tbuckley/cabot-search huggingface dataset:
Abstract 18049: Mathematical Modeling Predicts Treatment Efficacy in Transthyretin Cardiac Amyloidosis
Authors: Ashley F Stein-Merlob, Lihua Jin, Alan Garfinkel
Journal: Circulation (2023)

Introduction: Increased recognition of transthyretin cardiac amyloidosis (ATTR-CA) led to the development of treatments with different therapeutic targets. Optimal patient selection, treatment choice, timing and duration remain unclear. We evaluated the efficacy and timing of common and emerging ATTR-CA treatments with a mathematical model based on therapeutic mechanisms. Methods: We developed a system of ordinary differential equations describing transthyretin amyloid (ATTR) deposition and myocardial clearance by clusterin (Figure 1A,B). Published data and equilibrium analyses determined parameters for initial maximal ATTR density. Mechanisms of four therapies were modeled and simulated at varying levels of efficacy. Complete success of the mechanism defines 100% efficacy, i.e. full stabilization of tetramer. Expected clinical efficacy (ECE) is based on studies of clinical doses. Minimum effective clearance (MEC) is the theoretical efficacy required to reduce ATTR fibrils below the threshold for complete clearance. Results: All treatments reduced ATTR fibril density, correlating with efficacy (Fig 1C). At ECE, only NI006 demonstrated complete clearance of ATTR fibrils. With other current treatment strategies, amyloid density will be lowered but never cleared. The secondary mechanism of diflusinil did not change equilibrium behavior compared to tafamidis. MEC values and time to clearance at MEC were lowest for NI006 (14.7%; 65 days) and doxycycline (16.1%; 36 months). Tetramer stabilization required almost complete efficacy (99.3%) and about a decade (119 months) for tetramer clearance. Conclusion: This mathematical model predicts ATTR clearance by four distinct mechanisms of action. The novel anti-ATTR antibody NI006 is a promising treatment with predicted faster onset and higher effectiveness for clearance of ATTR fibrils from the myocardium. This model can evaluate future treatment strategies and therapeutic targets.
Abstract 14448: Graft Loss and Rejection Following COVID in Pediatric Heart Transplantation - A Pediatric Heart Transplant Society (PHTS) Propensity Matched Analysis
Authors: Joseph Spinner, Jennifer Conway, claire bocchini, Ryan S Cantor, Devin Koehl, James K Kirklin, Lydia Wright, Kimberly Molina, Fawwaz Shaw, Chet Villa, Shawn C West
Journal: Circulation (2023)

Introduction: While short-term outcomes following COVID among pediatric heart transplant (HT) recipients have been described, graft outcomes including the risks of subsequent graft loss and rejection following COVID are unknown. Hypothesis: We sought to determine the overall trends of post-HT survival during the COVID pandemic and determine if there was an increased risk for subsequent graft loss and/or rejection following post-HT COVID. Methods: All pediatric recipients of first HT between 1/2003-6/2022 in the Pediatric Heart Transplant Society ( PHTS) database were included. To assess if early post-HT survival changed during the COVID pandemic, 2-year HT survival was compared among those who underwent HT in 2014-2016, 2017-2019, and 2020-2022. To compare the risks of graft loss and rejection (acute cellular and/or antibody-mediated) between those with vs without post-HT COVID, a 1:2 (COVID vs non-COVID) propensity-score matched analysis using multiple pre-HT and post-HT factors (including exact matches for HT year and time post-HT) and Kaplan Meir analysis were performed. Patients with COVID within 3 months post-HT were excluded. Results: The 2-year post-HT survival was similar among patients who underwent HT across the 3 eras (Fig 1A). Among the overall 6634 patients (n = 888 [13%] with post-HT COVID), 861 patients with post-HT COVID and 1716 without post-HT COVID were included in propensity-score matching. There was no difference in the risk of subsequent graft loss (Fig 1B) or rejection (Fig 1C) among those with vs those without post-HT COVID. Conclusions: No differences were observed in early pediatric post-HT survival during the COVID pandemic compared to the immediately prior era. Post-HT COVID did not increase the risks of subsequent graft loss or rejection. Longer-term follow up is necessary to look at other potential post-HT COVID outcomes, such as coronary allograft vasculopathy.
Abstract 18489: Double Edged Sword: SGLT-2 Inhibitors in the Immunosuppressed Heart Failure Patient
Authors: Christina Brown, Jessica Addis, Fazad Mohamed
Journal: Circulation (2023)

Introduction: SGLT-2 inhibitors are often prescribed for patients with heart failure, as a part of Goal Directed Medical Therapy. There is a known risk of genitourinary tract infections with utilizing this medication class. We present a case of a patient on chronic immunosuppression therapy on Dapagliflozin who developed a prostate abscess. Case Description: 70-year-old male with history of cardiac sarcoidosis on prednisone and mycophenolate mofetil, non-ischemic cardiomyopathy, and atrial fibrillation who initially presented with suprapubic pain and urinary urgency for two weeks. Urinalysis was positive for glucose greater than 1,000 and urine culture positive for Klebsiella pneumoniae. CT imaging revealed a prostate abscess measuring 4.5 x 4.4 x 5.7cm. Patient underwent CT guided drainage of the prostate abscess with thick, purulent drainage that cultured positive for Klebsiella pneumonia. He was initially started on an 8-day course of Ceftriaxone but transitioned to Trimethoprim-Sulfamethoxazole for 6-weeks at discharge. He was previously prescribed Empagliflozin for heart failure, however, this was discontinued due to expense and was switched to Dapagliflozin four months prior to presentation. Discussion: SGLT-2 inhibitors are commonly prescribed in heart failure patients. We encourage special consideration in patients at increased risk of infection, prior to starting SGLT-2 inhibitors as they may have more complicated manifestations of side effects. In this case, the patient underwent procedural interventions and required long term antibiotic therapy as a consequence of SGLT-2 inhibitor use. Conclusion: Patients who are chronically immunosuppressed are at increased risk for infections, including genitourinary, compared to the general population. While trying to optimize patient's cardiomyopathy, it is imperative to consider their risk for developing complications when initiating SGLT-2 inhibitors in immunocompromised patients.
Abstract 15255: Auscultation and ECG for Detection of Valvular Pathologies and Ventricular Dysfunction: Can Machine Learning Help?
Authors: Hisaki Makimoto, Takeru Shiraga, Yoshie Imai, Yusuke Itani, Fabian Schölzel, Obaida Rana, Malte Kelm
Journal: Circulation (2023)

Introduction: Simple testing methods such as auscultation and electrocardiogram (ECG) that are widely used may offer easy opportunity for early diagnosis of cardiac pathologies and lead to prompt treatment. Hypothesis: Combination of multiple simple testing using machine learning (ML) will achieve diagnostic efficiency on valvular pathologies and ventricular dysfunction. Methods: Auscultation at three locations (second right sternal border, Erb, apex) and 12-lead electrocardiograms (ECG) were collected in 1052 patients undergoing echocardiography. Independent cases (N=103) were also enrolled for clinical validation. The cardiovascular diseases targeted for detection were severe aortic stenosis (AS), severe mitral regurgitation (MR), and left ventricular dysfunction (LVD) with ejection fraction ≤40%. Best neural networks were obtained by four-fold cross-validation training using heart sounds and ECG (12-lead, limb-lead and precordial-lead). The output from each model was integrated into one diagnostic prediction by stacking technique. The model performance was verified in the clinical validation cohort by area under the receiver-operator-characteristics curve (AUC). Results: The best performance was achieved by stacking auscultation of all three locations and 12-lead ECG for all three pathologies (AUC = 0.931 for AS, 0.801 for MR, and 0.736 for LVD). The contribution analyses demonstrated diverse patterns of diagnostic contributions of the auscultatory locations and ECG types depending on the target diseases. For AS detection, the heart sound played a greater role compared to the limb- and precordial ECG. Auscultatory and electrocardiographic data contributed similarly for MR detection. For LVD detection, the 12-lead ECG contributed largely followed by the heart sound at Erb. Conclusions: Severe AS, severe MR, and left ventricular dysfunction, which are currently only definitively diagnosed by imaging, can be detected with high efficiency by ML models combining auscultation and electrocardiography with synergistic effect. The contribution of each testing data differs depending on the target diseases. Our data suggests that single-modal AI may not necessarily diagnose multiple diseases.
Abstract 14896: Age is a Predictor of In-Hospital Mortality for Left Ventricular Assist Device: Implication in Post-2018 Donor Heart Allocation System
Authors: Akira Yamaguchi
Journal: Circulation (2023)

Background: The introduction of the new heart allocation system in 2018 has significantly changed the landscape of heart transplantation and trends of durable left ventricular assist device (LVAD) utilization. Although the quality of durable LVAD has improved, the impact of age on in-hospital mortality for LVAD implantation remains unknown under the new allocation system. Objective: We aimed to investigate the influence of age on the outcome following the LVAD implantation under the new heart allocation system. Method: We utilized the National Inpatient Sample to investigate patients who underwent LVAD implantation between 2019 and 2020. The primary endpoint was in-hospital mortality following LVAD implantation, stratified by different age groups. We also investigated independent predictors of in-hospital mortality. Result: A total of 7,375 patients underwent LVAD implantation between January 2019 and December 2020. Among these patients, individuals aged 18-49, 50-59, 60-69, and over 70 years old accounted for 26%, 26%, 31%, and 17%, respectively. In-hospital mortality rates in the aforementioned age groups were 7%, 6%, 12%, and 17%, respectively. Notably, the age groups of 60-69 and over 70 compared to age &lt;59 exhibited independent predictors of mortality, with an adjusted odds ratio (aOR) of 1.99 (p=0.02; 95% confidence interval [CI), 1.12-3.57) and 2.88 (p=0.002; 95% CI 1.45-5.71), respectively. Charlson Comorbidity Index (aOR, 1.39; p=0.02; 95% CI, 1.05-1.84) was also associated with increased risks of mortality. Conclusion: Our findings indicate that individuals over 60 years-old or with higher Charlson Comorbidity Index face a higher risk of in-hospital mortality following LVAD implantation.
Abstract 15419: Adiponectin’s Predictive Role in Long-Term Mortality and Major Adverse Cardiovascular Events in Patients With Stable Coronary Artery Disease: A Meta-Analysis of Prospective Studies
Authors: Sahas Reddy Jitta, Priyanka Vatsavayi, Chenna reddy Tera, Shobana Krishnamurthy, Saisree Reddy Adla Jala, Diksha Sanjana Pasnoor, Utheja Dasari, Aisha Farooq, Supriya Maramreddy, kavya jammula, Medha Reddy, Sridevi Tripuraneni, Rupak Desai
Journal: Circulation (2023)

INTRODUCTION: The relentless toll of cardiovascular disease in the United States demands a breakthrough in reliable and cost-effective prognostic markers. Amidst the limited knowledge surrounding the role of adiponectin in stable coronary artery disease (CAD), this study aims to unveil its power in predicting all-cause mortality and major adverse cardiovascular events (MACE) among patients with stable coronary artery disease (CAD). METHODS: We systematically screened PubMed, Scopus, and Google Scholar for articles until May 2023 to identify relevant studies. Random-effects model estimated the pooled odds ratio (OR) with 95% confidence intervals (CI), and I2 statistics assessed heterogeneity. The leave-one-out method was used for sensitivity analysis. RESULTS: Following the screening, five prospective studies involving 3225 patients with a median follow-up duration of 3.8 years were included. In the study population, hypertension, diabetes, hyperlipidemia, and smoking were prevalent risk factors, and common medications included angiotensin-converting enzyme inhibitors, beta-blockers, and statins. The pooled adjusted OR for all-cause mortality was 2.51 (95%CI: 1.36-4.62), with moderate heterogeneity (I2=65.51%, p=0.03), and the pooled adjusted OR for MACE was 1.04 (95%CI: 1.02-1.06), with no significant heterogeneity (I2=0%, p=0.68) (Fig. 1) . The leave-one-out sensitivity analysis showed that no single study significantly influenced the meta-analysis results, indicating robustness. CONCLUSION: Higher adiponectin levels were associated with higher odds of long-term mortality and MACE in stable CAD patients, highlighting its potential as a cost-effective marker for risk stratification and guiding management strategies. Further studies exploring the role of adiponectin can significantly impact clinical decision-making and resource allocation in cardiovascular care.
Abstract 12488: Oral Anticoagulation for New Onset Post-Operative Atrial Fibrillation After Combined Coronary Artery Bypass Grafting and Valve Surgery is Not Associated With Improved Outcomes
Authors: Ambika Tejpal, Joshua G Lee, Jiming Fang, Irene Jeong, Maral Ouzounian, Clare Atzema, Peter Austin, Andrew C Ha
Journal: Circulation (2023)

Introduction: Post-operative atrial fibrillation (POAF) after cardiac surgery is common and is associated with increased risk of stroke and death. The incidence of POAF is highest among patients who undergo combined CABG and valve surgery, at 40-60%. The risks and benefits of oral anticoagulation (OAC) in this high-risk population are not well established. Research Question: Among patients with POAF after combined CABG and valve surgery, what is the association between OAC use and clinical outcomes? Methods: From a population-based registry in Ontario, Canada, we identified consecutive patients &gt;65 years of age who developed POAF after combined CABG and left-sided, non-mechanical valve surgery from Oct/08-Mar/18. The exposure of interest was OAC prescription within 90 days after hospital discharge. Outcomes included death, cardiovascular death, stroke, MI, thromboembolism, and bleeding. Follow-up began at 90 days after discharge and continued for 24 months. Outcomes were analyzed using inverse probability of treatment weighting using the propensity score. Statistical measures of association were reported as hazard ratios with 95% confidence intervals. Results: Among 4,836 patients who had combined CABG/valve surgery, 1,939 (40.1%) developed POAF and these patients had a higher rate of death (HR 1.31, 95% CI 1.01-1.68 P=0.04). OAC was prescribed in 1,153 (59.5%) patients (86% warfarin and 14% DOAC). The use of OAC was not associated with a lower rate of death, stroke/MI/thromboembolism, or cardiovascular death but was associated with an increased rate of bleeding (HR 1.62, 95% CI 1.00-2.61, P=0.048). Conclusion: Among patients with POAF after combined CABG/valve surgery, use of warfarin or DOAC did not improve ischemic cardiovascular outcomes or survival and was associated with higher rates of bleeding. Randomized control trials are needed to define the risk and benefit of OAC use in this high-risk population. Until then, routine use of OAC is not recommended.
Abstract 252: End-Tidal CO2 and Glasgow Coma Scale in Non-Intubated Traumatic Brain Injury Patients: Evaluation of Prehospital Nasal Capnography and Level of Consciousness
Authors: Bruce J Barnhart, Daniel W Spaite, Dawn B Jorgenson, Kevin S Burgett, Seiver Adam, Amber D Rice, Joshua B Gaither, Samuel M Keim, Chengcheng Hu
Journal: Circulation (2023)

Background: The EMS traumatic brain injury (TBI) guidelines recommend limiting intubation (ETI) to patients with profoundly-depressed level of consciousness (LOC) and who cannot protect their airway or adequately ventilate with basic maneuvers. Thus, many major TBIs are managed without ETI in the field. Monitoring ETCO2 via nasal sensors (NC-CO2) in non-ETI patients may provide valuable information about ventilatory status and trends. However, EMS NC-CO2 remains unstudied. Objective: To evaluate the association between LOC and NC-CO2 in non-intubated TBI. Methods: Cases from 7 EMS agencies reporting continuous monitor data (Philips MRx™) in the EPIC TBI Study (NIH 1R01NS071049) were evaluated (4/13-4/18). Comparisons in patient-level mean, median, lowest and highest NC-CO2 levels were made across GCS categories using clinically meaningful thresholds: &lt;15, &lt;12, &lt;9, 3. Results: Included: 177 cases [median age: 52 (range: 9-94), 66% male]. Overall, while not statistically significant, NC-CO2 tended to be lower in patients with lower GCS (Table). In addition, minimum NC-CO2 was significantly lower (p=0.01) in patients with compromised LOC (Table). O2 management (Hi-flow/Lo-flow/No O2) was documented in 176 patients (99.4%). Among the 107 patients with all GCS = 15, 44 (41%) had Hi-flow administered compared to 47/69 (68%) with any GCS &lt;15 (p=0.0008). Conclusion: The utility of prehospital capnography in non-intubated patients is unknown. In this study, NC-CO2 tended to be lower in TBI patients with lower GCS. Whether this reflects physiological/respiratory differences with changes in LOC, or variations in methods of managing oxygenation is unclear. These intriguing new findings require future study to determine if NC-CO2 is directly reflective of LOC-related ventilatory patterns. Furthermore, studies are needed to evaluate whether NC-CO2 monitoring has clinical utility as a non-invasive adjunct to care in spontaneously-breathing, non-ETI patients.
Abstract 16420: Coronary Crown Length and Volume Assessed With Coronary CT Angiography Improves the Diagnosis of Ischemia
Authors: Shant Malkasian, Nick Nurmohamed, Hugo Marques, Logan Hubbard, Sabee Molloi, James K Min, James Earls
Journal: Circulation (2023)

Background: Coronary artery tree length and lumen volume follow an allometric power-scaling relationship via Length = K LV * Volume 0.78 . Derangement from this morphometric relationship may indicate atherosclerosis. Methods: This study was a retrospective analysis of the CREDENCE trial, a large multicenter international study. In CREDENCE, patients with suspected CAD underwent CCTA followed by invasive coronary angiography and fractional flow reserve (FFR). For this study, 315 patients with invasive FFR measurements were selected. There were 945 vessel territories, with 681 nonischemic territories (FFR &gt; 0.80) and 264 ischemic territories (FFR ≤ 0.80). Following AI-enabled quantitative CT analysis (AI-QCT) (Cleerly; Denver, CO), coronary territories were split into “stem-crown” units, every 1 cm along each territory. Territories were truncated at 1.5 mm lumen diameter. A single parameter allometric scaling model was employed using a previously validated exponential term (L CROWN = K LV * V CROWN 0.78 ). After log-transformation, K LV was determined via fitting with generalized estimating equations. Results: The mean K LV for ischemic and nonischemic territories was 28.92±4.77 and 25.02±4.84 (p &lt;0.001). The ROCAUC for K LV , diameter stenosis (DS AI-QCT ), and total plaque volume was 0.72 [0.69, 0.76], 0.85 [0.83, 0.88], and 0.70 [0.66, 0.73], respectively, for the diagnosis of ischemia (K LV vs. diameter stenosis: p-value &lt;0.001; K LV vs. total plaque volume: p-value=0.400; DS AI-QCT vs. total plaque volume: p-value &lt;0.001). Multivariable ROCAUC analysis of K LV and diameter stenosis (model 2), and K LV , diameter stenosis, and total plaque volume (model 3) was 0.87 [0.85, 0.90], 0.87 [0.85, 0.90], respectively. Conclusion: Ischemic coronary territories demonstrated significantly larger K LV than nonischemic territories. Moreover, using K LV and DS AI-QCT provided incremental improvement in the diagnosis of ischemia.
Abstract 14438: Loss of the ROR2 Tyrosine Kinase Receptor is Associated With Dysfunctional Angiogenesis in Pulmonary Hypertension via Inappropriate Focal Adhesion Activation and Disruption of the Endothelial Barrier
Authors: Ankita Mitra, Ananya Chakraborty, Brian Zhong, Stuti Agarwal, Lyong Heo, Ramesh Nair, Alexander R Dunn, Vinicio A Dejesus
Journal: Circulation (2023)

Background: Dysfunctional angiogenesis is a hallmark of pulmonary arterial hypertension (PAH), but its mechanisms are unclear. We recently demonstrated a key role for Wnt7a in lung angiogenesis. Wnt7a acts through ROR2, a Wnt pathway tyrosine kinase receptor. We elucidate how ROR2 controls angiogenic functions in pulmonary microvascular endothelial cells (PMVECs). Hypothesis: Loss of ROR2 activity is associated with PAH. Methods: Healthy and PAH PMVECs were obtained from explanted lungs. PMVECs were transfected with ROR2 siRNA/constructs, followed by functional and molecular studies. Focal adhesion (FA) activation and force generation was measured using FRET-based total internal reflection microscopy (TIRF). Mice with endothelial-specific conditional ROR2 KO (ROR2 ECKO) were phenotyped in normoxia and hypoxia. Results: ROR2 expression was found predominantly in the endothelium of healthy lung vessels but significantly reduced within PAH lesions. ROR2 knockdown (siROR2) reduced vascular sprouting comparable to PAH PMVECs. Interestingly, siROR2 and ROR2-deficient PAH PMVECs displayed increased fibronectin adhesion and hyperpermeability, which led us to look at focal adhesions (FA) and cell-cell junctions. Confocal and TIRF microscopy of siROR2 and ROR2-deficient PAH PMVECs revealed an increase in the FA number and force that inversely correlated with reduced VE-cadherin at cell junctions. However, transfection of a ROR2 construct in PAH PMVECs resulted in FAs activity normalization and junctional integrity accompanied by recovery of adhesion and permeability. Proteomic studies demonstrated that ROR2 interacts with Integrin b1 in focal adhesions, and its loss results in Integrin b1 activation, FA clustering, and high mechanical forces. In animal studies, we found that, compared to controls, ROR2 ECKO developed more severe pulmonary hypertension, right ventricular remodeling, microvascular reduction, and muscularization in hypoxia, which correlated with higher levels of integrin b1 activation and reduced VE-cadherin expression. Conclusions: ROR2 promotes PMVEC adhesion and barrier formation, and its loss is associated with dysfunctional angiogenesis. Restoring ROR2 could be a novel therapeutic strategy in PAH.