bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9192: Efficacy and Safety of Dabigatran in the Treatment and Secondary Prophylaxis of Children With Congenital Heart Disease
Authors: Albisetti Manuela , Tartakovsky Igor , Halton Jacqueline , Bomgaars Lisa , Chalmers Elizabeth , Mitchell Lesley , Luciani Matteo , Nurmeev Ildar , Gorbatikov Kirill , Kleine Eva , Brueckmann Martina , Brandao Leonardo
Published: April 2024

Introduction:
Congenital heart disease (CHD) is associated with an increased frequency of thrombotic events in children, particularly in cyanotic conditions (i.e., single ventricles). Phase IIb/III clinical trials in children with venous thromboembolism (VTE) reported the noninferiority of dabigatran etexilate (DE) versus standard of care in treating acute VTE (DIVERSITY, NCT01895777) and a favorable safety profile for VTE prevention (NCT02197416).

Aim:
To evaluate the efficacy and safety of DE in the treatment and secondary prophylaxis of VTE in children with CHD, including subsets with cyanotic CHD.

Methods:
The primary composite efficacy endpoint in DIVERSITY was complete thrombus resolution and freedom from VTE recurrence or VTE-related death; safety endpoints included bleeding events (BEs). Primary endpoints in the VTE prevention trial were VTE recurrence and BEs. CHD status was confirmed locally using standard diagnostic modalities.

Results:
In DIVERSITY, 48/267 (18.0%) children had CHD. DE was noninferior to standard of care in both the CHD and non-CHD groups for the composite primary endpoint (
Table
), irrespective of the presence of cyanotic or noncyanotic CHD (
Table
). BEs (mainly minor) appeared to be lower in the CHD (8.3%) than the non-CHD group (25.7%), regardless of treatment. In the secondary VTE prevention trial, 17/211 (8.1%) children had CHD. Recurrent VTE at 12 months occurred in 0 and 3 (1.5%) children in the CHD and non-CHD groups respectively (
Table
).

Conclusions:
In children with CHD, DE has an efficacy and safety profile consistent with the overall DIVERSITY trial. Furthermore, our results confirm the safety profile for secondary VTE prevention, suggesting that DE is a viable anticoagulant alternative for this population.
Abstract 9211: Utility of Transthoracic Echocardiography in Hospitalized Patients With Stroke or Transient Ischemic Attack
Authors: Namdarizandi Vahid , Tappuni Bassman , AlKhayru Ali , Elabidin Awfa , Pereira Leanne , Fatuyi Michael , Sharma Vivek , Kaseer Belal , Brandt Dominique , Shemisa Kamal
Published: April 2024

Background:
Stroke is a leading cause of mortality in the US. The AHA/ASA Stroke Guidelines recommend echocardiography (ECHO) as part of cardiac evaluation for prevention of recurrent stroke. This study investigated the utility and associated cost of TTE as a diagnostic tool in stroke or TIA.

Methods:
A retrospective study of adults admitted with a diagnosis of stroke or TIA was conducted from 2016-2019 using the Trihealth EHR. Patient characteristics, comorbidities, TTE findings were analyzed using descriptive statistics. Hospital total cost & length of stay (LOS) were compared between patients with &without TTE using Mann-Whitney test.

Results:
There were 3,894 patients hospitalized with a stroke or TIA. A TTE was ordered for 2,435 (2,202 stroke, 233 TIA). Among stroke patients, the Median (IQR) age was 71 (60-81), 52% were female, 76% had hypertension, 57% history of tobacco & 39% had Diabetes. TTE abnormalities were found in 74% with LVH or LA dilation most common and MVP or PFO least common (figure 1). Ejection fraction was normal in 83%, borderline in 5.5% & reduced in 6.4%. Median (IQR) hospitalization cost was lower in the TTE group 7,153 [4,754-12,412] vs.7,733 [4,754-12,412], p=0.009, but not LOS, 3[2-5] vs. 3[2-6], p=0.212.

Conclusion:
Echocardiogram abnormalities were prevalent in patients hospitalized with stroke/TIA. Abnormalities ranged from LVH or LA dilatation being most common to MVP or PFO least common. The evaluation with TTE in stroke & TIA patients may be cost saving. Further investigation is necessary.
Abstract 9217: Characterizing Barriers to Fetal Cardiac Care Within the Greater Chicago Area
Authors: Woo Joyce L , Gandhi Rupali , Davis Matthew M , Patel Angira , Yee Lynn , Johnson Joyce T
Published: April 2024

Introduction:
Prenatal diagnosis (PND) is key in the treatment of congenital heart disease (CHD), the most common birth defect. National PND rates remain only ~50%, yet barriers to PND are region-specific. We aimed to identify sociodemographic barriers to CHD PND within the Greater Chicago Area.

Methods:
Infants
<
12 months of age with CHD that could be diagnosed by fetal echocardiography, who received cardiac surgery between 2016 and 2020, were identified from the Society of Thoracic Surgeons (STS) database at Lurie Children’s Hospital. Sociodemographic variables of maternal-infant dyads were collected from STS and electronic medical records. ZIP codes were linked to US Census Bureau data. Multivariable logistic regression and mediation analysis were used to analyze relationships between sociodemographic variables and prenatal diagnosis.

Results:
In total, 558 dyads met inclusion criteria. Of these, 58% had PND. In unadjusted analysis, those with private insurance were 1.6 times likelier to have PND than those with public insurance (95% CI 1.1-2.2, Table 1). However, in adjusted analysis (Table 1), payor status was an effect modifier of the associations between critical CHD status (public vs. private payor OR 11.4 vs 3.1) and maternal ZIP within a far suburb (public vs. private payor OR 15.9 vs. 0.7) on PND. There were no differences in PND by maternal race or ethnicity. In a secondary mediation analysis, the indirect effect of receiving transportation aid mediated 54% (p=0.005) of the total effect between maternal public insurance status and PND.

Conclusions:
Maternal payor status is strongly associated with CHD PND, and modifies the relationship between geographic factors, critical CHD, and PND in the Greater Chicago area. For those residing in far suburbs, PND is paramount for access to surgical care. Transportation aid lies in the causal pathway between payor status and PND. Future study will identify modifiable factors to improve access to CHD PND at the state level.
Abstract 9220: Employing a Convolutional Neural Network Facilitates Unsupervised Clustering of Aortic Outflow Velocity Profiles from Patients With Severe Aortic Stenosis
Authors: Lachmann Mark , Rippen Elena , Harmsen Gerhard , Xhepa Erion , Rueckert Daniel
Published: April 2024

Introduction:
The aortic outflow velocity profile is key to diagnose severe aortic stenosis (AS), and its shape reflects both aortic valve obstruction and left ventricular contractility.

Hypothesis:
Hypothesizing that aortic outflow velocity profiles contain more valuable information than can be captured by the human eye, features of the complex geometry of Doppler tracings were extracted by a convolutional neural network (CNN) pre-trained on big data (transfer learning).

Methods:
After pre-training a CNN (VGG-16) on a large data set (ImageNet data set; 14 million images belonging to 1,000 classes), the convolutional part was employed to transform Doppler tracings to 1D arrays. Principal component analysis (PCA) and k-means clustering of those 1D arrays were performed, and association between cluster and 2-year all-cause mortality was hereinafter assessed. Among 366 eligible patients with pre-procedural echocardiography and right heart catheterization prior to transcatheter aortic valve replacement (TAVR) for severe AS, good quality Doppler tracings from 101 patients were analyzed.

Results:
Among 101 patients (mean age: 79.3 ± 6.78 years; 49 [48.5%] women), estimated 2-year survival was 83.0% (95% CI: 75.1-91.7%). The convolutional part of the pre-trained VGG-16 model in conjunction with PCA and k-means clustering distinguished 2 shapes of aortic outflow velocity profiles. Kaplan-Meier analysis revealed that mortality in patients from cluster 2 (n = 40 [39.6%]) was significantly increased (HR for 2-year mortality: 3 [95% CI: 1-8.9]). Apart from reduced cardiac output and mean aortic valve gradient (AVG
mean
), patients from cluster 2 were also characterized by signs of pulmonary hypertension, impaired right ventricular function and right atrial enlargement. Conventional dichotomization according to AVG
mean
confirmed that patients with AVG
mean
< 40 mmHg (n = 54 [53.5%]) decease earlier, but no statistical significance was reached (HR for 2-year mortality: 1.8 [95% CI: 0.59-5.2]).

Conclusions:
This is a proof-of-principle that transfer learning aids in agnostic interpretation of aortic outflow velocity profiles, thereby holding the promise to refine prognostic resolution for survival after TAVR.
Abstract 9292: Effect of High-Pain versus Low-Pain Structured Exercise on Walking Ability in People with Intermittent Claudication: A Systematic Review and Network Meta-Analysis
Authors: Perks Jemma , Zaccardi Francesco , Paterson Craig , Houghton John S , Nickinson Andrew T , Pepper Coral J , Yates Tom , Sayers Robert
Published: April 2024

Introduction:
Guidance for exercise and pain in intermittent claudication recommends structured exercise programs at moderate-maximum pain, which may overlook the benefit of structured low-pain exercise on walking ability. We undertook a network meta-analysis to determine the comparative benefits of structured high-pain exercise and low-pain exercise, and usual-care control, to identify which has the largest effect on walking ability in people with intermittent claudication.

Methods and Results:
We searched nine electronic databases; additional trials (RCTs) were identified by hand-searching bibliographies from included studies, relevant reviews and meta-analyses. RCTs were included if: they involved adults with intermittent claudication; included at least two of following arms structured low-pain exercise, structured-high pain exercise or a usual-care control; they had a maximal or pain free treadmill walking outcome. This search resulted in the inclusion of 14 studies (n = 657), reporting the comparison of 9 high-pain arms, 4 low-pain arms, and 13 usual-care arms for maximal walking ability (MWA); and 7 high-pain arms, 4 low-pain arms and 11 usual-care arms for pain free walking ability (PFWA). Results were pooled using SMD. Structured low-pain exercise had a large positive effect on MWA (SMD: 2.23; 95% CI: 1.11 to 3.35) and a large positive effect on PFWA (2.26;1.26 to 3.26) when compared to usual-care control; structured high-pain exercise had a large positive effect on MWA (SMD: 0.95; 95% CI: 0.20 to 1.70) and a moderate positive effect on PFWA (0.77; 0.01 to 1.53) when compared to usual-care control; and structured low-pain exercise, compared to structured high-pain exercise showed a large positive effect in favour of low-pain exercise on MWA (SMD: 1.28, 95% CI: -0.07 to 2.62) and PFWA (1.50; 0.24 to2.75).

Conclusions:
Our findings support the provision of structured high- and low-pain exercise to improve walking ability in people with intermittent claudication over usual-care alone, with low-pain exercise appearing to have a larger effect. Large head-to-head RCTs are required to confirm the efficacy and safety of different structured exercise programmes prescribed using pain on walking ability in people with intermittent claudication.
Abstract 9306: Association of Race and Ethnicity and Anticoagulation in Patients With Atrial Fibrillation Dually Enrolled in Va and Medicare: Effects of Medicare Part D on the Equity of Prescribing
Authors: Essien Utibe R , Kim Nadejda , Magnani Jared W , Good Chester , Litam Terrence , Hausmann Leslie , Mor Maria , Gellad Walid , Fine Michael J
Published: April 2024

Introduction:
Although oral anticoagulation (OAC) remains under-prescribed in racial/ethnic minority patients with atrial fibrillation (AF) managed through the Veterans Health Administration (VA) and Medicare, little is known about how dual VA and Medicare enrollment influences inequities in OAC therapy for AF.

Methods:
We compared OAC initiation by race/ethnicity in a national cohort of patients with new onset AF (2014-2018) who were dually enrolled in VA and Medicare, with and without Medicare Part D enrollment. Our primary outcome was initiation of any OAC or direct oral anticoagulants (DOAC) within 90 days of an index AF diagnosis. We used mixed effects logistic regression to model the adjusted odds of our outcomes, adjusting for patient, provider, and facility factors and a Medicare Part D by race/ethnicity interaction term.

Results:
Among 82,353 patients with AF, 53,657 (65.2%) initiated any OAC (65.4% White, 62.5% Black, 65.1% Hispanic); among OAC initiators, 34,473 (64.2%) patients initiated a DOAC (64.9% White, 59.8% Black, 57.0% Hispanic). Compared to White patients, the adjusted odds ratio (aOR) of initiating any OAC was significantly lower for Black (aOR, 0.87; 95% CI 0.82-0.93) but not Hispanic patients (aOR, 1.08; 95% CI 0.97-1.20) (
Figure
). Among OAC initiators, DOAC initiation was significantly lower for Black (aOR, 0.71; 95% CI, 0.65-0.78) and Hispanic (aOR, 0.80; 95% CI, 0.70-0.92) patients. Medicare Part D enrollment did not differentially affect initiating any OAC or DOAC by race/ethnicity (p>.05 for interaction terms in both models).

Conclusions:
In a national cohort of patients with AF dually enrolled in VA and Medicare, Black patients were less likely to initiate any OAC while DOACs were initiated less in Black and Hispanic vs. White patients. Medicare Part D enrollment did not moderate the associations between race/ethnicity and any OAC or DOAC use suggesting access alone may not be the driver of AF inequities.
Abstract 9308: Extreme Gamma Prime Fibrinogen Levels in COVID-19 Patients
Authors: Farrell David H , Hudkins Matthew , Hamilton Heather , Underwood Samantha J , Dewey Elizabeth N , Kazmierczak Diana E , Kazmierczak Steven C , Messer William B , Khan Akram , Schreiber Martin A
Published: April 2024

Introduction:
COVID-19 disease progression can be accompanied by a "cytokine storm" that leads to secondary sequelae such as thrombosis and acute respiratory distress syndrome. Several inflammatory cytokines have been associated with COVID-19 disease progression, but have far too much daily intra-individual variability to be useful in tracking the course of the disease. In contrast, we have shown that the inflammatory biomarker γ' fibrinogen (γ' Fbg) has a 6-fold lower coefficient of variability compared to other inflammatory markers such as hs-CRP. The aims of the study were to measure γ' Fbg in serial blood samples from COVID-19 patients at a tertiary care medical center in order to investigate its association with clinical measures of disease progression.

Hypothesis:
Our hypothesis was that γ' Fbg levels would be elevated in COVID-19 patients compared to historical controls, and that the degree of elevation would be associated with disease severity.

Methods:
COVID-19 patients at a tertiary care medical center were retrospectively enrolled between 3/16/2020 and 8/1/2020. γ' Fbg was measured using the GammaCoeur ELISA (Gamma Diagnostics, Patent Pending).

Results:
Our results showed that ten out of the eighteen patients with COVID-19 had the highest levels of γ' Fbg ever recorded. The previous highest γ' Fbg level of 80.3 mg/dL was found in a study of 10,601 participants in the ARIC study. γ' Fbg levels were significantly associated with the need for ECMO and mortality.

Conclusions:
We found that COVID-19 patients can develop extraordinarily high levels of γ' Fbg. This has several important clinical implications. γ' Fbg contains a high affinity binding site for thrombin that binds to anion-binding exosite II on thrombin and protects it from inactivation by heparin. High levels of γ' Fbg therefore provide a reservoir of heparin-resistant clot-bound thrombin when the γ' Fbg is clotted. These findings have potential clinical implications regarding prophylactic anticoagulation of COVID-19 patients and suggest that heparin prophylaxis may be less effective than using other anticoagulants, particularly direct thrombin inhibitors.
Abstract 9347: Biomarker-Based Risk Prediction of Adverse Outcomes in Double Valve Surgery
Authors: Tse Yi Kei Stephanie , Yu Si-Yeung , Li Hang Long , Wu Meizhen , Ren Qingwen , Yu Shuk Yin , Wong Pui Fai , Lam Lok Yee Jane , LI Kwan Yu , Leung Ka Lam Calvin , Tse Hung Fat , Yiu Kai Hang
Published: April 2024

Introduction:
Current strategies for risk assessment in patients undergoing double valve surgery are limited by suboptimal performance and a narrow focus on only symptoms and left ventricular performance.

Hypothesis:
We hypothesized that the application of a biomarker-based risk score would improve prognostication in patients undergoing double valve surgery.

Methods:
Between 2012 and 2020, 131 consecutive patients (age 64±8 years, 50% female) presenting for concomitant aortic and mitral valve surgery were prospectively included in the study. Based on optimal cut-offs derived from the Youden index, we developed an integer-based biomarker score: hsTnT ≥26pg/ml, NT-proBNP ≥258ng/ml, GDF-15 ≥290ng/ml, and galectin-3 ≥22pg/ml, with one point for each abnormal parameter. The rates of adverse outcomes (composite of all-cause mortality and heart failure [HF] hospitalization) were compared across biomarker score groups (0 to 4) using Cox proportional hazards analysis. The independent and incremental value of the biomarkers to EuroSCORE II was evaluated using Harrell’s
C
-statistics, continuous net reclassification improvement (cNRI), and integrated discrimination improvement (IDI).

Results:
Over a median follow-up of 3.8 years, 37 adverse events (23 HF hospitalizations and 14 deaths) occurred. Each biomarker result was independently associated with long-term adverse outcomes after adjustment for HF and EuroSCORE II (p<0.05 for each). The biomarker score demonstrated good discrimination (C-statistic: 0.75, p<0.01) and calibration (Wald χ
2
= 0.48, p=0.49). The rates of adverse events increased in a graded fashion with an increasing biomarker score, whereby a score of 1-2, 3, and 4 conferred a 3-, 7- and 19-fold increased risk of adverse outcomes, respectively. When the four biomarkers were added to EuroSCORE II, the
C
-Statistic improved from 0.70 to 0.78 (p<0.01); significant cNRI (0.66, 95% CI 0.27-1.03, p<0.01) and IDI (0.09, 95% CI 0.03-0.15, p<0.01) were also observed.

Conclusions:
In patients undergoing double valve surgery, a novel biomarker-testing strategy comprising hsTnT, NT-proBNP, GDF-15, and galectin-3 may improve risk assessment beyond conventional risk-scoring systems.
Abstract 9359: Intrarenal Release of Superoxide Act Synergistically With Interstitial Angiotensin II to Promote Hypertension During Chronic Acidotic Conditions
Authors: Aryal Dinesh , Chamcheu JeanChristophe , JACKSON Keith E
Published: April 2024

The capacity of chronic metabolic acidosis (CMA) to evoke hypertension has been previously evaluated. The superoxide mediated oxidative stress and the activation of intrarenal angiotensin II (Ang II), demonstrated a potential role in the pathogenesis of hypertension during CMA involving renal tubular sodium retention leading to volume expansion and strain to blood vessels. The primary focus of the present study was to determine whether the superoxide and the renal angiotensin II acts either synergistically or independently of each other to promote hypertension and the underlying mechanism of superoxide generation. Male Sprague Dawley Rats (100-150gms) were divided into four groups. Chronic acidosis was induced in all 4 groups by providing free access to ammonium chloride solution (0.28M) for 8 weeks in the drinking water. The second, third, and fourth groups were injected daily with captopril (12 mg/kg/day), tempol (100μmol/kg/day) and captopril+tempol respectively. After 8 weeks, blood and urine samples were collected for pH measurements and analyzed for sodium and potassium levels. Rats were anesthetized and in-line mean arterial pressure were determined. The renal cortical tissue homogenates from all four groups were analyzed for superoxide dismutase (SOD) and NADPH oxidase (NOX2) expression. Mean arterial pressure is significantly decreased in fourth group compared to the second and third groups. The serum sodium levels in fourth group were significantly reduced compared to the separately treated second and third groups, which suggested the declined reabsorption of sodium as the cause of decreased blood pressure in the fourth group. On the other hand, there was an increased SOD activity in the fourth group compared to the second and third groups, which implied intrarenal Ang II reduces the release of superoxide by increasing its dismutation. Moreover, our results demonstrated that there were no significant alterations in phagocytic NOX2 protein levels in all four treatment groups, which indicated that the superoxide release could be due to mitochondrial oxidative stress. Overall, blocking the release of intrarenal Ang II along with promoting the superoxide dismutation, showed a potential combined effect to control the observed hypertension.
Abstract 9360: Increasing Mass Transfer Flux of Low-Density Lipoproteins-Cholesterol or Apolipoprotein B at the Endothelium of Atherogenic Sites as a Primary Target of Atherosclerotic Cardiovascular Disease
Authors: WANG XING F
Published: April 2024

Major pathological evidences indicate that subendothelial low-density lipoproteins-cholesterol (LDL-c) accumulations at atherogenic sites cause atheroscleroticcardiovascular disease (ACD). As such, current guidelines focus on LDL-c as aprimary target of ACD. Accumulating data from clinical trials have suggested thata shift from LDL-c to apolipoprotein B (Apo B) may improve target accuracy. Inthis study, we assess the hypothesis that focuses on increasing mass transfer flux ofLDL-c or Apo B from the disturbed blood flow to the endothelium of atherogenicsites as a primary target of ACD. A set of multidisciplinary analysis models areused to describe dynamic behaviors of LDL-c or Apo B particles and create amultibiomarker analysis formula (MAF) for the assessment, prevention andtreatment of ACD. The models reveal that individuals’ atheroscleroticmultibiomarker such as elevated LDL-c levels or increasing Apo B, hypertension,rising heart rate and increasing atrial stiffness contribute to an increase in LDL-c orApo B mass transfer flux at the endothelium of atherogenic sites and the increasingLDL-c flux then directly triggers subendothelial LDL-c accumulations at the sites.Excitingly, we show that the individual ACD risks assessed by MAF correspondrobustly to the 2013 ACC/AHA Guideline. In conclusion, LDL-c or Apo B masstransfer flux at the endothelium of atherogenic sites is a primary target of ACD andthe flux combines the contributions of different biomarkers to ACD. MAFencompasses a multibiomarker approach that has been utilized to analyzescreening data from over 95,000 patients conducted by the Cleveland Heart Laband MDVIP, Inc., which highlights the potential to prevent ACD and savehundreds of millions of dollars in healthcare costs.
Abstract 9361: The Effect of Immune Checkpoint Inhibitors on the Right Ventricle and Pulmonary Vasculature: Autopsy/Biopsy and Echocardiographic Data
Authors: Ahlers Carolyn G , Orimoloye Olusola A , Annis Jeffrey , Beckermann Kathryn , Johnson Douglas , Moslehi Javid , Brittain Evan
Published: April 2024

Introduction:
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but can lead to cardiovascular toxicities including myocarditis which can present as left ventricular dysfunction. Little is known about the effect of ICIs on the right ventricle (RV) and pulmonary vasculature.

Methods:
We identified six patients at our institution with ICI-induced myocarditis and right ventricular dysfunction. We also compared pulmonary pressure estimates or tricuspid regurgitant velocity measurements in two independent cohorts of patients who had pre- and post-ICI treatment echocardiography (echo) data. The first cohort included 13 unselected patients with renal cell carcinoma (RCC) or melanoma treated with an ICI at this institution. The second cohort included 31 patients from an international registry who met European Society of Cardiology criteria for ICI myocarditis. Echo parameters pre- and post-ICI were compared using the Wilcoxon signed rank test.

Results:
Biopsy and autopsy results from the six patient case series revealed lymphocytic myocarditis affecting the interventricular septum and right ventricle (Table 1). All patients with autopsies had RV dilation, and five of the six patients had RV dysfunction on imaging during their hospitalization. In the melanoma/RCC cohort, tricuspid regurgitation velocity was significantly increased post-ICI versus pre-ICI [mean 2.42, SD 0.51 m/s vs. mean 2.16, SD 0.48 m/s, p=0.03]. Right ventricular systolic pressure (RVSP) pre-ICI [mean 24.00, SD 8.26 mmHg] was decreased compared to post-ICI [mean 31.93, SD 12.93 mmHg, p=0.05]. In the second cohort, RVSP was significantly increased post-ICI [median: 30.5, IQR: 26.7-38] as compared to pre-ICI [median: 27.5, IQR: 24.6-35, p=0.03].

Conclusion:
ICIs may negatively affect RV and pulmonary circulatory function. More research is needed to understand whether ICIs increase the risk of RV dysfunction and pulmonary vascular disease.
Abstract 9365: Psip1a is Critical for Vascular Development in Zebrafish
Authors: Chiang Chang-Ying , Ni Chih-wen
Published: April 2024

Transcription coactivators function in variety ways which effectively facilitate the process of transcription and play an essential role in gene regulation. Among them, Psip1, the gene codes LEDGF/p75, has been implicated in cell survival, cancer, autoimmune diseases and HIV pathogenesis. Especially for its role in HIV replication, psip1 tethers and targets HIV integrase to the bodies of active genes, which makes it a novel target for anti-HIV treatment. However, the basic biology of psip1 is not fully elucidated, and such antiviral drugs may have unexpected side effect. Here, we show that psip1a is essential for vascular development in zebrafish. Knockdown or knockout of psip1a caused the structure disruption in the caudal vein plexus suggesting the cell death of endothelial cells. Interestingly, RNA-seq data suggested that psip1a is the master regulator for p53 signal pathway. Indeed, our data showed that psip1a directly associates to the alternative p53 promoter and potentially regulates Δ113p53 expression to antagonize p53 pathway and exhibited an anti-apoptotic effect. Such function of psip1a is medicated by IBD domain which is important for recruiting its binding partners for different functions of psip1. Zebrafish embryos treated with non-catalytic integrase inhibitors (NCINIs) showed the same vascular defects as the knockdown of psip1a, which was also mediated by the IBD domain. This unexpectedly side effect suggests a unforeseen risk of using NCINIs in antiviral treatment. Our results demonstrate the importance of psip1 in vascular development and how it regulates the p53 pathway to inhibit apoptosis. We anticipate our study to provide a new insight into the role of psip1 in vascular development. Better understanding the mechanism of psip1 function would also help to prevent unexpectedly side effects of new antiviral drug in HIV treatment.
Abstract 9379: Ferroptosis Inhibitor Exerts Greater Efficacy Than Apoptosis and Necroptosis Inhibitors on Improving Cardiac Function via Restoring Cardiac Mitochondrial Function and Attenuating Cardiomyocyte Death in Rats With Iron-Overloaded Cardiomyopathy
Authors: Kumfu Sirinart , Sripetchwandee Jirapas , Siri-angkul Natthaphat , Sumneang Natticha , Maneechote Chayodom , Arunsak Busarin , Chunchai Titikorn , Chattipakorn Siriporn , Chattipakorn Nipon
Published: April 2024

Introduction:
Iron overload cardiomyopathy (IOC) is a common cause of death in iron overload patients. Previous studies reported that iron overload led to cardiac mitochondrial dysfunction and cardiomyocyte death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart remains to be clarified.

Hypothesis:
We tested the hypothesis that apoptosis, necroptosis and ferroptosis play equally important roles in IOC; and inhibitors of the three cell death pathways have equal beneficial effect on improving cardiac function in iron-overloaded rats.

Methods:
Male Wistar rats received intraperitoneal injection of iron dextran, 5 days/week for 4 weeks. Then, the rats were divided into 5 groups (n=4/group) being treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (necrostatin-1), ferroptosis inhibitor (ferrostatin-1) and iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, mitophagy, apoptosis, necroptosis and ferroptosis were determined.

Results:
Iron-overloaded rats showed impaired cardiac and mitochondrial function associated with excessive mitophagy and increased expression of apoptosis- and ferroptosis-related proteins. All cell death inhibitors could decrease cardiac mitophagy, apoptosis and ferroptosis in iron overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial depolarization and bax/bcl-2 ratio (Figure A). Therefore, ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by the restored left ventricular ejection fraction (Figure B), whereas z-VAD-FMK and necrostatin-1 only partially improved this parameter.

Conclusions:
Ferroptosis might be the dominant type of cardiomyocyte death in IOC, and inhibition of ferroptosis is a potential therapeutic strategy against this condition.
Abstract 9389: Apache Clinical Text Analysis Knowledge Extraction System (ctakes) Identifies One Out of Five Suspicious Symptoms of Acute Coronary Syndrome from Emergency Department Nursing Triage Notes
Authors: Frisch Stephanie O , Newman-Griffis Denis , Wang Zhendong , Zegre-hemsey Jessica K , CALLAWAY Clifton W , Hochheiser Harry , Devon Holli A , Bakken Suzanne , Sejdic Ervin
Published: April 2024

Introduction:
Acute coronary syndrome is a time sensitive condition requiring rapid identification, but nurses only identify 40%-50% of high-risk patients at emergency department (ED) triage. Symptoms are the driving force behind prompt ED care of patients with ACS. Symptom data are recorded as free text in nursing narratives. Standardized extraction of symptoms via natural language processing will create usable clinical data that could be used in predictive analytics, to improve early identification of ACS and ensure life-saving treatments.

Hypothesis:
The Apache Clinical Text Analysis and Knowledge Extraction System (cTAKES) will recognize symptom concepts in nursing narratives with an acceptable F1 score of greater than or equal to 0.9.

Methods:
A nurse scientist and a physician annotated 1200 ED nursing narratives of patients with suspicion of ACS for the following symptoms predictive of ACS: chest pain, chest discomfort, shortness of breath, fatigue and sweating. Inter-rater reliability (Cohen’s kappa statistic) was calculated with 10% overlap. cTAKES, which is an open-source natural language processing platform, was applied to extract evidence of the 5 annotated symptoms. Recall (sensitivity), precision (positive predictive value) and F1 score (harmonic mean of precision and recall) were calculated to assess extraction quality for each symptom.

Results:
Recall, precision and F1 score for each symptom are as follows: chest pain: 0.71, 0.97, 0.823; chest discomfort: 0.6, 0.9, 0.72; fatigue: 0.9, 0.26, 0.41; shortness of breath: 0.93, 0.96, 0.95; and sweating: 0.54, 1, 0.7, respectively. Cohen’s kappa was 0.9.

Conclusions:
cTAKES had fair results across all 5 ACS predictive symptoms, with shortness of breath meeting our hypothesized F1 score goal. Failure to recognize symptoms at a clinically acceptable value might be due to the linguistic and content variation present in ED nursing initial narratives. Customized natural language processing pipelines trained specifically for ED nursing narratives have significant potential for accurately identifying symptoms and improving early identification of ACS.
Abstract 9399: A Targeted Proteomic Approach Identifies Novel Biomarkers Associated With Risk of Myocardial Infarction in Post-Menopausal Women
Authors: Patel Siddharth M , Morrow David A , Tang Minao , Kamanu Frederick K , Im KyungAh , Sabatine Marc S , Odonoghue Michelle L
Published: April 2024

Introduction:
There may be unique pathways that contribute to heart disease in women. We used proteomics to evaluate the association between a panel of biomarkers and risk of incident MI in post-menopausal women and thus to inform risk prediction and potential disease biology.

Methods:
We analyzed 184 candidate biomarkers (Olink CVD II/III) in LOFT, a randomized trial of an osteoporosis drug in post-menopausal women. Cases and controls without prevalent CV disease were matched by age and follow-up time (123 MI cases, 123 controls). A Benjamini-Hochberg correction was applied for false discovery (adj P value <0.05). Conditional logistic regression was adjusted for the ACC/AHA pooled cohort equations (PCE).

Results:
16 biomarkers assessed at baseline were associated with incident MI at the FDR threshold (Fig). After multivariable adjustment, 8 markers remained significantly associated with incident MI, including BNP (adj OR per SD 2.52, 95% CI 1.49-4.28), NT-proBNP (adj OR 2.41, 95% CI 1.43-4.08) and metalloproteinases including MMP-2 (adj OR 1.86, 95% CI 1.08-3.22) and MMP-12 (adj OR 1.55, 95% CI 1.02-2.37; Fig). Network analyses suggested these markers were overall strongly concentrated in pathways of inflammation, cellular movement and immune cell trafficking.

Conclusions:
A targeted proteomic approach identified markers of inflammation and immune cell trafficking as predictors of MI in post-menopausal women independent of traditional risk markers. Metalloproteinases, markers of plaque rupture and erosion, may provide insights into plaque biology and atherogenesis in women and warrant further investigation.
Abstract 9801: Thiol-Disulfide Exchange Reaction Between Thioredoxin-1 (trx1) and Atg7 Promotes Transnitrosylation of Atg7
Authors: Oka Shinichi , Nagarajan Narayani , NAH Gihoon , Mukai Risa , Sadoshima Junichi
Published: April 2024

Thioredoxin 1 (Trx1) reduces proteins with disulfide bonds. However, when the oxidoreductase activity of Trx1 is inactivated, Trx1 is S-nitrosylated at Cys73 and acts as a trans-nitrosylase. Glucose deprivation (GD) inactivates the oxidoreductase activity of Trx1 and stimulates autophagy in cardiomyocytes. We investigated how Trx1 mediates S-nitrosylation of Atg7 in response to GD, thereby stimulating autophagy. GD-induced autophagy, evaluated with tandem fluorescent LC3 (mRFP-GFP-LC3), was inhibited in the presence of Trx1C73S, a transnitrosylation defective mutant (Relative GFP/RFP under GD, control 0.75; Trx1C73S 0.95*; p<0.05 vs. control), suggesting that Trx1 mediates GD-induced autophagy via Cys73. Mass spectrometric and biochemical analyses showed that Cys545-548 in Atg7, a thioredoxin motif (CXXC), undergoes thiol-disulfide exchange reactions with Trx1, whereas Atg7 Cys402 is S-nitrosylated by SNO-Trx1. Atg7 C402S impairs Atg7 functions, as evidenced by reduced LC3-II formation with and without bafilomycin (Baf) (relative LC3-II, Atg7: 2.5; Atg7C402S: 1.7*; Atg7 with Baf: 3.1; Atg7C402S with Baf: 1.6*; p<0.05). Thus, S-nitrosylation at Cys402 promotes Atg7 function, thereby promoting autophagy. On the other hand, Atg7 C545/548S inhibited both binding of Atg7 to Trx1 and Atg7 S-nitrosylation, suggesting that Trx1 S-nitrosylates Atg7 at Cys402 during thiol-disulfide exchange reactions between Atg7 Cys545-548 and Trx1. Knockdown of Trx1 prevented whereas overexpression of Trx1 promoted GD-induced Atg7 oxidation.
In vitro
redox reactions revealed that Atg7 can reduce Trx1. Thus, Trx1 mediates GD-induced autophagy through the following mechanism: 1) GD induces Trx1 oxidation at Cys32-35; 2) oxidized Trx1 is S-nitrosylated at Cys73; 3) Atg7 is S-nitrosylated at Cys402 during thiol-disulfide exchange reactions between Trx1 Cys32-35 and Atg7 Cys545-548; and 4) S-nitrosylated Atg7 at Cys402 promotes autophagy.
Abstract 9813: A Randomized, Double Blind, Clinical Trial to Evaluate Safety and Efficacy of Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial Dysfunction in Diabetic Subjects (ACESO)
Authors: Saltzman Russell G , Schulman Ivonne H , Hurwitz Barry E , Li Hua , caceres lina V , Vidro-Casiano Mayra , Tovar Jairo A , Desire Yvenie , Porras Valeria , Soto Jeanette , Khan Aisha , Jayaweera Dushyantha , Hare Joshua M
Published: April 2024

Introduction:
Endothelial dysfunction underlies the pathophysiology of cardiovascular disease (CVD) in patients with diabetes mellitus (DM), but no known effective therapies exist. The randomized, double-blind ACESO clinical trial evaluated the safety and efficacy of allogeneic human mesenchymal stem cells (allo-MSCs) infusion to target endothelial dysfunction in Type 2 DM subjects.

Methods:
An open label pilot phase (n=6) was followed by a blinded, randomized phase (n=10) study. DM subjects with endothelial dysfunction received a single peripheral intravenous infusion of either 20 or 100 million allo-MSCs (obtained from 3 healthy bone marrow donors) and followed for 1 yr. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAE) within 1-month post-infusion. Secondary endpoints assessed endothelial function via endothelial progenitor cell-colony forming units (EPC-CFUs) and flow-mediated dilation (FMD%).

Results:
Participants had well-controlled DM, blood pressure, and kidney function (GFR ≥50 ml/min), and most were taking statins. The 6 pilot-phase participants were men (1 Asian, 5 non-Hispanic white) with mean (±SD) age of 69.3 (9.6) years. The 10 randomized participants were 5 men and 5 women (5 Hispanic, 3 non-Hispanic Black), with mean age of 60.9 (10.6) years. No TE-SAEs were reported. None of the patients in the pilot phase developed Panel Reactive Antibodies (PRAs). One randomized subject had a moderate increase in PRAs after infusion. Both treatment groups (20 and 100M allo-MSCs) in the pilot and randomized phases showed increased EPC-CFUs over time, particularly at 14 and 28 days post-infusion, that was sustained at 6-12 months. FMD data followed a trend rising above baseline and peaking at days 7 to 14, and then subsided to pre-infusion levels by 1 yr.

Conclusion:
Peripheral infusion of allo-MSCs for patients with DM and endothelial dysfunction is safe. Allo-MSCs improve EPCs and FMD within 14 to 28 days post-infusion, and the effect is sustained for 6 to 12 months. Larger clinical trials are warranted to assess the efficacy of allo-MSC therapy for cardiovascular outcomes in diabetic patients.

Clinical Trial Registration:
URL: https://www.clinicaltrials.gov.; Unique ID: NCT02886884
Abstract 9818: Self-Care Self-Efficacy and Perception of Income Adequacy Influence Self-Care Among African Immigrants with Chronic Disease
Authors: Osokpo Onome H , Lewis Lisa M , Ikeaba Uchechukwu , Chittams Jesse , Barg Frances K , Riegel Barbara J
Published: April 2024

Introduction:
Self-care is vital in chronic illness management. Little is known about the self-care behaviors of African immigrants living in the US.

Objectives:
I) Describe the self-care behaviors of adult African immigrants in the US living with hypertension, diabetes, or other chronic illness. II) Identify significant determinants of self-care.

Methods:
Using a cross-sectional design and purposive sampling, 88 African immigrants to the US were enrolled if they self-identified as sub-Saharan African immigrants, were ≥35 years of age, had a symptomatic chronic illness, and could speak and understand English. Self-care was measured with the Self Care of Chronic Illness Inventory and the Self-Care Self-Efficacy scale. Scores are standardized 0-100 with scores >70 considered adequate. Acculturation was measured using a modified standardized acculturation instrument and predefined acculturation proxies (e.g., duration of residency and age at immigration). General linear modeling with backward elimination was used to identify potential determinants of self-care.

Results:
The 88 participants were between 35 and 78 years, most were married (67%) and reported either diabetes (18%) or hypertension (50%) as their major illness. Self-care scores were adequate (mean 78.6, 77.9, 75.6 for self-care maintenance, monitoring and management). Specific self-care behaviors low in this population were eating a special diet and monitoring for medication side-effects and fatigue. In response to symptoms, few modified their diet or called a healthcare provider. Most (56.8%) were acculturated and acculturation was not associated with self-care. Self-care self-efficacy was high (81.3) and a strong determinant of self-care maintenance (p<0.0001), monitoring (p<0.0001) and management (p<0.0001). Perceived inadequacy of income was a significant determinant of poor self-care management (p= 0.03).

Conclusions:
In this sample of African immigrants with primarily diabetes and hypertension, self-care was adequate. Self-care self-efficacy and perceived income adequacy were

determinants of self-care. These factors can be used to inform culturally concordant interventions to promote self-care.
Abstract 9857: Epicardial Hdac3 Promotes Myocardial Growth Through a Novel MicroRNA Pathway
Authors: Jang Jihyun , Li Deqiang
Published: April 2024

Growth cues from epicardium-derived cells (EPDCs) such as Insulin growth factors (IGFs) and Fibroblast Growth Factors (FGFs) are required for compact myocardial growth, although it is unclear whether/how their expression is regulated by chromatin modifications during this process. To understand the potential function of Histone deacetylase 3 (Hdac3) in the developing epicardium, we conditionally inactivated Hdac3 in the EPDCs. Strikingly, deletion of Hdac3 in the epicardium led to ventricular myocardial wall hypoplasia along with the reduction of EPDCs. To identify disrupted growth signals sending from epicardium to myocardium, we deleted Hdac3 in cultured mouse epicardial cells (MECs) by CRISPR/CAS9 and performed RNA Seq analyses. We found that IGF2 and FGF9 were significantly down regulated in Hdac3 knockout (KO) MECs, which can be rescued by re-expression of intact Hdac3 but not by catalytically dead Hdac3. Importantly, the proliferation of cultured primary embryonic cardiomyocytes was significantly decreased when treated with Hdac3 KO MEC supernatant as compared to those treated with control MEC supernatant, and this proliferation decrease was rescued by supplementation of IGF2 or FGF9. Next, we sought to understand how Hdac3 regulates the expression of IGF2 or FGF9. Interestingly, we found that miR-322/503 was significantly upregulated in Hdac3 KO MECs and Hdac3 epicardial KO hearts. Overexpression of miR-322/503 repressed the expression of IGF2 and FGF9, while knockdown of miR-322/503 restored the expression of IGF2 and FGF9 in

Hdac3 KO MECs. Altogether, our findings suggest that Hdac3 in the developing epicardium promotes compact myocardial growth by stimulating IGF2 expression through repressing miR-322/503. Our findings shed light on the potential novel mechanisms of congenital heart defects, and new strategies for myocardial regeneration.
Abstract 9865: Temporal Dynamics of T Cell Response After Cardiac Injury
Authors: Kino Tabito , Kraus Lindsay , Wagner Marcus J , Mohsin Sadia
Published: April 2024

Introduction:
Neonatal heart can regenerate after myocardial injury unlike adult heart. Its capacity diminishes and disappears by post neonatal day 7 (P7). Recent studies have shown that immune cells especially T cells plays an important role to regulate inflammation, however, their role in cardiac regeneration/repair after injury is understudied. Therefore, in the present study we will characterize the temporal dynamics of T cells in neonatal and adult heart after injury and will study how temporal regulation is essential to maintain repair processes.

Hypothesis:
Regulatory T cells plays an important role in mediating reparative processes after ischemic cardiac injury.

Methods and Results:
Myocardial infarction (MI) was induced in neonatal mice at P2 (n=30) and in 8-week-old (n=10) C57BL/6 mice by ligating the left anterior descending artery (LAD). CD4+, CD8+ and Foxp3+ T cells were sorted by FACS at post MI day 2, 3, 4, 5 and 7 in neonatal mice and post MI day 7 in adult mice and analyzed for the differences in transcriptome by ultra-low input RNA sequencing. Flow cytometry analysis showed CD4+ T cells peaked at post MI day 4 compared to CD8+ T cells that peaked at post MI day 7. FoxP3+ T cells increased at post MI day 2 and diminished by post MI day 7 which coincides with the non-regenerative window of the heart. CD4+ and Foxp3+ T subsets showed increased expression of transcript in anatomical structure morphogenesis and regulation of response to stimulus. Our data showed 11.2%, 12.8% and 13.4% genes in CD4+, CD8+ and Foxp3+ T cells subsets were upregulated in neonatal mice versus adult animals. Enrichment analysis resulted that cellular component morphogenesis and cell development were activated in CD4+ T cells, and cellular component biogenesis and organelle organization were elevated in Foxp3+ T cells in neonatal mice. In addition, chromosome organization and cell cycle were upregulated in CD8+ T cells. Additionally, Foxp3+ T cells showed 198 genes uniquely expressed in neonatal hearts which are involved in cardiomyocytes proliferation and myofibroblasts phenotype transition.

Conclusions:
CD4+/CD8+/Foxp3+ regulate inflammation and mediate reparative processes in cardiac cells including myocytes and fibroblast after myocardial ischemic injury.
Abstract 9872: Cardiac Enhancer Variants at the
Mtss1
Locus Are Associated with Smaller, More Contractile Hearts
Authors: Burke Megan F , Morley Michael P , Yang Yifan , Drivas Theodore G , choe dongwook , Day Sharlene , Musunuru Kiran , Li Mingyao , Ritchie Marylyn , Cappola Thomas P
Published: April 2024

Introduction:
Variants at the
MTSS1
locus influence cardiac structure, function, and failure in multiple genome wide association studies (GWAS), yet the genetic mechanisms remain unclear. We previously identified variants in a cardiac enhancer in
cis
to
MTSS1
that influence expression in the human left ventricle (LV). Here we used bioinformatic approaches to determine if these variants explain the association between common
MTSS1
variation and cardiac traits. We hypothesized that alleles that reduce
MTSS1
expression are cardioprotective.

Methods:
To confirm a shared causal variant, we combined expression quantitative trait locus (eQTL) data from GTEx with GWAS from the UKBiobank (UKBB) using co-localization. GTEx consists of 386 LV samples with RNAseq. The UKBB is a prospective study of over 500,000 patients recruited from the United Kingdom with extensive genotype and phenotype data. We obtained relevant data as part of approved protocol 65965, using 82 additional quantified cardiac MRI (cMRI) traits from return dataset 2383. Genome association tests were performed at the
MTSS1
locus (chr8:124550790-124728429) using Plink2.0; co-localization was performed with Coloc.

Results:
Co-localization analysis of 26,892 patients revealed 3 overlapping variants in the
MTSS1
enhancer region significantly associated with LV expression of
MTSS1
and multiple cMRI traits. These include LV ejection fraction (LVEF) (p=1.3 x 10
-10
), LV end-systolic volume (p=1.2 x 10
-8
), and global circumferential strain (p=1.1 x 10
-7
). Variants that decrease
MTSS1
expression are associated with decreased volumes, increased LVEF, and improved circumferential strain, consistent with smaller, more contractile hearts (see figure for detail).

Conclusion:
We utilize a bioinformatics approach to clarify genetic mechanisms by which a previously identified locus modulates cardiac traits. These results support a cardioprotective phenotype associated with reduced LV
MTSS1
expression.