tbuckley/cabot-search huggingface dataset:
Abstract 4140616: Proteomic biomarkers are associated with high-risk plaque phenotype and adverse events in the PROMISE trial
Authors: Anish Karpurapu, Lydia Kwee, Caroline de Calvacamp, Elizabeth Zhao, Khurram Nasir, Borek Foldyna, Pamela Douglas, Svati Shah
Journal: Circulation (2024)

Introduction: Cardiovascular events occur in patients without obstructive coronary artery disease (oCAD), indicating a need for better risk stratification tools. CT angiography (CTA)-based high-risk plaque (HRP) characteristics predict such events effectively but are not widely available. We performed comprehensive proteomics profiling in the PROMISE trial to identify biomarkers associated with HRP, oCAD, and major adverse cardiovascular events (MACE). Methods: The PROMISE trial randomized patients with stable chest pain to CTA vs. stress testing. Proteomic profiling (Olink, 524 proteins) was performed on 1724 participants with CTA and biospecimens. A high-risk composite phenotype (HRCP) was defined as presence of oCAD (≥50% stenosis in any major vessel), Leaman score &gt;5, coronary artery calcium score ≥400, or HRP features on CTA. Individual proteins were tested for association with HRCP (false discovery rate-adjusted p-value [q] &lt;5%), followed by pathway analyses, association testing with MACE, and Mendelian randomization. K-means phenoclustering was used to identify clinical clusters. Proteins were then tested for association with the clusters. Results: Thirty-seven proteins were significantly associated with HRCP in models adjusted for clinical covariables. These included GDF-15 (OR [95% CI]=1.4 [1.1-1.7], p=0.01), ACE2 (OR=1.4 [1.1-1.7], p=0.002), and LPL (OR=0.7 [0.6-0.9], p=0.01); proteins represented biologic pathways of metabolic regulation, inflammation, and protein degradation. Phenoclustering identified three patient subgroups with varying cardiovascular risk factors; levels of 32/37 proteins varied across the clusters. Seven of the 37 proteins were associated with MACE, including LPL (HR=0.5 [0.4-0.8], q=0.003), CTSD (HR=1.9 [1.2-2.9], q=0.009), GDF-15 (HR=1.7 [1.1-2.5], q=0.01), and ACE2 (HR=1.8 [1.3-2.6], q=0.002) with a direction of effect consistent with odds of HRCP. Mendelian randomization analyses suggest a causal role only for CTSD (cathepsin D) in CAD. Conclusion: This study identified novel biomarkers associated with high-risk CAD phenotypes and adverse outcomes in the PROMISE trial, most of which also differentiated clinical phenoclusters, suggesting they report on molecular heterogeneity underlying clinical differences in patients at risk for CAD. These findings highlight potential biomarkers with clinical utility for improved risk stratification and elucidate one potential therapeutic target (CTSD) in the causal pathway of CAD events.
Abstract 4139930: Low Ventricular Stiffness is Associated with Suboptimal Outcomes in Single Right Ventricle Patients after the Fontan Operation: A Novel Phenotype
Authors: Shahryar Chowdhury, Andrew Atz, Eric Graham, Varsha Bandisode, John Rhodes, Arni Nutting, carolyn taylor, Andrew Savage, Marc Hassid, Minoo Kavarana, Donald Menick
Journal: Circulation (2024)

Introduction: Despite a rigorous screening process, including cardiac catheterization, a subset of single right ventricle (SRV) patients demonstrate suboptimal short-term outcomes after the Fontan operation. The goal of this study was to perform a comprehensive assessment of diastolic function in pre-Fontan SRV patients using invasive reference-standard measures and determine their associations with post-Fontan outcomes. Methods: Children 2-6 years old with SRV physiology undergoing pre-Fontan heart catheterization were recruited prospectively. SRV patients were divided into those who had an optimal or suboptimal outcome. A suboptimal outcome was defined as length of stay ≥14 days or heart transplant/cardiac death in first year after Fontan. Patients with hemodynamically insignificant patent ductus arteriosus referred for catheterization closure were recruited as controls. Patients underwent pressure-volume loop analysis using reference-standard methods. The measure of ventricular stiffness, β, was obtained via preload reduction. Cardiac magnetic resonance imaging for extracellular volume (ECV) and serum draws for matrix metalloproteinase (MMP) activity were performed. Results: Of 19 SRV patients, 9 (47%) had a suboptimal outcome. 15 controls were included. Demographic and catheterizations are shown in Table 1. Echocardiographic and MRI data are shown in Table 2. Patients with suboptimal outcomes had lower ventricular stiffness, lower ECV, and lower MMP-2 compared to patients with optimal outcomes (Figure 1). Patients with suboptimal outcomes had similar stiffness to biventricular controls. Patients with optimal outcome had less total fluid in the first 24 hours than the suboptimal group (1107 (IQR 953, 1303) vs. 1482 (IQR 1305, 1598) mL, p = 0.03). The only invasive measure that had an association with suboptimal outcome was β, p=0.038. Conclusion: SRV patients with suboptimal outcome after Fontan had lower ventricular stiffness compared to patients with optimal outcome. Lower stiffness led to an increased need for fluid resuscitation and higher chest tube output after Fontan. The usual response in chronically increased RV afterload is for the RV to hypertrophy and stiffen over time in order to maintain cardiac output. This is not seen in low SRV stiffness patients and may represent a maladaptive extracellular matrix response to chronic afterload elevation. This novel phenotype that may have important clinical implications and requires further study.
Abstract 4140504: Effect Of Resmetirom On Lipid Panel: Meta-Analysis Of Randomized Controlled Trials
Authors: Sharath Kommu, Param Sharma, Milind Shah, Mohammad Alaoua, Deepa Soodi, Richard Berg
Journal: Circulation (2024)

Background: Resmetirom is useful in improving liver parameters in patients with nonalcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH). However, its beneficial effects on lipid panel parameters are unclear. Methods: We searched PubMed and ClinicalTrials.gov using the search term resmetirom. Among the studies identified, we looked for randomized-controlled trials with information on resmetirom and lipid panel. We identified four studies which compared resmetirom 80 mg to placebo, and performed a meta-analysis. A random effects model was utilized when heterogeneity was detected (p-value for heterogeneity&lt;0.1) Results: Our study shows that resmetirom, significantly improved lipid parameters of low-density lipoprotein cholesterol (LDL-C) (mean difference [MD] -13.01, 95% confidence interval (CI) -15.38 to -10.64, p&lt;0.0001), triglycerides (MD -30.61, 95% CI -48.30 to -12.93, p=0.0007), apolipoprotein B (MD -18.78, 95% CI -24.90 to -12.66, p&lt;0.0001), lipoprotein (a) (MD -24.89, 95% CI -38.67 to -11.11, p=0.0004). There was an improvement in high-density lipoprotein cholesterol (HDL-C), but it was not statistically significant (MD 1.32 95% CI -0.49 to 3.14, p=0.15). Conclusion: Resmetirom, used to treat NASH (or MASH), can significantly improve lipid panel parameters, potentially offering cardiovascular benefits. To fully understand its impact on cardiovascular health, large-scale randomized controlled trials focusing on cardiovascular outcomes are necessary.
Abstract 4140558: Circulating plasma proteins in the Fontan circulation predict mitochondrial oxidative stress
Authors: Sushrima Gan, Joiliana Lecointe, Shoko Ichimura, Ankit Kushwaha, Laura Mercer-Rosa, Sushma Reddy
Journal: Circulation (2024)

Background: Single ventricle congenital heart disease such as hypoplastic left heart syndrome (HLHS) with a Fontan circulation constitute the largest group of children hospitalized with circulation failure, experiencing an in-hospital mortality rate of 20-50%. We investigated the mechanisms leading to circulation failure so as to identify novel therapeutic targets. Methods: Blood was collected from patients with HLHS s/p Fontan and controls with normal cardiac anatomy and function (N=6/group). Plasma microvesicles (MV) were isolated, and proteomics assessed using data independent acquisition mass spectroscopy. Dysregulated proteins with a fold change &gt;1.5 or &lt; -1.5, p&lt;0.05, were evaluated using DAVID and Ingenuity pathway analysis. We assessed the association of most highly dysregulated proteins with NYHA class (clinical indicator of heart failure), right ventricular fractional area change (RV FAC) (echocardiographic indicator of RV systolic function), oxygen saturation and hemoglobin using Pearson correlation. Results: Age of Fontan patients vs. controls was 16.14±23 vs. 15.78±2; 40% were male in both groups. 80% of Fontan patients were in NYHA class II/III, 20% in NYHA class IV; 60% had Fontan-associated liver disease. Increasing expression of the following proteins was associated with worsening NYHA class: complement system (C1QA, r=0.91; C7, r=0.53; FCN3, r=0.52), membrane transporters (SLC2A1, r=0.82; SLC4A1, r=0.76), mitochondrial reactive oxygen species (mROS) generation (HSPD1, r=0.81; ATP5F1A, r=0.75) and cytoskeletal proteins (ANK1, r=0.63; ACTN1, r=0.76). Increasing expression of proteins involved in mROS generation were also associated with worsening RV FAC. Decreasing expression of the following proteins was associated with worsening NYHA class and RV FAC: B-cell lymphopoiesis (DOCK10; r=-0.80), adhesion (ADAM10, r=-0.72; CD151, r=-0.69), and coagulation (SERPINF2, r=-0.55). Higher expression of proteins involved in mitochondrial ROS generation and lower expression of proteins involved in lymphopoiesis and adhesion were associated with lower oxygen saturation and higher hemoglobin(Figure). Conclusion: Circulating plasma proteins in the Fontan circulation predict complement activation, mROS, cytoskeletal changes and decreased cell-cell adhesion. This circulating proteomic profile is associated with worsening heart failure and cyanosis providing mechanistic insight into heart failure progression and highlights novel therapeutic targets.
Abstract 4140585: Shifting in the settings of stroke fatalities during the COVID-19 pandemic
Authors: Hoang Nhat Pham, Farah Shrourou, April Olson, Abdulla Alabagi, Adam Habib, Kristina Terrani, Rafail Beshai, Tony Elias, Ibrahim Ramzi, Amitoj Singh, Kwan Lee
Journal: Circulation (2024)

Introduction: Stroke-related mortality poses significant challenges in the US. Increased at-home deaths since COVID-19 pandemic prompted changes in the provision of end-of-life care. Question: What were the settings of stroke deaths in the US during COVID-19 pandemic? Methods: Decedent-level mortality data from death certificates in CDC repository were obtained for the year 2020 (pandemic) and 2019 (comparison). Demographic data include age, sex, race/ethnicity, education, marital status, and place of stroke death, including inpatient, outpatient/emergency room (ER), hospice/nursing facilities (H/NF), and at-home. Multivariable logistic regression models assessed demographic impact on stroke mortality by place-of-death, yielding odds ratios (OR) with significance threshold of p&lt;0.05. Results: A total of 5,400 and 5,712 stroke-related deaths occurred in 2019 and 2020, respectively. During COVID-19, decedents &gt;65 years were more likely to die in H/NF (OR 10.05, p&lt;0.001) but less likely in outpatient/ER (OR 0.32, p&lt;0.001) or at home (OR 0.57, p=0.007) compared to those &lt;35 years. High education level did not significantly influence the place of death than having high school diploma or less (p&gt;0.05). Males were more likely to die at home (OR 1.38, p&lt;0.001) but less likely as inpatient (OR 0.79, p&lt;0.001) than females. Hispanic decedents had a higher likelihood of inpatient death (OR 1.22, p=0.041) but less likely to die in H/NF (OR 0.55, p&lt;0.001) compared to non-Hispanic decedents. Compared to White decedents, Black decedents were more likely to die in outpatient/ER (OR 1.44, p=0.018), while American Indian decedents were more likely to die as inpatient (OR 3.12, p=0.005). Asian/Pacific Islander decedents had a higher chance of inpatient death (OR 1.47, p=0.002) but a lower likelihood of dying in H/NF (OR 0.61, p=0.010). Married decedents were more likely than singles to die as inpatient (OR 1.37, p=0.001) or in outpatient/ER (OR 1.99, p&lt;0.001), but less likely to die in H/NF (OR 0.61, p=0.002) or at home (OR 0.56, p&lt;0.001). Conclusion: Our analysis revealed the influence of demographics on the settings of stroke fatalities during the COVID-19 pandemic. Further investigation is needed to determine contributing factors.
Abstract 4140001: Impact of White Matter Hyperintensity in the Corpus Callosum on Parahippocampal Atrophy and Prognosis in Heart Failure Patients Without Dementia
Authors: Tomomi Meguro, Yuko Meguro, Nobusada Funabashi
Journal: Circulation (2024)

Background: Aged heart failure (HF) patients without dementia have a risk of cognitive impairment (CI) that attenuates the effect of treatment for HF. White Matter Hyperintensity (WMH) and gray matter atrophy in parahippocampal gyrus (PHG) are a potential risk of CI. However, it is not clear whether location and volume of local WMH is associated with atrophy in PHG and predicts prognosis of HF patients. Hypothesis: In HF patients without dementia, local WMH volume is associated with brain atrophy of PHG and predicts prognosis. Methods: We enrolled sixty-one HF patients (age 76±11 years, NYHA class II, EF47±17 %) in the study. We excluded patients with dementia using mini-mental state examination. We took 3D-T1 weighted images and Fluid Attenuated Inversion Recovery (FLAIR) images of whole brain using 1.5T magnetic resonance imaging (MRI). We performed image analysis using 2mm voxel-based morphometry with Statistical Parametric Mapping to evaluate the local WMH volume in the frontal, temporal, parietal, and occipital lobes, as well as the corpus callosum ( CC ), and to assess the severity of PHG atrophy. We quantified the severity of PHG atrophy using Z-scores. We constructed receiver operating characteristic (ROC) curves to determine the cut-off point of the each local WMH volume for estimating cardiac death and admission due to HF. We constructed Kaplan-Meier Curves adjusted with age, sex, presence of atrial fibrillation, diabetes, dyslipidemia, and blood pressure using inverse probability weighting method. Results: Local WMH volume of CC demonstrated the highest prognostic accuracy (area under the ROC curve 0.73). We divided patients into High-WMH group (n=36, volume of WMH in CC 0.65±37 mL) and Low-WMH group (n=25, volume of WMH in CC 0.14±0.07 mL) according to the cut-off value (0.24 mL) of local WMH volume in CC. As shown in representative cases in Figure1, the Z-score value in PHG (pink circle) was higher in High-WMH group (1.43±0.77) compared to Low-WMH group (0.93±0.63, P=0.01). Adjusted Kaplan-Meier curves showed poor prognosis of High-WMH group (Figure 2). Conclusions: In HF patients without dementia, local WMH in corpus callosum is a potential risk of CI and predicts poor prognosis.
Abstract 4140045: Association of non-invasive liver fibrosis scores with disease severity and long-term adverse outcomes in patients with pulmonary arterial hypertension
Authors: Luyang Gao, sicheng zhang, Xin Li, Sicong Li, qing zhao, Zhihui Zhao, Anqi Duan, Zhihua Huang, Yijia Wang, Qin Luo, Zhihong Liu
Journal: Circulation (2024)

Background: Mounting evidence indicates that non-invasive liver fibrosis scores (LFs) are associated with various cardiovascular diseases, but their role in pulmonary arterial hypertension (PAH) is not yet clear. This study aims to explore the relationship between LFs and PAH. Methods: The study enrolled 1048 patients with PAH from January 2017 to January 2021, comprising individuals with idiopathic PAH and PAH related to congenital heart disease. Fibrosis-5 score (FIB-5), fibrosis-4 score (FIB-4), aspartate aminotransferase to alanine aminotransferase ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI) and Forns score (FC) were used to evaluate the degree of liver fibrosis in patients with PAH. The association of ILs with European Society of Cardiology (ESC) risk stratification was evaluated using one-way ANOVA. The correlation between LFs and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. Subgroup analyses, predicated on age, sex, World Health Organization functional class and body mass index, were carried out to evaluated interaction effects. Results: During a mean of 40.8 months’ follow-up, 283 participants experienced all-cause death or worsening condition. With higher ESC risk stratification, PAH patients had significantly lower FIB-5 (4.563±4.118 vs. 3.475±10.693 vs. 2.444±5.454 vs. 0.924±4.10, P=0.003) and higher FC (5.661±1.762 vs. 5.983±1.897 vs. 6.506±1.919 vs. 7.230±1.900，P&lt;0.001). After adjusting for confounding factors, multivariable Cox regression models indicated that FIB-5 (hazard ratio [HR] 0.968, 95% confidence interval [CI] 0.949-0.988, P = 0.005) and FIB-4 (HR 1.905, 95% CI 1.388-2.614, P＜0.001) independently predicted adverse outcomes. The highest predictive performance was observed for FIB-5 compared to other LFSs. No significant interaction effect was observed in the subgroup analysis. Conclusions: Liver fibrosis was associated with disease severity and long-term prognosis in patients with PAH. The markers FIB-5 and FIB-4 serve as independent predictors of clinical deterioration in patients with PAH.
Abstract 4140096: CCN2 Correlates with Early Markers of Right Ventricular Dysfunction in Adults with Pulmonary Arterial Hypertension
Authors: Jennifer Schramm, Carly Byrd, Anjira Ambade, Darin Rosen, Ilton Cubero Salazar, Catherine Simpson, Ryan Tedford, Steven Hsu, Paul Hassoun, Allen Everett, Rachel Damico
Journal: Circulation (2024)

Introduction: Cellular Communication Network 2 (CCN2, also known as CTGF and IGFBP8) is a cysteine-rich secreted matrix protein with four tandem modules and is an upstream regulator of TGFß, a key pathogenic molecule in pulmonary arterial hypertension (PAH). Altered right ventricular-pulmonary artery (RV-PA) coupling has been shown to be an early marker of right ventricular (RV) dysfunction associated with adverse outcomes in PAH. Research Question: We studied the relationship between CCN2 and the diagnosis, disease severity, hemodynamics, and metrics of pathologic RV structure and function in a deeply-phenotyped cohort of patients with suspected and established PAH. Methods: Adult PAH patients (N=38, median age 62 years, 79% female) and controls (N=8, median age 64.5 years, 100% female) had CCN2 levels measured from samples obtained the same day as simultaneous right heart catheterization, multi-beat pressure volume loop assessment, cardiac MRI and functional outcome assessment. CCN2 levels were log-transformed and adjusted for age and sex using linear and logistic regression to allow for comparison with clinical and hemodynamic variable. Analysis of composite outcome (death or transplant) was conducted using a Cox proportional hazard model and Kaplan Meier analysis. Results: CCN2 levels were associated with lower RV stroke volume (p&lt;0.05), lower RV end-systolic elastance (RV Ees, p&lt;0.02), and impaired RV-pulmonary arterial coupling (RV Ees/Ea, p&lt;0.05) by Spearman correlation. In linear regression models adjusted for age and sex, log(CCN2) was significantly associated with RV Ees and RV Ees/Ea (p&lt;0.001 and p = 0.04, respectively). CCN2 levels were not significantly correlated with other hemodynamics or functional status (p &gt;0.1 for all). Finally, higher log(CCN2) levels were correlated with lower transplant free survival with Cox Hazard Ratio of 3.99 (p&lt;0.04) in patients with PAH. Kaplan-Meier demonstrates patients with CCN2 level above a Youden cutoff of 43 ng/mL had increased mortality with median survival less than 7.5 years (Figure 1). Conclusions: CCN2 levels correlate with more impaired RV-PA coupling and worse outcomes for adults with PAH. This patient cohort were diagnosed early in the disease course with mild symptoms. There was an association between CCN2 levels with early markers of RV dysfunction, RV-PA uncoupling, RV stroke volume, and adverse outcomes. This implicates CCN2 as a potential biomarker of early RV dysfunction of PAH.
Abstract 4139864: Effect of P2Y12 Inhibitors on Plasma Metabolomic Changes in Patients with Acute Myocardial Infarction
Authors: Ceren Eyileten, Zofia Wicik, Michail Koutentakis, Aleksandra Gasecka, Jolanta Siller-Matula, Marek Postula
Journal: Circulation (2024)

Introduction/Background: Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Research Question/Hypothesis: The research question focuses on predictive analysis of drug response to P2Y12 inhibitors in patients with AMI prior to the initiation of treatment. Aim of the Study: In the present study, we aimed to investigate the metabolic profiles of plasma samples from AMI patients to identify potential disease biomarkers and to study patients after AMI treated with ticagrelor or clopidogrel. Methods: Twenty-two (22) patients with the first AMI were randomized to ticagrelor or clopidogrel. Plasma samples were obtained at three time points (24 hours, 72 hours, and 6 months) from AMI patients. Metabolic profiles of the plasma of 22 AMI patients and 11 controls (longitudinal sample size (N) = 77) were obtained, and over 1000 plasma metabolites were assayed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The Aligned Rank Transform (ARTool) R package was used as a nonparametric equivalent to the multi-factorial repeated measures analysis of variance (ANOVA) and post hoc analysis. Results: Trigonelline from the alkaloid group of metabolites was identified as a uniquely affected metabolite in paired comparisons for AMI patients. After 6 months, trigonelline levels were higher in patients on ticagrelor compared to those on ticagrelor at 72 hours after the switch and those on clopidogrel at 24 hours (p.adjusted (p.adj) = 0.017, p.adj = 0.038, respectively). Other affected groups of metabolites included triacylglycerols (TAGs) and triglycerides (TGs). Up and down-regulated metabolites are presented in Figure 1. Glycolithocholic acid sulfate (GLCAS) and Citrulline were upregulated, while TG was downregulated in clopidogrel group compared to ticagrelor group. phospholipids were found to be significantly lower in the AMI patients compared to control group (p&lt;0.001, see Figure 2). Conclusion: Our study showed that increasing levels of the trigonelline metabolite are associated with long-term response to ticagrelor treatment. Trigonelline is a product of niacin metabolism and a common plant alkaloid that has been shown to reduce platelet aggregation. It acts by affecting β-cell regeneration, insulin secretion, activities of enzymes related to glucose metabolism, reactive oxygen species (ROS), axonal extension, and neuron excitability.