bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12342: Depression and Anxiety Disorders in Peripheral Artery Disease Admissions: Associations With Post-Revascularization Amputation and Resource Utilization
Authors: Harris Kristie M , Mena-hurtado Carlos , Burg Matthew M , Smolderen Kim G
Published: April 2024

Introduction:
It is unknown whether depression or anxiety disorders may complicate the clinical pathway during a peripheral artery disease (PAD) admission, especially in the context of a revascularization. We therefore examined their co-occurrence in PAD admissions over time and association with amputation, length of stay (LOS), and costs among those undergoing a revascularization.

Methods:
In the 2011-2017 National Inpatient Sample, annual ICD-defined depression and anxiety disorder rates were calculated in primary PAD admissions, and trends evaluated with the Cochran-Mantel-Haenszel test. Excluding CLI ICD codes, PAD admissions with endovascular and surgical revascularizations were identified. In those, hierarchical multivariable logistic regression models examined the association of depression and anxiety with major amputation. Median LOS and cost by depression or anxiety were compared with the Wilcoxon rank sum test.

Results:
From 2011-2017, there were 1,415,888 PAD admissions (mean age=67 years; 41% female). Depression increased from 12 to 14% and anxiety from 6 to 13% (P
trend
<.0001) over time. In admissions with endovascular revascularization (n=293,209), depression and anxiety were associated with higher odds of amputation, longer LOS (3.2 vs. 2.3; 3.3 vs. 2.3 days), and higher cost ($75,046 vs. $70,385; $77,369 vs. $70,194; all
p
<.0001). In surgical revascularizations (n=298,810), depression was associated with higher odds of amputation (Fig. 1), and depression and anxiety were associated with longer LOS (both 3.7 vs. 3.2 days) and higher cost ($58,976 vs. $56,566; $59,925 vs. $56,513; all
p
<.0001).

Conclusions:
Depression and anxiety codes as part of a PAD admission increased over time, with depression rates twice that of community dwelling adults. Concomitant depression and anxiety disorders are associated with adverse outcomes following revascularization, including major amputation, longer hospitalization, and increased costs.
Abstract 12343: A Real-World Disproportionality Analysis of Atrial Fibrillation Adverse Events for Glucagon Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors
Authors: Thotamgari Sahith Reddy , Sheth Aakash , Grewal Udhayvir , Dominic Paari
Published: April 2024

Introduction:
Diabetes mellitus (DM) is a known risk factor for atrial fibrillation (AF). Anti-diabetic agents such as metformin and sodium glucose co-transporter-2 inhibitors have been proven to have a protective role against AF. Recent data suggest that glucagon-like peptide-1 receptor agonists (GLP-1 RA) do not increase the risk of AF whereas evidence regarding dipeptidyl peptidase-4 inhibitors (DPP-4i) is limited. We sought to examine the association between AF and GLP-1 RA, DPP-4i using the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database.

Hypothesis:
We hypothesized that GLP-1 RA and DPP-4i may have a protective role against AF.

Methods:
We interrogated the FAERS database for reports of AF in patients on linagliptin, sitagliptin, saxagliptin, and alogliptin in the DPP-4i group and exenatide, liraglutide, dulaglutide, albiglutide, and semaglutide in the GLP-1 RA group. Number of AF events reported for each drug were collected and compared with all the other drugs in the FAERS database. Disproportionality analysis was performed using the reporting odds ratio (ROR).

Results:
We identified a total of 159,901 and 44,071 adverse event reports in the GLP-1 RA and DPP-4i groups, respectively. The reporting of AF was significantly lower for GLP-1 RA compared to all other drugs in FAERS (ROR 0.56; 95% CI 0.49-0.63). The reporting of AF was significantly higher in DPP-4i (ROR 2.02; 95% CI 1.76-2.33). Saxagliptin demonstrated the highest reporting of AF (ROR 2.67; 95% CI 2.00-3.57) followed by linagliptin (ROR 1.87; 95% CI 1.41-2.47) in DPP-4i group.

Conclusions:
The reporting frequency of AF was significantly lower in GLP-1 RA group. This complements the existing evidence and alludes to the protective role of GLP-1 RA against AF. In contrast, the reporting frequency of AF was significantly higher in DPP-4i group, especially with saxagliptin and linagliptin. Validation with larger prospective clinical data is needed to confirm these findings.
Abstract 12352: Reducing Inflammation In Coronary Atherosclerosis: A Renewed Look At Colchicine
Authors: Alam Mustafa , Savinova Olga V , Jhamnani Sunny
Published: April 2024

Introduction:
Atherosclerosis is an inflammatory disease. Randomized controlled trials (RCT) have demonstrated that targeting inflammation is important for the secondary prevention of major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) and chronic coronary artery disease (CAD). Out of these trials, low-dose colchicine has emerged as an inexpensive therapy for coronary atherosclerosis. This meta-analysis focuses to understand colchicine’s anti-inflammatory efficacy via reduction in high sensitivity C-Reactive Protein (hs-CRP) in patients with ACS and CAD

Methods:
A computerized search of MEDLINE was conducted to retrieve journal articles reporting the results in human studies performed from January 1, 2005 to January 1, 2021 using the keywords: “Colchicine” AND “Coronary” OR “CRP” OR “Coronary Artery Disease.” Studies were included if they measured hs-CRP changes from baseline and colchicine or placebo were given to patients with ACS or CAD. Studies were graded on quality via the Jadad scoring criteria.

Results:
A total of nine studies with a total population of 1502 patients and mean Jadad score of 4 were included in the meta-analysis. Five studies were RCT. The mean/median age ranged from 57 to 67 years while the duration of therapy ranged from one day to one year. Overall, colchicine treatment reduced hs-CRP levels compared with placebo (standardized mean difference [SMD]: -0.45; 95% CI: -0.68, -0.22; p=0.0001).

Conclusions:
Colchicine reduces hs-CRP in patients with ACS and CAD. This finding supports the role of colchicine in the reduction of inflammation associated with ACS or CAD. Further randomized control trials are needed to quantify long-term inflammatory control and subsequent MACE reduction.
Abstract 12357: Discordant Mechanisms in Hypertrophy and Heart Failure
Authors: Binek Aleksandra , Fert-bober Justyna P , Kreimer Simion , Rivas Alejandro , Bradshaw Amy , Zile Michael R , Van Eyk Jennifer E
Published: April 2024

Introduction:
Patients with heart failure and a preserved ejection fraction (HFpEF) present heart function abnormalities that remain poorly understood. Defining proteomic signature of HF that is independent of left ventricular hypertrophy (LVH) should allow for stratification of its subtypes and potential mechanism that contributes to the disease.

Hypothesis:
We hypothesized that HFpEF proteomic signature would be comprised of the hypertrophy and contractile protein phenotype.

Methods:
Intraoperative left ventricular (LV) myocardial biopsies were obtained from patients (n=21) recruited to undergo coronary artery bypass grafting (CABG). Patients were categorized to: control non-hypertensive (n=9), LVH (n=5), and HFpEF (n=7). Myocardial tissue was subfractionated: cytoplasmic- (neutral pH), myofilament- (acidic pH), and membrane-enriched extract (SDS-soluble). Samples were assessed for protein quantity and Lys/Arg modifications using liquid chromatography mass spectrometry (LC-MS).

Results:
In HFpEF, 13% of the cardiac LV proteome changed compared to control heart, with a substantial proportion (77%) decreasing in quantity across all three cardiac fractions, while with LVH, 61% of the proteomic LV changes were increased. Although glycolysis and gluconeogenesis increased in both cardiopathies with respect to control, in HFpEF more subtly than in LVH. Modified proteome of the HFpEF was dominated by decreases in protein succinylation (e.g. ATP5L, THIM, IDHP, APOB, GSH1, KNTC1) and to a lesser degree in methylation (ROA3, HSP7C) or acetylation compared to control group. This general trend of down-regulation of succinylation can be attributed to depletion in the levels of succinyl-CoA, the cofactor of enzymatic Lys succinylation. Importantly, there was a striking discordant activation/inhibition of cell death and proliferation pathways between the HFpEF and LVH. Two major upstream regulator clusters linked the proteome changes in cell growth and proliferation to RICTOR and Myc that showed completely opposite trends in LVH and HFpEF groups.

Conclusions:
HFpEF has a unique proteome signature compared to LV hypertrophy profile which does not arise from sub-proteome involved in contraction but rather is involved in overall cell death.
Abstract 12362: Association Between GP130 Signaling, Microtubule Regulation, and RV Function in Porcine RV Pressure Overload
Authors: Eklund Megan , Kalra Rajat , Martin Cindy M , Prins Kurt W
Published: April 2024

Introduction:
Pulmonary arterial hypertension (PAH) is a rare but lethal disease, which results in rightventricle (RV) failure. Unfortunately, there are no available therapies to directly combat RV failure and improvesurvival in PAH. We previously showed antagonism of the GP130 signaling pathway prevents microtubuleremodeling and enhances RV function in rat PAH. However, rodent models does not always recapitulatehuman physiology, which may limit translatability of our finding. Therefore, we examined the relationshipsbetween GP130 activation, microtubule regulation, t-tubule structure, and RV function in porcine RV pressureoverload.

Methods:
Pulmonary artery banding (PAB) was performed on old Yorskhire piglets and animals wereevaluated 4 weeks after. Immunoblots of RV extracts were probed with GP130, STAT3, phosphorylatedSTAT3, α-tubulin, β-tubulin, and detyrosinated α-tubulin primary antibodies to quantify GP130 activation andmicrotubule remodeling respectively. T-tubule architecture was examined using confocal microscopy. Finally,cardiac MRI quantified RV structure and function.

Results:
PAB pigs exhibited induction of GP130 signaling with higher levels of GP130, STAT3, andpSTAT3. Additionally, there was evidence of microtubule remodeling with elevated expression of α-, β-, anddetyrosinated α-tubulin. Confocal microscopy revealed t-tubule derangements in PAB pigs. Cardiac MRIshowed PAB pigs had significantly increased RV end systolic volume, reduced RV ejection fraction, andimpaired RV-pulmonary artery coupling. Finally, GP130 and tubulin expression levels were inverselyassociated with RV ejection fraction and RV-pulmonary artery coupling.

Conclusion:
Increased expression of GP130 and tubulin is associated with lower RV ejection fraction andworse RV-PA coupling. Future studies are needed to determine if GP130 antagonism enhances RV function inporcine RV pressure overload.
Abstract 12363: Statin Use and Severity of First Manifestation of Coronary Heart Disease Across Age and Sex
Authors: Bergami Maria , Yoon Jinsung , Mendieta Guiomar , Kedev Sasko , Zdravkovic Marija , Vasiljevic Zorana , Milicic Davor , Manfrini Olivia , van der Schaar Mihaela , Gale Chris P , Badimon Lina , Cenko Edina , Bugiardini Raffaele
Published: April 2024

Introduction:
We investigate whether treatment recommendations for statins in primary prevention of cardiovascular disease (CVD) based on sex, age and risk factors translate to better CV outcomes in current routine clinical care.

Methods:
We studied a propensity match-weighted cohort of 14,542 Caucasian patients presenting with a first manifestation of CVD from the International Survey of Acute Coronary Syndromes (ISACS) Archives databank (NCT04008173) . Main outcome measures were the incidence of ST segment elevation myocardial infarction (STEMI) and acute heart failure (HF) on hospital admission.

Results:
Prior statin use was associated with a significantly decreased rate of STEMI (absolute difference 10.2%; RR ratio, 0.64; 95%CI 0.58 to 0.71) and acute HF (absolute difference 4.3%; RR ratio 0.72, 95% CI 0.62 to 0.83). Benefits were not attenuated when controlling for age 75 years and older (RR ratios 0.59, 95% CI 0.46 to 0.75 for STEMI and 0.66, 95% CI 0.50 to 0.87 for HF). Statin therapy had no effect in patients with 10-year ASCVD risk threshold less than 10% (RR ratios:0.85,95%CI:0.66- 1.08 for STEMI and 0.85,95%CI:0.60-1.20 for HF). Reductions in major CV events with statins diminished with female sex (interaction p=0.0200 for STEMI, and 0.2180 for HF). Moreover, statin use determined a lower risk of 30-day mortality in patients presenting with HF on admission (5.2 % absolute risk reduction and a 29% relative risk reduction).

Conclusions:
Prevention statin therapy reduces the risk of STEMI and acute HF with benefit in mortality from HF. The most gain is attained in male sex and in subjects with 10-year ASCVD risk ≥10%
Abstract 12372: Acute Supplementation of
Lactobacillus plantarum 299v
Improves Vascular Endothelial Function in Adults With Stable Coronary Artery Disease (CAD)
Authors: Hofeld Benjamin C , Puppala Venkata K , Nelton Elise , Anger Amberly , Schneider Rachel A , Pfeffer Molly , Widlansky Michael E
Published: April 2024

Introduction:
We have shown that dietary supplementation of
L. plantarum 299v
(Lp299v) over a six-week period in men with stable CAD improves endothelial function and reduces systemic inflammation. Prior
ex vivo
work with human resistance vessels suggests that this effect is at least partially mediated by non-genomic actions of post-probiotic supplementation plasma constituents. Whether acute supplementation with Lp299v favorably impacts
in vivo
endothelial function is not known. We investigated the impact of Lp299v on
acute
changes to endothelial function in individuals with stable CAD or CAD risk factors and hypothesized that endothelial function would improve within 24 hours.

Methods:
9 adult subjects with stable CAD or at least one traditional CAD risk factor were recruited. Baseline dietary information was collected. Subjects consumed 3 oz. of Lp299v (20x10^9 CFU) after an overnight fast, and brachial artery flow mediated dilation (FMD) was used to measure vascular endothelial function at baseline, 2 hours, and 24 hours following supplementation. Lipids, glucose, and insulin levels were obtained at these timepoints. Data were analyzed using paired t-tests and chi square tests as appropriate.

Results:
No significant changes were seen in blood pressure, heart rate, lipid levels, or insulin at the 2-hour or 24-hour timepoints, compared to baseline. A nonsignificant trend of improved brachial artery FMD from the 0 to 2-hr timepoints (3.57±0.62% to 4.04±0.71%, p=0.63, n=9) persisted to the 24-hour timepoint (3.57±0.62% to 5.01±0.85%, p=0.23, n=9). There was a statistically significant decrease in glucose at the 2-hr timepoint (p=0.04), likely related to continued fasting, which was not seen at a 24hr timepoint (p=0.72).

Conclusions:
A single dose of Lp299v supplement did not result in a statistically significant improvement of endothelial function within the first 24 hours. However, the number of subjects tested was small and the FMD data at 24 hours suggests that
Lp299v
could improve endothelial function through non-genomic mechanisms. This could be more definitively determined with a larger study.
Abstract 12376: Coronary Artery Bypass Graft Surgery in Spontaneous Coronary Artery Dissection
Authors: Lobo Angie S , Hayes Sharonne , Best Patricia J , Gulati Rajiv , Tweet Marysia
Published: April 2024

Introduction:
Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of acute coronary syndrome. While most patients are managed conservatively, some patients may require percutaneous or surgical revascularization. Limited data exist on SCAD patients referred for coronary artery bypass graft (CABG) surgery.

Hypothesis:
Examine the clinical characteristics, management, and outcomes of SCAD patients referred for CABG.

Methods:
Retrospective study of patients enrolled in the Mayo Clinic SCAD Registry between 2010-2020 who underwent CABG during the initial management of acute SCAD episode.

Results:
Among the 81 patients with SCAD referred for CABG, 3 (4%) were men, mean age was 40.6 +/- 8.4 years; the majority were white (91%), and 24 (30%) had pregnancy-associated SCAD (P-SCAD). The most common presenting symptom was chest pain 80 (99%); 57 (70%) presented with ST elevation myocardial infarction (STEMI), and 21 (26%) presented with non-ST elevation MI. Multivessel dissection occurred in 40 (49%), left anterior descending artery (LAD) involvement occurred in 66 (81%) and left main (LM) in 32 (40%). Left ventricular ejection fraction was <50% in 40 patients (49%) at time of initial SCAD. The most common reasons for CABG were the presence of high-risk anatomy (56%), hemodynamic instability/active ischemia (7%), failed PCI (9%), and other/unknown (12%). Most patients received venous plus arterial bypass grafts 42 (52%), saphenous vein grafts in 20 (25%), and left internal mammary artery in 17 (21%). Screening for underlying arteriopathy was performed in 50 (62%) of whom 29 (36%) had fibromuscular dysplasia. Recurrent SCAD occurred in 10 (12%) after an average of 6.2 +/- 5 years after initial SCAD. Of those with recurrent SCAD, none required repeat surgical revascularization and 6 required percutaneous intervention (PCI). There were no deaths.

Conclusions:
Patients undergoing CABG for SCAD commonly present with STEMI, LM, or multivessel dissection, and failed percutaneous intervention attempts. In addition, CABG for P-SCAD was more frequent than expected and may relate to the increased prevalence of multivessel dissection. CABG was associated with low mortality, but recurrent SCAD may still occur.
Abstract 12378: Encephaloduroarteryiosinangiosis (EDAS) is a Cost-Effective Treatment for Symptomatic Intracranial Atherosclerosis
Authors: Gonzalez Nestor R , Tseng Chi-Hong , Quintero-Consuegra Miguel , Chang Daniel , Barnard Zachary , Thomas George , Saver Jeffrey L
Published: April 2024

Introduction:
Encephaloduroarteriosynangiosis (EDAS) is being evaluated as a new treatment for symptomatic-intracranial-atherosclerotic-disease (sICAD) in high-risk patients. We present a cost-effectiveness analysis of EDAS compared with intensive-medical-management (IMM) for sICAD.

Hypothesis:
EDAS surgery is a cost-effective treatment for sICAD

Methods:
Clinical data was obtained from the EDAS-Revascularization-for- Symptomatic-Intracranial-Atherosclerotic-Steno-occlusive-Performance-Criterion-trial (ERSIAS-PC) (n=52) and propensity scored matched cohorts from SAMMPRIS and COSS. Outcomes were projected at 3.5 years. Conservatively, treatment-effect was set as annual-risk-reduction (ARR) of 3.4%/year, 55% of the observed effect in stroke-death reduction in ERSIAS-PC. Total costs of procedure and IMM were calculated using disabling stroke, non-disabling stroke, or death rates per group, adjusted to 2021US$. The quality-adjusted-life-year (QALY) of each intervention was estimated using the frequency of disabling and non-disabling stroke, death, and baseline-health. Incremental cost-effectiveness-ratio (ICER) was formulated for 3.5-years.

Results:
Rates of stroke/death in ERSIAS PC were 9.6% (EDAS+IMM) and 21.2% (IMM). Estimated rates of stroke/death at 3.5 years were 27.9% (EDAS+IMM) and 38.9%(IMM). Calculated net-costs at 3.5-years were US$40,883 (EDAS+IMM) and US$20,968 (IMM) QALYs were 0.77 (EDAS+IMM) and 0.69 (IMM) (range 0-0.89 corresponding to death-baseline health). The cost per QALY gained after EDAS+IMM was US$68,916, and US$63,916 for IMM. The corresponding ICER for EDAS+IMM versus IMM was $65,736, below the threshold of US$189,153 (3xGPD-per-capita) for cost effectiveness.

Conclusions:
ARR of stroke/death of at least 3.4% after EDAS is a cost-effective strategy for the treatment of high-risk sICAD patients. This ARR is conservative compared to the observed 5.9% ARR in the ERSIAS-PC trial. Further investigation of EDAS in a pivotal/phase III trial is supported as a cost-effective strategy
Abstract 12380: 1,5-anhydroglucitol is a Novel and Independent Predictor of Mortality in Patients With COVID-19
Authors: Button Eric , Ishibashi Hirotaka , Bliden Kevin , Clark Elizabeth , Holt Stewart , Singh Arvind , Tantry Udaya , Dahlen Jeffrey , Gurbel Paul A
Published: April 2024

Background:
Fasting hyperglycemia and diabetes are the independent predictors of morbidity and mortality in patients with COVID-19. Glycemic fluctuations may be independently associated with poor prognosis in adult patients hospitalized for COVID-19.

Hypothesis:
We hypothesize that 1,5-anhydroglucitol (1,5-AG), a marker of glycemic variability, is strongly associated with in-hospital mortality in patients with COVID-19.

Methods:
Medical history, demographic variables, and laboratory measurements were collected within 48 hours of hospitalization in COVID-19 patients (n=64), including 9 patients who died in the hospital. Serum 1,5AG was measured by an enzymatic colorimetric assay (GlycoMark, Precision Diabetes, Inc. Raleigh, NC). Multivariate regression analysis was performed to assess the relation between fasting glucose, hemoglobin (Hb)A1c and 1,5-AG and mortality.

Results:
Baseline mean ± SD for fasting blood glucose,1,5-AG and HbA1c (available in 40 patients) were 143 ± 69 mg/dL and 14.7 ± 8.8 ug/mL and 6.9±2.3%, respectively. Only 1,5-AG was an independent predictor of mortality (n=64, AUC = 0.69, p=0.017), but not fasting glucose (n=64, AUC =0.60, p=0.32) or HbA1c (n=40, AUC=0.58, p =0.46), respectively. With respect to clinical variables, a combination of BMI and Age was predictive of mortality (AUC = 0.77, p=0.004). Interestingly, when 1,5-AG was added to BMI and Age, the AUC increased to 0.94 (p <0.0001). When fasting glucose was added to BMI and Age the AUC was 0.79 (p =0.001). A cox regression analysis demonstrated that 1,5-AG < 10 ug/mL was associated with an odds ratio of 0.44 (95% CI =0.11-1.85) for mortality.

Conclusions:
This analysis demonstrated that 1,5-AG is a novel and independent predictor of COVID-19 mortality. 1,5-AG may provide important and unique information in the COVID-19 clinical setting. An algorithm of BMI, Age, and 1,5-AG can be used clinically to predict mortality. These findings warrant further investigation in larger studies specific for diabetic and non-diabetic populations.
Abstract 12400: Trends in Bivalirudin Resource Utilization Among Young Pediatric Ventricular Assist Device Recipients
Authors: Burstein Danielle S , Huang Yuan-Shung V , Katcoff Hannah , Griffis Heather , Rossano Joseph , Vanderpluym Christina J , Lorts Angela , Buchholz Holger , Maeda Katsuhide , O'Connor Matthew J , Edelson Jonathan , Lin Kimberly , Conway Jennifer
Published: April 2024

Introduction:
Despite recent data suggesting improved outcomes with bivalirudin (bival) vs. heparin in young children requiring ventricular assist devices (VAD) support, the significantly higher costs for bival remains a barrier. Data on bival resource utilization in this population is limited and may influence care practices.

Methods:
Index VAD hospitalization of pediatric VAD recipients age 0-6 yrs from 2009-2020 were identified in Pediatric Health Information System. Bival exposure was defined as any receipt of bival during hospitalization. Standardized costs inflated to 2020 US dollar and outcomes were compared using multivariate regression.

Results:
Of 639 young pediatric VAD recipients (median age 1 yr, IQR 0-2), 246 (40%) received bival with a significant increase over the past decade (trend p-value <0.01; Figure 1). Bival was associated with lower overall hospital mortality (23% vs. 36%; adjusted OR 0.38, 95% CI 0.23-0.63) and mortality before transplant (19% vs 31%; adjusted OR 0.34, 95% CI 0.19-0.55) vs. heparin, even after adjusting for era, age, diagnosis, and center VAD volume. Length of stay (LOS) was longer for bival (median 126 days, IQR 81-184) vs. heparin (median 87 days, IQR 49-152); p<0.01. After adjusting for LOS, overall hospital costs were similar between anticoagulation strategies ($931k bival vs. $859k heparin; adjusted cost ratio 1.09, 95% CI 0.96-1.24). Higher pharmacy costs associated with bival (cost ratio 1.67, 95% 1.05-2.66) were offset by lower laboratory (cost ratio 0.86, 95% CI 0.78-0.94) and supply costs (adjusted cost ratio 0.81, 95% CI 0.69-0.96).

Conclusions:
Bival use significantly increased over the past decade and is now used in >90% young pediatric VAD recipients. Mortality is lower among bival recipients, even after accounting for era and patient-level factors, while hospital costs are similar among both anticoagulation strategies after adjusting for LOS, supporting the cost-effectiveness of bival in this population.
Abstract 12425: Troponin Kinetics and Cardiovascular Events in Patients With Myocarditis After Immune Checkpoint Inhibitors Use
Authors: Silva Thiago , Drobni Zsofia , Zafar Amna , Gongora Carlos , Zubiri Leyre , Zlotoff Daniel , Gong Jingyi , Lee Charlotte , Hartmann Sarah , Gilman Hannah , Villani Alexandra-Chloe , Sullivan Ryan , Reynolds Kerry , Zhang Lili , Nohria Anju , Neilan Tomas
Published: April 2024

Introduction:
Immune checkpoint inhibitors (ICI) leverage the immune system against cancer. Myocarditis is an uncommon but serious complication of ICI use. There are limited data on the utility of serum troponin levels in this setting. We assessed whether troponin values measured at different time points during admission have prognostic significance.

Hypothesis:
Baseline (admission), peak and inter-value trajectory (slope) of high-sensitivity cardiac Troponin T (hs-cTnT) levels predict cardiovascular events in ICI-myocarditis.

Methods:
A retrospective cohort of all patients admitted with ICI-myocarditis in a single integrated academic network was performed. Troponin measures were included from the 24 hours preceding admission until time of event/censoring. Optimal threshold values for baseline, peak hs-cTnT, and slope changes were obtained through ROC curves (Youden index). Major adverse cardiac event (MACE) was defined as a composite of cardiogenic shock, cardiac arrest, complete heart block and cardiac death.

Results:
A total of 980 hs-cTnT measures from 63 patients were identified (figure 1). Over a median follow-up period of 16 days, 24 events occurred. A higher baseline (>1248 ng/l, HR: 3.75, 95% CI: 1.57–9.00, p= 0.003) (figure 2) and peak hs-cTnT (>1959 ng/l, HR: 3.66, 95% CI: 1.49–8.98, p= 0.01) were associated with MACE adjusted for age and left ventricular ejection fraction (LVEF). Additional optimal threshold hs-cTnT values based on LVEF were also identified. For those with an LVEF < 50%, a baseline value >265 ng/l (HR: 4.9, 95% CI: 1.5-15.8, p< 0.01) and for those with an LVEF >50%, a baseline value >780 ng/l (HR: 3.6, 95% CI: 1.03-12.4, p=0.04) were associated with MACE. The hs-cTnT trajectory slope changes (baseline-to-peak, slope in first 24 hours, slope in first 48 hours) were not associated with events.

Conclusion:
Baseline and peak hs-cTnT during admission for ICI-related myocarditis associated with MACE. Cutoff values may vary by LVEF strata.
Abstract 12430: Evolution of Anti-SARS-CoV-2 IgG Antibody and IgG Avidity Post Pfizer and Moderna mRNA Vaccinations
Authors: Bliden Kevin , Liu Tiancheng , sreedhar Deepika , Tantry Udaya , kost jessica , Hsiung Jessica , zhao su , Shan Dingying , Usman Abira , Walia Naval , Cho Alastair , Jerijan Christophe , Dai Hongjie , Tang Meijie , Gurbel Paul A
Published: April 2024

Introduction:
Messenger RNA (mRNA) based vaccines (Pfizer/BioNTech and Moderna) have shown to be highly effective at providing immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Aims:
To study the duration of immunity, evolution of IgG antibody levels and IgG avidity (an index of antibody-antigen binding strength), and differences in immune responses between (mRNA) based vaccines.

Methods:
We performed a prospective study of 72 subjects without a history of SARS-CoV-2 who received both doses of either the Pfizer (n=55) or Moderna (n=17) mRNA vaccine. Anti-spike protein receptor binding domain (RBD) IgG antibody levels and IgG avidity indices were measured longitudinally using a qualitative finger stick MidaSpot™ rapid test at the point-of-care and a quantitative dry blood spot-based pGOLD™ laboratory test over ~ 4 months post-vaccination.

Results:
On average, anti-RBD IgG antibody levels peaked at ~2 weeks after second vaccination dose and declined thereafter, while antibody avidity increased suggesting antibody maturation (Figure). Moderna vaccine recipients exhibited higher side effect severity, higher peak anti-RBD IgG antibody levels and higher avidity up to the 90 days point, when compared to Pfizer vaccine recipients. Nevertheless, the differences in antibody and avidity levels diminished at ~ 120 days post- vaccination, in line with the similar efficacy of the two vaccines. A qualitative MidaSpot finger stick rapid test detected 100% anti-SARS-CoV-2 RBD positivity for fully vaccinated subjects in both Pfizer and Moderna cohorts and turning negative greater than 90 days post-vaccination for 9% of subjects in the Pfizer cohort whose quantitative anti-IgG fell below the 25-percentile levels.

Conclusions:
Longitudinal quantitative measurements of anti-RBD antibody and avidity levels provide insight to immune responses and could aid the assessment of immunity and vaccine effectiveness.
Abstract 12437: Network-Based Identification of Tissue-Specific Regulators and Drug Repurposing Candidates for Coronary Artery Disease
Authors: Cheng Jenny , Blencowe Montgomery , Lusis Aldons J , Yang Xia
Published: April 2024

Coronary artery disease (CAD) is the leading cause of mortality worldwide. Recent genomic studies in human populations and mouse models have revealed numerous novel genetic loci that may affect pathways and gene networks in CAD relevant tissues. In this study, we aim to use network-based systems biology approaches to identify regulators and drug repurposing candidates based on CAD gene networks. Through integration of multiomics datasets encompassing genetic association studies, transcriptomic profiles, and tissue-specific gene regulation from human and mouse populations, we previously modeled gene networks in vascular and liver tissues that are affected by CAD genetic loci in both species. Based on the shared CAD gene networks between human and mouse, we predicted candidate key regulatory genes and further examined multiple single-cell RNA sequencing datasets of vascular and liver tissues to pinpoint the specific cell types and molecular pathways in each tissue through which the top predicted regulators function. We further used network-based drug repositioning approaches to predict drugs targeting the CAD networks in each tissue, revealing both currently used medications and potential novel therapeutic agents. The cross-species networks, predicted key regulatory genes, their cellular and tissue context, and the network-based drug repositioning analyses offer tissue and cell-type specific targets and potential existing drugs that can be repurposed for CAD treatment.
Abstract 12450: Inflammatory Gene Expression Changes and Immune System Depression in Rats Exposed to a Single 4-hr Exposure to Electronic Cigarette Vapor
Authors: Monterrosa Mena Jessica E , Hsu Heng-Wei , Arechavala Rebecca J , Hasen Irene , Ting Amanda , Bliss Bishop , Shi Jianru , Dai Wangde , Chavez Jesus N , Carreno Juan , Zhao Lifu , Kloner Robert A , Kleinman Michael T
Published: April 2024

Introduction:
lectronic cigarette (eC) or Vaping induced Lung Injury (EVALI) was first described in the summer of 2019 in patients presenting with acute respiratory distress. Several factors contributing to EVALI are suspected, including use of oil carriers, and heating and power elements. This study examined whether a single acute exposure to eC smoke using two popular heating elements on high or low power levels would induce inflammatory gene expression and proteins, and changes in alveolar macrophage function.

Hypothesis:
We hypothesize that nichrome, but not stainless-steel atomizers and high power wattage used in the eC device contribute to the extent of changes in pulmonary inflammatory response and alveolar macrophage activity.

Methods:
Adult Sprague Dawley rats were exposed to clean air (n=8) or eC vapor (50% propylene glycol, 50% vegetable glycerin, tobacco flavoring, no nicotine, n=8) for a single four hour period using devices equipped with stainless steel (SS) or nichrome (NC) heating elements at 45 or 70 wattage power (5 exposure conditions per sex group). Rats were euthanized and bronchoalveolar lavage was performed to collect alveolar macrophages for ex-vivo cell studies. The remaining lung tissue was homogenized for inflammatory protein and gene expression analyses.

Results:
Significant changes were observed in animals assigned to 70 watts. Increases ranging from 1.5-fold to 2-fold change in expression of the inflammation related genes IL-6, TNF-α and CRP occurred in rats assigned to NC atomizers (p ≤ 0.05), predominantly in males. While the concentration of CRP protein was significantly increased in females, CRP gene expression was decreased at the time point examined. Other proteins were not significantly elevated. Significant (p ≤ 0.05) changes in phagocytic activity were only observed in males exposed to 70 watts NC vapor, which generated exaggerated superoxide production by 4-fold during ex-vivo incubation. Evidence of depressed phagocytic activity was observed in other exposure groups, although not statistically significant.

Conclusions:
These results demonstrate that a single 4-hr exposure to e-cigarettes can initiate increased gene expression of inflammatory markers IL-6, TNF-α and CRP and oxidative changes in the lung.
Abstract 12452: Prevalence and Prognostic Significance of Diastolic Dysfunction Among Hospitalized Patients Referred for Echocardiography
Authors: Moriel Mady S , Butnaru Adi , Dadon Ziv , Karmi Mohammad , Farkash Rivka , Klutstein Marc W , Rosenmann David , Khoury Zahi , Glikson Michael , Gottlieb Shmuel
Published: April 2024

Introduction:
Left ventricular diastolic dysfunction (LVDD) is frequent among elderly patients (pts) with cardiovascular risk factors and is related to heart failure.

Purpose:
To assess the prevalence and prognostic significance of LVDD among hospitalized pts referred for echocardiography.

Methods:
3828 consecutive pts who underwent echocardiography, demonstrating normal/ preserved LV systolic function were included. LVDD grades I/II/II were defined according to 2016 ASE/EACVI recommendations. Mortality data were derived from the Israel National Population Registry.

Results:
The clinical characteristics and outcomes are shown in the table and figure. Independent predictors for all-cause mortality (Cox proportional hazards regression model) [HR, (95% CI)] were: Age, 1-year increment 1.07 (1.06-1.09); CHF 1.82 (1.35-2.46); moderate-severe AS/AR/MR 1.78 (1.37-2.32); Diabetes 1.74 (1.36-2.22); LVDD-II 1.75 (1.20-2.58); LVDD-III 2.55 (1.90-3.44); Hyperlipidemia 0.64 (0.50-0.81).

Conclusions:
LVDD grade II and more prominently grade III, were independent predictors of mortality among hospitalized pts with normal/preserved LV systolic function. It is conceivable that treatment targeting LVDD may improve pts outcomes.
Abstract 12456: Apelin Expressing Endothelial Stem-Like Cells Orchestrate Lung Microvascular Repair in a Model of Lung-Targeted Endothelial Cell Ablation
Authors: Soares Godoy Rafael , Cober Nicholas D , Deng Yupu , Cook David , Chakravarti Ananya , Wang Liyuan , Stewart Duncan J
Published: April 2024

Introduction:
Endothelial damage plays a central role in acute lung injury (ALI) contributing to alveolar leak and inflammatory cell trafficking. In preclinical models of ALI, repair and regeneration of lung vascular endothelium is required for its resolution. Therefore, we sought to define the cellular and molecular mechanisms underlying lung microvascular regeneration in acute lung injury induced by lung endothelial cell (EC) ablation.

Methods and Results:
Transgenic mice were created expressing endothelial-targeted human diphtheria toxin receptor. Intratracheal instillation of diphtheria toxin (DT) resulted in the ablation of ~70% of lung endothelial cells, producing severe acute lung injury, with complete resolution by 7 days. Changes in global lung cell populations and gene expression profiles were determined using single-cell RNA sequencing of dissociated lung cells (10x Genomics) at baseline (day 0), 3, 5 and 7 days after lung EC ablation. Single cell analysis revealed 8 distinct EC clusters, including type-A capillary ECs which were characterized by the unique expression of apelin at baseline. DT-induced EC ablation resulted in the emergence of novel endothelial stem-like cells within a transient population of ‘general’ capillary ECs, characterized by the
de novo
expression of apelin at day 3 post injury. As well, this population exhibited unique expression of the vascular endothelial stem cell marker, protein C receptor, together with the progenitor cell marker, CD34. This was followed by the appearance of proliferative ECs at day 5 expressing apelin receptor and the transcription factor, FoxM1, and these cells were responsible for replenishment of all depleted EC populations. Finally, treatment with an apelin receptor antagonist, ML221, prevented lung microvascular recovery and resulted in death at 4-5 days post DT.

Conclusion:
Targeted EC ablation revealed a remarkable regenerative capacity of the lung microvasculature. Using single cell transcriptomics, we have demonstrated that lung microvascular repair was orchestrated by newly emergent apelin-expressing endothelial stem-like cells.
Abstract 12457: Atrial Fibrillation is a Cardiovascular Risk Factor for Worse Prognosis in COVID-19
Authors: Cutler Michael J , May Heidi T , Bair Tami L , Crandall Brian , Osborn Jeffrey , Miller Jared D , Mallender Charles , Muhlestein Joseph B , Anderson Jeffrey L , Knowlton Kirk U , Knight Stacey
Published: April 2024

Background:
In the presence of comorbid conditions, COVID-19 infections are known to require more advanced treatment, poorer outcomes and have longer-term sequelae. New-onset atrial fibrillation (AF) during COVID-19 infection has been associated with worse cardiovascular outcomes but not mortality. However, it remains unclear whether a prior history (hx) of atrial fibrillation is a cardiovascular risk factor predicting a worse outcome in COVID-19 patients. As such, we examined, using propensity matching accounting for possible confounders, the need for advanced treatment and subsequent major cardiovascular events (MACE) in patients with a prior hx of AF with COVID-19 infection.

Methods:
From March 2020 to May 2021, patients testing positive for SARS-CoV-2 with a prior AF diagnosis (n=3119) were propensity matched for age, gender, race/ethnicity, prior coronary artery disease (CAD), prior heart failure (HF), prior stroke and hypertension to non-AF SARS-CoV-2 positive patients. Cox hazard regression analysis with multivariable adjustment was used to determine risk of subsequent MACE (all-cause death, myocardial infarction, HF and stroke).

Results:
Baseline characteristics, treatments, and outcomes stratified by AF status are shown in the Table. While the groups had similar baseline characteristics, AF COVID-19 patients were more likely to require hospitalization, ICU care, and ventilator support. Consistent with our hypothesis, composite MACE event rates were higher in the AF patients (HR=1.60, p<0.0001) secondary to increases in heart failure and all-cause mortality rates.

Conclusions:
These data support AF as a cardiovascular risk factor predicting worse outcomes in COVID-19 patients. Specifically, AF increases the need for advanced treatments such as hospitalization, ICU care and ventilator support resulting in an increase in subsequent heart failure and all-cause mortality.
Abstract 12461: Identification of Differentially Expressed Long Non-Coding RNAs in Human-Induced Pluripotent Stem Cell-Derived Endothelial Cells Triggered by E-cigarette Exposure
Authors: Le Hoai , Liu Chen-wei , Denaro Philip , Shao Ning-Yi , Ong Sang-Ging , Lee Won Hee
Published: April 2024

Introduction:
Electronic-cigarette (e-cig) usage, particularly in the youth population, is a growing concern. It is known that e-cig causes endothelial dysfunction, which is a risk factor for the development of cardiovascular diseases; however, the mechanisms involved remain unclear. We hypothesized that long non-coding RNAs (lncRNAs), a novel class of non-coding RNA that has been shown to affect endothelial function, may play a role in e-cig-induced endothelial dysfunction.

Methods and Results:
We profiled lncRNAs that are dysregulated in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from healthy individuals following 24 hours of e-cig aerosol extract treatment. Using microarray analysis, we identified that 183 lncRNAs and 132 mRNAs were upregulated while 297 lncRNAs and 413 mRNAs were downregulated. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analyses of the mRNAs dysregulated by e-cig exposure followed by the functional characterization of the top 5 differentially expressed (DE) lncRNAs by co-expressed protein-coding genes analysis. Interestingly, the lncRNA-mRNA association analysis revealed several mRNAs associated with metabolic disorders. Subsequently, we found that e-cig caused dysregulation of endothelial metabolism resulting in increased fatty acid oxidation activity, higher mitochondrial membrane potential, and decreased glucose uptake and glycolysis. These results suggest that e-cig-induced altered EC metabolism and increased fatty acid oxidation compensate for energy deficiency in ECs.

Conclusion:
Collectively, the identification of potential regulators and pathways of the interaction between lncRNAs and mRNAs in ECs treated with e-cig provides novel insights into endothelial biology and could have a significant impact on our understanding of vascular complications upon e-cig exposure.
Abstract 12466: Suppression of Inflammatory Activity in Vascular Endothelial Cells Reduces EndMT in Response to Oscillatory Shear Stress
Authors: Yao Qingzhou , Zhao Peng , Luo Zichao , The Erlinda , Zhai Yufeng , Ao Lihua , Fullerton David , Meng Xianzhong
Published: April 2024

Background:
The incidence of pro-atherogenic lesions is greater in the branching regions of artery compared to non-branching regions. Disturbed blood flow in the atheroprone regions exerts oscillatory shear stress (OSS) to the vascular wall, particularly endothelial cells (ECs), and OSS is a risk factor for the development of pro-atherogenic lesions. This study aims to assess the impact of OSS on phenotypic transition in artery ECs.

Methods and Results:
Immunofluorescence staining and image quantification revealed that inflammatory activity and endothelial-to-mesenchymal transition (EndMT) are greater in mouse aortic arch than in the descending thoracic aorta. Inflammatory biomarker ICAM-1 is colocalized with the EndMT biomarker, vimentin and α-smooth muscle actin, in ECs of the aorta arch. As cells in aortic arch sustain OSS, we tested the hypothesis that OSS induces EndMT in artery ECs by a pro-inflammatory mechanism, using a three-dimensional microengineered human artery-on-a-chip system. Human coronary artery ECs were cultured on the surface of a collagen I-coated membrane and subjected to OSS. Single-cell RNA sequencing analysis revealed that inflammatory and EndMT-related genes were enriched in ECs after being exposed to OSS for 24 h. OSS-induced inflammatory response and EndMT were confirmed by immunoblotting and immunofluorescence staining. These changes were abolished by inhibiting the p38 MAPK-NF-κB signaling pathway. Moreover, anti-inflammatory cytokine, IL-37, suppressed the inflammatory response and prevented EndMT in ECs exposed to OSS. Importantly, expression of IL-37 in mice markedly reduced the level of inflammatory biomarker and the density of cells displaying EndMT biomarkers in the endothelium of aortic arch.

Conclusion:
OSS induces EndMT in artery ECs through a pro-inflammatory mechanism involving the p38 MAPK-NF-κB signaling pathway and contributes to the pro-atherogenic microenvironment in regions sustaining disturbed blood flow. Anti-inflammatory cytokine IL-37 may have the therapeutic potential for suppressing endothelial phenotypic transition caused by disturbed blood flow.
Abstract 12470: miR-187 Mimic Targets Pro-Inflammatory Cytokynes in Cardiomyocytes Treated With Bacterial Endotoxin
Authors: Ektesabi Amin , Tsoporis James N , Gupta Sahil , Vaswani Chirag , Parker Thomas G , dos Santos Claudia C
Published: April 2024

Introduction:
1 in 18 Canadians dies from sepsis, a life-threatening dysfunction caused by a dysregulated host response to infection which can lead to sepsis-induced Cardiac dysfunction. In the past, we have shown that administration of mesenchymal stem cells (MSCs) in the cecal ligation and puncture (CLP) model of polybacterial sepsis leads to the mitigation of sepsis-induced cardiac dysfunction by modulating microRNAs in the septic heart. Differential expression of miRNAs alters mRNA expression profile leading to a change in cellular response. In our CLP model, we identified miR-187 as a host-derived MSC-regulated miRNA.

Hypothesis:
Here we investigate the broader immunoregulatory of miR-187. Therefore, we tested the hypothesis that miRNA-187 inversely regulates sepsis-induced cardiac dysfunction by attenuating pro-inflammatory gene expression.

Methods:
Primary cardiomyocytes were isolated from 1-2 days old CD1 neonates. Cultured cells were transfected with miR-187 mimic (25 nM/mL) for 24 hours. Transfected cells were then subsequentially exposed to lipopolysaccharide (LPS, 1 μg/mL) for an additional 24 hours post-transfection. We chose to measure the expression of pro and anti-inflammatory cytokines and some cardiac injury markers via Real-Time Polymerase Chain Reaction (RT-qPCR).

Results:
Cardiomyocytes treated with bacterial LPS showed a significant decline in expression of miR-187 (n=4, p<0.05) and a significant surge (n=4, p<0.05) in the expression of pro-inflammatory cytokines such as IL-1β, IL-6, TNFα and IL-12 in comparison to untreated cells. Conversely, LPS-stimulated cardiomyocytes transfected with exogenous miR-187 mimic versus non-transfected LPS-stimulated cardiomyocytes demonstrated reduced expression of IL-1β, IL-6, and IL-12 (n=3, p<0.05) and Fasl, S100A4 and S100A9 (n=3, p<0.05).

Conclusions:
Transfecting neonatal cardiomyocytes with mimic miR-187 in the presence of LPS decreases the production of key inflammatory genes involved in sepsis-induced cardiac dysfunction. Our findings show miR-187 to be a potential therapeutic target to improve cardiac function in a pre-clinical model of sepsis by reducing pro-inflammatory cytokine expression.