bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12567: Cardiomyocyte Hypertrophy is Regulated by P300 Binding Protein 1, a Novel Binding Protein
Authors: Ishima Ayaka
Published: June 2023

Background:
Hypertrophic stimuli such as hemodynamic overload activate the cardiac signaling pathway that terminates in cardiomyocyte nuclei, thus changing the pattern of gene expression associated with cardiomyocyte hypertrophy. This hypertrophy eventually leads to systolic dysfunction and decompensated heart failure. Nuclear acetylation is a critical event in the activation of this hypertrophic gene expression and is mediated in part by intrinsic histone acetyltransferases (HAT) such as coactivator p300. p300-HAT activity is a potential pharmacological target for the prevention of heart failure. However, the regulation mechanism of p300-HAT activity is still unclear. In this study, we identified novel p300 binding partners by proteomic analysis and investigated the role of one of these proteins, p300 binding protein 1 (p300BP1), in the hypertrophic responses of cardiomyocytes.

Methods and Results:
To identify novel p300 binding proteins, cardiac-specific FLAG-p300 overexpressing mice were generated. Protein fractions from heart tissues of these mice and wild-type mice were purified with anti-FLAG-M2 agarose. Mass spectrometry analysis identified 553 novel p300 binding proteins, including kinases, phosphatases, methyltransferases, and transcriptional regulators. p300BP1 was selected for analysis. Binding was found to occur between baculovirus-expressed the recombinant genes FLAG-p300 full length and HA-p300BP1. The aa762-aa1098 fragment of p300 was required for this binding. In cultured cardiomyocytes, knockdown of p300BP1 prevented phenylephrine-induced increases in cardiomyocyte surface area and hypertrophic gene transcription factors such as ANF and BNP. Conversely, the overexpression of p300BP1 increased the surface area of cardiomyocytes and hypertrophic gene transcriptions. Furthermore, overexpression of p300BP1 significantly increased H3K9 acetylation in cultured cardiomyocytes. A reporter gene assay showed that p300BP1 enhanced p300/GATA4-mediated ANF and BNP promoter activation in HEK293T cells.

Conclusions:
We have identified multiple novel p300 binding proteins using a proteomics approach. p300BP1 may play an important role in p300/GATA4-dependent hypertrophic responses in cardiomyocytes.
Abstract 12589: Left Ventricular Unloading Preserves Ventricular Function and Reduces New-Onset Atrial Fibrillation in Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock
Authors: Matsuda Junya , Ishihara Kakeru , Oka Eiichiro , Shiomura Reiko , Shibuya Junsuke , Nakata Jun , Miyachi Hideki , Shimizu Wataru , Yamamoto Takeshi
Published: June 2023

Introduction:
Left ventricular (LV) unloading by percutaneous ventricular assist device (pVAD) reduces myocardial workload and oxygen consumption and provides a new concept for improving outcome for acute myocardial infarction complicated with cardiogenic shock (AMI-CS). AMI results in reduced LV ejection fraction and left atrium remodeling, and increased the incidence of atrial fibrillation. The aim of this study is to investigate the effectiveness of LV unloading by pVAD in terms of mid-term mortality, LV function, and the incidence of atrial fibrillation.

Methods:
We retrospectively reviewed AMI-CS patients who were admitted to our hospital between July 2014 and December 2021. We investigated patient demographics and baseline characteristics, mid-term clinical outcome, re-admission rate as well as new-onset atrial fibrillation compared between the patients supported with pVAD and without pVAD group during 180-day follow-up.

Results:
A total of 82 AMI-CS patients treated with pVAD (n=54) or without pVAD (n=28) were analyzed. Mean age was 70±15 years old and 56 patients were male. Door to balloon time (110±56min vs. 91±53min, p=0.33) and Peak CK-MB (471.8±338mg/dl vs. 486.0±545mg/dl, p=0.43) were similar in both groups. During the 180-days follow-up, 23 patients died and 12 patients were re-hospitalized for heart failure (HF). New-onset atrial fibrillation occurred in 16 patients, which was significantly less frequent in pVAD group (11% vs. 36%. p=0.016). Between baseline and 180-days follow-up period, changes of LV ejection fraction (16% vs. 6%, p=0.02) and NT-proBNP (-28% vs. -5%, p=0.03) were significantly higher in pVAD group. There was no significant difference in 180-day all-cause mortality (28% vs. 29%, p=1.0) between the two groups. Multivariate logistic regression showed new-onset atrial fibrillation was independently associated with an increased risk of HF readmission (hazard ratio 2.63, 95% confidence interval 1.91-3.57; p=0.01).

Conclusion:
pVAD support preserves LV function following ventricular unloading and reduces new-onset atrial fibrillation, which might be contributed to the improvement of mid-term outcome.
Abstract 12601: Oral Xe-Cyclodextrin Provides Neuroprotection for Ischemic Stroke Treatment
Authors: Yin Xing , Frierson Brion , Wu Jean G , Moody Melanie R , Guo Wei , Claypool Jonathan , Savitz Sean I , Aronowski Jaroslaw A , McPherson David D , booher keith , Huang Shaoling
Published: June 2023

Introduction:
Ischemic stroke is one of the main causes of long-term morbidity/mortality and early treatment is key. Xenon (Xe) has demonstrated powerful neuroprotective effects on both ischemic and hemorrhagic stroke, but its clinical and long-term outpatient administration is limited by currently available delivery methods. Development of an oral Xe formulation is an attractive strategy for stroke treatment in the field. We developed a Xenon (Xe)-cyclodextrin (CD) oral formulation.

Hypothesis:
Xe-CD formulation can be delivered orally for acute stroke treatment.

Methods:
A stable, oral Xe-CD clathrate (Xe solid gas) was formed by pressurizing Xe (3 atm) into 14% alpha-cyclodextrin at room temperature. Xe concentration was measured by GC-MS. Rat middle cerebral artery occlusion (MCAO) was induced by intraluminar suture. The animals were divided into groups: stroke (n=4); stroke with CD (n=3); stroke with 0.5 ml Xe-CD (n=3); stroke with 1.0 ml Xe-CD (n=3); and stroke with 1.5 ml Xe-CD (n=3). Treatments were administered by gavage once a day for 3 days. At day 3, neurological behavior testing was conducted. The infarct size and neuronal death were assessed and normalized by total brain volume.

Results:
There are 1.56 mM Xe clathrate per 0.6 mM alpha-cyclodextrin. MCAO for 2 hours induced 21% ± 3.6% infarct volume. Xe-CD treatment dose-dependently reduced the infarct size to 18.9% ± 2.3% by 0.5 ml Xe-CD, 6.7% ± 1.8% by 1.0 ml Xe-CD, and 4.8% ± 1.2% by 1.5 ml Xe-CD (Fig. 1A). Behavioral test assessment using forelimb placement rate and Rotarod score matched infarct size. TUNEL staining demonstrated significant decreases in apoptosis in stroke rats treated with 1.5 ml Xe-CD (Fig. 1B).

Conclusions:
We have demonstrated oral Xe-CD formulation ameliorates neuronal apoptosis and reduces infarct size. Xe-CD represents a promising therapeutic for ischemic stroke treatment.
Abstract 12612: Prevalence, Risk Factors and Guideline Directed Medical Therapies Among Premature Peripheral and Coronary Arterial Disease in Large Integrated Healthcare System: Houston Methodist CVD Learning Health System Registry
Authors: Khan Safi U , Sammour Yasser , Thakkar Samarthkumar , BOSE BUDHADITYA , Gullapelli Rakesh , Nicolas Charlie , Nwana Nwabunie , Lahan Shubham , Roy Trisha , Lumsden Alan , Kleiman Neil S , Soliman Ahmed , Patel Kershaw , Cainzos Achirica Miguel , Andrieni Julia , Jones Stephen , Zoghbi William A , Nasir Khurram
Published: June 2023

Introduction:
Premature coronary artery disease (CAD) and peripheral arterial disease (PAD) are manifestations of accelerated atherothrombotic disease and pose a significant risk for CVD morbidity and mortality. There are scarce insights on prevalence, risk factors, and management practices for these high-risk groups.

Methods:
In this cross-sectional study, we analyzed patients aged 18-64 y in the Houston Methodist Cardiovascular Disease Learning Health System Registry (n= 1.127 million; June 2016-April 2022). CAD and PAD were identified using ICD 10-CM codes.

Results:
Among 811,097 individuals (58.6% women and 14.8% NH Blacks,
Table
), 2.1% (n=17,094) had premature CAD alone, 0.4% (n=3,243) had isolated premature PAD and 0.2% (n=1,658) had both. Compared to premature CAD alone, patients with isolated premature PAD were more likely to be women, NH Blacks, smokers, and diabetics, with the highest risk burden seen in those with both conditions. Patients with isolated premature PAD had the lowest rates of lipids, HBA1c, and SBP at goals and guideline-directed medical therapies (GDMT) compared to those with premature isolated CAD.

Conclusions:
Nearly 1 in 40 adults had premature CAD and PAD. Individuals with premature PAD have a more unfavorable CV risk profile and are less likely to achieve risk factor control and receive GDMT. Therefore, system-wide collaborative initiatives for early identification and risk factor optimization for this vulnerable population are warranted.
Abstract 12626: A Systematic Review and Meta-analysis of Factors Associated With Long-Term Mortality in Adults After Coronary Artery Bypass Graft Surgery
Authors: Talukder Suprateeka , Dimagli Arnaldo , Benedetto Umberto , Gray Alastair , Gerry Stephen , Lees Belinda , Krzych Lukasz , Gaudino Mario F , Taggart David , Flather Marcus D
Published: June 2023

Background:
With an ageing and increasingly multi-morbid population, the use of coronary artery bypass grafting (CABG) is expected to increase. As short-term CABG mortality rates have decreased, estimating long-term outcomes for patients with specific risk factors has become more relevant. Previous single observational studies have identified risk factors for adverse long-term outcomes, such as older age and diabetes.

Purpose:
Understanding the pre-operative characteristics that affect late mortality post-CABG can lead to effective risk stratification and enhancement of secondary prevention programmes, thereby aiming to improve long-term prognosis after the procedure.

Methods:
MEDLINE, Embase, Google Scholar, and Cochrane electronic databases were searched to identify all relevant articles evaluating associations between pre-operative risk factors and long-term mortality (≥5 years ) post-CABG. Studies with <500 patients were excluded.

Results:
From 1193 potentially eligible articles, 43 studies met the inclusion criteria. A total of 360,481 patients, with an average follow-up of 10 years, were included, representing an approximate cumulative total of 3,604,810 person-years. After pooling adjusted hazard ratios, 6 major risk factors were found to be independently associated with long-term mortality after CABG: age, ischaemia (peripheral vascular disease, prior cerebrovascular accident, left main stem coronary disease), diabetes mellitus, atrial fibrillation, renal impairment (chronic kidney disease and dialysis-dependent chronic kidney disease), and impaired left ventricular function (reduced LV ejection fraction or prior heart failure) (see Table 1).

Conclusion:
We have identified six groups of risk factors for long-term mortality post-CABG. Further work is needed to assess whether the influence of these risk factors varies over time and if targeted interventions for high-risk groups lead to improved long-term mortality.
Abstract 12654: Reduction of Tricuspid Regurgitation as Predictor of Successful Percutaneous Edge-to-Edge Repair: Clinical Outcomes Comparison Between Patients With Residual Severe and Moderate-or-Less Regurgitation
Authors: Patrascu Alexandru I , Ott Ilka
Published: June 2023

INTRODUCTION:
Transcatheter tricuspid valve repair (TTVR) for high-grade regurgitation (TR) is emerging as a viable option, but defining procedure-related clinical success is challenging, as considerable reduction is not possible in all patients with massive or torrential TR. This study compared clinical outcomes of edge-to-edge TTVR, in patients with residual severe vs moderate-or-less TR.

Methods:
Eligible patients had chronic symptomatic functional TR despite diuretic therapy, and were deemed inoperable by the local Heart Team. TR was assessed by the current five-grade classification. Efficacy and safety outcomes were compared at baseline and 6 months, with follow-up between January 2021 and May 2022.

Results:
Forty-three patients had ≥severe (III/V) functional TR, 65% presenting with massive (IV/V) and 14% with torrential (V/V) TR. Mean age was 81.8±4.9 years, with 10.8±6.3% STS-Score. The primary efficacy endpoint of at least one-grade TR reduction was recorded in 91% of all patients, with no device related complications.Residual severe TR (STR subgroup) was present in 15 patients, while 20 (MTR subgroup) had moderate-or-less (≤II/V). By 6 months, 4 patients died, 4 patients had no TR reduction, and MACE rate was 18.6%. Improvement in initial NYHA class III/IV occurred in 61% of STR and 77% of MTR patients. KCCQ Score increased by 17±10.6 pts. (p<0.001) vs 21±11.8 (p<0.001), and six-minute walk test by 69.6±48.7 meters (p<0.001) vs 74.2±63 (p<0.001). Renal and liver function equally improved in both groups [GFR 50±16ml/min/1,73m
2
to 57.8±20.4 (p=0.012) vs 57.4±18.5 to 65.5±21.2 (p=0.002); AST 27.5±9.3U/L to 22.9±7.3 (p=0.039) vs 37.2±25.6 to 26.8±7.3 (p=0.069)].

CONCLUSIONS:
Although TTVR should always aim for trace to mild TR, considerable reduction is not always possible. This study indicates that even one-grade TR reduction can significantly impact quality of life, functional capacity and multiorgan involvement, similarly in STR and MTR patients.
Abstract 12668: Coronary CTA Finding of Libman Sacks Endocarditis Presenting as Chest Pain
Authors: Babayale Omofolarin , Fashanu Oluwaseun E , Corteville David , baibhav bipul
Published: June 2023

Case Presentation:
A 65-year-old female with a history of hypertension, hyperlipidemia, microscopic colitis, fibromyalgia, left hand dupuytren's contractures, Grave’s disease and seronegative rheumatoid arthritis presented to the outpatient office for evaluation of right sided stabbing and heavy chest pain. ECG showed sinus bradycardia without any ST segment changes. She had an Echo and exercise stress Echo prior to her office visit. Her echo showed normal left ventricular size and systolic function with no regional wall motion abnormality and thickened aortic valve with mild aortic stenosis (peak transvalvular gradient 9.9 mmHg and mean 5.9 mmHg). Her stress echo was negative for ischemia although submaximal (exercised for 6.05 minutes, achieving only 75% MPHR, and double product of 18720). It was then decided to pursue a coronary CTA given the suboptimal nature of her stress testing and intermediate pretest probability of coronary artery disease. This revealed mild-to-moderate non-obstructive CAD and thickening of her left coronary cusp. The thickening was concerning for Libman-Sacks endocarditis vs native aortic valve thrombosis (see figure). Her Antinuclear antibody (ANA) titers was 1280. She was started on therapeutic anticoagulation with a plan for repeat imaging in six months.

Discussion:
Coronary cusp thickening represents a variety of differentials and has comparable structural and clinical qualities. Atypical chest pain in our patient led to the incidental finding of left coronary cusp thickening. In the presence of elevated ANA and her autoimmune disorder, Libman-Sacks endocarditis vs native aortic valve thrombosis was suspected hence the initiation of anticoagulation. Both have a propensity for fatal outcomes including, but not limited to myocardial infarction, embolic events, cardiogenic shock, or death. Follow-up imaging with a resolution of thrombus would confirm the diagnosis of native aortic valve thrombus.
Abstract 12676: Psychological Stress Stimulates Vascular Inflammatory Responses and Destabilizes Atherosclerotic Plaques as Assessed by High-Speed, High-Resolution Intravital Imaging
Authors: Song Joon Woo W , Jang Minseok , Kang Dong Oh , Kim Ryeong Hyun , Kim Hyun Jung , Kim Jin Hyuk , Park Eun Jin , Park Ye Hee , Lee Bo-Hyung , Kim Chi Kyung , Park Kyeongsoon , Yoo Hongki , Kim Jin
Published: June 2023

Backgrounds:
Psychological stress increases leukocyte accumulation within atherosclerotic lesions and exacerbates plaque vulnerability. However, the stress-induced real-time behavior of immune cells in the atheroma has been poorly defined
in vivo
. Here, we aim to investigate whether stress stimulates the inflammatory leukocyte dynamics in the atherosclerotic plaques and destabilizes the lesions using customized
in vivo
cell tracking strategies.

Methods and Results:
We developed a system and motion reconstruction algorithm that can probe and compensate for respiratory and pulsatile movements. Individual leukocytes near the atherosclerotic plaques were imaged in real-time by adapting a custom-built high-speed intravital microscopy system with multiple fluorescence channels. Stress was achieved by immobilization procedures and/or stereotaxic application of stress stimulus onto the brain amygdala. The high spatial and temporal resolution of our real-time cell tracking system allowed clear identification of rhodamine 6G-positive leukocytes
in vivo
. In the common femoral artery bifurcation of apolipoprotein E knockout mice, white blood cells firmly adhered to the inner layer of the vessel walls while some slowly flowed along the endothelium (Figure). We further demonstrate that the stress increased the rolling and adhesion of inflammatory leukocyte subsets near the atherosclerotic lesions, and enhanced the plaque macrophage activity as assessed by
in vivo
imaging. Confocal laser scanning microscopy and immunostaining analyses corroborated the
in vivo
findings that the stress induced the destabilization of the atherosclerotic plaques.

Conclusion:
Our data show that stress stimulated the dynamics of inflammatory leukocyte subsets in atherosclerotic environments and increased the plaque vulnerability as assessed by the customized high-resolution motion-compensated
in vivo
imaging strategy.
Abstract 12681: GWAS Meta-Analysis in SCAD, a Women Predominant Ischemic Heart Disease, Reveals Common Variants and Genes Related to Artery Integrity and Tissue-Mediated Coagulation
Authors: Adlam David , BERRANDOU Takiy E , Georges Adrien , Nelson Christopher P , Giannoulatou Eleni , Ma Lijiang , Blencowe Montgomory , Turley Tamiel , Yang Min-Lee , Iismaa Siiri , Tarr Ingrid , Muller David , Hesselson Stephanie , Junday Keerat , Fatkin Diane ,   CARDIoGRAMPlusC4D, COMBARET Nicolas ,   DISCO register investigators, Saw Jacqueline , Webb Tom , Tweet Marysia , Hayes Sharonne N , Xia Yang , Ganesh Santhi , Olson Timothy M , Kovacic Jason C , Graham Robert M , Samani Nilesh J , Bouatia-Naji Nabila
Published: June 2023

Introduction:
Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction due to hematoma formation in coronary arteries primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD).

Methods and Results:
Through a meta-analysis of 8 GWAS (1917 cases, 9292 controls of European ancestry), we identified 17 risk loci, including 12 new. Functional annotations pointed at enrichment in enhancer marks of arteries, specifically smooth muscle cells, and strong candidate genes, such as tissue factor gene (
F3
) on Chr1 near rs1146473 (OR=1.32, P=5.8 х10
-9
).
F3
is novel for SCAD or any cardiovascular disease. The risk allele correlated with
F3
lower expression in arteries, supporting a mechanism consistent with hematoma formation. Bayesian gene regulatory networks constructed from expression and genetics data indicated the extracellular matrix organization in arteries as the biological function where most prioritized genes clustered (e.g.
COL4A1/A2, HTRA1,
and
TIMP3
). Overall, we report substantial polygenicity for SCAD (LDSC:

h
2
SNP
=

0.71 ± 0.11) and shared genetics with several neurovascular diseases (e.g intracranial aneurysm). Intriguingly, for 6 loci, colocalization analyses showed that SCAD and CAD are likely to share the same causal variants but involve opposite risk alleles (e.g
COL4A1/A2
). In addition, a negative genetic correlation was found between SCAD and CAD (rg=-0.12; P=3.7х10
-3
), including after conditioning on BP (mt-COJO: rg
CAD/SBP
=-0.19, P=4.6х10
-6
). Mendelian randomization analyses indicated higher BP to associate with increased risk for SCAD (beta
IVW-SBP
=0.05, P=7.6х10
-6
, beta
IVW-DBP
=0.10, P=1.9х10
-6
) and CAD (beta
IVW-SBP
=0.04, P=8.6х10
-49
; DBP: beta
IVW-DBP
=0.06, P=1.6х10
-44
) but not BMI, lipids, or type 2 diabetes, which we confirmed as genetic risk factors for CAD

Conclusions:
Our results set the stage for future investigation of novel biological pathways relevant to both SCAD and CAD and potential therapeutic and preventive strategies specifically targeting this ischemic disease predominantly affecting women.
Abstract 12701: Structural Abnormalities and Arrhythmias - A Genetic Perspective
Authors: Uppalapati LakshmiPriya , Wilsbacher Lisa D , whippo beth A , Vassallo Patricia
Published: June 2023

Introduction:
Bicuspid aortic valves (BAV) are the most common congenital cardiac defect, with a prevalence of 1-2%. Further, 75% of BAV patients develop thoracic aortic aneurysm, which carries a nine-fold greater risk of dissection than the general population. Some BAV cases include a heritable component illustrated by a family history of BAV, but the underlying genes remain incompletely described. Our institution routinely refers patients with BAV and ascending aortic aneurysm/dissection for genetic testing.

Clinical Case:
A 43-year-old man presented to the Emergency Department with altered mental status; workup revealed a BAV and Stanford Type A Aortic Dissection (TAAD) that was emergently repaired. He was referred for genetic testing for TAAD and BAV as an outpatient. Eleven weeks post-operatively, he experienced multiple episodes of asymptomatic non-sustained ventricular tachycardia (NSVT) during cardiac rehabilitation. Given new NSVT, a cardiomyopathy and arrhythmia panel were added to his TAAD genetic testing panel. Results showed a pathogenic variant in PKP2 (c.2146-1G>C); PKP2 is associated with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC). Genetic testing also revealed a risk allele for drug-induced long QT (KCNE1 c.253G>A [p.Asp85Asn]). No Pathogenic Variants or Variants of Uncertain Significance for BAV or TAAD were identified. Cardiac MRI showed no features of ARVC, and VT was not inducible during an electrophysiology study. Given lack of evidence of ARVC or inducible VT, an implantable loop recorder was placed rather than an ICD. The patient was counseled to inform providers of QT prolongation risk and recommend first-degree relative testing for pathologic mutations.

Conclusion:
Genetic testing panels should be selected based on the clinical history, and multiple panels may be indicated if multiple phenotypes emerge. Given the frequency of associated anomalies, such investigation can greatly enhance preventative care and mitigate future risk, particularly for conditions that can result in sudden cardiac death.
Abstract 12715: Role of Novel Long Non-Coding RNA BAZ1A-AS1 in Neointima Formation in Human Saphenous Vein Graft Disease
Authors: Kim David S , Cave Stephen , Greenway Jacob , Mundkur Rohan , Goo Brandee , Ahmadieh Samah , Harb Ragheb , Shi Hong , Shi Yang , Patel Vijay , Lee Richard , Long Xiaochun , Miano Joseph M , Kim Ha W , Weintraub Neal L
Published: June 2023

Introduction:
Saphenous veins (SVs) are frequently used in CABG surgery, but over 50% of the SV grafts fail in the first 10 years after surgery due to neointima formation. Long non-coding RNAs (lncRNAs) have emerged as attractive therapeutic targets and biomarkers for cardiovascular disease. However, studies on their role and mechanisms in humans are limited. This study aimed to unravel epigenetic mechanisms of neointima formation in human SVs and investigate the role of candidate lncRNAs in key vascular cell functions pertinent to neointima formation.

Methods and Results:
By using an
ex vivo
model of human SV graft disease wherein segments of human SV are incubated in tissue culture, we performed RNA-sequencing on human SV with and without neointima formation to interrogate the global transcriptomic changes, and determined 699 differentially expressed novel lncRNAs during neointimal formation. We then identified
BAZ1A-antisense (AS)1
as a novel lncRNA highly upregulated during neointima formation.
BAZ1A-AS1
overlaps antisense to its
cis-
regulatory gene,
BAZ1A
, which was reported to play a role in oxidative stress and DNA damage repair response. We found that one isoform of
BAZ1A-AS1
primarily localizes to the nucleus of VSMCs. Interestingly, UV exposure of vascular smooth muscle cells (VSMCs) isolated from human SV induced significant upregulation of
BAZ1A and
BAZ1A-AS1,
suggesting that
BAZ1A-AS1
could be associated with chromatin repair processes activated during neointima formation. To investigate whether
BAZ1A-AS1
can regulate VSMC functions pertinent to neointima formation, VSMCs were transfected with
BAZ1A-AS1
antisense gapmers. Knockdown of
BAZ1A-AS1
showed reduced cell proliferation and migration, and increased cell death and DNA damage in VSMCs. Furthermore, role of BAZ1A during neointima formation
in vivo
is currently under investigation in a carotid artery ligation model using BAZ1A knockout mice.

Conclusions:
We identified
BAZ1A-AS1
as a novel lncRNA associated with neointima formation in human SV, and targeted inhibition of
BAZ1A-AS1
or its cis-regulator gene
BAZ1A
could be a promising strategy for SV graft disease.
Abstract 12739: Evaluation of Quantitative Decision-Making for Rhythm-Management of Atrial Fibrillation Using Tabular Q-Learning
Authors: Barrett Christopher , Suzuki Yuto , Hussein Sundous , CERBIN LUKASZ , Sabzwari Syed Rafay Ali , Garg Lohit , Tumolo Alexis , Sandhu Amneet , West John , Zipse Matthew , Aleong Ryan G , Varosy Paul D , Banaei-Kashani Farnoush , Tzou Wendy , Rosenberg Michael
Published: June 2023

Introduction:
Rhythm-management is among the most complex decisions for patients diagnosed with atrial fibrillation (AF). While clinical trials have identified subsets of patients who might have a benefit from a given rhythm-management strategy, for individual patients it is not always clear which strategy is expected to have the greatest mortality benefit or durability.

Hypothesis:
Combined application of unsupervised machine learning and reinforcement learning can assist with optimizing individualized treatment strategies for patients with AF.

Methods:
In this investigation of over 50K subjects with a new AF diagnosis between the dates of October 11, 2010 and October 26, 2020, we examined the application of a type of artificial intelligence called tabular Q-learning to identify the optimal initial rhythm-management strategy, based on a composite outcome of mortality, change in treatment, and sustainability of the given treatment, termed the reward function.

Results:
We first applied an unsupervised learning algorithm using a variational autoencoder with K-means clustering to cluster AF patients into 8 distinct phenotypes, which matched what has been observed in clinical practice. We then fit a Q-learning algorithm to predict the best outcome for each cluster, in which we found that while a rate-control strategy was most frequently selected by treating providers, the outcome was superior for rhythm-control strategies across all cluster groups, with those subjects in whom provider-selected treatment matched what the Q table recommended having fewer total deaths [4 (8.5%) vs 473 (22.4%), Odds ratio = 0.32, P = 0.02] and a greater reward [-0.0115±0.26 vs -0.392±2.06, P = 4.8x10
-6
]. We then demonstrated application of dynamic learning by updating the Q table prospectively using batch gradient descent, in which the optimal strategy in some clusters changed from cardioversion to ablation, although the reward was greatest when the largest amount of data was used for model fitting.

Conclusions:
We found that tabular Q-learning provides a dynamic and interpretable approach to apply artificial intelligence to clinical decision making for AF. Further work is needed to examine application of Q-learning prospectively in clinical patients.
Abstract 12741: Effect of One Year of Exercise Training on Left Ventricular Relaxation in Patients With Stage B Heart Failure
Authors: Karaaslan Doruk , Sarma Satyam , Hearon Christopher , Dias Katrin A , Hieda Michinari , Levine Benjamin D , Macnamara James P
Published: June 2023

Introduction:
Left ventricular hypertrophy (LVH) is a risk factor for developing heart failure (HF). Exercise training decreases LV stiffness in individuals with LVH, but the effects of exercise training on LV relaxation in these individuals are unknown.

Methods:
Patients with LVH (> 11 mm) and elevated cardiac biomarkers (N-terminal pro- B-type natriuretic peptide [>40 pg/mL] or high-sensitivity troponin T [>0.6 pg/mL]) were randomized 2:1 to 1 year of monitored exercise training 4-5 days a week, including high intensity intervals, and 1-2 days of strength training or an attention control. Isovolumetric relaxation time (IVRT) was measured with pulse wave Doppler echocardiography and pulmonary capillary wedge pressure (PCWP) was consecutively measured with right heart catheterization before and after intervention. LV relaxation time constant, Tau, was estimated by Tau = IVRT / (Ln End-systolic pressure (ESP) - Ln PCWP)
(Figure).
Maximal oxygen uptake (VO
2
Max; Douglas bags) was measured with an incremental treadmill test. LV Stiffness was significantly improved in exercise arm, previously reported.

Results:
Thirty-one participants completed the study (Control: n=11, 51±6 years, 55% men, Exercise: n=20 53±6, 65% men). VO
2
Max increased by 18.2% in the exercise arm (2.2±0.6 L/min to 2.5±0.6, but not in controls; group x time p<0.001). Exercise training did not change Tau (exercise 38.2±6.5 to 39.8±8.7 ms) compared to control(40.3 ± 5.9 to 39.2±6.8 ms, group x time p = 0.84,
Figure
). Exercise training resulted in no significant changes in IVRT (p = 0.35), SBP (p=0.89) or PCWP (p=0.69).

Conclusions:
In patients with LVH at risk for HF, one year of high intensity exercise training did not improve LV relaxation despite significant improvement in ventricular stiffness and exercise capacity. These results suggest the primary mechanism for HF risk reduction with exercise training is by lowering LV stiffness, and not necessarily altering LV relaxation.
Abstract 12760: Microvascular Endothelial Dysfunction in Postural Orthostatic Tachycardia Syndrome Associated With Post-Acute Sequelae of COVID-19
Authors: Mahdi Ali , Reistam Ulrika , Nickander Jannike , Fedorowski Artur , Desta Liyew , Nygren-Bonnier Malin , Runold Michael , Bruchfeld Judith , Pernow John , Stahlberg Marcus
Published: June 2023

Introduction:
Post-acute sequelae of COVID-19 (PASC) is a novel clinical syndrome. We have previously reported that PASC patients can develop postural orthostatic tachycardia syndrome (POTS) and that COVID-19 induce microvascular endothelial dysfunction in acutely ill, hospitalized patients, that persist up to four months post discharge. Whether microvascular endothelial dysfunction contributes to POTS pathophysiology in PASC remains unclear.

Hypothesis:
Patients with PACS combined with POTS have impaired microvascular endothelial function.

Methods:
PASC patients (n=44) with mild SARS-CoV-2 infection (not hospitalized) were recruited from the post-COVID multidisciplinary clinic at Karolinska University Hospital. PASC diagnosis was based on the WHO PASC criteria. POTS was diagnosed in 21 patients (PASC + POTS) while 23 had a negative head-up tilt test (PASC - POTS). Age- and gender-matched healthy subjects (n=15) served as controls. Microvascular endothelial function was quantified as reactive hyperemia index (RHI) determined from the changes in pulse amplitude tonometry before and after a 5 min episode of arterial occlusion. Stress-perfusion cardiac magnetic resonance imaging (cMRI) with adenosine was performed in a subset of patients.

Results:
Mean age was 42±11 years and 95 % were women among PACS patients. Time from COVID-19 symptom onset to study inclusion was 18±3 months. RHI was significantly lower in PASC + POTS than in healthy controls and PASC - POTS (Figure 1). The prevalence of cardiac microvascular dysfunction on cMRI did not differ between the PASC groups (8% in PASC + POTS vs. 13% in PASC - POTS, p=1.00). All subjects with microvascular dysfunction on cMRI except one had a RHI below the cutoff (1.67) indicating microvascular dysfunction.

Conclusions:
Microvascular endothelial dysfunction is common in patients with PACS-associated POTS and may cause stress-induced myocardial ischemia up to 18 months after a mild primary infection.
Abstract 12770: Immune Checkpoint Inhibitor Induced Myocarditis: An Interesting Case of Reversible Complete Heart Block
Authors: Sharifi Sasha , jaikumar likhitesh , Smith Christopher , Menon Vivek , Chib Anjula , Gangadharamurthy Dakshin , JAGTAP DO MANDAR , Volansky Paul
Published: June 2023

BACKGROUND:
Immune checkpoint inhibitors (ICI) have changed the treatment scope for malignancies. The mechanism of ICIs is targeting of immune checkpoints that can suppress a response to a stimulus which can effect any organ. Adverse effects are usually mild but myocarditis, although rare, is becoming more recognized as a life threatening entity. The increase in mortality seen with ICI-induced myocarditis is more frequent with combination therapy. Most cases of ICI-induced myocarditis are limited to direct myocardial injury but there is a lack of evidence regarding conduction disease.

CASE DESCRIPTION:
We present a 74-year-old man with known metastatic malignancy recently started on ICI with ipilimumab and nivolumab who presented with complaints of abdominal pain, SOB and chest pain. His ED workup was consistent with colitis and acute PE without RV strain. Troponins and BNP were elevated and his ECG showed 3rd degree AV block. A coronary angiogram was negative for obstructive CAD and a temporary trans-venous pacemaker was placed. Cardiac MR showed LGE with active inflammation of the mid-myocardium. The patient had complex presentation as a side effect of ICI leading to myocarditis, 3rd degree AV block, colitis and PE. He was started on high dose methylprednisolone 1gm daily. Within 24 hours there was improvement evidenced by intermittent return of intrinsic conduction. At 48 hours there was marked improvement with restoration of sinus rhythm without evidence of AV block and/or use of the temporary pacemaker.

Discussion:
Early recognition of disease processes is difficult when there is minimal data to support a cause and effect. Increasing clinical awareness regarding adverse effects of ICI is paramount in decreasing the risk for unnecessary therapies, in our case, placement of a permanent pacemaker. Although there have been case reports of ICI-induced myocarditis, there has not been expert consensus regarding management of conduction pathway abnormalities.
Abstract 12773: Computed Tomography Angiography Evaluation of Coronary Plaque Burden in South Asians and Non-Hispanic Whites Over 65 Years of Age
Authors: Manubolu Venkat S , Verghese Dhiran , Alalawi Luay , Aldana-Bitar Jairo , Kinninger April , Crabtree Tami , Seok Hoon J , Susarla Shriraj , Hamelynck Hollin , Tan Katelyn , Roy Sion , Min James K , Earls James , Budoff Matthew
Published: June 2023

Introduction:
South Asians (SA) have greater atherosclerotic cardiovascular disease (ASCVD) rates than non-Hispanic whites (NHW). SA ethnicity is a risk factor for cardiovascular disease, according to ACC/AHA guidelines. However, data on pattern of atherosclerosis in SA is limited. This study examines plaque burden in SA using quantitative plaque analysis from coronary CT angiography (CCTA).

Methods:
This is a cross-sectional study comparing the prevalence of atherosclerosis in SA to that of NHW. We identified 104 South Asians who underwent CCTA and quantitative plaque analysis. We then matched 1:1 with 104 non-Hispanic whites. Age, gender, diabetes, hypertension and smoking were utilized to perform a 1: 1 covariate match. Quantification of coronary plaque was conducted using automated plaque analysis software (Cleerly, NY, NY). Percentage atheroma volume (PAV), which is a measure of total plaque divided by total vessel volume, was calculated for each plaque subtypes.

Results:
A total of 208 subjects formed the study population. The mean age was 71.2±4.9, 66% being male, 38% had DM, 72% reported hypertension, and 10% were past smokers in each group. The SA cohort had significantly higher calcified plaque PAV compared to NHW cohort, median (IQR), 7.6(1.9, 15.5) versus 3.9(1.3, 9.6), (p=0.027). Noncalcified plaque PAV was higher in SA 5.2 (3.0, 7.9) versus 4.5 (2.6,7.2), but not statistically significant (p=0.35). The number of subjects with obstructive disease (>50% stenosis) trended higher in the SA cohort (71% of SA versus 60% of NHW) (p=0.08).

Conclusions:
South Asians had significantly higher calcified plaque PAV and a higher prevalence of obstructive disease compared to the NHW cohort. These results are suggestive of a unique plaque burden and distinctive characteristics in the SA population, which may explain the greater incidence of cardiovascular events and supports the current guidelines.
Abstract 12775: The Major Contribution and Characteristics of Smooth Muscle Cell Foam Cells in Human Atherosclerotic Lesions Based on Flow Cytometry and Single Cell RNA Sequencing
Authors: Allahverdian Sima , Blanchard Valentin , Sahin Basak , Ollivier Veronique , MICHEL Jean-Baptiste , Francis Gordon A
Published: June 2023

Background and Aims:
Smooth muscle cells (SMCs) comprise the majority of cells within human atherosclerotic intima. Our previous study of human coronary atherosclerosis found that ≥50% of foam cells are of SMC origin and not primarily of macrophage origin as previously thought. In a recent investigation we reported that ~70% of all foam cells in ApoE-/- mice fed a Western Diet for 6 weeks are SMC-derived. In the current investigation we utilized flow cytometry and single-cell RNA sequencing to study the contribution and characteristics of SMC-derived foam cells in human atherosclerotic plaques.

Hypothesis:
SMCs comprise the majority of foam cells in human atherosclerosis and SMC foam cells have a unique gene expression pattern compared to macrophage foam cells.

Methods:
Formalin-fixed coronary and aortic samples were digested, stained with the lipid dye BODIPY and CD45 antibody and separated into CD45+ (leukocyte) and CD45- (non-leukocyte) foam cell and non-foam cell populations using flow cytometry. Pieces of fresh human coronary artery with adventitia removed were subjected to gentle digestion and isolated cells used for single-cell RNA Sequencing (n=3) using 10X Genomics Chromium Single Cell 3’ Reagent Kits v3 Technology.

Results:
Flow cytometric analysis indicates that approximately 65% of total foam cells of human coronary and aortic atherosclerotic lesions are of non-leukocyte origin. Unsupervised Seurat-based clustering (R version 4.2.0) singled out multiple cell clusters including SMCs, leukocytes, and endothelial cells in all 3 samples. Combining data resulted in identification of 15 distinct clusters including 8 SMC clusters ranging from well-differentiated to varying degrees of dedifferentiation. Combining multiple markers identified by in vitro and in vivo studies of SMC foam cells we were able to identify 2 possible SMC foam cell clusters with gene expression patterns distinct from macrophage foam cells.

Conclusions:
Our findings further identify SMCs as the major contributors of foam cells in atherosclerosis, and provide novel tools to investigate the nature of SMC foam cells in human atherosclerosis and their responses to anti-atherosclerotic therapies.
Abstract 12789: Time-Dependent Changes in Mitochondrial Properties and Function in Dogs During Electrically Maintained Atrial Fibrillation
Authors: qi xiaoyan , Xiao Jiening , Xiong Feng , Nattel Stanley
Published: June 2023

Introduction:
Atrial fibrillation (AF) causes atrial remodeling, leading to progressive resistance to therapy. Changes in cell metabolism likely contribute to remodeling; here, we studied the nature and time course of mitochondrial (MITO) changes during AF
. Methods:
Atrial cardiomyocytes were isolated from control dogs and dogs kept in AF for 24 hrs, 3 days, 1 and 3 wks by atrial tachypacing at 600 bpm (N=10/group). MITO were visualized with transmission electron microscopy. [Ca
2+
]
Mito
(Rhod-2 AM), MITO ROS production (MitoSOX), membrane potential (αψ, JC-1), mPTP opening (TMRM) and FAD autofluorescence were measured via confocal microscope, NADH autofluorescence was determined under UV light. Protein expression was assayed by western blotting.

Results:
MITO elongation occurred following 24-hr and 3-day AF, while 3-week AF induced MITO fragmentation, rupture and shrinking (A). MITO fusion protein (MFN1) decreased from 3 days to 3 wks of AF and fission protein pDRP1ser-616 was increased at 1 and 3 wks of AF, potentially accounting for MITO fragmentation. [Ca
2+
]
Mito
increased progressively with AF-time (B). MITO ROS production increased at 24 hr AF, and remained elevated from 3 days to 3 wks of AF (C). SOD2 was reduced after 3 days AF. NOX4 expression was increased at 3 wks AF. mPTP opening frequency and duration increased progressively during AF (D). AF increased JC-1 fluorescence, indicating depolarized αψ, beginning 24 hours after AF-onset (E). NADH increased by 15% at 24 hr AF, and then decreased progressively with AF-time (F). FAD was decreased during AF. Mitotempo (5-μM) reversed AF-induced atrial-cell I
CaL
downregulation (G) and reduced triggered activity (H).

Conclusions:
MITO are activated early during AF, but then show progressive changes likely due to ROS autotoxicity. MITO dysfunction and impaired bioenergetics may contribute to AF maintenance/ progress. MITO-targeted antioxidant intervention may have potential as a novel therapeutic approach for AF.
Abstract 12791: Examining the Association Between Socioeconomic Factors and Left Ventricular Ejection Fraction Declines in Breast Cancer and Lymphoma Survivors Receiving Doxorubicin: WF-98213
Authors: Sutton Arnethea L , O'Connell Nathaniel S , Lucas Alexander R , Franco Robert L , Reding Kerryn W , Kim Youngdeok , Cheng Richard , Sheppard Vanessa B , Weaver Kathryn E , Lesser Glenn J , Hundley William G
Published: June 2023

Introduction:
Breast cancer and lymphoma survivors who have received doxorubicin are at risk of experiencing a decline in left ventricular ejection fraction (LVEF), yet whether socioeconomic factors further impact this decline is unknown.

Methods:
We performed a secondary analysis of data from a double-blinded clinical trial (NCT01988571) in breast cancer and lymphoma survivors that determined the impact of statin use on LVEF 6- and 24-months following initiation of doxorubicin. LVEF was measured via magnetic resonance imaging. Socioeconomic factors were collected via survey. Linear regression models assessed relationships between socioeconomic variables and change in LVEF from baseline to 24 months by individuals blinded to treatment group.

Results:
Of the 279 survivors included in this analysis, a majority were white (82.8%) (13.6% Black, 3.6% other races), college educated (56.3%), and employed (63.8%). Mean LVEF at baseline was 62.2% (SD=6.01) and mean LVEF declines at 6- and 24-months were 4.72% (SD=7.30) and 5.11% (SD=7.20), respectively. In the multivariable model, after controlling for age, race, body mass index, and smoking, patients who made >$75k per year had a significantly smaller LVEF drop (3.36, 95% CI: -0.53, 7.25) at 6-months than patients making less than <$35k per year (8.66, 95% CI: 4.87, 12.45),
p
=0.003. Employed patients making >$75k per year had significantly smaller LVEF declines (mean=5.00, 95% CI: 0.14, 9.86) than employed patients making less than 35k per year (mean=9.43, 95% CI: 4.30, 14.56), p=0.033. Lastly, employed patients making >75k had a marginally significantly lower EF drop than unemployed patients making >75k per year (mean=7.83, 95%CI: 3.32, 12.34), p=0.092. These findings occurred independent of statin use.

Conclusions:
Findings from this study highlight a need to understand how one’s socioeconomic status (SES), or in terms of social determinants of health, economic stability, may serve as a protective factor regarding LVEF decline during treatment with doxorubicin for breast cancer and lymphoma. Future work should also consider examining the association between SES and care delivery and how that may potentially impact LVEF decline.
Abstract 12796: An Unusual Case of Rapidly Progressive Severe Bioprosthetic Aortic Valve Stenosis: A Valve-In Valve Tavr Experience
Authors: Sanchez-Nadales Alejandro , Iddrisu Muftawu-Deen , Uppal Dipan , Lewis Antonio , Novaro Gian M
Published: June 2023

Case Presentation
69-year-old male with chronic HFrEF and VHD secondary to infective endocarditis in 1981; severe AR with SAVR in 2016 (Bioprosthetic Edwards Perimount size #25) who presented with worsening shortness of breath. Initial assessment with hypotension and crescendo-decrescendo holosystolic murmur (Grade V/VI). Shortly after admission, he had one episode of pulseless monomorphic VT. Laboratory showed NT Pro-BNP at 2,780 pg/mL. TTE: LVEF of 25% and severe AS (peak gradient 75 mmHg, mean gradient 47 mmHg, and dimensionless valve index: 0.16 cm/m
2
) (A). TEE confirmed severity of AS caused by prosthetic valve thickening and calcification (B-C). A post-SAVR TTE in 2017 showed normal EF and valve gradients. Right heart catheterization was significant for a peak gradient: 61 mmHg, mean gradient: 45 mmHg, and aortic valve area of 0.59 cm
2
. After multidisciplinary evaluation our patient underwent a valve-in-valve (ViV) TAVR (Evolut Pro Plus prosthetic valve, size #29) and ICD implantation for secondary prevention. Post-procedure TTE showed normal bioprosthetic valve function with dimensionless valve index of 0.4 cm/m
2
. Rest of hospital stay was uneventful with rapid resolution of symptoms

Discussion
Prosthetic valve restenosis is a common complication of aortic valve repair but this is expected to develop at around 10-15 years following implant, early bioprostetic valve dysfunction is commonly related to valve thrombosis, in this case a TEE and pre-operative CT failed to showed findings of thrombosis. Patient was deemed high risk for a repeat SAVR based on comorbidities and hemodynamic instability at presentation (STS risk stratification: 7.4% risk of mortality). A ViV TAVR was considered as a viable option, with a pre-procedural gated CTA showing favorable valve morphology (D)