tbuckley/cabot-search huggingface dataset:
Abstract 4147025: Obesity as an Underlying Driver of Differences in Racial and Socioeconomic Disparity Associated Cardiac DNA Methylation Among Men with End-stage Heart Failure
Authors: Samuel Chang, Kerstin Preuss, Benjamin Lin, Sayan Bakshi, C. Ryan Miller, Adam Wende
Journal: Circulation (2024)

Heart failure (HF) treatment advances have improved outcomes but HF heterogeneity leads to ~50% response to standard therapies, emphasizing a need to further study mechanisms of disparate outcomes. One serious disparity is increased cardiovascular disease risk and mortality in African Americans (AA) compared to Caucasian Americans (CA). Race is a social construct and thus poor proxy for physiology; hence, our lab studies epigenetics, stable yet reversible changes to DNA serving as a possible interface of how environment impacts gene regulation. We’ve previously implicated cardiac DNA methylation as a new indicator of socio-economic disparities in HF outcomes. Related to HF, US adult obesity rates are 40% and similar disparities exist with AA having higher rates, and studies on obesity show how inequity leads to disparate rates. Thus, our secondary analysis investigates the role of obesity, through its impact on cardiac epigenetics and transcription, as an underlying environment/molecular driver within HF disparities. Multi-omics data of left ventricular assist device placement biopsies of age-matched males were from our previous publication’s public dataset. Cardiac DNA methylation (850k-array) analyzed via minfi, and differential gene expression (RNA-seq) via DESeq2. Two-year survival is decreased in non-obese (NO) vs. obese (OB) patients (p&lt;0.01); specifically, decreased survival in AA-NO patients vs. CA-NO patients (Hazard Ratio=0.26, 0.08-0.91). Subgroup analyses reveal 2632 gene-associated differentially methylated CpG-probes between AA-NO vs. OB, and 5309 between CA-NO vs. OB (p&lt;0.05, |methyl-change|&gt;5%). Additionally, 19 differentially expressed genes between AA-NO vs. OB, and 236 between CA-NO vs. OB (q&lt;0.1, |Log FC|&gt;1.5); one key gene, TNFa induced protein 8 ( TNFAIP8 ), is increased in AA-NO vs. OB, but decreased in CA-NO vs. OB. Furthermore, the differential expression in each group correlates with canonical significant inverse DNA methylation at TNFAIP8 . Our survival data supports the literature of an “Obesity Paradox” where obese HF patients have better prognoses than non-obese patients. Through our analyses, we characterized impacts of obesity status on DNA methylation and gene expression within disparate HF outcomes and identified TNFAIP8 as a marker related to increased apoptosis in pathology progression. Thus, our work contributes molecular characterization of a possible effector of the differences seen in these specific patient populations.
Abstract 4146706: Amyloidogenic Medin Induces Prothrombotic Activation in Human Brain Microvascular Endothelial Cells
Authors: Kaleb Morrow, Nina Karamanova, Natalie Nabaty, Alana Maerivoet, Jillian Madine, Ming Li, Raymond Migrino
Journal: Circulation (2024)

Background: The endothelium plays a major role in preventing thrombosis. Aging leads to a hypercoagulable state with increased procoagulant factors without accompanying rise in anticoagulant factors, shifting the balance to a prothrombotic profile. This increases the risk for conditions such as stroke or myocardial infarction. The mediator/s of this change remains unknown. Medin is a 50 amino acid cleavage product of MFGE8, accumulates in the vasculature with aging and is the most common human amyloid. Vascular medin burden is increased in vascular dementia, Alzheimer’s disease and aortic aneurysms. Medin was shown to induce endothelial and smooth muscle dysfunction and endothelial pro-inflammatory activation. Its role in aging-associated prothrombotic activation is unknown. Aim: To determine the effect of medin on human brain microvascular endothelial cells (HBMVECs) expression and function of thrombomodulin (a transmembrane glycoprotein that is a major anticoagulant through its interaction with thrombin leading to activation of protein C and S which in turn degrades factors Va and VIIIa) and HBMVEC expression of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (major procoagulant proteins). Methods: Primary HBMVECs (passages 6-8) were exposed for 20 hours to physiologic doses of recombinant human medin (1 or 5 uM) and gene and protein expression of thrombomodulin, PAI-1 and tissue factor were measured using rtPCR or Western blot, respectively. In separate experiments, assessment of thrombomodulin function was determined by exposing HBMVECs for 20 hours to medin, after which human protein C (0.2 uM) and α-thrombin (10 nM) were added for 1 hour and amount of activated protein C in media was measured using ELISA. Results: Physiologic dose of medin (5 uM) given to HBMVECs resulted in reduced gene and protein expression of thrombomodulin (Fig. 1), increased gene and protein expression of PAI-1 (Fig. 2), and modest increased protein, but not gene expression of tissue factor (Fig. 3). Medin exposure also reduced HBMVEC ability to convert protein C to activated protein C in the presence of thrombin. Conclusions: Medin reduced HBMVEC production of anticoagulant protein thrombomodulin and increased protein expression of procoagulant proteins PAI-1 and tissue factor. Medin is a potential novel mediator of aging-associated hypercoagulability and could be a promising target in thrombotic diseases such as stroke.
Abstract 4146682: Rarer Than Rare: AL Amyloidosis Presenting as Abdominal Amyloidomas
Authors: Ahmed Wahaj, Naima Maqsood, Hormoz Ehya, Asya Varshavsky Yanovsky, Carly Fabrizio
Journal: Circulation (2024)

Case: A 52-yr-old man with weight loss and urinary hesitancy for 4 months underwent a CT urogram. No urologic abnormalities were noted but there was an incidental finding of intraperitoneal nodules and a perigastric mass. Biopsy of the perigastric lymph nodes showed abundant amyloid deposits, consistent with amyloidoma. Systemic amyloidosis workup was started. Serum immunofixation showed an IgG lambda M spike of 0.1 g/dL, and serum free light chain ratio was 0.17 (k/l = 10/60, mg/L). The tumor board recommended biopsy of other abdominal sites to distinguish plasmacytoma from amyloidoma. Biopsy showed amyloidosis with benign reactive lymph nodes and small clusters of lambda restricted plasma cells suggesting amyloidoma/plasmacytoma. Bone marrow biopsy showed 15% plasma cells, confirming multiple myeloma/amyloidosis overlap. Daratumumab-cyclophosphamide-bortezomib-dexamethasone (DARA-CyBorD) induction therapy was initiated. Transthoracic echocardiogram (TTE) showed normal biventricular function and moderate concentric hypertrophy. A cardiac MRI (CMR) then confirmed features of early amyloidosis. Light chains normalized with therapy but repeat bone marrow biopsy showed 5% lambda restricted plasma cells. Given the biopsy results and cardiac amyloid, consolidative autologous stem cell transplant was pursued to achieve a deep hematological response. Discussion: AL amyloidosis is a rare but fatal disease. Cardiac involvement is seen in &gt; 75% patients and degree of cardiac infiltration determines median survival. The initial presentation of intra-abdominal amyloidomas is highly unusual and only reported in case series in literature. A finding of amyloidoma should prompt workup for systemic amyloidosis. Cardiac workup should be undertaken even in the absence of overt symptoms. TTE findings in early cardiac amyloid are highly non-specific and can, therefore, be easily missed. A high index of suspicion is needed in this cohort with advanced imaging being pursued for any abnormality such as moderate concentric hypertrophy. Recognition of early cardiac involvement was key in deciding the chemotherapy regimen and in the decision to pursue autologous stem cell transplant for long term remission.
Abstract 4146705: Thrombo-inflammatory biomarker and blood cellular indices are predictive of 30-day mortality Outcome in Patients with Acute Pulmonary Embolism
Authors: Fakiha Siddiqui, Amir Darki, Alfonso Tafur, Bulent Kantarcioglu, Debra Hoppensteadt, Manuel Monreal, Jawed Fareed
Journal: Circulation (2024)

Introduction: Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is the leading cause of cardiovascular death. The pathophysiology of PE is complex and multifactorial. This study was designed to understand the relationship of thrombo-inflammatory biomarkers including endothelial dysregulation, platelet and coagulation activation, fibrinolysis, and inflammation along with blood cellular indices for 30-day mortality outcome in PE patients. Materials and Method: Citrated blood samples from 500 patients with the confirmed diagnosis of PE were collected from Loyola University Medical Center. Biomarkers including vWF, E-Selectin, P-Selectin, FVII, FIX, FX, FXIIIa, D-Dimer, PAI-1a, tPA, TAFIa, CRP, IL-6 and TNF-α were analyzed by Sandwich ELISA method. Blood cellular indices as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammation index (SII; NLR* platelets) were calculated from complete blood count. Thirty-day mortality data was obtained from chart review. Receiver operating curve (ROC) analysis to determine the optimal cutoff values, while for degree of association univariate chi-square and multivariate logistic regression analysis were performed for 30-day morality. Results: The study cohort includes 500 patients with equivalent distribution of male (52.1%) and female (47.9%) with the median age of 64-years. In first 30-day, 48 (9.7%) of the patients died. At baseline, patients who subsequently died had higher levels of vWF, P-selectin, tPA, PAI-1a, D-dimer, CRP, IL-6, TNF-α, NLR, PLR, and SII. Following ROC and univariate analysis, all the significant markers and indices were included in the multivariate logistic regression model. Of note, vWF &gt;140 (OR: 2.68; 95%CI: 1.04-6.92), F-X &lt;65 (OR: 4.55; 95%CI: 1.33-15.6), F-XIIIa &lt;58 (OR: 2.70; 95%CI: 1.13-6.47), D-Dimer &gt;13688 (OR: 3.51; 95%CI: 1.32-9.35), CRP &gt;12 (OR: 5.31; 95%CI: 1.01-28.0), TNF-α &gt;2 (OR: 2.65; 95%CI: 1.13-6.19), and NLR &gt;7 (OR: 4.44; 95%CI: 1.76-11.19) predicted risk of 30-day mortality in PE patients (Figure 1). Conclusion: This study suggests that patients with vWF &gt;140, FX &lt;65, FXIIIa &lt;58, D-Dimer &gt;13688, CRP &gt;12, TNF-α &gt;2, and NLR &gt;7 at baseline were at increased risk of death in 30-days. Study also suggests the integrated role of thrombo-inflammatory biomarkers and blood cellular indices for the risk stratification and prediction of the adverse outcomes.
Abstract 4146725: Young Adults with Migraine and Established Cardiovascular Disease Risk: Studying the Impact of Cannabis Use Disorder on Major Adverse Cardiac and Cerebrovascular Events in a Nationwide Study
Authors: Bhavin Patel, Boney Lapsiwala, Samir Vanani, Shaurya Patel, Aditya Suresh, Prayag Jariwala, Aayushi Rajani, Rupak Desai, Geetha Krishnamoorthy
Journal: Circulation (2024)

Background: With medical marijuana being used for migraine and high overlapping use of medicinal and recreational cannabis use with associated addiction potential, the impact on cardiovascular outcomes remains unexplored in the young population. Hence, we aim to analyze effect of cannabis use disorder (CUD) on major adverse cardiac and cerebrovascular events (MACCE) in patients with migraine. Methods: The National Inpatient sample from 2016-2020 was queried with pertinent ICD-10 codes to find inpatient encounters of young adults with migraine. A 1:1 propensity score-matched analysis was performed to obtain balanced CUD and without CUD cohorts matched on demographics and substance abuse. Multivariate logistic regression was used to analyze MACCE outcomes along with gender-based subgroup analyses. Results: We analyzed 490955 adults admitted with migraine with equal distribution of patients in both CUD and without CUD cohorts. Both the cohorts had significantly more females and patients with white ethnicity. Patients with CUD had significantly higher concomitant cocaine use disorder (6.8% vs 5.7%) but lower tobacco use disorder (50.6% vs 51.6%) compared to those without CUD. Surprisingly, non-CUD cohort had higher cardiometabolic comorbidities such as complicated hypertension (13.1% vs 9.8%), uncomplicated diabetes (9.8% vs 7.6%, hyperlipidemia (18.4% vs 16.2%), obesity (28.9% vs 19.9%). Multivariate regression analysis did not show any significant difference in overall MACCE outcomes. The subgroup analysis also did not show any difference in MACCE outcomes. Without CUD cohort had higher hospitalization cost compared to CUD cohort (32108$ vs 26721$). Conclusion: This nationwide covariate adjusted multivariate regression analysis shows no significant difference in all-cause mortality and other cardiovascular and cerebrovascular complications such as acute myocardial Infarction, atrial fibrillation, cardiac arrest, and stroke in young patients with migraine with and without CUD. Moreover, the subgroup analysis also shows comparable results in males and females.
Abstract 4146697: Computational Pipeline for Right Ventricular Hemodynamic Analysis from Pressure-Volume Loop Generation
Authors: Gyeongtae Moon, Vivek Jani, Ryan Tedford, Paul Hassoun, Steven Hsu
Journal: Circulation (2024)

Introduction: In patients with pulmonary hypertension (PH), right ventricular (RV) dysfunction is a key discriminator of clinical outcomes, However, current clinical indices of RV function are poor. The gold standard for evaluating RV function is the invasive pressure-volume (PV) loop, which is not acquired routinely clinically. Moreover, there is no streamlined pipeline for estimating PV loop derived from waveforms obtained by standard chart review. Here, we present a new semi-automated pipeline for single beat estimation of PV loops and load-independent RV contractile indices from clinically obtained waveforms from routine right heart catheterization. Methods: RV pressure waveforms were obtained from PH patients (n=24) ( Figure 1A ). Waveform reports were digitized using computer vision techniques and subsequently averaged for single-beat analysis. P isovol was calculated using a piece-wise sinusoidal fit. End-systolic (ESP) and end-diastolic pressures (EDP) were estimated using the square of the second derivative of the waveform. The end-diastolic pressure-volume relationship (EDPVR) was calculated by fitting an exponential function. Ejection was estimated using a cubic spline between (ESV, ESP) and (EDV, Pressure[dP/dt max ]). Clinically relevant RV functional parameters Ees (end systolic elastance) and Ea (effective arterial elastance) were obtained as previously described. Results: PV loops, Ees, and Ea were derived from 24 patients. Single-beat validation data were acquired by applying single-beat estimation to data collected from a standard pressure catheter. A representative pressure waveform and resulting PV loop estimate are shown in Figures 1A and B , respectively. The Bland-Altman analysis ( Figure 1C ) reported moderate to good agreement between two datasets, with a bias of -0.03 mmHg/mL (95% CI: -0.28, 0.21 mmHg/mL) and 0.08 mmHg/mL (95% CI: -0.29 to 0.45 mmHg/mL) for Ea and Ees, respectively. Conclusion: We have developed a novel and robust computational pipeline tool for digitization and single-beat analysis of RV pressure waveforms from an image of RV pressure waveform. Results from this pipeline were consistent with the single-beat validation data.
Abstract 4146636: Intensive Hypertension Management and Incident Heart Failure Risk for Blacks versus Non-Blacks: Insights From SPRINT
Authors: Racquel Hammonds, Richard Kazibwe, Mohanad Gabani, Saeid Mirzai, David Herrington, Michael Shapiro
Journal: Circulation (2024)

Background: Despite advances in blood pressure (BP) management, Black individuals continue to have disparate rates of uncontrolled hypertension and its sequelae, including heart failure (HF). The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated lower risk of cardiovascular diseases (CVD), including HF, among high-risk, hypertensive adults randomized to intensive (systolic BP [SBP] target &lt;120 mmHg) vs. standard (SBP target &lt;140 mmHg) BP control. Research Question: We asked if Black hypertensive adults in SPRINT had a higher risk of developing HF compared to non-Black adults and if intensive BP control reduced this risk. Aim: We aimed to highlight the disproportionate risk of HF in Black vs. non-Black individuals and the need for more intensive BP control in this population. Methods: The SPRINT participants were categorized by race into Black and non-Black groups, the latter incorporating non-Hispanic Whites, Hispanics, Indians, Hawaiians, Asians, and others. Cox proportional hazards regression models assessed the risk of incident HF adjusted for potential confounders, including age, sex, body mass index, subclinical CVD, smoking, SBP, number of anti-hypertensives, total cholesterol, aspirin use, statin use, estimated glomerular filtration rate, and BP treatment arm. Interaction testing assessed whether the effect of the BP treatment arm on incident HF risk differed by race. ARR was calculated as the difference in incident HF rates between the standard and intensive BP control groups for each racial group. Results: Of the 9,361 SPRINT participants, 31% identified as Black and 69% non-Black. Fully adjusted Cox regression analysis revealed increased risk of incidental HF among Black vs. non-Black participants (HR 1.45, 95% CI 1.05-2.00, p=0.002). There was no significant interaction between race and BP treatment arm for incident HF (p=0.79). Similar non-significant risk reduction with intensive vs. standard BP control was seen for Black (HR 0.78, 95% CI 0.47-1.31, p=0.35) and non-Black (HR 0.80, 95% CI 0.58-1.10, p=0.17) participants; however, ARR in incident HF was greater in Black (4.2%) vs. non-Black (3.1%) participants. Conclusion: Black participants had a higher risk for incident HF than non-Black participants. Despite similar relative risk reduction with intensive BP control by race, Black participants had higher ARR than non-Black participants, indicating potentially higher benefits with intensive BP control in Black individuals.
Abstract 4146669: Impacts of left ventricle–mitral annulus orifice area mismatch annuloplasty for advanced severe degenerative mitral regurgitation
Authors: Ming Chen, Zhang Yue, Pengning Fan, zhe chen, Yidan Zheng, Fuqiang Tong, haoyang zhai, Yuqi Liu, Xingyu Qian, zhenqi rao, Da Zhu, Xiangbin Pan, Nianguo Dong, Li Xu, Fei Li
Journal: Circulation (2024)

Background: In advanced severe degenerative mitral regurgitation (asDMR, i.e., C2 to D stage DMR), an overt deterioration of the mitral valve (MV) apparatus and left ventricular (LV) enlargement are typically observed. The negative impacts of a mismatch between the left ventricular end-systolic dimension (LVESD) and MV ring size on mitral regurgitation (MR) recurrence have been established in secondary MR, while its impacts on asDMR prognosis remains unknown. Hypothesis: LVESD/MV ring size ratio may impact on asDMR prognosis. Goals: To verify the impact and to reveal its side effects. Methods: We retrospectively analyzed patients diagnosed with asDMR who underwent mitral valve repair and annuloplasty from 2008 to 2019. Patients were followed up to April 2024. Primary outcomes included 10-year moderate or severe mitral stenosis (MS), recurrent MR, and death. Prosthetic orifice areas (POA) were obtained from official instructions. LVESD/POA was introduced as a novel parameter to identify LV-MV mismatch and non-mismatch. Results: A total of 450 eligible patients were enrolled. During the follow-up of 5.8 ± 2.3 years, 60 recurrent MRs, 71 MSs, and 46 deaths were observed. At 3rd, 5th, and 10th years after surgery, rates of freedom from recurrent MR were 98.1%, 92.4%, and 65.4%, respectively; rates of freedom from MS rates were 99.0%, 94.9%, and 59.4%, respectively; survival rates were 97.8%, 94.9%, and 69.6%, respectively. In multivariable Cox regression analysis, only a larger LVESD/POA ratio (HR: 3.50; 95% CI: 1.98-6.16; p &lt; 0.001) was associated with recurrent MR. ROC curve determined an optimal LVESD/POA cutoff value of 11.52 mm/m 2 (AUC = 0.88, p &lt; 0.001) for recurrent MR prediction. In subgroup analysis, mismatch group (LVESD/POA &gt; 11.52 mm/m 2 ) had higher cumulative recurrent MR rate (log-rank p &lt; 0.001), MS rate (log-rank p &lt; 0.001), and survival rate (log-rank p &lt; 0.001). In mismatch group, ring cohort exhibited higher cumulative MS rate (log-rank p = 0.027) and higher cumulative recurrent MR rate (log-rank p = 0.013). However, in the non-mismatch group, the cumulative MS and MR rates were comparable between the ring and band cohorts (log-rank p = 0.53). Conclusion: LV-MV mismatch annuloplasty increases the risks of recurrent MR, MS, and death. LVESD/POA ratio effectively predicts recurrent MR in asDMR. In patients with significant LV dilation, a posterior band may be preferable to a complete ring for downsized annuloplasty.
Abstract 4146678: Artificial Intelligence-enhanced Interpretation of Single-lead Electrocardiogram in Normal Sinus Rhythm to Detect and Predict Atrial Fibrillation and Flutter
Authors: Arya Aminorroaya, Lovedeep Dhingra, Aline Pedroso Camargos, Evangelos Oikonomou, Rohan Khera
Journal: Circulation (2024)

Background: Portable ECG devices can help identify symptomatic atrial fibrillation/flutter (AF) episodes outside healthcare settings. However, most individuals remain undiagnosed due to the transient and often asymptomatic nature of AF. Here, we developed an AI-ECG model to detect concomitant paroxysmal AF and predict its future risk using lead I ECG recordings in normal sinus rhythm (NSR), with special adaptation for noisy acquisition on portable devices. Methods: The model was developed using 1.6 million ECGs at Yale (2000-2015). ECGs in NSR associated with an ECG with AF rhythm from 30 days before to any time after were considered NSR with concomitant AF. A convolutional neural network was trained using lead I ECG to detect concomitant AF among NSR ECGs, augmented using random Gaussian noise during training to make them resilient to noisy acquisition on portable devices. We evaluated the model's probability as a predictor for incident AF (defined by AF ECGs or clinical diagnosis), in (1) a separate set of individuals in a temporally distinct population at Yale (2016-2023) and (2) the UK Biobank (UKB) (2014-2021), excluding those without a history of AF. We constructed age- and sex-adjusted Cox proportional hazards models with model probability as a key independent variable. Results: The AI-ECG model achieved an AUROC of 0.821 (95% CI, 0.818-0.824) for detecting concomitant AF based on a single-lead ECG in NSR with a sensitivity of 75%, a specificity of 75%, a PPV of 28%, and an NPV of 96%. In the predictive assessment, 312,533 individuals (52 [IQR, 32-66] years, 54% women) at Yale, and 41,711 individuals (65 [59-71] years, 52% women) in UKB had no known AF. In these groups, 3.1% at Yale and 1.4% in UKB had incident AF over median follow-ups of 3.1 [1.6-4.5] years and 3.0 [2.1-4.5] years, respectively. AI-ECG had high discrimination for future AF risk (Harrell’s C-statistic, 0.77 in Yale and 0.68 in UKB). After accounting for age and sex, a positive AI-ECG was associated with a 2-fold higher hazard of AF (adjusted HR: 1.93 [1.84-2.02] in Yale and 2.34 [1.98-2.76] in UKB). Conclusion: We developed an AI-ECG model capable of detecting concomitant paroxysmal AF and predicting incident AF using a single-lead ECG noted to be in NSR. With the growing availability and accessibility of portable ECGs, this model enables a scalable screening and risk stratification strategy for AF, especially in older adults at increased risk of stroke, in the community.