bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4144795: Air pollution exposure and effect of finerenone treatment in patients with chronic kidney disease and type 2 diabetes: A FIDELITY analysis
Authors: Al-Kindi Sadeer , Chen Zhuo , Dazard Jean-Eudes , Farag Youssef , Filippatos Gerasimos , Rossing Peter , Rohwedder Katja , Salerno Pedro , Scott Charlie , Zheng Zihe , Rajagopalan Sanjay
Published: November 2024

Background:
Finerenone significantly reduced the risk of CV and adverse kidney outcomes vs placebo in patients with CKD and T2D in FIDELITY, a prespecified pooled analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials. Exposure to particulate matter air pollution ≤2.5 microns (PM
2.5
) is established as the world’s leading environmental risk factor and is implicated in CV and kidney events. This FIDELITY post-hoc subanalysis aimed to examine the effect of finerenone across varying levels of PM
2.5
exposure.

Methods:
Patients in FIDELITY were on optimized renin–angiotensin system inhibition and randomized 1:1 to finerenone or placebo. Key outcomes included composite CV (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure), composite kidney (kidney failure, sustained ≥57% decrease in estimated glomerular filtration rate from baseline over at least 4 weeks, or kidney-related death), and combined composite CV and kidney. Participants were assigned to antecedent PM
2.5
exposure using site location at the time of enrollment (annual PM
2.5
using an integrated exposure model). The effect of finerenone vs placebo was assessed on outcomes across strata of PM
2.5
exposure (quartiles, ≤ vs > median) and as a continuous variable.

Results:
A total of 12,990 participants were included. Median PM
2.5
exposure was 15.5 (IQR 9.8–21.0) µg/m
3
. PM
2.5
exposure was associated with higher CV and kidney event rates (Fig 1). Although finerenone had a similar beneficial impact on composite CV and renal outcomes across strata of PM
2.5
exposure (P
interaction
=NS), the numbers needed to treat to prevent one composite CV/kidney event were 34 and 29 for participants at low (≤ median) and high (> median) PM
2.5
exposure, respectively. The finerenone safety profile was generally similar across PM
2.5
quartiles.

Conclusions:
In FIDELITY, finerenone lowered the risks of CV and kidney outcomes vs placebo in patients with CKD and T2D irrespective of PM
2.5
exposure levels. Given the association between PM
2.5
and risk of CV and kidney events, finerenone may be particularly beneficial in those exposed to higher air pollution levels.
Abstract 4144797: Interaction of Multiorgan Reserve Components Contributing to Exercise Intolerance in Heart Failure Patients: A Clinical Profiling Study
Authors: Landsteiner Isabela , Campain Joseph , Griskowitz Catharine , Malhotra Rajeev , Lewis Gregory
Published: November 2024

Background:
In heart failure patients, the multiorgan system reserve capacity required to meet physiologic demands of exercise can be impaired at multiple levels. Cardiopulmonary exercise testing (CPET) with invasive hemodynamics can help dissect contributions of different organ systems to exercise intolerance.

Aims:
To map exercise limitations in patients with exertional dyspnea, comparing reserve capacities between HF with preserved ejection fraction (HFpEF) and HF with reduced EF (HFrEF).

Methods:
From a cohort of patients undergoing invasive CPET, we included an “overt” HFpEF group defined by hemodynamic criteria (LVEF≥0.5 and PCWP rest supine≥15 mmHg) and a HFrEF group (LVEF≤0.4). We defined 7 exercise performance limitations: pulmonary mechanical impairment (VE/MVV>80% with FEV1<80% predicted [pred.]); exercise-induced steep elevation in cardiac filling pressures (PCWP/CO slope>2 mmHg/L/min); chronotropic incompetence (<80% pred. peak heart rate); reduced peak Fick stroke volume (<80% pred.); abnormal pulmonary vascular response (PVR>1.5WU at peak exercise); peripheral impairment (arteriovenous oxygen content difference<80% pred.); high metabolic cost of initiating exercise observed with excess body weight (internal work>30 watts).

Results:
Among 1,207 patients undergoing invasive CPET, 351 met criteria for "overt" HFpEF (mean age 60.0±14.5 years, 190 female [54%]) and 92 for HFrEF (mean age 57.9±12.9 years, 15 female [16%]). Compared to HFpEF, patients with HFrEF had more prevalent exercise-induced steep elevation in cardiac filling pressures (70% in HFrEF vs. 49% in HFpEF), chronotropic incompetence (74 vs. 48%), and deficient peak exercise stroke volume (49 vs. 12%) (
Figure
). Conversely, HFpEF patients exhibited higher peripheral impairment contributing to exercise limitation, with 45% of patients vs. 24% in HFrEF.

Conclusions:
This study highlights the distribution of physiologic deficits contributing to exercise intolerance in HFpEF and HFrEF patients that frequently extend beyond elevation in cardiac filling pressure and cardiac output reduction, especially in HFpEF. Mapping abnormal physiologic responses to exercise and their rank order may inform strategies to optimize functional capacity in HF.
Abstract 4144828: Increased Testosterone and Reduced Myofibroblast-like Smooth Muscle Cells are associated with Carotid Atherosclerotic Plaque Instability
Authors: Byun Jae Hyun , Gasbarrino Karina , Gianopoulos Ioanna , Papacostas Quintanilla Helena , Zheng Huaien , Daskalopoulou Styliani
Published: November 2024

Background:
Cardiovascular disease remains the leading cause of death worldwide. Unstable atherosclerotic plaques that reside in the carotid arteries are major etiological factors known to increase the incidence of ischemic strokes. Moreover, sex differences exist in plaque morphology and composition; males are more prone to develop unstable plaques and subsequent rupture, while females tend to develop more stable plaques but exhibit worse outcomes post-stroke. Despite these differences however, there is currently a lack of sex-specific guidelines for carotid atherosclerotic disease management.

Objective:
To investigate the association between endogenous sex hormones and the sex-specific cellular and genetic signatures linked to plaque instability.

Methods:
Carotid plaque specimens and pre-operative fasted blood samples were collected and analyzed (n=460; mean age of 71.0±9.0; 68.9% male) from recruited males and post-menopausal females who underwent carotid endarterectomy at McGill University-affiliated hospitals. Distribution and relative expression of sex hormones in plaques were evaluated using liquid chromatography mass spectrometry (LC-MS/MS)-based methods by quantifying levels of 17ß-estradiol (E
2
) and testosterone (T). Plaque single-cell suspensions (n=10) underwent single-cell RNA sequencing (scRNA-seq) to characterize differences in plaque cell expression phenotypes by identifying distinct cell subpopulation clusters.

Results:
Males with unstable plaques had significantly higher circulating T levels and T to E
2
ratio compared to males with stable plaques, with no significant differences in E
2
levels within all groups. Furthermore, scRNA-seq analysis of plaque samples revealed 15 subpopulations of cells; 6 non-immune cell clusters (smooth muscle cells [SMCs], myofibroblasts, and endothelial cells) and 9 immune cell clusters (macrophages, T-lymphocytes, B-lymphocytes, natural killer cells, and dendritic cells). In both sexes, stable plaques exhibited the highest abundance of myofibroblast-like SMCs and pro-fibrotic genes compared to unstable plaques. Similarly, female stable plaques exhibited significantly reduced number of myofibroblast-like SMCs compared to male stable atherosclerotic plaques.

Conclusions:
Our findings demonstrate that taken together, increased circulating testosterone levels and reduced myofibroblast-like SMCs expressing pro-fibrotic genes in the plaque may be associated with increased carotid atherosclerotic plaque instability.
Abstract 4144833: Large Language Models Improve Readability in Primary Responses to Coronary Artery Bypass Graft Questions for Patient Education
Authors: Paruchuri Venkata , Patel Dhaval , Fang Alexander , Levitch Ethan , Kiely Conor , Kaur Karmveer , Sikder Amit
Published: November 2024

Introduction:
The advent of Large Language Models (LLMs) such as ChatGPT and Google Gemini yields a new paradigm for patient education. Coronary artery bypass grafts (CABGs) are open-heart surgeries that naturally gives to many questions in potential patients. Prior research suggested that patient education material should be written at a 6
th
grade reading level maximally to be comprehended by the majority of the US adult population. However, most education material is written at a much higher literacy level. Now with the increasing use of LLMs, the potential for informing patients at an appropriate readability level exists.

Research Question:
Can ChatGPT and Google Gemini improve the readability of their primary responses to patient education questions about Coronary Artery Bypass Grafts to a 6
th
grade reading level?

Methods:
We obtained 80 questions from 4 independent participants regarding information they would want to know prior to undergoing a CABG procedure. Questions that could not be answered using public information, required clinician input, and repeats were filtered out leaving 20 questions. These questions were asked to ChatGPT 3.5 and Google Gemini. Then both LLMs were asked to answer the question at a 6
th
grade level within the same conversation. A new conversation was created each of the 20 questions. All responses were then evaluated using a Flesch-Kincaid calculator where the Flesch-Kincaid reading ease score (FKRE) and the Flesch-Kincaid grade level (FKGL) were obtained. Data analysis was performed using Microsoft Excel and Graphpad Prism.

Results:
For the ChatGPT responses, the average FKRE was 31.865 and FKGL was 12.545. Following the 6
th
grade level request for ChatGPT, the average FKRE was 74.57 (p < 0.0001) and FKGL was 5.93 (p < 0.0001). For the Google Gemini responses, the average FKRE was 46.395 and FKGL was 10.545. Following the 6
th
grade level request for Google Gemini, the average FKRE was 72.945 (p < 0.0001) and FKGL was 6.76 (p < 0.0001).

Conclusion:
Both LLMs significantly increased the readability of their responses and did so to a 6
th
grade level. However, ChatGPT was closer than Google Gemini in reaching the desired FKGL. Nonetheless, our work showed that both LLMs could successfully work with CABG information and yield responses at a readability level befitting the US population. Future studies need to assess the accuracy of this information for LLMs to have practical use in cardiac surgery patient education.
Abstract 4144840: Current Status and Challenges of Cardiac Transplantation in the MENA Region: A Narrative Review
Authors: Tanashat Mohammad , Ayyad Mohammed , Alhuneafat Laith , Abu Daoud Mouath , Nusier Jana , Al Taani Omar , Abu-Laila Mutaz , Al-Ajlouni Yazan
Published: November 2024

Background:
Cardiac transplantation has significantly evolved since its inception in 1967. While the USA and Europe lead in transplant numbers and innovations, the Middle East and North Africa (MENA) region is progressively developing its programs. Countries such as Saudi Arabia, Turkey, the UAE, and Jordan have made notable advancements; however, challenges including donor organ shortages, cultural and religious barriers, and economic constraints persist.

Research Question:
What is the current status of cardiac transplantation in the MENA region, and what are the main challenges and advancements faced by these programs?

Goals:
This narrative review aims to provide a comprehensive overview of the development, challenges, and outcomes of cardiac transplantation programs in the MENA region.

Methods:
A thorough literature review was conducted, examining scholarly articles, clinical reports, and data from national and international transplant registries. Key topics reviewed include the establishment and growth of cardiac transplant centers, advancements in surgical techniques and immunosuppressive therapies, patient outcomes, and barriers specific to the MENA region.

Results:
The review found variability in the development and outcomes of cardiac transplantation programs across the MENA region. Saudi Arabia has one of the most developed programs, with 1-year survival rates of 85% and 5-year rates of 75%. Turkey reports 1-year survival rates of approximately 80%. The UAE has recently expanded its transplant capabilities, yet faces challenges in donor organ availability and long-term patient follow-up. Jordan’s program shows promising outcomes with a 1-year survival rate of around 80%, but financial constraints are significant hurdles.

Common challenges include low donor registration rates, lack of public awareness about organ donation, and high operational costs. Disparities in healthcare infrastructure also hinder progress. Innovations such as ex-vivo heart perfusion and new immunosuppressive therapies are being adopted selectively, with Saudi Arabia and Turkey at the forefront.

Conclusions:
Enhancing public education on organ donation, establishing robust organ procurement systems, and developing specialized heart failure clinics are crucial. Addressing these issues could potentially improve cardiac transplantation success, leading to a subsequent reduction of cardiovascular disease burden in the MENA region.
Abstract 4144845: Clinical Characterization of Arrhythmia-Induced Cardiomyopathy in Patients With Persistent Tachyarrhythmia and Idiopathic Heart Failure: Insights from DECAAFII
Authors: Assaf Ala' , Feng Han , Bsoul Mayana , bidaoui ghassan , Younes Hadi , Mekhael Mario , Noujaim Charbel , Kreidieh Omar , Pandey Amitabh , Rao Swati , donnellan eoin , Sommer Philipp , mahnkopf christian , Marrouche Nassir , Sohns Christian
Published: November 2024

Background:
Catheter ablation (CA) for atrial fibrillation (AF) in patients with heart failure (HF) reduces mortality and hospitalizations and improves ejection fraction (EF). Arrhythmia-induced cardiomyopathy (AIC) is diagnosed after complete resolution of HF following AF ablation.

Aim:
We aim to identify the prevalence and pre-ablation predictors value of AIC among patients with persistent AF and HF enrolled in the DECAAF II trial.

Methods:
We utilized the DECAAF II database, where 815 patients with persistent AF underwent late-gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) before and three-months after receiving CA for AF. Patients were randomized to receive pulmonary vein isolation (PVI) in addition to substrate modification (SM) or standard PVI alone. Ejection fraction was collected before, and three months after CA. Patients were asked to submit a single-lead ECG every day or when feeling symptoms using a single-lead handheld ECG device. AF Burden was defined as the percentage of monitored time spent in AF. For this analysis, we only included patients diagnosed with HF with available LV function data before and after CA. We defined AIC as HF and AF patients who experience EF improvement to ≥50% after ablation, with at least 10% improvement in EF.

Results:
We identified 119 patients with HF and persistent AF; 72 (60.5%) fulfilled criteria for AIC, and 47 (39.5%) were non-AIC patients[SC1] . At baseline, AIC patients had an LVEF of 39.1±7.9, non-AIC had 39.2±7.9 (p=0.9). There was no difference between the two groups in baseline characteristics, AF burden [SC2] or AF recurrence (Table). The distribution of fibrosis from LGE-CMR prior to ablation was the only significant pre-ablation predictor of AIC among patients with HF and persistent AF. Patients with AIC had significantly lower percentage of fibrosis in the septal wall compared with non-AIC patients (12.2±10 vs 20.7±11.4, p <0.001), regardless of the total amount of LA fibrosis.

Conclusion:
In this post-hoc analysis of the DECAAF II trial, we found that up to 60% of patients with HF and persistent AF have AIC rather than primary cardiomyopathy. We also described LGE-MRI as a significant differentiator between AIC and other cardiomyopathies complicated with arrhythmia.
Abstract 4144852: Contemporary Practice Patterns of Vasoactive Agents in Cardiogenic Shock: An Analysis of the AHA Cardiogenic Shock Registry
Authors: Patel Siddharth , Berg David , Bohula Erin , Palazzolo Michael , Krucoff Mitchell , Morrow David
Published: November 2024

Background:
Contemporary practice patterns regarding selection of vasoactive agents in cardiogenic shock (CS) have not been well characterized.

Methods:
This analysis utilized CS admissions (n=4,311) captured in the American Heart Association (AHA) CS Registry across 64 sites from 2022-2024. Vasoactive agents used within 6h of CS onset were captured in the eCRF, and categorized as inodilators (dobutamine, milrinone), inopressors (norepinephrine, epinephrine, dopamine), or pure vasopressors (vasopressin, phenylephrine). CS etiology was classified as per the Shock Academic Research Consortium definitions: AMI-CS and HF-CS (acute-on-chronic and
de novo
HF). Subgroup analyses were performed by preceding cardiac arrest status.

Results:
Overall, 3,331 patients (77% of all CS) were treated with ≥1 vasoactive agents in the initial 6h of CS onset (46% with single vs. multiple agents). Inopressors were the most frequently used vasoactive category, with norepinephrine being the most frequently utilized agent (
Fig A
). Phenylephrine and dopamine were the least frequently employed (
Fig A
). Stratifying by CS etiology, inodilators were more commonly used for HF-CS vs. AMI-CS (OR [95% CI], 3.05 [2.59-3.59]), driven primarily by those with acute-on-chronic vs.
de novo
HF (OR 2.95 [2.30-3.78]), as well as in patients with pre-existing pulmonary HTN (OR 2.13 [1.61-2.81]). A total of 743 patients had preceding cardiac arrest; inopressors were more frequently used among those with vs. without preceding cardiac arrest (OR 7.96 [5.84-10.85];
Fig B
). Among patients who were treated with ≥2 agents in the initial 6h (n=1,788), the most common two-agent combinations were norepinephrine with epinephrine (45%), norepinephrine with vasopressin (40%) and norepinephrine with dobutamine (30%).

Conclusions:
Norepinephrine is the most commonly utilized vasoactive agent (~2/3) in a broad population presenting with CS in contemporary practice, with epinephrine being used in ~1/3. However, CS etiology and illness severity are associated with differential practice patterns for vasoactive selection. These data provide the first snapshot of the landscape of contemporary vasoactive therapy in the US in the AHA CS Registry.
Abstract 4144857: Large Language Models to Understand Reasons for Anticoagulation Nonprescription in Atrial Fibrillation
Authors: Somani Sulaiman , Kim Dale , Perez Eduardo , Ngo Summer , Hernandez-Boussard Tina , Rodriguez Fatima
Published: November 2024

Introduction/Aims:
Anticoagulation (AC) reduces the risk of stroke in atrial fibrillation (AF), yet nonprescription rates near 50%. Reasons for this care gap are not well understood. Large language models (LLMs) may be able to extract documented reasons for AC nonprescription from unstructured text in clinical notes.

Methods:
We created a cohort of all index patient encounters with a clinician-billed ICD10 diagnosis code for AF at Stanford Health Care from January 1, 2015 through December 31, 2023. Three trained reviewers annotated 10% of all AF- or AC-related note excerpts for whether the reason for AC nonprescription was documented and the reason for nonprescription with an overlap of 100 notes to assess annotator performance. Zero-shot prompts were designed for a proprietary LLM (GPT4) for the same tasks. Inter-annotator reliability (IRR) and model-annotator reliability (MAR) were assessed using Cohen’s kappa coefficient.

Results:
A total of 35,737 AF-related encounters were identified, of which 7,712 (21.6%) did not have an active AC prescription. These encounters contained 9,143 associated notes, from which 21,573 AF- and AC related excerpts were extracted. Ten percent of these (911 notes and 2,175 excerpts) were allocated for manual annotation. Reason for AC nonprescription was recorded in 497 (54.6%) notes, with antiplatelet use (N=172, 18.6%), perceived AC contraindication (N=134, 14.7%), and low burden of AF (N=131, 13.9%) being the most common. IRR across reviewers for identifying documented reasons was 0.776 (95% CI 0.716, 0.837), while MAR with GPT4 was 0.609, (95% CI 0.460, 0.758; P = 0.011). GPT4 achieved substantial agreement (MAR > 0.6) for identifying patient preference (MAR 0.763), antiplatelet use (MAR 0.676), and low stroke risk (mean MAR 0.891). There was moderate agreement for identifying perceived AC contraindication (MAR 0.589), fair agreement for low burden of AF (MAR 0.282), and poor agreement (MAR < 0.2) for identifying therapeutic inertia, existing AC use, and prior AF ablation.

Conclusions:
Across a contemporary AF cohort, LLMs categorized reasons for AC nonprescription including antiplatelet use as alternative agents, perceived AC contraindication, and low AF burden. This approach can be leveraged to understand and mitigate actionable barriers to guideline directed cardiovascular care.
Abstract 4144872: Feasibility and Outcomes of Using an Intraprocedural Artificial Intelligence System in Recognizing Regions of Dispersion and Generating Sequential Maps to Assist in Radiofrequency Ablations for Persistent Atrial Fibrillation
Authors: Gabrah Kirollos , Doty Brandon , Cain Jonathan , Maldonado Noel , Lee Bridget , Mahtani Arun , Brider Jamarcus , Al-Hindi Feross , Nair Devi
Published: November 2024

Background:
Pulmonary vein isolation (PVI) is the cornerstone therapy during catheter ablation of atrial fibrillation (AF) isolation. 30% of patients continue to have recurrent AF despite pulmonary vein (PV) isolation. Defining targets for catheter ablation in PV non responder subgroup continues to be challenging despite technological advances. Volta AF-Xplorer™ (VX) is an artificial intelligence (AI) system that analyzes intracardiac signals using electrocardiograms to recognize regions of spatial temporal dispersion and generate sequential maps as targets for ablation.

Objective:
We aim to assess the clinical feasibility and outcomes of the VX AI mapping algorithm during RF catheter ablations to treat recurrent persistent AF in PV non responders.

Methods:
A single center prospective analysis of patients undergoing repeat ablation for recurrent persistent AF using VX mapping software was performed. All patients had previous PVIs, with recurrence of AF and failed at least 2 antiarrhythmic drugs. Patients underwent 3D mapping using Carto and Ensite X mapping systems with real time detection and annotation of spatial temporal dispersion using the Volta technology. The identified targets were ablated until endpoints of termination and non inducibility was achieved and intraprocedural data points were recorded.

Results:
19 patients with a mean age of 67±10.15 years 63.2% male were included in this analysis. Average total procedure time was 68±33 min and average mapping time was 17±10 min. Ablations were performed under zero fluoroscopy. PVI was confirmed in all cases. Ablation was performed at dispersion points identified using the AI mapping system. Termination was achieved in 18 out of the 19 cases (94.7%). 16 patients converted directly to normal sinus rhythm (NSR) and 2 patients to atrial flutter and then to NSR. The one patient that did not terminate required cardioversion but was not inducible with pacing maneuvers.

Conclusion:
This experience highlights the clinical safety, utility, feasibility, and outcomes of the Volta AF-Xplorer AI mapping software during catheter ablation of PV non responders for recurrent persistent AF.
Abstract 4144881: Peak METs vs. Peak VO2: When is it not predictive?
Authors: Chaliki Kalyan , Sharma Anubhuti , Sharma Arundhati , Viggiano Taylor , Yee Claire , Reddy Satyajit
Published: November 2024

Introduction:
Metabolic equivalents (METs), a measure of energy use during a specified exercise intensity, and volume of oxygen consumed (VO2) are key measurements in cardiopulmonary exercise tests (CPETs). METs are traditionally converted to VO2 via multiplying METs by 3.5 ml/kg/min when VO2 data is not available, due to the fact that the latter requires more-expensive, accurate measurements of volume of inspired and expired oxygen and CO2. However, it is unclear which populations have significant variation between peak METs and peak VO2.

Research Question:
In a general cardiology population, do older women have a weaker relationship between peak METs and peak VO2?

Methods:
We present a retrospective study analyzing the relationship of peak METs and peak VO2 achieved on a CPET. Patients presenting to the cardiology clinic who received a CPET from 2017-2022 were included. Patients with severe valvular dysfunction, congenital heart disease, prior coronary artery bypass grafting, or ejection fraction < 50% were removed to limit confounding. A Spearman correlation coefficient was calculated for the whole sample comparing peak METs and peak VO2. Subsequently, a subgroup of women age 65 or greater were compared to the general sample by a fisher’s z transformation.

Results:
1907 patients were included. There was a strong positive correlation between peak VO2 and peak METs in the whole sample (r(1860) = 0.914), p<0,001), shown in Figure 1. Women age 65 or greater had a weaker correlation (r(190)=0.808, p<0.0001) compared to the those who were not (r(1668) = 0.915, p<0.0001; z = -5.656, p<0.001), shown in Figure 2.

Conclusions:
Peak METs and peak VO2 have an extremely strong positive correlation in a general cardiology population. However, these relationships weaken for women age 65 or greater. METs are an accurate, cost-effective proxy measurement of VO2 in a general population, however may lack reliability for certain demographics.
Abstract 4144882: Loss of function polymorphism in the ecto-5’-nucleotidase (NT5E) gene increases atherosclerotic burden.
Authors: Roman Ana , Dittrick Lauren , Gordon Kyle , Bermeo Blanco Oscar , Watson Samuel , Gurumurthy Channabasavaiah , Wells Quinn , Covarrubias Roman , Quadros Rolen , Gumina Richard
Published: November 2024

Objective:
To elucidate the molecular mechanisms by which CD73 variants contribute to inflammation and atherosclerosis in humans.

Approach and Results:
To explore this knowledge gap, we conducted phenotype-wide association analysis (PheWAS) in a cohort of 25,000 patients to identify ASCVD-associated variants in the
NT5E
(CD73) gene in a non-biased manner. PheWAS analysis of coding variants identified that the rs200648774 single nucleotide polymorphisms in ecto-5’-nucleotidase (NT5E; CD73) that was associated with atherosclerosis (ICD-9; 440.x codes) in this cohort. The SNP rs200648774 (C-->T; MAF 0.000188) results in an Arginine (R) to Cysteine (C) substitution at amino acid 354 within the active site of CD73 (OR: 10.18, SE: 1.1; P=0.035). This Arginine residue is evolutionarily conserved across species. The variant protein is expressed but displays a loss of function (LOF; CD73 Cys354 variant). To examine

the impact of the CD73 Cys354 variant

, we generated a murine model using
E
fficient
a
dditions with
s
sDNA
i
nserts-CRISPR (Easi-CRISPR) gene editing. CD73-Arg354/Arg354 (cd73
wt/wt
) and CD73-Cys354/Cys354 (cd73

Δ/Δ

) mice in an
Ldlr
-/-
background were placed on HFD for 12 weeks then sacrificed for quantification of aortic root atherosclerosis. Representative images of oil red O staining of aortic valve from CD73-Arg354/Arg354-
Ldlr
-/-
(cd73
wt/wt
,
Ldlr
-/-
) mice (Fig. A; Bar= 100 um) and CD73-Cys354/Cys354
Ldlr
-/-
(cd73

Δ/Δ
,

Ldlr
-/-
) mice (Fig. B; Bar= 100 um). Quantified area of atherosclerosis in CD73-Cys354/Cys354 (cd73

Δ/Δ

) aortic roots were significantly higher in CD73-Cys354/Cys354 (cd73

Δ/Δ

) than in CD73-Arg354/Arg354 (cd73
wt/wt
) (Fig. C; p=0.0096). The Percentage of Oil Red O staining in aortic root atherosclerotic lesions was also significantly higher in CD73-Cys354/Cys354 (cd73

Δ/Δ

) aortic roots compared to CD73-Arg354/Arg354 (cd73
wt/wt
) aortic roots. Together these data demonstrate that the rs200648774 single nucleotide polymorphisms resulting in cysteine substitution for arginine in the active site of CD73 results in a loss of CD73 function that also associates with

increased atherosclerosis in genetically susceptible mice

.

Conclusion:
The LOF rs200648774 single nucleotide polymorphisms associates with atherosclerosis in humans and generation of the CD73-Cys354/Cys354 polymorphism in
Ldlr
-/-
mice results in increased HFD induced atherosclerosis
Abstract 4144883: Management of Iron Deficiency in Heart Population Treated in Heart Failure Unit and the Outlier Setting, A Comparison Study.
Authors: Kakhi Sorayya , Baig Muminah , Ali Abdullah Muminah , Alalawi Mohammed , Eltahir Aya , Bijman Laura , Peterzan Mark , Ray Robin , Shanmugam Nesan , Anderson Lisa , Ghazal Heba , Jouhra Fadi
Published: November 2024

Background:
Iron deficiency (ID) is common amongst patients with heart failure (HF). The European Society of Cardiology (ESC) guidelines recommends intravenous (IV) Iron supplementation in symptomatic HF patients with reduced left ventricular ejection fraction (LVEF) and ID to alleviate HF symptoms and improve quality of life. The current study aims to assess adherence to the latest ESC guidelines in treatment of ID in HF patients admitted to non-cardiac (outlier) wards at St. George's University Hospital (SGH), London. The results were compared to standard practice at a dedicated heart failure unit (HFU) at SGH.

Methods:
Retrospective data was collected on consecutive HF patients, admitted to SGH between September 2022 and September 2023. 386 patients met the inclusion criteria, defined as HF with LVEF < 50% and ID according to ESC guidelines. Of total population, 190/386 patients were admitted to the outlier wards and 196/386 to the HFU. Patients considered ineligible for administration of IV Iron therapy, were those not meeting the guideline thresholds for treatment of ID, patients with active cancer or bleeding and patients on oral Iron supplementation.

Results:
The mean age of patients admitted to HFU was 71 +/- 13 SD, 66% male. 72% (141/196) of the patients were tested for ID, of which 51% (72/141) had ID as per inclusion criteria. 57% (41/72) of those with ID were prescribed IV Iron, whilst 43% (31/72) were not treated. The reason for not treating patients identified as Iron deficient was presence of active infection (19/31) or bleeding (3/31). In 9/31 of untreated patients with ID, the reason for not being prescribed with IV Iron was not identifiable through review of medical notes. It is important to note that 28% (55/196) were not tested for ID during their hospitalisation and missed the opportunity for treatment.
(Figure 1)
In outlier wards, mean age was 77 +/- 14 SD, 66% male. 46% (87/190) patients were tested for ID, of which 16% (14/87) were identified as Iron deficient and were prescribed IV Iron. 4% (12/87) were not treated for no obvious reason and 18% (16/87) met the criteria for ID, but due to presence of contraindication did not receive IV Iron. Missed opportunity was 54% in outlier population.
(Figure 2)

Conclusion:
This study demonstrated that patients admitted to HFU, were more likely to be tested for ID and receive IV Iron, compared to patients admitted to outlier wards but there is still room for considerable improvement in both settings.
Abstract 4144894: Patient Frailty Rather than Procedural Approach Associated with Loss of Life and Limb
Authors: Sorondo Sabina , Arnow Katherine , Kashikar Aditi , Fereydooni Arash , Trickey Amber , Arya Shipra , George Elizabeth
Published: November 2024

Objectives:
Evidence behind frail patients preferentially undergoing endovascular interventions for peripheral arterial disease remains sparse; thus, we evaluated the association of frailty and revascularization-approach with long-term mortality and major adverse limb events (MALE).

Methods:
VQI-Medicare linked VISION databases were queried for patients who had their first infrainguinal open or endovascular (endo) procedure between 2011-2015 [N=27,200]. Frailty was measured using the VQI-Risk Analysis Index (RAI) and dichotomized into “frail” (RAI≥37) and “non-frail” (RAI<37). The primary endpoints were 4-year mortality and MALE (major amputation and/or reintervention). Associations of frailty and approach were estimated using Kaplan-Meier analysis and multivariable Cox hazards regression using an interaction term and stratified by indication.

Results:
Frail patients experienced significantly worse mortality and amputation-free survival, but both frail and non-frail patients experienced worse survival following an endo first approach (Figure 1, both log-rank p < 0.001). In adjusted Cox regression, frail patients with CLTI were at significantly increased risk of amputation (HR = 1.36; 95% CI: 1.18-1.56; p <.0001), MALE (HR:1.09, 95% CI:1-1.19; P=.049) and mortality (HR = 2.70; 95% CI: 2.51-2.89; p <.0001); endo approach for CLTI demonstrated a similar pattern of adverse outcomes (Table 1). However, interaction terms were not significant - the effects of frailty and approach did not influence each other. In claudicants, frailty was associated with increased mortality (HR = 3.05; 95% CI: 2.40-3.86; p <.0001) but not MALE, and endo approach was associated with increased MALE but not amputation; again, interaction terms were not significant.

Conclusion:
Endovascular approach did not mitigate the adverse effects of frailty on life and limb-related outcomes, thereby underscoring the need for frailty screening and accordingly tailoring treatment and managing expectations given their high mortality risk.
Abstract 4144912: Doing Well, But Can We Do Better? Improving Outcomes and Equity After Stage I Single Ventricle Palliation
Authors: Wright Lydia , Carrillo Sergio Alejandro , Cua Clifford , Davis Jo Ann , Shustak Rachel , Texter Karen , Nandi Deipanjan
Published: November 2024

Introduction:
Infants with hypoplastic left heart syndrome undergoing single ventricle (SV) palliation may need early heart transplant. We aimed to evaluate predictors of transplant referral (TxR) and death without TxR, with focus on neighborhood opportunity and race/ethnicity, to determine if disparities in TxR contribute to increased mortality seen in certain populations.

Methods:
Retrospective cohort study of all infants undergoing stage 1 (S1) SV palliation enrolled in the National Pediatric Cardiology Quality Improvement Collaborative from 2016-2022 was performed. Competing risk analysis was used to evaluate predictors of TxR and death without TxR through one year.

Results:
A total of 3099 infants underwent S1 palliation during our study period. Black children had lower median birth weight compared to non-Hispanic white and Hispanic children (p <0.001) as did those from low compared to higher opportunity neighborhoods (p <0.001). There were no other significant pre-operative or S1 procedure differences. At one year, 79% of children were alive, 16% had died, and 5% had a TxR (Figure). In multivariable analysis, risk factors for TxR included hybrid S1 palliation [sHR 2.43 (95% CI 1.54, 3.81], moderate or greater tricuspid regurgitation (TR) [sHR 3.39 (95% CI 1.80 – 6.40)] and female sex [sHR 1.73 (95% CI 1.24 – 2.40)]. Lower birth weight, genetic syndrome, pre-operative TR, hybrid S1 palliation, and small S1 volume (<8 /yr) center were associated with death without TxR. Neither race/ethnicity nor neighborhood opportunity was associated with TxR or death without TxR when controlling for these risk factors. Among those with pre-operative moderate or greater TR, race/ethnicity was associated with TxR in multivariable analysis, with TxR less likely for Black and Other race children compared to white children (p<0.001 for both).

Conclusion:
One-year survival after S1 palliation without TxR approaches 80%. No clear disparities in death or TxR by race or neighborhood were seen overall, though lower rates of TxR for Black and Other race children with high-risk cardiac features were present. Standardized guidelines for timely TxR may help further reduce death and mitigate potential disparities in this SV population.
Abstract 4144929: Electronegative VLDL Impairs Mitochondrial Function and Promotes Cardiomyocyte Dysfunction in Heart Failure with Preserved Ejection Fraction
Authors: Chiang Huan-Hsing , Akyol Omer , Tsai Ming-Hsien , Hochman Camila , Vykoukal Jody , Fahrmann Johannes , Woodside Darren , Bhatt Deepak , Chen Chu-Huang
Published: November 2024

Background:
Heart failure with preserved ejection fraction (HFpEF) affects energy metabolism, increasing reliance on long chain fatty acids (LCFA). Alterations to VLDL, the main triglyceride transporter, may significantly influence disease progression. VLDL can be separated into 5 subfractions from V1 (most beneficial, least electronegative) to V5 (most electronegative). This study investigates whether VLDL electronegativity induces cardiomyocyte dysfunction through changes in cellular metabolism.

Goals:
We aim to explore the cellular mechanisms of V5-induced pathology in rat neonatal cardiomyocytes (RNC) and bovine aortic endothelial cells (BAEC), potentially accelerating the systemic inflammation that leads to the development of HFpEF.

Methods:
V1 and V5 were isolated from healthy blood bank donors. RNCs were treated with PBS (control), V1, or V5 at 25 or 50 µg/mL for 24 hours. Mitochondrial function was evaluated using the Seahorse ATP production rate, cell mito stress, and palmitate oxidation stress test assays. Immunofluorescence staining of RNCs and BAECs was performed to elucidate systemic inflammation. Comprehensive lipidomics characterized components potentially involved in V5’s cytotoxic effects.

Results:
For RNCs treated with V5, ATP production shifted remarkably towards glycolysis instead of oxidative phosphorylation (
Figure A
). V5 but not V1 severely impaired mitochondrial respiration, affecting basal respiration, spare respiratory capacity, and maximal respiration in a concentration-dependent manner (
Figure B
). When LCFA transport into mitochondria is blocked, V5-treated RNCs showed increased cellular uptake of palmitate, leading to heightened lipotoxicity. In both RNCs and BAECs, V5 but not V1 reduced cell viability and increased apoptosis (
Figure C
). Lipidomic studies revealed that compared to V1, V5 contains multiple glycated lipid components and a richer triglyceride content.

Conclusion:
We report novel findings that increased VLDL electronegativity provokes mitochondrial dysfunction through energy depletion and lipid overload, resulting in cardiomyocyte impairment. This explains how V5-rich VLDL, observed in metabolic syndrome, contributes to systemic inflammation and clinically manifests as HFpEF.
Abstract 4144933: Telomeric Repeat-Binding Factor 2 Interacting Protein (TERF2IP) S205 Phosphorylation Orchestrates LATS1/2 Degradation under Disturbed Flow Conditions
Authors: Kotla Sivareddy , Samanthapudi Venkata Subrahman K , Osborn Abigail , Lee Jonghae , Hoang Oanh , Mejia Gilbert , Ostos Mendoza Keila Carolina , Schadler Keri , Chau Khanh , LE NHAT TU , Martin James , Abe Junichi
Published: November 2024

Background:
While the shelterin complex, including TERF2IP, is established in its role of telomere protection, its interaction with the Hippo pathway, which also regulates senescence and inflammation, has not been reported. Our research aims to investigate whether TERF2IP influences the Hippo pathway, potentially linking it to endothelial cell (EC) responses under disturbed flow (d-flow).

Methods:
ECs were transduced with TERF2IP variants, and subjected to d-flow or static conditions. Post-transfection with makron-1 ubiquitin E3 ligase (MKRN1)/control siRNA, ECs underwent d-flow or remained static. Protein turnover was analyzed using cycloheximide (CHX) treatment. TERF2IP-MKRN1/LATS1/2 interactions were assessed via co-immunoprecipitation after d-flow exposure.

Results:
LATS1/2 depletion led to endothelial cell (EC) senescence and apoptosis, prompting investigation into the regulatory role of TERF2IP S205 phosphorylation on d-flow-induced LATS1/2 degradation. Adenoviral transduction with the TERF2IP S205A mutation significantly mitigated the d-flow-mediated decrease in LATS1/2 levels. The absence of changes in LATS1/2 mRNA post-d-flow and the protective effect of the protease inhibitor MG132 against LATS1/2 reduction implicate protein degradation mechanisms. Furthermore, MKRN1 depletion markedly curtailed the d-flow-induced decline in LATS1/2 and senescence, underscoring the involvement of the MKRN1 Ub E3 ligase in regulating LATS1/2 protein stability and d-flow-mediated EC senescence. CHX runoff assays following MKRN1 or control siRNA transfection revealed that MKRN1 is pivotal for LATS1/2 stability. The interaction between TERF2IP and MKRN1, enhanced by d-flow and attenuated by the TERF2IP S205A mutation, along with the inhibitory effect of TERF2IP c-myb domain overexpression on their association, indicates a binding site for MKRN1 on TERF2IP. Persistent TERF2IP-LATS1/2 binding until LATS1/2 expression declined suggests the formation of a TERF2IP-MKRN1-LATS1/2 complex that facilitates LATS1/2 degradation mediated by the recruitment of TERF2IP-MKRN1 complex.

Conclusion:
D-flow triggers the phosphorylation of TERF2IP at S205, leading to the formation of a TERF2IP-MKRN1-LATS1/2 complex. This complex initiates the degradation of LATS1/2, a key regulator of EC senescence. Thus, TERF2IP S205 phosphorylation under d-flow conditions is a crucial step in the pathway leading to LATS1/2 proteolysis, impacting our understanding of EC senescence and atherothrombosis.
Abstract 4144938: Echocardiographic Insights into Subclinical Cardiac Abnormalities in Genotype-Positive Phenotype-Negative Transthyretin (ATTR) Cardiomyopathy
Authors: Fahed Gracia , bagherzadeh shadi , Jimenez Isaiah , Adrianzen Fonseca Marina , Chun Lindsey , Tang Xiu , Salerno Michael , Witteles Ronald , Alexander Kevin , Haddad Francois
Published: November 2024

Background:
Hereditary transthyretin amyloidosis (ATTR) is often missed due to variable presentations, ranging from primarily neurologic to solely cardiac. Nearly 50% of ATTR mutation carriers develop cardiomyopathy; thus, understanding their subclinical echocardiographic abnormalities could inform early disease presentation.

Objective:
Define the echocardiographic profiles of ATTR genotype-positive, cardiac phenotype-negative (Gen+/Ph-) individuals compared to matched controls and those with confirmed cardiac disease (Gen+/Ph+).

Methods:
ATTR Gen+/Ph- individuals were identified based on positive genetic test and no signs of cardiac infiltration by routine echo or PYP scan. Baseline echocardiograms were analyzed and compared to age-, sex- and comorbidity-matched controls, and to Gen+/Ph+ patients with ejection fraction >50%. Structural indices, diastolic parameters and 2D strain analyses of the left ventricle (LV), left atrium (LA), right ventricle (RV) and right atrium (RA) were measured and compared for differences in rank (Mann-Whitney U test) and in effect size (Cliff’s δ).

Results:
In the ATTR Gen+/Ph- group (n=39), mean age was 52±12 years, 69% were female. Mutations were V122I (23%), V30M (30%) and T60A (26%). The distribution of functional echocardiographic indices differed significantly from controls (n=78) (Table 1), with the largest effect size observed for RA reservoir strain, RV free wall longitudinal strain and LA reservoir strain (Figure 1). The proportion of ATTR Gen+/Ph- patients meeting the guidelines abnormal thresholds was different from controls for E/e’>14 (1.3% vs 10.3%), p=0.04),RV strain>-20% (1.3% vs 12.8%, p=0.02) and RA reservoir strain>-25% (1.3% vs 17.9%, p<0.01). Compared to a Gen+/Ph+ group (n=43), the distribution of all measured parameters differed significantly from the Gen+/Ph- group.

Conclusion:
ATTR genetic carriers seem to be most different from controls in certain functional, rather than structural, echocardiographic indices. Longitudinal studies are needed to guide screening and early management in this population.
Abstract 4144947: Invasive Hemodynamic Validation of a Novel Echocardiographic Artificial Intelligence Screening Tool for HFpEF
Authors: Sachar Ryan , Latz Maria , Blair John , Allan Tess , Kim Gene , Grinstein Jonathan , woodward gary , Lang Roberto , Belkin Mark
Published: November 2024

Background:
Right heart catheterization (RHC) is the gold standard for diagnosing heart failure with preserved ejection fraction (HFpEF). An FDA-approved artificial intelligence (AI) technology uses a four-chamber transthoracic echocardiogram (TTE) image to screen patients for HFpEF.

Methods:
We compared invasive hemodynamic data between patients screened for HFpEF by this TTE AI algorithm. We retrospectively collected data from two cohorts of patients with an ejection fraction (EF) ≥ 50% undergoing RHC for the evaluation of HFpEF. The most recent TTE was screened using the AI tool and reported as either suggestive or non-suggestive for HFpEF – labeled as “positive” or “negative,” respectively. Invasive hemodynamic parameters at rest and during exercise were collected. Positive and negative groups were compared using Student’s t-test and Mann-Whitney U test.

Results:
A total of 47 patients (82% women, 79% Black, average EF 62%) had a previous RHC, with 23 undergoing subsequent exercise RHC. There were 18 patients (38%) with a positive AI result and 29 (62%) negative. Positive patients had significantly higher rates of atrial fibrillation (38% vs 11%, p=.03), NT-proBNP levels (median 451 vs 117 ug/mL, p=.001), and H2FPEF (median 6 vs 4, p<.001) and HFA-PEFF scores (median 5 vs 2, p=.005). Of 18 positive patients, 16 (89%) had a resting pulmonary capillary wedge pressure (PCWP) > 15 mmHg, consistent with HFpEF, compared to only 14 of 28 (50%) negative patients. With exercise 6 of 7 (86%) positive patients had PCWP ≥ 25 mmHg, consistent with HFpEF, compared to 11 of 20 (55%) negative patients. At rest, positive patients had significantly higher PCWP, mean pulmonary arterial pressure (mPAP), and pulmonary vascular resistance (PVR). After exercise, there were no significant differences in PCWP or mPAP between the two groups, but thermodilution cardiac output was significantly lower in the positive patients.

Conclusion:
Patients identified as HFpEF positive by a validated TTE-guided AI tool were more likely to have HFpEF confirmed invasively, indicating its potential for risk stratification. However, the negative predictive value for HFpEF confirmed by invasive hemodynamics was low in this population.