tbuckley/cabot-search huggingface dataset:
Abstract 4116340: The Effect of Periprocedural Statin Therapy on Mortality and Cardiovascular Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis
Authors: Aman Goyal, Yusra Mashkoor, Haleema Qayyum Abbasi, Rozi Khan, Hritvik Jain, Sawai Singh Rathore, Darshan Puttaswamy, Abdul Moeed, Samia Sulaiman, Agastya Belur
Journal: Circulation (2024)

Background: Transcatheter aortic valve replacement (TAVR) stands as a notable alternative to surgery for severe aortic stenosis (AS). Despite the established benefits of statins in cardiovascular pathologies, their specific impact in patients with severe AS undergoing TAVR remains uncertain. Our study aims to assess whether perioperative statin use improves survival and outcomes post-TAVR. Methods: A search was conducted across various databases to retrieve studies comparing perioperative statin use versus no statin use in patients undergoing TAVR. The primary outcome of interest was all-cause mortality (ACM). Secondary outcomes included stroke, acute kidney injury (AKI), 30-day mortality, myocardial infarction (MI), cardiovascular complications, and in-hospital mortality. Comprehensive Meta-Analysis Software (v. 3) was used to pool odds ratio (OR) under a random-effects model, with statistical significance set at p &lt; 0.05. Results: Our analysis encompassing 20663 patients from 15 observational studies found that perioperative statin use was associated with a significant reduction in ACM (OR= 0.71, 95% CI: 0.61-0.83, I 2 = 50.3%, p&lt;0.001). Although not statistically significant, perioperative statin use demonstrated a trend towards a decreased risk of stroke (OR= 0.90, 95% CI: 0.68-1.19, I 2 = 0%, p= 0.455), AKI (OR= 0.99, 95% CI: 0.75-1.31, I 2 = 49%, p= 0.968), and 30-day mortality (OR= 0.71, 95% CI: 0.46-1.10, I 2 = 0%, p= 0.126), and no difference was seen in the risk of MI (OR= 1.72, 95% CI: 0.73-4.04, I 2 = 0%, p= 0.214), cardiovascular complications (OR= 1.12, 95% CI: 0.91-1.37, I 2 = 0%, p= 0.297), and in-hospital mortality (OR= 0.42, 95% CI: 0.13-1.38, I 2 = 65.8%, p= 0.151) (Figure 1 and 2). Conclusion: Perioperative statin therapy reduces all-cause mortality in TAVR patients but shows limited impact on other outcomes. Further large-scale prospective studies and trials are necessary to corroborate our findings.
Abstract 4114198: Humanin Level is Inversely Correlated with NT-proBNP Level and Mortality in Heart Failure with Reduced Ejection Fraction
Authors: Crystal Yan, Luanda Grazette
Journal: Circulation (2024)

Background: Mitochondrial dysfunction contributes to heart failure (HF) progression via diminished energy supply, release of reactive oxygen species, and increased cell death. However, there has yet to be clinically relevant biomarkers that address mitochondrial-mediated cardiac injury in patients. Humanin (HN) is a mitochondria-derived peptide that protects cells through the interference of apoptosis and reduction of oxidative stress. The objectives of our study were to measure circulating plasma HN levels in patients with HF with reduced ejection fraction and describe the relationship of HN to validated, clinically relevant measures of HF. Methods: We conducted a prospective cohort study. To be included in the study, patients must have: 1) left ventricular ejection fraction &lt;40%, 2) high risk of future clinical instability, 3) medication and device treatment according to guidelines, and 4) stable medical therapy for at least 30 days prior to screening. Plasma HN levels were measured at time of study enrollment by an enzyme-linked immunoassay. Statistical analyses were performed to evaluate the relationships between HN levels and demographic variables, quantitative measures of HF, and clinical outcomes. Results: 54 HF patients were included in the study. Age and sex were not significantly associated with HN level. There was a significant difference in mean HN level by race with highest HN level seen in Caucasians and the lowest HN level seen in Hispanics (1310 pg/ml vs. 630 pg/ml, p=0.012). There was a significant inverse correlation between NT-proBNP level and HN level (r=-0.46, p &lt;0.001). After adjusting for race, higher NT-proBNP level, as both a continuous and categorical variable, was significantly associated with lower HN level. Furthermore, HN level was significantly lower in patients who died within 6 months compared to those who did not (520.7 pg/ml vs. 1146.9 pg/ml, p=0.013). After adjusting for race, lower HN level was significantly associated with increased odds of 6-month mortality (OR=0.784, 95% CI 0.620-0.943, p=0.018). Conclusions: To the best of our knowledge, this is the first study to describe plasma HN levels in HF patients. Its significant correlation with mortality and NT-proBNP level supports a potential role for HN as a novel prognostic biomarker in HF with reduced ejection fraction.
Abstract 4122257: Inhibition of Neutrophil Extracellular Traps Prevents Heart Failure by Preserving Mitochondrial Function of Cardiomyocytes in Mice
Authors: Shohei Ichimura, Tomofumi Misaka, Ryo Ogawara, Kazuto Nishiura, Yu Sato, Shunsuke Miura, Tetsuro Yokokawa, Takamasa Sato, Masayoshi Oikawa, Atsushi Kobayashi, Akiomi Yoshihisa, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2024)

Background: We have previously demonstrated that neutrophil extracellular traps (NETs) in myocardial tissue are associated with cardiac dysfunction and adverse outcomes in patients with heart failure with reduced ejection fraction. Here, we aimed to elucidate the underlying mechanisms and to clarify whether inhibiting NETs could rescue the cardiac phenotype using ex vivo and in vivo models. Methods and Results: Given that peptidyl arginine deiminase 4 (PAD4) is essential for the formation of NETs, PAD4 knockout mice were used for this study. First, we assessed the mitochondrial function of cardiomyocytes by conducting real-time measurements of the oxygen consumption rate in ex vivo . Extracellular flux analysis revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of adult mouse cardiomyocytes, while these effects were abolished when PAD4 in neutrophils was genetically ablated (Figure 1). In a murine model of pressure overload-induced heart failure, transverse aortic constriction (TAC) operation was performed on wild-type and PAD4 knockout mice. Immunohistological analysis demonstrated that TAC induced the formation of NETs in the myocardium, with the greatest number of NETs occurring at 1 day, persisting into the failing stage at 4 weeks in wild-type mice, while PAD4-deficient hearts displayed no presence of NETs in the heart tissue (Figure 2). Four weeks after TAC, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4 knockout mice displayed preserved left ventricular ejection fraction (Figure 2). Finally, we investigated the bioenergetics of cardiomyocytes isolated from PAD4 knockout mice after TAC. Maximal mitochondrial oxygen consumption rate in cardiomyocytes isolated from TAC-operated PAD4 knockout mice was significantly higher than in those from TAC-operated wild-type mice (Figure 3). Conclusion: Our data suggest that NETs directly derived impairment of mitochondrial function in cardiomyocytes. Inhibiting NETs represents a potential therapeutic approach for heart failure, preventing mitochondrial dysfunction of cardiomyocytes.
Abstract 4120687: Multi-Omics Insights into Recovery from Acute Fulminant Myocarditis Treated with Ruxolitinib
Authors: Juan Qin, Mandar Aras, Evelyn Song, Arun Padmanabhan, Andrew Connolly, Lylybell Zhou, Connor O'Brien, Javid Moslehi
Journal: Circulation (2024)

Background: There are currently no approved medical therapies for acute fulminant myocarditis (AFM). Janus kinase (JAK) inhibitors target the JAK-STAT signaling pathway, which is crucial in immune activation. We report the first use of ruxolitinib, a JAK inhibitor, for treatment of AFM. Multi-omics single-cell technologies, including RNA-seq, T-/B-cell receptor seq, and CITE-seq, were employed to analyze immune profiles pre- and post-ruxolitinib treatment. Results: A 20-year-old female presented with AFM with cardiogenic shock and was supported by VA-ECMO and impella CP. Endomyocardial biopsy showed lymphocytic myocarditis. The patient received pulsed steroids and was listed for orthotopic heart transplant. Due to deteriorating conditions, ruxolitinib (10 mg BID) was added with immediate improvement in cardiac and inflammatory biomarkers and hemodynamics. ECMO was decannulated on day 6 and impella CP was removed on day 8. Repeat TTE on day 9 showed normalization of cardiac function (LVEF 58%, increased from 10%). She was discharged on ruxolitinib and is doing well in follow-up. Multi-omics single-cell technologies were employed on PBMCs collected at four time points: prior to ruxolitinib treatment (but after treatment with corticosteroids), and post-ruxolitinib treatment on day 5, day 8, and 2-months. At baseline, prior to treatment, scRNA-Seq and CITE-seq analysis revealed upregulated JAK-STAT signaling in pathogenic immune cells such as NK cells, CCR2 + /CCR5 + /HLA-DR + monocytes and activated T cells. Ruxolitinib treatment significantly decreased these pathogenic immune cells, with inhibition of STAT1/STAT3 signaling. Ruxolitinib also significantly decreased key cytotoxic genes PRF1, GZMB, and TBX21 in T and NK cells. TCR sequencing revealed clonal expansions of activated T cells with high levels of pro-inflammatory genes (IL2/IL6/IFNg) at baseline which were dramatically reduced post-treatment with ruxolitinib. Longitudinal data indicated normalization of naive T and B cell levels and clonal diversity, mirroring her clinical improvement. Conclusions: Ruxolitinib significantly modulates immune profiles and disrupts pathogenic signaling in AFM. This first reported use of ruxolitinib in AFM, coupled with our multi-omics analysis, highlights profound immune reprogramming and supports targeted immune modulation for rapid recovery, underscoring ruxolitinib’s therapeutic efficacy.
Abstract 4119210: Differential Proteomic Expression of IGFßP-1 and IGFßP-2 in Primary Angioplasty for Acute Myocardial Infarction
Authors: Jin Un Kim, Callum Little, Vanessa Acquah, Markella Ponticos, Tushar Kotecha, Roby Rakhit
Journal: Circulation (2024)

Introduction: Insulin growth factor (IGF) binding protein-1 and 2 (IGFBP-1 and 2) are implicated in acute myocardial infarction (AMI) and have been suggested as predictors of mortality and development of heart failure. The IGF axis has been shown to play roles in cell proliferation and apoptosis. We analysed the serum IGFBP-1 and 2 levels in AMI before and after percutaneous coronary intervention (PCI) and correlated this with cardiac magnetic resonance (CMR) imaging to better establish their significance as biomarkers in AMI. Methods: Patients with AMI who presented to Royal Free Hospital, London, were recruited for proteomic analysis (O link Proximity Extension Immunoassay) at presentation, 24h and 72h following primary PCI. All underwent both admission and follow-up CMR at 6 months to assess for myocardial oedema, left ventricular volumes and function, and assessment of scar. Results: Proteomic evaluation in 20 AMI patients (male 95%; median age 59) revealed significant reduction in the average IGFBP-1 values at discharge compared with presentation, from 5.93 to 4.52 (24% reduction, p=0.003). Conversely, the average IGFBP-2 values at discharge significantly increased from 7.66 to 8.29 (8% increase, p=0.001). Higher discharge IGFBP-2 value was also correlated with increased indexed left ventricle end diastolic volume (LVEDV) at 6-month follow-up (R=0.54, p=0.032). Discussion: IGFBP-1 and 2 showed significant change following intervention for AMI. IGFBP-1 is a stress hormone, which is directly and indirectly activated by cytokines, dysglycaemia and vasopressin activation. Its subsequent reduction following PCI in AMI indicates relative resolution of inflammation, but this was not correlated with changes in infarct size or LV function at follow-up. IGFBP-2 showed significant upregulation, and higher values at discharge were significantly correlated with increased LDEDV at follow-up, suggesting adverse clinical outcomes within this setting. This data suggests differential roles of IGFBP-1 and 2 in the pathogenesis of AMI.
Abstract 4121527: Empagliflozin Improves Mitochondrial Biogenesis in Pulmonary Arterial Hypertension
Authors: Keimei Yoshida, Eszter Toth, Erik Duijvelaar, Beau Neep, Stuti Agarwal, Xiaoke Pan, Takayuki Sanada, Yu Yoshida, Jurjan Aman, Vinicio Dejesus, Louis Handoko, Kohtaro Abe, Xiao-Qing Sun, Harm Bogaard
Journal: Circulation (2024)

Background: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by endothelial proliferation and progressive pulmonary vascular (PV) remodeling. Empagliflozin (EMPA), a sodium glucose cotransporter 2 (SGLT2) inhibitor, benefits heart failure patients, potentially mediated by improved mitochondrial function. This study aimed to explore the impact of EMPA in PAH. Methods and Results: Immunohistochemistry of pulmonary arteries revealed the expression of SGLT2 in the intima of PAH patients. Microvascular endothelial cells (MVECs) were isolated from lungs of control subjects (CTRL) and PAH patients and found intense expression of SGLT2 in PAH MVECs. Western blot showed significantly higher expression of SGLT2, while PGC-1α, a transcriptional coactivator known as a master regulator of mitochondrial biogenesis, was lower in PAH MVECs compared to CTRL (Image 1). PAH MVECs were treated with EMPA (1 μM) and observed a significant increase of PGC-1α and BMPR2-pSmad1/5/9. Similarly, knockdown of SGLT2 using siRNA resulted in enhanced expression of PGC-1α. Moreover, Seahorse analysis revealed increased oxygen consumption rate and reduced extracellular acidification rate by EMPA, suggesting that EMPA improved mitochondrial respiration. In addition, EMPA attenuated reactive oxygen species and proliferation of PAH MVECs, as revealed by MitoTracker analysis and MTT assay respectively. For the in vivo study, Sprague-Dawley rats (120-180 gram) were injected with SU5416 (Week-0) and exposed to hypoxia for 3 weeks followed by normoxia. After randomization at Week-4, rats were treated with EMPA (300 mg/kg in chow, n=12) or placebo (PLAC, n=12). Catheterization and histological analysis were performed at Week-8. EMPA decreased PV resistance index (0.21±0.02 vs. 0.37±0.05 mmHg/mL/min/mm 2 , p=0.01), ameliorated intima thickening (21.0±7.5 vs. 40.0±7.8%, p&lt;0.01) and vessel occlusion (Image 2). We further conducted a single-center, open-label, single-arm interventional proof-of-concept study to assess the tolerability of 12 weeks of treatment with 10mg of EMPA as add-on therapy in eight patients with a prior PAH diagnosis. There were no treatment related adverse events during the study time course. Conclusions: EMPA directly improved mitochondrial biogenesis and attenuated proliferation of MVECs from PAH patients and reversed PV remodeling in experimental PAH. EMPA treatment was feasible in patients with PAH. EMPA may serve as a new therapeutic option for PAH.
Abstract 4120375: Penetrance and Phenotype Conversion Rate of Genetic Hypertrophic Cardiomyopathy in an Academic Biobank
Authors: Joseph Shin, Aeron Small, Carrie Zawatsky, Michael Fifer, Albree Tower-rader, Robert Green, Matthew Lebo, Pradeep Natarajan
Journal: Circulation (2024)

Introduction: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition with incomplete penetrance and variable expressivity. Given the increasing prevalence of sequencing and current guidelines on secondary finding disclosure, HCM P/LP alleles are increasingly being returned to patients who undergo genetic testing for other reasons. Whether individuals carrying P/LP HCM variants discovered in a genome-first context have progressive endophenotypes indicative of HCM remains poorly understood. Methods: To evaluate the penetrance and phenotype conversion rate of adults with P/LP HCM variants, we leveraged the Massachusetts General Brigham Biobank (MGBB), which consists of 36,417 participants with genotyping array and clinical data. Primary images of the earliest and latest TTE studies were reviewed for measurements of the posterior wall (PW), interventricular septum (IVS), and left ventricular morphology. Phenotype-positive (P+) status was defined by a PW or IVS thickness of at least 13 mm. Results: P/LP HCM variants were identified in 42 (0.1%) individuals with mean (SD) age 50.0 (16.6) years and 21 (50%) female sex. The most common HCM variants were in MYBPC3 (44%) and MYH7 (40%), followed by TNNI3(7%), MYL3 (7%), and TNNT2 (2%). Among the 42 genotype-positive (G+) individuals in MGBB, 17 (40%) had pre-existing HCM diagnoses prior to genomic return of results (gRoR). In contrast, 25 (60%) G+ individuals lacked a prior HCM diagnosis, among whom gRoR prompted TTE studies in 13 patients, revealing evidence of HCM in 9 individuals. Among the 42 G+ patients, 25 (58%) patients had completed at least two TTE studies, with a median [IQR] of 6 [3-9] TTE studies per patient, across a span of 10 [7-15] years follow-up. At the time of first TTE, 16 (64%) patients were P+ while 9 (36%) were P-. No G+, P- individuals converted to P+ over 10 years follow-up, nor was there any significant change in IVS or PW thickness. In contrast, individuals who were P+ at the initial TTE exhibited thickening PW (25% increase, CI 97.5% of 6 to 44) and IVS (26% increase, CI 97.5% of 4 to 49) over 8 years follow-up. Conclusion: In a genome-first approach, we identified 42 individuals in the MGBB with a P/LP HCM variant, among whom 60% lacked a prior clinical diagnosis of HCM. Targeted phenotyping revealed that nearly half of this newly identified group were P+. Over a median of 10 years follow-up, we observed a 0% phenotype conversion rate among G+, P- adult carriers of HCM variants.
Abstract 4117834: Utility of Abdominal Aortic Calcification Assessment for the Prediction of Major Adverse Cardiovascular Events in Liver Transplant Patients
Authors: Benjamin Cailes, Numan Kuitaba, Omar Farouque, Avik Majumdar, Layal Abdelganne, Shannon McNamara, Nikki Garrard, Ali Al-Fiadh, Terase Lancefield, Matias Yudi, Mark Horrigan, Julian Yeoh, Laurence Weinberg, Adam Testro, Marie Sinclair, Ruth Lim, Paul Gow, Anoop Koshy
Journal: Circulation (2024)

Background: Cardiovascular disease is a leading cause of postoperative morbidity and mortality following liver transplantation (LT). Presence of abdominal aortic calcification (AAC) has been linked to cardiovascular events in the general population. We investigated whether AAC on pre-transplant computed tomography (CT) predicts major adverse cardiovascular events (MACE) post-LT. Methods: Consecutive LT patients between 2010-2018 from the Victorian Liver Transplant Unit (Australia) were included. Extent of AAC was quantified in a blinded fashion, with high AAC defined as a calcium score of ≥500. MACE was defined as any recorded episodes of acute coronary syndrome (ACS), ventricular arrhythmia, decompensated heart failure, or stroke. The primary outcome was post-LT MACE at 30 days and the secondary outcome was all-cause mortality at maximal follow-up. Results: Of 461 patients undergoing LT, 350 had suitable CTs for analysis, of which 90 (25.7%) had also undergone CT coronary angiography. High AAC was identified in 98 patients (28.0%). This finding demonstrated a moderate correlation with high coronary artery calcium score (CACS) ≥400 (r=0.52, p&lt;0.001). Fifty-eight MACE occurred in 42 patients (12.0%) within 30-days. High AAC was associated with increased risk of 30-day MACE (OR=2.68 (95%CI 1.39-5.17), p=0.004), and long-term mortality (HR=2.52 (95%CI 1.29-4.92), p=0.007) at a median follow-up of 4.0 years. In addition, high AAC predicted an increased risk of ACS (OR 3.80 (95%CI 1.18-12.27), p=0.025), heart failure (OR 3.07 (95%CI 1.21-7.80), p=0.020) and atrial fibrillation (OR 2.04 (95%CI 1.02-4.07), p=0.048), with a trend to increased prevalence of ventricular arrhythmia (OR 2.67 (95%CI 0.84-8.50), p=0.10). Following multivariate analysis, high AAC remained a strong independent predictor of MACE (OR=3.49, 95%CI 1.21-10.06, p=0.021). Addition of AAC to the revised cardiac risk index (RCRI) improved model fit for predicting MACE (net reclassification improvement of 52.7% (p&lt;0.001)). Conclusions: This study demonstrates for the first time that high AAC on routine abdominal CT scans is associated with a 3-fold increased risk of 30-day MACE post-LT, and improves cardiovascular risk prediction compared to traditional risk scores. Quantification of AAC may offer a simple method of improving cardiovascular risk assessment and implementation of preventative strategies in liver transplant patients, using pre-existing scans without additional cost or patient risk.
Abstract 4119426: Enhancing early detection of ICI myocarditis cases during hospitalization: A role for large language models
Authors: Virginia Sun, Julius Heemelaar, Ibrahim Hadzic, Vineet Raghu, Chia-Yun Wu, Leyre Zubiri, Azin Ghamari, Giselle Suero-Abreu, Jessica Wu, Nora Hathaway, Hannah Gilman, Alexandra-Chloe Villani, Jor Sam Ho, Daniel Zlotoff, Steven Blum, Ryan Sullivan, Kerry Reynolds, Tomas Neilan
Journal: Circulation (2024)

Background: Immune-checkpoint inhibitor (ICI)-induced myocarditis is the most fatal immune-related adverse event (irAE). Early recognition and treatment of ICI myocarditis is associated with improved outcomes. However, current approaches to the diagnosis of ICI myocarditis have limitations. Open-source large language models (LLMs) are an accessible and scalable method of answering queries from human-generated text, and therefore may assist in the real-time early detection of ICI myocarditis among at-risk patients. Research Question: Can a free, open-source LLM detect cases of ICI myocarditis early in admission? Aims: We investigated the ability of a LLM pipeline to screen for ICI myocarditis within one day of admission using hospital medical records. Methods: Hospital admissions of patients on ICI therapy from November 4th, 2021, to September 5th, 2023 were retrospectively reviewed by a multidisciplinary immunotoxicity team using established, published definitions for the presence of ICI myocarditis. Progress notes written the day before, day of, and day after admission were fed into an open-source LLM pipeline built using Mistral 7B OpenOrca with retrieval augmentation generation (RAG). Performance of the LLM was measured via sensitivity and specificity in comparison to the gold standard of manual adjudication. Results: Of the 1874 hospital admissions of patients on ICI therapy, there were 22 (1.2%) cases of myocarditis. The average time to initiation of treatment was 2.45 days. Using notes written within one day after admission, the LLM detected ICI myocarditis with 95.5±8.7% sensitivity and 95.4±1.0% specificity, spending 2.13 seconds per chart. Conclusion: LLMs serve as a useful tool to screen for ICI myocarditis, detecting 95.5% of cases within one day of admission with 95.4% specificity. Future studies will investigate if integrating this tool into the real-time management of irAEs could lead to earlier diagnosis, faster initiation of treatment, and improved patient outcomes.