Castrichini, Ramin Garmany, Konstantinos Siontis, Michael Ackerman, John Giudicessi
Journal: Circulation (2024)

Background: Disease-causative variants in LMNA -encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular (AV) block, atrial fibrillation (AF) and ventricular arrhythmias (VA). Whether domain/variant-specific late gadolinium enhancement (LGE) patterns exist and carry prognostic significance is unclear. Objective: To determine if specific LGE patterns correlate with LMNA variant type/missense variant localization and clinical outcomes in a large cohort of cardiac laminopathy patients. Methods: Retrospectively, 621 genotype-positive arrhythmogenic/dilated cardiomyopathy patients were analyzed to identify those with a disease-causative variant in LMNA -encoded lamin A/C. After exclusion of patients without cardiac magnetic resonance data, pertinent demographic/clinical data was extracted from the electronic medical record. LGE distribution (subepicardial, midmyocardial, subendocardial, transmural) and location (septal, free wall, apical) patterns were analyzed by variant type (missense vs truncating) and missense variant localization (central rod domain vs tail domain) and correlated with advanced heart failure (AHF), MVA, AV block, AF and thromboembolic (TE) events. Results: 70 out of 116 (60%) LMNA variant-positive (mean age 39±12, 43% male and 94% Caucasian) were included. Missense variants localizing to the C-terminal tail region showed a higher prevalence of transmural and apical LGE (Table). Amongst the 5 (7%) patients with this distinct apical pseudo-infarct LGE pattern, p.Arg471His-LMNA was identified in all cases. Among the 48/70 (69%) of patients with clinically manifest disease, p.Arg471His-LMNA-positive patients (n=6) were noted to have an increased prevalence of TE events [3 (50%) vs 5 (12%), 0=0.050] despite a reduced prevalence of AF [2 (33%) vs 32 (76%), p= 0.031]. No difference in AHF or MVA were observed, but AV block was less prevalent [1 (20%) vs 29 (74%), p= 0.029]. Conclusion: p.Arg471His-LMNA causes a distinct apical pseudo-infarct LGE pattern associated with an increased risk of TE events and a decreased prevalence of AV block and AF. Future studies are needed to better refine the role of domain/variant-specific risk-stratification/anticoagulation in cardiac laminopathy.
Abstract 4137713: Epsin-Mediated PCSK9-LDLR Interaction: A New Therapeutic Target for Atherosclerosis
Authors: Krishan Gupta, Bo Zhu, Kaifu Chen, Hong Chen
Journal: Circulation (2024)

Introduction: Atherosclerosis, a leading cause of cardiovascular diseases, causes about 17.9 million deaths annually. It is driven by high levels of LDL cholesterol (LDL-C). The liver's LDL receptor (LDLR) removes LDL-C from the bloodstream, but its degradation by PCSK9 exacerbates the condition. Epsin, an endocytic adaptor protein crucial for clathrin-mediated endocytosis, plays a significant role in atherosclerosis, particularly lipid metabolism. Hypothesis: We propose that hepatic epsins significantly contribute to atherosclerosis by facilitating the PCSK9-induced degradation of LDLR, thus impeding LDL-C clearance. Objectives: This study aims to investigate hepatic epsins' role in PCSK9-mediated LDLR degradation and its effects on LDL-C levels and atherosclerosis development. Using bioinformatics, we will analyze enriched pathways and networks to study epsins modulation, which will be validated through biochemical assays and in vivo experiments. Methods: Liver-specific double knockout (DKO) mice lacking epsin1 and epsin2 were created on an ApoE -/- background. Atherosclerosis was induced using a Western diet (WD), and blood cholesterol and triglyceride levels were monitored. We employed high-resolution single-cell RNA sequencing (scRNA-seq) to analyze cellular transitions, intercellular interactions, and Gene Ontology pathway enrichment within hepatocyte-derived data. Results: RNA velocity reveals the transition from lipogenic Alb hi Hepatocytes to glucogenic Hnf4a hi Hepatocytes in Liver-DKO mice on an ApoE -/- background on a WD. Liver-DKO mice on an ApoE -/- background on a WD exhibited significantly reduced atherogenesis and lower blood cholesterol and triglyceride levels compared with wild-type on an ApoE -/- background on a WD. Gene Ontology enrichment analysis showed elevated pathways for LDL particle clearance and enhanced LDLR-cholesterol communication scores in Liver-DKO mice, suggesting improved LDL-C clearance. Nanoparticle-encapsulated siRNAs targeting liver epsins effectively inhibited atherosclerosis. Conclusion: Epsin depletion in the liver upregulated LDLR protein levels, and PCSK9-triggered LDLR degradation was abolished, preventing atheroma progression. Targeting liver epsins presents a novel therapeutic strategy for atherosclerosis, supported by network analysis and predictive modeling for effective interventions.