tbuckley/cabot-search huggingface dataset:
Abstract 14173: Generation and Characterization of Clinically Relevant Disease Models for Port Wine Birthmark Using Induced Pluripotent Stem Cells
Authors: Vi Nguyen, Chao Gao, Marcelo L Hochman, Harold I Friedman, Elliot H Chen, Yunguan Wang, Anil Jegga, John S Nelson, Wenbin Tan
Journal: Circulation (2023)

Introduction: Port Wine Birthmark (PWB) is a congenital vascular malformation with a progressive development. The current treatments for PWB are Pulse Dye Laser and Photodynamic Laser Treatment. However, the efficacy of blanching the birthmark is inadequate, and the reoccurrence after treatment is a major clinical barrier. Developing clinically relevant disease models that can be used for mechanistic and therapeutic development studies is the critical unmet need. Induced pluripotent stem cell (iPSC) is a powerful tool in different disease models and drug discovery. Besides, iPSC-derived cells can retain and exhibit the disease phenotypes from donors. Therefore, iPSCs and their-derived vascular cells could be potential models for PWB study. Hypothesis: It was hypothesized that PWB iPSC-derived endothelial cell (EC) could retain the disease phenotypes, thus serving as clinically relevant disease models. Methods: PWB lesions and normal skin biopsies were cultured for outgrowths of fibroblasts, followed by reprogramming using CytoTune-iPS Kit. The induction of PWB and normal iPSC into EC was performed using reported protocols with tailored modifications. Bulk RNA and ATAC-seq were performed on both iPSC and iPSC-derived EC. The functional phenotypes of iPSC-derived ECs were characterized using in vitro capillary formation and in vivo Matrigel plug-in assays. Results: PWB EC showed impaired tube formation in vitro with larger perimeters (p=6.22x10 -24 ) and thicker branches (p=1.07x10 -77 ) comparing with normal EC. In plug-in assay, the perfused human vasculatures were characterized by using UEA1 and anti-human CD31 antibodies. Perfused vasculature formed by PWB EC showed larger perimeters (p=8.45x10 -6 ) and greater densities (p=7.34x10 -8 ) than those formed by normal EC. Additionally, 16.6% of perfused vessels formed by PWB EC showed perimeters over 300 μm. KEGG analysis of RNA-seq DEGs showed significantly dysregulated pathways related to cell differentiation, organ development, and lipid metabolism in PWB iPSCs and ECs as compared with normal ones. Conclusions: PWB-derived EC retained critical disease related phenotypes including forming enlarged vessels and thick branches in vitro and in vivo, which can be utilized as valuable PWB models.
Abstract 13751: Clinical Characteristics With High Extracellular Volume Fraction in Patients Who Performed Cardiac Computed Tomography Angiography for the Purpose of Evaluating Coronary Arteries
Authors: TETSUYA OGUNI, Kuyama Naoto, Seiji Takashio, Masafumi Kidoh, Seitaro Oda, Kenichi Tsujita
Journal: Circulation (2023)

Background: Cardiac computed tomography angiography (CCTA) is useful for the evaluation of anatomical coronary artery lesions. Recently, extracellular volume fraction by computed tomography (ECV CT ) have become possible by imaging the delay phase after coronary CT angiography. ECV CT has been reported to be useful for detailed examination and prognosis prediction after therapeutic intervention of cardiomyopathy. Cardiac amyloidosis is known as a cardiomyopathy with noticeable increased ECV, and cardiac amyloidosis should be suspected in patients with high ECV. The aim of this study was to evaluate clinical characteristics of high ECV CT and incidental detection of cardiac amyloidosis in patients who underwent CCTA for the purpose of evaluation of coronary arteries. Methods and Results: We examined consecutive 875 patients (mean age; 74.3 ± 7.1 years, men; 64%) who underwent CCCA in men aged ≥ 60 years and women aged ≥ 70 years. ECV CT quantification was performed with pre-contrast and post-contrast delayed phase CT images with the subtraction-derived method. Mean ECV CT was 29.7 ± 5.2%, and a total of 109 patients (12.3%) had ECV CT ≥ 35%. The patients with ECV CT ≥ 35% were significantly older (75.8±8.1 years vs. 74.1±6.9 years; P=0.038) and male dominant 75.4% vs 63.1%; P=0.007). Increased of high-sensitivity cardiac troponin T and B-type natriuretic peptide levels, left ventricular diastolic diameter, left ventricular thickness, impaired left ventricular ejection fraction, and E/e’ were significantly associated with ECV CT ≥ 35%. The prevalence of cardiac amyloidosis was estimated to be at least 1.7% (15/875) in entire study patients and 14.2% (15/106) in patients with ECV CT ≥ 35%. In these cases, increased ECV CT was a clue of the diagnosis of cardiac amyloidosis. Conclusion: CCTA was useful not only for evaluation of coronary arteries but also for evaluation of myocardial properties by ECV CT . Elevated ECV CT was associated with elevated cardiac biomarkers and structural changes of myocardium. There is an incidental diagnosis of cardiac amyloidosis in approximately 1.7% of cases underwent CCTA for the purpose of coronary artery evaluation detected by increased ECV CT .
Abstract 17798: Plasma Cardiac miRNA Expression During ST Elevation Myocardial Infarction
Authors: Kurt Barringhaus, George Prousi, Stephanie Samani, Lisa Freeberg, Amelia Churillo, Sarah Slone, Francis G Spinale
Journal: Circulation (2023)

Introduction: MicroRNAs (miRs), short sequences of RNA that silence gene expression, have been proposed as biomarkers potentially capable of detecting myocardial infarction earlier and more accurately than troponin. Few studies have assessed expression patterns of cardiac-relevant miRs at the time of ST elevation myocardial infarction (STEMI). Hypothesis: Plasma levels of miRs known to regulate myocardial processes are altered in the plasma of patients early after STEMI onset. Aim: To establish a signature of miRs differentially expressed in plasma of patients with STEMI at the time of presentation. Methods: 10cc blood was obtained at the time of coronary angiography for patients presenting with STEMI(n=9), and plasma was recovered after centrifugation. Patients without coronary heart disease who had undergone coronary angiography served as referent normals(n=5). Following RNA extraction, RT-qPCR was performed to quantify levels of 84 cardiac miRs (Qiagen, Germany) with fold change calculated by the 2 - ΔΔCt method. Results: The mean age was similar between STEMI and referent normal control patients (59±9 vs 60±8), and the mean troponin was numerically higher in the STEMI group (15.4±21 vs 0.00±0; p=0.13). As shown in the table, the expression levels of 25 miRs were significantly increased, and 2 were decreased as compared with control patients (p&lt;0.10). Seven miRs were not detected, and the remaining 47 detectable miRs were not different between the groups(p≥0.10). Cardiac-specific miR-499a-5p and miR-208b-3p demonstrated the greatest fold-change relative to referent normal patients. Conclusions: Cardiac-specific miRs, most notably miR-499a-5p and 208b-3p, as well as many other miRs are differentially expressed early after STEMI onset. Further work is needed to determine whether miRs can detect STEMI earlier or more accurately than troponin or provide incremental diagnostic value for patients presenting with acute coronary syndromes.
Abstract 13000: Twiddler’s Syndrome - A Rare Cause of Pacemaker Malfunction
Authors: Amitoj Sachdeva, Jorge Gomez, Joseph Sarmiento
Journal: Circulation (2023)

Description of Case: A 76-year-old female with a past medical history of chronic atrial fibrillation and symptomatic tachycardia and bradycardia status-post dual-chamber pacemaker with right atrial and ventricular leads who presented with dyspnea on exertion. TTE showed normal biventricular function and no significant valvular abnormalities. Upon further evaluation of her pacemaker, she was found to have a very high ventricular capture threshold suggesting RV lead failure. The patient underwent RV lead replacement. The inspection of the pacemaker pocket during the procedure showed manual dislodgement of both tie-down sleeves and the pacemaker leads required untangling. A new RV lead was subsequently placed. Upon further imaging review, displacement of the previous RV lead was evident from initial placement. In addition, the patient had previously had a history of interval diaphragmatic stimulation as well. Overall, the presentation was felt to be consistent with Twiddler’s Syndrome. Discussion: Twiddler’s or Reel Syndrome occurs when conscious or subconscious self-manipulation and spinning of the pulse generator result in lead dislodgement and loss of pacing and pacemaker malfunction. The reeling of the leads around the generator can also cause stimulation of the brachial plexus or phrenic nerve stimulation and subsequent rhythmic arm twitching or diaphragmatic pacing, respectively. It has previously been reported in cases of single- and dual-chamber ICDs, deep brain stimulators, and spinal nerve stimulators with varying presentation. The diagnosis requires clinical suspicion based on history, physical exam, imaging, or surgical inspection suggesting the displacement of leads with evidence of coiling of the wires around the pacemaker. Treatment often requires revision and focus should be maintained on patient education for both primary and secondary prevention of Twiddler’s Syndrome.
Abstract 18691: Asporin Attenuates Pulmonary Arterial Smooth Muscle Cell Proliferation and Regulates Pulmonary Hypertension Development
Authors: Lejla Medzikovic, Wasila Sun, Gregoire Ruffenach, JASON HONG, Mansoureh Eghbali
Journal: Circulation (2023)

Introduction: Pulmonary arterial hypertension (PAH) is a devastating pulmonary vascular lung disease characterized by increased pressure in the pulmonary arteries (PA) leading to cardiac right ventricular (RV) hypertrophy, RV failure, and ultimately death. Current PAH therapies merely improve symptoms temporarily and patients often need lung and heart transplantation. There is dire need for new insights into PAH pathophysiology to find novel therapeutic approaches. A key mechanism driving PAH is medial hyperplasia resulting from enhanced pulmonary arterial smooth muscle cell (PASMC) proliferation. Methods: We employed an unbiased bioinformatics approach in online-available microarray expression and single-cell sequencing datasets of dissected PA from PAH patients. In vitro experiments were performed in PASMC isolated from a female donor and PAH patient. Human lung tissue sections were obtained from the Pulmonary Hypertension Breakthrough Initiative Biobank. The Sugen/Hypoxia model was used to induce PH in rats. Results: We discovered that a novel gene, small leucine-rich proteoglycan Asporin (Aspn), is highly and significantly upregulated in PAH compared to donor PA and is most highly expressed in PASMC. We validated higher Aspn mRNA expression in human lungs and PASMC from PAH patients compared to controls, supporting our bioinformatics approach. Moreover, Aspn protein expression is elevated in PASMC in lung tissue sections from PAH patients compared to donors, as well as in PAH patient plasma . Functionally, silencing Aspn in PASMC from PAH patients promoted proliferation, whereas recombinant Aspn exerted opposite effects. To find potential downstream mediators of Aspn, STRING database analysis revealed that Aspn binds to the pro-proliferative mediator TGFβ1. Accordingly, TGFβ1 downstream mediator p-SMAD2/3 is enhanced upon Aspn silencing in PASMC. Intratracheal delivery of Aspn siRNA in rats aggravated Sugen/Hypoxia-induced PH, as assessed by RVSP, echocardiography and vascular remodeling. Conclusions: We hypothesize that elevated Aspn expression in PAH is a compensatory mechanism that inhibits PASMC proliferation, leading to decreased PA vascular remodeling, and that Aspn may be a novel therapeutic target against PAH.
Abstract 15219: High-Sensitivity Cardiac Troponins and Sex-Differences in Prognostic Value for Cardiovascular Events and All-Cause Mortality
Authors: Nasir Saeed, Joerund Langoergen, Ole-Thomas Steiro, Hilde L Tjora, Rune Bjorneklett, Oyvind Skadberg, Vernon V Bonarjee, Øistein Mjelva, Tone M Norekval, Kjell Vikenes, Torbjorn Omland, Kristin Moberg M Aakre
Journal: Circulation (2023)

Background: Cardiac troponin (cTn) concentrations and the associated long-term cardiovascular risk differ between women and men in the general population. Research question: In patients with acute chest pain, does the prognostic value of cTn differ between sexes as assessed by different cTn assays? Methods: This prospective cohort study included 1500 patients (906 men and 594 women) admitted with suspected NSTE-ACS. Admission cTn was measured with three different high-sensitivity assays: hs-cTnT (Roche), hs-cTnI (Siemens) and hs-cTnI (Abbott). Patients were followed for a median of 1687 (range 4-2208) days. The primary endpoint was a composite of all-cause mortality, myocardial infarction, revascularization and heart failure. The secondary endpoint was all-cause mortality. Discriminatory performance was calculated by the receiver-operating characteristics area under the curve (ROC-AUC) whilst prognostic value was calculated by hazard ratios (HR) in unadjusted and adjusted Cox proportional hazard models. Results: The primary endpoint occurred in 18.1% of men and 15.0% of women. The secondary endpoint occurred in 10.3% of men and 8.9% of women. Women were older than men (median 65 years vs. 59 years, P&lt;0.001), and had higher cTn concentrations (P&lt;0.001 for all assays). All cTn assays had significantly higher discriminatory value in women compared to men for both endpoints (Table 1). Ln-transformed cTn for all assays were associated with increased risk of the primary endpoint and all-cause mortality in both sexes. Unadjusted HRs were higher in women than men with increasing hs-cTn, while in multivariate Cox model the adjusted HRs exhibited similar values between sexes (both endpoints) with no interaction between sex (P&gt;0.05 for all) (Table 1). Conclusions: In patients with suspected with NSTE-ACS, there is a difference in the discriminatory value of hs-cTn, but no clear trend between sexes regarding its prognostic in adjusting for a range of factors, including age.
Abstract 13367: Plasma Lipidomic Markers of Diet Quality Are Associated With Risk of Coronary Heart Disease in American Indians
Authors: Xiaoxiao Wen, Amanda M Fretts, Guanhong Miao, Kimberly Malloy, Ying Zhang, Jason G Umans, Shelley A Cole, Lyle G Best, Oliver Fiehn, Jinying Zhao
Journal: Circulation (2023)

Background: Diet quality can affect lipid profiles and subsequent risk of coronary heart disease (CHD). Identifying lipidomic markers of diet quality is needed to inform the development of biomarkers of diet, and to understand the mechanisms driving the diet-CHD relation. Objective: To identify lipidomic markers of diet quality and examine whether these lipids are associated with incident CHD. Methods: We studied 1,694 American Indians (aged 18-75, 62% women) who were free of CHD and had lipidomic and dietary data at baseline (2001-2003). Participants were followed for development of CHD through 2020 (mean follow-up: 17.8 years; total incident cases of CHD: 147). Information on past year diet was collected using the Block Food Frequency Questionnaire, and diet quality was assessed using the Alternative Healthy Eating Index-2010 (AHEI). Mixed effects linear regression was used to identify individual lipid species associated with AHEI at baseline. Cox frailty model was used to estimate the hazard ratio of each AHEI-related lipid for CHD risk. All models adjusted for age, sex, center, education, BMI, smoking, alcohol drinking, level of physical activity, energy intake, diabetes, hypertension, and use of lipid-lowering drugs. Results: Among 1,542 lipid species measured, 71 lipid species (23 known) were associated with AHEI at FDR&lt;0.05. Of these, 10 lipids (5 known) were associated with incident CHD (Figure 1 ). The 5 known lipids associated with incident CHD were CE(22:5) B, PC(p-14:0/22:1)/PC(o-14:0/22:1), PC(p-38:3)/PC(o-38:4) B, PE(p-18:0/20:4)/PE(o-18:0/20:4), and SM(d36:2) A. On average, per standard deviation increase in the baseline level of these lipids was associated with 17%-23% increased risk of CHD. These AHEI-related lipids are enriched in glycerophospholipid metabolism. Conclusion: We identified lipidomic markers of diet quality in American Indians. Some diet-related lipids are associated with risk of CHD beyond established risk factors.
Abstract 16022: Evaluating the Utility of OpenAI’s GPT-4 as a Diagnostic and Management Aid in Medicine
Authors: Alan Ge, Vidish Pandya, Kevin J Ferrick, andrew krumerman
Journal: Circulation (2023)

Introduction: The advent of deep learning in artificial intelligence has led to exponential growth in its capabilities to assist in medical decision making, diagnosis, and clinical reasoning. ChatGPT has recently gained popularity in the media, and while it has the potential to revolutionize modern medicine, its effectiveness in providing clinicians actionable management options is not fully understood. Methods: We investigated the capabilities and limitations of GPT-4, OpenAI’s most advanced model, by comparing its clinical decision making and differential diagnosis to expert clinicians from five NEJM cases published after GPT-4’s training cutoff date (9/2021). The cases were slowly fed to the program, which was prompted to provide management and next steps at each juncture. These recommendations were then compared to the clinicians’ decision making. Results: GPT-4’s final diagnosis was correct for only one out of the five cases. However, it considered the correct final diagnosis in its list of five differential diagnoses in all of the cases. GPT-4’s decisions matched 18-60% of the authors’ decisions (Table 1). Conclusion: GPT-4 considered the correct diagnosis in its differentials for all five cases that were tested. Ultimately it was only able to correctly identify the diagnosis in one case. GPT-4’s management decisions matched that of the authors 18-60% of the time. This initially appears to be lackluster, but GPT-4 was able to offer appropriate decisions for common problems and this match rate of decisions was heavily influenced by discrete lab orders. GPT-4 was able to recommend the final diagnostic test that would reveal the diagnosis in the majority of the cases. Our study was limited by sample size as well as the fact that case distribution included only rare and difficult to diagnose diseases. This brief study shows how large language models such as GPT-4 have the potential to be used to aid in clinical decision making.
Abstract 15562: Coronary Artery Calcium Score for Allocating Emerging Obesity Therapies: Implications for the Ongoing SURMOUNT-MMO Outcome Trial
Authors: Erfan Tasdighi, Gowtham Grandhi, Ellen Boakye, Michael J Blaha
Journal: Circulation (2023)

Background: Tirzepatide demonstrated substantial weight loss in patients with obesity yet without diabetes and the clinical trial (SURMOUNT-MMO) evaluating its CVD benefits is ongoing. We tested whether the CAC score provides substantial risk predictive value in this setting. Methods: Participants (N=16,163; mean age 53.0 ± 9.7 years; 72.5% men) with BMI≥ 27 kg/m 2 but without diabetes from the CAC Consortium were categorized based on the inclusion criteria of SURMMOUNT-MMO trial pertaining to individuals without an established CVD. The predictive value of CAC was evaluated for all-cause and cause-specific mortality after mean follow-up of 10.6 ± 2.9 years using multivariable-adjusted Cox proportional hazard and competing risks regression, respectively. Results: Of the 16,163 participants, 14,004 (86.6%) would not qualify for the SURMMOUNT-MMO trial. Of those, those with CAC ≥ 300 had a higher rate (per 1,000 person-years) of all-cause (7.10 vs. 1.43), CVD (2.62 vs. 1.0), and CHD (1.61 vs. 0.75) mortality compared to ones with CAC=0. After adjusting for age, sex, and race, individuals who would not qualify and with CAC≥ 300, had significantly higher risk of all-cause, CVD, and CHD mortality (all P-values &lt;0.001), compared to those who do not qualify and without CAC. Of note, individuals who would qualify but with CAC &lt;100 did not have increased all-cause, and cause-specific mortality compared to individual who would not qualify and without CAC (Table). Conclusions: CAC strongly predicts all-cause, CVD, and CHD mortality among individuals with obesity but without diabetes, and may better risk stratify than SURMOUNT-MMO inclusion criteria. CAC may serve as an effective risk stratification tool to prioritize the allocation of therapies for weight management.
Abstract 14317: Arterial Thromboembolism in a Patient With Primary Antiphospholipid Antibody Syndrome and a Mitral Valve Mass
Authors: Ali Jandal, Tyler Wark, Asad Anwar, Anand MuthuKrishnan, Tracy Hagerty, Trace Barrett
Journal: Circulation (2023)

Background: Antiphospholipid antibody syndrome (APLAS) is an immune-mediated thrombophilia with multisystem venous and arterial thrombosis. Valvular disease is the most common cardiac presentation of APLAS, usually involving the mitral valve, and rarely affects valve function. Arterial thrombosis leading to myocardial infarction (MI) and left ventricular dysfunction have been described but are rare. We present a challenging case of APLAS with mitral valve involvement complicated by MI and new decompensated heart failure. Case: A 48-year-old male with obesity, hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, and triple-positive primary antiphospholipid antibody syndrome presented with a 3-day history of angina and dyspnea. He was started on rivaroxaban 9 years prior to presentation for breakthrough venous thrombosis while non-adherent to warfarin. During admission, he was found to have a mitral valve mass complicated by moderate mitral valve regurgitation, decompensated systolic heart failure, ST-segment elevation myocardial infarction, and multifocal strokes. Multimodality imaging (figure 1) in the setting of negative blood cultures suggested a non-infectious mitral valve mass with embolization as the culprit for his presentation. He ultimately underwent successful mechanical mitral valve replacement and bypass grafting with pathology confirming the diagnosis. Discussion: We highlight a case of a non-bacterial thrombotic mitral valve mass leading to moderate valvular regurgitation, acute heart failure, and arterial thromboembolic events in the setting of probable rivaroxaban failure. This case highlights the use of multimodality imaging and a team-based approach to correctly diagnose and treat a high-risk patient with APLAS and surgical valvular disease, as well as the inherent challenges of perioperative thrombotic and hemorrhagic risk assessment and monitoring.