bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14021: Brief Composite Mobility Index Predicts Post-Stroke Fallers After Hospital Discharge
Authors: Plummer Prudence , Feld Jody , Mercer Vicki , Ni Pengsheng
Published: April 2022

Introduction:
Community-dwelling, ambulatory stroke survivors fall at very high rates in the first 3-6 months. Current inpatient clinical assessments for fall risk have inadequate predictive accuracy. We found that a pre-discharge obstacle-crossing test has excellent specificity (87%) but lacks acceptable sensitivity (67%) for identifying would-be fallers and non-fallers post discharge.

Hypothesis:
We assessed the hypothesis that combining the obstacle-crossing test with other highly discriminatory mobility factors would compensate for the obstacle-test’s fair sensitivity and yield an instrument with superior prediction accuracy.

Methods:
45 ambulatory stroke survivors (60±11 years old, 15±11 days post stroke) being discharged home completed a battery of mobility and dynamic balance performance-based and self-reported measures 1-3 days prior to discharge. After discharge, participants were prospectively followed for 3 months and classified as fallers (≥1 fall) or non-fallers at 3 months. Four pre-discharge measures with the largest effect sizes for differentiating fallers and non-fallers (obstacle-crossing test, Walk-12, 5-meter gait speed, and paretic-limb Step Test score) were combined into a composite index.

Results:
The composite index significantly differentiated those who subsequently fell (11.1±4.5 points) from non-fallers (4.8±4.1 points,
d
=1.46, p<0.001). A person with an index discharge score of 11 was 6 times more likely to fall in the first 3-months post discharge than a person with a score of 5. The goodness of fit of the regression model with the composite index was significantly better than the model with only the obstacle-crossing test, χ
2
(1) = 6.036, p=0.014. Furthermore, whereas the obstacle-crossing test had acceptable discrimination (AUC 0.75, 95% CI 0.60-0.90), the composite index had excellent discrimination ability (AUC 0.85, 95% CI 0.74-0.96).

Conclusion:
Strategic aggregation of performance-based and self-reported mobility measures, including a novel and demanding obstacle-crossing test, can predict post-discharge fallers with excellent accuracy. This brief tool is highly pragmatic for inpatient use and may facilitate identification of high-risk stroke survivors before the first fall.
Abstract 14023: PRG4 in Calcified Atherosclerotic Plaque Induces Immune Tolerance in Macrophages, and is Implicated in Inflammation-Driven Vascular Calcification
Authors: Waring Olivia J , Skenteris Nikolaos T , Seime Till , Jin Han , Lu Chang , Goossens Pieter , Schmidt Tannin , Donners Marjo , Matic Ljubica , Biessen Erik L
Published: April 2022

Atherosclerotic calcification is an independent predictor for a cardiovascular event, and its development is driven by macrophage-led inflammation. PRG4 was previously shown to be the most upregulated gene in microarray data of carotid endarterectomy-derived, high vs low-calcified atherosclerotic plaques. It was shown to be a pro-calcifying factor in the disease, modulating the pro-calcifying switch of vascular smooth muscle cells (VSMC). PRG4’s role in calcified plaque is largely unknown, however, we are able to show a profound effect on macrophage immune response. Transcriptomic data of a highly calcified plaque cohort (N=18 patients) shows PRG4 expression is correlated with inflammatory gene pathways, including toll-like receptor signalling; and immunohistochemistry of this cohort displays co-localization with CD68
+
cells. Despite this, PRG4 is not expressed in macrophages in plaque single-cell datasets or transcriptomics datasets, and plaque origin is likely fibroblast and VSMC. Human peripheral blood mononuclear cell (PBMC)-derived macrophage incubation with 100μg/ml recombinant human (rh)PRG4 shows strong NF-κB activation, and secretion of TNF, IL-6, IL-12p70 and IL-10. rhPRG4 stimulation also significantly enhances inflammasome activation, increasing ASC activation (p<0.003) and IL-1β secretion (p<0.001). Moreover, it suppressed macrophage phagocytosis of both zymosan particles (p>0.001), and hydroxyapatite particles (p=0.004). Subsequently, cells stimulated with rhPRG4 develop immune tolerance, a suppressed inflammatory response, to secondary stimulation with either rhPRG4 or lipopolysaccharide - with almost complete ablation of TNF secretion (p<0.001). This phenomenon is accompanied by a 5-fold A20 upregulation (p<0.001), a well-established key regulator of endotoxin tolerance. This immunosuppressive effect was coupled with increased resistance to mitochondrial stress (p<0.001). In conclusion, we see a PRG4-specific phenotype in macrophages; suppressed phagocytosis capability, and acute pro-inflammatory activation of NF-κB and inflammasome pathways, that over longer exposure develops into immunosuppression. This may have profound implications for the overall disease mechanism.
Abstract 14028: N-formyl Peptide Receptor 2 Activation via Annexin A1 Up-Regulates Hematoma Resolution After Germinal Matrix Hemorrhage
Authors: Flores Jerry J , Sherchan Prativa , Tang Jiping , Zhang John
Published: April 2022

Introduction:
Germinal matrix hemorrhage (GMH) is one of the leading causes of morbidity and mortality in preterm infants in the United States with little progress made in its clinical management. Survivors are often afflicted with long-term neurological sequelae, which include cerebral palsy, mental retardation, and post-hemorrhagic hydrocephalus. Blood clots disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage are key contributors towards post-hemorrhagic hydrocephalus development. n-formyl peptide receptor 2 (FPR2), a G-protein-coupled receptor, has been associated with the activation of scavenger receptor CD36. CD36, a transmembrane glycoprotein, plays an essential role in microglia phagocytic blood clot clearance after GMH. Currently, FPR2’s role in blood clot clearance after hemorrhagic stroke is unknown.

Hypothesis:
We hypothesize that FPR2 activation by Annexin A1 will enhance hematoma resolution via upregulation of the CD36 signaling pathway, thereby improving short- and long-term neurological outcomes.

Methods:
Bacterial collagenase (0.3 U) was infused intraparenchymally into the right hemispheric ganglionic eminence in male and female P7 rat pups to induce GMH. Annexin A1 and FPR2 Inhibitor (Boc2) were given at 1-hour post-GMH via intranasal administration. Short-term neurobehavior were assessed using negative geotaxis test. Hematoma volume was assessed using hemoglobin assay. Protein expression was assessed using western blots. Long-term neurocognitive deficits and motor coordination were assessed using Morris water maze, rotarod, and foot fault tests. Nissl staining was conducted on long-term samples to calculate ventricular dilation.

Results:
We have demonstrated that Annexin A1 treatment decreased hemoglobin content and improved neurobehavior at 72 hours post-ictus. Annexin A1 attenuated post-hemorrhagic hydrocephalus and neurological deficits 4 weeks post-ictus. Lastly, treatment increased FPR2 and CD36 protein expression.

Conclusions:
This present study demonstrates that FPR2 agonism via Annexin A1 enhances blood clot clearance, thereby improving outcomes after GMH.
Abstract 14033: Inhibition of the Prolyl Isomerase Pin1 Improves Endothelial Function and Attenuates Vascular Remodelling in Pulmonary Hypertension by Inhibiting TGF-β Signalling
Authors: Kurakula Kondababu , Hagdorn Quint , Van Der Feen Diederik , vonk noordegraaf anton , Dijke Peter , De Boer Rudolf A , Bogaard Harm J , Goumans Marie Jose , Berger Rolf M
Published: April 2022

Introduction:
Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β) / bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction and vascular remodelling in PAH is unknown.

Methods and Results:
Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding.

Conclusions:
Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH-MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.
Abstract 14041: The Association of Left Heart Pressures and Survival After Starting Veno-Arterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock
Authors: Tonna Joseph , Selzman Craig , Billia Filio , Luk Adriana , Baran David , Batchelor Wayne B , Tehrani Behnam N , Marashly Qussay , Kyriakopoulos Christos P , Taleb Iosif , Jones Tara , Nunez Jose , Grandin E. Wilson , Kapur Navin K , Rycus Peter , Drakos Stavros G ,   for the Extracorporeal Life Support Organization (ELSO) Member Cntrs
Published: April 2022

Introduction:
Despite the ability to provide full hemodynamic support in patients with refractory cardiogenic shock (CS), a potential limitation is elevated intracardiac filling pressures from increased left ventricular afterload. There is a paucity of data regarding the correlation of left atrial pressures (LAP) with outcomes.

Hypothesis:
Our objective was to determine association between LAP and survival for patients with refractory CS after 24 hours of VA ECMO support.

Methods:
Cohort analysis among 10,906 patients ≥18yrs from the Extracorporeal Life Support Organization (ELSO) Registry (2015 - 2020), with refractory CS on VA ECMO. LAP values were defined as pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) values if PCWP was missing. The exposure was LAP values at 24 hours on VA ECMO support. Our primary outcome was survival to discharge. We used multivariate regression, adjusted for age, and the following pre-ECMO variables: PaO2/FiO2, pH, mean arterial blood pressure (MAP), and SCAI classification; and the following variables after 24 hours of support: pH, MAP; and year.

Results:
Median age was 57 [IQR,46; 65] years old and 31% were females. Thirty two percent (n=3,465) presented with acute myocardial infarction, 29% (n=3,112) with acute heart failure and 1% (n=965) with both etiologies. Invasive hemodynamic monitoring was measured in 33% (n=3608) of patients. Median LAP was 18mmHg [IQR,14; 23]. Every 1 mm Hg incremental of LAP on support was associated with lower survival (aOR 0.97 [95% CI 0.95 to 0.98]; p<0.001), and 30% increase in duration of VA-ECMO support (beta-coeff 1.37 [95% CI 0.42 to 2.3]; p=0.005).

Conclusions:
Reduced LAP may be associated with higher adjusted hospital survival in patients with refractory CS on VA-ECMO. These findings merit further investigation and prospective validation to assess the relationship between hemodynamically tailored management and outcomes in this patient population.
Abstract 14053: Sumoylation of the Cardiac Sodium Channel Na
V
1.5 Does Not Increase Late Sodium Current
Authors: Yoon Jin-young , Greiner Alexander , Jacobs Julia , Kutschke William J , Kim Young-Rae , Matasic Daniel S , Mehdi Haider , Irani Kaikobad J , London Barry
Published: April 2022

Introduction:
The sodium current (I
Na
) controlling cardiac cell excitability is conducted via the Na
+
channel Na
V
1.5 (encoded by
SCN5A
). Dysregulation of Na
V
1.5 has been implicated in arrhythmia, with increased late Na
V
1.5 current (I
Na,L
) causing long QT type 3. Many Na
V
1.5 post-translational modifications have been reported by us and others, including SUMOylation, the addition of a Small Ubiquitin-like MOdifier (SUMO) at K442-Na
V
1.5. Plant et al. (2020) recently reported that hypoxia increases I
Na,L
by increased Na
V
1.5 SUMOylation.

Hypothesis:
SUMOylation modifies peak but not late Na
V
1.5 currents through membrane localization.

Methods:
SUMOylation of Na
V
1.5 by SUMO1 was detected by immunoprecipitation and immunoblot. The effects of SUMOylation on peak I
Na
and I
Na,L
were measured using patch clamp in HEK293 cells transfected with wild type (WT) or mutant K442R-Na
V
1.5 with/without the β1 subunit and in neonatal rat cardiac myocytes (NRCMs). Tetrodotoxin (TTX) was used to quantitate I
Na,L
in NRCMs. Na
V
1.5 trafficking was detected by immunofluorescence.

Results:
Na
V
1.5 was SUMOylated by SUMO1 in HEK cells, NRCMs, and human heart samples. Overexpressing or directly applying SUMO1 induced hyperSUMOylation of Na
V
1.5 at K442 and increased the amplitude of peak I
Na
in NRCMs and in HEK cells overexpressing WT but not K442R-Na
v
1.5. SUMOylation did not affect I
Na,L
in HEK293 cells expressing Na
V
1.5 with/without the β1 subunit or in NRCMs (Fig. 1A, B). SUMO1 enhanced membrane localization of Na
V
1.5 in HEK293 cells (Fig. 1C) with minimal changes to steady state activation, inactivation or channel kinetics.

Conclusion:
SUMOylation of Na
v
1.5 at K442 increases peak I
Na
without changing I
Na,L
, at least in part by altering membrane abundance. Our findings do not support SUMOylation as a mechanism for changes in I
Na,L
.
Abstract 14060: Gender Difference in Atherosclerotic Plaque Characteristics and Vascular Morphology Features by Coronary CTA in Coronary Artery Disease With and Without Ischemia (CREDENCE Substudy)
Authors: Dahal Suraj , Jonas Rebecca A , Crabtree Tami , Shafter Ahmed M , Lakshmanan Suvasini , Manubolu Venkat , Jennings Robert S , Choi Andrew , Min James K , Earls James P , Budoff Matthew
Published: April 2022

Introduction:
It is unknown whether gender differences exist in the atherosclerotic plaque characteristics (APCs) and vessel morphology of patients with and without ischemia.

Hypothesis:
There are no gender differences in the APCs or vessel morphology of patients with and without ischemia.

Methods:
The 303 patients in the CREDENCE (Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia) trial were enrolled following referral for non-emergent invasive coronary angiography with 3-vessel FFR and subsequently underwent CCTA per study protocol. Ischemic vessels were defined by FFR
<
0.8 or vessel diameter stenosis
>
90% on invasive investigation. A blinded quantitative analysis using artificial intelligence software was used to quantify APCs visualized on CCTA throughout the coronary tree (Cleerly Labs, Cleerly Inc., New York). APCs and vessel morphology data were stratified by gender for further analysis.

Results:
Among the 303 patients in the study cohort, 162 (53.4%) patients (22.8% females) had ischemic vessels and 141 (46.6%) patients (36.2% females) had non-ischemic vessels. While men were more likely to use tobacco (
p
<0.0001), there were no other gender differences in the age or comorbidity profile of the cohort. On imaging, men had more total plaque (non-ischemic group only) (
p
=0.018), low-density non-calcified plaque and non-calcified plaque (NCP) volume, as well as greater lesion length, and lumen volume than females. There were no gender differences in calcified plaque, remodeling, high risk plaques, stenosis diameter, or APCs normalized for vessel volume (PAV).

Conclusion:
In patients with and without ischemia, men have a higher prevalence of low-density NCP and total NCP volume, with no significant differences in remodeling or other atherosclerotic features. These composition plaque differences may be useful to determine gender-specific risks of coronary ischemia as compared to invasive FFR.
Abstract 14089: Phase Shift Microbubbles for the Treatment of Microvascular Obstruction
Authors: Mohammed Soheb Anwar , Chen Xucai , Acosta Maria Fernanda F , Hanrahan Dillon , Unger Evan C , MEUILLET Emmanuelle J , Pacella John
Published: April 2022

Introduction:
Microvascular obstruction (MVO) following coronary intervention is a common problem associated with worse clinical outcome, and has no consistent therapy. We are developing a new technique termed sonoreperfusion (SRP), to restore microvascular patency. This entails the use of ultrasound (US) to cause microbubble (MB) cavitation to dissolve microthrombi; this MB cavitation creates shear stress, activates nitric oxide release, and results in thrombolysis. In this pilot study, to further optimize SRP, we have used Phase Shift Microbubbles (PSMBs) (Microvascular Therapeutics, Inc). Owing to their much smaller size relative to standard MBs (~400 nm vs 3 μm) and greater microthrombus penetration, we will test the hypothesis that PSMBs attain successful reperfusion of MVO, and ultimately, will provide more rapid SRP, in our model of MVO.

Methods:
MVO of the rat (
n
=3) hindlimb was created by direct injection of microthrombi into the left femoral artery, followed by infusion of therapeutic PSMBs. Definity MBs (Lantheus Medical Imaging) were infused through the jugular vein for contrast enhanced ultrasound imaging (CEUS). A transducer was positioned vertically above the hindlimb for therapeutic US pulses during concomitant administration of PSMBs. CEUS cine loops with burst replenishment were obtained at baseline (BL), 10 min post MVO, and after each of the two SRP treatment sessions (TX1, TX2) and analyzed (MATLAB).

Results:
Fig. 1 depicts a typical example demonstrating successful creation of MVO and complete reperfusion after SRP treatment. Data are expressed as mean ± standard error. Blood volume (dB) at BL (15.3 ± 1.1), MVO (5.2 ± 1.3), TX1 (19.8 ± 2.4), TX2 (17.9
±
1.8) and flow rate (dB/sec) at BL (2.7 ± 0.4), MVO (0.2 ± 0.1) TX1 (2.1 ± 0.5), TX2 (2.7 ± 0.4).

Conclusions:
US targeted PSMB cavitation causes successful rapid reperfusion of rat hindlimb following MVO. Studies to explore the underlying molecular mechanisms associated with SRP of PSMBs are underway.
Abstract 14544: Cardiovascular Outcomes Among Patients With Acute Coronary Syndromes and Diabetes in India: Results From ACS QUIK Trial
Authors: Alfaddagh Abdulhamied , Khraishah Haitham , Kassab Mohamad , McMillan Zeb , Albaghdadi Mazen
Published: April 2022

Introduction:
Patients with diabetes are more likely to experience an acute myocardial infarction (AMI), heart failure, or death from cardiovascular (CV) causes than patients without diabetes. Despite cardiovascular disease being the leading cause of death in India, limited data exists on the outcome of patients with diabetes who suffer acute cardiovascular events.

Hypothesis:
Diabetes is common in patients with acute myocardial infarction (AMI) in India and is associated with worse in-hospital and 30-day cardiovascular outcomes.

Methods:
We examined 21374 patients with AMI enrolled in the Acute Coronary Syndrome Quality Improvement in Kerala trial. We compared those with and without diabetes with regards to the development of in-hospital and 30-day major adverse cardiac events including death, re-infarction, stroke, or major bleeding. The associations between diabetes and cardiac outcomes were adjusted for presentation and in-hospital management using logistic regression.

Results:
mean±SD age was 60.1±12.0 years and 24.3% were females. A total of 44.4% of AMI patients had diabetes. Those with diabetes were more likely to be older, female, with hypertension and have higher Killip class on presentation but less likely to present with STEMI. Patients with diabetes had longer symptoms onset-to-arrival (median 225 vs 290 min; P<0.001) and, in case of STEMI, longer door-to-balloon times (median, 75.0 vs 91 min; P<0.001). Diabetes was independently associated with higher in-hospital death (adjusted odds ratio [aOR], 1.46; 95% CI, 1.12-1.89), in-hospital reinfarction (aOR 1.52; 95% CI, 1.15-2.02). Diabetes was also associated with higher 30-day MACE (aOR, 1.33; 95% CI, 1.14-1.55) and 30-day death (aOR, 1.40; 95%CI, 1.16-1.69) but not 30-day stroke or 30-day bleeding.

Conclusion:
Among patients presenting with AMI in Kerala, India, a considerable proportion has diabetes and are at increased risk for in-hospital and 30-day adverse cardiovascular outcomes. Increased awareness of the increased CV risk and attention to the implementation of established cardiovascular therapies are indicated for patients with diabetes in lower-middle income countries who develop AMI.
Abstract 14587: Electrocardiogram Findings Amongst Latin American Immigrants at Risk for Chagas Disease in Florida
Authors: Betageri Omkar , Latner Joshua , Velez Laura , White Austin , Trejo Paola , Alcala Rodrigo , Duque Nelson , Carrasquilla Maria , Dinglasan Rhoel , Torres Vilma , Beatty Norman
Published: April 2022

Introduction:
Chagas disease (CD) is caused by the parasite
Trypanosoma cruzi
and can lead to chronic Chagas cardiomyopathy (CCC). Cardiac arrhythmias are common in CCC and include AV node pathology, intraventricular conduction disease, ventricular arrhythmias, and other abnormalities. In the U.S. there are at least 300,000 immigrants from Latin America living with CD, but it is estimated that only 1% have been diagnosed. Florida is suspected to carry the third highest burden with approximately 18,000 people living with CD.

Hypothesis:
The purpose of this study is to investigate the prevalence of electrocardiogram (ECG) findings amongst a Hispanic immigrant population at risk for CCC in Florida.

Methods:
Latin American immigrants who were either born or lived in endemic regions and now reside in Florida were enrolled in the study after informed consent. All participants completed an epidemiological survey, underwent 12-lead ECG testing, and provided a fingerstick and venous blood sample for further CD testing. ECGs were interpreted by a board-certified electrophysiologist.

Results:
A total of 151 individuals were enrolled with a mean age of 44 years and 58.9% being female. The most common countries of origin were Venezuela (34.4%), Mexico (18.5%), Honduras (12.6%), and Colombia (11.9%). Overall, 7.3% had an intraventricular conduction delay (LBBB 0.7% , RBBB 2.0%, LAFB 2.0%, and other IVCD 2.6%). A 1st degree AV block was found in 0.7% and no participants had a higher degree AV block. Ischemic changes were noted in 15.9% of participants, with infarct pattern in 3.3% and non-specific ST-T wave changes in 13.2%. Rhythm findings included normal sinus rhythm 77.5%, sinus bradycardia 21.2%, atrial fibrillation 0.7%, and ectopic atrial rhythm 0.7%. Other findings included borderline prolonged QTc 1.3%, prolonged QTc 2.0%, PACs 1.3% and no patients with PVCs.

Conclusions:
Review of this preliminary data shows a significant number of ECG abnormalities among this cohort of Latin American immigrants in Florida which can be associated with CD and CCC. Of particular interest is the high prevalence of sinus bradycardia as compared to prior population studies. A full comparative analysis of ECG findings amongst those who test positive for CD in this cohort is ongoing.
Abstract 8904: Predictors of Type 1 and Type 2 Myocardial Infarction
Authors: Wereski Ryan , Kimenai Dorien M , Bularga Anda , Taggart Caelan , Lowe David J , Mills Nicholas L , Chapman Andrew ,   High-STEACS Investigators
Published: April 2022

Background:
Our understanding of the risk factors for myocardial infarction (MI) is limited to type 1 events caused by atherosclerotic plaque rupture and thrombosis. It is unclear whether similar risk factors are related to future type 2 MI events.

Hypothesis:
Cardiovascular disease risk factors are important in predicting type 2 MI

Method:
We conducted a secondary analysis of a multi-centre randomised trial population of 48,282 consecutive patients attending hospital with suspected acute coronary syndrome. Cox regression was used to identify predictors of future type 1 and type 2 MI during a one-year follow-up period.

Results:
During one-year of follow up 1,331 patients had a subsequent MI, with 924 and 407 adjudicated as type 1 and type 2 myocardial infarction, respectively. Risk factors for type 1 and type 2 MI were similar, with age, hyperlipidaemia, diabetes, increasing creatinine concentration, and known coronary disease important predictors for both (P<0.05 for all). Whilst male sex is an established risk factor for type 1 MI, sex did not predict type 2 myocardial infarction (adjusted HR 0.82, 95% CI 0.66 to 1.01). The strongest predictor of type 2 MI was a prior history of type 2 events (aHR 6.18, 95% CI 4.70 to 8.12, Figure).

Conclusions:
Cardiovascular risk factors associated with type 1 MI are also important predictors of type 2 MI, suggesting common mechanisms including coronary disease are important. Treatment of these risk factors may reduce future susceptibility to both type 1 and type 2 MI.
Abstract 8907: Fatty-Acid-Binding Protein 3 as a Novel Inducer of Adhesion Molecules in Atherosclerosis
Authors: Wu Yen-Wen , Chen Jaw W , Chang Ting-Ting
Published: April 2022

Introduction:
Cardiovascular disease is accompanied by a considerable degree of morbidity and mortality, and the pathogenesis is complex. The fatty-acid-binding protein 3 (FABP-3) is a cytoplasmic protein and can be released from injured myocardium. We had demonstrated that FABP-3 was an independent predictor for cardiovascular outcomes in the patients with stable coronary artery disease (CAD). However, the mechanisms of FABP-3 in atherosclerosis were still unknown. Here we supposed that FABP-3 could lead to atherogenesis via activating the adhesion molecules.

Methods and Results:
Human coronary endothelial cells (HCAECs) and mononuclear cells (MNCs) cultured from CAD patients and healthy subjects were used for the in vitro study. The ox-LDL and TNF-α were used as stimulators in the in vitro experiments. The expressions of adhesion molecule were evaluated by Western blot analysis. MNCs from CAD patients had higher expressions of FABP-3 than those from healthy subjects. In addition, FABP-3 could be further up-regulated by ox-LDL and TNF-α stimulations in both MNCs from CAD patients and healthy subjects. Exogenous of FABP-3 could directly induce the adhesion molecules including integrin β2, integrin α4, and P-selectin glycoprotein ligand 1 expressions in MNCs from CAD patients and healthy subjects. Nevertheless, direct treatments of FABP-3 did not upregulate the adhesion molecules in HCAECs. Also, the adhesiveness of FABP-3-induced adhesiveness of HCAECs to THP-1 monocytic cells was not enhanced.

Conclusions:
According to the above results, we suggested that FABP-3 could directly lead to the atherogenesis via the MNC activation instead of endothelial cell activation. The findings of the serial studies may not only elucidate the prognostic role of plasma FABP-3 levels in patients with CAD but define the role of FABP-3 on the pathogenesis of atherosclerosis especially its influence in MNCs. The study might clarify the clinical impact of FABP-3 and as a potential novel therapeutic target for atherosclerosis.
Abstract 8914: Selective Phosphodiesterase-9 Inhibition With IMR-687 Mitigates Cardiac Hypertrophy and Renal Injury in Preclinical Mouse Models of Heart Failure With Preserved Ejection Fraction
Authors: Gupta Deepak K , Maciel Thiago T , Carvalho Caroline , Collins Sheila , Hemnes Anna R , Hill Joseph A , Lindenfeld Joann , Redfield Margaret M , Shah Sanjiv J , Attie Kenneth , Hopkinson Lynette , Wang Thomas J , Ballal Rahul
Published: April 2022

Introduction:
Through degradation of the cardio- and renal-protective second messenger cyclic GMP, phosphodiesterase-9 (PDE9) excess may contribute to cardiomyocyte hypertrophy, fibrosis, and renal dysfunction, common features in heart failure with preserved ejection fraction (HFpEF) development and progression.

Hypothesis:
Selective PDE9 inhibition with IMR-687 mitigates an adverse cardiac and renal phenotype in mouse models of HFpEF.

Methods:
Cardiac and renal responses to IMR-687 (60 mg/kg, 100 mg/kg) compared with vehicle were examined over 6-8 weeks in 3 adult male mouse models of HFpEF (1.5 mg/kg/d angiotensin-II infusion [ang-II]; uninephrectomy + 0.30 ug/h d-aldosterone infusion + 1% NaCl drinking water [neph-aldo]; and db/db [db]). Phenotyping included wheat germ agglutinin staining for cardiomyocyte cross-sectional area (CSA); RT-PCR for myocardial PDE9, natriuretic peptide, inflammatory and fibrosis marker transcript abundances; ELISA for plasma natriuretic peptides; and urinary albumin to creatinine ratio (UACR).

Results:
IMR-687 reduced median cardiomyocyte size (CSA) by 54, 58, and 35% compared with vehicle in the ang-II, neph-aldo, and db models, respectively; p < 0.003 for all. Myocardial PDE9, NPPA, NPPB, COL3A1, and IL-1β expression were decreased by IMR-687 in all models (Table). Median plasma BNP levels (pg/mL) were lower in IMR-687 vs. vehicle treated mice in all models (ang-II: 2376 vs. 5757; neph-aldo: 1216 vs. 1860; db: 830 vs. 1216); p < 0.007 for all, with similar findings for ANP (Table). UACR was lower in IMR-687 compared with vehicle treated mice in all models (Table). Heart rate and blood pressure did not differ between IMR-687 and vehicle treated mice.

Conclusion:
Selective PDE9 inhibition with IMR-687 was effective for prevention and treatment of cardiac hypertrophy and renal dysfunction in 3 different preclinical models of HFpEF. IMR-687 may be a promising candidate therapy for testing in clinical trials of human HFpEF.
Abstract 8918: Nstemi in a Patient With Anomalous Coronary Artery Origin
Authors: ababio priscilla A , Gonzalez Bonilla Hilda M , Awan Ahmad A , opoku-asare isaac
Published: April 2022

Introduction:
Anomalous origin of the coronary arteries is a rare condition that can be life threatening. We present the case of a patient with anomalous right coronary artery (RCA) origin who presented with atypical chest pain.

Case Presentation:
A 34-year old man with no medical history presented with atypical chest pain. Initial vital signs were within normal limits and physical examination was unremarkable. Laboratory results revealed a peak troponin of 16.56 Ng/ml and EKG did not show ischemic changes. Echocardiogram demonstrated mildly impaired right ventricular systolic function. Cardiac catheterization showed patent coronaries and anomalous RCA arising from the left coronary cusp (LCC). Cardiac CT showed anomalous origin of the RCA extending from the LCC and coursing between the aorta and the pulmonary artery. Patient remained asymptomatic and was referred for surgical evaluation

Discussion:
Anomalous RCA originating from the LCC occurs in 0.05%-0.1% of the general population. It may run posterior to the aorta, anterior to the pulmonary trunk, septal or between the pulmonary artery and the aorta itself, like in the case of our patient. Diagnosis of these anomalies can be done by cardiac MRI, cardiac coronary CT, or coronary angiography. Management depends on the nature of the anomalies and remains controversial. Options include coronary angioplasty, conservative medical management, or surgical correction. In patients with intramural course and symptoms of myocardial ischemia, most literature recommends surgical intervention.

Conclusions:
This case illustrates a unique case of a patient with an anomalous coronary artery origin presenting with NSTEMI. Management can be challenging, and it must be individualized.
Abstract 8922: Provider Preferences Drive AF Ablation Cost Variability
Authors: Zenger Brian , Li Haojia , Bunch T. J , Crawford Candice , Fang James C , Hess Rachel , Maires Chase , Ranjan Ravi , Zhang Yue , Steinberg Benjamin A
Published: April 2022

Background:
AF ablation approaches and outcomes vary. Very little work has been done to assess the variability of ablation costs to health systems and drivers of variability.

Objective:
Determine the drivers of cost variability in AF ablation procedures.

Methods:
We assessed the costs of AF ablation procedures performed between 2013-2020 at a single tertiary care center. Cost to the health system were inflation-adjusted and separated into facility, imaging, implant, pharmacy, supply, labs, and other services. Only patients who were outpatient and had an ablation by an operator who performed >10 procedures were included. Lasso multivariable regression was used to identify the primary drivers of variability in costs, including operator and patient characteristics.

Results:
1072 patients with 1284 AF ablations were included (age: 65.1, SD: 11.0; men: 68%; CHADS2-Vasc: 2.8, SD: 1.9, beta blockers: 63%, non-white race: 6%). Procedures were performed by 8 operators. Proportional contributions to overall costs are shown in the Figure. Regression analysis demonstrated higher average cost for men, (1.25%), non-white race (2.6%), beta-blocker use (1.9%), prior ablation (0.98%), anticoagulation use (1.4%), and operator (highest operator cost increase vs. lowest, 18%). There was no relation to CHADS2-Vasc or age. Cost variability was primarily driven by supplies including catheters and other equipment.

Conclusion:
Cost variability was only modestly related to patient characteristics. The largest contributor to cost in AF ablations was supplies, which are primarily operator dependent.
Abstract 8929: Mineralocorticoid Receptor as an Epigenetic Regulator of Vascular Aging
Authors: Ibarrola Ulzurrun Jaime , Kim Seung K , Lu Qing , Dupont Jennifer J , Biwer Lauren A , Man Joshua J , Jaffe Jacob D , Jaffe Iris Z
Published: April 2022

Introduction:
Vascular stiffness increases with age and independently predicts cardiovascular events but vascular fibrosis mechanisms are unclear. Epigenetic changes accumulate with age and contribute to aging pathology. We showed that aging-associated increase in vascular stiffness/fibrosis are mitigated by treating old mice with mineralocorticoid receptor (MR) antagonist (MRA) or by genetic deletion of MR in smooth muscle cells (SMC-MR-KO).

Hypothesis:
We hypothesized that SMC-MR regulates vascular fibrosis genes by modulating epigenetic histone modifications in the aging vasculature.

Methods and Results:
Global histone proteomic profiling revealed increased acetylation (ac) and decreased methylation (me) of histone H3 lysine 27 (H3K27) in old vs young mouse aorta that is attenuated by SMC-MR-KO. Similarly, RNA profiling shows downregulation of fibrotic genes (CTGF, MMP2 and Integrin-α5) with aging in mouse aortas from SMC-MR-KO mice. Mechanism was explored in primary low passage human aortic SMC (HASMC). Comparison of protein levels in HASMCs from old vs young people shows increased MR, decreased H3K27-specific methyltransferase EZH2, increased H3K27ac and increased fibrosis gene expression in aged HASMC. Treatment of young HASMC with H
2
O
2
(aging inductor) increased MR and decreased EZH2 in association with decreased H3K27me. These epigenetic changes were associated with increased H3K27ac and MR enrichment at the promoter of fibrosis genes by ChIP along with increased fibrosis gene expression. Conversely, treatment of aged HASMC with MRA increased EZH2 and H3K27me with decreased fibrosis gene expression. Finally, treatment of 12 month old mice with MR antagonist for 4 months or deletion of MR from SMC prevented aging induction of vascular stiffness by pulse wave velocity in association with decreased H3K27ac at promoters and decreased expression of fibrosis genes in aging aortas.

Conclusion:
These data support a model in which rising SMC-MR with aging contributes to vascular fibrosis via EZH2 reduction leading to decreased H3K27me and increased H3K27ac and MR recruitment to promote transcription of fibrotic genes. These findings suggest the therapeutic potential for MRAs for aging-associated vascular stiffening/fibrosis.
Abstract 8937: Type 2 Diabetes Significantly Modulates the Power of Lipoprotein(a) to Predict Cardiovascular Events and Mortality in Young Coronary Artery Disease Patients
Authors: Mader Arthur , Maechler Maximilian , Larcher Barbara , Sprenger Lukas , Mutschlechner Beatrix , Benda Magdalena , Leiherer Andreas , Muendlein Axel , Vonbank Alexander , Drexel Heinz , Saely Christoph H
Published: April 2022

Introduction:
Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor especially in young individuals.

Hypothesis:
We hypothesize that Lp(a) has the power to predict cardiovascular events in young coronary artery disease (CAD) patients with type 2 diabetes (T2DM).

Methods:
Lp(a) was measured in a cohort of 731 patients with angiographically proven CAD who were aged <65 years. Vascular events were recorded over a mean follow-up of 6.6±3.2 years. At baseline, 216 patients had T2DM, and 515 did not have diabetes.

Results:
During follow-up, 30.2% of our patients suffered cardiovascular events. Lp(a) proved to be a strong and independent predictor of vascular events in the total study cohort (standardized adjusted HR=1.30 [1.07-1.56]; p=0.007). In subgroup analyses by diabetes status, Lp(a) significantly predicted vascular events in non-diabetic patients (standardized adjusted HR= 1.39 [1.12-1.74]; p=0.003) but not in diabetic patients (standardized adjusted HR=0.93 [0.63-1.38]; p=0.731). An interaction term Lp(a)xT2DM was significant (p=0.002), indicating that T2DM significantly modulated the power of Lp(a) to predict cardiovascular events.

Conclusions:
We conclude that Lp(a) significantly modulates the power of Lp(a) to predict cardiovascular events in CAD patients <65 years.
Abstract 8955: Cardiopulmonary Phenotyping of Sex-Based Differences in a Feline Model of HFpEF
Authors: Eaton Deborah M , Berretta Remus M , Lynch Jacqueline E , Travers Joshua G , Woulfe Kathleen C , Pfeiffer Ryan D , Hulke Michelle L , Hobby Alexander R , Schena Giana , Johnson Jaslyn P , Wallner Markus , Tucker Nathan R , McKinsey Timothy A , Wolfson Marla R , Houser Steven R
Published: April 2022

Introduction:
Approximately 50% of all heart failure (HF) diagnoses can be classified as HF with preserved ejection fraction (HFpEF), which has no FDA approved therapies. HFpEF is more prevalent in females compared to males, but the underlying mechanisms for the development as a sex-based disorder are unknown. We previously described how slow progressive pressure overload (PO) in male felines recapitulates the HFpEF phenotype but have not investigated the female phenotype.

Hypothesis:
Females will develop a less severe HFpEF phenotype compared to males under the same pathological stress.

Methods & Results:
Male (m) and female (f) domestic short felines (age 2mo) underwent aortic constriction (m: n=11; f: n=10) using a customized pre-shaped band or a sham procedure (m: n=7; f: n=7). Before surgery (baseline), there was no difference in body weight (BW) between groups and lung compliance was not different. Echocardiography revealed no significant difference in the ratio of left atrium to aortic root (LA/Ao), LA ejection fraction (LA EF), left ventricle (LV) ejection fraction, LV wall-thickness, and E/A ratio. By 4mo post-surgery, both males and females had developed cardiac dysfunction and decreased lung compliance. At this time, females had significantly smaller BWs than males. Despite the difference in BW, LV wall thickness and changes in E/A ratio were similar in both sexes in banded vs. shams. Importantly, LV EF did not change in any group. There was a decrease in LA EF and increased LA/Ao in all banded animals. Invasive hemodynamics at 4mo post-surgery showed no differences between sexes for the systolic pressure gradient generated by aortic banding. Banded males had higher LV end-diastolic pressure vs. banded females (m: 15.0±2.7mmHg; f: 8.1±1.9mmHg). However, there was a trend towards prolongation of tau and lower dp/dt
min
in banded females, suggestive of abnormal relaxation. There were no differences between banded males and females in heart weight/BW or cardiomyocyte cross-sectional area and both developed fibrosis.

Conclusions:
Exposure of male and female felines to PO resulted in similar cardiac hypertrophy, fibrosis, and decreased lung compliance. Females had lower LVEDP than males suggesting they may be protected from diastolic dysfunction.
Abstract 9401: Relationship Between Circulating Levels of Angiotensinogen and Hypertension—The Multi-Ethnic Study of Atherosclerosis
Authors: Trainor Patrick J , Brambatti Michela , Carlisle Samantha M , Mullick Adam E , Kahlon Tanvir , Otero Diana , Mousavi Hossein , Michos Erin , Ouyang Pamela , Morgan Erin , Tami Yvonne , Tsimikas Sotirios , Defilippis Andrew P
Published: April 2022

Introduction:
Angiotensinogen (AGT) is a critical component of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure (BP), volume, and electrolyte levels. While physiological effects of AGT are primarily mediated by AGT-derived peptide hormones, effects of AGT independent of these peptides have been described recently in animal models. We sought to determine the relationship between AGT levels, sex, ethnicity, and hypertension (HTN).

Methods:
We measured baseline plasma AGT levels using an enzyme-linked immunoassay in 5,786 Multiethnic Study of Atherosclerosis (MESA) participants, aged 45 to 84 yrs. We determined the associations between AGT levels and clinical and demographic variables, medication usage, and BP at the first exam. The relationship between prevalent HTN was then determined using adjusted models.

Results:
Mean AGT levels (log-transformed) were significantly higher in females than males and differed across race/ethnicities with the ordering (from highest to lowest): White, Black, Hispanic, and Chinese adults. The difference between the sexes was greatest in White adults with females having 1.44 times greater levels than males (95% CI: 1.40, 1.48), and lowest in Chinese adults. In males not taking medications targeting RAAS, one SD higher log-AGT was associated with a 2.61 mmHg higher SBP (95% CI: 1.49, 3.80), in females it was associated with 0.97 mmHg higher SBP (95% CI: 0.30, 1.65). Use of RAAS-blocking medications attenuated these associations. In risk factor-adjusted models, higher levels of AGT were associated with higher odds of prevalent HTN.

Conclusions:
AGT levels differ between race/ethnicities and between the sexes. Higher levels of AGT are associated with higher BP and odds of prevalent HTN. Despite lower levels in males, the association between levels and BP was greater in males. Taken together, the difference in levels and in the association with BP suggests sex-specific regulation and effects of AGT.
Abstract 9402: Venous Thromboembolism During Pregnancy is Associated with Elevated Tricuspid Regurgitation Velocity in Sickle Cell Disease
Authors: Marshall William H , Cleary Erin M , Della-Moretta Sherraine , Samuels Philip , Desai Payal , Rajpal Saurabh
Published: April 2022

Introduction:
In patients with sickle cell disease (SCD), a tricuspid regurgitation velocity (TRV) > 2.5 m/s by echocardiogram is a non-invasive marker for underlying pulmonary hypertension (PH), and associated with increased mortality. During pregnancy, maternal and fetal adverse events are increased in women SCD, and in women with PH. Data on pregnancy outcomes in women with both SCD and elevated TRV are sparse; we hypothesized increased adverse events in this group.

Methods:
We retrospectively compared pregnancy outcomes in women with SCD and elevated TRV (>2.5 m/s) to those with SCD and normal TRV (≤ 2.5 m/s).

Results:
We identified 59 pregnancies in 43 women (mean age 28 ± 5 years at delivery) with SCD (31 pregnancies in women with elevated TRV, 28 with normal TRV). There was a trend towards more lifetime transfusions, and significantly lower hemoglobin in women with elevated TRV (
Figure A-B
). As expected, right ventricular systolic pressure was different between the groups, however other baseline characteristics, including SCD genotype, left ventricular systolic function, and pre-pregnancy venous thromboembolism (VTE) were similar (
Figure C-F
). No maternal deaths occurred in pregnancy or 1-year postpartum. VTE occurred in 7 (12%) pregnancies, only in women with elevated TRV; and postpartum readmission was more common in women with elevated TRV (
Figure G
). Other cardiac and hematologic outcomes occurred with similar incidence between the groups (
Figure G
). In viable pregnancies, preterm birth was more common in women with elevated TRV, while other adverse obstetric and fetal outcomes did not differ between the groups (
Figure G
).

Conclusion:
In conclusion, we identified a higher incidence of VTE, preterm birth and postpartum readmission in pregnant women with SCD and elevated TRV. These complications may be associated with worse SCD burden; however, the potential mechanistic link between pregnancy, VTE and PH as assessed by elevated TRV requires further study.
Abstract 9417: Prognostic Value and Predictors of Right Ventricular Dysfunction by Magnetic Resonance Imaging in Non-Ischemic Cardiomyopathy
Authors: Wang Tom , Kocyigit Duygu , Chan Nicholas , Anthony Chris , Bullen Jennifer , Popovic Zoran B , Tang Wai Hong W , Griffin Brian P , Flamm Scott D , Kwon Deborah H
Published: April 2022

Background:
Challenges remain in our understanding of implications of right ventricle (RV) dysfunction in heart failure. Cardiac magnetic resonance imaging (CMR) is the reference standard for RV quantification, but has seldomly been studied for this purpose in cardiomyopathy patients. We evaluated the predictors and outcomes of reduced CMR-derived right ventricle function in non-ischemic cardiomyopathy (NICM).

Methods:
Adult NICM patients undergoing CMR quantifying the RV during 2002-2017 were retrospectively studied. Multivariable linear and Cox proportional hazards regression were used to identify factors associated with reduced RV ejection fraction (RVEF) and adverse outcomes. The primary endpoint was all-cause mortality, heart transplant and/or left ventricular assist device implantation.

Results:
Amongst 624 NICM patients, mean age was 52.7±15.9 years, 253 (40.5%) were female, and RVEF was 43±13%. Factors independently associated with RVEF (beta-coefficients, P-values) were male (-3.26, P<0.001), New York Heart Association Class (-1.78, P=0.003), left ventricular ejection fraction (0.39, P<0.001), right ventricular end-diastolic volume indexed (-0.15, P<0.001), and mitral regurgitant fraction (MR-RF) (-0.18, P<0.001). Reduced RVEF was independently associated with the primary endpoint (occurring in 113 (18.1%) patients), hazards ratio 0.81 (95% confidence interval 0.74-0.89), with other predictors being age, diabetes, late gadolinium enhancement score and MR-RF(Table). Prognostic thresholds for clinically significant and severe RVEF were determined to be RVEF≤43% and ≤31% respectively.

Conclusion:
Reduced RVEF was prevalent in NICM patients, and was independently associated with worse prognosis in NICM. Important clinical and CMR factors associated with lower RVEF were identified, as well as the optimal prognostic RVEF thresholds.