bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17112: Transgenic Endothelial-Specific HIV-Nef Expression Induces Pulmonary Hypertension and Systemic Vascular Dysfunction, Which Can Be Reverted by Treatment With Statin
Authors: Bogatcheva Natalia , Chelvanambi Sarvesh , Chen Xingjuan , Obukhov Alexander , Clauss Matthias
Published: July 2021

Introduction:
HIV patients on ART perplexingly remain at higher risk for developing cardiovascular diseases including acute peripheral arterial disease and pulmonary hypertension. A likely culprit for observed vascular changes is HIV protein Nef, detected both intracellularly and extracellularly in the absence of HIV RNA or DNA. Nef is known to induce endothelial dysfunction through the activation of NADPH; statins are known to inhibit NADPH activation.

Hypothesis:
Nef expression in endothelial cells will trigger cardiopulmonary and vascular pathology; Nef effects will be reversed by statin.

Methods:
Endothelial-specific expression of HIV-Nef was achieved by mating the VE-Cadherin-Tet off mice with TRE-Nef mice. The resulting Nef+ double transgenics and their Nef- negative littermates were maintained without doxycycline to induce Nef expression. Changes in pulmonary acceleration and ejection times were analyzed by ultrasound (INVEVO2100). Additionally, we assessed the ability of bradykinin-preconstricted aortic rings to dilate in response to acetylcholine in NO-dependent manner.

Results:
Between week 10 and week 13 of age, Nef expressing mice displayed gradual reduction of PAT/PET ratio (down to the 75% of the original PAT/PET ratio at week 10), indicative of developing pulmonary hypertension (N=6). PAT/PET ratio in Nef-negative mice did not change significantly between week 10 and 13 of age. Importantly, statin treatment initiated at week 10 completely suppressed PAT/PET changes developing in Nef-expressing mice. Arterial rings from Nef expressing mice (n=4) showed significantly impaired dilatation in response to acetylcholine (10% relaxation in Nef+ mice vs 40% relaxation in Nef-negative littermates, p=0.03), indicative of changes in systemic circulation. This difference was significantly attenuated in Nef+ mice receiving statin treatment.

Conclusions:
Our data suggests that mice with endothelial expression of HIV-Nef display pathological changes in pulmonary and systemic circulation. Statin treatment significantly attenuates changes in parameters indicative of pulmonary and systemic hypertension, suggesting that statin will be beneficial for patients with HIV-induced cardiopulmonary and vascular diseases.
Abstract 17122: Cardioprotection With Proangiogenic Nanomaterials Formulated With CHIR99021 and FGF1
Authors: Fan Chengming , Oduk Yasin , Zhao Meng , Tang Yawen , Walcott Gregory P. , Zhang Jianyi , Zhu Wuqiang
Published: July 2021

Introduction:
We aimed at to investigate whether activation of both FGF1 and Wnt1 synergistically enhances angiogenesis and render the cardioprotection in hearts with post infarction LV remodeling.

Materials and methods:
CHIR99021 (a Wnt1 activator) and FGF1 were encapsulated into poly lactic-co-glycolic acid nanoparticles (CHIR99021/FGF1-NPs). Ischemic heart models were generated in C57BL/6 mice or Yorkshire swine by ligation of the left anterior descending coronary. The mice were randomly divided into 6 groups: Myocardial infarction (MI) Only (n=11), MI with nanoparticles (CHIR99021 or/and FGF1 loaded) injection (n=12, each), MI with non-loaded nanoparticles injection (n=11) and Sham group (n=10). The swine were divided into 3 groups: ischemic reperfusion injury (IRI) (n=4), IRI with CHIR99021/FGF-NPs injection (n=4) and Sham group (n=4). Left ventricle function 4 week after surgery were evaluated by Echocardiography. Cell proliferation was assessed via immunostaining in ischemic hearts and in cultivated human umbilical vein endothelial cells (HUVECs) and Human vascular smooth muscle cells (HVSMCs) using the following markers: Ki67, Brdu, PH3, and Aurora B. Apoptosis was determined with TUNEL staining. Cardiac fibrosis was evaluated via Sirius red and Fast green staining (mice) and magnetic resonance imaging (swine).

Results:
CHIR99021/FGF1-NPs treatment attenuated fibrosis and preserved heart contractile function in mice and swine models of postinfarction LV remodeling. The proportion of cells that expressed cell cycle markers (Ki67; BrdU; Aurora B and PH3) was significantly greater in CHIR99021+FGF1 treatment group than CHIR99021, FGF1 and PBS treatment group. The proportion of apoptotic cells was significantly smaller in CHIR99021+FGF1 treatment group than in groups of control, VEGF, CHIR99021, or FGF1 treatment alone.

Conclusions:
CHIR99021 and FGF synergistically activate cell cycle and reduce apoptosis, which accompanied by a significant improvement of cardiac function.
Abstract 17132: Atrial Fibrillation Ablation in Heart Failure: Temporal Trends and Outcomes in Hospitalized Patients
Authors: Agarwal Manyoo , Patel Brijesh , Garg Lohit , Shah Mahek , Khouzam Rami , Kabra Rajesh
Published: July 2021

Introduction:
Recent studies have shown catheter ablation for atrial fibrillation (AF) in patients with heart failure (HF) to have better outcomes over medical therapy. While AF ablation is predominantly an outpatient procedure, some patients may require longer hospitalization. Limited literature exists describing the trends of hospitalizations for HF patients undergoing AF ablation.

Methods:
Using ICD-9 (diagnosis and procedure codes) in nationwide inpatient sample database 2003 to 2014, we identified all HF adults who were admitted with a principal diagnosis code of AF (427.31) (n= 4,670,400) (AF-HF). Among these, we identified those with a principal procedure code of catheter ablation (37.34) and studied the temporal trends of clinical characteristics and outcomes (in-hospital mortality and complications) for this cohort (Table).

Results:
The overall number of AF-HF patients undergoing AF ablation was 62,653; with an increase from 1,928 in 2003 to 6,860 in 2014 (p trend<0.001). As shown in Table, over this 12-year period; mean age and proportion of females decreased, while there was an increase in blacks, clinical comorbidity burden, admissions to teaching hospitals and southern US region (all p trend<0.001). The overall procedure related complications (vascular, cardiac, respiratory, neurologic) increased, the in-hospital mortality rate decreased from 1.7% to 0.5% (all p trend<0.001).

Conclusions:
During 2003-2014, the annual incidence of AF ablation related hospitalizations in HF patients increased significantly. Despite increase in clinical comorbidities burden and procedural complication rates, the mortality rate declined.
Abstract 17134: Variation Within a Left Ventricle-Specific
Hand1
Enhancer Impairs Gata Transcription Factor Binding and Disrupts Ventricular Conduction System Development
Authors: Vincentz Joshua W , Firulli Beth A , Toolan Kevin P , Arking Dan E , Sotoodehnia Nona , Wan Juyi , Chen Peng-Sheng , de Gier-de Vries Corrie , Christoffels Vincent M , Rubart-von der Lohe Michael , Firulli Anthony B
Published: July 2021

The ventricular conduction system (VCS), composed of the His bundle, the left and right bundle branches, and the Purkinje fiber network, rapidly propagates electrical impulses through the ventricles to coordinate chamber contraction. An ECG depicts VCS-mediated ventricular depolarization as the QRS interval. Disorders of the VCS may manifest as arrhythmias, and are associated with increased risk of sudden cardiac death and overall mortality. The genetic and developmental mechanisms underlying VCS dysfunction are poorly understood. Genome-wide association studies have identified multiple single nucleotide polymorphisms (SNPs) associated with VCS arrhythmias. A majority of these SNPs occur outside of coding domains, within intergenic or intronic regions. We hypothesize that such pathogenic SNPs may impact VCS development and function by altering the expression of critical genes. Two intergenic SNPs associated with QRS prolongation occur near the bHLH cardiac transcription factor
HAND1
. We have identified a left ventricle (LV) enhancer, located between these two SNPs, that is necessary and sufficient for LV
cis
-regulatory activity. Two evolutionarily conserved GATA transcription factor consensus-binding sites within this enhancer are bound by GATA4 and necessary for
cis
-regulatory activity. CRISPR-mediated deletion of this enhancer dramatically reduced
Hand1
expression solely within the LV. Mice homozygous for this deleted enhancer displayed dysregulated LV gene expression, morphologically abnormal His bundles and left bundle branches, and a VCS phenotype consistent with right bundle branch block. Genome-wide association analyses of human patients with QRS prolongation revealed additional, linked SNPs, one of which overlaps with a critical GATA
cis
-regulatory element within the LV-specific
Hand1
enhancer. This SNP disrupts GATA4 binding. Ongoing studies of mice that genetically mimic these minor SNP variants will assess reduced
Hand1
expression and impaired VCS function. We conclude that a LV-specific
Hand1
enhancer is necessary for VCS development and a SNP associated with QRS prolongation directly influences GATA4 binding to a critical
cis
-regulatory element within this enhancer.
Abstract 17145: Outcomes of Transcatheter Occlusion of Patent Ductus Ateriouses in Infants ≤ 6 Mouths
Authors: Hua Yimin , Li Yifei , Zhou Kaiyu
Published: July 2021

Objectives:
We sought to analyze the outcomes of transcatheter patent ductus arteriosus (PDA) occlusion using a variety of devices in infants ≤ 6 mouths and discuss the transcatheter occlusion indication of PDA in early infants.

Methods and Results:
A total of 72 patients underwent successful transcatheter device closure. The mean age at catheterization was 4.9±1.8months (1-6 months) with a mean weight at catheterization of 5.1±1.9kg (1.9-6.7kg), the mean PDA diameter of 3.9±0.8mm (1.8-5.3mm),the mean systolic pulmonary arteriosus pressure of 55.7±8.9 mmHg (46-79mmHg). Among these suffered infants, companied with 72cases of growth retardation, 48 cases of recurrent lower respiratory tract infection, 35 cases associated with congestive heart failure, and 5 cases of respirator-oxygen-dependent. 4/6-8/10 PDA occluder was selected for transcatheter device closure, and intraoperative blood transfusion were performed in 46 cases. All subjects resulted with occluder position in good shape, no residual shunt; whileas 16 cases with aortic blood flow velocity increased slightly, 12 cases with left pulmonary artery blood flow velocity increased slightly just postoperation. And in follow-ups the increased velocity of and pulmonary blood flow gradually returned to normal. Follow-up data showed, all subjects resulted good outcomes with growth significantly improved, congestive heart failure cured and repeated lower respiratory tract infection significantly reduced postoperative.

Conclusions:
In experienced heart center, percutaneous closure of PDA should be considered even in infants ≤ 6 mouths. The indications include PDA infants with respirator-oxygen-dependent, congestive heart failure, and recurrent lower respiratory tract infection and growth retardation. Children underwent PDA occlusion would result with improved growth and development, recovered heart function and less lower respiratory tract infection.
Abstract 17150: LDL-C Response to Portfolio Foods Containing High Levels of Phytosterols, Whole Food Fiber, and Alpha-Linoleic Acid in Statin Reluctant Patients: Impact of CYP7A1-rs3808607 and APOE Isoforms
Authors: Kopecky Stephen L , Klodas Elizabeth , Alias Soumya , Bauman Jessica , Jew Stephanie , Jones Peter J
Published: July 2021

Introduction:
Up to 20% of outpatients receiving HMG-CoA reductase inhibitors (statins) experience treatment reluctance on the basis of side effects, leaving a large population at increased risk of CVD. We hypothesized that a practical food-based approach can be utilized to lower LDL-C in statin reluctant patients and that the lipid response can be predicted based upon CYP7A1-rs3808607 (CYP7A1) and APOE genetic isoforms.

Methods:
This was a multicenter, randomized, double-blind, free-living cross-over study composed of 2 phases of 4 wk each, separated by a 4 wk washout. Participants (n=54) received an assortment of individually packaged, shelf stable snacks along with printed instructions to ingest 2 servings of the foods per day as a substitute for similar items they were eating already. No other dietary or behavior adjustments were requested. Treatment products supplied at least 1800 mg alpha-linoleic acid (ALA), 5 g of fiber and 1g of phytosterols per serving. Control products were calorie-matched like items drawn from the general grocery marketplace. Lipid parameters were measured and averaged over 2 d at baseline and at 4 wk of each phase. Ingestion of study foods was confirmed by C18:3n3 serum level assessment. Single nucleotide polymorphisms and APOE isoform were assessed by Taqman genotyping assay.

Results:
As compared to control, LDL-C decreased 8.8% in the treatment arm (p<0.0001, range -37.6% to +20.5%) and total cholesterol fell 5.1% (p<0.004). No significant change was seen in HDL-C, TG or fasting glucose levels. LDL-C was reduced by diet in CYP7A1 T/T homozygotes (-0.3924+0.1271mmol/l, p = 0.0033) and APOE4 carriers ( -0.3808+0.098 mmol/l, p = 0.0003).

Conclusions:
Significant LDL-C reductions can be affected through a simple food intervention supplying high levels of phytosterols, fiber and ALA. CYP7A1 and APOE isoforms influence the variability in LDL-C response and can help identify individual patients especially appropriate for a food-based LDL-C lowering approach. Given the large number of patients unable/unwilling to take statins, our findings have significant impact for management of this challenging population.
Abstract 17157: Clinical Impact of Digoxin Discontinuation at Hospital Discharge in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Lodhi Fahad , Malik Awais , Qamer Syed Z , Arundel Cherinne , Sheriff Helen , Lam Phillip , Bhyan Poonam , Singh Nankumar , Deedwania Prakash , Fonarow Gregg , Ahmed Ali
Published: July 2021

Introduction:
Digoxin use is associated with a lower risk of hospital admission and readmission in patients with heart failure with reduced ejection fraction (HFrEF). Moreover, PROVED and RADIANCE trials have shown that digoxin discontinuation is associated with lower ejection fraction (EF), higher heart rate, and worse heart failure (HF) symptoms in chronic HFrEF patients. Despite these results, digoxin use has declined over recent years. In this study, we examined the clinical impact of digoxin discontinuation at hospital discharge in elderly patients with HFrEF.

Hypothesis:
Digoxin discontinuation at hospital discharge will increase mortality and heart failure readmission in HFrEF patients.

Methods:
Of 10,625 patients hospitalized with HFrEF (EF≤40%) in Medicare-linked OPTIMIZE-HF registry, 3,225 were receiving digoxin prior to admission but it was discontinued in 655 of these patients at the time of discharge. Propensity scores for digoxin discontinuation, estimated for each of the 3,225 patients, were used to match 616 pairs of patients (digoxin continued vs. discontinued) balanced on 60 baseline characteristics including age (mean 76 years), EF (mean 26%), gender (31% females) and race (15% African America) among others.

Results:
Among 1,232 matched patients, digoxin discontinuation was associated with a higher risk of all-cause mortality at 30-days (12% vs. 8%; HR 1.45; 95% CI 1.01-2.07; p=0.044) and 6-months (HR 1.32; p=0.009) but not at 1-year (HR 1.18; p=0.07). Digoxin discontinuation was also associated with increased combined heart failure readmission/all-cause mortality at 4-years of follow up (HR 1.16; 95% CI 1.03-1.30; p=0.017).

Conclusions:
In patients with HFrEF receiving digoxin prior to admission, digoxin discontinuation at discharge from hospital is associated with increased short-term all-cause mortality and long-term heart failure readmission/all-cause mortality.
Abstract 17160: Quantitative Characterization of Porcine Peripheral Artery Disease Models
Authors: Deppen Juline , Wang Lanfang , Qiu Deqiang , Leatherday Christopher , Oshinski John N , Levit Rebecca
Published: July 2021

Introduction:
Peripheral artery disease (PAD) is a significant age-related medical condition affecting over 200 million patients worldwide. PAD cell therapy clinical trials have shown minimal benefits, and questions remain regarding the optimal cell type, dose, and delivery method. A large animal preclinical PAD model has not been standardized nor quantitatively characterized, potentially contributing to the lack of success in these trials.

Hypothesis:
We hypothesize that a durable model of PAD can be created in swine to test cell therapy efficacy as determined through quantitative measurements of microvascular muscle perfusion and limb functionality while walking.

Methods:
Swine were divided into three cohorts and underwent unilateral ligation of 1) the external iliac and circumflex iliac arteries, 2) the external, internal, and circumflex iliac arteries, or 3) distal hind limb arteries to create models of PAD. Automated gait analysis with a pressure-sensitive walkway was performed at various time points pre- and post-model creation to quantify functional deficits of trotting animals. Objective calculation of various gait parameters was performed by walkway software. A pulsed arterial spin labeling (ASL) MRI sequence was used to measure perfusion in pig hind limbs during cuff-induced reactive hyperemia. Fluoroscopy-based angiography was performed during model creation and sixth week terminal procedures, and fluorescent microsphere perfusion measurements were obtained for limb muscles at study conclusions.

Results:
The most severe, durable functional deficits were exhibited in Cohort 2. Cohort 1 exhibited transient functional abnormalities in ischemic vs. non-ischemic hind limbs that returned to baseline in one week. Animals in Cohort 3 also displayed slight deficits early that quickly resolved. ASL MRI successfully quantified microvascular perfusion in hind limb skeletal muscle. Extensive collateral formation in ischemic hind limbs was detected at the end of each study.

Conclusions:
External and internal iliac artery ligation is a promising strategy to establish a durable model of hind limb ischemia in which to test the efficacy of cell and other therapeutics, better facilitating the transition of PAD therapies from bench to bedside.
Abstract 17163:
Nox4
Deletion Attenuates Age-Associated Vascular Inflammation and Atherosclerosis Burden in Hyperlipidemic Mice by Modulating Macrophage Phenotype
Authors: Vendrov Aleksandr E , Lozhkin Andrey , Madamanchi Nageswara R , Runge Marschall S
Published: July 2021

Introduction:
Increased vascular reactive oxygen species (ROS) levels and chronic inflammation are hallmarks of vascular aging. We previously reported that expression of NOX4 NADPH oxidase increases with age in mouse and human arteries and correlates with inflammatory cytokine secretion and atherosclerotic lesion progression.

Hypothesis:
To determine whether NOX4 promotes atherosclerosis in aging, we assessed vascular inflammation and atherosclerosis burden in Nox4
-/-
/
Apoe
-/-
and
Apoe
-/-
mice.

Results:
Aortic atherosclerotic lesion area was not different between 5-month old (young)
Nox4
-/-
/
Apoe
-/-
and
Apoe
-/-
mice fed a Western diet for 3 months. Lesion area increased significantly in 16-month old (aged) compared with young mice but was 51% lower in
Nox
4
-/-
/
Apoe
-/-
versus
Apoe
-/-
mice (n=12,
P
<0.0001). Immunofluorescence analysis of aorta transverse sections showed 30% lower ROS levels and significantly reduced expression of inflammatory cytokines - CCL2 and IL6 - in atherosclerotic lesions of aged
Nox4
-/-
/
Apoe
-/-
versus

Apoe
-/-

mice. Flow cytometry analysis of atherosclerotic aortas showed significantly higher number of CD11b
+
macrophages in the lesions of aged
Apoe
-/-
versus

Nox4
-/-
/Apoe
-/-

mice. However, the number of M1 pro-inflammatory macrophages (CD38
+
) was not different, whereas percentage of M2 macrophages (Egr2
+
) was significantly higher in aged

Nox4
-/-
Apoe
-/-

versus

Apoe
-/-

mice (46% vs. 33%, respectively). In addition,
Nox4
deletion increased the ratio of M2/M1 macrophages in the atherosclerotic aortas from aged

Apoe
-/-

mice (0.56 and 0.43 in
Nox
4
-/-
/
Apoe
-/-
and
Apoe
-/-
, respectively). Macrophages isolated from

Nox4
-/-

mice showed lower number of M1 cells after IFNγ+LPS treatment and higher number of M2 cells after IL4 treatment versus macrophages from the wild-type. Furthermore, wild-type macrophages showed significantly higher secreted IL1β levels after IFNγ+LPS treatment versus macrophages from

Nox4
-/-

mice.

Conclusions:
These data suggest that increased vascular NOX4 levels in aged

Apoe
-/-

mice promote a proinflammatory environment, enhancing plaque macrophage accumulation and skewing polarization to M1 phenotype resulting in inflammasome activation and atherosclerotic lesion expansion.
Abstract 17168: Stroke Stabilization Following Repetitive Xenon Liposomal Delivery
Authors: Yin Xing , Dandekar Manoj P , Peng Tao , Klegerman Melvin E , Moody Melanie R , Kim Hyunggun , McPherson David , Huang Shaoling
Published: July 2021

Introduction:
Stroke is a leading cause of brain injury. Most stroke survival has long-term disability due to cerebral damage. We have demonstrated that xenon(Xe) liposomal injection provides novel neuroprotection.

Hypothesis:
Repetitive Xe-liposomal administration over a longer period post stroke results in brain protection.

Methods:
Stroke was induced by middle cerebral artery occlusion(MCAO) for 6 hours. Xe-liposomes were intravenously administrated for varying duration and time periods to investigate the administration frequency and administration duration. Infarct size was evaluated by TTC staining. Forelimb placing/Grid walking were conducted to evaluate neurological function.

Results:
MCA occlusion for 6 hours generated a 23%±2.8% infarct volume. Repetitive injections at every one hour for 5 injections effectively reduced infract volume(3.8%±0.2%,p<0.05) than a single injection(11%±2.3). Extending Xe liposomal treatment to 3 days further decreased infarct volume to 1.9%%±0.7 (p<0.01,Fig.1A). Behavior tests results are correlated with TTC staining(Fig. 1B).

Conclusions:
Repetitive Xe-liposomal administration over the first 6 hours following MCAO and extending daily administration results in brain stabilization.This novel method may help may help extend the time window for stroke treatment.
Abstract 17171: Kruppel-Like Factor 4 Deletion Regulates Lymphatic Endothelial Cell Homeostasis
Authors: Mastej Victoria , Axen Cassondra , Wary Kishore
Published: July 2021

Introduction and Hypothesis:
Lymphatic vasculature exquisitely controls the clearance of metabolic end products, removal of bacterial endotoxins, and trafficking of immune cells. Signaling pathways that converge into endothelial cell kruppel-like factor 4 (KLF4) provide an atheroprotective role; however, the role of lymphatic endothelial cell (LEC)-KLF4 in these processes has not been clarified. Thus, we examined whether LEC-specific deletion of Klf4 alleles LECs.

Methods and Results:
After several generations of breeding, we transferred ROSA
mT/mG
(dual-fluorescent reporter allele mT/mG) to Prox1
CreERT2
(tamoxifen, TAM) inducible mice in C57 background to generate ROSA
mT/mG
::Prox1
CreERT2
mice. In the next breeding scheme, ROSA
mT/mG
::Prox1
CreERT2
female mice were crossed with male Klf4
fl/wt
(Klf4 floxed allele) mice to generate heterozygous ROSA
mT/mG
::Prox1
CreERT2
::Klf4
fl/wt
offspring (50%). Thereafter, we bred male ROSA
mT/mG
::Prox1
CreERT2
::Klf4
fl/wt
with female ROSA
mT/mG
::Prox1
CreERT2
::Klf4
fl/wt
to produce ROSA
mT/mG
::Prox1
CreERT2
::Klf4
fl/fl
genotype (25%). These mice (12-14 weeks old) received TAM for five consecutive days, and on 21
st
or 28
th
day all mice were sacrificed. To confirm LEC Cre activation after TAM administration, we prepared cryosections of lung and the heart tissues. Mice receiving TAM showed lively and clear separation of green fluorescent protein (GFP) and tomato-Red colors, showing LEC specificity of Prox1
CreERT2
transgenic methodology. Cryosectioning combined with low- and high-resolution microscopy, and morphometric analyses of H&E sections showed disruption of LEC function and integrity in these mice. Biochemical experiments underway will address the role of KLF4 in lymphatic vessels homeostasis.

Conclusion:
These results indicate a key role for Klf4 in the regulation of lymphatic vessels.
Abstract 17183: Genetically Engineered Calcification Increases Surface Roughness and Changes the Distribution of Atherosclerotic Plaques in Mice With Atherosclerosis
Authors: Mararenko Anton , Bar-El Ralph , Assaf Maryann , Singla Pranav , Kelly Ian , Carka Dorinamaria , Millan Jose Luis , Beatty Brian L , Savinova Olga V
Published: July 2021

Background:
Atherosclerosis is an inflammatory disease that contributes significantly to cardiovascular mortality. Arterial stiffening due to calcification can coexist with or directly influence pathogenesis of atherosclerosis. We hypothesize that arteriosclerosis caused by genetically engineered calcification in mice redistributes shear stress on the endothelial cells, which in turn leads to further accelerated rate of plaque formation.

Methods:
All of the mice had an LDL receptor mutation and were fed pro-atherogenic diet (1.25% cholesterol). The case group overexpressed tissue-nonspecific alkaline phosphatase in endothelial cells (eTNAP). The luminal surfaces of descending thoracic aorta (TA) and suprarenal abdominal aorta (AA) were scanned using Sensofar S Neox optical confocal microscope at 1 μm vertical resolution. The surface topographies per sample, each measuring 500 x 700 microns, were analyzed for ISO 25178-2 areal roughness parameters using SensoMap. Parameters were compared by t test (n=5 eTNAP, n=6-7 control).

Results:
We observed a significant difference in the incidence as well as the morphology of the plaques in the eTNAP group compared to control mice. There was a 4.8 fold increase in the number of topological motifs in the thoracic aorta of the eTNAP vs. controls (p < 0.01). Similarly, the number of motifs was increase in the abdominal aorta of the eTNAP mice compared to controls (2.8 fold; p=0.06). The average area of the motifs was significantly larger in the controls compared to the eTNAP group in both segments of the aorta (p=0.06 TA; p < 0.05 AA). The maximum height of the lesions in the TA was not different between the groups (p=0.62), however increased by 74% in the abdominal aorta of the eTNAP compared to controls (p<0.05). Finally, the surface developed interfacial area ratio (Sdr, a parameter of texture) was increased in the eTNAP group in both the TA (p < 0.05) and AA regions (p < 0.01).

Conclusion:
Arteriosclerosis increases surface roughness. In our model, the abdominal region had a high incidence of taller, irregular lesions whereas those in the thoracic aorta were flatter and more spaced. The high resolution scans will be further used to study the hemodynamic disturbances to the endothelial cells using flow dynamics simulations.
Abstract 17192: ALDH1A3 Induces NFY to Coordinate Transcription of Cell Cycle and Metabolic Genes Necessary for Smooth Muscle Proliferation in Pulmonary Hypertension
Authors: Li Dan , Shao Ningyi , Contrepois Kevin , Taylor Shalina , Otsuki Shoichiro , Wang Lingli , Rabinovitch Marlene
Published: July 2021

Background:
In developing disease modifying therapies for pulmonary arterial hypertension (PAH), it is important to understand the molecular basis for hyperproliferation of pulmonary arterial smooth muscle cells (PASMC) that progressively occlude the vessel lumen. Previously we presented studies using H3K27 ChIP Seq and RNA Seq in PAH vs. control PASMC, and showed that an increase in ALDH1A3 is responsible for both heightened proliferation and H3K27ac enhancer marks in cell cycle and metabolic enzyme genes.

Methods and Results:
We now present molecular and metabolic studies and experiments in transgenic mice that delineate the mechanism by which ALDH1A3 plays a critical role in PAH PASMC proliferation. Promoter binding motif analysis of sites that are ALDH1A3 dependent in PAH PA SMC identified NFY family members as putative transcription factors. We confirmed their role in increasing three energy producing metabolic enzymes PKM2, DLD and IDH1 and two cell cycle genes, CCNA2 and CDC20. We verified that their mRNA transcripts and protein levels are elevated in PAH PASMC and dependent on increased ALDH1A3 and NFY(n=3, p<0.05) The accumulation of acetyl-CoA is increased in PAH PASMC with siControl vs. siALDH1A3. The nuclear localization of increased PAH PASMC ALDH1A3 indicates that generation of acetyl CoA from acetylaldehde could acetylate histones at H3K27 target sites marked by NFY binding. From non-targeted metabolomic analyses by LC/MS, we found ALDH1A3 dependent metabolites in the glycolytic and pentose phosphate pathways in PAH PASMC, consistent with the functions of PKM2, DLD and IDH1. We then showed that ALDH1A3 is induced by hypoxia, and required for SMC proliferation and pulmonary hypertension in mice exposed to three weeks of chronic hypoxia (10% oxygen). Gender matched transgenic mice with SMC deletion of
Aldh1a3
had reduced pulmonary hypertension when compared to littermate controls, assessed by right ventricular systolic pressure (n=8, p<0.05).

Conclusions:
Our studies reveal an ALDH1A3-dependent coordination of histone acetylation at NFY transcription factor binding sites of key metabolic enzyme and cell cycle genes in highly proliferative PAH PASMC from PAH patients, that is critical in the development of pulmonary hypertension.
Abstract 17194: Incremental Value of JTc Interval in Improving Risk Stratification for Life-Threatening Ventricular Arrhythmias in Patients Considered Low Risk by LVEF
Authors: Khan Mohsin , Olet Susan , Mortada Mohammad E , Zahwe Firas , Zilinski Jodi , Nangia Vikram , Dhala Anwer , Choudhuri Indrajit , Bhatia Atul , Niazi Imran , Sra Jasbir , Jahangir Arshad
Published: July 2021

Introduction:
ICD implantation is recommended in patients with LVEF<35%, while those with LVEF between 35 to 40% are not considered at high risk for primary prevention ICD implantation. A subset of these patients develops life threatening ventricular arrhythmias (VA) and improvement in risk stratification may help identify and implement life-saving intervention.

Hypothesis:
Prolonged repolarization is a marker of electrical instability and JTc interval on ECG could provide prognostic information in patients with LVEF 35-40% incremental to that from LVEF.

Methods:
Patients ≥18 yr with no history of VA and an ECG and echocardiogram obtained at initial encounter between 11/2011 to 12/2016 with long-term follow-up were identified. The incremental predictive ability of JTc interval on improvement in risk stratification for VA was determined by receiver operating characteristics (ROC) curve, integrated discrimination improvement (IDA) and net reclassification improvement (NRI) analysis. All tests were performed at a 5% level of significance.

Results:
Out of 29,700 pts that met inclusion criteria, 1,102 (3.7%) had LVEF 35-40% (mean age 70.5±14.6 yrs, 49% males, CAD 67%) and 24,894 (84%) LVEF >40% (65.9±16.3 yrs , 61.8% M). Over the mean follow-up of 4.6±4.2 years, the incidence of VT/VF/cardiac arrest was 16.1% in patients with LVEF 35-40% compared to 4.1% with LVEF >40%. For every 50 ms increase in JTc interval above 300 ms, the risk for arrhythmic event in LVEF 35-40% increased two-fold (Odds Ratio=1.83 (95 % CI 1.72-1.94, P=0.013). Incorporation of JTc to LVEF improved the C statistics (95% Confidence Limit) in the model with only LVEF from 0.56 (0.54-0.57) to 0.72 (0.70-0.73) for the model combining LVEF and JTc. In addition, NRI was estimated at 0.57, which was statistically significant with p values <0.001 while IDI was estimated as 0.015 with p values <0.001 for the model incorporating JTc to LVEF.

Conclusions:
In patients with LVEF 35-40% considered low risk for life threatening VA by EF, incorporating JTc interval information improved risk stratification and identified those who subsequently developed VT/VF or cardiac arrest and thus identifies a subgroup that can benefit from prophylactic ICD implantation.
Abstract 17195: Accuracy of Fetal Echocardiography in the Current Era
Authors: Haberer Kim L , McBrien Angela , Young Aisling , Savard Winnie , Eckersley Luke , Colen Timothy , Hornberger Lisa K
Published: July 2021

Accuracy of Fetal Echocardiography in Defining Anatomical Details of Fetal Cardiac Pathology in the Current Era

Background:
Enhanced ultrasound technology and improvements in prenatal detection have provided opportunities to fine-tune fetal cardiac diagnoses. We sought to determine the accuracy of fetal echocardiography in defining anatomical details of major structural fetal heart disease(FHD)

Methods:
We queried the fetal echo database at the University of Alberta to identify pregnancies with a major FHD diagnosis between 2007-2018. We excluded simple septal defects, minor valve abnormalities and isolated coarctation. FHD was divided into 12 major categories to examine differences within subtypes. Fetal echocardiography reports were compared to post-natal echocardiography or autopsy when available, to assess segmental anatomy. Differences were described according to the following categories:1) No difference between fetal and postnatal findings 2) Minor differences with no impact on outcome (left superior vena cava), 3) Minor differences that could make a minor difference to the delivery plan or surgery (e.g. vascular ring), 4) Major differences that could lead to a change in the course of pregnancy, delivery or surgical planning (e.g. ductal dependency); 5) Errors of categorization that did not alter surgical planning but could have changed counseling (e.g. associations with extra-cardiac pathology).

Results:
In the study period 744 pregnancies with major FHD were encountered of which 151 (20.3%) had pregnancy termination, 43(6%) intrauterine demise, 6(1%) were lost to followup. 524(71%) were liveborn. Of the 744, 542 (524 echo and 18 autopsy) had confirmation of full cardiac anatomy. Table 1 details the number of cases in whom differences were demonstrated.

Conclusion:
Fetal echocardiography in the current era is highly accurate with few serious errors. Delineating the anatomy of the outflow tracts in complex cardiac lesions remains a challenge
Abstract 17197: Preventive Multivessel Percutaneous Coronary Intervention in St Segment Myocardial Infarction is Associated With Worse Outcomes Than Infarct Related Artery Intervention Alone - A Propensity Matched Comparison
Authors: Tripathi Byomesh , Arora Shilpkumar , Kumar Varun , Sharma Purnima , Mishra Abhishek , Atti Varunsiri , Malhotra Shikha , Patel Nileshkumar J , Deshmukh Abhishek , Gopalan Radha
Published: July 2021

Introduction:
Recent trials have suggested potential benefits of performing multivessel percutaneous coronary intervention (MVPCI) on non-infarct related artery (non-IRA) in ST-segment elevation myocardial infarction (STEMI) patients with multivessel disease.

Methods:
National Readmissions Database (NRD) 2010-14 was utilized to select study cohort. Appropriate International Classification of Diseases, 9th Revision (ICD-9-CM) diagnostic and procedural codes were utilized to identify STEMI patients undergoing multivessel PCI and infarct-related artery only PCI (IRA-PCI). Propensity score matched cohorts using greedy matching algorithm were generated for comparison of outcomes.

Results:
We identified 116592 IRA-PCI (83.97%) and 22257 MVPCI (16.03%) cases. With 1:3 propensity matched cohorts accounting for confounders such as age, gender, race and comorbidities, in comparison to IRA-PCI, MVPCI patients have higher 30-day readmission rate (10.40% vs 9.40%, p=0.001), in-hospital mortality (1.96% vs 1.57%,p<0.001), mechanical circulatory support utilization (4.27 vs 2.44%,p<0.001) as well as higher complication including vascular (0.51% vs 0.28%, p<0.001), cardiac (5.97% vs 3.97%, p<0.001), respiratory (4.89% vs 4.02%,p<0.001), neurologic complications (0.77% vs 0.58%,p=0.003), major bleeding (1.01% vs 0.79%, p=0.002) and cardiac arrest(3.48% vs 3.17%, p=0.027). We also noted higher cost of care ($27100 vs $20900, p<0.001) and length of stay (3.8 days vs 3.4 days, p<0.001) in MVPCI group compared to IRA-PCI group.

Conclusions:
We noted higher 30- day readmission rate, in-hospital mortality, complications and resource utilization with MVPCI compared to IRA-PCI approach among STEMI patients which further demands large-scale randomized control trials to determine the utility of MVPCI in the “real world”.
Abstract 17207: Cardiovascular Risks in Acute Leukemia Patients Treated With Anthracyclines
Authors: Kang Yu , Denduluri Srinivas , Assuncao Bruna M , Scherrer-Crosbie Marielle
Published: July 2021

Introduction:
The incidence of acute leukemia has been increasing by about 1.6% per year in the last decade. Anthracyclines remain a standard of care for patients with acute leukemia; survival is increasing at about 1.0% per year. However, little is known about the incidence and risk of major adverse cardiovascular events (MACE) in patients with acute leukemia.

Hypothesis:
To investigate the incidence of MACE and the risk factors for MACE in patients with acute leukemia treated with anthracyclines.

Methods:
All adult patients with acute leukemia treated with anthracyclines between January 2005 and April 2018 at the hospital of University of Pennsylvania were studied. MACE were defined as cardiovascular death, symptomatic heart failure, non-fatal acute coronary syndrome, non-fatal ventricular arrhythmia and non-fatal ischemic stroke. Differences between patients with or without MACE were compared by Student’s t test or the Wilcoxon rank comparison. Cox proportional hazard analysis was used to determine significant clinical and echocardiographic parameters associated with MACE.

Results:
Six hundred and seventy-four patients (234 acute lymphoblastic leukemia (ALL), 440 acute myeloid leukemia (AML), age range: 22 to 93 years) were studied. Seventy-one patients (10.5%) experienced MACEs during a median follow-up period of 16 months (4 to 146 months) after the initiation of chemotherapy. The median time to MACE was 13 months (5 to 107 months). In the patients with MACE,59 (8.8%) developed symptomatic heart failure, 7 (1.0%) died of cardiovascular causes, 3 (0.4%) experienced non-fatal acute myocardial syndrome and 2 (0.3%) had an ischemic stroke. The Table summarizes the characteristics of patients with and without MACE. In a multivariable analysis, a previous history of heart failure (HR: 4.632, P=0.000, 95% CI: 2.572-8.341), leukemia type (HR: 3.155, P=0.002, 95% CI: 1.544-6.446) and baseline LVEF (HR: 0.973, P=0.000, 95% CI: 0.955-0.991) remained associated with MACE.

Conclusion:
Patients with acute leukemia treated with anthracyclines have a high rate of MACE after chemotherapy. A previous history of heart failure, baseline LVEF and type of leukemia may help to stratify acute leukemia patients at highest risk for MACEs after anthracycline therapy.
Abstract 17208: Trends in Hospitalizations Due to Cocaine-Induced Acute Myocardial Infarction: Results From National Inpatient Sample, 2005-2014
Authors: Saxena Anshul , Rubens Muni , Das Sankalp , Ramamoorthy Venkataraghavan , McGranaghan Peter , Veledar Emir
Published: July 2021

Introduction:
According to the National Institute on Drug Abuse, lifetime cocaine use has remained stable since 2009. An estimated 1.5 million individuals aged ≥12 years reported cocaine use in 2014. Cocaine use is a significant risk factor for acute myocardial infarction (AMI), especially in the age group 18-45 years. Hence, we examined trends in hospitalizations due to cocaine-induced AMI in the United States.

Methods:
The current study was a retrospective analysis of the National Inpatient Sample, collected during the period 2005-2014. Participants between 18 and 45 years were included in the analysis. Cocaine-induced AMI hospitalizations were identified using ICD-9-CM codes 304.2X and 305.6X for cocaine dependence or abuse, and 410.XX for AMI diagnosis. We used Cochran Armitage test for categorical variables and Cuzick nonparametric test for trends for continuous variables.

Results:
A total of 49,715 weighted cocaine-induced AMI hospitalizations were reported during the study period. Cocaine-induced AMI hospitalizations increased from 4,619 in 2005 to 5,065 in 2014 (relative increase, 9.7%,
P
trend
=0.124). Majority of the patients were non-White (55.3%), men (79.3%), in the age group 41-45 years (83.1%), and with Medicare/Medicaid coverage (51.2%). Highest change in trend was observed for non-White population and Medicare/Medicaid payers.

Conclusion:
Our study showed that cocaine-induced AMI hospitalizations remained stable during the years 2005-2014. Initial results point towards structural and racial disparities in such hospitalizations, especially among non-White men and population with Medicare/Medicaid coverage. Effective interventions to reduce cocaine use are needed, and treatment must be based on 2008 AHA guidelines for cocaine-associated chest pain and myocardial infarction.
Abstract 17217: ActRIIA-Fc Rebalances Activin/GDF and BMP9 Signaling to Attenuate Experimental Pulmonary Hypertension
Authors: Yung Lai-Ming , Yang Peiran , Bocobo Geoffrey , Dinter Teresa , McNeil Megan , Chen Po-Sheng , Southwood Mark , Morrell Nicholas , Pearsall Scott , Joshi Sachindra , Sako Dianne , Li Gang , Kumar Ravindra , Yu Paul
Published: July 2021

Introduction:
Therapies targeting the underlying mechanisms of pulmonary arterial hypertension (PAH) might modify the natural history of disease. The genetics of heritable PAH implicate deficient BMP signaling as a pathogenetic driver. Lung tissues from experimental and human PAH exhibit deficient BMP & excessive TGFβ signaling. While previous studies suggest agonism of BMP9 signaling or inhibition of TGFβ signaling may prevent experimental PH, the roles of activin and growth and differentiation factor (GDF) ligand signaling are unclear. ACTRIIA-Fc (sotatercept) is an activin- and GDF8/11-specific ligand trap currently in Phase 2 studies for anemia and multiple myeloma.

Hypothesis:
ACTRIIA-Fc inhibits activin and GDF8/11 signaling in vascular cells to attenuate experimental PH and pulmonary vascular remodeling.

Methods:
Impact of ACTRIIA-Fc on BMP & TGFβ signaling was examined in human pulmonary microvascular endothelial (PMVEC) and pulmonary arterial smooth muscle cells (PASMC). ACTRIIA-Fc (15 mg/kg s.c. 2x/week), sildenafil (30 mg/kg p.o. BID) or vehicle were given prophylactically for 4 weeks to rats developing PH following a single injection of MCT (40 mg/kg s.c.), or via single injection of SU5416 (200 mg/kg s.c.) combined with hypoxia (FIO2=0.10, SU-Hx). Alternately, rats were allowed to develop PH following SU-Hx treatment for 3 weeks or MCT treatment for 4 weeks, and then treated with ACTRIIA-Fc (1, 3, or 10 mg/kg s.c. 2x/week) or isotype-matched control antibody (3 weeks under normoxia following SU-Hx, or 2 weeks following MCT). Invasive hemodynamics, RV mass and vascular remodeling were assessed.

Results:
In PMVEC, ACTRIIA-Fc enhanced BMP9-induced SMAD1/5/8 activation and transcriptional activity, and reversed inhibition of BMP9 signaling by GDF11. ACTRIIA-Fc inhibited GDF8-, GDF11- and activin A-mediated SMAD2 phosphorylation and myogenic differentiation of PASMC.
In vivo
, a standard dose of ACTRIIA-Fc prevented PH, RV hypertrophy and PV remodeling in MCT- and SU-Hx-rats, with more potency than sildenafil. All doses of ACTRIIA-Fc attenuated PH and RV hypertrophy when given in a delayed fashion after MCT- and SU-Hx-treatment, with graded effects on PV remodeling.

Conclusions:
ACTRIIA-Fc rebalances GDF11 vs. BMP9 signaling, with distinct effects in vascular endothelium vs. media, and potently inhibits experimental PH in several rodent models. Given its well-defined tolerability, dosing, and efficacy in previous human studies, ACTRIIA-Fc is an attractive candidate for PAH as a novel, mechanism-targeted therapy.
Abstract 17220: Risk Factors for Recurrent Peripartum Cardiomyopathy in 783 Women in California
Authors: Divanji Punag , Nah Gregory , Harris Ian , Agarwal Anu , Parikh Nisha I
Published: July 2021

Introduction:
Characterized by significant left ventricular (LV) dysfunction and clinical heart failure (HF), peripartum cardiomyopathy (PPCM) has an incidence of approximately 1/2200 live births (0.04%). Prior studies estimate that approximately 25% of those with recovered LV function will have recurrent clinical PPCM during subsequent pregnancies, compared to 50% of those without recovered LV function. Specific predictors of recurrent PPCM have not been studied in cohorts with large numbers.

Methods:
From 2005-2011, we identified 1,872,227 pregnancies by International Classification of Diseases, 9th Revision (ICD-9) codes in the California Healthcare Cost and Utilization Project (HCUP) database, which captures over 95% of the California hospitalized population. Excluding 15,765 women with prior cardiovascular disease (myocardial infarction, coronary artery disease, stroke, HF, valve disease, or congenital heart disease), yielded n=1,856,462 women. Among women without prior cardiovascular disease, we identified index and subsequent pregnancies with PPCM to determine episodes of recurrent PPCM. We considered the following potential predictors of PPCM recurrence in both univariate and age-adjusted logistic regression models: age, race, hypertension, diabetes, smoking, obesity, chronic kidney disease, family history, pre-eclampsia, ectopic pregnancy, income, and insurance status.

Results:
In HCUP, n=783 women had pregnancies complicated by PPCM (mean age=30.8 years). Among these women, n=133 had a subsequent pregnancy (17%; mean age=28.1 years), with a mean follow-up of 4.34 years (±1.71 years). In this group of 133 subsequent pregnancies, n=14 (10.5%) were complicated by recurrent PPCM, with a mean time-to-event of 2.2 years (±1.89 years). Among the risk factors studied, the only univariate predictor of recurrent PPCM was grand multiparity, defined as ≥ 5 previous deliveries (odds ratio: 22; 95% confidence interval 4.43-118.22). The other predictors we studied were not significantly associated with recurrent PPCM in either univariate or multivariable models.

Conclusion:
In a large population database in California with 783 cases of PPCM over a 6-year period, 17% of women had a subsequent pregnancy, of which 10.5% had recurrent PPCM. In age-adjusted logistic regression models, grand multiparity was the only statistically significant predictor of recurrent PPCM.