bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16879: Endothelial Prolyl Hydroxylase 3 Regulates Post-Ischemic Kidney Injury Through HIF Dependent Mechanisms
Authors: Tiwari Ratnakar , Sharma Rajni , Borkowski Gabriella S , Quaggin Susan E , Kapitsinou Pinelopi P
Published: December 2023

Introduction:
Acute kidney injury (AKI) is highly prevalent clinical condition after cardiac surgeries and is associated with high morbidity and mortality in hospitalized patients. Ischemia reperfusion injury (IRI) is one of the major causes of AKI. Previously, we have reported a critical role for the endothelial oxygen sensor prolyl hydroxylase (PHD2) in ischemic AKI. Recently, we found that prolyl hydroxylase 3 (PHD3) shows robust increase in kidney endothelium after renal IRI. However, its role in ischemic AKI is unknown.

Hypothesis:
We hypothesized that endothelial PHD3 regulates post-ischemic kidney injury.

Methods:
To delete endothelial PHD3, VECadherin (Cdh5)-CreER transgenic mice were crossed to mice carrying conditional PHD3 allele, generating

PHD3
iEC

mice. To test the HIF-dependent role of PHD3, we generated Cdh5CreER;

Phd3
flox/flox
Arnt
flox/flox

mice (

PHD3ARNT
iEC

). Inactivating ARNT (aryl hydrocarbon receptor nuclear translocator), also known as Hif-1β, blocks HIF signaling. Unilateral IRI was induced by renal artery clamping, and tamoxifen treatment was started at day 1 post IRI, followed by analysis at day 14.

Results:
Compared to

Cre
-

controls, inactivation of
Phd3
in endothelial cells (ECs) following IRI exacerbated kidney damage and inflammation, as indicated by increased expression of
kidney injury molecule 1
(
Kim1
) and profibrotic genes
lysyl oxidase-like 2
(
Loxl2
),
transforming growth factor-beta 1
(
Tgfb1
)
, smooth muscle actin
(
Acta2
) and collagen deposition assessed by Picro Sirius red staining (n=6-7; p< 0.05). Post-ischemic inactivation of ARNT along with PHD3 ameliorated the effects of only PHD3 inactivation and normalized levels of
Kim1
,
Loxl2
,
Tgfb1
and collagen deposition
(
n=7; p< 0.05)
.
In vitro suppression of
PHD3
in human primary EC using PHD3-siRNA showed significant upregulation of inflammatory molecules such as ICAM1 (Intercellular Adhesion Molecule 1), VCAM1 (Vascular Cell Adhesion Molecule 1), C-X-C motif chemokine ligand 9 and 10 (
CXCL9 and CXCL10
), which were again blunted by
ARNT-
siRNA treatment (n= 3; p< 0.05).

Conclusions:
In summary, our data support a critical role for endothelial PHD3 in regulating post-ischemic kidney inflammation and fibrosis through HIF-dependent mechanisms.
Abstract 16880: Perceived Control Moderates the Relationship Between Fatigue and Self-Care in Patients With Heart Failure
Authors: Higa Hiroko , Tsuchihashi-Makaya Miyuki
Published: December 2023

Introduction:
Fatigue is associated with poor self-care in patients with heart failure (HF). However, factors of fatigue include not only physical factors but also psychological factors, making it difficult to manage. Perceived control refers to the ability to cope with threats and has a significant impact on self-care and fatigue.

Hypothesis:
We hypothesized that a higher perceived control would lead to better self-care, even if the level of fatigue was comparable. This study aimed to determine whether the perceived control moderates the relationship between fatigue and self-care in patients with HF.

Methods:
In this cross-sectional study, outpatients with HF (n = 165, 78.8% male, mean age = 69.5 years) completed an assessment of fatigue using the Brief Fatigue Inventory (BFI) and perceived control using the Control Attitude Scale Revised (CAS-R). Participants were categorized into four groups with High (H) and Low (L), H/H, H/L, L/H, and L/L, using the median of BFI and CAS-R scores. Self-care was measured using the Self-Care of HF Index (SCHFI v 6.2), which consists of three subscales, maintenance (adherence to treatment), management (management of symptoms) and confidence. All SCHFI scores were standardized (0–100). A higher score indicates better self-care. Analysis of variance was used to examine differences in four groups using the SCHFI scores.

Results:
There was a significant difference in SCHFI-maintenance (p = 0.018), especially between H/L and L/H (61.8± 17.3 vs. 70.8 ± 17.3, p = 0.026). Additionally, H/H tended to be higher than H/L (71.3 ± 11.73 vs. 61.8 ± 17.3, p = 0.069). There was a significant difference in SCHFI-management (p <0.001). H/H was significantly higher than H/L (60.1 ± 18.6 vs. 38.3 ± 22.5, p = 0.000), and L/H was significantly higher than L/L (53.3 ± 23.8 vs. 33.3 ±22.9, p <0.001). Similarly, significant differences were found in SCHFI-confidence (p <0.001). H/H was significantly higher than H/L (47.2 ± 21.6 vs. 28.8 ± 15.1, p < 0.001), and L/H was significantly higher than L/L (50.2 ± 21.6 vs. 22.8 ± 10.7, p <0.001).

Conclusions:
Perceived control might moderate the relationship between fatigue and self-care. Interventions for HF self-care require improvements in perceived control as well as physical factors, such as symptoms.
Abstract 16891: High Molecular Weight Hyaluronan Inhibits Macrophage Phagocytosis
Authors: Howard Caitlin M , Little Danielle , Belcher Sarah , Smith Juliette , Wysoczynski Marcin , Brainard Robert , Jones Steven P
Published: December 2023

Background:
After a myocardial infarction (MI), macrophages are recruited to the site of injury to begin the process of wound healing. Macrophages are important because they clear cellular debris via phagocytosis. This period of acute inflammation in the heart coincides with extracellular matrix (ECM) remodeling. Hyaluronan (HA), one of the most abundant ECM components, accumulates in a high molecular weight form (HA
HMW
). The relationship between HA
HMW
accumulation and macrophage function in is not fully understood.

Goal:
To determine the extent to which hyaluronan impacts phagocytosis in polarized macrophages.

Methods and Results:
Tissue sections were collected from mice one-week post-MI and stained for hyaluronan binding protein (HABP) to assess HA accumulation. A significant increase in HA was seen in both male (n=4, p=0.0031) and female (n=4, p=0.0210) MI hearts compared to sham hearts. Separately, bone marrow was isolated from naïve mice and cells were treated in culture with macrophage colony stimulating factor (M-CSF) for 7-10 days. The resultant macrophages were then polarized into a pro-inflammatory (M1) phenotype using LPS and INF-γ, or pro-reparative phenotype (M2) using IL-4 and IL-13. Macrophage polarization was confirmed via qRT-PCR. In additional experiments, macrophages were polarized for 24 hours and then incubated for 30 min with FITC-labeled, IgG-coated latex beads in the presence or absence of 1 μM HA
HMW
. Flow cytometry was used to assess phagocytosis of the beads. HA
HMW
treatment resulted in a significant reduction in the percent of FITC positive cells in M1 female (n=6, p=0.005), M2 female (n=5, p=0.0406), and M2 male (n=5, p=0.0314) macrophage subsets indicating a decrease in phagocytosis. No significant changes were seen in the M0 and M1 male macrophage subsets. Additionally, the mean fluorescence intensity (MFI) measured in the FITC channel was significantly decreased in all the female subsets as well as the M2 male macrophages (n=5-6, p<0.05). No significant changes were seen in the M0 and M1 male subsets.

Conclusion:
HA
HMW
impairs opsonin-induced phagocytosis in macrophages. Given that HA
HMW
accumulates post-MI, these findings may partially explain the incomplete immune response in the failing heart.
Abstract 16952: Comparative Outcomes of Below-the-Knee Stent Deployment Interventions: A Report From the XLPAD Registry
Authors: Bruneman Blake M , Fernandez Vazquez David , Weideman Sarah , Nanjundappa Aravinda , Metzger Christopher , sayfo sameh , Rosol Zachary , Tsai Shirling , Shishehbor Mehdi H , Banerjee Subhash
Published: December 2023

Background:
Stent use in the below-the-knee (BTK) peripheral arteries remains controversial, with scarce data on real world outcomes.

Methods:
We examined 1572 patients from the XLPAD Registry (NCT01904851) from 2006-2021 that underwent BTK endovascular intervention and stratified them based on stent vs non-stent interventions. The primary outcome was the incidence of major adverse limb events (MALE), which includes death, clinically driven revascularization, amputation, non-fatal myocardial infarction, and stroke.

Results:
517 (33%) patients received a stent and 1055 did not. Mean age 68 years, predominantly male (72%). White race was more frequent in stent group (64% vs. 55%, p<0.0001), whereas Hispanic were more prevalent in the non-stent group (19% vs. 9%, p<0.0001). Higher proportion of stented patients were smokers (53% vs. 26%, p<0.0001), fewer were diabetic (63% vs. 72%, p=0.0003) and had chronic kidney disease (17% vs. 28%, p<0.0001). Multivessel treatment was more common in stented patients (1.8 vs 2.8 lesions per case, p<0.0001) and involved SFA (70% vs. 32%, p<0.0001) and popliteal arteries (36% vs. 24%, p<0.0001). Stented patients had more diffuse disease (60% vs. 48%, p<0.0001), in-stent restenosis (10% vs. 4%, p<0.0001) and CTOs (67% vs 46%, p<0.0001). Fluoroscopy time was longer (33 min vs. 30 min, p=0.005) with higher procedural (95% vs. 91%, p=0.008) and technical success rates (98% vs. 94%, p=0.0009). MALE (22 vs. 22%, p=NS) events at 12- months follow-up were similar in both groups. Only surgical revascularization after 12-months was more frequent in stent group (3% vs. 1%, p=0.02).

Conclusion:
A third of patients undergoing BTK artery intervention received stents in the XLPAD registry with higher rates of procedural and technical success and similar 12-month MALE events.
Abstract 16956: Historical Neighborhood Redlining and Bystander CPR Disparities in Out-of-Hospital Cardiac Arrest
Authors: Motairek Issam , Deo Salil V , Makhlouf Mohamed H.E. , Salerno Pedro R , Al-Araji Rabab , Wright Jackson T , Nasir Khurram , Rajagopalan Sanjay , Al-Kindi Sadeer ,   The CARES Surveillance Group
Published: December 2023

Introduction:
Out-of-hospital cardiac arrest (OHCA) is associated with low survival rates. Bystander cardiopulmonary resuscitation (CPR) is essential for improving outcomes, but its utilization remains limited, particularly among racial and ethnic minorities. Historical redlining, a practice that classified neighborhoods for mortgage risk in the 1930s, may have lasting implications for social and health outcomes.

Hypothesis:
This study sought to investigate the influence of redlining on the provision of bystander CPR during witnessed OHCA.

Methods:
We conducted an analysis using data from the comprehensive Cardiac Arrest Registry to Enhance Survival (CARES), encompassing 736,066 non-traumatic OHCA cases across the United States. The Home Owners' Loan Corporation (HOLC) map shapefiles were utilized to categorize census tracts of arrests into four grades (A signifying “best”, B “still desirable”, C “declining”, and D “hazardous”). Multivariable hierarchical logistic regression models were employed to predict the likelihood of CPR provision, adjusting for various factors including age, sex, race/ethnicity, arrest location, calendar year, and state of occurrence. Additionally, we accounted for the percentage of Black residents and residents below the poverty level.

Results:
Among the 43,186 witnessed cases of OHCA in graded HOLC census tracts, 37.2% received bystander CPR. The rates of bystander CPR exhibited a gradual decline across HOLC grades, ranging from 41.8% in HOLC grade A to 35.8% in HOLC grade D. In fully adjusted model, we observed significantly lower odds of receiving bystander CPR in HOLC grades C (OR 0.89, 95% CI 0.81-0.98, p=0.016) and D (OR 0.86, 95% CI 0.78-0.95, p=0.002) compared to HOLC grade A (Figure).

Conclusions:
Redlining, a historical segregation practice, is associated with reduced contemporary rates of bystander CPR during OHCA. Targeted CPR training in redlined neighborhoods may be imperative to enhance survival outcomes.
Abstract 16957:
PRKAG2
Directly Interacts With Myosin Heavy Chains to Modulate Myocyte Electrical and Morphological Changes in Cardiac Hypertrophy
Authors: Zhu Wandi , Saha Kusumika , Burch Micah , KC Ashmita , Homilius Max , Victorio Rachelle , Quan Dajun , Williams Alexander , Evans Chiara , Macrae Calum
Published: December 2023

Introduction:
Mutations in the
PRKAG2
gene cause a complex myocardial disorder characterized by hypertrophic cardiomyopathy (HCM) and conduction disturbances. While prior studies associated
PRKAG2
-linked hypertrophy with increased glycogen storage, many HCM phenotypes in the disorder remain unexplained by this effect alone. We aimed to uncover the molecular mechanisms by which
PRKAG2
mutations induce myocyte hypertrophy and electrical changes during cardiac development.

Methods:
We created transgenic zebrafish expressing WT (Tg
WT
) and pathological mutant (Tg
R299Q
) murine
Prkag2
cDNA under a myocardium-specific promoter. Using these models, we studied the impact of
Prkag2
variant on myocyte electrical activity, metabolism, and cytoarchitecture across cardiogenesis and in mature hearts.

Results:
Tg
R299Q
adult fish showed hypertrophic cardiomyocytes, swollen mitochondria, and shortened sarcomere length compared to Tg
WT
and WT, mirroring human HCM phenotypes. The glycogen content was elevated in adult hearts but not during early cardiogenesis. Despite the absence of glycogen accumulation at 6-day post fertilization, Tg
R299Q
hearts showed electrical abnormalities, including a reduced conduction velocity, decreased Ca
2+
amplitude, and prolonged action potential durations in both atria and ventricles, compared to Tg
WT
and WT. Co-immunoprecipitation and proximity ligation assay revealed physical interactions between Prkag2 and myosin heavy chain (MYH), with the R299Q variant enhancing this interaction and altering the subcellular localization of Prkag2 from mitochondria to sarcomeres. Knockdown of the fish homolog of
MYH7
(
vmhcl
) restored the early electrical disturbances caused by Tg
R299Q
. This abnormal MYH-Prkag2 interaction disturbed mitochondria and sarcomere organization contributing to altered myocyte cytoarchitecture observed in Tg
R299Q
.

Conclusions:
Mutant
PRKAG2
altered cardiac excitability and Ca
2+
handling during embryogenesis, preceding glycogen accumulation. Enhanced binding between Prkag2 and MYHs contributed to these early changes. Our study revealed a novel link between sarcomere proteins and metabolic regulators in cardiac hypertrophy, suggesting a new therapeutic avenue for treating HCM.
Abstract 16982: Baseline Diameter Does Not Predict Growth Rate in Ascending Thoracic Aortic Aneurysm
Authors: Marway Prabhvir S , Tjahjadi Nic , Campello Jorge Carlos Alberto , Knauer Heather A , Spahlinger Greg , Patel Himanshu J , Burris Nicholas S
Published: December 2023

Introduction:
Patients with ascending thoracic aortic aneurysm (aTAA) are recommended to undergo routine imaging surveillance. While maximal diameter is the primary metric of disease severity, recent AHA/ACC guidelines emphasize the importance of aortic growth in determining surgical candidacy and risk of complications. Increasing diameter is often assumed to confer higher aortic growth rate (GR) due to increased wall tension; however, this relationship is poorly studied.
Goal:
To investigate the relationship between aTAA diameter and GR using Vascular Deformation Mapping (VDM), a validated technique for 3D growth mapping with sub-millimeter accuracy.

Methods:
We identified 122 patients with ascending aortic dilation (≥4.0 cm) and serial gated CT angiograms (CTA) with an interval of ≥2 years. Ascending GR was defined as the 90th percentile of wall deformation (radial direction) by VDM, normalized by interval (mm/y). Maximal diameter measurements were taken from the baseline CTA report. Aortic height index (AHI, cm/m) and aortic cross-sectional area/height ratio (CSAH, cm^2/m) were calculated. Ascending aortic length (AL, mm) was measured from the annulus to the origin of the innominate artery.

Results:
122 patients (60.7% male, mean age 62.8 ± 10.9 y, 0% connective tissue disease) showed a mean baseline diameter of 44.7 ± 3.7 mm and mean GR of 0.30 ± 0.44 mm/y. No correlation was noted between GR and baseline diameter (r= -0.02, p= 0.86), AHI (r= -0.06, p= 0.54), CSAH (r= -0.04, p= 0.70), or AL (r= 0.08, p= 0.41). Diameter was modestly correlated with GR (r = 0.65, CI 95%: 0.11-0.89, p = 0.02) among the small subgroup with diameter ≥50mm (n=12). GR was not significantly correlated to age (r= -0.13, p= 0.17) and did not differ by sex (p= 0.91) or hypertension (p= 0.51). No demographic or anatomic variables were predictive of GR on multivariable analysis.

Conclusions:
Maximal aortic diameter is not predictive of aortic GR, especially at sizes under surgical thresholds (<50 mm).
Abstract 16986: Verticalize to Mobilize: A Pilot Study
Authors: Chan Alice T , Chonde Meshe , seidel suzanne , Villao Billy , Coleman Bernice L , Aronow Harriet , Hsu Sunny , Andreas Anthony , Velazquez Miguel
Published: December 2023

Introduction:
Early mobility in critical illnesses, like acute decompensated heart failure, is essential to preserving muscle strength. However, patients on mechanical support devices such as a femoral-inserted intra-aortic balloon pump (f-IABP) have traditionally had limited mobility due to potential complications. Unfortunately, this commonly leads to prolonged ICU stay and an increased need for rehabilitation.

Aim:
This study evaluates the safety and feasibility of implementing a nurse-led verticalization protocol for patients with an f-IABP.

Methods:
A total of 36 patients with f-IABP successfully verticalized utilizing the Kreg Catalyst™ bed between May 1, 2022, to May 4, 2023, for one hour-long session. The cohort selection required patients to be ambulatory before f-IABP placement, hemodynamically stable, and free of arrhythmias within the last 24 hours. The study carefully monitored hemodynamic stability by comparing baseline averages to peak tolerated angle (PTA) data.

Results:
A total of 322 verticalization sessions were completed without significant complications and only nine minor complications. Minor complications included five sessions (1.55%), resulting in a catheter readjustment of over 3 centimeters. They averaged 9±7 verticalization sessions per patient, averaging 55±13 minutes. Were19/36 patients (53%) achieved a PTA greater than 70 degrees. Mean arterial pressure decreased by 4±7mmHg. Pulmonary artery systolic pressure decreased by 2±3mmHg, the cardiac index fell by 0.1± 0.5L/min/m
2
, and the heart rate increased by 4±5bpm. Of the 36 patients, 29 (81%) received heart transplants during their hospitalization and had an average post-operative ICU stay of 7 days and a total postoperative hospital stay of 18 days. Of the cohort study, 23 patients (64%) were discharged home with home health, ten patients (27%) were transferred to a rehabilitation center, two patients (5%) were transferred to an outside hospital, and one patient transitioned to comfort care.

Conclusions:
The result of the study indicates that it is safe and feasible to verticalize patients with f-IABP.
Abstract 17019: The Missense W792R Mutation in C6 Domain of Cardiac Myosin Binding Protein-C Alters Morphology and Contractility in Mouse Myocardium
Authors: Ralphe John C , Giles Jasmine A , Farrell Emily T , Harbaugh Ella C , de Lange Willem J , Moss Richard L
Published: December 2023

Background:
Mutations in cardiac myosin binding protein C (cMyBP-C) are a common cause of hypertrophic cardiomyopathy (HCM) in humans. While many known cMyBP-C mutations lead to haploinsufficiency, others lead to amino acid substitutions which may impact protein function in unique ways The W792R mutation introduces a charge change and is known to be pathogenic in humans. This mutation, located remotely from both the regulatory amino terminus, and the C-terminus, has an unknown impact on the final protein structure and function.

Goal:
Generate a murine knock-in model to fully characterize the impact of the W792R mutation on cardiac morphology and function
in vivo.

Methods:
We generated a W792R knock-in (KI) mouse and produced heterozygous (HT) and homozygous (KI) offspring, and wild-type (WT) littermate controls. We performed histology, RNA and protein expression analyses, and mechanics on isolated trabeculae at postnatal day 12 (KI n=5; HT n=3; and LC n=4). One-way ANOVA used to compare KI and HT to WT samples, with p-values <
;
0.05 as significant.

Results:
The KI mice did not live past ~20 days old with massive hypertrophy, dilated atrium, myofibrillar disarray and fibrosis. Full-length mutant protein was expressed and incorporated into the sarcomere. Survival and morphology in the HT was similar to WT. Post-natal day 10 KI mice demonstrated severely enlarged atria and ventricles, interstitial fibrosis, a trend towards increased Ca
2+
sensitivity (pCA
50
KI 5.8 vs HT 5.65 vs LC 5.67 mM; p > 0.05), a trend towards increased cross-bridge cycling kinetics (k
tr
KI 24.00
+
2.42 vs HT 24.33
+
1.08 vs LC 21.25
+
0.87; p > 0.05) and increased levels of β-myosin heavy chain expression compared to both LC and HT mice.

Conclusions:
In our mouse HCM model, homozygous expression of the W792R-cMyBP-C mutation recapitulates severe human HCM and provides mechanistic insights into the pathology of this mutation. The trend towards accelerated crossbridge kinetics suggest that the W792R mutation disrupts the inhibitory effects of cMyBP-C on myosin-actin binding implicating the potential application of current myosin ATPase inhibitors in the treatment of patients carrying this mutation. Ongoing work will expand sample sizes to evaluate significance of findings.
Abstract 17025: Investigating Retinal Neurovascular Interactions via Multi-View Light-Sheet Microscopy
Authors: Zhu Enbo , Cho Jae Min , Zhang Yaran , Wang Jing , Lin Meng-chin , Aguirre Gamboa Brian , Chu Alison , Hsiai Tzung K
Published: December 2023

Introduction:
Vascular retinopathy is a leading cause of preventable blindness in diabetes and retinopathy of prematurity. While most studies focus on individual neural or vascular structures, there remains a knowledge gap in understanding the retinal neurovascular interactions after injury and during repair (Fig. 1A). We seek to demonstrate 3-D neurovascular interactions with a multi-view light-sheet imaging system.

Methods and Results:
Intact 3-D retinas from 2-month-old mice were fixed and permeabilized followed by the optical clearance (CytoVista). Retinal vessels were stained with biotinylated isolectin B4 for microvasculature and Alexa Fluor 488-conjugated streptavidin (Fig. 1B-C) for labeling, while bipolar cells were stained with anti-PKCα (rabbit host) for neurons and Alexa Fluor Plus 555-conjugated goat anti-rabbit IgG for labeling. Refractive index matching was performed to 1.53. Multi-view light-sheet imaging was performed at 5 different angles followed by 3-D registration and reconstruction. The point spread function (PSF) demonstrates a spatial resolution of less than 5 μm (Fig. 1B, inlet). This enabled 3-D co-registration of the vasculature (Fig. 1D, in green) in relation to the bipolar cells (Fig. 1D, in red) for visualization.

Conclusion:
We revealed the 3-D neuro-microvascular network providing both deep tissue penetration and high spatial resolution for investigating hyperoxia and diabetes-associated vascular retinopathy.
Abstract 17030: Phenome-Wide Mapping of Genetic Effects Distinguishes Etiological Modules Underlying the Phenotypic Spectrum of Heart Failure
Authors: Henry Albert , Lumbers Tom ,   HERMES Consortium
Published: December 2023

Introduction:
The heart failure (HF) syndrome has been associated with multiple risk factors of which causal effects on conventional HF subtypes remain unclear. Leveraging insights from human genetics, we characterized the associations of genetic loci associated with susceptibility to HF across a wide range of risk factors and diseases to identify causal risk factors and etiological modules underlying HF subtypes.

Methods:
Through a genome-wide association meta-analysis in 1.9 million individuals, we identified 66 independent genetic susceptibility loci across HF subtypes. We evaluated the pleiotropic effects of these loci across 294 disease phenotypes in 400,000 UK Biobank participants. Using graph modeling, we constructed a pleiotropy network of HF loci and identified distinct etiological clusters based on the network topology. Finally, we performed cross-trait genetic colocalization, genetic correlation, and Mendelian randomization analyses to investigate the causal effects of 24 HF-related phenotypes across HF subtypes.

Results:
We identified 207 associations between 49 genetic susceptibility loci of HF and 79 disease phenotypes. Network analysis revealed 18 distinct etiological clusters underlying these associations (Figure A), including clusters of interlinked ischemic phenotypes, cardiac arrhythmia / cardiomyopathies, hypertension, and diabetes / obesity. Through colocalization analysis, we found 105 causal genetic variants that are shared between HF and at least one other trait at 42 loci. We observed differential patterns of genetic correlation and causal associations, for instance, type 2 diabetes were genetically correlated to all HF subtypes but not causally associated with any (Figure B).

Conclusions:
Genetic analysis identifies distinct etiological modules and causal risk factors underlying different forms of HF, providing insights that may inform approaches to treatment and prevention.
Abstract 17037: Validation of Deep Learning System for Comprehensive 12-Lead ECG Interpretation
Authors: Herman Robert , Demolder Anthony , Vavrik Boris , Martonak Michal , Boza Vladimir , Fabbricatore Davide , Perl Leor , Bartunek Jozef , Hatala Robert
Published: December 2023

Introduction:
The electrocardiogram (ECG) is a widely available diagnostic tool for evaluating cardiac patients. Although automated ECG interpretation has made significant progress, it has yet to match the accuracy demonstrated by physicians.

Hypothesis:
In this study, we hypothesized that an artificial intelligence based ECG system can achieve comparable performance to physicians in accurately identifying 20 essential ECG patterns.

Methods:
An AI-powered system comprising six deep neural networks (DNNs) was trained to identify 20 diagnostic patterns from 12-lead ECGs categorized into six groups: rhythm, infarction, conduction abnormalities, ectopy, chamber enlargement, and axis. An independent test set with the consensus of two expert cardiologists was used as a reference standard. We compared the system's performance to that of three General Practitioners (GPs) and six individual cardiologists, using F1 scores as the evaluation metric.

Results:
The AI system was trained on 932,711 standard 12-lead ECGs from 173,949 patients. The independent test set comprised 11,932 annotated ECG labels. Figure 1 shows the respective F1 scores of the DNNs, average GP and average cardiologist as follows: Rhythm: 0.957 vs. 0.771 vs. 0.905; Infarction: 0.925 vs. 0.780 vs. 0.852; Conduction abnormalities: 0.893 vs. 0.714 vs. 0.851; Ectopy: 0.966 vs. 0.896 vs. 0.951; Chamber enlargement: 0.972 vs. 0.562 vs. 0.773; Axis: 0.897 vs. 0.601 vs. 0.685. The AI system's diagnostic performance exceeded that of GPs and was on par with cardiologists for all individual diagnostic patterns.

Conclusions:
The AI-powered ECG system is able to accurately identify electrocardiographic abnormalities from the 12-lead ECG, highlighting its potential as a clinical tool for healthcare professionals.
Abstract 17046: Accuracy of Apple Watch for Detection of Atrial Fibrillation: A Systematic Review and Meta-Analysis
Authors: Yasmin Farah , Moeed Abdul , Adil Mariam , Rahman Saad Ur , Wilson F. Perry
Published: December 2023

Background:
Apple Watch (AW) for the detection of silent atrial fibrillation (AF) has shown encouraging results due to its photoplethysmogram (PPG) sensors. However, clinical accuracy studies show varying results. To the best of our knowledge, this is the first meta-analysis conducted to ascertain the pooled sensitivity, and specificity in AF detection using the AW.

Methods:
PubMed, Google Scholar, and Scopus were queried till May 2023 for studies examining the accuracy of AW in AF detection. The outcomes of interest were the sensitivity and specificity of AW for the detection of AF. Sensitivities and specificities were calculated using true positives, true negatives, false positives, and false negatives wherever applicable. A random-effects meta-analysis was conducted using the generic inverse variance method to pool sensitivities and specificities. Further, sensitivity analysis was performed excluding studies using KardiaBand.

Results:
A total of 12 studies with a patient population of 421,156 were included with a mean age of 63 years. 6/12 studies used AW series 4 or higher while 3/12 studies evaluated the use of KardiaBand on top of the AW. AF was detected in 3,184 patients from a total of 420,312 patients. Following pooled analysis, an overall point estimate of sensitivity was observed to be [0.87 (0.76, 0.98); Figure 1A]. Ten studies evaluated specificity, with the pooled estimate being [0.91 (0.87, 0.95); Figure 1B]. After excluding studies using KardiaBand, the sensitivity was reported as 0.84 [0.68, 1.00] and specificity was observed to be 0.94 [0.91, 0.98].

Conclusion:
AW proved to be effective in detecting AF in our analysis owing to high overall sensitivity and specificity with and without the addition of KardiaBand. However, cardiologists should still exercise caution before undertaking action based on the electrocardiographic diagnosis generated by this wrist-worn monitor.
Abstract 17064: Reversible Myocardial Depression and Dilatation in COVID-19 Shock Patients
Authors: Fata Matthew J , Hollenberg Steven M , Klinkhammer Brent , Glotzer Taya , Jamal Sameer , Landers David , Rockett George , Tancredi Jana , Turi Zoltan , Parrillo Joseph E
Published: December 2023

Introduction:
A characteristic pattern of bacterial and fungal septic shock is decreased left ventricular ejection fraction (LVEF) and modest dilatation of the left ventricle. In survivors, the myocardial depression and dilatation are reversible within several days. Using echocardiography, we have previously reported a cohort of COVID-19 shock patients with reduced LVEF. We now report serial studies of COVID-19 shock patients.
Hypothesis:
Myocardial dysfunction and dilatation associated with COVID-19 are reversible.

Methods:
In COVID-19 patients with shock requiring vasopressors who underwent echocardiography, left ventricular ejection fraction (LVEF) by Simpson’s rule and stroke volume by doppler were analyzed. Based on the LVEF and CI, patients were categorized into groups with low or normal values using EF 45% and CI 2.2 liters/minute/meter as the respective thresholds. A subset of 18 patients underwent serial echocardiography which were performed at a median of 13(9,39) days after the initial. The LVEF and LV volumes recorded during initial and follow-up echo were analyzed retrospectively using paired t-testing.

Results:
Comparing initial with follow-up values, the mean LVEF was 34.7(2.0) vs 43.8(3.47), p=0.01, indexed stroke volume 29.6(1.9) ml vs 31.7(2.3) ml, p=0.52, LV end-diastolic volume 182(14.1) ml vs 152.1(12.9) ml, p=0.03 and LV end-systolic volume 120.2(13.1) ml vs 90.1(12.1) ml, p=0.03 respectively (see Figure).

Conclusions:
Serial echocardiographic studies of COVID-19 shock patients with reduced LVEF and ventricular dilatation demonstrate reversibility of myocardial depression and dilation with no change in stroke volume, a finding strikingly similar to that seen in bacterial and fungal induced septic shock. Thus, COVID-19 (viral) induced septic shock may have a similar pathogenetic mechanism of myocardial dysfunction to that seen with bacterial or fungal sepsis.
Abstract 17073: Evaluation of Impact of Septal Reduction Therapy on Deep Learning-Based Electrocardiographic Markers Hypertrophic Cardiomyopathy
Authors: Dhingra Lovedeep S , Aminorroaya Arya , Khunte Akshay , Sangha Veer , Oikonomou Evangelos K , Sen Sounok , Krumholz Harlan M , Kramer Christopher M , Desai Milind Y , Khera Rohan
Published: December 2023

Background:
Deep learning-based models could identify hypertrophic cardiomyopathy (HCM) signatures on ECG, with emerging evidence of being able to track disease modification with mavacamten. To explore the mechanism of HCM detection on ECG, we developed an AI-ECG model for echocardiographically confirmed HCM and evaluated HCM detection after septal reduction therapy (SRT, alcohol septal ablation [ASA] or ventricular myectomy [VM]).

Methods:
The AI-ECG model for HCM detection was developed in a cohort of 25,652 ECGs (1:10, age-sex matched HCM to control) obtained within 30 days of a transthoracic echocardiogram (TTE) at Yale (2015-21). We defined HCM by end-diastolic interventricular septal wall thickness > 15 mm with moderate to severe diastolic dysfunction on TTE. The model was developed using a convolutional neural network and transfer learning. HCM phenotype was defined by high predicted probabilities for HCM and was assessed on ECGs spanning SRT.

Results:
Our AI-ECG model for HCM had an AUROC of 0.93 (0.88-0.97), sensitivity of 0.90, and specificity of 0.89 in the held-out test set. The mean HCM probability among HCM patients vs control was 0.51±0.33 vs 0.07±0.20 (P<.001). The mechanism of detection was evaluated in 1400 ECGs from 78 patients (mean age 66 y; 47% women) spanning SRT (20 ASA, 58 VM). In this group, the mean HCM probability for all ECGs performed before & after SRT was 0.49±0.34 & 0.72±0.30, respectively. The mean HCM probability in the closest ECGs per patient before SRT (median 35 days before SRT) was 0.53±0.35, and in farthest ECGs after SRT (median 536 days) was 0.70±0.32 (P diff = 0.002).

Conclusion:
We developed and validated an AI-ECG model that detects HCM from 12-lead ECG. The model does not merely detect thickened septum, and the continued identification of HCM signature after SRT suggests HCM prediction based on disordered myocardial kinetics. This supports the role of AI-ECG in both detection and monitoring of phenotypic effects of therapies in HCM.
Abstract 17079: Relationship Between Neighborhood Level Deprivation and Cardiovascular Health Status Among 122,177 Adolescents, Analysis of PEDSnet Data
Authors: Baker-Smith Carissa M , Zhang Zugui , Eckrich Daniel , Prospero Carol , Zadokar Varsha , Falkner Bonita E , Akins Robert E
Published: December 2023

Introduction:
Preservation of cardiovascular health (CVH) across the lifespan is essential to reducing cardiovascular disease burden. Greater knowledge of the relationship between neighborhood level deprivation and CVH in youth is needed.

Hypothesis:
We hypothesized that worse socio/environmental deprivation is associated with poor/intermediate CVH status in adolescents.

Methods:
Data from 2009-2019 were extracted from PEDSnet (a PCORI-funded network of pediatric health data). We modeled the relationship between CVH and neighborhood deprivation. National Area Deprivation Index values (ADI; scaled 1-100) were coded into PEDSnet and divided into tertiles (ADI<25=best, 25-52,
>
52=worst) for analysis. CVH status was scored from a subset of available AHA Life’s Essential 8 (LE8) scores including blood pressure, blood glucose, blood cholesterol, body mass index, smoking/tobacco exposure, and sleep. Overall CVH scores were derived as the average of the sum of the individual scores. Univariate and multivariate analyses were performed. SAS 9.4 was used (
p<0.05)
.

Results:
Data from 122,177 youth, 13-17 years old were analyzed. 51% were female, 24% lived in neighborhoods with ADI <25; 35% lived in neighborhoods with ADI
>
52. 58% were non-Hispanic white and 22% non-Hispanic Black. According to a multivariate logistic model, ADI
>
52 was associated with a 48% greater odds of poor/intermediate CVH status compared to ADI <25 (Figure). Female sex, ethnic-race categories of Non-Hispanic White and Other, as well private or other forms of non-public insurance coverage were associated with a lower odds of intermediate/poor CVH (Table). Interaction terms for age, ADI, race and ethnicity were not significant.

Conclusions:
Higher neighborhood deprivation is associated with poor/intermediate CVH status. We recommend greater attention to preserving CVH status within high deprivation communities to preserve and promote CVH status across the lifespan.
Abstract 17084: Impact of Hereditary Gene Mutations on Outcomes in an Ethnically Diverse Patient Cohort With Nonischemic Dilated Cardiomyopathy
Authors: Kelso Cody , Prabhakar Apurv , Ding Jeffrey , Nair Pooja , Kumar Anjali , White Rachel , Bui Quan M , Adler Eric , Hong Kimberly N
Published: December 2023

Introduction:
Nonischemic cardiomyopathy (NICM) is a leading cause of heart failure (HF). Heritable gene mutations are found in a subset of these cases and help to identify at risk individuals. The purpose of this study is to characterize the impact of genotype on clinical outcomes.

Methods:
Data from a single center registry of patients who underwent cardiomyopathy and arrhythmias gene panel testing between 2018 and 2022 was used. Patients with an LVEF < 50% without a history of hypertrophic, infiltrative or ischemic cardiomyopathy were included. Genotyping, demographics, and clinical data including HF and major ventricular arrhythmia (MVA) outcomes were collected. Patients were stratified by genotype ((+): Pathogenic/Likely Pathogenic; (-): VUS/Likely Benign/Benign/no variant). Genotype (+) patients were also grouped by functional gene class. Chi Square and Wilcoxon testing were used for between group comparisons. Kaplan Meier with log-rank testing was used for time to event analyses.

Results:
This study included 350 patients with a median age of 54 years (IQR: 42-65 years) at last follow up. Table 1 shows demographics and outcomes. Genotype (+) patients had more HF and MVA events. There was a trend towards genotype predicting HF and MVA at all ages, with curves separating after age 26 (p = 0.0475) Figure 1. Genotype (+) LMNA patients had HF and MVA events at earlier ages compared to Genotype (-) (n=6, 85.7 %, p = 0.005).

Conclusion:
NICM patients with a hereditary gene identified have worse outcomes than those without, suggesting an opportunity to improve risk stratification and guide patient management decisions with genetic testing.
Abstract 17088: Pharmacological SERCA Activation Shifts Cardiac Fuel Preference Without Impairing Function in Obese Mice
Authors: Banerjee Deveena R , Rahim Mohsin , Hasenour Clinton M , Bednarski Tomasz K , Young Jamey D
Published: December 2023

Introduction:
Prior studies suggest that restoring Ca
2+
homeostasis by activating SERCA improves liver health and metabolism in a mouse model of metabolic syndrome. We were interested to know if these benefits extended to the heart. Here, we test the impact of pharmacological SERCA activation by CDN1163 on heart metabolism. We modeled data from
in vivo
13
C tracer experiments to determine cardiac metabolic fluxes in obese mice at the end of an 8-week CDN1163 treatment period. Flux measurements were combined with echocardiography data to assess the effects of SERCA activation on heart function and metabolism.

Methods:
All mice in the study were hyperphagic

Mc4r
-/-

mice. We studied three groups of

Mc4r
-/-

mice at 16 weeks of age (n≥6 per group): mice fed a chow diet (Chow) or those switched to a western diet at 8 weeks of age (WD) ± CDN1163 (3 injections per week). Stable and radio-labeled isotopes were infused and blood was sampled from unrestrained, conscious mice through jugular vein and carotid artery catheters, respectively. Fluxes were estimated by fitting a mathematical model of liver and cardiac metabolism to
13
C enrichment measurements of plasma and tissue metabolites taken at the end of the infusion. A separate cohort of mice was used for echocardiography and gene expression analysis.

Results:
We found that WD increased absolute cardiac glycolytic, anaplerotic, and citric acid cycle (CAC) fluxes (~2-fold; p<0.05). In contrast, CDN1163 treatment decreased these fluxes compared to both Chow and WD (~2-3-fold; p<0.05). Additionally, the pyruvate partitioning between pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) favored PDH with WD feeding (~2-fold), concurring with increased glycolysis. However, in WD+CDN1163 mice, pyruvate partitioning was restored to the Chow phenotype, favoring PC (p<0.05 WD vs. WD+CDN11163), suggesting decreased reliance on glucose for the generation of acetyl CoA for the CAC. These metabolic shifts occurred without changes in cardiac function or compensatory structural remodeling of the left ventricle.

Conclusions:
CDN1163 treatment changes metabolic fluxes in the hearts of obese mice. These metabolic changes do not impact heart function.
Abstract 17096: Immune Modulation to Treat Ischemic Heart Failure
Authors: Grijalva Adrian , Benson Daniel R , Fink Jordan , Zhang Xiaohong , Coletta Dawn , Langlais Paul , Pandey Amitabh C , Mangiola Massimo , Koevary Jen , Lancaster Jordan , Goldman Steven
Published: December 2023

Introduction:
Clinical use of induced pluripotent derived cardiomyocytes (iPSC-CMs) has been slow because their mechanism is not well defined. Our lab developed a cardiac patch composed of iPSC-CMs and human neonatal dermal fibroblast (NDF) seeded on a bioresorbable matrix. Implantation on the epicardium of the infarcted heart in immune competent animal models of ischemic CHF (mice, rats, swine) repaired the damaged heart, improved cardiac function/structure with increased viable myocardium, increased myocardial blood flow, improved left ventricular (LV) contractility, and reversal of maladaptive LV remodeling. Preliminary analysis indicates that the patch created a novel host derived immune response not observed in untreated animals.

Hypothesis:
The iPSC-CMs and NDFs coordinate an immunomodulatory response that results in reduction of inflammatory cytokine producing M1 macrophages with concomitant polarization to the M2 state.

Methods:
Spatial transcriptomics and histological analysis was utilized for investigation of patch driven immunomodulatory responses in WT BL6 mice. All animals underwent two procedures; 1) Infarct via left coronary ligation 2) Left lateral sternotomy with patch placement (N=5) (no patch for controls, N=3) 3 weeks post MI. Patch secretions underwent quantitative mass spectroscopy to identify drivers of immunomodulation.

Results:
Histology demonstrated reduction of left chamber dimension and presence of viable cardiomyocytes in the LV wall. IF demonstrated a novel immune response in the treated group absent in the controls. This response is isolated to the epicardial infarct-patch interface. Cellular deconvolution of the infarct region revealed macrophages and dendritic cells compose this response. Macrophage phenotype was assessed via expression of classical M1(CD68, NOS2, AXL) as well as M2 markers (RETNLA, MRC1, ADGRE1) which were found to be significantly elevated in treated groups. Proteomic analysis of the patch secretome indicates the patch has a role in coordinating this response by upregulation of Il-4/Il-13 signaling and wound healing that stimulates enrichment of pathways associated with reorganization of the ECM.
Abstract 17097: Carotid Artery Atherosclerosis and Mid-Life Cognitive Function: Evidence From Bogalusa Heart Study
Authors: JIN XUANYI , Naqvi Tasneem Z , Guo Yajun , Kang Soo , Alonso Camilo , Mills Katherine T , He Jiang , Urbina Elaine M , Chen Jing , Bazzano Lydia A
Published: December 2023

Background:
Little is known about the relationship between carotid plaque formation and cognitive function in a middle-aged population.

Hypothesis:
We hypothesize that there will be an association between carotid atherosclerotic burden and cognitive function in middle-aged adults.
Aim:
The purpose of the present study is to examine the relationship between carotid artery (CA) plaque and cognitive function in middle-aged white and black men and women from the Bogalusa Heart Study (BHS) cohort.

Methods:
We included a total of 1,107 BHS participants with echocardiography and carotid ultrasound performed between 2013 and 2016. Cognitive function was quantified in a global cognitive score (GCS) comprised of the z standardized sum of 7 neuropsychiatric tests. CA plaque was defined by carotid intima media thickness ≥1.5mm in any segment of the CA including right and left common artery (RCC/LCC), bulbs (RCB/LCB) as well as right and left internal carotid artery (RIC/LIC). We compared demographic, clinical, and echocardiographic characteristics in participants with or without CA plaque and used linear regression analysis for the association between CA and GCS adjusted for age, sex, race and education.

Results:
Among all, 373 (33.7%) of participants had one or more CA plaque. The most common locations of CA plaque formation differed according to laterality, with 230 (61.7%), 189 (50.7%), 108 (29.0%), 92 (24.7%), 83 (22.3%), 10 (2.7%) participants having plaque in the RCB, LCB, LCA, RIC, LIC, and RCA, respectively. Participants with CA plaque were likely to be older (49.9 vs. 47.2 years), male (52 vs.38.9%), white (70.2 vs.63.4%,), have larger left ventricular (LV) end-diastolic volume (97.4 vs.94 ml) and LV mass index (83.4 vs.76.3 g/m
2
, all
p
-value<0.01), but similar LV ejection fraction (60.1 vs.60.0%) as compared to those without CA plaque. Moreover, CA is associated with poorer cognitive function (GCS, standardized β coefficient=-0.07;
p
=0.02) adjusted for age, sex, and race. However, the association was attenuated after adjusting for education.

Conclusion:
CA plaque was highly prevalent and inversely associated with cognitive function. The association was attenuated by education emphasizing the importance of social determinants in cognitive health.
Abstract 17103: The Proteomic Fingerprint in Patients With Single Ventricle Disease in the Interstage Period: Evidence of Chronic Inflammation and Widespread Activation of Biological Networks
Authors: Thomson Lindsay M , Mancuso Christopher A , Wolfe Kelly R , Khailova Ludmila , Ali Eiman , DiMaria Michael , Mitchell Max B , Twite Mark , Morgan Gareth J , Frank Benjamin , Davidson Jesse
Published: December 2023

Introduction:
Children with single ventricle heart disease (SVHD) experience significant morbidity across systems and time: (AKI 70%, neurodevelopmental impairment 33%, growth failure 14%, NEC 5.5%). Proteomics is a novel method to identify new biomarkers and mechanisms of injury in complex physiologic states.

Hypothesis:
Does the proteome of patients with SVHD differ from healthy children, and which biological systems are activated or repressed?

Methods:
Infants with SVHD in the interstage period were compared to similar-age healthy controls. Serum samples were collected, stored at -80C, and run on a panel of 1500 proteins in single batch analysis (Somalogic Inc., CO). Partial Least Squares-Discriminant Analysis (PLS-DA) was used to compare the proteomic profile of cases and controls and t-tests to detect differences in individual proteins (FDR < 0.05). Protein network analysis with functional enrichment was performed in STRING and Cytoscape.

Results:
PLS-DA readily discriminated between cases (n=33) and controls (n=24) based on their proteomic pattern alone (Accuracy=0.96, R2=0.97, Q2=0.80) (Fig 1a). 568 proteins differed between groups (FDR < 0.05). The 15 proteins with the greatest effect on the proteomic phenotype between the groups are shown (Fig 1b). We identified 25 up-regulated functional clusters and 13 down-regulated (5 clusters highlighted in Fig 1c). Active biological systems fell into six key groups: angiogenesis and cell proliferation/turnover, immune system activation and inflammation, altered metabolism, neuronal development, gastrointestinal system, and cardiac development.

Conclusions:
We report a clear differentiation in the circulating proteome of patients with SVHD and healthy controls with >500 circulating proteins distinguishing the groups. This proteomic data identifies various dysregulated protein networks across multiple organ systems with promising biological plausibility as drivers of SVHD morbidity.