bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4142154: Risk of Suicide, Hair Loss, and Aspiration with Glucagon-like Peptide 1 Receptor Agonists: A Real-World Pharmacovigilance Study from the FAERS database
Authors: Nakhla Michael , V Ambica , Balani Prachi , Ujjawal Aditi , Arun Kumar Pramukh , Dasari Mahati , Yukselen Zeynep , Bansal Kannu , Ganatra Sarju , Dani Sourbha
Published: November 2024

Introduction:
With the increasing popularity of glucagon-like peptide 1 receptor agonists (GLP1-RAs), numerous safety concerns arose pertaining to suicide, hair loss, and aspiration risks. We attempted to validate these concerns.

Methods:
We queried the FDA Adverse Event Reporting System (FAERS) database; a post-marketing pharmacovigilance database, from Q4/2003 till Q3/2023 to analyze public reports of these adverse events with GLP1-RAs and other diabetes medications, including sodium-glucose transporter 2 inhibitors (SGLT2is), dipeptidyl peptidase 4 inhibitors (DPP4is), sulfonylureas, metformin, and insulin. OpenVigil 2.1 is an online tool that was utilized to perform disproportionality analysis. A positive signal signifying disproportionate reporting was detected if the proportional reporting ratio (PRR) > 2 and chi-squared (χ2) > 4 for any drug-event pair. The studied medications were arranged in descending order according to the corresponding reporting odds ratio (ROR), which is a measure of the likelihood of reporting a certain event with a certain drug in comparison to all other drugs in the database.

Results:
No positive signals were observed between GLP1-RAs and either suicide, hair loss, or aspiration events. Semaglutide [ROR= 0.601 (95% CI 0.51 - 0.71)] and liraglutide [ROR= 0.282 (95% CI 0.228 - 0.35)] had higher suicidal events than DPP4is and SGLT2is. GLP1-RAs were the most reported class with hair loss [ROR= 0.605 (95% CI 0.6 - 0.64)], and semaglutide, liraglutide, and dulaglutide were the three leading medications. GLP1-RAs ranked lower with aspiration events, which were led by sitagliptin and DPP4i as a group. Only metformin and glyburide generated positive signals with suicide risk.

Conclusion:
GLP1-RAs exhibit higher reporting of suicide, hair loss, and aspiration events when compared to several other antidiabetic medications, despite not meeting the criteria for positive signals yet. This warrants intensive monitoring and reporting.
Abstract 4142158: Murmur Detection and Classification Using Signal Processing and Sound Feature Analysis
Authors: Sivaraman Ram , Xiao Yizi
Published: November 2024

Introduction:
Heart murmurs are abnormal sound signals generated by turbulent blood flow and are closely associated with specific heart disorders. Current methods to detect and qualify murmurs do not recognize that an important part of diagnosing a patient depends upon murmur location in the heart valves and timing between fundamental heart sounds. This research presents HM-Detect, a novel algorithm to provide accurate heart murmur characteristics to cardiologists, specifically in telemedicine. In particular, can we use signal processing and machine learning techniques to detect and classify heart murmur characteristics (e.g. timing and location) from heart sound signals?

Approach:
HM-Detect analyzes heart sound features, namely the filterbank energies and spectral sub-band centroids. Four separate Random Forest Classifiers (RFCs) were built for each of the four valves of the heart using statistical moments of these features. Additionally, an undersampling technique on heart sound data and a novel “multi-modal” long short-term memory (MMLSTM) neural network incorporate the temporal aspect of heart sounds. The algorithms were validated on signals from the CirCor DigiScope dataset, which is a clinically verified dataset. Three different neural network architectures with varying number of cells and MMLSTM layers were compared.

Results and Data Analysis:
The feature importance of the first four statistical moments from the RFCs show that the variance has the lowest importance (max value < 0.010) while the mean, skewness, and kurtosis, have higher importance (max value > 0.020). All RFC models were evaluated using the area under their receiver operating characteristic curves (AUROCs). The RFCs were much more successful at classifying murmurs from the pulmonary and tricuspid valves (AUROC = 0.83 and 0.78, respectively) when compared with the aortic and mitral valves (AUROC = 0.72 and 0.65, respectively). Furthermore, the proposed method for murmur timing can achieve a performance accuracy of around 90%, with the best of the three MMLSTM-based models having an F1 score of 0.91 and a test accuracy of 87%.

Conclusions:
Heart sound features, namely filterbank energies and sub-band spectral centroids, were successfully used to build RFC algorithms which accurately classify murmur locations. The combination of undersampling and MMLSTMs allow for an encapsulation of the spatiotemporal profile of heart sounds and accurately detect and classify heart murmurs based on murmur timing.
Abstract 4142173: Inpatient Outcomes for Patients with Peripheral Artery Disease Hospitalized for Acute Myocardial Infarction
Authors: Gusdorf Jason , Faridi Kamil , Wang Tracy , Mena-Hurtado Carlos , Smolderen Kim , Rymer Jennifer , Curtis Jeptha , Secemsky Eric
Published: November 2024

Background:
Patients with peripheral artery disease (PAD) and coronary artery disease (CAD) are at high risk for adverse cardiovascular events. Prior research shows worse clinical outcomes for these patients, but contemporary in-hospital outcomes for PAD patients hospitalized with acute myocardial infarction (AMI) are not well characterized.

Objectives:
The objective of this study was to characterize in-hospital mortality and major bleeding events in PAD patients hospitalized with AMI in the U.S. We hypothesized that patients with PAD have higher rates of bleeding and mortality during AMI hospitalization.

Methods:
We assessed characteristics, major bleeding, and mortality of AMI patients with PAD, defined as atherosclerotic disease in peripheral arteries, at 670 hospitals in the NCDR Chest Pain MI Registry between January 01, 2019 and March 31, 2023. Primary endpoints were in-hospital mortality and major bleeding. Exploratory endpoints included cardiac arrest, cardiogenic shock, heart failure, stroke, and new dialysis requirement.

Results:
Of 493,740 patients, 36,274 (7.4%) had PAD. These patients were older with higher prevalences of comorbidities. In-hospital mortality was 8.2% for patients with PAD vs. 4.9% for those without PAD, while major bleeding occurred in 9.7% of patients with PAD and 6.3% of those without PAD. After multivariable adjustment, PAD was associated with increased mortality (aOR 1.25; 95% CI 1.19 to 1.31) and major bleeding (aOR 1.23; 95% CI 1.17 to 1.28). The elevated risk of in-hospital mortality was driven by patients with PAD who were 65 years of age or older (aOR 1.29; 95% CI 1.22 to 1.37), whereas no significant difference was observed in patients younger than 65 years (aOR 1.00; 95% CI 0.91 to 1.09). No significant interactions for mortality risk were observed based on sex (p=0.98) or race (p=0.84). For major bleeding, no significant interactions were observed based on age (p=0.41), sex (p=0.84), or race (p=0.27). Exploratory endpoints showed poorer outcomes in PAD vs. non-PAD patients regarding cardiac arrest (6.4% vs. 4.6%), cardiogenic shock (6.9% vs. 4.8%), heart failure (2.5% vs. 1.0%), stroke (1.4% vs. 0.9%), and new dialysis requirement (2.5% vs. 1.0%).

Conclusions:
This large, nationally representative study demonstrates that PAD patients hospitalized for AMI are at increased risk for in-hospital mortality and major bleeding compared to patients without PAD. Improved management strategies in the acute care setting are needed.
Abstract 4142190: Patient-Reported Health Status Among Patients with Heart Failure with Improved Ejection Fraction
Authors: Vasti Elena , Zheng Jimmy , Kalwani Neil , Dejong Colette , Bhatt Ankeet , Ambrosy Andrew , Din Natasha , Heidenreich Paul , Sandhu Alexander
Published: November 2024

Introduction:
The prevalence of heart failure with improved ejection fraction (HFimpEF) is growing. The association of ejection fraction recovery and changes in health status has not been previously reported.

Hypothesis:
We hypothesized patient-reported health status (HS) will be significantly better among patients with HFimpEF compared with those with HF with reduced ejection fraction (HFrEF) or HF with mid-range/preserved ejection fraction (HFmrEF/HFpEF).

Methods:
We identified patients with HF with at least 2 encounters with the Stanford cardiology clinic who completed a routinely collected Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 from 8/2020 to10/2023. HFimpEF was defined as most recent EF>40% from a preceding echocardiogram
>
30 days prior with EF
<
40%. We compared patient sociodemographic and clinical characteristics across EF classifications. We analyzed KCCQ-12 Overall Summary Score (OSS) across EF classifications with and without adjustment for patient characteristics via multivariable linear regression, from which we calculated the R
2
to determine the impact of clinical characteristics on variation in HS among patients with HFimpEF.

Results/Data:
A total of 2,519 patients were included in this analysis, of which 18.7% had HFimpEF, 55.7% had HFmrEF/HFpEF, and 25.6% had HFrEF. Median KCCQ-12 OSS was 80.3, 73.9, and 80.8 for HFimpEF, HFrEF and HFmr/HFpEF patients, respectively. Patients with HFimpEF were less likely to be women compared with patients with HFmrEF/HFpEF (41% vs 58%, p<0.01). There was substantial overlap in the KCCQ-12 OSS across EF classifications (
Figure
). KCCQ-12 OSS score was 5.2 points lower among patients with HFrEF compared with patients with HFimpEF [(95% CI: -8.2 to -2.3); p=0.01] but patients with HFimpEF had similar scores to those with HFmrEF/HFpEF [-1.1 (95% CI: -3.7 to 1.6); p=0.43]. Among patients with HFimpEF, a multivariable regression model explained 16% of the variation in the KCCQ-12 OSS.

Conclusions:
Despite improvement in EF, patients with HFimpEF continue to have impaired HS that is similar to patients with HFpEF and HFmrEF. Further research is needed to better understand impaired HS and to identify interventions to improve health status among patients with HFimpEF.
Abstract 4142209: Left Atrial Pressure at Time of Atrial Fibrillation Ablation: A Tool in The Diagnosis of Underlying CHF and Risk of Readmission
Authors: Jewulski Jacob , Schultz Thomas , Fabry Nicholas , Berger Marcie
Published: November 2024

Background:
Patients with CHF at time of AF ablation are more likely to have earlier (<90 days) AF recurrence, more CHF exacerbations, and prolonged index hospitalization. The diagnosis of CHF in those with AF can be confounded by their overlapping symptoms leading to under-recognition and delays in care. This study aims to determine whether elevated left atrial mean pressure (LAP) at time of AF ablation, measured immediately after transseptal catheterization, allows for detection of previously undiagnosed and undertreated CHF, and whether this may serve as a marker for patients at higher risk of AF recurrence and rehospitalization.

Methods:
A retrospective chart review was performed of all patients ≥18 years old at an academic medical center with a diagnosis of AF and who underwent AF ablation between 5/2022 and 9/2023. The cohort was divided into those with LAP ≥15 mmHg and those with LAP <15 mmHg at time of AF ablation. Baseline demographics, comorbidities, readmission rates, GDMT, and antiarrhythmic prescription rates were collected.

Results:
This analysis included 238 patients (31.5% female). At time of ablation, 77 (32.4%) had a LAP ≥ 15 mmHg, of which 34 (44.2%) did not have a pre-existing diagnosis of CHF. Those with LAP ≥15 were more likely to be on RAAS inhibition (57.1% vs 43.5%, p=0.048), MRA (23.4% vs 8.7%, p=0.002), and SGLT2i (23.4% vs 10.6% p=0.009) compared with those with a normal LAP. While not reaching statistical significance, elevated LAP was associated with higher NT-proBNP at time of ablation (1657 vs 930 p=0.129) despite higher BMIs (34.8 vs 30.1, p<0.001), with a trend towards increased 90-day readmission (9.1% vs 3.7%, p= 0.088).

Discussion:
LAP measurement identified a significant number of patients undiagnosed with CHF (44.2%). Elevated LAP also trended toward higher NT-proBNP despite having a higher BMI. Although rates of GDMT were higher for those with LAP ≥15 mmHg, the group remained significantly undermedicated, particularly with SGLT2i (29.3%, p<0.001) and MRA (26.3%, p<0.001). This may indicate suboptimal GDMT for both HFrEF and HFpEF. While not reaching statistical significance, this lack of recognition of CHF and subsequent lapse in GDMT prescription likely influenced the trend towards increased 90-day readmissions post ablation (p=0.088). Further work is needed to determine if identification of patients with elevated LAP at time of AF ablation can be prospectively optimized on GDMT improve outcomes post ablation.
Abstract 4142226: Quantifying the influence of baseline body weight on sex differences in semaglutide-associated weight loss
Authors: Levy Matthew , Telis Natalie , McEwen Lisa , Schiabor Barrett Kelly , Bolze Alexandre , White Simon , Stoller Douglas , Chapman Christopher , Chahal C. Anwar , Judge Daniel , Olson Douglas , Grzymski Joseph , Washington Nicole , Cirulli Elizabeth
Published: November 2024

Background:
Males tend to lose less weight than females with semaglutide, a GLP-1 receptor agonist, for unknown reasons. One hypothesis is that lower average body weight in females may result in greater drug exposure, leading to more weight loss.

Objective:
Leveraging a multi-state network of clinico-genomic cohorts, we aimed to quantify the extent to which sex differences in baseline body weight could explain semaglutide-associated weight loss differences between males and females.

Methods:
We utilized electronic health record data and clinical-grade sequencing from multiple U.S. cohorts (n>100k). Among individuals starting semaglutide with BMI ≥27 kg/m
2
(consistent with guidelines), we analyzed weight measurements over a 12-month use period. A BMI polygenic score (PGS) using 27k variants (PGS001228) was calculated. Percent weight change was modeled using mixed effects models with quadratic and cubic terms for time and interaction terms with baseline weight, sex, and confounders (semaglutide dose, age, ancestry, BMI PGS, comorbidities, medications). We also conducted a mediation analysis to test whether baseline weight mediated the relationship between sex and weight loss.

Results:
Among 959 females and 352 males, 7,381 weight measurements occurred over a median of 8.9 months (IQR: 6.2-10.8). Median baseline weight was 102 kg (IQR: 90-119) for females and 114 kg (IQR: 100-133) for males. Median weight loss at 6- and 12-months was 5.2% (IQR: 1.9-9.1) and 6.5% (IQR: 2.0-11.8) for females and 3.3% (IQR: 1.0-6.5) and 4.5% (IQR: 1.3-7.7) for males. After adjustment, male sex was associated with a lower rate of weight loss (β=+0.95% [per 6 months], p=0.003). Other factors associated with lower weight loss were BMI PGS (β=+1.28% [top vs bottom quintile], p=0.002), type 2 diabetes (β=+0.88%, p=0.006), hypertension (β=+0.72%, p=0.025), obstructive sleep apnea (β=+0.65%, p=0.032), and insulin use (β=+0.76%, p=0.035). In the mediation analysis, the proportion of the sex-weight loss association that could be explained by baseline weight was 8.4% (95% CI: 2.9-20.6) and 16.0% (95% CI: 10.7-26.2) at 6- and 12-months.

Conclusions:
Baseline body weight explained only a small fraction of the observed sex difference in semaglutide-associated weight loss, suggesting that other factors (e.g., hormonal) may play a more significant role. Findings also highlight the impact of traditional metabolic risk factors and BMI-associated genetic variants on weight loss with semaglutide.
Abstract 4142227: Accuracy Of Stroke Prediction Using The Predicting Risk Of CVD Events Equation Among Diverse Adults Of The Northern Manhattan Study
Authors: Mesa Robert , Gardener Hannah , Rundek Tatjana , Brown Scott , Yang Eugene , Elkind Mitchell , Gutierrez Jose , Besser Lilah , Gutierrez Carolina , Veledar Emir , Levin Bonnie , Agudelo Christian , Elfassy Tali
Published: November 2024

Background:
The Predicting Risk of CVD EVENTs (PREVENT) equations are a new set of sex-specific and race-free equations developed by the American Heart Association to calculate risk of cardiovascular disease, including stroke as an independent outcome.

Objective:
To describe the ten-year risk of stroke (ischemic and hemorrhagic) using the PREVENT equation and assess its validity in predicting stroke among racially and ethnically diverse adults.

Methods:
The Northern Manhattan Study is a community-based observational cohort of male and female participants who are of non-Hispanic White (NHW), non-Hispanic Black (NHB), and Hispanic background. Participants were aged 40 years or older and without a history of stroke at the baseline visit between 1993 and 2001. Information was collected on blood lipids, systolic blood pressure, body mass index, estimated glomerular filtration rate, smoking status, diabetes status, and anti-hypertensive or lipid lowering medication use. Using the base model PREVENT equation for stroke, we calculated the ten-year risk of stroke and categorized participants based on levels of risk. Participants were followed and stroke events occurring within ten years were adjudicated by an independent panel of clinicians. We calculated the stroke discordance rate by comparing the predicted to observed number of strokes overall, by sex, and by race/ethnicity.

Results:
Among 2,229 participants, mean age was 65 years, with 61% female, 17% NHW, 20% NHB, 60% Hispanic, and 2% Other. Overall, 25% had a <2.5% risk of stroke; 34% had a 2.5 to <5.0% risk of stroke, 25% had a 5.0 to <7.5% risk of stroke, 11% had a 7.5 to <10.0%, and 5% had a ≥10% risk of stroke. Men compared with women and NHB compared with NHW adults had a higher risk of stroke, p<0.05. Over ten years, 106 strokes were predicted, and 136 strokes were observed (discordance rate: 22%). Stroke was more likely to be underpredicted among females (discordance rate: 24%) than males (discordance rate: 20%), p<0.01 and among NHB (discordance rate: 42%) or Hispanic adults (discordance rate: 18%) compared with NHW adults (discordance rate: 0%), p <0.01.

Conclusion:
In this sample of urban dwelling adults, the base model PREVENT equation for stroke was most accurate in predicting stroke among NHW adults but performed with less accuracy among NHB and Hispanic adults. Additional factors, such as the social deprivation index, may be important for estimating stroke risk in NHB and Hispanic populations.
Abstract 4142231: Relationship between serum interleukin-6 levels and severity of STEMI undergoing percutaneous coronary intervention
Authors: Lam Pham Son , Toan Nguyen Duy , Pho Dinh Cong , Chien Do Van
Published: November 2024

Background:
Little is known about the clinical relevance of interleukin (IL)-6 and the severity of patients with acute ST-elevation myocardial infarction (STEMI). This study examined the possible associations of plasma IL-6 concentrations with TIMI scores in STEMI patients treated with primary percutaneous coronary intervention (PCI).

Methods:
The descriptive, cross-sectional study was conducted in patients with STEMI with a confirmed diagnosis and percutaneous coronary angiography at 108 Military Central Hospital from April 2023 to April 2024. All information about clinical and paraclinical parameters was recorded. Blood samples for biomarker analyses, including IL-6, were collected.

Results:
There were 64 consecutive STEMI patients. There was 75% of males. The ROC curve analysis performed in STEMI patients showed that IL-6 could be a powerful predictor marker in the TIMI score. The area under curve was 0.905 . The cut-off point was 14.9 ng/L, showing a < 4 or ≥ 4 TIMI score. Patients with IL-6 concentrations cut-off point showed a significantly higher time of STEMI, GOT, higher pulmonary arterial pressure, and longitudinal tracking of left atrial diameter. Patients with IL-6 concentrations cut-off point showed a significantly lower fractional shortening, and lower tricuspid annular plane systolic excursion.

Conclusions:
IL-6 levels were associated with the severity of STEMI assessed by the TIMI score. Based on the cut-off levels of IL-6 measured in patients with STEMI, our study strongly suggests that IL-6 could be a powerful marker in evaluating the time of STEMI and some echocardiography indexes.
Abstract 4142247: Granzyme B PET Imaging for Non-Invasive Early Diagnosis of Acute Heart Allograft Rejection
Authors: Wei Zhuxin
Published: November 2024

Background:
Cardiac transplantation remains the single most effective treatment for end-stage heart failure. Despite the routine use of anti-rejection drugs in clinical practice, approximately 40% of cardiac transplant patients still experience unavoidable rejection. Timely diagnosis of early acute rejection (AR) is essential to prevent further tissue damage. Transplant rejection and graft damage is primarily mediated by recipient cytotoxic CD8
+
T cells, which attack allografts by releasing perforin and granzyme B (GzmB).

Aim:
This study aimed to evaluate whether GzmB-targeted positron emission tomography (PET) imaging agent (
68
Ga-grazytracer) can characterize T lymphocyte infiltration in AR.

Method:
Mice were subjected to GzmB-targeted PET/CT on POD 3, 5, and 7. Autoradiography, Masson staining, immunohistochemistry, and flow cytometry were performed to verify the inflammatory infiltration and graft damage . Allograft-bearing mice were intraperitoneally administered with tacrolimus (2 mg kg
−1
) daily from operative day to post-operative day (POD) 7.

Result:
The uptake of
68
Ga-grazytracer was observed increased with the extension of rejection time(SUVmax:0.54 ± 0.07 vs. 0.19 ± 0.05 at POD 7 days, P<0.001). To assess
68
Ga-grazytracer sensitivity and specificity between isograft and allograft groups, POD 7 PET/CT imaging were analyzed for their catalytic activities by receiver-operating-characteristic(ROC)analysis (AUC=0.95, 95% CI = 0.8143–1). HE staining of the myocardium indicated massive inflammatory cell infiltration and disruption of the myocardial integrity in the allograft myocardium. Immunohistochemistry and flow cytometry showed significantly high expression of GzmB and CD8, in line with the PET/CT imaging results. Autoradiography revealed
68
Ga-grazytracer accumulation in the transplanted heart. The
68
Ga-grazytracer uptake of treated mice was significantly reduced compared with that in the allograft group (SUVmax: 0.262±0.05% vs. 0.54±0.07 at POD 7 days; P<0.001). Daily treatment with tacrolimus improved heart allograft outcome and graft survival curves revealed complete rejections of the allograft within POD 15±3 days.

Conclusion:
This study demonstrated the potential of
68
Ga-grazytracer imaging to delineate early non-invasive diagnosis of heart allograft rejection. This study provides an entirely imaging-based method for monitoring allograft status. In the future, the development of imaging of GzmB may be more readily translated into clinical applications.
Abstract 4142250: Circulating Progenitor Cells are Associated with Cognitive Impairment and Structural Brain Changes
Authors: Woods Edward , Gold Matthew , Rahbar Alireza , Hossain Mohammad , Hajjar Ihab , Waller Edmund , Quyyumi Arshed
Published: November 2024

Introduction:
Circulating progenitor cells (CPC’s) are mononuclear stem cells which originate in the bone marrow, and circulate in the blood, playing a role in promoting vascular regeneration and healing. Previous studies have shown associations between lower levels of CPC’s and increased all-cause mortality, MACE, and atherosclerosis. Additionally, those with cognitive disorders such as Alzheimer’s disease have been shown to have reduced levels of CPC’s, and some association between CPC’s and cognitive decline has been shown. Clinical surrogates for cognitive decline include a lower Montreal Cognitive Assessment (MoCA) score, and an increase in white matter hyperintensities (WMH) on MRI. We hypothesize that reduced circulating EPCs are associated with a lower MoCA score and an increased number of white matter hyperintensities (WMH) on MRI.

Methods:
In 181 participants (40.3% male, 41.4% Black) with and without mild cognitive impairment, CPCs were enumerated by flow cytometry as CD45
med
mononuclear cells expressing CD34 and co-expression with either CD133, chemokine CXC motif receptor 4 (CXCR4), or vascular endothelial growth factor receptor-2 (VEGF2R). Participants were followed for four years and underwent neuropsychiatric testing and MRI imaging. MoCA testing was used to evaluate multiple domain cognitive function. Diffusion weighted MRI was used to evaluate for WMH indicating microvascular damage. Linear regression modeling was used to determine the cross-sectional association between CPC’s and both the MoCA score and burden of WMH after adjusting for age, gender, race, body mass index, history of heart failure, and history of chronic kidney disease.

Results:
Lower levels of CD34/VEGF2R were associated with lower MoCA scores (β=1.31, p=0.025) and more WMH (β= -2109.1, p=0.011) when comparing first and fourth quartile of CPC concentration. Additionally, decreased CD34/133 and CD34/CXCR4 were associated with an increased burden of WMH (β=
-
3491.1, p=0.029 and β= -2419.8, p=0.012) when first and fourth quartiles were compared.

Conclusions:
Lower CPC counts of CD34 subsets were associated with worse performance on MoCA and more white matter hyperintensities on MRI, demonstrating that lower endothelial regenerative capacity may lead to decreased cognition and cognitive decline.
Abstract 4142260: Single-cell analysis on peripheral blood mononuclear cells reveals immunodeficiency in pediatric patients with conotruncal defects
Authors: He Qiyu , Wang Peng , Shen Huayan , Li Shoujun
Published: November 2024

Background:
Congenital heart diseases (CHD) are the most common birth defects. Previous studies have revealed the susceptibility of CHD patients to immunodeficiency; however, the heterogeneity of immune cells landscape underlying CHD patients remains poorly understood.

Research question:
Are peripheral blood mononuclear cells dysregulated in pediatric CHD patients?

Aims:

We aimed to investigate the landscape of peripheral blood mononuclear cells in CHD patients with conotruncal defects by comparison against healthy controls.

Methods:
Peripheral blood samples were collected in 5 patients with conotruncal defects and 3 healthy children. We conducted single-cell transcriptome analysis on peripheral blood mononuclear cells from these samples.

Results:
The scheme of whole study was shown in Figure 1A. A total of 44,530 cells were identified after quality-control, clustered into 8 groups, and annotated with canonical PBMC markers (Figure 1B). Compared with healthy controls, patients were characterized with a prominent decrease in natural killer T (NKT) cells and an increased proportion of monocytes were observed (Figure 1C). Zooming into NK-like cells confirmed a significant contribution of NKT cells in difference between groups, whilst other types were similar in both groups (Figure 2A). The differentially expressed gene in NKT were enriched in pathway involving T helper cells differentiation, signal transduction and regulation (Figure 2B). Furthermore, NKT in patients showed a significantly lower proliferation score in contrast with a higher apoptosis score (Figure 2C&D). Although monocytes in patients were more in quantity, the composition of CD14
+
and CD16
+
subtypes were comparable between groups (Figure 3A). Concordantly, apoptosis score of monocytes were similar. However, the T cell proliferation score was lower in case group (Figure 3B&C). In addition, CD14
+
and CD16
+
monocytes both showed distinct transcriptome between groups and the differentially expressed genes were prevalently enriched in inflammation-related pathways (Figure 3D&E).

Conclusion:
Single-cell analysis revealed a dysregulated PBMC landscape in pediatric patients with conotruncal defects, exhibiting a prominent decrease in NKT population and an increased proportion of monocytes. Transcriptome analysis further indicated a less mature immune phenotype in NKT and monocytes differentiation. Future study is warranted to further investigate the roles of these cells on immunoregulation in these patients.
Abstract 4142270: Epigenetics of Shared and Unique Pathways Associated with Atherogenic Lipoprotein Particle Content and Number Across the Early Adult Life Course
Authors: Wilkins John , Qu Yishu , Allen Norrina , Ning Hongyan , Hou Lifang , Lloyd-Jones Donald , Sniderman Allan , Joyce Brian , Zheng Yinan
Published: November 2024

Intro:
Exposure to atherogenic lipoproteins is a central determinant of atherosclerotic cardiovascular disease (ASCVD) events. Shared and unique biological pathways influence lipoprotein particle content (non-HDL-C, LDL-C) and number (apoB, LDL-P), but significant unexplained variance in blood lipoprotein levels remains. Understanding the associations between lipoprotein particle number, content, and repeated DNA methylation (DNAm) measures may provide novel insights into lipoprotein level determinants.

Methods:
We included 2962 participants from the Coronary Artery Risk Development in Young Adults study that had DNAm, LDL-C, non-HDL-C, apoB, and LDL-P measurements at exam years 15, 20, 25, and 30. Non-HDL-C and LDL-C were determined using standard laboratory technique. LDL particle number (LDL-P) and apoB were measured using NMR. DNAm was assessed using the Illumina Epic Array. We used separate mixed linear models adjusted for age, sex, race, and technical variables to quantify associations between DNAm sites and non-HDL-C, LDL-C, LDL-P, and apoB. We performed pathway analysis of DNAm located in gene promoter regions. We estimated % variance in lipid levels explained by associated DNAm sites using ANOVA.

Results:
There were 127, 182, 40, and 110 DNAm sites that were uniquely associated with LDL-C, non-HDL-C, LDL-P, and apoB, respectively. There were 114 DNAm sites associated with 3 or more of these atherogenic lipid measures. Of note, 6 DNAm sites were in the promoter of LDLR. Shared pathways included cholesterol and fatty acid metabolism, steroid and alcohol biosynthesis, as well as cellular protein transport (Table).Unique pathways generally included cholesterol synthesis for LDL-C, and energy metabolism, inflammation, and calcium transport for apoB and LDL-P. In total, identified CpGs in circulating blood leukocytes explained 14%, 24%, 16%, and 17% variance in LDL-C, non-HDL-C, LDL-P, and apoB, respectively.

Conclusions:
Assessment of longitudinal epigenetic patterns in peripheral leukocytes suggest unique and shared pathways mediate a large % variance in atherogenic lipids. Further exploration of the function of these DNAm sites may enhance mechanistic insight into the determinants of atherogenic lipid exposure.
Abstract 4142287: 4-Phenylbutyric Acid Reduces Endoplasmic Reticulum Retention and Partially Restores Function of LDLR p.D622N Mutation In Vitro: A Potential Therapy for Hypercholesterolemia
Authors: Wang Yongxiang , zhang piyi , bai ming , Zhang Zheng
Published: November 2024

Background:
We identified a family with familial hypercholesterolemia (FH). The proband presented with corneal arcus, skin, and tendon xanthomas, significant stenosis in the coronary circumflex and right coronary arteries, and severely elevated plasma LDL levels. Treatment with statins, ezetimibe, PCSK9 monoclonal antibodies (Alirocumab and Evolocumab), and inclisiran, which target LDLR function, resulted in minimal LDL reduction.In China, evinacumab is not available, so the patient has to rely on long-term lipid apheresis (plasma exchange).

Methods:
Genetic testing revealed the proband harbored three mutations in the LDLR gene: c.1864G>A (p.D622N), c.1448G>A (p.W483*), and c.292G>A (p.G98S). D622N and G98S were on the same allele, while W483* was on the other allele. Mutant plasmids were constructed and transfected into HEK293T cells. Western blot and immunofluorescence co-localization assays were used to assess LDLR protein expression and localization. The LDLR function was evaluated using Dil-LDL uptake assays. Additionally, cells were treated with 4 mM 4-phenylbutyric acid for 48 hours to examine its impact on LDLR function.

Results:
The Western Blot test showed that the W483* mutation broke down the LDLR protein almost completely. The D622N mutation, on the other hand, only showed the precursor form and not the mature form. Finally, the G98S mutation showed that LDLR expression was normal. According to immunofluorescence co-localization, the D622N mutation kept LDLR in the endoplasmic reticulum (ER). Di-LDL uptake tests showed that the G98S mutation could still bind and transport LDL normally. On the other hand, the W483* mutation had almost no LDLR expression or function, and the D622N mutation had ER-retained LDLR that could not bind or transport LDL. After 48 hours of treatment with 4 mM 4-phenylbutyric acid, some of the endoplasmic reticulum retention of D622N-mutant LDLR was alleviated. This facilitated its movement to the cell membrane, partially restoring its ability to bind and transport LDL.

Conclusions:
4-phenylbutyric acid may serve as a potential therapeutic approach for FH patients with LDLR mutations causing ER retention.
Abstract 4142296: Radiomic Texture Analysis of Peri-Coronary Adipose Tissue Significantly Improves Risk Prediction of Major Cardiac Events in the CORE320 Study
Authors: Chatterjee Devina , Singh Sangmita , Lima Joao AC , Ambale-Venkatesh Bharath , zadeh armin
Published: November 2024

Introduction:
Peri-coronary adipose tissue (PCAT) assessment using coronary computed tomography angiography (CCTA) is an evolving method for risk stratification in non-invasive evaluation of coronary artery disease. Radiomic texture analysis of PCAT has greater predictive value than traditional risk stratification metrics, detecting structural changes linked to heart disease

Aim:
To assess the effectiveness of radiomic texture features from peri-coronary adipose tissue in predicting cardiac events compared to traditional methods

Methods:
The CORE320 study enrolled 381 patients referred for invasive coronary angiography (ICA) due to known or suspected coronary artery disease (CAD). Participants underwent CCTA and were monitored for 5 years for major adverse cardiac events (MACE), defined as revascularization, all-cause death, and myocardial infarction. The analysis focused on the proximal 10-50 mm of the right coronary artery (RCA), where 284 RCA vessels were manually contoured using 3D Slicer. Using PyRadiomics Python, we extracted 113 radiomic features from the peri-coronary adipose tissue (PCAT), including previously published PCAT values. Feature importance for predicting a 5-year incidence of major adverse cardiac events (MACE) was determined using the XGBoost algorithm. These features were assessed in a multivariable model using Cox proportional hazards regression on a held-out test set

Results:
In the complete analysis, MACE occurred in 99 of the 381 patients (28%) during the follow-up period. Traditional measures of PCAT attenuation (HR 0.96, 95% CI 0.75-1.22, p=0.59) did not provide significant predictive value for MACE events. Among the 113 radiomic features extracted from the peri-coronary adipose tissue, the XGBoost classifier identified texture features associated with 5-year MACE after adjusting for clinical risk factors. The top-5 included homogeneity, entropy, energy, correlation, and cluster shade. In multivariate analysis, entropy and homogeneity remained independently associated with MACE after adjustment for clinical risk factors. The addition of these two radiomic features to a model with clinical risk factors significantly improved discrimination for 5-year MACE (C-statistic improved from 0.69 to 0.74, p=0.003)

Conclusions:
Radiomic texture analysis of PCAT on CCTA can significantly enhance risk stratification for major adverse cardiac events in patients with suspected coronary artery disease, surpassing traditional clinical risk factors
Abstract 4142298: Association Between Lp(a) and Cardiovascular Events in Individuals with Peripheral Artery Disease in the Mass General Brigham Lp(a) Registry
Authors: McClintick Daniel , Biery David , Berman Adam , Besser Stephanie , Shiyovich Arthur , Singh Avinainder , Huck Daniel , Weber Brittany , Bonaca Marc , Gerhard Marie , Januzzi James , Di Carli Marcelo , Secemsky Eric , Bhatt Deepak , Blankstein Ron , Divakaran Sanjay
Published: November 2024

Background:
Both lipoprotein(a) [Lp(a)] and peripheral artery disease (PAD) are independently associated with atherosclerotic cardiovascular disease (ASCVD) events. Whether elevated Lp(a) provides additional risk stratification among individuals with PAD is less well-established.

Methods:
The Mass General Brigham (MGB) Lp(a) registry includes all individuals with Lp(a) measured at two tertiary care centers from 2000-2019. Those with a history of PAD were grouped into quartiles according to Lp(a) percentile: 1
st
-25
th
(Q1, Lp(a) ≤ 14nmol/L), 26
th
-50
th
(Q2, 14 - 42nmol/L), 51
st
-75
th
, (Q3, 42-132nmol/L), and 76
th
-100
th
(Q4, 132-855nmol/L). Outcomes were major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction, ischemic stroke, or coronary revascularization) and major adverse limb events (MALE: composite of peripheral revascularization [endovascular or surgical], acute limb ischemia, or major lower extremity amputation). Cox proportional hazard modeling was used to assess the association between Lp(a) and the outcomes of interest. Analyses were adjusted for traditional risk factors.

Results:
Among 3,791 individuals with PAD, (39% female, median age 68 [IQR: 59-77]), 79% had hypertension, 81% had dyslipidemia, and 37% had diabetes. Relative to Q1, those in Q3 and Q4 had a 19% and 26% increased risk of MACE, respectively (adj. HR: 1.19, 95% CI 1.03-1.37, p=0.018; adj. HR: 1.26, 95% CI: 1.09-1.45, p=0.001,
Fig, A
). Individuals in Q4 had a 23% higher risk of MALE (adj. HR: 1.23, 1.03-1.48, p=0.022,
Fig, B
) relative to those in Q1. The overall event rate (per 1000 patient years) for MACE increased monotonically across all four subgroups while for MALE was increased only for those in the highest Lp(a) group.

Conclusions:
In individuals with PAD, Lp(a) levels provide additional prognostic information beyond traditional risk factors. Lp(a) above the 50
th
percentile was associated with higher risk of MACE, while levels greater than 75
th
percentile were associated with an increased risk of both MACE and MALE.
Abstract 4142314: ECG predictors for readmission in patients with heart failure: A meta-analysis
Authors: Kumar Reha , Zhou Shijie , Lee Douglas , Ha Andrew
Published: November 2024

Background:
Reducing heart failure (HF) readmission rates remains a global healthcare priority. Current strategies for preventing HF hospitalizations are limited by a lack of accurate predictive models to stratify readmission risk.

Electrocardiograms (ECG) provide pertinent information and are broadly available as part of routine cardiac care. We conducted a meta-analysis to identify ECG predictors of readmission in patients with HF.

Methods:
PubMed, Embase, Cochrane Central and CINAHL were searched, from inception to December 2023. The search strategy was comprised of indexed terms and keywords related
to HF, readmission
, and
electrocardiography.
Two reviewers screened relevant studies and extracted data around study design, patient demographics and outcomes.

Statistical analysis
: Odds Ratio (OR) data and 95% confidence intervals (CI) were calculated on a logarithmic scale using inverse variance method. Pooled OR and 95% CIs were computed using a random-effects model.

Results:
Of the 409 articles screened, 21 were included for final review. 32,337 patients were analyzed across 8 retrospective studies, 10 prospective cohort studies, 2 registry trials and 1 post-hoc analysis of a randomized control trial.

Outcome data were collected for 28 individual ECG variables, which were classified into 5 categories: conduction delay - defined as QRS >120ms (n=7), atrial fibrillation/flutter (n=6), sinus rhythm (n=3), heart rate (n=3), QT
C
interval (n=3) and QRS-T angle (n=2). Four remaining variables did not fit into these categories (1D).

On pooled analysis, presence of atrial fibrillation/flutter [OR 1.54, 95% CI 1.22-1.95, p <0.01] and conduction delay [OR 1.13, 95% CI 1.05-1.22, p <0.01] were associated with higher readmission risk (1A, 1B). Presence of sinus rhythm was associated with lower readmission risk [OR 0.62, 95% CI 0.53-0.72, p <0.01] (1C). Pooled data for heart rate, QRS-T angle and QT
C
interval were not statistically significant.

Conclusion:
Presence of atrial fibrillation/flutter and conduction delay on ECG are associated with increased risk while sinus rhythm is associated with lower risk of HF readmission. These findings should be explored further to identify those with HF at risk of readmission.
Abstract 4142315: Genetically enhanced CHA
2
DS
2
VASc score predicts post-ablation ischemic stroke in patients with atrial fibrillation
Authors: Park Je-Wook , Hong Myunghee , Kim Moon-Hyun , Kim Daehoon , Yu Hee Tae , Kim Tae-Hoon , Uhm Jae-Sun , Joung Boyoung , Lee Moon-Hyoung , Pak Hui-Nam
Published: November 2024

Introduction:
Although atrial fibrillation (AF) catheter ablation (AFCA) may reduce the risk of ischemic stroke (IS), those patients still have some risk. It is unclear whether post-AFCA IS has a genetic background as generally diagnosed IS. We explored the post-AFCA IS-associated single nucleotide polymorphisms (SNPs), and their polygenic risk score (PRS) has an incremental benefit to predict post-AFCA IS in addition to CHA
2
DS
2
VASc scores in the two independent cohorts.

Methods:
We developed PRS for post-AFCA IS from the UK Biobank (N=2,063) and validated from the independent Yonsei AF ablation cohort (N=2,897) after excluding the procedure-related IS (<14 days of the procedure). For sensitivity analysis of oral anticoagulant (OAC), the patients with ≥80% OAC prescriptions during follow-up were considered as OAC treatment patients. We evaluated the incidence and timing of IS after AFCA, comparing the predictive values of CHA
2
DS
2
VASc score and CHA
2
DS
2
VASc+PRS scores.

Results:
46 (2.2%) and 48 (1.7%) experienced IS after AFCA in discovery data with a median of 1873 days of follow-up and replication data with a median of 1500 days of follow-up, respectively. Five genome-wide significant loci for post-AFCA IS were identified and replicated in the two independent cohorts’ data. The PRS was higher in patients who experienced post-AFCA IS (1.9±2.2 vs. 0.3±0.7, p<0.001; hazard ratio 1.80 per 1 SD, [95% CI, 1.63-1.99]). CHA
2
DS
2
VASc+PRS score showed higher C statistic than CHA
2
DS
2
VASc alone (0.754 vs. 0.599, p<0.001). The superiority of CHA
2
DS
2
VASc+PRS score over CHA
2
DS
2
VASc was consistent in the patients with OAC<80% (C statistic 0.805 vs. 0.648, p<0.001) and those with OAC ≥80% (C statistic 0.720 vs. 0.646, p=0.012). In tertile analysis for CHA
2
DS
2
VASc+PRS score, predicted high-risk groups showed early onset overall IS within mean 288 days (p<0.001) after AFCA as compared to intermediate (mean 1231 days) and low (mean 2208 days) risk groups.

Conclusions:
The CHA
2
DS
2
VASc+PRS score improved the IS prediction after AFCA as compared to CHA
2
DS
2
VASc alone. The predicted high-risk group suffered from IS in a relatively earler perior (within a year) after AFCA.
Abstract 4142327: Pharmacosurveillance study of FDA Adverse Event Reporting System (FAERS) events of Apixaban and Rivaroxaban
Authors: Logvinsky Ilana , Maddineni Gautam , Wood Malissa , Delibasic Maja
Published: November 2024

Background:
Apixaban and rivaroxaban are common agents used for anticoagulation to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation.

Research question:
As anticoagulants, there is a risk of bleeding occurring. The question is, which of these two medications has a higher risk of bleeding from various organ systems.

Goals:
Using the FAERS database to calculate the reporting odds ratio (ROR) for the risk of ocular, cerebral, gastrointestinal, rectal, and renal hemorrhage in addition to epistaxis and hemoptysis of these medications.

Methods:
We manually extracted data from the FAERS database owned by the FDA on hemorrhagic events related to Apixaban and Rivaroxaban from January 2012 to March 2024. We calculated the reported odds ratio for both drugs to compare their respective hemorrhagic outcomes.

Results:
The total AE reported for apixaban and rivaroxaban from 2012 to March 2024 was 87490 and 88026, respectively. Rivaroxaban has an increased risk for cerebral (ROR 1.73, 95% CI 1.60 to 1.86), gastrointestinal (ROR 5.91, 95% CI 5.61 to 6.22), rectal (ROR 4.64, 95% CI 4.21 to 5.12), renal (ROR 3.83, 95% CI 2.87 to 5.11), epistaxis (ROR 2.06, 95% CI 1.93 to 2.20) and hemoptysis (ROR 3.20, 95% CI 2.80 to 3.66) compared to apixaban with a significant p-value. There was no statistical significance in reported cases of ocular hemorrhage in apixaban versus rivaroxaban.

Conclusion:
Apixaban and rivaroxaban are common medications used in the treatment of people with atrial fibrillation to reduce the risk of clots and stroke. The FAERs database compared the risk of ocular, cerebral, gastrointestinal, rectal, and renal hemorrhage and epistaxis and hemoptysis of these medications. There was no statistical significance in reported cases of ocular hemorrhage in apixaban versus rivaroxaban. Rivaroxaban overall has a significantly higher risk of bleeding in multiple organ systems, especially cerebral, gastrointestinal, rectal, and renal hemorrhage, as well as epistaxis and hemoptysis. Apixaban would be a better option for people at risk for or with a history of these complications.
Abstract 4142342: Association of Obesity with Declines in Kidney Function in Patients with Heart Failure with Preserved Ejection Fraction
Authors: Deng Lixia , Tighiouart Hocine , Oka Tatsufumi , Tuttle Marcelle , Downey Brian , Rowin Ethan , Sarnak Mark , McCallum Wendy
Published: November 2024

Background:
Obesity is considered one of the key drivers of the cardiovascular-kidney-metabolic syndrome. Obesity is highly prevalent among patients with heart failure with preserved ejection fraction (HFpEF) but there are few studies evaluating its relation with kidney function decline in this population.

Hypothesis:
We hypothesized that among patients with HFpEF, obesity measured by body mass index (BMI) and waist circumference (WC), is associated with increased risk of worse kidney outcomes.

Methods:
We performed a retrospective analysis using data from the TOPCAT (Spironolactone for Heart Failure with Preserved Ejection Fraction) trial, which was a multicenter, randomized trial assessing the effect of spironolactone vs placebo in patients with HFpEF. Our exposures of interest included BMI ≥30 kg/m
2
and WC ≥102cm in men and ≥88cm in women. The association between obesity with eGFR decline by >40%, a validated surrogate endpoint for kidney failure, was examined using multivariable Cox proportional hazards models. Covariates included age, sex, comorbidities, baseline eGFR, and treatment group.

Results:
Among 3445 subjects over a mean follow up of 3.3 years, mean baseline eGFR was 67 ml/min/1.73m2; 1902 (55%) had BMI ≥30 kg/m2 and 2284 (72%) had high WC. After multivariable adjustment, subjects with high BMI had an increased risk (HR 1.39 CI 1.14-1.70) of >40% eGFR decline. Similarly, those with high WC had a higher risk of >40% eGFR decline (HR 1.54 CI 1.19-2.01) (Figure 1, Table 1). There was no significant interaction by randomization to spironolactone. After adjusting for covariates, no significant interaction by sex was found in the BMI group. In the WC group, while interaction was significant (p=0.02), this effect was not observed when assessing WC as a continuous variable.

Conclusion:
Obesity, whether assessed by BMI or WC, is associated with higher risk of eGFR decline in patients with HFpEF. Further investigation stratifying men and women is needed.