tbuckley/cabot-search huggingface dataset:
Abstract 4139315: From Mutation to Dysfunction: The Effect of Na <sub>V</sub> 1.5 Selectivity Filter in Arrhythmia Pathogenesis
Authors: Zoja Selimi, Mikhail Tarasov, Xiaolei Meng, Patricia Dias, Bianca Moise, Rengasayee Veeraraghavan, Przemyslaw Radwanski
Journal: Circulation (2024)

Background: Mutations in the SCN5A gene, encoding the cardiac voltage-gates sodium channels (Na v 1.5) are associated with life threatening arrhythmias. Recently a missense mutation in the selectivity filter, SCN5A-K1419E, has been identified in patients with Brugada syndrome and has also been linked to long QT. Prior studies demonstrated that SCN5A-K1419E substitution alters ion selectivity of Na V 1.5, conferring Ca 2+ permeability, and thereby lowering overall conductance. However, the arrhythmogenic mechanism of selectivity filter mutations have not been established. Methods and results: To address this, we generated heterozygous Scn5a-K1421E mice (homolog of human SCN5A-K1419E). Cardiomyocytes from these mice exhibited reduced peak Na + current (I Na ) density with a reversal potential consistent with altered permeability to other ions relative to wild type (WT). Importantly, Na V 1.5 expression in Scn5a-K1421E hearts was unchanged compared to WT as revealed by confocal immunolabeling studies. Consistent with reduced I Na density in Scn5a-K1421E, conduction velocity (CV) slowing was observed in optical mapping experiments. Notably, flecainide (1µM) challenge profoundly slowed CV in Scn5a-K1421E relative to WT hearts, resulting in ventricular tachyarrhythmias (VT) in vivo . Intriguingly, despite reduction in peak I Na, Scn5a-K1421E cardiomyocytes exhibited enhanced late Na + influx relative to WT, which translated to prolonged QT interval in vivo . Conclusion: Overall, Scn5a-K1421E mice exhibit an overlap phenotype consistent with Brugada and long QT type 3 syndromes revealing complex effects of K1421E on Na V 1.5 function.
Abstract 4139371: Treatment of pulmonary arterial hypertension by blocking integrin a5b1, a potential disease-modifying strategy
Authors: Monica Montesinos, Sarah-Eve Lemay, Parmita Kapoor, Hailey Rapisardi, Minh Hai Nguyen, Haejin Kim, Muzaffar Akram, Dhawal Jain, Elizabeth Konopka, Terence I. Moy, Inese Smukste, T. Andrew McTeague, James Dowling, Sujan Lama, Jessica Pondish, Qi Qiao, Meghan Monroy Monroy, Albert Lin, Hua Wang, Olivier Boucherat, Melanie Sauvaget, Francois Potus, Sandra Breuils Bonnet, Charlie Theberge, Steeve Provencher, Adrian Ray, Blaise Lippa, Sebastien Bonnet, Bryan Goodwin, Min Lu
Journal: Circulation (2024)

Introduction: Pulmonary arterial hypertension (PAH) is marked by pathological remodeling of distal arteries, driven by hyperplasia of pulmonary arterial smooth muscle cells (PASMCs), dysfunction of pulmonary arterial endothelial cells (PAECs), and increased deposition of the extracellular matrix (ECM). Hypothesis: Considering the crucial role of ECM in vascular restructuring, we investigated the potential of therapeutically targeting a5b1, a fibronectin-binding integrin involved in cell proliferation and angiogenesis, for PAH treatment. Aim: To evaluate the therapeutic potential of targeting a5b1 for the treatment of PAH. Methods: We have developed potent, orally bioavailable small molecule inhibitors (SMis) and monoclonal antibodies (mAbs) targeting a5b1 to evaluate its therapeutic potential. The effect of a5b1 inhibition was assessed in cultured PASMCs, human precision-cut lung slices (PCLS), and a rat Sugen/hypoxia PAH model. Results: PAH patients exhibited increased expression of fibronectin and a5b1 in distal pulmonary arteries. Selective inhibition of a5b1 in cultured PASMCs modulated multiple pathways involved in cell cycle regulation at both transcriptional and post-transcriptional levels, thereby blocking cellular proliferation. PCLS treated with a5b1 inhibitors showed decreased expression of pathways involved in ECM deposition and reduced levels of smooth muscle cell markers. In the rat Sugen/hypoxia PAH model, a5b1 inhibition with either an SMi or mAb significantly improved cardiac and vascular function by reducing pulmonary arterial wall thickness, right ventricular hypertrophy, and fibrosis. Cardiac improvement is further evidenced by a reduction in circulating NT-proBNP and NT-proANP levels. Conclusion: These findings reveal a previously underappreciated role for a5b1 in PAH pathogenesis and support the potential of a5b1 inhibition as a disease-modifying therapeutic strategy for managing PAH.
Abstract 4138985: Prescription Pattern, Medication Burden, and Transplant-Free Survival in the Adult Fontan Population
Authors: Andrew Freddo, Molly Eron, Antara Mondal, Alexis Zavez, Srinivas Denduluri, Sara Partington, Emily Ruckdeschel, Allison Tsao, Juan Ortega-Legaspi, Yuli Kim, Sumeet Vaikunth
Journal: Circulation (2024)

Introduction: There are limited data on the medications taken by patients with Fontan circulation in adult congenital heart disease (ACHD) clinics. Research Questions/Hypothesis: We aim to describe the type and frequency of medications prescribed to adults with Fontan circulation and hypothesize that patients with higher medication burden have worse outcomes. Methods: We conducted a retrospective cohort study of adults with Fontan circulation followed in an outpatient ACHD clinic between 2009 and 2023. Demographics, clinical variables, and all prescribed outpatient cardiac medications were abstracted. The outcome of interest was transplant-free survival. Survival analysis was performed to evaluate the impact of medication type and burden on survival. Results: There were 429 patients (55.2% male, 72.5% White, 49.7% systemic left ventricle) with median age 29 years (IQR 25-35) at last visit. The commonly prescribed medication classes were antiplatelet agents (74.6%) followed by angiotensin converting enzyme inhibitors or angiotensin receptor blockers (59.0%), beta blockers (44.8%), anticoagulants (44.0%), loop diuretics (39.6%), mineralocorticoid receptor antagonists (MRA) (31.5%), antiarrhythmics (19.6%), and pulmonary vasodilators (16.1%). There were a smaller number of patients prescribed sacubitril-valsartan (0.9%) and sodium glucose cotransporter 2 inhibitors (1.9%). Being prescribed loop diuretics, antiarrhythmics, pulmonary vasodilators, or MRA was associated with decreased transplant-free survival (Table). There is a stepwise decrease in transplant-free survival with increasing number of cardiac medication classes prescribed (Figure). Conclusions: We report one of the first large-scale studies of prescription patterns in adult patients with Fontan circulation in a single ACHD clinic. We demonstrate an association between increasing number of medications with transplant-free survival.
Abstract 4138152: Impact Of Peripheral Arterial Disease On Outcomes In Patients With Acute Coronary Syndrome: A Meta-Analysis And Systemic Review
Authors: Nouman Shafique, Usman Akbar, Ahmed Muaaz Umer, Aman Ullah, Ali Haider, Fnu Muhibullah, Adeena Shafique, Ali Raza Khan, RANA MUHAMMAD TAHIR, Muhammad Haris Latif, Hassan Nawaz, Iqra Shafiq, Atta Ur Rehman, Zaigham ul Islam, Johar Abbas, Waqas Shahnawaz, Muhammad Omar Akram, Razan Elsayed, Munis Raza, Bilal Munir
Journal: Circulation (2024)

Background: Peripheral artery disease (PAD) is associated with worse outcomes in patients with underlying coronary artery disease (CAD). While the impact of PAD in stable CAD is well-studied, data on the impact of concomitant PAD in acute coronary syndrome (ACS) patients are limited. Our meta-analysis assesses cardiovascular and clinical outcomes in ACS patients with PAD compared to those without PAD. Methods: We conducted an extensive search using PubMed, EMBASE, and Cochrane Library for studies published prior to June 1, 2024, evaluating clinical and CV outcomes in patients diagnosed with PAD and concomitant ACS. Data were extracted and analyzed using R (v.4.3). Pooled proportions with 95% confidence intervals (95% CIs) were calculated using a random effects model. Odds ratios (ORs) with 95% confidence intervals were used as effect measures for dichotomous variables. Our outcomes of interest were all-cause mortality, major adverse cardiovascular events (MACE), recurrent CV events, and major bleeding. Results: We identified four studies, including 3,860,564 patients. Our inclusion criteria were adults (≥18 years) recently hospitalized or discharged with ACS (unstable angina, non-ST-elevation myocardial infarction, and ST-elevation myocardial infarction). PAD was defined as intermittent claudication and/or previous revascularization. The PAD group exhibited significantly higher likelihood of adverse outcomes compared to the non-PAD group. Specifically, the odds of mortality were significantly higher in the PAD group (OR: 2.79 [1.41, 5.53]; I2=99%; p=0.003), however there was substantial heterogeneity among the studies. The odds of MACE were also higher in the PAD group (OR: 2.12 [1.51, 2.96]; I2=71%; p&lt;0.0001), as were the odds of recurrent CV events in the PAD group (OR: 1.72 [1.52, 1.94]; I2=0%; p&lt;0.00001). Additionally, the PAD group had significantly increased odds of major bleeding events (OR: 2.48 [1.85, 3.33]; I2=0%; p&lt;0.00001). Conclusion: Our meta-analysis demonstrates that PAD significantly worsens cardiovascular and clinical outcomes in ACS patients, highlighting the need for identification and targeted management strategies in this high-risk population. Future research should focus on optimizing interventions to improve prognosis for ACS patients with PAD.
Abstract 4139360: Assessing the Impact of a Healthy Foods Center Program Has on Food Insecurity and Healthcare Outcomes: A Pilot Study
Authors: Charlotte Drury-Gworek, Kathleen Galper, Tyson Barrett, Amber Shergill, Elizabeth Cuevas, Colleen Ereditario
Journal: Circulation (2024)

Rationale: Food insecurity impacts millions of households in the United States and can be a strong predictor of poor mental and physical health, as well as avoidable chronic health conditions. Patients with food insecurity tend to have increased healthcare utilization and costs when compared to those without. To help alleviate this need, several healthy foods centers (HFCs) were established within a local hospital network to provide immediate food access to patients screening positive for food insecurity, as well as health-focused education on nutrition (e.g., impacts on HbA1C and cholesterol), budgeting, and meal preparation. We sought to conduct a preliminary examination to understand if the services provided by the HFCs were associated with improved healthcare utilization and costs, with an emphasis on utilization pertaining to cardiometabolic illness. Methods: We conducted a pilot retrospective review of the electronic medical records and claims data, for adult patients who were referred to HFCs between 2019 and 2023. Patients in the intervention (visited an HFC at least once) and control (referred but did not visit any HFC) groups needed at least 8 months of continuous enrollment (6 months baseline and ≥2 months following their first HFC visit or referral date) to assess outcomes. Difference-in-differences regression models were used to identify any changes in emergency department (ED) visits, total costs of care, and cardiometabolic disease-specific savings after controlling for baseline differences between groups. Results: Most patients were female (68%), white (65%), and single (39%), with an average age of 55 years. The intervention group averaged 4.8 visits to the HFC. The intervention group relative to the control group from baseline to follow-up saw average benefits of $579 in unadjusted ED costs and $2040 in unadjusted total costs. Effect sizes trended towards savings, though not initially statistically significant following covariate adjustment. Savings within the sample varied by overall medical complexity, with the highest benefits seen among those managing multiple chronic illnesses; savings were also higher when evaluating disease-specific spend. Conclusions: Results of this pilot study for patients referred and seen in the HFC compared to the patients referred and not seen, suggest improvements in ED and total costs may be present with healthy food center interventions, with the greatest benefit among the sickest of the population.
Abstract 4139237: Medical Therapy and Outcomes in Patients with Critical Limb Threatening Ischemia Randomized to an Everolimus Eluting Resorbable Scaffold or Angioplasty in the LIFE-BTK Randomized Trial
Authors: Marc Bonaca, Brian DeRubertis, Ramon Varcoe, Sahil Parikh
Journal: Circulation (2024)

Introduction: Patients with critical limb-threatening ischemia (CLTI) are at high risk of CV and limb outcomes yet established medical therapies are underutilized. The LIFE-BTK trial demonstrated that a drug-eluting resorbable scaffold (DRS) was superior to angioplasty (ANG) for limb outcomes. The background use of optimal medical therapy (OMT) and the effect of DRS vs. ANG based on OMT at baseline has not been described. Methods: Patients were randomized 2:1 to DRS vs. ANG, respectively. Sites reported baseline medications. OMT was defined as use of at least one antithrombotic and LDL-C lowering agent. The primary outcome was a composite of amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. A key secondary outcome was major amputation, target vessel re-occlusion, or clinically driven target lesion revascularization. Data are presented as event rates and relative risk (RR). Results: A total of 261 patients were randomized with follow up through 1 year. DRS was superior to ANG for the primary outcome (p&lt;0.001). Approximately 80% of patients received OMT at baseline with use similar between groups (Panel A). Increased adherence was associated with a history of hyperlipidemia and a history of coronary artery disease (CAD). In the ANG arm, use of OMT was associated with lower risk of the primary efficacy outcome (Panel B) and key secondary efficacy outcome (Panel C). Use of DRS was superior to ANG overall with consistent effects in those receiving OMT (RR 0.52, 95% CI 0.36 – 0.75) and those not receiving OMT (RR 0.21, 95% CI 0.08 – 0.58; Panel D). Conclusions: In a contemporary cohort of patients enrolled in a trial of endovascular therapy for CLTI, the use of OMT was ~80%. Use of OMT was higher in those with risk factors and known CAD. The risk of adverse limb outcomes in the ANG group were lower with OMT than without OMT. The benefit of DRS vs. ANG was consistent regardless of OMT. Efforts to improve use of OMT in PAD are needed and a combined “pharmaco-invasive” approach to CLTI using optimal devices and OMT may improve outcomes.
Abstract 4138211: A Machine Learning-Based Novel Risk Score Model for Takotsubo Cardiomyopathy
Authors: Ankit Agrawal, umesh bhagat, Elio Haroun, Aro Daniela Arockiam, Muhammad Majid, Tom Kai Ming Wang
Journal: Circulation (2024)

Background: Takotsubo cardiomyopathy (TC) is defined by acute but typically reversible left ventricular systolic dysfunction, typically precipitated by profound emotional or physical stress. Due to the scarcity of a prognostic scoring system for TC, we aimed to develop a novel machine learning-based risk score model to predict in-hospital mortality in TC patients. Methods: The National Inpatient Sample (NIS) 2016-2020 database was used to identify all adult patients (≥18 years of age) with TC, using ICD-10 code I51.81. Relevant clinical characteristics and outcomes were extracted. The primary endpoint was in-hospital all-cause mortality. The dataset was randomly split into 3 subsets: training, validation, and testing, with a ratio of 0.7, 0.2, and 0.1, respectively. The risk score was generated using the Autoscore package in R software, a machine learning-based tool for automatic clinical score generation. The performance was evaluated using the area under the receiver-operative characteristics curve (AUC) with 95% confidence intervals (95%CI). Results: Among the 38,662 TC patients identified [age 67.1±14.1 years, female 32,089 (83%)], there were 2499 (6.4%) primary outcome events. Out of the top 20 covariates seen in the Parsimony plot, we used eight for our risk score (0–127): age, comorbidity burden, cardiac arrest, cardiogenic shock, race, acute kidney injury, hypertension, and cardiac arrhythmia (Figure 1A). The AUC for the derivation and validation cohorts was 0.809 (0.780–0.837) and 0.838 (0.820–0.856), respectively (Figures 1B and 1C). Conclusion: We developed and internally validated a machine learning based-risk score model to predict outcomes in TC patients, achieving a high AUC of 0.838 (0.820-0.856). Risk score models guide risk stratification and management, and large future studies are needed to externally evaluate our results.
Abstract 4138819: KLF2-dependent transcriptional regulation safeguards the heart against pathological hypertrophy
Authors: Juan Huang, Yongqi Wu, Yujuan Song, Nan Xie, Wanqing Zhao, Hui Xiong, Li Wang
Journal: Circulation (2024)

BACKGROUND: Our previous single-cell RNA sequencing study in the adult human heart revealed that cardiomyocytes from both the atrium and ventricle display high activities of Krüppel-like factor 2 (KLF2) regulons. However, the role of the transcription factor KLF2 in cardiomyocyte biology remains largely unexplored. METHODS AND RESULTS: We employed transverse aortic constriction surgery in male C57BL/6J mice to develop an in vivo model of cardiac hypertrophy, and generated different in vitro cardiac hypertrophy models in neonatal rat ventricular myocytes and human embryonic stem cell-derived cardiomyocytes. Our results demonstrated a significant reduction in KLF2 expression during the progression of cardiac hypertrophy. In vitro, KLF2 deficiency exacerbates cardiac hypertrophy and enhances hypertrophic reprogramming, while KLF2 overexpression attenuates cardiac hypertrophy and reverses hypertrophic transcriptome reprogramming. Mechanistically, comprehensive RNA sequencing analysis revealed that KLF2 exerts its protective effects by activating the Hippo signaling pathway and inhibiting the MAPK signaling pathway. In vivo, overexpression of KLF2 specifically in cardiomyocytes effectively prevents TAC-induced cardiac hypertrophy in mice. Furthermore, we found that simvastatin elevates KLF2 expression in cardiomyocytes, which in turn mitigates cardiomyocyte hypertrophy. CONCLUSIONS: This study provides the first evidence that transcription factor KLF2 serves as a negative regulator of cardiac hypertrophy. Our findings highlight the therapeutic potential of enhancing KLF2 expression, particularly through simvastatin administration, as a promising strategy in the treatment of cardiac hypertrophy.
Abstract 4139238: A Multi-Population-First Approach Leveraging UK Biobank (UKBB) and All of Us (AoU) Datasets Reveals Higher Cardiomyopathy Variant Burden in Individuals with Myocarditis
Authors: Manasa Gurumoorthi, Kerrick Hesse, Babken Asatryan, Ravi Shah, Ghaith Sharaf Dabbagh, Rachel Wolfe, Vijay Shyam Sundar, Saidi Mohiddin, Nay Aung, Mohammed Khanji, Patricia Munroe, Steffen Petersen, Andrew Landstrom, Anwar Chahal
Journal: Circulation (2024)

Intro: Myocarditis is an inflammatory cardiac condition that may progress to dilated (DCM) or arrhythmic (ACM) cardiomyopathy. Prior cohort studies indicate genetic factors significantly influence myocarditis susceptibility and outcomes; yet, this has not been studied at a population level, which holds potential for clinical risk prediction. Objective: To investigate DCM and ACM gene variant burden and clinical consequences by a multi-population approach encompassing diverse genetic ancestries. Methods: Individuals with exome sequencing (ES) in UKBB and AoU were included, and poor-quality samples excluded. Individuals with myocarditis were identified by ICD code and compared with myocarditis-neg population. Cardiomyopathy (CM) genes in ClinGen DCM- and ARVC-associated genes with at least moderate evidence of disease causality were included and filtered by our previously published variant pipeline and ClinVar 2* criteria for pathogenic/likely pathogenic (P/LP). Cardiac phenotype and CM variant burden were analyzed by chi-squared analysis. Results: 200,580 individuals in UKBB and 230,013 in AoU had ES. 137 in UKBB and 284 in AoU had myocarditis. Myocarditis cohorts in both populations had increased phenotypic burden of CM, ventricular arrhythmia, and HF vs myocarditis-neg. Myocarditis-pos showed increased CM (16.8% vs 0.2%); VA (10.9% vs 0.9%) and HF (32.8% vs 3.1%) in UKBB (p&lt;0.001). Similarly in AoU, 44.5% of myocarditis-pos had CM (vs 2.8%); 22.3% had VA (vs 1.6%), and 55.8% had HF (vs 5.8%) when compared to myocarditis-neg. UKBB had increased DCM and ACM variant burden in myocarditis-pos cohort: 9.5% (5) with DCM ClinVar 2* P/LP and 3.6% (5) with ACM ClinVar 2* P/LP compared to 0.3% (561) and 0.3% (578) in myocarditis-neg (p&lt;0.001). Increased burden of DCM P/LPs by our peer-reviewed pipeline was noted in AoU myocarditis-pos (9.8%, 28) compared to AoU myocarditis-neg (6.2%, p=0.02). ACM variants were not significantly overrepresented in myocarditis cohort in AoU (p=0.4) but was underpowered to note significance by ClinVar2* P/LP. Conclusions: This study highlights a substantial burden of DCM and ACM variants in individuals with myocarditis, particularly in UKBB. The differential significance in AoU may represent diverse genetic ancestries and differences in recruitment methods. Future analyses include determining variant burden by outcome and genetic-ancestry based variant analysis to elucidate genetic risk myocarditis susceptibility and disease progression.
Abstract 4139307: Machine Learning Identifies Predictors of Poor Outcomes in Patients with Heart Failure Presenting to the Emergency Department for Chest Pain
Authors: Karina Kraevsky-Phillips, Rui Qi Ji, Sarumathi Thangavel, Salah Al-Zaiti
Journal: Circulation (2024)

Introduction: Heart failure (HF) is associated with unique comorbidities and sequelae, which can affect clinical presentation and patient outcomes. This is specifically challenging when patients are evaluated for suspected acute coronary syndrome (ACS). We sought to compare the most important predictors of poor outcomes in patients with and without HF seen in the emergency department (ED) for ACS. Methods: This was a secondary analysis of a prospective observational cohort study of consecutive patients seen for symptoms suggestive of ACS, such as chest pain (CP) and dyspnea, in the EDs of three UPMC-affiliated tertiary care hospitals (NCT04237688, clinicaltrials.gov). Primary outcome was 30-day major adverse cardiac events (MACE), adjudicated by two independent reviewers. Clinical data were collected form charts and we used KNN to impute missing data for features, most of which had less than 12.5% missingness. For features with greater than 12.5% missingness (i.e., BNP, Mg), binary indicators were added to flag missing values. Data were normalized using the Euclidean norm. Two random forest (RF) classifiers were trained using 10-fold cross validation with 71 manually selected features available early in the ED course (i.e., vital signs, labs, past medical history, ECG), and tested on patients with and without known HF. Model performance was evaluated using AUROC, and top features were identified with SHAP values. Results: The sample included 2400 patients (age 59 ± 16 years; 47% female, 41% Black, 15.9% ACS), of whom 438 had HF (age 66 ± 14 years; 45% female, 49% Black, 15.1% ACS). Individuals with HF were more likely to experience MACE (38% vs 23%, p &lt;.001). The model had higher classification performance in patients without HF (AUC 0.89 vs 0.70). Figure 1 shows top MACE predictors for patients with and without HF. Conclusion: The RF model performed sub-optimally among patients with HF, who were more likely to have poor outcomes moderated by characteristics such as low pulse oximetry, BNP measurement, and anemia, which are related to pathophysiology of HF. Current routine ED assessment tools for CP (i.e., HEART score) do not translate well to patients with HF, which requires more elaborate diagnostic testing.