bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4138781: Neuro-specific biomarkers for risk assessment of ischemic stroke and death in patients with atrial fibrillation not receiving oral anticoagulation
Authors: Aulin Julia , Sjolin Karl , Lindbäck Johan , Benz Alexander , Eikelboom John , Oldgren Jonas , Wallentin Lars , Burman Joachim
Published: November 2024

Background:
Biomarkers measured in plasma reflecting cardiorenal dysfunction and inflammation are associated with clinical outcomes in atrial fibrillation (AF). We recently showed an association between the plasma level of the neuronal biomarker neurofilament light chain (NFL) and subsequent stroke and death in patients with AF not receiving oral anticoagulation (OAC).

Purpose:
We aimed to compare NFL with other circulating neuro-specific biomarkers, specifically glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), concerning associations with the risk of stroke and other outcomes in patients with AF.

Methods:
Concentrations of NFL, GFAP, tau, and UCHL1 were determined with Single Molecule Array (Simoa®) in plasma samples obtained at baseline from 967 patients with AF randomized to aspirin in the ACTIVE A trial. Median follow-up was 3.6 years. Associations between baseline biomarker concentrations, clinical variables (age, sex, body mass index, smoking, alcohol consumption, type of AF, cardiac rhythm at baseline, heart failure, hypertension, diabetes, prior stroke/transient ischemic attack, peripheral arterial disease, and myocardial infarction), and outcomes (ischemic stroke, cardiovascular and all-cause death) were analysed with Cox regression, adjusting for clinical variables and other biomarkers.

Results:
Increasing age and female sex were associated with elevated levels of all four biomarkers. Plasma levels of NFL were positively correlated with those of GFAP (r=0.67, p<0.001), tau (r=0.12, p<0.001), and UCHL1 (r=0.37, p<0.001). NFL was independently associated with subsequent ischemic stroke (HR 1.27, 95% CI 1.03–1.56 for a doubling of NFL), cardiovascular death (HR 1.37, 95% CI 1.13–1.64 for a doubling of NFL), and all-cause death (HR 1.46, 95% CI 1.25–1.70 for a doubling of NFL) after adjustment for clinical factors and other biomarkers. In unadjusted analyses, GFAP was associated with ischemic stroke and death; tau and UCHL1 with death only, however, these associations were not significant after adjusting for clinical variables (Table).

Conclusions:
In patients with AF not receiving OAC, NFL was independently associated with ischemic stroke and death. Further investigation of NFL and its association with clinical outcomes in patients with cardiovascular disease is therefore warranted.
Abstract 4141828: Cardiovascular Adverse Events And Comparative Safety Of Ibrutinib Plus Venetoclax In Untreated Patients With Chronic Lymphocytic Leukemia: A Meta-Analysis Of Randomized Controlled Trials And Systematic Review
Authors: Cruz Akabane Maria Antonia , Toth Otávio , Mazetto Roberto , Park Amanda , Cavalcante Douglas , RIBEIRO Iury , Barbosa Imara
Published: November 2024

Background:
The combination of ibrutinib and venetoclax has emerged as a promising therapeutic option for patients with chronic lymphocytic leukemia (CLL), demonstrating significant advantages compared to traditional chemotherapy-based approaches. However, the potential adverse cardiovascular effects, especially in patients who have not previously undergone treatment, have not been fully elucidated.

Hypothesis:
The use of ibrutinib and venetoclax is associated with a higher incidence of cardiovascular adverse events.

Aims:
This study aims to analyze the incidence of cardiovascular adverse effects in patients treated with ibrutinib and venetoclax for CLL, who were previously naïve to treatment.

Methods:
PubMed, Embase, and Cochrane Central databases were systematically searched in April 2024 for randomized controlled trials (RCTs) that compared ibrutinib plus venetoclax to standard care therapies (ST) (chlorambucil-obinutuzumab; ibrutinib only and fludarabine-cyclophosphamide-rituximab) in untreated patients with CLL and reported the outcomes of (1) atrial fibrillation; (2) hypertension and (3) sudden death. We performed a systematic review and meta-analysis using RStudio version 2024.04.0. Heterogeneity was examined with the Cochran Q test and I2 statistics.

Results:
We included 4 RCTs in the final analysis, with a total of 885 participants, of whom 450 (50.8%) were on ibrutinib plus venetoclax. Ibrutinib plus venetoclax was associated with a significant increase in the incidence of atrial fibrillation compared with standard care therapy (OR 7.04; 95% CI 3.11-15.92; p<0.01; I2=0%; figure 1A). Hypertension (OR 2.90; 95% CI 0.75-11.25; p=0.124; figure 1B) and sudden death (OR 0.16; 95% CI 0.16-3.11; p=0.655) were not significantly different between groups.

Conclusion:
In patients with CLL who were previously naïve to treatment, the combination of ibrutinib plus venetoclax was associated with a higher incidence of atrial fibrillation as compared with ST, whereas hypertension and sudden death were not significantly different between groups.
Abstract 4141833: Age and Sex Multiplicatively Moderate the Association of Daily Sedentary Time with Depressive Symptoms in Rural Patients with Cardiovascular Diseases
Authors: Kang JungHee , Cha Geunyeong , Lin Chin-Yen , Wu Jia-Rong , Okoli Chizimuzo , Latimer Abigail , Lennie Terry , Biddle Martha , Chung Misook , Moser Debra
Published: November 2024

Background:
Depressive symptoms (DS) are highly prevalent in patients with cardiovascular diseases (CVD). Sedentary behavior is associated with DS, and together they worsen CVD health outcomes. Rural patients exhibit greater incidence of DS and physical inactivity than their urban counterparts. While females and younger adults are more likely to experience DS in general, how sedentary time (ST) interacts with age and sex on DS in rural patients with CVD has not been elucidated.

Hypothesis:
Age and sex multiplicatively moderate the association of daily ST with DS in rural patients with CVD.

Methods:
A total of 226 (58±12 [range 23-80] years old, 49% female) rural patients with CVD were included. The Patient Health Questionnaire-9 was used to measure DS. Patients wore the ActiGraph GT9X Link for 4 to 7 days to measure ST (minutes/day on average). We used PROCESS to test the moderated moderation model. The pick-a-point approach was used for probing a three-way interaction.

Results:
We found a significant three-way interaction among daily ST (
X
), age (
Z
), and sex (
W
) [B=-.0016,
t
(218)=-3.631,
p
=.0004], which indicates the magnitude of the moderation by sex on the effect of daily ST on DS depended on age. Moderated moderation explained 10.1% of the variance in DS (
p
=.002). The pick-a-point approach indicated significant conditional interactions between ST and sex at the youngest and oldest ages (Figure). Among younger adults, there was a significantly positive association of ST with DS in females compared to males [θ

XW

→

Y

|(
Z
=30)=.034;
F
(1;218)=8.363;
p
=.004], while a significantly positive association of ST with DS was found in males compared to females among older adults [θ

XW

→

Y

|(
Z
=70)=-.028;
F
(1;218)=11.431;
p
=.001]. However, among middle-aged adults, the association of sedentary time with DS was not significantly moderated by sex (
p
=.59).

Conclusions:
The findings of the study indicate a complex interaction of age and sex in the relationship of ST with DS and suggest an age- and sex-stratified intervention to improve depressive symptoms. Future research is warranted to examine factors that influence sex differences in the association of ST with DS in different age groups.
Abstract 4141840: SOX17 Deficiency is Additive to High Shear Stress in Reducing Endothelial Genes Linked to BMPR2 and NOTCH and Promoting Inflammation in Pulmonary Arterial Hypertension
Authors: Zhang Chongyang , Shinohara Tsutomu , Lee-yow Yannick , Guo Kathrine , Lago-Docampo Mauro , Engreitz Jesse , Rabinovitch Marlene
Published: November 2024

BACKGROUND:
Pulmonary arterial hypertension (PAH) is characterized by obliteration of distal pulmonary arteries (PA) in association with endothelial cell (EC) dysfunction, leading to smooth muscle proliferation. SOX17 is a transcription factor (TF) expressed in arterial EC that is critical in vascular development. Deleterious variants causing reduced expression of
SOX17
are linked to PAH, particularly in congenital heart defects (CHD) that cause increased PA flow and high shear stress (HSS).

HYPOTHESIS:
SOX17 deficiency is additive to HSS in compromising PAEC homeostasis and in promoting severe PAH.
METHODS:
SOX17
was reduced (>70%) by siRNA in primary human PAEC cultured in chamber slides in the IBIDI perfusion system. Computational modeling of distal PA indicated pathological HSS of 100 dyn/cm
2
in CHD with PAH whereas physiological laminar shear stress (LSS) is 15 dyn/cm
2
. EC were preconditioned under LSS for 24h, followed by HSS or LSS for 24h.

RESULTS:
SOX17 expression was increased under LSS versus static condition, as were known SOX17 target genes (e.g.,
GJA5
,
GJA4
,
CGNL1
,
JAG1
, and
CTNNB1). SOX17
siRNA and HSS similarly reduced SOX17 target genes and when combining
SOX17
siRNA with HSS they were further decreased owing to an interaction between SOX17 and ERG, a TF reduced by HSS. Indeed, SOX17 and ERG motifs marked most enhancer and promoter H3K27acetyl marks that were reduced under HSS. We then carried out RNAseq of PAEC to find genes co-regulated by SOX17 and ERG (reduced by siRNA for either TF under LSS), decreased under HSS and more-so with HSS +
SOX17
siRNA. Those downregulated included SOX17 targets (e.g.,
CGNL1
and
GJA5
) and others not previously described, with links to BMPR2 signaling,
YAP1
(inducer of BMP ligands and suppressor of NF-kB),
SETBP1
(inducer of BMPR2 co-receptor
BMPR1b),
and
TMEM100
and
SULT1B1
important in NOTCH signaling and EC specification. We also found novel extracellular matrix target genes, e.g., elastin (
ELN,
top DEG
)
,
HMCN1
,
TMTC1
and chromatin remodeler (
TOX)
. Among genes upregulated, were
NAMPT, FAS, LYN, HPSE
related to NF-kB activation and/or inflammation.

CONCLUSION:
HSS plus SOX17 deficiency profoundly compromises EC homeostatic genes, among which are those affecting BMPR2 and NOTCH pathways, ELN fiber assembly, and those promoting inflammation. This can explain why
SOX17
mutations are associated with severe PAH in HSS-related congenital heart defects.
Abstract 4141879: Post-procedure oral anticoagulation following pulsed-field ablation for atrial fibrillation
Authors: Mohanty Sanghamitra , Torlapati Prem Geeta , Compagnucci Paolo , La Fazia Vincenzo Mirco , gianni carola , MacDonald Bryan , QUINTERO MAYEDO ANGEL , allison John , Gallinghouse G , Burkhardt John , Horton Rodney , Al-Ahmad Amin , Di biase Luigi , Casella Michela , Dello Russo Antonio , Natale Andrea
Published: November 2024

Background:
Current guidelines recommend oral anticoagulation (OAC) for at least two months post-radiofrequency ablation (RFA) in all patients with atrial fibrillation (AF). The endothelial injury during RFA that can promote thrombus formation, does not happen in pulsed-field ablation (PFA).

Objective:
We evaluated the optimal duration of OAC therapy needed for effective stroke prevention following PFA.

Methods:
Consecutive patients undergoing PFA for AF were included in the study and prospectively followed-up for 1 year. Based on the duration of post-ablation OAC [non-vitamin K OAC (NOAC)] therapy they were classified into
group 1:
NOAC for 1 month and group 2: NOAC for ≥2 months. Patients were closely monitored for thromboembolic (TE) events via telemedicine. Stroke/transient ischemic attacks that occurred while the patients were in full compliance with the anti-thrombotic therapy, were counted as the reportable TE events.

Results:
A total of 120 patients were included in this analysis. The mean age of the study population was 59.80 ± 16.39 years; 70 (58%) were male and the CHA
2
DS
2
-VASc score was 4.27 ± 1.22. Mean number of PFA applications given was 76.64 ± 36.04.

G
roup 1
included 49 (40.8%) and
group 2
was comprised of 71 (59.2%) patients. Baseline characteristics were comparable between the groups.

At 1 year,
no stroke or transient ischemic attacks were reported in group 1 and 2
. At that time point, 42 (85.7%) and 60 (84.5%) patients were arrhythmia-free in group 1 and 2 respectively (p=0.85).

Conclusion:
In this series of patients, OAC could be safely discontinued after 1 month following the PFA procedure. Thus, it seems redundant to continue OAC beyond 1 month after PFA.
Abstract 4141905: ROS-Detoxifying Cerium Oxide Nanoparticles Attenuate the Pro-Arrhythmic Effect of Diesel Exhaust Particles in Isolated Rat Hearts
Authors: Ganse Gino Freddy Sena , Rodriguez Cristina , Ernst Lena , Ruiz-Meana Marisol , Inserte Javier , Martinez-Gonzalez Jose , Benito Begona , Puntes Victor , Ferreira-Gonzalez Ignacio , Rodriguez-Sinovas Antonio
Published: November 2024

Introduction:
Epidemiological evidence suggests a link between acute air pollution exposure and ventricular arrhythmias, with increased reactive oxygen species (ROS) production as a key mechanism. However, a cause-effect relationship remains unclear, studies on chronic effects are lacking, and the impact of strategies limiting ROS production has not been studied in detail.

Aims:
To analyze the effects of chronic intratracheal instillation of diesel exhaust particles (DEPs) on ventricular arrhythmogenesis, investigate the underlying mechanisms, and assess the impact of cerium oxide nanoparticles (CeO
2
NP) as a ROS-detoxifying strategy.

Methods:
Male and female Sprague-Dawley rats were intratracheally instilled with saline without or with DEPs (7.5 g/Kg, 0.375 mL/Kg, 3 times/week, for 1-3 weeks). Rats were then sacrificed and hearts perfused through the aorta in a Langendorff system. Incidence of premature ventricular beats (PVBs) and non-sustained and sustained (>30s) ventricular tachyarrhythmias (VT) were assessed by programmed electrical stimulation. Cardiac hypertrophy, collagen content, inflammation and oxidative stress were analyzed by conventional histology, Western Blot, RT-PCR, and the oxidized/reduced glutathione (GSH/GSSG) ratio. The potential protective effect of ROS-detoxifying CeO
2
NP (0.5 mg/Kg/week, i.p.) was also analyzed.

Results:
DEP exposure increased the incidence and duration of inducible sustained VTs. This pro-arrhythmic effect associated with a moderate rise in interstitial collagen deposition (from 3.11±0.12 in controls to 4.80±0.21 % in DEP-exposed rats, Student’s t test, p<0.001) and prolonged QRS complex and QTc in the ECG. Collagen expression was induced within one weeks of DEP exposure, as shown by RT-PCR. Additionally, the GSH/GSSG ratio decreased after 3 weeks of DEP exposure, while mRNA levels of the ROS-producing NOX1, NOX2 and NOX4 isoforms rose early after DEP exposure, and expression of the antioxidant thioredoxin reductase was reduced. CeO
2
NP attenuated the pro-arrhythmic effects of DEP exposure (sustained VT duration: 0.00±0.00, 51.09±18.99 and 20.00±20.00 ms in hearts from control, DEP-treated and CeO
2
-treated animals, Krustal-Wallis test, p<0.05 between controls and DEP-treated).

Conclusion:
DEP exposure increases the incidence and duration of sustained VTs in rats, effects associated with increased collagen deposition and oxidative stress. ROS-detoxifying CeO
2
NP attenuate the pro-arrhythmic effects of DEP exposure.
Abstract 4141946: Characterization of Cardiac, Autonomic, and Exercise Physiology in Patients with Long COVID
Authors: Suckow Emmett , Pierce Kate , wulff kyla , Arent Chelsea , Kreye Shelanna , Rosenberg Michael , Sabin Katie , Parker Hugh , Forbes Lindsay , McDonnell Barry , Stöhr Eric , Cornwell William
Published: November 2024

INTRODUCTION:
Mechanisms contributing to the post-acute sequelae of SARS-CoV-2 (PASC, aka Long COVID) and associated functional limitations are unclear.

RESEARCH QUESTION:
Determine cardiovascular, autonomic and exercise physiology among patients with Long COVID.

METHODS:
Twenty-one Long COVID patients (16 females, 41±12yrs) underwent cardiovascular assessment during head-up tilt at supine, 30
o
and 60
o
, a 10-minute upright standing orthostatic challenge and cardiopulmonary exercise testing (CPET). Baroreceptor sensitivity was determined with Valsalva maneuver. Heart rate (HR) and blood pressure (BP) were monitored continuously. Plasma norepinephrine (NE) was monitored during tilt.

RESULTS:
During tilt, HR increased with transition from supine to 30
o
and 60
o
(72±12 v. 80±14 v. 90±15bpm, P<0.001). Plasma NE increased (2519±896 v. 3407±1085 v. 4025 ±1153pg/mL, P<0.001) and MAP was maintained (92±10 v. 94±10 v. 97±10mmHg, P=0.103). HR increased during Phase IIA of the Valsalva in response to a reduction in systolic blood pressure with group-averaged baroreceptor sensitivity of 8.2±6.0ms/mmHg (
Figure 1
). During the 10-minute stand, HR increased and BP was maintained (
Figure 2
). CPET data are presented in
Table 1
demonstrating reduced peak oxygen uptake of 19.5±6.7ml/kg/min (74±18% predicted).

CONCLUSIONS:
Patients with Long COVID demonstrate preserved autonomic function, with appropriate increase in catecholamines and preservation of blood pressure in response to orthostatic challenge. HR and BP increased appropriately during exercise for the level of work achieved, but overall functional capacity was reduced. Further research is needed to identify novel treatment strategies to improve outcomes.
Abstract 4141954: Laser Ablation to Prevent Coronary Obstruction and Sustain Coronary Access in redo-TAVR: a Feasibility Study
Authors: Brlansky John , Qiu Dong , Azadani Ali
Published: November 2024

Introduction:
Redo-transcatheter aortic valve replacement (TAVR) is a promising treatment for transcatheter aortic valve degeneration, becoming increasingly relevant with an aging population. In redo-TAVR, the leaflets of the initial (index) transcatheter aortic valve (TAV) are displaced vertically when the second TAV is implanted, creating a cylindrical cage that can impair coronary cannulation and flow. The risk of coronary obstruction after redo-TAVR can reach as high as 20% and is affected by several factors, including the first TAV design, implantation depth, commissural alignment, and choice of the second TAV. Preventing coronary obstruction and maintaining coronary access is essential, especially in young and low-risk patients.

Hypothesis:
Laser ablation of TAV index leaflets can effectively create openings to prevent coronary obstruction and ensure coronary access in at-risk patients undergoing redo-TAVR.

Aim:
This study aimed to develop a new leaflet modification strategy using laser ablation to prevent coronary obstruction and facilitate coronary access after redo-TAVR.

Methods:
To evaluate the feasibility of the leaflet modification technique using laser ablation, initially, a medical-grade ultraviolet laser was used for ablation through pericardial leaflet tissue. Following this intervention, computational fluid dynamics simulations were utilized to assess the efficacy of the resulting perforations in promoting coronary flow after sinus sequestration in redo-TAVR. These simulations played a crucial role in ensuring that these changes would facilitate the restoration of coronary circulation.

Results:
Laser ablation of pericardium leaflets was successful, demonstrating the feasibility of creating openings in the TAV leaflets (Fig. 1a). Flow simulation results showed that ablation of index valve leaflets can effectively mitigate the flow obstruction caused by sinus sequestration in redo-TAVR, with the extent of restoration dependent on the number and location of the ablated openings (Fig. 1b).

Conclusions:
Laser ablation could be a viable method for leaflet modification in redo-TAVR, serving as a new tool in interventional procedures.
Abstract 4141960: Quality of Life Outcomes after the Dual Epicardial&Endocardial Procedure Approach for Treatment of Non-Paroxysmal Atrial Fibrillation
Authors: Khoynezhad Ali , KASIRAJAN Vigneshwar , La Meir Mark , de Asmundis Carlo , koneru Jayanthi , Johnkoski John , Rist Kevin , Mumtaz Mubashir , Link Michael , de Groot Joris , Driessen Antoine , Lee Mark , Hoff Steven , Bello David , Dunnington Gansevoort , Eisenberg Susan , Vloka Margot , Taylor Benedict , Jones Stephen , Philpott Jonathan , Beaver Thomas , Miles William , khan junaid , Kang Steven , Gandhi Gaurang , Okum Eric , Badhwar Nitesh , Baykaner Tina , Lee Anson , Vesco Paul , Smith J Michael , Gaynor Sydney , Frazier Ken , Ellembogen Kenneth
Published: November 2024

Background:
Quality-of-life (OQL) is recognized as a proven benefit of atrial fibrillation (AF) ablation. The DEEP trial (NCT02393885) showed safety (6.7%) and efficacy (71.8%) of an epicardial-endocardial hybrid ablation (HA) approach with left atrial appendage exclusion (LAAE) for non-paroxysmal AF; results were consistent with two randomized trials comparing HA+LAAE to catheter ablation (CA). Limited data exist on QOL after HA+LAAE.

Goal:
To evaluate QOL changes from baseline to 12-months post-HA+LAAE in the DEEP trial.

Methods:
DEEP is a 17-site prospective, international, single arm trial. Key eligibility: adults with non-paroxysmal AF, left atrial diameter ≤5.5cm, failed class I/III anti-arrhythmic drugs, and ≤2 prior failed CA. Stage 1 was thoracoscopic radiofrequency epicardial ablation to isolate the pulmonary veins and left atrial posterior wall, and LAAE. Stage 2 was endocardial mapping and touchup ablation. QOL was measured via the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire at baseline and 12-months post-HA+LAAE. AFEQT yields scores from 0 to 100 (0 as complete disability and 100 as no disability) and includes an overall and four subscale scores. A 5-point AFEQT change is clinically important. Mean differences with 95% CIs were calculated; p-values are from paired t-tests.

Results:
Of 85 patients, 82 completed both baseline and 12-month AFEQT. The mean change in overall score was 30.1 ± 19.8 (95% CI: 25.8-34.5; median 29.5, min, max: -15.4, 78.2; p<0.0001) (Figure). The greatest improvement was in the Treatment Satisfaction subscale with a mean score of 53.2 ± 29.9 (95% CI: 46.6-59.7; median 58.3, min, max: 0.0, 100.0; p<0.0001), followed by Treatment Concern, Daily Activities, and Symptoms subscale scores. All mean improvements from baseline exceeded a clinically meaningful 5-point change.

Conclusion:
In the DEEP trial, HA+LAAE resulted in patient-reported QOL improvements at 12-months post-procedure.
Abstract 4141967: The Role of Endothelial Dysfunction and Thromboinflammatory Biomarkers in the Mediation of the Pathogenesis of Atrial Fibrillation
Authors: Fareed Jawed , Dungan Gabriel , Odeh Ameer , Hoppensteadt Debra , Siddiqui Fakiha , Syed Mushabbar
Published: November 2024

Introduction:
Atrial Fibrillation (AF) is a common cardiovascular disease with complex pathophysiology. AF induces proinflammatory processes which incite vascular endothelial activation and dysfunction. This study seeks to examine the potential relationship between various endothelial, inflammatory, thrombotic, and renin-angiotensin-system (RAS) biomarkers in AF patients.

Materials and Methods:
Blood samples were from AF patients (n=110) prospectively enrolled in this study prior to their first AF ablation. Control plasma samples (n=100) were used as reference and obtained from non-smoking, healthy individuals from a commercial vendor (George King, Overland Park, KS, USA). All samples were analyzed for endothelial (NO, ICAM-1, VEGF, TF, TFPI, TM, Annexin V), inflammatory (IL-6, TNFα, CRP), thrombotic (vWF, tPA, PAI-1, TAFI, D-dimer), and RAS (Renin, Ang-II) biomarkers using commercially available ELISA methods. Biomarker average comparisons and Spearman correlations were performed.

Results:
AF patients showed varying levels of biomarker increase compared to controls. We observed a significant decrease of Ang-II in the AF population relative to controls when stratified for the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) upon study enrollment. AF patients showed statistically significant correlations between the following biomarkers: TNFα vs IL-6 (rs=0.317, p=.004), ICAM-1 vs TNFα (rs=0.527, p=.012), Annexin V vs VEGF (rs=0.620, p<.001), CRP vs VEGF (rs=0.342, p=.031), Ang-II vs tPA (rs=-0.592, p=.010), and tPA vs PAI-1 (rs=0.672, p<.001).

Conclusion:
Our study demonstrated significant elevation of endothelial, inflammatory, and thrombotic biomarkers in AF patients compared to controls, with significant correlations between these biomarkers in the AF population. Future investigations are required to better elucidate the mechanistic pathways that lead to endothelial dysfunction and thromboinflammation in AF. This may provide novel therapeutic targets, that in addition to current anticoagulation practices, can best curtail thromboinflammatory processes in AF.
Abstract 4141968: The relationship between Iron deficiency anemia and one year rehospitalization rate in Heart Failure Patients with Reduced Ejection Fraction: A Retrospective Cohort Study.
Authors: Reyad Mohamed , Adjei Nathanael , Najarian Lisa , Rangan Pooja , Gopalan Radha
Published: November 2024

Background:
Each heart failure (HF) hospitalization is associated with significant morbidity and mortality, reduced quality of life, and extensive use of healthcare resources. Iron deficiency anemia (IDA) frequently coexists with heart failure, exacerbating therapeutic outcomes and reducing patients' overall quality of life.

Hypothesis:
IDA increases the rate of overall rehospitalization in HFrEF patients.

Aim:
Assess the influence of IDA on rehospitalization rates among patients with HFrEF.

Methods:
A retrospective analysis was performed on adult patients at a Metroplex Health System in Arizona who had an ICD code of HFrEF between January 2016 and December 2017. The primary endpoint was all causes rehospitalization within 1- and 12-months post-discharge. The relationship between IDA and all causes rehospitalization was assessed using multivariate logistic regression, while adjusting for potential confounders.

Results:
Among 1,083 patients diagnosed with HFrEF, 115 (10.62%) had IDA. The mean age (SD) and BMI (SD) of the IDA group were 64.02 (14.59) years and 29.62 (8.22) kg/m2, respectively, with 69.57% being male and 52.17% non-Hispanic white. After adjusting for age, race, gender, diabetes, hypertension, dyslipidemia, coronary artery disease, and cerebrovascular disease, the competing risk survival analysis revealed a statistically significant increase in hospital readmission rates at 12 months for IDA (adjusted subhazard ratio [aSHR]: 1.78, 95% CI: 1.38-2.30, p < 0.001) and native American ethnicity (aSHR: 1.56, 95% CI: 1.056-2.311 p = 0.026). While the rate of rehospitalization at 1 month did not achieve statistical significance (aSHR: 1.19, 95% CI: 0.723-1.956, p = 0.491).

Conclusion:
Patients with HFrEF and IDA have higher all-cause hospital readmission rates within 12 months, highlighting the importance of managing IDA in HFrEF treatment. Addressing IDA may reduce rehospitalization burden and improve long-term outcomes.
Abstract 4141973: Comparison of Six Physical Frailty Assessments in Adults with Heart Failure with Preserved Ejection Fraction
Authors: Zainul Omar , Marshall Dylan , Lau Jennifer , Kelly Brooke , Zarzuela Kate , Damluji Abdulla , Pandey Ambarish , Pastva Amy , Goyal Parag
Published: November 2024

Background:
Frailty is a known prognostic marker of adverse outcomes in adults with heart failure with preserved ejection fraction (HFpEF); however, there are over 60 frailty assessment tools and no standardized method to assess frailty in HFpEF.

Goals/Aims:
This study aimed to conduct a head-to-head comparison of the prevalence and prognostic value of six commonly used frailty scales in adults with HFpEF.

Methods:
We examined 203 ambulatory patients with HFpEF seen at Weill Cornell Medicine from June 2018 - August 2022. The following frailty scales were assessed: the Clinical Frailty Scale (CFS), the FRAIL scale (the Fatigue, Resistance, Ambulation, Illnesses, and Loss of Weight scale), the 5-meter gait speed test, the five times sit-to-stand test (5-STS), hypoalbuminemia, and the modified body mass index (mBMI). Multivariable cox proportional-hazard models, adjusting for race and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) prognostic risk score, were used to examine the association between frailty and the primary endpoint (a 1-year composite of all-cause mortality and all-cause hospitalization). A Bonferroni correction was included into our models.

Results:
The median age was 76.7 years (IQR [69.7-83.9]), LVEF was 63.0 (IQR [59.0-68.0]), and MAGGIC score was 24.0 (IQR [19.0-28.0]). The prevalence of frailty ranged from 21.2% (hypoalbuminemia) to 77.8% (5-STS), and increased with advancing HFpEF severity on all frailty scales. In the adjusted analysis, the CFS, FRAIL scale and the 5-meter gait speed test were associated with the composite of all-cause mortality and all-cause hospitalization,
Figure 1
. A linear relationship was found between higher scores on the CFS, FRAIL scale, and the 5-meter gait speed test and the log-predicted odds of the composite of all-cause mortality and all-cause hospitalization.

Conclusion:
The CFS, FRAIL scale, and the 5-meter gait speed test demonstrated associations with adverse outcomes among adults with HFpEF. These specific tools are quick to administer and easy to interpret, and thus may be appropriate for routine use in patients with HFpEF.
Abstract 4142024: MicroRNA 486 is Myogenic and Remodels Dystrophic Transcriptome in Limb-Girdle Muscular Dystrophy Type 2B (Dysferlinopathy)
Authors: KIM JAE YONG , Vajravelu Bathri
Published: November 2024

Introduction:
Dysferlinopathy, a subgroup within muscular dystrophies, is an autosomal recessive myopathy that entails a spectrum of progressive muscle degeneration with a pathogenic mechanism of impaired sarcolemma. Its genetic etiology is rooted in mutations in the DYSF gene at Chromosome 2p13. The DYSF gene encodes for dysferlin, a type II transmembrane protein prominently expressed in skeletal muscle and cardiac tissue. Dysferlin plays a pivotal role in calcium-dependent membrane repair and regulate macrophage activation in skeletal muscles. MicroRNAs (miRNAs), highly conserved non-coding RNA transcripts under 25 nucleotides, modulate translational repression via mRNA degradation. Reduced expression of miR-486, a muscle enriched miRNA, has been correlated with the disease severity in Duchenne muscular dystrophy. However, the expression level of miR-486 and its role has not been elucidated in dysferlinopathy.

Hypothesis:
We hypothesized that miR-486 expression is differentially expressed in dysferlin-deficient skeletal muscle, function as a regulator of cell cycle kinetics, differentiation, and is essential for the sarcolemma repair machinery.

Methods:
Tissue expression analysis of miR-486 was performed across ten mice tissues. Subsequently, miR-486 was overexpressed and silenced in both wild type and dysferlin deficient murine myoblasts (C2C12 cells) via cellular transfection (n=3). Differential expression of miR-486 levels and various cell cycle genes were validated using qRT-PCR. Myoblast fusion assay, along with immunohistochemistry was undertaken to determine cellular differentiation. Bioinformatics approach was undertaken for pathway analysis of miR486 in dystrophic muscles.

Results:
We confirmed that miR486 is myogenic, demonstrated by highest expression in skeletal muscles. We found reduced expression of miR486 by more than two folds in dysferlin-deficient myoblasts compared to the wild-type. Overexpression of miR-486 increased Ki-67 and MCM2 expression in wild-type myoblasts, indicating its pro-proliferative role.

Conclusion:
The results thus far suggest that dysferlinopathy is associated with aberrant expression of miR-486, which plays a role in regulating myoblast proliferation. We are currently focused on elucidating how miR-486 influences myoblast differentiation and characterizing the underlying molecular mechanisms by quantifying the gene expression changes driven by modulation of miR-486.
Abstract 4142080: Bridge from Arrest to Recovery: Sudden Cardiac Arrest in a Young Patient with Concomitant Myocardial Bridge and Hypertrophic Cardiomyopathy
Authors: Iqbal Fatima , Khan Muhammad Jafar , Charitakis Konstantinos
Published: November 2024

Case Presentation:
A 27-year-old-male without any known medical history presented after witnessed sudden cardiac arrest. Initial rhythm in the field was ventricular fibrillation. He underwent CPR with three rounds of external defibrillation with 200 J and after return of spontaneous circulation (ROSC) was transferred to our facility. He was initially normotensive, bradycardic, hypothermic to 35.6°C and hypoxic requiring non-rebreather mask. He was intubated for airway protection. Post ROSC 12-lead surface ECG revealed sinus rhythm with a prolonged QT interval and left ventricular hypertrophy. Initial high-sensitivity Troponin I was elevated to 83 pg/ml that peaked to 4631 pg/m. On transthoracic echocardiogram, ejection fraction was 55-60% with moderate concentric left ventricular hypertrophy and an interventricular septum end diastolic thickness of 1.3 cm as well as normal left ventricular outflow tract pressure gradient. Coronary angiogram was notable for prominent myocardial bridge (MB) of the middle left anterior descending (LAD) artery without any evidence of atherosclerotic disease. Cardiac magnetic resonance imaging (CMR) showed asymmetric left ventricular hypertrophy with reverse septal curvature variant and evidence of patchy late gadolinium enhancement. A dual-chamber implantable cardioverter defibrillator was placed for secondary prevention of ventricular arrhythmias and sudden cardiac death. Metoprolol tartrate was started for management of hypertrophic cardiomyopathy (HCM) and MB. At follow-up visit he was asymptomatic and genetic testing was positive for heterozygous gene mutation in MYBPC3.

Discussion:
MBs have been recognized as a common congenital anomaly of the epicardial coronary arteries, with a higher prevalence reported in patients with HCM. We present a unique clinical scenario of a young patient with asymmetric HCM, patchy late gadolinium enhancement on CMR and evidence of prominent MB of the LAD artery. Hemodynamically significant MBs have been implicated in the degree of fibrosis in HCM which is significant due to the correlation between extent of fibrosis and adverse cardiac remodeling, and the consequent predisposition to arrhythmogenesis. However, the existing literature is inconclusive regarding the exact association between MBs and cardiovascular mortality in HCM. Here, we highlight the potentially increased risk of sudden cardiac arrest conferred by MB in HCM and the need for further studies to delineate this association.
Abstract 4142101: Preservation of Cardiac Function by Glucagon-Like Peptide-1 (28-36) through Metabolic Modulation and Coronary Vasodilation in a Juvenile Porcine Model of Donation after Circulatory Death
Authors: Kadowaki Sachiko , Siraj M. Ahsan , Deng Mimi , Lao Robert , Lamba Manya , Li Jing , Nagy Anita , Mueller Brigitte , Fan Steve , Parker Marlee , Kobayashi Junko , Husain Mansoor , Honjo Osami
Published: November 2024

Purpose and Hypothesis:
Despite the increasing number of donation after circulatory death (DCD) heart transplants over the last decade, there is no promising cardioprotective agent to improve DCD heart function in this clinical setting. There is some evidence that glucagon-like peptide (GLP)-1 (28-36), a metabolite of the insulinotropic GLP-1(7-36) incretin hormone, provides cytoprotection to the coronary vasculature without activating the GLP-1 receptor. This study aims to explore the potential benefits of GLP-1(28-36) on DCD hearts in juvenile pigs.

Methods and Results:
DCD heart procurement was performed on twelve Yorkshire juvenile pigs (9-12 kg) with a 15-min warm ischemic period, followed by reperfusion for 2 hours using
ex-vivo
heart perfusion (unloaded condition) with either GLP-1(28-36) or scrambled GLP-1(28-36) control (SCRAM) (each N=6, 6-nM), before switching to working mode (loaded condition). Between-group differences were analyzed using Wilcoxon rank-sum tests and linear mixed-effects models. Over the reperfusion period, venous lactate levels trended down in the GLP-1(28-36) group, compared to SCRAM (3.0±1.1
vs.
4.4±0.5, mmol/L at 120min, p=0.01;
Figure 1A
), despite no significant difference seen in plasma cardiac troponin I levels in working mode (GLP-1[28-36]
vs.
SCRAM, 61±20
vs.
83±18, ng/mL, p=0.08). Coronary vascular resistance was lower in the GLP-1(28-36) group
vs.
SCRAM (0.48±0.11
vs.
0.93±0.51 mmHg*min/mL/100g at 30min, p<0.01;
Figure 1B
). During working mode, GLP-1(28-36)-treated hearts showed better diastolic function (dp/dt min: -3357±784
vs.
-2372±471 mmHg/sec, p=0.03), with comparable systolic function (p=0.13). Higher levels of cardiac activated endothelial nitric oxide synthase (0.23±0.05
vs.
0.14±0.02, p<0.01) and plasma cyclic guanosine monophosphate (45±22
vs.
23±11, pmol/mL, p=0.03) were observed with GLP-1(28-36) treatment.

Conclusion:
GLP-1(28-36) preserves diastolic function of DCD hearts during
ex-vivo
heart perfusion by reducing anaerobic metabolism and maintaining coronary endothelial function.
Abstract 4142138: Prediabetes Subphenotypes Show Different Associations with Time to Type 2 Diabetes in the Diabetes Prevention Program
Authors: Stroebel Benjamin , Gadgil Meghana , Zhang Li , Lewis Kimberly , Longoria Kayla , Flowers Elena
Published: November 2024

Introduction:
Prediabetes is a prominent risk factor for cardiovascular disease (CVD) and type 2 diabetes (T2D). The clinical phenotype of individuals with prediabetes, however, is diverse, and characterization of subphenotypes may identify differing underlying physiology and outcomes. This study aimed to examine associations among prediabetes clusters and time to T2D development.

Methods:
We performed k-means cluster analyses in a subset of individuals with prediabetes (n=994) from the Diabetes Prevention Program (DPP). Clusters were based on 7 clinically measurable variables (age, body mass index (BMI), waist circumference, triglycerides, HDL cholesterol (HDL-C), fasting glucose (FG), and hemoglobin A1c (HbA1c)). Differences in time to T2D between clusters, overall and by treatment arm, were assessed via Kaplan-Meier survival estimates with post-hoc tests adjusted for multiple comparisons via a Bonferroni correction. Cox proportional Hazard models adjusted for treatment, sex, and race and ethnicity were used to determine T2D hazard ratios (HR) by cluster.

Results:
Five distinct clusters were identified. 1: “older protected” (highest age and HDL-C, lowest BMI and triglycerides); 2: “dyslipidemia” (highest triglycerides, lowest HDL-C); 3: “insulin resistant” (highest FG and HbA1c); 4: “younger protected” (lowest age, FG and HbA1c, lower BMI and waist circumference); and 5: “larger protected (highest BMI and waist circumference, lower triglycerides). Clusters differed significantly in gender and race and ethnicity. Time to diabetes differed between clusters overall and by DPP treatment arm (fig. 1). Post-hoc tests indicated significantly lower time to T2D, both overall and in placebo, in cluster 3 vs. 1, cluster 2 vs. 4, and cluster 3 vs. 5. Time to T2D was also significantly lower in cluster 5 vs. 4 overall and in lifestyle, and in cluster 3 vs. 4 overall and in all treatment arms (corrected p<0.05). Adjusted Cox models indicate that the HR (95% CI) for T2D vs. cluster 4 in cluster 1 is 1.92 (1.10, 3.36), 3.77 (1.88, 7.59) in cluster 2, 4.93 (2.96, 8.23) in cluster 3, and 2.74 (1.57, 4.81) in cluster 5.

Conclusions:
Clinical variables were used to identify 5 distinct subphenotypes of individuals with prediabetes, each demonstrating different rates of T2D development, with treatment-adjusted differences. This study highlights potential heterogeneity in individuals with prediabetes and potential clinically relevant clusters with increased risk of progression to T2D.
Abstract 4142193: Emerging Role of Sodium-glucose cotransporter-2 Inhibitors in the Management of Chemotherapy-Related Cardiac Dysfunction: A Systematic Review and Meta-analysis
Authors: Rahman Mansoor , Alayyat Ahmad , Ali Junaid , Asif Hamza , Ullah Waqas , Bhatt Deepak
Published: November 2024

INTRODUCTION:
Many anti-cancer agents, including alkylating, anthracycline-based, and anti-HER2 chemotherapies, have a high risk of causing clinically significant cardiac toxicity, manifesting as heart failure (HF). The efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i's) in HFrEF and HFpEF is well-established; their role, however, in managing chemotherapy-related cardiac dysfunction (CTRCD) remains unclear.

AIMS:
To analyze available data on the efficacy of SGLT2i's in CTRCD.

Methods:
Pubmed, Embase and Web of Science databases were queried to find relevant clinical studies on the use of SGLT2i's in CTRCD. Primary outcomes included HF incidence, HF exacerbations, and all-cause mortality. Using a random effects model, relative risk ratios (RRs) with 95% confidence intervals were computed for all outcomes.

Results:
Out of 807 retrieved citations, 4 observational studies with 6576 participants were included in the analysis. In SGLT2i's and non-SGLT2i's groups, the number of subjects, mean age, and proportion of males were 1551 vs. 5025, 67.6 vs. 68.9 years, and 42% (648) vs. 40% (2000) with median follow-up range of 1.5-3.4 years. Only one study enrolled patients with prior HF, while diabetes was common among all. Anthracyclines were the most common chemotherapy agents used and the majority of patients had a hematological malignany. Onset of HF in the SGLT2i's group, as reported by two studies, was 6/31 and 94/930 in the non-SGLT2is group. The pooled HF incidence rate was similar between the two groups, with an RR of 0.54 (0.25-1.16, p=0.11). SGLT2i's users had a significantly lower rate of HF exacerbations and all-cause mortality compared with those who did not receive SGLT2i's with RR of 0.54 (0.33-0.91, p=0.02) and 0.48 (0.32-0.73, p=0.0006), respectively. Additionally, SGLT2i's were associated with a significantly lower rate of arrhythmias [ RR 0.40 (0.22-0.70, p=0.001)]. The mortality effect was beleived to be influenced by the antitumor effects of SGLT2i's as well. Moreover, the rates of adverse events secondary to SGLT2i's, such as euglycemic ketoacidosis, hypoglycemia, and infections, were reported to be lower.

Conclusion:
The observational data on the efficacy of SGLT2i's in CTRCD are promising. These drugs were found to have favorable effects on HF exacerbations, all-cause mortality, and arrhythmias onset associated with CTRCD. Large-scale randomized clinical trials are needed to validate these findings.
Abstract 4142200: An Economic Evaluation of Non-HDL-Cholesterol and Apolipoprotein B as Treatment Targets for Lipid-Lowering Therapy in Primary Prevention
Authors: Luebbe Samuel , Wilkins John , Moran Andrew , Sniderman Allan , Kohli-Lynch Ciaran
Published: November 2024

Introduction:
Apolipoprotein B (ApoB) is a better marker of residual risk for cardiovascular disease in patients treated with lipid-lowering therapy (LLT) than low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). However, it is unclear if treating to an apoB target is more cost-effective than treating to an LDL-C or non-HDL-C target.

Methods:
We used the CVD Policy Model, a validated computer simulation model, to estimate the clinical and economic outcomes associated with atherogenic lipid targets for LLT in a cohort of statin-eligible and ASCVD-free U.S. adults. We considered non-HDL-C, and apoB targets for intensification of LLT. Treatments considered were intermediate-intensity statin therapy, high-intensity statin therapy, and ezetimibe, intensified in that order. Upon entering the model, all individuals commenced statin therapy. Under ‘usual care,’ patients with LDL-C ≥100 mg/dL after three months of treatment were escalated to higher-intensity treatment. Under non-HDL-C and apoB testing strategies, LLT was escalated if patients had non-HDL-C ≥119 mg/dL and apoB ≥78.7 mg/dL, respectively, based on percentile equivalence to the LDL-C target. The primary outcomes for our study were healthcare costs (2023 U.S. dollars) and quality-adjusted life years (QALYs). Secondary outcomes were CVD events prevented and life years gained. A lifetime horizon was adopted with a health sector perspective. Future costs and QALYs were discounted at 3% annually.

Results:
In a sex-balanced simulated cohort of 500,000 individuals, both non-HDL-C and apoB testing produced more QALYs and fewer costs than usual care (LDL-C target). Intensification based on apoB, produced 1,416 more QALYs than non-HDL-C-guided intensification, saving around $29,300,000 over the lifecourse of the simulated cohort. Compared to non-HDL-C testing, apoB testing would lead to 1,233 fewer CVD events and 3,800 more life years. Health gains were greater for men, though apoB screening was cost-saving (i.e., higher QALYs, lower cost) when compared to LDL-C and non-HDL-C testing for men and women.

Conclusion:
Making LLT intensification decisions based on apoB instead of LDL-C or non-HDL-C would save costs while improving population health.
Abstract 4142234: First-in-Human Multi-Perspective Mapping Approach Offers Mechanistic Insights in Atrial Fibrillation
Authors: Nguyen Andrew , Ling Ian , Chen Matthew , Partow-Navid Rod , Leung Steven , Zadeh Andrew , Ho Ivan , Zaman Junaid
Published: November 2024

Introduction:
The mechanisms underlying the persistence of atrial fibrillation (AF) are still debated. Studies in animal and human cardiac bench top models suggest that different mapping techniques influence the detection of localized sources or self-sustaining, transient wavelets in AF. Despite this, no human studies have examined the influence of a local versus global mapping approach on the detection of these sources simultaneously in the same patient.

Objective:
We hypothesize that local and global mapping of AF offer different spatiotemporal resolutions that influence the nature of sustaining mechanisms but not their location in the chamber. This will be particularly evident for rotational sources.

Methods:
16 patients who underwent catheter ablation for AF, atrial flutter (AFL), or premature atrial contractions (PACs) were studied. All patients underwent electroanatomic mapping of the left and right atria with both local and global approaches. Anatomical locations were subdivided into different regions (Figure 1A, 1B). Mechanisms were classified as focal, rotational, or localized irregular activation (LIA) using mapping algorithms. Analyses were done using Chi-squared tests.

Results:
A total of 40 AF, 12 AFL, and 4 PAC simultaneous electroanatomic maps were obtained. Both local and global mappings identified an AF source (n=52) within close anatomical proximity 86.5% of the time (
p
<0.001). However, mechanisms differed between AF sources identified with different views (34.6% same, 65.4% different,
p
=0.03) (Figure 1C). These different mechanisms were 47.1% rotational and 50% LIA on global maps (n=34,
p
<0.001) and 94.7% focal on local maps (n=19,
p
<0.001) (Figure 1D). AF sources with the same activation pattern across different scales were mostly identified as focal (94.4%,
p
<0.001). In contrast, AFL and PACs shared both location (100%,
p
=0.005) and mechanism (87.5%,
p
=0.03) across local and global maps.

Conclusion:
Local and global maps offer different spatiotemporal resolutions that influence how a mechanism of a source is portrayed, and hence ablation strategy. This has a greater impact on rotational sources in AF, and may explain the divergent results in pre-clinical and clinical AF mapping studies.