bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15231: Relationship Between Severe Aortic Stenosis, Chronic Kidney Disease, and Clinical Outcomes in Patients With Aortic Stenosis
Authors: Uqaily Muhammad R , Sulaiman Samian , Sankaramangalam Kesavan , Ludhwani Dipesh , Zeb Irfan
Published: June 2023

Introduction:
Patients with chronic kidney disease (CKD) often have cardiovascular calcification with a higher prevalence of AV disease. Aortic valve calcium (AVC) scores are often used to assess the severity of aortic stenosis (AS).

Methods:
We retrospectively studied 361 patients with AS who underwent a CTA at our institute from Nov 2018 to Mar 2022. GFR values closest to the CTA, but at most three months prior, along with the occurrence of the following outcomes: TAVR, SAVR, and all-cause mortality were recorded. An AVC score > 2000 for men and 1200 for women was defined as severe AS. Also, GFR values were split into 3 groups: >=60 (Group 1), 30-59 (Group 2), and <30 (Group 3). An interaction term (CKD x AS) was also used to evaluate the differential impact of severe AS on outcomes within the CKD groups.

Results:
There was no significant difference in AVC scores among the CKD groups (p = 0.21) using a Kruskal-Wallis test. However, severe AS was associated with a higher occurrence of outcomes (OR = 6.84 [1.67 - 27.96], p = 0.008*), along with a non-significant interaction term (OR = 0.63 [0.26 - 1.52], p = 0.3) using a logistic regression with severe AS, CKD groups, and the interaction term as independent variables. Moreover, using a cox proportional-hazards model with the same variables, severe AS had a significant association with the outcomes (HR = 2.51, p = 0.009*), with a non-significant interaction term (HR = 0.85, p = 0.43).

Conclusions:
There was no significant difference in AVC scores among the CKD groups. But irrespective of kidney function, severe AS was associated with worse outcomes. Therefore, similar thresholds of AVC scores can be used to define severe AS in patients with and without CKD.
Abstract 15237: Alterations in the Human Mitral Valve in-vivo Functional State in Mitraclip Repair
Authors: Simonian Natalie T , Liu Hao , Vakamudi Sneha , Pirwitz Mark J , Gorman Joseph H , Gorman Robert C , Sacks Michael S
Published: June 2023

Introduction:
The MitraClip for treatment of mitral regurgitation (MR) is a generally safe and effective procedure. However, recent clinical trials have reported contradictory outcomes, and long-term efficacy remains almost completely unknown. Therefore, there is an urgent need for quantitative, patient-specific treatment optimization grounded on a robust understanding of the functional consequences of the MitraClip repair procedure on each patient-specific mitral valve (MV).

Methods:
Real-time 3D echocardiography images of ten MR patients’ MVs were acquired during the MitraClip procedure. These images were analyzed using our validated noninvasive strain estimation method to compute the pre-operative leaflet strain fields in the circumferential and radial directions. For the post-operative analysis, 3D MitraClip models were implemented in the corresponding size and number in the simulation to directly grasp the MV leaflets at echo-dictated positions.

Results:
The MV pre-surgical states were highly variable in both geometry and deformation, underscoring the heterogeneity of the MR in the patient population. There were also no consistent post-surgical global or local strain patterns between MVs. However, the pre- and post-surgical strain fields in the same MV were significantly better correlated than random pre- and post-surgical pairs (p < 0.005). This quantitative result implies that the post-surgical state for each patient can be
predicted
from available pre-surgical data-derived modelling.

Conclusions:
Due to the highly variable pre-surgical state of regurgitant MVs, a patient-specific approach to MitraClip repair is crucial to improving long-term patient outcomes. Moreover, these findings suggest that the post-surgical state can be correlated to, and therefore predicted from, the pre-surgical state, which would lay the foundation for quantitative surgical planning, tailored patient selection, and ultimately, a more durable repair.
Abstract 15249: Evidence for Clonal Proliferation of Smooth Muscle Cells in Unstable Human Atherosclerotic Lesions
Authors: Kawai Kenji , Sakamoto Atsushi , Mokry Michal , Ghosh Saikat , Xu Weili , Kawakami Rika , SATO YU , Mori Masayuki , Konishi Takao , Vozenilek Aimee , Virmani Renu , Pasterkamp Gerard , Finn Aloke
Published: June 2023

Background:
Studies using techniques that relied on expression of an X-linked gene suggested predominant clones of smooth muscle cells (SMC) may exist in human atherosclerosis. These studies were limited by spatial resolution and nature of plaque types studied. We investigated whether clones of SMCs exist in unstable human atheroma.

Methods and Results:
We used a 25 nucleotide deletion in the 3’ UTR of the BGN gene, highly expressed by SMC and prevalent in 30% of females, to study clonal proliferation. Three different types of plaques (erosion, rupture, and adaptive intimal thickening) were selected from females heterozygous for the deletion mutant. Hybridization of target RNA-specific BaseScope probes was conducted to visualize the distribution of mutants and images displayed as a bubble plots. Clonality index was calculated as the percentage of each probe in each ROI. A clonality index equal to or exceeding the three times the standard deviation above the mean of the clonality index of the media in all plaques was considered clonal. In comparing clonality between media and intima, the mean percent ROI with clonality was significantly higher in the intima than in the media (42.3±18.2 vs 18.3±9.6%, P=0.003) and this was consistent for both eroded (27.0±9.8 vs 9.0±3.8%, P=0.04) and ruptured plaques (41.3±10.7 vs 20.0±3.5%, P=0.03). The relationship of dominant clone in the intima and media shows significant concordance in the majority of plaques studied (R=0.72, P<0.0001).

Conclusions and Relevance:
This novel approach suggests dominant clones exists within atherosclerotic lesions and may originate from the media.
Abstract 15255: Clinical Risk Factors for Infective Endocarditis in Patients With Staphylococcus Aureus Bacteremia and the Diagnostic Utility of Transesophageal Echocardiogram
Authors: Zaidi Syeda , Khan Umair , Majeed Harris , Lopez Erick , Gangwani Manesh Kumar , Tofighi Davood , Sheikh Abu Baker , Raizada Veena , ANDRE PAUL , Shekhar Rahul , Sagheer Shazib
Published: June 2023

Background:
Approximately 25% of patients with staphylococcus aureus bacteremia (SAB) develop infective endocarditis (IE), which has a consequent mortality of 46%. Current guidelines recommend routine transthoracic echocardiography (TTE) for patients with SAB; transesophageal echocardiogram (TEE) is reserved for those patients in whom initial TTE is negative and clinical suspicion for IE remains high. We sought to elucidate high risk features of SAB associated with the development of IE that warrant a TEE after a negative TTE.

Methods:
This retrospective study included 213 patients who were diagnosed with SAB at the University of New Mexico Hospital between 2010-2020. A pre-determined list of clinical risk factors along with TTE and TEE status was extracted from the electronic medical record (Table 1). Our primary outcome was the development of IE in patients with SAB. Multivariate logistic regression analysis was used to identify clinical risk factors for IE. Sensitivity and specificity of TTE and TEE was also calculated (Table 1).

Results:
Out of 213 patients with SAB, 68 patients met diagnostic criteria for infectious endocarditis. Most patients (n=209) underwent TTE and 117 patients underwent subsequent TEE. Initial TTE was diagnostic in 42 patients with a sensitivity of 63% and specificity of 94%; 45 patients had a diagnostic TEE with a sensitivity of 83% and specificity of 98%. Multivariate analysis showed significantly increased risk of IE in patients who had a permanent pacemaker (aOR 32.3, CI 5.23 - 281, p<0.001) or a persistent fever (aOR 6.97, CI 2.42 - 21.0, P<0.001).

Conclusions:
The routine use of TEE in patients with SAB for the diagnosis of IE may not be necessary and introduces unnecessary procedural risk. Based on our analysis, we recommend that SAB patients with a permanent pacemaker (or other intracardiac prosthetic) or a persistent fever despite appropriate antibiotic therapy be screened with TEE when initial TTE is negative.
Abstract 15277: High-Throughput Optical Oxygen Measurements for Human IPSC-Cardiomyocytes and Ventricular Fibroblasts in 96-Well Plates
Authors: Li Weizhen , McLeod David , Ketzenberger John , Kay Matthew W , Li Zhenyu , Entcheva Emilia
Published: June 2023

For metabolically active cells like ﻿cardiomyocytes, a balanced state of oxygen supply and demand is crucial for basic cell function. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a valuable experimental model due of their scalability and relevance to human physiology. Oxygen consumption and availability have not been characterized in high-throughput format (HT), used in pre-clinical studies. Here, we quantified pericellular oxygen in syncytia of hiPSC-CM and human cardiac fibroblasts, grown in glass-bottom 96-well plates (
Fig 1A-C
). We deployed Ruthenium-based oxygen sensors and a ratiometric optical oxygen measurement system (
Fig 1B
) to track pericellular oxygen over time across all wells. Measured ratios were calibrated to % oxygen using two-point calibration with 5% Na
2
SO
3
and upon saturation with ambient air. Solution height and cell density were varied (4 solution heights, 3 cell densities) to understand their role in oxygen diffusion and oxygen consumption rate (OCR) by the cells. ﻿Michaelis-Menten kinetics and the Thiele modulus were used to computationally simulate oxygen availability in matching conditions. Without active perfusion or mass transport, for all tested conditions in the hiPSC-CMs, oxygen was depleted to <5% within approximately an hour. The drop of oxygen occurred in two phases - a zero-order decrease phase, followed by ﻿Michaelis-Menten kinetic phase (
Fig 1D
). Increase in culture medium volume/ height was found to be a powerful determinate of oxygen availability in simulations and in experiments (
Fig 1E
n = 5 per group). Higher cell density correlated with steeper slope in the first phase of decline in oxygen availability, n = 4 per group. Cardiac fibroblasts followed a similar pattern (n = 4 per group) with noticeably slower OCR. Overall, our results indicate that pericellular oxygen in HT glass-bottom plates may reach hypoxic levels quickly; solutions for active mass transport need to be considered.
Abstract 15285: Exercise Adherence Among Older Persons With Hiv: Characteristics and Performance
Authors: Irwin Crista , Gary Rebecca , Murden Raphiel , Higgins Melinda
Published: June 2023

Introduction:
Despite optimal treatment adherence, the inflammatory response associated with HIV remains, which leads to premature vascular aging and a heightened risk for cardiovascular disease (CVD). Persons with HIV (PWH) are twice as likely to develop CVD at an average of 8 years earlier than non-HIV infected persons. Routine aerobic exercise as recommended by the AHA guidelines has been shown to lower inflammation, reduce cardiovascular risk factors and to benefit overall health. AHA guidelines recommend moderate to vigorous physical activity (MVPA) of at least 150 minutes per week, but less than 50% of the general population meets this standard and little is known about these parameters in older PWH (OPWH).

Hypothesis:
The purpose of this study was to examine adherence to a moderate intensity exercise regimen among OPWH (n=76).

Methods:
All participants (mean age 55 +/- 5.2, 65% male, 82% Black) were evaluated at baseline (BL) for cardiorespiratory fitness and target HR using the modified Balke VO2 test. Participants were provided an exercise prescription based on their individual target HR at 60 - 70 % max for at least 240 minutes per week and provided with activity trackers to monitor exercise adherence. Each participant was remotely monitored at regular intervals using MI techniques to determine exercise intensity and adherence to exercise prescription.

Results:
Mean exercise adherence at 3-, 6-, and 12-months was 63%, 60% and 61% respectively. Higher adherence was associated with higher baseline VO
2
max
and reported lower sleep disturbance, perceived stress, fatigue, and pain as well as greater emotional support throughout the study. Persons with higher adherence to exercise were also associated with greater improvement in vascular function measured by flow-mediated dilation at 6-months.

Conclusions:
OPLWH participating in an aerobic exercise program for 1 year consistently exceeded the recommended 150 minutes/week of moderate intensity exercise by 10+% more than the general population. Exercise adherent participants achieved a high degree of cardiovascular activity and a reduction in physical/emotional deterrents to exercise which may lead to reduced CVD risk.
Abstract 15286: Prolonged Exposure to Pesticides and the Risk of Atrial Fibrillation: The Particular Case of Chlordecone
Authors: Xiong Feng , Naud Patrice , Roy Colombe , shi yanfen , Tardif Jean-Claude , Tanguay Jean-Francois , Sirois Martin G , Hiram Roddy , FUNDERE Alexia
Published: June 2023

Introduction:
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Chlordecone (CLD) is a pesticide known for its carcinogenic effects. Data suggest that CLD may disrupt the activity of myocardial Na
+
/K
+
-ATPase, deregulate mitochondrial Mg2+/ATPase in cardiomyocytes (CM), and inhibit CM Ca
2+
/ATPase. Little is known about the link between CLD and AF.

Hypothesises:
1. Prolonged exposure to CLD induces arrhythmogenic cardiac remodeling in rats. 2.Cycle of CLD-withdrawal is accompanied by reduction of CLD-induced AF vulnerability.

Methods:
Male Wistar rats (250g) were exposed to CLD (0.1 μg/L or 1 μg/L) diluted in their daily water for 28 days. Control rats (CTRL) received water without CLD. Starting on day 29, all animals were exposed to CLD-free water. Electrophysiological study (EPS), echocardiography, and cardiac optical mapping (OM) were performed at days 28 and 56 to study cardiac function and atrial conduction. Expression levels of genes and proteins involved in inflammation, fibrosis and senescence were quantified by histology, immunoblot and qPCR.

Results:
At D28, all CLD-rats developed AF while CTRL rats did not. Compared to CTRL, weight up-take and water consumption were lower in animals exposed to CLD, although their food consumption was higher. Echocardiography revealed that CLD animals showed increased left ventricular contractility and atrial filling compared to CTRL. Acute CLD contamination caused a decrease in atrial conduction velocity and atrial action potential durations determined by cardiac OM
ex-vivo
. A 28-days CLD-withdrawal cycle was accompanied by weight normalization, and attenuation of AF inducibility, without improving atrial fibrosis and AF duration. CLD also decreased right and left atrial p21 mRNA expression, an effect not reversed by CLD weaning.

Conclusion:
CLD exposure is associated with increased AF vulnerability. CLD-weaning decreased (without abolishing), cardiac fibrosis and AF susceptibility.
Abstract 15292: Il21R-AS1 Long Non-Coding RNA as Potential Regulator in Therapeutic Angiogenesis in Peripheral Arterial Disease
Authors: Kovacs-Kasa Anita , Koseoglu Murat M , Annex Brian H
Published: June 2023

Background:
Peripheral arterial disease (PAD) is the major complication of systemic atherosclerosis. The clinical complications are intermittent claudication (IC) or its more severe form, critical limb ischemia (CLI). Potential therapeutic agents, to treat PAD failed in clinical studies. Vascular endothelial growth factor (VEGF) induced significant edema with no clinical benefit. Still today, no medical therapy exists to improve perfusion in PAD. Our lab has been studying the role of the interleukin-21 receptor (IL21R) in therapeutic angiogenesis. IL21 is undergoing clinical studies but its ability to be a therapeutic may be limited. IL21R transcribes a single human long non-coding RNA, the IL21R- antisense 1 (IL21R-AS1), with no mice homolog. Its role in PAD is not established yet.

Hypothesis:
IL21R-AS1 can serve as an activator of IL21R signaling to mediate hypoxia-induced angiogenesis without increasing vascular permeability.

Methods and Results:
Plasma from patients with IC, CLI, and non-PAD controls was obtained from whole blood. IL21R-AS1 was elevated in the plasma of patients with CLI. IL21R-AS1 expression was higher in endothelial cells (ECs) under hypoxia (2% O
2
) serum starvation (HSS), an
in vitro
model of PAD. To reduce the expression of IL21R-AS1 cells were transfected with gapmeR, and for the overexpression, IL21-AS1 pCMV-TnT plasmid was used. The knockdown of the IL21R-AS1 decreased tube formation in angiogenesis assay performed on growth factor reduced matrigel, while the overexpression of the lncRNA was pro-angiogenic in hypoxic endothelial cells. We detected IL21R-AS1 in the cytoplasm and showed its translocation to the cell surface in HSS. More importantly, in ECs under HSS, we detected IL21R-AS1 in IL21R immunoprecipitation samples; suggesting a direct interaction between IL21R-AS1 and the IL21R. Both IL21 treatment and IL21R-AS1 overexpression increased transendothelial resistance (TER) in hypoxic ECs, in contrast to the permeability induced by VEGF as measured by ECIS (Endothelial Cell Impedance Sensing).

Conclusion:
Collectively our data suggest that the lncRNA IL21R-AS1 serves as an activator of the IL21R that can mediate angiogenesis but without inducing vascular leakage.
Abstract 15299: Association Between Change in Liver Stiffness and Adverse Outcomes in Individuals With Fontan Circulation
Authors: Brayer Samuel W , Palermo Joseph J , Bari Khurram , Opotowsky Alexander R , Morin Cara E , Trout Andrew T , Dillman Jonathan R , Lubert Adam M
Published: June 2023

Introduction:
Fontan-associated liver disease (FALD) contributes to adverse outcomes late after the Fontan procedure. Elevated Magnetic Resonance Elastography-derived Liver Stiffness (MRE-LS) is associated with higher Fontan pressure and Fontan circulatory failure (FCF). How MRE-LS changes over time and if it can predict adverse outcomes has not been studied.

Methods:
Single center retrospective study of individuals >10 years-old post-Fontan with >1 MRE-LS study between 2010-2020. Absolute change in liver stiffness (shear modulus in kilopascals, kPa) was defined as the difference between first and second MRE-LS measures. Demographic and clinical data were collected. FCF was defined as the composite outcome of death, transplant, VAD placement, or unscheduled cardiac hospitalization following index MRE. To compare the effect of magnitude of change in liver stiffness, patients were ordered from lowest negative to highest positive (Quartile 1-4) change.

Results:
77 individuals were included (mean age at first MRI 19.9±6.7 years, 47% female). Baseline MRE-LS was 4.4±1.0 kPa, follow-up MRE-LS was 4.1±1.1 kPa with mean time between MRE examinations of 46±27 months. The median annual change in MRE-LS was -0.06 (IQR -0.2-0.05) kPa/year. There was no association between change in MRE-LS and age ventricular dysfunction, or Fontan pressure. FCF occurred in 18 (23%) individuals, and those with FCF had a greater increase in MRE-LS (0.12±0.83 vs -0.42±0.96 kPa, p=0.04, Figure).

Conclusions:
MRE-LS remains stable over short-term follow-up in most individuals with Fontan circulation. However, those with greater positive change in liver stiffness were more likely to experience adverse outcomes. An increase in MRE-LS is a potential non-invasive biomarker of clinical decompensation.

Figure: Probability of endpoint-free survival based on the change in liver stiffness quartiles (4 = largest increase in MRE-LS). Tick marks on curves indicate patients censored.
Abstract 15302: Successful Transesophageal Echocardiograms in Two Patients With Esophagectomy
Authors: Silverman Michael , Wengrofsky Perry , Chokshi Ravi , Waller Alfonso H
Published: June 2023

Clinical Presentation:
Case 1: A 74-year-old man was admitted to the ICU with altered mental status and shortness of breath. The patient had a history of esophageal adenocarcinoma and underwent an Ivor-Lewis esophagectomy 5 months prior. Blood cultures grew candida glabrata and the patient was started on an antifungal medication. A transthoracic echocardiogram was done without evidence of infective endocarditis. A transesophageal echocardiogram (TEE) was requested for higher quality imaging of the valves. Case 2: A 57-year-old man with a history of esophageal cancer with an esophagectomy done 4 years prior and atrial fibrillation (AF) presented for recurrence of AF. The patient had been maintained on apixaban and metoprolol but developed melena as well as reoccurrence of AF. An AF ablation was performed and a left atrial ablation appendage closure with a WATCHMAN device was planned for 6 weeks later. A TEE was requested intraoperatively for device guidance.

Imaging Findings:
In both cases, CT scans of the chest and abdomen within the last 4 months were reviewed to ensure patency of the esophagogastric anastomosis. In case 1, the TEE was performed with our standard scope without complication and showed no gross vegetations or abnormalities. In case 2, the TEE was performed with our standard scope without difficulty and showed a 20 mm x 21 mm x 20 mm left atrial appendage without thrombus. The WATCHMAN device was deployed successfully.

Summary and Discussion Points:
In our two patient cases, we were able to successfully perform TEE without complication in the setting of prior esophagectomy. Prior esophagectomy has traditionally been considered a barrier for TEE which can lead to limited evaluation and treatment of patients with esophagectomies where a TEE is required. In our cases, we consulted the patients’ surgeons who performed the esophagectomies and analyzed the CT images prior to performing the procedures to ensure the safety and feasibility of performing the TEE.
Abstract 15320: The Effects of Hydroxychloroquine on Electrocardiogram Intervals
Authors: Alawadhi Ahlam , El Kadri Moutaz , Al Falasi Omar A , Ahmed Rizwan , Altaha Zainab , Hillis Amany , Panikkaveetil Basheer , Abdalla Sara , Ansel Benette Honey , Almubarak Adhba , Saifuddin Mohammed , Alattar Yousef , Oulhaj Abderrahim , AlKaabi Salem
Published: June 2023

Background:
Hydroxychloroquine (HCQ) was widely used as a potential therapy for COVID-19 infection. We studied the effects of HCQ on electrocardiogram (ECG) intervals.

Methods:
We conducted a large-scale retrospective study of COVID-19 patients treated with HCQ admitted between March 1, 2020 and June 1, 2020. Extensive medical chart review was performed. Baseline and on treatment ECG intervals were manually measured by 3 electrophysiologists. The QT interval was corrected using Bazett formula (QTc). The paired t-test was used for the main analysis.

Results:
Paired ECG data from 1890 patients were analyzed. The mean age was 47.0 (±12.6) years with a strong male prevalence (85.6%). The commonest comorbidities were hypertension (39.6%) and diabetes mellitus (36.8%). The average duration of HCQ therapy was 6.3 (±2.3) days. 404 patients (21.4%) had severe COVID-19 infection and the mortality rate was 3.86%. Intensive care admission and mechanical ventilation was required in 209 (11.1%) and 166 (8.8%) patients, respectively. During therapy, heart rate (HR) decreased from 87.2 ± 16.8 bpm to 80.6 ± 14.7 bpm (
P
<0.001). The mean PR interval increased from 153.2 ± 21.9 ms to 162.9 ± 22.8 ms (
P
<0.001). The mean QRS duration increased from 92.8 ± 12.6 ms to 97.4 ± 13 ms (
P
<0.001). The average QTc increased from 427.4 ± 25.4 ms to 438.4 ± 29.9 ms (
P
<0.001).

Conclusions:
HCQ caused a modest but statistically significant prolongation in PR, QRS and QTc intervals. A reduction in HR was also noted mainly due to clinical improvement.
Abstract 15322: O-glcnac Modification on Runx2 Promotes Vascular Calcification
Authors: Byon Chang Hyun , Sun Yong , Heath Jack , Mao Xia , Zhao Xinyang , Wu Hui , Chen Yabing
Published: June 2023

Vascular calcification is prevalent in patients with diabetes mellitus and well documented in animal models of diabetes. We have previously reported that vascular calcification in diabetes is associated with elevated vascular protein
O
-linked GlcNAc modification (
O
-GlcNAcylation). The present studies sought to determine a causative link of
O
-GlcNAcylation with diabetic vascular calcification and the underlying molecular mechanisms. Using coronary arteries from diabetic subjects, we identified increased
O
-GlcNAcylation in the highly calcified lesions compared to those in the surrounding uncalcified areas. By generating a new mouse model with inducible SMC-specific deletion of the
O
-GlcNAc transferase (OGT), we demonstrated that smooth muscle cell (SMC)-specific OGT deletion significantly inhibited protein
O
-GlcNAcylation and calcification, and decreased aortic stiffness in the low-dose streptozotocin-induced diabetic mice. Consistent with the observations in human tissues, inhibition of vascular calcification by OGT ablation was associated with down-regulation of Runx2, the essential osteogenic regulator for vascular calcification. OGT deficiency in VSMC further attenuated Runx2-induced VSMC calcification. Immunoprecipitation analysis uncovered a direct O-GlcNAc modification on Runx2, which was abolished in the OGT-deficient VSMC. With a serial of Runx2 truncation mutants and point mutations on putative
O
-GlcNAcylation sites, we localized the essential Runx2 osteogenic functional domain between amino acids 391 and 432, and identified Runx2 T412 was responsible for Runx2
O
-GlcNAcylation and Runx2-induced VSMC calcification. Inhibition of Runx2
O
-GlcNAcylation by T412A mutation decreased Runx2 transcription activity and inhibited Runx2 binding with its key co-factors. Taken together, our studies have provided the first genetic proof demonstrating the causative effects of
O
-GlcNAcylation on vascular calcification in diabetes, and identified a novel mechanism underlying the essential role of
O
-GlcNAcylation of Runx2 in Runx2 osteogenic activity and Runx2-induced VSMC calcification. These results may shed lights on novel targets that are amenable to drug discovery for diabetic vascular calcification.
Abstract 15328: Investigating the Role of Endothelial Breast Cancer Susceptibility Gene 2 in Doxorubicin-Induced Cardiotoxicity
Authors: Rasheed Berk , Michels David , Nikfarjam Sepideh , Bu Shuhan , Nguyen Hien Chi , Frisbee Jefferson C , Hess David A , Gros Robert , Singh Krishna K
Published: June 2023

Background:
Doxorubicin (DOX) is a chemotherapeutic drug used to treat various malignancies including breast cancer. However, DOX use is limited by DOX-induced cardiotoxicity (DIC), which carries a poor prognosis and is frequently fatal. Accumulating evidence indicates a central role of oxidative stress, DNA damage, inducing cellular inflammation and apoptosis as common pathways during DIC. BRCA2 functions to maintain genome-wide stability by promoting DNA damage repair and also has anti-oxidative and anti-inflammatory roles. Thus, the pathways of DIC; DNA damage, oxidative stress, inflammation and endotheliotoxiciy; are specifically regulated by BRCA2. However, the role of endothelial BRCA2 in the mechanisms driving DIC remain unknown.

Hypothesis:
We hypothesize that endothelial cell-specific loss-of BRCA2 exacerbates and prevents DOX- induced DNA damage, inflammation, endotheliotoxicity, and cardiomyocyte death promoting DIC.

Methods and Results:
To understand the effect of DOX on BRCA2 expression
in vitro
, we cultured Human Umbilical Vein Endothelial Cells (HUVECs) and performed time and dose experiments and extracted RNA and protein to perform qPCR and immunoblot, respectively, for BRCA2. DOX inhibited BRCA2 expression in HUVECs at transcript and protein levels. We also measured the expression of pro-apoptotic p53, which appear to be up-regulated by DOX in a dose/time-dependent manner. We also have generated and characterized endothelial cell-specific BRCA2 knockout mice (BRCA2
endo
) using the Cre-Lox P method. DOX treatment to BRCA2
endo
mice induced significant weight loss in comparison to wild-type (WT) mice. Echocardiography done on DOX-treated BRCA2
endo
and WT mice showed significantly reduced cardiac function in BRCA2
endo
mice compared to WT mice. Our qPCR data performed on RNAs extracted from DOX-treated BRCA2
endo
and WT mice demonstrated significantly increased expression of heart failure markers in the heart of BRCA2
endo
mice compared to WT mice.

Conclusion:
Our studies’ will provide a novel mechanism for DIC by elucidating the roles of endotheliotoxicity and determining whether BRCA2’s function is a critical factor for restorative DNA damage repair and recovery of endothelial cell function following DOX treatment.
Abstract 15334: Tunable Elastin-Like Protein (Elp)-Based Hydrogels for Cell Transplantation in Vascular Repair
Authors: Shayan Mahdis , Navarro Renato S , Huang Michelle , Heilshorn Sarah C , Huang Ngan F
Published: June 2023

Introduction:
Endothelial cells (ECs) can improve blood perfusion in diseased blood vessels; however, direct injection of cells significantly decreases their survival and functionality for angiogenesis. To address these limitations, we study a family of engineered extracellular matrices with tunable biochemical and biomechanical cues for enhanced survival and improved angiogenic behavior of primary human ECs.

Hypothesis:
We hypothesize that the biomechanical properties of ELP-PEG hydrogels will modulate EC survival and function in vitro.

Methods:
Engineered hydrogels, termed ELP-PEG, consists of two components of a hydrazine-modified elastin-like protein (ELP-HYD) and an aldehyde- or benzaldehyde-modified, polyethylene glycol (PEG-ALD or PEG-BZA), which interact with each other through hydrazone dynamic covalent chemistry (DCC) bonds to form ELP-PEG hydrogels. Stiffness is controlled by altering the number of PEG-ALD or PEG-BZA crosslinks, and the stress relaxation rate is tuned by varying the PEG-ALD crosslinks vs. PEG-BZA. Stiffness and stress relaxation rates of the hydrogels were assessed by dynamic oscillatory rheology. Afterwards, human umbilical vein endothelial cells (HUVECs) were encapsulated within gels to assess cell viability and spreading using a Live/Dead Cytotoxicity assay and confocal fluorescence imaging.

Results:
Stress relaxation rate in ELP/PEG-ALD is much slower compared with similar combination in ELP/PEG-BZA. Rheology measurements of the RGD-ELP/PEG-BZA (1.75%/1%) and RGD-ELP/PEG-ALD (1.25%/1%) hydrogels demonstrated a storage modulus of 700Pa. It confirms the tunability of stress relaxation rate with a constant stiffness. Cell viability assay demonstrated that both hydrogels could support high cell viability (>90%) for 7 days. After 7 days, cell spreading increased in RGD-ELP/PEG-BZA hydrogels and tubular networks appeared inside the gels. However, cells did not form elongated morphology in RGD-ELP/PEG-ALD hydrogels, suggesting that stress relaxation rate and mechanical stiffness are key characteristics in modulating endothelial cell behavior.

Conclusions:
ELP/PEG-ALD/BZA promotes angiogenic behavior of ECs and is a promising candidate for cell delivery in vascular diseases.
Abstract 15358: Comparative Performance of Recurrent Heart Failure Prediction Models: Incorporating Social Determinants and Applying Machine Learning
Authors: Deshpande Aniruddha , Morris Alanna A , Ho Joyce C , Patel Shivani A
Published: June 2023

Introduction:
Improving performance of predictive algorithms for 30-d readmission following heart failure (HF) hospitalization may enhance clinical management decisions. Applying novel data (social determinants of health; SDOH) and novel methods (machine learning) have been proposed. We compared performance to predict 30-d HF readmission using models with and without SDOH and under traditional and machine learning techniques.

Hypothesis and Methods:
We used data on 27,071 admissions within Emory Healthcare (mean age: 66 , 48% female, 51% black). We categorized 69 covariates as patient-level clinical (e.g., diastolic blood pressure), patient-level demographic (e.g. gender, age), and zip code SDOH (e.g. percent unemployed). Logistic regression under generalized linear model (GLM) and gradient boosted model (GBM) frameworks were applied to test all combinations of covariate sets. We evaluated performance using 5-fold cross-validation calculating area under the curve (AUC; discrimination) and mean absolute error (MAE; calibration) statistics.

Results:
30-d readmission occurred in 17.7% of hospital admissions. Under GLM, model performance was similar across all covariate sets (AUCs .500 - .502). Under GBM, model performance measures were higher than GLM but similar across covariate sets (.500-.664). Notably, SDOH improved model discrimination (AUC .606 clinical only, AUC .664 clinical+SDOH) in the full dataset (“in-sample”) runs.

Conclusions:
Patient clinical data provided the richest information for prediction of HF readmission, with incremental gains through the addition of area SDOH data such as zip code level unemployment. Furthermore, these gains were only realized in GBM highlighting the marginal utility in flexible modeling methods. While non-clinical data sources can provide a rich understanding of the social mechanisms producing disease, their utility for clinical prediction may be outcome-specific.
Abstract 15389: Insulin Like Growth Factor Binding Proteins 1 and 2 Are Prognostic Survival Markers in Intermediate Risk Pulmonary Arterial Hypertension
Authors: Griffiths Megan , Simpson Catherine , Yang Jun , Torres Guillermo , Vaidya Dhananjay , Brandal Stephanie , Pauciulo Michael , Damico Rachel L , Hassoun Paul , Ivy Dunbar D , Austin Eric , Rosenzweig Erika , Nichols Bill , Everett Allen D
Published: June 2023

Introduction:
Pulmonary arterial hypertension (PH) is an often fatal disease of the pre-capillary pulmonary vasculature. Recognizing high risk PH in ambulatory patients is important for optimization of therapy to improve outcomes. We previously identified insulin like growth factor binding proteins 1 and 2 (IGFBP1, IGFBP2) as prognostic markers in severe PH; here, we evaluated IGFBP1/2 as prognostic markers in PH with intermediate risk features.

Methods:
A multiplex ELISA assay measured serum IGFBP1/2 in the multicenter PH Biobank (N=2450), and independent validation cohorts (Johns Hopkins, N=145, Vanderbilt N= 128, 388 observations over time). IGFBP1/2 concentrations were compared to hemodynamics, six-minute walk (6MW), and WHO functional class using linear/logistic regression adjusted for age and sex. Time to death/transplant by IGFBP1/2 levels was assessed by Cox proportional hazard models. Analysis was repeated in subjects with low to intermediate risk features defined as WHO functional class 1-2, 6MW >300 m, and NT-proBNP <1500 pg/mL, based on the REVEAL and ERS risk scores.
1, 2

Results:
In all cohorts, increased IGFBP1 and IGFBP2 were associated with lower cardiac output, higher mean pulmonary artery pressure and pulmonary vascular resistance (PVR, p<0.05 for all). In each sub-analysis, a higher IGFBP1 and IGFBP2 was associated with lower cardiac output, lower systemic blood pressure, and higher PVR (p<0.05 for all). Higher IGFBP1 and IGFBP2 were associated with shorter time to death/transplant in the overall cohort and each of the intermediate risk PH cohorts (Table 1), although underpowered in the Vanderbilt cohort.

Conclusions:
Identifying patients who will have adverse outcome in intermediate risk PH has proven challenging. These data suggest IGFBP1/2 are good prognostic markers in PH where functional class and exertional tolerance is preserved. IGFBP1/2 could further discriminate adverse outcomes in patients with low to intermediate risk PH.
Abstract 15411: Life After the Valve, Analyzing Post-Procedural Anemia and Mortality in Transcatheter Aortic Valve Replacement Patients
Authors: Polman David , Bhayani Siddharth , Ambalavanan Manoj , Zayyad Zaid , Sreepathy Pranati , Dohse Carlos , Twing Aamir , Tiu David , Dickens Helena , Kansal Mayank M , Ibrahim Khalil , Shroff Adhir R
Published: June 2023

Introduction:
Transcatheter Aortic Valve Replacement (TAVR) has become the primary therapeutic option for many patients with severe aortic stenosis (AS). As a result, anemia is a prevalent co-morbidity amongst the TAVR population. Recent studies have demonstrated pre-procedural anemia is associated with increased long-term mortality in TAVR patients. However, the comparison of TAVR patients’ post-procedural anemia and its effect on mortality has not been fully investigated.

Methods:
Retrospective analysis of electronic medical records from 2018-2021 at the University of Illinois at Chicago and Jesse Brown VA Medical Center identified TAVR patients. Primary outcomes included all-cause mortality and significant bleeding at 6-months and 12-months post-TAVR.

Results:
We included 160 patients in the analysis. They were 122 males, 56.88% non-white, and an average age of 73.88. At 6-months, patients who experienced all-cause mortality had an average hemoglobin of 9.85 (g/dL) compared to an average hemoglobin of 11.31 in those patients that survived (p = 0.020). There was no significant difference in major bleeding events between the two groups (p = 0.974) as well as no significant difference in past-medical history, including hypertension, hyperlipidemia (HLD), diabetes mellitus, history of stroke and history of myocardial infarction. At 12-months, patients who experienced all-cause mortality had an average hemoglobin of 10.18 compared to an average hemoglobin of 11.36 in those patients that survived (p = 0.014). There was no significant difference in major bleeding events (p = 0.753) and no significant difference in past-medical history, except for hyperlipidemia. The prevalence of HLD was 59.09% in those that experienced all-cause mortality compared to 78.72% in those that did not (p = 0.045).

Conclusions:
Our results suggest that patients with lower hemoglobin levels after TAVR are at a greater risk of all-cause mortality compared to those with higher hemoglobin levels. These patients may benefit from closer follow-up after the procedure.
Abstract 15420: Cgas-Sting Pathway-Mediated Cholesterol Metabolism Promotes Atherosclerosis Formation
Authors: Li Yang , Zhang Chen , luo wei , Rebello Kimberly , Chakraborty Abhijit , Li Yanming , Zhang Lin , Vasquez Hernan , Coselli Joseph S , Daugherty Alan , LeMaire Scott A , Lu Hong , Shen Ying H
Published: June 2023

Introduction:
The mechanisms underlying macrophage lipid accumulation and foam cell formation, the critical step in atherosclerosis initiation, remain to be understood. The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway triggers potent inflammation in response to cytosolic DNA accumulation.

Hypothesis:
In this study, we found that the cGAS-STING signaling pathway can promote macrophage lipid accumulation and atherosclerosis development.

Methods:
We developed an atherosclerosis mice model by a single intraperitoneal injection of an adeno-associated virus (AAV) containing a mouse PCSK9 gain-of-function mutation D377Y.

Results:
In the descending aorta of patients and aortic root of atherosclerotic mice, we detected profound cytosolic DNA accumulation that was associated with the activation of cGAS -STING in both human and mouse atherosclerotic plaques. In cultured macrophages, DNA uptake by macrophages activated the cGAS-STING pathway, which induced the biosynthesis of fatty acids and cholesterol. Interestingly, we found that STING can bind to SREBP2 (sterol regulatory element-binding protein 2) through SCAP (SREBP2 cleavage activating protein) and promote its cleavage and nuclear translocation, and subsequent induction of genes in fatty acid and cholesterol biosynthesis. Finally, in an AAV-PCSK9/high-fat diet-induced atherosclerosis model,

cGas
-/-

and SMC-
Sting

-/-

mice exhibited a reduction of SREBP2 activation and lipid content in macrophages and a reduction in atherosclerosis burden.

Conclusions:
Our findings indicated that DNA and cGAMP from damaged cells serve as a danger molecule that, by activating the cGAS-STING cytosolic DNA sensing signaling, promotes macrophage lipid biosynthesis and accumulation, contributing to atherosclerosis development.
Abstract 15433: Very Late Recurrence After Successful Ablation of Premature Ventricular Contractions in Patients Without Structural Heart Disease
Authors: Mohanty Sanghamitra , Shetty Sai Shishir , Della Rocca Domenico G , QUINTERO MAYEDO ANGEL , MacDonald Bryan , gianni carola , Baho Karim , Morris Trevor , Elchouemi Mohanad , Helmy Rami , Asfour Issa , Gallinghouse G , Burkhardt John , Horton Rodney , Al-Ahmad Amin , Natale Andrea
Published: June 2023

Background:
Earlier studies have shown the superiority of catheter ablation over pharmacological therapy in eliminating premature ventricular contractions (PVC) in patients without structural heart disease. We investigated very late recurrences after successful PVC ablation in this cohort.

Methods:
Consecutive patients undergoing clinically indicated radiofrequency ablation for symptomatic idiopathic PVCs, documented by standard ECG, were included in the analysis and prospectively followed up. Those with history of structural heart disease were excluded. For all patients, 12-lead ECGs were reviewed to assess PVC morphology. During the index procedure, all PVC morphologies were targeted for ablation. Standardized RF power settings (40-50 W) were used during the procedure. Ablation was performed using 4-mm irrigated tip catheter guided by 3-D mapping system and intra-cardiac echocardiography. Patients were followed up with remote monitoring as well as ICD interrogations and office visits every 6 months for 4 years. Long-term success was defined as absence of previously targeted PVCs or any new PVC morphology on 12-lead ECG or device interrogation during all follow-up visits.

Results:
In total, 638 patients were included (mean age 59.2±5.6 years, 69.75% male, LVEF 54±12%). At the index ablation, PVCs were detected to be localized in the right ventricular outflow tract in 268 (42%), left ventricular outflow tract in 299 (46.8%) and multiple sites of origin in 71 (11.2%) patients. Non-inducibility was achieved in all patients at the end of the index procedure. At 4 years, 585 (91.7%) patients remained arrhythmia-free. Remaining 53 patients (8.1%) experiencing recurrence underwent repeat procedure. Median time to recurrence was 29±6.2 months. At the redo, new PVC morphologies were detected and ablated in 46/53 (86.8%) patients. One year after the repeat ablation, 50/53 (94.3%) were arrhythmia-free.

Conclusion:
In this prospective single-center series, very late recurrence following index PVC ablation in patients with no structural heart disease was mostly associated with new PVC morphologies that were amenable to be successfully ablated at the repeat procedure.
Abstract 15440: Elevated Serum Transthyretin Concentration Found to be Associated With Increased Survival Rate in Hereditary Transthyretin Cardiomyopathy Patients
Authors: Rangaswamy Nandakumar Dhanish Revanth , Rim Austin , Steinberg Rebecca , Yalamanchili Sreeram , Patel Rahul , Brown Matthew T , Bhatt Kunal
Published: June 2023

Introduction:
Transthyretin amyloid cardiomyopathy (ATTR-CM) results from abnormal deposition of misfolded transthyretin (TTR) deposition in the myocardium. Prior studies have shown an association between lower serum concentrations of TTR with increased mortality in patients with wild-type TTR, suggesting that greater deposition of TTR from the blood into surrounding tissues may reflect increased disease severity.

Hypothesis:
Serum TTR levels are associated with mortality and HF hospitalization in hATTR patients with Val142Ile mutation.

Methods:
We conducted a retrospective chart review of patients diagnosed with hATTR-CM at Emory University's Cardiac Amyloidosis Clinic between January 2014 and April 2022 (n=65) and evaluated the association of serum TTR concentration with 1 year survival and 1 year HF hospitalization. We stratified patients on two TTR cut-offs: 18 mg/dL, based on a previous study in a wild-type cohort, and 14.9 mg/dL, the median TTR level in this cohort. Kaplan Meier Survival analysis and Cox proportional hazard modeling examined the association between serum TTR, overall survival, and HF hospitalization, adjusted for troponin-I, age, BMI, BNP, GFR and NYHA class as covariates.

Results:
Increased serum concentrations of TTR were significantly associated with decreased mortality within 1 year of diagnosis in multivariable models. Adjusted models showed a significant difference between the groups at both cut-offs only when the event was death within 1 year of diagnosis (Cutoff 14.9: HR = 14.02, 95% CI 2.4 - 82.5; cutoff 18: HR 367, 95% CI 35.24-3822.57), but no significant difference for the outcome of HF hospitalization at either cutoff point (
Table
).

Conclusions:
In our cohort of 65 hATTR patients with the Val142Ile mutation, lower TTR levels at the time of diagnosis were significantly associated with death at 1 year of diagnosis. TTR levels were not significantly associated with HF hospitalization within 1 year of diagnosis.
Abstract 15458: Incidence of Ventricular Arrhythmias Related to Covid Infection and Vaccination in Patients With Brugada Syndrome: Insights From a Large Italian Multicenter Study
Authors: Conti Sergio , Dello Russo Antonio , Compagnucci Paolo , Massara Francesca , Tondo Claudio , Ribatti Valentina , Marcon Lorenzo , Pelargonio Gemma , Narducci Maria Lucia , De Francesco Luca , Calo Leonardo , Martino Annamaria , Balla Cristina , Iacopino Saverio , Sgarito Giuseppe , Patti Giuseppe , Ghiglieno Chiara , Dell'Era Gabriele , Forleo Giovanni B , Schiavone Marco , Casella Michela
Published: June 2023

Introduction:
Brugada syndrome (BrS) is an inherited channelopathy leading to an increased risk of life-threatening arrhythmias. BrS patients have a dynamic ECG pattern that might be revealed by certain conditions such as fever. Covid infection/vaccination is associated with fever. Therefore, prompt treatment with antipyretic drugs is recommended.

Hypothesis:
We evaluated the incidence and management of fever-related arrhythmias from Covid infection/vaccination among BrS patients previously implanted with an implantable loop recorder (ILR) or an implantable cardioverter-defibrillator (ICD) and followed by remote monitoring.

Methods:
326 patients were retrospectively analyzed in 9 Italian Centers with a dedicated inherited disease ambulatory. All patients had a previously implanted device (ICD/ILR) and remote monitoring. We recorded ventricular arrhythmias (non-sustained VT, VT, FVT, VF) 6-month before Covid infection/vaccination, during Covid infection, at each vaccination, and up to 6-month post-Covid healing or 1-month after the last dose of vaccine. In ICD patients, we documented any device intervention (ATP/shock).

Results:
Mean age was 48.02±14.08, 240 patients were males (73.6%). 235 patients had an ICD (72.1%), and 91 had an ILR (27.9%). 175 patients had a spontaneous type 1 ECG pattern (53.7%). Fever occurred in 18.4% of all patients. The mean temperature was 38.2±0.6 degrees, 2.76% were hospitalized due to Covid. All patients developing fever received paracetamol, only a minority ibuprofen, antibiotics, and hydroxychloroquine. After Covid, we recorded 2 VT episodes in the same patient treated with paracetamol and hydroxychloroquine. After the 1st, 2nd, and 3rd vaccine doses we recorded: 10 NSVT; 16 NSVT and 2 VT; and 7 NSVT, respectively. After 1-month from the last dose, only 1 patient had an episode of FVT. The overall incidence of sustained VT is 1.2%. No ICD interventions, ATP and shocks, were recorded in the ICD population. Patients with an ILR had no ventricular arrhythmias.

Conclusions:
From this large multicenter study, fever treatment in patients with BrS is widely performed with paracetamol. The overall incidence of sustained ventricular arrhythmias after Covid infection/vaccination is relatively low.