bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14939: Changes in Estimated Glomerular Filtration Rate After Retransplantation in Children and Young Adults
Authors: Chan Melvin , Silveira Lori , Patterson Daniel J , Bock Margret E , Pietra Bill A , Everitt Melanie D , SIMPSON KATHLEEN E , Miyamoto Shelley D , Auerbach Scott R
Published: June 2023

Introduction:
Estimated glomerular filtration rate (eGFR) is abnormal in pediatric heart transplant (HT) patients with graft failure due to hemodynamic compromise and exposure to nephrotoxins. We aimed to evaluate differences in eGFR between primary HT (PT) and repeat HT (RT) in children and young adults. We hypothesized that eGFR will recover to baseline after HT, but RT will tend to have lower eGFR than PT.

Methods:
We reviewed all HT at our center from 1995-2021. eGFR was derived from the CKid U25 equation. eGFR was measured pre-HT, 1 week post-HT (peak creatinine), 1-3, 6, and 12 months post-HT, and most recent follow-up. We matched PT with RT patients based on age at HT, sex, and race. Changes in eGFR were measured within and between patients using a linear mixed effect model. Additionally, changes in eGFR were stratified between those with pre-HT eGFR < 60mL/min/1.73m2 and >= 60mL/min/1.73m2. We evaluated for associations between changes in eGFR and the number of rejections prior to RT, diagnosis, pre-HT eGFR, dialysis, prior VAD/ECMO support, waitlist time, bypass time, ischemic time, length of stay, time from HT, graft loss, and nephrotoxin exposure.

Results:
RT was performed in 47 patients (early death N=1).
Table 1
shows characteristics of the matched PT (n=36) and RT (n=36) cohort.
Figure 1
compares PT and RT mean eGFR at the specified time points. Those with a pre-retransplant eGFR < 60mL/min/1.73m2 rebounded to levels significantly higher than pre-retransplant (p< 0.001). RT eGFR was lower than PT eGFR, but RT eGFR rebounded to levels significantly higher than prior to RT (p<0.001). There were no associations between changes in eGFR and bypass time, ischemic time, length of stay, or graft loss.

Conclusions:
eGFR falls transiently early after both PT and RT but rebounds back to baseline in PT or above baseline in RT. These findings help to characterize expected changes in renal function after PT and RT and guide expectations for renal recovery afterwards.
Abstract 14960: Mutation to Troponin Inhibitor3 Switch Domain Causes Restrictive Cardiomyopathy by Reducing Sensitivity to Beta-Adrenergic Stimulus
Authors: Duran Jason M , Manso Maria , Bushway Paul , Kao Kerry , WANG Tsui-Min , Maisel Sofie , Gu Yusu , Fong Joshua , Chen Chao , Soto-Hermida Angel , cruz marina , Feng Wei , Cho Yoshi , Bogomolovas Julius , Ross Robert S , Chen Ju , Makarewich Cat A , McCulloch Andrew D , Regnier Michael , Adler Eric D
Published: June 2023

Introduction:
Troponin inhibitor3 (
TNNI3
) is a thin-filament protein that regulates contraction of thick filaments. The role of the switch domain of
TNNI3
(aa147-163), which interacts with the calcium-binding pocket of troponin C, is poorly defined. Pathogenic mutations to the switch domain cause restrictive cardiomyopathy in humans, but no therapies exist that address the underlying problem of this mutation at the sarcomeric level. Further, few models of genetic restrictive cardiomyopathy exist to aid in development of new therapies.

Hypothesis:
Substitution of alanine with valine at position 157 (A157V) in the switch domain of
TNNI3
causes restrictive cardiomyopathy by blunting response to adrenergic stimulus.

Methods:
A known pathogenic mutation to the
TNNI3
switch domain (A157V) was identified in a family of patients with cardiomyopathy and restrictive features. A mutant knock-in mouse homozygous for this mutation (A157V) was generated using CRISPR-Cas9 and used to elucidate the function of the switch domain.

Results:
Compared to wild type controls (WT), mutant A157V mice demonstrate significant restrictive features on invasive hemodynamics that worsen with age but do not show evidence of systolic dysfunction or hypertrophy on echocardiography. Heart size and myocyte cross-sectional area were significantly smaller in mutant A157V mice compared to WT controls. Molecular dynamics simulations revealed reduced
TNNI3
activation in response to PKA-mediated phosphorylation at serine23/24. Isolated myocytes from A157V mice demonstrated impaired relaxation, lower peak systolic calcium and delayed reuptake of calcium into the sarcoplasmic reticulum compared to WT controls.

Conclusions:
The A157V mutation to the switch domain of
TNNI3
, a critical regulatory domain that interacts with the calcium binding pocket of troponin C, causes diastolic dysfunction by impairing responsiveness to PKA-mediated phosphorylation of S23/24. This mouse model recapitulates the key restrictive features of human disease and could be used as a platform to study future targeted therapeutics for thin filament cardiomyopathy.
Abstract 14973: Upregulated Sphingosine-1-Phosphate Receptor 3 Disrupts Endothelial Cell Barrier and Mitochondrial Network Dynamics
Authors: Wu Jialin , Liang Ying , Sun Xutong , Lu Qing , Tieu Kim , Black Stephen M , Wang Ting
Published: June 2023

Introduction:
Ventilator-Induced Lung Injury (VILI) exacerbates existing Acute Lung Injury (ALI) of ICU patients via mechanical ventilation. However, the cellular and molecular mechanism behind VILI is still poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive lipid which usually enhances vascular endothelial barrier via S1P receptor 1 (S1PR1) to protect against ALI. VILI associated mechanical stress reduces S1PR1 while increases S1P receptor 3 (S1PR3) expression. S1PR3 couples to Rho, a central regulator of cytoskeleton and mitochondrial network dynamics. Therefore, the upregulation of S1P-S1PR3 pathway is highly likely to be involved in the deterioration of endothelial barrier and mitochondrial function during VILI.

Methods and Results:
Cyclic stretch (18%) significantly increased S1PR3 levels (1.85±0.12 fold, n=3, p<0.05) in human lung endothelial cells (EC). After S1PR3 overexpression (S1PR3 OE), EC basal resistance was reduced (62.8±4.3%, n=8, p<0.05) in ECIS experiments. Moreover, S1P (100 nM) increased 37.2±4.1% resistance in control cells (n=5, p<0.05), while decreased 32.0±3.2% resistance in S1PR3 OE cells (n=5, p<0.05). In contrast to S1P-induced junctional distribution of VE-cadherin in control cells, S1P failed to cause any VE-cadherin junctional redistribution in S1PR3 OE cells as shown by Immunofluorescence (Fig. 1). We further confirmed that S1PR3 OE suppresses VE-cadherin expression in human ECs by western blot. In addition, in S1PR3 OE cells, S1P challenge induced an increased mitochondrial ROS release as shown by MitoSOX assay (6.87±1.10 fold, n=3, p<0.05) and a mitochondrial fission phenotype that was not observed in control cells.

Conclusions:
VILI associated mechanical stress upregulates S1PR3, leading to the reprograming of endothelial cell cytoskeleton regulatory machinery and mitochondrial network dynamics. S1PR3 might be a promising target to ameliorate the damage caused by mechanical ventilation.
Abstract 15016: Inferior ST Segment Depression Identifies Proximal Left Anterior Descending Culprit Lesions in Anterior ST Elevation Myocardial Infarction
Authors: Anyanwu Brian , Mariano Sim Berlene , Shen Miles , He Lefan , Ghosh Bobby D , Chaudhary Ashok , Kassotis John , Coromilas James
Published: June 2023

Introduction:
Anterior wall ST elevation myocardial infarction (STEMI) is caused by occlusion of the left anterior descending (LAD) coronary artery. Proximal LAD occlusions are associated with larger infarcts and more complications. However, there is limited data demonstrating a relationship between ECG changes and the location of the LAD culprit lesion.

Objective:
To determine if patterns of ST elevations (STE)/depressions (STD) on the 12 lead ECG can predict if the culprit lesion in an anterior STEMI is in the proximal LAD.

Methods:
We performed a retrospective chart review of ECGs obtained from a database of patients diagnosed with myocardial infarction at Robert Wood Johnson University Hospital from January 2009 to December 2016. Lesions, defined as proximal or non-proximal with respect to the first diagonal of the LAD, were assigned according to the Bypass Angioplasty Revascularization Investigation (BARI) Protocol. Each lesion was assigned to one of the 4 ECG patterns described in Table 1. An analysis of variance was used to determine if the difference in ECG characteristics between groups was significant.

Results:
Of 447 ECGs denoted as anterior wall STEMIs, 227 met inclusion criteria. In total, 104 lesions were defined as proximal and 123 were non-proximal. There was a difference in the ECG pattern of proximal versus non-proximal culprits category (p = 0.006). Proximal culprit lesions were more likely to have STE in the precordial leads combined with STD in the inferior leads, whereas non-culprit lesions were more likely to have STE in the precordial leads without any STE or STD in the limb leads.

Conclusions:
In anterior STEMIs, proximal culprit lesions were more likely to exhibit ST elevations in precordial leads and ST depressions in inferior leads, compared to non-proximal culprit lesions, which were more likely to have ST elevations in only the precordial leads. Concomitant STE in lateral leads without inferior STD did not distinguish between the 2 groups.
Abstract 15034: Prediction of Imminent Out-of-Hospital Sudden Cardiac Arrest Based on Warning Symptoms
Authors: Reinier Kyndaron , Dizon Bernadine , Chugh Harpriya , Bhanji Ziana , Seifer Madison , Grogan Tristan , Elashoff David , Sorenson Chad , Sargsyan Arayik S , Uy-Evanado Audrey , Norby Faye L , Salvucci Angelo , Jui Jonathan , Chugh Sumeet S
Published: June 2023

Introduction:
At least 50% of individuals with sudden cardiac arrest (SCA) have warning symptoms. However, such symptoms are also commonly experienced in the community. Comparisons with a control group, currently unavailable, are needed to establish utility of these symptoms for prediction of imminent SCA.

Hypothesis:
Symptoms documented by emergency medical services (EMS) prior to SCA vs. other 911 calls are distinct.

Methods:
We performed a case-control analysis from the ongoing Ventura, CA PRESTO study. Cases (ages 18-85) had witnessed SCA attended by EMS (2015-2021). SCA was defined as a sudden, unexpected pulseless condition of likely cardiac origin. Controls were identified from 911 calls that required transport by Ventura County EMS for emergency care but were not SCA. All cases and controls were required to have at least one symptom recorded by EMS that has been previously associated with acute coronary syndrome or SCA (Figure).

Results:
Among 553 witnessed cases with detailed EMS narratives, 411 (74%) had at least one inclusion symptom (mean age 66 y, 31% female). From a random subset of eligible EMS calls (n=2,794), 1171 controls had ≥1 symptom (mean age 61 y, 55% female). Among cases, dyspnea (41%) and chest pain (33%) were most common; prevalence of other symptoms was <15%. Compared to controls, odds of chest pain, dyspnea, diaphoresis, and seizure-like activity were ≥45% higher in cases (p<0.01) (Figure). Controls’ symptoms were less specific (nausea/vomiting, weakness, dizziness, abdominal symptoms), and palpitations (p<0.01) (Figure). The sensitivity of chest pain (0.33) and dyspnea (0.41) for prediction of SCA was low, but specificities were higher (0.75 and 0.78, respectively).

Conclusions:
The prevalence of warning symptoms differed significantly between SCA cases and controls. However, sensitivity of individual symptoms was low; additional factors should be investigated to combine with warning symptoms to improve prediction of imminent SCA.
Abstract 15059: Effects of Cigarette Smoke on Inflammation and Atrial Fibrillation
Authors: Sirish Padmini , Diloretto Daphne , Kiaii Bob , Chiamvimonvat Nipavan
Published: June 2023

Introduction:
Cigarette smoking is a major risk factor for occurrence and progression of several cardiovascular diseases. Smoking is associated with an increased risk of Atrial Fibrillation (AF). AF is an extremely common cardiac rhythm disorder that is associated with substantial morbidity and mortality. One of the main contributors for the initiation, progression and persistence of AF is inflammation. Cigarette smoke (CS) is known to increase inflammation. CS is known to increase pro-inflammatory cytokines and AF progression is associated with increased levels of these pro-inflammatory cytokines. Therefore, it is of great clinical importance to elucidate the underlying mechanisms contributing to smoking induced inflammation. The amplification of the pro-inflammatory cytokines is mediated by
inflammasome
and recently, the direct involvement of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain containing protein 3), inflammasome and AF has been demonstrated in patients with AF. The central hypothesis to be tested is that patients with AF and exposed to CS will demonstrate a heightened inflammation through the activation of NLRP3 inflammasome compared to patients in normal sinus rhythm (NSR) and non-smoking AF patients.

Methods:
Human atrial tissues and blood were obtained from patients undergoing coronary artery bypass graft surgery at UC Davis Medical Center in accordance with the approved UC Davis IRB protocol. An integrated approach using molecular biology, flow cytometry, and electrophysiology was used to test the components of NLRP3 inflammasome, inflammatory cytokines and structural remodeling in smoking and non-smoking AF and NSR patients using blood and human atrial tissue.

Results:
Our results demonstrate a significant increase in protein expression of component of the NLRP3 inflammasome including NLRP3, ASC and Caspase-1 in smoking AF and NSR patients compared to non-smoking patients. There was a significant increase in inflammatory cytokines activated by the NLRP3 inflammasome, IL-18 and IL-1β in in smoking AF and NSR patients compared to non-smoking patients.

Conclusions:
Our study not only provides important mechanistic insights into the roles of inflammasome in AF patients exposed to CS
Abstract 15107: Comparative Therapeutic Efficacy and Mechanism of Stem Cells in Rat Myocardial Infarction Model
Authors: Gunasekaran Muthukumar , Mishra Rachana , Sharma Sudhish , Saha Progyaparamita , Krishnan Swetha T , Chen Ling , Guru Sameer A , Stefanowicz Artur , Bilewska Agata , Sinha Anshuman , Ciolak Emily , Ge Zhi-dong , Kaushal Sunjay
Published: June 2023

Introduction:
Successful cell therapy should be able to resist the hostile ischemic myocardium, should be retained for longer duration to continue secreting cardioprotective growth factors/exosomes and should not elicited immunological host response.

Hypothesis:
Analysis of 5 clinically relevant human stem/progenitor cells in a rodent model of acute myocardial infarction demonstrated that neonatal cardiac mesenchymal stromal cells (nMSCs) provide the strongest cardiac functional recovery.

Methods:
Cardiac functional outcome following nMSCs/aMSCs in rat MI model was measured by echocardiography. Transplanted cell retention,
in vivo
phagocytosis and CD68
+
cells was assessed by immunohistochemistry.
In vitro
phagocytosis analysis for aMSCs/nMSCs were performed with THP-1 derived macrophages. THP-1 differentiated macrophages were validated for the expression of CD68 and absence of CD31. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic analysis of nMSCs and aMSCs. CD47 expression in nMSCs was blocked by anti-CD47/ siRNA transections/lenti-virus expressing CD47 shRNAs approaches. CD47 knock down efficiency by siRNA and lenti-virus were validated by immunoblot. Isotype antibody, scrambled siRNA and lentivirus expressing empty vector served as control.

Results:
Transplanted nMSCs significantly increased the number of tissue reparative macrophages and regulatory T cells and significantly decreased monocyte-derived inflammatory macrophages and neutrophils. nMSCs also showed immune evasion in the host myocardium. mRNA microarray and single-cell analyses combined with targeted depletion studies established CD47 in nMSCs as a key molecule responsible for stem cell retention in the myocardium through an antiphagocytic mechanism regulated by miR34a-5p. Gain- and loss-of-function studies demonstrated that mir34a-5p regulated the production of exosomes and cardioprotective paracrine factors in the nMSC secretome.

Conclusions:
We conclude that the functional benefits of nMSCs are governed by a novel miR34a-5p pathway regulating immunomodulation, cell retention, exosome production, and cytokine secretion.
Abstract 15115: Causes and Predictors of 90-Day Readmission Among Patients Admitted With Acute Myocarditis
Authors: Vardar Ufuk , Atluri Ramtej , Murthi Mukunthan , Kumi Dennis , Shahi Anoj
Published: June 2023

Introduction:
Myocarditis contributes to the global burden of cardiovascular disease primarily through sudden death and dilated cardiomyopathy. We aimed to study patient characteristics, national readmission rates and predictors for patients admitted for acute myocarditis utilizing a nationally representative cohort of patients from the National Readmission Database.

Methods:
We utilized the National Readmission Database 2018 to identify the hospitalized adults with a primary diagnosis of acute myocarditis. We included subjects who were readmitted within 90 days after index admission. We excluded subjects with elective and traumatic admissions. We utilized a multivariate cox regression model to identify independent predictors of readmission.

Results:
During the study period, 3,524 hospitalized patients who had a primary diagnosis of acute myocarditis were discharged alive. Within 90 days of discharge, 356 (10.1%) subjects were readmitted. The top three causes of readmission were heart failure (37.1%), sepsis (16.1%) and ventricular tachycardia (10.6%). The in-hospital mortality rate (5.5 vs. 2.6%, p<0.001) was significantly higher during readmission. There was a trend in higher length of stay in readmission (5.6 vs. 4.3 days, p=0.055), however this difference was not statistically significant.
Figure 1
shows the Forest plot of multivariate analysis of independent factors associated with readmissions.

Conclusion:
Our study identified significant factors such as heart failure, atrial fibrillation, hypertension related to higher readmission odds for myocarditis patients. This data may contribute to the healthcare system to help modify strategies to minimize readmission.
Abstract 15134: Joint Associations of Fatty Acids With Inflammation and Lipid Profiles: A Mixture Analysis Approach
Authors: Riggs Daniel W , Gao Hong , Sears Clara G , McGraw Katlyn E , Bhatnagar Aruni , Hellmann Jason
Published: June 2023

Introduction:
The human diet consists of a complex mixture of fatty acids with differential effects on cardiovascular health. Saturated fatty acids have been shown to exert a hypercholesterolemic effect, while omega-3 polyunsaturated fatty acids have anti-inflammatory properties. Advanced statistical approaches are needed however to address whether their covarying relationships may contribute to varying outcomes on cardiovascular health.

Methods:
We used data on adult participants from the 2003-2004 and 2011-2012 National Health and Nutrition Examination Survey. Blood lipid levels were measured in 2,926 participants, and C-reactive protein (CRP) was measured in 1,339 participants. Fatty acids were measured in serum or plasma and analyzed as the percentage of total fatty acids. We used covariate-adjusted quantile g-computation to assess the joint effects of 6 saturated, 6 monounsaturated, and 11 polyunsaturated fatty acids on log-transformed outcomes, as well as examine the relative contribution of each fatty acid to the joint mixture effect.

Results:
We estimated positive associations between the mixture of saturated fatty acids with total cholesterol and LDL, which was primarily driven by myristic acid and docosanoic acid. The mixture of monounsaturated fatty acids was associated with lower total cholesterol and LDL, but higher CRP with a quartile increase in monounsaturated fatty acids associated with 21.1% (95% CI: 7.9, 35.9) higher CRP. The mixture of omega-6 polyunsaturated fatty acids was positively associated with both total cholesterol and LDL. We found that the mixture of omega-3 polyunsaturated fatty acids was negatively associated with CRP and LDL. A quartile increase in omega-3 fatty acids was associated with -11.6% (95% CI: -18.8, -3.7) lower CRP, and -2.1% (95% CI: -3.6, -0.4) lower LDL. The relationship with CRP was primarily driven by docosapentaenoic
n-3
acid and eicosapentaenoic acid, while the relationship with LDL was driven by docosapentaenoic
n-3
acid and docosahexaenoic acid.

Conclusions:
Assessing the complex mixture of fatty acids, we found distinct beneficial relationships between omega-3 fatty acids with inflammation and lipid profiles, with an important role of docosapentaenoic
n-3
acid.
Abstract 15185: BRD4-Mediated Genome Folding Controls Fibroblast Cell State Transition
Authors: Yang Rachel , Gardner Zachary , Koch-Bojalad Bailey , Kim Wonho , Nguyen Son C , Joyce Eric F , Padmanabhan Arun , Jain Rajan
Published: June 2023

Introduction:
Cardiac fibrosis is mediated by the activation of fibroblasts to myofibroblasts, a cell state transition which involves the coordination of expression of hundreds of genes. Previous studies have demonstrated that inhibition of bromodomain and extra-terminal domain (BET) proteins attenuates fibrosis. We recently discovered a novel role of bromodomain-containing protein 4 (BRD4), a BET family member, in maintaining genome folding by stabilizing the cohesin complex (necessary for genome-genome interactions). We hypothesize that BRD4-mediated genome folding is critical for maintaining the enhancer-promoter interactions at genes required for fibroblast activation.

Methods:
A cardiac fibroblast cell line was generated in which a degron epitope tag was appended biallelically to
Brd4
to enable acute BRD4 degradation. Fibroblasts were activated via addition of TGFβ.
Meox1
, a critical transcription factor mediating a broad fibrotic gene program, was used as a model locus to investigate chromatin looping. The proximity between the
Meox1
enhancer and promoter,
Meox1
expression, and protein occupancy at the locus were determined using DNA fluorescence in situ hybridization, RT-qPCR, and chromatin immunoprecipitation (ChIP)-qPCR, respectively.

Results:
The proximity between the
Meox1
enhancer and promoter and
Meox1
expression increased upon TGFβ-induced activation. BRD4 occupancy was enriched at the enhancer of
Meox1
upon activation, and BRD4 depletion reduced
Meox1
expression and the co-localization of the
Meox1
enhancer and promoter. BRD4 physically interacts with the cohesin agonist NIPBL, and we found that co-depletion of BRD4 and a cohesin antagonist normalizes the
Meox1
enhancer and promoter proximity and
Meox1
expression levels. Ongoing studies include genome-wide occupancy studies and expanding our findings to
in vivo
models of cardiac fibrosis.

Conclusions:
Our studies provide a mechanistic understanding of the functional relevance of genome organization during fibroblast activation. These studies will also expand our knowledge on how genome folding regulates cell plasticity and inform therapeutic approaches for targeting pathologic fibrotic remodeling.
Abstract 15252: Impact of Atrial Fibrillation on Patients With Carcinoid Syndrome: A National In-Patient Sample Analysis
Authors: Babbili Akhilesh , Thotamgari Sahith Reddy , Grewal Udhayvir , Thakre Anuj , Dominic Paari
Published: June 2023

Introduction:
Carcinoid heart disease is one of the major causes of mortality in patients with carcinoid syndrome. Although right-sided valvular dysfunction is well studied in carcinoid heart, there are limited data on the impact of atrial fibrillation (AF) on in-hospital mortality in these patients. We sought to assess the in-hospital outcomes in patients with carcinoid syndrome and a concurrent diagnosis of AF.

Methods:
We analyzed the National Inpatient Sample database from January 2016- December 2018 to identify hospitalizations for Carcinoid syndrome using the ICD 10 CM code E34.0. Study cohort was further divided into patients with and without AF. Chi-square test and multivariate logistic regression were used to analyze the association. All statistical analyses were performed using weighted values.

Results:
During the study period, 9320 hospitalizations with carcinoid syndrome were identified. Among these, 1430 (15.3%) had atrial fibrillation. Baseline characteristics and outcomes are shown in table 1. Patients with AF were older (71.8±9.8 vs 63.4±13.6, p<0.001) and had a higher Elixhauser comorbidity index (21.5±6.6 vs 17.6±6.5, p<0.001). AF is noted to be associated with significantly higher in-hospital mortality (OR 2.0, 95% CI 1.6-2.5, p<0.001), and respiratory failure requiring mechanical ventilation (OR 1.9, 95% CI 1.5-2.5, p<0.001). After adjusting for age, sex, race, and significant baseline comorbidities, AF was independently associated with higher in-hospital mortality (aOR 1.64, 95% CI 1.3-2.1, p<0.001*) and mechanical ventilation (aOR 1.88, 95% CI, 1.4-2.5, p<0.001*)

Conclusions:
Atrial fibrillation is associated with significantly higher in-patient hospital mortality and mechanical ventilation in patients with carcinoid syndrome. Further longitudinal observational studies are needed to validate these findings.
Abstract 15288: The Use of Cha2ds2-vasc Score to Predict Functional Outcomes of Mechanical Thrombectomy
Authors: Livesay James , Fogelson Benjamin , Stevens Shawna , Patel Chirag , Tahir Hassan , Dieter William , Wiseman Brian , Baljepally Raj
Published: June 2023

Introduction:
Mechanical thrombectomy is a widely used form of revascularization for ischemic strokes secondary to large vessel occlusions. Functional outcomes are typically assessed following mechanical thrombectomy using the modified Rankin scale. CHA
2
DS
2
-VASc score is commonly used to estimate the stroke risk of patients with atrial fibrillation, but there are a plethora of studies showing it can be used in various situations. Our study aimed to assess the utility of CHA
2
DS
2
-VASc score in predicting outcomes of patients undergoing mechanical thrombectomy.

Methods:
We performed a single center, non-randomized, retrospective study. The study included 448 patients that underwent mechanical thrombectomy for large vessel occlusion strokes. CHA
2
DS
2
-VASc score was calculated on each patient and the study population was divided into 3 groups based on CHA
2
DS
2
-VASc score (Score ≤ 2, Score 3-4 and Score ≥ 5). Association between CHA
2
DS
2
-VASc score and 90-day modified Ranking score and in-hospital, 30-day, and one year mortality was evaluated and compared between the three groups.

Results:
A total of 312 patients met criteria for the study. Patients in the high risk CHA
2
DS
2
-VASc score had a significantly higher modified Rankin score (4.48) when compared to low (2.57) and intermediate (3.82) groups (Image 1). Higher CHA
2
DS
2
-VASc scores were also associated with a significantly higher in-hospital, 30-day, and one year mortality.

Conclusion:
CHA
2
DS
2
-VASc score can predict worse functional and survival outcomes in patients undergoing mechanical thrombectomy for a large vessel occlusion. CHA
2
DS
2
-VASc score ≥ 5 was associated with higher modified Rankin score and mortality.
Abstract 15304: Apical Ballooning Syndrome in the Setting of Severe Chronic Obstructive Pulmonary Disease Exacerbation
Authors: Toquica Gahona Christian , Doukas Sotirios , Watts Abi , Santos Argueta Allan E , Raj Kavin
Published: June 2023

Apical ballooning syndrome (ABS), also known as Takotsubo cardiomyopathy, is a form of acute dilated cardiomyopathy associated with excessive catecholamine release. A 74-year-old female, chronic smoker with previously diagnosis of obstructive lung disease presented in the emergency department with severe shortness of breath and increase sputum production for the last 24hr. The patient was diagnosed with severe COPD exacerbation and received multiple doses of albuterol, methylprednisolone, ipratropium bromide/albuterol, and azithromycin. Despite this, the patient remained tachypneic and tachycardic with signs of impending respiratory failure. She was transferred to the ICU and intubated. After intubation, the patient received a continuous albuterol nebulizer, methylprednisolone, and ceftriaxone. A few hours later, the patient complained of chest pain, and EKG was done showing T wave inversion in lateral leads, troponin levels were 1.08 ng/mL (ULN 0.12ng/mL), and 2D Echo showed EF 50-55%, apical ballooning with dyskinesia, and inferior wall hypokinesis. Left heart catheterization showed non-obstructive coronary artery disease with 50% stenosis on the left anterior descending artery and distal ostial artery. Based on the previously recommended criteria, the diagnosis of the ABS was made. The patient had resolution of symptoms and echocardiogram findings after follow up. Although albuterol acts mainly on beta-2 receptors, cross-activation of beta-1 receptors can potentially lead to tachycardia. Previous case reports also support that excessive albuterol use in cases of asthma and COPD exacerbation may lead to ABS. This case may raise awareness that the extensive use of albuterol could have dramatic effects. Early switch to beta-2 agonist with higher specificity such as levalbuterol could be a reasonable approach in patients with severe COPD exacerbation.
Abstract 15329: Heart Failure is an Adverse Risk Factor for Peri-Procedural Complications in Patients Undergoing Pulmonary Vein Isolation and Ablation for Atrial Fibrillation
Authors: Kodali Mouna , Atluri Ramtej , Yalamanchili Sreeram , Vallabhaneni Meghana , Murthi Mukunthan , Velagapudi Sujitha
Published: June 2023

Introduction:
Percutaneous catheter ablation (PCA) for non-valvular atrial fibrillation (AF) is rapidly becoming commonplace for recently diagnosed paroxysmal AF. Heart failure (HF) and AF commonly coexist in patients. Elevated left ventricular and atrial pressures result in progressive left atrial dilation and remodeling which in turn predisposes to the generation of AF. Since many who undergo PCA for AF could have HF, we aimed to assess peri-procedural outcomes in this population.

Methods:
We utilized the National Inpatient Sample from 2016-2019 to identify 74,205 hospitalized adults who underwent PCA for AF. These hospitalizations were further stratified based on the presence of HF. A multivariate regression model was used to adjust for confounders and analyze the variables.

Results:
Of those who underwent PCA for AF, 33,435 (45%) had HF. In-hospital mortality was higher in those with HF (1.9% vs 1.14%; p=0.0001). Figure 1 shows the Forrest plot for multivariate analysis of peri-procedural complications when adjusted for patient demographics, co-morbidities, and hospital characteristics. When adjusted similarly, patients with HF who underwent PCA for AF had longer length of stay (LOS) by 1.5 days (p<0.001) and had additional hospital costs (HC) of $14,726 (p<0.001).

Conclusions:
In this study, patients undergoing Percutaneous catheter ablation (PCA) for AF with co-existing acute HF had significantly worse end points in terms of in-hospital mortality, LOS, HC, atrial flutter, AKI, sepsis, pneumonia, endotracheal intubation. One major limitation of our study is the lack of outpatient follow up. Although outcomes are worse in the acute setting of HF, there have been several studies such as CASTLE-AF, outlining that early ablation for AF in HF is associated with positive long-term effects including lower rates of death and hospitalization for HF. Despite unfavorable peri-procedural outcomes of HF in PCA, the long-term benefits should not be overlooked.
Abstract 15331: Epigenetic Interaction of Grk4 and Slc4a5 Variants Regulates Gene Transcription and Blood Pressure
Authors: Yaqub Daniel , Moore Shaun C , Polzin Jacob , Asico Laureano D , haile hanna , Armando Ines , Jose Pedro A
Published: June 2023

Salt sensitive hypertension is associated with variants of G protein-coupled receptor kinase 4γ (GRK4), as well as with activating variants of the solute carrier family 4 member 5 (rs7571842 and rs10177833; SLC4a5), which encodes the sodium bicarbonate transporter 2 (NBCe2). We tested the hypothesis that the effect of the R65L variant (rs2960306) of GRK4 (GRK4γ 65L) on salt-sensitivity involves a gene-gene interaction with SLC4a5 variants. We found that the renal expression of SLC4a5 is increased in salt sensitive transgenic mice expressing GRK4γ 65L and is higher (50%; n=4; P<0.02) than that in GRK4 γ expressing the wild type variant (WT). Moreover, that AAV9-mediated renal specific overexpression of SLC4a5 in GRK4γ 65L mice increases the blood pressure (BP) response to a high salt diet compared with mice expressing empty vector (n=3; P<0.05). We studied human renal proximal tubule cells (hRPTCs) endogenously expressing GRK4 WT and SLC4a5 WT, GRK4 65L, SLC4a5 variants and both GRK4 65L and SLC4a5 variants. SLC4A5 expression is increased in hRPTCs expressing GRK4 65L and in cells expressing both GRK4 65L and SLC4a5 variants (n=5, P<0.05) compared with GRK4 WT. GRK4 can interact with nuclear histone deacetylases (HDACs) and co-immunoprecipitates with HDAC1 in nuclear fractions of hRPTCs. Renal-selective downregulation of HDAC1 increases BP in C57Bl/6J (P<0.05) mice. hRPTCs carrying both GRK4 65L and SLC4a5 variants have decreased expression (60%; n=4; P<0.05) of HDAC1 compared with cells expressing GRK4 WT and SLC4a5 WT or GRK4 65L This correlates with increased histone H4 acetylation but unchanged H2A, H2B and H3 acetylation in cells carrying both variants. Our results indicate a complex interaction between these variants in the regulation not only of SLC4a5 expression but that of other genes involved in salt sensitivity.
Abstract 15338: The Essential Role of Fatty-Acid Binding Protein 3 in Endothelial Function
Authors: Nguyen Hien Chi , Bu Shuhan , Michels David , Nikfarjam Sepideh , Rasheed Berk , Qadura Mohammad , Singh Krishna
Published: June 2023

Background:
The endothelium lines blood vessel’s inner walls and interacts directly with the circulation, systemically influencing whole-body physiology through endothelial function. Fatty acid binding protein 3 (FABP3), abundant in myocardiocytes, serve as effective cardiac injury’s biomarkers when presented in circulation. Our lab has preliminary found that endothelial cells (ECs) express FABP3. The role of FABP3 in endothelial function and FABP3 exposure’s effects on ECs are unknown.

Objective:
Evaluate FABP3’s role in endothelial dysfunction.

Method:
Human umbilical vein endothelial cells (HUVECs) were grown under cell culture standards (370 C, 5% CO2) prior to treatment by lipopolysaccharide (LPS). FABP3 expression in treated HUVECs was evaluated by qPCR. Next, FABP3-silencing RNAs were transfected into HUVECs to knock-down FABP3 for 24 hours. HUVECs were also exposed to recombinant FABP3 as a gain of function model. HUVECs were then treated with LPS for 24 hours before subjected to molecular/phenotypic evaluation for aspects of endothelial function (migration, proliferation, angiogenesis, inflammation). The Delta-Ct method and One-way ANOVA with Tukey (HSD) test were used to analyze data from qPCR and comparisons between treatment groups, respectively; p-value < 0.05 is considered significant.

Results:
1) FABP3 is basally expressed in ECs, 2) LPS upregulated endothelial FABP3 expression; 3) loss of FABP3 protected ECs against LPS-induced endothelial dysfunction; FABP3 exposure exacerbated LPS-induced inflammation; 4) loss of FABP3 protects ECs against LPS-induced stress by promoting cell survival, anti-inflammatory and pro-angiogenic pathways.

Conclusions:
We identified the novel and basal expression of FABP3 in ECs and demonstrated that FABP3 influences endothelial function at both the molecular and phenotypic levels under stress in vitro. Loss- and gain- of endothelial FABP3 ameliorates and exacerbates LPS-induced endothelial dysfunction, respectively, by affecting cell survival and inflammatory and angiogenic pathways. Our findings suggest that circulating FABP3 may be detrimental to the endothelium; therefore, therapies aimed at inhibiting FABP3 may improve endothelial function in myocardial injury.
Abstract 15365: The Regulatory Role of Sirtuin 6 in Diabetic Cardiomyopathy
Authors: Wang Yang , Enrick Molly , Gadd James , Juguilon Cody , Clark Alyssa , Kolz Chris , Chilian William M , Zhang Yanqiao , Yin Liya
Published: June 2023

Introduction:
DCM is a complex disease with many possible causes and multifactorial pathophysiology, but its underlying mechanisms are poorly understood, and no specific therapeutic guideline has yet been established. Increasing evidence suggests that coronary microvascular dysfunction (CMD) might be one of the primary mechanisms in DCM development. CMD is characterized by impaired endothelial-dependent vasodilation, but detailed mechanisms have yet to be elucidated. Sirtuin 6 (Sirt6) has been implicated in obesity, insulin resistance, type 2 diabetes mellitus, and cardiovascular diseases. Sirt6 protects EC from premature senescence, oxidative stress, and atherosclerosis by sustaining high eNOS levels and preserving cell replication. How Sirt6 regulates coronary microvascular function remains to be determined.

Methods:
Inducible Sirt6 global knockout, endothelial-specific knockout, and wild-type (WT) mice were fed a diet high in fat and sugar (HFHS), and blood lipid and glucose were measured. Coronary arteries were isolated, and endothelial-dependent vasodilation (EDD) was assessed using myography (DMT). Echocardiography and treadmill exercise exertion tests were performed to evaluate cardiac function. Myocardial blood flow (MBF) was measured by doppler. Cardiac fibrosis was detected using trichrome staining, and molecular pathways were elucidated via gene and protein analysis.

Results:
Our preliminary data show that Sirt6 was downregulated in diabetes. The EDD of coronary arterioles Sirt6 global knockout and endothelial-specific knockout treated with HFHS was impaired, and the mediator of coronary vasodilation switched from NO to H
2
O
2
in the Sirt6 knockout mice. Compared to the WT mice, myocardial blood flow was decreased, ejection fraction (EF) was not changed, the running distance was reduced, and E/E’ ratio was increased in Sirt6 knockout mice. The Sirt6 targeted proteins were identified.

Conclusions:
Our suggest Sirt6 regulated coronary microvascular function through endothelial cells, and ablation of Sirt6 in endothelial cells caused CMD and diastolic dysfunction. Further genetic profiling will elucidate the pathways and mechanisms converging with Sirt6 to regulate microvascular function.
Abstract 15431: Engineered Nanovesicles With Microrna-126 Cargo Improve Cardiac Repair After Myocardial Infarction in a Rat Ischemia-Reperfusion Model
Authors: Bheri Sruti , Brown Milton E , Park Hyun-Ji , Hoffman Jessica , Davis Michael E
Published: June 2023

Introduction:
Ckit+ progenitor cells (CPCs) produce small extracellular vesicles (sEVs) which are pivotal for CPC-based cardiac repair after myocardial infarction (MI). sEVs encapsulate potent RNA cargo within a bilayer membrane which aids with sEV uptake. However, despite established benefits, sEV therapies are limited by inconsistent sEV release from cells and variable cargo encapsulation. Further, although synthetic sEV mimics allow cargo tunability, they suffer rapid clearance when administered. We have developed an sEV-like vesicle (ELV) which maintains an sEV-like membrane, important for efficient uptake, but allows cargo control like that of sEV-mimics. We
hypothesize
that ELVs with proangiogenic microRNA (miR) cargo improve cardiac repair in a rat ischemia-reperfusion (IR) model compared to sEVs and that this occurs in a dose-dependent manner.

Methods:
sEVs were isolated from CPC conditioned media via ultracentrifugation and sEV inherent cargo was depleted with sonication. ELVs with miR-126 cargo were synthesized from sEVs using square-wave electroporation and characterized. miR-126+ELVs and sEVs (at 5 μg/kg or 10 μg/kg) were administered intramyocardially to the failing left-ventricle (LV) of Sprague Dawley rats after 30-minute IR injury. Infarct size was quantified with TTC/Evans blue staining after 24 hours. LV global and segmental hemodynamic parameters were assessed at baseline, Day 7, 14, and 28. After 28 days, LV fibrosis, hypertrophy and vessel formation were assessed with picrosirius red, wheat germ agglutinin and isolectin staining, respectively.

Results:
miR-126+ELVs were of similar size and concentration to CPC-sEVs. Upon administration, all groups reduced infarct size 24 hours post-treatment compared to IR-only. Further, ELV groups improved global hemodynamic parameters compared to controls with a dose-dependent segmental response across the LV. Finally, miR-126+ELVs increased vessel density compared to sEVs.

Conclusion:
ELVs with an sEV-like membrane but tailored cargo allow for cardiac repair after MI in a rat IR model, with both global and regional hemodynamic improvements and tunable histological responses. This work highlights the scope of miR+ELV therapies for cardiac diseases even beyond MI.
Abstract 15484: Distinct Subcellular Localizations of Non-Muscle Myosin IIB and IIC in Cardiomyocytes
Authors: Andersen Brianna , Omi Kazuhiro , Wang Jessica J
Published: June 2023

Introduction:
Non-muscle myosin (NMII) contraction plays a role in generating cellular tension and its role in mediating myocardial hypertrophy is emerging. Non-muscle myosin is present in cardiomyocytes in two isoforms NMIIB and NMIIC. Prior literature suggests that NMIIB and NMIIC are found in the intercalated disc, while NMIIB is found in the Z discs. Recently, PKC was implicated in medating stiffness-dependent cardiomyocyte hypertrophy through NMII. Moreover, PKC and NMII were found to be upregulated at the costameres in heart disease. The respective role of NMIIB and NMIIC in mediating cardiac hypertrophy remains unknown.

Methods:
Cardiac tissues from 10w male C57BL6/J wildtype and Myh14-GFP mice were fixed in BE40 solution (70% ethanol, 1% glycerol, 0.5% glcial acetic acid, and 28.5% 0.5 x PBS) for 3 days. Tissues were washed in 70% ethanol and made into paraffin embedded sections. Sections were heated for 10 min at 50C, deparaffinized, washed in ethanol and rinsed in PBS. Antigen retrieval was performed by heating for 10 min in TET buffer (Tris-EDTA, pH9.0 and 0.05% Tween 20). After PBS rinse, sections were incubated in blocking buffer (3% NGS, 1% BSA, 0.15% Triton X 100, PBS) for 1 hour at RT. Then sections are incubated in primary antibodies in the blocking buffer for 1 hour at RT. After PBS rinse, sections were incubated in secondary antibodies in the blocking buffer for 1 hour at RT. After PBS rinse, sections were mounted in Vectashield with DAPI. Images were captured using a Nikon A1 confocal microscopy with 60X oil lens and 2X zoom.

Results:
NMIIB is expressed in a subset of intercalated discs and Z lines. NMIIC is expressed in a subset of intercalated discs and costameres. Phospho-Myosin light chain (P-MLC) partially co-localizes with NMIIC in the intercalated discs but is not found in costameres.

Conclusions:
NMIIB and NMIIC display distinct subcellular localization, including within the intercalated discs. Only NMIIB is found at Z lines. Only NMIIC is found at costameres. P-MCL is only found in the intercalated discs. These findings suggest differential regulation and function of NMIIB and NMIIC. Further characterization of specific subcellular NMIIB and NMIIC function may elucidate their respective roles in tensional homeostasis in the cardiomyocyte.
Abstract 15495: Cardiac Structural, Electrical and Mechanical Remodeling Induced by Moderate Endurance Exercise is Sex-Dependent
Authors: George Sharon Ann , Trampel Katy , Brunner Kelsey , Efimov Igor R
Published: June 2023

Introduction:
While moderate endurance exercise has several health benefits, its effects on cardiac physiology are not fully characterized. By improving metabolism, exercise has been reported to improve cardiac function. However, metabolic changes are sex-specific which could suggest sex dependent modulation of cardiac function by exercise.

Hypothesis:
Cardiac function modulation by moderate endurance exercise is sex-specific.

Methods:
Male and female C57BL/6J mice were trained to run on a treadmill for 6 weeks. ECG and echocardiography were performed every two weeks. After 6 weeks of exercise, mice were euthanized and triple parametric optical mapping was performed on Langendorff perfused hearts to assess cardiac physiology. Arrhythmia inducibility was tested by programmed electrical stimulation. Left ventricular (LV) tissue was fixed and RNAseq was performed to determine exercise-induced changes in gene expression.

Results:
Exercise induced LV dilation in female mice alone as evidenced by increased LV diameter (2.2±0.2 vs 2.5±0.1 mm, p<0.001) and reduced LV wall thickness (1.2±0.1 vs 1.1±0.1 mm, p=0.03). Increased cardiac output (14±1.5 vs 16±1.7 ml/min, p=0.02) and stroke volume were also observed in female mice alone, suggesting improved cardiac mechanical function. Optical mapping revealed further sex differences in exercise-induced modulation of cardiac electrophysiology. In female exercised mice, action potential duration prolongation (59±2 vs 72±7 ms, p=0.01) and decreased voltage-calcium activation delay (-7±3 vs -2±2 ms, p=0.02) were recorded. In males, calcium decay constant was reduced suggesting prolonged calcium reuptake time. Arrhythmia incidences were increased in male and female exercised mice. Lastly, exercise induced changes in gene expression were associated with potassium and calcium ion channels and skeletal muscle genes in females, while metabolism related genes were altered in males.

Conclusions:
These findings suggest that moderate endurance exercise can significantly alter cardiac physiology. While some of these effects are beneficial like improved cardiac mechanical function, others are pro-arrhythmogenic. Most importantly, exercise-induced cardiac function modulation is sex-specific.
Abstract 15520: The Relationships Between Daily Step Counts With All-Cause and Cardiovascular Mortality: A Meta-Analysis
Authors: Bytyci Ibadete , Surma Stanislaw , Lewek Joanna , Banach Maciej
Published: June 2023

Introduction:
There is good evidence that inactivity and walking less steps per day increase risk of cardiovascular (CV) disease and general health. However, the golden limit of steps and their role in health is still debatable.

Hypothesis:
The aim of this meta-analysis was to evaluate the relationship between step count and all-cause and CV mortality.

Methods:
We systematically searched all electronic databases from inception until 12
th
June 2022. Main endpoints were all-cause mortality and CV mortality. Inverse-variance weighted random effects model was used to calculate the number of steps per day and mortality.

Results:
Eighteen cohort studies with a total of 67,111 (general healthy subjects and/or patients at cardiovascular risk) with a median follow up 6.9 years were included in the meta-analysis. A 1000-step increment was associated with 12% decreased risk of all-cause mortality HR 0.88 (95%CI: 0.85 to 0.91; p<0.001), while a 500-step increment was associated with 6% decrease of CV mortality - HR 0.94 (95%CI 0.91 to 0.97; p<0.001,

Figure 1

]. Compared to quartile with median steps per day 4038 used as reference quartile, the quartile 1 (Q1, median steps: 6201), quartile 2 (Q2, median steps 7094) and quartile 3 (Q3, median steps 11275) were associated with lower risk for all-cause mortality (49%, 55% and 67% respectively; p≤0.001 for all), and reduced cardiovascular mortality by 10 and 55% for Q1 and Q2, respectively (p≤0.02 for all

; Figure 2

).

Conclusions:
This meta-analysis reveals the clear inverse association with the number of step count and all-cause and cardiovascular mortality with the largest health benefit for individuals with the highest number of steps daily.